Words of Wisdom

Re: Gonadal Steroids and Body Composition, Strength,

and Sexual Function in Men

Finkelstein JS, Lee H, Burnett-Bowie SA, et al.

N Engl J Med 2013;369:1011–22

Experts’ summary:

The investigators studied and reported on 400 healthy men

aged 20–50 yr who were given monthly injections of goserelin

acetate for 16 wk to suppress endogenous testosterone. Men

were randomly assigned to a placebo gel or one of four doses

of transdermal testosterone gel (1.25, 2.5, 5, or 10 g/d). An

additional 200 men received anastrazole, an aromatase inhi-

bitor, to block the conversion of testosterone to estradiol, in

addition to placebo or testosterone gel. The investigators

examined the changes in percentages of body fat and lean

mass as primary outcomes. The men were also assessed for

subcutaneous and intra-abdominal fat, muscle area and

strength, and sexual function. The findings were clear: Muscle

size and strength were androgen-dose dependent, body fat

was estrogen dependent, and sexual function (libido and

erectile strength) was both androgen dependent and estrogen

dependent.

Experts’ comments:

The Endocrine Society’s guidelines define

male hypogonadism

as a ‘‘clinical syndrome’’ in which the diagnosis is based on

symptoms or signs and unequivocally low serum testosterone

levels

[1]

. The symptoms of hypogonadism vary widely and

include sexual symptoms (eg, decreased erectile function and

decreased libido), decreased mood, decreased muscle mass

and increased fat mass, and decreased bone density. Although

self-reported questionnaires such as the Androgen Deficiency

in the Aging Male questionnaire

[2]

and the Aging Males’

Symptoms scale

[3]

have attempted to capture the spectrum

of this disease, their specificity remains poor. Because of the

controversy in diagnosis, practitioners uniformly treat men

with a low testosterone level and any one or several symp-

toms of hypogonadism. Consequently, prescriptions for tes-

tosterone products have increased by

170% in the previous

5yr

[4]

In this study, one of the striking findings is that different

symptoms of hypogonadism can develop at different

gonadal steroid levels. For example, visceral fat increases

even at testosterone levels between 300 and 400 ng/dl.

However, muscle strength and size are unaffected until

testosterone levels are

200 ng/dl. Therefore, the target

levels of testosterone supplementation in a man who is

concerned about weight gain and increase in abdominal

girth could be different from the target in a man who is

concerned about loss of muscle strength and size.

Research thus far has focused almost exclusively on how

estrogen affects women and how testosterone affects men.

This study highlights the important role of estrogen in the

regulation of body fat and sexual function in men. Losing

estrogen did not affect lean mass, muscle size, or leg

strength any more than did testosterone deprivation. The

most adverse effects of estrogen deficiency were on sexual

desire, with men in this group reporting dramatic declines

in arousal and erectile function. Additionally, the increase in

intra-abdominal fat seen in men with decreased estrogen

(due to aromatase inhibition) could increase the risk of

cardiovascular disease, diabetes, and metabolic syndrome if

long-term estrogen deficiency exists.

Some of the limitations of the study include a younger

participant profile and a short follow-up. In summary, this

study provides insight into the different roles of testoster-

one and estradiol in the body composition, strength, and

sexual function of men. The available evidence of long-term

risks and outcomes of testosterone replacement therapy is

still very limited, and much less has been studied about the

effect of estrogen on the same end points. Carefully

designed placebo-controlled trials of testosterone admin-

istration to assess the risks and benefits of both sex

hormones are required.

Conﬂicts of interest:

Larry I. Lipshultz has been a clinical trials participant,

a consultant, and a speaker for Auxilium and Endo. Ranjith Ramasamy has

nothing to disclose.

References

[1]

Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in

men with androgen de±ciency syndromes: an Endocrine Society

clinical practice guideline. J Clin Endocrinol Metab 2010;95:

2536–59.

EUROPEAN UROLOGY 65 (2014) 843–848

available at www.sciencedirect.com

journal homepage: www.europeanurology.com

0302-2838/$ – see back matter