Causes of Gynecomastia

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Gynecomastia Resultant from Genetic Disorders

Several genetic disorders can be associated with gynecomastia. The familial aromatase excess syndrome is caused by overexpression of the gene coding for aromatase, leading to increased aromatization of androgens to oestrogens. Affected male patients present with precocious puberty and gynecomastia. Absent or defective androgen receptors may lead to gynecomastia. Klinefelter Syndrome (KS) is the most common chromosomal deficiency associated with hypogonadism and thus gynecomastia. KS has a 47, XXY karyotype, which is not only a risk for gynecomastia but also for male breast cancer.

Causes of Gynecomastia – Malignancy

One of the most concerning sources of excess oestrogen comes from testicular tumors These can include gonadal stromal (nongerminal) neoplasms and germinal cell tumors. Nongerminal neoplasms include Leydig’s cell (interstitial) tumors, Sertoli’s cell tumors, and granulosa-theca cell tumors. Germ cell tumors include choriocarcinoma, seminoma, teratoma, and embryonal cell carcinoma. For this reason, a testicular examination is a mandatory part of the workup for gynecomastia. Any question of a mass should prompt an ultrasound and referral for urology consultation.
Some of these tumors, however, may be non-palpable, small focal lesions within the parenchyma of the testes.

Any young patient with gynecomastia that cannot be explained, is associated with other symptoms such as loss of libido or sexual dysfunction, or is associated with abnormal endocrine laboratory studies should also undergo a testicular ultrasound and be referred for urology consultation.

Other tumors can also lead to an excess oestrogen state. Tumors of the adrenal cortex, both adenomas and adrenocortical carcinoma, have been associated with gynecomastia, but this is rare. Adrenocortical carcinoma is a concern in the patient with gynecomastia and symptoms of Cushing’s disease or other mixed syndromes, or with other signs of feminization.

Lung carcinoma can lead to an increase in plasma chorionic gonadotropin and a simultaneous escalation in oestrogen secretion. Rare cases of malignant mesothelioma, kidney cancer, or gastric cancers producing human chorionic gonadotropin (hCG) have also been reported, but again are rare. Finally, hepatocellular carcinoma can be associated with gynecomastia, the consequence of increased aromatase activity in the hepatic neoplasm.

As androgen deprivation or androgen blockade is a primary treatment of prostate cancer, gynecomastia is often a result of therapy. Treatments such as systemic estrogens, luteinizing hormone-releasing hormone (LHRH) analogues, nonsteroidal antiandrogens (flutamide, bicalutamide), and bilateral orchiectomy can all lead to
the development of gynecomastia.

Prophylactic radiation therapy has been effective in decreasing the risk of developing gynecomastia, but there is concern regarding the long-term risks. Tamoxifen has also been shown to be effective at preventing gynecomastia in men about to begin antiandrogen therapy.

Causes of Gynecomastia – Thyroid Disorders

Approximately 10% to 40% of men with thyrotoxicosis may develop gynecomastia, although the reasons are not clear. In hyperthyroid individuals, it may be direct mammotrophic effects of thyroid hormone on ductal epithelium, although many people believe it may be mediated through alterations in estrogen metabolism, specifically the increased peripheral conversion of androgens to oestrogens and increased levels of sex hormone-binding globulin (SHBG). Regardless, the gynecomastia almost always resolves once the hyperthyroidism is treated.

Causes of Gynecomastia – Liver Disease

Several chronic diseases of the liver can result in gynecomastia, although the incidence may be less than originally suspected. Gynecomastia is present in up to 40% of cirrhotic men, but may also be present in age-matched controls. However, there are some physiologic reasons for gynecomastia among cirrhotic patients.
These patients have not only a decreased production of testosterone (alcohol has a direct toxic effect on gonadal function), but also a decreased clearance of androstenedione, leaving more substrate available for aromatization.

Patients with liver disease also have an increased concentration of SHBG, resulting in an increase in protein bound testosterone and a corresponding decrease in the free, biologically active fraction of plasma testosterone.

Gynecomastia has also been documented in other chronic liver diseases such as idiopathic hemochromatosis and fatty metamorphosis of the liver.

Causes of Gynecomastia – Renal Failure

Gynecomastia can be a common result of uremia and can be seen in up to half of patients undergoing dialysis. This may be secondary to histologic damage to the testes. In addition, decreased metabolic clearance by the kidneys may result in increased levels of luteinizing hormone (LH) and subsequent increased estradiol secretion. Many of these men may be nauseated and anorexic, which improves after initiating dialysis, leading to a re-feeding syndrome.

Causes of Gynecomastia – Drugs

Several drugs can lead to the development of gynecomastia. Some of these do so because they have direct oestrogenic activity. These include not only drugs such as oestrogens, oral contraceptives, and tamoxifen, but also anabolic steroids, heroin, digitalis, and tetrahydrocannabinol, which is found in marijuana.

Other drugs inhibit testosterone or decrease its synthesis. These include drugs such as cimetidine, diazepam, flutamide, phenytoin, or spironolactone.

Several other drugs have been linked to gynecomastia, although the mechanisms are unclear. It is estimated that approximately one in four cases of gynecomastia is related to drugs.

Oestrogens can clearly lead to gynecomastia, but oestrogen is rarely taken intentionally by men (except in the case of prostate cancer treatment or among male-to-female transsexuals). However, some men may be getting unintentional exposures to oestrogens. There may be oestrogen in certain skin creams or anti-balding lotions. It can sometimes be absorbed by men after intercourse with a woman using a vaginal oestrogen cream. Oestrogen exposure may also occur at work or through the diet, although large amounts are typically needed to develop gynecomastia (except in boys and young men, in whom smaller exposures may lead to gynecomastia).

Causes of Gynecomastia – HIV-Positive Men

Gynecomastia is being increasingly seen in men with human immunodeficiency virus (HIV) disease, although the reasons are unclear and likely multifactorial. Many of the anti-retroviral medications used to treat HIV are associated with gynecomastia. Some HIV-positive men use illicit drugs (marijuana, heroin) or have concomitant liver disease. Some HIV-positive patients have hypogonadism. There may also be a re-feeding mechanism at play.

This phenomenon was first seen after World War II when men liberated from prison camps developed gynecomastia after resuming a normal diet. During starving, men may develop hypogonadotropic hypogonadism, and when these men eat normally and begin to gain weight, there is a transient imbalance of oestrogens to androgens. This can also be seen in refugees, in impoverished individuals, or after dieting.