Semin Reprod Med 2017; 35(02): 130-138
DOI: 10.1055/s-0037-1599084
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Novel Insights into Gonadotropin-Releasing Hormone Action in the Pituitary Gonadotrope

Jessica L. Brown
1   Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, New York
,
Mark Roberson
1   Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, New York
› Author Affiliations
Further Information

Publication History

Publication Date:
17 February 2017 (online)

Abstract

The hypothalamic-pituitary-gonadal axis controls reproduction via a series of hormones regulating gonadal function through interconnected feedback loops. Secretion of hypothalamic-derived gonadotropin-releasing hormone (GnRH) integrates inputs from higher brain centers to coordinate the activity of the pituitary gonadotrope and the biosynthesis and secretion of the gonadotropins which ultimately regulate gonadal function. Failure of GnRH to serve as the central integrator of this system has been associated with hypogonadotropic-hypogonadism and clinical infertility, while pharmacological application of GnRH analogs and gonadotropins have important implications of the treatment of such infertility. Furthermore, the GnRH–GnRH receptor system has been characterized in several types of cancer and may offer therapeutic possibilities in their treatment. Given the central role of GnRH action in the control of fertility, it is of paramount importance to understand the molecular basis of control of GnRH action in the pituitary gonadotrope, including new and novel alternate ways to modulate GnRH action and gonadotropin secretion. The goal of this review is to discuss several new findings in this field focusing on novel regulators of GnRH action.

 
  • References

  • 1 Shacham S, Harris D, Ben-Shlomo H , et al. Mechanism of GnRH receptor signaling on gonadotropin release and gene expression in pituitary gonadotrophs. Vitam Horm 2001; 63: 63-90
  • 2 Du YX, Ma KY, Qiu GF. Discovery of the genes in putative GnRH signaling pathway with focus on characterization of GnRH-like receptor transcripts in the brain and ovary of the oriental river prawn Macrobrachium nipponense . Aquaculture 2015; 442: 1-11
  • 3 Finch AR, Sedgley KR, Caunt CJ, McArdle CA. Plasma membrane expression of GnRH receptors: regulation by antagonists in breast, prostate, and gonadotrope cell lines. J Endocrinol 2008; 196 (2) 353-367
  • 4 Grosse R, Schmid A, Schöneberg T , et al. Gonadotropin-releasing hormone receptor initiates multiple signaling pathways by exclusively coupling to G(q/11) proteins. J Biol Chem 2000; 275 (13) 9193-9200
  • 5 Liu F, Usui I, Evans LG , et al. Involvement of both G(q/11) and G(s) proteins in gonadotropin-releasing hormone receptor-mediated signaling in L beta T2 cells. J Biol Chem 2002; 277 (35) 32099-32108
  • 6 Dobkin-Bekman M, Naidich M, Pawson AJ, Millar RP, Seger R, Naor Z. Activation of mitogen-activated protein kinase (MAPK) by GnRH is cell-context dependent. Mol Cell Endocrinol 2006; 252 (1-2): 184-190
  • 7 Naor Z. Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor. Front Neuroendocrinol 2009; 30 (1) 10-29
  • 8 Mulvaney JM, Roberson MS. Divergent signaling pathways requiring discrete calcium signals mediate concurrent activation of two mitogen-activated protein kinases by gonadotropin-releasing hormone. J Biol Chem 2000; 275 (19) 14182-14189
  • 9 Mulvaney JM, Zhang T, Fewtrell C, Roberson MS. Calcium influx through L-type channels is required for selective activation of extracellular signal-regulated kinase by gonadotropin-releasing hormone. J Biol Chem 1999; 274 (42) 29796-29804
  • 10 Zhang T, Mulvaney JM, Roberson MS. Activation of mitogen-activated protein kinase phosphatase 2 by gonadotropin-releasing hormone. Mol Cell Endocrinol 2001; 172 (1-2): 79-89
  • 11 Salama N. Kallmann syndrome and deafness: an uncommon combination: A case report and a literature review. Int J Reprod Biomed (Yazd) 2016; 14 (8) 541-544
  • 12 Herbison AE. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat Rev Endocrinol 2016; 12 (8) 452-466
  • 13 Mitchell AL, Dwyer A, Pitteloud N, Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends Endocrinol Metab 2011; 22 (7) 249-258
  • 14 Wadhwa L, Khanna R, Gupta T, Gupta S, Arora S, Nandwani S. Evaluation of role of GnRH antagonist in intrauterine insemination (IUI) cycles with mild ovarian hyperstimulation (MOH): a prospective randomised study. J Obstet Gynaecol India 2016; 66 (Suppl. 01) 459-465
  • 15 Minhas V, Shrestha A, Wadhwa N, Singh R, Gupta SK. Novel sperm and gonadotropin-releasing hormone-based recombinant fusion protein: achievement of 100% contraceptive efficacy by co-immunization of male and female mice. Mol Reprod Dev 2016; 83 (12) 1048-1059
  • 16 Nakamura Y, Hattangady NG, Ye P , et al. Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA). Mol Cell Endocrinol 2014; 384 (1-2): 102-108
  • 17 Sakai M, Martinez-Arguelles DB, Patterson NH, Chaurand P, Papadopoulos V. In search of the molecular mechanisms mediating the inhibitory effect of the GnRH antagonist degarelix on human prostate cell growth. PLoS One 2015; 10 (3) e0120670
  • 18 Teng LH, Ahmad M, Ng WT , et al. Gonadotropin‑releasing hormone inhibits the proliferation and motility of nasopharyngeal carcinoma cells. Mol Med Rep 2015; 12 (4) 4909-4916
  • 19 Sakai M, Elhilali M, Papadopoulos V. The gnRH antagonist degarelix directly inhibits benign prostate hyperplasia cell growth. Horm Metab Res 2015; 47 (12) 925-931
  • 20 Sviridonov L, Dobkin-Bekman M, Shterntal B , et al. Differential signaling of the GnRH receptor in pituitary gonadotrope cell lines and prostate cancer cell lines. Mol Cell Endocrinol 2013; 369 (1-2): 107-118
  • 21 Lu M, Zhu J, Ling Y, Shi W, Zhang C, Wu H. The lower expression of gonadotropin-releasing hormone receptor associated with poor prognosis in gastric cancer. Int J Clin Exp Med 2015; 8 (8) 13365-13370
  • 22 Limonta P, Manea M. Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: current options and emerging strategies. Cancer Treat Rev 2013; 39 (6) 647-663
  • 23 Haisenleder DJ, Burger LL, Aylor KW, Dalkin AC, Marshall JC. Gonadotropin-releasing hormone stimulation of gonadotropin subunit transcription: evidence for the involvement of calcium/calmodulin-dependent kinase II (Ca/CAMK II) activation in rat pituitaries. Endocrinology 2003; 144 (7) 2768-2774
  • 24 Dang AK, Murtazina DA, Magee C, Navratil AM, Clay CM, Amberg GC. GnRH evokes localized subplasmalemmal calcium signaling in gonadotropes. Mol Endocrinol 2014; 28 (12) 2049-2059
  • 25 Durán-Pastén ML, Fiordelisio T. GnRH-induced Ca(2+) signaling patterns and gonadotropin secretion in pituitary gonadotrophs. Functional adaptations to both ordinary and extraordinary physiological demands. Front Endocrinol (Lausanne) 2013; 4: 127
  • 26 Ellsworth BS, White BR, Burns AT, Cherrington BD, Otis AM, Clay CM. c-Jun N-terminal kinase activation of activator protein-1 underlies homologous regulation of the gonadotropin-releasing hormone receptor gene in alpha T3-1 cells. Endocrinology 2003; 144 (3) 839-849
  • 27 Bliss SP, Miller A, Navratil AM , et al. ERK signaling in the pituitary is required for female but not male fertility. Mol Endocrinol 2009; 23 (7) 1092-1101
  • 28 Navratil AM, Dozier MG, Whitesell JD, Clay CM, Roberson MS. Role of cortactin in dynamic actin remodeling events in gonadotrope cells. Endocrinology 2014; 155 (2) 548-557
  • 29 Navratil AM, Knoll JG, Whitesell JD, Tobet SA, Clay CM. Neuroendocrine plasticity in the anterior pituitary: gonadotropin-releasing hormone-mediated movement in vitro and in vivo. Endocrinology 2007; 148 (4) 1736-1744
  • 30 Edwards BS, Dang AK, Murtazina DA , et al. Dynamin is required for GnRH signaling to L-type calcium channels and activation of ERK. Endocrinology 2016; 157 (2) 831-843
  • 31 Zhang P, Hinshaw JE. Three-dimensional reconstruction of dynamin in the constricted state. Nat Cell Biol 2001; 3 (10) 922-926
  • 32 Hislop JN, Everest HM, Flynn A , et al. Differential internalization of mammalian and non-mammalian gonadotropin-releasing hormone receptors. Uncoupling of dynamin-dependent internalization from mitogen-activated protein kinase signaling. J Biol Chem 2001; 276 (43) 39685-39694
  • 33 Caunt CJ, Finch AR, Sedgley KR, McArdle CA. GnRH receptor signalling to ERK: kinetics and compartmentalization. Trends Endocrinol Metab 2006; 17 (8) 308-313
  • 34 Benard O, Naor Z, Seger R. Role of dynamin, Src, and Ras in the protein kinase C-mediated activation of ERK by gonadotropin-releasing hormone. J Biol Chem 2001; 276 (7) 4554-4563
  • 35 Bar-Lev TH, Harris D, Tomić M , et al. Role of PI4K and PI3K-AKT in ERK1/2 activation by GnRH in the pituitary gonadotropes. Mol Cell Endocrinol 2015; 415: 12-23
  • 36 Mutiara S, Kanasaki H, Harada T, Oride A, Miyazaki K. The involvement of phosphatidylinositol 3-kinase in gonadotropin-releasing hormone-induced gonadotropin alpha- and FSHbeta-subunit genes expression in clonal gonadotroph LbetaT2 cells. Mol Cell Endocrinol 2008; 283 (01/02): 1-11
  • 37 Bédécarrats GY, Kaiser UB. Differential regulation of gonadotropin subunit gene promoter activity by pulsatile gonadotropin-releasing hormone (GnRH) in perifused L beta T2 cells: role of GnRH receptor concentration. Endocrinology 2003; 144 (5) 1802-1811
  • 38 Kaiser UB, Jakubowiak A, Steinberger A, Chin WW. Differential effects of gonadotropin-releasing hormone (GnRH) pulse frequency on gonadotropin subunit and GnRH receptor messenger ribonucleic acid levels in vitro. Endocrinology 1997; 138 (3) 1224-1231
  • 39 Control of the Rhesus Monkey Menstrual Cycle. Permissive Role of hypothalamic gonadotropin-releasing hormone. Obstetrical & Gynecological Survey. Available at: http://journals.lww.com/obgynsurvey/citation/1980/09000/control_of_the_rhesus_monkey_menstrual_cycle_.15.aspx . Accessed October 31, 2016
  • 40 Wildt L, Häusler A, Marshall G , et al. Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology 1981; 109 (2) 376-385
  • 41 Knobil E. The electrophysiology of the GnRH pulse generator in the rhesus monkey. J Steroid Biochem 1989; 33 (4B): 669-671
  • 42 Williams CL, Nishihara M, Thalabard J-C, Grosser PM, Hotchkiss J, Knobil E. Corticotropin-releasing factor and gonadotropin-releasing hormone pulse generator activity in the rhesus monkey. Electrophysiological studies. Neuroendocrinology 1990; 52 (2) 133-137
  • 43 Thompson IR, Ciccone NA, Zhou Q , et al. GnRH pulse frequency control of Fshb gene expression is mediated via ERK1/2 regulation of ICER. Mol Endocrinol 2016; 30 (3) 348-360
  • 44 Thompson IR, Kaiser UB. GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. Mol Cell Endocrinol 2014; 385 (1-2): 28-35
  • 45 Thompson IR, Ciccone NA, Xu S, Zaytseva S, Carroll RS, Kaiser UB. GnRH pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB. Mol Endocrinol 2013; 27 (4) 606-618
  • 46 Wang H, Hastings R, Miller WL, Kumar TR. Fshb-iCre mice are efficient and specific Cre deleters for the gonadotrope lineage. Mol Cell Endocrinol 2016; 419: 124-138
  • 47 Driancourt MA, Cox P, Rubion S, Harnois-Milon G, Kemp B, Soede NM. Induction of an LH surge and ovulation by buserelin (as Receptal) allows breeding of weaned sows with a single fixed-time insemination. Theriogenology 2013; 80 (4) 391-399
  • 48 Pirard C, Loumaye E, Laurent P, Wyns C. Contribution to more patient-friendly ART treatment: efficacy of continuous low-dose GnRH agonist as the only luteal support-results of a prospective, randomized, comparative study. Int J Endocrinol 2015; 2015: 727569
  • 49 Picard-Hagen N, Lhermie G, Florentin S, Merle D, Frein P, Gayrard V. Effect of gonadorelin, lecirelin, and buserelin on LH surge, ovulation, and progesterone in cattle. Theriogenology 2015; 84 (2) 177-183
  • 50 Hammar O, Roth B, Bengtsson M, Mandl T, Ohlsson B. Autoantibodies and gastrointestinal symptoms in infertile women in relation to in vitro fertilization. BMC Pregnancy Childbirth 2013; 13: 201
  • 51 Ohlsson B, Sand E, Veress B. Ganglioneuritis is common in rats with enteric neuropathy due to buserelin treatment. Regul Pept 2014; ;190-191: 43-45
  • 52 Nederpelt I, Vergroesen RD, IJzerman AP, Heitman LH. Persistent GnRH receptor activation in pituitary αT3-1 cells analyzed with a label-free technology. Biosens Bioelectron 2016; 79: 721-727
  • 53 Pereyra Pacheco B, Méndez Ribas JM, Milone G , et al. Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report. Gynecol Oncol 2001; 81 (3) 391-397
  • 54 Blumenfeld Z, von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update 2008; 14 (6) 543-552
  • 55 Mittan D, Lee S, Miller E, Perez RC, Basler JW, Bruder JM. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002; 87 (8) 3656-3661
  • 56 Eidne KA, Flanagan CA, Harris NS, Millar RP. Gonadotropin-releasing hormone (GnRH)-binding sites in human breast cancer cell lines and inhibitory effects of GnRH antagonists. J Clin Endocrinol Metab 1987; 64 (3) 425-432
  • 57 Studer UE, Whelan P, Wimpissinger F , et al; EORTC Genitourinary Cancer Group. Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: final results of EORTC randomized trial 30891 with 12 years of follow-up. Eur Urol 2014; 66 (5) 829-838
  • 58 Di Lauro L, Vici P, Barba M , et al. Antiandrogen therapy in metastatic male breast cancer: results from an updated analysis in an expanded case series. Breast Cancer Res Treat 2014; 148 (1) 73-80
  • 59 Cortes D, Holt R, de Knegt VE. Hormonal aspects of the pathogenesis and treatment of cryptorchidism. Eur J Pediatr Surg 2016; 26 (5) 409-417
  • 60 Newcombe JR, Peters AR. The Buserelin enigma; how does treatment with this GnRH analogue decrease embryo mortality?. J Veterinar Sci Tech 2014; 5 (1) 151
  • 61 Bernard DJ, Fortin J, Wang Y, Lamba P. Mechanisms of FSH synthesis: what we know, what we don't, and why you should care. Fertil Steril 2010; 93 (8) 2465-2485
  • 62 Thackray VG, Mellon PL, Coss D. Hormones in synergy: regulation of the pituitary gonadotropin genes. Mol Cell Endocrinol 2010; 314 (2) 192-203
  • 63 Yosten GL, Lyu RM, Hsueh AJ , et al. A novel reproductive peptide, phoenixin. J Neuroendocrinol 2013; 25 (2) 206-215
  • 64 Larco DO, Cho-Clark M, Mani SK, Wu TJ. The metabolite GnRH-(1-5) inhibits the migration of immortalized GnRH neurons. Endocrinology 2013; 154 (2) 783-795
  • 65 Wu TJ, Mani SK, Glucksman MJ, Roberts JL. Stimulation of luteinizing hormone-releasing hormone (LHRH) gene expression in GT1-7 cells by its metabolite, LHRH-(1-5). Endocrinology 2005; 146 (1) 280-286
  • 66 Treen AK, Luo V, Belsham DD. Phoenixin activates immortalized GnRH and kisspeptin neurons through the novel receptor GPR173. Mol Endocrinol 2016; 30 (8) 872-888
  • 67 Kim T, Lawson MA. GnRH regulates gonadotropin gene expression through nADPH/dual oxidase-derived reactive oxygen species. Endocrinology 2015; 156 (6) 2185-2199
  • 68 Bedard K, Krause K-H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007; 87 (1) 245-313
  • 69 Aziz N, Saleh RA, Sharma RK , et al. Novel association between sperm reactive oxygen species production, sperm morphological defects, and the sperm deformity index. Fertil Steril 2004; 81 (2) 349-354
  • 70 Bergström B, Jarkman S. Correlation between sperm oxidative stress and sperm DNA damage in subfertile men. 2013 . Available at: https://lup.lub.lu.se/student-papers/search/publication/3364456 . Accessed January 23, 2017
  • 71 Aktan G, Doğru-Abbasoğlu S, Küçükgergin C, Kadıoğlu A, Ozdemirler-Erata G, Koçak-Toker N. Mystery of idiopathic male infertility: is oxidative stress an actual risk?. Fertil Steril 2013; 99 (5) 1211-1215
  • 72 Navratil AM, Bliss SP, Berghorn KA , et al. Constitutive localization of the gonadotropin-releasing hormone (GnRH) receptor to low density membrane microdomains is necessary for GnRH signaling to ERK. J Biol Chem 2003; 278 (34) 31593-31602
  • 73 Bliss SP, Navratil AM, Breed M, Skinner DC, Clay CM, Roberson MS. Signaling complexes associated with the type I gonadotropin-releasing hormone (GnRH) receptor: colocalization of extracellularly regulated kinase 2 and GnRH receptor within membrane rafts. Mol Endocrinol 2007; 21 (2) 538-549
  • 74 Navratil AM, Bliss SP, Roberson MS. Membrane rafts and GnRH receptor signaling. Brain Res 2010; 1364: 53-61
  • 75 Allen-Worthington K, Xie J, Brown JL , et al. The F0F1 ATP synthase complex localizes to membrane rafts in gonadotrope cells. Mol Endocrinol 2016; 30 (9) 996-1011
  • 76 Tsutsui K, Bentley GE, Bedecarrats G, Osugi T, Ubuka T, Kriegsfeld LJ. Gonadotropin-inhibitory hormone (GnIH) and its control of central and peripheral reproductive function. Front Neuroendocrinol 2010; 31 (3) 284-295
  • 77 Soga T, Kitahashi T, Clarke IJ, Parhar IS. Gonadotropin-inhibitory hormone promoter-driven enhanced green fluorescent protein expression decreases during aging in female rats. Endocrinology 2014; 155 (5) 1944-1955
  • 78 Kriegsfeld LJ, Ubuka T, Bentley GE, Tsutsui K. Seasonal control of gonadotropin-inhibitory hormone (GnIH) in birds and mammals. Front Neuroendocrinol 2015; 37: 65-75
  • 79 Calisi RM, Rizzo NO, Bentley GE. Seasonal differences in hypothalamic EGR-1 and GnIH expression following capture-handling stress in house sparrows (Passer domesticus). Gen Comp Endocrinol 2008; 157 (3) 283-287
  • 80 Smith JT, Young IR, Veldhuis JD, Clarke IJ. Gonadotropin-inhibitory hormone (GnIH) secretion into the ovine hypophyseal portal system. Endocrinology 2012; 153 (7) 3368-3375
  • 81 Clarke IJ, Bartolini D, Conductier G, Henry BA. Stress increases gonadotropin inhibitory hormone cell activity and input to GnRH cells in ewes. Endocrinology 2016; 157 (11) 4339-4350