TitleRole for Kisspeptin and Neurokinin B in Regulation of Luteinizing Hormone and Testosterone Secretion in the Fetal Sheep.
Publication TypeJournal Article
Year of Publication2020
AuthorsAmodei, R, Gribbin, K, He, W, Lindgren, I, Corder, KR, Jonker, SS, Estill, CT, Coolen, LM, Lehman, MN, Whitler, W, Stormshak, F, Roselli, CE
Date Published2020 04 01
KeywordsAnimals, Female, Fetus, Gonadotropin-Releasing Hormone, Hypothalamus, Kisspeptins, Luteinizing Hormone, Male, Neurokinin B, Oligopeptides, Peptide Fragments, Pregnancy, Receptors, Kisspeptin-1, Receptors, Neurokinin-3, Sheep, Substance P, Testosterone

Evidence suggests that the hypothalamic-pituitary-gonadal (HPG) axis is active during the critical period for sexual differentiation of the ovine sexually dimorphic nucleus, which occurs between gestational day (GD) 60 and 90. Two possible neuropeptides that could activate the fetal HPG axis are kisspeptin and neurokinin B (NKB). We used GD85 fetal lambs to determine whether intravenous administration of kisspeptin-10 (KP-10) or senktide (NKB agonist) could elicit luteinizing hormone (LH) release. Immunohistochemistry and fluorescent in situ hybridization (FISH) were employed to localize these peptides in brains of GD60 and GD85 lamb fetuses. In anesthetized fetuses, KP-10 elicited robust release of LH that was accompanied by a delayed rise in serum testosterone in males. Pretreatment with the GnRH receptor antagonist (acyline) abolished the LH response to KP-10, confirming a hypothalamic site of action. In unanesthetized fetuses, senktide, as well as KP-10, elicited LH release. The senktide response of females was greater than that of males, indicating a difference in NKB sensitivity between sexes. Gonadotropin-releasing hormone also induced a greater LH discharge in females than in males, indicating that testosterone negative feedback is mediated through pituitary gonadotrophs. Kisspeptin and NKB immunoreactive cells in the arcuate nucleus were more abundant in females than in males. Greater than 85% of arcuate kisspeptin cells costained for NKB. FISH revealed that the majority of these were kisspeptin/NKB/dynorphin (KNDy) neurons. These results support the hypothesis that kisspeptin-GnRH signaling regulates the reproductive axis of the ovine fetus during the prenatal critical period acting to maintain a stable androgen milieu necessary for brain masculinization.

Alternate JournalEndocrinology
PubMed ID32005991
PubMed Central IDPMC7079722
Grant ListR01 OD011047 / OD / NIH HHS / United States
R01 HD039916 / HD / NICHD NIH HHS / United States
P51 OD011092 / OD / NIH HHS / United States
R01 HL142483 / HL / NHLBI NIH HHS / United States
P30 NS061800 / NS / NINDS NIH HHS / United States
P01 HD034430 / HD / NICHD NIH HHS / United States