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1.
Steroid hormones and pregnancy.
Noyola-Martínez, N, Halhali, A, Barrera, D
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019;(5):376-384
Abstract
Pregnancy is associated with physiological adjustments in order to allow adequate growth and fetal development. In particular, steroids are necessary to maintain in balance numerous functions during gestation. Steroidogenesis in the maternal, placental and fetal compartments and the biological effects of progestins and estrogens that play a pivotal role before and during pregnancy are described. Although it is well-known that androgens are considered as substrate for estrogens biosynthesis, their biosynthesis and functionality in placental and other tissues have been questioned. As compared with healthy pregnancy, steroid hormones levels have been found altered in complicated pregnancies and hormonal treatments have been used is some pathologies. Therefore, the aim of this work was to review the biosynthesis, function and regulation of progestins, androgens and estrogens during gestation. Furthermore, steroid hormones concentrations during healthy and complicated pregnancy as well hormonal therapies for the prevention of miscarriages and preterm deliveries are discussed in the present review.
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2.
Effects of vitamin D supplementation on androgens in men with low testosterone levels: a randomized controlled trial.
Lerchbaum, E, Trummer, C, Theiler-Schwetz, V, Kollmann, M, Wölfler, M, Heijboer, AC, Pilz, S, Obermayer-Pietsch, B
European journal of nutrition. 2019;(8):3135-3146
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Abstract
PURPOSE It has been hypothesized that vitamin D is associated with androgen levels in men. We, therefore, aimed to evaluate whether vitamin D supplementation increases serum total testosterone (TT) levels in men with low TT levels at baseline. METHODS The Graz Vitamin D&TT-RCT is a single-center, double-blind, randomized placebo-controlled trial conducted between March 2013 and November 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. One-hundred healthy men with serum TT levels < 10.4 nmol/l and 25-hydroxyvitamin D [25(OH)D] levels < 75 nmol/l participated in the trial. Subjects were randomized to receive 20,000 IU of vitamin D3/week (n = 50) or placebo (n = 50) for 12 weeks. Primary outcome was TT measured using mass spectrometry. Secondary outcomes were free testosterone, free androgen index, sex hormone-binding globulin, estradiol, follicle-stimulating hormone, luteinizing hormone, metabolic characteristics, and body composition. RESULTS Ninety-four men [mean age and 25(OH)D: 47 (± 12) years and 56.3 (± 18.3) nmol/l, respectively] completed the study. We found no significant treatment effect on serum TT or on the remaining secondary outcome variables. CONCLUSION Vitamin D treatment had no effect on serum TT levels in middle-aged healthy men with low TT levels.
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The effect of resistant dextrin as a prebiotic on metabolic parameters and androgen level in women with polycystic ovarian syndrome: a randomized, triple-blind, controlled, clinical trial.
Gholizadeh Shamasbi, S, Dehgan, P, Mohammad-Alizadeh Charandabi, S, Aliasgarzadeh, A, Mirghafourvand, M
European journal of nutrition. 2019;(2):629-640
Abstract
INTRODUCTION Polycystic ovary syndrome (PCOS) is one of the most common abnormalities in women of reproductive age that can lead to a variety of metabolic and reproductive disorders. Studies reveal that a healthy diet is the most effective way for treating the risk factors associated with metabolic disorders and place greater emphasis on the consumption of prebiotic foods. The present study aims to determine the effect of resistant Dextrin on metabolic parameters, including lipid profile, fasting blood glucose (FBS) and high sensitivity C-reactive protein (hsCRP), and androgen levels, including serum levels of dehydroepiandrosterone sulfate (DHEA-S) and free testosterone, as the primary outcomes, and manifestations of PCOS including menstrual cycle irregularity and hirsutism, as the secondary outcomes. METHODS This randomized, controlled, triple-blind, clinical trial was conducted on 62 women aged 18-45 in Tabriz, Iran, in 2016-2017. The participants were divided into a prebiotic group and a placebo group using block randomization. The prebiotic group consumed 20 g of resistant dextrin dissolved in a glass of water and the placebo group 20 g of maltodextrin also dissolved in a glass of water on a daily basis for 3 months. To measure the serum lipid profile, FBS, hsCRP, DHEA-S and free testosterone before and 3 months after the intervention, 5-ml blood samples were collected from the participants and analyzed using the ELISA method. The Ferriman-Gallwey scale for assessing hirsutism and a checklist for assessing menstrual cycle characteristics were completed before and 3 months after the intervention. A general linear model was used to analyze the data. RESULTS No statistically significant differences were observed between the two groups in terms of sociodemographic characteristics and baseline values. 3 months after the intervention, based on the ANCOVA and after adjusting for the baseline values, the mean serum levels of LDL-C (adjusted mean difference = - 29.79; 95% CI = - 43.37 to - 16.21; P < 0.001), triglyceride (AMD = - 38.50; 95% CI = - 59.73 to - 17.28; P = 0.001), total cholesterol (AMD = - 29.98; 95% CI = - 40.14 to - 19.82; P < 0.001), FBS (AMD = - 11.24; 95% CI = - 15.43 to - 7.06; P < 0.001), hsCRP (AMD = - 1.75; 95% CI = - 2.92 to - 0.57; P = 0.004), DHEA-S (AMD = - 0.7; 95% CI = - 1.34 to - 0.13; P = 0.017) and free testosterone (AMD = - 0.32; 95% CI = - 0.56 to - 0.08; P = 0.010) revealed a statistically significant decrease in the intervention group compared to the placebo group, while the mean serum HDL-C showed a statistically significant increase in this group compared to the placebo group (AMD = 5.82; 95% CI = 2.27-9.37; P = 0.002). 3 months after the intervention, there was a significant difference between the two groups in terms of menstrual cycle intervals and hirsutism (P < 0.001). CONCLUSION Resistant dextrin consumption can regulate metabolic parameters and androgen levels and manifestations including hirsutism and menstrual cycle irregularity in women with PCOS.
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Canonical and Noncanonical Androgen Metabolism and Activity.
Storbeck, KH, Mostaghel, EA
Advances in experimental medicine and biology. 2019;:239-277
Abstract
Androgens are critical drivers of prostate cancer. In this chapter we first discuss the canonical pathways of androgen metabolism and their alterations in prostate cancer progression, including the classical, backdoor and 5α-dione pathways, the role of pre-receptor DHT metabolism, and recent findings on oncogenic splicing of steroidogenic enzymes. Next, we discuss the activity and metabolism of non-canonical 11-oxygenated androgens that can activate wild-type AR and are less susceptible to glucuronidation and inactivation than the canonical androgens, thereby serving as an under-recognized reservoir of active ligands. We then discuss an emerging literature on the potential non-canonical role of androgen metabolizing enzymes in driving prostate cancer. We conclude by discussing the potential implications of these findings for prostate cancer progression, particularly in context of new agents such as abiraterone and enzalutamide, which target the AR-axis for prostate cancer therapy, including mechanisms of response and resistance and implications of these findings for future therapy.
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Androgens in Congenital Adrenal Hyperplasia.
Pignatelli, D, Pereira, SS, Pasquali, R
Frontiers of hormone research. 2019;:65-76
Abstract
Congenital Adrenal Hyperplasias (CAH) are genetic diseases transmitted in an autosomal recessive way and these diseases affect many aspects of human health. The majority of CAH cases is due to a deficiency in 21-hydroxylase as a result of the existence of mutations in both alleles of the CYP21A2 gene. Since the identification of mild, non-classic forms of this disease, CAH has been recognized to be one of the most common genetic diseases in human beings. This disease is generally associated with elevated secretion of androgens, sometimes resulting in virilizing syndromes, including genital ambiguity, precocious puberty in both sexes, or milder syndromes of androgen excess like precocious pubarche or the occurrence of hirsutism and oligomenorrhea in women. Accumulating precursors like 17-hydroxypregnenolone and 17-hydroxyprogesterone (17OHP) are directed to the synthesis of androgens through the enzyme 17-hydroxylase/17,20 lyase leading to the production of dehydroepiandrosterone that is then converted to testosterone and dihydrotestosterone (DHT) at the gonads and at other peripheral tissues. 17OHP, the hallmark of 21-hydroxylase deficiency, can be converted to androstenedione (in a low efficiency molecular process) but can also be converted to DHT through an alternative pathway that becomes active due to the large amounts of accumulated 17OHP - the backdoor pathway. Another important pathway that becomes significant in this disease is the 11-oxyandrogens pathway through which androstenedione is converted to 11β-hydroxyandrostenedione at the adrenal and from there to 11-ketotestosterone and 11-ketoDHT. The elevated androgens levels affect the hypothalamic-pituitary-gonadal axis and, in some cases, the ovary resulting in chronic anovulation and infertility.
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Understanding the Role of Androgen Action in Female Adipose Tissue.
Schiffer, L, Arlt, W, O'Reilly, MW
Frontiers of hormone research. 2019;:33-49
Abstract
Adipose tissue is an important target of androgen action in humans. Androgens exert important effects on adipose tissue biology, including fat mass expansion and distribution, insulin signalling and lipid metabolism. In conditions of female androgen excess such as polycystic ovary syndrome (PCOS), androgens exert metabolically deleterious effects on adipose tissue function in a depot-specific manner. Androgen excess in women is metabolically deleterious, and adverse metabolic effects may be mediated by effects on preadipocyte differentiation and adipocyte hypertrophy. Circulating androgen burden correlates with adiposity in women, and drives visceral fat mass accumulation. Adipose tissue is also an important organ of pre-receptor androgen metabolism, and is host to a complex network of androgen activating and inactivating enzymes. Adipose androgen generation is increased in subcutaneous (SC) adipose tissue in women with PCOS, and intra-adipose concentrations of potent androgens may exceed those measured in peripheral circulation. Increased expression of the key androgen-activating enzyme aldo-ketoreductase type 1C3 in PCOS SC adipose tissue leads to high concentrations of testosterone and dihydrotestosterone. Enhanced local androgen generation may further contribute to the adverse metabolic profile of women with PCOS by exerting lipotoxic effects on local adipose biology.
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A Clinical Perspective of Sleep and Andrological Health: Assessment, Treatment Considerations, and Future Research.
Liu, PY
The Journal of clinical endocrinology and metabolism. 2019;(10):4398-4417
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CONTEXT Sleep that is insufficient, misaligned, or disrupted causes hypersomnolence and neuropsychological deficits, adversely affects cardiometabolic health, and is increasingly recognized to impair other biological processes that lead to conditions important to men, such as hypogonadism, erectile dysfunction, and infertility. EVIDENCE ACQUISITION Literature review from 1970 to December 2018. EVIDENCE SYNTHESIS High-quality and complementary epidemiological and interventional studies establish that abnormal sleep is associated with increased mortality, hypertension, and other cardiometabolic disorders (insufficient, disrupted, and misaligned sleep), as well as reduced fecundity and total sperm count (insufficient sleep), erectile dysfunction (disrupted sleep), and low testosterone (both). Circadian misalignment shifts the peak of testosterone's diurnal rhythm to occur soon after waking up, irrespective of the biological clock time, but it does not change the mean concentration. Preliminary studies show that extending sleep in individuals who are chronically sleep deprived may become a strategy to reduce insulin resistance and hypertension. Continuous positive airway pressure therapy can improve erectile function, and possibly systemic testosterone exposure, but only when used adherently by men with obstructive sleep apnea. Both high-dose and replacement-dose testosterone therapies modestly worsen sleep-disordered breathing, but they also improve cardiometabolic function and sexual desire. Persistence of either the adverse or beneficial outcomes over the longer term requires further investigation. CONCLUSIONS Sleep is increasingly recognized to be essential for healthy living. Establishing the effect of abnormal sleep, and of improving sleep, on andrological issues of prime interest to men will promote prioritization of sleep, and may thereby improve overall long-term health outcomes.
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High DHEAS Level in Girls Is Associated with Earlier Pubertal Maturation and Mild Increase in Androgens throughout Puberty without Affecting Postmenarche Ovarian Morphology.
Merino, PM, Pereira, A, Iñiguez, G, Corvalan, C, Mericq, V
Hormone research in paediatrics. 2019;(6):357-364
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OBJECTIVE To assess whether the presence of high DHEAS (HD) at 7 years determines different timing, sequence, and rate of pubertal events, and whether it is associated with adrenal and/or ovarian hyperandrogenism and changes in ovarian morphology throughout puberty. METHODS In a longitudinal study of 504 girls, clinical evaluation was performed every 6 months after 7 years of age to detect Tanner stages; hormonal and anthropometric measurements were conducted at thelarche (B2), breast Tanner 4 (B4), and 1 year after menarche; ultrasonographic evaluation was also performed after menarche. The girls were classified as HD if their DHEAS level was >42.1 µg/dL (>75th percentile) around 7 years. RESULTS HD around 7 years is associated with a younger age at thelarche, pubarche, and menarche. Girls with HD had higher androstenedione and total testosterone levels, and a higher free androgen index (FAI), and lower levels of antimüllerian hormone (AMH) at B2, and higher levels of androstenedione and FAI at B4 and after menarche. All these results were significant even after adjusting for body mass index, age at first DHEAS determination, and birth weight. One year after menarche, polycystic ovarian morphology was detected in 7.6 and 7.3% of the HD and the normal DHEAS group, respectively. Ovarian volume was correlated with AMH, testosterone, androstenedione, and LH but not with DHEAS around 7 years. CONCLUSION Prepubertal HD in normal girls was associated with earlier thelarche, pubarche, and menarche, and a mild androgen increase throughout puberty. We believe continuous follow-up of this cohort is important to prospectively address the interrelationships between biochemical adrenarche and early growth as determinants of ovarian function.
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Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data.
Islam, RM, Bell, RJ, Green, S, Page, MJ, Davis, SR
The lancet. Diabetes & endocrinology. 2019;(10):754-766
Abstract
BACKGROUND The benefits and risks of testosterone treatment for women with diminished sexual wellbeing remain controversial. We did a systematic review and meta-analysis to assess potential benefits and risks of testosterone for women. METHODS We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for blinded, randomised controlled trials of testosterone treatment of at least 12 weeks' duration completed between Jan 1, 1990, and Dec 10, 2018. We also searched drug registration applications to the European Medicine Agency and the US Food and Drug Administration to identify any unpublished data. Primary outcomes were the effects of testosterone on sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42018104073. FINDINGS Our search strategy retrieved 46 reports of 36 randomised controlled trials comprising 8480 participants. Our meta-analysis showed that, compared with placebo or a comparator (eg, oestrogen, with or without progestogen), testosterone significantly increased sexual function, including satisfactory sexual event frequency (mean difference 0·85, 95% CI 0·52 to 1·18), sexual desire (standardised mean difference 0·36, 95% CI 0·22 to 0·50), pleasure (mean difference 6·86, 95% CI 5·19 to 8·52), arousal (standardised mean difference 0·28, 95% CI 0·21 to 0·35), orgasm (standardised mean difference 0·25, 95% CI 0·18 to 0·32), responsiveness (standardised mean difference 0·28, 95% CI 0·21 to 0·35), and self-image (mean difference 5·64, 95% CI 4·03 to 7·26), and reduced sexual concerns (mean difference 8·99, 95% CI 6·90 to 11·08) and distress (standardised mean difference -0·27, 95% CI -0·36 to -0·17) in postmenopausal women. A significant rise in the amount of LDL-cholesterol, and reductions in the amounts of total cholesterol, HDL-cholesterol, and triglycerides, were seen with testosterone administered orally, but not when administered non-orally (eg, by transdermal patch or cream). An overall increase in weight was recorded with testosterone treatment. No effects of testosterone were reported for body composition, musculoskeletal variables, or cognitive measures, although the number of women who contributed data for these outcomes was small. Testosterone was associated with a significantly greater likelihood of reporting acne and hair growth, but no serious adverse events were recorded. INTERPRETATION Testosterone is effective for postmenopausal women with low sexual desire causing distress, with administration via non-oral routes (eg, transdermal application) preferred because of a neutral lipid profile. The effects of testosterone on individual wellbeing and musculoskeletal and cognitive health, as well as long-term safety, warrant further investigation. FUNDING Australian National Health and Medical Research Council.
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Effects of testosterone supplementation therapy on lipid metabolism in hypogonadal men with T2DM: a meta-analysis of randomized controlled trials.
Zhang, KS, Zhao, MJ, An, Q, Jia, YF, Fu, LL, Xu, JF, Gu, YQ
Andrology. 2018;(1):37-46
Abstract
Testosterone supplementation may be effective for the treatment of hypogonadism in men with type 2 diabetes mellitus (T2DM), but the evidence from randomized controlled trials (RCTs) is inconclusive. We aimed to systematically summarize results from intervention studies and assess the effects of testosterone supplementation therapy (TST) on lipid metabolism in RCTs of hypogonadal men with T2DM by meta-analysis. PubMed, Embase, and Cochrane Library databases were searched for studies reporting the effect of TST on lipid metabolism in hypogonadal men with T2DM until December 31, 2016. Seven RCTs from 252 trials, enrolling a total of 612 patients in the experimental and control groups with a mean age of 58.5 years, were included in this study. The pooled results of the meta-analysis demonstrated that TST significantly decreased TC and TG levels in hypogonadal men with T2DM compared with the control group, with mean differences (MDs) of -6.44 (95% CI: -11.82 to -1.06; I2 = 28%; p = 0.02) and -27.94 (95% CI: -52.33 to -3.54; I2 = 76%; p = 0.02). Subgroup analyses revealed that the heterogeneity (I2 = 76%) of TG originated from different economic regions, in which economic development, genetic and environmental factors, and dietary habits affect lipid metabolism of human, with a decrease (I2 = 45%) in developed countries. Additionally, subgroup analyses showed that TST increased HDL-C level in developing countries compared with the control group (MD = 2.79; 95% CI: 0.73 to 4.86; I2 = 0%; p = 0.008), but there was no improvement in developed countries (MD = 1.02; 95% CI: -4.55 to 6.60; I2 = 91%; p = 0.72). However, LDL-C levels were not improved consistently. Because the relationship between lipid metabolism and atherosclerosis is unequivocal, TST, which ameliorates lipid metabolism, may decrease the morbidity and mortality of cardiovascular disease in hypogonadal men with T2DM by preventing atherogenesis.