Neuroendocrinology and Behavior
(W660) FETAL PROGRAMMING OF THE POSTNATAL RESPONSIVENESS OF LH TO ESTRADIOL NEGATIVE FEEDBACK IN SHEEP: TIME AND DURATION OF EXPOSURE AND QUALITY OF PRENATAL STEROID.
Lee, James1, Aizenburg, Esther1, Djoumbi, Danielle1, Forster, Douglas1, Padmanabhan, Vasantha1, 1 University of Michigan, Ann Arbor, MI
ABSTRACT- Female sheep exposed to excess testosterone (T) from days 30-90 of gestation (T60, 147 days is term) manifest hypergonadotropism, multifollicular ovaries and consequent elevation in estradiol (E) levels. The hypergonadotropism of T60 females involves, in part, decreased postnatal responsiveness of LH/GnRH to E negative feedback [BOR 68 (Supp l1):379, 2003]. The present studies tested the importance of developmental stage of T exposure and the type of the steroid involved in the programming. In the first, study, responsiveness to E negative feedback was assessed at 24 weeks of age in control (C, n=6), T60 (n=5) and T30 (200 mg T/week, from fetal days 60 to 90, n=6) females. This was done by monitoring time of resumption of LH pulsatility following blockade of LH pulsatility and endogenous E production by a GnRH antagonist (GnRH-A for 72h). LH pulse frequency 24h post GnRH-A was higher in T60 (p<0.05), but not in T30 compared to C females (C:1.7±0.4, T30:1.8±0.4 and T60: 3.0±0.4 pulses/6hr). Pulse amplitude was higher (p<0.05) in T60 females compared to T30 and C females (C:4.0±0.8ng/mL, T30:5.3±1.1, T60:10.7±1.8). The second study tested if T programming of reduced postnatal responsiveness to E is due to its androgenic action. E negative feedback responsiveness was tested at 20 weeks of age by comparing LH dynamics during reduced E (48h post-GnRH-A) and 72h after exogenous E (3mm implant) in C (n=7), T60 (n=5) and DHT60 (n=5) (200 mg/week, days 30-90) females. Estradiol suppressed LH pulse frequency less in DHT (p<0.01), and marginally in T (p=0.06)) compared to controls (C:87.5±12.5; T: 59.0±4.9; and DHT: 23.6±9.7%). LH pulse amplitudes in T and DHT females were also higher (p<0.05) than C females (C:1.2±0.3, T:2.7±0.1, DHT:2.3±0.3 ng/mL). These findings suggest that 1) the critical period for prenatal programming of reduced postnatal E negative feedback responsiveness is either between days 30 to 60 of gestation or requires prolonged T exposure (60 vs 30 days) and 2) this programming is mediated by the androgenic action of T. Supported by NIH HD 41098 & P01 HD 44232
KEY WORDS: neuroendocrinology, infertility, development, gonadotropin