Altered Steroid Research Articles

Association of ethylene oxide exposure with sex hormones in the general US population: a cross-sectional study.

Ethylene oxide (EO) is an environmental chemical widely used in industry and has been related to various conditions such as dyslipidemia and metabolic syndrome. However, it is not clear what effect EO has on sex hormones. This paper aims to investigate the connection between EO exposure and sex hormones. EO exposure was assessed by measuring blood levels of hemoglobin adducts of ethylene oxide (HbEO). Based on the National Health and Nutrition Examination Survey (NHANES) 2013-2016 dataset, we assessed linear and nonlinear associations between HbEO and sex hormone levels using weighted multivariate linear regression analyses and weighted generalized additive modeling approaches. We further calculated the threshold effect using a two-piecewise linear regression model. In addition, we performed subgroup analyses. In men, HbEO levels showed a U-shaped relationship with total testosterone (TT) and sex hormone binding globulin (SHBG), with inflection points ln (HbEO) (Natural logarithmic transformed value of HbEO) of 4.12 pmol/g Hb and 3.78 pmol/g Hb, respectively. HbEO levels in women showed an inverted U-shaped relationship with TT, with an inflection point ln (HbEO) of 4.54 pmol/g Hb. However, to the right of the inflection point, the relationship between HbEO and TT was not statistically significant (β =-0.09, 95%CI -0.21, 0.03). Female HbEO levels were negatively correlated with estradiol (E2) (β = -0.11, 95%CI -0.19, -0.03). In addition, we found a positive correlation between HbEO and SHBG in women with a body mass index (BMI) <25（β = 0.12, 95%CI 0.04, 0.20, P for interaction = 0.007). EO exposure leads to altered sex hormone levels in the general U.S. population, and further research is required in the future to validate our findings.

The hypothalamus and pituitary gland regulate reproduction and are involved in the development of polycystic ovary syndrome.

Background Polycystic ovary syndrome is a complex condition with unclear mechanisms, posing a challenge for prevention and treatment of PCOS. The role of the hypothalamus and pituitary gland in regulating female reproduction is critical. Abnormalities in the hypothalamus and pituitary can impair reproductive function. It is important to study hypothalamic and pituitary changes in patients with polycystic ovary syndrome. Summary This article reviews articles on the hypothalamus and polycystic ovary syndrome with the goal of summarizing what abnormalities of the hypothalamic-pituitary-ovarian axis are present in patients with polycystic ovary syndrome and to clarify the pathogenesis of polycystic ovary syndrome. We find that the mechanisms by which the hypothalamus and pituitary regulate reproduction in girls are complex and are associated with altered sex hormone levels, obesity and insulin resistance. Different animal models of polycystic ovary syndrome are characterized by different alterations in the hypothalamus and pituitary, and respond differently to different treatments, which correspond to the complex pathogenesis of patients with polycystic ovary syndrome. Key Messages ARC is associated with luteinizing hormone (LH) surges SCN, ARC and RP3V are associated with LH surges Animal models of PCOS have different characteristics.

Lactational high weight loss impairs follicular development by causing mitochondrial dysfunction of ovarian cells in sows and mitigated by butyrate supplement.

In modern sows, lactational high weight loss (HWL), caused by the large litter size and inadequate feed intake, has a negative effect on follicular development after weaning, resulting in poor reproductive performance in the subsequent parity. However, the underlying mechanism remains unclear. This research aimed to explore the mechanism that sows HWL during lactation damages follicular development and attempt to improve the reproductive function by treating with butyrate. Four multiparous sister sows were chosen to build a HWL model for lactating sows through feed restriction during the final week of a 21-day lactation. Spatially transcriptomics (ST) and tissue immunofluorescent staining were then utilized for the antral follicles in the ovarian surface to search for differentially expressed genes and proteins among different cell types. Subsequently, the mouse assay, including immunofluorescent staining, transmission electron microscopy, hormone detection and western blot, were conducted to verify the findings in sows and investigate the effect of butyrate on the follicular development in HWL mice. Based on the transcriptomic analysis, differentially expressed genes in granulosa cells, theca cells, and ovarian stromal cells were examined. The findings revealed that HWL disturbs the mitochondrial electron transport chain and steroidogenesis in all three cell types by downregulating the expression of NDUFB3, SDHB, CYCS, COX8A and CYP19A1, as well as upregulating the expression of STAR, CYP11A1 and CYP17A1. Furthermore, results from mouse assays demonstrated that HWL causes apoptosis and alters sex hormone secretion by impairing mitochondrial function and disordering the expression of steroidogenesis key enzymes in ovarian cells, while these effects were partially mitigated by butyrate. The mitochondrial dysfunction and abnormal steroidogenesis induced by HWL during lactation in ovarian cells harm the follicular development of weaning sows, which could be alleviated by butyrate.

The associations between paternal postpartum depressive symptoms and testosterone and cortisol levels in hair over the first two years postpartum.

After the birth of a child, also fathers may develop postpartum depression. Altered steroid hormone concentrations are discussed as a possible underlying mechanism, as these have been associated with depressive symptoms in previous studies outside the postpartum period. While higher paternal testosterone levels have been found to protect against paternal postpartum depressive symptoms (PPDS), an association between higher cortisol levels and PPDS has been seen in postpartum mothers, with no comparable studies available on fathers. This study aimed to investigate cross-sectional and longitudinal associations between testosterone and cortisol levels in hair and PPDS over a period of 2 years postpartum. Data from N = 226 fathers, who took part in the endocrine sub-study DREAMHAIR of the longitudinal prospective cohort study DREAM, were used. PPDS were assessed 8 weeks, 14 months, and 24 months after birth using the Edinburgh Postnatal Depression Scale. At the same time, fathers provided 2 cm scalp-near hair samples in which testosterone (HairT) and cortisol (HairF) levels were determined. Cross-sectional and longitudinal associations between HairT, HairF and paternal PPDS were investigated. Correlation analyses showed a negative cross-sectional association between HairF levels and paternal PPDS 14 months after birth. A random intercept cross-lagged panel model revealed prospective relationships between paternal PPDS 8 weeks postpartum and HairF 14 months postpartum, and additionally between 14 months and 2 years postpartum in an exploratory model with similarly good model fit. No further significant associations of HairF with paternal PPDS emerged, and none of the analyses with HairT became significant. The overall pattern of results was confirmed when controlling for the influence of batch and storage time on HairT and HairF levels. No consistent relationships between HairT or HairF and paternal PPDS emerged in this relatively healthy cohort. In HairF analyses with significant results, lower HairF was associated with more severe PPDS. Longitudinal results imply that altered cortisol secretion may rather follow than precede changes in paternal PPDS. Further research on hormonal changes in PPDS in fathers should consider possible covariates and examine fathers with higher depressive burden, which may help to identify fathers at risk and inform future preventive and interventive approaches.

Synergistic effect of synthetic phenolic antioxidant exposure and overweight/obesity on altered sex hormone levels: Normoglycemic rural Chinese population.

The widespread use of synthetic phenolic antioxidants (SPAs) has led to their ubiquity and may contribute to multiple adverse health outcomes by affecting hormone level disruption. This study aimed to assess the exposure levels of SPAs in the plasma of the normoglycemic rural Chinese population, investigate the association of single and mixed pollutant exposures with sex hormones, and analyze the moderating role of body mass index (BMI) in these relationships. A cross-sectional study including 763 individuals with normal blood glucose from the Henan Rural cohort was conducted. General linear models, restricted cubic spline models, quantile-based g computation (qgcomp), and Bayesian kernel machine regression (BKMR) were utilized to evaluate single, nonlinear, and mixed relationships between SPAs exposure and sex hormones. The combined and additive interactions of SPAs and BMI on sex hormones were further examined. SPAs were widely detected in the plasma samples of the normoglycemic rural Chinese population, and SPAs were significantly linked to altered progestogen and androgen levels in single exposure and varied by gender and menopausal status, and some of these associations were non-linear. Being overweight/obesity strengthened the effect of SPAs on androgens and estrogens. Mixture effect analyses suggested a positive joint mixture effect of SPAs with progesterone in men, and a negative joint mixture effect of SPAs with 17-hydroxyprogesterone, testosterone, and androstenedione in both men and postmenopausal women. The relative contribution of AO44B25, AO425, BHA, BHT-OH, and AO2246 to the overall mixing effect was higher in both mixture analyses. This study is the first to profile SPAs in plasma samples from the Chinese rural population and to identify significant associations between SPAs exposure and altered progestogen and androgen levels in men and postmenopausal women, providing epidemiological evidence for the endocrine-disrupting effects of SPAs and research basis for exploring the etiology of multiple diseases caused by environmental pollution.

Nano Spirulina platensis countered cisplatin-induced repro-toxicity by reversing the expression of altered steroid hormones and downregulation of the StAR gene.

Cisplatin is a commonly utilized chemotherapy medication for treating different sarcomas and carcinomas. Its ability interferes with cancer cells' DNA repair pathways and postpones unfavorable outcomes in cancer patients. The current investigation's goal was to ascertain if nano Spirulina platensis (NSP) might shield rat testicles from cisplatin damage by assessing the expression of the StAR and SOD genes, sex hormones, 17ß-hydroxysteroid dehydrogenase(17ß-HSD), sperm profile picture, oxidative condition of testes, testicular histology, and DNA damage. Four equal and random groups of 28 adult male Wistar rats were created; the control group was given saline for 8weeks. An extraction of NSP at a concentration of 2500mg/kg body weight was administered orally for 8weeks to the NSP group. For the first 4weeks, the cisplatin group was intraperitoneally injected with 2mg/kg/body weight of cisplatin, and for the next 4weeks, they were given a dosage of 4mg/kg/body weight. The cisplatin + NSP group was given both NSP and cisplatin. The results of the experiment showed that intake of NSP and cisplatin improved sperm profile; re-established the balance of oxidizing agents and antioxidant state; enhanced testicular histology; promoted the histometric parameters of seminiferous tubules including epithelial height, their diameter, and Johnsen's score, decreasing DNA breakage in testicular tissue; increased testosterone level; decreased 17ß-HSD concentration; and upregulated both the StAR and SOD gene expression in testicles compared to rats exposed to cisplatin alone. These results demonstrate that NSP is a promising agent for improving cisplatin-induced testicular injury and infertility.

Alternate-day fasting delays pubertal development in normal-weight mice but prevents high-fat diet-induced obesity and precocious puberty

Background/ObjectivesChildhood obesity, particularly in girls, is linked to early puberty onset, heightening risks for adult-onset diseases. Addressing childhood obesity and precocious puberty is vital to mitigate societal burdens. Despite existing costly and invasive medical interventions, introducing lifestyle-based alternatives is essential. Our study investigates alternate-day fasting’s (ADF) impact on pubertal development in normal-weight and high-fat diet (HFD)-induced obese female mice.MethodsFour groups of female mice were utilized, with dams initially fed control chow during and before pregnancy. Post-parturition, two groups continued on control chow, while two switched to an HFD. Offspring diets mirrored maternal exposure. One control and one HFD group were subjected to ADF. Morphometry and hormone analyses at various time points were performed.ResultsOur findings demonstrate that ADF in normal-weight mice led to reduced body length, weight, uterine, and ovarian weights, accompanied by delayed puberty and lower levels of sex hormones and growth hormone (GH). Remarkably, GH treatment effectively prevented ADF-induced growth reduction but did not prevent delayed puberty. Conversely, an HFD increased body length, induced obesity and precocious puberty, and altered sex hormones and leptin levels, which were counteracted by ADF regimen. Our data indicate ADF’s potential in managing childhood obesity and precocious puberty.ConclusionsADF reduced GH and sex hormone levels, contributing to reduced growth and delayed puberty, respectively. Therefore, parents of normal-weight children should be cautious about prolonged overnight fasting. ADF prevented HFD-induced obesity and precocious puberty, offering an alternative to medical approaches; nevertheless, further studies are needed for translation into clinical practice.

Features of true gynecomastia in adult males

In recent years, the incidence of gynecomastia in adult men has increased significantly. It is of interest to study the specific features of the disease in these patients. To identify the main characteristics of acute gynecomastia in adult men. A continuous one-stage study including 160 adult males with acute onset gynecomastia, who were he was treated in Endocrinology Research Centre, Moscow. Total bilirubin, hepatic transaminases, creatinine, urea, luteinizing hormone, prolactin, sex hormone binding globulin, estradiol, total testosterone, alpha-fetoprotein, chorionic gonadotropin and mammary gland condition were evaluated in all patients. Baseline significance threshold level of p&lt;0.05. The incidence of gynecomastia increased from 5,4% in 2020 to 14,4% in 2024. Tumor forms of gynecomastia were rare, with 1,2% (95% CI 0,0; 3,0) of cases. In 30% (95% CI 22,9; 37,1) of men, gynecomastia was due to the intake of anabolic steroids for athletic stimulation. In 11,2% (95% CI 6,4; 16,1) of patients, gynecomastia was hepatogenic. In 7,5% (95% CI 3,4; 11,6), it was due to elevated sex hormone binding globulin. 47,5% (95% CI 39,8; 55,2) were endocrine non-tumorigenic form of gynecomastia due to excess body weight with formation of changes in sex hormone levels. The patients who took anabolic steroids were characterized by young age, as well as decreased luteinizing hormone levels and increased testosterone levels. The group of patients with elevated sex hormone binding globulin had no clinically significant features. Men from the group of hepatogenic gynecomastia were characterized by hyperestrogenism. Patients in the group with altered sex hormone levels were characterized by high body mass index and either increased estradiol or decreased testosterone or a combination of both. The number of adult male patients with acute gynecomastia is progressively increasing. In the examined sample of patients, the main causes of gynecomastia were patients taking anabolic steroids, liver dysfunction and weight gain with the formation of changes in sex hormone levels. Patients taking anabolic steroids were characterized by a drug--induced increase in testosterone and estradiol levels, which was accompanied by suppression of pituitary gonadotropic function. Estradiol elevation was also characteristic of patients with hepatogenic form of gynecomastia and men with excess body weight with formation of changes in sex hormone levels.

Hysterectomy—a possible risk factor for operative intervention in female patients for degenerative lumbar spine conditions: a case control and cohort study

Researchers have recently linked hysterectomy, which alters sex hormone levels, to diseases like osteoporosis, lumbar spondylolisthesis, hypertension and diabetes etc. However, the association between hysterectomy and lumbar disc herniation (LDH)/lumbar spinal stenosis (LSS) remains unclarified. To determine whether there is a correlation between hysterectomy and surgical intervention for LDH/LSS in women, further substantiated through imaging and clinical research. A case control and cohort study. The study group comprised 1202 female patients aged 45 and older who had undergone operative treatment due to LDH/LSS (825 for LDH and 377 for LSS), and the comparison group comprised 1168 females without lumbar diseases who visited health examination clinic during the same period. One hundred and 2 hysterectomized patients were further selected (Hysterectomy cohort) and matched approximately with the control cohort at a 1:2 ratio from the study group with a minimum follow-up of 2 years. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were calculated to assess the association between hysterectomy and surgical intervention for LDH/LSS in women after adjusted by confounding factors. Patients from both the hysterectomy and control cohorts underwent a comprehensive assessment. This assessment included the evaluation of several parameters: the functional cross-sectional area, fat infiltration rate, relative functional cross-sectional area of the lumbar paravertebral muscles, facet joint degeneration grade, cartilage endplate damage, Modic changes for the L3/4-L5/S1 segments, Pfirrmann grade of lumbar disc degeneration, and disc height index for the L1/2-L5/S1 segments. Additionally, the Visual Analog Scale (VAS) and Japanese Orthopaedic Association (JOA) scores were recorded preoperatively and at the last follow-up. Associations between hysterectomy and patients treated surgically for LDH or LSS were analyzed using multivariate binomial logistic regression analysis. Lumbar X-ray, computed tomography (CT) and magnetic resonance imaging (MRI) were used to evaluate the imaging variables. Imaging and clinical variables were compared. Hysterectomized women were associated with requiring surgery due to LDH/LSS, with ORs of 2.613 (p<.001) and 2.084 (p=.006), respectively. The imaging evaluation further revealed that the hysterectomy cohort had more severe degeneration of the paraspinal muscles, facet joints, endplates, and intervertebral discs, Modic changes at L3/4-L5/S1 segments, and intervertebral height reduction at L1/2-L5/S1 segments when compared to the control cohort (p<.01). Compared to the control cohort, the hysterectomy cohort exhibited higher preoperative and last follow-up VAS scores for low back pain, and last follow-up JOA scores (p<.01). Based on the findings of this study, it seems that women who have had a hysterectomy are correlated with requiring surgical intervention due to LDH/LSS. Imaging and clinical studies also indicate that hysterectomized patients exhibited more severe lumbar degeneration and back pain.

Chronic dietary exposure to a glyphosate-based herbicide alters ovarian functions in young female broilers

Glyphosate (GLY)-based herbicide (GBH) formulations are widely used pesticides in agriculture. The European Union recently decided to extend the use of GLY in Europe until 2034. Previously, we showed that chronic dietary GBH exposure in adult hens resulted in a reversible increase in early mortality in chicken embryos. In this present study, we investigated the GBH effects on metabolism and ovarian functions by using a transcriptomic approach in vivo in young female broilers and in vitro in ovarian explant cultures. We exposed 11-day-old female broilers to 13 mg GLY equivalent/kg body weight/day (GBH13, n = 20), 34 mg GLY equivalent/kg body weight/day (GBH34, n = 20), or a standard diet (control [CT], n = 20) for 25 days. These two GBH concentrations correspond to approximatively one eighth and one third of the no observed adverse effect level (NOAEL) as defined by European Food Safety Authority in birds. During this period, we evaluated body weight, fattening, food intake, and the weight of organs (including the ovaries). Chronic dietary GBH exposure dose dependently reduced food intake, body weight, and fattening, but increased oxidative stress and relative ovary weight. We analyzed the ovarian gene expression profile in CT, GBH13, and GBH34 broilers with RNA sequencing and showed that differentially expressed genes are mainly enriched in pathways related to cholesterol metabolism, steroidogenesis, and RNA processing. With quantitative polymerase chain reaction and western blotting, we confirmed that GBH decreased ovarian STAR and CYP19A1 messenger RNA and protein expression, respectively. Furthermore, we confirmed that GBH altered steroid production in ovarian explants. We have identified potential regulatory networks associated with GBH. These data provide valuable support for understanding the ovarian transcriptional regulatory mechanism of GBH in growing broilers.

An environmentally relevant mixture of per- and polyfluoroalkyl substances (PFAS) impacts proliferation, steroid hormone synthesis, and gene transcription in primary human granulosa cells.

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals that are resistant to biodegradation and are environmentally persistent. PFAS are found in many consumer products and are a major source of water and soil contamination. This study investigated the effects of an environmentally relevant PFAS mixture (perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS], perfluorohexanesulfonic acid [PFHxS]) on the transcriptome and function of human granulosa cells (hGCs). Primary hGCs were harvested from follicular aspirates of healthy, reproductive-age women who were undergoing oocyte retrieval for in vitro fertilization. Liquid Chromatography with tandem mass spectrometry (LC/MS-MS) was performed to identify PFAS compounds in pure follicular fluid. Cells were cultured with vehicle control or a PFAS mixture (2 nM PFHxS, 7 nM PFOA, 10 nM PFOS) for 96 h. Analyses of cell proliferation/apoptosis, steroidogenesis, and gene expression were measured via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays/immunofluorescence, ELISA/western blotting, and RNA sequencing/bioinformatics, respectively. PFOA, PFOS, and PFHxS were detected in 100% of follicle fluid samples. Increased cell proliferation was observed in hGCs treated with the PFAS mixture with no impacts on cellular apoptosis. The PFAS mixture also altered steroid hormone synthesis, increasing both follicle-stimulating hormone-stimulated and basal progesterone secretion and concomitant upregulation of STAR protein. RNA sequencing revealed inherent differences in transcriptomic profiles in hGCs after PFAS exposure. This study demonstrates functional and transcriptomic changes in hGCs after exposure to a PFAS mixture, improving our knowledge about the impacts of PFAS exposures and female reproductive health. These findings suggest that PFAS compounds can disrupt normal granulosa cell function with possible long-term consequences on overall reproductive health.

High incidence of imperforate vagina in ADGRA3-deficient mice

BackgroundTen percent of the female population suffers from congenital abnormalities of the vagina, uterus, or oviducts, with severe consequences for reproductive and psychological health. Yet, the underlying causes of most of these malformations remain largely unknown. ADGRA3 (GPR125) is involved in WNT signaling and planar cell polarity, mechanisms vital to female reproductive tract development. Although ADGRA3 is a well-established spermatogonial stem cell marker, its role within the female urogenital system remains unclear.ResultsIn this study, we found Adgra3 to be expressed throughout the murine female urogenital system, with higher expression pre-puberty than after sexual maturation. We generated a global Adgra3−/− mouse line and observed imperforate vagina in 44% of Adgra3−/− females, resulting in distension of the reproductive tract and infertility. Ovarian morphology, plasma estradiol, ovarian Cyp19a1, and vaginal estrogen receptor α (Esr1) expression were unaffected. However, compared to controls, a significantly lower bone mineral density was found in Adgra3−/− mice. Whereas vaginal opening in mice is an estrogen-dependent process, 17β-estradiol treatment failed to induce vaginal canalization in Adgra3−/− mice. Furthermore, a marked reduction in vaginal and ovarian progesterone receptor expression was observed concomitant with an upregulation of apoptotic regulators Bcl2, Bid, and Bmf in adult Adgra3−/− females with a closed vagina.ConclusionsOur collective results shed new insights into the complex mechanisms by which the adhesion receptor ADGRA3 regulates distal vaginal tissue remodeling during vaginal canalization via altered sex hormone responsiveness and balance in apoptotic regulators. This highlights the potential of ADGRA3 as a target in diagnostic screening and/or therapy for obstructive vaginal malformations in humans.

Abstract A043: Building a mammary-specific microenvironment for investigating sex hormones in microvessels and tumors

Abstract The mammary gland is highly vascularized and is exposed to alterations in sex hormones, including estrogen (E2) and progesterone (P4), which also play a role in breast cancer development and progression. Yet, our understanding of hormonal changes on the microvasculature in mammary tissue is limited to studies in rodents and simple 2D cultures. Advances in organ-on-chip technology now allow for models of 3D human microvessels to be generated. However, most microvascular models lack tissue-specific cell types, limiting their physiologic relevance. Thus, we first aimed to generate a tissue-specific breast microvasculature, and next used this model to study the impact of sex hormones. Our final goal is to generate a combined vascularized model of luminal A tumor on-chip. In our recently archived work (doi: 10.1101/2023.04.21.537664), we achieved the first in vitro perfusable breast-specific microvessels. Optimal conditions were achieved to co-culture human mammary vascular endothelial cells HMVEC and mammary fibroblasts on-chip. Through image-based quantification, microvessel morphology, not barrier function, was shown to be strongly influenced by the abundance of fibroblasts, which were critical to achieve lumenized (patent) vessels. Attaining perfusable microvessels allowed the study of discreet phases of the menstrual cycle (period, follicular, ovular, and luteal). The most striking results were observed with high concentrations of E2 (mimic of ovulation phase), which presented with increased vascular growth, and in contrast with high concentrations of P4 (mimic of luteal phase) that resulted in vascular rarefaction (pruning). Effects from combined E2 and P4 were dose-dependent, as demonstrated by significant branching and remodeling in the follicular phase. Hormonal effects were also tissue-specific, as shown by HUVEC-derived microvessels with significantly different morphologic phenotypes in comparison to HMVEC. Interestingly, fibroblasts expressed significantly high levels of receptors for both hormones and likely are major contributors to the hormone-responsiveness of microvessels. With mammary vessels now established, model tumors, spheroids, were generated from luminal-like breast cancer cells. Namely, MCF-7 and T47D, were treated by the same E2 and P4 conditions as in the microvessels. For both tumor spheroids, phase-dependent responses were observed, with high E2 resulting in the most significant growth. Ongoing work has shown the capacity to incorporate these tumor spheroids into our microvascular model, which results in varied local changes in vascular density. Future work involves investigating the role of hormones in the combined tumor-microvascular model. This complex humanized model will be useful in highlighting potential cancer treatment timelines (relevant to female menstrual cycle) and may be used to uncover novel therapeutic targets for luminal A breast cancers. Citation Format: Carmen Moccia, Marta Cherubini, Guido Frigieri, Kristina Haase. Building a mammary-specific microenvironment for investigating sex hormones in microvessels and tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A043.

Assessment of the Cutaneous Hormone Landscapes and Microbiomes in Vulvar Lichen Sclerosus

Vulvar lichen sclerosus (VLS) is a progressive skin disease of unknown etiology. In this longitudinal case-control exploratory study, we evaluated the hormonal and microbial landscapes in 18 postmenopausal females (mean [SD] age: 64.4 [8.4] years) with VLS and controls. We reevaluated the patients with VLS after 10-14 weeks of daily topical class I steroid. We found that groin cutaneous estrone was lower in VLS than in controls (-22.33, 95% confidence interval [CI]=-36.96 to-7.70; P= .006); cutaneous progesterone was higher (5.73, 95% CI= 3.74-7.73; P < .0001). Forehead 11-deoxycortisol (-0.24, 95% CI=-0.42 to-0.06; P= .01) and testosterone (-7.22, 95% CI=-12.83 to-1.62; P= .02) were lower in disease. With treatment, cutaneous estrone (-7.88, 95% CI=-44.07 to 28.31; P= .62), progesterone (2.02, 95% CI=-2.08 to 6.11; P= .29), and 11-deoxycortisol (-0.13, 95% CI=-0.32 to 0.05; P= .15) normalized; testosterone remained suppressed (-7.41, 95% CI=-13.38 to-1.43; P= .02). 16S ribosomal RNA V1-V3 and ITS1 amplicon sequencing revealed bacterial and fungal microbiome alterations in disease. Findings suggest that cutaneous sex hormone and bacterial microbiome alterations may be associated with VLS in postmenopausal females.

Frontal Fibrosing Alopecia and Reproductive Health: Assessing the Role of Sex Hormones in Disease Development.

Frontal Fibrosing Alopecia (FFA) is a distinctive form of cicatricial alopecia characterized by gradual hairline recession, predominantly affecting postmenopausal individuals, thus implying a potential hormonal origin. This narrative review, spanning 2000 to 2023, delves into PubMed literature, focusing on the menopausal and hormonal status of women with FFA. The objective is to unravel the intricate nature of FFA and its plausible associations with hormonal dysregulations in women. While menopause remains a pivotal demographic characteristic linked to FFA, existing data suggest that its hormonal imbalances may not fully account for the development of FFA. Conversely, substantial evidence indicates a strong association between a reduction in fertile years, particularly through surgical interventions leading to an abrupt hormonal imbalance, and FFA in women. Additionally, exposure to hormone replacement therapy or oral contraceptives has shown varying degrees of association with FFA. Gynecologists should maintain a heightened awareness regarding the ramifications of their interventions and their pivotal role in overseeing women's fertility, recognizing the potential influence on the progression of FFA. The recurrent theme of hormonal disruption strongly implies a causal connection between alterations in sex hormones and FFA in women. Nevertheless, this relationship's extent and underlying mechanisms remain subjects of ongoing debate.

Impact of bariatric surgery on premenopausal women's womanliness: A qualitative systematic review and meta-synthesis.

Obesity is associated with several co-morbidities in women, including disturbed sex hormone regulation with menstrual disturbances, subfertility, hirsutism, and central fat dispersion, all with an impact on sexual function and quality of life. There are few investigations regarding women's experiences of obesity-related altered sex hormone regulation and resolution after bariatric surgery. This systematic review and interpretive meta-synthesis aim to identify the current qualitative knowledge base concerning women undergoing bariatric surgery and experiences of changes after weight loss, emphasising aspects of womanliness. A systematic review and qualitative meta-synthesis was conducted to gain a deeper and broader understanding of the available knowledge about premenopausal women's experienced changes after bariatric surgery. Relevant papers were identified by systematically searching PubMed, CINAHL, Embase, PsycInfo, PsycArticles, Scopus, Cochrane Library, Web of Science and Open Grey. The quality of the included studies was assessed, and the data was interpreted and synthesised using Gadamer's hermeneutics. The review protocol was registered on PROSPERO (CRD42023394225). A total of 10 studies were considered relevant and included in the qualitative meta-synthesis. Three fusions were identified and interpreted as: "Womanliness," "A healthy and functioning body," and "Mind and Body Connection." Women experienced a return to womanliness after undergoing bariatric surgery with restored menstruation cycles, improved fertility and changed hair and fat dispersion signalling restored sex hormones. Women value a return to a healthy and functioning body that improves their experience of life and ability to take part in it. However, women experienced difficulties in adapting mentally to the drastic physical changes that occur after undergoing surgery. Women that have undergone bariatric surgery report several benefits to their health and well-being, although difficulties in adapting mentally to changes in outer appearance need to be managed in order to successfully move forward with a new life after surgery.

Steroidogenesis and androgen/estrogen signaling pathways are altered in in vitro matured testicular tissues of prepubertal mice

Children undergoing cancer treatments are at risk for impaired fertility. Cryopreserved prepubertal testicular biopsies could theoretically be later matured in vitro to produce spermatozoa for assisted reproductive technology. A complete in vitro spermatogenesis has been obtained from mouse prepubertal testicular tissue, although with low efficiency. Steroid hormones are essential for the progression of spermatogenesis, the aim of this study was to investigate steroidogenesis and steroid signaling in organotypic cultures. Histological, RT-qPCR, western blot analyses, and steroid hormone measurements were performed on in vitro cultured mouse prepubertal testicular tissues and age-matched in vivo controls. Despite a conserved density of Leydig cells after 30 days of culture (D30), transcript levels of adult Leydig cells and steroidogenic markers were decreased. Increased amounts of progesterone and estradiol and reduced androstenedione levels were observed at D30, together with decreased transcript levels of steroid metabolizing genes and steroid target genes. hCG was insufficient to facilitate Leydig cell differentiation, restore steroidogenesis, and improve sperm yield. In conclusion, this study reports the failure of adult Leydig cell development and altered steroid production and signaling in tissue cultures. The organotypic culture system will need to be further improved before it can be translated into clinics for childhood cancer survivors.

OR04-05 Prenatal Phthalate Exposure Alters The Pattern Of Fetal And Neonatal Endocrine Puberty In A Sex-specific Manner

Abstract Disclosure: M.A. Bunnell: None. P. Lin: None. S. Zhou: None. C. Park: None. S. Wang: None. Q. Hu: None. B. Marzbanabbasabadi: None. J. Oh: None. B. Wang: None. M. Laws: None. E. Fletcher: None. Z. Liu: None. E. Joo: None. H. Qiao: None. J. Flaws: None. C. Ko: None. Endocrine puberties (EP) are sex-specific transient elevations of gonadotropins and testosterone (T) in males and estradiol (E2) in females. Fetal EP occurs mid-gestation, neonatal EP is stimulated by the clearance of maternal estrogen after birth, and finally, reproductive function arises during classical puberty. EPs are critical for normal development and the sexual dimorphism of reproductive and some somatic organs. Disrupted T or E2 levels during fetal or neonatal EP lead to reproductive abnormalities in adults. The endocrine disrupting effects of phthalates have been well-documented in humans and animal models. Prepubescent children are highly susceptible to phthalate toxicity. In utero, exposure to phthalates causes gender-specific reproductive abnormalities. In this study, we tested the working hypothesis that in utero exposure to phthalates alters T and E2 levels in fetal and newborn mice in a gender-specific manner. Pregnant CD-1 dams (n=5-6/treatment/time point) were orally administered an environmentally relevant phthalate mixture (20 μg/Kg/day) or vehicle daily from embryonic day (ED) 10.5 until birth. On ED16.5, and postnatal hours (h) 1, 3, and 6, fetal tissues and neonatal sera and tissues were sampled for hormonal assays. Fetal and neonatal gonads were collected for testicular T and ovarian E2 measurements. The amount of serum per embryo was insufficient for determining circulating hormone levels in the fetus. Hence, at ED16.5, hormonal content of the full-body (excluding gonads) was used to assess the impact of phthalate exposure. Hormone levels were quantified by ELISA. At ED16.5, full-body T level was lower in exposed females (2.93 vs. 12.23 pg/body in control, P&amp;lt;0.0001), but higher in exposed males (277 vs. 216 pg/body in control, P=0.022). However, there was no difference in fetal testicular T (871 vs. 1027 pg/2 testes in control, P=0.089), indicating that testicular steroidogenesis was unaltered. A rapid decline in serum T levels occurred in both newborn control (h1= 623 pg/mL, h6= 249 pg/mL, P=0.009) and exposed males (h1= 600 pg/mL, h6= 224 pg/mL, P=0.0015), but serum LH remained constant (Control: h1= 0.83 ng/mL, h6= 0.63 ng/mL, P=0.36; exposed: h1= 0.69 ng/mL, h6= 0.82 ng/mL, P=0.43). Phthalate exposure did not impact neonatal serum T or LH in males. However, at h6, exposed females had lower serum E2 than controls (0.7 vs. 8.51 pg/mL in control, P=0.001). This study found that prenatal phthalate exposure altered T and E2 levels of males and females distinctly, without disrupting LH secretion and gonadal steroidogenesis. The results indicate that T and E2 levels were likely disrupted by altered steroid clearance due to a sex-dependent impact on hepatic T and E2 metabolism, rather than pituitary or gonadal hormone production. In conclusion, prenatal exposure to a phthalate mixture alters the levels of T and E2 during fetal and neonatal EP in a gender-specific manner. Presentation: Thursday, June 15, 2023

Testis exposure to unopposed/elevated activin A in utero affects somatic and germ cells and alters steroid levels mimicking phthalate exposure.

Correct fetal testis development underpins adult male fertility, and TGFβ superfamily ligands control key aspects of this process. Transcripts encoding one such ligand, activin A, are upregulated in testes after sex determination and remain high until after birth. Testis development requires activin signalling; mice lacking activin A (Inhba KO) display altered somatic and germ cell proliferation, disrupted cord elongation and altered steroid synthesis. In human pregnancies with pre-eclampsia, the foetus is inappropriately exposed to elevated activin A. To learn how this affects testis development, we examined mice lacking the potent activin inhibitor, inhibin, (Inha KO) at E13.5, E15.5 and PND0. At E13.5, testes appeared similar in WT and KO littermates, however E15.5 Inha KO testes displayed two germline phenotypes: (1) multinucleated germ cells within cords, and (2) germ cells outside of cords, both of which are documented following in utero exposure to endocrine disrupting phthalates in rodents. Quantitation of Sertoli and germ cells in Inha KO (modelling elevated activin A) and Inhba KO (low activin A) testes using immunofluorescence demonstrated activin A bioactivity determines the Sertoli/germ cell ratio. The 50% reduction in gonocytes in Inha KO testes at birth indicates unopposed activin A has a profound impact on embryonic germ cells. Whole testis RNAseq on Inha KO mice revealed most transcripts affected at E13.5 were present in Leydig cells and associated with steroid biosynthesis/metabolism. In agreement, androstenedione (A4), testosterone (T), and the A4:T ratio were reduced in Inha KO testes at E17.5, confirming unopposed activin A disrupts testicular steroid production. E15.5 testes cultured with either activin A and/or mono-2-ethylhexyl phthalate (MEHP) generated common histological and transcriptional outcomes affecting germline and Leydig cells, recapitulating the phenotype observed in Inha KO testes. Cultures with activin A and MEHP together provided evidence of common targets. Lastly, this study extends previous work focussed on the Inhba KO model to produce a signature of activin A bioactivity in the fetal testis. These outcomes show the potential for elevated activin A signalling to replicate some aspects of fetal phthalate exposure prior to the masculinization programming window, influencing fetal testis growth and increasing the risk of testicular dysgenesis.

Are steroid hormones and autistic traits affected by metformin? First insights from a pilot

BackgroundDifferent lines of evidence imply that metformin could alter steroid hormone homeostasis and thereby improve social impairment. Here, we tried to correlate the impact of metformin treatment on alterations in steroid hormones and autism spectrum traits before versus after treatment with metformin. Material & methodsUrine steroid hormones were measured using gas chromatography mass spectrometry in 12 male subjects (54.2 ± 9.1 years, 177.3 ± 4.1 cm, 80 ± 10.4 kg) and 7 female subjects (64.14 ± 18.0 years, 162.7 ± 4.1 cm, 76.1 ± 10.4 kg). Furthermore, a questionnaire on autism spectrum traits (Autism Spectrum Questionnaire]) was administered prior to and after metformin treatment. ResultsOverall, a decrease of steroid hormones were detected, which were most pronounced in the metabolites of corticosterone, deoxycortisol, cortisol, as well as androgens. These remained after Bonferroni correction (three classes: glucocorticoid, mineralocorticoid, androgens). No effect on autism spectrum traits (social skills, attention switching skills, attention to detail skills, communication skills, imagination skills), was identified pre versus post metformin treatment. DiscussionThe decreased steroid hormone levels are based on different mechanisms; one effect is likely via mitochondria, another effect via activated protein kinase prior to post treatment. The finding on autistic traits must be taxed as negative and do not directly provide an argument for using metformin in the treatment of autism.