PSIV-17 - Postnatal obesity amplifies GnRH-induced LH release in prenatal testosterone-treated female sheep

Abstract: Polycystic ovary syndrome (PCOS) is the most common hormonal disorder in females of reproductive age. Hypersecretion of luteinizing hormone (LH), partly due to increased pituitary sensitivity to gonadotrophin-releasing hormone (GnRH), is a significant cause of infertility in women with PCOS. Moreover, obesity amplifies the severity of reproductive dysfunction in PCOS. In sheep, testosterone (T) excess during gestational days (GD) 30-90 results in GnRH-mediated LH hypersecretion and recapitulates the PCOS phenotype. This study investigated 1) if mid-gestation (GD 60-90) is the susceptibility window for programming pituitary hypersensitivity to GnRH and 2) the contribution of postnatal obesity in modulating LH responsiveness to GnRH. Suffolk ewes received T propionate (T; 100 mg i.m.) or corn oil (C; vehicle) twice weekly from GD 60-90 (term = 147 d). At 5 mo of age, T lambs were assigned randomly to either a maintenance (100% of NRC requirements) or overfed diet (130% of NRC requirements), and Control lambs were fed the maintenance diet. During the anestrous period (late summer), ewes (n = 8/group; ~17 mo of age) received a GnRH bolus injection (2ng/kg) intravenously every 1.5 h and blood samples were collected at 15-min intervals for a 6-h period. Despite animals being in seasonal anestrous, few endogenous LH pulses were evident during the 6 h-sampling period. To avoid confounding, only clear responses to GnRH challenge that occurred within 15-45 min after each GnRH injection were considered for further analyses. Mean number of exogenous GnRH-induced LH responses that met these criteria did not differ between groups and averaged 1.81 ± 0.27 pulses/animal. The parameters of these GnRH-induced responses were analyzed as one-way ANOVA with Tukey’s HSD post-hoc analysis. Mean LH pulse peak was greater (P < 0.05) in T overfed ewes (4.59 ± 0.49 ng/mL) compared to T maintenance (2.19 ± 0.61 ng/mL) and Control ewes (2.58 ± 0.53 ng/mL). Additionally, amplitude of LH pulses was greater (P < 0.05) in T overfed ewes (2.66 ± 0.39 ng/mL) compared to T maintenance (1.03 ± 0.48 ng/mL) and tended (P = 0.089) to be greater in T overfed compared to Control ewes (1.41 ± 0.42 ng/mL). LH pulse peak and amplitude in T maintenance did not differ from Control ewes. In conclusion, failure of GD 60-90 T treatment to increase GnRH responsiveness as opposed to our earlier finding of increased responsiveness in GD 30-90 T-treaded sheep indicates that the susceptibility window for programming pituitary hypersensitivity to GnRH lies between GD 30-60. Postnatal obesity may act as an independent activational signal in amplifying the pituitary sensitivity to GnRH in female sheep. This premise is supported by observations that obesity exacerbates pituitary-mediated LH hypersecretion in women with PCOS. Research support: NIH-NICHD (R01HD099096).