Search Results (735)

Background/Objectives: Androgen deprivation therapy (ADT) is the mainstay of prostate cancer treatment, especially in advanced disease. In particular, the gonadotropin-releasing hormone agonists (aGnRH) reduce the production of gonadotropin and, therefore, of testosterone. In about 10% of patients, the non-pulsatile stimulation of GnRH receptor initially causes a surge in LH and testosterone, defined as the “flare-up phenomenon”, leading to increased bone pain, spinal cord compression, bladder outlet obstruction and cardiovascular issues. To mitigate this effect, combining a first-generation antiandrogen agent (FGA) with aGnRH is recommended. However, second-generation anti-androgens, such as apalutamide, bind selectively and irreversibly to the androgen receptor (AR), exhibiting a more efficient inhibition of the AR pathway. Methods: This is a descriptive retrospective study of 27 patients (pts) with mHSPC, treated at a single center (“Santa Maria delle Grazie” Hospital in Pozzuoli, ASL Napoli 2 Nord, Italy) between June 2022 and April 2024. Patients received apalutamide monotherapy for 14 days followed by continuous combination with aGnRH plus apalutamide. Serum PSA and testosterone levels were measured at baseline, at day 14 (after 13 days of apalutamide monotherapy), at day 28 (after an additional 15 days of apalutamide plus a aGnRH), and at day 60. Results: PSA levels decreased from a mean of 45.2 (±63.1) ng/mL at baseline to a mean of 12.6 (±23.4) ng/mL at day 14 and to 3.3 ng/mL (±6.0) at day 28 of treatment. After 14 days of apalutamide monotherapy, 21 patients (77.8%) achieved a >50% PSA reduction and 4 (14.8%) a >90% PSA reduction. The number of patients with undetectable PSA was one (3.7%) at day 14, two (7.4%) at day 28, and nine (33.3%) at day 60. The mean serum testosterone levels were 6.56 (±4.46) ng/mL at baseline, 6.58 (±4.42) ng/mL at day 14, and 2.40 (± 3.38) ng/mL at day 28. No significant difference in PSA and testosterone level reduction during treatment emerged between subgroups of patients with low- vs. high-volume disease. Conclusions: Apalutamide alone is a viable option for mitigating the flare-up phenomenon, avoiding first generation anti-androgen therapy, and it can achieve rapid and deep biochemical control. Full article

Objective: This retrospective observational study evaluated the efficacy and safety of an ovarian stimulation protocol for embryo banking that involves continuous administration of clomiphene citrate (CC) in combination with gonadotropins, without the use of GnRH antagonists. Methods: Conducted at the Serum IVF Clinic in Athens, Greece, the study included 250 women aged 25–45 who underwent IVF for embryo banking. The protocol involved administering 150 mg of CC daily from day 2 of the menstrual cycle until the day before hCG trigger, alongside 150 IU/day of Meriofert. Outcomes assessed included oocyte yield, fertilization rates, incidence of ovarian hyperstimulation syndrome (OHSS), and hormonal correlations. Comparative and regression analyses explored differences between age groups and predictors of success. Results: The protocol demonstrated a favorable safety profile with no cases of OHSS and yielded a mean of 10.25 oocytes per patient. Group analysis showed significantly more oocytes retrieved in women under 40 (mean: 12.5) versus those over 40 (mean: 8.43), while fertilization rates were paradoxically higher in the older cohort (59.16% vs. 30.68%, p < 0.0001). Regression models revealed basal FSH to be a significant inverse predictor of oocyte yield, but it was positively associated with fertilization rate. Continuous CC use effectively suppressed premature LH surges without compromising oocyte or embryo quality, allowing flexible and cost-effective stimulation with minimal monitoring. Conclusions: Continuous administration of clomiphene citrate in combination with gonadotropins presents a promising, antagonist-free ovarian stimulation protocol for embryo banking. The approach is economically efficient, reduces monitoring requirements, and maintains safety and effectiveness and is particularly notable in women over 40. Further studies are warranted to validate these findings and refine protocol mechanisms. Full article

Background/Objectives: The effect of metformin on the secretory function of thyrotropic cells is sex-dependent. The current study aimed to investigate whether the impact of this drug on activity of the hypothalamic–pituitary–thyroid axis in women is impacted by the androgen status of patients. Methods: The study population included 48 levothyroxine-naïve reproductive-aged women with subclinical hypothyroidism and prediabetes receiving 3.0 g of metformin daily. Women with (n = 24) and without (n = 24) polycystic ovary syndrome were matched for age, insulin sensitivity, TSH, and reasons for thyroid hypofunction. Circulating levels of glucose, glycated hemoglobin, insulin, TSH, thyroid hormones, gonadotropins, androgens, estradiol, SHBG, prolactin, ACTH, and IGF-1 were measured before metformin treatment and six months later. Results: At entry, women with and without polycystic ovary syndrome differed in LH, LH/FSH ratio, androgens, and estradiol. The decrease in TSH, fasting glucose and glycated hemoglobin, and the improvement in insulin sensitivity were less pronounced in women with than in women without polycystic ovary syndrome. In each group, there were no differences in the impact on TSH and thyroid hormones between patients with subclinical hypothyroidism of autoimmune and non-autoimmune origin. The changes in TSH inversely correlated with total testosterone and free androgen index. Only in women with coexisting polycystic ovary syndrome, did metformin slightly reduce LH, LH/FSH ratio, testosterone, and free androgen index. Conclusions: The results suggest that concurrent polycystic ovary syndrome attenuates metformin action on TSH secretion, which can be explained by increased androgen production. Moreover, the drug seems to alleviate PCOS-associated changes in the activity of the reproductive axis. Full article

Background: Uterine fibroids (UFs) and endometriosis are gynecological conditions that significantly increase morbidity among women of reproductive age. Relugolix, a novel gonadotropin-releasing hormone receptor antagonist, is approved in combined therapy for the management of symptoms related to these disorders. However, its potential impact on bone mineral density (BMD) and osteoporosis risk should be considered when using a gonadotropin-releasing hormone (GnRH) antagonist. This systematic review aims to evaluate the effects of daily relugolix intake in monotherapy and combination therapy on BMD, ensuring safe long-term management. Methods: A systematic literature review was conducted following PRISMA 2020 guidelines. Searches were performed in PubMed, Medline, and the Cochrane Library. Relevant clinical guidelines from international societies were also reviewed. Studies assessing the impact of relugolix on BMD were selected, and data on treatment efficacy, adverse effects, and bone health outcomes were synthesized. Results: Relugolix monotherapy has been associated with significant BMD loss due to its potent estrogen-suppressing effect. To mitigate this, combination therapy with estradiol and norethisterone acetate has been developed. Although initial monotherapy before transitioning to combination therapy results in transient BMD reduction, clinical trials have demonstrated that relugolix combination therapy maintains BMD over two years while effectively reducing endometriosis- and UF-related symptoms. Conclusions: Relugolix combination therapy is an effective and well-tolerated treatment for UFs and endometriosis, minimizing the risk of hypoestrogenism-related bone loss while maintaining clinical benefits. Although monotherapy may lead to transient BMD reduction, combination therapy appears to stabilize bone health. Full article

Objectives: Research on the immunocastration vaccine is of great significance for animal management. In this study, the gonadotropin-releasing hormone (GnRH) ferritin nanoparticle vaccine was constructed using Spy Catcher-Spy Tag (SC-ST) as a delivery system; Methods: The Spy Catcher was constructed to fuse with the expression vector pET-30a-SF of ferritin nanoparticles. Two polypeptides, STG1: Spy Tag-GnRH I-PADRE and STG2: Spy Tag-GnRH I-GnRH II, coupled to SF in vitro to form two nanoparticles, were designed and synthesized to detect castration effects in mice. We mixed them with the adjuvant MONTANIDE ISA 206 VG to explore the adjuvant’s effect on immunogenicity; Results: All immunized groups produced anti-GnRH specific antibodies after the second immunization, which was significantly higher in the immunized group and the combined adjuvant group than in the control group, and the immune response could still be detected at the 12th week. The concentrations of testosterone, follicle-stimulating hormone, and luteinizing hormone in serum were significantly decreased. The number of sperm in the epididymis of mice in each immune group was significantly reduced, and the rate of sperm deformity was high; Conclusions: The two ferritin-based GnRH nanoparticles developed in this study can significantly cause testicular atrophy, decreased gonadal hormone concentration, decreased sperm count, and increased deformity rate in male mice. These findings provide experimental evidence supporting their potential application in animal immunocastration. Full article

Testicular germ cell tumors (TGCTs) are the most common malignancies affecting young men between the ages of 14 and 44, accounting for about 95% of all testicular cancers. Despite being relatively rare compared to other cancers (~3.0 cases per 100,000 population, with high worldwide variability), TGCTs’ incidence is increasing, particularly in industrialized countries. The initial phase of TGCT diagnosis is performed by detecting in the blood the presence of three proteins, i.e., alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG). Despite these proteins being defined as markers of TGCTs, they present limitations in specificity. Indeed, AFP is not elevated in pure seminomas; LDH serum levels can be elevated in other conditions, such as liver disease or tissue damage, and hCG can be elevated in both seminomas and non-seminomas, reducing its ability to differentiate between tumor types. However, the existence of hCG variants, characterized by distinct glycosylation profiles that are differentially expressed in TGCT types and subtypes, may increase the diagnostic and prognostic potential of this hormone. Furthermore, emerging molecular biomarkers, including miRNAs and tumor cells-related epigenetic status, may offer new promising alternatives to improve diagnostic accuracy. Nonetheless, standardized diagnostic protocols still need to be implemented. Finally, understanding the biological roles of hCG isoforms and their “canonical” (e.g., LHCGR) and “non-canonical” (e.g., TGF-βR) receptor interactions may help in understanding tumor biology and therapeutic targeting. Full article

Seasonal reproduction in sheep reduces reproductive efficiency. Melatonin (MT) plays a crucial role in reproductive processes. The purpose of this study was to assess the effects of a 5-day MT implant pretreatment on estrus synchronization and reproductive performance in sheep during seasonal anestrus. A total of 40 multiparous Mongolian sheep were selected and randomly divided into two groups. In the MT group (n = 20), the ewes received an MT implant for 5 days, and then, they were given a progesterone (P4)-containing vaginal sponge for 14 days with equine chorionic gonadotropin (eCG) administered (330 I.U. per ewe; I.M.) at sponge removal. Control (CON) ewes (n = 20) were similarly treated but did not receive MT implants. The results demonstrated that MT implantation significantly improved serum levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GSH-Px), increased post-ovulatory luteal diameter and serum P4 levels, and reduced ovarian apoptosis. Compared with the CON group, the MT group showed significantly higher pregnancy (68.23% vs. 50.59%) and lambing rates (63.53% vs. 47.06%; number of lambed ewes/number of total ewes) following cervical-timed artificial insemination. Ovarian transcriptome analysis revealed 522 differentially expressed genes (DEGs) in the MT group compared with the CON group, including 355 upregulated and 167 downregulated DEGs. In addition, MT significantly enhanced proliferation and inhibited apoptosis in cultured granulosa cells (GCs) and luteal cells (LCs) in vitro. Moreover, it enhanced the antioxidant capacity of GCs and LCs probably by activating the NRF2 signaling pathway as well as stimulating steroid hormone synthesis. In conclusion, MT implantation 5 days before applying the conventional P4-eCG protocol enhances ovine reproductive outcomes during seasonal anestrus. MT implantation has a beneficial role on the growth and function of ovarian cells. These findings offer novel evidence supporting the functional role of MT in mammalian reproduction, and would be informative for optimizing estrus synchronization in sheep. Full article

Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism (HH) characterized by gonadotropin-releasing hormone (GnRH) deficiency and anosmia due to defective neuronal migration. While traditionally considered irreversible, cases of spontaneous improvement of HH have been reported, suggesting residual GnRH neuronal function in some individuals. We present a case of a 29-year-old man with KS who exhibited spontaneous recovery of endogenous testosterone production following the cessation of long-term androgen therapy without the use of alternative hormonal agents. After ceasing testosterone therapy for several months, the patient’s total testosterone levels normalized (407–424 ng/dL), accompanied by increased secondary sexual characteristics, stable gonadotropin levels, and normal testicular volume. Persistent anosmia was noted, suggesting that restoration of reproductive endocrine function can occur independently of olfactory recovery. Genetic testing identified heterozygous mutations in PCSK1 and HS6ST1, genes implicated in GnRH regulation and KS pathogenesis. This case highlights the potential role of genetic variation in spontaneous HH improvement and underscores the need for individualized management strategies, including periodic reassessment of gonadal function and fertility potential. Further research is needed to elucidate the mechanisms driving spontaneous HH improvement, identify predictive biomarkers of reversibility, and explore therapeutic strategies that may promote endogenous GnRH activity in select patients with KS. Full article

This study investigated the effects of dietary Gonadotropin-releasing hormone (GnRH) and domperidone on the reproductive performance of Devario devario during a 40-day trial. Five treatment groups received varying doses of GnRH (100, 50, 25, 12.5 µg/kg body weight) in combination with domperidone (50, 25, 12.5, 6.25 mg/kg body weight), embossed in a gel-based diet alongside a control group without the exogenous hormones. Reproductive performance was examined by measuring the gonadosomatic index, fecundity, reproductive hormone levels, and histological features of the gonads, blood parameters, and antioxidant enzyme activity. The T1 group (100 µg GnRH + 50 mg domperidone) exhibited the highest GSI in both sexes. The histological analysis of testes from T1, T2 (50 µg GnRH + 25 mg domperidone), and T3 (25 µg GnRH + 12.5 mg domperidone) groups revealed an increased presence of late-stage spermatids and spermatozoa. In females, the T2 group produced the highest proportion of advanced-stage oocytes and demonstrated the greatest absolute fecundity (1300 ± 23 eggs). However, the control group showed the highest fertilization and hatching rates. Testosterone levels were significantly elevated in the T3 group, while vitellogenin levels increased in the T1 and T2 groups. Antioxidant enzyme activity varied, with the T1 group displaying higher superoxide dismutase activity in gills and liver, and the T2 group showing increased SOD activity in muscle and brain. Improvements in haematological parameters were observed across all treatments. These results suggest that an optimal dose of 50 µg GnRH + 25 mg domperidone can enhance reproductive performance in D. devario. Full article

Oocytes and cumulus cells undergo meiotic resumption and proliferation via gonadotropins and growth factors during maturation, and various small G proteins are activated when COCs undergo physiological changes. This study investigated the influence of gonadotropins and growth factors on Ras and its GTPases during porcine COC maturation. Unmatured COCs were treated with FSH, LH, or EGF for 44 h. The mRNA expression levels of the Ras subfamily (H-Ras, K-Ras, N-Ras, and R-Ras), its GTPases (RASA1 and SOS1), and proliferation factors (ERK, CCNB1, and Cdc2) were analyzed using RT-PCR. In contrast to other Ras subfamilies, R-Ras expression is upregulated during COC maturation. We evaluated the effects of FSH, LH, and EGF at various concentrations that most effectively regulated the expression of R-Ras and GTPases. The results demonstrated that 0.5 µg/mL FSH, 10 IU/mL human chorionic gonadotropin (hCG), and 10 ng/mL EGF effectively enhanced R-Ras expression and cell proliferation. FSH supplementation during porcine COC maturation significantly upregulated R-Ras and ERK expression, independent of LH and EGF, and downregulated Cdc2 expression. These results indicated that FSH regulates R-Ras expression, thereby promoting cell proliferation during COC maturation. These results provide fundamental knowledge for understanding the role of Ras and its family members in the development of follicular environments in pigs. Full article

Objectives: Our aim is to report an uncommon pituitary activation occurring during the desensitization phase of the gonadotropin-releasing hormone agonist (GnRHa) long protocol, a cornerstone of medically assisted reproduction (MAR) therapy, in a young woman. Results: We present a case of a 33-year-old female patient with secondary infertility, who exhibited a prolonged and asynchronous follicular development during ovarian stimulation using the GnRH antagonist protocol. Therefore, during a repeat attempt, the long GnRH agonist protocol was employed. Surprisingly, rather than achieving suppression with the agonist, ultrasound detected many large follicles in both ovaries, accompanied by extremely elevated estrogen levels, indicating imminent ovarian hyperstimulation syndrome (OHSS). This unusual phenomenon was also observed during a subsequent attempt using the long protocol in another reproductive center. As part of the work-up to identify the underlying etiology, contrast-enhanced magnetic resonance imaging (MRI) of the sella turcica was performed, which revealed an 11 × 13 × 10 mm pituitary macroadenoma without evidence of pathological hormone secretion. The luteinizing hormone-releasing hormone (LHRH) stimulation test showed a normal luteinizing hormone and follicle-stimulating hormone response. Other abnormalities of the hypothalamo–hypophyseal–target-organ axis were not found. Neurosurgical intervention was deemed unnecessary; radiological follow-up of the lesion was recommended. Conclusions: In this case, the clinical presentation was markedly different from the expected suppressive effects of GnRH agonist therapy, with profoundly elevated estrogen levels and clinical signs of imminent OHSS. Notably, hypersensitivity of the adenohypophysis was not demonstrated following a single physiological LHRH stimulation test. However, the presence of a pituitary adenoma identified on MRI raises the possibility that gonadotropin receptor function was altered by the lesion—an effect revealed only after repeated GnRH agonist exposure, resulting in a paradoxical stimulatory response. Full article

Per- and polyfluoroalkyl substances (PFASs) comprise a diverse array of synthetic chemicals that resist environmental degradation. They are increasingly recognised as endocrine-disrupting compounds (EDCs). These chemicals, found in non-stick cookware, food packaging, and industrial waste, accumulate in human tissues and fluids, raising substantial concerns regarding their impact on female reproductive health. Epidemiological studies have demonstrated associations between PFAS exposure and reduced fertility; nevertheless, the underlying molecular pathways remain inadequately understood. This narrative review investigates the multifaceted effects of PFASs on ovarian physiology, including its disruption of the hypothalamic–pituitary–ovarian (HPO) axis, alteration of anti-Müllerian hormone (AMH) levels, folliculogenesis, and gonadotropin receptor signalling. Significant attention is directed towards the emerging association between PFASs and polycystic ovarian syndrome (PCOS), wherein PFAS-induced hormonal disruption may exacerbate metabolic issues and elevated androgen levels. Furthermore, we analyse the current data regarding PFAS exposure in women undergoing treatment based on assisted reproductive technologies (ARTs), specifically in vitro fertilisation (IVF), highlighting possible associations with diminished oocyte quality, suboptimal embryo development, and implantation failure. We examine potential epigenetic and transgenerational alterations that may influence women’s reproductive capabilities over time. This study underscores the urgent need for further research and regulatory actions to tackle PFAS-related reproductive toxicity, particularly in vulnerable populations, such as women of reproductive age and those receiving fertility treatments. Full article

Objective: To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and clinical, hormonal, and auxological features in girls with idiopathic central precocious puberty (CPP). Methods: This retrospective study included 122 girls diagnosed with idiopathic CPP. Participants were stratified into three groups based on serum 25(OH)D concentrations: deficient (<20 ng/mL), insufficient (20–30 ng/mL), and sufficient (>30 ng/mL). Clinical and hormonal parameters were compared across groups. Spearman’s correlation and multiple linear regression analyses were used to explore the relationship between vitamin D levels and peak luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH) stimulation. Results: No significant differences were observed among the vitamin D groups in terms of age at diagnosis, body mass index (BMI), or other auxological measures. However, serum 25(OH)D levels showed a weak but significant positive correlation with LH peak values (rho = 0.23, p = 0.037). In multivariable regression analysis, vitamin D levels remained an independent predictor of LH peak (β = 0.125, p = 0.036), whereas BMI standard deviations (SDS), growth velocity SDS, and age at diagnosis did not show significant associations. Conclusions: Higher serum vitamin D levels are independently associated with greater LH peak responses in girls with idiopathic CPP. These findings support a potential modulatory role of vitamin D in the neuroendocrine mechanisms underlying pubertal onset and warrant further prospective studies to clarify its clinical relevance. Full article

Placenta accreta spectrum (PAS) and placenta previa (PP) are severe obstetric disorders associated with high maternal and perinatal morbidity. Early diagnosis of both conditions remains challenging, particularly in cases with subtle imaging findings. This study was aimed to evaluate the diagnostic value of first-trimester maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (β-hCG) in predicting PAS and PP. In this retrospective case–control study, a total of 100 pregnant women were included: 36 with PAS, 32 with PP, and 32 healthy controls. Serum levels were measured at 11–13⁶ weeks of gestation. Both biomarkers were significantly altered in pathological groups compared to controls: PAPP-A was lower in PP (3.04 [1.42–4.52] IU/L) and PAS (3.63 [2.51–5.39] IU/L) vs. controls (5.34 [3.72–8.41] IU/L; p < 0.001), while β-hCG was higher in PP (45.4 [40.1–54.9] IU/L) and PAS (51.4 [32.3–74.8] IU/L) vs. controls (33.5 [22.7–54.1] IU/L; p = 0.044 and p < 0.001, respectively). ROC analysis demonstrated that combined biomarker modeling improved diagnostic accuracy over single-marker use, with AUCs reaching 0.85 (sensitivity 85.2%, specificity 72%) for PAS and 0.88 (sensitivity 100%, specificity 72%) for PP. These findings support the integration of biochemical screening into first-trimester risk assessment protocols. Incorporating maternal serum biomarkers may enhance early identification of high-risk pregnancies, allow timely referral to specialized care, and reduce adverse outcomes. Further prospective studies are warranted to validate the utility of this dual-marker approach across diverse populations and clinical settings. Full article

Gonadotropin-Releasing Hormone (GnRH) is a crucial neuropeptide that regulates reproductive functions in vertebrates. The study identifies and characterizes (GnRH) in the brain of Tenualosa ilisha, an iconic and lucrative Clupeiform fish from River Ganga, India. The current study aimed to analyze the GnRH gene in T. ilisha using an in silico study. The GnRH gene of T. ilisha comprises a full-length nucleotide sequence of 605 base pairs with an open reading frame of 312 base pairs, which encodes 103 deduced amino acids (aa), respectively. It was found that leucine (L) is the most abundant amino acid in the GnRH protein. Additionally, the ligand interactions of the GnRH were analyzed using computational approaches. The structural validation showed an excellent stereochemical quality of the GnRH protein sequence, with over 88% of residues in Ramachandran plot-favored regions. The binding site prediction revealed 6 ligand-binding pockets, with the largest pocket containing 12 amino acids. After ADME screening, 16 drug-like compounds were docked to GnRH protein. Top five ligands N-Ac-(4-Cl-Phe)-Trp-Lys-AlaNH2, LHRH_LYS (6), Seabream_GnRH, Leuprolide, and LHRH_Des-tyr (5) had binding affinities ranging from −7.5 to −5.6 kcal/mol. The stable binding site was confirmed by 100 ns molecular dynamics simulations, with RMSD values below 10 Å and key residues retaining ligand contacts. The GnRH-protein resulted in the development of a suitable peptide sequence of T. ilisha, showing similarity with the similar anadromous American shad (Alosa sapidissima). This will certainly aid in future therapeutic and captive breeding advances, thereby fostering the culture and conservation of the wild species. Full article