Purpose of Review:As the life expectancy of people with multiple sclerosis (PwMS) increases, the importance of recognizing and addressing specific needs and challenges faced by those undergoing age-related sex hormone changes and hypogonadism is becoming increasingly evident. We present expert-led, practical recommendations from a consensus program that address gaps in age-related sex hormone changes and hypogonadism in PwMS not sufficiently addressed in current literature and guidelines. A multidisciplinary steering committee (SC) of 15 international experts identified 18 key clinical questions across 6 themes: climacteric symptoms in women with MS; impact of MS on the climacteric stage; impact of menopause on MS disease activity and progression; treatment and management of climacteric symptoms in women with MS; late-onset hypogonadism (LOH) in men with MS; and patient-centered care. After thorough review of the evidence from a systematic literature review, the SC formulated 18 clinical recommendations to address the questions. These recommendations were voted on by the SC and an extended faculty of 23 health care professionals from 16 countries, including 2 nurses and 1 patient association representative. Recent Findings:Consensus was reached when ≥75% of respondents expressed agreement, with a score of 7-9 on a 9-point scale. After a single voting round, all 18 recommendations reached consensus (14 reaching consensus at 90%-100% and 4 at 80%-90%). The clinical recommendations addressed the following: the potential overlap and exacerbation of MS symptoms during the climacteric stage; the need for preventive care and screening during the menopausal transition; the potential for, and a paucity of data on, differential efficacy and tolerability of MS medications in menopausal/postmenopausal women; the complex causal interplay between hormonal and/or immunologic changes and natural aging in PwMS switching to a more progressive phase of disease; consideration of behavioral/lifestyle interventions alongside pharmacologic treatments; effects of hormonal treatments on MS symptoms; and management of LOH in men with MS. Summary:These recommendations were based on a robust modified Delphi consensus approach and present a valuable framework for improved patient care. These results emphasize the need to address critical gaps in our understanding and management of PwMS undergoing age-related sex hormone changes and hypogonadism.

The two gonadotrophin receptors (GnRs), luteinizing hormone receptor (LHCGR) and follicle-stimulating receptor (FSHR), belong to the glycoprotein hormone receptor subgroup of type A G protein-coupled receptors (GPCRs). LHCGR binds specifically the two structurally similar gonadotrophins, luteinizing hormone (LH) and human chorionic gonadotrophin (hCG), and FSHR binds follicle-stimulating hormone (FSH). The receptors reside on plasma membrane and transmit the gonadotrophin signal to target cells using the classical Gs/adenylyl cyclase/cyclic AMP/protein kinase A signaling cascade. Other signaling pathways (e.g., inositol phosphate, calcium) are activated at pharmacological hormone concentrations or at high receptor density. LHCGR is expressed in testicular Leydig cells and in ovarian theca, luteinizing granulosa and luteal cells. FSHR is expressed in testicular Sertoli cells and ovarian granulosa cells. LHCGR activation stimulated Leydig cell steroidogenesis, in particular testosterone production, while FSHR maintains Sertoli cell metabolism, thereby indirectly stimulating spermatogenesis. Recent basic research, using GnR, expressing cells in vitro and genetically modified mice in vivo, has elucidated novel aspects of the molecular mechanisms of gonadotrophin receptor function. The crystal structure of GnRs has also been partly resolved. Numerous inactivating and activating GnR mutations that have been discovered in patients have unraveled the molecular basis of hypogonadism and other aberrations of reproductive endocrine functions. The purpose of this chapter is to review the recent trends of GnR research and how it has elucidated the molecular mechanisms of GnR function and the role of GnR in human reproductive physiology and pathophysiology.

Background and Objectives: Patients with obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome are at high risk of metabolic dysfunction-associated steatotic liver disease (MASLD), steatohepatitis (MASH), and advanced fibrosis. We assessed the prevalence and severity of MASLD and the diagnostic accuracy of a sequential algorithm using the Fibrosis-4 (Fib-4) index and liver stiffness (LS) measurement in a prospective cohort of patients with severe obesity, T2DM, and metabolic syndrome.Methods: Consecutive patients followed at the Civil Hospital of Baggiovara, University Hospital of Modena, underwent liver ultrasound for steatosis (SLD) detection, Controlled Attenuation Parameter (CAP) measurement via Fibroscan®, and LS evaluation using Fibroscan® and 2D-Shear Wave Elastography (2D-SWE).Results: Among 218 patients (median age 54.6 [43.9–61.8] years; 47.7% male), obesity, T2DM, hypertension, and dyslipidemia were present in 83.5%, 29.4%, 51.8%, and 63.3%, respectively.SLD, defined as ultrasound-detected steatosis and/or CAP ≥248 dB/m, was found in 188 (86.2%) cases, with MASLD as the cause in 95.7%. Advanced fibrosis (LS ≥8 kPa by Fibroscan® or ≥8 kPa by 2D-SWE in case of failure, 5.0%) was detected in 50 patients (22.9%). Fibrosis correlated with male sex (p<0.001), BMI (p=0.007), systolic BP (p=0.019), HOMA-IR (p=0.005), AST, ALT, GGT (all p<0.001), and SLD (p=0.022), and inversely with LDL (p=0.028) and HDL cholesterol (p=0.014).Application of the 2024 EASL-EASD-EASO algorithm (Fib-4 + LS) achieved 82.6% diagnostic accuracy, identifying 20 patients (9.2%) needing hepatology referral (8 with Fib-4 ≥2.67; 12/37 with Fib-4 1.3/2.0–2.67 and LS ≥8 kPa) and 198 (90.8%) not requiring it. Among 173 low-risk patients (Fib-4 <1.3/2.0), 34 (19.7%) had LS ≥8 kPa; they were more frequently male, younger, severely obese (BMI >40 kg/m²), and had higher ALT, SBP, and SLD prevalence. On multivariate analysis, male sex [OR 3.82 (1.48–9.85), p=0.006] and BMI >40 kg/m² [OR 4.13 (1.54–11.09), p=0.005] were independently associated with LS ≥8 kPa.A stricter advanced fibrosis definition (LS ≥8 kPa on both methods, 12 patients, 5.9%) improved accuracy to 95.1%, with only 5/161 (3.1%) low-risk cases showing LS ≥8 kPa, suggesting single-method overestimation. Fifteen patients underwent biopsy: MASH and fibrosis ≥F2 were found in 8 (53.3%), including 2 with cirrhosis.Conclusions: Sequential screening using Fib-4 and LS accurately identifies high-risk MASLD patients requiring hepatology referral. Severe obesity independently associates with LS ≥8 kPa even in low-risk Fib-4 individuals. Dual elastographic assessment may outperform Fibroscan® alone, reducing false negatives and improving advanced fibrosis detection in obese populations.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) and male hypogonadism are increasingly prevalent, metabolically interrelated conditions. Testosterone (T) deficiency has been implicated in hepatic lipid dysregulation, insulin resistance, and visceral adiposity, whereas MASLD may impair the hypothalamic-pituitary-gonadal axis. We conducted a systematic review and meta-analysis to evaluate the bidirectional association between circulating T levels and MASLD in adult men. METHODS:Following PRISMA guidelines, a literature search was performed from inception to July 31, 2025. Twenty-eight studies met the inclusion criteria (9 comparing hypogonadal vs. eugonadal men; 19 comparing MASLD vs. non-MASLD men). Random-effects models were used to pool effect sizes for dichotomous and continuous outcomes. Meta-regression analyses assessed the influence of age, anthropometric features, glycemic markers, liver enzymes, and hormonal parameters. RESULTS:Hypogonadal men showed a significantly higher prevalence of MASLD than eugonadal men (p = 0.001) and exhibited higher fatty liver index scores (p < 0.001). Total T concentrations were significantly lower in men with MASLD than in controls (p = 0.014). Meta-regression analyses did not identify significant effects of study-level differences in age, body mass index, or biochemical variables on the observed associations. Sex hormone-binding globulin levels were also significantly reduced in MASLD (p < 0.001), with age emerging as the only significant modifier. No significant differences were observed for luteinizing hormone, estradiol, or fibrosis-4 index. Across studies evaluating MASLD severity, moderate-to-severe disease was associated with lower T levels, particularly in analyses based on imaging. CONCLUSIONS:This meta-analysis supports a clinically relevant association between testosterone deficiency and MASLD, although evidence for the bidirectional nature of this relationship remains asymmetric but supports a clinically relevant endocrine-hepatic axis. T deficiency appears independently linked to MASLD onset and severity beyond the effects of age and adiposity. These findings underscore the need for reciprocal screening of liver health and gonadal status in at-risk men and highlight the importance of prospective studies and randomized trials to determine whether correcting T deficiency may modify MASLD progression.

Couple infertility is estimated to affect between 13

The exploration of gender differences in non-andrological fields was the core focus of a series of discussions, which took place at the Endocrinology Unit in Modena, Italy in the form of the aporetic dialogue of ancient Greece. This second episode reports the transcript of the actual debate on testosterone's role in defining empathic behavior in males and females. The two groups of discussants sustained that empathic gender differences may rely either on testosterone exposure (group 1) or on other factors (group 2). The first group supported the hypothesis that females are more empathic than males due to reduced exposure to fetal testosterone, which correlates with higher empathic scores at all ages and lower sensitivity to testosterone in adulthood. This hypothesis is also supported by evolutionary mechanisms and evidence in animal ethology. Conversely, the second group affirmed that gender differences rely on structural diversities in brain organization, hormonal factors such as vasopressin, oxytocin, and cortisol, as well as sociological aspects. An expert in neurophysiology, acting as a referee, moderated the discussion and decided whether the two theories were equivalent or one was predominant.

Follicle-stimulating hormone (FSH) therapy improves spermatogenesis, sperm quality, and reproductive outcomes. However, variability in patients’ response and limited data on pregnancy rate complicate its extensive application in male idiopathic infertility. The aim of the study was to identify predictors of FSH efficacy in male idiopathic infertility in terms of pregnancy. A retrospective, observational study was conducted at two Italian clinics from 2019 to 2024, enrolling men with idiopathic infertility, serum FSH < 8 IU/L, treated with FSH. Data were collected at baseline (V0) and at the final follow-up visit (V1) when FSH treatment was discontinued. Different, putative “testicular indexes” (TI) were calculated. Pregnancy rate was defined at ultrasound confirmation of fetus heartbeat. A total of 84 achieved pregnancy (19

This report is the transcript of what was discussed in a convention at the Endocrinology Unit in Modena, Italy, in the form of the aporetic dialogs of ancient Greece. It is the third episode of a series of four discussions on the differences between males and females, with a multidisciplinary approach. In this work, the role of testosterone in gender differences in the aptitude for mathematics is explored. First, the definitions of mathematical abilities were provided together with any gender difference in the distribution of females and males in science, technology, engineering, and mathematics subjects. A clear predominance of males is evident at most science, technology, engineering, and mathematics education levels, especially in advanced academic careers. Then, the discussants were divided into two groups: group 1, which illustrated the thesis that testosterone promotes the development of logical‒mathematical skills, and group 2, which, in contrast, asserted the inconsistency of a direct role of testosterone in improving cognitive abilities and that socio-cultural factors should be considered on the basis of this gender gap. In the end, an expert referee (a female engineer) tried to resolve the aporia: are the two theories equivalent or is one superior?

Abstract Study question Do Rekovelle® and Gonal-F® modulate preparation-specific signalling? Summary answer Gonal-F® and Rekovelle® induce preparation-specific pattern of intracellular signalling. What is known already Rekovelle® and Gonal-F® are two commercial preparations of recombinant FSH used in assisted reproduction. These preparations differ in originator cells (PER.C6® cell line of human fetal retinal origin for Rekovlle®; modified Chinese Hamster Ovary cell line for Gonal-F®), likely reflecting glycosylation profiles impacting their mode of action. Study design, size, duration 3-year in vitro functional comparison of Rekovelle® and Gonal-F®, using the transfected HEK293 cell line expressing FSH receptor (FSHR). Participants/materials, setting, methods FSHR-expressing HEK293 cells were treated with increasing concentrations of GonalF® and Rekovelle® (pM-µM) to evaluate receptor-receptor interaction and trafficking, intracellular cyclic adenosine monophosphate (cAMP) and Ca2+ increase by bioimaging techniques, as well as phospho-protein by Western blotting, and genomic effects by CRE-luciferase reporter gene activity. Main results and the role of chance Both the preparations induced similar, dose-dependent increase of receptor trafficking through intracellular organelles. These data were obtained by evaluation of the interaction between FSHR and endosomal markers RAB-GTPases (Rab) 5 and 7. Rekovelle® induced more pronounced steroifogenic signals than Gonal-F®, detected as FSHR-FSHR interactions at the cell membrane, cAMP accumulation, cAMP-responsive elements binding protein (CREB) phosphorylation and CRE promoter activity. Interestingly, while cell treatment by Gonal-F® mediated complete dose-response of cAMP, consisting in the continuous increase of the second messenger together with the increase of FSH concentration, Rekovelle® had biphasic action where cAMP increased from 0 to 100 nM although decreased at 1 µM Rekovelle® dose. Moreover, Rekovelle® was 10-times more potent than Gonal-F® in activating intracellular Ca2+ activation. The two preparations induced similar pattern of extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation. In conclusion, Rekovelle® has higher potency than Gonal-F® in activating cAMP- and Ca2+-dependent intracellular events, potentially resulting in preparation-specific steroidogenic pattern. Limitations, reasons for caution Experiments were performed in the transfected HEK293 cell line in vitro and should be confirmed by clinical observations. Wider implications of the findings We described different intracellular events mediated by Gonal-F® and Rekovelle® in vitro, likely originated by different glycan profiles and possibly impacting the ovarian response during assisted reproduction. Trial registration number Not Applicable

Introduction:Several studies indicate that a specific genotype profile could influence ovarian sensitivity to exogenous gonadotropin. However, most of the previous studies were observational and retrospective and thereby more prone to bias. The aim of this study was to evaluate the impact of gonadotropin single nucleotide polymorphisms (SNPs) on the outcomes of in-vitro fertilization (IVF) in infertile patients undergoing their first ovarian stimulation (OS) cycle. Method:A multicenter, longitudinal, prospective, interventional cohort study was carried out in four clinical centers of medically assisted reproduction from August 2016 to November 2018. Only expected normo-responder women, estimated through standardized-computerized antral follicle count (AFC), stimulated with a fixed 150 IU daily dose of recombinant follicle-stimulating hormone (FSH), were included. The study population consisted of infertile normo-gonadotropic patients, aged between 34 and 39, at their first OS, with normal ovarian reserve (AFC between 8 and 16) measured with 3D automated ultrasonography and undergoing standardized OS protocol. Results:One hundred nineteen patients were enrolled, and the following five SNPs were studied (FSHR c.-29G>A, FSHR p.N680S, FSHB c.-211G>T, LHCGR p.S312N, and LHβ "V-LH" p.W8R). Separate and multivariate analysis of investigated polymorphisms did not show any statistical impact on the number of oocytes retrieved. However, adopting an overdominant model, heterozygosis of FSHR p.N680S SNP was associated with significantly lower duration of OS compared with homozygotic women. Considering LHCGR p.S312N polymorphism, N allele carriers required a longer duration of OS in the codominant, dominant, and log-additive models. Multivariate analysis revealed that specific genotype combinations could affect the ovarian sensitivity. A significantly higher follicle-to-oocyte index (FOI) was observed when the S or N allele of both FSHR p.N680S and LHCGR p.S312N were combined (S allele combination: difference 0.18, CI 95% 0.04-0.33, p = 0.011; N allele combination: difference 0.18, CI 95% 0.01-0.34, p = 0.037; N allele combination). Discussion:Based on our results, the combination of specific genetic variants could impact ovarian sensitivity to gonadotropin. This research adds to the controversy in the literature regarding the effect of genetic variants in IVF and ovarian response.

This is the fourth and last episode of a series of four discussions on the differences between males and females in apparently non-andrological fields. You will read the transcript of discussions that actually took place at the Endocrinology Unit in Modena, Italy, in the form of the aporetic dialogues of ancient Greece. In this episode, the role of testosterone in gender differences in approaches to love will be explored. The discussants were divided into two groups: Group 1, which supports the thesis of a predominant role of testosterone, and Group 2, which opposes it. The first group argued that endogenous testosterone could shape approaches to love, regardless of psychological predispositions or sociocultural context. The second group highlighted the multifactorial nature of love, pointing to other hormonal and non-hormonal influences, such as neurotransmitters, cortisol, and sociological and psychological factors. In the end, an expert professor of endocrinology, acting as a referee, sought to resolve the aporia: Are the two theories equivalent, or is one superior?

In brief:Granulosa cells from small antral follicles (SFs; diameter <10 mm), collected at the end of controlled ovarian cycles, differ from large ovarian follicles (LFs; >16 mm) for their molecular signatures. SFs retain characteristic of early antral follicles and the ratio between follicle-stimulating hormone receptor (FSHR) and G protein-coupled receptor (GPER) discriminates between mature and immature-like follicles. Abstract:Ovarian follicle maturation is regulated by a network of genes involved in cell growth, differentiation, oocyte selection, and steroidogenesis. In this study, we compared the expression of developmental markers and intrafollicular steroid levels in granulosa cells from small (SFs; diameter <10 mm) vs large human ovarian follicles (LFs; >16 mm). Since samples were collected from both conventional ovarian stimulation cycles and the second phase of DuoStim protocol, differences between follicles of follicular and luteal origin were also evaluated. Although both SFs and LFs displayed periovulatory markers, such as LHCGR gene expression, SFs exhibited relatively high expression levels of early antral markers, i.e., FSHR, GPER, AMHR2, CCND2 and CYP19A1 genes. This was different in LFs, which have overall homogeneous gene expression pattern. Gene expression data reflect the capability to convert androgens to estrogens, which is higher in SFs than LFs. These differences did not change when follicles from conventional and the second stimulation of DuoStim protocol were compared, confirming previous clinical observations that suggested similar quality and outcomes from oocytes collected in different follicular waves. In conclusion, SFs and LFs exhibit distinct characteristics, including specific size, gene expression patterns, and steroidogenic capabilities, regardless of their follicular or luteal origin. According to previous reports, the FSHR/GPER ratio could discriminate between mature and immature-like follicles collected at the end of controlled ovarian cycles, and between two sub-populations of LFs.

Male fertility is progressively impairing over time, probably related to a multifactorial genesis. The aim of the study was the evaluation if a Temporal trend in serum testosterone levels exists in healthy men. A search of the literature between 1971 and July 2024 was performed, selecting study groups in which testosterone serum levels were measured for any reason in healthy men. Exclusion criteria were: (i) age < 18 years old, (ii) conditions affecting testosterone levels, (iii) subjects’ enrolment based on testosterone serum levels and (iv) blood examinations performed in a time-frame interval > 10 years. Secondary endpoints: luteinising hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG) serum levels and body mass index (BMI). 1,256 papers, accounting for 1,504 study groups, were selected, including 1,064,891 subjects (age 42.0 ± 7.0 years). A significant negative linear regression between testosterone serum levels and year of measurement was detected (p = 0.033). The comprehensive decline in testosterone serum levels over the years was confirmed adjusting meta-regression analysis using the number of subjects included in each study, subjects’ age, BMI and the the assay used for testosterone measurement. No temporal trend was observed regarding BMI in this population. LH serum levels showed a significant decline over the years, adjusting for subjects’ age, while no trend emerged considering FSH. This study is the first comprehensive analysis suggesting a progressive decrease in serum testosterone and LH levels in healthy men, independent of age and BMI. The observed decline in both testosterone and LH levels could be a consequence of an ongoing resetting of the hypothalamic-pituitary-testicular function.

Luteinizing hormone (LH) and human choriogonadotropin (hCG) support distinct reproductive events via differential activation of the luteinizing hormone receptor (LHCGR). LH-mediated LHCGR trafficking is known to be key in activating and regulating its signal responses, yet whether LH and hCG differentially direct LHCGR trafficking is unknown. Bioluminescence resonance energy transfer (BRET) trafficking biosensors and high-resolution TIRF imaging demonstrated that LH induces rapid internalization and recycling via an APPL1-linked very early endosomal pathway, while hCG-mediated receptor trafficking and recycling is slower, and preferentially involves β-arrestins and accumulation in endocytic compartments positive for early and late endosomal markers. Receptor internalization was differentially required for Gq, Gi and Gs protein-mediated signals, revealing distinct LH- vs hCG-trafficking signatures that may be fundamental to preserving unique hormone signalling patterns and their impact at the genomic level. This study supports different LH vs hCG modes of action on the LHCGR through differential post-endocytic sorting of the receptor, providing a potential 'location bias' mechanism underlying the distinct physiological roles of these two gonadotropins. Short title: LH vs hCG receptor internalization.

Idiopathic male infertility can be empirically treated with follicle-stimulating hormone (FSH). Although this hormonal stimulation is not focused on the causes behind spermatogenesis impairment, its efficacy should be evaluated considering the couple. This study aimed to assess the FSH efficacy in male idiopathic infertility, considering the infertile couples. A retrospective, observational, real-world study was carried out. Male partner of infertile couples were enrolled and divided according to FSH administration: Group (1) Study group, FSH-treated; Group (2) Control group, non-FSH-treated. Group 1 was then subdivided according to the attending assisted reproduction technology (ART) procedure: Group 1 A. Couples attending ART; Group 1B. Couples non attending ART. For Group 1, baseline (FSH first prescribed) and follow-up (FSH stopped) evaluations were recorded, while Group 2 was evaluated only at baseline. 1951 men were enrolled (Group 1 A: 25, Group 1B:140, Group 2:1786). The pregnancy rate was higher in study than control groups, not statistical significance (31.7

Differentiated thyroid carcinoma (DTC) incidence is rising globally, with a higher prevalence in women. Male patients often present with more aggressive disease, leading to more frequent use of radioactive iodine (RAI) therapy. While the gonadotoxic effects of RAI in females have been studied, its impact on male reproductive health remains unclear. This study is aimed to assess the effects of RAI therapy on gonadal function in men with DTC, focusing primarily on follicle-stimulating hormone (FSH) serum levels as a biomarker of testicular function. We analyzed studies reporting FSH levels before and after RAI administration in male DTC patients. The primary outcome was the change in FSH levels over time, with secondary outcomes including luteinizing hormone (LH) levels and semen parameters. Seven studies comprising 460 men met inclusion criteria. FSH levels significantly increased 12 months post-RAI (mean difference6.56 IU/L; p < 0.001), but not at 3 or 6 months. Meta-regression revealed that FSH elevation was positively associated with patient age and RAI dosage. No significant changes were observed in LH levels or standard semen parameters. Despite high heterogeneity (I²=99

Gonadotropins and anti-Müllerian hormone (AMH) regulate reproductive development and ovarian function. While AMH plays a well-established role in early folliculogenesis by counteracting gonadotropins, luteinizing hormone (LH) becomes more active later, during the antral phase, when granulosa and theca cells express their respective receptors. There are hints suggesting the existence of an interplay between these hormones regulating granulosa cell functions at late stages of the folliculogenesis., but the mechanisms remain unclear. In this context, we explored whether gonadotropin LH can modulate AMH action in cells of ovarian origin. Primary human granulosa lutein cells isolated from in vitro fertilization (IVF) patients were pretreated with recombinant LH, followed by stimulation with recombinant AMH. AMH receptor type II (AMHR2) expression, AMH signaling activation, and the expression of AMH-responsive genes were assessed through RT-PCR, ELISA, and Western blotting. The involvement of the LH receptor was confirmed using siRNA-mediated knockdown. Our findings showed that LH treatment downregulates AMHR2 transcripts and protein, impairing AMH-induced phosphorylation of small mothers against decapentaplegic (SMAD) 1, 5, and preventing osterix (OSX) and matrix metalloprotease 2 (MMP2) gene expression. These data are consistent with the possible interplay between gonadotropins and AMH in cells from antral/luteal stages and provide the molecular basis for further studies evaluating the impact of LH in modulating AMH signaling and follicular responsiveness during the antral stage.