Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism

Abstract

Context and objective: The optimal strategy for inducing fertility in men with congenital hypogonadotropic hypogonadism (CHH) is equivocal. Albeit a biologically plausible approach, pretreatment with recombinant FSH (rFSH) before GnRH/human chorionic gonadotropin administration has not been sufficiently assessed. The objective of the study was to test this method.

Design and setting: This was a randomized, open-label treatment protocol at an academic medical center.

Patients and interventions: GnRH-deficient men (CHH) with prepubertal testes (<4 mL), no cryptorchidism, and no prior gonadotropin therapy were randomly assigned to either 24 months of pulsatile GnRH therapy alone (inducing endogenous LH and FSH release) or 4 months of rFSH pretreatment followed by 24 months of GnRH therapy. Patients underwent serial testicular biopsies, ultrasound assessments of testicular volume, serum hormone measurements, and seminal fluid analyses.

Results: rFSH treatment increased inhibin B levels into the normal range (from 29 ± 9 to 107 ± 41 pg/mL, P < .05) and doubled testicular volume (from 1.1 ± 0.2 to 2.2 ± 0.3 mL, P < .005). Histological analysis showed proliferation of both Sertoli cells (SCs) and spermatogonia, a decreased SC to germ cell ratio (from 0.74 to 0.35), and SC cytoskeletal rearrangements. With pulsatile GnRH, the groups had similar hormonal responses and exhibited significant testicular growth. All men receiving rFSH pretreatment developed sperm in their ejaculate (7 of 7 vs 4 of 6 in the GnRH-only group) and showed trends toward higher maximal sperm counts.

Conclusions: rFSH pretreatment followed by GnRH is successful in inducing testicular growth and fertility in men with CHH with prepubertal testes. rFSH not only appears to maximize the SC population but also induces morphologic changes, suggesting broader developmental roles.

Trial registration: ClinicalTrials.gov NCT00064987.

Figure 1.

Testis histology at baseline, after 4 months of rFSH pretreatment, and after 4 months of GnRH. A and D, Light micrographs (×1000) showing immature testes before treatment with few SPGA (asterisks) and SCs (triangles). B, Light micrograph (×1000) after rFSH treatment showing multiple spermatogonia at the basement membrane. C, Light micrograph (×2800) showing a pseudopod (white arrow) extending from a spermatogonium as the cell migrates from the cord center to the basement membrane. Images A, B, and C are from the same subject. E, Light micrograph (×1000) showing Leydig cells (LC) in the interstitium and columnar SCs with nuclei near the base of the tubule and supranuclear cytoplasm extending toward the tubule lumen (L). The SCs are now polarized, and this is a sign of their maturity. Images D and E are from the same subject.

Figure 2.

Hormonal responses of men with CHH to rFSH pretreatment and GnRH treatment. ○, rFSH-pretreated group (group 1, n = 7); ●, GnRH-only group (group 2, n = 6). The shaded region of the graph represents the pretreatment period; limits of normal ranges are shown with dashed horizontal lines. A, Both groups increased serum FSH levels with pulsatile GnRH (releasing endogenous LH + FSH), with no significant differences with long-term treatment. B, Both groups rapidly normalized LH levels with pulsatile GnRH. C, Group 1 serum IB levels increased significantly (*, P < .05) during the rFSH pretreatment (shaded region). D, Pulsatile GnRH was effective in maintaining normal serum T levels with long-term therapy in both groups. E, Group 1 TV doubled after 4 months of pretreatment (*, P < .005); the final TV was not different between groups. F, Maximal sperm counts for study subjects are depicted by circles; 2 subjects in group 2 remained azoospermic. Means ± SEM are shown as squares with error bars.