Benign proliferation of glandular tissue in the male breast is a common disorder. Approximately one third of normal adult men are affected, most often after 50 years of age . Some pathologic cases of breast enlargement are the result of renal , hepatic, nutritional, or endocrine dysfuction, and several drugs have also been implicated in the origin of gynecomastia . Methotrexate (MTX) is the disease modifying antirheumatic drug, most frequently used for rheumatoid arthritis (RA) and psoriatic arthritis.
Although MTX is generally well tolerated, it has some side effects; mainly on the central nervous system, liver, blood, and lungs. Several cases of sexual dysfunction (diminished libido, sexual impotence)  and gynecomastia  in men with RA receiving MTX treatment have been reported. Fibroadenoma is extremely rare in the male breast. It is explicable considering the absence of lobules in the normal male breast. A variety of drugs, including MTX, can, at levels or durations beyond that required for the development of gynecomastia, induce formation of lobules in the male breast.
These drugs may, therefore, predispose to the development of fibroadenoma. We recently observed one patient who was RA treated with low dose methotrexate (MTX) and who developed fibroadenoma in gynecomastia. There was no cause other than MTX found, despite extensive investigation. To our knowledge, there are no previous report of fibroadenoma in gynecomastia following low dose MTX therapy for RA. Case Report A 48-year-old man, with a 4-year history of seropositive RA, was treated with sodium aurothiomalate (GSTM) for only 3 months because of cutaneous intolerance.
Dpenicillamine was tried but discontinued a few months later because of poor efficacy. Oral MTX, 10 mg weekly, was then started. Six months later he complained of tenderness in the left breast. Concentric enlargement of both breasts and approximately 1cm sized movable nodule was found in the left upper outer portion of breast on physical examination. On the breast sonogram, there was high echoic breast parenchyma in both subareolar areas that characterized gynecomastia. About 0. 81×0. 49cm sized oval shaped hypoechoic nodule was found in left 3 o’clock area (Fig. ).
Doppler study showed no evidence of increased blood flow in this nodule. The patient had a subtotal excision of the breast tissue of the left breast under general anesthesia through hemicircular para-areolar incision, and a hard tumor with a capsule was found in the left upper outer portion of breast. Fibroadenoma was diagnosed histologically and the surrounding breast tissue was consistent with gynecomastia. Discussion Fibroadenoma is the most common benign tumor of the female breast. It is second only to fibrocystic changes in its frequency.
Fibroadenoma is thought to have a lobular origin. Therefore, due to their extreme rarity in the male breast, it is understandable when considering the absence of lobules in the normal male breast. The frequency of gynecomastia in association with fibroadenoma may suggest that a stimulated, proliferative background breast serves as the milieu for their development. Gynecomastia is a common lesion in the male breast, which a benign enlargement of the breast is provoked by several factors. In a consecutive and unselected series of 100 male autopsies, gynecomastia was found in 55 cases .
The development of gynecomastia has been attributed to a relative increase in estrogenic (or estrogen-like) activity and, to a lesser extent, decreased androgenic activity. Liver disease and a variety of drugs are known to cause gynecomastia, however a majority of cases are idiopathic. Despite the frequency of gynecomastia, fibroadenoma is rare because lobular development is uncommon in gynecomastia. Possible causes of fibroadenoma in men are repeatedly a somewhat injured, chronic inflammation, hypergonadotropic hormones, adolescent mastitis, and chronic interstitial mastitis . A definite causal relationship has not been established.
Since the 1980s, MTX has been the disease-modifying antirheumatic drug most frequently used to treat RA and the polyarticular form of psoriatic arthritis. This drug acts on folate metabolism by inhibiting dihydrofolate reductase (DHFR) and other folate dependent enzymes such as thymidylate synthetase and 5-aminoimidazole-4- carboxamide-ribonucleotied transformylase (AICAR) . So, MTX depletes folate, which is required for purine and pyrimidine synthesis. Additional effects of MTX include decreasing the production of IgM rheumatoid factor and interleukin 1 (IL-1) and IL-2, and reducing polymorphonuclear chemotaxis and IL-6 activity .
MTX thus possesses immunosuppressant and anti-inflammatory properties. The mechanism of possible low dose MTX induced gynecomastia in patients with RA is not clear. Sexual dysfunction associated with treatment with low dose MTX is rarely occured. Only 13 cases of sexual impotence  and 5 of gynecomastia  related to MTX administration have been reported in recent years. The symptoms appeared 2 weeks to 4 years after the therapy with the weekly doses ranged from 5 to 20 mg. Symptoms subsided within a few weeks after withdrawal or reduction of MTX. MTX might disrupt the estrogentestosterone balance (i. . , increase estrogen activity relative to testosterone activity), which is the origin of most cases of gynecomastia .
This might result from increased aromatization of androgenic agents, enhanced synthesis of androgen carriers, or increased estrogen bioavailability resulting from removal from their carrier proteins. One other possible mechanism of action for MTX is interaction with intracellular testosterone receptors. The sexual dysfunction associated with treatment with low doses of MTX should be considered in rheumatic patients on account of its reversibility.
To our knowledge, there are no previous report of an fibroadenoma developed in gynecomastia following low dose MTX therapy for RA. There were no specific radiologic findings in fibroadenoma developing gynecomastia following low dose MTX therapy for RA. The development of fibroadenoma associated with gynecomastia may suggest that there was a stimulated, proliferative background of lobules of the breast. And MTX was thought to contribute the milieu for development of lobule and fibroadenoma in gynecomastia in our case.