Low Progesterone Levels Research Articles

#129 : The Ratio of Luteal Phase Serum Progesterone and Estradiol Can be Used to Predict Pregnancy in Frozen Embryo Transfer Cycles

Background and Aims: Low serum progesterone (P) levels on day of embryo transfer (ET) and luteal phase have been associated with poorer pregnancy outcome. This study aimed to know if serum estradiol (E2) and P levels during mid and late luteal phase are related with ongoing pregnancy. Method: The serum E2 and P levels from mid luteal phase (5 days after ET) to the day of the [Formula: see text]-hCG check (11 days after ET) in both fresh and frozen embryo transfer (FET) cycles was investigated between January 2019 and December 2021. Eligible patients were reproductive aged women with a normal uterus. Single blastocyst transfer cycles were included. Estradiol valerate (2 mg/bid) was started from day 3 of cycle as hormone replacement and vaginal micronized P (400 mg/bid) was started 5 days before ET in all FET cycles. The 2-degree polynomial fitted data were analysed and logistic linear model and ROC analysis were performed to assess E2 and P4 polynomial coefficients as a predictive test for ongoing pregnancy. Results: A total of 388 patients were included. The overall pregnancy rate was 43.8% and 31.3% for FET and fresh ET, respectively. On day 5 post ET, the serum P levels correlated significantly with ongoing pregnancy and live birth rates, especially in FET cycles. The ROC curve showed that there is a significant day 5 post ET predictive value of serum P4/E2 levels for pregnancy rate, being the AUC (95% CI) = 0.596 (0.539–0.653) for the combination of both fresh and FET cycles; and 0.611 (0.548–0.674) for FET cycles, with best cut-off values of 0.079 and 0.077, respectively. Conclusion: Serum P levels in mid and late luteal phase days are associated with pregnancy outcome both in fresh and frozen ET cycles. Ongoing pregnancies can be predicted using the day 5 post ET serum P4/E2 levels.

Initiating luteal phase support with sc progesterone based on low serum progesterone on the transfer day in true natural cycle frozen embryo transfers.

Concerning contemporary in-vitro fertilisation (IVF) practice, the use of frozen embryo transfer (FET) cycles has become more common than fresh transfers. Natural cycle (NC), programmed artificial cycle and mild stimulation cycle are primary endometrium preparation cycles. Monitoring serum progesterone levels in FET cycles are in the scope of current research focus. Low progesterone levels on the day of embryo transfer is presumed to negatively affect pregnancy outcomes, while progesterone supplementation may improve pregnancy rates. The purpose of our trial is to evaluate whether initiating subcutaneous (SC) progesterone supplementation on the day of embryo transfer when serum progesterone levels are below 10 ng/mL in tNC-FET will result in pregnancy rates comparable to those of patients with sufficient serum progesterone. Retrospective single centre study was conducted between August 2022 and April 2023 with 181 tNC-FETs. Patients were separated into groups according to serum progesterone concentrations (≥10 ng/mL and <10 ng/mL) on embryo transfer (ET) day. S.c progesterone (25 mg) was given on the day of ET when serum progesterone was <10 ng/mL, continuing until the 10th gestational week. Blood samples for pregnancy tests were collected 12 days after ET. Outcome parameters were pregnancy rate, clinical pregnancy rate (CPR), miscarriage rate, multiple pregnancy rate, biochemical pregnancy, and ongoing pregnancy rate (OPR). About half (49.7%) had adequate progesterone concentrations (≥10ng/mL) on ET day. There was no significant difference between the groups regarding positive pregnancy test, OPR, multiple pregnancies, and miscarriage rates (57.8% versus 52.7%; 34.4% versus 29.7%, 1.1% versus 2.2%; 7.8% versus 5.5%; respectively, for progesterone concentrations on ET day ≥10 ng/mL and <10 ng/mL). With 55.2% of transfers leading to clinical pregnancy, significant differences emerged in biochemical pregnancy and CPR (3.3% vs 12.1%, P=0.02; 54.4% vs 40.7%, P=0.03, for ≥10 ng/mL and <10 ng/mL progesterone concentrations on ET day). This study indicates that nearly half of the tNC-FETs may need luteal phase support due to low progesterone. However, 25 mc sc progesterone rescued the luteal support and yielded similar OPR as compared to normal progesterone group. Further studies are needed for understanding optimal progesterone levels, supplementation effectiveness, and potential benefits of earlier supplementation in FETs.

Preliminary evidence of increased alcohol use associated with ethinyl estradiol levels in women using oral contraceptives

Alcohol use is highly prevalent in young adult women and rates of alcohol use disorder are rising rapidly in this population. Further, emerging evidence suggests that circulating levels of ovarian hormones influence alcohol consumption, with increased consumption associated with higher estradiol and lower progesterone levels. However, less is known about the influence of synthetic hormones (contained in oral contraceptive (OC) pills) on alcohol use. The current study examined the influence of OC pill phase, ethinyl estradiol (EE) levels, and progestin levels on self-reported alcohol consumption in healthy female drinkers. Young adult female drinkers using OCs (N = 21) reported alcohol use across one OC pill pack using the Timeline Followback and provided blood samples during both pill phases to measure synthetic hormone levels. We compared alcohol use between OC pill phases (active vs. inactive) using linear mixed effects models for repeated measures and examined correlations between alcohol use and EE and progestin levels. Results showed that women with higher EE levels reported increased alcohol consumption (r = 0.56, p = 0.01) and binge drinking (r = 0.45, p = 0.04) in the active pill phase. Progestin levels and pill phase were not significantly associated with alcohol consumption. These findings provide preliminary data suggesting increased levels of EE from OC pills are associated with excessive alcohol consumption in women. Further research is needed to determine if EE plays a causal role in increased alcohol consumption. This line of research could inform female-specific AUD prevention and treatment strategies among the large subpopulation of women using hormonal contraceptives.

Effect of different levels of serum progesterone on day of frozen ET on clinical outcome

BackgroundProgesterone (P4) plays a critical role in a natural menstrual cycle. It is an essential hormone to have successful embryo implantation into the endometrium.ObjectiveIn the current study, we compared the clinical outcomes of patients with different levels of P4 on embryo transfer day and aimed to determine the optimum threshold for P4 in the luteal phase.Material and methodsWe performed a prospective cohort study on 100 patients who were referred to the Taleqani Infertility Treatment Institute to undergo frozen embryo transfer (FET). Endometrial preparation was programmed using an estrogen (E2) and progesterone supplement. FET was carried out 3 days after administration of the first dosage of progesterone. We measured serum progesterone levels on embryo transfer day. Clinical pregnancy was the main investigated outcome. We used a parametric receiver operating characteristic curve (ROC) to determine the best-cut points of P4 on embryo transfer day.ResultsOverall, the average endometrial thickness was 7.9 ± 0.2 mm. We observed no association between endometrial thickness and clinical pregnancy (P value = 0.719). The mean number of the transferred embryos in all investigated cycles was 1.5 ± 0.5, and 80.0% of the transferred embryos were high quality (high and medium level). The average progesterone level in cycles with clinical pregnancy was 17.2 ± 3.3 ng/mL. It was only 13.4 ± 9.4 in patients without clinical pregnancy. The observed difference was statistically significant (P value = 0.032). The estimated AUC for the drawn ROC curve was 0.71 indicating a high predictive value.ConclusionThe current study demonstrated that high and low serum progesterone (P4) levels on embryo transfer day were associated with reduced clinical outcomes following blastocyst transfer during IVF/ICSI. However, more studies with large sizes are required in this regard.

A model for predicting low progesterone levels on the day of embryo transfer in hormonally prepared vitrified-warmed embryo transfer cycles: A secondary analysis of a prospective cohort study.

To develop a model that predicts low progesterone (P) levels on the day of embryo transfer (ET) based on patient and cycle characteristics, including serum estradiol (E2 ) concentration after vaginal administration of micronized E2 for endometrial preparation. A prospective cohort of 193 patients scheduled for cryopreserved blastocyst transfer during an artificial endometrial preparation cycle, using micronized E2 vaginally for first 4 days (4 mg/day), followed by oral administration (6 mg/day). Blood sampling for E2 was performed prospectively on day-5 of vaginal administration and analysis was performed retrospectively. On sixth day of P treatment (daily 300 mg of vaginal micronized P tablets), P levels were measured on ET day. Primary outcome measure was serum P levels after vaginal E2 administration. Patients with low P levels on the day of ET (<7.8 ng/mL, 25th percentile) were heavier (p < 0.001) and exhibited lower day 5 serum E2 levels (p < 0.001) compared with patients with adequate P levels. Multivariate linear regression analysis revealed that weight (p = 0.003) and day 5 E2 levels (p < 0.001) were independently associated with the P levels. The sensitivity, specificity, and positive and negative predictive values (%) were 71.4, 55.6, 35.4, and 85.1 for weight ≥ 65 kg; 71.4, 61.8, 38.9, and 86.4 for day 5 E2 ≤ 1615 pg/mL; 59.2, 83.3, 54.7, and 85.7 for the combination of these two variables; and 82.9, 62.5, 54.7, and 87.0 for the sequential inclusion of these variables, respectively. Low day 5 E2 levels following vaginal administration and high weight are independently associated with low P levels on the day of ET. Predictive performance is enhanced when these variables are considered sequentially or in combination.

SAT020 Is Testosterone The Male Sex Hormone Responsible For Increased Male Mortality In Melanoma? In-vitro Studies On Two Human Melanoma (BLM, 1205Lu) Cell Models

Abstract Disclosure: P. Ramaraj: None. Epidemiological data pointed to increased male mortality in melanoma and clinical studies pointed to better protection of menstruating females in melanoma than post-menopausal women and men of any age. Our in-vitro studies with progesterone (P) on human melanoma (BLM and 1205Lu) cell lines showed a significant decrease in cell growth along with a decrease in the secretion of proinflammatory cytokine IL-8 by these cells. These in-vitro studies correlated with the hormonal data which showed that progesterone levels in menstruating females ranged between 1000 - 1500 ng/dl, compared to post-menopausal women 20 - 100 ng/dl and men 27-90 ng/dl, suggesting low progesterone levels meant no protection in melanoma. This observation prompted us to hypothesize that lack of progesterone in males could be a cause for increased male mortality. This hypothesis also raised the question of the role of male sex hormones (AD-androstenedione and T-testosterone) in increased male mortality. In order to address these questions in-vitro experiments were planned. First, to indirectly induce endogenous IL-8 by pretreating the cells with endothelin and then adding steroid hormones (AD, T, P). Secondly, to add IL-8 directly to the cells and then add steroid hormones. Finally, to suppress endogenous IL-8 with curcumin and then add T to one set of cells and IL-8 + T to another set of cells. For the first experiment, the result was a marginal increase in cell growth (67%) in cells pretreated with endothelin followed by T-treatment compared to straight T-treated cells (60% cell growth) without endothelin pretreatment. For the second experiment, there was a slight increase in cell growth in IL-8-added cells, but it was not statistically significant. For the final experiment, the cells treated with IL-8 + T after curcumin pretreatment showed a partial restoration of cell growth (49%) compared to cells (40% cell growth) treated with plain T after curcumin treatment, suggesting T was not able to control or regulate IL-8 action like progesterone. These in-vitro experiments suggested that in males 2 reasons 1) a deficiency of progesterone and 2) inefficiency of T to control endogenous IL-8 could possibly result in increased IL-8 levels. This increased IL-8 level in males could lead to increased cell growth and metastasis in melanoma leading to death. So, a situation arising out of male reproductive endocrine physiology could probably be responsible for increased male mortality in melanoma. Presentation: Saturday, June 17, 2023

Use of progestagens to preserve pregnancy: modern approaches

Review objectives: to summarize current and clinical data on the role of progesterone support in women at risk of miscarriage and premature pregnancy according to the standards of evidence-based medicine. Control of plasma progesterone levels is a fundamental tool for managing the effectiveness of assisted reproductive technologies. The association of a low level of serum progesterone with lower rates of current pregnancy and live birth in cycles of assisted reproductive technologies was revealed. Patients with low serum progesterone on the day of embryo transfer need individualized support of the luteal phase, which involves adding additional doses of progesterone to standard regimens.&#x0D; Vaginal micronized progesterone is currently believed to be the only progestogen that increases the likelihood of a live birth in women with bleeding in early pregnancy which has one or more miscarriages.&#x0D; Vaginal progesterone can be considered for patients with a high risk of miscarriage in the following modes: with vaginal bleeding and a history of one or more miscarriages (threatened miscarriage) – 400 mg twice a day, starting with the detection of vaginal bleeding up to 16 full weeks of pregnancy; with a history of three or more pregnancy losses of unknown etiology (habitual miscarriage) – asymptomatic patients — 200 mg twice a day up to 12 full weeks of pregnancy; patients with vaginal bleeding – 400 mg 2 times a day up to 16 weeks of pregnancy. Currently, there is no evidence of the effectiveness other forms of progesterone and other doses.&#x0D; Conclusions. Vaginal micronized progesterone demonstrated: high efficiency as a standard of luteal phase support; increasing the chance of a live birth in women with a double risk factor for miscarriage (vaginal bleeding in the 1st trimester and ≥1 previous miscarriage); the absence of safety problems for the fetus and the health of newborns when used in the early and late stages of pregnancy.

Relationship between Serum Sex Hormones and Coronary Artery Disease in Premenopausal Women – A Missing Link?

Objectives: The reported incidence of coronary artery disease (CAD) is on the upsurge in middle-aged women of 35–54 years, whereas decreasing in similar aged matched men. The current clinical trial studies have revealed that attention is drawn away from estrogens and shifted toward androgens and sex hormone-binding globulin considered potential mediators of increasing cardiovascular risk in women at midlife. Data evaluating the endocrinological basis for CAD in premenopausal Indian women is infrequent. We aimed to assess the incidence of CAD among premenopausal women undergoing coronary angiography, identify the prevalence of various risk factors for CAD, and compare clinical characteristics and hormonal levels among premenopausal women with and without CAD to elucidate endocrinological explanations for CAD in premenopausal women. Materials and Methods: Ninety-nine consecutive premenopausal women undergoing coronary angiography between January 2014 and January 2017 were enrolled in this single-center and cross-sectional study. The reproductive hormone levels were quantified using commercially available electrochemiluminescence immunoassay. Results: Sixty-six (66.7%) premenopausal women had CAD on coronary angiography. Multivariate linear regression analysis was used, for diabetes mellitus (adjusted odds ratio [AOR] 16.46; P = 0.006 [95% confidence interval, CI: 2.21–122.41]), triglycerides (AOR 1.05; P = 0.002 [95% CI: 1.02–1.10]), progesterone (AOR 0.68; P = 0.015 [95% CI: 0.50–0.93]), and insulin (AOR 0.51; P &lt; 0.0001 [95% CI: 0.38–0.70]) were observed to independently anticipate the development of CAD in premenopausal women. Conclusion: Approximately two-thirds of premenopausal women undergoing coronary angiography are detected to have CAD. Patients having diabetes, high serum triglyceride levels, low progesterone, and low insulin levels are considered in the high-risk category for developing CAD, thereby in premenopausal women providing a hormonal basis for the development of CAD.

Estrogens receptors, nuclear coactivator 1 and ligand-dependent corepressor expression are altered early during induced ovarian follicular persistence in dairy cattle

Failure of ovulation can lead to follicular persistence, one of the main components of the pathogenesis of cystic ovarian disease (COD) in dairy cattle. Follicular persistence causes the permanence of a functional follicular structure in the ovary, which alters the cyclicity of the female and causes infertility. The aim of the present study was to evaluate the expression of estrogen receptors (ESR) 1 and 2, and the coregulatory proteins NCOA1, NRIP1 and LCOR by immunohistochemistry, in antral and preovulatory/persistent follicles in a model of follicular persistence induced by low levels of progesterone, to detect incipient changes during COD development, on the expected day of ovulation (P0) and after 5 (P5), 10 (P10) and 15 (P15) days of follicular persistence. Twenty-five Holstein cows were used, which were distributed in 5 groups: control group (n = 5), group P0 (n = 5), group P5 (n = 5), group P10 (n = 5), group P15 (n = 5). ESR1 expression was lower in antral follicles of the P5 (theca), P10 and P15 (theca and granulosa) groups relative to the control group (p < 0.05), and also lower in granulosa cells of persistent follicles of the P5, P10 and P15 groups than in dominant follicles of the control group (p < 0.05), without differences in theca cells. ESR2 expression showed no differences between groups. The ESR1:ESR2 balance favored ESR2 expression along the development of persistent follicles, as from 5 days of persistence (p < 0.05). NCOA1 expression was higher in granulosa cells of both antral and persistent follicles from the P0 group relative to the P5 and P10 groups, but showed no differences with the control and P15 groups (p < 0.05). Theca cells of antral and persistent follicles showed higher expression in the P0 and P15 groups in relation to the control, P5 and P10 groups (p < 0.05). No differences were detected for NRIP1 in antral, dominant and persistent follicles between groups. LCOR expression showed a decrease in granulosa cells of antral follicles from all persistence groups relative to the control group (p < 0.05). In theca cells, antral follicles of the P10 group showed lower LCOR expression than the control group (p < 0.05). LCOR expression was similar for dominant and persistent follicles. Considering that the ESR1:ESR2 balance favored ESR2 expression along the development of persistent follicles, as well as the decreased LCOR and NCOA1 expression, we may assume that, at the early stages of persistence, there is a negative regulation of ESR transcription. This coincides with the effects of estrogens through ESR on proliferation and apoptosis among other processes that favor follicular persistence. The results obtained provide relevant information in the knowledge of local events during the development of follicular persistence that could explain the failures in the reversion of the disease through hormonal treatments and the high recurrence rates reported for COD. In addition, it contributes to the study and identification of possible therapeutic targets, for the design of new treatments.

Mechanistic study of copper nanoparticle (CuNP) toxicity on the mouse uterus via apelin signaling.

Copper nanoparticles (CuNPs) have been widely utilized in various applications. Due to its wider application, humans are at risk of its exposure. It has been reported that the exposure of CuNPs can lead to organ accumulation and affect organ toxicity. Recent study suggested that CuNPs can translocate into the uterus and affect uterine injury in rat, whereas uterine toxicity still remains unclear. The uterus is an important female organ which is required to sustain pregnancy. Thus, uterine structure and physiology are important. Therefore, this study hypothesized that CuNPs might have a toxic effect on the uterine features of mice. In this study, we have investigated the potential effects of CuNPs on the uterus of mice both in vivo and in vitro. In in vivo study, two groups of female mice were exposed to 5 and 50 mg/kg/day via oral exposure. In vivo results showed that CuNP treatment decreases the body weight and uterus weight and changes in antioxidant status with low estrogen and progesterone levels. Furthermore, CuNPs up-regulated the expression of caspase3 and down-regulated the expression of apelin receptor (APJ). Immunolocalization of apelin showed low abundance in the CuNP-treated uterus. These results suggest a poor apelin signaling in the uterus after CuNP treatment. The in vivo findings were further supported by the in vitro studies. Firstly, the uterus was cultured with 5 and 40 μg of CuNPs, and in the second in vitro experiment, the uterus was divided into 4 groups: control, 40 μg of CuNPs, 40 μg of CuNPs with apelin, and 40 μg of CuNPs with apelin receptor antagonist (ML221). In vitro study showed that CuNPs could directly induce the oxidative stress and apoptosis as well as changing antioxidant status in the uterus. The in vitro apelin 13 (APLN 13) treatments alleviated the expression of BCL2 and improved the antioxidant markers in CuNP-treated uterus. These results also provided an evidence of apelin-mediated signaling in the CuNP-treated uterus. In summary, our results present evidence that CuNPs can stimulate apoptotic pathways which may lead to uterine impairment due to weak apelin signaling.

P-330 Is 17 alpha hydroxyprogesterone caproate an adequate alternative to improve reproductive outcomes in artificially prepared frozen embryo transfer cycles (FET)?

Abstract Study question Is 17 alpha-hydroxyprogesterone caproate an adequate option to improve reproductive outcomes in patients with low serum progesterone (P4) level the day of frozen embryo transfer? Summary answer Patients with serum P4&amp;lt;10ng/ml may benefit with the addition of intramuscular 17alpha-hydroxyprogesterone caproate injections, and have similar ongoing pregnancy rates than patients with serum P4≥10ng/ml. What is known already Indications of embryo cryopreservation have expanded in the last years. Recently published papers highlight that low serum progesterone levels before frozen embryo transfers decrease pregnancy and live birth rates and increase miscarriage rates, even in cases of euploid embryos transfers. Other studies have published a beneficial effect with the addition of daily subcutaneous progesterone injections in patients with low serum progesterone levels around the time of embryo transfers. In Argentina subcutaneous progesterone has been available since October 2022, not before. 17alpha-hydroxyprogesterone caproate is a synthetic progestin used for luteal phase support and approved for the prevention of preterm birth. Study design, size, duration This prospective cohort study was performed between May 2021 and August 2022 in 114 patients undergoing 138 FET cycles after an artificial endometrial preparation with estradiol valerate 4mg daily and micronized vaginal progesterone 200mg, three times daily. Participants/materials, setting, methods Patients &amp;lt;50 years old with triple-layer endometrium ≥7mm underwent frozen embryo transfer. Progesterone was measured immediately before the embryo transfer. Group 1 (N = 47): P4&amp;gt;10ng/ml; Group 2 (N = 46): P4&amp;lt;10ng/ml with addition of 17 alpha-hydroxyprogesterone caproate after embryo transfer; Group 3 (N = 46): P4&amp;lt;10ng/ml without addition of 17 alpha-hydroxyprogesterone. Primary endpoint was to compare ongoing pregnancy rate beyond week 12 between the three groups. Secondary endpoints were pregnancy rate and miscarriage rate. Main results and the role of chance Parameters were comparable between the groups in terms of age, body mass index, estradiol, P4 levels at the beginning of endometrial preparation and number of embryos transferred. Ongoing pregnancy rate was: Group 1 = 38.3% (18/47); Group 2 = 39.1% (18/46); Group 3 = 28.3% (13/46) (p = 0,337). Pregnancy rate was: Group 1 = 48,9% (23/47); Group 2 = 50% (23/46); Group 3 = 50% (23/46) (p&amp;gt;0,05). Miscarriage rate was: Group 1 = 21.73% (5/23), Group 2 = 26.1% (6/23) and Group 3 = 43.47% (10/23) (p = 0,208). Although there were no significant differences between the groups, both, Group 1 and Group 2, had higher ongoing pregnancy rates and lower miscarriage rates than group 3. This is probably due to the limited sample size. Limitations, reasons for caution The main limitation of our study is the sample size and the fact that most of the embryos were not genetically evaluated before being transferred, which would eliminate a variable that could interfere with the results obtained. Only micronized progesterone and 17alpha-hydroxyprogesterone caproate were studied. Wider implications of the findings The addition of exogenous 17alpha-hydroxyprogesterone caproate on the embryo transfer day may improve ongoing pregnancy rates in cases of low serum progesterone levels, being a simple and safe strategy to individualize luteal phase support when no other form of progesterone administration is available. Trial registration number NOT APPLICABLE

P-499 Individualization of the mean luteal phase after frozen embryo transfer with hormone replacement therapy

Abstract Study question Objective: To determine in embryo cryotransfer cycles with hormone replacement therapy whether progesterone levels five days after transfer &amp;lt; 15.7 ng/mL correlate with reproductive outcomes. Summary answer Conclusion: We cannot affirm that low levels of progesterone in the mid luteal phase after cryotransfer are an independent factor of evolutionary gestation. What is known already n the transfer of frozen embryos with hormone replacement therapy after a period of endometrial preparation with estrogens for 10-12 days, luteal phase support with vaginal progesterone is administered as many days as the embryo to be transferred, as reported by Van de Vijver et al 2001. After reporting that low progesterone levels on the day of transfer were associated with worse outcomes, our purpose is to evaluate progesterone levels after transfer with the first prospective study monitoring post-transfer progesterone levels to see if its supplementation correlates with better reproductive outcomes. Study design, size, duration Study desing: Analytical, observational, longitudinal, prospective study conducted at the Assisted Reproduction Unit of Hospital Quironsalud Barcelona between December 2021 and May 2022. 159 patients aged 18-42 years who have undergone a cycle of frozen embryo transfer (CT) of their own or donated embryos with hormone replacement therapy. Participants/materials, setting, methods Material and methods: Determine in embryo cryotransfer cycles with hormone replacement therapy with estradiol, luteal phase support of micronized natural progesterone five full days prior to the transfer of a blastocyst.Determination of progesterone levels five days after transfer, if levels &amp;gt; = 15.7ng (group C) we followed the same guideline, if &amp;lt; 15.7 ng one group was supplemented with 25 mg Psc (group A), and another group of patients (group B) was not supplemented. Main results and the role of chance Results: Total of 159 patients with mean age of 37.86 years, mean antimuleriana value 2.95 ng/ml, antral follicle count of 11.54 and mean endometrial thickness of 8.93mm. 55.97%(n = 89) TC had P4D+10 &amp;lt;15.7ng. Pregnancy rate (BHCG&amp;gt;5mIUI/mL) was higher in the group with progesterone 5 days after transfer ( P4D+10) &amp;gt; =15.7ng with 65.71% CI95%[53.31,76.38] p = 0.65, and in the group of P4D+10 &amp;lt; 15.7 ng became pregnant 53.57% CI95%[34. 21,71.99] p = 0.53 of group A with respect to 45.90% IC95%[33.26,59.06] p = 0.45 group B. Clinical evolutionary pregnancy rate was higher in group A 80% vs 67.86% of group B, p-value=0.06. Abortion rate lower in group A 20% vs 32.14% group B, p = 0.01. Limitations, reasons for caution Limitations. There are few previous studies that allow us to support our arguments, the variability of progesterone levels in blood throughout the day can alter the results,nevertheless, and the sample size is small and it is difficult to find significant differences. Wider implications of the findings We did observe that &amp;gt;50% (55.97%) of the patients presented low values of progesterone after the embryo frozen transfer, with an improvement in pregnancy rate 53.57% vs 45.90% when these were rescued with subcutaneous progesterone. About 7% of pregnancies would be lost without this monitoring and supplementation. Trial registration number not applicable

P-500 Relationship of midluteal serum progesterone levels and pregnancy outcomes after day-3 embryo-transfer(ET) in hormonal replacement therapy (HRT) cycles with intramuscular progesterone: a prospective cohort study

Abstract Study question Does midluteal(day-9 of progesterone) serum progesterone level in HRT cycles with intramuscular progesterone affect the clinical pregnancy rate (CPR)/early miscarriage rate(MR) and live birth rate(LBR)? Summary answer Midluteal serum progesterone between 32.2-43.7ng/ml results in significantly greater CPR versus that with lower/higher levels and significantly greater LBR compared to that with lower levels. What is known already Evidence points to low serum progesterone levels at the time of FET being associated with lower ongoing pregnancy rates. Recently, the relation of midluteal serum progesterone levels in HRT cycles with vaginal progesterone as luteal phase support (LPS) has been elaborated indicating better pregnancy outcomes with an optimum range of serum progesterone/higher levels. There is no data establishing the association of pregnancy outcomes with midluteal serum progesterone levels when intramuscular progesterone is used as LPS in HRT cycles. Study design, size, duration A prospective cohort study conducted between December 2019-March 2022 at a tertiary centre with 196 patients(204 cycles), both-autologus(AO)-56.3% and donor oocytes(DO)- 43.6%: fresh ET-16.6% and frozen ET(FET)-83.3% with similar ICSI, vitrification and ET protocols(2/3 Grade A day-3 embryos). CPR, early MR (≤13 weeks miscarriage/clinical pregnancy) and LBR (≥28 weeks, LBs/ETs) were compared. Serum progesterone was measured on the morning of day-5 post-ET(day 9th from the start of progesterone). Most patients delivered at the same institute. Participants/materials, setting, methods Patients were non-smokers with normal hysteroscopy. Oral estradiol 6-8mg was initiated from Day 1-2 (for 10-17 days). When ET ≥ 7mm and serum progesterone &amp;lt;1ng/ml, intramuscular progesterone 100mg/day was started (daily till day-4 post-ET, then every 3rd day till week 8). Vaginal progesterone gel was added from day 5 post-ET till week 10. Serum progesterone levels were categorized in tertiles. Chi-square, t-tests and multiple regression analysis was used for statistical analysis. Two-tailed P&amp;lt;.05 indicated statistical significance. Main results and the role of chance Mean age was 34.76±5.36 years with a mean BMI 26.4±4.38kg/m2 Overall, CPR was 106/204(51.9%), LBR 78/204(38.2%) and early MR 28/106(26.4%) Midluteal serum progesterone levels ranged from 11.1-261ng/ml and were divided into tertiles(T) T1&amp;lt;32.0ng/ml(n = 68),T2 32.2-43.7ng/ml(n = 68),T3 &amp;gt;43.7ng/ml (n = 68) Median progesterone levels of T1,T2,T3 were 27.7ng/ml(Interquartile range [IQR] 7.0), 38.4ng/ml (IQR 5.0) and 51.2ng/ml (IQR 12.6) respectively. Mean age and mean BMI was not significantly different across the tertiles P=.27, P=.20 respectively CPR was significantly different across T1 32/68(47%),T2 45/68(66.1%)and T3 29/68(42.6%) P=.014. CPR was significantly more in T2 versus T1 and T3, (OR:2.2, 95%CI:1.1-4.4 P =.02) and (OR:2.6,95%CI:1.3-5.3, P=.006), respectively. T3 versus T1, P =.60 LBR was also significantly different across the tertiles [T1 20/68(29.4%), T2 34/68(50%),T3 24/68(35.3%) P=.03] LBR in T2 was significantly more than in T1(OR: 2.4,95% CI:1.2-4.9, P=.02). There was no significant difference betweenT3 versus T1 and T2 versus T3, P=.46, P=.08, respectively. Early MR wasn’t significantly different across T1 12/32(37.5%), T2 11/45(24.4%) and T3 5/29(17.2%), P=.18 Serum progesterone levels were not significantly affected by age r = 0.0257, P=.71 or BMI r = 0.0097, P=.89 Multivariate logistic regression showed that age affected CPR after adjusting for BMI, midluteal serum progesterone levels, origin of oocytes, fresh ET/FET(AOR 0.92: 95% CI:0.86-0.98, P=.01). Limitations, reasons for caution This is a single centre study with limited sample size. Including the measurement of serum progesterone at the time of ET would have given a better perspective of the patient specific behavior of progesterone as LPS. Larger studies with different LPS protocols are needed to validate the results. Wider implications of the findings In HRT cycles with intramuscular progesterone, an optimum midluteal serum progesterone level is related to better pregnancy outcomes. Factors causing the wide variation of progesterone levels need to be evaluated so as to individualize the dose. Identifying the appropriate time frame for optimising the midluteal progesterone levels should be explored. Trial registration number not applicable

P-633 Progesterone elevation on the day of trigger in the presence of low ovarian response signifies abnormal follicular environment and poorer oocyte health

Abstract Study question Is progesterone elevation (PE) in the presence of low number of follicles (unexpected PE) associated with oocyte or embryo quality? Summary answer PE on day of trigger in cycles with ≤4 follicles is associated with significantly reduced fertilisation rates and fewer top-quality blastocysts What is known already The negative effect of PE on pregnancy rates in fresh IVF cycles has been demonstrated by multiple studies and meta-analyses, and most studies support no negative effect on oocyte and embryo quality. However, as it is thought that PE is the product of cumulative secretion of low levels of progesterone from multiple developing follicles, PE in the presence of a low number of follicles (unexpected PE) is considered a different pathophysiological entity. It has been hypothesized, but never proven, that in these cases, PE is the result of follicular dysregulation and that it might indicate poorer follicular and oocyte health. Study design, size, duration This is a multi-centre retrospective analysis of a large cohort (n = 1,393) of IVF/ICSI cycles with a low response to ovarian stimulation (1-4 follicles ≥14mm) performed from January 2018 to April 2022. Only cycles of ovarian stimulation using gonadotrophins and GnRH analogues with a measurement of serum progesterone on the day of triggering final oocyte maturation were included. Natural cycles and cycles involving the administration of clomiphene were excluded. Participants/materials, setting, methods Unexpected PE was defined as serum progesterone levels greater than 4.77 nmol/L (1.5 ng/mL) on day of trigger. The primary outcome was the number of usable blastocysts. Secondary outcomes included the number of oocytes retrieved, two pronuclei (2PN) oocytes, number of top-quality embryos, fertilisation rate and blastocyst formation rate. Generalised estimating equations were used to account for the clustered nature of data. Multivariable regression analysis was performed to control for the effect of multiple confounders. Main results and the role of chance In the univariate regression analysis, the number of oocytes retrieved was not significantly different between cycles with and without PE (mean 2.3 vs. 2.1 respectively; p = 0.550). The number of 2PN oocytes was significantly (p = 0.021) lower in the PE group (mean 0.72, 95%CI 0.31-1.14) compared to the non-PE group (mean 1.21, 95%CI 1.12-1.31). The number of top-quality blastocysts was also significantly (p = 0.003) lower in the PE group (mean 0.03, 95%CI -0.03-0.10) compared to the non-PE group (mean 0.14, 95%CI 0.11-0.17). Fertilisation rates per oocyte retrieved, fertilisation rates per oocyte inseminated and the top-quality blastocyst rate per oocyte retrieved were consistently lower in the PE group at 33.3% (95% CI 19.0-47.6), 26.9% (95% CI 14.8-39.0) and 0.7% (95% CI -0.8-2.1) compared to 58.7% (95% CI 55.8-61.7), 52.3% (95% CI 49.3-55.2) and 5.5% (95% CI 4.3-6.8) in the non-PE group. The negative association of PE with the primary outcome measure of this study was confirmed in the multivariable regression analysis where the number of usable blastocysts was significantly lower in the PE group (adjusted mean 0.14, 95%CI 0.03-0.25) compared to the non-PE group (adjusted mean 0.27, 95%CI 0.23-0.31) after adjusting for confounders. Limitations, reasons for caution This is a retrospective observational study, thus not all confounders may be accounted for. Despite being one of the largest studies conducted in poor responders, the sample size of unexpected PE cycles is relatively small due to its rarity. Therefore, this study may be underpowered to detect smaller effect sizes. Wider implications of the findings This study demonstrates for the first time that unexpected PE on the day of trigger (i.e. in cycles with low ovarian response) is associated with poorer oocyte health as reflected in the reduced fertilisation rates and fewer blastocysts available for transfer. This information can aid in better understanding this phenomenon. Trial registration number Not applicable

P-438 Does artificial endometrial preparation for frozen embryo transfers have poorer outcomes compared to other endometrial preparation?

Abstract Study question Do artificial thaw cycles increase miscarriage rates compared to Letrozole and natural thaw cycles? Summary answer After adjusting for potential confounders, artificial thaw cycles had twice the risk of miscarriage compared to both natural and Letrozole thaw cycles. What is known already In frozen embryo transfers, miscarriage rates have been shown to be higher with artificial cycle regimen than with natural cycles whereas there is inconsistent evidence regarding live birth rates between the two types of endometrial preparation. Studies comparing artificial to Letrozole thaw cycles also gave inconsistent data as to whether one had better outcomes than the other. There is lack of studies comparing these three types of endometrial preparation with regards to pregnancy, miscarriage and live birth rates. Study design, size, duration This is a retrospective study on 712 frozen embryo transfers from August 2019 to March 2021 for women between 23 to 45 years old. The endometrial preparation distribution is as follow: 288 Letrozole cycles, 200 artificial cycles and 224 natural cycles. Only single blastocyst transfers were included. Exclusion criteria included women with endometrial cancer/hyperplasia, recurrent pregnancy loss, Mullerian anomalies or sexual dysfunction, cycles with preimplantation genetic testing and use of donor gametes. Participants/materials, setting, methods Anonymised data of patients undergoing frozen embryo transfers were obtained from the database in a fertility centre in Singapore. Primary outcome is miscarriage rate and secondary outcomes are pregnancy and live birth rates. Data was analyzed with Stata. Continuous variables of the different groups were compared using Student’s T-test while chi-square test was used for dichotomous variables. Logistic regression analysis was performed to assess the effect of independent variables on the outcomes. Main results and the role of chance Artificial thaw cycles had the highest miscarriage rate at 43.8%, compared to 25.3% in natural thaw and 33.0% in Letrozole thaw cycles (p = 0.028). Clinical pregnancy rate was highest in artificial thaw cycles at 48.0%, compared to 40.6% in natural thaw and 34.7% in Letrozole thaw cycles (p = 0.013). Live birth rate was highest in natural thaw cycles at 30.3%, followed by 27.0% in artificial thaw and 23.2% in Letrozole thaw cycles (p = 0.028). After adjusting for confounding factors, artificial thaw cycles have approximately twice the risk of miscarriage compared to Letrozole thaw (p = 0.007) and natural thaw cycles (p = 0.032). The chance of pregnancy was 1.5 times higher in artificial compared to Letrozole thaw cycles (p = 0.027) but similar to that in natural thaw cycles. The chance of a live birth in natural thaw cycle was 1.6 times higher than that in Letrozole thaw cycle (p = 0.027) but similar in artificial thaw cycle. The mean age of participants in the artificial group was significantly lower at 33.9 years, compared to 35.3 years and 35.5 years in the Letrozole and natural group respectively (p &amp;lt; 0.001). However in multivariate analysis, increasing age did not have a significant impact on either miscarriage (p = 0.907) or live birth rate (p = 0.066). Limitations, reasons for caution The retrospective nature of this study may have resulted in selection biases and unrecognized confounders may influence the results of this study. Wider implications of the findings A possible hypothesis which can explain higher miscarriage rates in artificial thaw cycles may be insufficient progesterone support due to the lack of corpus lutea unlike in natural or Letrozole thaw cycles. Optimizing progesterone support in women with low progesterone levels undergoing artificial thaw can be further explored. Trial registration number not applicable

The effect of sex hormones on decision-making in healthy young women

Risky decision-making is associated with several mental health disorders and deleterious health behaviours. As men are known to engage in riskier behaviours, the effects of testosterone on decision-making have been extensively studied. However, few studies have been conducted in women and by extension, examined female sex hormones (progesterone and estradiol). This study aimed to understand the role of sex hormones (progesterone, estradiol, and testosterone) on decision-making. Forty healthy young women provided saliva samples to assess their sex hormones before completing the Iowa Gambling Task. The goal of this decision-making task was to maximize monetary profits by drawing cards from four decks: two with large gains and larger losses (risky decks) and two with small gains and smaller losses (safe decks). For the purposes of data analysis, card draws were separated into five blocks of 20 draws each, allowing us to quantify the learning rate of the advantageous safe decks. Multilevel linear models revealed two inverse interactions: time*testosterone and time*progesterone. Specifically, lower levels of progesterone and higher levels of testosterone were independently associated with riskier decision-making. In both cases, this effect led to slower learning of the advantageous safer decks. These data suggest that the effects of testosterone on risk-taking are not unique to men. Moreover, the results suggest that progesterone also influence risk-taking. This raises important questions regarding risk-taking tendencies in women throughout the menstrual cycle (which induces endogenous hormonal variations) and in women using hormonal contraceptives (which dampen the menstrual cycle).

РОЛЬ ИММУННОГО МЕХАНИЗМА В РАЗВИТИИ ДИСФУНКЦИИ ЭНДОТЕЛИЯ И АПОПТОЗА У БЕРЕМЕННЫХ ЖЕНЩИН С ТЯЖЕЛЫМИ ОСЛОЖНЕНИЯМИ

In order to identify the role of cellular and humoral immunity, nonspecific resistance, cytokine spec-trum in the development of endothelial dysfunction and apoptosis in the pathogenesis of obstetric complications, 40 women with severe pregnancy complications and critical conditions associated with thrombotic micro angiopathy and 30 patients with physiologically occurring pregnancy were exam-ined. The assessment of cellular elements of peripheral blood, indicators of cellular and humoral im-munity, the level of cytokines, a disintegrin and metalloprotease with thrombospondin-1-like domains, member 13 (ADAMTS – 13), Willebrand factor, apoptosis-inducing factor, CD95, progesterone and the number of endotheliocytes is given.&#x0D; The conducted study indicates the failure of the functional state of both innate and acquired immunity in women with complicated pregnancy. The leading role in the development of endothelial dysfunction and the mechanism of apoptosis in pregnant women with severe complications and criti-cal cases associated with thrombotic microangiopathy belongs to an insufficient reserve of nonspecific resistance, impaired cellular and humoral immunity with low background progesterone level and high cytokine activity

Atretic preovulatory follicles could be precursors of ovarian lutein cysts in the pig

Ovarian cysts contribute to reduced reproductive performance in pigs. Unfortunately, the mechanism of lutein cysts formation remains unknown. Here, we compared the endocrine and molecular milieus of intact, healthy preovulatory follicles (PF), gonadotropin (eCG/hCG)-induced healthy and atretic-like PF, as well as gonadotropin-provoked and spontaneous ovarian cysts in gilts. Several endocrine and molecular indicators and microRNA were compared in walls of PF and cysts. Intact and healthy PF, showed high estradiol/androstendione and low progesterone levels associated with CYP17A1, HSD17B1, and CYP19A1 elevation and reduced StAR/HSD3B1 protein expression. In contrast, low estradiol/androstendione and high progesterone concentrations, accompanied by decreased CYP17A1, HSD17B1, CYP19A1 and increased HSD3B1 protein abundance, appeared in atretic-like PF, gonadotropin-induced and spontaneous cysts. High progesterone receptor (PGR) protein abundance was maintained in intact and healthy PF, while it dropped in atretic-like PF, gonadotropins-induced and spontaneous cysts. The atretic PF showed high level of TNFα compared to healthy PF. In conclusion, follicular lutein cysts could be recruited from atretic-like PF with lost estrogenic milieu and inability to ovulate. Ovulatory cascade was presumably disrupted by a low PGR and high TNFα levels associated with earlier luteinization of follicular walls. These results suggest a novel mechanism of lutein ovarian cysts development in pigs and, perhaps, other species.

New Pharmacological Approaches to the Management of Premenstrual Dysphoric Disorder.

Premenstrual symptoms are experienced by many female individuals during their fertile age. Premenstrual dysphoric disorder (PMDD), a sex-specific mood disorder, affects about 5% of female individuals during the luteal phase of the menstrual cycle. Treatment with selective serotonin reuptake inhibitors represents a valid solution to manage PMDD for many, but not all, patients. Owing to maladaptive neural reactivity to gonadal hormone fluctuations, that is, the putative mechanism postulated to underlie PMDD, drugs suppressing or stabilizing such variations have been tested. Recently, a clinically significant reduction in the severity of the mental symptoms of PMDD was observed upon treatment with a selective progesterone receptor modulator (SPRM), as demonstrated when comparing ulipristal acetate with placebo in a randomised controlled trial. Stable and low progesterone levels, with maintained low-medium oestradiol levels, define the endocrine profile of this treatment. Importantly, the efficacy of SPRM treatment was accompanied by negligible side effects. These promising results represent a headway to understanding the mechanisms behind PMDD symptomatology and opening up new solutions in the management of PMDD. They also call for studies on the long-term efficacy, safety, and viability of SPRMs in female individuals during their fertile age to further support the development of targeted management of female's mental ill-health in relation to the menstrual cycle. The present overview thus seeks to inform about current and new pharmacological approaches to the management of premenstrual dysphoric disorder.

Effect of BMI on the value of serum progesterone to predict clinical pregnancy outcome in IVF/ICSI cycles: a retrospective cohort study.

Numerous research have investigated the predictor role of progesterone (P) level on the human Chorionic Gonadotropin (hCG) trigger day of assisted reproductive technology (ART) outcomes. However, the relationship of progesterone levels on hCG day to clinical pregnancy outcomes in IVF/ICSI cycles for patients with different BMI groups is still elusive. This study aimed to investigate the effects of progesterone elevation on triggering day on clinical pregnancy rate (CPR) of IVF/ICSI cycles in patients with different female BMI. We conducted a retrospective cohort study included 6982 normal-weight parents (18.5Kg/m2≤BMI<25Kg/m2) and 2628 overweight/obese patients (BMI≥25Kg/m2) who underwent fresh day 3 cleavage embryo transfer (ET) in IVF/ICSI cycles utilizing GnRH agonist to control ovarian stimulation. The interaction between BMI and P level on triggering day on CPRs was significant (p<0.001). The average level of serum P was reduced with the increase in maternal BMI. Serum P adversely affected CPR in distinct BMI groups. In the normal weight group, CPRs were decreasedas serum P concentrations gradually increased (p<0.001 for overall trend). The CPRs (lower than 65.8%) of progesterone level > 1.00 ng/ml on triggering day were significantly lower than that (72.4%) of progesterone level <0.5 ng/ml. In the overweight/obese group, CPRs showed a decrease statistically with progesterone levels of ≥2.00 ng/ml compared to progesterone levels of <0.5 ng/ml (51.0% VS. 64.9%, p=0.016). After adjusting for confounders, progesterone elevation (PE) negatively correlated with CPRs only in the normal weight group (OR: 0.755 [0.677-0.841], p<0.001), not in the overweight/obese group (p=0.063). Women with higher BMI exhibited a lower progesterone level on triggering day. Additionally, PE on hCG day is related to decreased CPRs in GnRH agonist IVF/ICSI cycles with cleavage embryo transfers regardless of women's BMI level (normal weight VS. overweight/obesity).