ANDROPAUSE:

A Summary
WULAN REKSA FORTUNA
GI1A114085
 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;
 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.

Table 1. Influence of age on hormone levels in men

Age Total SHBG (nM) Free

Testosterone Testosterone
(nM) (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
 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 Lower GnRH pulse amplitude

Attenuation of diurnal pulsatility
More sensitive to negative feedback

Pituitary

E
Reduced Leydig cell number
Impaired Leydig cell function
Testes

T
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 Relative

 Documented hx of  Hct 52% or more

prostate CA
 Untreated sleep apnea
 Hx of breast CA
 Severe obstructive sx of
 Hct 55% or more BPH

 Sensitivity to ingredients  Advanced CHF (NYHA

in T formulations 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