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Endocrine Reviews Jan 2024Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone... (Review)
Review
Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and pulsatile GnRH secretion. Their critical role in reproductive health was first identified after inactivating variants in genes encoding for KP or NKB signaling were shown to result in congenital hypogonadotropic hypogonadism and a failure of pubertal development. Over the past 2 decades since their discovery, a wealth of evidence from both basic and translational research has laid the foundation for potential therapeutic applications. Beyond KP's function in the hypothalamus, it is also expressed in the placenta, liver, pancreas, adipose tissue, bone, and limbic regions, giving rise to several avenues of research for use in the diagnosis and treatment of pregnancy, metabolic, liver, bone, and behavioral disorders. The role played by NKB in stimulating the hypothalamic thermoregulatory center to mediate menopausal hot flashes has led to the development of medications that antagonize its action as a novel nonsteroidal therapeutic agent for this indication. Furthermore, the ability of NKB antagonism to partially suppress (but not abolish) the reproductive endocrine axis has supported its potential use for the treatment of various reproductive disorders including polycystic ovary syndrome, uterine fibroids, and endometriosis. This review will provide a comprehensive up-to-date overview of the preclinical and clinical data that have paved the way for the development of diagnostic and therapeutic applications of KP and NKB.
Topics: Pregnancy; Female; Humans; Neurokinin B; Kisspeptins; Gonadotropin-Releasing Hormone; Reproduction; Hypothalamus
PubMed: 37467734
DOI: 10.1210/endrev/bnad023 -
ELife Apr 2024Prolactin suppresses the ovarian cycles of lactating mice by directly repressing the activity of a cell population known as kisspeptin neurons.
Prolactin suppresses the ovarian cycles of lactating mice by directly repressing the activity of a cell population known as kisspeptin neurons.
Topics: Female; Mice; Animals; Gonadotropin-Releasing Hormone; Lactation; Fertility; Prolactin; Neurons; Kisspeptins
PubMed: 38591514
DOI: 10.7554/eLife.97432 -
Endocrine Regulations Jan 2023Hypothalamic-pituitary gonadal (HPG) axis is responsible for the development and regulation of the female reproductive system. In polycystic ovary syndrome (PCOS), there... (Review)
Review
Hypothalamic-pituitary gonadal (HPG) axis is responsible for the development and regulation of the female reproductive system. In polycystic ovary syndrome (PCOS), there is a disturbance in the HPG axis. Kisspeptin, a neuropeptide produced by the KISS1 gene, plays a vital role in the regulation of HPG axis by binding with its receptors KISS1R/GPR54, and stimulates gonadotropin secretion from the hypothalamus into pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Polymorphisms or mutations in the KISS1 gene can cause disturbance in the kisspeptin signaling pathway and is thought to disrupt HPG axis. Altered signaling of kisspeptin can cause abnormal secretion of GnRH pulse, which leads to increased LH/FSH ratio, thereby affecting androgen levels and ovulation. The increased levels of androgen worsen the symptoms of PCOS. In the present article, we review the molecular physiology and pathology of kisspeptin and how it is responsible for the development of PCOS. The goal of this review article is to provide an overview and metabolic profile of kisspeptin in PCOS patients and the expression of kisspeptin in PCOS animal models. In the present article, we also review the molecular physiology and pathology of kisspeptin and how it is responsible for the development of PCOS.
Topics: Animals; Female; Humans; Polycystic Ovary Syndrome; Kisspeptins; Androgens; Luteinizing Hormone; Follicle Stimulating Hormone
PubMed: 38127687
DOI: 10.2478/enr-2023-0032 -
Gynecological Endocrinology : the... Dec 2023The purpose of this study was to determine the association between kisspeptin levels and obesity in patients with polycystic ovary syndrome (PCOS) or in healthy...
The purpose of this study was to determine the association between kisspeptin levels and obesity in patients with polycystic ovary syndrome (PCOS) or in healthy controls and to explore the correlation between levels of kisspeptin and various endocrine and metabolic indices in each group. From August 2020 to December 2021, the clinical data of 78 patients with polycystic ovary syndrome and 78 healthy individuals were collected. The two groups were further divided into obese and non-obese groups based on a BMI cutoff of 25. Serum kisspeptin levels were measured using enzyme linked immunosorbent assay (ELISA). Pearson's correlation analysis was used to determine the correlation between PCOS and kisspeptin levels. The weight, body mass index (BMI), and waist circumference (WC), estradiol (E2), and testosterone (T) of the obese PCOS group were significantly higher than those of the study group ( < .05). WC, kisspeptin, triglycerides (TG), glucose (GLU), alanine amiotransferase (ALT), blood urea nitrogen (BUN), uric acid (UA), E2, luteinizing hormone (LH), prolactin (PRL), and T in the non-obese PCOS group were higher than those in the control group, and the difference was statistically significant ( < .05). Levels of E2 and TG in the obese PCOS group were significantly higher than those in the non-obese PCOS group ( < .05). Kisspeptin levels in the PCOS group exhibited a significant positive correlation with LH, T, and AMH levels; kisspeptin level positively correlated with T in the non-obese PCOS group and with anti-Müllerian hormone (AMH) in the obese PCOS group. Serum kisspeptin levels are associated with hormone levels in patients with PCOS. Kisspeptin correlates with distinct biochemical indices in obese versus non-obese groups, indicating that kisspeptin may play a role in the prognostication, treatment, and clinical evaluation of patients with varying BMI.
Topics: Female; Humans; Anti-Mullerian Hormone; Biomarkers; Body Mass Index; Follicle Stimulating Hormone; Kisspeptins; Luteinizing Hormone; Obesity; Polycystic Ovary Syndrome; Triglycerides; Case-Control Studies
PubMed: 37236245
DOI: 10.1080/09513590.2023.2215869 -
Current Opinion in Pharmacology Aug 2023Gonadotropin-releasing hormone (GnRH) neurons are the final output pathway for the brain control of reproduction. The activity of this neuronal population, mainly... (Review)
Review
Gonadotropin-releasing hormone (GnRH) neurons are the final output pathway for the brain control of reproduction. The activity of this neuronal population, mainly located at the preoptic area of the hypothalamus, is controlled by a plethora of metabolic signals. However, it has been documented that most of these signal impact on GnRH neurons through indirect neuronal circuits, Kiss1, proopiomelanocortin, and neuropeptide Y/agouti-related peptide neurons being some of the most prominent mediators. In this context, compelling evidence has been gathered in recent years on the role of a large range of neuropeptides and energy sensors in the regulation of GnRH neuronal activity through both direct and indirect mechanisms. The present review summarizes some of the most prominent recent advances in our understanding of the peripheral factors and central mechanisms involved in the metabolic control of GnRH neurons.
Topics: Humans; Gonadotropin-Releasing Hormone; Reproduction; Hypothalamus; Neuropeptides; Neurons
PubMed: 37307655
DOI: 10.1016/j.coph.2023.102382 -
Metabolism: Clinical and Experimental Jul 2023Kiss1 neurons in the hypothalamic arcuate-nucleus (ARC) play key roles in the control of GnRH pulsatility and fertility. A fraction of ARC Kiss1 neurons, termed KNDy,...
BACKGROUND
Kiss1 neurons in the hypothalamic arcuate-nucleus (ARC) play key roles in the control of GnRH pulsatility and fertility. A fraction of ARC Kiss1 neurons, termed KNDy, co-express neurokinin B (NKB; encoded by Tac2). Yet, NKB- and Kiss1-only neurons are also found in the ARC, while a second major Kiss1-neuronal population is present in the rostral hypothalamus. The specific contribution of different Kiss1 neuron sub-sets and kisspeptins originating from them to the control of reproduction and eventually other bodily functions remains to be fully determined.
METHODS
To tease apart the physiological roles of KNDy-born kisspeptins, conditional ablation of Kiss1 in Tac2-expressing cells was implemented in vivo. To this end, mice with Tac2 cell-specific Kiss1 KO (TaKKO) were generated and subjected to extensive reproductive and metabolic characterization.
RESULTS
TaKKO mice displayed reduced ARC kisspeptin content and Kiss1 expression, with greater suppression in females, which was detectable at infantile-pubertal age. In contrast, Tac2/NKB levels were fully preserved. Despite the drop of ARC Kiss1/kisspeptin, pubertal timing was normal in TaKKO mice of both sexes. However, young-adult TaKKO females displayed disturbed LH pulsatility and sex steroid levels, with suppressed basal LH and pre-ovulatory LH surges, early-onset subfertility and premature ovarian insufficiency. Conversely, testicular histology and fertility were grossly conserved in TaKKO males. Ablation of Kiss1 in Tac2-cells led also to sex-dependent alterations in body composition, glucose homeostasis, especially in males, and locomotor activity, specifically in females.
CONCLUSIONS
Our data document that KNDy-born kisspeptins are dispensable/compensable for puberty in both sexes, but required for maintenance of female gonadotropin pulsatility and fertility, as well as for adult metabolic homeostasis.
SIGNIFICANCE STATEMENT
Neurons in the hypothalamic arcuate nucleus (ARC) co-expressing kisspeptins and NKB, named KNDy, have been recently suggested to play a key role in pulsatile secretion of gonadotropins, and hence reproduction. However, the relative contribution of this Kiss1 neuronal-subset, vs. ARC Kiss1-only and NKB-only neurons, as well as other Kiss1 neuronal populations, has not been assessed in physiological settings. We report here findings in a novel mouse-model with elimination of KNDy-born kisspeptins, without altering other kisspeptin compartments. Our data highlights the heterogeneity of ARC Kiss1 populations and document that, while dispensable/compensable for puberty, KNDy-born kisspeptins are required for proper gonadotropin pulsatility and fertility, specifically in females, and adult metabolic homeostasis. Characterization of this functional diversity is especially relevant, considering the potential of kisspeptin-based therapies for management of human reproductive disorders.
Topics: Male; Female; Mice; Humans; Animals; Kisspeptins; Gonadotropins; Neurons; Puberty; Gonadotropin-Releasing Hormone; Arcuate Nucleus of Hypothalamus; Fertility
PubMed: 37121307
DOI: 10.1016/j.metabol.2023.155556 -
International Journal of Molecular... Feb 2024Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an... (Review)
Review
Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an important role in regulating lactation in mammals, as well as other actions. Acting in an endocrine and paracrine/autocrine manner, PRL regulates the hypothalamic-pituitary-ovarian axis, thus influencing the maturation of ovarian follicles and ovulation. This review provides a detailed discussion of the current knowledge on the role of PRL in the context of ovulation and ovulatory disorders, particularly with regard to hyperprolactinemia, which is one of the most common causes of infertility in women. Much attention has been given to the PRL structure and the PRL receptor (PRLR), as well as the diverse functions of PRLR signaling under normal and pathological conditions. The hormonal regulation of the menstrual cycle in connection with folliculogenesis and ovulation, as well as the current classifications of ovulation disorders, are also described. Finally, the state of knowledge regarding the importance of TIDA (tuberoinfundibular dopamine), KNDγ (kisspeptin/neurokinin B/dynorphin), and GnRH (gonadotropin-releasing hormone) neurons in PRL- and kisspeptin (KP)-dependent regulation of the hypothalamic-pituitary-gonadal (HPG) axis in women is reviewed. Based on this review, a rationale for influencing PRL signaling pathways in therapeutic activities accompanying ovulation disorders is presented.
Topics: Animals; Female; Humans; Kisspeptins; Mammals; Ovulation; Pituitary Gland, Anterior; Prolactin; Receptors, Prolactin
PubMed: 38396659
DOI: 10.3390/ijms25041976 -
Acta Obstetricia Et Gynecologica... Aug 2023Miscarriage is a major concern in early pregnancy among women having conceived with assisted reproductive treatments. This study aimed to examine potential...
INTRODUCTION
Miscarriage is a major concern in early pregnancy among women having conceived with assisted reproductive treatments. This study aimed to examine potential miscarriage-related biophysical and biochemical markers at 6 weeks' gestation among women with confirmed clinical pregnancy following in vitro fertilization (IVF)/embryo transfer (ET) and evaluate the performance of a model combining maternal factors, biophysical and biochemical markers at 6 weeks' gestation in the prediction of first trimester miscarriage among singleton pregnancies following IVF/ET.
MATERIAL AND METHODS
A prospective cohort study was conducted in a teaching hospital between December 2017 and January 2020 including women who conceived through IVF/ET. Maternal mean arterial pressure, ultrasound markers including mean gestational sac diameter, fetal heart activity, crown rump length and mean uterine artery pulsatility index (mUTPI) and biochemical biomarkers including maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), kisspeptin and glycodelin-A were measured at 6 weeks' gestation. Logistic regression analysis was carried out to determine significant predictors of miscarriage prior to 13 weeks' gestation and performance of screening was estimated by receiver-operating characteristics curve analysis.
RESULTS
Among 169 included pregnancies, 145 (85.8%) pregnancies progressed to beyond 13 weeks' gestation and had live births whereas 24 (14.2%) pregnancies resulted in a miscarriage during the first trimester. In the miscarriage group, compared to the live birth group, maternal age, body mass index, and mean arterial pressure were significantly increased; mean gestational sac diameter, crown rump length, mUTPI, serum sFlt-1, glycodelin-A, and the rate of positive fetal heart activity were significantly decreased, while no significant differences were detected in PlGF and kisspeptin. Significant prediction for miscarriage before 13 weeks' gestation was provided by maternal age, fetal heart activity, mUTPI, and serum glycodelin-A. The combination of maternal age, ultrasound (fetal heart activity and mUTPI), and biochemical (glycodelin-A) markers achieved the highest area under the curve (AUC: 0.918, 95% CI 0.866-0.955), with estimated detection rates of 54.2% and 70.8% for miscarriage before 13 weeks' gestation, at fixed false positive rates of 5% and 10%, respectively.
CONCLUSIONS
A combination of maternal age, fetal heart activity, mUTPI, and serum glycodelin-A at 6 weeks' gestation could effectively identify IVF/ET pregnancies at risk of first trimester miscarriage.
Topics: Pregnancy; Female; Humans; Infant; Placenta Growth Factor; Abortion, Spontaneous; Prospective Studies; Glycodelin; Kisspeptins; Gestational Age; Biomarkers; Reproductive Techniques, Assisted; Uterine Artery; Pre-Eclampsia; Vascular Endothelial Growth Factor Receptor-1; Pulsatile Flow
PubMed: 37377341
DOI: 10.1111/aogs.14618 -
Frontiers in Endocrinology 2023Male reproduction is under the control of the hypothalamus-pituitary-gonadal (HPG) axis. The endocannabinoid system (ECS) and the kisspeptin system (KS) are two major...
INTRODUCTION
Male reproduction is under the control of the hypothalamus-pituitary-gonadal (HPG) axis. The endocannabinoid system (ECS) and the kisspeptin system (KS) are two major signaling systems in the central and peripheral control of reproduction, but their possible interaction has been poorly investigated in mammals. This manuscript analyzes their possible reciprocal modulation in the control of the HPG axis.
MATERIALS AND METHODS
Adolescent male rats were treated with kisspeptin-10 (Kp10) and endocannabinoid anandamide (AEA), the latter alone or in combination with the type 1 cannabinoid receptor (CB1) antagonist rimonabant (SR141716A). The hypothalamic KS system and GnRH expression, circulating sex steroids and kisspeptin (Kiss1) levels, and intratesticular KS and ECS were evaluated by immunohistochemical and molecular methods. Non-coding RNAs (i.e., , , , ) were also considered.
RESULTS
Circulating hormonal values were not significantly affected by Kp10 or AEA; in the hypothalamus, Kp10 significantly increased mRNA and aromatase Cyp19, Kiss1, and Kiss1 receptor (Kiss1R) proteins. By contrast, AEA treatment affected the hypothalamic KS at the protein levels, with opposite effects on the ligand and receptor, and SR141716A was capable of attenuating the AEA effects. Among the considered non-coding RNA, only the expression of miR145-5p was positively affected by AEA but not by Kp10 treatment. Localization of Kiss1+/Kiss1R+ neurons in the arcuate nucleus revealed an increase of Kiss1R-expressing neurons in Kp10- and AEA-treated animals associated with enlargement of the lateral ventricles in Kp10-treated animals. In the brain and testis, the selected non-coding RNA was differently modulated by Kp10 or AEA. Lastly, in the testis, AEA treatment affected the KS at the protein levels, whereas Kp10 affected the intragonadal levels of CB1 and FAAH, the main modulator of the AEA tone. Changes in pubertal transition-related miRNAs and the intratesticular distribution of Kiss1, Kiss1R, CB1, and CB2 following KP and AEA treatment corroborate the KS-ECS crosstalk also showing that the CB1 receptor is involved in this interplay.
CONCLUSION
For the first time in mammals, we report the modulation of the KS in both the hypothalamus and testis by AEA and revealed the KP-dependent modulation of CB1 and FAAH in the testis. KP involvement in the progression of spermatogenesis is also suggested.
Topics: Male; Rats; Animals; Kisspeptins; Receptors, Kisspeptin-1; Endocannabinoids; Rimonabant; Hypothalamus; Gonadotropin-Releasing Hormone; Mammals; Reproduction; RNA, Untranslated; MicroRNAs
PubMed: 37900144
DOI: 10.3389/fendo.2023.1269334 -
Scientific Reports Apr 2024Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-20% of reproductive-age women. However, the treatment of PCOS is mainly based on...
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-20% of reproductive-age women. However, the treatment of PCOS is mainly based on symptoms and not on its pathophysiology. Neuroendocrine disturbance, as shown by an elevated LH/FSH ratio in PCOS patients, was thought to be the central mechanism of the syndrome, especially in lean PCOS. LH and FSH secretion are influenced by GnRH pulsatility of GnRH neurons in the hypothalamus. Kisspeptin is the main regulator of GnRH secretion, whereas neurokinin B (NKB) and dynorphin regulate kisspeptin secretion in KNDy neurons. This study aims to deepen the understanding of the neuroendocrine disorder in lean PCOS patients and its potential pathophysiology-based therapy. A cross-sectional study was performed at Dr. Cipto Mangunkusumo Kencana Hospital and the IMERI UI HRIFP cluster with 110 lean PCOS patients as subjects. LH, FSH, LH/FSH ratio, kisspeptin, NKB, dynorphin, leptin, adiponectin, AMH, fasting blood glucose, fasting insulin, HOMA-IR, testosterone, and SHBG were measured. Bivariate and path analyses were performed to determine the relationship between variables. There was a negative association between dynorphin and kisspeptin, while NKB levels were not associated with kisspeptin. There was no direct association between kisspeptin and the LH/FSH ratio; interestingly, dynorphin was positively associated with the LH/FSH ratio in both bivariate and pathway analyses. AMH was positively correlated with the LH/FSH ratio in both analyses. Path analysis showed an association between dynorphin and kisspeptin levels in lean PCOS, while NKB was not correlated with kisspeptin. Furthermore, there was a correlation between AMH and the LH/FSH ratio, but kisspeptin levels did not show a direct significant relationship with the LH/FSH ratio. HOMA-IR was negatively associated with adiponectin levels and positively associated with leptin and FAI levels. In conclusion, AMH positively correlates with FAI levels and is directly associated with the LH/FSH ratio, showing its important role in neuroendocrinology in lean PCOS. From the path analysis, AMH was also an intermediary variable between HOMA-IR and FAI with the LH/FSH ratio. Interestingly, this study found a direct positive correlation between dynorphin and the LH/FSH ratio, while no association between kisspeptin and the LH/FSH ratio was found. Further research is needed to investigate AMH and dynorphin as potential therapeutic targets in the management of lean PCOS patients.
Topics: Female; Humans; Luteinizing Hormone; Polycystic Ovary Syndrome; Dynorphins; Leptin; Kisspeptins; Cross-Sectional Studies; Adiponectin; Neurokinin B; Gonadotropin-Releasing Hormone; Follicle Stimulating Hormone
PubMed: 38589425
DOI: 10.1038/s41598-024-58064-0