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Context:Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone–dependent diseases in women.Objective:We evaluated the pharmacokinetics and pharmacodynamics of elagolix.Design, Setting, and Participants:This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit.Interventions:Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days.Main Outcome Measures:Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events.Results:Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush.Conclusions:Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone–dependent diseases in women.Elagolix rapidly suppressed gonadotropins and ovarian sex hormones in healthy premenopausal women in a dose-dependent manner.

Background In our recent publications, we reported the identification of three different molecular forms of total luteinizing hormone (LH) in urine, the intact LH, the free beta‐subunit (LHβ), and its core fragment of LHβ (LHβcf), the latter two establishing the nonintact portion of LH. Following the discontinuation of the Delfia immunofluorometric assay (IFMA) (Wallac, PerkinElmer Finland, Finland), a leading method for detecting urinary LH for 30 years, this study seeks to assess the efficacy of three alternative commercial immunoassays in identifying various forms of U‐LH. Methods Diluted urine samples underwent gel filtration to separate them into fractions, each containing different forms of LH. These were then assayed using Delfia IFMA, Architect LH (Abbott, USA), Elecsys LH Cobas (Roche, Switzerland), and Immulite 2000 LH (Siemens, Germany) immunoassays. Results Both Delfia and Immulite assays detected total U‐LH, that is, all three forms of U‐LH, including intact LH, LHβ, and LHβcf. Cobas detected only intact LH and LHβ, whereas Architect detected solely the intact LH. Conclusions Immulite assay can be an alternative tool to detect all forms of urinary LH, a feature likely to be instrumental in developing noninvasive, practical, and scalable solutions for evaluating total U‐LH changes during minipuberty in neonates, during the onset of central puberty in peripubertal children, puberty‐associated disorders in adolescents, and the fertility window in women, with a special focus on postpeak changes. In our study, we evaluated alternative assays to replace a discontinued method for detecting all forms of urinary LH, including its degradation products. By analyzing LH in gel‐filtrated urine samples, we assessed the comprehensive detection capabilities of various diagnostic tests. Our novel findings revealed diverse fields of utility for different assays, offering a nuanced understanding of their specific clinical applications as choosing the correct assay with an informed decision would facilitate enhanced clinical practice in investigating minipuberty in neonates, the onset of central puberty in peripubertal children, puberty‐associated disorders in adolescents, and the fertility window in women, with a particular emphasis on postpeak changes.

To explore the therapeutic effect of estrogen replacement therapy combined with autologous serum therapy in controlling severe dry eye disease in perimenopausal women. A total of 1249 perimenopausal female patients who visited Ziyang Hospital of West China Hospital, Sichuan University from January 2021 to December 2023 were included in this study. After screening, the patients were randomly divided into the normal group, control group, estrogen replacement therapy group (ERT), autologous serum group (AS), and estrogen replacement therapy + autologous serum group (ERT + AS). There were 20 cases in each group, totaling 100 cases. Eye surface data, total luteinizing hormone (LH), estradiol (E2), follicle stimulating hormone (FSH), and endometrial changes were collected before and after treatment in each group. After treatment, the corneal staining area and staining intensity in the ERT + AS group decreased. Compared with the average tear film rupture time of the normal group (15.16 ± 0.73) s, the Control group (5.11 ± 0.45) s decreased to the lowest level while the ERT group (8.27 ± 0.59) s, AS group (8.15 ± 0.72) s, and ERT + AS group (13.37 ± 0.85) s increased, and the ERT + AS group had the most significant increase. Besides, the Schirmer experiment results showed a consistent trend with BUT, with a statistically significant difference ( P  < 0.05). Meanwhile, our research had shown that after estrogen replacement therapy, FSH and LH in the ERT group and ERT + AS group were significantly reduced, while E2 was significantly increased. There was no statistically significant difference between the two groups ( P  > 0.05). The Elisa experiment results showed that compared with the normal group, the expression intensity of VEGF, IL-1β, PGE2, and TNF-α inflammatory factors was significantly increased in the control group. After treatment with ERT, AS, and ERT + AS, the expression of thses inflammatory factors gradually decreased, with the ERT + AS group showing the most significant downregulation ( P  < 0.05). The HE staining results of the endometrium indicated that after intervention measures, the thickness of the endometrium in the ERT group and ERT + AS group significantly increased, the connective tissue arrangement of the endometrium was tight, the structure of the uterine glands was dense, and there was a single layer of columnar epithelium covered with circular uterine glands. The Kupperman score demonstrated that with the prolongation of treatment time, the Kupperman scores of the ERT group and ERT + AS group gradually decreased. After 4 weeks of treatment, both groups had the lowest values, and there was no statistically significant difference between the groups ( P  > 0.05). Furthermore, the results of the Elisa experiment on endometrial tissue protein fluid showed that compared with the normal group, the expression intensity of IFN-α, IL-12, and TNF-α inflammatory factors was significantly increased in the control group. After treatment with ERT, AS, and ERT + AS, the expression of IFN-α, IL-12, and TNF-α inflammatory factors in the ERT group and ERT + AS group gradually decreased. There was no statistically significant difference between the two groups ( P  > 0.05). The Elisa experiment results showed that compared with the normal group, the expression intensity of LZM, LF, ALB and sIgA in the control group was significantly decreased, and the difference between the two groups was statistically significant ( P  < 0.05). After treatment with ERT, AS, and ERT + AS, the expression of inflammatory factors LZM, LF, ALB and sIgA gradually increased, with the ERT + AS group showing the most significant upregulation, and the difference was statistically significant ( P  < 0.05). The combination of estrogen replacement therapy and autologous serum therapy can effectively ameliorate the symptoms of severe dry eye disease in perimenopausal women and improve their quality of life, which is worthy of further research.

Ovulation in the mouse and other mammals is controlled by hormones secreted by the hypothalamo-pituitary-ovarian axis. We describe anovulation and infertility in female mice lacking the microRNAs miR-200b and miR-429. Both miRNAs are strongly expressed in the pituitary gland, where they suppress expression of the transcriptional repressor ZEB1. Eliminating these miRNAs, in turn, inhibits luteinizing hormone (LH) synthesis by repressing transcription of its β-subunit gene, which leads to lowered serum LH concentration, an impaired LH surge, and failure to ovulate. Our results reveal roles for miR-200b and miR-429, and their target the Zebl gene, in the regulation of mammalian reproduction. Thus, the hypothalamo-pituitary-ovarian axis was shown to require miR-200b and miR-429 to support ovulation.

Triptorelin is an established treatment for central precocious puberty (CPP) as 1- and 3-month formulations. The current triptorelin 22.5 mg 6-month formulation is approved for prostate cancer therapy. This is the first study in patients with CPP. The efficacy and safety of the triptorelin 6-month formulation in CPP were investigated. The primary objective was to evaluate the efficacy in achieving luteinizing hormone (LH) suppression to pre-pubertal levels at month 6. This was an international, non-comparative phase III study over 48 weeks. Eighteen medical centers in the US, Chile and Mexico participated. Forty-four treatment naïve patients (39 girls and five boys) aged at treatment start 2–8 years for girls and 2–9 years for boys with an advancement of bone age over chronological age ≥1 year were to be included. Triptorelin was administered im twice at an interval of 24 weeks. LH, follicle stimulating hormone (FSH) (basal and stimulated), estradiol (girls), testosterone (boys), auxological parameters, clinical signs of puberty and safety were assessed. Forty-one patients (93.2%) showed pre-pubertal LH levels (stimulated LH ≤5 IU/L) at month 6 and maintained LH suppression through month 12. The percentage of patients with LH suppression exceeded 93% at each time point and reached 97.7% at month 12. No unexpected drug-related adverse events were reported. The triptorelin 6-month formulation was safe and effective in suppressing the pituitary-gonadal axis in children with CPP. The extended injection interval may improve compliance and increase comfort in the management of CPP.

Background D-aspartic acid is an amino acid present in neuroendocrine tissues of invertebrates and vertebrates, including rats and humans. Here we investigated the effect of this amino acid on the release of LH and testosterone in the serum of humans and rats. Furthermore, we investigated the role of D-aspartate in the synthesis of LH and testosterone in the pituitary and testes of rats, and the molecular mechanisms by which this amino acid triggers its action. Methods For humans: A group of 23 men were given a daily dose of D-aspartate (DADAVIT ® ) for 12 days, whereas another group of 20 men were given a placebo. For rats: A group of 10 rats drank a solution of either 20 mM D-aspartate or a placebo for 12 days. Then LH and testosterone accumulation was determined in the serum and D-aspartate accumulation in tissues. The effects of D-aspartate on the synthesis of LH and testosterone were gauged on isolated rat pituitary and Leydig cells. Tissues were incubated with D-aspartate, and then the concentration (synthesis) of LH and cGMP in the pituitary and of testosterone and cAMP in the Leydig cells was determined. Results In humans and rats, sodium D-aspartate induces an enhancement of LH and testosterone release. In the rat pituitary, sodium D-aspartate increases the release and synthesis of LH through the involvement of cGMP as a second messenger, whereas in rat testis Leydig cells, it increases the synthesis and release of testosterone and cAMP is implicated as second messenger. In the pituitary and in testes D-Asp is synthesized by a D-aspartate racemase which convert L-Asp into D-Asp. The pituitary and testes possesses a high capacity to trapping circulating D-Asp from hexogen or endogen sources. Conclusion D-aspartic acid is a physiological amino acid occurring principally in the pituitary gland and testes and has a role in the regulation of the release and synthesis of LH and testosterone in humans and rats.

Background Luteinizing hormone (LH) plays a crucial role in the postnatal development and maturation of gonads. Inactivating mutations of the luteinizing hormone beta subunit ( LHB )gene are extremely rare and can result in congenital hypogonadotropic hypogonadism (CHH). Methods We conducted DNA sequencing on an 18-year-old female patient with undetectable LH and clinical symptoms of CHH. Pulsatile GnRH was administered to promote puberty development. In vitro construction of mutant genes, confocal microscopy, and protein functional assays were used to investigate the effects of genetic variants on hormone function and secretion. Experiments were conducted in HEK293T cells to examine the colocalization and dimerization of LH subunits, as well as to measure intracellular and extracellular LH concentrations. Results Compound heterozygous mutations of c.252C>G (p.F84L) and c.364G>A (p.G122S) were found in the patient’s genome. Pulsatile GnRH therapy was effective in promoting puberty development and ovulation. The LH alpha subunit was found to co-localize with both mutant beta subunits after immunofluorescence staining, and immunoprecipitation detected the dimerization of the LH alpha subunit with both mutant beta subunits. Higher intracellular LH concentrations and lower extracellular LH concentrations compared to the wild type indicate secretion dysfunction for LH. Conclusion Compound heterozygous mutations of c.252C>G (p.F84L) and c.364G>A (p.G122S) in the LHB gene may lead to CHH for female patient. These mutations do not impair the expression and dimerization of the alpha and beta subunits, but they do prevent the secretion of LH. The study expands our understanding of the clinical manifestation of LHB gene mutations in females and provides a treatment for these patients.

Abstract Context Glucagon increases energy expenditure; consequently, glucagon receptor agonists are in development for the treatment of obesity. Obesity negatively affects the reproductive axis, and hypogonadism itself can exacerbate weight gain. Therefore, knowledge of the effects of glucagon receptor agonism on reproductive hormones is important for developing therapeutics for obesity; but reports in the literature about the effects of glucagon receptor agonism on the reproductive axis are conflicting. Objective The objective of this work is to investigate the effect of glucagon administration on reproductive hormone secretion in healthy young men. Design A single-blinded, randomized, placebo-controlled crossover study was conducted. Setting The setting of this study was the Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean ± SEM: age 25.1 ± 1.0 years; body mass index 22.5 ± 0.4 kg/m2; testosterone 21.2 ± 1.2 nmol/L) participated in this study. Intervention An 8-hour intravenous infusion of 2 pmol/kg/min glucagon or rate-matched vehicle infusion was administered. Main Outcome Measures Luteinizing hormone (LH) pulsatility; LH, follicle-stimulating hormone (FSH), and testosterone levels were measured. Results Although glucagon administration induced metabolic effects (insulin area under the curve: vehicle 1065 ± 292 min.µU/mL vs glucagon 2098 ± 358 min.µU/mL, P < .001), it did not affect LH pulsatility (number of LH pulses/500 min: vehicle 4.7 ± 0.4, glucagon 4.2 ± 0.4, P = .22). Additionally, there were no significant differences in circulating LH, FSH, or testosterone levels during glucagon administration compared with vehicle administration. Conclusions Acute administration of a metabolically active dose of glucagon does not alter reproductive hormone secretion in healthy men. These data are important for the continued development of glucagon-based treatments for obesity.

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood. Excess anti-Müllerian hormone during pregnancy results in polycystic ovary syndrome-like phenotypes in female offspring, possibly explaining its pathogenesis as well as suggesting a possible therapy.

The production of spermatozoa, a process known as spermatogenesis, is primarily controlled by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-driven testosterone. LH acts on the Leydig cells, stimulating steroid production, predominantly testosterone, and activating critical inter-related spermatogenesis regulatory pathways. Despite evidence that exogenous gonadotropins containing LH activity can effectively restore spermatogenesis in males with hypogonadotropic hypogonadism, the use of these drugs to treat other forms of male infertility is the subject of an ongoing debate. In this review, we delve into the molecular properties and functions of LH activity in spermatogenesis regulation and explore available preparations for therapeutic use. We also examine the evidence regarding the effectiveness of LH-containing drugs in treating specific male infertility conditions and identify the main areas for future research. Our review highlights the critical role of LH in spermatogenesis and emphasizes the potential of LH-containing drugs in treating male infertility. However, further research is required to completely elucidate the mechanisms underlying the effects of LH activity on sperm production and to establish the most effective dosages and treatment durations.