ANDROPAUSE:
A Summary
Resident’s Conference
September 27, 2005
David W. Wilde, M.D.

Definition
 “Andras” in Greek meaning human male
 “Pause” in Greek meaning a cessation
 A syndrome in which the changes accompanying
ageing are associated with the signs and symptoms
of androgen deficiency in the older male
(traditionally age >50). Signs and symptoms are
accompanied by a low serum testosterone level.

Definition Continued…
 This is not the same as the mid-life crisis
 Other terms:
Male Menopause
Male Climacteric
Androclise
Androgen Decline in the Ageing Male
(ADAM)
Ageing Male Syndrome (AMS)
Late Onset Hypogonadism

History: An Old Concept
 16TH century Chinese text of Medicine
provided a series of symptoms believed to
be the male equivalent of menopause
 In 1889, at age 72, distinguished French
neurologist & physiologist Charles E. Brown-
Sequard reported in Lancet, the
rejuvenating effects of self-administered
extracts of dog and guinea pig testes

History Continued…
 Brown-Sequard administered 5
subcutaneous doses of extract
prepared from dog testicles over a
three day period. This was followed by
5 more injections of extract from
guinea-pig testes over the following 18
days. He reported in Lancet...

History Continued…
The day after the first subcutaneous injection, and
still more after the two succeeding ones, a radical
change took place in me…I had regained almost all
the strength I possessed a good many years
ago…My limbs, tested with a dynamometer, for a
week before my trial and during the month following
the first injection, showed a decided gain of
strength…I have had a greater improvement with
regard to the expulsion of fecal matters than in any
other function…With regard to the facility of
intellectual labour, which had diminished within the
last few years, a return to my previous ordinary
condition became quite manifest.

History…
 1935, Butenandt & Ruzicka received the
Nobel Prize in Chemistry after synthesizing
testosterone in the laboratory.
 1946, Werner published a landmark paper in
JAMA entitled, “The male climacteric”.
Climacteric characterized by nervousness,
reduced potency, decreased libido,
irritability, fatigue, depression, memory
problems, sleep disturbances, and hot
flushes.

Epidemiology
 Fig. 1. Hypogonadism in aging men. Total testosterone less than 11.3 nmol/L (325 ng/dL) (shaded bars). Total testosterone/SHBG (free T index) less
than 0.153 nmol/nmol (striped bars). Numbers above each pair of bars indicate the number of men who were studied. (From Harman SM, Metter EJ, Tobin
JD, Pearson J, Blackman MR. Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy
men. J Clin Endocrinol Metab 2001;86:724–31;

Table 1. Influence of age on hormone levels in men
Age Total
Testosterone
(nM)
SHBG (nM) Free
Testosterone
(nM)
25-34 21.4 +/- 5.9 35.5 +/- 8.8 0.43 +/- 0.1
35-44 23.1 +/- 7.4 40.1 +/- 7.9 0.36 +/- 0.04
45-54 21.0 +/- 7.4 44.6 +/- 8.1 0.31 +/- 0.08
55-64 19.5 +/- 6.8 45.5 +/- 8.8 0.29 +/- 0.07
65-74 18.2 +/- 6.8 48.7 +/- 14.2 0.24 +/- 0.08
75-84 16.3 +/- 5.8 51.0 +/- 22.7 0.21 +/- 0.08
85-100 13.0 +/- 4.6 65.9 +/- 22.8 0.19 +/- 0.08
Data from Vermeulin A, Kaufman JM, Giagulli VA. Influence of some biological
indexes on sex hormone-binding globulin and androgen levels in ageing or
obese males. J Clin Endocrinol Metab 1996; 81: 1821-6.

Prevalence of Hypogonadism When
Measuring Total Testosterone
 <5% for men in 20s & 30s
 12% for men in 50s
 19% for men in their 60s
 28% for men in their 70s
 49% for men >80
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of ageing on serum
total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin
Endocrinol Metab 2001; 86(2): 724-31.

Prevalence of Hypogonadism Using
Bioavailable Testosterone and Free
Androgen Index
From Morley JE, Perry HM. Andropause: an old concept in new clothing. Clinics in Geriatric
Medicine 2003; Vol 19, No 3.
Table 2. Prevalence of hypogonadism in older men.
Age (y) Percent Hypogonadal
Baltimore Longitudinal Mayo Clinic Canadian Physicians
40-49 2 2 5
50-59 9 6 30
60-69 34 20 45
70-79 68 34 70
80+ 91 -- --

Testosterone Effects
Schematic diagram of androgen action. Testosterone, secreted by the testis, binds to the androgen receptor in a target cell, either directly
or after conversion to dihydrotestosterone. Dihydrotestosterone binds more tightly than testosterone. The major actions of
androgens,shown on the right, are mediated by testosterone (solid lines) or by dihydrotestosterone (broken lines). (From Griffin JE.
Androgen resistance the clinical and molecular spectrum. N Engl J Med 326:611–618, 1992. Copyright 1992, Massachusetts Medical
Society).

Testosterone Effects Contd…
 Maintenance of male secondary sexual
characteristics & fertility
 Bone & muscle mass
 Muscle strength
 Erythropoiesis
 Cognition
 Sexual function
 Sense of well-being

Signs and Symptoms of the
Andropause
 Endocrine, somatic, sexual, psychological.
 Endocrine Symptoms:
erectile dysfunction, reduced
erectile quality, diminished
nocturnal erections, increased
abdominal fat/increased waist size

Signs & Symptoms Contd…
 Physical Symptoms:
 decreased vigor
 easily fatigued
 poor exercise tolerance
 diminished strength and muscle mass
 decrease in bone mineral density
 decreased body hair

Signs & Symptoms Contd…
Sexual Symptoms:
 decreased libido
 decreased sexual activity
 limited quality of orgasm
 reduced ejaculate strength
 reduced ejaculate volume

Signs and Symptoms Contd…
Psychological Symptoms:
 Mood changes
 Poor concentration
 Loss of motivation
 Reduced initiative
 Memory impairment
 Anxiety
 Depression
 Irritability
 Insomnia
 General reduction in intellectual activity
 Poor work performance

Normal HPTA

Pathophysiology of Andropause
Hypothalamus
Pituitary
Testes
Reduced Leydig cell number
Impaired Leydig cell function
Lower GnRH pulse amplitude
Attenuation of diurnal pulsatility
More sensitive to negative feedback
T
E

Pathophysiology contd…
Partition of testosterone in the circulation in young and old men

Diagnosis of Late Onset
Hypogonadism
 Screening beginning age 50 or 55
ADAM, MMAS
 Positive screen should be followed by check of total
testosterone
 If total testosterone (T) <200ng/dL, hypogonadism is present
regardless of age
 For total T 200ng/dL-400ng/dL, repeat and then obtain
calculated free T or obtain free T by equilibrium dialysis if
available
 Once T defficiency is established, obtain LH and prolactin

When to obtain an MRI?
1. Total T <150ng/dL
2. Subnormal or inappropriately low LH
3. Elevated prolactin
4. Patients complaining of new onset headaches,
reduced nocturnal penile tumescence and
impotence, who are found on exam to have
bitemporal hemianopsia

Other causes of post-pubertal
hypogonadism
 Pituitary adenomas
 Uremia
 Systemic illness
 Hyperprolactinemia
 Hemochromatosis
 Cushing’s Syndrome
 Cirrhosis
 Morbid obesity
 Cranial irradiation

Medications and low T
Decrease Leydig Cell T Production
corticosteroids
ethanol
ketoconazole
Bind to the Androgen Receptor
spironolactone
flutamide
cimetidine
Decrease Gonadotropin Secretion
corticosteroids
ethanol
estrogens
progestins (Megace)
Rx that raise prolactin (opiates, metoclopramide, psych meds)
Decreases Conversion of T to DHT
finasteride

Contraindications to
Testosterone Replacement
Therapy (TRT)
Absolute
 Documented hx of prostate
CA
 Hx of breast CA
 Hct 55% or more
 Sensitivity to ingredients in
T formulations
Relative
 Hct 52% or more
 Untreated sleep apnea
 Severe obstructive sx of
BPH
 Advanced CHF (NYHA
III/IV)

TRT Monitoring
Baseline
 Voiding hx
 Hx of sleep apnea
 Digital rectal examination
 Baseline Hb/Hct, PSA, T
 Prostate bx if PSA above 4.0 ng/ml or abnormal
prostate exam

Monitoring TRT Contd…
Follow-up
 Sx monitoring
 T levels
 DRE & PSA at 3 mos., 6 mos., then annually
 CBC with PSA
 Urinary sx, sleep apnea sx, gynecomastia

Available T Preparations
Testosterone Esters for IM Injection
Testosterone cypionate and enanthate
100mg-200mg every 7 to 14 days
 Inexpensive
 Well tolerated
 Provides robust T levels
 Large fluctuations in T levels
 Up to 25% of users develop polycythemia

Preparations contd…
Transdermal Patches
 Restores normal circadian variations in T levels
 Patches are applied daily
 Scrotal (Testoderm), apply in the morning
 Non-scrotal (Androderm, Testoderm TTS), apply at bedtime
 Skin irritation common
 Patches may fall off during exercise
 More expensive than injections
 Dosages more difficult to adjust
 Require monitoring of peak a.m. T levels
 Lower incidence of erythrocytosis than I.M. preparations

Preparations contd…
Transdermal Testosterone Gel (Androgel, Testostim)
 1% testosterone gel
 Provides steady serum T levels within reference range
 10% of T is absorbed
 Dose 5g-10g daily, easy to titrate
 Pump now available
 Disadvantages: $$$, transfer to intimate contacts, need to check
a.m. peak T. Skin irritation rare

Serum testosterone (a) and free testosterone concentrations (b) in patients receiving
testosterone gel 5 (closed circles), 7.5(closed squares), and 10g/d(closed triangles). The dotted
lines represent the adult male reference range
Jockenhovel F et al. The good, the bad, and the unknown of late onset hypogonadism: the urological perspective.
Journal of Men’s Health and Gender. September 2005, Vol 2, No. 3.

Preparations Contd…
Buccal Delivery (Striant)
Buccal tablets are applied to the gums bid. The tablet swells
and adheres to the gum. Testosterone levels are maintained
within the normal physiologic range
Oral Preparations
Alkylated androgens not used for tx of hypogonadism.
Hepatotoxicity
Andriol—not alkylated, not widely used. Absorbed via
intestinal lymphatics—must be taken with a fatty meal

Risks of Therapy
Coronary Artery Disease
 1940s T was used to treat angina.
 Relation of androgens and cardiovascular dz complex
 Testosterone administered to hypogonadal and eugonadal men is
associated with a small, dosage-dependant reduction in HDL.
 Studies overwhelmingly show reduced or no change in total
cholesterol and LDL.
 Cross sectional studies consistently show a strong correlation
between low T and hyperinsulinemia, reduced glucose tolerance.
 Available literature suggests a neutral or favorable relationship
between serum androgen levels and cardiovascular disease in men.

Risks contd…
Erythrocytosis
 Most common with I.M. preparations
and tends to be dose-related.
 Theoretic risk of thromboembolic
events but no reports of this
 Easily treated by dosage reduction,
blood donation or therapeutic
phlebotomy

Testosterone and the
Prostate
BPH
 At least 8 recent studies have failed to demonstrate
exacerbation of voiding symptoms during T
supplementation
 Complications such as urinary retention do not
occur at higher rates than in controls
 In hypogonadic men, prostate volumes do increase
rapidly after initiation of T therapy to values similar
to men without hypogonadism

Testosterone and the
Prostate
Prostate Cancer
 Prospective studies have demonstrated a
low frequency of prostate cancer in
association with TRT
 A compilation of published prospective
studies demonstrated 5 cases of prostate CA
among 461 men (1.1%)
 However, the men in these studies were
only followed for 6-36 months

Study Duration Prostate CA T Prep
mo placebo T
Hajjar et al (1997) 24 0/27 0/45 I.M.
Sih et al. (1997) 12 0/15 0/17 I.M.
Dobs et al. (1999) 24 -- 1/33 I.M.
Snyder et al.(1999) 36 0/54 1/54 Patch
Snyder et al.(2000) 36 -- 0/18 Scrotal
Wang et al. (2000) 6 1/227 Transder
Kenny et al. (2001) 12 0/33 0/34 Patch

Testosterone and the
Prostate
 Occult Prostate CA in hypogonadal men has been reported
 Routine sextant bx in men with ED and low T revealed CA in
11 (14%) (Morgentaler A, Bruning CO, JAMA 1996)
 Most men were >60 years
 All had normal PSA and DRE
 There have been a handful of case reports of TRT unmasking
an occult prostate CA

Testosterone and the
Prostate
Prostate biopsy recommended when:
1. Change in DRE
2. PSA rises above 4.0.ng/ml or if it
increases by more than 1.5ng/ml/yr
or by more than 0.75ng/ml/yr over 2
yr (Endocrine Society)

Other Potential Side Effects
Hepatic
Alkylated agents associated with
hepatotoxicity and benign and
malignant tumors. I.M. and
transdermal preparations do not
appear to be associated with hepatic
dysfunction

Side Effects Contd…
Sleep Apnea
TRT has been associated with the
development or exacerbation of sleep apnea
in some studies. Upper airway dimensions
do not seem to be affected. It is believed
this is mediated centrally. Association is
most clear in men on higher doses of
parenteral T with other risk factors for sleep
apnea.

Side Effects Contd…
 Breast tenderness
 Gynecomastia
 Compromised fertility
 Change in testicle size
 Skin reactions
 Fluid retention
 Acne/oily skin
 Increased body hair

So Why Treat?

Summary
 Dx requires symptoms of hypogonadism with low
serum testosterone
 Current evidence is lacking regarding screening for
hypogonadism in the general population
 Total T is currently most validated test
 Prostate screening is essential
 Monitor prostate, hct, and T levels. Also ask pt’s
about sleep apnea and adverse rxn’s
 Goal is to keep T in mid-normal range
 Never use T in pt with hx of prostate or breast CA