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ARTHRITIS & RHEUMATISM
Vol. 54, No. 8, August 2006, pp 2550–2557
DOI 10.1002/art.21955
© 2006, American College of Rheumatology
Mortality in Systemic Lupus Erythematosus
S. Bernatsky,1 J.-F. Boivin,2 L. Joseph,3 S. Manzi,4 E. Ginzler,5 D. D. Gladman,6 M. Urowitz,6
P. R. Fortin,6 M. Petri,7 S. Barr,8 C. Gordon,9 S.-C. Bae,10 D. Isenberg,11 A. Zoma,12
C. Aranow,13 M.-A. Dooley,14 O. Nived,15 G. Sturfelt,15 K. Steinsson,16 G. Alarcón,17
J.-L. Senécal,18 M. Zummer,19 J. Hanly,20 S. Ensworth,21 J. Pope,22 S. Edworthy,8 A. Rahman,11
J. Sibley,23 H. El-Gabalawy,24 T. McCarthy,24 Y. St. Pierre,1 A. Clarke,1 and
R. Ramsey-Goldman25
Objective. To examine mortality rates in the largest systemic lupus erythematosus (SLE) cohort ever
assembled.
Methods. Our sample was a multisite international SLE cohort (23 centers, 9,547 patients). Deaths
were ascertained by vital statistics registry linkage.
Standardized mortality ratio (SMR; ratio of deaths
observed to deaths expected) estimates were calculated
for all deaths and by cause. The effects of sex, age, SLE
duration, race, and calendar-year periods were determined.
Results. The overall SMR was 2.4 (95% confidence interval 2.3–2.5). Particularly high mortality was
seen for circulatory disease, infections, renal disease,
non-Hodgkin’s lymphoma, and lung cancer. The highest
SMR estimates were seen in patient groups character-
Supported by the Systemic Lupus International Collaborating
Clinics (SLICC) investigators group, in collaboration with the Canadian Network for Improved Outcomes in Systemic Lupus (CaNIOS).
Dr. Bernatsky’s work was supported by Lupus Manitoba. Dr. Bernatsky is recipient of a Canadian Institutes of Health Research Junior
Investigator award, a Lupus Canada Fellowship, and a Canadian
Arthritis Network Scholar award. Dr. Joseph is recipient of a Canadian
Institutes of Health Research Senior Investigator award. Dr. Fortin’s
work was supported by the Arthritis Centre of Excellence at the
University of Toronto, Arthritis & Autoimmunity Research Centre,
University Health Network, and Lupus Canada. Dr. Fortin is recipient
of an Investigator award from The Arthritis Society and the Canadian
Institutes of Health Research. Dr. Petri’s work was supported by the
NIH (grant R01-AR-437337) and the CRC (grant M01-RR-00052).
Dr. Gordon’s work was supported by Lupus UK. Drs. Nived and
Sturfelt’s work was supported by the Swedish Medical Research
Council (grant 13489). Dr. Steinsson’s work was supported by The
Science Fund of Landspitalinn University Hospital. Dr. Senécal’s work
was supported by the Canadian Institutes of Health Research (grant
MOP-62687). Dr. Clarke’s work was supported by the National Cancer
Institute of Canada (grant 013135), The Arthritis Society (grant
99105), the Canadian Institutes of Health Research (grant 100005),
and the Singer Family Fund for Lupus Research. Dr. Clarke is
recipient of a Canadian Institutes of Health Research Investigator
award. Dr. Ramsey-Goldman’s work was supported by the Arthritis
Foundation (Clinical Science grant), the Greater Chicago Chapter of
the Arthritis Foundation, the NIH (grants AR-02138 and AR-48098),
and the Lupus Foundation of Illinois (Chapter grant).
1
S. Bernatsky, MD, PhD, Y. St. Pierre, MSc, A. Clarke, MD,
MSc: Montreal General Hospital, Montreal, Quebec, Canada; 2J.-F.
Boivin, MD, ScD: McGill University, Montreal, Quebec, Canada; 3L.
Joseph, PhD: Montreal General Hospital, and McGill University,
Montreal, Quebec, Canada; 4S. Manzi, MD, MPH: University of
Pittsburgh School of Medicine and Graduate School of Public Health,
Pittsburgh, Pennsylvania; 5E. Ginzler, MD: State University of New
York–Downstate Medical Center, Brooklyn; 6D. D. Gladman, MD, M.
Urowitz, MD, P. R. Fortin, MD, MPH: Toronto Western Hospital,
Toronto, Ontario, Canada; 7M. Petri, MD, MPH: Johns Hopkins
University School of Medicine, Baltimore, Maryland; 8S. Barr, MD,
MSc, S. Edworthy, MD: University of Calgary, Calgary, Alberta,
Canada; 9C. Gordon, MD, FRCPC: University of Birmingham, Birmingham, UK; 10S.-C. Bae, MD, PhD, MPH: Hospital for Rheumatic
Diseases, Hanyang University, Seoul, South Korea; 11D. Isenberg,
MD, A. Rahman, PhD, MRCP: University College, London, UK; 12A.
Zoma, MB, ChB: Hairmyres Hospital, Glasgow, UK; 13C. Aranow,
MD: Albert Einstein College of Medicine, Bronx, New York; 14M.-A.
Dooley, MD, MPH: University of North Carolina at Chapel Hill; 15O.
Nived, MD, PhD, G. Sturfelt, MD, PhD: University Hospital, Lund,
Sweden; 16K. Steinsson, MD, PhD: Landspitalinn University Hospital,
Reykjavik, Iceland; 17G. Alarcón, MD, MPH: University of Alabama
at Birmingham; 18J.-L. Senécal, MD: University of Montreal School of
Medicine, and Hôpital Notre-Dame, Montreal, Quebec, Canada; 19M.
Zummer, MD: Hôpital Maisonneuve-Rosemont, Montreal, Quebec,
Canada; 20J. Hanly, MD: Queen Elizabeth II Health Sciences Centre
and Dalhousie University, Halifax, Nova Scotia, Canada; 21S. Ensworth, MD: University of British Columbia, Vancouver, British Columbia, Canada; 22J. Pope, MD, MPH: St. Joseph’s Hospital, University of Western Ontario, London, Ontario, Canada; 23J. Sibley, MD:
Royal University Hospital, Saskatoon, Saskatchewan, Canada; 24H.
El-Gabalawy, MD, T. McCarthy, MD: University of Manitoba, Winnipeg, Manitoba, Canada; 25R. Ramsey-Goldman, MD, DrPH: Northwestern University, Chicago, Illinois.
Drs. Clarke and Ramsey-Goldman contributed equally to this
work.
Address correspondence and reprint requests to S. Bernatsky,
MD, PhD, Division of Clinical Epidemiology, Montreal General Hospital
Research Institute, 1650 Cedar Avenue, Room L10-424, Montreal, Quebec H3G 1A4, Canada.
Submitted for publication November 24, 2005; accepted in
revised form March 30, 2006.
2550
MORTALITY AND LUPUS
ized by female sex, younger age, SLE duration <1 year,
or black/African American race. There was a dramatic
decrease in total SMR estimates across calendar-year
periods, which was demonstrable for specific causes
including death due to infections and death due to renal
disorders. However, the SMR due to circulatory diseases tended to increase slightly from the 1970s to the
year 2001.
Conclusion. Our data from a very large multicenter international cohort emphasize what has been
demonstrated previously in smaller samples. These
results highlight the increased mortality rate in SLE
patients compared with the general population, and
they suggest particular risk associated with female sex,
younger age, shorter SLE duration, and black/African
American race. The risk for certain types of deaths,
primarily related to lupus activity (such as renal disease), has decreased over time, while the risk for deaths
due to circulatory disease does not appear to have
diminished.
Systemic lupus erythematosus (SLE) is a chronic
autoimmune disorder that can be severe and life threatening. Death in patients with SLE may be due to lupus
activity (when vital organs or systems are involved), to
complications of treatment (particularly infections), or
to long-term sequelae (such as cardiovascular disease).
Although the literature regarding mortality in
SLE has been growing, it is still important to consolidate
and confirm what previous findings have suggested.
Through collaborations with the Systemic Lupus International Collaborating Clinics (SLICC) (1) and the
Canadian Network for Improved Outcomes in Systemic
Lupus (CaNIOS) investigator groups, we have constructed a unique multicenter international cohort of
unprecedented size. We compared the mortality in this
SLE cohort with geographically appropriate age-, sex-,
and calendar-year period–matched general population
mortality rates. Because of the exceptionally large number of patients and person-years of observation in our
sample, we provide novel data comparing all-cause and
disease-specific relative mortality (in SLE compared
with the general population) across groups characterized
by sex, age, SLE duration, geographic location, race, and
calendar-year period.
PATIENTS AND METHODS
Study subjects. All adult (age ⬎16 years) patients with
definite SLE according to American College of Rheumatology
(ACR) (2,3) or clinical criteria were eligible for inclusion. A
2551
patient was considered to have met the clinical criteria if a
rheumatologist had confirmed that he/she had a definite
diagnosis of SLE whether or not 4 ACR criteria had been met.
However, the vast majority of our patients did in fact meet the
ACR criteria. The study base encompassed 23 collaborating
lupus centers in 7 countries. These centers, listed in Appendix
A, were located in North America (Canada and the US), the
UK (England and Scotland), Iceland, Sweden, and South
Korea. Patients have been followed up in outpatient clinics
and/or in the inpatient hospital setting. Although most investigators are based at tertiary academic centers, they actively
encourage the enrollment of patients from community physician practices, and thus, the patients represent a spectrum of
disease. This cohort has been used to examine cancer incidence in SLE (4).
Most of the patients at the participating centers were
prospectively enrolled, although some had been retrospectively
enrolled after being followed up for a period of time in the
clinic at the respective center (see Appendix A). At each
center, patients lost to followup were not excluded; in general,
patients seen more than once at any of the participating study
centers were included in the study.
Data collection. Data were collected on each patient’s
date of birth, sex, dates of SLE diagnosis and cohort entry, and
date of death, if applicable. Probabilistic linkage to vital
statistics registries was performed for patients deceased or lost
to followup, with the National Death Index in the US cohorts
and with regional vital statistics registries for the non-US
cohorts. In probabilistic linkage (the current standard for
linking with administrative databases), registries are provided
with key data on patients (name, date of birth, and unique
numeric identifier), and previously validated algorithms are
used for selecting matches on the basis of probability of a
correct match. For 3 centers (2 in Canada [Winnipeg and
Vancouver] and 1 in the UK [London]), linkage of lost-tofollowup patients to vital status registries was not permitted by
local ethics approvals; death data at these centers consisted of
the information recorded in the clinical records. These 3
centers contributed only a small number of patients (513 of the
sample total of 9,547 patients), very few of whom were lost to
followup. To be conservative, in the primary analysis, we
assumed that any lost-to-followup patients from these centers
remained alive until the end of the observation interval; in
sensitivity analyses, we repeated the standardized mortality
ratio (SMR) calculations using the last date seen for all
lost-to-followup patients.
Analysis. For death overall and for cause of death, we
determined the ratio of the observed number of deaths to the
expected number of deaths (the SMR). We examined the most
common identified causes of death, calculating event rates and
cause-specific SMRs. In secondary analyses, SMRs were estimated for subgroups according to sex, age group, duration of
SLE, and geographic location (country). We also estimated
SMRs across calendar-year periods (1970–1979, 1980–1989,
and 1990–2001). In addition, we generated race-specific SMRs
for the US patients only, since the US mortality rates were the
only available general population figures that were stratified by
race (for whites and blacks/African Americans).
To calculate SMRs, the expected numbers of deaths
were obtained by multiplying person-years at risk in the cohort
by the geographically appropriate age-, sex-, and calendar-year
2552
BERNATSKY ET AL
period–matched mortality rates. The person-years for each
patient were determined by subtracting the later of 2 entry
dates (the beginning of the vital statistics registry observation
interval or the first visit to the respective lupus clinic) from the
earlier of 2 exit dates (end date of vital statistics registry data
or death). The SMRs were calculated by dividing the observed
number of deaths by the expected number, and 95% confidence intervals (95% CIs) were calculated using methods
described elsewhere (5) for Poisson parameters. Information
on deaths by cause was grouped according to International
Classification of Diseases, Ninth Revision (ICD-9) codes.
In additional secondary analyses, we used the entire
sample to perform a multivariate hierarchical regression to
determine independent effects of the factors examined (sex,
age group, SLE duration, calendar-year period, country) on
the SMRs among the patients in the SLE cohort. The hierarchical model allowed for differences in effects from one
country to the next. Poisson regression methods were used,
with the logarithm of the expected number of deaths serving as
the offset variable. The model included an extra variance term
to handle slight overdispersion in the data. For each variable in
the model, one of the categories was chosen as a reference, and
the estimate for each of the other categories is thus interpretable as the relative risk compared with the reference, adjusted
for the other factors in the model. Finally, we undertook
secondary analyses of the 291 deaths for which lupus was the
assigned cause, evaluating stratified rates of lupus-related
death for groups characterized by demographics, SLE duration, and calendar-year period.
RESULTS
The 9,547 patients were observed for a total of
76,948 person-years (average followup 8.1 years). The
calendar-year period of observation was 1958–2001,
although the majority of the observation interval occurred between 1970 and 2001. Most of the patients
(71%) entered into the observation interval within the
first 2 years of their SLE diagnosis. As expected, given
that SLE is a disease primarily of women, 90% of the
patients were female (n ⫽ 8,607). The number of
person-years of observation was divided among the age
groups ⬍40 years (33,001 person-years), 40–59 years
(30,976 person-years), and ⱖ60 years (12,971 personyears). Regarding SLE duration, the person-years of
observation were fairly equally divided among the duration groups of 0–4 years (27,037 person-years), 5–9 years
(21,931 person-years), and ⱖ10 years (27,980 personyears).
Within the observation interval, 1,255 deaths
occurred; lupus was the assigned cause of death in 291
cases (3.8 events per 1,000 person-years). The most
common types of deaths not directly attributed to SLE
were deaths due to circulatory disease (ICD-9 codes
390–459); this includes all types of heart disease, arterial
disease, and cerebrovascular events (strokes). Other
common types of deaths resulted from neoplasms
(ICD-9 codes 140–239), nephritis (ICD-9 codes 580–
589), and infections (ICD-9 codes 001–139; these codes
do not include pneumonia [ICD-9 codes 480–486] or the
term bacteremia [ICD-9 code 790.7], although they do
include the term septicemia [ICD-9 code 038]). Circulatory disease was the identified cause of 313 deaths, for
a rate of 4.1 events per 1,000 person-years; cancer was
the cause ascribed to 114 deaths, for a rate of 1.5 events
per 1,000 person-years; and infection (not including
pneumonia) was identified as the cause of 45 deaths, for
a rate of 0.6 events per 1,000 person-years.
The overall (all-cause) SMR estimate was 2.4
(95% CI 2.3–2.5). For death due to circulatory disease,
the SMR was 1.7 (95% CI 1.5–1.9). For the ICD
category of infectious causes of death, the SMR was 5.0
(95% CI 3.7–6.7); for pneumonia (which in the ICD
codes is classified under respiratory diseases), the SMR
was 2.6 (95% CI 1.6–4.1). For cancer overall, the SMR
was 0.8 (95% CI 0.6–1.0); in terms of cancer types, for
Table 1. Unadjusted SMR estimates for all-cause mortality and for
death by cause*
Cause of death (ICD-9 code)
All deaths
Disease of the circulatory system†
All disease (390–459)
Heart disease (390–429)‡
Stroke (430–459)‡
Malignancy†
All neoplasms (140–239)
All hematologic cancer
(200–208)‡
NHL (200, 201)‡
Lung cancer (162)‡
Infections†
Infections (001–139)
Pneumonia (480–486)‡
Other†
Respiratory, excluding
pneumonia (460–479,
487–519)
Renal (580–589)
Observed Expected
1,255
SMR
(95% CI)
526
2.4 (2.3–2.5)
313
126
21
184.3
73.8
19.3
1.7 (1.5–1.9)
1.7 (1.4–2.0)
1.1 (0.7–1.7)
114
15
138
7.2
0.8 (0.6–1.0)
2.1 (1.2–3.4)
8
44
2.8
19.4
2.8 (1.2–5.6)
2.3 (1.6–3.0)
45
19
9.0
7.2
5.0 (3.7–6.7)
2.6 (1.6–4.1)
14
10.4
1.3 (0.8–1.6)
34
4.3
7.9 (5.5–11.0)
* Data shown are for 23 participating sites in North America, Europe,
Iceland, and Asia, for a total 9,547 patients (76,948 person-years), and
for the calendar-year period 1958–2001. SMR ⫽ standardized mortality ratio; ICD-9 ⫽ International Classification of Diseases, Ninth
Revision; 95% CI ⫽ 95% confidence interval; NHL ⫽ non-Hodgkin’s
lymphoma.
† Cause-specific death data on this level of detail were available from
all centers except for Iceland (n ⫽ 221), Sweden (n ⫽ 114), Saskatchewan (n ⫽ 306), and Manitoba (n ⫽ 158).
‡ Cause-specific death data on this level of detail were available from
all centers except for Iceland (n ⫽ 221), Sweden (n ⫽ 114), Saskatchewan (n ⫽ 306), Manitoba (n ⫽ 158), and Scotland (n ⫽ 1,937).
MORTALITY AND LUPUS
2553
Table 2. Unadjusted SMR estimates, stratified by sex, age, and SLE
duration*
SMR
(95% CI)
Sex
Female
Male
Age, years
⬍40†
40–59
ⱖ60
SLE duration, years
⬍1
1–4
5–9
10–19
ⱖ20
2.5 (2.3–2.7)
1.9 (1.7–2.2)
10.7 (9.5–11.9)
3.7 (3.3–4)
1.4 (1.3–1.5)
5.4 (4.7–6.3)
2.5 (2.2–2.8)
2.1 (1.9–2.4)
2.0 (1.8–2.3)
2.0 (1.7–2.4)
* SMR ⫽ standardized mortality ratio; SLE ⫽ systemic lupus erythematosus; 95% CI ⫽ 95% confidence interval.
† Within the age group ⬍40 years, the SMR for very young adults
(ages 16–24 years) was particularly high, at 19.2 (95% CI 14.7–24.7).
The SMR for adults ages 25–39 years was 8.0 (95% CI 7.0–9.1).
non-Hodgkin’s lymphoma (NHL), the SMR was 2.8
(95% CI 1.2–5.6), and, for lung cancer, the SMR was 2.3
(95% CI 1.6–3.0) (Table 1).
Patient groups characterized by any of the following: female sex, younger age, or SLE duration ⬍1 year,
all had particularly high SMR estimates (Table 2). This
phenomenon was evident not only for all-cause mortality, but also for cause-specific mortality estimates, including death due to circulatory diseases, infections, and
renal disorders. Within the age group ⬍40 years, the
SMR for very young adults (ages 16–24 years) was
particularly high, at 19.2 (95% CI 14.7–24.7). Figure 1
presents the unadjusted SMR estimates by calendar-year
period. Across calendar-year periods, there was a dramatic decrease in total SMR estimates, which was
demonstrable for specific causes, including death due to
infections and death due to renal disorders. However,
Figure 1. Unadjusted standardized mortality ratio (SMR) estimates,
by calendar-year period.
Figure 2. Unadjusted standardized mortality ratio (SMR) estimates,
stratified by country. Korea represents South Korea.
the SMR due to circulatory diseases tended to increase
slightly from the 1970s to the year 2001.
Unadjusted SMR estimates stratified according
to geographic location are shown in Figure 2. Although
slight differences may be present, overall the evidence
suggests a relatively consistent increased risk of death
(⬃2-fold) in SLE patients compared with the general
population. However, although Figure 2 indicates that
the unadjusted country-specific estimates are largely
overlapping, it appears that the magnitude of effect may
be somewhat less for certain groups, notably the Swedish. This may in part relate to various factors, including
differences in demographic makeup or clinical characteristics of the cohort members; an important factor may
also relate to site-specific variations in the enrollment
criteria and methods (as outlined in Appendix A).
Race-specific SMR estimates for the US patients were
as follows: whites 1.4 (95% CI 1.2–1.7), blacks/African
Americans 2.6 (95% CI 2.3–2.9). The overall raceadjusted SMR for the US sites was 2.2 (95% CI 2.0–2.4).
In sensitivity analyses, when we repeated the SMR
calculations using the last date seen for all lost-tofollowup patients, the results were essentially unchanged.
Table 3 presents the results of the multivariate
hierarchical regression to determine independent effects
of the factors examined (sex, age group, SLE duration,
calendar-year period of SLE diagnosis, country) on the
relative SMR estimates among SLE patients. These
adjusted estimates were consistent with the unadjusted
results in terms of suggesting independent effects for
each variable of interest (female sex, younger age, SLE
duration ⬍1 year, calendar-year period) on the risk of
death among the SLE patients (relative to the general
population). However, the 95% CIs were wider, and in
the case of the effects of different calendar-year periods,
the estimates did overlap and include the null value.
Regarding secondary stratified analyses for rates
of death due to SLE, we found that lupus-related death
2554
BERNATSKY ET AL
Table 3. Results of adjusted multivariate regression to determine
independent effect of variables on SMR estimates*
Adjusted SMR
(95% CI)†
Female sex
Age, years
⬍40
40–59
ⱖ60
SLE duration, years
⬍1
1–4
5–9
10–19
ⱖ20
Calendar-year period of SLE diagnosis
1970–1979
1980–1989
1990–2001
Country
Canada
England
Scotland
Iceland
US
Sweden
South Korea
1.2 (1.0–1.4)
6.4 (5.5–7.5)
2.6 (2.3–3.0)
1.0 (reference group)
7.7 (5.9–10.2)
3.2 (2.5–4.1)
2.4 (1.8–3.0)
1.8 (1.4–2.2)
1.3 (1.0–1.5)
1.2 (1.0–1.4)
1.8 (1.6–2.1)
1.6 (1.2–2.2)
1.3 (1.1–1.5)
1.2 (0.9–1.6)
0.8 (0.5–1.4)
0.7 (0.3–2.0)
* SMR ⫽ standardized mortality ratio; 95% CI ⫽ 95% confidence
interval. SLE ⫽ systemic lupus erythematosus.
† Variables adjusted concomitantly for all others (sex, age, SLE
duration, calendar-year period, and country).
rates were a little higher for men (3.6 deaths per 1,000
person-years) than for women (2.7 deaths per 1,000
person-years), although the 95% CIs for these estimates
overlapped. With respect to age, very young individuals
(ages ⬍25 years) had the highest rate of deaths due to
SLE (5.3 deaths per 1,000 person-years, 95% CI 3.7–7.5)
compared with other age groups; the estimates across
other age groups (for those ages ⱖ25 years) were all very
similar, with an average of 2.5 deaths due to SLE per
1,000 person-years (95% CI 2.2–3.5). There were generally very few differences regarding lupus-related death
rates for groups characterized by SLE duration, and no
trend over calendar time was observed for deaths due to
lupus.
DISCUSSION
The primary value of this work is that it formally
presents the increased risk of mortality in SLE compared with that in the general population, and it examines the particular risk in groups of patients characterized by demographic and other factors. The increased
risk of mortality in SLE is by no means a new phenomenon; on the contrary, it has been a point of concern for
some years. However, our results do emphasize what has
been demonstrated previously in smaller samples. In
addition, because of the large numbers of patients and
person-years of observation in the multicenter cohort,
we were able to provide data comparing all-cause and
disease-specific relative mortality (in SLE patients compared with the general population) across groups characterized by age, sex, SLE duration, calendar-year period, geographic location, and race.
In terms of the slightly higher total SMR estimates suggested for females, some prior work by others
has suggested greater mortality in male than in female
SLE patients (6,7). However, this previous work did not
calculate mortality rates relative to the general population. The longevity of males is generally lower than that
of females; thus, when comparing the effect of sex on
mortality in SLE patients, it is preferable to use a
parameter such as the SMR. Similarly, the SMR provides a clearer understanding of which age group of SLE
patients has the greatest increased risk (compared with
the general population counterparts), since mortality
rates in the general population increase with age.
Although the highest SMR estimates for our
sample were seen within the first year, there was evidence that death rates in SLE patients are much higher
than those in the general population throughout the
course of SLE, even up to 20 years of SLE duration.
Overall, across countries, we noted a relatively consistent increased risk of death in SLE patients compared
with the general population. Slight regional differences
were present (Figure 2); adjusting for sex, age, SLE
duration, and calendar-year period appeared to remove
most of this variation (Table 3). Small residual regional
differences may be due in part to differences in cohort
assembly (see details in Appendix A) and may reflect
variations in other factors, including disease characteristics (and severity), medication exposures, comorbidity,
and racial mix. We note that the cohorts from countries
with the lowest SMR point estimates (Sweden, Iceland,
and Scotland) were population based. This may indicate
the potential role of sample recruitment in the findings.
Among SLE patients in the US, the question of
why blacks/African Americans have a higher SMR than
whites is an interesting one; previous work has also
shown this phenomenon (8,9). Since the results of other
studies have suggested worse renal involvement and
outcomes in black/African American (and also black
Caribbean) patients (10–13), a reasonable hypothesis is
that the higher SMR estimate in blacks is driven in part
by SLE severity and comorbidity. Another related factor
may be economic status, since poverty has been sug-
MORTALITY AND LUPUS
gested to contribute to increased mortality in SLE
(6,14). Previous work has suggested high mortality in
Asian SLE patients as well (15), but estimates relative to
the general population are lacking. We are unable to
comment about racial groups other than white and
black/African American patients in the US.
Early work by Urowitz et al (16,17) first drew
attention to the importance of mortality due to circulatory disease in SLE, particularly late in the disease
course. As their work and that of others has suggested,
circulatory disease (related to the heart, arteries, and
cerebrovascular events) is a common cause of death in
SLE (9,18,19). Previous work by Manzi et al (20) has
shown a very high incidence of cardiac events (specifically, myocardial infarction and angina) in SLE patients
compared with the general population. Our data substantiate an increased risk of death due to circulatory
causes in SLE patients compared with the general
population.
We identified an increased risk of death due to
specific cancers, including hematologic malignancies
(particularly NHL) and lung cancer. This is of interest
given recent data showing a heightened incidence of
these types of cancer in SLE (4), and it is not concordant
with surveillance bias as the explanation for the observed
association between cancer and SLE. An increased risk
of death was also estimated for infections and renal
disease. It is well known that infections, often attributed
to the use of immunosuppressant medications, are a
frequent cause of death in SLE (9,18,21). An increase in
the rate of death due to renal disease reflects the
potential seriousness of nephritis in SLE (9,22).
Our work shows a dramatic 60% decrease over
time in the standardized all-cause mortality rates, from
1970–1979 (SMR 4.9) to 1990–2001 (SMR 2.0). Work in
several SLE cohorts over the last 3 decades has suggested an improvement in survival, at least early in the
course of SLE (17,23–25). Results of our work are
consistent with increased survival over time, in keeping
with previous findings, although we note that the use of
different methodologies may produce somewhat different estimates from one study to the next. It is important
to keep in mind that, since the SMR estimate compares
the observed number of deaths in SLE patients with the
expected number of deaths in the general population,
the decrease over the last 2 decades probably reflects
improvements specific to the excess mortality in SLE
rather than a general increase in population longevity. A
decrease in deaths due to infections over time may be
due to the evolution of strategies to limit the incidence
of infections when immunomodulators are used (for
2555
example, by limiting cumulative exposure). An alternative explanation is that in more recent eras, there is more
effective recognition and treatment of infectious complications.
It seems clear that certain types of deaths, primarily related to lupus activity (such as renal disease),
have decreased over time. However, the trend for circulatory disease shows no such decline, a finding suggested
as well by Bjornadal et al (19). This may reflect in part
the complex nature of cardiovascular disease in SLE.
Classic atherosclerosis risk factors, such as hypertension
and hypercholesterolemia, do play a role, although
recent work has suggested that additional risk is conferred by some disease-related characteristics, such as
SLE duration and, perhaps, severity (26). However,
other elements, such as medication exposures, may also
alter atherosclerosis risk in SLE.
Limitations of our study should be considered.
We cannot be certain that the causes of death in our
SLE patients were identified correctly, since we relied
primarily on death registry linkage results. However,
important biases in our estimates would only arise if
misclassification occurred differentially between SLE
patients versus the general population. A fairly large
number of deaths were ascribed to SLE itself; it is
possible that the primary cause of death was actually
another condition (e.g., cardiovascular disease or infection), but the patient’s preexisting diagnosis of SLE may
have led to this being listed as the cause of death. This
might lead to an underestimation of some of the causespecific SMR estimates; however, the data on causes of
death recorded for SLE patients do not suggest that this
effect is likely (27).
Although we believe that our cohort is probably
representative of the general population of lupus patients, it is not a random sample. Therefore, claims of
representativeness must be made very cautiously, since
unobserved selection biases may certainly operate. Most
investigators involved in our multicenter cohort are
based at tertiary academic centers, although they actively encourage the enrollment of patients from community physician practices. The patients enrolled do
represent a spectrum of disease severity, but sicker
patients may indeed be overrepresented. We do note
that our findings are consistent with the results reported
by Bjornadal et al (19) in their assessment of a
population-based cohort, which was assembled using
administrative databases (which are not without their
own sources of bias and error).
In conclusion, the data from our very large
multicenter international cohort emphasize what has
2556
BERNATSKY ET AL
been demonstrated previously in smaller samples. The
results highlight the increased mortality rate in SLE
patients compared with the general population. This
increased mortality is highest in patient groups characterized by female sex, younger age, or SLE duration ⬍1
year, although an increased risk of mortality in SLE
patients compared with the general population was
generally seen across all demographic groups. The
country-specific estimates also showed a relatively consistent increased risk of death in SLE patients compared
with the general population. There was evidence of a
striking increase in mortality among black/African
American SLE patients in the US, although a smaller
increase in mortality was also present for white SLE
patients in the US. The decrease in SMR estimates over
time for our lupus cohort is encouraging, but the residual increased risk of death in SLE suggests that continued efforts should focus on developing better means of
preventing and treating the sequelae of SLE as well as
other comorbidity, particularly cardiovascular disease.
ACKNOWLEDGMENTS
Angela Allen, Natalie Gonzalez, and Katie Arrigo
functioned as research co-coordinators responsible for all US
sites. We wish to thank the following physicians for their
significant assistance in providing access to patients and collecting data: Simon Bowman, Linda Lee, Moon-Ho Leung,
Ibraheem Nahr, and Martha Sanchez. Stephanie Heaton, RN,
assisted with data collection for the Birmingham, UK, lupus
cohort. The National Death Index and regional or national
vital statistics registries provided vital status information on
deceased and lost-to-followup patients.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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2557
APPENDIX A: INTERNATIONAL SYSTEMIC LUPUS
ERYTHEMATOSUS COHORT, PARTICIPATING CENTERS
Country
(no. of patients)*
North America
Canada (2,688)†
US (3,558)†
UK
England (712)†
Scotland (1,937)#
Other
Sweden (114)†
Iceland (221)†
South Korea (317)†
Total ⫽ 9,547
Centers
Calgary, Alberta‡; Halifax, Nova Scotia‡;
London, Ontario§; Montreal, Quebec
(Hôpital Maisonneuve-Rosemont§,
Montreal General Hospital‡, Hôpital
Notre-Dame¶); Saskatoon,
Saskatchewan‡; Toronto, Ontario‡;
Vancouver, British Columbia§;
Winnipeg, Manitoba (Health Science
Centre and Manitoba Clinic)§
Baltimore, Maryland¶; Birmingham,
Alabama‡; Chapel Hill, North
Carolina¶; Chicago, Illinois¶; New
York, New York (Albert Einstein
College of Medicine, Bronx§; State
University of New York–Downstate
Medical Center, Brooklyn‡);
Pittsburgh, Pennsylvania¶
Birmingham‡; London‡
Lanarkshire§
Lund‡
Reykjavik¶
Seoul¶
* The number of patients at each center corresponds to the number of
patients present during the time that vital status registry data were
available.
† At least 95% of cohort members met 4 of the American College of
Rheumatology (ACR) diagnostic criteria for systemic lupus erythematosus (SLE) (2,3); patients diagnosed clinically as having SLE but
meeting fewer than 4 ACR criteria are not excluded.
‡ Prospective assembly.
§ Retrospective assembly.
¶ Retrospective and prospective assembly.
# Any hospital discharge diagnosis of SLE, primary or nonprimary.
Cohort entry date is first discharge date with SLE as a diagnosis.
Downloaded from ard.bmj.com on June 10, 2013 - Published by group.bmj.com
58
CONCISE REPORT
Suicide attempts in patients with systemic lupus
erythematosus
F B Karassa, M Magliano, D A Isenberg
.............................................................................................................................
Ann Rheum Dis 2003;62:58–60
Background: Suicide and suicide attempts, although well
recognised in patients with systemic lupus erythematosus
(SLE), have been commented on relatively little.
Objective: To obtain a better understanding of the
reasons for suicidal behaviour in patients with SLE.
Methods: The records of 300 patients with SLE were
reviewed to identify completed or attempted suicides.
Results: Five patients made seven attempts at suicide over
a 20 year follow up period; one of them was fatal. All of
those attempting suicide had a history of neuropsychiatric
SLE (NPSLE) presenting with depression and they made the
attempts soon after the onset of NPSLE (median time
12.5 months). Two patients had appreciable disease
activity at the time of the suicide attempt. Lymphopenia
was present in five suicide attempts. Anti-SSA/Ro antibodies were detected in three patients, none of whom had
anti-SSB/La. All patients apart from one responded to
treatment for depression; the remaining female patient
made two subsequent suicide attempts, with a fatal
outcome despite intensive treatment.
Conclusion: Greater awareness of the risk of suicide in
patients with psychiatric manifestations of SLE may help to
reduce the incidence of this potentially fatal phenomenon.
A
suicide attempt is an act of self inflicted harm accompanied by explicit or implicit intent to cause death.
Although only one in eight to 10 people attempting
suicide succeed, suicide remains a major cause of death. More
than 90% of suicide victims are psychiatrically ill and 45–77%
of them have a mood disorder at the time of death.1 Chronic
physical illness is an important risk factor for suicide.
Systemic lupus erythematosus is one with a risk quoted to be
fivefold higher than expected.2 Many factors may contribute to
this occurrence: pathophysiological changes in the brain
resulting from the underlying disease (NPSLE), depression
related to the variable course and the unpredictable nature of
the disease, and corticosteroids may rarely induce mental disturbance.
METHODS
We reviewed the medical records of the first 300 patients with
SLE attending our lupus clinic over a 20 year period to identify
attempted and completed suicides. Our aim was to identify
any potential risk factors for the suicide in these patients
related to their underlying condition.
All patients fulfilled the American College of Rheumatology
(ACR) 1982 revised criteria for the classification of SLE.3
Demographic, clinical, and laboratory data as well as current
and previous treatments were recorded from patients’ charts.
Disease activity was evaluated using the British Isles Lupus
Assessment Group (BILAG) index (version 3).4 Neuropsychiatric lupus (NPSLE) was defined according to the ACR
definitions.5 Table 1 lists the details.
www.annrheumdis.com
RESULTS
Since 1979 five patients with SLE (2%), four women and one
man, made seven suicide attempts, although only one was
fatal. The mean age of the patients at the time of the suicide
attempt was 41 (SD 8.69) years and median disease duration
2.5 years (range 1–11 years). All patients had a history of
depression at the time of the suicide attempt. None of them
were inpatients at the time of the attempt. Only one patient
had expressed prior suicidal intent and was found to have left
a suicide note (patient 1); none of the others had, as far as we
could ascertain, expressed suicidal thoughts or gave warnings.
After two attempts patients were unable to describe clearly
how they became vulnerable to suicidal impulses; however,
four patients expressed difficulties in coming to terms with
the diagnosis of SLE. One patient (patient 3) reported sleeping
difficulties and irritability in the year before the attempt at
suicide. Psychological factors such as unemployment, being
separated, and being isolated in the community due to the
chronic illness were present in all patients. Ingestion was the
only form of suicidal behaviour and involved analgesic drugs
regularly used by patients in six cases; the other ingestion was
of turpentine fluid. All patients were reviewed by a
psychiatrist and received treatment for depression.
All of the patients had evidence of NPSLE before the time of
attempted suicide. Patients 2–5 all had depression with or
without an anxiety state at the time of the attempt. Patient 1
had a complicated history and two psychiatrists who were
seeing her gave divergent opinions. On balance we thought it
reasonable to regard her as being depressed at the time of her
first suicide attempt but this was not as clear cut at the time of
the second attempt. She had progressive cognitive dysfunction
as manifested by a decline in verbal IQ and memory
impairment, with a profound effect on the patient’s mood and
feeling of hopelessness.
Median time from the onset of involvement of the central
nervous system (CNS) to the attempt at suicide was 12.5
months (range 3–27 months). In two out of three patients
who were evaluated with brain MRI multiple white matter
lesions were found.
Two patients had appreciable disease activity at the time of
the attempt. Lymphopenia was present in six instances, in two
the lymphocyte count was less than 0.7×109/l. Anti SSA/Ro
antibodies were detected in three patients whereas none of
them had anti-SSB/La. After the suicide attempt patient 1 was
treated with pulses of cyclophosphamide and methylprednisolone (the first cycle was followed by the suicide attempt),
patient 4 received three pulses of methylprednisolone and oral
prednisolone was increased in patients 2, 3, and 5 (by a mean of
.............................................................
Abbreviations: ACR, American College of Rheumatology; BILAG, British
Isles Lupus Assessment Group; CNS, central nervous system; NPSLE,
neuropsychiatric systemic lupus erythematosus; SLE, systemic lupus
erythematosus
53/F/I
29/F/W
40/F/B
44/M/W
*The BILAG index is scored as follows: A, disease of sufficient activity to warrant disease modifying treatment with high dose steroids or immunosupression; B, disease of less activity than in A, requiring only symptomatic treatment,
antimalarial drugs, or low dose steroids; C, stable mild disease; D, system was previously affected but currently inactive; E, system was never involved; †no data available on patient 1 at the time of the last suicide attempt; ‡DNA:
normal range <50 units/ml; §C3: normal values 0.75–1.75 mg/ml; B, black; I, Indian; W, white; M, male; F, female; CNS, central nervous system; CVS, cardiovascular system.
2.2
1.1
–
0.3
1.2
1.2
0.6
3
5
–
14
43
–
9
0.87
0.9
–
0.93
1.16
1.2
1.2
260
262
–
1800
68
170
10
8
6
–
13
3
13
7
D
C
–
B
C
C
C
E
E
–
E
D
E
E
C
C
–
D
E
D
E
D
D
–
C
B
D
E
D
D
–
B
C
C
B
B
D
–
B
D
A
B
1
1
1
2
3
4
5
39/F/W
5/99
9/00
4/01†
8/89
10/95
12/99
7/99
B
B
–
B
C
C
C
C
C
–
D
D
C
D
Musculoskeletal
CNS
Mucocutaneous
BILAG index for each organ system
General
manifestations
Date of
suicide
Age/sex/
ethnic
group
Patient
No
Table 1
BILAG index (version 3) for each organ system on suicidal attempts*
CVS/
respiratory
Vasculitis
Renal
Haematological
Total
score
DNA‡
C3§
ESR
Lymphocytes
(109/l)
Suicide attempts in patients with systemic lupus erythematosus
59
20 mg/day). Patient 1 continued to deteriorate cognitively
despite the treatment with cyclophosphamide and anti-CD20
monoclonal antibody directed at NPSLE manifestations. This
patient made two subsequent attempts of suicide, the last one
being fatal.
DISCUSSION
Patients with SLE are at almost five times greater risk for suicide
than expected.2 In our cohort of patients 2% had a documented
history of attempted suicide. Could we have missed more
suicide attempts? We cannot completely exclude this possibility
but consider it unlikely as the BILAG form that we complete at
every patient assessment specifically records depression and
any worsening of this feature would have led to further enquiries about suicide attempts. As a control we reviewed the notes of
140 patients with primary Sjogren’s syndrome followed up by
us from 1988 to 2001. To date none have attempted suicide.
All our patients who made attempts at suicide had been
diagnosed with depression at some time before the attempt.
Psychiatric dysfunction represents a common NPSLE manifestation and may range from mild affective disorders to
severe psychosis.6 7 Our patients with NPSLE made suicide
attempts within two years of the onset of involvement of the
CNS; all but one had favourable outcomes with more intense
treatment. Similarly, five out of seven previously reported suicidal patients with SLE presented either with depression or
schizophrenia; all three survivors had a favourable response to
increased dose of steroids or immunosupressant drugs.8 To our
knowledge none of our 300 patients have attempted suicide
after treatment with large amounts of corticosteroids. Insomnia was a feature in all patients before the suicide attempts,
and the presence of hypocomplementaemia and reducing dose
of steroids possibly resulting in suboptimal control of the disease activity were implied as important suicidal risk factors.8
Futrell et al described six suicide attempts in 31 patients
with NPSLE with major behavioural changes.9 Suicidal
patients with SLE coupled with depression and aggressive
behaviour have also been reported.10 11
Although a link between lupus psychosis and antiribosomal
P antibodies has been claimed,12 assays to detect these
antibodies are not readily available for identifying patients at
risk in routine clinical practice. Interestingly anti-SSA/Ro was
detected in three of our patients; this is twice the 30% prevalence of these antibodies in our patients with SLE overall
(relative risk=3.66; D A Isenberg, unpublished observations).
None of them had concomitant anti-SSB/La antibodies. The
relevance of this finding is unknown.
Patients with SLE are at greater risk of suicide, and
vigilance to identify and treat symptoms and signs of depression is crucial. Although involvement of the CNS creates an
additional risk we should not underestimate the importance
of the psychosocial factors that coping with life threatening
and unpredictable illness creates.
.....................
Authors’ affiliations
F B Karassa, M Magliano, D A Isenberg, Centre for Rheumatology,
The Middlesex Hospital, University College London, UK
Correspondence to: Professor D A Isenberg, The Middlesex Hospital
University College, London, Arthur Stanley House, 40–50 Tottenham
Street, London W1T 4NJ, UK; d.isenberg@ucl.ac.uk
Accepted 7 June 2002
REFERENCES
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eds. Textbook of Psychiatry. 3rd ed. Washington, DC: The American
Psychiatric Press, 1999:1383–400.
2 Harris EC, Barraclough BM. Suicide as an outcome for medical
disorders. Medicine 1994;73:281–96.
3 Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al.
The 1982 revised criteria for the classification of systemic lupus
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4 Hay EM, Bacon PA, Gordon C, Isenberg DA, Maddison P, Snaith ML, et
al. The BILAG index: a reliable and valid instrument for measuring
clinical disease activity in systemic lupus erythematosus. Q J Med
1993;86:447–58.
5 ACR Ad Hoc committee on neuropsychiatric lupus nomenclature case
definitions for neuropsychiatric syndrome in systemic lupus
6 West SG. Neuropsychiatric lupus. Rheum Dis Clin North Am
1994;20:129–58.
7 Karassa FB, Ioannidis JP, Boki KA, Touloumi G, Argyropoulou MI,
Strigaris KA, et al. Predictors of clinical outcome and radiologic
progression in patients with neuropsychiatric manifestations of systemic
lupus erythematosus. Am J Med 2000;109:628–34.
8 Matsukawa Y, Sawada S, Hayama T, Usui H, Horie T. Suicide in
patients with systemic lupus erythematosus: a clinical analysis of seven
suicidal patients. Lupus 1994;3:31–35.
9 Futrell N, Schultz LR, Millikan C. Central nervous system disease in
patients with systemic lupus erythematosus. Neurology
1992;42:1649–57.
10 Goodwin JM, Goodwin JS, Kellner R. Psychiatric symptoms in disliked
medical patients. JAMA 1979;241:1117–20.
11 MacNeil A, Grennan DM, Ward D, Dick WC. Psychiatric problems in
systemic lupus erythematosus. Br J Psychiatry 1976;128:442–5.
12 Sterling G, West MD. Neuropsychiatric lupus. Rheum Dis Clin North Am
1994;20:129–56.
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Beware of Fraudulent
‘Dietary Supplements’
F
ederal regulators continue
to warn consumers about
tainted, dangerous
products that are marketed as
dietary supplements. These
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serious injury or even death.
The Food and Drug Administration
(FDA) has found nearly 300 fraudulent products—promoted mainly for
weight loss, sexual enhancement, and
bodybuilding—that contain hidden or
deceptively labeled ingredients, such as
• t he ac t ive ing redients in F DAapproved drugs or their analogs
(closely-related drugs)
• other compounds, such as novel synthetic steroids, that do not qualify as
dietary ingredients
“These products are masquerading as
dietary supplements—they may look
like dietar y supplements but they
are not legal dietary supplements,”
says Michael Levy, director of FDA’s
Division of New Drugs and Labeling
Compliance. “Some of these products
contain hidden prescription ingredients at levels much higher than those
found in an approved drug product
and are dangerous.”
FDA has received numerous reports
of harm associated with the use of
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Advice for Consumers
“We need consumers to be aware of
these dangerous products and to learn
how to identif y and avoid them,”
says Lev y. Consumers should look
for potential warning signs of tainted
products marketed as dietary supplements, such as
• products claiming to be alternatives
to FDA-approved drugs or to have
effects similar to prescription drugs
• products claiming to be a legal alternative to anabolic steroids
• products that are marketed primarily
in a foreign language or those that are
marketed through mass e-mails
• sexual enhancement products promising rapid effects, such as working
in minutes to hours, or long-lasting
effects, such as working for 24 to 72
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• product labels warning that you may
test positive in performance enhancement drug tests
Generally, if you are using or consid-
1 / FDA Consumer Health Infor mat ion / U. S. Food and Drug Administrat ion
ering using any product marketed as
a dietary supplement, FDA suggests
that you
• c heck with your health care professional or a registered dietician about
any nutrients you may need in addition to your regular diet
• ask your health care professional for
help distinguishing between reliable
and questionable information
• ask yourself if it sounds too good to
be true
° B e cautious if the claims for the
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° Watch out for extreme claims—for
example, “quick and effective,”
“cure-all,” “can treat or cure diseases,” or “totally safe.”
° Be skeptical about anecdotal information from personal “testimonials” about incredible benefits
or results obtained from using a
product.
M A R C H 2 0 11
Consumer Health Information
www.fda.gov/consumer
Keep Up-to-Date on Tainted Products
Get the latest news on tainted products by using FDA’s “widget” (www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/MedicationHealthFraud/ucm242603.htm) and “RSS
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Dietary supplements, in general, are
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(Dietary Supplement Health and Education Act of 1994), dietary supplement firms do not need FDA approval
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Just because you see a supplement
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FDA has worked with industry to
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• more than 40 products marketed for
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sexual enhancement
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ucts on the market to identify those
that contain potentially harmful hidden ingredients. Consumers must also
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FDA last alerted the public to tainted
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criminal prosecutions. In December
2010, a woman pleaded guilty to an
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the illegal importation and distribution of more than four million diet pills
that contained a controlled substance,
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Remember, FDA cannot test all prod-
2 / FDA Consumer Health Infor mat ion / U. S. Food and Drug Administrat ion
M A R C H 2 0 11
Vol. 46, No. 11, November 2002, pp 2924–2927
DOI 10.1002/art.10615
Dehydroepiandrosterone Treatment of Women With
Mild-to-Moderate Systemic Lupus Erythematosus
A Multicenter Randomized, Double-Blind, Placebo-Controlled Trial
Deh-Ming Chang,1 Joung-Liang Lan,2 Hsiao-Yi Lin,3 and Shue-Fen Luo4
cant between the two groups (DHEA ⴚ5.5 versus placebo 5.4; P ⴝ 0.005). The number of patients with
serious adverse events, most of which were related to
SLE flare, was significantly lower in DHEA-treated
patients compared with placebo-treated patients (P ⴝ
0.010). Expected hormonal effects, including increased
testosterone levels and increased incidence of acne, were
observed. No life-threatening reactions or serious safety
issues were identified during this study.
Conclusion. The overall results confirm that
DHEA treatment was well-tolerated, significantly reduced the number of SLE flares, and improved patient’s
global assessment of disease activity.
Objective. To evaluate the efficacy and tolerability
of dehydroepiandrosterone (DHEA) at a dosage of 200
mg/day in adult women with active systemic lupus
erythematosus (SLE).
Methods. In a multicenter randomized, doubleblind, placebo-controlled trial, 120 adult women with
active SLE received oral DHEA (200 mg/day; n ⴝ 61) or
placebo (n ⴝ 59) for 24 weeks. The primary end point
was the mean change from baseline in the Systemic
Lupus Activity Measure (SLAM) score at 24 weeks of
therapy. Secondary end points included time to first
flare, change in SLE Disease Activity Index (SLEDAI)
score, and physician’s and patient’s global assessment
scores at week 24.
Results. The two groups were well balanced for
baseline characteristics. Mean reductions in SLAM
scores from baseline were similar and were not statistically significantly different between treatment groups
(DHEA ⴚ2.6 ⴞ 3.4 versus placebo ⴚ2.0 ⴞ 3.8, mean ⴞ
SD). The number of patients with flares was decreased
by 16% in the DHEA group (18.3% of DHEA-treated
patients versus 33.9% of placebo-treated patients; P ⴝ
0.044, based on time to first flare). The mean change in
the patient’s global assessment was statistically signifi-
Systemic lupus erythematosus (SLE) is a multisystem autoimmune inflammatory disease with diverse
clinical and laboratory manifestations and with a variable course and prognosis. Although the etiology of SLE
is unknown, hormonal influences may play a key role in
disease development and progression.
The adrenal steroid dehydroepiandrosterone
(DHEA) is secreted primarily as its sulfated metabolite
DHEAS. Although the biologic function of DHEA in
humans has not been ascertained, it has mild intrinsic
androgenic properties, and in peripheral tissues, both
DHEA and DHEAS can be converted to various other
androgens as well as aromatized to estrogenic steroids
(1). The potential for using DHEA in the treatment of
SLE was suggested by such observations as the female
predominance of SLE, the low circulating levels of
DHEA and DHEAS in patients with active disease (2),
the immunomodulatory effects of DHEA (3), and the
delayed onset of and reduced mortality from SLE in
NZB ⫻ NZW mice that were fed DHEA (4).
The present study was designed to evaluate the
safety and efficacy of DHEA treatment in female pa-
Supported in part by Genelabs Biotechnology Company, Ltd.,
and by a grant from the National Science Council (NSC90-2314-B016-069).
1
Deh-Ming Chang, MD: Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China;
2
Joung-Liang Lan, MD: Veteran’s General Hospital, Taichung, Taiwan, Republic of China; 3Hsiao-Yi Lin, MD: Veteran’s General
Hospital, Taipei, Taiwan, Republic of China; 4Shue-Fen Luo, MD:
Chang-Gung Memorial Hospital, Taipei, Taiwan, Republic of China.
Address correspondence and reprint requests to Deh-Ming
Chang, MD, Deputy Director, Tri-Service General Hospital, 325
Cheng-Kung Road, Section 2, Neihu 114, Taipei, Taiwan, Republic of
China. E-mail: ming0503@ms3.hinet.net.
Submitted for publication February 6, 2002; accepted in
revised form July 26, 2002.
2924
DHEA TREATMENT IN WOMEN WITH SLE
tients with mild-to-moderate SLE disease activity. Our
findings are presented herein.
Study design. This study was a randomized, doubleblind, placebo-controlled trial conducted at 4 medical centers
in Taiwan using the same protocol. Adult Chinese women with
SLE according to the American College of Rheumatology
criteria (5) who were receiving a dosage of 0–10 mg/day of
prednisone (or its equivalent) at study entry were enrolled.
Patients had active SLE, which was originally defined as a
Systemic Lupus Activity Measure (SLAM) score ⱖ7 (6). This
was subsequently amended to also require a baseline SLE
Disease Activity Index (SLEDAI) score ⬎2 (7). In patients
treated with hydroxychloroquine, azathioprine, methotrexate,
or cyclophosphamide, either alone or in combination, the
regimen had to have been stable, with no changes in the dosage
or drug combination, for at least 6 weeks prior to study entry.
This regimen was to remain unchanged throughout the study.
Patients who were receiving androgens, immunoglobulins,
cyclosporin A, or immunosuppressive agents other than those
noted above were excluded.
After a 10-day screening and qualifying baseline period, patients were assigned by predetermined randomization
code to receive DHEA at a dosage of 200 mg/day or placebo
for 24 weeks. Scheduled evaluations at baseline and at weeks 4,
12, and 24 included a physical examination, routine laboratory
determinations, the SLAM score, and patient’s and physician’s
global assessments (using a 100-mm visual analog scale
[VAS]). The SLEDAI score was measured at baseline and at
weeks 12 and 24 only. Serum levels of sex hormones and
DHEAS were measured at baseline and at the last visit.
The protocol was approved by the Institutional Review
Board at each center. All patients gave their written informed
consent.
Efficacy end point. The primary end point was the
mean change in the SLAM score at 24 weeks of therapy
compared with baseline. Secondary end points included SLE
flare, change in SLEDAI score, and physician’s and patient’s
VAS scores at 24 weeks. Our definition of disease flare was
similar to that of the ongoing SELENA (Safety of Estrogens in
Lupus Erythematosus: National Assessment) study (8), except
that we included an increase in glucocorticoid dosage of ⱖ2.5
mg for at least 7 days for SLE-related reasons as a component.
Safety variables. Adverse events were coded according
to the COSTART system. The variables were summarized by
treatment group and body system.
Laboratory measurements. Laboratory assessments included a urinalysis, a Westergren erythrocyte sedimentation
rate (ESR), and routine serum biochemistries. Anti–doublestranded DNA (anti-dsDNA) antibody, C3 and C4 complement, serum 17␤-estradiol, total testosterone, and DHEAS
levels were also measured.
Statistical analysis. All statistical tests were 2-sided
and evaluated at the 0.05 level of significance. Continuous
variables were analyzed using an analysis of variance model.
Categorical variables were analyzed using chi-square test.
2925
Table 1.
Efficacy variables in the study patients, by treatment group*
SLAM score
Baseline
Mean change
SLEDAI score
Baseline
Mean change
Patient’s VAS score
Baseline
Mean change
Physician’s VAS score
Baseline
Mean change
DHEA-treated
patients
(n ⫽ 61)
Placebo-treated
patients
(n ⫽ 59)
P†
10.3 ⫾ 2.8
⫺2.6 ⫾ 3.4
10.4 ⫾ 2.6
⫺2.0 ⫾ 3.8
0.355
8.2 ⫾ 4.9
⫺1.2 ⫾ 5.4
6.6 ⫾ 3.4
⫺1.4 ⫾ 4.6
0.742
37.0 ⫾ 18.8
⫺5.5 ⫾ 20.0
33.7 ⫾ 17.9
5.4 ⫾ 26.6
0.005
31.0 ⫾ 11.3
⫺9.2 ⫾ 13.9
31.4 ⫾ 14.0
⫺6.3 ⫾ 16.9
0.104
* Values are the mean ⫾ SD baseline scores and the mean ⫾ SD
change in scores at the last visit in the intent-to-treat population.
DHEA ⫽ dehydroepiandrosterone; SLAM ⫽ Systemic Lupus Activity
Measure; SLEDAI ⫽ Systemic Lupus Erythematosus Disease Activity
Index; VAS ⫽ visual analog scale.
† P values were determined by analysis of variance, with treatment,
center, and treatment by center interaction as factors.
RESULTS
Characteristics of the study patients. A total of
120 patients were randomized into the study and received treatment as follows: 61 patients received DHEA
200 mg/day and 59 patients received placebo. The two
treatment groups were well balanced with regard to
baseline characteristics. The patients were of similar age
and menopause status, and their prednisone dosage/use,
use of cytotoxic agents, use of antimalarials, and scores
on the SLE activity instruments were similar at baseline.
Patients were evaluated for 24 weeks or until
early termination of the study drug. Fifty-eight patients
in the DHEA group (95.1%) and 55 patients in the
placebo group (93.2%) completed the study. The mean
duration of exposure was approximately the same in
both treatment groups (164 ⫾ 26.6 days in DHEA group
and 163.7 ⫾ 23.5 in placebo group; P ⫽ 0.986); the
median duration of exposure was identical (169.0 days).
Efficacy of DHEA. The primary end point was the
change in SLAM scores from baseline. No significant
difference in SLAM scores between the two treatment
groups was detected (P ⫽ 0.355) (Table 1). As shown in
Table 2 and Figure 1, significantly fewer patients in the
DHEA group had disease flares.
The DHEA group showed significantly greater
improvement in patient’s VAS scores compared with the
placebo group. Patient’s VAS scores decreased by 5.5
from a baseline score of 37.0 in the DHEA group and
2926
CHANG ET AL
Table 2. Frequency of disease flares in the study patients, by treatment group*
First disease flare
No. of patients
% of patients
DHEA-treated
patients
(n ⫽ 60)
Placebo-treated
patients
(n ⫽ 59)
11
18.3
20
33.9
* There was a statistically significant difference between groups for the
time to first disease flare (P ⫽ 0.044). DHEA ⫽ dehydroepiandrosterone.
increased by 5.4 from a baseline score of 33.7 in the
placebo group (P ⫽ 0.005) (Table 1).
Safety of DHEA. DHEA was well tolerated in
these study patients. Expected androgenic effects, including increased testosterone levels and increased incidence of acne, were observed. No life-threatening reactions or serious safety issues were identified during this
study.
Adverse events. Adverse events that were assessed by the investigators as being serious were reported in a significantly higher proportion of patients in
the placebo group than in the DHEA group. One or
more serious adverse events were reported for 7 of 61
patients treated with DHEA (11.5%) and for 18 of 59
patients treated with placebo (30.5%); the difference
was statistically significant (P ⫽ 0.010 by chi-square
test). In most cases, the types of serious adverse events
reported were consistent with SLE flares or hospitalization for manifestations of SLE, rather than being adverse effects of the study drug.
Findings of clinical laboratory evaluations. For
all standard laboratory tests of safety, the two groups
appeared to be well matched at baseline. There were no
overall trends in the results of hematologic, biochemical,
or lipid tests that would be suggestive of an adverse
effect of DHEA treatment. Levels of triglycerides decreased in the DHEA group compared with the placebo
group (P ⬍ 0.05).
Estradiol levels decreased in both groups. The
median decrease was slightly larger for the DHEA group
(39.3 pg/ml versus 31.5 pg/ml in the placebo group).
Mean and median testosterone levels increased in the
DHEA group and decreased in the placebo group (46.6
and 39.5 pg/ml versus ⫺6.6 and ⫺6.5 pg/ml, respectively;
P ⬍ 0.05).
The mean and median levels of C3 and C4 serum
complement decreased in patients in the DHEA group,
whereas a small increase or no change was noted in
patients in the placebo group (P ⬍ 0.05). Anti-dsDNA
antibody titers decreased in both treatment groups, but
the mean and median decreases were greater in the
placebo group. In both treatment groups, the majority of
patients had abnormally high anti-dsDNA titers at the
baseline visit and at the final visit. The ESR was
comparable in the two treatment groups at baseline.
Small decreases in the median ESR values at each visit
were observed in both treatment groups.
Most patients in both treatment groups had
DHEAS levels of 0–200 ␮g/dl at baseline. At the assessments after baseline, ⬃60% of patients in the DHEA
group had DHEAS levels ⬎1,000 ␮g/dl. The levels in the
remaining patients were distributed over each of the
lower 200-␮g/dl incremental ranges. There was no evidence of elevated DHEAS levels in the placebo group at
baseline or at subsequent visits.
DISCUSSION
Figure 1. Time to first flare in Chinese women with mild-to-moderate
systemic lupus erythematosus treated with dehydroepiandrosterone
(DHEA) versus placebo (P ⫽ 0.044).
In this double-blind study evaluating the efficacy
and safety of DHEA for the treatment of mild-tomoderate SLE in women, we found significant reductions in the time to disease flare and serious lupusrelated adverse events, as well as improvement in
patient’s global assessment in the DHEA-treated group
compared with the placebo-treated group. This is of
particular interest since almost all patients were already
receiving treatment with standard medications, including glucocorticoids and other immunosuppressive
agents. While the planned primary analysis, change in
SLAM score from baseline to last visit, did not demonstrate significant differences between the two treatment
groups, it is important to recognize that this study was of
relatively short duration (6 months), and there are as yet
DHEA TREATMENT IN WOMEN WITH SLE
no fully validated end points for therapeutic interventions in lupus trials. Given the multiple end points of this
study, its findings should be confirmed in a trial of longer
duration.
Multiple mechanisms could be mediating these
effects, including favorable changes in inflammatory
cytokines such as interleukin-6 (IL-6), which is increased
in patients with active SLE (9). DHEA has been reported to reduce the release of IL-6 from human
mononuclear cells in vitro (3,10). Decreases in complement levels without SLE flare during DHEA treatment
were observed in this study as well as in two other
clinical studies (11,12). A presumed reduction in IL-6
production during DHEA administration might be associated with a reduction in the levels of C3, which is an
acute-phase reactant (13).
DHEA was well tolerated by the patients in this
study, with no evidence of unexpected or serious adverse
effects of the drug. Most of the serious adverse events
reported in this study appeared to be related to SLE
flares or to hospitalization for manifestations of SLE,
rather than to adverse study drug effects. The proportion of patients experiencing serious adverse events was
statistically significantly higher in the placebo group.
This finding is consistent with the reduction in SLE
flares observed in the efficacy analysis of this study.
A double-blind study conducted at Stanford University suggested that DHEA at a dosage of 200 mg/day
was well tolerated and may have steroid-sparing effects
and reduce the number of flares in patients with mildto-moderate SLE (14). Furthermore, in two subsequent
multicenter studies, DHEA treatment at a dosage of 200
mg/day allowed for a reduction in the prednisone dosage
to near-physiologic levels in a significantly greater proportion of patients than did placebo (11), and it stabilized or improved the SLE activity and its symptoms and
prevented bone loss (12).
In summary, in this 24-week study of adult Chinese women with mild-to-moderate SLE, treatment with
DHEA at a dosage of 200 mg once a day resulted in a
stabilization of the overall lupus activity, with fewer
flares and fewer hospitalizations and without serious or
unexpected adverse effects. Concurrent use of DHEA
will offer meaningful benefit, especially for steroiddependent lupus patients. Confirmation in a larger study
of longer duration will be necessary to further define the
role of DHEA in SLE.
2927
ACKNOWLEDGEMENT
We deeply appreciate Dr. Peter H. Schur for his advice
and revision of the manuscript.
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7. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang DH,
and the Committee on Prognosis Studies in SLE. Derivation of the
SLEDAI: a disease activity index for lupus patients. Arthritis
Rheum 1992;35:630–40.
8. Petri M, Buyon J, Kim M. Classification and definition of major
flares in SLE clinical trials. Lupus 1999;8:685–91.
9. Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T,
Klinenberg JR. Elevated levels of endogenous IL-6 in systemic
lupus erythematosus: a putative role in pathogenesis. J Immunol
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10. Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich
J, et al. Serum dehydroepiandrosterone (DHEA) and DHEA
sulfate are negatively correlated with serum interleukin-6 (IL-6),
and DHEA inhibits IL-6 secretion from mononuclear cells in man
in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 1998;83:2012–17.
11. Petri MA, Lahita RG, Van Vollenhoven RF, Merrill JT, Schiff M,
Ginzler EM, et al. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a doubleblind, randomized, placebo-controlled trial. Arthritis Rheum 2002;
46:1820–9.
12. Mease PJ, Merrill JT, Lahita RG, Petri MA, Ginzler EM, Katz RS,
et al. GL701 (prasterone, dehydroepiandrosterone) improves systemic lupus erythematosus [abstract]. Arthritis Rheum 2000;43
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13. Zhao YX, Andoh A, Shimada M, Takaya H, Hata K, Fujiyama Y,
et al. Secretion of complement components of the alternative
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cell line A549. Int J Mol Med 2000;5:415–9.
14. Van Vollenhoven RF, Engleman EG, McGuire JL. Dehydroepiandrosterone in systemic lupus erythematosus: results of a doubleblind, placebo-controlled, randomized clinical trial. Arthritis
Rheum 1995;38:1826–31.
Vol. 50, No. 9, September 2004, pp 2858–2868
DOI 10.1002/art.20427
Effects of Prasterone on Disease Activity and Symptoms in
Women With Active Systemic Lupus Erythematosus
Results of a Multicenter Randomized, Double-Blind, Placebo-Controlled Trial
Michelle A. Petri,1 Philip J. Mease,2 Joan T. Merrill,3 Robert G. Lahita,4 Mark J. Iannini,5
David E. Yocum,6 Ellen M. Ginzler,7 Robert S. Katz,8 Oscar S. Gluck,† Mark C. Genovese,9
Ronald Van Vollenhoven,10 Kenneth C. Kalunian,11 Susan Manzi,12 Maria W. Greenwald,13
Jill P. Buyon,14 Nancy J. Olsen,15 Michael H. Schiff,16 Arthur F. Kavanaugh,11
Jacques R. Caldwell,17 Rosalind Ramsey-Goldman,18 E. William St.Clair,19 Allan L. Goldman,20
Rita M. Egan,21 Richard P. Polisson,22 Kevin G. Moder,23 Naomi F. Rothfield,24
Robert T. Spencer,25 Kathryn Hobbs,16 Barri J. Fessler,26 Leonard H. Calabrese,27
Larry W. Moreland,26 Stanley B. Cohen,28 Betty J. Quarles,29 Vibeke Strand,9 Marc Gurwith,29
and Kenneth E. Schwartz29
Objective. To determine whether prasterone administration results in improvement or stabilization of
systemic lupus erythematosus (SLE) disease activity
and its symptoms.
Methods. Women with active SLE were treated
with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for
up to 12 months in this randomized, double-blind
investigation conducted at 27 centers. Standard SLE
treatments included prednisone (<10 mg/day), antimalarials, and immunosuppressive agents; dosages were
required to be stable for >6 weeks prior to enrollment
and remain unchanged during protocol treatment. Re-
Presented in part at the 64th Annual Scientific Meeting of the
American College of Rheumatology, Philadelphia, PA, November
2000, and at the Annual Meeting of the British Society for Rheumatology, Manchester, UK, April 2003.
Supported by Genelabs Technologies, Inc., Redwood City, CA.
1
Michelle A. Petri, MD, MPH: Johns Hopkins University
Medical Center, Baltimore, Maryland; 2Philip J. Mease, MD: Seattle
Rheumatology Associates, Seattle, Washington; 3Joan T. Merrill, MD:
Oklahoma Medical Research Foundation, Oklahoma City; 4Robert G.
Lahita, MD, PhD: Liberty Health, Jersey City, New Jersey; 5Mark J.
Iannini, MD, MPH: Carondelet Medical Group, Tucson, Arizona;
6
David E. Yocum, MD: University of Arizona Health Sciences Center,
Tucson; 7Ellen M. Ginzler, MD, MPH: SUNY Health Science Center
at Brooklyn, Brooklyn, New York; 8Robert S. Katz, MD: Rheumatology Associates, Chicago, Illinois; 9Mark C. Genovese, MD, Vibeke
Strand, MD: Stanford University School of Medicine, Stanford, California; 10Ronald Van Vollenhoven, MD, PhD: Karolinska Hospital,
Stockholm, Sweden; 11Kenneth C. Kalunian, MD, Arthur F. Kavanaugh, MD: University of California, San Diego School of Medicine,
San Diego; 12Susan Manzi, MD, MPH: University of Pittsburgh School
of Medicine, Pittsburgh, Pennsylvania; 13Maria W. Greenwald, MD:
Advances in Medicine, Rancho Mirage, California; 14Jill P. Buyon,
MD: New York University School of Medicine, New York; 15Nancy J.
Olsen, MD: Vanderbilt University School of Medicine, Nashville,
Tennessee; 16Michael H. Schiff, MD, Kathryn Hobbs, MD: Denver
Arthritis Clinic, Denver, Colorado; 17Jacques R. Caldwell, MD: Halifax Clinical Research Institute, Daytona Beach, Florida; 18Rosalind
Ramsey-Goldman, MD, DrPH: Northwestern University Feinberg
School of Medicine, Chicago, Illinois; 19E. William St.Clair, MD: Duke
University Medical Center, Durham, North Carolina; 20Allan L.
Goldman, MD: Rheumatic Disease Center, Milwaukee, Wisconsin;
21
Rita M. Egan, MD: Arthritis Center of Lexington, Lexington,
Kentucky; 22Richard P. Polisson, MD, MHS: Massachusetts General
Hospital, Boston; 23Kevin G. Moder, MD: Mayo Clinic Foundation,
Rochester, Minnesota; 24Naomi F. Rothfield, MD: University of
Connecticut Medical Center, Farmington; 25Robert T. Spencer, MD:
Colorado Arthritis Center, Englewood; 26Barri J. Fessler, MD, Larry
W. Moreland, MD: University of Alabama School of Medicine at
Birmingham; 27Leonard H. Calabrese, DO: Cleveland Clinic Foundation, Cleveland, Ohio; 28Stanley B. Cohen, MD: St. Paul Medical
Center, Dallas, Texas; 29Betty J. Quarles, BS, Marc Gurwith, MD, JD
(current address: Vaxgen, Inc., San Bruno, California), Kenneth E.
Schwartz, MD: Genelabs Technologies, Inc., Redwood City, California.
†
Dr. Gluck is deceased.
Drs. Petri, Kalunian, Ramsey-Goldman, and Strand have
served as consultants to Genelabs Technologies, Inc.
Address correspondence and reprint requests to Michelle A.
Petri, MD, MPH, Professor of Medicine, Division of Rheumatology,
Department of Medicine, Johns Hopkins University Medical Center,
1830 East Monument Street, Suite 7500, Baltimore, MD 21205.
E-mail: mpetri@welch.jhu.edu.
Submitted for publication August 15, 2003; accepted in
revised form April 29, 2004.
2858
PRASTERONE TREATMENT IN SLE
sponders were patients who experienced no clinical
deterioration and had improvement or stabilization
over the duration of the study in 2 disease activity
measures (the SLE Disease Activity Index [SLEDAI]
and the Systemic Lupus Activity Measure) and 2 quality
of life measures (patient’s global assessment and the
Krupp Fatigue Severity Scale).
Results. A total of 381 women with SLE were
enrolled. Among patients with clinically active disease
at baseline (SLEDAI score >2), 86 of 147 in the
prasterone group (58.5%) demonstrated improvement
or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P ⴝ
0.017). Acne and hirsutism were reported in 33% and
16%, respectively, of the prasterone group and in 14%
and 2%, respectively, of the placebo group (P < 0.05 for
both comparisons). However, most cases of acne and
hirsutism were mild and did not require withdrawal
from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and
15%, respectively) than in the placebo group (36% and
23%, respectively) (P < 0.05 for both comparisons).
Serum levels of high-density lipoprotein cholesterol,
triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser
extent, estradiol increased in the prasterone group.
Conclusion. In adult women with active SLE,
administration of prasterone at a dosage of 200 mg/day
improved or stabilized signs and symptoms of disease
and was generally well tolerated.
Systemic lupus erythematosus (SLE) is a chronic,
potentially fatal autoimmune disease that occurs 9 times
more frequently in women than in men (1). Although
the multifactorial etiology of this disease is poorly
understood, abnormalities of both estrogen and androgen metabolism in SLE patients have been reported
(2,3).
Dehydroepiandrosterone (DHEA) is a naturally
occurring steroid produced by the adrenal glands. It is
secreted primarily as its metabolite, DHEA sulfate
(DHEAS), which is the most abundant circulating adrenal steroid in humans (4). Both DHEA and DHEAS are
subsequently converted into androgenic and estrogenic
steroids in peripheral tissues (5,6). Decreases of ⬃50%
in circulating levels of DHEA and DHEAS have been
observed in patients with SLE (7,8). Previous studies in
animal models of SLE have demonstrated improvement
with androgen administration, including DHEA (9–14).
In addition to serving as a precursor for other androgenic and estrogenic steroids (5), there is evidence that
2859
DHEA has an immunomodulatory role, including upregulation of interleukin-2 (IL-2) and down-regulation
of IL-6 expression (9,15–17), both of which have been
reported to be abnormal in SLE (18–20).
Prasterone is the United States Adopted Names
generic designation for dehydroepiandrosterone. In
open-label and placebo-controlled studies, Van Vollenhoven et al (21,22) reported that SLE patients receiving
oral prasterone 200 mg/day had improvement in a
number of outcome variables, including reduction of
steroid dosages, the number of disease flares, and global
assessments of disease activity (21,22). In an initial
phase II/III trial comparing placebo with 100 and 200
mg/day of prasterone, it was demonstrated that 200
mg/day of prasterone allowed a sustained reduction in
the glucocorticoid dosage (23). In addition, delay in time
to SLE flare has been reported for women treated with
prasterone (24).
The present study was conducted to determine
whether prasterone administration results in improvement or stabilization in SLE disease activity and its
symptoms.
Study participants. This prospective randomized,
double-blind, placebo-controlled trial conducted at 27 study
sites evaluated female patients with active SLE. Patients were
required to meet the American College of Rheumatology 1982
criteria for a diagnosis of SLE (25) and have active disease, as
determined by 2 disease activity indices. Initially, active disease
was defined as a Systemic Lupus Activity Measure (SLAM)
score ⱖ7 at baseline (26). While the study was ongoing and
blinded, this was amended to also require a Systemic Lupus
Erythematosus Disease Activity Index (SLEDAI) score ⬎2 at
baseline (27). Eligibility was determined at screening and
qualifying visits, which occurred no more than 10 days apart.
Patients in both treatment groups were allowed to
continue taking standard SLE medications. Baseline medications that were allowed included oral glucocorticoids (ⱕ10
mg/day of prednisone or equivalent), hydroxychloroquine,
and/or immunosuppressive agents, including methotrexate,
azathioprine, cyclophosphamide, and mycophenolate mofetil.
Interventions. Patients were assigned by predetermined randomization codes to receive either prasterone 200
mg/day or placebo as once-daily morning doses for up to 52
weeks. Capsules containing placebo were identical to those
containing prasterone. Physicians and patients were instructed
to maintain the dosages of prednisone and other baseline SLE
medications at the baseline dosages during protocol participation.
Outcomes. The primary end point was the proportion
of patients who were “responders.” Responders were patients
who showed improvement or stabilization in SLE disease
activity and constitutional symptoms without clinical deterioration over the duration of the study.
2860
Responder status was designed prospectively, in conjunction with lupus experts and with significant input by the US
Food and Drug Administration, to be a single composite end
point that integrated 3 domains of SLE: disease activity, organ
damage, and health-related quality of life (28). Responders
were those who demonstrated improvement or stabilization in
mean on-treatment scores for 2 disease activity measures (the
SLEDAI and the SLAM) and 2 health-related quality of life
assessments (patient’s global assessment and the Krupp Fatigue Severity Score [KFSS]) (29) without evidence of clinical
deterioration (reflecting organ damage). A patient was
deemed to have improved or stabilized in terms of each of the
disease activity and health-related quality of life measures if
the time-weighted mean of all on-treatment visit measurements for each of the instruments for that patient was less than
the mean of 2 pretreatment values for each of the 4 parameters. “No change” was defined prospectively, while the
study was ongoing and blinded. The definition of “no change”
allowed for test–retest variability in these scoring instruments,
which was defined as ⫾0.5 for the SLEDAI and KFSS, ⫾1.0
for the SLAM, and ⫾10 mm for the patient’s global assessment
(30,31).
The clinical deterioration component of the responder
end point was prospectively defined to include serious drug
toxicity attributable to the study drug or other lupus therapy if
it occurred during treatment with the study drug or within 6
weeks after discontinuation of the study drug, serious new or
progressive lupus-related conditions, or requirement for increased dosage or institution of new therapy with immunosuppressive or cytotoxic agents for treatment of lupus. The
occurrence of clinical deterioration and its onset date was
determined by Genelabs’ study monitors before the blinding
was broken.
The following conditions qualified as serious drug
toxicity: new-onset diabetes mellitus, defined as diabetes requiring drug therapy for ⱖ 3 months; new gastric or duodenal ulcer
not due to Helicobacter pylori and requiring hospitalization or
transfusion; new-onset hypertension requiring drug therapy for
ⱖ3 months; new myocardial infarction, as demonstrated by
electrocardiographic or enzymatic criteria; new steroid myopathy; new elevation in serum transaminase levels (increases in
aspartate aminotransferase or alanine aminotransferase levels
to ⱖ8 times the upper limit of normal or a single measurement
showing levels ⱖ3 times the upper limit of normal at multiple
measurements over 3 months); or new fracture and/or vertebral collapse due to osteoporosis.
The following conditions qualified as major new or
progressive organ disease. These conditions were assessed by
the treating physician as being attributable to lupus or its
treatment and which occurred during treatment with the study
drug or within 6 weeks after discontinuation of the study drug.
Central nervous system conditions were cerebrovascular accident transverse myelitis, retinal vascular occlusion, new onset
of psychosis of ⬎3 months’ duration, or new onset of seizures
that were refractory to therapy for at least 3 months. Renal
conditions were new onset of end-stage renal disease or loss of
renal function that required dialysis for at least 3 months.
Pulmonary conditions were new or worsened pulmonary hypertension and/or interstitial lung disease with reduction in
diffusion capacity, mean pulmonary artery pressure, and/or
dyspnea at rest (New York Heart Association class IV).
PETRI ET AL
Cardiovascular conditions were pericarditis that was refractory
to treatment for ⬎3 months or that required pericardiectomy,
cardiomyopathy that was refractory to therapy for ⬎3 months
with hemodynamic compromise (decreased cardiac index, left
ventricular ejection fraction, and/or dyspnea at rest), or refractory arrhythmia. Gastrointestinal conditions were ischemic
bowel disease that required bowel resection. Vasculitic conditions were vasculitis that resulted in infarction (excluding
vasculitis described under any other organ systems). Hematologic conditions were thrombocytopenia that resulted in clinically significant hemorrhage with sequelae that did not resolve
for at least 3 months or persistent leukopenia (white blood cell
count ⬍1,500/mm3) that resulted in recurrent infections without improvement in the incidence of recurrent infections for at
least 3 months.
The following qualified as unacceptable increases in
immunosuppressive or cytotoxic therapy for lupus: any SLErelated increase in dosages of concomitant methotrexate or
azathioprine, or institution of new therapy with cytotoxic or
immunosuppressive agents (methotrexate, azathioprine, cyclophosphamide, or cyclosporine), at any time during treatment
with the study drug or within 6 weeks after discontinuation of
study drug; and except for stress doses, prescribed prednisone
dosage increase to ⬎10 mg/day over the baseline dosage within
the first 2 months of participation or, through the remainder of
the study, prednisone dosage increase to ⬎5 mg/day over the
daily baseline dose for ⬎2 consecutive months.
Secondary analyses. Prospectively defined secondary
analyses included time to lupus flare and mean changes in
individual scores on the SLEDAI, SLAM, KFSS, and patient’s
global assessment instruments. Time to lupus flare was not part
of the initial protocol design. However, given the interest in
lupus flares as a potential study outcome for future lupus
protocols, it was proposed as a secondary outcome in this
study.
Time to first lupus flare was analyzed from data
derived from chart reviews of all enrolled patients and was
determined while the study was ongoing and blinded. SLE
flare was defined according to the following 5 criteria: 1) new
or worse central nervous system lupus, vasculitis, or myositis
requiring scoring on the SLEDAI and not present at a previous
visit; 2) thrombocytopenia (⬍60,000 platelets/mm3), a hemoglobin value ⬍7 gm/dl, or a decrease in the hemoglobin level of
at least 3 gm/dl; 3) proteinuria with pyuria and/or hematuria
treated with new use or increased dosage of glucocorticoids or
immunosuppressive agents; 4) an increase in the glucocorticoid
dose of ⱖ2.5 mg for at least 7 days for SLE-related reasons; or
5) new use or increase in dosage of immunosuppressive agents
or antimalarials for at least 7 days for SLE-related reasons or
hospitalization for new manifestation of SLE.
Procedures. Scheduled evaluations at baseline and
every 3 months included physical examinations, laboratory
determinations, and scoring of the SLAM, the SLEDAI,
patient’s and physician’s global assessments using 100-mm
visual analog scales (VAS), and the KFSS.
Laboratory assessments were performed every 3
months. Blood samples were drawn after an 8-hour fast but
were not timed to prasterone administration. Assessments
included anti–double-stranded DNA (anti-dsDNA) antibodies, C3 and C4 levels, IgG and IgM anticardiolipin antibodies,
serum lipid levels (total cholesterol, HDL-cholesterol, calcu-
2861
Table 1. Baseline characteristics of the study patients, by treatment group*
Intent-to-treat analysis group
(all randomized patients)
Age, mean years
Caucasian, %
Postmenopause, %
Prednisone dose, mean (median) mg/day
Medication use, %
Prednisone
Immunosuppressives
Antimalarials
Prednisone, immunosuppressives, or
antimalarials
Composite responder index components,
mean (median) score
SLEDAI
SLAM
Patient’s global assessment
KFSS
Laboratory values, mean (median) [no. tested]
DHEAS, ␮g/dl
C3 complement, mg/dl
C4 complement, mg/dl
Anti-dsDNA antibody, IU/dl
Active SLE group
(baseline SLEDAI ⬎2)
Placebo
(n ⫽ 192)
Prasterone
(n ⫽ 189)
Placebo
(n ⫽ 146)
Prasterone
(n ⫽ 147)
43.8
71.4
47.9
3.7 (2.5)
44.4
77.2
43.9
3.5 (3.8)
43.6
67.8
46.6
4.1 (5.0)
43.8
74.8
42.9
3.6 (5.0)
53.7
15.1
60.9
79.7
54.5
18.0
54.0
82.0
58.2
17.8
59.6
80.8
56.5
21.1
48.3
79.6
5.8 (5.0)
12.0 (12.0)
55.4 (57.0)
5.6 (5.7)
6.5 (6.0)
12.2 (12.0)
55.2 (57.0)
5.5 (5.9)
7.34 (6.0)
12.46 (12.0)
55.17 (56.7)
5.56 (5.7)
8.04 (8.0)
12.69 (12.5)
57.08 (58.5)
5.61 (5.9)
103 (50) [n ⫽ 163]
102.9 (102.0) [n ⫽ 192]
17.9 (16.0) [n ⫽ 192]
23.45 (1.95) [n ⫽ 192]
107 (61) [n ⫽ 165]
104.3 (100.0) [n ⫽ 187]
18.2 (17.0) [n ⫽ 187]
36.08 (2.6) [n ⫽ 187]
91 (47) [n ⫽ 121]
99.3 (97.0) [n ⫽ 146]
17.0 (15.0) [n ⫽ 146]
29.4 (2.4) [n ⫽ 146]
105 (61) [n ⫽ 127]
99.1 (97.0) [n ⫽ 146]
17.2 (15.0) [n ⫽ 146]
43.5 (3.4) [n ⫽ 146]
* Baseline values for some of the clinical laboratory tests were not obtained on all patients. SLE ⫽ systemic lupus erythematosus; SLEDAI ⫽
Systemic Lupus Erythematosus Disease Activity Index; SLAM ⫽ Systemic Lupus Activity Measure; KFSS ⫽ Krupp Fatigue Severity Scale;
DHEAS ⫽ dehydroepiandrosterone sulfate; anti-dsDNA ⫽ anti–double-stranded DNA.
lated LDL-cholesterol, and total triglycerides), serum chemistries, complete blood cell counts, urinalyses, and 24-hour urine
collections for creatinine clearance and protein quantitations.
Serum levels of 17␤-estradiol, testosterone, and DHEAS were
measured at baseline and the last visit. To avoid unblinding,
these results were not reported to the investigators or study
monitors until completion of the trial. All blood and urine
assays were conducted at a central laboratory (Covance Laboratories, Indianapolis, IN), with the exception of DHEAS
levels, which were performed by radioimmunoassay at
Genelabs Technologies.
The protocol was conducted in accordance with the
Declaration of Helsinki and was approved by the institutional
review board at each center. All patients gave written informed
consent.
Statistical analysis. Given that this protocol utilized a
responder end point that had never been used in a clinical trial,
Table 2. Number (percentage) of patients completing the study and
reasons for early withdrawal
Completed study drug
Discontinued study drug early
Lack of efficacy
Adverse event
Other
Placebo
(n ⫽ 192)
Prasterone
(n ⫽ 189)
142 (74.0)
50 (26.0)
9 (4.7)
11 (5.7)
30 (15.6)
124 (65.6)
65 (34.4)
11 (5.8)
27 (14.3)
27 (14.3)
there could be no a priori estimation of responder rates.
Hence, the sample size of 300 randomized patients was based
on practical, rather than statistical, calculations.
The original protocol entry criterion required a SLAM
score of ⱖ7 for the definition of active disease. There was no
restriction on the SLEDAI score for patient entry. While the
double-blind study was ongoing, the protocol was subsequently
amended to incorporate a baseline SLEDAI score of ⬎2 as an
additional entry requirement. This requirement was based
upon the outcome of an earlier Genelabs study, which revealed
that SLE patients with little or no disease activity (SLEDAI
ⱕ2) are likely to exhibit a high response regardless of treatment (23).
All randomized patients were included in the intentto-treat analysis of safety (n ⫽ 381). All patients who met
criteria for active disease (SLEDAI ⬎2) at both the baseline
and screening visits were included in the analysis of efficacy
(n ⫽ 293). Patients without postbaseline assessments were
designated, by default, as nonresponders.
The primary efficacy variable, proportion of responders, was analyzed using a logistic regression model using
treatment as a factor. For secondary analyses, betweentreatment comparisons of mean changes in disease activity
indices (the SLEDAI and the SLAM), patient’s global assessment, and the KFSS, and laboratory values were analyzed
utilizing one-way analysis of variance, with treatment as a
factor. Between-treatment comparisons for the number of
patients with specific adverse events or clinically important
treatment-associated changes in laboratory values were per-
2862
PETRI ET AL
Table 3. Percentages of responders and patients with at least 1 definite SLE flare*
Patients with at least 1 SLE flare‡
P
Responders†
Patients with active SLE
All patients
Placebo
Prasterone
P
Placebo
Prasterone
SLE flare
Time to first flare
44.5 (65/146)
42.2 (81/192)
58.5 (86/147)
51.3 (97/189)
0.017
0.074
34.2 (50/146)
29.7 (57/192)
24.5 (36/147)
23.8 (45/189)
0.097
0.266
0.066
0.195
* Active SLE was defined as a baseline SLEDAI score ⬎2. Approximately 80% of patients in both treatment groups were receiving antimalarials,
glucocorticoids, or other immunosuppressive agents at baseline. P values for the responders and for SLE flare were determined by logistic regression
analysis using treatment as a factor. P values for time to first SLE flare were determined by log-rank test. Values are the percentage (number
responding/number in group or the number with at least 1 SLE flare/number in group). See Table 1 for definitions.
† A patient was classified as a responder if no clinical deterioration was observed and if the weighted average of measures of disease activity and
health-related quality of life improved or did not deteriorate during treatment relative to baseline values (weighted average increase from baseline
for the SLAM ⱕ1, for the SLEDAI ⱕ0.5, for the KFSS ⱕ0.5, and for the patient’s global assessment ⱕ10).
‡ An SLE flare was defined according to the following 5 criteria: 1) new or worse central nervous system lupus, vasculitis, or myositis requiring
scoring on the SLEDAI and not present at a previous visit; 2) thrombocytopenia (⬍60,000 platelets/mm3), a hemoglobin value ⬍7 gm/dl, or a
decrease in the hemoglobin level of at least 3 gm/dl; 3) proteinuria with pyuria and/or hematuria treated with new use or increased dosage of
glucocorticoids or immunosuppressive agents; 4) an increase in the glucocorticoid dose of ⱖ2.5 mg for at least 7 days for SLE-related reasons; or
5) new use or increase in dosage of immunosuppressives or antimalarials for at least 7 days for SLE-related reasons or hospitalization for new
manifestation of SLE.
formed using chi-square test or Fisher’s exact test. All statistical tests were 2-sided, and P values less than or equal to 0.05
were considered significant.
RESULTS
Characteristics of the study patients. The trial
was conducted at 27 office- or university-based rheumatology practices in the US, from February 1996 to June
1999. Three hundred eighty-one patients were randomized to receive treatment: 189 in the prasterone group
and 198 in the placebo group. Treatment groups were
well balanced at baseline with regard to age, menopause
status, race, concomitant SLE medications, SLE scores,
DHEAS levels, and other important laboratory values.
Approximately 80% of patients in both groups were
receiving standard SLE treatments at baseline, which
included antimalarials, glucocorticoids, and/or other immunosuppressive agents. There were no statistically
significant between-group differences in baseline characteristics for either the all-patient intent-to-treat analysis or the predefined patient group with active SLE
(baseline SLEDAI ⬎2) (Table 1).
Seventy-four percent of the placebo group and
65.6% of the prasterone group completed 1 year of
treatment (Table 2). There were no meaningful differences in withdrawals across the 2 groups, except for
withdrawals due to adverse events, for which 5.7% in the
placebo group and 14.3% in the prasterone group
withdrew (P ⫽ 0.005). The differences in withdrawals
primarily reflected androgenic adverse events in the
prasterone group, the majority of which were mild, since
there were no differences in the patterns of withdrawals
for other types of adverse events.
Primary outcome measure, responder analysis.
The overall responder rates among the intent-to-treat
group were 42.2% (81 of 192 patients) in the placebo
group and 51.3% (97 of 189 patients) in the prasterone
group (P ⫽ 0.074) (Table 3). In the population with
active disease (SLEDAI ⬎2), 44.5% (65 of 146 patients)
in the placebo group and 58.5% (86 of 147 patients) in
the prasterone group were responders (P ⫽ 0.017). In a
post hoc analysis, significant differences between treatment groups persisted with increasing SLEDAI scores
(Figure 1).
Secondary outcome measures, time to SLE flare
and mean changes in individual scoring instruments.
Among patients with active disease at baseline, fewer
patients in the prasterone treatment group experienced
a first flare during the study (24.5% taking prasterone
versus 34.2% taking placebo, P ⫽ 0.066), and a trend for
prolongation in time to flare was seen among patients
who received prasterone (P ⫽ 0.097) (Table 3).
There were no statistically significant betweengroup differences in change from baseline in any of the
individual components of the responder index (data not
shown), but statistically significant differences in individual components of the responder analysis resulted in
patients being classified as nonresponders (Table 4),
suggesting a worsening of individual components of the
composite responder index in more of the placebotreated patients than prasterone-treated patients. The
greatest differences between the prasterone and placebo
treatment groups were defined by the proportion of
patients reporting a worsening in the patient’s global
assessment (10.9% of the prasterone group versus 22.6%
of the placebo group, P ⫽ 0.007) and in the SLEDAI
Figure 1. Percentage of responders to treatment with prasterone or
placebo, by baseline Systemic Lupus Erythematosus Disease Activity
Index (SLEDAI) score. Values within the bars are the number
responding/number in group.
scores (only 9.5% of the prasterone group versus 17.8%
of the placebo group, P ⫽ 0.039 (Table 4).
Although not defined in the specified analysis
plan, it was of interest to assess responders among the
patients who were not receiving antimalarials, glucocorticoids, or other immunosuppressive agents at baseline
(⬃20% of patients), given the high rate of background
medication use in both treatment groups. Among patients not receiving these medications at baseline and
who had active disease at study entry (i.e., baseline
SLEDAI ⬎2), responder rates were 42.9% (12 of 28
patients) in the placebo group and 70.0% (21 of 30
patients) in the prasterone group (P ⫽ 0.037).
Adverse events. Study drug administration was
discontinued early in 65 (34%) of the 189 prasterone-
2863
treated patients and 50 (26%) of the 192 placebo-treated
patients (P ⫽ 0.076). Early discontinuations were similar
between treatment groups, with the exception of an
increased number in the prasterone group withdrawing
due to reported androgenic adverse events. Eleven
patients (5.8%) with acne and/or hirsutism indicated
these events as reasons for treatment discontinuation in
the prasterone treatment group.
Serious adverse events were reported in 14% (27
of 189 patients) in the prasterone group and 17% (33 of
192 patients) in the patients in placebo treatment
groups, respectively. Fourteen of these events in the
prasterone group and 16 in the placebo group resulted in
treatment discontinuation. While there were no deaths
in the prasterone treatment group, there were 5 deaths
during or shortly after completion of treatment in the
placebo group, including 2 suicides, 1 death due to
pulmonary hypertension, 1 sudden death, and 1 death
from non-Hodgkin’s lymphoma 6 weeks following protocol completion. Three patients were diagnosed as
having cancer during the study, all of whom were in the
placebo group: the patient with non-Hodgkin’s lymphoma noted previously, 1 patient with carcinoma of the
breast, and 1 patient with carcinoma of the lung.
Adverse events reported in 10% or more of the
active and control treatment populations are shown in
Table 5. Androgenic adverse events, including acne and
hirsutism, were more commonly reported in patients
receiving prasterone (42%) than in patients receiving
placebo (18%) (P ⬍ 0.05). Most androgenic complaints
were characterized as mild or moderate; none was
severe.
Adverse events such as myalgias, stomatitis (oral
ulcers), alopecia, and fever were reported less frequently
in patients receiving prasterone in comparison to placebo (Table 5). These differences were statistically sig-
Table 4. Patients with a baseline SLEDAI ⬎2 who failed to meet individual response criteria, by
treatment group*
Criterion
Clinical deterioration
Worsening of composite responder index
component scores
SLEDAI score
SLAM score
Patient’s global assessment score
KFSS score
No. (%) of
placebo group
(n ⫽ 146)
No. (%) of
prasterone group
(n ⫽ 147)
P
13 (8.9)
15 (10.2)
0.705
26 (17.8)
15 (10.3)
33 (22.6)
21 (14.4)
14 (9.5)
10 (6.8)
16 (10.9)
16 (10.9)
0.039
0.288
0.007
0.367
* Patients could have failed to meet ⬎1 criterion. Approximately 80% of patients in both treatment groups
were receiving antimalarials, glucocorticoids, or other immunosuppressive agents at baseline. P values
were determined by chi-square test. See Table 1 for definitions.
2864
PETRI ET AL
nificant for myalgias and oral ulcers, suggesting potential
beneficial effects of prasterone treatment on some of the
typical signs and symptoms of SLE.
Treatment-associated changes in laboratory values. Total cholesterol, high-density lipoprotein (HDL)
cholesterol, low-density lipoprotein (LDL) cholesterol,
and total triglyceride levels decreased in the prasterone
treatment group, although decreases in LDL cholesterol
were minimal (Figure 2). Treatment-associated decreases in total cholesterol and HDL cholesterol were
significantly greater in the prasterone group compared
with the placebo group. Serum triglycerides were also
statistically significantly decreased in the prasterone
group compared with the placebo group, in which they
were increased. Reductions in serum HDL cholesterol,
total cholesterol, and triglyceride levels were evident in
the prasterone treatment group by month 3, and the
reductions were maintained with subsequent study drug
administration (data not shown). HDL cholesterol levels
decreased from normal levels at baseline in 133 and 148
patients in the prasterone and placebo groups, respectively, to below 40 mg/dl (the currently recommended
lower limit for HDL cholesterol [32]) at the end of
treatment in 38 patients receiving prasterone (26.6%)
compared with 15 patients receiving placebo (10.1%)
(P ⫽ 0.001 by chi-square test).
Mean serum levels of C3 complement declined in
the prasterone treatment group: –7% from baseline
Table 5. Adverse events reported by ⱖ10% of patients in either
treatment group*
Adverse event
No. (%) of
placebo group
(n ⫽ 192)
No. (%) of
prasterone group
(n ⫽ 189)
Rash
Arthralgia
Acne
Asthenia
Arthritis
Headache
Myalgia
Flu syndrome
Hirsutism
Stomatitis (mucosal ulcers)
Depression
Alopecia
Abdominal pain
Fever
Peripheral vascular disease
Sinusitis
Chest pain
62 (32.3)
71 (37.0)
27 (14.1)
51 (26.6)
42 (21.9)
56 (29.2)
69 (35.9)
42 (21.9)
3 (1.6)
44 (22.9)
30 (15.6)
39 (20.3)
30 (15.6)
28 (14.6)
20 (10.4)
20 (10.4)
20 (10.4)
75 (39.7)
68 (36.0)
63 (33.3)†
45 (23.8)
45 (23.8)
42 (22.2)
42 (22.2)†
39 (20.6)
31 (16.4)†
28 (14.8)†
28 (14.8)
28 (14.8)
27 (14.3)
22 (11.6)
19 (10.1)
17 (9.0)
14 (7.4)
* Approximately 80% of the patients in both treatment groups were
receiving antimalarials, glucocorticoids, or other immunosuppressive
agents at baseline.
† P ⬍ 0.05 by chi-square test.
Figure 2. Mean baseline concentrations of lipids and mean change in
lipid levels from baseline to the last visit during treatment. Values
above the x-axis represent the placebo group on the left and the
prasterone group on the right. ⴱ ⫽ P ⬍ 0.05 for within-treatment
change from baseline. Tot-C ⫽ total cholesterol; HDL-C ⫽ highdensity lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein
cholesterol; Tot-TG ⫽ total triglycerides.
values compared with –2% in the placebo group (P ⫽
0.015). This decline was not associated with renal deterioration or with institution of new immunosuppressive
treatment. There were minor decreases in C4 complement levels in both treatment groups, but the differences
between groups were not significant. Mean ⫾ SD
changes in anti-dsDNA levels from the baseline visit to
the last visit were 5.8 ⫾ 145.6 IU/ml (median 0.0) in the
placebo group and 20.0 ⫾ 130.0 IU/ml (median 0.0) in
the prasterone group; the differences between treatment
groups were not statistically significant.
Treatment-associated changes in sex hormone
levels. As expected, serum DHEAS values increased to
pharmacologic levels in the prasterone treatment group.
The mean DHEAS concentrations at the last visit were
811 ␮g/dl (median 607) in the prasterone treatment
group. These levels were unchanged in the placebo
treatment group 120 ␮g/dl (median 50).
Serum testosterone levels increased in
prasterone-treated patients, especially among those who
were postmenopausal (Table 6). In contrast, treatmentassociated changes in estrogenic hormones were less
consistent. In premenopausal women, no meaningful
changes in serum estradiol were evident in either the
prasterone-treated patients or the placebo-treated patients (Table 6). Changes in estradiol levels in postmenopausal women were analyzed according to the presence
or absence of hormone replacement therapy (HRT).
Patients reported by investigators to be postmenopausal
but with baseline estradiol levels ⱖ20 pg/ml were excluded from this analysis as being perimenopausal.
Mean serum estradiol levels increased in postmeno-
2865
Table 6. Change in testosterone and estradiol levels, by menopause status*
P
Testosterone, mean (median) ng/dl
Premenopausal patients
Placebo (n ⫽ 63)
Prasterone (n ⫽ 71)
Postmenopausal patients
Placebo (n ⫽ 68)
Estradiol, mean (median), pg/ml
Premenopausal patients
Placebo (n ⫽ 63)
Postmenopausal patients (no HRT)†
Placebo (n ⫽ 14)
Postmenopausal patients taking HRT
Placebo (n ⫽ 35)
Baseline
Last visit
Change
Change from
baseline
Treatment
comparison
20.5 (16.0)
23.8 (19.0)
19.3 (16.0)
58.9 (56.0)
⫺1.2 (⫺2.0)
35.0 (32.0)
0.5541
0.0001
0.0001
20.4 (17.0)
17.9 (12.5)
18.2 (12.5)
74.8 (54.0)
⫺2.1 (0.0)
57.0 (41.5)
0.1648
0.0001
0.0001
97.8 (74.2)
85.6 (63.9)
88.9 (62.8)
86.5 (65.2)
⫺8.9 (0.3)
1.0 (1.5)
0.5098
0.9367
0.5884
2.5 (1.4)
3.7 (1.9)
2.3 (1.4)
24.8 (22.2)
⫺0.1 (0.0)
21.1 (19.4)
0.8127
0.0003
0.0003
104.4 (64.7)
85.6 (79.4)
82.4 (66.5)
128.1 (105.1)
⫺22.0 (1.7)
42.4 (34.1)
0.2950
0.0170
0.0210
* Not all patients had measurements of estradiol or testosterone levels at both baseline and the end of treatment. Therefore, the total number of
patients does not equal the total number randomized.
† At baseline, estradiol levels were ⬍20 pg/ml, and the patients were not taking hormone replacement therapy (HRT).
pausal patients receiving prasterone and HRT; however,
the cotreatment with HRT makes the interpretation of
these findings difficult. In postmenopausal patients who
were not receiving HRT, prasterone led to increases in
serum estradiol levels that were similar to the levels
previously reported with low-dose HRT (33). There
were no correlations between changes in sex hormone
levels and responder outcomes (data not shown).
DISCUSSION
In this double-blind, randomized, placebocontrolled trial of prasterone treatment at 200 mg/day
for up to 52 weeks, we found significant improvements in
the patients taking prasterone. Significantly more patients in the prasterone group than in the placebo group
experienced either improvement or stabilization of disease activity (P ⫽ 0.017).
Given the complexity of SLE, it was important to
assess the disease in its entirety, and this study was the
first of its kind to utilize an innovative composite end
point that was designed to integrate all 3 SLE domains—
disease activity, organ damage, and health-related quality of life—into an overall “responder” end point. Patients categorized as “responders” had to exhibit
simultaneous improvement or stabilization in each of 2
disease activity measures (SLEDAI and SLAM) and 2
quality of life measures (KFSS and patient’s global
assessment), without clinical deterioration.
To qualify for enrollment in this study, patients
had to have stable disease activity at baseline, without
recent changes in cotreatments, including glucocorticoids, antimalarials, and immunosuppressives. Cotreatments with these drugs were required to be held at a
fixed dosage for the duration of the study The high
response rate (45%) in the placebo treatment group
should be interpreted in the context that this was not a
true placebo-controlled trial, since most patients were
cotreated with standard SLE therapies during the study.
Thus, the statistically significant improvement in the
prasterone group (59% taking prasterone versus 45%
taking placebo were responders) is both statistically and
clinically meaningful.
Deterioration in the mean postbaseline measures
in any 1 of the scoring instruments relative to baseline or
clinical deterioration caused a patient to be designated
as a “nonresponder.” Significantly more patients in the
placebo group as compared with the prasterone group
failed to achieve responder status based on the SLEDAI
or patient’s global assessment values. The latter is
particularly noteworthy, in that significant differences in
patient’s global assessments, in favor of prasterone, have
also been reported in 2 other studies comparing prasterone with placebo (22,24).
As noted above, the protocol was amended to
incorporate baseline SLEDAI scores of ⬎2 as an additional patient entry requirement while the double-blind
study was ongoing. This requirement was based upon the
outcome of an earlier Genelabs study, which revealed
2866
that patients with little or no disease activity (SLEDAI
ⱕ2) are not the most appropriate candidates for clinical
study, since patients with little or no disease activity are
likely to exhibit high response rates (23). The importance of requiring minimum disease activity as a criterion for enrollment into SLE clinical trials is consistent
with the approach taken in other clinical trials of other
rheumatologic conditions.
Patients enrolled in this study represented a wide
spectrum of SLE disease activity. The differences between treatment groups persisted with increasing baseline disease activity. This observation is similar to the
findings in an earlier study assessing steroid-sparing
properties of prasterone versus placebo, in which the
greatest difference between placebo and prasterone
treatment occurred in the groups with baseline SLEDAI
scores ⬎8 (23). The 2 instruments that provided the
greatest sensitivity to responder analysis appeared to be
the SLEDAI and the patient’s global assessment.
There were no significant differences between
treatment groups in the individual components of the
responder analysis, which may reflect the fact that most
of the patients were receiving cotreatment with standard
SLE therapies. Furthermore, only patients who had had
stable disease and no change in treatments for at least 6
weeks prior to entry into the study were eligible for
enrollment, and as such, the population we studied
primarily comprised those with active, yet stable disease.
The responder analysis, however, required simultaneous
stabilization or improvement across 4 variables (2 disease activity measurement instruments, 2 health-related
quality of life measurements) and no clinical deterioration, while holding cotreatments constant. It is in this
composite end point that significant differences occurred between treatment groups.
The responder end point was designed to assess
simultaneous improvement or stabilization across all 3
domains of lupus: disease activity, organ damage, and
health-related quality of life. As such, it was designed to
assess a treatment effect on overall lupus disease. While
it would be desirable to determine how many patients
“improved” or how many “stabilized,” there is no established definition as to what constitutes improvement
versus stabilization. Furthermore, due to the stringent
responder criteria in this trial, each of the scoring
instruments and clinical deterioration was given equal
weight in the outcome. So, to improve in only some
scoring instruments while worsening in others would
deem a patient a “nonresponder.” Thus, we believe that
overall stabilization, which is in fact reflective of a
combination of improvement in some instruments and
PETRI ET AL
no worsening in others, is also a successful outcome for
lupus patients.
Additionally, there were trends toward a lower
number of patients with a first flare and a delay in time
to disease flare among patients with active SLE who
received treatment with prasterone. These findings are
qualitatively similar to those reported in a population of
Taiwanese women with SLE, almost all of whom were
receiving cotreatment with glucocorticoids and/or immunosuppressives. In that study, there was a statistically
significant delay in time to disease flare among patients
treated with prasterone (24).
Administration of prasterone appeared to be well
tolerated in this randomized clinical trial. Reported
adverse events were predictably related to known pharmacologic effects of androgenic steroids and were generally mild and primarily confined to acne and, to a
lesser extent, some hirsutism.
While prasterone is a precursor of both androgenic and estrogenic hormones, changes in estradiol
levels in patients receiving prasterone were less consistent than changes in testosterone levels. In premenopausal patients, there were no differences in estradiol
levels between treatment groups. In postmenopausal
women receiving prasterone who were not also receiving
HRT, there were modest increases in estradiol levels
compared with placebo. During prasterone treatment,
mean estradiol concentrations were similar to the mean
serum estradiol concentrations observed during transdermal estradiol administration (33) and remained well
under the pretreatment baseline estradiol levels observed in SLE patients who were receiving HRT at
baseline. Reported adverse events related to estrogenic
effects, such as menometrorrhagia, thrombotic events,
or weight gain, were not increased in either premenopausal or postmenopausal women receiving prasterone,
suggesting that the biologic effects of prasterone are
primarily androgenic rather than estrogenic. This is in
contrast to postmenopausal women, in whom unopposed estrogen therapy has been associated with a
menorrhagia rate as high as 66% (34).
Clinical laboratory findings associated with prasterone treatment in this randomized controlled trial also
reflected androgenic activity, including declines in HDL
cholesterol and triglyceride levels. These findings have
also been observed in 2 other controlled studies with
prasterone (23,24).
Reductions in triglyceride and HDL cholesterol
levels with administration of androgenic hormones have
been reported to be a manifestation of increased hepatic
lipase activity, which results in enhanced clearance of
HDL particles (35–37). Thus, the decreases in HDL
cholesterol and triglyceride levels may represent increased reverse cholesterol transport (i.e., removal of
cholesterol from peripheral tissues via enhanced HDL
clearance) rather than decreased production of HDL
(38). However, since lupus is associated with increased
cardiovascular morbidity and mortality (39) and since
long-term studies will be needed to further characterize
these effects, it may be prudent to follow the National
Cholesterol Education Program guidelines (32) while
monitoring lipids in patients who are receiving prasterone.
Although the mechanism that results in decreased serum levels of complement C3 levels is incompletely defined, in vitro incubation of human peripheral
blood mononuclear cells and bone marrow cells with
DHEA has been demonstrated to reduce the production
of IL-6 (16,17). Since IL-6 levels are elevated in active
SLE (20,40) and can stimulate hepatic secretion of C3 as
an acute-phase reactant (41), decreased levels of C3
during prasterone treatment may reflect either a direct
or an indirect effect on hepatic C3 production. Decreased serum C3 complement levels were observed
during administration of prasterone 200 mg/day to normal premenopausal women who were participating in a
preclinical pharmacokinetic/pharmacodynamic study
(Genelabs, Inc.: unpublished observations), which is
consistent with a physiologic effect of prasterone on
hepatic complement production. Serum complement
levels also decline modestly without evidence of autoimmunity during testosterone replacement therapy in patients with Klinefelter’s syndrome (42).
It is important to note this clinical trial enrolled
only adult women with SLE. There are no data from
randomized controlled studies of prasterone administration in men or in children with SLE. A previous openlabel clinical trial in a small number of patients in which
administration of a synthetic, more-potent androgenic
steroid was examined suggested worsening of disease in
men with SLE (43).
Finally, current therapeutic options are limited
for patients with mild-to-moderate active SLE. The
available drugs (e.g., nonsteroidal antiinflammatory
drugs, antimalarials, glucocorticoids) can manage the
disease temporarily in many patients; however, control
of the underlying inflammatory disease is often incomplete, and many patients continue to have residual signs
and symptoms, with fluctuations in disease activity and
with disease flares. In these situations, it is often a major
therapeutic step for the physician and patient to contemplate initiation of additional immunosuppressive
2867
agents or large doses of glucocorticoids, which also do
not necessarily provide the hoped-for efficacy and are
associated with significant side effects. Prasterone could
bring benefits to patients who cannot or do not wish to
take additional therapies of immunosuppressive agents
or large doses of glucocorticoids. Prasterone is not
intended, however, to be a replacement for glucocorticoids or immunosuppressive treatments that are needed
during acute flares of lupus.
In summary, prasterone treatment improved or
stabilized overall SLE disease activity in women with
mild-to-moderate SLE. The most common adverse
events associated with prasterone treatment were androgenic in nature and included acne and hirsutism, which
were generally mild and treatable.
ACKNOWLEDGMENTS
The authors greatly appreciate the advice of, and
careful study monitoring by, Karen Colbert and Bettina
Sporkenbach. ACRO, Inc. (Morris Plains, NJ) were the statistical consultants for the study.
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Interventions (PEPI) Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. JAMA
1996;275:370–5.
Haffner SM, Kushwaha RS, Foster DM, Applebaum-Bowden D,
Hazzard WR. Studies on the metabolic mechanism of reduced
high density lipoproteins during anabolic steroid therapy. Metabolism 1983;32:413–20.
Kantor MA, Bianchini A, Bernier D, Sady SP, Thompson PD.
Androgens reduce HDL2-cholesterol and increase hepatic triglyceride lipase activity. Med Sci Sports Exerc 1985;17:462–5.
Hazzard WR, Haffner SM, Kushwaha RS, Applebaum-Bowden D,
Foster DM. Preliminary report: kinetic studies on the modulation
of high-density lipoprotein, apolipoprotein, and subfraction metabolism by sex steroids in a postmenopausal woman. Metabolism
1984;33:779–84.
Wu FC, Von Eckardstein A. Androgens and coronary artery
disease. Endocr Rev 2003;24:183–217.
Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr,
Jansen-McWilliams L, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus
erythematosus: comparison with the Framingham Study. Am J
Epidemiol 1997;145:408–15.
Zietz B, Reber T, Oertel M, Gluck T, Scholmerich J, Straub RH.
Altered function of the hypothalamic stress axes in patients with
moderately active systemic lupus erythematosus. II. Dissociation
between androstenedione, cortisol, or dehydroepiandrosterone
and interleukin 6 or tumor necrosis factor. J Rheumatol 2000;27:
911–8.
Falus A, Rokita H, Walcz E, Brozik M, Hidvegi T, Meretey K.
Hormonal regulation of complement biosynthesis in human cell
lines. II. Upregulation of the biosynthesis of complement components C3, factor B and C1 inhibitor by interleukin-6 and interleukin-1 in human hepatoma cell line. Mol Immunol 1990;27:
197–201.
Yesilova Z, Ozata M, Kocar IH, Turan M, Pekel A, Sengul A, et
al. The effects of gonadotropin treatment on the immunological
features of male patients with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2000;85:66–70.
Lahita RG, Cheng CY, Monder C, Bardin CW. Experience with
19-nortestosterone in the therapy of systemic lupus erythematosus:
worsened disease after treatment with 19-nortestosterone in men
and lack of improvement in women. J Rheumatol 1992;19:547–55.
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MEMORANDUM
DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
DATE:
March 12, 2001
FROM:
Claudia B. Karwoski, Pharm.D.
Postmarketing Safety Evaluator Team Leader
Division of Drug Risk Evaluation I, HFD-430
THROUGH: Julie Beitz, M.D., Director signed 3/13/01
Division of Drug Risk Evaluation I, HFD-430
TO:
Jonca Bull, M.D. Acting Director
Division of Antiinflammatory, Analgesic, and Ophthalmic Drug Products,
HFD-550
SUBJECT:
OPDRA Postmarketing Safety Review (PID 000665)
Drug: Prasterone NDA 21-239 (Dehydroepiandrosterone-DHEA)
Reaction: Summary of Spontaneous Postmarketing Case Reports
EXECUTIVE SUMMARY
This document provides an overview of postmarketing adverse events reported in
association with the use of Dehydroepiandrosterone (DHEA). These cases were retrieved
from the Adverse Event Reporting System (AERS), CFSAN’s postmarketing database,
and the medical literature.
There were 65 postmarketing adverse event cases possibly associated with the use of
DHEA. Other than the single report of worsening metastatic prostate cancer1 previously
described in the review by Parivash Nourjah, Ph.D, entitled Epidemiologic evidence of
DHEA in the etiology of neoplasia, there were no additional reports of neoplasia found in
the any of the above databases or the medical literature.
Forty-two of the 65 cases fall into the following body systems: urologic/renal (5),
reproductive/endocrine (5), cardiovascular (9), gastrointestinal (8), central nervous
system (7), dermatological (7), and hematological (2). There were also five individuals
with psychiatric adverse events and 17 cases with general symptoms or miscellaneous
events that could not easily be categorized into a body system. Four of the 65 cases were
published in the medical literature.1-4
Approximately 40% of the cases were concerning. The adverse events involving the
urologic/renal, cardiovascular, and gastrointestinal body systems as well as the
psychiatric adverse events were particularly concerning because they had the highest
number of hospitalizations (> 50%). However, because the overall numbers of cases in
each of these body systems were small and in many cases confounded by concomitant or
co-suspect medication, we identified no clear safety signals with this product.
INTRODUCTION
Dehydroepiandrosterone (DHEA) is an endogenous hormone secreted by the adrenal
cortex. It has been widely available in the US as a dietary supplement and promoted for
its anti-aging effects as well as other uses. Prasterone (the pharmaceutical generic
designation for DHEA) is currently under review in the Division of Anti-inflammatory,
Analgesic, and Ophthalmic Drug Products (DAAODP), for the treatment of mild to
moderate systemic lupus erythematosis (SLE) in women.
This serves as a companion document to the review by Parivash Nourjah, Ph.D, entitled
Epidemiologic evidence of DHEA in the etiology of neoplasia which focused on a review
of the literature for any published epidemiologic studies that examined cancer risk
associated with exogenous DHEA administration. The primary objective in this review
was to determine if there were any case reports in our postmarketing databases or the
medical literature of neoplasia in association with the use of DHEA. Our secondary
objective was to provide an overview of postmarketing adverse events reported in
association with the use of DHEA
REVIEW OF SPONTANEOUS POSTMARKETING REPORTS
Selection of Cases
We searched AERS on February 13, 2001 for all reports with dehydroepiandrosterone
and prasterone. We also requested a query of CFSAN’s adverse event reporting database
for case reports with DHEA. Four additional case reports were found in the medical
literature. All searches resulted in a total of 64 unique reports involving 68 consumers or
patients. Three AERS reports were excluded because the drug products did not appear to
contain DHEA. Below is an overall summary and summary by body system of the 65
cases.
Summary of Cases
Of the 65 cases identified in the AERS database, CFSAN ARMS database, and the
medical literature, there was only one report of neoplasia1 . This was summarized in Dr.
Nourjah’s review and is described in the urologic/renal section below.
Forty-two of the 65 cases fall into the following body systems: urological/renal (5),
events that could not easily be categorized into a body system. Four of cases were
published in the medical literature.
2
Approximately 40% of the cases were concerning. The adverse events involving the
urologic/renal, cardiovascular, and gastrointestinal body systems as well as the
psychiatric adverse events were particularly concerning because they had the highest
number of hospitalizations (> 50%). The concerning cases are briefly summarized below
but may be described in greater detail under the specific body system summaries.
•
•
•
•
Urological/renal system -Literature case of worsening metastatic prostate cancer (1),
increased symptoms of prostatism in patients with BPH (2), and renal failure (1).
Cardiovascular system - Literature case of cardiac arrhythmia with a positive
rechallenge (1), other arrhythmia’s (4), MI (1), DVT (1), and hypertensive urgency
(1).
Gastrointestinal system– liver failure (1) and hepatitis (3)
Psychiatric events – two patients with mania and one patient with psychosis required
hospitalization.
The overall numbers of cases in each of these body systems were small and in many
cases confounded by concomitant or co-suspect medication.
1.
Urological and Renal Events
There are five cases involving the urologic or renal system. The cases involved all males.
The patient’s ages were 5, 34, 68, and 71 years old (not reported-1). The events include
resurgence of prostate carcinoma (1), worsening symptoms of prostatism (2), renal failure
(1), and dysuria (1). The following additional information was noted in the cases.
DHEA daily dose:
Time to onset:
Outcome:
Indications for use:
Dechallenge:
Rechallenge:
Event year:
Reporter:
25mg-2, 50mg-1, up to 700mg-1 (not reported-1)
2 to 180 days
Emergency room treatment/hospitalization-2, required
intervention-3
Short stature-1
Increase muscle strength-1
Low hemoglobin (anemia)-1
Not reported-2
Positive-3
Positive-0
1995-1, 1996-2, 1997-2
Health care professional-3, Consumer-2
The literature case report (described in Dr. Nourjah’s review) involves a 68-year-old
male with metastatic prostate cancer who was treated with escalating doses of DHEA
(200 to 700mg per day) presumably for the treatment of anemia unresponsive to
erythropoetin. His blood cells increased during DHEA eliminating his need for
transfusions. However, the patient began to develop facial numbness, increase in prostate
size, and difficulty voiding. His PSA levels increased to greater than 10,000 ng/mL (2726
ng/mL prior to DHEA). DHEA was discontinued and DES was initiated with
improvement in symptoms and decrease in PSA. Although, he exhibited a positive
3
dechallenge after discontinuation of DHEA, his improvement may have been due to
treatment with DES.1
There were two patients with a history of BPH who developed worsening symptoms. One
case described increased symptoms of prostatism (not specified) after several months of
DHEA. This patient was on Cardura and Dilacor at the time. The second case described
difficulty urinating after taking DHEA for two weeks.
The renal failure case was reported by the patient’s mother and was not well described.
She reported that her 34-year-old son took seven different dietary supplement products
(including DHEA) for about one month and developed renal failure. He was hospitalized
and partial renal function returned. No additional information was provided.
The last case involves a 5-year-old who started bedwetting (coded as dysuria) two days
after taking DHEA 50mg per day for central core disease. He was taking many other
concomitant dietary products including enzymes, vitamins and atomadine. All products
were discontinued and his event abated.
2.
Reproductive and Endocrine Events
There are five cases involving reproductive or endocrine events in patients ranging in age
from 39 to 50 years old (mean-44.7, median-45). The cases involved three males and two
females. The events include gynecomastia (1), resumption of menstruation (1), increased
estrogen levels and hot flashes (1), hyperglycemia (1), and painful intercourse and
hematuria (1). The following additional information was noted in the cases.
DHEA daily dose:
Time to onset:
Outcome:
Dechallenge:
Rechallenge:
Event year:
Reporter:
25mg – 3 (not reported-2)
7 days - 1, 30 days - 2, several months -1 (not reported-1)
No serious outcomes
Menopausal symptoms-1
Immune system booster-1
Aging-1
Not reported-2
Positive-4
Positive-1
1996-3, 1999-1 (not reported-1)
None of the cases involved a serious outcome but four sought medical care from a
physician. All cases are summarized below for your review. The first three were possibly
related to the use of DHEA. Underlying disease and use of another product that was more
temporally associated with the event confounded the last two cases.
AERS image # 1923242, CFSAN 11859, 1996
A 39-year-old male developed bilateral breast enlargement during use of DHEA 25mg
per day for 1 to 1.5 months. They were described as very inflamed, bright red, and very
4
tender. He reported no relevant medical history or concomitant medications. The event
reportedly abated after discontinuation of the DHEA.
AERS image # 2055734, CFSAN 12028, 1996
A 42-year-old female stated that she had not menstruated since February 1996. In
December 1996, seven days after initiating DHEA 25mg per day, she started a full
menstrual cycle.
AERS image # 2000126, 1997
A male consumer (age unknown) began using DHEA 10mg and then increased to 25mg
after 2-3 weeks. Less than 1 month later, he experienced extreme pain during intercourse
and observed large amounts of blood in both semen and urine. Urologists ruled out both
cancer and STD as causes. He discontinued using the product and one week later his
symptoms disappeared.
CFSAN 13543, 1999
A 48-year-old female complained of hot flashes. Was taking Rejuvex (for several
months) and DHEA (duration unknown). She was status post hysterectomy with one
ovary and was not receiving hormone replacement therapy. FSH, LH, and estradiol levels
measured were measured and estradiol levels were noted to be markedly elevated 2777
pg/ml. Both products were discontinued for 2 months with levels normalizing (estradiol
54 pg/ml). Rejuvex was restarted and within two weeks the estradiol level was 498 pg/ml.
Rejuvex contains several vitamins and ground up bovine endocrine organs.
AERS image # 1927333, CFSAN 12220, 1997
A 50-year-old Ethiopian male presented with fatigue, polyuria, and polydipsia and was
found to have a blood sugar of 600. He was receiving DHEA 50mg per day for an
unknown duration. His DHEA was discontinued and he was started on Glucotrol. With
diet management and Glucotrol his blood glucose decreased to low normal and Glucotrol
was discontinued. On follow up the reporter mentioned that the patient was subsequently
diagnosed with late onset type I diabetes.
3.
Cardiovascular Events
There are nine cases involving cardiovascular events in patients ranging in age from 23 to
72 years old (mean-44.7, median-45). The cases involved seven males and two females.
The events include cardiac arrhythmias in five patients (unspecified-3, PVC’s-1, and
SVT-1). The remaining four patients experienced chest pain and palpitations (1),
myocardial infarction (1), deep vein thrombosis (1), and hypertensive urgency (1). The
following additional information was noted in the cases.
DHEA dose:
Time to onset:
Outcome:
25mg-3, 50mg-2, 100mg-1 (not reported-3)
range of 1 to 120 days; mean-49, median 30 (not reported-2)
Death-1, hospitalization-3, emergency room-4, required
intervention (unspecified)-1
Build muscle mass-1
5
Dechallenge:
Rechallenge:
Event year:
Reporter:
Maintain general health-1
Treat decreased adrenal function expected with increased age-1
Not reported-6
Positive-6
Positive-1
1996-1, 1997-4, 1998-2, 1999-1 (not reported-1)
Possible cofounders were noted in three cases including the case resulting in death. The
death involved a 37-year-old male who was found dead at home. The cause of death was
not reported, however the medical examiner inquired whether any of eight dietary
supplements could be responsible for a cardiac arrhythmia. One case involved a 72-yearold male who developed a DVT approximately one month after he initiated use of DHEA
and DMSO. Both products were listed as suspect. Another case involved a 41-year-old
male with a history of increased heart rate who was admitted to the ER for unspecified
cardiac arrhythmia 2.5 months after starting DHEA and creatine. The remaining cases
reported both a negative cardiac history and no concomitant medication (3) or they did
not provide medical history information (3). Several interesting cases are summarized
below for your review.
Literature Case Report, 1998
A 55-year-old male presented to an ER with palpitations two weeks after initiating
DHEA 50mg. Benign premature atrial contractions (PAC) and some premature
ventricular contractions (PVC) were noted. Work-up including thyroid-stimulating
hormone levels, cardiac echocardiogram, potassium levels, and exercise stress test results
were unremarkable. Past medical history was not provided other than his use of Redux
for the previous 12 months, which had been discontinued two weeks before initiating
DHEA. He was discharged on propranolol and continued use of DHEA for three months.
Three to four months later, he reinitiated DHEA (presumably off beta-blocker) and
within 36 hours arrhythmias recurred and PAC and PVC was noted on a Holter Monitor.
The arrhythmias were controlled with atenolol and DHEA was discontinued.2
AERS Image # 3030083-5-00, direct report, 1997
A 45-year-old male was admitted for an acute MI that occurred during exercise. He
received a thrombolytic agent with resolution. Cardiac catherization for recurrent pain
showed “fairly normal coronary arteries with only mild irregularities with occluding
thrombus in the right coronary artery”. His only reported cardiac risk factor was
moderately elevated cholesterol. His cholesterol was 230, HDL 49, and LDL 160.
Baseline values were not provided.
CFSAN # 12219, direct report, 1997
A 23-year-old male initiated use of DHEA to build up muscle tone. He was reported to
have taken up to 20 tablets per day for 3 to 4 months. His mother (nurse) noticed that he
had put on over 40 pounds of weight and decided to check his blood pressure, which was
found to be in the range of 240/140. His blood pressure was confirmed in the ER. He was
also noted to have elevated liver functions tests (LFT). . He was treated for hypertension.
6
Two weeks following discontinuation of DHEA his LFTs appeared to be returning to
normal however his blood pressure remained labile.
4.
Gastrointestinal System Events
There are eight cases involving gastrointestinal system adverse events in patients ranging
in age from 21 to 63 years old (mean-41.6, median-43, not reported-3). The cases
involved four males and four females. Serious events occurred in five individuals and
include liver failure (1), hepatitis (3), abdominal pain requiring exploratory laparotomy,
and possible GI bleed (1). Two patients experienced less severe reactions, which include
unspecified stomach problems (1) and gas (1). The following additional information was
noted in the cases.
DHEA daily dose:
Time to onset:
Outcome:
Dechallenge:
Rechallenge:
Event year:
Reporter:
14 days – 1, 60 days – 1, 11 months - 1 (not reported-5)
Hospitalization – 3 (not reported-5)
SLE-1
Build muscle-1
Aging-2
Not reported-4
Positive-3
Positive-0
1996-1, 1997-1, 1998-2 (not reported-4)
There was one study report of a 36-year-old female with SLE who was hospitalized three
times for recurrent abdominal pain. She had been enrolled in a clinical trial for SLE for
~10 months and was receiving DHEA 200mg/day. On her third admission she underwent
exploratory laparotomy. The findings were not provided. The report mentioned that she
had a history of previous abdominal surgery with possible adhesions.
There were three consumer reports. Two did not appear to be serious and only reported
gas and “stomach problems. The third consumer claimed that she experienced vomiting
with blood and blood per rectum for five days. She did not mention seeking medical
treatment.
There were four liver related events. One physician reported two of the cases. He
reported a 43-year-old female and a 45-year-old male who developed hepatitis while
taking an unknown dose of DHEA. Neither of the reports were well documented other
than stating that neither patient had a relevant medical history nor were they taking
concomitant OTC medications. In both of the other two cases, concomitant medications
might have played a role. These cases are described below for your review.
AERS image # 3193812-6-00 , 1998
A 21-year-old male experienced cold symptoms for 1-2 weeks and began taking
acetaminophen 1-2 q4-6h prn (6-10gm). He was a wrestler and was taking DHEA 50mg
7
per day for approximately 2-3 months prior to the event. He had 8 beers/5 shots x 3 days
w/APAP. Within two weeks he developed RUQ pain, dark urine, jaundice, and was
admitted with hepatic failure. Underwent liver transplant. Although acetaminophen
possibly in conjunction with alcohol are suspect, the role of DHEA cannot be dismissed.
CFSAN # 13200, 1998
A 63-year-old male was diagnosed with cholestatic hepatitis while taking an unknown
dose of DHEA and Pantothenic Acid 8gm/day. This was discovered during blood
donation. He presented with elevated ammonia, transaminases, bilirubin, and PT/INR.
All viral hepatitis screening was negative. He was hospitalized for two days
neurologically intact. No additional information was provided. The pantothenic dose was
> 1000 times the recommended daily allowance for adults.
5.
Central Nervous System Events
There are seven cases involving central nervous system events in patients ranging in age
from 49 to 59 years old (mean-54.2, median-56, not reported-2). The cases involved four
males and three females. Serious events occurred in three individuals and include
transient ischemic attack (1), seizure (1), and sensory peripheral neuropathy (1). The
remaining four patients experienced less severe reactions which include headaches (2),
numbness (1), and sleepiness (1). The following additional information was noted in the
cases.
DHEA dose:
Time to onset:
Outcome:
Dechallenge:
Rechallenge:
Event year:
Reporter:
range of 3 to 90 days; mean-35, median-7 (not reported-2)
Hospitalization-1, disability-1, saw physician-3, (not reported-2)
Muscle pain-1
Entered study (Hormone Replacement Program)-1
Not reported-4
Positive-3
Positive-2
1997-3, 1998-1, 1999-1, 2000-1 (not reported-1)
The four cases involving headache, numbness, and sleepiness did not appear to be
serious. In one case a mother reported an event (described in Psychiatric Adverse Event
section of this document) in her son but also mentioned that she experienced migraine
headaches while taking DHEA. One patient experienced numbness, coldness, and
tingling of her face, scalp, and neck. Her neurological exam however was found to be
normal.
There were three serious cases involving seizure, TIA, and Sensory Peripheral
Polyneuropathy. The case involving seizure exhibited a positive rechallenge and did not
appear to be confounded by past medical history or concomitant medication. Consumers
reported two cases and in one case the event appeared to be more temporally related to
8
the concomitant use of another product. These cases are summarized below for your
review.
AERS image # 20411530, CFSAN # 12603, 1997
A 51-year-old male reported having a TIA approximately two weeks after starting DHEA
25mg per day. He was diagnosed and hospitalized for three days. According to report, he
underwent numerous tests which were negative (CT, MRI, ECG, and EEG)
CFSAN # 13160, 1998
A 56-year-old male had taken DHEA for three months and experienced two seizures
during that time. He discontinued use for several months and then restarted and
experienced a seizure after seven days. His past medical history and concomitant
medications were not reported. An EEG, MRI and exam were found to be normal.
AERS image # 3551903-1-00, 2000
A 49-year-old male reported enrolling in a Hormone Replacement Program offered by
the[
]. As part of the program, he began taking DHEA 50mg per day, desiccated
thyroid (Armour, 1gm per day), melatonin, B complex, testosterone cream, and human
growth hormone (HGH) injections (4IU per week). After one month, he started to
experience numbness in both feet. He discontinued use of the HGH for a few weeks and
the problem disappeared. He restarted the injections and the numbness and pain came
back. A second discontinuation did not result in resolution of his symptoms. He was
diagnosed with Sensory Peripheral Polyneuropathy and reported that he was partially
disabled (difficulty walking, pain interrupts sleep).
6.
Dermatological Events
There are seven cases involving dermatological reactions in patients ranging in age from
29 to 83 years old (mean-58.2, median-62, not reported-1). The cases involved four males
and three females. The events include rash in four patients (unspecified-3, macular
erythematous eruption-1). The remaining three patients experienced alopecia (2), and
acne with pustules (1). The following additional information was noted in the cases.
DHEA dose:
Time to onset:
Outcome:
Dechallenge:
Rechallenge:
Event year:
Reporter:
25mg-1, 50mg-3 (not reported-3)
range of 4 to 55 days; mean-14.4, median 14 (not reported-2)
Required (unspecified) intervention-1, saw physician-1 (not
reported-5)
Aging-1
Hormone deficiency-1
Impotence-1
Not reported-4
Positive-3
Positive-0
1995-1, 1997-3 (not reported-3)
9
None of these cases reported a serious outcome as a result of the events. One case is
summarized below for your review.
AERS image # 1933056, CFSAN # 12099, 1997
An 83-year-old male developed a macular erythematous eruption from the mid-thigh to
his toes varying in diameter from 1mm to 1cm approximately seven weeks after starting
DHEA. They were non-tender with no subcutaneous hemorrhage. The rest of the physical
exam was normal. He was on concomitant Nicotine patches intermittently for 18 months.
The rash reportedly began to fade after the DHEA was discontinued.
7.
Hematological Events
There were two individuals that experienced hematological events. One case involves a
50-year-old male that presented with fever, cough, malaise, and aching approximately six
weeks after starting DHEA 50mg per day. A complete blood count revealed a platelet
count of 38K. DHEA was discontinued and a repeat CBC two and three weeks later was
69K and 122K, respectively. The patient did not appear to require hospitalization. He had
a history of chronic low platelets secondary to a splenectomy. He also reported receiving
a flu shot 1week prior to symptoms.
The second case involves a 46-year-old male who started taking DHEA 50mg BID on
4/14/99 and Celebrex 100mg BID on 4/26/99. On 5/3/99, he presented to his physician
with bruising all over his chest, arms, and legs. He had not sustained any trauma.
Celebrex was discontinued but it is unclear if DHEA was continued. No further
information was provided.
8.
Psychiatric Events
There are five individuals who experienced psychiatric events while receiving DHEA.
Two of these cases were reported in the medical literature. The cases involved individuals
ranging in age from 20 to 68 years old (mean 36.6, median-51). The cases involved three
males and one female (not reported-1). The events include mania (2), manic depression
(1), psychosis (1), and panic attacks (1). The following additional information was noted
in the cases.
DHEA daily dose:
Time to onset:
Outcome:
Dechallenge:
Event year:
Reporter:
25mg-1, 50mg-1, 150mg-1, 200-300mg-1 (not reported-1)
range of 40 to 120 days; (not reported-1)
Hospitalization-3
General health-1
Impotence-1
To increase energy-1
Not reported-2
Positive-2
1996-1, 1998-1, 1999-1 (not reported-2)
10
All cases were confounded by either concomitant medication or other dietary products (3)
and/or past psychiatric history (3). In one, the individual was taking five different dietary
supplements including ephedrine and ephedra. A second was taking concomitant beef
liver extract and a multivitamin. Another report listed Celexa as a co-suspect agent. Past
psychiatry histories include history of panic attacks, history of manic depression, and
history of daily alcohol consumption (possible alcoholism). Both literature reports is
described below for your review.
A 68-year-old male with no documented psychiatric history was admitted to an inpatient
psychiatric hospital after his family members noting increasingly odd behavior.
Symptoms included agitation, delusional thinking, decreased sleep and appetite, and
spending sprees which started approximately three months prior to admission. He had
begun taking DHEA six months prior to admission at dose of 100mg daily. This dose was
increased to 200-300mg per day. He had a history of daily alcohol use as much as one
case of beer. On admission his use was said to be ~ two beers per day. Drug and urine
screens were negative. He was treated with valproic acid and his symptoms improved. He
was discharged seven days later.3
A 51-year-old male with no prior psychiatric history was involuntarily hospitalized
because of grandiose delusions, expansive and irritable mood, and extreme psychomotor
agitation. He had begun taking DHEA 50mg per day several months earlier to increase
his energy level. He was also taking beef liver extract and a multivitamin. The severity of
his psychosis necessitated the appointment of a temporary personal guardian. He was
treated during his hospitalization with a combination of haloperidol and divaproex. He
responded well and his symptoms disappeared after several weeks. 4
9.
General Symptoms or Miscellaneous Adverse Events
There are 17 individuals who experienced general symptoms or miscellaneous events that
could not easily be categorized into one organ system. The cases involved individuals
ranging in age from 28 to 84 years old (mean-49.5, median-47, not reported-4). The cases
involved nine males and six females (not reported-2). The following additional
information was noted in the cases.
DHEA dose:
Time to onset:
Outcome:
Dechallenge:
25mg-3, 35mg-1, 50mg-5, overdose-1 (not reported-7)
range of 1 day to 1.5 years; mean-98, median 5 (not reported-4)
Hospitalization/ER-3, life-threatening-1, saw physician-3, required
unspecified intervention-2 (not reported-8)
Aging/to stay young-4
Headache-1
Hormone supplement-1
Not reported-9
Positive-12, negative-1
11
Rechallenge:
Event year:
Reporter:
Positive-1
1996-4, 1997-6, 1998-1 (not reported-6)
Overall most cases were not well documented. One interesting case involves a 41-yearold female who reports taking DHEA 25mg sublingually. After 2 weeks she developed a
benign submandibular tumor. She stopped taking the product for 1 week and the tumor
reduced in size. She took the product again orally and the tumor returned.
There were four patients that reported requiring hospitalization, emergency room
treatment, and/or reported the event as life-threatening. One involved a female (who
spoke little English) who may have taken an entire bottle of DHEA for a headache. She
was hospitalized with a low-grade temperature and a low blood pressure (100/50). One
patient reportedly developed an anaphylactic reaction after taking one dose of DHEA
50mg. She was given epinephrine and Benadryl with good results. An elderly male listed
numerous subjective “serious” adverse events to a single dose of DHEA that he reported
as life threatening and requiring hospitalization. His physician noted that he has a history
of reporting drug reactions. The reactions include weakness, fatigue, ataxia, insomnia,
decreased appetite, SOB, rapid heart rate, and sensation of doom. The last involves a 60year-old male with severe HTN who became hypokalemic and syncopal after four days
of DHEA. This was reported life threatening, however no additional information was
provided.
The remaining cases listed numerous adverse events that in most cases did not appear to
be serious and generally resulted only in discontinuation of DHEA and/or other products.
These events include weakness, insomnia, headache, CP, indigestion, constipation,
tremors, dizziness, fainting spells, depression, muscle cramps, nightmares, guilt feelings,
shortness of breath, weight gain, swelling of neck, malaise, memory loss, arm numbness,
venous distension, chest heaviness, tinnitus, possible drug interaction, feet tingling,
tachycardia, and hyperactivity.
CONCLUSIONS
There were 65 postmarketing adverse event cases possibly associated with the use of
DHEA. Other than the single report of worsening metastatic prostate cancer previously
described in the review by Parivash Nourjah, Ph.D, entitled Epidemiologic evidence of
DHEA in the etiology of neoplasia, there were no additional reports of neoplasia found in
the any of the above databases or the medical literature.
Forty-two of the 65 cases fall into the following body systems: urologic/renal (5),
events that could not easily be categorized into a body system. Four cases were published
in the medical literature.
12
Approximately 40% of the cases were concerning. The urologic/renal, cardiovascular,
gastrointestinal, and psychiatric adverse events were particularly concerning because they
had the highest number of hospitalizations (> 50%). However, because the overall
numbers of cases in each of these body systems were small and in many cases
confounded by concomitant or co-suspect medication, we identified no clear safety
signals with this product.
REFERENCES
1.
2.
3.
4.
Jones J.A., Nguyen A., Straub M, Leidich R, Veech R.L., and Wolf S. Use of
DHEA in patient with advanced prostate cancer: a case report and review.
Urology 1997; 50:784-8.
Sahelian R, Borken S. Dehydroepiandrosterone and cardiac arrhythmia. Ann
Intern Med 1998; 129(7): 588.
Markowitz JS, Carson WH, Jackson CW. Possible dihydroepiandrosteroneinduced mania. Biol Psychiatry 1999; 45(2): 241-2.
Kline MD, Jaggers ED. Mania onset while using dehydroepiandrosterone. Am J
Psychiatry 1999; 156(6): 971.
Signed _3/12/01______________________
Claudia B. Karwoski, Pharm.D.
13
Scientific Verdict Still Out
PERHAPS NO drug better illustrates
the problem with the US Dietary Supplement Health and Education Act of 1994
than does the adrenal hormone dehy-$
droepiandrosterone (DHEA).
Although mounting evidence suggests
that DHEA may have a broad range of
clinical uses, the long-term effects of the
substance are unknown. But that hasn't
prevented the creation of a large and
growing market for what many are calling a miraculous "Fountain of Youth."
DHEA has become the latest drug of
choice for talk shows and reports in the
print and broadcast media, where it is
being touted as an "antidote for aging"
and a "superhormone" that can help burn
fat, build muscle mass, boost libido,
strengthen the immune system, prevent
heart disease, cancer, and non\p=m-\insulin-$
dependent diabetes, retard memory loss,
help in the treatment of systemic lupus
erythematosus, and prevent or slow the
progression of Alzheimer and Parkinson diseases.
All this, despite the fact that not one
of these benefits has yet been demonstrated in a large randomized placebocontrolled clinical trial. What's more,
some animal and epidemiologie studies
suggest that higher serum levels of the
hormone may be associated with in¬
creased risk for ovarian and perhaps
prostate or other types of cancers.
Fulfilling the intent of many of its sup¬
porters, the US Dietary Supplement
Health and Education Act of 1994 has
partially short-circuited the nation's drug
developing and testing system. The law
allows a wide variety of substances to be
sold for human consumption without ap¬
proval from the Food and Drug Admin¬
istration (FDA), as long as they are sold
as "dietary supplements" and the prod¬
uct labeling includes no "drug intent."
"This whole thing has gotten out of
hand," says Arthur Schwartz, PhD, pro¬
fessor of microbiology, Fels Institute for
Cancer Research and Molecular Biology,
Temple University School of Medicine,
Philadelphia, Pa. "There's no evidence
that this hormone is found in any food—
unless, of course, you consider primate
adrenal glands food. So why is it being
sold as a food supplement? This is as
crazy as health food stores being allowed
to sell cortisone supplements."
Schwartz, a pioneer in DHEA research,
has begun to speak out against the media
hype, in part because his name and re-
on
search are being used deceptively to sell
DHEA to the public, he says. For ex¬
ample, the Web page on the Internet for
Life Plus Vitamins promotes its own brand
of DHEA with the following claim: "Dr.
A. Schwartz, a researcher at Temple Uni¬
versity, has now proven beyond question,
DHEA's effectiveness in weight control."
"That's totally false," says Schwartz,
who has been studying the metabolic
effects of DHEA since the 1970s. "No
human data exist whatsoever that show
DHEA can help a person lose weight.
Rodent studies show some type of antiobesity effect, but its mechanism is
still not known."
What is known is that mice and rats
are not humans; circulating DHEA se¬
rum levels in rodents are about 5 orders
of magnitude lower than levels in hu¬
mans and other primates, he says. To
produce weight loss, rodents must be
given high doses of hormones that are
known to be androgenic in humans. The
low doses that many people are now
taking as supplements (25 to 50 mg/d,
which is sufficient to raise serum levels
in the elderly to levels normally found in
young adults) probably are not andro¬
genic, he adds, but they probably are
not very effective either.
According to Schwartz, the health food
industry, with the help of some physi¬
cians, is exposing large numbers of
people to a drug whose long-term ef¬
fects are unknown. In addition, virtu¬
ally nothing is known about DHEA's
interactions with other drugs.
'Call of the Hucksters'
Schwartz's concerns are shared by
many of his colleagues who took part in
the international conference, Dehydroepiandrosterone (DHEA) and Aging, in
Washington, DC, June 17-19, 1995. Al¬
though speakers at the conference, which
was sponsored by the New York Acad¬
emy of Sciences, spoke optimistically
about the many potential clinical uses
for DHEA, they also urged caution in
promoting or prescribing the drug to
the public until much more is known
about the hormone's long-term effects.
In his introduction to Dehydroepiandrosterone (DHEA) and Aging: An¬
nals of the New York Academy of Sci¬
ences (1995;774:ix-xi), an editor of the
Annals volume and conference orga¬
nizer, John E. Nestler, MD, Division of
Endocrinology and Metabolism, Medi-
DHEA
cal College of Virginia, Richmond, told
how DHEA for many years had the repu¬
tation of a "snake oil" because of the
overzealous way some scientists had
been promoting it.
"One can almost hear the hucksters
calling out: 'Come get your DHEA, come
get your Fountain of Youth. Cures all"
that ails you. Helps you live forever,'
Nestler wrote. "DHEA was reputed to
remedy almost any bodily ill, even though
evidence for the beneficial effects of
DHEA in humans was virtually nonex¬
istent and its cellular or molecular mechanism(s) of action remained a mystery. Be¬
cause ofthis nefarious reputation, DHEA
research was regarded by many as a du¬
bious, or at best, avant garde adventure."
According to Nestler, some physicians
unjustifiably dispensing DHEA "in a
are
cavalier fashion for almost any indica¬
tion.
Although the results of human
DHEA studies appear promising and tan¬
talizing, as evidenced by the reports in
this volume of the Annals, they need to
be confirmed in large-scale and properly
controlled studies. A beneficial effect of
DHEA administration in humans has not
yet been firmly established, and we know
virtually nothing about the side-effect
profile of chronic DHEA administration.
Without confirmed beneficial actions in
humans and a better understanding of
associated risks, it does not seem rea¬
sonable to dispense DHEA."
However, many in addition to physi¬
cians now are prescribing and dispens¬
ing DHEA. Advertisements in newspa¬
pers and magazines and on the Internet
are promoting and offering the "anti¬
dote to aging" directly to the public. "If
you are searching for the Fountain of
Youth, DHEA is a must" says one such
article recently posted to the Internet
newsgroup, misc.health.alternative. The
article promotes a "colloidal" form of
DHEA called "LiquidLightning MetaD-10" and claims that DHEA's "cogni¬
tion-enhancing benefits for Alzheimer's
and Parkinson's patients have been
proven in clinical studies."
Other advertisements are recruiting
people to join in multilevel marketing of
DHEA with promises of a "faster, surer
way to wealth." One company's DHEA
Internet web page is illustrated with 4
photographs across the page: a table full
of fruits and vegetables, captioned "The
Problem" (the "nutrient" DHEA is not
found in foods); a bottle of one of the
...
Downloaded from jama.ama-assn.org at Overlook Hospital Library on March 28, 2011
company's nutritional supplements, captioned "The Solution;" a white-smocked
man holding a bottle of the supplements,
captioned "The Creator;" and a fist full
of $20 bills, captioned "The Opportu¬
nity." The usual retail price for a month's
supply of DHEA in 25-mg to 50-mg daily
doses is approximately $15.
What Is DHEA?
The hormone is made in exceptionally
large quantities as the sulfated form
(DHEAS) by the adrenal cortex only in
primates and a few nonprimate species.
Only humans and apes show the curious
life pattern of having very high prenatal
serum levels of DHEA and
DHEAS that
drop to virtually none after birth, then
rise sharply at puberty and reach very
high levels during young adulthood, and
finally drop progressively until only neg¬
ligible levels are left in old age.
While the average serum level of
DHEAS in men 25 to 34 years of age
ranges around 6.44±2.29 µ ß/ , it falls
to 1.15±0.52 µ 1ß/ in men age 75 to 84
years, and DHEA serum levels fall from
15.91 ±6.05 nmol/L to 5.36+1.68 nmol/L
(Dehyroepiandrosterone (DHEA) and
Aging: Annals of the New York Acad¬
emy of Sciences. 1995:774:121-127). The
decline rate for both DHEA and DHEAS
is relatively constant at about 2% per
year. Most studies show that the levels
in young women are 10% to 30% lower
than in young men, but the sex differ¬
ences appear to decline with age.
The hormone is a universal precursor
of a number of androgenic and estrogenie products that are made by periph¬
eral tissues to supply local requirements,
says Fernand Labrie, MD, PhD. Labrie,
at Le Centre Hospitalier de l'Université
Laval (Quebec), CHUL Research Cen¬
ter, has introduced the term "intracrinology" to describe how individual tis¬
sues use a series of DHE A-metabolizing
enzymes to transform the precursor hor¬
mone into much more physiologically ac¬
tive sex steroids.
Speaking at the New York Academy
of Sciences conference, Labrie estimated
that "30% to 50% of total androgens in
men are synthesized in peripheral intracrine tissues from inactive adrenal pre¬
cursors, whereas in women, peripheral
estrogen formation is even more impor¬
tant.
Intracrinology represents
an eco¬
nomical system which requires minimal
amounts of hormone to exert maximal
function. In classic endocrine systems,
large amounts of hormones are needed
with only a small fraction used for regu¬
lation while the rest is degraded."
A recent groundswell in human
DHEA-related research suggests that
the hormone may have a wide variety of
therapeutic applications, says Nestler:
"Given the diverse nature of DHEA's
putative biologic actions, it seems likely
that several independent mechanisms
for DHEA action may be operative."
Among the research reported at the
conference was a pilot study that sug¬
gests DHEA may improve mood, en¬
ergy, libido, and, in some cases, memory
performance in the elderly. In the openlabel study, 3 men and 3 women 51 to 72
years of age, who had major depression
as defined by the American Psychiatric
Association's Diagnostic and Statisti¬
cal Manual of Mental Disorders, Third
Edition, and low basal serum levels of
DHEA, were given 30 mg to 90 mg of
DHEA a day orally for 4 weeks, said
Owen M. Wolkowitz, MD, Department
of Psychiatry, University of California,
San Francisco. He and colleagues evalu¬
ated patients weekly using the 21-item
Hamilton Depression Rating Scale, Beck
Depression Inventory, Symptom Check¬
list 90, and Bunny-Hamburg Global De¬
pression Rating, along with a test of
verbal memory. All of the depression
evaluations showed significant improve¬
ment during treatment, which returned
to baseline after the treatment was
gradually withdrawn. One of the 6 pa¬
tients was treated for 5 additional
months with an increase in DHEA dos¬
age after 4 months. Improvement in her
depression was found to be dose related.
"These preliminary results raise the
possibility that age- and/or illness-asso¬
ciated decreases in circulating DHEA
and DHEAS levels in depressed patients
may be pathophysiologically relevant
and are amenable to pharmacologie
treatment," Wolkowitz reports. Larger,
double-blind, placebo-controlled trials
are under way.
Research by Etienne-Emile Baulieu,
MD, INSERM, Le Kremlin-Bicetre,
France, and colleagues presented at the
conference suggests that DHEA is a neuroactive neurosteroid that has multiple
pharmacologie effects on the nervous sys¬
tem. These investigators are calling for
trials aimed at offsetting the profound
decrease in DHEA serum levels in the
elderly. "The nervous system is one of
the most important potential targets of
the prospective trials under consider¬
ation," Baulieu said. "Experimental data
on the control of mood changes and re¬
inforcement of memory storage, com¬
bined with clinical evidence of DHEA
activity on the nervous system in vivo
in humans, based on electroencephalographic data, are very encouraging."
Boosting the Immune System
Evidence that DHEA may be an ef¬
fective vaccine adjuvant for elderly pa¬
tients was presented by Barbara A. Araneo, PhD, University of Utah School of
Medicine Department of Pathology, Salt
Lake City, and colleagues.
Attempts to vaccinate elderly patients
with antigens to which they have never
been exposed often result in failure to
elicit the desired immune response. In
contrast, immune responses are usually
induced more reliably when the anti¬
gens have been previously encountered.
This suggests that immunologie memory
remains intact during the aging process,
Araneo and colleagues said.
The researchers reported the results
of 2 double-blind, randomized, placebocontrolled clinical studies that tested the
adjuvant potential of DHEAS. In one
study, elderly volunteers were vacci¬
nated with tetanus toxoid (to elicit an
antigen recall response). In the other,
the volunteers received the 1994-1995
licensed trivalent influenza vaccine (to
elicit a primary response).
The tetanus study involved 66 men
over age 65 years, of whom 36 received
placebo and 30 received DHEAS. The
hormone appeared to have no significant
adjuvant effect or a detrimental effect on
the outcome of tetanus immunization.
In the influenza vaccine study, 67 el¬
derly men and women were given placebo
or 50 mg of DHEAS orally for 2 consecu¬
tive days starting on the day of vaccina¬
tion. Serum samples were collected the
day before the first drug dose and 28 days
and 90 days after vaccination. The re¬
searchers found that significantly more of
the volunteers who had a 4-fold increase
in influenza hemagglutination inhibition
(HAI) titers after vaccination had been
given DHEAS compared with those given
placebo, and the overall increase in HAI
titers was highest in the DHE AS-treated
group. They conclude that further studies
should justify the use of DHEAS as an
adjuvant for antigens that represent pri¬
mary responses in the elderly.
Preventing Heart Disease?
Some epidemiologie studies have found
association between low DHEA se¬
levels and heart disease and some
have not. At the conference, Elizabeth
Barrett-Connor, MD, and Deborah Goodman-Gruen, MD, Department of Family
and Preventive Medicine, University of
California, San Diego, School of Medi¬
cine, La Jolla, updated what they say is
the only prospective community-based
study of the association of natural
DHEAS serum levels and fatal cardio¬
vascular disease outcomes in men and
women. The 19-year follow-up study of
1029 men aged 30 to 82 years and 942
women aged 50 to 88 years showed a
statistically significant, modestly reduced
risk of death from cardiovascular disease
(relative risk [RR]=0.85) in men who had
higher DHEAS serum levels, but a nonan
rum
significant increased risk of fatal cardio¬
vascular disease (RR=1.11) in women
with higher levels.
David M. Herrington, MD, MHS, Di¬
vision of Cardiology, Bowman Gray
School of Medicine, Winston-Salem, NC,
reported on 2 studies that looked at
DHEA and DHEAS plasma levels in
patients undergoing elective coronary
angiography and in a group of cardiac
transplant patients at risk for acceler¬
ated cardiac allograft vasculopathy. Tis¬
sue culture, animal studies, and epide¬
miologie studies suggest that DHEA
may inhibit atherosclerosis through its
potent antiproliferative effects. The re¬
sults of his study support those find¬
ings: their data "suggest that low plasma
levels of DHEA may facilitate, and high
levels may retard, the development of
coronary atherosclerosis and coronary
allograft vasculopathy," Herrington says.
"These observations are consistent with
our understanding of coronary athero¬
sclerosis as a complex multifactorial dis¬
ease process in which DHEA may play
a small but important role."
The findings of a clinical study by
Robert L. Jesse, MD, Division of Car¬
diology, Medical College of Virginia,
Richmond, suggest that DHEA inhibits
platelet aggregation. In a study of 10
healthy men aged 23 to 35 years, 5 were
given placebo and 5 received 300 mg of
DHEA 3 times a day for 14 days. The
rate of platelet aggregation did not
change in any of the placebo group, but
was prolonged in 4 of the 5 in the DHE Atreated group. In 1 of the 4, platelet
aggregation was inhibited completely.
None of the men reported any adverse
effects while taking DHEA and none
was able to tell if he was taking DHEA
or the placebo. "Inhibition of platelet
activity by DHEA may contribute to
the putative antiatherogenic and cardioprotective effects of DHEA," Jesse
concludes.
Insulin Sensitivity and Lupus
Some researchers believe that DHEA
may protect against non-insulin-depen¬
dent diabetes. In a 3-week, randomized,
double-blind, placebo-controlled trial of
15 postmenopausal women, Gordon
Wright Bates, Jr, MD, then at the De¬
partment of Obstetrics and Gynecology,
University of Tennessee, Memphis, and
colleagues at Baylor College of Medicine,
Houston, Tex, found that insulin sensi¬
tivity was significantly (P=.04) enhanced
in women given 50 mg of DHEA a day
compared with women receiving placebo.
"Whether this effect is reproducible in
larger studies remains to be determined.
If DHEA supplementation in aged sub¬
jects enhances insulin sensitivity, DHEA
replacement may help attenuate age-re-
lated increases in insulin resistance," the
investigators conclude.
Other possible therapeutic uses of
DHEA have been reported elsewhere.
For example, a study found that the hor¬
mone may help patients with systemic
lupus erythematosus (Arthritis Rheum.
1994;37:1305-1310). Not surprisingly, such
reports have whetted the interest of re¬
searchers in studying—and the appetite
of the public for buying—this latest "in"
drug.
In a commentary (Lancet. 1995;
345:1193-1194), Joe Herbert, MD, Cam¬
bridge Centre for Brain Repair, Univer¬
sity of Cambridge in England, says,
"Enough is known or suspected to war¬
rant investigation of DHEA(S) as an
effective, worthwhile, and relatively riskfree replacement therapy in advancing
age. This can only be done by a controlled
prospective trial of DHEA treatment;
no
amount of correlational evidence, how¬
ever
carefully collected, is enough."
The FDA's Position
"The FDA hasn't formally reviewed
the data concerning DHEA," said Rob¬
ert Moore, PhD, senior regulatory sci¬
entist in the agency's Office of Special
Nutritionals, Washington, DC, in an in¬
terview. "We would advise physicians
to recognize that this substance isn't an
approved drug for any indication."
The FDA in 1985 responded to the first
wave of Fountain of Youth fever over
DHEA by prohibiting over-the-counter
sales of the drug. That ban was ended
by passage of the health food industrybacked Dietary Supplement Health and
Education Act of 1994. The law shifted
the burden onto the FDA to prove that
a nutritional supplement is harmful be¬
fore the agency could regulate its sale.
As a result, many powerful and poten¬
tially dangerous drugs can now be mar¬
keted as nutritional supplements with¬
out proof of safety or efficacy.
"Physicians need to routinely ask their
patients about the food supplements they
are taking," says Moore. "That's the only
way we can find out if there are ad¬
verse reactions to the supplements."
Without being asked, people who think
of supplements as "natural"—and there¬
fore harmless—are not going to men¬
tion taking them to their physicians. Phy¬
sicians should report all suspect adverse
reactions to any dietary supplement to
the FDA's MEDWatch program by call¬
ing (800) FDA-1088.
Other Caveats
Some evidence exists that justifies con¬
cern about the safety of DHEA supple¬
ments. According to Nestler, there has
been at least one published report of tran¬
sient hepatitis associated with DHEA use
by a woman. Large doses of DHEA can
be converted to
potent androgens, such
can masculinize
While the effects of DHEA on
the development or promotion of pros¬
tate cancer are unknown, there is evi¬
dence to suggest that DHEA may in¬
crease some women's risk for ovarian
cancer. In a nested, case-control prospec¬
tive study of serum samples collected from
more than 20 000 residents of Washing¬
ton County, Maryland, Kathy J. Helzlsouer, MD, Department of Oncology,
Johns Hopkins University School of Medi¬
cine, Baltimore, Md, found that the risk
of ovarian cancer was associated with in¬
creased levels of DHEA and DHEAS
as
testosterone, which
women.
(JAMA. 1995;274:1926-1930).
If people are going to take DHEA, they
should do so as part of a clinical trial so
that its risks and benefits can be followed,
says Temple's Schwartz. At the very least,
no one should take this drug without his
or her physician's knowledge. It would be
unwise for people younger than 30 years
to take DHEA because the supplements
might suppress the body's natural pro¬
duction of the hormone. If used at all, it
should be used as a replacement therapy
in older people whose serum DHEA lev¬
els have declined substantially.
Some experts recommend that DHEA
serum level be measured before a per¬
son takes supplements. Patients also
should be informed that they are not
going to boost their DHEA levels with
Mexican yam (Dioscorea mexicana) or
wild yam (Dioscorea villosa) products
that are being touted as containing natu¬
ral precursors for the body's production
of the hormone, says Schwartz.
John Renner, MD, clinical professor of
family medicine, University of Missouri,
Kansas City, School of Medicine and
president of Consumer Health Informa¬
tion Research Institute, also recommends
that people not take DHEA on their own.
Recalling that impurities in tryptophan—
the superstar food supplement of a few
years ago—led to a number of deaths
and hundreds of cases of eosinophiliamyalgia syndrome, Renner notes that
there is still no governmental regulation
of the potency and purity of so-called
nutritional supplements.
"If people do take it, then I recom¬
mend that they keep track of the batch
number by saving the original bottle
along with the last 5 pills and that they
store it in a cool dark place," Renner
says. Asked how long the samples should
be kept, he said, "Until the legal statute
of liability runs out." He also recom¬
mends against buying from a mail order
establishment or from any fly-by-night
operation. "Buy it from a large health
food chain that can afford to be sued in
case of adverse reactions," he says.
\p=m-\byAndrew A. Skolnick
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed
to use PRASTERA® safely and effectively. See full
prescribing information for PRASTERA®.
PRASTERA® prasterone oral softgels 200mg are for oral
use only.
INDICATIONS AND USAGE
PRASTERA® prasterone 200 mg oral softgels is a medical
food indicated in female patients with mild to moderate, active
(SLEDAI >2) systemic lupus erythematosus (SLE) to restore
serum 5-dehydroandrosterone sulfate to levels typical of
women without SLE. In Phase III clinical trials in female
patients with mild to moderate active SLE, prasterone 200 mg
was associated with reduced risk of auto-immune flare. (§§1,
6.2, 6.4, 6.5)
DOSAGE AND ADMINISTRATION
The recommended dose is one (1) softgel daily. (§2)
DOSAGE FORMS AND STRENGTHS
200mg oral softgel capsules supplied in a convenience
package with ibuprofen oral tablets 300mg. (§3)
•
•
•
•
•
•
•
•
•
•
CONTRAINDICATIONS
Known hypersensitivity to any of its ingredients. (§4)
Undiagnosed abnormal genital bleeding. (§4)
Known, suspected or history of breast cancer. (§4, §6.5)
History of, or known, deep vein thrombosis, pulmonary
embolism, arterial thromboembolic disease (e.g., stroke,
myocardial infarction). (§4)
Hypercholesterolemia or ischemic heart disease. (§4,
§7.2.4)
Hepatic or renal impairment (pharmacokinetic data
lacking). (§4, §7.2)
Breast-feeding or known or suspected pregnancy. (§4)
History of psychiatric disorder. (§4, §8)
•
•
PRASTERA® may in certain patients elevate serum levels
of 5-dehydroepiandrosterone, testosterone or estrogen
above the normal range for healthy, non-afflicted women
of similar age. Periodic measurement of serum hormones
is prudent. (§7.2.1)
Hypertension may occur with prasterone treatment.
Monitor blood pressure closely. (§6.3.2)
ADVERSE REACTIONS
The most common adverse event with PRASTERA® is acne.
This is generally treatable with topical anti-acne medication.
(§6.1)
Another common adverse reaction is hirsutism. Both acne and
hirsutism are reversible on cessation of prasterone. (§6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
QPharma Pharmacy Fulfillment Services, Inc. at 1888_742-7620
or
FDA
(1-800-FDA-1088
or
www.fda.gov/medwatch) or your doctor.
•
•
•
DRUG INTERACTIONS
PRASTERA® may interact with certain psychiatric drugs.
(§8)
Concomitant administration of PRASTERA® with
endogenous testosterone or estrogens, or dietary
supplements containing DHEA or dehydroepiandrosterone,
is not generally recommended unless serum sex hormone
levels are monitored, because of the potential to elevate
levels above the ranges considered normal in healthy
individuals. (§§7.1, 7.2.1, 8, 10, 16.3)
USE IN SPECIFIC POPULATIONS
Not recommended for use in nursing nor pregnant women,
pediatric patients, or men (safety data is lacking). (§9)
See § 16 for PATIENT COUNSELING INFORMATION.
Revised: 05/2013
WARNINGS AND PRECAUTIONS
PRASTERA® is not intended for use in nursing or pregnant
women, children nor males (safety data is lacking). (§§4,
9)
PRASTERA® use may be prohibited by certain athletic
anti-doping regulations. (§9.5)
TABLE OF CONTENTS
1
2
2.1
GENERAL INSTRUCTIONS
2.2
SPECIAL PRECAUTIONS
3
4
5
6
CONTRAINDICATIONS
4.1
ALLERGY WARNING
ADVERSE REACTIONS
6.1
INCREASED RISK OF ACNE AND
HIRSUTISM
6.2
REDUCED RISK OF MYALGIA AND OTHER
FLARE SYMPTOMS
6.3
OTHER COMMON ADVERSE EVENTS
6.3.1
Hypertension
6.4
REDUCED RISK OF DEATH
6.5
REDUCED RISK OF BREAST CANCER
6.6
OTHER SERIOUS ADVERSE EVENTS
7
SAFETY
7.1
RELATIONSHIP OF DOSE TO SAFETY
7.2
CLINICAL LABORATORY EVALUATION
7.2.1
Serum Hormone Levels
7.2.2
Serum Creatinine
7.2.3
Serum Complement
7.2.4
Serum Lipids
7.2.5
Liver Function
7.2.6
Renal Function
7.2.7
Proteinuria
7.2.8
Hematuria
7.3
POST-MARKETING EXPERIENCE
8
DRUG INTERACTIONS
9
9.1
MALES
9.2
PATIENTS WITH ACTIVE SLE DISEASE
9.3
PREGNANCY
9.4
PEDIATRIC USE
9.5
ATHLETIC ANTI-DOPING
10 OVERDOSE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
PHARMACODYNAMICS
12.2
PHARMACOKINETICS
12.2.1
Time To Peak Concentration
12.2.2
Absorption
12.2.3
Distribution
12.2.4
Metabolism
12.2.5
Excretion
13
12.2.6
Special Populations
PRE-CLINICAL TOXICOLOGY
14
CLINICAL STUDIES
14.1
REDUCTION IN RISK OF FLARE
14.1.1
Clinical Study GLB96-01
14.1.2
Clinical Study GL95-02
14.2
REDUCTION IN RISK OF DEATH
14.2.1
Clinical Study GL94-01
15 HOW SUPPLIED / DOSAGE AND
HANDLING
16
PATIENT COUNSELING INFORMATION
16.1
PATIENT / CAREGIVER INSTRUCTIONS
16.2
BENEFITS
16.3
OTHER MEDICATIONS
16.4
ADVERSE REACTIONS
16.5
PREGNANCY
17 MEDICATION GUIDE
FULL PRESCRIBING INFORMATION
1
Oral prasterone (200mg per day) in female patients with active systemic lupus
erythematosus (SLE) has in several blinded, placebo-controlled randomized clinical studies been
associated with a reduced risk of auto-immune flare, §§6.2, 14.1.1, and a reduced risk of death
from any cause, §§6.4, 14.2.
Patients with SLE may have depressed serum levels of 5-dehydroepiandrosterone sulfate
(5-DHEAS). Oral prasterone has been shown to restore SLE patients’ serum 5-DHEAS levels.
Prastera® oral softgels are intended for use in patients for whom medical evaluation shows a
depressed serum level of DHEA and thus a distinctive need for exogenous DHEA.
Prastera® oral prasterone softgels are intended to be used under medical supervision, for
a patient receiving active and ongoing medical supervision, wherein the patient obtains medical
care on a recurring basis for, among other things, instructions on the use of this product.
Prastera® oral prasterone softgels are intended for the dietary management of SLE by
meeting the distinctive nutritional requirement of women with mild-to-moderate active SLE.
Prastera® oral prasterone softgels are intended for oral intake only.
Prastera® does not cure, treat, mitigate or prevent SLE. To the contrary, patients taking
Prastera® will continue to have SLE, and thus may require other appropriate therapy.
2
2.1
General Instructions
The recommended dose is one 200mg Prastera® oral prasterone softgel daily, with or
without food.
2.2
Special Precautions
None.
3
Prastera® oral prasterone is provided as oral softgels. Each softgel contains 200mg of
prasterone (>99% pure). Inactive ingredients: olive oil NF, gelatin NF, beeswax NF, lecithin
NF, titanium dioxide USP.
4
CONTRAINDICATIONS
Prastera® oral softgels should not be used in patients with any of the following conditions:
a) Known hypersensitivity to prasterone (or the dietary supplement DHEA), testosterone,
estrogens or any component of Prastera® oral prasterone softgels. §4.1.
b) Undiagnosed abnormal genital bleeding.
c) Known, suspected, or history of breast cancer. §6.5.
d) Active deep vein thrombosis, pulmonary embolism or history of these conditions.
e) Active arterial thromboembolic disease (for example, stroke and myocardial
infarction), or a history of these conditions. §6.3.2.
f) Patients with hypercholesterolemia, §7.2.4, or ischemic heart disease.
g) Liver disease or renal impairment (pharmacokinetic data lacking).
h) Known or suspected pregnancy; breast-feeding (safety data lacking).
i) Patients with or a history of psychiatric disorders (risk of exacerbation). The risk of mania
may be increased during concomitant use with antidepressants (tricyclic or SSRIs) and/or
alcohol, or with high prasterone doses, or in patients with a history of mood disorders.
4.1
Allergy Warning
Prastera® oral prasterone softgels contain no milk, eggs, fish, crustacean shellfish, tree
nuts, wheat, peanuts or soy bean.
5
PRASTERA® is not intended for use in children, nor males, nor women who are
breastfeeding, pregnant, or who expect to become pregnant. §9.
Monitoring of blood pressure, serum lipids, serum sex hormones is prudent. See Clinical
Laboratory Evaluation, §§7.2.1, 7.2.4.
6
ADVERSE REACTIONS
The most-frequent adverse reactions observed in placebo-controlled, blinded clinical
studies GL94-01, GL95-01, GL95-02 and GLB96-01 are as follows:
6.1
Increased Risk of Acne and Hirsutism
Acne was the most frequently reported adverse event. Acne was reported less frequently
by African American patients, in approximately 26%, compared to approximately 36% in
Caucasian patients.
The second most-frequent adverse event was hirsutism. In study GLB96-01 involving
patients of Chinese extraction, hirsutism was not reported; this may indicate a decreased racial
susceptibility to hirsutism.
Acne and hirsutism were both reversible on cessation of prasterone therapy. In addition,
both were more likely to be reported early in treatment; patients who had not developed these
within the first 6 months of exposure are less likely to develop them later.
6.2
Reduced Risk of Myalgia and Other Flare Symptoms
Placebo-treated patients had higher incidences of myalgia, joint disorder, anorexia, nasal
ulcers and LE skin rash than did prasterone-treated patients. These differences may be due to the
decreased risk of flare observed in prasterone-treated patients. §14.1.
6.3
Other Common Adverse Events
No adverse events increase in frequency with longer duration of treatment. The Table
displays all adverse events reported in a frequency of 10% or greater from either the 200 mg
dose group or the placebo group for the pooled double-blind phases of Studies GL94-01 and
GL95-02. Because the number of patients who received prasterone 100 mg was substantially
fewer, adverse events for this group are only presented for those adverse events which were
reported in > 10% of either placebo or prasterone 200 mg patients.
ADVERSE EVENTS WITH FREQUENCY >10%*
(pooled GL94-01 and GL95-02 results)
COSTART TERM
Rash
Acne
Arthralgia
Asthenia
Headache
Arthritis
Myalgia
Pain Abdomen
Flu Syndrome
Stomatitis Ulcer
Hirsutism
Fever
Depression
Alopecia
Infection
Sinusitis
Placebo
N=256
77 (30.1%)
39 (15.2%)
95 (37.1%)
70 (27.3%)
76 (29.7%)
58 (22.7%)
79 (30.9%)
34 (13.3%)
46 (18.0%)
50 (19.5%)
6 (2.3%)
39 (15.2%)
33 (12.9%)
48 (18.8%)
37 (14.5%)
33 (12.9%)
100mg
N=63
14 (22.2%)
28 (44.4%)
15 (23.8%)
23 (36.5%)
17 (27.0%)
17 (27.0%)
14 (22.2%)
8 (12.7%)
1 (1.6%)
15 (23.8%)
7 (11.1%)
9 (14.3%)
5 (7.9%)
7 (11.1%)
18 (28.6%)
4 (6.3%)
200mg
N=253
93 (36.8%)
91 (36.0%) **
88 (34.8%)
68 (26.9%)
60 (23.7%)
57 (22.5%)
55 (21.7%) **
41 (16.2%)
40 (15.8%)
38 (15.0%)
36 (14.2%) **
36 (14.2%)
35 (13.8%)
35 (13.8%)
26 (10.3%)
22 (8.7%)
Pain Chest
27 (10.5%)
5 (7.9%)
22 (8.7%)
*Frequency > 10% in either prasterone 200 mg or placebo patients.
** P< 0.05, Placebo vs. prasterone 200 mg.
For adverse events occurring in < 10% of patients, the following showed an absolute
difference of at least 3% between placebo or prasterone 200 mg, or, if less than 3% difference,
the difference was significant (p < 0.05):
ADVERSE EVENTS WITH FREQUENCY <10%
AND AT LEAST A 3% OR A SIGNIFICANT DIFFERENCE
(pooled GL94-01 and GL95-02 results)
COSTART TERM
Less Frequent in Prasterone
Anorexia
Nasal Septum Disorder (nasal ulcers)
Rash Lupus Erythematosus
Joint Disorder
More Frequent in Prasterone
Creatinine Increase
Hypertension
Hematuria
Insignificant Difference
Back Pain
Pharyngitis
Dyspnea
Lymphadenopathy
Placebo
N=256
prasterone 200 mg
N=253
10 (3.9%)
14 (5.5%)
13 (5.1%)
14 (5.5%)
2 (0.8%) **
5 (2.0%) **
4 (1.6%) **
4 (1.6%) **
0 (0.0%)
7 (2.7%)
1 (0.4%)
6 (2.4%)**
20 (7.9%) **
9 (3.6%) **
16 (6.3%)
14 (5.5%)
22 (8.6%)
21 (8.2%)
24 (9.5%)
6 (2.4%)
11 (4.3%)
12 (4.7%)
** P< 0.05, Placebo vs. prasterone 200 mg.
The pattern of adverse events in clinical study GLB96-01 showed a similar, but not
identical pattern. Acne was the most common adverse event; this may reflect the fact that almost
all patients were also receiving corticosteroids. This may also reflect racial differences in
sensitivity to prasterone. By contrast, hirsutism was not reported at all in GLB96-01.
ADVERSE EVENTS REPORTED BY AT LEAST 10%
OF EITHER TREATMENT GROUP
(GBL96-01)
Arthralgia
Acne *
Pharyngitis
Myalgia
Placebo
N= 59
37 ( 62.7%)
17 ( 28.8%)
32 ( 54.2%)
24 ( 40.7%)
Treatment
N= 61
39 ( 63.9%)
36 ( 59.0%)*
34 ( 55.7%)
28 ( 45.9%)
Headache *
Pain Abdomen
Asthenia
Cough Increase
Dizziness
Pain Chest
Dyspnea
Rash
Fever
Alopecia
Pain
Diarrhea
Rhinitis
Stomatitis Ulcer
Pain Back
Edema
Injury Accident
Insomnia
Pruritus
Infection*
Dry Eye
Vomit
Peripheral Edema
Rash Lupus Erythematosus
Conjunctivitis
Nausea
37 ( 62.7%)
25 ( 42.4%)
19 ( 32.2%)
18 ( 30.5%)
19 ( 32.2%)
11 ( 18.6%)
8 ( 13.6%)
16 (27.1%)
17 ( 28.8%)
8 ( 13.6%)
8 ( 13.6%)
11 ( 18.6%)
13 ( 22.0%)
17 ( 28.8%)
10 ( 16.9%)
6 ( 10.2%)
6 ( 10.2%)
7 ( 11.9%)
7 ( 11.9%)
15 ( 25.4%)
10 ( 16.9%)
8 ( 13.6%)
8 ( 13.6%)
7 ( 11.9%)
7 ( 11.9%)
9 ( 15.3%)
26 ( 42.6%)*
23 ( 37.7%)
18 ( 29.5%)
18 ( 29.5%)
15 ( 24.6%)
14 ( 23.0%)
14 ( 23.0%)
14 ( 23.0%)
13 ( 21.3%)
13 ( 21.3%)
11 ( 18.0%)
11 ( 18.0%)
11 ( 18.0%)
10 ( 16.4%)
9 ( 14.8%)
9 ( 14.8%)
8 ( 13.1%)
8 ( 13.1%)
8 ( 13.1%)
6 ( 9.8%)*
6 ( 9.8%)
5 ( 8.2%)
5 ( 8.2%)
5 ( 8.2%)
5 ( 8.2%)
4 ( 6.6%)
*P-value<0.05, Treatment vs. Placebo, chi-square test
Of adverse events reported by at least 10% of patients, acne was the only event
significantly more frequent in the treatment group. Headache and infection were more frequent
in the placebo group. Of the adverse events reported with an incidence of less than 10%, the
only statistically significant difference was for seborrhea (0 placebo vs. 5 treatment patients).
6.3.1 Hypertension
Hypertension was reported as an adverse event more frequently in the prasterone 200 mg
group than placebo. When measures of increased (changed) blood pressure were included, there
appeared to be no difference between the groups. Whether prasterone increases hypertension is
thus not clear.
6.4
Reduced Risk of Death
In the GL94-01, GL95-01 and GL95-02 placebo-controlled clinical studies (pooled data),
the placebo group experienced 6 deaths in 77 patients, a risk of death of 7.8%. In contrast, the
prasterone group (pooled treatment and cross-over) experienced 8 deaths in 495 patients, a risk
of death of 1.6%. The risk of death from any cause was therefore five times higher in the
placebo group.
6.5
Reduced Risk of Breast Cancer
In the GL94-01, GL95-01 and GL95-02 placebo-controlled clinical studies (pooled data),
incidence of breast cancer was 1 in 336 patient-years (0.29%) for placebo and 3 in 1573 patientyears (0.19%) for prasterone (pooled treatment and cross-over). Prasterone was thus associated
with reducing the risk of breast cancer by one third.
For patients over 44 years of age, the difference between placebo and prasterone groups
was more pronounced. For women at least 45 years of age, the rate of breast cancer was 1 in 24
patient-years (4.2%) for placebo and 3 in 206 patient-years (1.5%) for prasterone treatment and
cross-over patients. Prasterone was thus associated with reducing the risk of breast cancer by
two thirds.
6.6
Other Serious Adverse Events
Adverse events that were assessed as “severe” occurred in similar frequencies in both
treatment and placebo groups, with asthenia being the most common adverse event reported as
severe in both placebo and treated patients. Although the patient numbers are small, abdominal
pain reported as a severe adverse event occurred in 6 treated 200 mg patients, 2 treated 100mg
patients, and no placebo patients.
Serious adverse events occurred in 39 200 mg, 7 100 mg, and 47 placebo patients
participating in GL94-01 and GL95-02. However, only 3 serious adverse events were
considered possibly related, 2 in the placebo group (one suicide and one patient with
menomettrorhagia) and one in 200 mg (a patient with an acute psychosis).
In the Taiwan study, serious adverse events were reported in a significantly higher
proportion of patients in the placebo group than in the treatment group. In most cases, the types
of serious adverse events reported were consistent with SLE flares or hospitalization for
manifestations of SLE, rather than adverse effects of the study drug.
SEVERE ADVERSE EVENTS OCCURRING IN AT LEAST 2 PATIENTS*
(GL94-01 and GL95-02)
COSTART TERM
Asthenia
Headache
Arthralgia
Pain Abdomen
Rash
Arthritis
Dyspnea
Depression
Diabetes Mellitus
Emotional Lability
Infection
Myalgia
Pain
Pain Chest
Paresthesia
Pleural Disorder
Vasculitis
Joint Disorder
Peripheral Edema
Sepsis
Cyst
Thinking Abnormal
Placebo
N=256
22 (8.6%)
11 (4.3%)
6 (2.3%)
0 (0%)
5 (2.0%)
2 (0.8%)
1 (0.4%)
4 (1.6%)
0 (0%)
0 (0%)
0 (0%)
5 (2.0%)
1 (0.4%)
4 (1.6%)
1 (0.4%)
1 (0.4%)
0 (0%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
prasterone 100 mg
N=63
4 (6.3%)
1 (1.6%)
3 (4.8%)
2 (3.2%)
1 (1.6%)
3 (4.8%)
0 (0%)
1 (1.6%)
0 (0%)
0 (0%)
4 (6.3%)
1 (1.6%)
0 (0%)
1 (1.6%)
0 (0%)
0 (0%)
1 (1.6%)
0 (0%)
2 (3.2%)
0 (0%)
0 (0%)
0 (0%)
prasterone 200 mg
N=253
22 (8.7%)
8( 3.2%)
6 (2.4%)
6 (2.4%)
6 (2.4%)
5 (2.0%)
4 (1.6%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
2 (0.8%)
1 (0.4%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
*Frequency at least 2 patients in either prasterone 200 mg or placebo
7
SAFETY
7.1
Relationship Of Dose To Safety
Neither adverse events nor laboratory values showed a dose relationship.
7.2
Clinical Laboratory Evaluation
7.2.1 Serum Hormone Levels
In the placebo-controlled trials, testosterone was increased in a dose related manner in
SLE patients, both pre- and post-menopausal, receiving prasterone; and androgenic adverse
events such as acne and hirsutism showed an increased frequency, as did lipid changes usually
associated with administration of androgens. In non-pregnant women, the most serious risks
associated with increased levels of testosterone would be virilization, i.e., evidence of
irreversible androgenic changes such as deepening of the voice, androgenic alopecia, or clitoral
hypertrophy. Such events were not reported in the prasterone clinical trials. However, the longterm risks of the increased testosterone levels caused by prasterone are not yet known.
7.2.2 Serum Creatinine
In the pooled data from GL94-01 and GL95-02, 0 of 256 patients in the placebo group
had creatinine increase reported as an adverse event, while 6 of 253 patients (2.4%) in the
prasterone 200 mg group had this adverse event, p=0.015, placebo vs. prasterone 200 mg.
Although there was an imbalance in the few patients with creatinine increase reported as an
adverse event, overall serum creatinine (as judged by a mean or median increase in serum
creatinine) did not increase in any of the groups, and also there was no difference in change in
creatinine between groups. Taken as a whole, these findings suggest renal dysfunction, as
identified by increased serum creatinine, was quite uncommon, and generally not related to the
findings of increased proteinuria, new onset hematuria or decreased C3.
7.2.3 Serum Complement
Prasterone caused an increased number of patients (in comparison to placebo) to have a
decrease in C3, the decline in C3 was not associated with renal dysfunction, suggesting the effect
may be mediated by a reduction in complement synthesis rather than an enhancement of
consumption. The medical literature suggests that a decline in serum complement may be a
direct effect of suppression of complement production by androgens.
7.2.4 Serum Lipids
Decreases in lipids, particularly HDL-C and triglycerides, were consistently seen in
studies of prasterone. The reduction was most evident for HDL-C and triglycerides, less so for
total cholesterol and minimal for LDL cholesterol. These findings suggest that administration of
prasterone consistently causes an early, but not progressive, decrease in serum lipids, primarily
HDL-C and triglycerides. Reduction in HDL-C observed with prasterone may not necessarily
signify an increased risk of atherosclerosis. However, it would be prudent to follow NCEP
guidelines while monitoring lipids in patients receiving prasterone.
7.2.5 Liver Function
There were no changes of potential significance in liver function tests (ALT, AST,
alkaline phosphatase, or total bilirubin) within and between the treatment groups. Equally,
serum calcium, phosphorus, uric acid, total protein and albumin showed no clinically relevant
differences between treatment groups, or changes from baseline. In the Taiwan study, there were
no clinically significant differences in liver function tests though the placebo group demonstrated
increases in SGOT and SGPT.
7.2.6 Renal Function
BUN and creatinine levels did not change during study and were similar within or
between treatment groups. Mean changes in 24-hour urine protein excretion increased in all
treatment groups, but to a greater extent in prasterone patients. However, a few patients with
very high values impacted 24-hour urine protein; and median changes were only slightly higher
in the prasterone groups. In the Taiwan study, there were no differences between treatment
groups.
Creatinine showed a mean increase from baseline of 0.2 mg/dl (an increase of 2.8%) in
the prasterone treatment group. However, the mean was influenced by one patient with an
increase of 6.1 mg/dl and the group median change was 0.0 mg/dl. No patient in the prasterone
treatment group had a shift from a normal baseline value to a high value at final visit.
7.2.7 Proteinuria
There was a higher mean change from baseline for 24 urinary protein with prasterone: the
mean change was 44.9 mg/24 hours for placebo, and 329.4 mg/24 hours for the prasterone 200
mg group, respectively. Less than 5% of patients with pre-existing proteinuria in the treatment
group demonstrated a meaningful increase in proteinuria.
7.2.8 Hematuria
There does not appear to be a difference between placebo and prasterone for new
hematuria accompanied by SLE renal involvement, as manifested by changes in urinary protein
excretion, increased creatinine, or new therapy for renal SLE.
7.3
Post-Marketing Experience
The following adverse reactions have been reported with unregulated dietary supplements
containing DHEA or dehydroepiandrosterone. These reactions have been reported voluntarily
from populations of uncertain size, the identity, purity and strength of the product used was not
always known, and none these patients were taking concomitant prednisone or other first-line
SLE therapy. It is therefore not always possible to reliably establish a causal relation to prasterone
exposure.
Cardiovascular Effects: Benign premature atrial contractions and occasional premature
ventricular contractions occurred in a 55-year-old man after administration of DHEA; DHEA
was discontinued and arrhythmias controlled by beta-blockers.1
Hepatic Effects: No significant changes in transaminases or other hepatic function tests
were seen during long-term use (e.g., 6 months).2,3 One case of hepatitis has been reported in a
patient with high pre-treatment anti-nuclear antibody (ANA) titers; causality is uncertain.4
Psychiatric Effects: Manic reactions during DHEA use (50 to 500 mg daily) have been
described.5,6 Risk factors for development of mania / psychosis are considered to be higher
doses, combined use with antidepressants (tricyclics or selective serotonin-reuptake inhibitors) or
alcohol or benzodiazepines, young patients (20 to 30 years, due to peaking endogenous
dehydroepiandrosterone levels), and cytochrome P450 polymorphisms (poor metabolizers).
8
DRUG INTERACTIONS
There is no known pharmacokinetic effect (bioavailability, pharmacokinetics, or
pharmacodynamics) of prasterone on prednisone or hydroxychloroquine, with the possible
exception of increasing the magnitude of a decrease in triglycerides seen with hydroxyquinoline.
Informal reports indicate that prasterone may theoretically interact with one or more of
the following drugs: carbamazepine, phenothiazines (e.g., acetophenazine, chlorpromazine,
chlorprothixene, ethopropazine, fluphenazine, mesordiazine, methdilazine, perazine,
perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, propiomazine,
thioridazine, trifluoperazine, triflupromazine), citalopram; escitalopram; clozapine, conjugated
estrogens; estherified estrogens; estradiol; estradiol cypionate; estropipate; ethinyl estradiol,
fluoxetine, fluvoxamine; haloperidol, lithium, loxapine, molindone, olanzapine, paroxetine,
quetiapine, risperodone, sertraline, testosterone, triazolam and valproic acid. For further
information on potential interactions with these drugs, please see The Cochrane Review
monograph for prasterone.
9
9.1
Males
The placebo-controlled, double-blind clinical studies involved women. Use in men at
this time is not recommended because data is lacking.
9.2
Patients with Active SLE Disease
In the GL94-01 and GL95-02 clinical studies, the difference in responder rates between
placebo and prasterone increased with increasing baseline SLEDAI.
9.3
Pregnancy
Safety and effectiveness in nursing and pregnant women has not been established. Use
is not recommended.
9.4
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Use in pediatric
patients is not recommended.
9.5
Athletic Anti-Doping
Prasterone use is prohibited by certain athletic anti-doping regulations.
10 OVERDOSE
Oral prasterone of up to 1.6 grams per day has not provoked overdose in post-menopausal
women.7 In case of suspected overdose, Prastera® softgels should be discontinued and the patient
should be treated symptomatically.
11 DESCRIPTION
PRASTERA® prasterone oral softgels are oblong, bi-colored white and blue, liquidfilled soft gelatin capsules for oral administration. Each PRASTERA® prasterone oral
O
softgel contains 200mg prasterone (>98% pure), in an olive oil NF vehicle.
Prasterone is chemically identical to the naturally-occurring prohormone 5-dehydroepiandrosterone secreted by the adrenal cortex,
gonads and brain tissue.
It is designated chemically as
(3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl3,4,7,8,9,10,11,12,13,14,15,16
–dodecahydro-1H- HO
cyclopenta[a]phenanthren-17(2H)-one. Its molecular weight is
288.424 g/mol. Its molecular formula is C19H28O2.
12 CLINICAL PHARMACOLOGY
H
H
H
Prastera® oral prasterone softgels are an oral dosage form of prasterone (pharmaceutical
grade), chemically identical to prasterone of native human origin, in a lipophilic vehicle.
12.1 Pharmacodynamics
Oral prasterone has been shown to increase serum levels of 5-DHEAS. The precise
mechanism by which normal serum levels of 5-DHEAS may act to reduce the risk of autoimmune flare and death is not known.
12.2 Pharmacokinetics
12.2.1 Time To Peak Concentration
Oral prasterone reaches a peak serum concentration at 1.5 to 2 hours after
administration.8,9 In healthy young women (mean age, 30 years) receiving prasterone 200 mg
daily (given with prednisone), mean peak plasma levels on day 29 of prasterone and 5-DHEAS
were 1.3 mcg/dL (13 ng/mL) and 942 mcg/dL (9.4 mcg/mL), and occurred in 2 hours and 2.4
hours, respectively, after administration.10 In elderly women (mean, 69 years) and elderly men
(mean, 69 years), mean peak plasma concentrations (times to peak levels) after a single 200-mg
micronized oral dose were 27 ng/mL (1.4 hours) and 22 ng/mL (1.3 hours) in elderly women and
men, respectively. After a single 200 mg dose, mean serum levels of 5-DHEAS increased 5-fold
in men (to 7 mcg/mL) and 21-fold in women (to 7.5 mcg/mL) relative to baseline healthy levels;
the time to peak serum levels of 5-DHEAS were shorter in women than men (2.1 versus 3.3
hours).11
12.2.2 Absorption
During two weeks of daily administration (200 mg), plasma levels (and times to peak
levels) of both 5-dehydroepiandrosterone and its sulfated metabolite did not change significantly in
either women or men, indicating a lack of accumulation.12
12.2.3 Distribution
Approximately 10% to 20% of prasterone is bound to serum protein; approximately 80% to
90% of 5-DHEAS is bound to protein.13 5-DHEAS penetrates the blood-brain barrier; cerebrospinal fluid levels of 5-DHEAS range from 0.2% to 5% of corresponding plasma levels.14, 15
12.2.4
Metabolism
Oral prasterone is sulfated to 5-DHEAS ester in the intestine and liver by
sulfotransferases.16
Prasterone and 5-DHEAS are converted in peripheral tissues to
androstenedione,17 androsterone sulfate,18 estradiol, estriol and estrone,19 dihydrotestosterone,20
7-oxo-prasterone,21 and testosterone.22 It remains controversial whether the pharmacologic
effects of 5-DHEAS are direct, or due solely to its conversion to other metabolites.23
12.2.5
Excretion
Prasterone (200mg dose) elimination half-life: young women, 11 hours; elderly men, 7
24
hours. In elderly women, the elimination half-life progressively declined, from about 12 hours
(day 1), to 9 hours (day 8), to 7 hours (day 15).25 5-DHEAS half-life: young women, 12 hours;
elderly men, 20-25 hours; elderly women, 24-27 hours.26
12.2.6 Special Populations
The pharmacokinetics of Prastera® oral prasterone softgels have not been assessed in low
body weight or obese patients. There is insufficient information available from placebocontrolled clinical trials to compare prasterone pharmacokinetics in different racial groups, nor
for patients with renal or hepatic impairment.
13 PRE-CLINICAL TOXICOLOGY
The non-clinical literature indicates that prasterone may be either chemo-protective or
carcinogenic, depending on the model. Prasterone may thus be inhibitory or stimulatory to
hormone-senentive tumors. The literature, however, suggests that prasterone is less potent than
its androgenic and estrogenic metabolites. Similarly to androgenic and extrogenic compounds, it
is expected to be difficult to define the carcinogenic potential of prasterone.27
14 CLINICAL STUDIES
The placebo-controlled studies (GL94-01, GL95-01, GL95-02 and GLB96-01) had very
different study designs and efficacy endpoints. Pooling of efficacy data is thus not meaningful.
Consequently, results are presented by individual study.
14.1 Reduction In Risk Of Flare
14.1.1 Clinical Study GLB96-01
GLB96-01 was a six month, multi-center, randomized, parallel group, double-blind,
placebo-controlled
study
of
prasterone (200mg daily) in
predominately
(+84%)
prePrasterone
menopausal (mean age = 32
years) Asian women with active
SLE (97% had baseline SLEDAI
score > 2). The treatment group
(n = 60) had a somewhat higher
baseline
SLEDAI
(Mean
(Median) baseline SLEDAI = 8.2
(8.0)). The placebo group (n =
59) a somewhat lower baseline
SLEDAI
(Mean
(Median)
baseline SLEDAI = 6.6 (6.0)).
In
this
study,
the
Time to first flare (p = 0.044)
treatment group had fewer
patients with at least one definite
flare. The number of patients
with definite flares in the
treatment group was 46.0% less than in the placebo group (18.3% vs. 33.9%, p = 0.044 based on
survival analysis using Cox model). The Time to First Definite Flare Survival Curve for
GBL96-01 is shown here. The percent of patients without a definite flare began to diverge after
28 days of treatment, and widened progressively. There was a statistically-significant decrease
in the number of patients who experienced at least one flare as compared to the placebo group
14.1.2 Clinical Study GL95-02
Study GL95-02 was a 12 month, multi-center, randomized, parallel group, double-blind,
placebo-controlled study of prasterone (200mg daily) in women (n = 346) with active SLE
(SLAM score >7 excluding ESR, SLEDAI score >2) receiving <10 mg/day prednisone (or its
equivalent of other cortico-steroids). A secondary efficacy variable (flare) was defined as a
modified SELENA definition flare.
Three hundred eighty one (381) patients were randomized, of whom 346 were in the perprotocol population. For all patients, 47/176 (27%) of placebo and 37/170 (22%) of prasterone
patients experienced a definite flare. Time to First Definite Flare Survival Curve in ITT
Population (Study 95-02) is shown in the survival curve.
For the subset of patients with a baseline SLEDAI>2, treated patients had a 23.7%
decrease in the risk of experiencing at least one definite flare, compared to placebo. During the
study period, 41/133 (31%) of placebo patients and 31/132 (23.5%) of prasterone patients
experienced a definite flare. See bar chart. Thus, for patients with a baseline SLEDAI>2, treated
patients had a 23.7% decrease in the risk of experiencing at least one definite flare, compared to
placebo (p=0.201, log-rank test for time to first definite flare).
% of Patients With Definite Flare
(Baseline SLEDAI >2)
Placebo, 31%
Prast erone,
24%
14.2 Reduction In Risk of Death
In the GL95-02 study (discussed above), five placebo patients died, and no prasteronetreated patients died. These data show a statistically significant and clinically meaningful
reduction in risk of death by any cause. In the GL94-01, GL95-01 and GL95-02 clinical trials
(pooled data), the prasterone treated group (including prasterone-treated crossover patients)
experienced 8 deaths among 495 patients, or a risk of death of 1.62%. In contrast, the placebo
group experienced 6 deaths among 77 patients, or a risk of death of 7.80%.
14.2.1 Clinical Study GL94-01
Study GL94-01 compared the proportion of patients achieving sustained reduction of
daily corticosteroid dose, without worsening of signs and symptoms of SLE (“Responders”), in
placebo (n = 64) and prasterone 200 mg (n = 64) groups for about 7 months.
For all randomized patients, 26/64 (41%) placebo and 35/64 (55%) prasterone 200 mg
patients responded: a strong trend in favor of prasterone (p = 0.110). For patients with baseline
SLEDAI >2, 13/45 (29%) placebo and 23/45 (51%) prasterone 200mg patients responded (p =
0.031).
15 HOW SUPPLIED / DOSAGE AND HANDLING
Prastera® (prasterone, pharmaceutical grade) softgels 200mg are oblong, bi-colored blue
and white soft, liquid filled gelatin capsules, NDC 55607-798-21.
Store at not more than 25° C (77° F). Excursions are permitted to 15° C to 30° C (59° F
to 86° F). See United States Pharmacopoeia, Controlled Room Temperature. Protect from
excessive moisture or humidity.
Dispense in a tight, light-resistant container as defined in USP/NF, using a child-resistant
closure system, accompanied by a Patient Insert and in a convenience pack together with
clindamycin phosphate topical pledgets.
Keep out of reach of children.
Manufactured for:
Health Science Funding, LLC
55 Madison Avenue, 4th floor
Morristown, NJ 07960
info@healthsciencefunding.com
16 PATIENT COUNSELING INFORMATION
See Medication Guide (§17) for specific patient instructions.
16.1 Patient / Caregiver Instructions
Inform patients of the following information before initiating therapy with PRASTERA®
and periodically during the course of on-going therapy. Encourage patients to read the
Medication Guide that accompanies each prescription dispensed, prior to using PRASTERA®.
16.2 Benefits
Oral prasterone 200 mg / day reduced the risk of auto-immune flare, §§6.2, 14.1, and
significantly reduced the risk of death, §§6.4, 14.2, in placebo-controlled, randomized, blinded
clinical studies (GL94-01, GL95-01, GL95-02 and GLB96-01) in female patients with Systemic
Lupus Erythematosus. Results observed in clinical trials may not, however, reflect the rates
observed in practice.
PRASTERA® does not cure, mitigate, treat or prevent the patient’s underlying SLE. To
the contrary, the patient will continue to have SLE. The patient therefore should continue to be
monitored by a physician and should continue other therapy (e.g., prednisone, NSAID) as
believed appropriate.
Oral prasterone reduced the risk of auto-immune flare and death. See above.
PRASTERA® may not, however, make the patient feel significantly different on a day-to-day
basis. This does not mean PRASTERA® is not working; it may take at least six months of
continuous therapy to achieve a statistically-significant reduction in risk of flare and death. §14.
16.3 Other Medications
PRASTERA® is a synthetic form of 5-dehydroepiandrosterone. PRASTERA® should
not be combined with dietary supplements containing “DHEA” or “dehydroepiandrosterone.”
PRASTERA® is a precursor to testosterone and estrogens. If PRASTERA® is used in
conjunction with testosterone or estrogens, levels of serum testosterone and estrogens should be
monitored closely to assure levels do not exceed the range seen in healthy women of similar age.
16.4 Adverse Reactions
PRASTERA® may cause acne. Your Prastera® includes a topical anti-acne drug should
you need it. Prasterone-associated acne is reversible on cessation of prasterone therapy.
PRASTERA® may cause hirsutism, reversible on cessation of prasterone therapy.
PRASTERA® may cause hypertension, §6.3.2, and/or changes in serum lipids, §7.2.4, or
serum hormone levels, §7.2.1. These should be monitored, and are reversible on cessation of
prasterone therapy.
16.5 Pregnancy
Instruct patients who are nursing, pregnant or intending to become pregnant, not to use
PRASTERA®.
17 MEDICATION GUIDE
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Sahelian R & Borken S: Dehydroepiandrosterone and cardiac arrhythmia. Ann Intern Med 1998; 129(7):588.
Morales AJ, Haubrich RH, Hwang JY, et al: The effect of six months treatment with a 100 mg daily dose of
dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age- advanced
men and women. Clin Endocrinol 1998; 49:421-432.
3
Villareal DT, Holloszy JO, & Kohrt WM: Effects of DHEA replacement on bone mineral density and body
composition in elderly women and men. Clin Endocrinol 2000a; 53:561-568.
4
Buster JE, Casson PR, Straughn AB, et al: Postmenopausal steroid replacement with micronized
dehydroepiandrosterone: preliminary oral bioavailability and dose proportionality studies. Am J Obstet Gynecol 1992;
166(4):1 163-1170.
5
Dean CE: Prasterone (DHEA) and mania. Ann Pharmacother 2000b; 34(12):1419-1 422.
6
Pies R: Adverse neuropsychiatric reactions to herbal and over-the-counter "antidepressants". J Clin Psychiatry
2000; 61(11 ):81 5-820.
7
Mortola, J.F. et al., The Effects of Oral Dehydroepiandrosterone Supplementation in Early and Late
Menopause, Gynecol. Endocrinol. vol. 14 pp. 342-63 (2000).
8
Arlt W, Justl H-G, Callies F, et al: Oral dehydroepiandrosterone for adrenal androgen replacement:
pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone
suppression. J Clin Endocrinol Metab 1998; 83:1928-1 934.
9
Meno-Tetang GML, Blum RA, Schwartz KE, et al: Effects of oral prasterone
(dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women. J
Clin Pharmacol 2001; 41(1 1):1 195-1 205.
10
Meno-Tetang GML, Blum RA, Schwartz KE, et al: Effects of oral prasterone
(dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women. J
Clin Pharmacol 2001; 41(1 1):1 195-1 205.
11
Frye RF, Kroboth PD, Kroboth FJ, et al: Sex differences in the
pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple- dose administration in healthy older
adults. J Clin Pharmacol 2000b; 40(6):596- 605.
12
13
Longcope C: Dehydroepiandrosterone metabolism. J Endocrinol 1996; 1 50(suppl):S1 25-S1 27.
14
Barrett-Connor E, von Muhlen D, Laughlin GA, et al: Endogenous levels of dehydroepiandrosterone sulfate,
but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo study. J Am
Geriatr Soc 1999; 47:685-691.
15
Friess E, Schiffelholz T, Steckler T, et al: Dehydroepiandrosterone - a neurosteroid. Eur J Clin Invest 2000;
30(Suppl 3):46-50.
16
Sulcova J, Hill M, Hampl R, et al: Effects of transdermal application of DHEA on the levels of steroids,
gonadotropins and lipids in men. Physiol Res 2000; 49(6):685-693.
17
Haning RV Jr, Flood CA, Hackett RJ, et al: Metabolic clearance rate of dehydroepiandrosterone sulfate,
its metabolism to testosterone, and its intrafollicular metabolism to dehydroepiandrosterone, androstenedione,
testosterone, and dihydrotestosterone in vivo. J Clin Endocrinol Metab 1991; 72(5):1 088-1095; Morales AJ, Haubrich RH,
Hwang JY, et al: The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on
circulating sex steroids, body composition and muscle strength in age- advanced men and women. Clin Endocrinol
1998; 49:421-432.
18
Bird CE, Murphy J, Boroomand K, et al: Dehydroepiandrosterone: kinetics of metabolism in normal men and
women. J Clin Endocrinol Metab 1978; 47(4):81 8-822.
19
Schwarz HP: Conversion of dehydroepiandrosterone sulfate (DHEA-S) to estrogens and testosterone in young
non-pregnant women. Horm Metab Res 1990; 22(5):309-310.
20
21
Davidson M, Marwah A, Sawchuk RJ, et al: Safety and pharmacokinetic study with escalating doses of 3acetyl-7-oxo-dehyd roepiand rosterone in healthy male volunteers. Clin Invest Med 2000; 23(5):300-310.
2
22
23
Davidson M, Marwah A, Sawchuk RJ, et al: Safety and pharmacokinetic study with escalating doses of 3acetyl-7-oxo-dehyd roepiand rosterone in healthy male volunteers. Clin Invest Med 2000; 23(5):300-310.
24
25
26
27
Wilson, Susan D., Non-Clinical Evaluation of GL701 [prasterone]: NDA 21-239 (April 19, 2001).
13 September 2012
Dr. Benson SILVERMAN, M.D.
Director – Infant Formula & Medical Foods (Dept DHK3)
CPK- 1 Bldg., Room 4C-095
5100 Paint Branch Road
College Park, MD 20740
benson.silverman@fda.hhs.gov
BY ELECTRONIC MAIL
Re:
Medical Food Package Insert Review
Dear Dr. Silverman,
Almost two years ago, you generously took your time to discuss with me the regulation
of medical foods. I’d like to ask you for some further guidance.
We’re readying the commercial launch of a new medical food. We’re simply taking a
product already freely on sale, and restricting it to prescription access to assure a physician stays
involved. We have several placebo-controlled, double-blinded randomized clinical studies
supporting efficacy. (These studies were done to support an NDA, but the Sponsor ran out of
money. We thus have perhaps the most thorough efficacy and toxicology package in the history
of medical foods.)
=> Might I ask you to look at our proposed package insert (enclosed) and let me know if
you would like any required changes?
I enclose a copy of our draft insert, together with copies of several of the supporting
clinical studies. If you like, I can also send pharmacology, toxicology, etc., but I sense the
enclosed information may be adequate for the current inquiry.
!"# $!%"! &' ' '
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13 September 2012
Page 2
Many thanks in advance for your help, and please let me know if you need anything
further!
Kind regards,
HEALTH SCIENCE FUNDING, LLC
/s/
Mark Pohl,
Tel. + 1 (973) 984-0076
Mark.Pohl@LicensingLaw.Net
Enclosures:
PRASTERA® package insert (13 Sept 2012 draft)
Chang et al. (2002)
Petri et al. (2002)
Petri et al. (2004)
5 November 2012
Re:
Dear Dr. Silverman,
Many thanks for your letter of Oct. 17th. From it, I understand that your office does not
generally do pre-marketing reviews, but in this case you have done me the courtesy of taking the
extra effort to review our proposed insert nonetheless. Many thanks for your help.
Might I ask for a bit more help? Your letter mentions “serious questions and concerns.”
Might I ask what those questions and concerns are? With that information, I can perhaps provide
acceptable answers and fixes for you.
Many thanks in advance for your help, and I look forward to hearing from you soon,
/s/
Mark Pohl,
Tel. + 1 (973) 984-0076
!"# $!%"! &' ' '
27 November 2012
Re:
Dear Dr. Silverman,
I trust this note finds you well. Having received no response to my letter of 05 November
(copy enclosed), I sense that you have thought through my proposed product and its
accompanying labeling, and now see how it all comports with the statute.
We're thus planning to launch commercially as soon as stability testing is complete.
Thus, with my apologies in advance for any inconvenience, if you have any lingering concerns,
objections or questions, you'll need to let me know exactly what they are (email is fine,
Mark.Pohl@LicensingLaw.Net) not later than close of business (Washington, D.C. time) on
Friday Dec. 7th, 2012. If I don’t hear from you by then, I’ll assume the agency has no
objections.
Many thanks in advance for your help, and I look forward to hearing from you soon,
/s/
Mark Pohl,
Tel. + 1 (973) 984-0076
!"# $!%"! & ' ' '
11 December 2012, 15:09
Ms. Shawne Sugs-Anderson from the FDA Medical Foods staff (202) 402-1459, calling in response to
a letter dated Nov. 27th that we just received about the ... intended launch of product that contains
DHEA.
We definitely have some concerns regarding the product.
Primarily, the assumption that because this product contains an ingredient that is commonly used as a
dietary supplement that somehow that automatically allows it to be used in medical food, and that
couldn't be farther from the truth.
The other issue is that we acknowledge that the ingredient proposed to be used on included in the
product could or may be effective in managing the symptoms of certain individuals with SLE, we are
not aware of any distinctive nutritional requirements that have been established by medical or scientific
evaluation for SLE.
Many products, naturally occurring as well as formulated, will provide benefits to individuals affected
affected by multiple diseases and conditions. However, efficacy alone does not qualify a product to be
marketed as a Medical Food.
First and foremost, the product must meet the burden of the statutory definition of medical food.
Based on the materials you provided, along with other publicly-accessible studies and resources,
this product does not appear to meet that standard.
So please by all means get back in touch with us.
Bye
!
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Warning Letter to Metagenics, Inc.
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Your Guide to Health-Related Legal Matters
Public Health Service
Food and Drug Administration
Los Angeles District
19701 Fairchild
Irvine, California 92612-2506
Telephone (949) 608-2900
CERTIFIED MAIL
Return Receipt Requested
October 1, 2003
WARNING LETTER
W/L 53-03
Jeffrey J. Katke, CEO
Metagenics, Inc.
100 Avenida La Pata
San Clemente, California 92673
Dear Mr. Katke:
Investigators from the U.S. Food and Drug Administration (FDA) performed an inspection of your
facility from May 6, 2003, to May 19,2003. During the inspection, the investigators collected labels
from your products UltraClear®, UltraMeal®, UltraInflamX™, and UltraGlycemX™. FDA reviewed
the labels for these products and found that the labels cause the products to violate the Federal Food,
Drug, and Cosmetic Act (the Act) in several respects.
The products are labeled as “medical foods,” and are represented on the labels as intended for use with
a variety of medical conditions. The products do not meet the definition of a medical food in 21 USC
360ee(b)(3), which defines a medical food as a food which is formulated to be consumed or
administered enterally under the supervision of a physician and which is intended for the specific
dietary management of a disease or condition for which distinctive nutritional requirements, based on
recognized scientific principles, are established by medical evaluation. The regulations further define a
medical food as one that is intended for the dietary management of a patient who has special medically
determined nutrient requirements, the dietary management of which cannot be achieved by the
modification of the diet alone [21 CFR 101.9(j)(8)(ii)]. Your products UltraClear®, UltraMeal®,
UltraInflamX™, and UltraGlycemX™ are not medical foods because the diseases and conditions
described in the product labels do not have distinct nutritional requirements and because the products
do not have any unique impact on the dietary management of those diseases and conditions beyond
that which could be achieved by modification of the normal diet alone.
5/21/2012 12:14 PM
2 of 3
Because UltraClear®, UltraMeal®, UltraInflamX™, and UltraGlycemX™ do not meet the definition
of a medical food, they are not subject to the exemption from nutrition labeling afforded medical
foods. Therefore, your products are misbranded within the meaning of Section 403(q)(1) of the Act
because the labels do not bear nutrition labeling in the appropriate format, as prescribed in 21 CFR
101.9. In addition, your products bear label claims suggesting that they are useful in the treatment of
various diseases. These claims include:
UltraClear’ is formulated to nutritionally support overall liver detoxification activity and the
removal of potentially harmful toxins associated with health conditions such as food allergies,
chronic fatigue syndrome, . . . and migraine headaches.
“UltraMeal® is . . .designed to nutritionally support the management of conditions associated
with altered body composition, including . . . hypertension . . . .”
“UltraInflamX™ NUTRITIONAL SUPPORT FOR INFLAMMATION” and “UltraInflamX™ is
designed to nutritionally support patients with chronic inflammatory conditions, such as
osteoarthritis, rheumatoid arthritis, psoriasis and eczema, as well as other conditions associated
with excessive inflammation.”
“Designed to provide nutritional support for those with insulin resistance, or type 2 diabetes,
UItraGIycemX™ promotes a healthy insulin and glucose response.”
The presence of the above referenced claims indicates that the products are intended to treat, cure, or
mitigate diseases. Such claims are evidence that the products are intended for use as drugs within the
meaning of Section 201(g)(1)(B) of the Act. The products are new drugs under section 201(p) of the
Act because there is no evidence that these products are generally recognized as safe and effective for
their intended uses.
Therefore, they may not be legally marketed in the United States without approved New Drug
Applications (Section 505 of the Act). These products are also misbranded within the meaning of
Section 502(f)(1) of the Act because the labeling fails to bear adequate directions for use. The above
violations are not meant to be an all-inclusive list of deficiencies in your products and their labeling. It
is your responsibility to ensure that products marketed by your firm comply with the Act and its
implementing regulations.
The Act authorizes the seizure of illegal products and injunctions against manufacturers and
distributors of those products. You should take prompt action to correct these deviations and prevent
their future recurrence. Failure to do so may result in enforcement action without further notice.
Please advise this office, in writing, within fifteen (15) working days of the receipt of this letter, as to
the specific steps you have taken to correct the violations noted above and to assure that similar
violations do not occur. If corrective actions cannot be completed within fifteen working days, state
the reason for the delay and the time within which the corrections will be completed.
Your response should be directed to Mr. Larry Stevens, Compliance Officer, U.S. Food and Drug
Administration, 19900 MacArthur Blvd., Suite 300, Irvine, CA 92612.
Sincerely,
/s/
Alonza E. Cruse
Director, Los Angeles District
5/21/2012 12:14 PM
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5/21/2012 12:14 PM
MEMORANDUM
DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
DATE:
February 20, 2001
FROM:
Parivash Nourjah, Ph.D. Signed 02-26-01
Division of Postmarketing Drug Risk Assessment I, HFD-430
THROUGH:
Julie Beitz, M.D.
Signed 02-21-01
Director, Division of Postmarketing Drug Risk Assessment I
HFD-430
TO:
Kent Johnson, M.D.
Division of Anti-Inflammatory, Analgesic, and
Ophthalmologic Drug Products
HFD-550
SUBJECT:
Epidemiologic evidence of DHEA in the etiology of neoplasia
PID#: D000665
SUMMARY
We are not aware of any published epidemiologic studies that examine the cancer risk associated with
exogenous dehydroepiandrosterone (DHEA) administration. However, one case-report was found to
describe the medical condition of a patient with advanced prostate cancer after receiving DHEA. The
cancer condition worsened after receiving DHEA, but when the patient stopped taking DHEA, the
cancer regressed. Since the discontinuation of DHEA was accompanied by the initiation of estrogen
therapy, the association of exogenous use of DHEA with the cancer progression is unclear.
In general the epidemiologic studies reviewed in this report have many limitations. Temporal precedence
bias, small size, inability to control for confounding variables, and the method of DHEA measurement
1
are among the most common limitations of studies reviewed in this report. No meaningful conclusion
about the association of exogenously administered DHEA and cancer risk can be made based on these
epidemiologic studies of endogenous levels of DHEA.
INTRODUCTION
This consult follows Dr. Brinker’s comprehensive report on the relationship of endogenous sex
hormones and etiology of cancer dated January 4, 2000. The purpose of this consult is to review the
literature again to identify any reports on exogenous use of DHEA and cancer risk.
In general, the epidemiological data addressing the association of endogeneous DHEA with cancer are
very limited and the results are conflicting. The studies varied in study design and size, method of
DHEA assessment, stage of cancer and ability to control for confounding variables. The study designs
are either prevalence case-control or nested case-control studies. In general, the temporal association
between DHEA levels and cancer cannot be established in prevalence case-control studies. In these
studies, one cannot determine whether the change in DHEA level is caused by the cancer or whether
any change in DHEA level is a predisposing factor for cancer. The size of the studies is often very
small,so that, adjustment for confounding variables (even if they were collected) is not possible. In most
studies reviewed, some of the important confounding variables were controlled by conducting a
matched design followed by matched analysis.
In recent years, DHEA can be found at local health food stores, supermarkets, pharmacies, and Web
pages from many companies, and is advertised as an antiaging agent. Therefore, any recent study of
DHEA and cancer should consider both the use of DHEA as a dietory supplement and the level of
endogenous DHEA. None of the recent studies ascertained any information on the exogenous use of
DHEA. The method of measuring DHEA is also crucial and often is far from perfect in these studies.
DHEA levels in serum change by diurnal and menstrual cycles. Thus any studies which examine DHEA
should consider these cyclic sources of variability in their design.
2
We found one case-report study from the literature in which the author suggested that the administration
of DHEA to patients with prostate cancer should be done with caution.
METHOD
We conducted a literature search by using the National Library of Medicine’s PubMed search engine to
identify epidemiological studies. We used neoplasia and DHEA to identify the studies. For the purpose
of this report, we selected those studies which were not reported by Dr. Brinker previously.
STUDY SUMMARIES
Prostate Cancer:
Stahl et al (1992) conducted a prevalence case-control study to compare the DHEA levels in 19
prostate cancer patients with the DHEA levels in 23 age-matched controls. The DHEA level was
assayed by RIA kits. They found that the levels of both DHEA and DHEAS (DHEA-sulfate) were
significantly lower in prostate cancer patients than the control group. This study lacked any information
on the quality of DHEA samples.
Comstock et al (1993) conducted a nested case-control study within a cohort of volunteers who
participated in a [
] Blood Bank study. From August to November 1974, 25,620 volunteers
donated blood to study serum factor precursors of cancer. Comstock et al compared the
DHEA/DHEAS level of 81 prostate cancer patients with 81 age-sex-race matched controls. All the
cancer patients were diagnosed for the first time between 1974 and 1987. All blood specimens were
frozen after donation and rethawed before reading. The serum samples of cases and their controls were
assayed on the same day. DHEA/DHEAS levels were assayed by using radioimmunoassay (RIA) kits
from Wein Laboratory. Although not statistically significant, this study showed that both DHEA and
DHEAS levels were lower in prostate cancer patients than their control group. The authors noted no
dose-response association with either DHEA or DHEAS. One potential limitation of this study is
3
temporal precedence bias. The possibility of this bias cannot be ruled out, since the latency of prostate
cancer is long and the cancer patients could have had cancer at the time of blood donation.
Jones et al (1997) published a case report in which a patient with advanced prostate cancer was treated
with DHEA. The administration of DHEA flared up his cancer while it reduced some of his symptoms.
Upon the discontinuation of DHEA, the size and firmness of the prostate diminished, and the level of
prostate-specific antigen (PSA) and testosterone decreased. Since the discontinuation of DHEA was
followed by the initiation of estrogen therapy, it is not clear whether the improvement of his cancer was
due to estrogen therapy or due to the discontinuation of DHEA. It is noteworthy that the patient was
previously unresponsive to hormonal therapy, and whether the DHEA treatment had any impact on his
conversion to being responsive to estrogen therapy is an interesting question.
Ovarian cancer
Helzlsouer et al (1995) conducted a nested case-control study within the [
] blood blank study.
They identified 31 newly diagnosed ovarian cancers between 1975 and 1989. For these cases, 62
controls were matched on age, menopausal status, and for premenopausal women, the number of days
from the beginning of the last menstrual period. Serum samples were frozen at –70° C after donation
and thawed right before preparing the aliquots for this study. The DHEA/DHEAS levels were assayed
by using RIA kits and performed for each case and matched control set at the same day. The
investigators showed that the levels of DHEA/DHEAS in serum were much higher in cases than
controls. There could have been a temporal precedence bias in this study since the cases were identified
within a year of blood donation. Whether some women had cancer at the time of blood donation is
unknown. Weight, a known risk factor for ovarian cancer, was not collected, so the study could not
control for its effect.
Breast cancer:
Zumoff et al (1981) conducted a prevalence case-control study, in which the 24-hr mean levels of
4
serum dehydroisoandrosterone (DHA) level and dehydroisoandrosterone sulfate (DHAS) of 11 women
with primary operable breast cancer were compared with 37 healthy women. The DHA level was
assayed by the radioimmunoassay technique as described by Rosenfeld and the DHAS was assayed by
radioimmnoassay as described by Nieschlag. The study showed that postmenopausal breast cancer
patients had higher DHA and DHAS plasma levels than the healthy women, while the premenopausal
breast cancer patients had lowered DHA and DHAS than controls.
Solid tumors:
Lissoni et al(1998) conducted a prevalence case-control study to examine the association of DHEAS
with stage of cancer. The study consisted of 70 patients with solid tumors and 100 age-sex-matched
healthy controls. The histologic types of cancer were: gastrointestinal tract tumors:28; breast cancer: 24;
non-small cell lung cancer: 18. There were 28 patients without and 42 patients with distant metastases.
Blood sera were collected in the morning after an overnight fast, and DHEAS was assayed by RIA
method using commercially available kits. The result of this study showed that irrespective of tumor
histologic types, the serum level of DHEAS was similar between early cancer patients and the control
group. Advanced cancer patients had much lower DHEAS levels than controls.
DISCUSSION
DHEA and DHEA-Sulfate are major adrenal secretory products in humans. They possess androgenic
activity as they are metabolized to steroids such as testosterone. Thus, the association of testosterone
and estrogen on the risk of breast cancer and prostate cancer can shed some light on the association of
DHEA and neoplasia. While the evidence for an association between testosterone and the risk of
prostate cancer is still conflicting, there is substantial evidence of an association between estrogen and
breast cancer.
There are epidemiologoic studies which directly examined the association between endogenous DHEA
and cancer risk; however, the epidemiologic evidence for an association is not consistent. For prostate
5
cancer, two epidemiologic studies [Stahl (1992) and Comstock (1993)] showed that cancer patients
had lower DHEA levels than their non-cancer counterparts. Based on these studies, one might expect
that DHEA therapy may improve the prostate cancer, however, the result from the case-report
[Jones(1997)] suggests that the use of exogenous DHEA may worsen prostate cancer.
For ovarian cancer, compared to prostate cancer, a different result is suggested for the association of
endogenous DHEA and cancer risk. The serum DHEA level was found to be higher in ovarian cancer
patients than the control counterparts [Helzlsouer (1995)]. The association of DHEA and breast cancer
could be different in pre- and post-menopausal women. In postmenopausal women, a positive
association between DHEA level and breast cancer was reported by Cauley(1999) and Zumoff (1998)
studies. The latter study showed that in premenopausal women, the level of endogenous DHEA was
lower in breast cancer patients than the healthy controls.
In general the epidemiologic studies reviewed in this report have many limitations. Temporal precedence
bias, small size, inability to control for confounding variables, and the method of DHEA measurement
are among the most common limitations of studies reviewed in this report. No meaningful conclusion
about the association of exogenously administered DHEA and cancer risk can be made based on these
epidemiologic studies of endogenous levels of DHEA.
____Signed by__________
Parivash Nourjah, Ph.D.
Epidemiologist
__Signed by_______
Anne Trontell, M.D.
Deputy Director
6
REFERECES
Cauley JA, Lucas FL, Kuller LH, et al: Elevated serum estradiol and testosterone concentrations are
associated with a high risk for breast cancer. Study of Osteoporotic fractures Reseach Group. Ann
Intern Med 1999;130:270-7.
Comstock G.W., Gordon G.B., and Ann w Hsing: The relationship of serum dehydroepiandrosterone
and its sulfate to subsequent cancer of the prostate: cancer epidemiology, Biomarkers and prevention
1993 Vol 2, 219-221
Lissoni P, Rovelli F, Giani L, Mandala M, Meregalli S, Barni S, Confalonieri G, Bonfanti A.
Dehydroepiandrosterone sulfate (DHEAS) secretion in early and advanced solid neoplasm: Selective
deficiency in metastatic disease. Int J Biol Markers 1998; 13:154-157.
Helzisourer K.J., Alberg A.J., Gordon G.B., Longcope C., Bush T.L, Hoffman S.C., Comstock G.W.:
Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;
274:1926-1930.
Jones J.A., Nguyen A., Straub M, Leidich R, Veech R.L., and Wolf S.: Use of DHEA in patient with
advanced prostate cancer: a case report and review. Urology 1997 50:784-788.
Schatzl G, Reiter WJ, Thurridl T, Waldmuller J, Roden M., Soregi S, and Madersbacher S.: Endocrine
patterns in patients with benign and malignant prostatic diseases. Prostate 2000 44:219-224
Stahl F., Schnorr D, Pitz C., and Dorner G: Dehydroepiandrosterone (DHEA) levels in patients with
prostatic cancer, heart disease and under surgery stress. Exp Clin Endocrinol 1992, Vol 99, 68-70.
Zumoff, b., Levin, J., Rosenfeld R.S., Markham, M. Strain, G. W. and Fukushima, D.K. Abnormal 24hr mean plasma concentrations of DHEA and DHEA-sulfate in women with primary operable breast
cancer. Cancer Res. 41:3360-3363, 1981
7

Natrol DHEA 25mg, 180 Tablets (Pack of 2)

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