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Gynaecomastia is enlargement of the male breast tissue. Gynae means 'woman' and mastos means 'breast' in Greek. It can be defined as the presence of >2 cm of palpable, firm, subareolar gland and ductal breast tissue.
It may occur at any time and there are a number of causes, some physiological and others pathological. Pathological causes involve an imbalance between the activity of androgens and oestrogens - the former is decreased compared with the latter.
- Gynaecomastia is common and is thought to be present in more than 30% of men, with much higher rates in men over the age of 70 years (eg up to 55% at autopsy). In comparison, breast cancer is only detected in 1% of cases of male breast enlargement.
- 65-90% of male neonates have gynaecomastia due to the transfer of maternal oestrogen and progesterone.
Oestrogen stimulates breast tissue growth whilst androgens inhibit it. The important factor is the ratio of active androgens to oestrogens. The ratio can be altered as a result of reduced testosterone production/action or enhanced oestrogen production/action or both. Once this ratio falls, breast tissue is stimulated to grow. This leads to proliferation of breast ducts and fibroblastic stroma. If the stimulus to proliferation continues then the ducts and fibroblastic stroma are replaced by fibrosis and gynaecomastia becomes well established and irreversible.
Aromatase is one of the cytochrome P450 enzymes and is involved in the aromatisation of androgens to oestrogens, eg changing androstenedione to estrone and testosterone to estradiol. This enzyme is found in many tissues, eg brain, adipose tissue, blood vessels and the gonads. Enhanced adipose tissue, as in obesity, provides increased levels of the enzyme and, hence, increased production of oestrogens leading to gynaecomastia.
Causes of gynaecomastia
- Increasing age - associated with low testosterone levels.
- Lack of testosterone:
- Congenital absence of testes.
- Androgen resistance.
- Klinefelter's syndrome (XXY syndrome).
- Viral orchitis.
- Renal failure.
- Increased oestrogen levels:
- Testicular tumours, eg Leydig's cell tumour which secrete estradiol.
- Neoplasms producing human chorionic gonadotrophin (hCG), eg lung - hCG stimulates Leydig's cells to excrete estradiol.
- Adrenal tumours - these can release oestrogens.
- Liver disease (cirrhosis).
Drugs account for 20% of all cases in adult men:
- Oestrogen, eg oral contraceptive pill (OCP), digoxin, diethylstilbestrol.
- Antipsychotics (blocks dopamine - leading to increased prolactin release from the pituitary).
- Flutamide - blocks androgen receptors.
- Inhibitors of testosterone, eg finasteride, metronidazole, spironolactone, alkylating agents.
- Anabolic steroid abuse.
- Others, eg amiodarone, isoniazid, cimetidine, methyldopa, tricyclic antidepressants, diazepam, calcium-channel blockers, heroin.
- Cosmetics eg lavender and tea tree oil products (stops once the offending cosmetic is removed).
- Gynaecomastia of unclear cause:
Some points regarding specific causes of gynaecomastia
- Newborn babies can have gynaecomastia, which is the result of maternal oestrogens, and the gynaecomastia resolves after a few weeks.
- Adolescent boys can develop gynaecomastia around puberty (at an average age of 14 years) and it can affect one breast more than the other. It is often tender and resolves spontaneously.
In congenital anorchia there are absent levels of testosterone with normal estradiol levels and patients experience severe gynaecomastia. Similarly, low testosterone levels in Klinefelter's syndrome lead to gynaecomastia. In Klinefelter's syndrome gynaecomastia is associated with an increased risk of breast cancer and this needs to be considered (risk is increased up to 20 times that of other patients with gynaecomastia).
In liver disease there is a lack of breakdown of androstenedione which results in increased conversion of androgens to oestrogens in extraglandular tissues, resulting in gynaecomastia.
Digoxin causes gynaecomastia by virtue of an oestrogen-like effect and the effect is enhanced if liver derangement is co-existent. Other drugs interfere with testosterone synthesis or action, eg spironolactone, cimetidine and alkylating agents.
Other more rare causes of male breast enlargement include metastases from the lung or liver, haematological malignancies, eg lymphoma, haemangiomas and hamartomas.
Antiretrovirals and gynaecomastia
The exact mechanism by which antiretrovirals cause gynaecomastia is unknown. It often presents as unilateral and tender gynaecomastia. Efavirenz has been implicated and stopping it results in resolution of gynaecomastia. However, there can be more sinister causes for the gynaecomastia which should not be missed, eg lymphoma.
Approach to a patient presenting with gynaecomastia
- Commonly, gynaecomastia is asymptomatic.
- Onset and duration of breast enlargement.
- Presence of sexual dysfunction.
- Drug history.
- Any use of drugs of abuse, eg alcohol, heroin and marijuana (controversial as a cause of gynaecomastia).
- Is it true enlargement of breast tissue?
- Enlargement of breast tissue may represent adipose tissue (pseudogynaecomastia) or true proliferation of breast tissue. This can be examined by pinching breast tissue between the thumb and forefinger - true proliferation can be felt as a distinct disc of tissue under the skin. If there is any doubt ultrasonography or mammography may help.
- Size and asymmetry.
- Any evidence of liver disease or renal impairment, eg palmar erythema, bruising, spider naevi, hepatomegaly.
- Evidence to suggest lack of testosterone, eg hairless, shiny skin, testicular size, testicular masses, tenor of voice.
- Presence or absence of sexual characteristics.
- Signs of hyperthyroidism or Cushing's syndrome.
These should be performed on a clinical basis, ieaccording to the history and examination. For example, if the patient is on gynaecomastia-inducing medication then these tests may not be necessary.
- Renal function.
- Liver function tests.
- Thyroid function tests.
- Serum androstenedione or urinary 17-ketosteroids (for feminising adrenal states and oestrogen-producing adrenal tumours).
- hCG level.
- Luteinising hormone (LH) and follicle-stimulating hormone (FSH).
- LH high and testosterone low - indicates testicular failure.
- LH and testosterone both low - indicates increase in oestrogens.
- LH and testosterone both high - androgen resistance or neoplasm secreting gonadotrophins.
- Prolactin - usually normal.
- Testosterone and estradiol levels.
- Ultrasonography or mammography of breasts.
- Ultrasonography of testes.
- CXR if a lung lesion is suspected.
- Chromosomal karyotyping may need to be considered
- Biopsy will provide a definitive diagnosis, eg proliferation of ductules and loose connective tissue confirm gynaecomastia.
An underlying cause is found in fewer than 50 % of patients.
Gynaecomastia and male breast cancer
See full separate article Male Breast Cancer.
- Male breast cancer only accounts for 1% of all breast cancer, but is higher in sub-Saharan Africa (7-14% incidence).
- Mean age of male breast cancer is 65 years - but it can occur at any age.
- There is increased risk in Klinefelter's syndrome (as mentioned above under 'Pathological' heading) and treatment with oestrogens.
- Levels are also increased with a positive family history and breast cancer risk genes, eg BRCA1 and BRCA2.
- Red flags which increase suspicion of breast cancer in men:
- Unilateral enlargement.
- Hard or irregular breast tissue.
- Rapidly enlarging.
- Recent onset.
- Fixed mass.
- Nipple or skin abnormalities.
- >5 cm.
- Axillary lymphadenopathy.
In these cases, breast imaging with fine needle aspiration (FNA) or biopsy may be required. Refer to a local 'one-stop' breast clinic if there is any doubt or suspicion of a sinister cause.
- Refer any man with red flag symptoms, as mentioned above under 'Gynaecomastia and male breast cancer' heading. Also refer if the underlying cause is unclear and/or gynaecomastia is causing significant distress to the patient.
- Treat the underlying cause if found, eg androgen replacement in testicular failure or removal of the offending drug.
- If no underlying cause is discovered or gynaecomastia is longstanding with development of fibrosis, then surgical removal of breast tissue is the only effective therapy. Surgery involves subcutaneous mastectomy or liposuction associated mastectomy. However, surgery can be associated with nipple inversion, nipple necrosis, painful scar tissue and possible sensory changes.
- In prostatic carcinoma the development of gynaecomastia is a common reason for poor treatment adherence. Prophylactic breast irradiation prior to starting treatment with diethylstilbestrol or oestrogens has been used with good results. A randomised controlled trial showed that tamoxifen is superior to radiotherapy in patients with prostatic carcinoma, taking bicalutamide.
- Other treatments that have been used include clomifene, androgens, danazol and aromatase inhibitors.
- Aromatase inhibitors such as testolactone have also been used with occasional benefit. Most reports are case studies which show an increase in levels of plasma testosterone with some reduction in breast tissue. However, further studies are required and it is not licensed for this use.
- Clomifene has been used in adolescent gynaecomastia and the results in patients appear to be disappointing, although the number of patients in the studies is small. Again it is not licensed for this use.
- Alternatively, tamoxifen (not licensed for use in gynaecomastia) has fared better in adolescents with gynaecomastia, with reduction in breast tissue and breast tenderness. Low doses of tamoxifen have also been used in men with prostatic carcinoma taking flutamide and finasteride - the benefit was related to reduced breast tenderness rather than reduction in breast tissue.
Gynaecomastia associated with obesity may respond to weight loss although breast tissue usually remains.
- Gynaecomastia is mostly a benign condition.
- Complete resolution can occur if the underlying cause is identified and treatment initiated before fibrosis of breast tissue occurs.
- Gynaecomastia can be physically embarrassing and psychologically distressing for patients and this should not be underestimated.
Further reading & references
- Niewoehner CB, Schorer AE; Gynaecomastia and breast cancer in men. BMJ. 2008 Mar 29;336(7646):709-13.
- Bembo SA, Carlson HE; Gynecomastia: its features, and when and how to treat it. Cleve Clin J Med. 2004 Jun;71(6):511-7.
- Ismail AA, Barth JH; Endocrinology of gynaecomastia. Ann Clin Biochem. 2001 Nov;38(Pt 6):596-607.
- Jayapaul M, Williams MR, Davies DP, Large DM; Recurrent painful unilateral gynaecomastia with relapsing hyperthyroidism. Endocrine Abstracts; 2003
- Braunstein GD; Aromatase and gynecomastia. Endocr Relat Cancer. 1999 Jun;6(2):315-24.
- Harmon J, Aliapoulios MA; Gynecomastia in marihuana users. N Engl J Med. 1972 Nov 2;287(18):936.
- Dobs A, Darkes MJ; Incidence and management of gynecomastia in men treated for prostate cancer. J Urol. 2005 Nov;174(5):1737-42.
- Autorino R, Perdona S, D'Armiento M, et al; Gynecomastia in patients with prostate cancer: update on treatment options. Prostate Cancer Prostatic Dis. 2006;9(2):109-14. Epub 2006 Jan 24.
- Widmark A, Fossa SD, Lundmo P, et al; Does prophylactic breast irradiation prevent antiandrogen-induced gynecomastia? Evaluation of 253 patients in the randomized Scandinavian trial SPCG-7/SFUO-3. Urology. 2003 Jan;61(1):145-51.
- Perdona S, Autorina R, De Placido 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 Oncology 2005, April 14th: 1-6 - published on-line
- Plourde PV, Kulin HE, Santner SJ; Clomiphene in the treatment of adolescent gynecomastia. Clinical and endocrine studies. Am J Dis Child. 1983 Nov;137(11):1080-2.
- Staiman VR, Lowe FC; Tamoxifen for flutamide/finasteride-induced gynecomastia. Urology. 1997 Dec;50(6):929-33.
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|Original Author: Dr Gurvinder Rull||Current Version: Dr Gurvinder Rull|
|Last Checked: 19/11/2010||Document ID: 1301 Version: 23||© EMIS|