Gynaecomastia

Gyne means "woman" and mastos means "breast" in Greek.

Gynaecomastia is enlargement of the male breast tissue. It can be defined as the presence of:¹

"....>2cm palpable, firm, subareolar gland and ductal 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 to the latter.²

• 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 (e.g. up to 55% at autopsy).^1,2 In comparison breast cancer is only detected in 1% of cases of male breast enlargement.
• 65-90% of neonates have gynaecomastia due to the transfer of maternal oestrogen and progesterone.¹

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 e.g. changing androstenedione to estrone and testosterone to oestradiol. This enzyme is found in many tissues e.g. 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.

Testicular tissue only secretes 15% of the male oestradiol - the rest is produced from the conversion of testosterone peripherally via aromatisation in extraglandular tissues e.g. adipose tissue.³ This explains why obesity is associated with gynaecomastia - there is increased conversion of testosterone to oestradiol in the excessive adipose tissue.

Physiological

• Newborn
• Adolescence
• Increasing age - associated with low testosterone levels

Pathological

• Lack of testosterone:
  • Congenital absence of testes
  • Androgen resistance
  • Klinefelters syndrome (XXY syndrome)
  • Viral orchitis
  • Trauma
  • Castration
  • Renal failure
• Increased oestrogen levels:
  • Testicular tumours e.g. Leydig cell tumour which secrete oestradiol²
  • Hermaphroditism
  • Neoplasms producing hCG e.g. lung - hCG stimulates the Leydig cells to excrete oestradiol⁴
  • Adrenal tumours - these can release oestrogens
  • Liver disease (cirrhosis)⁴
  • Malnourishment
  • Hyperthyroidism⁵
  • Obesity³
• Drugs:
  Drugs account for 20% of all cases in adult men:⁴
  • Oestrogen e.g. OCP, digoxin, diethylstilbestrol
  • Gonadotrophins
  • Antipsychotics (blocks dopamine - leading to increased prolactin release from the pituitary)
  • Flutamide - blocks androgen receptors²
  • Inhibitors of testosterone e.g. finasteride, metronidazole, spironolactone, alkylating agents
  • Anabolic steroid abuse
  • Others e.g. amiodarone, isoniazid, cimetidine, methyldopa, tricyclic antidepressants, diazepam, calcium channel blockers, heroin
  • Cosmetics e.g. lavender and tea tree oil products (stops once offending cosmetic removed)¹
• Gynaecomastia of unclear cause:
  • Chronic illness
  • Refeeding after starvation²
  • HIV
  • Spinal cord injury
  • Haemodialysis induced²
• Idiopathic

Physiological

• Newborn babies can have gynaecomastia which is the result of maternal oestrogens and the gynaecomastia resolves after a few weeks.⁴
• Adolescent boys can develop gynaecomastia around puberty (average age of 14 years) and can affect one breast more than the other. It is often tender and resolves spontaneously.

Pathological

In congenital anorchia there are absent levels of testosterone with normal oestradiol 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.³

Digoxin causes gynaecomastia by virtue of an oestrogen like effect and the effect is enhanced if liver derangement is coexistent. Other drugs interfere with testosterone synthesis or action e.g. spironolactone, cimetidine and alkylating agents.

Other more rare causes of male breast enlargement includes metastases from lung or liver, haematological malignancies e.g. lymphoma, haemangiomas and hamartomas.

The exact mechanism by which anti-retrovirals 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 e.g. lymphoma.

Thorough history

• Commonly gynaecomastia is asymptomatic
• Onset and duration of breast enlargement
• Tenderness
• Presence of sexual dysfunction
• Drug history
• Any use of drugs of abuse e.g. alcohol, heroin and marijuana (controversial as a cause of gynaecomastia)⁶

Examination

• Is it true enlargement of breast tissue?
• Enlargement of breast tissue may represent adipose tissue (pseudogynaecomastia) or true proliferation of breast tissue.² 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 e.g. palmar erythema, bruising, spider naevi, hepatomegaly.
• Evidence to suggest lack of testosterone e.g. hairless, shiny skin, testicular size, testicular masses, tenor of voice.
• Presence or absence of sexual characteristics.
• Signs of hyperthyroidism or Cushing's disease.

These should be performed on a clinical basis i.e.according to the history and examination e.g. 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)⁴
• Oestradiol
• hCG level
• LH & FSH⁴
  • 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 normal⁴
• Testosterone & oestradiol levels
• Ultrasonography or mammography of breasts
• Ultrasonography of testes
• CXR if suspect a lung lesion
• Chromosomal karyotyping may need to be considered
• Biopsy will provide a definitive diagnosis e.g. proliferation of ductules and loose connective tissue confirm gynaecomastia

An underlying cause is found in less than 50 % of patients.

Gynaecomastia and male breast cancer¹

See full article on 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 - but it can occur at any age.
• Increased risk in Klinefelter's syndrome (as mentioned above) and treatment with oestrogens.
• Levels are also increased with a positive family history and breast cancer risk genes e.g. BRCA1 and BRCA2.
• Red flags which increase suspicion of breast cancer in men:⁷
  • Unilateral enlargement
  • Hard or irregular breast tissue
  • Rapidly enlarging
  • Recent onset
  • Fixed mass
  • Nipple or skin abnormalities
  • Painful
  • >5cm
  • Axillary lymphadenopathy

In these cases breast imaging with FNA or biopsy may be required. Refer to local one stop breast clinic if any doubt or suspicion of a sinister cause.

• Refer any man with red flag symptoms as mentioned above. Also refer if underlying cause is unclear and /or gynaecomastia is causing significant distress to the patient.
• Treat the underlying cause if found e.g. androgen replacement in testicular failure or removal of the offending drug.
• If no underlying cause discovered or gynaecomastia long-standing 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.^8,9 Prophylactic breast irradiation prior to starting treatment with diethylstilboestrol or oestrogens has been used with good results.¹⁰ A randomised controlled trial showed that tamoxifen is superior to radiotherapy in patients with prostatic carcinoma on bicalutamide.¹¹
• Other treatments that have been used include clomiphene, androgens, danazol and aromatase inhibitors.²

• 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.³ However, further studies are required and it is not licensed for this use.
• Clomiphene has been used in adolescent gynaecomastia and results in patients appear to be disappointing - although the number of patients in the studies are small.¹² 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 on flutamide and finasteride - the benefit was related to reduced breast tenderness rather than reduction in breast tissue.¹³

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.