GnRHa Does Not Preserve Ovarian Function in Young Women With Lymphoma

Gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in young women with lymphoma, according to the final long-term results of a trial published today in the Journal of Clinical Oncology.

“This report extends the results of the previously published analysis of a 1-year follow-up,” wrote researchers led by Isabelle Demeestere, MD, PhD, of the Université Libre de Bruxelle in Belgium. “The trial confirmed our previous data, showing the inefficiency of GnRHa for reducing chemotherapy-induced POF in young patients with lymphoma.”

According to the researchers, previous trials looking at the effect of GnRHa on preservation of ovarian function lacked large patient populations and had controversial results. In their earlier results from this analysis, Demeestere and colleagues found a similar rate of POF in the control group and the group assigned to GnRHa. These early results, however, suggested that GnRHa might have an effect on the protection of the ovarian reserve.

The study included 129 women with lymphoma with a median age of 26. Patients were randomly assigned to either GnRHa or norethisterone alone during their chemotherapy. The primary endpoint of the study was POF, defined as at least one follicle-stimulating hormone (FSH) value of greater than 40 IU/L after 2 years. Ovarian function and fertility were reported at 2, 3, 4, and 5 to 7 years follow-up.

After follow-up of about 5 years, 67 patients had available data. Patients assigned GnRHa had a significantly lower mean FSH level compared with the control group at the conclusion of chemotherapy; however, this difference disappeared with longer follow-up.

Six of 31 patients (19.4%) assigned GnRHa and eight of 32 patients (25%) in the control group had POF. Using multivariate logistic regression analysis, the researchers found increased risk for POF associated with patients who received a conditioning regimen for transplantation (P = .002) or a cumulative dose of cyclophosphamide of 5 g/m² or greater (P = .019). Increased risk of POF was found according to age (P = .047).

No difference in ovarian reserve was found between the two study groups.  Fifty-three percent of patients assigned GnRHa and 43% of patients in the control group achieved pregnancy.

“Surprisingly, five pregnancies (two in the GnRHa group and three in the control group) were reported in patients with protocol-defined POF during the follow-up,” the researchers wrote. “These data confirm the possibility of incidental ovarian cycle recovery, leading to fertility restoration several years after treatment in this young population.”

In an editorial published along with the study, Kutluk Oktay, MD, and Giuliano Bedoschi, MD, of New York Medical College and the Innovation Institute for Fertility Preservation, discussed several strengths of this research.

“It used an established biologic description of POF with long-term follow-up; it was the only randomized study with that healthy combination. It validated its findings by secondary outcome measures, such as the lack of diminished ovarian reserve reflected by serum FSH levels less than 15 mIU/mL, longitudinal serum anti-Müllerian hormone measurements, and fertility rates, all of which were in agreement with the primary outcome measure,” they wrote. “Moreover, the study proved its internal consistency by showing the positive correlation of POF with age and cyclophosphamide dose.”

The editorial authors noted that a noninvasive method of fertility preservation is highly desirable. “However,” they wrote, “when carefully scrutinized from a scientific point of view and considered together with ovarian biology, ovarian suppression by GnRHa is highly unlikely to be the answer.”