Effects Of Androgens Research Articles

Exogenous Versus Endogenous Nandrolone in Doping Investigations: A Systematic Literature Review

Nandrolone, or 19-nortestosterone, is an anabolic steroid derived from testosterone, known for its androgenic and anabolic effects. Often used illicitly by athletes to boost performance, its use is banned by the World Anti-Doping Agency (WADA) in and out of competition. Nandrolone’s main metabolites, 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE), are typically detected in urine. This systematic review, registered with PROSPERO and following PRISMA guidelines, examines nandrolone’s metabolism, factors affecting its natural production, and the analytical methods used in doping tests. Searches on PubMed, Scopus, and Web of Science yielded 517 studies, of which 57 were selected for analysis after excluding duplicates and unrelated articles. Descriptive statistics were applied to assess data on metabolic pathways, endogenous production influences, and detection techniques. Based on this review, it clearly emerges that the only technique that can distinguish endogenous production from an exogenous intake is gas chromatography/combustion/isotope ratio mass spectrometry (GC-C-IRMS). In addition, factors influencing endogenous production are considered and explored. Overall, this review provides useful information regarding nandrolone and its main metabolites.

CAGn Polymorphic Locus of Androgen Receptor (AR) Gene in Russian Infertile and Fertile Men

The androgen receptor (AR) is critical for mediating the effects of androgens. The polymorphic CAGn locus in exon 1 of the AR gene is associated with several diseases, including spinal and bulbar muscular atrophy (SBMA), prostate cancer, and male infertility. This study evaluated the CAGn locus in 9000 infertile Russian men and 286 fertile men (control group). The CAGn locus was analyzed using the amplified fragment length polymorphism method. In the infertile cohort, the number of CAG repeats ranged from 6 to 46, with a unimodal distribution. The number of CAG repeats in infertile and fertile men was 22.15 ± 0.93 and 22.02 ± 1.36, respectively. In infertile men, variants with 16 to 29 repeats were present in 97% of the alleles. A complete mutation (≥42 CAG repeats) was found in three patients, while three others had 39-41 repeats. The incidence of SBMA was 1:3000 infertile men. Significant differences (p < 0.05) were observed between infertile and fertile men in alleles with 21, 24 and 25 repeats. This study revealed certain differences in the CAGn polymorphic locus of the AR gene in Russian infertile and fertile men and determined the frequency of SBMA in infertile patients.

Sex differences in elite track and field performances and inferences about steroid doping.

Females likely experience larger performance benefits from androgenic-anabolic steroids than males. We set out to determine if there were temporal differences in select athletics (track and field) records between females and males. Exploratory aims included: (1) evaluating the improvements in female and male world records over time, and (2) investigating the influence of doping programs on male and female world records before and after 1990, when sports governing bodies began to implement random out-of-competition and systematic in-competition drug testing. We collected the top 500 performances of all time for both sexes from an online database (worldathletics.org) in four running events (100, 200, 400 and 800m) and two throwing events (discus throw and shot-put). Data were stratified into quintiles based on world record ranking (1st to 100th, 101st to 200th, etc.). The temporal distribution of the top 100 female performers was significantly earlier than the top 100 male performers (year: 2000±1 vs. 2005±1, respectively; P<0.0001). Within the event, the top performances occurred significantly earlier for females in the 800m (year: 1995±15 vs. 2003±12; P=0.0007) and shot-put (year: 1992±14 vs. 2003±17; P=0.0004). Among females, world records rapidly improved through the 1980s, but following 1990, the world records ceased to improve. Geographically, there was a greater representation of countries with state-sponsored doping programs, specifically among female performances. We postulate these sex differences in the temporal distribution of top performances are likely associated with enhanced effectiveness of exogenous androgens (steroid doping) among female athletes with lower endogenous androgen hormones compared to males.

Effect of 5β-dihydrotestosterone on vasodilator function and on cell proliferation.

Aging is one of the main factors associated with cardiovascular diseases. Androgens exert beneficial effects on the cardiovascular system and testosterone (TES) replacement therapy improves cardiometabolic risk factors. However, TES is contraindicated in patients with prostate cancer due to its proliferative effects on prostatic tumor cells. Additionally, TES and its reduced metabolites 5α- and 5β-dihydrotestosterone (5α-DHT and 5β-DHT) exert vasodilatory effects. Since androgen levels decrease during aging and 5β-DHT lacks genomic effects, this study is focused on analyzing its effect on vasodilator function and the proliferation rate of prostatic tumor and vascular smooth muscle cells. To study the vascular function, mesenteric arteries from aged-orchidectomized Sprague-Dawley rats were used. Mesenteric segments were divided into one control (without treatment) and three groups with the androgens (10 nM, 30 min) to analyze: acetylcholine- and sodium nitroprusside-induced responses and nitric oxide and superoxide anion production. To analyze cell proliferation, the effect of androgens on cell viability was determined. The results showed that 5β-DHT improves vasodilator function in arteries from aged-orchidectomized rats and induces antioxidant action, while the proliferation rate of the androgen-dependent prostatic tumor cells remains unaltered. These results make 5β-DHT a promising therapeutic agent for the treatment of cardiovascular pathologies.

High SHBG and Low Bioavailable Testosterone are Strongly Causally Associated with Increased Forearm Fracture Risk in Women: An MR Study Leveraging Novel Female-Specific Data

The effects of androgens on women’s bone health are not fully understood. Mendelian randomization (MR) studies using sex-combined data suggest that sex hormone-binding globulin (SHBG) and bioavailable testosterone (BioT) causally affect bone traits. Given significant sex differences in hormone regulation and effects, female-specific MR studies are necessary. In the current study, we explored the causal relationships of SHBG, BioT, and total testosterone (TT) with forearm fracture (FAFx) risk in women using two-sample MR analyses. We utilized a unique female-specific FAFx outcome dataset from three European biobanks (UFO, HUNT, Estonian Biobank) comprising 111,351 women and 8823 FAFx cases, along with female-specific genetic instruments of SHBG, BioT, and TT identified in the UK Biobank. We also assessed bone mineral density (BMD) at the forearm (FA), femoral neck (FN), and lumbar spine (LS) using female-specific GWAS data from the GEFOS consortium. High SHBG (odds ratio per standard deviation increase (OR/SD): 1.53, 95% confidence intervals (CIs): 1.34–1.75), low BioT (OR/SD: 0.77, 0.71–0.84) and low TT (OR/SD 0.90, 0.83–0.98) were causally associated with increased FAFx risk. BioT was positively, and SHBG inversely, causally associated with especially FA-BMD, but also LS-BMD and FN-BMD, while TT was only significantly positively associated with FA-BMD and LS-BMD. We propose that endogenous androgens and SHBG are important for women’s bone health at distal trabecular-rich bone sites such as the distal forearm and may serve as predictors for FAFx risk.

Interactions between androgen and IGF1 axes in prostate tumorigenesis.

Androgen signalling through the androgen receptor (AR)is essential for prostate tumorigenesis. However, androgen signalling pathways also interact with other growth factor-mediated signalling pathways to regulate the prostatic cell cycle, differentiation, apoptosis and proliferation in the initiation and progression of prostate cancer. Insulin-like growth factor 1 (IGF1) is one of the most prominent growth factors in prostate tumorigenesis. Clinical and experimental evidence has demonstrated that IGF1 signalling supports both androgen-dependent and androgen-independent prostate tumorigenesis, suggesting that improved understanding of the interactions between the IGF1 and androgen axes might aid the development of new therapeutic strategies. Available data have shown a dynamic role of androgen-AR signalling in the activation of IGF1-signalling pathways by augmenting transcription of the IGF1 receptor in prostatic basal epithelial cells and by increasing IGF1 secretion through the suppression of IGF-binding protein 3 expression in prostatic stromal cells. In turn, IGF1 stimulates Wnt-β-catenin signalling in prostatic basal progenitors to promote prostatic oncogenic transformation and prostate cancer development. These findings highlight the cooperative, autocrine and paracrine interactions that underlie the oncogenic effects of androgens and IGF1 and open up new opportunities for therapeutic targeting.

8354 OVARIAN HYPERTHECOSIS: AN UNCOMMON CAUSE OF HYPERANDROGENISM IN A POSTMENOPAUSAL WOMAN

Abstract Disclosure: M.D. Severino: None. F.P. Silva: None. M.V. Lopes: None. C. Nunes: None. M.I. Alexandre: None. M.J. Bugalho: None. Introduction: Severe hirsutism in postmenopausal women demands a careful clinical evaluation to exclude a malignant cause, such as adrenal or ovarian androgen-secreting tumors. Ovarian hyperthecosis is an uncommon and benign cause of hyperandrogenism and, consequently, hirsutism. It is caused by persistent testosterone synthesis due to proliferation of ovarian stromal cells and nests of luteinized theca cells. It occurs more often in postmenopausal women, as aromatization of testosterone to estradiol decreases due to the loss of granulosa cells. It is also frequently associated with obesity and insulin resistance. Clinical case: We present the case of a 61-year-old woman, with a history of hypertension and dyslipidemia, referred to Endocrinology Clinic due to a year long history of hirsutism, most severe on her face, chest, and abdomen. She also mentioned slight clitoromegaly. She had no other virilization symptoms such as acne, male-pattern alopecia, voice deepening or mammary atrophy. Her menarche occurred at the age of 14 and she had regular menses until menopause, at the age of 51. She had a BMI of 32 kg/m2 and an uncharacteristic phenotype. At observation, she had a mild hirsutism (Ferriman-Gallwey score of 9). This contrasted with the biochemical findings of severe androgenism - total testosterone of 366 ng/dL (reference values [RV] for women between 5-48) with free testosterone 7.8 pg/mL and SHBG 74 nmol/L (RV 32-128), resulting in a Free Androgen Index of 17,16 (RV &amp;lt;6.6). DHEAS, androstenedione, 17-hydroxyprogesterone and prolactin were normal, and gonadotropins were in the menopausal range. Blood tests also showed hyperinsulinemia and pre-diabetes with HbA1c 6,2%. She denied exposure to steroids in the form of new medication, supplements, or creams/gels (including second-hand exposure through her partner) and she had no exposure to other drugs with androgenic effect. Abdominal and pelvic CT scan, as well as transvaginal ultrasound, showed no adrenal or ovarian lesions. An ovarian cause was deemed the most likely and laparoscopic diagnostic bilateral salpingo-oophorectomy was performed. Gross pathology revealed ovaries of regular size, while histology showed bilateral ovarian stromal hyperthecosis. Testosterone levels returned to normal one month after surgery (14,2 ng/dL). Conclusion: Benign, ovarian causes of hyperandrogenism are uncommon in postmenopausal women, requiring a high index of suspicion. The diagnosis is difficult, and laparoscopic bilateral salpingo-oophorectomy is essential as both a diagnostic and therapeutic tool. Presentation: 6/2/2024

8354 Ovarian Hyperthecosis: an Uncommon Cause of Hyperandrogenism in a Postmenopausal Woman

Abstract Disclosure: M.D. Severino: None. F.P. Silva: None. M.V. Lopes: None. C. Nunes: None. M.I. Alexandre: None. M.J. Bugalho: None. Introduction: Severe hirsutism in postmenopausal women demands a careful clinical evaluation to exclude a malignant cause, such as adrenal or ovarian androgen-secreting tumors. Ovarian hyperthecosis is an uncommon and benign cause of hyperandrogenism and, consequently, hirsutism. It is caused by persistent testosterone synthesis due to proliferation of ovarian stromal cells and nests of luteinized theca cells. It occurs more often in postmenopausal women, as aromatization of testosterone to estradiol decreases due to the loss of granulosa cells. It is also frequently associated with obesity and insulin resistance. Clinical case: We present the case of a 61-year-old woman, with a history of hypertension and dyslipidemia, referred to Endocrinology Clinic due to a year long history of hirsutism, most severe on her face, chest, and abdomen. She also mentioned slight clitoromegaly. She had no other virilization symptoms such as acne, male-pattern alopecia, voice deepening or mammary atrophy. Her menarche occurred at the age of 14 and she had regular menses until menopause, at the age of 51. She had a BMI of 32 kg/m2 and an uncharacteristic phenotype. At observation, she had a mild hirsutism (Ferriman-Gallwey score of 9). This contrasted with the biochemical findings of severe androgenism - total testosterone of 366 ng/dL (reference values [RV] for women between 5-48) with free testosterone 7.8 pg/mL and SHBG 74 nmol/L (RV 32-128), resulting in a Free Androgen Index of 17,16 (RV &amp;lt;6.6). DHEAS, androstenedione, 17-hydroxyprogesterone and prolactin were normal, and gonadotropins were in the menopausal range. Blood tests also showed hyperinsulinemia and pre-diabetes with HbA1c 6,2%. She denied exposure to steroids in the form of new medication, supplements, or creams/gels (including second-hand exposure through her partner) and she had no exposure to other drugs with androgenic effect. Abdominal and pelvic CT scan, as well as transvaginal ultrasound, showed no adrenal or ovarian lesions. An ovarian cause was deemed the most likely and laparoscopic diagnostic bilateral salpingo-oophorectomy was performed. Gross pathology revealed ovaries of regular size, while histology showed bilateral ovarian stromal hyperthecosis. Testosterone levels returned to normal one month after surgery (14,2 ng/dL). Conclusion: Benign, ovarian causes of hyperandrogenism are uncommon in postmenopausal women, requiring a high index of suspicion. The diagnosis is difficult, and laparoscopic bilateral salpingo-oophorectomy is essential as both a diagnostic and therapeutic tool. Presentation: 6/2/2024

Developmental programming of reproduction in sheep and goat: Association of fraternity size and sex ratio with reproductive performance of ewes and does at the first pregnancy

Various prenatal factors including the number of littermates (fraternity size) and exposure to male littermate (fraternity sex ratio) during fetal period have been reported to influence postnatal fertility in the mammals. The present research was conducted to study the association of fraternity size and sex ratio with reproductive performance of nulliparous ewes and does. To this end, data associated with number of littermates, exposure to male littermate, birth weight, age at first pregnancy, as well as litter size, sex ratio of offspring, litter weight, and birth weight of female and male offspring after the first parturition retrieved from the database of sheep (n = 536 Romane and 289 Blanche du Massif Central ewes) and goat (n = 174 Alpine and 267 Saanen does) flocks. Fraternity size was negatively associated with birth weight of ewes and does (P < 0.05). Exposure to male littermate during fetal period was associated with younger age at first pregnancy and larger litter size in the does (P < 0.05), but not in the ewes (P > 0.05). Exposure to male littermate during fetal period was positively associated with the odds of male-biased litters in the ewes and does (P < 0.05). Fraternity size was positively associated with litter weight in the does (P < 0.05), but not in the ewes (P > 0.05). In conclusion, the present study showed that the number and sex of littermates during fetal period could impact postnatal reproduction of ewes and does. In this context, some associations, particularly those related to exposure to male littermate during fetal period, were only observed in does, which implicates that the effect of androgens on developmental programming of reproduction may be species-specific.

Protocolo diagnóstico del hirsutismo

Hirsutism is defined as the appearance of excess hair in women in androgen-dependent areas. It has different degrees of severity. The Ferriman-Gallwey scale is used to diagnose hirsutism and quantify its severity. A score equal to or greater than eight indicates the presence of this disease. Hirsutism is usually secondary to a state of hyperandrogenism. Polycystic ovary syndrome is the most common cause of hyperandrogenism in women of childbearing age. Other possible causes include congenital adrenal hyperplasia, androgen-secreting tumors, and use of drugs with androgenic effect, among others. The medical record, together with laboratory tests, helps to clearly guide the diagnosis and be able to choose the best treatment in each case.

Sex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player

As a biological variable, sex influences the metabolism of and/or response to certain drugs. Vicagrel is being developed as an investigational new drug in China; however, it is unknown whether sex could affect its metabolic activation and platelet responsiveness. This study aimed to determine whether such differences could exist, and to elucidate the mechanisms involved. Orchiectomized (ORX) or ovariectomized (OVX) mouse models were used to investigate the effects of androgens or estrogens on the metabolic activation of and platelet response to vicagrel. Plasma vicagrel active metabolite H4 concentrations, platelet inhibition of vicagrel, and protein levels of intestinal hydrolases Aadac and Ces2 were measured, respectively. Further, p38-MAPK signaling pathway was enriched, whose role was determined using SB202190. Results showed that female mice exhibited significantly elevated systemic exposure of H4 and enhanced platelet responses to vicagrel than males, and that protein expression levels of Aadac and Ces2 differed by sex. OVX mice exhibited less changes than sham mice. ORX mice exhibited increases in protein levels of intestinal hydrolases, systemic exposure of H4, and platelet inhibition of vicagrel, but dihydrotestosterone (DHT) reversed these changes in ORX mice and suppressed these changes in OVX mice. Phosphorylated p38 levels were reduced in female or ORX mice but increased in ORX mice by DHT. SB202190 reversed DHT-induced changes observed in ORX mice. We concluded that sex differences exist in metabolic activation of and platelet response to vicagrel in mice through elevation of p38 phosphorylation by androgens, suggesting sex-based vicagrel dosage adjustments for patient care.

Hipogonadismo masculino

Male hypogonadism (HG) is defined as the functional incompetence of the gonads with suboptimal or altered production of hormones and germ cells. The prevalence between 30 and 70 years of age is 10% and increases with age. It is classified according to the origin, as primary hypergonadotropic HG, secondary hypothalamic-pituitary hypogonadotropic HG and HG due to peripheral resistance to the androgenic effect. The diagnosis requires clinical suspicion and hormonal determinations that confirm it. The main treatment is the administration of testosterone by transdermal or injectable route, with the option of using GnRH or gonadotropins.

Anabolic Androgenic Steroids Misuse in the Fitness Industry

Anabolic-androgenic steroids (AAS) are synthetic variations of the male sex hormone testosterone. They mimic testosterone’s effects, primarily promoting muscle growth (anabolic effects) and enhancing male traits (androgenic effects). The misuse of AAS has extended beyond high-performance athletes and is now prevalent among the general population, particularly among fitness and gym enthusiasts. Epidemiological data highlight the widespread abuse of these substances, driven by the aspiration to enhance muscle mass, strength, and overall physical performance. The misuse of AAS in the fitness industry poses significant health risks and ethical concerns. This review highlights the prevalence, consequences, and prevention strategies related to AAS misuse in the fitness industry.

Development of a comprehensive open access "molecules with androgenic activity resource (MAAR)" to facilitate risk assessment of chemicals.

The increasing prevalence of endocrine-disrupting chemicals (EDCs) and their potential adverse effects on human health underscore the necessity for robust tools to assess and manage associated risks. The androgen receptor (AR) is a critical component of the endocrine system, playing a pivotal role in mediating the biological effects of androgens, which are male sex hormones. Exposure to androgen-disrupting chemicals during critical periods of development, such as fetal development or puberty, may result in adverse effects on reproductive health, including altered sexual differentiation, impaired fertility, and an increased risk of reproductive disorders. Therefore, androgenic activity data is critical for chemical risk assessment. A large amount of androgenic data has been generated using various experimental protocols. Moreover, the data are reported in different formats and in diverse sources. To facilitate utilization of androgenic activity data in chemical risk assessment, the Molecules with Androgenic Activity Resource (MAAR) was developed. MAAR is the first open-access platform designed to streamline and enhance the risk assessment of chemicals with androgenic activity. MAAR's development involved the integration of diverse data sources, including data from public databases and mining literature, to establish a reliable and versatile repository. The platform employs a user-friendly interface, enabling efficient navigation and extraction of pertinent information. MAAR is poised to advance chemical risk assessment by offering unprecedented access to information crucial for evaluating the androgenic potential of a wide array of chemicals. The open-access nature of MAAR promotes transparency and collaboration, fostering a collective effort to address the challenges posed by androgenic EDCs.

The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice

Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

POLYCYSTIC OVARY SYNDROME AND BONE TURNOVER IN POSTMENOPAUSAL WOMEN

Considering the metabolic and hormonal changes associated with polycystic ovary syndrome (PCOS), their potential affect bone health has been proposed. The aim of the current study was to evaluate the effect of several hormonal and metabolic alterations associated with polycystic ovary syndrome on bone in postmenopausal women. Materials and methods: The study included 56 patients with PCOS and 42 women without this disease aged 50–65 years. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) of the lumbar spine and femoral neck. Serum levels of amino-terminal propeptide of procollagen 1 (P1NP) and carboxy-terminal telopeptide of type I collagen (b-CTx), as well as levels of parathyroid hormone (PTH), vitamin D (25(OH)D3), anti-Mullerian hormone (AMH), insulin, testosterone (T), 17-hydroxyprogesterone (17-OHP), dehydroepiandrostenedione sulfate (DHEAS), follicle stimulating hormone, luteinizing hormone, and estradiol were determined. The HOMA-IR index and anthropometric indicators were calculated. Statistical data were analyzed by nonparametric testing using BioStat Pro 6.2.2.0 software (AnalystSoft Inc., Walnut, USA). Quantitative data are presented as median and quartiles 1 and 3 (Me [Q1; Q3]); The significance of intergroup differences was established using the Mann–Whitney U test (p&lt;0.05). To identify relationships between indicators, a univariate analysis was carried out with the calculation of the Spearman rank correlation coefficient (r). Results. Women with PCOS had late-onset menopause (p=0.007) and a higher body mass index (BMI, p=0.009) than the control group. Additionally, women with PCOS had higher levels of DHEAS, total T, and 17-OHP than controls. P1NP and b-CTx were significantly different from controls (p=0.028 and p=0.032, respectively). A direct relationship was found between BMI and the activity of the resorption marker b-CTx (r=0.342, p=0.002) and an inverse collinear relationship between AMH values with b-CTx (r=–0.507, p=0.001). BMD in PCOS was higher compared to controls. An inverse relationship exists between BMD of L1–L4 and b-CTx level (r=–0.387, p=0.026) and positive with insulin (r=0.267, p=0.042), AMH (r=0.561, p=0.031) and testosterone (r=0.458, p=0.039). Higher DHEAS levels were associated with higher femoral neck BMD (r=0.473, p=0.035). P1NP was negatively correlated with femoral neck BMD (r=-0.429, p=0.038). Conclusions. Bone mineral density in women with polycystic ovary syndrome declines more slowly with age compared to their peers, possibly due to the effects of excess androgens and insulin. In postmenopausal women with polycystic ovary syndrome, metabolic processes in bone tissue accelerate, while bone resorption exceeds bone formation. Thus, women affected by polycystic ovary syndrome may be considered at risk of developing osteopenic syndrome.

Using behavioural network mapping to investigate dyadic play in girls with congenital adrenal hyperplasia.

Examining mechanisms underlying sex differences in children's play styles, we studied girls with congenital adrenal hyperplasia (CAH) who provide a test of the relative effects of prenatal androgens versus rearing, and of behavioural similarity versus gender identity and cognitions. In this exploratory study, 40 focal children (girls and boys with and without CAH), aged 3-8 years, played for 14 min with a same-sex peer in a task designed to elicit rough-and-tumble play. Time-indexed ratings of positive affect and vigour of activity were evaluated via network mapping for sex-related differences in both levels and play dynamics (temporal relations among behaviours). Results suggest influences of both gender identity-aligned social cognitions and prenatal androgens: there was greater dyadic synchrony between positive affect for girls (regardless of CAH status) than boys, but girls with CAH displayed positive affect levels and directed vigorous peer play dynamics similar to boys.

Androgen Effects on Alcohol-induced Liver Fibrosis Are Controlled by a Notch-dependent Epigenetic Switch

BackgroundAlcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. Sex is an important variable, however, the mechanism behind sex differences is not yet established. MethodsKdm5b flox/flox Kdm5c flox male mice were subjected to gonadectomy or sham surgery. Mice were fed a Western diet and 20% alcohol in the drinking water for 18 weeks. To induce knockout, mice received 2x1011 genome copies of AAV8-CMV-Cre or AAV8-control. To test the role of Notch, mice were treated with 10mg/kg of Avagacestat for 4 weeks. ResultsWe found that Kdm5b/Kdm5c knockout promoted alcohol induced liver disease, while gonadectomy abolished this effect, suggesting that male sex hormones promote liver disease in the absence of KDM5 demethylases. In contrast, in the thioacetamide-induced fibrosis model, male sex hormones showed a protective effect regardless of genotype. In human liver disease samples, we found that androgen receptor expression positively correlated with fibrosis levels when KDM5B levels were low and negatively when KDM5B was high, suggesting that a KDM5B-dependent epigenetic state defines the AR role in liver fibrosis.Using isolated cells, we found that this difference was due to the differential effect of testosterone on hepatic stellate cell activation in the absence or presence of KDM5B/KDM5C. Moreover, this effect was mediated by KDM5-dependent suppression of Notch signaling. In KDM5-deficient mice, Notch3 and Jag1 gene expression was induced, facilitating testosterone-mediated induction of Notch signaling and stellate cell activation. Inhibiting Notch with Avagacestat greatly reduced liver fibrosis and abolished the effect of Kdm5b/Kdm5c loss. ConclusionsMale sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state.

P21-65 Androgenic and anti-androgenic effects of nanoplastics

P21-65 Androgenic and anti-androgenic effects of nanoplastics