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and Prostatic (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 apparently caused by alterations in the ratio of oestrogen : levels. It is common in the general population, resulting from normal physiological changes and various patholo- gical causes. Gynaecomastia is also induced by many treatments, including hormonal therapies for . Prophylactic radiotherapy appears to be effective against gynaecomastia in this population. 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; ; 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 suggest equivalent ef®cacy to standard tissue, often accompanied by breast . 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 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 and , 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 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 -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 ( ) and nonsteroidal (¯uta- formed by peripheral aromatisation of and mide, , ) antiandrogens have (from the adrenal glands) in extragona- been developed which block the effects of testosterone dal tissues. Circulating oestrogens and are at the cellular level, and have been used most often in bound by 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 , 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 channel blockers Diethylstilboestrol There is a transient occurrence associated with high Polyoestradiol levels of maternal hormones in newborns of both sexes. Fofestrol tetrasodium Diltiazem Gynaecomastia also occurs during puberty, and generally Ethinyloestradiol glycosides regresses spontaneously within 6 months to 3 years. Androgens Neuroleptics Pubertal gynaecomastia is thought to be caused by the Anabolic 24-h activity of oestrogen at the breast, which is unop- Tri¯uoperazine Antiandrogens posed during the daytime when circulating levels of androgens fall to a nadir.1 Another peak is commonly 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 oestrogen or a decrease in testosterone have been asso- Cancer chemotherapeutics ciated with gynaecomastia. They include endocrino- phosphate pathies, primary or secondary , hyper- thyroidism, adrenal disorders, tumours of the testes, breast, , , , adrenal and pituitary glands, and chronic diseases such as hepatic failure due to , renal failure, human immunode®ciency virus (HIV) infection and pulmonary and Mechlorethamine disorders. Additional causes include enhanced breast tissue sensitivity to oestrogens, ingestion of exogenous oestrogens and drug-induced gynaeco-mastia.6,7 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 , 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 , 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 of testosterone on the 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 ( 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 (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 .4 In one study, , 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 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 with 40% receiving ical treatment may be options for the treatment of DES.21 gynaecomastia. Gynaecomastia and have also been observed among a similar proportion of patients receiv- ing nonsteroidal antiandrogens as monotherapy in clin- ical trials. In a large study, ¯utamide monotherapy was Radiotherapy associated with breast tenderness in 49% of patients, The ®rst study to demonstrate prevention of gynaeco- compared with 14% ± 19% of patients receiving combina- mastia in prostate cancer patients receiving oestrogens tion therapy with ¯utamide and either surgical or medical was published in 1962, when Larsson and Sundbom castration.22 Gynaecomastia and breast pain developed in successfully treated six patients with 1000 to 1500 cGy 47.1% and 38.8%, respectively, of 314 patients receiving in a single dose.26 The prophylactic use of radiotherapy bicalutamide monotherapy, compared with 3.8% and since that time is well documented, and a list of English 1.9% among 160 patients treated by castration, in a language studies is presented in Table 2. recent randomised study.23 In a smaller study 50% of 26 Two controlled trials have investigated the ef®cacy of patients receiving nilutamide monotherapy reported prophylactic radiotherapy in the prevention of gynaeco- gynaecomastia.24 Although there were relatively few mastia. In a randomised study of 47 patients, Waterfall withdrawals from these trials because of gynaecomastia, and Glaser15 found an incidence of gynaecomastia of 85% the patients involved did have advanced prostate cancer. following DES therapy, compared with just 11% in those The similarity of the mechanisms of action of the non- who received prophylactic radiation of 900 cGy in three steroidal antiandrogens discussed would lead one to fractions. Alfthan and Holsti13 found that gynaecomastia expect a similar incidence of gynaecomastia associated developed in the untreated breast of 90% of 78 patients with each of these agents when used as monotherapy. receiving polyoestradiol phosphate. This was totally or partially inhibited in 83% of treated with either one (800 ± 1250 cGy) or two (800 cGy) doses of radiation.13 Similarly, among 87 patients treated with DES in conjunc- Treatment tion with prophylactic radiotherapy (1200 ± 1500 cGy in three fractions) only 13% developed moderate or severe In many cases gynaecomastia may not require active gynaecomastia, and 17% mammalgia.29 treatment, depending on the etiology. Physiological Although irradiation following the development of gynaecomastia in adolescents can be expected to resolve gynaecomastia is generally ineffective in reducing breast spontaneously, and counselling may be suf®cient.1 Where size, it may be effective in alleviating pain. Alfthan and the gynaecomastia is caused by underlying conditions, Kettunen35 reported relief of soreness and pain among 17 treatment of those conditions may lead to improvement. patients with gynaecomastia of 1 to 72 months' duration In drug-related cases, discontinuation of the agent treated with a single dose of 1425 or 2375 cGy, but involved may cause regression.7 However, withdrawal gynaecomastia persisted in 9 of 17 cases. Eleven patients of treatment is usually not an option for patients with with painful gynaecomastia following |DES therapy prostate cancer as the underlying disease may then pro- reported satisfactory pain relief with radiotherapy doses gress. Therefore, the breast growth must be suppressed, from 2000 cGy in 5 fractions up to 4000 cGy in 20 frac- or a change in treatment considered, such as castration. tions, persisting in all seven patients for whom 6-month The duration of gynaecomastia is important in evalu- follow-up data were available.36 However, only 3 of the ating possible treatment; gynaecomastia if less than 1 year 11 patients had a decrease in breast size.

Table 2 English-language studies of irradiation to prevent gynaecomastia

Reference No. patients Total dose (cGy) Fraction % of patients with no or only mild gynaecomastia

Alfthan & Holsti, 196913 78 800 ± 1250 single dose 83 1600 2 Brown & Rubenfeld, 197427 13 800 ± 1500 3 ± 5 100 Cook & Rodriguez-Antunez, 197328 70 900 single dose 83 Fass et al, 198629 87 1200 ± 1500 3 87 Gagnon et al, 197930 32 1500 3 81 Gangai et al, 196731 10 900 3 100 Larsson & Sundbom, 196226 6 1000 or 1500 single dose 67 Malis et al, 196932 18 900 3 100 Srinivasan et al, 197233 39 2750* 11 97 Waterfall & Glaser, 197915 47 900 3 89 Wolf et al, 196934 17 1000 single dose 94

*An estimated tumour dose of 1200 cGy to each breast. Gynaecomastia: aetiology and treatment options CJ Tyrrell 170 Surgery mastia. Recent studies have suggested that monotherapy with nonsteroidal antiandrogens may offer similar ef®- In gynaecomastia of long duration, or cases of macro- cacy to standard treatments, such as castration, but with gynaecomastia where extensive ®brosis has taken place, potential quality-of-life bene®ts. If increasing numbers of surgery my be the only option.37 Periareolar subcuta- patients are to be offered this treatment, effective preven- neous mammoplasty is recommended, and should be tion or relief of gynaecomastia may be necessary. undertaken by surgeons trained in cosmetic surgery.38 Although there is a paucity of published literature Adjunctive has been widely adopted to evaluating medical treatment of gynaecomastia, a improve cosmetic results,39 but in cases of glandular number of options have been investigated. Prophylactic hypertrophy surgical excision is still required.37 A radiotherapy appears to be effective in the prevention of number of innovations in recent years have been pro- gynaecomastia induced by hormonal therapy in patients posed to further improve cosmetic results. These include with prostate cancer; however, it is not as effective when surgical excision and removal of tissue via the small used as a treatment for established gynaecomastia. Sur- incisions made for liposuction,40 and endoscopic techni- gery is an option for severe or prolonged gynaecomastia, ques which facilitate accurate dissection and haemostasis and the adoption of liposuction and other techniques may by enabling visualisation of the procedure.41 confer improved cosmetic results. Anti-oestrogens and inhibitors, which should theoretically be effec- tive in treating gynaecomastia, are not registered for such Medical use, and their role needs to be de®ned further. There is very little published literature evaluating medical treatment of gynaecomastia. The administration of andro- gens (particularly , which is not con- verted to oestradiol in the body) may be effective in cases of idiopathic gynaecomastia,42 but is obviously contra- References indicated in the treatment of patients with prostate cancer. The synthetic , a derivative of 17 a-ethinyl- 1 Mahoney CP. Adolescent . Differential diagnosis and management. Pediatr Clin North Am 1990; 37: 1389 ± 1404. testosterone that inhibits the release of pituitary gonado- 2 Wilson JD, Aiman J, MacDonald PC. The pathogenesis of gyne- trophic hormones, has been used to treat idiopathic comastia. Adv Intern Med 1980; 25: 1 ± 32. gynaecomastia.43,44 However, its usefulness may be lim- 3 Nuttall FQ. Gynecomastia as a physical ®nding in normal men. ited by undesirable including , dizzi- J Clin Endocrinol Metab 1979; 48: 338 ± 340. ness, reactions, mood changes, and . 4 Braunstein GD. Gynecomastia. 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Clinical pro®le of a new non-steroidal it must be remembered that anti-oestrogens such as antiandrogen. J Steroid Biochem Mol Biol 1990; 37: 921 ± 924. tamoxifen are not licensed for this indication. In the 10 Nydick M, Bustos J, Dale JH, Rawson RW. Gynecomastia in largest investigational study of tamoxifen treatment, adolescent boys. JAMA 1961; 178; 449 ± 454. 80% of 61 men had complete regression of idiopathic 11 Niewoehner CB, Nuttall FQ. Gynecomastia in a hospitalized male gynaecomastia.45 In smaller controlled studies, tamoxifen population. Am J Med 1984; 77: 633 ± 638. decreased breast size and=or pain in seven of ten and ®ve 12 GarcõÂ RodrõÂguez LA, Jick H. Risk of gynaecomastia associated of six patients, respectively.46,47 More recently, tamoxifen with cimetidine, , and other antiulcer drugs. Br Med J 1994; 308: 503 ± 506. alleviated pain in ®ve of six patient with ¯utami- 13 Alfthan O, Holsti LR. 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Comparison of Conclusions LHRH analogue (Zoladex with orchidectomy in patients with 3 metastatic prostatic carcinoma. Br J Urol 1991; 67: 502 ± 508. Gynaecomastia is a common physiological condition, 17 Tyrrell CJ et al. A multicenter randomized trial comparing the 8 and is also caused by a wide variety of drugs. As one -releasing hormone analogue goserelin acet- might expect, hormone therapies for prostate cancer, such ate alone and with ¯utamide in the treatment of advanced as oestrogens and the investigational use of nonsteroidal prostate cancer. The International Prostate Cancer Study Group. antiandrogen monotherapy, are associated with gynaeco- J Urol 1991; 146: 1321 ± 1326. Gynaecomastia: aetiology and treatment options CJ Tyrrell

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