kiss1-protein--human and Infertility--Female

Recent studies have found that kisspeptin/neurokinin B/dynorphin neurons (KNDy neurons) in the infundibular nucleus play a crucial role in the reproductive axis. Analogs, both agonists and antagonists, of kisspeptin and neurokinin B (NKB) are particularly important in explaining the physiological role of KNDy in the reproductive axis in animals. The use of kisspeptin and NKB analogs has helped elucidate the regulators of the hypothalamic reproductive axis.. This review describes therapeutic uses of Kiss-1 and NKB agonists, most obviously the use of kisspeptin agonists in the treatment for infertility and the induction of ovulation. Kisspeptin antagonists may have potential clinical applications in patients suffering from diseases associated with enhanced LH pulse frequency, such as polycystic ovary syndrome or menopause. The inhibition of pubertal development using Kiss antagonists may be used as a therapeutic option in precocious puberty. Kisspeptin antagonists have been found capable of inhibiting ovulation and have been proposed as novel contraceptives. Hypothalamic amenorrhea and delayed puberty are conditions in which normalization of LH secretion may potentially be achieved by treatment with both kisspeptin and NKB agonists. NKB antagonists are used to treat vasomotor symptoms in postmenopausal women, providing rapid relief of symptoms while supplanting the need for exogenous estrogen exposure.. There is a wide spectrum of therapeutic uses of Kiss-1 and NKB agonists, including the management of infertility, treatment for PCOS, functional hypothalamic amenorrhea or postmenopausal vasomotor symptoms, as well as contraceptive issues. Nevertheless, further research is needed before kisspeptin and NKB analogs are fully incorporated in clinical practice.

Topics: Female; Humans; Infertility, Female; Kisspeptins; Neurokinin B; Neurons; Ovulation Induction; Puberty

The aim of this review is to analyse the effectiveness of exogenous kisspeptin administration as a novel alternative of triggering oocyte maturation, instead of currently used triggers such as human chorionic gonadotropin (hCG) or gonadotropin releasing hormone (GnRH) agonist, in women undergoing in vitro fertilisation (IVF) treatment. Kisspeptin has been considered a master regulator of two modes of GnRH and hence gonadotropin secretion, pulses and surges. Administration of kisspeptin-10 and kisspeptin-54 induces the luteinising hormone (LH) surge required for egg maturation and ovulation in animal investigations and LH release during the preovulatory phase of the menstrual cycle and hypothalamic amenorrhoea in humans. Exogenous kisspeptin-54 has been successfully administered as a promising method of triggering oocyte maturation, following ovarian stimulation with gonadotropins and GnRH antagonists in women undergoing IVF, due to its efficacy considering achieved pregnancy rates compared to hCG and GnRH agonists. Also, its safety in patients at high risk of developing ovarian hyperstimulation syndrome is noteworthy. Nevertheless, further studies would be desirable to establish the optimal trigger of egg maturation and to improve the reproductive outcome for women undergoing IVF treatment.

Topics: Adult; Animals; Female; Fertility Agents, Female; Fertilization in Vitro; Humans; Infertility, Female; Kisspeptins; Oogenesis; Ovarian Hyperstimulation Syndrome; Ovulation; Ovulation Induction; Peptide Fragments; Pregnancy; Pregnancy Rate; Recombinant Proteins; Risk

Ovarian hyperstimulation syndrome (OHSS) complicates a considerable part of stimulated in-vitro fertilization (IVF) cycles and is a potential iatrogenic cause of death in otherwise healthy women undergoing fertility treatment. The triggering factor of OHSS is the widespread use of human chorionic gonadotropin (hCG) to induce final oocyte maturation. The aim of this review is to summarize different approaches available, using alternative triggering protocols such as gonadotropin-releasing hormone agonist (GnRHa) or kisspeptin for final oocyte maturation.. According to the latest European Society of Human Reproduction and Embryology report, the incidence of OHSS ranges from 0.18 to 1.40% in European countries. However, OHSS is still subject to substantial underreporting. New triggering protocols using GnRHa have shown to be similar to the gold standard hCG-trigger with regard to the reproductive outcome, but with a significant decrease in - and almost elimination of - OHSS. Lately, promising results have been reported for the use of kisspeptin to induce final oocyte maturation. Although until now no study has been performed in an OHSS risk population, theoretically, the risk of OHSS development might be even further reduced after kisspeptin trigger.. GnRHa trigger is currently the best tool we have to prevent OHSS and at the same time maintain good reproductive outcomes. Future research will explore the safety and efficacy of kisspeptin trigger.

Topics: Adult; Chorionic Gonadotropin; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Iatrogenic Disease; Infertility, Female; Kisspeptins; Oocytes; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Pregnancy; Pregnancy Rate; Sperm Injections, Intracytoplasmic; Treatment Outcome

The Damaraland mole-rat is a subterranean mammal exhibiting extreme reproductive skew with a single reproductive female in each colony responsible for procreation. Non-reproductive female colony members are physiologically suppressed while in the colony, exhibiting reduced concentrations of plasma luteinizing hormone (LH) and a decreased response of the pituitary, as measured by the release of bioactive LH, to an exogenous dose of gonadotrophin releasing hormone (GnRH). Removal of the reproductive female from the colony results in an elevation of LH and an enhanced response of the pituitary to a GnRH challenge in non-reproductive females comparable to reproductive females, implying control of reproduction in these individuals by the reproductive female. The Damaraland mole-rat is an ideal model for investigating the physiological and behavioral mechanisms that regulate the hypothalamo-pituitary-gonadal axis. In contrast, we know less about the control of reproduction at the level of the hypothalamus. The immunohistochemistry of the GnRH system of both reproductive and non-reproductive female Damaraland mole-rats has revealed no significant differences with respect to morphology, distribution or numbers of immunoreactive GnRH perikarya. We examined whether the endogenous opioid peptide beta-endorphin was responsible for the inhibition of the release of the GnRH from the neurons indirectly by measuring LH concentrations in these non-reproductive females following single, hourly and 8 hourly injections of the opioid antagonist naloxone. The results imply that the endogenous opioid peptide, beta-endorphin, is not responsible for the inhibition of GnRH release from the perikarya in non-reproductive females. Preliminary data examining the circulating levels of cortisol also do not support a role for circulating glucocorticoids. The possible role of kisspeptin is discussed.

Topics: Africa, Southern; Animals; beta-Endorphin; Female; Gonadotropin-Releasing Hormone; Gonads; Hydrocortisone; Hypothalamo-Hypophyseal System; Immunohistochemistry; Infertility, Female; Kisspeptins; Luteinizing Hormone; Mole Rats; Naloxone; Social Environment

Prolactin (PRL) is a protein hormone secreted by the anterior pituitary gland that regulates pituitary hormones. Hyperprolactinemia (HPRL), a pathological phenomenon of excessive PRL, can cause infertility in severe cases and is currently treated mainly with Western drugs, such as bromocriptine, a dopamine agonist (DA). Unfortunately, DAs produce psychological side effects which limit their long-term use. Traditional Chinese medicine (TCM) has minimal side effects and good results spanning many years of research. The combined treatment of TCM and Western medicine may enhance treatment efficacy and improve the long-term prognosis in HPRL. To analyze the effects of Bu-shen-zhu-yun decoction (BSZY-D) combined with bromocriptine on serum hormones, anxiety, and pregnancy in hyperprolactinemic infertile patients.. One hundred patients diagnosed with HPRL infertility from June 2020 to June 2021 in the gynecology clinic of Jiangsu Provincial Hospital of Traditional Chinese Medicine were selected and grouped by envelope method. After excluding patients who withdrew or missed visits, 37 cases assigned to the control group were treated with bromocriptine, and 40 cases assigned to the observation group were treated with bromocriptine combined with BSZY-D. The patients' PRL and kisspeptin (KP) serum indexes, improvements in infertility, Anxiety Self-Assessment Scale (SAS) scores, and improvements in the Insomnia Severity Index Scale (ISI) scores were compared between the two groups.. At 3 and 6 months of treatment, serum PRL, SAS, and ISI scores were significantly lower, and serum KP was significantly higher in the observation group than in the control group (P<0.05). During the study period, the pregnancy rates were 62.50% (25/40) and 37.84% (14/37) in the observation and control groups, respectively. The observation group also had significantly fewer early miscarriages [10.00% (4/40) vs. 32.43% (12/37)] and less adverse reactions [7.50% (3/40) vs. 24.32% (9/37)] than the control group (all P<0.05).. The combination of bromocriptine with BSZY-D was superior to bromocriptine alone in treating HPRL and HPRL-related infertility, which also demonstrated a positive effect on patients' sleep and low mood.

Topics: Anxiety; Bromocriptine; Drugs, Chinese Herbal; Female; Humans; Hyperprolactinemia; Infertility, Female; Kisspeptins; Pregnancy; Pregnancy Rate; Prolactin; Sleep

To analyze and compare the expression profile of TAC3, TACR3, KISS1, and KISS1R in mural granulosa and cumulus cells from healthy oocyte donors and patients with different infertility etiologies, including advanced maternal age, endometriosis, and low ovarian response.. Genetic association study.. Private fertility clinic and public research laboratory.. Healthy oocyte donors and infertile women undergoing in vitro fertilization (IVF) treatment.. IVF.. Gene expression levels of KISS1, KISS1R, TAC3, and TACR3 in human mural granulosa and cumulus cells.. Infertile women showed statistically significantly altered expression levels of KISS1 (-2.57 ± 2.30 vs. -1.37 ± 2.11), TAC3 (-1.21 ± 1.40 vs. -1.49 ± 1.98), and TACR3 (-0.77 ± 1.36 vs. -0.03 ± 0.56) when compared with healthy oocyte donors. Advanced maternal age patients, endometriosis patients, and low responders showed specific and altered expression profiles in comparison with oocyte donors.. Abnormal expression levels of KISS1/KISS1R and TAC3/TACR3 systems in granulosa cells might be involved in the decreased fertility associated to advanced maternal age, endometriosis, and low ovarian response.

Topics: Adolescent; Adult; Cumulus Cells; Female; Gene Expression; Genetic Association Studies; Granulosa Cells; Humans; Infertility, Female; Kisspeptins; Neurokinin B; Receptors, Kisspeptin-1; Receptors, Neurokinin-3; Young Adult

In vitro fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication, ovarian hyperstimulation syndrome (OHSS).. This study aimed to investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.. This was a phase 2, multi-dose, open-label, randomized clinical trial of 60 women at high risk of developing OHSS carried out during 2013-2014 at Hammersmith Hospital IVF unit, London, United Kingdom.. Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomly assigned to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2 nmol/kg, n = 5; 6.4 nmol/kg, n = 20; 9.6 nmol/kg, n = 15; 12.8 nmol/kg, n = 20). Oocytes were retrieved 36 h after kisspeptin-54 administration, assessed for maturation, and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS.. Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥ 14 mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy.. Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8 nmol/kg kisspeptin-54, which was +69% (confidence interval, -16-153%) greater than following 3.2 nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy, and live birth rates per transfer (n = 51) were 63, 53, and 45%, respectively. Highest pregnancy rates were observed following 9.6 nmol/kg kisspeptin-54 (85, 77, and 62%, respectively). No woman developed moderate, severe, or critical OHSS.. Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Topics: Adult; Drug Therapy, Combination; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility, Female; Kisspeptins; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Pregnancy; Risk Factors

Kisspeptin has recently emerged as a key regulator of the reproductive axis in women. Kisspeptin, acting centrally via the kisspeptin receptor, stimulates the secretion of the gonadotrophin-releasing hormone (GnRH).. To investigate serum kisspeptin levels in infertility patients for its clinical utilisation in management and understanding of the pathophysiology of infertility in a wide array of patients.. This prospective case-control study analysis involved 92 primary infertile women with PCOS, diminished ovarian reserve (DOR), unexplained infertility (UEI), and male factor infertility between 20 and 42 years of age. Serum samples were collected between the second and fifth day of the menstrual cycle. The kisspeptin level was determined using a human kisspeptin ELISA kit according to the manufacturer's procedure.. The median value of serum kisspeptin in the PCOS infertility group was significantly higher than that in the UEI group (p = 0.011). There was a statistically significant (p = 0.015, r =  -0.182) negative weak correlation found between serum kisspeptin levels and age. The optimal cutoff value obtained to differentiate the UEI from others (PCOS infertility + DOR + male factor infertility) according to the serum kisspeptin level was 214.3 ng/L with a sensitivity of 55% and specificity of 80.9%.. Understanding the role of kisspeptin may lead to its use as a biomarker in infertility diagnosis in UEI patients and might guide the use of kisspeptin analogues in selected patients for infertility management.

Topics: Case-Control Studies; Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Infertility, Male; Kisspeptins; Male; Polycystic Ovary Syndrome

Topics: Female; Humans; Infertility, Female; Kisspeptins; Polymorphism, Genetic; Receptors, Kisspeptin-1

Topics: Cumulus Cells; Female; Genetic Association Studies; Humans; Infertility, Female; Kisspeptins; Neurokinin B

To relate serum and follicular fluid (FF) kisspeptin and estradiol levels in different stages of stimulation during Intracytoplasmic Sperm Injection (ICSI) with oocyte maturity and endometrial thickness among unexplained infertile females.. This cross-sectional study was carried out at the Australian Concept Infertility Medical Centre from March 2017 till March 2018. Fifty unexplained infertile females, booked for ICSI, were included in the study. Serum kisspeptin and estradiol were estimated by Enzyme-Linked Immunosorbent Assay in all four stages; 1: follicular stimulation, 2: ovulation induction, 3: oocyte pickup, and 4: embryo transfer. FF was aspirated during oocyte retrieval (stage 3) for the analysis of KP and estradiol. Pregnancy outcomes were categorized as non-pregnant, preclinical abortion, and clinical pregnancy.. The age of the study subjects was 32.04 ± 2.29 (Mean±SD) years, with mean BMI of 28.51 ± 4.15 (Mean±SD) kg/m2. Mean serum kisspeptin and estradiol levels increased in all subjects as the stimulation proceeded stages 1-3; however, the mean dropped after retrieval of the oocytes (stage 4). Out of 27 female subjects who completed the cycle, 17 remained non-pregnant, 4 had preclinical abortion, and 6 acquired clinical pregnancy. The FF kisspeptin concentration was significantly higher than serum concentrations and positively correlated with serum and FF estradiol concentrations. FF-kisspeptin correlated with serum kisspeptin in Stage 3 (r = 0.930, p<0.001), maturity of oocyte (r = 0.511, p = 0.006) and endometrial thickness (r = 0.522, p = 0.005). Kisspeptin in stage 3 was also found to correlate with endometrial thickness (r = 0.527, p = 0.005) and with estradiol (r = 0.624, p = 0.001) independently.. Increase in serum and FF-kisspeptin and estradiol levels from stages 1 to 3, resulted in an optimum endometrial thickness, probability of fertilization of oocytes and chances of clinical pregnancy in Assisted Reproductive Techniques /ICSI cycles of unexplained infertile females.

Topics: Adult; Australia; Cross-Sectional Studies; Endometrium; Estradiol; Female; Follicular Fluid; Humans; In Vitro Oocyte Maturation Techniques; Infertility, Female; Kisspeptins; Oocyte Retrieval; Oocytes; Oogenesis; Ovulation Induction; Pregnancy; Pregnancy Outcome; Sperm Injections, Intracytoplasmic

Kisspeptin (KP), a hypothalamic peptide, is known as an important marker for neuroendocrine regulation during the human reproduction process. The unexplained infertility (UI) group comprised 30 patients, polycystic ovary syndrome (PCOS) group comprised 29 patients and the male factor infertility (MFI) group comprised 27 patients. An observational cohort study was conducted. The basic characteristics of the study population, BMI, and serum FSH, LH, E2, AMH, KP, TSH, and PRL levels and antral follicle count (AFC) on the 3rd menstruation day were evaluated. The mean KP level was 281.98 ± 73.9 ng/ml in the UI group, 525.49 ± 164.17 ng/ml in the PCOS group, and 354.313 ± 111.38 ng/ml in the MFI group (p < .001). KP levels were significantly higher in the PCOS group than in the UI and MFI groups (p < .001 for both). AUC was 83% (95% CI: 73%-93%), with 375.15 (pg/ml) as the cutoff value in the PCOS group with 83% sensitivity and 79% specificity. UI may be treated by KP injection therapies and higher levels of KP may be a reliable marker for AFC and diagnosis of PCOS. Clinical Trials registration number: NCT03018314.

Topics: Adult; Anti-Mullerian Hormone; Biomarkers; Estradiol; Female; Follicle Stimulating Hormone; Humans; Infertility, Female; Kisspeptins; Luteinizing Hormone; Polycystic Ovary Syndrome; Prolactin; Thyrotropin; Young Adult

Kisspeptin, a peptide hormone, plays a pivotal role in fertility and neuroendocrine regulation of hypothalamo-pituitary-gonadal axis. Increased kisspeptin and reproductive hormones are responsible for fertility in male and females. This study aimed to explore the role of kisspeptin on hypothalamo-pituitary-gonadal axis by comparing the levels of kisspeptin in fertile and infertile subjects and identifying single nucleotide polymorphisms (SNPs) of KISS1 gene in exon 2 and exon 3 of infertile male and female cohorts. A cross-sectional study was carried out on 80 males (44 infertile and 36 fertile) and 88 females (44 in each group). Significantly high levels of kisspeptin (KP), follicle-stimulating hormone (FSH), luteinizing hormone and testosterone were observed in fertile male and female subjects except low FSH levels in comparison with infertile female subjects. One polymorphism in exon 2 (E1225K [G/A 3673]) and three in exon 3 (P1945A [C/G 5833]; Insertion of T at 6075; G2026G [C/G 6078]) in infertile group were detected, with low KP and hormonal levels. Male subjects had abnormal sperm parameters and unsuccessful attempt of intracytoplasmic sperm injection in females. Expression of SNP in exon 2 and exon 3 of KISS1 could be responsible for alteration in release of reproductive hormones and gonadal functions, hence causing infertility.

Topics: Adult; Cross-Sectional Studies; Exons; Female; Follicle Stimulating Hormone; Humans; Hypothalamo-Hypophyseal System; Infertility, Female; Infertility, Male; Kisspeptins; Luteinizing Hormone; Male; Middle Aged; Mutation; Pakistan; Polymorphism, Single Nucleotide; Testosterone

To investigate association of kisspeptin levels in infertile women with different ovarian reserve patterns.. In this prospective cross-sectional study, 157 participants were recruited. The women were divided into three groups: (i) adequate ovarian reserve (AOR) (n = 57), (ii) high ovarian reserve (PCOS) (n = 60), (iii) diminished ovarian reserve (DOR) (n = 40). Weight, height, waist circumference (WC), hip circumference (HC), body mass index (BMI), waist/hip ratio (WHR) were measured. The blood samples were analyzed for estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), 17-hydroxy progesterone (17OHP), dehydroepiandrosterone sulfate (DHEAS), antimullerian hormone (AMH), kisspeptin measurements.. FSH concentration was higher and AMH concentration was lower in DOR group (p < .001, p < .001, respectively). The mean LH, TT and DHEAS levels were higher in PCOS group (p = .001, p < .00 and p = .003, respectively). The 17OHP level did not differ among the groups (p = .15). Women with PCOS possessed the highest kisspeptin level (p = .01). The kisspeptin level was negatively correlated with FSH level (r = -0.18, p = .02) and positively correlated with TT and DHEAS levels (r = 0.17, p = .02 and r = 0.23, p = .003, respectively).. Women with PCOS had increased serum kisspeptin levels. Kisspeptin concentrations were negatively correlated with serum FSH and positively correlated with serum TT and DHEAS levels.

Topics: Adult; Body Mass Index; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Female; Follicle Stimulating Hormone; Hospitals, University; Humans; Infertility, Female; Kisspeptins; Outpatient Clinics, Hospital; Ovarian Reserve; Overweight; Polycystic Ovary Syndrome; Prospective Studies; Severity of Illness Index; Testosterone; Turkey; Up-Regulation; Young Adult

A cross-sectional study was carried out at the Australian Concept Infertility Medical Centre from June 2014 to June 2015 to relate serum kisspeptin levels on human chorionic gonadotrophin (HCG) day with pregnancy outcome after intracytoplasmic sperm injection (ICSI). A total of 176 women aged 20 to 42 years, with regular menstrual cycles, normal thyroid function and prolactin levels selected for ICSI were included in the study. Patients with uterine fibroids, metabolic disorders, short agonist and antagonist protocol were excluded. Long protocol for down-regulation of ovaries was observed and kisspeptin levels were estimated on HCG day. Results were categorized into groups: Group A, non-pregnant with β-HCG <25 mIU/ml; and Group B, clinical pregnancy with β-HCG >25 mIU/ml and cardiac activity on transvaginal scan. Kisspeptin levels were significantly higher in Group B versus Group A (P < 0.001), independently associated with positive pregnancy (r = 0.388; P < 0.001), but just borderline with endometrial thickness (r = 0.294; P = 0.05). The area under the curve was highest for kisspeptin, 0.784 (95% CI, 0.681 to 0.886) for positive pregnancy, which indicated that kisspeptin measured on HCG day can be used as a marker for success of treatment in women after ICSI.

Topics: Adult; Australia; Chorionic Gonadotropin; Cross-Sectional Studies; Embryo Implantation; Female; Follicle Stimulating Hormone; Humans; Infertility, Female; Kisspeptins; Ovary; Pregnancy; Pregnancy Outcome; Sensitivity and Specificity; Sperm Injections, Intracytoplasmic; Young Adult

The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility and kisspeptin (KP) is a potent trigger of GnRH secretion from GnRH neurons. KP signals via KISS1R, a Gαq/11-coupled receptor, and mice bearing a global deletion of Kiss1r (Kiss1r(-/-)) or a GnRH neuron-specific deletion of Kiss1r (Kiss1r(d/d)) display hypogonadotropic hypogonadism and infertility. KISS1R also signals via β-arrestin, and in mice lacking β-arrestin-1 or -2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of Gαq/11 in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that Gαq/11-independent GnRH secretion would be sufficient to maintain fertility. To test this, Gnaq (encodes Gαq) was selectively inactivated in the GnRH neurons of global Gna11 (encodes Gα11)-null mice by crossing Gnrh-Cre and Gnaq(fl/fl);Gna11(-/-) mice. Experimental Gnaq(fl/fl);Gna11(-/-);Gnrh-Cre (Gnaq(d/d)) and control Gnaq(fl/fl);Gna11(-/-) (Gnaq(fl/fl)) littermate mice were generated and subjected to reproductive profiling. This process revealed that testicular development and spermatogenesis, preputial separation, and anogenital distance in males and day of vaginal opening and of first estrus in females were significantly less affected in Gnaq(d/d) mice than in previously characterized Kiss1r(-/-) or Kiss1r(d/d) mice. Additionally, Gnaq(d/d) males were subfertile, and although Gnaq(d/d) females did not ovulate spontaneously, they responded efficiently to a single dose of gonadotropins. Finally, KP stimulation triggered a significant increase in gonadotropins and testosterone levels in Gnaq(d/d) mice. We therefore conclude that the milder reproductive phenotypes and maintained responsiveness to KP and gonadotropins reflect Gαq/11-independent GnRH secretion and activation of the neuroendocrine-reproductive axis in Gnaq(d/d) mice.. The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility. Over the last decade, several studies have established that the KISS1 receptor, KISS1R, is a potent trigger of GnRH secretion and inactivation of KISS1R on the GnRH neuron results in infertility. While KISS1R is best understood as a Gαq/11-coupled receptor, we previously demonstrated that it could couple to and signal via non-Gαq/11-coupled pathways. The present study confirms these findings and, more importantly, while it establishes Gαq/11-coupled signaling as a major conduit of GnRH secretion, it also uncovers a significant role for non-Gαq/11-coupled signaling in potentiating reproductive development and function. This study further suggests that by augmenting signaling via these pathways, GnRH secretion can be enhanced to treat some forms of infertility.

Topics: Animals; Blastocyst; Embryonic Development; Female; Gene Expression Profiling; Genitalia, Female; Genitalia, Male; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; GTP-Binding Protein alpha Subunits; Hypogonadism; Hypothalamo-Hypophyseal System; Hypothalamus; Infertility, Female; Infertility, Male; Kisspeptins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Oligopeptides; Ovariectomy; Ovulation; Peptide Fragments; Peptides; Phenotype; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Spermatogenesis

People on a diet to lose weight may be at risk of reproductive failure. To investigate the effects of nutrient restriction on reproductive function and the underlying mechanism, changes of reproductive traits, hormone secretions and gene expressions in hypothalamus-pituitary-gonadal axis were examined in postpubertal gilts at anestrus induced by nutrient restriction. Gilts having experienced two estrus cycles were fed a normal (CON, 2.86 kg/d) or nutrient restricted (NR, 1 kg/d) food regimens to expect anestrus. NR gilts experienced another three estrus cycles, but did not express estrus symptoms at the anticipated fourth estrus. Blood samples were collected at 5 days' interval for consecutive three times for measurement of hormone concentrations at the 23th day of the fourth estrus cycle. Individual progesterone concentrations of NR gilts from three consecutive blood samples were below 1.0 ng/mL versus 2.0 ng/mL in CON gilts, which was considered anestrus. NR gilts had impaired development of reproductive tract characterized by absence of large follicles (diameter ≥ 6 mm), decreased number of corepus lutea and atrophy of uterus and ovary tissues. Circulating concentrations of IGF-I, kisspeptin, estradiol, progesterone and leptin were significantly lower in NR gilts than that in CON gilts. Nutrient restriction down-regulated gene expressions of kiss-1, G-protein coupled protein 54, gonadotropin-releasing hormone, estrogen receptor α, progesterone receptor, leptin receptor, follicle-stimulating hormone and luteinizing hormone and insulin-like growth factor I in hypothalamus-pituitary-gonadal axis of gilts. Collectively, nutrient restriction resulted in impairment of reproductive function and changes of hormone secretions and gene expressions in hypothalamus-pituitary-gonadal axis, which shed light on the underlying mechanism by which nutrient restriction influenced reproductive function.

Topics: Animal Feed; Animals; Caloric Restriction; Estradiol; Estrogen Receptor alpha; Estrus; Female; Gene Expression Regulation; Genetic Fitness; Gonadotropin-Releasing Hormone; Hypothalamo-Hypophyseal System; Hypothalamus; Infertility, Female; Insulin-Like Growth Factor I; Kisspeptins; Leptin; Ovary; Pituitary Gland; Pituitary-Adrenal System; Progesterone; Receptors, G-Protein-Coupled; Swine

Kisspeptins are known to be the principle regulators of the hypothalamic-pituitary gonadal (HPG) axis. In addition, the role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of pituitary gonadotropins has been elucidated. We measured plasma concentrations of kisspeptin and PACAP and determined whether the levels of these peptides varied in proportion to circulating gonadotropin levels. Plasma luteinizing hormone (LH) levels were higher in postmenopausal women and in patients with premature ovarian failure (POF) and lower in patients with idiopathic hypogonadotropic hypogonadism (IHH) compared with the LH level in normally menstruating women. Similarly, serum follicle-stimulating hormone levels were higher in postmenopausal women and in patients with POF but lower in pregnant women and patients with IHH compared with normally menstruating women. Plasma levels of kisspeptins were significantly higher in pregnant women compared with normally menstruating women. However, no significant differences were observed in postmenopausal women, patients with POF, and patients with IHH. On the other hand, plasma levels of PACAP were significantly lower in pregnant women, patients with POF, and in IHH patients when compared with normally menstruating women. No significant differences were observed in PACAP concentration between postmenopausal women and in normally menstruating women. Our observations suggest that the serum levels of kisspeptins and PACAP did not correlate with variations in serum gonadotropin levels.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Blood Chemical Analysis; Female; Gonadotropins; Humans; Infertility, Female; Kisspeptins; Menstrual Cycle; Middle Aged; Pituitary Adenylate Cyclase-Activating Polypeptide; Postmenopause; Pregnancy; Young Adult

Homozygous androgen receptor (AR)-knockout (ARKO) female mice are subfertile due to both intra- and extraovarian (neuroendocrine) defects as defined by ovary transplantation. Using ARKO mice, this study set out to reveal the precise AR-regulated pathways required for optimal androgen-regulated ovulation and fertility. ARKO females exhibit deficient neuroendocrine negative feedback, with a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) (P < 0.01). Positive feedback is also altered as intact ARKO females, at late proestrus, exhibit an often mistimed endogenous ovulatory LH surge. Furthermore, at late proestrus, intact ARKO females display diminished preovulatory serum estradiol (E2; P < 0.01) and LH (P < 0.05) surge levels and reduced Kiss1 mRNA expression in the anteroventral periventricular nucleus (P < 0.01) compared with controls. However, this reduced ovulatory LH response in intact ARKO females can be rescued by OVX and E2 priming or treatment with endogenous GnRH. These findings reveal that AR regulates the negative feedback response to E2, E2-positive feedback is compromised in ARKO mice, and AR-regulated negative and positive steroidal feedback pathways impact on intrahypothalamic control of the kisspeptin/GnRH/LH cascade. In addition, intraovarian AR-regulated pathways controlling antral to preovulatory follicle dynamics are disrupted because adult ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte/follicle diameter ratios (P < 0.01) and increased proportions of unhealthy large antral follicles (P < 0.05) compared with controls. As a consequence of aberrant follicular growth patterns, proestrus ARKO ovaries also exhibit fewer preovulatory follicle (P < 0.05) and corpora lutea numbers (P < 0.01). However, embryo development to the blastocyst stage is unchanged in ARKO females, and hence, the subfertility is a consequence of reduced ovulations and not altered embryo quality. These findings reveal that the AR has a functional role in neuroendocrine regulation and timing of the ovulatory LH surge as well as antral/preovulatory follicle development.

Topics: Animals; Corpus Luteum; Estradiol; Estrous Cycle; Female; Hypothalamus; Infertility, Female; Kisspeptins; Luteinizing Hormone; Mice; Mice, Knockout; Ovarian Follicle; Ovary; Ovulation; Receptors, Androgen

Preventing reproduction during nutritional deprivation is an adaptive process that is conserved and essential for the survival of species. In mammals, the mechanisms that inhibit fertility during starvation are complex and incompletely understood. Here we show that exposure of female mice to fibroblast growth factor 21 (FGF21), a fasting-induced hepatokine, mimics infertility secondary to starvation. Mechanistically, FGF21 acts on the suprachiasmatic nucleus (SCN) in the hypothalamus to suppress the vasopressin-kisspeptin signaling cascade, thereby inhibiting the proestrus surge in luteinizing hormone. Mice lacking the FGF21 co-receptor, β-Klotho, in the SCN are refractory to the inhibitory effect of FGF21 on female fertility. Thus, FGF21 defines an important liver-neuroendocrine axis that modulates female reproduction in response to nutritional challenge.

Topics: Animals; Energy Metabolism; Female; Fibroblast Growth Factors; Hypothalamus; Infertility, Female; Kisspeptins; Klotho Proteins; Luteinizing Hormone; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Proestrus; Reproduction; Signal Transduction; Starvation; Suprachiasmatic Nucleus; Vasopressins

Fibroblast growth factor (FGF) signaling is essential for the development of the gonadotropin-releasing hormone (GnRH) system. Mice harboring deficiencies in Fgf8 or Fgf receptor 1 (Fgfr1) suffer a significant loss of GnRH neurons, but their reproductive phenotypes have not been examined. This study examined if female mice hypomorphic for Fgf8, Fgfr1, or both (compound hypomorphs) exhibited altered parameters of pubertal onset, estrous cyclicity, and fertility. Further, we examined the number of kisspeptin (KP)-immunoreactive (ir) neurons in the anteroventral periventricular/periventricular nuclei (AVPV/PeV) of these mice to assess if changes in the KP system, which stimulates the GnRH system, could contribute to the reproductive phenotypes. Single hypomorphs (Fgfr1(+/-) or Fgf8(+/-)) had normal timing for vaginal opening (VO) but delayed first estrus. However, after achieving the first estrus, they underwent normal expression of estrous cycles. In contrast, the compound hypomorphs underwent early VO and normal first estrus, but had disorganized estrous cycles that subsequently reduced their fertility. KP immunohistochemistry on Postnatal Day 15, 30, and 60 transgenic female mice revealed that female compound hypomorphs had significantly more KP-ir neurons in the AVPV/PeV compared to their wild-type littermates, suggesting increased KP-ir neurons may drive early VO but could not maintain the cyclic changes in GnRH neuronal activity required for female fertility. Overall, these data suggest that Fgf signaling deficiencies differentially alter the parameters of female pubertal onset and cyclicity. Further, these deficiencies led to changes in the AVPV/PeV KP-ir neurons that may have contributed to the accelerated VO in the compound hypomorphs.

Topics: Animals; Anterior Thalamic Nuclei; Cell Communication; Estrous Cycle; Female; Fibroblast Growth Factor 8; Gonadotropin-Releasing Hormone; Infertility, Female; Kisspeptins; Mice; Mice, Transgenic; Midline Thalamic Nuclei; Neurons; Receptor, Fibroblast Growth Factor, Type 1; Reproduction; Sexual Maturation; Signal Transduction