[en] Estrogens act through nuclear and membrane-initiated signaling. Estrogen receptor alpha (ERα) is critical for reproduction, but the relative contribution of its nuclear and membrane signaling to the central regulation of reproduction is unclear. To address this question, two complementary approaches were used: estetrol (E4) a natural estrogen acting as an agonist of nuclear ERs but as an antagonist of their membrane fraction and the C451A-ERα mouse lacking mERα. E4 dose-dependently blocks ovulation in female rats, but the central mechanism underlying this effect is unknown. To determine whether E4 acts centrally to control ovulation, its effect was tested on the positive feedback of estradiol (E2) on neural circuits underlying LH secretion. In ovariectomized females chronically exposed to a low dose of E2, estradiol benzoate (EB) alone or combined with progesterone (P) induced an increase in the number of kisspeptin (Kp) and gonadotropin-releasing hormone (GnRH) neurons co-expressing Fos, as a marker of neuronal activation. However, E4 blocked these effects of EB when provided alone, but not when combined to P. These results indicate that E4 blocked the central induction of the positive feedback in the absence of P, suggesting an antagonistic effect of E4 on mERα in the brain as shown in peripheral tissues. In parallel, as opposed to wild-type females, C451A-ERα females did not show the activation of Kp and GnRH neurons in response to EB unless they are treated with P. Together these effects supports a role for membrane-initiated estrogen signaling in the activation of the circuit mediating the LH surge.Significance statement Estrogen receptor alpha (ERα) is critical for the activation of the neural circuits underlying ovulation. However, the relative contribution of its nuclear and membrane signaling to this neuroendocrine phenomenon is unclear. Using two complementary approaches to block membrane ERα signaling the present study reveals that membrane ERα signaling is required for the activation by estrogens of gonadotropin-releasing hormone (GnRH) and kisspeptin (Kp) neurons, two key neuronal populations underlying the surge of luteinizing hormone (LH) which triggers ovulation. Interestingly, the absence of activation of Kp and GnRH neurons is alleviated in both models by progesterone (P). Collectively the results of these two approaches converge to provide evidence that membrane estrogen signaling contributes to this key event for the central regulation of reproduction.
Abot A, et al. (2014) The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med 6:1328–1346.
Abraham IM, Han S-K, Todman MG, Korach KS, Herbison AE (2003) Estrogen receptor Beta mediates rapid estrogen actions on gonadotropin-releasing hormone neurons in vivo. J Neurosci 23:5771–5777.
Acconcia F, Fiocchetti M, Busonero C, Fernandez VS, Montalesi E, Cipolletti M, Pallottini V, Marino M (2021) The extra-nuclear interactome of the estrogen receptors: implications for physiological functions. Mol Cell Endocrinol 538:111452.
Adlanmerini M, et al. (2014) Mutation of the palmitoylation site of estrogen receptor alpha in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc Natl Acad Sci U S A 111: E283–290.
Alvisi RD, Diniz GB, Da-Silva JM, Bittencourt JC, Felicio LF (2016) Suckling-induced Fos activation and melanin-concentrating hormone immunoreactivity during late lactation. Life Sci 148:241–246.
Apter D, Zimmerman Y, Beekman L, Mawet M, Maillard C, Foidart JM, Coelingh Bennink HJ (2016) Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception 94:366–373.
Arnal JF, et al. (2017) Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev 97:1045–1087.
Bakker J, Baum MJ (2000) Neuroendocrine regulation of GnRH release in induced ovulators. Front Neuroendocrinol 21:220–262.
Balthazart J (2021) Membrane-initiated actions of sex steroids and reproductive behavior: a historical account. Mol Cell Endocrinol 538:111463.
Benoit T, et al. (2017) Estetrol, a fetal selective estrogen receptor modulator, acts on the vagina of mice through nuclear estrogen receptor α activation. Am J Pathol 187:2499–2507.
Brock O, Bakker J (2013) The two kisspeptin neuronal populations are differentially organized and activated by estradiol in mice. Endocrinology 154:2739–2749.
Bronson FH (1976) Serum FSH, LH, and prolactin in adult ovariectomized mice bearing silastic implants of estradiol: responses to social cues. Biol Reprod 15:147–152.
Bronson FH (1981) The regulation of luteinizing hormone secretion by estrogen: relationships among negative feedback, surge potential, and male stimulation in juvenile, peripubertal, and adult female mice. Endocrinology 108:506–516.
Bronson FH, Vom Saal FS (1979) Control of the preovulatory release of luteinizing hormone by steroids in the mouse. Endocrinology 104:1247–1255.
Campbell RE, Herbison AE (2007) Definition of brainstem afferents to gonadotropin-releasing hormone neurons in the mouse using conditional viral tract tracing. Endocrinology 148:5884–5890.
Chappell PE, Schneider JS, Kim P, Xu M, Lydon JP, O’Malley BW, Levine JE (1999) 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.
Cheong RY, Czieselsky K, Porteous R, Herbison AE (2015) Expression of ESR1 in glutamatergic and GABAergic neurons is essential for normal puberty onset, estrogen feedback, and fertility in female mice. J Neurosci 35:14533–14543.
Cheong RY, Porteous R, Chambon P, Abrahám I, Herbison AE (2014) Effects of neuron-specific estrogen receptor (ER) α and ERβ deletion on the acute estrogen negative feedback mechanism in adult female mice. Endocrinology 155:1418–1427.
Christian CA, Glidewell-Kenney C, Jameson JL, Moenter SM (2008) Classical estrogen receptor alpha signaling mediates negative and positive feedback on gonadotropin-releasing hormone neuron firing. Endocrinology 149:5328–5334.
Chu Z, Andrade J, Shupnik MA, Moenter SM (2009) Differential regulation of gonadotropin-releasing hormone neuron activity and membrane properties by acutely applied estradiol: dependence on dose and estrogen receptor subtype. J Neurosci 29:5616–5627.
Chung L (2015) A brief Introduction to the transduction of neural activity into Fos signal. Dev Reprod 19:61–67.
Chuon T, Feri M, Carlson C, Ondrejik S, Micevych PE, Sinchak K (2022) Progesterone receptor-Src kinase signaling pathway mediates neuroprogesterone induction of the luteinizing hormone surge in female rats. J Neuroendocrinol 34:e13071.
Clarkson J, Boon WC, Simpson ER, Herbison AE (2009) Postnatal development of an estradiol-kisspeptin positive feedback mechanism implicated in puberty onset. Endocrinology 150:3214–3220.
Clarkson J, d’Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE (2008) Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci 28:8691–8697.
Clarkson J, Herbison AE (2006) Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147:5817–5825.
Clarkson J, Yip SH, Porteous R, Kauff A, Heather AK, Herbison AE (2023) CRISPR-Cas9 knockdown of ESR1 in preoptic GABA-kisspeptin neurons suppresses the preovulatory surge and estrous cycles in female mice. eLife 12:RP90959.
Coelingh Bennink HJ, Skouby S, Bouchard P, Holinka CF (2008) Ovulation inhibition by estetrol in an in vivo model. Contraception 77:186–190.
Corpechot C, Collins BE, Carey MP, Tsouros A, Robel P, Fry JP (1997) Brain neurosteroids during the mouse oestrous cycle. Brain Res 766:276–280.
Czieselsky K, Prescott M, Porteous R, Campos P, Clarkson J, Steyn FJ, Campbell RE, Herbison AE (2016) Pulse and surge profiles of luteinizing hormone secretion in the mouse. Endocrinology 157:4794–4802.
Day JR, Morales TH, Lu JK (1988) Male stimulation of luteinizing hormone surge, progesterone secretion and ovulation in spontaneously persistent-estrous, aging rats. Biol Reprod 38:1019–1026.
de Bournonville C, Lemoine P, Foidart JM, Arnal JF, Lenfant F, Cornil CA (2023) Role of membrane estrogen receptor alpha (ERalpha) in the rapid regulation of male sexual behavior. J Neuroendocrinol 35: e13341.
Dror T, Franks J, Kauffman AS (2013) Analysis of multiple positive feedback paradigms demonstrates a complete absence of LH surges and GnRH activation in mice lacking kisspeptin signaling. Biol Reprod 88:146.
Dubois SL, Acosta-Martínez M, DeJoseph MR, Wolfe A, Radovick S, Boehm U, Urban JH, Levine JE (2015) Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons. Endocrinology 156:1111–1120.
Duijkers IJ, Klipping C, Zimmerman Y, Appels N, Jost M, Maillard C, Mawet M, Foidart JM, Coelingh Bennink HJ (2015) Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: results of a phase II dose-finding pilot study. Eur J Contracept Reprod Health Care 20:476–489.
Evans NP, Dahl GE, Padmanabhan V, Thrun LA, Karsch FJ (1997) Estradiol requirements for induction and maintenance of the gonadotropin-releasing hormone surge: implications for neuroendocrine processing of the estradiol signal. Endocrinology 138:5408–5414.
Franklin K, Paxinos G (2001) The mouse brain in stereotaxic coordinates, Ed 2. New York, NY: Academic Press.
Gal A, Lin PC, Cacioppo JA, Hannon PR, Mahoney MM, Wolfe A, Fernandez-Valdivia R, Lydon JP, Elias CF, Ko C (2016) Loss of fertility in the absence of progesterone receptor expression in kisspeptin neurons of female mice. PLoS One 11:e0159534.
Gallez A, et al. (2023) Comparison of estetrol exposure between women and mice to model preclinical experiments and anticipate human treatment. Int J Mol Sci 24:9718.
Gérard C, et al. (2015a) Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. J Endocrinol 224:85–95.
Gérard C, et al. (2022) Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Expert Rev Clin Pharmacol 15:121–137.
Gérard C, Mestdagt M, Tskitishvili E, Communal L, Gompel A, Silva E, Arnal JF, Lenfant F, Noel A, Foidart JM, Péqueux C (2015b) Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms. Oncotarget 6:17621–17636.
Giretti MS, et al. (2014) Effects of estetrol on migration and invasion in T47-D breast cancer cells through the actin cytoskeleton. Front Endocrinol (Lausanne) 5:80.
Glidewell-Kenney C, Hurley LA, Pfaff L, Weiss J, Levine JE, Jameson JL (2007) Nonclassical estrogen receptor a signaling mediates negative feedback in the female mouse reproductive axis. Proc Natl Acad Sci U S A 104:8173–8177.
Gonzalez-Martinez D, De Mees C, Douhard Q, Szpirer C, Bakker J (2008) Absence of gonadotropin-releasing hormone 1 and Kiss1 activation in alpha-fetoprotein knockout mice: prenatal estrogens defeminize the potential to show preovulatory luteinizing hormone surges. Endocrinology 149:2333–2340.
Goodman RL, Herbison AE, Lehman MN, Navarro VM (2022) Neuroendocrine control of gonadotropin-releasing hormone: pulsatile and surge modes of secretion. J Neuroendocrinol 34:e13094.
GottschML,NavarroVM,ZhaoZ,Glidewell-KenneyC,WeissJ,Jameson JL, Clifton DK, Levine JE, Steiner RA (2009) Regulation of Kiss1 and dynorphin gene expression in the murine brain by classical and non-classical estrogen receptor pathways. J Neurosci 29:9390–9395.
Guivarc’h E, et al. (2018) Predominant role of nuclear versus membrane estrogen receptor α in arterial protection: implications for estrogen receptor α modulation in cardiovascular prevention/ safety. J Am Heart Assoc 7:e008950.
Hamilton KJ, Arao Y, Korach KS (2014) Estrogen hormone physiology: reproductive findings from estrogen receptor mutant mice. Reprod Biol 14:3–8.
Herbison AE (1998) Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons. Endocr Rev 19:302–330.
Herbison AE (2009) Rapid actions of oestrogen on gonadotropin-releasing hormone neurons; from fantasy to physiology? J Physiol 587:5025–5030.
Herbison AE (2020) A simple model of estrous cycle negative and positive feedback regulation of GnRH secretion. Front Neuroendocrinol 57:100837.
Herbison AE, Pape JR (2001) New evidence for estrogen receptors in gonadotropin-releasing hormone neurons. Front Neuroendocrinol 22:292–308.
Hoffman GE, Smith MS, Verbalis JG (1993) c-Fos and related immediate early gene products as markers of activity in neuroendocrine systems. Front Neuroendocrinol 14:173–213.
Holinka CF, Diczfalusy E, Coelingh Bennink HJ (2008) Estetrol: a unique steroid in human pregnancy. Climacteric 11[Suppl 1]:1.
Hudson AE (2018) Genetic reporters of neuronal activity: c-Fos and G-CaMP6. Methods Enzymol 603:197–220.
Jiang Y, et al. (2023) Membrane estrogen receptor α signaling modulates the sensitivity to estradiol treatment in a dose-and tissue dependent manner. Sci Rep 13:9046.
Johns MA, Feder HH, Komisaruk BR, Mayer AD (1978) Urine-induced reflex ovulation in anovulatory rats may be a vomeronasal effect. Nature 272:446–448.
Kelly MJ, Rønnekleiv OK (2015) Minireview: neural signaling of estradiol in the hypothalamus. Mol Endocrinol 29:645–657.
Khbouz B, de Bournonville C, Court L, Taziaux M, Corona R, Arnal JF, Lenfant F, Cornil CA (2019) Role for the membrane estrogen receptor alpha in the sexual differentiation of the brain. Eur J Neurosci 52:2627–2645.
Klipping C, Duijkers I, Mawet M, Maillard C, Bastidas A, Jost M, Foidart JM (2021) Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception 103:213–221.
Kovacs KJ (2008) Measurement of immediate-early gene activationc-fos and beyond. J Neuroendocrinol 20:665–672.
Kow L-M, Pfaff DW (2004) The membrane actions of estrogens can potentiate their lordosis behavior-facilitating genomic actions. Proc Natl Acad Sci U S A 101:12354–12357.
Kuo J, Hamid N, Bondar G, Prossnitz ER, Micevych P (2010) Membrane estrogen receptors stimulate intracellular calcium release and progesterone synthesis in hypothalamic astrocytes. J Neurosci 30:12950–12957.
Legan SJ, Coon GA, Karsch FJ (1975) Role of estrogen as initiator of daily LH surges in the ovariectomized rat. Endocrinology 96:50–56.
Luckman SM, Dyball RE, Leng G (1994) Induction of c-fos expression in hypothalamic magnocellular neurons requires synaptic activation and not simply increased spike activity. J Neurosci 14:4825–4830.
Matt DW, Coquelin A, Lu JK (1987) Neuroendocrine control of luteinizing hormone secretion and reproductive function in spontaneously persistent-estrous aging rats. Biol Reprod 37:1198–1206.
McDevitt MA, Glidewell-Kenney C, Jimenez MA, Ahearn PC, Weiss J, Jameson JL, Levine JE (2008) New insights into the classical and non-classical actions of estrogen: evidence from estrogen receptor knock-out and knock-in mice. Mol Cell Endocrinol 290:24–30.
MemiF,AbeP,CariboniA,MacKayF,ParnavelasJG,StummR(2013) CXC chemokine receptor 7 (CXCR7) affects the migration of GnRH neurons by regulating CXCL12 availability. J Neurosci 33:17527–17537.
Micevych PE, Chaban V, Ogi J, Dewing P, Lu JK, Sinchak K (2007) Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures. Endocrinology 148:782–789.
Micevych P, Sinchak K (2008) Estradiol regulation of progesterone synthesis in the brain. Mol Cell Endocrinol 290:44–50.
Micevych P, Sinchak K, Mills RH, Tao L, LaPolt P, Lu JK (2003) The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats. Neuroendocrinology 78:29–35.
Micevych PE, Wong AM, Mittelman-Smith MA (2015) Estradiol membrane-initiated signaling and female reproduction. Compr Physiol 5:1211–1222.
Mittelman-Smith MA, Wong AM, Kathiresan AS, Micevych PE (2015) Classical and membrane-initiated estrogen signaling in an in vitro model of anterior hypothalamic kisspeptin neurons. Endocrinology 156:2162–2173.
Mittelman-Smith MA, Wong AM, Micevych PE (2018) Estrogen and progesterone integration in an in vitro model of RP3V Kisspeptin neurons. Neuroendocrinology 106:101–115.
Moenter SM, Chu Z (2012) Rapid nongenomic effects of oestradiol on gonadotrophin-releasing hormone neurones. J Neuroendocrinol 24:117–121.
Moffatt CA, Rissman EF, Shupnik MA, Blaustein JD (1998) Induction of progestin receptors by estradiol in the forebrain of estrogen receptor-alpha gene-disrupted mice. J Neurosci 18:9556–9563.
Mohr MA, Esparza LA, Steffen P, Micevych P, Kauffman AS (2021) Progesterone receptors in AVPV kisspeptin neurons are sufficient for positive feedback induction of the LH surge. Endocrinology 162:1–8.
Mohr MA, Keshishian T, Falcy BA, Laham BJ, Wong AM, Micevych P (2022) Puberty enables oestradiol-induced progesterone synthesis in female mouse hypothalamic astrocytes. J Neuroendocrinol 34: e13082.
Mohr MA, Wong AM, Tomm RJ, Soma KK, Micevych PE (2019) Pubertal development of estradiol-induced hypothalamic progesterone synthesis. Horm Behav 111:110–113.
Morgan JI, Curran T (1989) Stimulus-transcription coupling in neurons: role of cellular immediate-early genes. Trends Neurosci 12:459–462.
Pedram A, Razandi M, Lewis M, Hammes S, Levin ER (2014) Membrane-localized estrogen receptor α is required for normal organ development and function. Dev Cell 29:482–490.
Pluchino N, Drakopoulos P, Casarosa E, Freschi L, Petignat P, Yaron M, Genazzani AR (2015) Effect of estetrol on beta-endorphin level in female rats. Steroids 95:104–110.
Pluchino N, Santoro AN, Casarosa E, Giannini A, Genazzani A, Russo M, Russo N, Petignat P, Genazzani AR (2014) Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats. J Steroid Biochem Mol Biol 143:285–290.
Porteous R, Herbison AE (2019) Genetic deletion of Esr1 in the mouse preoptic area disrupts the LH surge and estrous cyclicity. Endocrinology 160:1821–1829.
Romanò N, Herbison AE (2012) Activity-dependent modulation of gonadotrophin-releasing hormone neurone activity by acute oestradiol. J Neuroendocrinol 24:1296–1303.
Romano N, Lee K, Abraham IM, Jasoni CL, Herbison AE (2008) Nonclassical estrogen modulation of presynaptic GABA terminals modulates calcium dynamics in gonadotropin-releasing hormone neurons. Endocrinology 149:5335–5344.
Rusidzé M, et al. (2022) Loss of function of the maternal membrane oestrogen receptor ERα alters expansion of trophoblast cells and impacts mouse fertility. Development 149:dev200683.
Seredynski AL, Balthazart J, Christophe VJ, Ball GF, Cornil CA (2013) Neuroestrogens rapidly regulate sexual motivation but not performance. J Neurosci 33:164–174.
Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA (2005) Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146:3686–3692.
Stephens SB, Tolson KP, Rouse ML Jr, Poling MC, Hashimoto-Partyka MK, Mellon PL, Kauffman AS (2015) Absent progesterone signaling in kisspeptin neurons disrupts the LH surge and impairs fertility in female mice. Endocrinology 156:3091–3097.
Steyn FJ, Wan Y, Clarkson J, Veldhuis JD, Herbison AE, Chen C (2013) Development of a methodology for and assessment of pulsatile luteinizing hormone secretion in juvenile and adult male mice. Endocrinology 154:4939–4945.
Sun J, Chu Z, Moenter SM (2010) Diurnal in vivo and rapid in vitro effects of estradiol on voltage-gated calcium channels in gonadotropin-releasing hormone neurons. J Neurosci 30:3912–3923.
Szymanski L, Bakker J (2012) Aromatase knockout mice show normal steroid-induced activation of gonadotrophin-releasing hormone neurones and luteinising hormone surges with a reduced population of kisspeptin neurones in the rostral hypothalamus. J Neuroendocrinol 24:1222–1233.
Taziaux M, Bakker J (2015) Absence of female-typical pheromone-induced hypothalamic neural responses and kisspeptin neuronal activity in alpha-fetoprotein knockout female mice. Endocrinology 156:2595–2607.
Terasawa E, Kenealy BP (2012) Neuroestrogen, rapid action of estradiol, and GnRH neurons. Front Neuroendocrinol 33:364–375.
Tetel MJ, Lange CA (2009) Molecular genomics of progestin actions. In: hormones, brain and behavior (Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, eds), pp 1439–1465. San Diego, CA: Academic press.
Vasudevan N, Kow L-M, Pfaff DW (2001) Early membrane estrogenic effects required for full expression of slower genomic actions in a nerve cell line. Proc Natl Acad Sci U S A 98:12267–12271.
Vasudevan N, Pfaff DW (2007) Membrane initiated actions of estrogens in neuroendocrinology: emerging principles. Endocr Rev 28:1–19.
Wang L, Burger LL, Greenwald-Yarnell ML, Myers MG Jr, Moenter SM (2018) Glutamatergic transmission to hypothalamic kisspeptin neurons Is differentially regulated by estradiol through estrogen receptor α in adult female mice. J Neurosci 38:1061–1072.
Wang L, DeFazio RA, Moenter SM (2016) Excitability and burst generation of AVPV kisspeptin neurons are regulated by the estrous cycle via multiple conductances modulated by estradiol action. eNeuro 3:ENEURO.0094-16.2016.
Wang L, Moenter SM (2020) Differential roles of hypothalamic AVPV and arcuate kisspeptin neurons in estradiol feedback regulation of female reproduction. Neuroendocrinology 110:172–184.
Wang L, Vanacker C, Burger LL, Barnes T, Shah YM, Myers MG, Moenter SM (2019) Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction. eLife 8:e43999.
Waring DW, Turgeon JL (1992) A pathway for luteinizing hormone releasing-hormone self-potentiation: cross-talk with the progesterone receptor. Endocrinology 130:3275–3282.
Wersinger SR, Haisenleder DJ, Lubahn DB, Rissman EF (1999) Steroid feedback on gonadotropin release and pituitary gonadotropin sub-unit mRNA in mice lacking a functional estrogen receptor alpha. Endocrine 11:137–143.
Whitten WK (1956) Modification of the oestrous cycle of the mouse by external stimuli associated with the male. J Endocrinol 13:399–404.
Whitten WK (1958) Modification of the oestrous cycle of the mouse by external stimuli associated with the male; changes in the oestrous cycle determined by vaginal smears. J Endocrinol 17:307–313.
Wintermantel TM, et al. (2006) Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. Neuron 52:271–280.
Yeo SH, Herbison AE (2014) Estrogen-negative feedback and estrous cyclicity are critically dependent upon estrogen receptor-α expression in the arcuate nucleus of adult female mice. Endocrinology 155:2986–2995.
Zhang C, Kelly MJ, Rønnekleiv OK (2010) 17 β-estradiol rapidly increases ATP-sensitive potassium channel activity in gonadotropin-releasing hormone neurons [corrected] via a protein kinase signaling pathway. Endocrinology 151:4477–4484.
