Feature Article
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Testosterone Replacement in the Elderly: A Clinical Approach Dr. Asnani is in the Division of Endocrinology, and Dr. Naval-Srinivas is in the Division of Geriatric Medicine, Tulane University School of Medicine; and Cefalu is in the Department of Family Medicine, LSU School of Medicine, New Orleans, LA. In aging men, serum testosterone levels decline progressively, and the prevalence of hypogonadism increases. These changes are associated with alteration in androgen-regulated physiological functions. The diagnosis of androgen deficiency is made in the presence of both clinical signs and symptoms with subnormal plasma testosterone levels. In older men, short-term treatment with testosterone suggests benefits. Addition of testosterone to postmenopausal women who continue to be symptomatic on estrogen (+/- progesterone) therapy deserves due thought as well. The therapy is not without adverse effects, and close monitoring is mandated. (Annals of Long-Term Care: Clinical Care and Aging 2003;11[12]:44-50)
Introduction Androgens play several important physiological roles in the human male. Testosterone is required for virilization, normal sexual function, and both stimulation and maintenance of bone and muscle mass. Expansion of the clinical indications and the development of newer delivery methods have engendered a new interest in testosterone replacement.
Clinical Significance of Testosterone Deficiency in Elderly Men Gonadal function declines with aging in women and men. Although the decrease in ovarian estrogen production occurs at menopause in a dramatic manner, the decline in testosterone (T) secretion known as andropause develops slowly over several decades in most men.1-6 Most studies have shown a decrease in both total and free testosterone (FT) levels with aging. Because many of the catabolic sequelae associated with aging, such as sarcopenia, increased adiposity, and osteoporosis, are similar to those seen in hypogonadal young men, it has been tempting to recommend treating andropausal men with T replacement therapy. Moreover, the successful treatment of HIV infection-associated wasting syndrome with androgens has renewed interest that androgen therapy might prove useful to combat frailty in aging men and women.7 Authors now agree that even healthy men have a slow, continuous, age-dependent decline in T levels, which is more pronounced for FT than for total T, a consequence of the age-associated increase of the levels of sex hormone-binding globulin (SHBG). Moreover, the circadian rhythm of plasma T levels is generally lost in elderly men.1 About 20% of males over age 70, however, have T levels in the upper one-third of males 20-40 years old.8 This is clearly distinct from postmenopausal women. Further, the androgen deficiency in elderly men is generally moderate, thus prompting the term partial androgen deficiency in the aging male (PADAM). The decline in T levels with aging appears to result from a dual defect in Leydig cell function and the hypothalamic-pituitary axis. A decreased Leydig cell mass9 and function,10,11 and a secretory defect in hypothalamus12 are the putative mechanisms. The role of PADAM in age-associated decrease of bone mineral density (BMD) remains to be established. Recent large-scale studies found T levels to be significantly associated with bone density at the radius, spine, and hip;13,14 however, the correlation with estradiol was even stronger,15 suggesting that part of the androgen effects on bone are at least partially indirect, mediated via their aromatization.16 Abdominal fat mass is inversely correlated with FT levels, independent of age.17,18 Whether abdominal obesity is a consequence of low T levels or vice versa is not clear. Indeed, obesity induces a decrease of T levels via a decrease in SHBG levels, and morbid obesity also induces a decrease of FT.19 Synthetic androgens, such as anabolic steroids, induce insulin resistance.20 In contrast, testosterone treatment in obese men with low-normal T levels improves insulin sensitivity (SI),21 whereas supraphysiologic doses of T given to eugonadal men did not change the SI.22 Carefully designed trials are needed to better elucidate the relation between T levels and SI. Young men with hypogonadism have decreased lean body mass and decreased muscle strength, which improves with T replacement. Further, the administration of supraphysiologic doses of T to young men resulted in increased muscle size and strength.23 In elderly men, a correlation is seen between FT levels and muscle mass.24 Lower T concentrations are associated with severity of loss of muscle function,25 but androgen replacement only increased the lean muscle mass without an increase in muscle strength.26 No randomized, placebo-controlled trials have evaluated the effects of androgens on atherosclerotic heart disease. The prevalence of atherosclerosis increases in men with aging. In the view of higher prevalence in men than in women, the sporadic reports of premature cardiovascular disease in athletes abusing anabolic/androgenic steroids, and the atherogenic lipid profile in hirsute women, this difference is generally considered to be related to higher androgen levels in men. However, Alexandersen et al27 reviewed 30 cross-sectional studies in men, reporting that most studies suggest either a favorable or neutral effect of normal T levels on cardiovascular diseases in men, and they concluded that low androgen levels increase the risk of cardiovascular disease in men. The Rotterdam study28 investigated the association of the levels of T with aortic atherosclerosis, and concluded that an inverse relationship exists between the two. Indeed, a positive correlation is seen between FT levels and high-density lipoprotein cholesterol (HDL-C)29-31 and a negative correlation with fibrinogen and plasminogen activator inhibitor-132 as well as with coronary artery disease.33,34 Interestingly, the correlation between T levels and HDL-C was only observed within the physiologic male concentration of T.35,36 The impact of androgens on lipids seems to depend on the type of androgen, the dose given, and the route of administration. Most studies agree that administration of androgens to older men results in a decrease in total cholesterol levels, with little if any change in HDL-C.37 Nilsson et al,38 in an epidemiological study of over 400 51-year-old men, observed that low levels of T were associated with low sexual activity. Other authors,39,40 however, did not observe any correlation between plasma T levels within normal range and sexual activity. Wang and associates41 demonstrated an improvement in libido and potency after T levels are normalized in men with hypogonadism. They observed that once T levels are in the normal range, there is no added benefit from doubling the dose. Thus, there seems to be a critical T level in the low-normal range below which libido and potency are impaired. Androgen deficiency is rarely the major cause of impotence in elderly males, a condition that increases dramatically with age. Indeed, hypogonadism and erectile dysfunction appear to be independently distributed in elderly men. Christiansen42 has done an extensive review on mood and behavior as correlates of T. In the Rancho-Bernardo study,43 a significant inverse correlation was seen between T levels and depression scores. Finally, there is good evidence for a strong association between T levels and cognitive performance in healthy males.44 Studies specifically in elderly men are lacking.
Diagnosis of Hypogonadism in Elderly Men Many symptoms of hormone deficiency in elderly men (eg, decreased energy, muscle strength, libido, and potency) are common and nonspecific. Serum T levels therefore have been used to define hypogonadism in these patients. Androgen replacement therapy (ART) is only warranted in the presence of both clinical symptoms suggestive of hormone deficiency and decreased hormone levels (Figure). A recent consensus statement by the Endocrine Society45 recommends that a total testosterone level of less than 200 ng/dL be used to make the diagnosis of hypogonadism in older men. Given the circadian rhythm of T secretion, multiple early morning samples are needed to make the diagnosis. In older men, the time of the sample may not be as important, since the circadian rhythmicity of T becomes attenuated with aging.1
Testosterone Replacement Multiple preparations are now available for T replacement therapy (Table I). Oral T was the first to be used in a clinical setting. The earlier 17-a alkylated T derivatives had considerable hepatotoxicity and are no longer used. T undecanoate is an oral preparation presently used in Europe, Canada, and Australia (not available in the United States). It bypasses the first-pass metabolism by the liver, thereby avoiding the hepatotoxicity seen with earlier oral preparations. Intramuscular T preparations include the long- acting esters of T (enanthate and cypionate), which are typically administered every 2-3 weeks. These preparations are the least expensive form of androgen replacement, but they have large fluctuations in T levels. Transdermal preparations have a more favorable pharmacokinetic profile. Earlier patches had to be applied to the scrotal skin; however, newer preparations can be applied to nongenital skin. Cost, skin irritation, and poor skin adherence are limiting factors. Gel preparations are now available and offer less skin irritability and lack of visibility. Unpleasant odor and the risk of transferring the medication to a sexual partner are the disadvantages. Subdermal implantable T pellets, which maintain normal T levels for 6 months, are also available in Europe. Newer, longer-acting injectable T esters are being developed that do not have the unfavorable pharmacokinetic profile of the present intramuscular preparations. Recent interests also are directed toward the development of a selective androgen receptor modulator, which will have the desirable end organ effects without any prostatic stimulation. Effects of Testosterone Replacement in Elderly Men Supplementation of T to elderly men has been reported to significantly increase muscle mass,46-48 whereas fat mass is decreased.46 Conflicting data exist regarding the effect of T supplementation on muscle strength in elderly men.46,49 It remains to be seen whether this increase in muscle mass and power would translate into improved mobility and stability, thereby preventing falls and fractures. Authors agree that T replacement in hypogonadal men increases bone mass.50-52 Adult bone mass is however not reached, and the effects in elderly men are less convincing. The effects of T on bone may involve both increased osteoblastic activity47 and decreased bone resorption.53 There again seems to be a critical T level, below which the effect of T on BMD is most convincing. Androgen replacement in hypogonadal males improves mood, energy, and sense of well-being.46 Substantial improvement in libido is also observed.54 Most studies on T replacement also report a fall in total and low-density lipoprotein cholesterol (LDL-C), with no significant effect on HDL-C.47,53,55 Decrease in visceral abdominal fat mass56,57 with improvement in SI58 may influence cardiovascular morbidity. The effects on memory and cognition are still debatable. In summary, testosterone supplementation in elderly hypogonadal men seems to have a beneficial effect on muscle mass and strength, BMD, SI, lipid profile, mood, libido, and a sense of well-being. These advantages are limited to men with subnormal T levels, and no effects are generally seen above a certain threshold level of T. Large-scale epidemiological studies are needed to further evaluate whether the beneficial effects of T replacement will translate into clinically significant endpoints as well.
Testosterone and Women Physiological mechanisms regulating the homeostatic control of androgens in women are not clear. The ovaries and the adrenals are the sources of androgen in women. The effects of androgen replacement on sexual function in women are controversial. Mixed results are noticed with the use of vaginal T propionate preparations on the sexual function. Some studies have reported improvements in libido and sexual arousal with T therapy,59-62 while others have been unable to detect a significant benefit from androgen therapy.63,64 Improvement in mood and well-being65 are considered by many authors to be the most important benefits of T therapy. Androgen replacement therapy has been used for postmenopausal women who remain symptomatic despite estrogen or estrogen–progestin treatment. Indeed, some studies suggest that a combination of estrogen/androgen (E/A) may have better outcomes than estrogen replacement alone. Dobs et al66 examined the effects of estrogen replacement versus E/A combination on postmenopausal women. Compared with estrogen treatment alone, women in the E/A group increased their total lean body mass, reduced their fat percentage for all body parts, and increased lower body strength. More improvement was noted in sexual functioning and quality of life in the E/A group when compared with patients receiving estrogen alone.66 The E/A combination supplementation has also been shown to exert a protective effect on memory performance in postmenopausal women67 and to improve spatial cognition68 and verbal fluency.69 All of these effects were either better than or comparable to conventional HRT treatment. Further, a cross-sex hormone treatment study of transsexuals demonstrated that T had an enhancing effect on spatial ability performance in female-to-male transsexuals;70 these data suggest that the androgen portion of the E/A combination supplementation is responsible for these cognitive effects. Potential side effects of androgen therapy include acne, weight gain, excess facial and body hair, and adverse lipid changes. Potential virilization of a female fetus is a serious risk in women of reproductive age. Lastly, estrogenic side effects are also potential consequences of androgen therapy, including increased risk of breast and ovarian cancer. This calls for a guarded approach and watchful monitoring if E/A combination supplementation is considered in women.
Side Effects of Testosterone Replacement The most important possible side effect of T replacement in elderly men is exacerbation of prostate disease. Nonobstructive benign prostatic hyperplasia (BPH) is not a contraindication for T substitution; however, obstructive BPH is a clear contraindication. Androgen therapy increases prostate- specific antigen (PSA) levels in humans,53 though no human studies have thus far shown an increased rate of prostate cancer with T replacement. Because all prostate cancers are androgen-sensitive, its presence is an absolute contraindication for androgen therapy. While evidence is lacking that initiation of prostate cancer is influenced by androgens, the promotion of subclinical lesions to clinical carcinomas cannot be excluded. Many studies of T replacement have demonstrated increases in hematocrit, sometimes exceeding the normal range. Twenty-five percent of elderly patients had an increase in hematocrit of over 51%.48,54 Greater stimulation of erythropoiesis occurs with intramuscular than with transdermal preparations of T, which may be related to the pharmacokinetics of the former. Sleep apnea has been reported in a few cases with T administration,71 and use must be judicious in overweight patients with obstructive pulmonary disease. No adverse effect on lipids is observed. Table II lists some common contraindications to T replacement. Monitoring with serial PSA, digital rectal examinations, hematocrit, and plasma lipids during T replacement seems prudent.
Conclusions The role of testosterone replacement in older men is still uncertain. Many signs and symptoms of aging in males are reminiscent of the symptoms in younger hypogonadal males. It may be reasonable to assume that the age-associated decrease in T levels is in part responsible for these symptoms. Studies indicate a threshold level of T below which bone health and sexual function are abnormal. It seems logical that in elderly men with clinical symptoms suggestive of androgen deficiency and subnormal testosterone levels, T replacement will result in increased muscle mass and strength, BMD, and a general sense of well-being. Lessons learned from HRT in women indicate a cautious approach and further evaluation of possible risks. Large randomized placebo-controlled trials are needed to address functional and other hard endpoints, such as fracture rates, falls, cardiovascular morbidity, and mortality. G References 1. Bremner WJ, Vitiello MV, Prinz PN. 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