Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging Study.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle. METHODS: In this longitudinal case-control study, we acquired 118 [11C]DASB positron emission tomography scans measuring 5-HTT nondisplaceable binding potential (BPND) in 30 patients with PMDD and 29 controls during 2 menstrual cycle phases (periovulatory, premenstrual). The primary outcome was midbrain and prefrontal cortex 5-HTT BPND. We tested whether BPND changes correlated with depressed mood. RESULTS: Linear mixed effects modeling (significant group × time × region interaction) showed a mean increase of 18% in midbrain 5-HTT BPND (mean [SD] periovulatory = 1.64 [0.40], premenstrual = 1.93 [0.40], delta = 0.29 [0.47]: t29 = -3.43, p = .0002) in patients with PMDD, whereas controls displayed a mean 10% decrease in midbrain 5-HTT BPND (periovulatory = 1.65 [0.24] > premenstrual = 1.49 [0.41], delta = -0.17 [0.33]: t28 = -2.73, p = .01). In patients, increased midbrain 5-HTT BPND correlated with depressive symptom severity (R2 = 0.41, p < .0015) across the menstrual cycle. CONCLUSIONS: These data suggest cycle-specific dynamics with increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients with PMDD. These neurochemical findings argue for systematic testing of pre-symptom-onset dosing of selective serotonin reuptake inhibitors or nonpharmacological strategies to augment extracellular serotonin in people with PMDD.

Calcitonin and complementary biomarkers in the diagnosis of hereditary medullary thyroid carcinoma in children and adolescents.

OBJECTIVES: Medullary thyroid carcinoma (MTC) is a rare malignancy that is effectively curable by surgery. Unlike in adults, hereditary MTC has a predominant role in children. A fast and safe diagnosis is important to assure the good prognosis for the patients. A major cornerstone is the assessment of biomarkers, but the interpretation must respect their pre-, post- and analytical features. Especially calcitonin (Ctn) is a challenging biomarker in daily laboratory diagnostics. However, Ctn is of particular relevance for the diagnostic in MTC. The American Thyroid Association recommends thyroidectomy if the upper reference range of Ctn is exceeded. Interestingly, age-dependent reference ranges for children and adolescents have become available only recently for Ctn assays. With this review, we aim to highlight the importance of a timely diagnosis of MTC in children and adolescents. CONTENT: Recent developments in pediatric biochemical diagnostics of MTC were summarized. This includes guidance on interpretation of RET, Ctn, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 19-9, and chromogranin A. SUMMARY: Currently, Ctn is the most investigated biomarker in the diagnosis of MTC in children and adolescents. Other biomarkers as PCT suggest complementary evidence about pediatric MTC but their interpretation based largely on adult's data. A successful treatment of MTC requires, besides results of biomarkers, information about medical history, RET gene analysis and recent guideline knowledge. OUTLOOK: More research is required to validate complementary biomarkers of Ctn in children. Additionally, the effect of different confounder on pediatric Ctn levels has to be further clarified.

Pediatric Reference Intervals for Thyrotropin, Free Triiodothyronine, and Free Thyroxine and the Relevance of Body Mass Index and Puberty in Measurement Interpretation.

Background: The present study aimed to establish age- and sex-specific reference intervals for serum concentrations of thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) in healthy children and adolescents. Additionally, we investigated the association of TSH, fT3, and fT4 with putative influencing factors, such as sex, body mass index (BMI), and puberty. Methods: A total of 9404 blood serum samples from 3140 children and adolescents without thyroid affecting diseases were included in determining TSH, fT3, and fT4 levels and age- and sex-specific reference ranges. To investigate the association of TSH, fT3, and fT4 with age, sex, weight status, and the role of puberty-based changes, the hormone levels and BMI values were converted to standard deviation scores (SDS). Results: In general, TSH, fT3, and fT4 were found to be age- and sex-dependent. Puberty was accompanied by decreased TSH, decreased fT3 with a temporary peak in males, and a temporary nadir of fT4 in Tanner stage 3 for both sexes. BMI-SDS was positively associated with TSH-SDS (ß = 0.081, p < 0.001); the effect was more pronounced in overweight subjects (ß = 0.142, p < 0.01) and insignificantly negative in underweight subjects (ß = -0.047, p > 0.05). BMI-SDS was positively associated with fT3-SDS (ß = 0.066, p < 0.001) and negatively associated with fT4-SDS (ß = -0.135, p < 0.001), with the effect insignificantly less negative in overweight children (ß = -0.055, p > 0.05). Conclusions: Age- and sex-specific reference intervals are important for the interpretation of measurements of TSH, fT3, and fT4 in children and adolescents. Influencing factors such as BMI and puberty should be taken into consideration when using measurements of TSH and thyroid hormones in the diagnosis, treatment, and monitoring of thyroid diseases. Clinical Trial Registration number: NCT02550236.

Global FT4 immunoassay standardization: an expert opinion review.

OBJECTIVES: Results can vary between different free thyroxine (FT4) assays; global standardization would improve comparability of results between laboratories, allowing development of common clinical decision limits in evidence-based guidelines. CONTENT: We summarize the path to standardization of FT4 assays, and challenges associated with FT4 testing in special populations, including the need for collaborative efforts toward establishing population-specific reference intervals. The International Federation of Clinical Chemistry and Laboratory Medicine Committee for Standardization of Thyroid Function Tests has undertaken FT4 immunoassay method comparison and recalibration studies and developed a reference measurement procedure that is currently being validated. Further studies are needed to establish common reference intervals/clinical decision limits. Standardization of FT4 assays will change test results substantially; therefore, a major education program will be required to ensure stakeholders are aware of the benefits of FT4 standardization, planned transition procedure, and potential clinical impact of the changes. Assay recalibration by manufacturers and approval process simplification by regulatory authorities will help minimize the clinical impact of standardization. SUMMARY: Significant progress has been made toward standardization of FT4 testing, but technical and logistical challenges remain. OUTLOOK: Collaborative efforts by manufacturers, laboratories, and clinicians are required to achieve successful global standardization of the FT4 assays.

Unraveling the steroid hormone response in male marathon runners: Correlation of running time with aldosterone and progesterone.

Marathon running is a physical and psychological stressor. We aimed to characterize the response of nine steroid hormones, which include estradiol, progesterone, testosterone, cortisol, aldosterone, 17-hydroxyprogesterone, cortisone, androstenedione, and dehydroepiandrosterone sulfate, to marathon running and their association with performance. Blood samples of sixty men (age: 49.3 ± 5.9 years) who participated in the Berlin marathon were collected within 3 days before, within 30 min and within 58 h after the end of the marathon. The nine steroid hormones in serum were quantified using liquid chromatography-tandem mass spectrometry. The responses of nine steroid hormones to marathon running were characterized. Aldosterone (fold change: 8.5), progesterone (fold change: 6.6), and cortisol (fold change: 3.7) showed significant increases within 30 min after the marathon (all p < 0.0001). Estradiol but not testosterone increased in the male runners. Marathon running time was significantly related to aldosterone increase (beta=-0.238, p = 0.008) and progesterone increase (beta=-0.192, p = 0.036) in addition to body mass index, self-reported training distance, and age. Serum progesterone correlated with aldosterone and cortisol (r = 0.81 and r = 0.92, respectively, p < 0.001). Progesterone, as a precursor hormone, is increased after the completion of marathon running in association with the increase of aldosterone and cortisol. These findings reveal a contribution of progesterone during the response to the psycho-physical stress of marathon running in males.

Associations Between Anxiety, Body Mass Index, and Sex Hormones in Women.

Background: Several studies have shown a positive association between anxiety and obesity, particularly in women. We aimed to study whether sex hormone alterations related to obesity might play a role in this association. Patients and methods: Data for this study were obtained from a population-based cohort study (the LIFE-Adult-Study). A total of 3,124 adult women (970 premenopausal and 2,154 postmenopausal) were included into the analyses. The anxiety symptomatology was assessed using the GAD-7 questionnaire (cut-off ≥ 10 points). Sex hormones were measured from fasting serum samples. Results: We did not find significant differences in anxiety prevalence in premenopausal obese women compared with normal-weight controls (4.8% vs. 5.5%). Both obesity and anxiety symptomatology were separately associated with the same sex hormone alteration in premenopausal women: higher total testosterone level (0.97 ± 0.50 in obese vs. 0.86 ± 0.49 nmol/L in normal-weight women, p = 0.026 and 1.04 ± 0.59 in women with vs. 0.88 ± 0.49 nmol/L in women without anxiety symptomatology, p = 0.023). However, women with anxiety symptomatology had non-significantly higher estradiol levels than women without anxiety symptomatology (548.0 ± 507.6 vs. 426.2 ± 474.0 pmol/L), whereas obesity was associated with lower estradiol levels compared with those in normal-weight group (332.7 ± 386.5 vs. 470.8 ± 616.0 pmol/L). Women with anxiety symptomatology had also significantly higher testosterone and estradiol composition (p = 0.006). No associations of sex hormone levels and BMI with anxiety symptomatology in postmenopausal women were found. Conclusions: Although both obesity and anxiety symptomatology were separately associated with higher testosterone level, there was an opposite impact of anxiety and obesity on estradiol levels in premenopausal women. We did not find an evidence that the sex hormone alterations related to obesity are playing a significant role in anxiety symptomatology in premenopausal women. This could be the explanation why we did not find an association between obesity and anxiety. In postmenopausal women, other mechanisms seem to work than in the premenopausal group.

Reference intervals of nine steroid hormones over the life-span analyzed by LC-MS/MS: Effect of age, gender, puberty, and oral contraceptives.

New reference intervals need to be established for a new analytical method with improved sensitivity and specificity. We aimed to establish the new reference intervals from infancy to senescence of nine steroid hormones (cortisol, cortisone, progesterone, 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone, estradiol, DHEAS, and aldosterone) for LC-MS/MS method. Serum samples from 4678 reference individuals (age range: 0.3-79 years) were measured with LC-MS/MS. Samples were collected between 7 a.m. and 10 a.m. Exclusion criteria were concomitant endocrine diseases and body mass index ≥ 33. Generalized additive model for location, scale and shape, the nonparametric or robust method was applied. We established the reference intervals of the nine steroid hormones by sex, age, and pubertal stage. Below the age of one, we observed the surge of androgen and estrogen which implied mini-puberty. At the same period of life, aldosterone and cortisone levels were very high reflecting physiological hyperaldosteronism. An increase of steroid hormones during the pubertal development and slow decrease towards senescence after the peak at early adulthood were observed. Due to the increase of CBG synthesis, cortisol levels were increased under oral contraceptives (OC) significantly (p < 0.0001), while OC suppressed progesterone, 17-OHP, androstenedione, and estradiol (p < 0.0001). Our results will facilitate the interpretation of patient data in routine diagnostics with the use of LC-MS/MS method. Since LC-MS/MS methods have shown good comparability among the different laboratories, our reference intervals can be further adopted in other laboratories equipped with LC-MS/MS, once the validation with a small number of reference samples is performed.

Acute psychosocial stress alters thalamic network centrality.

Acute stress triggers a broad psychophysiological response that is adaptive if rapidly activated and terminated. While the brain controls the stress response, it is strongly affected by it. Previous research of stress effects on brain activation and connectivity has mainly focused on pre-defined brain regions or networks, potentially missing changes in the rest of the brain. We here investigated how both stress reactivity and stress recovery are reflected in whole-brain network topology and how changes in functional connectivity relate to other stress measures. Healthy young males (n = 67) completed the Trier Social Stress Test or a control task. From 60 min before until 105 min after stress onset, blocks of resting-state fMRI were acquired. Subjective, autonomic, and endocrine measures of the stress response were assessed throughout the experiment. Whole-brain network topology was quantified using Eigenvector centrality (EC) mapping, which detects central hubs of a network. Stress influenced subjective affect, autonomic activity, and endocrine measures. EC differences between groups as well as before and after stress exposure were found in the thalamus, due to widespread connectivity changes in the brain. Stress-driven EC increases in the thalamus were significantly correlated with subjective stress ratings and showed non-significant trends for a correlation with heart rate variability and saliva cortisol. Furthermore, increases in thalamic EC and in saliva cortisol persisted until 105 min after stress onset. We conclude that thalamic areas are central for information processing after stress exposure and may provide an interface for the stress response in the rest of the body and in the mind.

Testosterone imbalance may link depression and increased body weight in premenopausal women.

Accumulating evidence supports a link between depression and being overweight in women. Given previously reported sex differences in fat accumulation and depression prevalence, as well as the likely role of sex hormones in both overweight and mood disorders, we hypothesised that the depression-overweight association may be mediated by sex hormones. To this end, we investigated the association of being overweight with depression, and then considered the role of sex hormones in relation to being overweight and depression in a large population-based cohort. We included a total of 3124 women, 970 premenopausal and 2154 postmenopausal from the LIFE-Adult cohort study in our analyses. We evaluated associations between being overweight (BMI >25 kg/m2), sex hormone levels, and depressive symptomatology according to Centre for Epidemiologic Studies Depression (CES-D) scores, and explored mediation of depression in a mediation model. Being overweight was significantly associated with depressive symptoms in premenopausal but not postmenopausal women. Both premenopausal and postmenopausal overweight women had higher free testosterone levels compared with normal weight women. Premenopausal women with depressive symptomatology had higher free testosterone levels compared to women without. We found a significant mediation effect of depressive symptomatology in overweight premenopausal women through free testosterone level. These findings highlight the association between being overweight and depressed, and suggest that high free testosterone levels may play a significant role in depression of overweight premenopausal women. Based on this, pharmacological approaches targeting androgen levels in overweight depressed females, in particular when standard anti-depressive treatments fail, could be of specific clinical relevance.

Association of Estradiol and Visceral Fat With Structural Brain Networks and Memory Performance in Adults.

Importance: Changes in estradiol during aging are associated with increased dementia risk. It remains unclear how estradiol supports cognitive health and whether risk factors, such as midlife obesity, are exacerbated by estrogen loss. Objectives: To assess whether visceral adipose tissue (VAT) moderates the association between age and brain network structure and to investigate whether estradiol moderates the association between VAT and brain network structure. Design, Setting, and Participants: Cross-sectional study of data from 974 cognitively healthy adults in Germany who participated in the Health Study of the Leipzig Research Centre for Civilization Diseases, a previously described population-based cohort study. Two moderation analyses were performed, including VAT as the moderator variable between age and brain network structure and estradiol as the moderator variable between VAT and brain network structure. The study was conducted from August 1, 2011, to November 23, 2014. Analyses were conducted from August 2017 to September 2018. Exposures: Serum estradiol levels from fasting blood and visceral adipose tissue volume from T1-weighted magnetic resonance imaging (MRI). Main Outcomes and Measures: Brain network covariance (individual loading on structural network derived from T1-weighted MRI) and memory performance (composite score from the Consortium to Establish a Registry for Alzheimer Disease [CERAD] verbal episodic memory test on learning [score range, 0-30], recall [score range, 0-10], and recognition [score range, 0-20]). Results: Final analyses included data from 473 women (mean [SD] age, 50.10 [15.63] years) and 501 men (mean [SD] age, 51.24 [15.67] years). Visceral adipose tissue was associated with an exacerbation of the negative association of aging with network covariance for women (interaction term ß = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P = .001) and men (interaction term ß = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P < .001). Estradiol level was associated with a reduction in the negative association of VAT with network covariance in women (interaction term ß = 0.63; 95% bias-corrected bootstrap CI, 0.14-1.12; P = .01), with no significant association in men. In the female midlife subgroup (age range, 35-55 years, when menopause transition occurs), low estradiol levels were associated with lower memory network covariance (Cohen d = 0.61; t80 = 2.76; P = .007) and worse memory performance (Cohen d = 0.63; t76 = 2.76; P = .007). Conclusions and Relevance: This study reports a novel association between VAT, estradiol, and structural brain networks as a potential mechanism underlying cognitive decline in women. These findings appear to highlight the need for sex-specific strategies, including VAT and hormonal screening during midlife, to support healthy cognitive aging.

Calcitonin measurement in pediatrics: reference ranges are gender-dependent, validation in medullary thyroid cancer and thyroid diseases.

BACKGROUND: There is only limited information on serum reference ranges of calcitonin (CT) in infants, children and adolescents. This gap hampers valid diagnostics in patients with multiple endocrine neoplasia type 2 (MEN 2) and planned prophylactic thyroidectomy. In addition, age-dependent reference ranges for CT are necessary to define a cure in medullary thyroid carcinoma (MTC). We asked whether the reference ranges for CT levels were age- and gender-dependent in the serum of a pediatric cohort. METHODS: A total of 6090 serum samples of 2639 subjects of the LIFE-Child cohort aged between 1 month and 17.9 years were analyzed by the CT electrochemiluminescence immunoassay (ECLIA). Reference intervals were estimated using the LMS method. For clinical validation the serum of 28 patients (61 samples) with MEN 2 and 106 patients (136 samples) with thyroid diseases were analyzed. RESULTS: CT levels showed a clear age- and gender-dependence with significantly higher values in boys (p<0.01). An accelerated decline of CT levels from newborn to children at the age of 4 and 5 years was observed for both sexes. A cure for MTC was demonstrated in 71% of MEN 2 patients after thyroidectomy, whereas 5 patients remained suspicious for micrometastasis or relapse. Only 1.5% of our patients with thyroid diseases revealed increased CT levels. CONCLUSIONS: This is the largest study to establish novel pediatric reference ranges from the CT values of healthy subjects. It allows a precise laboratory monitoring of CT in pediatric patients with MEN 2. Thyroid diseases did not have a relevant influence on CT levels in our pediatric cohort.

Adaptation and Validation of the Korean Version of the Urticaria Control Test and Its Correlation With Salivary Cortisone.

PURPOSE: Frequent changes in chronic urticaria (CU) activity over time can cause psychological stress, which also serves as a trigger of CU. To measure the control status of CU, the Urticaria Control Test (UCT) was developed in Germany. This study aimed to investigate the validity, reliability and responsiveness to changes in CU for the Korean version of the UCT (K-UCT) and its relation with salivary cortisol and cortisone levels. METHODS: Linguistic adaptation of the UCT into Korean was conducted. A total of 96 CU patients were enrolled, and 80 of them completed the study. The K-UCT and other outcome scores for CU were measured and repeated after 4 weeks of treatment. Control status was classified by physicians into well-controlled, partly-controlled, and uncontrolled CU. Salivary cortisol and cortisone were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Excellent internal consistency and intra-class reliability were obtained. Strong correlations between the K-UCT and disease severity, reflected in the Urticaria Activity Score (UAS)/global assessment of urticaria control by physicians/patient assessment of symptom severity/CU-specific quality of life were noted. K-UCT scores ≥12 were found to be optimal for determining well-controlled CU (sensitivity, 75.0%; specificity, 758%; area under the curve, 0.824). Perceived stress scale scores were significantly correlated with the UAS and the K-UCT. Salivary cortisone levels were significantly correlated with K-UCT (r = 0.308, P = 0.009) and differed significantly according to control status determined by a K-UCT ≥12. CONCLUSIONS: This study demonstrated that the K-UCT can be a valid instrument with which to gauge CU control status in Korean patients. Further studies are needed to validate salivary cortisone as a biomarker for CU control.

Salivary cortisone, as a biomarker for psychosocial stress, is associated with state anxiety and heart rate.

BACKGROUND: Stress activates the central nervous, the autonomic nervous, and the endocrine system. This study aimed to (1) test the usability of salivary cortisone in a standardized psychosocial stressor, (2) create a comprehensive profile of hormonal responses to determine laboratory parameters with high discriminatory power, and (3) analyze their association with psychometric and autonomic stress measures. METHODS: Healthy young men (18-35 years) completed either the Trier Social Stress Test (TSST) (n = 33) or a Placebo-TSST (n = 34). Blood and saliva were collected at 14 time points along with state-anxiety (STAI) and heart rate. Serum steroids (cortisol*, cortisone*, dehydroepiandrosterone-sulfate, androstenedione*, progesterone*, 17-hydroxyprogesterone*, testosterone, estradiol*, aldosterone*), salivary cortisol* and cortisone*, copeptin*, adrenocorticoptropic hormone*, corticosteroid-binding globulin, and salivary alpha-amylase* were analyzed. We used mixed-design ANOVAs to test group differences, receiver operator characteristic (ROC) curve analyses to assess the discriminatory power of each measure, and Spearman correlation analyses to probe the association between measures. RESULTS: The largest area under the ROC curve was observed in salivary cortisone at 20 min after the end of the TSST (AUC = 0.909 ± 0.044, p < 0.0001). Significant time-by-group interactions were found in the parameters marked with * above, indicating stress-induced increases. The peak response of salivary cortisone was significantly associated with those of STAI (rho = 0.477, p = 0.016) and heart rate (rho = 0.699, p < 0.0001) in the TSST group. CONCLUSION: Our study found salivary cortisone to be a stress biomarker with high discriminatory power and significant correlations with subjective and autonomic stress measures. Our results can inform future stress studies of sampling time for different laboratory parameters.

Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes.

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is a novel strategy to treat hypercholesterolemia and reduce cardiovascular events. However, the potential role of circulating plasma PCSK9 concentrations as a diagnostic and predictive biomarker remains uncertain as of now. Here, we aimed to identify genetic variants associated with plasma PCSK9 and investigate possible causal effects on atherosclerotic vascular disease phenotypes. METHODS: We performed the first genome-wide association study of plasma PCSK9 levels in a cohort of suspected and confirmed coronary artery disease (LIFE-Heart; n=3290). RESULTS: Several independent variants at the PCSK9 gene locus were associated with circulating PCSK9 levels at genome-wide significance (lead SNP rs11591147, PCSK9-R46L; P=1.94×10-17). We discovered 4 independent PCSK9 SNPs explaining 4.4% of the variance of plasma PCSK9. In addition, we identified a genome-wide significant locus at chromosome 7p22.1 (rs6957201; P=7.01×10-9) and 7 suggestive hits (P<1×10-6). Using MR (Mendelian Randomization), we detected significant causal effects of circulating PCSK9 on coronary artery disease status and severity, carotid plaques, and intima-media thickness. CONCLUSIONS: Variants at the PCSK9 gene locus seem to be the major genetic determinants of plasma PCSK9 levels with 4 independent variants at the PCSK9 gene locus expressing allelic heterogeneity. The detected MR estimates support the hypothesis of a causal effect of PCSK9 on coronary artery disease and other vascular phenotypes. Other observed genetic associations for PCSK9 require validation in independent cohorts. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00497887.

Adipokines in human breast milk.

The review describes the molecular characteristics of so far detected breast milk adipokines and ranks their breast milk level compared to the respective levels in maternal and infant blood. Moreover, analytical knowledge for measurements of breast milk adipokines will be delineated. Next, we summarized data about two main potential influencing factors on adipokine concentration in breast milk, maternal weight and pasteurization of milk. Finally, associations between adipokines in breast milk and weight gain in infants as well as the putative mechanisms for effects of breast milk adipokines on food intake and weight gain in later life will debated. Our findings suggest that a source of adipokines in human breast milk cannot be uniformly defined. In dependence on the ratio between serum and breast milk levels the major quantity of these proteins may be derived from peripheral tissues, from the breast tissue itself or from both. Thus, leptin and in part adiponectin levels in breast milk are dependent on a plenty of influencing factors with an important relevance of maternal anthropometric characteristics There is some evidence that leptin, adiponectin and ghrelin levels in breast milk may be associated with growth gain of infants and even with increased risk for being overweight during infancy or childhood. We hypothesize that a dysregulation in adipokine homeostasis in early life could promote obesity and metabolic disturbance in later life.

Vitamin D and calcium in the human breast milk.

Vitamin D and calcium in the human milk is essential for the growth and the prevention of rickets in infants. In this review, we will discuss the physiology and the functions of vitamin D and calcium and the mechanisms of vitamin D and calcium transfer into the human breast milk. This review describes the recommended intake of vitamin D and calcium for infants and lactating mothers and the factors influencing the content of vitamin D and calcium in human milk. Furthermore, the measurement of vitamin D compounds and calcium in human breast milk is described in this review.

Associations of Sex Hormones and Anthropometry with the Speaking Voice Profile in the Adult General Population.

OBJECTIVE: There is evidence that sexual hormone concentrations and anthropometric factors influence the human voice. The goal of this study was to investigate to what extent body mass index (BMI), body height, body weight, breast-to-abdomen-ratio, testosterone, estradiol, dehydroepiandrosterone-sulfate (DHEA-S), follicle-stimulating hormone, and luteinizing hormone are associated with the sound pressure level and the fundamental frequency of the speaking voice in a cross-sectional approach among adults in the general population. METHODS: Speaking voice profiles with four different intensity levels, hormone concentrations, and anthropometric parameters were assessed for 2,381 individuals aged 40-79 years, who were randomly sampled from the population of a large city in Germany. Multivariate analysis was performed, adjusting for age and stratified by sex. RESULTS: Taller body height was associated with lower frequencies. Higher body weight was associated with lower frequencies and higher sound pressure levels. The ratio of chest to abdominal circumference was associated with the sound pressure levels in males and females: participants with larger breast-to-abdomen-ratio were found to have higher sound pressure levels. Among the sexual hormones, higher concentrations of DHEA-S were associated with lower fundamental frequencies of the voice while using the normal speaking voice. In addition, bioavailable testosterone was associated with the sound pressure level of the normal speaking voice in men and the softest speaking voice in women. CONCLUSION: Our findings suggest that BMI, body height, body weight, breast-to-abdomen-ratio, bioavailable testosterone, and DHEA-S are associated with the speaking voice in adults. No associations between testosterone and the frequency of the speaking voice were found.

Increased estrogen level can be associated with depression in males.

BACKGROUND: Several studies have shown a positive association between depression and obesity; however the underlying mechanisms are not fully understood. It is not known if this association is driven by altered sex hormone levels in men due to increased BMI. PATIENTS AND METHODS: Data were obtained from the LIFE-Adult-Study, a population-based cohort study. A total of 3925 men (2244<60years and 1681>60years) were included into analyses. Associations between BMI, sex hormones and depressive symptomatology according to CES-D score were evaluated. RESULTS: Obese men had compared to normal weight controls lower total testosterone (12.6±4.7 vs 19.4±5.5 nmol/L, p<0.001 in <60years, and 13.8±6.9 vs 18.3±5.9 nmol/L, p<0.001 in >60years group) and free testosterone (249.0±73.9 vs 337.2±82.0pmol/L, p<0.001, and 217.8±71.2 vs 263.4±72.2pmol/L, p<0.001), and increased estradiol in older group only (97.3±43.0 vs 82.3±34.2pmol/L, p<0.001 in obese). Men <60years old with depressive symptomatology had higher estradiol levels compared to those without depressive symptomatology (96.3±40.7 vs 84.4±36.6pmol/L, p<0.001), however no association with BMI was observed. CONCLUSIONS: Selected sex hormone parameters were significantly different in overweight and obese compared to normal weight males and certain differences could be seen between younger and older males. Depressive symptomatology was associated with increased estradiol levels in younger men, regardless of BMI.

United States and European Multicenter Prospective Study for the Analytical Performance and Clinical Validation of a Novel Sensitive Fully Automated Immunoassay for Calcitonin.

BACKGROUND: The objective of this study is the validation and proof of clinical relevance of a novel electrochemiluminescence immunoassay (ECLIA) for the determination of serum calcitonin (CT) in patients with medullary thyroid carcinoma (MTC) and in different diseases of the thyroid and of calcium homeostasis. METHODS: This was a multicenter prospective study on basal serum CT concentrations performed in 9 US and European referral institutions. In addition, stimulated CT concentrations were measured in 50 healthy volunteers after intravenous calcium administration (2.5 mg/kg bodyweight). RESULTS: In total, 1929 patients and healthy controls were included. Limits of blank, detection, and quantification for the ECLIA were 0.3, 0.5, and 1 ng/L, respectively. Highest intra- and interassay coefficients of variation were 7.4% (CT concentration, 0.8 ng/L) and 7.0% (1.1 ng/L), respectively. Medians (interval) of serum CT concentrations in 783 healthy controls were 0.8 ng/L (<0.5-12.7) and 3 ng/L (<0.5-18) for females and males, respectively (97.5th percentile, 6.8 and 11.6 ng/L, respectively). Diagnostic sensitivity and specificity were 100%/97.1% and 96.2%/96.4%, for female/males, respectively. Patients (male/female) with primary hyperparathyroidism, renal failure, and neuroendocrine tumors showed CT concentrations >97.5th percentile in 33%/4.7%, 18.5%/10%, and 8.3%/12%, females/males, respectively. Peak serum CT concentrations were reached 2 min after calcium administration (161.7 and 111.8 ng/L in males and females, respectively; P < 0.001). CONCLUSIONS: Excellent analytical performance, low interindividual variability, and low impact of confounders for increased CT concentrations in non-MTC patients indicate that the investigated assay has appropriate clinical utility. Calcium-stimulated CT results suggest good test applicability owing to low interindividual variability.