(251) Prenatal Testosterone in Combination with Postnatal Obesity Amplifies the LH Secretion in Response to a Neurokinin-3 Receptor Agonist in a Sheep Model of PCOS Phenotype

Jessica F. Sustaita-Monroe¹, Leslie N. King¹, Sarah M. West¹, Viviana Garza¹; Lucas O. e Silva²; Hayden Feist¹; Vasantha Padmanabhan³; and Rodolfo C. Cardoso¹

¹Department of Animal Science, Texas A&M University, College Station, TX, USA

²Department of Animal Science, Luiz de Queiroz College of Agriculture, University of São Paulo (ESALQ/USP), Piracicaba, SP, Brazil

³Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

Abstract Text:

Polycystic ovary syndrome (PCOS) first described in 1935, has now become the second most prevalent cause of female infertility. Changes in the kisspeptin/neurokinin B/dynorphin A (KNDy) neuronal network are thought to be the drivers of neuroendocrine dysfunction that play a role in PCOS development. Moreover, obesity has been reported as a synergistic factor to neuroendocrine defects, amplifying this syndrome. Our objectives were to investigate 1) the effects of prenatal testosterone (T) exposure on the responsiveness of the neuroendocrine axis to Senktide, a Neurokinin 3-receptor (NK3R) agonist; and 2) the role of obesity in amplifying those effects. Suffolk ewes received T propionate (T; 100 mg i.m.) or corn oil (C; vehicle) twice weekly during mid-gestation (GD 60-90; term = 147d). At 5 mo of age, T lambs were assigned either to a maintenance (TM; 100% of NRC) or overfed diet (TO; 130% of NRC), while C lambs were fed the maintenance diet. In total, 7 C, 8 TM, and 8 TO ewes had a 3-cm silastic estradiol implant inserted subcutaneously during seasonal anestrous (late summer). Two weeks later, the ewes underwent a serial blood collection of 15-min increments for 9 h with two periods of 3 Saline and 3 Senktide (20 µg/kg) bolus injections administered intravenously every 1.5 h. Despite the seasonal anestrous and the presence of estradiol implants, endogenous LH pulses were detected. Therefore, only those pulses occurring 15-45 min post-injection were considered for further analysis. The mean number of exogenously-induced LH pulses did not differ between groups within Saline and Senktide periods (1.4 ± 0.6 and 1.5 ± 0.71 pulses/animal, respectively). LH response was analyzed as one-way ANOVA with Tukey’s HSD and Dunnett’s post-hoc analysis. Comparison between the Saline versus Senktide periods indicated a greater (P>0.05) response in pulse peak (Saline 0.69 ± 0.15; Senktide 1.26 ± 0.18 ng/mL) and amplitude (Saline 0.36 ± 0.09; Senktide 0.72 ± 0.11 ng/mL) during the Senktide period but not for mean LH concentration (Saline 0.85 ± 0.09; Senktide 0.96 ± 0.09 ng/mL). Mean LH pulse amplitude did not differ between groups within the two periods. Only prenatal T (TM 1.04 ± 0.15 ng/mL) increased (P< 0.05) mean LH concentration in the saline period versus C (0.51 ± 0.16 ng/mL), while postnatal obesity had no impact amplifying those effects (C 0.51 ± 0.16 ng/mL vs. TO 0.96 + 0.15 ng/mL). During the Senktide period, prenatal T and postnatal obesity both played a role in increasing mean LH concentration evident by a greater (P< 0.05) response from both T groups (TM 1.19 ± 0.13 ng/mL; TO 1.11 ± 0.13 ng/mL) compared to C (0.61± 0.14 ng/mL). Results for mean LH pulse peak show prenatal T alone (TM 1.49 ± 0.19 ng/mL) once again caused a greater (P< 0.05) response compared to C (0.67 ± 0.23 ng/mL) but not postnatal obesity (TO 1.15 ± 0.28 ng/mL). This was different from the results of the mean LH pulse peak during the Senktide period where postnatal obesity (1.80 ± 0.16 ng/mL) amplified (P=0.01) the response versus C (1.04 ± 0.19 ng/mL) but not prenatal T (TM 1.25 ± 0.23 ng/mL). In conclusion, mid-gestation (GD 60-90) T exposure alters NK3R sensitivity resulting in an increased responsiveness and greater LH secretion, which was amplified by postnatal obesity when exogenously stimulated by Senktide.