Introduction

Gynecomastia, referred to enlargement of the male breast tissue (Figure 1), it is a common finding in childhood reported to be between 30 and 60%. Although, most cases are benign and self-limited, it may be a sign of an underlying systemic disease or drug-induced. It is usually bilateral but sometimes unilateral, and results from proliferation of the glandular component of the breast. It is defined clinically by the presence of a rubbery or firm mass extending con-centrically from the nipple. Gynecomastia should be differentiated from peusogynecomastia (lipomastia), which is characterized by desposition of fat without, glandular proliferation [1-6].

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   Figure 1:

   A 15 year old boy with gynecomastia.
   
   
   

In this brief review we highlight the pathophysiology, etiology, diagnosis and discuss the various modalities of therapy (medical and surgical).

Pathophysiology

The mechanism and pathophysiology of gynecomastia are not really clear (Figure 2). However, the major cause in believed to be an altered imbalance between estrogen and androgen effects, absolute increase in estrogen effects either an increase in estrogen production, relative decrease in androgen production, or a combination of both. Estrogen acts as a growth hormone of the breast and, therefore, excess of estradiol in men leads to breast enlargement by inducing ductal epithelial hyperplasia, dual elongation and branching, and the proliferation of periductal fibroblasts and vascularity. Local tissue factors in the breast can also be important, for example, increased aromatic activity that can cause excessive local production of estrogen, decreased estrogen degradation and changes in the levels or activity of estrogen, and androgen receptors.

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   Figure 2:

   Pathophysiological mechanisms leading to gynecomastia.
   
   
   

Although prolactin (PRL) receptors are present in male breast tissue, hyperprolacticemia may lead to gynecomastia through effects on the hypothalamia causing central hypogonadism. Activation of PRL, also, leads to decreased androgens and increased estrogen and progesterone receptors. The role of PRL, progesterone and other growth factors such as insulin like growth factors (IGF-1) and epidermal growth factor (EGF), in the development of gynecomastia need to be clarified [5-10].

Classification

The spectrum of gynecomastia severity has been categorized into a grading system [11]:

Grade I Minor enlargement, no skin excess

Grade II Moderate enlargement, no skin excess

Grade III Moderate enlargement, skin excess

Grade IV Marked enlargement, skin excess

Etiology of gynemastia

Generally can be subdivided, according to the cause, into; (Table 1) [12-24].

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   Table 1:

   Gynecomastia related conditions.
   
   

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   Table 1: Gynecomastia related conditions.

   Physiological

   Neonatal

   Pubertal

   Involutional

   Pathological

   Cirrhosis/liver disease

   Starvation

   Male hypogonadism (Primary or secondary)

   Testicular neoplasms (germ cell tumours, leydig cell tumours, sex-cord tumours)

   Hyperthyroidism

   Renal failure and dialysis

   Feminizing adrenocortical tumours

   Ectopic HCG production

   True hermaphroditism

   Androgen insensitivity syndromes

   Aromatase excess syndrome

   Stressfull life events

   Type 1 DM

   Kennedy's syndrome

   Drugs

   Idiopathic

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Pathological: Gynecomastia can occur at any age, as a result of a number of medical conditions such as liver cirhossis primary hypogonadism and trauma.

Medicational: Medication induced gynecomastia is the most common cause. Agents associated with gynecomastia are listed in Table 2.

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   Table 2:

   Drug related gynecomastia.
   
   

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   Table 2: Drug related gynecomastia.

   Drug

   Estrogens, including topical preperations

   Aromatisable androgens

   hCG

   Digitoxin, herbal products

   GnRH agonistor antagonist

   Leydig cell damage or inhibition

   Ketoconazole, Metronidazole

   Spironolactone, cancer chemotherapy

   Finasteride or dutasteride

   Flutamide, bicalutamide

   Spironolactone, cancer chemotherapy

   Cimetidine, Marijuana

   Antipsychotic Agents

   Metoclopramide, Verapamil

   Isoniazid, Amiodarone, Antidepressants

   Human GH, Proton pump inhibitors

   Highly active retroviral therapy

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Diagnosis of Gynecomastia

The history and physical examination should direct the laboratory and radiological imaging studies (Figure 3).

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   Figure 3:

   Algorithm for the diagnosis of gynecomastia.
   
   
   

Clinical Evaluation: (History and physical examinations)

All boys with gynecomastia should be evaluated thoroughly by an experienced clinician. A detailed history should include the onset and duration of the breast enlargement, pain or tenderness, weight loss or gain, nipple discharge, virilization, medication history, and family history of gynecomastia which may suggest androgen insensitivity syndrome, familial aromatase excess or sestoli cell tumours. Physical examination should differentiate between true gynecomastia and pseudogynecomastia and should include signs of tomours, liver and kidney diseases, or hyperthyroidism and should also include genital examination [5,6,25-31].

Diagnostic testing

In cases without a clear cause, laboratory investigations should be pursued and must include liver, kidney and thyroid function tests as well as hormonal tests, estrogen, and free testosterone, luteinizing hormone (LH) , follicle-stimulating hormone (FSH), prolactin, human chorlonic gonadtrophin (HCG), dehydro epiandrosterone sulphate (DHEA-SO4) and α Feto protein (α FP). If testes are small the patients Karyotype should be obtained to roll out Klinefelter’s Syndrome. Mammography (MMG) is the primary imaging when there is any suspicion of malignancy. Breast ultrasonography (USG), scrotal USG and abdominal computerized tomography (CT) of the abdomen can also be used as well as magnetic resonance imaging of the pituitary. A percutaneous biopsy should be taken, at times, when it is difficult to differentiate gynecomastia and breast cancer [5,6,32-36].

Treatment of gynecomastia

Most cases of gynecomastia regress overtime without treatment. However, if gynecomastia is caused by an underlying conditions such hypogonadism, malnutrition or Cirrhosis, that condition may need treatment. If the patient taking medications that can cause gynecomastia, the clinician may recommend stopping or substituting them with other medication. In adolescents with no apparent cause, gynecomastia often goes away without treatment in less than 2 years. Reassurance and frequent follow up 3-6 months that’s what needed. However, treatment may be necessary if gynecomastia does not improve on its own or if it causes significant pain tenderness or embarrassment [1,6,37].

Medical treatment

Although no medical treatment cause complete regression of gynecomastia, they may provide partial regression, or symptomatic relief. Several agents regulate the hormonal imbalance. The major medical intervention options are androgens, anti-estrogens and aromatase inhibitors. Androgen testosterone replacement can be used to improve gynecomastia secondary to hypogonadism. Topical preparations are preferable as they lead to more steady state levels of testosterone in the body as compared with the injectable forms, which can worsen breast enlargement by aromatizing to estardiol. In recent years, anti-estrogens such as tamoxifen and anastrozole has been shown to be effective. More studies are needed to assess the effectiveness of aromatose inhibitors such as anastrozle and testalactone, which are powerful agents that block estrogen [32,38-43].

Surgical treatment

Surgical treatment should be individualized to each patient. Numerous techniques have been described for the correction of gynecomastia and the surgery is forced with a wide range of excisional and liposuction procedures. The most frequently encountered complication was a residual subareolar lump. Although skin excess remains a challenge, it can be satisfactorily managed without excessive scarring. A practical approach to the surgical management of gynecomastia, should take into account breast size, consistency, skin excess and skin quality. However generally it is not recommended until the testis has reached adult size, because if surgery is performed before achieving puberty, breast tissue may regrow [44-47].

If pseudogynecomastia is suspected no work up is needed and the patient can be reassured that weight loss will lead to resolution of pseudogynecomastia. If necessary liposuction procedures can reduce breast enlargement secondary to subareolar fat accumulation.

Acknowledgement

The author would like to thank Ms. Cecile Sael for typing the manuscript, and extend his thanks and appreciation to Miss Hadeel N. Al Jurayyan for her help in preparing this manuscript.