Testosterone Cypionate Gynecomastia: Alternatives Without This Side Effect

Why does cypionate cause gynecomastia?

Testosterone is converted to estradiol by aromatase [3]. In breast tissue estrogens stimulate growth and androgens inhibit it; most gynecomastia comes from excess estrogen action relative to androgen action [4]. The Depo-Testosterone label lists gynecomastia among reported reactions and says it may develop and occasionally persists during treatment for hypogonadism [1].

Can a different testosterone product avoid it?

Other testosterone products are still testosterone, the substrate for estradiol [3]. In a retrospective review of hypogonadal men on a single formulation (47 on gels, 57 on injections, 74 on pellets), estradiol increased in all three groups, and throughout follow-up in the injection and gel groups [11]. That review compared hormone levels, not gynecomastia rates.

Does dose or schedule change it?

The Depo-Testosterone label lists gynecomastia without tying it to a dose or injection interval [1]. For hypogonadal men, the labeled dosage is 50 to 400 mg by deep gluteal intramuscular injection every 2 to 4 weeks, and the labeled half-life after intramuscular injection is about 8 days [1].

Do SERMs or aromatase inhibitors help?

A retrospective chart review of 38 patients with persistent pubertal gynecomastia, who received reassurance alone or a 3- to 9-month course of tamoxifen or raloxifene, found mean breast nodule reduction of 2.1 cm with tamoxifen and 2.5 cm with raloxifene; a decrease greater than 50% occurred in 41% on tamoxifen and 86% on raloxifene [6]. It was not randomized and did not involve men on cypionate [6]. In a randomized trial of 37 older men with low or borderline testosterone (12 on daily anastrozole, 11 on twice-weekly anastrozole, 14 on placebo), 12 weeks of anastrozole lowered estradiol from 26 +/- 8 to 17 +/- 6 pg/mL in the daily group and from 27 +/- 8 to 17 +/- 5 pg/mL in the twice-weekly group [7]. That trial measured hormone levels rather than breast tissue. The EAA guideline says SERMs and aromatase inhibitors are not justified in general [2].

Are non-aromatizable androgens an option?

In a 1983 study, 40 men with persistent idiopathic gynecomastia were treated with percutaneous dihydrotestosterone 125 mg twice daily for 4 to 20 weeks; gynecomastia disappeared completely in 10, regressed partially in 19 and was unchanged in 11 [8]. That was idiopathic gynecomastia, not cypionate-related gynecomastia, and the 40 men were compared with healthy control groups only for hormone levels. The EAA guideline says non-aromatizable androgens are not justified in general [2].

What about clomiphene?

Clomiphene raises endogenous testosterone rather than replacing it. In a comparison of 31 men on clomiphene, 31 on injections and 31 on gels, median testosterone rose from 247 to 504 ng/dL with clomiphene, from 224 to 1,104 ng/dL with injections and from 230 to 412 ng/dL with gels, and satisfaction was similar across groups [10]. Gynecomastia was not an outcome of that study.

What if breast tissue appears?

The EAA guideline says assessment should look for underlying pathology and reversible causes and distinguish gynecomastia from breast cancer, with breast and genital examination, testicular ultrasound and laboratory tests including testosterone, estradiol, SHBG, LH and FSH; breast imaging is used when the examination is equivocal [2]. It says testosterone treatment should be offered to men with proven testosterone deficiency, and that for long-lasting gynecomastia surgery is the treatment of choice [2].