Semin Reprod Med 2019; 37(02): 071-083
DOI: 10.1055/s-0039-3400254
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Does the KNDy Model for the Control of Gonadotropin-Releasing Hormone Pulses Apply to Monkeys and Humans?

Michael N. Lehman
1   Department of Biological Sciences, Brain Health Research Institute, Kent State University, Kent, Ohio
,
Wen He
1   Department of Biological Sciences, Brain Health Research Institute, Kent State University, Kent, Ohio
,
Lique M. Coolen
1   Department of Biological Sciences, Brain Health Research Institute, Kent State University, Kent, Ohio
,
Jon E. Levine
2   Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin
,
Robert L. Goodman
3   Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia
› Author Affiliations
Further Information

Publication History

Publication Date:
17 December 2019 (online)

Abstract

There is now considerable evidence supporting the role of a subpopulation of neurons in the arcuate nucleus of the hypothalamus that coexpress kisspeptin, neurokinin B, and dynorphin (abbreviated as KNDy neurons) as the long sought-after gonadotropin-releasing hormone (GnRH) pulse generator. The “KNDy hypothesis” of pulse generation has largely been based on findings in rodents and ruminants, and there is considerably less information about the anatomical and functional organization of the KNDy subpopulation in the primate hypothalamus. In this review, we focus on the applicability of this hypothesis, and the roles of kisspeptin, neurokinin B, and dynorphin in reproduction, to humans and nonhuman primates, reviewing available data and pointing out important gaps in our current knowledge. With recent application of drugs that target KNDy peptides and their receptors to therapeutic treatments for reproductive disorders, it is imperative we fully understand the primate KNDy network and its role in the control of GnRH secretion, as well as species differences in this system that may exist between humans, nonhuman primates, and other mammals.

 
  • References

  • 1 Goodman RL, Coolen LM, Lehman MN. Unraveling the mechanism of action of the GnRH pulse generator: a possible role for kisspeptin/neurokinin B/Dynorphin (KNDy) neurons. In: Conn MD. , ed. Cellular Endocrinology in Health and Disease. Amsterdam: Elsevier; 2014: 133-152
  • 2 Herbison AE. The gonadotropin-releasing hormone pulse generator. Endocrinology 2018; 159 (11) 3723-3736
  • 3 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 (38) 11859-11866
  • 4 Wakabayashi Y, Nakada T, Murata K. , et al. 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 (08) 3124-3132
  • 5 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 (08) 3479-3489
  • 6 Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 2005; 146 (09) 3686-3692
  • 7 Smith JT, Dungan HM, Stoll EA. , et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 2005; 146 (07) 2976-2984
  • 8 Dungan HM, Clifton DK, Steiner RA. Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion. Endocrinology 2006; 147 (03) 1154-1158
  • 9 Moore AM, Coolen LM, Porter DT, Goodman RL, Lehman MN. KNDy cells revisited. Endocrinology 2018; 159 (09) 3219-3234
  • 10 Dubois SL, Acosta-Martínez M, DeJoseph MR. , et al. Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons. Endocrinology 2015; 156 (03) 1111-1120
  • 11 Wang L, Burger LL, Greenwald-Yarnell ML, Myers Jr MG, Moenter SM. Glutamatergic transmission to hypothalamic kisspeptin neurons is differentially regulated by estradiol through estrogen receptor α in adult female mice. J Neurosci 2018; 38 (05) 1061-1072
  • 12 Clarkson J, Han SY, Piet R. , et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc Natl Acad Sci U S A 2017; 114 (47) E10216-E10223
  • 13 Smith JT, Li Q, Yap KS. , et al. Kisspeptin is essential for the full preovulatory LH surge and stimulates GnRH release from the isolated ovine median eminence. Endocrinology 2011; 152 (03) 1001-1012
  • 14 Higo S, Iijima N, Ozawa H. Characterization of Kiss1r (Gpr54)-expressing neurons in the arcuate nucleus of the female rat hypothalamus. J Neuroendocrinol 2017; 29 (02) DOI: 10.1111/jne.12452.
  • 15 Li XF, Kinsey-Jones JS, Cheng Y. , et al. Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS One 2009; 4 (12) e8334
  • 16 Goodman RL, Hileman SM, Nestor CC. , et al. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology 2013; 154 (11) 4259-4269
  • 17 García-Galiano D, van Ingen Schenau D, Leon S. , et al. Kisspeptin signaling is indispensable for neurokinin B, but not glutamate, stimulation of gonadotropin secretion in mice. Endocrinology 2012; 153 (01) 316-328
  • 18 Fergani C, Navarro VM. Expanding the role of tachykinins in the neuroendocrine control of reproduction. Reproduction 2016; 153 (01) R1-R14
  • 19 Noritake K, Matsuoka T, Ohsawa T. , et al. Involvement of neurokinin receptors in the control of pulsatile luteinizing hormone secretion in rats. J Reprod Dev 2011; 57 (03) 409-415
  • 20 de Croft S, Boehm U, Herbison AE. Neurokinin B activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse. Endocrinology 2013; 154 (08) 2750-2760
  • 21 Li Q, Millar RP, Clarke IJ, Smith JT. Evidence that neurokinin B controls basal gonadotropin-releasing hormone secretion but is not critical for estrogen-positive feedback in sheep. Neuroendocrinology 2015; 101 (02) 161-174
  • 22 Fergani C, Mazzella L, Coolen LM. , et al. Do substance P and neurokinin A play important roles in the control of LH secretion in ewes?. Endocrinology 2016; 157 (12) 4829-4841
  • 23 Yamamura T, Wakabayashi Y, Ohkura S, Navarro VM, Okamura H. Effects of intravenous administration of neurokinin receptor subtype-selective agonists on gonadotropin-releasing hormone pulse generator activity and luteinizing hormone secretion in goats. J Reprod Dev 2015; 61 (01) 20-29
  • 24 Weems PW, Coolen LM, Hileman SM. , et al. Evidence that dynorphin acts upon KNDy and GnRH neurons during GnRH pulse termination in the ewe. Endocrinology 2018; 159 (09) 3187-3199
  • 25 Qiu J, Nestor CC, Zhang C. , et al. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. eLife 2016; 5: 5
  • 26 Grachev P, Li XF, Kinsey-Jones JS. , et al. Suppression of the GnRH pulse generator by neurokinin B involves a κ-opioid receptor-dependent mechanism. Endocrinology 2012; 153 (10) 4894-4904
  • 27 Mostari P, Ieda N, Deura C. , et al. dynorphin-kappa opioid receptor signaling partly mediates estrogen negative feedback effect on LH pulses in female rats. J Reprod Dev 2013; 59 (03) 266-272
  • 28 Ruka KA, Burger LL, Moenter SM. Regulation of arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin by modulators of neurokinin 3 and κ-opioid receptors in adult male mice. Endocrinology 2013; 154 (08) 2761-2771
  • 29 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 2012; 153 (11) 5384-5393
  • 30 Vanacker C, Moya MR, DeFazio RA, Johnson ML, Moenter SM. Long-term recordings of arcuate nucleus kisspeptin neurons reveal patterned activity that is modulated by gonadal steroids in male mice. Endocrinology 2017; 158 (10) 3553-3564
  • 31 Han SY, Kane G, Cheong I, Herbison AE. Characterization of GnRH pulse generator activity in male mice using GCaMP fiber photometry. Endocrinology 2019; 160 (03) 557-567
  • 32 Navarro VM, Gottsch ML, Wu M. , et al. Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology 2011; 152 (11) 4265-4275
  • 33 Ruka KA, Burger LL, Moenter SM. Both estrogen and androgen modify the response to activation of neurokinin-3 and κ-opioid receptors in arcuate kisspeptin neurons from male mice. endocrinology 2016; 157 (02) 752-763
  • 34 Smith MS, Fox SR, Chatterton RT. Role of proestrous progesterone secretion in suppressing basal pulsatile LH secretion during estrus of the estrous cycle. Neuroendocrinology 1989; 50 (03) 308-314
  • 35 McQuillan HJ, Han SY, Cheong I, Herbison AE. GnRH pulse generator activity across the estrous cycle of female mice. Endocrinology 2019; 160 (06) 1480-1491
  • 36 Kanaya M, Iwata K, Ozawa H. Distinct dynorphin expression patterns with low- and high-dose estrogen treatment in the arcuate nucleus of female rats. Biol Reprod 2017; 97 (05) 709-718
  • 37 Nestor CC, Briscoe AM, Davis SM, Valent M, Goodman RL, Hileman SM. Evidence of a role for kisspeptin and neurokinin B in puberty of female sheep. Endocrinology 2012; 153 (06) 2756-2765
  • 38 Yamamura T, Wakabayashi Y, Sakamoto K. , et al. The effects of chronic subcutaneous administration of an investigational kisspeptin analog, TAK-683, on gonadotropin-releasing hormone pulse generator activity in goats. Neuroendocrinology 2014; 100 (2-3): 250-264
  • 39 Goodman RL, Inskeep EK. Control of the ovarian cycle of the sheep. In: Plant TM, Zeleznik AJ. , eds. Knobil and Neill's Physiology of Reproduction. 4th ed. Vol 2. Amsterdam: Elsevier; 2015: 1259-1305
  • 40 Nestor CC, Bedenbaugh MN, Hileman SM, Coolen LM, Lehman MN, Goodman RL. Regulation of GnRH pulsatility in ewes. Reproduction 2018; 156 (03) R83-R99
  • 41 Seminara SB, Messager S, Chatzidaki EE. , et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349 (17) 1614-1627
  • 42 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 2003; 100 (19) 10972-10976
  • 43 Dhillo WS, Chaudhri OB, Patterson M. , et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005; 90 (12) 6609-6615
  • 44 Jayasena CN, Nijher GM, Comninos AN. , et al. The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. J Clin Endocrinol Metab 2011; 96 (12) E1963-E1972
  • 45 Lapatto R, Pallais JC, Zhang D. , et al. Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology 2007; 148 (10) 4927-4936
  • 46 Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, de Roux N. Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab 2007; 92 (03) 1137-1144
  • 47 Topaloglu AK, Tello JA, Kotan LD. , et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012; 366 (07) 629-635
  • 48 Martínez de la Escalera G, Choi AL, Weiner RI. Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line. Proc Natl Acad Sci U S A 1992; 89 (05) 1852-1855
  • 49 Young J, George JT, Tello JA. , et al. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology 2013; 97 (02) 193-202
  • 50 Chan YM, Broder-Fingert S, Wong KM, Seminara SB. Kisspeptin/Gpr54-independent gonadotrophin-releasing hormone activity in Kiss1 and Gpr54 mutant mice. J Neuroendocrinol 2009; 21 (12) 1015-1023
  • 51 O'Byrne KT, Knobil E. Electrophysiological approaches to gonadotrophin releasing hormone pulse generator activity in the rhesus monkey. Hum Reprod 1993; 8 (Suppl. 02) 37-40
  • 52 Keen KL, Wegner FH, Bloom SR, Ghatei MA, Terasawa E. An increase in kisspeptin-54 release occurs with the pubertal increase in luteinizing hormone-releasing hormone-1 release in the stalk-median eminence of female rhesus monkeys in vivo. Endocrinology 2008; 149 (08) 4151-4157
  • 53 Plant TM, Ramaswamy S, Dipietro MJ. Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology 2006; 147 (02) 1007-1013
  • 54 Ramaswamy S, Guerriero KA, Gibbs RB, Plant TM. Structural interactions between kisspeptin and GnRH neurons in the mediobasal hypothalamus of the male rhesus monkey (Macaca mulatta) as revealed by double immunofluorescence and confocal microscopy. Endocrinology 2008; 149 (09) 4387-4395
  • 55 Moore AM, Prescott M, Czieselsky K. , et al. Synaptic innervation of the GnRH neuron distal dendron in female mice. Endocrinology 2018; 159 (09) 3200-3208
  • 56 Watanabe G, Terasawa E. In vivo release of luteinizing hormone releasing hormone increases with puberty in the female rhesus monkey. Endocrinology 1989; 125 (01) 92-99
  • 57 Guerriero KA, Keen KL, Terasawa E. Developmental increase in kisspeptin-54 release in vivo is independent of the pubertal increase in estradiol in female rhesus monkeys (Macaca mulatta). Endocrinology 2012; 153 (04) 1887-1897
  • 58 Terasawa E, Guerriero KA, Plant TM. Kisspeptin and puberty in mammals. Adv Exp Med Biol 2013; 784: 253-273
  • 59 Molnár CS, Vida B, Sipos MT. , et al. Morphological evidence for enhanced kisspeptin and neurokinin B signaling in the infundibular nucleus of the aging man. Endocrinology 2012; 153 (11) 5428-5439
  • 60 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 2007; 92 (07) 2744-2750
  • 61 Eghlidi DH, Haley GE, Noriega NC, Kohama SG, Urbanski HF. Influence of age and 17beta-estradiol on kisspeptin, neurokinin B, and prodynorphin gene expression in the arcuate-median eminence of female rhesus macaques. Endocrinology 2010; 151 (08) 3783-3794
  • 62 Alçin E, Sahu A, Ramaswamy S. , et al. Ovarian regulation of kisspeptin neurones in the arcuate nucleus of the rhesus monkey (Macaca mulatta). J Neuroendocrinol 2013; 25 (05) 488-496
  • 63 Shibata M, Friedman RL, Ramaswamy S, Plant TM. Evidence that down regulation of hypothalamic KiSS-1 expression is involved in the negative feedback action of testosterone to regulate luteinising hormone secretion in the adult male rhesus monkey (Macaca mulatta). J Neuroendocrinol 2007; 19 (06) 432-438
  • 64 Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Interactions between neurokinin B and kisspeptin in mediating estrogen feedback in healthy women. J Clin Endocrinol Metab 2016; 101 (12) 4628-4636
  • 65 Lippincott MF, Chan YM, Rivera Morales D, Seminara SB. Continuous kisspeptin administration in postmenopausal women: impact of estradiol on luteinizing hormone secretion. J Clin Endocrinol Metab 2017; 102 (06) 2091-2099
  • 66 Topaloglu AK, Reimann F, Guclu M. , et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet 2009; 41 (03) 354-358
  • 67 Rance NE, Young III WS. Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology 1991; 128 (05) 2239-2247
  • 68 Goodman RL, Ohkura S, Okamura H, Coolen LM, Lehman MN. The KNDy hypothesis for generation of GnRH pulses: evidence from sheep and goats. In: Plant TM, Herbison A. , eds. The GnRH Neuron and Its Control. Hoboken, NJ: John Wiley and Sons, Ltd; 2018: 289-324
  • 69 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 (09) 4494-4503
  • 70 Ramaswamy S, Dwarki K, Ali B, Gibbs RB, Plant TM. The decline in pulsatile GnRH release, as reflected by circulating LH concentrations, during the infant-juvenile transition in the agonadal male rhesus monkey (Macaca mulatta) is associated with a reduction in kisspeptin content of KNDy neurons of the arcuate nucleus in the hypothalamus. Endocrinology 2013; 154 (05) 1845-1853
  • 71 Hrabovszky E, Ciofi P, Vida B. , et al. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci 2010; 31 (11) 1984-1998
  • 72 Hrabovszky E, Molnár CS, Sipos MT. , et al. Sexual dimorphism of kisspeptin and neurokinin B immunoreactive neurons in the infundibular nucleus of aged men and women. Front Endocrinol (Lausanne) 2011; 2: 80
  • 73 Hrabovszky E, Sipos MT, Molnár CS. , et al. Low degree of overlap between kisspeptin, neurokinin B, and dynorphin immunoreactivities in the infundibular nucleus of young male human subjects challenges the KNDy neuron concept. Endocrinology 2012; 153 (10) 4978-4989
  • 74 Hrabovszky E, Takács S, Göcz B, Skrapits K. New perspectives for anatomical and molecular studies of kisspeptin neurons in the aging human brain. Neuroendocrinology 2019; 109 (03) 230-241
  • 75 Skrapits K, Borsay BA, Herczeg L. , et al. Colocalization of cocaine- and amphetamine-regulated transcript with kisspeptin and neurokinin B in the human infundibular region. PLoS One 2014; 9 (08) e103977
  • 76 Skrapits K, Borsay BA, Herczeg L, Ciofi P, Liposits Z, Hrabovszky E. Neuropeptide co-expression in hypothalamic kisspeptin neurons of laboratory animals and the human. Front Neurosci 2015; 9: 29
  • 77 Gianetti E, Tusset C, Noel SD. , et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 2010; 95 (06) 2857-2867
  • 78 Sidhoum VF, Chan YM, Lippincott MF. , et al. Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system. J Clin Endocrinol Metab 2014; 99 (03) 861-870
  • 79 Lippincott MF, León S, Chan YM. , et al. Hypothalamic reproductive endocrine pulse generator activity independent of neurokinin B and dynorphin signaling. J Clin Endocrinol Metab 2019; 104 (10) 4304-4318
  • 80 Young J, Bouligand J, Francou B. , et al. TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab 2010; 95 (05) 2287-2295
  • 81 Francou B, Bouligand J, Voican A. , et al. Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations. PLoS One 2011; 6 (10) e25614
  • 82 Coiro V, Volpi R, Capretti L. , et al. Luteinizing hormone response to an intravenous infusion of substance P in normal men. Metabolism 1992; 41 (07) 689-691
  • 83 Hrabovszky E, Borsay BA, Rácz K. , et al. Substance P immunoreactivity exhibits frequent colocalization with kisspeptin and neurokinin B in the human infundibular region. PLoS One 2013; 8 (08) e72369
  • 84 Skorupskaite K, George JT, Veldhuis JD, Anderson RA, Neurokinin B. Neurokinin B regulates gonadotropin secretion, ovarian follicle growth, and the timing of ovulation in healthy women. J Clin Endocrinol Metab 2018; 103 (01) 95-104
  • 85 Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men. Clin Endocrinol (Oxf) 2017; 87 (06) 748-756
  • 86 Fraser GL, Ramael S, Hoveyda HR, Gheyle L, Combalbert J. The NK3 receptor antagonist ESN364 suppresses sex hormones in men and women. J Clin Endocrinol Metab 2016; 101 (02) 417-426
  • 87 Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Neurokinin 3 receptor antagonism reveals roles for neurokinin B in the regulation of gonadotropin secretion and hot flashes in postmenopausal women. Neuroendocrinology 2018; 106 (02) 148-157
  • 88 George JT, Kakkar R, Marshall J. , et al. Neurokinin B receptor antagonism in women with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 2016; 101 (11) 4313-4321
  • 89 Kalil B, Ramaswamy S, Plant TM. The distribution of substance P and kisspeptin in the mediobasal hypothalamus of the male rhesus monkey and a comparison of intravenous administration of these peptides to release GnRH as reflected by LH secretion. Neuroendocrinology 2016; 103 (06) 711-723
  • 90 Fraser GL, Hoveyda HR, Clarke IJ. , et al. The NK3 receptor antagonist ESN364 interrupts pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle. Endocrinology 2015; 156 (11) 4214-4225
  • 91 Narayanaswamy S, Prague JK, Jayasena CN. , et al. Investigating the KNDy hypothesis in humans by coadministration of kisspeptin, neurokinin B, and naltrexone in men. J Clin Endocrinol Metab 2016; 101 (09) 3429-3436
  • 92 Ramaswamy S, Seminara SB, Plant TM. Evidence from the agonadal juvenile male rhesus monkey (Macaca mulatta) for the view that the action of neurokinin B to trigger gonadotropin-releasing hormone release is upstream from the kisspeptin receptor. Neuroendocrinology 2011; 94 (03) 237-245
  • 93 Garcia JP, Guerriero KA, Keen KL, Kenealy BP, Seminara SB, Terasawa E. Kisspeptin and neurokinin B signaling network underlies the pubertal increase in GnRH release in female rhesus monkeys. Endocrinology 2017; 158 (10) 3269-3280
  • 94 Garcia JP, Keen KL, Kenealy BP, Seminara SB, Terasawa E. Role of kisspeptin and neurokinin B signaling in male rhesus monkey puberty. Endocrinology 2018; 159 (08) 3048-3060
  • 95 Yen SS, Quigley ME, Reid RL, Ropert JF, Cetel NS. Neuroendocrinology of opioid peptides and their role in the control of gonadotropin and prolactin secretion. Am J Obstet Gynecol 1985; 152 (04) 485-493
  • 96 Rossmanith WG, Wirth U, Sterzik K, Yen SS. The effects of prolonged opioidergic blockade on LH pulsatile secretion during the menstrual cycle. J Endocrinol Invest 1989; 12 (04) 245-252
  • 97 Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A 1993; 90 (12) 5391-5393
  • 98 Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 1995; 18 (01) 22-29
  • 99 Abe J, Okamura H, Kitamura T. , et al. Immunocytochemical demonstration of dynorphin(PH-8P)-like immunoreactive elements in the human hypothalamus. J Comp Neurol 1988; 276 (04) 508-513
  • 100 Burke MC, Letts PA, Krajewski SJ, Rance NE. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: morphologic evidence of interrelated function within the arcuate nucleus. J Comp Neurol 2006; 498 (05) 712-726
  • 101 Goodman RL, Lehman MN, Smith JT. , et al. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 2007; 148 (12) 5752-5760
  • 102 Rometo AM, Rance NE. Changes in prodynorphin gene expression and neuronal morphology in the hypothalamus of postmenopausal women. J Neuroendocrinol 2008; 20 (12) 1376-1381
  • 103 True C, Takahashi D, Kirigiti M. , et al. Arcuate nucleus neuropeptide coexpression and connections to gonadotrophin-releasing hormone neurones in the female rhesus macaque. J Neuroendocrinol 2017; 29 (06) 29
  • 104 Foradori CD, Goodman RL, Adams VL, Valent M, Lehman MN. Progesterone increases dynorphin a concentrations in cerebrospinal fluid and preprodynorphin messenger ribonucleic acid levels in a subset of dynorphin neurons in the sheep. Endocrinology 2005; 146 (04) 1835-1842
  • 105 Kim W, Jessen HM, Auger AP, Terasawa E. Postmenopausal increase in KiSS-1, GPR54, and luteinizing hormone releasing hormone (LHRH-1) mRNA in the basal hypothalamus of female rhesus monkeys. Peptides 2009; 30 (01) 103-110
  • 106 Quigley ME, Yen SS. The role of endogenous opiates in LH secretion during the menstrual cycle. J Clin Endocrinol Metab 1980; 51 (01) 179-181
  • 107 Reid RL, Quigley ME, Yen SS. The disappearance of opioidergic regulation of gonadotropin secretion in postmenopausal women. J Clin Endocrinol Metab 1983; 57 (06) 1107-1110
  • 108 DeFazio J, Verheugen C, Chetkowski R, Nass T, Judd HL, Meldrum DR. The effects of naloxone on hot flashes and gonadotropin secretion in postmenopausal women. J Clin Endocrinol Metab 1984; 58 (03) 578-581
  • 109 Melis GB, Paoletti AM, Gambacciani M, Mais V, Fioretti P. Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women using naloxone. Neuroendocrinology 1984; 39 (01) 60-63
  • 110 Casper RF, Alapin-Rubillovitz S. Progestins increase endogenous opioid peptide activity in postmenopausal women. J Clin Endocrinol Metab 1985; 60 (01) 34-36
  • 111 Shoupe D, Montz FJ, Lobo RA. The effects of estrogen and progestin on endogenous opioid activity in oophorectomized women. J Clin Endocrinol Metab 1985; 60 (01) 178-183
  • 112 Veldhuis JD, Rogol AD, Samojlik E, Ertel NH. Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man. J Clin Invest 1984; 74 (01) 47-55
  • 113 Goodman RL, Gibson M, Skinner DC, Lehman MN. Neuroendocrine control of pulsatile GnRH secretion during the ovarian cycle: evidence from the ewe. Reprod Suppl 2002; 59: 41-56
  • 114 Portoghese PS, Lipkowski AW, Takemori AE. Binaltorphimine and nor-binaltorphimine, potent and selective kappa-opioid receptor antagonists. Life Sci 1987; 40 (13) 1287-1292
  • 115 Ferin M, Van Vugt D, Wardlaw S. The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res 1984; 40: 441-485
  • 116 Steele PA, Judd SJ. Role of endogenous opioids in reducing the frequency of pulsatile luteinizing hormone secretion induced by progesterone in normal women. Clin Endocrinol (Oxf) 1986; 25 (06) 669-674
  • 117 Foradori CD, Coolen LM, Fitzgerald ME, Skinner DC, Goodman RL, Lehman MN. Colocalization of progesterone receptors in parvicellular dynorphin neurons of the ovine preoptic area and hypothalamus. Endocrinology 2002; 143 (11) 4366-4374
  • 118 Goodman RL, Coolen LM, Anderson GM. , et al. Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep. Endocrinology 2004; 145 (06) 2959-2967
  • 119 Ropert JF, Quigley ME, Yen SS. Endogenous opiates modulate pulsatile luteinizing hormone release in humans. J Clin Endocrinol Metab 1981; 52 (03) 583-585
  • 120 Van Vugt DA, Bakst G, Dyrenfurth I, Ferin M. Naloxone stimulation of luteinizing hormone secretion in the female monkey: influence of endocrine and experimental conditions. Endocrinology 1983; 113 (05) 1858-1864
  • 121 Van Vugt DA, Lam NY, Ferin M. Reduced frequency of pulsatile luteinizing hormone secretion in the luteal phase of the rhesus monkey. Involvement of endogenous opiates. Endocrinology 1984; 115 (03) 1095-1101
  • 122 Orstead KM, Hess DL, Spies HG. Opiatergic inhibition of pulsatile luteinizing hormone release during the menstrual cycle of rhesus macaques. Proc Soc Exp Biol Med 1987; 184 (03) 312-319
  • 123 Raynor K, Kong H, Chen Y. , et al. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol 1994; 45 (02) 330-334
  • 124 Abel TW, Rance NE. Proopiomelanocortin gene expression is decreased in the infundibular nucleus of postmenopausal women. Brain Res Mol Brain Res 1999; 69 (02) 202-208
  • 125 Wardlaw SL, Wehrenberg WB, Ferin M, Antunes JL, Frantz AG. Effect of sex steroids on beta-endorphin in hypophyseal portal blood. J Clin Endocrinol Metab 1982; 55 (05) 877-881
  • 126 Petersen SL, LaFlamme KD. Progesterone increases levels of mu-opioid receptor mRNA in the preoptic area and arcuate nucleus of ovariectomized, estradiol-treated female rats. Brain Res Mol Brain Res 1997; 52 (01) 32-37
  • 127 Smith YR, Zubieta JK, del Carmen MG. , et al. Brain opioid receptor measurements by positron emission tomography in normal cycling women: relationship to luteinizing hormone pulsatility and gonadal steroid hormones. J Clin Endocrinol Metab 1998; 83 (12) 4498-4505
  • 128 Gallo RV. Kappa-opioid receptor involvement in the regulation of pulsatile luteinizing hormone release during early pregnancy in the rat. J Neuroendocrinol 1990; 2 (05) 685-691
  • 129 Goodman RL, Parfitt DB, Evans NP, Dahl GE, Karsch FJ. Endogenous opioid peptides control the amplitude and shape of gonadotropin-releasing hormone pulses in the ewe. Endocrinology 1995; 136 (06) 2412-2420
  • 130 Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology 2010; 151 (01) 301-311
  • 131 Goubillon ML, Forsdike RA, Robinson JE, Ciofi P, Caraty A, Herbison AE. Identification of neurokinin B-expressing neurons as an highly estrogen-receptive, sexually dimorphic cell group in the ovine arcuate nucleus. Endocrinology 2000; 141 (11) 4218-4225
  • 132 Goodman RL, Lehman MN. Kisspeptin neurons from mice to men: similarities and differences. Endocrinology 2012; 153 (11) 5105-5118
  • 133 Iijima N, Takumi K, Sawai N, Ozawa H. An immunohistochemical study on the expressional dynamics of kisspeptin neurons relevant to GnRH neurons using a newly developed anti-kisspeptin antibody. J Mol Neurosci 2011; 43 (02) 146-154
  • 134 Xu Z, Kaga S, Mochiduki A. , et al. Immunocytochemical localization of kisspeptin neurons in the rat forebrain with special reference to sexual dimorphism and interaction with GnRH neurons. Endocr J 2012; 59 (02) 161-171
  • 135 Desroziers E, Mikkelsen JD, Duittoz A, Franceschini I. Kisspeptin-immunoreactivity changes in a sex- and hypothalamic-region-specific manner across rat postnatal development. J Neuroendocrinol 2012; 24 (08) 1154-1165
  • 136 Overgaard A, Ruiz-Pino F, Castellano JM, Tena-Sempere M, Mikkelsen JD. Disparate changes in kisspeptin and neurokinin B expression in the arcuate nucleus after sex steroid manipulation reveal differential regulation of the two KNDy peptides in rats. Endocrinology 2014; 155 (10) 3945-3955
  • 137 Adachi S, Yamada S, Takatsu Y. , et al. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev 2007; 53 (02) 367-378
  • 138 Kauffman AS, Gottsch ML, Roa J. , et al. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology 2007; 148 (04) 1774-1783
  • 139 Homma T, Sakakibara M, Yamada S. , et al. Significance of neonatal testicular sex steroids to defeminize anteroventral periventricular kisspeptin neurons and the GnRH/LH surge system in male rats. Biol Reprod 2009; 81 (06) 1216-1225
  • 140 Takumi K, Iijima N, Ozawa H. Developmental changes in the expression of kisspeptin mRNA in rat hypothalamus. J Mol Neurosci 2011; 43 (02) 138-145
  • 141 Ruiz-Pino F, Navarro VM, Bentsen AH. , et al. Neurokinin B and the control of the gonadotropic axis in the rat: developmental changes, sexual dimorphism, and regulation by gonadal steroids. Endocrinology 2012; 153 (10) 4818-4829
  • 142 Chan YM, Butler JP, Pinnell NE. , et al. Kisspeptin resets the hypothalamic GnRH clock in men. J Clin Endocrinol Metab 2011; 96 (06) E908-E915
  • 143 Chan YM, Butler JP, Sidhoum VF, Pinnell NE, Seminara SB. Kisspeptin administration to women: a window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle. J Clin Endocrinol Metab 2012; 97 (08) E1458-E1467
  • 144 Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A 2005; 102 (06) 2129-2134
  • 145 Jayasena CN, Abbara A, Veldhuis JD. , et al. Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of Kisspeptin-54. J Clin Endocrinol Metab 2014; 99 (06) E953-E961
  • 146 Prague JK, Roberts RE, Comninos AN. , et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2017; 389 (10081): 1809-1820
  • 147 True C, Kirigiti M, Ciofi P, Grove KL, Smith MS. Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat. J Neuroendocrinol 2011; 23 (01) 52-64
  • 148 Weems P, Smith J, Clarke IJ, Coolen LM, Goodman RL, Lehman MN. Effects of season and estradiol on KNDy neuron peptides, colocalization with D2 dopamine receptors, and dopaminergic inputs in the ewe. Endocrinology 2017; 158 (04) 831-841
  • 149 Ahn T, Fergani C, Coolen LM, Padmanabhan V, Lehman MN. Prenatal testosterone excess decreases neurokinin 3 receptor immunoreactivity within the arcuate nucleus KNDy cell population. J Neuroendocrinol 2015; 27 (02) 100-110
  • 150 Weems PW, Witty CF, Amstalden M, Coolen LM, Goodman RL, Lehman MN. κ-Opioid receptor is colocalized in GnRH and KNDy cells in the female ovine and rat brain. Endocrinology 2016; 157 (06) 2367-2379