Hypothalamus-Pituitary-Gonadal Axis: It is Time for Revision
School of Medicine, Democritus University of Thrace, Greece
- *Corresponding Author:
- Dr. Byron Asimakopoulos
School of Medicine
Democritus University of Thrace, Greece
E-mail: [email protected]
Received Date: November 22, 2012; Accepted Date: November 23, 2012; Published Date: November 25, 2012
Citation: Asimakopoulos B (2012) Hypothalamus-Pituitary-Gonadal Axis: It is Time for Revision. Human Genet Embryol 2:e106. doi: 10.4172/2161-0436.1000e106
Copyright: © 2012 Asimakopoulos B. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The structure and the function of the Hypothalamus-Pituitary- Gonadal (HPG) axis is an integral part of the knowledge on the physiology of the human body that every bioscientist receives during his/her education. Especially for those scientists who work in the fields of assisted reproduction and endocrinology, the function of HPG axis is of paramount importance.
The HPG axis drives reproduction: Hypothalamus secretes Gonadotrophin Releasing Hormone (GnRH), GnRH stimulates the gonadotroph cells of pituitary to secrete Follicular Stimulating Hormone (FSH) and Luteinizing Hormone (LH) and in turn these two hormones regulate the gonadal function in both sexes. Steroid hormones as well as inhibins and activins, produced by gonads, influence the secretion of gonadotrophins. It is also well known that internal and external cues influence the HPG axis. For example, stress hormones, leptin and the opioid system modulate the secretion of GnRH and gonadotrophins. However, it has become obvious that they are not main regulators. GnRH, FSH and LH, androgens, and oestrogens are the main players in this classical schema and until recently, GnRH was recognized as the neurohormone having the pivotal role in the physiology of reproduction. This is the basic knowledge on the function of HPG axis. However, during the last ten years, novel findings on the actions of RFamide peptides have challenged this knowledge. RFamides are small peptides possessing the motif Arg-Phe-NH2 at C-terminus. Two groups of RFamide peptides proved to participate in HPG axis: Gonadotropin Inhibiting Hormone (GnIH) and its related peptides and the group of kisspeptins.
In 2000, Tsutsui et al.  discovered a new RFamide in the hypothalamus of Japanese quail that was found to decrease gonadotropin secretion in a dose-dependent manner and also to inhibit biosynthesis of gonadotropin α and β subunits [1-3]. This RFamide was designated as GnIH and subsequent studies revealed GnIH and similar peptides in the brain of other avian species, amphibians and fish [4-7]. In mammals, the existence of RFamide peptides similar to avian GnIH first was predicted by a search in gene databases  and soon after, two RFamide related peptides (RFRPs): RFRP-1 and RFRP-3 were isolated from bovine , rat , rhesus macaque  and human brain . The RFRP-3 was found to inhibit LH release in rats , sheep  and cattle . Thus, RFRP-3 seems to be the mammalian ortholog of GnIH. In human brain, neurons expressing RFRP-3 are located in the dorsomedial region and their fibers come in contact with GnRH neurons in the preoptic area and they also give projections to the median eminence .
The actions of GnIH and RFRPs are mediated through a G proteincoupled receptor (GPCR) that was first identified in the brain of Japanese quail . In mammals, two putative receptors for GnIH and RFRPs were found: GPR-74 and GPR-147 . In humans, GPR-147 is expressed in the hypothalamus and in the gonadotroph cells of pituitary .
As it was mentioned before, GnIH and RFRPs inhibit in vivo and in vitro gonadotrophin release from hypophysis in avian and mammal species. The projection of GnIH fibers in median eminence and hypophysis further document and explain this action. The existence of close contacts between GnIH fibers and GnRH neurons indicates a regulatory action of GnIH on GnRH release, although the expression of GPR-74 and GPR-147 in mammalian GnRH neurons has not been observed.
Recently, Oishi et al.  reported that RFRP-3 and GPR147 are expressed in granulosa cell layer of human preovulatory follicles as well as in the human corpus luteum and they showed that RFRP-3 suppresses gonadotropin induced progesterone production in human granulosa cell cultures.
Studies on the regulation of RFRPs have shown that in hamsters, RFRP neurons express estrogen receptor-α and it was found that estrogen treatment increased FOS expression in these neurons . This finding suggests an activation of RFRP neurons by estrogens and thus it can be postulated that these neurons participate in the feedback system between gonadal steroids and hypothalamus. Kirby et al.  have also presented findings suggesting a regulation of RFRPs by stress hormones in rats: Stress increased RFRP hypothalamic expression and this increase could be blocked by adrenalectomy.
The other groups of RFamides that draw the attention due to their actions on HPG-axis are kisspeptins, the products of the gene kiss- 1 . The gene encodes for a 145 amino acid precursor that after cleavage gives several peptides with a length of 54, 14, 13 or 10 amino acids. The receptor for kisspeptins is an orphan one known as GPR- 54 . It is notable that kisspeptins are highly conserved through the evolution of vertebrates: kiss-1 gene has been found in a plethora of vertebrate species, including mammals . In 2003, it was reported that several patients suffering from idiopathic hypogonadotropic hypogonadism had mutations in the GPR-54 [24,25]. This finding fuelled the investigation on the role of kisspeptins and their receptor in reproductive physiology.
Today, it is known that in mammals, kisspeptins are expressed by hypothalamic neurons [26-32]. In primates, kisspeptin neurons are primarily located in the arcuate nucleus and the preoptic area giving also projections to the median eminence and, in humans, to the ventromedial nucleus as well [33-36]. Kisspeptin neurons establish synaptic contacts with GnRH neuronal bodies and particularly in the median eminence with terminals of GnRH neurons . The majority of GnRH neurons express GPR-54 [27,37].
Kisspeptins stimulate GnRH secretion and subsequently they stimulate the secretion of LH and, in a less degree, of FSH. This was found in mouse , rat , sheep , cow , rhesus macaque  and humans [42,43].
Kisspeptin neurons express estrogen receptor α (ERα) and a large body of evidence suggests that kisspeptin neurons of the arcuate nucleus are responsible for the negative feedback of sex steroids on HPG axis [30,33-35]. Besides, in rodents, the kisspeptin neurons of the anteroventral periventricular area increase the expression of kiss-1 mRNA when estrogens are at high levels and decrease the expression in absence or low levels of estrogens . This finding indicates that in rodents, the kisspeptin neurons of the anteroventral periventricular area are responsible for the positive feedback of sex steroids on HPG axis. In primates, who do not have kisspeptin neurons in the anteroventral periventricular area, it seems that different subpopulations of the arcuate nucleus and the preoptic area respond differentially to estrogen levels mediating both positive and negative feedbacks.
Furthermore, metabolic status is implicated in the regulation of kisspeptins: fasting decreases their expression , whereas a considerable number of kisspeptin neurons express leptin receptors .
The above findings outline a new, more complete perception of the HPG axis: the gonadotropin release in pituitary is positively regulated by GnRH and negatively by GnIH/RFRPs. GnRH release is under the control of kisspeptins that are subjected to negative and positive feedback from gonadal steroids. Kisspeptins expression is influenced by metabolic signals. GnIH/RFRPs are also subjected to feedback by gonadal steroids and they are influenced by stress hormones.
This new perception of the HPG axis suggests new therapeutic options. Already, the treatment with kisspeptins has proved to be successful in cases of functional hypothalamic amenorrhea . It is reasonable to postulate that treatment with GnIH and RFRPs could be proved useful for the cessation of gonadotropin release.
Although further investigation is needed, particularly on the actions of RFRPs in humans, the new findings on the structure and the function of HPG axis enter us in a new era with a better knowledge of the physiology of reproduction and new options for the treatment of related disorders.
- Tsutsui K, Saigoh E, Ukena K, Teranishi H, Fujisawa Y, et al. (2000) A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem Biophys Res Commun 275: 661-667.
- Ciccone NA, Dunn IC, Boswell T, Tsutsui K, Ubuka T, et al. (2004) Gonadotrophin inhibitory hormone depresses gonadotrophin alpha and follicle-stimulating hormone beta subunit expression in the pituitary of the domestic chicken. J Neuroendocrinol 16: 999-1006.
- Ubuka T, Ukena K, Sharp PJ, Bentley GE, Tsutsui K (2006) Gonadotropin-inhibitory hormone inhibits gonadal development and maintenance by decreasing gonadotropin synthesis and release in male quail. Endocrinology 147: 1187-1194.
- Bentley GE, Perfito N, Ukena K, Tsutsui K, Wingfield JC (2003) Gonadotropin-inhibitory peptide in song sparrows (Melospiza melodia) in different reproductive conditions, and in house sparrows (Passer domesticus) relative to chicken-gonadotropin-releasing hormone. J Neuroendocrinol 15: 794-802.
- Osugi T, Ukena K, Bentley GE, O’Brien S, Moore IT, et al. (2004) Gonadotropin-inhibitory hormone in Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii): cDNA identification, transcript localization and functional effects in laboratory and field experiments. J Endocrinol 182: 33-42.
- Koda A, Ukena K, Teranishi H, Ohta S, Yamamoto K, et al. (2002) A novel amphibian hypothalamic neuropeptide: isolation, localization, and biological activity. Endocrinology 143: 411-419.
- Sawada K, Ukena K, Satake H, Iwakoshi E, Minakata H, et al. (2002) Novel fish hypothalamic neuropeptide. Eur J Biochem 269: 6000-6008.
- Hinuma S, Shintani Y, Fukusumi S, Iijima N, Matsumoto Y, et al. (2000) New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol 2: 703-708.
- Fukusumi S, Habata Y, Yoshida H, Iijima N, Kawamata Y, et al. (2001) Characteristics and distribution of endogenous RFamide-related peptide-1. Biochim Biophys Acta 1540: 221-232.
- Ukena K, Iwakoshi E, Minakata H, Tsutsui K (2002) A novel rat hypothalamic RFamide-related peptide identified by immunoaffinity chromatography and mass spectrometry. FEBS Lett 512: 255-258.
- Ubuka T, Lai H, Kitani M, Suzuuchi A, Pham V, et al. (2009) Gonadotropin-inhibitory hormone identification, cDNA cloning, and distribution in rhesus macaque brain. J Comp Neurol 517: 841-855.
- Ubuka T, Morgan K, Pawson AJ, Osugi T, Chowdhury VS, et al. (2009) Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PloS One 4: e8400.
- Johnson MA, Tsutsui K, Fraley GS (2007) Rat RFamide-related peptide-3 stimulates GH secretion, inhibits LH secretion, and has variable effects on sex behavior in the adult male rat. Horm Behav 51: 171-180.
- Clarke IJ, Sari IP, Qi Y, Smith JT, Parkington HC, et al. (2008) Potent action of RFamide-related peptide-3 on pituitary gonadotropes indicative of a hypophysiotropic role in the negative regulation of gonadotropin secretion. Endocrinology 149: 5811-5821.
- Kadokawa H, Shibata M, Tanaka Y, Kojima T, Matsumoto K, et al. (2009) Bovine C-terminal octapeptide of RFamide-related peptide-3 suppresses luteinizing hormone (LH) secretion from the pituitary as well as pulsatile LH secretion in bovines. Domest Anim Endocrinol 36: 219-224.
- Yin H, Ukena K, Ubuka T, Tsutsui K (2005) A novel G protein-coupled receptor for gonadotropin-inhibitory hormone in the Japanese quail (Coturnix japonica): identification, expression and binding activity. J Endocrinol 184: 257-266.
- Gouardères C, Mazarguil H, Mollereau C, Chartrel N, Leprince J, et al. (2007) Functional differences between NPFF1 and NPFF2 receptor coupling: high intrinsic activities of RFamide-related peptides on stimulation of [35S]GTPgammaS binding. Neuropharmacology 52: 376-386.
- Oishi H, Klausen C, Bentley GE, Osugi T, Tsutsui K, et al. (2012) The human Gonadotropin-Inhibitory Hormone ortholog RFamide-Related Peptide-3 suppresses gonadotropin-induced progesterone production in human granulosa cells. Endocrinology 153: 3435-3445.
- Kriegsfeld LJ, Mei DF, Bentley GE, Ubuka T, Mason AO, et al. (2006) Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals. Proc Natl Acad Sci USA 103: 2410-2415.
- Kirby ED, Geraghthy AC, Ubuka T, Bentley GE, Kaufer D (2009) Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proc Natl Acad Sci USA 106: 11324-11329.
- Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, et al. (1996) KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 88: 1731-1737.
- Lee DK, Nguyen T, O’Neill GP, Cheng R, Liu Y, et al. (1999) Discovery of a receptor related to the galanin receptors. FEBS Lett 446: 103-107.
- Lee YR, Tsunekawa K, Moon MJ, Um HN, Hwang JI, et al. (2009) Molecular evolution of multiple forms of kisspeptins and GPR54 receptors in vertebrates. Endocrinology 150: 2837-2846.
- de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, et al. (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 100: 10972-10976.
- Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, et al. (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349: 1614-1627.
- Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, et al. (2004) A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145: 4073-4077.
- Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, et al. (2004) Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80: 264-272.
- Kinoshita M, Tsukamura H, Adachi S, Matsui H, Uenoyama Y, et al. (2005) Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology 146: 4431-4436.
- Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA (2006) Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci 26: 6687-6694.
- Adachi S, Yamada S, Takatsu Y, Matsui H, Kinoshita M, et al. (2007) Involvement of Anteroventral Periventricular Metastin/Kisspeptin Neurons in Estrogen Positive Feedback Action on Luteinizing Hormone Release in Female Rats. J Reprod Dev 53: 367-378.
- Clarkson J, Tassigny X, Colledge WH, Caraty A, Herbison AE (2009) Distribution of kisspeptin neurones in the adult female mouse brain. J Neuroendocrinol 21: 673-682.
- Desroziers E, Mikkelsen J, Simonneaux V, Keller M, Tillet Y, et al. (2010) Mapping of kisspeptin fibres in the brain of the pro-oestrus rat. J Neuroendocrinol 22: 1101-1112.
- Rometo AM, Krajewski SJ, Voytko ML, Rance NE (2007) Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab 92: 2744-2750.
- Ramaswamy S, Guerriero KA, Gibbs RB, Plant TM (2008) 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 149: 4387-4395.
- Ramaswamy S, Seminara SB, Ali B, Ciofi P, Amin NA, et al. (2010) Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus. Endocrinology 151: 4494-4503.
- Hrabovszky E, Ciofi P, Vida B, Horvath MC, Keller E, et al. (2010) The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci 31: 1984-1998.
- Herbison AE, de Tassigny X, Doran J, Colledge WH (2010) Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 151: 312-321.
- Navarro VM, Castellano JM, Fernández-Fernández R, Tovar S, Roa J, et al. (2005) Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology 146: 156-163.
- Arreguin-Arevalo JA, Lents CA, Farmerie TA, Nett TM, Clay CM (2007) KiSS-1 peptide induces release of LH by a direct effect on the hypothalamus of ovariectomized ewes. Anim Reprod Sci 101: 265-275.
- Kadokawa H, Matsui M, Hayashi K, Matsunaga N, Kawashima C, et al. (2008) Peripheral administration of kisspeptin-10 increases plasma concentrations of GH as well as LH in prepubertal Holstein heifers. J Endocrinol 196: 331-334.
- Plant TM, Ramaswamy S, Dipietro MJ (2006) 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 147: 1007-1013.
- Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, et al. (2005) Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 90: 6609-6615.
- Dhillo WS, Chaudhri OB, Thompson EL, Murphy KG, Patterson M, et al. (2007) Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women. J Clin Endocrinol Metab 92: 3958-3966.
- Roa J, Vigo E, García-Galiano D, Castellano JM, Navarro VM, et al. (2008) Desensitization of gonadotropin responses to kisspeptin in the female rat: analyses of LH and FSH secretion at different developmental and metabolic states. Am J Physiol Endocrinol Metab 294: E1088-E1096.
- Smith JT, Acohido BV, Clifton DK, Steiner RA (2006) KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol 18: 298-303.
- Jayasena CN, Nijher GM, Chaudhri OB, Murphy KG, Ranger A, et al. (2009) Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab 94: 4315-4323.