Sex Steroids Research Articles

Abstract P148: Loss of Ovarian Estrogen Downregulates Renal Steroidogenesis

Hypertension impacts half of US adults and importantly is more prevalent in men than premenopausal women. Sex hormones, particularly estrogen, have been implicated in this sex-difference. Recently we showed renal medullary estrogenic signaling via the G protein-coupled estrogen receptor 1 promotes sodium excretion in female, but not male, Sprague Dawley (SD) rats which implicates estrogen as a possible female-specific natriuretic factor. This led us to question whether the kidney could produce its own steroids, including estrogen, to respond to salt load changes locally. Evidence in cultured COS-7 and fetal kidney cells indicates the expression and activity of steroidogenic enzymes. Recently, we showed the outer medulla of the female SD rat kidney expresses key enzymes and metabolites involved in sex steroid biosynthesis. It is unknown how ovarian estrogen regulates steroidogenesis in the kidney. We hypothesize that ovarian estrogen stimulates the intrarenal capacity to biosynthesize sex steroids. To test this, we measured mRNA expression of several steroidogenic enzymes in the renal outer medulla of gonadally-intact female or ovariectomized SD rats (N=6). Cholesterol is the initial substrate for steroid synthesis. Thus, we first measured HMG-CoA reductase (HMGCR), the key synthesizing enzyme for cholesterol and steroidogenic acute regulatory protein (StAR), which helps commit cholesterol to steroid synthesis. Ovariectomy (OVX) reduced mRNA expression of both when compared to intact females (HMGCR: 63.5 ± 6.2 vs 100.0 ± 10.7 P=0.0169; StAR: 66.6 ± 12.4 vs 100.0 ± 6.4 P=0.0298). Although not significantly different, OVX seemed to reduce the expression of hydroxysteroid 3-β Dehydrogenase, which converts several intermediate steps in androgen and estrogen synthesis, compared to intact females (73.4 ± 13.3 vs 100.0 ± 9.7 P=0.1283). Hydroxysteroid 17-β Dehydrogenase (17β-HSD) 1, which converts estrone to estradiol, was unchanged in OVX compared to intact females (107.6 ± 13.2 vs 100.0 ± 10.1 P=0.6537). OVX reduced expression of 17β-HSD2 (28.34 ± 7.8 vs 100.0 ± 12.85 P=0.0008) and 17β-HSD3 (71.1 ± 7.5 vs 100.0 ± 5.7 P=0.0097) which interconvert androstenedione and testosterone compared to intact females. Combined these data suggest that ovariectomy blunts the intrarenal machinery for steroidogenesis. Additional experiments are required to test whether menopause downregulates renal sex steroid biosynthesis and predisposes postmenopausal women to hypertension.

Is selected aquaporin expression in the chicken adrenal gland affected by disturbed sex steroid action?

Is selected aquaporin expression in the chicken adrenal gland affected by disturbed sex steroid action?

Abstract P142: Cross Sex Steroid Therapy and Cardiac Function in a Rodent Model of Gender Affirming Hormone Therapy in the Male Rat.

Transgender females ( TGF ) are individuals born biologically male, but identify as female. Gender-Affirming Hormone Therapy ( GAHT ) consists of 17β-Estradiol ( E2 ) supplementation with androgen suppression or a surgical intervention in order to match physical characteristics with perceived gender. Whether the prevalence of cardiovascular ( CV ) disease is enhanced in TGFs on GAHT is not clear. We previously reported that baseline cardiac morphology and function is not altered in a rat model of cross sex hormone therapy ( CSHT ) that mimics GAHT in the TGF. This study tested the hypothesis that myocardial ischemia will result in enhanced cardiac susceptibility in the male rat on CSHT. Adult male Sprague Dawley rats (13 weeks of age) were randomly assigned to either Control or E2+CTX ; E2 at 5 mg/day, pellet sc, replaced every 3 weeks with castration ( CTX ) performed at 15 weeks of age. At 25 weeks of age, rats in each group were randomly subdivided into Sham (n=8) or myocardial ischemia/reperfusion ( MIR ) , 1 hour occlusion, n=6-7. Statistics: Two-way ANOVA with Tukey’s post-hoc test. *Denotes significance vs. Control Sham. Results ( Table ): At 27 weeks of age, total lean mass (EchoMRI) was significantly decreased in Sham and I/R E2+CTX (p<0.05). At one week post I/R, stroke volume and cardiac output (echocardiogram, VEVO 3100) were significantly decreased in E2+CTX Sham vs. Control Sham (p<0.05); yet, ejection fraction, end-diastolic volume, and end-systolic volume did not differ. Thus, these data suggest that the biological effects of CSHT in the male does not enhance susceptibility to cardiac ischemia in young adulthood; yet, the long-term effect of CSHT on CV health remains unknown.

Autotaxin Expression in the Uterus of Cycling Rats.

Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP 2), is an enzyme with lysophospholipase D activity that converts lysophosphatidylcholine into lysophosphatidic acid (LPA). One of the LPA receptors, LPA3, is positively and negatively regulated by progesterone and estrogen, respectively. Furthermore, ATX expression in the rat uterus could be under the control of estrous cycle. In the present study, we used young normal cycling rats for further assess the uterine ATX expression and localization by reverse transcription PCR (RT-PCR) and immunohistochemistry, respectively. In the RT-PCR study, ATX mRNA level at Metestrus (1.00±0.026 AU) was significantly higher than that at Proestrus (0.42±0.046 AU, p<0.001) and the level at Diestrus (0.75±0.107 AU, p<0.05) was significantly higher than that at Proestrus. Among the luminal epithelial cells, the order of the ATX signal intensities was Metestrus>Diestrus>Proestrus>Estrus. Among the myometrial cells, the order of the signal intensities was Diestrus>Proestrus>Estrus>Metestrus. Among the glandular epithelial cells, the order of the signal intensities was Proestrus>Estrus=Metestrus= Estrus. The present study indicates that expression and localization of uterine ATX may be under the control of sex steroids during the estrous cycle. Further studies on the ATX signaling-sex steroid relationship will be providing better understanding on in normal and pathophysiological state of uterus.

Reduced voluntary wheel running behaviour in Kiss1r knockout mice

Kisspeptin and its receptor, Kiss1r, are novel players in the central balance of energy intake and expenditure. Recent evidence also indicates that kisspeptin signalling is important in thermoregulation and generation of the circadian rhythm. We used global Kiss1r knockout mice (Kiss1r KO), which are hypogonadal and develop obesity, to determine the impact of kisspeptin on circadian related behaviour. Voluntary wheel running was examined in Kiss1r KO and wild-type (WT) mice, using gonad intact and gonadectomised (GDX) mice to account for the effects of kisspeptin on gonadal sex steroids. Intact male and female Kiss1r KO mice covered only 10% and 30% of the distance travelled each day by their respective WT controls. In all mice, most of the running activity occurred during the dark phase. GDX WT mice ran significantly less during dark periods than the intact WT. GDX Kiss1r KO male mice ran significantly less than the GDX WT male mice, but the decrease was attenuated compared to intact mice. There was no difference between the female GDX Kiss1r KO and GDX WT. In contrast to the obese phenotype that develops in Kiss1r KO mice, body mass at the end of the study was significantly lower in the GDX Kiss1r KO than it was in the GDX WT mice. The difference in wheel running activity was not associated with any histological change in WAT, BAT, or muscle diameter. No difference in immunohistochemistry expression was seen in lateral hypothalamic orexin neurons or dopamine neurons in the ventral tegmental area / substantia nigra. We observed increased Iba1 expression (activation of microglia) in the arcuate nucleus of male Kiss1r KO mice. Overall, the circadian locomotor activity in male Kiss1r KO mice appears dependent on kisspeptin signalling and the obese phenotype does not develop in Kiss1r KO mice when they engage in voluntary activity.

Diverse modulatory effects of sex steroids on depressive-like behavior in socially stressed female rats.

Diverse modulatory effects of sex steroids on depressive-like behavior in socially stressed female rats.

Effects of inulin on intestinal flora and metabolism-related indicators in obese polycystic ovary syndrome patients

ContextPolycystic ovary syndrome (PCOS), a common endocrine disorder in women of reproductive age, is closely associated with chronic low-grade inflammation and metabolic disturbances. In PCOS mice, dietary inulin has been demonstrated to regulate intestinal flora and inflammation. However, the efficacy of dietary inulin in clinical PCOS remains unclear.ObjectiveThe intestinal flora and related metabolic indexes of obese patients with polycystic ovary syndrome (PCOS) after 3 months of inulin treatment were analyzed.Setting and designTo analyze the intestinal flora and related metabolic indexes in healthy controls and obese patients with polycystic ovary syndrome after 3 months of inulin treatment.ResultsThe results showed that dietary inulin improved sex hormone disorders, reduced BMI and WHR levels in obese women with PCOS. In addition, the inulin intervention reduced plasma TNF-α, IL-1β, IL-6, and MCP-1levels. Inulin intervention increased the abundance of Actinobacteria, Fusobacteria, Lachnospira, and Bifidobacterium, as well as decreased the ratio of F/B and the abundance of proteobacteria, Sutterella, and Enterobacter. Correlation analyses showed a strong relationship among plasma inflammatory factors, sex steroid hormones, and the intestinal flora of patients.ConclusionsDietary inulin may improve obese PCOS women disease through the gut flora–inflammation–steroid hormone pathway.The clinical trial registration number: ChiCTR-IOR-17012281.

Improving Beef Cattle Production: Safety and Effectiveness of New Immunocastration Vaccine.

Reproductive control in mammals, particularly in beef production systems, is crucial for managing behaviors driven by sex steroids, which can cause biosecurity issues, reduced weight gain, and decreased meat quality. Additionally, controlling sexual activity in females prevents unwanted pregnancies when both sexes are housed together for fattening. Surgical castration in cattle, commonly performed under field conditions, is associated with significant welfare concerns due to pain and infection risks. Furthermore, castrating female cattle in the field is often impractically expensive. Hence, new reproductive control methods that prioritize animal welfare and are suitable for both sexes are essential. Immunocastration (IC), which involves vaccination against the GnRH-I hormone, has emerged as a promising alternative, demonstrating efficacy and safety in various species. Immunocastration has proven to be an effective alternative to surgical castration in controlling reproduction and promoting animal welfare in several species. This study aims to evaluate the safety, immunogenicity, immunocastration effect, and productive impact of a novel IC vaccine developed in Chile for female cattle. Two consecutive trials were conducted, the first under controlled conditions and the second under field conditions. The results demonstrated that the new vaccine is safe and effective for use in beef cattle, inducing specific immunity against GnRH-I, reducing gonadal functionality, and improving productive parameters. These findings suggest that this new IC vaccine can significantly benefit the beef cattle industry by providing a welfare-friendly and efficient method of reproductive control.

Per- and polyfluoroalkyl substances (PFAS) and hypertensive disorders of Pregnancy- integration of epidemiological and mechanistic evidence

BackgroundHypertensive disorders of pregnancy (HDP) remain a significant global health burden despite medical advancements. HDP prevalence appears to be rising, leading to increased maternal and fetal complications, mortality, and substantial healthcare costs. The etiology of HDP are complex and multifaceted, influenced by factors like nutrition, obesity, stress, metabolic disorders, and genetics. Emerging evidence suggests environmental pollutants, particularly Per- and polyfluoroalkyl substances (PFAS), may contribute to HDP development. ObjectiveThis review integrates epidemiological and mechanistic data to explore the intricate relationship between PFAS exposure and HDP. Epidemiological evidenceStudies show varying degrees of association between PFAS exposure and HDP, with some demonstrating positive correlations, particularly with preeclampsia. Meta-analyses suggest potential fetal sex-specific differences in these associations. Mechanistic insightsMechanistically, PFAS exposure appears to disrupt vascular hemodynamics, placental development, and critical processes like angiogenesis and sex steroid regulation. Experimental studies reveal alterations in the renin-angiotensin system, trophoblast invasion, oxidative stress, inflammation, and hormonal dysregulation – all of which contribute to HDP pathogenesis. Elucidating these mechanisms is crucial for developing preventive strategies. Therapeutic potentialTargeted interventions such as AT2R agonists, caspase inhibitors, and modulation of specific microRNAs show promise in mitigating adverse outcomes associated with PFAS exposure during pregnancy. Knowledge gaps and future directionsFurther research is needed to comprehensively understand the full spectrum of PFAS-induced placental alterations and their long-term implications for maternal and fetal health. This knowledge will be instrumental in developing effective preventive and therapeutic strategies for HDP in a changing environmental landscape.

A Review on Testosterone: Estradiol Ratio-Does It Matter, How Do You Measure It, and Can You Optimize It?

There is a natural balance between the major sex steroids, testosterone and estradiol, controlled by gonadal secretion and peripheral conversion by aromatase. This balance is impacted by a variety of inborn and acquired conditions, and, more recently, by a growing use of exogenous testosterone therapy and off-label aromatase use under the guise of "men's health." We summarize reported testosterone:estradiol ratios, both naturally occurring and with pharmacologic manipulation and consider the ramifications of significant changes in these ratios. However, significant limitations exist in terms of steroid separation and measurement techniques, timing of samples, and lack of consistency from one assay to another, as well as definition of normative data. Limited data on the testosterone:estradiol ratio in men exists, particularly due to the scan data on concurrent estradiol values in men receiving testosterone therapy or aromatase inhibitors. Nonetheless, there seems to be a range of apparently beneficial values of the testosterone: estradiol radio at between 10 and 30, calculated as: testosterone in ng/dL/estradiol in pg/mL. Higher values appear to be associated with improved spermatogenesis and reduced bone density while lower values are associated with thyroid dysfunction. While there is growing awareness of the significance of the testosterone:estradiol ratio, and a sense of a desired range, the optimal value has not yet been determined. Further work is needed to clarify the measurement strategies and clearly-defined outcome measures related to the testosterone:estradiol ratio.

Molluscicidal activity and biochemical impacts of borrelidins against an aquatic invasive snail Pomacea canaliculata for crop protection

The invasive golden apple snail Pomacea canaliculata is one of the devastating threats to aquatic ecosystems and wetland agriculture worldwide. Macrolides from microbes display various advantages over other compounds in controlling snails. However, emergence of antibiotic-resistant phenotypes against certain macrolides in the field appeals for exploring more effectively molluscicidal macrolides. Here, two borrelidins, borrelidin BN1 and BN2, from the extract of a Streptomyces strain fermentation were evaluated for molluscicidal potential against P. canaliculata using both immersion and contact bioassay methods. Borrelidin BN1 (borrelidin A) presented a significant molluscicidal activity comparable to the chemical pesticide metaldehyde, and had a much lower median lethal concentration value (LC50, 522.984 μg·ml−1) than avermectin B1 at 72 h of contact-killing treatment. Snail growth was inhibited by borrelidin BN1 more than by metaldehyde at sublethal concentrations, consistent with responses of key biochemical parameters. Exposure to borrelidin BN1 decreased the activity of acetylcholinesterase (AChE), glutathione S-transferase (GST), aspartate aminotransferase (AST), alanine aminotransferase (ALT) as well as the levels of energy reserves and sex steroids in snail tissues, while increased the activity of superoxide dismutase (SOD), catalase (CAT), lactate dehydrogenase (LDH) and the level of lipid peroxidation (LPO). Further application assay confirmed that borrelidin BN1 protected crop plant Zizania latifolia from P. canaliculata damage via suppressing snail population density. These findings suggest great potential of borrelidin BN1 as a molluscicide. Additionally, its higher activity than the stereoisomeric borrelidin BN2 (borrelidin F) implied better molluscicidal borrelidins could be acquired through structural optimization.

Influence of estrogen on right ventricular mitochondrial function in pulmonary hypertension

There is a female predominance in pulmonary arterial hypertension (PAH) with a ~4:1 female-to-male ratio. However, female PAH patients exhibit better right ventricular (RV) function and thus better survival than the males. The majority of the current PAH therapies target pulmonary vascular remodeling and/or vasoconstriction in the pulmonary vasculature. However, no therapies directly target the RV, partially because the underlying mechanisms of RV failure in PAH are not fully understood. Since the RV serves as the main determinant of mortality, clarifying the mechanism of RV failure and the associated sex differences in PAH may promote the development of novel therapeutic strategies. Numerous molecular abnormalities have been detected in RV in PAH, particularly due to the suppression of mitochondrial function, including the inhibition of glucose oxidation and a shift to uncoupled aerobic glycolysis (Warburg metabolism) and excessive mitochondrial fission. The mitochondrial suppression is associated with hypocontractility and increased apoptosis in RV cardiomyocytes, and the hyperproliferative, pro-fibrotic, and apoptosis-resistant phenotypes in RV fibroblasts in PAH. Mitochondria also serve as the site for sex steroid synthesis, and in turn, the sex steroids, particularly estradiol (E2), influence the mitochondria both indirectly and directly. It is not well understood how E2 affects mitochondrial function in RV in PAH. Hence, this review focuses on the key mitochondrial genes and proteins that are influenced by PAH, E2, and sex.

Molecular characterization and expression profiling of 3 beta-hydroxysteroid dehydrogenase and hydroxysteroid 17-beta dehydrogenase in response to HCG stimulation in striped murrel, Channa striata (Bloch, 1793)

Striped murrel (Channa striata) is highly valued in the Indian subcontinent and Southeast Asia for its nutritional and medicinal benefits. However, the limited availability of high-quality seeds of murrel and the asynchronous maturation of brooders, particularly during peak spawning seasons creates problems in aquaculture. Beta-hydroxysteroid dehydrogenases (β-HSDs) are steroidogenic enzymes involved in the biosynthesis of active steroids in gametogenesis and steroidogenesis. This study aimed to clone and characterize the full-length cDNA sequences of two crucial enzymes, 3-beta hydroxysteroid dehydrogenase (Hsd3β) and 17-beta hydroxysteroid dehydrogenase (Hsd17β). It resulted in full-length cDNA sequences for Hsd3β and Hsd17β with 1101bp and 771bp length, respectively, encoding 366 and 256 amino acids. Signal peptide analysis indicated that both proteins are secretory, and hydropathy profiles suggested their hydrophilic nature. Notably, Rossmann-fold NAD(P)(+)-binding domains characteristic of Short-chain dehydrogenases/reductases (SDR) family genes were identified in Hsd3β (between 9-355 aa) and in Hsd17β (between 10-254 aa). Gene expression analyses were performed in testes and ovaries using qPCR at three key stages: preparatory, mature, and 16 h post human chorionic gonadotropin (hCG) injection (16 hpi). Results demonstrated a significant 2-fold upregulation of Hsd17β in mature and 16 hpi testes, while Hsd3β showed a significant 10-fold upregulation in mature testes compared to premature and 16 hpi stages. Ovarian expression of Hsd3β and Hsd17β showed minimal expression upon hCG injection (P < 0.05). These findings contribute to our understanding of Beta-hydroxysteroid dehydrogenases (β-HSDs), providing insights into regulating sex steroid hormone synthesis during the gonadal development of striped murrel.

Androgen Inhibition of Reproductive Neuroendocrine Function in Females and Transgender Males.

Ovarian function is controlled by pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which in turn are governed by gonadotropin releasing hormone (GnRH) secreted from the brain. A fundamental principle of reproductive axis regulation is negative feedback signaling by gonadal sex steroids back to the brain to fine-tune GnRH and gonadotropin secretion. Endogenous negative feedback effects can be mimicked by exogenous steroid treatments, including androgens, in both sexes. Indeed, a growing number of clinical and animal studies indicate that high levels of exogenous androgens, in the typically male physiological range, can inhibit LH secretion in females, as occurs in males. However, the mechanisms by which male-level androgens inhibit GnRH and LH secretion still remain poorly understood, and this knowledge gap is particularly pronounced in transgender men (individuals designated female at birth but identifying as male). Indeed, many transgender men take long-term gender-affirming hormone therapy that mimics male-level testosterone levels. The impact of such gender-affirming testosterone on the reproductive axis, both at the ovarian and neuroendocrine level, is a long-understudied area that still requires further investigation. Importantly, the few concepts of androgen actions in females mostly come from studies of polycystic ovary syndrome, which does not recapitulate a similar androgen milieu or a pathophysiology of inhibited LH secretion as occurs in testosterone-treated transgender men. This review summarizes clinical evidence indicating that exogenous androgens can impair neuroendocrine reproductive function in both female individuals and transgender men and highlights emerging experimental data supporting this in recently developed transgender rodent models.

Efficacy and safety of Resmetirom, a selective thyroid hormone receptor-β agonist, in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD): a systematic review and meta-analysis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity and mortality secondary to progressive liver disease and cardiovascular events. Resmetirom, a selective thyroid hormone receptor-β agonist has been developed as a therapeutic modality for MASLD. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of resmetirom compared to a placebo in the treatment of MASLD. Eligible studies were systematically identified by screening PubMed, Scopus, Web of Science, Cochrane library, Embase, and ClinicalTrials.gov from 2014 to 2024. Only randomized controlled trials comparing the efficacy and safety of resmetirom in the treatment of MASLD against placebo were included in the analysis. Meta-analysis was performed using RevMan 5.4 software. Four studies with low risk of bias and involving a total of 2359 participants were identified. The metanalysis included only three clinical trials with 2234 participants. A significant reduction in MRI-proton density fat fraction (MRI-PDFF) with 80 mg Resmetirom compared to that with placebo [SMD − 27.74 (95% CI − 32.05 to − 32.42), p < 0.00001] at 36–52 weeks as well as at 12–16 weeks [SMD − 30.92 (95% CI − 36.44 to − 25.40), p < 0.00001]. With Resmetirom 100 mg dose at 36–52 weeks [SMD − 36.05 (95% CI − 40.67 to − 31.43), p < 0.00001] and 12–16 weeks [SMD − 36.89 (95% CI − 40.73 to − 33.05), p < 0.00001] were observed. Resmetirom treatment was associated with a significant reduction in LDL-c triglyceride, lipoproteins. and liver enzymes. There was significant reduction FT4 and increase in SHBG and sex steroids with Resmetirom compared to placebo. There was no major difference in the overall treatment emergent adverse events at 80 mg [OR 1.55 (95% CI 0.84 to 2.87), and 100 mg [OR 1.13 (95% CI 0.78 to 1.63), doses of Resmetirom compared to placebo. However, gastrointestinal adverse events diarrhoea and nausea occurred in ≥ 10% in the Resmetirom group compared to placebo at < 12 week. Resmetirom treatment showed modest efficacy in treating MASLD with reduction in MRI-PDFF, LDL-c, triglyceride, lipoproteins, liver enzymes and NASH biomarkers without significant safety concerns. Larger and long-term RCTs may further confirm this promising outcomes of Resmetirom use in MASLD.

Transcriptome analysis of four types of gonadal tissues in largemouth bass (Micropterus salmoides) to reveal its sex-related genes.

The sex determination system of largemouth bass (Micropterus salmoides, LMB) is XX/XY; however, the underlying molecular mechanisms involved in early sex differentiation, gonadal development, and exogenous hormone-induced sex reversal remain unknown. In this study, LMB at 15days post-hatching (dph) were fed diets containing 20mg/kg of 17α-methyltestosterone (17α-MT) or 30mg/kg of 17β-estradiol (17β-E2) for 60days, respectively. Serum steroid levels, histological observations of the gonads, and identification of sex-specific markers were employed to screen the gonads of 60-day-old normal female fish (XX-F), normal male fish (XY-M), 17β-E2 induced pseudo-female fish (XY-F), and 17α-MT-induced pseudo-male fish (XX-M) for transcriptome sequencing in order to uncover genes and pathway involved in the process of sexual reversal. The results from histology and serum sex steroid hormone analysis showed that both 17α-MT and 17β-E2 were capable of inducing sex reversal of LMB at 15dph. Transcriptome results revealed a total of 2,753 genes exhibiting differential expression, and the expression pattern of these genes in the gonads of XX-M or XY-F resembled that of normal females or males. The male sex-biased genes that are upregulated in XX-M and downregulated in XY-F are referred to as key genes for male reversal, while the female sex-biased genes that are upregulated in XY-F and downregulated in XX-M are referred to as key genes for female reversal. Finally, 12 differentially expressed genes (DEGs) related to male sex reversal were screened, including star2, cyp17a, cyp11b1, dmrt1, amh, sox9a, katnal1, spata4, spata6l, spata7, spata18 and foxl3. 2 DEGs (foxl2a and cyp19a1b) were found to be associated with female sex reversal. The changes in these genes collectively influence the direction of sex differentiation of LMB. Among them, star2, dmrt1 and cyp19a1b with significantly altered expression levels may play potentially crucial role in the process of gender reversal. The expression patterns of 21 randomly selected genes were verified using qRT-PCR which confirmed the reliability and accuracy of the RNA-seq results. These findings not only enhance our understanding of the molecular basis underlying sex reversal but also provide crucial data support for future breeding research on unisexual LMB.

Leptins regulate the migration, proliferation, apoptosis, and synthesis of sexual steroid in tongue sole (Cynoglossus semilaevis) ovarian cells

Leptin is an important hormone in mammals, which plays a key role in regulating reproduction and energy metabolism. However, there are few studies on the function of leptin in reproductive regulation in fish, especially on tongue sole (Cynoglossus semilaevis). Thus, in this study, we firstly exploited the basic function of tongue sole leptins, the migration and growth rate of ovarian cells were reduced after knocking down lepA and lepB in ovarian cells, while increasing the apoptosis rate. Then both rlepA and rlepB were proved to be combined with lepR to further exert functions by dual luciferase assay. Transcriptome sequencing showed that differentially expressed genes (DEGs) were mainly enriched in KEGG pathways related to membrane receptors, fatty acid synthesis, growth, etc. when lepA and lepB were knocked down or additionally added in vitro. Additionally, the estradiol (E2) hormone was increased significantly after knocking down lepB. Finally, based on DEGs and the signaling pathways they participated in, we proposed a hypothesis about the signaling pathways in which leptin may be involved in ovarian cells. Taken together, these results provide new insights into the role of leptin in the regulation of physiological functions such as ovarian growth and development.

Time to Gender-Affirming Hormone Therapy Among US Military–Affiliated Adolescents and Young Adults

Use of exogenous sex steroid hormones, when indicated, may improve outcomes in adolescents and young adults with gender incongruence. Little is known about factors associated with the time from diagnosis of gender dysphoria to initiation of gender-affirming hormone therapy. Identification of inequities in time to treatment may have clinical, policy, and research implications. To evaluate factors associated with time to initiation of gender-affirming hormone therapy after a diagnosis of gender dysphoria in adolescents and young adults receiving care within the US Military Health System. This retrospective cohort study used TRICARE Prime billing and pharmacy data contained in the Military Health System Data Repository. Patients aged 14 to 22 years, excluding service members and their spouses, who received a diagnosis of gender dysphoria between September 1, 2016, and December 31, 2021, were included. The data were analyzed between August 30 and October 12, 2023. Included patient characteristics were race and ethnicity, age group, first sex assigned in the medical record, and TRICARE Prime sponsor military rank and service at the time of diagnosis. Health care and contextual characteristics included the year of diagnosis and the primary system in which the patient received health care. The primary outcome was the time between initial diagnosis of gender dysphoria to the first prescription for gender-affirming hormone medication within a 2-year period. A Poisson generalized additive model was used to evaluate this primary outcome. Adjusted probability estimates were calculated per specified reference categories. Of the 3066 patients included (median [IQR] age, 17 [15-19] years; 2259 with first assigned gender marker of female [74%]), an unadjusted survival model accounting for censoring indicated that 37% (95% CI, 35%-39%) initiated therapy by 2 years. Age-adjusted curves indicated that the proportion initiating therapy by 2 years increased by age category (aged 14-16 years, 25%; aged 17-18 years, 39%; aged 19-22 years, 55%). Incidence rate ratios (IRRs) and 2-year adjusted probabilities indicated that longer times to hormone initiation were experienced by adolescents aged 14 to 16 years (IRR, 0.36; 95% CI, 0.30-0.44) and 17 to 18 years (IRR, 0.66; 95% CI, 0.54-0.79) compared with young adults aged 19 to 22 years and Black compared with White adolescents (IRR, 0.73; 95% CI, 0.54-0.99). Senior officer compared with junior enlisted insurance sponsor rank (IRR, 1.93; 95% CI, 1.04-3.55) and civilian compared with military health care setting (IRR, 1.21; 95% CI, 1.02-1.43) was associated with shorter time to hormone initiation. In this cohort study, most adolescents and young adults with a diagnosis of gender dysphoria receiving health care through the US military did not initiate exogenous sex steroid hormone therapy within 2 years of diagnosis. Inequities in time to treatment indicate the need to identify and reduce barriers to care.

The Current Understanding of Molecular Mechanisms in Adenomyosis-Associated Infertility and the Treatment Strategy for Assisted Reproductive Technology.

Adenomyosis, endometriosis of the uterus, is associated with an increased likelihood of abnormal endometrial molecular expressions thought to impair implantation and early embryo development, resulting in disrupted fertility, including the local effects of sex steroid and pituitary hormones, immune responses, inflammatory factors, and neuroangiogenic mediators. In the recent literature, all of the proposed pathogenetic mechanisms of adenomyosis reduce endometrial receptivity and alter the adhesion molecule expression necessary for embryo implantation. The evidence so far has shown that adenomyosis causes lower pregnancy and live birth rates, higher miscarriage rates, as well as adverse obstetric and neonatal outcomes. Both pharmaceutical and surgical treatments for adenomyosis seem to have a positive impact on reproductive outcomes, leading to improved pregnancy and live birth rates. In addition, adenomyosis has negative impacts on reproductive outcomes in patients undergoing assisted reproductive technology. This association appears less significant after patients follow a long gonadotropin-releasing hormone agonist (GnRHa) protocol, which improves implantation rates. The pre-treatment of GnRHa can also be beneficial before engaging in natural conception attempts. This review aims to discover adenomyosis-associated infertility and to provide patient-specific treatment options.

Genome-wide variation study and inter-tissue communication analysis unveil regulatory mechanisms of egg-laying performance in chickens

Egg-laying performance is of great economic importance in poultry, but the underlying genetic mechanisms are still elusive. In this work, we conduct a multi-omics and multi-tissue integrative study in hens with distinct egg production, to detect the hub candidate genes and construct hub molecular networks contributing to egg-laying phenotypic differences. We identifiy three hub candidate genes as egg-laying facilitators: TFPI2, which promotes the GnRH secretion in hypothalamic neuron cells; CAMK2D, which promotes the FSHβ and LHβ secretion in pituitary cells; and OSTN, which promotes granulosa cell proliferation and the synthesis of sex steroid hormones. We reveal key endocrine factors involving egg production by inter-tissue crosstalk analysis, and demonstrate that both a hepatokine, APOA4, and an adipokine, ANGPTL2, could increase egg production by inter-tissue communication with hypothalamic-pituitary-ovarian axis. Together, These results reveal the molecular mechanisms of multi-tissue coordinative regulation of chicken egg-laying performance and provide key insights to avian reproductive regulation.