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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.

Testicular volume ≥4 ml and appearance of breast budding are the first signs of puberty. Delayed puberty is diagnosed in the absence of thelarche by 13 y or menarche by 15 y in girls and absence of testicular enlargement by 14 y in boys. Delayed puberty can be due to hypogonadotrophic hypogonadism, hypergonadotrophic hypogonadism or eugonadotrophic eugonadism characterised by low, elevated and normal gonadotrophin levels, respectively. Constitutional Delay of Growth and Puberty (CDGP) and systemic illness should be considered before pathological causes. Assessment of sexual maturity by Tanner's staging and anthropometric assessment on growth chart is pivotal. Lack of menarche in girls with thelarche suggests structural abnormalities of reproductive tract or disorders of sexual development. Measurement of bone age helps to interpret hormone measurements and decide on timing of pubertal induction. Ultrasound assessment of abdomen gives valuable clues to pubertal onset (in girls) and possible underlying etiology. Karyotyping is mandatory in all girls with delayed puberty and short stature, and delayed menarche and boys with hypergonadotrophic hypogonadism. Gonadotrophin releasing hormone analogue stimulation test may help distinguish hypogonadotrophic hypogonadism from CDGP. Pubertal induction is done with intramuscular testosterone and oral estradiol in boys and girls, respectively. Hormone replacement is begun at low doses and slowly escalated over 2 y to mimic a physiological puberty process. Short course of testosterone for 3 to 6 mo is helpful in adolescent boys with CDGP and psychological distress. Attainment of adult sexual maturity by 18 y is mandatory to rule out disorders of hypothalamic pituitary gonadal axis. [ABSTRACT FROM AUTHOR]

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]

This study investigated the effects of age and FSH treatment on the ovarian response, follicular fluid (FF) biochemical composition, nuclear maturation, and molecular profile of cumulus-oocytes complexes (COCs) recovered from prepubertal gilts. Thirty-five prepubertal gilts were separated according to age [140 (n = 20) or 160 (n = 15) days], and within each age, the gilts were allotted to receive either 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)]. Thus, four experimental groups were included in this study. In the FSH-treated gilts, the percentage of medium follicles increased (P < 0.0001) in the same proportion with which the percentage of small follicles decreased (P < 0.0001). In addition, the glucose concentration in the FF obtained from medium follicles increased (P < 0.05), while that of triglycerides decreased (P < 0.05) in the FSH-treated gilts. The FSH stimulation also improved (P < 0.05) the number of grade I COCs obtained from medium follicles and the meiotic maturation and BCB + rates. FSH treatment only upregulated (P < 0.05) HMGCR expression in immature COCs from prepubertal gilts. The metaphase II and BCB + rates, FF glucose and plasma IGF-1 levels were greater (P < 0.05) in prepubertal gilts at 160 than at 140 days of age. Age had no effect (P > 0.05) on the transcript abundance of the target genes in immature COCs. Hence, oocytes obtained from 140-day-old prepubertal gilts appeared less meiotically competent than those of 160-day-old prepubertal gilts. Our study suggests a possible strategy of using FSH treatment to improve oocyte quantity, quality, and nuclear maturation in 140 and 160-day-old prepubertal gilts. • FSH treatment was efficient at improving the oocyte quality of prepubertal gilts at 140 or 160 days of age. • The biochemical composition of the follicular fluid differed based on age and FSH treatment. • Prepubertal gilt oocytes increase the capacity to resume meiosis from 140 to 160 days of age. [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.

Postmenopausal hot flushes are caused by lack of estradiol (E2) but their neuroendocrine basis is still poorly understood. Here, we investigated the interrelationship between norepinephrine and hypothalamic neurons, with emphasis on kisspeptin neurons in the arcuate nucleus (ARC), as a regulatory pathway in the vasomotor effects of E2. Ovariectomized (OVX) rats displayed increased tail skin temperature (TST), and this increase was prevented in OVX rats treated with E2 (OVX + E2). Expression of Fos in the hypothalamus and the number of ARC kisspeptin neurons coexpressing Fos were increased in OVX rats. Likewise, brainstem norepinephrine neurons of OVX rats displayed higher Fos immunoreactivity associated with the increase in TST. In the ARC, the density of dopamine‐ß‐hydroxylase (DBH)‐immunoreactive (ir) fibers was not altered by E2 but, importantly, DBH‐ir terminals were found in close apposition to kisspeptin cells, revealing norepinephrine inputs to ARC kisspeptin neurons. Intracerebroventricular injection of the α2‐adrenergic agonist clonidine (CLO) was used to reduce central norepinephrine release, confirmed by the decreased 3‐methoxy‐4‐hydroxyphenylglycol/norepinephrine ratio in the preoptic area and ARC. Accordingly, CLO treatment in OVX rats reduced ARC Kiss1 mRNA levels and TST to the values of OVX + E2 rats. Conversely, CLO stimulated Kiss1 expression in the anteroventral periventricular nucleus (AVPV) and increased luteinizing hormone secretion. These findings provide evidence that augmented heat dissipation in OVX rats involves the increase in central norepinephrine that modulates hypothalamic areas related to thermoregulation, including ARC kisspeptin neurons. This neuronal network is suppressed by E2 and its imbalance may be implicated in the vasomotor symptoms of postmenopausal hot flushes. [ABSTRACT FROM AUTHOR]

Summary: Regulation of the transforming growth factor beta (TGFβ) superfamily by gonadotrophins in swine follicular cells is not fully understood. This study evaluated the expression of steroidogenic enzymes and members of the TGFβ superfamily in prepubertal gilts allocated to three treatments: 1200 IU eCG at D −3 (eCG); 1200 IU eCG at D −6 plus 500 IU hCG at D −3 (eCG + hCG); and the control, composed of untreated gilts. Blood samples and ovaries were collected at slaughter (D0) and follicular cells were recovered thereafter. Relative gene expression was determined by real-time PCR. Serum progesterone levels were greater in the eCG + hCG group compared with the other groups (P < 0.01). No differences were observed in the expression of BMP15, BMPR1A, BMPR2, FSHR, GDF9, LHCGR and TGFBR1 (P > 0.05). Gilts from the eCG group presented numerically greater mean expression of CYP11A1 mRNA than in the control group that approached statistical significance (P = 0.08) and greater expression of CYP19A1 than in both the eCG and the control groups (P < 0.05). Expression of BMPR1B was lower in the eCG + hCG treatment group compared with the control (P < 0.05). In conclusion, eCG treatment increased the relative expression of steroidogenic enzymes, whereas treatment with eCG + hCG increased serum progesterone levels. Although most of the evaluated TGFβ members were not regulated after gonadotrophin treatment, the downregulation of BMPR1B observed after treatment with eCG + hCG and suggests a role in luteinization regulation. [ABSTRACT FROM AUTHOR]

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]

Do follicular fluid hormone concentrations and the mRNA expression of LHCG, FSH and androgen receptors, aromatase and anti-Müllerian hormone (AMH) in cumulus granulosa cells differ in naturally matured and stimulated follicles? Cross-sectional study involving 57 natural cycle IVF (NC-IVF) and 36 conventional gonadotrophin-stimulated IVF (cIVF) cycles performed between 2014 and 2016. cIVF was performed by ovarian stimulation with human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonists. Hormone concentrations were determined in the follicular fluid of the leading follicle, and mRNA concentrations were quantified by reverse transcription polymerase chain reaction in RNA extracted from granulosa cells of the cumulus oophorus complex obtained from these fluids. Follicular fluid hormone concentrations were significantly lower in cIVF compared with NC-IVF follicles. Median concentrations were 0.50 and 14.5 mIU/ml for LH (P < 0.001), 16.1 and 46.5 nmol/l for testosterone (P < 0.001), 1270 and 2675 nmol/l for oestradiol (P < 0.001), and 12.3 and 28.9 pmol/l for AMH (P < 0.001), respectively. In cumulus granulosa cells, mRNA concentrations for LH receptor, FSH receptor, androgen receptor, aromatase and AMH did not differ between cIVF and NC-IVF follicles. Several hormone and mRNA concentrations were quantitatively associated in natural cycles such as follicular fluid AMH and cumulus granulosa cells AMH RNA (r 2 = 0.107, P = 0.013), follicular fluid testosterone and cumulus granulosa cell AMH RNA (r 2 = 0.158, P = 0.002), follicular fluid oestradiol and cumulus granulosa cell AMH RNA (r 2 = 0.105, P = 0.014) and follicular fluid oestradiol and aromatase (r 2 = 0.113, P = 0.011). In contrast, these associations were not observed in stimulated cycles. These findings indicate some effects of gonadotrophin stimulation on follicular physiology, which could be a cause for the previously suggested lower oocyte quality in cIVF compared with NC-IVF. [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.

Background: Infertility is a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercours. It affects nearly 10% of the world’s population Aim of study: To evaluate correlation between total gonadotrophin dose, duration of controlled ovarian stimulation and maternal age with oocyte maturity, embryo grades, and clinical pregnancy in IVF cycle. Methods: A prospective study in Kamal Al-Samarai Hospital for infertility and IVF in Baghdad / Iraq for a period of one year from 1st of Jun. 2019 till 1st of Jun. 2020. It included 122 infertile females had IVF-ICSI cycles. Results: The antagonist protocol in 52.5% of patients; long agonist protocol in 47.5%. A patient of IVF was seen in 68% of study patients. The highest prevalence of pregnancy failure was significantly seen in patients aged ≥ 40 years (83.3%, P= 0.03), obese patients (80.5%, P= 0.032), in patients had primary infertility (72.6%, P= 0.041), and in patients with infertility for > 12 years’ duration (90%, P= 0.036). Means of duration of stimulation, total number of oocyte pick, MII, embryo grade I were significantly higher in patients who got pregnant. Conclusion: individualization & adjustment of the dose gonadotropin according to female response, drug costs and efficacy, financial status in order not to increase or decrease duration of stimulation to be within 10 -12 days to achieve sufficient number of M II oocytes, good quality embryos selected for matching endometrium receptivity in fresh embryo transfer, the remaining embryos can be cryopreserved. [ABSTRACT FROM AUTHOR]

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.

Pharmacological ovarian control required for the implementation of artificial insemination and embryo-related technologies usually includes the use of eCG, naturally produced in pregnant mares. In this study, we report the superovulatory response and embryo development in mice obtained with a new glycoprotein with eCG-like activity (reCG) produced by recombinant DNA technology. A total of 150 females from three different mouse strains (C57BL/6J, BALB/cJ and B6D2F1/J) were subjected to a superstimulatory protocol consisting of 5 IU of natural eCG (n = 50), 5 IU of reCG (n = 50), or received a placebo (no-eCG, n = 50) by intraperitoneal route, followed by 5 IU of human chorionic gonadotropin 48 h later. Overall, no significant differences were observed in the total number of ova/zygotes (33.6 ± 2.4 vs 28.7 ± 2.6; P = NS) and viable ova/zygotes (31.5 ± 2.4 vs 25.8 ± 2.5; P = NS) collected per female among eCG and reCG treated females, respectively, which were greater (P < 0.05) than those obtained in no-eCG treated females (6.9 ± 0.7 and 5.9 ± 0.7, respectively). Zygotes derived from the three experimental groups (n = 2914) were subjected to in vitro culture until hatching 4.5 days post coitum (dpc). Regardless of the mouse strain, no differences were observed among eCG and reCG treated females for overall cleavage rate 1.5 dpc (58.5% vs 60.5%), development rate 3.5 dpc (47.2% vs 48.9%) and hatching rate 4.5 dpc (49.5% vs 54.5) (P = NS). Control females from no-eCG treated group showed lower cleavage and development rates (36.4% and 29.7%, respectively; P < 0.05). In conclusion, this study reports for the first time comparable superovulatory response and embryo development between recombinant and natural eCG treatment, which has important implications for reproductive technologies in several species. • A new recombinant eCG-like activity glycoprotein (reCG) was compared with natural eCG in mice. • Superovulatory response induced with reCG was similar to eCG, and greater than no eCG treatment. • Embryo developmental competence was similar to natural eCG, and greater than no eCG treatment. • We report for the first time the success of a recombinant eCG-like glycoprotein for superovulation/embryo production in mammals. [ABSTRACT FROM AUTHOR]

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]

Pregnant Mare Serum Gonadotropin (PMSG), which is known as Equine Chorionic Gonadotropin (eCG), has been used as a reproductive biologic for more than 50 years, both nationally and internationally, in livestock farming, especially in sow management and veterinary medicine widely used. The eCG macromolecule is bivalent. It combines two endocrine effects, the effects of FSH (follicle stimulating hormone) and LH (luteinizing hormone). The use of eCG preparations provides advantages for performance-oriented herd management, animal hygiene and economic efficiency within the scope of group farrowing in the piglet production plants. Nevertheless, questions of acceptance of hormone use in sows are increasing. This justifies further efforts to develop alternative solutions for cycle stimulation in sows without eCG. [ABSTRACT FROM AUTHOR]

Background: The use of gonadotrophins as a first‐line treatment for anovulatory infertility has been limited by a perception of a risk of multi‐fetal gestation and ovarian hyperstimulation syndrome (OHSS). However, it has recently been recognised as an acceptable first‐line treatment if appropriate monitoring is performed. Aims: To determine the cumulative live birth rate, incidence of multiple gestation, cycle cancellation rate and incidence of OHSS for therapy‐naïve anovulatory women undergoing ovulation induction with gonadotrophins. Materials and Methods: A prospective observational study of 258 patients undergoing ovulation induction with a 'low‐dose step‐up' protocol was performed over a three‐year period across two fertility centres (40% of patients were currently or recently prescribed metformin). Results: Twenty‐six percent of patients required concurrent use of luteinising hormone. The cumulative pregnancy and live birth rates were 22.5% and 18.2%, 40.3% and 34.5%, 47.7% and 41.1% after completion of the first, second and third cycles of stimulation, respectively, with a median duration of stimulation of 15 days. No patients developed OHSS and 10.5% of cycles were cancelled due to an excessive or no follicular response. The multiple pregnancy rate was 2%. The cumulative pregnancy rate was reduced for women over 35 years of age (23.8 vs 55.3%, P = 0.006) and for women with a body mass index greater than 25 kg/m2 (40.6 vs 56.7%, P = 0.027). Conclusions: This study demonstrated that ovulation induction with gonadotrophin therapy, in the context of appropriate monitoring, is a safe and effective treatment for young therapy‐naïve patients with anovulatory infertility. [ABSTRACT FROM AUTHOR]

What is the real-world effectiveness of Fertistartkit® in women undergoing assisted reproductive technology (ART)? Retrospective cohort study including anonymized data of women undergoing ovarian stimulation for ART with Fertistartkit between April 2016 and November 2017 and follow-up of clinical outcomes up to February 2018. Data were collected from the electronic patient databases of 12 French ART centres. The main outcome was number of oocytes retrieved. All data were categorized according to female age (<25, 25–29, 30–34, 35–37, 38–39 and >39 years). A total of 1006 cycles from 914 women treated with Fertistartkit were included. At the time of first ovarian stimulation in the study, women were 34.9 ± 5.0 years old, with a median body mass index of 22.7 kg/m². Couples had been infertile for more than 4 years, with all patterns of causes of infertility. Ovarian stimulation was started with a median dose of 300 IU (interquartile range [IQR]: 150–300 IU) of Fertistartkit for 10 days (IQR: 9–11 days), so a median total dose of 2700 IU (IQR: 1800–3300 IU). The mean number of oocytes retrieved per cycle was 9.5 ± 6.8, and the mean number of mature oocytes per cycle was 7.4 ± 5.5. The obtained ongoing pregnancy per started cycle was 26.0% (95% confidence interval [CI]: 24.1–27.9) and the obtained ongoing pregnancy per puncture was 27.0% (95% CI: 25.0–29.0). This is the first cohort to describe Fertistartkit treatment management in real-life conditions. The real-world data show that Fertistartkit is an effective option for ovarian stimulation. [ABSTRACT FROM AUTHOR]

Objectives: The current evaluating study was launched to assess endometrial thickness (ET), follicular growth (FG), and serum estradiol (SE) levels in spontaneous (fertile) vs induced (infertile) cycles via clomiphene or gonadotropin. Patients and methods: The work included two groups; a study group (SG) and a control group (CG). The SG contained 196 patients who suffered infertility and was divided into two subgroups according to the treatment that the patients received, clomiphene (SGC) or gonadotrophin (SGG). The CG included 130 healthy, fertile, individuals who received no treatment. Transvaginal ultrasonography (TVU) was used to evaluate the treatment effects on the ET and FG plus ovulation. The SE levels of the group members were measured using a competitive radioimmunoassay (CRIA). Results:A trilaminar endometrium was ultrasonically recognized in the SGC and the CGshowing three hyper-echogenic lines with inner hypo-echogenic regions. ET was significantly (p<0.05)reduced in the SGCwhen compared with that in the CG.The follicular diameter (FD) was significantly (p<0.05) larger in the SGs than that in the CG. However, the FD significantly (p<0.05) increased in the SGG in comparison to that in the CG. The SE levels were significantly (p<0.05) higher during the mid of the cycle in the SGs than those in the CG. Conclusion: The assessed effects of the clomiphene or gonadotropin on the endometrial features, ovulation, and serum estradiol levels provide significant prognostic information regarding the use of those treatments in infertile women. [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]

At present, infertility is a key-issue. When applicable, in vitro fertilization (IVF) has become the standard approach to treat this condition but a thorough investigation and, whenever possible, the individual diagnosis of the underlying causes of infertility are required. For many female causes, indeed, efficient medical therapies are available to achieve a fast solution of the problem. This review is based on the relevant literature indexed in PubMed and SCOPUS and is focused on the most recent clinical literature on the treatment of women (and couples) affected from infertility. The reduction in IVF treatment burden and risks are now considered pivotal to set 'patient-friendly' therapies and represent crucial issues for both patients and physicians. To this end, the researchers are now focusing their attention on old drugs with new indications and new compounds with more appropriate functions, to improve the compliance of the women and reduce the burden of infertility, a condition that is becoming an important issue in the modern world, also for the Public Health System. [ABSTRACT FROM AUTHOR]

Using recombinant DNA technologies, a chimeric gene containing the coding sequences of follicle stimulating hormone (FSH) β-subunit and C-terminal peptide of the human chorionic gonadotrophin (hCG) β-subunit have been designed to generate a new gonadotrophin named corifollitropin alfa (CFA). CFA has longer elimination half-life and slower rate of absorption compared with FSH, which makes CFA a long-acting hormone employed as a substitute of the recombinant FSH (recFSH) in the controlled ovarian stimulation (COS). The purpose of this study is to compare the gene expression profiles elicited by bioequivalent doses of CFA or recFSH in primary cultures of human granulosa cells (hGCs). Gonadotrophins exert their functions by binding FSH receptors (FSHRs), activating signaling pathways that increase the cyclic adenosine monophosphate (cAMP) intracellular content. Bioequivalence has been defined as the dose/duration of gonadotrophin treatment able to promote the same amount of intracellular cAMP. hGCs were treated with different doses of either gonadotrophin and the cAMP was measured after different incubation times to establish the bioequivalence. Results obtained by comparing the bioequivalent treatments, showed that CFA is more effective than recFSH in inducing aromatase gene expression after 6 and 24 h from the initial stimulation in agreement with its long-acting characteristic. [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]

Visfatin and resistin appear to interfere with reproduction in the gonads, but their potential action at the hypothalamic-pituitary level is not yet known. The aim of the present study was to investigate the mRNA and protein expression of these adipokines in murine gonadotroph cells and to analyse the effects of different concentrations of recombinant mouse visfatin and resistin (0.01, 0.1, 1 and 10 ngmL-1) on LH secretion and signalling pathways in LβT2 cells and/or in primary female mouse pituitary cells. Both visfatin and resistin mRNA and protein were found in vivo in gonadotroph cells. In contrast with resistin, the primary tissue source of visfatin in the mouse was the skeletal muscle, and not adipose tissue. Visfatin and resistin both decreased LH secretion from LβT2 cells after 24 h exposure of cells (P<0.03). These results were confirmed for resistin in primary cell culture (P<0.05). Both visfatin (1 ngmL-1) and resistin (1 ngmL-1) increased AMP-activated protein kinase a phosphorylation in LβT2 cells after 5 or 10 min treatment, up to 60 min (P<0.04). Extracellular signal-regulated kinase α phosphorylation was transiently increased only after 5 min resistin (1 ngmL-1) treatment (P<0.01). In conclusion, visfatin and resistin are expressed in gonadotroph cells and they may affect mouse female fertility by regulating LH secretion at the level of the pituitary. [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]

Cheetah are induced ovulators, experiencing short, variable oestrogen waves year-round. Exogenous gonadotrophin administration induces ovulation, but success is variable and often improves if ovaries are quiescent. After affirming the presence of short-term oestrogenic waves, we examined the effect of the timing of administration of exogenous equine and human chorionic gonadotrophins (eCG-hCG) within the oestrogen concentration pattern on subsequent follicle development and oocyte and corpus luteum quality. We also investigated ovarian suppression using an oral progestin (Altrenogest, 7 days) and assessed whether Altrenogest moderated adrenal activity by reducing glucocorticoid metabolites. All cheetahs exhibited short (every ~7-10 days), sporadic, year-round increases in faecal oestradiol punctuated by unpredictable periods (4-10 weeks) of baseline oestradiol (anoestrous). Gonadotrophin (eCG-hCG) efficacy was not affected by oestradiol 'wave' pattern if administered ≥ 3 days after an oestrogen peak. Such cheetahs produced normative faecal progestagen patterns and higher numbers (P < 0.06) of mature oocytes than females given gonadotrophins ≤2 days after an oestradiol peak. Altrenogest supplementation expanded the interval between oestradiol peaks to 12.9 days compared with 7.3 days without progestin pretreatment. Altrenogest-fed females excreted less (P < 0.05) glucocorticoid metabolites than non-supplemented counterparts. Results show that Altrenogest is effective for suppressing follicular activity, may contribute to reduced glucocorticoid production and may result in more effective ovulation induction via gonadotrophin therapy. [ABSTRACT FROM AUTHOR]

Conventional ovarian stimulation protocols for IVF are designed to achieve maximum oocyte yields. Conventional protocols, however, are associated with patient discomfort, increased risk of ovarian hyperstimulation syndrome and higher costs. In recent years, mild stimulation protocols have risen in popularity. These protocols typically use lower doses (≤150 IU/day), shorter duration of exogenous gonadotrophins, or both, compared with conventional protocols, with the goal of limiting the number of retrieved oocytes to less than eight. The pregnancy rate per cycle (fresh embryo transfer only) is lower with mild stimulation compared with conventional stimulation; however, the cumulative pregnancy rate seems to be comparable between the approaches. Reports are conflicting on the effects of mild versus conventional stimulation on embryo quality. This article expands on a live debate held at the American Society for Reproductive Medicine 2015 Annual Meeting to compare the advantages and disadvantages of the ‘more is better’ (conventional protocol) versus ‘less is best’ (mild protocol) approaches to ovarian stimulation. Both protocols are associated with benefits and challenges, and physicians must consider the needs of the individual patient when determining the best treatment options. Further prospective studies comparing a variety of outcomes with conventional and mild stimulation are needed. [ABSTRACT FROM AUTHOR]