Fetal programming: excess prenatal testosterone reduces postnatal luteinizing hormone, but not follicle-stimulating hormone responsiveness, to estradiol negative feedback in the female.
Exposure of female sheep fetuses to excess testosterone (T) during early to midgestation produces postnatal hypergonadotropism manifest as a selective increase in LH. This hypergonadotropism may result from reduced sensitivity to estradiol (E2) negative feedback and/or increased pituitary sensitivity to GnRH. We tested the hypothesis that excess T before birth reduces responsiveness of LH and FSH to E2 negative feedback after birth. Pregnant ewes were treated with T propionate (100 mg/kg in cotton seed oil) or vehicle twice weekly from d 30-90 gestation. Responsiveness to E2 negative feedback was assessed at 12 and 24 wk of age in the ovary-intact female offspring. Our experimental strategy was first to arrest follicular growth and reduce endogenous E2 by administering the GnRH antagonist (GnRH-A), Nal-Glu (50 microg/kg sc every 12 h for 72 h), and then provide a fixed amount of exogenous E2 via an implant. Blood samples were obtained every 20 min at 12 wk and every 10 min at 24 wk before treatment, during and after GnRH-A treatment both before and after E2 implant. GnRH-A ablated LH pulsatility, reduced FSH by approximately 25%, and E2 production diminished to near detection limit of assay at both ages in both groups. Prenatal T treatment produced a precocious and selective reduction in responsiveness of LH but not FSH to E2 negative feedback, which was manifest mainly at the level of LH/GnRH pulse frequency. Collectively, these findings support the hypothesis that prenatal exposure to excess T decreases postnatal responsiveness to E2 inhibitory feedback of LH/GnRH secretion to contribute to the development of hypergonadotropism.
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Hirendra N
HN
Sarma
Mohan
M
Manikkam
Carol
C
Herkimer
James
J
Dell'Orco
Kathleen B
KB
Welch
Douglas L
DL
Foster
Vasantha
V
Padmanabhan
D000818:Animals; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005246:Feedback; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000502:physiology*; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D011247:Pregnancy; D012741:Sexual Maturation / Q000187:drug effects; D012756:Sheep; D013739:Testosterone / Q000494:pharmacology*
D004343:Drug Implants; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone