DEFINITION:

  • Enlargement of male breast due to hyperplasia of glandular breast tissue (beyond a diameter of 2cm)
  • Literally “woman-breast” via the greek roots “gyné” for female/woman and “mastós” for “breast”

EPIDEMIOLOGY

  • Common condition
  • Affects:
    •  65-90% of neonates
    • ~50-60% of pubertal males
    • ~30% of males under 30 years and up to 50% of those over 45 years of age.

 

AETIOLOGY AND PATHOPHYSIOLOGY

In a nutshell, oestrogens stimulate glandular breast tissue to grow, whilst androgens inhibit growth. Hence, gynaecomastia results from an increase in oestrogen: androgen ratio, where oestrogen’s effects on breast tissue will be only partially opposed. This hormonal imbalance may result from:

1) Reduced androgen levels, due to:

a. Inhibition of testosterone synthesis

b. Increase in SHBG (sex-hormone binding globulin)  concentration

c. High prolactin (PRL) levels

2) Inhibition of/ reduced testosterone action in the breast region

3) Increase in oestrogen levels due to:

 a. High androgen levels, resulting in high oestrogen levels

b. Increase in aromatase action in peripheral tissues or in breast area ( due to mutations/ high body fat)

c. Exogenous oestrogen administration

d. Testicular malignancy

4)  Increased action of oestrogen in the breast region

 a. Increased sensitivity of  breast tissue to oestrogens [ as in familial/idiopathic gynaecomastia]

5)      Several of the above.

 

 

Fig 1

A quick note about aromatase and SHBG

  • Aromatase –member of the cytochrome p450 enzymes, it is found in various tissues but is especially abundant in adipose tissue. Aromatase converts testosterone and androstenedione to oestradiol and oestrone repectively, hence increasing oestrogen levels. Its action can be increased as a result of mutations, or an increase in its concentration: as in the overweight individual with high body fat. It is thought to be one of the causes behind pubertal, physiological gynaecomastia.
  • SHBG: Sex hormone binding globulin is a plasma protein to which ~50% of all circulating testosterone is bound. Only free testosterone is active, so an increase in SHBG will bind more testosterone, causing a drop in free testosterone and hence active androgen levels. SHBG’s higher affinity for androgens than oestrogens also contributes to an increased oestrogen: androgen ratio.
Fig 2

NOTE: It is important to differentiate gynaecomastia from pseudogynaecomastia/lipomastia (“fatty breasts”: male breast enlargement due to deposition of excess adipose tissue rather than glandular hyperplasia in overweight/ obese patients). See later for clinical differentiation).

 

 

Physiological causes of gynaecomastia:

1) Neonatal gynaecomastia: in 65-90% of neonates due to exposure to maternal oestrogen and progesterone in the womb; resolves within several months

2) Pubertal gynaecomastia: in ~60% of pubertal males.  Resolves within 2 years. Proposed mechanisms:

a. Increased aromatase activity

b. Reduced secretion of testosterone in the day time allows for oestrogen: androgen imbalance

3) Ageing: due to accumulation of adipose tissue and progressive testicular dysfunction with low serum testosterone.

 

Illnesses associated with gynaecomastia:

1)  Low androgen levels

  • Hypogonadism
    • Primary – defect inherent within the gonad
      • Klinefelter syndrome (XXY)
      • Viral orchitis
      • Trauma
    • Secondary (hypogonadotropic hypogonadism)- defect lies outside the gonad (e.g. the pituitary)
      • Kallmann syndrome
      • Haemochromatosis
  • Hyperprolactinaemia => high PRL suppresses GnRH production, reducing LH production = reduction in testosterone production by Leydig cells.
  • Renal failure
  • Androgen insensitivity syndrome => unopposed oestrogen action on the breast glandular tissue.
  • Congenital absence of testes
  • True hermaphrodism.

2) High androgen and high oestrogen levels

  • Testicular germ cell or Leydig cell tumour cause direct secretion of excess oestrogens.
  • hCG-secreting tumour => since similar in structure to LH, can cause excess leydig cell stimulation; tumours may also convert oestrogen precursors to oestradiol
  • congenital adrenal hyperplasia
  • testicular feminisation

3) High oestrogen levels

  • Abnormal aromatase action (mutation/ obesity)
  • Feminising adrenal carcinoma
  • Sertoli cell tumour
  • Refeeding after starvation => malnutrition/ chronic illness causes a reduction in gonadotropin secretion; during the recovery period, gonadotropin levels rise and may result in excessive Leydig cell production of oestrogens.

4) High SHBG levels (leading to low levels of free testosterone in circulation)

  • Hyperthyroidism (10-40% of pts), increases SHBG levels + aromatase activity
  • Hepatic cirrhosis è increases SHBG levels.

5) Other/Multifactorial

  • Hepatic cirrhosis => Alcohol-induced inhibition of hypotahalamic-pituitary-testicular axis = low testosterone levels in addition to raising SHBG
  • Renal failure => low serum testoerone, raised oestradiol, LH and prolactin

6) Idiopathic (25% of cases)

Drugs associated with gynaecomastia

7) Drug-induced gynaecomastia (~20% of cases):

  • Antibiotics:
    • Isoniazid
    • Ketoconazole => inhibition of testosterone synthesis
    • Metronidazole=> inhibiton of testosterone synthesis
  • Anti-androgens/ inhibitors of androgen synthesis:
    • Cyproterone
    • Flutamide
  • Hormones
    • Androgens and anabolic steroids
    • hCG => stimulation of Leydig cell oestrogen secretion
    • Oestrogens/oestrogen agonists
    • Growth hormone
  • Proton-pump inhibitors/ H2-receptor antagonists:
    • Omeprazole
    • Cimetidine => androgen receptor antagonist
    • Ranitide
  • Chemotherapeutic agents (esp alkylating agents) => Leydig cell damage resulting in primary hypogonadism
  • Cardiovascular drugs:
    • Spironolactone => via antagonism of androgen receptors + inhibition of testosterone synthesis at high levels;
    • Verapamil
    • Methyldopa
    • Captopril
    • Reserpine
  • Psychoactive agents
    • Diazepam
    • Haloperidol
    • Phenothiazines => increased serum prolactin
    • TCAs
  • Drugs of abuse
    • Alcohol
    • Amphetamines
    • Heroin
    • Marijuana => androgen receptor antagonism
  • Other:
    • Phenytoin
    • Penicillamine

INVESTIGATIONS

  • Exclude physiological/drug-induced gynaecomastia
  • LFTs and renal tests
  • If normal, test for: serum hCG, LH, testosterones and oestradiol levels should be measured

 

Fig 3

CLINICAL FEATURES

  • Commonly bilateral and symmetric
    • But may be unilateral (usually on left side) and asymmetric
  • Classically, palpable, ridged “button” of firm, sub-areolar tissue felt on examination.
  • Often asymptomatic
  • May be accompanied with nipple/breast tenderness (~40%) , but usually resolves within ~1 year.
  • Nipple discharge (4% of pts)
  • Signs and symptoms affected with underlying cause, if any.

 

CLINICAL EXAMINATION

  • Perform thorough breast examination
  • Look for breast skin/nipple changes and axillary lymphadenopathy (red flags, see later)
  • To differentiate between pseudogynecomastia and true gynaecomastia:
    • Place patient supine with hands behind head
    • For each breast: place one thumb on either side of the tissue
    • Slowly bring thumbs together
    • If patient has gynaecomastia, a concentric ridge of glandular tissue can be felt, symmetrical to the areola and nipple
    • In patients with pseudogynaecomastia, however, no ridge is felt
  • It is also important to examine the testicles for masses, size and consistency:
    • testicular tumours may first manifest as  gynaecomastia
      • testicular masses/asymmetric testes may be noted
    • Bilaterally small testes may be due to testicular failure (secondary to anabolic steroid abuse / testicular torsion/ trauma/ orchitis/ haemochromatosis/congenital abnormalities e.g. Klinefelter’s etc.)
  • Look out for any signs of feminization, thyrotoxicosis, liver or kidney failure etc. as clues to underlying causes

 

RED FLAGS FOR POSSIBLE BREAST CARCINOMA:

  • Unilateral distribution
  • Axillary lymphadenopathy
  • Recent onset
  • Hard breast tissue
  • Fixed, immobile breast  mass
  • Dimpling/ulceration of breast skin
  • Nipple discharge
  • Pain (late symptom of breast cancer)
  • Enlargmenet beyond 5 cm diameter

Fine needle aspiration or biopsy may be required for further investigations. Refer to “one-stop breast clinic” if cancer is suspected.

 

DIFFERENTIAL DIAGNOSIS

  • Lipoma
  • Neurofibroma
  • Breast carcinoma: these present with painless, unilateral and eccentric breast enlargement, whereas gynaecomastia classically presents in the subareolar regions and enlargement is concentric.
    • Breast carcinoma patients may also present with ulceration, dimpling or ‘fixing’ of breast tissue + nipple abnormalities.
    • See above “red flag” symptoms/signs

Other possibilities:

  • Dermoid cyst
  • Lymphangioma
  • Haemaoma
  • Metastases from neuroblastoma/ lymphocytic leukaemia/ lymphoma/rhabdomyosarcoma

 

PROGNOSIS

  • Neonatal/ pubertal gynaecomastia usually regress within a few months/two years respectively.
  • Cosmetic appearance can be source of great psychological distress.
  • Some studies have shown that gynaecomastia sufferers have a 5 fold increased chance of developing breast cancer (this is increased to 58 fold if they have Klinfelter’s syndrome).

 

TREATMENT

Many choose not to treat gynaecomastia - especially if it is physiological( and hence almost always transient), painless or mild.  However, for those concerned with the cosmetic appearance of the condition, and for those in whom an underlying cause is identified, the following options are possible:

[NOTE: Chronic gynaecomastia will often revert to a fibrotic state which is irreversible and can only be “repaired” surgically].

Medical Tx:

  • Correct underlying disease (if possible)
  • Withdrawal and replacement of offending drugs
    • E.g. Replace spironolactone with eplerenone
  • In some patients, aromatase inhibitors (e.g. Letrozole or testolactone) and oestrogen antagonists (e.g. tamoxifen or clomiphene) may reduce/reverse the gynaecomastia and relieve associated discomfort

Surgical Tx:

  • Reduction mammoplasty/ Liposuction/ Gland excision/ ”Skin sculpture”
    • May be used in patients with chronic and irreversible (fibrotic) gynaecomastia that can’t be cured otherwise.

    Radiologic Tx (ONLY FOR PATIENTS WITH PROSTATE CARCINOMA, PRIOR TO RECEIVEING OESTROGEN THERAPY):

    • Low-dose radiation therapy to the breasts may prevent or reduce gynaecomastia associated with oestrogen therapy given to prostatic carcinoma patients

    NOTE: No other patients should receive this therapy!!!

       

      REFERENCES

      1)     Bembo S, Carlson H (2004) Gynaecomastia: Its features, and when and how to treat it. Cleveland Clinic Journal of Medicine 71: 511-517.  

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

      3)     Singer-Granick C, Granick M (2009) Gynecomastia: What the Surgeon Needs to Know, [online] Available at:http://www.medscape.com/viewarticle/711880>         [Accessed 22 April 2011]. 

      4)     Greenspan F, Gardner D (2004) Lange Basic and Clnical Endocrinology. 7th ed. San Francisco: Appleton and Lange.

      5)     Turner H, Wass J (2002) Oxford handbook of Endocrinology. 1st ed. Oxford University Press.

      6)     http://bestpractice.bmj.com/best-practice/monograph/869/diagnosis/step-by-step.html 

      8)     Braunstein, G (2001) Epidemiology and pathogenesis of gynecomastia, [online] Available at: <http://www.uptodate.com/contents/epidemiology- and-pathogenesis- of-gynecomastia> [Accessed 28 April 2011]

      Fig 1 adapted from a figure in reference 2

      Fig 3 adapted from a flowchart in reference 4

       

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