Article

Calculation of free and bound fractions of testosterone and estradiol-17?? to human plasma proteins at body temperature

July 1982
Journal of Steroid Biochemistry 16(6):801-10

DOI: 10.1016/0022-4731(82)90038-3

Source
PubMed

Project: GABA-A modulating steroids (GAMS) and GABA-A modulating steroid antagonists (GAMSA)

Authors:

Torbjorn C Backstrom

Umeå University

A mathematical model for the calculation of free and protein bound concentrations of testosterone and estradiol in plasma is presented. The method is based on the knowledge of the total concentrations of all steroids competing for the same binding site on testosterone-estradiol-binding globulin (TeBG), the concentration of albumin, the binding capacity of TeBG, and the association constants of the steroids to the two binding proteins. For the calculations we have determined the total concentrations of testosterone and estradiol. TeBG binding capacity, albumin concentration and the association constants for the binding of testosterone, estradiol and 5 alpha-dihydrotestosterone (DHT) to TeBG and albumin at 37 degrees C. Physiological concentrations of some androgen metabolites reported in the literature were also included in the calculations, namely: DHT, 5-androstene-3 beta, 17 beta-diol (Ae) and 5 alpha-androstane-3 alpha, 17 beta-diol (Aa). The binding constants for Ae and Aa to TeBG and albumin were also from the literature. Mean values of testosterone were calculated for 11 normal men and expressed as percentages of total: 2.0% was unbound, 53--55% bound to albumin and 43--45% bound to TeBG. For 16 normal women of a fertile age the corresponding values were 1.5%, 36--37% and 62%. For estradiol they were 2.4% 68--70% and 28--30% in the men and 2.0%, 52% and 45--46% in the women. Variations in the concentrations of DHT. Ae and Aa did not influence the free concentrations of testosterone and estradiol to any significant extent. It was furthermore concluded that the androgen metabolites could be omitted from the calculations without affecting the calculated concentrations.

Estradiol induces Allosteric Coupling and Partitioning of Sex Hormone Binding Globulin Monomers Among Conformational States

Article

Full-text available

Apr 2021

Sex hormone-binding globulin (SHBG) regulates the transport and bioavailability of estradiol. The dynamics of estradiol's binding to SHBG are incompletely understood although it is believed that estradiol binds to each monomer of SHBG dimer with identical affinity (Kd ∼2 nM). Contrary to the prevalent view, we show that estradiol’s binding to SHBG is nonlinear and the "apparent" Kd changes with varying estradiol and SHBG concentrations. Estradiol’s binding to each SHBG monomer influences residues in the ligand binding pocket of both monomers, and differentially alters the conformational and energy landscapes of both monomers. Monomers are not energetically or conformationally equivalent even in fully-bound state. Conclusion: Estradiol’s binding to SHBG involves bidirectional, inter-monomeric allostery that changes the distribution of both monomers among various energy and conformational states. Inter-monomeric allostery offers a mechanism to extend the binding range of SHBG and regulate hormone bioavailability as estradiol concentrations vary widely during life.

Higher testosterone and testosterone/estradiol ratio in men are associated with better epigenetic estimators of mortality risk

Preprint

Full-text available

Feb 2023

Introduction: Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations. Methods: We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort (FHS), the Baltimore Longitudinal Study of Aging (BLSA), and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex hormone concentrations were standardized with mean 0 and standard deviation of 1, for each study and sex separately. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sensitivity analysis was performed excluding the previously used training-set for the development of Pheno and Grim age. Results: Sex Hormone Binding Globulin (SHBG) is associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, 1 SD increase in total testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11). Conclusion: SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1.

Association of sex steroid hormones and new bone formation rate after iliac onlay grafting: a prospective clinical pilot study

Article

Full-text available

Nov 2022

Purpose The present prospective study evaluates the association between new bone formation rate in the iliac onlay graft and sex steroid hormone serum levels. Methods A total of 15 partially or completely edentulous postmenopausal females and 9 males with less than 5 mm height of the remaining alveolar bone underwent iliac onlay grafting followed by dental implant placement using a two-stage approach. Sex hormone binding globulin and 17β-estradiol serum levels were investigated by electrochemiluminescence immunoassay, while total testosterone level was analyzed using radioimmunoassay. At the time of implant placement, 12 weeks after grafting, bone biopsies were obtained and analyzed histomorphometrically. Statistical analysis was performed using linear mixed models. Results Grafting procedure was successfully performed in all patients. The mean new bone formation rate was 32.5% (116 samples). In men the mean new bone formation rate (38.1%) was significantly higher ( p < 0.01) than in women (27.6%). Independent of gender 17β-estradiol and testosterone were positively associated to overall new bone formation rate, albeit a significant influence was only seen for 17β-estradiol in men ( p = 0.020). Sex hormone binding globulin had no influence on new bone formation rate ( p = 0.897). There was no significant association between new bone formation rate and age ( p = 0.353) or new bone formation rate and body mass index ( p = 0.248). Conclusion Positive association of 17ß-estradiol as well as testosterone with new bone formation rate after iliac onlay grafting indicates a role of sex steroid hormones in alveolar bone regeneration, although the observed influence was only significant for 17ß-estradiol in men. Graphical Abstract

Reference Intervals for Free Testosterone in Adult Men Measured Using a Standardized Equilibrium Dialysis Procedure

Article

Oct 2022

Background: Free testosterone (FT) determination may be helpful in evaluating men suspected of testosterone deficiency especially in conditions with altered binding-protein concentrations. However, methods for measuring FT by equilibrium dialysis and reference intervals vary among laboratories. Objective: To determine reference intervals for FT in healthy, nonobese men by age groups as well as in healthy young men, 19-39 years, using a standardized equilibrium dialysis procedure METHODS: We measured FT in 145 healthy, nonobese men, 19 years or older, using a standardized equilibrium dialysis method performed for 16-h at 37°C using undiluted serum and dialysis buffer that mimicked the ionic composition of human plasma. FT in dialysate was measured using a CDC-certified liquid chromatography tandem mass spectrometry assay. Results: In healthy nonobese men, the 2.5th, 10th, 50th, 90th, and 97.5th percentile values for FT were 66, 91, 141, 240, and 309 pg/ml, respectively; corresponding values for men, 19-39 years, were 120, 128, 190, 274, and 368 pg/ml, respectively. FT levels by age groups exhibit the expected age-related decline. FT levels were negatively associated with body mass index, age, and sex hormone-binding globulin (SHBG) levels. Percent FT was lower in middle-aged and older men than young men adjusting for SHBG level. Discussion: Further studies are needed to determine how these reference intervals apply to the diagnosis of androgen deficiency in clinical populations and in men of different races and ethnicities in different geographic regions. Conclusion: Reference intervals for free FT levels (normative range 66-309 pg/ml [229-1072 pmol/L] in all men and 120-368 pg/ml [415-1274 pmol/L] in men, 19-39 years), measured using a standardized equilibrium dialysis method in healthy nonobese men, provide a rational basis for categorizing FT levels. These intervals require further validation in other populations, in relation to outcomes, and in randomized trials.

Associations between endogenous sex hormones and FGF-23 among women and men in the Multi-Ethnic Study of Atherosclerosis

Article

Full-text available

May 2022
PLOS ONE

Elevated levels of testosterone and fibroblast growth factor 23 (FGF-23) are both independently associated with a higher risk of cardiovascular disease (CVD). However, the relationship between sex hormones and FGF-23 is not well established. We explored the association between sex hormones and FGF-23 among middle-aged to older men and women in MESA. We studied 3,052 men and 2,868 postmenopausal women free of CVD at the time of enrollment with baseline serum sex hormones [total testosterone (T), free T, estradiol (E2) and sex hormone binding globulin (SHBG)] and intact FGF-23. In sex-stratified analyses, we examined the cross-sectional associations between log-transformed sex hormones (per 1 SD) and log-transformed FGF-23 using multiple linear regression adjusted for socio-demographics, CVD risk factors, estimated glomerular filtration rate and mineral metabolites (25-hydroxyvitamin D, calcium, phosphorus and parathyroid hormone). The mean (SD) age of study participants was 64 (10) years. The median (IQR) of FGF-23 was similar in women and men [38 (30-46) vs 38 (31-47) pg/mL]. In adjusted analyses, among women, 1 SD increment in free T was associated with 3% higher FGF-23 while SHBG was associated with 2% lower FGF-23. In men, 1 SD increment in E2 was associated with 6% higher FGF-23 whereas total T/E2 ratio was associated with 7% lower FGF-23. In conclusion, this exploratory analysis found that a more androgenic sex hormone profile was directly associated with FGF-23 in women and inversely associated with FGF-23 in men. Longitudinal studies are required to determine whether FGF-23 mediates the relationship between sex hormones and CVD risk.

The Role of Sex Hormones on Bone Mineral Density, Marrow Adiposity, and Muscle Adiposity in Middle-Aged and Older Men Citation

Article

Full-text available

Feb 2022

Purpose The etiology of age-related bone loss is less clear in men. This study is aimed to observe the variations of endogenous sex hormone concentrations with increasing of age in men, and investigate their relations to bone mass, marrow adiposity, and muscle adiposity. Methods A total of 199 community-dwelling Chinese men (aged 41 to 82 years) were included and measured of serum total estradiol, total testosterone, and follicle-stimulating hormone (FSH) concentrations by enzyme-linked immunosorbent assay (ELISA). Vertebral trabecular volumetric bone mineral density (vBMD) was measured by quantitative computed tomography for all participants, and vertebral marrow fat content and erector muscle fat content were quantified by Chemistry-shift-encoding magnetic resonance imaging in 62 participants. Results In this population, FSH concentration increased ( p < 0.001) gradually with aging. Lower vBMD was independently associated with higher FSH concentration (β = -0.216, p < 0.001), but not with total estradiol or total testosterone. For each standard deviation increase in FSH there was a 50% higher risk of an individual having osteopenia or osteoporosis (vBMD < 120 mg/cm ³ ). Marrow fat content and erector muscle fat content were greater in osteopenic and osteoporotic men, but there were no associations with sex hormones concentrations. Conclusion In summary, FSH but not total estradiol or total testosterone is related to vertebral trabecular vBMD in middle-aged and older Chinese men. Neither marrow adiposity nor muscle adiposity is associated with sex hormones.

Androgen Misuse and Abuse

Article

Jan 2021

David J Handelsman

Androgens are potent drugs requiring prescription for valid medical indications but are misused for invalid, unproven, or off-label reasons as well as being abused without prescription for illicit non-medical application for performance or image enhancement. Following discovery and first clinical application of testosterone in the 1930s, commercialisation of testosterone and synthetic androgens proliferated in the decades after World War II. It remains among the oldest marketed drugs in therapeutic use, yet after 8 decades of clinical use the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the male reproductive system. Nevertheless, wider claims assert unproven, unsafe, or implausible benefits for testosterone, mostly representing wishful thinking about rejuvenation. Over recent decades this created an epidemic of testosterone misuse involving prescription as a revitalizing tonic for anti-ageing, sexual dysfunction and/or obesity, where efficacy and safety remains unproven and doubtful. Androgen abuse originated during the Cold War as an epidemic of androgen doping among elite athletes for performance enhancement before the 1980s when it crossed over into the general community to become an endemic variant of drug abuse in sufficiently affluent communities that support an illicit drug industry geared to bodybuilding and aiming to create a hypermasculine body physique and image. This review focuses on the misuse of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription or valid indications, typically by athletes, body-builders and others for image-oriented, cosmetic or occupational reasons.

Sex differences in the associations of body size and body shape with platelets in the UK Biobank cohort

Article

Full-text available

Feb 2023

Background Obesity is accompanied by low-grade inflammation and leucocytosis and increases the risk of venous thromboembolism. Associations with platelet count, however, are unclear, because several studies have reported positive associations only in women. Associations with body shape are also unclear, because waist and hip circumferences reflect overall body size, as well as body shape, and are correlated strongly positively with body mass index (BMI). Methods We evaluated body shape with the allometric body shape index (ABSI) and hip index (HI), which reflect waist and hip size among individuals with the same weight and height and are uncorrelated with BMI. We examined the associations of BMI, ABSI, and HI with platelet count, mean platelet volume (MPV), and platelet distribution width (PDW) in multivariable linear regression models for 125,435 UK Biobank women and 114,760 men. We compared men with women, post-menopausal with pre-menopausal women, and older (≥ 52 years) with younger (< 52 years) men. Results BMI was associated positively with platelet count in women, more strongly in pre-menopausal than in post-menopausal, and weakly positively in younger men but strongly inversely in older men. Associations of BMI with platelet count were shifted towards the inverse direction for daily alcohol consumption and current smoking, resulting in weaker positive associations in women and stronger inverse associations in men, compared to alcohol ≤ 3 times/month and never smoking. BMI was associated inversely with MPV and PDW in pre-menopausal women but positively in post-menopausal women and in men. ABSI was associated positively with platelet count, similarly in women and men, while HI was associated weakly inversely only in women. ABSI was associated inversely and HI positively with MPV but not with PDW and only in women. Platelet count was correlated inversely with platelet size and positively with leucocyte counts, most strongly with neutrophils. Conclusions Competing factors determine the associations of BMI with platelet count. Factors with sexually dimorphic action (likely thrombopoietin, inflammatory cytokines, or cortisol), contribute to a positive association, more prominently in women than in men, while age-dependent factors (likely related to liver damage and fibrosis), contribute to an inverse association, more prominently in men than in women.

Association of total and free testosterone with cardiovascular disease in a nationally representative sample of white, black, and Mexican American men

Article

Full-text available

Dec 2022

Associations of total testosterone (T) and calculated free T with cardiovascular disease (CVD) remain poorly understood. Particularly how these associations vary according to race and ethnicity in a nationally representative sample of men. Data included 7058 men (≥20 years) from NHANES. CVD was defined as any reported diagnosis of heart failure (HF), coronary artery disease (CAD), myocardial infarction (MI), and stroke. Total T (ng/mL) was obtained among males who participated in the morning examination. Weighted multivariable-adjusted logistic regression models were conducted. We found associations of low T (OR = 1.57, 95% CI = 1.17–2.11), low calculated free T (OR = 1.53, 95% CI = 1.10–2.17), total T (Q1 vs Q5), and calculated free T (Q1 vs Q5) with CVD after adjusting for estradiol and SHBG. In disease specific analysis, low T increased prevalence of MI (OR = 1.72, 95% CI = 1.08–2.75) and HF (OR = 1.74, 95% CI = 1.08–2.82), but a continuous increment of total T reduced the prevalence of CAD. Similar inverse associations were identified among White and Mexican Americans, but not Blacks (OR = 0.93, 95% CI = 0.49–1.76). Low levels of T and calculated free T were associated with an increased prevalence of overall CVD and among White and Mexican Americans. Associations remained in the same direction with specific CVD outcomes in the overall population.

Article

Nov 2022

Sleep disruption and circadian disruption have been proposed to be risk factors of breast cancer. The present study examined the associations of sleep-related factors, referring to night shift work, sleep habits, and sleep disturbances, with the plasma levels of sex hormones in premenopausal Japanese women. Study participants were 432 women who had regular menstrual cycles less than 40 days long. Information on their history of night shift work and sleep disturbances was obtained using a self-administered questionnaire. Information on their sleep habits, such as usual wake-up times, bedtimes, and ambient light level while sleeping, was obtained in an interview. The participants’ height and weight were measured. Plasma concentrations of estradiol, testosterone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), FSH, and LH were also measured. After controlling for the phase of the menstrual cycle and other covariates, more years of night shift work ≥ once a week during the past 10 years was significantly associated with a lower SHBG and a higher free estradiol level. Shorter sleep duration was significantly associated with the higher total, bioavailable, and free testosterone levels. Sleep disturbance by awaking after sleep onset was significantly associated with a high free estradiol level. The data suggest that long-term night shift work, short sleep duration, and arousal during sleep are associated with higher estradiol or testosterone levels in premenopausal women.

Diagnosis of hypogonadism in ageing men

Article

Full-text available

Nov 2022
REV ENDOCR METAB DIS

Jean-Marc Kaufman

To make the diagnosis of hypogonadism in an ageing man, in absence of rare organic cause often referred to as functional or late onset hypogonadism (LOH), he should present with a clinical syndrome suggestive of androgen deficiency and have consistently low serum testosterone (T) levels. This does not differ from the diagnosis of any other form of hypogonadism. Particular to LOH diagnostic are uncertainties surrounding this entity: signs and symptoms of androgen deficiency (including sexual symptoms) are nonspecific in older men; clinical significance of only moderately low T levels is uncertain; comorbidity plays a substantial role with potential for reversibility; the place of T therapy in these men is debatable. This context demands for a pragmatic, but appropriately conservative approach to diagnosis. Evaluation should be stepwise with clinical evaluation, if suggestive for androgen deficiency, followed by measurement of a fasting morning serum T, if unequivocally low to be confirmed in a separate morning sample by a second low T or, if initial T borderline low or in presence of factors known to affect SHBG, by a low calculated free T level. All other (free) T results make hypogonadism an unlikely cause of the patient’s symptoms. In the absence of consensus cut-off levels for total and free T in the published clinical guidelines for diagnosis of hypogonadism, it seems appropriate in the context of LOH to use stringent criteria indicating a convincingly low serum T. The approach to the diagnosis of LOH is not fundamentally different from that of other forms of hypogonadism but should put extra weight on prioritizing the shunning of overdiagnosis above the risk of underdiagnosis.

Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology

Article

Full-text available

Oct 2022
CELL MOL LIFE SCI

According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC–MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.

Endogenous Levels of Circulating Androgens Are Not Associated with Risk of Microscopic Colitis

Article

Full-text available

Aug 2022
DIGEST DIS SCI

Background Microscopic colitis is a chronic inflammatory disease that most commonly affects post-menopausal women. Exogenous hormone use has recently been linked with increased risk of microscopic colitis. Yet, it is unclear whether levels of endogenous sex hormones are also associated with risk of microscopic colitis.AimTo evaluate the association between prediagnostic plasma androgens and subsequent risk of microscopic colitis.Methods We conducted a case–control study nested within prospective cohort studies of the Nurses' Health Study (NHS) and NHSII. Cases of microscopic colitis were each matched to two controls according to age, cohort, menopause status, fasting status, and season of plasma collection. Prediagnosis plasma levels of androgens including dehydroepiandrosterone sulfate, testosterone, and sex hormone-binding globulin were measured. We examined the association of each analyte with risk of microscopic colitis using conditional logistic regression models.ResultsOur study included 96 cases of microscopic colitis matched to 190 controls. Plasma levels of testosterone were not associated with risk of microscopic colitis (Ptrend = 0.70). Compared to participants in the lowest quartile of plasma testosterone levels, the aOR of microscopic colitis for women in the highest quartile was 0.88, 95% CI 0.45–1.71. Similarly, we did not observe an association between dehydroepiandrosterone sulfate and sex hormone–binding globulin and risk of microscopic colitis (all Ptrend > 0.52).Conclusion Among women, prediagnostic circulating levels of testosterone, dehydroepiandrosterone sulfate, and sex hormone–binding globulin are not associated with risk of microscopic colitis.

The relationship between 2D:4D ratio and postpartum adult female variables in a Ghanaian population

Article

Full-text available

Sep 2021
AM J HUM BIOL

Objectives: Postpartum hematological and anthropometric assessment is a requirement for optimal maternal and child health. The study aimed to determine the relationship between the 2D:4D ratio and postpartum hematological and anthropometric variables in adult females. Methods: The study was cross-sectional from December 2020 to April 2021 involving 272 postpartum adult females, aged between 18 and 36 years. The right (2D:4DR) and the left (2D:4DL) digit ratios were measured using computer-assisted analysis. Fasting venous samples were collected at a median (interquartile range) of 111 (44-210) days postpartum and analyzed for total testosterone (TT), estradiol, sex hormone-binding globulin, and complete blood count. Results: The mean ± standard deviation 2D:4DR and 2D:4DL were 0.94 ± 0.04 and 0.93 ± 0.04, respectively. As expected, the TT (r = À0.198, p = .015) and the free androgen index (FAI: r = À0.186, p = .019) were inversely correlated with the 2D:4DL while free testosterone (FT%: r = À0.157, p = .038) was inversely correlated with the 2D:4DR. The absolute basophile count (BASO: r = À0.124, p = .040) and the platelet-neutrophil ratio (PLR: r = À0.153, p = .016) were inversely correlated with the 2D:4DL and the 2D:4DR respectively. In addition, the mean cell volume was inversely correlated with the 2D:4DR (r = À0.139, p = .024) and the 2D:4DL (r = À0.122, p = .045). Moreover, the 2D:4DR was inversely correlated with height (r = À0.164, p = .007). Unexpectedly, the red blood cell count (RBC: r = 0.138, p = .025) was positively correlated with the 2D:4DR. Conclusion: There are significant relationships between the 2D:4D ratio and postpartum female variables. These findings are useful preliminary reference data for postpartum research and subsequent 2D:4D ratio studies.

Associations of body shape phenotypes with sex steroids and their binding proteins in the UK Biobank cohort

Article

Full-text available

Jun 2022

Associations of sex steroids and their binding proteins with body shape are unclear, because waist and hip circumference are correlated strongly with body size. We defined body shape using “a body shape index” (ABSI) and hip index (HI), which are independent of weight and height by design, and examined associations in multivariable generalised linear models for the UK Biobank cohort (179,902 men, 207,444 women). Total testosterone was associated inversely with ABSI, especially in men. Free testosterone was lowest for large-ABSI-large-HI (“wide”) and highest for small-ABSI-small-HI (“slim”) in men, but lowest for small-ABSI-large-HI (“pear”) and highest for large-ABSI-small-HI (“apple”) in women. Oestradiol was associated inversely with ABSI in obese pre-menopausal women but positively with HI in obese men and post-menopausal women not using hormone replacement therapy. Sex-hormone binding globulin (SHBG) was associated inversely with ABSI but positively with HI and was lowest for “apple” and highest for “pear” phenotype in both sexes. Albumin was associated inversely with HI in women, but matched the pattern of free testosterone in obese men (lowest for “wide”, highest for “slim” phenotype). In conclusion, sex steroids and their binding proteins are associated with body shape, including hip as well as waist size, independent of body size.

Article

Full-text available

May 2022
BMC Oral Health

Background Sex hormones influence circulation, periodontitis, and wound healing. The aim of the study was to compare the endothelium-dependent and independent vasodilation in human gingiva in men and women. Methods Gingival blood flow was evaluated in twelve male and twelve female subjects with healthy gingiva and no systemic conditions after acetylcholine or nitric oxide donor (NitroPOHL). Agonists were administered into the gingival sulcus at the right secondary incisor (test site). Regional gingival blood flow (GBF) was imaged by Laser Speckle Contrast Imager from the marginal gingiva to the mucogingival junction in four consecutive regions (coronal, midway1, midway2 and apical). Blood flow was expressed in Laser Speckle Perfusion Unit (LSPU). The absolute maximal blood flow change (Dmax), the area under the blood flow curve (AUC), and the time to peak (TTP) were calculated. Results Males had higher baseline GBF than females (257 ± 18.2 vs. 225 ± 18.8 LSPU, p < 0.001). Acetylcholine and NitroPOHL significantly increased the GBF in all test regions. The Dmax after the acetylcholine was reduced apically compared to the coronal (90 ± 13 LSPU vs. 117 ± 7 LSPU, p < 0.01), but it was similar after NitroPOHL (78 ± 9 LSPU vs. 86 ± 6 LSPU, p = 0.398) in both sexes. The Dmax and AUC were higher, and the TTP was smaller in men in most regions after acetylcholine but not after NitroPOHL. Conclusion In the human gingiva, the endothelium-independent vasodilation propagates without attenuation in the line of the vascular supply in both sexes. At the same time, the endothelium-dependent ascending vasodilation attenuates similarly in men and women. However, men had more pronounced endothelium-dependent vasodilation than women. Therefore, it might contribute to the increased severity of periodontal disease in men. Trial registration The study was registered with ClinicalTrials.gov on 09.06.2021 (NCT04918563).

Low testosterone and high cholesterol levels in relation to all-cause, cardiovascular disease, and cancer mortality in White, Black, and Hispanic men: NHANES 1988–2015

Article

Full-text available

Mar 2022

Purpose: The role of testosterone (T) deficiency (T ≤ 300 ng/dL) and hypercholesterolemia (total cholesterol ≥ 240 mg/dL) in the risk of all-cause cardiovascular diseases (CVD) and cancer mortality among a nationally representative sample of non-Hispanic White (NHW), non-Hispanic Black (NHB) and Hispanic men remains poorly understood. Methods: Data included a full sample (NHANES 1988-1991, 1999-2004, 2011-2014) and subset sample (excluding 2011-2012, no estradiol and SHBG levels available) of 5379 and 3740 men, respectively. Participants were aged ≥ 20 y with serum T and cholesterol data (median follow-up 7.6 years). Weighted multivariable-adjusted Cox proportional hazards models were used in this study. Results: In the overall population of full and subset samples, hypercholesterolemia was inversely associated with all-cause (HR = 0.76, 95% CI, 0.63-0.91) and cancer mortality (HR = 0.56, 95% CI, 0.34-0.90). Similar findings were observed among NHW men, but higher T levels increased the risk of CVD mortality in the subset sample (T3 vs T1, Ptrend = 0.02). Among NHB men in the full and subset samples, T deficiency increased the risk of CVD mortality, but T3 vs. T1 decreased it (Ptrend = 0.03), and hypercholesterolemia decreased cancer mortality. Among Hispanic men in the full and subset samples, T deficiency increased, and hypercholesterolemia decreased the risk of CVD mortality. Conclusion: Hypercholesterolemia was inversely associated with cancer mortality. However, higher levels of T were positively associated with CVD mortality among NHW and were inversely associated with CVD mortality among NHB and Hispanic men. Larger prospective studies are warranted to clarify the underlying relationship between T and cholesterol with mortality among racial and ethnic groups.

High-intensity training elicits greater improvements in cardio-metabolic and reproductive outcomes than moderate-intensity training in women with polycystic ovary syndrome: A randomized clinical trial

Article

Mar 2022
HUM REPROD

Study question: Does 12 weeks of high-intensity interval training (HIIT) result in greater improvements in cardio-metabolic and reproductive outcomes compared to standard moderate-intensity continuous training (MICT) in women with polycystic ovary syndrome (PCOS)? Summary answer: HIIT offers greater improvements in aerobic capacity, insulin sensitivity and menstrual cyclicity, and larger reductions in hyperandrogenism compared to MICT. What is known already: Exercise training is recognized to improve clinical outcomes in women with PCOS, but little is known about whether HIIT results in greater health outcomes compared to standard MICT. Study design, size, duration: This was a two-armed randomized clinical trial enrolling a total of 29 overweight women with PCOS between May 2016 and November 2019. Participants/materials, setting, methods: Women with PCOS aged 18-45 years were randomly assigned to 12 weeks of either MICT (60-75% peak heart rate, N = 14) or HIIT (>90% peak heart rate, N = 15), each completed three times per week. The primary clinical outcomes were aerobic capacity (VO2peak) and insulin sensitivity (euglycaemic-hyperinsulinaemic clamp). Secondary outcomes included hormonal profiles, menstrual cyclicity and body composition. Main results and the role of chance: Both HIIT and MICT improved VO2peak (HIIT; Δ 5.8 ± 2.6 ml/kg/min, P < 0.001 and MICT; Δ 3.2 ± 2 ml/kg/min, P < 0.001), however, the HIIT group had a greater improvement in aerobic capacity compared to MICT (β = 2.73 ml/kg/min, P = 0.015). HIIT increased the insulin sensitivity index compared to baseline (Δ 2.3 ± 4.4 AU, P = 0.007) and MICT (β = 0.36 AU, P = 0.030), and caused higher increases in sex hormone-binding globulin compared to MICT (β = 0.25 nmol/l, P = 0.002). HIIT participants were 7.8 times more likely to report improved menstrual cyclicity than those in the MICT group (odds ratio 7.8, P = 0.04). Limitations, reasons for caution: This study has a small sample size and the findings of the effect of the exercise interventions are limited to overweight reproductive-aged women, who do not have any co-existing co-morbidities that require medication. Wider implications of the findings: Exercise, regardless of intensity, has clear health benefits for women with PCOS. HIIT appears to be a more beneficial strategy and should be considered for promoting health and reducing cardio-metabolic risk in overweight women with PCOS. Study funding/competing interest(s): This work was supported by a Project Support Grant from the Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence in PCOS. The authors have no conflicts of interest to disclose. Trial registration number: ACTRN12615000242527. Trial registration date: 19 February 2015. Date of first patient’s enrolment: 27 May 2016.

The role of soy and soy isoflavones on women's fertility and related outcomes: an update

Article

Full-text available

Mar 2022

Soy is a key food in human nutrition. It is widely used in eastern traditional cuisine and it has recently diffused among self-conscious and vegetarian diets. The success of soy mainly depends on versatility and supposed healthy properties of soy foods and soy components. Meanwhile, the possible influence on endocrine system, in particular by isoflavones, raised concerns among some researchers. The present paper aims to conduct a review of available data on the effect of soy, soy foods and soy components on women's fertility and related outcomes. Eleven interventional studies, eleven observational studies and one meta-analysis have been selected from the results of queries. A weak, not clinically relevant effect has been highlighted on cycle length and hormonal status. However, a suggestive positive influence has been shown among women with fertility issues and during assisted reproductive technologies. Overall, soy and soy components consumption do not seem to perturb healthy women's fertility and can have a favourable effect among subjects seeking pregnancy. However, because of the paucity of studies exploring the impact of soy intake on women's fertility, as well as the limited population sample size, the frequently incomplete specimens' collection to investigate all cycle phases and the insufficient characterisation of participants, the evidence is suggestive and it needs further in-depth research taking into account all these aspects.

Associations of endogenous sex hormone levels with the prevalence and progression of valvular and thoracic aortic calcification in the Multi-Ethnic Study of Atherosclerosis (MESA)

Article

Full-text available

Nov 2021
Atherosclerosis

Background and aims Sex hormones (SH) may contribute to sex differences in cardiovascular disease (CVD). High free testosterone (T) and low sex hormone binding globulin (SHBG) have been associated with progression of coronary artery calcification in women. We now examined the association of SH with extra-coronary calcification (ECC) prevalence and progression among MESA participants. Methods We studied 2,737 postmenopausal women and 3,130 men free of clinical CVD with baseline SH levels. ECC measurements [ascending and descending thoracic aortic calcification (ATAC, DTAC), mitral annular calcification (MAC), aortic valve calcification (AVC)] were done by computed tomography at baseline and after 2.4 ± 0.9 years. We used multivariable Poisson regression to evaluate associations with ECC prevalence and incidence (Agatston scores >0) and linear mixed effects models for ECC progression, per 1-SD increment in log(SH) in women and men separately. Results The mean age was 65 ± 9 and 62 ± 10 years for women and men, respectively. In women, greater free T and lower SHBG were associated with MAC incidence in a demographic-adjusted model only. In men, lower free T was associated with MAC prevalence, DTAC incidence and progression, while greater SHBG was associated with MAC prevalence and DTAC progression after further adjusting for CVD risk factors. Conclusions In this diverse cohort free of CVD, we found some associations of SH with ECC measures. In particular, free T was inversely associated with prevalent MAC and DTAC progression in men independent of CVD risk factors. SH may influence vascular calcification, but further work is needed to understand clinical implications of these findings.

Profile of Daughters and Sisters of Women With Polycystic Ovary Syndrome: The Role of Proband’s Glucose Tolerance

Article

Nov 2021

Context First-degree relatives of women with polycystic ovary syndrome (PCOS) present hormonal and metabolic alterations compared to girls unrelated to PCOS. It is unknown whether glucose intolerance in the PCOS proband confers a more severe metabolic predisposition on their first-degree relatives. Objective To determine whether glucose tolerance status in women with PCOS is associated with worsened glucose metabolism and sex hormone levels in their peripubertal daughters or sisters. Design Cross-sectional study. Setting Seven academic centers in North America, South America and Europe. Patients Sixty-four pairs of women with PCOS and their daughters or younger sisters aged between 8 and 14 years were recruited. Twenty-five mothers or older sisters with PCOS were glucose intolerant (GI) and 39 were normal glucose tolerant (NGT). Intervention None. Main Outcome Measures Beta-cell function estimated by the insulin secretion-sensitivity index-2 (ISSI-2) during an oral glucose tolerance test and by the disposition index (DI) during a frequently sampled iv glucose tolerance test. Free testosterone and 17-hydroxyprogesterone (17-OHP) levels. Results Being related to a GI PCOS proband was associated with a lower ISSI-2 (p-value=0.032) after adjusting for ethnicity, body mass index z-score, and pubertal stage. They also had higher free testosterone (p-value=0.011) and 17-OHP levels compared to girls with an NGT proband, the latter becoming significant after adjusting for confounders (p-value=0.040). Conclusions Compared to first-degree female relatives of women with PCOS and NGT, first-degree relatives of women with PCOS and GI display lower beta-cell function and hyperandrogenemia, putting them at higher risk of GI and PCOS development.

Endogenous Circulating Sex Hormone Concentrations and Colon Cancer Risk in Postmenopausal Women: A Prospective Study and Meta-Analysis

Article

Full-text available

Sep 2021

Background Observational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk. However, epidemiological studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results. Methods We investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone binding globulin (SHBG) with colon cancer risk in a nested case–control study of 1,028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were non-current users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided. Results In the multivariable model, a non-statistically significant positive relationship was found between circulating estrone and colon cancer risk (OR per log2-1 unit increment = 1.17, 95%CI = 1.00–1.38; ORquartile4-quartile1 = 1.33, 95%CI = 0.89–1.97, Ptrend = 0.20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol, and estrone concentrations with colorectal, colon, and rectal cancer risk. Conclusion Our observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women.

The relationship between offspring's 2D:4D ratio and postpartum maternal circulating testosterone, estradiol, and their indices in a Ghanaian population

Article

Full-text available

Sep 2021

Objectives The 2D:4D ratio is influenced by prenatal testosterone (PT) and estrogen (PE) exposure in utero. This study sought to determine whether evidence of Manning's hypothesis can still be observed even in the postpartum period. We hypothesize that the offspring 2D:4D ratios will be inversely correlated with maternal postpartum circulating testosterone but positively correlated with estradiol. Methods This study was conducted between December 2020 and April 2021 and was cross-sectional in nature. There were 272 mother-offspring pairs; the mothers were aged between 18 and 36 years while the median (IQR) age of their offspring was 111 (44–210) days. Offspring right (2D:4DR) and left (2D:4DL) digit ratios were measured using computer-assisted analysis. Sampling was done at 111 (44–210) days postpartum and blood was analyzed for total testosterone (TT), estradiol (E2) and sex hormone-binding globulins using the enzyme-linked immunosorbent assay technique. Results The 2D:4DR of sons was significantly lower compared to daughters (p = .031). Mothers with sons had significantly increased levels of serum TT (p = .001) while mothers with daughters had significantly increased levels of E2 (p = .000). As hypothesized, the maternal serum free testosterone (FT%) was inversely correlated with their daughters' (r = −0.320, p = .003), and also with their sons' (r = −0.213, p = .047), 2D:4DL. Unexpectedly, daughters' 2D:4DL was inversely correlated with maternal circulating free E2 (r = −0.255, p = .015). Conclusions In humans, evidence of the relationship between maternal testosterone levels and their offspring's 2D:4D ratio may persist even into the postpartum period.

Development of Polydiacetylene-Based Testosterone Detection as a Model Sensing Platform for Water-Insoluble Hormone Analytes

Article

Full-text available

Jul 2021

We have developed a polydiacetylene (PDA)-based sensing platform to detect testosterone (T) as a potential biomarker of preterm birth. The insolubility of the steroid hormone in water, where PDA assemblies are dispersed, poses a major issue, since they can hardly interact with each other. To overcome this challenge, acetonitrile was used as a suitable solvent. In addition, to minimize false signals of PDA assemblies caused by the solvent, a mixture of acetonitrile and distilled water was selected. To prove a concept of PDA-based sensing platform for targeting T hormone, we conjugated anti-T antibodies to surface of PDA assemblies to induce selective binding between T and anti-T antibodies. The fluorescence sensory signaling of the PDA-anti-T antibody conjugate was selectively generated for T, over 3.4 times higher sensitivity of the signaling compared to that from other sex steroid hormones studied (β-estradiol and progesterone).

The effect of sex hormones on skeletal muscle adaptation in females

Article

Apr 2021

Sex steroids, commonly referred to as sex hormones, are integral to the development and maintenance of the human reproductive system. In addition, male (androgens) and female (estrogens and progestogens) sex hormones promote the development of secondary sex characteristics by targeting a range of other tissues, including skeletal muscle. The role of androgens on skeletal muscle mass, function and metabolism has been well described in males, yet female specific studies are scarce in the literature. This narrative review summarises the available evidence around the mechanistic role of androgens, estrogens and progestogens in female skeletal muscle. An analysis of the literature indicates that sex steroids play important roles in the regulation of female skeletal muscle mass and function. The free fractions of testosterone and progesterone in serum were consistently associated with the regulation of muscle mass, while estrogens may be primarily involved in mediating the muscle contractile function in conjunction with other sex hormones. Muscle strength was however not directly associated with any hormone in isolation when at physiological concentrations. Importantly, recent evidence suggests that intramuscular sex hormone concentrations may be more strongly associated with muscle size and function than circulating forms, providing interesting opportunities for future research. By combining cross-sectional, interventional and mechanical studies, this review aims to provide a broad, multidisciplinary picture of the current knowledge of the effects of sex steroids on skeletal muscle in females, with a focus on the regulation of muscle size and function and an insight into their clinical implications. • Highlights • Free testosterone, but not total testosterone, is associated with lean mass but not strength in pre- and post-menopausal females. • Progesterone and estrogens may regulate muscle mass and strength, respectively, in females. • Intra-muscular steroids may be more closely associated to muscle mass and strength, compared to systemic fractions.

Testosterone Use and Abuse : Methodological Aspects in Forensic Toxicology and Clinical Diagnostics

Book

Full-text available

Mar 2021

Yvonne Lood

Risk of Insulin Resistance and Metabolic Syndrome in Women with Hyperandrogenemia: A Comparison between PCOS Phenotypes and Beyond

Article

Full-text available

Feb 2021

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women, with a wide spectrum of possible phenotypes, symptoms and sequelae according to the current clinical definition. However, there are women who do not fulfill at least two out of the three commonly used “Rotterdam criteria” and their risk of developing type 2 diabetes or obesity later in life is not defined. Therefore, we addressed this important gap by conducting a retrospective analysis based on 750 women with and without PCOS. We compared four different PCOS phenotypes according to the Rotterdam criteria with women who exhibit only one Rotterdam criterion and with healthy controls. Hormone and metabolic differences were assessed by analysis of variance (ANOVA) as well as logistic regression analysis. We found that hyperandrogenic women have per se a higher risk of developing insulin resistance compared to phenotypes without hyperandrogenism and healthy controls. In addition, hyperandrogenemia is associated with developing insulin resistance also in women with no other Rotterdam criterion. Our study encourages further diagnostic and therapeutic approaches for PCOS phenotypes in order to account for varying risks of developing metabolic diseases. Finally, women with hyperandrogenism as the only symptom should also be screened for insulin resistance to avoid later metabolic risks.

Plasma sex hormones and risk of conventional and serrated precursors of colorectal cancer in postmenopausal women

Article

Full-text available

Jan 2021
BMC MED

Background Sex hormones have been suggested to play a role in colorectal cancer (CRC), but their influence on early initiation of CRC remains unknown. Methods We retrospectively examined the associations with risk of CRC precursors, including conventional adenomas and serrated polyps, for plasma estrone, estradiol, free estradiol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and the ratio of estradiol to testosterone among 5404 postmenopausal women from the Nurses’ Health Study I and II. Multivariable logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Given multiple testing, P < 0.005 was considered statistically significant. Results During 20 years of follow-up, we documented 535 conventional adenoma cases and 402 serrated polyp cases. Higher concentrations of SHBG were associated with lower risk of conventional adenomas, particularly advanced adenomas (multivariable OR comparing the highest to the lowest quartile, 0.40, 95% CI 0.24–0.67, P for trend < 0.0001). A nominally significant association was found for SHBG with lower risk of large serrated polyps (≥ 10 mm) (OR, 0.47, 95% CI 0.17–1.35, P for trend = 0.02) as well as free estradiol and free testosterone with higher risk of conventional adenomas (OR, 1.54, 95% CI 1.02–2.31, P for trend = 0.03 and OR, 1.33, 95% CI 0.99–1.78, P for trend = 0.03, respectively). Conclusions The findings suggest a potential role of sex hormones, particularly SHBG, in early colorectal carcinogenesis.

Pubertal Testosterone and the Structure of the Cerebral Cortex in Young Men

Article

Jan 2021
CEREB CORTEX

Adolescence is a period of brain maturation that may involve a second wave of organizational effects of sex steroids on the brain. Rodent studies suggest that, overall, organizational effects of gonadal steroid hormones decrease from the prenatal/perinatal period to adulthood. Here we used multimodal magnetic resonance imaging to investigate whether 1) testosterone exposure during adolescence (9-17 years) correlates with the structure of cerebral cortex in young men (n = 216, 19 years of age); 2) this relationship is modulated by the timing of testosterone surge during puberty. Our results showed that pubertal testosterone correlates with structural properties of the cerebral cortex, as captured by principal component analysis of T1 and T2 relaxation times, myelin water fraction, magnetization transfer ratio, fractional anisotropy and mean diffusivity. Many of the correlations between pubertal testosterone and the cortical structure were stronger in individuals with earlier (vs. later) testosterone surge. We also demonstrated that the strength of the relationship between pubertal testosterone and cortical structure across the cerebral cortex varies as a function of inter-regional profiles of gene expression specific to dendrites, axonal cytoskeleton, and myelin. This finding suggests that the cellular substrate underlying the relationships between pubertal testosterone and cerebral cortex involves both dendritic arbor and axon.

Sexual Dimorphism in Colon Cancer

Article

Full-text available

Dec 2020

A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18–44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.

Visceral Adipose Tissue is Negatively Associated with Bone Mineral Density in NHANES 2011-2018

Article

Full-text available

Jan 2023

Context The relationship of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with bone mineral density (BMD) is not well established. Objective To examine the associations of VAT and SAT with total body BMD in a large, nationally representative population with a wide range of adiposity. Methods We analyzed 10,641 subjects aged 20-59 in NHANES 2011-2018 who had undergone total body BMD and had VAT and SAT measured by DXA. Linear regression models were fitted while controlling for age, gender, race or ethnicity, smoking status, height, and lean mass index. Results In a fully adjusted model, each higher quartile of VAT was associated with an average of 0.22 lower T-score (95% CI -0.26 - -0.17, p < 0.001), while SAT had a weak association with BMD but only in men (-0.10, 95% CI -0.17 - -0.04, p = 0.002). However, the association of SAT to BMD in men was no longer significant after controlling for bioavailable sex hormones. In subgroup analysis, we also found differences in the relationship of VAT to BMD in Black and Asian subjects, but these differences were eliminated after accounting for racial and ethnic differences in VAT norms. Conclusions Visceral adipose tissue has a negative association with BMD. Further research is needed to better understand the mechanism of action and, more generally, to develop strategies for optimizing bone health in obese subjects.

Associations of Sex-related Steroid Hormones and Proteins with Alcohol Dependence: a United Kingdom Biobank Study

Article

Mar 2023
DRUG ALCOHOL DEPEN

Background: Sex-related steroid hormones and proteins may contribute to the sex differences in the characteristics and health consequences of alcohol use disorder. This study aimed to examine the associations between alcohol dependence (AD) and sex-related hormones/proteins using a population-based dataset. Methods: We retrieved serum total testosterone (TT) and estradiol (TE2), sex hormone binding globulin (SHBG), and albumin levels along with clinical data from the UK Biobank. Hormone/protein levels were compared between AD (lifetime AD and/or related diagnoses; 2218 males; 682 females) and control (no aforementioned diagnoses and AUDIT<8; 198,058 males; 250,830 females) groups with sex-dependent linear regression models adjusting for age and body mass index. Moderation and mediation analyses were performed to test whether SHBG was a moderator and/or mediator between hormones and AD or current drinking. Results: AD males had higher TT, TE2, and SHBG levels but lower bioavailable testosterone, bioavailable estradiol, and albumin levels than controls (padjusted<0.001). After adjusting for menopause, AD females had higher TT and lower albumin levels than controls (padjusted<0.001). These differences remained after accounting for current drinking frequency (p < 0.001). SHBG moderated TT's effect on AD in males (pinteraction<0.001). SHBG was a positive mediator between TT and AD in both sexes and between TE2 and AD in males (p < 0.001), but a negative mediator between TT and current drinking in controls (both sexes) and AD males (p < 0.001). Conclusions: Testosterone and estradiol levels are altered in males and females with AD distinctly regardless of current drinking frequency. SHBG may play a critical role in these associations.

Associations between endogenous sex hormone levels and adipokine levels in the Multi-Ethnic Study of Atherosclerosis

Article

Full-text available

Jan 2023

Background Differences in sex hormone levels contribute to differences in cardiovascular disease (CVD) risk. Adipokines play a role in cardiometabolic pathways and have differing associations with CVD. Adipokine levels differ by sex; however, the association between sex hormone profiles and adipokines is not well established. We hypothesized that a more androgenic sex hormone profile would be associated with higher leptin and resistin and lower adiponectin levels among postmenopausal women, with the opposite associations in men. Methods We performed an analysis of 1,811 adults in the Multi-Ethnic Study of Atherosclerosis who had both sex hormones and adipokines measured an average of 2.6 years apart. Sex hormones [Testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA)] were measured at exam 1; free T was estimated. Serum adipokines (leptin, resistin, adiponectin) were measured at exams 2 or 3. We used multivariable linear regression to examine the cross-sectional associations between sex hormones and adipokines. Results The mean (SD) age was 63 (10) years, 48% were women; 59% non-White participants. For leptin, after adjusting for demographics only, higher free T and lower SHBG, were associated with higher leptin in women; this association was attenuated after further covariate adjustment. However in men, higher free T and lower SHBG were associated with greater leptin levels in fully adjusted models. For adiponectin, lower free T and higher SHBG were associated with greater adiponectin in both women and men after adjustment for CVD risk factors. For resistin, no significant association was found women, but an inverse association with total T and bioT was seen in men. Conclusion Overall, these results further suggest a more androgenic sex profile (higher free T and lower SHBG) is associated with a less favorable adipokine pattern. These findings may provide mechanistic insight into the interplay between sex hormones, adipokines, and CVD risk.

Endogenous Steroid Hormone Concentrations and Risk of Endometriosis in the Nurses’ Health Study II

Article

Dec 2022
AM J EPIDEMIOL

Few studies have assessed endogenous steroid hormone levels and subsequent endometriosis diagnosis. We prospectively evaluated premenopausal plasma sex hormone levels and the risk of laparoscopically-confirmed endometriosis in a nested case-control study within the Nurses’ Health Study II. Between blood collection (1996-1999) and 2009, we ascertained 446 women with incident endometriosis and matched them to 878 controls through risk-set sampling. We conducted multivariable conditional logistic regression accounting for matching and confounders to estimate relative risks (RR) and 95% confidence intervals (CI). Women with greater early follicular total or free estradiol levels had a non-linear increased risk of endometriosis (early follicular total estradiol: 2nd quartile vs 1st, RR=2.23(CI=1.44-3.47); 3rd quartile, RR=1.83(CI=1.16-2.88); 4th quartile, RR=1.68(CI=1.05-2.68); early follicular free estradiol: 2nd quartile vs 1st, RR=1.63(CI=1.05-2.54); 3rd quartile, RR=2.02(CI=1.31-3.12); 4th quartile, RR=1.04(CI=0.66-1.65)). Free testosterone assessed in quartile categories was not associated with endometriosis, although a threshold effect was observed with a positive association among women in the top 2% of free testosterone levels. Mid-luteal total and free estradiol, follicular and luteal estrone, total testosterone, progesterone, and sex hormone binding globulin levels were not associated with endometriosis risk. These results support the role of sex steroids in endometriosis etiology, although the relationships suggest complex threshold effects.

Androgens impact on psychopathological variables according to CPRS, and EDI 2 scores: In women with bulimia nervosa, and eating disorder not otherwise specified

Article

Nov 2022
J STEROID BIOCHEM

Bulimia nervosa (BN) is characterized by binge eating, compensatory behavior, over-evaluation of weight and shape, which often co-occur with symptoms of anxiety and depression. Depression is the most common comorbid diagnosis in women with eating disorders. The role of androgens in the pathophysiology of depression has been recognized in recent years. However, the research on psychopathological comorbidity and androgen levels in bulimic disease is sparse. This study aimed to investigate, if there were any correlations between the androgens, testosterone (T), dehydroepiandrosterone sulphate (DHEAS), androstenedione (A4), 5α-dihydrotestosterone, (5α-DHT), and test scores of psychopathological variables, in women with bulimia nervosa (BN), eating disorder not otherwise specified of purging subtype (EDNOS-P) assessed by CPRS, and EDI 2. Women with DSM-IV diagnosis of BN (n = 36), EDNOS-P (n=27), and healthy control subjects (n=58) evaluated for fifteen psychopathological variables, i.a. depressive symptoms, impulsivity, personal traits, as well as serum androgen levels. All women were euthyroid, and polycystic ovarian syndrome (PCOS) diagnosis was excluded. Although androgen levels were almost equal for all three groups, significant correlations between core psychopathological symptoms (9/15) of bulimia nervosa and the most potent endogenous androgen, 5α-DHT, was found only in the EDNOS-P group. The role of 5α-DHT in women is not fully elucidated. Both animal and human studies have shown that the brain is able to locally synthesize steroids de novo and is a target of steroid hormones. Maybe these results can be interpreted in the light of differences in androgen receptor variability, metabolism and origin of T and 5α-DHT.

Parity History and Later Life Sex Hormone Levels in the Multi-Ethnic Study of Atherosclerosis (MESA)

Article

Sep 2022
CAN J CARDIOL

Background Multiparity is a risk factor for cardiovascular disease (CVD). A more androgenic sex hormone profile, with a higher testosterone/estradiol (T/E2) ratio, is associated with worse CVD outcomes in women and may be one mechanism linking multiparity to increased CVD risk. We investigated the relationship between parity and sex hormones at mid-to-older age. Methods We performed a cross-sectional analysis of 2,979 women with data on parity and endogenous sex hormone levels from MESA, a community-based cohort. Parity and gravidity (our exposures) were categorized as 0 (reference), 1-2, 3-4, or ≥5. Our outcome measures were testosterone (T), estradiol (E2), sex-hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), and T/E2 ratio. Progressively-adjusted linear regression was used to evaluate the association of parity/gravidity with sex hormones. Results In multivariable-adjusted models, there were no significant associations of parity with E2, DHEA, and SHBG. Compared to nulliparity, after adjustment for CVD risk factors, women with 1-2 and 3-4 live births had higher T, but this was not significant for grand multiparity (≥5 live births). However, grand multigravidity (≥5 pregnancies) was associated with 10% (95% CI: 1%, 20%) higher T and 14% (1%, 29%) higher T/E2, compared to null-gravidity. Grand multiparity was associated with an 18% (4%, 34%) higher T/E2 ratio compared to nulliparity, after adjustment for CVD risk factors. Conclusions In this multiethnic cohort, women with grand multigravidity and grand multiparity had higher T/E2 levels, reflecting a more androgenic sex hormone profile. Longitudinal studies evaluating sex hormones’ influence on the relationship between multiparity and CVD are warranted.

Androgens in postmenopausal women

Article

Aug 2022

Androgen therapy can improve sexual wellbeing, libido and sexual arousal in postmenopausal women through its effect on the central nervous system. Testosterone levels gradually decline throughout a woman’s lifespan and testosterone therapy may be useful for menopausal women with sexual dysfunction, in whom estrogen therapy alone has been ineffective. To understand the physiology and the potential impact of changes in testosterone levels in postmenopausal women. To be aware of the potential role of androgen therapy in postmenopausal women with low sexual desire causing distress. To review the available evidence behind the use of androgen therapy for female sexual dysfunction in the menopause. More women are spending a greater proportion of their lives in the postmenopausal period, so it is important to gain a greater understanding of the role of testosterone replacement after the menopause in improving sexual dysfunction. Off‐label use of testosterone gels and creams is common; when prescribing these, clinicians must inform women of the potential benefits and risks as well as the fact that long‐term safety data is still lacking.

Association of the vitamin D and parathyroid hormone status with the ageing‐related decline of bone microarchitecture in older men – the prospective STRAMBO study

Article

Jul 2022

Poor vitamin D status and high parathyroid hormone (PTH) level are associated with impaired bone microarchitecture, but these data are mainly cross‐sectional. We studied the association of the baseline PTH and 25‐hydroxycholecalciferol (25OHD) levels with the prospectively assessed deterioration of bone microarchitecture and in estimated bone strength in older men. Distal radius and tibia bone microarchitecture was assessed by high resolution peripheral quantitative computed tomography (HR‐pQCT) at baseline, then after 4 and 8 yrs in 826 men aged 60‐87. At distal radius, total bone mineral density (Tt.BMD), cortical thickness (Ct.Thd), cortical area (Ct.Ar), cortical BMD (Ct.BMD) and trabecular BMD (Tb.BMD) decreased, whereas trabecular area (Tb.Ar) increased more rapidly in men with 25OHD≤20ng/mL vs. the reference group (>30ng/mL). Men with 25OHD≤10ng/mL had faster decrease in reaction force and failure load than men with 25OHD>30ng/mL. At the distal tibia, Tt.BMD, Ct.Thd, Ct.Ar, Ct.BMD, failure load and reaction force decreased, whereas Tb.Ar increased more rapidly in men with 25OHD between 10 and 20 ng/mL versus the reference group. The results were similar when 12ng/mL was used as a threshold of severe vitamin D deficiency. At distal radius, men with PTH levels above the median (>44pg/mL) had more rapid decrease in Tt.BMD, Ct.Ar, Ct.BMD, Ct.Thd, reaction force and failure load, and more rapid increase in Tb.Ar vs. the lowest quartile (≤34pg/mL). At the distal tibia, men in the highest PTH quartile had faster decrease in Tt.BMD, Ct.Thd, Ct.Ar, Ct.BMD, reaction force, and failure load and faster increase in Tb.Ar versus the lowest quartile. The results were similar in men with glomerular filtration rate >60mL/min. The results were similar in men who took no vitamin D or calcium supplements for 8 years. In summary, vitamin D deficiency and secondary hyperparathyroidism are associated with more rapid prospectively assessed cortical and trabecular bone decline in older men. This article is protected by copyright. All rights reserved.

Circulating anti-Müllerian hormone levels and markers of subclinical cardiovascular disease in middle-aged and older men

Article

Jun 2022
MATURITAS

Context Recent research suggests that higher circulating anti-Müllerian hormone (AMH) levels are associated with lower rate of occurrence of (subclinical) cardiovascular disease (CVD) in women, but evidence in men is limited. Objective We investigated whether circulating AMH levels are associated with measures of subclinical CVD in middle-aged and older men. Design Prospective cohort study with a median follow-up time of 8.7 years. Serum AMH was measured at baseline. We assessed both cross-sectional and longitudinal associations using linear regression models adjusted for confounders. Setting Dutch middle-aged and older men from the community. Participants 394 men (aged 40–80 years) with an available AMH measurement at baseline. Main outcome measures At baseline (2001−2002): carotid intima-media thickness (CIMT), pulse wave velocity (PWV), abdominal aortic diameter, and Framingham risk score (FRS) predictions. At follow-up (2010−2011): CIMT, mean carotid aortic plaque score, PWV, and FRS predictions. All outcomes were transformed using rank-based inverse normal transformation to meet the normality assumption. Results Higher AMH levels were associated with lower CIMT at baseline (β = −0.04; 95%CI = 0.07, −0.01), but not with the other baseline measures of subclinical CVD. Longitudinal analyses suggested that higher baseline AMH levels were associated with lower mean plaque scores at follow-up (β = −0.03, 95%CI = −0.07, 0.00), but not with the other follow-up outcomes. Conclusions Our results suggest that AMH is associated with current CIMT and future carotid aortic plaque burden in men, implying that circulating AMH levels are potentially associated with local atherosclerosis rather than with total aortic stiffness.

Correlation between different equations to calculate free testosterone for improved detection of hypogonadism in people living with HIV

Article

Apr 2022

The diagnosis of hypogonadism in people living with HIV (PLWH) remains challenging by the lack of a standardised diagnostic algorithm. Since sexual hormone-binding globulin levels are commonly increased in PLWH, guidelines recommend assessing free testosterone (FT) along with total testosterone levels. We compared different online equations available to estimate FT levels and found a good correlation amongst all algorithms. Estimating FT levels increased diagnostic accuracy of hypogonadism and therefore should be encouraged in clinical practice in PLWH with clinical symptoms of hypogonadism, even when total testosterone levels are normal.

Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never‐smoking women

Article

Mar 2022

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never‐smoking women. A case‐control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Pre‐diagnostic concentrations of sex hormones was quantitated using LC‐MS/MS assays in plasma. The product‐substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable‐adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case‐control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34 to 0.90; Ptrend = 0.03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34 to 0.96; Ptrend = 0.04). This study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never‐smoking women.

Accurate Measurement and Harmonized Reference Ranges for Total and Free Testosterone Levels

Article

Mar 2022
ENDOCRIN METAB CLIN

Diagnosing testosterone deficiency requires accurate and precise measurement of total testosterone levels by an accurate method, such as liquid chromatography-tandem mass spectrometry in a laboratory certified by an accuracy-based program (eg, Centers for Disease Control and Prevention's Hormone Standardization (HoST) Program), and, if needed, free testosterone level. Free testosterone level should ideally be measured by equilibrium dialysis method. Testosterone levels should be measured in 2 or more fasting samples obtained in the morning. Harmonized reference ranges for total testosterone can be applied to laboratories that certified by the HoST Program.

Prevalence of female pattern hair loss in postmenopausal women: a cross-sectional study

Article

Feb 2022

Objective: To identify the prevalence of female pattern hair loss (FPHL), hair characteristics, and associated factors in healthy postmenopausal women. Methods: Two hundred postmenopausal women aged 50 to 65 years were recruited. Each participant was evaluated for FPHL according to Ludwig's classification using standardized global photography in all six views and trichoscopy for hair density and diameter. Three dermatologists re-evaluated all pictures for confirmation of FPHL. The time since menopause, levels of scalp sebum, serum testosterone, estradiol, thyroid stimulating hormone, and hemoglobin; family history of hair loss, as well as an evaluation of low self-esteem were evaluated. Women who underwent recent hair loss treatments were excluded. We used simple and multivariable logistic regression analysis to identify the factors affecting FPHL. Results: In total, 178 postmenopausal women were evaluated for hair-loss patterns. The average age and time since menopause were 58.8±4.1 and 9.2 ± 5.6 years, respectively. The prevalence of FPHL was 52.2% (95% CI, 44.6-59.8). Severity of FPHL by Ludwig grades I, II, and III was 73.2% (95% CI, 62.9-81.8), 22.6% (95% CI, 14.6-32.4), and 4.3% (95% CI, 1.2-10.7), respectively. Logistic regression analysis revealed that age, time since menopause, and body mass index were all significantly associated with FPHL. After adjusting for age and family history of FPHL, only body mass index ≥25 kg/m2 was significantly associated with FPHL (adjusted OR = 2.65, 95% CI, 1.23-5.70). Conclusion: The prevalence of FPHL was high in postmenopausal women, raising the need for hair loss awareness in menopause clinics. Early detection and proper treatment of FPHL may increase the quality of life in postmenopausal women.

Fat Mass Has Negative Effects on Bone, Especially in Men: A Cross-sectional Analysis of NHANES 2011-2018

Article

Feb 2022

Context The effect of high levels of obesity on bone health are not clear. Objective We aimed to examine the associations of body composition and bone mineral density (BMD) in a large, nationally representative population with a wide range of body mass index. Methods We analyzed 10,814 subjects aged 20-59 from NHANES 2011-2018 who had total body BMD and body composition data. Body composition was examined as lean mass index (LMI) and fat mass index (FMI). Linear regression models were created with BMD as the outcome, while examining LMI and FMI and controlling for age, gender, race/ethnicity, height, and smoking status. Results In multivariable modeling, every 1 kg/m 2 additional LMI was associated with 0.19 higher T-score, while every additional 1 kg/m 2 in FMI was associated with 0.10 lower T-score (p<0.001 for both). The negative association of FMI with BMD was mainly seen when adjusting for LMI. Effects of LMI were similar in men and women, but the effect of FMI was more negative in men (0.13 lower T-score per additional 1 kg/m 2 of FMI in men vs. 0.08 lower BMD T-score in women, p-for-interaction<0.001). Conclusions In subjects under 60 years old, lean mass had a strong positive association with BMD. Conversely, fat mass had a moderate, negative association with BMD that was most notable in men at high levels of fat. Our results emphasize the importance of bone health in obesity and may explain site-specific increases in fracture rates in some studies of obese subjects.

The Association Between HIV Status, Estradiol, and Sex Hormone Binding Globulin Among Premenopausal Women in the Women's Interagency HIV Study

Article

Jan 2022

Background: Characterizing estradiol among women with HIV may have implications for breast cancer and cardiovascular disease risk but has not been adequately explored. We quantified differences in total (E2), free (FE2) estradiol, and sex hormone binding globulin (SHBG) by HIV and viral suppression status. Methods: Women from a substudy (2003-2006) within the Women's Interagency HIV Study (IRB approved at each participating site) were included if they reported: a period in the last six months, were not pregnant/breastfeeding, no oophorectomy, and no exogenous hormone use in the prior year. Serum was collected on days 2-4 of the menstrual cycle. We assessed differences in biomarkers at 25th, 50th, and 75th percentiles by HIV and viral suppression status using weighted quantile regression. Results: Among 643 women (68% with HIV) median age was 37 years. All E2 percentiles were significantly (p < 0.05) lower in women with suppressed viral load versus women without HIV (4-10 pg/mL). The 25th and 50th percentile of E2 were 4-5 pg/mL lower in women with unsuppressed viral load compared to women without HIV (p < 0.05). The 25th and 50th percentile of SHBG was significantly higher in women with unsuppressed viral load compared to women without HIV (10 and 12 nmol/L, respectively). There were no consistent differences in estradiol or SHBG by suppression status. Conclusions: There were no differences in FE2 but significantly lower E2 and higher SHBG among women with HIV versus without HIV. Further research is merited in a large contemporary sample to clarify the clinical implications of these findings.

Prevalence of pre-sarcopenia among postmenopausal women younger than 65 years

Article

Oct 2021

Objective: Sarcopenia is associated with high morbidity and mortality in older women. Early detection and intervention during the postmenopausal period were hypothesized to help maintain muscle mass and performance. Although the Asian Working Group has developed guidelines for sarcopenia management, the condition has not been sufficiently investigated in the middle-aged cohort of the Asian population. This study aimed to measure the prevalence of pre-sarcopenia and sarcopenia in middle-aged postmenopausal women and to determine the factors associated with low muscle mass. Methods: In this cross-sectional study conducted in the Menopause Clinic, King Chulalongkorn Memorial Hospital, we used the bioelectrical impedance analysis method to determine the appendicular muscle mass using a body composition analyzer (TANITA MC980 Plus). Appendicular muscle mass index, handgrip strength, and 6-m gait speed were measured in 340 women aged 45 to 65 years. Hormonal profiles, anthropometric data, and relevant history were recorded. Results: The mean age of the study participants and time since menopause were 57.8 ± 4.5 years and 9.4 ± 5.5 years, respectively. The proportion of pre-sarcopenic, sarcopenic, and nonsarcopenic women were 11.8%, 2.7%, and 85.6%, respectively. A body mass index ≤ 20 kg/m2 had the strongest correlation with low muscle mass (odds ratio 7.1; 95% confidence interval 3.0-16.8, P < 0.001). Conclusion: Nearly 12% of Thai middle-aged postmenopausal women were pre-sarcopenic. Early detection of symptoms of pre-sarcopenia and maintenance of a healthy body mass index may reduce the burden of this condition for middle-aged and older women.

Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses

Article

Aug 2021

Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)−1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses. The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR. In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22–1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66–2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67–0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk. Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.

What to Measure: Testosterone or Free Testosterone?

Chapter

Jul 2021

Accurate and precise measurement of serum testosterone is adequate for the diagnosis and monitoring of testosterone replacement for most men with testosterone deficiency. Serum testosterone measurement should be obtained in the morning, preferably in fasting state, and a repeat sample for confirmation is advisable. The sample should be sent to a reliable laboratory that practices accuracy-based proficiency tests or external quality control programs and quotes a reference range of serum testosterone levels of adult men between 250 and 1000 ng/dL (8.7–34.7 nmol/L). The use of free testosterone measurements as a primary diagnostic tool for male hypogonadism has remained controversial. Free testosterone measurements may provide additional information if there are issues with the concentration or the binding of testosterone to sex hormone binding globulin (SHBG). Free testosterone should be measured by equilibrium dialysis which is available in reference laboratories or by calculated free testosterone using formulae that had been validated based on accurate and precise measurements of both testosterone and SHBG. The most common clinical use of free testosterone is for the diagnosis of older men with testosterone deficiency who may be overweight.

Serum Levels of Androgens, Estrogens, and Sex Hormone Binding Globulin and Risk of Primary Gastric Cancer in Chinese Men: A Nested Case-Control Study

Article

Mar 2021

Gastric cancer shows a strong male predominance, and sex steroid hormones have been hypothesized to explain this sex disparity. Previous studies examining the associations between sex hormones and sex hormone binding globulin (SHBG) and risk of gastric cancer come primarily from western populations and additional studies in diverse populations will help us better understand the association. We performed a nested case–control study in Linxian Nutrition Intervention Trials cohorts to evaluate the associations among Chinese men, where we had sufficient cases to perform a well-powered study. Using radioimmunoassays and immunoassays, we quantitated androgens, estrogens, and SHBG in baseline serum from 328 men that developed noncardia gastric cancer and matched controls. We used multivariable unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) and explored interactions with body mass index (BMI), age, alcohol drinking, smoking, and follow-up time. Subjects with SHBG in the highest quartile, as compared with those in the lowest quartile, had a significantly increased risk of gastric cancer (OR = 1.87; 95% CI, 1.01–3.44). We found some evidence for associations of sex steroid hormones in men with lower BMI. Our study found a novel association suggesting that higher serum concentrations of SHBG may be associated with risk of gastric cancer in men. We found no overall associations with sex hormones themselves, but future studies should expand the scope of these studies to include women and further explore whether BMI modifies a potential association. Prevention Relevance It was the first study to investigate the association of gastric cancer with prediagnostic sex steroid hormones and SHBG in an Asian male population. Although there were no overall associations for sex steroid hormone concentrations, higher concentrations of SHBG was associated with increased risk of noncardia gastric cancer.

Pubertal Testosterone and Brain Response to Faces in Young Adulthood: An Interplay between Organizational and Activational Effects in Young Men

Article

Feb 2021

According to the organizational-activational hypothesis, organizational effects of testosterone during (prenatal) brain development moderate activational effects of adult testosterone on behavior. Accumulating evidence supports the notion that adolescence is another period during which sex hormones organize the nervous system. Here we investigate how pubertal sex- hormones moderate the activational effects of adult sex-hormones on social cognition in humans. To do so, we recruited a sample of young men (n=507, ∼ 19 years of age) from a longitudinal birth cohort, and investigated if testosterone exposure during adolescence (from 9 to 17 years of age) moderates the relation between current testosterone and brain response to faces in young adulthood, as assessed with functional magnetic resonance imaging (fMRI). Our results showed that the cumulative exposure to testosterone during adolescence moderated the relation between adult testosterone and both the mean fMRI response and functional connectivity (i.e., node strength). Specifically, in participants with low exposure to testosterone during puberty, we observed a positive relationship between current testosterone and the brain response to faces; this was not the case for participants with medium and high pubertal testosterone. Furthermore, we observed a stronger relationship between the brain response and current testosterone in parts of the angry-face network associated with (vs. without) motion in the eyes region of an observed (angry) face. We speculate that pubertal testosterone modulates the relationship between current testosterone and brain response to social cues carried by the eyes, and signaling a potential threat.SIGNIFICANCE STATEMENTAccumulating evidence supports the organizational effects of pubertal testosterone, but the body of literature examining these effects on social cognition in humans is in its infancy. With a sample of young men from a longitudinal birth cohort, we showed that the cumulative exposure to testosterone during adolescence moderated the relation between adult testosterone and both the mean BOLD signal change and functional connectivity. Specifically, we observed a positive relationship between adult testosterone and the brain response to faces in participants with low exposure to testosterone during puberty, but not in participants with medium and high pubertal testosterone. Results of further analysis suggest that sensitivity to cues carried by the eyes might underlie the relationship between testosterone and brain response to faces, especially in the context of a potential threat.

Isolation and characterization of the testosterone-estradiol-binding globulin from human plasma. Use of a novel affinity column

Article

Full-text available

Dec 1975

This report concerns the purification and characterization of the testosterone-estradiol-binding globulin (TeBG) from human plasma. Cohn fraction IV was submitted sequentially to ammonium sulfate preciptation, affinity chromatography, gel filtration, and isoelectric focusing. The final product was homogeneous in polyacrylamide gel electrophoresis and sodium dodecyl sulfate gel electrophoresis. Its activity was demonstrated by the finding of slightly more than one binding site/mole for dihydrotestosterone. Association constants (M-1) at 4 and 37degreesC were ascertained for three steroids: dihydrotestosterone; 2.4 x 10(9) and 0.99 x 10(9); testosterone, 1.1 x 10(9) and 0.35 x 10(9); estradiol, 0.60 x 10(9) and 0.22 x 10(9). TeBG is a glycoprotein having a molecular weight of 94000 and both the amino acid and carbohydrate content are presented along with other physical properties.

A Further Study of a Testosterone-binding Component of Human Pregnancy Serum

Article

Full-text available

Apr 1969

Equilibrium constants of association were determined by a technique based on the principle of equilibrium dialysis but utilizing Sephadex G-25 for the strong binding exhibited by human pregnancy serum (or by the material precipitated from late pregnancy serum by ammonium sulfate at 50% saturation) for: (a) testosterone-1,2-³H, (b) radioinert 17β-estradiol (in competition with testosterone-1,2-³H), and (c) 17β-estradiol-6,7-³H. The respective values for the intrinsic association constant, k, were all quite high: (a) 4.5 × 10⁸M⁻¹, (b) 1.35 × 10⁸M⁻¹, and (c) 0.4 × 10⁸M⁻¹. These findings are in accord with the view that the testosterone-binding component of pregnancy serum also binds 17β-estradiol but not as strongly. The binding of 17β-estradiol by bovine serum albumin, measured by the same technique, gave nk = 9 × 10⁴M⁻¹. Reagents which react with —SH groups, and other reagents which reduce the disulfide bonds, depressed in striking fashion the testosterone-binding activity of pregnancy serum. It is suggested that the testosterone-binding component contains both cysteine and cystine, and that their maintenance intact is important for steroid-binding activity.

Steroid-Protein Interaction with Particular Reference to Testosterone Binding by Human Serum

Article

Full-text available

Feb 1967

The binding affinity of serum protein for testosterone (and also of serum albumin as a reference protein) was determined by a technique based on the principle of equilibrium dialysis but with the use of the cross-linked dextran, Sephadex G-25, in a batchwise fashion on a semimicro scale. The binding parameters were shown to be dependent on the concentrations of both protein and steroid. The logarithm of the reciprocal of the protein concentration and the logarithm of the reciprocal of the bound steroid concentration (at 50% steroid binding) were in linear relationship. A sensitive and rapid method thus evolved for the detection and quantitative estimation of serum protein, or proteins, exhibiting a specific or high binding affinity for testosterone. This new technique, entailing a novel treatment of the experimental data, may also prove to be useful in the general study of steroid-protein interaction. Testosterone-binding levels in various human sera were determined in a comparative survey; markedly elevated levels were observed in advanced pregnancy.

The attractions of proteins for small molecules and ions

Article

G. Scatchard

Secretion rates of androgens in human subjects

Article

Jan 1969

A. Vermeulen

Multiple Equilibria in Proteins, Molecular Biology

Article

Jan 1969

A paper chromatographic saturation analysis method for measuring estradiol, testosterone and 5alpha-dihydrotestosterone from the same sample

Article

Jan 1976
J STEROID BIOCHEM

Protein-Steroid Interactions and Their Role in the Transport and Metabolism of Steroids

Chapter

Dec 1966

Steroid-protein interactions Complex formation between aj-acid glycoprotein and steroid hormones

Article

Jan 1968
BBA-GEN SUBJECTS

Applied Numerical Analysis

Article

Jan 1978

C.F. Gerald

Capacity of the Testosterone-Binding Globulin in Human Plasma and Influence of Specific Binding of Testosterone on Its Metabolic Clearance Rate

Article

Nov 1969

The binding capacity (TeBC) and binding index (BI) of the testosterone-binding globulin (TeBG) have been studied in several groups of patients. Before puberty, TeBC and BI are similar in both sexes and in the adult female range, but are higher in adult females than in adult males. Increased. TeBC and BI values were observed in male hypogonadism in hyperthyroidism, and in males with chronic asthmatic bronchitis or cirrhosis of the liver. During pregnancy increased TeBC and BI values were observed but at delivery low normal TeBC and BI values were found. Decreased TeBC and BI values were observed in hirsutism, in female obese patients, and in patients with the nephrotic syndrome. Progestogens do not increase TeBC, whereas estrogens (contraceptives) increase significantly the TeBC and BI values; decreased values were observed after testosterone treatment of females; corticoids decrease the TeBC values of patients with chronic asthmatic bronchitis. The metabolic clearance rate (MCR) of testosterone, ...

The Attraction of Proteins for Small Molecules and Ions

Article

Dec 2006
ANN NY ACAD SCI

George Scatchard

Calcium, Phosphate and Albumin in Serum

Article

Jan 1977

ABSTRACT Serum values for calcium, phosphate and albumin have been determined in a population study of 2 322 49–50-year-old men participating in a health examination survey. Calcium and albumin were significantly correlated (r=0.34) but adjustment for albumin only caused minor effects on the distribution of calcium. No inverse relationship was found between calcium and phosphate. Seasonal variations over the three years of the health survey could not be established for either calcium or phosphate, whereas there was a slight tendency for albumin to decline during summer. The prevalence of hyperparathyroidism (HPT) in this population of men up to the age of 50 was 0.3% and among those with recurrent renal stones 5.3%. All subjects with verified HPT had a history of recurrent renal stones. One man on thiazide treatment had a slight elevation of calcium which returned to normal after cessation of the drug. No other case of hypercalcemia besides those caused by HPT was found. Mean values and frequency distributions for calcium, phosphate and albumin were almost identical in renal stone formers and matched controls. Hence it seems likely that other factors than those which markedly affect serum levels of calcium and phosphate are of major importance in common renal stone formation.

Studies on the Protein Binding of Dihydrotestosterone in Human Plasma in Different Physiological Conditions and Effect of Medroxyprogesterone

Article

Feb 1972
STEROIDS

The binding of dihydrotestosterone (DHT) by plasma proteins has been studied by equilibrium dialysis. The effects of time, temperature, pH and dilution are given. The binding of DHT is higher than that of testosterone (T). It has a sex difference in adults, but not in children, and it is increased by estrogens.The apparent association constant (KDHT) of testosterone estradiol binding globulin (Te BG) was estimated, and found identical in children and females (K 37° C: 1.21 to 1.3 × 109 L/M). In contrast the capacity of children plasma was higher than that of adult females. The K 37° C for albumin was similar for human and bovine albumin (KA: 1.5 and 1.6 × 104 L/M).Medroxyprogesterone decreases significantly the percentages binding of T and DHT in girls.

Study of steroid-protein binding by means of competitive adsorption: Application to Cortisol binding in plasma

Article

Dec 1967
CLIN CHIM ACTA

The distribution of a steroid between a solution of steroid-binding proteins and a steroid-adsorbing solid added to this solution, depends not only on the properties of the adsorbent but also on the properties of the binding proteins and thus may be used for the study of steroid-protein interactions. Different types of distribution can be distinguished and were applied to the study of cortisol binding in plasma. 1.(1) Endogenous steroids were removed from plasma by incubation with a rather large amount of adsorbent.2.(2) The cortisol-binding capacity of plasma transcortin was measured after incubation with a balanced amount of adsorbent and cortisol.3.(3) A relative index of cortisol-protein binding proportional to the ratio of bound to unbound cortisol, was determined by incubation of charcoal-treated plasma with a trace of [1,2-3H]cortisol and appropriate amounts of adsorbent.4.(4) From this relative index of cortisol—protein binding in plasma an estimate of the cortisol-binding affinity of plasma transcortin was derived.

Applied Numerical Analysis

Book

Jan 1994

The fifth edition of this book continues teaching numerical analysis and techniques. Suitable for students with mathematics and engineering backgrounds, the breadth of topics (partial differential equations, systems of nonlinear equations, and matrix algebra), provide comprehensive and flexible coverage of numerical analysis.

Methods of multiple steroid radioimmunoassay

Article

Feb 1975

Modifications of partition column chromatography techniques have allowed the simultaneous elution of 7 plasma steroids using celite columns 5 cm. in length. Utilizing specific antisera, blood levels of estradiol17β (E2), progesterone, 17-hydroxy-progesterone, testosterone, androstenedione, dehydroepiandrosterone (DHA) and 5α-dihydrotestosterone (DHT), have been determined in normal men and normal and hirsute women. The results are in close accord to steroid levels found by various investigators using other methods of analysis. The method has considerable advantage over published methods in its versatility and the need for only small blood samples for multiple steroid determinations.

Steroids and the practical aspects of performing binding studies

Article

Jun 1976

Many cellular regulatory processes are described by ligand interactions with macromolecules. Steroid complexing with specific cytoplasmic receptor proteins and the subsequent binding of these complexes to nuclear constituents are two such processes which are fundamental to the understanding of steroid hormone action. These reactions are characterized by the binding parameters k, the equilibrium association constant, and M0, the binding site molarity. The current methods used to determine these two parameters are discussed in relation to the general theory of binding parameter measurement. A number of practical aspects of binding parameter measurement are considered. These include problems encountered by working at dilute non-uniform protein concentrations, non-specific binding, and the limitations of all such experimental systems. An exact solution to the non-linear Scatchard plot is presented for the case when only two non-interacting classes of binding sites need be considered. Finally, a set of specific conclusions is offered which should enable investigators to obtain the most accurate information possible whenever carrying out steroid hormone or receptor binding studies.

Relative Binding of Testosterone and Estradiol to Testosterone-Estradiol-Binding Globulin*

Article

Jan 1980

The binding of estradiol (E2) and testosterone (T) to testosterone-estradiol-binding globulin (TeBG) was studied in vivo at 37 C by three independent methods: equilibrium dialysis, steady state polyacrylamide gel electrophoresis, and TeBG-ligand dissociation kinetics. Equilibrium dialysis was performed at 37 C with the dialysate containing human serum albumin in amounts equivalent to that of the plasma dialysand. Scatchard analysis indicated that under these conditions E2 does not measurably bind to TeBG, while T has a Kd of 3.7 X 10(-10) M. Similarly, Scatchard-type analysis of E2 binding to TeBG in steady state polyacryalmide gel electrophoresis at 37 C revealed no high affinity saturable binding, while dihydrotestosterone was bound with a Kd of 2.7 X 10(-10) M. Examination of the dissociation kinetics of T and E2 ffrom TeBG revealed that the mean (+/-SD) T1/2 of dissociation of T from plasma at 37 C (10.8 +/- 2.4 min) was significantly shortened to 3.5 +/- 0.4 min by saturation of plasma with dihydrotestosterone (P less than 0.01), whereas that of E2 (8.9 +/- 1.4 min) was not changed (9.6 +/- 3.0 min). These data suggest that TeBG is not an important binder of plasma E2 at physiological temperatures and explain the observation that in diseases characterized by high TeBG levels, such as hyperthyroidism and liver disease, the MCR and free E2 levels have generally been normal.

Calcium, phosphate and albumin in serum. A population study with special reference to renal stone formers and the prevalence of hyperparathyroidism in middle aged men

Article

Feb 1977
Acta Med Scand

Serum valuse for calcium, phosphate and albumin have been determined in a population study of 2322 49-50-year-old men participating in a health examination survey. Calcium and albumin were significantly correlated (r = 0.34) but adjustment for albumin only caused minor effects on the distribution of calcium. No inverse relationship was found between calcium and phosphate. Seasonal variations over the three years of the health survey could not be established for either calcium or phosphate, whereas there was a slight tendency for albumin to decline during summer. The prevalence of hyperparathyroidism (HPT) in this population of men up to the age of 50 was 0.3% and among those with recurrent renal stones 5.3%. All subjects with verified HPT had a history of recurrent renal stones. One man on thiazide treatment had a slight elevation of calcium which returned to normal after cessation of the drug. No other case of hypercalcemia besides those caused by HPT was found. Mean values and frequency distributions for calcium, phosphate and albumin were almost identical in renal stone formers and matched controls. Hence it seems likely that other factors than those which markedly affect serum levels of calcium and phosphate are of major importance in common renal stone formation.

Free and Protein-Bound Plasma Estradiol17 During the Menstrual Cycle

Article

Sep 1976

Methods are described for the measurement of the estradiol-binding capacity of TeBG and of the free, TeBG-bound, and non-specifically protein-bound fractions of plasma estradiol. Each determination used undiluted plasma at 37 C, and a total volume of less than 2.0 ml of plasma was required to complete all the assays. The measurement of the per cent of free estradiol was affected by changes in plasma dilution. The measurement of the other fractions of estradiol was not influenced by changes in either the dilution or the volume of plasma. The distribution of plasma estradiol was determined daily throughout 5 individual menstrual cycles. The per cent of free, the per cent of TeBG-bound, and the TeBG binding capacity of estradiol remained constant throughout the cycle with mean values of 2.21 +/- 0.04% (SE), 38.4 +/- 0.7%, and 16.6 +/- 0.43 ng/ml, respectively. The mean association constant of TeBG for estradiol was 6.58 +/- 0.25 x 10(7)M-1. The concentration of the free and non-specifically protein-bound fractions of estradiol paralleled the total plasma concentration of estradiol. The results show that biologic events related to normal cyclic changes of plasma estradiol may be attributed to fluctuations in the free estradiol and to estradiol which is bound with low affinity to non-specific plasma proteins.

Concentration of estradiol, testosterone and progesterone in cerebrospinal fluid compared to plasma unbound and total concentrations

Article

Jun 1976

Estradiol, progesterone and testosterone are measured in plasma and CSF in 17 women and 11 men. The results show a transfer from plasma to CSF of about 4% for estradiol, 10% for progesterone and 2.5% for testosterone. There was found to be a clear correlation between the plasma and CSF levels of these steroids. A comparison is also made between the calculated levels of unbound estradiol and testosterone in plasma and the levels in the CSF. The results show approximately the same concentrations of these steroids in the CSF as the calculated levels of unbound steroids in the plasma.

An assay for sex hormone binding globulin based on affinity chromatography

Article

Jan 1977
CLIN CHIM ACTA

Plasma dihydrotestosterone in normal adult males and its relation to testosterone

Article

Jul 1975
Acta Endocrinol

A radioimmunoassay for dihydrotestosterone (DHT) in plasma was developed using an antiserum raised against testosterone-3-oxime-bovine-serum-albumin. After extraction of 1 ml male plasma with diethylether, DHT was separated from testosterone (T) by thin-layer chromatography. A dextran-charcoal-suspension was used for the separation of bound and free ligand. The inter-assay variability was 10.4 % (C. V.) and the detection limit 1.77 ng/100 ml. The accuracy of the method as determined by mass recoveries and the specificity were shown to be satisfactory. Normal values were obtained in 45 young to middle-aged (22–61 years) and 37 old (68–93 years) men. The median and the 95 percentiles were 20.5– 51.9 –76.3 (ng/100 ml) and 19.5– 50.9 –101.5 (ng/100 ml) respectively. While DHT did not change in old age T fell by 20.6%. DHT and T showed a significant correlation: r S = 0.426, P < 0.01 (young men), r S = 0.752, P < 0.001 (old men). After 3 daily im injections of 5000 IU human chorionic gonadotrophin (HCG), DHT increased 1.50 times (range: 1.15–2.09, n = 12), T 1.86 times (range: 1.20–2.91, n = 12). After 4 daily administrations of 40 mg fluoxymesterone DHT fell to 29.6% of the control level (range: 16.0–48.2%, n = 12). Blood samples were obtained from a 24 year old man every 15 min for 24 h. A close parallelism was observed between the concentrations of DHT and T in the plasma.

Elevated free testosterone in the plasma of early pregnant women bearing male fetuses and of hypersexual men

Article

Aug 1975
Endokrinologie

Significantly elevated free testosterone plasma values were found in early pregnant women (weeks 7 to 10 of pregnancy) bearing male fetuses, as compared wih those bearing female fetuses, and in hypersexual men as compared with normosexual men.

A paper chromatographic saturation analysis method for measuring estradiol, testosterone and 5α-dihydrotestosterone from the same sample

Article

Mar 1976

A new method permitting the estimation of estradiol, testosterone and 5α-dihydrotestosterone in the same plasma sample is presented. This is made possible by a 20 h overflow paper chromatography system used to purify the plasma extract prior to steroid analysis. Estradiol is well separated from estrone as is testosterone from 5α-dihydrotestosterone. The method has low blank values, good agreement between duplicates, acceptable recovery through the extraction and purification and a good recovery of steroids added to plasma prior to extraction. Plasma levels of steroids measured using this method agree well with the values obtained by other methods.

Androstenediol Levels in Human Peripheral Plasma 1 2

Article

Jan 1973

Unconjugated androstenediol has been identified and measured in the plasma of normal adults. Identification of the steroid in ether extracts of plasma was based upon its affinity for “testosterone binding globulin,” chromatographic mobility before and after derivative formation, and identity after acetylation with carrier androstenediol diacetate upon recrystallization. By means of competitive protein binding analysis, peripheral plasma androstenediol levels were determined to be 68.2 ± 24 (sd) ng/100 ml in normal women, 124 ± 45 ng/100 ml in normal men. The androstenediol concentration in men averages twenty percent of the testosterone level, that of women is nearly twice their testosterone level. Since available data indicates that androstenediol is moderately androgenic, this steroid appears to contribute significantly to total androgenicity in women and may play a role in certain hyperandrogenic states.

Sex-Hormone-Binding Globulin is an Oestrogen Amplifier

Article

Dec 1972

WE suggest a novel biological role for a specific plasma-binding protein in the regulation of oestrogen and androgen activity in man. The biological activity of oestradiol and testosterone, as with other steroids1, is probably exerted by the unbound fraction in plasma; this is only 1-3% of the total concentration. The plasma proteins that bind testosterone and oestradiol include sex-hormone-binding β globulin (SHBG)2, which has high affinity for both steroids; and albumin, which has low affinity but is present in three thousand times the concentration. Further, corticosteroid-binding globulin (CBG) binds testosterone3 though its main affinity is for cortisol and progesterone.

Binding of 5 -androstane-3,17 -diol to human plasma proteins

Article

Jun 1973

The binding of 5α androstane 3α,17β diol to human plasma proteins was studied by equilibrium dialysis. The mean value of 96.6% for men was significantly less than that of 97.5% for women. These values are higher than those found for 5α dihydrotestosterone (95.0 and 97.3%, respectively) and for testosterone (92.4 and 95.3%, respectively). When the distribution of labeled steroid in the different protein fractions was studied by paper electrophoresis, male plasma showed a larger fraction of 5α androstane 3α,17β diol radioactivity in the albumin fraction and less in the β globulin area than did female plasma. Similar findings were made when 5α dihydrotestosterone was studied. No inter α globulin peak of radioactivity was found for 5α androstane 3α,17β diol and 5α dihydrotestosterone as occurs for testosterone. Albumin binds more 5α androstane 3α,17β diol than 5α dihydrotestosterone or testosterone when studied by equilibrium dialysis, and this is due to a higher apparent association constant between albumin and the dihydroxysteroid.

Studies on the binding of testosterone to human plasma

Article

Jun 1968
STEROIDS

Binding of testosterone by plasma proteins has been studied by equilibrium dialysis and Sephadex® filtration. Testosterone in human plasma is bound by albumin (K25°C = 2.38 × 104 liter per mole) and by a specific β globulin of limited capacity (capacity = 4 − 6 × 10−8 mole per liter) but high affinity (K25°C = 4 − 16 × 108). Binding capacity increases by estrogen treatment and pregnancy. The testosterone binding globulin is specific for steroids with a 17β hydroxylgroup; as a consequence it also binds oestradiol.

Testosterone, Androstenedione and Dehydroepiandrosterone in Plasma During Pregnancy and at Delivery: Concentration and Protein Binding

Article

Feb 1968

Pregnancy produces a significant (p <0.01) increase in the concentration of testosterone (T) in plasma (nonpregnant females 49 ±13; pregnant females 114 ±38 mμg/100 ml), a nonsignificant increase in the androstenedione (A) concentration (nonpregnant 181 ±59; pregnant 249 ±82 mμg/100 ml) and a nonsignificant decrease in the dehydroepiandrosterone (D) concentration (nonpregnant 502 ±88; pregnant 363 ±233 mμg/100 ml). There was no correlation between fetal sex and maternal concentration of T and D. Mothers bearing a male fetus tended to have Δ values higher than those of mothers bearing a female fetus; the difference, however, was not significant. At delivery, the plasma concentrations of Δ and D were significantly higher than those during pregnancy, while the plasma concentration of T was similar. In every instance, the concentrations of T, Δ and D in the plasma of cord vein were lower than those of the corresponding maternal plasma. There was no correlation between the sex of the newborn and the concentrations of the 3 androgens in the plasma of cord vein. Pregnancy significantly increased the percentage of T-binding and D-binding, but it did not change that of Δ-binding, when using equilibrium dialysis at 37 C, with diluted plasma samples.

Status of Estrogen-Androgen Balance in Hyperthyroid Men with Graves' Disease

Article

Mar 1974

The authors studied the serum concentrations of total testosterone (T), unbound T, dihydrotestosterone (DHT), total estradiol 17β (E2), unbound E2 and luteinizing hormone (LH) in 15 hyperthyroid men with Graves' disease, 4 of whom had gynecomastia. The mean serum T concentration of 1895 ng per 100 ml in hyperthyroid patients was significantly higher than the mean value of 621 in normal men. It could be explained by an increase in serum concentration of sex hormone binding globulin (SHBG) in hyperthyroidism; the mean serum unbound T, 21.9 ng per 100 ml, in hyperthyroid patients was not statistically different from the corresponding value of 17.3 in normal men. Serum DHT concentration was also elevated in hyperthyroid patients. Similarly, the mean serum E2, 10.8 ng per 100 ml, in hyperthyroid men, was significantly greater than the corresponding mean value of 2.7 in normal men. However, it could not be explained entirely by elevation of serum SHBG in hyperthyroidism. The average unbound E2 concentration, 135 pg per 100 ml, in patients under study, was also higher than the corresponding value of 55.6 in normal men; it was comparable to the mean value of 144 in normal women. The ratio of serum total E2 to (E2/T x 100) averaged 0.57 in hyperthyroid men, which did not differ significantly from the mean ratio of 0.43 in normal men. The mean ratio of unbound E2 and unbound T of 0.65 in hyperthyroid men was, however, significantly higher than that of 0.34 in normal men. The mean serum LH concentration was also elevated in hyperthyroid patients. The values of serum T, DHT and unbound T in presence of gynecomastia were not different from those in its absence. However, serum E2, unbound E2, unbound E2/T and LH were significantly higher in patients with gynecomastia than in those without it. It is proposed that alterations in balance between circulating unbound estrogen and unbound androgen may have a significant role in genesis of gynecomastia in hyperthyroidism, and that the combination of the findings of supranormal serum LH, elevated total E2, unbound E2, total T and a normal serum unbound T in hyperthyroid men may be a result of supranormal setting of hypothalamo hypophyseal gonadal axis, presumably due to enhanced production or effectiveness of hypothalamic luteinizing hormone releasing hormone (LHRH) in hyperthyroidism. Normal serum unbound T under these circumstances would suggest some limitation in testicular secretion of T in response to LH in patients with hyperthyroidism.

Plasma concentrations of free and non-TeBG bound T in women on oral contraceptives

Article

Jan 1975
CONTRACEPTION

PIP Differential precipitation of plasma proteins after equilibration of the plasma with tracer amounts of testosterone (T) was used to measure free and not-T-estradiol binding globulin (TeBG)-bound T in 20 women and 10 men. Tritiated T was the tracer used. Comparison of this method with the equilibration dialysis method produced a good agreement in accuracy. The method is described as simple and reproducible, allowing routine assay of 20 plasma samples in duplicate by 1 technician. Normal values for men were 497 ng/100 ml (total T), 42 ng/100 ml(free T), 137 ng/100 ml (non-TeBG bound), and .5 mcg/100 ml (TeBG). Women's values were 52 ng/100 ml (Total T), 2.6 ng/100 ml (free T), 5 ng/100 ml (nonTeBG) and .9 mcg/100 ml (TeBG). Significant increases in total (p less than .05), free (p less than .01), non-TeBG-bound (p less than .05), and TeBG-T (p less than .01) were found for women taking norethindrone and mestranol. Women taking norgestrel-ethinyl estradiol had significant increase (p less than .01) in non-TeBG-bound T. It is concluded that estrogens increase the binding capacity of TeBG, and this is inhibited by norgestrel.

Further Studies on Leydig Cell Function in Old Age

Article

Aug 1974

Pathophysiological mechanisms leading to a decreased Leydig cell function in old males were studied. Increased basal plasma LH and FSH levels, an increased pituitary reaction to LHRH 200 μg iv, and a decreased responsiveness of the Leydig cells to hCG (chorionic gonadotrophin) stimulation, lead to the conclusion that the decreased Leydig cell function in old age has a primary testicular origin. The plasma estrone and estradiol levels are slightly but significantly increased in elderly males; the free estradiol concentration is however unchanged. There exists a highly significant correlation between the (log transformed) apparent free testosterone concentration and LH and FSH levels, suggesting that the feedback of the gonadotropin secretion is regulated via the free rather than via total testosterone levels.

Kinetics of [3H]-testosterone metabolism in normal young men: Effects of medroxyprogesterone acetate (provera) administration

Article

Oct 1972

We studied the effects of oral medroxyprogesterone acetate (provera) administration on the kinetics of testosterone metabolism in normal young men. We investigated changes in the metabolic clearance rate, transport and metabolic rate constants, volumes of distribution, plasma levels, blood production rates and levels of binding to plasma proteins. In all subjects the plasma level and blood production rate for testosterone decreased during provera administration. When provera was administered for 5 days the metabolic clearance rate and volumes of distribution decreased. After 10 days of administration, the changes in the metabolic clearance rate were variable. In the 5 day studies, the levels of binding of testosterone to plasma proteins increased; they showed variable changes after 10 days.

Further studies on the temperature dependence of the binding of testosterone to human pregnancy plasma proteins

Article

Apr 1973
STEROIDS

The binding of testosterone by pregnancy plasma proteins has been studied by a new equilibrium dialysis system. The temperature dependence on the association constant has been investigated and the enthalpy change ΔH and entropy change ΔS have been calculated.By a computer optimization program, the binding constant of the high affinity testosterone binding protein has been estimated from Scatchard plots. The binding reactions were carried out at 5°, 25° and 37° C. The corresponding values were 3.1.10 1.2.109 and 7.2.108 liter/mole. The resulting enthalpy and entropy changes were −2.0 kcal/mole and 35.0 cal/(mole.degree) respectively.It can be concluded that the binding of testosterone to the specific binding protein is an exothermic reaction and is stabilized by hydrophobic binding forces.

The measurement of sex steroid binding globulin by differential ammonium sulphate precipitation

Article

Aug 1973

The binding parameters of the sex steroid binding globulin (SSBG) for testosterone and estradiol have been measured by a method using differential precipitation of plasma proteins by ammonium sulphate. The method is relatively simple and can be applied in a routine manner for the analysis of large numbers of plasma samples. The values for the binding capacity and association constant are similar to those reported for other methods. The method also enables the calculation of the circulating plasma levels of unbound steroids.

A New Method for the Determination of the Binding Capacity of Testosterone-Estradiol-Binding Globulin in Human Plasma

Article

Oct 1973

Vithaldas P. Shanbhag

Calculation of free and bound fractions of testosterone and estradiol-17?? to human plasma proteins at body temperature

Abstract

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