Gonadotropin Secretion Research Articles

Sex-independent timing of the onset of central puberty revealed by nocturnal luteinizing hormone concentrations.

We designed a longitudinal study to investigate the association between the ages of central pubertal activation and the appearance of clinical signs of puberty and determined total luteinizing hormone (LH) immunoreactivity in daytime- and nocturnal sleeptime-excreted urine samples. Thirty healthy volunteers (17 boys and 13 girls, aged 3.4-15.2years and 4.3-14.3years, respectively, at the beginning of the study) were included. Male and female subjects were followed for an average of 15 visits during 5.5 and 5.8 years on average, respectively. At each visit, subjects provided 24-h urine samples divided into nocturnal sleeptime and waketime portions according to the participant's sleep-and-wake rhythm. Total urinary LH (U-LH) concentrations were measured in duplicate by Delfia® IFMA (Wallac), which has been designed specifically to detect intact LH as well as the beta subunit and its core fragment, but not the human chorionic gonadotropin. The initial increases in nocturnal sleeptime total U-LH concentrations over the cutoff value of 0.7 IU/L occurred at around the same time (around 9-10 years of age) in both sexes, which could not be detected in waketime urine samples. The mean first age for the nocturnal sleeptime total U-LH concentrations to reach or surpass the cutoff was 10.7 years (range: 10.2-11.6years) in boys and 11.8 years (range: 10.7-13.4years) in girls, showing no statistically significant difference between the sexes (p = .15). The mean time span from the age at which sleeptime total U-LH concentration first exceeded the 0.7 IU/L level to observing pubertal stage 2 was 1.5years in boys and 0.1years in girls. Findings in our population with a limited sample size suggest that the timing of central pubertal activation is a sex-independent phenomenon, which can be observed by monitoring the nocturnal sleeptime total LH concentrations in urine. The lag time from central pubertal activation of gonadotropin secretion to the clinical onset of puberty is significantly longer in boys.

Beyond reproduction: Exploring the Non-Canonical roles of the Kisspeptin System in Diverse Biological Systems

G protein-coupled receptors are integral membrane proteins in cell signaling processes. Activation of G protein-coupled receptors by specific agonists promotes the activation of different G-proteins, activating different intracellular signaling pathways, including adenylate cyclase activation and intracellular calcium release. One of the G protein-coupled receptors studied is the kisspeptin receptor, which regulates reproduction and gonadotropin secretion. However, recent studies have shown that kisspeptin and its receptor have non-canonical roles in cell signaling and several biological systems. In the present review, we will present these different functions exerted by the kisspeptin system in different biological systems, such as the central nervous system, the cardiovascular system, and the immune system, as well as the role of this system in pathologies such as preeclampsia, diabetes, and cancer. Understanding their non-canonical roles in cell signaling may have important implications in developing new therapies for various diseases. Keywords: Kisspeptin-1 Receptor, Kisspeptins, G-protein coupled receptor, Signal Transduction, Cancer, Diabetes Mellitus, Preeclampsia.

Interaction of pre- and postnatal nutrition on expression of leptin receptor variants and transporter molecules, leptin transport, and functional response to leptin in heifers†.

Perinatal nutrition modulates the hypothalamic neurocircuitries controlling GnRH release, thus programming pubertal maturation in female mammals. Objectives of experiments reported here were to test the hypotheses that prenatal nutrition during mid- to late gestation interacts with postnatal nutrition during the juvenile period in heifer offspring to alter expression of leptin receptor (LepR) variants (ObRa, ObRb, ObRc, ObRt), and lipoprotein transporter molecules (LRP1 and 2) in the choroid plexus, leptin transport across the blood-brain barrier, and hypothalamic-hypophyseal responsiveness to exogenous ovine leptin (oleptin) during fasting. Nutritional programming of heifers employed a 3 × 2 factorial design of maternal (high, H; low, L; and moderate, M) × postnatal (H and L) dietary treatments. Results (Expt. 1) demonstrated that prepubertal heifers born to L dams, regardless of postnatal diet, had reduced expression of the short isoform of ObRc compared to H and M dams, with sporadic effects of undernutrition (L or LL) on ObRb, ObRt, and LRP1. Intravenous administration of oleptin to a selected postpubertal group (HH, MH, LL) of ovariectomized, estradiol-implanted heifers fasted for 56h (Expt. 2) did not create detectable increases in third ventricle cerebrospinal fluid but increased gonadotropin secretion in all nutritional groups tested. Previous work has shown that leptin enhances gonadotropin secretion during fasting via effects at both hypothalamic and anterior pituitary levels in cattle. Given the apparent lack of robust transfer of leptin across the blood-brain barrier in the current study, effects of leptin at the adenohypophyseal level may predominate in this experimental model.

ВЛИЯНИЕ ПЕРЕНЕСЕННОЙ ИНФЕКЦИИ SARS-COV-2 НА МЕНСТРУАЛЬНУЮ ФУНКЦИЮ У ЖЕНЩИН РАННЕГО РЕПРОДУКТИВНОГО ВОЗРАСТА

The pandemic has had a significant impact on the lives of people around the world. Both those who have directly had a coronavirus infection, and those who have been exposed to stress in conditions of social isolation, deteriorating financial well-being and other changes associated with long-term quarantine. Human existence is subject to biological rhythms, adapting the body to changing environmental conditions. One of the most important regulatory roles is played by circadian (daily) rhythms, namely the cycle of sleep and wakefulness. Pineal hormone - melatonin, is involved in the regulation of pigment metabolism, but its main effect is inhibition of the secretion of gonadotropins. In women, the highest level of melatonin is observed during menstruation, the lowest - during ovulation. This hormone plays an important role in the female reproductive system. In turn, SARS-CoV-2 can cause mental disorders by affecting the central nervous system. The most common symptoms and conditions: headaches and dizziness, taste and smell disorders (hyposmia and anosmia), weakness, anxiety, obsessive-compulsive disorders, insomnia, impaired attention and concentration. With prolonged illness, serious disorders of the central nervous system are observed. This study aims to correlate changes in sleep quality and changes in menstrual function in patients who have had SARS-CoV-2 infection.

Role of Metformin in Polycystic Ovary Syndrome (PCOS)-Related Infertility.

Polycystic ovarian syndrome (PCOS) is considered the most prevalent endocrinological disorder, whichaffects some women and it is characterized by anovulation and hyperandrogenism, with morphologic changes in the ovary, inappropriate gonadotropin secretion, and insulin resistance (IR) with accompanying compensatory hyperinsulinemia. PCOS was associated with some degree of IR which probably contributes to hyperandrogenism. Many studies showed that metformin, when used to treat PCOS, significantly reduced serum androgen levels, improved insulin sensitivity, restored menstrual cyclicity, and was successful in triggering ovulation. As a result, metformin may be useful in treating PCOS-related infertility. The aim of this review was to clarify PCOS, its prevalence, particularly in Saudi Arabia, its pathogenesis, its impact on the patient's health, and to explain the uses of metformin, its mechanism of action, and its role in the treatment of PCOS-related infertility.

Effect of fsh on lipid profile in postmenopausal women

The World Health Organization (WHO) and Stages of Reproductive Aging Workshop (STRAW) define menopause as a permanent endpoint of the menstrual cycle for one year that occurs naturally or by induction of surgical procedure, chemotherapy or radiation .The etiology of menopause is classified into physiological and non-physiological. Pathophysiology of menopause includes the decline of ovary function in menopause, response to a loss of ovarian feedback mechanism, and the decline of the hypothalamus and pituitary function. Endocrine changes in menopause lead to alteration of gonadotropin secretion cycle patterns, changes in steroid and peptide hormones through monophasic patterns to increase gonadotropin, and decreased estrogen .Aim: This study aims to investigate the effect of FSH on lipid profile in postmenopausal women. Study design: A cross-section observational study. Method: The study is a cross-sectional study done on 90 women. These women aged more than 50 years had cessation of menstrual cycle for over a year. The blood samples were taken from 90 postmenopausal women, and interviews were conducted using a questionnaire. FSH measure, by ElectroChemiLuminescence (ECL) technology for immunoassay analysis done by Cobas e411 device. Lipid profile measure, by manual techniques done by use of spectrophotometer device. Result: We observed increase in Follicle-stimulating hormone (FSH) during postmenopause has a positive significant correlation with body mass index (BMI) (r 0.350, p 0.001), total cholesterol (TC) (r 0.397, p 0.001) and Low-density lipoprotein (LDL) ( r 0.421, p 0.001) FSH also correlated positively but insignificant correlation with triglyceride (TG) (r 0.175, p 0.098) and very low-density lipoproteins (VLDL) ( r 0.055, p 0.604). FHS has a negative significant correlation with Estradiol ( r -0.509, p 0.001) and Vit.D( r-0.220, p 0.037) as well as FSH correlated negative but insignificant with age ( r -0.142, p 0.183) and High-density lipoprotein (HDL) (r -0.048, p 0.656). Conclusion: The current study showed a significant positive correlation of FSH with TC and LDL, an insignificant positive correlation with TG, and an insignificant negative correlation with HDL. Keywords: Postmenopause, FSH, Lituenizing Hormone, HDL

Gonadal Feedback Alters the Relationship between Action Potentials and Hormone Release in Gonadotropin-Releasing Hormone Neurons in Male Mice.

In vertebrates, the pulsatile release of gonadotropin-releasing hormone (GnRH) from neurons in the hypothalamus triggers secretion of anterior pituitary gonadotropins, which activate steroidogenesis, and steroids in turn exert typically homeostatic negative feedback on GnRH release. Although long-term episodic firing patterns of GnRH neurons in brain slices resemble the pulsatile release of GnRH and LH in vivo, neither the relationship between GnRH neuron firing and release nor whether this relationship is influenced by gonadal feedback are known. We combined fast-scan cyclic voltammetry and patch-clamp to perform simultaneous measurements of neuropeptide release with either spontaneous action potential firing or in response to neuromodulator or action-potential-spike templates in brain slice preparations from male mice. GnRH release increased with higher frequency spontaneous firing to a point; release reached a plateau after which further increases in firing rate did not elicit further increased release. Kisspeptin, a potent GnRH neuron activator via a Gq-coupled signaling pathway, triggered GnRH release before increasing firing rate, whether globally perfused or locally applied. Increasing the number of spikes in an applied burst template increased release; orchidectomized mice had higher sensitivity to the increased action potential number than sham-operated mice. Similarly, Ca2+ currents triggered by these burst templates were increased in GnRH neurons of orchidectomized mice. These results suggest removal of gonadal feedback increases the efficacy of the stimulus-secretion coupling mechanisms, a phenomenon that may extend to other steroid-sensitive regions of the brain.SIGNIFICANCE STATEMENT Pulsatile secretion of GnRH plays a critical role in fertility. The temporal relationship between GnRH neuron action potential firing and GnRH release remains unknown as does whether this relationship is influenced by gonadal feedback. By combining techniques of fast-scan cyclic voltammetry and patch-clamp we, for the first time, monitored GnRH concentration changes during spontaneous and neuromodulator-induced GnRH neuron firing. We also made the novel observation that gonadal factors exert negative feedback on excitation-secretion coupling to reduce release in response to the same stimulus. This has implications for the control of normal fertility, central causes of infertility, and more broadly for the effects of sex steroids in the brain.

The role of GnRH in Tibetan male sheep and goat reproduction.

The hypothalamic-pituitary-gonadal (HPG) axis connects the hypothalamus, pituitary gland, and gonads. The regulation of reproductive processes includes integrating various factors from structural functions and environmental conditions in the HPG axis, with the outcome indication of these processes being the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. These factors include feed consumption and nutritional condition, sex steroids, season/photoperiod, pheromones, age, and stress. GnRH pulsatile secretion affects the pattern of gonadotropin secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which then regulates both endocrine function and gamete maturation in the gonads. This regulates gonadotropins and testosterone (T) production. There is evidence that in males, GnRH participates in a variety of host behavioural and physiological processes such as the release of reproductive hormones, progression of spermatogenesis and sperm function, aggressive behaviour, and physiological metabolism. GnRH activates receptors expressed on Leydig cells and Sertoli cells, respectively to stimulate T secretion and spermatogenesis in the testis. Photoperiod affects the reproductive system of the hypothalamic-pituitary axis via rhythmic diurnal melatonin secretion. Increased release of melatonin promotes sexual activity, GnRH production, LH stimulation, and T production. This induces testicular functions, spermatogenesis, and puberty. GnRH reduces the release of LH by the pituitary through the cascade effect and decreases plasma concentration of T. Gut microbiota maintain sex steroid homeostasis and may induce reduction in reproduction productivity. Recently, findings of kisspeptin-neurokinin-dynorphin neuronal network in the brain have resulted in fast advances in how GnRH secretion is controlled. Emerging studies have also indicated that other neuropeptide analogues could be used in control reproduction procedures in various goat and sheep breeds. The Tibetan male sheep and goats reproduce on a seasonal basis and have high reproductive performance. This is a review for the role of GnRH in Tibetan male sheep and goats reproduction. This is intended to enhance reproductive knowledge for understanding the key roles of GnRH relating to male reproductive efficiency of Tibetan sheep or goats.

A novel lncRNA LOC105613571 binding with BDNF in pituitary promotes gonadotropin secretion by AKT/ERK-mTOR pathway in sheep associated with prolificacy.

The pituitary is a vital endocrine organ for synthesis and secretion of gonadotropic hormones (FSH and LH), and the gonadotropin showed fluctuations in animals with different fecundity. Long non-coding RNAs (lncRNAs) have been identified as regulatory factors for the reproductive process. However, the profiles of lncRNAs and their roles involved in sheep fecundity remains unclear. In this study, we performed RNA-sequencing for the sheep pituitary gland associated with different fecundity, and identified a novel candidate lncRNA LOC105613571 targeting BDNF related to gonadotropin secretion. Our results showed that expression of lncRNA LOC105613571 and BDNF could be significantly upregulated by GnRH stimulation in sheep pituitary cells in vitro. Notably, either lncRNA LOC105613571 or BDNF silencing inhibited cell proliferation while promoted cell apoptosis. Moreover, lncRNA LOC105613571 knockdown could also downregulate gonadotropin secretion via inactivation AKT, ERK and mTOR pathway. In addition, co-treatment with GnRH stimulation and lncRNA LOC105613571 or BDNF knockdown showed the opposite effect on sheep pituitary cells in vitro. In summary, BDNF-binding lncRNA LOC105613571 in sheep regulates pituitary cell proliferation and gonadotropin secretion via the AKT/ERK-mTOR pathway, providing new ideas for the molecular mechanisms of pituitary functions.

Gonadotropin inhibitory-hormone modulates neurosteroids-synthesizing enzymes expression and aggressive behavior in male sea bass, Dicentrarchus labrax

Neurosteroids are involved in the regulation of multiple behavioral and physiological processes and metabolic activities in the vertebrate brain. However, central mechanisms of how neurosteroid synthesis is regulated is far to be understood. Gonadotropin-inhibitory hormone (GNIH) is a hypothalamic neuropeptide that negatively regulates gonadotropin secretion but also inhibits sexual and aggressive behaviors in birds and mammals by modulating aromatase enzyme and neuroestrogen synthesis. In a previous study performed in male sea bass, we reported that Gnih inhibited the reproductive axis by acting at the three levels of the brain-pituitary-gonad axis. Moreover, the presence of Gnih cells and fibers in the telencephalon, mesencephalon and rhombencephalon suggests a role of Gnih in regulating other important brain functions in sea bass, including behavior. In this study, we have analyzed the effects of the intracerebroventricular (icv) injection of sbGnih-2 on the brain and pituitary expression of the main neurosteroids-synthesizing enzymes (stAR, cyp17, 3β-hsd, 17β-hsd, cyp19b, cyp7b), as well as on estrogen and androgen receptors (erα, erβ1, erβ2, ar). A combination of immunohistochemistry and in situ hybridization was also used to identify putative interaction of Gnih- and aromatase-positive cells. We also performed a mirror test study as a proxy to measure aggression levels and agonistic behavior after icv injection of sbGnih-2. Central administration of sbGnih-2 at different doses reduced the transcript levels of 3β-hsd and 17β-hsd, and increased the expression of cyp19b (brain aromatase) in the sea bass brain. Neuroanatomical results suggest that paracrine and neuroendocrine actions could mediate Gnih effects on aromatase expression. Central administration of sbGnih-2 also decreased the pituitary expression of 17β-hsd and estrogen receptors (erβ2). The mirror test analysis showed that sbGnih-2 affected the agonistic/aggressive behavior of sea bass as revealed by the decreased interaction with the mirror, lower time spent in the mirror zone, increased latency to establish contact with the mirror and higher mean distance to the mirror zone. In contrast, locomotor activity parameters measured were not affected by sbGnih-2 injection. Taken together, our results showed for the first time in fish that Gnih inhibits social-aggressive behavior and affects the gene expression of neurosteroid-synthesizing enzymes giving rise to neuroandrogens and neuroestrogens in the sea bass brain.

P-702 Secretion of beta-human chorionic gonadotropin (b-hCG) by post-implantation embryos differs according to different chromosomal status.

Abstract Study question To evaluate secretion of b-hCG hormone by human post-implantation embryos cultured in-vitro up to day 10 according to their chromosomal status. Summary answer Secreted b-hCG levels differs among embryos with different chromosomal load, being severely diminished in monosomic embryos when compared either to euploid or trisomic embryos. What is known already Exploring early post-implantation embryo development is subject of growing interest because errors in correct embryo development at this period might cause early pregnancy losses or development of pathologies affecting postnatal health. Down's Syndrome (DS) is one of the most common examples of chromosomal supernumerary (trisomy 21; T21) aneuploidy that leads to live birth but associated to pathology in postnatal life while monosomy of chromosome 21 (M21) is more likely to cause embryo developmental arrest. Furthermore, conclusions extracted from our previous studies put forward the idea of different gene and metabolite expression according to different chromosomal load (Sanchez-Ribas et al., 2019). Study design, size, duration This is an exploratory comparative study which includes a total of 33 supernumerary science-donated human blastocysts on day 6 from in-vitro fertilization cycles followed by preimplantation genetic test for aneuploidies. Euploid (n = 10), pure T21 (n = 13) and pure M21 (n = 10) were included in the study. All day 6 blastocyst included were good-quality embryos and were initiating hatching at the time of vitrification. Embryos degenerated during culture were not used for b-hCG quantifications. Participants/materials, setting, methods Euploid, T21 and M21 day blastocysts were thawed and cultured in-vitro until day 10. Embryos were cultured in culture medium specifically designed to support post-implantation embryo development. Each day of culture, half volume of culture media was replaced by fresh media. Levels of b-hCG in conditioned embryo media were quantified by ELISA immunoassay at day 7, 9, and 10. Results are expressed as mean ± standard deviation. Embryo morphology was tracked by bright-field images. Main results and the role of chance All euploid and T21 embryos thawed managed to hatch completely and expand the blastocoel cavity, while 40% of M21 embryos failed to hatch being arrested inside the zona pellucida on day 7. On day 7, mean concentration of b-hCG secreted did not differ among euploid, T21 and M21 embryos (37,29±6,27; 36,05±6,61 and 27,16±9,95 ng/mL respectively). Interestingly, euploid and T21 embryos reported a progressive time-dependent increase in b-hCG levels along post-implantation in-vitro culture while secreted levels of b-hCG by M21 embryos showed a decreasing trend, reporting diminished b-hCG secretion at the end of the culture (day 10) compared to day 7 (14,86±2,57 vs 27,16±9,95 ng/mL; p < 0.05). No significant differences in b-hCG secretions were observed between euploid and T21 embryos neither on day 9 d.p.f. (61,05±8,47 and 56,08±8,10 ng/mL respectively) nor on day 10 (74,88±6,36 and 71,75±7,01 ng/mL respectively). However, b-hCG secreted by M21 embryos on day 9. and day 10 (27,11±11,45 and 14,86±2,57 ng/mL respectively) were significantly reduced (p < 0.01) compared with euploid or T21 embryos. Besides, while all euploid and T21 embryos developed until day 10, 16,67% of expanded M21 embryos degenerated before day 9. Limitations, reasons for caution This research focused only on embryo development, no maternal tissues were considered. Further proteins should be investigated to reveal other pathways implicated in healthy embryo development and not only trophoblast proliferation. Wider implications of the findings Monosomic embryos, associated to implantation failures, secrete lower b-hCG when compared to either euploid or trisomic embryos, which show similar behavior. Besides, b-hCG in culture media could become a non-invasive marker to track embryo progression along post-implantation stages and detect embryos with increased likelihood of developmental arrest or early miscarriage. Trial registration number Not Applicable

Low-Dose Estrogens as Neuroendocrine Modulators in Functional Hypothalamic Amenorrhea (FHA): The Putative Triggering of the Positive Feedback Mechanism(s).

Functional hypothalamic amenorrhea (FHA) is a non-organic reversible chronic endocrine disorder characterized by an impaired pulsatile secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus. This impaired secretion, triggered by psychosocial and metabolic stressors, leads to an abnormal pituitary production of gonadotropins. As LH and FSH release is defective, the ovarian function is steadily reduced, inducing a systemic hypoestrogenic condition characterized by amenorrhea, vaginal atrophy, mood changes and increased risk of osteoporosis and cardiovascular disease. Diagnosis of FHA is made excluding other possible causes for secondary amenorrhea, and it is based upon the findings of low serum gonadotropins and estradiol (E2) with evidence of precipitating factors (excessive exercise, low weight, stress). Treatments of women with FHA include weight gain through an appropriate diet and physical activity reduction, psychological support, and integrative approach up to estrogen replacement therapy. If no spontaneous ovarian function is restored, assisted reproductive technologies may be used when pregnancy is desired. Because subjects with FHA are hypoestrogenic, the use of low-dose estrogens has been proposed as a putative treatment to positively modulate the spontaneous restart of gonadotropin secretion, counteracting the blockade of the reproductive axis triggered by stress acting through the neuroendocrine pathways at the basis of positive feedback of estrogens. The mechanism through which low-dose estrogens acts is still unknown, but kisspeptin-secreting neurons may be involved.

Effect of induced molting on ovarian function remodeling in laying hens

Induced molting (IM) can restore the laying rate of aged laying hens to the peak level of laying and rejuvenate ovarian function for the second laying cycle. To explore the mechanism of ovarian function remodeling during IM in laying hens, in this study, ninety 71-wk-old laying lady hens with 60% laying rate and uniform weight were selected for molting induction by fasting. Samples (serum and fresh ovarian tissue) were collected on the day before fasting (F0), the 3rd and 16th days of fasting (F3, F16), and the 6th, 15th, 32nd days of refeeding (R6, R15, and R32), and the number of follicles in each period was counted. Then, the reproductive hormone levels in serum and antioxidant levels in ovarian tissues were detected at different stages, and the gene expression of the KIT-PI3K-PTEN-AKT pathway and GDF-9 in ovaries was measured by qRT-PCR. The results showed that the laying rate increased rapidly after refeeding and returned to the prefasting level by R32. At F16 and R6, the number of mature follicles significantly decreased; the number of primary and secondary follicles significantly increased; the contents of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (P4) in serum decreased; the relative expression of KIT, PI3K, AKT, and GDF-9 significantly increased; and that of PTEN significantly decreased. At R15 and R32, except for GDF-9, which maintained a high expression state, other indicators showed opposing trends to those observed at F16 and R6. In conclusion, IM activated the KIT-PI3K-PTEN-AKT signaling pathway and promoted the activation of primordial follicles during the fasting period and early resumption of feeding; gonadotropin secretion increased gradually, which promoted the rapid development of primary and secondary follicles to mature follicles and ovulation. This study explained the mechanism of ovarian function remodeling in the process of IM and provided a theoretical basis for improving the ovarian function of laying hens and optimizing the IM program.

Vitamin D Status Determines the Impact of Metformin on Gonadotropin Levels in Postmenopausal Women.

Metformin was found to decrease elevated levels of anterior pituitary hormones. Its impact on lactotrope secretory function was absent in women with vitamin D insufficiency. This study investigated whether vitamin D status determines metformin action on overactive gonadotropes. We compared the effect of six-month metformin treatment on the plasma levels of gonadotropins, TSH, prolactin, ACTH, estradiol, free thyroid hormones, IGF-1, and 25-hydroxyvitamin D, as well as on glucose homeostasis markers between three matched groups of postmenopausal women at high risk for diabetes: untreated subjects with vitamin D insufficiency (group A), untreated women with normal vitamin D status (group B), and individuals receiving vitamin D supplementation with normal 25-hydroxyvitamin D levels (group C). Only in groups B and C did metformin reduce FSH levels and tend to decrease LH levels, and these effects correlated with baseline gonadotropin levels, baseline 25-hydroxyvitamin D levels, and the improvement in insulin sensitivity. Follow-up gonadotropin levels were higher in group A than in the other two groups. The drug did not affect circulating levels of TSH, prolactin, ACTH, estradiol, free thyroid hormones, IGF-1, or 25-hydroxyvitamin D. The obtained results suggest that the impact of metformin on gonadotropin secretion in women after menopause is determined by vitamin D status.

Corticotropin releasing factor-1 receptor antagonism associated with favorable outcomes of male reproductive health biochemical parameters.

Disruption in androgen profiles and testicular adrenal rest tumors in males with congenital adrenal hyperplasia (CAH) can negatively affect sexual activity and fertility. Adrenal hyperandrogenism suppresses gonadotropin secretion and testicular adrenal rest tumors (TARTS), despite being noncancerous lesions, cause obstructive azoospermia and impaired testosterone (T) production. Circulating T in men with uncontrolled CAH is often predominantly adrenal in origin, which is reflected in high androstenedione/testosterone ratios (A4/T). Therefore, decreased luteinizing hormone (LH) levels and an increased A4/T are markers of impaired fertility in these individuals. Oral tildacerfont 200 to 1000 mg once daily (QD) (n=10) or 100 to 200 mg twice daily (n=9 and 7) for 2 weeks (Study 201), and 400 mg QD (n=11) for 12 weeks (Study 202). Outcomes measured changes from baseline in A4, T, A4/T, and LH. Mean T levels increased in Study 201 from 375.5 ng/dL to 390.5 ng/dL at week 2 (n=9), 485.4 ng/dL at week 4 (n=4) and 420.7 ng/dL at week 6 (n=4). In Study 202, T levels fluctuated in the normal range from 448.4 ng/dL at baseline to 412.0 ng/dL at week 12. Mean LH levels increased in Study 201 from 0.68 IU/L to 1.59 IU/L at week 2 (n=10), 1.62 IU/L at week 4 (n=5) and 0.85 IU/L at week 6 (n=4). In Study 202, mean LH levels increased from 0.44 IU/L at baseline to 0.87 IU/L at week 12. Mean A4/T decreased across both studies. In Study 201, the mean A4/T changed from a baseline of 1.28 to 0.59 at week 2 (n=9), 0.87 at week 4 (n=4), and 1.03 at week 6 (n=4). In Study 202, the A4/T decreased from baseline of 2.44 to 0.68 at week 12. Four men were hypogonadal at baseline; all experienced improved A4/T and 3/4 (75%) reached levels <1. Tildacerfont treatment demonstrated clinically meaningful reductions in A4 levels, and A4/T with concomitant increased LH levels indicating increased testicular T production. The data suggests improvement in hypothalamic-pituitary-gonadal axis function, but more data is required to confirm favorable male reproductive health outcomes.

Review: Manipulation of follicle development to improve fertility of cattle in timed-artificial insemination programs.

The development of an ovulatory follicle is a fundamental premise for any reproductive management program that aims to optimize fertility in cattle. Controlling follicular development comprises the synchronized emergence of a new follicular wave, selection and growth of the dominant follicle, and synchronized ovulation of a high-quality oocyte. All these follicular events, primarily driven by gonadotropin secretion, occur under a very dynamic hormonal environment. In this sense, controlling follicular development demands essentially a precise manipulation of the hormonal environment to modulate gonadotropin secretion. Furthermore, the effectiveness of hormonal manipulation strategies in the management of follicular development depends on specific particularities of each situation, which can vary widely according to genetic groups (Bos taurus vs Bos indicus), nutritional, metabolic, and reproductive status. In this regard, the constant search for the refined synchrony between the hormonal treatments and reproductive events, considering these distinctions and particularities, have provided valuable information that contributed to the development of efficient reproductive programs. This manuscript discusses the physiological bases behind the development of fine-tuned timed-artificial insemination protocols for beef and dairy cattle that resulted in great improvements in reproductive efficiency of beef and dairy herds.

Self-assembled human placental model from trophoblast stem cells in a dynamic organ-on-a-chip system.

The placental barrier plays a key role in protecting the developing fetus from xenobiotics and exchanging substances between the fetus and mother. However, the trophoblast cell lines and animal models are often inadequate to recapitulate the key architecture and functional characteristics of human placental barrier. Here, we described a biomimetic placental barrier model from human trophoblast stem cells (hTSCs) in a perfused organ chip system. The placental barrier was constructed by co-culture of hTSCs and endothelial cells on the opposite sides of a collagen-coated membrane on chip. hTSCs can differentiate into cytotrophoblasts (CT) and syncytiotrophoblast (ST), which self-assembled into bilayered trophoblastic epithelium with placental microvilli-like structure under dynamic cultures. The formed placental barrier displayed dense microvilli, higher level secretion of human chorionic gonadotropin (hCG), enhanced glucose transport activity. Moreover, RNA-seq analysis revealed upregulated ST expression and activation of trophoblast differentiation-related signalling pathways. These results indicated the key role of fluid flow in promoting trophoblast syncytialization and placental early development. After exposure to mono-2-ethylhexyl phthalate, one of the endocrine disrupting chemicals, the model showed inhibited hCG production and disturbed ST formation in trophoblastic epithelium, suggesting impaired placental structure and function elicited by environmental toxicants. Collectively, the hTSCs-derived placental model can recapitulate placenta physiology and pathological response to external stimuli in a biomimetic manner, which is useful for the study of placental biology and associated diseases.

Dissecting the KNDy hypothesis: KNDy neuron-derived kisspeptins are dispensable for puberty but essential for preserved female fertility and gonadotropin pulsatility

BackgroundKiss1 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. MethodsTo 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. ResultsTaKKO 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. ConclusionsOur 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 statementNeurons 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.

Gonadotrophin-releasing hormone receptors in GtoPdb v.2023.1

GnRH1 and GnRH2 receptors (provisonal nomenclature [39], also called Type I and Type II GnRH receptor, respectively [85]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [85, 84, 114]. GnRH I (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [85, 84, 114] including GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [85, 84, 114]. GnRH1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [58]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [58]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH2 receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [88]. Phylogenetic classifications divide GnRH receptors into three [85] or five groups [130] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH1 receptor in complex with elagolix has been elucidated [133].

Changes in serum progesteron and 17beta-estradiol concentration after application of Suprelorin (4,7 deslorelin acetate) implant for estrus induction in bitches

Since bitches are monoestrous animals, their sexual cycle occurs much less often than other domestic animals, and their reproductive capacity is potentially less. That is why manipulations with the sexual cycle of bitches and their correction are gaining more and more interest. Estrus induction is essential to commercial breeding owners for several reasons. Understanding the processes that occur during each stage of the sexual cycle, it can be safely manipulated. There are many methods for stimulating estrus, but not all of them have found their practical application. The implant Suprelorin (4.7 mg Deslorelin), which is primarily registered for the pharmacological castration of dogs and cats, has also found its use for the induction of estrus in bitches, since at the beginning of its activities, it stimulates the secretion of gonadotropin (GnRH), which triggers the synthesis of follicle-stimulating and luteinizing pituitary hormones. This initial mechanism of action of Deslorelin implants is known as the flash effect and causes heat in almost 100 % of bitches. Despite numerous publications on the use of the implant, its impact is still being investigated. The article presents changes in progesterone and estradiol after using the Suprelorin implant for estrus induction and compares the course of an induced sexual cycle with a spontaneous one. The study was conducted on 13 sexually mature bitches, 7 of them received the Suprelorin implant no earlier than 150 days after the last estrus, and 6 of them were bitches with spontaneous estrus, which were included in the control group. The implant was removed at the beginning of estrus when the progesterone level increased above 3 ng/ml. In 6/7 females, this day fell on the 10th day after the implant was inserted, and in 1/7 – on the 9th. Ovulation occurred two days after the LH peak in all bitches from the experimental group, which corresponded to the 12th day in 6/7 bitches and the 11th day in 1/7 bitches from the introduction of the implant. The estradiol peak in the control group was observed faster than in the experimental group. It occurred on average on the 8th day (mediam 8 (7–9)) from the beginning of estrus, in one bitch on the 7th day, in three - on the 8th, and in two – on the 9th day, respectively. In the experimental group, the estradiol peak occurred on the 9th day after the implant (mediam 9 (8–9), in two bitches on the 8th, and five – on the 9th. But the obtained results indicate that in most bitches of the research group, the estradiol peak occurred one day before the LH peak (5/7) and only in 2/7 two days before the LH peak, which is typical for spontaneous estrus, so despite, that,, the peak of estradiol in the experimental group was observed later than in the control group, and ovulation itself occurred faster. Quantitatively, the level of sex hormones was higher in the experimental group, and the sexual cycle was more predictable.