José Antonio Miguel Marcondes

Influence of different genotypes on 17‐hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21‐hydroxylase deficiency

The diagnosis of the nonclassical form of 21‐hydroxylase (NC‐21OH) deficiency, established before molecular studies, is based on basal 17OH‐progesterone (17OH‐P) values > 15 nmol/l or ACTH‐stimulated 17OH‐P values > 30 nmol/l. This disease is caused by mutations in the structural gene that can be grouped into three categories: A, B and C, according to the predicted level of enzymatic activity. So, the genotype of the nonclassical form is a combination of mutations that cause moderate impairment of enzymatic activity in one allele and mutations which cause total (A), severe (B: 3%) or moderate (C: 20–60%) impairment of enzymatic activity in the other allele.

Salivary cortisol for the evaluation of Cushing's syndrome

Cortisol concentrations were measured in matched plasma and salivary samples from 8 healthy controls, 8 patients with Cushings syndrome and 4 patients suspected of having spontaneous hypercortisolism. In healthy subjects, the circadian rhythm in salivary cortisol paralleled that in plasma. Absence of the diurnal rhythm in Cushings syndrome was seen in saliva as well as in plasma. After ACTH stimulation, mean peak cortisol in saliva showed a 3-fold increase while in plasma there was a 2.5-fold increment above baseline. Cushings syndrome, due to pituitary or adrenal adenoma was diagnosed equally well by measuring the cortisol response to cosyntropin in either plasma or saliva. Finally, the low- and high-dose dexamethasone suppression test was reflected equally well in both plasma and saliva. In patients suspected of having Cushings syndrome dynamic tests can be performed in both plasma and saliva. However, in some samples, the salivary cortisol measurement appears advantageous over plasma cortisol determination.

Low Frequency of CYP21B Deletions in Brazilian Patients with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

The frequency of large mutations was determined in 131 Brazilian patients with different clinical forms of 21-hydroxylase deficiency, belonging to 116 families. DNA samples were examined by Southern blotting hybridization with genomic CYP21 and C4cDNA probes after TaqI and BglII restriction. Large gene conversions were found in 6.6% and CYP21B deletions in 4.4% of the alleles. The breakpoint in these hybrid genes occurred after exon 3 in 92% of the alleles. All rearrangements involving CYP21B gene occurred in the heterozygous form, except in a patient with simple virilizing form who presented homozygous CYP21B deletion. Our data showed that in these Brazilian patients, CYP21B deletions were less frequent than in most of the large series previously reported.

Metabolic syndrome in women with polycystic ovary syndrome: prevalence, characteristics and predictors

The aim of this study was to determine the prevalence of metabolic syndrome in women with polycystic ovary syndrome, as well as its characteristics and predictors. Seventh-three women, with body mass index of 30.4 +/- 7.8 kg/m2 and 25.0 +/- 6.0 years old, subdivided according to body mass index, were studied retrospectively. There was no significant mean age difference among body mass index groups (p = 0.228). Prevalence of metabolic syndrome was 38.4%, with a null prevalence for normal (n = 18), 23.8% for overweight (n = 17), 62.9% for obese (n = 28), and 85.5% for morbidly obese women (n = 7). Women with metabolic syndrome were older than women without metabolic syndrome (27.3 +/- 5.3 vs. 24.2 +/- 4.6 vs. years old; p = 0.031) and presented a higher body mass index (36.3 +/- 7.7 vs. 26.9 +/- 5.4; p < 0.001). There was no difference for degree of hirsutism and menstrual patterns between women with and without metabolic syndrome (p = 0.593 and p = 0.119, respectively). Regarding laboratory parameters, DHEAS was lower (1,646 +/- 1,007 vs. 2,594 +/- 1,563; p = 0.007) and HOMA-IR were higher (9.9 +/- 9.7 vs. 4.6 +/- 4.7; p = 0.004) in women with metabolic syndrome (p = 0.031 and p < 0.001, respectively). The best predictors of metabolic syndrome were waist circumference > 88 cm, HDL-cholesterol < 50 mg/dL and triglycerides >or= 150 mg/dL.

Prevalence of abnormalities of glucose metabolism in patients with polycystic ovary syndrome.

Patients with polycystic ovary syndrome (PCOS) present a higher risk for abnormalities of glucose metabolism (AGM). For to study this in our population, we submitted 85 patients, with body mass index (BMI) of 28.5 +/- 6.6 kg/m(2) and aged 25.5 +/- 5.4 years old, to an oral glucose tolerance test (OGTT), and assessed the impact of BMI on the prevalence of impaired glucose tolerance (IGT) and of diabetes mellitus (DM). The states of glucose tolerance were classified considering fasting plasma glucose (FPG) according to the American Diabetes Association (ADA) criterion and plasma glucose at 120 minutes according to the Word Health Organization (WHO) criterion. According to the ADA criteria, 83.5% classified as normal and 16.5% as with AGM, with 15.3% presenting impaired fasting glucose and 1.2% DM, while according to the WHO criteria, 68.2% were classified as normal and 31.8% as with AGM, with 27.0% of them presenting IGT and 4.8% DM. Seventy-three percent of PCOS patients with IGT by WHO criterion had normal FPG by ADA criterion. The prevalence of AGM for both criteria increased with the body mass index. In conclusion, we found a higher prevalence of AGM in PCOS patients than that found in the general population, being the highest in obese patients. Glycemia at 120 minutes on the OGTT identified more patients with AGM than fasting glycemia. We recommended that the assessment of AGM must be done by the OGTT in all patients with PCOS.

Metformin versus lifestyle changes in treating women with polycystic ovary syndrome

Objective: To compare the efficacy of metformin with that of lifestyle changes in patients with polycystic ovary syndrome (PCOS).Design: Prospective, randomized clinical trial of 40 women with PCOS to analyze the effects of metformin and lifestyle intervention treatments on menstrual pattern and hormone and metabolic profile. The duration of treatment was 6 months. Statistical analysis was done using Student’s t-test.Results: Fifteen women in the metformin group and 12 in the lifestyle changes group completed the study. The menstrual pattern improved by ~67% in both groups. There was a significant decrease in waist circumference in the lifestyle changes group (101.8 ± 3.9 and 95.1 ± 3.6, at baseline and at 6 months of treatment, respectively; p < 0.001) and in body mass index (BMI) in both groups. The predictor of menstrual pattern improvement was BMI.Conclusions: Both metformin and lifestyle changes may increase the number of menstrual cycles in PCOS. This effect was related to a decrease in BMI.

Metformin in normal-weight hirsute women with polycystic ovary syndrome with normal insulin sensitivity

Fifteen normal-weight (body mass index (BMI) 21.50 ± 1.65 kg/m2) hirsute women with polycystic ovary syndrome and normal insulin sensitivity were treated with 850 mg metformin orally, three times daily, for 4 months. Before and at the end of the treatment, clinical data as well as serum concentrations of sex steroid hormones, gonadotropins, fasting plasma glucose and insulin, insulin resistance – homeostasis model assessment (HOMA-IR), carbohydrate tolerance and the area under the curve for insulin (AUCinsulin) were analyzed. Three patients withdrew from the study. Seven of the remaining 12 patients presented menstrual pattern improvement, followed by ovulatory cycles at the end of the treatment period. There were no changes in BMI and hirsutism score. A significant (p < 0.05) decrease in luteinizing hormone (LH) (from 8.18 ± 4.34 to 5.05 ± 1.53 IU/ml), testosterone (from 104.66 ± 27.54 to 82.00 ± 23.05 ng/dl), fasting insulin (from 9.66 ± 4.79 to 7.83 ± 3.06 µIU/ml), AUCinsulin (from 9239 ± 3285 to 7660 ± 2565 µUI/ml × min) and HOMA-IR (from 2.15 ± 1.2 to 1.67 ± 0.74), and a significant increase in follicle-stimulating hormone (FSH) (from 4.05 ± 1.53 to 5.96 ± 2.13 IU/ml), were observed at the end of the treatment period. A higher LH and a lower FSH predicted clinical improvement, while basal insulin and AUCinsulin showed lower predictive value.

Analysis of gonadotropin pulsatility in hirsute women with normal menstrual cycles and in women with polycystic ovary syndrome

OBJECTIVE To study the relation between plasma gonadotropin pulsatility, androgen levels, and estrogen levels in patients with polycystic ovary syndrome (PCOS), in hirsute women with normal menstrual cycles, and in healthy women. DESIGN Prospective study. SETTING University medical center-based cellular and molecular endocrinology laboratory. PATIENT(S) Eight healthy women (group 1), 9 hirsute women with normal menstrual cycles (group 2), and 19 women with PCOS (group 3). INTERVENTION(S) Plasma concentrations of LH and FSH were measured by RIA every 15 minutes for 12 hours. MAIN OUTCOME MEASURE(S) Rhythmic parameters of 12-hour LH and FSH secretion. RESULT(S) Rhythmic parameters of 12-hour LH secretion were significantly higher in patients with PCOS (group 3) than in controls (group 1) or in hirsute women with normal menstrual cycles (group 2). The frequency of LH pulses was statistically higher in patients with PCOS (group 3) than in controls (group 1). Statistically significant correlations were found when the frequency of LH pulses was plotted against basal LH concentrations and rhythmic parameters of 12-hour LH secretion. CONCLUSION(S) Luteinizing hormone pulse amplitude was higher in patients with PCOS than in hirsute women with normal menstrual cycles or in healthy women. The LH pulse frequency was increased only in patients with PCOS compared with healthy women and not in hirsute women with normal menstrual cycles.

Bone histomorphometry in Cushing's syndrome

Bone involvement is a common finding in Cushing’s syndrome. The actions of corticosteroids on bone have been studied quite intensively but only a few studies of bone histomorphometry in this syndrome have been published. In this paper we present histomorphometric measurements of bone activity in 7 patients with a postoperative reevaluation in two. The results show irregular alterations on histomorphometric parameters with an increased bone resorption and decreased bone formation rate. After surgery the abnormalities changed towards normal.

Metabolism of triglyceride-rich lipoproteins and lipid transfer to high-density lipoprotein in young obese and normal-weight patients with polycystic ovary syndrome

OBJECTIVE To clarify whether the metabolism of triglyceride-rich lipoproteins and lipid transfer to high-density lipoprotein (HDL) are altered in patients with polycystic ovary syndrome (PCOS). DESIGN Case-control study. SETTING Endocrinology clinics. PATIENT(S) Eight normal-weight (NW) and 15 obese (Ob) patients with PCOS were compared with 10 NW and 10 Ob women without PCOS paired for age and body mass index. INTERVENTION(S) Determination of triglyceride-rich lipoprotein metabolism and lipid transfer to HDL. MAIN OUTCOME MEASURE(S) Participants were injected triglyceride-rich emulsions labeled with (14)C-cholesteryl esters and (3)H-triglycerides and the fractional clearance rate (FCR, in min(-1)) of labels was determined. Lipid transfer from artificial nanoemulsions to HDL was performed by incubating radioactively labeled lipid nanoemulsions with plasma during 1 hour, followed by radioactive counting of HDL-containing supernatant after chemical precipitation. RESULT(S) Lipolysis estimated by triglyceride FCR was equal in PCOS groups (NW = 0.043 +/- 0.032, Ob = 0.033 +/- 0.009) and respective controls (NW = 0.039 +/- 0.015, Ob = 0.044 +/- 0.019). However, the remnant removal as estimated by cholesteryl ester FCR was reduced in both PCOS groups (NW = 0.005 +/- 0.006, Ob = 0.005 +/- 0.005) compared with controls (NW = 0.016 +/- 0.006, Ob = 0.011 +/- 0.072). Lipid transfer rates were not different among groups, but triglyceride transfer rates were positively correlated with homeostasis model assessment estimate of insulin resistance in PCOS. CONCLUSION(S) PCOS patients showed decreased removal of atherogenic remnants even when fasting glucose was <100 mg/dL. This reinforces the usefulness of the measures taken to prevent cardiovascular events in PCOS patients.