Gonadotropin-releasing Hormone Secretion Research Articles

Congenital Hypogonadotrophic Hypogonadism: Minipuberty and the Case for Neonatal Diagnosis.

Congenital hypogonadotrophic hypogonadism (CHH) is a rare but important etiology of pubertal failure and infertility, resulting from impaired gonadotrophin-releasing hormone secretion or action. Despite the availability of effective hormonal therapies, the majority of men with CHH experience unsatisfactory outcomes, including chronic psychosocial and reproductive sequelae. Early detection and timely interventions are crucial to address the gaps in medical care and improve the outlook for these patients. In this paper, we review the clinical implications of missing minipuberty in CHH and therapeutic strategies that can modify the course of disease, as well as explore a targeted approach to identifying affected male infants by integrating clinical and biochemical data in the early postnatal months.

Autocrine production of reproductive axis neuropeptides affects proliferation of canine osteosarcoma in vitro

BackgroundOsteosarcoma strikes hundreds of people each year, of both advanced and younger ages, and is often terminal. Like many tumor types, these bone tumors will frequently undergo a neuroendocrine transition, utilizing autocrine and/or paracrine hormones as growth factors and/or promoters of angiogenesis to facilitate progression and metastasis. While many of these factors and their actions on tumor growth are characterized, some tumor-derived neuropeptides remain unexplored.MethodsUsing validated canine osteosarcoma cell lines in vitro, as well as cells derived from spontaneous tumors in dogs, we explored the autocrine production of two neuropeptides typically found in the hypothalamus, and most closely associated with reproduction: gonadotropin-releasing hormone (GnRH) and kisspeptin (Kiss-1). We evaluated gene expression and protein secretion of these hormones using quantitative RT-PCR and a sensitive radioimmunoassay, and explored changes in cell proliferation determined by MTS cell viability assays.ResultsOur current studies reveal that several canine osteosarcoma cell lines (COS, POS, HMPOS, D17, C4) synthesize and secrete GnRH and express the GnRH receptor, while COS and POS also express kiss1 and its cognate receptor. We have further found that GnRH and kisspeptin, exogenously applied to these tumor cells, exert significant effects on both gene expression and proliferation. Of particular interest, kisspeptin exposure stimulated GnRH secretion from COS, similarly to the functional relationship observed within the neuroendocrine reproductive axis. Additionally, GnRH and kisspeptin treatment both increased COS proliferation, which additionally manifested in increased expression of the bone remodeling ligand rankl within these cells. These effects were blocked by treatment with a specific GnRH receptor inhibitor. Both neuropeptides were found to increase expression of the specific serotonin (5HT) receptor htr2a, the activation of which has previously been associated with cellular proliferation, suggesting that production of these factors by osteosarcoma cells may act to sensitize tumors to circulating 5HT of local and/or enteric origin.ConclusionsHere we report that kisspeptin and GnRH act as autocrine growth factors in canine osteosarcoma cells in vitro, modulating RANKL and serotonin receptor expression in a manner consistent with pro-proliferative effects. Pharmacological targeting of these hormones may represent new avenues of osteosarcoma treatment.

High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of normal pubertal development due to deficient gonadotropin-releasing hormone (GnRH) secretion or action, and is caused by genetic defects in several genes. Mutations in the CHD7 gene cause CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and Ear abnormalities), but have also been found in patients with isolated CHH. The aim of this study was to identify CHD7 mutations in patients with CHH. Fifty Portuguese patients with CHH were screened for mutations in the CHD7 gene by DNA sequencing. Eight (16%) patients had CHD7 rare sequence variants that consisted of six missense (p.Gly388Glu, p.His903Pro, p.Thr1082Ile, p.Val1452Leu, p.Asp1854Gly, and p.Arg2065His) and two synonymous (p.Ser559Ser, and p.Ala2785Ala) mutations. Five of these mutations have never been reported before. Three CHD7 mutations occurred in patients that had mutations in additional CHH-genes. This study uncovered novel genetic variants that expand the known spectrum of mutations associated with CHH. The frequency of CHD7 mutations in this cohort was higher than that of other major CHH-genes and confirms the importance of including CHD7 in the genetic testing of CHH, even in the absence of additional CHARGE features.

Feedback regulation of 17β-estradiol on two kisspeptin genes in the Dabry's sturgeon (Acipenser dabryanus).

In tetrapods, kisspeptins are a group of peptides that play essential roles in the regulation of the Gonadotropin-releasing hormone secretion, and may participate in the feedback regulation of sex steroids as well. In this study, two kiss paralogs, designated as dskiss1 and dskiss2 were identified in Acipenser dabryanus. The full-length cDNA sequences of dskiss1 and dskiss2 are 1265 and 744 base pairs (bp), encoding 130 and 146 amino acids, respectively. Multiple sequence alignment indicated that both Kiss1 and Kiss2 decapeptides were highly conserved among vertebrates. Besides, Kiss1 of Dabry's sturgeon shared closer evolutionary relationship with the holostean species spotted gar (Lepisosteus oculatus), while Kiss2 of Acipenser dabryanus was conservatively grouped with the early sarcopterygian coelacanth (Latimeria chalumnae) in the phylogenetic analysis. Tissue distribution analysis showed that dskiss1 transcribed exclusively in the brain, whereas dskiss2 exhibited wider tissue distribution including brain, testis and ovary. Furthermore, male Dabry's sturgeons were intraperitoneally injected with 17β-estradiol (E2) and the effect of E2 on hypothalamus kiss and its receptors kissr mRNA levels was evaluated by relative real-time PCR. The transcription levels of dskiss2 and dskissr1 were significantly increased by E2 injection (P < .05). However, the mRNA levels of dskiss1 and dskissr2 were not changed in E2-treated group compared to the control group. These results indicate that E2 exerts positive feedback effects through dskiss2/dskissr1 in male Dabry's sturgeon.

Peripheral administration of κ-opioid receptor antagonist stimulates gonadotropin-releasing hormone pulse generator activity in ovariectomized, estrogen-treated female goats

Pulsatile gonadotropin-releasing hormone (GnRH) secretion is indispensable for reproduction in mammals. Kisspeptin neurons in the hypothalamic arcuate nucleus (ARC), referred to as KNDy neurons because of the coexpression of neurokinin B and dynorphin A, are considered as components of the GnRH pulse generator that produces rhythmic GnRH secretion. The present study aimed to investigate if peripheral administration of PF-4455242, a κ-opioid receptor (KOR, a dynorphin A receptor) antagonist, facilitates pulsatile luteinizing hormone (LH) secretion and GnRH pulse generator activity in estrogen-treated ovariectomized Shiba goats to determine the possibility of using KOR antagonists to artificially control ovarian activities. PF-4455242 was intravenously infused for 4 h (1 or 10 μmol/kg body weight/4 h) or as a single subcutaneous injection (1 or 10 μmol/kg body weight). In a separate experiment, the same KOR antagonist (10 μmol/kg body weight/4 h) was intravenously infused during the recording of multiple unit activity (MUA) in the ARC that reflects the activity of the GnRH pulse generator to test the effects of KOR antagonist administration on GnRH pulse generator activity. Intravenous infusion and single subcutaneous injection of the KOR antagonist significantly increased the frequency of LH pulses compared with controls. Intravenous infusion of KOR antagonist also significantly increased the frequency of episodic bursts in the MUA. The present study demonstrates that peripherally administered KOR antagonist stimulates pulsatile LH secretion by acting on the GnRH pulse generator, and peripheral administration of PF-4455242 can be used to facilitate pulsatile LH secretion, which in turn facilitates ovarian activities in farm animals.

EAP1 regulation of GnRH promoter activity is important for human pubertal timing.

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.

Arcuate nucleus kisspeptin response to increased nutrition in rams.

Rams respond to acute nutritional supplementation by increasing the frequency of gonadotrophin-releasing hormone (GnRH) pulses. Kisspeptin neurons may mediate the effect of environmental cues on GnRH secretion, so we tested whether the ram response to nutrition involves activation of kisspeptin neurons in the arcuate nucleus (ARC), namely kisspeptin, neurokin B, dynorphin (KNDy) neurons. Rams were given extra lupin grain with their normal ration. Blood was sampled before feeding, and continued until animals were killed for collection of brain tissue at 2 or 11h after supplementation. In supplemented rams, LH pulse frequency increased after feeding, whereas control animals showed no change. Within the caudal ARC, there were more kisspeptin neurons in supplemented rams than in controls and a higher proportion of kisspeptin cells coexpressed Fos, regardless of the time the rams were killed. There were more Fos cells in the mid-ARC and mid-dorsomedial hypothalamus of the supplemented compared with control rams. No effect of nutrition was found on kisspeptin expression in the rostral or mid-ARC, or on GnRH expression in the preoptic area. Kisspeptin neurons in the caudal ARC appear to mediate the increase in GnRH and LH production due to acute nutritional supplementation, supporting the hypothesised role of the KNDy neurons as the pulse generator for GnRH.

Polycystic ovary syndrome (PCOS) and kisspeptin - A Sri Lankan study.

Context:Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting young women. Kisspeptins are a family of closely related peptides encoded by Kiss1 gene that controls the hypothalamic–pituitary–gonadal axis by binding to its receptor (GPR54) expressed in gonadotropin-releasing hormone (GnRH) neurons and releases GnRH. Since GnRH secretion is deregulated in PCOS, we hypothesized that dysregulated gonadotropin secretion in PCOS is reflected by kisspeptin levels.Aim:We aimed to measure serum kisspeptin levels of subjects with well-characterized PCOS versus controls and explore any correlation between kisspeptin and PCOS-related reproductive and metabolic disturbances.Materials and Methods:Consecutive women with PCOS manifesting from adolescence (n = 55) and adult controls (n = 110) were recruited. Pre-treatment baseline clinical, anthropometry, and biochemical parameters were measured in all. Serum kisspeptin and testosterone levels were determined by enzyme-linked immunosorbent assay method.Results:Serum kisspeptin and testosterone concentrations were significantly higher in women with PCOS (kisspeptin 4.873 nmol/L; testosterone 4.713 nmol/L) than controls (kisspeptin 4.127 nmol/L; testosterone 3.415 nmol/L; P < 0.05). Serum kisspeptin levels were positively associated with PCOS (odds ratio: 1.853; 95% confidence interval: 1.246–2.755; P = 0.002) in our studied population.Conclusion:Serum kisspeptin levels are higher in Sri Lankan women with PCOS manifesting from adolescence compared with controls regardless of body mass index. We propose serum kisspeptin concentration as a useful marker to recognize PCOS that manifests from adolescence.

Adiponectin in male reproduction and infertility

Adiponectin is an adipokine that has the highest plasma concentration among all other adipokines. It is a white adipose tissue secretion essential for the regulation of energy metabolism owing to its antiatherogenic insulin-resistance, and anti-inflammatory properties. Studies have put forth that adiponectin is a potent endocrine regulator with mechanisms relating energy balance with reproductive function in different species, including humans. The two adiponectin receptors, AdipoR1 and AdipoR2 have been found to be expressed in the prime regulatory axis of reproduction, the hypothalamic-pituitary-gonadal axis. The activation of adiponectin receptors has been shown to regulate the secretion and gene expressions of kisspeptin, gonadotropin-releasing hormone and gonadotropins. Adiponectin finds relevance in the regulations of most of the vital testicular functions, such as steroidogenesis, germ cell proliferation and their coordinated apoptosis, as well as in modulation of testicular redox status and oxidative stress. Since metabolic syndrome and their associations with male infertility have been gaining immense research interest, adiponectin seems to be one of the important mediators of metabolic syndrome-induced male reproductive dysfunctions. This article aims to review the patterns of adiponectin expression in the male reproductive tissues and the mechanism by which adiponectin modulates male reproductive functions.

Ghrelin and male reproduction

Ghrelin is a multifunctional peptide hormone, conventionally known to be secreted by the stomach. The synthesis of ghrelin by the reproductive organs signifies its autocrine and/or paracrine actions upon the gonads. Expression of the functional ghrelin receptor is observed in different levels of the hypothalamic-pituitary-gonadal axis, suggesting its action on hypothalamic secretion of gonadotropin-releasing hormone and the pulsatile secretion of pituitary gonadotropins. It mainly acts to inhibit the secretion of the luteinizing hormone and thereby may also hinder proper testicular functions. This review article aims to provide a concise concept on (a) the characteristics, secretion and mode of actions of ghrelin, and (b) the role of ghrelin as a potential regulator of male reproductive functions. It may act upon the hypothalamic-pituitary-gonadal axis as well as directly regulate key testicular functions such as testosterone secretion, Leydig cell proliferation and expressions of prime functional proteins in the seminiferous tubule. These actions of ghrelin on testicular functions appear to be species-specific. Ghrelin and its versatile biological functions bring to a consensus that further research on ghrelin may establish one of the associations between body energy status with alterations in male reproductive functions.

PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Gα-protein leads to biased signaling.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disorder caused by the deficient production, secretion, or action of gonadotropin-releasing hormone. Prokineticin (PROK) receptor 2 ( PROKR2), a causative gene for IHH, encodes a GPCR PROKR2. When PROKR2 binds to its ligands PROKs, it may activate several signaling pathways, including IP3/Ca2+, MAPK, and cAMP pathways. However, the mutational spectrum of PROKR2 in Chinese patients with IHH has not been established. In the present study, we found that up to 13.3% (18/135) of patients with IHH in China carried mutations in PROKR2. Most of the variants in this study were private; however, a PROKR2 (c.533G > C; p.W178S) mutation was identified in 10 independent patients, implying a possible founder mutation. Functional studies indicated that 6 novel PROKR2 mutations led to decreased signaling to various extents. Two IHH-associated mutations (L218P and R270H) disrupted Gαq-dependent signaling but maintained normal Gαs and ERK1/2 signaling. A glutathione S-transferase pull-down experiment demonstrated that R270H mutation disrupted the interaction of intracellular loop 3 of PROKR2 to Gαq protein but not Gαs protein. Our results indicated that selective disruption of the interaction with a specific Gα-protein might underlie the biased signaling for certain IHH-associated PROKR2 mutations.-Zhao, Y., Wu, J., Jia, H., Wang, X., Zheng, R., Jiang, F., Chen, D.-N., Chen, Z., Li, J.-D. PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Gα-protein leads to biased signaling.

A new class of pentapeptide KISS1 receptor agonists with hypothalamic–pituitary–gonadal axis activation

The kisspeptin (Kp, Kp-54, metastin)/KISS1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for KISS1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.

4 Induction of ovulation by kisspeptin in llamas

After mating, female camelids ovulate in response to nerve growth factor (NGF) present in semen (formerly referred to as ovulation-inducing factor). The ovulatory effect appears to be induced by stimulation of hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and LH secretion. Recent studies have identified kisspeptin as an important mediator of GnRH secretion in several species. In the present study, we tested the hypothesis that kisspeptin is involved in the ovulatory pathway in llamas and investigated the mechanism of this effect. In Experiment 1, ovarian function in non-pregnant, non-lactating adult female llamas was synchronized by intramuscular administration of a GnRH analogue (50µg of gonadorelin acetate; Fertiline, Vetoquinol, Quebec, QC, Canada). When a growing dominant follicle ≥8mm in diameter was detected, llamas were assigned randomly to 3 treatment groups and given an intravenous dose of purified seminal NGF (1mg, single dose; n=5), kisspeptin (0.1mg kg−1 of body weight, 2 doses 1h apart; n=5), or PBS (n=4). The bioactive 10 amino acid fragment of murine kisspeptin was used. Ovulation and corpus luteum development were assessed by transrectal ultrasonography every other day from the day of treatment (Day 0) to Day 8. In Experiment 2, ovarian function among female llamas was synchronized, as in Experiment 1. When a growing dominant follicle ≥8mm in diameter was detected, llamas were given kisspeptin (0.1mg kg−1 of body weight IV, 2 doses 1h apart) beginning 2h after pretreatment with either a GnRH receptor blocker (cetrorelix acetate, 1.5mg per llama IV; Sigma, Oakville, ON, Canada; n=6) or saline (n=6). Llamas were examined 48h later by transrectal ultrasonography to detect ovulation and 8 days later to determine the presence of a corpus luteum. Chi-square tests were used to compare ovulation rates, and ANOVA for repeated measures was used to compare diameter profiles of the corpus luteum. In Experiment 1, ovulation rate did not differ between the NGF and kisspeptin groups (5/5 in each; 100%) and was greater than in the control group (0/4; 0% P&amp;lt;0.05). Corpus luteum diameter did not differ between llamas that ovulated in response to treatment with NGF or kisspeptin (13.2±0.8 and 14.0±1.2mm on Day 8, respectively). In Experiment 2, none of the llamas pretreated with cetrorelix ovulated in response to kisspeptin treatment (0/6; 0%), whereas all of the llamas pretreated with saline ovulated in response to kisspeptin treatment and had a corpus luteum at Day 8 (6/6; 100%; P&amp;lt;0.05). Results supported the hypothesis that kisspeptin induces ovulation in llamas. Because a GnRH receptor antagonist blocked ovulation, our interpretation is that the site of action of kisspeptin is upstream of the pituitary gland and involves control of GnRH release from the hypothalamus. These findings raise the possibility that kisspeptin mediates the ovulation-inducing effect of NGF. Research was supported by the Natural Sciences and Engineering Research Council of Canada.

Effects of Kisspeptin-10 on Hypothalamic Neuropeptides and Neurotransmitters Involved in Appetite Control.

Besides its role as key regulator in gonadotropin releasing hormone secretion, reproductive function, and puberty onset, kisspeptin has been proposed to act as a bridge between energy homeostasis and reproduction. In the present study, to characterize the role of hypothalamic kisspeptin as metabolic regulator, we evaluated the effects of kisspeptin-10 on neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) gene expression and the extracellular dopamine (DA), norepinephrine (NE), serotonin (5-hydroxytriptamine, 5-HT), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIIA) concentrations in rat hypothalamic (Hypo-E22) cells. Our study showed that kisspeptin-10 in the concentration range 1 nM–10 μM was well tolerated by the Hypo-E22 cell line. Moreover, kisspeptin-10 (100 nM–10 μM) concentration independently increased the gene expression of NPY while BDNF was inhibited only at the concentration of 10 μM. Finally, kisspeptin-10 decreased 5-HT and DA, leaving unaffected NE levels. The inhibitory effect on DA and 5-HT is consistent with the increased peptide-induced DOPAC/DA and 5-HIIA/5-HT ratios. In conclusion, our current findings suggesting the increased NPY together with decreased BDNF and 5-HT activity following kisspeptin-10 would be consistent with a possible orexigenic effect induced by the peptide.

Photoperiodic Regulation of Reproduction in Vertebrates.

Organisms use changes in photoperiod for seasonal reproduction to maximize the survival of their offspring. Birds have sophisticated seasonal mechanisms and are therefore excellent models for studying these phenomena. Birds perceive light via deep-brain photoreceptors and long day-induced thyroid-stimulating hormone (TSH, thyrotropin) in the pars tuberalis of the pituitary gland (PT), which cause local thyroid hormone activation within the mediobasal hypothalamus. The local bioactive thyroid hormone controls seasonal gonadotropin-releasing hormone secretion and subsequent gonadotropin secretion. In mammals, the eyes are believed to be the only photoreceptor organ, and nocturnal melatonin secretion triggers an endocrine signal that communicates information about the photoperiod to the PT to regulate TSH. In contrast, in Salmonidae fish the input pathway to the neuroendocrine output pathway appears to be localized in the saccus vasculosus. Thus, comparative analysis is an effective way to uncover the universality and diversity of fundamental traits in various organisms.

Kisspeptin and the regulation of the reproductive axis in domestic animals.

The control of reproductive processes involves the integration of a number of factors from the internal and external environment, with the final output signal of these processes being the pulsatile secretion of gonadotrophin releasing hormone (GnRH) from the hypothalamus. These factors include the feedback actions of sex steroids, feed intake and nutritional status, season/photoperiod, pheromones, age and stress. Understanding these factors and how they influence GnRH secretion and hence reproduction is important for the management of farm animals. There is evidence that the RF-amide neuropeptide, kisspeptin, may be involved in relaying the effects of these factors to the GnRH neurons. This paper will review the evidence from the common domestic animals (sheep, goats, cattle, horses and pigs), that kisspeptin neurons are i) regulated by the factors listed above, ii) contact GnRH neurons, and iii) involved in the regulation of GnRH/gonadotrophin secretion.

Gonadotropin-releasing hormone analog therapeutics

Dysregulation at any level of the hypothalamic-pituitary-gonadal (HPG) axis results in, or aggravates, a number of hormone-dependent diseases such as delayed or precocious puberty, infertility, prostatic and ovarian cancer, benign prostatic hyperplasia, polycystic ovarian syndrome, endometriosis, uterine fibroids, lean body mass, as well as metabolism and cognitive impairment. As gonadotropin-releasing-hormone (GnRH) is an essential regulator of the HPG axis, agonist and antagonist analogs are efficacious in the treatment of these conditions. GnRH analogs also play an important role in assisted reproductive therapies. This review highlights the current and future therapeutic potential of GnRH analogs and upstream regulators of GnRH secretion.

Role of Kisspeptin and Neurokinin B in Puberty in Female Non-Human Primates. Review

Pubertal onset and subsequently reproduction result from the awakening of a complex neuroendocrine machinery leading to the acceleration of the gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus. Several neuronal, glial or peripheral factors have been identified as playing a major role in the onset of puberty1. This paper reviews data obtained in non-human primates illustrating the crucial role played by kisspeptin and neurokinin B (NKB) in this pubertal activation of GnRH secretion. Both kisspeptin and NKB signaling appear to contribute to the pubertal increase in GnRH release independently or in concert in females while there seems to have no interaction between kisspeptin and NKB in sexually immature females. The contribution of direct NKB signaling to GnRH release, however, may be secondary, as NKB signaling to GnRH release does not change across puberty, whereas NKB signaling to kisspeptin release greatly increases. Thus, in females, kisspeptin signaling appears to be the main force driving the pubertal GnRH release increases. The role of NKB in the pubertal increase in GnRH release, however, requires further experiments. In females, reciprocal signaling pathways between kisspeptin and NKB neurons could provide the necessary efficiency and flexibility for the stimulation of GnRH release, which ensures complex reproductive functions, such as cyclic ovulations and pregnancy.

Hypothalamic Epigenetics Driving Female Puberty

Puberty involves a series of morphological, physiological and behavioural changes during the last part of the juvenile period that culminates in the attainment of fertility. The activation of the pituitary-gonadal axis by increased hypothalamic secretion of gonadotrophin-releasing hormone (GnRH) is an essential step in the process. The current hypothesis postulates that a loss of transsynaptic inhibition and a rise in excitatory inputs are responsible for the activation of GnRH release. Similarly, a shift in the balance in the expression of puberty activating and puberty inhibitory genes exists during the pubertal transition. In addition, recent evidence suggests that the epigenetic machinery controls this genetic balance, giving rise to the tantalising possibility that epigenetics serves as a relay of environmental signals known for many years to modulate pubertal development. Here, we review the contribution of epigenetics as a regulatory mechanism in the hypothalamic control of female puberty.

POLYCYSTIC OVARY SYNDROME: PATHOGENESIS, TREATMENT AND SECONDARY ASSOCIATED DISEASES

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. It is characterized by hyperandrogenism, polycystic ovaries, and chronic anovulation along with insulin resistance, hyperinsulinemia, abdominal obesity, hypertension, and dyslipidemia as frequent metabolic traits (metabolic syndrome) that culminate in serious long-term consequences such as type 2 diabetes mellitus, endometrial hyperplasia, and coronary artery disease. It is one of the most common causes of anovulatory infertility. A complete understanding of the underlying Pathophysiology of PCOS is still lacking. Because of the heterogeneity of this disorder, there are most likely multiple underlying pathophysiologic mechanisms. Pathogenesis of PCOS is explaining as alteration in gonadotropin-releasing hormone secretion results in increased luteinizing hormone (LH) secretion. An alteration in insulin secretion and insulin action results in hyperinsulinemia and insulin resistance. A defect in androgen synthesis that results in increased ovarian androgen production.Treatment of PCOS include maintaining a normal endometrium, antagonizing the actions of androgens on target tissues, reducing insulin resistance (when present), and correcting anovulation. Women with polycystic ovary syndrome (PCOS) are at higher risk for several other health conditions as Insulin Resistance, Metabolic Syndrome, Type 2 Diabetes, Obesity, Heart Disease and High Blood Pressure (Cardiovascular Disease)&#x0D;