High Estradiol Research Articles

Novel variants associated with adiponectin-related traits in Awassi ewes

BackgroundAdipose tissue secretes adiponectin (ADIPOQ), a hormone related to fat oxidation, glucose metabolism, and reproduction. The polymorphism of adiponectin is associated with productive traits in domestic animals. Thus, this study investigated the association of adiponectin gene polymorphism with lipid profile and reproductive hormones in Awassi ewe. In this study, 200 ewes between the ages of 2.5 and 5 years, neither pregnant nor lactating, were included. To determine the lipid profile and reproductive hormones, sera were separated from the blood. DNA extraction, genotyping, and sequencing reactions were used to verify the variants in the amplified fragments (exon 1).ResultsThree genotypes, CC, CA, and AA, were identified from 368 bp amplicons (exon 1). A sequencing reaction revealed a novel mutation, c.198473337C > A, in the CA genotype. The results revealed significant differences (P ≤ 0.05) in cholesterol and HDL levels in the AA genotype than CC and CA genotypes. The AA genotype had higher estradiol and progesterone levels (50.52 ± 0.64) (pg/ml) and (7.10 ± 0.04) (ng/ml), respectively, than those with the CC and CA genotypes.ConclusionsThese results conclude that the ADIPOQ gene affects lipid profiles and sex hormone levels in Awassi sheep. Choosing sheep that are polymorphic for the ADIPOQ gene should be a future study, as this gene could be linked to high prolificacy.

Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine.

A migraine is a neurological condition that can cause multiple symptoms. It is up to three times more common in women than men, thus, estrogen may play an important role in the appearance attacks. Its exact pathomechanism is still unknown; however, the activation and sensitization of the trigeminal system play an essential role. We aimed to use an animal model, which would better illustrate the process of repeated episodic migraine attacks to reveal possible new mechanisms of trigeminal pain chronification. Twenty male (M) and forty ovariectomized (OVX) female adult rats were used for our experiment. Male rats were divided into two groups (M + SIF, M + IS), while female rats were divided into four groups (OVX + SIF, OVX + IS, OVX + E2 + SIF, OVX + E2 + IS); half of the female rats received capsules filled with cholesterol (OVX + SIF, OVX + IS), while the other half received a 1:1 mixture of cholesterol and 17β-estradiol (OVX + E2 + SIF, OVX + E2 + IS). The animals received synthetic interstitial fluid (SIF) (M + SIF, OVX + SIF, OVX + E2 + SIF) or inflammatory soup (IS) (M + IS, OVX + IS, OVX + E2 + IS) treatment on the dural surface through a cannula for three consecutive days each week (12 times in total). Behavior tests and immunostainings were performed. After IS application, a significant decrease was observed in the pain threshold in the M + IS (0.001 < p < 0.5), OVX + IS (0.01 < p < 0.05), and OVX + E2 + IS (0.001 < p < 0.05) groups compared to the control groups (M + SIF; OVX + SIF, OVX + E2 + SIF). The locomotor activity of the rats was lower in the IS treated groups (M + IS, 0.01 < p < 0.05; OVX + IS, p < 0.05; OVX + E2 + IS, 0.001 < p < 0.05), and these animals spent more time in the dark room (M + IS, p < 0.05; OVX + IS, 0.01 < p < 0.05; OVX + E2 + IS, 0.001 < p < 0.01). We found a significant difference between M + IS and OVX + E2 + IS groups (p < 0.05) in the behavior tests. Furthermore, IS increased the area covered by calcitonin gene-related peptide (CGRP) immunoreactive (IR) fibers (M + IS, p < 0.01; OVX + IS, p < 0.01; OVX + E2 + IS, p < 0.001) and the number of neuronal nitric oxide synthase (nNOS) IR cells (M + IS, 0.001< p < 0.05; OVX + IS, 0.01 < p < 0.05; OVX + E2 + IS, 0.001 < p < 0.05) in the caudal trigeminal nucleus (TNC). There was no difference between M + IS and OVX + IS groups; however, the area was covered by CGRP IR fibers (0.01 < p < 0.05) and the number of nNOS IR cells was significantly higher in the OVX + E2 + IS (p < 0.05) group than the other two IS- (M + IS, OVX + IS) treated animals. Overall, repeated administration of IS triggers activation and sensitization processes and develops nociceptive behavior changes. CGRP and nNOS levels increased significantly in the TNC after IS treatments, and moreover, pain thresholds and locomotor activity decreased with the development of photophobia. In our model, stable high estradiol levels proved to be pronociceptive. Thus, repeated trigeminal activation causes marked behavioral changes, which is more prominent in rats treated with estradiol, also reflected by the expression of the sensitization markers of the trigeminal system.

Treatment safety of ART cycles with extremely high oestradiol concentrations using GnRH agonist trigger

Research questionAre IVF treatments with extremely high peak oestradiol levels and gonadotrophin releasing hormone (GnRH) agonist trigger associated with higher complication rates? DesignA retrospective cohort study including patients from two large medical centres treated between 2019 and 2021. A study group with extremely high peak oestradiol levels (≥20,000 pmol/l on the day of ovarian stimulation, or ≥15,000 pmol/l on the previous day) and a control group with normal range oestradiol levels (3000–12000 pmol/l) that received GnRH agonist triggering. Patients were surveyed about complaints and medical care related to ovum retrieval and medical files were reviewed. Major complication rates and the need for medical assistance were compared. ResultsSeveral differences between the study and control group were observed because of the study design: mean age was 33.01 ± 5.14 versus 34.57 ± 4.52 (P < 0.001), mean peak oestradiol levels was 26645.34 ± 8592.57 pmol/l versus 7229.75 ± 2329.20 pmol/l (P < 0.001), and mean number of oocytes were 27.55 ± 13.46 versus 11.67 ± 5.76 (P < 0.001) for the study and control group, respectively. Major complications and hospitalization rates were similar between the study and control groups (three [1.25%] versus one [0.48%]; P = 0.62 and three [1.25%] versus two [0.96%]; P = 1.0, respectively). Thirty-six patients (15.1%) in the study group and 11 (5.3%) in the control group sought medical care after retrieval, mostly due to abdominal pain, without the need for further workup or hospitalization (P < 0.001). ConclusionsExtremely high oestradiol levels were not associated with thromboembolic events, higher major complication or hospitalization rates, and therefore may be considered safe. Nevertheless, patients may be informed of possible higher rates of discomfort, mostly abdominal pain. Larger studies are warranted to confirm our results.

Etiopathological Factors Associated with Gynecomastia Patients Seeking Surgical Correction in the South Indian Population.

Background Although several medical conditions are associated with gynecomastia, around 60% of cases are idiopathic. The role of endocrine testing in idiopathic gynecomastia is controversial. This study was done to determine the etiological and lifestyle factors associated with different grades of gynecomastia. Patients and Methods This was a descriptive study conducted at the department of plastic surgery in a tertiary care hospital in South India between January 2014 and December 2016, among the patients seeking corrective surgery for gynecomastia. Results A total of 73 patients were included in the study with a mean age of 22.56 years. The majority of the patients displayed Simon's Grade IIa gynecomastia (56.2%). The etiological factors identified in this study were hormonal abnormalities (47.95%), hypogonadism (2.7%), and drug intake (1.4%). The most common hormonal abnormality discovered was high estradiol values (15.1%) followed by decreased testosterone levels (13.7%). The chi-squared test revealed no statistically significant relationship between the hormonal values, type of food, body mass index (BMI), or physical activity and the grades of gynecomastia. Conclusion Most of the patients (50.68%) in our study had idiopathic gynecomastia. The most common hormonal abnormality detected was high estradiol values. No correlation was found between the hormonal values, type of food, BMI, or physical activity and the grades of gynecomastia.

The influence of sex and reproductive cycle on cocaine-induced behavioral and neurobiological alterations: a review

This systematic review (SR) was aimed at answering two questions: (1) how sex and ovarian hormones alter behavior associated with cocaine use; (2) which possible neurobiological mechanisms explain behavioral differences. Three different researchers conducted a search in PUBMED for all kinds of articles published between the years of 1991 to 2021 on the theme "reproductive cycle and cocaine", "estrous cycle and cocaine", "menstrual cycle and cocaine", "fluctuation of ovarian hormones and cocaine", "estrogen and cocaine" and "progesterone and cocaine". Sixty original studies were identified and subdivided into experimental rodent studies and clinical trials. Experimental studies were characterized by author/year, species/strain, sex/number, age/weight, dose/route/time of administration, hormonal assessment, or administration. Clinical trials were characterized by author/year, sex/number, age, exclusion criterion, dose/route of administration/time of cocaine, and hormonal assessment. Results gathered showed that rodent females develop increased consumption, seeking behavior, craving, relapse, locomotion, increases in stress and anxiety, among other behavioral alterations during peaks of estrogen. These observations are related to the direct effects played by ovarian hormones (in particularly estradiol), in dopamine, but also in serotonin neurons, and in brain regions such as the tegmental area, the nucleus accumbens, the hypothalamus, the amygdala and the prefrontal cortex. Increased sensitization to cocaine presented by high estradiol females was linked to the activation of a CBR1-mediated mechanism and GABA-A-dependent suppression of inhibitory synaptic activity of the prelimbic prefrontal cortex. Estradiol facilitation of cocaine-increased locomotion and self-administration was shown to require the release of glutamate and the activation of metabotropic glutamate receptors subtype 5. Clinical studies also tend to point to a stimulatory effect of estradiol on cocaine sensitization and a neuroprotective effect of progesterone. In conclusion, the results of the present review indicate a need for further preclinical and clinical trials and neurobiological studies to better understand the relationship between sex and ovarian hormones on cocaine sensitization.

Gonadotrophin independent puberty (GIPP) with unusually high oestradiol level in an infant with mccune albright syndrome (MAS)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Fetal programming: in utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging.

In this study we investigated the effects of multigenerational exposures to acrylamide (ACR) on ovarian function. Fifty-day-old Wistar albino female rats were divided into the control and ACR-treated groups (2.5, 10, and 20 mg/kg/day) from day 6 of pregnancy until delivery. The obtained females of the first (AF1) and second generation (AF2) were euthanized at 4 weeks of age, and plasma and ovary samples were collected. We found that in utero multigenerational exposure to ACR reduced fertility and ovarian function in AF1 through inducing histopathological changes as evidenced by the appearance of cysts and degenerating follicles, oocyte vacuolization, and pyknosis in granulosa cells. TMR red positive cells confirmed by TUNEL assay were mostly detected in the stroma of the treated groups. Estradiol and IGF-1 concentrations significantly decreased as a result of decreased CYP19 gene and its protein expression. However, ACR exposure in AF2 led to early ovarian aging as evidenced by high estradiol and progesterone levels among all treated groups compared to control group, corresponding to the upregulation of the CYP19 gene and protein expression. The apoptotic cells of the stroma were greatly detected compared to that in the control group, whereas no significant difference was reported in ESR1 and ESR2 gene expression. This study confirms the developmental adverse effects of ACR on ovarian function and fertility in at least two consecutive generations. It emphasizes the need for more effective strategies during pregnancy, such as eating healthy foods and avoiding consumption of ACR-rich products, including fried foods and coffee.

Inter-individual Variability In Passive Leg Movement-induced Hyperemia And Arterial Stiffness Across The Menstrual Cycle

There is variability in the impact of menstrual phase on arterial stiffness with some, but not all, studies reporting a decrease in arterial stiffness from the early follicular (EF; low estradiol) to the late follicular (LF; high estradiol) phase at the group or individual level. However, the mechanisms driving inter-study and inter-individual phase differences in arterial stiffness remain unknown. Vasorelaxation reduces arterial resistance and arterial stiffness. Variable increases in the endothelial-derived vasodilator nitric oxide with elevated LF estrogen may result in variable smooth muscle relaxation and thus variability in the impact of phase on arterial stiffness. It is speculated that inter-individual phase changes in nitric oxide dependent endothelial function will be related to inter-individual phase changes in arterial stiffness. PURPOSE: to investigate whether changes in endothelial function are related to changes in arterial stiffness across the menstrual cycle. METHODS: 11 premenopausal women (22±4 years) completed two visits; 1 in EF and 1 in LF phase. Salivary estradiol and leg endothelial function and arterial stiffness were tested during each visit. Endothelial function was quantified by the hyperemic response to passive leg movement (PLM) characterized by area under the curve leg blood flow (AUC LBF) and leg vascular conductance (AUC LVC) assessed via duplex ultrasound. Leg femoral-foot pulse wave velocity (PWV) was assessed via applanation tonometry. RESULTS: Estradiol increased from the EF to LF phase (p=0.014; EF=1.43±0.38, LF=1.60±0.43 pg/ml). At the group level, PWV decreased from the EF to LF phase (p=0.022; EF=7.98±1.48, LF=7.21±1.85 m/s). There were no group-level phase changes in AUC LBF (p=0.308; EF=132.50, LF=149.07 ml/min) or AUC LVC (p=0.344; EF=1.76±1.13, LF=1.96±1.06 ml/min/mmHg). Phase changes in PWV were not associated with phase changes in AUC LBF (r=0.171, p =0.616) or AUC LVC (r=0.247, p=0.464). CONCLUSION: Peripheral arterial stiffness decreased with a rise in estrogen in the LF phase, however, individual phase changes in arterial stiffness were not related to individual changes in endothelial function. Future research is needed to understand the mechanisms resulting in individual responses to fluctuations in endogenous estradiol. Funded by NSERC

Physiological interindividual variability in endogenous estradiol concentration does not influence adipose tissue and hepatic lipid kinetics in women.

Increased triglyceride (TG) and apolipoprotein B-100 (apoB-100) concentrations in plasma are important risk factors for cardiovascular disease in women. Administration of some estrogen preparations raises plasma TG and apoB-100 concentrations by increasing hepatic very low-density lipoprotein (VLDL) TG and apoB-100 secretion rates. However, the influence of physiological variation in endogenous estradiol on VLDL-TG and VLDL-apoB-100 metabolism and on free fatty acid (FFA) release into plasma (the major source of fatty acids for VLDL-TG production) is not known. We measured basal VLDL-TG, VLDL-apoB-100, and plasma FFA kinetics by using stable isotopically labeled tracers in 36 eumenorrheic, premenopausal women (age: 33 ± 2 years, BMI: 31 ± 1 kg/m2; mean ± s.e.m.) during the follicular phase of the menstrual cycle; participants were divided into two groups based on low (n = 18) or high (n = 18) plasma estradiol concentrations (defined as below or above the median value of 140 pmol/L in the whole group). Mean plasma estradiol concentration was >3-fold higher in the high-estradiol than in the low-estradiol group (299 ± 37 and 96 ± 7 pmol/L, P < 0.001); there was no difference in plasma progesterone concentrations between the two groups (P = 0.976). There were no significant differences in plasma FFA concentration, FFA rate of appearance in plasma, VLDL-TG and VLDL-apoB-100 concentrations, hepatic VLDL-TG and VLDL-apoB-100 secretion rates, VLDL-TG and VLDL-apoB-100 plasma clearance rates, and mean residence times (all P ≥ 0.45). No significant associations were found between plasma estradiol concentration and FFA, VLDL-TG, and VLDL-apoB-100 concentrations and kinetics (all P > 0.19). Plasma estradiol concentration is not an important correlate of basal plasma FFA, VLDL-TG, and VLDL-apoB-100 kinetics in premenopausal women.

G protein-coupled estrogen receptor (GPER/GPR30) levels in pelvic floor muscles and its association with estrogen status in female rabbits

Objective: To assess the relative expression of the G-protein coupled estrogen receptor (GPER) in the bulbospongiosus (Bsm) and pubococcygeus (Pcm) muscles in control, ovariectomized (OVX), and OVX with estradiol benzoate supplementation (OVX + EB) rabbits.Methods: We used tissues from C, 1-month OVX, and OVX plus 15-day EB implanted (OVX + EB) groups. The GPER expression was evaluated by Western blot and immunohistochemistry for both Bsm and Pcm. Results: Both muscles showed a GPER immunoreactivity in blood vessels, inside myofibers next to myonuclei, and in polymorphonuclear cells. Four-week ovariectomy did not modify the GPER expression in the Bsm and Pcm, but two-week estradiol benzoate increased it in the latter muscle alone.Conclusions: We demonstrated that the Bsm and Pcm of female rabbits express GPER. High serum estradiol levels elevate GPER relative expression in the Pcm alone. The present study supports the remarkable estrogen sensitivity of the Pcm.

The value of serum estradiol concentration on the day of endometrial transformation in predicting the outcome of frozen-thawed embryo transfer in hormone replacement cycle

To analyze whether the serum concentration of estradiol on the day of progesterone conversion could predict the pregnancy outcome of frozen-thawed embryo transfer in hormone replacement cycle. In this paper, a case-control study was conducted to retrospectively analyze the 230 cycles of hormone replacement therapy-frozen thawed embryo transfer(HRT-FET)conducted by the Department of Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University from January 2018 to December 2020. The concentration of serum estradiol was between 139.5-3 941.0 pg/ml. According to the percentile of serum estradiol concentration on the day of endometrial transformation, patients were divided into three groups: control group (<25th percentile, n=58), high estradiol group (25th-75th percentile, n=112) and ultra-high estradiol group (>75th percentile, n=60). Comparing the basic characteristics and pregnancy outcome of the three groups, the main observation index was the live birth rate, and the secondary observation index was the clinical pregnancy rate. F test and Kruskal-Wallis (H) test were used to compare the measurement data, and χ2 test was used to compare the counting data. The results showed that there was no significant difference in age, anti-Müllerian hormone(AMH), antral follicle count(AFC), body mass index(BMI), years of infertility and the proportion of primary infertility among the three groups(F=2.375, H=5.479, H=5.374, F=1.391, H=4.779, χ²=1.969, P>0.05). FET cycle treatment: There was no significant difference in the concentration of progesterone (P) before transformation, the thickness of endometrium on the day of transformation, the proportion of single embryo transfer and blastocyst transfer among the three groups (H=5.359, H=5.957, χ²=0.626, χ²=4.532, P>0.05). The days of estrogen administration before endometrial transformation in the three groups during the FET cycle were 13.0 (12.0, 14.0) days in the high estradiol group and 13.0 (12.0, 15.0) days in the ultra-high estradiol group, which were significantly longer than those in the control group 13.0(12.0, 13.3)days. The E2 concentration before intimal transformation in high estradiol group was 1 560.4 (1 170.2, 1 848.2) pg/ml, while that in ultra-high estradiol group was 2 420.9 (2 131.0, 2 849.2) pg/ml, which was significantly higher than that in control group 238.8 (206.9, 287.0) pg/ml. The pregnancy outcome of the three groups: the clinical pregnancy rate of the three groups was 37.9% in the control group, 51.8% in the high estradiol group and 40.0% in the ultra-high estradiol group, of which the high estradiol group had the highest clinical pregnancy rate, followed by the ultra-high estradiol group. But there was no significant difference among the three groups (χ²=3.853, P>0.05). The embryo implantation rate of the three groups was 19.3%, 25.0%, 32.8%, respectively, and the embryo implantation rate of the ultra-high estradiol group was the highest, but there was no significant difference among the three groups (χ²=5.544,P>0.05).The live birth rate of the three groups was 37.9%, 39.3%, 40.0%, respectively, and the difference was not statistically significant (χ²=0.05, P>0.05). A total of 14(13.5%) abortions occurred in 104 clinical pregnancies, all of which occurred in the high estradiol level group. Of the 104 clinical pregnancies, 24 (23.1%) had twin pregnancies, which occurred in the high estradiol level group (10 cases) and the ultra-high estradiol level group (14 cases). There were no twin pregnancies in the control group. Ectopic pregnancy occurred in 4 of 230 FET cycles (1.7%), 2 in control group and 2 in high estradiol group, and no ectopic pregnancy in ultra-high estradiol group.

The association between serum estradiol levels and sperm DNA integrity.

In men from the general population, BMI has been associated with a lower sperm DNA fragmentation index (DFI). We wondered whether this could be due to estradiol, which is associated with BMI and reported important for sperm function. Our objective was to investigate the association between estradiol and DFI. In 2008-2010, we recruited 284 young men from the general population to deliver samples of semen and blood and answer questionnaires. Serum concentrations of reproductive hormones and DFI were analyzed, the latter using the Sperm Chromatin Structure Assay. Associations were studied using general linear models. The first model utilized metric values of estradiol, whereas the second model compared men with high and low levels, dichotomized by the median value. A possible interaction between estradiol and testosterone was also examined. When investigating metric estradiol levels and DFI, an inverse association was seen without adjustments (p= .02), but the statistical significance was lost at adjustments for potential confounders (p= .08). Men with lower estradiol levels (<88 pmol/L, mean 71 pmol/L) had a statistically significantly higher DFI than men with higher levels of estradiol (≥88 pmol/L, mean 110 pmol/L). Mean ratio difference was 1.21 (p= .002) without adjustments and 1.18 (p= .01) with adjustments. A statistically significant difference in DFI was observed in men with testosterone levels below median when comparing high and low estradiol (p< .001). This study supports the idea that serum estradiol levels are protective for sperm DNA integrity, at least at lower testosterone levels.

The effect of higher estradiol levels during stimulation on pregnancy complications and placental histology

IntroductionWe aimed to assess obstetric outcomes and placental histology in stimulated in vitro fertilization (IVF) cycles with a high serum estradiol level. MethodsThis was a historic cohort of live singleton deliveries after IVF, at a single university affiliated medical center between 2009 and 2017. Included were pregnancies following controlled ovarian stimulation with fresh embryo transfer. Excluded were IVF cycles with oocyte recipients and with a diagnosis of diminished ovarian reserve. High estradiol was defined as peak value above the upper quartile for the cohort, corresponding to 8700 pg/mL. ResultsA total 147 deliveries in the higher estradiol group were compared to 427 deliveries in the control group. No differences were demonstrated in patient demographics and infertility workup, except for a significantly higher antral follicle count in the high estradiol group, 21.5 ± 13.1 vs. 17.3 ± 10.7 follicles, p < 0.001 and lower rate of single embryo transfer, 51.7% vs. 73.5%, p < 0.001. No differences were demonstrated between the groups in pregnancy and obstetric outcomes investigated, including gestational age, preterm delivery, preeclampsia, cesarean delivery, birthweight and low birth weight. Placental histological examination was notable for a higher rate of velamentous cord insertion in the higher estradiol group - 12.2% vs. 6.7%, p = 0.03, more so in a sub analysis of cases of very high estradiol - 15.7% vs. 7.3%, p = 0.02. DiscussionPlacental histology following IVF with high estradiol level was notable for a higher rate of velamentous cord insertion.

P-634 Safety of ART cycles with extremely high estradiol levels - A retrospective cohort study

Abstract Study question Are IVF treatments with extremely high peak estradiol levels during ovarian hyperstimulation associated with higher complication rates? Summary answer Extremely high estradiol levels were not associated with higher major complication rates, but patients were more likely to seek medical care following retrieval. What is known already The freeze-all policy and the increasing popularity of social oocyte freezing, have led to an increase in gonadotropin doses and number of oocytes retrieved and, as a direct effect, higher estradiol levels. Studies reporting major ART complications (OHSS, bleeding, infection, torsion, thromboembolic events) are based on heterogeneous patient populations without stratification by oocyte number or estradiol levels, except for a single study reporting an association between peak estradiol levels and the risk of ovarian torsion. Extreme estradiol levels, are associated with larger ovaries, repeated ovarian punctures, and possibly a thrombogenic effect. Therefore, higher complication rates can be expected. Study design, size, duration A retrospective cohort study including patients from two large medical centers treated between 2019-2021. Participants/materials, setting, methods A study group (239 patients) with extremely high peak estradiol levels (&amp;gt;20,000 pmol/L on the day of ovulation induction, or &amp;gt; 15,000 pmol/L on the previous day) and a control group (208 patients) with normal range estradiol levels (3000-12000pmol/L), treated at two large units were included. Patients were surveyed about complaints and medical care related to ovum pick up (OPU), and medical files were reviewed. Complication rates and the need for medical assistance were compared. Main results and the role of chance Several differences between the study and control group were observed as a consequence of the study design: Mean age was 33.01±5.14 vs. 34.57±4.52 (p = 0.01), Mean peak estradiol levels was 26645.34±8592.56 vs.7229.750±2329.20 (p &amp;lt; 0.001), mean number of oocytes were 27.55±13.46 vs. 11.63±5.77 (p &amp;lt; 0.001) for the study and control group respectivly. More patients in the control group underwent fertility preservation. Mean FSH levels and total gonadotropin dosage were higher in the control group. Major complications [3 (1.25%) in the study group vs. 1 (0.96%) in the control group] were similar between groups (p = 0.62). In the study group Two patients were diagnosed with ovarian torsion (0.83%), and one (0.41%) with early severe OHSS as a result of a positive BhCG related to an undiagnosed pregnancy prior to OPU. All three were admitted (1.25%). In the control group one patient was diagnosed with PID requiring inpatient IV antibiotic treatment (0.48%). One more patient was admitted with severe abdominal pain following OPU, for a total of 2 admissions (0.96%) (p = 1). 33 patients (13.8%) in the study group and 10 (4.8%) in the control group sought medical care after OPU, mostly due to abdominal pain, without further workup or hospitalization (p = 0.001). Limitations, reasons for caution A retrospective study with possible recall bias. Major adverse events are rare in IVF and may not be fully captured in the study population. Wider implications of the findings Based on our results, extremely high estradiol levels during ovarian hyperstimulation were not associated with thromboembolic events, higher major complication or hospitalization rates, thus may be considered safe. Nevertheless, patients may be informed of possible higher rates of discomfort, mostly abdominal pain. Larger studies are warranted to confirm our results. Trial registration number 0090-21-ASF

P-670 Phytoestrogen concentration in women’s urine and follicular fluid are associated with better IVF outcomes in euploid single embryo transfer cycles

Abstract Study question What is phytoestrogen exposure impact on the reproductive outcomes of women undergoing IVF treatment? Summary answer Increased urinary and follicular fluid phytoestrogen concentration were associated with better IVF outcomes. What is known already The impact and safety of phytoestrogens, plant-derived isoflavones with estrogenic activity predominantly present in soy, on female reproductive health and on IVF outcomes continues to be hotly debated. Numerous studies suggest healthy benefits of phytoestrogen consumption: protection against reprotoxic substances, reductions in breast and other cancers, fibroids, menopausal symptoms, cardiovascular disease, inflammation, and metabolic syndrome and obesity. However, many studies suggest a harmful effect due to the endocrine-disruptor properties of phytoestrogens in both male and female reproductive tissues. Its impact on IVF treatments success is still understudied. Study design, size, duration 60 women attending IVI-RMA New Jersey undergoing IVF with single-embryo transfer (SET) of euploid good-quality blastocyst after PGT analysis were recruited. Patients underwent PGT-SET cycles following standard protocols. Concentrations of two phytoestrogens (daidzein and genistein) were measured in follicular fluid (FF) and urine collected at oocyte pick-up (UOP) and urine collected at transfer day (UT). These measurements were correlated with IVF clinical outcomes. Participants/materials, setting, methods Participants were aged 18-42 years old 18.5-29.9 kg/m2 BMI. Measure of both phytoestrogens’ concentration in follicular fluid and urine samples collected at two different time-points was performed by UPLC-MSMS, with internal standards. Urine phytoestrogen concentrations were normalized by creatinine, measured by Jaffe reaction. Generalized linear models were employed to explore IVF outcomes association, estimated as percentile 20th to 80th increase (95% confidence intervals), among log-transformed phytoestrogen concentration. Both unadjusted and age-BMI-adjusted models were applied. Main results and the role of chance In fully adjusted models, higher sum of phytoestrogen concentration in follicular fluid (FF) were significantly associated with higher estradiol at hCG [1.31 (1.04, 1.65), p = 0.023]; whereas the sum of creatinine-corrected phytoestrogens measured in oocyte pick-up urine (UOP) were significantly associated with higher MII oocytes number [1.29 (1.07, 1.56), p = 0.008] and higher fertilized oocytes number [1.34 (1.10, 1.64), p = 0. 004]. Regarding clinical IVF outcomes, in fully adjusted models a higher follicular fluid and oocyte pick-up urine phytoestrogens concentration was significantly associated with higher implantation ratio [8.60 (1.09, 68.03), p = 0. 023] for FF, and [5.01 (0.96, 26.21), p = 0. 05] for UOP; higher clinical pregnancies ratio [5.58 (1.31, 23.73), p = 0.017] for FF, and [3.25 (0.99, 10.63), p = 0.045] for UOP; higher live newborns ratio [5.58 (1.31, 23.73), p = 0.017] for FF, and [3.25 (0.99, 10.63), p = 0.045] for UOP; and higher number of women with live newborns among those who started treatment [4.29 (1.28, 14.38), p = 0.016] for FF, and [2.83 (0.99, 8.07), p = 0.047] for UOP. Limitations, reasons for caution Further studies are needed to confirm this association in other populations, including the measurement of other estrogenic isoflavones and its metabolites. Wider implications of the findings This is the first work evaluating the association between phytoestrogens concentrations in different biofluids and IVF reproductive outcomes. Our results, using an euploid SET, suggest a beneficial effect of phytoestrogen consumption in women undergoing IVF treatment, further studies are needed to assess the benefit of phytoestrogen supplementation on IVF outcomes. Trial registration number -

O-217 Associations between endometrial stem cells quantities, serum levels of progesterone and estradiol and expression of their respective receptors in endometrial tissue during the mid-luteal phase

Abstract Study question Is the percentage of endometrial stem cells linked to serum progesterone, serum estradiol, and their receptors expression in human endometrium during the mid-luteal phase? Summary answer We found an association between CD117+ endometrial stem cells and serum progesterone, estradiol, as well as with the expression of their receptors in the endometrium. What is known already Various types of stem cells including NOTCH1+ and CD117+ stromal cells have been found in the endometrium. Their quantities have been hypothesised to fluctuate with the menstrual cycle and to have a link with endometrial receptivity. It has been well established that progesterone and estradiol play a crucial role in the preparation of the endometrium for implantation and the expression of their receptors also varies with the menstrual cycle. Nonetheless, the relationship between stem cells and other established markers of endometrial receptivity, such as the sex hormones signaling system, constitutes a novel field of research. Study design, size, duration The present observational study included 87 women aged 26-56 (mean 39.5 years old) undergoing in-vitro fertilisation and for whom a peripheral blood sample and an endometrial biopsy were obtained during the mid-luteal phase (LH + 7) of a natural cycle. Immunohistochemical (IHC) markers for NOTCH1 (E-AB-12815, Elabscience), CD117 (CD117/c-Kit/SCF-Receptor RB-9038-RQ, Epredia), progesterone (PR) and estrogen receptors (ER) (1-PR026-07, 1-ES006-07, Quartett) were used to stain endometrial tissue. The investigation was carried out between March 2020 and January 2022. Participants/materials, setting, methods Serum progesterone and estradiol were measured via electrochemiluminescence using Cobas e411 analyser (Roche Diagnostics, Germany) on the day of obtaining the endometrial biopsy. Stem cells (count and percentage) and the expression of hormone receptors (6-point scale) were determined using ImageJ. Stem cells percentage was compared between groups with high and low progesterone (analogously for estradiol) using Wilcoxon signed-rank test. To assess the link between stem cell percentages and receptor expression, Spearman correlation was used. Main results and the role of chance The mean percentage of positively stained NOTCH1 endometrial stromal stem cells was 0.13 ± 0.29% and CD117+ cells was 0.034 ± 0.039%. The hormone serum levels ranged from 0.2 to 60 ng/mL (median of 14.9 ng/mL) for progesterone and from 12 to 1985 pg/mL (median of 135.6 pg/mL) for estradiol. While the quantities of the two stem cell types demonstrated a positive correlation with each other (R = 0.379, p &amp;lt; 0.001), the percentage of NOTCH1+ stem cells showed no difference between the studied serum hormone levels (p &amp;gt; 0.05), nor revealed a relationship with the expression of their receptors (p &amp;gt; 0.05). In contrast, the amount of CD117+ cells differed significantly between patients with high and low serum progesterone (cutoff 14.9 ng/mL, p = 0.001) and estradiol levels (cutoff 135.6 pg/mL, p = 0.019). Furthermore, the quantity of stem cells positive for CD117 correlated positively with the two hormone receptor levels in the endometrium – PR (R = 0.277, p = 0.019) and ER (R = 0.318, p = 0.007). Limitations, reasons for caution A limitation of the study was the sample size. These findings should be confirmed using a larger population. In addition, confounding variables such as the immunological profile of the tissue should also be taken into account. Wider implications of the findings This study shows that certain endometrial stem cell types (CD117+) but not others (NOTCH1+) are associated with sex hormone signaling during the mid-luteal phase. This relationship highlights the role these cells play in preparing the endometrium for embryo implantation and their quantity might be an indirect indicator of endometrial receptivity. Trial registration number not applicable

Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer.

BackgroundHigh levels of estrogen are associated with increased risk of breast and endometrial cancer and have been suggested to also play a role in the development of ovarian cancer. Cancerogenic effects of estradiol, the most prominent form of estrogen, have been highlighted as a side effect of estrogen-only menopausal hormone therapy. However, whether high levels of endogenous estrogens, produced within the body, promote cancer development, has not been fully established.ObjectiveWe aimed to examine causal effects of estradiol on breast, endometrial, and ovarian cancer.MethodsHere we performed a two-sample Mendelian randomization (MR) to estimate the effect of endogenous estradiol on the risk of developing breast, endometrial, and ovarian cancer, using the UK Biobank as well as 3 independent cancer cohorts.ResultsUsing 3 independent instrumental variables, we showed that higher estradiol levels significantly increase the risk for ovarian cancer (OR = 3.18 [95% CI, 1.47-6.87], P = 0.003). We also identified a nominally significant effect for ER-positive breast cancer (OR = 2.16 [95% CI, 1.09-4.26], P = 0.027). However, we could not establish a clear link to the risk of endometrial cancer (OR = 1.93 [95% CI, 0.77-4.80], P = 0.160).ConclusionOur results suggest that high estradiol levels promote the development of ovarian and ER-positive breast cancer.

Baseline Serum Estradiol Level Is Associated with Acute Kidney Injury in Patients with Moderately Severe and Severe Acute Pancreatitis.

Background Sexual dimorphism with critical diseases has been documented. However, the role of serum sex hormones for the presence of acute kidney injury (AKI) in moderately or severe acute pancreatitis (MSAP and SAP) patients remains controversial. Here we set out to evaluate whether early (first 48 h) serum estradiol level is associated with AKI in patients with MSAP and SAP. Patients and Methods. We retrospectively collected data from patients with preliminary diagnosis of MSAP and SAP from the Affiliated Hospital of Yangzhou University between January 2014 and June 2018. Serum sex hormones were extracted for further assessment within first 48 h following admission. Logistic regression analysis and the receiving operating characteristic (ROC) curve were applied to evaluate the association and correlation between serum sex hormones and AKI. Results Data from a total of 122 patients with MSAP or SAP were enrolled in this study. There were no differences in the incidence of AKI between males and females. However, comparing with patients without AKI, those with AKI saw higher estradiol level (p ≤ 0.01) and slight higher progesterone level (p = 0.014) but similar testosterone level (p = 0.668). Interestingly, during both the manual selection and the stepwise backward logistic regression analysis, serum estradiol level was independently associated with AKI in patients with MSAP and SAP (OR 4.699, CI 1.783-12.386, and p = 0.002). Additionally, area under the curve of ROC (AUCROC) showed that serum estradiol level was a proper predictor for AKI (area under the curve 0.875). Specifically, the serum estradiol level of 223.15 pg/mL demonstrated a 92.3% sensitive and a 79.3% specificity in predicting AKI of MSAP and SAP patients, respectively. Conclusions High baseline serum estradiol level appears to be an independent risk factor for AKI in patients with MSAP and SAP. It also tends to be an appropriate indicator for AKI.

Falsely elevated serum estradiol in woman of reproductive age led to unnecessary intervention and delayed fertility opportunity: a case report and literature review

BackgroundThe optimal management of patients in reproductive endocrinology relies on the accuracy and validity of sex hormone assays. Endogenous or exogenous substances can compete with the analyte. This competition can result in interfering errors and falsely indicate elevated serum levels. Obvious interference in estradiol assays appears to occur rarely. Consequently, clinicians who are not familiar with the potential of interference could be misled. In addition to unnecessary investigations and interventions and severe mental stress, falsely elevated estradiol results can result in missed or delayed fertility opportunities.CaseA 28-year-old female with pregnancy demand was diagnosed with polycystic ovary syndrome, Hashimoto’s thyroiditis and subclinical hypothyroidism. She was found to have persistently elevated levels of serum estradiol in the early follicular phase (between 527 and 642 pg/mL). Screening workup was performed for nearly 11 months to find the causes. Serum tumor biomarkers were normal. Abdominal and pelvic computed tomography were negative for adrenal or adnexal masses. A left mesosalpinx cyst and benign pathological results were achieved by laparoscopic surgery. Hormonal substances and dietary supplements were absent, as determined by dietary records. Ultrasound confirmed follicles could grow slowly and eventually ovulate. Falsely elevated estradiol levels were suspected due to the discrepancy among high estradiol levels, follicle growth and normal gonadotropin levels. Immunological interference by heterophile antibody was finally verified by two competitive chemiluminescent immunoassay platforms (estradiol levels in the early follicle phase: 619 pg/mL, Siemens ADVIA CENTAUR and 60 pg/mL, Beckman, DxI 800). Successful clinical pregnancy was eventually achieved by combining induced ovulation, ultrasound monitoring and intercourse guidance.ConclusionsAnalytical interference and laboratory error should be suspicious at first when the clinical characteristics contradict the laboratory results of serum hormones. Measuring serum estradiol with another immunoassay platform is an easy and non-time-consuming method to exclude the heterophile interfering.

Influence of Estradiol-Producing Ovarian Tumors on the Maturation Index of Cervical Cytology in Postmenopausal Women

Introduction: The aim of the study was to evaluate the influence of estradiol-producing ovarian tumors, including surface epithelial-stromal tumors, on the cervical cytology of postmenopausal women. Methods: This case-controlled study included 160 postmenopausal women who underwent a gynecological surgery between January 2009 and December 2016. The relationship between serum estradiol levels and the maturation index of cervical cytology was examined. Patients with ovarian tumors and a high estradiol level (≥28 pg/mL) constituted the estradiol-producing ovarian tumor group (30 women, including 23 with surface epithelial-stromal tumors). The maturation index of this group was compared with that of the control group (130 women with normal estradiol levels [<28 pg/mL] with either ovarian tumors or uterine tumors). Results: For all patients, the serum estradiol levels were significantly correlated with the maturation index (p < 0.001, r = 0.65). The maturation index of the estradiol-producing ovarian tumor group was significantly higher than that of the control group (0.67 ± 0.21 vs. 0.075 ± 0.16, p < 0.001). The area under the receiver operating characteristic curve for the maturation index was 0.94. The best maturation index cut-off level for estradiol-producing ovarian tumors was 0.20. Using this cut-off, the sensitivity and specificity were 94% and 82%, respectively. Conclusion: Estradiol-producing ovarian tumors influence cervical epithelial maturation in postmenopausal women. An increased maturation index may trigger the early detection of asymptomatic ovarian tumors.