title: Sexual differentiation of the external genitalia and the timing of puberty in the presence of an antiandrogen in sheep.
abstract: Testicular steroids during midgestation sexually differentiate the steroid feedback mechanisms controlling GnRH secretion in sheep. To date, the actions of the estrogenic metabolites in programming neuroendocrine function have been difficult to study because exogenous estrogens disrupt maternal uterine function. We developed an approach to study the prenatal actions of estrogens by coadministering testosterone (T) and the androgen receptor antagonist flutamide, and tested the hypothesis that prenatal androgens program estradiol inhibitory feedback control of GnRH secretion to defeminize (advance) the timing of the pubertal increase in LH. Pregnant sheep were either untreated or treated with T, dihydrotestosterone (DHT) (a nonaromatizable androgen), or T plus flutamide from d 30-90 of gestation. To study the postnatal response to steroid negative feedback, lambs were gonadectomized and estradiol-replaced, and concentrations of LH were monitored in twice-weekly blood samples. Although T and DHT produced penile and scrotal development in females, the external genitalia of T plus flutamide offspring remained phenotypically female, regardless of genetic sex. Untreated females and females and males treated with T plus flutamide exhibited a pubertal increase in circulating LH at 26.4+/-0.5, 26.0+/-0.7, and 22.4+/-1.6 wk of age, respectively. In females exposed to prenatal androgens, the LH increase was advanced (T: 12.0+/-2.6 wk; DHT: 15.0+/-2.6 wk). These results demonstrate the usefulness of combining T and antiandrogen treatments as an approach to increasing prenatal exposure to estradiol. Importantly, the findings support our hypothesis that prenatal androgens program sensitivity to the negative feedback actions of estradiol and the timing of neuroendocrine puberty.
authors.affiliation: Reproductive Sciences Program, Department of Obstetrics and Gynecology, University of Michigan, 300 North Ingalls Room 1135, Ann Arbor, Michigan 48109, USA. lmjackso@umich.edu
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Jackson
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Timmer
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Foster
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D013196:Dihydrotestosterone / Q000494:pharmacology; D012734:Disorders of Sex Development / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D004958:Estradiol / Q000097:blood; D005260:Female; D005835:Genitalia / Q000033:anatomy & histology / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008954:Models, Biological; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000473:pathology; D012733:Sex Differentiation / Q000187:drug effects* / Q000502:physiology; D012741:Sexual Maturation / Q000187:drug effects*; D012756:Sheep; D013739:Testosterone / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000726:Androgen Antagonists; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone