Sex Steroid Concentrations Research Articles

Targeted long-read sequencing identifies missing pathogenic variant in unsolved 11β-hydroxylase deficiency

Background11β-hydroxylase deficiency (11β-OHD), caused by homozygosity or compound heterozygosity CYP11B1 variants, is the second most common cause of congenital adrenal hyperplasia (CAH). Due to the high degree of sequence identity between CYP11B1 and CYP11B2, chimeric genes, and complex structural variants (SVs), the conventional approach to gene testing for 11β-OHD is facing challenges. The study aimed to clarify the underlying genetic causes of two siblings of a Chinese family with 11β-OHD.MethodsPeripheral blood samples and clinical information were collected from subjects and their family members. Sex steroid concentrations were measured using LC-MS/MS. Long-range PCR-based next-generation sequencing (NGS), PCR assay and target long-read sequencing were used to detect the pathogenic variants.ResultsEarly onset hypertension, increased serum levels of adrenocorticotropin (ACTH), progesterone, testosterone, and decreased cortisol and potassium were detected in both affected siblings. Long-range PCR-based NGS identified a heterozygous missense variant (NM_000497.4:c.281 C > T, p.P94> L) in CYP11B1 gene in the two siblings. PCR detected no chimeric CYP11B2/CYP11B1 gene. We finally identified a second pathogenic variant in CYP11B1 gene via target long-read sequencing (T-LRS). This novel variant was a deletion-insertion variant and located chr8:143957269–143,957,579 (hg19) with the insertion of ‘ACAG’ (NM_000497.4:c.954 + 78_980delinsACAG), which was in trans with CYP11B1: c.281 C > T.ConclusionsOur study suggests that the integrated long-range PCR-based NGS and T-LRS seem to be the most reliable and accurate method for 11β-OHD genetic diagnosis and carrier sequencing.

Physiological influences on neurovascular coupling: A systematic review of multimodal imaging approaches and recommendations for future study designs.

In this review, we have amalgamated the literature, taking a multimodal neuroimaging approach to quantify the relationship between neuronal firing and haemodynamics during a task paradigm (i.e., neurovascular coupling response), while considering confounding physiological influences. Original research articles that used concurrent neuronal and haemodynamic quantification in humans (n ≥ 10) during a task paradigm were included from PubMed, Scopus, Web of Science, EMBASE and PsychINFO. Articles published before 31 July 2023 were considered for eligibility. Rapid screening was completed by the first author. Two authors completed the title/abstract and full-text screening. Article quality was assessed using a modified version of the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. A total of 364 articles were included following title/abstract and full-text screening. The most common combination was EEG/functional MRI (68.7%), with cognitive (48.1%) and visual (27.5%) tasks being the most common. The majority of studies displayed an absence/minimal control of blood pressure, arterial gas concentrations and/or heart rate (92.9%), and only 1.3% monitored these factors. A minority of studies restricted or collected data pertaining to caffeine (7.4%), exercise (0.8%), food (0.5%), nicotine (2.7%), the menstrual cycle (0.3%) or cardiorespiratory fitness levels (0.5%). The cerebrovasculature is sensitive to numerous factors; thus, to understand the neurovascular coupling response fully, better control for confounding physiological influences of blood pressure and respiratory metrics is imperative during study-design formulation. Moreover, further work should continue to examine sex-based differences, the influence of sex steroid hormone concentrations and cardiorespiratory fitness.

Combined gonadotropin therapy to replace mini-puberty in male infants with congenital hypogonadotropic hypogonadism.

Infants born with severe central disorders of the hypothalamic-pituitary-gonadal axis leading to gonadotropin deficiency not only lack pubertal development in adolescence, but also lack infantile mini-puberty. This period of mini-puberty, where infants have gonadotropin and sex steroid concentrations up into the adult range, is vital for future reproductive capacity, particularly in boys. At present, there is no consensus on the diagnosis or management of infants with gonadotropin deficiency due to congenital hypogonadotropic hypogonadism or multiple pituitary hormone deficiency. Case series suggest that gonadotropin treatment in male infants with absent mini-puberty is effective in promoting both testicular descent in those with undescended testes and also facilitating increased penile size. Moreover, replacement with follicle-stimulating hormone increases the testicular Sertoli cell population, measurable as an increase in testicular volume and inhibin B, thus hypothetically increasing the capacity for spermatogenesis in adult life for these patients. However, long-term follow-up data is limited for both outcomes pertaining to fertility and nonreproductive sequelae, including neurodevelopment and psychological well-being. The use of international registries for patients with gonadotropin deficiency is a key element in the collection of high-quality, geographically widespread data to inform best-practice management from birth to adulthood.

Estrogen and alcohol use in women: a targeted literature review.

Alcohol is posited to affect sex steroid hormone concentrations, and a growing body of research has demonstrated menstrual cycle effects on women's use of alcohol. The present targeted review synthesizes the literature examining the relationship between alcohol use and estradiol in women and suggests directions for future research. Articles were identified using the PubMed database using the following criteria: published in English, presented original findings for women, were peerreviewed, and included measures of estradiol levels in the analyses. Twenty-nine articles were identified for inclusion. Results from this review indicate acute alcohol use temporarily increases estradiol levels in women, and this may be strongest when gonadotropins are high. Regular alcohol use (≥1 drink per day) increases estradiol levels, but estradiol appears to be suppressed in women with alcohol use disorders and physiologic dependence. Alcohol use tends to be highest in women during ovulation, when estradiol is high, and progesterone is low. Alcohol use increases estradiol levels in women, particularly in the presence of gonadotropins. More research is needed to assess the effect of estradiol on alcohol use in women. Research on the relationship of estrogen and alcohol use in women is needed to elucidate health outcomes through the lifespan.

Insights into neurosteroids and their role in women with epilepsy.

Epilepsy, is a serious neurological condition, characterized by recurring, unprovoked seizures and affects over 50 million people worldwide. Epilepsy has an equal prevalence in males and females, and occurs throughout the life span. Women with epilepsy (WWE) present with unique challenges due to the cyclical fluctuation of sex steroid hormone concentrations during their life course. These shifts in sex steroid hormones and their metabolites are intricately intertwined with seizure susceptibility and affect epilepsy during the life course of women in a complex manner. Here we present a review encompassing neurosteroids-steroids that act on the brain regardless of their site of synthesis in the body; the role of neurosteroids in women with epilepsy through their life-course; exogenous neurosteroid trials; and future research directions. The focus of this review is on progesterone and its derived neurosteroids, given the extensive basic research that supports their role in modulating neuronal excitability.

Abstract PS07-01: Exemestane and breast cancer prevention: how low can we go? Drug and biomarker tissue levels in a randomized presurgical trial on exemestane alternative dosing regimen

Abstract Exemestane is an effective drug to reduce breast cancer risk reaching an overall 65% reduction in breast cancer in the placebo–controlled phase III MAP.3 trial. To improve its acceptability in primary prevention programs, we are seeking the minimal effective dose. In a 3-arm presurgical trial of 4-6 weeks before breast surgery in 180 postmenopausal women with ER-positive breast cancer, we investigated the activity of alternative exemestane schedules: 25 mg per day (QD), 25 mg three times/week (TIW) or 25 mg per week (QW) and showed that in adherent participants TIW was not inferior to QD in reducing circulating estradiol (Serrano et al JAMA Oncol. doi:10.1001/jamaoncol.2023.0089). Moreover, Ki67 reduction was seen in all arms with no significant difference among arms. Here, we analyzed the concentration of sex steroids, exemestane, and its main metabolite in the cancer and adjacent non-cancerous breast tissue. Tissues samples were homogenized before liquid-liquid extraction. After reconstitution, samples were analyzed by coupling liquid chromatography with tandem mass spectrometry (Sciex QTRAP 6500, Nexera system, Shimadzu). We obtained breast cancer tissue from 93 and non-cancerous breast tissue from 117 participants to measure exemestane, 17-OH-exemestane, and sex steroids. Exemestane and 17-OH-exemestane concentrations were detectable only in the QD arm, while in TIW and QW arms levels were below the Lower Limit of Detection (< LLD). Median exemestane level was 3807 fmol/g and 17485 fmol/g and median 17-OH-exemestane level was 338 fmol/g and 1343 fmol/g in cancer and non-cancerous tissue, respectively. Interestingly, drug and its metabolite accumulated 4-5-fold in non-cancerous tissue compared to cancer tissue in the QD arm. Despite the between-arm drug concentration difference, estradiol was almost completely suppressed in all arms in the non-cancerous tissue, attaining level < LLD in QD and TIW arms, and barely detectable in QW arm. The median in the QW arm was < LLD (< LLD, interquartile range < LLD, 25.5 fmol/g) showing no differences in QD vs TIW and QD vs QW (p = 0.364 and p = 0.693 respectively). While a dose-response trend was observed in cancer tissue, estradiol level was < LLD (< LLD,52.2 fmol/g) on QD, 17.1 (< LLD, 125.3) on TIW, and 128 (< LLD, 224.8) on QW (p=0.046 QD vs TIW arms). Estrone showed a clear dose response trend among arms, whereas no differences were observed for testosterone and androstenedione for both cancer and non-cancerous tissue in all arms. The Ki-67 change was analyzed in the previous paper; here we report the data for those patients who had drug and hormones tissue concentration measured, where Ki-67 decreased in all arms: median Ki67 change from baseline was QD -8 (-10, -3), TIW -6 (-11, -2), QW -4 (-8, -1). Conclusions: Exemestane 25 mg three times a week maintains comparable activity to the standard dose on tissue estradiol suppression and Ki67 decrease. Considering the estradiol suppression in non-cancerous tissue of the lowest exemestane dose, QW might even be considered for breast cancer risk reduction in primary prevention. Further analyses are ongoing to investigate the correlation with other biomarkers including the role of polymorphic UGT2B17 genotype that could identify candidates to lower exemestane dosage. Citation Format: Davide Serrano, Harriet Johansson, Bjørn-Erik Bertelsen, Gunnar Mellgren, Parijatham Thomas, Katherine Crew, Nagi B Kumar, Debora Macis, Valentina Aristarco, Aliana Guerrieri Gonzaga, Sara Gandini, Mauro D’Amico, Tania Buttiron Webber, Irene Maria Briata, Stefano Spinaci, Viviana Galimberti, Giuseppe Viale, Lana A. Vornik, Eduardo Villar-Sanchez, Powel Brown, Brandy M Heckman-Stoddard, Eva Szabo, Bernardo Bonanni, Andrea De Censi. Exemestane and breast cancer prevention: how low can we go? Drug and biomarker tissue levels in a randomized presurgical trial on exemestane alternative dosing regimen [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 PS07-01.

Associations of pentachlorophenol exposure during pregnancy with maternal and infant reproductive hormones based on a birth cohort

Pentachlorophenol (PCP), a typical environmental endocrine disruptor and a new persistent organic pollutant, has been extensively used as a pesticide worldwide. Although its use has been restricted for decades, PCP remains prevalent in both the environment and human bodies. Despite the known endocrine-disrupting and exogenous hormonal effects of PCP, few epidemiological studies examined such impact, especially among sensitive populations and during critical periods. Based on a prospective birth cohort in Wuhan, China, we collected maternal (first trimester; 13.0 ± 1.02 gestational weeks) and infant urine samples (1.16 ± 0.22 months postpartum) from 720 mother-infant pairs. We aimed to examine the association of PCP exposure during early pregnancy with maternal and infant urinary sex steroid hormones, including estrogens (estrone, E1; estradiol, E2; estriol, E3), progestogens (progesterone, P4; pregnenolone, P5; 17α-OH-Progesterone, 17OHP4; 17α-OH-Pregnenolone, 17OHP5), and androgens (testosterone, Testo; dihydrotestosterone, DHT; dehydroepiandrosterone, DHEA; androstenedione, A4). Additionally, gonadotropins [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] were measured in infant urine. Detection frequencies of all the sex steroid hormones in the maternal urine samples (>99 %) were higher than those in the infants' [most ≥80 %, except for E1 (3.36 %) and E2 (21.4 %)]. Maternal urinary PCP concentration was found to be significantly related with increased maternal sex steroid hormone concentrations; each interquartile increase in PCP concentration was positively related with percent change of the hormones (%Δ) ranging from 26.6 % to 48.5 %. On the other hand, maternal PCP exposure was associated with significantly increased P4 in male infants [%Δ (95 % confidence interval): 10.5 (0.56, 21.4)] but slightly decreased P4 in female infants [−11.9 (−21.8, 0.68)]. In addition, maternal PCP exposure was significantly associated with decreased FSH [%Δ (95 % CI): −9.90 (−17.0, −2.18)] and LH [−8.44 (−16.0, −0.19)] in the female infants, but not in the male infants. Sensitivity analyses, excluding infertility related treatment, pregnancy complications, preterm birth, or low birth weight, showed generally consistent results. Our findings implied that maternal/prenatal PCP exposure might disrupt the homeostasis of maternal and infant reproductive hormones. However, further studies are needed to confirm the findings.

Effect of Glycyrrhizic Acid on the Viability of Hela Cervical Adenocarcinoma Cell Line at Different Concentrations of Sex Steroid Hormones

Effect of Glycyrrhizic Acid on the Viability of Hela Cervical Adenocarcinoma Cell Line at Different Concentrations of Sex Steroid Hormones

Estradiol mediates greater germinal center responses to influenza vaccination in female than male mice.

Adult females of reproductive age develop greater antibody responses to inactivated influenza vaccines (IIV) than males. How sex, age, and sex steroid concentrations impact B cells and durability of IIV-induced immunity and protection over 4 months post-vaccination (mpv) was analyzed. Vaccinated adult females had greater germinal center B cell and plasmablast frequencies in lymphoid tissues, higher neutralizing antibody responses 1-4 mpv, and better protection against live H1N1 challenge than adult males. Aged mice, regardless of sex, had reduced B cell frequencies, less durable antibody responses, and inferior protection after challenge than adult mice, which correlated with diminished estradiol among aged females. To confirm that greater IIV-induced immunity was caused by sex hormones, four core genotype (FCG) mice were used, in which the testes-determining gene, Sry, was deleted from chromosome Y (ChrY) and transferred to Chr3 to separate gonadal sex (i.e., ovaries or testes) from sex chromosome complement (i.e., XX or XY complement). Vaccinated, gonadal female FCG mice (XXF and XYF) had greater numbers of B cells, higher antiviral antibody titers, and reduced pulmonary virus titers following live H1N1 challenge than gonadal FCG males (XYM and XXM). To establish that lower estradiol concentrations cause diminished immunity, adult and aged females received either a placebo or estradiol replacement therapy prior to IIV. Estradiol replacement significantly increased IIV-induced antibody responses and reduced morbidity after the H1N1 challenge among aged females. These data highlight that estradiol is a targetable mechanism mediating greater humoral immunity following vaccination among adult females.IMPORTANCEFemales of reproductive ages develop greater antibody responses to influenza vaccines than males. We hypothesized that female-biased immunity and protection against influenza were mediated by estradiol signaling in B cells. Using diverse mouse models ranging from advanced-age mice to transgenic mice that separate sex steroids from sex chromosome complement, those mice with greater concentrations of estradiol consistently had greater numbers of antibody-producing B cells in lymphoid tissue, higher antiviral antibody titers, and greater protection against live influenza virus challenge. Treatment of aged female mice with estradiol enhanced vaccine-induced immunity and protection against disease, suggesting that estradiol signaling in B cells is critical for improved vaccine outcomes in females.

102 Estradiol and follicular growth are associated with estrous behavior monitored by an accelerometer in grazing beef cows

Abstract In beef cattle, 40% of cows that display estrus do not remain pregnant after embryo transfer (ET). Estrus is a physiological behavior influenced by the concentration of sex-steroids. The use of accelerometer devices for estrus detection is a common practice in dairy operations. It remains unclear if this same artificial intelligence software can accurately measure reproductive behavior in beef females. We hypothesized that estrous variables detected by an accelerometer are associated with ovarian, hormonal, pregnancy outcome, and fertility-related variables measured in the cow. Fifty Bos indicus-influenced, cyclic, primiparous cows were fitted with an accelerometer collar (SCR Engineers, Israel) and a breeding indicator (Estrotectâ) to detect estrus after a synchronization protocol in five subsequent experimental replicates (n = 50*5 = 250). Only cows that showed estrus (d 0) remained in the study. The following variables were used from the accelerometer software: Activity Peak, Rumination Nadir, Estrus Duration, and Heat Index, calculated by proprietary algorithms. Dominant follicle (DF) diameter and plasma concentration of estradiol were measured on d -2 (day of progesterone device removal) and on d 0. On d -1 and d 4, endometrial thickness and luminal fluid accumulation were measured by ultrasonography. On d 7, two embryos were transferred/cow. Pregnancies were diagnosed on d 45 and terminated. After 30 d, a new replicate started. Cows included in at least two replicates that remained pregnant 100%, 99-50%, or less than 50% were classified as fertile, sub fertile, and infertile, respectively. Estrus display was recorded for 166 cows (66%). Estrus detection by accelerometer and Estrotect had excellent agreement rate (kappa coefficient 0.76). Cows detected in estrus only by Estrotect had 66% less pregnancy/ET than cows in estrus by both (9/21 vs. 97/145; P = 0.01). The DF diameter on d 0 was not associated with accelerometer variables. Cows with greater and moderate Activity Peak had a greater growth rate of the DF from d -2 to d 0 than lower Activity Peak cows (interaction day*Activity Peak; P = 0.06). Estradiol on d -1 was positively associated with the Activity Peak (P < 0.0001). Cows with lower Activity Peak had a thicker endometrium on both d -1 and d 4 (P=0.02), and greater uterine luminal fluid score on d -1 (P=0.03). Fertility status was not associated with any accelerometer variables. In conclusion, the Activity Peak is associated positively with estradiol concentration and DF growth, however no association was found with pregnancy outcome and fertility. Therefore, the main advantage of accelerometers in beef ranches is the ability to detect estrus at a similar accuracy as breeding indicators, using less labor. Future enhancements in hardware and software to allow prediction of pregnancy outcomes are expected to increase reproductive efficiency in cow-calf operations.

Hormone Concentration Measurement in Intracranial Dural Arteriovenous Fistulae

Intracranial dural arteriovenous fistulae (DAVFs) represent a subset of cerebral vascular malformations associated with significant morbidity and mortality. In Japan, DAVF exhibits sex-based differences in anatomical distribution, with female predominance in the cavernous sinus (CS) and male predominance in the transverse sinus (TS). Nevertheless, the pathophysiology of DAVF is not fully understood, and hormonal influences are hypothesized to play a role in its development. This study aimed to investigate changes in the concentrations of sex steroid hormones between intracranial and peripheral sampling sites in patients with CS- and TS-DAVF. We recruited 19 patients with CS-DAVF (n= 12) and TS-DAVF (n= 7) in this study. Blood hormone measurements were obtained from peripheral and jugular bulb samples during endovascular intervention. Hormone concentrations were analyzed using enzyme-linked immunosorbent assay kits, and statistical analyses were performed. Our study revealed a higher prevalence of CS-DAVF in females and TS-DAVF in males, which is consistent with previous studies. Estradiol concentration was significantly lower in the jugular bulb compared with in the periphery in both patients with CS- and TS-DAVF. This decrease in estradiol was observed irrespective of the patient's sex and independent of follicle-stimulating hormone levels. These findings indicate a local decrease in estradiol levels within the intracranial vasculature of patients with DAVF. This suggests a potential multifactorial role of estradiol in the pathomechanism of DAVFs, warranting further investigation to understand its influence on DAVF formation and potential targeted therapies, thereby enhancing patient outcomes.

Sex steroid and cognitive function among community-dwelling older men with or without vascular risk factors: a cross-sectional study

BackgroundThe relationship of testosterone and estradiol concentrations with cognitive function among community-dwelling older men was inconclusive. To examine the association of serum testosterone and estradiol concentrations with cognitive function in older men with or without vascular risk factors (VRFs).MethodsThis cross-sectional study consisted of 224 community-dwelling men aged 65–90 years in the Songjiang District of Shanghai, China. Serum testosterone and estradiol were measured by electrochemiluminescence immunoassay. The following five factors were defined as VRFs in this study: obesity, history of hypertension, diabetes, stroke, and coronary heart disease. Multivariable linear regression was used to examine the association of testosterone and estradiol with the Mini-Mental State Examination (MMSE) in participants with or without VRF. Restricted cubic spline (RCS) regression was performed to account for the nonlinearity of these associations.ResultsAn inverted “U” shaped non-linear relationship was found between testosterone concentration and MMSE score in men with one VRF (P overall =.003, non-linear P =.002). Estradiol showed an inverted “U” shaped non-linear relationship with MMSE score independent of VRFs (men without VRF, P overall =.049, non-linear P =.015; men with one VRF, overall P =.007, non-linear P =.003; men with two or more VRFs, overall P =.009, non-linear P =.005).ConclusionIn older men, an optimal level of sex steroid concentration may be beneficial to cognitive function and the VRFs should be considered when interpreting the relationship between sex steroid and cognitive function.

Assessment of stress levels and reproductive condition in giant pandas: insights from hair, faecal and saliva samples.

Concerted conservation efforts have brought the giant panda (Ailuropoda melanoleuca) back from the brink of extinction, but pandas continue to face anthropogenic threats in the wild and breeding success in captivity remains low. Because stress can have detrimental impacts on reproduction, monitoring stress- and sex-steroid levels would help assess the effectiveness of conservation mitigation measures in panda populations as well as monitor the welfare and reproductive health of captive animals. In this proof-of-concept study, we used faecal sex steroid and cortisol concentrations (n = 867 samples collected from five males and five females at Beijing Zoo every 4 days over the course of 12months) as a reference to investigate if testosterone, estradiol, progesterone and cortisol can be meaningfully measured in panda hair (n = 10) using radio-immuno-assays. Additionally, we calculated the ratio of testosterone to cortisol (T:C ratio) for each male, which can provide a biomarker of stress and physical performance. Our findings revealed distinct monthly variations in faecal sex-steroid and cortisol concentrations, reflecting reproductive seasonality and visitor-related stress among individual pandas. Notably, the oldest male had a significantly lower T:C ratio than other males. Our results confirm that the level of sex steroids and cortisol can be assayed by panda hair, and the hair cortisol concentrations correlate significantly with that in faeces with one month lag behind (r = 0.68, P = 0.03). However, the concentrations of hormones detected in saliva are lower than those in faeces by two orders of magnitude, making it difficult to ensure accuracy. By assessing the applicability of hair, faecal and salivary sampling, we can infer their utility in monitoring the reproductive status and acute and chronic stress levels of giant pandas, thereby providing a means to gauge the success of ongoing habitat restoration efforts and to discuss the feasibility of sample collection from wild populations.

Predicting comorbidities of pregnancy: A comparison between total and free 25(OH)D and their associations with parathyroid hormone

Pregnancy is a unique time when amplified sex steroid concentrations promote an escalation in vitamin D binding protein (DBP) synthesis, associated with increased total vitamin D and metabolites, including 25-hydroxyvitamin D (25(OH)D). Free 25(OH)D concentration increases disproportionately to total 25(OH)D during pregnancy, likely an adaptation to supply the woman and fetus with readily available 25(OH)D. Highlighting the importance of the calcium metabolic stress during pregnancy, the interactional relationship between serum 25(OH)D and PTH has been evaluated. Maternal total 25(OH)D and total 25(OH)D/iPTH are measures of vitamin D status and biomarkers for potential pregnancy complications. It has been proposed that free 25(OH)D and free 25(OH)D/iPTH could be better indicators of vitamin D status and predictors of pregnancy complications such as gestational diabetes (GDM), hypertensive disorders of pregnancy, and preterm delivery. This study aims to determine if free 25(OH)D and its association with PTH are more accurate predictors of comorbidities of pregnancy than total 25(OH)D and its association with PTH. In this post hoc analysis of the Kellogg Pregnancy Study, a double-blind randomized placebo-controlled trial, participants included 297 women with singleton pregnancies: 191 participants were randomized into a group receiving a daily prenatal (400 IU vitamin D3) while 196 received a prenatal plus extra supplementation (4400 IU vitamin D3). Blood and urine samples were collected monthly. 297 participants’ serum total 25(OH)D concentrations were measured using radioimmunoassay at baseline (visit 1) and 5–7 months’ gestation (visit 6–7). 93 participants’ serum free 25(OH)D and PTH concentrations were measured using ELISA and immunoradiometric assay, respectively, at visit 1 and 6–7; 66 participants had paired samples and were included in this analysis. Data were analyzed using SAS 9.4, Cary, N.C. or SPSS v28, IBM Corporation, Armonk, N.Y. Results were considered significant with a p < 0.05. A significant relationship exists between the ratio of total 25(OH)D/iPTH and free 25(OH)D/iPTH grouped by total 25(OH)D ≥ 30 ng/mL and < 30 ng/mL as an indicator of maternal vitamin D status. There was a statistically significant relationship between lower mean free 25(OH)D/iPTH and the development of GDM at visit 1 (p = 0.0003) and at visit 6–7 (p = 0.001) while total 25(OH)D/iPTH and GDM were significantly related only at visit 1 (p = 0.029). In this exploratory cohort, neither free 25(OH)D/iPTH nor total 25(OH)D/iPTH were significantly associated with increased incidence of preterm delivery, hypertensive disorders, or combined comorbidities of pregnancy. An univariate logistic regression evaluating the outcome of gestational diabetes while independently controlling for independent factors showed the ratio of free 25(OH)D/iPTH was more closely associated with gestational diabetes than the ratio of total 25(OH)D/iPTH, although neither were significant. This proof-of-concept analysis suggests that the ratio of free 25(OH)D/iPTH is associated with the development of gestational diabetes throughout pregnancy while total 25(OH)D/iPTH is only associated with the outcome early in pregnancy. Further investigation is warranted to explore this relationship between calcium metabolic stress during pregnancy with a larger cohort to improve validity,reproducibility, and relevance to other pregnancy comorbidities.

Impacts of Long-Term Exposure to Ocean Acidification and Warming on Three-Spined Stickleback (Gasterosteus aculeatus) Growth and Reproduction

The warming and acidification of surface waters as predicted by the IPCC leads aquatic species to face major multifaceted changes in their environment. Although teleosts have efficient regulatory systems to cope with these changes, such changes clearly have the potential to impact their physiological functions. Hence, it is crucial to estimate the ability of teleost fishes to cope with multi-stresses to predict how they will deal with future environments. In this context, we investigated the joint effect of warming and acidification on three-spined stickleback (Gasterosteus aculeatus) from the juvenile stage to adulthood, focusing on parameters linked to growth, sexual maturation, and reproduction. Juvenile sticklebacks were split in 2 climate scenarios: a “Current” scenario corresponding to the current seasonal physico-chemical parameters of the water of the “Rade de Brest” in France, and a “RCP8.5” scenario with a warming of 3 °C and an acidification of 0.4 pH units. After 7 months, fish in the RCP8.5 scenario reached the same size and mass as those in the Current scenario, but they needed greater amounts of food to reach satiety. Furthermore, the mortality rate over the experiment was higher in the RCP8.5 scenario. Muscle lipid content, an indicator of energy reserves, was lower in females in the RCP8.5 scenario, suggesting an increased need for energy to maintain homeostasis and other physiological functions or a divergence in energy allocation strategy. Moreover, females exhibited lower sexual maturation and egg quality under the RCP8.5 scenario, which could have contributed to the lower fertilisation rate observed. Males were more resilient to the RCP8.5 scenario, exhibiting only a trend for lower kidney somatic index scores. Altogether, these results suggest a delay and/or an inhibition of gametogenesis and maturation in fish in warmed and acidified waters. The analysis of blood sex steroid concentrations, brain gene expression profiles, and physiological indexes did not allow us to discriminate between a delay and an inhibition of maturation in the RCP8.5 scenario. Overall, these findings clearly indicate that there is a long-term global impact of combined acidification and warming on the mortality and reproductive performance of three-spined stickleback.

Phytoestrogen-Based Hormonal Replacement Therapy Could Benefit Women Suffering Late-Onset Asthma.

It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid concentrations during menstrual periods are closely related to asthma symptoms, while menopause induces severe physiological changes that might require hormonal replacement therapy (HRT), that could influence asthma symptoms in these women. Late-onset asthma (LOA) has been categorized as a specific asthmatic phenotype that includes menopausal women and novel research regarding therapeutic alternatives that might provide relief to asthmatic women suffering LOA warrants more thorough and comprehensive analysis. Therefore, the present review proposes phytoestrogens as a promising HRT that might provide these females with relief for both their menopause and asthma symptoms. Besides their well-recognized anti-inflammatory and antioxidant capacities, phytoestrogens activate estrogen receptors and promote mild hormone-like responses that benefit postmenopausal women, particularly asthmatics, constituting therefore a very attractive potential therapy largely due to their low toxicity and scarce side effects.

SAT413 Feminising Gender Affirming Hormone Therapy Prolongs QTc Interval

Abstract Disclosure: L. Angus: Speaker; Self; Kirin Brewery. T. Lin: None. S. Leemaqz: None. M. Grossmann: None. J.D. Zajac: None. A.S. Cheung: None. Background: In trans people using feminising hormone therapy there is an increased risk of cardiovascular events including conduction disorders. It is known that the QTc interval is longer in cisgender women of reproductive age than cisgender men, attributed to factors including serum sex steroid concentrations. Androgen deprivation therapy in men with prostate cancer is associated with prolongation of the QTc interval, but the effects of feminising hormone therapy in trans women are unclear. Methods: We measured the automated QTc interval from a 12-lead electrocardiogram at baseline and 6 months in trans women newly commencing feminising hormone therapy. Sex steroid concentrations were measured by LCMS. Participants were part of a randomised controlled double-blind trial of spironolactone 100mg daily versus cyproterone acetate 12.5mg daily in transgender women commencing estradiol for feminisation (ANZCTR 12620000339954) and this was a prespecified secondary outcome. Statistical analysis was performed using a linear mixed effects model looking at the effects of treatment over time. Results: Sixty-three participants were randomised and 55 participants completed the trial and were included in analysis (spironolactone group n=27, cyproterone acetate group n=28). Baseline group characteristics were comparable. Overall, the QTc interval increased by 18ms (95% CI 14 - 23 ms; p&amp;lt;0.001) at 6 months compared to baseline, but there was no between group difference (p=0.23). One participant had a QTc interval above 450ms. The mean serum total testosterone concentrations were similar between groups at baseline (spironolactone group 16.9 (13.5 - 20.3) nmol/L vs cyproterone acetate group 18.0 (15.0 - 21.0) nmol/L, p=0.60) but higher in the spironolactone group 4.3 (2.0 - 6.5) nmol/L than the cyproterone acetate group 1.5 (0.0 - 2.9) nmol/L, p&amp;lt;0.05 at 6 months. The mean serum estradiol and serum potassium concentrations were similar between groups at baseline and 6 months. Conclusions: Feminising hormone therapy with estradiol and either spironolactone or cyproterone acetate in trans women is associated with prolongation of the QTc interval over a six-month period. Further research is required to investigate the incidence of cardiac arrhythmia in this population. Presentation: Saturday, June 17, 2023

THU651 Testosterone Treatment And Sexual Function In Men With Or At Risk Of T2D: The T4DM Study

Abstract Disclosure: G.A. Wittert: Advisory Board Member; Self; Bayer Schering Pharma. Speaker; Self; Bayer Schering Pharma, Besin. K. Robledo: None. M. Grossmann: None. B.B. Yeap: Advisory Board Member; Self; Bayer Schering Pharma. Grant Recipient; Self; Bayer Schering Pharma, Lawley. B.G. Stuckey: None. W.J. Inder: None. K. Bracken: None. D.R. Jesudason: None. C.A. Allan: None. D.J. Handelsman: None. Background: In T4DM (men aged 50 – 74 yrs., waist circumference (WC) ≥95cm cm, prediabetes, or newly diagnosed type 2 diabetes (T2D) and serum testosterone (T) ≤ 14 nmol/L), 2 years treatment with T-undecanoate (1000 mg IM 3 monthly) vs placebo while enrolled in a lifestyle weight management program, decreased fat mass, and reduced the risk of T2D by 40%. Aim: To determine baseline predictors and T treatment effects on sexual function (SF) over time, including interactions with changes in waist circumference (WC), blood pressure (BP), glucose and mood. Methods: Adjusting for baseline sociodemographic, clinical parameters and serum sex steroid (LCMS) concentrations, linear mixed effects models were fitted to assess T treatment effects on measures of SF (erectile function (EF), sexual desire (SD), orgasmic function (OF), intercourse satisfaction (IS) and overall satisfaction (OS) via questionnaire (IIEF)) completed by each participant at baseline and weeks 30, 54, 78, and 102, together with WC, BP, glucose, trough T, estradiol (E), T:E ratio and mood (Center for Epidemiologic Studies Depression Scale (CES-D) at weeks 0, 54 and 102. Results Among men on T (504) or placebo (503) at baseline, age was inversely associated with all SF scales (p &amp;lt;0.001), and WC and CES-D score inversely associated with EF (p=0.041) and SD (p=0.029). There was no effect of baseline T, E or T:E ratio on SF. T treatment improved all SF measures (p&amp;lt;0.001) peaking at 30-54 weeks). The T treatment effect on SD and OF (both p-int=0.014) was greater in older men. Increasing WC over time was inversely associated with EF (p=0.036) and SD (p=0.043) scores, with no interaction with T treatment. SF scores were unaffected by changes in glucose, BP, or trough T, E or T:E ratio. Increase in depression scores corresponded to decreases in all SF scores (p &amp;lt;0.001). T treatment increased SD more in those with higher depression scores (p int=0.026) while not affecting the CES-D scores. Conclusion: Baseline age, WC, and depression scores, but not T were inversely associated with SF measures which improved with T treatment regardless of baseline T, E, or T:E ratio. T treatment improved SD and OF more in older men, and SD in those with more depressive symptoms. Change in WC was inversely associated with EF and SD, independent of T treatment. A pharmacological effect of T treatment to improve SF, particularly in older and depressed men, coexists with benefits from reduced central adiposity. Presentation: Thursday, June 15, 2023

FRI453 Genetic Heterogeneity of Hypothalamic Hypogonadism DIsorders

Abstract Disclosure: C. Bheeman: None. O. Astapova: None. Title: Genetic Heterogeneity of Hypothalamic Hypogonadism disorders. Introduction: Hypothalamic hypogonadism (HH) can be defined as having inappropriately low serum concentrations of gonadotropins in the presence of low circulating concentrations of sex steroids. It represents a group of genetically and clinically heterogeneous disorders. Case A 32-year-old female who presented to the endocrine clinic for evaluation of infertility. Patient had menarche at age 12 but became amenorrhoeic at age 14. Her physical exam was notable for normal female secondary sexual characteristics and intact sense of smell. She had no history of bone fracture or menopausal symptoms. The patient had failed the progesterone withdrawal test twice, but had withdrawal bleeding with the birth control pill or with hormonal replacement therapy. She had failed ovulation induction with clomiphene citrate, but was able to conceive 3 pregnancies through in vitro fertilization. Patient’s labs off of hormonal replacement and birth control were: LH &amp;lt;0.3. FSH 0.6, Estradiol &amp;lt;5, Progesterone 0.4. Her prolactin level was within normal limits at 6.6 and her TSH was 1.08. MRI of the brain showed no abnormalities in the pituitary gland. Genetic testing showed that the patient was heterozygous for a duplication mutation in the ANOS1 gene. Conclusion The genotypic and phenotypic heterogeneity that can be seen in HH disorders is due to the numerous genes involved in hypothalamic hypogonadism and their intricate interactions. Mutations contributing to HH can be involved in either the neurodevelopmental or neuroendocrine pathways of the hypothalamic pituitary gonadal axis or in both. There are mutations that can be inactivating variants while some can play the role of the modifier genes. The later may be able to explain the incomplete penetrance and variable expressivity sometimes seen in HH. It is important to note that though &amp;gt; 60 genes have been implicated in HH 50% of the cases remain genetically undiagnosed. This case is particularly interesting as this patient is a female with a heterozygous mutation on the ANOS1 gene, the primary gene associated with Kallmann syndrome. Kallmann syndrome is a X-linked recessive disorder and therefore the patient having phenotypical expression of the mutation is unexpected. Through the presentation of this case we aim to explore different modes of genetic expression and the different mechanisms that could have led to this patient hypothalamic hypogonadism. Presentation Date: Friday, June 16, 2023

Assessment of pubertal onset and disorders of puberty in Indian children and youth with type-1 diabetes.

Disorders of pubertal development are enlisted as associated conditions in children and adolescents with type-1 diabetes (T1D). We conducted this study with objective (1) To estimate the median age at onset of puberty and luteinizing hormone (LH) and sex-steroid concentrations in Indian adolescents with T1D and (2) To assess the impact of puberty on glycemic control and insulin resistance (IR). This cross-sectional study included 399 children and youth aged 6-23 years with T1D. Demographic, anthropometric, biochemical and pelvic ultrasound data were collected using standard protocols. IR was calculated using estimated glucose disposal rate and puberty was assessed using Tanner staging. Median age at onset of thelarche, pubarche and menarche were 11.3, 11.4 and 12.8 years in girls and that of gonadarche and pubarche were 10.6 and 12.7 years for boys. The mean LH and sex-steroid concentrations of subjects with T1D were similar to healthy subjects at each stage of puberty. The cut-offs of LH and sex-steroids derived from healthy Indian children yielded high sensitivity and specificity in determining pubertal onset. The prevalence of precocity, delayed puberty, ovarian cysts and polycystic ovaries was 0.9 , 5.1, 5.1 and 8.6 %, respectively. Glycaemic control and insulin sensitivity was poor in pubertal subjects. The age at onset of puberty, LH, and sex-steroid concentrations in subjects with T1D were like otherwise healthy Indian children with poor glycemic control and IR in pubertal subjects. Although most complications of T1D are associated with poor glycemic control, pubertal disorders were significantly low despite the less-than-optimal glycemic control.