Testosterone Replacement: When Is There a Role?

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 evaluation 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 endocrine 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 test method to rule out an endocrine evaluation in a man complaining of ED abnormality in serum T. However, the results may be should include serum T. Initially, a more comprehen- misleading, particularly in obese and in elderly men sive assessment may not be justi®ed, but further

International Journal of Impotence Research Testosterone replacement of erectile dysfunction A Morales S114 assessment is clearly indicated if hypogonadism evident that androgen supplementation for condi- is documented. For instance, the measurement of tions such as osteoporosis requires a prolonged course pituitary gonadotropins, follicle stimulating hormone of no less than several years before an objective (FSH) and luteinizing hormone (LH) can provide an improvement can be documented.22 indication whether primary, secondary or tertiary hypogonadism is the cause. However, it must be remembered that at middle age and beyond, there is a Treatment options diminution in pituitary function that results in a ¯attening in the circadian production of gonadotropins.18 Therefore, it is not uncommon to encounter Androgens can be administered by several routes, men with erectile problems (who are most commonly each one offering a different set of advantages and in these age groups) and primarily testicular failure drawbacks.23 resulting from a breakdown of the feedback mechan- isms, ie, a low serum T with normal or only minimally elevated gonadotropins. Parenteral Measurement of other endocrinological parameters (ie DHEA, growth hormone, melatonin, and leptin) is not indicated in the context of erectile dysfunction, Injectable esters of T have been available for the but thyroid function may have an impact on sexual longest period of time and their effects are well performance. Such an occurrence is exceedingly rare recognized.24 They are inexpensive and safe but their and the routine assessment of thyroid function is use carries several major drawbacks which include: unlikely to be productive. However, hyprothyroidism (a) the need for periodic (every 2 ± 3 weeks) deep may result in hyperprolactinemia, therefore, assess- intramuscular injection; ment of thyroid function in hyperprolactenemic (b) the administration of injectable preparations patients is indicated.19 On the other hand, levels of results, in the ®rst 72 hours, in supraphysiolo- total testosterone may appear abnormally high in the gical levels of serum T followed by a steady presence of normal bioavailable T in patients with decline over the next 10 ± 14 days;25 hyperthyroidism.20 (c) the steady decline in T levels frequently results in a very low nadir immediately before the next injection. This phenomenon translates into Justi®cation for androgen supplementation wide swings in mood and well being (the roller-coaster effect) which is disconcerting and upsetting to both patients and their In the context of ED, exogenous androgens are partners; indicated if hypogonadism is documented with or (d) parental androgens do not provide the normal without alteration in sexual desire. Libido is a poor circadian patterns of serum testosterone and the indicator of androgenic homeostasis unless there intermittent supra-physiological levels they is a profound hypotestosteronemia. Low serum T produce may result in the development of breast levels may co-exist with a variety of other important tenderness and gynecomastia. conditions which are well recognized causes of erectile failure (atherosclerosis, diabetes and a variety The most widely used parenteral preparations are of erectolytic medications21). However, in the pre- the 17-b-hydroxyl esters of testosterone which in- sence of hypogonadism and ED it is justi®ed to clude the short acting propionate and the longer acting consider a trial of exogenous androgen therapy. The enanthate and cypionate. Currently, the propionate is reasons for this view include the simplicity and safety rarely used because its short half-life requires that it be of the treatment and the presence of a documented administered every other day. The enanthate and etiology. The response, in terms of recovery of erectile cypionate, on the other hand, can be administered in function and improvement in sexual interest, is not doses between 200 mg and 400 mg every 10 ± 21 d to spectacular. Our experience and that of others clearly maintain normal average testosterone levels.26 Higher indicates that only a limited number of men undergo doses will not maintain T levels in the normal range restoration of erections and improvement in libido beyond the 3-week limit. Appropriate treatment of secondary to androgen supplementation.9,10,21 Pa- hypogonadism with injectable esters of T has been tients not responding to T administration require re- shown to improve libido, sexual function, energy evaluation to rule out associated causes. A trial of levels, mood and bone density if the symptoms are androgen administration should be not shorter than 3 caused by an androgen de®ciency.18 Persistent supra- months. At the end of this period a re-assessment of physiologic levels of serum T may result in infertility sexual function and other parameters is indicated. due to suppression of LH and FSH production.27 Continuation of T administration would then depend Although concern exists about the psychosexual on the clinical response and possible alter-ations in effects of markedly elevated levels serum T, published other organ systems resulting from treatment. It is evidence indicates that, even in eugonadal men,

International Journal of Impotence Research Testosterone replacement of erectile dysfunction A Morales S115 amounts up to ®ve times the normal physiological result in various degrees of dermatitis, occasionally replacement doses of T cypionate have only producing signi®cant chemical burns. minimal psychosexual effects.28,29

Other preparations Oral preparations Delivery forms not widely prescribed but worth These demand special consideration because they mentioning include long acting implantable subcuta- undergo rapid hepatic metabolism and may, therefore, neous pellets and microcapsules.34,35 The subcuta- fail to result in adequate serum levels of androgens. In neous implants are not associated with high DHT order to prevent metabolism by the liver, oral agents levels, which is desirable when treating older hypo- available in the USA are alkylated preparations. gonadal man in whom concerns regarding the prostate However, these alkylated preparations generally gland are of paramount importance. The signi®cance provide erratic androgenic activity and exhibit a of elevated levels of DHT, which are more common potential for signi®cant liver toxicity which has with oral or scrotal administration of T still remains to included: hepatocellular adenomas, cholestatic jaun- be clari®ed. Similarly, MENT (7a-methyl-19 nortes- dice and hemorrhagic liver cysts.30 Testosterone tosterone), which is not reduced to DHT but aroma- undecanoate is yet another oral preparation that is tized to estradiol, would be more desirable in the not, at present, available in the USA but it is widely presence of urinary obstructive symptoms. used throughout the world. As the only effective oral testosterone ester, when taken with meals it circum- vents the ®rst passage through the liver. It is free of New frontiers in androgen therapy liver toxicity and brings serum T levels within physiological range. It is liposoluble and for this reason it must be taken with meals. None of the oral It is recognized that androgen receptors (AR) are medications cited above results in a faithful re¯ection widely distributed among reproductive and non- of the circadian level variations. However, careful reproductive tissues in the body. Of interest in the selection of the timing and amount of the dosing may treatment of sexual dysfunction is their ubiquitous ameliorate this problem. presence in the pineal gland and brain cortical and subcortical regions and male external genitalia. This wide distribution permits envisioning the hypo- thetical exploitation of selective androgen receptor Transdermal T therapy modulators (SARMS)36 with a speci®c activity in the target tissue of interest. Since SARMs are not 35 Transdermal T therapy (TTT) results in serum T levels substrates for 5a-reductase activity, it would be within the range observed in normal men over the 24 h possible to achieve adequate levels of androgens in the circadian cycle. TTT is available in both scrotal and brain and genitalia without a concomitant increase in non-scrotal patches. The former has lost appeal due to the prostate or seminal vesicles. The development of 37 inconveniences such as its ability to remain in place such molecules is currently becoming a reality. and the need for frequent shaving of the scrotal skin. In addition, due to the high concentrations of 5-alpha reductase in the scrotal skin, abnormally high serum Responsibility with treatment levels of dihydrotestosterone (DHT) have been reported.31 Either patch applied at bedtime will result in peak T levels in the early morning and a nadir just Male hypogonadism, as mentioned before, affects a prior to their replacement. Transdermal non-scrotal variety of organs and the limited view of its exclusive patches also produce normal levels of estradiol, but, importance in sexual function is too con®ning and unlike the scrotal patches, these do not result in may be detrimental to patient care. However, for the abnormal levels of DHT.31 In addition to producing purposes of this review, it can be categorically physiologically appropriate serum levels of T, they established that low T levels in a man with sexual actually lower the level of sex hormone binding dysfunction are a clear indication for hormone globulin (SHBG), promote virilization and increase replacement therapy (HRT). If there are no correctable bone mineral density.32 Finally, the T patches, causes attributable to the endocrine dysfunction, a compared to injectable forms of T, minimize excessive limited period of hormonal treatment (ie, 3 ± 6 eryth-ropoiesis and suppression of gonadotropins.33 months) is usually suf®cient to establish a cause ± The most common side effects of the non-scrotal symptom relationship. Obviously, if adequate transdermal patches are related to the enhancers used HRT does not result in an appropriate response, a to facilitate absorption; these enhancers frequently search for other co-morbidities becomes mandatory.

International Journal of Impotence Research Testosterone replacement of erectile dysfunction A Morales S116 Other sequelae of hypogonadism may coexist with ED; (7) Although not yet proven, in hypogonadal men, in this situation, prolonged T administration is co-administration of T with an erectogenic indicated even if the sexual problems fail to show drug may show synergistic or supra-additive improvement. ef®cacy.39 There is a persistent and somewhat justi®ed (8) In men over the age of 40 y a digital rectal concern about undesirable side effects that may result examination (DRE) and prostatic speci®c anti- when some of the currently available androgen gen (PSA) determination are mandatory. preparations are prescribed ethically or when abused Biopsy of the prostate is reserved for those in by athletes and body builders. The potential for whom an abnormality is detected. adverse effects is of particular concern in the liver, (9) The suspicion or presence of cancer of the the prostate, lipid pro®le and cardiovascular system, prostate or breast are absolute contraindica- sleep patterns and social behavior and emotional tions for androgen therapy. state. These considerations have been reviewed (10) The T preparation, dose and route of adminis- recently.16 tration need to be selected carefully depending on the individual needs and circumstances of the patient. (11) For the ®rst year after the onset of therapy, Recommendations patients should be followed quarterly to assess response to therapy (clinical and biochemical) including hemoglobin, DRE and PSA. Patients The current state of knowledge within the narrow who remain stable may subsequently be fol- con®nes of androgen therapy in men with ED permits lowed annually, at which time other tests of the development of a set of recommendations (not yet liver function and lipid pro®le should be guidelines) which appear appropriate until a perti- included. nent scienti®c society or regulatory agency develops (12) During therapy serum T levels may ¯uctuate guidelines or standards with universal credibility and considerably, particularly with the use of the appeal. They are as follows: intramuscular preparations. In the speci®c (1) The diagnosis of adult hypogonadism based on situation of the hypogonadal impotent man, a history of low sexual desire is notoriously the clinical response is the most reliable guide unreliable. The physical examination is also to dose requirements. unreliable except in the most profound cases. Biochemical determinations are, therefore, recommended to establish a ®rm diagnosis. Either a total T and SHBG or bioavailable T are Conclusions the most dependable tests. (2) Due to the pulsatile nature of T production, it is prudent to con®rm an abnormal result. Hypogonadism is not a common cause of ED. How- (3) T administration must be supported by a clear ever, its clinical diagnosis in the adult is dif®cult and indication (clinical judgement and biochemical normally requires biochemical investigations. A information). serum T determination is justi®ed in men complain- (4) Borderline levels of serum T may be of limited ing of ED with or without alterations in sexual desire. relevance and may not correlate well with The prevalence of ED is particularly common at a sexual desire and performance. Such cases point in life when alterations occur in men's hormonal demand careful consideration of the advan- environment. Even though ED may not be a conse- tages and drawbacks of androgen therapy. quence of the changing hormonal mileu, the con- Nevertheless, a limited therapeutic trial is sequences of hypogonadism in other organ systems usually warranted. are increasingly recognized and timely diagnosis and (5) In a man with concomitant hypogonadism and appropriate treatment may signi®cantly improve the ED, a 3 ± 6 month period of hormonal supple- patient's quality of life. mentation is indicated. Failure to respond to therapy despite reaching eugonadal serum T levels is an indication to search diligently for References co-morbidity. In the absence of a response and if no other sequelae of hypotestosteronemia exist, discontinuation of treatment should be 1 Feldman HA et al. Impotence and its medical and psychoso- considered. cial correlates: Results of the Massachusetts Male Aging (6) Men with secondary hypogonadism (of hy- Study. J Urol 1994; 151: 54 ± 61. pothalamic-pituitary origin) may experience 2 Replacing testosterone in men. Drug Ther Bull 1999; 37: 3±6. 3 Bancroft J, Wu, CFW. Changes in erectile responsiveness bene®t by treatment with gonadotropins or during androgen replacement therapy. Arch Sex Behav. 1983; clomiphene.38 12: 59.

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International Journal of Impotence Research Testosterone replacement of erectile dysfunction A Morales S118 Appendix example, polycythemias, and some people develop sleep apnea on testosterone replacement.

Open discussion following Dr Morales' presentation Dr Eid: Is there such a thing as a low testosterone level? Is it abnormal or normal? The concept of low testosterone, is that real or is that something we've Dr Pryor: In evaluating testosterone levels, we need made up? to remember that it's a biorhythm that peaks in the morning and troughs in the afternoon. If you get a borderline or low level in a patient whose appoint- Dr Morales: I think it's real. Dr Lisa Tanover says ment is in the afternoon, you should repeat the test in that, in America if your testosterone is less than 250, the morning. that's de®nitely abnormal; no question about it. You have to use clinical judgement. Given three months of Dr Morales: Yes. In fact, in older impotent men and testosterone, if the patient doesn't improve, you in obese men, there is also a ¯attening of the cycle. should look for comorbidity. One thing we have to Testosterone may be normal, but these people have eliminate is the urologists' parochial view that very high levels of sex hormone binding globulin. testosterone is sex. Testosterone has many other Always take measurements between 8:00 and functions. I believe it's a central conditioner. I have a 11:00 am. In the afternoon the levels are going to be patient with a testosterone level of one, and cancer of lower. the prostate. Two months ago I put a penile prosthesis in him and his libido is pretty good. But, because we Dr Pryor: Another point I'd like to make is about the don't understand many of these things, I don't think side effects that some are not as familiar with, for that's an argument for not treating these patients.

International Journal of Impotence Research