The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization.

This study aimed to examine the association between sex hormone-binding globulin (SHBG) and osteoporosis through a cross-sectional study and a two-sample bidirectional Mendelian randomization (MR). We used the National Health and Nutrition Examination Survey (NHANES) 2013-2014 and 2015-2016 data, with exposure as serum SHBG and outcome as osteoporosis and performed multivariate logistic regression to test the correlation between SHBG and osteoporosis. To determine the causal relationship between SHBG and osteoporosis, a two-sample bidirectional MR was employed. The genome-wide association study (GWAS) dataset for SHBG (n = 189,473) was obtained from the IEU database, and the GWAS dataset for osteoporosis (n = 212,778) was obtained from the FinnGen bioBank. The principal MR technique was inverse-variance weighting (IVW). In MR analyses, the MR-Egger intercept and Cochran Q test were used to detect multiple validity and horizontal heterogeneity. 1249 older adult participants (age ≥ 60) were involved in the cross-sectional study, including 113 osteoporosis cases. We identified a significant relationship between circulating SHBG concentration and osteoporosis risk [OR 3.963, 95% CI (2.095-7.495), P < 0.05]. Subgroup analysis indicated that SHBG was closely linked to the risk of osteoporosis in the female population [OR 1.008, 95% CI (1.002-1.013), P = 0.005] but not in males (P = 0.065). In addition, The IVW approach suggested a causal connection between SHBG and increased osteoporosis risk [OR 1.479, 95% CI (1.144-1.912), P = 0.003], and the MR-Egger intercept and the Cochran Q test validated the consistency of the MR results. Finally, the reverse MR analysis declined to identify a causal relation between SHBG and osteoporosis. Our research demonstrates a significant causal connection between circulating SHBG levels and increased osteoporosis risk. These results indicate that high SHBG may be associated with the risk of osteoporosis in postmenopausal women, but more research is needed.

Molecular interactions between sex hormone-binding globulin and nonsteroidal ligands that enhance androgen activity.

Sex hormone-binding globulin (SHBG) determines the equilibrium between free and protein-bound androgens and estrogens in the blood and regulates their access to target tissues. Using crystallographic approaches and radiolabeled competitive binding-capacity assays, we report here how two nonsteroidal compounds bind to human SHBG, and how they influence androgen activity in cell culture. We found that one of these compounds, (-)3,4-divanillyltetrahydrofuran (DVT), present in stinging nettle root extracts and used as a nutraceutical, binds SHBG with relatively low affinity. By contrast, a synthetic compound, 3-(1H-imidazol-1-ylmethyl)-2phenyl-1H-indole (IPI), bound SHBG with an affinity similar to that of testosterone and estradiol. Crystal structures of SHBG in complex with DVT or IPI at 1.71-1.80 Šresolutions revealed their unique orientations in the SHBG ligand-binding pocket and suggested opportunities for the design of other nonsteroidal ligands of SHBG. As observed for estradiol but not testosterone, IPI binding to SHBG was reduced by ∼20-fold in the presence of zinc, whereas DVT binding was almost completely lost. Estradiol-dependent fibulin-2 interactions with SHBG similarly occurred for IPI-bound SHBG, but not with DVT-bound SHBG. Both DVT and IPI increased the activity of testosterone in a cell culture androgen reporter system by competitively displacing testosterone from SHBG. These findings indicate how nonsteroidal ligands of SHBG maybe designed to modulate the bioavailability of sex steroids.

Trends of SHBG and ABP levels in male farmers: Influences of environmental fluoride exposure and ESR alpha gene polymorphisms.

A number of epidemiological studies have reported that chronic exposure to high concentrations of fluoride not only causes dental and skeletal fluorosis but additionally affects serum levels of reproductive hormones. However, possible interaction between fluoride exposure and estrogen receptor alpha (ESRα) gene polymorphisms on sex hormone-binding globulin (SHBG) and androgen binding protein (ABP) of male farmers has not been detailed. Here, we conducted a cross-sectional study including 348 male farmers with different fluoride exposure levels from drinking water in Henan province of China to explore effects of fluoride exposure and ESRα genetic variation on serum SHBG and ABP levels. We found serum SHBG levels in male farmers from the high exposure group to be lower than those of the low exposure group. We also found that concentrations of SHBG affected ABP levels. Furthermore, fluoride exposure and single nucleotide polymorphisms at the XbaI and rs3798577 loci of the ESRα gene affected serum ABP levels. Our findings suggest that chronic fluoride exposure from drinking water is associated with alterations of serum SHBG and ABP concentrations in local male farmers and that the effect of fluoride exposure on ABP levels vary depending on ESRα gene polymorphisms.

Poor levels of agreement between serum and saliva testosterone measurement following exercise training in aging men.

Testosterone (T) is a biologically important androgen that demonstrates a widely-known natural decline with advancing age. The use of salivary T (sal-T), as a determinant of systemic T, has shown promising results in recent years. However, the strength of the salivary-serum T relationship may be affected by measurement method and binding capacity with salivary proteins. The potential influence exercise may impact on this relationship is unstudied in aging men. Therefore, the aim of the present investigation was to examine the relationship of the delta change (Δ) in sal-T with Δserum T following six weeks exercise training. Fifteen sedentary (SED) males (aged 60.4 ± 5.0 years of age) and 20 lifelong exercising (LE) males (60.4 ± 4.7 years of age) were participated. Pearson's correlation coefficient revealed sal-T did not correlate with total testosterone (TT), sex hormone binding globulin (SHBG), bioactive T (bio-T), or free T (free-T) at week 0 or week 6. Δsal-T did not correlate with ΔTT, ΔSHBG, Δbio-T or Δfree-T (r = 0.271, p = 0.180; r = 0.197, p = 0.335; r = 0.258, p = 0.205; and r = 0.257, p = 0.205, respectively). In conclusion, poor levels of agreement existed between saliva and serum measurements of T in response to exercise amongst aging men.

Symptoms and physiological responses to prolonged, repeated, low-level tooth clenching in humans.

BACKGROUND: The traditional view contends bruxism, such as tooth grinding/clenching, is part of the etiology of temporomandibular disorders (TMD) including some subtypes of headaches. The purpose of this study is to investigate if a low-level but long-lasting tooth-clenching task initiates TMD symptoms/signs. METHODS: Eighteen healthy participants (mean age ± SD, 24.0 ± 4.3 years) performed and repeated an experimental 2-hour tooth-clenching task at 10% maximal voluntary occlusal bite force at incisors (11.1 ± 4.6 N) for three consecutive days (Days 1-3). Pain and cardiovascular parameters were estimated during the experiment. RESULTS: The task evoked pain in the masseter/temporalis muscles and temporomandibular joint after 40.0 ± 18.0 minutes with a peak intensity of 1.6 ± 0.4 on 0-10 numerical rating scale (NRS) after 105.0 ± 5.0 minutes (Day 1). On Day 2 and Day 3, pain had disappeared but the tasks, again, evoked pain with similar intensities. The onset and peak levels of pain were not different between the experimental days (P = .977). However, the area under the curve of pain NRS in the masseter on Day 2 and Day 3 were smaller than that on Day 1 (P = .006). Cardiovascular parameters changed during the task but not during the days. CONCLUSIONS: Prolonged, low-level tooth clenching evoked short-lived pain like TMD. This intervention study proposes that tooth clenching alone is insufficient to initiate longer lasting and self-perpetuating symptoms of TMD, which may require other risk factors.

The association between sex hormones and periodontitis among American adults: A cross-sectional study.

Introduction: After adulthood, as a person grows older, the secretion of sex hormones in the body gradually decreases, and the risk of periodontitis increases. But the relationship between sex hormones and periodontitis is still controversial. Methods: We investigated the association between sex hormones and periodontitis among Americans over 30 years old. 4,877 participants containing 3,222 males and 1,655 postmenopausal females who had had periodontal examination and detailed available sex hormone levels, were included in our analysis from the 2009-2014 National Health and Nutrition Examination Surveys cycles. We applied multivariate linear regression models to estimate the connection between sex hormones and periodontitis after converting sex hormones into categorical variables through tertile. Additionally, to ensure the stability of the analysis results, we carried out a trend test, subgroup analysis, and interaction test. Results: After fully adjusting the covariates, estradiol levels were not associated with periodontitis in both males and females with a P for trend = 0.064 and 0.064, respectively. For males, we found that sex hormone-binding globulin was positively associated with periodontitis (tertile3 vs tertile1: OR=1.63, 95% CI=1.17-2.28, p = 0.004, P for trend = 0.005). Congruously, free testosterone (tertile3 vs tertile1: OR=0.60, 95% CI=0.43-0.84, p = 0.003), bioavailable testosterone (tertile3 vs tertile1: OR=0.51, 95% CI=0.36-0.71, p < 0.001), and free androgen index (tertile3 vs tertile1: OR=0.53, 95% CI=0.37-0.75, p < 0.001) was found to be negatively associated with periodontitis. Moreover, subgroup analysis of age found a closer relationship between sex hormones and periodontitis in those younger than 50 years. Conclusion: Our research suggested that males with lower bioavailable testosterone levels affected by sex hormone-binding globulin were at a higher risk of periodontitis. Meanwhile, estradiol levels were not associated with periodontitis in postmenopausal women.

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

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 17ß-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 17ß-estradiol and testosterone were positively associated to overall new bone formation rate, albeit a significant influence was only seen for 17ß-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.

Validating the salivary testosterone and cortisol concentration measures in response to short high-intensity exercise.

AIM: To validate the testosterone (T) and cortisol (C) concentration measures in saliva in response to short high-intensity exercise. METHODS: Nine healthy males provided matching saliva and plasma samples before and after a 30-second Wingate cycle test. Saliva was assayed for T (Sal-T) and C (Sal-C) concentrations, and plasma for total T and total C, sex hormone-binding globulin, corticosteroid-binding globulin (CBG) and albumin concentrations. The plasma free and bioavailable hormones were calculated. RESULTS: The Sal-T and plasma T correlations were weak to moderate (r=0.57-0.61) when examined between individuals (pooled data for all participants), but these relationships improved (r = 0.71-0.73) within individuals (data for each participant on average). The Sal-C and plasma C correlations were strong both between individuals (r=0.81-0.84) and within individuals (r=0.83-0.84). The peak relative increases in Sal-T (35+/-9%) and Sal-C (63+/-29%) concentrations exceeded the plasma total and/or free hormones, but not the bioavailable hormones. Albumin (10+/-3%) and CBG (16+/-4%) also increased with exercise, along with blood lactate (943+/-119%). CONCLUSION: The Sal-T and Sal-C concentration measures were validated in response to short high-intensity exercise, especially for individuals. The hormonal changes in saliva were also more sensitive to exercise (i.e. greater relative responses) than the plasma total and/or free hormones, potentially arising from changes in the binding proteins and blood lactate. These findings support the use of saliva as a medium for steroid determination in sport.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for simultaneous measurement of salivary testosterone and cortisol in healthy men for utilization in the diagnosis of late-onset hypogonadism in males.

It is well known that late-onset hypogonadism in males can cause a variety of symptoms, and the differential diagnosis is relatively difficult, including psychological disorders, stress, and mood disturbances. The level of serum cortisol can be measured to reflect a patient's level of stress. Salivary hormones facilitate the evaluation of physiological hormonal actions based on free hormone assay. For the simultaneous measurement of testosterone and cortisol levels in saliva, we validate a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Concerning accuracy and precision, the lower limit of quantification of salivary testosterone and cortisol were established as 5 and 10 pg/mL, respectively. Testosterone and cortisol in saliva is stable for 2 days, 14 days, and 28 days at room temperature, refrigeration and frozen, respectively. Freezing and thawing for 3 cycles and stimulation of salivation with gum chewing do not alter the measured values of testosterone and cortisol. Total, bioavailable, and free serum testosterone showed slight diurnal changes, but total and bioavailable serum cortisol showed marked diurnal changes. Salivary testosterone levels negatively correlate with age, regardless of the time of saliva collection (r=0.64, p<0.05). However, there is no relationship between salivary cortisol and age (r=0033, p>0.05). LC-MS/MS allows rapid, simultaneous, sensitive, and accurate quantification of testosterone and cortisol in saliva for the diagnosis late-onset hypogonadism or other hormone related disease.

Assessment of free testosterone concentration.

Testosterone (T) is strongly bound to sex hormone binding globulin and measurement of free T may be more appropriate than measuring total serum T, according to the free hormone theory. This view remains controversial and it has its detractors who claim that little extra benefit is gained than simply measuring total T, but it is endorsed by recent clinical practice guidelines for investigation of androgen disorders in both men and women. Free T measurement is very challenging. The gold standard equilibrium dialysis methods are too complex for use in routine clinical laboratories, assays are not harmonized and consequently there are no common reference intervals to aid result interpretation. The algorithms derived for calculating free T are inaccurate because they were founded on faulty models of testosterone binding to SHBG, however they can still give clinically useful results. To negate the effects of differences in binding protein constants, some equations for free T have been derived from accurate measurement of testosterone in large population studies, however a criticism is that the equations may not hold true in different patient populations. The free androgen index is not recommended for use in men because of inaccuracy at extremes of SHBG concentration, and in women it can also give inaccurate results when SHBG concentrations are low. If the free hormone hypothesis is to be believed, then calculated free testosterone may offer the best way forward but better equations are needed to improve accuracy and these should be derived from detailed knowledge of testosterone binding to SHBG. There is still much work to be done to improve harmonization of T and SHBG assays between laboratories because these can have a profound effect on the equations used to calculate free testosterone.

Evaluation of occupational physical load during 6-month international crisis management operation.

OBJECTIVES: Generally, operational military duties are associated with a variety of stressors, such as prolonged physical activity (PA). However, limited information is available on the occupational workload or changes in PA during international military operations. Thus, the aim of the study was to investigate the changes in body composition, stress biomarkers, PA, and heart rate (HR) responses of 79 male soldiers during a 6-month international crisis management operation. MATERIAL AND METHODS: Measurements were conducted 3 times in South-Lebanon during the operation. Body composition was assessed by the bioelectrical impedance method. Blood samples were analyzed for serum testosterone, sex-hormone binding globulin (SHBG), cortisol and insulin-like growth factor. Saliva sampling was used for analyzing stress biomarkers, cortisol and α-amylase. Heart rate and physical activity were monitored by a recordable belt and tri-axial accelerometer, respectively. RESULTS: Increases in muscle mass (39.2±4.1 vs. 39.5±4.2 kg, p < 0.05) and testosterone (15.9±4.6 vs. 17.2±4 nmol/l, p < 0.01), and reductions in PA variables (e.g., daily step count 9472±2547 vs. 8321±2720, p < 0.05) were observed during the first half (i.e., PRE-MID) of the study. The increase in muscle mass remained significant during the latter half (PRE-POST, 39.2±4.1 vs. 39.6±4.4 kg, p < 0.05), but also fat mass increased (MID-POST, 10.6±4.6 vs. 11.0±4.7 kg, p < 0.05) while SHBG (MID-POST, 31.8±12.1 vs. 26.6±13.2 nmol/l, p < 0.01) and cortisol (MID-POST, 445±116 vs. 400±123 nmol/l, p < 0.05) decreased. With the exception of increased concentration of salivary α-amylase (PRE-POST, 36.5±33.7 vs. 55.1±39.7 U/ml), the acute stress biomarkers and HR responses remained unchanged. Furthermore, the low quantity of PA, low HR values and subjective ratings of exertion refer to rather light physical workload. CONCLUSIONS: Due to the operatively calm nature of the working environment, the present soldiers did not express any significant signs of physical overload during the study period. Int J Occup Med Environ Health 2018;31(2):185-197.

Sex Hormones, Gonadotropins, and Sex Hormone-binding Globulin in Infants Fed Breast Milk, Cow Milk Formula, or Soy Formula.

Measurement of endogenous hormones in early life is important to investigate the effects of hormonally active environmental compounds. To assess the possible hormonal effects of different feeding regimens in different sample matrices of infants, 166 infants were enrolled from two U.S hospitals between 2006 and 2009. The children were classified into exclusive soy formula, cow milk formula or breast milk regimens. Urine, saliva and blood samples were collected over the first 12 months of life. Estradiol, estrone, testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) levels were measured in the three matrices. Lower estradiol and LH levels were found in urine and saliva samples of soy formula-fed boys compared to cow formula-fed boys. Higher LH level was found in urine samples of soy formula-fed girls compared to cow formula-fed girls. However, we found neither a neonatal testosterone rise in the boys nor a gender-specific difference in testosterone levels, which suggests that urinary testosterone levels may not accurately reflect blood levels during mini-puberty. Nevertheless, our study shows that blood, urine and saliva samples are readily collectible and suitable for multi-hormone analyses in children and allow examination of hypotheses concerning endocrine effects from dietary compounds.

Peripheral hormone levels in controls and patients with prostatic cancer or benign prostatic hyperplasia: results from the Dutch-Japanese case-control study.

The possible relationship between changes in peripheral hormone levels and the occurrence of prostatic pathology was studied in a case-control study, involving estimation of various plasma hormones in 368 Dutch and 258 Japanese men, who were grouped as controls and patients with benign prostatic hyperplasia, focal prostatic carcinoma, or clinically evident prostatic carcinoma. Results of a number of previous, smaller studies concerning interrelationships between hormone levels in elderly men were confirmed within the Dutch and Japanese groups. Plasma levels of testosterone and estradiol were significantly lower in the Japanese men, when compared with those in Dutch men. Probably as a result of this difference in testosterone levels, the ratio between serum levels of testosterone and sex hormone-binding globulin (SHBG) was decreased in the Japanese men, while the ratio between the concentrations of dihydrotestosterone and testosterone was increased. These differences were also found when results from Japanese subgroups (controls and patients with prostate pathology) were compared with those from the Dutch subgroups. There were no significant differences in plasma androgen levels between Japanese or Dutch prostate cancer cases and their respective control subgroups. These findings do not support a correlation between the lower plasma testosterone levels and a lower incidence of prostate cancer in the Japanese men. Furthermore, no significant differences were found between salivary levels of testosterone or the ratio between testosterone and SHBG in the various Dutch subgroups. In Japanese benign prostatic hyperplasia patients, the testosterone to SHBG ratio was significantly increased. In conclusion, the results of this retrospective, cross-sectional study do not indicate that hormonal levels play a primary role in the origin or promotion of prostatic abnormalities. The finding of a lower plasma testosterone in the Japanese men, however, remains suggestive, warranting a more extensive prospective study.

Associations of cortisol/testosterone and cortisol/sex hormone-binding globulin ratios with atherosclerosis in middle-age women.

BACKGROUND AND AIMS: The cortisol/testosterone (C/T) ratio has been hypothesized to be a better predictor of atherosclerosis than cortisol alone. No study has assessed whether the C/T and C/sex hormone-binding globulin (SHBG) ratios are associated with atherosclerosis in a U.S. population sample. METHODS: This substudy included 367 women who had both cortisol from year 15 and testosterone and SHBG at year 16 of the Coronary Artery Risk Development in Young Adults study, an ongoing observational cohort in the United States. Of these, intima-media thickness (IMT) was available at follow-up year 20 in 339 (n = 332 with measurement at carotid bulb), and 303 were free of prevalent coronary artery calcium (CAC) at year 15. Area under the curve (AUC) of salivary cortisol was available in 302 individuals. Ratios of AUCs of cortisol to total testosterone, free testosterone, and SHBG were categorized into tertiles. Associations with CAC and IMT were assessed by regression models adjusted for age, race, body mass index, systolic blood pressure, menopause, oral contraceptive use, diabetes, alcohol, and smoking. RESULTS: Only the highest tertile of the AUC/free testosterone ratio was positively associated with carotid bulb IMT (ß = 0.088, P = 0.006). This tertile was also positively associated with new onset CAC between year 15 and 25 (OR 3.45, 95% CI 1.18-10.06). Tertiles of cortisol or testosterone alone were not associated with new onset CAC. CONCLUSION: AUC/Free testosterone ratio may be more associated with atherosclerosis in women than either indicator alone. The ratio may serve as a suitable biomarker of cortisol-linked stress.

Associations Between Sex Hormone Levels and Periodontitis in Men: Results From NHANES III.

BACKGROUND: Sex hormones are linked to inflammation and bone turnover. The goal of this study is to explore the association between sex hormone levels and periodontitis in men using data from the third National Health and Nutrition Examination Survey (NHANES III). METHODS: Data from 755 men (aged ≥ 30 years), including serum levels of testosterone, estradiol, sex hormone binding globulin, and androstenediol glucuronide, were analyzed. Calculated bioavailable testosterone (CBT) and estradiol-to-testosterone ratio were calculated. Periodontitis was defined using the latest classification of extent and severity of periodontitis for NHANES data (≥ 2 interproximal sites with ≥ 3 mm attachment loss, ≥ 2 interproximal sites with probing depth [PD] ≥ 4 mm not on the same tooth, or one site with PD ≥ 5 mm). Sex hormones were evaluated as categorized and continuous variables. Correlations between the presence and severity of periodontitis and levels of sex hormones were determined and expressed as odds ratios (ORs). RESULTS: When adjusted for confounding factors, high total testosterone (TT) and CBT levels correlated with both the prevalence (OR [95% confidence interval (CI)], 2.1 [1 to 4.5] and 3.9 [1 to 14.8], respectively) and severity (OR [95% CI], 2.1 [1 to 4.3] and 3.4 [1.2 to 9.8]) of periodontitis. When continuous variables were used, the ORs (95% CIs) for presence and severity of periodontitis were 1.4 (0.6 to 3.3) and 1.5 (0.6 to 3.6) for TT and 1.3 (0.9 to 1.9) and 1.3 (0.9 to 1.8) for CBT, respectively. CONCLUSIONS: These findings are consistent with the existence of an association of periodontitis with sex hormone levels, especially testosterone, in men.

Salivary testosterone in hirsutism: correlations with serum testosterone and the degree of hair growth.

Testosterone (T) concentrations in saliva and serum were measured in 53 women with various degrees of hirsutism and hyperandrogenism. The bioavailability of T was judged by comparing the correlations among the grade of hirsutism, salivary testosterone (SaT), and serum total and free T (fT) and sex hormone-binding globulin (SHBG) levels. The effect of body mass index on the correlations was also studied. The high SaT concentrations [mean, 237.6 +/- 66.7 (+/- SD) pmol/L] compared to the serum fT concentrations (mean, 29.1 +/- 11.8 pmol/L) in hirsute women may reflect the bioavailability of albumin-bound T or an ability of the salivary glands to metabolize steroids. SaT was more closely related to the T/SHBG ratio (mean, 82.5 X 10(-3) +/- 54.8), reflecting the non-SHBG-bound fraction of T, than to serum fT, which might support the former theory. SaT correlated better to the degree of hirsutism (rho = 0.45; P less than 0.01) than did any of the serum T parameters or SHBG. The correlation between SaT and hirsutism was partly dependent on the effect of body mass index. After eliminating this effect, SaT still correlated with hair growth on the total body area (rho = 0.36; P less than 0.05). On the basis of the results, SaT seems to relate to the bioavailable fraction of the hormone and, thus, appears to be an optimal method for studying hirsute women.

Salivary testosterone in men: further evidence of a direct correlation with free serum testosterone.

An excellent correlation was found between salivary testosterone (T) and serum T concentrations, as measured by RIA. Using polyacrylamide gel electrophoresis, we have demonstrated that sex steroid-binding globulin could not be identified in the saliva of men with serum sex steroid-binding globulin. After exogenous T administration, saliva and serum T rose abruptly and in parallel. Salivary T concentrations in male patients with thyrotoxicosis were similar to those in normal males, whereas the serum T and sex steroid-binding globulin values were significantly higher in the hyperthyroid patients. This study demonstrates that salivary T levels may be used as an index of free serum T.

Serum bioavailability and tissue metabolism of testosterone and estradiol in rat salivary gland.

The concentration of testosterone in saliva is probably in equilibrium with the concentration of cellular exchangeable testosterone in salivary gland, and these pools are a function of hormone transplant from the plasma compartment, and hormone metabolism in salivary gland cells. Both of these processes were examined in the present study using the carotid injection technique in normal and pilocarpine-stimulated ketamine-anesthetized rats. Both testosterone and estradiol were rapidly transported across salivary gland capillaries in vivo from the circulating albumin-bound pool. Estradiol, but not testosterone, was also rapidly transported into salivary gland from the circulating human sex hormone-binding globulin-bound pool. Hormone transport was several-fold greater than the capillary transport of [3H]bovine albumin, indicating that bound hormone was available for transport across salivary gland capillaries via an enhanced dissociation mechanism, with the plasma protein primarily residing in the plasma compartment. This result was confirmed by thaw-mount autoradiography, which showed diffuse distribution of [3H]testosterone in salivary gland, but vascular retention of [3H]bovine albumin. The concentration of exchangeable cellular testosterone in rat saliva was less than 4% of the total or plasma exchangeable testosterone in the rat. This marked discrepancy between the concentration of plasma and cellular exchangeable hormone suggested that there was rapid metabolism of androgen by salivary gland in vivo. This was confirmed by chromatographic separation of [3H] testosterone and labeled metabolites in homogenates of salivary gland. By 60 sec after injection, approximately 30% of the radioactivity in the salivary gland was in the form of androgen metabolites, which primarily comigrated with an androstenedione standard. The data indicate that albumin-bound testosterone, albumin-bound estradiol, and sex hormone-binding globulin-bound estradiol are all exchangeable in salivary gland capillaries. The low concentration of cellular exchangeable testosterone in salivary gland appears to be due to rapid tissue metabolism of this hormone. Thus, changes in androgen metabolism may alter salivary gland hormone concentrations independent of any change in the concentration of biologically active hormone in plasma.

Oral testosterone undecanoate in the management of delayed puberty in boys: pharmacokinetics and effects on sexual maturation and growth.

Therapeutic induction of puberty using oral testosterone (T) undecanoate (TU) 40 mg daily was performed in 4 pubertal boys aged 12.7-17.1 yr with constitutional delayed puberty and/or short stature. Single-dose pharmacokinetics study was performed on matched plasma and saliva samples obtained half-hourly for 10 h after the first dose and then repeated 3 and 6 months later. Treatment was continued for 15-21 months. Peak plasma total T concentration was achieved at 255 +/- 51 (SEM) min after the first 40 mg dose of TU, 300 +/- 76 min at 3 months, and 293 +/- 103 min at 6 months, the levels remaining elevated above baseline for at least 8 h after a single oral dose. Total T levels were initially high (mean 13.0 +/- 2.5; peak 38.7 +/- 4.2 nmol/L) but dropped significantly at 3 months (mean 8.3 +/- 1.8; peak 23.6 +/- 5.6 nmol/L) and at 6 months (mean 9.2 +/- 1.6; peak 24.8 +/- 3.5 nmol/L) paralleled by a dramatic fall in sex hormone binding globulin (73.9 +/- 18.0 to 35.1 +/- 9.7 at 3 month and 29.2 +/- 6.0 nmol/L at 6 month). Mean concentrations of unbound and free T (non-sex hormone binding globulin-bound T, free T, and salivary T) were below the normal adult range and remained unchanged over the same period. Plasma dihydrotestosterone concentrations were elevated after the first dose (mean 5.4 +/- 1.3; peak 11.0 +/- 2.5 nmol/L), the extent of this rise being less after 6 months (mean 4.1 +/- 0.8; peak 7.1 +/- 1.1 nmol/L) as was the case with mean estradiol (51.5 +/- 8.9 to 38.1 +/- 3.7 pmol/L). Signs of virilization progressed to Tanner stage G3 PH2-3 with testicular volumes increasing to 3-4 mL at 12 months, and G4 PH4-5 with further testicular growth to 6-10 mL at 24 months. Height velocity rose from 3.2 +/- 0.3 cm/yr (pretreatment) to 7.2 +/- 1.0 cm/yr in the first year and was maintained at 7.3 +/- 0.4 cm/yr despite cessation of therapy during the second year. Bone age advanced by 1.1 +/- 0.1 yr at 12 months and a further 0.8 +/- 0.3 yr at 24 months. Predicted adult height remained unchanged. No side effects were observed. Our preliminary data suggest that oral TU is a well accepted, effective, and safe treatment for the initiation of male puberty without disproportionate skeletal maturation. Continued pubertal advance was evident after cessation of treatment in all patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Exogenous estrogen and endogenous sex hormones.

Estrogen replacement therapy is widely used to treat menopausal symptoms and prevent osteoporosis. The mechanism of these and other estrogen effects is currently under investigation. We studied the plasma steroid hormone and sex hormone binding globulin levels in frozen plasma obtained from 977 women aged 50 to 79 years from 1972 to 1974. Almost all of the 301 women who reported current use of noncontraceptive estrogen were taking conjugated estrogen by mouth; none reported use of a progestin. Women taking estrogen were significantly younger, thinner, and more likely to smoke cigarettes than women not taking estrogen. Sex hormone binding globulin and all endogenous hormones except testosterone were negatively correlated with age; estradiol was positively and cortisol and sex hormone binding globulin were negatively associated with obesity. After adjusting for age and obesity, dehydroepiandrosterone sulfate, androstenedione, and free testosterone were significantly lower in women currently taking estrogen than in women not using estrogen. These differences were independent of cigarette smoking. As expected, estrogens (including free estradiol), sex hormone binding globulin, and cortisol levels were higher in treated than untreated women. The possibility that some of the benefits and risks of replacement estrogen are secondary to altered adrenal steroid metabolism and androgen levels needs further evaluation.