Growth Hormone increases gonadotropin receptors in poor-prognosis patients

Abstract

Introduction: Growth hormone (GH) exerts multiple functions including its effect on the reproductive system1. We have recently reported that GH supplementation improves implantation and pregnancy rates for poor-prognosis patients undertaking stimulated IVF2. The purpose of this study was to understand the underlying mechanism of action of GH on developing human follicles and possibly oocytes, leading to such improvement. Material and Methods: Granulosa cells were collected at trans-vaginal oocyte recovery from 137 age-matched gonadotrophin-stimulated patients with or without GH supplementation. Such patients were those achieving few mature oocytes despite high dose gonadotrophin stimulation. Their cells were purified, immuno-labelled with fluorescent antibodies and analyzed by flow cytometry to quantify receptors (R) of GH, FSH, LH and Bone Morphogenetic Proteins (BMPs).Results: The levels of GHR on granulosa cells were significantly elevated (p < 0.003) in patients treated with exogenous GH, suggesting an auto-upregulation mechanism. In addition, GHR was significantly increased (p < 0.02) in cells from older (>35y, n = 69) patients than from younger (<35y, n = 54). Of further interest, the expression of FSHR and LHR was significantly increased (p < 0.001 and p < 0.05, respectively) on granulosa cells from treated patients (n = 36) compared with age-matched (39-45y) untreated patients (n = 40). On the other hand, the levels of BMPR which correlates with early apoptosis were also significantly increased (p < 0.0005 and p < 0.005, respectively) in cells from treated patients (n = 36) compared with untreated (n = 40). Conclusions: We conclude that treatment of poor-responder patients using exogenous GH leads to an increase in the levels of FSHR and LHR on granulosa cells hence increasing the sensitivity of follicles to gonadotrophin stimulation. Enhanced response to gonadotrophins may explain the beneficial clinical response previously reported by us. There may also be indirect effects operating that improve the developmental potential of the oocytes. Regardless of the mechanism, this outcome endorses the simple clinical practice of GH supplementation to improve the fertility rates of poor-prognosis patients, particularly those in the older reproductive age range.