Prenatal influence of an androgen agonist and antagonist on the differentiation of the ovine sexually dimorphic nucleus in male and female lamb fetuses

Charles Roselli, Radhika C. Reddy, Charles T. Estill, Melissa Scheldrup, Mary Meaker, Fred Stormshak, Hernán J. Montilla

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 maletypical 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.

Original languageEnglish (US)
Pages (from-to)5000-5010
Number of pages11
JournalEndocrinology
Volume155
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

Androgen Antagonists
Flutamide
Sheep
Fetus
Dihydrotestosterone
Testosterone
Androgen Receptor Antagonists
Androgens
Androgen Receptors
Kisspeptins
Hormones
Pituitary Gonadotropins
Sex Differentiation
Hypothalamus
Pregnancy
Messenger RNA
Injections
Brain
Therapeutics

ASJC Scopus subject areas

  • Endocrinology

Cite this

Prenatal influence of an androgen agonist and antagonist on the differentiation of the ovine sexually dimorphic nucleus in male and female lamb fetuses. / Roselli, Charles; Reddy, Radhika C.; Estill, Charles T.; Scheldrup, Melissa; Meaker, Mary; Stormshak, Fred; Montilla, Hernán J.

In: Endocrinology, Vol. 155, No. 12, 01.12.2014, p. 5000-5010.

Research output: Contribution to journalArticle

Roselli, Charles ; Reddy, Radhika C. ; Estill, Charles T. ; Scheldrup, Melissa ; Meaker, Mary ; Stormshak, Fred ; Montilla, Hernán J. / Prenatal influence of an androgen agonist and antagonist on the differentiation of the ovine sexually dimorphic nucleus in male and female lamb fetuses. In: Endocrinology. 2014 ; Vol. 155, No. 12. pp. 5000-5010.
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