Male andropause: myth, reality, and treatment - Semantic Scholar

International Journal of Impotence Research (2002) 14, Suppl 1, S93–S98 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir

Male andropause: myth, reality, and treatment E Wespes1* and CC Schulman2 1

Department of Urology, C.H.U. de Charleroi, Charleroi, Belgium; and 2Erasme Hospital, Brussels, Belgium A progressive decrease in androgen production is common in aging men. The physiological causes for this phenomenon seem to be multifactorial. The magnitude of the decline in testosterone with age and the prevalence of older men with low testosterone levels have not been well established. The extent to which an age-dependent decline in androgen levels leads to health problems that might affect or alter the quality of life remains under debate. In men older than middle age, total testosterone levels may be misleading because of an increase in sex hormone-binding globulin levels. The mechanism of the age-associated decrease of the endocrine testicular function is also essentially due to primary testicular failure, but important changes occur at the hypothalamopituitary level. The most prominent endocrinological alterations with aging are related to the sex steroids, but others, such as growth hormone, melatonin cortisol, and thyroxine, are also affected. The clinical picture of andropause syndrome is characterized by diminished sexual desire and erectile capacity, decrease in intellectual activity, fatigue, depression, decrease in lean body mass, skin alterations, decrease in body hair, decrease in bone mineral density that results in osteoporosis, and increase in visceral fat and obesity. Current medical treatments for androgen supplementation include oral tablets, intramuscular injections, and scrotal and nonscrotal patches. Unfortunately, none of these preparations mimic the circadian rhythm, even if some of them may approximate the circadian rhythm by dose adjustments. Moreover, the androgen supplementation could have adverse effects on different organs, namely, the liver, lipid profile, cardiovascular disease, prostate, sleep disorders, and emotional behavior. Clinical response is a better guide to dose requirements, regardless of serum testosterone levels. This important field must be actively investigated by the medical, behavioral, and social sciences. International Journal of Impotence Research (2002) 14, Suppl 1, S93–S98. DOI: 10.1038= sj=ijir=3900798 Keywords: erectile dysfunction; male andropause; androgen; testosterone

Introduction Many investigations suggest that aging men experience reductions in androgen levels, virility, and fertility, along with related metabolic changes. Nonetheless, the question of andropause remains controversial, in part because of the difficulty in discriminating the effects of age-related confounding variables, such as stress, nonendocrine illnesses, malnutrition, obesity, and drug or medication use, from aging per se, on the other hand. The reproductive changes that occur in the aging male are more subtle than the profound modifications in gonadal function that occur in women. The term male menopause or andropause should not be used.

*Correspondence: E Wespes, Department of Urology, C.H.U. de Charleroi, Bld Paul Janson 92, 6000 Charleroi, Belgium. E-mail: [email protected]

Modifications of testosterone levels in diseases and lifestyle Acute critical illness1,2 or surgical injury3 cause a profound, generally transient, decrease of free testosterone ([F]T) levels. As far as chronic diseases are concerned, decreased testosterone and sex hormone-binding globulin (SHBG) levels are observed in elderly men with diabetes mellitus, with an inverse correlation between testosterone and plasma glucose.4 Coronary atherosclerosis has been reported to be associated with low testosterone levels.5 Chronic renal failure generally induces a hypogonadotropic hypogonadism with impaired pulsatile release of pituitary luteinizing hormone (LH).6 Chronic liver disease is accompanied by decreased (F)T levels and increased SHBG.7 Sleep apnea syndrome, with its hypoxia, is accompanied by lowered testosterone levels, secondary to a hypogonadotropism; these patients are often obese, which may aggravate the hypogonadism.8

Male andropause E Wespes and CC Schulman

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Among drugs that may adversely affect Leydig cell function in the elderly, the frequently used glucocorticoids, as long-term therapy, often induce a marked suppression of (F)T levels as the result of both testicular and central actions of the drug, as well as a decrease of SHBG levels.9 Smokers have higher testosterone levels than nonsmokers.10 Alcohol intake, even without cirrhosis of the liver, may accentuate the age-associated decline of testosterone levels.10 The influence of diet can influence testosterone levels. Fasting may affect testosterone production through diminished gonadotropic testicular control.10

ing growth hormone or insulin-like growth factor level.16 The best parameter to determine hypogonadism is measurement of bioavailable testosterone, which includes free and albumin-bound fractions. In the aging male, total testosterone may be misleading due to alterations in SHBG and flattening of the circadian rhythm. Serum testosterone assessment should be done between 8 and 11 am. If the testosterone level is below or at the lower limit, it is prudent to confirm the results with a second determination with assessment of LH and folliclestimulating hormone (FSH).

Aging effects on androgen target tissues Androgen changes with normal male aging The causes for a decline in testosterone production with age are multifactorial. The most important change appears in the testes, where there is a decline and an alteration of Leydig cell number.11 Moreover, young adult men exhibit a circadian rhythm in their serum levels of total testosterone, with peak levels in the morning and falling slowly by about 35% during the day. This daily fluctuation in serum testosterone is attenuated in older men.12,13 The ability of the testes to increase testosterone secretion in response to increased gonadotropin stimulation is also attenuated in older men.14 There is evidence that age-related alterations in hypothalamopituitary function also contribute to the decline in testosterone production. Elderly men fail to demonstrate an appropriate increase in LH secretion in response to a hypoandrogenic state. Most older men with low testosterone levels have gonadotropin levels (especially LH levels) that are within the normal range for young adult men, resulting in a relative hypogonadotropic hypogonadism. It has been also clearly demonstrated that the hypothalamopituitary compartment of the gonadal axis is more sensitive to the negative feedback effects of sex hormones than is the case in young adults.15 A third aspect of the physiopathological mechanisms responsible for the age-related changes in circulating testosterone levels, in addition to primary testicular factors and deficient neuroendocrine feedback regulation, consists of a progressive increase of plasma SHBG binding capacity.16 The cause of this increase with age remains unclear. The decreased testosterone levels per se are probably not responsible for the increased SHBG levels; at the latter, increase is observed at an earlier age than the decrease of testosterone, whereas estradiol levels are similar in young and elderly men. A plausible hypothesis is that the increase in SHBG levels is related to the age-dependent decline in circulatInternational Journal of Impotence Research

Aging might also reduce androgen effect by causing a loss of sensitivity of target tissues to testosterone or dihydrotestosterone (DHT). Both decreased and increased sensitivity of pituitary gonadotropin secretion to feedback regulation by androgens has been reported in older men. Binding of DHT to exhormone responsive skin is also decreased with age, suggesting than an age-related reduction in responsivity to androgens may result from alterations in receptor number or affinity.17

Clinical manifestations Aging in men is generally accompanied by a decrease in general wellbeing; changes in mood with concomitant decrease in intellectual activity; spatial orientation ability fatigue; depression and anger; decrease in virility, sexual desire and erectile quality; decrease in skin thickness; decrease in energy; decrease in muscular mass and in strength; an increase in upper- and central-body fat; decrease in bone mineral density resulting in osteoporosis; and decrease in body hair.18 – 20

Androgen supplementation in aging men With the paucity of data both on the consequences of the relative hypogonadism of the elderly and on the effects of androgen replacement therapy, it would certainly not be justified to propose a strategy of systematic androgen supplementation in elderly men presenting with only moderately decreased plasma testosterone levels. Meanwhile, there are probably also no reasons to withhold treatment for selected patients with clinical and biochemical manifestation of hypogonadism, after careful screening.


Available preparation for testosterone substitution Testosterone is not suited for oral treatment since it undergoes near-total first-passage metabolization in the liver and there is a considerable interindividual variation in the testosterone plasma levels achieved with relatively high plasma levels for dihydrotestosterone; moreover, adequate substitution requires the intake of a dose of 40 – 80 mg two or three times per day.21 Preparations of intramuscular injection have been the most widely available preparations for testosterone substitution. Injection of 200 mg of testosterone every 2 – 3 weeks results in supraphysiological testosterone levels during the first days following administration with thereafter a progressive decline to subphysiological testosterone levels during the days preceding the next injection.22 A gel formulation for percutaneous administration of dihydrotestosterone has been available for many years; adequate substitution requires the application of large doses to the skin.23 Patches for transdermal testosterone administration have been developed, aimed at achieving more physiological profiles of plasma testosterone concentration.24 Daily patches applied to the shaved scrotal skin can produce plasma testosterone levels around mid-normal values 4 to 8 h following application, with progressive decline of the testosterone levels in the subsequent hours. The more recently introduced permeation-enhanced nonscrotal patch produces mid to normal range testosterone levels 8 – 12 h following nightly application. Unfortunately, because of the lack of relevant controlled clinical trials of sufficient duration, it is not possible to propose an ideal therapeutic regimen for androgen substitution in aging men.

group may not uniformly lead to problems with polycythemia.27 Testosterone administration has been reported to exacerbate pre-existing sleep apnea, but none of the reports of testosterone therapy in older men have noted the development of sleep apnea.28 Since these apneic events and the ensuing oxygen desaturation may lead to cardiovascular complications, it is pertinent to ask older men about this symptom and to measure and follow up hematocrit values before and during androgen administration. Care must be exercised in men who are overweight, heavy smokers or who have chronic obstructive airway disease.

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Androgens and gynecomastia Administration of aromatizable androgens may lead to gynecomastia in the aging male, in all likelihood when the subsequent increases of estrogens and androgens tip the balance in favor of a higher estrogen=androgen ratio.29 Patients with liver or renal disease may be particularly predisposed to the development of gynecomastia.

Androgens and body composition

Adverse effects of androgen substitution

Although testosterone replacement studies in older men have varied in design, mode, duration of therapy, the data consistently demonstrate changes in body composition with testosterone — a decrease in body fat, increase in lean body mass, and a change in some aspects of muscle strength.30 Testosterone therapy inhibits triglyceride uptake and lipoprotein lipase activity and causes a more rapid turnover of triglycerides only in the abdominal adipose tissue region.31

Androgen and hematopoiesis and sleep apnea

Androgens and bone

The stimulatory effects of androgen on erythropoiesis are well known. Both testosterone and 5adihydrotestosterone stimulate renal production of erythropoietin. There is evidence for a direct effect of androgens on erythropoietic stem cells.25 Androgen receptors have been found in cultured erythroblasts.26 Studies in which young hypogonadal or eugonadal men have been supplemented with testosterone have shown an increase in hemoglobin and hematocrit levels with treatment. Because healthy older men tend to have slightly lower hematocrit values and hemoglobin levels than do young adult men, the erythropoietic effects of testosterone in the older age

Several studies have evaluated the effect of testosterone on parameters of bone turnover and=or bone density in older men.30 A significant decline in urinary excretion of hydroxyproline, or an increase in serum osteocalcin, was reported in men after 3 months of testosterone therapy. After 18 months of testosterone therapy in older men, a 5 – 13% increase is noted in trabecular bone density, depending on modality of measurement used. Bone density may be increased and bone turnover slows in elderly men undergoing testosterone therapy, although additional longer-term data are needed to confirm that androgen replacement can sustain a stabilization or reversal of bone loss in this age group. International Journal of Impotence Research


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Androgens and mood, cognition, and sexual behavior In elderly men, the effects of testosterone therapy on mood, aspects of cognition, and sexual behavior have been evaluated. Several studies have shown improvement in spatial cognition with androgen therapy. Others have reported improvement in sense of wellbeing and=or an increase in libido with testosterone. Impotence in older men is usually multifactioral and testosterone therapy often has not been beneficial.32,33 Effect on body fluid and glucose metabolism The administration of testosterone can produce fluid retention, aggravating hypertension, peripheral edema, and compulsive heart failures.34 Men treated with testosterone produce a decrease in fasting glucose in blood and a decrease in insulin resistance.35

the possible promotional role of androgens in this disease. The possibility cannot be excluded that promotion of precursor lesions is stimulated by androgens; therefore, androgen substitution should not lead no superphysiological plasma levels of androgenic steroids. PSA monitoring, which is a solid marker for prostate cancer, can be used to assess the androgen action on neoplastic cells in the prostate. The problem is to define the cut-off since we know that we will miss about 14% of cancer with a PSA below 4 mg=ml with normal rectal examination and about 29% of cancer when the patients are older than 60 y.38 Is it justified to do a biopsy before testosterone treatment? The controversy exists; several investigators believe that it is mandatory to do biopsies in everybody who is going to have supplemental androgen therapy,39 whereas others not.40 Effects on sexual function

Androgens have a profound effect on the skin. Androgens regulate, by means of receptors, the sebaceous glands and hair growth function, and remarkably they do so on two different types of target cells in the skin: the epithelial sebocyte of the sebaceous gland and the mesenchymal cells of the hair follicle dermal papilla.17

In humans, testosterone seems to have an effect on central events rather than on erectile tissues. Exogenous testosterone significantly increases frequency of masturbation and sexual activity and enhances the rigidity of nocturnal penile erections in normal men and in hypogonadal men.41 It also increases the number of nocturnal penile erections but does not modify the responses to audiovisual sexual stimulation.42,43 Recent studies have shown that testosterone could have a control of cavernous tissue in animals but not in men (see ‘Smooth muscle pathology and erectile dysfunction’ by E Wespes in this issue44).

Androgens and prostate

The potential risks of androgen therapy

Androgens and skin effects

The development of benign prostatic hyperplasia is mediated by intracellular events resulting from the action of 5a-dihydrotestosterone. Prostate size and prostate-specific antigen (PSA) are shown to increase in hypogonadal men treated with testosterone substitution.36 However, the prostate still remains within the normal size range for eugonadal men of the same age and within normal levels of PSA for controlled population. There is only a mild reduction in urine flow. Metastatic or local prostate cancer is usually dependent on androgens in its growth.37 Based on epidemiological and autopsy studies in the pathogenesis of human prostate cancer, a phase of initiation and promotion can be differentiated. Incidental prostatic carcinoma is present in approximately 10% of patients undergoing transurethral resection of prostatic hyperplasia.37 Is focal prostate cancer stimulated by androgens? This is a crucial question for the understanding of International Journal of Impotence Research

Androgen supplementation could carry some potential risks, especially in the older man who may have certain coexistent medical problems. Water retention, development of polycythemia, hepatotoxicity, exacerbation of sleep apnea, development of detrimental effects on the cardiovascular system, and exacerbation of pre-existent benign or malignant prostate disease can be observed. Water retention could lead to hypertension, peripheral edema, or exacerbation of congestive heart failure.

Conclusions Several studies suggest that aging men with low serum testosterone levels could benefit from testosterone replacement therapy for bone, muscle, and psychosexual functions. However, in short-term follow-up, significant adverse effects can be observed, and for long-term follow-up, larger clinical


studies are needed before a risk-benefit profile for testosterone therapy in hypogonadal aging men can be assessed.

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23 de Lignieres B. Transdermal dihydrotestosterone treatment of ‘andropause’. Ann Med 1993; 25: 235 – 241. 24 Meikle AW et al. Enhanced transdermal delivery of testosterone across the nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab 1992; 74: 623 – 628. 25 Shahidi NT. Androgens and erythropoiesis. New Engl J Med 1973; 289: 72. 26 Claustres M, Sultan C. Androgen and erythropoiesis: evidence for an androgen receptor in erythroblasts from human bone marrow cultures. Horm Res 1988; 29: 17. 27 Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992; 75: 1092 – 1098. 28 Stewart DA. Androgen blockade does not affect sleepdisordered breathing or chemosensitivity in men with obstructive sleep apnea. Am Rev Respir Dis 1992; 146: 1389 – 1393. 29 Glass AR. Gynecomastia. Endocrinol Metab Clin North Am 1994; 23: 825 – 837. 30 Wang C et al. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men — a clinical research center study. J Clin Endocrinol Metab 1996; 81: 3654 – 3662. 31 Ozata M et al. Effects of gonadotropin and testosterone treatments on Lipoprotein(a), high density lipoprotein particles, and other lipoprotein levels in male hypogonadism. J Clin Endocrinol Metab 1966; 81: 3372 – 3378. 32 Wang C et al. Testosterone replacement therapy improves mood in hypogonadal men: a clinical research center study. J Clin Endocrinol Metab 1996; 81: 3578 – 3583. 33 Morales A, Johnston B, Heaton JPW, Lundie M. Testosterone supplementation for hypogonadal impotence: assessment of biochemical measures and therapeutic outcomes. J Urol 1997; 157: 849 – 854. 34 Vermeulen A, Kaufman JM. Androgens and cardiovascular disease in men and women. Aging Male 1998; 1: 35 – 40. 35 Simon D, Nahoul K, Charles MA. Sex hormones, aging, ethnicity and insulin sensitivity in men: an overview of the TELECOM study. In: Odens B, Vermeulen A (eds). Androgens and the Aging Male. The Parthenon Publishing Group: New York, 1996, pp 85 – 102. 36 Behre HM. Prostate volume in treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol 1994; 40: 341 – 349. 37 Schro¨ der FH. The prostate and androgens: the risks of supplementation. In: Oddens BJ, Vermeulen A (eds). Androgens and the Aging Male. The Parthenon Publishing Group: New York, 1996, pp 111 – 125. 38 Morgentaler A, Bruning CO, DeWolf WC. Occult prostatic cancer in men with low serum testosterone levels. JAMA 1996; 276: 1904 – 1906. 39 Bruning CO, DeWolf WC, Morgentaler A. Occult prostate cancer in hypogonadal men prior to testosterone therapy. J Urol 1995; 153: 330A. 40 Morales A, Johnston B, Heaton JWP, Clark A. Oral androgens in the treatment of hypogonadal important men. J Urol 1994; 152: 1115 – 1118. 41 Schiavi RC. Androgens and sexual function in men. In: Oddens BJ, Vermeulen A (eds). Androgens and the Aging Male. The Parthenon Publishing Group: New York, 1996, pp 111 – 125. 42 Carani C, Scuteri A, Marrama P, Bancroft J. The effects of testosterone administration and visual erotic stimuli on nocturnal penile tumescence in normal men. Horm Behav 1990; 24: 435 – 441. 43 Carni C, Granata AR, Bancroft J, Marrama P. The effects of testosterone replacement on nocturnal penile tumescence and rigidity and erectile response to visual erotic stimuli in hypogonadal men. Psychoneuroendocrinology 1995; 20: 743 – 753. 44 Wespes E. Smooth muscle pathology and erectile dysfunction. Int J Impot Res 2001; 14(Suppl 1): S17 – S21.

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Appendix Open discussion following Dr Wespe’s presentation Dr Montorsi: I don’t know whether this is a semantic problem or a conceptual problem. You said that at least 25% of men in the aging population may benefit from testosterone supplementation because their testosterone level would be low. I believe that you mean that, potentially, testosterone could give some positive effect. If we only look at erectile function, there is no evidence that testosterone given to a 56-y-old man who has a testosterone level at the lower border or below the normal limit will improve his erectile function. Dr Wespes: In humans we don’t have any scientific data showing that testosterone has an influence on erectile physiology. Maybe on nocturnal erection it can have a central effect, but it doesn’t seem to have a peripheral effect. We know that when you are castrated after puberty you can still have a normal erection. So what is the role of testosterone in erectile dysfunction in humans? I cannot give you the answer. Dr Nehra: To carry that a step further, in our clinics, we all see patients who have read the effects of testosterone replacement who are either borderline or even above the borderline of normal range. They say, ‘I’ve read all of these effects of testosterone; can you possibly supplement me with testosterone so I will not go through the changes that occur in a normal male?’ How do you respond to that? Dr Pryor: With these patients with minimally subnormal levels, if you give them testosterone, they will feel better in a general sense. They will feel more active. Dr Carson: They also have higher levels of sexual thoughts and fantasies. Dr Wespes: Yes, of course. It’s the same with another drug that’s prescribed in the United States that you cannot find in the pharmacy, DHEA. Dr Hatzichristou: So are you going to prescribe to this man?

International Journal of Impotence Research

Dr Wespes: Up to now, I don’t do that. But when we discuss with a patient taking DHEA or testosterone, they say that they are better with DHEA. Dr Porst: We have a general dilemma with androgen supplementation. Morgentaler once more has seen that hypogonadal men with low free testosterone levels have a much higher likelihood to have prostate cancer. In the University of Mannheim study, Juenemann et al have investigated all the men who were referred for prostate cancer for surgery, and it turned out that between 60% and 70% of these men were hypogonadal. So the general question is what are the requests for checking hypogonadal patients for prostate cancer, because we know that these males have a low PSA and a high likelihood of prostate cancer. Are we forced to do biopsies in all or any of these men before we are supplementing this, because we know now from several studies that we have a higher likelihood of prostate cancer in hypogonadal men. Dr Wespes: Because we know that we have undifferentiated prostate cancer with low testosterone levels and because the cells are undifferentiated, these patients don’t secrete PSA. Then you have a lower level of PSA also. Dr Althof: Twice a year I see a man with a perfectly normal testosterone level and a lifelong history of no sexual interest in anything whatsoever. Is there work on testosterone receptors that suggests that people who may have normal levels of free and bound testosterone may have more difficulty utilizing what’s in their system, thereby producing effects like in this man, which is quite unusual? Dr Wespes: There is one study, published 20 y ago in 1980, that shows that we have a very, very small number of androgen receptors in the penis. Dr Pryor: Possibly these fit into androgen insensitivity. Dr Meuleman: I’m aware of a lot of studies on androgen receptors in infertile men, and it didn’t turn out that there was lesser receptivity in these men or there were mutations in the androgen receptor gene.