Administration Of Follicle-stimulating Hormone Research Articles

C/EBPβ/δ‐secretase Signaling Drives Neurodegenerative Diseases

AbstractBackgroundC/EBPb/AEP pathway are escalated in the brain in an age‐dependent manner and proteolytically cleaves APP and Tau and a‐Synuclein, facilitating AD and PD pathologies.MethodC/EBPb/AEP pathway couples different risk factors that elicit inflammation to Alzheimer’s disease. To explore why women are more vulnerable for AD, we investigated different hormones altered during menopause and found FSH (follicle‐stimulating hormone) strongly activated this signalling, leading to AD pathogenesis in different mouse models. Employing immuno‐EM and knockout tissues, we demonstrated that FSHR is expressed in mouse and human brain neurons. Notably, FSH administration drives AD onset in young male and female mice, whereas anti‐FSH robustly diminishes AD progression in overiactomized female 3xTg mice. Moreover, deletion of FSHR or C/EBPb from the neurons of 3xTg mice attenuates AD pathologies.ResultElevated FSH during menopause activates C/EBPb/AEP signalling, which subsequently cleaves both APP and Tau, triggering AD onset. Blockade of FSH abrogates overiactomy‐induced AD pathologies and restores the cognitive dysfunctions in AD mouse models.ConclusionFSH elevation after menopause elicits women susceptibility to AD via activating C/EBPb/AEP pathway. Inhibition of FSH/FSHR may provide an innovative therapeutic strategy for treating AD.

Gonadotropins in the Management of Couple Infertility: Toward the Rational Use of an Empirical Therapy.

Although epidemiology shows that both men and woman can experience infertility, the female partner usually experiences most of the diagnostic and therapeutic burden. Thus, management of couple infertility is a unique example of gender inequality. The use of exogenous gonadotropins in assisted reproductive technology (ART) to induce multifollicular growth is well consolidated in women, but the same is not done with the same level of confidence and purpose in infertile men. Indeed, the treatment of idiopathic male infertility is based on an empirical approach that involves administration of the follicle-stimulating hormone (FSH) in dosages within the replacement therapy range. This treatment has so far been attempted when the endogenous FSH serum levels are within the reference ranges. According to the most recent evidence, a "substitutive" FSH administration may not be effective enough, while a stimulatory approach could boost spermatogenesis over its basal levels without adverse extragonadal effects. This article aims to describe the rationale behind the empirical application of gonadotropins in couple infertility, highlighting the need for a change in the therapeutic approach, especially for the male partner.

FSH and ApoE4 contribute to Alzheimer’s disease-like pathogenesis via C/EBPβ/δ-secretase in female mice

Alzheimer’s disease (AD) is the most common dementia. It is known that women with one ApoE4 allele display greater risk and earlier onset of AD compared with men. In mice, we previously showed that follicle–stimulating hormone (FSH), a gonadotropin that rises in post–menopausal females, activates its receptor FSHR in the hippocampus, to drive AD–like pathology and cognitive impairment. Here we show in mice that ApoE4 and FSH jointly trigger AD-like pathogenesis by activating C/EBPβ/δ-secretase signaling. ApoE4 and FSH additively activate C/EBPβ/δ-secretase pathway that mediates APP and Tau proteolytic fragmentation, stimulating Aβ and neurofibrillary tangles. Ovariectomy-provoked AD-like pathologies and cognitive defects in female ApoE4-TR mice are ameliorated by anti-FSH antibody treatment. FSH administration facilitates AD-like pathologies in both young male and female ApoE4-TR mice. Furthermore, FSH stimulates AD-like pathologies and cognitive defects in ApoE4-TR mice, but not ApoE3-TR mice. Our findings suggest that in mice, augmented FSH in females with ApoE4 but not ApoE3 genotype increases vulnerability to AD-like process by activating C/EBPβ/δ-secretase signalling.

Predictive role of 17α-hydroxy-progesterone serum levels of response to follicle-stimulating hormone in patients with abnormal sperm parameters

To study the possible role of serum 17α-hydroxy-progesterone (17αOH-P) levels in predicting favorable responses to follicle-stimulating hormone (FSH) administration in patients with normal serum FSH levels and idiopathic abnormal sperm parameters. Prospective cohort study. University-affiliated fertility center. Fifty patients with oligozoospermia, asthenozoospermia, and/or teratozoospermia and normal serum levels of gonadotropins and total testosterone (TT). Treatment with exogenous FSH is administered subcutaneously at a dose of 150 IU 3 times a week for 3 consecutive months. Luteinizing hormone levels, FSH levels, TT levels, 17αOH-P levels, testicular volume, conventional sperm parameters, and seminal spermatid concentration were evaluated before and after therapy. To evaluate the predictive role of pretreatment serum 17αOH-P levels on FSH responsiveness, the doubling of sperm concentration at the end of the FSH administration was considered a positive outcome. After therapy, patients showed a significant increase in sperm concentration, total sperm count (TSC), progressive motility, percentage of normal forms, FSH levels, TT levels, and testicular volume. There was a negative correlation between pretreatment 17αOH-P levels and the posttreatment increase in sperm concentration, TSC, progressive motility, and normal morphology, and a positive correlation with the posttreatment increase in spermatids. Predictive analysis showed that 17αOH-P levels (<1.18 ng/mL) foretold a doubling of sperm concentration with a sensitivity of 90.0% and a specificity of 73.3%, and of TSC with a sensitivity of 91.3% and a specificity of 81.48%. The results of this study suggest that pretreatment serum levels of 17αOH-P, a marker of steroidogenic function, appear to be able to predict the success of subcutaneous administration of exogenous FSH in terms of spermatogenesis improvement. Receiver operating characteristic curves indicated that 17αOH-P levels (<1.18 ng/mL) predict a doubling of sperm concentration and TSC after exogenous FSH administration to patients with idiopathic abnormal sperm parameters and normal gonadotropin levels.

Sperm Concentration Improvement May Be a Parameter Predicting Efficacy of FSH Therapy of Male Idiopathic Infertility.

Testis stimulation with follicle-stimulating hormone (FSH) is one of the empirical treatments proposed for male idiopathic infertility, although reliable markers to predict its efficacy are still lacking. This study aimed to identify parameters able to predict FSH efficacy in terms of pregnancy achievement. A real-world study was conducted, enrolling idiopathic infertile men treated with FSH 150IU three times weekly. Patients were treated until pregnancy achievement or for a maximum of two years and two visits were considered: V0 (baseline) and V1 (end of FSH treatment). Primary endpoints were the V1-V0 percentage change in sperm concentration, total sperm count, and total motile sperm number. In total, 48 pregnancies were recorded (27.7%) among 173 men (age 37.9 ± 6.2 years). All three endpoints increased after FSH administration, and only the V1-V0 percentage of sperm concentration significantly predicted pregnancy (p = 0.007). A V1-V0 sperm concentration of 30.8% predicted pregnancy, and the sperm concentration V1-V0 percentage (Y) required to obtain a pregnancy was predicted according to its baseline values (x): Y = 9.8433x2 - 203.67x + 958.29. A higher number of pregnancies was reached in men with baseline sperm concentration below 7.3 million/mL. Thus, the percentage of sperm concentration increasing after FSH administration could predict the treatment efficacy in terms of pregnancy. At the dosage used, the efficacy was significantly higher in patients with a starting sperm concentration < 7.3 mill/mL. Mathematical analyses identified a function able to predict the sperm concentration increase required to obtain a pregnancy in relation to the baseline sperm number.

The impact of FSH stimulation and age on the ovarian and uterine traits and histomorphometry of prepubertal gilts

This study investigated the effect of age and follicle stimulating hormone (FSH) treatment on the estradiol (E2) plasma concentration, ovarian follicle development, endometrial histomorphometry, and ultrasonographic parameters of the ovaries and uterus in prepubertal gilts. Thirty-five prepubertal gilts were grouped according to age (140 or 160 d), and within each age, gilts were allotted to receive 100 mg of FSH (treated; G140 + FSH [n = 10] and G160 + FSH [n = 7]) or saline solution (control; G140 + control [n = 10] and G160 + control [n = 8]). The total dose of FSH was divided into 6 similar doses administered every 8 h (days 0–2). Before and after FSH treatment, blood sample was collected, and transabdominal scanning of the ovaries and uterus was performed. Twenty-four hours after the last FSH injection, the gilts were slaughtered and their ovaries and uterus were processed for histological and histomorphometric analysis. The histomorphometric parameters of the uterus differed (P < 0.05) between prepubertal gilts at 160 d and 140 d of age. Moreover, changes (P < 0.05) in uterine and ovarian ultrasound images occurred between 140 and 160 d of age. Age and FSH treatment did not affect (P > 0.05) E2 plasma concentrations. Follicle stimulating hormone treatment did not affect (P > 0.05) the early stage of folliculogenesis in the prepubertal gilts; however, the number of early atretic follicles decreased (P < 0.05) after the FSH treatment. Follicle stimulating hormone administration increased (P < 0.05) the number of medium follicles and decreased (P < 0.05) the number of small follicles in 140 and 160 d old gilts. In the endometrium, luminal/glandular epithelium height and glandular diameter increased (P < 0.05) after FSH treatment. Thus, injections of 100 mg of FSH stimulate the endometrium epithelium and induce follicular growth to a medium follicle size without affecting the preantral stages in prepubertal gilts; also, the uterine macroscopic morphometry does not change from 140 to 160 d of age.

Follicle-stimulating hormone effectiveness in male idiopathic infertility: What happens in daily practice?

To assess the effectiveness of follicle-stimulating hormone (FSH) administration in male idiopathic infertility in a clinical setting. A retrospective real-world study was carried out, including all consecutive FSH-treated infertile men attending the Andrology Unit of Modena (Italy) from June 2015 to May 2022. Medical history, physical and andrological examinations, hormonal and seminal parameters, therapeutic management and pregnancy data were collected. The primary endpoint was the number of pregnancies obtained after FSH administration, whereas semen parameters change was the secondary outcome. A total of 194 of 362 (53.6%) infertile men, eligible according to the Italian Health System regulations, were treated with FSH (mean age 37.9±6.1 years). Following FSH administration (mean therapy duration 9.1±7.1 months), 43 pregnancies were recorded (27.6%), of which 22 occurred naturally and 21 after assisted reproduction. A significant increase in sperm concentration (9.9±12.2 vs. 18.9±38.9 million/mL, p=0.045) was detected after treatment, together with a significant increase in normozoospermia (from 1.0% to 5.1%, p=.044) and a reduction in azoospermia rate (from 9.8% to 7%, p=0.044). Dividing the cohort in FSH-responders and non-responders, in terms of pregnancy achieved, higher sperm concentrations (15.7±26.6 vs. 22.2±25.7 million/mL, p=0.033) and progressive sperm motility (18.0±18.2 vs. 27.3±11.3, p=0.044) were found in pregnancy group. Our experience suggests that FSH, empirically administered to men with idiopathic infertility, leads to pregnancy in one out of four patients and increases sperm concentration. Although the expected limits because of a real-world data study, the number of FSH-treated patients required to achieve one pregnancy seems to be lower in clinical setting if compared to previously published data.

Real-world evidence analysis of the follicle-stimulating hormone use in male idiopathic infertility.

Male idiopathic infertility remains a therapeutic challenge in the couple infertility management. In this setting, an empirical treatment with follicle-stimulating hormone (FSH) is allowed, although not recommended. Twenty-one clinical trials and four meta-analyses highlighted an overall increased pregnancy rate in case of FSH administration, but the indiscriminate FSH prescription is still unsupported by clinical evidence in idiopathic infertility. This context could represent an example in which real-world data (RWD) could add useful information. From a nationwide clinical practice survey performed in Italy, emerged the clinicians' attitude to prescribe FSH in the case of impaired semen with a significant improvement of semen parameters, identifying FSH treatment as a therapeutic card in the real-life management. Although more robust data are still needed to optimize FSH treatment in male idiopathic infertility, RWD should be included in the body of evidence considered in healthcare decision-making.

Testosterone Serum Levels Are Related to Sperm DNA Fragmentation Index Reduction after FSH Administration in Males with Idiopathic Infertility.

Purpose: Although a robust physiological rationale supports follicle stimulating hormone (FSH) use in male idiopathic infertility, useful biomarkers to evaluate its efficacy are not available. Thus, the primary aim of the study was to evaluate if testosterone serum levels are related to sperm DNA fragmentation (sDF) index change after FSH administration. The secondary aim was to confirm sDF index validity as a biomarker of FSH administration effectiveness in male idiopathic infertility. Methods: A retrospective, post-hoc re-analysis was performed on prospectively collected raw data of clinical trials in which idiopathic infertile men were treated with FSH and both testosterone serum levels and sDF were reported. Results: Three trials were included, accounting for 251 patients. The comprehensive analysis confirmed FSH’s beneficial effect on spermatogenesis detected in each trial. Indeed, an overall significant sDF decrease (p < 0.001) of 20.2% of baseline value was detected. Although sDF resulted to be unrelated to testosterone serum levels at baseline, a significant correlation was highlighted after three months of FSH treatment (p = 0.002). Moreover, testosterone serum levels and patients’ age significantly correlated with sDF (p = 0.006). Dividing the cohort into responders/not responders to FSH treatment according to sDF change, the FSH effectiveness in terms of sDF improvement was related to testosterone and male age (p = 0.003). Conclusion: Exogenous FSH administration in male idiopathic infertility is efficient in reducing sDF basal levels by about 20%. In terms of sDF reduction, 59.2% of the patients treated were FSH-responders. After three months of FSH administration, a significant inverse correlation between sDF and testosterone was detected, suggesting an association between the FSH-administration-related sDF improvement and testosterone serum levels increase. These observations lead to the hypothesis that FSH may promote communications or interactions between Sertoli cells and Leydig cells.

O-132 Is there an association between sDF index and serum testosterone in human follicle stimulating hormone alfa (r-hFSH alfa) treated males with idiopathic infertility?

Abstract Study question Is there correlation between testosterone serum levels and sperm DNA fragmentation (sDF) index before and after follicle-stimulating hormone (FSH) administration in male idiopathic infertility? Summary answer Correlation between testosterone and sDF was highlighted for the first time in FSH-treated men. Significant amelioration of conventional semen parameters and sDF index were confirmed. What is known already Testicular overstimulation is the yearned therapeutic goal when exogenous FSH is empirically administered in male idiopathic infertility. Although a robust physiological rationale theoretically supports the FSH use in male idiopathic infertility, useful markers to evaluate its efficacy are still far to be identified. Whether pregnancy outcomes remain the expected valuable endpoint for couple infertility treatment, the identification of reliable, and possibly early, markers of therapeutic response to FSH in males is mandatory. Randomized controlled clinical trials (RCTs) on this topic focused, as main outcomes of FSH treatment effectiveness, on testicular seminiferous component, not considering involvement of testosterone-secreting compartment. Study design, size, duration A retrospective post-hoc analysis of raw data extracted from two RCTs in which 148 idiopathic infertile men were treated with FSH. Participants/materials, setting, methods A retrospective post-hoc re-analysis was performed on raw data of RCTs in which idiopathic infertile men were treated with FSH and both testosterone serum levels and sDF were reported among primary and/or secondary endpoints. Additional data regarding couple infertility history, age, anthropometric variables, FSH treatment scheme and semen variables were included in a single dataset. Data were evaluated by logistic regression analyses. Main results and the role of chance Two RCTs were included accounting for 148 patients (median age 37, 25-52 years). After three months of FSH administration, a significant increase was observed in FSH levels (p &amp;lt; 0.001), inhibin B (p = 0.012), sperm concentration (p = 0.003), total sperm number (p = 0.021), progressive motility (p &amp;lt; 0.001) and normal sperm morphology (p &amp;lt; 0.001). Moreover, an overall sDF index reduction was confirmed after treatment (19.3±9.4 versus 16.4±6.8, p = 0.002). SDF was found significantly inversely related to sperm concentration both at baseline and after FSH treatment (Rho -0.325, p &amp;lt; 0.001 and Rho -0.316, p = 0.001, respectively). Interestingly, sDF index after treatment showed a significant inverse correlation with testosterone serum levels (Rho -0.327, p = 0.002). Multivariate stepwise linear regression analyses using sDF index as dependent variable identified testosterone as a predictor for sDF index change (p = 0.005). Similarly, logistic regression analysis highlighted testosterone and SHBG levels as predictive of sDF reduction after FSH administration (p = 0.043 and p = 0.005, respectively). Combining raw data of published RCTs investigating FSH administration to idiopathic infertile men, a significant amelioration of conventional semen parameters together with a reduction in sDF were confirmed. Intriguingly, a potential correlation between serum testosterone and sDF was highlighted for the first time. Limitations, reasons for caution Since the analysis was performed on raw data obtained in previous RCTs, heterogeneity among patients enrolled and evaluated should be considered interpreting these results. Moreover, a real and accurate evaluation of intratesticular testosterone levels, rather than serum levels should be more informative to the objective of the study. Wider implications of the findings The highlighted significant correlation between testosterone serum levels and sDF is opening a completely unexplored field in the possibility to identify early predictors of FSH therapy response in male idiopathic infertility. Trial registration number Not applicable

O-069 Does dual stimulation with continuous FSH administration increase the total number of metaphase II oocytes in poor responders?

Abstract Study question Is there an increase in the total number of metaphase II (MII) oocytes between a conventional ovarian stimulation and a dual uninterrupted stimulation? Summary answer Dual stimulation with continuous follicle stimulating hormone (FSH) administration is not superior to conventional stimulation in terms of number of MII oocytes. What is known already In the last decade, the concept of multiple follicular waves during one menstrual cycle has gained a lot of interest. Translated into clinical practice, combining two stimulations in the same ovarian cycle has appeared beneficial with regard to the number of retrieved oocytes, without affecting the embryo quality or ploidy status. Usually, this so-called dual stimulation approach is characterized by a discontinuation of FSH administration for approximately 5 days between two consecutive stimulations. The role of dual uninterrupted ovarian stimulation has not yet been studied. Study design, size, duration This was an open-label randomized controlled trial (RCT) with superiority design, performed in a single tertiary center. Power analysis indicated a required sample of 46 patients to detect superiority (defined as two surplus MII oocytes) of the dual stimulation group. Between October 2020 and September 2021, 70 patients were screened, 48 were randomized and 46 completed the study. Participants/materials, setting, methods Women aged 25-40 with a serum anti-Müllerian hormone (AMH) level of ≤ 1.5 ng/mL, antral follicle count (AFC) of ≤ 6, or ≤ 5 oocytes after a previous stimulation, were eligible for inclusion. Randomization occurred only in case of ≤ 9 follicles of ≥ 11mm on the trigger day. In the control group, patients underwent one round of ovarian stimulation and oocyte retrieval only, while the study group had two uninterrupted rounds of ovarian stimulation and two retrievals. Main results and the role of chance Baseline characteristics were similar between both groups. The cumulative number of COC and MII oocytes after completion of the second oocyte retrieval was similar in the control and study group [5.3 ± 2.7 versus 5.3 ± 3.1 [difference 95%CI (-1.7 to 1.7), p = 0.92] and 4.1 ± 2.5 versus 4.3 ± 2.7 [difference 95%CI (-1.7 to 1.3), p = 0.82]. Likewise, a comparable number of good quality embryos at day 3 was available (3.0 ± 2.0 versus 2.7 ± 2., p = 0.63). In the study group, the cancellation rate due to insufficient response to the second round of stimulation was 39.1%. When focusing on the first stimulation in both groups, there were no significant differences regarding basal FSH, FSH consumption and the number of preovulatory follicles. After the first oocyte retrieval, the mean number of COC and MII oocytes was significantly higher in the control group (who had human chorionic gonadotropin (hCG) triggering), compared to the study group (who had Gonadotropin Releasing Hormone (GnRH) agonist triggering) (5.3 ± 2.7 versus 3.3 ± 2.2, p = 0.004 and 4.2 ± 2.4 versus 2.9 ± 2.2, p = 0.05). Likewise, the number of good quality embryos on day 3 was significantly higher (3.0 ± 2.0 versus 1.9 ± 1.7, p = 0.04). Limitations, reasons for caution This study was powered to demonstrate superiority for number of MII oocytes. Investigating the impact of dual stimulation on pregnancy rates would have required a larger sample size. Wider implications of the findings The observed suboptimal oocyte yield after agonist triggering in poor responders is a reason for concern and further scrutiny, given that previous RCTs have shown similar outcomes in normal and high responders after hCG and GnRH agonist trigger. Trial registration number NCT03846544

Follicle stimulating hormone promotes production of renin through its receptor in juxtaglomerular cells of kidney

BackgroundPost-menopausal hypertension has been attributed solely to declining estrogen levels. The purpose of the research is to elucidate the mechanism by which follicle stimulating hormone(FSH) increases renin production involved in the regulation of blood pressure.MethodsThe expression of follicle stimulating hormone receptors (FSHRs) in renal juxtaglomerular cells and a As4.1 juxtaglomerular mouse cell line was evaluated. We established a mouse model by ovariectomy (OVX). Ovariectomized mice were treated with gonadotropin-releasing hormone agonist (GnRHa) (OVX + GnRHa). Ovariectomized mice initially received physiological doses of estrogen and were then injected with recombinant FSH (OVX + E + FSH).ResultsWe found that FSHR was expressed in mouse renal juxtaglomerular cells labeled by renin antibody and in As4.1 cells. FSH promoted renin synthesis via Gsα-coupled FSHRs that activated protein kinase A, cyclic adenosine monophosphate(cAMP) response element-binding protein, extracellular signal-regulated kinase (Erk1/2), Protein kinase B(AKT), and c-Jun N-terminal kinase signaling pathways in As4.1 cells. We found increased serum FSH levels in the ovariectomized mouse with concurrent increases in renin, angiotensin II, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP). Additionally, increases in serum renin, angiotensin II, HR, SBP, DBP, and MAP were reduced by the additional injection of GnRHa. Exogenous FSH administration completely reversed decreases in renin, angiotensin II, HR, SBP, DBP, and MAP even in mice that received physiological doses of estrogen to maintain normal estradiol levels.ConclusionsElevated FSH stimulates renin production involving a mechanism that may be relevant to the expression of FSH receptors in renal juxtaglomerular cells.

The Effect of Epidural Application of FSH on Superovulatory Response in Eastern Anatolian Red Cow

This study aimed to evaluate the superovulation response in Eastern Anatolian Red (EAR) cows treated with a single epidural injection or traditional administration of follicle stimulating hormone (FSH). Eight cows were randomly divided into two groups, as control (CG) and experiment (EG). Four replications were applied for each animal in the groups. A total of 16 studies were carried out in each group. In this study, 300 mg intramuscular (i.m) FSH injection was applied with decreasing doses twice daily for four days to the cows in the CG. (70:70, 50:50, 20:20, 10:10 mg). On the other hand, 300 mg FSH was administered as 150 mg epidural and 150 mg intramuscular injection to the cows in EG. The number of untransferable embryos and the total CLs were found statistically significant (p&amp;lt;0.05). However, the number of transferable embryos and unfertilized oocyte (UFO) were found statistically insignificant among the groups (p&amp;gt;0.05). According to the obtained data, it was observed that the epidural administration of FSH for superovulation in EAR cows did not provide sufficient follicle and oocyte development. In conclusion, different studies with different superovulation protocols and FSH doses in local breed EAR cows will be needed for further studies.

P–650 Body weight is the main determinant of systemic follicle stimulating hormone (FSH) concentrations during controlled ovarian stimulation with follitropin delta

Abstract Study question Which individual subject characteristics affect systemic FSH concentrations in women undergoing controlled ovarian stimulation with follitropin delta? Summary answer Body weight is the main determinant of systemic FSH concentrations. Renal function, Asian race, country/region, hepatic function and age have at most a small influence. What is known already After administration of FSH, systemic FSH concentrations are inversely related to body weight. It has been observed that the impact of body weight on ovarian response is clinically relevant at low doses but not at high doses. In patients with anti-Müllerian hormone (AMH) ≥15 pmol/L, follitropin delta is dosed according to each patient’s body weight, which influences systemic FSH concentrations, and her AMH level which predicts ovarian response. Study design, size, duration Serum FSH concentrations were assessed in five randomised, controlled, assessor-blinded, multicentre trials of follitropin delta in women undergoing an assisted reproductive technology programme. The trials were conducted in Europe, America and Asia. In all, 1.665 women treated with follitropin delta contributed to the evaluation with 4052 serum FSH concentrations, measured at steady state by an immunoassay. Participants/materials, setting, methods FSH concentrations were described with a pre-specified one-compartment population pharmacokinetic model. The key model parameters were the apparent total clearance (CL/F) of follitropin delta, the interindividual variability herein and the effects of baseline values of body weight, age, race, country/region, renal and hepatic function on CL/F. Renal function was assessed using the estimated glomerular filtration rate (eGFR) and hepatic function by alanine transaminase (ALT) and bilirubin levels. Main results and the role of chance The area under the FSH concentration-time curve during a dosing interval (AUC) was derived from dose and CL/F. Body weight was the covariate with the most pronounced effect on AUC, both in terms of the effect magnitude and statistical significance. AUC was 1.51-fold higher (90% confidence limits: 1.48; 1.54) in women with the lowest observed body weight of 40 kg compared to women with a typical body weight of 58 kg. The effect of renal function on AUC was small and in the same order of magnitude as the bioequivalence limits (0.8; 1.25). AUC was 1.28-fold higher (90% confidence limits: 1.23; 1.33) in women with the lowest observed eGFR value of 44 mL/min/1.73m2, compared to women with a typical eGFR value of 98 mL/min/1.73m2. The effects of Asian race and country/region (Japan, China, Other Asian) were confounded with each other and well within the bioequivalence limits when evaluated independently. The effects of age and the hepatic function markers ALT and bilirubin were well within the bioequivalence limits. Limitations, reasons for caution The women participating in the trials were generally healthy and the results cannot be transferred to women with renal or hepatic disease. A limited number of Black women contributed to the present analysis but the trend was similar. Data is forthcoming from ongoing trials including larger numbers of Black women. Wider implications of the findings: The findings support dosing follitropin delta by body weight and without adjustment for renal function, hepatic function, race, age or country/region. Trial registration number NCT01426386, NCT02309671, NCT01956110, NCT03228680 and NCT03296527

Effects of FSH treatment and withdrawal during proestrus on uterine proliferation and steroid hormone receptor expression in beef heifers.

To determine the effects of Follicle Stimulating Hormone (FSH) treatment and subsequent withdrawal on uterine proliferation and estrogen receptor (ESR), Brahman crossbred heifers (n = 12) were twice daily injected with FSH (4, 3, and 2 mg/injection) on Days 17-19 of the estrous cycle (FSH 3 days) and (4 and 3 mg/injection) on Days 17-18 (FSH 2 days) and withdrawal with saline on Day 19 and (4 mg/injection) on Day 17 (FSH 1 day) and withdrawal with saline on Days 18-19. Uterine tissue was subjectively collected on Day 20 and microscopically classified to four regions: endometrial stroma (ES), surface endometrial gland (EG), deep endometrial gland (DG), and myometrium (Myo). The cell proliferation marker, Ki-67, was quantified as labeling index (LI) in uterine regions, and tissues were immunostained to detect ESR2 followed by image analysis. The LI of ES, EG, and DG was greater (P = 0.0018, P = 0.0005, and P = 0.0103; respectively) in heifers received FSH for 3 days. The expression of ESR2 protein on ES and EG was greatest (P < 0.0001 and P = 0.0036, respectively) in FSH 3 days-treated group. Thus, FSH administration during proestrus stimulates uterine cell proliferation, and ESR2 expressions are affected by FSH during proestrus and differentially distributed in the uterine regions.

FSH Stimulation with Short Withdrawal Improves Oocyte Competence in Italian Mediterranean Buffalo (Bubalus bubalis).

Simple SummaryThe high embryo production cost in buffalo, compared to cattle, is currently the major factor limiting the commercial application of ovum pick-up and in vitro embryo production technologies. This is mainly due to the lower number of follicles that develop during each estrous cycle and consequently oocytes recovered per session. In this work, we tested two different hormonal treatments based on commercial follicle-stimulating hormone (FSH) and progesterone (P4) to enhance the number of follicles and competent oocytes. Furthermore, in the second experiment, we tested three different coasting times, i.e., periods between the last FSH administration and ovarian aspiration, which is known be the key period for the final oocyte maturation and competence acquisition. The results, in terms of number of aspirated follicles, oocyte quality, blastocyst yield, and superior quality blastocyst yield, allow us to suggest the use of high doses of FSH (40 mg given six times every 12 h) combined with the shorter coasting time (28–32 h) as the ideal protocol for ovarian superstimulation in buffalo.The aim of this work was to evaluate the efficiency of different FSH doses and FSH coasting times before ovum pick-up (OPU) on follicular growth and oocyte competence in buffalo. Experiment 1 involved two different FSH treatments: 40 mg FSH given three (FSH3) or six (FSH6) times, 2 days after dominant follicle removal were tested, with OPU carried out after 40–44 h of coasting. In experiment 2, OPU was carried out after FSH6 protocol followed by 28–32 h (C1), 40–44 h (C2), or 64–68 h (C3) of coasting time. Cumulus oocyte complexes (COCs) were classified, in vitro matured, fertilized, and cultured. The results demonstrated that FSH6 increased the total number of follicles, the number and percentages of medium and large follicles, the number and the proportion of good quality oocytes, and the number of grade 1,2 and fast-developing blastocysts compared to the control. C3 decreased the percentage of good quality oocyte and blastocyst rates compared to C1 and C2. A higher percentage of fast blastocysts and average number of grade 1,2 blastocysts was observed in C1 compared to C3, with intermediate values found in C2. The improved efficiency in terms of blastocyst yields suggests the use of FSH6 + C1 protocol for ovarian superstimulation in buffalo.

The Impact of Controlled Ovarian Stimulation Hormones on the Metabolic State and Endocannabinoid System of Human Cumulus Cells.

Different Follicle Stimulating Hormone (FSH) formulation and Luteinizing Hormone (LH) are used in Assisted Reproductive Technology (ART) to induce follicles development and oocytes maturation, but it is still under debate which protocol is to be preferred. In the present study, the different effects on cumulus cells (CCs) of three controlled ovarian stimulation (COS) protocols, based on urinary FSH, recombinant FSH, or human Menopausal Gonadotropin (hMG) administration, were assessed. CCs were obtained from 42 normal-responders women undergoing COS, randomly divided into three groups according to the used gonadotropin formulation. Differences were found in the expression of genes belonging to the endocannabinoid system (the receptors CNR1, CNR2 and TRPV1, and the enzymes involved in the metabolisms of anandamide, NAPE-PLD and FAAH, and 2-acylglycerol, DAGL and MAGL); consistently, changes in lipid (PPARα, and FASN) and carbohydrate (GLUT1 and GLUT9) metabolisms, in CCs’ macromolecules composition (highlighted by Fourier Transform Infrared Microspectroscopy, FTIRM), and in the number of retrieved oocytes were found. For the first time, statistically significant evidence on the differences related to each COS protocol on the endocannabinoid system, metabolism and macromolecular composition of CCs was found, representing a proof of concept to be further confirmed in a larger cohort of patients.

Enhancing effect of FSH on follicular development through yolk formation and deposition in the low-yield laying chickens

Healthy and efficient development of ovarian follicles largely determines poultry laying performance. In low-yield laying chickens, retarded follicle progression resulted in decreased prehierarchical follicles. In this study the extenuating effect of follicle-stimulating hormone (FSH) on delayed follicular development was investigated in the low-yield chickens. Results showed that FSH administration in vivo accelerated development of prehierarchical follicles, with increased expression of steroidogenic enzymes and follicular angiogenesis through elevating plasma levels of 17β-estradiol, progesterone, luteinizing hormone and the expression of vascular endothelial growth factor and its receptor as well as angiopoietins. Furthermore, treatment with FSH raised expression of lipid uptake and adipogenesis-related proteins and decreased tight junctions between granulosa cells. Meanwhile, the results of the in vivo studies were confirmed by the in vitro studies as FSH promoted development of the cultured prehierarchical follicles with increased angiogenesis, cell proliferation, steroid hormones synthesis and yolk deposition. These results indicated FSH enhanced follicular development in the low-yield laying chickens involving increased follicular angiogenesis.

Follicle-Stimulating Hormone Treatment and Male Idiopathic Infertility: Effects on Sperm Parameters and Oxidative Stress Indices according to FSHR c. 2039 A/G and c. -29 G/A Genotypes.

Scientific evidence shows that the administration of follicle-stimulating hormone (FSH) to infertile patients with normal serum FSH concentrations improves sperm parameters in oligozoospermic men. The aim of this study was to evaluate the effects of highly purified urofollitropin (hpFSH) on conventional and bio-functional sperm parameters and on oxidative stress indices in patients with idiopathic infertility. We also evaluated the response to hpFSH on these parameters in relationship to FSHR c. 2039 A/G and FSHR c. -29 G/A genotypes. A prospective longitudinal study was conducted on 42 patients with idiopathic male infertility, 23 of whom underwent to FSHR c. 2039 A/G and FSHR c. -29 G/A genotyping. Each patient was asked to collect two semen samples before and after administration of 150 IU hpFSH three times a week for 16 weeks. Patients were divided into responders or non-responders based on whether their total sperm count had at least doubled or was less than double at the end of treatment, respectively. Responders showed a significantly higher semen volume, sperm concentration, spermatids, and leukocytes. Non-responders had a significant decrease of the percentage of spermatozoa in early apoptosis after hpFSH administration. Oxidative stress indexes did not differ significantly after FSH administration in both groups. Conventional and bio-functional sperm parameters did not differ in patients with FSHR c. 2039 GG and AA genotypes, and FSHR c. -29 GG genotype both before and after FSH administration. The FSHR c. 2039 and FSHR -29 G/A genotypes and allelic distribution did not differ between responders and non-responders. FSH showed to be capable of ameliorating sperm parameters in about half patients treated, therefore it may be helpful in patients with idiopathic infertility.

Prospects for FSH Treatment of Male Infertility.

Despite the new opportunities provided by assisted reproductive technology (ART), male infertility treatment is far from being optimized. One possibility, based on pathophysiological evidence, is to stimulate spermatogenesis with gonadotropins. We conducted a comprehensive systematic PubMed literature review, up to January 2020, of studies evaluating the genetic basis of follicle-stimulating hormone (FSH) action, the role of FSH in spermatogenesis, and the effects of its administration in male infertility. Manuscripts evaluating the role of genetic polymorphisms and FSH administration in women undergoing ART were considered whenever relevant. FSH treatment has been successfully used in hypogonadotropic hypogonadism, but with questionable results in idiopathic male infertility. A limitation of this approach is that treatment plans for male infertility have been borrowed from hypogonadism, without daring to overstimulate, as is done in women undergoing ART. FSH effectiveness depends not only on its serum levels, but also on individual genetic variants able to determine hormonal levels, activity, and receptor response. Single-nucleotide polymorphisms in the follicle-stimulating hormone subunit beta (FSHB) and follicle-stimulating hormone receptor (FSHR) genes have been described, with some of them affecting testicular volume and sperm output. The FSHR p.N680S and the FSHB -211G>T variants could be genetic markers to predict FSH response. FSH may be helpful to increase sperm production in infertile men, even if the evidence to recommend the use of FSH in this setting is weak. Placebo-controlled clinical trials, considering the FSHB-FSHR haplotype, are needed to define the most effective dosage, the best treatment length, and the criteria to select candidate responder patients.