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Background: Demonstration of central: Peripheral adrenocorticotropic hormone (ACTH) gradient is important for diagnosis of Cushing′s disease. Aim: The aim was to assess the utility of internal jugular vein (IJV): Peripheral vein ACTH ratio for diagnosis of Cushing′s disease. Materials and Methods: Patients with ACTH-dependent Cushing′s syndrome (CS) patients were the subjects for this study. One blood sample each was collected from right and left IJV following intravenous hCRH at 3 and 5 min, respectively. A simultaneous peripheral vein sample was also collected with each IJV sample for calculation of IJV: Peripheral vein ACTH ratio. IJV sample collection was done under ultrasound guidance. ACTH was assayed using electrochemiluminescence immunoassay (ECLIA). Results: Thirty-two patients participated in this study. The IJV: Peripheral vein ACTH ratio ranged from 1.07 to 6.99 ( n = 32). It was more than 1.6 in 23 patients. Cushing′s disease could be confirmed in 20 of the 23 cases with IJV: Peripheral vein ratio more than 1.6. Four patients with Cushing′s disease and 2 patients with ectopic ACTH syndrome had IJV: Peripheral vein ACTH ratio less than 1.6. Six cases with unknown ACTH source were excluded for calculation of sensitivity and specificity of the test. Conclusion: IJV: Peripheral vein ACTH ratio calculated from a single sample from each IJV obtained after hCRH had 83% sensitivity and 100% specificity for diagnosis of CD.

Aim of Study: To assess the utility of internal jugular vein (IJV) / peripheral adrenocorticotropic hormone (ACTH) gradient in determining the etiology of ACTH- dependent Cushing's syndrome. Materials and Methods: Patients with ACTH-dependent Cushing's syndrome, (except children less than 12 years), had IJV blood collection under ultrasound guidance using a linear 7 MHZ probe. Blood was collected with a 21 G needle at the level of mandible with the patient in supine position. Six ml of blood was collected sequentially from right and left internal jugular veins for ACTH and prolactin estimation. Peripheral blood for ACTH and prolactin was taken from a previously placed IV cannula in the antecubital vein. Results: Thirty patients (20 F, 10 M, age 14 to 50 yrs) were enrolled for this study. Source of ACTH excess was pituitary in 22, ectopic ACTH in 4, and unknown in 4 cases. Using an IJV: Peripheral ACTH ratio of ≥ 1.6, 15 out of 22 Cushing's disease patients were correctly identified. However, 1 out of 4 ectopic Cushing also had IJV: Peripheral ratio ≥ 1.6. Overall, it had sensitivity of 68% with specificity of 75% while MRI pituitary and HDDST had sensitivity of 86% and 59%, respectively, with specificity of 100% each. Conclusion: IJV: Peripheral ACTH gradient was observed in 68% of patients with Cushing's disease. Simultaneous IJV and peripheral sample collection with CRH stimulation may improve sensitivity and specificity of this test.

Introduction: Children with congenital adrenal hyperplasia (CAH) provide us an opportunity to study the clinical effects of androgen excess in humans. We studied the sequence of pubertal development in girls with congenital adrenal hyperplasia initiated on treatment at different ages, to assess the effects of androgen exposure on the Hypothalamic-Pituitary-Ovarian (HPO) axis. Materials and Methods: Girls more than 18 years of age, with CAH, on follow-up at this hospital were the subjects for this study. Details of history, physical findings, laboratory evaluation, and medication were noted from their case records and verified from the patients and their / parents, in addition to assessment of their present health status. Result: We studied 24 patients of classical CAH (SW-2, SV-22, average age - 24.5 ± 6.6 years). All had varying degrees of genital ambiguity (Prader stage 3 (n = 13), Prader stage 2 (n = 10), Prader stage 1 (n = 1). Among them were13 girls, who were started on steroids after eight years of age. Girls who received treatment from infancy and early childhood had normal pubertal development (mean age at menarche 11.4 ± 1.7 years). Hirsutism was not a problem among them. Untreated children had progressive clitoral enlargement throughout childhood, developed pubic hair at around three to six years of age, and facial hair between nine and eleven years. Plasma testosterone ranged from 3 to 6 ng / ml prior to treatment. Six of the 13 untreated CAH girls had subtle breast development starting at ages 11 - 16 years and three had spontaneous infrequent vaginal bleeding starting at ages 11 - 17. Steroid supplementation initiated pubertal changes in older girls in two-to-six months' time. Conclusion: There was a delay in HPO axis maturation (as evidenced by delayed pubertal development) in the absence of treatment in girls with CAH. This could be corrected with steroid supplementation.

Background & objectives: Diabetes mellitus (DM) is an important risk factor for tuberculosis and has received increasing emphasis. However, the reverse association of tuberculosis impacting blood sugar levels has not been well studied. The present study was conducted to evaluate the prevalence of hyperglycemia in patients with tuberculosis and assess its resolution following successful treatment of tuberculosis. Methods: In this prospective study, a total of 582 patients with tuberculosis were evaluated for hyperglycaemia [DM or impaired glucose tolerance (IGT)] with random blood sugar (RBS) and all patients with RBS >100 mg/dl were subjected to a 75 g oral glucose tolerance test (OGTT). All patients received thrice weekly intermittent Directly Observed Treatment Short Course (DOTS) for tuberculosis. Patients with hyperglycaemia were re-evaluated at the end of anti-tuberculosis treatment with an OGTT and glycated hemoglobin (HbA1c) levels to assess for glycaemic status. Results: In the present study, 41 of the 582 patients were found to have DM [7%, 95% confidence interval (CI) (5.2, 9.4)] while 26 patients were found to have IGT [4.5%, 95% CI (3, 6.5)]. Three patients were lost to follow up. Of the 26 patients with IGT, 17 [65.4%, 95% CI (46.1, 80.7)] reverted to euglycaemic status following successful treatment of tuberculosis, while the blood sugar levels improved in all patients with DM following treatment of tuberculosis. Interpretation & conclusions: Our study results show that tuberculosis adversely impacts glycaemic status with improvement in blood sugar levels at the end of successful treatment of tuberculosis. Longitudinal studies with large sample size are required to confirm these findings.

ObjEctIvE: Offspring of type 2 diabetics have an increased risk of dyslipidemia, glucose intolerance and obesity. the aim of this study was to assess the lipid levels in the offspring of diabetics with normal glucose tolerance and normal body weight. DEsIGN: Normal weight offspring of patients with type 2 diabetes mellitus (DM) who had normal glucose tolerance, and healthy gender matched controls of comparable age without a family history of diabetes mellitus, were the subjects of this study. Lipid profiles were determined in cases and controls. rEsULts: the study included 114 subjects (64 males and 50 females) in each group, aged (mean±sD) 24.0±7.9 in cases and 24.1±8.0 years in controls. the body mass index (bMI) was 20.8±3.0 and 20.2±3.1 kg/m 2 in cases and controls, respectively. serum total cholesterol, triglycerides, plasma glucose, fasting insulin, c-peptide and proinsulin levels were comparable in cases and controls. serum high density lipoprotein (HDL) cholesterol was lower (p

Background: The pathogenesis of type 1 diabetes mellitus (T1DM) requires a genetic predisposition to particular environmental triggers that may activate mechanisms leading to progressive loss of pancreatic beta cells. Aims: We tried to compare the impact of some demographic and environmental factors and breast-feeding on children (aged < 18 years) with recent onset diabetes mellitus (≤1 year) with that on age, sex, and socioeconomic status-matched controls. Material and Methods: A total of 43 consecutive patients (male, 24, mean age ± SD = 12.58 ± 9.6 years) and equal number of controls without diabetes mellitus or dysglycemia were included in this hospital-based case-control study. Results and Conclusions: A distinct peak in the incidence noted in the early adolescence with segregation in the winter months. Our patients did not differ significantly from the controls with regard to birth order, mode of delivery, parental age, parental education, dietary practices, breast-feeding, and migration in the family. Growth characteristics and nutritional status were also similar. A population study with more power will be better equipped to answer such queries.

Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease characterized by a progressive lymphocytic infiltration of the exocrine glands with varying degrees of systemic involvement. Chronic inflammation compromises the glands' function that leads to dry symptoms in the mouth/eyes. Renal involvement is a well recognized extraglandular manifestation of pSS. Metabolic bone disease (MBD), however, rarely occurs as the primary manifestation of a renal tubule disorder due to pSS. To the best of our knowledge there are only 6 reported cases of metabolic bone disease as the primary manifestation of pSS to date. Four of these had distal renal tubular acidosis (RTA), and 2 had a combined picture of distal and proximal tubular dysfunction. We herein present our experience of 3 cases who presented to us with a clinical picture suggestive of MBD. While investigating these patients, we found evidence of RTA, which was found to be secondary to pSS.

Premature ovarian insufficiency (POI) is defined as the cessation of ovarian function under the age of 40 years and is characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotrophin concentration (FSH). It is a heterogeneous disorder with a multicausal pathogenesis; however, majority of cases are idiopathic. In idiopathic POI, involvement of unknown mechanisms may increase rate of oocyte apoptosis. Studies have shown that elevated reactive oxygen species (ROS) levels affect the quality of gametes. Mitochondrial mutations in different complexes of electron transport chain have been reported to disrupt the electron flow which lead to formation of more superoxide ions or increased levels of ROS. This study was aimed to screen the mitochondrial genome for variations in idiopathic POI (n = 25) and occult ovarian insufficiency (OI) (n = 5) patients. 30 patients diagnosed with POI and occult OI were enrolled in this study. Blood samples were collected from the patients and controls. DNA was extracted using phenol chloroform method. A total of 102 nucleotide variations were observed in patients as compared with 58 nucleotide variations in controls. 24% variations were found to be non-synonymous and 76% were synonymous. It was found that 48% variations were in complex I, 8% in complex III, 24% in complex IV, and 20% in complex V of electron transport chain. We found most of the non-synonymous mitochondrial variations in complex I (48%) of the respiratory chain which is the largest enzyme complex and is associated with oxidative stress. Some non-synonymous pathogenic alterations (p.M31T, p.W239C, p.L128Q) and non pathogenic alterations (ATPase6:p.T53I, ATPase6:p.L190F, ATPase6:p.L199L) were found to be significantly higher in cases as compared with controls. The preliminary data suggest that the mitochondrial mutations and subsequent decline in ATP levels may accelerate follicular atresia and lead to POI. The results of this preliminary study highlight the need to extend this study by analyzing large number of samples in different ethnic populations and analyze for ROS levels and mitochondrial mutations in oocytes as they are of different embryonic origin and develop in a different microenvironment.

Aim: To identify the genotype of two Indians with male pseudohermaphroditism. Methods: Standard radioimmunoassay procedure was used for estimating hormonal levels. Conventional cytogenetic analysis was carried out for diagnosing the genetic sex in these subjects with genital ambiguity. Molecular analysis was carried out by standard polymerase chain reaction procedure using different sets of primers and reaction conditions specific for the 5αreductase type 2 gene (SRD5A2) gene. Direct sequencing was carried out using the ABI Prism dye terminator sequencing kit and the ABI 310 sequencing apparatus. Results: We found an SRD5A2 gene mutation in exon 5, where arginine is substituted with glutamine (R246Q), in two males with pseudohermaphroditism and ambiguous genitalia from unrelated families. This is the first time this mutation has been reported in individuals from India. Conclusion: Identification of the R246Q mutation of the SRD5A2 gene from two unrelated Indian families possibly extends the founder gene effect. (Asian J Androl 2008 Sep; 10: 815–818)

Context: Congenital adrenal hyperplasia (CAH) is an autosomal recessive metabolic disorder caused by mutations in the CYP21A2 gene. Genetic diagnosis of 21-OH deficiency causing CAH is more complicated than any other monogenic disorder due to high variability of the locus. The disease has a wide spectrum of clinical variants making it difficult to establish a genotype-phenotype correlation. Therefore, family studies are necessary to ascertain parental genotype and segregation of the mutant allele among the offspring. Aim: The present study aimed to identify CYP21A2 gene mutations and analyze the segregation pattern in CAH trios (patients and their parents). Materials and Methods: A total of ten families having at least one CAH child were recruited. Results: Out of 31 children from ten families, 15 were affected with CAH and 13 of /them (12 females and 1 male) were available for genetic testing. One family had all the children affected with CAH. Compound heterozygous mutations were identified in seven patients (53.8%) whereas p.P30L, In2 and δ8 bp mutations were present in homozygous state in three (23.1%), two (15.3 %) and one (7.6%) patient respectively. Conclusions: In majority of the families, mutant alleles observed in the patients were inherited from the parents whereas three families showed sporadic mutations without any paternal or maternal origin. This indicated their novel occurrence due to misalignment of the parental genes and /or large deletion of the gene. Female preponderance was noted in the CAH families and also among the patients raising the possibility of survival advantage among females.

Deficiency of the 5α-reductase 2 enzyme impairs the conversion of testosterone to dihydrotestosterone (DHT) and differentiation of external genitalia, seminal vesicles and prostate in males. The present study describes the phenotype, genotype and gender identity in a large cohort of patients with 5αRD2. All patients underwent detailed clinical evaluation, hormonal profile, karyotyping and molecular analysis of the SRD5A2 gene. The molecular analysis of the SRD5A2 gene showed the presence of mutant alleles in 24 patients. We found 6 novel mutations IVS(1-2) T>C, p.A52T, 188-189insTA, 904-905ins A, p.A12T and p.E57X in our patients. All patients had ambiguous genitalia and the degrees of under-virilization ranged from penoscrotal hypospadias and microphallus to clitoromegaly. The position of gonads was variable in patients with same mutation. All the patients with mutations in the SRD5A2 gene had male gender identity. Those reared as female had gender dysphoria and underwent gender reassignment. Though a specific genotype-phenotype correlation could not be established in our patient but confirming the diagnosis of 5αRD2 with assessment of the SRD5A2 gene may help in appropriate gender assignment.

OBJECTIVE—To determine the microbiological profile and antibiotic susceptibility patterns of organisms isolated from diabetic foot ulcers. Also, to assess potential risk factors for infection of ulcers with multidrug-resistant organisms (MDROs) and the outcome of these infections. RESEARCH DESIGN AND METHODS—Pus samples for bacterial culture were collected from 80 patients admitted with diabetic foot infections. All patients had ulcers with Wagner’s grade 3–5. Fifty patients (62.5%) had coexisting osteomyelitis. Gram-negative bacilli were tested for extended spectrum β-lactamase (ESBL) production by double disc diffusion method. Staphylococcal isolates were tested for susceptibility to oxacillin by screen agar method, disc diffusion, and mec A–based PCR. Potential risk factors for MDRO-positive samples were explored. RESULTS—Gram-negative aerobes were most frequently isolated (51.4%), followed by gram-positive aerobes and anaerobes (33.3 and 15.3%, respectively). Seventy-two percent of patients were positive for MDROs. ESBL production and methicillin resistance was noted in 44.7 and 56.0% of bacterial isolates, respectively. MDRO-positive status was associated with presence of neuropathy (P = 0.03), osteomyelitis (P = 0.01), and ulcer size >4 cm2 (P < 0.001) but not with patient characteristics, ulcer type and duration, or duration of hospital stay. MDRO-infected patients had poor glycemic control (P = 0.01) and had to be surgically treated more often (P < 0.01). CONCLUSIONS—Infection with MDROs is common in diabetic foot ulcers and is associated with inadequate glycemic control and increased requirement for surgical treatment. There is a need for continuous surveillance of resistant bacteria to provide the basis for empirical therapy and reduce the risk of complications.

Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease characterized by a progressive lymphocytic infiltration of the exocrine glands with varying degrees of systemic involvement. Overt or latent renal tubular acidosis (RTA), caused by tubulointerstitial nephropathy, is a common extraglandular manifestation of pSS. Hypokalemic paralysis is a well known, albeit rare complication of severe distal RTA from any cause. Cases of pSS manifesting for the first time as hypokalemic paralysis caused by distal RTA have been rarely reported. We herein present our experience of two cases, who presented to us for evaluation of hypokalemic paralysis and on work up found evidence of distal RTA, which on further work up found to be secondary to pSS. A high index of suspicion for pSS should be kept in all patients with hypokalemic paralysis.

Mutations in the GnRH receptor (GNRHR) have been described as a cause of reproductive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set out to determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define their distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Exon segments in the GNRHR were screened for mutations using temperature gradient gel electrophoresis, and all mutations were confirmed by direct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of ...

Objective: To evaluate the sensitivity of computed tomography (CT) and magnetic resonance imaging (MRI) of the pituitary gland in detecting pituitary adenomas in patients with Cushing’s disease. Methods: Twenty-five patients aged 8–55 years (average age 30 years), clinically and biochemically diagnosed as having Cushing’s disease, were evaluated with a contrast-enhanced CT scan and MRI of the pituitary gland. Contrast-enhanced CT scans of direct 2-mm-thick coronal sections were performed. Pre- and post-enhanced MRI of the pituitary gland was performed on a 1.5-tesla superconducting magnet, taking 2-mm-thick sections in the sagittal and coronal planes. Results: MRI revealed adenomas in 16 patients (12 microadenomas and 4 macroadenomas). Twelve (75%) adenomas were delineated more clearly on post-gadolinium MRI scans. Nine (56%) adenomas were better delineated on coronal images. Out of 16 adenomas identified on the MRI, only 5 were seen on the CT scan. All patients underwent trans-sphenoid surgery and the MRI findings were confirmed. Conclusion: Contrast-enhanced MRI is the preferred modality for the detection of ACTH-secreting adenomas, which are difficult to visualize on CT scans due to their small size. A focal hypointense lesion is the commonest finding on T1-weighted images and, if identified on coronal sections, is the most sensitive diagnostic criterion. However, a negative MRI does not exclude the presence of a microadenoma.

Objective: To evaluate the computed tomography (CT) morphology of the adrenal glands of patients with adrenal dysfunction. Methods: CT examination of adrenal glands was performed in 331 consecutive patients with symptoms suggestive of adrenal dysfunction. CT was performed using 4-mm contiguous sections for the adrenal area. Intravenous contrast was injected in 78 cases of the adrenal mass lesions. Results: We analyzed 331 consecutive CT scans performed over a 10-year period. One hundred and twenty-seven patients had hypercortisolism, 23 had unilateral adrenal tumor, 18 had bilateral adrenal hyperplasia and 86 had normal adrenals. The CT diagnosis was confirmed at surgery in all 23 unilateral adrenal tumors except in 1 case (tuberculosis in a hyperplastic adrenal gland). Among the 91 cases of hypertension, 86 were being evaluated for pheochromocytoma and 5 for Conn’s syndrome. Forty-three had adrenal pheochromocytoma (1 bilateral) and 10 had extra-adrenal pheochromocytoma detectable on CT. Two of the 5 cases of hyperaldosteronism (Conn’s syndrome) had adrenal tumor. Adrenal enlargement was observed in 17 of the 33 cases of Addison’s disease. Four of them were cases of histoplasmosis. Conclusion: CT scanning is a sensitive tool for the imaging of adrenal glands. Both neoplastic and inflammatory lesions can alter adrenal gland morphology. Our results highlight the importance of studying adrenal morphology. CT morphology is helpful to decide the modality of treatment.

Background: Onset of puberty in boys usually occurs by 14 years of age. Some boys may exhibit delayed sexual maturation till about 17-18 years of age. However, pubertal onset beyond 18 years of age is exceedingly rare. Materials and Methods: Patients diagnosed as idiopathic hypogonadotropic hypogonadism (IHH) who had onset of puberty (increase in testicular volume >10 ml) while on androgen therapy were studied. These patients were evaluated prospectively. Results: There were nine subjects that were included in the study. The pre-therapy testicular volumes ranged from 3 to 6 ml. Luteinizing hormone (LH) levels increased from 1.2 ± 0.96 to 2.8 ± 1.0 IU/L, follicular stimulating hormone (FSH) levels increased from 1.5 ± 0.79 to 3.5 ± 1.9 IU/L, and testosterone increased from 0.36 ± 0.16 to 3.4 ± 2.1 ng/ml. Three out of nine patients had testosterone levels below 3 ng/ml. Conclusion: Our present study indicates that pubertal development can occur in patients presenting with hypogonadotropic hypogonadism after 18 years of age. However, acquired pubertal status may be subnormal

Results Case 1 3 years old girl presented with progressive bilateral breast enlargement over 1 year, irregular vaginal bleeding for 10 months and pubic hair development for 2 months. Her past history was unremarkable. Her general examination and vitals were normal. Tanners staging was B3P3. There was no axillary hair or genital ambiguity. Cardiac, thoracic and neurological examinations were normal. A solitary well defined pelvic mass firm to hard, mobile was palpable in right lower abdomen. Her bone age, height age and chorological age were respectively 8yr 10months, 4 year(100cm) and 3 year. Her investigations showed normal hemogram, liver, renal and thyroid functions. Hormonal profile: LH 1000pg/ml. CT pelvis showed a heterogeneously enhancing abdominopelvic mass with non visualization of ovaries separately suggestive of ovarian mass. She underwent resection of right tuboovarian mass which was suggestive of juvenile granulose cell tumor. Repeat hormonal profile done showed markedly reduced Estradiol levels 17pg/ml. At one year follow-up, there was no vaginal bleeding so far. Case 2 6 year old girl presented as precocious puberty with progressive bilateral breast enlargement over 7 months, cyclical vaginal bleeding (3/25-30days) for 4 months and pubic hair development for 2 months. She had a recent height gain over last 1 year. Her past history was unremarkable. Her general examination and vitals were normal. Tanners staging was B3P3. There was no axillary hair or genital ambiguity. Systemic examination was normal. Her investigations showed normal hemogram, liver, renal and thyroid functions. Her bone age, height age and chorological age were respectively 7.8yr, 7 year (119cm) and 6 year. Hormonal profile: LH 162.8pg/ml. CT pelvis showed a bulky left ovary of size 5.4cm predominantly solid with follicles seen at periphery – possibility of ovarian tumor and pubertal proportion of uterus. She underwent laparascopic resection of right tuboovarian mass which was suggestive of mixed germ cell sex cord stromal tumor. Post-operatively, repeat hormonal profile showed Estradiol levels 14.37pg/ml. At 6 months follow up, there was no vaginal bleeding so far.

To analyze the therapeutic results of intervention and the factors affecting the outcome of patients with Cushing’s disease (CD) cared for at the All Indian Institute of Medical Science (AIIMS), New Delhi. DESIGN. Patients with Cushing’s disease treated at a teritiary care centre from January 2000 to December 2009 were prospectively studied. RESULTS. Ninety-seven patients received treatment for CD during this period. Mean duration of follow-up was 3.4 ± 2.2 (mean±SD) years. Eighty-one patients (83.5%) underwent transsphenoidal surgery (TSS) as the primary treatment modality. Fifty-four patients (66.7%) went into remission after initial TSS; ten (18.5%) of them relapsed after a mean follow-up period of 2.9±2.1 (mean±SD) years. Histopathologic examination of resected tissue showed corticotroph adenoma in 48 of the 54 (88.9%) who went into remission and 17 of the 27 (63.0%) who did not go into remission after the initial TSS. Sixteen patients with severe hypercortisolism underwent bilateral adrenalectomy (BA) as a life-saving measure which was followed by pituitary surgery 6 to 12 months later. Five patients including one with a large macroadenoma required three or more procedures to achieve eucortisolism. Fifty-four out of 81 (66.7%) of our patients with CD had remission following initial TSS, ten of whom relapsed later on. Sixteen patients unerwent BA as a life-saving procedure. Factors affecting outcome were, age, gender, low dose dexamethasone suppression test cortisol value and histologic confirmation of corticotroph adenoma.

Edavan P Praveen1, Jaya Prakash Sahoo1, Bindu Kulshreshtha2, Madan L Khurana3, Nandita Gupta1, Sada Nand Dwivedi3, Guresh Kumar3, Ariachery C Ammini11Department of Endocrinology, All India Institute of Medical Sciences, 2Ram Manohar Lohia Hospital, 3Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, IndiaBackground: There is no consensus on the role of cortisol in the pathogenesis of obesity and metabolic syndrome (MS). This cross-sectional study aimed to analyze the relationship of morning plasma cortisol and adrenocorticotropic hormone (ACTH) levels with body mass index (BMI) and glucose tolerance.Subjects and methods: The sample frame was the “Offspring of individuals with diabetes study” database. A total of 358 offspring of individuals with type 2 diabetes mellitus (T2DM) and 287 individuals without a known family history of T2DM were recruited for the study. Subjects who were ≥10 years of age were selected from the database for analysis. Subjects with T2DM were excluded. All participants underwent a 75 g oral glucose tolerance test (OGTT), and blood samples were collected at 0, 30, 60, and 120 minutes for glucose, insulin and C-peptide. Plasma cortisol, ACTH, and lipid profile were estimated from the fasting sample.Results: Four hundred and ninety-five participants (305 males [62%] and 190 females [38%]) were included in the analysis. ACTH and cortisol levels were higher in normal-weight subjects than in overweight/obese subjects. Both ACTH and cortisol increased as fasting plasma glucose increased. Cortisol levels were significantly lower in offspring of T2DM subjects with MS than in offspring of T2DM subjects without MS. When adjusted for BMI, the significance was marginal. In males, cortisol levels were negatively correlated with early insulin secretion during OGTT (insulinogenic index [0–30]) and positively with waist circumference and serum high-density lipoprotein cholesterol. In females, fasting glucose and systolic blood pressure were significantly and positively correlated.Conclusion: Body weight was correlated negatively with morning plasma cortisol and ACTH, whereas fasting glucose was correlated positively.Keywords: cortisol and body weight, cortisol and obesity, cortisol and glucose tolerance, ACTH, cortisol, metabolic syndrome

In 46,XY disorders of sex development, 5α-reductase deficiency is rare and is not usually the first-intention diagnosis in newborn ambiguous genitalia, contrary to partial androgen insensitivity syndrome. Yet the cause of ambiguous genitalia may guide sex assignment, and rapid, precise diagnosis of 5α-reductase deficiency is essential.The aim of the study was to describe relevant data for clinical diagnosis, biological investigation, and molecular determination from 55 patients with srd5A2 mutations identified in our laboratory over 20 yr to improve early diagnosis.The study was performed at Montpellier University Hospital.We studied a cohort of 55 patients with srd5A2 gene mutations.Genetic analysis of srd5A2 was conducted.Clitoromegaly (49.1%) and microphallus with various degrees of hypospadias (32.7%) were frequent phenotypes. Female external genitalia (7.3%) and isolated micropenis (3.6%) were rare. Seventy-two percent of patients were initially assigned to female gender; five of them (12.5%) switched to male sex in peripuberty. Over 72% of patients were considered for 5α-reductase deficiency diagnosis when the testosterone/dihydrotestosterone cutoff was 10. In 55 patients (with 20 having a history of consanguinity), we identified 33 different mutations. Five have never been reported: p.G32S, p.Y91H, p.G104E, p.F223S, and c.461delT. Homozygous mutations were present in 69.1% of cases, compound heterozygous mutations in 25.5%, and compound heterozygous mutations alone with the V89L polymorphism in 5.4%. Exons 1 and 4 were most affected, with 35.8 and 21.7% mutant alleles per exon, respectively.In the largest cohort to date, we demonstrate a wide spectrum of phenotypes and biological profiles in patients with 5α-reductase deficiency, whatever their geographical or ethnic origins.

Familial combined pituitary hormone deficiency is a rare endocrine disorder. We describe growth patterns of four children (3 females and 1 male) from two families with combined pituitary hormone deficiency. These children received growth hormone at ages ranging from 14.5 years to 19 years. While all the female siblings reached their target height, the male sibling was much shorter than mid parental height. The reasons for sexual dimorphism in growth patterns in these children are unclear.

The occurrence of gonadoblastoma in XY phenotypic females has been well documented. This condition may rarely present in a familial form. In this present study, we present a family of 5 siblings born of non-consanguineous parents. Three sisters (age 13, 15 and 17 years) with XY karyotype presented with complaints of primary amenorrhoea. They had a normal female phenotype. The younger two brothers were apparently normal. All the three affected siblings have undergone laparoscopic removal of the gonads. The histopathology of gonads in the elder sibling (II 1) revealed ovarian stroma along with rete testes like elements. Bilateral tubes and the gonads of the younger sibling (II 2) showed fallopian tubes (both sides) and a small portion of ovarian stroma. No focus of gonadoblastoma was identified in these two elder siblings. Histopathology of the youngest sibling (II 3) revealed presence of bilateral gonadoblastoma. The occurrence of gonadoblastoma in the youngest sibling of 3 affected XY siblings is unusual.

Insulinoma presents with myriad manifestations and severe neurological deficit may develop due to delay in diagnosis. We report a lady who presented with Glasgow coma scale of E1 M2 V1, which did not improve after correction of hypoglycemia. There was complete reversal of neurological deficit and brain magnetic resonance imaging changes of hypoglycemia on follow-up after resection of pancreatic insulinoma. This is the first report which shows reversal of hypoglycemic changes in MRI after resection of insulinoma. Insulinoma, pre and post surgery provides a model for study of the effect of hypoglycemia and its improvement after euglycemia.

Background & objectives: Since our previous study in 2006, several new modalities for localization of cause of endogenous hyperinsulinemic hypoglycaemia such as multiphasic computed tomography (CT), multiphasic magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), intraoperative ultrasound, and intra-arterial calcium infusion with arterial stimulation venous sampling (ASVS) have become available. Therefore, to evaluate the relative usefulness of various imaging modalities to guide future management in terms of diagnosis and patient care, we analyzed presentation and management of patients of endogenous hyperinsulinemic hypoglycaemia. Methods: In this retrospective study, medical records of patients admitted with endogenous hyperinsulinemic hypoglycaemia were retrieved. Data pertaining to clinical features, diagnosis, imaging, surgery and patient outcome were extracted. The localization of insulinoma by preoperative imaging techniques was compared with the findings at surgery to assess the accuracy of localization. Results: Fasting hypoglycaemia was present in all, and post-prandial hypoglycaemia (plasma glucose ≤50 mg/dl within four hours of meal) in 25.8 per cent. Mean duration of symptoms before reaching a diagnosis of hyperinsulinemic hypoglycaemia was 3.9 years. Mean duration of provocative fast was 21.8 h (range 6-48 h). Among the currently used imaging modalities, the sensitivity of localizing tumour was 79.3 per cent for multiphasic CT, 85 per cent for multiphasic MRI and 95 per cent for EUS. EUS detected tumour missed by both CT and MRI. All, except one of the operated patients, were cured by surgery. Interpretation & conclusions: Our results suggest that patients with insulinoma have a varied presentation. Multiphasic contrast-enhanced MRI/CT scan, EUS and ASVS may be complimentary in pre-operative localization.

Background Genetic markers conferring susceptibility to diabetes specific renal disease remains to be identified for early prediction and development of effective drugs and therapies. Inconsistent results obtained from analysis of genes from classical pathways generate need for examination of unconventional genetic markers having role in regulation of renal function. Experimental and clinical evidences suggest that dopamine is an important natriuretic hormone. Therefore, various genes involved in regulation of dopamine bioavailability could play a role in diabetic chronic renal insufficiency (CRI). We investigated the contribution of 12 polymorphisms from five Dopaminergic pathway genes to CRI among type-2 diabetic Asian Indian subjects. Methods Genetic association of 12 polymorphisms (SNPs) from five genes namely-dopamine receptor-1 (DRD1), DRD2, DRD3, DRD4, andcatechol-O-methyltransferase (COMT) with diabetic CRI was investigated using a case-control approach. Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes. Results SNPs -141 ins/del C and G>A (1 kb upstream from exon 2) in DRD2 gene showed significant allelic and genotypic association. Allele -141 insC and genotype -141 insC/insC of -141 ins/del C polymorphism, and allele A of G>A SNP were found to be predisposing to CRI. Our result of allelic and genotypic association of -141 insC/delC SNP was also reflected in the haplotypic association. Heterozygous genotype of polymorphism 900 ins/del C in COMT gene was predisposing towards CRI. Conclusion Some polymorphisms in DRD2 and COMT genes are significantly associated with susceptibility to CRI in the Asian Indian population which, if confirmed would be consistent with a suggested role of dopamine metabolism in disease occurrence.

Background Renal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects. Methods Twelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a case-control approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes. Results Of the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01–3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88–4.59 for Thr/Thr genotype and O.R. 2.68, 95%CI: 1.97–3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16–2.14 and O.R. 1.81, 95%CI: 1.21–2.71 respectively), and genotypic association of GA genotype of G>A (-1903) in chymase gene (O.R. 2.06, 95%CI: 1.34–3.17) were also observed. Conclusion SNPs Met235Thr in angiotensinogen, T>C (-344) in aldosterone synthase, and G>A (-1903) in chymase genes are significantly associated with diabetic chronic renal insufficiency in Indian patients and warrant replication in larger sample sets. Use of such markers for prediction of susceptibility to diabetes specific renal disease in the ethnically Indian population appears promising.

Dear Editor, We would like to write to you on the era of 'omics—genomics revolution on andrology, the way that has taken into a new dimension for tackling the emerging pressure on male infertility and for normal successful fertility outcome. In the Special Issue on Semen Analysis of Asian Journal of Andrology, Aitken 1 has extensively discussed the causes of male infertility, the past and the future developmental methods for its treatment and possible modes of prevention have been. The author stated that in the 21st century, molecular andrologists will have wide range of methods to examine the defective spermatozoa of infertile patients. We would like to present the supporting data on sperm chromosomal abnormalities in infertile men and their implications on fertility. Abnormal semen parameters in chromosomally normal men are an indicator of an increased risk of sperm aneuploidy 2. These authors found the meiotic segregation and an interchromosomal effect in carriers of (11;18) by multicolor fluorescence in situ hybridization (FISH). They concluded that FISH analysis provides useful information for genetic counseling and assisted reproduction. The risk of male's sperm aneuploidy used for intracytoplasmic sperm injection (ICSI) needs to be evaluated to prevent the further aneuploidy in the offspring of these men. Some studies 3, 4 revealed that the infertile men with normal karyotypes possessed higher frequency of sperm aneuploidy, specifically the sex chromosomes. Male carriers of Robertsonian translocations are vulnerable for fertility problems as evident from 14 Robertsonian carriers 5. We also observed the similar findings as evident from the above mentioned literature with respect to the chromosomal pattern, translocations and sperm chromosomal (Y chromosome) microdeletions in our tertiary referral hospital, All India Institute of Medical Sciences, New Delhi, India. Hence evaluation of spermatozoa with different techniques, such as single cell gel electrophoresis (COMET assay), terminal transferase dUTP Nick End Labeling (TUNEL), sperm chromatin structure assay (SCSA), in situ nick translation (ISNT), acridine orange test, germ cell chromosomal aneuploidies and microdeletions, will help detecting the defecfective spermatozoa in men opting for assisted reproduction 6, 7, 8, 9, 10, 11, 12, 13. Preimplantation genetic diagnosis is an added new promising approach at the molecular level with the application of polymerase chain reaction (PCR)-based protocols. These protocals are carried out for translocation analysis utilizing multiplexed short tandem repeat (STR) markers located on both segments of the translocated chromosomes 14. When the need arises for in vitro fertilization (IVF)/ICSI for the treatment of male infertility, the use of the above mentioned cytomolecular diagnostic tests may be taken into consideration with proper consent of the subject. This molecular diagnostic approach will enable us to study the integrity of the sperm DNA because it is the essential and prerequisite criteria for the accurate transmission of genetic material from parents to offspring.

To The Editor: In the article by Madhavarao et al., recently published in Indian Journal of Pediatrics, the authors have described response to Dihydrotestosterone (DHT) gel in a case with 5 α-reductase 2 deficiency (5αRD). The child was put on three monthly intramuscular testosterone injections (25 mg), which increased the stretched penile length (SPL) to 2.1 cm from initial SPL of 1.3 cm and both the testes descended to labioscrotal folds with increase in rugosity. The authors also reported that the application of DHT gel increased SPL to 3 cm within 1 mo and later to 3.4 cm after 5 mo [1]. We also observed increase in SPL after application of DHT cream in one of our patients with 5αRD. Our patient, born of a consanguineous marriage, was reared as female until 13 y when diagnosis of 46, XY DSD was made. He had small phallus (SPL 2.5 cm) with chordee, bifid scrotum and penoscrotal hypospadias. USG revealed left testis was in labioscrotal fold and right testis in inguinal canal. His basal hormonal levels were LH 5.96 mIU/mL, FSH 15.83 mIU/mL, Testosterone (T) 4.35 ng/mL, DHT 210 pg/mL, T/DHT 20.7, Androstenedione (A) 0.92 ng/mL, T/A 4.7. DHT and Awere estimated by radio immuno assay (RIA) after Celitechromatography. He was advised to apply DHT cream over the phallus. On next follow up at 7 mo, the SPL had increased to 5 cm. Psychological evaluation revealed male gender identity. Most of our peri-pubertal children with 5αRD had opted for male genitoplasty [2]. Molecular genetic studies revealed homozygous missense mutation of R246Q on exon 5 of SRD5A2 gene. This mutation has been reported by some centers from India [3, 4]. To correct cryptorchidism, alternative treatment with hCG is recommended [5].

A case of primary hypothyroidism in a pre-pubertal girl presenting with vaginal bleeding and unilateral ovarian cyst is reported. The cyst resolved spontaneously after the institution of thyroid hormone therapy.Watchful expectancy is recommended when an ovarian cyst is found in association with primary hypothyroidism and precocious puberty.

Hyperandrogenism is a common disorder among women in the reproductive age group. One of the rare causes for androgen excess is sex cord- stromal tumors of the ovary. These are usually unilateral. Here we report case of a 48 year old woman who presented with hyperandrogenism due to bilateral ovarian thecoma. Androgen levels normalized following resection of the tumor. This, to the best of our knowledge, is the first case of bilateral thecoma presenting as hirsutism in a premenopausal woman.

A rare case of unexplained absence of both fallopian tubes and ovaries from their normal position, resulting infertility is presented. On careful search an ectopic ovary containing dermoid cyst was found in the omentum. Possible mechanism and clinical significance of such a rare occurrence is discussed.

Background & objectives: Premature ovarian failure (POF) is defined as the cessation of ovarian function under the age of 40 yr and is characterized by amenorrhoea, hypoestrogenism and elevated serum gonadotrophin levels. The cause of POF remains undetermined in majority of the cases. This study was aimed to investigate the type and frequency of cytogenetic abnormalities in patients with idiopathic POF and also to study the role of oxidative stress in such cases. Methods: Seventy five women with idiopathic POF were included in this study. Chromosome analysis was done in peripheral blood lymphocytes by conventional GTG banding to identify numerical or structural abnormalities. Cytogenetically normal cases were investigated for reactive oxygen species (ROS) levels in their blood by luminol-chemiluminescence assay. Results: Eighteen chromosomal anomalies were identified in POF patients (24%). Majority of the cases were found to have X-chromosome abnormalities (28%). Overall median ROS range was found to be significantly higher (P

Precocious puberty in girls can be due to number of factors of which idiopathic central precocious puberty is the most common etiology. Here, we describe 3 cases of precocious puberty where the first case had premature thelarche in the background history of mother with Type 2 Diabetes Mellitus, cases 2 and 3 had ovarian tumours with heterogeneity in presentation.

Background Cytokines play an important role in the development of diabetic chronic renal insufficiency (CRI). Transforming growth factor β1 (TGF β1) induces renal hypertrophy and fibrosis, and cytokines like tumor necrosis factor-alpha (TNFα), chemoattractant protein-1 (MCP-1), and regulated upon activation and normal T cell expressed and secreted (RANTES) mediate macrophage infiltration into kidney. Over expression of these chemokines leads to glomerulosclerosis and interstitial fibrosis. The effect of MCP-1 and RANTES on kidney is conferred by their receptors i.e., chemokine receptor (CCR)-2 and CCR-5 respectively. We tested association of nine single nucleotide polymorphisms (SNPs) from TGFβ1, TNFα, CCR2 and CCR5 genes among individuals with type-2 diabetes with and without renal insufficiency. Methods Type-2 diabetes subjects with chronic renal insufficiency (serum creatinine ≥ 3.0 mg/dl) constituted the cases, and matched individuals with diabetes of duration ≥ 10 years and normoalbuminuria were evaluated as controls from four centres in India. Allelic and genotypic contributions of nine SNPs from TGFβ1, TNFα, CCR2 and CCR5 genes to diabetic CRI were tested by computing odds ratio (OR) and 95% confidence intervals (CI). Sub-analysis of CRI cases diabetic retinopathy status as dependent variable and SNP genotypes as independent variable in a univariate logistic regression was also performed. Results SNPs Tyr81His and Thr263Ile in TGF β1 gene were monomorphic, and Arg25Pro in TGF β1 gene and Δ32 polymorphism in CCR5 gene were minor variants (minor allele frequency A SNP of CCR5 gene has been observed and the allele 59029A seems to confer predisposition to development of diabetic CRI (OR 1.39; CI 1.04–1.84). In CRI subjects a compound group of genotypes "GA and AA" of SNP G>A -800 was found to confer predisposition for proliferative retinopathy (OR 3.03; CI 1.08–8.50, p = 0.035). Conclusion Of the various cytokine gene polymorphisms tested, allele 59029A of CCR5 gene is significantly associated with diabetic renal insufficiency among Asian Indians. Result obtained for 59029G>A SNP of CCR5 gene is in conformity with reports from a Japanese population but due to sub-optimal power of the sample, replication in larger sample set is warranted.

Thyroid hyperfunction in a patient with long-standing hypothyroidism is uncommon. Here, we describe and discuss the unusual scenario of development of severe skin rash to carbimazole, with subsequent acute toxicity to lithium in clinically indicated doses, in a patient who manifested hyperthyroidism after being on treatment for hypothyroidism for 7 years.

Background To determine association of nine single nucleotide polymorphisms (SNPs) in ADP ribosyltransferase-1 (ADPRT1), aldo-keto reductase family 1 member B1 (AKR1B1), receptor for advanced glycation end-products (RAGE), glutamine:fructose-6-phosphate amidotransferase-2 (GFPT2), and plasminogen activator inhibitor-1 (PAI-1) genes with chronic renal insufficiency (CRI) among Asian Indians with type 2 diabetes; and to identify epistatic interactionss between genes from the present study and those from renin-angiotensin-aldosterone system (RAAS), and chemokine-cytokine, dopaminergic and oxidative stress pathways (previously investigated using the same sample set). Methods Type 2 diabetes subjects with CRI (serum creatinine ≥3.0 mg/dl) constituted the cases (n = 196), and ethnicity and age matched individuals with diabetes for a duration of ≥ 10 years, normal renal functions and normoalbuminuria recruited as controls (n = 225). Allelic and genotypic constitution of 10 polymorphisms (SNPs) from five genes namely- ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 with diabetic CRI was investigated. The genetic associations were evaluated by computation of odds ratio and 95% confidence interval. Multiple logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study epistatic interactions between SNPs in different genes. Results Single nucleotide polymorphisms -429 T>C in RAGE and rs7725 C>T SNP in 3' UTR in GFPT2 gene showed a trend towards association with diabetic CRI. Investigation using miRBase statistical tool revealed that rs7725 in GFPT2 was a perfect target for predicted miRNA (hsa miR-378) suggesting the presence of the variant 'T' allele may result in an upregulation of GFPT2 contributing to diabetic renal complication. Epistatic interaction between SNPs in transforming growth factor TGF-β1 (investigated using the same sample set and reported elsewhere) and GFPT2 genotype was observed. Conclusions Association of SNPs in RAGE and GFPT2 suggest that the genes involved in modulation of oxidative pathway could be major contributor to diabetic chronic renal insufficiency. In addition, GFPT2 mediated overproduction of TGF-β1 leading to endothelial expansion and thereby CRI seems likely, suggested by our observation of a significant interaction between GFPT2 with TGF-β1 genes. Further, identification of predicted miRNA targets spanning the associated SNP in GFPT2 implicates the rs7725 SNP in transcriptional regulation of the gene, and suggests GFPT2 could be a relevant target for pharmacological intervention. Larger replication studies are needed to confirm these observations.