ANDROPAUSE A Summary Residents Conference September 27 2005

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

Definition n “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… n n 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 n n 16 TH 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… n 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… n n 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 n Fig. 1. Hypogonadism in aging men. Total testosterone less than 11. 3 nmol/L (325 ng/d. L) ( ) (shaded bars). Total testosterone/SHBG (free T index) less than 1. Hypogonadism nmol/L (325 ng/d. L 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, 0. 153 nmol/nmol ( 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 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 Testosterone (n. M) SHBG (n. M) Free Testosterone (n. M) 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 v <5% for men in 20 s & 30 s v 12% for men in 50 s v 19% for men in their 60 s v 28% for men in their 70 s v 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 or after conversion to dihydrotestosterone. androgens, shown on the right, are mediated by testosterone ( (broken lines). (From Griffin JE. androgens, shown on the right, are mediated by testosterone (solid lines) or by dihydrotestosterone ( Androgen resistance the clinical and molecular spectrum. N Engl J Med 326: 611– 618, 1992. Copyright 1992, Massachusetts Medical Society).

Testosterone Effects Contd… n n n n 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 n n Endocrine, somatic, sexual, psychological. Endocrine Symptoms: erectile dysfunction, reduced erectile quality, diminished nocturnal erections, increased abdominal fat/increased waist size

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

Signs and Symptoms Contd… Psychological Symptoms: Ø Ø Ø 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 Gn. RH pulse amplitude Attenuation of diurnal pulsatility More sensitive to negative feedback Pituitary E Testes T Reduced Leydig cell number Impaired Leydig cell function

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 § If total testosterone (T) <200 ng/d. L, hypogonadism is present regardless of age § § testosterone For total T 200 ng/d. L-400 ng/d. L, 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 <150 ng/d. L 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 Ø Ø Ø Ø Ø 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 100 mg-200 mg 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 5 g-10 g 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 10 g/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 § § § 1940 s 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 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 Hajjar et al (1997) Sih et al. (1997) Dobs et al. (1999) Snyder et al. (2000) Wang et al. (2000) Kenny et al. (2001) Duration Prostate CA T Prep mo placebo T 24 12 24 36 36 6 12 0/27 0/45 0/15 0/17 -1/33 0/54 1/54 -0/18 1/227 0/33 0/34 I. M. Patch Scrotal Transder Patch

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

Testosterone and the Prostate biopsy recommended when: 1. 2. Change in DRE PSA rises above 4. 0. ng/ml or if it increases by more than 1. 5 ng/ml/yr or by more than 0. 75 ng/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 Ø Ø Ø Ø 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