leptin and Adrenal-Hyperplasia--Congenital

An established fact in the polycystic ovarian syndrome (POS) is an abnormal ovarian steroidogenesis. Though this suggest an intrinsic ovarian defect, the syndrome could also be influenced by factors outside the ovaries. Although of unknown etiology, the POS is one of the most frequent endocrine disorders in the gynecologic practice. The disorder is characterized by ultrasound findings of enlarged polycystic ovaries, hyperandrogenism, menstrual disorders, obesity and including the appearance of infertility. There are a series of mechanisms involved in the extraovarian androgen increase in patients with POS. Among these mechanisms are implicated those of central and peripheral origin, genetic factors and adrenocortical dysfunction. In the same way, the alterations produced could imply genetic, molecular biological, biochemical, physiological and endocrinological factors. Sometimes all these factors could interact at the same time. The high serum androgen level could stop the pituitary gonadotropin production, either as a direct mechanism or as a result of its peripheral conversion. The increased androgens also explain the manifestations of clinical acne, hirsutism, and the detention in follicular ovarian maturation. All these manifestations are related with the menstrual disorders, anovulation, and infertility that these patients develop. The characteristics of the extraovarian POS include the 17-hydroxyprogesterone elevation in response to the ACTH test and the dexamethasone suppression of adrenal androgens. It is possible to improve the ovarian function in some patients with POS. This could be achieved with clomiphene citrate associated with glucocorticoids to induce ovulation.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; 17-alpha-Hydroxyprogesterone; 3-Hydroxysteroid Dehydrogenases; Adrenal Cortex; Adrenal Hyperplasia, Congenital; Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Adult; Androgens; Catecholamines; Clomiphene; Corticotropin-Releasing Hormone; Cortisone; Dexamethasone; Female; Glucocorticoids; Gonadal Steroid Hormones; Humans; Hydroxysteroid Dehydrogenases; Hyperinsulinism; Hyperprolactinemia; Hypothalamo-Hypophyseal System; Infant, Newborn; Infertility, Female; Insulin Resistance; Leptin; Mineralocorticoids; Obesity; Ovary; Ovulation Induction; Pituitary-Adrenal System; Polycystic Ovary Syndrome; Pseudopregnancy; Steroid 11-beta-Hydroxylase; Steroid 17-alpha-Hydroxylase; Steroids; Sterol Esterase; Stress, Psychological

Patients with congenital adrenal hyperplasia (CAH) appear to have adverse cardiovascular risk profile and other long-term health problems in adult life, but there are limited data in young CAH patients. We aim to evaluate the cardio-metabolic risk factors in adolescents and young adults with classical 21-hydroxylase deficiency (21-OHD). We performed a cross-sectional study of 21 patients (17 females) with classic CAH detected clinically and not through newborn screening, aged 15.2 ± 5.8 years, and 21 healthy matched controls. Anthropometric, biochemical, inflammatory markers, and body composition using dual-energy X-ray absorptiometry were measured. Obesity was observed in 33% of the CAH patients. The waist/hip ratio and waist/height ratio were significantly higher in CAH patients. Five out of 21 patients (24%) had elevated blood pressure. Silent diabetes was diagnosed in one patient (4.8%), but none in the control group. Serum leptin and interleukin-6 levels were not different between groups, but hs-CRP levels tended to be higher in CAH patients. Other metabolic profiles and body composition were similar in CAH and controls.. Adolescents and young adults with CAH appear to have an increased risk of obesity and cardio-metabolic risk factors. Close monitoring, early identification, and secondary prevention should be implemented during pediatric care to improve the long-term health outcomes in CAH patients. What is Known: • Lifelong glucocorticoid (GC) replacement is the main treatment modality in patients with congenital adrenal hyperplasia which predispose to an adverse metabolic profile. • Adult CAH patients have adverse cardiovascular risk profile and other long-term health problems. What is New: • Adolescents and young adults with CAH appear to have an increased risk of obesity and cardio-metabolic risk factors.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Body Composition; Cardiovascular Diseases; Case-Control Studies; Child; Cross-Sectional Studies; Female; Humans; Leptin; Male; Metabolic Syndrome; Obesity; Risk Factors; Young Adult

The objective of this study was to evaluate patients with classic CAH before and after treatment with glucocorticoids/mineralocorticoid and compare the metabolic profile of the well controlled (WC) and poorly controlled (PC) group.. We selected newly diagnosed patients and patients monitored for CAH, classical form, regularly using or not glucocorticoids/mineralocorticoid in the Genetics Service Hupes-UFBA, seen from March/2004 to May/2006. All patients underwent detailed clinical evaluation and laboratory tests (glucose, sodium and potassium; total cholesterol, HDL, LDL, triglycerides and uric acid; leptin, 17-hydroxyprogesterone, total testosterone, C peptide, and insulin). Patients with normal androgens were classified as well controlled (WC), and those with high levels of androgens either using or not glucocorticoids/mineralocorticoids were classified as poorly controlled (PC).. We studied 41 patients with CAH: 11 in the WC group and 30 in PC group. Leptin and LDL cholesterol levels were higher in WC than in the PC group (p < 0.05). Uric acid values were lower in WC compared with the PC group (p < 0.05).. Adequate control of CAH with steroids seems safe, as it is associated with only mild changes in lipid profile and leptin values. No other metabolic abnormality was associated with glucocorticoid use. The reason for lower uric acid levels found in WC CAH patients is unknown and should be further studied.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Body Mass Index; Child; Child, Preschool; Cholesterol, LDL; Female; Glucocorticoids; Humans; Infant; Leptin; Male; Metabolome; Mineralocorticoids; Statistics, Nonparametric; Uric Acid; Young Adult

Hypogonadotropic hypogonadism (HH) secondary to hypothalamic gonadotropin-releasing hormone deficiency is a notable feature of a number of rare syndromes, where unlike idiopathic (isolated) HH, other endocrinopathies may also be apparent. The presence of a particular spectrum of clinical features in addition to HH may suggest a particular underlying diagnosis. Placing the diagnosis of HH into that context will then have important implications in terms of management and predicting long-term functional outcome. In some instances, establishing the genetic basis of a particular syndrome or disorder has advanced the understanding of normal hypothalamo-pituitary-gonadal function (e.g. LEP deficiency, DAX-1 and CHARGE syndrome) whilst in other disorders much has still to be learnt (e.g. Bardet-Biedl and Prader-Willi syndrome). In this chapter the above syndromes, where HH is a feature in most or all affected individuals, will be discussed. Recent advances in our understanding of the pathophysiology of the HH will be highlighted and management options presented. Longer term therapy with sex steroid replacement is becoming even more important if improvements in life expectancy are to be matched by improvements in quality of life.

Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Animals; Bardet-Biedl Syndrome; CHARGE Syndrome; DAX-1 Orphan Nuclear Receptor; Female; Genetic Diseases, X-Linked; Hormone Replacement Therapy; Humans; Hypoadrenocorticism, Familial; Hypogonadism; Leptin; Male; Mice; Prader-Willi Syndrome; Proprotein Convertase 1

Congenital adrenal hyperplasia (CAH) patients are at a higher risk to develop obesity. The role of leptin in CAH is still controversial. Our study aimed to evaluate serum levels of leptin, the soluble leptin receptor (sOB-R), and the sOB-R: leptin molar ratios in a cohort of CAH children and adolescents, and their associations with clinical and metabolic parameters.. We studied 51 CAH patients, aged 5.6-19.6 years (median 11.8, n=30 females) cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. Blood specimens were taken after overnight fasting between 0800 and 1000 h. For the analyses of leptin and sOB-R, matched pairs were built with healthy Caucasian patients for sex, Tanner stage (TS), chronologic age (CA), and body mass index (BMI).. BMI and SDS were significantly elevated compared with the reference population. Leptin levels were not different between matched pairs, whereas sOB-R levels were significantly lower in CAH. Consequently, the sOB-R: leptin molar ratios were significantly decreased in CAH. Correlation analyses in CAH patients revealed significant relationship between leptin and CA, TS, BMI, and homeostasis model assessment of insulin resistance. Similar results were obtained for the matched control group. For sOB-R, we found no significant correlation for CA, TS, or BMI in CAH, but we did in the controls. There were significant correlations for androgens within the CAH group. Additional analyses revealed no correlation with steroid medication or metabolic control.. Our data show that an altered leptin axis with normal serum leptin concentrations but decreased sOB-R serum levels may contribute to the increased risk of overweight and obesity in CAH.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Models, Statistical; Obesity; Overweight; Pregnanetriol; Prospective Studies; Receptors, Leptin; Risk Factors; Steroid 21-Hydroxylase; Testosterone; Young Adult

There is a tendency to adiposity in patients with congenital adrenal hyperplasia (CAH) despite physiological corticosteroid doses. This study investigated body fatness in children with CAH under corticosteroid replacement therapy. Seventeen children with CAH (female:male, 9:8; age range 1.6-10.5 years) and 18 controls (female:male, 9:9; age range 1.4-10.2 years) were studied. Serum lipids, leptin, insulin, anthropometry, body circumferences, skinfold thickness, and body fat ratio as measured with bioelectrical impedance analysis (BIA) were the study parameters. Weight standard deviation scores (SDS), body mass index (BMI), BMI-SDS, body circumferences, skinfold thickness, and body fat ratio were higher and leptin was positively correlated with all of the body circumference and skinfold thickness parameters as well as body fat ratio in the study group. Waist/hip ratio was lower in the study group. Body fatness is a serious problem starting in early childhood in CAH patients and further refinement of the glucocorticoid replacement regimens as well as lifestyle measures are needed.

Topics: Adrenal Hyperplasia, Congenital; Adrenocortical Hyperfunction; Androstenedione; Anthropometry; Child; Child, Preschool; Cholesterol; Electric Impedance; Female; Humans; Infant; Insulin; Leptin; Male; Obesity; Progesterone; Skinfold Thickness

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common inherited disorder of adrenal steroid biosynthesis. Patients with the classic form of CAH show androgen excess, with or without salt wasting. There are few studies reporting on higher rates of overweight and obesity among children with CAH. In addition to its role in the regulation of energy balance, leptin is involved in various endocrine and metabolic pathways. In this context, elevated serum leptin levels were reported recently for patients with CAH and were thought to be involved in the development of obesity among these patients. Therefore, the aim of this study was to analyze BMI values, compared with population-based references, for children and adolescents with CAH. Possible contributing factors, such as glucocorticoid therapy, skeletal maturation, birth weight and length, and parental BMI, were correlated with current BMI SD scores (SDS). In addition, the implications of serum leptin levels, corrected for BMI, gender, and Tanner stage, were investigated.. We performed a cross-sectional retrospective study of 89 children and adolescents with cah (48 female and 41 male subjects; age: 0.2-17.9 years) who presented in our outpatient department during 1 year. All individuals had classic cah, confirmed with molecular genetic analyses, and received substitution therapy (glucocorticoids and mineralocorticoids, if necessary). The quality of therapy was monitored in follow-up visits every 3 to 6 months, on the basis of clinical presentation and laboratory measurement findings according to current guidelines. We grouped the patients into salt wasting and simple virilizing groups, as well as according to current metabolic control. Leptin levels were measured with a commercial radioimmunoassay and calculated as sds. For statistical analyses, standard parametric and nonparametric methods were used.. The chronologic ages of the children with CAH were between 0.20 and 17.9 years (mean +/- SD: 8.9 +/- 4.6 years). The BMI SDS of the whole group ranged from -2.7 to 4.3 (mean +/- SD: 0.88 +/- 1.3) and was significantly elevated above 0. Fifteen subjects (16.8%) had BMI SDS of >2.0, which indicated a significantly greater frequency of obesity among patients with CAH than expected for the normal population (expected: 2.27%). There was no significant difference in age and BMI between genders and clinical forms (salt wasting versus simple virilizing). BMI SDS was correlated positively with chronologic age. The BMI SDS did not differ significantly between children receiving hydrocortisone, prednisone, or dexamethasone. Hydrocortisone dosages (including equivalent dosages of prednisone and dexamethasone) ranged from 6.2 to 30.1 mg/m2 body surface area (mean +/- SD: 14.7 +/- 4.8 mg/m2 body surface area). Hydrocortisone dosages were correlated positively with BMI SDS. The relative risk of having a BMI SDS of >2.0 was not significantly elevated among children with prednisone/dexamethasone medication, compared with those with hydrocortisone treatment. In contrast to this, fludrocortisone dosage was not correlated with BMI SDS. Bone age delay, as calculated from the difference of bone age and chronologic age, ranged from -2.9 years to 5.6 years (mean +/- SD: 1.11 +/- 1.8 years) and was significantly elevated; it was correlated positively with BMI SDS. The BMI of parents ranged from 17.8 to 39.0 kg/m2 (median: 24.2 kg/m2). Median BMI values did not differ significantly between fathers and mothers. The relative risk for obesity among our children (BMI SDS of >2.0) was significantly elevated for children with obese parents, compared with those with nonobese parents (relative risk: 4.86). There was no significant correlation of birth length, birth weight, or gestational age with BMI SDS. Serum leptin values ranged from 0.10 to 32 microg/L (median: 4.4 microg/L); they were correlated positively with BMI SDS, chronologic age, and Tanner stage. After transformation into leptin concentration SDS values, the median SDS of 0.42 (range: -5.4 to 3.1) did not differ significantly from 0.. Children and adolescents with CAH have a higher risk of obesity. Glucocorticoid dosage, chronologic age, advanced bone age maturation, and parental obesity contributed to elevated BMI SDS, whereas birth weight and length, serum leptin levels, used glucocorticoid, and fludrocortisone dosage were not associated with obesity. Therefore, children with CAH who become obese should be tightly monitored and should participate concurrently in weight management programs that include obese family members.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Age Determination by Skeleton; Body Mass Index; Child; Child, Preschool; Family Health; Female; Glucocorticoids; Humans; Infant; Leptin; Male; Obesity

Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency suffer from glucocorticoid and mineralocorticoid deficiency. They have insufficient epinephrine reserves and increased basal leptin levels and are often insulin resistant. In healthy subjects, an inhibitory effect of acute catecholamine elevation on the leptin plasma concentrations has been reported. However, it is not yet known how leptin levels respond to exercise in CAH patients.. We performed a cycle ergometer test in six CAH patients to measure the response of plasma leptin, glucose and the catecholamines, epinephrine (E) and norepinephrine (N), as well as their respective metabolites, metanephrine (M) and normetanephrine (NM), to intense exercise.. Baseline leptin concentrations in CAH patients were not different from those of controls. Leptin levels decreased significantly with exercise in healthy controls, whereas they remained unchanged in CAH patients. In contrast to controls, CAH patients showed no rise of plasma glucose. Basal and stimulated E and M levels were significantly lower in CAH patients compared to controls. Baseline and stimulated N and NM levels were comparable, showing a significant rise after exercise. Peak systolic blood pressure and peak heart rate in both groups were comparable.. CAH patients do not manifest exercise-induced leptin suppression. The most probable reason for this is their severely impaired epinephrine stress response. In addition, epinephrine deficiency is leading to secondary changes in various catecholamine dependent metabolic pathways, e. g., energy balance. Although obvious clinical sequelae are so far unknown, the catecholamine-deficient state and the resulting hyperleptinemia might contribute to the severity of the disease in CAH.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Blood Glucose; Epinephrine; Exercise; Female; Heart Rate; Humans; Leptin; Male

Children and adolescents with classical congenital adrenal hyperplasia have been shown to be at risk for obesity associated with higher insulin and leptin levels. Because these factors are also known to cause hypertension, the aim of this study was to analyze 24-h blood pressure profiles and their relation to different clinical and laboratory parameters.. Fifty-five subjects, aged between 5.3 and 19.0 yr, were enrolled in a prospective, cross-sectional study. All patients had genetically proven 21-hydroxylase deficiency and underwent ambulatory 24-h blood pressure monitoring during a period off school/work. RESULTS (MEDIAN, RANGE): The median body mass index of the cohort was significantly elevated [1.09 sd score (SDS), -2.45 to 3.77]. Daytime and nighttime systolic blood pressures were also significantly elevated (0.67 SDS, -1.5-4.1; 0.63 SDS, -0.91 to 3.3), whereas daytime diastolic blood pressure was significantly lowered (-0.81 SDS, -2.6 to 3.2) and normal during the night (0.11 SDS, -2.0 to 2.0). Overall, there was a normal nocturnal drop of systolic (12.8%, 2.1-22.8) but not diastolic blood pressure (17.2%, 0.90-25.8). The different parameters of systolic and diastolic blood pressures were significantly correlated with body mass index and skinfold thickness (r(s) = 0.271-0.486). There was no correlation with equivalent hydrocortisone and fludrocortisone dosage and laboratory parameters except for serum leptin and insulin.. Our data show altered 24-h blood pressure profiles with elevated systolic levels correlated with the degree of overweight and obesity, whereas normal-weight patients tended to diastolic hypotension.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Child; Child, Preschool; Cross-Sectional Studies; Female; Glucocorticoids; Humans; Insulin; Leptin; Male; Obesity; Overweight; Steroid 21-Hydroxylase

Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NC-CAH) is associated with hyperandrogenemia, chronic anovulation, hirsutism, acne and adrenal hyperplasia. A few studies have shown hyperinsulinemia and insulin insensitivity in NC-CAH. Hyperinsulinemia can stimulate leptin secretion, and androgens can inhibit leptin secretion. Thus, we designed a study to investigate the insulin levels and insulin sensitivity and the effect of chronic endogenous hyperinsulinemia and androgens on leptin in patients with NC-CAH.. Eighteen women with untreated NC-CAH and 26 normally cycling control women with a similar body mass index (BMI) were studied. Basal hormones, fasted and fed insulin levels, leptin and stimulated 17-hydroxyprogesterone (17-OHP) concentrations were studied. Homeostasis model assessment was used to assess insulin sensitivity.. The basal 17-OHP, the free testosterone (fT) and dehydroepiandrosterone sulfate (DHEA-S) were significantly different in the 2 groups (p < 0.05). Fasting and fed insulin levels of the NC-CAH group were higher than those of the control group (p < 0.05) and insulin sensitivity was lower in NC-CAH than in controls (p < 0.05). Insulin levels were correlated with fT and 17-OHP (p < 0.05). Serum leptin levels for NC-CAH (25.9 +/- 12.5 microg/l) did not differ from the controls (25.4 +/- 12.06 microg/l) and were positively correlated with BMI (r = 0.725) and percent body fat (r = 0.710) for both groups (both p < 0.001). Leptin levels were not correlated with estrogen or androgens, gonadotropins or insulin levels.. Hyperinsulinemia and insulin insensitivity associated with hyperandrogenism were detected in untreated NC-CAH patients as in previous reports, whereas serum leptin levels did not differ from those of controls.

Topics: Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Blood Glucose; Dehydroepiandrosterone Sulfate; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hydrocortisone; Hyperinsulinism; Insulin Resistance; Leptin; Luteinizing Hormone; Prolactin; Statistics, Nonparametric; Steroid 21-Hydroxylase; Testosterone

Leptin is secreted by the white adipose tissue and modulates energy homeostasis. Nutritional, neural, neuroendocrine, paracrine, and autocrine factors, including the sympathetic nervous system and the adrenal medulla, have been implicated in the regulation of leptin secretion. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in cortisol and aldosterone secretion, impaired development and function of the adrenal medulla, and adrenal hyperandrogenism. To examine leptin secretion in patients with classic CAH in relation to their adrenomedullary function and insulin and androgen secretion, we studied 18 children with classic CAH (12 boys and 6 girls; age range 2-12 yr) and 28 normal children (16 boys and 12 girls; age range 5-12 yr) matched for body mass index (BMI). Serum leptin concentrations were significantly higher in patients with CAH than in control subjects (8.1 +/- 2.0 vs. 2.5 +/- 0.6 ng/ml, P = 0.01), and this difference persisted when leptin values were corrected for BMI. When compared with their normal counterparts, children with CAH had significantly lower plasma epinephrine (7.1 +/- 1.3 vs. 50.0 +/- 4.2, P < 0.001) and free metanephrine concentrations (18.4 +/- 2.4 vs. 46.5 +/- 4.0, P < 0.001) and higher fasting serum insulin (10.6 +/- 1.4 vs. 3.2 +/- 0.2 microU/ml, P < 0.001) and testosterone (23.7 +/- 5.3 vs. 4.6 +/- 0.5 ng/dl, P = 0.003) concentrations. Insulin resistance determined by the homeostasis model assessment method was significantly greater in children with classic CAH than in normal children (2.2 +/- 0.3 vs. 0.7 +/- 0.04, P < 0.001). Leptin concentrations were significantly and negatively correlated with epinephrine (r = -0.50, P = 0.001) and free metanephrine (r = -0.48, P = 0.002) concentrations. Stepwise multiple linear regression analysis indicated that serum leptin concentrations were best predicted by BMI in both patients and controls. Gender predicted serum leptin concentrations in controls but not in patients with classic CAH. No association was found between the dose of hydrocortisone and serum leptin (r = -0.17, P = 0.5) or insulin (r = 0.24, P = 0.3) concentrations in children with CAH. Our findings indicate that children with classic CAH have elevated fasting serum leptin and insulin concentrations, and insulin resistance. These most likely reflect differences in long-term adrenomedullary hypofunction and glucocorticoid therapy. Elevated leptin and insulin concentrations in patients with CAH may

Topics: Adrenal Hyperplasia, Congenital; Body Mass Index; Child; Child, Preschool; Epinephrine; Fasting; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Metanephrine; Osmolar Concentration; Reference Values; Testosterone

Topics: Adrenal Hyperplasia, Congenital; Age Determination by Skeleton; Body Composition; Child; Female; Humans; Hydrocortisone; Leptin; Sex Characteristics; Testosterone