title: Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons.
abstract: Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), whereas E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice. Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERαKO mice, E2 also effectively decreased LH levels in OVX KERαKO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERαKO mice. These experiments clearly demonstrate that ERα in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KERαKO mice to exhibit GnRH/LH surges reflects the role of ERα in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.
authors.affiliation: Neuroscience Training Program (S.L.D.), Department of Neuroscience (S.L.D., J.E.L.), University of Wisconsin-Madison, Madison, Wisconsin 53715; Department of Physiology and Biophysics (M.A.-M.), Stony Brook University, Stony Brook, New York 11794; Department of Physiology and Biophysics (M.R.D., J.H.U.), Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064; Department of Pediatrics (A.W., S.R.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pharmacology and Toxicology (U.B.), University of Saarland School of Medicine, Homburg, Germany D-66421; and Wisconsin National Primate Research Center (J.E.L.), Madison, Wisconsin 53715.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Dubois
authors.forename: Maricedes
authors.initials: M
authors.lastname: Acosta-Martínez
authors.forename: Mary R
authors.initials: MR
authors.lastname: DeJoseph
authors.forename: Andrew
authors.initials: A
authors.lastname: Wolfe
authors.forename: Sally
authors.initials: S
authors.lastname: Radovick
authors.forename: Ulrich
authors.initials: U
authors.lastname: Boehm
authors.forename: Janice H
authors.initials: JH
authors.lastname: Urban
authors.forename: Jon E
authors.initials: JE
authors.lastname: Levine
mesh_terms: D000818:Animals; D004958:Estradiol / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D017403:In Situ Hybridization; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D059648:Kisspeptins; D012333:RNA, Messenger; D004958:Estradiol; D007986:Luteinizing Hormone