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Practice Clinical updates

Gynaecomastia

BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i4833 (Published 22 September 2016) Cite this as: BMJ 2016;354:i4833
  1. Paul Thiruchelvam, clinical lecturer in surgery and Winston Churchill fellow1,
  2. Jonathan Neil Walker, consultant in endocrinology and diabetes2,
  3. Katy Rose, specialist trainee year 2 in paediatrics3,
  4. Jacqueline Lewis, consultant oncoplastic surgeon1,
  5. Ragheed Al-Mufti, consultant oncoplastic and reconstructive breast surgeon1
  1. 1Academic Department of Surgery, Imperial College NHS Trust, Charing Cross Hospital, London W6 8RF, UK
  2. 2Royal Devon and Exeter Foundation Trust, Exeter, UK
  3. 3Queen Charlotte’s and Chelsea Hospital, London, UK
  1. Correspondence to: P Thiruchelvam paul.thiruchelvam{at}imperial.ac.uk

What you need to know

  • Gynaecomastia typically results from an imbalance between the level or action of oestrogen and androgen

  • Physiological gynaecomastia is common in newborns, adolescents, and older men and most do not require investigation

  • Removal of the underlying cause often leads to resolution of gynaecomastia

  • Early treatment with tamoxifen (unlicensed) is the most effective medical option in men with symptoms

  • Surgery is the only effective treatment option once gynaecomastia becomes fibrotic

Gynaecomastia is the benign proliferation of glandular breast tissue in men. It is characterised by the presence of a palpable, firm, subareolar gland and ductal tissue (not fat) resulting in breast enlargement.1 2 Gynaecomastia occurs in 35% of men and is most prevalent between the ages of 50 and 69.3 4 5 6 7 In pseudogynaecomastia there is a lack of glandular proliferation, with increase in breast size due purely to excess adiposity.8 9 10 11 It can be difficult to differentiate gynaecomastia from pseudogynaecomastia, as some patients will have an element of both adiposity and glandular proliferation. This article highlights the assessment and treatment of gynaecomastia but does not cover the management of breast cancer in men.

Sources and selection criteria

We searched Medline and Embase from 1980 to date, limited to publications in English and to studies in men. Our search strategy used a combination of MeSH, textwords, and appropriate word variants of “gynaecomastia” or “gynecomastia” and “male breast disease”. We supplemented these sources with selected systematic reviews. Additional information cited includes evidence based guidelines and published consensus statements, where available.

What causes gynaecomastia?

Oestrogens directly stimulate the breast duct development of both sexes, whereas testosterone is a potent inhibitor of breast growth.12 13 14 Gynaecomastia occurs predominantly as a result of either an excess of oestrogens or oestrogen precursors or a reduction in androgens or impairment of their actions (fig 1).16 The cause of the hormone imbalance can be physiological (box 1), drug induced (box 2), or disease (box 3).

Figure1

Fig 1 Glandular and extraglandular origins and interactions of androgens: testosterone, dihydrotestosterone, androstenedione, and the oestrogens, oestradiol and oestrone, and their effect on breast tissue. Thick arrows denote major sources of hormone. Adapted from from McLeod and Iversen 200015

Box 1: Physiological gynaecomastia

Transient neonatal gynaecomastia

This affects up to 90% of neonates as a result of transplacental transfer of maternal oestrogens. Reassurance is sufficient as the condition usually resolves spontaneously within a few weeks.17 One large prospective cohort study found breast tissue was still present in 45.6% of male infants at 10 months, suggesting that investigations are not required until after 18 months 18 These studies require further validation

Transient pubertal gynaecomastia

This affects approximately 60% of adolescent males, with a mean onset between 12 and 14 years19 20 21 and typically lasting 6-12 months, with spontaneous regression in 90% of cases.22 23 Putative causation includes an increase in oestrogen levels, lagging free testosterone production, and increased tissue sensitivity to normal oestrogen levels.24 25 Gynaecomastia occurs at a time when body perception and self image are of great importance, and development of female characteristics leads to distress and social embarrassment.22 We only recommend investigations or treatment in persistent cases (>18-24 months).2 26 27 28 29 In approximately 10% of cases gynaecomastia persists into adulthood30

Age related gynaecomastia

Gynaecomastia can occur in up to 65% of men aged more than 65 and is likely to relate to reduced testosterone levels and testicular involution.4 31 Increased obesity in this age group is also likely to have a contributory effect.32 Disease related causes are still prevalent within this patient group; therefore we advise further investigation if the history is suggestive of a pathological cause or the gynaecomastia is of rapid onset

Box 2: Drug induced gynaecomastia33343536

Drugs known to cause gynaecomastia
  • Antiandrogens—bicalutamide, flutamide, finasteride, dutasteride (AA)

  • Antihypertensive—spironolactone (AA)

  • Antiretrovirals—protease inhibitors (saquinavir, indinavir, nelfinavir, ritonavir, lopinavir), reverse transcriptase inhibitors (stavudine, zidovudine, lamivudine) (UM)

  • Environmental exposures—phenothrin (antiparasitical)

  • Exogenous hormones—oestrogens (EP), prednisone (male teenagers), human chorionic gonadotrophin (E)

  • Gastrointestinal drugs—H2 histamine receptor blockers (cimetidine) (AA), proton pump inhibitors (eg, omeprazole) (AA)

  • Analgesics—opioid drugs (RA)

  • Antifungals—ketoconazole (prolonged oral use) (AA)

  • Antihypertensives—calcium channel blockers (amlodipine, diltiazem, felodipine, nifedipine, verapamil) (UM)

  • Antipsychotics (first generation)—haloperidol (IP), olanzapine, paliperidone (high doses), risperidone (high doses), ziprasidone

  • Antiretrovirals—efavirenz (UM)

  • Chemotherapy drugs—methotrexate, alkylating agents—eg, cyclophosphamide, melphalan (AA); carmustine, etoposide, cytarabine, bleomycin, cisplatin (AA), vincristine (AA), procarbazine

  • Exogenous hormones—androgens (misuse by athletes) (EP)

  • Cardiovascular drugs—phytoestrogens (soya based products, high quantity) (EP)

  • Recreational/illicit substances—marijuana, amphetamines (UM), heroin (UM), methadone (UM), alcohol

  • Herbals—lavender, tea tree oil, dong quai (female ginseng), Tribulus terrestris, soy protein (300 mg/day), Urtica dioica (common nettle)

Drugs rarely causing gynaecomastia
  • Amiodarone (UM), aripiprazole, atorvastatin (UM), captopril (UM), cetirizine, clonidine, cyproterone acetate, dasatinib, diazepam (ISHBG), digoxin (EP), domperidone, entecavir, fenofibrate (UM), fluoxetine (UM), gabapentin, imatinib, lisinopril, loratadine, metronidazole (AA), misoprostol, paroxetine (UM), penicillamine (AA), phthalates (UM),37 pravastatin (UM), pregabalin, ranitidine (AA), rosuvastatin (UM), sulindac, sulpiride, sunitinib, theophylline (UM), venlafaxine (UM)

  • AA=antiandrogenic; RA=reduced androgens; E=oestrogenic; IAM=increased androgen metabolism; ISHBG=increased concentration of sex hormone binding globulin; IP=increased prolactin; UM=unknown mechanism

Box 3: Pathological causes of gynaecomastia

Gonadal failure
  • Primary hypogonadism results in failure of testicular function. The causes of primary failure include trauma, chemotherapy, and inflammatory damage. Consider chromosomal causes of hypogonadism, including Klinefelter’s syndrome. In Klinefelter’s syndrome the reported incidence of gynaecomastia syndrome ranges between 56% and 88%38

  • Secondary hypogonadism is caused by failure of the hypothalamic-pituitary axis, leading to lack of stimulation. Causes include non-functioning pituitary adenomas

  • Hyperprolactinaemia can result in secondary hypogonadism as well as causing galactorrhoea, through a direct effect on breast tissue

Thyroid dysfunction
  • Hyperthyroidism can increase levels of sex hormone binding globulin, thereby reducing the availability of free testosterone. This may cause gynaecomastia in 10-40% of cases, depending, among other factors, on the severity of hyperthyroidism.39 40 Restoration of a euthyroid state will resolve the gynaecomastia41 42 43 44

Liver cirrhosis
  • The liver is the main site of oestrogen degradation. Injury to the liver impairs this process and increases sex hormone binding globulin and peripheral oestrogen levels. The leading cause of liver cirrhosis is alcohol damage, and alcohol directly inhibits testosterone synthesis

Renal insufficiency
  • Testosterone production is suppressed in renal failure possibly from suppression of testosterone production and direct testicular damage caused by uraemia45

Hormone secreting tumours
  • Testicular tumours that secrete oestrogen (often Sertoli or Leydig cell tumours) and tumours that secrete human chorionic gonadotrophin (stimulating oestrogen production) are often associated with gynaecomastia. In 7-11% of cases of testicular tumours, gynaecomastia might be the only presenting symptom.46 47 Testicular tumours are present in 3% of men with gynaecomastia.48 49 Ectopic human chorionic gonadotrophin secreting tumours and choriocarcinoma are also associated with gynaecomastia. Adrenocortical tumours might also produce oestrogens and steroid precursors, with the overall effect of disruption to the ratio of oestrogen and testosterone

Obesity
  • Obesity is more often associated with pseudogynaecomastia than gynaecomastia, but it also results in increased levels of leptin and aromatase activity, increasing oestrogen levels50

Other conditions associated with gynaecomastia
  • Ulcerative colitis

  • Cystic fibrosis

  • Refeeding syndrome after a prolonged period of malnutrition

  • Testicular infiltration—tuberculosis, haemochromatosis

Who gets gynaecomastia?

Most men with gynaecomastia are asymptomatic and unaware of their excess breast tissue. Gynaecomastia typically occurs as part of normal physiological changes (physiological gynaecomastia) and is often seen in newborns, adolescents, and older men (box 1). The condition is strongly correlated with obesity, which is known to cause increased peripheral aromatisation of oestrogen precursors.4 5 6 51 There are several drugs and pathological causes known to cause gynaecomastia, which are discussed in boxes 2 and 3.

Psychological impact of gynaecomastia

Gynaecomastia is associated with poorer general health and body image, social withdrawal, increased mental health issues, low self esteem, low sexual function, and eating disorders such as bulimia nervosa.8 26 30 52 53 One large single institution study of idiopathic adolescent gynaecomastia highlighted conditions such as adjustment disorder (72.9%), anxiety disorder (16.7%), dysthymia (16.7%), generalised anxiety disorder (4.2%), and social phobia (4.2%).30

How is gynaecomastia diagnosed?

The history is typically of slow breast enlargement, which is either bilateral or unilateral.4 19 Size can vary, from a small amount of extra tissue around the nipples to prominent breasts. The Simon classification is commonly used to grade gynaecomastia into four groups (fig 2).54 Breast tenderness and pain around the nipple area are common symptoms, owing to proliferation of glandular tissue. Consider malignancy and refer urgently to a breast specialist any man who presents with a suspicious breast mass.55

Figure2

Fig 2 Simon classification of gynaecomastia. Broken line represents the inframammary fold

What important areas need to be considered in the history?

Several medical conditions can result in gynaecomastia. Table 1 lists the mechanism of action and clinical features associated with pathological gynaecomastia. A detailed review of prescription drugs is required as well as consideration of environmental exposures that cause gynaecomastia (box 2). In younger men explore the use of illicit drugs and body building supplements. Anabolic androgenic steroids suppress the hypothalamo-pituitary system, resulting in low circulating endogenous testosterone levels, which causes gynaecomastia.56 Some athletes attempt to overcome hypogonadism by taking human chorionic gonadotrophin6; this may be combined with tamoxifen or clomiphene to counteract the increased oestrogen levels caused by human chorionic gonadotrophin, which induces or worsens the gynaecomastia.57 Several potent “designer anabolic steroids,” such as dimethazine, methylclostebol, mentabolan, methoxygonadiene, methylepitiostanol, and methylstenbolone are associated with gynaecomastia. These products are also known as prohormones, natural steroids, and testosterone boosters.58

Table 1

Mechanism of action and clinical features of pathological gynaecomastia

View this table:

The evidence for marijuana induced gynaecomastia is conflicting, but our clinical experience suggests this is a potential cause of gynaecomastia. However, the mechanism of action is not fully understood.59 60 61 62 63Box 2 lists the non-prescription, recreational, and herbal drugs associated with gynaecomastia.64

Inquire about occupational or unintentional exposure to oestrogens—eg, compounds containing phthalates. These are esters of phthalic acid with antiandrogenic and oestrogenic effects and are found in cosmetics, perfumes, clothing, paints, solvents, insecticides, plasticisers, food, water, and pharmaceutical products.65 66 Their effects depend on dose and duration of exposure.37 Ask about alcohol consumption, as long term intake of high levels causes increased aromatase activity and increased adrenal production of oestrogen precursors.67 68 69 70 71 The presence of biologically active phytoestrogenic congeners in alcohol has also been suggested as a potential source of exogenous oestrogens.34 72 73 Ask about family history of gynaecomastia and breast problems as 58% of patients with benign persistent pubertal gynaecomastia have a positive family history.74

Examination

Calculate body mass index and assess secondary sexual characteristics. Examine the breasts by palpating all areas of the breast tissue (including the nipple) and examine the axilla. Compare and note if enlargement is unilateral or bilateral. Palpable, firm, glandular tissue (>2 cm) in a concentric glandular mass around the nipple areola complex is most consistent with gynaecomastia. Breast tissue less than 2 cm in men is defined as palpable breast tissue, the prevalence of which increases with age and adiposity.3 Offer urgent referral to a breast specialist if you detect any suspicious breast masses. Offer testicular examination if the history is suggestive of hypogonadism (to measure testicular volume) or if there is any suggestion of a testicular mass. If testicular examination reveals a mass, request urgent ultrasonography and refer to a urologist. Consider Klinefelter’s syndrome and Kallmann syndrome75 in pubertal patients with hypogonadism.

Further investigations

Further investigations are not needed if the patient is within the age limits for physiological gynaecomastia (box 2) providing the enlargement has occurred gradually, and there are no clinical features of underlying disease. Outside of these age groups, if there is no clear underlying drug cause, consider blood tests and further imaging as guided by the history.

Blood tests

Initial blood tests include morning testosterone (9 am),76 liver function, thyroid function, and renal function. If the testosterone level is low, further investigations should include luteinising hormone, follicle stimulating hormone, oestradiol, sex hormone binding globulin (to allow estimation of free testosterone levels), and prolactin. Referral to endocrinology is recommended in the event of any abnormality. If the history or examination is suggestive of testicular malignancy, check levels of β human chorionic gonadotrophin, α-fetoprotein, and lactate dehydrogenase.

What imaging is required?

Imaging is not required for patients with signs and symptoms typical of gynaecomastia. However, a pragmatic approach is to refer patients where clinical examination is indeterminate or suspicious. This is in keeping with recent US guidelines.77

When and who to treat?

Gynaecomastia will be transient in 90% of adolescents presenting to primary care.22 We advise delaying treatment in adolescents until symptoms have persisted for more than two years74 and providing reassurance that symptoms persist in only 10%.22 78 Men with pathological gynaecomastia should be considered for referral to an appropriate specialist for treatment of the underlying cause. Offer alternative treatment to men with gynaecomastia likely to be secondary to drugs. The clinical course of gynaecomastia is proliferation of glandular tissue followed by fibrosis (thickening of tissue). If clinically the breast tissue feels fibrotic then treating the cause or stopping the implicated drug may stop progression but is unlikely to reduce the excess breast tissue. It is not often possible to predict in which patients gynaecomastia will resolve and who will experience progression to the fibrotic stage.

Treatment options

Medical

Medical management is associated with a high success rate and avoids surgical intervention, but once fibrosis occurs it is largely ineffective. In the United Kingdom, danazol is licensed for the treatment of gynaecomastia, with response rates of 58-64% reported.79 80 A six week course is initially recommended, with reassessment of symptoms at eight weeks.7 Danazol is, however, associated with weight gain, which may exacerbate gynaecomastia and therefore is rarely recommended. Clomiphene has also been used with some reported benefit.81

Tamoxifen is the most widely used medical treatment, but it is not licensed for gynaecomastia. Response rates of up to 95% have been reported with tamoxifen (trials of between two and 12 month treatment durations).82 83 84 85 86 87 Tamoxifen has been shown to improve breast pain (mastodynia), which is the primary indication for the drug being prescribed, and is more effective when gynaecomastia is less than 4 cm.85 88 Trial doses vary and there is no clear guidance on treatment dose or duration.88 89 90 91 There are no good data to support treatment beyond nine months, and effects are usually seen after three months. In one longitudinal study of 20 patients receiving a four month course of tamoxifen for pubertal gynaecomastia and followed up for one year after completion of treatment, no statistically significant effect on skeletal maturation was observed.92

In the early prostate cancer programme, the incidence of gynaecomastia within 6-9 months of starting antiandrogen treatment was approximately 74%.93 Development of this side effect resulted in discontinuation of treatment in 16.7% of patients. A recent systematic review showed that tamoxifen (10-20 mg) was more effective than anastrozole in both preventing and treating gynaecomastia and mastodynia in patients receiving antiandrogen (bicalutamide or flutamide) treatment for prostate cancer.94

The most common reported reasons for discontinuation of tamoxifen in one single centre retrospective review of men with breast cancer were thromboembolic events (31%), loss of libido (23%), bone pain (15%), neurocognitive deficits (15%), leg cramps (8%), and ocular events (8%).95

Surgery

No trials directly compare outcomes after medical or surgical treatment. Surgery remains the only definitive treatment for late fibrotic gynaecomastia. Referral for surgery is rarely appropriate in the first year of symptoms, and it is not recommended while spontaneous resolution is a possibility. In patients with persistent idiopathic gynaecomastia for more than one year, bypassing conservative treatments in favour of immediate surgical correction may be appropriate.

Surgical treatment aims to restore a normal symmetrical chest contour, reduce displacement of the nipple areolar complex, and correct skin excess. The most commonly used technique involves direct excision of glandular tissue with or without liposuction.96 Recent studies have also reported success using endoscopic surgical techniques, although long term comparative studies are lacking.97 98 Complications include recurrence (8%), breast retraction (37%), hypertrophy (14%), hyperaesthesia (14%), and skin redundancy (7%) and asymmetry.55 Even in studies with high complication rates (53%), patient reported satisfaction rates were 86%.55 One patient survey study highlighted that 85% of patients had surgery for reasons of self confidence and emotional distress.99 Only a few had surgery for pain or discomfort. The most common reason for litigation arising from surgery is dissatisfaction with the aesthetic outcome. Therefore provision of appropriate preoperative information and ensuring realistic expectations are essential.

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Footnotes

  • Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following: none.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

References

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