International Journal of Impotence Research (2000) 12, Suppl 4, S112±S118 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Testosterone replacement: when is there a role? A Morales1* 1Queens University, Department of Urology, Kingston General Hospital, Kingston, Canada Hypogonadism is an uncommon cause of erectile dysfunction. Unfortunately, hypogonadal states in adult males are dif®cult to diagnose on purely clinical grounds and it is necessary to seek biochemical support. The simplest way to establish the diagnosis of hypogonadism is by determination of serum testosterone levels. Several methods exist but total testosterone determination plus assessment of sex hormone-binding globulin or bio-available testosterone appear to be the most reliable and accessible. Once a diagnostic of hypogonadism has been established in a man with erectile dif®culties, a trial of androgen supplementation is warranted if no contraindications exist. Knowledgeable monitoring is essential. In the absence of an adequate response, co-morbidities should be diligently sought out. In the absence of reliable guidelines for androgen administration to patients with erectile failure, a set of recommendations are provided. International Journal of Impotence Research (2000) 12, Suppl 4, S112±S118. Keywords: erectile dysfunction; pharmacotherapy; androgens; review Introduction Testosterone and sexual function The aging process in men is associated with variable Although it is possible to obtain erections and but sometimes profound hormonal alterations and a maintain some semblance of libido with minimal decrease in sexual performance.1 This should not be levels of androgens, in general castrate levels of T construed to imply that the latter is exclusively a result in suppression of both sexual interest and consequence of the endocrine changes. The Massa- performance.3 Nevertheless, the prevalence of hypo- chusetts Male Aging Study (MMAS) was unable to gonadism in men with ED is low4 and its presence may associate the coexistence of ED and changes in the not re¯ect causality. serum levels of sex hormones with the notable Solid evidence has shown that profound hypogo- exception of a direct correlation between sexual nadism results in the early abolition of erections dysfunction and a serum de®cit in dehydroepian- associated with rapid eye movement (REM) sleep drosterone (DHEA) and its sulfated form (DHEAS). while erotically stimulated erectile function may This ®nding is dif®cult to interpret because, although be preserved during wakefulness.5 In addition hypotestosteronemia and aging show a very marked to having a detrimental effect on erectile activity, inter-individual variability, the association of low hypogonadism brings a diminution in the frequency DHEA and advancing age exhibits a more predictable, of sexual thoughts and intercourse. Its adverse effect constant and profound association. In other words, ED on the volume of the ejaculate and semen quality are and the decease in serum levels of DHEA is so also well recognized.6 prevalent in the elderly that their relationship may simply be coincidental, and not necessarily related. It is widely accepted that androgens are important for general sexual function and the role of androgens in Should men with ED be investigated for erectile physiology is particularly fundamental. Cur- hypogonadism? rent estimates indicate that 1 in 200 male adults have abnormally low levels of testosterone (T) and most of these men are candidates for androgen supplementa- A great deal of controversy has existed in the literature tion therapy.2 regarding this issue. Those opposing the routine hormonal assessment argue that hypogonadism is a rare cause of ED, the cost of the testing is considerable and, above all, it can be suspected by its effect on *Correspondence: A Morales, Queens University, Department of Urology, Kingston General Hospital, Kingston, ON K7L 2V7 libido. Let us examine these points individually. Canada. The prevalence of hypogonadism in the age group E-mail: [email protected] with the highest incidence of ED (middle age and Testosterone replacement of erectile dysfunction A Morales S113 beyond) is higher than initially suspected.7 Morley et because this subset of patients commonly exhibit al8 reported a signi®cant incidence of androgen increased levels of sex-hormone binding globulin de®ciency in males, as measured by serum levels of (SHBG), which prevents T from becoming metaboli- bioavailable T. Nevertheless, it is recognized that cally active. Free T levels may provide a better hypogonadism is rarely the main etiological factor in estimation of testicular endocrine function but the ED, a view further supported by the limited success of fastidiousness required in the technique results in adequate exogenous T supplementation in the treat- inter- and intra-laboratory variability, casting reserva- ment of ED.9,10 tions on the accuracy of the test. Measuring bioavail- The cost of determining serum T is dif®cult to able T (the sum of free albumin-bound T) may be the assess and depends on a number of variables. These most reliable measurement because it determines the variables include: the degree of laboratory sophistica- amount of T which is available to target tissues. tion, the type of T determination (total, free or Unfortunately, determinations of bioavailable T are bioavailable), the number of tests requested and the not widely performed and are more costly. An type and number of supplementary tests ordered appropriate compromise that takes into consideration (determination of sex hormone-binding globulin, the accuracy of test results, cost and availability is the gonadotropins) to facilitate accurate interpretation of simultaneous determination of total T and SHBG by the results. The basic determination of total serum T is immunoassay.15 Regardless of the test employed, if an inexpensive (under $10.00). abnormal value is obtained with the initial determina- The view that the diagnosis of hypogonadism can tion, the results should be con®rmed with a second be established on the basis of history and physical test, particularly when the abnormality is borderline. examination is a fallacy. Adult hypogonadism, except If the abnormality is con®rmed, it may then be in the most extreme cases, is dif®cult to diagnose appropriate to further investigate the hypothala- accurately without biochemical investigations.11 mus ± pituitary ± gonadal axis by measuring levels of Thus, sexual interest is a notoriously unreliable gonadotropins (FSH and LH). The measurement of symptom that may be prominent in men with normal prolactin may also be appropriate in this case, since T levels but affected by other conditions (eg depres- hyperprolactinemia is frequently seen in the presence sion12). Testicular size and consistency in the adult of hypotestosteronemia. As opposed to the clinical male show marked inter-individual variability and manifestations of low T levels (where libido is a poor the appearance of secondary sex characteristics are clinical marker), this author has not yet observed a not suf®cient to suspect or rule out the presence of patient with a functional prolactinoma who did not hypoandrosteronemia.13 The clinician is, therefore, also present with a marked decrease in sexual desire. obliged to seek biochemical assistance before embark- ing upon treatment of ED. It should be noted, however, that the diagnosis of a medically signi®cant hypogo- Other hormones nadism should be based on a comprehensive evalua- tion of the patient and his biochemical test results. Finally, the author's opinion is that it is clinically Further hormonal evaluation depends on the interest, parochial and inappropriate to consider hypogonad- expertise and commitment of the physician and, ism only from a purely sexual perspective. After all, as obviously, the patient's clinical picture. Despite noted above, men seeking professional help for ED overwhelming evidence to support its existence, belong to an age group in which there is clear and androgen decline in the aging male (ADAM) also signi®cant increase in the prevalence of deterioration known as the andropause, continues to be debated. in the function of the hypothalamic-pituitary-gonadal Part of the controversy is based on the vagaries and axis.1,6,9,12 Unquestionably, it is the responsibility of inconsistencies of the syndrome16 and production of the clinician (in general) and the urologist (speci®- several other hormones are frequently affected during cally) to rule out the presence of a hypo- the aging process. For instance, diminution in muscle gonadal state with its subtle but dire consequences mass and strength have long been recognized as a beyond sexual problems (ie, depression, osteoporosis, sequelae of hypogonadism,17 more recently, similar detrimental alterations in lipid pro®le, etc).14 alterations were documented in adults with growth hormone de®ciency. Disturbances in sleep patterns may equally be attributed to low levels of T or The minimal hormonal evaluation melatonin. These close interactions between endo- crine systems and their target organs are poorly understood but our limitations in knowledge should Measuring total serum T levels, preferably in the not justify the denial of their existence. morning between 8 and 10 am can determine the The alterations in the hormonal milieu occurring androgenic milieu. This is the simplest, least expen- with age are incontrovertible. Basic biochemical sive and readily accessible