Trial of Recombinant Follicle Stimulating Hormone (rFSH) Pre-treatment for GnRH-induced Fertility in Patients with Congenital Hypogonadotropic Hypogonadism
Dwyer AA, Sykiotis GP, Hayes FJ, Boepple PA, Lee H, Loughlin KR, Dym M, Sluss PM, Crowley WF Jr, Pitteloud N. J Clin Endocrinol Metab. 2013 Sep 13. [Epub ahead of print]


Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit, Department of Medicine, MA General Hospital, Boston, MA 02114 (AAD, GPS, FJH, PAB, PS, WFC, NP); Endocrinology, Diabetes, and Metabolism Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland 1011 (AAD, NP); Department of Internal Medicine, Division of Endocrinology, University of Patras Medical School, Patras, Greece 26500 (GPS); Department of Biostatistics and General Clinical Research Center, MA General Hospital, Boston, MA 02114 (HL); Department of Surgery, Brigham & Women's Hospital, Boston MA 02115 (KRL); Department of Cell Biology, Georgetown University School of Medicine, WA, DC 20057 (MD); Department of Pathology, MA General Hospital and Harvard Medical School, Boston, MA 02114 (PMS).


Context & Objective:The optimal strategy for inducing fertility in men with congenital hypogonadotropic hypogonadism (CHH) is equivocal. Albeit a biologically plausible approach, pre-treatment with recombinant FSH (rFSH) prior to GnRH/hCG administration has not been sufficiently assessed. The objective of the study was to test this method.Design & Setting:Randomized, open-label treatment protocol at an academic medical center.Patients & Interventions:GnRH-deficient men (CHH) with prepubertal testes (<4 mL), no cryptorchidism, and no prior gonadotropin therapy were randomized to either 24 months of pulsatile GnRH therapy alone (inducing endogenous LH and FSH release) or 4 months of rFSH pre-treatment followed by 24 months of GnRH therapy. Patients underwent serial testicular biopsies, ultrasound assessments of testicular volume (TV), serum hormone measurements, and seminal fluid analyses.Results:rFSH treatment increased inhibin B (IB) levels into the normal range (29±9→107±41 pg/mL, p<0.05) and doubled TV (1.1±0.2→2.2±0.3 mL, p<0.005). Histology showed proliferation of both Sertoli cells (SC) and spermatogonia; decreased SC to germ cell ratio (0.74→0.35); and SC cytoskeletal rearrangements. On pulsatile GnRH, the groups had similar hormonal responses and exhibited significant testicular growth. All men receiving rFSH pre-treatment developed sperm in their ejaculate (7/7 vs. 4/6 in the GnRH-only group) and trended towards higher maximal sperm counts.Conclusions:rFSH pre-treatment followed by GnRH is successful in inducing testicular growth and fertility in CHH men with prepubertal testes. rFSH not only appears to maximize the SC population, but also induces morphologic changes suggesting broader developmental roles.Precis:When administered to CHH patients with prepubertal testes as part of a fertility treatment strategy, rFSH induces Sertoli cell and spermatogonia proliferation, triggers cytoskeletal rearrangements in the seminiferous tubules, and promotes testicular growth.