The Developmental Unfolding of ADHD Symptoms from Early Childhood Through Adolescence: Early Effects of Exuberant Temperament, Parenting and Executive Functioning.

Temperament, parenting, and executive functioning (EF) are individual and contextual factors that have been identified to play a role in the development of Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. Specifically, exuberant temperament in toddlerhood has been associated with both adaptive and maladaptive outcomes, including ADHD symptoms. Therefore, it is important to understand factors that predict which exuberant children experience increased ADHD symptoms and the specific mechanisms through which early exuberant temperament impacts later ADHD symptoms. Using a multi-method, prospective longitudinal design, this study examined a moderated mediation model wherein the interactive effects of observed exuberance and parenting at age 3 predicted the development of parent-reported ADHD symptoms from childhood through adolescence (age 5, 7, 9, 12, and 15) via child EF (i.e., inhibitory control) at age 4. Parent-child dyads (n = 291) from a longitudinal study on child temperament were included. A piecewise model of ADHD symptom growth demonstrated stability in ADHD symptoms from age 5-9 and a decrease from age 9-15. Results support a moderated mediation model wherein an increase in ADHD symptoms throughout childhood was predicted from early childhood exuberant temperament by way of EF, but only for children whose parents displayed less directive parenting. Findings suggest identifiable early markers of risk, including temperament, parenting, and EF- pointing to possible targets for early intervention/prevention.

Differentiating neural sensitivity and bias during face-emotion processing in youth: a computational approach.

The ability to interpret face-emotion displays is critical for the development of adaptive social interactions. Using a novel variant of a computational model and fMRI data, we examined behavioral and neural associations between two metrics of face-emotion labeling (sensitivity and bias) and age in youth. Youth and adults (n = 44, M age = 20.02, s.d. = 7.44, range = 8-36) completed an explicit face-emotion labeling fMRI task including happy to angry morphed face emotions. A drift-diffusion model was applied to choice and reaction time distributions to examine sensitivity and bias in interpreting face emotions. Model fit and reliability of parameters were assessed on adult data (n = 42). Linear and quadratic slopes modeled brain activity associated with dimensions of face-emotion valence and ambiguity during interpretation. Behaviorally, age was associated with sensitivity. The bilateral anterior insula exhibited a more pronounced neural response to ambiguity with older age. Associations between sensitivity and bias metrics and activation patterns indicated that systems encoding face-emotion valence and ambiguity both contribute to the ability to discriminate face emotions. The current study provides evidence for age-related improvement in perceptual sensitivity to facial affect across adolescence and young adulthood.

Examining the Relations Between Children's Vagal Flexibility Across Social Stressor Tasks and Parent- and Clinician-Rated Anxiety Using Baseline Data from an Early Intervention for Inhibited Preschoolers.

Early behavioral inhibition (BI) is a known risk factor for later anxiety disorder. Variability in children's parasympathetic nervous system (PNS) functioning may provide insight into the substantial heterogeneity in anxiety outcomes for children high in BI. However, gaps persist due to an over-reliance on static measures of functioning, which limits our ability to leverage PNS functioning to identify risk for anxiety. We address these gaps using baseline data from an early intervention study of inhibited preschoolers by characterizing vagal flexibility (VF), an index of non-linear change in PNS functioning, across social stressor tasks and by examining the associations between VF and anxiety. One hundred and fifty-one parents and their 3.5- to 5-year-old children were selected on the basis of BI to participate in an early intervention program (ClinicalTrials.gov registration: NCT02308826). A structural equation modeling framework was used to model children's VF across tasks designed to mimic exposure to novel social interactions and to test the predictive links between VF and anxiety. Children who showed less VF, characterized by less suppression and flatter recovery, were rated by both parents and clinicians as more anxious. Moreover, a multiple group model showed that children meeting diagnostic criteria for social anxiety disorder demonstrated significantly less VF across social stressor tasks. Among inhibited youth, reduced VF is a risk factor for anxiety and may reflect an individual's reduced capacity to actively cope with external demands. Study results contribute to our understanding of the regulatory processes underlying risk for anxiety in early childhood.

Lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: new insights attained by mass spectrometry.

PURPOSE: Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level which is currently defined as less than 50 ng/dl. The results of previous studies are based on testosterone immunoassays that have insufficient accuracy in the low range. In this study we reevaluated serum testosterone concentrations in men on androgen deprivation therapy using isotope dilution-liquid chromatography-tandem mass spectrometry, an accurate method of measuring testosterone in the castrate range. MATERIALS AND METHODS: Subjects underwent surgical castration (34) or received a luteinizing hormone-releasing hormone agonist (32). Serum samples were obtained more than 3 months after surgery or initiation of luteinizing hormone-releasing hormone agonist therapy. Testosterone levels were determined using isotope dilution-liquid chromatography-tandem mass spectrometry. Dihydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and inhibin B levels were determined. RESULTS: All subjects had serum testosterone values less than 50 ng/dl and 97% had testosterone concentrations less than 20 ng/dl. Medically castrated men had significantly lower testosterone levels (median 4.0 ng/dl, range less than 2.9 to 20.2) than those surgically castrated (median 9.2 ng/dl, range less than 2.9 to 28.8, p <0.001). No difference was found in dehydroepiandrosterone sulfate, androstenedione and sex hormone-binding globulin levels between the groups, whereas inhibin B levels were significantly higher in the luteinizing hormone-releasing hormone agonist treated group. CONCLUSIONS: Using an accurate technique for testosterone measurement, subjects on luteinizing hormone-releasing hormone agonist therapy had significantly lower testosterone concentrations than men who underwent surgical castration. The clinical relevance of these findings remains to be determined.

Intraprostatic testosterone and dihydrotestosterone. Part I: concentrations and methods of determination in men with benign prostatic hyperplasia and prostate cancer.

Owing to inconsistencies and methodological differences, the present peer-reviewed literature lacks conclusive data on the intraprostatic levels of androgens, in particular dihydrotestosterone (DHT), in untreated benign prostatic hyperplasia (BPH) and prostate cancer. To date, no difference has been shown between DHT concentrations in normal prostatic tissue and BPH, and nor has a difference been shown in DHT concentrations between the histologically distinct regions of the prostate. Recent literature has also failed to show a consistent difference in androgen level between BPH and prostate cancer. The role of intraprostatic DHT in the pathogenesis of BPH and in the initiation and progression of prostate cancer thus remains to be established. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels may lead to more optimized and more personalized forms of treatment, and probably new therapeutic targets as well.

Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer.

Androgen deprivation therapy (ADT) and 5-α-reductase (5AR) inhibition are used in the treatment of men with advanced or metastatic prostate cancer and benign prostatic hyperplasia (BPH), respectively. These drugs exert their effect by lowering androgen levels in the serum and allegedly, the prostate gland. It is, however, unknown whether (increased) intraprostatic androgen levels are associated with the pathogenesis of BPH and with the initiation and progression of prostate cancer. Also, it is unclear whether intraprostatic dihydrotestosterone (DHT) levels correlate with a response to initial hormonal therapy or with patient outcome. These uncertainties have resulted from the finding that serum testosterone levels do not necessarily reflect those in the prostate gland. Intraprostatic DHT levels of men being treated with 5AR inhibition, of those treated with ADT for hormone-naive prostate cancer, and of those with castration-resistant prostate cancer are all altered in an equivalent manner because of hormonal manipulation. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels, may lead to treatment that is tailored to the needs of the individual patient, and probably to new therapeutic targets as well.

Transdiagnostic Implications of Parental Socialization of Child and Adolescent Emotional Development: Commentary and Future Directions.

This special issue consists of 23 articles focusing on parent socialization of emotion in children and adolescents as a transdiagnostic factor for the development of psychopathology. The papers in this special issue span various emotion socialization domains, methodologies, ages, and clinical and non-clinical populations, highlighting the promise, as well as complexities of, such transactional work. Our goals for this commentary include synthesizing the articles, highlighting common themes, and suggesting future research initiatives involving measurement, developmental, and cultural considerations. It is our hope that the research presented in this special issue will inspire future, high-quality research on this topic and ultimately improve outcomes for children and adolescents at risk for poor emotion regulation and psychopathology.

Dynamics of serum testosterone during the menstrual cycle evaluated by daily measurements with an ID-LC-MS/MS method and a 2nd generation automated immunoassay.

BACKGROUND: Testosterone concentrations in normally cycling women are assumed to be elevated around the time of ovulation. The clinical relevance of changing testosterone concentrations during the menstrual cycle, however, is unclear. Poor performance of current direct immunoassays for testosterone at low concentrations confounds this issue. Therefore, our objective was to assess daily testosterone fluctuation during the menstrual cycle by a thoroughly validated isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) method and to evaluate whether an ARCHITECT® 2nd Generation Testosterone fully automated immunoassay is equally suited for this purpose. METHODS: Testosterone was measured in serum obtained daily during the menstrual cycle of 25 healthy women, characterized by biochemical and physical examination. RESULTS: Performance of the ID-LC-MS/MS method was concordant with a published reference method (y=1.007x-0.056 nmol/L; r=0.9998). Comparison of the immunoassay to ID-LC-MS/MS yielded y=1.095x+0.104 nmol/L (r=0.9031). Overall, testosterone concentrations were higher mid-cycle, but a peak was not discernible in each individual. Apart from a persistent positive bias, the immunoassay measured the same testosterone profiles as the ID-LC-MS/MS method. The reference interval in women was 0.30-1.69 nmol/L (8.7-48.7 ng/dL) for ID-LC-MS/MS and 0.50-2.00 nmol/L (14.4-57.7 ng/dL) for the immunoassay. CONCLUSION: The elevation of mid-cycle testosterone concentrations is statistically significant, although not clinically relevant since day-to-day variation is higher and independent of the menstrual cycle. In this light, a single testosterone measurement might not be reflective of the overall testosterone status in an individual. Measurements obtained using the 2nd generation immunoassay gave comparable results across the menstrual cycle.

Salivary testosterone in female-to-male transgender adolescents during treatment with intra-muscular injectable testosterone esters.

INTRODUCTION: In our hospital, female-to-male (FtM) transgender adolescents from the age of 16 are treated with two- or four-weekly intra-muscular injections of testosterone-esters. Some patients treated with four-weekly injections have complaints of fatigue and experience mood swings towards the end of the inter-injection period, which calls for an evaluation of the time-course of testosterone levels between injections. Evaluation of salivary testosterone is a practical approach for sequential measurements. Since only ∼2% of total serum testosterone is present in saliva, a sensitive assay is necessary. The objective was to develop an isotope dilution-liquid chromatography-tandem mass spectrometry method (ID-LC-MS/MS) for salivary testosterone measurements and to evaluate the testosterone profiles after testosterone-ester mixture injections in FtM-adolescents. EXPERIMENTAL: FtM treated with 125 mg/2 weeks or with 250 mg/4 weeks depots of testosterone-ester mixture collected saliva at different time intervals. Salivary testosterone was measured by a thoroughly validated ID-LC-MS/MS assay. RESULTS: An ID-LC-MS/MS method for measuring salivary testosterone was developed with adequate accuracy and specificity. The reference range was established at 135-400 pmol/L. Testosterone levels peaked supra-physiologically immediately post-injection, and decreased to levels within the male reference range after nine days in all patients. 250 mg/4 weeks depots resulted in values below the reference range at the end of the 4 weeks. DISCUSSION: The development of an adequate ID-LC-MS/MS method for measuring salivary testosterone allowed us to investigate the testosterone profile in FtM-adolescents after testosterone-esters mixture injections. These injections lead to extreme concentrations which may affect the wellbeing of the patients.

Relationship between body mass index and serum testosterone concentration in patients receiving luteinizing hormone-releasing hormone agonist therapy for prostate cancer.

OBJECTIVE: To evaluate the relationship between the body mass index (BMI) and serum testosterone concentrations in men receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer. MATERIALS AND METHODS: A total of 66 white men were included in the present study. All subjects had received LHRH agonist therapy for ≥ 3 months. The BMI was calculated, and the subjects were classified as normal weight (i.e. BMI <25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI >30 kg/m(2)). The serum testosterone concentration was determined using the highly sensitive isotope dilution-liquid chromatography-tandem mass spectrometry technique. The sex hormone-binding globulin level was determined using an immunometric assay, and the free serum testosterone concentration was calculated. RESULTS: The median serum testosterone concentration of the patients with a BMI <25 kg/m(2) was 5.5 ng/dL. The patients with a BMI of 25-30 kg/m(2) had a median serum testosterone concentration of 3.8 ng/dL. Those patients with a BMI >30 kg/m(2) had a median concentration of 5.7 ng/dL. No significant difference in the serum testosterone concentrations among the 3 groups was found. The sex hormone-binding globulin levels declined with an increasing BMI. The concentration of free testosterone was significantly greater in the obese men. CONCLUSION: Using an ultrasensitive technique of serum testosterone measurement, the present data have shown that no difference exists in the serum testosterone concentration in the castrate range among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer. From our findings and current knowledge, more stringent follow-up or changes in dosage or dosage intervals of LHRH agonist therapy in those with a greater or high BMI is not warranted.

Reduction in 24-hour plasma testosterone levels in subjects who showered 15 or 30 minutes after application of testosterone gel.

STUDY OBJECTIVE: To investigate whether showering, to prevent the involuntary transfer of testosterone to others through skin contact, either 15 or 30 minutes after application of testosterone gel would significantly affect plasma testosterone levels. DESIGN: Prospective 3-way crossover trial. SETTING: University hospital in the Netherlands. SUBJECTS: Ten agonadal female-to-male transsexuals who had sex-reassignment surgery at least 3 months earlier. INTERVENTION: Subjects were randomized to one of three application regimens for testosterone gel 50 mg/day, each lasting 7 days: testosterone application after showering (standard regimen), shower was taken 30 minutes after testosterone application, or shower was taken 15 minutes after testosterone application. Subjects then crossed over to each of the other two application regimens for a total of 21 days of study participation. MEASUREMENTS AND MAIN RESULTS: On day 7 of each application regimen, mean plasma testosterone levels were determined before testosterone application and at 1, 4, 7, and 10 hours after application. With the standard regimen, mean plasma testosterone levels at all time points after application were in the normal range: mean ± SD average concentration 994 ± 1026 ng/dl. When a shower was taken 30 or 15 minutes after application, plasma testosterone levels at 1, 4, 7, and 10 hours were significantly lower: mean ± SD average concentration 401 ± 231 ng/dl for 30 minutes after application (p<0.01) and 320 ± 248 ng/dl for 15 minutes after application (p<0.01). CONCLUSION: Showering within 30 minutes after application of testosterone gel 50 mg/day reduces absorption of testosterone and results in unacceptably low plasma testosterone levels in most users. Therefore, this strategy cannot be recommended to prevent involuntary transfer of testosterone.

Serum testosterone levels measured by isotope dilution-liquid chromatography-tandem mass spectrometry in postmenopausal women versus those in women who underwent bilateral oophorectomy.

BACKGROUND: Differentiation between subtle changes in low serum testosterone concentrations, common in women and children, is not possible with current commercially available assays. The objectives of the study were to develop a method based on stable isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) with adequate sensitivity and specificity and to investigate the applicability of this assay in serum samples from pre- and postmenopausal women. METHODS: For 16 women, testosterone levels were measured in blood samples drawn two years before and after physiological menopause, and for eight women in samples drawn before and after bilateral oophorectomy. Testosterone was extracted from serum, derivatized and analysed on an LC-MS/MS. RESULTS: The developed ID-LC-MS/MS method allowed for specific and reproducible measurement of testosterone. Comparison with stable isotope dilution-gas chromatography coupled to mass spectrometry detection by Deming regression analysis gave a slope of 1.025 and an intercept of 0.055 nmol/L (r = 0.9998). A significant decrease was found in testosterone concentrations before and after bilateral oophorectomy (P = 0.02), whereas no significant difference was found before and after natural menopause (P = 0.4). CONCLUSIONS: The ID-LC-MS/MS assay measures serum testosterone with acceptable accuracy and is useful in female samples, supporting the conclusion that the postmenopausal ovary contributes to circulating testosterone. To our knowledge, our analytical method compares favourably to similar published methods in terms of sensitivity. The sensitivity and specificity of this method comply with the reference method for measurement of testosterone in serum samples of women, children and men suffering from hypogonadism and can also be used for men with testosterone in the reference range.