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University of California Los Angeles, School of Medicine Los Angeles, California 90095-1682
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Men over fifty present to me either because of sexual dysfunction, (usually erectile failure), loss of sexual interest, or loss of energy and well-being. In one study, measurement of their serum total and bioavailable testosterone (BT) demonstrated a much higher proportion of men with a BT two SD or more below the mean for young men than of abnormally low T levels (1). The mean BT falls from ages forty to seventy by three times the fall of T (2). The LH level does not exceed the range of normal in most of these men, so we must diagnose hypogonadism on the basis of the steroid hormone level alone. We believe that there is no reason to think that the tissues of older men require less BT than those of younger men, thus we define hypogonadism as a fasting, morning BT below 67 ng/dL (2.3 nM).
To rule out a pituitary tumor we measure LH, FSH, and prolactin in all hypogonadal men. We limit pituitary magnetic resonance imaging to men under 50, to those with visual changes or recent onset headaches, to those with hyperprolactinemia unassociated with antidopaminergic drugs, to those with very low gonadotropins (below the limit of normal for the assay), and to those with a very low BT (<20 ng/dL). Other circumstances may precipitate a pituitary magnetic resonance imaging examination, but it is important to remember that hypogonadism is very common, and clinically significant pituitary tumors are rare in older men. Should we treat symptomatic men meeting the criterion of hypogonadism, or alternatively all symptomatic men with androgens? That depends on the negative consequences of replacement doses of androgen therapy.
Most likely, the putative long-term adverse effects of androgens inhibit physicians from utilizing replacement doses and encourage them to withdraw therapy at the first sign of a possible problem. The principal issues surrounding androgen administration include an increased risk of clinically progressive prostate carcinoma, precipitation or exacerbation of benign prostatic hyperplasia (BPH), an increased hematocrit due to persistent erythropoietic stimulation, occasional exacerbation of sleep-apnea syndrome, a tendency toward thrombosis, and a reduction of total and high density lipoprotein (HDL)-cholesterol. There are also the occasional development of pedal edema, a physiologic increase of appetite, and an increase of blood volume that may increase mean blood pressure. The scientific basis for these concerns needs to be addressed.
There is no evidence that exogenous T at any dose will stimulate the development of clinically significant prostate carcinoma. Because androgen withdrawal inhibits the progression of existing prostate carcinomas, a carcinogenic effect of T has been suspected. Data are inconsistent regarding a relation between endogenous T and prostate carcinoma. Two studies (3, 4) failed to show a relationship between endogenous T and subsequent development of prostate carcinoma, while one study demonstrated that the calculated BT [T corrected for sex hormone-binding globulin (SHBG)] resulted in a linear increase of risk ratio for prostate carcinoma (5). However, in this study SHBG was highly correlated with T (meaning that most men with higher T levels are protected), and estradiol levels were inversely correlated with risk as well, making it very difficult to determine risk in an individual. Prostate specific antigen (PSA) levels did not correlate with T levels. I routinely follow the digital rectal exam and the PSA in men receiving T. Those few who demonstrate increases of PSA to above normal are followed up with prostate biopsies under ultrasound control to discover small, and we hope resectable, tumors.
There has been no relationship established between endogenous T and BPH (6). With regard to administered T, the only relevant study we found indicated that T, either as the enanthate or as the nonscrotal patch, increased prostate volume modestly and not progressively, but did not cause any clinical symptoms or increased AUA screening scores (7). In my practice, I have not observed treatment with physiologic doses of T to increase the symptoms of clinical BPH by the criteria of frequency, hesitancy, dysuria, or nocturia.
T routinely increases the hematocrit within the normal range. When it reaches 51%, we suggest that the patient donate blood regularly or reduce the T dose or frequency; and if it reaches 54%, we stop therapy. This is not a rare occurrence in older men (8). Daily administration of T patches, yielding more physiologic peak levels of T, may produce less erythropoietic stimulation than injection of long-acting T esters.
T therapy at hyperphysiologic dosage reduces total and HDL-cholesterol levels (9). However, physiological doses of androgens in hypogonadal or elderly men actually reduced total and LDL cholesterol and had no effect on HDL, HDL2, or HDL3 cholesterol (10). Whether these changes make any difference in cardiovascular risk is unknown. Because T also increases energy and exercise tolerance, and because patients can be given low fat diets, exercise, aspirin and, when indicated, a cholesterol-lowering agent, this limitation seems minimal. T does not seem to have an adverse effect on clotting (11). T also sensitizes to coumarin anticoagulants, requiring a reduction in dose in patients taking these agents.
A role for T in the sleep-apnea syndrome has been reported in very few cases. The possible incidence of this syndrome in men taking physiological amounts of T is not known. A possible effect of T on respiratory function may be most relevant to substantially overweight individuals and to those with chronic lung disease. One should question patients receiving T as to their snoring and the quality of their sleep.
We routinely treat any hypogonadal older man, (with a BT below 2.3 nM) with a 3-month trial of testosterone in one of its available therapeutic forms, after verifying that the subject is unlikely to have a pituitary tumor. A therapeutic trial should have a defined end-point, but unfortunately, the end-points for androgen therapy are largely subjective both for the patient and for the physician. This is especially true in the milder cases of hypogonadism seen in association with the aging process. Although many patients with hypogonadism and erectile dysfunction (ED) report an improvement in erectile function, we do not expect restoration of erectile function to be a consequence of T therapy (1, 12). Hypogonadism is the sole cause of ED in 10% or less of cases. The vast majority have other risk factors, including intrinsic penile disease, atherosclerotic vascular disease, pelvic surgery, autonomic neuropathies, depression, as well as drugs for central nervous system, cardiovascular (including hypertension), and endocrine disorders (including diabetes) (13). When we treat with T we follow sense of well-being, including strength, energy, mood, and self-esteem, as well as libido, which is the only response directly increased by androgens. T therapy increases bone density in men with osteoporosis, which can be followed radiographically(14).
In this era of evidence-based medicine the following may be suspect, but I have found that men who respond to T enter the examining room with more vigor, communicate with greater assurance, and are viewed by their partners as more vigorous and energetic and more interested in sex. Those who don’t respond, show no improvement and usually have no interest in remaining on androgen therapy. I do not believe that there is much of a placebo effect from T therapy.
How do we approach the question of treating men with loss of sexual interest and/or loss of energy and feeling of well-being who have a normal T and BT? Are we justified in giving them a trial of T therapy? I would not treat a patient whose main complaint is erectile dysfunction with T because it is not likely to be effective and because other forms of therapy are available. For men who are not obviously depressed, but who complain of loss of energy and/or libido, one might argue that a 3-month trial with a physiological dose of androgen is not likely to cause any adverse effects and may provide symptomatic relief. If so, continuation of therapy may be warranted with due attention to the possible complications noted above and a realization that many of the fears of T therapy are unfounded.
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This article has been cited by other articles:
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  M. Wald, R. B. Meacham, L. S. Ross, and C. S. Niederberger Testosterone Replacement Therapy for Older Men J Androl, March 1, 2006; 27(2): 126 - 132. [Full Text] [PDF]
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