Gynaecomastia—pathophysiology, diagnosis and treatment

Key Points

  • Gynaecomastia is a common condition and is usually benign

  • Gynaecomastia typically results from an (absolute or relative) deficiency of androgen action or excessive estrogen action in the breast tissue

  • Gynaecomastia often resolves by itself or upon removal of the underlying cause (such as medication)

  • Treatment is indicated in men with symptoms (particularly pain and tenderness in the breast) and involves the use of androgens or antiestrogens

  • Surgery can be offered to selected patients when the condition does not resolve spontaneously or respond to medical treatment

Abstract

Gynaecomastia (enlargement of the male breast tissue) is a common finding in the general population. Most cases of gynaecomastia are benign and of cosmetic, rather than clinical, importance. However, the condition might cause local pain and tenderness, could occasionally be the result of a serious underlying illness or a medication, or be inherited. Breast cancer in men is much less common than benign gynaecomastia, and the two conditions can usually be distinguished by a careful physical examination. Estrogens are known to stimulate the growth of breast tissue, whereas androgens inhibit it; most cases of gynaecomastia result from deficient androgen action or excessive estrogen action in the breast tissue. In some cases, such as pubertal gynaecomastia, the breast enlargement resolves spontaneously. In other situations, more active treatment might be required to correct an underlying condition (such as hyperthyroidism or a benign Leydig cell tumour of the testis) or medications that could cause breast enlargement (such as spironolactone) might need to be discontinued. For men with hypogonadism, administration of androgens might be helpful, as might antiestrogen therapy in men with endogenous overproduction of estrogens. Surgery to remove the enlarged breast tissue might be necessary when gynaecomastia does not resolve spontaneously or with medical therapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The action of different hormones on breast tissue.
Figure 2: Suggested algorithm for the evaluation and treatment of gynaecomastia.

References

  1. 1

    Carlson, H. E. Approach to the patient with gynecomastia. J. Clin. Endocrinol. Metab. 96, 15–21 (2011).

  2. 2

    Narula, H. S. & Carlson, H. E. Gynecomastia. Endocrinol. Metab. Clin. North Am. 36, 497–519 (2007).

  3. 3

    Nydick, M., Bustos, J., Dale, J. H. Jr & Rawson, R. W. Gynecomastia in adolescent boys. JAMA 178, 449–454 (1961).

  4. 4

    Carlson, H. E. Gynecomastia. N. Engl. J. Med. 303, 795–799 (1980).

  5. 5

    Nuttall, F. Q. Gynecomastia as a physical finding in normal men. J. Clin. Endocrinol. Metab. 48, 338–340 (1979).

  6. 6

    Bannayan, G. A. & Hajdu, S. I. Gynecomastia: clinicopathologic study of 351 cases. Am. J. Clin. Pathol. 57, 431–437 (1972).

  7. 7

    Georgiadis, E. et al. Incidence of gynaecomastia in 954 young males and its relationship to somatometric parameters. Ann. Hum. Biol. 21, 579–587 (1994).

  8. 8

    Niewoehner, C. B. & Nuttal, F. Q. Gynecomastia in a hospitalized male population. Am. J. Med. 77, 633–638 (1984).

  9. 9

    Williams, M. J. Gynecomastia. Its incidence, recognition and host characterization in 447 autopsy cases. Am. J. Med. 34, 103–112 (1963).

  10. 10

    Braunstein, G. D. Clinical practice. Gynecomastia. N. Engl. J. Med. 357, 1229–1237 (2007).

  11. 11

    Lapid, O., Jolink, F. & Meijer, S. L. Pathological findings in gynecomastia: analysis of 5,113 breasts. Ann. Plast. Surg. http://dx.doi.org/10.1097/SAP.0b013e3182920aed.

  12. 12

    Kornegoor, R., Verschuur-Maes, A. H., Buerger, H. & van Diest, P. J. The 3-layered ductal epithelium in gynecomastia. Am. J. Surg. Pathol. 36, 762–768 (2012).

  13. 13

    Nicolis, G. L., Modlinger, R. S. & Gabrilove, J. L. A study of the histopathology of human gynecomastia. J. Clin. Endocrinol. Metab. 32, 173–178 (1971).

  14. 14

    Sasano, H., Kimura, M., Shizawa, S., Kimura, N. & Nagura, H. Aromatase and steroid receptors in gynecomastia and male breast carcinoma: an immunohistochemical study. J. Clin. Endocrinol. Metab. 81, 3063–3067 (1996).

  15. 15

    Dimitrakakis, C., Zhou, J. & Bondy, C. A. Androgens and mammary growth and neoplasia. Fertil. Steril. 77 (Suppl. 4), S26–S33 (2002).

  16. 16

    Kanhai, R. C., Hage, J. J., van Diest, P. J., Bloemena, E. & Mulder, J. W. Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men. Am. J. Surg. Pathol. 24, 74–80 (2000).

  17. 17

    Burgess, H. E. & Shousha, S. An immunohistochemical study of the long-term effects of androgen administration on female-to-male transsexual breast: a comparison with normal female breast and male breast showing gynaecomastia. J. Pathol. 170, 37–43 (1993).

  18. 18

    Eigeliene, N. et al. Androgens inhibit the stimulatory action of 17β-estradiol on normal human breast tissue in explant cultures. J. Clin. Endocrinol. Metab. 97, E1116–E1127 (2012).

  19. 19

    Dejager, S. et al. A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length. J. Clin. Endocrinol. Metab. 87, 3893–3901 (2002).

  20. 20

    Zinn, A. R. et al. Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome. J. Clin. Endocrinol. Metab. 90, 5041–5046 (2005).

  21. 21

    Southren, A. L. et al. The conversion of androgens to estrogens in hyperthyroidism. J. Clin. Endocrinol. Metab. 38, 207–214 (1974).

  22. 22

    Gordon, G. G., Olivo, J., Rafil, F. & Southren, A. L. Conversion of androgens to estrogens in cirrhosis of the liver. J. Clin. Endocrinol. Metab. 40, 1018–1026 (1975).

  23. 23

    Binder, G. et al. Dominant transmission of prepubertal gynecomastia due to serum estrone excess: hormonal, biochemical, and genetic analysis in a large kindred. J. Clin. Endocrinol. Metab. 90, 484–492 (2005).

  24. 24

    Braunstein, G. D. Aromatase and gynecomastia. Endocr. Relat. Cancer 6, 315–324 (1999).

  25. 25

    Cleland, W. H., Mendelson, C. R. & Simpson, E. R. Effects of aging and obesity on aromatase activity of human adipose cells. J. Clin. Endocrinol. Metab. 60, 174–177 (1985).

  26. 26

    Reed, M. J. & Purohit, A. Breast cancer and the role of cytokines in regulating estrogen synthesis: an emerging hypothesis. Endocr. Rev. 18, 701–715 (1997).

  27. 27

    Ryde, C. M., Nicholls, J. E. & Dowsett, M. Steroid and growth factor modulation of aromatase activity in MCF7 and T47D breast carcinoma cell lines. Cancer Res. 52, 1411–1415 (1992).

  28. 28

    Christeff, N., Benassayag, C., Carli-Vielle, C., Carli, A. & Nunez, E. A. Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J. Steroid Biochem. 29, 435–440 (1988).

  29. 29

    Vona-Davis, L. & Rose, D. P. The obesity–inflammation–eicosanoid axis in breast cancer. J. Mammary Gland Biol. Neoplasia 18, 291–307 (2013).

  30. 30

    Irahara, N. et al. Possible involvement of aromatase overexpression induced by cyclo-oxygenase-2 in the pathogenesis of idiopathic gynecomastia. Endocr. Res. 31, 219–227 (2005).

  31. 31

    To, S. Q., Simpson, E. R., Knower, K. C. & Clyne, C. D. Involvement of early growth response factors in TNFα-induced aromatase expression in breast adipose. Breast Cancer Res. Treat. 138, 193–203 (2013).

  32. 32

    Czajka-Oraniec, I., Zgliczynski, W., Kurylowicz, A., Mikula, M. & Ostrowski, J. Association between gynecomastia and aromatase (CYP19) polymorphisms. Eur. J. Endocrinol. 158, 721–727 (2008).

  33. 33

    Eren, E. et al. Genetic variants of estrogen β and leptin receptors may cause gynecomastia in adolescent. Gene 541, 101–106 (2014).

  34. 34

    Gill, S., Peston, D., Vonderhaar, B. K. & Shousha, S. Expression of prolactin receptors in normal, benign, and malignant breast tissue: an immunohistological study. J. Clin. Pathol. 54, 956–960 (2001).

  35. 35

    Ormandy, C. J. et al. Coexpression and cross-regulation of the prolactin receptor and sex steroid hormone receptors in breast cancer. J. Clin. Endocrinol. Metab. 82, 3692–3699 (1997).

  36. 36

    Carlson, H. E., Kane, P., Lei, Z. M., Li, X. & Rao, C. V. Presence of luteinizing hormone/human chorionic gonadotropin receptors in male breast tissues. J. Clin. Endocrinol. Metab. 89, 4119–4123 (2004).

  37. 37

    Humphreys, R. C., Lydon, J. P., O'Malley, B. W. & Rosen, J. M. Use of PRKO mice to study the role of progesterone in mammary gland development. J. Mammary Gland Biol. Neoplasia 2, 343–354 (1997).

  38. 38

    Ormandy, C. J. et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev. 11, 167–178 (1997).

  39. 39

    Anderson, E. & Clarke, R. B. Steroid receptors and cell cycle in normal mammary epithelium. J. Mammary Gland Biol. Neoplasia 9, 3–13 (2004).

  40. 40

    Kleinberg, D. L. Role of IGF-I in normal mammary development. Breast Cancer Res. Treat. 47, 201–208 (1998).

  41. 41

    Ruan, W. & Kleinberg, D. L. Insulin-like growth factor I is essential for terminal end bud formation and ductal morphogenesis during mammary development. Endocrinology 140, 5075–5081 (1999).

  42. 42

    Stewart, A. J., Johnson, M. D., May, F. E. & Westley, B. R. Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J. Biol. Chem. 265, 21172–21178 (1990).

  43. 43

    Ruan, W., Monaco, M. E. & Kleinberg, D. L. Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing insulin-like growth factor-I action. Endocrinology 146, 1170–1178 (2005).

  44. 44

    Dundar, B., Dundar, N., Erci, T., Bober, E. & Büyükgebiz, A. Leptin levels in boys with pubertal gynecomastia. J. Pediatr. Endocrinol. Metab. 18, 929–934 (2005).

  45. 45

    Catalano, S. et al. Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J. Biol. Chem. 278, 28668–28676 (2003).

  46. 46

    Dieudonné, M.-N. et al. Sex steroids and leptin regulate 11β-hydroxysteroid dehydrogenase I and P450 aromatase expressions in human preadipocytes: sex specificities. J. Steroid Biochem. Mol. Biol. 99, 189–196 (2006).

  47. 47

    Fusco, R. et al. Cellular and molecular crosstalk between leptin receptor and estrogen receptor-α in breast cancer: molecular basis for a novel therapeutic setting. Endocr. Relat. Cancer 17, 373–382 (2010).

  48. 48

    Catalano, S. et al. Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor α in MCF-7 cells. J. Biol. Chem. 279, 19908–19915 (2004).

  49. 49

    Ozata, M., Ozdemir, I. C. & Licinio, J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J. Clin. Endocrinol. Metab. 84, 3686–3695 (1999).

  50. 50

    Seminara, S. B., Oliveira, L. M., Beranova, M., Hayes, F. J. & Crowley, W. F. Genetics of hypogonadotropic hypogonadism. J. Endocrinol. Invest. 23, 560–565 (2000).

  51. 51

    Layman, L. C. Genetics of human hypogonadotropic hypogonadism. Am. J. Med. Genet. 89, 240–248 (1999).

  52. 52

    Gutzman, J. H., Miller, K. K. & Schuler, L. A. Endogenous human prolactin and not exogenous human prolactin induces estrogen receptor α and prolactin receptor expression and increases estrogen responsiveness in breast cancer cells. J. Steroid Biochem. Mol. Biol. 88, 69–77 (2004).

  53. 53

    Nahta, R., Hortobágyi, G. N. & Esteva, F. J. Growth factor receptors in breast cancer: potential for therapeutic intervention. Oncologist 8, 5–17 (2003).

  54. 54

    Peres, R., Betsholtz, C., Westermark, B. & Heldin, C. H. Frequent expression of growth factors for mesenchymal cells in human mammary carcinoma cell lines. Cancer Res. 47, 3425–3429 (1987).

  55. 55

    McTernan, P. G. et al. Gender differences in the regulation of P450 aromatase expression and activity in human adipose tissue. Int. J. Obes. 24, 875–881 (2000).

  56. 56

    Hembree, W. C. et al. Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 94, 3132–3154 (2009).

  57. 57

    Oh, W. K. The evolving role of estrogen therapy in prostate cancer. Clin. Prostate Cancer 1, 81–89 (2002).

  58. 58

    Dobs, A. & Darkes, M. J. M. Incidence and management of gynecomastia in men treated for prostate cancer. J. Urol. 174, 1737–1742 (2005).

  59. 59

    DiRaimondo, C. V., Roach, A. C. & Meador, C. K. Gynecomastia from exposure to vaginal estrogen cream. N. Engl. J. Med. 302, 1089–1090 (1980).

  60. 60

    Cimorra, G. A., Gonzalez-Peirona, E. & Ferrandez, A. Percutaneous oestrogen-induced gynaecomastia: a case report. Br. J. Plast. Surg. 35, 209–210 (1982).

  61. 61

    Finkelstein, J. S., McCully, W. F., MacLaughlin, D. T., Godine, J. E. & Crowley, W. F. Jr. The mortician's mystery. Gynecomastia and reversible hypogonadotropic hypogonadism in an embalmer. N. Engl. J. Med. 318, 961–965 (1988).

  62. 62

    Harrington, J. M., Stein, G. F., Rivera, R. O. & de Morales, A. V. The occupational hazards of formulating oral contraceptives—a survey of plant employees. Arch. Environ. Health 33, 12–15 (1978).

  63. 63

    Pacyński, A., Budzyńska, A., Przylecki, S. & Robaczynski, J. Hyperestrogenism in pharmaceutical factory workers and their children as an occupational disease [Polish]. Endokrynol. Pol. 22, 149–154 (1971).

  64. 64

    Diamanti-Kandarakis, E. et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr. Rev. 30, 293–342 (2009).

  65. 65

    McLachlan, J. A. Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocr. Rev. 22, 319–341 (2001).

  66. 66

    Degen, G. H. & Bolt, H. M. Endocrine disruptors: update on xenoestrogens. Int. Arch. Occup. Environ. Health 73, 433–441 (2000).

  67. 67

    Aksglaede, L., Juul, A., Leffers, H., Skakkebaek, N. E. & Andersson, A.-M. The sensitivity of the child to sex steroids: possible impact of exogenous estrogens. Hum. Reprod. Update 12, 341–349 (2006).

  68. 68

    Hotchkiss, A. K. et al. Fifteen years after “Wingspread”—environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go. Toxicol. Sci. 105, 235–259 (2008).

  69. 69

    Teilmann, G., Juul, A., Skakkebaek, N. E. & Toppari, J. Putative effects of endocrine disrupters on pubertal development in the human. Best Pract. Res. Clin. Endocrinol. Metab. 16, 105–121 (2002).

  70. 70

    Den Hond, E. et al. Internal exposure to pollutants and sexual maturation in Flemish adolescents. J. Expo. Sci. Environ. Epidemiol. 21, 224–233 (2011).

  71. 71

    Daxenberger, A., Ibarreta, D. & Meyer, H. H. Possible health impact of animal oestrogens in food. Hum. Reprod. Update 7, 340–355 (2001).

  72. 72

    Gavaler, J. S., Rosenblum, E. R., Deal, S. R. & Bowie, B. T. The phytoestrogen congeners of alcoholic beverages: current status. Proc. Soc. Exp. Biol. Med. 208, 98–102 (1995).

  73. 73

    Messina, M. Soybean isoflavone exposure does not have feminizing effects on men: a critical examination of the clinical evidence. Fertil. Steril. 93, 2095–2104 (2010).

  74. 74

    Goh, S. Y. & Loh, K. C. Gynaecomastia and the herbal tonic “Dong Quai”. Singapore Med. J. 42, 115–116 (2001).

  75. 75

    Toorians, A. W., Bovee, T. F., De Rooy, J., Stolker, L. A. & Hoogenboom, R. L. Gynaecomastia linked to the intake of a herbal supplement fortified with diethylstilbestrol. Food Addit. Contam. Part A Chem. Anal. Control. Expo. Risk Assess. 27, 917–925 (2010).

  76. 76

    Jameel, J. K., Kneeshaw, P. J., Rao, V. S. & Drew, P. J. Gynaecomastia and the plant product “Tribulis terrestris”. Breast 13, 428–430 (2004).

  77. 77

    Geyer, H. et al. Nutritional supplements cross-contaminated and faked with doping substances. J. Mass Spectrom. 43, 892–902 (2008).

  78. 78

    Gourgari, E., Saloustros, E. & Stratakis, C. A. Large-cell calcifying Sertoli cell tumors of the testes in pediatrics. Curr. Opin. Pediatr. 24, 518–522 (2012).

  79. 79

    Stratakis, C. A., Kirschner, L. S. & Carney, J. A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J. Clin. Endocrinol. Metab. 86, 4041–4046 (2001).

  80. 80

    Stratakis, C. A. & Horvath, A. Carney complex. GeneReviews® [online], (2012).

  81. 81

    Lefevre, H. et al. Prepubertal gynecomastia in Peutz–Jeghers syndrome: incomplete penetrance in a familial case and management with an aromatase inhibitor. Eur. J. Endocrinol. 154, 221–227 (2006).

  82. 82

    Young, S. et al. Feminizing Sertoli cell tumors in boys with Peutz–Jeghers syndrome. Am. J. Surg. Pathol. 19, 50–58 (1995).

  83. 83

    Gabrilove, J. L., Nicolis, G. L., Mitty, H. A. & Sohval, A. R. Feminizing interstitial cell tumor of the testis: personal observations and a review of the literature. Cancer 35, 1184–1202 (1975).

  84. 84

    Bercovici, J. P., Nahoul, K., Tater, D., Charles, J. F. & Scholler, R. Hormonal profile of Leydig cell tumors with gynecomastia. J. Clin. Endocrinol. Metab. 59, 625–630 (1984).

  85. 85

    Forest, M. G., Lecoq, A. & Saez, J. M. Kinetics of human chorionic gonadotropin-induced steroidogenic response of the human testis. II. plasma 17α-hydroxyprogesterone, Δ4-androstenedione, estrone, and 17β-estradiol: evidence for the action of human chorionic gonadotropin on intermediate enzymes implicated in steroid biosynthesis. J. Clin. Endocrinol. Metab. 49, 284–291 (1979).

  86. 86

    Kirschner, M. A., Lippman, A., Berkowitz, R., Mayrer, E. & Drejka, M. Estrogen production as a tumor marker in patients with gonadotropin-producing neoplasms. Cancer Res. 41, 1447–1450 (1981).

  87. 87

    Hassan, H. C., Cullen, I. M., Casey, R. G. & Rogers, E. Gynaecomastia: an endocrine manifestation of testicular cancer. Andrologia 40, 152–157 (2008).

  88. 88

    Hasle, H., Mellemgaard, A., Nielsen, J. & Hansen, J. Cancer incidence in men with Klinefelter syndrome. Br. J. Cancer 71, 416–420 (1995).

  89. 89

    Gabrilove, J. L., Sharma, D. C., Wortiz, H. H. & Dorfman, R. I. Feminizing adrenocortical tumors in the male: a review of 52 cases including a case report. Medicine 44, 37–79 (1965).

  90. 90

    Young, J. et al. Aromatase expression in a feminizing adrenocortical tumor. J. Clin. Endocrinol. Metab. 81, 3173–3176 (1996).

  91. 91

    Zayed, A., Stock, J. L., Liepman, M. K., Wollin, M. & Longcope, C. Feminization as a result of both peripheral conversion of androgens and direct estrogen production from an adrenocortical carcinoma. J. Endocrinol. Invest. 17, 275–278 (1994).

  92. 92

    Lafemina, J. & Brennan, M. F. Adrenocortical carcinoma: past, present, and future. J. Surg. Oncol. 106, 586–594 (2012).

  93. 93

    Fukami, M. et al. Genomic basis of aromatase excess syndrome: recombination- and replication-mediated rearrangements leading to CYP19A1 overexpression. J. Clin. Endocrinol. Metab. 98, E2013–E2021 (2013).

  94. 94

    Stratakis, C. A. An aroma of complexity: how the unique genetics of aromatase (CYP19A1) explain diverse phenotypes from hens and hyenas to human gynecomastia, and testicular and other tumors. J. Clin. Endocrinol. Metab. 98, 4676–4681 (2013).

  95. 95

    Agarwal, V. R. et al. Molecular basis of severe gynecomastia associated with aromatase expression in a fibrolamellar hepatocellular carcinoma. J. Clin. Endocrinol. Metab. 83, 1797–1800 (1998).

  96. 96

    Cavanaugh, J., Niewoehner, C. B. & Nuttall, F. Q. Gynecomastia and cirrhosis of the liver. Arch. Intern. Med. 150, 563–565 (1990).

  97. 97

    Wilson, J. D. Androgen abuse by athletes. Endocr. Rev. 9, 181–199 (1988).

  98. 98

    Basaria, S. Androgen abuse in athletes: detection and consequences. J. Clin. Endocrinol. Metab. 95, 1533–1543 (2010).

  99. 99

    Carpenter, P. C. Performance-enhancing drugs in sport. Endocrinol. Metab. Clin. North Am. 36, 481–495 (2007).

  100. 100

    Deepinder, F. & Braunstein, G. D. Drug-induced gynecomastia: an evidence-based review. Expert Opin. Drug Saf. 11, 779–795 (2012).

  101. 101

    Bowman, J. D., Kim, H. & Bustamante, J. J. Drug-induced gynecomastia. Pharmacotherapy 32, 1123–1140 (2012).

  102. 102

    Friedman, N. M. & Plymate, S. R. Leydig cell dysfunction and gynaecomastia in adult males treated with alkylating agents. Clin. Endocrinol. (Oxf.) 12, 553–556 (1980).

  103. 103

    Smyth, C. M. & Bremner, W. J. Klinefelter syndrome. Arch. Intern. Med. 158, 1309–1314 (1998).

  104. 104

    Lanfranco, F., Kamischke, A., Zitzmann, M. & Nieschlag, E. Klinefelter's syndrome. Lancet 364, 273–283 (2004).

  105. 105

    Swerdlow, A. J. et al. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J. Natl Cancer Inst. 97, 1204–1210 (2005).

  106. 106

    Zitzmann, M., Depenbusch, M., Gromoll, J. & Nieschlag, E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J. Clin. Endocrinol. Metab. 89, 6208–6217 (2004).

  107. 107

    Nuttall, F. Q. Gynecomastia. Mayo Clin. Proc. 85, 961–962 (2010).

  108. 108

    Large, D. M. & Anderson, D. C. Twenty-four hour profiles of circulating androgens and oestrogens in male puberty with and without gynaecomastia. Clin. Endocrinol. (Oxf.) 11, 505–521 (1979).

  109. 109

    Moore, D. C., Schlaepfer, L. V., Paunier, L. & Sizonenko, P. C. Hormonal changes during puberty: V. Transient pubertal gynecomastia: abnormal androgen-estrogen ratios. J. Clin. Endocrinol. Metab. 58, 492–499 (1984).

  110. 110

    Mieritz, M. G. et al. Elevated serum IGF-I, but unaltered sex steroid levels, in healthy boys with pubertal gynaecomastia. Clin. Endocrinol. (Oxf.) 80, 691–698 (2014).

  111. 111

    Juul, A. et al. Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J. Clin. Endocrinol. Metab. 78, 744–752 (1994).

  112. 112

    Bagatell, C. J. & Bremner, W. J. Androgens in men—uses and abuses. N. Engl. J. Med. 334, 707–714 (1996).

  113. 113

    Harman, S. M. et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 86, 724–731 (2001).

  114. 114

    Jacobs, E. C. Effects of starvation on sex hormones in the male. J. Clin. Endocrinol. Metab. 8, 227–232 (1948).

  115. 115

    Smith, S. R., Chhetri, M. K., Johanson, J., Radfar, N. & Migeon, C. J. The pituitary–gonadal axis in men with protein-calorie malnutrition. J. Clin. Endocrinol. Metab. 41, 60–69 (1975).

  116. 116

    Platt, S. S., Schulz, R. Z. & Kunstadter, R. H. Hypertrophy of the male breast associated with recovery from starvation. Bull. US Army Med. Dep. 7, 403–405 (1947).

  117. 117

    Linn, S., Almagor, G. & Lamm, S. Gynecomastia among Ethiopian Jews. Public Health Rep. 101, 237 (1986).

  118. 118

    Sattin, R. W., Roisin, A., Kafrissen, M. E., Dugan, J. B. & Farer, L. S. Epidemic of gynecomastia among illegal Haitian entrants. Public Health Rep. 99, 504–510 (1984).

  119. 119

    Schmitt, G. W., Shehadeh, I. & Sawin, C. T. Transient gynecomastia in chronic renal failure during chronic intermittent hemodialysis. Ann. Intern. Med. 69, 73–79 (1968).

  120. 120

    Karagiannis, A. & Harsoulis, F. Gonadal dysfunction in systemic diseases. Eur. J. Endocrinol. 152, 501–513 (2005).

  121. 121

    Handelsman, D. J. & Dong, Q. Hypothalamo-pituitary gonadal axis in chronic renal failure. Endocrinol. Metab. Clin. North Am. 22, 145–161 (1993).

  122. 122

    Sievertsen, G. D., Lim, V. S., Nakawatase, C. & Frohman, L. A. Metabolic clearance and secretion rates of human prolactin in normal subjects and in patients with chronic renal failure. J. Clin. Endocrinol. Metab. 50, 846–852 (1980).

  123. 123

    Hou, S. H., Grossman, S. & Molitch, M. E. Hyperprolactinemia in patients with renal insufficiency and chronic renal failure requiring hemodialysis or chronic ambulatory peritoneal dialysis. Am. J. Kidney Dis. 6, 245–249 (1985).

  124. 124

    Kley, H. K. et al. Conversion of androgens to estrogens in idiopathic hemochromatosis: comparison with alcoholic liver cirrhosis. J. Clin. Endocrinol. Metab. 61, 1–6 (1985).

  125. 125

    Farthing, M. J., Green, J. R., Edwards, C. R. & Dawson, A. M. Progesterone, prolactin, and gynaecomastia in men with liver disease. Gut 23, 276–279 (1982).

  126. 126

    Van Thiel, D. H. Ethanol: its adverse effects upon the hypothalamic-pituitary-gonadal axis. J. Lab. Clin. Med. 101, 21–33 (1983).

  127. 127

    Ashkar, F. S., Smoak, W. M., Gilson, A. J. & Miller, R. Gynecomastia and mastoplasia in Graves' disease. Metabolism 19, 946–951 (1970).

  128. 128

    Becker, K. L., Winnacker, J. L., Matthews, M. J. & Higgins, G. A. Gynecomastia and hyperthyroidism. An endocrine and histological investigation. J. Clin. Endocrinol. Metab. 28, 277–285 (1968).

  129. 129

    Ridgway, E. C., Maloof, F. & Longcope, C. Androgen and oestrogen dynamics in hyperthyroidism. J. Endocrinol. 95, 105–115 (1982).

  130. 130

    Nomura, K. et al. High serum progesterone in hyperthyroid men with Graves' disease. J. Clin. Endocrinol. Metab. 66, 230–232 (1988).

  131. 131

    Ford, H. C., Cooke, R. R., Keightley, E. A. & Feek, C. M. Serum levels of free and bound testosterone in hyperthyroidism. Clin. Endocrinol. (Oxf.) 36, 187–192 (1992).

  132. 132

    Wang, Y. et al. Unilateral gynecomastia and hypokalemic periodic paralysis as first manifestations of Graves' disease. Am. J. Med. Sci. 345, 504–506 (2013).

  133. 133

    Alesini, D. et al. Multimodality treatment of gynecomastia in patients receiving antiandrogen therapy for prostate cancer in the era of abiraterone acetate and new antiandrogen molecules. Oncology 84, 92–99 (2013).

  134. 134

    Evans, D. L., Pantanowitz, L., Dezube, B. J. & Aboulafia, D. M. Breast enlargement in 13 men who were seropositive for human immunodeficiency virus. Clin. Infect. Dis. 35, 1113–1119 (2002).

  135. 135

    Gewurz, B. E., Dezube, B. J. & Pantanowitz, L. HIV and the breast. AIDS Read. 15, 392–396, 399–402 (2005).

  136. 136

    Piroth, L. et al. Incidence of gynecomastia in men infected with HIV and treated with highly active antiretroviral therapy. Scand. J. Infect. Dis. 33, 559–560 (2001).

  137. 137

    Biglia, A. et al. Gynecomastia among HIV-infected patients is associated with hypogonadism: a case–control study. Clin. Infect. Dis. 39, 1514–1519 (2004).

  138. 138

    Imami, N., Antonopoulos, C., Hardy, G. A., Gazzard, B. & Gotch, F. M. Assessment of type 1 and type 2 cytokines in HIV type 1-infected individuals: impact of highly active antiretroviral therapy. AIDS Res. Hum. Retroviruses 15, 1499–1508 (1999).

  139. 139

    New, M. I. Male pseudohermaphroditism due to 17 α-hydroxylase deficiency. J. Clin. Invest. 49, 1930–1941 (1970).

  140. 140

    Goldsmith, O., Solomon, D. H. & Horton, R. Hypogonadism and mineralocorticoid excess. The 17-hydroxylase deficiency syndrome. N. Engl. J. Med. 277, 673–677 (1967).

  141. 141

    Hershkovitz, E. et al. Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency. J. Clin. Endocrinol. Metab. 93, 3584–3588 (2008).

  142. 142

    Rhéaume, E. et al. Congenital adrenal hyperplasia due to point mutations in the type II 3 β-hydroxysteroid dehydrogenase gene. Nat. Genet. 1, 239–245 (1992).

  143. 143

    Lutfallah, C. et al. Newly proposed hormonal criteria via genotypic proof for type II 3β-hydroxysteroid dehydrogenase deficiency. J. Clin. Endocrinol. Metab. 87, 2611–2622 (2002).

  144. 144

    OMIM Phenotypic Series. Hypogonadotropic hypogonadism with or without anosmia—147950 [online], (2014).

  145. 145

    Buck, C., Balasubramanian, R. & Crowley, W. F. Isolated gonadotropin-releasing hormone (GnRH) deficiency. GeneReviews® [online], (2013).

  146. 146

    Sykiotis, G. P. et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc. Natl Acad. Sci. USA 107, 15140–15144 (2010).

  147. 147

    Pitteloud, N., Durrani, S., Raivio, T. & Sykiotis, G. P. Complex genetics in idiopathic hypogonadotropic hypogonadism. Front. Horm. Res. 39, 142–153 (2010).

  148. 148

    Miraoui, H. et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am. J. Hum. Genet. 92, 725–743 (2013).

  149. 149

    Layman, L. C. Hypogonadotropic hypogonadism. Endocrinol. Metab. Clin. North Am. 36, 283–296 (2007).

  150. 150

    Bhagavath, B. et al. Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil. Steril. 85, 706–713 (2006).

  151. 151

    Hiort, O. Clinical and molecular aspects of androgen insensitivity. Endocr. Dev. 24, 33–40 (2013).

  152. 152

    Shozu, M. et al. Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene. N. Engl. J. Med. 348, 1855–1865 (2003).

  153. 153

    Stratakis, C. A. et al. The aromatase excess syndrome is associated with feminization of both sexes and autosomal dominant transmission of aberrant P450 aromatase gene transcription. J. Clin. Endocrinol. Metab. 83, 1348–1357 (1998).

  154. 154

    Ham, S. et al. Overexpression of aromatase associated with loss of heterozygosity of the STK11 gene accounts for prepubertal gynecomastia in boys with Peutz–Jeghers syndrome. J. Clin. Endocrinol. Metab. 98, E1979–E1987 (2013).

  155. 155

    Wit, J. M., Hero, M. & Nunez, S. B. Aromatase inhibitors in pediatrics. Nat. Rev. Endocrinol. 8, 135–147 (2012).

  156. 156

    Bertherat, J. et al. Mutations in regulatory subunit type 1A of cyclic adenosine 5′-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J. Clin. Endocrinol. Metab. 94, 2085–2091 (2009).

  157. 157

    Braunstein, G. D. Gynecomastia. N. Engl. J. Med. 328, 490–495 (1993).

  158. 158

    Fentiman, I. S., Fourquet, A. & Hortobagyi, G. N. Male breast cancer. Lancet 367, 595–604 (2006).

  159. 159

    Ottini, L. et al. Male breast cancer. Crit. Rev. Oncol. Hematol. 73, 141–155 (2010).

  160. 160

    Risch, H. A. et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J. Natl Cancer Inst. 98, 1694–1706 (2006).

  161. 161

    Tai, Y. C., Domchek, S., Parmigiani, G. & Chen, S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J. Natl Cancer Inst. 99, 1811–1814 (2007).

  162. 162

    Rizzolo, P. et al. Male breast cancer: genetics, epigenetics, and ethical aspects. Ann. Oncol. 24 (Suppl. 8), viii75–viii82 (2013).

  163. 163

    Niewoehner, C. B. & Schorer, A. E. Gynaecomastia and breast cancer in men. BMJ 336, 709–713 (2008).

  164. 164

    Perryman, R. L. & Thorner, M. O. The effects of hyperprolactinemia on sexual and reproductive function in men. J. Androl. 2, 233–242 (1981).

  165. 165

    Ikard, R. W., Vavra, D., Forbes, R. C., Richman, J. C. & Roumie, C. L. Management of senescent gynecomastia in the Veterans Health Administration. Breast J. 17, 160–166 (2011).

  166. 166

    Hanavadi, S., Monypenny, I. J. & Mansel, R. E. Is mammography overused in male patients? Breast 15, 123–126 (2006).

  167. 167

    Nguyen, C. et al. Male breast disease: pictorial review with radiologic–pathologic correlation. Radiographics 33, 763–779 (2013).

  168. 168

    Boccardo, F. et al. Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J. Clin. Oncol. 23, 808–815 (2005).

  169. 169

    Perdonà, S. et al. Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial. Lancet Oncol. 6, 295–300 (2005).

  170. 170

    Tunio, M. A., Al-Asiri, M., Al-Amro, A., Bayoumi, Y. & Fareed, M. Optimal prophylactic and definitive therapy for bicalutamide-induced gynecomastia: results of a meta-analysis. Curr. Oncol. 19, e280–e288 (2012).

  171. 171

    Khan, H. N., Rampaul, R. & Blamey, R. W. Management of physiological gynaecomastia with tamoxifen. Breast 13, 61–65 (2004).

  172. 172

    Lawrence, S. E., Faught, K. A., Vethamuthu, J. & Lawson, M. L. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J. Pediatr. 145, 71–76 (2004).

  173. 173

    Lapid, O., van Wingerden, J. J. & Perlemuter, L. Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review. J. Pediatr. Endocrinol. Metab. 26, 803–807 (2013).

  174. 174

    Plourde, P. V., Kulin, H. E. & Santner, S. J. Clomiphene in the treatment of adolescent gynecomastia. Clinical and endocrine studies. Am. J. Dis. Child. 137, 1080–1082 (1983).

  175. 175

    Serretta, V. et al. A randomized trial comparing tamoxifen therapy vs. tamoxifen prophylaxis in bicalutamide-induced gynecomastia. Clin. Genitourin. Cancer 10, 174–179 (2012).

  176. 176

    Viani, G. A., Bernardes da Silva, L. G. & Stefano, E. J. Prevention of gynecomastia and breast pain caused by androgen deprivation therapy in prostate cancer: tamoxifen or radiotherapy? Int. J. Radiat. Oncol. Biol. Phys. 83, e519–e524 (2012).

  177. 177

    Plourde, P. V. et al. Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 89, 4428–4433 (2004).

  178. 178

    Zachmann, M., Eiholzer, U., Muritano, M., Werder, E. A. & Manella, B. Treatment of pubertal gynaecomastia with testolactone. Acta Endocrinol. Suppl. 279, 218–226 (1986).

  179. 179

    Rhoden, E. L. & Morgentaler, A. Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole. Int. J. Impot. Res. 16, 95–97 (2004).

  180. 180

    Benveniste, O., Simon, A. & Herson, S. Successful percutaneous dihydrotestosterone treatment of gynecomastia occurring during highly active antiretroviral therapy: four cases and a review of the literature. Clin. Infect. Dis. 33, 891–893 (2001).

  181. 181

    Kuhn, J.-M. et al. Studies on the treatment of idiopathic gynaecomastia with percutaneous dihydrotestosterone. Clin. Endocrinol. (Oxf.) 19, 513–520 (1983).

  182. 182

    Van Poppel, H. et al. Efficacy and tolerability of radiotherapy as treatment for bicalutamide-induced gynaecomastia and breast pain in prostate cancer. Eur. Urol. 47, 587–592 (2005).

  183. 183

    Fruhstorfer, B. H. & Malata, C. M. A systematic approach to the surgical treatment of gynaecomastia. Br. J. Plast. Surg. 56, 237–246 (2003).

  184. 184

    Kasielska, A. & Antoszewski, B. Surgical management of gynecomastia: an outcome analysis. Ann. Plast. Surg. 71, 471–475 (2013).

  185. 185

    Song, Y.-N. et al. Surgical treatment of gynecomastia: mastectomy compared to liposuction technique. Ann. Plast. Surg. http://dx.doi.org/10.1097/SAP.0b013e31827c7949.

  186. 186

    Rifka, S. M., Pita, J. C., Vigersky, R. A., Wilson, Y. A. & Loriaux, D. L. Interaction of digitalis and spironolactone with human sex steroid receptors. J. Clin. Endocrinol. Metab. 46, 338–344 (1978).

  187. 187

    Kaplan, S. A., Chung, D. E., Lee, R. K., Scofield, S. & Te, A. E. A 5-year retrospective analysis of 5α-reductase inhibitors in men with benign prostatic hyperplasia: finasteride has comparable urinary symptom efficacy and prostate volume reduction, but less sexual side effects and breast complications than dutasteride. Int. J. Clin. Pract. 66, 1052–1055 (2012).

Download references

Author information

H.S.N. researched data for the article, contributed to discussion of the content and wrote the article. H.E.C. researched data for the article, contributed to discussion of the content and reviewed/edited the manuscript before submission.

Correspondence to Harold E. Carlson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Narula, H., Carlson, H. Gynaecomastia—pathophysiology, diagnosis and treatment. Nat Rev Endocrinol 10, 684–698 (2014). https://doi.org/10.1038/nrendo.2014.139

Download citation

Further reading