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Testosterone Cypionate and Gynecomastia: Supplements With the Best Evidence

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At a glance

  • Cause / Excess estrogen action relative to androgen action in breast tissue [4]
  • Label status / Gynecomastia listed as an adverse reaction, may occasionally persist [3]
  • DIM human data / Single doses of 50 to 300 mg, pharmacokinetics and tolerability [1]
  • Zinc human data / Serum testosterone rose in marginally zinc-deficient older men [2]
  • Guideline view / SERMs and aromatase inhibitors not justified in general [5]
  • Tamoxifen study / Complete resolution in 18 of 23 patients with idiopathic gynecomastia [6]

Why testosterone cypionate can cause gynecomastia

Most gynecomastia results from deficient androgen action or excessive estrogen action in breast tissue; estrogens stimulate breast tissue growth and androgens inhibit it [4]. Aromatase converts androgens to estrogens, so raising testosterone raises estradiol [7]. The Depo-Testosterone label, the intramuscular cypionate product, states that gynecomastia may develop and occasionally persists in patients treated for hypogonadism and lists it under adverse reactions [3].

What the human supplement studies measured

DIM. A single-dose study of absorption-enhanced DIM gave 50, 100, 150, 200 and 300 mg to healthy men and women [1]. No DIM-related adverse effects were reported at doses up to 200 mg; at 300 mg, one of six subjects reported mild nausea and headache and one reported vomiting, and only the vomiting was judged probably related to the study agent [1]. The volunteers were healthy adults, not men taking testosterone, and the study was designed to measure absorption and tolerability [1].

Zinc. Nine marginally zinc-deficient older men took oral zinc gluconate for 3 to 6 months, and after six months their serum testosterone rose from 8.3 to 16.0 nmol/L [2]. The study measured testosterone, not estradiol or breast tissue [2].

What prescription treatment looks like

The 2019 European Academy of Andrology guideline on gynecomastia, which covers gynecomastia in general, states that selective estrogen receptor modulators (SERMs), aromatase inhibitors and non-aromatizable androgens are not justified in general, recommends watchful waiting after discontinuation of a substance associated with gynecomastia, and calls surgery the treatment of choice for long-lasting gynecomastia [5].

In a retrospective review of clinical records of patients with idiopathic gynecomastia, 18 of 23 treated with tamoxifen 20 mg per day had complete resolution, compared with 8 of 20 treated with danazol 400 mg per day; all 5 recurrences were in the tamoxifen group [6]. These were not men with gynecomastia during testosterone cypionate treatment [6].

Frequently asked questions

Do any supplements reduce gynecomastia from testosterone cypionate?
Neither DIM nor zinc has been shown to reduce breast tissue in men using testosterone cypionate. The DIM study measured blood levels and tolerability of single doses, and the zinc study measured serum testosterone in marginally deficient older men [1][2].
Does DIM lower estradiol?
The human DIM study was a pharmacokinetics and tolerability study of single doses from 50 to 300 mg in healthy volunteers; it did not test an effect on estradiol [1].
What does the testosterone cypionate label say about gynecomastia?
The Depo-Testosterone label lists gynecomastia as an adverse reaction and states it may develop and occasionally persists in patients treated for hypogonadism [3].
Is tamoxifen proven for testosterone-related gynecomastia?
No. The tamoxifen data come from patients with idiopathic gynecomastia: 18 of 23 (78.2%) had complete resolution versus 8 of 20 (40%) on danazol, with 5 recurrences on tamoxifen [6].

References

  1. Reed GA, Sunega JM, Sullivan DK, Gray JC, Mayo MS, Crowell JA, et al. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3'-diindolylmethane in healthy subjects. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2619-24. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3'-diindolylmethane in healthy subjects
  2. Prasad AS, Mantzoros CS, Beck FW, Hess JW, Brewer GJ. Zinc status and serum testosterone levels of healthy adults. Nutrition. 1996;12(5):344-8. Zinc status and serum testosterone levels of healthy adults
  3. U.S. National Library of Medicine, DailyMed. Depo-Testosterone (cypionate) intramuscular, Pharmacia & Upjohn/Pfizer (testosterone cypionate) prescribing information. Depo-Testosterone (cypionate) intramuscular, Pharmacia & Upjohn/Pfizer (testosterone cypionate) label
  4. Narula HS, Carlson HE. Gynaecomastia--pathophysiology, diagnosis and treatment. Nat Rev Endocrinol. 2014;10(11):684-98. Gynaecomastia--pathophysiology, diagnosis and treatment
  5. Kanakis GA, Nordkap L, Bang AK, Calogero AE, Bártfai G, Corona G, et al. EAA clinical practice guidelines-gynecomastia evaluation and management. Andrology. 2019;7(6):778-793. EAA clinical practice guidelines-gynecomastia evaluation and management
  6. Ting AC, Chow LW, Leung YF. Comparison of tamoxifen with danazol in the management of idiopathic gynecomastia. Am Surg. 2000;66(1):38-40. Comparison of tamoxifen with danazol in the management of idiopathic gynecomastia
  7. Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in Male Physiology. Physiol Rev. 2017;97(3):995-1043. Estrogens in Male Physiology
Evidence overview for Testosterone Cypionate and Gynecomastia: Supplements With the Best Evidence