When Gynecomastia on Testosterone Cypionate Becomes a Reason to Stop

What the testosterone cypionate label says

Depo-Testosterone's warnings say that "gynecomastia may develop and occasionally persists in patients being treated for hypogonadism" [1]. Gynecomastia also appears in the label's adverse reactions section under endocrine and urogenital effects, beside excessive frequency and duration of penile erections [1].

The same label does contain stop instructions, just not for breast tissue. It says to discontinue treatment if a venous thromboembolic event is suspected, and that the drug should be discontinued if hypercalcemia occurs in an immobilized patient [1].

Depo-Testosterone lists male breast carcinoma as a contraindication [1]. Gynecomastia is a separate, much more common condition, and a careful physical examination can usually tell the two apart [3].

Why the breast tissue responds

Estrogens stimulate growth of male breast tissue and androgens inhibit it, and most gynecomastia comes from deficient androgen action or excessive estrogen action in the breast [3]. Aromatase is the enzyme that converts androgens to estrogens [4]. Raising testosterone raises estradiol through aromatization [4].

Where estradiol testing fits

The European Academy of Andrology (EAA) guideline recommends a history and physical examination of the breast and genitalia, including testicular ultrasound, and says laboratory tests may be part of the evaluation: testosterone, estradiol, SHBG, LH, FSH, TSH, prolactin, hCG, alpha-fetoprotein and liver and renal function [2]. Breast imaging may be used when the examination is equivocal; in suspicious lesions, core needle biopsy should be sought directly [2]. The stated purpose of that assessment is to find an underlying or reversible cause, including a drug, and to tell gynecomastia apart from breast cancer [2].

What the guideline recommends

The EAA guideline states that the use of SERMs, aromatase inhibitors and non-aromatizable androgens "is not justified in general" for gynecomastia [2]. It says surgical treatment is the therapy of choice for patients with long-lasting gynecomastia [2]. Where a substance linked to gynecomastia has been discontinued, or an underlying cause has been treated, the guideline recommends watchful waiting [2].

The tamoxifen evidence is not from men on testosterone

A 2004 retrospective chart review included 38 consecutive patients with persistent pubertal gynecomastia. Some received reassurance alone; others received a 3- to 9-month course of tamoxifen or raloxifene [5]. Mean breast nodule diameter fell 2.1 cm with tamoxifen and 2.5 cm with raloxifene, some improvement occurred in 86% and 91% respectively, and the authors concluded that further study was needed to confirm a treatment effect [5]. Those patients were adolescents with pubertal gynecomastia; the review had no randomized control arm and did not involve testosterone cypionate [5]. A separate pediatric review notes that tamoxifen has been tried in adolescents and that clomiphene, danazol, letrozole and anastrozole have not been consistently useful in that age group [6].