Why Does AndroGel Cause Gynecomastia? The Biology of Testosterone-to-Estrogen Conversion

What does aromatase do with the testosterone in AndroGel?

Aromatase is the enzyme that converts androgens into estrogens [1]. It is active in male tissue, including Leydig cells, the seminiferous epithelium and other male organs, and estradiol is measurable in the blood of men [1].

The gel raises serum testosterone quickly. In a study of 227 men with hypogonadism, serum testosterone rose into the normal adult male range on the first day of gel use, and about 9% to 14% of the applied dose was bioavailable. The authors reported that an earlier study found steady-state levels 48 to 72 hours after the first application [4]. More circulating testosterone means more substrate for aromatase, and estradiol is the product of that reaction [1].

Estradiol increased during follow-up in men using testosterone gels, but those results do not show how much estradiol an individual gel dose produces [5].

How estrogen action enlarges male breast tissue

Gynecomastia is enlargement of the male breast. Estrogens stimulate breast tissue growth and androgens inhibit it, and most cases of gynecomastia result from deficient androgen action or excessive estrogen action in breast tissue [2]. That relative balance, rather than testosterone acting on the breast directly, is what the pathophysiology describes.

How often does a testosterone gel label report gynecomastia?

The 180-day phase 3 trial in the generic testosterone gel 1% label counted adverse events the investigator judged at least possibly related to treatment. Gynecomastia was reported by 1% of the 77 men on 50 mg, 0% of the 40 men on 75 mg and 3% of the 78 men on 100 mg; breast pain was reported by 1%, 3% and 1% respectively [3]. In the 3-year flexible-dose extension study of 162 men, gynecomastia was reported in 2.5% [3]. The results do not establish that dose changes the risk.

Can gynecomastia from testosterone go away?

Pubertal gynecomastia sometimes resolves on its own; that finding does not establish whether gynecomastia arising during testosterone treatment will resolve [2]. A review also says surgery to remove the enlarged breast tissue might be necessary when gynecomastia does not resolve spontaneously or with medical therapy [2]. For gynecomastia during testosterone replacement, a review of testosterone side effects says management usually relies on aromatase inhibitors and tamoxifen [7].

The direct evidence in men on testosterone is thin. A 2004 report of two men on testosterone replacement described gynecomastia that resolved with the aromatase inhibitor anastrozole [8]. A 12-week randomized trial of anastrozole enrolled 37 men aged 62 to 74 with low or borderline-low testosterone who were not on testosterone therapy: 1 mg daily lowered mean estradiol from 26 to 17 pg/mL and raised total testosterone from 343 to 572 ng/dL [9]. That trial did not study gynecomastia, and it did not study men on gel.

Tamoxifen data come mostly from idiopathic gynecomastia. In a review of records from 68 men with idiopathic gynecomastia, 23 were treated with tamoxifen 20 mg daily; 18 (78.2%) had complete resolution, and 5 later had a recurrence [10]. These men were not taking testosterone.