Risk of Premature Menopause After Treatment for Hodgkin's Lymphoma
Authors: R. D. Barr
Journal: JNCI Journal of the National Cancer Institute (2014)

Gonadal toxicity from chemotherapy and radiotherapy in patients with cancer is a well-recognized complication of treatment. The germinal epithelium of the testis may be more sensitive in this regard than the corresponding tissue in the ovary, reflecting the fact that continuing gametogenesis is limited to the male gonad. As a corollary, the risk of premature andropause is less than that of premature menopause because of the relative resistance of the Leydig cells in the testis to radiation and radiomimetic chemotherapy, exemplified by the use of alkylating agents such as cyclophosphamide. Consequently, while men are more likely to experience loss of fertility with the same exposure to antineoplastic therapy, women face the added burden of estrogen deprivation with its attendant morbidities. Oncofertility, a term coined less than a decade ago by Dr. Teresa Woodruff (1), has become a “hot button” issue for young people with cancer (2), but for women premature ovarian failure carries health hazards that extend beyond the end of the reproductive period (3). As a result, the findings reported by Prof. Swerdlow and colleagues in young women who were treated for Hodgkin’s lymphoma (HL) (4) are of considerable clinical relevance. Moreover, as a populationbased study to which a large number of subjects were recruited, the results have important implications for the long-term health of young adult female cancer survivors. The plot thickens for women who received treatment for HL that included radiotherapy to the chest, because they are at high risk of developing breast cancer, as has been reported by Swerdlow et al. (5). If they are also menopausal, they will not be able to take estrogen-containing hormone replacement therapy when they have estrogen-receptor positive tumors. Reports from the Childhood Cancer Survivor Study provide useful additional context. Acute ovarian failure (AOF), defined as loss of ovarian function within five years of diagnosis, occurred in 6% of subjects (6). However, those with HL experienced AOF twice as frequently (12%) and accounted for almost one third of the total. Premature menopause, defined as cessation of menses before the age of 40, occurred in 4% of subjects with a cumulative incidence of 15% (7). In almost half of them, this was induced surgically. Among the remaining subjects who underwent premature menopause, more than 50% had been treated for HL. Indeed, in a multiple Poisson regression model, HL was an independent risk factor for premature menopause—independent even of treatment variables—though residual confounding could not be excluded completely. Hodgkin’s lymphoma is a unique example of a malignant disease that is associated with a burden of gonadal dysfunction, exhibited as subfertility in both sexes, prior to the initiation of therapy. Although this is well established in men (8), the evidence in women is much more limited (9,10). In the latter, diminished ovarian reserve has been reflected in low levels of anti-Mullerian hormone in the blood (10) or assumed from histological evidence of follicular vacuolization (9). It has been hypothesized that the mechanism of subfertility, manifest before treatment in men with HL, relates to disordered cellular immunity and that this may be correctable by nongonadotoxic therapy, such as supradiaphragmatic irradiation (11), the entry criterion for the study by Swerdlow et al. (4). The mechanism for diminished ovarian reserve is less clear, but the possibility of perturbed humoral immunity has been raised (9). Do the results of the study from the UK (4) shed any light on the aforementioned hypothesis? Although the authors did not address fertility as an outcome measure, their data on ovarian function are of relevance in this regard. Of women who were treated with only supradiaphragmatic radiotherapy (n = 574), 15 (2.6%) experienced premature menopause (data provided on request by the authors). Among those who were treated with adriamycin, bleomycin, vinblastine, and dacarbazine only, in addition to supradiaphragmatic radiotherapy (n = 144), only two (1.4%) experienced premature menopause. These proportions must be compared with the figure of 1.0% in the general population (12) and suggest that women with HL who are treated during their reproductive years with relatively nongonadotoxic therapy may retain their fertility, as has