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Estradiol Membrane‐Initiated Signaling and Female Reproduction

Paul E Micevych, Angela May Wong, Melinda Anne Mittelman‐Smith

10.1002/cphy.c140056

Source: Volume 5, Issue 3, July 2015

Published online: June 2015

Full Article on Wiley Online Library



ABSTRACT

The discoveries of rapid, membrane‐initiated steroid actions and central nervous system steroidogenesis have changed our understanding of the neuroendocrinology of reproduction. Classical nuclear actions of estradiol and progesterone steroids affecting transcription are essential. However, with the discoveries of membrane‐associated steroid receptors, it is becoming clear that estradiol and progesterone have neurotransmitter‐like actions activating intracellular events. Ultimately, membrane‐initiated actions can influence transcription. Estradiol membrane‐initiated signaling (EMS) modulates female sexual receptivity and estrogen feedback regulating the luteinizing hormone (LH) surge. In the arcuate nucleus, EMS activates a lordosis‐regulating circuit that extends to the medial preoptic nucleus and subsequently to the ventromedial nucleus (VMH)—the output from the limbic and hypothalamic regions. Here, we discuss how EMS leads to an active inhibition of lordosis behavior. To stimulate ovulation, EMS facilitates astrocyte synthesis of progesterone (neuroP) in the hypothalamus. Regulation of GnRH release driving the LH surge is dependent on estradiol‐sensitive kisspeptin (Kiss1) expression in the rostral periventricular nucleus of the third ventricle (RP3V). NeuroP activation of the LH surge depends on Kiss1, but the specifics of signaling have not been well elucidated. RP3V Kiss1 neurons appear to integrate estradiol and progesterone information which feeds back onto GnRH neurons to stimulate the LH surge. In a second population of Kiss1 neurons, estradiol suppresses the surge but maintains tonic LH release, another critical component of the estrous cycle. Together, evidence suggests that regulation of reproduction involves membrane action of steroids, some of which are synthesized in the brain. © 2015 American Physiological Society. Compr Physiol 5:1211‐1222, 2015.

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Figure 1. Figure 1. Female rats were anesthetized with pentobarbital and injection (i.v.) with 100 μCi/100 g body weight of 2,4,6,7,16,17‐[3H]estradiol (specific activity 130 Ci/mmol, New England Nuclear). At 2 h after injection of the isotope, animals were killed, brains removed and cryosectioned (l0 μm) through the medial preoptic nucleus (MPN) and lateral preoptic area (LPOA). Sections were collected under safe‐light conditions and thaw‐mounted onto slides which had been coated with nuclear track emulsion and exposed at −70°C for 28 weeks, then photodeveloped. The MPN contains many cells that concentrate 3H‐estradiol as indicated by the accumulation of silver grains over nuclei (arrow). In the LPOA, some cells have accumulations of silver grains (arrow) but levels are much lower in both the estradiol‐accumulating cells and the surrounding background compared with the MPN. Bar in LPOA is 20 μm and applies to both images. Sections are adapted, with permission, from a study by Akesson TR and Micevych PE (4).
Figure 2. Figure 2. The estradiol (E2) induction of sexual receptivity in the female rat is indicated by lordosis behavior. The CNS regulation of this global response to hormonal and sensory input is regulated by a diffuse circuit that extends from the limbic system to the spinal cord. Within this lordosis regulating circuit, E2 acts rapidly through estrogen membrane signaling (EMS) to release neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH), which activates β‐endorphin (β‐END) projection neurons that extend to the medial preoptic nucleus (MPN). The MPN is an important integrative node receiving accessory olfactory and limbic input. β‐END activates μ‐opioid receptors (MOR), producing a transient inhibition of the MPN which is relieved by progesterone in the cycling female. The MPN MOR neurons in turn project to the ventromedial nucleus of the hypothalamus (VMH), the final common output of the hypothalamus. The integrated hypothalamic output is modified by inputs from the periaquaductal gray, and the vestibular complex on its way to the motoneurons mediating lordosis behavior. The EMS that mediates this activation of the circuit requires the transactivation of metabotropic glutamate receptor‐1a (mGluR1a), which leads to the phosphorylation of PKCθ and the release of NPY and activation of the Y1 receptor on β‐END projection cells. The EMS and resulting transient inhibition is necessary for the full expression of lordosis behavior in the rat [adapted, with permission, from (116)].
Figure 3. Figure 3. A model showing proposed estradiol (E2) actions on hypothalamic cells. In Kiss1 neurons, E2 acts at both membrane and nuclear estrogen receptors. During diestrus, classical nuclear E2 signaling induces PR expression in kisspeptin (Kiss1) neurons in the RP3V. On proestrus, rising E2 leads to transactivation of mGluR1a in astrocytes, which increases [Ca2+] i leading to stimulation of a kinase cascade resulting in the activation of translocator protein (TSPO) and steroid acute regulatory protein (StAR), which results in an increase of cholesterol import into the mitochondrion—the rate limiting step in steroidogenesis. The resulting pregnenolone (PREG) is converted to progesterone (neuroP) by 3β‐HSD. Simultaneously, E2 activates an ERα‐mGluR1a complex in neurons leading to the expression of Kiss1. Newly synthesized neuroP diffuses out of the astrocytes and activates E2‐induced PR, which have been trafficked to the Kiss1 neuronal membrane. This leads to a series of events culminating in Kiss1 secretion onto GPR54 expressing GnRH neurons. We hypothesize that signaling through the membrane PR involves transactivation of another receptor (indicated by [?]) to stimulate [Ca2+]i, and induce Kiss1 release, activating GnRH neurons and triggering the E2‐induced LH surge from anterior pituitary gonadotrophs.


Figure 1. Female rats were anesthetized with pentobarbital and injection (i.v.) with 100 μCi/100 g body weight of 2,4,6,7,16,17‐[3H]estradiol (specific activity 130 Ci/mmol, New England Nuclear). At 2 h after injection of the isotope, animals were killed, brains removed and cryosectioned (l0 μm) through the medial preoptic nucleus (MPN) and lateral preoptic area (LPOA). Sections were collected under safe‐light conditions and thaw‐mounted onto slides which had been coated with nuclear track emulsion and exposed at −70°C for 28 weeks, then photodeveloped. The MPN contains many cells that concentrate 3H‐estradiol as indicated by the accumulation of silver grains over nuclei (arrow). In the LPOA, some cells have accumulations of silver grains (arrow) but levels are much lower in both the estradiol‐accumulating cells and the surrounding background compared with the MPN. Bar in LPOA is 20 μm and applies to both images. Sections are adapted, with permission, from a study by Akesson TR and Micevych PE (4).


Figure 2. The estradiol (E2) induction of sexual receptivity in the female rat is indicated by lordosis behavior. The CNS regulation of this global response to hormonal and sensory input is regulated by a diffuse circuit that extends from the limbic system to the spinal cord. Within this lordosis regulating circuit, E2 acts rapidly through estrogen membrane signaling (EMS) to release neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH), which activates β‐endorphin (β‐END) projection neurons that extend to the medial preoptic nucleus (MPN). The MPN is an important integrative node receiving accessory olfactory and limbic input. β‐END activates μ‐opioid receptors (MOR), producing a transient inhibition of the MPN which is relieved by progesterone in the cycling female. The MPN MOR neurons in turn project to the ventromedial nucleus of the hypothalamus (VMH), the final common output of the hypothalamus. The integrated hypothalamic output is modified by inputs from the periaquaductal gray, and the vestibular complex on its way to the motoneurons mediating lordosis behavior. The EMS that mediates this activation of the circuit requires the transactivation of metabotropic glutamate receptor‐1a (mGluR1a), which leads to the phosphorylation of PKCθ and the release of NPY and activation of the Y1 receptor on β‐END projection cells. The EMS and resulting transient inhibition is necessary for the full expression of lordosis behavior in the rat [adapted, with permission, from (116)].


Figure 3. A model showing proposed estradiol (E2) actions on hypothalamic cells. In Kiss1 neurons, E2 acts at both membrane and nuclear estrogen receptors. During diestrus, classical nuclear E2 signaling induces PR expression in kisspeptin (Kiss1) neurons in the RP3V. On proestrus, rising E2 leads to transactivation of mGluR1a in astrocytes, which increases [Ca2+] i leading to stimulation of a kinase cascade resulting in the activation of translocator protein (TSPO) and steroid acute regulatory protein (StAR), which results in an increase of cholesterol import into the mitochondrion—the rate limiting step in steroidogenesis. The resulting pregnenolone (PREG) is converted to progesterone (neuroP) by 3β‐HSD. Simultaneously, E2 activates an ERα‐mGluR1a complex in neurons leading to the expression of Kiss1. Newly synthesized neuroP diffuses out of the astrocytes and activates E2‐induced PR, which have been trafficked to the Kiss1 neuronal membrane. This leads to a series of events culminating in Kiss1 secretion onto GPR54 expressing GnRH neurons. We hypothesize that signaling through the membrane PR involves transactivation of another receptor (indicated by [?]) to stimulate [Ca2+]i, and induce Kiss1 release, activating GnRH neurons and triggering the E2‐induced LH surge from anterior pituitary gonadotrophs.
References
 1. Abel TW , Voytko ML , Rance NE . The effects of hormone replacement therapy on hypothalamic neuropeptide gene expression in a primate model of menopause. J Clin Endocrinol Metab 84: 2111‐2118, 1999.
 2. Abraham IM , Todman MG , Korach KS , Herbison AE . Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain. Endocrinology 145: 3055‐3061, 2004.
 3. Adachi S , Yamada S , Takatsu Y , Matsui H , Kinoshita M , Takase K , Sugiura H , Ohtaki T , Matsumoto H , Uenoyama Y , Tsukamura H , Inoue K , Maeda K . Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev 53: 367‐378, 2007.
 4. Akesson TR , Micevych PE . Endogenous opioid‐immunoreactive neurons of the ventromedial hypothalamic nucleus concentrate estrogen in male and female rats. J Neurosci Res 28: 359‐366, 1991.
 5. Akesson TR , Micevych PE . Evidence for an absence of estrogen concentration by CCK‐immunoreactive neurons in the hypothalamus of the female rat. J Neurobiol 19: 3‐16, 1988.
 6. Alger BE . Retrograde signaling in the regulation of synaptic transmission: Focus on endocannabinoids. Prog Neurobiol 68: 247‐286, 2002.
 7. Alreja M . Electrophysiology of kisspeptin neurons. Adv Exp Med Biol 784: 349‐362, 2013.
 8. Arnold AP , Burgoyne PS . Are XX and XY brain cells intrinsically different? Trends Endocrinol Metab 15: 6‐11, 2004.
 9. Ashley RL , Clay CM , Farmerie TA , Niswender GD , Nett TM . Cloning and characterization of an ovine intracellular seven transmembrane receptor for progesterone that mediates calcium mobilization. Endocrinology 147: 4151‐4159, 2006.
 10. Bashour NM , Wray S . Progesterone directly and rapidly inhibits GnRH neuronal activity via progesterone receptor membrane component 1. Endocrinology 153: 4457‐4469, 2012.
 11. Beach FA. Hormones and Behavior. New York: Paul B Hoeber, 1948.
 12. Blaustein JD , Feder HH . Cytoplasmic progestin receptors in female guinea pig brain and their relationship to refractoriness in expression of female sexual behavior. Brain Res 177: 489‐498, 1979.
 13. Blaustein JD , Feder HH . Nuclear progestin receptors in guinea pig brain measured by an in vitro exchange assay after hormonal treatments that affect lordosis. Endocrinol 106: 1061‐1069, 1980.
 14. Blaustein JD , Wade GN . Ovarian influences on the meal patterns of female rats. Physiol Behav 17: 201‐208, 1976.
 15. Bondar G , Kuo J , Hamid N , Micevych P . Estradiol‐induced estrogen receptor‐alpha trafficking. J Neurosci 29: 15323‐15330, 2009.
 16. Booth JE . Sexual differentiation of the brain. In: Finn CA , editor. Oxford Reviews of Reproductive Biology. Oxford: Clarendon Press, 1979, pp. 58‐158.
 17. Bosch MA , Tonsfeldt KJ , Ronnekleiv OK . mRNA expression of ion channels in GnRH neurons: Subtype‐specific regulation by 17beta‐estradiol. Mol Cell Endocrinol 367: 85‐97, 2013.
 18. Boulware MI , Weick JP , Becklund BR , Kuo SP , Groth RD , Mermelstein PG . Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element‐binding protein. J Neurosci 25: 5066‐5078, 2005.
 19. Brom GM , Schwartz NB . Acute changes in the estrous cycle following ovariectomy in the golden hamster. Neuroendocrinology 3: 366‐377, 1968.
 20. Brown LM , Gent L , Davis K , Clegg DJ . Metabolic impact of sex hormones on obesity. Brain Res 1350: 77‐85, 2010.
 21. Buckingham JC , Deohler KD , Wilson CA . Activity of the pituitary‐adrenocortical system and thyroid gland during the oestrous cycle of the rat. J Endocrinol 78: 359‐366, 1978.
 22. Carmeci C , Thompson DA , Ring HZ , Francke U , Weigel RJ . Identification of a gene (GPR30) with homology to the G‐protein‐coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics 45: 607‐617, 1997.
 23. Chaban VV , Lakhter AJ , Micevych P . A membrane estrogen receptor mediates intracellular calcium release in astrocytes. Endocrinology 145: 3788‐3795, 2004.
 24. Chaban VV , Mayer EA , Ennes HS , Micevych PE . Estradiol inhibits atp‐induced intracellular calcium concentration increase in dorsal root ganglia neurons. Neuroscience 118: 941‐948, 2003.
 25. Chappell PE , Levine JE . Stimulation of gonadotropin‐releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors. Endocrinology 141: 1477‐1485, 2000.
 26. Chappell PE , Schneider JS , Kim P , Xu M , Lydon JP , O'Malley BW , Levine JE . Absence of gonadotropin surges and gonadotropin‐releasing hormone self‐ priming in ovariectomized (OVX), estrogen (E2)‐treated, progesterone receptor knockout (PRKO) mice. Endocrinology 140: 3653‐3658, 1999.
 27. Chen C , Kuo J , Wong A , Micevych P . Estradiol modulates translocator protein (TSPO) and steroid acute regulatory protein (StAR) via protein kinase A (PKA) signaling in hypothalamic astrocytes. Endocrinology 155: 2976‐2985, 2014.
 28. Cholanian M , Krajewski‐Hall SJ , Levine RB , McMullen NT , Rance NE . Electrophysiology of arcuate neurokinin B neurons in female Tac2‐EGFP transgenic mice. Endocrinology 155: 2555‐2565, 2014.
 29. Christensen A , Dewing P , Micevych P . Membrane‐initiated estradiol signaling induces spinogenesis required for female sexual receptivity. J Neurosci 31: 17583‐17589, 2011.
 30. Christensen A , Micevych P . CAV1 siRNA reduces membrane estrogen receptor‐alpha levels and attenuates sexual receptivity. Endocrinology 153: 3872‐3877, 2012.
 31. Christensen A , Micevych P . A novel membrane estrogen receptor activated by STX induces female sexual receptivity through an interacation with mGluR1a. Neuroendocrinology 97:363‐368, 2013.
 32. Claing A , Laporte SA , Caron MG , Lefkowitz RJ . Endocytosis of G protein‐coupled receptors: Roles of G protein‐coupled receptor kinases and beta‐arrestin proteins. Prog Neurobiol 66: 61‐79, 2002.
 33. Clarkson J , d'Anglemont de Tassigny X , Moreno AS , Colledge WH , Herbison AE . Kisspeptin‐GPR54 signaling is essential for preovulatory gonadotropin‐releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci 28: 8691‐8697, 2008.
 34. Clarkson J , Herbison AE . Oestrogen, kisspeptin, GPR54 and the pre‐ovulatory luteinising hormone surge. J Neuroendocrinol 21: 305‐311, 2009.
 35. Clarkson J , Herbison AE . Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin‐releasing hormone neurons. Endocrinology 147: 5817‐5825, 2006.
 36. Corander MP , Challis BG , Thompson EL , Jovanovic Z , Loraine Tung YC , Rimmington D , Huhtaniemi IT , Murphy KG , Topaloglu AK , Yeo GS , O'Rahilly S , Dhillo WS , Semple RK , Coll AP . The effects of neurokinin B upon gonadotrophin release in male rodents. J Neuroendocrinol 22: 181‐187, 2010.
 37. Daaka Y , Pitcher JA , Richardson M , Stoffel RH , Robishaw JD , Lefkowitz RJ . Receptor and G betagamma isoform‐specific interactions with G protein‐coupled receptor kinases. Proc Natl Acad Sci U S A 94: 2180‐2185, 1997.
 38. Danzer SC , Price RO , McMullen NT , Rance NE . Sex steroid modulation of neurokinin B gene expression in the arcuate nucleus of adult male rats. Brain Res Mol Brain Res 66: 200‐204, 1999.
 39. de Croft S , Boehm U , Herbison AE . Neurokinin B activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse. Endocrinology 154: 2750‐2760, 2013.
 40. de Croft S , Piet R , Mayer C , Mai O , Boehm U , Herbison AE . Spontaneous kisspeptin neuron firing in the adult mouse reveals marked sex and brain region differences but no support for a direct role in negative feedback. Endocrinology 153: 5384‐5393, 2012.
 41. de Roux N , Genin E , Carel JC , Matsuda F , Chaussain JL , Milgrom E . Hypogonadotropic hypogonadism due to loss of function of the KiSS1‐derived peptide receptor GPR54. Proc Natl Acad Sci U S A 100: 10972‐10976, 2003.
 42. DePaolo LV . Attenuation of preovulatory gonadotrophin surges by epostane: A new inhibitor of 3 beta‐hydroxysteroid dehydrogenase. J Endocrinol 118: 59‐68, 1988.
 43. DePaolo LV , Barraclough CA . Dose dependent effects of progesterone on the facilitation and inhibition of spontaneous gonadotropin surges in estrogen treated ovariectomized rats. BiolReprod 21: 1015‐1023, 1979.
 44. Dewing P , Boulware MI , Sinchak K , Christensen A , Mermelstein PG , Micevych P . Membrane estrogen receptor‐alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats. J Neurosci 27: 9294‐9300, 2007.
 45. Dewing P , Christensen A , Bondar G , Micevych P . Protein kinase C signaling in the hypothalamic arcuate nucleus regulates sexual receptivity in female rats. Endocrinology 149: 5934‐5942, 2008.
 46. Dominguez R , Dewing P , Kuo J , Micevych P . Membrane‐initiated estradiol signaling in immortalized hypothalamic N‐38 neurons. Steroids 78: 607‐613, 2013.
 47. Dominguez R , Hu E , Zhou M , Baudry M . 17Beta‐estradiol‐mediated neuroprotection and ERK activation require a pertussis toxin‐sensitive mechanism involving GRK2 and beta‐arrestin‐1. J Neurosci 29: 4228‐4238, 2009.
 48. Dominguez R , Micevych P . Estradiol rapidly regulates membrane estrogen receptor alpha levels in hypothalamic neurons. J Neurosci 30: 12589‐12596, 2010.
 49. Dorling AA , Todman MG , Korach KS , Herbison AE . Critical role for estrogen receptor alpha in negative feedback regulation of gonadotropin‐releasing hormone mRNA expression in the female mouse. Neuroendocrinology 78: 204‐209, 2003.
 50. Dumalska I , Wu M , Morozova E , Liu R , van den Pol A , Alreja M . Excitatory effects of the puberty‐initiating peptide kisspeptin and group I metabotropic glutamate receptor agonists differentiate two distinct subpopulations of gonadotropin‐releasing hormone neurons. J Neurosci 28: 8003‐8013, 2008.
 51. Dungan Lemko HM , Elias CF . Kiss of the mutant mouse: How genetically altered mice advanced our understanding of kisspeptin's role in reproductive physiology. Endocrinology 153: 5119‐5129, 2012.
 52. Eckersell CB , Micevych PE . Opiate receptors modulate estrogen‐induced cholecystokinin and tachykinin but not enkephalin mRNA levels in the limbic system and hypothalamus. Neuroscience 80: 473‐485, 1997.
 53. Eckersell CB , Popper P , Micevych PE . Estrogen‐induced alteration of mu‐opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala. J Neurosci 18: 3967‐3976, 1998.
 54. Ferin M , Tempone A , Zimmering PE , Van de Wiele RL . Effect of antibodies to 17beta‐estradiol and progesterone on the estrous cycle of the rat. Endocrinology 85: 1070‐1078, 1969.
 55. Frazao R , Cravo RM , Donato J, Jr , Ratra DV , Clegg DJ , Elmquist JK , Zigman JM , Williams KW , Elias CF . Shift in Kiss1 cell activity requires estrogen receptor alpha. J Neurosci 33: 2807‐2820, 2013.
 56. Gaskins GT , Glanowska KM , Moenter SM . Activation of neurokinin 3 receptors stimulates GnRH release in a location‐dependent but kisspeptin‐independent manner in adult mice. Endocrinology 154: 3984‐3989, 2013.
 57. Ge L , Ly Y , Hollenberg M , De Fea K . A beta‐arrestin‐dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease‐activated receptor‐2‐induced chemotaxis. J Biol Chem 278: 34418‐34426, 2003.
 58. Gorosito SV , Lorenzo AG , Cambiasso MJ . Estrogen receptor alpha is expressed on the cell‐surface of embryonic hypothalamic neurons. Neuroscience 154: 1173‐1177, 2008.
 59. Gorski RA . Sexual differentiation of the endocrine brain and its control. In: Motta M , editor. Brain Endocrinology (2nd ed). New York: Raven Press, 1991, pp. 71‐104.
 60. Gorski RA . Sexual dimorphisms of the brain. J Anim Sci 61(Suppl 3): 38‐61, 1985.
 61. Gottsch ML , Navarro VM , Zhao Z , Glidewell‐Kenney C , Weiss J , Jameson JL , Clifton DK , Levine JE , Steiner RA . Regulation of Kiss1 and dynorphin gene expression in the murine brain by classical and nonclassical estrogen receptor pathways. J Neurosci 29: 9390‐9395, 2009.
 62. Gottsch ML , Popa SM , Lawhorn JK , Qiu J , Tonsfeldt KJ , Bosch MA , Kelly MJ , Ronnekleiv OK , Sanz E , McKnight GS , Clifton DK , Palmiter RD , Steiner RA . Molecular properties of Kiss1 neurons in the arcuate nucleus of the mouse. Endocrinology 152: 4298‐4309, 2011.
 63. Han SK , Gottsch ML , Lee KJ , Popa SM , Smith JT , Jakawich SK , Clifton DK , Steiner RA , Herbison AE . Activation of gonadotropin‐releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 25: 11349‐11356, 2005.
 64. Hanna R , Pang Y , Thomas P , Zhu Y . Cell‐surface expression, progestin binding, and rapid nongenomic signaling of zebrafish membrane progestin receptors alpha and beta in transfected cells. J Endocrinol 190: 247‐260, 2006.
 65. Heine PA , Taylor JA , Iwamoto GA , Lubahn DB , Cooke PS . Increased adipose tissue in male and female estrogen receptor‐alpha knockout mice. Proc Natl Acad Sci U S A 97: 12729‐12734, 2000.
 66. Herbison AE , de Tassigny X , Doran J , Colledge WH . Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin‐releasing hormone neurons. Endocrinology 151: 312‐321, 2010.
 67. Herbison AE , Theodosis DT . Localization of oestrogen receptors in preoptic neurons containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone‐releasing hormone in the male and female rat. Neuroscience 50: 283‐298, 1992.
 68. Hibbert ML , Stouffer RL , Wolf DP , Zelinski‐Wooten MB . Midcycle administration of a progesterone synthesis inhibitor prevents ovulation in primates. Proc Natl Acad Sci U S A 93: 1897‐1901, 1996.
 69. Irwig MS , Fraley GS , Smith JT , Acohido BV , Popa SM , Cunningham MJ , Gottsch ML , Clifton DK , Steiner RA . Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS‐1 mRNA in the male rat. Neuroendocrinology 80: 264‐272, 2004.
 70. Isensee J , Meoli L , Zazzu V , Nabzdyk C , Witt H , Soewarto D , Effertz K , Fuchs H , Gailus‐Durner V , Busch D , Adler T , de Angelis MH , Irgang M , Otto C , Noppinger PR . Expression pattern of G protein‐coupled receptor 30 in LacZ reporter mice. Endocrinology 150: 1722‐1730, 2009.
 71. Itzhak Y , Roig‐Cantisano A , Norenberg MD . Ontogeny of peripheral‐type benzodiazepine receptors in cultured astrocytes and brain from rat. Brain Res Dev Brain Res 84: 62‐66, 1995.
 72. Karsch FJ , Legan SJ , Hauger RL , Foster DL . Negative feedback action of progesterone on tonic luteinizing hormone secretion in the ewe: Dependence on the ovaries. Endocrinology 101: 800‐806, 1977.
 73. Karteris E , Zervou S , Pang Y , Dong J , Hillhouse EW , Randeva HS , Thomas P . Progesterone signaling in human myometrium through two novel membrane G protein‐coupled receptors: Potential role in functional progesterone withdrawal at term. Mol Endocrinol 20: 1519‐1534, 2006.
 74. Kawato S , Yamada M , Kimoto T . Brain neurosteroids are 4th generation neuromessengers in the brain: Cell biophysical analysis of steroid signal transduction. Adv Biophys 37: 1‐48, 2003.
 75. Kelly M , Wagner E . Estrogen modulation of G‐protein‐coupled receptors. Trends Endocrinol Metab 10: 369‐374, 1999.
 76. Kelly MJ , Moss RL , Dudley CA . Differential sensitivity of preoptic‐septal neurons to microelectrophoresed estrogen during the estrous cycle. Brain Res 114: 152‐157, 1976.
 77. Kelly MJ , Moss RL , Dudley CA . The effects of microelectrophoretically applied estrogen, cortisol and acetylcholine on medial preoptic‐septal unit activity throughout the estrous cycle of the female rat. Exp Brain Res 30: 53‐64, 1977.
 78. Kelly MJ , Zhang C , Qiu J , Ronnekleiv OK . Pacemaking kisspeptin neurons. Exp Physiol 98: 1535‐1543, 2013.
 79. King CM , Hentges ST . Relative number and distribution of murine hypothalamic proopiomelanocortin neurons innervating distinct target sites. PLoS One 6: e25864, 2011.
 80. Kinoshita M , Tsukamura H , Adachi S , Matsui H , Uenoyama Y , Iwata K , Yamada S , Inoue K , Ohtaki T , Matsumoto H , Maeda K . Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology 146: 4431‐4436, 2005.
 81. Kirilov M , Clarkson J , Liu X , Roa J , Campos P , Porteous R , Schutz G , Herbison AE . Dependence of fertility on kisspeptin‐Gpr54 signaling at the GnRH neuron. Nat Commun 4: 2492, 2013.
 82. Klinge CM . Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res 29: 2905‐2919, 2001.
 83. Kow LM , Mobbs CV , Pfaff DW . Roles of second‐messenger systems and neuronal activity in the regulation of lordosis by neurotransmitters, neuropeptides, and estrogen: A review. Neurosci Biobehav Rev 18: 251‐268, 1994.
 84. Kow LM , Pfaff DW . The membrane actions of estrogens can potentiate their lordosis behavior‐facilitating genomic actions. Proc Natl Acad Sci U S A 101: 12354‐12357, 2004.
 85. Krajewski SJ , Burke MC , Anderson MJ , McMullen NT , Rance NE . Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract‐tracing and monosodium glutamate lesions in the rat. Neuroscience 166: 680‐697, 2010.
 86. Krietsch T , Fernandes MS , Kero J , Losel R , Heyens M , Lam EW , Huhtaniemi I , Brosens JJ , Gellersen B . Human homologs of the putative G protein‐coupled membrane progestin receptors (mPRalpha, beta, and gamma) localize to the endoplasmic reticulum and are not activated by progesterone. Mol Endocrinol 20: 3146‐3164, 2006.
 87. Kuo J , Hamid N , Bondar G , Dewing P , Clarkson J , Micevych P . Sex differences in hypothalamic astrocyte response to estradiol stimulation. Biol Sex Differ 1: 7, 2010.
 88. Kuo J , Hamid N , Bondar G , Prossnitz ER , Micevych P . Membrane estrogen receptors stimulate intracellular calcium release and progesterone synthesis in hypothalamic astrocytes. J Neurosci 30: 12950‐12957, 2010.
 89. Kuo J , Hariri OR , Bondar G , Ogi J , Micevych P . Membrane estrogen receptor‐alpha interacts with metabotropic glutamate receptor type 1a to mobilize intracellular calcium in hypothalamic astrocytes. Endocrinology 150: 1369‐1376, 2009.
 90. Kuo J , Micevych P . Neurosteroids, trigger of the LH surge. J Steroid Biochem Mol Biol 131: 57‐65, 2012.
 91. Labhsetwar AP . Role of estrogens in ovulation: A study using the estrogen‐antagonist, I.C.I. 46,474. Endocrinology 87: 542‐551, 1970.
 92. Lefkowitz RJ , Shenoy SK . Transduction of receptor signals by beta‐arrestins. Science 308: 512‐517, 2005.
 93. Lehman MN , Coolen LM , Goodman RL . Minireview: Kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: A central node in the control of gonadotropin‐releasing hormone secretion. Endocrinology 151: 3479‐3489, 2010.
 94. Lehman MN , Merkley CM , Coolen LM , Goodman RL . Anatomy of the kisspeptin neural network in mammals. Brain Res 1364: 90‐102, 2010.
 95. Leonelli M , Torrao AS , Britto LR . Unconventional neurotransmitters, neurodegeneration and neuroprotection. Braz J Med Biol Res 42: 68‐75, 2009.
 96. Levin ER . G protein‐coupled receptor 30: Estrogen receptor or collaborator? Endocrinology 150: 1563‐1565, 2009.
 97. Li XF , Kinsey‐Jones JS , Cheng Y , Knox AM , Lin Y , Petrou NA , Roseweir A , Lightman SL , Milligan SR , Millar RP , O'Byrne KT . Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS One 4: e8334, 2009.
 98. Liu X , Lee K , Herbison AE . Kisspeptin excites gonadotropin‐releasing hormone neurons through a phospholipase C/calcium‐dependent pathway regulating multiple ion channels. Endocrinology 149: 4605‐4614, 2008.
 99. London SE , Monks DA , Wade J , Schlinger BA . Widespread capacity for steroid synthesis in the avian brain and song system. Endocrinology 147: 5975‐5987, 2006.
 100. Lydon JP , DeMayo FJ , Funk CR , Mani SK , Hughes AR , Montgomery CA, Jr , Shyamala G , Conneely OM , O'Malley BW . Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9: 2266‐2278, 1995.
 101. Ma L , Pei G . Beta‐arrestin signaling and regulation of transcription. J Cell Sci 120: 213‐218, 2007.
 102. MacLusky NJ , Naftolin F . Sexual differentiation of the central nervous system. Science 211: 1294‐1302, 1981.
 103. Mahavongtrakul M , Kanjiya MP , Maciel M , Kanjiya S , Sinchak K . Estradiol dose‐dependent regulation of membrane estrogen receptor‐alpha, metabotropic glutamate receptor‐1a, and their complexes in the arcuate nucleus of the hypothalamus in female rats. Endocrinology 154: 3251‐3260, 2013.
 104. Mahesh VB , Brann DW . Interaction between ovarian and adrenal steroids in the regulation of gonadotropin secretion. J Steroid Biochem Mol Biol 41: 495‐513, 1992.
 105. Mahesh VB , Brann DW . Neuroendocrine mechanisms underlying the control of gonadotropin secretion by steroids. Steroids 63: 252‐256, 1998.
 106. Mani SK , Allen JM , Clark JH , Blaustein JD , O'Malley BW . Convergent pathways for steroid hormone‐ and neurotransmitter‐induced rat sexual behavior. Science 265: 1246‐1249, 1994.
 107. Mani SK , Blaustein JD . Neural progestin receptors and female sexual behavior. Neuroendocrinology 96: 152‐161, 2012.
 108. Mani SK , Blaustein JD , Allen JM , Law SW , O'Malley BW , Clark JH . Inhibition of rat sexual behavior by antisense oligonucleotides to the progesterone receptor. Endocrinology 135: 1409‐1414, 1994.
 109. Mann DR , Barraclough CA . Role of estrogen and progesterone in facilitating LH release in 4‐day cyclic rats. Endocrinol 93: 694‐699, 1973.
 110. Mann DR , Korowitz CD , Barraclough CA . Adrenal gland involvement in synchronizing the preovulatory release of LH in rats. Proc Soc Exp Biol Med 150: 115‐120, 1975.
 111. Meitzen J , Luoma JI , Boulware MI , Hedges VL , Peterson BM , Tuomela K , Britson KA , Mermelstein PG . Palmitoylation of estrogen receptors is essential for neuronal membrane signaling. Endocrinology 154: 4293‐4304, 2013.
 112. Meitzen J , Mermelstein PG . Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways. J Chem Neuroanat 42: 236‐241, 2011.
 113. Meng D , Lynch MJ , Huston E , Beyermann M , Eichhorst J , Adams DR , Klussmann E , Houslay MD , Baillie GS . MEK1 binds directly to betaarrestin1, influencing both its phosphorylation by ERK and the timing of its isoprenaline‐stimulated internalization. J Biol Chem 284: 11425‐11435, 2009.
 114. Merkley CM , Porter KL , Coolen LM , Hileman SM , Billings HJ , Drews S , Goodman RL , Lehman MN . KNDy (kisspeptin/neurokinin B/dynorphin) neurons are activated during both pulsatile and surge secretion of LH in the ewe. Endocrinology 153: 5406‐5414, 2012.
 115. Mermelstein P , Becker J , Surmeister D . Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor. J Neurosci 16: 595‐604, 1996.
 116. Micevych P , Christensen A . Membrane‐initiated estradiol actions mediate structural plasticity and reproduction. Front Neuroendocrinol 33: 331‐341, 2012.
 117. Micevych P , Dominguez R . Membrane estradiol signaling in the brain. Front Neuroendocrinol 30: 315‐327, 2009.
 118. Micevych P , Mills R , Sinchak K , Lapolt P , Chen J , Tao L , Lu J . Estrogen stimulates progesterone synthesis in rat hypothalamus. Soc Neurosci Abstr, San Diego, CA, 2001.
 119. Micevych P , Sinchak K . The neurochemistry of limbic‐hypothalamic circuits regulating sexual receptivity. In: Lajtha A , editor. Handbook of Neurochemistry and Molecular Neurobiology (3rd ed). New York: Springer, 2007, pp. 151‐193.
 120. Micevych P , Sinchak K . Estradiol regulation of progesterone synthesis in the brain. Mol Cell Endocrinol 290: 44‐50, 2008.
 121. Micevych P , Sinchak K , Mills RH , Tao L , LaPolt P , Lu JK . The luteinizing hormone surge is preceded by an estrogen‐induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats. Neuroendocrinology 78: 29‐35, 2003.
 122. Micevych P , Soma KK , Sinchak K . Neuroprogesterone: Key to estrogen positive feedback? Brain Res Rev 57: 470‐480, 2008.
 123. Micevych PE , Abelson L , Fok H , Ulibarri C , Priest CA . Gonadal steroid control of preproenkephalin mRNA expression in the limbic‐hypothalamic circuit: Comparison of adult with neonatal steroid treatments. J of Neurosci Res 38: 386‐398, 1994.
 124. Micevych PE , Chaban V , Ogi J , Dewing P , Lu JK , Sinchak K . Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures. Endocrinology 148: 782‐789, 2007.
 125. Micevych PE , Chaban V , Ogi J , Lakhter A , Lu JKH , Sinchak K . Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures. Endocrinology 148: 782‐789, 2007.
 126. Micevych PE , Dewing P . Membrane‐initiated estradiol signaling regulating sexual receptivity. Front Endocrinol 2: 26, 2011.
 127. Micevych PE , Eckersell CB , Holland KL , Smith A . Induction of CCK mRNA levels in the limbic‐hypothalamic circuit: Time course and site‐specific effects of estrogen. J Neurobiol 30: 465‐479, 1996.
 128. Micevych PE , Kelly MJ . Membrane estrogen receptor regulation of hypothalamic function. Neuroendocrinology 96: 103‐110, 2012.
 129. Micevych PE , Mermelstein PG . Membrane estrogen receptors acting through metabotropic glutamate receptors: An emerging mechanism of estrogen action in brain. Mol Neurobiol 38: 66‐77, 2008.
 130. Micevych PE , Rissman EF , Gustafsson JA , Sinchak K . Estrogen receptor‐alpha is required for estrogen‐induced mu‐opioid receptor internalization. J Neurosci Res 71: 802‐810, 2003.
 131. Micevych PE , Sinchak K . The neurosteroid progesterone underlies estrogen positive feedback of the LH surge. Front Endocrinol 2: 2011.
 132. Miller WE , Lefkowitz RJ . Expanding roles for beta‐arrestins as scaffolds and adapters in GPCR signaling and trafficking. Curr Opin Cell Biol 13: 139‐145, 2001.
 133. Mills R , Chiang I , Abdian P , Sinchak K , Romeo H , Lu J , Micevych P . Reproductive aging is associated with loss of hypothalamic progesterone synthesis but not decreased estrogen and progesterone receptor mRNA expression. Soc Neurosci Abstr, Orlando, FL, 2002.
 134. Mills RH , Sohn RK , Micevych PE . Estrogen‐induced mu‐opioid receptor internalization in the medial preoptic nucleus is mediated via neuropeptide Y‐Y1 receptor activation in the arcuate nucleus of female rats. J Neurosci 24: 947‐955, 2004.
 135. Mittelman‐Smith MA , Williams H , Krajewski‐Hall SJ , Lai J , Ciofi P , McMullen NT , Rance NE . Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. Endocrinology 153: 2800‐2812, 2012.
 136. Mittelman‐Smith MA , Wong AM , Kathiresan AQ , Micevych PE . Classical and membrane‐initiated estrogen signaling in an in vitro model of anterior hypothalamic kisspeptin neurons. Endocrinology, In Press.
 137. Mostari P , Ieda N , Deura C , Minabe S , Yamada S , Uenoyama Y , Maeda K , Tsukamura H . dynorphin‐kappa opioid receptor signaling partly mediates estrogen negative feedback effect on LH pulses in female rats. J Reprod Dev 59: 266‐272, 2013.
 138. Moussatche P , Lyons TJ . Non‐genomic progesterone signalling and its non‐canonical receptor. Biochem Soc Trans 40: 200‐204, 2012.
 139. Nakamura NH , Rosell DR , Akama KT , McEwen BS . Estrogen and ovariectomy regulate mRNA and protein of glutamic acid decarboxylases and cation‐chloride cotransporters in the adult rat hippocampus. Neuroendocrinology 80: 308‐323, 2004.
 140. Navarro VM , Castellano JM , McConkey SM , Pineda R , Ruiz‐Pino F , Pinilla L , Clifton DK , Tena‐Sempere M , Steiner RA . Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. Am J Physiol Endocrinol Metab 300: E202‐210, 2011.
 141. Neill JD . Sexual differences in the hypothalamic regulation of prolactin secretion. Endocrinology 90: 1154‐1159, 1972.
 142. Neves SR , Ram PT , Iyengar R . G protein pathways. Science 296: 1636‐1639, 2002.
 143. Novaira HJ , Sonko ML , Hoffman G , Koo Y , Ko C , Wolfe A , Radovick S . Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism. Mol Endocrinol 28: 225‐238, 2014.
 144. Otto C , Fuchs I , Kauselmann G , Kern H , Zevnik B , Andreasen P , Schwarz G , Altmann H , Klewer M , Schoor M , Vonk R , Fritzemeier KH . GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol Reprod 80: 34‐41, 2009.
 145. Paaske LK , Chuon T , Micevych P , Sinchak K . AVPV kisspeptin neurons mediate neuroprogesterone induction of the leuteinizing hormone surge. Soc Neurosci Abstr, Washington, DC, 2014.
 146. Paaske LK , Micevych PE , Sinchak K . Kisspeptin mediates neuroprogesterone induction of the luteinizing hormone surge. The Endocrine Society's 95th Annual Meeting & Expo, San Francisco, CA, USA 2013.
 147. Pang Y , Dong J , Thomas P . Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors delta and {epsilon} (mPRdelta and mPR{epsilon}) and mPRdelta involvement in neurosteroid inhibition of apoptosis. Endocrinology 154: 283‐295, 2013.
 148. Papadopoulos V , Baraldi M , Guilarte TR , Knudsen TB , Lacapere JJ , Lindemann P , Norenberg MD , Nutt D , Weizman A , Zhang MR , Gavish M . Translocator protein (18 kDa): New nomenclature for the peripheral‐type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27: 402‐409, 2006.
 149. Parhar IS , Ogawa S , Sakuma Y . Laser‐captured single digoxigenin‐labeled neurons of gonadotropin‐releasing hormone types reveal a novel G protein‐coupled receptor (Gpr54) during maturation in cichlid fish. Endocrinology 145: 3613‐3618, 2004.
 150. Parsons B , Rainbow TC , Pfaff DW , McEwen BS . Hypothalamic protein synthesis essential for the activation of the lordosis reflex in the female rat. Endocrinology 110: 620‐624, 1982.
 151. Petersen SL , LaFlamme KD . Progesterone increases levels of μ‐opioid receptor mRNA in the preoptic area and arcuate nucleus of ovariectomized, estradiol‐treated female rats. Brain Res Mol Brain Res 52: 32‐37, 1997.
 152. Pfaff DW . Uptake of 3H‐estradiol by the female rat brain. An autoradiographic study. Endocrinology 82: 1149‐1155, 1968.
 153. Phan J , Mahavongtrakul M , Sinchak K . Progesterone receptor‐B and Src kinase complex in the plasma membrane of the arcuate nucleus of the hypothalamus of female rats. Soc Neurosci Abstr, 2014.
 154. Pielecka‐Fortuna J , Chu Z , Moenter SM . Kisspeptin acts directly and indirectly to increase gonadotropin‐releasing hormone neuron activity and its effects are modulated by estradiol. Endocrinology 149: 1979‐1986, 2008.
 155. Piet R , de Croft S , Liu X , Herbison AE . Electrical properties of kisspeptin neurons and their regulation of GnRH neurons. Front Neuroendocrinol pii: S0091‐3022(14)00053‐3, 2014.
 156. Popper P , Priest CA , Micevych PE . Regulation of cholecystokinin receptors in the ventromedial nucleus of the hypothalamus: Sex steroid hormone regulation. Brain Res 715: 335‐339, 1996.
 157. Prast H , Philippu A . Nitric oxide as modulator of neuronal function. Prog Neurobiol 64: 51‐68, 2001.
 158. Priest CA , Vink KL , Micevych PE . Temporal regulation by estrogen of beta‐preprotachykinin mRNA expression in the rat ventromedial nucleus of the hypothalamus. Brain Res Mol Brain Res 28: 61‐71, 1995.
 159. Prossnitz ER , Barton M . The G‐protein‐coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 7: 715‐726, 2011.
 160. Putnam CD , Brann DW , Mahesh VB . Acute activation of the adrenocorticotropin‐adrenal axis: Effect on gonadotropin and prolactin secretion in the female rat. Endocrinology 128: 2558‐2566, 1991.
 161. Qiu J , Bosch MA , Tobias SC , Grandy DK , Scanlan TS , Ronnekleiv OK , Kelly MJ . Rapid signaling of estrogen in hypothalamic neurons involves a novel G‐protein‐coupled estrogen receptor that activates protein kinase C. J Neurosci 23: 9529‐9540, 2003.
 162. Quinones‐Jenab V , Jenab S , Ogawa S , Inturrisi C , Pfaff DW . Estrogen regulation of mu‐opioid receptor mRNA in the forebrain of female rats. Mol Brain Res 47: 134‐138, 1997.
 163. Rance NE , Bruce TR . Neurokinin B gene expression is increased in the arcuate nucleus of ovariectomized rats. Neuroendocrinology 60: 337‐345, 1994.
 164. Rance NE , Young WS, 3rd . Hypertrophy and increased gene expression of neurons containing neurokinin‐B and substance‐P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology 128: 2239‐2247, 1991.
 165. Razandi M , Oh P , Pedram A , Schnitzer J , Levin ER . ERs associate with and regulate the production of caveolin: Implications for signaling and cellular actions. Mol Endocrinol 16: 100‐115, 2002.
 166. Razandi M , Pedram A , Greene G , Levin E . Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: Studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol Endocrinol 13: 307‐319, 1999.
 167. Razandi M , Pedram A , Park ST , Levin ER . Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem 278: 2701‐2712, 2003.
 168. Remohi J , Balmaceda JP , Rojas FJ , Asch RH . The role of pre‐ovulatory progesterone in the midcycle gonadotrophin surge, ovulation and subsequent luteal phase: Studies with RU486 in rhesus monkeys. Hum Reprod 3: 431‐435, 1988.
 169. Revankar CM , Cimino DF , Sklar LA , Arterburn JB , Prossnitz ER . A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307: 1625‐1630, 2005.
 170. Roepke TA , Qiu J , Bosch MA , Ronnekleiv OK , Kelly MJ . Cross‐talk between membrane‐initiated and nuclear‐initiated oestrogen signalling in the hypothalamus. J Neuroendocrinol 21: 263‐270, 2009.
 171. Rometo AM , Krajewski SJ , Voytko ML , Rance NE . Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab 92: 2744‐2750, 2007.
 172. Roseweir AK , Kauffman AS , Smith JT , Guerriero KA , Morgan K , Pielecka‐Fortuna J , Pineda R , Gottsch ML , Tena‐Sempere M , Moenter SM , Terasawa E , Clarke IJ , Steiner RA , Millar RP . Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci 29: 3920‐3929, 2009.
 173. Rudd CD , Short RV , McFarlane JR , Renfree MB . Sexual differentiation of oestradiol‐LH positive feedback in a marsupial. J Reprod Fertil 115: 269‐274, 1999.
 174. Ruka KA , Burger LL , Moenter SM . Regulation of arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin by modulators of neurokinin 3 and kappa‐opioid receptors in adult male mice. Endocrinology 154: 2761‐2771, 2013.
 175. Safe S . Transcriptional activation of genes by 17 beta‐estradiol through estrogen receptor‐Sp1 interactions. Vitam Horm 62: 231‐252, 2001.
 176. Sanathara NM , Moraes J , Kanjiya S , Sinchak K . Orphanin FQ in the mediobasal hypothalamus facilitates sexual receptivity through the deactivation of medial preoptic nucleus mu‐opioid receptors. Horm Behav 60: 540‐548, 2011.
 177. Sanathara NM , Moraes J , Mahavongtrakul M , Sinchak K . Estradiol upregulates progesterone receptor and orphanin FQ colocalization in arcuate nucleus neurons and opioid receptor‐like receptor‐1 expression in proopiomelanocortin neurons that project to the medial preoptic nucleus in the female rat. Neuroendocrinology, 2014.
 178. Sanchez‐Criado JE , Hernandez G , Bellido C , Gonzalez D , Tebar M , Diaz‐Cruz MA , Alonso R . Periovulatory LHRH, LH and FSH secretion in cyclic rats treated with RU486: Effects of exogenous LHRH and LHRH antagonist on LH and FSH secretion at early oestrus. J Endocrinol 141: 7‐14, 1994.
 179. Sandoval‐Guzman T , Rance NE . Central injection of senktide, an NK3 receptor agonist, or neuropeptide Y inhibits LH secretion and induces different patterns of Fos expression in the rat hypothalamus. Brain Res 1026: 307‐312, 2004.
 180. Schumacher M , Guennoun R , Robert F , Carelli C , Gago N , Ghoumari A , Gonzalez Deniselle MC , Gonzalez SL , Ibanez C , Labombarda F , Coirini H , Baulieu EE , De Nicola AF . Local synthesis and dual actions of progesterone in the nervous system: Neuroprotection and myelination. Growth Horm IGF Res 14(Suppl A): S18‐33, 2004.
 181. Schumacher M , Hussain R , Gago N , Oudinet JP , Mattern C , Ghoumari AM . Progesterone synthesis in the nervous system: Implications for myelination and myelin repair. Front Neurosci 6: 10, 2012.
 182. Seminara SB , Messager S , Chatzidaki EE , Thresher RR , Acierno JS, Jr. , Shagoury JK , Bo‐Abbas Y , Kuohung W , Schwinof KM , Hendrick AG , Zahn D , Dixon J , Kaiser UB , Slaugenhaupt SA , Gusella JF , O'Rahilly S , Carlton MB , Crowley WF, Jr. , Aparicio SA , Colledge WH . The GPR54 gene as a regulator of puberty. N Engl J Med 349: 1614‐1627, 2003.
 183. Serey CS , Huss B , Chuon T , Mahavongtrakul M , Sinchak K . The signaling pathways of progesterone receptor, Src kinase, and dopamine D1 receptor converge in the arcuate nucleus of the hypothalamus to facilitate lordosis. Soc Neurosci Abstr, Washington, DC, 2014.
 184. Shaikh AA , Shaikh SA . Adrenal and ovarian steroid secretion. Endocrinology 96: 37‐44, 1975.
 185. Shaywitz AJ , Greenberg ME . CREB: A stimulus‐induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68: 821‐861, 1999.
 186. Shivers BD , Harlan RE , Morrell JI , Pfaff DW . Absence of oestradiol concentration in cell nuclei of LHRH‐immunoreactive neurones. Nature 304: 345‐347, 1983.
 187. Shivers BD , Harlan RE , Morrell JI , Pfaff DW . Immunocytochemical localization of luteinizing hormone‐releasing hormone in male and female rat brains. Quantitative studies on the effect of gonadal steroids. Neuroendocrinology 36: 1‐12, 1983.
 188. Simpson ER , Waterman MR . Regulation by ACTH of steroid hormone biosynthesis in the adrenal cortex. Can J Biochem Cell Biol 61: 692‐707, 1983.
 189. Sinchak K , Dewing P , Cook M , Micevych P . Release of orphanin FQ/nociceptin in the medial preoptic nucleus and ventromedial nucleus of the hypothalamus facilitates lordosis. Horm Behav 51: 406‐412, 2007.
 190. Sinchak K , Dewing P , Ponce L , Gomez L , Christensen A , Berger M , Micevych P . Modulation of the arcuate nucleus‐medial preoptic nucleus lordosis regulating circuit: A role for GABAB receptors. Horm Behav 64: 136‐143, 2013.
 191. Sinchak K , Micevych PE . Progesterone blockade of estrogen activation of μ‐opioid receptors regulates reproductive behavior. J Neurosci 21: 5723‐5729, 2001.
 192. Sinchak K , Mills RH , Eckersell CB , Micevych PE . Medial preoptic area delta‐opioid receptors inhibit lordosis. Behav Brain Res 155: 301‐306, 2004.
 193. Sinchak K , Romeo HE , Micevych PE . Site‐specific estrogen and progestin regulation of orphanin FQ/nociceptin and nociceptin opioid receptor mRNA expression in the female rat limbic hypothalamic system. J Comp Neurol 496: 252‐268, 2006.
 194. Sinchak K , Shahedi K , Dewing P , Micevych P . Sexual receptivity is reduced in the female mu‐opioid receptor knockout mouse. Neuroreport 16: 1697‐1700, 2005.
 195. Smith JT , Clay CM , Caraty A , Clarke IJ . KiSS‐1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season. Endocrinology 148: 1150‐1157, 2007.
 196. Smith JT , Cunningham MJ , Rissman EF , Clifton DK , Steiner RA . Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146: 3686‐3692, 2005.
 197. Smith JT , Popa SM , Clifton DK , Hoffman GE , Steiner RA . Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci 26: 6687‐6694, 2006.
 198. Snyder BW , Beecham GD , Schane HP . Inhibition of ovulation in rats with epostane, an inhibitor of 3 beta‐hydroxysteroid dehydrogenase. Proc Soc Exp Biol Med 176: 238‐242, 1984.
 199. Soma KK , Sinchak K , Lakhter A , Schlinger BA , Micevych PE . Neurosteroids and female reproduction: Estrogen increases 3beta‐HSD mRNA and activity in rat hypothalamus. Endocrinology 146: 4386‐4390, 2005.
 200. Szego CM , Davis JS . Adenosine 3′,5′‐monophosphate in rat uterus: Acute elevation by estrogen. Proc Natl Acad Sci U S A 58: 1711‐1718, 1967.
 201. Tang YT , Hu T , Arterburn M , Boyle B , Bright JM , Emtage PC , Funk WD . PAQR proteins: A novel membrane receptor family defined by an ancient 7‐transmembrane pass motif. J Mol Evol 61: 372‐380, 2005.
 202. Thomas P , Pang Y . Membrane progesterone receptors: Evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells. Neuroendocrinology 96: 162‐171, 2012.
 203. Thomas P , Pang Y , Dong J , Groenen P , Kelder J , de Vlieg J , Zhu Y , Tubbs C . Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor alpha subtypes and their evolutionary origins. Endocrinology 148: 705‐718, 2007.
 204. Todman MG , Han SK , Herbison AE . Profiling neurotransmitter receptor expression in mouse gonadotropin‐releasing hormone neurons using green fluorescent protein‐promoter transgenics and microarrays. Neuroscience 132: 703‐712, 2005.
 205. Topaloglu AK , Reimann F , Guclu M , Yalin AS , Kotan LD , Porter KM , Serin A , Mungan NO , Cook JR , Ozbek MN , Imamoglu S , Akalin NS , Yuksel B , O'Rahilly S , Semple RK . TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 41: 354‐358, 2009.
 206. Toran‐Allerand CD , Gerlach JL , McEwen BS . Autoradiographic localization of [3H]estradiol related to steroid responsiveness in cultures of the newborn mouse hypothalamus and preoptic area. Brain Res 184: 517‐522, 1980.
 207. Torii M , Kubo K , Sasaki T . Influence of opioid peptides on the priming action of estrogen on lordosis in ovariectomized rats. Neurosci Lett 212: 68‐70, 1996.
 208. Torii M , Kubo K , Sasaki T . Naloxone and initial estrogen action to induce lordosis in ovariectomized rats: The effect of a cut between the septum and preoptic area. Neurosci Lett 195: 167‐170, 1995.
 209. Webb P , Nguyen P , Valentine C , Lopez GN , Kwok GR , McInerney E , Katzenellenbogen BS , Enmark E , Gustafsson JA , Nilsson S , Kushner PJ . The estrogen receptor enhances AP‐1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 13: 1672‐1685, 1999.
 210. Wintermantel TM , Campbell RE , Porteous R , Bock D , Grone HJ , Todman MG , Korach KS , Greiner E , Perez CA , Schutz G , Herbison AE . Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin‐releasing hormone neurons and fertility. Neuron 52: 271‐280, 2006.
 211. Wong AM , Abrams MC , Micevych P . Beta‐Arrestin‐1 regulates estrogen membrane signaling in hypothalamic neurons. PLoS One, in press, 2015.
 212. Yang JJ , Caligioni CS , Chan YM , Seminara SB . Uncovering novel reproductive defects in neurokinin B receptor null mice: Closing the gap between mice and men. Endocrinology 153: 1498‐1508, 2012.
 213. Yen SS , Tsai CC . Acute gonadotropin release induced by exogenous estradiol during the mid‐follicular phase of the menstrual cycle. J Clin Endocrinol Metab 34: 298‐305, 1972.
 214. Yeo SH , Herbison AE . Estrogen‐negative feedback and estrous cyclicity are critically dependent upon estrogen receptor‐alpha expression in the arcuate nucleus of adult female mice. Endocrinology 155: 2986‐2995, 2014.
 215. Yoshikuni M , Nagahama Y . Involvement of an inhibitory G‐protein in the signal transduction pathway of maturation‐inducing hormone (17 alpha,20 beta‐dihydroxy‐4‐pregnen‐3‐one) action in rainbow trout (Oncorhynchus mykiss) oocytes. Dev Biol 166: 615‐622, 1994.
 216. Zhang C , Roepke TA , Kelly MJ , Ronnekleiv OK . Kisspeptin depolarizes gonadotropin‐releasing hormone neurons through activation of TRPC‐like cationic channels. J Neurosci 28: 4423‐4434, 2008.
 217. Zhang J , Barak LS , Winkler KE , Caron MG , Ferguson SS . A central role for beta‐arrestins and clathrin‐coated vesicle‐mediated endocytosis in beta2‐adrenergic receptor resensitization. Differential regulation of receptor resensitization in two distinct cell types. J Biol Chem 272: 27005‐27014, 1997.
 218. Zhang J , Yang L , Lin N , Pan X , Zhu Y , Chen X . Aging‐related changes in RP3V kisspeptin neurons predate the reduced activation of GnRH neurons during the early reproductive decline in female mice. Neurobiol Aging 35: 655‐668, 2014.
 219. Zuloaga DG , Yahn SL , Pang Y , Quihuis AM , Oyola MG , Reyna A , Thomas P , Handa RJ , Mani SK . Distribution and estrogen regulation of membrane progesterone receptor‐beta in the female rat brain. Endocrinology 153: 4432‐4443, 2012.
 220. Zwain IH , Yen SS . Neurosteroidogenesis in astrocytes, oligodendrocytes, and neurons of cerebral cortex of rat brain. Endocrinol 140: 3843‐3852, 1999.

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Article Title: Estradiol Membrane‐Initiated Signaling and Female Reproduction
 

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Paul E Micevych, Angela May Wong, Melinda Anne Mittelman‐Smith. Estradiol Membrane‐Initiated Signaling and Female Reproduction. Compr Physiol 2015, 5: 1211-1222. doi: 10.1002/cphy.c140056