Follicle-stimulating hormone (FSH) administration is applied in the management of subjects affected by hypogonadotropic hypogonadism. Whilst this application is widely recognized and established alone or in combination with human chorionic gonadotropin (hCG), a similar strategy is empirically advocated in idiopathic male factor infertility (MFI). In this setting, FSH therapy has been used to increase sperm quantity, quality, and pregnancy rate when FSH plasma concentrations are below 8 IU/L and when the seminal tract is not obstructed. In the literature, several studies suggested that giving FSH to patients with idiopathic MFI increases sperm count and motility, raising the overall pregnancy rate. However, this efficacy seems to be limited, and about 10-18 men should be treated to achieve one pregnancy. Thus, several papers suggest the need to move from a replacement approach to an overstimulating approach in the management of FSH therapy in idiopathic MFI. To this aim, it is imperative to determine some pharmacologic markers of FSH efficacy. Furthermore, it should be useful in clinical practice to distinguish, before starting the treatment, among patients who might respond or not to FSH treatment. Indeed, previous studies suggest that infertile men who have normal levels of gonadotropins in plasma might not respond to FSH treatment and about 50% of patients might be defined as \"non-responders\". For these reasons, identifying predictive markers of FSH action in spermatogenesis and clinical markers of response to FSH treatment is a fascinating area of study that might lead to new developments with the aim of achieving personalization of the treatment of male infertility. From this perspective, seminal parameters (i.e., spermatid count), testicular cytology, genetic assessment, and miRNA or protein markers in the future might be used to create a tailored FSH therapy plan. The personalization of FSH treatment is mandatory to minimize side effects, to avoid lost time with ineffective treatments, and to improve the efficacy, predicting the most efficient dose and the duration of the treatment. This narrative review\'s objective is to discuss the role of the different putative factors which have been proposed to predict the response to FSH treatment in idiopathic infertile men.

Introduction: Pubertal attainment is critical to reproductive longevity in heifers. Previously, four heifer pubertal classifications were identified according to attainment of blood plasma progesterone concentrations > 1 ng/ml: 1) Early; 2) Typical; 3) Start-Stop; and 4) Non-Cycling. Early and Typical heifers initiated and maintained cyclicity, Start-Stop started and then stopped cyclicity and Non-Cycling never initiated cyclicity. Start-Stop heifers segregated into Start-Stop-Discontinuous (SSD) or Start-Stop-Start (SSS), with SSD having similar phenotypes to Non-Cycling and SSS to Typical heifers. We hypothesized that these pubertal classifications are heritable, and loci associated with pubertal classifications could be identified by genome wide association studies (GWAS). Methods: Heifers (n = 532; 2017 - 2022) genotyped on the Illumina Bovine SNP50 v2 or GGP Bovine 100K SNP panels were used for variant component estimation and GWAS. Heritability was estimated using a univariate Bayesian animal model. Results: When considering pubertal classifications: Early, Typical, SSS, SSD, and Non-Cycling, pubertal class was moderately heritable (0.38 ± 0.08). However, when heifers who initiated and maintained cyclicity were compared to those that did not cycle (Early+Typical vs. SSD+Non-Cycling) heritability was greater (0.59 ± 0.19). A GWAS did not identify single nucleotide polymorphisms (SNPs) significantly associated with pubertal classifications, indicating puberty is a polygenic trait. A candidate gene approach was used, which fitted SNPs within or nearby a set of 71 candidate genes previously associated with puberty, PCOS, cyclicity, regulation of hormone secretion, signal transduction, and methylation. Eight genes/regions were associated with pubertal classifications, and twenty-two genes/regions were associated with whether puberty was attained during the trial. Additionally, whole genome sequencing (WGS) data on 33 heifers were aligned to the reference genome (ARS-UCD1.2) to identify variants in FSHR, a gene critical to pubertal attainment. Fisher\'s exact test determined if FSHR SNPs segregated by pubertal classification. Two FSHR SNPs that were not on the bovine SNP panel were selected for additional genotyping and analysis, and one was associated with pubertal classifications and whether they cycled during the trial. Discussion: In summary, these pubertal classifications are moderately to highly heritable and polygenic. Consequently, genomic tools to inform selection/management of replacement heifers would be useful if informed by SNPs associated with cyclicity and early pubertal attainment.

Context: It is very necessary to delay ovarian aging and prevent age-related health problems. The active ingredient in Honghua Xiaoyao tablet (HHXYT) has the effects of anti-oxidation, anti-inflammation, immune regulation and so on. Objective: To explore the effect and mechanism of Honghua Xiaoyao tablet on aging model mice. Materials and methods: The aging model was established by intraperitoneal injection of D-galactose in model mice. The mice in the HHXYT-L,M,H group were given 0.3 g/kg, 0.6 g/kg and 1.2 g/kg Honghua Xiaoyao tablet suspension respectively, and the HHXYT-M + E2 group was given 0.6 g/kg HHXYT +0.13 mg/kg estradiol valerate for 30 days. In this study, ELISA, HE, Western blot, IH and TUNEL were used. Results: HHXYT + E2 can improve the gonadal index, estrous cycle of aging mice. In HHXYT-M + E2 group, the level of FSH and LH decreased, while E2 and AMH increased significantly. The number of growing follicles in HHXYT-M + E2 group increased, which was better than that of HHXYT alone. Western blot results showed that HHXYT-M + E2 group decreased the expression of Bax, cleaved-Parp, cleaved-Casp-3 and CytC molecules and increased the expression of Bcl-2 in ovarian tissue. FSHR expression decreased in model group and increased in HHXYT group. TUNEL staining showed that the number of apoptotic cells in HHXYT group was reduced, and the HHXYT-M + E2 group was the most significantly. Discussion and conclusion: HHXYT can improve the level of sex hormones and increase the number of growing follicles in aging mice. HHXYT-M + E2 group has the best effect, and its mechanism may be related to reducing ovarian granulosa cell apoptosis.

Polycystic ovary syndrome (PCOS) is a complex disorder. Genome-wide association studies (GWAS) have identified several genes associated with this condition, including DENND1A. DENND1A encodes a clathrin-binding protein that functions as a guanine nucleotide exchange factor involved in vesicular transport. However, the specific role of DENND1A in reproductive hormone abnormalities and follicle development disorders in PCOS remain poorly understood. In this study, we investigated DENND1A expression in ovarian granulosa cells (GCs) from PCOS patients and its correlation with hormones. Our results revealed an upregulation of DENND1A expression in GCs from PCOS cases, which was positively correlated with testosterone levels. To further explore the functional implications of DENND1A, we generated a transgenic mouse model overexpressing Dennd1a (TG mice). These TG mice exhibited subfertility, irregular estrous cycles, and increased testosterone production following PMSG stimulation. Additionally, the TG mice displayed diminished responsiveness to FSH, characterized by smaller ovary size, less well-developed follicles, and abnormal expressions of FSH-priming genes. Mechanistically, we found that Dennd1a overexpression disrupted the intracellular trafficking of follicle stimulating hormone receptor (FSHR), promoting its internalization and inhibiting recycling. These findings shed light on the reproductive role of DENND1A and uncover the underlying mechanisms, thereby contributing valuable insights into the pathogenesis of PCOS and providing potential avenues for drug design in PCOS treatment.

Experimental evidence indicates that follicle-stimulating hormone (FSH), an essential hormone for reproduction, can act directly on endothelial cells inducing atherosclerosis activation and development. However, it remains unknown whether the FSH-receptor (FSHR) is expressed in human atherosclerosis plaques. To demonstrate the FSHR presence, we used immunohistochemical and immunoelectron microscopy involving a specific monoclonal antibody FSHR1A02 that recognizes an epitope present in the FSHR-ectodomain. In all 55 patients with atherosclerotic plaques located in carotid, coronary, femoral arteries, and iliac aneurysm, FSHR was selectively expressed in arterial endothelium covering atherosclerotic plaques and endothelia lining intraplaque neovessels. Lymphatic neovessels were negative for FSHR. M1-macrophages, foam cells, and giant multinucleated cells were also FSHR-positive. FSHR was not detected in normal internal thoracic artery. Immunoelectron microscopy performed in ApoEKO/hFSHRKI mice with atherosclerotic plaques, after injection in vivo with mouse anti-hFSHR monoclonal antibody FSHR1A02 coupled to colloidal gold, showed FSHR presence on the luminal surface of arterial endothelial cells covering atherosclerotic plaques. Therefore, FSHR can bind, internalize, and deliver into the plaque circulating ligands to FSHR-positive cells. In conclusion, we report FSHR expression in endothelial cells, M1-macrophages, M1-derived foam cells, giant multinucleated macrophages, and osteoclasts associated with human atherosclerotic plaques.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play key roles in regulating testosterone secretion and spermatogenesis in male mammals, respectively, and they maintain the fertility of male animals by binding to their corresponding receptors. We designed and prepared a recombinant LH receptor (LHR) subunit vaccine and a recombinant FSH receptor (FSHR) subunit vaccine and used male Sprague Dawley (SD) rats as a model to examine their effects on testicular development, spermatogenesis, and testosterone secretion in prepubertal and pubertal mammals. Both vaccines (LHR-DTT and FSHR-DTT) significantly decreased the serum testosterone level in prepubertal rats (p < 0.05) but had no effect on the testosterone secretion in pubertal rats; both vaccines decreased the number of cell layers in the seminiferous tubules and reduced spermatogenesis in prepubertal and pubertal rats. Subunit vaccine FSHR-DTT decreased the sperm density in the epididymis in both prepubertal and pubertal rats (p < 0.01) and lowered testicular index and sperm motility in pubertal rats (p < 0.05), whereas LHR-DTT only reduced the sperm density in the epididymis in pubertal rats (p < 0.05). These results indicate that the FSHR subunit vaccine may be a promising approach for immunocastration, but it still needs improvements in effectiveness.

Around 70 percent of cases of Primary Ovarian Insufficiency (POI) etiology remain unexplained. The aim of our study is to contribute to the etiology and genetic background of POI. A total of 37 POI patients and 30 women in the reproductive period were included in this prospective, case-control study between August 2020 and December 2021. The women were examined for 36 genes with next-generation sequencing (NGS) panel. Gene variations were detected in 59.5 percent of the patients in the case group. FSHR p.S680N (rs6166, c.2039 G>A) and FSHR p.A307T (rs6165, c.919 G>A) gene variants, which are most frequently located in exon 10 of the FSHR gene, were detected in both groups. Although it was not found that these gene variants were significantly different between the groups, it was also found that they were significantly different in POI patients under 30 years of age and in those with a family history of POI. Variations were detected in 12 genes in POI patients. Two gene variants (FGFR1 [c.386A>C, rs765615419] and KISS1 [c.58 G>A, rs12998]) were detected in both groups, and the remaining gene variants were detected only in POI patients. No differences were detected between the groups in terms of gene variations. However, the gene variations detected only in POI patients may play a role in the etiology of POI.

BACKGROUND: The results of studies on the association between polymorphisms in the FSHR gene and the risk of POR undergoing IVF have been inconsistent with each other, so we conducted a meta-analysis of all the available studies to explore the association between polymorphisms in the FSHR gene and the risk of POR.
METHODS: Literature that met the inclusion criteria was collected by searching six electronic databases and basic data from included studies were extracted. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between follicle-stimulating hormone receptor (FSHR) gene polymorphism and poor ovarian response (POR) risk. Begg\'s and Egger\'s tests were used to determine whether there was publication bias, and sensitivity analysis and TSA analysis were used to verify the stability and reliability of the results.
RESULTS: We included 24 articles, 22 of which explored rs6166, including 2,206 cases and 3,897 controls. 6 articles explored rs6165, including 444 cases and 875 controls. Under additive, heterozygote, and dominant models, rs6166 was significantly associated with POR (S vs. N: OR = 1.29, 95 % CI = 1.05-1.59, P = 0.017; NS vs. NN: OR = 1.33, 95 % CI = 1.02-1.74, P = 0.038; NS + SS vs. NN: OR = 1.38, 95 % CI = 1.04-1.84, P = 0.025). In ethnicity-based subgroup analyses, the additive, homozygote, heterozygote, and dominant models increased Asian POR risk. Among the five genetic models, rs6165 was significantly associated with POR (T vs. C: OR = 1.64, 95 % CI = 1.25-2.16, P = 0.000; TT vs. CC: OR = 2.76, 95 % CI = 1.43-5.32, P = 0.003; CT vs. CC: OR = 1.58, 95 % CI = 1.19-2.10, P = 0.001; TT vs. CC + CT: OR = 2.32, 95 % CI = 1.67-3.23, P = 0.000; CT + TT vs. CC: OR = 1.80, 95 % CI = 1.22-2.65, P = 0.003). In ethnicity-based subgroup analyses, all five genetic models increased the risk of POR in Caucasians.
CONCLUSIONS: According to the current meta-analysis, the rs6166 S allele was significantly associated with an increased risk of POR, especially in Asian populations. The rs6165 T allele was significantly associated with an increased risk of POR, especially in Caucasian populations.

UNASSIGNED: The function of follicle-stimulating hormone (FSH) is mediated by binding to its G-protein coupled receptor (GPCR) which is expressed on granulosa cells of the ovary. The purpose of the current study was to examine the impact of FSHR G2039A polymorphism (rs6166; Ser680Asn) on clinical and radiology profiles of women with primary amenorrhea (PA) in Gujarat, India.
UNASSIGNED: A total of 90 women (45 controls and 45 cases) were recruited for the study after obtaining informed consent. The DNA extraction was performed on the venous blood samples collected from the participants, followed by polymerase chain reaction (PCR). The presence of polymorphism was then analyzed using restriction fragment polymorphism (RFLP) with the BSeNI enzyme. The statistical analysis was conducted using an independent t-test, chi-square test, and ANOVA. Significance was determined by a p<0.05.
UNASSIGNED: Results revealed that homozygous wild type genotype was observed in 46.7% (n=21) of the control group and 11.1% (n=5) of the case group. Heterozygous genotype was observed in 33.3% (n=15) of the control group and 55.6% (n=25) of the case group (p<0.001). Homozygous mutant genotype was observed in 20% (n=9) of the control group and 33.3% (n=15) of the case group (p<0.01). The hormonal profile revealed that serum levels of FSH and luteinizing hormone (LH) were significantly higher (p<0.05) in the AA and AG genotypes compared to the GG genotypes.
UNASSIGNED: The FSHR rs6166 G2039A was associated with PA in women, and the A allele could be considered a causative risk factor in developing the condition.

UNASSIGNED: Malathion (MAL), a pesticide used for decades, is a highly toxic substance. Several studies have documented the negative effects of such agents on reproductive organ physiology, but the precise mechanism of action in the induction of ovarian dysfunction remains unclear. Therefore, the purpose of this research was to examine the effects of the antioxidant hesperidin (HES) on ovarian damage and toxicity caused by malathion.
UNASSIGNED: In this experiment, forty adult female bulb/c mice weighing 27-30 g were categorized into four groups, namely hesperidin (20 mg/kg, i.p.), malathion (3 mg/kg, i.p.), malathion + hesperidin, and control groups. Following a period of 35 consecutive days of treatment, mice were euthanized, and their ovarian tissues were gathered for the purposes of histopathological analysis by H&E staining, immunohistochemical assessment via proliferating cell nuclear antigen (PCNA) and follicle-stimulating hormone receptor (FSHR) immunostaining, and biochemical evaluation via measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). In addition, serum samples were collected from the blood of mice to perform hormonal analyses, especially 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).
UNASSIGNED: The results demonstrated that MAL exposure resulted in the development of abnormalities in the architecture and structure of ovaries. Also, the treatment of mice with MAL led to declined follicular counts at all three stages, namely, primary, secondary, and tertiary, reduced serum levels of sex hormones, decreased immunoreactivity of FSHR and PCNA, and diminished activity of CAT and SOD enzymes. In contrast, it caused an increase in MDA, IL-1β, and TNF-α, as well as the count of atretic follicles. Nonetheless, it was observed that HES exhibited the ability to ameliorate the deleterious impacts of malathion across all the aforementioned parameters.
UNASSIGNED: Treatment with HES via upregulating the protein expression of PCNA and FSHR and activating antioxidant defense was able to ameliorate the adverse effects of MAL on ovarian tissues.