Persistently expressed human chorionic gonadotropin induces premature luteinization and progressive alterations on the reproductive axis in female mice.

The hypothalamic-pituitary-gonadal axis plays a fundamental role in the endocrine regulation of the reproductive function in mammals. Any change in the function of the participating hormones or their receptors can lead to alterations in sexual differentiation, the onset of puberty, infertility, cancer development, and other dysfunctions. In this study, we analyzed the influence of persistently elevated levels of the human chorionic gonadotropin hormone (hCG), a powerful agonist of pituitary luteinizing hormone (LH), on the reproductive axis of female mice. As a consequence of chronic hCG hypersecretion through a global expression of the hCGbeta-subunit in transgenic (TG) female mice, a series of events perturbed the prepubertal to juvenile transition. The imbalance in gonadotropin action was first manifested by precocious puberty and alterations in gonadal hormone production, with the consequent ovarian function disruption and infertility in adulthood. The expansion of cumulus cells in vivo and in vitro, ovulatory capacity, and gene expression of ovulation-related marker genes after hormone stimulation were normal in 3-week-old TG females. However, the expression of genes related to steroidogenesis and luteinization such as Lhcgr, Prlr, and the steroidogenic enzymes Cyp11a1, Cyp17a1, and Cyp19a1 were significantly elevated in the TG females. This study demonstrates that the excessive secretion of hCG in concert with high prolactin, induced premature luteinization, and enhanced ovarian steroidogenesis, as was shown by the up-regulation of luteal cell markers and progesterone synthesis in the TG mice. Furthermore, progressively impaired reproductive function of the TG females occurred from the peripubertal stage to adulthood, thus culminating in infertility.

Comparison of fixed and flexible progestin-primed ovarian stimulation protocols to prevent premature luteinization in patients with diminished ovarian reserve.

PURPOSE: Flexible progestin-primed ovarian stimulation (PPOS) protocol is demonstrated to be effective in suppressing premature luteinization in few studies. We aimed to compare fixed and flexible PPOS protocols in preventing premature luteinization in patients with diminished ovarian reserve. METHODS: This retrospective cohort study included patients with a diminished ovarian reserve who were administered PPOS protocols for pituitary suppression during ovarian stimulation in a tertiary center in between January 2019 and June 2022. At fixed protocol, 20 mg/day dydrogesterone was started in cycle day two or three along with gonadotropins and continued until trigger day. In contrast, at flexible protocol, 20 mg/day dydrogesterone was commenced when the leading follicle reached 12 mm or serum estradiol (E2) level was > 200 pg/mL. RESULTS: A total of 125 patients, of whom 83 were administered fixed PPOS protocol and 42 were administered flexible PPOS protocol, were included in the analysis. Both groups had similar baseline characteristics and cycle parameters, including total days of gonadotropin administration and total gonadotropin dose (p > 0.05). Premature luteinization occurred at 7.2% and 11.9% of patients in fixed and flexible PPOS protocols, respectively (p = 0.505). Retrieved oocytes numbers, metaphase II oocyte numbers, and 2PN numbers were also similar (p > 0.05). Clinical pregnancy rates per transfer were 52.5% in fixed and 36.4% in flexible protocols (p = 0.499). CONCLUSION: Both fixed and flexible PPOS protocols had statistically similar outcomes in preventing premature luteinization and other cycle parameters. The flexible PPOS protocol seems to be as effective as the fixed PPOS protocol for patients with diminished ovarian reserve; however, further prospective studies should be conducted to validate the results of our research.

Excessive follicle-stimulating hormone during ovarian stimulation of cattle may induce premature luteinization of most ovulatory-size follicles†.

High follicle-stimulating hormone (FSH) doses during ovarian stimulation are detrimental to ovulatory follicle function and decrease live birth rate in cattle and women. However, the mechanism whereby excessive FSH causes ovarian dysfunction is unknown. This study tested the hypothesis that excessive FSH during ovarian stimulation induces premature luteinization of ovulatory-size follicles. Small ovarian reserve heifers were injected twice daily for 4 days with 70 IU (N = 7 heifers) or 210 IU (N = 6 heifers) Folltropin-V [commercial FSH-enriched preparation of porcine pituitary glands with minor (<1%) luteinizing hormone (LH) contamination, cpFSH]. Ovulatory-size (≥10 mm) follicles were excised from ovaries after the last cpFSH injection and hormone concentrations in follicular fluid (FF) were determined using ELISA. Luteinization was monitored by assessing cumulus cell-oocyte complex (COC) morphology and measuring concentrations of estradiol (E), progesterone (P), and oxytocin (O) in FF. COCs were classified as having compact (cCOC) or expanded (eCOC) cumulus cell layers, and as estrogen-active (E:P in FF ≥1), estrogen-inactive (EI, E:P in FF ≤1 > 0.1), or extreme-estrogen-inactive (EEI, E:P in FF ≤0.1). A high proportion (72%) of ovulatory-size follicles in 210 IU, but not 70 IU, dose heifers displayed eCOCs. The high doses also produced higher proportions of EI or EEI follicles which had lower E:P ratio and/or E but higher P and/or O concentrations compared with the 70 IU dose heifers. In conclusion, excessive cpFSH doses during ovarian stimulation may induce premature luteinization of most ovulatory-size follicles in heifers with small ovarian reserves.

Fertility preservation immediately after therapeutic abortion results in multiple normal follicular growth with the absence of mature oocytes due to early luteinization: a case report and literature review.

Cancer therapy has priority over fertility preservation. The time available for fertility preservation in patients with cancer is often very limited and depends on the condition of the underlying disease. This case report presents the results of two rounds of controlled ovarian stimulations (COSs) performed after an induced abortion. The patient had mixed phenotype acute leukemia diagnosed during early pregnancy and underwent a surgical abortion, followed by ovarian stimulation using urinary follicle-stimulating hormone (uFSH) and gonadotropin-releasing hormone (GnRH) agonists. Oocyte retrieval was subsequently performed for oocyte cryopreservation. Despite good hormonal and ultrasonic follicular growth, no oocytes were obtained. During a second COS performed at a low human chorionic gonadotropin (hCG) level (less than 100 IU/L), several mature oocytes were obtained, suggesting that higher hCG levels during COS induce the absence of mature oocytes during normal follicular growth. It is recommended to start COS post-abortion after confirming a low hCG level while considering the timing of cancer treatment.

Late follicular phase progesterone elevation during ovarian stimulation is not associated with decreased implantation of chromosomally screened embryos in thaw cycles.

STUDY QUESTION: What is the impact of a late follicular phase progesterone elevation (LFPE) during controlled ovarian hyperstimulation (COH) on embryonic competence and reproductive potential in thaw cycles of preimplantation genetic testing for aneuploidy (PGT-A) screened embryos? SUMMARY ANSWER: Our study findings suggest that LFPE, utilizing a progesterone cutoff value of 2.0 ng/ml, is neither associated with impaired embryonic development, increased rate of embryonic aneuploidy, nor compromised implantation and pregnancy outcomes following a euploid frozen embryo transfer (FET) cycle. WHAT IS KNOWN ALREADY: Premature progesterone elevation during COH has been associated with lower pregnancy rates due to altered endometrial receptivity in fresh IVF cycles. Also, increased levels of progesterone (P) have been suggested to be a marker for ovarian dysfunction, with some evidence to show an association between LFPE and suboptimal embryonic development. However, the effect of LFPE on embryonic competence is still controversial. STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis in a single, academic ART center from September 2016 to March 2020. In total, 5244 COH cycles for IVF/PGT-A were analyzed, of those 5141 were included in the analysis. A total of 23 991 blastocysts underwent trophectoderm biopsy and PGT analysis. Additionally, the clinical IVF outcomes of 5806 single euploid FET cycles were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohorts were separated in two groups: Group 1: oocytes retrieved from cycles with normal P levels during ovulation trigger (P ≤ 2.0 ng/ml); Group 2: oocytes retrieved after cycles in which LFPE was noted (P > 2.0 ng/ml). Extended culture and PGT-A was performed. Secondly, IVF outcomes after a single euploid FET were evaluated for each cohort. MAIN RESULTS AND THE ROLE OF CHANCE: Four thousand nine hundred and twenty-five cycles in Group 1 were compared with 216 cycles on Group 2. Oocyte maturity rates, fertilization rates and blastulation rates were comparable among groups. A 65.3% (n = 22 654) rate of utilizable blastocysts was found in patients with normal P levels and were comparable to the 62.4% (n = 1337) observed in those with LFPE (P = 0.19). The euploidy rates were 52.8% (n = 11 964) and 53.4% (n = 714), respectively, albeit this difference was not statistically significant (P = 0.81). Our multivariate analysis was fitted with a generalized estimating equation (GEE) and no association was found with LFPE and an increased odds of embryo aneuploidy (adjusted odds ratio 1.04 95% CI 0.86-1.27, P = 0.62). A sub-analysis of subsequent 5806 euploid FET cycles (normal P: n = 5617 cycles and elevated P: n = 189 cycles) showed no differences among groups in patient's BMI, Anti-Müllerian hormone (AMH), endometrial thickness at FET and number of prior IVF cycles. However, a significant difference was found in patient's age and oocyte age. The number of good quality embryos transferred, implantation rate, clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate and clinical pregnancy loss rates were comparable among groups. Of the registered live births (normal P group: n = 2198; elevated P group: n = 52), there were no significant differences in gestational age weeks (39.0 ± 1.89 versus 39.24 ± 1.53, P = 0.25) and birth weight (3317 ± 571.9 versus 3 266 ± 455.8 g, P = 0.26) at delivery, respectively. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and probable variability in the study center's laboratory protocol(s), selected progesterone cutoff value and progesterone assay techniques compared to other ART centers may limit the external validity of our findings. WIDER IMPLICATIONS OF THE FINDINGS: Based on robust sequencing data from a large cohort of embryos, we conclude that premature P elevation during IVF stimulation does not predict embryonic competence. Our study results show that LFPE is neither associated with impaired embryonic development nor increased rates of aneuploidy. Embryos obtained from cycles with LFPE can be selected for transfer, and patients can be reassured that the odds of achieving a healthy pregnancy are similar to the embryos exposed during COH cycles to physiologically normal P levels. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the realization of this study. Dr A.B.C. is advisor and/or board member of Sema 4 (Stakeholder in data), Progyny and Celmatix. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NA.

Revisiting debates of premature luteinization and its effect on assisted reproductive technology outcome.

The impact of the prematurely elevated serum progesterone on the late follicular phase, commonly known as premature luteinization (PL), is a matter of continuing debate. Available evidence supports that serum progesterone ≥ 1.5 ng/ml on the day of ovulation triggering could reduce the pregnancy potential in fresh in vitro fertilization (IVF) cycles by jeopardizing endometrial receptivity. Causes of PL during ovarian stimulation are unclear. Recent studies point toward the daily follicle-stimulating hormone dosage, duration of controlled ovarian stimulation, number of oocytes retrieved, and peak estradiol level as factors affecting the incidence of PL. Emerging data show additional influence on embryo quality. The prevention of PL has been challenging. The key elements in preventing PL include individualization of ovarian stimulation according to patient's ovarian reserve, proper ovulation trigger timing, and use of medications such as corticosteroids and metformin. Embryo cryopreservation with deferred embryo transfer is the established strategy to overcome PL, yet it is an extra burden to the IVF laboratory and increased cost for patients. Herein, we review the up-to-date knowledge of this frequent IVF problem including causes, proposed diagnostic criteria, and its impact on endometrial receptivity, embryo quality, and pregnancy outcomes. The preventive measures and rescue strategies are also discussed.

GnRH antagonist does not prevent premature luteinization and ovulation in stimulated cycles with gonadotropins for IVF: two case reports.

The use of GnRH antagonists (GnRHant) is increasing in the ovarian stimulation protocol. Among several other benefits, GnRHant should prevent a premature luteinization and premature ovulation, the first described either as a 'reassuringly rare event' or 'frequent event', while the second as occurring more frequently in women with decreased ovarian reserve, advanced age and poor ovarian response. Two cases of associated premature luteinization and premature ovulation, during treatment with gonadotropins and GnRHant in IVF cycles, are here reported. In both cases, premature luteinization occurred and ovulation took place during ovarian stimulation protocols with exogenous gonadotropins and GnRHant, before reaching the criteria of hCG administration, regardless of the age of the patients and their ovarian reserve. Ovulation was documented by the disappearance of most of the developing follicles, by the transformation of endometrium from a triple line picture into a uniform hyper-echogenic image, by the presence of fluid in the pouch of Douglas, by the increase of progesterone plasma levels and the simultaneous reduction of estradiol plasma levels. This evidence can be important for a correct counseling with infertile patients in preparation for an IVF cycle.

The curious case of premature luteinization.

PURPOSE: Premature luteinization (PL) affects 12.3-46.7% of fresh in vitro fertilization cycles, and there is accumulating evidence confirming its negative effect on success rates. However, despite its clinical significance, PL is poorly understood and defined. This narrative review aims to provide a fresh look at the phenomenon of PL by summarizing the existing evidence and re-evaluating fundamental issues. METHODS: A thorough electronic search was conducted covering the period from 1978 until January 2018 in PubMed, Embase, and Medline databases, and references of relevant studies were cross-checked. Meeting proceedings of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine were also hand searched. RESULTS: In the curious case of PL, one should go back to the beginning and re-consider every step of the way. The pathogenesis, definition, measurement methods, clinical implications, and management strategies are discussed in detail, highlighting controversies and offering "food for thought" for future directions. CONCLUSIONS: Authors need to speak the same language when studying PL in order to facilitate comparisons. The terminology, progesterone cut-off, measurement methods and days of measurement should be standardized and globally accepted; otherwise, there can be no scientific dialog. Future research should focus on specific patient profiles that may require a tailored approach. Progesterone measurements throughout the follicular phase possibly depict the progesterone exposure better than an isolated measurement on the day of hCG. Adequately powered randomized controlled trials should confirm which the best prevention and management plan of PL is, before introducing any strategy into clinical practice.

Are extremely high progesterone levels still an issue in IVF?

BACKGROUND: Premature luteinization of one or more developing follicles complicates 1-2 % of controlled ovarian stimulation cycles for assisted reproduction. The management of this complication is controversial, with cycle cancellation likely representing the most commonly used strategy. The aim of this study was to evaluate the efficacy of the "freeze-all" policy-where the entire cohort of blastocysts is cryopreserved for subsequent frozen-thawed embryo transfer-in treating cases of premature luteinization. METHODS: Patients experiencing premature luteinization during controlled ovarian stimulation-identified by extremely high progesterone levels at induction (P levels ≥3.0 ng/ml and/or P/estradiol ratio ≥1, n = 42)-were included in a "freeze-all" program and compared to controls undergoing a "freeze-all" program with normal progesterone levels at induction (P < 1.5 ng/ml, n = 67). RESULTS: Blastulation rate was comparable between patients with premature luteinization and controls (48.1 ± 20.5 % in Cases vs. 52.3 ± 24.9 % in Controls, p = 0.36). Ongoing pregnancy rates after the first frozen-thawed embryo transfer (38.1 % in Cases and 41.0 % in Controls, p = 0.83) and cumulative ongoing pregnancy rates after three frozen-thawed embryo transfer cycles (40.5 % in Cases vs. 47.8 % in Controls, p = 0.55) were also similar. CONCLUSIONS: These results show that extremely marked progesterone elevation throughout controlled ovarian stimulation does not impair blastocyst development and implantation potential in the context of a "freeze-all" strategy. Based on this, adoption of the "freeze-all" strategy represents a valuable tool in treating premature luteinization. In contrast, cycle cancellation-likely the most frequently used method for management of this complication-currently represents a misconduct.

Atrazine enhances progesterone production through activation of multiple signaling pathways in FSH-stimulated rat granulosa cells: evidence for premature luteinization.

Premature luteinization is a possible cause of infertility in women. It is currently unknown whether environmental chemicals can induce changes associated with premature luteinization. Using rat granulosa cells (GC) in vitro, we demonstrated that exposure to atrazine (ATR), a widely used herbicide, causes GC phenotype that resembles that of human premature luteinization. At the end of the 48-h stimulation with FSH, ATR-exposed GC showed (1) higher levels of progesterone, (2) overexpression of luteal markers (Star and Cyp11a1), and (3) an increase in progesterone:estradiol ratio above 1. Mechanistic experiments were conducted to understand the signaling events engaged by ATR that lead to this phenotype. Western blot analysis revealed prolonged phosphorylation of protein kinase B (AKT) and cAMP response element-binding protein (CREB) in ATR- and FSH-exposed GC. An increased level of ERK1/2-dependent transcriptional factor CCATT/enhancer-binding protein beta (CEBPB) was observed after 4 h of ATR exposure. Inhibitors of PI3K (wortmannin) and MEK (U0126) prevented ATR-induced rise in progesterone level and expression of luteal markers in FSH-stimulated GC. Atrazine intensified AKT and CEBPB signaling and caused Star overexpression in forskolin-stimulated GC but not in epidermal growth factor (EGF)-stimulated GC. In the presence of rolipram, a specific inhibitor of phosphodiesterase 4 (PDE4), ATR was not able to further elevate AKT phosphorylation, CEBPB protein level, and Star mRNA in FSH-stimulated GC, suggesting that ATR inhibits PDE4. Overall, this study showed that ATR acts as a FSH sensitizer leading to enhanced cAMP, AKT, and CEBPB signaling and progesterone biosynthesis, which promotes premature luteinization phenotype in GC.

Premature luteinization and pregnancy outcomes in depot goserelin-downregulated assisted reproductive technology cycles: A cross-sectional study from Ethiopia.

OBJECTIVE: To compare the rate of premature luteinization in depot goserelin-downregulated in vitro fertilization (IVF) cycles with other IVF protocols at a teaching hospital in Ethiopia. METHODS: We conducted a cross-sectional study on the effects of premature luteinization on IVF outcomes at St. Paul's Hospital Millennium Medical College, a tertiary teaching hospital in Ethiopia. Patients who had IVF at this hospital between 2019 and 2020 were included in the study. Patient records were reviewed and collected on Open Data Kit. We used Stata release 15 to analyze the data. A simple descriptive analysis and bivariate analysis  were performed as appropriate. A P-value less than 0.05 was considered as statistically significant. RESULTS: A total of 305 patients (40 cases with premature luteinization and 265 without premature luteinization) were included. There was no difference in the rate of premature luteinization in the depot goserelin long protocol cycles (6.4%), compared to minimal stimulation (14.1%) and antagonist protocols (16.7%), P = 0.19. Embryo transfer was carried out in 27 (67.5%) patients in the premature luteinization group, which was lower than the 86.0% (228/265) in the non-premature luteinization group, P = 0.003. There was no difference in the median number of oocytes retrieved (8.5 [interquartile range 5.0, 13.0] per cycle in the premature luteinization group vs 5.0 [interquartile range 3.0, 10.0] in those without premature luteinization, P = 0.10). CONCLUSION: A depot goserelin-downregulated long protocol for IVF is a cost-effective and convenient option for controlled ovarian hyperstimulation without increased risk of having premature luteinization compared to antagonist and minimal stimulation protocols.

Double daily doses of cetrorelix may raise follicular phase progesterone more compared to single doses in poor ovarian response patients.

PURPOSE: There is evidence that follicular phase progesterone rise [FPPR] adversely affects fresh in vitro fertilization [IVF] cycles. A single daily dose of cetrorelix has been used to prevent early luteinizing Hormone (LH) surge. We speculated that doubling the daily dose might have a positive effect in patients who have early LH surges despite receiving the single daily dose treatment. However, a double daily dose of cetrorelix seems to cause FPPR in poor ovarian response (POR) patients. MATERIALS AND METHODS: On human chorionic gonadotropin [hCG] injection days, the progesterone levels of POR patients who received a single daily dose of cetrorelix (group 1, n = 59) were compared with progesterone levels of the patients who received a double daily dose of cetrorelix (group 2, n = 75). The two groups had statistically similar demographic data. The patients who had FPPR were detected, and a comparison of progesterone levels, using 0.8, 1.0, and 1.2 [ng/mL] of progesterone as cut-off levels, was made between patients of both groups. RESULTS: FPPR patients in group 2 had significantly higher progesterone levels during hCG day, contrary to expectations. When progesterone cut-off levels of 0.8, 1.0, and 1.2 [ng/mL] were used for group 1 patients, 15.3%, 13.6%, and 6.8% of the patients developed FPPR, respectively When the progesterone cut-off levels of 0.8, 1.0, and 1.2 [ng/mL] were used for group 2, the results detected were 45.3%, 30.7%, and 21.3%, respectively. A significant statistical difference in progesterone levels was observed between the groups. CONCLUSION: While the double daily dose of cetrorelix was initially thought to more effectively suppress early LH rise by some authors, we have seen that it increases the FPPR more when compared to a single daily dose regime. We suggest using frozen cycles instead of fresh cycles in order to have better endometrial receptivity in patients who seem to benefit from higher daily doses of cetrorelix.

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.

Diminished Ovarian Reserve Predisposes to Premature Luteinizing Hormone Surges in Gonadotropin-Releasing Hormone Antagonist Cycles in In vitro Fertilization.

CONTEXT/BACKGROUND: A premature luteinizing hormone (LH) surge, in in vitro fertilization (IVF) cycles with gonadotropin-releasing hormone (GnRH)-antagonist downregulation, leads to cycle cancellation. Currently, risk factors for the development of premature LH surge remain unknown. OBJECTIVE: The aim of the study was to determine the incidence and identify the contributing factors for premature LH surge in IVF cycles with GnRH antagonist suppression. DESIGN: This was a retrospective cohort study. SETTING: IVF-embryo transfer program at a fertility and research center. MATERIALS AND METHODS: The study included all patients undergoing IVF from December 1, 2014, to November 30, 2018, in whom GnRH-antagonist (cetrorelix 0.25 mg/d) flexible protocol was used. The primary outcome measure was the identification of premature LH surges (documented by a 2.5-fold increase in LH from the baseline above a threshold of 17 mIU/mL) with or without a decrease in E2 and appearance of free fluid on ultrasound. RESULTS: Premature LH surges occurred in 15 (2.16%) of 692 patients undergoing IVF with GnRH-antagonist suppression. Patients with premature surges had significantly lower ovarian reserve as compared to the controls (as seen from their higher age group, higher day 2 follicle-stimulating hormone (FSH), lower antral follicle counts, and lower anti-Müllerian hormone). CONCLUSIONS: Premature LH surge in a GnRH-antagonist cycle can lead to cycle cancellation and disappointment. Although this is a rare event, the incidence is higher in patients with diminished ovarian reserve. Further studies are needed to determine if giving the human chorionic gonadotropin trigger a day earlier or giving higher doses of GnRH-antagonist can benefit such cases.

Effect of oral Utrogestan in comparison with Cetrotide on preventing luteinizing hormone surge in IVF cycles: A randomized controlled trial.

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.

Correlation between Serum Progesterone Level on the Day of Ovulation Trigger During In vitro Fertilization and Its Effect on Treatment Outcome.

BACKGROUND: Premature luteinization (PL) is defined as a premature rise in serum progesterone concentration on or before the day of ovulation trigger with human chorionic gonadotropin. The incidence of PL varies between 5% and 30% during in vitro fertilization and embryo transfer (IVF-ET). MATERIALS AND METHODS: The prospective observational study comprising 380 patients undergoing IVF-ET. Blood samples were collected for serum progesterone level estimation on the day of ovulation trigger. Ovum pickup was done 36 h later and serum progesterone levels were correlated with IVF-ET outcome. STUDY OUTCOME: To correlate serum progesterone level on the day of ovulation trigger during IVF and its effect on treatment outcome. RESULTS: Mean serum progesterone level in the positive pregnancy group and negative pregnancy group was 0.892 ± 0.752 ng/ml and 0.91 ± 0.688 ng/ml, respectively (P = 0.961). The overall incidence of PL was 12.8% with 12.7% and 13.6% in the agonist and antagonist protocol respectively (P = 0.9001). PL incidence was 13.5% and 13.4% in positive pregnancy and negative pregnancy group (P = 0.223). CONCLUSION: PL has been associated with 12.8% of the IVF cycles. There was no statistically significant difference observed in the incidence of PL between different IVF stimulation protocols. PL does not seem to affect IVF outcome.

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

OBJECTIVE: To evaluate the effect of the GnRH antagonist on gonadotropin ovulation induction in women with PCOS. MATERIALS AND METHODS: A 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. RESULTS: As 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). CONCLUSIONS: Adding 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.

Comparison of Two Regimens of Gonadotropin-releasing Hormone Antagonists in Clomiphene-gonadotropin Induced Controlled Ovulation and Intrauterine Insemination Cycles: Randomized Controlled Study.

CONTEXT: Gonadotropin-releasing hormone (GnRH) antagonists in fixed or flexible regimens are used for prevention of premature luteinizing hormone (LH) surge, however, data comparing these regimens in stimulated intrauterine insemination (IUI) cycles are lacking. AIMS: The aim of this study is to evaluate the effectiveness of GnRH antagonists in fixed and flexible regimens on the rate of premature luteinization (PL) and ovulation rate in sequential clomiphene-gonadotropin controlled ovulation-IUI cycles. SETTINGS AND DESIGN: This study was conducted at tertiary care center; this was randomized controlled study. MATERIALS AND METHODS: A total of 45 infertile women randomized into three groups of 15 each received clomiphene citrate + human menopausal gonadotrophin. GnRH antagonist was added according to fixed (n = 15) and flexible (n = 15) protocol. No antagonist in control group (n = 15). PL was defined as LH level ≥10 mIU/ml and progesterone level ≥1.0 ng/ml. STATISTICAL ANALYSIS: Mean values compared using the Student's t-test or one-way analysis of variance. Categorical variables distribution tested using either Pearson's Chi-square or Fisher's exact test as appropriate. RESULTS: Of a total of 45 women, 58% (n = 26) presented with primary and 42% (n = 19) secondary infertility with mean age of 30.8 ± 3.43 years and BMI 26.57 ± 3.22 kg/m2. Fixed regimen (3.7%) showed most reduction in PL compared to flexible (15.38%, P = 0.33) or control (36.67%, P = 0.004). On human chorionic gonadotropin day, mean LH (P = 0.002) and progesterone (P = 0.079) levels in fixed, flexible, and control groups were as follows: 5.04 ± 5.47 mIU/ml, 3.95 ± 4.16 mIU/ml, 9.57 ± 7.91 mIU/ml, and 0.409 ± 0.320 ng/ml, 0.579 ± 0.727 ng/ml, and 1.033 ± 1.022 ng/ml, respectively. Ovulation (P = 0.813) and pregnancy rates (P = 0.99) were 88.9%, 84.6%, and 90% and 22.2%, 19.23%, and 10% in fixed, flexible, and control groups, respectively. CONCLUSIONS: Addition of antagonist in any regimen appears to lower PL rates and improve pregnancy rates in controlled ovarian stimulation and IUI cycles.

With low ovarian reserve, Highly Individualized Egg Retrieval (HIER) improves IVF results by avoiding premature luteinization.

BACKGROUND: Highly Individualized Egg Retrieval (HIER), defined as age-specific early oocyte retrieval (ER), has been demonstrated to avoid premature luteinization in women ≥43. We here investigated whether HIER also applies to younger women with premature ovarian aging (POA), and what best lead follicle size should be for administration of ovulation-triggers. METHODS: Fifty-six women ≥43, and 37 POA patients underwent IVF cycles. Granulosa cells (GCs) were isolated, cultures were established, RNA was extracted and real-time PCR analyses performed, with gene expressions at mRNA level investigated for FSH receptor (FSHR), luteinizing hormone receptor (LHCPR), P450 aromatase (CYP19a1) and progesterone receptor (PGR). POA was defined by age < 40, FSH above 95%CI and/or AMH below 95%CI for age. Women ≥43 years were divided into very early retrieval (VER), with human chorionic gonadotropin (hCG) trigger at 13.5-15.5 mm, ER at 16.0-18.0 mm or standard retrievel (SR) at 18.5-20.5 mm; POA patients were divided into ER and SR. Pregnancy rates and and molecular markers of premature luteinization (PL) were main outcome measures. RESULTS: ER resulted in a significantly higher clinical pregnancy rate (16.7%) than VER (5.9%) or SR (6.7%; both P < 0.05). Molecular markers of PL were highest with SR and lowest with VER. In POA, ER improved pregnancy chances even more than in women ≥43 (7.7% with SR vs. 41.7% with ER), while also reducing molecular markers of PL. With low ovarian reserve (LOR), by avoiding PL, ER with hCG trigger at 16.0-18.0 mm, thus, improves clinical pregnancy rates at all ages. As VER demonstrated lowest molecular PL marker but equally poor pregnancy rates as SR, too early ovulation triggers, likely, result in cytoplasmatic immaturity. CONCLUSIONS: HIER is even more effective in POA patients than women above age 43, demonstrating that HIER should be further investigated going into even more advanced ages.

Are good patient and embryo characteristics protective against the negative effect of elevated progesterone level on the day of oocyte maturation?

OBJECTIVE: To evaluate if an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration is associated with a decrease in live-birth rate in patients with a good prognosis. DESIGN: Retrospective cohort study. SETTING: Large, private, assisted reproductive technology (ART) practice. PATIENT(S): One thousand six hundred twenty fresh autologous ART cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rate. RESULT(S): A total of 934 blastocyst and 686 cleavage-stage embryo transfer (ET) cycles were evaluated. Serum P levels were not associated with markers of oocyte or embryo quality, including fertilization, embryo stage at transfer, and embryos available for cryopreservation. Patient age, stage of ET, embryo quality, the number of embryos transferred, and P level on the day of hCG administration were all significantly associated with live birth. Higher P levels were associated with decreased odds of live birth for cleavage- and blastocyst-stage embryos, poor-fair and good-quality embryos, and poor- and high-responder patients. The nonsignificance of interaction tests of P levels with embryo stage, embryo quality, patient age, and ovarian response indicated that the relationship between P level and live birth was similar regardless of these factors. CONCLUSION(S): An elevated serum P level on the day of hCG administration was negatively associated with live birth, even in ETs with a good prognosis.