Trude Dimetz

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.

Microalbuminuria and associated clinical features among Brazilians with insulin dependent diabetes mellitus

With the objective to determine the frequency of microalbuminuria, macroalbuminuria and the associated clinic and metabolic features among insulin dependent diabetes mellitus (IDDM) Brazilian patients attending at a general University Hospital, a total of 50 outpatients, aged 21.9 +/- 7 years with IDDM duration of 6.8 +/- 5.8 years were studied cross-sectionally. Urinary albumin excretion rate (AER) was determined in timed overnight urine samples. Microalbuminuria was defined when two out of three urine samples had AER ranging 20-200 micrograms/min. Microalbuminuria was present in 12% of our patients. No macroalbuminuric patient was found. Among patients with diabetes duration < or = 5 years (n = 24), 8.3% (n = 2) had microalbuminuria. Retinopathy was strongly associated with microalbuminuria (P = 0.004) although no proliferative retinopathy was noted. No difference was observed concerning FBG and HBAI between normo and microalbuminuria patients. Univariate analysis has revealed no influence of these variables in AER. Systolic blood pressure (sBP) was high in microalbuminuria patients and stepwise multiple regression analysis has shown that it was the only significant independent variable to influence AER. (R = 0.42 r2 = 0.18 P = 0.002). In conclusion, the frequency of microalbuminuria in this sample of IDDM Brazilian patients was similar to other populational groups and was associated with retinopathy and sBP.

The C-peptide response to a standard mixed meal in a group of Brazilian type 1 diabetic patients

In order to analyze the different parameters used in the interpretation of C-peptide response in a functional test, we compared a group of 26 type 1 diabetics aged 21.1 +/- 8.2 years, with a diabetes duration of 7.9 +/- 6.7 months, with a group of 24 non-diabetic subjects aged 25.0 +/- 4.4 years. A standard mixed meal of 317 kcal was used as a stimulus. Blood sampling for C-peptide determinations was performed at regular intervals. Although all the studied C-peptide variables were significantly lower in the diabetic group (P < 0.0001), some overlapping of parameters was observed between the two groups. The highest degree of overlapping was found for basal value (BV) (30.8%) and percent increase (42.31%), and the lowest for incremental area, absolute increase, peak value (PV) (3.8%), and total area (7.7%) (chi 2 = 31.6, P < 0.0001). We did not observe a definite pattern in the time of maximum response among the 21 diabetics who showed an increase in C-peptide levels after the stimulus. In this group, however, there was a highly significant number of late responses (120 min) (chi 2 = 5.7, P < 0.002). Although BV showed a significant correlation with PV (rS = 0.95, P < 0.0001), the basal levels of C-peptide did not differentiate the groups with and without response to the stimulus. We conclude that the diabetic group studied showed delayed and reduced C-peptide responses, and that the functional test can be an important tool for the evaluation of residual beta cell function.

Influence of first morning urine volume, fasting blood glucose and glycosylated hemoglobin on first morning urinary albumin concentration.

The aim of the present study was to evaluate the effect of first morning urinary volume (collected on three different non-consecutive days), fasting blood glucose (determined on the first and third days of urine collection), and glycosylated hemoglobin (determined on the first and third days of urine collection) on the albumin concentration in first morning urine samples collected on three different days. We found 3.6% asymptomatic bacteriuria in the urine samples; therefore, every urine sample must be tested to exclude infection. One hundred and fifty urine samples were provided by 50 IDDM patients aged 21.9 +/- 7 (12-38) years with a disease duration of 6.8 +/- 5.8 (0.4-31) years attending the Diabetes Clinic at the State University Hospital of Rio de Janeiro. There were no differences in albumin concentration (6.1 vs 5.8 vs 6.2 micrograms/ml; P = NS) or urinary volume (222.5 vs 210 vs 200 ml) between the three samples. In addition, there were no differences in fasting blood glucose (181.9 +/- 93.6 vs 194.6 +/- 104.7 mg%; P = NS) or glycosylated hemoglobin (HbA1) (8.4 +/- 1.3 vs 8.8 +/- 1.5%; P = NS) between the first and third blood samples. Six patients (group 1) had a mean urinary albumin concentration of more than 20 micrograms/ml for the three urine samples. This group was compared with the 44 patients (group 2) with a mean urinary albumin concentration for the three urine samples of less than 20 micrograms/ml. No difference was found between groups 1 and 2 in relation to fasting blood glucose (207.1 +/- 71.7 vs 187.6 +/- 84.6 mg/dl), HbA1 (8.1 +/- 0.9 vs 8.6 +/- 1.1%) or urinary volume [202 (48.3-435) vs 246 (77.3-683.3) ml]. Stepwise multiple regression analysis with albumin concentration of first morning urine samples as the dependent variable, and urinary volume, fasting blood glucose and glycosylated hemoglobin as independent variables, showed that only 12% (P = 0.01) of the albumin concentration could be accounted for by the independent effect of morning urine volume on the first day of urine collection. No urine samples showed a change in the cutoff level of 20 micrograms/ml of albumin concentration as the result of volume. Fasting blood glucose and glycosylated hemoglobin did not influence the urinary albumin concentration. Considerable variability in urinary albumin concentration was found in the three morning urine samples with a mean intraindividual coefficient variation of 56%. In conclusion, in the present study, urinary volume had a minimal, though not constant, effect on first morning urinary albumin concentration. Day-to-day metabolic and clinical control of IDDM patients, except probably for ketoacidosis, should not contraindicate microalbuminuria screening in first morning urine samples.

Discriminative capacity of fasting C-peptide levels in a functional test according to different criteria of response to a stimulus

Abstract In order to study the discriminative capacity of the C-peptide basal values (BV) in a functional test, we analysed the C-peptide response curve after a mixed meal in 26 insulin-dependent patients. The five criteria of response used were: (1) any increment after the stimulus; (2) percentual increment above 21%; (3) absolute in-crement above 0.35 ng/ml; (4) incremental area above 42.76 ng ⋅ min ⋅ml–1, and (5) peak value above 2.16 ng/ml. Considering the first two criteria, many patients showed positive responses, in the diabetic group as a whole and when we analysed patients with BV ≥ 0.74 ng/ml and <0.74 ng/ml separately. When we applied only the last three criteria the number of positive responses was considerably smaller. Moreover, the majority of patients with BV < 0.74 ng/ml could not increase their levels over the ones established above. In patients with BV ≥ 0.74 ng/ml, the number of positive and negative responses were similar. The comparison between the subgroups achieves statistical significance only for incremental area (χ2 = 3.55, P = 0.03). We conclude that the functional test was important mainly for patients with BV ≥ 0.74 ng/ml, and could have been omitted for patients with BV < 0.74 ng/ml. The best criteria of response were those based on the mean minus two standard deviations of each parameter in a non-diabetic group (the last three criteria), especially the incremental area.

Albumin Concentration is Underestimated in Frozen Urine

Long-term storage of urine is common in tropical countries because of socio-economic factors such as expensive kits, lack of automated methods and difficulty of finding suitable patients. A number of studies have described different effects of specimen storage at 20°C on the determination of urinary albumin.’-’ The aim of this study was to investigate the effect of storing urine samples at 20°C under developing world conditions.

Sensibilidade, especificidade e valor preditivo dos níveis basais da 17-hidroxiprogesterona no diagnóstico da forma não-clássica da hiperplasia adrenal congênita por deficiência da 21-hidroxilase

Screening for non-classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is performed with baseline 17-hydroxyprogesterone (17OHPb) and confirmed with the ACTH test. Because the cutoff level of 17OHPb that prompts an ACTH testing is still a matter of discussion, we evaluated the levels of 17OHPb in diagnosing CAH caused by 21OHD. An ACTH (0.25 mg IV) test was performed in 87 hyperandrogenic women, 24.8±0.8 years old. 17OHP levels greater than 1,500 ng/dL, 60min after administration of ACTH were considered diagnostic. 21OHD was confirmed in 11 patients (12.6%); in the remainder 76 the test was negative. Sensitivity, specificity, positive and negative predictive values for 17OHPb >200 ng/dL were 0.91, 0.62, 0.26 and 0.98, respectively. For 17OHPb >350 ng/dL these values were 0.91, 0.91, 0.59 and 0.99 and for 17OHPb >500 ng/dL, 0.82, 0.99, 0.9 and 0.97. Clinical findings (hirsutism, menstrual irregularities and obesity) and levels of androstenedione and total testosterone were similar between both groups. We conclude that clinical findings and androgen levels cannot differentiate patients with and without 21OHD, and suggest the ACTH test to be performed whenever 17OHPb is >350 ng/dL, a highly sensitive cutoff with good negative predictive value.

Papel dos Androgênios Adrenais e Periféricos na Modulação dos Níveis da Globulina Ligadora dos Hormônios Sexuais na Pubarca Precoce

We investigated in 26 girls with premature pubarche (PP) and 14 age-matched controls (7.3±1.0 x 7.0±2.0 years) the role of adrenal and peripheral androgens in the regulation of sex hormone-binding globulin (SHBG) during childhood. Bone age (BA) and body mass index (BMI) were determined, together with androstenedione (A), testosterone (T), dehydroepiandrosterone and its sulfate (DHEA and DHEAS), dihydrotestosterone (DHT), 3a-androstanediol glucuronide (3a-diolG) and SHBG. Although BA was similar (8.0±1.4 x 8.3±1.4 years), BMI was higher in PP (18.7±3.1 x 16.7±2.0, p=0.03). Plasma levels of DHEAS (0.7±0.4 x 0.3±0.2µg/mL, p<0.001), 3a-diolG (1.1±0.7 x 0.6±0.6ng/mL, p=0.06) and DHT (180±95 x 132±68pg/mL, p=0.09) were greater, whereas SHBG (60±24 x 89±26nmol/L, p=0.001) was lower; and levels of DHEA (4.8±2.6 x 3.3±2.0ng/mL), T (133±149 x 90±59pg/mL) and A (603±330 x 420±318pg/mL) were similar. SHBG was negatively correlated with BMI (r= -0.53, p< 0.001), DHT (r= -0.43, p=0.005) and 3a-diolG (r= -0.46, p=0.02), but in the multiple regression model, SHBG correlated only with BMI and 3a-diolG. These findings suggest that increased levels of SDHEA result from a greater secretion of adrenal androgens, whereas 3a-diolG and DHT may reflect a greater skin utilization of androgens in the PP. Moreover, both body weight and 3a-diolG, but not T and adrenal androgens, could be important regulators of SHBG during childhood.

Terapia de reposição hormonal contínua na pós-menopausa: ênfase no hormônio do crescimento, insulina, fator de crescimento semelhante à insulina I (IGF-I) e proteína ligadora 3 do IGF (IGFBP-3)

The importance of the hormone replacement therapy (HRT) in the quality of life at the postmenopause is unquestionable. However not all the effects determinated by its use are well established yet. This study has the aim to evaluate the influence of the HRT on serum levels of the growth hormone (GH), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), glucose and insulin. We performed a controlled, prospective, longitudinal and comparative clinical trial, in which 53 natural or surgical postmenopausal women were submitted or not to a continuous HRT, during a 6 months period, with conjugated estrogens (CE-0.625mg/d) associated or not to the medroxiprogesterone acetate (MPA-2.5mg/d), by the oral route. The participants were subdivided in 3 groups: Group CE + MPA > composed by 20 women with uterus, who utilized CE and MPA; Group CE > composed by 20 hysterectomized women, who used CE; Group C > formed by 13 women, without HRT. Basal levels of GH, IGF-I and IGFBP-3 were measured in the beginning and at the end of the study. We have also performed a 2-hour oral glucose tolerance test (OGTT), with determination of glucose and insulin levels; area under curve (AUC) of glucose and insulin and insulin resistance index (IRI). The HRT use decrease the IGF-I levels in CE + MPA (p= 0.01) and CE (p= 0.0007), without change in the IGFBP-3 levels. The GH levels increased during the use of the HRT (EC + AMP: p= 0.004 e EC: p= 0.0003), however the serum concentrations of IGF-I and IGFBP-3 did not seem to be good markers of the circadian secretion of GH. At 6 months, it was noticed a negative correlation of the IGF-I with the AUC of glucose in the three groups (CE + MPA: r= -0.42, p= 0.06; CE: r= -0.58, p= 0.007 and C: r= -0.64, p= 0.01). The IGFBP-3 and the AUC of glucose showed a significant negative correlation in the group CE (r= -0.45, p= 0.04) and a tendency in CE + MPA (r= -0.42, p= 0.06). The association of MPA determined the appearance of IGT in 30% of the patients from the group EC + AMP (n= 6). Our results suggested an interaction between the carbohydrate metabolism with the IGF-I and IGFBP-3. The effects caused by the prolonged use of continuous HRT in the regulation of GH, IGF-I and IGFBP-3 still require elucidation.

Interrelações entre SHBG e esteróides sexuais com medidas antropométricas, pressão arterial e lipídeos em mulheres com e sem diabetes mellitus tipo 2

In order to investigate the relationship between plasma leveis of SHBG, sex steroids and glucose metabolism, lipid profile, anthropometric measurements, clinical and demographic variables, we studied a group of 80 post-menopausal women, 40 with type 2 diabetes (DM2) aged 64.9±7.1 and with known DM duration of 13.4± 1.4 years and 40 non-diabetic aged 61 ±8.9. We analyzed: age, body mass index (BMI), waist to hip ratio (WHR), waist, systolic (sBP) and diastolic blood pressure (dBP). Diabetic women had higher frequency of android adiposity (75% vs. 50%, p= 0.03), higher sBP (p= 0.01), higher total testosterone (p= 0.003), free testosterone index (p= 0.02) and insulin resistance index (IRI) (p= 0.000) than non-diabetic women. Non-diabetics with android adiposity had lower levels of SHBG than those with ginecoid adiposity (p= 0.008). In the group with BMI ³30kg/m2 and in the group with waist ³88cm diabetic women had higher total testosterone and free testosterone index than non-diabetic women. Non-diabetics with android adiposity had higher free testosterone index than those with ginecoid adiposity (p= 0.01). Diabetic women with android adiposity had higher estradiol than those with ginecoid adiposity (p= 0.02). In conclusion, diabetic women had higher frequency of android adiposity, associated with high total testosterone, free testosterone index and estradiol and low levels of SHBG. These results suggest that hyperandrogenism with low SHBG could be indicators of the insulin resistance syndrome, and could somehow increase the insulin resistance in these subjects.