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Editorial: Andropause

Is It Time for the Geriatrician to Treat It?

^a Division of Geriatric Medicine, Saint Louis University and Geriatric Research Education and Clinical Center, VA Medical Center, St. Louis, Missouri

THE concept of a male "menopause," or andropause, is not new, having been first alluded to in the 16th-century Chinese text of Internal Medicine ⁽¹⁾. The French neurologist Brown-Sequard claimed to reverse many of the aging effects he experienced at 70 years of age with the injection of testicular extracts, although he did acknowledge that this could be a placebo effect. Ernest Hemingway took testosterone to boost his failing energy and libido for the last 10 years of his life.

However, until recently, much controversy has existed as to whether or not testosterone levels in men decline with age. Cross-sectional studies have clearly demonstrated a decline in testosterone and an increase in sex hormone binding globulin with age ⁽²⁾. Recently, this was confirmed by a longitudinal study ⁽³⁾. When bioavailable or "weakly bound" testosterone (a measure of the free and albumin-bound testosterone) is measured, there is an even more marked decline with age ⁽⁴⁾. Studies using bioavailable testosterone suggest that 5% of males aged 40 to 50 years and 70% of males aged 70 years are hypogonadal ⁽⁵⁾. The majority of these males have secondary hypogonadism due to chaotic secretion of gonadotrophin-releasing hormone from the hypothalamus ^{(6) (7)}.

Decline in sexual activity with age is found in most men ⁽⁸⁾. Testosterone replacement therapy has been clearly demonstrated to reverse diminished libido in older men ⁽⁹⁾. Testosterone, because of its effect on nitric oxide synthase, may also improve erectile capacity in older men ⁽¹⁾.

However, the major effects of the testosterone decline with age appear to place the older man at risk for developing frailty ^{(10) (11)}. In fact, low bioavailable testosterone levels have been found to predict frailty in inner-city African-American males ⁽¹²⁾, and Bakshi and colleagues ⁽¹³⁾ found that testosterone increased the functional index measure in men undergoing rehabilitation. Testosterone has been demonstrated to increase muscle mass ⁽¹⁴⁾. When testosterone is administered at pharmacological doses, it increases strength and muscle protein synthesis ^{(13) (15) (16) (17)}.

Testosterone administration in older men decreases body fat ⁽¹⁴⁾. Leptin, a hormone produced by adiocytes, decreases food intake and increases resting metabolic rate ⁽¹⁸⁾. In male rodents ⁽¹⁹⁾ and humans ⁽²⁰⁾, leptin levels increase with age. Testosterone administration inhibits this increase in leptin levels ⁽¹⁷⁾. The increase in leptin levels has been suggested to cause the greater decline in food intake seen in older men compared with older women ⁽²¹⁾.

Bone mineral density (BMD) declines with age in men, and this has been demonstrated to be related to the decline in testosterone ⁽²²⁾. Minimal trauma hip fracture is associated with low testosterone levels ⁽²³⁾, and hip fracture is associated with major disability and frailty ^{(24) (25) (26)}. Snyder and colleagues ⁽²⁷⁾ previously reported an increase in BMD in older men with low testosterone who were receiving testosterone replacement.

In this issue of the Journal, Kenny and colleagues ⁽²⁸⁾ report a highly significant increase in femoral neck BMD compared with placebo control in men aged 65 to 87 who received a transdermal testosterone patch. This occurred even though all men received calcium and vitamin D as well. They also reported an increase in lean body mass and a decrease in body fat. There was a tendency for lower extremity strength to increase (p = .06). Because vitamin D levels decline with age and vitamin D deficiency is associated with muscle weakness ⁽²⁹⁾, they attributed this failure to see a significant increase in strength to the vitamin D replacement. However, three other possibilities exist: (i) lower limb strength is less sensitive than upper limb strength to testosterone replacement, (ii) higher serum levels of testosterone than can be obtained with the transdermal patch are necessary to improve strength, or (iii) larger numbers are necessary to demonstrate an increase in strength (i.e., the study was inadequately powered to detect significant changes in strength).

Whereas most authors have concentrated on the physical characteristics of frailty (i.e., generalized weakness, impaired mobility and balance, and poor endurance), it is clear that frailty can also be related to a decline in cognitive function. Testosterone is highly correlated with the decline in cognition that occurs with age ^{(30) (31)}. Two interventional studies have supported the concept that testosterone can improve cognitive function in older men ^{(32) (33)}. In the SAMP8, an animal model of Alzheimer's disease ^{(34) (35)}, testosterone replacement reverses memory deficits ⁽³⁶⁾. The testosterone replacement reduces the overproduction of amyloid precursor protein in the SAMP8. In vitro, testosterone decreases ß-amyloid production ⁽³⁷⁾. These studies support the concepts that testosterone may play an integral role in the age-related cognitive impairment that occurs in males and that low testosterone levels may play a permissive role in the pathogenesis of Alzheimer's disease.

Testosterone administration appears to have minimal side effects ^{(1) (9)}. The major side effect is an increase in hemoglobin. Some patients may develop gynecomastia or water retention. Testosterone is contraindicated in persons with prostatic cancer but appears to be safe in those with benign prostatic hypertrophy ⁽³⁸⁾. Transdermal preparations produce skin irritation.

Interestingly, in an editorial suggesting that "testosterone [may be] a natural tonic for the failing heart" ⁽³⁹⁾, testosterone has recently emerged as having positive effects on the cardiovascular system. Low testosterone levels are associated with increased atherosclerosis, and testosterone causes coronary artery vasodilation.

The development of the Saint Louis University symptom checklist for diagnosing the andropause clinically represents a major advance for the practicing clinician's ability to recognize this syndrome ⁽⁵⁾. This questionnaire has excellent sensitivity and specificity, and symptoms have been shown to be responsive to testosterone therapy. The availability of Androgel (a testosterone gel that can be applied directly to the skin) in addition to the patches and injections in the United States and Andriol (an oral form of testosterone that is absorbed through the lymphatics) in the rest of the world represents increasing choices for the patient's convenience and ease of administration.

In addition to andropause, older men are at increased risk of developing erectile dysfunction ⁽⁴⁰⁾. In the majority of cases, erectile dysfunction in older men has been demonstrated to be due to vascular disease ^{(41) (42)}. Older men with erectile dysfunction due to vascular disease have a markedly increased chance of having a stroke or myocardial infarction in the next 2 years ⁽⁴³⁾. For this reason it is essential to aggressively treat risk factors for atherosclerosis in these men. In the February issue of the Journal, Wagner and colleagues ⁽⁴⁴⁾ demonstrated that older men have an excellent erectile response to the phosphodiesterase-5 inhibitor sildenafil with minimal side effects.

A final question is whether or not women should receive testosterone postmenopausally. Hakkinen and colleagues ⁽⁴⁵⁾ suggest that a low level of testosterone in older women may be a limiting factor in developing adequate strength during resistance training. Testosterone replacement therapy in postmenopausal women has been shown to increase libido ⁽⁴⁶⁾ and provide an increase in BMD beyond that obtained with estrogen alone and to increase muscle mass ⁽⁴⁷⁾. At present there are inadequate data to recommend testosterone use routinely in postmenopausal women, but there are certainly sufficient data to support further studies in this area.

The emerging data seem to create a clear imperative for the geriatrician to look aggressively for hypogonadism in the older man and treat it when it is present. Testosterone treatment in older men who are hypogonadal appears to enhance quality of life and decrease many of the factors responsible for the development of the frailty syndrome. However, as previously pointed out by Evans ⁽⁴⁸⁾ in an editorial in the Journal, exercise still remains the safest and best approach to enhance muscle strength and to decrease the risk of frailty. Exercise may also delay the loss of BMD with aging (49).

	References

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