Definition of Gynecomastia
Gynecomastia can be defined as the glandular enlargement of breasts in males. It is important to differentiate between breast enlargements due to fat as in obesity, and gynecomastia in which there is increased proliferation of glandular breast tissue which gives the breast a characteristic rubbery nature that is also glandular.
Epidemiology of Gynecomastia
Gynecomastia is a very common condition that has a prevalence of approximately 40% in males. Gynecomastia is common in three main age groups.
Neonates can have gynecomastia at birth which is believed to be due to elevated estrone and estradiol concentrations in fetal blood. Dehydroepiandrosterone (DHEA) and DHEA-sulfate get converted to estrone and estradiol respectively by the placenta during pregnancy. Gynecomastia in this age group is believed to be physiological and should regress by the age of 3 weeks of life.
Pubertal boys are also expected to have gynecomastia which should regress within 18 months of puberty and is not common after the age of 17 years. The third age group for gynecomastia is in the elderly. The elderlies have an increased body fat content which is responsible for converting androgens to estrogens.
Etiology of Gynecomastia
While gynecomastia can be a normal change that would regress spontaneously as is the case in neonates and pubertal boys, it can also be a pathologic consequence due to certain disease processes and factors.
Men with stromal tumors, such as Leydig or Sertoli cell tumors, with human chorionic gonadotropin tumors such as seminomas and nonseminomas, and who have adrenocortical tumors, are at the risk of developing gynecomastia. Gynecomastia develops in these patients because they have an elevated serum estrogen level.
Several drugs have been linked to the development of gynecomastia. Estrogen containing cosmetics and drugs can be expected to cause gynecomastia. Cimetidine, glutamide, metronidazole and bicalumatide can all cause gynecomastia.
Digitalis, even though not an estrogen, still has an estrogen-like effect and can cause gynecomastia. Diazepam, heroin, tricyclic antidepressants, captopril and methyldopa might cause gynecomastia by unknown mechanisms.
Liver disease is associated with increased production of androstenedione from the adrenals which is then aromatized to estrogen. This explains why patients with liver cirrhosis can also develop gynecomastia.
Male hypogonadism is associated with a decrease in testosterone levels which results in an imbalance in estrogen to androgen ratio and can lead to gynecomastia. Finally, type 1 diabetes, hyperthyroidism and renal failure have also been linked to gynecomastia.
Pathophysiology of Gynecomastia
Most of the etiologies described above for gynecomastia share a common pathophysiology in which there is an estrogen-to-androgen imbalance.
Once estrogen is increased, androgen is decreased, or androgens are increased and then aromatized to estrogen, gynecomastia might develop. The end result is excess in estrogen or increased estrogen activity or availability.
Estrogen is a potent growth hormone for the breast’s glandular tissue and its excess will lead to increased glandular tissue proliferation.
Clinical Presentation of Gynecomastia
In addition to the glandular enlargement of the breast which can be appreciated by palpation, other associated symptoms should be sought in a patient presenting with gynecomastia. For example, weight loss or gain can be related to malignancies and adrenocortical gland disorders, while nipple discharge is related to hyperprolactinemia.
Additionally, family history is important because certain conditions, such as androgen insensitivity syndrome or familial aromatase excess, are known to run in families.
Physical examination is important to differentiate between gynecomastia and possible breast tumors. Abdominal examination to look for signs of liver disease is also needed. Hyperthyroidism should be excluded by looking for tremors, thyroid gland nodules, hypertension and/or tachycardia.
Diagnostic Work-up for Gynecomastia
Laboratory investigations for gynecomastia
Laboratory investigations are of most importance when the cause of gynecomastia is not known at time of presentation. Common etiologies should be excluded by evaluating the liver, kidney and thyroid function status.
Once liver disease, kidney disease and hyperthyroidism are excluded, the next step would be to evaluate certain hormones’ levels in the blood. Estradiol, testosterone and DHEA should be checked to exclude excess estrogen or low androgen etiologies. Luteinizing hormone and follicle stimulating hormone levels should be also checked to exclude hypogonadism due to a decrease in gonadotropins. Human chorionic gonadotropins are elevated in certain tumors and should be checked.
Imaging evaluation for gynecomastia
Patients with suspicion of breast cancer should undergo a mammography. Breast ultrasonography can be used to visualize the glandular nature of the enlarged breast.
Testicular ultrasound might be indicated to exclude testicular tumors, such as seminomas or nonseminomas, which are linked to increased human chorionic gonadotropin levels.
Abdominal computed tomography scans or ultrasonography can be used to exclude liver tumors or liver cirrhosis respectively.
Histologic examination in gynecomastia
When mammography is not sufficient to exclude breast cancer as the cause of gynecomastia, breast tissue biopsy is usually indicated. Histologic examination will easily role out breast cancer, but is unlikely to confirm the diagnosis of gynecomastia because the amount of cells taken in the biopsy is usually not sufficient to diagnose gynecomastia.
Treatment of Gynecomastia
Gynecomastia should not be treated in pubertal boys or in neonates because it regresses in most cases. Patients with gynecomastia secondary to estrogen-androgen imbalance should be followed up for six months because the glandular tissue is known to be spontaneously replaced by fibrous tissue in a significant number of cases.
Specific treatment of secondary causes of gynecomastia such as liver disease, kidney disease, hyperthyroidism, testicular tumors, adrenal tumors or obesity, should be provided according to the current recommendations and guidelines and is not going to be covered in this article.
When gynecomastia is a side effect of a drug, the drug should be discontinued if possible. Patients with tumors, once they have their tumor resected, are likely to have regression in their gynecomastia. Patients with hemodialysis related gynecomastia should be reassured that the condition is very likely to regress spontaneously without any intervention. Men with hypogonadism might benefit from testosterone administration.
If gynecomastia is very symptomatic, i.e. breast tenderness with significant enlargement, medical treatment should be initiated within the first 12 months of onset. Aromatase inhibitors are very potent drugs that prevent the peripheral aromatization of testosterone to estrogen, and are known to be at least partly effective in inducing regression.
Unfortunately, aromatase inhibitors are known to have several side effects and are not well tolerated by a significant number of cases. Patients with breast tenderness might also benefit from anti-estrogens.
After one year of onset, if gynecomastia persists and is symptomatic, surgical treatment might be needed. Surgery involves removing breast glandular tissue by a subcutaneous mastectomy approach.
Several complications are associated with subcutaneous mastectomy in males which include hematoma, nipple numbness and breast asymmetry. Unfortunately, 50% of the surgical patients are not satisfied with the cosmetic results of the procedure. Because of these complications, surgery should be offered only as a last resort in patients with severely symptomatic gynecomastia that is longstanding.