Madan L. Khurana

Improved efficacy of low-dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six-month, open-label randomized study.

CONTEXT To improve the treatment outcomes in women with polycystic ovary syndrome (PCOS), various drugs like glitazones, oral contraceptive pills, or antiandrogens have been combined with metformin. OBJECTIVE The aim of the study was to compare the efficacy of the combination of low-dose spironolactone and metformin with either drug alone in the management of women with PCOS. DESIGN AND SETTING The present study was an open-label, randomized study conducted at a tertiary care referral center. PATIENTS AND INTERVENTION Of 204 women who met the 2006 Androgen Excess-PCOS criteria for PCOS, 198 were randomized into 3 equal groups to receive metformin (1000 mg/d), low-dose spironolactone (50 mg/d), or a combination of both drugs for a period of 6 months. A total of 169 subjects (n = 56 metformin, 51 spironolactone, 62 combination) completed the study. MAIN OUTCOME MEASURES Menstrual cycle pattern, Ferriman-Gallwey score, body mass index (BMI), waist-hip ratio, blood pressure, LH, FSH, total T, glucose and insulin sensitivity indices were measured at baseline (0 mo) and 3 and 6 months after the intervention. Recording of adverse events and drug compliance was assessed at each of the visits. RESULTS The 3 groups had comparable mean age and BMI at baseline. By 6 months, menstrual cycles/y increased, whereas Ferriman-Gallwey score, serum total T, and area under the curve-glucose and -insulin decreased significantly (P < .05) in the combination group as compared to either drug alone. There was no significant change in body weight, BMI, waist-hip ratio, and blood pressure in any of the 3 groups. The combination group had better compliance than either drug alone, and the adverse event rate was not higher. CONCLUSION The combination of low-dose spironolactone with metformin seems superior to either drug alone in terms of clinical benefits and compliance in women with PCOS.

Association of subclinical hypothyroidism and phenotype, insulin resistance, and lipid parameters in young women with polycystic ovary syndrome

OBJECTIVE To determine whether subclinical hypothyroidism (SCH) alters the phenotype, insulin resistance, or lipid parameters in young women with polycystic ovary syndrome (PCOS). DESIGN Prospective case-control study. SETTING Tertiary care setting. PATIENT(S) Sixty-two young women with PCOS and SCH (group I) and 291 euthyroid women with PCOS (group II). INTERVENTION(S) Recording of clinical, biochemical, hormonal profile, and parameters of insulin resistance. MAIN OUTCOME MEASURE(S) Whether SCH has any association with clinical parameters like hirsutism, menstrual disturbances, lipid profile, and parameters of insulin sensitivity. RESULT(S) Mean (±SD) TSH was 7.13±1.28 IU/L in group I and 2.51±1.21 IU/L in group II, with comparable free triiodothyronine and free thyroxine. The two groups were comparable in age, weight, and body mass index. Parameters like blood pressure, menstrual pattern, and degree and duration of hirsutism did not differ between the two groups. Serum concentrations of triglycerides were significantly higher in the SCH group compared with controls. Plasma glucose concentrations both in fasting and after oral glucose tolerance test were similar between the two groups. Fasting insulin and other parameters of insulin resistance were not altered by SCH. CONCLUSION(S) Mild TSH elevation in the face of normal serum free triiodothyronine and free thyroxine results in a mild increase in serum lipids. Subclinical hypothyroidism is not associated with alteration in phenotypic expression and insulin resistance in young women with PCOS.

Insulin response to oral glucose in healthy, lean young women and patients with polycystic ovary syndrome.

Background and aim. Insulin resistance and consequent hyperinsulinemia are common among patients with polycystic ovary syndrome (PCOS). Ethnicity and dietary habits affect insulin levels. There is little published information from India on insulin levels in PCOS patients. Thus the present study aimed to determine the insulin response to oral glucose in women with PCOS and healthy women. Methods. In a case–control study design, women with PCOS and lean healthy women without a family history of diabetes mellitus underwent oral glucose tolerance testing. Samples were collected at 0, 1 and 2 h after glucose ingestion. Results. Two hundred and eighty-five women with PCOS and 27 lean healthy young women were enrolled into the study. The mean age of controls was 22.8 ± 4.5 years (range 15–32 years) and their mean body mass index (BMI) was 19.7 ± 2.6 kg/m2. Mean blood glucose at 0, 1 and 2 h was 88.2 ± 7.2, 115.5 ± 25.5 and 91.8 ± 20.5 mg/dl, respectively. Corresponding plasma insulin levels were 5.8 ± 1.1, 32.7 ± 26.5 and 14.6 ± 9.6 mIU/l. Peak insulin levels were seen at 1 h and these came down to less than 40% of the peak value by 2 h. Glucose/insulin ratio at 0, 1 and 2 h was 15.6 ± 3.1, 7.0 ± 3.1 and 11.4 ± 7.0. Homeostasis model assessment of insulin resistance (HOMA-IR) was 1.2 ± 0.2. The age of the PCOS women ranged from 15 to 40 years (mean 23.4 ± 6.2 years) and their BMI ranged from 16.4 to 50.4 kg/m2 (mean 27.7 ± 6.3 kg/m2). One hundred and seventy-six (62%) PCOS patients had normal glucose tolerance (NGT), 39 (14%) had impaired fasting glucose (IFG), 49 (17%) had impaired glucose tolerance (IGT) and 21 (7%) had type 2 diabetes mellitus (T2DM). Insulin response was higher in women with PCOS. Peak insulin was observed at 1 h. The difference between 1-h and 2-h post-glucose insulin decreased with worsening glucose tolerance. Both plasma insulin and BMI showed a rising trend from NGT to IFG to IGT. There was no further increase in either insulin or BMI from IGT to T2DM. Glucose/insulin ratio at 0, 1 and 2 h was lower (8.3 ± 4.2, 2.0 ± 1.6 and 3.2 ± 3.5) than that of healthy controls. HOMA-IR was 3.1 ± 3.0. Conclusion. Women with PCOS had an exaggerated insulin response to glucose. Thirty-eight percent of PCOS women had some form of abnormal glucose tolerance. Greater insulin response was seen with impairment of glucose tolerance. Obesity had no effect on fasting insulin or insulin response to oral glucose in PCOS women with NGT.

Morning cortisol is lower in obese individuals with normal glucose tolerance

Background 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.

Insulin sensitivity and β-cell function in normoglycemic offspring of individuals with type 2 diabetes mellitus: Impact of line of inheritance

Aims: The aim was to study the effect of family history of type 2 diabetes mellitus (T2DM) on insulin sensitivity and β-cell function in normoglycemic offspring. Material and Methods: Offspring of T2DM patients (cases) and individuals without family history of T2DM (controls) were the subjects for this cross-sectional study. All participants underwent 75 g OGTT and samples were collected for plasma insulin, C-peptide, and proinsulin at 0, 30, 60, and 120 minutes. Results: A total of 271 cases (age 22 ± 10 years; 53% males) and 259 controls (28 ± 10 years, 66% males) were enrolled for the study. BMI, plasma insulin, C-peptide, proinsulin, HOMA-IR, and insulinogenic index (0-120) were significantly higher and whole-body insulin sensitivity (WBISI) and disposition index (0-120) [DI 120] were lower in cases compared to controls. After adjusting for BMI, proinsulin at 120 minutes, area under the curve (AUC) of proinsulin (during OGTT) and AUC proinsulin/AUC C-peptide were significantly higher in cases. Cases were subdivided into four groups according to inheritance pattern; paternal DM (PDM), maternal DM (MDM), grandparental DM (GPDM), and both parents DM (BPDM). The magnitude of differences varied with relationship (greater when both parents and grandparents were affected). Mean HOMA-IR was higher by 127% and 50% and DI 120 was lower by 33% and 18% (adjusted for age and gender) in the BPDM and GPDM groups respectively compared to controls. Conclusions: We observed higher BMI, plasma insulin, C-peptide, and proinsulin and lower insulin sensitivity and β-cell compensation in normoglycemic offspring of T2DM subjects compared to controls. Differences were greater when both parents and grandparents had T2DM.

Fertility among women with classical congenital adrenal hyperplasia: report of seven cases where treatment was started after 9 years of age.

Background and aim. Androgen excess is believed to be one of the major factors responsible for poor fertility outcomes in females with congenital adrenal hyperplasia (CAH). Some believe that the adverse effect of androgens on fertility could have its origins as early as the antenatal years. To assess the impact of prolonged androgen exposure on fertility in CAH patients, we compiled the data of females with CAH followed in our clinic during the last 25 years who were sexually active and had not been initiated on steroids until age 9 years. Study design and patients. This was an observational case study on seven patients with classical CAH who fulfilled the inclusion criteria. The age at initiation of therapy in these females ranged from 9 years to 29 years. Results. All patients had varying degrees of genital ambiguity. The most common presenting complaints were genital ambiguity, non-development of secondary sexual characteristics, hirsutism and primary amenorrhea. Genital surgery was performed in all patients at ages ranging from 12 to 29 years, except for one patient who underwent surgery at age 5 years without a diagnosis of CAH being made. Breast development ensued within 2 to 12 months and periods started in all patients within 2–24 months of steroid initiation. There were 13 pregnancies (seven normal vaginal deliveries, two spontaneous abortions and four pregnancies were medically terminated). Conclusions. Late initiation of steroid therapy did not affect fertility in our cohort of CAH women. Androgen excess in situations of subnormal cortisol may not adversely affect fertility in females with CAH.

Obesity and Metabolic Abnormalities in Offspring of Subjects with Diabetes Mellitus

BACKGROUND Some recent studies observed that a number of obese children had family members with type 2 diabetes. The aim of the present study was to assess prevalence of obesity and metabolic abnormalities among offspring of subjects with type 2 diabetes mellitus. METHODS Children of patients with type 2 diabetes mellitus were studied. Detailed medical history, physical examination, hemogram, renal and liver function tests, lipid profile, body composition, and oral glucose tolerance tests were done for all subjects. Plasma insulin was also done in addition to glucose at 0, 30, 60, and 120 min after oral glucose. RESULTS A total of 355 subjects from 208 families (194 males [55%] and 161 females [45%], mean age 23 +/- 11 years) were studied. Among them, 209 (58.9%) were lean, 91 (25.6%) were overweight, and 55 (15.5%) were obese. Seventeen (4.8%) subjects had impaired fasting glucose, 29 (8.2%) had impaired glucose tolerance, and 10 (2.8) had diabetes mellitus. Twenty (35.7%) of 56 with abnormal glucose tolerance were lean. One hundred six (29.8%) subjects had triglyceride levels greater than 150 mg/dL, 137 (38.6%) had low levels of high-density lipoprotein-cholesterol, and 67 (18.9%) had high total cholesterol levels. Prevalence of obesity, elevated plasma triglyceride, and glucose intolerance was higher among older subjects and subjects both of whose parents had diabetes. CONCLUSIONS Children from families with type 2 diabetes are at increased risk for obesity. Risk increases by fivefold when both parents have diabetes.

Comparison of Gliclazide with Insulin as Initial Treatment Modality in Newly Diagnosed Type 2 Diabetes

AIM This study was designed to compare effectiveness and remission rate between gliclazide and insulin as initial treatment in newly diagnosed, drug-naive patients with type 2 diabetes. METHODS Newly diagnosed, drug-naive subjects with type 2 diabetes having mean fasting blood glucose >200 mg/dL were enrolled into either of two groups (gliclazide or insulin). The former received gliclazide modified-release 60 mg daily, while the insulin group received 16 units of premixed insulin as two divided doses along with medical nutrition therapy. Premeal blood glucose was monitored, and the dose was adjusted accordingly. Glycosylated hemoglobin (HbA1c), lipid profile, and postmeal C-peptide were estimated at baseline and 6 months. Remission was defined as euglycemia off drug for a minimum duration of 1 month. RESULTS Baseline and 6-month blood glucose, HbA1c, and lipid profile were comparable between groups. Blood glucose levels normalized in 2-6 weeks in both groups. At 6 months, one of 30 (3.33%) in the gliclazide group and 24 of 30 (80%) in the insulin group were in remission. Ten of 16 (62.5%) in the insulin group and one of 20 (.5%) in the gliclazide group continued to maintain euglycemia off all pharmacological treatment at 12 months. At 6 months, C-peptide increased in the insulin group (3.21+/-1.61 ng/mL at baseline vs. 5.82+/-2.23 ng/mL at 6 months), while it remained unchanged in the gliclazide group (3.4+/-1.87 ng/mL at baseline vs. 3.82+/-1.78 ng/mL at 6 months) (P=0.0003). CONCLUSIONS Comparable glycemic control could be achieved with both insulin and oral hypoglycemic agent in newly diagnosed type 2 diabetes subjects. Insulin treatment exceeded gliclazide in the remission (drug-free) rate.

Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia.

Context: Congenital adrenal hyperplasia (CAH) is one of the inborn errors of metabolic disorder inherited in an autosomal recessive manner caused by the defects in the steroid 21 hydroxylase CYP21A2 gene. We analyzed the genotype of 62 patients with classic CAH. Aims: To find out the underlying mutations of CYP21A2 gene. Settings and Design: Cohort of CAH patients. Materials and Methods: Sixty-two patients with CAH were recruited from the endocrine clinic at AIIMS. Electrochemiluminiscence method was used for estimating the levels of cortisol. Radioimmunoassay kit-based method was used for estimating the 17 OHP levels. Polymerase chain reaction amplification was done using specific primers to amply the CYP21A2 gene. Statistical Analysis Used: Statistical analysis was done by using Epi Info Version 3.5.1.2008. Results: Out of 62 patients, 50 were simple virilizers (SV) and 12 were salt wasters (SW). Fifty-six were females and six were males. Five 46, XX children were reared as males. Age at presentation varied from 8 months to 38 years. Molecular genetic analysis revealed that the highest number of patients harboured (In 2) IVS2-13 A/C > G (48%), followed by p.P30L (46%), p.Q318X (35%), (D 8 bp) deletion 8 bp (26%), p.I172N (26%), and p. R356W (20%) mutations. Conclusion: This is among the few studies to analyze the mutational spectrum of CYP21A2 gene in a large CAH cohort from India. Molecular diagnosis of CYP21A2 gene should be considered as part of the CAH evaluation to assess the risk of the patients/parents/siblings and to offer genetic counseling.

Phenotype, hormonal profile and genotype of subjects with partial androgen insensitivity syndrome: report of a family with four adult males and one child with disorder of sexual differentiation

There is little information on the molecular basis of intrafamilial and inter‐familial phenotypic heterogeneity with the same androgen receptor (AR) mutation in patients with partial androgen insensitivity syndrome. A genetic analysis was performed in a large kindred with ambiguous genitalia and the genotype–phenotype correlations were analysed. The index case was brought for sex assignment. Family history revealed four other affected members who had hypospadias and varying degrees of virilisation. All the affected males had hemizygous mutations in the third exon of the AR gene (A596T). One was also found to have a heterozygous mutation in the fourth exon of the 5 alpha reductase type 2 gene (G196S). This affected male with double mutations was better virilised compared with the other affected members with a single mutation. The degree of virilisation correlated with serum testosterone levels. Gynaecomastia was not present in any of these subjects. It is concluded that the subject with dual gene defects also had higher levels of testosterone and pubertal virilsation. Testosterone levels possibly govern the degree of pubertal virilisation in subjects with A596T gene defects. It is not clear whether the better pubertal virilsation and higher testosterone are in any way causally related to the SRD5A2 gene defect.