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Food and water are closely associated with reproductive willingness in vertebrates. These are important for animals and their non-availability act as stressors which decrease sex steroid secretion suppressing reproductive behaviour. Oestrogen plays a crucial role in reproduction via its receptors alpha (ERα) and beta (ERβ). This study tested the hypothesis that ERα in testes of male Japanese quail is regulated during water and food deprivations. The present study reveals that both water and food deprivations cause oxidative stress and subsequently decrease catalase and superoxide dismutase activity, while these increase malondialdehyde and hydrogen peroxide. Both deprivations reduce plasma oestradiol whereas elevate corticosterone level. The immunofluorescent localization of ERα in the testes occurs predominantly in the seminiferous tubules of control while reduces after both food and water deprivations. All types of spermatogenic cells were seen in control testis, while after water and food deprivations size of seminiferous tubules and spermatogenic cells population decreased. Scanning electron microscopic study exhibited fully mature sperms in clusters with head and elongated flagellum, whereas after water deprivation maximum sperms were distorted, scattered with highly reduced head. On food deprivation, only few sperms were seen with head and tail. Thus, taking into account the localization of ERα in testis, it is obvious that oestrogens produced locally are involved in regulation of spermatogenesis and spermiogenesis during stress.

Background Sex steroid hormone receptors are classified into three classes of receptors: estrogen receptors (ER) α and β, androgen receptor (AR), and progesterone receptor (PR). They belong to the nuclear receptor superfamily and activate their downstream genes in a ligand-dependent manner. Since sex steroid hormones are involved in a wide variety of physiological processes and cancer development, synthetic chemical substances that exhibit sex steroid hormone activities have been applied as pharmaceuticals and consumed in large amounts worldwide. They are potentially hazardous contaminants as endocrine disruptors in the environment because they may induce inappropriate gene expression mediated by sex steroid hormone receptors in vivo. Results To develop simple reporter gene assays with enhanced sensitivity for the detection of sex steroid hormones, we newly established mutant yeast strains lacking the CWP and PDR genes encoding cell wall mannoproteins and plasma membrane drug efflux pumps, respectively, and expressing human ERα, ERβ, AR, and PR. Reporter gene assays with mutant yeast strains responded to endogenous and synthetic ligands more strongly than those with wild-type strains. Sex steroid hormone activities in some pharmaceutical oral tablets and human urine were also detectable in these yeast assays. Conclusions Yeast reporter gene assay systems for all six steroid hormone receptors, including previously established glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) assay yeasts, are now available. Environmental endocrine disrupters with steroid hormone activity will be qualitatively detectable by simple and easy procedures. The yeast-based reporter gene assay will be valuable as a primary screening tool to detect and evaluate steroid hormone activities in various test samples. Our assay system will strongly support the detection of agonists, antagonists, and inverse agonists of steroid hormone receptors in the field of novel drug discovery and assessments of environmental pollutants.

Recognized for its traditional roles, estrogen is ever-present in all vertebrates, regulates reproduction by binding and activating estrogen receptors (ERs), and also controls several functions of vertebrates, including reproductive immune, and central nervous systems. In order to access any other possible functions of the estrogen receptors in the development of the juvenile Hybrid grouper (Epinephelus fuscoguttatus â™€× Epinephelu polyphekadion ♂), full-length of ERs cDNA sequences were isolated and analyses were found to be 2391 bp for hgERα, 2626 bp for gERb1 and 2339 bp for hgERb2, respectively. The results of amino acid and phylogenetic analysis revealed that each hgER was grouped in consistent taxonomic groups of perciformes and demonstrated great evolutional conservation in functional domains. Real-time PCR examination discovered that the receptors expressed in all tissues examined, though, at a different level, the ERα mRNA level expressed higher than ERβ1, and ERβ2 in tissues examined. The ERα mRNA level of expression was found to be highest in the tissue of the heart, followed by muscle, and liver. The ERβ1 mRNA level was greatest in heart tissue, trailed by liver and muscle and ERβ2 was highest in the heart trailed by stomach and liver. The minimal expression was recorded in the kidney, the gill, and the brain for ERα, ERβ1, and ERβ2 respectively. These results put forward that steroid hormone estrogen receptors might be playing a significant part in the controlling of social behavior complexity, plasticity behavior, and the assessment of a gratifying inducement in Hybrid grouper. Key words: Estrogen receptors, Real-time POR, tissue expression, hybrid grouper.

Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant owing to its efficient fire-breaking property. However, leaching of TBBPA into the environment has been a global health concern due to the endocrine-disrupting activity (EDA) associated with TBBPA exposure. Limited studies are available on the hazardous effects of TBBPA on reproductive function. The aim of the present study was the structural characterization of potential EDA of TBBPA in reproductive hormone signaling and transport including steroid nuclear receptors, such as estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), androgen receptor (AR), progesterone receptor (PR), and the steroid transport protein, sex hormone-binding globulin (SHBG). The structural binding characterization of TBBPA with the sex steroid nuclear receptors and transport protein was performed by induced-fit docking using the Schrödinger 2017 suite. The results revealed that the TBBPA binding pattern and molecular interactions with the indicated receptors and transport protein displayed overall similarity with their respective native ligands. The estimated binding energy value of TBBPA for ERα was similar to the native ligand, estradiol, indicating tight binding and greater potential for TBBPA to disrupt ERα signaling. For ERβ, AR, PR and SHBG, the estimated binding energy values were also close to their respective native ligands, indicating potential for interference in native hormone signaling and transport. In conclusion, TBBPA exposure in humans may potentially cause disruption of sex steroid signaling and transport, and thus lead to reproductive dysfunction.

Pejerrey Odontesthes bonariensis spawning period takes place during the end of winter and spring and, depending on temperature conditions, during late summer and autumn. Nevertheless, the occurrence and quality of the summer–autumn spawning period have not been well documented and are not considered for aquaculture production. In this context, this study aimed to characterize the reproductive activity of pejerrey reared in captivity under natural conditions of temperature and photoperiod throughout a year in order to summarize the spawning quality of the two spawning periods. The present results showed that pejerrey might spawn from late winter to the end of the spring with a peak in October (mid‐spring) and, also during summer and early autumn, interrupted by a period of 56 days without spawning activity in between. The extension of both spawning periods was almost equal (67 and 69 days). Nevertheless, higher relative fecundity and larger egg size were observed during the first spawning period, associated with higher levels of oestradiol measured in females demonstrating that it is better than the second spawning. The fertilization rate was not affected throughout the reproductive periods. These differences in the reproductive parameters are discussed in order to design specific strategies to increase seed production.

The red-sided garter snake exhibits a dissociated reproductive pattern, mating at a time when their gonads are quiescent and circulating sex steroids, initially reported to be low, have been found to be elevated during the breeding season. However, the only cue identified that initiates courtship behavior and mating in the red-sided garter snake is an extended period of low-temperature dormancy (LTD) followed by exposure to warm temperatures. In this study, we examined a possible association between winter dormancy, sex steroid hormone metabolism, and initiation of reproductive behavior in the male red-sided garter snake. Upon emergence from winter dormancy, courtship behavior was assessed using attractive females as stimuli. Animals receiving implants containing 1,4,6-androstatriene-3,17-dione (ATD), an aromatase inhibiter, showed little or no courtship behavior, while animals implanted with ATD + 17β estradiol (E2 ) or blank implants exhibited normal courtship. In addition, neurons in the pathways critical in the control of reproductive behavior were examined using the Golgi method. Examination of brains collected upon emergence revealed animals implanted with ATD had a significantly reduced number of dendritic spines compared to controls and animals treated with ATD + E2 . This study provides the first documentation that courtship behavior and mating in the male red-sided garter snake appears to be controlled not by LTD alone, but in conjunction with sex steroid hormones. Moreover, behavioral data suggest that the aromatization of androgens during LTD appears to be critical for the initiation of reproductive behavior in the male red-sided garter snakes.

Objective This systematic review included clinical trials of Food and Drug Administration-approved vaginal estrogens. The primary objective of this systematic review was to examine the comparative safety of the Food and Drug Administration-approved vaginal estrogen preparations among postmenopausal women. Methods We performed a PubMed search of the primary literature from January 1, 1966 to July 16, 2019 for English-language clinical trials. Manual review of retrieved citations identified additional citations. Results Of 882 retrieved citations, 75 clinical trials met inclusion criteria. Maximum trial duration was 52 weeks. None of the trials predesignated breast or endometrial cancer, cardiovascular events, or venous thromboembolism as primary outcomes. Studies were not designed to rule out an increase in endometrial carcinoma risk with long-term use of vaginal estrogen. There were few head-to-head comparisons. Fifty trials examined serum sex steroid and gonadotrophin levels; assay methodologies varied. Serum estradiol levels were 11 pg/mL at baseline or during placebo use and increased to a mean of 30 pg/mL after treatment. Estradiol levels were usually highest during the first 12 weeks of treatment, and were higher for estrogen creams than for inserts or rings. The 22 trials of endometrial thickness and the 15 trials of endometrial biopsy did not clearly demonstrate endometrial proliferation after vaginal estrogen treatment, but data were limited, and studies did not always perform systematic endometrial biopsy. Conclusions Newer low-dose estradiol rings, tablets, and inserts appear to induce the least increases in serum hormones, possibly indicating greater safety. Limited evidence in trials lasting up to 52 weeks suggest endometrial safety of vaginal estrogen use. Long-term trials are needed. : Video Summary:http://links.lww.com/MENO/A513.

Asthma is defined as chronic inflammation of the airways and is characterized by airway remodeling, hyperresponsiveness, and acute bronchoconstriction of airway smooth muscle (ASM) cells. Clinical findings suggest a higher incidence and severity of asthma in adult women, indicating a concrete role of sex steroids in modulating the airway tone. Estrogen, a major female sex steroid mediates its role through estrogen receptors (ER) ERα and ERβ, which are shown to be expressed in human ASM, and their expression is upregulated in lung inflammation and asthma. Previous studies suggested rapid, nongenomic signaling of estrogen via ERs reduces intracellular calcium ([Ca2+]i), thereby promoting relaxation of ASM. However, long-term ER activation on [Ca2+]iregulation in human ASM during inflammation or in asthma is still not known. In Fura-2-loaded nonasthmatic and asthmatic human ASM cells, we found that prolonged (24 h) exposure to ERα agonist (PPT) increased [Ca2+]iresponse to histamine, whereas ERβ activation (WAY) led to decreased [Ca2+] compared with vehicle. This was further confirmed by ER overexpression and knockdown studies using various bronchoconstrictor agents. Interestingly, ERβ activation was more effective than 17β-estradiol in reducing [Ca2+]iresponses in the presence of TNF-α or IL-13, while no observable changes were noticed with PPT in the presence of either cytokine. The [Ca2+]i-reducing effects of ERβ were mediated partially via L-type calcium channel inhibition and increased Ca2+sequestration by sarcoplasmic reticulum.Overall, these data highlight the differential signaling of ERα and ERβ in ASM during inflammation. Specific ERβ activation reduces [Ca2+]iin the inflamed ASM cells and is likely to play a crucial role in regulating ASM contractility, thereby relaxing airways.

Gynaecological diagnoses were carried in three adult female orangutans (Pongo spp.) using ultrasound, and their estrous states were estimated by measuring urinary sex steroid hormone concentrations using enzyme immunoassay. Ultrasound diagnosis revealed that the endometrial thickness and follicle size were correlated with the oestrogen‐3‐glucuronide concentrations in the follicular phase. In addition, administration of the ovulation inducer human chorionic gonadotropin (hCG) had the strongest effect on the pregnanediol‐3‐glucuronide (PdG) concentration when the follicle size was 22.3 mm, suggesting that the follicle reaches this size before ovulation. The similarity between this and the maximum ovarian follicle size in humans (approximately 20 mm) indicates that the ancestral reproductive characteristics may have been retained in these species., In orangutans, endometrium thickness and follicle size were correlated with estrogen concentration. And follicle may increase to around 22.3 mm prior to ovulation. Orangutans and humans have similar reproductive physiology.

Objective: The objective of this study was to report CYB5A deficiency, to discuss the contribution of steroid metabolomics to diagnosis and interpretation, and to highlight the presence of testicular microlithiasis. Methods: Two siblings with ambiguous genitalia at birth were later found to carry novel CYB5A variants, with resulting isolated 17, 20 lyase deficiency. We compared urine steroid data obtained between birth and adulthood with that from other cases. Results: Neonatal urine steroid profiles show a relative increase of 16-hydroxylated pregnenolone metabolites. Thereafter, there are no distinguishing features until puberty, when sex steroid deficiency drives gonadotrophin production, resulting in marked increases of 17-hydroxyprogesterone metabolites derived from the gonads. This excess may be revealed pre-pubertally by gonadotrophin stimulation testing. Novel findings are first, a considerable capacity for DHEA synthesis in the neonatal period compared to childhood and adulthood, suggesting that DHEAS production is much less dependent on CYB5A at birth; second, no consistent change in “backdoor pathway” intermediates; third, side chain cleavage of cortisol is largely unaffected, supporting the existence of a different lyase not dependent on CYB5A; fourth, increased 17-hydroxyprogesterone metabolites and very low androgen metabolites are diagnostic post-pubertally. Conclusion: This is the fourth disease-causing variant in CYB5A in isolated 17, 20 lyase deficiency and the first associated with testicular microlithiasis. Establishing a biochemical diagnosis pre-pubertally should now be possible using urine steroid profiling, supported by synacthen and gonadotrophin stimulation testing. We recommend liquid chromatography-mass spectrometry/mass spectrometry rather than immunoassay for serum steroid analysis, early methaemoglobin measurement and surveillance should testicular microlithiasis be detected.

We examined the effect of human chorionic gonadotropin (hCG) treatment 5 days after estrus on ovarian dynamics and plasma progesterone (P4) and estradiol (E2) concentrations when the first-wave dominant follicle (DF) was ipsilateral or contralateral to the corpus luteum (CL) in lactating dairy cows. Seventy cows were divided into two groups: (1) ipsilateral group (IG; n = 37), in which the first-wave DF was ipsilateral to the CL, and (2) contralateral group (CG; n = 33), in which the first-wave DF was contralateral to the CL. IG and CG were further subdivided into two groups: non-treatment group (IG, n = 18; CG, n = 19), and hCG treatment group: administrated 1500 IU of hCG 5 days after estrus (IG, n = 19; CG, n = 14). Blood sampling and ovarian examination were performed at 3, 5, 7, 9, 11, and 13 days after estrus. Mean diameter of the first-wave DF on Day 9 tended (P = 0.067) to be larger in IG than in CG in the non-treatment group. Mean diameter of CL and plasma P4 and E2 concentrations did not differ between IG and CG in the non-treatment and hCG treatment groups. Accessory CL development did not differ between IG and CG in the hCG treatment group. Our findings indicate that CL development and plasma P4 and E2 concentrations were not affected by the existence of the first-wave DF; however, first-wave DF development was affected by the existence of a CL in the same ovary.

We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone–binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS-E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose–response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for postmenopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer. See related reviews by Lynch et al., p. 11 and Swain et al., p. 16

BACKGROUND Sex differences in psychiatric disorders are common and could involve sex steroids. Aromatase, the product of the CYP19A1 gene, is the key enzyme in the conversion of androgen to estrogen. Whether CYP19A1 variants could be associated with depression differently in men and women has not been examined. METHODS This population-based study included 405 men and 602 women aged ≥65 years. A clinical level of depression (DEP) was defined as having a score ≥16 on the Center for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) spanning the CYP19A1 gene were genotyped and circulating levels of estradiol and testosterone were determined. Multivariable analyses were adjusted for age, body mass index, ischemic pathologies, cognitive impairment, and anxiety. RESULTS Five SNPs were associated with DEP in women specifically and this varied according to a history of major depression (p-values .01 to .0005). Three SNPs were associated with an increased risk of late-life DEP in women without a history of major depression, while two SNPs were associated with a decreased DEP risk in women with a history of major depression and were also associated with higher estradiol levels. CONCLUSIONS Variants of the CYP19A1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner. The polymorphisms decreasing the risk of recurrent depression in postmenopausal women also influence estradiol levels.

Environmental stimuli, including sex hormones and oxidative stress (OS), affect bone balance, modifying the epigenetic profiles of key osteogenic genes. Nonetheless, the interplay between sex steroids, epigenome and OS has yet be fully elucidated. This paper aims to study in vitro the role of sex steroids in OS-induced alteration in bone cells’ homeostasis, and to assess the possible contribution of epigenetic modifications. Toward this purpose, osteoblast (MC3T3-E1) and osteocyte (MLOY-4) cell lines were exposed to two different sources of free oxygen radicals, i.e., tert-butyl hydroperoxide and dexamethasone, and the protective effect of pre-treatment with androgens and estrogens was evaluated. In particular, we analyzed parameters that reflect bone cell homeostasis such as cell viability, cell migration, transcriptomic profile, transcriptional activity, and epigenetic signature. Our findings indicate that estrogens and androgens counteract OS effects. Using partially overlapping strategies, they reduce OS outcomes regarding cell viability, cell migration, the transcriptomic profile of gene families involved in bone remodeling, and epigenetic profile, i.e., H3K4me3 level. Additionally, we demonstrated that the protective effect of steroids against OS on bone homeostasis is partially mediated by the Akt pathway. Overall, these results suggest that the hormonal milieu may influence the mechanisms of age-related bone disease.

During the teleost radiation, extensive development of the direct innervation mode of hypothalamo-pituitary communication was accompanied by loss of the median eminence typical of mammals. Cells secreting follicle-stimulating hormone and luteinizing hormone cells are directly innervated, distinct populations in the anterior pituitary. So far, ∼20 stimulatory and ∼10 inhibitory neuropeptides, 3 amines, and 3 amino acid neurotransmitters are implicated in the control of reproduction. Positive and negative sex steroid feedback loops operate in both sexes. Gene mutation models in zebrafish and medaka now challenge our general understanding of vertebrate neuropeptidergic control. New reproductive neuropeptides are emerging. These include but are not limited to nesfatin 1, neurokinin B, and the secretoneurins. A generalized model for the neuroendocrine control of reproduction is proposed. Hopefully, this will serve as a research framework on diverse species to help explain the evolution of neuroendocrine control and lead to the discovery of new hormones with novel applications. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Sex hormone‐binding globulin (SHBG) regulates the bioavailability of sex steroid hormones in the blood. Levels of SHBG increase markedly in brown bears (Ursus arctos) during hibernation, suggesting that a key regulatory role of this protein is to quench sex steroid bioavailability in hibernation physiology. To enable characterization of ursine SHBG and a cross species comparison, we established an insect cell‐based expression system for recombinant full‐length ursine and human SHBG. Compared with human SHBG, we observed markedly lower secretion levels of ursine SHBG, resulting in a 10‐fold difference in purified protein yield. Both human and ursine recombinant SHBG appeared as dimeric proteins in solution, with a single unfolding temperature of ~ 58 °C. The thermal stability of ursine and human SHBG increased 5.4 and 9.5 °C, respectively, in the presence of dihydrotestosterone (DHT), suggesting a difference in affinity. The dissociation constants for [3H]DHT were determined to 0.21 ± 0.04 nm for human and 1.32 ± 0.10 nm for ursine SHBG, confirming a lower affinity of ursine SHBG. A similarly reduced affinity, determined from competitive steroid binding, was observed for most steroids. Overall, we found that ursine SHBG had similar characteristics to human SHBG, specifically, being a homodimeric glycoprotein capable of binding steroids with high affinity. Therefore, ursine SHBG likely has similar biological functions to those known for human SHBG. The determined properties of ursine SHBG will contribute to elucidating its potential regulatory role in hibernation physiology., We established an insect cell‐based expression system to characterize recombinant ursine SHBG. Ursine SHBG appeared to have two signal peptide cleavage sites, was dimeric in solution, and had a single unfolding temperature which increased in the presence of dihydrotestosterone. Determination of dissociation constants for several steroids revealed that ursine SHBG binds steroids with lower affinity than human SHBG.

Aim: To estimate the prevalence of impaired glucose tolerance (IGT) and diabetes mellitus type 2 (DMT2), as well as the predictors for glucose abnormalities in women with polycystic ovary syndrome (PCOS). Material and methods: A cross-sectional study with 80 consecutive patients with newly diagnosed PCOS who underwent the standard 75g oral glucose tolerance test (OGTT) and the measurement of sex steroid hormone and lipid profile. Results: According to the results from the OGTT, 63% had a normal test (NT), 23% had IGT, and 9% had DMT2. The NT group was younger with lower BMI than IGT and DMT2 groups (25.1 ± 7.3, 31.5 ± 6.5, 37.4 ± 4.0 years, and 29.1 ± 8.3 kg/m2, 31.7 ± 4.6 kg/m2, and 34.5 ± 5.6 kg/m2, respectively). The testosterone levels were highest in the group with a normal test (2.7 ± 0.8 nmol/l) and lowest in the DMT2 group (1.9 ± 0.8 nmol/L), with statistical significance. The sex hormone bounding globulin (SHBG) levels were low in all three groups, with statistically significant differences between NG and IGT, and the NT and DMT2 groups. The multivariate linear regression model identified age, BMI, SHBG and testosterone as major independent predictors for abnormal glucose metabolism. Conclusion: It seems that the prevalence of IGT and DMT2 among PCOS women in our country is not as high as in Western countries. Age, BMI, and SHBG increase the risk for the development of IGT and DMT2. Thus, close monitoring of older, obese women with low SHBG is needed because of the higher risk for the development of IGT and DMT2 in such patients.

Although elevated estradiol levels facilitate chronic pelvic pain in animal models, it remains to be determined whether sex steroid levels are altered in a cross-section of women with chronic pelvic pain (CPP) and those at-risk for developing CPP. We sought to determine if sex steroid levels are increased in women with menstrual pain and whether those changes were more extreme in two groups of women with worsened pelvic pain profiles: a) dysmenorrhea plus evidence of bladder pain sensitivity and b) bladder pain syndrome. Serum samples were collected during the mid-luteal phase to measure estradiol, progesterone, testosterone, and sex hormone-binding globulin. We also compared quantitative sensory testing profiles to evaluate how sex steroid differences influence proposed pain sensitivity mechanisms. Women with combined dysmenorrhea and bladder sensitivity had higher estradiol concentrations than controls (487 [IQR 390 – 641] vs 404 [336 – 467] pmol/L, p = 0.042). Bladder pain syndrome participants had greater sex hormone-binding globulin than controls (83 [71 – 108] vs 55 [42 – 76 nmol/L; p = 0.027). Levels of pain sensitivity and mood were different across the groups, but the only significant relationship to sex steroids was that sex hormone-binding globulin was correlated to somatic symptoms ( r = 0.26, p = 0.03). These findings show women potentially at-risk for CPP and women with diagnosed CPP exhibit altered circulating levels of sex steroids. Because these hormonal differences appear to be independent of mood or pain sensitivity, the role of sex steroids in the emergence of CPP may be via sensitization of visceral afferents.

Context Urinary cadmium (Cd) excretion is associated with cancer and cardiovascular morbidity. A potential mechanism could be disturbance of steroidogenesis in gonads and adrenal glands. Objective We tested whether urinary excretion of Cd is correlated with that of cortico- and sex steroid metabolites in the general adult population. Setting The Swiss Kidney Project on Genes in Hypertension is a multicentric, family-based population study. Measures Urinary excretions of steroid hormone metabolites and Cd were measured with separate day and night collections. Associations were analyzed by mixed linear models. Results Urinary Cd and testosterone excretions in men were significantly correlated (respective day and night β values [standard error (SE)], 1.378 [0.242], P < 0.0005; and 1.440 [0.333], P < 0.0005), but not in women [0.333(0.257), P = 0.2; and 0.674 (0.361), P = 0.06]. Urinary Cd and cortisol excretions were positively associated in both sexes [day: β = 0.475 (SE, 0.157), P = 0.0025, and 0.877 (SE, 0.194), P < 0.0005, respectively; night: β = 0.875 (SE, 0.253), P < 0.0005 and 1.183 (SE, 0.277), P = 0.00002, respectively]. Cd excretion was correlated with mineralocorticoid metabolites excretion, except tetrahydroaldosterone, in both sexes (P < 0.01). There was an independent effect of Cd on sex hormone and corticosteroid synthesis and an interdependent effect on gluco- and mineralcorticoid production. Conclusion Our findings provide evidence for a global stimulating effect on steroid synthesis already at low-dose Cd exposure. These findings might explain the association of Cd with diseases such as steroid-sensitive cancers or metabolic disorders.

Sarcopenia, characterized by the excessive loss of skeletal muscle mass, strength, and function, is associated with the overall poor muscle performance status of the elderly, and occurs more frequently in those with chronic diseases. The causes of sarcopenia are multifactorial due to the inherent relationship between muscles and molecular mechanisms, such as mitochondrial function, inflammatory pathways, and circulating hormones. Age-related changes in sex steroid hormone concentrations, including testosterone, estrogen, progesterone, and their precursors and derivatives, are an important aspect of the pathogenesis of sarcopenia. In this review, we provide an understanding of the treatment of sarcopenia through the regulation of sex steroid hormones. The potential benefits and future research emphasis of each sex steroid hormone therapeutic intervention (testosterone, SARMs, estrogen, SERMs, DHEA, and progesterone) for sarcopenia are discussed. Enhanced understanding of the role of sex steroid hormones in the treatment for sarcopenia could lead to the development of hormone therapeutic approaches in combination with specific exercise and nutrition regimens.

* Abbreviations: aBMD — : areal bone mineral density BMAD — : bone mineral apparent density DXA — : dual energy radiograph absorptiometry GnRHa — : gonadotropin hormone releasing hormone agonists Recognition and support are growing for the estimated 0.7% of American teenagers who identify as transgender or gender fluid.1 Many children’s hospitals now offer multidisciplinary care to patients to assist them in transitioning from their designated sex at birth (natal sex or sex assigned at birth) to their affirmed gender. Therapy can begin in early puberty with suppression of sex steroid hormone production followed by supplementation with sex steroids appropriate for their gender identity. The duration of pubertal suppression with gonadotropin hormone releasing hormone agonists (GnRHa) varies but can be as long as 4 years for younger patients who must wait until age 16 to consent for receipt of gender-affirming sex steroid replacement. Much remains unknown about how these manipulations in sex steroids will impact bone geometry, turnover, mass, and strength, all of which contribute to peak bone mass and strength in early adulthood. Peak bone mass and strength attained by early adulthood reflects the culmination of genetic and modifiable influences on bone density and microstructure.2 Sex steroids have differing effects on bone geometry during puberty, with testosterone fostering apposition of bone on the outer cortical surface and estrogen modifying the internal, endocortical area of bone.3 Research into the skeletal effects of hormone therapy for transgender youth is a high priority. The treatment protocols provide a valuable opportunity to distinguish the relative influence of sex steroids versus genetic preprogramming in determining bone development. Beyond the academic questions to be addressed, the onus is on providers to determine if their patients will sustain any adverse effects with respect to their long-term bone health. The influence of this treatment on the skeleton can be assessed noninvasively with dual energy radiograph absorptiometry (DXA), standard or high-resolution peripheral computed tomography, and/or MRI. These tools … Address correspondence to Laura K. Bachrach MD, Department of Pediatrics, Stanford University, 453 Quarry Road, Stanford, CA 94305-5660. E-mail: lkbach{at}stanford.edu

ImportanceSystemic sex steroid hormone aberrations often manifest in skin disease. The sebaceous, apocrine, and eccrine glands all play an important role in the response and production of these hormones in the skin. However, our ability to quantify hormonal secretions at the skin surface is limited.ObjectiveOur study aims to characterize the hormonal landscape of the skin at different anatomical sites and between the sexes through analysis of skin secretions.DesignIn this observational pilot study, we collected skin secretions from twelve male and ten female control subjects using commercially available, Sebutape®, from the antecubital fossa, forehead, back, and axilla. We then developed a method to extract and quantify the amount of sex steroid hormones from these secretions through liquid chromatography tandem mass spectrometry (LC-MS/MS).SettingOutpatient clinicParticipants34 participants were enrolled in the study, with 22 participants meeting criteria. Eligibility criteria included age of 18 to 40 and BMI between 15-35. Exclusion criteria included participants outside the ages of 18 to 40, use of antibiotics in the last 6 months, history of hormonal aberrations or chronic skin disorders, and use of hormone altering medications (except oral contraception).ResultsOur study detected anatomical site differences most notably in elevated dehydroepiandrosterone in the axilla and androstenedione in the forehead. Several hormonal differences were also detected between male and females consistent with known systemic hormone differences between the sexes.ConclusionsWe developed a method to quantify the hormonal levels in skin secretions using Sebutape®. Our approach found that hormonal composition varies based on sex and anatomical site. Additional studies will need to be completed to determine relevant hormonal shifts in clinical skin conditions.KEY POINTSSex steroid hormones of skin secretions varies between males and femalesDehydroepiandrosterone is produced in elevated amounts in the axillaAndrostenedione is produced in elevated amounts in the forehead

The sexual maturation and spawning of teleosts are regulated by the external environment and the endocrine system. When the environmental conditions are artificially adjusted at a fish farm, the maturity and spawning of fish can be controlled. In this study, sexual maturation and spawning of the starry flounder, Platichthys stellatus, were artificially induced by adjusting the water temperature and photoperiod at a fish farm to accelerate the species’ natural spawning period. One experimental group acted as a control and was exposed to a natural photoperiod and natural water temperature (NPNT). In contrast, another experimental group was exposed to an adjusted environment consisting of a regulated photoperiod and temperature (RPRT). Daylight time was reduced by 10 minutes every 3 days from 13 hours to a duration of 8 hours. The water temperature was first reduced by 1oC every day, starting at 22oC and ending at 8oC, and then raised to 10oC until the spawning period. Both experimental groups were treated with gonadotropin-releasing hormone analog (GnRHa) pellets to induce ovulation. The results show that when the water temperature and photoperiod were artificially controlled, ovulation could be induced 97 days earlier than the natural spawning. Plasma testosterone levels of RPRT and NPNT tended to increase and then decrease 1–2 months before spawning, and plasma levels of 17α,20β-dihydroxy-4-pregnen-3-one increased 1–2 months before spawning. The concentration of estradiol-17β (E2) in plasma was not associated with spawning.

The study is aimed at investigating the association of serum irisin, neuregulin 4 (NRG4), and anti-müllerian hormone (AMH) with adolescent obesity with polycystic ovary syndrome (PCOS) and the efficacy of weight management interventions. Serum levels of irisin, NRG4, AMH, sex steroid hormone, body mass index (BMI), serum insulin, and C-peptide were measured in 52 obese adolescent girls with PCOS (PCOS group) and 43 obese adolescent girls without PCOS (non-PCOS group). The levels of AMH, NRG4, serum irisin, sex steroid hormones, BMI, serum insulin, and C-peptide were evaluated in obese PCOS girls before and after one year weight management. The levels of AMH, serum insulin, NRG4, and total testosterone of PCOS group were significantly higher than those of non-PCOS group. On the contrary, serum irisin and serum C-peptide in PCOS group were significantly lower than that in non-PCOS group. The levels of fat mass, percent body fat, total testosterone, AMH, NRG4, and serum insulin in the obese girls with PCOS showed significant decreases compared with before weight management intervention. On the contrary, after one year of body weight management intervention, serum irisin and serum C-peptide was significantly increased. Adolescent obesity complicated with PCOS is significantly associated with glucose and lipid metabolism and sex steroid hormone disorders, but the exact pathophysiological and clinical features are highly variable. Weight management intervention can significantly improve the clinical symptoms and hematological indicators, serum irisin and NRG4 can be used as two essential biomarkers for evaluating weight management.

Endometriosis is major gynecological disease that affects over 10% of women worldwide and 30%-50% of these women have pelvic pain, abnormal uterine bleeding and infertility. The cause of endometriosis is unknown and there is no definite cure mainly because of our limited knowledge about its pathophysiology at the cellular and molecular levels. Therefore, demystifying the molecular mechanisms that underlie endometriosis is essential to develop advanced therapies for this disease. In this regard, HOX genes are remarkable because of their critical role in endometrial development and receptivity during implantation, which is attributed to their ability to mediate some of the sex steroid functions during the reproductive period. Access to the expression profiles of these genes would provide the necessary information to uncover new genes for endometriosis and assist with disease diagnosis and treatment. In this study we demonstrate an altered expression pattern for the HOX clusters (A-D) and their cofactors in both eutopic and ectopic conditions compared to control tissue biopsies. Remarkably, most of the intensive changes occurred in eutopic samples from endometriosis patients compared to control tissue biopsies. Pathway analysis revealed the involvement of differentially expressed genes in cancer that correlate with an association between endometriosis and cancer. Our results suggest critical roles for the HOX cluster and their cofactors in endometriosis pathophysiology.

Polycystic ovary syndrome (PCOS) is extremely heterogeneous in terms of clinical manifestations. The variability of the syndrome’s phenotype is derived from the genetic and molecular heterogeneity, with a great deal of environmental factors that may have long-term health consequences, such as metabolic and cardiovascular (CV) diseases. There is no doubt that women with PCOS suffer from metabolic complications more than their age-matched counterparts in the general population and at an earlier age. Obesity, low steroid hormone-binding globulin (SHBG), hyperandrogenemia, insulin resistance, and compensatory hyperinsulinemia are biomediators and early predictors of metabolic complications in PCOS. Doubts remain about the real risk of CV diseases in PCOS and the molecular mechanisms at the basis of CV complications. Based on that assumption, this review will present the available evidence on the potential implications of some biomediators, in particular, hyperandrogenism, estrogen-progesterone imbalance, insulin resistance, and low SHBG, in the processes leading to CV disease in PCOS, with the final aim to propose a more accurate CV risk assessment.

Uterine adenomyosis is a common chronic disorder frequently encountered in reproductive-age women, causing heavy menstrual bleeding, intense pelvic pain, and infertility. Despite its high prevalence, its etiopathogenesis is not yet fully understood, so there are currently no specific drugs to treat the disease. A number of dysregulated mechanisms are believed to contribute to adenomyosis development and symptoms, including sex steroid signaling, endometrial proliferation and invasiveness, and aberrant immune response. Abnormal sex steroid signaling, particularly hyperestrogenism and subsequent progesterone resistance, are known to play a pivotal role in its pathogenesis, which is why various antiestrogenic agents have been used to manage adenomyosis-related symptoms. Among them, gonadotropin-releasing hormone (GnRH) antagonists are swiftly gaining ground, with recent studies reporting efficient lesion regression and symptom alleviation. The aim of the present review is to compile available information on the pathogenesis of adenomyosis, explore the etiology and mechanisms of hyperestrogenism, and discuss the potential of antiestrogenic therapies for treating the disease and improving patient quality of life.

In teleost fish, sex steroids are involved in sex determination, sex differentiation, and fertility. Cyp17a1 (Cytochrome P450 family 17 subfamily A member 1) is thought to play essential roles in fish steroidogenesis. Therefore, to further understand its roles in steroidogenesis, sex determination, and fertility in fish, we constructed a cyp17a1 gene mutant in Nile tilapia (Oreochromis niloticus). In XX fish, mutation of the cyp17a1 gene led to a female-to-male sex reversal with a significant decline in 17β-estradiol (E2) and testosterone (T) production, and ectopic expression of male-biased markers (Dmrt1 and Gsdf) in gonads from the critical window of sex determination. Sex reversal was successfully rescued via T or E2 administration, and ovarian characteristics were maintained after termination of E2 supplementation in the absence of endogenous estrogen production in cyp17a1–/– XX fish. Likewise, deficiencies in T and 11-ketotestosterone (11-KT) production in both cyp17a1–/– XX sex-reversed males and cyp17a1–/– XY mutants resulted in meiotic initiation delays, vas deferens obstruction and sterility due to excessive apoptosis and abnormal mitochondrial morphology. However, 11-KT treatment successfully rescued the dysspermia to produce normal sperm in cyp17a1–/– male fish. Significant increases in gonadotropic hormone (gth) and gth receptors in cyp17a1–/– mutants may excessively upregulate steroidogenic gene expression in Leydig cells through a feedback loop. Taken together, our findings demonstrate that Cyp17a1 is indispensable for E2 production, which is fundamental for female sex determination and differentiation in XX tilapia. Additionally, Cyp17a1 is essential for T and 11-KT production, which further promotes spermatogenesis and fertility in XY males.

Over the last ten years, the interpretation of the presence of vertebrate sex steroids in molluscs has changed dramatically. Evidence has been accumulating that CYP11A and CYP19A genes (encoding cholesterol side-chain cleavage enzyme and aromatase), that are crucial for the biosynthesis of sex steroids in vertebrates, as well as key functional sex steroid receptors, are missing in molluscan genomes. To provide further evidence, we sequenced the whole transcriptome of the central nervous system of the great pond snail (Lymnaea stagnalis) and screened it for sequences homologous to those used in the generally accepted vertebrate sex steroidogenesis pathway as well as the known sex steroid receptor-related genes (such as CYP11A, CYP19A, 3β-HSD, nPR, and nAR). Our screening confirmed the absence of several key sequences that are essential to accomplish a full sex steroid biosynthesis pathway similar to that of vertebrates. There was also no evidence for nuclear sex steroid receptors. Our findings support the contention that molluscan endocrinology differs from the well-characterized vertebrate endocrine system.

With estrogen regulation of the reproductive system, G-protein-coupled membrane estrogen receptor (GPER) and estrogen-related receptors (ERRs) are implicated. Non-canonical receptors can bind estrogens such as environmental and pharmacological chemicals. These compounds induce rapid non-genomic pathways or receptor interaction including autoactivation. Testicular tumors occur in dogs more frequently than in other domestic animals. Also, in recent decades there were increased occurrences of various tumor types in dogs. Using qRT-PCR, Western blot and immunohistochemistry procedures in the present study, there was determination of abundance pattern of GPER, ERRα, β and γ in dog tests when there were intratubular germ cell tumors. There was quantitation of estradiol, cyclic GMP and calcium ions (Ca2+). There were changes (P

Hormonal contraceptives (HCs) are commonly used among reproductive aged women and alter the physiological state of the user by interfering with endogenous hormone concentrations and their actions on the reproductive tract. As hormones such as estradiol and progesterone modulate the incidence of substance abuse disorders in women, it is important to consider the influence HCs have on the female brain and behavior. This experiment explores how female sex steroid hormonal states associated with the rat estrous cycle, and modulating those states with HCs, influences measures of drug preference and responsivity. First, rats underwent food-light Pavlovian conditioning to measure conditioned orienting, a known predictor of amphetamine (AMP) place preference. Then, rats were conditioned and tested for AMP place preference with either an HC-implant or during estrous cycle stages associated with different ovarian hormone levels (i.e., proestrus (P) or metestrus/diestrus (M/D) while recording ultrasonic vocalizations (USVs) as an index of hedonic responsivity. Because of dopamine’s (DA) role in modulation of AMP actions, DA cell activity and availability were examined using tyrosine hydroxylase and FOS immunohistochemistry after final AMP challenge. Conditioned orienting did not differ between cycling and HC-implanted. P rats emitted more USVs during conditioning, showed higher AMP place preference throughout testing, and had higher DA cell activity in the substantia nigra compared to M/D and HC-implanted rats. Sex steroid hormone serum concentration and uterine horn thickness predicted some but not all of these measures. This experiment suggests ovarian hormones affect drug preference and responsivity, while providing novel insight into how hormone-altering contraceptives may reduce these measures.

Aggression is an adaptive behavior that plays an important role in gaining access to limited resources. Aggression may occur uncoupled from reproduction, thus offering a valuable context to further understand its neural and hormonal regulation. This review focuses on the contributions from song sparrows (Melospiza melodia) and the weakly electric banded knifefish (Gymnotus omarorum). Together, these models offer clues about the underlying mechanisms of non-breeding aggression, especially the potential roles of neuropeptide Y (NPY) and brain-derived estrogens. The orexigenic NPY is well-conserved between birds and teleost fish, increases in response to low food intake, and influences sex steroid synthesis. In non-breeding M. melodia, NPY increases in the social behavior network, and NPY-Y1 receptor expression is upregulated in response to a territorial challenge. In G. omarorum, NPY is upregulated in the preoptic area of dominant, but not subordinate, individuals. We hypothesize that NPY may signal a seasonal decrease in food availability and promote non-breeding aggression. In both animal models, non-breeding aggression is estrogen-dependent but gonad-independent. In non-breeding M. melodia, neurosteroid synthesis rapidly increases in response to a territorial challenge. In G. omarorum, brain aromatase is upregulated in dominant but not subordinate fish. In both species, the dramatic decrease in food availability in the non-breeding season may promote non-breeding aggression, via changes in NPY and/or neurosteroid signaling.

Many studies have shown that the human endocrine system modulates brain function, reporting associations between fluctuations in hormone concentrations and both brain activity and connectivity. However, how hormonal fluctuations impact fast changes in brain network structure over short timescales remains unknown. Here, we leverage “edge time series” analysis to investigate the relationship between high-amplitude network states and quotidian variation in sex steroid and gonadotropic hormones in a single individual sampled over the course of two endocrine states, across a natural menstrual cycle and under a hormonal regimen. We find that the frequency of high-amplitude network states are associated with follicle-stimulating and luteinizing hormone, but not the sex hormones estradiol and progesterone. Nevertheless, we show that scan-to-scan variation in the co-fluctuation patterns expressed during network states are robustly linked with the concentration of all four hormones, positing a network-level target of hormonal control. We conclude by speculating on the role of hormones in shaping ongoing brain dynamics.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin dryness, inflammation, and itch. A major hallmark of AD is an elevation of the immune cytokines IL-4 and IL-13. These cytokines lead to skin barrier disruption and lipid abnormalities in AD, yet the underlying mechanisms are unclear. Sebaceous glands are specialized sebum-producing epithelial cells that promote skin barrier function by releasing lipids and antimicrobial proteins to the skin surface. Here, we show that in AD, IL-4 and IL-13 stimulate the expression of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), a key rate-limiting enzyme in sex steroid hormone synthesis, predominantly expressed by sebaceous glands in human skin. HSD3B1 enhances androgen production in sebocytes, and IL-4 and IL-13 drive lipid abnormalities in human sebocytes and keratinocytes through HSD3B1. Consistent with our findings in cells, HSD3B1 expression is elevated in the skin of AD patients and can be restored by treatment with the IL-4Rα monoclonal antibody, Dupilumab. Androgens are also elevated in a mouse model of AD, though the mechanism in mice remains unclear. Our findings illuminate a connection between type 2 immunity and sex steroid hormone synthesis in the skin and suggest that abnormalities in sex steroid hormone synthesis may underlie the disrupted skin barrier in AD. Furthermore, targeting sex steroid hormone synthesis pathways may be a therapeutic avenue to restoring normal skin barrier function in AD patients.

Our present knowledge on interrelation between morphology/ultrastructure of mitochondria of the Leydig cell and its steroidogenic function is far from satisfactory and needs additional studies. Here, we analyzed the effects of blockade of androgen receptor, triggered by exposure to flutamide, on the expression of steroidogenic proteins (1) and ultrastructure of Leydig cells’ constituents (2). We demonstrated that increase in the expression level of steroidogenic (StAR, CYP11A1, 3β-HSD, and CYP19A1) proteins (and respective mRNAs) in rat testicular tissue as well as elevation of intratesticular sex steroid hormone (testosterone and estradiol) levels observed in treated animals correspond well to morphological alterations of the Leydig cell ultrastructure. Most importantly, up-regulation of steroidogenic proteins’ expression apparently correlates with considerable multiplication of Leydig cell mitochondria and subsequent formation of local mitochondrial networks. Interestingly, we showed also that the above-mentioned processes were associated with elevated transcription of Drp1 and Mfn2 genes, encoding proteins implicated in mitochondrial dynamics. Collectively, our studies emphasize the importance of mitochondrial homeostasis to the steroidogenic function of Leydig cells.

Background It was reported that steroid-related gene expressions in the adipose tissue (AT) of women differ between women affected with polycystic ovary syndrome (PCOS) and non-PCOS. Although association between PCOS in mother and offspring’s health is a crucial issue, there are few studies focusing on AT of pregnant women suffering from PCOS. Our objectives were to determine the differences between mRNA expression levels of key steroid-converting enzymes in abdominal subcutaneous AT of pregnant women afflicted with PCOS and non-PCOS. Methods Twelve pregnant women with PCOS (case) and thirty six non-PCOS pregnant women (control) (1:3 ratio; age- and BMI-matched) undergoing cesarean section were enrolled for the present study. Expressions of fifteen genes related to steriodogenesis in abdominal subcutaneous AT were investigated using quantitative real-time PCR. Results No significant differences were detected with respect to age, BMI (prior pregnancy and at delivery day), gestational period and parity among pregnant women with PCOS and non-PCOS. Most of the sex steroid-converting genes except 17β-Hydroxysteroid dehydrogenases2 (17BHSD2), were highly expressed on the day of delivery in subcutaneous AT. Women with PCOS showed significantly higher mRNA levels of steroidgenic acute regulator (STAR; P 0.001), cytochrome P450 monooxygenase (CYP11A1; P 0.05), 17α-hydroxylase (CYP17A1; P 0.05), and 11β-Hydroxysteroid dehydrogenase (11BHSD1 and 11BHSD2; P 0.05). The expression of steroid 21-hydroxylase (CYP21) in non-PCOS was fourfold higher than those of women with PCOS (P (CYP19A1), 3β-hydroxysteroid dehydrogenase (3BHSD1 and 3BHSD2), and 17BHSD family (1, 3, 5, 7, and 12) between the two groups. Conclusion The expression levels of genes related to sex steroids metabolism were similar to age-matched and BMI- matched pregnant non-PCOS and pregnant women with PCOS at delivery day. However, the alterations in gene expressions involved in glucocorticoids and mineralocorticoids metabolism were shown. It is necessary to point out that further studies regarding functional activity are required. More attention should be given to AT of pregnant women with PCOS that was previously ignored.

Background There is considerable interest globally in understanding the influence of exogenous sex steroids/hormones on the vaginal microbiota (VM). We conducted a systematic review summarising the influence of hormonal contraception (HC) and hormone replacement therapy (HRT) on the VM among reproductive-aged women and peri/post-menopausal women, respectively. PROSPERO registration: CRD42018107730. Methods To be eligible for inclusion, studies had to report on sex steroid use (HC or HRT) and provide a measurement of the VM by molecular methods. Two authors systematically identified and extracted data from eligible studies. Data regarding the ‘positive’, ‘negative’ or ‘neutral’ effect of exogenous sex steroid use on the VM was summarised. A positive effect was defined as an increased abundance of lactobacilli, decreased abundance of bacteria associated with a non-optimal VM, decreased bacterial diversity and/or increased bacterial stability, relative to partcipants’ pre-treatment specimen or compared to a non-exposed control population. A negative effect was defined as parameters in the opposite direction, and a neutral effect was defined as no specific effect identified. Results Of the 2647 unique studies screened for inclusion, 266 full-texts were assessed for eligibility and 33 studies were included in qualitative data analysis. Among 28 studies of reproductive-aged women using HCs, 15/28 reported on >1 HC type. Oestrogen-containing contraceptives, mostly reflecting the combined-oral contraceptive pill, had a positive effect on the VM in 11/15 studies. The effect of progesterone-only contraceptives were less clear; of 21 studies, 8 showed a positive effect, 8 a negative effect and 5 a neutral effect. In particular, the effect of Depo-Provera was negative in 7, positive in 4, and neutral in 2 studies. All 5 studies investigating HRT-use demonstrated a positive influence of HRT-use on the VM. Conclusion Exogenous sex steroids, particularly containing oestrogen, may play a role in supporting an optimal VM in both reproductive-aged and peri/post-menopausal women.

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8–10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.

Human populations of Black African ancestry have a relatively high risk of aggressive cancer types, including keratinocyte‐derived squamous cell carcinomas (SCCs). We show that primary keratinocytes (HKCs) from Black African (Black) versus White Caucasian (White) individuals have on average higher oncogenic and self‐renewal potential, which are inversely related to mitochondrial electron transfer chain activity and ATP and ROS production. HSD17B7 is the top‐ranked differentially expressed gene in HKCs and Head/Neck SCCs from individuals of Black African versus Caucasian ancestries, with several ancestry‐specific eQTLs linked to its expression. Mirroring the differences between Black and White HKCs, modulation of the gene, coding for an enzyme involved in sex steroid and cholesterol biosynthesis, determines HKC and SCC cell proliferation and oncogenicity as well as mitochondrial OXPHOS activity. Overall, the findings point to a targetable determinant of cancer susceptibility among different human populations, amenable to prevention and management of the disease., Differences in individuals' cancer susceptibility can be attributed, in part, to specific genetic and epigenetic variations. Human populations of Black African ancestry have a higher risk of aggressive cancer of various types, including keratinocyte‐derived squamous cell carcinomas (SCCs).

Although lynxes and domestic cats are both felids, their luteal life cycles differ. As in many species, corpora lutea (CLs) of domestic cats regress after pregnancy or pseudopregnancy. By contrast, CLs of lynxes do not functionally regress following the cycle of their formation. They stay physiologically active and persist for several years. To obtain an improved understanding of the life cycle of both species, we comparatively studied the CLs of these species in detail. In this review, we summarize the similarities and differences of their CLs regarding sex steroid and prostaglandin generation and receptors. The most evident differences were visible in the CLs of lynxes, which persist from previous cycles, compared with CLs of lynxes and domestic cats from the recent luteal cycle. We assume that these differences could indicate processes ensuring long-term luteal survival and functionality, for example, by high estrogen production/metabolism or by antioxidative effects.

Through the release of hormones, the neuro-endocrine system regulates the immune system function promoting adaptation of the organism to the external environment and to intrinsic physiological changes. Glucocorticoids (GCs) and sex hormones not only regulate immune responses, but also control the hematopoietic stem cell (HSC) differentiation and subsequent maturation of immune cell subsets. During the development of an organism, this regulation has long-term consequences. Indeed, the effects of GC exposure during the perinatal period become evident in the adulthood. Analogously, in the context of HSC transplantation (HSCT), the immune system development startsde novofrom the donor HSCs. In this review, we summarize the effects of GCs and sex hormones on the regulation of HSC, as well as of adaptive and innate immune cells. Moreover, we discuss the short and long-term implications on hematopoiesis of sex steroid ablation and synthetic GC administration upon HSCT.

Sex differences in cerebrovascular disease rates indicate a possible role for ovarian sex steroid hormones in cerebrovascular function. To synthesise and identify knowledge gaps, a systematic review and meta-analysis was conducted to assess how ovarian sex steroid hormone changes across the lifespan affect cerebrovascular function in women. Three databases (EMBASE, MEDLINE and Web of Science) were systematically searched for studies on adult cerebrovascular function and ovarian sex steroid hormones. Forty-five studies met pre-defined inclusion criteria. Studied hormone groups included hormone replacement therapy (HRT; n = 17), pregnancy (n = 12), menstrual cycle (n = 7), menopause (n = 5), oral contraception (n = 2), and ovarian hyperstimulation (n = 2). Outcome measures included pulsatility index (PI), cerebral blood flow/velocity (CBF), resistance index (RI), cerebral autoregulation, and cerebrovascular reactivity. Meta-analysis was carried out on HRT studies. PI significantly decreased [−0.05, 95% CI: (−0.10, −0.01); p = 0.01] in post-menopausal women undergoing HRT compared to post-menopausal women who were not, though there was considerable heterogeneity (I2 = 96.8%). No effects of HRT were seen in CBF (p = 0.24) or RI (p = 0.77). This review indicates that HRT improves PI in post-menopausal women. However, there remains insufficient evidence to determine how changing ovarian sex steroid hormone levels affects cerebrovascular function in women during other hormonal phases (e.g., pregnancy, oral contraception).

We have used the four core genotypes (FCG) mouse model, which allows a distinction between effects of gonadal secretions and chromosomal complement, to determine when sex differences in the immune system first appear and what influences their development. Using splenic T cell number as a measure that could be applied to neonates with as yet immature immune responses, we found no differences among the four genotypes at postnatal day 1, but by day 7, clear sex differences were observed. These sex differences were unexpectedly independent of chromosomal complement and similar in degree to gonadectomized FCG adults: both neonatal and gonadectomized adult females (XX and XY) showed 2-fold the number of CD4+ and 7-fold the number of CD8+ T cells versus their male (XX and XY) counterparts. Appearance of this long-lived sex difference between days 1 and 7 suggested a role for the male-specific perinatal surge of testicular testosterone. Interference with the testosterone surge significantly de-masculinized the male CD4+, but not CD8+ splenic profile. Treatment of neonates demonstrated elevated testosterone limited mature cell egress from the thymus, whereas estradiol reduced splenic T cell seeding in females. Neonatal male splenic epithelium/stroma expressed aromatase mRNA, suggesting capacity for splenic conversion of perinatal testosterone into estradiol in males, which, similar to administration of estradiol in females, would result in reduced splenic T cell seeding. These sex steroid effects affected both CD4+ and CD8+ cells and yet interference with the testosterone surge only significantly de-masculinized the splenic content of CD4+ cells. For CD8+ cells, male cells in the thymus were also found to express one third the density of sphingosine-1-phosphate thymic egress receptors per cell compared to female, a male characteristic most likely an indirect result of Sry expression. Interestingly, the data also support a previously unrecognized role for non-gonadal estradiol in the promotion of intra-thymic cell proliferation in neonates of both sexes. Microarray analysis suggested the thymic epithelium/stroma as the source of this hormone. We conclude that some immune sex differences appear long before puberty and more than one mechanism contributes to differential numbers and distribution of T cells.