Gynecomastia; Gynecomazia; Hypertrophy of male breast
Gynecomastia is a benign proliferation of the glandular component of the male breast caused by an increased ratio of estrogen to androgen activity. Gynecomastia can be unilateral or bilateral and consists of a palpable mass of tissue with a diameter of at least 0.5 cm, usually presenting as a disk of tissue underlying the nipple. This condition is diagnosed clinically and radiologically, even if there is no consensus on which method should be used to define gynecomastia. Therefore, a careful history of the patient and a good clinical examination represent the first approach to diagnosis. Radiographic investigations using mammography or ultrasound are recommended to confirm the diagnosis. The severity of gynecomastia can be evaluated by using a four-grade score on the basis of the largest diameter: grade 1, <2 cm; grade 2, 2–4 cm; grade 3, 4–6 cm; and grade 4, >6 cm. Recently, Van Poppel et al. introduced a questionnaire (Breast Symptom Questionnaire, BSQ) that correlates well with patients’ subjective perceptions of gynecomastia.
Gynecomastia is the most common breast abnormality in the male population. It can result from physiological changes in growth and development, or it can be caused pathologically by a chronic disease (e.g., chronic liver disease due to alcohol abuse) or a tumor (e.g., choriocarcinoma). Gynecomastia also can be induced by drug treatments affecting the balance between estrogens and androgens, such as hormonal therapies for prostate cancer.
The incidence of gynecomastia following treatments for prostate cancer varies. Antiandrogen monotherapy is associated with a higher incidence of gynecomastia than other prostate cancer treatments. The mechanisms of induced gynecomastia in prostate cancer patients are shown in Fig. 1.
The profile of patients with prostate cancer has significantly changed in recent years. Men are being diagnosed at earlier stages of the disease and at younger ages. Consequently, prostate cancer patients are still physically and sexually active, and quality of life has become an important issue in their management.
Hormonal therapies that have a more favorable impact on quality of life than castration are clearly required. Antiandrogen monotherapy with bicalutamide (150 mg) offers potential quality-of-life benefits over other treatment modalities for prostate cancer. Gynecomastia with or without breast pain is a recognized adverse effect of bicalutamide, with an incidence of ~70% of patients within the first 6–9 months of hormonal therapy. This adverse event can be a major concern for the patient, sometimes causing treatment withdrawal. Because gynecomastia may compromise treatment outcome, simple and safe methods of managing this condition are needed.
Therefore, clinicians who treat prostate cancer need information on the management of gynecomastia in their patients. In this setting, three options can be considered: surgery, radiation therapy, and medical therapy as prophylaxis or treatment. Although surgery has been used prophylactically, it is generally reserved for patients who have advanced gynecomastia. Recent data have shown that prophylactic, low-dose (10–12 Gy) breast irradiation is an effective and well-tolerated strategy for prevention or treatment of bicalutamide-induced gynecomastia.
In an interesting comparative study by Perdonà et al., the efficacy of tamoxifen (10 mg/day) versus radiotherapy (12 Gy) in the management of gynecomastia/breast pain due to bicalutamide (150 mg) monotherapy was investigated. Tamoxifen was extremely effective in preventing the development of bicalutamide-induced gynecomastia/breast pain and was significantly more effective than radiotherapy. These positive findings were in agreement with previous reports of different treatment schedules, such as those by Boccardo et al. and Saltzstein et al. using 20 mg tamoxifen daily and the report by Eaton et al. using 20 mg tamoxifen weekly.
Fradet et al. have conducted a trial to define the optimal tamoxifen dose for treating gynecomastia without compromising disease control. In this double-blind, parallel-group, multicenter trial, 282 patients with PC were randomized to receive bicalutamide (150 mg/day) plus either daily tamoxifen (1, 2.5, 5, 10, or 20 mg) or placebo for 12 months. At 6 and 12 months, tamoxifen decreased the incidence of breast events in a dose-dependent manner. These findings suggest that the optimal prophylactic dose of tamoxifen is 20 mg/day.
However, other issues remain unresolved:
There may be some concerns regarding the use of tamoxifen in PC. Although blocking the effects of estrogen may effectively prevent or treat gynecomastia, the consequences of such treatment are unknown. Indeed, such therapy might be expected to increase androgen secretion by blocking the negative feedback of estradiol on the hypothalamic–pituitary axis. However, it is reassuring that most studies have reported no detrimental effects of tamoxifen on bicalutamide-induced PSA suppression.
The optimal duration of medical therapy is unknown. Clinical trials addressing longer treatment duration and follow-up are necessary, although ethical concerns may be raised.
Tamoxifen is generally well tolerated at all doses. However, there are some minor, reversible side effects in tamoxifen-treated patients, and this should be discussed with the patient before therapy is initiated.
There are financial considerations associated with the use of tamoxifen to prevent gynecomastia because the cost is not reimbursed by health insurances/systems in Europe. However, this is not a serious problem for most patients because tamoxifen is available as a relatively cheap generic drug.
At present, a consensus on the most suitable method to assess gynecomastia is lacking. In the absence of a standardized parameter of evaluation, any comparison among different trials is of questionable value.
In conclusion, two approaches for the management of gynecomastia are recommended, a prophylactic and a therapeutic approach. The first approach aims to prevent this embarrassing condition, and the second avoids unnecessary treatment of those patients who would not have suffered from gynecomastia. Radiotherapy and medical therapy with tamoxifen are both applicable and effective. When unsatisfactory results are obtained with one therapy, the other can be offered as a second-line option. In this setting, the role of surgery remains limited. Switching to a different hormonal treatment for prostate cancer is another option that can be considered by clinicians and patients (Fig. 2).
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