(2003) 15, Suppl 4, S3 S8 & 2003 Nature Publishing Group All rights reserved 0955-9930/03 $25.00 www.nature.com/ijir Original Research 1 * 1 Wesley Woods Health Center, Atlanta, Georgia, USA Age-related decline in male sex hormones, particularly testosterone, is referred to as andropause. Like menopause, andropause is associated with physical and emotional changes that may be alleviated by hormone replacement therapy. Hypogonadism in aging men, as defined by a low free testosterone index, is due to declining testosterone production and increased sex hormone-binding globulin levels. About 30% of men in their 60s and more than 80% of men over 80 y may have a low free testosterone index. Diagnosis of hypogonadism is based on clinical symptoms (eg, decreased muscle mass, fractures, loss of libido) and laboratory determinations of serum testosteroneusually total testosterone levels. Measuring bioavailable testosterone, or free testosterone, is expensive and time-consuming, but may more accurately detect hypogonadism. Testosterone replacement therapy is generally safe in aging men and may improve libido, cognition, bone mineral density, body mass composition, and serum lipoproteins. Although contraindicated in men with prostate or breast cancer, testosterone replacement therapy in aging men warrants examination. Any of the available testosterone formulations can be used, but injectable forms have certain advantages, including excellent dose adjustability, lack of skin irritation, and low cost. (2003) 15, Suppl 4, S3 S8. doi:10.1038/sj.ijir.3901029 Keywords: andropause; hypogonadism; testosterone replacement therapy Introduction The reproductive changes that women undergo with age are well recognized, but only in the past few decades has attention turned to andropause, or hormonal changes in aging men. Andropause differs in many ways from menopause: for example, declines in sex hormone levels occur gradually in men, rather than abruptly as in women. Nevertheless, there are some similarities between andropause and menopause, including hormonal changes that may be accompanied by mood, libido, or physical transformations. 1 As with women, selecting an appropriate hormone replacement therapy has the potential to ameliorate some of these symptoms and improve overall well-being in aging men. Declining testosterone levels with age are primarily due to changes in the testes, which show decreases in the number of Leydig cells (the cells that produce testosterone), the activity of enzymes *Correspondence:, MD, PhD, Wesley Woods Health Center, 1841 Clifton Road, NE, Atlanta, GA 30329, USA. E-mail: jtenove@emory.edu that contribute to testosterone production, and the ability to increase testosterone production in response to gonadotropin stimulation. 1 Testosterone production also is influenced by a negative feedback system involving gonadotropin-releasing hormone and luteinizing hormone. Levels of both of these hormones increase with age, but do not increase enough to overcome declining testosterone levels. 2 Serum levels of sex hormone-binding globulin (SHBG) also increase with age. 2,3 SHBG is the major serum carrier of testosterone, and testosterone bound to SHBG is not bioavailable. The concomitant decrease in testosterone production and increase in SHBG levels result in a more profound decline in bioavailable testosterone than in total testosterone in aging men (Figure 1). 4 In longitudinal data from the Massachusetts Male Aging Study, total testosterone decreased at a rate of 1.6% per year, while bioavailable testosterone decreased at a rate of 2 3%/y. 3 Prevalence of hypogonadism in aging men In the Baltimore Longitudinal Study on Aging, testosterone levels in samples obtained from 890 men at 5-y intervals over an approximately 30-y
S4 Figure 2 Prevalence of hypogonadism in aging men. This graph shows the percent of men in the Baltimore Longitudinal Study on Aging with at least 1 testosterone value in the hypogonadal range during the 10-y period shown. For total testosterone, o11.3 nmol/ l (325 ng/dl) was considered hypogonadal. For free testosterone (T) index (testosterone/shbg), o0.153 nmol/nmol was considered hypogonadal. The numbers above each pair of bars indicate the number of men studied in the corresponding decade. Reprinted with permission from Harman et al (The Endocrine Society). 5 Diagnosis of hypogonadism in aging men Figure 1 Age-related changes in serum total testosterone (upper panel), fraction of testosterone bound to SHBG (middle panel), and bioavailable testosterone (testosterone not bound to SHBG, shown as free testosterone [T] index; lower panel). Data are from a cross-sectional analysis of serum samples from 106 normal men aged 17 86 y. Regression lines were calculated by least-squares method. Adapted with permission from Blackman et al (The Endocrine Society). 4 period were determined. Hypogonadism was found to increase progressively with age, with an approximately 5- to 10-fold higher prevalence in men over 80 y of age compared with men less than 50 y of age, depending on whether total testosterone or free testosterone index (testosterone/shbg) was used to determine hypogonadism (Figure 2). 5 For this study, hypogonadism was defined as total testosterone less than 11.3 nmol/l (325 ng/dl) or free testosterone index less than 0.153 nmol/nmol. As might be expected from the increased SHBG levels observed with age, a higher prevalence of hypogonadism was found if free testosterone was used as an index value than if total testosterone was used as a guide, and the difference between these two assessments increased with age. 5 In aging men, a diagnosis of hypogonadism should rely on both symptoms and laboratory tests. Unfortunately, the symptoms of testosterone deficiency in this population are difficult to separate from consequences of aging. Both are associated with decreased muscle tissue mass and strength, increased fatigue, increased body fat mass (particularly intra-abdominal fat), decreased bone mass and an increased incidence of osteoporosis and fractures, loss of libido, erectile dysfunction (ED), impaired cognitive function, and depression (Table 1). 1 Other factors, such as chronic illness, medications, and other hormone deficiencies, can contribute to all of these, making it difficult to pinpoint the contribution of testosterone deficiency. 1 Various screening questionnaires have been developed to help clinicians identify patients who might be suffering from testosterone deficiency, including the Androgen Deficiency in Aging Males (ADAM) questionnaire and a self-screening questionnaire developed from data obtained in the Massachusetts Male Ageing Study. 6,7 The most frequently observed physical findings in aging males with hypogonadism are subtle gynecomastia and soft, small testes. 1 Laboratory tests are necessary to confirm a suspected diagnosis of hypogonadism. The several assays for testosterone each measure a slightly different parameter. For initial diagnosis, a morning, nonfasting, serum total testosterone level is often used. A morning sample is taken because testoster-
Table 1 Symptoms of hypogonadism in aging men a,1 Decreased libido Erectile dysfunction Infertility Increased irritability Decreased ability to concentrate Depression Decreased muscle mass and strength Decreased stamina Low bone mass (osteoporosis) Decreased amount of axillary and pubic hair Soft testes of decreased volume Gynecomastia Vasomotor instability a Adapted from Tenover et al 1 (Copyright 1998, with permission from Elsevier Science). one is secreted in a circadian rhythm: levels are highest in the early morning and decrease during the day. However, this secretory pattern is often attenuated or absent in elderly men. 8 Radioimmunoassays are typically used to quantify total testosterone in serum. Although total testosterone assays are usually the least expensive and easiest to perform, a study has found that these tests misclassified 42% of the patients, with 26% being false negatives and 16% being false positives as determined by bioavailable testosterone assays. 9 Bioavailable testosterone assays measure the portion of testosterone not bound to SHBG (free testosterone plus albumin-bound testosterone). These assays are more expensive and complex than total testosterone assays, but can more accurately reflect the level of testosterone deficiency. Free testosterone assays measure nonprotein-bound testosterone and involve either a dialysis procedure or ultracentrifugation. These assays are viewed by some as the best physiologic method for measuring free testosterone, but they are time-consuming and labor-intensive. 9 Recent studies suggest that the free testosterone index, which is calculated from the total testosterone and SHBG serum levels, may provide an accurate alternative to these more complex assays. 9,10 As both total testosterone and SHBG can be determined by radioimmunoassay, the assays involved are rapid and convenient. The definition of hypogonadism varies from study to study. In clinical practice, many clinicians find that treatment of patients with total testosterone levels below 325 ng/dl, bioavailable testosterone below 70 ng/dl, or free testosterone below 50 ng/ml often provides benefits. For patients with higher testosterone levels who do not appear to have other explanations for their symptoms, initial testosterone treatment may be appropriate. If an older man is found to be clearly hypogonadal (total testosterone level below 200 ng/dl), additional laboratory tests, including thyroid-stimulating hormone (to assess hypothyroidism), gonadotropin levels, and prolactin (to rule out possibility of a pituitary tumor), should be conducted to try to determine the etiology of the testosterone deficiency. Low gonadotropin (eg, luteinizing hormone and follicle-stimulating hormone) levels indicate central hypogonadism. In the absence of clear hypogonadism, however, gonadotropin assays are rarely helpful in older men because values usually fall within the normal range. 1,11 Testosterone replacement is contraindicated in patients with pre-existing prostate or breast cancer, because testosterone may promote the growth of these tissues. Possible contraindications include symptomatic benign prostatic hyperplasia (BPH) and sleep apnea. 1 Studies of testosterone replacement in aging men Several studies have examined testosterone replacement therapy in younger hypogonadal men, but only a few have addressed this issue in aging men. It is important to note that the effects observed in younger men cannot necessarily be extrapolated to the elderly. The following summary, although not exhaustive, highlights some of the key findings of testosterone replacement studies in aging men. Safety Overall, studies of testosterone replacement in aging men have established an excellent safety profile, especially for injectable testosterone formulations, which have been available for the longest period of time and were therefore used in the bulk of the studies. One of the major concerns with testosterone treatment has been the potential for acceleration of abnormal prostate growth. Available data indicate that testosterone replacement therapy, when given to men screened for no evidence of pre-existing symptomatic BPH or prostate cancer, has minimal effects on the prostate. A study of prostate volume and prostate-specific antigen (PSA) found no significant differences in these parameters between testosterone-treated hypogonadal men and a control group of untreated nonhypogonadal men. 12 Studies conducted in elderly men thus far have led to similar conclusions with respect to the minimal effects of testosterone on prostate size, PSA, and BPH, 13 15 although one study did find significant increases in PSA levels in testosterone-treated elderly males. 13 The effect of testosterone replacement therapy on the prostate has been studied for up to 3 y on treatment, but whether there are effects on the prostate with long-term therapy is unknown. Androgens are known to stimulate erythropoiesis, and increases in blood cell mass and hemoglobin S5
S6 levels are fairly common in older men receiving testosterone replacement therapy. In a retrospective analysis of 45 elderly hypogonadal men receiving 200 mg of testosterone cypionate or enanthate by intramuscular (i.m.) injection every 2 weeks, the only statistically significant difference observed between treated patients and a control group at the 2-y follow-up was in hematocrit. In all, 11(24%) patients in the testosterone group developed polycythemia. However, the two groups did not differ significantly in coronary artery disease, peripheral vascular disease, myocardial infarctions, angina, or transient ischemic attacks. 14 Effects on sexual function and libido In older men, testosterone replacement therapy is more likely to have a positive effect on libido than on ED. In a study of men with ED whose testosterone levels were raised through treatment with clomiphene citrate, no overall improvements in sexual function were observed in older men (mean age 66 y, n ¼ 9). However, in younger men, some significant improvements were observed (mean age 53 y, n ¼ 8). 16 Although this study was small, these data suggest that testosterone is more likely to improve ED in younger men than in older men. Even in older men, however, testosterone has profound effects on libido. Dramatic improvements in libido were observed in a 2-y study of long-term testosterone replacement therapy in older hypogonadal males. In self-assessments of libido, approximately 10% of the control group (hypogonadal older men not receiving testosterone therapy, n ¼ 27) reported improved libido, compared with over 80% of the testosterone replacement group (n ¼ 45). 14 The effect of testosterone therapy on mood has not been specifically examined in older men. In younger, hypogonadal men (age range 22 60 y), however, testosterone replacement resulted in significant increases from baseline in energy level, friendliness, and sense of well-being, and significant decreases from baseline in anger, irritability, sadness, tiredness, and nervousness. Improvements in mood occurred within the first 3 weeks of therapy and were sustained, but not increased, during prolonged treatment (up to 6 months). 17 It is likely, then, that testosterone therapy may also improve mood in some older men. Effects on cognition Data on the effects of testosterone replacement therapy on cognition in elderly men are conflicting. In a study of 25 healthy older men, weekly i.m. testosterone injections for 6 weeks resulted in significant improvements in spatial memory, spatial ability, and verbal memory compared with baseline and with a placebo group. 18 In contrast, no significant changes in memory, recall, or verbal fluency tests were observed in 15 hypogonadal elderly men who received biweekly i.m. testosterone injections for 12 months compared with a control group. 15 The effect of testosterone replacement on cognition in aging men thus remains unresolved. Effects on bone Studies of bone changes in response to testosterone therapy in older men have, in general, demonstrated increases in bone mineral density and reduced bone degradation. 1 These effects may be more profound in men with very low testosterone levels. A 3-y study involving 108 men over 65 y of age was unable to detect a significant difference in bone mineral density between men wearing a testosterone patch and those wearing a placebo patch. However, linear regression analysis demonstrated that the lower the pretreatment testosterone level, the greater the improvement in bone mineral density. For men with baseline total testosterone levels of 400 ng/dl, the increase in bone mineral density was 0.9%, while for those with baseline testosterone levels of 200 ng/dl, the increase was almost 6%. 19 Effects on body composition and muscle mass Testosterone replacement therapy increases lean body mass in aging men by about 3 5%, but these changes are typically less dramatic than those observed in younger men (approximately 9 19%). 1 In a study of healthy men over 65 y of age who were not necessarily hypogonadal (mean serum testosterone of 367 ng/dl), 3 y of treatment with a testosterone patch resulted in significant decreases in fat mass and increases in lean mass compared with patients receiving placebo. The decrease in fat mass occurred primarily in the arms and legs, rather than in visceral fat, which is more commonly associated with cardiovascular risk factors. The increase in lean mass was primarily in the trunk. 20 Some studies of elderly men undergoing testosterone replacement therapy have found a significant increase in muscle strength, with the majority of these studies examining grip strength. 1 However, not all studies have found improvements in muscle strength in elderly testosterone-treated patients. In the 3-y testosterone replacement study discussed above, muscle strength was assessed by both knee extension and grip strength. The testosterone-treated group was not significantly different from the placebo group in these assessments. 20 For elderly
men, the benefit of maintaining or improving muscle strength lies primarily in the potential to preserve function. However, this study was also unable to identify functional improvements associated with testosterone therapy, as measured by the time to walk 25 feet, the number of steps taken in walking 25 feet, and the time to climb 12 stairs. 20 It is possible that other functional tests, such as those measuring other activities of daily living, might uncover more subtle changes in functional ability. Effects on serum lipoproteins Testosterone replacement therapy appears to exert beneficial effects on surrogate markers of cardiovascular risk, resulting in reduced total cholesterol and low-density lipoprotein cholesterol. 13,21 Improvements in lipoprotein parameters become more pronounced with increasing age, an observation that may have potential clinical relevance (Figure 3). 21 However, large-scale studies that examine the influence of testosterone therapy on cardiovascular end points, such as cardiovascular mortality, stroke, or myocardial infarction, have not yet been conducted. Choosing a testosterone replacement therapy The advantages and disadvantages of the various testosterone formulations discussed in the introduction to this publication also apply to aging men. However, there are some unique additional factors that should be considered. Cost is a significant consideration for older people, as Medicare does not provide coverage for medications. Even including the cost of injections by a health-care provider, Figure 3 Change in LDL levels vs age in hypogonadal men receiving testosterone replacement therapy. The dashed line is derived from linear regression analysis. Adapted with permission from Dobs et al (The Endocrine Society). 21 injectable testosterone formulations are far less costly than scrotal patches, transdermal patches, or gels. In addition, dosage adjustments are easiest to accomplish with injectable formulations. To help avoid adverse effects associated with fluctuations in testosterone serum levels, such as gynecomastia, mood swings, and polycythemia, injectable testosterone should be administered once weekly or, if weekly therapy is not possible, at intervals of no more than 2 weeks. Older people are more likely to experience skin irritation from skin patches. Conclusions Testosterone replacement therapy, to date, has had an excellent safety profile and may exert multiple beneficial effects in hypogonadal aging males, ranging from improved mood to stronger bones to reduced cardiovascular risk. Although more studies are required to confirm these benefits, the available data suggest that, as the population ages, testosterone replacement therapy may play a role in preserving a high quality of life in some aging males. Of the available testosterone formulations, injectable testosterones have the benefit of dose adjustability, lack of skin irritation, and low cost, features that may be particularly important to older patients. Discussion Dr Glenn R. Cunningham: You ve talked about adjusting dosages in older men. How do you go about doing this? Dr Tenover: I usually start older men on 150 mg of injectable testosterone every 2 weeks, or 75 mg every week. Because testosterone metabolism slows down with age, I find that 200 mg every 2 weeks is too much in most older men. I also have learned, however, that no matter what formulation you use, there is no way of predicting what kind of level you might get with treatment, so you have to monitor testosterone levels in the patient. I have male patients with very small body mass index who need a lot of testosterone, because either they don t absorb it well or they metabolize it faster than the average older man. Also I ve got some big guys who don t need very much testosterone; you just can t predict. So I try to start out with an average dose, then measure the testosterone levels and readjust the dose. Dr Cunningham: What do the rest of you use as a cut-off level for hypogonadism? Dr Ridwan Shabsigh: I think that the current recommendation is that total testosterone of between 200 and 400 ng/dl is a gray zone, with below 200 considered abnormal and above 400 normal. This is a reasonable guideline, but it s not perfect. I S7
S8 think it s also important to pay attention to other details, including the time of day the blood is drawn and the lab you use, as well as the patient s symptoms. Dr Tenover: I have to say that, in clinical practice, if I have a man with several of the clinical symptoms associated with low testosterone, no other reason for those symptoms, and his testosterone is right around 400 ng/dl, I might try him on testosterone replacement therapy for a period of time, if there are no contraindications. Now, obviously, you have the whole placebo effect issue, because a lot of people do want to get better and you are assessing subjective symptoms. I think there is a difference between what we as researchers advocate as the testosterone level to define hypogonadism, and what we might do in our clinical practice. I like the idea of a gray zone area because I think you evaluate each patient individually. You might be a little more generous about what cutoff you accept if a man s symptoms really fit and there is no other detectable reason for those symptoms. References 1 Tenover JL. Male hormone replacement therapy including andropause. Endocrinol Metab Clin N Am 1998; 27: 969 987. 2 Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991; 73: 1016 1025. 3 Feldman HA et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2002; 87: 589 598. 4 Blackman MR, Weintraub BD, Rosen SW, Harman SM. Comparison of the effects of lung cancer, benign lung disease, and normal aging on pituitary gonadal function in men. J Clin Endocrinol Metab 1988; 66: 88 95. 5 Harman SM et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001; 86: 724 731. 6 Morley JE et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000; 49: 1239 1242. 7 Smith KW, Feldman HA, McKinlay JB. Construction and field validation of a self-administered screener for testosterone deficiency (hypogonadism) in ageing men. Clin Endocrinol (Oxf) 2000; 53: 703 711. 8 Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab 1983; 56: 1278 1281. 9 Morley JE, Patrick P, Perry III HM. Evaluation of assays available to measure free testosterone. Metabolism 2002; 51: 554 559. 10 Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84: 3666 3672. 11 Basaria S, Dobs AS. Hypogonadism and androgen replacement therapy in elderly men. Am J Med 2001; 110: 563 572. 12 Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf) 1994; 40: 341 349. 13 Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992; 75: 1092 1098. 14 Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab 1997; 82: 3793 3796. 15 Sih R et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997; 82: 1661 1667. 16 Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab 1995; 80: 3546 3552. 17 Wang C et al. Testosterone replacement therapy improves mood in hypogonadal menfa clinical research center study. J Clin Endocrinol Metab 1996; 81: 3578 3583. 18 Cherrier MM et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 2001; 57: 80 88. 19 Snyder PJ et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999; 84: 1966 1972. 20 Snyder PJ et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999; 84: 2647 2653. 21 Dobs AS et al. Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system. J Clin Endocrinol Metab 2001; 86: 1026 1033.