Low Total Testosterone Concentrations Research Articles

Associations between cognitive function and endogenous levels of estradiol and testosterone in adults with Type 2 diabetes?

AbstractBackgroundType 2 diabetes mellitus (T2D) accelerates cognitive decline in women and men. Among older women, prior reports suggest that higher endogenous estradiol levels may further accelerate the cognitive decline associated with T2D and increase risks for cognitive impairment. Testosterone may interact directly with cognitive decline in T2D, or through its conversion to estradiol via the aromatase enzyme.MethodsEstradiol (E2) and total testosterone (TT) concentrations were determined using stored serum from 996 individuals, mean (±SD) age 69±6 and not receiving hormone therapies, collected at two times (averaging 4 years apart). Serum was collected during follow‐up years 8‐18 of the Look AHEAD cohort, a randomized controlled clinical trial of a 10‐year behavioral weight loss intervention in individuals with T2D and overweight or obesity at trial enrollment. One to four standardized assessments of attention, executive function, memory, and verbal fluency were collected during follow‐up years 8‐18. Mixed effects models were used to assess associations that E2 and TT concentrations had with current body mass index (BMI) and cognitive function.ResultsGreater current BMI was associated with higher E2 concentrations in women and men, and greater TT concentrations in women, but lower TT concentrations in men (all p<0.001). The weight loss intervention did not leave a legacy of differences in E2 and TT concentrations. E2 concentrations were not associated with cognitive function in women or men. TT concentrations were not associated with cognitive function in women, but greater TT concentrations were associated with better verbal fluency in men (p<0.001), most strongly among those carrying the APOE‐e4 allele (interaction p = 0.02). While the weight loss intervention left a legacy of relatively lower cognitive functioning among women, this was not mediated by current concentrations of E2 and TT.ConclusionsContrary to prior reports, we found no evidence that higher endogenous E2 concentrations were related to worse cognitive functioning in women with T2D. Higher TT concentrations were associated with better verbal fluency in men, but not women. The legacy of modestly lower cognitive function in women left by a 10‐year weight loss intervention was unrelated to any long‐term alterations in E2 or TT concentrations.

Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men.

The influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria. To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men. Cohort study. UK Biobank prospective cohort. Community-dwelling men aged 40 to 69 years. Testosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors. Of 210700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]). Observational study; single baseline measurement of testosterone and SHBG. Men with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined. Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

Low testosterone is associated with increased risk of major adverse cardiovascular events in smokers with erectile dysfunction

Abstract Purpose Tobacco cigarette smoking and decreased concentrations of testosterone are major risk factors of erectile dysfunction (ED) and independent predictors of cardiovascular disease (CVD). We investigated, whether testosterone deficiency has a complementary predictive value for CVD events in smokers with ED. Methods A cohort of 398 men with ED and without known atherosclerotic CVD (mean age: 55±10 years) were followed for the occurrence of major adverse cardiovascular events (MACE), (CVD death, coronary artery disease, stroke). Total testosterone (TT) levels were measured in all patients. Results Among the study population, 205 (52%) were smokers. During a mean follow-up of 6 years (range: 1–11 years), 30 (7.5%) patients demonstrated a MACE. Baseline TT levels were significantly lower and prevalence of smoking was higher in the CV-event group than the event-free survival group (P<0.01 and P<0.05, respectively). Kaplan–Meier analysis showed that patients with low TT (≤4.0 ng/mL) had a worse prognosis than patients with TT >4.0 ng/mL (log rank: 6.52, P=0.011), and that smokers had a greater risk of adverse events than never smokers (log rank: 4.42, P=0.04). We then stratified all patients into four groups, on the basis of smoking status (current/never smokers) and low or high TT (≤ or >4.0 ng/mL) and cardiac event-free survival curves were constructed by Kaplan–Meier analysis (figure). The event-free rate in smokers with low TT is significantly lower than that of smokers with low TT or never smokers with normal TT (log rank: 11.3, P=0.02). Smokers with low TT had an almost 4-fold higher risk of MACEs compared to never smokers with normal TT (adjusted hazard ratio: 3.91; P=0.030). Conclusion Cigarette smoking combined with low TT concentration is associated with a shorter event-free period compared with either smoking or testosterone deficiency alone. The measurement of testosterone concentration may be useful to further stratify the risk of ED smokers without known CVD. Funding Acknowledgement Type of funding sources: None. Smoking testosterone deficiency and MACE

Pregnancy-related hormones and COMT genotype: Associations with maternal working memory

Women experience different degrees of subjective cognitive changes during pregnancy. The exact mechanism underlying these changes is unknown, although endocrine alterations and genetics may be contributing factors. We investigated whether multiple pregnancy-related hormones were associated with working memory function assessed with the Digit Span Test (DST) in late pregnancy. Moreover, we examined whether the catechol-O-methyltransferase (COMT) genotype, previously related to working memory, was an effect modifier in this association.In this population-based panel study, we recorded psychiatric history, medication use, socio-demographic characteristics, and psychological well-being, gathered blood and saliva samples, and administered the DST at gestational weeks 35–39 (N = 216). We conducted multivariate linear regressions with DST as outcome, with different hormones and COMT genotype, adjusting for covariates including maternal age, BMI, education, depressive symptoms, and parity. We repeated these analyses excluding women with elevated depressive symptoms.Higher DST total scores were associated with increased free estradiol concentrations (B = 0.01, p = 0.03; B = 0.01, p = 0.02) in all participants and in participants without depressive symptoms, respectively, whereas DST forward was positively associated with free estradiol only in women without depressive symptoms (B = 0.01, p = 0.04). Lower total testosterone concentrations (B = −0.03, p = 0.01) enhanced DST backward performance in non-depressed women. Maternal higher education was significantly associated with the DST subscales in all participants. No significant differences emerged when considering the COMT genotype.Our results suggest differential associations of free estradiol and total testosterone levels with working memory function in late pregnancy.

Measurement of Free Testosterone in Serum Using Equilibrium DialysisCoupled With ID-UHPLC-MS/MS: Comparison Between Equilibrium Devices

Free testosterone (FT) has been used as a biomarker in clinical patient care and public health research to assess and manage patients with androgenic abnormalities. The latest Endocrine Society clinical practice guideline for testosterone therapy in men with hypogonadism recommends measuring FT for those with borderline and low total testosterone concentrations, or those who have conditions that change SHBG concentrations, such as some metabolic or hormonal diseases, certain medication use, or SHBG genetic polymorphisms. Measuring FT is technically challenging and shows high variability. The CDC clinical standardization program is developing a high throughput method using the gold-standard equilibrium dialysis (ED) procedure with isotope dilution ultra-high-performance liquid chromatography tandem mass spectrometry (ID-UHPLC-MS/MS).A serum sample was dialyzed against a protein-free HEPES buffer (pH 7.4) at 37 °C until equilibrium. After isolating endogenous FT from protein-bound testosterone by ED, isotope-labeled internal standard (13C3-testosterone) was added to the dialysate for quantification. Certified pure primary reference material (National Measurement Institute M914) was used to prepare calibrators, enabling traceable quantitation and ensuring measurement trueness. FT was further isolated from the dialysate matrix using supported liquid extraction and a chromatographic separation from interfering compounds and quantitation by tandem MS. The dialysis step requires maintaining the endogenous free hormone equilibrium so that results in dialysate reflect FT concentrations in the blood without influence from dilution, temperature, or pH. The dialyzer system has a 1:1 sample-to-buffer volume and has been used in reference measurement procedures for free hormone measurements, serving as the standard for method performance comparison. Four commercially available devices designed for high throughput in a multiple well-plate format, requiring respective sample-to-buffer ratios, were evaluated for their recovery, speed, ease of automation by a liquid handling system, repeatability, and robustness. Preliminary results showed that a device with 1:1 sample-to-buffer volume had the most comparable results to those obtained from the standard dialyzer, with the mean bias less than 15%. The device with the highest sample-to-buffer ratio showed bias as high as 50%. These data suggest that controlling sample-to-buffer ratio is a critical step in ED FT method.

Relationship between Testosterone and Sex Hormone Binding Globulin Concentrations with Cardiometabolic Parameters and Macrovascular Disease in Afro-Caribbean Men with Type 2 Diabetes

Introduction: Low testosterone concentrations have been reported in type 2 diabetes (T2D) and Coronary Artery Disease (CAD). Contrary to diabetes, the prevalence of CAD is lower in Afro-Caribbean (AC) from French West Indies islands than in people from mainland France. However, CAD is a frequent complication of T2D. To evaluate this paradoxical situation, we investigated the prevalence of sex steroids deficiency that might be associated with CAD in AC men with T2D and the relationships with metabolic parameters. Methods: We performed a cross-sectional study in the Department of Diabetology of the University Hospital of Guadeloupe. Clinical and biological data were collected from men with T2D. Total Testosterone (TT) and Sex Hormone Binding Globulin (SHBG) concentrations were measured using electrochemiluminescence and immunoradiometric assays. Results are expressed as mean ± SD or percentages. The data were analyzed using the Mann–Whitney and chi-squared tests, Pearson correlations and logistic regression. P values<0.05 were considered significant. Results: One hundred thirty-three AC men with T2D were included. Prevalence of testosterone deficiency was 43.5%. The mean TT and SHBG concentrations were 12.06 ± 6.24 and 35.9 ± 17.54 nmol/l respectively. Low TT concentrations were more frequently found in obese subjects compared to subjects with normal weight and low SHBG concentrations were high rather in subjects with overweight. Both sex steroids levels were higher in subjects with dyslipidemia than subjects without dyslipidemia. TT deficiency was more frequent in subjects with macrovascular disease including CAD, peripheral artery disease or stroke than subjects without macrovascular disease. Conclusion: Testosterone deficiency and low SHBG concentrations occur frequently in AC men with T2D and are associated with metabolic profile that may promote the development of macrovascular disease. In this population, it may be necessary to systematically apply a testosterone replacement in case of deficiency, to improve cardiometabolic profiles without forget the risk of prostate cancer.

Positive association between testosterone, blood pressure, and hypertension in women

The association between sex hormones and blood pressure (BP) in women has been investigated mostly in cross-sectional studies yielding inconsistent results. Data from 1428 women from the population-based Study of Health in Pomerania were used. Associations of total testosterone, androstenedione, sex hormone-binding globulin (SHBG), and free testosterone concentrations with BP and hypertension were analyzed in multivariable cross-sectional and longitudinal regression models in the full sample and stratified by menopausal status. A positive association between total testosterone and BP was revealed in the full sample [SBP: β per standard deviation (SD) increase: 3.22; pulse pressure (PP): β per SD increase: 2.30] and among postmenopausal women (DBP: β per SD increase: 3.33; SBP: β per SD increase: 7.11; PP: β per SD increase: 3.77). Longitudinal analyses also showed a positive association between baseline total testosterone and follow-up BP. Furthermore, low total testosterone concentrations were associated with a decreased risk of prevalent hypertension in all women [relative risk (RR) quartile 1 (Q1) vs. Q4, 0.79; 95% confidence interval, CI 0.67-0.94]. Low SHBG was associated with prevalent hypertension in postmenopausal women (RR 1.27; 95% CI 1.06-1.53) and with incident hypertension in the full sample (RR 1.73; 95% CI 1.10-2.75). The present population-based study is the first to show a consistent positive association between total testosterone and BP in both, cross-sectional and longitudinal analyses, suggesting high total testosterone as a risk marker of increased BP, as well as prevalent hypertension in women.

Low Testosterone Concentrations in Men Contribute to the Gender Gap in Cardiovascular Morbidity and Mortality

Across the industrialized world, men experience an earlier onset of cardiovascular disease (CVD) and a life expectancy 5 to 10 years shorter than women. Low total testosterone (TT) concentrations in men have been suggested as a novel CVD risk factor, but its contribution to this gender gap is less well studied. We used data of 4152 individuals (2113 women and 2039 men) aged 20 to 79 years from the longitudinal population-based cohort Study of Health in Pomerania, Germany. Multivariable Poisson and Cox proportional hazard regression models were used to investigate the risk of incident cardiovascular morbidity (5-year examination follow-up), as well as all-cause and CVD mortality (10-year follow-up) between men and women. Additionally, the added risk attributable to low TT in men (<10th percentile) was assessed. Compared with women, men were uniformly at higher risk of incident cardiovascular morbidity, including overweight, hypertension, dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus. Men were also at increased all-cause mortality (hazard ratio = 2.05; 95% CI, 1.61-2.60) and 10-year CVD risk compared with women. In subgroup analyses, men with low TT showed the highest 10-year CVD and mortality risk compared with both men with higher TT and women. TT was also negatively associated with cardiovascular risk as defined by the Framingham risk score (P < 0.001), after multivariable adjustment. Analyzing a large population-based sample, we observed that men have a generally higher risk of incident cardiovascular morbidity and mortality. Furthermore, men with low TT concentrations were identified as high-risk individuals with regard to 10-year CVD and mortality risk.

Relationship of sex steroid hormones with body size and with body composition measured by dual-energy X-ray absorptiometry in US men

To evaluate the association of body size-captured via whole-body dual-energy X-ray absorptiometry (DXA) and physical measurement-with serum sex steroid hormones and sex hormone binding globulin (SHBG), we utilized cross-sectional data and serum samples from the National Health and Nutrition Examination Survey (NHANES; 1999-2004). Testosterone, androstanediol glucuronide (3-alpha-diol-G), estradiol, and SHBG were measured via immunoassay in serum samples from a total of 898 adult men (ages 20-90) participating in the morning examination. As part of the NHANES data collection, DXA scans and measurements of weight, height, and waist circumference were performed by trained staff. Linear regression was used to estimate associations between body size and hormone levels adjusted for potential confounders and NHANES sampling procedures. Total bone area (cm(2)) was inversely associated with total testosterone (ng/mL) [beta = -0.12; p value < 0.01], while bone mineral density (g/cm(2)) was inversely associated with SHBG (nmol/L) [beta = -17.16; p value = 0.01]. Increased percent body fat was associated with lower concentrations of total testosterone [beta = -0.16; p value < 0.01] and SHBG [beta = -1.11; p value < 0.01] and higher concentrations of free estradiol (fg/mL) [beta = 12.52; p value < 0.01]. Clinical measures of body fat (measured via DXA scan) and anthropometric measures of body fat (BMI and waist circumference) provided similar inferences regarding the association between increased body fat and hormone levels in men. Increased body fat was associated with lower circulating levels of testosterone (total and free) and SHBG and higher circulating levels of free estradiol in men, while decreased bone mineral density was associated with higher circulating levels of SHBG.

The androgen receptor CAG repeat polymorphism as a risk factor of low serum testosterone and its cardiometabolic effects in men

Previous studies reported correlations of CAG repeat length with sex hormone serum concentrations and cardiometabolic risk factors, but were limited by small cross-sectional samples. We used data of 1859 men aged 20-79 years from the population-based Study of Health in Pomerania (SHIP) to investigate the direct and modulating effects of CAG repeat length on androgen action and cardiometabolic risk factors. We performed cross-sectional and longitudinal linear and Poisson regression models adjusted for age, smoking, physical activity, alcohol consumption and body mass index. The CAG repeat length was categorized into quartiles and low total testosterone (TT) defined according to the age-specific (by decades) 10th percentile, respectively. Age-adjusted cross-sectional linear regression models showed a positive association between CAG repeat length and serum testosterone concentrations [β coefficient for TT, 0.099 (p = 0.028) and for free T, 0.002 (p = 0.001), respectively]. After a 5.0 year median follow-up period, men with CAG repeat length in the lowest quartile had an increased risk of incident low TT concentrations [relative risk (RR), 2.31; 95% confidence interval (CI), 1.18-4.55]. We found no direct association between CAG repeat length and cardiometabolic risk factors in cross-sectional and longitudinal multivariable linear regression analyses; whereas men with longer CAG repeat length and low TT concentrations showed the highest risk of incident MetS (RR, 1.51; 95% CI, 1.05-2.16). CAG repeat length is a risk factor of incident low TT concentrations and a contributing factor of testosterone-related cardiometabolic effects. The added clinical value of a combined assessment of CAG repeat length and serum TT concentrations merits further investigation.

Low Serum Testosterone Is Associated with Increased Mortality in Men with Stage 3 or Greater Nephropathy

Background: Chronic kidney disease (CKD) and low serum total testosterone (TT) concentrations are independent predictors of mortality risk in the general population, but their combined potential for improved mortality risk stratification is unknown. Methods: We used data of 1,822 men from the population-based Study of Health in Pomerania followed- up for 9.9 years (median). The direct effects of kidney dysfunction (estimated glomerular filtration rate <60 ml/min/ 1.73 m²), albuminuria (urinary albumin-creatinine ratio ≧2.5 mg/mmol) and their combination (CKD) on all-cause and cardiovascular mortality were analyzed using multivariable Cox regression models. Serum TT concentrations below the age-specific 10th percentile (by decades) were considered low and were used for further risk stratification. Results: Kidney dysfunction (hazard ratio, HR, 1.40; 95% confidence interval, CI, 1.02–1.92), albuminuria (HR, 1.38; 95% CI, 1.06–1.79), and CKD (HR, 1.42; 95% CI, 1.09–1.84) were associated with increased all-cause mortality risk, while only kidney dysfunction (HR, 2.01; 95% CI, 1.21–3.34) was associated with increased cardiovascular mortality risk after multivariable adjustment. Men with kidney dysfunction and low TT concentrations were identified as high-risk individuals showing a more than 2-fold increased all-cause mortality risk (HR, 2.52; 95% CI, 1.08–5.85). Added to multivariable models, nonsignificant interaction terms suggest that kidney dysfunction and low TT are primarily additive rather than synergistic mortality risk factors. Conclusion: In the case of early loss of kidney function, measured TT concentrations might help to detect high-risk individuals for potential therapeutic interventions and to improve mortality risk assessment and outcome.

Low total testosterone is associated with increased risk of incident type 2 diabetes mellitus in men: results from the Study of Health in Pomerania (SHIP)

Objective. There is increasing evidence suggesting that low total testosterone concentration is associated with incident type 2 diabetes mellitus (T2DM) in men. The aim of this study was to evaluate the association between total testosterone and incident T2DM in a large population-based cohort.Methods. Of 2117 men at baseline, 1589 were followed up 5 years later. Low total testosterone concentration at baseline determined by <10th percentile (10-year age-strata) were used as a risk factor for incident T2DM at follow-up. To evaluate for potential non-response bias, drop out weights were used in sensitivity analysis.Results. From 1339 men eligible for analyses, 68 (5.1%) developed T2DM. Men with low total testosterone concentration had an increased risk of developing T2DM (odds ratio [OR] 3.4, 95% CI 1.9–6.1), even after adjustment for age, waist circumference and smoking, OR 3.0; (95% CI 1.6–5.7). Recalculated weighted models revealed almost identical estimates indicating no relevant non-response bias.Discussion. Our prospective findings suggest that low total testosterone concentration is associated with incident T2DM in men and might represent a biomarker that might causally be involved in the risk of T2DM. This underlines the importance of measuring total testosterone in men as the predominant male sex hormone.

Low total testosterone is associated with increased risk of incident type 2 Diabetes mellitus in men: Results from the Study of Health in Pomerania (SHIP)

Objective. There is increasing evidence suggesting that low total testosterone concentration is associated with incident type 2 diabetes mellitus (T2DM) in men. The aim of this study was to evaluate the association between total testosterone and incident T2DM in a large population-based cohort.Methods. Of 2117 men at baseline, 1589 were followed up 5 years later. Low total testosterone concentration at baseline determined by <10th percentile (10-year age-strata) were used as a risk factor for incident T2DM at follow-up. To evaluate for potential non-response bias, drop out weights were used in sensitivity analysis.Results. From 1339 men eligible for analyses, 68 (5.1%) developed T2DM. Men with low total testosterone concentration had an increased risk of developing T2DM (odds ratio [OR] 3.4, 95% CI 1.9–6.1), even after adjustment for age, waist circumference and smoking, OR 3.0; (95% CI 1.6–5.7). Recalculated weighted models revealed almost identical estimates indicating no relevant non-response bias.Disc...

Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia

Earlier studies have suggested that total testosterone concentrations influence the lipid metabolism. Whether these concentrations are prospectively associated with an adverse lipid profile and an increased risk of incident dyslipidemia has not yet been investigated. Our study population consisted of 1468 men, aged 20–79 years, who were repeatedly examined as part of the population-based Study of Health in Pomerania. Serum total testosterone concentrations measured by the chemiluminescent enzyme immunoassays were categorized into age-specific quartiles. We used generalized estimating equations models to assess the prospective association between total testosterone concentrations and lipid profile components including total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride (TG) concentrations, as well as incident dyslipidemia after 5 years of follow-up. Multivariate models revealed that total testosterone concentrations in the lowest quartile were associated with higher TC and TG concentrations in both cross-sectional [TC: 0.23 mmol/l (95% confidence interval, CI, 0.02–0.42); TG: 0.73 mmol/l (95% CI, 0.53–0.94)] and longitudinal analyses [TC: 0.20 mmol/l (95% CI, 0.03–0.27); TG: 0.62 mmol/l (95% CI, 0.43–0.80)], but not with high-density lipoprotein cholesterol or low-density lipoprotein cholesterol concentrations. Baseline prevalence of dyslipidemia was 57.1% with a crude incidence rate of 46.6 per 1000 person-years. Total testosterone concentrations in the lowest quartile predicted dyslipidemia; age-adjusted relative risks (RR) for men in quartiles 1, 2, and 3 as compared to quartile 4 (highest, reference) were 1.28 (95% CI, 1.06–1.54), 1.10 (95% CI, 0.91–1.33), and 1.05 (95% CI, 0.86–1.29), respectively. This effect was particularly strong among men aged 20–39 years (relative risk, 1.51; 95% CI, 1.08–2.10). Low total testosterone concentrations are prospectively associated with an adverse lipid profile and increased risk of incident dyslipidemia. These findings are particularly interesting and may contribute to an explanation for the higher cardiovascular disease risk in men with lower total testosterone concentrations.

Testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex-hormone-binding globulin in pregnant alcohol abusers

We compared serum concentrations of total and free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), and sex-hormone-binding globulin in 40 pregnant women exhibiting consistent alcohol abuse and in 20 abstinent pregnant controls. Sixteen drinkers gave birth to infants with fetal alcohol effects; the remaining 24 drinkers delivered healthy infants. Drinking patients with healthy infants had normal concentrations of total and free testosterone, sex-hormone-binding globulin, and DHEAS, but their levels of androstenedione increased between weeks 20-40 of pregnancy. Maternal drinking leading to fetal alcohol effects was accompanied by lowered concentrations of sex-hormone-binding globulin throughout pregnancy and by low total testosterone concentrations, although the latter difference reached statistical significance only at 16-20 weeks' gestation. In contrast, drinking leading to fetal damage was associated with higher free testosterone levels between weeks 16-20 of pregnancy and lowered concentrations of DHEAS between weeks 16-32 of gestation, whereas the androstenedione levels tended to be high throughout pregnancy. These changes in androgens can be explained in part by low sex-hormone-binding globulin concentrations, an insufficient supply of DHEAS by the adrenals, and reduced peripheral conversion of androstenedione to testosterone.