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“All-In-One” Genetic Tool Assessing Endometrial Receptivity for Personalized Screening of Female Sex Steroid Hormones

ABSTRACT: Endometrium is the uterine lining that undergoes hundreds of cycles of proliferation, differentiation, and desquamation throughout a woman's reproductive life. Recently, much attention is paid to the appropriate endometrial functioning, as decreased endometrial receptivity is stated to be one of the concerns heavily influencing successes of embryo implantation rates and the efficacy of in vitro fertilization (IVF) treatment. In order to acquire and maintain the desired endometrial receptivity during IVF cycles, luteal phase support by various progestagens or other hormonal combinations is generally recommended. However, today, the selection of the specific hormonal therapy during IVF seems to be empirical, mainly due to a lack of appropriate tools for personalized approach. Here, we designed the genetic tool for patient-specific optimization of hormonal supplementation schemes required for the maintenance of endometrial receptivity during luteal phase. We optimized and characterized in vitro endometrial stromal cell (ESC) decidualization model as the adequate physiological reflection of endometrial sensitivity to steroid hormones. Based on the whole transcriptome RNA sequencing and the corresponding bioinformatics, we proposed that activation of the decidual prolactin (PRL) promoter containing ancient transposons MER20 and MER39 may reflect functioning of the core decidual regulatory network. Furthermore, we cloned the sequence of decidual PRL promoter containing MER20 and part of MER39 into the expression vector to estimate the effectiveness of ESC decidual response and verified sensitivity of the designed system. We additionally confirmed specificity of the generated tool using human diploid fibroblasts and adipose-derived human mesenchymal stem cells. Finally, we demonstrated the possibility to apply our tool for personalized hormone screening by comparing the effects of natural progesterone and three synthetic analogs (medroxyprogesterone 17-acetate, 17?-hydroxyprogesterone caproate, dydrogesterone) on decidualization of six ESC lines obtained from patients planning to undergo the IVF procedure. To sum up, we developed the “all-in-one” genetic tool based on the MER20/MER39 expression cassette that provides the ability to predict the most appropriate hormonal cocktail for endometrial receptivity maintenance specifically and safely for the patient, and thus to define the personal treatment strategy prior to the IVF procedure.

SUBMITTER: Deryabin P

PROVIDER: S-EPMC7917288 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Project description:ObjectiveSex steroid hormones may play a role in insulin resistance and glucose dysregulation. However, evidence regarding associations between early-pregnancy sex steroid hormones and hyperglycemia during pregnancy is limited. The primary objective of this study was to assess the relationships between first trimester sex steroid hormones and the subsequent development of hyperglycemia during pregnancy; with secondary evaluation of sex steroid hormones levels in mid-late pregnancy, concurrent with and subsequent to diagnosis of gestational diabetes.MethodsRetrospective analysis of a prospective pregnancy cohort study was conducted. Medically low-risk participants with no known major endocrine disorders were recruited in the first trimester of pregnancy (n=319). Sex steroid hormones in each trimester, including total testosterone, free testosterone, estrone, estradiol, and estriol, were assessed using high-performance liquid chromatography and tandem mass spectrometry. Glucose levels of the 1-hour oral glucose tolerance test and gestational diabetes diagnosis were abstracted from medical records. Multivariable linear regression models were fitted to assess the associations of individual first trimester sex steroids and glucose levels.ResultsIn adjusted models, first trimester total testosterone (β=5.24, 95% CI: 0.01, 10.46, p=0.05) and free testosterone (β=5.98, 95% CI: 0.97, 10.98, p=0.02) were positively associated with subsequent glucose concentrations and gestational diabetes diagnosis (total testosterone: OR=3.63, 95% CI: 1.50, 8.78; free testosterone: OR=3.69; 95% CI: 1.56, 8.73). First trimester estrone was also positively associated with gestational diabetes (OR=3.66, 95% CI: 1.56, 8.55). In mid-late pregnancy, pregnant people with gestational diabetes had lower total testosterone levels (β=-0.19, 95% CI: -0.36, -0.02) after adjustment for first trimester total testosterone.ConclusionEarly-pregnancy sex steroid hormones, including total testosterone, free testosterone, and estrone, were positively associated with glucose levels and gestational diabetes in mid-late pregnancy. These hormones may serve as early predictors of gestational diabetes in combination with other risk factors.

Project description:AbstractIn patients with coronavirus disease 2019 (COVID-19), men are more severely affected than women. Multiple studies suggest that androgens might play a role in this difference in disease severity. Our objective was to assess the association between sex hormone levels and mortality in patients with severe COVID-19.We selected patients from the Amsterdam University Medical Centers COVID-19 Biobank, in which patients admitted to hospital in March and April 2020, with reverse transcription-polymerase chain reaction proven severe acute respiratory syndrome-coronavirus-2 infection, were prospectively included. Specifically, we included postmenopausal women (>55 years) and age-matched men, with a mortality of 50% in each group. Residual plasma samples were used to measure testosterone, estradiol, sex hormone binding globulin (SHBG), and albumin. We investigated the association of the levels of these hormones with mortality in men and women.We included 16 women and 24 men in March and April 2020 of whom 7 (44%) and 13 (54%), respectively, died. Median age was 69 years (interquartile range [IQR] 64-75). In men, both total and free testosterone was significantly lower in deceased patients (median testosterone 0.8 nmol/L [IQR 0.4-1.9] in deceased patients vs 3.2 nmol/L [IQR 2.1-7.5] in survivors; P < .001, and median free testosterone 33.2 pmol/L [IQR 15.3-52.2] in deceased patients vs 90.3 pmol/L [IQR 49.1-209.7] in survivors; P = .002). SHBG levels were significantly lower in both men and women who died (18.5 nmol/L [IQR 11.3-24.3] in deceased patients vs 34.0 nmol/L [IQR 25.0-48.0] in survivors; P < .001). No difference in estradiol levels was found between deceased and surviving patients.Low SHBG levels were associated with mortality rate in patients with COVID-19, and low total and free testosterone levels were associated with mortality in men. The role of testosterone and SHBG and potential of hormone replacement therapy needs further exploration in COVID-19.

Project description:BackgroundNeighborhood stressors (e.g., crime and deprivation) have been associated with adverse pregnancy outcomes including preterm birth and low birth weight. A potential mechanism is disruption of maternal endocrine pathways. While stress hormones (e.g., cortisol) have received much attention, other relevant hormones, including sex steroids, have been overlooked.MethodsPregnant women in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaires, and medical record data (n = 262). In each trimester, maternal serum total testosterone [TT], estrone, estradiol, and estriol were measured using LC/MS-MS and serum free testosterone was measured by equilibrium dialysis. In the third trimester, participants reported on neighborhood stress over the last year through the validated City Stress Inventory. We examined two subscales: 11-item neighborhood disorder (e.g., vacant buildings, crime) and 7-item exposure to violence (personal experiences of violence). Composite scores were calculated and examined categorically (quartile (Q) for neighborhood disorder and any/none for exposure to violence). We fitted linear mixed models examining associations between neighborhood stressors and sex steroid hormones across pregnancy as well as trimester-specific linear regression models, all adjusting for confounders. Secondarily, we stratified by fetal sex. Results are presented as percentage change (∆%) and 95% confidence interval (CI) in hormones.ResultsMost participants (73%) reported one or more exposures to neighborhood disorder; 22% reported any exposure to violence. In adjusted models, neighborhood disorder was associated with higher TT across pregnancy (Q2: %∆= 37.3, 95%CI: 13.2, 66.5; Q3: %∆= 22.2, 95%CI: 1.2, 47.5; and Q4: %∆= 25.7, 95%CI: 1.6, 55.3), with the strongest associations observed in the third trimester (Q2: %∆= 38.0, 95%CI: 10.6, 72.1; Q3: %∆= 29.2, 95%CI: 4.4, 59.9; and Q4: %∆=33.4, 95%CI: 4.9, 69.6). In stratified models, neighborhood disorder was associated with higher TT among women carrying male fetuses (%∆ range: 48.2-84.8). Exposure to violence was not associated with any hormones.ConclusionNeighborhood disorder is associated with higher maternal testosterone levels, which may have implications for maternal and child health. Additional research is needed to understand the mechanisms by which neighborhood stress impacts endocrine physiology.

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“All-In-One” Genetic Tool Assessing Endometrial Receptivity for Personalized Screening of Female Sex Steroid Hormones

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