065IC Testosterone - American Urological Association

Transcription

065IC
Testosterone: Diagnosis and
Management of the Hypogonadal
Male
Monday, May 19, 2014
1:00 PM – 3:00 PM
Faculty
Wayne J.G. Hellstrom, MD - Course Director
Andre T. Guay, MD
Mohit Khera, MD, MBA, MPH
3/4/2014
AUA 2014: Orlando, FLA
Welcome, Agenda & Cases
Testosterone: Diagnosis and Management
of the Hypogonadal Male: 2014 Update
Wayne JG Hellstrom, MD,
FACS
Professor of Urology;
Chief, Section of Andrology
Department of Urology
Tulane University School of
Medicine
New Orleans, Louisiana
André Guay MD, FACP,
FACE
Director, Center For Sexual
Function & Endocrinology
Lahey Clinic Northshore
Peabody, MA
Tufts Univ School of Medicine
Boston, MA
Wayne JG Hellstrom, MD, FACS
Professor of Urology; Chief, Section of Andrology
Tulane University School of Medicine
Mohit Khera, MD, MBA,
MPH
Assistant Professor of Urology
Division of Male Reproductive
Medicine and Surgery
Scott Department of Urology
Baylor College of Medicine,
Houston TX
Learning Objectives:
Testosterone: Diagnosis and Management of the
Hypogonadal Male: 2014 Update
At the conclusion of this educational activity, participants should be able to:
•
•
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•
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•
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Introduction/Course Aims/Housekeeping (WJGH- 5 mins)
Background: definition, physiology, prevalence (WJGH -10 mins)
Diagnosis (history, physical, laboratory) (WJGH- 10 mins)
Cardiovascular issues, metabolic syndrome & recent public
controversies on androgen replacement therapies (AG- 25 mins)
Prostate Cancer and androgens (MK – 15 mins)
Replacement Therapies (MK- 15 mins)
Alternate Therapies (AG- 10 mins)
Follow-Up Guidelines (WJGH - 5 mins)
Additional Cases ( panel -10 mins)
Audience Questions and Panel Answers (10 mins)
Recognize the clinical presentation and standard diagnostic methods used for identifying male
hypogonadism /testosterone deficiency syndrome (TDS)
•
• Fully comprehend the cardiovascular implications of recently published papers questioning the
benefits of male hormone replacement therapy and the relationship of the metabolic syndrome to
testosterone deficiency syndrome (TDS)
• Understand the scientific basis for androgen replacement therapy
• Appraise the controversy regarding testosterone supplementation & prostate cancer
• Gain knowledge about the short and long-acting testosterone products currently available in
current clinical practice and become aware about alternate therapies
•Devise a cost-effective treatment and follow-up algorithm for the hypogonadal male
1
3/4/2014
Case 1
43 year old nurse anesthetist (5’ 7”, 200 lbs.)
CC: ED for 6 months
Avoided his wife because “fear of failure,” etc.
Saw PCP who prescribed PDE5i, which worked
Over time, lost desire to have sex, became
disinterested in wife and family
• Wife sent him back to PCP
•
•
•
•
•
Case 1 Cont’d…
• PCP prescribed SSRI and ED became worse
• At follow-up changed to Cymbalta®, which helped
sexual problems somewhat
• Curbside consult – check serum testosterone
• Total testosterone = 200 ng/ml
• Placed on testosterone 200 mg IM q2 wks x 6 mos
• Life returned completely back to normal – off
everything, except for a daily testosterone gel
ARS Question Case 1
• 43 yr old, heavy set male with new onset ED
– What work-up do you institute at initial visit?
1.None, start trial PDE5i & determine at F/U
2.Total testosterone & PSA
3.Full testosterone panel (total, free, & SHBG)
4.BMP, CBC, testosterone & lipid panels, PSA,
prolactin
5.If family history of cardiac disease, refer him to
cardiologist
Case #2
• 41 year old athletic male; always thin & unable to put on
muscle mass despite intensive weight training
• Had Lasik surgery nine years earlier (retrospectively, had
recently noted progressive near sightedness)
• Adopted; PSA (0.6) and total testosterone (223 ng/ml)
• Had a previous vasectomy & planning remarriage and
future children (MESA/cryopreservation procedure)
• Clomid 50 mg q o d x 1 year (total test ≈ 800 ng/ml)
• Excellent response with energy, sex, & vision improved
2
3/4/2014
Case 2 Cont’d …
• Underwent MESA/cryopreservation of gametes
• Switched to Testopel® option, but didn’t F/U
• 6 months later noted a decrease in energy, no
change in sexual activity or erections, but
progressive return of near sightedness
• Total testosterone ≈ 190 ng/ml
• Underwent Testopel® retreatment with
expected results in energy return
• Within 2 weeks of Rx vision improved
(effect on eye muscles?)
Sales in millions of dollars
Testosterone Prescription Sales
Background Facts
U.S. annual testosterone sales approaching $1 Billion
(Year over year growth in %)
500
450
900
400
800
350
20%
20%
700
300
250
200
14%
600
500
150
100
16%
Androgel®
Launch
400
0
oral (methylated-T)
injectable
patch/buccal
25%
gel
87%
300
50
8%
32%
total
200
1988 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Year
Source: IMS Sales Data, BMC Corp.
Courtesy: Reed Selby, ALZA Corporation; Michael Bailey, SmithKline Beecham; Kevin Rose, Solvay-Unimed
100
0
2000
2001
2002
2003
2004
2005
2006
2007
2008
Source: IMS
3
3/4/2014
Testosterone Quarterly Market Growth* – TRx
Volume
Wolters Kluwer PHAST Data – Sept 2012
* -- Market growth data do not include Testopel
The Equalizer: Age
13
Life Expectancy of Men & Women
Influence of Age on Free Testosterone
85
80
75
70
Women
Men
65
Life
Expectancy 60
(Years)
55
50
45
40
1900
1920
1940
1960
1980
2000
Year of Birth
Statistisches Jahrbuch. 1998
Vermeulen, 1993
4
3/4/2014
Prevalence and
Treatment of Hypogonadism
Definition of Hypogonadism
• A reduction in testosterone production
4 to 5 Million Men with Hypogonadism
• Primary: testicular failure
• Secondary: hypothalamic or pituitary
dysfunction
• Combined: decreased pulsatility of
gonadotropins plus decreased Leydig cell
response
• Congenital or acquired
• May be multifactorial: aging, chronic
disease, unhealthy behavioral habits,
and side effects from medications
US Food and Drug Administration Updates. December 10, 1999.
Incidence of Hypogonadism
in Men Increases With Age
30
Proportion of
Patients (%)
25
20
15
10
5
0
(n=279)
40-49
(n=332)
(n=350)
(n=251)
50-59
60-69
70-79
Age Range
(Years)
Harman SM et al. J Clin Endocrinol Metab. 2001;86:724-731.
5
3/4/2014
Higher Incidence of Hypogonadism
in Men with Concomitant Conditions
Effects of Aging
• Decline in testosterone production
– Decreased testosterone levels
• Long-term complications due to
low testosterone levels
–
–
–
–
–
Increased body fat mass
Decreased muscle mass
Decreased bone mass
Increased incidence of osteoporosis, osteopenia. & fracture
Decline in libido, erectile function
•
Diabetes
•
Glucocorticoid or neuroleptic use
•
Chronic obstructive pulmonary disease
•
AIDS
•
Chronic renal failure
•
Rheumatoid arthritis
• Alcohol abuse
•
Chronic liver disease
•
Testicular irradiation or cancer chemotherapy
Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.
Sources: Kaufman JM, Vermeulen A. Ballière’s Clin Endocrinol Metab. 1997;11:289-309; Tenover
JL. Endocrinol Metab Clin North Am. 1998;27:969-987.
The Influence of Testosterone
Hair growth,
balding, sebum
production
Liver
Synthesis of serum
proteins
Bone
Accelerated linear
growth, closure of
epiphyses
Male sexual organs
Penile growth,
spermatogenesis,
prostate growth and
function
Brain
Libido, Mood, ? Cognition
Muscle
Increase in strength
and volume
Kidney
Stimulation of
erythropoietin
production
Bone marrow
Stimulation of stem
cells
Morley JE, et al. Metab. 2000;49: 1239-2.
AACE Hypogonadism Task Force Endocrine Pract.
2002;8:439-456
Total Testosterone (ng/dL)
Skin
Variations in Total Testosterone
Levels Over Life Cycle
600
400
200
100
0
Fetal
Neo- Pre- Pubertal
Natal Pubertal
Adult
Senescence
Schlegel PN, Hardy M. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed.
Philadelphia, Pa: W.B. Saunders; 2002:1437-1456.
6
3/4/2014
Normal Testosterone Secretion
• 3 to 10 mg/day
• Serum concentration ~ 300 to 1,000 ng/dL
• Diurnal variation – peak in AM, trough in PM
Recognized Effects of Testosterone
Replacement in Hypogonadal Men
Signs and Symptoms
of Male Hypogonadism
• Impotence / ED
• Enhances libido, including sexual thoughts
and perceived arousal
• Leads to increased frequency of sexual acts
• Increases frequency of sleep-related erections,
but no effect on fantasy or visually induced
erections
• Decreased sexual desire (libido)
• Fatigue
• Loss of energy
• Mood depression
• Impairment of cognition
• Regression of secondary sex characteristics
• Osteoporosis, osteopenia, and fractures
Nolten WE. Curr Urol Rep. 2000;1:313-319.
7
3/4/2014
Diagnosis of Hypogonadism
(History, Physical, Laboratory)
Male Hypogonadism
• Definition
– Failure of the testes to produce sufficient
testosterone
• Causes
Secondary –
Primary –
hypothalamic/pituitary
abnormalities
testicular failure
30
Primary Low Testosterone:
Testicular Failure
• Aging
– Obesity
– Severe systemic illness
– Medications
• Anorchia
• Cryptorchidism
• Genetic disorders
•
•
•
•
•
•
Idiopathic
Malnutrition
Neurodegenerative illnesses
Respiratory disorders
Trauma
Viral orchitis
– Klinefelter’s syndrome
Winters SJ. Arch Fam Med. 1999;8:257-263.
Secondary Low Testosterone:
Pituitary or Hypothalamic Disruption
• Chronic diseases (eg, cirrhosis)
• Feedback inhibition due to rising estrogen levels
Alcohol abuse
Anabolic steroid use or abuse
Drug-induced alteration of metabolic clearance
Obesity
Hormonal deficiency (eg, hypothyroidism,hyperprolactinemia)
–
–
–
–
•
• Iatrogenic (medications)
• Inflammatory diseases (eg, Crohn’s disease, arthritis)
• Genetic disorders (eg, Prader-Willi, Kallmann syndromes)
Boyadjiev NP, et al. J Sports Med Phys Fitness. 2000;40:271-274. Gordon GG, et al. J Clin Endocrinol Metab. 1975;40:1018-1026.
MacKelvie KJ, et al. Br J Sports Med. 2000;34:273-278. Straub RH, et al. J Rheumatol. 2000;59:108-118. Tenover JL. Endocrinol Metab
Clin North Am. 1998;27:969-987. Winters SJ. Arch Fam Med. 1999;8:257-263.
8
3/4/2014
Hypothalamic-Pituitary-Testicular Axis
in Aging Males
 Altered hypothalamic secretion of GnRH
 Altered signal to pituitary to release LH
 Altered signal to testes
 Low testosterone levels
Drugs Associated With Low Testosterone
• Antiarrhythmics
(eg, amiodarone)
• Anticonvulsants
(eg, phenytoin)
• Antifungals
(eg, ketoconazole)
• Chemotherapeutic agents
• Estrogens, progestins
• GnRH agonists,
antagonists
• Opiates
• Phenothiazine
antipsychotics
• Progestins
• Statins (high doses)
• Steroids
(eg, glucocorticoids,
spironolactone)
• Thiazide diuretics
• Ulcer drugs
(eg, cimetidine)
GnRH=Gonadotropin-Releasing Hormone, LH=Luteinizing Hormone.
1. Morley JE. J Gend Specif Med. 2001;4:49-53.
2. Tenover JL. Int J Androl. 1999;22:300-306.
3. Matsumoto AM, J. Gerontol: Med. Sciences. 2002;57A(2):M76-M99.
Dobs AS, et al. Metab. 2000;49:1234-1238. The Endocrine Society. Summary from the Second Annual Andropause Consensus
Meeting; April 20-22, 2001; Beverly Hills, Ca. Perry HM 3rd, et al. J Am Geriatr Soc. 1993;41:818-822. Rinieris P, et al. Eur Arch
Psychiatry Neurol Sci. 1988;237:189-193. Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.
Signs and Symptoms of Low Testosterone in
Adult Males
•
•
•
•
•
•
•
•
•
•
•
Loss of libido
Erectile dysfunction (ED)
Progressive decrease in muscle mass
Lethargy
Depression
Osteoporosis
Occasional menopausal-type hot flashes
(with acute onset of low testosterone)
Oligospermia or azoospermia
Decrease in cognitive abilities
Regression of secondary sexual characteristics
Total testosterone levels < 300 ng/dL
Braunstein JD. Testes. In: Greenspan FS, Strewler GJ, eds. Basic & Clinical Endocrinology.
5th ed. Stamford, Conn: Appleton & Lange; 1997:403-433. Petak SM, et al, for the AACE Hypogonadism Task Force.
Endocr Pract. 2002;8:439-456. Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.
Diagnosing Low Testosterone:
Physical Examination




Stature
Body hair (amount and distribution)
Presence of gynecomastia, galactorrhea
Penis stretched (length and width)
– Prepubertal: 4 to 8 cm  < 2 cm (flaccid)
– Adult: 10 to 17 cm  > 3 cm (flaccid)
 Scrotum
 Testes (length and width), consistency
– Prepubertal: 3 to 4 mL volume, < 2 cm long
– Peripubertal: 4 to 15 mL volume, > 2 cm long
– Adult: 20 to 30 mL volume, 4.5 to 6.5 cm  2.8 to 3.3 cm
 Prostate
Petak SM, et al, for the AACE Hypogonadism Task Force. Endocr Pract. 2002;8:439-456.
9
3/4/2014
Serum Testosterone Levels
in Typical Males
Diagnostic Testosterone Testing
• Serum Total Testosterone (free plus protein-bound)
Morning sample recommended
•
Total Testosterone Normal Range
<300 ng/dL (10.4 nmol/L) suggests hypogonadism*
• Serum Free Testosterone (non protein-bound)
Recommended in older patients
•
<50 pg/mL (173 pmol/L) suggests hypogonadism*
• Serum Bioavailable (weakly bound) Testosterone
 300 ng/dL to 1000 ng/dL
Release of testosterone is pulsatile and
exhibits diurnal variation
Measures albumin-bound and free testosterone
•
<70 ng/dL suggests hypogonadism*
*Range varies by laboratory.
1.
Braunstein GD. In: Basic & Clinical Endocrinology . 5th ed. Stamford, Conn: Appleton & Lange; 1997:403-433.
Mean Curves and Range of
Circadian Patterns in Healthy Young Men
Testosterone
42
800
35
800
28
600
21
400
14
200
7
0
4.0
8.0
12.0
16.0
Time (hours)
20.0
nmol/L
ng/dL
1000
0.0
10 PM
Diurnal Variation in Serum Total
Testosterone Levels
0
24.0
10 PM
Typical circadian rhythm patterns of testosterone in healthy young men. Symbols correspond to mean curves reported in different
studies (N=46).
Bremner WJ, et al. J Clin Endocrinol Metab. 1983;56:1278-1281. Mazer NA, et al. In: Pulsatile Drug Delivery: Current Applications and Future Trends. Stuttgart,
Germany: 1993:73-97. Winters SJ. Arch Fam Med. 1999;8:257-263. Copyrighted 1999. American Medical Association.
Total Testosterone (ng/dL)
1200
Full Prescribing Information,Testim® 1% (testosterone gel) CIII
2. Morales A et al. Aging Male. 2001:4:151-162.
700
Young Men
600
500
Old Men
400
0800
1200
1600
2000
2400
0400
0800
Clock Time (Hours)
Bremner WJ et al. J Clin Endocrinol Metab. 1983;56:1278-1281.
10
3/4/2014
Diagnosing Low Testosterone:
Initial Laboratory Tests
Testosterone in Normal Males
• Plasma total testosterone test
– Measures free plus protein-bound fractions
– Morning sample recommended
– < 300 ng/dL suggests low testosterone*
• Plasma free testosterone test
–
–
–
–
Measures non-protein–bound testosterone fractions
Measures bioavailable testosterone
Recommended in older patients & in special conditions
< 50 pg/mL suggests low testosterone*
2% free testosterone (unbound)
30% tightly bound to SHBG
2% free testosterone
(unbound) and 68%
loosely bound to
albumin constitute the
70% of bioavailable
testosterone
Plasma Binding Proteins and Concept of Free
and Bioavailable Testosterone
Unbound or Free
0.5 – 3.0%
Albuminbound
50-68%
SHBGbound
30-45%
MEN
Bioavailable
Testosterone
1.
SHBGbound
70%
AACE Hypogonadism Task Force. Endocri Pract. 2002;8:439-456.
2. Winters SJ et al. Clin Chem. 1998;44:2178-2182.
Testosterone Deficiency in Aging Males
•
Albuminbound
25%
68% loosely bound to albumin
Serum levels of SHBG
increase with age
•
SHBG tightly binds
testosterone
•
Results in decreased
levels of bioavailable
testosterone
90
80
70
SHBG (nmol/L)
*Range varies by laboratory.
Braunstein JD. Testes. In: Greenspan FS, Strewler GJ, eds. Basic & Clinical Endocrinology. 5th ed. Stamford, Conn:
Appleton & Lange; 1997:403-433. Petak SM, et al, for the AACE Hypogonadism Task Force. Endocr Pract. 2002;8:439456. Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.
SHBG=Sex Hormone-Binding Globulin.
60
50
40
30
20
10
0
WOMEN
Free T = unbound T
Bioavailable = unbound + albumin bound
SHBG=Sex Hormone-Binding Globulin.
20–29 30–39
40–49 50–59
60–69 70–80
Age (years)
1. Leifke E et al. Clin Endocrinol. 2000;53:689-695.
11
3/4/2014
Distribution of serum testosterone in men
Bioavailable
testosterone
Testosterone (ng/dl)
500
SHBG-T
Albumin-T
CBG-T
Free-T
400
300 BAT
200
100
0
Young
Adult
Obese
Elderly
ISA, ISSAM, EAU, EAA & ASA
Recommendations
• Evidence based
• Multi-disciplinary
• Simultaneously published in multiple specialty journals:
–
–
–
–
Int J Impotence Res 21:1-8, 2009
Aging Male 12(1): 5-12, 2009
J of Andrology 30:1-9, 2009
Eur Urol 55:121-130, 2009
Indications for the Measurement of
Free Testosterone
 Total testosterone is between 200 and 400 ng/dL
 SHBG abnormality is suspected:
INCREASED SHBG
DECREASED SHBG
HIV
Opioids
Liver disease
Androgens
Hyperthyroidism
Hypothyroidism
Estrogens
Nephrotic syndrome
Anticonvulsants
Glucocorticoids
Low testosterone
Acromegaly
Age (1%/year)
Obesity (IR)
Recommendations
Rec #1 Late Onset Hypogonadism (L3,grA)
• Clinical and biochemical syndrome
• Associated with advancing age
• Symptoms and T levels below young, healthy adult
male range
• May result in decreased quality of life
• May adversely affect function of multiple organ systems
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3/4/2014
Recommendations
Rec #2 Clinical Dx and Questionnaires (L 3, gr A)
• Clinical symptoms and signs present
–
–
–
–
–
Decreased libido
Erectile dysfunction
Disturbed lean body/adipose ration
Decreased bone mineral density
Symptoms corroborated with low serum T
• Questionnaires (AMS, ASAM) not recommended due to lack of
low specificity (L 3, gr B)
Recommendations
Recommendations
Rec #3 Laboratory Diagnosis
• Total T drawn 7-10AM (L2, gr A)
– No generally accepted lower limit of normal
– T > 350ng/100 ml does not need Rx
– T < 230ng/100ml benefit from Rx
• Variations in assay methods need to be considered
• LH differentiates primary/secondary (L3, gr B)
– Prolactin when T < 150ng/100ml
Diagnosis and Treatment Algorithm for
Testosterone Deficiency
Suspected or At Risk For Low Testosterone
Rec #3 Laboratory Diagnosis
Assess Symptoms
• Free or Bioavailable drawn when Total T non diagnostic (L2b, gr A)
– No generally accepted lower limit of normal
– Free T < 225 pmol l-1 benefit from Rx
• Equilibrium dialysis is gold standard
• Measuring serum SHBG with reliable Total T allows accurate
Calculation of Free T
• Calculated Free T correlates well with Equilibrium Dialysis level
If
Present
If Testosterone is
Low (<300 ng/dL)
DRE
PSA
LH/FSH
Prolactin
Normal
TRT
Morning Testosterone Levels
Normal
Seek
Other
Causes
Abnormal
Evaluate
Further
DRE=Digital Rectal Exam, PSA=Prostate Specific Antigen,
TRT=Testosterone Replacement Therapy,
LH=Lutenizing Hormone, FSH=Follicle Stimulating Hormone.
13
3/4/2014
Cardiovascular issues, metabolic
syndrome & recent public
controversies about TRT
André Guay MD, FACP, FACE
Director, Center For Sexual Function
Endocrinology
Peabody, MA
Tufts University School of Medicine
Boston, MA
Meta-Analyses For CV Events on T Therapy
2
3
1. Calof OM et al. J Gerontology 2005;11:1451–57. 2. Haddad RM et al. Mayo Clin Proc. 2007;82:29-39. 3. Fernández-Balsells NM et al. J. Clin. Endocrinol. Metab . 2010;95:2560-2575
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Prevalence of and Major
Risk Factors for Hypogonadism
Overall Prevalence of Hypogonadism in Clinical Practice: 38.9%
Risk Factor
Low Testosterone Associated With
Cardiovascular Risk Factors
(95% CI)
72
Men With Erectile Dysfunction (ED) Have Hypogonadism
Due to Varied Chronic Illnesses
(N=990)
Condition
N
# Hypo. ( % )
#1 o Hypo ( % ) # 2 o Hypo (% )
Diabetes mellitus
Hypertension
ASCAD
Asthma
Seizures
OSA
Roh 
Anxiety/Depression
Work stress
229
354
197
42
53
42
140
208
197
78 (35.6)
109 (34.6)
69 (35.0)
19 (45.2)
18 (34.4)
27 (64.3)
38 (27.1)
77 (37.0)
86 (43.6)
12 (5.2)
15 (4.2)
17 (8.6)
1 (2.4)
3 (5.7)
2 (4.8)
7 (5.0)
17 (8.2)
6 (3.0)
66 (30.4)
94 (30.4)
52 (26.4)
18 (42.8)
15 (28.7)
25 (59.5)
31 (22.1)
60 (28.8)
80 (40.6)
(6%)
(30%)
TOTAL
(36 %)
*Lahey Clinic Northshore, Peabody, MA; †Case Western Reserve, Cleveland, OH.
Guay AT, et al. Int J Imp Res. 2010; 22(3):9-19.
Hypogonadisma
Prevalence
Odds Ratio
(95% CI)
Obesity
52.4 (47.9-56.9)
Type 2
diabetes
2.38 (1.93-2.93)
50.0 (45.5-54.5)
2.09 (1.70-2.58)
Hypertension
42.4 (39.6-45.2)
1.84 (1.53-2.22)
Hyperlipidemia
40.4 (37.6-43.3)
1.47 (1.23-1.76)
Asthma or
COPD
43.5 (36.8-50.3)
1.40 (1.04-1.86)
Prostate
disease
41.3 (36.4-46.2)
1.29 (1.03-1.62)
HIM Study (N = 2085)
Adapted from Mulligan T, et al. Int J Clin Pract. 2006;60:762-769.
Low Testosterone and SHBG May Be
a Predictor of Other Conditions
Coronary Heart
Disease (CHD)
Low Total Testosterone
and Low SHBG
METABOLIC SYNDROME
Type 2 Diabetes
Low TT and SHBG levels independently
predict development of the metabolic
syndrome and diabetes in middle-aged men.1
Metabolic syndrome prospectively
identifies risk for CHD and even more
strongly predicts new-onset diabetes.2
1. Laaksonen DE, et al. Diabetes Care. 2004;27(5):1036-1041.
2. Sattar N, et al. Circulation. 2003;108(4):414-419.
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Metabolic Syndrome: Defined by the Presence of
Any 3 of 5 Components
1. Abnormality of blood sugar/insulin resistance
2. Enlarged waist circumference/BMI (visceral fat)
3. Elevated blood pressure
4. Elevated triglycerides
Low Testosterone Related To
Increased Mortality
5. Decreased HDL cholesterol
Androgen deficiency/“hypogonadism”
Obesity
Hypertension
Dyslipidemia
Hyperglycemia
Insulin resistance
Metabolic syndrome
Low Serum Testosterone and Mortality in
Male Veterans
•
•
N=858 men > age of 40
Low T = total T < 250 ng/mL
Low Testosterone and Increased Mortality (N >500)
Recent
Studies
HR (95% CI)
Nature
Men, n
FollowUp, yrs
Mortality
Shores, 2006
1.88 (1.34–2.63)
Retrospective
858
8
All-cause
Laughlin, 2008
1.38 (1.02–1.85)
Prospective
794
20
CVD
Khaw, 2007
2.29 (1.60–3.26)
Prospective
2314 of
11,606
10
All-cause/ CVD
Haring, 2010
2.32 (1.38–3.89)
Prospective
1954
7.2
All-cause
2.56 (1.15-6.52)
– < 8.7 nmol/L
•
CVD
Mortality over 5 years
– 20.1% with normal T
• 2 levels > 250
– 24.6% with equivocal T
• Equal # N and low
• Odds Ratio 1.38 (P=0.06)
– 34.9% with low T
• 2 levels < 250
• Odds Ration 1.88 (P<0.001)
Malkin, 2010
2.27 (1.45–3.60)
Prospective
930
6.9
All-cause in
men with CAD
Tivesten, 2009
1.65 (1.29–2.12)
Prospective
3014
4.5
All-cause
Menke, 2010
1.43 (1.09–1.87)
Prospective
1114
9
All-cause
Vikan, 2009
1.24 (1.01–1.54)
Prospective
1568
11.2
All-cause
2.3 (1.2-4.2)
3.0 if sex sx
Prospective
2599
4.3
All Cause/CVD
Jones 2013
2.02 (1.2-3.4)
Prospective
581
5.8
All cause
Corona, 2010
7.1 (1.8–28.6)
Prospective
1687
4.3
CVD
Pye 2014
Shores et al (Seattle) Arch Int Med 2006; 166: 1660-1665
HR=hazard ratio; CI=confidence interval.
16
3/4/2014
Association of ADT with CV Deaths with Prostate
Cancer A Meta-Analysis
Androgen Deprivation Therapy, Insulin Resistance,
and Cardiovascular Mortality: An Inconvenient Truth
Basaria S. (Baltimore) J Andrology 2008; 29: 534-539
•
•
N=2257 ADT group
N=2278 Control group
•
ADT was not related to an
an increased risk of CV
death….vs controls
•
ADT was related to a lower
risk of Pros Ca deaths….vs
controls
Nguyen P, et al J.A.M.A. 2011; 306: 2359-2366
Testosterone-Treated Hypogonadal Men Have a
Longer Survival Time than Untreated Men*
Can Testosterone Replacement in
Hypogonadism Ameliorate
Cardiometabolic Risks ?
Log Rank p = 0.029
Treated (n=398)
mortality 10.3%
3.4 deaths/100 pat yrs
Untreated (n=633)
mortality 20.7%
5.7 deaths/100 pat yrs
*in 1031 men (mean age ~ 60 years; 38% with type 2 diabetes; 22% with cardiac disease)
Shores MM et al. J Clin Endocrinol Metab 97(6): 2050-2058 (2012)
17
3/4/2014
In Older Men an Optimal Plasma Testosterone is Associated with
Reduced All-Cause Mortality and Higher Dihydrotestosterone
With Reduced Ischemic Heart Disease Mortality , While Estradiol
Levels Do Not Predict Mortality
• Health in Men Study
– Perth Australia
– 4248 men studied at 5 yrs
– Of men that qualified:
• N = 2716 remained alive
• N = 974 died
• Men who died had an
association with low T at
baseline
– No relation of E2 with
Mortality
• Normal T related to
increased survival
Yeap, et al (Aus) J Clin Endo Metab Epub 20 Nov 2013 doi:10.1210/jc.2013-3272
High Serum Testosterone Is Associated With Reduced Risk Of
Cardiovascular Events In Elderly Men
The MrOS (Osteoporotic Fractures in Men) Study in Sweeden
•
•
•
•
N = 2,416 men (69-81 yrs)
5 year follow-up
485 CV events
Men in the upper quartile of T
•
“High serum testosterone predicted a
reduced 5-year risk of CV events in elderly
men”
T Therapy Improves Metabolic Syndrome Components
 FBG
 HbA1c
 Fasting insulin
 HOMA index of insulin resistance
 Waist circumference, BMI, cholesterol
 Prevalence of metabolic syndrome (after 1 year)
_________________________________________________
Kapoor D,* et al. Eur J Endocrinol. 2006;154(6):899-906.
• 3-month trial
Heufelder AE,† et al. J Androl. 2009;30(6):726-733.
• 12-month trial
*United Kingdom; †Germany,
Jones TH, et. al. Diabetes Care. 2011;34:828-837.
Low Testosterone Predicts Increased Mortality
and Testosterone Therapy Improves Survival in 587 Men with Type 2 Diabetes
(mean Follow-up: 5.8 years)
Low T treated
– > 550 ng/dL
– Had a lower risk of CV events
• HR of 0.71
Normal T
Low T untreated
Mean TRT was for 41.6 months….HR 2.3 for untreated
Ohlsson, Barret-Connor et al (Sweeden, US) J Am Col Card 2011; 58: 1674-1681
Muraleedharan V et al. Eur J Endo 2013; 169: 725-733
18
3/4/2014
Effects of Testosterone Undecanoate on Cardiovascular Risk Factors
and Atherosclerosis in Middle-Aged Men With Late-Onset
Hypogonadism and Metabolic Syndrome: Results From a 24month, Randomized, Double-Blind, Placebo-Controlled Study
Changes in Fasting Glucose and Waist Circumference After 12 Months
of Placebo (n=10) or Nebido® (n=40); Placebo Group Switched
to Nebido® After 12 Months for a Total of 24 Months
.
• N=50 men, between 45 and 65 years
• N=25 men on T Therapy and 25 men on
placebo
• Mean age, 57-58 years
• Hypogonadism: TT <300 ng/dL (<11
nmol/L), or
cFT <10 pg/mL (<250 pmol/L)
* P< 0.0001
 Results were so positive at 12 months that
the placebo patients were started on T
Therapy as well
Aversa A,* et al. J Sex Med. 2010;7(10):3495-3503
*Rome, Italy.
*
*
*
*
CIMT After 12 Months of Nebido® Treatment (n=40) and
Correlation Between Change in Testosterone and CIMT
.
Correlation of CIMT vs TT
CIMT
Recent Reports About Testosterone
Therapy Related To Cardiovascular Events
P<0.0001
CIMT=carotid intima media thickness.
r5 = 0.31; P<0.0001
19
3/4/2014
Meta-Analyses For CV Events on T Therapy
2
TOM Trial NEJM 2010
3
1. Calof OM et al. J Gerontology 2005;11:1451–57. 2. Haddad RM et al. Mayo Clin Proc. 2007;82:29-39.
3. Fernández-Balsells NM et al. J. Clin. Endocrinol. Metab. 2010;95:2560-2575
Adverse Events Associated With Testosterone
Administration: TOM Study
•
•
•
•
TOM = “Testosterone in Older Men with Mobility Limitation”
N = 209 men, > 65 years of age (of the 252 desired by power analysis)
Baseline TT 100-350 ng/dL ( free T < 50 pg/mL or 170 pmol/L )
1% testosterone gel used, 10 Gm QD, titrated to 5.0 or 15.0, 6 mo rx
•
Results of muscle performance and physical functionwere positive
•
– Cv disease
– Hypertension
• And HTN meds
– Aimed for TT between 500 and 1000 ng/dL
Basaria, Bhasin et al (Boston) N.E.J.M. 2010; E-pub 30 June:10.1056/NEJMoa1000485
More risks in T Rx group
– Statin therapy
•
But not statistically significant
20
3/4/2014
• Placebo Group
•
Hazard Ratio of 2.0 for men who
had TT levels between 512 ng/dL
to 1957 ng/dL
•
At baseline, men with lower TT
levels were at greater risk
•
Elevated Hct seems to be a great
aggravating factor in men at this
age at risk
•
Interesting that BMI, smoking,
the presence of DM did not
increase risk…..but age did
– No major CV event
• Testosterone Group
–
–
–
–
MI x2
Death, presumed MI x1
CVA x1
Acute coronary
syndrome
• X1
– Serious CHF x2
•
Despite all of problems int the design of the paper:
•
There is a signal for increased CV events:
– Study not powered to find CV events
– Poor randomization (due to underpowering)
• T treatment group had patients at higher risk
– Poor inclusion criteria
• Class I and II CHF
• Creatinine levels < 3.5 ng/mL
– T gel not started at lowest dose before titration
– Did not aim for midrange T levels
• Aimed for T levels between 500-1000 ng/dL
•
Reasonable assumption that men had salt and water retention and
it resulted in the 7 major CV events
– Where there were none for the placebo group
In Older Men an Optimal Plasma Testosterone is Associated with Reduced
All-Cause Mortality and Higher Dihydrotestosterone With Reduced Ischemic
Heart Disease Mortality , While Estradiol Levels Do Not Predict Mortality
• Optimal androgen levels are
a biomarker for survival
because older men with
midrange levels of T and
DHT had the lowest death
rates from any cause
• Note the trend for
increasing mortality with
higher T and DHT levels:
– Especially TT > 30 nmol/L
(864ng/dL)
– Or cFT > 500 pmol/L
• ? Explanation for TOM trial
results ?
Yeap, et al (Aus) J Clin Endo Metab Epub 20 Nov 2013 doi:10.1210/jc.2013-3272val
21
3/4/2014
Do the Effects of Testosterone on Muscle strength, Physical Function,
Body Composition, and Quality of Life Persist Six Months After
Treatment in Intermediate-Frail and Frail Elderly Men
•
•
N=274 frail men, ages 65-90
Treated for 6 months
•
•
Total T < 12 nmol/L
Calculated free T < 250 pmol/L
•
Total from 11.3 to 18.4 nmol/L
•
Calc free T went from 175 to 365
pmol/L
Effect of Long-Acting Testosterone treatment on Functional Exercise
Capacity, Skeletal Muscle Performance, Insulin Resistance, and
Baroreflex Sensitivity in Elderly Patients With Chronic Heart Failure
– 25 – 75 mg/d
– Declined to 10.5 nmol/L at 12 months
– Declined to 172 pmol/L at 12 months
•
•
•
•
• Need to continnue Rx
•
NO ADVERSE CV EVENTS
N=70 elderly men with stable CHF, median age 70 years
Peak O2 (VO2) increased with T rx, as did muscle strength, 6MWT
MVC (max vol muscle contraction) increased on T Rx
EF increased but not significantly
O’Connell, Srinivas-Shankar, Wu et al (UK) J.C.E.M. 2011; 96:454-458
Cardiorespiratory and Muscular Results before and after 3 mo of
Treatment with Nebido in 64 Frail Elderly Men
with Chronic Heart Failure
*
Caminiti, Rosano et al (It) J Am Coll Card 20019; 54: 919-927
Metabolic and Hormonal Results before and after 3 mo of
Treatment with Nebido in 64 Frail Elderly Men with Chronic Heart
Failure
*p<0.05
*
*
*
*
6- Minute Walking Test (m)
*
*
*
*p<0.05
Caminiti G et al. J Am Coll Cardiol 54: 919-927 (2009)
Caminiti G et al. J Am Coll Cardiol 54: 919-927 (2009)
22
3/4/2014
Testosterone Therapy and Cardiovascular Events Among Men:
A Systematic Review and Meta-Analysis of Placebo-Controlled
Randomized Trials
Xu et al Biomedical Central
On-Line Journal 2013
•
1,882 papers obtained; 27 used
•
Table 1: men who had low T
and/or chronic disease
– Search Terms: “tetosterone”,
“androgen”, “random”, “trial”
– 12 had TT < 10.4 nmol/L
• Or 300 ng/dL
– 12 had TT > 10.4 nmol/L
•
•
No Rx T levels available
No correlation of CV events with
any T levels
Xu L, et al BMC Medicine 2013, 11:108
Testosterone Therapy and Cardiovascular Events Among Men:
A Systematic Review and Meta-Analysis of Placebo-Controlled
Randomized Trials
o Conclusion ? Biased, ?Relevant:
o The effects of testosterone on
cardiovascular-related events varied
with source of funding
o Fig 4
o Upper panel sponsored by Pharma
o 3 studies had inadequate levels
Vigen et al JAMA November 2013
o Lower panel, no Pharma support
o 4 studies had inadequate levels
o Eliminate Basaria 2010
o Would have changed the OR
o If a number of men had  T, then
one can make the case for low T
related to CV events
Xu L, et al BMC Medicine 2013, 11:108
23
3/4/2014
Association of Testosterone Therapy With Mortality,
Myocardial Infarction, and Stroke in Men With Low
Testosterone Levels
•
•
Study Population: at risk population of
veterans who underwent coronary
arteriography
N = 8709 men with TT < 300ng/dL
Association of Testosterone Therapy With Mortality, Myocardial
Infarction, and Stroke in Men With Low Testosterone Levels

Since population biased for CAD

How to generalize this data to apply to a general
population?

Applied the stabilized inverse probability of
treatment weighting
 There are no standardized method of
assigning statistical weights
 Subjective definitions by each study
group

Over 50 variables were weighted, but it was not
clear if there was any adjustment for multiple
risk factors, or whether and how the authors
took into consideration to correlations between
the factors

N=1132 men excluded from the study
 Not available for the T-risk Group
– (<10.4 nmol/L)
•
Of 7486 men NOT RECEIVING T Rx:
– 681 died, 420 had MI, 486 had CVA
– Incidence of AE: 21.2%
•
Of 1223 men RECEIVING T Rx:d
– 67 dies, 23 had MI, 33 had CVA
– Incidence of AE: 10.0%
 Should have been added to the NON-T
Group
 Could have made a separate arm
Vigen, et al (VA Study in USA) J.A.M.A. 2013; 310:1829-1836
JAMA Abstracts Before and after Revision
“The absolute rate of events were 19.9%
in the no testosterone group vs 25.7% in
the testosterone therapy group, with an
absolute risk difference of 5.8% at 3 years
after coronary arteriography”
“At 3 years after coronary arteriography, the
Kaplan-Meier estimated cumulative
percentages with events were 19.9% in the
no testosterone therapy group vs 25.7% in
the testosterone therapy group, with an
absolute risk difference of 5.8%”
Diagnosis and Treatment of Hypogonadism
•
Diagnosis of Hypogonadism
•
The definition of testosterone deficiency involves a biochemical number plus
consistent signs and symptoms of androgen deficiency
– Total T < 300 ng/dL (10.4 nmol/L) has been the standard in the past
– Bhasin S, et al. J Clin Endocrinol Metab 2010; 95: 2536-2559
– There is no mention in the JAMA report of any symptomotology
•
No mention of any confirmatory blood test being done
•
No mention of the time of day the test was done
•
Only 60% of the men had post rx Testosterone levels
– Up to 30% of low TT has been shown to be normal on retesting
– Brambilla DJ, et al. Clin Endocrinol (Oxf) 2007; 67: 853-862
– Even many repeat TT in Am in older men were found to be normal
– Brambilla DJ, et al. Clin Endocrinol (Oxf) 2007; 67: 853-862
– The 40% with no tests should have been eliminated from the study
24
3/4/2014
Diagnosis and Treatment of Hypogonadism
•
Treatment of Testosterone Deficiency….? Inadequate
•
63.9% of the men were given the low, 2.5 mg, Testosterone patch
– The VA requires that T treatment is begun with patches
– Most clinicians would start at 5.0 mg
Finkle et al PLOS-one
On-line Journal January 2014
• Also, nearly half of the men develop dermatitis
– The mean number of refills was 6
• So, 80% of the men were treated for about 6 months
– The mean treatment T level was 332 ng/dL (11.5 nmol?L) and levels of T on
treatment was only carried out in 60% of the men
• Many feel that the cutoff for testosterone deficiency should be a TT < 350 ng/dL
(12.1 nmol/L)
– Wang C, et al. J Androl 2009 doi: 10.2164/jandrol.108.006486
– Maggi M, et al. J Sex Med 2013; 10: 661-677
– Bhasin S,et al. J Clin Endocrinol Metab 2011; 95: 2430-2439
Increased Risk of Non-Fatal Myocardial Infarction
Following Testosterone Therapy Prescription in Men
•
Cohort Formation
– 1st Prescription for Testosterone……….N = 55,593 (48,539 men < 65)
– “Comparison population”……1st Prescription for PDE5….N = 167,279
Increased Risk of Non-Fatal Myocardial Infarction Following
Testosterone Therapy Prescription in Men
•
 Post Prescription F/U……90 days……..then from 91-180 days
because many men dropped out in the first 90 days
 Pre Prescription…..25 months !!!!.......how cam you compare 90 days and 25
months?
 Why PDE5 as “comparison group”
 “…because some indications for prescription are similar to those for T
Transcription”…….WRONG !!!
Only indication for PDE5 is ED, and ED not an indication for TT
 “…because PDE5’s not associated with cardiovascular events
•
“PDE5 patients were weighted to
match the TT cohort on odds of
testosterone prescription.. So a guess
141,031 ./. 167,279 = 84%
– …chance of needing a prescription
•
Without weighting there are more
men with hyperlipidemia,
hypertension, heart disease, asthma,
SSRI’s, Corticosteroids, insulin and
anti-diabetic drugs in the T Rx group
•
Putting the odds at 84% evens the
groups out wonderfully well
 Makes populations quite different….. Men with multiple medical co-factors may not be eligible to
receive a PDE5
Finkle WD, et al PLOS/one Jan 2014/ V9/ Issue 1/ e85805
www.plosone.org
www.plosone.org
25
3/4/2014
Increased Risk of Non-Fatal Myocardial Infarction Following
Testosterone Therapy Prescription in Men
So what is the true prevalence of hypogonadism in ED ?
1. Kohler. Prevalence of And Def in ED. Urology 2008
Prostate Cancer and
androgens
Prevalence of 23% (TT < 300ng/dL)
2. Somani. Screening for MS and T Def in ED. BJU Int 2010
Prevalence of 27% ( with cFT < 220 pmol/L)
3. Guay. Characterization of men in an endocrine clinic. Endo Prac 1999
Prevalence of 36% (TT < 300 ng/dL)
4. Wu. Identification of LOH in Eur Male Aging Study. N.E.J.M. 2010
Prevalence of 33% (with cFT < 220 pmol/L)
5. Isidori. Critical analysis of Testosterone on erectile function. Eur Urol 2013
Mohit Khera
Prevalence between 23% and 36%
Why bother to worry about the prevalence ?
There is no mention of T levels, before or after a rx for testosterone
There is no assurance that the men ever took the medication
www.plosone.org
Physician Concerns About the Prostate
in 2006
•
Multinational physician survey on testosterone therapy
– Most common physician concern is prostate cancer risk
Brazil
Saudi Arabia
South Korea
Concerns Rated “Very Important”
Germany
Spain
United Kingdom
Historical Basis for Concern
In 1941 – Huggins & Hodges
reported:
1.Reducing T to castrate
levels caused prostate
cancer to regress
2.Administration of
exogenous T caused
prostate cancer to grow
BPH, benign prostatic hyperplasia.
Reproduced from Gooren LJ et al. Aging Male. 2007;10(4):173-181.
26
3/4/2014
Historical Basis for Concern
Number of articles showing testosterone
therapy causes prostate cancer in PSA era
In 1941 – Huggins & Hodges
reported:
1. Reducing T to castrate
levels caused prostate
cancer to regress
2. Administration of
exogenous T caused
prostate cancer to grow
None!
(based on a single patient)
Discussion
• Effect of TRT on Normal Prostate Tissue
• Prostate Saturation Theory
• Low Testosterone as a Risk Factor for Prostate
Cancer
• TRT in Men with a History of Prostate Cancer
• TRT in Men with Untreated Prostate Cancer
• Androgens and Erectile Function
Effect of TRT on Normal
Prostate Tissue?
27
3/4/2014
Effects of TRT on Prostate Tissue of
Aging Men with Low Serum T
• R, DB, PC trial of 44 men (44-78 years)
• Inclusion criteria:
*
• T < 300 ng/dl
• Symptoms of hypogonadism
• Randomly assigned to receive 150 mg TE or placebo
q 2 weeks X 6 months
• 12-core TRUS prostate biopsies were performed at
baseline and 6 months
• Primary outcomes: 6-month change in prostate T &
DHT
**
* p < .001
** p < .002
Placebo (n=19)
TRT (n=21)
Marks L, et al, JAMA, 296:2351, 2006.
Prostate Saturation Model
Saturation Model of Physiologic Testosterone Replacement
“Normal Physiologic Range”
Prostate Growth (PSA)
Virtually
Castrate
Saturation Effect
d
at e
tur
sa
Un
0
TRT (n=21)
Placebo (n=19)
100
200
300
400
500
600
Serum testosterone level (ng/dL
(ng/dL))
700
800
Morgentaler A, Traish AM. Eur Urol. 2008;55:310-320
28
3/4/2014
PSA at Supraphysiologic Levels of
Testosterone
Testosterone
PSA
2000
8
1500
6
1000
4
500
2
0
0
25
50
125
300
600
Testosterone Therapy Weekly Dose, mg
Serum Testosterone, ng/dL
10
800
16
700
14
600
12
Testosterone
500
10
PSA
400
8
300
6
200
4
100
2
0
Serum PSA, ng/mL
Testosterone, ng/dL
2500
PSA, ng/mL
• Testosterone 600 mg or
placebo weekly for 10
weeks
• PSA did not change
significantly from
baseline despite
supraphysiologic
testosterone levels
(>2500 ng/dL)
Serum PSA and Testosterone Flare
0
0
4
8
12
16
20
24
28
Time Since Injection, d
Data from Tomera K et al. J Urol. 2001;165(5):1585-1589.
Reproduced from Morgentaler A, Traish AM. Eur Urol. 2009;55(2):310-320
Bhasin S et al. N Engl J Med. 1996;335(1):1-7.
• 451 hypogonadal men started on TRT for 12 months
• Divided into 2 groups
• Group A: Testosterone < 250ng/dl
• Group B: Testosterone > 250ng/dl
• ONLY in group A (Testosterone < 250ng/dl):
• PSA correlates with testosterone and free testosterone
• Significant rise in PSA after 12 months of TRT
If one assumes that higher
testosterone levels increase the
risk for prostate cancer, then are
lower testosterone levels
considered protective against the
development of prostate cancer?
Khera et al J Urol Sept 2011:186; 1005-1011
29
3/4/2014
Low Testosterone Associated with Increased
Risk of Prostate Cancer
• Isom-Batz,et al. J Urol. 2005; 173: 1935-1937
– Lower testosterone correlated with higher:
• Pathological stage
• Clinical stage
• Biopsy Gleason grade
• Teloken, et al. J Urol. 2005; 174: 2178-2180
– Lower testosterone correlated with:
• Increased positive surgical margins
– 39% in low TT vs 14.6% in normal TT
• Schatzl, et al. J Urol. 2003; 169: 1312-1315
– Lower testosterone correlated with:
• Higher tumor density
• Higher Gleason score
Lower Pre-operative Testosterone Levels Increase
the Risk for Prostate Cancer Recurrence
• 272 patients with localized prostate cancer were treated with
radical prostatectomy
• Preoperative testosterone measured in all patients
– <300 ng/dl: 49 patients
– >300 ng/dl: 223 patients
• Independent and significant predictors of PSA recurrence
were:
–
–
–
–
Gleason score (p=0.006),
Surgical margin status (p=0.0001),
PSA (p=0.0001)
Preoperative testosterone level (p=0.021)
• Five-year PSA failure-free survival rates:
– <300 ng/dl: 67.8%
– >300 ng/dl: 84.9%
(p=0.035)
Yamamoto, Eur Urol, 2007
Does giving testosterone to men with
a history of prostate cancer increase
the risk of recurrent prostate cancer?
30
3/4/2014
High Risk
No History of
Prostate Cancer
(High Grade P.I.N.)
High Risk
No History of
Prostate Cancer
(High Grade P.I.N.)
TRT and Risk for
Prostate Cancer
TRT and Risk for
Prostate Cancer
Treated
Prostate Cancer
Treated
Prostate Cancer
Radiation
Radical Prostatectomy
Radiation
Incidence of Prostate Cancer in Men on TRT
• Prostate cancer rate in over 7 published TRT trials was
similar to screening trials of general population1
• Meta-analysis of 19 placebo-controlled testosterone
therapy studies in men with low or low-normal
testosterone ²
• Comparison of men treated with testosterone vs placebo
revealed no difference in:
– PCa incidence
– Change in PSA
– Urinary symptom scores
¹ Hsing AW Epidemiol Rev 2001
² Calof OM, et al. J Gerontol A Bio Sci Med Sci. 2005;60(11):1451-1457
Global Pooled Longitudinal Study of
Hormones and PCa Risk
• 3886 men with PCa
• 6448 age-matched
controls
• No significant
relationship between
androgens and PCa
Endogenous Hormones and Prostate Cancer Collaborative Group. J Natl
Cancer Inst. 2008;100(3):170-183.
31
3/4/2014
High Risk (HGPIN)
High Risk
No History of
Prostate Cancer
(High Grade P.I.N.)
– 55 men had benign biopsies (-PIN)
– 20 men with PIN (+PIN)
TRT and Risk for
Prostate Cancer
• Results
– No significant change in PSA in either group
– One patient in +PIN group found to have prostate cancer on
biopsy after abnormal DRE
– Conclusion: After 1 year of TRT, men with PIN did not have a
greater increase in PSA or a significant increased risk of cancer
than men without PIN
Treated
Prostate Cancer
Radiation
Rhoden EL, Morgentaler A, J Urol 170:2348-51, 2003
High Risk
No History of
Prostate Cancer
(High Grade P.I.N.)
TRT and Risk for
Prostate Cancer
Treated
Prostate Cancer
• HGPIN: 25-30% chance of prostate cancer on
subsequent biopsies
• 75 hypogonadal men treated with TRT for 12 months
• All men underwent prostate biopsy prior to TRT
Testosterone Replacement Therapy
After Brachytherapy
• 31 men started TRT for a median of 2 years
after brachytherapy
• Patients received TRT for a median 4.5 years
• Follow-up ranged 1.5 to 9.0 years (median, 5
years)
• Testosterone rose from 188 ng/dl to 498 ng/dl
• No patient stopped TRT because of cancer
recurrence or demonstrated cancer
progression
Radiation
Sarosdy A, Cancer, 2006.
32
3/4/2014
after External Beam Radiotherapy
High Risk
Normal
• Five hypogonadal men treated with TRT after
EBRT
• Follow-up of 14.5 months
• Testosterone levels significantly increased
• One patient had a transient increase in PSA, but none had
levels >1.5 ng/ml
(High Grade P.I.N.)
TRT and
Prostate Cancer
• Thirteen hypogonadal men treated with TRT after
EBRT or brachytherapy²
• Follow-up 29.7 months
• Significant increase in testosterone levels
• No significant increases in PSA or CaP recurrences
Treated
Prostate Cancer
Radiation
¹Morales et al. BJU 2008; 103: 62
² Pastuszak et al Int J Impot Res 2013 Jan;25(1):24-8.
Testosterone After Radical
Prostatectomy
•
Study
No. of
Patients
Follow-up
(months)
Pre TRT
PSA
Post TRT
PSA
Pre T
Post T
Agarwal et al
10
19
<0.1
<0.1
197
591
Kaufman et al
7
24
<0.1
<0.1
97
434
Khera et al
57
17
0.005
0.005
275
440
Pastuszak et al
103
27.5
0.004
(median)
0.007*
(median)
261
460
Retrospective review of 103 hypogonadal men treated with TRT after RP
between 2003-2011 and 49 eugonadal controls having undergone RP
treated during this time
• High Risk CaP - post-surgical pathology with one or more of the following: 1)
Gleason score ≥8, 2) positive surgical margins, or 3) positive lymph nodes
– TRT Group - 77 men with low/intermediate risk CaP (non-high risk) and 26
with high-risk CaP
– Control Group – 34 men non-high risk and 15 men high-risk CaP
•
Results:
– 12 biochemical recurrences ONLY in high risk patients after 36 months
• 4 biochemical recurrence in TRT group (15.3%)
• 8 biochemical recurrences in control (non-TRT group) (53.3%)
* 4 PSA recurrences
Agarwal J Urol 2005.
Kaufman et al J Urol 2004.
Khera et al JSM 2009
Pastuskaz et al J Urol 2013
Pastuszak et al J Urol. 2013 Aug;190(2):639-44
33
3/4/2014
TRT and Prostate Cancer Cell
Suppression
TRT after Prostate Cancer
• A total of 8 studies (abstracts + manuscripts) thus far
have provided information on TRT after treatment
for prostate cancer (RP, brachytherapy, EBRT)
– Total of 386 patients treated with testosterone after
prostate cancer
• Only 6 men, or 1.5% of men, were noted to have a
biochemical recurrence
• Recurrence rate is less than published series in
favorable groups²
• TRT protective?
• Hatzoglou et al- membrane androgen receptor
activation induced apoptotic regression of
human prostate cancer cells in vitro and in vivo¹
• Sonnenschein et al. - androgens were able to
trigger an inhibition of prostate cancer cell
proliferation at higher concentration²
• Chuu et al. - androgens caused growth
suppression and then reversion of androgen
independent tumors to an androgen dependent
tumors³
¹ Hatzoglou et al J Clin Endocrinol Metab 2005, 90:893-903
²Sonnenschein et al. Cancer Res 1989, 49:3474-81
³Chcuu et al Cancer Res 2005, 65:2082-4
¹Morgentaler J Urol 2009; 181:972
²van Oort et al. Urol Oncol 2008 Epub
Current Clinical Trial: NCT00848497
•
•
•
•
FDA approved
Randomized placebo controlled trial
TRT in hypogonadal men starting 3 months after radical prostatectomy
Inclusion Criteria:
– Must have undergone a bilateral nerve sparing radical prostatectomy.
– Nadir PSA values should be less than 0.01 ng/ml on two consecutive occasions
separated by 4 weeks at the start of treatment.
•
Exclusion Criteria:
–
–
–
–
Testosterone level greater than 300 ng/ dl
Pre-operative SHIM score less than 17.
Positive surgical margins or evidence of residual prostate cancer.
Clinically suspected advanced disease or actual evidence of metastatic prostate
cancer.
– Primary Gleason Grade greater than 3 or secondary Gleason Grade greater than 4
in the final pathologic specimen will be excluded.
http://clinicaltrials.gov/ct2/show/NCT00848497
34
3/4/2014
Risk of Occult Prostate Cancer?
• Retrospective study of 13 men who elected
surveillance of prostate cancer and received
testosterone therapy for minimum of 6 months
• 12 men had Gleason grade 6 at initial biopsy, and 1 had
Gleason 7 (3+4)
• Mean duration of testosterone therapy after diagnosis
of prostate cancer was 23.5 months (range, 9-43 mo)
Morgentaler A et al. J Urol. 2011;185(4):1256-1260.
Testosterone Therapy With
Untreated Prostate Cancer: Results
TRT Following Radical Prostatectomy
• No significant change in PSA
– Initial: 5.5±6.4 ng/mL (range, 0.6-24.1 ng/mL)
– Most recent: 3.7±2.6 ng/mL (P=.29)
• No change in prostate volume
– Initial: 45.6±14.5 mL
– Most recent: 52.4±19.8 mL (P=.11)
• No cancer progression seen in any individual
• No cancer identified in 54% of follow-up biopsies
Safety
Efficacy
PSA, prostate-specific antigen.
orgentaler A et al. J Urol. 2011;185(4):1256-1260.
35
3/4/2014
Androgens and Erectile Function
Nitric Oxide
Synthase
Phosphodiesterase
Type 5 Activity
Androgens
Veno-occlusive
Erectile Function
Penile Nerve
Function
Khera M. J Sex Med 2009;6(suppl 3):234–238
The Focus of Erectile Preservation Following
The Focus of Erectile Preservation Following
Nerves
Trabecular
Smooth Muscle
Endothelium
Traish et al. J Androl. 2005: 26:242.
36
3/4/2014
Conclusion
• While TRT does significantly impact PSA levels at low levels of
serum testosterone, TRT does not appear to affect prostate size,
or intra-prostatic testosterone levels. These findings may be due
to the early saturation of androgen receptors within the prostate
• There is currently no evidence that TRT promotes the initiation
of PCa in hypogonadal men
• Low testosterone is associated with higher incidence of prostate
cancer, more aggressive prostate cancer, and PSA biochemical
recurrence.
• Androgens play a key role in overall erectile function through
their effects on nitric oxide synthase, PDE5 activity, penile nerve
function, and veno-occlusive disease
Thank you for your attention
Final Thought…..
• After a radical prostatectomy, if you do not
replace testosterone levels in hypogonadal
men to make them eugonadal, then how can
you justify not lowering testosterone levels in
eugonadal men to make them hypogonadal?
Treatment Options For The
Hypogonadal Patient
Baylor College of Medicine
37
3/4/2014
TRT Market Overview
Drivers Behind
Future Growth
TRT Market $ (000)
2500
2000
•
Aging population
•
Increased link of
Low T with poor
general health
•
Reduced concern of
TRT and PCa
•
New entries with
increased promotion
•
Direct to consumer
advertising
Two new gels
1500
TESTOPEL
1000
Androgel
Testiim
500
0
00
01
02
03
04
05
06
07
TRT Treatment Options
08
09
10
11
12
13
14
Important Considerations
The ideal testosterone formulation for hypogonadism would:
 Produce physiologic levels of testosterone for prolonged periods
 Have a favorable safety profile
 The dosing schedule and administration method would be
convenient for the patient.
 Ideally, the formulation would be reasonably priced.
Buccal
 April 2011: Actient Pharmaceuticals LLC Acquires
U.S. Rights to STRIANT from Columbia
Laboratories
 Applied: upper gum just above the incisor tooth
 Starting dose: 30mg q12 hours
 Max dose: 30mg q12 hours
Emerging Drugs for Hypogonadism
Expert Opin Emerging Drugs 2006; 11(4): 685-707
ELDELSTEIN D, DOBS A, BASARIA S.
38
3/4/2014
Striant Adverse Events
Androderm Adverse Events
TRT Share
14%
-0
9
13%
TRT Market
9
M
ay
-0
9
Ju
n09
200mg IM every 2 weeks
100mg IM every week
60 mg IM twice a week
14%
0
-0
9
•
•
•
15%
50
r-0
• Dosage
15%
100
Ap
4%
17%
16%
14.7%
M
ar
Allergic contact dermatitis
18%
16%
15.1% 15.1%
08
4%
150
15.8%
15.4%
Fe
b
Headache
Sesame oil
T1/2 = 10.5 days
200
15.6%
08
5%
•
•
15.4%
n09
Prostate abnormalities
• Testosterone enanthate
18%
17%
250
ec
-
6%
300
Ja
Vesicles at application site
17.2%
16.8% 16.8%
16.5%
D
7%
17.5%
17.1%
350
8
Erythema at application site
400
ov
-
12%
Cottonsead oil
T1/2 = 12 days
Greater fluid retention
N
Burn-like blister reaction
•
•
•
8
37%
08
Pruritis at application site
• Main advantage: cost
• Testosterone cypionate
ct-
Percent of Patients
(n=122)
O
Adverse Event
Testosterone Injections
8
2.0%
-0
Gum Edema
• Applied: back, abdomen, upper arms, or
thighs
• Available doses: 2.5grams and 5 grams
• Starting dose: 24.3mg (5 grams) daily
• Max dose: 48.6mg (10 grams) daily
-0
3.1%
Se
p
3.1%
Headache
Au
g
3.1%
Gum Tenderness
TRT TRxs (000)
4.1%
Gum Pain
n08
9.2%
Bitter Taste
Ju
l-0
Gum or Mouth Irritation
Ju
Adverse Events
Androderm
Percent
(n=98)
Generic Injections
39
3/4/2014
Different Testosterone Levels After
Replacement Therapy
Testosterone ng/dL
Patch or Gel
Normal range
Injection
Testim





Applied: shoulders/upper arms
Starting dose: 50 mg (1 tube)
Max dose: 100mg (2 tubes)
Follow up: 14 days after initiation of therapy
Swim or shower: 2 hours
Day
Adapted from Bhasin and Bremner. J Clin Endocrinol Metab. 1997;82:3-8
Testosterone gel (AndroGel ®1%) Unimed Pharmaceuticals and Solvay Pharmaceuticals, 2002
Testim Adverse Events
Testim
50mg
Testim
100mg
Application Site Reaction
2%
4%
BPH
0%
1%
HTN
1%
1%
Gynecomastia
1%
0%
Headache
1%
1%
Erythrocytosis
1%
2%
Taste Disorder
1%
1%
Adverse Events
New TRT Gels in the Market
40
3/4/2014
Suggested Titration Schedule
Fortesta
•
•
•
•
•
Applied: Inner thighs
Starting dose: 40 mg (4 pumps)
Max dose: 70mg (7 pumps)
Swim or shower 2 hours after application
Follow up: blood draw 2 hours after applying
gel at approximately 14 days and 35 days
after starting treatment or after making a
dose adjustment
Fortesta Adverse Events
Adverse Events
Skin reaction
Total Serum Testosterone
Concentration 2 hours Post
FORTESTA Application
Dose Titration
Equal to or greater than
2,500 ng/dL
Decrease daily dose by 20 mg (2 pump
actuations)
Equal to or greater than 1,250 and
less than 2,500 ng/dL
actuation)
Equal to or greater than 500 and less
than 1,250 ng/dL
No change: continue on current dose
Less than 500 ng/dL
Increase daily dose by 10 mg (1 pump
actuation)
Axiron
Number (%) of Patients
N = 149
24 (16.1%)
Prostatic specific antigen increased
2 (1.3%)
Abnormal dreams
2 (1.3%)
•Applied: axilla
•Starting dose: 60 mg (2 pumps)
•Max dose: 120mg (4 pumps)
•Follow up: blood draw 2 – 8 hours after
applying and at least 14 days after starting
treatment
41
3/4/2014
Axiron Adverse Effects
Axiron Application Instructions
Adverse Event
• “Keeping the applicator upright, patients
should place it up into the axilla and wipe
steadily down and up into the axilla. If the
solution drips or runs, it can be wiped back up
with the applicator cup.”
• Apply deodorant BEFORE applying Axiron.
• Swim or shower after 2 hours
8%
Application Site Erythema
7%
Headache
6%
Erythrocytosis
7%
Diarrhea
4%
Vomiting
4%
PSA increase
4%
Androgel 1.62%
•
•
•
•
Applied: shoulders and upper arms
Starting dose: 40.5 mg (2 pumps)
Follow up: a single blood draw at approximately
14 days and 28 days after starting treatment
• Swim or Shower after 2 hours
Percent at 180 days
Application Site Irritation
Androgel Comparison
Application site
Starting pumps
Starting dose
Androgel 1%
Androgel 1.62%
Shoulders, upper arms,
abdomen
Shoulders, upper arms
4
2
50mg
40.5mg
Maximum dose
100mg
81mg
Time to swim or shower
6 hours
2 hours
$250 to $300
???
Cost
42
3/4/2014
Androgel 1.62% Serum Concentrations
Testopel®
• Applied: subcutaneously in side of hip or
abdomen
• Dose: 1 pellet = 75 mg of testosterone
• Starting dose: 10-12 pellets
• Duration: 3-6 months
• Follow up: serum testosterone at 1 and 4
months after insertion
Subcutaneous Testosterone Pellets
43
3/4/2014
Results:
Side Effects
• Medical records of 80 patients with 292
insertions evaluated. (Dec 2003 – April 2008)
• The patients had between 1 (n=22) and 13
(n=1) insertions
• Mean age: 46.6
• Mean dose: 13 pellets (975 mg)
Four (4) adverse events reported (1.3%,
4/292)
– contact dermatitis (1); pruritis and erythema (1); infection
(1);
foreign body reaction (1)
Infection rate (0.3%, 1/292)
No spontaneous pellet extrusion (0.0%, 0/292)
Cavender, RK Fairall, M . J Sex Med. 2009;6:3177-3192
Summary of Adverse Effects
Oral tablets
− Effects on liver and cholesterol
(methyltestosterone)
Pellet implants
− Infection
− Expulsion of pellet
− Pain at implant site
Intramuscular injections
(testosterone enanthate or cyplonate)
– Fluctuation in mood or libido
– Pain at injection site
– Excessive erythrocytosis (especially
in older patients)
– Nonreversible, cannot be extracted
Transdermal patches
− Skin reaction at application site
Transdermal gel
− Potential risk of secondary
exposure
Buccal testosterone tablet
– Alterations in taste
– Irritation of gums
Bhasin S, et al. J Clin Endocrinol Metab. 2006;91:1995-2010.
Cavender, RK Fairall, M J Sex Med 2009;6:3177-3192
Testosterone: Recommended Monitoring
Testosterone enanthate or
cypionate IM
Midpoint morning
total testosterone
Testosterone patch
3-12 h post dose
Testosterone gel
Any time after 1-2 wks
Bioadhesive buccal
testosterone
Immediate preRx
Testosterone pellets
Not specified
Testosterone undecanoate
Not specified
Bhasin S, et al J Clin Endocrinol Metab 2006;91:1995-2010
44
3/4/2014
Monitoring after Initiation of Testosterone
Replacement Therapy
• Symptom Assessment
• Testosterone Levels
On the Horizon
• OriTex by Clarus (phase III)
• Androxal by Repros (phase III)
• New longer acting (>1 year) testosterone delivery
systems are currently in development
• PSA
• DRE
• Hematocrit
Conclusion
Too Much Testosterone Can Be Harmful
To Your Health
• There continues to be is rapid growth of the TRT
market
• There are now numerous testosterone treatment
options available for the hypogonadal patient
• Convenience, compliance, cost, and serum
concentrations all play an important role in patient
and physician TRT selection
45
3/4/2014
Alternative Therapies
To Stimulate Testosterone
Clomiphene
André Guay MD, FACP, FACE
Director, Center For Sexual Function
Endocrinology
Peabody, MA
Tufts University School of Medicine
Boston, MA
CLOMIPHENE CITRATE REVERSES FUNCTIONAL
HYPOGONADOTROPIC HYPOGONADISM WITH
VARIABLE EFFECT ON ERECTILE DYSFUNCTION
CNS
Stimulation
_
Hypothalamus
Hypothalamic-Pituitary
Portal System
GnRH
Posterior
Pituitary
Anterior
Pituitary
LH
FSH
+
Testis
Sertoli
Cells
Sperm
Inhibin

N = 178

Clomiphene 50mg MWF
– For 4 months
– Success: >75% int.
success
 Home logs of activity
_

+
Leydig
Cells
Testosterone
Estradiol
Norm. Sex.Function: 39%
– Partial improvement: 36%
25
Base
4moRx
21.2
20
Free T (pg/ml)
Production and Regulation of Testosterone
18
17.6
15
10
9.3
9.2
Resp
Part
Resp
9.8
5
0
NonResp
Guay et al. Int J Imp Res. 2003; 15:
46
3/4/2014
CLOMIPHENE CITRATE REVERSES FUNCTIONAL
HYPOGONADOTROPIC HYPOGONADISM WITH
VARIABLE EFFECT ON ERECTILE DYSFUNCTION
Clomiphene Citrate Effects on Testosterone / Estrogen
Ratio in Male Hypogonadism
Predictors of Clomiphene Response
Condition
Younger age
Hypertension
Diabetes Mellitus
Multiple Medications
Odds Ratio
2.27
0.78
0.45
0.54
Message: When normalization of testosterone does not
correct the sexual problem, other medical (org. or psych.)
factors are playing a part.
•
•
•
N = 36 men, mean age 39 years
Clomiphene, 25 mg QD for 6 weeks
T/E ratio increased from 8.7 to 14.2
Guay et al. Int J Imp Res. 2003; 15:
Shapsigh et al J Sex Med 2005
Outcomes of Clomiphene Citrate Treatment in
Young Hypogonadal Men
Clomiphene citrate and Testosterone Gel Replacement Therapy for Male
Hypogonadism: Efficacy and Treatment Cost
•
•
•
•
Treatment with the gels much more
expensive than with clomiphene
No difference in Hct, PSA, or lipids
(PSA rose 0.2 ng/mL)
No difference on blood levels
No difference in + sexual effects
•
•
•
N = 86 men, aged 22-37
Hypogonadism: TT < 300 ng/dL
Most had cc of infertility
•
Rx: CC 25 mg QOD (70%)
•
Rx duration = mean 19 months
•
Long-term follow-up shows CC to be
safe and effective
– 30%  to 50 mg QOD
– No side effects recorded during the
study
Taylor and Levine (Chicago) J Sex Med 2010; 7: 269-276
Katz, Mulhall, et al (NYC) BJU Int 2011; e-pub DOI: 10.1111/j.1464-410X.2011.10702
47
3/4/2014
Androxal Background
•
•
•
•
•
Androxal
Composition and use patent applications for trans isomer of clomiphene
citrate
Anti-estrogen
Only therapy in development that restores testicular function
Therapy addresses majority of men with low T
Clomid has been used off label but company believes estrogenic activity
and half-life of cis isomer prevent approval for indication
RO
RO
Cl
C
C
C
trans
Cl
C
cis
R=(C2H5)2NCH2CH2
ZA-003 Interim Analysis
Total Testosterone by Month of Treatment
LH by Month of Treatment
12.5 mg Androxal
25 mg Androxal
Androgel
14
500
12
400
10
LH mIU/ml
Total Testosterone ng/dl
Androgel
600
300
200
100
0
12.5 mg Androxal
25 mg Androxal
8
6
4
2
baseline
Month1
Month 2
Month 3
Bars indicate 95% Confidence Interval
Month 4
0
baseline
Month1
Month 2
Month 3
Month 4
Note: Approximately 15 patients have completed Month 4
48
3/4/2014
Comparison of FSH
Baseline vs Month 3
Androgel
12.5 mg Androxal
25 mg Androxal
15
12
Arimidex
FSH
9
6
3
0
Baseline
3 Months
Exogenous T suppresses FSH and leads to infertility
Androxal maintains or improves fertility via FSH effects
Production and Regulation of Testosterone
CNS
Stimulation
_
Hypothalamus
Hypothalamic-Pituitary
Portal System
GnRH
Posterior
Pituitary
Anterior
Pituitary
LH
FSH
+
Testis
Sertoli
Cells
Sperm
Inhibin
• Effect of aromatase inhibition in older hypogonadal men
– Clin Endo 2009; 70: 116-123
• T, DHT, Bio T, LH increased
• Estradiol and SHBG decreased
• PSA, BPH symptoms, Hct, lipids did not change
_
• Aromatase inhibition in idiopathic hypogonadotropic
hypogonadism
+
– South Med J 2003; 96: 544-547
Leydig
Cells
Testosterone
Stimulation of Androgens with
Aromatase Inhibition
Estradiol
• TT, Free T, LH were elevated
• Good alternative to raise T in secondary hypogonadism
49
3/4/2014
Effects of Aromatase Inhibition on bone Mineral
Density and Bone Turnover in Older Men with Low
Testosterone Levels
•
•
•
1 mg anastrozole QD for 12 mo
N=69 men completed the study
Hypogonadism= T bet 150-300
•
TT, Bio T, DHT increased with
anastrozole rx
Estradiol decreased
•
Effects of Aromatase Inhibition in Hypogonadal Older Men: a
Randomized, Double-Blind, Placebo-Controlled Trial
Burnett-Bowie et al (Boston) Clin Endocrinol 2009; 70: 116-123
– From 15 +/- 4 to 12 +/- 4
SHBG decreased as it does with T
therapy
•
Effects of Aromatase Inhibition on bone
Mineral Density and Bone Turnover in
Older Men with Low
•
•
•
BMD decreased in the
anastrozole group
•
CONCLUSION
Burnett-Bowie et al (MGH) J Clin Endo Metab 2009; 94: 4785-4792
No sig differences in fat or
muscle mass was seen
N=198 healthy men (20-50 yrs)
– GnRH agonist to  T and E
– 1% T gel: 1.25G, 2.5G ,5G ,10G
•
N = 202 healthy men (20-50 yrs)
– GnRH agonist
– 1% T gel at same doses
– Anastrozole to block E2 formation
•
– Aromatase inhibition does not
improve skeletal health in
aging men with low or lownormal testosterone levels
•
Gonadal Steroids and Body Composition, Strength,
and Sexual Function in Men
•
1 mg anastrazole QD for 12
months
T DHT, Bio T increased
Estradiol decreased 15 to 12
pg/mL
PSA did not change
•
•
•
Fig 2 A…….T levels increased the
same in the 2 cohorts
Fig 2 B…….E2 levels nearly
unmeasurably in the Anastrazole
group
Finkelstein et al (MGH) 2013; 369: 1011-22
50
3/4/2014
•
Panels A, C, D
– %  in body fat was + and not –
in men with E2 blockade
•
•
Panels B, E, F
•
Increases in sexual desire and
erectile function were not as
robust when estrogen was blocked
– So sexual function depends both
on androgen and estrogen
– %  in muscle mass and strength
was + with T levels and not E2
•
Androgen deficiency accounted for
decrease in muscle mass and
function
Estrogen deficiency accounted for
increase in body fat
Human Chorionic Gonadotropin (HCG)
• Predominantly LH
• Used to test Leydig Cell integrity
– In cases of early primary testicular atrophy
– Research
Human Chorionic Gonadotropin (HCG)
• Other indications:
– Ovulation induction
– Treatment of Kallman’s syndrome (hypo hypo)
• GnRH deficiency of the hypothalamus
• Lack of sense of smell and midline defects
• No data on chronic use and safety
• ? Effect on fertility potential
51
3/4/2014
Concomitant Intramuscular Human Chorionic
Gonadotropin Preserves Spermatogenesis in Men
Undergoing Testosterone Replacement Therapy
•
•
TRT leads to azoospermia in a minimum of 40%
Studied TRT concomitant with HCG therapy
•
•
N = 26 men, mean age of 35.9 years
Mean F/U was 6.2 months
Follow-up Guidelines
– 500 IU QOD
• No difference in semen parameters was seen in the men (up to 1 yr)
• No cases of azoospermia were noted
•
Giving HCG along with TRT seems to preserve fertility
Hsieh, Lipshultz et al (Houston) J Urol 2013; 189: 647-650
Potential Risks/Adverse
Effects of HRT
Testosterone Impacts on a Wide
Range of Male Functions
•
•
•
•
•
•
•
•
1
Sexual function and libido
1
Depression and fatigue
1
Body mass (muscle and fat)
1
Muscle strength
1
Bone mineral density
2
Red blood cells
Cognition
Sense of well-being / Quality of Life
•
•
•
•
•
•
•
•
Fluid and electrolyte disturbances
Hematologic reactions i.e.polycythemia
Liver toxicity (oral supplements)
Spermatogenesis suppression
Lipid abnormalities
Sleep apnea
Gynecomastia
Effects on prostate gland
1. Morales A et al. J Urol. 2000;163:705-712.
2. Morales A et al. Aging Male. 2001;4:151-162.
52
3/4/2014
Considerations with Testosterone
Replacement Therapy
RECOMMENDATIONS FOR
STANDARDIZED MONITORING
Baseline
 Hematocrit
1. DRE
2. PSA
3. AUA or IPSS score (<22)
4. Hct
(5.LFT’s)
 PSA, BPH*, and Prostate Cancer
 Sleep Apnea
F/U at 3- 6 months, 12 months, then yearly
 Edema in patients with or without pre-existing cardiac,
renal, or hepatic disease
1. DRE
2. PSA
3. AUA or IPSS score (<22)
4. Hct
5. (LFT’s)
 Patient monitoring required
Dean JD, et al. Rev Urol 2004;6 (suppl 6):S22-9.
Bhasin, Cunningham et al. J Andrology 2003; 24: 299-311
Summary
• Hypogonadism is underdiagnosed and undertreated
• As men age, their testosterone levels gradually diminish;
to hypogonadal levels in some men
• Andropause is characterized by changes in body fat/lean muscle
ratio; bone mineral density; cognition, memory, & mood; sexual
desire & function in the setting of low testosterone levels
• Testosterone replacement therapy can increase hormone levels to
normal ranges and improve symptoms
• Assessment of serum testosterone is essential for diagnosis
• Monitoring of hematocrit, PSA and DRE on a regular basis is
recommended for physicians prescribing testosterone
53
3/4/2014
Case History
52 year old male computer programmer
Additional Cases
C/O:  libido, early loss of erections (before ejaculation)
muscle strength  mental sharpness
energy and  fatigue (requiring PM naps)
moodiness and irritability (per wife)
Progressive symptoms for 2-3 years
Risk factors: HTN, chronic hepatitis C
Medications: HCTZ and Beta-blocker
Laboratory (in chart): SGOT 73 IU/L (11-40); SGPT 116 IU/L (7-40);
Alk Phos 75 IU/L (30-115); FBS 101 mg/dL; Tot Chol 210 mg/dL
Examination: Testes: 17-18cc bilaterally, normal consistency
Rectal examination normal
ARS Question
Case History (Con’t)
Does this man have enough symptoms to warrant a
testosterone level?
1.
Yes
2.
No, it is more likely that symptoms are due to his
hypertension and/or his meds
3.
No, His hepatitis C is probably the cause of his symptoms
4.
I don’t know ! That’s why I came to this meeting
Total Testosterone: 421 ng/dL…….at noon
Quest Laboratories……by LCMS
This looks very normal !!!
What now !!
54
3/4/2014
ARS Question
What should we do next?
1.
Change his BP medications
2.
Go back and evaluate the hepatitis C more closely
3.
Send the patient for a stress management course
4.
The testosterone level and symptoms do not jive
Repeat the testosterone level
Repeat Total Testosterone……at 8AM…..fasting
411 ng/dL
Well that rules out a laboratory error…..
ARS Question
OK, what do we do now…..
1.
Really need to refer him for a stress management course
2.
Refer to an endocrinologist / andrologist
3.
He has liver disease. Maybe his SHBG is 
I should get a free testosterone
4. He might have worse liver disease than I thought. He should
see his gastroenterologist
SHBG 91 nmol/L (13-71) Total T 430 ng.dL
Calculated free testosterone: 133 pmol/L (> 225)
Equilibrium dialysis free T: 36 pg/mL (50-200)
Further laboratories: LH 5 IU/L (2-9); Prolactin normal
PSA 1.2 ng/mL
Started testosterone gel treatment……5 Gm QD
In 1 month: calculated free T was 320 pmol/L
55
3/4/2014
Case #4
Case History (Con’T)
Factors Affecting SHBG Levels
INCREASES SHBG
DECREASES SHBG
HIV
Opioids
Liver disease
Androgens
Hyperthyroidism
Hypothyroidism
Estrogens
Nephrotic syndrome
Anticonvulsants
Glucocorticoids
Low testosterone
Acromegaly
Age (1%/year)
Obesity (IR)
• JB is a 44 y/o male with DM, HTN, obesity and
history of back pain. He complains of
decreased energy and new onset ED for the
past 9 months. He is married and has a 6
month old daughter.
• PE:
•
•
•
•
Height: 5’4”, Weight 220 lbs
BP: 157/90
Testis 14cc, normal circ phallus
DRE 30 grams, benign
Adapted from Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010.
Important considerations before
starting TRT
• Does JB want to have any further children?
• Is he on chronic opioids for his back pain?
• What other causes could be contributing to JBs
ED and fatigue?
Which of the following TRT options would
not be a good option for JB?
1.
2.
3.
4.
5.
Testosterone patches
Testosterone gels
Testosterone injections
All of the above
56
3/4/2014
What lab does not need to be
monitored regularly during TRT?
1.
2.
3.
4.
5.
LFTs
Hemoglobin
PSA
Testosterone
None of the above
Case #5
• 66-yr-old urologist returns from 2 wk European
trip
• Unsuccessful welcome home intercourse
• Partner noted low libido x 6 months,
– not appreciated by patient
• PDE5i trial unsuccessful
• Labs: total T <85ng/dl, free test <1
• Called tertiary MD for a replacement program
– “Physician who treats himself has a fool for a
patient”
• Testosterone 200mg q 2wks – return of erections
Case #5 Cont’d
• Recheck labs: Total T = 450ng/dl; prolactin =
185
• MRI – solitary 1cm lesion involving pituitary
stalk
• Started Dosimex (caberlogine) 20mg 2x/wk
• Repeat labs: prolactin WNLs
• Repeat MRI: tumor now ½ cm
57
3/4/2014
Before – 11-23-09
After - 6-4-10
Questions & Answers
58
TREATMENT OPTIONS FOR THE
HYPOGONADAL PATIENT
Baylor College of Medicine
TRT Market Overview
Drivers Behind
Future Growth
TRT Market $ (000)
2500
2000

Aging population

Increased link of
Low T with poor
general health

Reduced concern of
TRT and PCa

New entries with
increased promotion

Direct to consumer
advertising
Two new gels
1500
TESTOPEL
1000
Androgel
Testiim
500
0
00
01
02
03
04
05
06
07
08
09
10
11
12
13
14
TRT Treatment Options
1
Important Considerations
The ideal testosterone formulation for hypogonadism would:
 Produce physiologic levels of testosterone for prolonged periods
 Have a favorable safety profile
 The dosing schedule and administration method would be
convenient for the patient.
 Ideally, the formulation would be reasonably priced.
Emerging Drugs for Hypogonadism
Expert Opin Emerging Drugs 2006; 11(4): 685-707
ELDELSTEIN D, DOBS A, BASARIA S.
Buccal




April 2011: Actient Pharmaceuticals LLC
Acquires U.S. Rights to STRIANT from
Columbia Laboratories
Applied: upper gum just above the incisor
tooth
Starting dose: 30mg q12 hours
Max dose: 30mg q12 hours
Striant Adverse Events
Adverse Events
Gum or Mouth Irritation
Percent
(n=98)
9.2%
Bitter Taste
4.1%
Gum Pain
3.1%
Gum Tenderness
3.1%
Headache
3.1%
Gum Edema
2.0%
2
Androderm
Applied: back, abdomen, upper arms,
or thighs
 Available doses: 2.5grams and 5 grams
 Starting dose: 24.3mg (5 grams) daily
 Max dose: 48.6mg (10 grams) daily

Androderm Adverse Events
Percent of
Patients
(n=122)
Adverse Event
Pruritis at application site
37%
Burn-like blister reaction
12%
Erythema at application site
7%
Vesicles at application site
6%
Prostate abnormalities
5%
Headache
4%
Allergic contact dermatitis
4%
Testosterone Injections
Main advantage: cost
Testosterone cypionate
18%
17%
150
16%
16%
15.1% 15.1%
14.7%
15%
TRT Share
15.8%
15.4%
15%
100
14%
50
14%
0
ay
-0
9
Ju
n-0
9
ar09
Ap
r- 0
9
M
8
13%
TRT Market
M
 200mg IM every 2 weeks
 100mg IM every week
 60 mg IM twice a week
200
15.6%
8
Ja
n-0
9
Fe
b09
Dosage
15.4%
No
v-0

18%
17%
250
De
c-0
 Sesame oil
 T1/2 = 10.5 days
17.2%
16.8% 16.8%
16.5%
300
Au
g08
Se
p08
O
ct08
Testosterone enanthate
17.5%
17.1%
350
TRT TRxs (000)

400
8
 Cottonsead oil
 T1/2 = 12 days
 Greater fluid retention
Ju
l-0
8

Ju
n-0

Generic Injections
3
Different Testosterone Levels
After Replacement Therapy
Patch or Gel
Normal range
Injection
Testosterone ng/dL
1400
1200
1000
800
600
400
200
0
0
3
5
7
12
Day
17
21
30
34
Adapted from Bhasin and Bremner. J Clin Endocrinol Metab. 1997;82:3-8
Testosterone gel (AndroGel ®1%) Unimed Pharmaceuticals and Solvay Pharmaceuticals, 2002
Testim





Applied: shoulders/upper arms
Starting dose: 50 mg (1 tube)
Max dose: 100mg (2 tubes)
Follow up: 14 days after initiation of therapy
Swim or shower: 2 hours
Testim Adverse Events
Testim
50mg
Testim
100mg
Application Site Reaction
2%
4%
BPH
0%
1%
HTN
1%
1%
Gynecomastia
1%
0%
Headache
1%
1%
Erythrocytosis
1%
2%
Taste Disorder
1%
1%
Adverse Events
4
New TRT Gels in the Market
Fortesta
Applied: Inner thighs
Starting dose: 40 mg (4 pumps)
 Max dose: 70mg (7 pumps)
 Swim or shower 2 hours after application
 Follow up: blood draw 2 hours after
applying gel at approximately 14 days
and 35 days after starting treatment or
after making a dose adjustment


Suggested Titration Schedule
Total Serum Testosterone
Concentration 2 hours Post
FORTESTA Application
Equal to or greater than
2,500 ng/dL
Dose Titration
actuations)
Equal to or greater than 1,250 and Decrease daily dose by 10 mg (1 pump
actuation)
Equal to or greater than 500 and
No change: continue on current dose
Less than 500 ng/dL
Increase daily dose by 10 mg (1 pump
actuation)
5
Fortesta Adverse Events
Adverse Events
Skin reaction
Number (%) of Patients
N = 149
24 (16.1%)
Prostatic specific antigen increased
2 (1.3%)
Abnormal dreams
2 (1.3%)
Axiron
 Applied:
axilla
dose: 60 mg (2 pumps)
 Max dose: 120mg (4 pumps)
 Follow up: blood draw 2 – 8 hours
after applying and at least 14 days
after starting treatment
 Starting
Axiron Application
Instructions
“Keeping the applicator upright, patients
should place it up into the axilla and wipe
steadily down and up into the axilla. If the
solution drips or runs, it can be wiped back
up with the applicator cup.”
 Apply deodorant BEFORE applying Axiron.
 Swim or shower after 2 hours

6
Axiron Adverse Effects
Percent at 180
days
Adverse Event
Application Site Irritation
8%
Application Site Erythema
7%
Headache
6%
Erythrocytosis
7%
Diarrhea
4%
Vomiting
4%
PSA increase
4%
Androgel 1.62%





Applied: shoulders and upper arms
Starting dose: 40.5 mg (2 pumps)
Follow up: a single blood draw at
approximately 14 days and 28 days after
starting treatment
Swim or Shower after 2 hours
Androgel Comparison
Application site
Starting pumps
Starting dose
Androgel 1%
Androgel 1.62%
Shoulders, upper arms,
abdomen
Shoulders, upper arms
4
2
50mg
40.5mg
Maximum dose
100mg
81mg
Time to swim or shower
6 hours
2 hours
$250 to $300
???
Cost
7
Androgel 1.62% Serum Concentrations
Testopel®





Applied: subcutaneously in side of hip or
abdomen
Dose: 1 pellet = 75 mg of testosterone
Starting dose: 10-12 pellets
Duration: 3-6 months
Follow up: serum testosterone at 1 and 4
months after insertion
8




Medical records of 80 patients with 292
insertions evaluated. (Dec 2003 – April 2008)
The patients had between 1 (n=22) and 13
(n=1) insertions
Mean age: 46.6
Mean dose: 13 pellets (975 mg)
Cavender, RK Fairall, M . J Sex Med. 2009;6:3177-3192
Results:
Side Effects

Four (4) adverse events reported (1.3%, 4/292)
– contact dermatitis (1); pruritis and erythema (1); infection (1);
foreign body reaction (1)


Infection rate (0.3%, 1/292)
No spontaneous pellet extrusion (0.0%, 0/292)
Cavender, RK Fairall, M J Sex Med 2009;6:3177-3192
9
Summary of Adverse Effects
Oral tablets
Transdermal patches
− Effects on liver and cholesterol
(methyltestosterone)
− Skin reaction at application site
Pellet implants
Transdermal gel
− Infection
− Expulsion of pellet
− Pain at implant site
− Potential risk of secondary
exposure
Intramuscular injections
Buccal testosterone tablet
(testosterone enanthate or cyplonate)
– Fluctuation in mood or libido
– Pain at injection site
– Excessive erythrocytosis (especially
in older patients)
– Nonreversible, cannot be extracted
– Alterations in taste
– Irritation of gums
Bhasin S, et al. J Clin Endocrinol Metab. 2006;91:1995-2010.
Testosterone: Recommended Monitoring
Testosterone enanthate or
cypionate IM
Midpoint morning
total testosterone
Testosterone patch
3-12 h post dose
Testosterone gel
Any time after 1-2 wks
Bioadhesive buccal
testosterone
Immediate preRx
Not specified
Testosterone undecanoate
Not specified
Bhasin S, et al J Clin Endocrinol Metab 2006;91:1995-2010
Monitoring after Initiation of
• Symptom Assessment
• Testosterone Levels
• PSA
• DRE
• Hematocrit
10
On the Horizon



OriTex by Clarus (phase III)
Androxal by Repros (phase III)
New longer acting (>1 year) testosterone
delivery systems are currently in development
Conclusion



There continues to be is rapid growth of the
TRT market
There are now numerous testosterone
treatment options available for the hypogonadal
patient
Convenience, compliance, cost, and serum
concentrations all play an important role in
patient and physician TRT selection
Too Much Testosterone Can Be
Harmful To Your Health
11

065IC Testosterone - American Urological Association

Transcription

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