Gonadorelin

Abstract

Patients who menstruate during treatment for hematologic malignancies have a higher risk of heavy vaginal bleeding due to thrombocytopenia caused by malignancy and myelosuppressive chemotherapy. Heavy menstrual bleeding is associated with significant morbidity in this patient population, and menstrual suppression is a standard of supportive care. Options for prophylactic menstrual suppression include gonadotropin-releasing hormone agonists, progestin-only therapy, and combined hormonal contraception. Various factors impact the choice of menstrual suppression agent, including efficacy, presence of emergent acute uterine bleeding, desire for contraception, and presence of thrombotic risk factors. The purpose of this review is to discuss the nuances of available menstrual suppression agents in patients with hematologic malignancies and develop a methodical approach to consider patient-specific factors that impact agent selection.

Abstract

Surge release of luteinizing hormone (LH) from the pituitary is essential for fertility, as it triggers ovulation. Secretoneurin (SN), a conserved peptide derived from secretogranin-2, stimulates LH release, but its relationship to periovulatory changes in classical reproductive hormones remains unclear.

Abstract

Disrupted gonadotropin-releasing hormone (GnRH) secretion patterns can impair fertility as in polycystic ovary syndrome (PCOS).We used prenatally androgenized (PNA) female mice, which recapitulate neuroendocrine abnormalities observed in PCOS patients, to study how changes in GnRH neuron intrinsic properties during development (prepubertal 3-week-old versus adult females) and with PNA treatment shape their postsynaptic response to GABAergic input. The properties of isolated GABAergic postsynaptic currents in GnRH neurons were used to generate representative model conductances of 1, 2, 5, and 10 nS, with decay time constants representing prepubertal and adult mice (7 vs. 10 ms). These conductances were applied to GnRH neurons from each experimental group using dynamic clamp, and response was measured. Neither development nor PNA altered the response of GnRH neurons to small conductances (1 or 2 nS), and these conductances did not initiate action potentials. In response to the 5 nS conductance, dynamic-clamp-induced postsynaptic potentials were larger in 3-week-old controls versus 3-week-old PNA mice at the 7 ms decay time constant and larger than vehicle-treated (VEH) adults at the 10 ms decay time constant. In response to larger conductances, only seven of 78 GnRH neurons from adults generated action potentials, whereas 14 of 73 GnRH neurons from 3-week-old females did. Interestingly, an altered action potential waveform was observed only in 3-week-old PNA females. The changes in GnRH neuron intrinsic properties occurring with development and PNA treatment result in differential responses to the same physiologic GABA input and may contribute to the action potential firing changes previously reported in this model.

Abstract

Background & objectives Though sexual dysfunction are common in individuals with opioid dependence, the relative contribution of hormonal and psychological determinants remains unclear. Studies assessing sexual functioning and sex hormone levels together in this population remain limited. This study aimed to evaluate self-reported sexual dysfunction and sex hormone alterations, and their association with demographic, psychosocial, and hormonal factors in men with opioid dependence, primarily using heroin. Methods In this cross-sectional study, 143 sexually active males (aged 18-50 yr) with opioid dependence were recruited. Sexual functioning was assessed using the international index of erectile function (IIEF-15). Hormonal assays included total testosterone, prolactin (PRL), luteinising hormone (LH), follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulphate (DHEA-S). Descriptive statistics, Spearman's rank correlation with FDR (false discovery rate) correction, and hierarchical multiple regression with bootstrapped confidence intervals (1000 samples) were conducted. A sensitivity analysis restricted to married participants (n=78) allowed inclusion of intimate partner violence as predictor. Results The median age of participants (n=143) was 26 yr [Interquartile range (IQR):24-30], with 93 per cent identifying as heterosexual. Erectile dysfunction (93.7%, n=134), orgasmic dysfunction (95.1%, n=136), low sexual desire (94.4%, n=135), dissatisfaction with sexual intercourse (99.3%, n=142), and premature ejaculation (72%, n=103) were highly prevalent. Hormonal analysis showed low testosterone in 7.7 per cent (n=11), high PRL in 8.4 per cent (n=12), and elevated GnRH in 57.3 per cent (n=82) of participants. Median hormone levels were: Testosterone 20.5 (15.0-27.3) nmol/L, PRL 5.8 (3.5-11.2) ng/mL, and GnRH 160.3 (132.2-178.1) pg/mL. No significant correlations were observed between hormone levels and sexual function. In regression analysis, demographic and psychosocial variables predicted sexual functioning, while hormonal measures did not contribute independently. The final model explained 17 per cent of variance (adjusted R2 = 0.17). Interpretation & conclusion Sexual dysfunction in men with opioid dependence primarily using heroin was driven more by psychosocial and demographic determinants than by hormonal changes. Endocrine alterations were not sufficient to explain the high burden of dysfunction. Addressing sexual health in opioid dependence requires a multifactorial approach, with attention to social and psychological contributors alongside biological assessment.

Abstract

Congenital hypogonadotropic hypogonadism (СНH) is a group of diseases caused by impaired synthesis or secretion of gonadotropin-releasing hormone (GnRH) and gonadotropin hormones. At present, more than twenty genes involved in the development of СНН have been described. In the structure of HGH, the most common forms of the disease are caused by pathogenic variants in genes involved in the ontogenesis, migration and survival of GnRH neurons, whereas pathology of genes involved in the action/transmission of GnRH signals in normally developed GnRH neurons is less common. This article describes a rare variant of СНН as a result of pathogenic variants in the POLR3B gene, occurring in 1.1% of cases of СНН, which is a component of hypomyelinating leukodystrophy 4H and includes hypomyelination, CHН, hypodontia. Identification of the genetic nature of the disease in this patient made it possible not only to establish the cause of CНН, but also to diagnose comorbid conditions.

Abstract

Objective: To evaluate the efficacy and safety of triptorelin acetate microspheres for injection compared with triptorelin acetate for injection in the treatment of endometriosis. Methods: A total of 392 patients with endometriosis were prospectively enrolled from 47 research centers across China between October 25, 2021, and February 14, 2023. Participants were randomly assigned in a 1∶1 ratio to either the experimental group (n=196) or the control group (n=196). Both groups received intramuscular injections of the respective drugs once every 4 weeks for a total of 6 doses. The primary efficacy endpoint was the percentage of subjects with suppressed estradiol levels after treatment. Secondary endpoints included pain relief, amenorrhea rate, changes in ovarian endometrioma diameter, and adverse drug reactions. Results: For the primary efficacy endpoint, the percentages of subjects with suppressed estradiol levels at week 12 in the experimental and control groups were 97.3% (177/182) and 98.4% (181/184), respectively. The rate difference was -1.1% (95%CI: -4.8% to 2.3%), the lower limit of the 95%CI for the rate difference was greater than the non-inferiority margin of -10%. Compared to baseline, visual analog scale (VAS) scores for dysmenorrhea and non-menstrual pelvic pain decreased at all post-treatment time points in both groups, with no statistically significant differences between two groups (all P>0.05). Estradiol, luteinizing hormone, and follicle stimulating hormone levels significantly decreased from baseline at all post-treatment time points in both groups (all P<0.05), with no significant intergroup differences (all P>0.05). No significant differences were observed in amenorrhea rates between two groups at week 8, 12, and 24 post-treatment (all P>0.05). However, the time to menstruation recovery after drug discontinuation was significantly earlier in the experimental group than that in the control group (P=0.003). Carbohydrate antigen 125 levels significantly decreased from baseline at week 12 and 24 post-treatment in both groups (all P<0.001), but no significant intergroup differences were found (all P>0.05). In the experimental group, only the diameter of the right ovarian endometrioma showed a significant decrease from baseline at week 24 post-treatment (P=0.016). In the control group, neither left nor right ovarian endometrioma diameters showed significant changes from baseline (all P>0.05). The overall incidence of adverse drug reactions was similar between the experimental and control groups [77.6% (152/196) vs 78.6% (154/196), respectively; P>0.05]. Conclusions: Triptorelin acetate microspheres for injection is an effective treatment for endometriosis. It could maintain low estrogen levels, consistently alleviate endometriosis-associated pain, achieve a high rate of amenorrhea during treatment, and reduce the size of ovarian endometrioma to some extent, demonstrating a favorable safety profile.

Abstract

Long COVID (LC) may involve endocrine dysfunction; however, the underlying mechanism remains unclear. To examine hypothalamic-pituitary responses in patients with LC, we conducted a single-center retrospective study of patients with refractory LC referred to our University Hospital who underwent anterior pituitary stimulation tests. Between February 2021 and November 2025, 1251 patients with long COVID were evaluated, of whom 207 (19%) had relatively low random ACTH or cortisol levels. Ultimately, 16 underwent anterior pituitary stimulation tests and were included. All tests were performed in an inpatient setting without exogenous steroids. Fifteen patients (six women, mean age 35.6 years) underwent corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH) tests. All patients had mild acute COVID-19, eight had ≥2 vaccinations, and the mean interval from infection was 343 days. Frequent symptoms included fatigue (100%), insomnia (66.7%), headache (60.0%), anorexia/nausea (40.0%), and brain fog (40.0%). Mean early-morning cortisol and 24 h urinary free cortisol were 7.5 μg/dL and 41.0 μg/day, respectively. MRI showed an empty sella in one case. Peak hormonal responses were preserved (ΔACTH 247%, ΔTSH 918%, ΔPRL 820%, ΔFSH 187%, ΔLH 1150%); however, peaks were delayed beyond 60 min in ACTH (13%), LH (33%), and FSH (87%). Notably, significantly delayed elevations remained at 120 min in the responses of TSH (4.1-fold), PRL (1.8-fold), LH (9.3-fold), and FSH (2.8-fold), suggesting possible hypothalamic involvement, particularly in the gonadotropin responses. Additionally, serum IGF-I was lowered (-0.70 SD), while GH response (mean peak 35.5 ng/mL) was preserved by growth hormone-releasing peptide (GHRP)-2 stimulation. Low-dose hydrocortisone and testosterone were initiated for three patients. Although direct viral effects and secondary suppression have been proposed, our findings may suggest that, at least in part, the observed response characteristics are consistent with functional secondary hypothalamic dysfunction rather than irreversible primary injury. These findings highlight the need for objective endocrine evaluation before initiating hormone replacements.

Abstract

Humans and rhesus macaques are known to express two molecular forms of gonadotropin-releasing hormone (GnRH-I and GnRH-II), which appear to differentially contribute to the regulation of the menstrual cycle. Specifically, there is evidence to suggest that GnRH-I is the primary mediator of negative estrogen feedback to the hypothalamus and pituitary gland, while GnRH-II is the primary mediator of the positive feedback that stimulates the preovulatory surge of luteinizing hormone. Therefore, it is plausible that selective silencing of GnRH-II would block ovulation and lay the platform for development of a novel contraceptive. To test this possibility female rhesus macaques were actively immunized against GnRH-II (and/or GnRH-I), and serum estradiol and progesterone concentrations were monitored for an additional ∼2.5 years. Despite multiple booster immunizations every ∼6 weeks, and elevated GnRH antibody titers, none of the animals ceased ovulating (i.e., revealed by monthly peaks of serum progesterone concentrations followed by menstruation). Taken together, these findings question the efficacy of GnRH vaccines as a stratagem for selectively blocking ovulation in humans. However, they do not negate the potential value of pharmacological interventions aimed at selectively silencing GnRH-II function and its involvement in stimulating the preovulatory luteinizing hormone surge.

Abstract

To examined whether body mass index (BMI) affects basal gonadotropin secretion in premenarcheal girls with idiopathic central precocious puberty (ICPP).

Abstract

Fertility preservation (FP) and adequate counseling are crucial for young breast cancer patients in the early setting. We provide a brief summary of FP in young breast cancer patients, including current international guidelines, available FP treatments, and the safety of pregnancy. This review explores embryo/oocyte cryopreservation, ovarian tissue cryopreservation (OTC), and gonadotropin-releasing hormone agonists (GnRHa), along with evidence on temporary endocrine therapy interruption to attempt pregnancy. Despite strong recommendations, FP uptake remains low, underscoring the need for timely multidisciplinary counseling. Literature data underline that pregnancy can be considered after treatment, even for hormone receptor-positive and BRCA mutation-positive patients. Reproductive planning should be integrated into the oncologic treatment, balancing oncologic priorities with patients' reproductive desires.

Abstract

We compared conception rates among Japanese Black cows undergoing ovulation synchronization protocols using intravaginal progesterone-releasing devices (CIDR) across three different treatment durations. Cows received CIDR treatment for 7 days in the Ovsynch (OS) group (n = 40), 8-10 days in the short-extended (SE) group (n = 42), and 11-14 days in the long-extended (LE) group (n = 67). Gonadotropin-releasing hormone (GnRH) was injected concurrently with the CIDR insertion. On the day of CIDR withdrawal (Day 0), all cows received a prostaglandin F2α injection. When estrus signs were visually observed from Days 0 to 2, artificial insemination (AI) was performed concurrent with the GnRH injection. Cows without any estrus signs received GnRH injection on Day 2, followed by timed AI 16-20 h later. Data from 149 AIs performed on 144 cows were analyzed. The LE group tended to show a higher estrus expression rate than the OS group (13.4% vs. 0.0%, respectively). Pregnancy per AI was comparable among all three groups (OS: 47.5%, SE: 47.6%, LE: 50.7%). In conclusion, extending the CIDR treatment duration did not affect the conception rates of Japanese Black cows. In LE group cows, AI following estrus detection is recommended to enhance pregnancy outcomes.

Abstract

About 2 decades ago, researchers discovered that glucagon-peptide 1 (GLP-1) stimulates insulin secretion and can treat type 2 diabetes. Some of the physiological effects of this drug class that allow for glycemic control include delayed gastric emptying, enhanced satiety, and anti-inflammatory effects. Since their discovery, the scope of GLPs has expanded into treatment for obesity, sleep apnea, osteoarthritis of the knees, renal failure, and heart failure across a wide range of drug variations. The aim of this study is to review and evaluate the currently available data on GLP-1 agonist use for the treatment of obesity-associated reproductive dysfunction. This narrative review used targeted searches of terms including "GLP1," "GLP1 receptor agonist," and "GLP1 receptor" in combination with "female," "male," "reproduction," "fertility," "polycystic ovary syndrome," "PCOS," "oral contraceptives," "gastric emptying," "drug interactions," "major congenital anomalies," and "pregnancy" through March 1, 2025. Prescribing information from FDA drug labels was also reviewed. Obesity is strongly associated with reproductive dysfunction in both men and women, with well-documented hormonal, structural, and gamete cell effects. In men, obesity can cause problems like reduced luteinizing hormone, testosterone, semen volume, and sperm count. These can cause diminished fertility through increased inflammation and oxidative stress, and reduced connection between the hypothalamic-pituitary-gonadal axis. Early evidence suggests that GLP-1 improves these pathways, with preclinical research showing action on gonadotropin-releasing hormone and Kiss neurons, remodeling testicular architecture, reduced oxidative stress, and improved testosterone and gonadotropin levels. Clinical studies of men have shown increased luteinizing hormone and follicle-stimulating hormone, improved sexual function, and greater sperm quality. Women have GLP-1 receptors in their ovarian and uterine tissue, and animal models of PCOS show improvements in ovarian follicle development, steroidogenesis, estrous cyclicity, and inflammatory markers. In clinical studies of women with PCOS, GLP-1 agonists improve androgen profiles, increase SHBG, reduce ovarian volume, regulate menstrual cycles, enhance ovulation, and improve both spontaneous and assisted pregnancy rates. Observational data also suggest lower rates of gestational diabetes, hypertensive disorders, preterm birth, and cesarean delivery among women who used GLP-1 agonists before pregnancy, even when matched for BMI, implying additional benefits beyond weight loss. At the same time, preclinical toxicology demonstrates fetal harm, and weight loss during pregnancy is associated with adverse fetal outcomes, underscoring the need for careful preconception management. Current recommendations emphasize counseling on improved fertility potential, possible reduced oral contraceptive efficacy due to altered gastric emptying, and the need for reliable contraception during GLP-1 therapy. Most experts recommend discontinuing long-acting GLP-1 agonists 2 months before attempting conception, though this may lead to weight regain and loss of glycemic control, requiring individualized support. GLP-1 agonists may play a role in treating hypogonadism and infertility in obese men and potentially offer meaningful benefits for women with PCOS. Further research is needed to characterize paternal risks, evaluate GLP-1 effects in women with obesity without PCOS, determine weight-loss thresholds for reproductive benefit, and clarify whether GLP-1 agonists can be safely continued during pregnancy. Long-term registries and strategies to maintain weight after discontinuation will be essential to guide future clinical practice.

Abstract

The objective of this study was to evaluate the effects of exogenous GnRH administration at the beginning of estrus synchronisation in mares during the spring transitional period. Estrus was synchronised using a progesterone releasing intravaginal device (PRID). The PRID was left in the vagina for 10 days, followed by an injection of 0.4 mg of cloprostenol at PRID removal. The GnRH group (n = 32) was subjected to intramuscular administration of 100 μg of the GnRH agonist triptorelin at PRID insertion, while the control group (n = 32) received 1 mL of sterile physiological saline solution. Ovulation was induced by an intramuscular injection of 3000 IU of human chorionic gonadotropin until the dominant follicle reached a diameter of 35 mm. The mares were examined and insemination was performed. Subsequently, insemination was carried out every 12 h until ovulation. Transrectal palpation and ultrasound were carried out 15 days after ovulation to confirm the presence or absence of an embryonic vesicle. The days of ovulation induction and insemination in the control group were more dispersed than in the GnRH group. Compared with the control group, the time of ovulation induction and insemination in the GnRH group were accelerated and concentrated. In summary, GnRH given at the beginning of the estrus synchronisation program significantly increased synchronisation of ovulation in mares; however, it did not increase pregnancy rates.

Abstract

The objective was to evaluate the fertility of Bos indicus cows submitted to an ovulation synchronization protocol without estrogen (E2). In experiment 1, injectable P4 (P4i) was administered 10 days (D-10) before the TAI protocol. On D0, cows received one intravaginal P4 device and estradiol benzoate (EB; Control) or buserelin acetate (GnRH/EC and 2GnRH). On D8, devices were removed, and all cows received eCG and PGF2α. Additionally, cows received estradiol cypionate (EC) on D8 (Control and GnRH/EC) or buserelin acetate on D10 (2GnRH). In Experiment 2, cows in the Control group underwent a protocol similar to Experiment 1. Cows in the GnRH/EC, 2GnRH/48h, and 2GnRH/54h groups were pre-synchronized with an intravaginal P4 device (D-7) and received gonadorelin and an intravaginal P4 device on D0. P4 devices were removed on D8, and all cows received eCG and PGF2α. Furthermore, the GnRH/EC group received EC, and cows in the 2GnRH/48h and 2GnRH/54h groups were administered GnRH 48 h (h) after removal of the P4 device. TAI was performed 48 (2GnRH/48h) or 54h (2GnRH/54h) after removal of the P4 device. In all experiments, the follicular diameter on D8 was greater in cows that received GnRH on D0 (P ≤ 0.01) as well as a greater ovulation rate on D0 (P ≤ 0.01). Furthermore, estrus expression was greater in cows receiving EC (P = 0.001; Exp. 2). P/AI was greater in the Control group (P = 0.001; Exp. 2). In conclusion, removal of estradiol in ovulation synchronization protocols resulted in lower fertility relative to E2-based controls.

Abstract

Kallmann syndrome (KS) is a genetic disorder characterized by impaired reproductive system and olfactory development. This study aimed to identify a novel variant of SEMA3A in a KS patient and explore its potential pathogenic mechanism.

Abstract

The Spotted Babylon (Babylonia areolata) is an economically marine species in Thailand and other Asian countries. Due to the high demand for its meat, improving aquaculture practices for this species is essential. Regarding the lack of neuroendocrine control of reproduction in this species, we performed transcriptome analysis of the central nervous system and ovaries, and we searched against the reported genome of this animal species to find out the neurohormones. Here, we reported the identification of corazonin (ba-Crz)-like and gonadotropin-releasing hormone (ba-GnRH)-like mRNAs in B. areolata. The ba-Crz-like mRNA encoded mature ba-Crz-like peptide as QNYHYSNGWHP. Two ba-GnRH-like mRNAs encoded ba-GnRH-I-, and ba-GnRH-II-like peptides containing active peptides as QIHFSPTWGT and QIHFSHSWGT. Two introns were found in the ba-Crz-like gene while one intron was present in each ba-GnRH-like gene. These three peptides were phylogenetically placed in the molluscan Crz and GnRH clades. RT-PCR of these three mRNAs revealed their ubiquitous expressions across various organs, with all three predominantly expressed in ganglia, which was further confirmed by in situ hybridization of the cerebral ganglia. Immunohistochemistry showed positive signals for the Crz-like peptide in both the CNS and ovaries. To examine expression across ovarian cycle, the ba-Crz-like, and ba-GnRH-I-like mRNAs were consistently expressed in the CNS and ovaries of both immature and mature female snails, while the ba-GnRH-II-like mRNA significantly reduced its expression in the CNS of mature snails. Conclusively, this study was preliminary to report on the existence of GnRH/AKH/Crz peptides in the B. areolata, Further characterization of their receptors and biological functions is ongoing to ensure the GnRH, AKH, and Crz identification in this species.

Abstract

Breast cancer is one of the most common malignant tumors among women, with approximately 50-60 % of cases overexpressing the luteinizing hormone-releasing hormone receptor (LHRH-R), making it an important therapeutic target. To overcome the limitations of conventional chemotherapy, this study designed and synthesized a novel LHRH-R-targeting peptide, LHRH-III', based on the structure of natural LHRH-III with rational structural modifications. Fluorescence labeling experiments demonstrated that this peptide binds to 4T1 cells with an affinity comparable to or superior to that of the classical LHRH-R targeting peptide [D-Lys6]-LHRH-I, while its cellular internalization efficiency was increased by more than 6-fold. Subsequently, LHRH-III' was conjugated to camptothecin (CPT) or doxorubicin (Dox) via a disulfide bond linker to construct peptide-drug conjugates (PDCs). Among these conjugates, LHRH-III'-SS-CPT exhibited more efficient glutathione (GSH)-responsive drug release than LHRH-III'-SS-Dox. In antitumor evaluations, LHRH-III'-SS-CPT demonstrated significant antitumor activity both in vitro and in vivo. Biodistribution studies revealed that hepatic accumulation of LHRH-III' was only one-sixth of that observed with the control peptide [D-Lys6]-LHRH-I, substantially reducing the risk of potential hepatotoxicity caused by off-target accumulation. In summary, the novel targeting peptide LHRH-III' developed in this study exhibits excellent targeting capability for breast cancer. The lead PDC based on LHRH-III' (LHRH-III'-SS-CPT) demonstrate promising antitumor efficacy and low toxicity, highlighting their potential application value as a targeted therapeutic strategy for breast cancer.

Abstract

The objective of this study was to evaluate the effect of insemination timing with sex-sorted semen on fertility in dairy cows subjected to a timed artificial insemination (TAI) protocol. A total of 611 Holstein cows (46 ± 3 DIM) were enrolled and subjected to a presynchronized Ovsynch protocol (G7G; PGF₂α-2d-GnRH-7d-GnRH-7d-PGF₂α-56 h-GnRH), and randomly allocated to four treatment groups. The control group (CONV-14, n = 154) was inseminated with conventional semen 14 h after the final GnRH, while cows in the sex-sorted semen groups were inseminated at 14 (SS-14, n = 152), 18 (SS-18, n = 153), or 22 h (SS-22, n = 152) after the same treatment. The same bull was used for all inseminations. All cows were examined by ultrasonography to individually evaluate ovarian responses to the protocol and pregnancy status. No significant differences were observed among groups in body condition score, milk yield, cyclicity at the beginning of the protocol, response to the protocol, or follicle size at TAI. Pregnancies per artificial insemination were similar with 50.0% (77/154) in the CONV-14 group, 42.8% (65/152), 48.4% (74/153), and 43.4% (66/152) in the SS-14, SS-18, and SS-22 groups, respectively. No significant difference was observed in embryonic loss rates among groups: 5.2% in CONV-14, 9.2% in SS-14, 4.1% in SS-18, and 13.6% in SS-22, while SS-22 was numerically higher (~7%) than the average of the other SS groups. Overall, conception rates were higher in cows responding to the first GnRH than in non-responders (49.7% vs. 32.3%, p < 0.0005), with a significant difference observed only in the CONV-14 and SS-18 groups (p < 0.005). Estrous expression during TAI was associated with higher conception rates in the CONV-14 group (75.0% vs. 45.4%, p = 0.008), while no such difference was detected in the combined SS groups (51.8% vs. 43.3%). However, the conception rate in the SS-22 group (36.7%) was distinctly lower (p < 0.02) than in other SS groups (53.6% in SS-14, 68.0% in SS-18). In conclusion, contrary to the expectation that advancing insemination closer to ovulation with sex-sorted semen would be advantageous, fixed time insemination at 22 h within the TAI program showed poorer outcomes compared to 18 h, which achieved a relative conception rate of 97% compared with conventional semen. It was also concluded that TAI at 22 h should not be recommended in cows exhibiting estrus on the day of insemination.

Abstract

This study aimed to reconstruct the hypothalamic-pituitary axis using an organ-on-a-chip (OOC) model and to evaluate the modulatory role of phoenixin-20 (PNX) in the regulation of the gonadotrophic axis in sheep. Sixteen female Polish Merino lambs were used as tissue donors to create microfluidic chips containing paired hypothalamic and pituitary slices connected via perfused channels. This system enabled continuous medium flow and maintenance of functional neuroendocrine interactions under ex vivo conditions. The OOC platform was used to analyze changes in the expression of gonadotropin-releasing hormone (GnRH), kisspeptin (Kiss), neurokinin B (NKB), and prodynorphin (pDYN) in the hypothalamus, as well as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) expression and secretion in the pituitary. PNX treatment significantly increased hypothalamic GnRH expression, while the blockade of neuropeptide Y receptors (NPY1R and NPY5R) diminished this response, suggesting that PNX effects are at least partially mediated through NPY-dependent pathways. Moreover, PNX altered the transcription of Kiss, NKB, and pDYN, key components of the GnRH pulse generator, and modulated LHβ mRNA expression in the pituitary. Changes in the LH and FSH concentrations further supported a receptor-specific mechanism of PNX action. The developed hypothalamo-pituitary OOC model proved valuable for studying neuroendocrine control of reproduction. This system offers a physiologically relevant and ethically sustainable alternative to in vivo experiments, enabling precise investigations of molecular and hormonal mechanisms within the gonadotrophic axis.

Abstract

This study analyzed clinical pregnancy outcomes in patients undergoing in vitro fertilization-embryo transfer with donor sperm (IVF-D) using different ovulation induction protocols, to provide reference data for selecting appropriate protocols.

Abstract

While neoadjuvant endocrine therapy (NET), with or without a CDK4/6 inhibitor, is an established treatment option for estrogen receptor-positive breast cancers, optimal patient selection and second-line treatment for non-responders remain uncertain.

Abstract

MED12 exon 2 mutation is the most frequent mutation associated with uterine leiomyomas. MED12 wild-type leiomyomas have a higher growth potential than mutant leiomyomas, suggesting that the mutation limits leiomyoma growth. MED12 forms a complex with CDK8 and is involved in the phosphorylation of RNA polymerase II, playing a role in transcriptional regulation. However, its mechanism of action in leiomyoma growth is not clear. We aimed to clarify the relationship between MED12 mutation status, response to gonadotropin-releasing hormone (GnRH) agonist treatment, and CDK8 activity in leiomyomas. We also examined the effects of CDK8 inhibitors on primary cultured uterine leiomyoma cells. We classified 44 surgically removed uterine leiomyomas into four groups according to GnRH agonist use and MED12 mutation status. CDK8 was co-immunoprecipitated from leiomyoma tissue extracts using MED12 antibody to test its kinase activity in vitro, and the amount of phosphorylated substrate was measured. Cell proliferation and apoptosis of primary cultured MED12 wild-type leiomyoma cells were evaluated in the presence of a CDK8 inhibitor and sex steroid hormones. Of the 44 leiomyomas tested, 11 MED12 wild-type leiomyomas without preoperative GnRH agonist treatment had significantly higher CDK8 activity than nine GnRH agonist-treated MED12 wild-type leiomyomas and 15 leiomyomas with MED12 mutations without GnRH agonist treatment. Treatment of primary cultured MED12 wild-type cells with CDK8 inhibitors significantly inhibited cell growth and increased apoptosis. MED12 wild-type leiomyoma cells without GnRH agonist treatment showed high CDK8 activity, and inhibition of CDK8 activity suppressed cell growth in vitro.

Abstract

Bleeding complications significantly contribute to morbidity and mortality of patients with hematologic malignancies. Although there is some evidence for treatment and prevention of uterine bleeding in patients with cancer, there is no specific guidance used universally for hematologic malignancies. This study evaluated prescribing patterns of agents used for treatment and prevention of uterine bleeding in patients receiving intensive chemotherapy for hematologic malignancies to provide guidance for a standardized approach for treatment and prevention of uterine bleeding within a single health system.

Abstract

Hormonal contraceptives modulate the hypothalamic-pituitary-ovarian (HPO) axis; however, underlying mechanisms and differences between contraceptives are underexplored. The Women's Health Injectable Contraception and HIV trial randomised 521 women to intramuscular depot medroxyprogesterone acetate (DMPA-IM) or norethisterone enanthate (NET-EN) and showed similar decreased estradiol levels, but more amenorrhea for DMPA-IM users. This secondary study excluded for misreporting contraceptive use for 128 participants (DMPA-IM n = 65; NET-EN n = 63). Peripheral blood serum collected at initiation and one week after the 24-week injection (25W), at peak progestin levels, was analysed for gonadal steroids, progestins and peptide hormones. While no changes were detected in peripheral gonadotropin-releasing hormone levels, DMPA-IM decreased luteinising hormone (LH) less than NET-EN. DMPA-IM increased, while NET-EN decreased follicle-stimulating hormone (FSH). Both contraceptives substantially decreased gonadal steroid levels, more so in NET-EN users for testosterone and estradiol. Post-menopausal-like hypoestrogenic effects were greater than previously reported, consistent with the substantial reduction in LH levels. Whether reduced LH levels are due to direct pituitary, hypothalamic, or supra-hypothalamic effects by progestins, is unclear. MPA, unlike NET, increased fsh expression in LβT2 cells, likely via the glucocorticoid receptor, consistent with direct effects on the pituitary by MPA in women. Amenorrhea associated in a time-varying manner with MPA and HPO hormone levels and LH/FSH, for DMPA-IM but not NET-EN users. HPO hormone profiles differ between DMPA-IM and NET-EN users and compared to pre- and post-menopausal women. Mechanisms affecting amenorrhea likely differ between contraceptives, with lower 25W LH/FSH being consistent with more amenorrhea for DMPA-IM.

Abstract

This study aimed to analyze the effect of progesterone (P) levels on the human chorionic gonadotropin (hCG) trigger day and the progesterone on hCG day-to-basal progesterone (PhCG/Pbasal) ratio on pregnancy outcomes in patients with a normal ovarian response undergoing fresh embryo transfer in a gonadotropin-releasing hormone antagonist (GnRH-ant) cycle.

Abstract

Suppression of an LH surge is fundamental to successful oocyte retrieval after controlled ovarian stimulation. This study evaluates the efficacy and cost-effectiveness of progestin-primed ovarian stimulation (PPOS) using oral medroxyprogesterone acetate in fertility preservation cycles. The design is a retrospective single-centre study (January 2022-August 2023) comparing two ovarian stimulation protocols: PPOS and the gonadotrophin-releasing hormone antagonist (GnRHant) protocols. Cycles began at any time of the menstrual cycle. The primary outcome was the number of metaphase II oocytes retrieved. Secondary outcomes included total oocytes retrieved, maturity ratio, stimulation duration, incidence of premature LH rise/ovulation events, and the cost of medication used to prevent ovulation. The study included 125 fertility preservation cycles: 54 in the PPOS group and 71 in the GnRHant group. Median body mass index, antral follicle count, and anti-Mullerian hormone levels were comparable between the two groups. The median age was younger in the PPOS group; 28 years vs. 32 years, p = 0.03. Mature oocyte retrieval was similar; mean 9.33 [SD 5.87] vs. 8.97 [SD 5.44], p = 0.73. No premature LH rises occurred in either group. Secondary outcomes showed no significant differences, except for the cost of medication used to prevent ovulation. The PPOS protocol was considerably more cost-effective, by achieving a 98.06% cost reduction (medroxyprogesterone acetate, mean £4.38 [SD, £1.10] vs cetrorelix acetate £226.2 [SD £64.36], p= <0.0001. PPOS is a practical, cost-effective strategy for fertility preservation. Its appeal lies in its patient-centric focus, with a less invasive injection-based administration, while maintaining comparable effectiveness and significant cost reduction compared with the GnRH antagonist ovarian stimulation protocol.

Abstract

Selective breeding of broilers has significantly improved growth rates, muscle mass, and feed efficiency and may have influenced the neuroendocrine systems that regulate growth and metabolism. Embryonic development represents one-third of the life of a modern broiler. To assess the impact of genetic selection on the neuroendocrine regulation of growth and metabolism during embryonic development, we examined mRNA expression of growth-related genes in the hypothalamus and anterior pituitary of two chicken breeds: the modern Ross 708 broiler and the Athens Canadian Random Bred (ACRB) line, the oldest established strain for meat-type chickens. Hypothalami and pituitary glands were dissected from embryos at days 10, 12, 14, 16, and 18 of incubation (n = 4 for each combination of breed, age, and gender). Levels of mRNA for each target gene were quantified using reverse transcription-quantitative PCR. In the adrenocorticotropic axis, pituitary corticotropin-releasing hormone receptor 1 mRNA levels were influenced by the interaction of breed, age, and gender (P < 0.05). In the thyrotropic axis, pituitary thyroid-stimulating hormone β-subunit mRNA levels were affected by the interaction of breed, age, and gender (P < 0.05). In the somatotropic axis, mRNA levels of hypothalamic somatostatin were higher in ACRB than Ross, whereas overall pituitary growth hormone mRNA levels were greater in Ross than ACRB (P < 0.05). Pituitary growth hormone-releasing hormone receptor 2 and pituitary adenylate cyclase-activating polypeptide receptor 1 were influenced by the interaction between breed and age (P < 0.05). In the gonadotropic axis, hypothalamic gonadotropin-releasing hormone 1 and gonadotropin-inhibiting hormone were influenced by breed, age, and gender, while mRNA levels of pituitary follicle-stimulating hormone β-subunit were affected by the interaction between breed and age (P < 0.05). Hypothalamic agouti-related peptide, neuropeptide Y, and proopiomelanocortin mRNA levels were higher in ACRB than Ross in females (P < 0.05). These findings indicate that genetic selection of broilers has altered the adrenocorticotropic, somatotropic, thyrotropic, and gonadotropic axes, as well as hypothalamic control of appetite and metabolism during embryonic development.

Abstract

Background and Objectives: To evaluate the impact of gonadotropin-releasing hormone agonist (GnRHa) triggering compared to human chorionic gonadotropin (hCG) triggering on frozen-thawed and fresh embryo transfer outcomes in patients with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF). Materials and Methods: This retrospective cohort study analyzed 267 IVF cycles of 261 PCOS patients treated with GnRH antagonist protocols. Patients were divided into three groups: GnRHa-triggered frozen-thawed embryo transfer (ET) (n = 126), hCG-triggered frozen-thawed ET (n = 68), and hCG-triggered fresh ET (n = 73). Baseline characteristics, stimulation parameters, and cycle outcomes were compared between groups. A binary logistic regression analysis was established to identify independent predictors of clinical pregnancy. Results: The GnRHa-triggered group had significantly higher numbers of retrieved oocytes, mature (MII) oocytes, and fertilized oocytes compared to both hCG-triggered groups (p < 0.001). The number of obtained embryos and frozen embryos (good-quality embryos) was highest in the GnRHa group (p < 0.001). However, clinical pregnancy rates were comparable between the groups with a similar number and grade of transferred embryos (32.53%, 38.23%, and 32.87%, respectively). Multivariate regression analysis revealed that the grade of the transferred embryo was a significant predictor of clinical pregnancy (p = 0.034). Conclusions: This study provides insights into different triggering strategies for final oocyte maturation in PCOS patients. GnRH-agonist-triggered frozen-thawed cycles showed comparable clinical pregnancy outcomes to those of hCG-triggered cycles, with a potentially lower OHSS risk. The findings suggest that individualized triggering approaches based on patient characteristics and OHSS risk may be beneficial for PCOS patients undergoing IVF.

Abstract

The final trigger of oocyte maturation is a pivotal step in assisted reproductive technology (ART). Different molecules and protocols-including human chorionic gonadotropin (hCG), gonadotropin-releasing hormone agonists (GnRHa), the dual trigger, the double trigger, and emerging agents such as kisspeptin-have been investigated to optimize oocyte competence, embryo development, and pregnancy outcomes while minimizing the risk of ovarian hyperstimulation syndrome (OHSS). HCG remains the most widely used trigger, but its pharmacological profile is associated with a significant risk of OHSS. GnRHa has emerged as an alternative in antagonist cycles, abolishing the risk of severe OHSS but often requiring tailored luteal phase support. Several strategies, including hCG, GnRHa, and combined approaches, have shown improvements in specific outcomes such as the oocyte maturity (MII) rate, fertilization rate, embryo development parameters, and, in selected contexts, a reduction in OHSS risk. Kisspeptin represents a promising option; however, its use remains predominantly within the research setting, with clinical application still limited to early-phase or highly selected studies. Beyond the choice of molecule, the timing of trigger administration-adjusted to follicle size, estradiol concentrations, and progesterone levels-also influences oocyte competence and subsequent clinical outcomes. Triggering final oocyte maturation remains a multifaceted decision that should be individualized according to patient characteristics, ovarian response, and risk of OHSS. Although hCG remains the historical reference standard, accumulating but heterogeneous evidence suggests that GnRHa-based strategies, including dual-trigger protocols, may improve specific outcomes in selected patient subgroups. However, results across trials are inconsistent, particularly in poor responders, and any exposure to hCG maintains a residual risk of OHSS. Kisspeptin represents a promising but still experimental option, with current data largely limited to early-phase clinical studies in highly selected high-risk populations. Well-designed randomized trials are required to clarify the true impact of these strategies on live birth, to refine timing and dosing, and to better define which patients are most likely to benefit.

Abstract

Ovarian cancer remains one of the most lethal gynecologic malignancies and requires more effective and targeted treatment strategies. Luteinizing hormone-releasing hormone (LHRH), or gonadotropin-releasing hormone (GnRH), receptors are expressed in approximately 80% of ovarian tumors, representing a promising target for targeted drug delivery. This narrative review aimed to explore the development and advancements of LHRH-receptor targeted therapies in ovarian cancer. A bibliographic search was performed using PubMed, Scopus, Google Scholar, and Web of Science. The search strategy included studies on LHRH-peptide drug delivery systems and LHRH-conjugate nanosystems. Literature search covered in vitro studies, preclinical models, and ongoing clinical trials from 2000 to 2025. A total of 19 studies were included for peptide-drug delivery, and 30 studies were included for LHRH-conjugated nanosystems. Overall findings demonstrated enhanced preclinical efficacy, achieving ~50-80% tumor-growth inhibition and 2-4-fold higher cellular uptake, alongside reduced systemic toxicity. Early clinical studies, although limited, reported an overall response/disease-control rate of approximately 50%, supporting improved tumor accumulation of drugs, small interfering RNA (siRNA), and diagnostic agents. Ovarian cancer-specific therapy, targeting LHRH receptors, represents a promising strategy to enhance therapeutic outcomes. Further efforts in preclinical and clinical research are essential to refine personalized treatments and integrate them with a combination of therapies.