Testosterone Cypionate Gynecomastia That Won't Go Away: When to Worry and What to Do

What the label says about testosterone cypionate and gynecomastia

Depo-Testosterone is the branded testosterone cypionate injection. Its label lists gynecomastia among the adverse reactions reported with androgens, and the warnings section states that gynecomastia may develop and occasionally persists in patients being treated for hypogonadism [1].

Gynecomastia is not rare outside testosterone use either: reported prevalence in men runs from 32 to 65% depending on age and the definition used, and pubertal cases usually resolve without treatment [2].

Why it happens: aromatase, estradiol and breast tissue

Aromatase converts androgens into estrogens [3]. In male breast tissue, estrogens stimulate growth and androgens inhibit it, and most gynecomastia comes from deficient androgen action or excessive estrogen action in the breast [4]. In a retrospective review of 178 hypogonadal men on gel, injectable or pellet testosterone, estradiol increased in all testosterone groups, and throughout follow-up in the injectable and gel groups [7].

When it does not resolve: what the guidance says

The 2019 European Academy of Andrology clinical practice guideline on gynecomastia makes several points that bear on breast enlargement that has not settled:

• Assessment should look for an underlying condition and for reversible causes, and should separate gynecomastia from other breast lumps, particularly breast cancer [2]. In adults, investigation may reveal an underlying pathology in 45 to 50% of cases [2].
• Watchful waiting is recommended after the underlying condition is treated or the substance linked to the gynecomastia is discontinued [2].
• Testosterone treatment should be offered to men with proven testosterone deficiency [2].
• Use of SERMs, aromatase inhibitors and non-aromatizable androgens is not justified in general [2].
• Surgical treatment is the therapy of choice for patients with long-lasting gynecomastia [2].

Tamoxifen and raloxifene: what the studies show

Neither study below involved men taking testosterone cypionate.

Tamoxifen. A prospective audit at a single UK breast unit followed 36 men with physiological gynecomastia, median age 31, treated with tamoxifen 20 mg once daily for 6 to 12 weeks [5]. Tamoxifen resolved the mass in 30 of the 36 men: complete resolution in 22 and partial resolution in 8 [5]. Tenderness was present in 25 men and resolved in 21 (84%) [5]. The lump type of gynecomastia responded better than the fatty type (100% vs 62.5%, P = 0.0041) [5]. It was a prospective audit, not a randomized or placebo-controlled trial [5].

Raloxifene. A retrospective chart review of 38 consecutive patients with persistent pubertal gynecomastia (mean age of treated patients 14.6 years, mean duration 28.3 months), some of whom received reassurance alone, assessed 3 to 9 months of tamoxifen or raloxifene [6]. Mean breast nodule reduction was 2.5 cm with raloxifene and 2.1 cm with tamoxifen [6]. Some improvement occurred in 91% of those given raloxifene and 86% of those given tamoxifen, and a reduction of more than 50% was more common with raloxifene (86% vs 41%) [6]. The authors called for further study to confirm that this is a treatment effect [6].

How gynecomastia is evaluated

Examination of the breast is part of the assessment, which is built around separating gynecomastia from other breast lumps, particularly breast cancer [2]. The guideline describes a thorough history and an examination of the breast and genitalia, including testicular ultrasound, and says laboratory tests may be part of the evaluation: testosterone, estradiol, sex hormone-binding globulin, LH, FSH, TSH, prolactin, hCG, alpha-fetoprotein, and liver and renal function [2]. When the clinical examination is equivocal, breast imaging may be used; in suspicious lesions, core needle biopsy should be sought directly instead [2].

The Depo-Testosterone label lists carcinoma of the breast in men and known or suspected carcinoma of the prostate as contraindications [1].