Low estrogen levels may play role in hypogonadism

Insufficient estrogen levels in men may be at least partially to blame for symptoms that are often attributed to hypogonadism, according to a recently published study.

"This study establishes testosterone levels at which various physiological functions start to become impaired, which may help provide a rationale for determining which men should be treated with testosterone supplements,” said corresponding author Joel Finkelstein, MD, of Massachusetts General Hospital, Boston. “But the biggest surprise was that some of the symptoms routinely attributed to testosterone deficiency are actually partially or almost exclusively caused by the decline in estrogens that is an inseparable result of lower testosterone levels.”

In addition to its direct action on some physical functions, a small portion of the testosterone that men make is normally converted into estrogen by aromatase. The higher the testosterone level in a normal man, the more is converted into estrogen. Since any drop in testosterone means that there is less to be converted into estrogen, men with low testosterone also have low estrogen levels, making it unclear which hormones support which functions.

Dr. Finkelstein and colleagues authors set out to determine the levels of hormone deficiency at which symptoms begin to occur in men and whether those changes are attributable to decreased levels of testosterone, estrogens, or both.

For the study, which was published in the New England Journal of Medicine (2013; 369:1011-22), the authors enrolled two groups of men with normal reproductive function, ages 20 to 50 years. The authors provided 198 men with goserelin acetate (Zoladex) and randomly assigned them to either a placebo gel or testosterone gel. Another 202 men received goserelin acetate; testosterone gel or placebo; and anastrozole (Arimidex), the latter of which suppressed conversion of testosterone to estradiol.

Among participants in whom estrogen production was not blocked, increases in body fat were seen at what would be considered a mild level of testosterone deficiency. Decreases in lean body mass, the size of the thigh muscle, and leg strength did not develop until testosterone levels became quite low. In terms of sexual function, sexual desire was reported to decrease progressively with each drop in testosterone levels, whereas erectile function was preserved until testosterone levels were extremely low.

In study participants also receiving anastrozole, increases in body fat were seen at all testosterone dose levels, but suppressing estrogen production had no effect on lean mass, muscle size or leg strength. Adverse effects on sexual function were much more obvious when estrogen synthesis was suppressed regardless of participants' testosterone levels, the researchers reported.

Overall, the results imply that testosterone levels regulate lean body mass, muscle size, and strength, while estrogen levels regulate fat accumulation. Sexual function-both desire and erectile function-is regulated by both hormones.

Dr. Finkelstein pointed out that the study artificially induced the hormone deficiency usually seen in aging men to provide a controlled model and that follow-up studies are needed to confirm the accuracy of the model. Currently, he said, decisions about whether an individual is a candidate for testosterone replacement should be made based on his symptoms and not just his testosterone level. The findings regarding estrogen’s effects suggest that the forms of testosterone used for therapy should be capable of being aromatized into estrogen, he added.

Abbott Laboratories provided testosterone gel and AstraZeneca Pharmaceuticals provided anastrozole and goserelin acetate for the study. Solvay Pharmaceuticals (now Abbott Laboratories) provided funding for the study.

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