Progestin vs. Gonadotropin-Releasing Hormone Antagonist for the Prevention of Premature Luteinizing Hormone Surges in Poor Responders Undergoing in vitro Fertilization Treatment: A Randomized Controlled Trial.
ABSTRACT: Objective: Progestin was recently used as an alternative of gonadotropin-releasing hormone (GnRH) analog for preventing premature luteinizing hormone (LH) surge with the aid of vitrification techniques, however, limited data were available about the potential of progestin in poor responders undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. We performed a randomized parallel controlled trial to investigate the difference of progestin and GnRH antagonist in poor responders. Methods: A total of 340 poor responders who met with Bologna criteria were randomly allocated into the progestin-primed ovarian stimulation (PPOS) group and GnRH antagonist group. Fresh embryo transfer was preferred in the GnRH antagonist group and freeze-all was performed in the PPOS group. The primary outcome was the incidence of premature LH surge, secondary outcomes were the number of retrieved oocytes, the number of viable embryos and the pregnancy outcomes. Results: The results showed that the incidence of premature LH surge in PPOS group was lower than that in antagonist group (0 vs. 5.88%, P < 0.05). In PPOS group, the average numbers of oocytes and viable embryos were comparable to those in GnRH antagonist group (3.7 ± 2.6 vs. 3.4 ± 2.4; 1.6 ± 1.7 vs. 1.4 ± 1.3, P > 0.05), the live birth rate was similar between the two groups (21.8 vs. 18.2%, RR 1.25 (95% confidence interval 0.73, 2.13), P > 0.05). Conclusions: The study demonstrated that PPOS had a more robust control for preventing premature LH rise than GnRH antagonist in poor responders, but PPOS in combination with freeze-all did not significantly increase the probability of pregnancy than GnRH antagonist protocol for poor responders.
Project description:Progress in vitrification techniques has allowed reproductive physicians to consider new strategies for using progestin as an alternative to a GnRH analogue to improve in vitro fertilisation (IVF). However, the role of progestin in blocking luteinising hormone (LH) surges and its potential in clinical practice are unclear, especially for poor responders. We designed a prospective randomised controlled trial (RCT) to compare the efficacy of a gonadotropin-releasing hormone (GnRH) antagonist and progestin in blocking LH surges and premature ovulation in poor responders.Poor responders who meet the Bologna criteria will be randomised to one of two stimulation regimens-gonadotropin-releasing hormone (GnRH) antagonist or progestin-primed ovarian stimulation (PPOS)-using a computer-generated random number. Fresh embryos were transferred in the GnRH antagonist group and frozen embryos were transferred in the PPOS group. The primary outcome is the incidence of premature LH surges. Secondary outcomes include the number of oocytes retrieved, the number of embryos available for transfer, implantation rates and clinical pregnancy. The sample size for this trial is estimated as 340 participants, with 170 participants in each group. The data analysis will be by intention to treat.To our knowledge, this is the first RCT to examine the efficacy of administering progestin orally to block LH surges and premature ovulation compared with the GnRH antagonist protocols in poor responders undergoing IVF treatment.www.chictr.org.cn . ChiCTR-IPR-17010906 . Registered on 18 March 2017.
Project description:<b>Introduction: </b>Women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF) protocols are typically characterised by an increased number of oocytes retrieved. The oocytes are often of poor quality, leading to lower pregnancy rates, higher miscarriage rates and an increased risk of developing ovarian hyperstimulation syndrome (OHSS). Since our previous preliminary study showed that a novel progestin-primed ovarian stimulation (PPOS) protocol blocked the luteinising hormone (LH) surge during IVF and achieved a higher pregnancy rate with a lower incidence of OHSS, we designed a prospective randomised controlled trial to compare the efficacy and safety of this PPOS protocol with the flexible gonadotropin-releasing hormone (GnRH) antagonist protocol in patients with PCOS who are undergoing IVF procedures.<br><br><b>Methods and analysis: </b>Patients with PCOS will be randomised to one of two controlled ovarian stimulation regimens-GnRH antagonist or PPOS-using a computer-generated random number. A freeze-all strategy using embryo vitrification techniques and frozen embryo transfer will be performed in both groups. The primary outcome is the live-birth rate per transfer. Secondary outcomes include the incidence of premature LH surges, the duration and total dose of human menopausal gonadotropin stimulation, the number of oocytes retrieved, the incidence of moderate or severe OHSS, the number of embryos available for transfer, implantation rates, clinical pregnancy rates, pregnancy loss rates, ectopic pregnancy rates, pregnancy and neonatal complications, and congenital anomalies. The necessary sample size for this trial was estimated as 392 participants, with 196 participants in each group. Intention-to-treat analysis was used in processing our experimental data.<br><br><b>Ethics and dissemination: </b>This study was approved by the Institutional Review Board of the hospital (2016-133-T82). The trial will be conducted according to the principles of the World Medical Association's Declaration of Helsinki and in accordance with Good Clinical Practice standards. The findings of this trial will be published in a peer-reviewed journal.<br><br><b>Trial registration number: </b>ChiCTRIPR16009580.
Project description:Background:Oral progesterone is recommended as an alternative to gonadotropin-releasing hormone (GnRH) agonists and antagonists to prevent luteinizing hormone (LH) surge in assisted reproductive technology (ART) cycles. However, there are little data regarding its use. Objective:We aimed to compare the effect of oral Utrogestan and Cetrotide (a GnRH antagonist) on preventing LH surge in ART cycles. Materials and Methods:In this randomized clinical trial, 100 infertile women undergoing ART who received recombinant follicle-stimulating hormone (FSH) at 150-225 IU/day were randomly assigned to receive either Utrogestan 100 mg twice a day (case group) or GnRH antagonist protocol (control group) from cycle day 3 until the trigger day. Triggering was performed with 10,000 IU hCG) when there were at least three mature follicles. Viable embryos were cryopreserved for transfer in the next cycle for both groups. The number of oocytes retrieved and transferred embryos were compared between groups. Results:The case group had significantly higher progesterone levels on triggering day, more follicles of > 14 mm with higher maturity, and more oocytes retrieved with a higher rate of embryos transferred. A small increase in the pregnancy rate was observed in the case group, with no significant between-group differences. The most important result was the lack of premature LH surge in either group upon serum LH assessment on the triggering day. Conclusion:Utrogestan is an alternative treatment that could reduce the LH surge rate and increase the ART outcomes including the number of oocytes retrieved and transferred embryos compared with GnRH agonists and antagonists.
Project description:Interactions between brain IGF-I receptors and estrogen receptors regulate female reproductive physiology and behavior. The present study investigated potential mechanisms by which IGF-I receptors in the neuroendocrine hypothalamus regulate GnRH neuronal activation and LH release in young and middle-aged female rats under estradiol (E2) positive feedback conditions. We infused vehicle, IGF-I, or JB-1, a selective antagonist of IGF-I receptors, into the third ventricle of ovariectomized female rats primed with E2 and progesterone or vehicle. In young females, blockade of IGF-I receptors attenuated the steroid hormone-induced LH surge, reduced the percent of GnRH neurons expressing c-fos on the day of the LH surge, and decreased the total number of neurons expressing c-fos in the preoptic area. Middle-aged females had fewer GnRH neurons expressing c-fos during the LH surge than young females, and the LH surge amplitude was attenuated. Infusion of an IGF-I dose previously shown to increase LH surge amplitude did not increase the percent of GnRH neurons expressing c-fos in middle-aged females. Brain IGF-I receptor blockade did not modify E2 induction of progestin receptor-immunoreactive neurons in the preoptic area, arcuate, or ventromedial hypothalamus of young rats. These findings indicate that brain IGF-I receptors are required for E2 activation of GnRH neurons in young rats and for robust GnRH release from axon terminals in middle-aged females. IGF-I likely exerts its effects by actions on E2-sensitive neurons that are upstream of GnRH neurons and terminals.
Project description:Progesterone can block the oestradiol-induced GnRH/LH surge and inhibit LH pulse frequency. Recent studies reported that progesterone prevented premature LH surges during ovarian hyperstimulation in women. As the most potent stimulator of GnRH/LH release, kisspeptin is believed to mediate the positive and negative feedback effects of oestradiol in the hypothalamic anteroventral periventricular (AVPV) and arcuate (ARC) nuclei, while the region-specific role of progesterone receptors in these nuclei remains unknown. This study examined the hypothesis that progesterone inhibits LH surge and pulsatile secretion via its receptor in the ARC and/or AVPV nuclei. Adult female rats received a single injection of pregnant mare serum gonadotropin followed by progesterone or vehicle. Progesterone administration resulted in a significant prolongation of the oestrous cycle and blockade of LH surge. However, microinjection of the progesterone receptor antagonist, RU486, into the AVPV reversed the prolonged cycle length and rescued the progesterone blockade LH surge, while RU486 into the ARC shortened LH pulse interval in the progesterone treated rats. These results demonstrated that progesterone's inhibitory effect on the GnRH/LH surge and pulsatile secretion is mediated by its receptor in the kisspeptin enriched hypothalamic AVPV and ARC respectively, which are essential for progesterone regulation of oestrous cyclicity in rats.
Project description:Two modes of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion are necessary for female fertility: surge and episodic secretion. However, the neural systems that regulate these GnRH secretion patterns are still under investigation. The neuropeptide somatostatin (SST) inhibits episodic LH secretion in humans and sheep, and several lines of evidence suggest SST may regulate secretion during the LH surge. In this study, we examined whether SST alters the LH surge in ewes by administering a SST receptor (SSTR) 2 agonist (octreotide) or antagonist [CYN154806 (CYN)] into the third ventricle during an estrogen-induced LH surge and whether endogenous SST alters episodic LH secretion. Neither octreotide nor CYN altered the amplitude or timing of the LH surge. Administration of CYN to intact ewes during the breeding season or anestrus increased LH secretion and increased c-Fos in a subset GnRH and kisspeptin cells during anestrus. To determine if these stimulatory effects are steroid dependent or independent, we administered CYN to ovariectomized ewes. This SSTR2 antagonist increased LH pulse frequency in ovariectomized ewes during anestrus but not during the breeding season. This study provides evidence that endogenous SST contributes to the control of LH secretion. The results demonstrate that SST, acting through SSTR2, inhibits episodic LH secretion, likely acting in the mediobasal hypothalamus, but action at this receptor does not alter surge secretion. Additionally, these data provide evidence that SST contributes to the steroid-independent suppression of LH pulse frequency during anestrus.
Project description:Reproductive success depends on a robust and appropriately timed preovulatory LH surge. The LH surge, in turn, requires ovarian steroid modulation of GnRH neuron activation by the neuropeptide kisspeptin and glutamate and gamma-aminobutyric acid (GABA) neurotransmission in the medial preoptic area (mPOA). Middle-aged females exhibit reduced excitation of GnRH neurons and attenuated LH surges under estrogen-positive feedback conditions, in part, due to increased GABA and decreased glutamate neurotransmission in the mPOA. This study tested the hypothesis that altered kisspeptin regulation by ovarian steroids plays a role in age-related LH surge dysfunction. We demonstrate that middle-aged rats exhibiting delayed and attenuated LH surges have reduced levels of Kiss1 mRNA in the anterior hypothalamus under estrogen-positive feedback conditions. Kisspeptin application directly into the mPOA rescues total LH release and the LH surge amplitude in middle-aged rats and increases glutamate and decreases GABA release to levels seen in the mPOA of young females. Moreover, the N-methyl-D-aspartate receptor antagonist MK801 blocks kisspeptin reinstatement of the LH surge. These observations suggest that age-related LH surge dysfunction results, in part, from reduced kisspeptin drive under estrogen-positive feedback conditions and that kisspeptin regulates GnRH/LH release, in part, through modulation of mPOA glutamate and GABA release.
Project description:Progestin-primed ovarian stimulation (PPOS) is a new ovarian stimulation regimen for in vitro fertilization (IVF), with the advantages of an oral administration route and more control over preovulatory luteinizing hormone (LH) levels. Assessing the safety of this novel regimen is an important premise for its routine practice.We conducted a large retrospective cohort study for infants born between August 2014 and April 2017 from IVF and embryo transfer cycles after either PPOS and the conventional gonadotropin-releasing hormone-agonist (GnRH-a) short protocol at our center. Around 1589 live-born infants were finally enrolled, corresponding to 1258 frozen-thawed (FET) cycles, which led to 855 live-born infants from PPOS (659 FET cycles) and 734 live-born infants from the short protocol (599 FET cycles).Birth characteristics regarding gestational age, birth weight and length, infant sex, and early neonatal death were comparable between the 2 groups. The incidence of live-birth defects in the PPOS group (1.52%) was similar to that in the short protocol group (1.63%) and was not statistically significant. For birth defects, the risk significantly increased for multiple births, and the adjusted odds ratio was 3.14 (95% confidence interval [CI]: 1.25-7.88). No associations were found between congenital birth defects and maternal age, body mass index (BMI), the duration of infertility, method of insemination, infant sex, embryo stage at transfer, the number of embryos transferred or ovarian stimulation regimen.Our study shows that the neonatal outcomes and risk of congenital malformations were similar between the PPOS and conventional GnRH-a short protocol. However, multiple pregnancy led to a higher likelihood of birth defects.
Project description:Background: Bologna criteria poor ovarian responders have a very low prognosis. Although, it has been proposed that LH supplementation could be beneficial in women with previous hypo-response to FSH. There are no studies comparing the cumulative live birth rates (LBRs) between corifollitropin alfa (CFA) and highly purified human menopausal gonadotrophin (hp-hMG). Objective: To compare cumulative LBRs in Bologna poor ovarian responders undergoing ovarian stimulation with CFA followed by hp-hMG vs. hp-hMG alone in a GnRH antagonist protocol. Design: This is a retrospective cohort study. We included in total 917 poor responders fulfilling the Bologna criteria for poor ovarian response (POR) at a university-affiliated tertiary center from January 2011 until March 2017. Patients were administered either fixed daily doses of 300-450 IU of hp-hMG (group A) or a single dose of 150 ?g of CFA followed by daily injections of ?300 IU of hp-hMG from Day 8 of stimulation until the day of ovulation trigger (group B), in a fixed GnRH antagonist protocol. Results: LBRs after fresh embryo transfer (ET) were similar in group A 71/510 (14%) and B 42/407 (10%). Cumulative LBR per cycle was significantly higher in group A (16.9%) compared to group B (11.8%); (P = 0.03). However, logistic regression analysis showed no association between the type of gonadotropin administered and cumulative LBR. Only age was significantly associated with cumulative LBR (OR = 0.93, P = 0.007). Conclusion: Cumulative LBRs are similar in Bologna poor responders stimulated with CFA followed by hp-hMG compared to hp-hMG monotreatment in an antagonist protocol.
Project description:Background: The impact of controlled ovarian stimulation (COS) during medically assisted reproduction (MAR) on human embryogenesis is still unclear. Therefore, we investigated if early embryonic development is affected by the type of gonadotropin-releasing hormone (GnRH) analog used to prevent a premature LH surge. We compared embryo morphology and morphokinetics between GnRH agonist and antagonist cycles, both involving human chorionic gonadotropin (hCG)-trigger. To reduce possible confounding factors, we used intraindividual comparison of embryo morphokinetics in consecutive treatment cycles of the same patients that underwent a switch in the COS protocol. Methods: This retrospective cohort study analyzed morphokinetics of embryos from patients (n = 49) undergoing a switch in COS protocols between GnRH agonists followed by GnRH antagonists, or vice versa, after culture in a time-lapse incubator (EmbryoScope®, Vitrolife) in our clinic between 06/2011 and 11/2016 (n = 49 GnRH agonist cycles with n = 172 embryos; n = 49 GnRH antagonist cycles with n = 163 embryos). Among time-lapse cycles we included all embryos of the two consecutive cycles before and after a switch in the type of COS in the same patient. In-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was performed and embryos were imaged up to day 5. Data were analyzed using Mann-Whitney U test or Fisher's exact test. The significance level was set to p = 0.05. Patients with preimplantation genetic screening cycles were excluded. Results: The mean age (years ± standard deviation) of patients at the time of treatment was 35.7 ± 4.3 (GnRH agonist) and 35.8 ± 4.0 (GnRH antagonist) (p = 0.94). There was no statistically significant difference in the number of oocytes collected or the fertilization rate. The numbers of top quality embryos (TQE), good-quality embryos (GQE), or poor-quality embryos (PQE) were also not different in GnRH agonist vs. antagonist cycles. We found no statistically significant difference between the analyzed morphokinetic parameters between the study groups. Conclusions: Our finding supports the flexible use of GnRH analogs to optimize patient treatment for COS without affecting embryo morphokinetics.