Impaired LH surge amplitude in gonadotrope-specific progesterone receptor knockout mice

in Journal of Endocrinology

Correspondence should be addressed to D J Bernard: daniel.bernard@mcgill.ca*(C Toufaily and G Schang contributed equally to this work)
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The progesterone receptor (PR, encoded by Pgr) plays essential roles in reproduction. Female mice lacking the PR are infertile, due to the loss of the protein’s functions in the brain, ovary, and uterus. PR is also expressed in pituitary gonadotrope cells, but its specific role therein has not been assessed in vivo. We therefore generated gonadotrope-specific Pgr conditional knockout mice (cKO) using the Cre-LoxP system. Overall, both female and male cKO mice appeared phenotypically normal. cKO females displayed regular estrous cycles (vaginal cytology) and normal fertility (litter size and frequency). Reproductive organ weights were comparable between wild-type and cKO mice of both sexes, as were production and secretion of the gonadotropins, LH and FSH, with one exception. On the afternoon of proestrus, the amplitude of the LH surge was blunted in cKO females relative to controls. Contrary to predictions of earlier models, this did not appear to derive from impaired GnRH self-priming. Collectively, these data indicate that PR function in gonadotropes may be limited to regulation of LH surge amplitude in female mice via a currently unknown mechanism.

 

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  • AbdilnourGBourneGA 1995 Adenosine 3′,5′-cyclic monophosphate and the self-priming effect of gonadotrophin-releasing hormone. Molecular and Cellular Endocrinology 1–7. (https://doi.org/10.1016/0303-7207(94)03418-s)

    • Search Google Scholar
    • Export Citation
  • AguilarRBellidoCSanchez-CriadoJE 2003 The role of estrogen-dependent progesterone receptor in protein kinase C-mediated LH secretion and GnRH self-priming in rat anterior pituitary glands. Journal of Endocrinological Investigation 527–532. (https://doi.org/10.1007/BF03345215)

    • Search Google Scholar
    • Export Citation
  • AnBSPoonSLSoWKHammondGLLeungPC 2009 Rapid effect of GNRH1 on follicle-stimulating hormone beta gene expression in LbetaT2 mouse pituitary cells requires the progesterone receptor. Biology of Reproduction 243–249. (https://doi.org/10.1095/biolreprod.109.076216)

    • Search Google Scholar
    • Export Citation
  • AttardiBScottRPfaffDFinkG 2007 Facilitation or inhibition of the oestradiol-induced gonadotrophin surge in the immature female rat by progesterone: effects on pituitary responsiveness to gonadotrophin-releasing hormone (GnRH), GnRH self-priming and pituitary mRNAs for the progesterone receptor A and B isoforms. Journal of Neuroendocrinology 988–1000. (https://doi.org/10.1111/j.1365-2826.2007.01613.x)

    • Search Google Scholar
    • Export Citation
  • CaligioniCS 2009 Assessing reproductive status/stages in mice. Current Protocols in Neuroscience A.4I.1–A.4I.8. (https://doi.org/10.1002/0471142301.nsa04is48)

    • Search Google Scholar
    • Export Citation
  • ChappellPELevineJE 2000 Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors. Endocrinology 1477–1485. (https://doi.org/10.1210/endo.141.4.7428)

    • Search Google Scholar
    • Export Citation
  • ChappellPELydonJPConneelyOMO’MalleyBWLevineJE 1997 Endocrine defects in mice carrying a null mutation for the progesterone receptor gene. Endocrinology 4147–4152. (https://doi.org/10.1210/endo.138.10.5456)

    • Search Google Scholar
    • Export Citation
  • ChappellPESchneiderJSKimPXuMLydonJPO’MalleyBWLevineJE 1999 Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E2)-treated, progesterone receptor knockout (PRKO) mice. Endocrinology 3653–3658. (https://doi.org/10.1210/endo.140.8.6895)

    • Search Google Scholar
    • Export Citation
  • CheungLYMGeorgeASMcGeeSRDalyAZBrinkmeierMLEllsworthBSCamperSA 2018 Single-cell RNA sequencing reveals novel markers of male pituitary stem cells and hormone-producing cell types. Endocrinology 3910–3924. (https://doi.org/10.1210/en.2018-00750)

    • Search Google Scholar
    • Export Citation
  • ColinIMBauer-DantoinACSundaresanSKoppPJamesonJL 1996 Sexually dimorphic transcriptional responses to gonadotropin-releasing hormone require chronic in vivo exposure to estradiol. Endocrinology 2300–2307. (https://doi.org/10.1210/endo.137.6.8641179)

    • Search Google Scholar
    • Export Citation
  • CzieselskyKPrescottMPorteousRCamposPClarksonJSteynFJCampbellREHerbisonAE 2016 Pulse and surge profiles of luteinizing hormone secretion in the mouse. Endocrinology 4794–4802. (https://doi.org/10.1210/en.2016-1351)

    • Search Google Scholar
    • Export Citation
  • DafopoulosKKotsovassilisCGMilingosSKallitsarisAGalaziosGZintzarasESotirosPMessinisIE 2004 Changes in pituitary sensitivity to GnRH in estrogen-treated post-menopausal women: evidence that gonadotrophin surge attenuating factor plays a physiological role. Human Reproduction 1985–1992. (https://doi.org/10.1093/humrep/deh383)

    • Search Google Scholar
    • Export Citation
  • d’Anglemont de TassignyXFaggLACarltonMBColledgeWH 2008 Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology 3926–3932. (https://doi.org/10.1210/en.2007-1487)

    • Search Google Scholar
    • Export Citation
  • Fernandez-ValdiviaRJeongJMukherjeeASoyalSMLiJYingYDemayoFJLydonJP 2010 A mouse model to dissect progesterone signaling in the female reproductive tract and mammary gland. Genesis 106–113. (https://doi.org/10.1002/dvg.20586)

    • Search Google Scholar
    • Export Citation
  • FortinJBoehmUDengCXTreierMBernardDJ 2014 Follicle-stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2. FASEB Journal 3396–3410. (https://doi.org/10.1096/fj.14-249532)

    • Search Google Scholar
    • Export Citation
  • GalALinPCCacioppoJAHannonPRMahoneyMMWolfeAFernandez-ValdiviaRLydonJPEliasCFKoC 2016 Loss of fertility in the absence of progesterone receptor expression in kisspeptin neurons of female mice. PLoS ONE e0159534. (https://doi.org/10.1371/journal.pone.0159534)

    • Search Google Scholar
    • Export Citation
  • HaisenlederDJSchoenfelderAHMarcinkoESGeddisLMMarshallJC 2011 Estimation of estradiol in mouse serum samples: evaluation of commercial estradiol immunoassays. Endocrinology 4443–4447. (https://doi.org/10.1210/en.2011-1501)

    • Search Google Scholar
    • Export Citation
  • HiguchiTKawakamiM 1982 Luteinizing hormone responses to repeated injections of luteinizing hormone releasing hormone in the rat during the oestrous cycle and after ovariectomy with or without oestrogen treatment. Journal of Endocrinology 161–168. (https://doi.org/10.1677/joe.0.0930161)

    • Search Google Scholar
    • Export Citation
  • HoCCZhouXMishinaYBernardDJ 2011 Mechanisms of bone morphogenetic protein 2 (BMP2) stimulated inhibitor of DNA binding 3 (Id3) transcription. Molecular and Cellular Endocrinology 242–252. (https://doi.org/10.1016/j.mce.2010.10.019)

    • Search Google Scholar
    • Export Citation
  • HutchensEGRamseyKAHowardLCAbshireMYPatrieJTMcCartneyCR 2016 Progesterone has rapid positive feedback actions on LH release but fails to reduce LH pulse frequency within 12 h in estradiol-pretreated women. Physiological Reports e12891. (https://doi.org/10.14814/phy2.12891)

    • Search Google Scholar
    • Export Citation
  • KnoxKLSchwartzNB 1992 RU486 blocks the secondary surge of follicle-stimulating hormone in the rat without blocking the drop in serum inhibin. Biology of Reproduction 220–225. (https://doi.org/10.1095/biolreprod46.2.220)

    • Search Google Scholar
    • Export Citation
  • KnoxKLRingstromSJSchwartzNB 1993 RU486 blocks the effects of inhibin antiserum or luteinizing hormone on the secondary follicle-stimulating hormone surge. Endocrinology 277–283. (https://doi.org/10.1210/endo.133.1.8319576)

    • Search Google Scholar
    • Export Citation
  • LasleyBLWangCFYenSS 1975 The effects of estrogen and progesterone on the functional capacity of the gonadotrophs. Journal of Clinical Endocrinology and Metabolism 820–826. (https://doi.org/10.1210/jcem-41-5-820)

    • Search Google Scholar
    • Export Citation
  • LiYSchangGBoehmUDengCXGraffJBernardDJ 2017 SMAD3 regulates follicle-stimulating hormone synthesis by pituitary gonadotrope cells in vivo. Journal of Biological Chemistry 2301–2314. (https://doi.org/10.1074/jbc.M116.759167)

    • Search Google Scholar
    • Export Citation
  • LiYFortinJOngaroLZhouXBoehmUSchneyerABernardDJLinHY 2018a Betaglycan (TGFBR3) functions as an inhibin A, but not inhibin B, coreceptor in pituitary gonadotrope cells in mice. Endocrinology 4077–4091. (https://doi.org/10.1210/en.2018-00770)

    • Search Google Scholar
    • Export Citation
  • LiYSchangGWangYZhouXLevasseurABoyerADengCXTreierMBoehmUBoerboomD, et al. 2018b Conditional deletion of FOXL2 and SMAD4 in gonadotropes of adult mice causes isolated FSH deficiency. Endocrinology 2641–2655. (https://doi.org/10.1210/en.2018-00100)

    • Search Google Scholar
    • Export Citation
  • LivakKJSchmittgenTD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 402–408. (https://doi.org/10.1006/meth.2001.1262)

    • Search Google Scholar
    • Export Citation
  • LydonJPDeMayoFJFunkCRManiSKHughesARMontgomeryJr CAShyamalaGConneelyOMO’MalleyBW 1995 Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes and Development 2266–2278. (https://doi.org/10.1101/gad.9.18.2266)

    • Search Google Scholar
    • Export Citation
  • McGillivraySMThackrayVGCossDMellonPL 2007 Activin and glucocorticoids synergistically activate follicle-stimulating hormone beta-subunit gene expression in the immortalized LbetaT2 gonadotrope cell line. Endocrinology 762–773. (https://doi.org/10.1210/en.2006-0952)

    • Search Google Scholar
    • Export Citation
  • MessagerSChatzidakiEEMaDHendrickAGZahnDDixonJThresherRRMalingeILometDCarltonMB, et al. 2005 Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. PNAS 1761–1766. (https://doi.org/10.1073/pnas.0409330102)

    • Search Google Scholar
    • Export Citation
  • PickeringAJFinkG 1976 Priming effect of luteinizing hormone releasing factor: in-vitro and in-vivo evidence consistent with its dependence upon protein and RNA synthesis. Journal of Endocrinology 373–379. (https://doi.org/10.1677/joe.0.0690373)

    • Search Google Scholar
    • Export Citation
  • RoaJVigoECastellanoJMGaytanFGarcia-GalianoDNavarroVMAguilarEDijcksFAEderveenAGPinillaL, et al. 2008a Follicle-stimulating hormone responses to kisspeptin in the female rat at the preovulatory period: modulation by estrogen and progesterone receptors. Endocrinology 5783–5790. (https://doi.org/10.1210/en.2008-0604)

    • Search Google Scholar
    • Export Citation
  • RoaJVigoECastellanoJMGaytanFNavarroVMAguilarEDijcksFAEderveenAGPinillaLvan NoortPI, et al. 2008b Opposite roles of estrogen receptor (ER)-alpha and ERbeta in the modulation of luteinizing hormone responses to kisspeptin in the female rat: implications for the generation of the preovulatory surge. Endocrinology 1627–1637. (https://doi.org/10.1210/en.2007-1540)

    • Search Google Scholar
    • Export Citation
  • SchauerCTongTPetitjeanHBlumTPeronSMaiOSchmitzFBoehmULeinders-ZufallT 2015 Hypothalamic gonadotropin-releasing hormone (GnRH) receptor neurons fire in synchrony with the female reproductive cycle. Journal of Neurophysiology 1008–1021. (https://doi.org/10.1152/jn.00357.2015)

    • Search Google Scholar
    • Export Citation
  • StephensSBTolsonKPRouseJr MLPolingMCHashimoto-PartykaMKMellonPLKauffmanAS 2015 Absent progesterone signaling in kisspeptin neurons disrupts the LH surge and impairs fertility in female mice. Endocrinology 3091–3097. (https://doi.org/10.1210/en.2015-1300)

    • Search Google Scholar
    • Export Citation
  • SteynFJWanYClarksonJVeldhuisJDHerbisonAEChenC 2013 Development of a methodology for and assessment of pulsatile luteinizing hormone secretion in juvenile and adult male mice. Endocrinology 4939–4945. (https://doi.org/10.1210/en.2013-1502)

    • Search Google Scholar
    • Export Citation
  • ThackrayVGMellonPL 2008 Synergistic induction of follicle-stimulating hormone beta-subunit gene expression by gonadal steroid hormone receptors and Smad proteins. Endocrinology 1091–1102. (https://doi.org/10.1210/en.2007-1498)

    • Search Google Scholar
    • Export Citation
  • ThackrayVGMcGillivraySMMellonPL 2006 Androgens, progestins, and glucocorticoids induce follicle-stimulating hormone beta-subunit gene expression at the level of the gonadotrope. Molecular Endocrinology 2062–2079. (https://doi.org/10.1210/me.2005-0316)

    • Search Google Scholar
    • Export Citation
  • TurgeonJLWaringDW 1994 Activation of the progesterone receptor by the gonadotropin-releasing hormone self-priming signaling pathway. Molecular Endocrinology 860–869. (https://doi.org/10.1210/mend.8.7.7984148)

    • Search Google Scholar
    • Export Citation
  • TurgeonJLWaringDW 1999 Androgen modulation of luteinizing hormone secretion by female rat gonadotropes. Endocrinology 1767–1774. (https://doi.org/10.1210/endo.140.4.6642)

    • Search Google Scholar
    • Export Citation
  • TurgeonJLWaringDW 2001 Luteinizing hormone secretion from wild-type and progesterone receptor knockout mouse anterior pituitary cells. Endocrinology 3108–3115. (https://doi.org/10.1210/endo.142.7.8282)

    • Search Google Scholar
    • Export Citation
  • TurgeonMOSilanderTLDoychevaDLiaoXHRigdenMOngaroLZhouXJoustraSDWitJMWadeMG, et al. 2017 TRH action is impaired in pituitaries of male IGSF1-deficient mice. Endocrinology 815–830. (https://doi.org/10.1210/en.2016-1788)

    • Search Google Scholar
    • Export Citation
  • VeldhuisJYangRRoelfsemaFTakahashiP 2016 Proinflammatory cytokine infusion attenuates LH’s feedforward on testosterone secretion: modulation by age. Journal of Clinical Endocrinology and Metabolism 539–549. (https://doi.org/10.1210/jc.2015-3611)

    • Search Google Scholar
    • Export Citation
  • WaringDWTurgeonJL 1980 Luteinizing hormone-releasing hormone-induced luteinizing hormone secretion in vitro: cyclic changes in responsiveness and self-priming. Endocrinology 1430–1436. (https://doi.org/10.1210/endo-106-5-1430)

    • Search Google Scholar
    • Export Citation
  • WaringDWTurgeonJL 1992 A pathway for luteinizing hormone releasing-hormone self-potentiation: cross-talk with the progesterone receptor. Endocrinology 3275–3282. (https://doi.org/10.1210/endo.130.6.1317780)

    • Search Google Scholar
    • Export Citation
  • WenSSchwarzJRNiculescuDDinuCBauerCKHirdesWBoehmU 2008 Functional characterization of genetically labeled gonadotropes. Endocrinology 2701–2711. (https://doi.org/10.1210/en.2007-1502)

    • Search Google Scholar
    • Export Citation
  • WenSAiWAlimZBoehmU 2010 Embryonic gonadotropin-releasing hormone signaling is necessary for maturation of the male reproductive axis. PNAS 16372–16377. (https://doi.org/10.1073/pnas.1000423107)

    • Search Google Scholar
    • Export Citation
  • WenSGotzeINMaiOSchauerCLeinders-ZufallTBoehmU 2011 Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain. Endocrinology 1515–1526. (https://doi.org/10.1210/en.2010-1208)

    • Search Google Scholar
    • Export Citation
  • WuSChenYFajobiTDiVallSAChangCYehSWolfeA 2014 Conditional knockout of the androgen receptor in gonadotropes reveals crucial roles for androgen in gonadotropin synthesis and surge in female mice. Molecular Endocrinology 1670–1681. (https://doi.org/10.1210/me.2014-1154)

    • Search Google Scholar
    • Export Citation
  • ZhouXWangYOngaroLBoehmUKaartinenVMishinaYBernardDJ 2016 Normal gonadotropin production and fertility in gonadotrope-specific Bmpr1a knockout mice. Journal of Endocrinology 331–341. (https://doi.org/10.1530/JOE-16-0053)

    • Search Google Scholar
    • Export Citation