Growth hormone therapy is associated with improved uterine dimensions in girls with Turner syndrome prior to oestrogen replacement.

BACKGROUND: Adult women with Turner syndrome (TS) have high rates of miscarriage, presumably due to the abnormal size and shape of the uterus. There is a paucity of data regarding the determinants of uterine volume (UtVol) in young girls with TS before the initiation of oestrogen replacement therapy (ERT). METHODS: We performed a cross-sectional study on premenarchal girls with TS, aged 5-15 years, pubertal stage B1-B3, not having received ERT (n = 73) and 50 age-matched healthy controls. Anthropometric parameters and a history of growth hormone (GH) therapy (≥1 year) were noted. Uterine length (UtL), UtVol, and mean-ovarian-volume (MOV) standard-deviation scores (SDS) were determined from transabdominal ultrasonography data. RESULTS: Girls with TS had lower median UtVol-SDS (-1.07 vs. 0.86; p < .001), UtL-SDS (-3.72 vs. -0.41; p < .001) and MOV-SDS (-5.53 vs. 1.96; p < .001) compared to age-matched controls. Among TS girls, recipients of GH (n = 38) had higher UtVol-SDS (-0.63 vs. -1.39; p = .0001), UtL-SDS (-1.73 vs. -6.49; p < .0001) but similar MOV-SDS compared to nonrecipients (n = 35). Those with normal uterine volume for age (NUVA, n = 29) had earlier initiation (7.8 vs. 9.3 years; p = .03) and a longer duration of GH (3.71 vs. 2.14 years; p = .002) than those with low UtVol for age (n = 44). UtVol-SDS correlated with duration of GH (ρ = 0.411, p = .01) and negatively with age at GH initiation (ρ = -0.479, p = .003). In a model adjusted for pubertal status, karyotype and height-SDS, GH use could independently predict having NUVA (odds ratio: 5.09, confidence interval: 1.63-15.94, p = .005). CONCLUSION: GH therapy has a stimulatory effect on uterine dimensions in pre-and peripubertal girls with TS. Earlier initiation and longer duration of GH is important in TS girls before ERT.

Association of adipocyte size and SREBP-1c in visceral and subcutaneous adipose tissue in non-obese type 2 diabetes mellitus.

OBJECTIVE: Non-obese type 2 diabetes seems to be common in India; hence the current study tried to understand the pathogenesis of diabetes in this group focusing on the role of adipocytes especially abdominal fat compartment. Comparison was made between non-obese subjects with newly detected diabetes and those without diabetes, in relation to levels of adipogenic factor and adipokines in pre-adipocytes and mature adipocytes respectively. RESEARCH DESIGN METHODS: Non-obese subjects (BMI-18-25 Kg/m2) were consecutively selected of whom 15 had newly-detected, treatment naïve type 2 diabetes (HbA1% ≥6.5) while 25 were control (HbA1c% ≤5.6). We examined the expression of adipocyte differentiation factor - SREBP-1c from preadipocytes and adipocyte specific adipokines- HMW isoform and total adiponectin, leptin, FABP-4, TNF-α and IL-6 from adipocytesisolated from abdominal visceral and subcutaneous adipose tissues (VAT and SCAT) by RT-PCR and as well as from serum by ELISA. Size of cultured adipocytes was measured in a fully automated imaging system microscope. RESULT: Both in SCAT and VAT, SREBP-1c and adiponectin had significantly lower expression along with increased mRNA level of inflammatory adipokinesdiabetes.Average adipocyte size and frequency of large(hypertrophied) adipocytes were comparatively higher in T2DM subjects and had significant negative correlation with SREBP-1c. HMW adiponectin level significantly reduced in the secretion from VAT and SCAT of T2DM subjects compared to control. CONCLUSION: Reduced expression of SREBP-1c in preadipocytes may lead to increased number of hypertrophied adipocytes in T2DM. Therefore, these dysfunctional hypertrophied adipocytes could cause imbalanced expression of insulin resistant and insulin sensitive adipokines.

Abnormal Body Composition Increases the Cardiometabolic Risk in Adolescents and Young Adults With Turner Syndrome.

OBJECTIVE: To determine the cardiometabolic risk of adolescents and adults with Turner syndrome (TS) and whether and how anthropometry and body composition predict this risk. METHODS: We compared the anthropometric, biochemical, and dual-energy x-ray absorptiometry-derived body composition parameters of 103 girls and women with TS aged 12 to 30 years and 103 controls of the same age and body mass index: (1) between TS with and without metabolic syndrome (MetS), (2) between the different karyotypes of TS, and (3) between growth hormone recipients and nonrecipients. RESULTS: Individuals with TS had higher prevalence rates of truncal obesity (57.2%), MetS (37.9%), prediabetes (20.4%), dyslipidemia (73.8%), hypertension (9.7%), and hepatic steatosis (15.5%) and a greater total body fat percentage (38.43% vs 34.26%) and fat mass index (9.15 vs 6.71 kg/m2) but a lower lean mass index (11.05 vs 12.49 kg/m2) than controls (P <.001). Individuals with TS and MetS (n = 39) had a higher total body fat percentage (41.74% vs 36.42%, P <.0001), truncal fat percentage (44.66% vs 36.09%, P <.0001), and visceral adipose tissue mass (495.57 vs 276 g, P <.0001) than those with TS but without MetS. Those with classic TS (45,X) had a higher prevalence of prediabetes (32.6% vs 10.5%, P =.01). Growth hormone recipients had a lower prevalence of MetS and lesser truncal obesity. Altered body composition was significantly correlated with metabolic risk. The truncal fat percentage independently predicted MetS (odds ratio, 1.12; 95% confidence interval, 1.003-1.24; P =.04). Waist circumference and waist-hip ratio predicted metabolic risk with good sensitivity and specificity. CONCLUSION: Adverse cardiometabolic risk and altered body composition start early in life in TS. Postpubertal women with TS should be routinely assessed for truncal obesity, dysglycemia, dyslipidemia, and liver steatosis, irrespective of body mass index and karyotype.

Prevalence and Predictors of Prediabetes in Adolescents and Young Adults with Turner Syndrome: A Cross-Sectional Study from Eastern India.

Background: Individuals with Turner syndrome (TS) have a high risk for prediabetes/type 2 Diabetes Mellitus (T2DM). There is scarce data regarding risk factors for prediabetes in TS, specially from South Asia. Methods: We conducted a cross-sectional study on girls with TS aged 12-30 years who had achieved pubertal stage B3 and above-spontaneously or with oestrogen. Anthropometric measurements and biochemical tests were conducted, and medical records were reviewed for details about pubertal onset and progression, growth hormone (GH) and oestrogen therapy. Results: Out of 129 patients with TS in our database, 99 met the criteria for inclusion, mean age 18.33+/-3.78 years and mean BMI 20.57+/- 3.71 kg/m2. Prevalence of prediabetes was 23.23%. Plasma-glucose measured after 75 g-oral-anhydrous-glucose-load (OGTT-PPG) identified five additional prediabetes cases, who had normal fasting plasma glucose (FPG) or HbA1c%. Compared to those without prediabetes, TS with prediabetes (n = 23) had higher mean body weight, BMI, waist circumference (WC) [42.02+/- 5.83 vs 36.22+/-8.07, 22.77+/-2.78 vs 19.91+/- 3.72, 85.26+/- 3.52 vs 81.08+/- 4.59, pall < 0.03 ], higher median WC-to-height ratio (WHtR) and WC-to-hip ratio (WHR)((0.64 [0.6-0.69] vs 0.59[0.56- 0.66], 0.9[0.84-1.12] vs 0.85[0.75-1.01], pboth < 0.02), and higher LDL-cholesterol, triglycerides, and greater prevalence of hepatosteatosis (47.1% vs 21.1%, P < 0.01). Among GH recipients (n = 36), those with prediabetes had delayed initiation and shorter duration of GH therapy. There were no differences in cardiometabolic parameters or the prevalence of diabetes between different karyotypic variants of TS. BMI, WC and WHR had significant positive correlation with FBG, OGTT-PPG and HbA1c% (pall < 0.004). Delay in oestrogen initiation had a significant correlation with OGTT-PPG (Spearman's-rho = 0.69, P < 0.004). BMI, WHR and pubertal status were independent predictors for prediabetes (OR: 1.27 [1.03-1.57]), 1.18 [1.04-1.34]) and 0.09[0.02-0.38], respectively, pall < 0.02), but karyotype was not. BMI had the highest sensitivity [cut-off: 21.04 kg/m2 (sensitivity: 82.6%, specificity: 62.2%) and WHR had the highest specificity [cut-off: 0.89 (sensitivity: 73.9%, specificity 78.4%)] for predicting prediabetes. Conclusion: Indian girls with TS have a high risk for prediabetes, irrespective of underlying karyotype and should be screened with oral glucose challenge to identify prediabetes. Timely intervention against central obesity and early initiation of GH and oestrogen should be ensured in TS. Late presenting girls should be closely monitored for dysglycaemia before and during treatment with GH and/or oestrogen.

Aromatase deficiency in a tall man: Case report of two novel mutations and review of literature.

Aromatase (CYP19A1) is the only enzyme known to catalyse the conversion of androgen to estrogen. Aromatase deficiency occurs due to mutation in CYP19A1gene which has an autosomal recessive inheritance pattern. It leads to decrease in estrogen synthesis and delayed epiphyseal closure, eunuchoid habitus and osteopenia. We are presenting here, a 24 years old male, with history of progressive increase in height and knock knees. X-ray showed open wrist and knee epiphysis. The serum testosterone level was normal and serum estradiol level was undetectable. Semen analysis showed azoospermia. Clinical exome sequencing gave two novel mutations in CYP19A1. The first variant was a novel single nucleotide deletion of thiamine at 570th base of the cDNA (c.570delT) of CYP19A1 gene. The second variant detected was again a novel one in the same gene in Exon 5 corresponding 344th base of the cDNA (c344G>A) resulting in a missense mutation of 115th arginine to glutamine in the protein. Sanger sequencing showed that the later mutation was inherited from the father. The patient was started on oral estradiol valerate for epiphyseal closure to prevent further increase in height. Only 15 mutations have been reported in the aromatase gene in males till date, our report of these novel mutations will be an add-on to the literature.

Diagnostic and prognostic utility of SF-1 in adrenal cortical tumours.

Background and Aims: Superior imaging techniques have increased the recognition of adrenal pathology. Distinguishing benign from malignant adrenocortical tumors is not always easy. Several criteria and immunohistochemical markers have been discovered which help to differentiate between adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC). Our aim here was to evaluate the diagnostic and prognostic role of steroidogenic factor-1 (SF-1) in adult adrenocortical tumors (ACT) diagnosed using the Weiss criteria. In this cohort, we have also analyzed Ki67 and p53 expression and the extent of agreement between SF-1 and Ki-67. Methodology: This was a retrospective, observational study comprising 24 cases of adult ACT over 10 years. Immunohistochemical staining for SF-1, Ki67, and p53 was done in all the cases, and the results correlated with the morphological diagnosis made using Weiss criteria. Results: SF-1 was 100% sensitive and 80% specific as a marker of malignancy. Increased SF-1 expression correlated with worse survival. There was a moderate degree of agreement between Ki-67 labeling-index and SF-1 as a marker of malignancy with the kappa coefficient being 0.75. The sensitivity of p53 was lower than Ki67 in diagnosing ACC. Conclusion: In adult ACTs, SF-1 has diagnostic significance and prognostic implication. SF-1 is a crucial, dosage-dependent survival factor in ACC. There is a moderate extent of agreement between Ki-67 and SF-1 as a marker of malignancy.

Fabkin and glucose homeostasis.

BACKGROUND AND AIMS: The pathophysiology of different types of diabetes is incompletely understood. Fatty acid binding protein 4 (FABP4), an intracellular lipid chaperone, is secreted from adipocytes (during lipolysis) and macrophage. FABP4 is known to be associated with insulin resistance. However its precise role in the pathogenesis of T2DM is unclear. Fabkin, the hormonal complex of FABP4 with ADK (Adenosine Kinase) and NDPK (Nucleoside Diphosphate Kinase) is suggested to fill this gap in understanding pathogenesis. Herein, we summarize the role Fabkin in glucose homeostasis. METHODS: Published relevant manuscripts that discussed the effect of FABP4 and Fabkin on glucose homeostasis were reviewed. RESULTS: The formation of Fabkin complex is driven by the strong affinities of FABP4 to ADK and to inherent high-affinity interaction of ADK with NDPK. It does not have any definite receptors. The complex acts through the following pathways: i) by modulation of Glucose-Stimulated Insulin Signalling (GSIS) through extracellular ADP/ATP interaction via G-protein-coupled purinergic P2Y1 receptors in pancreatic ß-cells which are potently agonized by ADP and antagonized by ATP. Fabkin drives ADK to produce ATP, coupled with reduced generation of ADP. This results in low extracellular ADP/ATP ratio which leads to impairment of insulin secretion, ii) by regulating intracellular calcium dynamics iii) by producing Endoplasmic Reticulum (ER) stress. CONCLUSIONS: Fabkin may integrate energy balance with functions of metabolic organs and thus play a major role in glucose homeostasis.