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Address correspondence to Andrea M. Isidori, MD, PhD, Department ofMedical Pathophysiology, University of Rome “La Sapienza,” Viale delPoliclinico 155, 00161 Rome, Italy (e-mail: andrea.isidori@uniroma1.it).

© 2007 Mayo Foundation for Medical Education and Research

Mayo ClinicProceedings

January 2007Volume 82Number 1

See also pages20 and 29

Testosterone Replacement Therapy:What We Know Is Not Yet Enough

Scientific investigations into the endocrine correlates ofaging and disease have awakened an increasing interest

in the use of testosterone for a wide range of problems inaging men. Male hypogonadism, defined as chronic, oftenirreversible, severe androgen deficiency, has a low preva-lence. However, epidemiological studies have revealed thataging in men is accompanied by a progressive decline infree and total testosterone levels. In addition to chronologi-cal aging, the various illnesses occurring in mid to lateadult life and the medication used to treat them furthercontribute to lower circulating testosterone levels. Anyacute severe illness produces hypogonadotrophic hypogo-nadism. Additionally, chronic illnesses (eg, diabetes, car-diovascular disease, and hypertension), substance abuse(eg, tobacco and alcohol), and nutritional factors (frommalnutrition to obesity) account for and accentuate the age-related decline of serum androgen levels. Thus, the ques-tion is, should we treat the reduction of male hormones inaging men? There is no uncertainty that male hypogo-nadism deserves treatment in the case of severely alteredandrogen levels, regardless of the age of the patient. How-ever, is it worthy to treat a “marginal,” possibly transitory,decline of testosterone without a precise etiology or with-out specific symptoms to monitor? Such a clinical scenariocan apply to 10% of all men older than 50 years andtherefore cannot be dismissed as irrelevant. The problem inproperly caring for such patients is that we do not yet havean operational definition for “normal” testosterone valuesat different ages, nor have we identified specific signs andsymptoms to accurately discriminate between those whoneed treatment and those who do not. Another issue relates

to the health outcomes affected by testosterone treatment.If one decides to correct a man’s testosterone levels, oneshould know what to expect from treatment. Here we ben-efit from recent research aimed at identifying appropriatetargets of androgen treatment in theaging male. The 2004 analysis, pub-lished by the US Institute for Medi-cine,1 although rigorously conducted,was mainly a qualitative review of the literature, anddoubts have been expressed about the accompanying rec-ommendations. Limitations of that research promptedsubsequent investigations that have attempted to quantify(using objective and reproducible methods) the effects oftestosterone. This goal was addressed by our group when,in 2005, we published 2 separate meta-analyses on 4 majorareas in which an adequate number of randomized placebo-controlled trials were available: body composition, bonedensity, lipid profile, and sexual function.2,3 Meta-analysisis a reproducible, powerful tool that can be used to summa-rize a large number of studies and provide an estimate ofwhat to expect from a certain treatment compared withplacebo. The analyses revealed unexpected findings (eg, a6% reduction in body fat, a 3% to 4% increase in lean bodymass and bone density, and a diversified threshold effect onlibido and erectile function) with possible “wide implica-tions”4 for testosterone treatment in the disease process ofmale hypogonadism. Recently, other groups independentlyperformed parallel systematic reviews of the literature thatproduced 3 further important reports on the effects andadverse effects of testosterone,5-7 2 of which appear inMayo Clinic Proceedings.

In the current issue of the Proceedings, Boloña et al7 andHaddad et al6 explored the efficacy on sexual performanceand cardiovascular safety of testosterone replacementtherapy, respectively. The former demonstrated that testos-terone supplementation provided small improvements insatisfaction with erectile sexual function and moderate im-

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provements in libido. The latter demonstrated that tes-tosterone supplementation was relatively safe in terms ofcardiovascular health. The issue of cardiovascular adverseeffects of sexual hormone therapy is of great interest be-cause in the 1960s a trial of estrogen given to men forsecondary prevention of myocardial infarction wasabruptly discontinued after estrogen produced more events(myocardial infarctions and death) than placebo. In con-trast, several reports have described consistent improve-ment in both anginal symptoms and ischemia on electrocar-diograms in men treated with older injectable testosteronepreparations. More recent studies in humans have reportedthat low blood levels of androgens are associated withosteoporosis, adverse cardiovascular risk factors (includingan atherogenic lipid profile), systolic and diastolic hyper-tension, obesity, insulin resistance, and increased fibrino-gen values.8 Jones et al have published a series of articles9,10

that consistently document that testosterone replacement isbeneficial for cardiovascular disease. In addition, testoster-one replacement has been demonstrated as having positiveeffects on numerous metabolic parameters (eg, insulinsensitivity, glucose control, visceral adiposity, and hyper-lipidemia) in patients with type 2 diabetes mellitus andchronic heart failure.11

The problem that Haddad et al faced in evaluating thesafety of androgen replacement in men is that none of theavailable randomized controlled trials (RCTs) were de-signed to assess this outcome. Meta-analysis depends onthe quality of the original source—the published trials—and we cannot overlook the possibility that adverse eventswere censored or simply ignored when the final reportswere written. Therefore, the potency of the meta-analysisto answer this question is weak. Only large randomizedplacebo-controlled studies expressly designed to investi-gate the safety of androgen treatment will provide an au-thoritative answer. Nevertheless, while waiting for thisinformation to become available, the conclusions derivedfrom the meta-analyses can guide physicians and re-searchers in the rather underinvestigated field of late-onset male hypogonadism. The value of the studies byHaddad et al and Boloña et al is that they are not intended toobviate the need for high-quality prospective RCTs, butinstead to support current clinical guidelines and poten-tially direct future research. The finding of a small butsignificant effect of testosterone on erectile function,3 con-firmed by the article by Boloña,7 has challenged the datedand widely held opinion that the effects of testosterone onsexual function were mainly secondary to its effect onlibido. This interpretation does not add a new indicationnor does it discover a new treatment for erectile dysfunc-tion; instead, its relevance is to clarify the role of androgensin pharmacologically manipulating a complex vascular-

smooth muscle system such as that of the corporacavernosa. Recent molecular studies confirmed thesedata,12 and most andrological societies now recommend thecombination of an androgen plus a phosphodiesterase type5 to treat selected patients with reduced testosterone lev-els and erectile dysfunction.13-14

The past and current meta-analyses have summarizedwhat it is known from the available published trials on theeffects of testosterone on sexual function, bone density,serum lipids, fat, and lean body mass. Thanks to the effortof these collective authors, we now have a much clearerpicture of testosterone effects in these areas. The questionnow is whether such outcomes are of real interest forpatients and physicians. Is it appropriate to treat men withborderline testosterone levels to achieve the results shownin these reports? We suspect that we have only begun toexplore the potential effects and adverse effects of thishormone and related compounds. The clinically relevantand most awaited findings are those on the role of testoste-rone in the metabolic syndrome, inflammation, and cardio-vascular disease.

McKinlay15 recently suggested that we are not yet readyto embark on a large RCT of testosterone use in men.Important scientific questions need to be answered withsolid data from well-designed observational studies beforean optimal trial can be designed. It is crucial that weidentify the targets of androgen treatment that are relevantenough to justify the risks and costs of a large RCT. Thepotential market for androgen replacement drugs is huge,which means that the potential benefit and harm are alsolarge. The opportunities for scientific investigation are im-mense. We can only hope that these studies will be per-formed rigorously and expeditiously.

Andrea M. Isidori, MD, PhDAndrea Lenzi, MD, PhDDepartment of Medical PathophysiologyUniversity of Rome “La Sapienza”Rome, Italy

1. Liverman CT, Blazer DG, eds. Testosterone and Aging: Clinical Re-search Directions. Washington, DC: National Academies Press; 2004.

2. Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on bodycomposition, bone metabolism and serum lipid profile in middle-aged men: ameta-analysis. Clin Endocrinol (Oxf). 2005;63:280-293.

3. Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone onsexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf).2005;63:381-394.

4. Liu PY, Wang C, Swerdloff RS. Male sex matters. Clin Endocrinol(Oxf). 2005;63:601-602.

5. Tracz MJ, Sideras K, Bolona ER, et al. Testosterone use in men and itseffects on bone health: a systematic review and meta-analysis of randomizedplacebo-controlled trials. J Clin Endocrinol Metab. 2006 Jun;91:2011-2016.Epub 2006 May 23.

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Mayo Clin Proc. • January 2007;82(1):11-13 • www.mayoclinicproceedings.com 13

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6. Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardio-vascular risk in men: a systematic review and meta-analysis of randomizedplacebo-controlled trials. Mayo Clin Proc. 2007;82:29-39.

7. Boloña ER, Uraga MV, Haddad RM, et al. Testosterone use in men withsexual dysfunction: a systematic review and meta-analysis of randomizedplacebo-controlled trials. Mayo Clin Proc. 2007;82:20-28.

8. Isidori AM, Giannetta E, Pozza C, Bonifacio V, Isidori A. Androgens,cardiovascular disease and osteoporosis. J Endocrinol Invest. 2005;28(10,suppl):73-79.

9. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dosetransdermal testosterone therapy improves angina threshold in men withchronic stable angina: a randomized, double-blind, placebo-controlled study.Circulation. 2000;102:1906-1911.

10. Pugh PJ, Jones TH, Channer KS. Acute haemodynamic effects oftestosterone in men with chronic heart failure. Eur Heart J. 2003;24:909-915.

11. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS.Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006 Jan;27:57-64.Epub 2005 Aug 10.

12. Morelli A, Filippi S, Mancina R, et al. Androgens regulate phospho-diesterase type 5 expression and functional activity in corpora cavernosa[published correction appears in Endocrinology. 2004;145:3152]. Endo-crinology. 2004 May;145:2253-2263. Epub 2004 Feb 5.

13. Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improvecavernous vasodilation and response to sildenafil in patients with erectiledysfunction. Clin Endocrinol (Oxf). 2003;58:632-638.

14. Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment andmonitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAUrecommendations. Int J Androl. 2005;28:125-127.

15. McKinlay JB. Should we begin a large clinical trial of testosterone inmen? “not yet.” JMHG. 2006;3:33-35.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.