The function of the central aspects of the hypothalamic-pituitary-gonadal axis has been assessed in a number of ways including direct measurements of the hypothalamic output and indirect measures using gonadotropin release from the pituitary as a bioassay for reproductive neuroendocrine activity. Here, methods for monitoring these various parameters are briefly reviewed and then examples presented of both concordance and discrepancy between central and peripheral measurements, with a focus on situations in which elevated gonadotropin-releasing hormone neurosecretion is not reflected accurately by pituitary luteinizing hormone release. Implications for the interpretation of gonadotropin data are discussed.

1.
Smith PE: The disabilities caused by hypophysectomy and their repair: the tuberal (hypothalamic) syndrome in the rat. J Am Med Assoc 1927;88:158-161.
2.
Harris GW: The induction of ovulation in the rabbit by electrical stimulation of the hypothalamo-hypophyseal mechanism. Proc Royal Soc Lond B 1937;122:374-394.
3.
Dierschke DJ, Bhattacharya AN, Atkinson LE, Knobil E: Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinology 1970;87:850-853.
4.
Matsuo H, Baba Y, Nair RMG, Arimura A, Schally AV: Structure of the porcine LH- and FSH-releasing hormone. I. The proposed amino acid sequence. Biochem Biophys Res Commun 1971;43:1334-1339.
5.
Belchetz P, Plant TM, Nakai Y, Keogh EJ, Knobil E: Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science 1978;202:631-633.
6.
Bertelloni S, Baroncelli GI: Current pharmacotherapy of central precocious puberty by GnRH analogs: certainties and uncertainties. Expert Opin Pharmacother 2013;14:1627-1639.
7.
Millar RP, Pawson AJ, Morgan K, Rissman EF, Lu Z-L: Diversity of actions of GnRHs mediated by ligand-induced selective signaling. Front Neuroendocrinol 2008;29:17-35.
8.
Limonta P, Marelli MM, Mai S, Motta M, Martini L, Moretti RM: GnRH receptors in cancer: from cell biology to novel targeted therapeutic strategies. Endocr Rev 2012;33:784-811.
9.
Brodie TD, Crowley WF Jr: Neuroendocrine control of reproduction and its therapeutic manipulation with GnRH and its analogs. Int J Fertil 1985;30:66-70, 74-75.
10.
Wilson RC, Kesner JS, Kaufman JM, Uemura T, Akema T, Knobil E: Central electrophysiologic correlates of pulsatile luteinizing hormone secretion in the rhesus monkey. Neuroendocrinology 1984;39:256-260.
11.
Mori Y, Nishihara M, Tanaka T, Shimizu T, Yamaguchi M, Takeuchi Y, Hoshino K: Chronic recording of electrophysiological manifestation of the hypothalamic gonadotropin-releasing hormone pulse generator activity in the goat. Neuroendocrinology 1991;53:392-395.
12.
Hiruma H, Nishihara M, Kimura F: Hypothalamic electrical activity that relates to the pulsatile release of luteinizing hormone exhibits diurnal variation in ovariectomized rats. Brain Res 1992;582:119-122.
13.
O'Byrne KT, Knobil E: Electrophysiological approaches to gonadotrophin releasing hormone pulse generator activity in the rhesus monkey. Hum Reprod 1993;8:37-40.
14.
Kinsey-Jones JS, Li XF, Luckman SM, O'Byrne KT: Effects of kisspeptin-10 on the electrophysiological manifestation of gonadotropin-releasing hormone pulse generator activity in the female rat. Endocrinology 2008;149:1004-1008.
15.
Sarkar DK, Fink G: Luteinizing hormone releasing factor in pituitary stalk plasma from long-term ovariectomized rats: effects of steroids. J Endocrinol 1980;86:511-524.
16.
Sarkar DK, Chiappa SA, Fink G, Sherwood NM: Gonadotropin-releasing hormone surge in pro-oestrous rats. Nature 1976;264:461-463.
17.
Clarke IJ, Cummins JT: The temporal relationship between gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinology 1982;111:1737-1739.
18.
Moenter SM, Brand RM, Midgley AR, Karsch FJ: Dynamics of gonadotropin-releasing hormone release during a pulse. Endocrinology 1992;130:503-510.
19.
Fuenzalida LC, Keen KL, Terasawa E: Colocalization of FM1-43, Bassoon, and GnRH-1: GnRH-1 release from cell bodies and their neuroprocesses. Endocrinology 2011;152:4310-4321.
20.
Glanowska KM, Venton BJ, Moenter SM: Fast scan cyclic voltammetry as a novel method for detection of real-time gonadotropin-releasing hormone release in mouse brain slices. J Neurosci 2012;32:14664-14669.
21.
Caraty A, Delaleu B, Chesneau D, Fabre-Nys C: Sequential role of E2 and GnRH for the expression of estrous behavior in ewes. Endocrinology 2002;143:139-145.
22.
DePaolo LV, King RA, Carrillo AJ: In vivo and in vitro examination of an autoregulatory mechanism for luteinizing hormone-releasing hormone. Endocrinology 1987;120:272-279.
23.
Xu C, Xu XZ, Nunemaker CS, Moenter SM: Dose-dependent switch in response of gonadotropin-releasing hormone (GnRH) neurons to GnRH mediated through the type I GnRH receptor. Endocrinology 2004;145:728-735.
24.
Glanowska KM, Moenter SM: Differential regulation of GnRH secretion in the preoptic area (POA) and the median eminence (ME) in male mice. Endocrinology 2015;156:231-241.
25.
Kenealy BP, Kapoor A, Guerriero KA, Keen KL, Garcia JP, Kurian JR, Ziegler TE, Terasawa E: Neuroestradiol in the hypothalamus contributes to the regulation of gonadotropin releasing hormone release. J Neurosci 2013;33:19051-19059.
26.
Watanabe G, Terasawa E: In vivo release of luteinizing hormone releasing hormone increases with puberty in the female rhesus monkey. Endocrinology 1989;125:92-99.
27.
Sisk CL, Richardson HN, Chappell PE, Levine JE: In vivo gonadotropin-releasing hormone secretion in female rats during peripubertal development and on proestrus. Endocrinology 2001;142:2929-2936.
28.
O'Byrne KT, Chen MD, Nishihara M, Williams CL, Thalabard JC, Hotchkiss J, Knobil E: Ovarian control of gonadotropin hormone-releasing hormone pulse generator activity in the rhesus monkey: duration of the associated hypothalamic signal. Neuroendocrinology 1993;57:588-592.
29.
Xia L, Van Vugt D, Alston EJ, Luckhaus J, Ferin M: A surge of gonadotropin-releasing hormone accompanies the estradiol-induced gonadotropin surge in the rhesus monkey. Endocrinology 1992;131:2812-2820.
30.
Clarke IJ, Thomas GB, Yao B, Cummins JT: GnRH secretion throughout the ovine estrous cycle. Neuroendocrinology 1987;46:82-88.
31.
Moenter SM, Caraty A, Karsch FJ: The estradiol-induced surge of gonadotropin-releasing hormone in the ewe. Endocrinology 1990;127:1375-1384.
32.
Moenter SM, Caraty A, Locatelli A, Karsch FJ: Pattern of gonadotropin-releasing hormone (GnRH) secretion leading up to ovulation in the ewe: existence of a preovulatory GnRH surge. Endocrinology 1991;129:1175-1182.
33.
Evans NP, Dahl GE, Caraty A, Padmanabhan V, Thrun LA, Karsch FJ: How much of the gonadotropin-releasing hormone (GnRH) surge is required for generation of the luteinizing hormone surge in the ewe? Duration of the endogenous GnRH signal. Endocrinology 1996;137:4730-4737.
34.
Adams JM, Taylor AE, Schoenfeld DA, Crowley WF Jr, Hall JE: The midcycle gonadotropin surge in normal women occurs in the face of an unchanging gonadotropin-releasing hormone pulse frequency. J Clin Endocrinol Metab 1994;79:858-864.
35.
Hall JE, Taylor AE, Martin KA, Rivier J, Schoenfeld DA, Crowley WF Jr: Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women. Proc Natl Acad Sci USA 1994;91:6894-6898.
36.
Kesner JS, Wilson RC, Kaufman JM, Hotchkiss J, Chen Y, Yamamoto H, Pardo RR, Knobil E: Unexpected responses of the hypothalamic gonadotropin-releasing hormone ‘pulse generator' to physiological estradiol inputs in the absence of the ovary. Proc Natl Acad Sci USA 1987;84:8745-8749.
37.
Knobil E, Plant TM, Wildt L, Belchetz PE, Marshall G: Control of the rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone. Science 1980;207:1371-1373.
38.
Testart J, Frydman R: Minimum time lapse between luteinizing hormone surge or human chorionic gonadotropin administration and follicular rupture. Fertil Steril 1982;37:50-53.
39.
Gosden RG, Everett JW: Luteinizing hormone requirements for ovulation in the pentobarbital-treated proestrous rat. Endocrinology 1976;99:1046-1053.
40.
Evans NP, Dahl GE, Mauger D, Karsch FJ: Estradiol induces both qualitative and quantitative changes in the pattern of gonadotropin-releasing hormone secretion during the presurge period in the ewe. Endocrinology 1995;136:1603-1609.
41.
Perrett RM, Voliotis M, Armstrong SP, Fowkes RC, Pope GR, Tsaneva-Atanasova K, McArdle CA: Pulsatile hormonal signaling to extracellular signal-regulated kinase: exploring system sensitivity to gonadotropin-releasing hormone pulse frequency and width. J Biol Chem 2014;289:7873-7883.
42.
McIntosh RP, McIntosh JE: Dynamic characteristics of luteinizing hormone release from perifused sheep anterior pituitary cells stimulated by combined pulsatile and continuous gonadotropin-releasing hormone. Endocrinology 1985;117:169-179.
43.
Webster JR, Moenter SM, Barrell GK, Lehman MN, and Karsch FJ: Role of the thyroid gland in seasonal reproduction. III. Thyroidectomy blocks seasonal suppression of gonadotropin-releasing hormone secretion in sheep. Endocrinology 1991;129:1635-1643.
44.
Caraty A, Locatelli A: Effect of time after castration on secretion of LHRH and LH in the ram. J Reprod Fertil 1988;82:263-269.
45.
Caraty A, Locatelli A, Schanbacher B: Augmentation, by naloxone, of the frequency and amplitude of LH-RH pulses in hypothalamo-hypophyseal portal blood in the castrated ram. C R Acad Sci III 1987;305:369-374.
46.
Veldhuis JD, Johnson ML: Cluster analysis: a simple versatile, and robust algorithm for endocrine pulse detection. Am J Physiol 1986;250:E486-E493.
47.
Glanowska KM, Burger LL, Moenter SM: Development of gonadotropin-releasing hormone secretion and pituitary response. J Neurosci 2014;34:15060-15069.
48.
Coquelin A, Desjardins C: Luteinizing hormone and testosterone secretion in young and old male mice. Am J Physiol 1982;243:E257-E263.
49.
Steyn FJ, Wan Y, Clarkson J, Veldhuis JD, Herbison AE, Chen C: Development of a methodology for and assessment of pulsatile luteinizing hormone secretion in juvenile and adult male mice. Endocrinology 2013;154:4939-4945.
50.
Selmanoff MK, Goldman BD, Ginsburge BE: Developmental changes in serum luteinizing hormone, follicle stimulating hormone and androgen levels in males of two inbred mouse strains. Endocrinology 1977;100:122-127.
51.
Prevot V, Rio C, Cho GJ, Lomniczi A, Heger S, Neville CM, Rosenthal NA, Ojeda SR, Corfas G: Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes. J Neurosci 2003;23:230-239.
52.
Michael SD, Kaplan SB, Macmillan BT: Peripheral plasma concentrations of LH, FSH, prolactin and GH from birth to puberty in male and female mice. J Reprod Fertil 1980;59:217-222.
53.
Kirk SE, Dalkin AC, Yasin M, Haisenleder DJ, Marshall JC: Gonadotropin-releasing hormone pulse frequency regulates expression of pituitary follistatin messenger ribonucleic acid: a mechanism for differential gonadotrope function. Endocrinology 1994;135:876-880.
54.
Burger LL, Dalkin AC, Aylor KW, Haisenleder DJ, Marshall JC: GnRH pulse frequency modulation of gonadotropin subunit gene transcription in normal gonadotropes-assessment by primary transcript assay provides evidence for roles of GnRH and follistatin. Endocrinology 2002;143:3243-3249.
55.
Wildt L, Hausler A, Marshall G, Hutchison JS, Plant TM, Belchetz PE, Knobil E: Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology 1981;109:376-385.
56.
Duran-Pasten ML, Fiordelisio T: GnRH-induced Ca2+ signaling patterns and gonadotropin secretion in pituitary gonadotrophs. Functional adaptations to both ordinary and extraordinary physiological demands. Front Endocrinol (Lausanne) 2013;4:127.
57.
Thompson IR, Kaiser UB: GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. Mol Cell Endocrinol 2014;385:28-35.
58.
Conn PM, Janovick JA: Trafficking and quality control of the gonadotropin releasing hormone receptor in health and disease. Mol Cell Endocrinol 2009;299:137-145.
59.
Perrett RM, McArdle CA: Molecular mechanisms of gonadotropin-releasing hormone signaling: integrating cyclic nucleotides into the network. Front Endocrinol (Lausanne) 2013;4:180.
60.
Hayes FJ, McNicholl DJ, Schoenfeld D, Marsh EE, Hall JE: Free alpha-subunit is superior to luteinizing hormone as a marker of gonadotropin-releasing hormone despite desensitization at fast pulse frequencies. J Clin Endocrinol Metab 1999;84:1028-1036.
61.
Doudna JA, Charpentier E: The new frontier of genome engineering with CRISPR-Cas9. Science 2014;346.
62.
Oakley AE, Clifton DK, Steiner RA: Kisspeptin signaling in the brain. Endocr Rev 2009;30:713-743.
63.
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 2010;151:3479-3489.
64.
d'Anglemont de Tassigny X, Fagg LA, Carlton MBL, Colledge WH: Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology 2008;149:3926-3932.
65.
Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA: Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA 2005;102:1761-1766.
66.
Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA: Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 2009;29:11859-11866.
67.
Billings HJ, Connors JM, Altman SN, Hileman SM, Holaskova I, Lehman MN, McManus CJ, Nestor CC, Jacobs BH, Goodman RL: Neurokinin B acts via the neurokinin-3 receptor in the retrochiasmatic area to stimulate luteinizing hormone secretion in sheep. Endocrinology 2010;151:3836-3846.
68.
Ramaswamy S, Seminara SB, Ali B, Ciofi P, Amin NA, Plant TM: Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with Kisspeptin in the arcuate nucleus. Endocrinology 2010;151:4494-4503.
69.
Kinsey-Jones JS, Grachev P, Li XF, Lin YS, Milligan SR, Lightman SL, O'Byrne KT: The inhibitory effects of neurokinin B on GnRH pulse generator frequency in the female rat. Endocrinology 2012;153:307-315.
70.
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 2010;22:181-187.
71.
Wakabayashi Y, Nakada T, Murata K, Ohkura S, Mogi K, Navarro VM, Clifton DK, Mori Y, Tsukamura H, Maeda K-I, Steiner RA, Okamura H: Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci 2010;30:3124-3132.
72.
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 2013;154:3984-3989.
73.
Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S, Boehm U, Levine JE: Timing and completion of puberty in female mice depend on estrogen receptor α signaling in kisspeptin neurons. Proc Natl Acad Sci USA 2010;107:22693-22698.
74.
Campos P, Herbison AE: Optogenetic activation of GnRH neurons reveals minimal requirements for pulsatile luteinizing hormone secretion. Proc Natl Acad Sci USA 2014;111:18387-18392.
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