How phytochemicals influence reproductive outcomes in women receiving assisted reproductive techniques: a systematic review.

CONTEXT: Over the past few years, there has been an increasing amount of scholarly literature suggesting a connection between the nutritional status of pregnant mothers and early fetal development, as well as the long-term health consequences of their offspring. Multiple studies have documented that alterations in dietary patterns prior to conception have the potential to affect the initial stages of embryonic development. OBJECTIVES: The aim of this study was to perform a comprehensive review of the research pertaining to the correlation between phytochemicals ( specifically, polyphenols, carotenoids and phytoestrogens) and assisted reproductive technology (ART). DATA SOURCES: PubMed, Scopus, Web of Science, and Clinical Trials databases were searched from January 1978 to March 2023. STUDY SELECTION: This study comprised observational, randomized controlled, and cohort studies that examined the effects of phytochemicals on ART results. The study's outcomes encompass live birth rate, clinical pregnancy, and ongoing pregnancy. DATA EXTRACTION: The assessment of study quality was conducted by 2 researchers, independently, using the Quality Criteria Checklist for Primary Research. RESULTS: A total of 13 studies were included, of which there were 5 randomized controlled studies, 1 nonrandomized controlled study, 6 prospective cohort studies, and 1 retrospective cohort study. CONCLUSION: This research focused on investigating the impact of phytochemicals on ART and has highlighted a dearth of articles addressing that topic. Collaboration among patients, physicians, and nutritionists is crucial for doing novel research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023426332.

Is endometriosis due to evolutionary maladaptation?

Similar to diabetes and unlike many pathogen-induced diseases, endometriosis is likely a result of maladaptation to the evolutionary heritage of humans. The objective of this article is to review the literature and improve understanding of the evolutionary factors behind endometriosis, leading to more effective prevention and treatment approaches. In primates, spontaneous decidualization of the endometrium evolved to ensure optimal implantation of a limited number of early embryos, unlike many non-primates which depend on early embryos to induce decidualization and subsequent pregnancy. Spontaneous decidualization results in menstrual bleeding when embryo implantation does not occur, and endometriosis is commonly believed to be caused by retrograde menstruation. Although direct evidence is lacking, it is likely that hunter-gatherer women experienced fewer menstrual periods due to pregnancy shortly after menarche, followed by repeated pregnancies and lactation. However, the mismatch between the evolved uterine physiology and rapid societal changes has led to modern women delaying pregnancy and experiencing numerous menstrual periods, potentially increasing the incidence of endometriosis. The symptoms of endometriosis are often managed by suppressing menstruation through systemic hormonal treatments, but these may have side effects. For patients with a family history of endometriosis or in the early stages of the disease, intrauterine devices releasing progesterone locally could prevent uterine bleeding and the development of endometriosis while preserving fertility and minimizing side effects.

The true natural cycle frozen embryo transfer - impact of patient and follicular phase characteristics on serum progesterone levels one day prior to warmed blastocyst transfer.

BACKGROUND: In a true-natural cycle (t-NC), optimal progesterone (P4) output from the corpus luteum is crucial for establishing and maintaining an intrauterine pregnancy. In a previous retrospective study, low P4 levels (< 10 ng/mL) measured one day before warmed blastocyst transfer in t-NC were associated with significantly lower live-birth rates. In the current study, we aim to examine the relationship between patient, follicular-phase endocrine and ultrasonographic characteristics, and serum P4 levels one day prior to warmed blastocyst transfer in t-NC. METHOD: 178 consecutive women undergoing their first t-NC frozen embryo transfer (FET) between July 2017-August 2022 were included. Following serial ultrasonographic and endocrine monitoring, ovulation was documented by follicular collapse. Luteinized unruptured follicle (LUF) was diagnosed when there was no follicular collapse despite luteinizing-hormone surge (> 17 IU/L) and increased serum P4 (> 1.5 ng/mL). FET was scheduled on follicular collapse + 5 or LH surge + 6 in LUF cycles. Primary outcome was serum P4 on FET - 1. RESULTS: Among the 178 patients, 86% (n = 153) experienced follicular collapse, while 14% (n = 25) had LUF. On FET-1, the median serum luteal P4 level was 12.9 ng/mL (IQR: 9.3-17.2), ranging from 1.8 to 34.4 ng/mL. Linear stepwise regression revealed a negative correlation between body mass index (BMI) and LUF, and a positive correlation between follicular phase peak-E2 and peak-P4 levels with P4 levels on FET-1. The ROC curve analyses to predict < 9.3 ng/mL (< 25th percentile) P4 levels on FET-1 day showed AUC of 0.70 (95%CI 0.61-0.79) for BMI (cut-off: 23.85 kg/m2), 0.71 (95%CI 0.61-0.80) for follicular phase peak-P4 levels (cut-off: 0.87 ng/mL), and 0.68 (95%CI 0.59-0.77) for follicular phase peak-E2 levels (cut-off: 290.5 pg/mL). Combining all four independent parameters yielded an AUC of 0.80 (95%CI 0.72-0.88). The adjusted-odds ratio for having < 9.3 ng/mL P4 levels on FET-1 day for patients with LUF compared to those with follicle collapse was 4.97 (95%CI 1.66-14.94). CONCLUSION: The BMI, LUF, peak-E2, and peak-P4 levels are independent predictors of low serum P4 levels on FET-1 (< 25th percentile; <9.3 ng/ml) in t-NC FET cycles. Recognition of risk factors for low serum P4 on FET-1 may permit a personalized approach for LPS in t-NC FET to maximize reproductive outcomes.

Comparison of the efficacy of subcutaneous versus vaginal progesterone using a rescue protocol in vitrified blastocyst transfer cycles.

RESEARCH QUESTION: Does administration of subcutaneous (s.c.) progesterone support ongoing pregnancy rates (OPR) similar to vaginal progesterone using a rescue protocol in hormone replacement therapy frozen embryo transfer cycles? DESIGN: Retrospective cohort study. Two sequential cohorts - vaginal progesterone gel (December 2019-October 2021; n=474) and s.c. progesterone (November 2021-November 2022; n=249) -were compared. Following oestrogen priming, s.c. progesterone 25 mg twice daily (b.d.) or vaginal progesterone gel 90 mg b.d. was administered. Serum progesterone was measured 1 day prior to warmed blastocyst transfer (i.e. day 5 of progesterone administration). In patients with serum progesterone concentrations <8.75 ng/ml, additional s.c. progesterone (rescue protocol; 25 mg) was provided. RESULTS: In the vaginal progesterone gel group, 15.8% of patients had serum progesterone <8.75 ng/ml and received the rescue protocol, whereas no patients in the s.c. progesterone group received the rescue protocol. OPR, along with positive pregnancy and clinical pregnancy rates, were comparable between the s.c. progesterone group without the rescue protocol and the vaginal progesterone gel group with the rescue protocol. After the rescue protocol, the route of progesterone administration was not a significant predictor of ongoing pregnancy. The impact of different serum progesterone concentrations on reproductive outcomes was evaluated by percentile (<10th, 10-49th, 50-90th and >90th percentiles), taking the >90th percentile as the reference subgroup. In both the vaginal progesterone gel group and the s.c. progesterone group, all serum progesterone percentile subgroups had similar OPR. CONCLUSIONS: Subcutaneous progesterone 25 mg b.d. secures serum progesterone >8.75 ng/ml, whereas additional exogenous progesterone (rescue protocol) was needed in 15.8% of patients who received vaginal progesterone. The s.c. and vaginal progesterone routes, with the rescue protocol if needed, yield comparable OPR.

The effect of ≤6 cm sized noncavity-distorting intramural fibroids on in vitro fertilization outcomes: a systematic review and meta-analysis.

IMPORTANCE: The potential detrimental effects of fibroids on natural fecundity and in vitro fertilization (IVF) outcomes may be influenced by their size, location, and number. The impact of small noncavity-distorting intramural fibroids on reproductive outcomes in IVF is still controversial, with conflicting results. OBJECTIVE(S): To determine whether women with noncavity-distorting intramural fibroids of ≤6 cm size have lower live birth rates (LBRs) in IVF than female age-matched controls with no fibroids. DATA SOURCES: MEDLINE, Embase, Global Health, and Cochrane Library databases were searched from inception until July 1, 2022. STUDY SELECTION AND SYNTHESIS: Women undergoing IVF with noncavity-distorting intramural fibroids ≤6 cm constituted the study group (n = 520), whereas women with no fibroid formed the controls (n = 1392). Female age-matched subgroup analyses were performed to evaluate the impact of different cut-offs for size (≤6, ≤4, and ≤2 cm), location (the International Federation of Gynecology and Obstetrics [FIGO] type-3), and the number of fibroids on reproductive outcomes. Mantel-Haenszel odds ratios (ORs) with 95% confidence intervals (CIs) were used for outcome measures. All statistical analyses were performed using RevMan 5.4.1 MAIN OUTCOME MEASURE(S): The primary outcome measure was LBR. Secondary outcome measures were clinical pregnancy, implantation, and miscarriage rates. RESULT(S): After adopting the eligibility criteria, 5 studies were included in the final analysis. Women with ≤6 cm noncavity-distorting intramural fibroids had significantly lower LBRs (OR: 0.48, 95% CI: 0.36-0.65, 3 studies, I2=0; low-certainty evidence) compared with women with no fibroids. A significant reduction in LBRs was noted in ≤4 cm but not in the ≤2 cm subgroups. The FIGO type-3 fibroids of 2-6 cm size were associated with significantly lower LBRs. Owing to a lack of studies, the impact of the number of noncavity-distorting intramural fibroids (single vs. multiple) on IVF outcomes could not be assessed. CONCLUSION(S): We conclude that 2-6 cm sized noncavity-distorting intramural fibroids have a deleterious effect on LBRs in IVF. The presence of FIGO type-3 fibroids of 2-6 cm size is associated with significantly lower LBRs. Conclusive evidence from high-quality randomized controlled trials, the reference standard study design for studies of health care interventions, is needed before myomectomy might be offered in daily clinical practice to women with such small fibroids before undergoing IVF treatment.

A drop in serum progesterone from oocyte pick-up +3 days to +5 days in fresh blastocyst transfer, using hCG-trigger and standard luteal support, is associated with lower ongoing pregnancy rates.

STUDY QUESTION: Do early- and mid-luteal serum progesterone (P4) levels impact ongoing pregnancy rates (OPRs) in fresh blastocyst transfer cycles using standard luteal phase support (LPS)? SUMMARY ANSWER: A drop in serum P4 level from oocyte pick-up (OPU) + 3 days to OPU + 5 days (negative ΔP4) is associated with a ∼2-fold decrease in OPRs. WHAT IS KNOWN ALREADY: In fresh embryo transfer cycles, significant inter-individual variation occurs in serum P4 levels during the luteal phase, possibly due to differences in endogenous P4 production after hCG trigger and/or differences in bioavailability of exogenously administered progesterone (P) via different routes. Although exogenous P may alleviate this drop in serum P4 in fresh transfer cycles, there is a paucity of data exploring the possible impact on reproductive outcomes of a reduction in serum P4 levels. STUDY DESIGN, SIZE, DURATION: Using a prospective cohort study design, following the initial enrollment of 558 consecutive patients, 340 fulfilled the inclusion and exclusion criteria and were included in the final analysis. The inclusion criteria were: (i) female age ≤40 years, (ii) BMI ≤35 kg/m2, (iii) retrieval of ≥3 oocytes irrespective of ovarian reserve, (iv) the use of a GnRH-agonist or GnRH-antagonist protocol with recombinant hCG triggering (6500 IU), (v) standard LPS and (vi) fresh blastocyst transfer. The exclusion criteria were: (i) triggering with GnRH-agonist or GnRH-agonist plus recombinant hCG (dual trigger), (ii) circulating P4 >1.5 ng/ml on the day of trigger and (iii) cleavage stage embryo transfer. Each patient was included only once. The primary outcome was ongoing pregnancy (OP), as defined by pregnancy ≥12 weeks of gestational age. PARTICIPANTS/MATERIALS, SETTING, METHODS: A GnRH-agonist (n = 53) or GnRH-antagonist (n = 287) protocol was used for ovarian stimulation. Vaginal progesterone gel (Crinone, 90 mg, 8%, Merck) once daily was used for LPS. Serum P4 levels were measured in all patients on five occasions: on the day of ovulation trigger, the day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days; timing of blood sampling was standardized to be 3-5 h after the morning administration of vaginal progesterone gel. The delta P4 (ΔP4) level was calculated by subtracting the P4 level on the OPU + 3 days from the P4 level on the OPU + 5 days, resulting in either a positive or negative ΔP4. MAIN RESULTS AND THE ROLE OF CHANCE: The median P4 (min-max) on the day of triggering, day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days were 0.83 ng/ml (0.18-1.42), 5.81 ng/ml (0.80-22.72), 80.00 ng/ml (22.91-161.05), 85.91 ng/ml (15.66-171.78) and 13.46 ng/ml (0.18-185.00), respectively. Serum P4 levels uniformly increased from the day of OPU to OPU + 3 days in all patients; however, from OPU + 3 days to OPU + 5 days, some patients had a decrease (negative ΔP4; n = 116; 34.1%), whereas others had an increase (positive ΔP4; n = 220; 64.7%), in circulating P4 levels. Although the median (min-max) P4 levels on the day of triggering, the day of OPU, and OPU + 3 days were comparable between the negative ΔP4 and positive ΔP4 groups, patients in the former group had significantly lower P4 levels on OPU + 5 days [69.67 ng/ml (15.66-150.02) versus 100.51 ng/ml (26.41-171.78); P < 0.001] and OPU + 14 days [8.28 ng/ml (0.28-157.00) versus 19.01 ng/ml (0.18-185.00), respectively; P < 0.001]. A drop in P4 level from OPU + 3 days to OPU + 5 days (negative ΔP4) was seen in approximately one-third of patients and was associated with a significantly lower OPR when compared with positive ΔP4 counterparts [33.6% versus 49.1%, odds ratio (OR); 0.53, 95% CI; 0.33-0.84; P = 0.008]; this decrease in OPR was due to lower initial pregnancy rates rather than increased overall pregnancy loss rates. For negative ΔP4 patients, the magnitude of ΔP4 was a significant predictor of OP (adjusted AUC = 0.65; 95% CI; 0.59-0.71), with an optimum threshold of -8.73 ng/ml, sensitivity and specificity were 48.7% and 79.2%, respectively. BMI (OR; 1.128, 95% CI; 1.064-1.197) was the only significant predictor of having a negative ΔP4; the higher the BMI, the higher the risk of having a negative ΔP4. Among positive ΔP4 patients, the magnitude of ΔP4 was a weak predictor of OP (AUC = 0.56, 95% CI; 0.48-0.64). Logistic regression analysis showed that blastocyst morphology (OR; 5.686, 95% CI; 1.433-22.565; P = 0.013) and ΔP4 (OR; 1.013, 95% CI; 0.1001-1.024; P = 0.031), but not the serum P4 level on OPU + 5 days, were the independent predictors of OP. LIMITATIONS, REASONS FOR CAUTION: The physiological circadian pulsatile secretion of P4 during the mid-luteal phase is a limitation; however, blood sampling was standardized to reduce the impact of timing. WIDER IMPLICATIONS OF THE FINDINGS: Two measurements (OPU + 3 days and OPU + 5 days) of serum P4 may identify those patients with a drop in P4 (approximately one-third of patients) associated with ∼2-fold lower OPRs. Rescuing these IVF cycles with additional P supplementation or adopting a blastocyst freeze-all policy should be tested in future randomized controlled trials. STUDY FUNDING/COMPETING INTEREST(S): None. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. P.H. has received unrestricted research grants from MSD and Merck, as well as honoraria for lectures from MSD, Merck, Gedeon-Richter, Theramex, and IBSA. H.Y. declares receipt of honorarium for lectures from Merck, IBSA and research grants from Merck and Ferring. The remaining authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: The study was registered at clinical trials.gov (NCT04128436).

Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review.

Despite the worldwide increase in frozen embryo transfer, the search for the best protocol to prime endometrium continues. Well-designed trials comparing various frozen embryo transfer protocols in terms of live birth rates, maternal, obstetric and neonatal outcome are urgently required. Currently, low-quality evidence indicates that, natural cycle, either true natural cycle or modified natural cycle, is superior to hormone replacement treatment protocol. Regarding warmed blastocyst transfer and frozen embryo transfer timing, the evidence suggests the 6th day of progesterone start, LH surge+6 day and hCG+7 day in hormone replacement treatment, true natural cycle and modified natural cycle protocols, respectively. Time corrections, due to inter-personal differences in the window of implantation or day of vitrification (day 5 or 6), should be explored further. Recently available evidence clearly indicates that, in hormone replacement treatment and natural cycles, there might be marked inter-personal variation in serum progesterone levels with an impact on reproductive outcomes, despite the use of the same dose and route of progesterone administration. The place of progesterone rescue protocols in patients with low serum progesterone levels one day prior to warmed blastocyst transfer in hormone replacement treatment and natural cycles is likely to be intensively explored in near future.

Double or dual stimulation in poor ovarian responders: where do we stand?

Recent advances in our recognition of two to three follicular waves of development in a single menstrual cycle has challenged the dogmatic approach of ovarian stimulation for in vitro fertilization starting in the early follicular phase. First shown in veterinary medicine and thereafter in women, luteal phase stimulation-derived oocytes are at least as competent as those retrieved following follicular phase stimulation. Poor ovarian responders still remain a challenge for many decades simply because they do not respond to ovarian stimulation. Performing follicular phase stimulation and luteal phase stimulation in the same menstrual cycle, named as double stimulation/dual stimulation, clearly increases the number of oocytes, which is a robust surrogate marker of live birth rate in in vitro fertilization across all female ages. Of interest, apart from one study, the bulk of evidence reports significantly higher number of oocytes following luteal phase stimulation when compared with follicular phase stimulation; hence, performing double stimulation/dual stimulation doubles the number of oocytes leading to a marked decrease in patient drop-out rate which is one of the major factors limiting cumulative live birth rates in such poor prognosis patients. The limited data with double stimulation/dual stimulation-derived embryos is reassuring for obstetric and neonatal outcome. The mandatory requirement of freeze-all and lack of cost-effectiveness data are limitations of this novel approach. Double stimulation/dual stimulation is an effective strategy when the need to obtain oocytes is urgent, including patients with malignant diseases undergoing oocyte cryopreservation and patients of advanced maternal age or with reduced ovarian reserve.

Subcutaneous luteal phase progesterone rescue rectifies ongoing pregnancy rates in hormone replacement therapy vitrified-warmed blastocyst transfer cycles.

RESEARCH QUESTION: Will luteal phase rescue with additional progesterone increase serum progesterone concentrations and improve reproductive outcomes in patients with low serum progesterone concentrations undergoing hormone replacement therapy (HRT) cycles? DESIGN: Case-control study including 40 consecutive patients with serum progesterone concentrations <8.75 ng/ml on the 5th day of progesterone supplementation who underwent rescue with a daily bolus of 25 mg s.c. progesterone, starting on the afternoon of the 5th day of progesterone administration. For every patient who underwent progesterone rescue, three patients matched by age, body mass index, number of previous attempts and number of blastocysts transferred, with serum progesterone concentration >8.75 ng/ml on the 5th day of progesterone administration served as controls (n = 120). The main outcome measure was ongoing pregnancy rate (OPR). RESULTS: Baseline demographic features and embryological data of the rescue and control groups were comparable. As expected, the mean serum progesterone concentration was lower in the rescue group on the 5th day of progesterone administration (7.84 ± 0.92 versus 15.32 ± 5.02 ng/ml; P < 0.001). Following rescue, the mean serum progesterone concentration on the day of vitrified-warmed embryo transfer (6th day of progesterone administration) was 33.43 ± 10.83 ng/ml (range 14.61-82.64 ng/ml), and the OPR of the rescue and control groups were comparable. CONCLUSIONS: In patients undergoing HRT vitrified-warmed blastocyst transfer with serum progesterone concentrations lower than 8.75 ng/ml 1 day prior to the scheduled embryo transfer (6th day of progesterone administration), additional supplementation with a 25 mg s.c. daily progesterone dose seems to rescue the cycle, resulting in OPR comparable to those of patients with serum progesterone >8.75 ng/ml.

Addition of intramuscular progesterone to vaginal progesterone in hormone replacement therapy in vitrified-warmed blastocyst transfer cycles.

RESEARCH QUESTION: Does intramuscular progesterone supplementation ensure ongoing pregnancy rates (OPR) comparable with vaginal progesterone only in hormone replacement therapy cycles for vitrified-warmed embryo transfer; and is there a window of serum progesterone concentration out of which reproductive outcomes may be negatively affected? DESIGN: Retrospective longitudinal cohort study carried out at a single IVF clinic. In total, 475 consecutive, day-5 to day-6 vitrified-warmed embryo transfer cycles using hormone replacement therapy regimen were included. Vaginal progesterone only was given to 143 patients; supplementation of vaginal progesterone only with intramuscular progesterone supplementation every third day was given to 332 patients. On the sixth day of progesterone administration, immediately before frozen-thawed embryo transfer, circulating progesterone levels were measured. Main outcome measure was OPR. RESULTS: The baseline demographic features and embryological data of the vaginal progesterone only and intramuscular progesterone supplementation groups were comparable. The OPR were 48.3% and 51.8%, respectively (P = 0.477). Neither the circulating progesterone level nor the type of progesterone administration were independent predictors of OPR. The effect of serum progesterone levels on OPR was evaluated by percentiles (<10%, 10-49%, 50-90% and >90%), taking 50-90% as the reference sub-group. All percentiles in the intramuscular progesterone supplementation group and in the vaginal progesterone only group had similar OPR. CONCLUSIONS: Intramuscular progesterone supplementation every third day, overall, does not enhance OPR compared with vaginal progesterone only.

Anti-Müllerian hormone as a diagnostic tool for PCOS under different diagnostic criteria in an unselected population.

RESEARCH QUESTION: Is anti-Müllerian hormone (AMH) a valid tool to diagnose polycystic ovary syndrome (PCOS) according to different subsets of criteria among an unselected group of women? DESIGN: In this cross-sectional study, AMH concentrations were measured in an unselected group of women. The ability of AMH to diagnose PCOS according to National Institutes of Health (NIH), Rotterdam-2003 and Androgen Excess and PCOS Society (AE-PCOS) criteria was tested by using frozen serum aliquots (n = 392) that had been collected from a previous prevalence study of PCOS. RESULTS: The respective age and body mass index adjusted area under the curve (aAUC, 95% confidence interval) values were 0.80 (0.71-0.89), 0.74 (0.67-0.81) and 0.71 (0.64-0.79). When the definition of polycystic ovary morphology (PCOM) was set to an antral follicle count (AFC) of 20 instead of 12, the prevalence of syndrome dropped from 19.9% to 10.2% and from 15.3% to 8.9% according to Rotterdam-2003 and AE-PCOS criteria, respectively. In patients with Phenotype A, who had hyperandrogenism, ovulatory dysfunction and PCOM, AMH had an aAUC of 0.85 (0.77-0.92) to diagnose the syndrome. In Phenotypes B (hyperandrogenism + ovulatory dysfunction), C (hyperandrogenism + PCOM) or D (ovulatory dysfunction + PCOM), AMH had poor to fair ability to diagnose the syndrome. CONCLUSION: AMH has poor to fair validity to diagnose PCOS among an unselected group of women, except for patients bearing all features of the syndrome (Phenotype A). This finding is valid using the NIH, Rotterdam-2003 and AE-PCOS criteria and even after revising the definition of PCOM as AFC ≥20.

Examination of cervical swabs of patients with endometriosis using Fourier transform infrared spectroscopy.

PURPOSE: There is no established non-invasive method to diagnose patients with endometriosis. As a nondestructive type of radiation, infrared light might be used for discrimination by causing vibration of the covalent bonds of the molecules when absorbed by the tissues. The aim of the study was to test whether cervical swab can be used to diagnose women with endometriosis using Fourier transform infrared spectroscopy (FTIR). METHODS: In this prospective case-control study, women between 18-45 years old and undergoing laparoscopy due to various reasons were recruited (n = 20). According to the findings during laparoscopy, patients were stratified as stage I-II or stage III-IV endometriosis groups. Women lacking any visible lesions of endometriosis were recruited as controls. A cervical swab was taken from all patients just before the surgical procedure and pulled into a tube containing saline solution. FTIR spectra were obtained and the fingerprint region (1750-850 cm-1) was used for analyses. RESULTS: Finally, three samples in stage I-II, five samples in stage III-IV and five samples in the control group were analyzed. Hierarchical cluster analysis and principal component analysis were performed as the chemometric method. A total of ten observable peaks were detected in the absorbance spectra of samples. The peaks at 1450 and 1405 cm-1 originating from lipids and proteins significantly increased in the stage III-IV endometriosis group when compared with controls. In addition, nucleic acid/carbohydrate ratio was significantly lower in the stage I-II group indicating that the alteration of the carbohydrate level might be important. CONCLUSIONS: Examination of cervical swab with FTIR spectroscopy might be a proper candidate for a non-invasive diagnostic approach of endometriosis.

The effect of performing hysteroscopy prior to the first in vitro fertilization (IVF) cycle on live birth rate.

In this retrospective cohort study, a total of 707 couples underwent in vitro fertilization (IVF) at Hacettepe University Hospital between 01 January 2010 and 01 November 2014 with their chronologically first cycle were evaluated. Patients who have diagnostic hysteroscopy prior to first IVF cycle served as a study group (n = 42) and patients without diagnostic hysteroscopy served as control group (n = 282). In study group in all patients, diagnostic hysteroscopy was performed at the follicular phase of previous menstrual cycle, namely immediately before ovarian stimulation (OS) cycle. Demographic features, clinical characteristics and treatment outcomes were compared between the groups. The logistic regression analysis was performed in order to assess independent predictors of live birth rates (LBRs). There was no statistically significant difference between the groups for demographic features and OS cycle characteristics. Implantation rate (22.2% vs. 21.5%, p=.840), clinical pregnancy rate (33.3% vs. 28.7%, p=.541), and LBRs (23.8% vs. 18.5%, p=.420) were comparable. In logistic regression analysis, performing hysteroscopy prior to first IVF cycles per se without correcting anatomic abnormalities was not an independent predictor of LBRs (OR: 0.72, 95% CI: 0.310-1.68, p=.45). In conclusion, performing diagnostic hysteroscopy prior to first IVF treatment cycle without correcting any anatomic abnormalities did not improve LBRs.

Progesterone Elevation and Preventive Strategies to Avoid Implantation Failure.

Despite the wide utilization of gonadotropin-releasing hormone analogs, progesterone elevation (P4E) in the late follicular phase occurs in 5 to 30% of all ovarian stimulation (OS) cycles. Although the detrimental effect of P4E on pregnancy rates in fresh in vitro fertilization cycles is valid in all subsets of cases, higher levels of P4 and a longer duration of P4E may be needed in patients with a hyper-ovarian response in order for a negative impact on pregnancy rates to occur. Available preclinical and clinical data suggest that aggressive OS with high doses of follicle-stimulating hormone might increase 3ß-hydroxy steroid dehydrogenase and 17ß-hydroxy steroid dehydrogenase enzyme activity in human granulosa cells, which leads to high P4 production and hence a higher amount of leakage to the systemic circulation due to a lack of 17α-hydroxylase enzyme expression in human species. High P4 concentrations appear to alter gene expression in the endometrium; however, caution is necessary regarding its potential effect on oocyte/embryo quality with respect to the role of inherent follicular disruption in some women. In terms of the mechanism of overproduction in P4 synthesis, the main preventive strategy should be avoiding aggressive stimulation. Unfortunately, there is lack of large-scale randomized controlled trials for other approaches, including deferred embryo transfer in the thaw cycle. Since there is a significant inter-assay variability for P4 measurement, it may be wise to recommend that every center should define their own P4E and the level needed for harm to occur based on their own assays and datasets before deciding the best approach.

Metabolic Syndrome During Menopause.

The metabolic syndrome (MetS) comprises individual components including central obesity, insulin resistance, dyslipidaemia and hypertension and it is associated with an increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The menopause per se increases the incidence of MetS in aging women. The effect(s) of menopause on individual components of MetS include: i) increasing central obesity with changes in the fat tissue distribution, ii) potential increase in insulin resistance, iii) changes in serum lipid concentrations, which seem to be associated with increasing weight rather than menopause itself, and, iv) an association between menopause and hypertension, although available data are inconclusive. With regard to the consequences of MetS during menopause, there is no consistent data supporting a causal relationship between menopause and CVD. However, concomitant MetS during menopause appears to increase the risk of CVD. Furthermore, despite the data supporting the association between early menopause and increased risk of T2DM, the association between natural menopause itself and risk of T2DM is not evident. However, the presence and the severity of MetS appears to be associated with an increased risk of T2DM. Although the mechanism is not clear, surgical menopause is strongly linked with a higher incidence of MetS. Interestingly, women with polycystic ovary syndrome (PCOS) have an increased risk of MetS during their reproductive years; however, with menopausal transition, the risk of MetS becomes similar to that of non-PCOS women.

The Impact of a Long-Acting Oral Sphingosine-1-Phosphate Analogue on Ovarian Aging in a Rat Model.

In animal studies, intravenous continuous infusion or peritoneal injection of sphingosine-1-phosphate (S1P) has been shown to decrease chemotherapy- and radiotherapy-induced apoptosis on primordial follicles. Although a long-acting oral form of an S1P analogue (FTY720, fingolimod) has been recently developed and utilized in women with multiple sclerosis, there are no data exploring its ability to avoid spontaneous follicle apoptosis. Thirty 10-month-old female rats were randomly assigned to 3 groups to investigate whether fingolimod would be able to decrease the spontaneous ovarian follicle apoptosis ratio. An oral analogue form of S1P was administered for 60 days at a dose of 0.1 mg/kg (n = 10) or dose of 1 mg/kg (n = 10) per day. The control group (n = 10) received physiological serum via an orogastric feeding tube. The main outcome measures were anti-Müllerian hormone (AMH) level and nonapoptotic follicle ratio. While low-dose S1P group had comparable AMH levels to high-dose S1P group and controls, high-dose S1P group had higher mean levels of AMH, reaching marginal significance with controls (5.72 ± 0.61 vs 4.81 ± 0.85 ng/mL, P = .050). For the nonapoptotic primordial follicle ratio, both low-dose S1P group (67.0% ± 16.4% vs 29.9% ± 19.5%, P < .001) and high-dose S1P group (51.1% ± 11.5% vs 29.9% ± 19.5%, P = .023) had superior rates when compared with controls. Interestingly, low-dose S1P groups also had a statistically higher nonapoptotic primordial follicle ratio than high-dose S1P group ( P = .047). Our findings suggest that a long-acting oral analogue of S1P might decrease spontaneous follicular apoptosis based on the nonapoptotic primordial follicle ratio and AMH levels when compared with placebo.

Duration of blastulation may be associated with ongoing pregnancy rate in single euploid blastocyst transfer cycles.

Not all euploid embryos implant, necessitating additional tools to select viable blastocysts in preimplantation genetic screening cycles. In this retrospective cohort study, 129 consecutive patients who underwent 129 single euploid blastocyst transfers in cryopreserved embryo transfer cycles were included. All embryos were individually cultured in a time-lapse incubator from intracytoplasmic sperm injection up to trophoectoderm biopsy. Twenty-three time-lapse morphokinetic variables were tested among patients with (n = 68) or without (n = 61) ongoing pregnancy. All 23 time-lapse morphokinetic variables, apart from duration of blastulation (tB-tSB), were comparable between patients with or without ongoing pregnancy. Duration of blastulation was significantly shorter in patients with ongoing pregnancy (8.1 ± 3.2 versus 9.5 ± 3.4 h; P = 0.014); shorter duration of blastulation remained an independent predictor for ongoing pregnancy, when tested by logistic regression analysis (OR 0.81; 95% CI 0.70 to 0.93). One important limitation of this study, and a reason for caution, is the use of multiple comparisons, which can lead to differences at the 0.05 level simply by chance or random variation. Nonetheless, the study suggests that when more than one euploid blastocyst is available, priority might be given to those with a shorter duration of blastulation.

Which is worse? Comparison of ART outcome between women with primary or recurrent endometriomas.

STUDY QUESTION: Are live birth rates (LBR) different after ART cycles between women with primary or recurrent endometrioma? SUMMARY ANSWER: Women with recurrent endometrioma have similar LBR as compared to patients with primary endometrioma. WHAT IS ALREADY KNOWN: Recurrence rate can be as high as 29% after endometrioma excision. Prior studies on management of endometrioma before ART involve primary endometriomas. There is limited information regarding the prognosis of women with recurrent endometriomas. STUDY DESIGN, SIZE, DURATION: A multicenter retrospective cohort study, including 76 women with primary and 82 women with recurrent endometriomas treated at the participating centers over a 6-year period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with endometrioma who underwent ART at three academic ART centers. Couples with another indication for ART were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Female age, median number of prior failed ART cycles, proportion of patients with bilateral endometrioma (28 versus 28.9%), ovarian stimulation protocols, and total gonadotropin consumption were similar between the study groups. Numbers of metaphase two oocytes (5 versus 6), number of embryos transferred, and the proportion of patients undergoing blastocyst transfer were similar across the study groups. Clinical pregnancy rates (36.6 versus 34.2%, absolute difference 2.4%, 95% CI: -12.5 to 17.3%, P = 0.83) and LBR (35.4 versus 30.3%, absolute difference 5.1%, 95% CI: -9.5 to 19.7%, P = 0.51) per started cycle in recurrent and primary endometrioma were similar. Comparable success rates were also confirmed with logistic regression analysis (OR: 1.14, 95% CI: 0.78-0.57, P = 2.3). LIMITATIONS, REASONS FOR CAUTION: The retrospective design has inherent limitations. Some women with severely decreased ovarian reserve after primary endometrioma excision may not have pursued further treatment. WIDER IMPLICATIONS OF THE FINDINGS: The management of endometrioma prior to ART is controversial but a different management strategy is not required for recurrent endometriomas. Since recurrent endometriomas do not have a worse impact on ART outcome than primary endometriomas, and repeat surgery has a higher risk for complications, conservative management without surgery can be justified. STUDY FUNDING/COMPETING INTEREST(S): No funding or competing interests to declare. TRIAL REGISTRATION NUMBER: None.

Does pituitary suppression affect live birth rate in women with congenital hypogonadotrophic hypogonadism undergoing intra-cytoplasmic sperm injection? A multicenter cohort study.

In this retrospective multicenter cohort study, women with congenital hypogonadotrophic hypogonadism (CHH) (n = 57) who underwent intra-cytoplasmic sperm injection in-between 2010-2014 were compared to age-matched controls with tubal factor infertility (n = 114) to assess ovarian stimulation cycle and pregnancy outcomes. Live birth rates (LBRs) per started cycle were 31.6 and 24.6% in CHH and controls groups, respectively (p = 0.36). Comparable success rates were also confirmed with the logistic regression analysis (OR: 1.44, 95% CI: 0.78-2.67, p = 0.24). Of the 57 women with CHH, 19 were stimulated with the gonadotropin-releasing hormone (GnRH) antagonist protocol, 13 with the long-GnRH-agonist protocol. Pituitary suppression (PS) was not employed in the remaining 25 cases. Compared to women with PS, women without PS had significantly higher embryo implantation rates (21.6 versus 52.6%, p = 0.03). Although there was a trend favoring no PS, LBRs (25.0 versus 40.0%, p = 0.26) per cycle were short of statistical significance. LBRs per cycle (57.1 versus 31.2%, p = 0.11) and miscarriage rates (11.1 versus 16.7%, p = 0.75) were similar between CHH women who were given estrogen + progesterone and progesterone alone to support the luteal phase. In conclusion, the optimal stimulation protocol appears to be exogenous gonadotropin stimulation alone, without PS, and progesterone-only luteal phase support in CHH patients.