In vitro fertilization results of GNRH antagonists and medroxyprogesterone acetate used to prevent premature LH surge during ovarian hyperstimulation.

The aim of this study was to evaluate the effects of medroxyprogesterone acetate (MPA) treatment in comparison to those of gonadotropin releasing hormone (GnRH) antagonists for the prevention of premature luteinizing hormone surges during controlled ovarian hyperstimulation (OS) and the impact of these effects on developing embryos and pregnancy outcomes. Data from 757 cycles of GnRH antagonist treatment and 756 cycles of MPA treatment were evaluated at the Akdeniz University Faculty of Medicine Assisted Reproductive Treatment Center between October 2018 and April 2022. Patient records were obtained from the electronic database of the centre and analysed. In our centre, GnRH antagonist protocols were used between 2018 and 2020, and MPA protocols were used between 2020 and 2022. We chose our study population by year. Our study is a comparative retrospective study. All methods in this study were performed in accordance with the relevant guidelines and regulations. Patients using MPA were significantly older (33.9 ± 5.6 vs. 32.6 ± 5.6, p < 0.001) and had a lower number of antral follicles (AFC) (10.7 ± 8.6 vs. 11.9 ± 10.8, p = 0.007) than those using GnRH antagonists. Both MPA (2.9%) and GnRH antagonists (2.2%) had similar effectiveness in preventing premature ovulation (p = 0.415). There was no significant difference between the two groups in terms of the number of total developed embryos (1.3 ± 1.3 vs. 1.2 ± 1.2, p = 0.765). There was no significant difference in the clinical pregnancy rates with the first ET (%35.4 vs. %30.1, p = 0.074), per total number of transfers (35.3% vs. 30.1%, p = 0.077). MPA was found to be effective at preventing premature ovulation during OS treatment, and the incidence of developing embryo and pregnancy outcomes in patients using MPA were similar to those in patients using GnRH antagonists. Therefore, the use of MPA instead of GnRH antagonists during OS may be a viable alternative for patients not scheduled for fresh ET.

Medroxyprogesterone Acetate versus Gonadotropin-Releasing Hormone Antagonist for the Prevention of Premature Luteinizing Hormone Surge in hyper-responder women undergoing controlled ovarian stimulation for IVF/ICSI Cycles.

OBJECTIVE: To compare the effect of Medroxyprogesterone acetate versus Gonadotropin releasing hormone antagonist for the prevention of premature luteinizing hormone (LH) surge in infertile hyper-responder women undergoing controlled ovarian stimulation for in vitro fertilization (IVF) /intracytoplasmic sperm injection (ICSI) cycles. METHODS: One hundred infertile hyper-responder women who were candidate for IVF/ICSI were randomly assigned into two groups. Group 1 was given 20 mg Medroxyprogesterone acetate from day 1 of the menstrual cycle till trigger day. Group 2 was given GnRH antagonist (injection Cetrorelix 0.25 mg s/c) from the day when the leading follicle reached 14 mm until the day of trigger for the prevention of premature LH surge (flexible protocol). We measured LH serum levels on day 1, day 7 of cycle and on trigger day. The primary outcome measured was the incidence of premature LH surge. Other outcome measures were total number of mature follicles on trigger day, total number of mature oocytes retrieved and number of good quality day-3 embryos. RESULTS: There was no premature luteinizing hormone surge in both groups of our study. The mean number of follicles on trigger day, mean number of M2 oocytes retrieved and mean number of good quality day-3 embryos were comparable in both the groups, with no statistically significant difference. CONCLUSIONS: The results of this study stated that MPA can be an effective alternative to GnRH antagonist for the prevention of premature LH surge in hyper-responder women undergoing COS for IVF. It is easy to use, widely available and cost-effective. It may establish a new regimen of ovarian stimulation using MPA as an oral alternative to GnRH antagonist treatment in hyper-responders.

Progestin-primed ovarian stimulation versus GnRH antagonist protocol in poor responders: Risk of premature LH surge and outcome of oocyte retrieval.

PURPOSE: For poor ovarian responders (PORs), gonadotropin-releasing hormone (GnRH) antagonist was commonly used for prevention of premature LH surge during controlled ovarian stimulation (COS) over the past two decades. The application of progestin-primed ovarian stimulation (PPOS) recently increased, but the role of PPOS for PORs was uncertain. We aimed to analyze the incidence of premature luteinizing hormone (LH) surge and the outcome of oocyte retrieval among PPOS and GnRH antagonist protocol for PORs. METHODS: This was a single-center retrospective study, which enrolled the PORs (defined by the Bologna criteria) undergoing COS with PPOS or flexible GnRH antagonist protocol during January 2018 to December 2021. We compared the incidence of premature LH surge (LH > 10 mIU/mL) and the outcome of oocyte retrieval between the PPOS group and the GnRH antagonist group. RESULTS: A total of 314 women were recruited, with 54 in the PPOS group and 260 in the GnRH antagonist group. The PPOS group had lower incidence of premature LH surges compared with the GnRH antagonist protocol group (5.6% vs 16.9%, P value 0.035). There was no significant difference between the two groups regarding the number of oocytes retrieved (3.4 vs 3.8, P value 0.066) and oocyte retrieval rates (88.9% vs 88.0%, P value 0.711). CONCLUSION: Compared with PPOS, GnRH antagonist protocol had higher risk of premature LH surges for PORs but may not affect pregnancy rates. PPOS is suitable for oocyte or embryo cryopreservation, but should not totally replace GnRH antagonist protocol for patients undergoing in vitro fertilization (IVF).

Successful pregnancy outcome after fresh embryo transfer in a dual stimulation cycle - a case report.

Controlled ovarian stimulation by antagonist protocol sometimes presents unpleasant surprises in the form of unexpected premature rupture of follicles despite well-timed daily administration of the antagonist. In such cases ovum pick up cannot be done, dual stimulation of the next crop of follicles may be pursued to salvage the cycle. A 'freeze all' strategy is usually implemented in all cases of dual stimulation because of embryo-endometrial asynchrony. Here we present a case where dual stimulation was followed by fresh embryo transfer with a successful pregnancy outcome.

Preventing Growth Stagnation and Premature LH Surge Are the Keys to Obtaining a Viable Embryo in Monofollicular IVF Cycles: A Retrospective Cohort Study.

How LH levels influenced the outcomes of monofollicular IVF cycles using different stimulation protocols was controversial. In this single-center, retrospective study, we analyzed 815 monofollicular IVF cycles between 2016−2022 using natural cycle (NC), medroxyprogesterone acetate (MPA) or clomiphene citrate (CC) in addition to human menopausal gonadotropin (hMG), with or without GnRH antagonist. A viable embryo was obtained in 35.7% of all cycles. Growth stagnation and premature LH surge are two markedly negative factors for obtaining viable embryos (odds ratios of 0.12 [0.08−0.65], p < 0.0001 and 0.33 [0.26,0.42], p < 0.0001, respectively). NC/hMG cycles are prone to premature LH surge (40.4%), yielding a significantly lower opportunity of obtaining embryos (24.7%, p = 0.029). The administration of GnRH antagonist on the background of MPA resulted in a significant decrease in LH levels (from 2.26 IU/L to −0.89 IU/L relative to baseline, p = 0.000214), leading to a higher risk of growth stagnation (18.6%, p = 0.007). We hypothesized that the abrupt decline of LH might increase the risk of apoptosis in granulosa cells. We proposed a "marginal effect" framework to emphasize that the change of LH was the key to its bioactivity, rather than the traditional "window" concept with fixed cutoff values of a threshold and a ceiling.

Does elevated luteinizing hormone level before trigger mean premature luteinizing hormone surge in advanced-aged women undergoing mild ovarian stimulation?

OBJECTIVE: To explore whether elevated luteinizing hormone (LH) level before trigger means premature LH surge in advanced aged women undergoing mild ovarian stimulation. METHODS: To retrospectively analyze 235 in vitro fertilization/intracytoplasmic sperm injection cycles in women >35 years old with the poor ovarian response (POR) from January 2012 to March 2016. Cycles are named Group 1, Group 2, and Group 3, being treated with gonadotropin-releasing hormone antagonist protocol (76 cycles), mild stimulation protocol using clomiphene citrate (73 cycles), and tamoxifen (86 cycles), respectively. MAIN OUTCOME MEASURE(S): The dynamic change of LH level during stimulation; the proportion of an elevated LH level defined as >10 IU/L on trigger day; the proportion of premature ovulation in each group. RESULTS: Serum LH level increased early in Group 2 and Group 3 and remained significantly higher than that in Group 1 during stimulation. In a sequence of three groups, the proportion of elevated LH levels before the trigger was 11.84, 43.8, and 37.21% (p＜.001) respectively. And the proportion of premature ovulation in patients with elevated LH levels was 11.11, 18.75, and 25% (p = .11) respectively. CONCLUSION: Elevated LH level before trigger does not mean premature LH surge in women more than 35 years old with POR undergoing mild ovarian stimulation with clomiphene or tamoxifen.

Clinical pregnancy resulting from intracytoplasmic sperm injection of prematurely ovulated oocytes retrieved from the posterior cul-de-sac.

OBJECTIVE: To report a clinical pregnancy resulting from intracytoplasmic sperm injection of prematurely ovulated oocytes retrieved from the posterior cul-de-sac. DESIGN: Case report. SETTING: Academic center. PATIENTS: A 40-year-old nulligravid woman underwent ovarian stimulation for in vitro fertilization (IVF). Daily injections of gonadotropin-releasing hormone antagonist were initiated on cycle day 8. A 10,000 IU dose of human chorionic gonadotropin was administered on cycle day 15 to trigger follicular maturation. The estradiol and luteinizing hormone levels on the trigger day were 1528 pg/mL and 2.4 mIU/mL, respectively. The patient underwent oocyte retrieval 35 hours after the trigger. Transvaginal sonography at the time of the retrieval revealed a large pocket of free fluid in the posterior cul-de-sac. Only 3 follicles measuring 10-12 mm were noted in both ovaries. No lead follicles were visualized. INTERVENTIONS: Aspiration of free fluid from the posterior cul-de-sac. MAIN OUTCOME MEASURES: Clinical pregnancy. RESULTS: The fluid in the posterior cul-de-sac was aspirated, and 3 mature oocytes were retrieved. Aspiration of the smaller ovarian follicles measuring 10-12 mm did not yield oocytes. All mature oocytes retrieved from the posterior cul-de-sac were fertilized with intracytoplasmic sperm injection. Three cleavage-stage embryos were transferred 3 days later. A single intrauterine pregnancy with cardiac activity was confirmed at a gestational age of 7 weeks. CONCLUSIONS: In the setting of premature ovulation, aspiration of free fluid from the posterior cul-de-sac can result in the retrieval of mature oocytes, which may result in clinical pregnancies.

Progestin-Primed Ovarian Stimulation Protocol for Patients in Assisted Reproductive Technology: A Meta-Analysis of Randomized Controlled Trials.

Objectives: Progestin-primed ovarian stimulation (PPOS) is a new ovarian stimulation protocol that can block the luteinizing hormone (LH) surge through progesterone instead of traditional down regulating or gonadotropin-releasing hormone (GnRH) antagonist, and in order to achieve multi-follicle recruitment. This paper aims to investigate the effectiveness of PPOS and its suitability for infertile patients with different ovarian reserve functions. Methods: We searched published randomized controlled trials (RCTs) about PPOS on Cochrane Library, PubMed, Embase, and Web of Science. The search period spanned from January 1, 2015 to November 16, 2020. The data were extracted, and the meta-analysis was performed on ovarian stimulation as well as embryological and clinical outcomes. The outcomes were pooled by a random effects model, and the risk of heterogeneity was evaluated. Subgroup analysis was performed for different ovarian reserve patients. Results: The clinical pregnancy rates and live birth or ongoing pregnancy rates with the PPOS protocol were not different from those with the control group. In the diminished ovarian reserve (DOR) subgroup, the PPOS protocol had a lower rate of premature LH surge [RR = 0.03, 95% CI = 0.01 to 0.13, p < 0.001]. The PPOS protocol had a lower rate of ovarian hyperstimulation syndrome (OHSS) [RR = 0.52, 95% CI = 0.36 to 0.76, p < 0.001, I2 = 0.00%]. The secondary outcomes showed that the number of oocytes retrieved, MII oocytes, and viable embryos was higher than that of the control protocol in DOR patients [(MD = 0.33, 95% CI = 0.30 to 0.36, p < 0.001), (MD = 0.30, 95% CI = 0.27 to 0.33, p < 0.001), (MD = 0.21, 95% CI = 0.18 to 0.24, p < 0.001)] and normal ovarian reserve (NOR) patients [(MD = 1.41, 95% CI = 0.03 to 2.78, p < 0.001), (MD = 1.19, 95% CI = 0.04 to 2.35, p < 0.001), (MD = 1.01, 95% CI = 0.21 to 1.81, p = 0.01)]. Conclusion: The findings suggest that PPOS is an effective ovarian stimulation protocol and is beneficial for patients with different ovarian reserve functions, which needs to be validated in more RCTs with larger samples.

Successful outcome of a pregnancy derived from premature ovulation in a gonadotropin-releasing hormone antagonist protocol: A case report.

In the gonadotropin-releasing hormone (GnRH) antagonist protocol, it is necessary to reinforce contraceptive guidance assuming that luteinizing hormone surge is not detected by measurement of serum level and ovulation is not suppressed by GnRH antagonist.

The relationship between a novel evaluation parameter of premature luteinization and IVF outcomes.

RESEARCH QUESTION: Can premature luteinization of granulosa cells (PLGC) act as a novel parameter of premature luteinization and affect IVF outcomes? STUDY DESIGN: In this retrospective cohort study, infertile patients undergoing fresh IVF cycles between January 2006 and December 2016 at the Reproductive Medicine Center in Tongji Hospital were included. A total of 42,468 cycles were conducted. Propensity score matching was carried out to match the baseline characteristics, and participants were assigned to the PLGC group and control group. The main outcomes were pregnancy rate and live birth rate. RESULTS: Patient characteristics and clinical outcomes were compared before and after matching. In general, the fate of oocytes in the PLGC group was much worse than those in the control group after matching, including metaphase II rate, two-pronuclei rate, available embryo rate, blastocyst formation rate, high-quality blastocyst rate, pregnancy rate, implantation rate and live birth rate. Among those potential risk factors, gonadotrophin duration, oestradiol and progesterone on HCG day were positively associated with the occurrence of PLGC in the multivariate logistic regression model, with gonadotrophin dosage negatively related. Moreover, cumulus-oocyte complexes with PLGC showed a high correlation with elevated progesterone levels over 1.5 ng/ml. CONCLUSIONS: Our findings demonstrated the adverse effect of PLGC on oocyte competency. In evaluating cumulus-oocyte complexes, PLGC provide an available novel parameter for premature luteinization judgement in clinical and individualized precise treatment. Close monitoring of progesterone level as well as critical analysis of progesterone elevation can reduce the occurrence of premature luteinization.

Late Follicular Phase Ovarian Stimulation Without Exogenous Pituitary Modulators.

Introduction: A gonadotropin-releasing hormone antagonist is the most common modulator used to prevent the premature luteinizing hormone (LH) surge when ovarian stimulation was initiated in the late follicular phase. We aimed in this study to evaluate the feasibility of performing ovarian stimulation in the late follicular phase without the use of exogenous pituitary modulators. Methods: Data were retrospectively collected from 404 normo-ovulatory patients who underwent their first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment in our department. One hundred sixteen subjects in the study group received ovarian stimulation when a dominant follicular diameter of ≥ 10 mm was confirmed by transvaginal ultrasonography after menstrual cycle day 6, which entailed a daily injection of gonadotropin until the trigger day, while 288 subjects in the control group received ovarian stimulation in the early follicular phase under a progesterone protocol. The primary outcome was the number of mature oocytes. Results: There was no statistical difference in the number of mature oocytes between the two groups (9.67 ± 5.33 in the study group vs. 9.38 ± 5.15 in the control group, P = 0.693). No secondary LH surges in the study group and no premature LH surges in the control group were found during ovarian stimulation. The good-quality embryo rate per oocyte retrieved showed no significant difference between the two groups (35.22 vs. 35.91%, P = 0.665). The clinical pregnancy rate per transfer was 54.55% in the study group and 56.48% in the control group (P = 0.718), and the implantation rate was similar between the two groups (36.94 vs. 37.77%, P = 0.829). Conclusions: Our study revealed that late follicular phase ovarian stimulation could be performed without an exogenous pituitary modulator.

Comparison Between PPOS and GnRHa-Long Protocol in Clinical Outcome with the First IVF/ICSI Cycle: A Randomized Clinical Trial.

PURPOSE: To investigate whether progestin-primed ovarian stimulation (PPOS) can be an alternative as gonadotrophin-releasing hormone agonist (GnRHa) long protocol for infertile women with normal ovarian reserve during IVF/ICSI. METHODS: A prospective randomized controlled trial (RCT) including 257 patients was conducted between 1 August 2017 to 1 January 2018. Computerized randomization was performed to assign participants into two treatment groups at a 1:1 ratio: PPOS (130 patients) or GnRHa long protocol (127 patients) followed by their first IVF/ICSI with fresh/frozen embryo transfer. The primary outcome was the number of oocytes retrieved. Patients with normal ovarian reserve undergoing their first IVF/ICSI procedure were included. The embryological and clinical outcomes were measured. Only the first embryo transfer cycle was followed-up. RESULTS: Basic characteristics such as infertility duration, age, and body mass index (BMI) were comparable in both groups. No significant difference was found in the number (mean ± SD) oocytes retrieved [11.8 ± 6.5 for PPOS vs 11.3 ± 5.6 for GnRHa long protocol] or viable embryos [4.5 ± 3.0 for PPOS vs 4.2 ± 2.9 for GnRHa long protocol] between the groups. No patient from either group experienced a premature LH surge during the whole process of ovarian stimulation. Besides, there was no moderate or severe ovarian hyperstimulation syndrome during the ovarian stimulation in PPOS group while three patients suffered it in the GnRHa long protocol group. There was no significant difference in the clinical pregnancy rate of the first embryos transfer cycle between the two groups. CONCLUSION: PPOS in combination with embryo cryopreservation as an ovarian stimulation regimen was as effective as GnRHa long protocol during controlled ovarian stimulation (COH) under different endocrinal mechanisms. It can also achieve comparable embryological and clinical outcomes while reducing the incidence of moderate and severe ovarian hyperstimulation syndrome (OHSS) and HMG dosage. It can be an alternative of the treatments for infertile patients with normal ovarian reserve undergoing IVF as well as traditional protocols. TRIAL REGISTRATION NUMBER: ChiCTR-INR-17012089. TRIAL REGISTRATION DATE: Chictr.org.cn: 23 July 2017. DATE OF FIRST PATIENT'S ENROLLMENT: 1 August 2017.

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.

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.

Evaluation of Ovarian Stimulation Initiated From the Late Follicular Phase Using Human Menopausal Gonadotropin Alone in Normal-Ovulatory Women for Treatment of Infertility: A Retrospective Cohort Study.

Objective: To investigate the feasibility of ovarian stimulation initiated in the late follicular phase using human menopausal gonadotropin (hMG) alone in ovulatory patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments by comparison with that of the short gonadotropin-releasing hormone agonist (GnRH-a) protocol in terms of ovarian response, embryological characteristics, and pregnancy outcomes following frozen-thawed embryo transfer (FET) cycles. Design: Retrospective cohort study. Setting: A university-affiliated tertiary hospital. Patients: 135 infertile women undergoing their first IVF/ICSI treatment with the freeze-all strategy. Interventions: In the study group, ovarian stimulation was initiated in the late follicular phase using hMG alone, with the confirmation of dominant follicular diameter ≥ 14 mm, while a short GnRH-a protocol was adopted in the control group. Oocyte maturation was induced by human chorionic gonadotropin in both groups. All good quality embryos were cryopreserved for later transfer. Main Outcome Measures: The primary outcome was the incidence of premature luteinizing hormone (LH) surge. Secondary outcomes were the number of mature oocytes retrieved, good-quality embryo rate per oocyte retrieved, and clinical pregnancy rate following FET cycles. Results: No premature LH surge was detected during ovarian stimulation in the study group. There was no statistically significant difference in the number of mature oocytes between the two groups (10 ± 5.6 in the study group vs. 8.51 ± 5.03 in the control group, P = 0.11). Good-quality embryo rate per oocyte retrieved did not differ between the two groups: 40.18% (313/779) vs. 36.67% (253/690), P = 0.167. Clinical pregnancy rate per transfer following FET was comparable between the two groups (61.33 vs. 52.5%, P = 0.267). Conclusions: Our study shows that ovarian stimulation initiated in the late follicular phase using hMG alone may be a feasible alternative for normal-ovulatory women undergoing IVF/ICSI treatment with the freeze-all strategy.

New trial of progestin-primed ovarian stimulation using dydrogesterone versus a typical GnRH antagonist regimen in assisted reproductive technology.

PURPOSE: To compare the clinical and ongoing pregnancy rates between a protocol using oral dydrogesterone with human menopausal gonadotropin (HMG) for progestin-primed ovarian stimulation (PPOS) and the typical gonadotropin-releasing hormone (GnRH) antagonist regimen in women undergoing controlled ovarian hyperstimulation (COH). METHODS: This was a prospective, controlled study of 251 women who underwent COH for in vitro fertilization between October 2016 and July 2017. The patients were allocated alternately into two groups: a dydrogesterone protocol (study group) and a GnRH antagonist protocol (control group). In study group, dydrogesterone (20 mg/day) plus HMG (150 or 225 IU) were administered simultaneously beginning on days 2 or 3 of the menstrual cycle. In both groups, all high-quality embryos were cryopreserved for later transfer. The primary outcome was the ongoing pregnancy rate at 12 weeks per frozen-thawed embryo transfer (FET) and the secondary outcome was the clinical pregnancy rate. RESULTS: None of the patients experienced a premature luteinizing hormone surge. During the follow-up period, 397 FET cycles were completed. The ongoing pregnancy rates at 12 weeks were 40.0% in study group versus 38.1% in control group (absolute difference 1.9%; 95% CI - 6.83 to 17.2%). The clinical pregnancy rate in study group (52.8%) was also not inferior to that in control group (49.5%; absolute difference 3.3%; 95% CI - 4.02 to 20.2%). CONCLUSIONS: The clinical and ongoing pregnancy rates in study group were comparable to those in control group. Therefore, PPOS with dydrogesterone is a reasonable option to provide COH.

New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles.

STUDY QUESTION: Can dydrogesterone (DYG) be used as an alternative progestin in a progesterone primed ovarian stimulation (PPOS) protocol? SUMMARY ANSWER: DYG can be used as an appropriate alternative progestin in a PPOS protocol. WHAT IS KNOWN ALREADY: PPOS is a new ovarian stimulation regimen based on a freeze-all strategy that uses progestin as an alternative to a GnRH analog for suppressing a premature LH surge during the follicular phase. Medroxyprogesterone acetate (MPA) has been successfully used as an adjuvant to gonadotrophin in the PPOS protocol. However, the use of MPA may lead to stronger pituitary suppression and thus may require a higher dosage of hMG and a longer duration of ovarian stimulation than that of conventional ovarian stimulation protocol. STUDY DESIGN SIZE, DURATION: A prospective RCT including 516 patients was performed between November 2015 and November 2016. Computerized randomization was conducted to assign participants at a 1:1 ratio into two treatment groups: an hMG + DYG group (260 patients) or an hMG + MPA group (256 patients) followed by IVF or ICSI with the freeze-all strategy. One cycle per patient was included. The primary outcome of the trial was the number of oocytes retrieved. The sample size was chosen to detect a difference of two oocytes with a power of 90%. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients under 36 years of age with normal ovarian reserve who were undergoing their first IVF/ICSI procedure due to tubal factor infertility were randomized into two groups based on the oral progestin protocol used: hMG co-treatment with DYG (hMG + DYG) or hMG co-treatment with MPA (hMG + MPA). The different progestin was simultaneously administered at the beginning of menstrual cycle 3 (MC3). Oocyte maturation was co-triggered by administration of a GnRH agonist and hCG. All viable embryos from both protocols were cryopreserved for later transfer. Only the first frozen embryo transfer (FET) cycle was included in our study. The embryological and clinical outcomes were measured. MAIN RESULTS AND THE ROLE OF CHANCE: Basic characteristics, such as age, BMI and infertility duration, in both groups were comparable. There was no significant difference in the number (mean ± SD) of oocytes retrieved [10.8 ± 6.3 for the hMG + DYG group versus 11.1 ± 5.8 for the hMG + MPA group, P = 0.33] or the oocyte retrieval rate [74.3 ± 19.6% for the hMG + DYG group versus 75.0 ± 19.5% for the hMG + MPA group, P = 0.69] between the groups. The viable embryo rate per oocyte retrieved did not differ between the two groups [odds ratio (OR): 1.08, 95% CI: 0.97-1.21, P = 0.16]: 37.4% (1052/2815) for the hMG + DYG group versus 35.6% (1009/2837) for the hMG + MPA group. During the whole process of ovarian stimulation, the mean LH level in the hMG + DYG group was always higher than that in the hMG + MPA group (P < 0.001); however, no patient from either group experienced a premature LH surge. In addition, no patients experienced moderate or severe ovarian hyperstimulation syndrome during the ovarian stimulation. No significant difference was found in the clinical pregnancy rate of the first FET cycle between the two groups (OR: 0.82, 95% CI: 0.56-1.21, P = 0.33): 57.6% for the hMG + DYG group (125/217) versus 62.3% for the hMG + MPA group (132/212). LIMITATIONS REASONS FOR CAUTION: The patients and physician were not blinded to the study. Further, a large proportion of patients were still pregnant at the end of the clinical trial, therefore live birth rates were not observed in the follow-up period. The dose-effectiveness of DYG administration was not addressed in the trial design. WIDER IMPLICATIONS OF THE FINDINGS: DYG, which exhibits no or only weak inhibition of ovulation in normal dosage, can serve as an hMG adjuvant during ovarian stimulation. This finding suggests the possibility of a new application of DYG: as an appropriate alternative progestin for a PPOS protocol in IVF. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by The National Nature Science Foundation of China (Grant no. 81503603), Shanghai Three-year Plan on Promoting TCM Development (Grant no. ZY3-LCPT-2-2006) and the Natural Science Foundation of Shanghai (Grant nos. 15401932700 and 15ZR1424900). None of the authors declare any conflict of interest. TRIAL REGISTRATION NUMBER: Chictr.org.cn: ChiCTR-IPR-15007251. TRIAL REGISTRATION DATE: Chictr.org.cn: 22 October 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 1 November 2015.

Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing in vitro fertilization/intracytoplasmic sperm injection: A prospective randomized controlled trial.

OBJECTIVE: To compare the endocrinological profiles, cycle characteristics and pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) with or without clomiphene citrate (CC) supplementation in normal ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: Prospective randomized controlled study. PATIENT(S): A total of 320 infertile women undergoing IVF/ICSI. Medroxyprogesterone acetate (MPA) and human menopausal gonadotropin (hMG) were simultaneously administered on menstrual cycle day 3. The women were randomized into 2 equal groups with or without CC supplementation. MEASURES: The primary outcome measure was the percentage of women with profound pituitary suppression (luteinizing hormone [LH] <1.0 IU/L on the trigger day). The secondary outcomes were endocrinological profiles, cycle characteristics and pregnancy outcomes. RESULTS: The percentage of women with profound pituitary suppression was significantly lower in the study group (hMG + MPA + CC) than in the control group (hMG + MPA) (1.9% vs 33.1%, P < .001). The mean LH level during controlled ovarian stimulation (COS) was higher in the study group than in the control group (P < .001), but none of the patients in either group exhibited a premature LH surge. The doses of Gn in the study group were significantly lower than those in the control group (1334.06 ± 212.53 IU vs 1488.28 ± 325.08 IU, P < .001). The number of oocytes retrieved was similar between the 2 groups (10.03 ± 5.97 vs 10.34 ± 7.52, P > .05). No significant differences were observed in either the number of viable embryos or the pregnancy outcomes between the 2 groups. CONCLUSION(S): Clomiphene citrate is an effective adjuvant to alleviate pituitary suppression in the PPOS protocol; however, it has no impact on clinical outcomes.

Duphaston and human menopausal gonadotropin protocol in normally ovulatory women undergoing controlled ovarian hyperstimulation during in vitro fertilization/intracytoplasmic sperm injection treatments in combination with embryo cryopreservation.

OBJECTIVE: To evaluate endocrine characteristics and clinical outcomes in normal ovulatory patients undergoing controlled ovarian hyperstimulation (COH) with the use of a Duphaston and hMG protocol during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments in combination with frozen-thawed embryo transfer (FET) compared with the characteristics and outcomes of patients undergoing an Utrogestan and hMG protocol. DESIGN: Prospective controlled study. SETTING: Tertiary care academic medical center. PATIENT(S): A total of 250 infertile patients undergoing IVF/ICSI treatments. INTERVENTION(S): Duphaston (20 mg/d) or Utrogestan (100 mg/d) was taken orally from cycle day 3 until the trigger day, with hMG (150-225 IU) administered when appropriate. When the dominant follicles reached maturity, 0.1 mg GnRH agonist was used as the trigger. Viable embryos were cryopreserved in both protocols for transfer at a later time. MAIN OUTCOME MEASURE(S): The primary outcome was the number of oocytes retrieved. Secondary outcomes included the incidence of premature LH surge, the number of viable embryos, and clinical pregnancy outcomes from FET cycles. RESULT(S): Consistent LH suppression was achieved during COH. None of the participants experienced a premature LH surge. The number of oocytes retrieved (8.22 ± 5.46 vs. 8.8 ± 5.62) was similar between the two groups. No between-group significant differences were observed in the number of mature oocytes (7.2 ± 4.72 vs. 6.98 ± 4.68), fertilized oocytes (6.16 ± 4.34 vs. 6.32 ± 4.23), and viable embryos (2.96 ± 2.22 vs. 3.4 ± 2.54). Furthermore, the clinical pregnancy rates (53.04% vs. 51.7%), early miscarriage rates (8.2% vs. 11.84%), implantation rates (38.68% vs. 35.71%), and cumulative pregnancy rates per woman (66.67% vs. 69.47%) were also similar. CONCLUSION(S): Duphaston administration during COH was similar to Utrogestan in the prevention of LH surge, embryonic characteristics, and pregnancy outcomes. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IOR-15007265.

Use of Utrogestan during controlled ovarian hyperstimulation in normally ovulating women undergoing in vitro fertilization or intracytoplasmic sperm injection treatments in combination with a "freeze all" strategy: a randomized controlled dose-finding study of 100 mg versus 200 mg.

OBJECTIVE: To compare the clinical characteristics in a Utrogestan and hMG protocol with the use of different doses of Utrogestan in normally ovulating women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments. DESIGN: Prospective controlled study. SETTING: Tertiary-care academic medical center. PATIENT(S): A total of 150 infertile patients undergoing IVF/ICSI treatments. INTERVENTION(S): Utrogestan and hMG were administered simultaneously beginning on cycle day 3. The dose of Utrogestan was 100 mg/d in the study group and 200 mg/d in the control group. When the dominant follicles reached mature, 0.1 mg GnRH agonist was used for trigger. Viable embryos were cryopreserved in both protocols for later transfer. MAIN OUTCOME MEASURE(S): The primary outcome measure was the incidence of premature LH surge. Secondary outcomes included the embryo results and clinical pregnancy outcomes. RESULT(S): Consistent LH suppression was achieved during controlled ovarian hyperstimulation with Utrogestan at 100 mg, and the number of patients with profound LH suppression (LH <1.2 IU/L) in the low-dose group was significantly less than that in the high-dose group. The number of oocytes retrieved in the low-dose group was similar to that in the high-dose group (9.87 ± 5.77 vs. 10.25 ± 5.43). No significant differences were observed in the number of mature oocytes, viable embryos, clinical pregnancy rate, or implantation rate. CONCLUSION(S): Utrogestan at 100 mg is as effective as Utrogestan at 200 mg in reducing premature LH surge during controlled ovarian hyperstimulation. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OOC-14005277.

Dose-finding study of Leuplin depot for prevention of premature luteinizing hormone surge during controlled ovarian stimulation: a pilot study in intrauterine insemination treatment.

OBJECTIVE: The standard dose of depot gonadotropin releasing hormone agonist (GnRHa) may be too much to prevent premature luteinizing hormone (LH) surge in controlled ovarian stimulation (COS). The purpose of this study was to find out the minimal effective dose of Leuplin depot to prevent premature LH surge in patients undergoing intrauterine insemination (IUI). MATERIALS AND METHODS: From January 2006 to December 2007, unexplained infertile patients who were going to undergo IUI were recruited into the study. They were assigned sequentially to one of the following treatment groups. The first 50 patients received the 1/3-dose of Leuplin depot in the midluteal phase of the cycle preceding COS. If no premature LH surge occurred in the 50 patients, the study was continued with 1/4-dose of Leuplin depot in the subsequent 50 patients. Similarly, if no premature LH surge occurred with 1/4 dose, the study was continued with 1/5-dose of Leuplin depot in the following 50 patients. Ovarian stimulation was started with human menopausal gonadotropin (hMG) at 112.5 IU/d after downregulation, then IUI was performed 36 hours after human chorionic gonadotropin (hCG) injection. RESULTS: Premature LH surge was effectively prevented with 1/3-dose and 1/4-dose of Leuplin depot. Premature LH surge occurred in three of the 50 patients (6%) in the 1/5-dose group. The patients in the 1/4-dose group received a significantly lower amount of hMG and fewer days of COS, compared with the 1/3-dose group. CONCLUSION: The 1/4 dose of Leuplin depot is the minimal effective dose to prevent premature LH surge. Further trial is worthwhile to compare the reducing dose Leuplin depot and daily low-dose leuprolide in in vitro fertilization (IVF) programs.