High Estradiol Research Articles

Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women.

We uncover the unique underpinnings establishing how the systemic host environment contributes to the aged breast tumor microenvironment, characterized by high local estradiol and chronic inflammation with immune dysregulation, and show that targeting avenues of estrogen conversion and chronic inflammation work to restore anti-tumor immunity.

The High Estradiol Environment after IVF Causes the Increased Risk of Glucose Metabolic Dysfunction in Offspring.

Assisted reproductive technology (ART) is associated with increased metabolic risks in offspring. The effect of high maternal estradiol (E2) levels during early pregnancy on the glucose metabolism of offspring remains unclear. To evaluate glucose metabolism in in vitro fertilization (IVF)-conceived children and assess whether high E2 exposure during early pregnancy is associated with metabolic alterations. This retrospective analysis included 500 singletons aged 3-10 years born after fresh embryo transfer (ET) (n=200), frozen ET (n=100), and natural conception (NC) (n=200) from a university hospital. Children underwent anthropometric measurements and examinations for fasting glucose, insulin, and lipid levels. A mouse model of high E2 exposure during early pregnancy was established to study glucose and insulin tolerance, and insulin secretion. Compared with NC, children born after fresh ET showed higher fasting glucose/insulin levels, increased insulin resistance, and higher incidence of impaired fasting glucose, which might be associated with a higher maternal E2 levels. Frozen ET showed intermediate results. In mice, offspring exposed to high E2 levels during gestation exhibited impaired glucose/insulin tolerance and defects in insulin secretion. High maternal E2 levels in early pregnancy are associated with altered glucose metabolism and increased metabolic risks in IVF-conceived children. Further studies are needed to elucidate the underlying mechanisms.

7940 Is Urocortin 2 A Mediator Of Stress-induced Suppression Of The Luteinizing Hormone Surge?

Abstract Disclosure: H.F. Bell: None. R.A. Carrasco: None. M.J. Kreisman: None. R.B. McCosh: None. K.M. Breen Church: None. Stress is thought to be a contributing factor to the reduction of reproductive function and infertility observed in many different species. Although this is a well-documented phenomenon, the neural mechanisms mediating the suppression of reproductive neuroendocrine activity in response to stress are not yet fully understood. The paraventricular nucleus (PVN) of the hypothalamus is an integral part of the neural response to stress. The PVN initiates activation of Corticotropin Releasing Hormone (CRH) neurons and, in addition to CRH, the PVN contains a population of neurons expressing Urocortin 2 (UCN2), a CRH-like family member, with high affinity for CRH receptor 2. In females, stress has been shown to inhibit both the pulse and surge modes of Luteinizing Hormone (LH) secretion. We have preliminary evidence that kisspeptin neurons, controlling either type of LH secretion, contain CRH receptor 2. In this study we tested the sufficiency of UCN2 to disrupt the estradiol-induced LH surge. Female mice were ovariectomized and given a high estradiol treatment to induce a circadian-timed LH surge. Two days later, UCN2 or Vehicle was administered into the lateral ventricle via ICV injection on the morning of the expected surge (10 AM). Blood and brains were collected in the evening (6 PM), at the time of the expected surge. Whole blood from the tail tip was measured by LH ELISA and a surge was defined as > 0.5 ng/mL. A majority of saline-treated animals expressed an LH surge (8 of 9 females). In contrast, 0% of UCN2-treated animals surged (n=7), suggesting that UCN2 impaired the positive feedback response to estradiol. Additionally, immunohistochemistry was performed to observe colocalization of c-Fos within Kisspeptin neurons in the rostral periventricular region of the third ventricle (RP3V) which are responsible for surge generation. Lower Kisspeptin/C-Fos co-expression in animals treated with UCN2 demonstrated the efficacy of UCN2 to impair estradiol-induced activation of RP3V Kisspeptin neurons which are critical for LH surge generation. These results support the hypothesis that UCN2 signaling plays a mediatory role in the stress-induced reduction of ovulatory function in the female mouse. Presentation: 6/1/2024

Understanding sex differences in extinction retention: Pre-extinction stress and sex hormone status

Difficulties in fear regulation can sometimes result in maladaptive fear responses. To better understand how to improve fear regulation, it is important to determine how known factors, such as sex hormone status and stress, might interact to influence fear memory. Research has shown that women with high estradiol levels (mid-cycle) and men exhibit better extinction retention compared to women with low estradiol levels (women in the early follicular cycle or using oral contraceptives). Stress has also been demonstrated to affect both the learning and retention of extinction. Despite documented interactions between stress and sex hormones, their combined effects have not been thoroughly studied. This study aims to examine the impact of stress as a function of sex hormone status on extinction learning and retention.A total of 168 non-clinical participants were studied, including men (n = 46), women using oral contraceptives (n = 38), women in the early follicular phase (n = 40), and women in mid-cycle (n = 44). On Day 1, fear acquisition training was performed. On day 2, prior to extinction training, half of the participants were exposed to a psychosocial stressor, while the other half performed a non-stressful control task. On day 3, extinction retention was tested. Fear was quantified using skin conductance responses, while stress hormones were quantified through saliva samples.Exposure to stress prior to extinction training did not affect extinction learning, regardless of sex hormone status. In contrast, pre-extinction stress exposure had different effects on extinction retention depending on hormone status. Stressed men showed impairment in extinction retention compared to controls, while the experimental condition had no effect on naturally cycling women. Regardless of stress exposure, early follicular women exhibited a deficit in fear regulation, while mid-cycle women showed effective fear regulation. Among women using oral contraceptives, the stress group demonstrated better extinction retention compared to the control group.These results demonstrate the importance of considering sex hormone status and stress exposure during extinction learning, as both components may modulate extinction retention. These results could help identifying hormonal conditions that may enhance the effectiveness of extinction-based psychological therapies used in the treatment of fear-related disorders.

Effect of High Serum Estradiol Levels and Duration of Vaginal Estradiol Administration on Reproductive Outcomes in Frozen-Thawed Embryo Transfer Cycles

Effect of High Serum Estradiol Levels and Duration of Vaginal Estradiol Administration on Reproductive Outcomes in Frozen-Thawed Embryo Transfer Cycles

Hormonal dynamics of matrotrophy vs. lecithotrophy in live-bearing fish reproduction

We explored the relationship between gestational states, fecundity, and steroid hormone levels in three species of live-bearing fish with different maternal provisioning strategies. We studied two lecithotrophic species, Gambusia affinis and Xiphophorus couchianus, where embryos feed exclusively on yolk stored in the eggs, and one matrotrophic species, Heterandria formosa, which actively transfers nutrients to embryos through a follicular placenta. We measured water-borne cortisol, estradiol, and progesterone along with brood size (fecundity) and gestational stage(s). We examined the physiological costs of both maternal provisioning modes. Matrotrophy likely imposes energetic demands due to active nutrient transfer, while lecithotrophy may incur costs from carrying many large embryos. We hypothesized that fecundity, gestational stage, and hormones would covary differently in lecithotrophic vs. matrotrophic species. We found no relationships between hormones and fecundity or gestational stage in any species. However, in H. formosa, we found a positive relationship between estradiol levels and female mass, and a negative relationship between progesterone levels and female mass indicating a change in the circulating levels of both hormones as females grow. We observed differences in average hormone levels among species: the matrotrophic species had higher progesterone and lower estradiol compared to lecithotrophic species. Higher estradiol in lecithotrophic species may relate to egg yolk formation, while placental structures could play a role in progesterone production in matrotrophic species. Elevated cortisol in H. formosa suggests either higher energetic costs or a preparative role for reproduction. Our findings highlight progesterone's importance in maintaining gestation in matrotrophic species, like other placental species.

P-627 Does artificial hormonal therapy increase the TSH levels in frozen embryo transfer?

Abstract Study question Does administration of estradiol valerate for frozen embryo transfer (FET) increase the TSH value and the risk of miscarriage? Summary answer TSH is increased at the time of endometrial thickness and pregnancy test in HRT cycles. Women with higher TSH have an increased risk of miscarriage. What is known already Several studies describe the correlation between estradiol and TSH levels during menstrual cycles. The circulated TSH is upregulated by estradiol, in fact, TSH increases in the periovulatory phase and in women taking oral contraceptive therapy. A higher estradiol in the first trimester is correlated with an increased risk of thyroid dysfunction in offspring. TSH is also correlated to beta-Human Chorionic Gonadotropin (b-HCG) levels, many studies reported an increase of TSH values at b-HCG peak during 10-12 weeks of gestation. Study design, size, duration This is a retrospective, single-center, observational study enrolling 607 patients at IVI Roma from April 2022 to June 2023.Patients with 30-47 years old with single blastocyst transfer were included in the study. Both euploid frozen embryo transfer (FET) from autologous oocyte ICSI-PGT-A cycles and FET from ICSI cycles using donated oocytes were considered. FET performed under artificial endometrial preparation with HRT using exogenous estradiol and progesterone (vaginal, subcutaneous and intramuscular) were included in the study. Participants/materials, setting, methods TSH was evaluated before estradiol valerate administration (T0), at the control for endometrial thickness (T1), the day of embryo transfer (T2), and the day of b-HCG evaluation (T3). Accordingly, the patients were divided into two groups based on their TSH levels (low-normal group, ≤ 2.5 mIU/L; high group, > 2.5 mIU/L). The primary outcome was TSH values at different times. The secondary outcome evaluated the miscarriage rate (MR) calculated for FET. Main results and the role of chance TSH mean at T0 was 1.65 ± 0.87. The mean value of TSH after estradiol valerate administration was 1.97 ± 1.28. TSH value increased during the estradiol valerate administration with a mean increase of 0.29 mIU/L reaching statistical significance (p < 0.0001). No statistical differences were reported between T0-T2 (p = 0.64) while the statistical difference was reported in time T0-T3 with a mean increase of 0.40 mIU/L (p < 0.0001). Women with T1-TSH value > 2.5 mIU/L were 18.95%. The miscarriage rate in the group with TSH value >2.5 mIU/L was 17.81%. The univariate analysis showed that T1-TSH values >2.5 mIU/L did not affect the miscarriage rate OR 0.79 (95 CI% 0.37-1.67), p = 0.54. The multivariate analysis considering age, BMI and source of oocytes showed no statistical significance on the miscarriage rate OR 0.82 (95 CI% 0.39-1.72), p = 0.62. T2-TSH values did not affect the miscarriage rate in the univariate and multivariate analyses. Regarding T3-TSH, the univariate analysis showed that THS >2.5 mIU/L affects the miscarriage rate OR 1.97(95 CI% 1.07-3.65), p = 0.03. Multivariate analysis considering possible confounders showed that women with THS >2.5 mIU/L have a higher risk of miscarriage OR 1.96 (95 CI% 1.02-3.78), p = 0.04. Limitations, reasons for caution The retrospective design and patients with different female infertility factors for IVF were included in the study, leading to a possible biased population. The T1-TSH assessment was not scheduled at the same time for each patient. Women with TSH >2.5 mIU/L at the T1-TSH value were treated with levothyroxine. Wider implications of the findings This study emphasizes the correlation between estradiol valerate administration and TSH values and the possible relation with increasing risk of miscarriage in women with higher TSH. Patients undergoing FET with HRT should consider thyroid supplementation or increasing dosage to reduce the risk of miscarriage. Trial registration number not applicable

P-474 State-Trait Anxiety Inventory (STAI) punctuations as a non-invasive method for evaluating endometrial prognosis associated with cortisol and estradiol endometrial levels in IVF patients

Abstract Study question Are STAI State punctuations a potential non-invasive marker of endometrial prognosis in IVF patients? Summary answer Being stressed (determined by STAI State punctuations) is positively and negatively correlated with endometrial cortisol and estradiol levels, respectively, and highly associated with pregnancy consecution. What is known already Despite it is well known IVF treatments are a source of stress, this factor is frequently overlooked mainly due to the difficulty of stress evaluation and the lack of accurate biomarkers, not being standardized in the clinical setting. Steroid hormones are essential for reproductive physiology and highly related to well-known stress biomarkers such as cortisol. The lack of correlation between endometrial and serum steroid levels creates the need to look for non-invasive tools reflecting the endometrial microenvironment. In this study, by molecularly and psychologically characterizing patients, we aim to unveil non-invasive potential markers of stress associated to pregnancy consecution. Study design, size, duration This prospective cohort study included a total of 74 IVF patients (<45 years old, no uterine or systemic pathologies and good quality embryos) who underwent endometrial biopsy collection in mid-secretory phase for metabolites measurement between 2019 and 2023. These patients also underwent psychological evaluation by stress related questionnaires. Participants/materials, setting, methods The endometrial concentration of eleven steroid metabolites was measured by ultra-performance liquid chromatography-tandem mass spectrometry. Patients also underwent stress and anxiety evaluation (STAI), and reproductive outcomes in the first embryo transfer after biopsy collection were followed up. Wilcoxon and Barnard’s test were applied to compare the mean and proportion of stressed/unstressed, pregnant/not pregnant patients and metabolites levels. Correlations between metabolites’ levels and the proportion of stressed patients were evaluated by Pearson’s correlation coefficient. Main results and the role of chance Patients with STAI State punctuations > 60 presented higher mean endometrial cortisol levels (8.01 ng/g (n = 23) vs 5.08 ng/g (n = 35), p-value = 0.05) and lower mean estrone levels (54.97 ng/g (n = 23) vs 56.31 ng/g (n = 35), p-value = 0.049) than those patients with STAI State punctuations < 60. Also, in patients with high endometrial estradiol levels (>2 ng/g) a higher significant proportion of unstressed patients (STAI State < 60) was observed (88.9% vs 52% of unstressed patients in > 2 ng/g and < =2 ng/g estradiol concentrations, respectively) (n = 34, p-value = 0.036). As expected, a significant positive correlation between endometrial cortisol levels and stress (measured by STAI State questionnaire) (cor = 0.977, p-value = 0.023) and a negative correlation between endometrial estradiol levels and stress (cor = -0.9945, p-value = 0.0055) was evidenced. Additionally, a higher proportion of pregnant patients was observed when endometrial estradiol concentrations were high (>1 ng/g) (78.9% vs 50% pregnant in > 1 ng/g vs < =1 ng/g estradiol respectively, p-value = 0.035) and a higher proportion of not pregnant patients was observed when endometrial cortisol concentrations were high ( > =13.9 ng/g) (80% vs 34.4% not pregnant in > =13.9 ng/g and <13.9 ng/g cortisol respectively, p-value = 0.029). Limitations, reasons for caution Although we have employed validated psychological questionnaires and stress biomarkers, a causal relationship between stress and reproductive outcomes should be further explored. Wider implications of the findings This study demonstrated a significant correlation between stress and cortisol and estradiol levels. Since both metabolites’ levels were also related to pregnancy chances, STAI State psychological evaluation could be implemented in the clinical practice as a non-invasive method to prevent endometrial failure through psychological counseling. Trial registration number Not applicable

P-445 High serum estradiol on the day of frozen blastocyst transfer is associated with higher early miscarriage rates in hormonal replacement therapy cycles using transdermal estrogens

Abstract Study question Do serum estradiol(E2) levels on the day of frozen blastocyst transfer(FBT) affect the live birth rate (LBR) in hormonal replacement therapy(HRT) cycles using transdermal estrogens? Summary answer E2 levels ≥ 313 pg/mL on the day of FBT are associated with increased early miscarriage rates, but no significant impact on LBR. What is known already E2 plays a crucial role in endometrial receptivity during the periconceptional period and a massive role in placentation. However, the impact of serum E2 levels measured around the time of a FBT in HRT cycles outcomes remains controversial, with some studies showing a detrimental impact of high levels, and others underlining no difference. To this date, there is no study focusing on HRT cycles with transdermal estrogens only, though it is the safest way of estrogen administration regarding thrombo-embolic complications. Study design, size, duration Observational cohort study with 2364 patients undergoing HRT-FBT cycles at a university hospital, between January 2019 and December 2022. Women were only included once during the study period. Participants/materials, setting, methods Patients undergoing single autologous FBT under HRT using transdermal estrogens and vaginal micronized progesterone. The serum E2 level was measured in the morning of the FBT, in a single laboratory. The primary outcome was the LBR, secondary outcomes included clinical pregnancy rates, early miscarriage rates(EMR), and obstetrical outcomes. Patients were divided into three groups based on the 25th and the 75th percentiles of E2 levels and compared using univariate and multivariate logistic regression models. Main results and the role of chance A total of 2364 patients were divided into 3 groups: group A < 122 pg/mL (n = 590), group B 122-312 pg/mL (n = 1184), and group C ≥ 313 pg/mL (n = 590). Mean serum E2 level on the day of FBT was 247.8 pg/mL ± 209.01 pg/ml. The LBR was 32.0% (756/2364), and the early miscarriage rate was 26.3% (280/1075) in the overall population. Multivariate logistic regression showed a negative impact of high E2 levels (≥ 313 pg/mL) on EMR: an increase in the EMR was noted between group C and referent group B (30.3% versus 24.6%, OR 1.5 95%CI (1.06-2.17)). However, no significant impact of E2 levels was noted regarding the LBR (group C vs group B, adjusted OR 0.9 95%CI (0.69-1.10)), the clinical pregnancy rates, or the obstetrical outcomes (birthweight and term of delivery Limitations, reasons for caution The main limitation of our study is linked to its observational design. Extrapolation of our results to other laboratories, or other routes and/or doses of administering estrogens also needs to be validated. Wider implications of the findings Limiting high serum E2 levels on the day of FBT in HRT cycles may improve ART outcomes. Further studies are needed to evaluate if modifications of estrogen doses may improve pregnancy chances, in an approach to individualize the management of ART patients. Trial registration number not applicable

P-706 The pregnancy rates in a large cohort of patients with thin endometrium when stratified according to estradiol levels on the day of triggering

Abstract Study question Is there any difference in ongoing pregnancy rate in women with thin endometrium (<8 mm) when scrutinized based on estradiol levels on triggering day? Summary answer Either with a low, moderate, or high estradiol level on the day of triggering, ongoing pregnancy rates do not change in patients with thin endometrium. What is known already Endometrial thickness has been argued to be one of the proxy determinants of endometrial receptivity. In that context, although the optimal thickness has been widely stated to be between 8-14 mm, the negative effect of thin endometrium on pregnancy outcome is still controversial in in-vitro-fertilization (IVF) cycles. Nevertheless, particularly lack of large sample size of women with thin endometrium among the available literature, is the leading factors that avoids to solid conclusion.Furthermore, it might be hypothesized that patients with thin endometrium and accompanying low estradiol might be distinct from women with thin endometrium despite relatively high estradiol level. Study design, size, duration A retrospective cohort study was designed among patients that has undergone in-vitro fertilization (IVF) treatment between January-2018 and June-2023 in Bahceci Health Group. Only patients having an endometrial thickness <8 mm on the day of triggering were recruited. Other inclusion criteria was having at least one blastocyst to be transferred. All frozen-thawed embryo transfer cycles were excluded. Female age and body mass index were not considered as an exclusion criterion. Participants/materials, setting, methods During the study period, a total of 3076 IVF cycles with fresh ET were employed. Of them, 814 had an endometrial thickness of < 8 mm on the day of triggering. Among 814 IVF cycles, 25th, 50th and 75th quartiles of estradiol levels on the day of triggering referred to 322.8, 755.7 and 1310.5 pg/ml, respectively. The number of IVF-ET cycles in the 1st, 2nd, 3th and 4th quartiles were 203, 204, 204 and 203. Main results and the role of chance The mean (SD) age of women recruited in the final analyses was 36.5 (5.5) years and endometrial thickness was 7.2 (0.8) mm. The pregnancy rates per ET with regard to 1st, 2nd, 3th and 4th quartiles were 37.6%, 33.0%, 37.3% and 44.3%, respectively without any statistical significance (p = 0.134). However, the respective ongoing pregnancy rates were 26.1%, 18.1%, 22.1%, 31.0 % and the highest quartile had a statistically superior ongoing pregnancy rates than the second (p = 0.003) and third quartiles (p = 0.022). When binary logistic regression analysis was performed by inserting the female age, body-mass index, duration of infertility and quartiles of estradiol levels on the day of triggering, only female age remained as an independent factor for the prediction of an ongoing pregnancy (RR: 0.92 CI95%: 0.87 to 0.98, p = 0.008). Utilization of estradiol level as a continuous variable in the same model also failed to present the independent validity of it to predict an ongoing pregnancy. Notably, the lowest thickness of a positive pregnancy resulting with an ongoing pregnancy was 4.7 mm. Limitations, reasons for caution The inherent risks cannot be excluded due to the retrospective nature of the current study, which had been efforted to overcome with regression analysis. Wider implications of the findings The current study includes one of the largest numbers of experience particularly with thin endometrium on the day of triggering. However, having a thin endometrium despite low or relatively high estradiol level does yield any prediction for the pregnancy outcome. Trial registration number Not Applicable

A Positive Feedback Loop Exists between Estradiol and IL-6 and Contributes to Dermal Fibrosis.

Systemic sclerosis (SSc) is characterized by dermal fibrosis with a female predominance, suggesting a hormonal influence. Patients with SSc have elevated interleukin (IL)-6 levels, and post-menopausal women and older men also have high estradiol (E2) levels. In the skin, IL-6 increases the enzymatic activity of aromatase, thereby amplifying the conversion of testosterone to E2. Therefore, we hypothesized that an interplay between E2 and IL-6 contributes to dermal fibrosis. We used primary dermal fibroblasts from healthy donors and patients with diffuse cutaneous (dc)SSc, and healthy donor skin tissues stimulated with recombinant IL-6 and its soluble receptor (sIL-6R) or E2. Primary human dermal fibroblasts and tissues from healthy donors stimulated with IL-6+sIL-6R produced E2, while E2-stimulated dermal tissues and fibroblasts produced IL-6. Primary dermal fibroblasts from healthy donors treated with IL-6+sIL-6R and the aromatase inhibitor anastrozole (ANA) and dcSSc fibroblasts treated with ANA produced less fibronectin (FN), type III collagen A1 (Col IIIA1), and type V collagen A1 (Col VA1). Finally, dcSSc dermal fibroblasts treated with the estrogen receptor inhibitor fulvestrant also generated less FN, Col IIIA1, and Col VA1. Our data show that IL-6 exerts its pro-fibrotic influence in human skin in part through E2 and establish a positive feedback loop between E2 and IL-6.

High circulating concentrations of estradiol are anabolic for bone mass and strength in an adult male to female transgender mouse model

The effects of gender affirming hormone therapy (GAHT) on bone microarchitecture and fracture risk in adult transgender women is unclear. To investigate the concept that skeletal integrity and strength in trans women may be improved by treatment with a higher dose of GAHT than commonly prescribed, we treated adult male mice with a sustained, high dose of estradiol. Adult male mice at 16 weeks of age were administered ~1.3 mg estradiol by silastic implant, implanted intraperitoneally, for 12 weeks. Controls included vehicle treated intact females and males. High-dose estradiol treatment in males stimulated the endocortical deposition of bone at the femoral mid-diaphysis, increasing cortical thickness and bone area. This led to higher stiffness, maximum force, and the work required to fracture the bone compared to male controls, while post-yield displacement was unaffected. Assessment of the material properties of the bone showed an increase in both elastic modulus and ultimate stress in the estradiol treated males. Treatment of male mice with high dose estradiol was also anabolic for trabecular bone, markedly increasing trabecular bone volume, number and thickness in the distal metaphysis which was accompanied by an increase in the histomorphometric markers of bone remodelling, mineralizing surface/bone surface, bone formation rate and osteoclast number. In conclusion, a high dose of estradiol is anabolic for cortical and trabecular bone in a male to female transgender mouse model, increasing both stiffness and strength. These findings suggest that increasing the current dose of GAHT administered to trans women, while considering other potential adverse effects, may be beneficial to preserving their bone microstructure and strength.

Abstract PS10-03: Impact of Baseline Oestradiol and Testosterone on the Preventive Effect of Anastrozole

Abstract It is well known that serum levels of oestradiol and testosterone, esp free hormone levels, influence the risk of developing breast cancer in postmenopausal women (Thomas et al 1997, Hankinson et al 1998, Kaaks et al 2005, Tin Tin et al 2021). However very little is known about how these hormone levels influence the effectiveness of aromatase inhibitors. In the IBIS-II Prevention Trial we compared anastrozole to placebo in 3864 women at high risk of breast cancer (Cuzick et al 2020). Of these women 3644 (94.3%) had a baseline blood sample. In those with a valid blood sample, 72 in the anastrozole arm and 142 in the placebo arm developed breast cancer (including DCIS) after 12.9 years of follow up (OR = 0.49, 95% CI 0.37–0.66 P< 0.0001). For each case two controls were selected, matched on age, treatment arm and follow up longer than the matching case. In these women oestradiol (E2), testosterone (Testo) and SHBG were measured by liquid chromatography – tandem mass spectroscopy, and E2/SHBG and Testo/SHBG ratios were computed to approximate free hormone levels, and analysed in quartiles. Hormone replacement therapy was not allowed during the trial, and women with use within 3 months prior to entry or outlier hormone values were excluded from these analyses. In the placebo arm higher levels of both of these ratios were associated with a higher breast cancer rate (OR per quartile 1.25 (1.04-1.59), P=0.018) for E2/SHBG and (OR per quartile 1.22 (1.02-1.47), P = 0.032) for Testo/SHBG), whereas no significant effect was seen in the anastrozole arm (OR = 1.05 (0.81-1.37), and 1.16 (0.90-1.49), resp) (Table). Neither treatment interaction was significant. Absolute numbers of cases were similar between the anastrozole and placebo arms in the lowest quartile of E2/SHBG (18 anastrozole, 22 placebo), but higher numbers were seen in the placebo arm for the other quartiles. Similar results were seen for testo/SHBG, and supportive, but weaker results were seen for these two hormones without an SHBG adjustment, SHBG and BMI at entry. Adjusting for other risk factors had no influence on these findings. Effect sizes were similar during the 5 year treatment period and thereafter. There were too few ER negative cases to compare results by receptor status. Vasomotor side effects were higher with increasing E2/SHBG levels in both arms, but no other hormone showed an effect, and no hormone level was significantly associated with gynaecologic or musculoskeletal side effects. As aromatase inhibitors effectively eliminate the production of oestradiol in postmenopausal women, these results suggest they may be more effective in postmenopausal women with high oestradiol or testosterone levels, and raise questions about their value in women in the lower quartile of serum levels for these hormones for prevention and possibly adjuvant treatment. Table: Risk of breast cancer by quartiles of the oestradiol/SHBG in ratio high risk women treated with anastrozole or placebo. Citation Format: Jack Cuzick, Kim Chu, Brian Keevil, Antony Howell, Bernardo Bonanni, Evans Gareth, Kaija Holli, Sibylle Loibl, Nicholas Zdenkowski, Steven Cummings, Mitch Dowsett. Impact of Baseline Oestradiol and Testosterone on the Preventive Effect of Anastrozole [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-03.

Myostatin deletion alters hormone metabolism shifts in obese skeletal muscle of C57/Bl6 mice

Objective: Myostatin deletion improves cardiometabolic disease outcomes observed in obesity without any changes in activity in mice. Hormone balance is dysregulated in obesity, resulting in low testosterone and high estradiol levels, which have been shown to correlate with higher risk for developing associated cardiometabolic disease outcomes. However, the basis of these alterations and how they impact factors that improve obese cardiometabolic outcomes are unknown. Methods: Control and obese mice ( db/db) with or without myostatin deletion to induce hypermuscularity were used. Plasme from mice were analyzed for hormone levels via radioimmunoassay (RIA). Aromatase inhibition was performed via dosing 10mg/kg/day via water. Quantitative PCR was used cytochrome P450 enzymes involved in estrogen metabolism in the liver, skeletal muscle, and visceral white adipose tissue. C2C12 overexpression of CYP1B1 and treatment with hydroxyestrogens in vitro was performed and respective enzyme mRNA expression assessed. Results: Deletion of myostatin increased muscle mass by >30% and resulted in and improved glucose tolerance in the context of obesity without any changes in activity. Obesity decreased plasma testosterone 30% and increased estrogen 20% with no change in gonadal weight, which was improved in the absence of myostatin. CYP1B1, an enzyme that converts estradiol to toxic hydroxy estrogens, showed 2.5-fold expression in obese skeletal muscle, which is reduced in the absence of myostatin, with no change in other cytochrome P450s involved in estrogen metabolism. Inhibition of aromatase reduces estrogen and improves testosterone plasma concentration, indicating the excess estrogen in obesity is derived primarily from testosterone conversion. Aromatase expression was increased in obesity but unaffected by changes in muscle mass, this indicates an alteration to downstream estrogen metabolism. In C2C12 cells, overexpression of myostatin recapitulated changes in CYP1B1 expression seen in vivo, suggesting a direct link between the myokine and sex hormone metabolism. In addition, treatment of C2C12 cells with CYP1B1 derived hydroxyestrogens caused a tandem increase in SCD1 expression, indicating a causal link between CYP1B1 activity in obesity to increased triglyceride synthesis. Conclusion: In summary, obesity causes a shift in sex hormone levels towards estrogen production, which is improved by myostatin deletion. A potential mechanism responsible could be altered estrogen metabolism, leading to decreased estrogen levels without restoration of androgen levels. These data suggest CYP1B1 drives the conversion of estrogen to hydroxestrogens, known to harbor carcinogenic and pro-lipidemic influences, in skeletal muscle which may also contribute to cardiometabolic disease. Whether targeting CYP1B1 improves cardiometabolic function in obesity remains to be determined. D.W. Stepp and D.J. Fulton are supported by NIH 1R01HL147159. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Predictive Validity of Multifactorial Injury Risk Models and Associated Clinical Measures in the U.S. Population.

Background: Popular movement-based injury risk screens were shown to lack predictive precision, leading to interest in multifactorial models. Furthermore, there is a lack of research regarding injury risk assessment for those currently or planning to be recreationally active. This study aims to provide injury risk insights by analyzing multifactorial injury risk models and associated clinical measures in the U.S. population. Methods: Data related to injury, inflammatory markers, physical functioning, body composition, physical activity, and other variables from 21,033 respondents were extracted from NHANES. Odds ratios for self-reported injury were calculated for single predictors and risk models. Case-control and principal component analyses (PCA) were conducted to elucidate confounders and identify risk factor clusters, respectively. Receiver operating characteristic analysis was used to test the precision of a risk factor cluster to identify pain points and functional difficulties. Results: Sociodemographic, individual, and lifestyle factors were strongly associated with higher odds of injury. Increases in fibrinogen and C-reactive protein were significantly associated with all risk groups. Membership to the high-risk group (age over 40, obesity, no muscle-strengthening activities, sedentary lifestyle, and low back pain) predicted at least one functional difficulty with 67.4% sensitivity and 87.2% specificity. In the injury group, bone turnover markers were higher, yet confounded by age, and there was a significantly higher prevalence of self-reported osteoporosis compared to the control. In males, low testosterone was associated with injury, and high estradiol was associated with pain and functional difficulties. In females, high follicle-stimulating hormone was associated with functional difficulties. PCA revealed four high-risk profiles, with markers and activities showing distinct loadings. Conclusions: A comprehensive approach to injury risk assessment should consider the nexus of aging, lifestyle, and chronic disease to enhance tailored injury prevention strategies, fostering safe and effective physical activity participation and reducing the burden of musculoskeletal disorders.

Association between serum estradiol and cardiovascular health among transgender adults using gender-affirming estrogen therapy.

Gender-affirming estrogen therapy (GAET) is commonly used for feminization in transgender and nonbinary (TNB) individuals, yet the optimal rate of change (ROC) in estradiol levels for cardiovascular health is unclear. We examined the association between serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were systematically searched (inception-April 2023) for original articles reporting serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Data extraction was completed in duplicate following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Stratified random effect meta-analyses using serum estradiol ROC (serum estradiolbaseline - serum estradiolfollow-up/study duration) was used to assess longitudinal studies (low, 0 < ROC ≤ 1 pg/mL/mo; moderate, 1 < ROC ≤ 3 pg/mL/mo; high, ROC ≥ 3 pg/mL/mo). Thirty-five studies (13 cross-sectional, 19 cohort, and 3 trials) were included. Two studies collectively reported 50 cardiovascular-related deaths, and four collectively reported 23 adverse cardiovascular events. Nineteen studies reporting cardiovascular risk factors were meta-analyzed by ROC stratum (low = 5; moderate = 6; high = 8), demonstrating an association between moderate [0.40, 95% confidence interval (CI): 0.22, 0.59 kg/m2, I2 = 28.2%] and high (0.46, 95% CI: 0.15, 0.78 kg/m2; I2 = 0.0%) serum estradiol ROC and increased body mass index. High (-6.67, 95% CI: -10.65, -2.68 mg/dL; I2 = 0.0%) serum estradiol ROC was associated with decreased low-density lipoproteins. Low (-7.05, 95% CI: -10.40, -3.70 mmHg; I2 = 0.0%) and moderate (-3.69, 95% CI: -4.93, -2.45 mmHg; I2 = 0.0%) serum estradiol ROCs were associated with decreases in systolic blood pressure. In TNB adults using GAET, serum estradiol ROC may influence cardiovascular risk factors, which may have implications for clinical cardiovascular outcomes.NEW & NOTEWORTHY In this systematic review and meta-analysis of 35 studies involving 7,745 participants, high rates of serum estradiol change were associated with small increases in body mass index. Moderate to high rates of change were associated with decreases in low-density lipoprotein. Low rates of change were associated with small decreases in systolic blood pressure. Rate of serum estradiol change in adults using gender-affirming estrogen therapy may influence cardiovascular risk factors, though further research is warranted.

High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes.

There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2ng/mL or 3-day area under the curve > 4.5ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol 4000pg/mL had a greater likelihood of GBO compared to cycles < 1000pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000pg/mL versus 1000-1999pg/mL and 1000-1999pg/mL versus 2000-2999pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999pg/mL versus 3000-3999pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999pg/mL versus 4000pg/mL, aRR 0.96, 95% CI 0.9-1.04). In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

An investigation of the role of estradiol in fear reduction during a single session of exposure therapy

ABSTRACT Research suggests that estradiol may moderate fear extinction. It is unclear whether these results generalize to exposure therapy. The aim of the current study was to determine whether estradiol moderates outcomes in exposure therapy among women with anxiety disorders. Participants were 35 women with a primary diagnosis of an anxiety disorder who participated in the study as part of routine care at an anxiety specialty clinic. Endogenous estradiol was assessed via saliva. They provided subjective distress ratings before (pre) and after (post) an exposure session, as well as after a brief delay (recall). Contrary to predictions, there were no significant differences in exposure outcomes between the high and low estradiol groups. However, among participants with primary obsessive-compulsive disorder (OCD), results were partially consistent with the hypotheses. Women with lower estradiol initially demonstrated more improvement in subjective distress from pre- to post-exposure, but after the delay, significantly greater distress (attenuated extinction recall). Results suggest that women with lower estradiol may respond less favorably to exposure therapy for OCD relative to women with higher estradiol. These findings await replication in larger samples with longer recall delays. Should replication occur, these results may inform the use of estradiol to augment exposure therapy.

The effect of serum estrogen level on male infertility &amp; semen parameters on Sudanese males attending Khartoum Dermatology Teaching Hospital

Background Infertility is defined as the inability to achieve pregnancy after one year of unprotected intercourse. As estimated 10–15% of couples were considered infertile by W.H.O. One of the major causes of non-obstructive infertility is hormonal disturbance. Testosterone and Estrogen, traditionally, have been regarded as male and female sex hormones respectively. However, Estradiol, the predominant form of Estrogen, also plays a pivotal role in male sexual function. Estradiol in men is quintessential in many sexual physiological processes. Objectives To evaluate the effect of Estrogen levels on infertile men and their semen parameters Method In this prospective case-control hospital based study, a total number of 50 infertile men with primary and secondary infertility (case group) and 50 fertile men (control group) were included. The medical histories of all the participants were taken and physical examinations were conducted thoroughly. Serum Estradiol (E2) levels were measured for both infertile and fertile group. Seminal analysis was done for the infertile group. Serum E2 was measured by Radio-Immunosorbent Assay (RIA) using Estradiol kits for measurement. Standard semen analysis was done by computer-assisted seminal analysis (CASA) using the WHO manual 2010. The collected data were analyzed using Statistical Package for the Social Sciences (SPSS) version 25. The results were obtained and presented in tables and diagrams. The significance of testing was assessed by Chi-Square T test with P value ≤0.05 was considered statistically significant. Results A significant correlation was observed between the fertility status and serum E2 levels. 18% (n=9) of the subfertile patients were found to have serum E2 levels more than 55 pg/ml. on the other hand, only 6% (n=3) of the fertile group (control group) were above 55 pg/ml (P value less than 0.05). Azoospermia was found to be the most semen parameter among patients with elevated serum E2 level (P value less than 0.05). It is also observed that 46% of the infertile patients were found to be overweight (BMI=25–29.9) &amp; they have significantly high serum E2 levels (P value less than 0.05). Conclusion High serum Estradiol levels were found significantly correlated with male infertility; Azoospermia was the most commonly observed abnormal semen parameter. Overweight patients have significantly elevated Serum E2 levels.

Changes in the femoral trochlear induced with estradiol exposure, an experimental study on rats.

It is well known that estrogen is closely related to bone and joint tissue. Findings indicate that estradiol, injected during pregnancy, passes through the placental barrier and reaches the fetuses in utero where it exerts its action. Since trochlea appears well established in the prenatal period, however, whether trochlear dysplasia is related to estradiol exposure has not been confirmed, and the pathological process of estradiol exposure-induced trochlear dysplasia remains unclear. This study aimed to establish an estradiol exposure animal model in fetuses and to analyze the morphology of the femoral trochlear in neonatal rats. 30 pregnant Wistar rats provided by the local Animal Center were assigned randomly into three groups, a high dose estradiol injection group, a low dose estradiol injection group and a blank control group. Gross, cross-sectional observation, histological staining measurement and microcomputed tomography of the rat offspring were conducted to evaluate the morphological changes of the femoral trochlea. The incidence of trochlear dysplasia increased with the concentration of estradiol injection. Gross and cross-sectional observation showed a shallower trochlea groove in two groups with estradiol injection. Histological staining measurement indicated that the trochlear sulcus angle and trochlear sulcus depth were significantly different between the two groups with estradiol injection and the blank control group at 0,5 and 10 days after birth. Subchondral bone loss was observed in the two estradiol injection groups by micro-CT, and the bone loss was found to deteriorate over time. In this study, estradiol exposure in fetuses had an adverse effect on intrauterine development and could induce trochlear dysplasia and bone loss in rat offspring. In addition, this study also showed that the higher concentration of estradiol injection in pregnant rats, the more incidence of trochlear dysplasia in rat offspring.