Preventing recurrence of endometriosis-related pain by means of long-acting progestogen therapy: the PRE-EMPT RCT.

Background: Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. Objectives: To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. Design: A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women's lived experience of endometriosis and a pretrial economic model. Setting: Thirty-four United Kingdom hospitals. Participants: Women of reproductive age undergoing conservative surgery for endometriosis. Interventions: Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). Main outcome measures: The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Results: Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: -0.8, 95% confidence interval -5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval -0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. Limitations: Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. Conclusions: At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. Future work: Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Trial registration: This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word 'woman' is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary.

Endometriosis is a condition where cells similar to ones that line the womb are found elsewhere in the body. Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Unfortunately, symptoms often return and some women will need repeat operations. Hormonal contraceptives can prevent the return of endometriosis-related pain: either long-acting reversible contraceptives (injections or a coil, fitted inside the womb) or the combined oral contraceptive pill (often called 'the pill'). We do not know which is the best option. The aim of this trial was to find out which of these two hormone treatments was more effective in terms of symptom relief, avoidance of further surgery and costs. Four hundred and five women with endometriosis, who were not intending to get pregnant, participated in a clinical trial. Half of the participants took long-acting reversible contraceptives, and the other half took the pill for 3 years following endometriosis surgery. The choice of treatment was made at random by a computer to ensure a fair comparison, although those allocated to the long-acting contraceptive could choose between injections or the coil. Participants completed questionnaires about their symptoms and life quality at intervals up to 3 years. Both treatments were equally good at reducing pain but more women using the pill had repeat operations. The pill was a little more costly overall but associated with a slightly higher quality of life. Both treatments are equally effective in reducing pain up to 3 years after surgery for endometriosis. The differences in costs are small and the choice of treatment should be based on personal preference.

Comparing the outcomes of in-vitro fertilization in patients receiving vaginal, subcutaneous, and intramuscular progesterone for luteal phase support: a three-armed randomized controlled trial.

BACKGROUND: The optimal approach to luteal-phase support in infertility treatment remains a subject of debate. This study was conducted to investigate the clinical outcomes, side effects, and patient satisfaction associated with vaginal, subcutaneous, and intramuscular progesterone administration in infertile women undergoing Frozen Embryo Transfer (FET). METHODS: This three-armed randomized clinical trial assigned infertile patients eligible for FET to three progesterone treatment groups: vaginal suppositories (400 mg twice daily; n = 100), subcutaneous injections (25 mg daily; n = 102), and intramuscular injections (50 mg daily; n = 108). The primary outcomes were chemical and clinical pregnancy rates per embryo transfer cycle, with chemical pregnancy defined as beta-human chorionic gonadotropin levels > 50 IU/mL two weeks post-transfer and clinical pregnancy confirmed by ultrasound four weeks later. Exploratory outcomes included progesterone-related adverse effects and participant satisfaction, assessed via a Likert-scale survey 12 weeks post-transfer. Statistical analyses included Chi-square tests for categorical data, one-way analysis of variances, and Kruskal-Wallis tests for continuous data. RESULTS: The intramuscular progesterone group had significantly higher chemical pregnancy rates compared to the vaginal and subcutaneous groups (41.7% vs. 26.0% and 27.5%, respectively; p = 0.026). Although the clinical pregnancy rate was also higher in the intramuscular group (32.4%) compared to the vaginal (23.0%) and subcutaneous groups (21.6%), this difference was not statistically significant (p = 0.148). Additionally, patient satisfaction was greater with vaginal and subcutaneous applications than with intramuscular injections (p < 0.001), likely due to a significantly higher incidence of side effects, such as pain and edema at the injection site, in the intramuscular group (p < 0.001). CONCLUSIONS: We found that intramuscular progesterone resulted in higher chemical pregnancy rates than vaginal or subcutaneous routes, but this did not translate into higher clinical pregnancy rates. Despite its effectiveness, intramuscular administration was associated with more adverse effects and lower patient satisfaction. Future research should explore optimizing progesterone regimens to balance efficacy and patient comfort. TRIAL REGISTRATION: The trial protocol was registered on December 6, 2020, in the Iranian Registry of Clinical Trials (IRCT), a primary registry in the World Health Organization (WHO) Registry Network, under the registration number IRCT20141217020351N12.

Comparative effects of different treatments based on the levonorgestrel intrauterine system in endometrial carcinoma and endometrial hyperplasia patients: a network meta-analysis.

OBJECTIVE: Levonorgestrel intrauterine system (LNG-IUS) has been widely used in patients with endometrial carcinoma (EC), endometrial hyperplasia without atypical (EH), and atypical endometrial hyperplasia (AEH). The purpose of our Network meta-analysis (NMA) is to evaluate the efficacy of the treatments based on the LNG-IUS in patients with EC and EH with or without atypical. METHODS: We examined PubMed, EMBASE, Web of Science and the Cochrane Library up to 22 April 2024 to determine studies reporting treatment outcomes in EC and EH patients receiving LNG-IUS therapy, LNG-IUS + metformin (MET), oral progestins (OP), etc. We used EndNote 9 to select studies, Jadad scale and NOS scale to assess quality, stata(16.0) and R (4.3.1) to analysis the data. RESULTS: Overall, 28 studies involving 3752 patients were included in our NMA. As for EH patients, LNG-IUS (RR 1.21; 95% CrI [1.11, 1.34]) and LNG-IUS + MET (RR 323.57; 95% CrI [1.61, 214,223,188.1])] significantly increased CR rate in comparison with OP. Based on SUCRA, LNG-IUS + OP was the best treatment to improve CR(SUCRA = 67.2%) in patients with EC, whereas LNG-IUS + MET was superior in increasing CR (SUCRA = 99.8%) than any other treatments for EH patients. Besides, the ranking based on SUCRA illustrated that LNG-IUS alone was the best choice to raise CR rates (SUCRA = 76.7%) for AEH patients. In head-to-head meta-analysis, OP has a higher progression rate (RR 4, 95% CI 1.89-8.46, p = 0.062; I2 = 71.3%), a higher nausea rate (RR 1.93, 95% CI 1.24-3.01, p = 0.187; I2 = 40.4%) than LNG-IUS in patients with EH. In contrast, LNG-IUS had a irregular vaginal bleeding rates (RR 0.76, 95% CI 0.64-0.90, p = 0.034; I2 = 77.7%) than OP in EH patients. In addition, as for AEH patients, OP has a higher persistence rate (RR 4.31, 95% CI 1.43-13.00, p = 0.93; I2 = 0.0%) than LNG-IUS. CONCLUSION: According to the NMA, LNG-IUS related studies are feasible for conservative therapy in patients with EC and EH with or without atypical. Therefore, concerning the curative effect, we recommend LNG-IUS-based treatments as the best conservative therapy for EC and EH patients. However, future studies require large sample sizes and more outcomes to further evaluate the differences of treatment selections based on LNG-IUS.

Progestin-primed ovarian stimulation with letrozole using different doses of medroxyprogesterone acetate per day: a retrospective cohort study.

Background: In the progestin-primed ovarian stimulation protocol, the oral administration of medroxyprogesterone acetate has been observed to effectively inhibit the LH surge during ovarian stimulation in patients experiencing infertility. Nevertheless, the use of utilizing medroxyprogesterone acetate during ovarian stimulation can result in more pronounced pituitary suppression, potentially necessitating increased doses of gonadotropins and extended treatment durations. Therefore, it is necessary to determine the optimal dose of medroxyprogesterone acetate, aiming to use relatively lower concentrations of medroxyprogesterone acetate to effectively and safely suppress early LH surges. Method: This retrospective cohort study included 710 patients who underwent cycles of in vitro fertilization or intracytoplasmic sperm injection and were subjected the progestin-primed ovarian stimulation protocol utilizing letrozole between from 1st January 2021 to 31st December 2021. The study population was divided into low, medium, and high concentration groups based on the daily dosage of medroxyprogesterone acetate.The primary focus of this investigation was on the cumulative live birth rate. Secondary outcomes encompassed the occurrence of a premature surge in luteinizing hormone, the quantity of retrieved oocytes, viable embryos, and high-quality embryos, as well as clinical pregnancy rate, abortion rate, ectopic pregnancy rate, and multiple pregnancy rate. Results: In this study, significant differences were observed among three groups in various parameters including body mass index, baseline levels of Anti-Müllerian hormone and luteinizing hormone, antral follicle count, total dose of gonadotropin, and duration of gonadotropin administration (p<0.05). The number of oocytes and viable embryos were significantly higher in medium group and higher than those in the low dose group. Following adjustments for confounding factors related to medroxyprogesterone acetate for various outcome measures, we conducted multiple regression analysis to investigate the independent effects of daily medroxyprogesterone acetate dosage within the combined progestin-primed ovarian stimulation and letrozole protocol. Following multivariable regression analysis, no disparities were found in embryo characteristics (number of oocytes retrieved, number of available embryos, number of high-quality embryos) or pregnancy outcomes (clinical pregnancy rate, cumulative live birth rate) among the three groups. Conclusion: Progestin-primed ovarian stimulation with letrozole using different dose of medroxyprogesterone acetate per day was comparable in terms of the number of oocytes retrieved, the number of high-quality embryos, clinical pregnancy rate and cumulative live birth rate after frozen embryo transfer.

Vaginal Progesterone for Pregnancy Prolongation After Arrested Preterm Labor: A Randomized Clinical Trial.

Importance: Women with arrested preterm labor (APTL) are at very high risk for spontaneous preterm delivery (SPTD), the leading cause of neonatal mortality and morbidity. To date, no maintenance therapy has been found to be effective for pregnancy prolongation. A few clinical trials with considerable methodological limitations have demonstrated some efficacy for 400 mg vaginal micronized progesterone (VMP) in women with APTL. Objective: To investigate the effectiveness of daily 400 mg VMP for the prolongation of pregnancy after APTL. Design, Setting, and Participants: This randomized clinical trial was conducted between December 19, 2018, and February 27, 2023, in 3 university-affiliated medical centers in Israel. Participants included women with singleton and twin pregnancies after APTL following tocolysis at 24 weeks 0 days to 34 weeks 0 days' gestation. Women with a history of preterm delivery or asymptomatic cervical shortening in the current pregnancy were excluded. Interventions: Participants were randomly allocated to receive VMP 200 mg twice a day or no treatment until 36 weeks 6 days' gestation. Main Outcomes and Measures: The primary end points were mean number of days from study enrollment to delivery and the rate of SPTD prior to 37 weeks' gestation. Results: A total of 129 participants were enrolled (65 in the VMP group and 64 in the no-treatment group). Mean (SD) age was 27.6 (5.1) years. Between the VMP and no-treatment groups, there was no difference in pregnancy prolongation (mean [SD], 40.0 [17.8] vs 37.4 [20.3] days; P = .44) and the rate of SPTD (16 [25%] vs 19 [30%]; relative risk, 0.8; 95% CI, 0.5-1.5; P = .52). In twin pregnancies, including 12 and 15 pairs in the VMP and no-treatment groups, respectively, VMP prolonged pregnancy (mean [SD], 43.7 [18.1] vs 26.1 [15.2] days; P = .02), postponed the delivery week (36.5 [1.4] vs 34.7 [2.2] weeks; P = .01), shortened the length of stay in the neonatal intensive care unit (4.9 [10.6] vs 13.2 [18.5] days; P = .03) and overall hospital stay (8.3 [9.6] vs 15.1 [17.2] days; P = .03), and was associated with a higher birth weight (2444 [528] vs 2018 [430] g; P = .01). Conclusions and Relevance: These findings show that VMP given in a dosage of 200 mg twice a day following APTL is not an effective treatment to prolong pregnancy or prevent SPTD. However, VMP demonstrated beneficial effects in twin pregnancies, warranting further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02430233.

Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis.

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

Rectal versus vaginal progesterone administration for luteal phase support in the hormone replacement therapy frozen embryo transfer (HRT-FET) cycle: protocol for a non-inferiority randomised controlled trial.

INTRODUCTION: This study compares rectal administration with vaginal administration of progesterone as luteal phase support in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles. The reason for comparing the two routes of administration is that rectal administration has been suggested to be more patient friendly. METHODS AND ANALYSIS: This study is a randomised controlled trial comparing the ongoing pregnancy rate (OPR) at week 12 in HRT-FET cycles after rectal administered progesterone as the only administered progesterone compared with a vaginal luteal phase support regimen. All patients are enrolled from a Danish public fertility clinic and randomised to one of two groups, with 305 patients receiving embryo transfer assigned to each group. Endometrial preparation includes 6 mg oestradiol daily. The intervention group receives rectally administered progesterone (400 mg/12 hours) and the control group receives vaginally administered progesterone (400 mg/12 hours). If P4 is <35 nmol/L on blastocyst transfer day an additional rectal luteal phase rescue regimen is started (control group). Thawing and transferring of a single autologous vitrified blastocyst is scheduled on the sixth day of progesterone administration in both groups. The power calculation is based on a non-inferiority analysis with an expected OPR in both groups of 44% and the upper limit of a one-sided 95% CI will exclude a difference in favour of the control group of more than 10.0%. An interim analysis will be conducted once half of the study population has been enrolled. ETHICS AND DISSEMINATION: The trial was approved on 21 November 2023 by the Danish National Ethical Committee and the Danish Medicines Agency and is authorised by the Clinical Trials Information System (EUCT number 2023-504616-15-02). All patients will provide informed consent before being enrolled in the study. The results will be published in an international journal. TRIAL REGISTRATION NUMBER: EUCT number: 2023-504616-15-02.

Effect of progestin-based contraceptives on HIV-associated vaginal immune biomarkers and microbiome in adolescent girls.

Adolescent girls bear a disproportionate burden of both the HIV epidemic and unintended pregnancies; yet important questions remain unanswered regarding the effects of hormonal contraceptives on the vaginal immune microenvironment, which can impact HIV susceptibility in this group. Multiple studies report genital immune alterations associated with the progestin-based contraceptive Depot medroxyprogesterone acetate (DMPA) in adult women, but there is little available data in adolescents. The objective of this longitudinal cohort study was to evaluate the effects of short-term use of three progestin-based contraceptives, levonorgestrel intrauterine device (LNG-IUD), subdermal etonogestrel (ETNG), and injectable DMPA, on HIV-associated vaginal immune biomarkers and microbiome in adolescent girls. Fifty-nine sexually active, HIV-uninfected girls aged 15-19, were recruited from the Washington DC metro area and self-selected into Control (condoms only), combined oral contraceptive pills, LNG-IUD, ETNG and DMPA groups. Vaginal swabs were collected at baseline prior to contraceptive use and at 3-month follow-up visit. Vaginal secretions were tested for pro-inflammatory (IL-1α, IL-1ß, TNF-α, IL-6, IL-8, MIP-3α, IP-10, RANTES, MIP-1α, MIP-1ß) and anti-inflammatory/anti-HIV (Serpin-A1, Elafin, Beta-Defensin-2, SLPI) immune biomarkers using ELISA and for anti-HIV activity using TZM-bl assay. Vaginal microbiome was evaluated using 16S rRNA gene sequencing. Data were analyzed using SAS Version 9. Among the 34 participants who completed both visits, no significant changes in median biomarker concentrations, HIV inhibition and microbiome composition were observed between baseline and follow-up visits for any of the contraceptive groups. IL-8 (p<0.01), MIP-3α (0.02), Elafin (p = 0.03) and RANTES (p<0.01) differed significantly by race whereas IL-6 was significantly different by age (p = 0.03). We conclude that 3-month use of LNG-IUD, ETNG and DMPA have minimal effects on adolescent vaginal immune microenvironment, and therefore unlikely to impact HIV risk. Future studies with larger sample size and longer follow-up are recommended to continue to evaluate effects of contraceptives on the lower genital tract immunity and susceptibility to sexually transmitted infections.

Fertility-sparing re-treatment for endometrial cancer and atypical endometrial hyperplasia patients with progestin-resistance: a retrospective analysis of 61 cases.

OBJECTIVE: This study aimed to evaluate the oncological and reproductive outcomes of fertility-preserving re-treatment in progestin-resistant endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) women who desire to maintain their fertility. METHODS: Our study included 61 progestin-resistant EC/AEH patients. These patients underwent treatment with gonadotropin-releasing hormone agonist (GnRHa) solely or a combination of GnRHa with levonorgestrel-releasing intrauterine system (LNG-IUD) or aromatase inhibitor (AI). Histological evaluations were performed every 3-4 months. Upon achieving complete remission (CR), we recommended maintenance treatments including LNG-IUD, cyclical oral contraceptives, or low-dose cyclic progestin until they began attempting conception. Regular follow-up was conducted for all patients. The chi-square method was utilized to compare oncological and fertility outcomes, while the Cox proportional hazards regression analysis helped identify risk factors for CR, recurrence, and pregnancy. RESULTS: Overall, 55 (90.2%) patients achieved CR, including 90.9% of AEH patients and 89.7% of EC patients. The median re-treatment time was 6 months (ranging from 3 to 12 months). The CR rate for GnRHa alone, GnRHa + LNG-IUD and GnRHa + AI were 80.0%, 91.7% and 93.3%, respectively. After a median follow-up period of 36 months (ranging from 3 to 96 months), 19 women (34.5%) experienced recurrence, 40.0% in AEH and 31.4% in EC patients, with the median recurrence time of 23 months (ranging from 6 to 77 months). Among the patients who achieved CR, 39 expressed a desire to conceive, 20 (51.3%) became pregnant, 11 (28.2%) had successfully deliveries, 1 (5.1%) was still pregnant, while 8 (20.5%) suffered miscarriages. CONCLUSION: GnRHa-based fertility-sparing treatment exhibited promising oncological and reproductive outcomes for progestin-resistant patients. Future larger multi-institutional studies are necessary to confirm these findings.

Prophylactic progesterone and preterm birth.

This review summarises the present knowledge of prophylactic progesterone and preterm birth. Preterm birth (less-than 37 weeks) is a leading cause of neonatal mortality and morbidity worldwide. The incidence varies globally but remains low in the Nordic countries (5-6%). Prediction and prevention are complicated due to diverse aetiology, but obstetric history and cervical length can improve prediction. Prophylactic vaginal progesterone initiated between 12 and 24 weeks of gestation is recommended to reduce preterm birth less-than 33-35 weeks in singleton pregnancies with a history of preterm birth or with a short cervix (less-than 25 mm) and can be considered for twin pregnancies with the same risk factors.

Benefit from luteal phase progestin primed ovarian stimulation with clomiphene citrate supplementation in young women with diminished ovarian reserve: a retrospective study. / å¹´è½»åµå·¢å‚¨å¤‡åŠŸèƒ½å‡é€€æ‚£è€ åµæ³¡æœŸä¸Žé»„ä½“æœŸåº”ç”¨é«˜å­•æ¿€ç´ çŠ¶æ€è¶ ä¿ƒæŽ’åµæ–¹æ¡ˆæ•ˆæžœæ¯”è¾ƒ.

OBJECTIVES: To compare the pregnancy outcomes of luteal phase and follicular phase progestin-primed ovarian stimulation protocol with clomiphene citrate supplementation (LPPOS+CC and FPPOS+CC) in young women with diminished ovarian reserve (DOR). METHODS: A total of 483 women aged ≤35 years with DOR, who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)/embryo transfer (ET) with controlled ovarian stimulation using LPPOS+CC (n=257) or FPPOS+CC (n=226) protocols during June 2018 and December 2021 at the First Affiliated Hospital of Wenzhou Medical University, were included in this retrospective study. The baseline characteristics, superovulation results, laboratory related indicators between the two groups, and the pregnancy outcomes of women who achieved at least one high-quality cleavage-stage embryo or good-morphology blastocyst were compared between the two groups. RESULTS: No statistically significant differences were identified between the groups with respect to age, duration of infertility, proportion of secondary infertility, previous failed cycles, body mass index, anti-Müllerian hormone, antral follicle count, basal luteinizing hormone level, basal progesterone level, number of oocytes retrieved, oocyte maturation rate, high-quality cleavage-stage embryo cycle rate, the percentage of women with profound pituitary suppression, live birth rate and preterm birth rate (all P>0.05). The LH levels on the day of trigger [4.0 (2.7, 5.3) vs. 5.1 (3.2, 7.2) IU/L], the percentage of women with LH levels of >10 IU/L on the trigger day (3.13% vs. 10.67%), and the two pronucleus (2PN) rate of ICSI oocytes (72.16% vs. 79.56%) were significantly lower in the LPPOS+CC group than those in the FPPOS+CC group (P<0.05 or P<0.01). The duration of stimulation [11 (9, 12) vs. 9 (8, 11) d], the consumption of total gonadotropin [2213 (1650, 2700) vs. 2000 (1575, 2325) IU], the progesterone levels on the day of trigger [1.3 (0.8, 2.9) vs. 0.9 (0.6, 1.2) ng/mL], the clinical pregnancy rate [61.88% vs. 46.84%], and implantation rate [42.20% vs. 31.07%] in the LPPOS+CC group were significantly higher than those in the FPPOS+CC group (all P<0.01). CONCLUSIONS: Compared to FPPOS+CC, the LPPOS+CC protocol appears to have better pregnancy outcomes for young women with DOR undergoing IVF/ICSI-ET.

Menopausal hormone therapy and breast cancer risk: a population-based cohort study of 1.3 million women in Norway.

BACKGROUND: It is important to monitor the association between menopausal hormone therapy (HT) use and breast cancer (BC) risk with contemporary estimates, and specifically focus on HT types and new drugs. METHODS: We estimated hazard ratios (HR) of BC risk according to HT type, administration route and individual drugs, overall and stratified by body mass index (BMI), molecular subtype and detection mode, with non-HT use as reference. RESULTS: We included 1,275,783 women, 45+ years, followed from 2004, for a median of 12.7 years. Oral oestrogen combined with daily progestin was associated with the highest risk of BC (HR 2.42, 95% confidence interval (CI) 2.31-2.54), with drug-specific HRs ranging from Cliovelle®: 1.63 (95% CI 1.35-1.96) to Kliogest®: 2.67 (2.37-3.00). Vaginal oestradiol was not associated with BC risk. HT use was more strongly associated with luminal A cancer (HR 1.97, 95% CI 1.86-2.09) than other molecular subtypes, and more strongly with interval (HR 2.00, 95% CI: 1.83-2.30) than screen-detected (HR 1.33, 95% CI 1.26-1.41) BC in women 50-71 years. HRs for HT use decreased with increasing BMI. CONCLUSIONS: The use of oral and transdermal HT was associated with an increased risk of BC. The associations varied according to HT type, individual drugs, molecular subtype, detection mode and BMI.

PREVALENCE OF PRETERM DELIVERY AMONG WOMEN WHO RECEIVE PROGESTERONE SUPPLEMENTATION DURING PREGNANCY: CROSS-SECTIONAL OBSERVATIONAL STUDY.

Preterm birth (PTB) is defined as birth before 37 completed weeks of gestation. It is generally agreed, preterm delivery is the most important obstetrical complication leading to perinatal morbidity and mortality. The aim of this study is to assess the prevalence of progesterone prescription, the route of administration, the prevalence of PTB, and the route of delivery as well as to look at the rates of PTB among those who received progesterone and those who did not. An observational cross-sectional study among postpartum women was done between April and September 2023. A convenience sample of 300 women were interviewed at maternity hospitals and primary health centers in Duhok. A survey of postpartum women up to 1 year postpartum was completed. Patients were questioned about basic pregnancy information, risk factors, and complications, as well as the use (if any) of progesterone. The preterm birth (<37 week) rate is 12%. From the 300 patients in the sample, 114 (38%) women had history of single or multiple progesterone therapies. The most common single route of progesterone therapy was the parenteral route (29.8%), but more patients received progesterone via multiple routes (32.4%). Pre-term birth was reported in 19 women who received progesterone treatment compared to 17 women among those who did not receive progesterone treatment. No statistically significant variations were found between the two groups (P=0.08). There were no statistically significant differences in prevalence of PTB or route of delivery between women who received progesterone supplementation and those who did not receive progesterone (P=0.08 and P= 0.14 respectively). Prior research has shown that the clearest evidence of benefit for progesterone in pregnancy is among those with short cervix. Perhaps the lack of significant difference found in this study was because of prescriptions outside of established indications. More randomized controlled trials are needed to assess the effects of progesterone supplementation during pregnancy.

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

Cerclage Plus Adjuvant Vaginal Progesterone for Preterm Birth Prevention in Patients with a Short or Dilated Cervix without Prior Preterm Birth.

OBJECTIVE: The primary objective was to determine if vaginal progesterone following cerclage for cervical length <10 mm or cervical dilation in patients without a history of spontaneous preterm birth (sPTB) decreased the risk of preterm birth at <34 weeks' gestation compared with cerclage alone. Secondary objectives were to determine if vaginal progesterone following cerclage (1) decreased the risk of preterm birth at <24, <28, and <37 weeks' gestation and (2) increased the latency period from cerclage placement to delivery compared with treatment with cerclage alone. STUDY DESIGN: Multicenter retrospective cohort study from 2015 to 2020 of singleton pregnancies, without prior sPTB, who had cerclage placement <24 weeks' gestation for cervical length <10 mm or cervical dilation. Exposure defined as cerclage plus vaginal progesterone postoperatively (dual therapy) and unexposed as cerclage alone (monotherapy), based on surgeon preference. RESULTS: We included 122 patients, 78 (64%) treated with dual therapy and 44 (36%) treated with monotherapy. In the crude analysis, dual therapy was associated with a lower risk of delivery at <28 weeks' gestation (13%) compared with monotherapy (34%; crude risk ratio: 0.38 [95% confidence interval (CI): 0.19-0.75]). When adjusted for preoperative vaginal progesterone, results were attenuated (adjusted risk ratio: 0.45 [95% CI: 0.20-1.01]). In both the crude and adjusted analyses, the risk of sPTB was not statistically different at <24, <34 or <37 weeks' gestation. Dual therapy was associated with a greater pregnancy latency from cerclage to delivery (16.3 vs. 14.4 weeks; p = 0.04), and greater gestational age at delivery (37.3 vs. 35.8 weeks' gestation; p = 0.02) compared with monotherapy. CONCLUSION: While not statistically significant, the risk of sPTB was lower at all gestational ages studied in patients treated with dual therapy compared with monotherapy. Dual therapy was associated with longer pregnancy latency and greater gestational age at delivery compared with monotherapy. KEY POINTS: · Dual therapy did not decrease preterm birth risk compared with monotherapy.. · Dual therapy prolonged pregnancy compared with monotherapy.. · Dual therapy can be considered but further studies are needed..

The hormonal profile in women using combined monophasic oral contraceptive pills varies across the pill cycle: a temporal analysis of serum endogenous and exogenous hormones using liquid chromatography with tandem mass spectroscopy.

Oral contraceptive pills, of all types, are used by approximately 151 million women worldwide; however, a clear understanding of the concentrations of endogenous and exogenous hormones across a 28-day combination monophasic oral contraceptive pill pack is not well described. In our study of 14 female participants taking various combination monophasic oral contraceptive pills, we found significant fluctuations in endogenous and exogenous hormone levels throughout the pill cycle. Our analysis revealed significantly greater levels of ethinyl estradiol on the 20th and 21st days of active pill ingestion, compared with days 1-2 (active) and days 27-28 (inactive pill ingestion). Conversely, estradiol concentrations decreased during active pill consumption, while progestin and progesterone levels remained stable. During the 7 days of inactive pill ingestion, estradiol levels rose sharply and were significantly higher at days 27-28 compared with the mid and late active phase time points, while ethinyl estradiol declined and progestin did not change. These findings challenge the previous assumption that endogenous and exogenous hormones are stable throughout the 28-day pill cycle.NEW & NOTEWORTHY The results from this study have wide-ranging implications for research and treatment in women's health including considerations in research design and interpretation for studies including women taking oral contraceptives, the potential for more precise and personalized methods of dosing to reduce unwanted side effects and adverse events, and the potential treatment of a variety of disorders ranging from musculoskeletal to neurological with exogenous hormones.

Effect of medroxyprogesterone acetate dose in progestin-primed ovarian stimulation on pregnancy outcomes in poor ovarian response patients with different body mass index levels.

Background: For the poor ovarian response (POR) population, the relationship between medroxyprogesterone acetate (MPA) dose in progestin-primed ovarian stimulation (PPOS) and clinical outcome is still unclear. This study aims to explore the effect of MPA dose in PPOS on clinical outcomes in POSEIDON group 3 and 4 patients with different body mass index (BMI) levels, hoping to provide clinical doctors with better options for controlled ovarian hyperstimulation (COH) programs. Methods: This is a retrospective analysis of 253 oocyte retrieval cycles of POSEIDON group 3 and 4 patients who underwent PPOS protocol in IVF/ICSI treatment at the Reproductive Medical Center of Renmin Hospital of Wuhan University from March 2019 to April 2022. The effects of different MPA doses (8 mg/d or 10 mg/d) on pregnancy outcomes were compared in normal BMI (18.5-24 kg/m2) and high BMI (≥24 kg/m2) patients, and multivariate logistic regression analysis was performed to analyze the factors affecting pregnancy outcomes. Results: For normal BMI patients, the 8-mg/d MPA group had a higher embryo implantation rate (33.78% vs. 18.97%, P = 0.012). For high BMI patients, the 10-mg/d MPA group had a higher HCG positive rate (55.00% vs. 25.00%, P = 0.028), clinical pregnancy rate (50.00% vs. 20.00%, P = 0.025), and cumulative pregnancy rate (37.74% vs. 13.79%, P = 0.023) compared with the 8-mg/d MPA group. There was no significant difference in cumulative live birth rate between the 8-mg/d and 10-mg/d MPA groups in patients with normal or high BMI. The results of multivariate logistic regression showed a significant correlation between MPA dose and cumulative pregnancy in the high BMI population (OR = 0.199, 95% CI: 0.046~0.861, P = 0.031). Conclusions: For POR patients with high BMI, 10 mg/d of MPA in the PPOS protocol had a higher cumulative pregnancy rate than 8 mg/d of MPA, but it had no significant effect on the cumulative live birth rate.

Cervical elastography in predicting spontaneous preterm birth in singleton pregnancy with a short cervix receiving progesterone treatment at 18 to 24 weeks' gestation.

BACKGROUND: A short cervix in the second trimester is known to increase the risk of preterm birth, which can be reduced with the administration of vaginal progesterone. However, some studies have suggested that a significant number of cases still experience preterm birth despite progesterone treatment. OBJECTIVE: This study was aimed to investigate the potential value of transvaginal cervical elasticity measured by E-Cervix as a predictor for spontaneous preterm birth (sPTB) in singleton pregnancies receiving progesterone treatment for a short cervix (CL ≤ 2.5 cm) diagnosed at 18 to 24 weeks' gestation. STUDY DESIGN: This prospective study was conducted at a single center premature high-risk clinic from January 2020 to July 2022. Singleton pregnancies with a short cervix at 18 to 24 weeks' gestation were enrolled. Cervical elastography using E-Cervix was performed, and maternal and neonatal demographic characteristics, cervical length (CL), elasticity contrast index (ECI), cervical hardness ratio, mean internal os strain (IOS), and mean external os strain (EOS) were compared before and after progesterone treatment in sPTB and term birth groups. Multivariate logistic regression was used to analyze the association between elasticity parameters and spontaneous preterm birth. The screening performance of CL and optimal cervical elasticity parameters in predicting sPTB was evaluated using receiver-operating characteristic (ROC) curve analysis. RESULTS: A total of 228 singleton pregnant women were included in the study, among which 26 (11.4%) had sPTB. There were no significant differences in maternal characteristics and gestational age at enrollment between women with and without sPTB. At the start of progesterone treatment, there were no significant differences in cervical elasticity parameters between the two groups. After two weeks of progesterone treatment, women who had sPTB showed significantly higher levels of ECI, IOS, EOS (p = 0.0108, 0.0001, 0.016), and lower hardness ratio (p = 0.011) compared to those who had a full-term birth. Cervical length did not show significant differences between the two groups, regardless of whether progesterone treatment was administered before or after. Among the post-treatment cervical elasticity parameters, IOS and EOS were associated with a 3.38-fold and 2.29-fold increase in the risk of sPTB before 37 weeks (p = 0.032, 0.047, respectively). The AUROC of the combined model including CL, IOS, and EOS (0.761, 95% CI0.589-0.833) was significantly higher than the AUROC of CL alone (0.618, 95% CI 0.359-0.876). At a fixed false-positive of 13%, the addition of IOS and EOS in the CL model increased sensitivity from 34.6% to 57.6%, PPV from 25.7% to 36.5%, and NPV from 91.1% to 94.1%. CONCLUSION: When assessing the risk of sPTB in singleton pregnancies with a short cervix receiving progesterone therapy, relying solely on cervical length is insufficient. It is crucial to also evaluate cervical stiffness, particularly the strain of the internal and external os, using cervical elastography.

Comparison of the pregnancy outcomes of progestin-primed vs. antagonist ovarian stimulation in patients with poor ovarian response: a retrospective study.

OBJECTIVES: Progestin-primed ovarian stimulation (PPOS) is an efficient controlled ovarian stimulation (COS) method. The study explored the pregnancy outcomes between PPOS and antagonist ovarian stimulation protocol (GnRH-ant) in infertile patients with poor ovarian response (POR). METHODS: This retrospective study included patients with POR who underwent COS at the Reproductive Medical Center of Shanxi Maternal and Child Health Hospital from January 2021 to April 2022. The cycles were grouped as the GnRH-ant group and the PPOS group. The primary outcome was the clinical pregnancy rate; the secondary outcomes included the biochemical pregnancy abortion rate and live birth rate. RESULTS: Frozen embryo transfer was used in all cycles in this study. The cycles were divided into the GnRH-ant (n = 236 cycles) and PPOS (n = 273 cycles) groups. Age, BMI, type of infertility, infertility duration, FSH, LH, PRL, E2, T, P, and the number of cycles in the hospital were similar between the two groups (all p > 0.05). No statistically significant differences were observed in the clinical pregnancy rate (primary outcome, 32.71% vs. 43.90%, p = 0.082), total Gn dose, total Gn days, ART mode (IVF or ICSI), AFC, MII follicles, 2PN embryos, fertility, cycle cancelation rate, biochemical pregnancy rate, abortion rate, or live birth rate between the two groups (all p > 0.05). The PPOS group exhibited a higher rate of high-quality embryos than the GnRH-ant group (50.12% vs. 42.90%, p = 0.045). CONCLUSIONS: The PPOS protocol was comparable to the GnRH-ant protocol regarding induction parameters and cycle cancelation, biochemical pregnancy, clinical pregnancy, and abortion rates but might be associated with a higher proportion of high-quality embryos.