The role of growth hormone (GH), GH-receptor and GH-binding protein in reproduction and ovulation induction.

In the last decade the potential importance of intraovarian regulators of follicular development has been recognized, and the effects of various growth factors on granulosa cell responses to gonadotropins have been extensively investigated. Ovarian responses to exogenous gonadotropins were improved by adjuvant growth hormone (GH) treatment of GH-deficient patients, and responses to hMG were apparently predicted by estimated GH reserve. However, the results of different studies of GH/hMG cotreatment were equivocal. Therefore, a randomized, prospective, cross-over study protocol between GH/hMG/hCG versus hMG/hCG was undertaken. Whereas 18 pregnancies were achieved in the 32 clonidine negative patients (56%) either in the GH/hMG cycle (13) or in the succeeding one (5), no benefit was detected in 10 clonidine positive patients from the GH/hMG combination. The recently described GH-binding protein (BP) may reflect the GH-receptor. GH-BP levels were evaluated in the sera and follicular fluids (FF) of patients undergoing ovulation induction with either hMG/hCG or GH/hMG/hCG. GH-BP increase in serum correlated with E2 and progesterone (P4) concentrations. The FF GH-BP correlated with serum GH-BP levels and was dose-dependent, highly specific, of high affinity, and low capacity. Lower FF GH-BP levels were measured in older compared to younger women, while increased values were obtained both in patients with elevated E2 concentrations in serum and in FF, and when more than 5 oocytes were retrieved. Longitudinal measurements of GH-BP levels showed an initial sharp increase during early gestation, followed by a gradual decrease from the 2nd trimester to term. The late gestational decrease in GH-BP levels may be attributed to the decreasing hCG concentrations, and/or to the increasing secretions of placental lactogen and GH with advancing gestation. Primary increased GH-BP in unexplained infertility may suggest a new mechanism whereby excessive GH-BP levels may prevent GH from binding to its receptor and thus decrease intraovarian IGF-1 production. Whereas GH-BP significantly increased in correlation with moderately (300-1500 pg/ml, 1100-5500 pmol/l), or with severely increased (> 1500 pg/ml, > 5500 pmol/l) E2 concentrations, the serum IGF-1 levels increased with moderately elevated but decreased at severely increased E2 concentrations, as measured in ovarian hyperstimulation (OHSS). This observation may suggest IGF-1's involvement in a mechanism by which OHSS is detrimental to early conception. The clonidine test may identify patients who may benefit from this combination, during the GH/hMG cycle and possibly also during the succeeding cycle.