Perspective

Estrogen, testosterone play role in development of hypogonadal symptoms

In a study published in The New England Journal of Medicine, researchers suggest revisiting the approach to evaluation and management of hypogonadism due to data showing that declining levels of estrogen as well as androgens contribute to negative changes in body composition, strength and sexual desire in men.

Researchers evaluated two cohorts of healthy men aged 20 to 50 years. All patients received goserelin acetate (Zoladex, AstraZeneca) 3.6 mg subcutaneously at weeks 0, 4, 8 and 12 to suppress endogenous gonadal steroids. Subsequently, patients in cohort 1 (n=198) were randomly assigned to placebo or 1.25 g, 2.5 g, 5 g or 10 g of topical 1% testosterone gel (AndroGel, Abbott Laboratories) daily for 16 weeks. In addition to goserelin acetate and placebo or the same doses of testosterone, patients in cohort 2 (n=202) received anastrozole (Arimidex, AstraZeneca) 1 mg daily to block aromatization of testosterone to estrogen, researchers wrote.

In cohort 1, body fat percentage increased significantly among patients who received placebo or testosterone 1.25 g or 2.5 g daily vs. those who received higher doses, according to data. Additionally, lean mass and thigh-muscle area decreased in patients who received placebo and in patients who received testosterone 1.25 g daily vs. higher doses. Leg-press strength was weakened in the placebo group only, according to data.

In cohort 2, body fat percentage rose in all groups, with similar increases seen in the placebo and testosterone 1.25-g, 2.5-g and 5-g groups. Significant decreases in total-body lean mass were observed in the placebo group vs. the testosterone 1.25-g, 2.5-g or 10-g groups. Researchers found reductions in thigh-muscle area in patients receiving placebo vs. any dose of testosterone. Similar to cohort 1, leg-press strength decreased in the placebo group, researchers wrote.

Overall, sexual desire declined with decreased testosterone doses in both cohorts, they added.

“By examining these relationships with and without suppression of estrogen synthesis, we found that lean mass, muscle size, and strength are regulated by androgens; fat accumulation is primarily a consequences of estrogen deficiency; and sexual function is regulated by both androgens and estrogens,” Joel S. Finkelstein, MD, from the endocrine unit in the department of medicine at Massachusetts General Hospital, and colleagues wrote.

In an accompanying editorial, David J. Handelsman, MB, BS, PhD, director of the ANZAC Research Institute and head of the department of andrology at Concord Hospital and the University of Sydney, Australia, wrote that longer studies are required to separate the effects of testosterone on bone density and fractures or on prostate growth and diseases.

“Nevertheless, this excellent study contributes to our expanding appreciation of the complex mechanisms of action of testosterone,” Handelsman wrote.

For more information:

Finkelstein JS. N Engl J Med. 2013;369:1011-1022.

Handelsman DJ. N Engl J Med. 2013;369:1058-1059.

Disclosure: Finkelstein reports receiving grants from Solvay Pharmaceuticals (now Abbott), money to his institution from Abbott and AstraZeneca, and royalties from Up To Date. All other researchers report no relevant financial disclosures. Handelsman reports grants pending from Organon (now Merck), Schering (Bayer), Ascend/Besins, Lilly, Pharmacia, Serono and Lawley.

In a study published in The New England Journal of Medicine, researchers suggest revisiting the approach to evaluation and management of hypogonadism due to data showing that declining levels of estrogen as well as androgens contribute to negative changes in body composition, strength and sexual desire in men.

Researchers evaluated two cohorts of healthy men aged 20 to 50 years. All patients received goserelin acetate (Zoladex, AstraZeneca) 3.6 mg subcutaneously at weeks 0, 4, 8 and 12 to suppress endogenous gonadal steroids. Subsequently, patients in cohort 1 (n=198) were randomly assigned to placebo or 1.25 g, 2.5 g, 5 g or 10 g of topical 1% testosterone gel (AndroGel, Abbott Laboratories) daily for 16 weeks. In addition to goserelin acetate and placebo or the same doses of testosterone, patients in cohort 2 (n=202) received anastrozole (Arimidex, AstraZeneca) 1 mg daily to block aromatization of testosterone to estrogen, researchers wrote.

In cohort 1, body fat percentage increased significantly among patients who received placebo or testosterone 1.25 g or 2.5 g daily vs. those who received higher doses, according to data. Additionally, lean mass and thigh-muscle area decreased in patients who received placebo and in patients who received testosterone 1.25 g daily vs. higher doses. Leg-press strength was weakened in the placebo group only, according to data.

In cohort 2, body fat percentage rose in all groups, with similar increases seen in the placebo and testosterone 1.25-g, 2.5-g and 5-g groups. Significant decreases in total-body lean mass were observed in the placebo group vs. the testosterone 1.25-g, 2.5-g or 10-g groups. Researchers found reductions in thigh-muscle area in patients receiving placebo vs. any dose of testosterone. Similar to cohort 1, leg-press strength decreased in the placebo group, researchers wrote.

Overall, sexual desire declined with decreased testosterone doses in both cohorts, they added.

“By examining these relationships with and without suppression of estrogen synthesis, we found that lean mass, muscle size, and strength are regulated by androgens; fat accumulation is primarily a consequences of estrogen deficiency; and sexual function is regulated by both androgens and estrogens,” Joel S. Finkelstein, MD, from the endocrine unit in the department of medicine at Massachusetts General Hospital, and colleagues wrote.

In an accompanying editorial, David J. Handelsman, MB, BS, PhD, director of the ANZAC Research Institute and head of the department of andrology at Concord Hospital and the University of Sydney, Australia, wrote that longer studies are required to separate the effects of testosterone on bone density and fractures or on prostate growth and diseases.

“Nevertheless, this excellent study contributes to our expanding appreciation of the complex mechanisms of action of testosterone,” Handelsman wrote.

For more information:

Finkelstein JS. N Engl J Med. 2013;369:1011-1022.

Handelsman DJ. N Engl J Med. 2013;369:1058-1059.

Disclosure: Finkelstein reports receiving grants from Solvay Pharmaceuticals (now Abbott), money to his institution from Abbott and AstraZeneca, and royalties from Up To Date. All other researchers report no relevant financial disclosures. Handelsman reports grants pending from Organon (now Merck), Schering (Bayer), Ascend/Besins, Lilly, Pharmacia, Serono and Lawley.

    Perspective
    Peter Y. Liu

    Peter Y. Liu

    Part of the action of testosterone is actually mediated by aromatization to estradiol. Men with genetic aromatase deficiency cannot produce estrogens and show increased adiposity, decreased bone mass and reduced libido. This study shows that in normal men estrogens are important for body fat; androgens are important for muscle; and both estrogens and androgens are important for libido. These data explain why different men have differing sexual symptoms and metabolic risk profiles, despite equivalent systemic testosterone exposure and could lead to a rational approach to developing designer androgens, with varying aromatizability that would promote certain actions and not others. The full clinical implications of this important mechanistic study require the development of these novel androgens and estrogens.

    • Peter Y. Liu, MD, PhD, FRACP
    • Visiting professor in the division of endocrinology, metabolism and nutrition Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

    Disclosures: Liu reports no relevant financial disclosures.