Serum Steroid Concentrations Research Articles

Increased body fat mass and androgen metabolism – A twin study in healthy young women

ObjectiveObesity may alter serum steroid concentrations and metabolism. We investigated this in healthy young women with increased body fat and their leaner co-twin sisters. DesignAge and genetic background both strongly influence serum steroid levels and body composition. This is a cross-sectional study of 13 female monozygotic twin pairs (age, 23–36 years), ten of which were discordant for body mass index (median difference in body weight between the co-twins, 19 kg). MethodsWe determined body composition by dual energy X-ray absorptiometry and magnetic resonance imaging, serum androgens by liquid chromatography-tandem mass spectrometry, and mRNA expression of genes in subcutaneous adipose tissue and adipocytes. ResultsThe heavier women had lower serum dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) (P < 0.05 for all) compared to their leaner co-twins with no differences in serum testosterone or androstenedione levels. Serum DHEA correlated inversely with %body fat (r = −0.905, P = 0.002), and DHT positively with SHBG (r = 0.842, P = 0.002). In adipose tissue or adipocytes, expressions of STS (steroid sulfatase) and androgen-related genes were significantly higher in the heavier compared to the leaner co-twin, and within pairs, correlated positively with adiposity but were not related to serum androgen levels. None of the serum androgen or SHBG levels correlated with indices of insulin resistance. ConclusionsSerum DHEA levels were best predicted by %body fat, and serum DHT by SHBG. These or other serum androgen concentrations did not reflect differences in androgen-related genes in adipose tissue. General or intra-abdominal adiposity were not associated with increased androgenicity in young women.

Evaluation of Prenatal Exposure to Bisphenol Analogues on Development and Long-Term Health of the Mammary Gland in Female Mice.

Background:Continued efforts to phase out bisphenol A (BPA) from consumer products have been met with the challenges of finding safer alternatives.Objectives:This study aimed to determine whether early-life exposure to BPA and its related analogues, bisphenol AF (BPAF) and bisphenol S (BPS), could affect female pubertal mammary gland development and long-term mammary health in mice.Methods:Timed pregnant CD-1 mice were exposed to vehicle, BPA (0.5, 5, ), BPAF (0.05, 0.5, ), or BPS (0.05, 0.5, ) via oral gavage between gestation days 10–17. Mammary glands were collected from resulting female offspring at postnatal day (PND) 20, 28, 35, and 56, and at 3, 8, and 14 months for whole mount, histopathological evaluation, and quantitative real-time polymerase chain reaction (qPCR); serum steroid concentrations were also measured at these time points.Results:In the bisphenol-exposed mice, accelerated mammary gland development was evident during early puberty and persisted into adulthood. By late adulthood, mammary glands from bisphenol-exposed female offspring exhibited adverse morphology in comparison with controls; most prominent were undifferentiated duct ends, significantly more lobuloalveolar hyperplasia and perivascular inflammation, and various tumors, including adenocarcinomas. Effects were especially prominent in the BPAF and BPS groups. Serum steroid concentrations and mammary mRNA levels of Esr1, Pgr, Ar, and Gper1 were similar to controls.Conclusions:These data demonstrate that prenatal exposure of mice to BPAF or BPS induced precocious development of the mammary gland, and that siblings were significantly more susceptible to spontaneous preneoplastic epithelial lesions and inflammation, with an incidence greater than that observed in vehicle- and BPA-exposed animals. https://doi.org/10.1289/EHP3189

Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice.

Hydroxysteroid (17β) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd17b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcarnitines, suggesting impaired mitochondrial β-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsd17b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.-Adam, M., Heikelä, H., Sobolewski, C., Portius, D., Mäki-Jouppila, J., Mehmood, A., Adhikari, P., Esposito, I., Elo, L. L., Zhang, F.-P., Ruohonen, S. T., Strauss, L., Foti, M., Poutanen, M. Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice.

Abstract 4968: Importance of tumor microenvironment in the preclinical estrogen receptor positive breast cancer- Primary tumor and bone metastasis models

Abstract Estrogen receptor positive (ER+) breast cancer has ability to metastasize to bone in high frequency. Bone is known to be fertile soil for metastasized cancer cells to survive and in turn, metastasized tumor cells alter normally balanced bone environment. Prevention and treatment of bone metastasis is challenging and better understanding why bone metastasis are resistant to current therapies is needed. Aim of the present study was to explore the role of tumor microenvironment and estrogen supplementation on growth of primary breast cancer tumor and bone metastasis to establish predictive ER+ breast cancer models for drug development. ER+ human breast cancer MCF-7 cells were inoculated into mammary fat pad and in the tibia of female athymic nude mice. Mice received either hormonal supplementation (17-beta estradiol pellet, E2) or placebo. Tumor growth was followed for 5 and 9 weeks. From one group, E2 supplementation was removed on study week 5 and tumor growth was followed for 4 weeks. During the study, blood samples were collected for serum steroid concentration measurements and at the end, histopathological evaluation and immunohistochemical (IHC) stainings were performed to examine tumor steroid hormone receptor expression. Orthotopic MCF-7 tumor growth was clearly hormone dependent. E2 supplementation, that increased serum estradiol for app. 3-fold, supported tumor growth and when E2 was removed, tumor size decreased and no tumor growth was observed thereafter. In the full absence of E2 supplement, no orthotopic tumor growth was observed. In contrast, when MCF-7 cells were inoculated into tibia, tumor growth was observed both with and without E2 supplement. IHC stainings confirmed orthotopic tumor to express ER, PR and AR when animals received E2. After E2 removal, orthotopic tumors expressed still ER and AR but no longer PR. Also intratibial tumors expressed ER and PR in the presence of E2, but no PR in the absence of E2 supplement. E2 is needed to support MCF-7 tumor growth when cancer cells are inoculated orthotopically into mammary fat pad. No orthotopic tumor growth is observed in the absence of E2 supplement. In contrast, in the bone microenvironment, MCF-7 cells form tumor even in the absence of E2 supplement. Results highlight importance of tumor microenvironment in the breast cancer progression and also refer why tumor in the different sites may be resistant to therapy. Taking together, when developing new therapies against breast cancer, focus should be addressed not only on primary tumor growth but also on bone metastasis where cancer cells are under influence of bone environment. Citation Format: Jenni Bernoulli, Mari I. Suominen, Tiina Kähkönen, Jenni Mäki-Jouppila, Jussi M. Halleen, Riikka Oksala. Importance of tumor microenvironment in the preclinical estrogen receptor positive breast cancer- Primary tumor and bone metastasis models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4968. doi:10.1158/1538-7445.AM2017-4968

Metabolism of sex steroids is influenced by acquired adiposity—A study of young adult male monozygotic twin pairs

Obesity and ageing are associated with lower serum testosterone levels in men. How fat distribution or adipose tissue metabolism, independent of genetic factors and age, are related to sex steroid metabolism is less clear. We studied the associations between adiposity and serum sex hormone concentrations, and mRNA expression of genes regulating sex hormone metabolism in adipose tissue in young adult male monozygotic (MZ) twin pairs. The subjects [n=18 pairs; mean age, 32 years; individual body mass indexes (BMIs) 22–36kg/m2] included 9 male MZ twin pairs discordant for BMI [intra-pair difference (Δ) in BMI ≥3kg/m2]. Sex steroid concentrations were determined by liquid chromatography–tandem mass spectrometry, body composition by dual-energy X-ray absorptiometry and magnetic resonance imaging, and mRNA expressions from subcutaneous adipose tissue by Affymetrix. In BMI-discordant pairs (mean ΔBMI=5.9kg/m2), serum dihydrotestosterone (DHT) was lower [mean 1.9 (SD 0.7) vs. 2.4 (1.0) nmol/l, P=0.040] and mRNA expressions of DHT-inactivating AKR1C2 (P=0.021) and cortisol-producing HSD11B1 (P=0.008) higher in the heavier compared to the leaner co-twins. Serum free 17β-estradiol (E2) was higher [2.3 (0.5) vs. 1.9 (0.5) pmol/l, P=0.028], and in all twin pairs, serum E2 and estrone concentrations were higher in the heavier than in the leaner co-twins [107 (28) vs. 90 (22) pmol/l, P=0.006; and 123 (43) vs. 105 (27) pmol/l, P=0.025]. Within all twin pairs, i.e. independent of genetic effects and age, 1) the amount of subcutaneous fat inversely correlated with serum total and free testosterone, DHT, and sex hormone-binding globulin (SHBG) concentrations (P<0.01 for all), 2) intra-abdominal fat with total testosterone and SHBG (P<0.05), and 3) liver fat with SHBG (P=0.006). Also, 4) general and intra-abdominal adiposity correlated positively with mRNA expressions of AKR1C2, HSD11B1, and aromatase in adipose tissue (P<0.05). In conclusion, acquired adiposity was associated with decreased serum DHT and increased estrogen concentrations, independent of genetic factors and age. The reduction of DHT could be linked to its increased degradation (by AKR1C2 and HSD11B1) and increased estrogen levels to increased adiposity-related expression of aromatase in adipose tissue.

Estradiol cypionate aided treatment for experimentally induced ascending placentitis in mares

The overall goal of this study was to assess the efficacy of various therapeutic combinations of estradiol cypionate (ECP, a long-acting estrogen) and altrenogest (ALT, a long-acting progestin) in addition to basic treatment for placentitis with trimethoprim-sulfamethoxazole (TMS) and flunixin meglumine (FM). Specific outcomes measured in this experiment were (i) time from induction of bacterial placentitis to delivery, and foal parameters (high-risk, survival, and birth weight); and (ii) serum steroid concentrations (progesterone, 17α-hydroxyprogesterone, 17β-estradiol, and cortisol) in response to treatment. Pregnant mares (∼300 days gestation, n = 46) were randomly assigned into healthy mares (control group, CONT, n = 8) and mares with experimentally induced ascending placentitis (n = 38). Placentitis was induced via intracervical inoculation of Streptococcus equi subspecies zooepidemicus. Thereafter, placentitis induced mares were randomly assigned into: (1) basic treatment, TMS+FM (n = 8); (2) basic treatment with ALT supplementation, TMS+FM+ALT (n = 8); (3) basic treatment with ECP supplementation, TMS+FM+ECP (n = 6); (4) basic treatment with ALT and ECP supplementation TMS+FM+ALT+ECP (n = 6); and (5) no treatment (INOC, n = 10). Treatments were started 48 h after bacterial inoculation and carried out for ten consecutive days. Blood samples were collected daily, and mares were assessed for signs of placentitis until the mare delivered, or for ten consecutive days after onset of treatment. Steroids were analyzed via RIA. Continuous data were analyzed by ANOVA, and categorical data analyzed by Fisher's exact test. Significance was set at p < 0.05. Foal survival at parturition and seven days post-delivery were similar across treated groups (66.7–100%), and to the CONT group. Similar to CONT group, mares in the TMS+FM+ECP group had no high-risk foals while mares in the other groups had higher incidences (50–75%) (p < 0.05). The inclusion of ECP in the treatments resulted in foals with body weight similar to CONT group (p > 0.05). There were no group effects or time by group interactions on concentrations of steroids assessed herein (p > 0.05). In conclusion, in addition to basic treatment TMS+FM, mares with experimentally induced ascending placentitis benefited from ECP supplementation. Conversely, ALT did not appear to make a difference in outcomes. The immunoassays used for measurements of steroid concentrations did not appear useful to assess treatment response.

Expression of anti-Müllerian hormone in two rat models of polycystic ovary syndrome.

Anti-Müllerian hormone (AMH) levels are two to three times higher in patients with polycystic ovary syndrome (PCOS), but the mechanism of increased AMH levels in PCOS remains unclear. The purpose of our experiment was to investigate a change in AMH levels in two kinds of commonly used rat models and to determine an ideal model for future research of AMH in the pathogenesis of PCOS. Thirty female Sprague Dawley rats were treated using two modeling methods: implantation of a levonorgestrel silastic implant or injection with sodium prasterone sulfate plus human chorionic gonadotropin (hCG). Rats in the control group were implanted with a blank silastic stick. Serum steroid concentrations, ovarian morphology and ovarian expression of AMH and AMH-receptor II (RII) proteins were determined and their correlations were studied. The results from the levonorgestrel and hCG group were closer to those displayed by human PCOS patients than the sodium prasterone sulfate and hCG group. Ovarian local expression of AMH and AMH-RII was increased in these both models compared with the control group; however, an elevation of serum AMH concentration was not observed (12.53 ± 0.99 ng/ml and 13.22 ± 1.09 ng/ml vs 16.30 ± 0.98 ng/ml). The levonorgestrel and hCG model is more suitable for the study of PCOS in puberty.

Adrenocorticotropic hormone elicits gonadotropin secretion in premenopausal women.

Does adrenocorticotropic hormone (ACTH) induce gonadotropin release in premenopausal women? Administration of ACTH stimulates gonadotropin release, most likely by stimulation of the production of cortisol, in premenopausal women. In animal models, acute activation of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to induce gonadotropin release in the presence of sufficiently high estrogen levels. However, it is unknown whether the HPA axis has a similar influence on gonadotropin release in humans. This study had a mixed factorial design. A total of 60 healthy female participants participated in the experimental study. The study sample comprised three distinct hormonal-based populations according to their levels of progesterone (PROG) and estradiol (E2): (i) low-PROG-low-E2, (ii) low-PROG-high-E2 and (iii) high-PROG-high-E2 women. A low dose (1 µg) of ACTH was administered to all study participants. Serum steroid and gonadotropin concentrations were measured prior to, and at 30 and 90 minutes after, intravenous ACTH administration. Mean serum cortisol levels increased significantly following ACTH administration in all groups (P<0.001). Similarly, the serum levels of 17-OH-PROG, androstenedione, dehydroepiandrosterone and testosterone increased significantly in all groups (P<0.01). The low-PROG-high-E2 and high-PROG-high-E2 groups exhibited a significant increase in LH and FSH levels (P<0.001), whereas the low-PROG-low-E2 group demonstrated blunted LH and FSH responses to ACTH administration (P<0.05). Testing was performed during the luteal phase of the natural menstrual cycle. Testing during the follicular phase might have elicited premature, or more pronounced, LH surges in response to ACTH administration. Our findings suggest a novel mechanism by which the adrenal cortex functions as a mediator of gonadotropin release. These findings contribute to a greater understanding of the influence of acute stress on reproductive endocrinology. Funding was received from the Erasmus University Medical Center. The authors have no conflicts of interest. EudraCT Number 2012-005640-14.

Cortisol intermediates and hydrocortisone responsiveness in critical neonatal disease

Objective: Therapy-resistant hypotension complicates diseases in neonates. Our objective was to investigate whether lack of therapeutic response to plasma expanders and inotropes associates with serum levels of cortisol and its precursors.Methods: We investigated 96 infants with hypotension and critical neonatal disease for cortisol metabolism and are divided into responders and non-responders to plasma expanders and inotropes. Serum concentrations of steroids were analysed soon after the onset of volume expansion and inotrope treatment for shock. The 48 non-responders were treated with intravenous hydrocortisone (HC) and serum cortisol concentrations were monitored a week later.Results: The mean cortisol concentrations did not differ between the responders and non-responders: 13.6 ± 2.5 and 12.5 ± 4.5 μg/dL, respectively. Dehydroepiandrosterone (37.3 ± 19.5 versus 324.0 ± 106.3; p < 0.0001) and 17-hydroxy-pregnenolone concentrations were lower in responders than in non-responders. Dehydroepiandrosterone levels in non-responders were inversely associated with postnatal age (r = 0.50, p < 0.0001). There were no differences in 17-hydroxy-progesterone, 11-deoxy-cortisol and cortisone between the responders and non-responders. Hydrocortisone administration acutely increased blood pressure. Six non-responders who died despite HC administration had low levels of cortisol. The responders had normal serum cortisol after HC treatment.Conclusion: Precursors of cortisol, proximal to the 3β-hydroxysteroid dehydrogenase activity, accumulated in neonates with hypotension, responding to HC treatment.

Self-reported onset of puberty and subsequent semen quality and reproductive hormones in healthy young men.

Is there an association between pubertal onset and subsequent reproductive health in young men? Self-reported later onset of puberty was associated with reduced semen quality and altered serum levels of reproductive hormones among 1068 healthy, young Danish men. The long-term effects of variations in the onset of male puberty on subsequent reproduction remain largely unstudied. In a cross-sectional study, young healthy Danish men were approached when they attended a compulsory medical examination to determine their fitness for military service from 2008 to 2012. A total of 1068 healthy, young Danish men (mean age 19 years) participated. They were asked to assess whether onset of penile and testicular growth, development of pubic hair and voice break occurred earlier, at the same time as or later than their peers. Their semen quality (semen volume, sperm concentration, total sperm count and percentages of motile and morphologically normal spermatozoa) and serum concentrations of sex hormones (LH, FSH, total testosterone, SHBG, inhibin B) and testicular size were determined. The response rate was 29%. Of the 1068 men who then participated, 652 answered the questions about penile growth and pubic hair development and were therefore included in the analysis. Self-reported later onset of puberty was associated with a 25% reduction in sperm concentration (95% CI -41%; -4%), a 40% reduction in total sperm count (-55%; -21%), a 1.6% age point reduction in morphological normal spermatozoa (-2.9; -0.3) and a 1.6 ml reduction in testicular size (-2.4 and -0.8 ml), after adjustment for confounders. Self-reported later onset of puberty was also associated with a 9% (3%; 15%) reduction in free testosterone and a 16% (2%; 31%) increase in FSH, after adjustment for confounders. Our study was cross-sectional and reverse causality cannot be ruled out. In addition, we cannot rule out the possibility that the men with late puberty onset had not yet fully matured although most were in Tanner stage 5. Approximately 15% of young Danish men have self-reported later onset of puberty than their peers. We found poorer testicular function in young men with a history of later pubertal development, suggesting that timing of pubertal onset may be a fundamental marker of male reproductive health. However, we cannot exclude the possibility that these men had not fully matured at the time of examination and therefore their semen quality may yet improve, which makes follow-up important. This work was supported by the Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (project number 2101-08-0058), Rigshospitalet (grants 961506336 and R42-A1326), European Union, DEER (grant agreement no 212844), the Danish Ministry of Health and the Danish Environmental Protection Agency and Kirsten and Freddy Johansens Foundation (grant 95-103-72087). There are no competing interests.

Characterization of ovarian adrenal rest tumors in children and adolescent females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

To summarize the characterization of ovarian adrenal rest tumors (OART) in children and adolescent females with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). We have diagnosed 4 cases of CAH 21-OHD with OART in the recent 5 years in pediatric endocrinology unit of the first affiliated hospital of Sun Yat-Sen University. Clinical characterizations were summarized, including symptoms, growth patterns and bone age advancements, serum steroid concentrations, imaging results and the follow-up data. The 4 cases of OART accounted for 2.5 % of the CAH 21-OHD girls, which was much lower than the detection rate, 29.5%, of testicular ART in our patient group during the same period. The 4 cases included 3 salt wasters and 1 with simple virilizm. OART were diagnosed at the age of 8.9 years, 15.8 years, 21.4 years and 9.3 years, respectively. Before the diagnosis of OART, their daily hydrocortisone doses reached 16 mg/(m(2)·d)to 24 mg/(m(2)·d). The patients presented with deteriorated acne, deepened voice, amenorrhea (2 cases), accelerated growth and advanced bone age, ΔBA/ΔCA reached 1.2(during GnRHa treatment)and 2.0. Their serum adrenal steroids increased significantly and hyperplasia of adrenal glands were found in all patients. The diagnosis could be confirmed before the operation in only 1 case. The diagnosis could not be made until the planned sub-total adrenalectomy in the other 3 cases. The follow-up periods of OART were 4.8, 4.7, 3.8 and 2.7 years, respectively. Removal of OART resulted in symptoms relief at least partialy and lowered daily hydrocortisone doses, 14 to 19 mg/(m(2)·d). The detection rate of OART was much lower than testicular ART. Before the diagnosis of OART, the patients presented with deteriorated virilescence, accelerated growth and advanced bone age, elevated serum adrenal steroids and hyperplasia of adrenal glands. Removal of the OART resulted in symptoms relief at least partialy.

Serum steroid concentrations remain within normal postmenopausal values in women receiving daily 6.5 mg intravaginal prasterone for 12 weeks

This study integrates all data obtained in women aged 40–80years enrolled with moderate to severe symptoms of vulvovaginal atrophy (VVA) who received daily intravaginal administration of 0.50% (6.5mg) dehydroepiandrosterone (DHEA; prasterone) for 12weeks (n=723; ITT-S population) as compared with placebo (n=266; ITT-S population). To this end, serum steroid levels (DHEA, DHEA-sulfate (DHEA-S), androst-5-ene-3β, 17β-diol (5-diol), testosterone, dihydrotestosterone (DHT), androstenedione (4-dione), estrone (E1), estradiol (E2), estrone sulfate (E1-S), androsterone glucuronide (ADT-G), and androstane-3α, 17β-diol 17-glucuronide (3α-diol-17G)) were measured at Day 1 and Week 12 by liquid chromatography-tandem mass spectrometry (LC–MS/MS) following validation performed according to the FDA guidelines [1–6]. In agreement with the mechanisms of intracrinology where DHEA is exclusively transformed intracellularly into active sex steroids which act and are inactivated locally before being released as glucuronided or sulfated metabolites for elimination by the kidneys and liver, all sex steroids remained well within normal postmenopausal values following administration of intravaginal DHEA. Serum estradiol, the most relevant sex steroid, was measured after 12weeks of treatment at 3.36pg/ml (cITT-S population) or 19% below the normal postmenopausal value of 4.17pg/ml. On the other hand, serum E1-S, the best recognized marker of global estrogenic activity, shows an average value of 209pg/ml at 12 weeks compared to 220pg/ml in normal postmenopausal women. Moreover, serum ADT-G, the main metabolite of androgens, also remains well within normal postmenopausal values. The present data shows that a low daily intravaginal dose (6.5mg) of DHEA (prasterone) which is efficacious on the symptoms and signs of VVA, permits to achieve the desired local efficacy without systemic exposure, in agreement with the stringent mechanisms of menopause established after 500 million years of evolution where each cell in each tissue is the master of its sex steroid exposure.

High prevalence of hypogonadism and associated impaired metabolic and bone mineral status in subfertile men.

It is yet unknown to which degree young subfertile men present with signs of hypogonadism and whether low testosterone concentration, like in older men, is associated with risk of osteoporosis and metabolic derangements in those subjects. The objective was therefore to investigate the prevalence of hypogonadism and its association with metabolic and bone parameters in young subfertile men. Cross-sectional case-control study. Men from infertile couples (n = 192); 18-50 years; sperm concentration <20 × 10(6) /ml and population-based age-matched controls (n = 199). Blood sampling, anthropometrics, blood pressure, ankle-brachial index and assessment by dual-energy X-ray absorptiometry were undertaken. Odds ratios of biochemical hypogonadism (total testosterone <8·0 nmol/l and/or luteinizing hormone ≥8·6 IU/l and/or ongoing androgen replacement therapy) were calculated. Serum concentrations of sex hormones, lipids, glucose, insulin and HbA1c were assessed and bone mineral density (BMD) evaluated. Compared to controls, the risk of hypogonadism was increased among subfertile men (OR 10; 95% CI, 5·1, 22), being highest in those with nonobstructive azoospermia. Hypogonadal men had higher HbA1c concentration (mean diff. 2·8 mmol/mol; 95% CI, 0·64, 4·9; P = 0·011) and lower lumbar spine BMD (mean diff. 0·05 g/cm(2) ; 95% CI, 0·01, 0·10; P = 0·032) compared to eugonadal subfertile men, even more pronounced in subfertile men with subnormal testosterone levels. Young subfertile men have 10 times increased OR of hypogonadism, which is linked to increased HbA1c and decreased bone mineralization. Endocrine assessment and, if needed, measures to prevent metabolic sequelae and osteoporosis should be included in the routine management of men from infertile couples.

Association between premature ovarian failure, polymorphisms in MTHFR and MTRR genes and serum homocysteine concentration

This study investigated the association between premature ovarian failure (POF), MTHFR C677T/A1298C and MTRR A66G genotypes and serum homocysteine (Hcy) concentration. A prospective study was conducted in Chinese women, which included POF patients (n = 180) and controls (n = 195). Peripheral blood samples were used to determine MTHFR C677T/A1298C and MTRR A66G genotypes, and serum Hcy and sex hormone concentrations. Results showed that serum Hcy concentrations of POF patients were significantly higher than those of controls (P < 0.0001). In POF patients, serum Hcy concentrations were significantly correlated with oestradiol and FSH concentrations (r = −0.174, P = 0.037 and r = +0.238, P = 0.006, respectively). There were no significant differences in the distributions of MTHFR C677T/A1298C or MTRR A66G genotypes between the two groups. However, these genetic variants influenced serum Hcy concentrations in POF patients, especially for MTRR 66 AA/AG/GG genotypes, which were significantly correlated with the patients' Hcy concentrations (τ = 0.166, P = 0.033). These results suggest that serum Hcy concentrations in Chinese POF patients are increased and correlated with serum oestradiol/FSH concentrations. In conclusion, MTHFR C667T/A1298C and MTRR A66G genotypes are not associated with POF development, but they affect the patients' serum Hcy concentrations.

GW26-e4723 Serum Concentrations of Sex Hormones in Patients with Idiopathic Pulmonary Arterial Hypertension

GW26-e4723 Serum Concentrations of Sex Hormones in Patients with Idiopathic Pulmonary Arterial Hypertension

Can steroidal ovarian suppression during the luteal phase after oocyte retrieval reduce the risk of severe OHSS?

BackgroundOvarian stimulation in IVF cycle results in luteal supraphysiological steroid concentrations especially for high response patients. The aim of this study was to evaluate the efficacy of ovarian steroid hormone suppression in luteal phase after oocyte retrieval for preventing severe ovarian hyperstimulation syndrome (OHSS) in high-risk patients with embryo cryopreservation.Methods281 patients with high risk of OHSS were enrolled in this study among 4735 infertile women undergoing their first IVF treatment. The subjects were allocated into treatment and control group. The treatment group (n = 161) received letrozole (n = 43), mifepristone (n = 51), cetrotide (n = 39) and three-drug combinations (n = 28) during the luteal phase after oocyte retrieval, respectively. The control group (n = 120) received no medicine. Fertilization rate, good embryo rate, serum steroid concentration, clinical outcome, and incidence of severe OHSS were compared between the two groups.ResultsOn days 2, 5 and 8 after oocyte retrieval, serum estradiol levels in the letrozole and three-drug combination therapy group were significantly lower than in the other three groups at the same time (P < 0.001, respectively). There were no significantly difference of serum luteinizing hormone concentration on days 2, 5 and 8 and progesterone concentration on day 8 after oocyte retreival among the five groups (P > 0.05, respectively). Compared with the control group, the incidence of severe OHSS, the paracentesis rate, the duration of hospitalization and the days of luteal phase in each subgroup of treatment groups was not significantly decreased (P > 0.05, respectively).ConclusionsOur findings indicate that steroidal ovarian suppression in luteal phase after oocyte retrieval seems to be unable to prevent severe OHSS in high-risk patients with embryo cryopreservation.

Impact of Diet-Induced Obesity and Testosterone Deficiency on the Cardiovascular System: A Novel Rodent Model Representative of Males with Testosterone-Deficient Metabolic Syndrome (TDMetS).

IntroductionCurrent models of obesity utilise normogonadic animals and neglect the strong relationships between obesity-associated metabolic syndrome (MetS) and male testosterone deficiency (TD). The joint presentation of these conditions has complex implications for the cardiovascular system that are not well understood. We have characterised and investigated three models in male rats: one of diet-induced obesity with the MetS; a second using orchiectomised rats mimicking TD; and a third combining MetS with TD which we propose is representative of males with testosterone deficiency and the metabolic syndrome (TDMetS).MethodsMale Wistar rats (n = 24) were randomly assigned to two groups and provided ad libitum access to normal rat chow (CTRL) or a high fat/high sugar/low protein “obesogenic” diet (OGD) for 28 weeks (n = 12/group). These groups were further sub-divided into sham-operated or orchiectomised (ORX) animals to mimic hypogonadism, with and without diet-induced obesity (n = 6/group). Serum lipids, glucose, insulin and sex hormone concentrations were determined. Body composition, cardiovascular structure and function; and myocardial tolerance to ischemia-reperfusion were assessed.ResultsOGD-fed animals had 72% greater fat mass; 2.4-fold greater serum cholesterol; 2.3-fold greater serum triglycerides and 3-fold greater fasting glucose (indicative of diabetes mellitus) compared to CTRLs (all p<0.05). The ORX animals had reduced serum testosterone and left ventricle mass (p<0.05). In addition to the combined differences observed in each of the isolated models, the OGD, ORX and OGD+ORX models each had greater CK-MB levels following in vivo cardiac ischemia-reperfusion insult compared to CTRLs (p<0.05).ConclusionOur findings provide evidence to support that the MetS and TD independently impair myocardial tolerance to ischemia-reperfusion. The combined OGD+ORX phenotype described in this study is a novel animal model with associated cardiovascular risk factors and complex myocardial pathology which may be representative of male patients presenting with TDMetS.

Serum levels of sex steroids and metabolites following 12 weeks of intravaginal 0.50% DHEA administration

The objective of the present phase III, placebo-controlled, double-blind, prospective and randomized study was to confirm the efficacy of daily intravaginal administration of 0.50% dehydroepiandrosterone (DHEA; prasterone) ovules for 12 weeks on moderate to severe dyspareunia (or pain at sexual activity) as most bothersome symptom of vulvovaginal atrophy (VVA) while having serum steroid concentrations within normal postmenopausal values. To this end, serum levels of DHEA, DHEA-sulfate (DHEA-S), Androst-5-ene-diol-3β, 17β-diol (5-diol), testosterone, dihydrotestosterone (DHT), androstenedione (4-dione), estrone (E1), estradiol (E2), estrone sulfate (E1-S), androsterone glucuronide (ADT-G), and androstane-3α, 17β-diol 17-glucuronide (3α-diol-17G) were measured by validated liquid chromatography–tandem mass spectrometry (LC–MS/MS). In agreement with the mechanisms of intracrinology, all serum sex steroids and metabolites concentrations after 12 weeks of daily intravaginal administration of 0.50% DHEA remain well within the limits of normal postmenopausal women. More specifically, the 12-week serum E2 concentration was measured at 22% below the average normal postmenopausal value (3.26 versus 4.17pg/ml), thus eliminating any fear of E2 exposure outside the vagina. In addition, serum E1-S, a particularly reliable indicator of global estrogenic activity, shows serum levels practically superimposable to the value observed in normal postmenopausal women (219 versus 220pg/ml). Similarly, serum ADT-G, the major metabolite of androgens, remains within normal postmenopausal values.The present data confirm the intracellular transformation of DHEA in the vagina resulting in local efficacy without any systemic exposure to sex steroids, observations which are in agreement with the physiological mechanisms of menopause.

Serum sex hormone levels in different severity of male adult obstructive sleep apnea-hypopnea syndrome in East Asians.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a serious health issue, which can impact the hormone secretion. The aim of this study is to analyze the relationship between serum sex hormone concentrations and different severity degree of OSAHS, and to evaluate the influence of OSAHS on sex hormone levels. We enrolled 116 subjects who were subjected to polysomnography (PSG). They were divided into three groups: control group (n=10) [apnea hypopnea index (AHI) <5/h], mild-moderate OSAHS group (n=15) (5≤AHI<30/h), and severe OSAHS group (n=91) (AHI≥30/h). The patients in OSAHS group were subdivided into obesity and non-obesity subgroups. The parameters such as AHI, body mass index (BMI), lowest oxygen saturation (LSaO2), and mean oxygen saturation (MSaO2) were recorded. Serum levels of testosterone, polactin, estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined in the morning immediately after waking up. Mean levels of hormones were compared among groups. The correlation between hormone levels and sleep-breathing parameters was analyzed. No significant differences in serum sex hormone levels were found among control, mild-moderate OSAHS, and severe OSAHS groups (P>0.05). There was no correlation between AHI and sex hormone levels (P>0.05). Testosterone was significantly negatively correlated with BMI (P<0.05). These results suggested that BMI might have a direct effect on testosterone level, and it might be an important factor affecting testosterone level in male OSAHS patients, and there may be no correlation between severity of OSAHS and sex hormones levels.

Glucocorticoid receptor is involved in the breed-dependent transcriptional regulation of 3β-hydroxysteroid dehydrogenase in the liver of preweaning piglets

BackgroundHepatic 3β-hydroxysteroid dehydrogenase (3β-HSD) plays an important role in steroid inactivation and catabolism. Serum concentrations of steroid hormones differ significantly between breeds in pigs, however the molecular mechanism regulating hepatic 3β-HSD expression in different breeds of pigs is poorly understood. In the present study, we used preweaning purebred male Large White (LW) and Erhualian (EHL) piglets as model to investigate the breed difference in the expression and regulation of 3β-HSD gene in porcine liver.ResultsThe hepatic expression of 3β-HSD mRNA was significantly lower (P < 0.01) in EHL piglets compared to that in LW piglets. Significant breed differences were detected for the hepatic expression of transcription factors such as androgen receptor (AR), glucocorticoid receptor (GR), and CCAAT/enhancer binding protein β (C/EBPβ). The nucleoprotein contents of AR (P < 0.05), GR (P < 0.01) and phospho-Ser211GR (P < 0.01) were significantly higher in the liver of EHL piglets. Chromatin immunoprecipitation (ChIP) assay demonstrated significantly lower binding of GR, but not AR or C/EBPβ, to 3β-HSD gene promoter in EHL piglets (P < 0.05). GR was not detected to interact with C/EBPβ or AR in the co-immunoprecipitation analysis.ConclusionsThese results indicate that GR binding to 3β-HSD promoter is involved in the breed-dependent 3β-HSD expression in the liver of piglets.