TAKE-HOME POINTS FROM LECTURES BY CLEVELAND CLINIC A N D VISITING FACULTY

MEDICAL GRAND ROUNDS WILLIAM 5. iU j n 1 j j j i >1 J ^mwÊÊÊÊÊÊm

Andropause, testosterone therapy, and quality of life in aging men

Hypogonadism may affect 5 million men in the US

JOHN E. MORLEY, MB, BCH* D i r e c t o r , D i v i s i o n o f G e r i a t r i c M e d i c i n e , S t . L o u i s U n i v e r s i t y H e a l t h S c i e n c e s C e n t e r , M i s s o u r i ; G e r i a t r i c R e s e a r c h , E d u c a t i o n , a n d C l i n i c a l C e n t e r , S t . L o u i s V e t e r a n s A d m i n i s t r a t i o n M e d i c a l C e n t e r

• ABSTRACT

Testosterone therapy can improve quality of life in aging men because aging is accompanied by declining testosterone levels that may contribute to decreases in muscle mass, bone density, libido, stamina, and cognition. Hypogonadal men can be identified by a test for bioavailable testosterone or by a free testosterone assay that uses dialysis or ultracentrifugation methods.

".. .The sixth age shifts Into the lean and slippered pantaloon With spectacles on nose and pouch on side; His youthful hose, well saved, a world too wide For his shrunk shank, and his big manly voice, Turning again toward childish treble, pipes And whistles in his sound..."

(William Shakespeare, As You Like It)

F T H E S E SYMPTOMS—muscle wasting, regression of secondary sexual charac-

teristics, a rising voice pitch—were to develop in a young man, we would have no difficulty in diagnosing hypogonadism. These symp-toms may signal hypogonadism in aging men as well.

' T h e a u t h o r h a s i n d i c a t e d t h a t h e h a s r e l a t i o n s h i p s w h i c h , i n t h e c o n t e x t o f h i s p r e s e n t a t i o n , c o u l d b e p e r c e i v e d a s p o t e n t i a l c o n f l i c t o f i n t e r e s t . H e h a s r e c e i v e d g r a n t s o r r e s e a r c h s u p p o r t f r o m M e r c k , N e s t e c , Baye r , a n d B. B r a u n M c G a w , a n d h a s s e r v e d o n t h e s p e a k e r ' s b u r e a u f o r L X N , O r g a n o n , G e r i M e d o f A m e r i c a , U n i M e d , E s s e n t i a , A l z a , P h a r m a c i a & U p j o h n , G l a x o W e l l c o m e , B. B r a u n M c G a w , B r i s t o l - M y e r s S q u i b b , H o e c h s t M a r i o n R o u s s e l , M e r c k , N o v a r t i s , P a r k e - D a v i s , S m i t h k l i n e B e e c h a m , a n d P f i ze r .

The common wisdom that men do not undergo menopause is being replaced: many aging men—perhaps 5 million in the United States—do experience androgen deficiencies that impair quality of life. For these men, testosterone replacement therapy may improve libido, muscle mass, bone mass, cog-nition, and energy levels.

• NATURAL HISTORY OF TESTOSTERONE

After age 30, levels of total and bioavailable testosterone in men decrease by 1% to 2 % per year.1 This decrease may be caused in part by decreased testosterone production and in part by slowly rising levels of sex hor-mone-binding globulin, the protein that binds testosterone and removes it from circu-lation. Levels of luteinizing hormone, which also affects testosterone bioavailability, do not rise until age 85 to 95.

These subtle changes may be easy to over-look because they develop over a longer peri-od of time than the changes associated with female menopause.

• IDENTIFYING TESTOSTERONE DEFICIENCY

"Andropause" can be defined as a complex of androgen-related symptoms that occur in the presence of low levels of testosterone.2 Symptoms include: • Decreased muscle mass or strength • Cognitive changes • Increased fat mass, particularly visceral fat • Osteoporosis • Low sense of well-being • Decreased sexual desire and impaired sex-

ual function • Mood changes, including depression, irri-

tability, loss of motivation, and lethargy

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• Regression of secondary sexual character-istics

• Impaired sperm production. Because many of these symptoms can be

attributed to aging or other medical causes, they may be ignored by both patients and physicians.2-^ Recently, evidence has accumu-lated that testosterone also plays an important role in maintaining function with aging.5

The Androgen Deficiency in Aging Males ( A D A M ) Questionnaire, together with a complete history and physical examination, is useful in identifying patients who may benefit from testing for hypogonadism (TABLE 1 ) . 6

• OTHER CAUSES OF H Y P O G O N A D I S M

Age is not the only cause of hypogonadism, which has an estimated prevalence of 4 to 5 million men.7 Other causes include primary testicular failure (either congenital, develop-mental, or acquired),8 obesity, severe systemic illnesses, malnutrition, AIDS, uremia, sickle cell disease, or hepatic cirrhosis.4

• TESTING FOR TESTOSTERONE

Plasma free testosterone tests are a good measure of the amount of bioavailable testos-terone because they measure serum testos-terone unbound by sex hormone-binding globulin. The traditional free testosterone test is actually an analog assay and is not as informative as a test that uses dialysis or ultra-centrifugation (which is cheaper and easier to perform than dialysis). The test that appears to be most useful at present is the bioavailable or weakly bound testosterone assay, which measures both free and albumin-bound testos-terone.

In contrast, the plasma total testosterone level may be less informative because it mea-sures both free testosterone and protein-bound testosterone.3 This test can produce normal readings even when age-related increases in sex hormone-binding globulin lower concentrations of bioavailable testos-terone. In addition, the test may have false-positive results in insulin-resistant men, because excess insulin lowers the concentra-tion of sex hormone-binding globulin, which can lower total testosterone levels even when

T A B L E 1

The ADAM* quest ionnaire

1. Has your libido or sex drive decreased? 2. Do you have a lack of energy? 3. Have your strength or endurance decreased? 4. Have you lost weight? 5. Have you noticed a decreased enjoyment of life? 6. Are you sad or grumpy? 7. Are your erections less strong? 8. Have you noted a recent deterioration in your ability to play sports? 9. Do you fall asleep after dinner?

10. Has your work performance deteriorated recently? Consider testosterone testing in any patient who answers "yes" to questions 1 or 7, or to any three others.

' A n d r o g e n Def ic iency in Ag ing Ma les

bioavailable testosterone is adequate. Another option is the calculated free

testosterone index. This has been validated in a recent study.9

Healthy men experience wide hour-to-hour and day-to-day fluctuations in testos-terone levels (up to 2 0 % over the course of a week), so symptomatic men with normal test results should be tested more than once.

If any of these tests confirm testos-terone deficiency, tests of gonadotropin lev-els will help determine whether the cause of the hypogonadism is primary (hyper-gonadotropic hypogonadism) or secondary to pituitary disease (hypogonadotropic hypogonadism). In the latter condition, gonadotropins fail to rise in response to low testosterone levels.

Serum prolactin levels should also be measured to screen for hyperprolactinemia. This can be caused by heart or renal failure, hypothyroidism, or a number of drugs.

• TESTOSTERONE THERAPY

The goals of testosterone therapy are to pro-vide and maintain normal levels of testos-terone, thus improving libido, psychological disposition, body mass, strength, stamina, and

The bioavailable testosterone assay is the test of choice for older men

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MEDICAL G R A N D R O U N D S

bone d e n s i t y . 2 - 3 , 1 0 Testosterone replacement improves quality of life but probably does not affect length of life.

Testosterone is available in oral capsules, intramuscular injections, transdermal patch-es, and transdermal gel.4 Unfortunately, intramuscular injections can produce widely fluctuating serum testosterone levels.11 The transdermal patch, although it provides more physiologic testosterone levels, may cause rashes.12

The latest addition to our armamentari-um is a 1% testosterone gel, available at dosages of either 50 mg daily or 100 mg daily. A large randomized trial found that this prod-uct provided steadier serum testosterone con-centrations than a 5 mg/day transdermal patch.13 Using testosterone gel may also min-imize skin reactions.

Both testosterone gel and the patch were

associated with improved libido within 30 days and continuing for up to 90 days. Gel therapy was also associated with improved mood and sense of well-being and a higher level of sexual enjoyment.

Other documented effects of testosterone therapy are increased upper body strength, improved lipid balance, better memory, beard growth, and coronary artery vasodilation. In a mouse model of Alzheimer disease, testos-terone reversed memory deficits by inhibiting overproduction of amyloid precursor pro-tein.'4 Testosterone may be beneficial for car-diovascular risk factors and for benign prosta-tic hyperplasia.5'15-17

Testosterone may increase the hematocrit and the risk of strokes. Testosterone therapy is not indicated for men with prostatic cancer, but there is no evidence that testosterone increases the risk of prostate cancer. •

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ADDRESS: John E. Morley, MB, BCh, St. Louis University Health Sciences Center, 1402 South Grand Boulevard, Room M238, St. Louis, MO 63104.

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