Gestational diabetes in women living with HIV in Botswana: lower rates with dolutegravir- than with efavirenz-based antiretroviral therapy.

BACKGROUND: There are few data on the prevalence of gestational diabetes (GDM) in pregnant women living with HIV (WLHIV) in sub-Saharan Africa, particularly those using integrase strand transfer inhibitors such as dolutegravir (DTG). METHODS: We prospectively enrolled pregnant WLHIV and pregnant women without HIV ≥18 years old in Gaborone, Botswana, excluding those with pre-existing diabetes. We screened for GDM using a 75 g oral glucose tolerance test (OGTT) performed at 24-28 weeks' gestation or at the earliest prenatal visit for those presenting after 28 weeks. Logistic regression models were fitted to assess the association between maternal HIV infection and GDM. Subgroup analyses were performed among WLHIV to assess the association between maternal antiretroviral therapy (ART) in pregnancy [DTG vs. efavirenz (EFV) with tenofovir/emtricitabine] and GDM. RESULTS: Of 486 pregnant women, 66.5% were WLHIV, and they were older than women without HIV (median age 30 vs. 25 years, P < 0.01). Among WLHIV, 97.8% had an HIV-1 RNA level < 400 copies/mL at enrolment. Overall, 8.4% had GDM with similar rates between WLHIV and those without HIV (9.0% vs. 7.4%). The WLHIV receiving DTG-based ART had a 60% lower risk for GDM compared with those on EFV-based ART (adjusted odds ratio = 0.40, 95% CI: 0.18-0.92) after adjusting for confounders. CONCLUSIONS: Pregnant WLHIV on ART in Botswana were not at increased risk of GDM compared with women without HIV. Among WLHIV, the risk of GDM was lower with DTG- than with EFV-based ART. Further studies with larger cohorts are warranted to confirm these findings.

Improvement in lipids after switch to boosted atazanavir or darunavir in children/adolescents with perinatally acquired HIV on older protease inhibitors: results from the Pediatric HIV/AIDS Cohort Study.

OBJECTIVES: Dyslipidaemia is common in perinatally HIV-infected (PHIV) youth receiving protease inhibitors (PIs). Few studies have evaluated longitudinal lipid changes in PHIV youth after switch to newer PIs. METHODS: We compared longitudinal changes in fasting lipids [total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and TC:HDL-C ratio] in PHIV youth enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP) study who switched to atazanavir/ritonavir (ATV/r)- or darunavir/ritonavir (DRV/r)-based antiretroviral therapy (ART) from an older PI-based ART and those remaining on an older PI. Generalized estimating equation models were fitted to assess the association of a switch to ATV/r- or DRV/r-based ART with the rate of change in lipids, adjusted for potential confounders. RESULTS: From 2007 to 2014, 47 PHIV children/adolescents switched to ATV/r or DRV/r, while 120 remained on an older PI [primarily lopinavir/r (72%) and nelfinavir (24%)]. Baseline age ranged from 7 to 21 years. After adjustment for age, Tanner stage, race/ethnicity, and HIV RNA level, a switch to ATV/r or DRV/r was associated with a more rapid annual rate of decline in the ratio of TC:HDL-C. (ß = -0.12; P = 0.039) than remaining on an older PI. On average, TC declined by 4.57 mg/dL/year (P = 0.057) more in the switch group. A switch to ATV/r or DRV/r was not associated with the rate of HDL-C, LDL-C, or TG change. CONCLUSIONS: A switch to ATV/r or DRV/r may result in more rapid reduction in TC and the TC:HDL-C ratio in PHIV youth, potentially impacting long-term cardiovascular disease risk.

Primary Care Provider Management of Congenital Hypothyroidism Identified Through Newborn Screening.

OBJECTIVE: To assess Primary Congenital Hypothyroidism (CH) management patterns and feasibility of providing long-term care for patients with CH identified through newborn screening by Primary Care Providers (PCPs) in California and Hawaii. STUDY DESIGN: A survey was mailed to all physicians (N=823) listed as the referral doctor for confirmed patients with CH identified through newborn screening programs in both states between 01/01/2009-12/31/2013. Information was collected on CH management patterns, barriers to providing care, and knowledge on CH treatment. Descriptive statistics and bivariate logistic regression results were reported. RESULTS: 206 PCPs completed the survey. Among these, 78% currently have patients with CH and 91% indicated willingness to provide long-term care to new patients with CH. Among PCPs currently caring for patients with CH, 17% managed CH by themselves with limited assistance from endocrinologists; 63% were involved in managing CH but endocrinologists played a larger role than PCPs; 19% were not involved in CH care. Only 49% of PCPs correctly answered questions regarding recommended follow-up frequencies and 23% knew the correct age for a trial off levothyroxine for suspected transient CH. Top two perceived barriers to providing long-term care included "need guidance or support from endocrinologists" (61%) and "not familiar with CH treatment guidelines" (28%). CONCLUSION: The majority of PCPs surveyed are willing to provide long-term care to patients with CH, but need support from endocrinologists and increased knowledge about current treatment guidelines.

Effects of exenatide on weight and appetite in overweight adolescents and young adults with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS. OBJECTIVE: The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS. METHODS: Ten overweight and obese subjects with PWS (13-25 years) were recruited for a 6-month open-label, non-randomized, longitudinal study conducted at Children's Hospital Los Angeles. Exenatide was given using standard diabetes dosing without dietary modifications. Weight, body mass index (BMI), truncal fat, appetite and plasma acylated ghrelin were measured over 6 months. Mixed meal tolerance tests were performed at 0 and 6 months. RESULTS: Appetite scores significantly decreased from baseline (32.2 ± 8.7) after 1, 3 and 6 moths of treatment (27.5 ± 8.8, 25.4 ± 9.3, and 25.4 ± 7.2 respectively; p = 0.004). Hemoglobin A1c decreased significantly after treatment, but weight, BMI z-score and adiposity did not. There was no significant change in ghrelin. CONCLUSIONS: This is the first longitudinal investigation of the effects of exenatide in subjects with PWS. It was effective in decreasing appetite, without change in weight or BMI in the short term. Larger, controlled, longer-term trials in patients with PWS are needed to confirm the efficacy and safety of exenatide and to evaluate whether its use might induce weight loss when given in conjunction with behavioural modification.

A four-year, open-label, multi-center, randomized, two-arm study of Genotropin® in patients with idiopathic short stature: comparison of an individualized, target-driven treatment regimen to standard dosing of Genotropin® - analysis of two-year data.

BACKGROUND: Several models have been developed to predict growth response to growth hormone (GH) based on auxological and biochemical parameters for children with non-GH-deficient, idiopathic short stature (ISS). OBJECTIVE: To demonstrate if an individualized, formula-based, target-driven GH regimen for children with ISS would lead to a height (Ht) gain to -1.3 SDS during the first 24 months of treatment of this 4-year study, with less variability than with standard weight-based dosing. METHODS: A 4-year, open-label, multi-center, randomized, two-arm study comparing formula-based dosing of Genotropin® GH from 0.18 to 0.7 mg/kg/week versus standard FDA-approved ISS dosing of Genotropin® (0.37 mg/kg/week). Subjects (n = 316, 89 females) were prepubertal, 3-14 years of age, bone age 3-10 years (m) and 3-9 years (f), naive to GH treatment, Ht SDS -3 to -2.25, Ht velocity <25th percentile for bone age, and peak GH >10 ng/ml. RESULTS: The majority (83%) of subjects had Ht SDS within the normal range by 2 years. All subjects displayed catch-up growth consistent with other studies of GH treatment of ISS. CONCLUSION: The formula-based therapy did not meet the primary endpoint achieving targeted gain with lower variability. No new safety concerns were found.

Plasma C-type natriuretic peptide forms and thyroid status in prepubertal children with acquired thyroid disease.

OBJECTIVE: C-type natriuretic peptide (CNP) and thyroid hormone (TH) are essential for normal skeletal growth. Plasma CNP peptides correlate with growth velocity, but the relationship between thyroid status and CNP production is unknown. This study examined the impact of restoring normal TH levels on CNP and height velocity (HV) in children with acquired hypo- and hyperthyroidism. DESIGN: We performed a prospective, observational study in prepubertal children with acquired hypothyroidism (n = 15) and hyperthyroidism (n = 12). MEASUREMENTS: Blood levels of CNP, amino-terminal proCNP (NTproCNP), bone-specific alkaline phosphatase (BSAP), IGF-I and TH levels were measured before and during the first 6 months of standard treatment for hypo- and hyperthyroidism, and correlations were determined. RESULTS: At baseline, HV, CNP, NTproCNP and BSAP were significantly higher in hyper- than in hypothyroid subjects. Changes in TH after treatment were closely coupled to change in CNP and NTproCNP in hyperthyroid, but not in hypothyroid, children. In addition, a positive association of HV with CNP peptides was found during treatment of hyperthyroidism. Normalizing TH did not correlate with changes in BSAP or IGF-I in either group. CONCLUSIONS: Plasma CNP peptides are higher in children with hyperthyroidism than in those with hypothyroidism at diagnosis and, in hyperthyroid children, change concordantly with TH and HV during treatment. Differential responses of CNP in the two groups suggest CNP production is dependent on growth plate activity and not a direct effect of TH on CNP gene expression. Our findings suggest novel mechanisms underlying changes in skeletal response during treatment in children with acquired thyroid disease.

Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

OBJECTIVES: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. METHODS: A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. RESULTS: The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). CONCLUSIONS: HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.

Effect of protease inhibitors combined with standard antiretroviral therapy on linear growth and weight gain in human immunodeficiency virus type 1-infected children.

Children with HIV-1 infection and poor growth have a significant increase in the risk of death. We studied the effects of protease inhibitors on the height and weight of 27 HIV-1-infected children and found that in our small pilot study, protease inhibitor therapy had a positive effect on the heights of HIV-1-infected children. Accelerated height velocity was sustained for at least 18 to 20 months.

Trans-sphenoidal and sphenoethmoidal encephalocele: report of two cases and review of the literature.

Basal encephaloceles are the least common form of encephalocele. Due to the critical position of the bony defect, visual and endocrinological abnormalities are frequently associated with basal encephaloceles. There is significant confusion in the classification of basal encephaloceles, particularly among trans-sphenoidal, sphenoethmoidal and intrasphenoidal subtypes. Two cases of basal encephaloceles are presented (one trans-sphenoidal and one sphenoethmoidal), along with a review of the literature. The relationship between the basal encephaloceles and endocrinological abnormalities is also emphasized.

Near-normal linear growth in the setting of markedly reduced growth hormone and IGF-1. A case report.

A 14.2-year-old prepubertal boy diagnosed with complete-type growth hormone deficiency and tertiary hypothyroidism, keeps growing in the height range between -1 and -2 SD. He has been treated with levothyroxine only. To understand the growth mechanism of this boy, we analyzed the serum growth hormone (GH) with a radioimmunoassay (RIA), serum GH bioactivity with Nb2 and erythroid progenitor cell bioassays, and growth hormone-binding protein (GHBP) with a ligand-mediated immunofunctional assay (LIFA). In addition, IGF-1 and free IGF-1 were analyzed by immunoradiometric assay (IRMA) and insulin-like growth factor-binding protein-3 (IGFBP-3) by Western immunoblot. Peak GH-RIA responses to insulin, arginine and GH-releasing factor, and nocturnal GH secretion, were low (0.5-2.3 ng/ml); bioactive GH was low (0.313 ng/ml), and GHBP was elevated (84 ng/ml). The serum levels of IGF-1 and free IGF-1 were continuously low, 17.1-39.3 and 0.17-0.26 ng/ml, respectively. Moreover, serum IGFBP-3 levels were low (1.68- 1.39 mg/l) and IGFBP-3 protease activity was negative. Prolactin and insulin were in the normal range. The result of the assay for growth-promoting activity showed that the patient's serum stimulated normal erythroid progenitor cells twice as potently as did healthy thin adult control serum. These results suggest that GH and IGF-1 are not indispensable for maintaining physical growth in this boy. Thus, it appears that circulating GH and IGF-1 are not mandatory requirements for maintaining normal physical growth, and other, as yet uncharacterized, pathways or growth factors might be sufficiently compensatory under certain conditions.

Aplasia of right internal carotid artery and hypopituitarism.

BACKGROUND: The pathogenesis of congenital hypopituitarism is unknown in many cases. OBJECTIVE: We report a case of congenital pan-anterior hypopituitarism in association with a complex vascular abnormality involving the central nervous system, nasal pyriform aperture stenosis, and a single central maxillary incisor. MATERIALS AND METHODS: MRI and MRA were used to define this patient's complex vascular anomaly. RESULTS: The vascular abnormality consists of absence of the right common carotid artery, the right internal carotid artery, the A1 segment of the right anterior cerebral artery, the anterior communicating artery, and partial absence of the M1 segment of the right middle cerebral artery. CONCLUSION: This unusual vascular anomaly may contribute to the pathogenesis of some cases of congenital hypopituitarism and related midline abnormalities, or may result from a common defect that causes pituitary insufficiency.

Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor.

We have analyzed the GH receptor (GHR) gene in four individuals with Laron syndrome, and a missense mutation was identified for each patient in the extracellular domain of the GHR (D152H, I153T, Q154P, and V155G). The D152H mutation was previously reported. We have reproduced the three novel mutations in the GHR complementary DNA and analyzed their consequences in human 293 transfected cells. In cells expressing the I153T and V155G mutants, binding of [125I]human GH at the cell surface was very low, whereas binding to total membrane fractions was much less affected, suggesting impaired cell surface expression. Binding assays with cells expressing the Q154P mutant revealed severe defects both at the cell surface and in total particulate membrane fractions. Immunofluorescence experiments confirmed that cell surface expression of the three mutants was altered, and colocalization studies suggested that most of the mutant receptors are retained in the endoplasmic reticulum. Endoglycosidase H resistance tests also indicated that the majority of I153T and V155G GHRs are trapped in the endoplasmic reticulum. Thus, mutations on contiguous amino acids of the GHR result in various defects. The I153T, Q154P, and V155G mutations mainly affect intracellular trafficking and binding affinity of the receptor, whereas the D152H mutation affects receptor expression, dimerization, and signaling.

Minipuberty of infancy and adolescent pubertal function in adrenal hypoplasia congenita.

An infant and his uncle, both with adrenal hypoplasia congenita, shared the same DAX1 mutation. The adolescent uncle had hypogonadotropic hypogonadism, but the infant had a normal minipuberty of infancy. These observations suggest differences in the physiologic mechanisms regulating the hypothalamic-pituitary-gonadal axis in infancy and adolescence.

Normal growth in a patient with septo-optic dysplasia despite both growth hormone and IGF-I deficiency.

A 17 year-old female with septo-optic dysplasia (SOD) and hypopituitarism who has grown normally despite GH deficiency is presented. Her serum was examined to test current hypotheses to explain the phenomenon of growth without GH. The patient's serum possessed potent in vitro growth-promoting activity (GPA) in an erythroid progenitor-cell clonal proliferation assay consistent with the patient's normal growth performance. In contrast to previously reported cases of growth without GH, total IGF-I concentrations were very low in this patient, precluding IGF-I being responsible for the observed GPA and normal growth pattern. Furthermore, circulating free IGF-I was also low which is reported for the first time in such a case. A detailed picture of IGF-binding proteins is also presented. To test the hypothesis that hyperinsulinemia might be responsible for the observed GPA, in vitro GPA experiments were performed before and after removal of insulin by immunodepletion. Neither partial nor complete removal of insulin abolished the in vitro cell proliferation response. These data demonstrate that neither IGF-I nor insulin is the factor responsible for GPA in at least this patient with SOD and growth without GH.

Impact of overnight dexamethasone suppression on the adrenal androgen response to an oral glucose tolerance test in women with and without polycystic ovary syndrome.

In order to test the hypothesis that adrenocortical overactivity, possibly related to the stress of testing, may impact on the measurement of circulating androgen concentrations during glucose-induced hyperinsulinaemia, we prospectively screened 10 patients with the polycystic ovary syndrome (PCOS) and nine healthy control women with an oral glucose tolerance test (OGTT), before and after the administration of dexamethasone. Blood sampling was performed at 0, 30, 60, 90, and 120 min following the oral ingestion of 75 g of glucose, before and after the administration of 1.0 mg dexamethasone on the evening prior to testing. Total and free testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), cortisol, glucose and insulin were assessed during the 2 h OGTT. Women with PCOS had increased basal concentrations of free testosterone, total testosterone, androstenedione, and insulin compared to control women. In women with PCOS an acute decline in circulating concentrations of DHEAS occurred during the OGTT. In PCOS women there were no changes in other ovarian or adrenal androgens during OGTT before or following dexamethasone administration. In control women DHEA concentrations declined during the OGTT. Following overnight dexamethasone suppression in control women, circulating concentrations of DHEAS and testosterone also declined. It is concluded that: (i) in PCOS women only the concentration of circulating DHEAS decreased during glucose-induced hyperinsulinaemia and dexamethasone administration did not further alter androgen responses to an OGTT; (ii) it is possible that, in these hyperandrogenic patients, the insulin-related suppression of adrenocortical testosterone and DHEA is negated by their much greater ovarian secretion of these androgens; (iii) in control women DHEA concentrations acutely declined during the OGTT and the administration of dexamethasone resulted in the acute decline of DHEA, DHEAS, and testosterone; (iv) it appears that the stress related to testing impacts on the androgen response to OGTT, at least in healthy women.