Hormones and the fountain of youth

Promoting the Fountain of
Youth: Low-T and Estrogen
Deficiency
Adriane Fugh-Berman MD
Georgetown University Medical Center
ajf29@georgetown.edu
Hormone Therapy in Women
•  Animal glandulars became popular in the 1890s
•  First recorded menopausal HT
–  Administration of cow ovaries to a young
oophorectomized woman in Berlin circa 1900
•  In the U. S.
–  Fresh, ground ovaries first used in 1910
–  Later, desiccated and then extracted preparations
were used
The Estrogen Era
•  1920s: Estrone (theelin)
isolated from pregnant women
•  1928: Progynon (from human
placenta)
•  1933: Progynova (estradiol)
•  1938: Ethinyl estradiol
•  1942: Premarin (conjugated
equine estrogens)
1945
1947
1957
1957
1959
“Difficult family situations
can often be wholly
remedied by estrogen
therapy for the woman
involved.”
Wilson, Feminine Forever, 1966
JAMA
1968;206(9):2150
JAMA July 1,
205(1):8
1968;
“Expand Menopause”
•  2002: $5.5 million was budgeted in the United
States to expand the definition of menopause.
–  $3.7 million was devoted to developing “long-term
benefits.”
•  Wyeth aimed to convince physicians and
consumers that “estrogen deficiency” not only
caused unattractiveness and ill-health, but also
an early death.
Persuading Women
•  Wyeth coached physicians on how to “Present
the benefits of HRT ‘from top to bottom, brain
to bladder.’...HRT offers multiple benefits for
now and a better future”
•  Physicians were encouraged to provide
“Personal anecdotes: Mother, wife’s
experience of menopause/HRT; What I would/
did do; Coaxing: only need to make a
temporary commitment...”
1998
HERS: Second CHD Events
70
Placebo
HRT
60
Number of 50
Second
CHD Events
40
Year
RR
95% CI
1
2
3
4+5
1.52
1.00
0.87
0.67
1.01-2.29
0.67-1.49
0.55-1.37
0.43-1.04
30
20
1
*P=.009 for trend-time analysis.
2
Year
3
4+5
*
•  Wyeth’s “physician awareness and use
study” found
“— Among physicians aware of HERS data,
half (51%) recall benefits of HRT, particularly
cardiovascular benefits (40%) as main
conclusion of the information, while onequarter (25%) came away with negative
impressions about cardiovascular risk
associated with HRT...”
•  Even for women at high risk for
cardiovascular disease, only a minority
(13%) of physicians said they planned
to decrease their prescribing of Prempro
•  More than two-thirds (69%) said the
HERS study will have no impact on use
of Prempro for women at high risk for
cardiovascular disease.
Doubt is Our Product
Even physicians who understood that
HERS showed that hormone therapy
did not benefit women with heart
disease still believed that
hormone therapy could
benefit healthy women.
The Women’s Health Initiative
2002:
Estrogen-progestin arm of the WHI
halted because the treated group
experienced higher rates of breast
cancer, CVD, and overall harm
(WGWHI 2002)
The Women’s Health Initiative
2004:
Estrogen-only arm halted because
of increased stroke risk in the
treated group, and because estrogen
failed to show any cardiovascular
benefit
The Women’s Health Initiative
2004:
E/P is shown to double the risk of
VTE (Cushman 2004) and
dementia (Shumaker 2004)
The Fountain of Youth for
Men: Testicular Extracts
1889:
• Charles Édouard BrownSéquard, age 72, announced
to the Société de Biologie
that he had reversed his
physical decline by injecting
an extract of dog and guinea
pig testicles
Surgical Rejuvenation
•  Eugen Steinach, a Viennese surgeon,
was famous for his vasectomies
•  Serge Voronoff, in Paris, transplanted
sliced ape testicles into human scrota
•  L.L. Stanley transplanted the testicles of
executed prisoners at San Quentin
Penitentiary
Testosterone & Male Menopause
•  1935: Testosterone synthesized
•  1939: Male menopause diagnosed
•  1942: “The male climacteric presents
one of the complex problems of
aging. ..Its symptomology is uninvolved,
tremendously varied, and rarely brought
to the attention of the physician in all its
diversity”
Hoberman, Testosterone Dreams, 2005
Condition Branding: Low-T
Provenance of the Low-T Quiz
•  Developed by Dr. Morley for Organon BioSciences, the Androgen Deficiency in Aging Males (ADAM) test was later rebranded as the ‘Is It Low T?’ Quiz •  “Dr. Morley recalls that he draJed the quesLonnaire in 20 minutes in the bathroom, scribbling the quesLons on toilet paper and giving them to his secretary the next day to type up.” •  “I have no trouble calling it a crappy quesLonnaire,” he says. (Singer N, NYT 11/23/13) Testosterone and CVD Risk
•  The only placebo-controlled trial of
testosterone therapy that specifically
examined cardiovascular disease and
mortality endpoints, a study of 209 men
over the age of 65 with low
testosterone, was stopped early
because of an increased risk of
cardiovascular events.
(Basaria 2010)
CVD Risks: Meta-Analysis
•  A meta-analysis of 2,994 men in 27
trials identified 180 heart attacks
and other cardiovascular-related
event; testosterone therapy
significantly increased the risk of
cardiovascular events (odds ratio
1.54).
•  Trials funded by the pharmaceutical
industry found no increased risk,
while studies not funded by the
pharmaceutical industry found that
treatment doubled risk (OR 2.06).
Treatment of Men for “Low
Testosterone”: A Systematic Review
•  Databases were searched between 1950
and 2013
•  217 randomized, placebo-controlled studies
of testosterone for cardiovascular benefit,
sexual function, mood and behavior, or
cognition in men were identified
–  studies involving body building or contraceptive
effectiveness were excluded
(Huo S, Scialli AR, McGarvey S, Hill E, Tügertimur B, Fugh-Berman A, in submission)
Testosterone and CVD
•  Evidence supporting the use of testosterone for
preventing or treating cardiovascular disease is
inconsistent and unconvincing.
•  Studies are mixed on angina (2/4 showed no
effect)
•  Three studies from the same group found a
benefit for symptoms associated with congestive
heart failure.
•  One study was stopped early for adverse
cardiovascular events.
Testosterone & Sexual Function
•  23/41 studies that assessed sexual
function as a primary or secondary
endpoint found no testosteroneassociated improvements in any sexual
function end point.
•  Sixteen studies reported beneficial
effects of testosterone treatment for at
least one measure of sexual function or
satisfaction; 2 studies were mixed.
Testosterone &
Erectile Dysfunction
•  Two-thirds (20/32) of the studies that
evaluated erectile function or sexual
function showed no improvement with
testosterone
•  8/10 studies of men with erectile
dysfunction found no benefit of
testosterone over placebo
•  11/21 studies that reported changes in
libido found no effect
Testosterone, Muscle & Mood
•  Testosterone supplementation
consistently increased muscle
strength but did not have beneficial
effects on physical function.
•  Most studies on mood-related end
points found no beneficial effect of
testosterone treatment on
personality, psychological wellbeing, or mood.
Conclusions
•  Estrogen and testosterone have both
been promoted as anti-aging therapies
and as disease preventives.
•  Both have been promoted for CVD
prevention.
•  Both have been linked with an increase
in cardiovascular events and other
serious adverse events
•  The Fountain of Youth remains elusive