Gynaecomastia: Aetiology and Treatment Options
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Prostate Cancer and Prostatic Diseases (1999) 2, 167±171 ß 1999 Stockton Press All rights reserved 1365±7852/99 $15.00 http://www.stockton-press.co.uk/pcan Review Gynaecomastia: aetiology and treatment options CJ Tyrrell1* 1Oncology Research Unit, Derriford Hospital, Plymouth, UK This paper reviews the aetiology, prevalence and treatment of gynaecomastia. Gynaecomastia is a proliferation of male breast tissue apparently caused by alterations in the ratio of oestrogen : androgen levels. It is common in the general population, resulting from normal physiological changes and various patholo- gical causes. Gynaecomastia is also induced by many drug treatments, including hormonal therapies for prostate cancer. Prophylactic radiotherapy appears to be effective against gynaecomastia in this population. Surgery is an option for intractable cases, and some medical treatments have been reported, although there is a paucity of data evaluating such therapies. Keywords: gynaecomastia; prostate cancer; nonsteroidal antiandrogen; mono- therapy; radiotherapy Introduction bined androgen blockage [CAB]). More recently, preli- minary results of monotherapy with nonsteroidal Gynaecomastia is a benign proliferation of the male breast antiandrogens suggest equivalent ef®cacy to standard tissue, often accompanied by breast pain. In its early stages treatments and potential quality-of-life bene®ts.5 the condition is characterised by proliferation of both the There is no evidence that the addition of antiandrogens ®broblastic stroma and ductal tissue. Physical examination to castrated patients is associated with an increase in the reveals a dense mass of subareolar tissue, which feels like incidence of gynaecomastia. However, gynaecomastia is coiled rope.1 With time progressive ®brosis and hyalinisa- particularly common following oestrogen treatment, and tion can occur, which can be irreversible.2 the incidence is also raised in investigational studies of Gynaecomastia is a common condition resulting from nonsteroidal antiandrogen monotherapy, as predicted by an excess of oestrogen relative to androgen at the site of the pharmacological effects of these agents. the breast. It occurs naturally in newborns, boys at The incidence of gynaecomastia among prostate cancer puberty and in older men.3 Although there is often no patients receiving hormonal therapy has prompted this established aetiology, many pathological causes of gynae- review of the aetiology, prevalence and treatment of this comastia have been determined including congenital condition. defects, endocrinopathies, tumours, chronic disease and drugs, including hormonal therapies for prostate cancer.4 Hormonal therapies have been used for many years to reduce endogenous androgen production in patients with Aetiology prostate cancer. Surgical castration is perhaps the oldest The underlying aetiology of gynaecomastia is thought to treatment, while castration can also be achieved medi- be an alteration in the ratio of oestrogen to androgen cally using luteinising hormone-releasing hormone activity at the site of the breast.2 (LHRH) analogues. Oestrogens, such as diethylstilboes- In men, the testes produce only a small percentage of trol (DES), were the ®rst widely used drug therapy. Both circulating oestrogens (maximum 15%); the remainder is steroidal (cyproterone acetate) and nonsteroidal (¯uta- formed by peripheral aromatisation of testosterone and mide, bicalutamide, nilutamide) antiandrogens have androstenedione (from the adrenal glands) in extragona- been developed which block the effects of testosterone dal tissues. Circulating oestrogens and androgens are at the cellular level, and have been used most often in bound by sex hormone binding globulin (SHBG).6 There- combination with medical or surgical castration (com- fore, there are a number of mechanisms whereby the oestrogen : androgen ratio can be affected, potentially *Correspondence: CJ Tyrrell, Consultant Oncologist, Oncology leading to gynaecomastia. These include altered produc- Research Unit, Derriford Hospital, Plymouth, PL6 8DH, UK. tion of hormones, alterations in peripheral aromatisation Received 29 March 1999; revised 26 July 1999; accepted 28 July 1999 or interactions with SHBG. Such causes can be further Gynaecomastia: aetiology and treatment options CJ Tyrrell 168 divided into those that are physiological and those that Table 1 Drugs associated with gynaecomastia are pathological. Physiological gynaecomastia occurs in three peaks. Oestrogens Calcium channel blockers Diethylstilboestrol Verapamil There is a transient occurrence associated with high Polyoestradiol phosphate Nifedipine levels of maternal hormones in newborns of both sexes. Fofestrol tetrasodium Diltiazem Gynaecomastia also occurs during puberty, and generally Ethinyloestradiol Digitalis glycosides regresses spontaneously within 6 months to 3 years. Androgens Neuroleptics Pubertal gynaecomastia is thought to be caused by the Anabolic steroids Thioridazine 24-h activity of oestrogen at the breast, which is unop- Growth hormone Tri¯uoperazine Antiandrogens Prochlorperazine posed during the daytime when circulating levels of Cyproterone acetate Ethanol androgens fall to a nadir.1 Another peak is commonly Flutamide Marijuana seen in older men, aged 50 ± 70 y, thought to be associated Bicalutamide with decreased levels of testosterone.3 Nilutamide Many pathologies leading to an increase in circulating Ketoconazole Spironolactone oestrogen or a decrease in testosterone have been asso- Cancer chemotherapeutics ciated with gynaecomastia. They include endocrino- Estramustine phosphate pathies, primary or secondary hypogonadism, hyper- Cisplatin thyroidism, adrenal disorders, tumours of the testes, Vinblastine breast, lung, liver, kidney, adrenal and pituitary glands, Bleomycin malnutrition and chronic diseases such as hepatic failure Doxorubicin Cyclophosphamide due to cirrhosis, renal failure, human immunode®ciency Dactinomycin virus (HIV) infection and pulmonary and nervous system Mechlorethamine disorders. Additional causes include enhanced breast Procarbazine tissue sensitivity to oestrogens, ingestion of exogenous Prednisone oestrogens and drug-induced gynaeco-mastia.6,7 Vincristine Approximately 10 ± 20% of presentations with gynae- comastia are drug induced. A wide variety of drugs have been implicated, including hormonal therapies, anti- biotics, antiulcer medications, cancer chemotherapeutic agents, cardiovascular drugs, psychotropic drugs, ana- bolic steroids, drugs of abuse and other miscellaneous compounds (Table 1).6,8 However, the pathophysiology underlying drug-induced gynaecomastia, with the excep- tion of hormonal therapies, is not always well under- stood. Exogenous oestrogens, such as DES, directly stimulate breast growth, and hence their administration in men with prostate cancer leads to gynaecomastia. Antiandro- gens, which act by blocking the action of androgens at the cellular receptor, may increase the probability of gynae- comastia development in two ways. First, by blocking androgen receptors in the hypothalamic pituitary axis they can inhibit the negative feedback of testosterone on the secretion of luteinising hormone, leading to higher levels of testosterone and, following peripheral aromati- Figure 1 Effect of exogenous oestrogens and antiandrogens on breast sation, higher oestrogen levels.9 Second, they block the growth. inhibitory effects of circulating androgens at the breast, reinforcing the stimulatory effect of the increased oestro- gen activity. A simpli®ed demonstration of the main spironolactone and verapamil were associated with a mechanisms by which gynaecomastia may be induced signi®cant increase in the risk of gynaecomastia com- by oestrogen or antiandrogen therapy for prostate cancer pared with nonusers (relative risk 7.2, 9.3 and 9.7, respec- is presented in Figure 1. tively, P < 0.05).12 Hormonal therapies for prostate cancer are an obvious cause of gynaecomastia. In controlled studies, gynaecomastia developed in 77 ± 90% of patients treated Prevalence=incidence with oestrogens.13 ± 15 A lower incidence has been reported following treatment with the LHRH analogue Physiological gynaecomastia affects around 60 ± 90% of goserelin (5 ± 13%),16,17 with a similar incidence reported newborns,7 and pubertal gynaecomastia has been for the combination of LHRH analogues and nonsteroidal reported in almost 40% of 10 to 16-year-old boys.10 antiandrogens (5 ± 6%).18 Gynaecomastia is also common among adults, with pre- The cancer chemotherapeutic compound estramustine valences of between 36 and 72% reported.3,11 Drug- phosphate, which contains oestradiol phosphate, was also induced gynaecomastia is the next most common reason associated with gynaecomastia in 37 ± 38% of 88 patients, for presentation to a physician.4 In one study, cimetidine, despite prophylactic irradiation of the breast prior to the Gynaecomastia: aetiology and treatment options CJ Tyrrell initiation of therapy.19 In a smaller study, gynaecomastia may respond well to therapy, whereas in cases of longer 169 was reported in all patients treated with estramustine duration the gynaecomastia may become irreversible.25 phosphate who had not previously received oestrogens.20 Prophylactic radiotherapy is known to be effective The steroidal antiandrogen cyproterone acetate was asso- against gynaecomastia among patients receiving hormo- ciated with gynaecomastia in 6% of subjects with nal therapy for prostate cancer, while surgery and med- advanced prostate cancer, compared