Kisspeptin and the regulation of the hypothalamic-pituitary-gonadal axis in the rhesus monkey (Macaca mulatta)

The present article reviews recent studies of monkeys and, in some cases, humans that have been conducted to examine the role of kisspeptin-GPR54 signaling in the regulation of the hypothalamic-pituitary-gonadal axis in higher primates. This area of peptide biology was initiated in 2003 by the discovery that loss of function mutations of GPR54 in man were associated with hypogonadotropic hypogonadism and absent or delayed puberty. Puberty in the monkey, an experimental model commonly used to study this fundamental developmental stage, is first described. This is followed by a review of the role of kisspeptin in the regulation of the postnatal ontogeny of GnRH pulsatility. The roles of kisspeptin in GnRH pulse generation and in the feedback loops governing gonadotropin secretion in primates are then discussed. A brief section on kisspeptin-GPR54 signaling at the pituitary and gonadal levels is also included. The review concludes with a discussion of the phenomenon of GPR54 downregulation by continuous exposure to kisspeptin and its therapeutic implications.     

Ichthyosis and hypogonadism in two brothers with deletion of the short arm of the X chromosome

Two brothers were examined because of ichthyosis and hypogonadism. Their testes were small. There was no response of plasma testosterone to human chorionic gonadotropin and no response of plasma luteinizing hormone and follicle-stimulating hormone to intravenous luteinizing-hormone-releasing hormone. They both had hyposmia. Steroid sulfatase activity in white blood cells was zero. Flow cytometry and the use of special probes indicated that these two brothers had a large deletion of the short arm of the X chromosome which included the STS locus, the closely linked locus DXS237 and probably the gene for hypogonadism, findings which offer the opportunity for speculations on the locus of control of normal testicular development and function.     

Luteinizing Hormone and Follicle Stimulating Hormone-Releasing Hormone Test in Patients with Hypothalamic Pituitary-Gonadal Dysfunction

A standard intravenous 100 μg luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH) test was used to assess the pituitary gonadotrophin responses in 155 patients with a variety of diseases of the hypothalamic-pituitary-gonadal axis. In all but nine patients there was an increase in circulating levels of either LH or FSH in response to the releasing hormone though 137 (88%) were clinically hypogonadal. It was not possible with this test to distinguish between hypothalamic and pituitary causes of hypogonadotrophic hypogonadism, since a variety of LH and FSH responses emerged within the disease groups. However, primary gonadal failure characteristically resulted in exaggerated gonadotrophin response. The potential therapeutic use of the gonadotrophin releasing decapeptide is suggested in certain patients with hypogonadotrophic hypogonadism.     

Familial hypothalamic hypogonadotropic hypogonadism

Clinical findings and endocrine studies are reported concerning six subjects (from two pedigrees) suffering from isolated hypogonadotropic hypogonadism. Their complete lack of any gonadotropin response to clomiphene stimulation, together with positive responses of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to LH-releasing-hormone stimulation (LH-RH) provide evidence for a hypothalamic basis for this disorder. Additional data are presented indicating that variables such as circulating estrogen levels may influence the gonadotropin response to LH-RH.     

A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia,hypogonadotropic hypogonadism and growth hormone deficiency

Heterozygous de novo mutations in SOX2 have been reported in approximately 10–20% of patients with unilateral or bilateral anophthalmia or microphthalmia. An additional phenotype of hypopituitarism, with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, has been reported in patients carrying SOX2 alterations. We report a novel heterozygous mutation in the SOX2 gene in a male affected with congenital bilateral anophthalmia, hypogonadotrophic hypogonadism and growth hormone deficiency. The mutation we describe is a cytosine deletion in position 905 (c905delC) which causes frameshift and an aberrant C-terminal domain. Our report highlights the fact that subjects affected with eye anomalies and harboring SOX2 mutations are at high risk for gonadotropin deficiency, which has important implications for their clinical management.     

脊椎动物促性腺激素释放激素的分子结构变异型和功能多样性

综述了近十几年来有关对脊椎动物促性腺激素释放激素的结构和功能的研究进展,阐明促性腺激素释放激素分子结构的变异型和它们在脊椎动物的分布和进化,分析促性腺激素释放激素的多种功能及其受体的结构与特异性。     

Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism

GnRH is the central regulator of reproductive function responding to central nervous system cues to control gonadotropin synthesis and secretion. GnRH neurons originate in the olfactory placode and migrate to the forebrain, in which they are found in a scattered distribution. Congenital idiopathic hypogonadotropic hypogonadism (CIHH) has been associated with mutations or deletions in a number of genes that participate in the development of GnRH neurons and expression of GnRH. Despite the critical role of GnRH in mammalian reproduction, a comprehensive understanding of the developmental factors that are responsible for regulating the establishment of mature GnRH neurons and the expression of GnRH is lacking. orthodenticle homeobox 2 (OTX2), a homeodomain protein required for the formation of the forebrain, has been shown to be expressed in GnRH neurons, up-regulated during GnRH neuronal development, and responsible for increased GnRH promoter activity in GnRH neuronal cell lines. Interestingly, mutations in Otx2 have been associated with human hypogonadotropic hypogonadism, but the mechanism by which Otx2 mutations cause CIHH is unknown. Here we show that deletion of Otx2 in GnRH neurons results in a significant decrease in GnRH neurons in the hypothalamus, a delay in pubertal onset, abnormal estrous cyclicity, and infertility. Taken together, these data provide in vivo evidence that Otx2 is critical for GnRH expression and reproductive competence.     

Activating and inactivating hormone receptor mutations

The unravelling of gene structures of hormones, their receptors and the various components of their signal transduction apparatus has enabled diagnosis of the aetiology of hormone resistance at the molecular level. Inactivating mutations can be found in hormone receptor genes or those encoding components of the post-receptor signal transduction cascade. Another category of receptor mutation is that causing constitutive receptor activation, which results in ligand-independent, inappropriate or supraphysiological hormone action and in some cases malignant growth. The purpose of this contribution is to review the different types of inactivation and activation mechanisms that are induced by receptor mutations, using some of the best characterised mutations as examples. In addition, the currently known mutations of hormone receptors are briefly summarised.     

2013 William Allan Award: My Multifactorial Journey

Gonadotropin-releasing hormone (GnRH) neurons originate outside the CNS in the olfactory placode and migrate into the CNS, where they become integral components of the hypothalamic-pituitary-gonadal (HPG) axis. Disruption of this migration results in Kallmann syndrome (KS), which is characterized by anosmia and pubertal failure due to hypogonadotropic hypogonadism. Using candidate-gene screening, autozygosity mapping, and whole-exome sequencing in a cohort of 30 individuals with KS, we searched for genes newly associated with KS. We identified homozygous loss-of-function mutations in FEZF1 in two independent consanguineous families each with two affected siblings. The FEZF1 product is known to enable axons of olfactory receptor neurons (ORNs) to penetrate the CNS basal lamina in mice. Because a subset of axons in these tracks is the migratory pathway for GnRH neurons, in FEZF1 deficiency, GnRH neurons also fail to enter the brain. These results indicate that FEZF1 is required for establishment of the central component of the HPG axis in humans.     

Kallmann syndrome 1 gene is expressed in the marsupial gonad

Kallmann syndrome is characterized by hypogonadotrophic hypogonadism and anosmia. The syndrome can be caused by mutations in several genes, but the X-linked form is caused by mutation in the Kallmann syndrome 1 (KAL1). KAL1 plays a critical role in gonadotropin-releasing hormone (GnRH) neuronal migration that is essential for the normal development of the hypothalamic-pituitary-gonadal axis. Interestingly, KAL1 appears to be missing from the rodent X, and no orthologue has been detected as yet. We investigated KAL1 during development and in adults of an Australian marsupial, the tammar wallaby, Macropus eugenii. Marsupial KAL1 maps to an autosome within a group of genes that was added as a block to the X chromosome in eutherian evolution. KAL1 expression was widespread in embryonic and adult tissues. In the adult testis, tammar KAL1 mRNA and protein were detected in the germ cells at specific stages of differentiation. In the adult testis, the protein encoded by KAL1, anosmin-1, was restricted to the round spermatids and elongated spermatids. In the adult ovary, anosmin-1 was not only detected in the oocytes but was also localized in the granulosa cells throughout folliculogenesis. This is the first examination of KAL1 mRNA and protein localization in adult mammalian gonads. The protein localization suggests that KAL1 participates in gametogenesis not only through the development of the hypothalamic-pituitary-gonadal axis by activation of GnRH neuronal migration, but also directly within the gonads themselves. Because KAL1 is autosomal in marsupials but is X-linked in eutherians, its conserved involvement in gametogenesis supports the hypothesis that reproduction-related genes were actively recruited to the eutherian X chromosome.     

Familial hypogonadotropic hypogonadism with alopecia.

In one family several male and female members had hypogonadism and frontoparietal alopecia, whereas other members with normal sexual development had normal scalp hair. Clinical and laboratory evaluation of three affected young men (two brothers and their cousin) revealed that the hypogonadism was the result of decreased serum concentrations of follicle stimulating and luteinizing hormones. There was no evidence of a deficiency of any other pituitary hormone. Long-term treatment of the three patients with human chorionic gonadotropin resulted in an increase in the serum testosterone concentration, the appearance of male secondary sex characteristics and an increase in the size of the external genitalia.     

Therapeutic indications for delayed puberty and hypogonadism in adolescent boys.

Testosterone and synthetic androgens have formerly been used indiscriminately, but are now applied more selectively. They are the only treatment of primary hypogonadism, but are also useful in gonadotropin deficiency and constitutional delay. 17-Alkylated androgens are no longer used. Oral testosterone undecanoate is not suitable for adolescents because of unreliable absorption. The prototype disorder where replacement is necessary is congenital anorchia. As a physiological replacement, an initial dose of 35 mg/m2 per month for 6 months, followed by 70 mg/m2 for 1 year, and 150 mg/m2 thereafter, is recommended. No general rules can be given for other types of primary hypogonadism. In testicular atrophy after cryptorchidism, defects of testosterone biosynthesis, galactosemia or other causes, it is advisable to carry out periodic testosterone determinations and to wait until the levels drop below normal. Progress has been made in the treatment of gonadotropin deficiency, and pulsatile gonadotropin-releasing hormone (GnRH) has been shown to be effective in the hypothalamic type. Nevertheless, androgens still have a temporary place in this condition. In constitutional delay of growth and adolescence, treatment is not necessary somatically, but there are often psychosocial reasons. Gonadotropins, GnRH or growth hormone (GH)-releasing hormone have been used. Also treatment with human GH is successful in accelerating height velocity. The most simple and economic treatment is still testosterone in a physiological dose for 3-6 months. Oxandrolone or other synthetic androgens have no advantages.     

Effect of hypo-osmotic environmental changes on the expression of gonadotropin-releasing hormone,its receptor,and gonadotropin hormone subunit mRNA in adult chum salmon (Oncorhynchus keta)

Migrating fish such as salmonids are affected by external environmental factors and salinity changes are particularly important, influencing spawning migration. The aim of this study was to test whether changes in salinity would affect the expression of the hypothalamic-pituitary-gonadal (HPG) axis hormones (gonadotropin-releasing hormones (GnRHs) [salmon GnRH and chicken GnRH-II], GnRH receptors [GnRHR1 and GnRHR5], and mRNA of the gonadotropin hormone [GTH] subunits [GTHα, follicle stimulating hormone β, and luteinizing hormone β]) in chum salmon (Oncorhynchus keta). Fish were progressively transferred from seawater (SW) through 50% SW to freshwater (FW), and the relationship between the osmoregulatory hormone prolactin (PRL) and sexual maturation was determined. The expression and activity of HPG hormones and their receptors, and levels of estradiol-17β and PRL increased after fish were transferred to FW, demonstrating that changes in salinity stimulate the HPG axis and PRL production in migrating chum salmon. These findings reveal details about the role of the endocrine system in maintaining homeostasis and stimulating sexual maturation and reproduction in response to salinity changes in this species.     

Alterations in gonadal steroidogenesis in individuals expressing a common genetic variant of luteinizing hormone

Some pathologies of the pituitary-gonadal function have recently been found to be due to mutations of the gonadotropin or gonadotropin receptor genes. Although these conditions are extremely rare, they are very informative, by elucidating some less well characterized facets of normal gonadotropin function and the molecular pathogenesis of disturbances in sexual differentiation and fertility. In contrast, there is a common polymorphism in the Luteinizing Hormone (LH) β-subunit gene, where two point mutations cause two alterations in the amino acid sequence (Trp⁸→Arg and Ile¹⁵→Thr) and introduce an extra glycosylation signal to Asn¹³. The carriers of this variant gene are largely healthy, but certain mild differences in their gonadal function have been found, as reflected by alterations in gonadal steroidogenesis, pubertal development and predisposition to diseases such as infertility, polycystic ovarian syndrome, and breast and prostatic cancer. The purpose of this chapter is to review the current knowledge of the occurrence, special functional features and clinical correlates of this LH variant.     

Hypomorphic phenotype in mice with pituitary‐specific knockout of steroidogenic factor 1

Summary: The bacteriophage Cre recombinase provides a powerful approach for tissue‐specific gene inactivation. Using a Cre transgene driven by the common alpha subunit of glycoprotein hormones (αGSU‐Cre), we have previously inactivated steroidogenic factor 1 (SF‐1) in the anterior pituitary, causing hypogonadotropic hypogonadism with sexual infantilism, sterility, and severe gonadal hypoplasia. We now explore the molecular mechanisms underlying a hypomorphic gonadal phenotype in mice carrying two floxed SF‐1 alleles (F/F) relative to mice carrying one recombined and one floxed allele (F/R). Because their Cre‐mediated disruption of the locus encoding SF‐1 was less efficient, αGSU‐Cre, F/F mice retained some gonadotropin‐expressing cells in the anterior pituitary, thereby stimulating some gonadal function. This novel in vivo model for exploring the effects of differing levels of gonadotropins on gonadal development highlights the need for careful genotype‐phenotype comparisons in studies using Cre recombinase to produce tissue‐specific knockouts. genesis 30:65–69, 2001. © 2001 Wiley‐Liss, Inc.     

Cytokines and the hypothalamic-pituitary-adrenal axis

After administration of the cytokines interleukin 1 (IL1), tumor necrosis factor (TNF), interleukin 2 and interleukin 6 to laboratory animals or humans, plasma levels of glucocorticoids are elevated. This effect is mediated by activation of the hypothalamic-pituitary unit. IL1 and TNF inhibit aldosterone production by rat adrenocortical cells in vitro and stimulate renin release by rat renal cortical cells. Administration of IL1 or TNF in rats suppresses hypothalamic-pituitary-thyroid function, whereas IL1 acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion.

During stimulation of the immune system (e.g. during infectious diseases), peculiar alterations in hormone secretion occur (hypercortisolism, hyperreninemic hypoaldosteronism, euthyroid sick syndrome, hypogonadism). The role of cytokines in these alterations remains to be established.     

DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation

The unusual orphan member of the nuclear hormone receptor superfamily DAX-1 (NR0B1) owes its name to its double role in human pathology. On one side, duplications in Xp21, containing the DAX-1 gene, cause phenotypic sex reversal in XY individuals. On the other side, DAX-1 gene mutations are responsible for adrenal hypoplasia congenita, invariably associated with hypogonadotropic hypogonadism. DAX-1 functions as a global negative regulator of steroid hormone production by repressing the expression of multiple genes involved in the steroidogenic pathway. Here we review the mechanism of DAX-1 function in adrenal and gonadal differentiation, with special emphasis on recent results showing the critical role of DAX-1 protein misfolding in the pathogenesis of adrenal hypoplasia congenita.     

A regulator of G Protein signaling, RGS3, inhibits gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion

Background  

Luteinizing hormone secreted by the anterior pituitary gland regulates gonadal function. Luteinizing hormone secretion is regulated both by alterations in gonadotrope responsiveness to hypothalamic gonadotropin releasing hormone and by alterations in gonadotropin releasing hormone secretion. The mechanisms that determine gonadotrope responsiveness are unknown but may involve regulators of G protein signaling (RGSs). These proteins act by antagonizing or abbreviating interaction of Gα proteins with effectors such as phospholipase Cβ. Previously, we reported that gonadotropin releasing hormone-stimulated second messenger inositol trisphosphate production was inhibited when RGS3 and gonadotropin releasing hormone receptor cDNAs were co-transfected into the COS cell line. Here, we present evidence for RGS3 inhibition of gonadotropin releasing hormone-induced luteinizing hormone secretion from cultured rat pituitary cells.