Effect of Combined Low Dose hCG, FSH and Testosterone therapy (LFT Regimen) versus Conventional High Dose hCG and FSH on Spermatogenesis and Biomarkers in Men with Hypogonadotropic Hypogonadism.

OBJECTIVE: In male Congenital hypogonadotropic hypogonadism(CHH), it was observed that lower dose human gonadotropic hormone(hCG) can maintain normal intratesticular testosterone(ITT) levels. We propose this study to compare the Low-Dose hCG, follicle stimulating hormone(FSH), and Testosterone(T) [LFT Regimen] to conventional treatment to induce virilization and fertility. DESIGN: This open-label randomized pilot study was conducted from June 2020 to December 2021. SUBJECTS AND OUTCOME MEASURES: CHH were randomly assigned to either the LFT regimen (Group A)-low-dose hCG (500U thrice per week), FSH(150U thrice per week) and T(100mg biweekly) or conventional therapy(GroupB) with high hCG dose(2000U thrice per week) and the same FSH dose. The hCG dosage was titrated to reduce Anti-mullerian hormone(AMH) by 50% and normalization of plasma T in groups A and B, respectively. The primary objective was to compare the percentage of individuals who achieved spermatogenesis between the two groups. RESULTS: Out of 30 patients, 23(76·7%) subjects achieved spermatogenesis, and the median time was 12(9-14·9)months. There was no difference in achieving spermatogenesis between the two groups (64·3%vs87·5%,p=0·204), and even the median time for spermatogenesis was similar (15monthsvs12months,p=0·248). Both groups had non-significant median plasma AMH at spermatogenesis,[6·6ng/ml(3·3-9·76) vs 4·41ng/ml(2·3-6·47),p=0·298]. Similarly, the median plasma Inhibin B at spermatogenesis between groups were comparable[152·4pg/ml(101·7-198·0)vs149·1pg/ml(128·7-237·3),p=0·488]. CONCLUSIONS: A reasonable approach to induce fertility in male CHH is to initiate combination therapy using FSH, low-dose hCG targeting AMH <6·9 ng/ml, along with T to achieve normal range. Monitoring AMH could serve as a proxy indicator of spermatogenesis.

Limited Invasive Protocol: Optimizing Diagnostic Modalities in Corticotropin Mediated Cushing Syndrome.

BACKGROUND: To limit the role of bilateral inferior petrosal sinus sampling (BIPSS) in distinguishing between Cushing disease (CD) and ectopic Cushing syndrome (ECS), recent reports have proposed a noninvasive approach based on a combination of biochemical testing and radiological imaging as an alternative to the conventional invasive strategy (CIS). However, this strategy requires further validation. The current study aimed to evaluate 2 limited invasive protocols (LIP-1 and LIP-2) in limiting the role of BIPSS while maintaining a diagnostic accuracy similar to that of CIS. METHODS: This was a single-center study conducted on individuals with corticotropin-dependent Cushing syndrome. The LIPs were based on performing high-dose dexamethasone suppression (>50% cut-off in first [LIP-1] and >80% in second [LIP-2]) and magnetic resonance imaging of the sella in all individuals and selective use of computed tomography of the chest and abdomen before BIPSS. These LIPs were evaluated for limiting the use of BIPSS, their accuracy, and cost in comparison to CIS. RESULTS: Of the 206 individuals, 114 (97 of CD and 21 of ECS) were eligible for the current study. Using LIP-1, LIP-2, and CIS, BIPSS could have been avoided in 62.3%, 35.9%, and 25.4% of individuals, respectively. The positive predictive value for CD using LIP-1 and LIP-2 was 98.9% and 100%, respectively. The cost per patient evaluated using LIP-1, LIP-2, and CIS was $602.21, $966.81, and $1107.78, respectively. CONCLUSION: LIPs represent an equally accurate, less invasive, and more cost-effective alternative to the CIS for distinguishing between CD and ECS.

Four cases of Graves' disease following viral vector severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) vaccine.

Mass immunization has led to a decrease in the transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) worldwide. At the same time, awareness regarding possible adverse effects of newly developed vaccines is critical. The present study was undertaken to report the cases of Graves' disease occurring after administration of viral vector vaccine (ChAdox1nCoV-19) and describe the clinical profile, response to treatment, and effect of administration of a second dose in patients developing Graves' disease. Four cases of Graves' disease after administration of the vaccine were noted. Two of these had a mild thyroid eye disease. Three cases were female and had a family/self-history of autoimmune disease. All cases responded well to treatment and became euthyroid within two to four months. Two patients exhibited worsening thyrotoxicosis after receiving a second dose of the vaccine. We propose that the temporal relationship between administration of the vaccine and the onset of symptoms establishes Graves' disease as an adverse event after the SARS-CoV-2 viral vector vaccine. Close follow-up is advisable in individuals developing Graves' disease after SARS-CoV-2 vaccination.

Differential loss of fat in polycystic ovary syndrome: A welcome or warning sign?

Lipodystrophy syndrome is a rare disorder characterized by selective deficiency of adipose tissue and severe insulin resistance resulting in metabolic complications. Its presentation as polycystic ovary disease (PCOD) is even rarer. We present a 23-year-old woman who came with complaints of oligomenorrhoea and hirsutism. When specifically asked, she accepted noticing loss of fat from some areas of her body. Examination showed loss of fat from the face, buttocks and thighs. Her investigations revealed deranged blood sugars, transaminitis, dyslipidaemia and elevated serum testosterone; ultrasonography showed fatty liver and polycystic ovary. Fat composition measurement revealed loss of fat from lower limbs and increased ratio of trunk-to-leg fat. Based on these findings, a diagnosis of lipodystrophy was made. She was started on metformin, statins and ursodeoxycholic acid. Blood sugars, lipid profile and dyslipidaemia improved over a period of 6 months. We suggest that in lean patients with PCOD, lipodystrophy becomes a differential diagnosis, so attention should be paid to body fat distribution in them. Despite normal body mass index (BMI), these patients tend to develop metabolic complications as in our patient (BMI 21.5). This diagnosis has long-term implications in view of its association with metabolic complications.

Etiology-, Sex-, and Tumor Size-Based Differences in Adrenocorticotropin-Dependent Cushing Syndrome.

OBJECTIVE: To examine demographic, clinical, and biochemical differences in patients with adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS) based on etiology, sex, and tumor size. METHODS: This was a single-center study of 211 patients with ACTH-dependent CS followed for 35 years. Patients were stratified into 3 groups based on etiology: Cushing disease (CD)/transsphenoidal surgery, Cushing disease/total bilateral adrenalectomy (CD/TBA), and ectopic ACTH secretion (EAS). Patients were also stratified based on sex and tumor size (nonvisualized, microadenoma, and macroadenoma). RESULTS: CD was the commonest cause of ACTH-dependent CS (190; 90%). Most patients presented in the third decade (median age, 29 years). Clinical features, cortisol, and ACTH were significantly greater in the EAS group. The CD/TBA group had more nonvisualized tumors (22% vs 8%; P = .000) and smaller tumor size (4 vs 6 mm; P = .001) compared with the CD/transsphenoidal surgery group. There was female predominance in CD (2.06:1) and male predominance in EAS (2:1). Men had shorter duration of symptoms (2 years; P = .014), were younger (23 years; P = .001), had lower body mass index (25.1 kg/m2; P = .000), and had more severe disease (low bone mineral density, hypokalemia). Macroadenomas were frequent (46; 24.2%), and ACTH correlated with tumor size in CD (r = 0.226; P = .005). CONCLUSION: Our cohort presented at an earlier age than the Western population with a distinct, but slightly lower, female predilection. Patients with CD undergoing TBA had frequent negative imaging. Men had a clinical profile suggesting aggressive disease. Microadenoma and macroadenoma were difficult to distinguish on a clinicobiochemical basis.

Differential independent impact of the intraoperative use of navigation and angled endoscopes on the surgical outcome of endonasal endoscopy for pituitary tumors: a prospective study.

Despite widespread popularity of navigation and angled endoscopes in endonasal endoscopy, there are hardly few studies on their efficacy with the extent of resection or retreatment. This is probably the first study to assess the independent impact of these adjuncts among pituitary tumors. Patients with pituitary tumors undergoing endonasal endoscopy were prospectively studied for their demographics, clinico-radiological features, intraoperative use of navigation, and angled endoscopes, in relation to gross total resection (GTR), near total resection (NTR), endocrine remission, and retreatment. Pertinent statistical analyses were performed. Among a total of 139 patients, navigation and angled endoscopes could be used in 54 and 48 patients, respectively, depending upon their availability rather than chosen as per the case. There was no significant difference in baseline characteristics in relation to their use. The surgeon's perception of immediate benefit was noted among 51.9% while using navigation. The use of angled endoscopes towards the end of resection could help with additional tumor removal in 62.5% of patients. Overall, the use of navigation resulted in a significantly higher GTR (80.8% vs. 59.7%, OR 2.83, p = 0.01), a higher GTR/NTR (86.5% vs. 70.8%, OR 2.65, p = 0.04), and a lower retreatment rate (7.7% vs. 20.8%, OR 3.15, p = 0.05) than the others. In functioning tumors with cavernous sinus invasion, navigation had significantly increased remission rates (69.2% vs. 0%, p = 0.03). The use of angled endoscopes yielded a significantly higher GTR/NTR (91.7% vs. 70.6%, p = 0.04) and a lower retreatment rate (0% vs. 15.7%, p = 0.05) among only non-functioning adenomas. In multivariate analyses, the use of neuronavigation had a significant association with both GTR and retreatment rates (p values 0.005 and 0.02 respectively), independent of other confounding factors. The elective intraoperative use of navigation has a significant independent impact on the extent of resection and retreatment overall. While navigation results in better remission rates among functioning tumors with cavernous sinus invasion, angled endoscopy has a significant association with surgical outcomes in non-functioning tumors.

Effectiveness of dietary diabetes insipidus bundle on the severity of postoperative fluid imbalance in pituitary region tumours: A randomized controlled trial.

AIM: To test the effectiveness of nurse-led dietary diabetes insipidus (DI) bundle on the severity of postoperative fluid imbalance in pituitary region tumours. DESIGN: Blinded randomized controlled trial. METHODS: Patients aged 18-65 operated for sellar-suprasellar tumours in an Indian tertiary care centre were enrolled through total enumeration sampling and underwent randomization with allocation concealment during Sep 2018-Feb 2019. Pre-operative DI, postoperative ventilation, renal failure or decompensated diabetes mellitus were excluded. Patients in the intervention group received a nurse-led DI bundle (validated by three Delphi rounds) with four dietary components: intake of only water during thirst and avoidance of the following-added salt, high-protein foods and caffeinated drinks. Treating clinicians and the investigator assessing outcome were blinded about enrolment. Urine output, serum sodium, vasopressin requirement and hospital stay were assessed as primary outcomes. The outcome measures were monitored daily till the 6th postoperative day. Analyses were performed on 'intention-to-treat' basis, irrespective of compliance. Independent t-test and Chi-square test were used. RESULTS: Of the initial 63 patients, 50 fulfilling criteria were randomized to two groups and assessed over six days yielding 150 patient-days per group. There were no significant baseline differences between groups. The mean daily urine output was significantly lower in the DI bundle group than in control, both overall and among endonasal operated pituitary adenomas [3000.09(462.7) vs. 4095.71(896.4)ml & 2987.14(419.5) vs. 4064.73(1051)ml], with the greatest difference on the second postoperative day. Though hypernatraemia in controls became most prominent during days 2-3 and resolved in a week, it was significantly lower in the intervention group (12.7% vs. 30.7% overall, 11.4% vs. 29.4% endonasal adenomas). The need for vasopressin analogues and hospital stay were also significantly lower with DI bundle (p < 0.001). CONCLUSION: This is probably the first ever report of dietary DI bundle among operated pituitary patients, which seem to flatten the DI trend with significant benefits in polyuria, hypernatraemia, vasopressin requirement and hospital stay. TRIAL REGISTRATION: CTRI/2018/07/015127 of ICMR. IMPACT: The nurse-led dietary DI bundle has effectively reduced the severity of DI among operated pituitary patients with significant benefits in polyuria, hypernatraemia, vasopressin requirement and hospital stay. Its implementation is simple and easy to carry out, especially in resource-constrained institutions, where continuous monitoring and repeated serum sodium estimation are difficult.

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo-controlled study.

Impaired mitochondrial autophagy (mitophagy) and NLRP3 inflammasome activation have been incriminated in the pathogenesis of T2DM. Metformin besides being an insulin sensitizer also induces autophagy; however, its effect on mitophagy and NLRP3 activation in patients with T2DM still remains elusive. Forty-five drug-naïve T2DM patients with HbA1C 7%-9% (53-75 mmol/mol) were randomly assigned to receive either metformin, voglibose, or placebo for 3 months, and were also recommended for lifestyle intervention programme (n = 15 each). Mitochondrial oxidative stress (MOS) parameters, qPCR and immunoblotting of mitophagy-related markers (PINK1, PARKIN, MFN2, NIX, LC3-II, LAMP2), p-AMPKα (T172), and NLRP3 proteins, as well as transmission electron microscopy (TEM) for assessing mitochondrial morphology were performed in the mononuclear cells of study patients. Both metformin and voglibose showed a similar efficacy towards the reduction in HbA1c and MOS indices. However, multivariate ANCOVA divulged that mRNA and protein expression of mitophagy markers, NLRP3 and p-AMPKα (T172), were significantly increased only with metformin therapy. Moreover, PINK1 expression displayed a significant positive association with HOMA-ß indices, and TEM studies further confirmed reduced distortions in mitochondrial morphology in the metformin group only. Our observations underscore that metformin upregulates mitophagy and subsequently ameliorates the altered mitochondrial morphology and function, independent of its glucose-lowering effect. Further, restoration of normal mitochondrial phenotype may improve cellular function, including ß-cells, which may prevent further worsening of hyperglycaemia in patients with T2DM.

ACTH increment post total bilateral adrenalectomy for Cushing's disease: a consistent biosignature for predicting Nelson's syndrome.

PURPOSE: Nelson's syndrome (NS) is regarded as an aggressive complication of total bilateral adrenalectomy (TBA) for Cushing's disease (CD). This challenge may be addressed by using clinical criteria to guide frequency of neuroimaging to enable timely management of NS and also avoid unnecessary frequent imaging. METHODS: All patients (n = 43) with CD subjected to TBA over 35 years at a tertiary care centre were included. NS was defined as a newly appearing or expanding (> 2 mm) pituitary adenoma with or without ACTH levels exceeding 500 pg/ml. Pre-and post-TBA parameters like clinical symptomatology, cortisol, ACTH and radiology were analysed for the prediction of NS. RESULTS: NS developed in 39.5% (n = 17) patients with a median follow-up of 7 years. Half of them had new appearance, while rest had an expansion of pre-existing pituitary tumour. Majority (90%) had ACTH above 500 pg/ml. On Cox proportional hazards analysis, frequent discriminatory features of protein catabolism (≥ 4) (HR 1.15, CI 0.18, 7.06), proximal myopathy (HR 8.82, CI 1.12, 69.58) and annual ACTH increment of 113 pg/ml (HR 12.56, CI 1.88, 88.76) predicted NS. First post-operative year ACTH indices predicting NS included ACTH rise of 116 pg/ml and absolute ACTH of 142 pg/ml (sensitivity, specificity exceeding 90%). Annual ACTH increment exceeding 113 pg/ml, ≥ 4 discriminatory features and uncontrolled hypertension had the best overall prediction. CONCLUSION: Patients who developed NS had higher rebound rise of ACTH following TBA and a more severe disease phenotype at baseline. Consistent ACTH increment can be used as a marker for predicting the development of NS.

Acquired neuro-secretory defect in growth hormone secretion due to Imatinib mesylate and the efficacy of growth hormone therapy in children with chronic myeloid leukemia.

Imatinib results in growth retardation in children with chronic myeloid leukemia (CML). The study was planned to assess the GHRH-GH-IGF1 axis in children with CML, receiving Imatinib and to evaluate the efficacy of human growth hormone (hGH) therapy. Twenty children with CML, receiving Imatinib for a period exceeding 6 months, with resultant growth retardation were included. The GHRH-GH-IGF1 axis was assessed using growth hormone stimulation tests. IGF-1 generation test was performed for the evaluation of GH insensitivity. The mean age at inclusion was 15.2 years. The mean duration of treatment with Imatinib was 5.7 years. The mean decrease in height SDS since the start of Imatinib was -0.95 (p = 0.008). IGF-1 SDS was <-2 in all the patients. 71.4% of patients had a suboptimal GH response following stimulation with GHRH-Arginine. All patients had stimulable, although a delayed GH response with glucagon stimulation. 20% of patients had GH insensitivity. Four patients were treated with hGH for a mean duration of 5.75 months, achieved normalization of IGF-1 levels and improvement in growth velocity improved from 0.21 to 0.86 cm/month. Imatinib results in an acquired neurosecretory defect in GH secretion. Treatment with growth hormone leads to an improvement in growth velocity and normalization of IGF-1.

Incomplete functional and morphological recovery after acute and acute recurrent pancreatitis in children.

BACKGROUND AND AIM: There is lack of data on functional and morphological recovery after an attack of acute pancreatitis (AP) or acute recurrent pancreatitis (ARP) in children. This study aims to evaluate the functional impairment and morphological changes in the pancreas after recovery. METHODS: All consecutive patients presenting with AP (n = 61) or ARP (n = 35), as per standard diagnostic criteria, were enrolled. After 2 months of pancreatitis, fecal elastase-1 (FE-1) (µg/g) and 2-h oral glucose tolerance test to calculate oral disposition index (DIo ) (mmol/L) (ß-cell function) were performed. Morphological changes were assessed by endoscopic ultrasound and transabdominal ultrasound. Patients with chronic pancreatitis (CP) (n = 27) and healthy children (HC) (n = 26) were included as controls for functional parameters. RESULTS: At a median follow up of 12 (4-44) and 11 (2-108) months, 66.7% and 75.9% (P = 0.57) of AP and ARP demonstrated exocrine insufficiency (FE-1 < 200), respectively. Mean (SD) FE-1 was 183.64 ± 150.94 (AP), 135.70 ± 103.80 (ARP), 46.56 ± 30.20 (CP), and 240.00 ± 181.83 (HC) (P < 0.001; anova) (AP vs CP, ARP vs CP, and CP vs HC; P < 0.001). Prediabetes due to insulin resistance was seen in 16.6% and 22.6% (P = 0.56) of AP and ARP. Median (interquartile range) DIo (mmol/L) was comparable between AP (4.20 [2.36, 8.3]) and HC (5.20 [2.89, 8.68]), but was low in ARP (2.97 [1.80, 5.12]), which was comparable with CP (1.91 [1.20, 2.83]). Endoscopic ultrasound demonstrated morphological changes in 25% and 37% (P = 0.34) of AP and ARP, respectively. CONCLUSION: There was high frequency of biochemical evidence of exocrine insufficiency. ß-Cell function (DIo ) was preserved among AP but was poor in ARP. Nearly one-third showed morphological changes in imaging.

UTILITY OF A SINGLE LATE-NIGHT PLASMA CORTISOL AND ACTH FOR THE DIAGNOSIS OF CUSHING SYNDROME.

OBJECTIVE: To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing syndrome (CS). METHODS: Thirty-five patients with CS and 16 patients of pseudo-CS were enrolled. Assessment of 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ONDST), late-night plasma cortisol (LNPC), and adrenocorticotropic hormone (ACTH) on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission. RESULTS: We found that 24-h UFC performed the best among the screening tests with sensitivity, specificity and areas under the curve (AUCs) of 96.0%, 99%, and 0.988, respectively, at a cut-off of 144.6 µg/24 h. A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2%, and an AUC of 0.897. A cut-off of 412.4 nmol/L for LNPC on outpatient basis had sensitivity 88.2%, specificity 91.2%, and an AUC of 0.957. Cut-offs of 215 and 243.3 nmol/L for LNPC during sleep and awake states after acclimatization had sensitivity, specificity, and an AUC of 94.1%, 88.2%, and 0.958, respectively. An ONDST cut-off of 94.6 nmol/L provided sensitivity, specificity, and an AUC of 96.0%, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/mL for late-night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9%, and an AUC 0.796.A cut-off of 22.6 pg/mL for ACTH during sleep state after acclimatization had sensitivity, specificity, and an AUC of 73.5%, 99.2%, and 0.827, respectively. CONCLUSION: UFC is the best screening test for CS. Furthermore, single measurements of LNPC and ACTH help to establish the diagnosis and ACTH dependency of CS in the majority of patients with CS. ABBREVIATIONS: ACTH = adrenocorticotropic hormone AUC = area under the curve CRH = corticotropin-releasing hormone CS = Cushing syndrome ECLIA = electrochemiluminescence immuno-assay LDDST = low-dose dexamethasone suppression test LNPC = late-night plasma cortisol LNSC = late-night salivary cortisol ONDST = overnight dexamethasone suppression test RIA = radio-immuno assay UFC = urinary free cortisol.

Frequency & predictors of pancreatitis in symptomatic primary hyperparathyroidism.

BACKGROUND & OBJECTIVES: The frequency and predictors of pancreatitis in primary hyperparathyroidism (PHPT) are not well understood. The objective of the present study was to evaluate the frequency of pancreatitis in patients with PHPT and its association with clinical and biochemical parameters of the disease. METHODS: In this retrospective study all consecutive patients with PHPT registered in the PHPT registry (www.indianphptregistry.com) from the year 2004 to 2013 were included. The clinical, biochemical and radiological parameters related to pancreatitis were evaluated in histologically proven PHPT patients. RESULTS: A total of 218 patients (63 men; mean age: 40.6±14.4 yr) underwent surgery for PHPT during the study. Pancreatitis occurred in 35 [16%, 18 acute and 17 chronic pancreatitis (CP)] patients and male:female ratio was 1:0.94. Skeletal manifestations were seen less frequently in PHPT with pancreatitis as compared to that of PHPT without pancreatitis. PHPT with pancreatitis had significantly higher serum calcium (12.4±2.0 vs. 11.7±1.5 mg/dl, P <0.05) in comparison to PHPT without pancreatitis. PHPT with acute pancreatitis (AP) had higher serum calcium (P <0.05) and parathyroid hormone (PTH) (P <0.05) levels than PHPT with CP. Curative parathyroidectomy improved the symptoms associated with pancreatitis as there was no recurrence in AP group, whereas recurrence was observed only in about 10 per cent patients of the CP group. INTERPRETATION & CONCLUSIONS: Pancreatitis was observed in 16 per cent of PHPT patients with male predominance in the study population. No recurrence of AP was observed after curative surgery. It may be proposed that serum amylase with calcium and PTH should be measured in all patients of PHPT with pain abdomen to rule out pancreatitis.

Randomised controlled trial of diazoxide for small for gestational age neonates with hyperinsulinaemic hypoglycaemia provided early hypoglycaemic control without adverse effects.

AIM: Hyperinsulinaemic hypoglycaemia (HH) is a very common cause of hypoglycaemia in small for gestational age (SGA) neonates. We compared using early oral diazoxide or a placebo for this patient group. METHODS: This was a randomised, double-blind, placebo-controlled trial that focused on SGA neonates born at at least 32 weeks of gestation with HH during the first five days of life. Neonates with severe perinatal asphyxia, sepsis or contraindications for oral feeds were excluded. The primary outcome was the hours taken to achieve hypoglycaemic control, with a glucose infusion rate of ≤4 mg/kg/min. The secondary outcomes were the duration of intravenous fluids, sepsis episodes, time to achieve full feeds and mortality. RESULTS: We screened 490 neonates and 30 neonates were eligible for randomisation and completed the trial. Half received diazoxide and half received a placebo. The median time to achieve hypoglycaemia control (40 vs 71.5 hours, p = 0.015), the total duration of intravenous fluids (114 vs 164 hours, p = 0.04) and time to achieve full feeds (74 vs 124 hours, p = 0.02) were significantly lower in the diazoxide group, with no adverse effects attributed to the drug. CONCLUSION: Using oral diazoxide for SGA neonates with HH provided early hypoglycaemic control with no apparent adverse effects.

Diagnostic utility of testosterone priming prior to dynamic tests to differentiate constitutional delay in puberty from isolated hypogonadotropic hypogonadism.

CONTEXT: Differentiation between constitutional delay in puberty (CDP) and isolated hypogonadotropic hypogonadism (IHH) during adolescence is a great clinical challenge, and the available diagnostic tests are of limited value. OBJECTIVE: To study the effect of withdrawal of short-term, low-dose testosterone therapy (testosterone priming) on the discriminatory power of dynamic tests for hypothalamo-pituitary-testicular axis to differentiate CDP from IHH. DESIGN: A prospective study (n = 30) consisting of 20 boys with delayed puberty (group A) and 10 patients with IHH (group B). INTERVENTION: Patients in groups A and B underwent Triptorelin and hCG stimulation tests, prior to and 2 months after withdrawal of 'testosterone priming' (100 mg intramuscularly 4 weekly for 3 months) and were followed up until the onset of puberty or 18 years of age, whichever was earlier. RESULTS: At baseline, Triptorelin-stimulated 4 h LH, with a cut-off of 2·8 IU/l, and hCG-stimulated day 7 testosterone with a cut-off of 3·8 nmol/l had sensitivities of 80% each, and specificities of 93% and 87%, respectively, to diagnose CDP. After withdrawal of testosterone, a 4 h LH cut-off of 14·7 IU/l and day 7 testosterone cut-off of 10·3 nmol/l had sensitivities of 93% and 88% respectively, and specificity and positive predictive value of 100% each. A basal inhibin B > 94·7 ng/l was discriminatory for diagnosing CDP after withdrawal of testosterone priming. CONCLUSIONS: Inhibin B levels or 4 h LH after Triptorelin stimulation are the best discriminatory tests to differentiate CDP from IHH, when performed after withdrawal of 'testosterone priming'.

Spectrum of phenotype and genotype of congenital isolated hypogonadotropic hypogonadism in Asian Indians.

BACKGROUND: Congenital isolated hypogonadotropic hypogonadism (IHH) is caused due to defect in GnRH neuronal development, migration and action. Although genetic aetiology of IHH is increasingly being studied, Asian Indian data on phenotypic spectrum and genetic basis are scarce. OBJECTIVE: To investigate the phenotypic and genotypic spectrum of IHH in Asian Indian subjects. DESIGN, SETTING AND SUBJECTS: A cohort of 135 IHH probands were characterized phenotypically for reproductive and nonreproductive features and screened for rare sequence variations (RSVs) in five genes KAL1, FGFR1, FGF8, GNRHR and KISS1R. RESULT: Of 135 probands [56 normosmic IHH (nIHH) and 79 Kallmann syndrome (KS)], 20 were familial cases. KS group had more male dominance (M:F ratio of 8:1) as compared to nIHH group (M:F ratio of 1·5:1). Complete absence of puberty was more prevalent in KS probands (81% in KS vs 46% in nIHH). The prevalence of MRI abnormalities was more in anosmic group (92·8%) as compared to hyposmic (37·5%) and normosmic groups (15·4%). No particular nonreproductive phenotypic predominance was seen in any group. Genotyping revealed rare sequence variation (RSV) detection rate of 15·5% in five genes studied: (KAL1 - 4·4%, FGFR1 - 4·4%, GNRHR - 6·7%, oligogenicity - 1·5%). Prevalence of RSV was more common in familial cases (35%) as compared to sporadic (12·2%). GNRHR RSV p.C279Y (not reported in patients of ethnicities other than south Asians) was recurring in four unrelated patients. CONCLUSION: In our cohort, 60% were KS with majority of males and a severe reproductive phenotype as against nIHH. Contribution of the genetic burden for the five genes studied was 15·5%. RSV p.C279Y in GNRHR may have a founder effect originating from south Asia. This study provides a model for molecular and phenotypic representation of Asian Indian subjects with IHH.

Vitamin B and its derivatives for diabetic kidney disease.

BACKGROUND: Diabetes is a leading cause of end-stage kidney disease (ESKD) mainly due to development and progression of diabetic kidney disease (DKD). In absence of definitive treatments of DKD, small studies showed that vitamin B may help in delaying progression of DKD by inhibiting vascular inflammation and endothelial cell damage. Hence, it could be beneficial as a treatment option for DKD. OBJECTIVES: To assess the benefits and harms of vitamin B and its derivatives in patients with DKD. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 29 October 2012 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials comparing vitamin B or its derivatives, or both with placebo, no treatment or active treatment in patients with DKD. We excluded studies comparing vitamin B or its derivatives, or both among patients with pre-existing ESKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias and extracted data. Results were reported as risk ratio (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random-effects model. MAIN RESULTS: Nine studies compared 1354 participants randomised to either vitamin B or its derivatives with placebo or active control were identified. A total of 1102 participants were randomised to single vitamin B derivatives, placebo or active control in eight studies, and 252 participants randomised to multiple vitamin B derivatives or placebo. Monotherapy included different dose of pyridoxamine (four studies), benfotiamine (1), folic acid (1), thiamine (1), and vitamin B12 (1) while combination therapy included folic acid, vitamin B6, and vitamin B12 in one study. Treatment duration ranged from two to 36 months. Selection bias was unclear in three studies and low in the remaining six studies. Two studies reported blinding of patient, caregiver and observer and were at low risk of performance and detection bias, two studies were at high risk bias, and five studies were unclear. Attrition bias was high in one study, unclear in one study and low in seven studies. Reporting bias was high in one study, unclear in one study, and low in the remaining seven studies. Four studies funded by pharmaceutical companies were judged to be at high risk bias, three were at low risk of bias, and two were unclear.Only a single study reported a reduction in albuminuria with thiamine compared to placebo, while second study reported reduction in glomerular filtration rate (GFR) following use of combination therapy. No significant difference in the risk of all-cause mortality with pyridoxamine or combination therapy was reported. None of the vitamin B derivatives used either alone or in combination improved kidney function: increased in creatinine clearance, improved the GFR; neither were effective in controlling blood pressure significantly compared to placebo or active control. One study reported a significant median reduction in urinary albumin excretion with thiamine treatment compared to placebo. No significant difference was found between vitamin B combination therapy and control group for serious adverse events, or one or more adverse event per patient. Vitamin B therapy was reported to well-tolerated with mild side effects in studies with treatment duration of more than six months. Studies of less than six months duration did not explicitly report adverse events; they reported that the drugs were well-tolerated without any serious drug related adverse events. None of the included studies reported cardiovascular death, progression from macroalbuminuria to ESKD, progression from microalbuminuria to macroalbuminuria, regression from microalbuminuria to normoalbuminuria, doubling of SCr, and quality of life. We were not able to perform subgroup or sensitivity analyses or assess publication bias due to insufficient data. AUTHORS' CONCLUSIONS: There is an absence of evidence to recommend the use of vitamin B therapy alone or combination for delaying progression of DKD. Thiamine was found to be beneficial for reduction in albuminuria in a single study; however, there was lack of any improvement in kidney function or blood pressure following the use of vitamin B preparations used alone or in combination. These findings require further confirmation given the limitations of the small number and poor quality of the available studies.

Clinical profile and outcome of patients with acromegaly according to the 2014 consensus guidelines: Impact of a multi-disciplinary team.

AIM: The diagnosis and treatment of acromegaly, a rare and possibly curable disease, has undergone a paradigm shift in the past few decades. Our aim was to study the changing trends in clinical presentation, management and outcome of the disease in the last fifteen years. METHODOLOGY: 271 consecutive patients with acromegaly treated at the Departments of Endocrinology and Neurosurgery, PGIMER, Chandigarh, between 2000 and 2014, were included in the study. Clinical and hormonal profiles, comorbidities, treatment modalities, outcome and mortality data were evaluated. The cure rate was assessed according to the present consensus criteria. RESULTS: The gender distribution was equal with the mean age (±SD) of 37.1 ± 12.3 years at diagnosis. The average lag period to diagnosis was 4.7 ± 4.2 years. The most common presenting manifestations were acral enlargement and headache followed by visual deficits. The overall mortality rate was 5%, with the perioperative mortality being 1.5%. The most prevalent comorbidities in our series were hypertension (17.7%), diabetes mellitus (16.2%), arthropathy (11.8%) and obstructive sleep apnea (10.3%). Overall, 2 patients in our series suffered from extra-pituitary neoplasms and 12 patients had apoplexy as the presenting manifestation. As per the present consensus criteria, cure rate in our series was 28.5%. The cure rate was only 7.9% when many surgeons were operating. It increased to 25.5% when surgeries were being performed by one surgeon exclusively; and, when a sub-specialty clinic exclusively for pituitary diseases was set up, the cure rates improved upto 56%. CONCLUSION: Acromegaly has wide-ranging manifestations from acral enlargement to altered sensorium; incidental diagnosis was not prevalent in our series. Majority of the cases were due to the presence of a pituitary macroadenoma. Better cure rate can be achieved only when a dedicated group of multi-disciplinary team is involved.

High prevalence of cardiovascular risk factors in Asian Indians: a community survey - Chandigarh Urban Diabetes Study (CUDS).

BACKGROUND & OBJECTIVES: Studies conducted to assess the prevalence of cardiovascular (CV) risk factors among different regions of the country show variation in risk factors in different age groups and urban and rural population. We undertook this study to determine the prevalence of cardiovascular risk factors among urban adults in a north Indian city. METHODS: In a cross-sectional survey, 2227 subjects aged ≥ 20 yr were studied from April 2008 to June 2009 in Urban Chandigarh, a north Indian city. Demographic history, anthropometry and blood pressure were assessed. Fasting, and 2 h capillary plasma glucose after 75 g glucose load, HDL-C and triglycerides were estimated. RESULTS: The most prevalent cardiovascular risk factors in the age group of 20-29 yr was sedentary lifestyle (63%), while from fourth decade and onwards, it was overweight/obesity (59-85%). The second most common prevalent cardiovascular risk factor in the age group of 20-29 yr was overweight/obesity, in 30-49 yr sedentary lifestyle, in 50-69 yr hypertension and in subjects ≥70 yr, it was hypertriglyceridaemia. The prevalence of overweight/obesity, hypertension, dysglycaemia and smoking was almost double in subjects in the fourth decade of life, as compared to those in the third decade of life. The prevalence of CV risk factors significantly increased with age irrespective of gender and prevalence of low HDL-C was significantly more common in women as compared to men. INTERPRETATION & CONCLUSIONS: Sedentary lifestyle, obesity and low HDL-C are the most prevalent CV risk factors in subjects in the third and fourth decade of life in this north Indian population and clustering of these cardiovascular risk factors increases with advancing age. Strategies need to be formulated to target this population to prevent the epidemic of cardiovascular disease.