Gonadotropin-induced Ovulation Research Articles

PKC-βII is downregulated in the premature ovarian failure SD rat model.

We investigated the role of protein kinase c (PKC) -α and -β during the ovarian follicular dynamics using estrous cycle, gonadotropin-induced ovulation, and antral follicle culture, 4-vinylcyclohexene diepoxide (VCD)-induced premature ovarian failure (POF) in the SD rat models. We found the higher activity of PKC during the proestrus stage along with expression of PKC-α during the estrus and metestrus stages of the estrous cycle while PKC-β expression was increased during the diestrus, proestrus, and estrus stages. In response to pregnant mare gonadotropin (PMSG)-induced follicular recruitment and ovulation, the phosphorylated (Thr-642) PKC-β was increased. PKC activity inhibition by hispidin during the proestrus stage resulted in decreased antral follicles and corpus luteum. Treatment with hispidin resulted in the downregulation of granulosa cell (GC) biomarker, follicle stimulating hormone receptor (FSHR) expression in the cultured pre-antral follicle.During the forskolin-induced luteinization of human granulosa cells, the expression level of PKC-α and β (I and II) was decreased. In the POF condition, the activity of total PKC and the expression levels of PKC-α and β (I and II) were increased. Immunostaining depicted ubiquitous expression of PKC-α in the ovary during the estrous cycle and POF conditions. Taken together, we conclude the association of PKC-α and -β (I and II) during ovarian follicular dynamics where the expression level of PKC-α is increased, but the expression level of PKC-β (I and II) is suppressed in the POF condition in the SD rat model.

Comparison of letrozole with gonadotropins and letrozole_gonadotropin combination for ovulation induction in PCOS women after clomiphene citrate failure

The aim of this study is to compare the efficacy of letrozole with gonadotropin and letrozole plus gonadotropin for ovulation induction in PCOS women after clomiphene citrate failure, Seventy eight women with PCO failed to conceive with clomiphene citrate divided in to three groups A,B,C treated with letrozole tablet, , letrozole plus follicular stimulating hormone and follicular stimulating hormone injection alone respectively for ovulation induction..Results: ovulation rate was (65.4%),(76.9%) and(76.9%) in group A,B &C respectively, pregnancy rate in study groups were (50%),(69.2%)and(65.4%) in A,B,&C respectivelyConclusion: Letrozole appears to be a suitable ovulation inducing agent in PCOS women with CC failure and significant higher pregnancy rate was observed in letrozole co treatment with gonadotropins as compared to other two protocoles

Gene expression of equine cumulus cells during in vitro and in vivo oocyte maturation

In vivo matured oocytes collected from dominant, pre-ovulatory follicles have superior developmental competence when compared to their in vitro matured counterparts, indicating that in vitro maturation (IVM) methods are sub-optimal. Cumulus cells (CC) have a critical role during oocyte maturation; thus, their gene expression holds key information regarding cellular processes associated with oocyte development. Understanding these biological events occurring during in vivo maturation of equine oocytes has the potential to improve IVM conditions. The aim of this study was to compare gene expression profiles of CC obtained from in vitro matured oocytes (IVM-CC) and in vivo matured oocytes (IVV-CC) by identifying differentially expressed genes (DEG) and significant biological pathways related to maturation. For the IVM-CC group, cumulus-oocyte complexes (COCs; n =12) were collected and matured in vitro as previously described (Meyers et al. Reprod Fertil Dev. 2019; 12:1874-1884). COCs for the IVV-CC group (n = 12) were collected after gonadotropin induction of ovulation as previously described (Foss et al. EVJ. 2013; 45:39-43). Extracted RNA from CC was sequenced, generating an average of 24 million reads/sample. The raw reads were trimmed (Trimmgalore) and mapped (STAR) to the current equine reference genome. Mapped reads were quantified (Featurecount) and compared between IVM-CC and IVV-CC groups,using the DESeq2 package in R software. A total of 14,479 genes were expressed in the cumulus cells. Principal component analysis showed a uniform pattern of gene expression among the IVV-CC, in contrast to a more scattered pattern in IVM-CC samples. We found 6,677 DEGs with 4,490 downregulated and 2,187 upregulated genes in the IVM-CC group. The enrichment pathway analysis demonstrated that downregulated genes were involved in transmembrane signaling receptors and chemical stimulus detection, while upregulated genes were associated with chromosome segregation, DNA repair, sister chromatid segregation, DNA replication, mitotic cell cycle process, and nuclear division. We found abnormal expression of genes involved in cumulus expansion and gonadotropin receptors in the IVM-CC group. Our data highlights that IVM culture conditions seem to be a distant replica of the in vivo conditions, as demonstrated by the divergent gene expression of the cumulus cells. The difference observed in gene expression and associated pathways could explain the variability in developmental competence between the in vivo and in vitro matured gametes. Lastly, this data serves as a starting point to determine modifications of current in vitro maturation culture protocols necessary to mimic in vivo conditions. This study was funded by the Theriogenology Foundation and Center for Equine Health at UC Davis.

Differential effects of the immunosuppressive calcineurin inhibitors cyclosporine-A and tacrolimus on ovulation in a murine model.

STUDY QUESTIONDo therapeutic levels of cyclosporine-A and tacrolimus affect ovulation in a rat gonadotrophin-induced ovulation model?SUMMARY ANSWERCyclosporine-A, but not tacrolimus, decreases ovulation rate when administered for 5 days before induced ovulation.WHAT IS KNOWN ALREADYThe mainstays of immunosuppression in solid organ transplantation, to prevent rejection, are the calcineurin inhibitors cyclosporine-A or tacrolimus. These drugs could potentially affect fertility in transplanted patients. Since ovulation is an inflammation-like process with pivotal roles for several immune cells and modulators, it is possible that the calcineurin inhibitors, with broad effects on the immune system, could interfere with this sensitive, biological process.STUDY DESIGN, SIZE, DURATIONExperimental design at university-based animal facilities. A total of 45 immature Sprague–Dawley rats were used. The study was carried out over 3 months.PARTICIPANTS/MATERIALS, SETTING, METHODSImmature Sprague–Dawley rats (n = 45) were randomly assigned to receive equivalent doses of tacrolimus (0.5 mg/kg/day; TAC), cyclosporine-A (10 mg/kg/day; CyA) or vehicle (Control). Ovarian hyperstimulation was induced with 10 IU of equine chorionic gonadotrophin, and ovulation was triggered with 10 IU of hCG. Oocytes were retrieved from the oviducts and ovulation rates were calculated. Various subpopulations of white blood cells were counted in peripheral blood and ovarian tissue samples.MAIN RESULTS AND THE ROLE OF CHANCEAnimals in the CyA group showed a lower ovulation rate when compared to the TAC and Control groups (CyA: mean 9 oocytes (range 0–22); TAC: 21 oocytes (8–41); Control: 22 oocytes (6–39); P = 0.03). Regarding counts of the white blood cell subpopulations and resident neutrophils in the ovary, no significant differences were observed between the groups.LIMITATIONS, REASONS FOR CAUTIONAlthough the ovulation process is highly conserved within species, the differences between rodents and humans may limit the external translatability of the study.WIDER IMPLICATIONS OF THE FINDINGSThese findings suggest that tacrolimus should be the preferred calcineurin inhibitor of choice in transplanted patients who are aiming for pregnancy.STUDY FUNDING/COMPETING INTEREST(S)Swedish Research Council and ALF of Sahlgrenska Academy, Sweden. Rio Hortega Grant from the Instituto de Salud Carlos III, Spain (CM09/00063). There are no conflicts of interest.

Effects of the Interval between Ovulation Induction using Clomiphene Citrate and Frozen Embryo Transfer on Pregnancy Outcome

Abstract Objective: To explore the best timing for frozen embryo transfer (FET) after ovarian stimulation and egg retrieval using the clomiphene citrate (CC) + human menopausal gonadotropin (hMG) ovulation induction regimen through a retrospective analysis. Methods: Data of patients who underwent CC + hMG ovulation induction and FET from January 2014 to December 2019 were analyzed retrospectively. The patients were divided into three groups according to the interval from egg retrieval to FET: CC1 (within 1 menstrual cycle), CC2 (2 menstrual cycles), and CC3 (≥ 3 menstrual cycles). Indicators such as hormone levels and pregnancy outcomes were recorded to explore the effect of different intervals on pregnancy outcome. Results: A total of 1,082 transfer cycles were included in this retrospective analysis. The implantation, clinical pregnancy, and live birth rates in the CC1 group were significantly lower than those in the CC2 and CC3 groups (P < 0.05). The E2/P4 ratio on progesterone injection day (3 days before thawed embryo transfer) was lower in the CC1 group than in the other groups (P < 0.05). After adjusting for all factors using multifactor regression analysis, the interval between egg retrieval and FET was found to be an independent predictor of the implantation, pregnancy, and live birth rates. Conclusion: An interval of more than one menstrual cycle between the day of egg retrieval after ovarian stimulation with the CC + hMG ovulation induction regimen and the day of FET can result in high implantation, clinical pregnancy, and live birth rates, which can lead to an improved pregnancy outcome.

Endometriozisli hastalarda ovulasyon indüksiyonu ajanı olarak letrozol ve gonedotropinlerin karşılaştırılması: prospektif randomize çalışma

Purpose: This study aimed to compare the effects of letrozole and gonadotropins for ovulation induction in infertile patients with stage 1-2 endometriosis. Materials and methods: Twenty patients who underwent diagnostic laparoscopy and histologically diagnosed stage 1-2 endometriosis were included in this prospective randomized study. Patients who planned to continue with timed sexual intercourse were randomized into two treatment groups including letrozole (n=10) or gonadotropins (n=10) for minimum three and maximum five treatment cycles. Results: Ovulation occurred in 37/45 cycles (82.2%) in the letrozole group and 32/37 cycles (86.4%) in the gonadotropin group, without statistically significant difference ( p =0.590). Total number of follicles was significantly higher in gonadotropin group on the day of hCG administration (2.33±0.71 vs. 3.05±0.91, p < 0.001). Clinical pregnancy rates both per completed cycles and per patients were similar between two groups (8.1% vs. 9.4%, p =0.850 and 30% vs. 30%, p =1.000; respectively). Conclusions: Letrozole is well tolerated and cost effective ovulation induction agent in patients with endometriosis and effects of letrozole for ovulation induction were comparable to gonadotropins.

A romatase enzyme inhibitor versus gonadotropin for induction of ovulation in patients with polycystic ovary syndrome resistant to clomiphene citrate a randomized controlled trial

A romatase enzyme inhibitor versus gonadotropin for induction of ovulation in patients with polycystic ovary syndrome resistant to clomiphene citrate a randomized controlled trial

Gonadotropin releasing hormone antagonist use in controlled ovarian stimulation and intrauterine insemination cycles in women with polycystic ovary syndrome

ObjectiveTo evaluate the effect of the GnRH antagonist on gonadotropin ovulation induction in women with PCOS. Materials and methodsA total of 175 intrauterine insemination (IUI) cycles in women with polycystic ovary syndrome (PCOS) were included in the study. Women in the control group (n = 87) underwent controlled ovarian stimulation (COS) with recombinant follicle stimulating hormone (r-FSH) only, while women in the study group (n = 88) were administered r-FSH plus cetrorelix. ResultsAs expected, the mean value of luteinizing hormone and progesterone, on the day of human chorionic gonadotropin administration were statistically significantly lower in patients receiving GnRH antagonist than the control group (p = 0.002). Premature luteinization occurred in only one of the patients in the GnRH antagonist group (1.1%) and in 15 of the 88 cycles in the control group (17.2%), showing a significant difference between the two groups (P = 0.001). The clinical pregnancy rate per cycle was higher in GnRH-antagonist group compared to the control group but the difference did not reach to a statistical significance (25% vs 14.9%, P = 0.096). ConclusionsAdding GnRH-antagonist in COS/IUI cycles in women with PCOS resulted in a lower incidence of premature luteinization but did not improve pregnancy rates. However, owing to some benefits, antagonist therapy could be considered as a reasonable alternative to IVF in order to reduce PCOS patients'emotional distress.

Gonadotrophins for ovulation induction in women with polycystic ovary syndrome.

Gonadotrophins for ovulation induction in women with polycystic ovary syndrome.

Cost-effectiveness of progesterone (p) luteal support after gonadotropin ovulation induction and intrauterine insemination (GND-IUI)

Cost-effectiveness of progesterone (p) luteal support after gonadotropin ovulation induction and intrauterine insemination (GND-IUI)

Follicular flushing in natural cycle IVF does not affect the luteal phase – a prospective controlled study

In contrast to multifollicular IVF, follicular flushing seems to increase the efficacy of monofollicular IVF treatments such as natural cycle IVF (NC-IVF). However, because follicular flushing causes loss of granulosa cells, it might negatively affect luteal phase length and endocrine function of the luteal body. A prospective cohort Phase II study was performed in 24 women undergoing NC-IVF. Women underwent a reference cycle with human chorionic gonadotrophin-induced ovulation without follicle aspiration and analysis of the length of the luteal phase and luteal concentrations of progesterone and oestradiol. In addition, they underwent a NC-IVF cycle which was performed identically but follicles were aspirated and flushed three times. The luteal phase was shorter in 29.2%, equal in 16.7% and longer in 50.0% of cases following flushing of the follicles. Overall, neither difference in luteal phase length was significant [median duration (interquartile range) in reference cycle: 13 (12; 14.5), IVF (flushing) cycle: 14 (12.5; 14.5), median difference (95% CI): 0.5 (–0.5 to 1.5)] nor median progesterone and oestradiol concentrations. In conclusion, follicular flushing in NC-IVF affects neither the length of the luteal phase nor the luteal phase concentrations of progesterone and oestradiol, questioning the need for luteal phase supplementation.

Pregnancy in patients with thalassemia major: a cohort study and conclusions for an adequate care management approach.

An improvement in quality of life and survival occurred among thalassemia major (TM) patients: pregnancy in such patients has become a reality. Safe pregnancy and delivery require efforts to ensure the best outcomes. Between 2007 and 2016, 30 TM patients had 37 pregnancies. We analyzed the hematological parameters before, during, and after pregnancies and in 19 patients a cardiovascular magnetic resonance (CMR) T2* was performed. The mean age at first pregnancy was 30±4years; the current mean age is 35±5years. Twenty-four patients (80%) had a single pregnancy, five patients (17%) had two pregnancies, and one patient (3%) became pregnant three times. Seventeen pregnancies (46%) were spontaneous, 20 (64%) needed gonadotrophin-induced ovulation and/or reproductive technologies. All pregnancies resulted in live births. Seven were twin pregnancies (19%). The mean gestational hemoglobin was 9.2±0.5g/dl, lower than pre- and postpregnancy (9.8±1g/dl, p=ns and 9.6±1g/dl, p=0.02, respectively). Median ferritin levels increased progressively (1071, range 409-5724ng/ml, before pregnancy vs 2231, range 836-6918ng/ml, after pregnancy, p<0.0001). CMR before pregnancy showed a normal cardiac T2* (mean 35.34±8.90ms) and a mean liver iron concentration (LIC) of 3.37±2.11mg/g dry weight (dw). After pregnancy, the mean cardiac T2* was 31.06±13.26ms and the mean LIC was significantly increased (9.06±5.75mg/gdw, p=0.0001). Pregnancy is possible and safe in thalassemia major. During pregnancy, iron accumulates, especially in the liver; a prompt resumption of chelation after delivery is mandatory.

Success rates vary by ovulation induction protocol and body mass index: toward personalized medicine for intrauterine insemination

Obesity rates are increasing worldwide. Along with others, we have demonstrated that body mass index (BMI) influences fertility treatment success rates in a protocol-dependent fashion. Much less is known about intrauterine insemination (IUI) success because of the absence of IUI data in national reporting registries, such as the one maintained by the Society for Assisted Reproductive Technologies (SART). To investigate the effectiveness of ovulation induction with gonadotropins versus ovulation induction with oral agents and gonadotropins (aka “mini-stim”) in relation to BMI in patients undergoing IUI in a large, multi-center, retrospective analysis. We analyzed 67,662 treatment cycles from 33,867 patients undergoing IUI ovulation induction (OI) with gonadotropins alone versus oral agents and gonadotropin from 2009 to 2016. Discrete-time proportional-odds models with time-dependent covariates were used to model the odds of achieving ongoing pregnancy during a given cycle. Interaction terms between BMI and stimulation type were included in the models to test the hypothesis that the effect of BMI was modified by stimulation type. BMI was treated continuously and categorized according to NIH guidelines (<18.5, 18.5–25, 25–30, 30–35, >35). Models were adjusted for age, antral follicle count, medication type, sperm motility, clinic, diagnoses, and were weighted toward more recent data. Overall, OI with only gonadotropin agents had significantly higher odds of achieving ongoing pregnancy compared to OI with oral agents and gonadotropins (OR = 1.16, p < 0.05). However, we found that the impact of BMI on success rates also differed significantly with the type of IUI treatment protocol. The effect of BMI was nonlinear and peaked in the obesity categories of both protocols (p < 0.05, see Figure 1). At lower levels of BMI, there was no significant difference in the odds of having an ongoing pregnancy between stimulation types. However, there was a pronounced divergence in success rate as BMI increased; gonadotropin OI alone performed better than gonadotropin OI with oral agents. When subcategories of BMI were assessed, a statistically significant difference in success was observed in women with a BMI of 25–30. Additionally, gonadotropin OI alone was associated with higher odds of multiples than gonadotropin with oral agents (OR = 1.53, p < 0.05), independent of patient BMI. Oral OI agents when used in conjunction with gonadotropins appear to be less effective for obese women. We previously demonstrated oral agents alone result in lower pregnancy rates with both timed intercourse and IUI in obese women. However, the detrimental effect of increased BMI was not observed with gonadotropin alone. Here, we demonstrate that OI with only gonadotropin agents is associated with higher success rates than OI with oral agents and gonadotropins. This difference is most pronounced in higher BMI patients. Additionally, we demonstrated gonadotropin OI alone is related to a higher probability of multiples than oral and gonadotropin independent of BMI. These data suggest that the best IUI protocol for a given patient varies with respect to their BMI.

Individualised gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: A prospective, observational study

ObjectiveThe aim of this study was to evaluate an individualised gonadotrophin starting dose regimen for women with anovulatory infertility. Study designWe included 71 normogonadotrophic anovulatory infertile women in a prospective, observational study. All underwent one ovulation induction cycle in a flexible, low-dose step-up protocol. The gonadotrophin starting dose (75–150IU/day) was individualised according to a nomogram incorporating menstrual cycle pattern (oligo- or amenorrhoea), BMI, and mean ovarian volume. The number of women who fulfilled the criteria for human chorionic gonadotrophin (hCG) administration (one follicle ≥17mm or 2–3 follicles ≥15mm) was assessed. ResultsOf the 50 women (70.4%) who fulfilled the hCG criteria and underwent intrauterine insemination, 34 (47.9%) achieved monofollicular growth and 16 (22.5%) developed 2–3 mature follicles. Seventeen (23.9%) cycles were converted to in vitro fertilisation (IVF) due to the development of >3 mature follicles, and one (1.4%) cycle was cancelled due to risk of ovarian hyperstimulation syndrome. Baseline total antral follicle count was found to be significantly associated with fulfillment of the hCG criteria (OR 0.96, 95% CI: 0.92–0.99, P=0.01). ConclusionsThe nomogram-based dose regimen was not considered suitable for ovulation induction due to a tendency to overestimate the gonadotrophin starting dose. However, the model may serve as a mild IVF regimen, especially in women prone to excessive follicle growth.

Does intrauterine insemination timing matter for achieving pregnancy during ovulation induction using gonadotropins? A retrospective cohort study

BackgroundIntrauterine insemination (IUI) is a commonly used procedure to increase the infertile couples' chance of pregnancy. Single or double insemination and different timing choices are modifications of this intervention. The aim of this study was to elucidate the effect of the IUI procedure on clinical pregnancy rates when performed at 24 hours or 36 hours after ovulation triggered by human chorionic gonadotropin (hCG) following ovulation induction with gonadotropins. MethodsOne hundred and thirteen women diagnosed with polycystic ovarian syndrome (PCOS) (as per Rotterdam's criteria) or unexplained infertility, who were treated using gonadotropins for ovulation induction and IUI for increasing fertilization potential, were recruited from the medical records of the infertility clinic. Demographic features, cycle outcomes, and clinical pregnancy rates of the patients were compared based on two different timing strategies of IUI (24 hours and 36 hours) following ovulation trigger using hCG. ResultsClinical pregnancy rates per cycle were 22.9% in the PCOS group and 26.9% in the unexplained group. The clinical pregnancy rates according to the timing of IUI were found to be similar for PCOS patients, unlike patients with unexplained infertility whose clinical pregnancy rates were significantly better when the IUI procedure was performed 24 hours following the hCG trigger. The cycle day of hCG trigger was also found to be significantly related to clinical pregnancy rate as utilizing a later hCG trigger day appeared to positively affect the odds of clinical pregnancy establishment. ConclusionIUI performed at either 24 hours or 36 hours after ovulation triggered by hCG injection does not change clinical pregnancy rates for PCOS patients. Patients with unexplained infertility seem to benefit from earlier IUI procedures, which increases their fertility potential during ovulation induction with gonadotropins. Avoiding earlier than physiologically needed artificial-hCG triggering before IUI procedures results with better pregnancy rates.

The role of kisspeptin and RFRP in the circadian control of female reproduction

In female mammals, reproduction shows ovarian and daily rhythms ensuring that the timing of the greatest fertility coincides with maximal activity and arousal. The ovarian cycle, which lasts from a few days to a few weeks, depends on the rhythm of follicle maturation and ovarian hormone production, whereas the daily cycle depends on a network of circadian clocks of which the main one is located in the suprachiasmatic nuclei (SCN). In the last ten years, major progress has been made in the understanding of the neuronal mechanisms governing mammalian reproduction with the finding that two hypothalamic Arg-Phe-amide peptides, kisspeptin (Kp) and RFRP, regulate GnRH neurons. In this review we discuss the pivotal role of Kp and RFRP neurons at the interface between the SCN clock signal and GnRH neurons to properly time gonadotropin-induced ovulation. We also report recent findings indicating that these neurons may be part of the multi-oscillatory circadian system that times female fertility. Finally, we will discuss recent investigations indicating a role, and putative therapeutic use, of these neuropeptides in human reproduction.

Gonadotrophins for ovulation induction in women with polycystic ovarian syndrome.

Ovulation induction with follicle stimulating hormone (FSH) is the second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate (CC). To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation induction in women with CC-resistant PCOS. We searched the Menstrual Disorders & Subfertility Group's Specialist Register of controlled trials, the Cochrane Central Register of Controlled Trials, MEDLINE (1966 to October 2014), EMBASE (1980 to October 2014), CINAHL (1982 to October 2014), National Research Register and web-based trials databases such as Current Controlled Trials. There was no language restriction. All randomised controlled trials reporting data on comparing clinical outcomes in women with PCOS who did not ovulate or conceive on CC, and undergoing ovulation induction with urinary FSH (uFSH: FSH-P or FSH-HP), HMG/HP-HMG or recombinant FSH. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that used co-treatment with CC, metformin, LH or letrozole. Three review authors (NW, MN and MvW) independently selected studies for inclusion, assessed study quality and extracted study data. Primary outcomes were live birth rate per woman (effectiveness outcome) and incidence of ovarian hyperstimulation syndrome (OHSS) per woman (safety outcome). Secondary outcomes were clinical pregnancy, miscarriage, multiple pregnancy, total gonadotrophin dose and total duration of stimulation per woman. We combined data using a fixed-effect model to calculate the odds ratio (OR). We summarised the overall quality of evidence for the main outcomes using GRADE criteria. The review includes 14 trials with 1726 women. Ten trials compared rFSH versus urinary-derived gonadotrophins (three rFSH versus HMG and seven rFSH versus FSH-HP), four trials compared FSH-P with HMG. We found no trials that compared FSH-HP with FSH-P.We found no evidence of a difference in live birth for rFSH versus urinary-derived gonadotrophins (OR 1.26, 95% CI 0.80 to 1.99, 5 trials, 505 women, I² = 0%, low-quality evidence) or clinical pregnancy rate (OR 1.08, 95% CI 0.83 to 1.39, 8 trials, 1330 women, I² = 0, low-quality evidence). This suggests that for the observed average live birth per woman with urinary-derived FSH of 16%, the chance of live birth following rFSH is between 13% and 26%.For the comparison HMG or HP-HMG versus FSH-P there was also no difference in the evidence on live birth rate (OR 1.36, 95% CI 0.58 to 3.18, 3 trials, 138 women, I² = 0%, low-quality evidence). This suggests that for a woman with a live birth rate of 18% with HMG or HP-HMG, the chance of live birth following uFSH is between 9% and 37%.Trial authors used various definitions for OHSS. Pooling the data, we found no evidence of a difference for rFSH versus urinary-derived gonadotrophins (OR 1.52, 95% CI 0.81 to 2.84, 10 trials, 1565 women, I(2) = 0%, very low-quality evidence) and for HMG or HP-HMG versus FSH-P (OR 9.95, 95% CI 0.47 to 210.19, 2 trials, 53 women, I² = 0%, very low-quality evidence). In women with PCOS and CC resistance or CC failure, we found no evidence of a difference in live birth and OHSS rates between urinary-derived gonadotrophins and rFSH or HMG/HP-HMG. Evidence for all outcomes was of low or very low quality. We suggest weighing costs and convenience in the decision to use one or the other.

WITHDRAWN: Recombinant FSH versus urinary gonadotrophins or recombinant FSH for ovulation induction in subfertility associated with polycystic ovary syndrome.

Reason for Withdrawal This review has been replaced by a review entitled 'Gonadotrophins for ovulation induction in women with polycystic ovarian syndrome'. To view the published versions of this article, please click the 'Other versions' tab.

Regulation of mitogen-activated protein kinase 3/1 activity during meiosis resumption in mammals.

In vivo, resumption of oocyte meiosis occurs in large ovarian follicles after the preovulatory surge of luteinizing hormone (LH). The LH surge leads to the activation of a broad signaling network in mural granulosa cells equipped with LH receptors. The signals generated in the mural granulosa cells are further augmented by locally produced peptides or steroids and transferred to the cumulus cell compartment and the oocyte itself. Over the last decade, essential progress has been made in the identification of molecular events associated with the final maturation and ovulation of mammalian oocytes. All new evidence argues for a multiple roles of mitogen-activated protein kinase 3/1 (MAPK3/1) in the gonadotropin-induced ovulation processes. However, the knowledge of gonadotropin-induced signaling pathways leading to MAPK3/1 activation in follicular cells seems limited. To date, only the LH-induced transactivation of the epidermal growth factor receptor/MAPK3/1 pathway has been described in granulosa/cumulus cells even though other mechanisms of MAPK3/1 activation have been detected in other types of cells. In this review, we aimed to summarize recent advances in the elucidation of gonadotropin-induced mechanisms leading to the activation of MAPK3/1 in preovulatory follicles and cultured cumulus-oocyte complexes and to point out a specific role of this kinase in the processes accompanying final maturation of the mammalian oocyte.

Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion.

Premature ovarian failure (POF) affects 1% of women in reproductive age, but its etiology remains uncertain. Whereas kisspeptins, the products of Kiss1 that act via Kiss1r (aka, Gpr54), are known to operate at the hypothalamus to control GnRH/gonadotropin secretion, additional actions at other reproductive organs, including the ovary, have been proposed. Yet, their physiological relevance is still unclear. We present here a series of studies in Kiss1r haplo-insufficient and null mice suggesting a direct role of kisspeptin signaling in the ovary, the defect of which precipitates a state of primary POF. Kiss1r hypomorph mice displayed a premature decline in ovulatory rate, followed by progressive loss of antral follicles, oocyte loss, and a reduction in all categories of preantral follicles. These alterations were accompanied by reduced fertility. Because of this precocious ovarian ageing, mice more than 48 weeks of age showed atrophic ovaries, lacking growing follicles and corpora lutea. This phenomenon was associated with a drop in ovarian Kiss1r mRNA expression, but took place in the absence of a decrease in circulating gonadotropins. In fact, FSH levels increased in aged hypomorph animals, reflecting loss of follicular function. In turn, Kiss1r-null mice, which do not spontaneously ovulate and have arrested follicular development, failed to show normal ovulatory responses to standard gonadotropin priming and required GnRH prestimulation during 1 week in order to display gonadotropin-induced ovulation. Yet, the magnitude of such ovulatory responses was approximately half of that seen in control immature wild-type animals. Altogether, our data are the first to demonstrate that Kiss1r haplo-insufficiency induces a state of POF, which is not attributable to defective gonadotropin secretion. We also show that the failure of follicular development and ovulation linked to the absence of Kiss1r cannot be fully rescued by (even extended) gonadotropin replacement. These findings suggest a direct ovarian role of kisspeptin signaling, the perturbation of which may contribute to the pathogenesis of POF.