Our traditional thinking about sex steroids is being challenged.
Lawrence Ross, MD
Hypogonadism is an increasingly common finding in aging men, those treated for prostate cancer or other diseases involving hormone therapy or chemotherapy, and men with erectile dysfunction. Testosterone replacement therapy (TRT) has grown exponentially in recent years. It is most commonly given in the form of exogenous testosterone as topical gels, subcutaneous implants, or biweekly intramuscular or subcutaneous injections.
In men concerned about reproductive potential, exogenous testosterone must be avoided as it suppresses spermatogenesis. In these patients, alternate therapy with clomiphene to increase gonadotropin secretion, or in men with elevated levels of estradiol, use of aromatase inhibitors to drive estradiol conversion back to testosterone, can be employed.
The clinical hallmarks of hypogonadism are decreasing libido, decreased or absent erectile function, decreased muscle mass and exercise tolerance, depression, and weight gain. Not all of these symptoms are seen in men with low testosterone levels, but lack of libido and ED top the list.
At this year’s AUA, a study linking estradiol levels in men on TRT to higher levels of libido is reported. Estrogens are traditionally associated with female reproductive and sexual function, while testosterone is thought to be the main driver of male reproduction, libido, and sexual function. In recent years, several studies have attempted to link reduced testosterone levels in postmenopausal women to decreased libido.
Treatment of these women with testosterone has been less than convincing. However, a recent report on the role of testosterone and estrogen on male muscle mass, fat distribution, and sexual function suggests that male sexual function is dependent on both androgen and estrogen (N Engl J Med 2013; 369:1011-22).
Over the past 10 to 15 years, studies in men (XY karyotype) with either a mutation of the estrogen receptors in the brain (ERa, ERb) or mutation of the gene encoding aromatase showed that they lacked sexual desire and activity. When one male with aromatase mutation, no detectable estrogen, and extremely low testosterone was treated with exogenous estrogen alone, his sexual activity and libido were restored. In mice, knockout of aromatase or brain receptors for estrogen results in loss of male sexual behavior.
It’s clear that our traditional thinking about sex steroids is being challenged. We need more translational research and understanding of this complex problem to better manage hypogonadism, libido, and erectile dysfunction in our patients.UT
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