February 5-8, 1998 in Geneva, Switzerland
The life span of males is shorter than that of females - even in industrialized countries with good medical care. The International Society for the Study of The Aging Male was established with the aim of improving the quality of life in aging men . More than 350 scientists, clinicians and experts of different fields of interest, and representing 42 countries, met at the 1st World Congress in Geneva to consider the present knowledge, to pose open questions and appraise the best ways to solve them.
Some cornerstones on the way to healthy aging were revealed in the prospective Massachusetts Male Aging Study (MMAS):
Screening for prostate specific antigen (PSA) and intervention at rising levels lowers mortality from prostate cancer. Since risk factors for erectile dysfunction are in part similar to those known for cardiovascular disease, prevention is possible by stopping smoking, control of hypertension and diabetes. Benign prostate hyperplasia (BPH) clearly decreases quality of life. Treating the symptoms of prostism makes the patient feel better. Beyond the age of 55, many men are aware of decreasing virility, decreasing muscle strength, decreasing physical and cognitive performance, mood and sleep disorders and disturbances of sexuality. Although many suffer mostly from erectile impotence, they often remain reticent and suffer silently. If a urologist is consulted, the complaints center around BPH symptoms - as long as the physician does not ask the patient about other symptoms and signs of aging or inquire into the patient's sexual function (the patient will only rarely volunteer such information), the patient's quality of life will deteriorate, underlying causes of disease may go undiagnosed and preventive or therapeutic measures may be ignored.
Which role do hormones play?
According to recent studies, many of the symptoms of aging and decreasing virility show an association with declining hormone levels. But beyond all doubt, most of these symptoms are multifactorial. No substitution what so ever should be started without clear evidence of relevant symptoms supported by results from laboratory investigations and screening for prostate cancer. For the time being, scientifically established risk-benefit ratios for most of the substitution candidates have not been validated, and controlled randomized studies are urgently needed.
Testosterone: There is firm evidence of a decline of free and total testosterone, beginning at the age of 40. Total testosterone levels decrease approximately one percent per year - although wide individual differences are documented. Twenty to 30 percent of men over 65 show levels below the lower limit, which would define a young man as hypogonadal. There is however no consensus on the specific threshold level for testosterone deficiency in older men - nor is there agreement on the protocols or forms of testosterone replacement. Most experts will treat older men with clear symptoms of partial androgen deficiency. The open question is: Do aging males need substitution to levels of young men or should they be given smaller or higher doses, because some of the androgen responsive organs of the aged male are more and some less sensitive? Open for discussion is also the preferred form of replacement - tablets, plaster, ointments, depots? Still in research are new developments such as: selectively acting androgens like MENT, androgen receptor modulators (SARMs) as well as alpha-reductase-blocker(s). Testosterone substitution may have the risk of exacerbating an existing prostate cancer. On the other hand, a definitely higher risk for prostate cancer is associated with longevity: If men grow older, the percentage of detected carcinomas will rise, as do the cases of symptomatic BPH irrespective of any hormonal intervention. Uncontrolled studies, misuse, and charlatans can therefore easily bring testosterone substitution into discredit.
In a 3-year controlled study performed in Atlanta the side effects of testosterone replacement therapy were limited and predictable as long as PSA levels were controlled. On a long-term basis the benefits for bone and body composition will still have to be proven in larger well controlled studies, which may reveal also a positive effect on myocardial infarction and stroke, and will permit assessing the magnitude of unwanted reactions such as liquid retention, exacerbation of sleep apnea, and stimulation of an undiagnosed BPH, or prostate cancer.
Estrogens: Estrogens are declining in aging men. These sex hormones act as anti-androgens, are antiatherogenic and are supposed to play a crucial role in bone and brain metabolism. For men, non-feminizing estrogen derivatives such as scavestrogens are under active investigation.
Melatonin: In aging men melatonin secretion decreases, and the circadian periodicity of melatonin is gradually disrupted. This deterioration is correlated with increase in sleep disorders. Sleep in these older men is shallow and fragmented. These alterations influence particular growth hormone secretion, which occurs with deeper stages of sleep (Slow wave sleep). Melatonin, the "sleep hormone" can not generate sleep, but initiates it and modulates its quality. To date, with the present short acting preparations there is no consensus on either the criteria for substitution or the dosage. Physiological and pharmacological doses showed only minor differences on sleep quality. Studies on long acting preparations imitating the physiological nightly elevations of melatonin are being actively studied. Such preparations should be suitable for patients with disorders in sleep rhythm, which are frequent in aging men and can also be induced by benzodiazepines. Growth Hormone (GH): A lot of "white spots" cover the ground of the growth hormone, which declines in age - and crucially in men with disturbances in the first period of deep sleep. During the slow wave sleep men produce, in contrast to women, the major proportion of this hormone. Sleeping disturbances can therefore cause GH deficiency, which can be aggravated by inactivity and obesity. The risks of a possible substitution - impaired glucose tolerance, tumor promotion - are still to be evaluated, as are the doses.
Dehydroepiandrosterone (DHEA): The decline of DHEA with age is much sharper compared to testosterone. DHEA could therefore be a marker for physiological aging. The MMAS revealed a positive association with spatial performance; but there is a major lack of studies concerning substitution. The effect will become somewhat clearer after a study is finished in which DHEA is given to patients suffering from DHEA deficiency (some adrenal dysfunctions).
Prophylaxis has to start at home
Patients can be counseled to start their "own antiaging program" in getting more active, start to exercise, and loose weight if obese. This will quite physiologically lead to tiredness, better sleep, and consequently higher GH levels. Melatonin secretion will rise, too - provided the patient does not sleep in front of the TV or with full lights; the secretion can also be increased by eating only small portions or nothing at all before going to bed (dinner canceling). How to increase testosterone was an open secret in the old days in China: coitus and scrotum massage. The general feeling on testosterone substitution was that since most of the symptoms of hormone deficiency in the aging male are multifactorial, substitution therapy can not be based on a single complaint and must be supported by laboratory evidence. Before substituting testosterone, laboratory and clinical tests (including lipids, glucose metabolism, blood pressure, PSA, rectal exam) are mandatory.
Outlook for the future
In the not too distant future, it should be possible to treat the aging male by substituting one or more hormones according to his symptoms and proven deficiencies. This should prolong their self-sufficiency, delay or avoid many of the symptoms of aging and give them - if not a longer - at least a healthier life. This was the consensus and hope of the experts. But before recommending substitution therapy to the broad public, the open questions have to be answered by controlled studies with statistical power. The International Society for the Study of the Aging Male therefore will not be content with creating awareness for the problems, but calls for a multidisciplinary effort in research and study to end up with clear guidelines for healthy aging of men.
Renate Leinmuller, Germany and Bruno Lunenfeld, Israel