Marília M. Guimarães

Insulin resistance in adolescents with Down syndrome: a cross-sectional study

BackgroundThe prevalence of diabetes mellitus is higher in individuals with Down syndrome (DS) than in the general population; it may be due to the high prevalence of obesity presented by many of them. The aim of this study was to evaluate the insulin resistance (IR) using the HOMA (Homeostasis Model Assessment) method, in DS adolescents, describing it according to the sex, body mass index (BMI) and pubertal development.Methods15 adolescents with DS (8 males and 7 females) were studied, aged 10 to 18 years, without history of disease or use of medication that could change the suggested laboratory evaluation. On physical examination, the pubertal signs, acanthosis nigricans (AN), weight and height were evaluated. Fasting plasma glucose and insulin were analysed by the colorimetric method and RIA-kit LINCO, respectively. IR was calculated using the HOMA method. The patients were grouped into obese, overweight and normal, according to their BMI percentiles. The EPIINFO 2004 software was used to calculate the BMI, its percentile and Z score.ResultsFive patients were adults (Tanner V or presence of menarche), 9 pubertal (Tanner II – IV) and 1 prepubertal (Tanner I). No one had AN. Two were obese, 4 overweight and 9 normal. Considering the total number of patients, HOMA was 1.7 ± 1.0, insulin 9.3 ± 4.8 μU/ml and glucose 74.4 ± 14.8 mg/dl. The HOMA values were 2.0 ± 1.0 in females and 1.5 ± 1.0 in males. Considering the nutritional classification, the values of HOMA and insulin were: HOMA: 3.3 ± 0.6, 2.0 ± 1.1 and 1.3 ± 0.6, and insulin: 18.15 ± 1.6 μU/ml, 10.3 ± 3.5 μU/ml and 6.8 ± 2.8 μU/ml, in the obese, overweight and normal groups respectively. Considering puberty, the values of HOMA and insulin were: HOMA: 2.5 ± 1.3, 1.4 ± 0.6 and 0.8 ± 0.0, and insulin: 13.0 ± 5.8 μU/ml, 7.8 ± 2.9 μU/ml and 4.0 ± 0.0 μU/ml, in the adult, pubertal and prepubertal groups respectively.ConclusionThe obese and overweight, female and adult patients showed the highest values of HOMA and insulin.

Decreased Serum Inhibin B/FSH ratio as a marker of Sertoli cell function in male survivors after chemotherapy in childhood and adolescence

OBJECTIVE Inhibin B produced by Sertoli cells may be an important marker of seminiferous tubule function in patients treated with chemotherapy (CT). The aim of this study was to evaluate the inhibin B/FSH ratio to detect male gonadal dysfunction in cancer survivors treated in childhood and adolescence. PATIENTS Twenty-one male patients (group A) treated with 6-10 courses of CT for Hodgkins disease during childhood and adolescence were examined 3-11 years after the conclusion of treatment. Twenty healthy young men (18-23 years old) were used as controls (group B). METHODS Serum samples for the determination of inhibin B, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), sex hormone-binding globulin (SHBG) and semen for analysis were collected. RESULTS The median testicular volume of patients of group A was lower than those of group B (p = 0.001) and a positive correlation was found between testicular size and sperm count (r = -0.5, p = 0.01). Semen analysis revealed azoospermia in 11 patients, severe oligospermia in four and normal sperm count in three. No significant difference was found in the median of T, LH, SHBG, inhibin B concentrations and T/LH ratio between the groups. Serum inhibin B was correlated with the serum FSH levels (r = -0.5, p = 0.02). Median FSH was significantly higher (p = 0.0001), and median inhibin B/FSH ratio was significantly lower in group A than in controls (p = 0.0002), but the inhibin B/FSH ratio was higher in the patients with normal sperm count than in those with oligospermia (p = 0.00004). CONCLUSIONS These results show that the cytotoxic effects of CT cause severe damage to the germinal epithelium with subtle effects on Sertoli cells. To assess Sertoli cell function in men with primary testicular damage after treatment with CT in childhood and adolescence, the inhibin B level needs to be interpreted in the context of the circulating FSH, especially when normal FSH levels are observed.

Isolated Premature Pubarche: Report of Anthropometric and Metabolic Profile of a Brazilian Cohort of Girls

Aims: Isolated premature pubarche (PP) is commonly caused by premature adrenarche (PA), and links between PA, children born small for gestational age (SGA) and insulin resistance haAims: Isolated premature pubarche (PP) is commonly caused by premature adrenarche (PA), and links between PA, children born small for gestational age (SGA) and insulin resistance have already been made in some populations. Subjects and Methods: We assessed anthropometric data, pubertal landmarks and metabolic profile at diagnosis and during the study in 52 girls with the diagnosis of isolated PP from a Brazilian cohort. Results: The prevalence of obesity (25%), dyslipidemia (63.5%) and born SGA children (21.2%) was greater among PP girls than in the reference population (4, 46.8 and 10%, respectively). There was no increase in the prevalence of insulin resistance and no correlation with birth weight, onset of PP or other pubertal signs. The Z score of heights at PP diagnosis was greater than the Z score of mid-parental height, but achieved final height (n = 16 girls, p = 0.002) was similar to normal population standards and to the predicted final height based on bone age at PP diagnosis (p = 0.08). Thelarche and menarche occurred at normal age, just earlier than expected. Conclusion: The prevalence of children born SGA, obese and dyslipidemic, but not of hyperinsulinemic children, was high in our cohort of PP girls. Puberty started earlier than usual but within the normal range.

Insulin resistance and body composition in Turner syndrome: Effect of sequential change in the route of estrogen administration

The aim of the present study was to examine the impact of sequential change in the route of estrogen administration on body composition and insulin resistance in patients with Turner syndrome (TS) using cyclical hormone replacement therapy (HRT) with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA). We carried out a self-controlled study of nine non-obese patients with TS, with an average age of 23 ± 4.9 years. Body mass index (BMI), waist-to-hip ratio (WHR), fasting glycemia, insulin tolerance (glucose disappearance constant during an insulin tolerance test, kITT) and body composition (dual-energy X-ray absorptiometry) were studied after 1 years use of CEE plus MPA and repeated after 1 years use of 17β-estradiol gel with the same schedule of MPA administration. We did not observe any difference between the oral and percutaneous HRT with regard to BMI, WHR and insulin tolerance (kITT: 4.9 ± 1.5 vs. 5.3 ± 1.5%/min, p = 0.8). During administration of the 17β-estradiol gel a tendency to increased total lean mass (p = 0.054) was observed. We conclude that sequential change in the route of estrogen administration in TS patients using cyclical HRT with CEE and MPA does not affect insulin resistance, although use of percutaneous 17β-estradiol gel seems to exert favorable changes in body composition.

Pubertal development profile in patients with Turner syndrome.

Abstract Introduction: Puberty can be divided into two independent events: adrenarche and gonadarche. In healthy children, adrenarche is followed by gonadarche, but in patients with gonadal dysgenesis there is partial or complete dissociation between these two events. Objective: To evaluate the age and chronology of the development of secondary sexual characteristics and occurrence of these events and their relationship to the induction of puberty in patients with Turner syndrome (TS). Materials and methods: A descriptive analysis with historical records of the patients with clinical and cytogenetic TS was conducted. The following variables were recorded: karyotype; age of thelarche, pubarche, and menarche; occurrence of spontaneous puberty; maintenance of puberty or secondary failure; and the onset of hormone replacement therapy (HRT) with estrogen. Results: We evaluated 123 medical charts. Seven (5.7%) patients were prepubertal, 10 (8.1%) had only pubarche, and 5 (4%) had only thelarche. Forty-seven (38.2%) patients entered puberty spontaneously. Among these, 35 (28.5%) remained in puberty, and 12 (9.8%) required subsequent HRT; 54 (44%) had puberty induced. Sixty-six (56.9%) patients had pubarche started before thelarche. Menarche occurred in 67 patients, spontaneously in 19. Pubarche spontaneously presented in 91 (78.4%) patients, and in 25 (21.5%) after HRT introduction. Conclusions: Spontaneous puberty occurred in approximately one-third of the patients. Pubarche was the first feature in most patients and about 20% showed pubarche only after estrogen therapy.

Gonadotropin levels in Turner's syndrome: correlation with breast development and hormone replacement therapy

We conducted a study of the basal levels of gonadotropins in 38 patients with Turners syndrome ,14 of whom were using hormone replacement therapy (HRT). The gonadotropin levels were compared with pubertal development and HRT. Seven patients had presented spontaneous menarche; five patients maintained their periods and normal gonadotropin levels ,and two developed secondary amenorrhea and high gonadotropin levels. The majority of patients on HRT had high gonadotropin levels. Follicle stimulating hormone (FSH) levels were significantly lower (p = 0.001) in patients with breast development at stage 5, regardless of whether the patient had undergone a spontaneous or a hormonally induced puberty. We concluded that gonadotropin levels are normal in those patients with spontaneous periods ,and are high in most patients on HRT; and that FSH levels are significantly lower in those patients with breasts at stage 5.

The relationship between ovarian structure and serum insulin, insulin-like growth factor-I (IGF-I) and its binding protein (IGFBP-1 and IGFBP-3) levels in premature pubarche.

The aim of this study was to determine serum insulin, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-1 and IGFBP-3) levels and their relationship with androgen levels and ovarian structure in 23 girls with premature pubarche (PP). Fasting levels of testosterone, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), androstenedione (delta4A), sex hormone binding globulin (SHBG), glucose (G), insulin (I), IGF-I, IGFBP-1, IGFBP-3 were measured. Androgens or steroid hormone levels > 3 SD of normal postpubertal levels were considered as an exaggerated response to the ACTH test. The fasting I to G ratio (FIGR) was calculated and FIGR > 22 was suggestive of insulin resistance (IR). A pelvic ultrasound (US) was carried out and the ovarian structure was divided into five classes (c): c1--homogeneous, c2--microcystic, c3--multicystic, c4--polycystic and c5--follicular. The girls with PP were divided into two groups according to the main ovarian classes observed: PPc1 (n = 6) and PPc2 (n = 15). The FIGR showed IR in 44% of patients. The androgens, SHBG, G, I, FIGR, IGF-I and IGFBP-1 levels were similar among the groups (PPc1 vs PPc2). An exaggerated response to ACTH was more common and IGFBP-3 levels were higher in the PPc2 than in the PPc1 group (p = 0.04). Regression analysis revealed that I was correlated with DHEAS (r = -0.43, p = 0.04) and IGFBP-1 (r = -0.51, p = 0.01); IGF-I was correlated with DHEA (r = -0.42, p = 0.05), delta4A (r = -0.47, p = 0.02), SHBG (r = -0.43, p = 0.04), IGFBP-1 (r = -0.61, p = 0.002) and IGFBP-3 (r = 0.56, p = 0.005); IGFBP-1 was correlated with SHBG (r = 0.56, p = 0.005). These findings suggest that there might be interactions between the insulin-IGF-I-IGFBPs system and hyperandrogenism. However, the possible causal role of adrenal androgen hypersecretion on the insulin-IGF-I-IGFBPs axis and ovarian structure in girls with PP remains to be established. Since studies reveal that IGFBP-3 levels could be a negative predictor for insulin sensitivity throughout puberty, we hypothesize that girls with PP and microcystic ovaries are at risk of developing IR in the course of normal puberty.

Triagem neonatal para hiperplasia adrenal congênita: experiência do estado do Rio de Janeiro

OBJECTIVE To determine the 17OH progesterone (17OHP) levels in the neonatal screening for Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency (CAH-21OHD). CASUISTIC AND METHOD The evaluation was performed using 76,360 paper filter samples, obtained from newborn screening in Rio de Janeiro from June 1992 to December 2000. The 17OHP were assayed by fluoroimmunoassay method using the blood collected onto filter paper cards. The cut-off level was 10 ng/mL. The infants with 17OHP levels above this cut-off were recalled to undergo a new dosage. RESULTS Thirty-eight patients presented 17OHP levels above the cut-off limit. In 11 (4 males, 6 females, 1 undefined gender) the diagnoses of CAH-21OHD were confirmed. Their 17OHP levels ranged from 25 to 254.5 ng/mL (mean: 133.84 ng/mL) on the first analysis and from 46.86 to 360 ng/mL (mean: 218.84 ng/mL) on the second analysis. The patients with the salt-wasting form showed higher 17OHP levels when compared to simple virilizers, both on the first analysis (mean: 169.21 ng/mL vs 27.46 ng/mL) and on the second one (mean: 227.16 ng/mL vs 110.95 ng/mL). Among the 27 infants without confirmed disease (false-positives), 17OHP levels ranged from 10.27 to 27.5 ng/mL (mean: 14.8 ng/mL) on the first sample and from 2.39 to 32.39 ng/mL (mean: 10.07 ng/mL) on the second. In this group, 8 children maintained borderline 17OHP levels during a variable period, but in 7 of them it was normalized before the first year of life. In the remaining case, who was asymptomatic after 8 years of follow-up, a cortrosin stimulation test was compatible with the non-classic form of the disease. CONCLUSION These data confirm that 17OHP analysis was a reliable test to CAH-21OHD neonatal screening and was able to differentiate between normal infants and those with the classical form of CAH-21OHD.

Effect of puberty on the relationship between bone markers of turnover and bone mineral density in Turner's syndrome.

It has been suggested that the appropriate timing of puberty is necessary for normal bone mineral acquisition which may not be achieved amongst patients with Turner’s syndrome (TS). The aim of this study was to assess bone mineral density (BMD) and bone turnover in 34 patients with TS (age range 2.2–39.0 years). The areal BMD (aBMD) was determined by dual-energy X-ray absorptiometry, and the volumetric BMD was calculated. Blood and second voided urine samples were taken the morning after an overnight fast for evaluation of the biochemical markers of bone turnover: bone-specific alkaline phosphatase (BAP) and N-telopeptides of type I collagen (NTX), respectively. Both were determined by enzyme-linked immunosorbent assay. The patients were divided into three groups: group 1 (n = 13; prepubertal; age range 2.2–19.0 years), group 2 (n = 10; teenagers; age range 12.4–19.0 years), and group 3 (n = 11; adults; chronological age >20 years). They were also grouped by breast development according to Tanner stage into B1 (n = 12), B2–3 (n = 9), and B4–5 (n = 13). The aBMD was significantly lower in group 1 and was higher at Tanner stages 4 and 5 as compared with patients at Tanner stage 1. The bone turnover markers were significantly higher in group 1 (NTX: p = 0.002; BAP: p = 0.0005) and declined, as puberty progressed. A negative correlation was observed between aBMD and biochemical bone markers at the lumbar spine (NTX: r = –0.54, p = 0.05; BAP: r = –0.44, p = 0.01) and in the whole body (NTX: r = –0.60, p = 0.0008; BAP: r = –0.19, p = 0.002). We conclude that the negative relationships between aBMD and biochemical markers suggest a high bone turnover, mainly in prepubertal patients and that the results observed in relation to aBMD and puberty are imputed to the delayed puberty which occurs amongst TS patients.

Endocrine diseases, perspectives and care in Turner syndrome

Turner syndrome is a frequent chromosome disorder in clinical practice. It is characterized by short stature, gonadal dysgenesia and multisystemic involvement, responsible for a high morbidity and reduced life expectancy. The aim of the present paper is to describe the endocrinopathies and major problems at different ages, and to present suggestion for follow-up care in these patients.