Gynecomastia is defined as enlargement of the glandular tissue in the male breast. It is often found incidentally and ignored. In contrast, symptomatic gynecomastia is less common. The lesion is usually bilateral, but may present with unilateral mass, which is firm, mobile and disc-like, centrally located under the nipple-areola complex . On palpation it is painful and tender. The pathologic findings of gynecomastia include hyperplasia of ductal epithelium, inflammatory cells infiltration of the periductal stroma and increased alveolar fat . The pathophysiological process of gynecomastia includes imbalance between free estrogen and androgens acting in the breast tissue. This imbalance may occur through multiple mechanisms. Elevation of serum estrogen may result from estrogen secreting tumor, such as testicular or adrenocortical tumors. It may also be caused by an increased extra-gonadal conversion of androgen to estrogen by tissue aromatase . Imbalance between testosterone and estrogen is caused by some kinds of sex hormone-binding globulin, which may be present in hyperthyroidism, chronic liver diseases and the use of medications, such as spironolactone. Spironolactone can block androgen production, block androgens from binding to their receptors, and increase both total and free estrogen levels [8, 9]. During the course of imatinib mesylate treatment, there were three GIST patients who had received low dose spironolactone (20 mg daily) occasionally. However, gynecomastia did not occur in these three patients.
Gambacorti-Passerini et al measured hormone concentration in 38 men receiving imatinib for chronic leukemia at baseline and during treatment. Seven cases of gynecomastia were noted (18%) . The incidence of gynecomastia is about 10% in our cohort patitents, which seems higher than we expected in clinical practice. The first reason we speculated may be that the patient felt shy and was reluctant to report his discomfort to physician. The second reason may be that the physicians apt to ignore this abnormality during regular physic examination On the contrary, we surgeons may be more sensitive to the changes of surgical condition.
Receptor tyrosine kinases c-Kit and platelet-derived growth-factor receptors alpha (PDGFRa) are expressed in the testis. They are believed to be involved in the bio-synthetic process of testosterone. Imatinib mesylate inhibits both c-Kit and PDGFRa and thus the production of testosterone may be decreased during its administration. Second-generation TKIs, such dasatinib and nilotinib, are multi-target inhibitor, including receptor tyrosine kinases c-Kit and PDGFRa. In fact, dasatinib exerts a more potent inhibitory action on c-Kit and PDGFRa . Caocci et al reported a male patient suffered gynecomastia after treatment with dasatinib for CML .
In comparison of hormone concentration before and during imatinib treatment Gambacorti-Passerini et al found that patients who developed gynecomastia had more reduction in free testosterone concentration than those who did not . Kim et al reported a patient who developed gynecomastia when treated with imatinib for GIST and demonstrated a lower serum concentration of testosterone and decreased libido. The patient concurrently had hydrocele of the testis which was improved when imatinib was discontinued, but the lesion recurred when the treatment was restarted. The authors concluded that inhibition of c-Kit and PDGFRa is the cause of the lesions described . Animal studies demonstrated that PDGF signaling may constitute a common mechanism in the control of multiple steroidogenic lineages, and the c-Kit gene plays a fundamental role during the establishment, the maintenance and the function of germ cells [11–13].
In this study we did not find a decrease in free testosterone level in our patients with gynecomastia. There was no significant difference of free testosterone level in patients with or without gynecomastia who were taking regular dose (400 mg daily) of imatinib. In addition, our patients with gynecomastia do not have changes in their sexual behavior except one who was 76 years old with decreased libido. The factor of aging cannot be ruled out in this case. The increase in estrogen levels in half of our patients seems to suggest that an imbalance of sex-hormones may be the cause of gynecomastia development.
Generally there are three options for the treatment of gynecomastia, including radiation, surgery and medical therapy. Medicines including androgens, antiestrogens, aromatase inhibitors, danazol have been used to treat gynecomastia . Our patients with gynecomastia had a good response to tamoxifene administration. Since imatinib metabolized in vivo mainly through CYP3A4, and tamoxifene is a substrate of CYP3A4. Their concomitant use may enhance the effect of tamoxifene .