Hormone Treatments and Preventive Strategies in the Aging Male: Whom and When to Treat?

THE AGING MALE Hormone Treatments and Preventive Strategies in the Aging Male: Whom and When to Treat? Jeremy P.W. Heaton, MD Department of Urology, Department of Pharmacology and Toxicology, Queen’s University, Kingston, Ontario, Canada Sex hormones have a broad range of actions in regulating very diverse systems throughout life. Testosterone and other related hormones change with age to varying degrees and may induce pathophysiological changes and the clinical condition known as andropause. Androgen replacement is the accepted but not the only possible treatment for andropause. The presence of clinical symptoms, including a loss of sexual function, intellectual capacity, lean body mass, or bone mineral density; alterations in body hair, skin, or sleep pattern; or increases in visceral fat, together with low levels of serum testosterone characterize andropause. An appreciation of the potentially undesirable impact of androgens on the biology of prostate cancer, as well as possibly the cardiovascular system, is necessary. However, proper evaluation of aging men with symptoms of andropause will result in a decision to initiate androgen therapy in some aging men. [Rev Urol. 2003;5(suppl 1):S16–S21] © 2003 MedReviews, LLC Key words: Andropause • Testosterone • Erectile dysfunction • Bone mineral density ormones and their dependent organ systems change with age, and it is difficult to distinguish between normal (acceptable) deterioration and abnormal (accelerated or unacceptable) change. Is this a condition of increasing prevalence or a statistical issue based on an unnecessary preoccupation with a portion of the population who age prematurely? Simplistically, an evolutionarily driven selective genetic strategy should protect us from diseases that disadvantage us. However, this only applies to problems that provide a short-term reproductive disadvantage—where the problem degrades reproductive potential and H S16 VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY Hormone Treatment for Men: Whom and When to Treat? Table 1 Four Possible Circumstances for Treatment with Androgen Therapy 1. Clinical hypogonadism • Diseases of the HPG axis 2. Clinical andropause • Clinical and biochemical age-related hypogonadism 3. Complex age-related issues • Multisystem subfunction with possible androgen basis • Clinical picture justifying a trial of therapy if not contraindicated 4. Targeted prevention • Osteoporosis – fracture prevention • Muscle – retention of strength • Mentation and mood – prevention of deterioration HPG axis, hypothalamic–pituitary–gonadal axis transmission of the genetic basis of disease. We now live so far beyond the normal reproductive years that “natural selection," as related to reproductive fitness, has unpredictable consequences in the reproductively irrelevant “extra" years we now experience.1 At the core of this issue lies the fact that different tissues experience deterioration at different rates. Diseases of aging are not inherently evolutionarily disadvantageous. These factors are the very ones that now impact on those who experience aging and andropause and explain why this condition is likely to increase in prevalence. As stated elsewhere, “Aging should, therefore, be viewed [as] more of a trade-off than a disease."2 Management of andropause overlaps with management of other androgen-related conditions. Urologists are familiar with clinical hypogonadism, such as occurs after surgical orchidectomy, and have the theoretical background for understanding other clinical conditions related to profoundly low levels of testosterone. Andropause raises issues and is considered separately because of its less marked changes both in the clinical and biochemical picture. The fact that it is age related serves to help identify patients who may have andropause but also creates ambiguity as to what is normal. Table 1 lists circumstances in which androgens may be considered as a therapeutic modality. The recognized conditions causing profound lowering of serum testosterone are not the primary subject of this review. These conditions of clinical hypogonadism are attributed to abnormalities in the hypothalamic– pituitary–gonadal axis; because this is the entire control pathway for androgens, the faults in andropause must share this origin. It is the degree and clinical context that marks the problem as andropause. Some of the issues relating to androgen replacement and the risks of androgen therapy will be the same in hypogonadism as for andropause, and these are discussed in greater detail elsewhere in this supplement. The dividing line is made clearer by the report from Morales and Lunenfeld published in 2002, in which an operating definition of andropause is advanced: “A biochemical syndrome associated with advancing age and characterized by a deficiency in serum androgen levels with or without a decreased genomic sensitivity to androgens. It may result in significant alterations in the quality of life and adversely affect the function of multiple organ-systems."3 Clinical Characteristics of Andropause The clinical features of andropause are strongly influenced by several key issues (see Table 2). The variability in the clinical burden of relative androgen deficit explains why the symptoms of andropause may be difficult to detect clinically. At any point, the Table 2 Key Issues Contributing to the Clinical Picture, Recognition, and Management of Andropause • Associated with advancing age • Primary association with decreasing androgen effect • Also attributable to other hormonal changes • Variable ❍ Time of onset ❍ Speed of progression ❍ Degree of effect ❍ In different body systems in different people VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY S17 Hormone Treatment for Men: Whom and When to Treat? continued 140 Percent of value at 30 y 120 Leptin 100 Estradiol Cortisol 80 Prolactin 60 Thyroxine Testosterone 40 GH DHEA 20 0 30 – 40 40 – 50 50 – 60 60 – 70 > 70 Decade Figure 1. Conceptual representations of changes in hormones with age by decade. The values have been normalized to the level at age 30 years. The values are approximate. GH, growth hormone; DHEA, dehydroepiandrosterone. Data adapted from Morales et al.3 cross-sectional detail of the condition is different from man to man. It can almost be said that there is no truly typical patient, only groups of findings to observe for change in men who possibly have andropause. The variability in population averages for the most important hormones may be summarized as shown in Figure 1. These are the recognized hormonal changes that are thought to drive the clinical changes in men suffering from andropause. Not listed in the figure, because it is not a hormonal change, is the change in levels of sex hormone-binding globulin (SHBG). Levels of SHBG increase with age and decrease the availability of testosterone to dependent cells and organs. There will undoubtedly be other important variations identified in the bodies of aging men. These will help explain the variabilites in presentation that are currently grouped under “individual variation." For instance, interleukin-6 is a cytokine that is elevated in men with andropause and may be causally related to some of the symptoms of andropause. It is a factor in other aging-associated diseases, including osteoporosis and neoplasia.4 Androgen deficiency in aging males, or andropause, is a syndrome char- S18 VOL. 5 SUPPL. 1 2003 acterized primarily by the six key clinical changes summarized in Table 3. The six major symptom areas have been encapsulated in the report from The International Society for the with melatonin.5 Perhaps the most obvious change associated with andropause is the decrease in sexual desire and erectile quality, particularly nocturnal and early morning erections.6 There are subtle and extensive cognitive alterations that manifest as changes in mood and measurable decreases in intellectual activity, spatial orientation ability, as well as fatigue and increased irritability.7 Andropause is associated with a decrease in lean body mass due to a diminution in muscle volume that also causes a measurable reduction in muscle strength.8,9 There are changes in the skin and hair, typified by the development of hair in ears and nose, a decrease in body hair, and thinning and hyperpigmentation of the skin.10 The decrease in bone mineral density that results in osteopenia It can almost be said that there is no truly typical andropause patient, only groups of findings to observe for change. Study of the Aging Male.3 In further discussion of these, it would be helpful to adhere to the categorization provided, but it is worth adding changes in sleep patterns because they are clearly age-related, a feature of early senescence, and most likely associated REVIEWS IN UROLOGY and osteoporosis is analogous with the changes of menopause, although in men these changes typically occur later in life.11 The increase in truncal and visceral fat is a further marker for andropause.12 The hormones currently believed to Table 3 Clinical Changes Attributable to Andropause Matched with the Hormones Believed to be Most Responsible 1. Decreased sexual desire and erectile quality T, DHEA 2. Decreased intellectual capacity (depression, fatigue) T, DHEA, GH, M 3. Decreased lean body mass T, DHEA, GH 4. Body hair and skin alterations T, DHEA 5. Decreased bone mineral density T, GH 6. Increased visceral fat T, L, GH [Altered sleep patterns] M, T T, testosterone; DHEA, dehydroepiandrosterone; GH, growth hormone; M, melatonin; L, leptin. Hormone Treatment for Men: Whom and When to Treat? Free Albumin Bound Bioavailable Total SHBG Bound Figure 2. A conceptual representation of the proportions of free, albumin-bound, and sex hormone-binding globulin (SHBG)-bound testosterone that may be detected in serum. be most responsible for each of the six symptom groupings of andropause are also listed in Table 3. A consequence of the key issues identified in Table 2 is that these clinical changes need not all be present to make the diagnosis of andropause; they may not all be present in a man with andropause, their severity may vary widely, and they may appear as the condition progresses. This variability presents difficulties in giving a simple clinical picture; but whatever components exist, there should also be a decrease in measurable androgens if the symptoms are to be blamed on andropause. The six clinical groupings help define the areas to be examined in a medical and sexual history and physical examination relevant to finding andropause. Urologists will be familiar with the clinical findings of sexual dysfunction and the appropriate examination. There is no clear distinction between the usual vascular-based erectile dysfunction (ED) and ED associated with andropause. Alterations in nocturnal erections and the absence of other markers of vascular disease may provide clues; however, the nonvascular causes of ED may very well include depression, which provides another area of overlap between age, ED, and other possibly unrelated conditions. ED is not a necessary component of andropause, although from a urologic viewpoint it must be a very common trigger for the search for a more global problem— andropause—to explain the various complaints of an aging man. Formal assessment of intellectual, mood, and cognitive changes may be arranged. Changes in lean body mass will be apparent from history and examination, as will changes in hair, skin, and fat distribution. Bone mineral density decrease may be apparent from a history of recent fractures, but documentation will depend on formal studies. Formal evaluative scales or psychometric instruments men less than 60 years of age but is evident in over 20% of men over 60.13 The decrease in testosterone with age is a matter of record—within any aged population, men will be with and without symptoms of andropause. SHBG increases with age, which causes a decrease in bioavailable (free plus albumin-bound fractions) testosterone (see Figure 2). When the measurements of bioavailable testosterone were studied in middle aged men (40–62 years of age), about 25% of this population had low bioavailable testosterone. In older men the number was higher still.14 The accepted value for testosterone in andropause is defined to be This variability in symptoms presents difficulties in giving a simple clinical picture; but whatever components exist, there should also be a decrease in measurable androgens if the symptoms are to be blamed on andropause. for the assessment of men with suspected clinical andropause have been under development; these and their utility are discussed elsewhere in this supplement. Biochemical Picture of Andropause The total testosterone level in a sample of men decreases after the age of 50 years at a rate of approximately 1% per year; biochemical hypogonadism is seen in only about 7% of 2 standard deviations below normal values for young men (317 ng/dL total testosterone, 7.34 ng/dL free testosterone,15 and 86–231 ng/dL for bioavailable testosterone). The normal ranges and methods vary widely, and physicians are urged to consult with their local laboratories for the applicable values in their clinical practice environment. The actual value in an individual does not tell the whole story, for the following reasons: the history of what has been a normal Table 4 Factors Influencing the Variability in Presentation of Andropause and the Attendant Testosterone Values • Normal ranges vary widely • History of individual normal testosterone is unknown • Sensitivity of target organs (brain, muscle, bone, etc) varies • Other unmeasured hormones contribute • Potential, unrecognized endocrine disruptors VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY S19 Hormone Treatment for Men: Whom and When to Treat? continued testosterone level for a given patient in previous years is almost always unknown; the sensitivity of different target organs (brain, muscle, bone, etc) varies; there are other, unmeasured hormones contributing to the condition (testosterone is a major factor but not the only one); and there may be unrecognized molecules (endocrine disruptors) blocking the normal action of testosterone (see Table 4). The need for hormonal evaluation of men with ED and the possibility of andropause as a factor in some ED has been debated. This is the overlapping symptom complex that most often presents to the urologist. There is no single answer, but the prudent course is to assume the possibility of overlap, or at least of a hormonal component for the ED, and to do the appropriate clinical evaluations and biochemical studies. Because hypogonadal men may be capable of adequate sexual erections, and hormonal replacement may not result in restoration of erections in hypogonadal men with ED, physicians would do well to remember that erectile function and androgen status have a complex relationship. The choice of which testosterone value to measure is still debated. Total testosterone is widely available but must be interpreted carefully in the elderly, in whom SHBG will be elevated. Measurement of free testosterone by the equilibrium dialysis method is difficult to perform, and the method is largely unavailable. The radioimmunoassay for free testosterone is widely available but unreli- hormone, luteinizing hormone, and prolactin should also be measured. Indications for Treatment Testosterone treatment should only be undertaken after a careful evaluation of the potential risks and benefits. The risks inherent in modern testosterone preparations are small; the molecule The prudent course is to assume the possibility of a hormonal component for erectile dysfunction and to do the appropriate clinical evaluations and biochemical studies. able. Measurement of bioavailable testosterone is expensive, and the methodology is not always reliable, but there are strong advocates of this method as the most relevant. Calculated free testosterone is a good compromise, because total testosterone and SHBG are most often available and relatively cheap.15 Whatever method is chosen, the serum sample for testosterone determination should be taken between 8:00 and 11:00 AM. If the testosterone level is at or below the lower limit of normal for the laboratory, the results should be confirmed with a second determination, at which time follicle stimulating being introduced into the body is testosterone itself in the form of various salts and esters (the exceptions are the alkylated preparations, which should not be given). The particular risks of any increase in serum testosterone relate to the normal actions of endogenous testosterone and whether these will be increased to the point of causing adverse changes when exogenous testosterone is added. This debate revolves around whether aging testosterone (lower) levels are natural and whether there is any novel harm induced by restoring testosterone levels to an age-adjusted norm. There is no common reason Main Points • Andropause is characterized by loss of sexual function, intellectual capacity, lean body mass, or bone mineral density; alterations in body hair, skin, or sleep pattern; or increases in visceral fat, together with low levels of serum testosterone. • Because of the variability in the clinical burden of relative androgen deficit, symptoms of andropause may be difficult to detect clinically. • The recognized hormones whose changes are thought to drive the clinical changes in andropause are primarily testosterone and also leptin, estradiol, cortisol, prolactin, thyroxine, growth hormone, and dehydroepiandrosterone. • The accepted value for testosterone in andropause is defined to be 2 standard deviations below normal values for young men; serum sample for testosterone measurement should be taken between 8:00 and 11:00 AM, and results at or below the lower limit of normal should be confirmed with a second measurement. • The major domains of risk associated with testosterone treatment are prostate health, cardiovascular health, red cell mass, and lipid profile. • The goals of testosterone treatment are the reversal or remediation of the clinical symptoms most probably associated with the hypogonadism of aging; if there is no pre-eminent symptom but testosterone is low, then a trial of therapy may be indicated. S20 VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY Hormone Treatment for Men: Whom and When to Treat? to attempt to establish supranormal testosterone levels. The major domains of risk are prostate health, cardiovascular health, red cell mass, and lipid profile. These will be discussed else- eminent symptom but testosterone is low, then a trial of therapy may be indicated. In all cases, therapy should be undertaken with the understanding that if there is no 4. 5. 6. 7. For sexual problems, intellectual deterioration, or altered sleep associated with low levels of serum testosterone, the benefit of replacement therapy is readily balanced against the known caveats. where in this supplement, along with the treatments themselves; but it is not possible to identify who should be treated without establishing a reason and a risk. A firm reason for treatment should be established before treatment is begun. The goals of treatment are the reversal or remediation of the clinical symptoms most probably associated with the hypogonadism of aging. For sexual problems, intellectual deterioration, or altered sleep associated with low levels of serum testosterone, the benefit of replacement therapy is readily balanced against the known caveats. It may be reasonable to begin testosterone replacement therapy for asthenia (muscle loss) and low testosterone. It may be appropriate to take preventive action against further bone loss if this part of the andropause complex is prominent.16 If there is no pre- measurable benefit over a suitable period of time (depending on the index problem), then treatment will be stopped. In summary, a clear indication (a clinical picture together with biochemical support) should exist prior to initiation of androgen therapy. Age is clearly a factor in the development of andropause and a complicating factor in determining who will benefit from testosterone treatment. If identifiable reasons for testosterone treatment exist, then age should not be the sole factor in denying a patient a trial of treatment. References 1. 2. 3. Wick G, Jansen-Durr P, Berger P, et al. Diseases of aging. Vaccine. 2000;18:1567–1583. Heaton JP. Andropause: coming of age for an old concept? Curr Opin Urol. 2001;11:597–601. Morales A, Lunenfeld B. Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. International Society for the Study of the Aging Male. Aging Male. 2002;5:74–86. 8. 9. 10. 11. 12. 13. 14. 15. 16. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245–270. Youngstedt SD, Kripke DF, Elliott JA, Klauber MR. Circadian abnormalities in older adults. J Pineal Res. 2001;31:264–272. Morales A, Heaton JPW. Hormonal erectile dysfunction: evaluation and management. Urol Clin North Am. 2001;28:279–288. 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