Low Estrogen Explains Some Hypogonadal Symptoms in Men

Testosterone deficiency in men accounts for decreases in lean mass, muscle size, and strength, whereas estrogen deficiency primarily accounts for increases in body fat, according to a new study. Deficiency of both hormones contributes to a decrease in sexual function.

“Our findings support changes in the approach to evaluation and management of hypogonadism in men,” investigators concluded in the New England Journal of Medicine (2013;369:1011-1022).

Joel S. Finkelstein, MD, and colleagues at Massachusetts General Hospital in Boston, studied 198 healthy men aged 20-50 years who were given goserelin acetate to suppress endogenous testosterone and estradiol (cohort 1). They randomized subjects to receive a placebo gel or 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. Another 202 healthy men (cohort 2) received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress conversion of testosterone to estradiol).

More than 80% of circulating estradiol in men is derived from the conversion of testosterone, the investigators noted, so decreases in serum testosterone levels are accompanied by a decline in serum estradiol levels. “Nevertheless, the consequences of male hypogonadism are routinely attributed solely to androgen deficiency; the potential role of the concomitant decline in estrogens is typically ignored,” they observed.

In the men who did not receive anastrozole (cohort 1), the percentage of body fat increased significantly in those who received placebo or 1.25 or 2.5 grams of testosterone daily compared with subjects who received 5 grams of testosterone daily. Lean mass declined significantly in men who received placebo or 1.25 grams of testosterone daily compared with men who received 2.5, 5, or 10 grams of testosterone daily. Only placebo recipients experienced a decrease in leg-press strength.

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In cohort 2, the percentage of body fat increased in all groups. The magnitudes of these increases were similar with placebo and 1.25, 5, and 5 grams of testosterone daily, a finding that suggests a predominantly estrogenic effect. Total-body lean mass decreased significantly in men who received placebo versus those who received 1.25, 2.5, and 10 grams of testosterone daily, “a finding that implies an independent effect of testosterone.” Subcutaneous-fat area increased in all groups in cohort 2, although only the comparison of changes between the 1.25 and 10 gram dose groups was significant.

Thigh-muscle area decreased significantly in men who received placebo compared with men who received any of the four testosterone doses, Dr. Finkelstein's group reported. Leg-press strength declined significantly in men who received placebo compared with those who received the three highest testosterone doses.

In cohort 1, sexual desire decreased progressively with declining testosterone doses. Erectile function worsened significantly in men who received placebo compared with men who received testosterone, and declined more in men who received 1.25 grams of testosterone daily than in those in the three highest dose groups. In cohort 2, sexual desire declined significantly in men who received placebo compared with men in the three highest dose groups, and declined more in men who received 1.25 grams of testosterone daily than in subjects in the two highest dose groups. Erectile function decreased more in men who received placebo than in those who received testosterone.

“Our finding that estrogens have a fundamental role in the regulation of body fat and sexual function, coupled with evidence from prior studies of the crucial role of estrogen in bone metabolism, indicates that estrogen deficiency is largely responsible for some of the key consequences of male hypogonadism and suggest that measuring estradiol might be helpful in assessing the risk of sexual dysfunction, bone loss, or fat accumulation in men with hypogonadism,” the authors wrote.

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