Malignant Melanoma: It Pays to Be a Woman

Jacob Mashiah, MD, Sarah Brenner, MD

Disclosures

Skinmed. 2003;2(3) 

In This Article

Do Sex Hormones Play a Role in Melanoma?

The gender differences in melanoma demand an investigation of the effect of sex hormones on this malignancy. Sex hormones bind to the classical type I estrogen receptor, then translocate to the nucleus and bind to DNA. Breast and prostate tumors are affected by endocrine therapy through type I estrogen receptors found on the tumor cells. When several studies were reviewed for the presence of such receptors in melanoma cells,[11] estrogen receptors were found in some of the biochemical and histochemical tests, but not in the immunohistochemical tests using monoclonal antibodies. One study[12] utilizing all three methods detected estrogen receptors only with the biochemical method. These findings could be considered false positive results and attributed to binding of the hormone to a protein other than the type I estrogen receptor, binding of the hormone to nonmelanoma cells,[13] detection of binding to type II cytoplasmic and type III cell membrane estrogen receptors, or the existence of a new and antigenically different estrogen receptor that cannot be detected by the specific monoclonal antibody. Such a change in the receptor region would, however, result in a diminished response to the estrogens.[11,12,14] Apparently estrogen receptors do exist on melanoma cells, albeit low-affinity receptors and not the type I high-affinity receptors.

In view of the efficacy of the antiestrogenic drug tamoxifen in patients with estrogen receptor-positive breast cancer, many attempts have been made to achieve the same benefit in melanoma patients. Tamoxifen was evaluated as a single agent in 12 studies covering 213 patients with metastatic melanoma[15]; the response rate was only 7%. The combination of tamoxifen with other drugs such as dacarbazine, carmustine, and cisplatin produced a synergistic effect.[16] The synergistic effect was confirmed in a randomized trial[17] comparing tamoxifen and dacarbazine vs. dacarbazine alone. The response rates were 28% and 12%, and the survival was 48 weeks and 29 weeks, respectively. It is notable that the improvement of the response and survival in the combination therapy group was seen mainly in women, with response rates in women and men of 38% vs. 19% and survival of 69 weeks vs. 31 weeks, respectively. Another interesting finding in this study[17] was longer survival for men with higher basal metabolic index: 43 weeks vs. 24 weeks for low basal metabolic index. Obese men have a high estrogen/dihydrotestosterone ratio, possibly ameliorating their prognosis as it does for women.

It has been suggested that tamoxifen -- rather than act through classical estrogen receptors -- may inactivate the insulin-like growth factor I receptor, an important plasma membrane receptor of melanoma cells.[18] Others[19] suggest that melanoma-derived growth factors may act on stromal cells that are adjacent to the tumor: lymphocytes, fibroblasts, and macrophages. In turn, these cells exert their activity of regulating tumor growth, adhesion, angiogenesis, motility, and metastasis.[19] The autocrine and paracrine production of angiogenic factors, expression of adhesion molecules, activity of proteolytic enzymes, and host immune responses to melanoma may all be altered by the sex hormones via transcriptional repression on the interleuken-8 promoter.[19] Additionally, it is claimed that tamoxifen and quercetin are capable of inhibiting melanoma cell growth by inter-acting with type II estrogen-binding sites situated on melanoma cells.[20] Tamoxifen clearly possesses some antineoplastic, as well as definite antiestrogenic, properties that it exerts through pathways other than the antiestrogenic activity via type I estrogen receptors.

Oral contraception, pregnancy, and hormone replacement therapy change the hormonal balance. There are several controlled studies on the prognosis of melanoma diagnosed during pregnancy. Several of them[21,22,23,24,25] reported no statistically significant differences in survival rates between controls (nonpregnant women with malignant melanoma) and women diagnosed with melanoma state I or stage II during pregnancy. Some authors[21,24,25] found that the study group had tumors of greater thickness, while another[22] found no significant difference in this parameter. A shorter disease-free interval in the study group was reported in only two studies.[21,24]

The literature varies on whether prior or subsequent pregnancy affects the prognosis and like-lihood of developing melanoma. Excluding a more favorable prognosis in the case of more than five prior pregnancies, one study[26] demonstrated that prior pregnancy had no effect on prognosis. Others[27,28] found that a single preg-nancy increased the risk for melanoma, but multiparity was associated with decreased risk. Altered susceptibility to cancer due to exposure to fetal antigen might account for the decreased risk. Pregnant women have antibodies to fetal antigens on melanoma cells because melanoma antigens cross-react with fetal antigens produced by malignant cells.[29] Previous investigators[21,25] failed to find any effect of subsequent pregnancy on the prognosis of melanoma with regard to survival and disease-free interval.

According to the data published on pregnancy and melanoma, pregnancy appears to have no significant effect on the survival of melanoma patients. The greater tumor thickness reported in some studies might stem from the delay in diagnosis due to misinterpretation of the first signs of melanoma as pregnancy-related physiologic changes. Circulating growth factors in pregnancy have been suggested as a cause of excessive selective growth of melanoma.[30] Larger cohorts and longer follow-up periods may yield different results regarding disease-free interval.

The possible effect of oral contraceptives on melanoma has been studied extensively. An increased risk for melanoma was linked to oral contraceptives,[31] but the results of this work are limited by small sample and control group sizes. Women using oral contraceptives for more than 5 years showed increased risk for melanoma, but the findings were not statistically significant.[32,33] Most other studies found no association between melanoma and oral contraceptives. Some argued that if an increased risk for melanoma existed among oral contraceptive users, it should have been noticed as an increased incidence of melanoma among women of childbearing age after the introduction of oral contraceptives.[34] Instead, the rates of melanoma for women and men were unchanged in the 10 years before and the 10 years after the introduction of oral contraceptives. More recent meta-analyses[35,36] found no evidence of an etiologic role of oral contraceptives in the development of melanoma.

Data on the relationship between melanoma and hormone replacement therapy is meager. Only one study[37] showed an increased risk for melanoma in those on hormone replacement therapy, while no other studies[38,39,40] reported such an increased risk. In light of the studies performed to date, it seems that exogenous hormones do not influence the risk for malignant melanoma.

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