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In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution, metabolism, and biological activity. According to the free hormone hypothesis, which has been debated extensively, only the unbound or free fraction is biologically active in target tissues. Consequently, accurate determination of the partitioning of testosterone between bound and free fractions is central to our understanding of how its delivery to the target tissues and biological activity are regulated and consequently to the diagnosis and treatment of androgen disorders in men and women. Here, we present a historical perspective on the evolution of our understanding of the binding of testosterone to circulating binding proteins. On the basis of an appraisal of the literature as well as experimental data, we show that the assumptions of stoichiometry, binding dynamics, and the affinity of the prevailing models of testosterone binding to sex hormone-binding globulin and human serum albumin are not supported by published experimental data and are most likely inaccurate. This review offers some guiding principles for the application of free testosterone measurements in the diagnosis and treatment of patients with androgen disorders. The growing number of testosterone prescriptions and widely recognized problems with the direct measurement as well as the computation of free testosterone concentrations render this critical review timely and clinically relevant.This appraisal of the dynamics of testosterone binding to proteins and of the free hormone hypothesis offers guidance for the application of free testosterone in the evaluation of androgen disorders.

Abstract Context A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial. Objective Determine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy. Design Randomized, active-controlled, open-label study. Setting and Patients Academic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old. Methods Patients were randomized 3:1 to oral TU, as prescribed (JATENZO®; n = 166) or a topical T product once daily (Axiron®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (Cavg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography–mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP). Results 87% of patients in both groups achieved mean T Cavg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T Cavg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to Cavg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg. Conclusion A new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.

Key Points Cardiometabolic syndrome is a cluster of diseases (including type 2 diabetes mellitus (T2DM) and atherosclerosis) that can result in cardiovascular disease (CVD), a leading cause of mortality in developed countries The incidence of CVD differs between men and women, but the reason for this dimorphism remains elusive because most basic and clinical research has been conducted predominantly in men Premenopausal women have a reduced risk of CVD compared with age-matched men, and mortality as a result of CVD is higher in premenopausal women than in age-matched men; however, questions remain about the protective role of oestrogens Physiological concentrations of oestrogens in men seem to protect against the development of T2DM and might mediate reductions in the risk of CVD Oestrogens act in target tissues through oestrogen receptors and G protein-coupled oestrogen receptor 1 to reduce the risk of CVD Sex hormones and their contribution to the risk of CVD should be evaluated by looking at the relative ratios of oestrogens to androgens rather than to their specific effects in isolation This Review discusses what is known about how gonadal steroids mediate the risk of cardiometabolic diseases, highlighting the role of oestrogens, their receptors and androgens, as well as the effect of the relative ratios of these hormones. Cardiovascular disease (CVD) is one of the leading causes of mortality in developed countries. The incidence of CVD is sexually dimorphic, and research has focused on the contribution of sex steroids to the development and progression of the cardiometabolic syndrome, which is defined as a clustering of interrelated risk factors that promote the development of atherosclerosis (which can lead to CVD) and type 2 diabetes mellitus. Data are inconclusive as to how sex steroids and their respective receptors increase or suppress the risk of developing the cardiometabolic syndrome and thus CVD. In this Review, we discuss the potential role, or roles, of sex hormones in cardiometabolic health by first focusing on the influence of oestrogens and their receptors on the risk of developing cardiometabolic syndrome and CVD. We also highlight what is known about testosterone and its potential role in protecting against the development of the cardiometabolic syndrome and CVD. Given the inconclusive nature of the data regarding the direct effects of each sex hormone, we advocate and highlight the importance of studying the relative levels and the ratio of sex hormones to each other, as well as the use of cross sex hormone therapy and its effect on cardiometabolic health.

The hypothalamic–pituitary–gonadal axis is of relevance in many processes related to the development, maturation and ageing of the male. Through this axis, a cascade of coordinated activities is carried out leading to sustained testicular endocrine function, with gonadal testosterone production, as well as exocrine function, with spermatogenesis. Conditions impairing the hypothalamic–pituitary–gonadal axis during paediatric or pubertal life may result in delayed puberty. Late-onset hypogonadism is a clinical condition in the ageing male combining low concentrations of circulating testosterone and specific symptoms associated with impaired hormone production. Testosterone therapy for congenital forms of hypogonadism must be lifelong, whereas testosterone treatment of late-onset hypogonadism remains a matter of debate because of unclear indications for replacement, uncertain efficacy and potential risks. This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypogonadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development. Male hypogonadism is a disorder associated with low testosterone levels and impaired spermatogenesis. The condition can arise from inherent defects in the testes or abnormalities in the regulation of testosterone secretion at the hypothalamic or pituitary level. This Primer summarizes the conditions that can lead to hypogonadism in boys and men.

Little is known about the role of the endocrine system in financial risk taking. Here, we report the findings of a study in which we sampled, under real working conditions, endogenous steroids from a group of male traders in the City of London. We found that a trader's morning testosterone level predicts his day's profitability. We also found that a trader's cortisol rises with both the variance of his trading results and the volatility of the market. Our results suggest that higher testosterone may contribute to economic return, whereas cortisol is increased by risk. Our results point to a further possibility: testosterone and cortisol are known to have cognitive and behavioral effects, so if the acutely elevated steroids we observed were to persist or increase as volatility rises, they may shift risk preferences and even affect a trader's ability to engage in rational choice.

Obesity is a complex metabolic disease that is a serious detriment to both children and adult health, which induces a variety of diseases, such as cardiovascular disease, type II diabetes, hypertension and cancer. Although adverse effects of obesity on female reproduction or oocyte development have been well recognized, its harmfulness to male fertility is still unclear because of reported conflicting results. The aim of this study was to determine whether diet-induced obesity impairs male fertility and furthermore to uncover its underlying mechanisms. Thus, male C57BL/6 mice fed a high-fat diet (HFD) for 10 weeks served as a model of diet-induced obesity. The results clearly show that the percentage of sperm motility and progressive motility significantly decreased, whereas the proportion of teratozoospermia dramatically increased in HFD mice compared to those in normal diet fed controls. Besides, the sperm acrosome reaction fell accompanied by a decline in testosterone level and an increase in estradiol level in the HFD group. This alteration of sperm function parameters strongly indicated that the fertility of HFD mice was indeed impaired, which was also validated by a low pregnancy rate in their mated normal female. Moreover, testicular morphological analyses revealed that seminiferous epithelia were severely atrophic, and cell adhesions between spermatogenic cells and Sertoli cells were loosely arranged in HFD mice. Meanwhile, the integrity of the blood-testis barrier was severely interrupted consistent with declines in the tight junction related proteins, occludin, ZO-1 and androgen receptor, but instead endocytic vesicle-associated protein, clathrin rose. Taken together, obesity can impair male fertility through declines in the sperm function parameters, sex hormone level, whereas during spermatogenesis damage to the blood-testis barrier (BTB) integrity may be one of the crucial underlying factors accounting for this change.

Background Intensified training is important for inducing adaptations to improve athletic performance, but detrimental performance effects can occur if prescribed inappropriately. Monitoring biomarker responses to training may inform changes in training load to optimize performance. Objective This systematic review and meta-analysis aimed to identify biomarkers associated with altered exercise performance following intensified training. Methods Embase, MEDLINE, CINAHL, Scopus and SPORTDiscus were searched up until September 2017. Included articles were peer reviewed and reported on biomarkers collected at rest in well-trained male athletes before and after periods of intensified training. Results The full text of 161 articles was reviewed, with 59 included (708 participants) and 42 (550 participants) meta-analysed. In total, 118 biomarkers were evaluated, with most being cellular communication and immunity markers ( n  = 54). Studies most frequently measured cortisol ( n  = 34), creatine kinase ( n  = 25) and testosterone ( n  = 20). Many studies reported decreased immune cell counts following intensified training, irrespective of performance. Moreover, reduced performance was associated with a decrease in neutrophils ( d  = − 0.57; 95% confidence interval (CI) − 1.07 to − 0.07) and glutamine ( d  = − 0.37; 95% CI − 0.43 to − 0.31) and an increase in urea concentration ( d  = 0.80; 95% CI 0.30 to 1.30). In contrast, increased performance was associated with an increased testosterone:cortisol ratio ( d  = 0.89; 95% CI 0.54 to 1.24). All remaining biomarkers showed no consistent patterns of change with performance. Conclusions Many biomarkers were altered with intensified training but not in a manner related to changes in exercise performance. Neutrophils, glutamine, urea and the testosterone:cortisol ratio exhibited some evidence of directional changes that corresponded with performance changes therefore indicating potential to track performance. Additional investigations of the potential for these markers to track altered performance are warranted.

Current evidence suggests a strong correlation between specific body hormones and skeletal maturation; however, there is very limited literature available on salivary hormonal levels and their correlation with craniofacial skeletal growth. The primary objective of this study was to collect preliminary data on the salivary Growth Hormone, Cortisol, Testosterone, and 17β-Estradiol levels of orthodontic patients with specific age groups. In this cross-sectional cohort study, a total of 80 patients (40 females and 40 males) were recruited. 5 ml saliva was collected by a passive drooling method for an ELISA test of Cortisol, 17β-Estradiol, Testosterone, and Growth Hormone (GH). Lateral cephalograms were acquired for the middle phalanx of the third figure (MP3) stages and Cervical Vertebral Maturity Indicator (CVMI). We observed that the GH concentration was highest for females between the ages of 10–11 years (12.0 ± 4.2 pg/ml) and for males between the ages of 13–14 years (13.4 ± 11.6 pg/ml). The prepubertal stage (10–12 years) for female subjects, MP3, and CVMI stages were observed to be 2.5. This study concludes that the salivary growth hormone was highest for ages 10–11 females and age 13–14 males, then gradually declined as the age of the subjects increased. The trend for the Testosterone level was identical between males and females till the age of 13; thereafter, males showed higher salivary Testosterone than female subjects. These findings show promising application of salivary hormonal analysis for the growth prediction. Specifically, level of salivary GH can be used as a non-invasive tool for the skeletal maturation assessment.

In this study, our aim was to validate whether the automated measurement of salivary testosterone and cortisol concentrations and the testosterone-to-cortisol (T/C) ratio, considering their individual circadian rhythms can be used to assess the stress response of male athletes to different exercise intensities accurately and effectively. We measured the salivary testosterone and cortisol concentrations and their respective serum concentrations that were collected from 20 male long-distance runners via passive drooling in the morning and evening for two consecutive days involving different exercise intensities. An electrochemiluminescence immunoassay was performed to evaluate the salivary testosterone and cortisol concentrations. The results showed a positive correlation between the salivary testosterone and cortisol concentrations and their respective serum concentrations. The participants were divided into two groups: with and without interval training. The interval training group showed a significantly higher rate of change in the salivary cortisol concentration and a significantly lower rate of change in the T/C ratio in the evening interval training on day 1 than lower-intensity running on day 2. Our results indicated that the salivary cortisol concentrations and the T/C ratio could distinguish between exercises at different intensities, which may be beneficial for detecting differences in stress responses among athletes.

The diagnosis of hypogonadism in human males includes identification of low serum testosterone levels, and hence there is an underlying assumption that normal ranges of testosterone for the healthy population are known for all ages. However, to our knowledge, no such reference model exists in the literature, and hence the availability of an applicable biochemical reference range would be helpful for the clinical assessment of hypogonadal men. In this study, using model selection and validation analysis of data identified and extracted from thirteen studies, we derive and validate a normative model of total testosterone across the lifespan in healthy men. We show that total testosterone peaks [mean (2.5-97.5 percentile)] at 15.4 (7.2-31.1) nmol/L at an average age of 19 years, and falls in the average case [mean (2.5-97.5 percentile)] to 13.0 (6.6-25.3) nmol/L by age 40 years, but we find no evidence for a further fall in mean total testosterone with increasing age through to old age. However we do show that there is an increased variation in total testosterone levels with advancing age after age 40 years. This model provides the age related reference ranges needed to support research and clinical decision making in males who have symptoms that may be due to hypogonadism.