Recent long-term studies have shown that Growth Hormone (GH) improves pregnancy rates in poor prognosis patients undertaking stimulated IVF treatment from 9% to 25% with no improvement in oocyte recovery number [1]. The purpose of this study was to determine the possible mode of action of GH on human developmental potential of the oocyte and follicle. Granulosa cells were collected from age-matched gonadotropin-stimulated patients (n=137), with or without GH supplementation. The cells were purified, immunolabelled with fluorescent antibodies and analysed by flow cytometry to quantify receptors of FSH, LH, GH and Bone Morphogenetic Protein 1B (BMPR 1B) and early follicle cell apoptosis.
Our research for the first time has shown that GH co-treatment significantly upregulates FSHR and LHR expression (p 0.001 & p 0.05). The improvement in FSH and LH sensitivity appears likely to be responsible for the positive outcome in pregnancy rate experienced by poor prognosis patients [1]. In addition, GHR expression was significantly elevated (p 0.0009) in patients co-treated with GH indicating an auto upregulation of the receptors in response to increased levels of GH. Furthermore, age appeared to be a dominant factor in determining receptor expression compared to follicle size, estrogen, testosterone and progesterone trends. Our in vivo human research has shown that older patients treated with GH significantly upregulates GHR, FSHR and LHR with no significant difference in oocyte or follicle number recorded [1], suggesting that the receptor upregulation is a stimulatory mechanism on oocyte quality and not on cyclic recruitment or maturation of follicles.
On the other hand, our research has also demonstrated that BMPR 1B expression and the rate of apoptosis are significantly increased (p 0.0005 & p 0.001) in cells from age matched older GH treated patients compared to untreated. In support of this, our previous human in vivo data has shown that BMPR expression and apoptosis decreased with increased follicle size confirming the inhibitory role of BMPs with follicular development (SRB/WSRB 2011, Cairns poster presentation). Therefore, our observed significant increase in apoptosis would explain the lack of difference in oocyte recovery number reported [1] in GH treated patients compared to untreated.
We propose that GH supplementation with gonadotropin stimulation may lead to a bi-phasic mode of action on the oocyte and follicle cells using two different pathways. The bi-phasic action of GH increases FSHR and LHR to improve oocyte developmental competence and it promotes BMPR on granulosa cells hence promoting apoptosis which minimises follicular maturation. Our findings support the clinical practice of combined high dose gonadotropin stimulation and GH supplementation to improve the response of poor-responder patients, oocyte quality and pregnancy rate.