title: Prenatal influence of an androgen agonist and antagonist on the differentiation of the ovine sexually dimorphic nucleus in male and female lamb fetuses.
abstract: The ovine sexually dimorphic nucleus (oSDN) is 2 times larger in rams than in ewes. Sexual differentiation of the oSDN is produced by testosterone exposure during the critical period occurring between gestational day (GD)60 and GD90 (term, 147 d). We tested the hypothesis that testosterone acts through the androgen receptor to control development of the male-typical oSDN. In experiment 1, pregnant ewes received injections of vehicle, androgen receptor antagonist flutamide, or nonaromatizable androgen dihydrotestosterone (DHT) propionate during the critical period. Fetuses were delivered at GD135. Both antagonist and agonist treatments significantly reduced mean oSDN volume in males but had no effects in females. Experiment 2, we analyzed the effect of treatments on the fetal hypothalamic-pituitary-gonadal axis to determine whether compensatory changes in hormone secretion occurred that could explain the effect of DHT. Pregnant ewes were injected with vehicle, flutamide, or DHT propionate from GD60 to GD84, and fetuses were delivered on GD85. Flutamide significantly increased LH and testosterone in males, whereas DHT significantly decreased both hormones. In females, LH was unaffected by flutamide but significantly reduced by DHT exposure. DHT significantly decreased pituitary gonadotropin and hypothalamic kisspeptin mRNA expression in males and females. These results suggest that androgen receptor mediates the effect of testosterone on oSDN masculinization, because this process was blocked by the androgen receptor antagonist flutamide in eugonadal males. In contrast, the reduction of oSDN volume observed after DHT exposure appears to be mediated by a negative feedback mechanism exerted on the hypothalamus to reduce LH and testosterone secretion. The reduced androgen exposure most likely accounted for the decreased oSDN volume. We conclude that, during the critical period, the male reproductive axis in long gestation species, such as sheep, is sufficiently developed to react to perturbations in serum androgens and mitigate disruptions in brain masculinization.
authors.affiliation: Department of Physiology and Pharmacology (C.E.R., R.C.R., M.S.), Oregon Health and Science University, Portland, Oregon 97239-3098; and Departments of Animal and Rangeland Sciences (C.T.E., M.M., F.S.) and Clinical Sciences (C.T.E., H.J.M.), College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331-4501.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Roselli
authors.forename: Radhika C
authors.initials: RC
authors.lastname: Reddy
authors.forename: Charles T
authors.initials: CT
authors.lastname: Estill
authors.forename: Melissa
authors.initials: M
authors.lastname: Scheldrup
authors.forename: Mary
authors.initials: M
authors.lastname: Meaker
authors.forename: Fred
authors.initials: F
authors.lastname: Stormshak
authors.forename: Hernán J
authors.initials: HJ
authors.lastname: Montilla
mesh_terms: D000726:Androgen Antagonists; D000728:Androgens; D000818:Animals; D013196:Dihydrotestosterone; D005260:Female; D005485:Flutamide; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D059648:Kisspeptins / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D011247:Pregnancy; D011301:Preoptic Area / Q000196:embryology*; D011944:Receptors, Androgen / Q000378:metabolism*; D012727:Sex Characteristics; D012756:Sheep; D013739:Testosterone / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D059648:Kisspeptins; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D005485:Flutamide; D007986:Luteinizing Hormone