Gynaecomastia

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

Gynaecomastia is enlargement of the male 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 to the latter¹.

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 years¹.

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 tissue². 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 oestradiol.¹
  • Hermaphroditism.
  • Neoplasms producing hCG e.g. lung - hCG stimulates the Leydig cells to excrete oestradiol.³
  • Adrenal tumours - these can release oestrogens.
  • Liver disease (cirrhosis).³
  • Malnourishment.
  • Hyperthyroidism.⁴
  • Obesity.²
• Drugs
  Drugs account for 20% of all cases in adult men:³.
  • Oestrogen e.g. OCP, digoxin, diethylstilbestrol.
  • Gonadotrophins.
  • Antipsychotics (blocks dopamine - leading to increased prolactin release from the pituitary).
  • Flutamide - blocks androgen receptors.¹
  • 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.
• Gynaecomastia of unclear cause:
  • Chronic illness.
  • Refeeding after starvation.¹
  • HIV.
  • Spinal cord injury.
  • Haemodialysis induced.¹
• Idiopathic.

Physiological

Newborn babies can have gynaecomastia which is the result of maternal oestrogens and the gynaecomastia resolves after a few weeks³.
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 gynaecomastia².
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.

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).

Examination:

• Is it true enlargement of breast tissue?

Enlargement of breast tissue may represent adipose tissue (pseudogynaecomastia) or true proliferation of breast tissue¹. 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 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).³
• Oestradiol.
• hCG level.
• LH & FSH.³
  • 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.³
• Testosterone & oestradiol levels.
• Ultrasonography or mammography of breasts.
• Ultrasonography of testes.
• CXR if suspect a lung lesion.
• Chromosomal karyotyping may need to be considered.

Investigate further if rapidly enlarging, recent onset, painful, >5cm, hard or irregular breast tissue as there may be an underlying breast neoplasm.
In these cases breast imaging with FNA or biopsy may be required.
An underlying cause is found in less than 50 % of patients.
Male breast cancer should always be considered and investigated⁵.

• 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 adherence⁶, ⁷. Prophylactic breast irradiation prior to starting treatment with diethylstilboestrol or oestrogens has been used with good results⁸. A randomised controlled trial showed that tamoxifen is superior to radiotherapy in patients with prostatic carcinoma on biclutamide⁹.
• Other treatments that have been used include clomiphene, androgens, danazol and aromatase inhibitors¹.

• 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 tissue². However, further studies are required.
• Clomiphene has been used in adolescent gynaecomastia and results in patients appear to be disappointing - although the number of patients in the studies are small¹⁰.
• Alternatively, tamoxifen 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 tissue¹¹.

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.