Luteal phase support using micronized vaginal progesterone as pessaries or capsules in artificial cycles: is there any difference?

RESEARCH QUESTION: Is there a difference between the proportion of patients with serum progesterone <8.8 ng/ml on the day of embryo transfer when micronized vaginal progesterone (MVP) for luteal phase support (LPS) is given as pessaries versus capsules? DESIGN: This retrospective, matched-cohort, single-centre study compared pessaries (Cyclogest) versus capsules (Utrogestan, Progeffik) for LPS in hormone replacement treatment-embryo transfer (HRT-ET) cycles. Patients under 50 years old with a triple-layer endometrial thickness of ≥6.5 mm underwent transfer of one or two blastocysts. Serum progesterone concentrations were measured on the day of transfer; patients with concentrations <8.8 ng/ml received a single 'rescue' dose of additional progesterone by subcutaneous injection. RESULTS: In total 2665 HRT-ET cycles were analysed; 663 (24.9%) used pessaries for LPS and 2002 (75.1%) used capsules. Mean serum progesterone concentrations with standard deviations on the day of embryo transfer were significantly higher in the group using MVP pessaries compared with those using capsules (14.5 ± 5.1 versus 13.0 ± 4.8 ng/ml; P = 0.000). The percentage of participants with suboptimal serum progesterone concentrations on the day of embryo transfer (<8.8 ng/ml) was significantly lower in the pessary group than the capsule group (10.3%, 95% confidence interval [CI] 7.9-12.6% versus 17.9%, 95% CI 16.2-19.6%; adjusted odds ratio 0.426, 95% CI 0.290-0.625; P = 0.000). No differences in pregnancy outcome were observed between the groups. CONCLUSIONS: Using MVP pessaries rather than capsules for LPS resulted in significantly fewer patients having suboptimal serum progesterone concentrations on the day of embryo transfer. Consequently, almost 50% fewer patients in the pessary group needed rescue treatment.

Comparison between oral dydrogesterone versus micronized vaginal progesterone gel in clinical outcome within the first HRT-FET cycle: a retrospective analysis.

OBJECTIVE: The purpose of this study is to compare the clinical efficacy of oral dydrogesterone and micronized vaginal progesterone (MVP) gel during the first HRT-FET cycle. METHODS: A retrospective cohort study based on a total of 344 women undergoing their first HRT-FET cycles without Gonadotropin-Releasing Hormone agonist (GnRH-a) pretreatment was conducted. All the cycles were allocated to two groups in the reproductive medical center at the University of Hong Kong-Shenzhen Hospital. One group (n = 193) received oral dydrogesterone 30 mg/d before embryo transfer, while the other group (n = 151) received MVP gel 180 mg/d. RESULTS: The demographics and baseline characteristics of two groups were comparable. We found no statistically significant difference in live birth rate (24.35% vs. 31.13%, P = 0.16), clinical pregnancy rate (34.72% vs. 36.42%, P = 0.74), embryo implantation rate (25.09% vs. 28.36%, P = 0.43), positive pregnancy rate (42.49% vs 38.41%, P = 0.45), miscarriage rate (9.33% vs 3.97%, P = 0.05), or ectopic pregnancy rate (0.52% vs. 0.66%, P = 0.86) between the oral dydrogesterone group and MVP gel group. In the multivariate logistic regression analysis for covariates, medication used for luteal support was not associated with live birth rate (OR = 0.73, 95% CI: 0.32-1.57, P = 0.45). And the different luteal support medication did not have a significant positive association with the live birth rate in the cycles with day 2 embryo transferred (OR = 1.39, 95% CI:0.66-2.39, P = 0.39) and blastocyst transferred (OR = 1.31 95% CI:0.64-2.69, P = 0.46). CONCLUSION: 30 mg/d oral dydrogesterone and 180 mg/d MVP gel revealed similar reproductive outcomes in HRT-FET cycles in the study.

Menopausal Hormone Therapy, an Ever-Present Topic: A Pilot Survey about Women's Experience and Medical Doctors' Approach.

Background and Objective: Menopause can be associated with many clinical manifestations: vasomotor symptoms, urogenital problems, and additional psychological disturbances, such as anxiety, mood changes, and sleep alterations. The prolonged lack of hormones also increases the risk of long-term consequences. Hormone Replacement Treatment (HRT) in menopause consists of the administration of estrogen, alone or associated to progesterone, to relieve these uncomfortable disturbances and to prevent the onset of other pathologic conditions. The aim of this study is to examine the prevalence of HRT use in a sample of menopausal women and their experience with menopause and HRT. This study also investigates the knowledge of general practitioners (GPs) and gynecologists about HRT and its prescription. Materials and Methods: We conducted a cross-sectional population survey on 126 women of 50-59 years in an industrial city in the North of Italy, Vercelli (Novara), in Eastern Piedmont. We also presented a questionnaire on the topic to 54 medical doctors (GPs and gynecologists) of the same area. Results: The prevalence of HRT use in our sample was 11.9%. In total, a good percentage of the users affirmed to be satisfied with HRT. Additionally, a minority of women reported being ideally against the use of replacement hormones, were advised against using HRT by doctors, and did not use it because of the fear of side effects. We found a positive association between patient education, health care attitude, and HRT usage. A significant number of women knew about HRT from the media, and most of them were not informed by a health professional. Despite this, the interviewed doctors considered their knowledge about HRT as 'good' and would recommend HRT: only 5.6% would not prescribe it. Conclusions: Our results highlight the need for information about HRT among patients and health professionals, along with the need for more effective communication, evaluation, and suggestion of treatment.

Letrozole-stimulated endometrial preparation protocol is a superior alternative to hormone replacement treatment for frozen embryo transfer in women with polycystic ovary syndrome, a cohort study.

BACKGROUND: The current routine endometrial preparation protocol for women with polycystic ovary syndrome (PCOS) is hormone replacement treatment (HRT). Letrozole is rarely used in frozen embryo cycles. Evidence confirming whether letrozole-stimulated (LS) protocol is suitable for frozen embryo transfer in patients with PCOS and for whom is suitable remains lacking. METHODS: This was a retrospective cohort study involving all frozen embryo transfer cycles with LS and HRT for PCOS during the period from Jan 2019 to December 2020 at a tertiary care center. Multivariate Logistic regression was used to analyze the differences in clinical pregnancy rate, live birth rate, miscarriage rate, the incidence of other pregnancy and obstetric outcomes between LS and HRT protocols after adjusting for possible confounding factors. Subgroup analysis was used to explore the population for which LS protocol was suitable. RESULTS: The results of multivariate logistic regression showed that LS was significantly associated with a higher clinical pregnancy rate (70.9% vs. 64.4%;aOR:1.41, 95%CI: 1.18,1.68), live birth rate (60.5% vs. 51.4% aOR:1.49, 95%CI: 1.27,1.76), and a lower risk of miscarriage (14.7% vs. 20.1% aOR: 0.68, 95%CI: 0.53,0.89), hypertensive disorders of pregnancy (6.7% vs. 8.9% aOR: 0.63, 95%CI: 0.42,0.95), and gestational diabetes mellitus (16.7% vs. 20.7% aOR:0.71, 95%CI: 0.53,0.93) than HRT. There were no significant differences in other outcomes such as preterm birth, cesarean delivery, small for gestational age, or large for gestational age between the two endometrial preparation protocols. Subgroup analysis showed that LS had higher live birth rates than HRT in most of the subgroups; in the three subgroups of maternal age ≥ 35 years, menstrual cycle < 35 days, and no insulin resistance, the live birth rates of the two endometrial preparation protocols were comparable. CONCLUSIONS: LS protocol could improve the live birth rate and reduce the incidence of miscarriage, hypertensive disorders of pregnancy and gestational diabetes mellitus in patients with PCOS. LS protocol is suitable for all types of patients with PCOS. LS should be considered the preferred endometrial preparation protocol for women with PCOS.

The influence of endogenous and exogenous hormonal factors on migraine in spontaneous postmenopausal women: A nationwide population-based study in South Korea.

BACKGROUND: Hormonal and menstrual factors are known to influence migraines in women. However, studies in the postmenopausal period are relatively insufficient for clinical translation. This study investigated the influence of endogenous and exogenous hormonal factors on migraines in spontaneous menopausal women. METHODS: We obtained and analyzed the data related to hormonal factors from the Korean Health Examination database. A migraine diagnosis was identified using the Korean National Health Insurance Service database between 2009 and 2018. We observed migraine occurrence in spontaneous postmenopausal women. Study populations were divided into two groups depending on new diagnosis of migraine during the follow up periods. We investigated the association between endogenous and exogenous hormonal factors and migraine. RESULTS: 1,114,742 spontaneous postmenopausal women were enrolled. Migraine risk tended to increase in the shorter lifetime number of years of menstruation group compared to the group with lifetime number of years of menstruation ≥40 years. All of the hormone replacement therapy (HRT) groups showed higher risk compared with the non-HRT group. Migraine risk tends to increase with greater postmenopausal years compared to the postmenopausal <5 years group. CONCLUSION: Our study suggests that female hormonal factors, including endogenous and exogenous estrogen exposure, may be associated with migraine occurrence in spontaneous menopausal women.

Comparison of two mainstream endometrial preparation regimens in vitrified-warmed embryo transfers after PGT.

RESEARCH QUESTION: Which of the two mainstream endometrial preparation regimens, assisted natural cycle (NC) or hormone replacement treatment cycle (HRT), help frozen-thawed embryo transfer (FET) cycles after preimplantation genetic testing (PGT) achieve better clinical outcomes? DESIGN: This retrospective analysis included 3400 vitrified-warmed single blastocyst transfer cycles after PGT from January 2011 to November 2020, and involved 2332 patients with regular menstrual cycles. The decision to proceed with an assisted NC (n = 827) or HRT (n = 2573) before FET was reached based on a combination of patient preference and physician guidance. Clinical pregnancy rate, live birth rate, early miscarriage rate and obstetric outcomes were compared. RESULTS: No significant difference was observed between the assisted NC and HRT groups in terms of clinical pregnancy rate (51.6% versus 50.7%, P = 0.634), live birth rate (44.0% versus 43.4%, P = 0.746) or early miscarriage rate (12.6% versus 12.0%, P = 0.707). Multivariate analysis indicated that the endometrial preparation protocol was not an independent factor for a clinical pregnancy or live birth. In the HRT group, the Caesarean section rate (64.7% versus 51.9%, P < 0.001) and pregnancy complication rate (20.2% versus 13.8%, P = 0.003) were significantly higher. The two groups were not statistically different with respect to gestational age, early preterm birth rate, fetal weight or fetal birth defect rate. CONCLUSIONS: For patients undergoing a PGT-FET cycle involving a single blastocyst transfer, using assisted NC and HRT for the endometrial preparation could lead to comparable rates of clinical pregnancy and live birth. Additionally, NC is safer than HRT in terms of avoiding pregnancy complications and adverse obstetric outcomes.

Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study.

STUDY QUESTION: Does an individualised luteal phase support (iLPS), according to serum progesterone (P4) level the day prior to euploid frozen embryo transfer (FET), improve pregnancy outcomes when started on the day previous to embryo transfer? SUMMARY ANSWER: Patients with low serum P4 the day prior to euploid FET can benefit from the addition of daily subcutaneous P4 injections (Psc), when started the day prior to FET, and achieve similar reproductive outcomes compared to those with initial adequate P4 levels. WHAT IS KNOWN ALREADY: The ratio between FET/IVF has spectacularly increased in the last years mainly thanks to the pursuit of an ovarian hyperstimulation syndrome free clinic and the development of preimplantation genetic testing (PGT). There is currently a big concern regarding the endometrial preparation for FET, especially in relation to serum P4 levels around the time of embryo transfer. Several studies have described impaired pregnancy outcomes in those patients with low P4 levels around the time of FET, considering 10 ng/ml as one of the most accepted reference values. To date, no prospective study has been designed to compare the reproductive outcomes between patients with adequate P4 the day previous to euploid FET and those with low, but restored P4 levels on the transfer day after iLPS through daily Psc started on the day previous to FET. STUDY DESIGN, SIZE, DURATION: A prospective observational study was conducted at a university-affiliated fertility centre between November 2018 and January 2020 in patients undergoing PGT for aneuploidies (PGT-A) IVF cycles and a subsequent FET under hormone replacement treatment (HRT). A total of 574 cycles (453 patients) were analysed: 348 cycles (leading to 342 euploid FET) with adequate P4 on the day previous to FET, and 226 cycles (leading to 220 euploid FET) under iLPS after low P4 on the previous day to FET, but restored P4 levels on the transfer day. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall we included 574 HRT FET cycles (453 patients). Standard HRT was used for endometrial preparation. P4 levels were measured the day previous to euploid FET. P4 > 10.6 ng/ml was considered as adequate and euploid FET was performed on the following day (FET Group 1). P4 < 10.6 ng/ml was considered as low, iLPS was added in the form of daily Psc injections, and a new P4 analysis was performed on the following day. FET was only performed on the same day when a restored P4 > 10.6 ng/ml was achieved (98.2% of cases) (FET Group 2). MAIN RESULTS AND THE ROLE OF CHANCE: Patient's demographics and cycle parameters were comparable between both euploid FET groups (FET Group 1 and FET Group 2) in terms of age, weight, oestradiol and P4 levels and number of embryos transferred. No statistically significant differences were found in terms of clinical pregnancy rate (56.4% vs 59.1%: rate difference (RD) -2.7%, 95% CI [-11.4; 6.0]), ongoing pregnancy rate (49.4% vs 53.6%: RD -4.2%, 95% CI [-13.1; 4.7]) or live birth rate (49.1% vs 52.3%: RD -3.2%, 95% CI [-12; 5.7]). No significant differences were also found according to miscarriage rate (12.4% vs 9.2%: RD 3.2%, 95% CI [-4.3; 10.7]). LIMITATIONS, REASONS FOR CAUTION: Only iLPS through daily Psc was evaluated. The time for Psc injection was not stated and no serum P4 determinations were performed once the pregnancy was achieved. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides information regarding an 'opportunity window' for improved ongoing pregnancy rates and miscarriage rates through a daily Psc injection in cases of inadequate P4 levels the day previous to FET (P4 < 10.6 ng/ml) and restored values the day of FET (P4 > 10.6 ng/ml). Only euploid FET under HRT were considered, avoiding one of the main reasons of miscarriage and implantation failure and overcoming confounding factors such as female age, embryo quality or ovarian stimulation protocols. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. B.C. reports personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, IBSA and Gedeon Richter outside the submitted work. N.P. reports grants and personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, Theramex and Besins International and personal fees from IBSA and Gedeon Richter outside the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT03740568.

Oestrogen dose tapering during luteal phase does not affect clinical outcomes after hormone replacement treatment-frozen-thawed embryo transfer cycles: a retrospective analysis.

STUDY QUESTION: Does oestrogen dose tapering during the luteal phase affect the clinical outcome after hormone replacement treatment-frozen-thawed embryo transfer (HRT-FET) cycles? SUMMARY ANSWER: Our results suggest that tapering oestrogen doses during the luteal phase results in similar clinical outcomes to those obtained with the traditional luteal phase support (LPS). WHAT IS KNOWN ALREADY: Traditional LPS with oestrogen and progesterone is considered necessary in HRT-FET cycles. However, case reports have shown successful clinical pregnancies and live births in the absence of oestrogen administration after embryo transfers. STUDY DESIGN, SIZE, DURATION: This was a retrospective study on 6035 HRT-FET cycles extending over 7 years from January 2011 to June 2018 at the reproductive medicine centre of Xiangya Hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: We compared the clinical outcomes of 1632 HRT-FET cycles with tapered oestrogen doses from 12 days after embryo transfer (study group) to those of 4403 HRT-FET cycles maintained on constant oestrogen doses during the luteal phase (control group) in the case of positive serum HCG test. MAIN RESULTS AND THE ROLE OF CHANCE: We found similar biochemical pregnancy rates (52.1% vs. 51.9, P = 0.864), clinical pregnancy rates (44.9% vs. 43.2%, P = 0.249), implantation rates (29.8% vs. 29.3%, P = 0.591) and miscarriage rates (16.0% vs. 14.6%, P = 0.379) between the studied groups. LIMITATIONS, REASONS FOR CAUTION: Retrospective, design-associated biases are possible. In addition, some baseline characteristics differed between groups. Finally, we did not compare live birth rates between groups. WIDER IMPLICATIONS OF THE FINDINGS: Our study showing similar outcomes between traditional LPS and oestrogen tapering during the luteal phase indicates that oestrogen may be cautiously tapered during the luteal phase after HRT-FET cycles. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (grant no. 81401269) and the class General Financial Grant from the China Postdoctoral Science Foundation (grant no. 2017M620360). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Endometrium cytokine profiles are altered following ovarian stimulation but almost not in subsequent hormone replacement cycles.

PURPOSE: To investigate the impact of ovarian stimulation and hormone replacement treatment on key regulatory cytokines in endometrial secretion during endometrium implantation window. METHODS: Fifty-six patients undergoing ovarian stimulation (OS) with gonadotropin releasing hormone antagonist and frozen embryo transfer with hormone replacement treatment (HRT) were recruited. Endometrial secretion aspiration was performed repeatedly during implantation window in natural, OS and HRT cycles of every patient. The concentrations of 17 mediators, known to be involved in human embryo implantation, were assessed by multiplex immunoassay. RESULTS: Compared with natural cycle (NC), the concentration of IFN-γ, G-CSF and IL-8 within endometrium were almost the same following OS and HRT. Furthermore, increased MCP-1 levels were observed following HRT and OS. In addition, an increase in IL-1b, IL-7, IL-17, IL-6, TNF-a, IL-12, IL-4, IL-13, IL-10, IL-5, VEGF and MIP-1b concentrations were found in OS cycle only. The level of GM-CSF was lower in HRT cycle and higher in OS cycle, when compared with NC. Among all 17 cytokines, no correlation was found between cytokine concentrations and serum estradiol and progesterone, while only IL-7 concentration has a low correlation with serum LH level. CONCLUSION: Compared to natural and hormone replacement cycle, patients' endometrium cytokine profiles present an increased inflammatory response following ovarian stimulation.

Prospective, randomized, double-blind, placebo-controlled phase IIa clinical trial on the effects of an estrogen-progestin combination as add-on to inpatient psychotherapy in adult female patients suffering from anorexia nervosa.

BACKGROUND: There is a need for novel treatment approaches in anorexia nervosa (AN). While there is broad knowledge with regard to altered appetite regulation and neuropsychological deficits in AN patients on the one hand, and the effects of estrogen replacement upon neuropsychological performance in healthy subjects on the other, up to now, no study has implemented estrogen replacement in AN patients, in order to examine its effects upon AN-associated and general psychopathology, neuropsychological performance and concentrations of peptide components of the hypothalamus-pituitary-adrenal (HPA) axis and within appetite-regulating circuits. METHODS: This is a randomized placebo-controlled clinical trial on the effects of a 10-week oral estrogen replacement (combination of ethinyl estradiol 0.03 mg and dienogest 2 mg) in adult female AN patients. The primary target is the assessment of the impact of sex hormone replacement upon neuropsychological performance by means of a neuropsychological test battery consisting of a test for verbal intelligence, the Trail making test A and B, a Go/No-go paradigm with food cues and the Wisconsin Card Sorting Test. Secondary targets include a) the examination of safety and tolerability (as mirrored by the number of adverse events), b) assessments of the impact upon eating disorder-specific psychopathology by means of the Eating Disorder Examination Questionnaire (EDE-Q) and the Eating Disorder Inventory-2 (EDI-2), c) the influence upon anxiety using the State-Trait-Anxiety Inventory (STAI), d) assessments of plasma cortisol levels during a dexamethasone-suppression test and appetite-regulating plasma peptides (ghrelin, leptin, insulin, glucose) during an oral glucose tolerance test and, e) a possible impact upon the prescription of antidepressants. DISCUSSION: This is the first study of its kind. There are no evidence-based psychopharmacological options for the treatment of AN. Thus, the results of this clinical trial may have a relevant impact on future treatment regimens. Novel approaches are necessary to improve rates of AN symptom remission and increase the rapidity of treatment response. Identifying the underlying biological (e.g. neuroendocrinological) factors that maintain AN or may predict patient treatment response represent critical future research directions. Continued efforts to incorporate novel pharmacological aspects into treatments will increase access to evidence-based care and help reduce the burden of AN. TRIAL REGISTRATION: European Clinical Trials Database, EudraCT number 2015-004184-36, registered November 2015; ClinicalTrials.gov Identifier: NCT03172533 , retrospectively registered May 2017.

Effect of GnRH agonist down-regulation combined with hormone replacement treatment on reproductive outcomes of frozen blastocyst transfer cycles in women of different ages.

Objective: To investigate the effect of GnRH agonist (GnRH-a) down-regulation prior to hormone replacement treatment (HRT) to prepare the endometrium in frozen embryo transfer (FET) cycles in women of different ages. Methods: This was a retrospective study, and after excluding patients with adenomyosis, endometriosis, severe endometrial adhesions, polycystic ovary syndrome (PCOS), and repeated embryo implantation failures, a total of 4,091 HRT cycles were collected. Patients were divided into group A (<35 years old) and group B (≥35 years old), and each group was further divided into HRT and GnRHa-HRT groups. The clinical outcomes were compared between groups. Results: There was no statistically significant difference in clinical outcomes between the HRT and GnRHa-HRT groups among women aged <35 years. In women of advanced age, higher rates of clinical pregnancy and live birth were seen in the GnRHa-HRT group. Logistic regression analysis showed that female age and number of embryos transferred influenced the live birth rate in FET cycles, and in women aged ≥ 35 years, the use of GnRH-a down-regulation prior to HRT improved pregnancy outcomes. Conclusions: In elderly woman without adenomyosis, endometriosis, PCOS, severe uterine adhesions, and RIF, hormone replacement treatment with GnRH agonist for pituitary suppression can improve the live birth rate of FET cycles.

Pretreatment with a long-acting GnRH agonist for frozen-thawed embryo transfer cycles: how to improve live birth?

BACKGROUND: Whether pretreatment with gonadotropin-releasing hormone agonist (GnRHa) can improve the pregnancy outcomes in frozen-thawed embryo transfer (FET) cycles is controversial. The inconsistencies in the results of different studies would be related to the characteristics of the included patients and the protocol of GnRHa use. In this study, we investigated the efficacy of pretreatment with a long-acting GnRH agonist in the early follicular phase of FET cycles and determined which population was suitable for the protocol. RESULTS: We retrospectively included 630 and 1141 patients in the GnRHa FET and hormone replacement treatment (HRT) FET without GnRHa groups respectively, between October 2017 and March 2019 at a university-affiliated in vitro fertilization center. On the second or third day of menstruation, 3.75 mg of leuprorelin was administered. After 14 days, HRT was initiated for endometrial preparation. No significant differences were observed between the two groups in terms of patient characteristics. However, the GnRHa FET group showed a higher percentage of endometrium with a triple line pattern (94.8% vs 89.6%, p < 0.001) on the day of progesterone administration, with increased implantation (35.6% vs 29.8%, p = 0.005), clinical pregnancy (49.8% vs 43.3%, p = 0.008), and live birth rate (39.4% vs 33.7%, p = 0.016), than the HRT FET cycles with similar endometrial thickness, ectopic pregnancy and early miscarriage rates. Binary logistic regression analysis showed the GnRHa FET group to be associated with an increased chance of clinical pregnancy (P=0.028, odds ratio [OR] 1.32, 95% confidence interval [CI] 1.03-1.70) and live birth (P=0.013, odds ratio [OR] 1.34, 95% confidence interval [CI] 1.06-1.70) compared to the HRT FET without GnRHa group. After subgroup analysis, we found that the GnRHa FET group showed a significantly higher live birth rate in the subgroups of age < 40 years, primary infertility, with polycystic ovary syndrome (PCOS), and irregular menstruation. CONCLUSIONS: Pretreatment with a long-acting GnRHa during the early follicular phase improved the live birth rate in FET cycles. Age < 40 years, primary infertility, PCOS, and irregular menstruation are effective indications for endometrial preparation with GnRHa pretreatment in FET cycles. However, further randomized controlled trials are required to verify these results.

Young women were associated with higher risk of hypertensive disorders of pregnancy and cesarean section from hormone replaced cycles in frozen-thawed embryo transfer: a retrospective study of 5316 singleton deliveries.

Background: The utilization of frozen-thawed embryo transfer (FET) cycles has been linked to heightened risks of adverse perinatal outcomes. However, the potential association between adverse perinatal outcomes and distinct endometrial preparation regimens remains unclear. Therefore, we aim to investigate the maternal and neonatal outcomes after hormone replacement treatment (HRT) cycles, natural cycles (NC) and HRT cycles with pretreatment using GnRHa (HRT + GnRHa) for ovulatory women undergoing FET cycles. Methods: A large sample retrospective cohort study was carried out from 2016 to 2020. The data included a total of 5316 women who had singleton deliveries undergoing FET cycles and which were divided into three groups based on different endometrial preparation protocols: 4399 patients in HRT groups, 621 in GnRHa+HRT groups, 296 in NC groups. The outcomes consisted of maternal outcomes (cesarean section, hypertensive disorders of pregnancy (HDP), placenta previa, gestational diabetes mellitus (GDM));and neonatal outcomes (preterm birth, newborn birthweight, low birthweight, small for gestational age (SGA), macrosomia, large for gestational age (LGA), fetal malformation). Results: After adjusting for a series of confounding variables, we found an increased risk of HDP (aOR=3.362; 95%CI, 1.059-10.675) and cesarean section (aOR=1.838; 95%CI, 1.333-2.535) in HRT cycles compared with NC, especially for ovulatory women under 35 years old. However, in all three groups, newborn birth weight was not significantly different. Meanwhile, perinatal outcomes did not differ significantly in terms of perinatal outcomes in HRT +GnRHa cycles compared with HRT cycles solely. Conclusion: During FET cycles, singletons from HRT were related to higher risks of HDP and cesarean section, particularly for young women. GnRHa pretreatment didn't bring any benefit to perinatal outcomes compared with HRT cycles alone. Therefore, the natural cycle may be a more appropriate and safer option for young ovulatory women.

Hormone replacement treatment regimen is associated with a higher risk of hypertensive disorders of pregnancy in women undergoing frozen-thawed embryo transfer.

Introduction: In frozen-thawed embryo transfer (FET) cycles, hormone replacement treatment (HRT) was associated with a higher risk of hypertensive disorders of pregnancy (HDP) compared with natural cycles (NC). Multiple pregnancy was a risk factor for HDP and several studies did not conduct subgroup analysis of singleton pregnancy and multiple pregnancy. Objective: To investigate whether HRT regimen could be a risk factor for HDP in women undergoing FET cycles in singleton and twin pregnancies. Methods: A retrospective cohort study at a tertiary hospital, including a total of 9120 women who underwent FET and achieved ongoing pregnancy; 7590 patients underwent HRT-FET and 1530 NC-FET. The main outcome was HDP. HDP were analyzed for singleton and twin pregnancies, respectively. Results: In the singleton pregnancy, the risk of HDP in the HRT-FET group was significantly higher than that in the NC-FET group (6.21% vs. 4.09%; P=0.003). After adjusting for female age oocyte pick up, female age at FET and body mass index (BMI), HRT was found as a risk factor for HDP (adjusted odds ration [aOR]: 1.43; 95% confidence interval [CI]: 1.07 to 1.91; P=0.017). In the multiple pregnancy, the risk of HDP in the HRT-FET and NC-FET groups was similar. Conclusion: HRT was associated with a higher risk of HDP in women who underwent FET and achieved singleton pregnancy.

Programmed frozen embryo transfer cycles are associated with a higher risk of abnormal placental development: a retrospective cohort study of singleton live births.

Introduction: Abnormal placental development can lead to adverse outcomes for both mother and fetus. The effect of different types of endometrium preparation regimens of frozen-thawed cycles on the placental development features associated with the perinatal outcomes remains unclear. Hence, we conducted a retrospective cohort study to assess the impact of specific endometrial preparation regimens on placenta-mediated pregnancy complications in singleton live births. Methods: A retrospective cohort study was conducted evaluating data of all singleton live births both conceived naturally or by in vitro fertilization (IVF) therapy from 2018 to 2020 at our hospital. Two exposed groups of frozen-thawed embryo transfer (FET) were created by the endometrium preparation regimen as the modified natural cycles (mNC) and the programmed cycles. The nonexposed group was the singleton pregnancies conceived naturally. The obstetrical and perinatal outcomes were compared among the three groups using multivariate analysis to adjust the results for determinants potentially associated with the abnormal placental development. Results: A total of 2186 pregnant women with singleton live births were included in our final analysis and were divided into three groups as naturally conceived group (n=1334), mNC-FETs group (n=217) and programmed-FETs group(n=635). After adjusting for maternal age and parity, no significant difference was observed on the risk of placental disorders between mNC-FET cycles and natural conceived pregnancies (aOR 1.16; 95%CI 1.31-7.01), while programmed-FET cycles were associated with a higher occurrence of placental disorders (aOR 5.36; 95%CI 3.63-8.05). Using the mNC-FET group as a reference and adjusting for confounders such as maternal age, parity, endometrial thickness, and number of embryos transferred, we found that the main manifestation of abnormal placentation in programmed FET cycles was abnormal placental attachment, including placental adhesion and placenta increta (aOR 2.50, 95%CI 1.36-4.90). The dysfunction of placentation in programmed-FET cycles was independently associated with the type of infertility, the total dose of Femostone and thinner endometrium. Additionally, placental disorders in the programmed-FET group were associated with higher rate of preeclampsia, postpartum hemorrhage and Cesarean section. Conclusion: Our retrospective study revealed that the programmed-FET has a substantial impact on placental development, resulting in a higher incidence of preeclampsia, postpartum hemorrhage and Cesarean section. These findings have significant implications on clinical decision-making.

Low serum progesterone on day of transfer adversely impacts ongoing pregnancy rates in hormonally prepared single blastocyst frozen embryo transfer cycles.

OBJECTIVE: To evaluate if serum progesterone (P) levels on the day of transfer influence ongoing pregnancy rate (OPR) in hormonally prepared single blastocyst frozen embryo transfer (FET) cycles? STUDY DESIGN: Single center prospective cohort study conducted between June 2021 and August 2022 analyzed 217 single good quality blastocyst FET cycles hormonally prepared with oral estradiol valerate and micronized vaginal progesterone 400 mg twice daily. RESULTS: Mean serum P on the day of embryo transfer (ET) was 9.76 ± 5.19 ng/ml. Receiver operator curve (ROC) showed a significant predictive value of serum P levels on the day of ET for OPR, with an area under curve (AUC) (95 %CI) = 0.58 (0.49-0.66). Optimal serum P threshold for OPR was 7.7 ng/ml (Sensitivity 76.8%, Specificity 43.7%). 35.9% patients had serum P below this threshold. BMI was significantly higher (26.8 ± 3.7 vs 25.6 ± 4.3; p = 0.048) in patients with serum P < 7.7 ng/ml vs ≥ 7.7 ng/ml. OPR was significantly lower (24.4% vs 45.3%; p = 0.002) and clinical miscarriage rates significantly higher (37.9% vs 19.2%; p = 0.042) if serum P < 7.72 ng/ml vs ≥ 7.7 ng/ml. CONCLUSION: This study found that serum P level on the day of transfer in hormonally prepared FET cycles was a significant predictor of OPR.

Natural cycle increases the live-birth rate compared with hormone replacement treatment for frozen-thawed single euploid blastocyst transfer.

Background: A number of studies have compared the clinical outcomes between the two endometrial preparation methods: natural cycles (NCs) and hormone replacement treatment (HRT) before frozen embryo transfer, but the results were conflicting. In order to mitigate the potential effect of embryos per se, several researchers have worked on this subject for euploid blastocyst transfer, but the results were still inconsistent. Therefore, the present study was aimed to investigate the clinical outcomes between HRT and NC for autologous single vitrified-warmed euploid blastocyst transfer based on our data. Methods: A total of 598 frozen-thawed single euploid blastocyst transfer cycles in the assisted reproductive center of Northwest Women's and Children's Hospital from January 2014 to May 2021 were retrospectively analyzed. Women were stratified into the NC (n = 125) or HRT (n = 473) group according to the patient's preference and the physician's guidance. Multivariate regression models and subgroup analysis were constructed to analyze the association between endometrial preparation and live birth. Results: Women in the NC group had a higher live birth rate (68.80% versus 58.35%, P = 0.034) and a lower risk of total pregnancy loss (8.51% versus 21.14%, P = 0.005) when compared with women in the HRT group. The biochemical pregnancy rate (75.20% versus 74.00%, P = 0.784) and clinical pregnancy rate (74.40% versus 69.98%, P = 0.334) were similar between the two groups (NC versus HRT). NC was associated with an increased odds of live birth compared with HRT by different multivariable analysis models (Model 1: adjusted odds ratio [aOR], 95% confidence interval [CI]: 0.57, 0.36 - 0.90; Model 2: aOR, 95%CI: 0.57, 0.35 - 0.92). In addition, the increased chance of live birth in the NC group was found in all subgroups. No major obstetrical complications and two malformation livebirths were reported. Conclusions: In women undergoing single euploid frozen blastocyst transfers, the NC group was associated with a lower pregnancy loss rate and an ultimately higher live birth rate than the HRT group. Although HRT is convenient for both clinicians and patients, the lower live birth rate should be taken into account and NC might be the first choice of endometrial preparation method.

GnRH-agonist pretreatment in hormone replacement therapy improves pregnancy outcomes in women with male-factor infertility.

Objective: This study aimed to examine the efficacy of HRT with gonadotropin-releasing hormone agonist (GnRH-a) pre-treatment in women with male-factor infertility who underwent a frozen embryo transfer (FET) programme. Design: Between January 2016 and October 2020, 2733 women with male-factor infertility who underwent the HRT protocol as the endometrial preparation method were enrolled at two Reproductive Medicine Centres. Patients were divided into two groups based on whether they had GnRH-a pre-treatment before HRTs: the GnRHa-HRT group and the HRT group. The inverse probability of treatment weighting (IPTW) method was conducted to balance patient baseline characteristics between treatment cohorts to reduce selection bias. The live birth rate was considered regarded as the primary pregnancy outcome. Results: Multivariate logistic regression adjusted for confounding factors, the GnRHa-HRT group showed a notably higher rate of live birth (OR 2.154, 95% CI 1.636~2.835, P<0.001) when compared to the HRT group. Additionally, the rate of miscarriage was significantly lower in the GnRHa-HRT group. The GnRHa-HRT group had significantly higher rates of biochemical pregnancy, clinical pregnancy, multiple pregnancy, and term birth. Conclusion: The endometrial preparation protocol of HRT with GnRH-a pre-treatment could obviously increase the live birth rate for women with male-factor infertility undergoing the FET programme.

Patterns of Migraine in Postmenopausal Women: A Systematic Review.

INTRODUCTION: Migraine prevalence is higher in fertile than in postmenopausal women. However, few literature data are available on the prevalence and characteristics of migraine after the menopause and on the effect of hormones in postmenopausal women with migraine. METHODS: We performed a systematic literature review of studies available on Scopus and Web of Science from the beginning off indexing until October 18th, 2020. We included both randomized trials and observational studies. RESULTS: We included 12 papers, six of which assessed the prevalence and characteristics of migraine in postmenopausal women, while the other six assessed the effect of hormones on migraine after the menopause. One of the studies was a randomized trial, while the remaining 11 were observational studies. Ten studies were clinic-based, while the remaining two were population-based. Studies assessing the prevalence and characteristics of migraine after the menopause reported inconsistent findings; in studies performed in headache clinics, likely affected by selection bias towards the most severe cases, a relevant proportion of women reported migraine worsening after the menopause. Studies assessing the effect of hormones on migraine after the menopause showed that postmenopausal hormone replacement therapy was invariably associated with migraine worsening, if containing estrogen. CONCLUSION: Our systematic review showed that migraine could be a relevant health problem in postmenopausal women, mostly in headache clinics. However, the available studies allow a limited assessment of the prevalence and characteristics of postmenopausal migraine. Further large studies are needed to better determine the burden of migraine after the menopause according to migraine characteristics and the impact of hormonal treatments.

Endometrial Preparation for Frozen-Thawed Embryo Transfer With or Without Pretreatment With GnRH Agonist: A Randomized Controlled Trial at Two Centers.

Objective: This prospective randomized controlled trial compared the reproductive outcomes of frozen embryo transfer (FET) with hormone replacement treatment (HRT) with or without gonadotropin-releasing hormone agonist (GnRHa) pretreatment. Methods: A total of 133 patients scheduled for HRT-FET mainly because of tubal and/or male factors who received two high-quality cleavage-stage embryos were enrolled at two participating centers. The GnRHa group (n = 65) received GnRHa pretreatment, while the control group (n = 68) did not. Analysis was based on the intention-to-treat (ITT) principle. Results: Among the 133 participants, 130 (97.7%) underwent embryo transfer and 127 (95.5%) completed the protocol. The clinical pregnancy rate according to ITT did not differ between the GnRHa and control groups [39/65 (60.0%) vs. 41/68 (60.3%), p = 0.887]. The implantation rate (47.6% vs. 45.3%, p = 0.713), early pregnancy loss rate (5.1% vs. 19.5%, p = 0.09), and live birth rate (49.2% vs. 50.0%, p = 0.920) were also comparable between groups. Conclusion: Pretreatment with GnRHa does not improve the reproductive outcomes for women receiving HRT-FET. Clinical Trial Registration: The study was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-17014170; http://www.chictr.org.cn).