Debated Role of Ovarian Protection With Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Women With Cancer.

TO THE EDITOR: In 2015, two large randomized controlled trials (RCTs) in patients with breast cancer (ie, Prevention of Early Menopause Study–Southwest Oncology Group [POEMS-SWOG] S0230 and Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6 [PROMISE-GIM6]) demonstrated improvement in both ovarian function and fertility with gonadotropin-releasing hormone agonist (GnRHa) administration during chemotherapy. The consistent absolute and relative results support the reliability of these findings (Table 1). The largest meta-analysis including all RCTs in patients with breast cancer confirmed a reduced risk of premature ovarian failure (POF; odds ratio [OR], 0.36; P, .001) and an increased chance of achieving pregnancy (OR, 1.83; P5 .04) with GnRHa during chemotherapy. On the basis of these findings, current guidelines recommend use of GnRHa as a strategy to offer patients with breast cancer who are interested in fertility and/or ovarian function preservation. Demeestere et al have recently reported follow-up data from their RCT investigating use of GnRHa during chemotherapy for preservation of ovarian function and fertility in patients with lymphoma. The authors concluded that after more than 5 years of follow-up, GnRHa administration did not significantly reduce POF or increase pregnancy rate. However, several issues should be considered in interpreting the results. Although there is no standard definition of chemotherapyinduced POF, a composite end point using both clinical and laboratory measures (eg, irregular periods or amenorrhea with follicle-stimulating hormone [FSH] levels . 40 mIU/mL) lends greater specificity. The role of anti-müllerian hormone (AMH), a marker of ovarian reserve commonly used in fertility clinics, is controversial in predicting chemotherapy-induced gonadal damage and subsequent fertility loss. Demeestere et al relied only on FSH or AMH levels, which might have increased false-positive results that incorrectly identified patients as having POF who did not in fact develop the event, as confirmed by the observation of five pregnancies in women with protocol-defined POF. Although pregnancy represents the best marker of fertility, prevention of POF has other advantages in preserving quality of life. None of the RCTs of ovarian protection with GnRHa required interest in future pregnancy for eligibility, and only a minority reported pregnancies. The POEMS-SWOG S0230 trial, the only study to include pregnancy as a predefined secondary end point, showed a significantly higher pregnancy rate with use of GnRHa. In the study by Demeestere et al, the use of the hormone norethisterone acetate in both study arms during chemotherapy may have diminished the observed protective effect of GnRHa. Norethisterone acetate directly affects the hypothalamic-pituitary axis, slowing gonadotropin-releasing hormone pulse frequency and lowering gonadotropins; this effect would only be seen in the control arm, because the pituitary gonadotropin-releasing hormone receptors would be downregulated by the GnRHa in the experimental arm. Furthermore, 46% of patients had no information on the use of hormonal contraceptives at the time of ovarian function assessment. Hormonal contraceptives can suppress FSH, which may have further confounded the results, especially if use was unbalanced between the two treatment arms. According to the original analysis plan, 157 patients were required; however, only 129 women were randomly assigned, with 84 patients (65%) completing 1 year of follow-up and included in the primary analysis. Long-term analyses were not preplanned; hence, the time points for ovarian function evaluation were not prespecified or mandatory. Only 63 patients (49%) and 37 patients (29%) had information on FSH and AMH, respectively. Although reported as a negative study, the ORs for POF and pregnancy seen in the trial by Demeestere et al are consistent with the protective effect of GnRHa seen in other studies (Table 1) and may not have achieved statistical significance only because of lack of power.