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This research aims to document the harmful effects of exposure to aflatoxin-B1 in the prepubertal stage on the reproductive efficiency of male rats after puberty. Sixty male rats (35 days old) were divided equally into control and treatment groups. Control males were orally supplemented with distilled water. Treatment males were orally supplemented with aflatoxin-B1 (0.3mg/kg/day). After 15 days (50 days old; prepubertal stage), 25 days (60 days old; pubertal stage), and 35 days (70 days old; postpubertal stage) of treatment, ten males from each group were weighed, anesthetized, and blood samples were collected for assessment the serum concentrations of reproductive hormones. Pituitary and testicular tissue samples were obtained to analyze the expression levels of pituitary and testicular genes. Testes and epididymis were obtained for histopathological examination. Compared to control, treated males showed a decrease in serum concentration of gonadotrophin releasing hormone, follicle stimulating hormone, luteinizing hormone, and testosterone, and the expression level of pituitary GNRHR1, FSHβ, and LHβ genes and testicular LHR, FSHR, ABP, 3β-HSD, and 17β-HSD genes, in all experimental periods. Histological sections of the testicles of treated males showed atrophy of some seminiferous tubules, empty lumen, and massive vacuolization and exfoliation of the germ cells. The histological results of the epididymis showed obliteration of the lumen, necrosis of the epithelial layer, deformed cavities, a climbing epithelial layer, and epithelium hyperplasia compared to the control group. In conclusion, exposure to aflatoxin-B1 at the prepubertal stage can reduce reproductive efficiency at puberty.

Follicle stimulating hormone (FSH) is produced by the pituitary gland in a coordinated hypothalamic-pituitary-gonadal (HPG) axis event, plays important roles in reproduction and germ cell development during different phases of reproductive development (fetal, neonatal, puberty, and adult life), and is consequently essential for fertility. FSH is a heterodimeric glycoprotein hormone of two dissociable subunits, α and β. The FSH β-subunit (FSHβ) function starts upon coupling to its specific receptor: follicle-stimulating hormone receptor (FSHR). FSHRs are localized mainly on the surface of target cells on the testis and ovary (granulosa and Sertoli cells) and have recently been found in testicular stem cells and extra-gonadal tissue. Several reproduction disorders are associated with absent or low FSH secretion, with mutation of the FSH β-subunit or the FSH receptor, and/or its signaling pathways. However, the influence of FSH on germ cells is still poorly understood; some studies have suggested that this hormone also plays a determinant role in the self-renewal of germinative cells and acts to increase undifferentiated spermatogonia proliferation. In addition, in vitro, together with other factors, it assists the process of differentiation of primordial germ cells (PGCLCs) into gametes (oocyte-like and SSCLCs). In this review, we describe relevant research on the influence of FSH on spermatogenesis and folliculogenesis, mainly in the germ cell of humans and other species. The possible roles of FSH in germ cell generation in vitro are also presented.

Introduction: Polycystic ovary syndrome (PCOS) seems to be associated with increased ovarian sympathetic nerve activity and in rodent models of PCOS reducing the sympathetic drive to the ovary, through denervation or neuromodulation, improves ovulation rate. We hypothesised that sympathetic nerves work with gonadotropins to promote development and survival of small antral follicles to develop a polycystic ovary phenotype. Methods: Using a clinically realistic ovine model we showed a rich sympathetic innervation to the normal ovary and reinnervation after ovarian transplantation. Using needlepoint diathermy to the nerve plexus in the ovarian vascular pedicle we were able to denervate the ovary resulting in reduced intraovarian noradrenaline and tyrosine hydroxylase immunostained sympathetic nerves. We developed an acute polycystic ovary (PCO) model using gonadotrophin releasing hormone (GnRH) agonist followed infusion of follicle stimulating hormone (FSH) with increased pulsatile luteinising hormone (LH). This resulted in increased numbers of smaller antral follicles in the ovary when compared to FSH infusion suggesting a polycystic ovary. Results: Denervation had no effect of the survival or numbers of follicles in the acute PCO model and did not impact on ovulation, follicular and luteal hormone profiles in a normal cycle. Discussion: Although the ovary is richly inervated we did not find evidence for a role of sympathetic nerves in ovarian function or small follicle growth and survival. [ABSTRACT FROM AUTHOR]

IntroductionPolycystic ovary syndrome (PCOS) seems to be associated with increased ovarian sympathetic nerve activity and in rodent models of PCOS reducing the sympathetic drive to the ovary, through denervation or neuromodulation, improves ovulation rate. We hypothesised that sympathetic nerves work with gonadotropins to promote development and survival of small antral follicles to develop a polycystic ovary phenotype.MethodsUsing a clinically realistic ovine model we showed a rich sympathetic innervation to the normal ovary and reinnervation after ovarian transplantation. Using needlepoint diathermy to the nerve plexus in the ovarian vascular pedicle we were able to denervate the ovary resulting in reduced intraovarian noradrenaline and tyrosine hydroxylase immunostained sympathetic nerves. We developed an acute polycystic ovary (PCO) model using gonadotrophin releasing hormone (GnRH) agonist followed infusion of follicle stimulating hormone (FSH) with increased pulsatile luteinising hormone (LH). This resulted in increased numbers of smaller antral follicles in the ovary when compared to FSH infusion suggesting a polycystic ovary.ResultsDenervation had no effect of the survival or numbers of follicles in the acute PCO model and did not impact on ovulation, follicular and luteal hormone profiles in a normal cycle.DiscussionAlthough the ovary is richly inervated we did not find evidence for a role of sympathetic nerves in ovarian function or small follicle growth and survival.

Abstract Objective To explore the association between ovulation induction drugs and ovarian cancer. Design Systematic review and meta-analysis. Setting Not applicable. Patient(s) Women without ovarian cancer who ever or never underwent ovarian induction. Intervention(s) An extensive electronic search of the following databases was performed: PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library and CNKI, from inception until January 2022. A total of 34 studies fulfilled our inclusion criteria and were included in the final meta-analysis. The odds ratio (OR) and random-effects model were used to estimate the pooled effects. The Newcastle-Ottawa Scale was used to assess the quality of included studies. Funnel plots and Egger tests were used to assess publication bias. Main outcomes New diagnosed borderline ovarian tumor (BOT) and invasive ovarian cancer (IOC) between ovulation induction (OI) group and control (CT) group considering fertility outcome, OI cycles and specific OI drugs. Results Primarily, there was no significant difference in the incidence of IOC and BOT between the OI and CT groups. Secondly, OI treatment did not increase the risk of IOC and BOT in the multiparous women, nor did it increase the risk of IOC in the nulliparous women. However, the risk of BOT appeared to be higher in nulliparous women treated with OI treatment. Thirdly, among women exposed to OI, the risk of IOC and BOT was higher in nulliparous women than in multiparous women. Fourthly, the risk of IOC did not increase with increasing OI cycles. Lastly, exposure to specific OI drugs also did not contribute to the risk of IOC and BOT. Conclusion Overall, OI treatment did not increase the risk of IOC and BOT in most women, regardless of OI drug type and OI cycle. However, nulliparous women treated with OI showed a higher risk of ovarian cancer, necessitating their rigorous monitoring and ongoing follow-up.

STUDY QUESTION Can artificial intelligence (AI) algorithms developed to assist embryologists in evaluating embryo morphokinetics be enriched with multi-centric clinical data to better predict clinical pregnancy outcome? SUMMARY ANSWER Training algorithms on multi-centric clinical data significantly increased AUC compared to algorithms that only analyzed the time-lapse system (TLS) videos. WHAT IS KNOWN ALREADY Several AI-based algorithms have been developed to predict pregnancy, most of them based only on analysis of the time-lapse recording of embryo development. It remains unclear, however, whether considering numerous clinical features can improve the predictive performances of time-lapse based embryo evaluation. STUDY DESIGN, SIZE, DURATION A dataset of 9986 embryos (95.60% known clinical pregnancy outcome, 32.47% frozen transfers) from 5226 patients from 14 European fertility centers (in two countries) recorded with three different TLS was used to train and validate the algorithms. A total of 31 clinical factors were collected. A separate test set (447 videos) was used to compare performances between embryologists and the algorithm. PARTICIPANTS/MATERIALS, SETTING, METHODS Clinical pregnancy (defined as a pregnancy leading to a fetal heartbeat) outcome was first predicted using a 3D convolutional neural network that analyzed videos of the embryonic development up to 2 or 3 days of development (33% of the database) or up to 5 or 6 days of development (67% of the database). The output video score was then fed as input alongside clinical features to a gradient boosting algorithm that generated a second score corresponding to the hybrid model. AUC was computed across 7-fold of the validation dataset for both models. These predictions were compared to those of 13 senior embryologists made on the test dataset. MAIN RESULTS AND THE ROLE OF CHANCE The average AUC of the hybrid model across all 7-fold was significantly higher than that of the video model (0.727 versus 0.684, respectively, P  = 0.015; Wilcoxon test). A SHapley Additive exPlanations (SHAP) analysis of the hybrid model showed that the six first most important features to predict pregnancy were morphokinetics of the embryo (video score), oocyte age, total gonadotrophin dose intake, number of embryos generated, number of oocytes retrieved, and endometrium thickness. The hybrid model was shown to be superior to embryologists with respect to different metrics, including the balanced accuracy (P  ≤ 0.003; Wilcoxon test). The likelihood of pregnancy was linearly linked to the hybrid score, with increasing odds ratio (maximum P -value = 0.001), demonstrating the ranking capacity of the model. Training individual hybrid models did not improve predictive performance. A clinic hold-out experiment was conducted and resulted in AUCs ranging between 0.63 and 0.73. Performance of the hybrid model did not vary between TLS or between subgroups of embryos transferred at different days of embryonic development. The hybrid model did fare better for patients older than 35 years (P  < 0.001; Mann–Whitney test), and for fresh transfers (P  < 0.001; Mann–Whitney test). LIMITATIONS, REASONS FOR CAUTION Participant centers were located in two countries, thus limiting the generalization of our conclusion to wider subpopulations of patients. Not all clinical features were available for all embryos, thus limiting the performances of the hybrid model in some instances. WIDER IMPLICATIONS OF THE FINDINGS Our study suggests that considering clinical data improves pregnancy predictive performances and that there is no need to retrain algorithms at the clinic level unless they follow strikingly different practices. This study characterizes a versatile AI algorithm with similar performance on different time-lapse microscopes and on embryos transferred at different development stages. It can also help with patients of different ages and protocols used but with varying performances, presumably because the task of predicting fetal heartbeat becomes more or less hard depending on the clinical context. This AI model can be made widely available and can help embryologists in a wide range of clinical scenarios to standardize their practices. STUDY FUNDING/COMPETING INTEREST(S) Funding for the study was provided by ImVitro with grant funding received in part from BPIFrance (Bourse French Tech Emergence (DOS0106572/00), Paris Innovation Amorçage (DOS0132841/00), and Aide au Développement DeepTech (DOS0152872/00)). A.B.-C. is a co-owner of, and holds stocks in, ImVitro SAS. A.B.-C. and F.D.M. hold a patent for 'Devices and processes for machine learning prediction of in vitro fertilization' (EP20305914.2). A.D. N.D. M.M.F. and F.D.M. are or have been employees of ImVitro and have been granted stock options. X.P.-V. has been paid as a consultant to ImVitro and has been granted stocks options of ImVitro. L.C.-D. and C.G.-S. have undertaken paid consultancy for ImVitro SAS. The remaining authors have no conflicts to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Objective: To explore the association between ovulation induction drugs and ovarian cancer. Design: Systematic review and meta-analysis. Setting: Not applicable. Patient(s): Women without ovarian cancer who ever or never underwent ovarian induction. Intervention(s): An extensive electronic search of the following databases was performed: PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library and CNKI, from inception until January 2022. A total of 34 studies fulfilled our inclusion criteria and were included in the final meta-analysis. The odds ratio (OR) and random-effects model were used to estimate the pooled effects. The Newcastle-Ottawa Scale was used to assess the quality of included studies. Funnel plots and Egger tests were used to assess publication bias. Main outcomes: New diagnosed borderline ovarian tumor (BOT) and invasive ovarian cancer (IOC) between ovulation induction (OI) group and control (CT) group considering fertility outcome, OI cycles and specific OI drugs. Results: Primarily, there was no significant difference in the incidence of IOC and BOT between the OI and CT groups. Secondly, OI treatment did not increase the risk of IOC and BOT in the multiparous women, nor did it increase the risk of IOC in the nulliparous women. However, the risk of BOT appeared to be higher in nulliparous women treated with OI treatment. Thirdly, among women exposed to OI, the risk of IOC and BOT was higher in nulliparous women than in multiparous women. Fourthly, the risk of IOC did not increase with increasing OI cycles. Lastly, exposure to specific OI drugs also did not contribute to the risk of IOC and BOT. Conclusion: Overall, OI treatment did not increase the risk of IOC and BOT in most women, regardless of OI drug type and OI cycle. However, nulliparous women treated with OI showed a higher risk of ovarian cancer, necessitating their rigorous monitoring and ongoing follow-up. [ABSTRACT FROM AUTHOR]

Purpose: An impact of different gonadotrophins selection for ovarian stimulation (OS) on oocyte competence has yet to be defined. In this study, we asked whether an association exists between OS protocol and euploid blastocyst rate (EBR) per metaphase-II (MII) oocytes. Methods: Cycles of first preimplantation genetic testing for aneuploidies conducted by women ≥ 35 years old with their own metaphase-II oocytes inseminated in the absence of severe male factor (years 2014–2018) were clustered based on whether recombinant FSH (rec-FSH) or human menopausal gonadotrophin (HMG) was used for OS, then matched for the number of fresh inseminated eggs. Four groups were outlined: rec-FSH (N = 57), rec-FSH plus rec-LH (N = 55), rec-FSH plus HMG (N = 112), and HMG-only (N = 127). Intracytoplasmic sperm injection, continuous blastocyst culture, comprehensive chromosome testing to assess full-chromosome non-mosaic aneuploidies and vitrified-warmed euploid single embryo transfers (SETs) were performed. The primary outcome was the EBR per cohort of MII oocytes. The secondary outcome was the live birth rate (LBR) per first SETs. Results: Rec-FSH protocol was shorter and characterized by lower total gonadotrophin (Gn) dose. The linear regression model adjusted for maternal age showed no association between the Gn adopted for OS and EBR per cohort of MII oocytes. Similarly, no association was reported with the LBR per first SETs, even when adjusting for blastocyst quality and day of full blastulation. Conclusion: In view of enhanced personalization in OS, clinicians shall focus on different endpoints or quantitative effects related to Gn action towards follicle recruitment, development, and atresia. Here, LH and/or hCG was administered exclusively to women with expected sub/poor response; therefore, we cannot exclude that specific Gn formulations may impact patient prognosis in other populations. [ABSTRACT FROM AUTHOR]

Background: A combination of controlled ovarian hyperstimulation and intrauterine insemination (IUI) remains an important treatment option for couple having infertility. Success rate of IUI with ovulation induction ranges from 8-20% depending on many factors. Aims and Objectives: To assess the factors affecting the success rate of IUI and to evaluate the success of ovulation Induction by different methods of controlled stimulation protocol. Materials and Methods: It is a duration-based prospective cross-sectional study where total of 67 couples were included by inclusion and exclusion criteria. They underwent 90 cycles of IUI with each couple having a maximum of three cycles. Ovulation induction was done by clomiphene citrate or letrozole or gonadotrophins. Semen preparation was done by density gradient method. The outcome was measured by positive urine pregnancy test. Range, percentage, confidence interval, mean with standard deviation, median, range, and P-value were calculated. P21 sqmm, endometrial thickness >9 mm, post wash count >15 million/ml, >2 cycles of IUI and on the number of follicles 2 or more on the day of trigger. Conclusion: The study concluded that IUI after ovulation induction can be a simple and safe cost-effective procedure in selected group of infertile couple. Clinical significance IUI following ovulation induction can be a successful approach for specific indications in a low-resource setting where options for other ART interventions are absent or limited.

Forty Nelore cows were submitted to timed artificial insemination (TAI) protocol and randomly assigned to groups according to estradiol (E2) ester (cypionate or benzoate, i.e. EC or EB) and equine chorionic gonadotrophin treatment (eCG or No-eCG) in a factorial 2x2 design. On a random day of the estrous cycle (Day 0), cows received a P4 intravaginal device plus 2 mg im injection of EB. At the time of P4 device removal (Day 8), cows were treated with 0.150 mg im of D-cloprostenol (PGF) and randomly divided to receive or not 400 UI im of eCG, as well as randomly assigned to receive 1 mg of EC immediately (D8), or 1 mg of BE, 24 h after it (D9) as ovulatory stimuli. Therefore, the groups formed were EC, EC+eCG, EB and EB+eCG. Were evaluated the effects of treatments on VEGF, OXTR, and PGR gene expression, E2/P4 concentrations, and Doppler-flowmetry of the reproductive tract of the investigated models. Ovulation rate was higher in animals subjected to the EC + eCG treatment (p < 0.05). Follicular vascularization was not influenced by the ovulation inducer (p > 0.05), although it was influenced by the eCG treatment (p < 0.05). EB enabled higher vascularized area rate in CL (P = 0.0192). VEGF and PGR genes were more expressed in animals treated with EB and eCG. On the other hand, OXTR expression was less evident in eCG-treated cows. EC has led to higher E2:P4 ratio in follicular fluid. This outcome indicated higher follicular estrogenic activity at D10, which justified the higher ovulation rate, when EC was associated with eCG (p < 0.05). Finally, the results of the present study corroborate the hypothesis that the different E2 esters and eCG differentially regulate vascularization, steroidogenesis, and utero-ovarian gene expression in Bos indicus cows submitted to TAI protocols. [ABSTRACT FROM AUTHOR]

Background: A combination of controlled ovarian hyperstimulation and intrauterine insemination (IUI) remains an important treatment option for couple having infertility. Success rate of IUI with ovulation induction ranges from 8-20% depending on many factors. Aims and Objectives: To assess the factors affecting the success rate of IUI and to evaluate the success of ovulation Induction by different methods of controlled stimulation protocol. Materials and Methods: It is a duration-based prospective cross-sectional study where total of 67 couples were included by inclusion and exclusion criteria. They underwent 90 cycles of IUI with each couple having a maximum of three cycles. Ovulation induction was done by clomiphene citrate or letrozole or gonadotrophins. Semen preparation was done by density gradient method. The outcome was measured by positive urine pregnancy test. Range, percentage, confidence interval, mean with standard deviation, median, range, and P-value were calculated. P<0.05 was taken as statistically significant. Results: Out of 90 IUI cycles 8 were successful resulting in a success rate of 8.8% per cycle and 11.9% per couple. Factors that had a positive impact were follicle size >21 sqmm, endometrial thickness >9 mm, post wash count >15 million/ml, >2 cycles of IUI and on the number of follicles 2 or more on the day of trigger. Conclusion: The study concluded that IUI after ovulation induction can be a simple and safe cost-effective procedure in selected group of infertile couple. Clinical Significance: IUI following ovulation induction can be a successful approach for specific indications in a low-resource setting where options for other ART interventions are absent or limited. [ABSTRACT FROM AUTHOR]

Research on nutrition and feed development for the broodstock of the Pacific white shrimp, Litopenaeus vannamei, is rare, and a poor broodstock quality is a critical factor restricting the seed supply in shrimp farming. As an essential nutrient for the gonadal development of L. vannamei, one control diet (no phospholipid) and three typical phospholipids (soybean lecithin, egg yolk lecithin, and krill oil) were evaluated in a semipurified diet of 4% phospholipid for a 28-day trial (initial weight 34.7 ± 4.2 g). Dietary phospholipid supplementation significantly promoted the ovarian maturation of female L. vannamei. Compared with soybean lecithin and egg yolk lecithin, krill oil showed the best positive results. Shrimp fed with a diet krill oil has obtained a significantly higher gonadosomatic index, yolk particle deposition, lipid accumulation, and estrogen secretion than from other sources. Ovary lipidomic analysis showed that the krill oil enriched the lipid composition of the ovary. The “glycerophospholipid metabolism” and “sphingolipid metabolism” pathways were significantly varied via topological pathway analysis. Genes and hub genes, with significantly different expression levels, were significantly enriched in the “fatty acid metabolism pathway,” “glycerophospholipid metabolism,” and “arachidonic acid metabolism” pathways by transcriptomic analysis. Correlation analysis of the transcriptome and lipidomics showed that the differential gene “hormone-sensitive lipase-like” (HSL) was positively correlated with various lipids [triglycerides (TG), phosphatidic acid (PA), phosphatidylserine (P), phosphatidylethanolamine (PE), glucosylceramide (GlcCer), phosphatidylglycerol (PG), and phosphatidylinositol (PI)] but was negatively correlated with diacylglycerol (DG), lysophosphatidylethanolamine (LPE), and sphingomyelin (SM). In conclusion, the dietary phospholipids, especially krill oil as a phospholipid source, can promote the development of L. vannamei ovaries by increasing the accumulation of nutrients such as triglycerides and sterols, and the secretion of estrogen or related hormones, such as estradiol and methylfarneside, by affecting the metabolism of glycerol phospholipids and some key fatty acids.

Male reproductive functions are mediated by different hormones whose orchestrations remain a major research interest. The ‘master’ regulator hormonal axis is the hypothalamo- pituitary-gonadal/testicular axis which is led by the pulsatile release of hypothalamic gonadotropin-releasing hormone. This, in turn, stimulates the anterior pituitary trophic hormones, the luteinizing hormone and follicle-stimulating hormone. Luteinizing hormone and follicle-stimulating hormone act upon the testicular cells, the Leydig cells for steroidogenesis and Sertoli cells to aid spermatogenesis, respectively. This primary axis is influenced by an array of other testicular hormones, metabolic hormones, and different regulatory factors. These hormonal crosstalks influence the intricate testicular functions, sexual behavior and semen quality in men. Given the growing concern in the last few decades over the increasing prevalence of male subfertility and/or infertility mostly in terms of deteriorating semen quality, it is required to find its underlying mechanisms. In this regard, the endocrine regulation of testicular functions is of prime importance in the determination of semen quality and sperm functions. This review article aims to present a concise updated overview on the mechanism by which the key hormones integrate the male reproductive functions and maintain the semen quality.

STUDY QUESTION Is gonadotrophin stimulation as part of IVF associated with an increased risk of relapse in breast cancer? SUMMARY ANSWER Controlled ovarian stimulation (COS) in connection with IVF in women with previous breast cancer was not associated with an increased risk of breast cancer relapse. WHAT IS KNOWN ALREADY Breast cancer is the most common malignancy among women worldwide and the leading cause of cancer death among females. The use of COS with gonadotrophins with subsequent cryopreservation of oocytes or embryos in order to enhance the chances of pregnancy after cancer treatment is the current most established fertility preservation method for women with breast cancer. To date, there are only a few small retrospective hospital-based controlled studies evaluating the risk of breast cancer relapse in patients undergoing fertility preservation with or without COS, showing no evident risk of relapse in breast cancer after the use of gonadotoxic agents. STUDY DESIGN, SIZE, DURATION This was a retrospective, population-based cohort study comprising 5857 women with previous breast cancer of whom 337 were exposed to COS. Exposure (COS) and outcomes (relapse and death) were identified for all patients from 2005 to 2014 by assessing the National Quality Register for Assisted Reproduction, the Swedish Medical Birth Register, the National Patient Register, the Swedish Prescribed Drug Register, the Swedish Cause of Death Register, the National Breast Cancer Register and the Swedish Cancer Register. Matching according to set criteria was possible for 334 women, who constituted the control group. A total of 274 women had undergone IVF after completing breast cancer treatment and 63 women had undergone COS for fertility preservation at the time of breast cancer diagnosis. PARTICIPANTS/MATERIALS, SETTING, METHODS Women aged 20–44 years previously diagnosed with breast cancer and exposed to COS were matched for age at breast cancer diagnosis ±5 years, tumour size and lymph node involvement with a non-exposed control group, including women with known T- and N-stages. In a subsequent analysis, the matched cohort was assessed by also including women with unknown T- and N-stages. A secondary analysis comprised the entire non-matched cohort, including all women with known T- and N-stages. Also here, a subsequent analysis included women with missing data for T- and N-stages. The risk of relapse in breast cancer was estimated as crude hazard ratios (HRs) and 95% CI using Cox proportional hazards models in the primary and secondary analyses where T- and N-stages were known: otherwise the risks of relapse were only given descriptively. MAIN RESULTS AND THE ROLE OF CHANCE In the primary matched analysis, relapse occurred in 20 of 126 women exposed to COS (15.9%) compared with 39 of 126 (31.0%) in the control cohort (HR = 0.70; 95% CI 0.39–1.45; P  =   0.22). In the subsequent analysis, also including women with unknown T- and N-stages, relapse occurred in 27 of 337 (8.0%) women having undergone COS compared with 71/334 (21.3%) among the non-exposed. In the secondary adjusted analysis, relapse occurred in 20 of 126 (15.9%) exposed women and in 918 of 3729 (24.6%) non-exposed women (HR = 0.81; 95% CI 0.49–1.33; P  =   0.70). In the subsequent analysis, including unknown T- and N-stages, relapse occurred in 27 of 337 (8.0%) women in the exposed group and 1176 of 5520 (21.3%) in the non-exposed cohort. LIMITATIONS, REASONS FOR CAUTION A substantial degree of missing data on important prognostic variables was a limitation, particularly when analysing the total cohort. Furthermore, data on confounding factors, such as BMI, were not completely covered. Another limitation was that a pre-specified variable for relapse was not in use for the majority of the National Breast Cancer Register. Furthermore, the follow-up time from available register data (2005–2014) is rather short. Finally, we cannot be sure whether the prognostic information from receptor status, showing a lower incidence in the exposed group, is representative. Information on T- and N-stages was missing in more than half of the patients. WIDER IMPLICATIONS OF THE FINDINGS In this large, retrospective, matched cohort study, we found no increased risk of relapse in breast cancer among women who had been exposed to gonadotrophins as part of IVF. This is reassuring but might be confounded by the selection of a group of women with a more favourable prognosis than those not undergoing IVF. The present study strengthens previous findings by being large, national and register based. Its results are applicable to women undergoing fertility preservation as well as to those undergoing regular IVF treatment. STUDY FUNDING/COMPETING INTEREST(S) Supported in part by grants from the Swedish state under the agreement between the Swedish government and the county councils the ALF-agreement (ALFGBG-720291), The Assar Gabrielsson Fund (FB 15-20), The Breast Cancer Fund and the Swedish Association of Local authorities and Regions, SKR. There are no conflicts of interest to declare. TRIAL REGISTRATION N/A [ABSTRACT FROM AUTHOR]

Objective(s): The purpose of this study was to investigate the change in plasma anandamide (AEA) levels throughout the normal menstrual cycle, and to analyze the relationship among AEA, sex steroids and gonadotrophins. Materials and Methods: The patients were fertile women with normal menstrual cycle, proposed to get in vitro fertilization (IVF) treatment due to oviduct obstruction or male infertility. Patients were divided into two groups, cross-sectional (n=79) and longitudinal (n=10). The plasma AEA levels were examined by the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) system. The serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (P) were measured by chemiluminescence. Results: The AEA levels in the late follicular phase were slightly higher than those in the early follicular phase. Subsequently, the AEA levels peaked at the time of ovulation in both two cohorts. Finally, the lowest AEA levels were measured in the luteal phase. Moreover, there were highly significant positive correlations between the plasma AEA concentration and the serum levels of FSH, LH and E2, whereas the AEA level was not correlated with P during the normal menstrual cycle. Conclusion: Our observations reveal a dynamic change in the plasma AEA level, which is closely associated with the levels of gonadotrophin and sex steroid hormones, suggesting that the hormones may be involved in the regulation of AEA levels during the menstrual cycle. Our studies help to design new strategies to improve implantation and treatments for reproductive diseases.

Molecular mechanisms responsible for gonadotrophic control of ovarian follicle development and ovulation have not been fully delineated. In this study, prepubertal female rabbits were subjected to a combined PMSG/hCG treatment for the induction of follicle maturation and ovulation. Ovaries of 6 does at different time points during gonadotrophic stimulation were collected for histomorphological examination and genome-wide analysis of miRNA and mRNA transcriptomes, and the plasma were separated for detecting melatonin (MT), prostaglandin E2 (PGE2), estradiol (E2), and progesterone (P4) levels. The results suggested that PMSG promoted the development of the reproductive tract by decreasing plasma levels of E2 and slightly increasing those of MT and PGE2 and that hCG induced ovulation and corpus luteum formation by significantly increasing MT, PGE2, and P4 levels. At the transcriptomic level, a total of 1,122 differentially expressed genes (DEGs) and 12 DE miRNAs were identified using three-group comparisons. Meanwhile, pairwise comparisons revealed that 279 and 103 genes as well as 36 and 20 miRNAs were up- and down-regulated during PMSG-stimulated follicle development while 11 and 5 genes as well as 33 and 16 miRNAs were up- and down-regulated during hCG-induced luteinization. KEGG enrichment analysis of the DEGs derived from both three-group- and two-group comparisons as well as the predicted target genes of DE miRNAs highlighted the crucial roles of pathways involving tissue remodeling, energy metabolism, and regulation of cellular functions in mediating gonadotrophin-induced follicle maturation. Specifically, 3 genes including the matrix metallopeptidase 13 (MMP13), protein phosphatase 1 regulatory subunit 3C (PPP1R3C), and solute carrier family 2 member 12 (SLC2A12), together with 2 miRNAs including the miR-205-1 and miR-34c, were predicted to be the promising downstream targets of both PMSG and hCG. Significantly, the miRNA-mRNA interaction pairs containing top 10 up- and down-regulated mRNAs/miRNAs upon PMSG/hCG stimulation were established, and so were those involved in the PI3K-Akt, ECM-receptor interaction, and focal adhesion pathways during PMSG-induced follicle maturation. Finally, qRT-PCR analysis confirmed the results from RNA-Seq and Small RNA-Seq. Our work may contribute to a better understanding of the regulatory mechanisms of gonadotrophins on ovarian follicle development and ovulation.

Molecular mechanisms responsible for gonadotrophic control of ovarian follicle development and ovulation have not been fully delineated. In this study, prepubertal female rabbits were subjected to a combined PMSG/hCG treatment for the induction of follicle maturation and ovulation. Ovaries of 6 does at different time points during gonadotrophic stimulation were collected for histomorphological examination and genome-wide analysis of miRNA and mRNA transcriptomes, and the plasma were separated for detecting melatonin (MT), prostaglandin E2 (PGE2), estradiol (E2), and progesterone (P4) levels. The results suggested that PMSG promoted the development of the reproductive tract by decreasing plasma levels of E2 and slightly increasing those of MT and PGE2 and that hCG induced ovulation and corpus luteum formation by significantly increasing MT, PGE2, and P4 levels. At the transcriptomic level, a total of 1,122 differentially expressed genes (DEGs) and 12 DE miRNAs were identified using three-group comparisons. Meanwhile, pairwise comparisons revealed that 279 and 103 genes as well as 36 and 20 miRNAs were up- and down-regulated during PMSG-stimulated follicle development while 11 and 5 genes as well as 33 and 16 miRNAs were up- and down-regulated during hCG-induced luteinization. KEGG enrichment analysis of the DEGs derived from both three-group- and two-group comparisons as well as the predicted target genes of DE miRNAs highlighted the crucial roles of pathways involving tissue remodeling, energy metabolism, and regulation of cellular functions in mediating gonadotrophin-induced follicle maturation. Specifically, 3 genes including the matrix metallopeptidase 13 (MMP13), protein phosphatase 1 regulatory subunit 3C (PPP1R3C), and solute carrier family 2 member 12 (SLC2A12), together with 2 miRNAs including the miR-205-1 and miR-34c, were predicted to be the promising downstream targets of both PMSG and hCG. Significantly, the miRNA-mRNA interaction pairs containing top 10 up- and down-regulated mRNAs/miRNAs upon PMSG/hCG stimulation were established, and so were those involved in the PI3K-Akt, ECM-receptor interaction, and focal adhesion pathways during PMSG-induced follicle maturation. Finally, qRT-PCR analysis confirmed the results from RNA-Seq and Small RNA-Seq. Our work may contribute to a better understanding of the regulatory mechanisms of gonadotrophins on ovarian follicle development and ovulation. [ABSTRACT FROM AUTHOR]

Often there is a need of application of the methods of treatment, directed on increase in quantity of spermatozoa in an ejaculate. In the research efficiency of the combined therapy by preparation follicle-stimulating hormone was estimated and a chorionic gonadotrophin in cases of the previous inefficiency monotherapy a chorionic gonadotrophin and an anti-estrogen. The efficiency of treatment concerning an oligoteratozoospermiya made 65 %. Positive changes of morphology of spermatozoa included improvement of condensation of a chromatin and decrease of the degrading forms. At the same time this treatment was safe and didn»t lead to development of side effects.

Purpose: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) mediate intracellular functions by binding their specific protein G-coupled gonadotrophin receptor, respectively FSH receptor (FSHR) and LH/choriogonadotrophin receptor (LHCGR). Whereas the expression of FSHR and LHCGR in mammals was considered gonad-specific and cell-specific, studies identified gonadotrophin receptors in human female extragonadal reproductive tissues. This study aims to demonstrate that gonadotrophin receptors are expressed in endometrium and mediates intracellular functions.Methods: Collected endometria (n = 12) from healthy patients (mean age of 36 ± 6) were primary cultured for 24 h. The presence of gonadotrophin receptors was evaluated by RT-PCR followed by the sequencing of the resulted amplicons and by immunohistochemistry in original samples. Endometrial primary cultures were treated with increasing concentration (range 0-100 ng/ml) of either recombinant human LH (rhLH) or recombinant human FSH (rhFSH). Endometria controls had gonadotrophin replaced by the same volume of the culture medium. In gonadotrophin-treated samples, it was evaluated the intracellular cyclic adenosine monophosphate (cAMP) content by enzymatic immunoassay and the expression of steroidogenic genes by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR).Results: The sequencing of the RT-PCR amplicons confirmed the presence of both gonadotrophin receptors and immunohistochemistry localized them on the membrane of endometrial glands cells throughout the glandular epithelium. The gonadotrophin-receptor complex was able to increase the intracellular cAMP in a dose-response and time-course manner and to induce steroidogenic genes expression.Conclusion: This study demonstrates that both gonadotrophin receptors are expressed along the glandular epithelium of endometria and they mediate the effects of gonadotrophins on intracellular functions. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine the relationship between marital violence and distress level among women with a diagnosis of infertility. Materials and Methods: In this prospective randomized study, a total of 180 patients were included in the study. Amongst these, pertubation of the uterine cavity was carried out in 79 patients prior to insemination. One patient in the pertubation group was later excluded because insemination could not be performed due to cycle cancellation. Results: There were no significant differences in demographic characteristics between the study and control groups. When the pregnancy rates of both groups were evaluated, 14(17.8%) patients in the study group achieved pregancy. Three (3.8%) had a biochemical pregnancy, 1(1.3%) miscarried and 10(12.7%) had live births. In the control group, a total of 24(23.8%) pregnancies were achieved, amongst which one (1%) had a biochemical pregnancy, 3(3%) miscarried and 20(19.8%) resulted in live births. There was no significant difference between groups in terms of total pregnancy and live birth rates (p > 0.05). There was a 21% total pregnancy loss rate. There was no significant difference between the control and study groups in terms of pregnancy loss rates (p > 0.05). Conclusion: This study on a homogenous group of unexplained infertile patients determined that the addition of pertubation to a controlled ovarian hyperstimulation plus intrauterine insemination (COH+IUI) treatment protocol did not affect pregnancy rates (Registration Number: NCT01999959).

Study Question: What is the genetic landscape within the testis of the juvenile rhesus monkey (Macaca mulatta) that underlies the decision of undifferentiated spermatogonia to commit to a pathway of differentiation when puberty is induced prematurely by exogenous LH and FSH stimulation?Summary Answer: Forty-eight hours of gonadotrophin stimulation of the juvenile monkey testis resulted in the appearance of differentiating B spermatogonia and the emergence of 1362 up-regulated and 225 down-regulated testicular mRNAs encoding a complex network of proteins ranging from enzymes regulating Leydig cell steroidogenesis to membrane receptors, and from juxtacrine and paracrine factors to transcriptional factors governing spermatogonial stem cell fate.What Is Known Already: Our understanding of the cell and molecular biology underlying the fate of undifferentiated spermatogonia is based largely on studies of rodents, particularly of mice, but in the case of primates very little is known. The present study represents the first attempt to comprehensively address this question in a highly evolved primate.Study Design, Size, Duration: Global gene expression in the testis from juvenile rhesus monkeys that had been stimulated with recombinant monkey LH and FSH for 48 h (N = 3) or 96 h (N = 4) was compared to that from vehicle treated animals (N = 3). Testicular cell types and testosterone secretion were also monitored.Participants/materials, Setting, Methods: Precocious testicular puberty was initiated in juvenile rhesus monkeys, 14-24 months of age, using a physiologic mode of intermittent stimulation with i.v. recombinant monkey LH and FSH that within 48 h produced 'adult' levels of circulating LH, FSH and testosterone. Mitotic activity was monitored by immunohistochemical assays of 5-bromo-2'-deoxyuridine and 5-ethynyl-2'-deoxyuridine incorporation. Animals were bilaterally castrated and RNA was extracted from the right testis. Global gene expression was determined using RNA-Seq. Differentially expressed genes (DEGs) were identified and evaluated by pathway analysis. mRNAs of particular interest were also quantitated using quantitative RT-PCR. Fractions of the left testis were used for histochemistry or immunoflouresence.Main Results and the Role Of Chance: Differentiating type B spematogonia were observed after both 48 and 96 h of gonadotrophin stimulation. Pathway analysis identified five super categories of over-represented DEGs. Repression of GFRA1 (glial cell line-derived neurotrophic factor family receptor alpha 1) and NANOS2 (nanos C2HC-type zinc finger 2) that favor spermatogonial stem cell renewal was noted after 48 and 96 h of LH and FSH stimulation. Additionally, changes in expression of numerous genes involved in regulating the Notch pathway, cell adhesion, structural plasticity and modulating the immune system were observed. Induction of genes associated with the differentiation of spermatogonia stem cells (SOHLH1(spermatogenesis- and oogenesis-specific basic helix-loop-helix 1), SOHLH2 and KIT (V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)) was not observed. Expression of the gene encoding STRA8 (stimulated by retinoic acid 8), a protein generally considered to mark activation of retinoic acid signaling, was below our limit of detection.Large Scale Data: The entire mRNA data set for vehicle and gonadotrophin treated animals (N = 10) has been deposited in the GEO-NCBI repository (GSE97786).Limitations Reasons For Caution: The limited number of monkeys per group and the dilution of low abundance germ cell transcripts by mRNAs contributed from somatic cells likely resulted in an underestimation of the number of differentially expressed germ cell genes.Wider Implications Of the Findings: The findings that expression of GDNF (a major promoter of spermatogonial stem cell renewal) was not detected in the control juvenile testes, expression of SOHLH1, SOHLH2 and KIT, promoters of spermatogonial differentiation in mice, were not up-regulated in association with the gonadotrophin-induced generation of differentiating spermatogonia, and that robust activation of the retinoic acid signaling pathway was not observed, could not have been predicted. These unexpected results underline the importance of non-human primate models in translating data derived from animal research to the human situation.Study Funding/competing Interest(s): The work described was funded by NIH grant R01 HD072189 to T.M.P. P.A. was supported by an Endocrine Society Summer Research Fellowship Award and CONICET (Argentine Research Council), S.N. by a grant from Vali-e-Asr Reproductive Health Research Center of Tehran University of Medical Sciences (grant #24335-39-92) to Dr Batool Hosseini Rashidi, and M.P.H. by grants from the National Health and Medical Research Council of Australia, and the Victorian State Government's Operational Infrastructure Support Program. The authors have nothing to disclose. [ABSTRACT FROM AUTHOR]

Aim: The present study was aimed at finding out the age specific best protocol for ovarian stimulation, particularly for advanced age group. Materials and Methods: This retrospective analysis was carried out from July 2005 to June 2009 in 617 cycles of In-vitro Fertilization (IVF) in different age group patients, performed at our centre. 617 patients having indications for female factor infertility were randomly divided into 3 age groups, as 26 to 30 years (younger age group); 31 to 35 years (middle age group) and 36 to 40 years (advanced age group). They were selected for IVF program, after routine investigations. 4 different stimulation protocols, e.g., Long Down Regulation (LDR), Ultra Long Down Regulation (ULDR), Soft Stimulation (SS) Protocol and Antagonist Protocol utilized were analyzed primarily on the basis of the amount of Gonadotrophin (Gn) ampoules required for ovarian stimulation, terminal estradiol (E2) value, oocyte recovery rate, clinical pregnancy rate (PR) and take home baby rate (THBR). Results: LDR was proved to be the protocol of choice for all the other groups except advanced age group where SS proved to be the best with antagonist protocol being the close follower. Conclusion: As least amount of ovarian stimulation is used in SS, it is cost effective and imposes minimum risk of ovarian hyperstimulation syndrome (OHSS) and offers maximum PR for advanced age group patients, and reasonable PR for other age groups.

Background: Ovarian response varies considerably among individuals and depends on various factors. Poor response in IVF yields lesser oocytes and is associated with poorer pregnancy perspective. Cycle cancellation due to poor response is frustrating for both clinician and the patient. Studies have shown that women conceiving after poor ovarian response have more pregnancy complications like PIH and preeclampsia than women with normal ovarian response. In addition, poor ovarian response could be a predictor of early menopause. This paper studies various demographic and clinical profiles of poor responders and tries to look at the known and unknown factors which could contribute to poor ovarian response in IVF. Materials and Methods: Data were collected retrospectively from 104 poor responders who had less than four oocytes at retrieval and compared with 324 good responders for factors like age, BMI, type of sub fertility, duration of sub fertility, environmental factors like stress at work, smoking, pelvic surgery, chronic medical disorder, indication of IVF, basal FSH, mean age of menopause in their mothers etc. Results: Among the poor responders, 60.57% were above 35 years of age compared to 36.41% in control group, which is statistically significant. Mean age of menopause in mother was found to be four years earlier in poor responder group. Male factor and unexplained infertility were significantly (P

"n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Polycystic ovary syndrome (PCOS) is a common cause of ovulation insufficiency and then infertility. Therapeutic options to induce ovulation in anovulatory PCOS patients are clomiphene citrate, metformin, tamoxifen, dopamine agonists (bromocriptin), Gonadotrophin and laparoscopic ovarian electrocautery (LOE). Gonadotrophin and LOE are important options in anovulatory clomiphene citrate-resistant patients with PCOS. Literature data regarding compare of the efficacy of these two treatments are few. Therefore we aimed to study the pregnancy rates of these treatments in infertile clomiphene citrate-resistant patients with PCOS."n"nMethods: A randomized clinical trial study was carried out in infertile clomiphene citrate-resistant patients with PCOS, referred to infertility clinic of Mirza Koochackhan Hospital of Tehran University of Medical Science in Tehran, Iran, between 2003 and 2008."n"nResults: A total of 100 patients women were randomly allocated in two groups. There were no differences in age and pimary and secondary infertility duration. In LOE treatment group, eight cases (16%) were pregnant and all delivered at term. in gonadotrophin treatment 14 cases (28%) were pregnant, 10 cases (20%) delivered at term but four cases aborted. The cost in gonadotrophin treatment was significantly more than laparoscopic ovarian diathermy (p

Objective: Carrot (Daucus carota L.) is known to possess antifertility properties in female.However, according to Iranian traditional medicine, it can increase the potency in men. Theaim of this study was to investigate the influence of carrot seed extract (CSE) on spermatogenesis,number and motility of sperms in cauda epididyme in male rats.Materials and Methods: Forty adult male rats were randomly divided into 5 groups: controlgroup, groups receiving low- and high doses of CSE, animals that received high-dose of CSEwith gentamicin, and a gentamicin only group. After 4 weeks treatment, fasting serum sampleswere obtained for the sex hormone analysis. Under anesthesia, testis, cauda epididymidesand sperm ducts were dissected and sperm count, motility and cauda epididymis spermreserves (CESR) were determined. Histopathological changes of testis were also studied toassess spermatogenesis. Data analysis was performed using one-way ANOVA followed byTukey HSD tests.Results: Administration of CSE caused a significant increase in CESR compared with thecontrol (28.2 ± 1.8 vs. 45.1 ± 2.0, ×106). The extract could also protect testis from the gentamicin-induced necrosis. The CSE administration caused about 3.5-times increase in theLH levels even in spite of receiving 5 mg/kg/day gentamicin with no significant effect on FSHlevels. The testosterone concentrations in the group received 400 mg/kg CSE were 30% and83% higher than its levels in the control and the gentamicin treated group, respectively.Conclusion: CSE can overcome reproductive toxicity of gentamicin and induces spermatogenesisprobably mainly through the elevation of testosterone levels.

Strategies to maximize individual fertility chances are constant requirements of ART. In vitro folliculogenesis may represent a valid option to create a large source of immature ovarian follicles in ART. Efforts are being made to set up mammalian follicle culture protocols with suitable FSH stimuli. In this study, a new type of recombinant FSH (KN015) with a prolonged half-life is proposed as an alternative to canonical FSH. KN015 supports the in vitro development of mouse follicles from primary to preovulatory stage with higher efficiency than canonical FSH and enhanced post-fertilization development rates of the ovulated oocytes. The use of KN015 also allows us to compare the dynamic transcriptome changes in oocytes and granulosa cells at different stages, in vivo and in vitro. In particular, KN015 facilitates mRNA accumulation in growing mouse oocytes and prevents spontaneous luteinization of granulosa cells in vitro. Novel analyses of transcriptome changes in this study reveal that the in vivo oocytes were more efficient than in vitro oocytes in terms of maternal mRNA clearing during meiotic maturation. KN015 promotes the degradation of maternal mRNA during in vitro oocyte maturation, improves cytoplasmic maturation and, therefore, enhances embryonic developmental potential. These findings establish new transcriptome data for oocyte and granulosa cells at the key stages of follicle development, and should help to widen the use of KN015 as a valid and commercially available hormonal support enabling optimized in vitro development of follicles and oocytes., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Understanding and improving IUI pregnancy rates has enormous global appeal and application. This pilot study goes one step further by utilising consecutive ejaculates from men with oligozoospermia and comparing with normozoospermic male group. Materials and Methods: A retrospective analysis was performed on 117 IUI-stimulated treatment cycles in a small fertility clinic in North Middlesex University Hospitals Trust, UK, within a NHS setting. Risks of OHSS and multiple births are carefully controlled. Results: In our cohort, several factors are associated with positive IUI pregnancies and these were: age of the woman, inseminating with ≥5 total progressive motile sperm; having ≥50 % Grade A sperm progression and having ≥1 follicle achieved with a realistic hMG dosage, hCG trigger and IUI of 29.7 h (2.5-38.4 h), with an endometrial thickness of 10.7 mm (6.6-13.4 mm). Bifollicular presence in at least half the cases along with hMG protocols added usefully to the pregnancy outcomes. Conclusions: The pregnancy rates per cycle were 19 and 23 % in the consecutive ejaculates and non-consecutive ejaculate groups, respectively, P = 0.59. For the whole cohort, the pregnancy rate was 20.51 % per cycle and 33.8 % per women. This approach if validated with large RCT will have universally beneficial effects. [ABSTRACT FROM AUTHOR]

Background: Human reproduction depends on an intact hypothalamic-pituitary-gonadal (HPG) axis. Hypothalamic gonadotrophin-releasing hormone (GnRH) has been recognized, since its identification in 1971, as the central regulator of the production and release of the pituitary gonadotrophins that, in turn, regulate the gonadal functions and the production of sex steroids. The characteristic peculiar development, distribution and episodic activity of GnRH-producing neurons have solicited an interdisciplinary interest on the etiopathogenesis of several reproductive diseases. The more recent identification of a GnRH/GnRH receptor (GnRHR) system in both the human endometrium and ovary has widened the spectrum of action of the peptide and of its analogues beyond its hypothalamic function.Methods: An analysis of research and review articles published in international journals until June 2015 has been carried out to comprehensively summarize both the well established and the most recent knowledge on the physiopathology of the GnRH system in the central and peripheral control of female reproductive functions and diseases.Results: This review focuses on the role of GnRH neurons in the control of the reproductive axis. New knowledge is accumulating on the genetic programme that drives GnRH neuron development to ameliorate the diagnosis and treatment of GnRH deficiency and consequent delayed or absent puberty. Moreover, a better understanding of the mechanisms controlling the episodic release of GnRH during the onset of puberty and the ovulatory cycle has enabled the pharmacological use of GnRH itself or its synthetic analogues (agonists and antagonists) to either stimulate or to block the gonadotrophin secretion and modulate the functions of the reproductive axis in several reproductive diseases and in assisted reproduction technology. Several inputs from other neuronal populations, as well as metabolic, somatic and age-related signals, may greatly affect the functions of the GnRH pulse generator during the female lifespan; their modulation may offer new possible strategies for diagnostic and therapeutic interventions. A GnRH/GnRHR system is also expressed in female reproductive tissues (e.g. endometrium and ovary), both in normal and pathological conditions. The expression of this system in the human endometrium and ovary supports its physiological regulatory role in the processes of trophoblast invasion of the maternal endometrium and embryo implantation as well as of follicular development and corpus luteum functions. The GnRH/GnRHR system that is expressed in diseased tissues of the female reproductive tract (both benign and malignant) is at present considered an effective molecular target for the development of novel therapeutic approaches for these pathologies. GnRH agonists are also considered as a promising therapeutic approach to counteract ovarian failure in young female patients undergoing chemotherapy.Conclusions: Increasing knowledge about the regulation of GnRH pulsatile release, as well as the therapeutic use of its analogues, offers interesting new perspectives in the diagnosis, treatment and outcome of female reproductive disorders, including tumoral and iatrogenic diseases. [ABSTRACT FROM AUTHOR]

Two experiments were performed to determine the endocrine and ovarian changes in medroxyprogesterone acetate (MAP)-primed ewes after ram introduction. Experiment 1 was performed during the mid-breeding season with 71 ewes primed with an intravaginal MAP sponge for 12 days. While the control (C) ewes (n = 35) were in permanent contact with rams, the ram effect (RE) ewes (n = 36) were isolated for 34 days prior to contact with rams. At sponge withdrawal, all ewes were joined with eight sexually experienced marking Corriedale rams and estrus was recorded over the next 4 days. The ovaries were observed by laparoscopy 4–6 days after estrus. Four weeks later, pregnancy was determined by transrectal ultrasonography. In eight ewes from each group, ovaries were ultrasonographically scanned; FSH, LH, and estradiol-17β were measured every 12 hours until ovulation or 96 hours after estrus. The response to the rams was not affected by the fact that ewes had been kept or not in close contact with males before teasing. No differences were found in FSH, LH, estradiol-17β concentrations, growth of the ovulatory follicle, onset of estrus, ovulation rate, or pregnancy rate. Experiment 2 was performed with 14 ewes during the nonbreeding season. Ewes were isolated from rams for 1 month, and received a 6-day MAP priming. Ovaries were ultrasonographically scanned every 12 hours, and FSH, LH, estradiol-17β, and progesterone were measured. Ewes that ovulated and came into estrus had higher FSH and estradiol-17β levels before introduction of the rams than did ewes that had a silent ovulation. The endocrine pattern of the induced follicular phase of ewes that came into estrus was more similar to a normal follicular phase, than in ewes that had a silent ovulation. The follicle that finally ovulated tended to emerge earlier and in a more synchronized fashion in those ewes that did come into estrus. All ewes that ovulated had an LH surge and reached higher maximum FSH levels than ewes that did not ovulate, none of which had an LH surge. We conclude that (a) the effect of ram introduction in cyclic ewes treated with MAP may vary depending on the time of the breeding season at which teasing is performed; (b) patterns of FSH, and estradiol-17β concentrations, as indicators of activity of the reproductive axis, may be used to classify depth of anestrus; and (c) the endocrine pattern of the induced follicular phase, which is related to the depth of anestrus, may be reflected in the behavioral responses to MAP priming and the ram effect.

The testosterone production by Leydig cells of mice adversely affected with nutritional or social factors and exposed to chronic stress was studied in vitro. Both basal and gonadotrophin stimulated testosterone production were highly significantly decreased (P < 0.01) as in groups given the hypothyreotics or potassium nitrate alone as in combination with stress. Stimulated in vitro testosterone production was not significantly changed in groups fed with synthetic diets, however, in mice given modified diets and exposed to stress decreased responsivity of Leydig cells stimulated by gonadotrophin was found. Basal and stimulated testosterone production in vitro in most of gonadotrophin concentrations was non-significantly lower in mice affected only by stress when compared with undisturbed controls. In isolated male mice the basal testosterone production was significantly (P < 0.05) decreased and gonadotrophin stimulated production highly significantly (P < 0.01) decreased when compared with group caged males. The testosterone production was most severely suppressed in aggressive individuals. Serum testosterone levels were detected in all animals, corticosterone, T3and T4 in selected groups of mice. We can conclude that the testosterone production was adversely affected by nutritional factors, and the impact was more profound when exerted together with chronic stress. The adverse effect of individual caging of male mice was also proved.

Background: The aim of this study was to determine the relationship between marital violence and distress level among women with a diagnosis of infertility. Materials and Methods: In this prospective randomized study, a total of 180 patients were included in the study. Amongst these, pertubation of the uterine cavity was carried out in 79 patients prior to insemination. One patient in the pertubation group was later excluded because insemination could not be performed due to cycle cancellation. Results: There were no significant differences in demographic characteristics between the study and control groups. When the pregnancy rates of both groups were evaluated, 14(17.8%) patients in the study group achieved pregnancy. Three (3.8%) had a biochemical pregnancy, 1(1.3%) miscarried and 10(12.7%) had live births. In the control group, a total of 24(23.8%) pregnancies were achieved, amongst which one (1%) had a biochemical pregnancy, 3(3%) miscarried and 20(19.8%) resulted in live births. There was no significant difference between groups in terms of total pregnancy and live birth rates (p>0.05). There was a 21% total pregnancy loss rate. There was no significant difference between the control and study groups in terms of pregnancy loss rates (p>0.05). Conclusion: This study on a homogenous group of unexplained infertile patients determined that the addition of pertubation to a controlled ovarian hyperstimulation plus intrauterine insemination (COH+IUI) treatment protocol did not affect pregnancy rates. [ABSTRACT FROM AUTHOR]

Background: We performed this study to investigate and compare the effects of Letrozole and gonadotrophins versus Clomiphene Citrate and gonadotrophins in women undergoing superovulation for Intrauterine Insemination (IUI). Methods: We performed this prospective cohort study at Australian Concept and Fertility centre, Karachi Pakistan. Women younger than 40 years of age with patent fallopian tubes and infertility of more than 2 years in duration who were undergoing IUI and gonadotrophins therapy were divided into two groups, one received Letrozole for 5 days and another received Clomiphene Citrate for 5 days. Results: All 500 IUI treatment cycles conducted from March 2008 to March 2010 were included. Patients co-treated with Letrozole required fewer gonadotrophins administrations (median difference, 300 IU (95% confidence interval (CI), 225-375 IU), developed more follicles larger than 14 mm (median difference, 1 follicle, 95% CI, 1-2 follicles), and had a thicker endometrium (median difference, 1 mm, 95% CI, 0.4-1.6 mm). The pregnancy rate was not significantly different between two groups (11% vs. 12.6%). Conclusion: The addition of Letrozole to gonadotrophins decreases gonadotrophins requirements and improves endometrial thickness, without a significant effect on pregnancy rates. An improved pregnancy rate has been observed in older age group, >35 years with Letrozole. [ABSTRACT FROM AUTHOR]

STUDY QUESTION How are ovarian steroid concentrations, gonadotrophins and menstrual cycle characteristics inter-related within normal menstrual cycles? SUMMARY ANSWER Within cycles, measures of estradiol production are highly related to one another, as are measures of progesterone production; however, the two hormones also show some independence from one another, and measures of cycle length and gonadotrophin concentrations show even greater independence, indicating minimal integration within cycles. WHAT IS KNOWN ALREADY The menstrual cycle is typically conceptualized as a cohesive unit, with hormone levels, follicular development and ovulation all closely inter-related within a single cycle. Empirical support for this idea is limited, however, and to our knowledge, no analysis has examined the relationships among all of these components simultaneously. STUDY DESIGN, SIZE, DURATION A total of 206 healthy, cycling Norwegian women participated in a prospective cohort study (EBBA-I) over the duration of a single menstrual cycle. Of these, 192 contributed hormonal and cycle data to the current analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Subjects provided daily saliva samples throughout the menstrual cycle from which estradiol and progesterone concentrations were measured. FSH and LH concentrations were measured in serum samples from three points in the same menstrual cycle and cycle length characteristics were calculated based on hormonal data and menstrual records. A factor analysis was conducted to examine the underlying relationships among 22 variables derived from the hormonal data and menstrual cycle characteristics. MAIN RESULTS AND THE ROLE OF CHANCE Six rotated factors emerged, explaining 80% of the variance in the data. Of these, factors representing estradiol and progesterone concentrations accounted for 37 and 13% of the variance, respectively. There was some association between measures of estradiol and progesterone production within cycles; however, cycle length characteristics and gonadotrophin concentrations showed little association with any measure of ovarian hormone concentrations. LIMITATIONS, REASONS FOR CAUTION Our summary measures of ovarian hormones may be imprecise in women with extremely long or short cycles, which could affect the patterns emerging in the factor analysis. Given that we only had data from one cycle on each woman, we cannot address how cycle characteristics may covary within individual women across multiple cycles. WIDER IMPLICATIONS OF THE FINDINGS Our findings are generalizable to other healthy populations with typical cycles, however, may not be applicable to cycles that are anovulatory, extreme in length or otherwise atypical. The results support previous findings that measures of estradiol production are highly correlated across the cycle, as are measures of progesterone production. Estradiol and progesterone concentrations are associated with one another, furthermore. However factor analysis also revealed more complex underlying patterns in the menstrual cycle, highlighting the fact that gonadotrophin concentrations and cycle length characteristics are virtually independent of ovarian hormones. These results suggest that despite integration of follicular and luteal ovarian steroid production across the cycle, cycle quality is a multi-faceted construct, rather than a single dimension. STUDY FUNDING/COMPETING INTEREST(S) The EBBA-I study was supported by a grant from the Norwegian Cancer Society (49 258, 05087); Foundation for the Norwegian Health and Rehabilitation Organizations (59010-2000/2001/2002); Aakre Foundation (5695-2000, 5754-2002) and Health Region East. The current analyses were completed under funding from the National Institutes of Health (K12 ES019852). No competing ... [ABSTRACT FROM AUTHOR]

Background: In women with polycystic ovary syndrome (PCOS), despite a high prevalence of insulin resistance, hyperandrogenemia, and disturbances in the secretion of gonadotrophin, the principal causes of biochemical abnormalities and the best endocrine markers for PCOS have not been fully identified. Subjects and methods: Serum levels of insulin, glucose, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, estrogen, sex hormone-binding capacity (SHBG), and other related indices such as homeostasis model assessment, insulin glucose ratios, LH/FSH ratios, and the free androgen index (FAI) were determined and compared in women with PCOS (n = 50) and women without PCOS (n = 50). Results: In multivariate logistic regression analyses, among all insulin resistance indices, only hyperinsulinemia (odds ratio [OR] = 2.6; confidence interval [CI]: 1.3-5.2; P = 0.008) was significantly and independently associated with PCOS when adjusted for body mass index (BMI), hyperandrogenemia, and LH/FSH ratios. The LH/FSH ratio (OR = 5.4; CI: 1.2-23.0, P = 0.03) was the only marker among those indices for inappropriate gonadotrophin secretion that significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. Among those indices for hyperandrogenemia, FAI (OR = 1.1; CI: 1.0-2.7; P = 0.02) and SHBG (OR = 1.2; CI: 1.2-3.4; P = 0.03) were significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. In addition, receiver operating characteristic analysis showed that the best predictive markers for PCOS were insulin (area under the curve [AUC] = 0.944; CI: 0.887-0.989), FAI (AUC = 0.932; CI: 0.895-0.993), SHBG (AUC = 0.924; CI: 0.87-0.978), and LH/FSH ratios (AUC = 0.906; CI: 0.821-0.965). Conclusion: For insulin and LH/FSH ratios, FAI, and SHBG seemed the best predictors and markers for insulin resistance, inappropriate gonadotrophin secretion, and hyperandrogenemia, respectively, with high sensitivity and specificity for identifying Bahraini women with and without PCOS. [ABSTRACT FROM AUTHOR]

Follicle-stimulating hormone, both naturally synthesized and as commercial preparations, exists as different isoforms. Variation in the process of glycosylation, particularly in the number of terminal sialic-acid residues, gives rise to isoforms of varying acidic profiles with differences in half-life and bioactivity. Based on the known follicle-stimulating hormone isoform variation across the reproductive cycle, it is possible that the follicle-stimulating hormone isoform profile used in controlled ovarian stimulation may impact follicular recruitment and clinical treatment outcomes. In light of the uncertainty regarding the clinical relevance of follicle-stimulating hormone isoforms in fertility treatment, published studies exploring this topic are reviewed. [ABSTRACT FROM AUTHOR]

Background: The LH surge promotes ovulation via activation of multiple signaling networks in the ovarian follicle. Studies in animal models have shown the importance of LH-induced activation of the epidermal growth factor (EGF)signaling network in critical peri-ovulatory events. We investigated the biological significance of regulatory mechanisms mediated by EGF-like growth factors during LH stimulation in humans.Methods: We characterized the EGF signaling network in mature human ovarian follicles using in vivo and in vitro approaches. Amphiregulin (AREG) levels were measured in 119 follicular fluid (FF) samples from IVF/ICSI patients. Biological activity of human FF was assessed using in vitro oocyte maturation, cumulus expansion and cell mitogenic assays.Results: AREG is the most abundant EGF-like growth factor accumulating in the FF of mature follicles of hCG-stimulated patients. No AREG was detected before the LH surge or before hCG stimulation of granulosa cells in vitro, demonstrating that the accumulation of AREG requires gonadotrophin stimulation. Epiregulin and betacellulin mRNA were detected in both human mural and cumulus granulosa cells, although at significantly lower levels than AREG. FF from stimulated follicles causes cumulus expansion and oocyte maturation in a reconstitution assay. Immunodepletion of AREG abolishes the ability of FF to stimulate expansion (P < 0.0001) and oocyte maturation (P < 0.05), confirming the biological activity of AREG. Conversely, mitogenic activity of FF remained after depletion of AREG, indicating that other mitogens accumulate in FF. FF from follicles yielding an immature germinal vesicle oocyte or from an oocyte that develops into an aberrant embryo contains lower AREG levels than that from follicles yielding a healthy oocyte (P = 0.008).Conclusions: EGF-like growth factors play a role in critical peri-ovulatory events in humans, and AREG accumulation is a useful marker of gonadotrophin stimulation and oocyte competence. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to identify baseline predictors of live birth in anovulatory patients undergoing ovulation induction, and based on these predictors, develop nomograms for estimation of the probability of live birth in a single cycle.Methods: Univariate and multivariate logistic regression were used for retrospective analysis of clinical, sonographic and endocrinological parameters collected prior to the start of ovarian stimulation in a cohort of anovulatory World Health Organization (WHO) Group II patients (n = 335), who were resistant to clomiphene citrate (CC) and therefore stimulated with gonadotrophins using a low-dose step-up protocol.Results: The univariate analysis identified age [OR = 0.91 (95% CI: 0.84-0.98), P = 0.015], duration of infertility [OR = 0.71 (95% CI: 0.56-0.91), P = 0.007], serum follicle stimulating hormone (FSH) concentration at the start of stimulation [OR = 0.83 (95% CI: 0.69-0.99), P = 0.034] and menstrual cycle pattern (P = 0.022) as significant predictors of live birth. Baseline concentrations of luteinizing hormone, androgens, glucose and insulin, as well as body mass index, were not predictors of live birth. In the multivariate analysis, duration of infertility, FSH and menstrual cycle pattern were independent predictors, and nomograms were designed with these three parameters for individual prediction of the probability of live birth.Conclusions: The chances of live birth in women with WHO Group II anovulatory infertility resistant to CC undergoing ovulation induction with gonadotrophins is highly influenced by the menstrual cycle pattern. Increases in duration of infertility and concentration of FSH (within the normal range) before the start of stimulation have negative influences on the likelihood of achieving a live birth. [ABSTRACT FROM AUTHOR]

Objective: To provide recommendations for the standardized use of the Antral follicle count (AFC) which is used to predict ovarian response to gonadotrophin stimulation during assisted reproductive technology treatment. However, the nature of the follicles that are visualized by ultrasound and the competence of the oocytes held within are largely unknown. In addition, there is considerable variability in the clinical definitions and technical methods used to count and measure antral follicles in both published studies and clinical practice. Design and Setting: In December 2007, specialist reproductive medicine clinicians and scientists attended a workshop in an effort to address these issues. Literature concerning the physiology and measurement of ovarian antral follicles was reviewed, clinical and technical considerations regarding antral follicle measurement were discussed, and an operational definition of AFC was developed. Patient(s): None. Intervention(s): None. Outcome Measures: Simple recommendations were established for the standardization of AFC assessment in routine clinical practice. The basic clinical and technical requirements required for AFC evaluation were agreed upon, and a systematic method of measuring and counting antral follicles in routine practice was proposed. Conclusion(s): The use of a standardized approach according to the practical recommendations for antral follicle counting as presented is encouraged in future clinical trials and routine practice. The authors also advocate a systematic evaluation of these recommendations as standardized study data become available. [ABSTRACT FROM AUTHOR]

Objective: To further investigate the relationship between plasma anandamide (AEA), sex steroids, and gonadotrophins to improve our understanding of how AEA may be involved in human fertility.Design: Cross-sectional and longitudinal study.Setting: University Hospital of Leicester NHS Trust, Leicester Royal Infirmary.Patient(s): Healthy premenopausal and postmenopausal volunteers.Intervention(s): UPLC-MS/MS-measured plasma AEA and ELISA-measured serum FSH, LH, estradiol, and progesterone levels at five different phases of the menstrual cycle and postmenopause.Main Outcome Measure(s): Plasma AEA, serum steroids and gonadotrophins.Result(s): Changes in AEA levels were similar in the two cohorts. The mean +/- SEM levels in the early follicular phase (0.89 +/- 0.06) for the cross-sectional cohort and the longitudinal cohort (0.73 +/- 0.03) were higher than those in the late follicular phase (0.77 +/- 0.09 cross-sectional; 0.63 +/- 0.08 longitudinal). The highest AEA levels were measured at ovulation (1.38 +/- 0.14 and 1.33 +/- 0.16) and the lowest level was measured in the late luteal phase (0.66 +/- 0.07 and 0.56 +/- 0.06). There was a statistically significant positive correlation between AEA, estradiol (P=0.0015), LH (P<0.0001) and FSH levels but not progesterone (P=0.022).Conclusion(s): Peak plasma AEA occurred at ovulation and positively correlated with estradiol and gonadotrophin levels suggesting that these may be involved in the regulation of AEA levels. [ABSTRACT FROM AUTHOR]

Two experiments were performed to determine the endocrine and ovarian changes in medroxyprogesterone acetate (MAP)-primed ewes after ram introduction. Experiment 1 was performed during the mid-breeding season with 71 ewes primed with an intravaginal MAP sponge for 12 days. While the control (C) ewes (n = 35) were in permanent contact with rams, the ram effect (RE) ewes (n = 36) were isolated for 34 days prior to contact with rams. At sponge withdrawal, all ewes were joined with eight sexually experienced marking Corriedale rams and estrus was recorded over the next 4 days. The ovaries were observed by laparoscopy 4-6 days after estrus. Four weeks later, pregnancy was determined by transrectal ultrasonography. In eight ewes from each group, ovaries were ultrasonographically scanned; FSH, LH, and estradiol-17ß were measured every 12 hours until ovulation or 96 hours after estrus. The response to the rams was not affected by the fact that ewes had been kept or not in close contact with males before teasing. No differences were found in FSH, LH, estradiol-17ß concentrations, growth of the ovulatory follicle, onset of estrus, ovulation rate, or pregnancy rate. Experiment 2 was performed with 14 ewes during the nonbreeding season. Ewes were isolated from rams for 1 month, and received a 6-day MAP priming. Ovaries were ultrasonographically scanned every 12 hours, and FSH, LH, estradiol-17ß, and progesterone were measured. Ewes that ovulated and came into estrus had higher FSH and estradiol-17ß levels before introduction of the rams than did ewes that had a silent ovulation. The endocrine pattern of the induced follicular phase of ewes that came into estrus was more similar to a normal follicular phase, than in ewes that had a silent ovulation. The follicle that finally ovulated tended to emerge earlier and in a more synchronized fashion in those ewes that did come into estrus. All ewes that ovulated had an LH surge and reached higher maximum FSH levels than ewes that did not ovulate, none of which had an LH surge. We conclude that (a) the effect of ram introduction in cyclic ewes treated with MAP may vary depending on the time of the breeding season at which teasing is performed; (b) patterns of FSH, and estradiol-17ß concentrations, as indicators of activity of the reproductive axis, may be used to classify depth of anestrus; and (c) the endocrine pattern of the induced follicular phase, which is related to the depth of anestrus, may be reflected in the behavioral responses to MAP priming and the ram effect. [ABSTRACT FROM AUTHOR]

Although male factors contribute to over half of all cases of infertility, most infertile men are described as ‘idiopathic oligo/asthenozoospermic’ rather than diagnosed precisely; hence, specific medical treatment is not possible. One uncommon but treatable cause of male infertility is gonadotrophin deficiency in which gonadotrophin replacement therapy is highly effective at inducing spermatogenesis and fertility. Hormonal therapy is a logical approach for empirical drug therapy given the fundamental role of hormonal regulation in spermatogenesis. However, treatment with GnRH analogues, gonadotrophins, androgens, anti-estrogens, aromatase inhibitors, growth hormone- and prolactin-suppressing drugs is ineffective in unselected infertile men. Prolonged high-dose glucocorticoid therapy for sperm autoimmunity may improve pregnancy rates modestly, but the risks are generally unacceptable compared with IVF or ICSI. For these reasons, modern reproductive technologies, notably ICSI/IVF, have become the de-facto standard empirical treatment of male infertility, despite involving significant though infrequent risks to the fetus and mother. There remains a potential for hormonal methods to improve sperm quality or ultrastructure in subgroups of infertile men more responsive to hormonal manipulation or using novel protein or gene-targeted therapies or biochemical approaches based on post-hormonal receptor mechanisms that stimulate spermatogenesis. How such novel hormonal methods will develop in conjunction with improved ICSI/IVF or cloning technologies, and the potential role of adjunctive hormonal therapy remains to be clarified. [ABSTRACT FROM PUBLISHER]