SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men.

CONTEXT: Genetic variation in sex hormone-binding globulin (SHBG) structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration. OBJECTIVE: To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men. DESIGN, SETTING AND PARTICIPANTS: Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean: 34.5) years. MAIN OUTCOME MEASURES: Genotyping using microarray (Illumina®) for SNPs suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis. RESULTS: Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; p < 0.05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all p < 0.05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all p < 0.05). No clear effects on measured free T were found, except for a trend towards higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; p < 0.05) in the larger global study population. CONCLUSION: In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.

The association between newborn cord blood steroids and ambient prenatal exposure to air pollution: findings from the ENVIRONAGE birth cohort.

Knowledge of whether prenatal exposure to ambient air pollution disrupts steroidogenesis is currently lacking. We investigated the association between prenatal ambient air pollution and highly accurate measurements of cord blood steroid hormones from the androgenic pathway.This study included 397 newborns born between the years 2010 and 2015 from the ENVIRONAGE cohort in Belgium of whom six cord blood steroid levels were measured: 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, dehydroepiandrosterone, pregnenolone, androstenedione, and testosterone. Maternal ambient exposure to PM2.5 (particles with aerodynamic diameter ≤ 2.5 µm), NO2, and black carbon (BC) were estimated daily during the entire pregnancy using a high-resolution spatiotemporal model. The associations between the cord blood steroids and the air pollutants were tested and estimated by first fitting linear regression models and followed by fitting weekly prenatal exposures to distributed lag models (DLM). These analyses accounted for possible confounders, coexposures, and an interaction effect between sex and the exposure. We examined mixture effects and critical exposure windows of PM2.5, NO2 and BC on cord blood steroids via the Bayesian kernel machine regression distributed lag model (BKMR-DLM).An interquartile range (IQR) increment of 7.96 µg/m3 in PM2.5 exposure during pregnancy trimester 3 was associated with an increase of 23.01% (99% confidence interval: 3.26-46.54%) in cord blood levels of 17α-hydroxypregnenolone, and an IQR increment of 0.58 µg/m³ in BC exposure during trimester 1 was associated with a decrease of 11.00% (99% CI: -19.86 to -0.012%) in cord blood levels of androstenedione. For these two models, the DLM statistics identified sensitive gestational time windows for cord blood steroids and ambient air pollution exposures, in particular for 17α-hydroxypregnenolone and PM2.5 exposure during trimester 3 (weeks 28-36) and for androsterone and BC exposure during early pregnancy (weeks 2-13) as well as during mid-pregnancy (weeks 18-26). We identified interaction effects between pollutants, which has been suggested especially for NO2.Our results suggest that prenatal exposure to ambient air pollutants during pregnancy interferes with steroid levels in cord blood. Further studies should investigate potential early-life action mechanisms and possible later-in-life adverse effects of hormonal disturbances due to air pollution exposure.

Physiological declines in sex steroid exposure in relation to changes in body composition in healthy men-a prospective cohort study.

OBJECTIVE: Androgen levels decline from early adulthood and decreases are steeper in men with increasing body mass index. It is, however, unclear to what extent changes in other indices of body composition and metabolism associate with changes in sex steroid levels in healthy men. Therefore, this study investigated longitudinal changes in body composition and metabolic health in relation to sex steroid levels in healthy adult men. DESIGN: This is a longitudinal, population-based study. A total of 676 healthy men aged 24-46 years were measured at baseline and after ±12 years. METHODS: Serum sex hormone-binding globulin (SHBG) was measured by immunoassay, testosterone (T), estradiol (E2), and dihydrotestosterone byliquid chromatography with tandem mass spectrometry (LC-MS/MS), calculated free T and calculated free E2 (cFE2), and homeostasis model assessment for insulin resistance (HOMA-IR) were calculated. Grip strength was measured by hand-grip dynamometry. Body composition was determined using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. RESULTS: Mean fat mass (FM), lean mass (LM), and HOMA-IR increased (all P < .001). Decreasing androgen and SHBG levels was associated with increasing FM, whereas decreasing (cF)E2 levels were associated with decreasing FM (all P < .005). Decreasing (cF)E2 levels and increasing SHBG levels associated with decreasing LM (all P < .002). Changes in sex steroid levels and HOMA-IR or grip strength were not interrelated. CONCLUSION: Aging leads to increases in FM indices and insulin resistance, whereas changes in parameters of LM are less unequivocal. In healthy adult men, physiological changes in sex steroid exposure clearly correlate with changes in adiposity but not so with lean mass, insulin resistance, or grip strength. CLINICAL TRIAL: The SIBEX study was registered on ClinicalTrials.gov (#NVT02997033).

GRACE-trial: a randomised active-controlled trial for vulvovaginal atrophy in patients with breast cancer on endocrine therapy - study protocol.

INTRODUCTION: Breast cancer is the most common cancer type in women worldwide. Due to hormone receptor positivity in the majority of the breast cancer tumours is endocrine therapy a crucial part in the treatment landscape of breast cancer. Endocrine therapy consists of the use of selective oestrogen-receptor modulators or aromatase inhibitors. These medicines generate a hypoestrogenic environment by reducing circulating oestrogen or by altering the effect of oestrogen on tissue cells by receptor blockade. As a common side effect, vulvovaginal atrophy occurs in the majority of patients with breast cancer using endocrine therapy. Vulvovaginal atrophy has a significant impact on physical and psychological well-being due to negative influence on quality-of-life, self-esteem and sexuality. As a consequence, adherence to endocrine therapy for the standard duration of 5-10 years is challenging, resulting in higher rates of therapy interruption, leading to poorer prognosis with shorter distant disease-free survival. The standard treatment for vulvovaginal atrophy in postmenopausal women is based on the use of local hormonal treatment. However, when a patient has a history of breast cancer, delay of treatment and undertreatment are ubiquitous. METHODS AND ANALYSIS: In this first ever prospective randomised trial patients with breast cancer on endocrine therapy with vulvovaginal atrophy will be treated with the available local treatment modalities with a 1:1:1:1 randomisation: oestrogen, dehydroepiandrosterone, moisturisers and a co-treatment of oestrogen and probiotics. Patient-reported outcomes measurements will be implemented to investigate the efficacy of the implemented treatments. Safety of the treatments will be evaluated by assessing systemic sex hormones concentrations. ETHICS AND DISSEMINATION: This study was approved by the Ethical Committee of Ghent University Hospital and by the Federal Agency for Medicines and Health Products. Results will be published in peer-reviewed journals and released in international conferences. TRIAL REGISTRATION NUMBER: 2021-001921-31.

Sex differences and sex steroids influence on the presentation and severity of cardiovascular autonomic neuropathy of patients with type 1 diabetes.

BACKGROUND: Sex differences characterize cardiovascular outcomes in patients with type 1 diabetes. Cardioautonomic neuropathy is a common complication of type 1 diabetes that associates increased morbi-mortality. Data regarding the interplay between sex and cardiovascular autonomic neuropathy are scarce and controversial in these patients. We aimed to address sex-related differences in the prevalence of seemingly asymptomatic cardioautonomic neuropathy in type 1 diabetes, and their associations with sex steroids. METHODS: We conducted a cross-sectional study including 322 consecutively recruited patients with type 1 diabetes. Cardioautonomic neuropathy was diagnosed using Ewing's score and power spectral heart rate data. We assessed sex hormones by liquid chromatography/tandem mass spectrometry. RESULTS: When considering all subjects as a whole, asymptomatic cardioautonomic neuropathy prevalence was not significantly different between women and men. When age was taken into account, the prevalence of cardioautonomic neuropathy was similar among young men and those > 50 years. However, in women > 50 years, the prevalence of cardioautonomic neuropathy doubled that of young women [45.8% (32.6; 59.7) vs. 20.4% (13.7; 29.2), respectively]. The OR of having cardioautonomic neuropathy was 3.3 higher in women > 50 years than in their younger counterparts. Furthermore, women presented more severe cardioautonomic neuropathy than men. These differences were even more marked when women were classified according their menopausal status instead of age. Peri- and menopausal women had an OR 3.5 (1.7; 7.2) of having CAN compared with their reproductive-aged counterparts [CAN prevalence: 51% (37; 65) vs. 23% (16; 32), respectively]. A binary logistic regression model (R2: 0.161; P = 0.001) displayed age > 50 years as a significant determinant of cardioautonomic neuropathy only in women. Androgens were positively associated with heart rate variability in men, and negatively in women. Accordingly, cardioautonomic neuropathy was associated with increased testosterone/estradiol ratio in women but to decreased testosterone concentrations in men. CONCLUSIONS: Menopause in women with type 1 diabetes is accompanied by an increase in the prevalence of asymptomatic cardioautonomic neuropathy. This age-related excess risk of cardioautonomic neuropathy is not observed in men. Men and women with type 1 diabetes have opposite associations between circulating androgens and indexes of cardioautonomic function. Trial registration ClinicalTrials.gov Identifier: NCT04950634.

Changes in Serum Testosterone and Adrenal Androgen Levels in Transgender Women With and Without Gonadectomy.

BACKGROUND: Initiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy. METHODS: Transgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3 months, 12 months, and 2 to 4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione (A4) were measured using liquid chromatography tandem mass spectrometry. RESULTS: After 3 months of GAHT, mean TT, calculated free testosterone (cFT), and A4 decreased by 18.4 nmol/L (95% CI, -19.4 to -17.4, P < 0.001 [ie, -97.1%]), 383 pmol/L (95% CI, -405 to -362, P < 0.001 [ie, -98.3%]), and 1.2 nmol/L (95% CI, -1.4 to -1.0, P < 0.001 [ie, -36.5%]), respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95% CI, -9.7 to -5.1 [ie, -28.0%]) and 1.8 µmol/L (95% CI, -2.2 to -1.4 [ie, -20.1%]), respectively, after 1 year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS, and A4 compared with those who did not undergo gonadectomy. CONCLUSIONS: Our findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.

Not within spitting distance: Salivary immunoassays of estradiol have subpar validity for predicting cycle phase.

Salivary steroid immunoassays are widely used in psychoneuroendocrinological studies of menstrual cycle phase, puberty, and menopause. Though manufacturers advertise their assays as suitable, they have not been rigorously validated for these purposes. We collated data from eight menstrual cycle studies across > 1200 female participants and > 9500 time points. Seven studies collected saliva and one collected serum. All assayed estradiol and progesterone and had an independent measure of cycle phase (LH-surge, menstrual onset). In serum, cycle phase measures strongly predicted steroid concentrations. In saliva, cycle phase poorly predicted estradiol values, which showed an upward bias compared to expectations from serum. For salivary progesterone, predictability from cycle phase was mixed, low for enzyme-linked assays and moderate for tandem mass spectrometry. Imputing the population-average serum steroid changes from cycle phase may yield more valid values of hormonal changes for an independent person than directly assessing their hormone levels using salivary immunoassays.

Modest Changes in Sex Hormones During Early and Middle Adulthood Affect Bone Mass and Size in Healthy Men: A Prospective Cohort Study.

Bone metabolism in men is in part determined by sex steroid exposure. This is especially clear during puberty and senescence but it remains to be established whether declines in sex steroid levels during young and middle adulthood are associated with changes in bone mass and size. This study investigated changes in bone mineral content (BMC), areal bone mineral density (aBMD), volumetric BMD (vBMD), and bone size in relation to sex steroid levels in 999 young adult men (age 24-46 years) of whom 676 were re-evaluated after a mean period of 12 years. Sex hormone-binding globulin (SHBG) levels were measured using immunoassay, testosterone (T) and estradiol (E2) using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and free fractions were calculated (cFT and cFE2, respectively). Areal bone parameters and BMC were measured at the hip and lumbar spine using dual-energy X-ray absorptiometry (DXA). Radial and tibial vBMD and bone size were determined using peripheral quantitative computed tomography (pQCT). Linear mixed models were used for statistical analyses. With aging, we observed decreases in almost all bone mass and density indices, whereas changes in bone geometry resulted in larger bones with thinner cortices. These changes in bone mass and size appeared related to sex steroid levels. Specifically, decreases in cFT (but not total T) levels were associated with larger decreases in lumbar spine BMC and especially with geometric changes in cortical bone at the tibia. Similarly, decreases in total E2 and cFE2 were associated with larger decreases in bone mass (all sites) and also with some geometric changes. Also increases in SHBG were independently associated with aging-related changes in bone mass and size in these men. In summary, even small changes in T, E2, and SHBG levels during young and middle adulthood in healthy men are associated with changes in bone mass and size. © 2022 American Society for Bone and Mineral Research (ASBMR).

The relationship between circulating hormone levels, bone turnover markers and skeletal development in healthy boys differs according to maturation stage.

INTRODUCTION: This study investigates peri-pubertal changes in bone turnover markers, Wnt-signalling markers, insulin-like growth factor-1 (IGF-1) and sex steroid levels, and how they reflect skeletal development in peri-pubertal boys. MATERIALS AND METHODS: Population-based study in 118 peri-pubertal boys from the NINIOS cohort (age range at baseline 5.1-17.3 years) with repeated measurements at baseline and after two years. Serum levels of the classical bone turnover markers (BTM) procollagen type 1 N-terminal propeptide and carboxy-terminal collagen crosslinks, as well as sex-hormone binding globulin, IGF-1, osteoprotegerin, sclerostin and dickkopf-1 were measured using immunoassays. Sex steroids (estradiol, testosterone, and androstenedione) were measured using mass spectrometry and free fractions calculated. Dual energy x-ray absorptiometry was used for bone measurements at the lumbar spine and whole body. Volumetric bone parameters and bone geometry at the proximal and distal radius were assessed by peripheral QCT. Pubertal development was categorized based on Tanner staging. RESULTS: During puberty, sex steroid and IGF-1-levels along with most parameters of bone mass and bone size increased every next Tanner stage. In contrast, classical bone turnover markers and sclerostin peaked around mid-puberty, with subsequent declines towards adult values in late puberty. Especially classical BTM and sex steroid levels showed consistent associations with areal and volumetric bone parameters and bone geometry. However, observed associations differed markedly according to pubertal stage and skeletal site. CONCLUSION: Serum levels of sex steroids, IGF-1 and bone metabolism markers reflect skeletal development in peri-pubertal boys. However, skeletal development during puberty is nonlinear, and the relations between skeletal indices and hormonal parameters are nonlinear as well, and dependent on the respective maturation stage and skeletal site.

Labile glycated hemoglobin: an underestimated laboratory marker of short term glycemia.

OBJECTIVES: Diabetes mellitus is a major public health problem. Hemoglobin A1c (HbA1c) is a key laboratory parameter in the management of diabetes patients. However, in diabetes monitoring, interpretation of HbA1c results is hampered by the important interindividual variation in red blood cell (RBC) life span. Furthermore, HbA1c only slowly responds to changes in glucose metabolism. Besides HbA1c, there exists a labile HbA1c fraction (l-HbA1c), exhibiting much faster kinetics. As both HbA1c and l-HbA1c are measured by modern standard chromatography, we explored the possibilities of using the l-HbA1c fraction for monitoring glycemia. METHODS: l-HbA1c and HbA1c fractions were simultaneously assayed on a Tosoh G8 analyzer and expressed as %. l-HbA1c results were compared with serum glucose and HbA1c. Concomitantly, RBC distribution width (RDW) was determined on a Sysmex SN analyzer as a marker for erythrocyte life span. RESULTS: l-HbA1c could be measured with between-run coefficient of variations (CVs) between 2.2 and 2.3%. l-HbA1c correlated with both glycemia (r=0.80) and HbA1c results (r=0.73). In a multiple regression model (r2=0.752), glycemia and HbA1c were the most determining factors. To a lesser extent, RDW correlated with l-HbA1c (r=0.158). Furthermore, the l-HbA1c/HbA1c ratio weakly positively correlated with RDW (r=0.247). CONCLUSIONS: L-HBA1c represents an additional marker for monitoring the rapid occurrence of glycemic disorders that escape detection when using only HbA1c and blood glucose. RDW can be used as an indicator of atypical RBCs life span, in which the l-HbA1c fraction may be helpful.

Clinical Value of Serum Levels of 11-Oxygenated Metabolites of Testosterone in Women With Polycystic Ovary Syndrome.

CONTEXT: Recent data suggested that 11-oxygenated androgens may be the preponderant circulating androgens in women with PCOS. However, the pathophysiological significance of these hormones remains unclear. OBJECTIVE: The aim of this study was to evaluate the relationships between serum 11-OH testosterone (11-OHT) and 11-keto testosterone (11-KetoT) and clinical and biochemical hyperandrogenism, as well as the metabolic parameters, in women with PCOS. METHODS: The main classic and 11-oxygenated androgens were measured by LC-MS/MS and direct equilibrium dialysis in 123 women with PCOS, diagnosed according to the Rotterdam criteria, and 38 healthy controls. Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp. RESULTS: Serum 11-oxygenated androgens were higher in women with PCOS than in controls. Elevated levels of 11-OHT and 11-KetoT were found in 28.5% and 30.1% of PCOS women, respectively, whereas free testosterone (FT) was increased in 61.0% of them. Serum 11-oxygenated androgens showed a limited performance in recognizing women with classically defined hyperandrogenism. Unlike FT, 11-oxygenated androgens did not show significant relationships with anthropometric and metabolic parameters, except for a direct association with insulin sensitivity. In multivariable analysis, 11-OHT and 11-KetoT, directly, and FT, inversely, remained significant independent predictors of insulin sensitivity. CONCLUSIONS: Serum levels of 11-oxygenated androgens are higher in women with PCOS than in controls. However, these hormones show a poor performance in recognizing women with hyperandrogenism, as currently defined. The relationships of these androgens with insulin sensitivity strongly differ from that of FT, suggesting a different role of classic and 11-oxygenated androgens in the pathophysiology of PCOS.

Analysis of ergonomic occupational accidents and near misses in a large Belgian university hospital.

INTRODUCTION: Health-care organizations are facing a high burden of ergonomic occupational accidents, and prevention is a continuous point of interest. In this manuscript, we describe the characteristics of ergonomic accidents in a large Belgian university hospital and discuss the value of near misses. METHODS: Combining databases, we identified the frequency [number of accidents × 106 hours worked per year], severity (number of days off work × 103 hours worked per year), and profile of the victims of occupational ergonomic accidents (with absence from work) or incidents or near-misses (without absence from work). Ergonomic accidents and incidents include slips, trips, falls, injurious body movements, overexertion, and handling heavy weights. RESULTS: In a period of 23 years, we noticed a significant decrease in the frequency of ergonomic accidents (from about 7 to about 4 standard units), without changes in the severity. The decrease in the frequency of accidents is mirrored by an increase in the frequency of incidents (from about 4 to about 6 standard units). Female and older employees are more vulnerable to accidents, and the frequency was between two and four times higher for employees mostly involved in manual tasks compared to employees mostly involved in managerial tasks. The profile of the victims and the causes of accidents and incidents were identical. CONCLUSION: Although it is premature to assume a cause-consequence relationship between incidents and accidents, it is tempting to speculate that the increased ratio of the frequencies of incidents over accidents might be one of the variables reflecting the adequacy of preventive measures and the growth of safety behavior.

Insulin-Mediated Substrate Use in Women With Different Phenotypes of PCOS: the Role of Androgens.

CONTEXT: Few studies have explored in vivo insulin action on substrate use in women with PCOS. In particular, no data are available in women with different PCOS phenotypes. OBJECTIVE: The aim of the study was to evaluate insulin action on glucose (Gox) and lipid (Lox) oxidation, nonoxidative glucose metabolism (Gnonox), and serum free fatty acids (FFAs) in different PCOS phenotypes. METHODS: Participants included 187 nondiabetic women with PCOS diagnosed according to the Rotterdam criteria. Data from a historical sample of 20 healthy women were used as reference values. Whole-body substrate use data were obtained by the hyperinsulinemic euglycemic clamp associated with indirect calorimetry. Serum androgens were assessed by liquid chromatography-mass spectrometry and equilibrium dialysis. RESULTS: During hyperinsulinemia, the increase of Gox (ΔGox), Gnonox, as well as the suppression of Lox (ΔLox) and serum FFA (Δ% FFA) were altered in each PCOS phenotype. Moreover, Gnonox and Δ% FFA were lower in women with the classic phenotype than in those with the ovulatory or the normoandrogenic phenotypes, and ΔGox was lower in women with the classic than in those with the ovulatory phenotype. In multivariable analysis fat mass and free testosterone were independent predictors of ΔGox, Gnonox, and Δ% FFA, whereas only fat mass predicted ΔLox. CONCLUSION: In women with PCOS, regardless of phenotype, insulin-mediated substrate use is impaired. This phenomenon is greater in individuals with the classic phenotype. Free testosterone plays an independent role in insulin action abnormalities in glucose and lipid metabolism.

Metabolism of testosterone during weight loss in men with obesity.

OBJECTIVE: Men with obesity often have low total and, with increasing adiposity, also low free testosterone (T) levels, which can partially restore during weight loss. Although this is partly explained by lower sex hormone binding globulin (SHBG) production and hypothalamic-pituitary downregulation, it is still not unravelled whether changes in androgen metabolism contribute to this phenomenon. Therefore, early changes in urinary excretion of T and its metabolites, during weight loss, in men with obesity are investigated. DESIGN: Longitudinal study. METHODS: Fourteen men with obesity (age 52(45-60)years, BMI 42.6(41.8-44.8)kg/m²) underwent gastric bypass surgery (GBS). Before surgery and 3 weeks, 6 weeks, 6 months and 1 year thereafter, 24 h urine and fasting serum samples were collected. Serum T and estradiol (E2) levels were analyzed using LC-MS/MS and urinary metabolites of T with GC-MS/MS. RESULTS: Already three weeks after GBS, serum SHBG and total T levels increased and remained increased as compared to baseline (all,p < 0.0125). Gonadotropins and (free) E2 levels were unchanged, serum E2/T ratio decreased (p < 0.0125). Total amount of urinary T increased non-significantly with mean increases of 53 % one year after GBS (p = 0.026). Urinary E2/T, estrone/T, 3α-androstanediol/T and androsterone/T ratios decreased after GBS (p < 0.0125). CONCLUSIONS: Restoration of circulating T levels during weight loss in this population is not only brought about by normalization of circulating SHBG levels, but increased production of and alterations in T metabolism also contribute. More specifically, relative decreases in aromatization and lower 5α-reductase activity might also be involved in restoring T levels in men with obesity.

Early Decline of Androgen Levels in Healthy Adult Men: An Effect of Aging Per Se? A Prospective Cohort Study.

CONTEXT: Androgen levels have been shown to decline in aging men. However, there is no consensus on the effect of aging, (changes in) body mass index (BMI), lifestyle factors, and intercurrent disease. OBJECTIVE: Investigating longitudinal changes in serum androgen levels in healthy men in relation to body composition, lifestyle factors, and intercurrent disease. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal, population-based sibling pair study at a university research center. 999 healthy men aged 24 to 46 years of whom 691 were reevaluated after a mean period of 12 years. MAIN OUTCOME MEASURES: Serum SHBG, LH, and FSH levels measured using immuno-assays. Testosterone (T), estradiol (E2), dihydro-testosterone (DHT), and androstenedione (Adione) measured using liquid chromatography-tandem mass spectometry, free T calculated (cFT). RESULTS: Baseline age was 34 ±â€…6 years. Mean BMI increased by 1.19 kg/m2, T levels decreased by 14.2% (20.8 nmol/L vs. 17.8 nmol/L), cFT by 19.1% (392 pmol/L vs. 317 pmol/L), DHT by 15.6% (1.5 nmol/L vs.1.3 nmol/L), and Adione by 10.7% (3.7 nmol/L vs. 3.3 nmol/L; all P < 0.001). E2 did not change over time. SHBG increased by 3.0% (39.8 nmol/L vs. 41.0 nmol/L), LH by 5.8% (4.6 U/L vs. 4.9 U/L) and FSH by 14.7% (4.3 U/L vs. 5.1 U/L) (all P < 0.001). For T, cFT, DHT, Adione, and SHBG, these longitudinal changes persisted after adjustment for confounders (all P < 0.001). CONCLUSION: Serum androgen levels start declining early during adult life and independently from changes in BMI and other lifestyle factors, suggesting that aging per se leads to an altered sex steroid status. Given the concurrent rise in gonadotropin levels, the decline in androgen status most likely arises from primary decrease in testicular function.

Serum Androgens Are Independent Predictors of Insulin Clearance but Not of Insulin Secretion in Women With PCOS.

CONTEXT/OBJECTIVE: In insulin-resistant individuals, hyperinsulinemia is a key compensatory mechanism, aimed at maintaining glucose homeostasis. Increased secretion and reduced clearance of insulin may both potentially contribute to this phenomenon. Insulin resistance and hyperinsulinemia are common findings in women with polycystic ovary syndrome (PCOS). While there is some information on insulin secretion, very few studies have investigated metabolic clearance rate of insulin (MCRI) in these women. Moreover, there is paucity of data on the relationships between MCRI and the pathophysiological characteristics of PCOS. The aim of the study was to explore these issues. PATIENTS: One hundred ninety women with PCOS, diagnosed according to the Rotterdam criteria, with normal glucose tolerance. DESIGN: Assessment of MCRI and clinical, hormonal, and metabolic characteristics of subjects. MCRI and insulin sensitivity were measured by the hyperinsulinemic euglycemic clamp. Serum androgens were assessed by liquid chromatography-mass spectrometry and equilibrium dialysis. A historical sample of healthy women was used to define the corresponding reference intervals. RESULTS: MCRI was impaired in about two-thirds of women with PCOS. Subjects with low MCRI differed from those with normal MCRI for a number of anthropometric, metabolic, and endocrine features. In multivariate analysis, the degree of adiposity, estimates of insulin secretion, and serum androgen concentrations were independent predictors of MCRI. Conversely, age, adiposity, MCRI, and insulin sensitivity, but not serum androgens, were independent predictors of insulin secretion. CONCLUSIONS: In women with PCOS, metabolic clearance of insulin is reduced, contributing to generating hyperinsulinemia. Serum androgens are independent predictors of this phenomenon.

A practical approach towards the evaluation of aberrant thyroid function tests.

Objective: To provide insight in patterns and causes of aberrant thyroid function tests (TFT) and to propose a practical approach for clinicians.Methods: Starting from an illustrative case report, an extensive literature search was performed, resulting in a narrative literature review.Results: TFT that cannot be explained by the negative feedback principle of the hypothalamo-pituitary-thyroid axis are a challenge for every clinician. Various alternative explanations for these TFT should be considered before drawing the conclusion of thyroid disorder, since incorrect diagnosis and treatment can have severe consequences for the patient.For example, the combination of elevated or normal TSH with elevated free T4 or T3 levels may result from the use of certain drugs or lab interference, while low or normal TSH with low T3 or T4 can often be explained by non-thyroidal illness or central hypothyroidism due to pituitary failure. Correct identification of these clinical situations requires understanding thyroid hormone metabolism and action, knowledge of some laboratory techniques, and a multistep evaluation process.Conclusion: To avoid incorrect diagnosis and thus treatment, clinicians should be aware of the existence of aberrant TFT and know how to decipher them.

Histologically proven hepatic steatosis associates with lower testosterone levels in men with obesity.

Men with obesity often present with low testosterone (T) and sex hormone-binding globulin (SHBG) levels. Several mechanisms for this have been proposed, but as SHBG is secreted by hepatocytes and sex steroids undergo hepatic metabolization, this study investigates whether severity and histological components of nonalcoholic fatty liver disease (NAFLD) are associated with sex steroid levels in obese men. This cross-sectional study included 80 obese men (age: 46 ± 11 years; body mass index: 42.2 ± 5.5 kg m-2). Serum levels of total T and estradiol (E2) were measured using liquid chromatography coupled with tandem mass spectroscopy (LC/MS-MS) and SHBG and gonadotropins by immunoassay. Liver biopsies were evaluated using Steatosis, Activity, and Fibrosis scoring. Participants with steatohepatitis had similar median (1stquartile-3rd quartile) total T levels (7.6 [5.0-11.0] nmol l-1 vs 8.2 [7.2-10.9] nmol l-1; P = 0.147), lower calculated free T (cFT) levels (148.9 [122.9-188.8] pmol l-1 vs 199.5 [157.3-237.6] pmol l-1; P = 0.006), and higher free E2/T ratios (10.0 [6.4-13.9] x10-3 vs 7.1 [5.7-10.7] x10-3.

The effects of age and obesity on postprandial dynamics of serum testosterone levels in men.

OBJECTIVE: Guidelines recommend using fasting samples to evaluate testosterone (T) levels in men, as free and total T levels decrease postprandially. However, it is not clear whether these dynamics are affected by age or obesity. This could be relevant given the obesity epidemic, ageing population and the barrier for screening which fasting could impose. DESIGN/PARTICIPANTS: A total of 43 men underwent a solid mixed meal tolerance test. Serum samples were taken fasting, and at 30, 60 and 120 minutes postprandially. A commercial immunoassay was used to determine sex hormone-binding globulin (SHBG) levels, liquid chromatography coupled to tandem mass spectroscopy for total T concentrations and free T levels were calculated. RESULTS: Postprandially, both total and free T were lower at all-time points compared with fasting (all, P < .005). At 60 minutes, maximum mean decreases of 15 ± 15% and 17 ± 16% were seen for total and free T levels, respectively. Younger men had greater decreases in both total and free T levels compared with men older than 40 years (all, P < .05). A greater decrease at 30 and 60 minutes postprandially was observed for both total and free T levels in nonobese vs obese men (all, P < .05). CONCLUSIONS: After a mixed meal, total and free T serum levels decreased whereas SHBG levels did not change. Interestingly, postprandial decreases were less pronounced in men older than 40 years and/or with obesity. Although this study indicates less pronounced decreases in certain men, fasting samples remain a prerequisite for establishing correct diagnosis of male hypogonadism.

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.