title: The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle.
abstract: Women's health disorders such as uterine fibroids and endometriosis are currently treated by GnRH modulators that effectively suppress the hypothalamic-pituitary-gonadal axis. The neurokinin-3 receptor (NK3R) is an alternative target with an important role in the modulation of this axis. In this report, we demonstrate that systemic administration of an NK3R antagonist (ESN364) prolongs the LH interpulse interval in ovarectomized ewes and significantly lowers plasma LH and FSH concentrations in castrated nonhuman primates (Macaca fascicularis). Moreover, daily oral dosing of ESN364 throughout the menstrual cycle in M fascicularis lowered plasma estradiol levels in a dose-dependent manner, although nadir levels of estradiol were maintained well above menopausal levels. Nevertheless, estradiol levels during the follicular phase were sufficiently inhibited at all doses to preclude the triggering of ovulation as evidenced by the absence of the LH surge and failure of a subsequent luteal phase rise in plasma progesterone concentrations, consistent with the absence of normal cycle changes in the uterus. Apart from the point at surge, FSH levels were not altered over the course of the menstrual cycle. These effects of ESN364 were reversible upon cessation of drug treatment. Together these data support the proposed role of neurokinin B-NK3R signaling in the control of pulsatile GnRH secretion. Furthermore, in contrast to GnRH antagonists, NK3R antagonists induce a partial suppression of estradiol and thereby offer a viable therapeutic approach to the treatment of ovarian sex hormone disorders with a mitigated risk of menopausal-like adverse events in response to long-term drug exposure.
authors: Euroscreen SA (G.L.F., H.R.H.), 6041 Gosselies, Belgium; Department of Physiology (I.J.C.), Monash University, Clayton 3800, Victoria, Australia; Department of Obstetrics, Gynecology, and Reproductive Sciences (S.R., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Covance Laboratories GmbH (C.R.), 48163 Münster, Germany; Mammal Research Unit (R.P.M.), University of Pretoria and Medical Research Center Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7701 Cape Town, South Africa.
authors: Graeme L
authors: GL
authors: Fraser
authors: Euroscreen SA (G.L.F., H.R.H.), 6041 Gosselies, Belgium; Department of Physiology (I.J.C.), Monash University, Clayton 3800, Victoria, Australia; Department of Obstetrics, Gynecology, and Reproductive Sciences (S.R., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Covance Laboratories GmbH (C.R.), 48163 Münster, Germany; Mammal Research Unit (R.P.M.), University of Pretoria and Medical Research Center Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7701 Cape Town, South Africa.
authors: Hamid R
authors: HR
authors: Hoveyda
authors: Euroscreen SA (G.L.F., H.R.H.), 6041 Gosselies, Belgium; Department of Physiology (I.J.C.), Monash University, Clayton 3800, Victoria, Australia; Department of Obstetrics, Gynecology, and Reproductive Sciences (S.R., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Covance Laboratories GmbH (C.R.), 48163 Münster, Germany; Mammal Research Unit (R.P.M.), University of Pretoria and Medical Research Center Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7701 Cape Town, South Africa.
authors: Iain J
authors: IJ
authors: Clarke
authors: Euroscreen SA (G.L.F., H.R.H.), 6041 Gosselies, Belgium; Department of Physiology (I.J.C.), Monash University, Clayton 3800, Victoria, Australia; Department of Obstetrics, Gynecology, and Reproductive Sciences (S.R., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Covance Laboratories GmbH (C.R.), 48163 Münster, Germany; Mammal Research Unit (R.P.M.), University of Pretoria and Medical Research Center Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7701 Cape Town, South Africa.
authors: Suresh
authors: S
authors: Ramaswamy
authors: Euroscreen SA (G.L.F., H.R.H.), 6041 Gosselies, Belgium; Department of Physiology (I.J.C.), Monash University, Clayton 3800, Victoria, Australia; Department of Obstetrics, Gynecology, and Reproductive Sciences (S.R., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Covance Laboratories GmbH (C.R.), 48163 Münster, Germany; Mammal Research Unit (R.P.M.), University of Pretoria and Medical Research Center Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7701 Cape Town, South Africa.
authors: Tony M
authors: TM
authors: Plant
authors: Euroscreen SA (G.L.F., H.R.H.), 6041 Gosselies, Belgium; Department of Physiology (I.J.C.), Monash University, Clayton 3800, Victoria, Australia; Department of Obstetrics, Gynecology, and Reproductive Sciences (S.R., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Covance Laboratories GmbH (C.R.), 48163 Münster, Germany; Mammal Research Unit (R.P.M.), University of Pretoria and Medical Research Center Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7701 Cape Town, South Africa.
authors: Claudia
authors: C
authors: Rose
authors: Euroscreen SA (G.L.F., H.R.H.), 6041 Gosselies, Belgium; Department of Physiology (I.J.C.), Monash University, Clayton 3800, Victoria, Australia; Department of Obstetrics, Gynecology, and Reproductive Sciences (S.R., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Covance Laboratories GmbH (C.R.), 48163 Münster, Germany; Mammal Research Unit (R.P.M.), University of Pretoria and Medical Research Center Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7701 Cape Town, South Africa.
authors: Robert P
authors: RP
authors: Millar
mesh_terms: D000818:Animals; D002369:Castration; D004958:Estradiol / Q000097:blood*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood*; D008252:Macaca fascicularis; D008297:Male; D008597:Menstrual Cycle / Q000097:blood / Q000187:drug effects*; D011374:Progesterone / Q000097:blood*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D012756:Sheep
chemical_list: D018042:Receptors, Neurokinin-3; D011374:Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone