Maurizio Capelli

Effect of obesity and body fat distribution on sex hormones and insulin in men

To investigate the relationship between body fat distribution, sex hormones, and hyperinsulinemia in male obesity, we examined 52 obese men (body mass index [BMI], 35.0 +/- 6.1, mean +/- SD) and 20 normal-weight controls. Their waist to hip circumference ratio (WHR), which was used as an index of fat distribution, was 0.985 +/- 0.052 and 0.913 +/- 0.061 (P less than .005), respectively. Compared with controls, obese men presented significantly lower levels of total (357 +/- 132 v 498 +/- 142 ng/dL; P less than .005) and free testosterone (14.2 +/- 2.9 v 17.1 +/- 2.6 pg/mL; P less than .05) and sex hormone-binding globulin (SHBG; 41.7 +/- 31.9 v 66.2 +/- 18.6 nmol/L; P less than .001) without any significant difference on the other sex steroid or on gonadotropin concentrations. Fasting and glucose-stimulated insulin and C-peptide levels were significantly higher in obese than in controls, and in obese with the WHR value greater than 0.97 (corresponding to the distribution median) than in those with WHR lower or equal to 0.97. BMI was negatively correlated with testosterone (P less than .005), free testosterone (P less than .01), and SHBG (P less than .001) and positively with fasting (P less than .001) and glucose-stimulated (P less than .005) C-peptide concentrations, whereas no relationship was found between these variables and WHR values. On the contrary, WHR was significantly correlated with fasting and post-glucose insulin levels (P less than .05), but not with those of sex steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationships Between Growth Factors (Somatomedin-C and Growth Hormone) and Body Development, Metabolic Control, and Retinal Changes in Children and Adolescents With IDDM

We used the radioimmunoassay (RIA) method to determine somatomedin-C (SmC) basal values in 59 diabetic children and adolescents (20 prepubertal and 39 pubertal subjects; age range 2.75–20.16 yr; duration of diabetes 0.08–15.83 yr) and in 274 control subjects. In comparing diabetic subjects with controls, we considered only those 50 diabetic subjects who were age matched with the controls, i.e., those not over 16 yr chronological age. SmC basal levels in pubertal diabetic patients were no different from those of pubertal age-matched control children, whereas in prepubertal diabetic patients SmC was significantly lower than in the respective control children (P < .001). No correlation was found between the z score for SmC (i.e., the number of standard deviations each SmC level is from the age- and sex-normalized mean) and duration of disease, velocity standard deviation score, severity of fluoroangiographic retinal changes, basal C-peptide values and HbA, levels. No differences were encountered in mean SmC and SmC z-score values in the separate groups of poorly, fairly, and well-controlled diabetic children, in the groups with and without residual pancreatic activity, and in the group with and without retinal changes. In 16 of the pubertal diabetics and in 15 pubertal controls, serum glucose, growth hormone (GH), and SmC concentrations were determined during the night. The integrated nocturnal secretion of SmC was no different in diabetics than in controls, whereas the integrated nocturnal secretion of GH was significantly (P < .025) higher in diabetics than in controls. These data suggest a partial block in somatomedin production, which would be compensated by a hypersecretion of GH through a negative-feedback relationship. On the other hand, it may be that GH hypersecretion is primary and that the normal or low SmC secretion is a response to low-efficiency GH.

Different gonadotropin and leuprorelin ovulation induction regimens markedly affect follicular fluid hormone levels and folliculogenesis

OBJECTIVES To clarify the endocrine mechanisms underlying the outcome of different ovulation induction regimens with gonadotropins and GnRH agonists (GnRH-a). DESIGN Prospective study. SETTING Reproductive Endocrinology Center, University of Bologna. PATIENTS Forty eumenorrheic women randomly assigned to four groups of 10 subjects each. INTERVENTIONS Ovulation induction regimens: group A, purified FSH only; group B, purified FSH and flare-up GnRH-a; group C, purified FSH and long GnRH-a; and group D, hMG and long GnRH-a. MAIN OUTCOME MEASURES Pelvic ultrasound and hormone levels in daily serum samples and in follicular fluid drawn immediately before hCG administration. RESULTS Exogenous gonadotropin dose did not differ among groups. Group B had fewer preovulatory follicles than group C. Group B had higher serum LH, FSH, E2, P, T, and follicular fluid LH, E2, T, and alpha-inhibin than groups C and/or D. Groups C and D did not differ. CONCLUSIONS Long GnRH-a regimens improved follicle yield and the endocrine milieu in spite of comparable exogenous gonadotropin dose and lower serum FSH and thus appear to be preferable in assisted reproduction. Reduced folliculogenesis found in flare-up GnRH-a regimens could be mediated by the atretic effects of high intraovarian androgens. Efficacy of purified FSH and hMG was comparable.

Growth and thyroid function in children treated with growth hormone

We examined the effect of growth hormone (GH) therapy on thyroid function in 57 children with isolated GH deficiency and whether this effect could influence their growth response. Thyroid function and insulin-like growth factor I levels were measured before and after 3, 6, and 12 months of recombinant-GH therapy (20 U/m2 per week, given subcutaneously), after a 1-month withdrawal from therapy, and after a further 6 months of GH administration. The serum concentration of triiodothyronine (T3) and the T3/T4 (thyroxine) ratio increased after 12 months of GH treatment, whereas total T4 and free T4 levels decreased; thyrotropin levels did not change significantly during treatment but increased after a 1-month withdrawal. After a further 6 months of GH therapy, an increase in T3 levels and in the T3/T4 ratio and a decrease in total T4 and free T4 levels were found again, and thyrotropin levels decreased. The increment in growth velocity after 12 months of therapy correlated positively with the T3/T4 ratio and negatively with total T4 and free T4 values. These data confirm in children a GH-induced enhancement of peripheral conversion of T4 to T3. This effect appears to be more evident in children who are most sensitive to GH in terms of growth-promoting activity.

Effects of obesity on gonadotropin secretion in patients with polycystic ovarian disease

To investigate the interrelationships between body weight and gonadotropin secretion of polycystic ovarian disease (PCO), basal hormonal pattern and responses of gonadotropins and 17 β estradiol (E2) to 25 μg (bolus) and 175 μg (4-h infusion) of synthetic luteinizing hormone-releasing hormone (LHRH) were studied in two age-matched groups of 18 obese (OB-PCO) and 18 normal-weight (NO-PCO) women suffering from the syndrome. Unlike other hormone levels, plasma LH and the LH/FSH ratio values were significantly higher (p < 0.001) in NO-PCO than in OB-PCO females. Moreover, LH response to both stimuli was significantly greater in NO-PCO with respect to OB-PCO. No differences were found in FSH response, whereas E2 response was significantly higher (p < 0.05) in the NO-PCO group during the continuous infusion test. These results emphasize the role of body weight in the development of PCO in obese females.

Weight loss and sex steroid metabolism in massively obese man

To evaluate the effect of weight loss and diet therapy on plasma sex hormone behavior in male obesity, 9 men with a BMI of 43.4 ± 6.3 participated in an 8-week semistarvation program [whose energy content ranged from 320 to 500 kcalorie/day (proteins 44 to 60 g and carbohydrates 54 to 81 g per day)] followed by a two-week hypocaloric (1000 kcalorie/day) refeeding. In basal conditions, obese patients presented higher estrogen and lower dehydroepiandrosterone sulphate, testosterone (total and free) and sex-hormone binding globulin concentrations with respect to a group of control normal-weight subjects. Cumulative weight loss was 23.9 ± 3.6 kg after semistarvation and 24.4 ± 4.8 kg after refeeding (p = NS). A significant increase in testosterone, free testosterone and dehydroepian-drosterone sulfate was observed throughout the study, irrespective of dietary intake. A transient increase occurred in estrone levels while 17B-estradiol did not change. Gonadotropins and sex-hormone binding globulin values remained unaltered. No relationship was found between sex hormones and dietary energy content or composition. Daily urine free cortisol, which was used as a parameter of adrenal function, fell approximately 50% during semistarvation but returned to baseline values after refeeding. These results show that in massively obese patients weight loss per se may partially reverse sex hormone abnormalities but not sex-hormone binding globulin concentrations. It remains to be determined whether the return to “normal weight” can normalize steroid metabolic derangements in the obese man.

Differences in somatomedin-C between short-normal subjects and those of normal height*

We evaluated basal somatomedin-C (SmC) levels in 98 subjects 2 to 16.6 years of age, with height less than 3rd centile (Tanner), and in 274 healthy controls 2 to 15.8 years, with height greater than 10th centile. Growth-retarded subjects were defined as short-normal when they had normal GH release (greater than 8 ng/ml) in at least one of three tests: arginine, L-dopa, and sleep. In control subjects, there was a significant positive correlation between SmC levels and chronologic age, bone age, and pubertal stage (pubic hair, breast or testicular volume). The same correlations were present in short-normal subjects, but SmC levels were significantly lower than in normal children. The percentage of subjects with very low SmC values (less than or equal to 0.25 IU/ml in those older than 6 years, and less than 0.1 IU/ml in those younger than 6 years) was higher in the short-normal group of children older than 6 years. In growth-retarded subjects, SmC values were significantly higher (P less than 0.005) in subjects with normal GH response in at least one of the two pharmacologic tests, compared with those with normal GH response only during sleep. We conclude that short-normal subjects have, on average, low SmC values, which might indicate insufficient GH release. Therefore, current criteria to define GH deficiency and children needing treatment may be too restrictive.

ENDOGENOUS OPIOID SYSTEM AND ATRIAL NATRIURETIC FACTOR IN NORMOTENSIVE OFFSPRING OF HYPERTENSIVE PARENTS AT REST AND DURING EXERCISE TEST

Objective: To investigate the effects of the endogenous opioid system on plasma atrial natriuretic factor (ANF) levels during sympathetic hyperactivity. Design: We studied the young normotensive offspring of parents who both had essential hypertension, who are characterized by a hyperactive sympathetic nervous system. Methods: We assessed plasma β-endorphin, met-enkephalin, dynorphin B, ANF and noradrenaline levels, blood pressure and heart rate values in eight normotensive offspring and in 10 young normotensive subjects with no family history of hypertension (controls) at rest and during two exercise tests: the first test performed with the infusion of placebo (1.5 ml/min saline) and the second test with the infusion of an opioid antagonist (9.5 μg/kg per min naloxone hydrochloride). ANF and opioids were radioimmunoassayed after chromatographic pre-extraction. Results: At rest plasma met-enkephalin, dynorphin B, ANF and noradrenaline values in the normotensive offspring were significantly higher than in the controls. Exercise with placebo significantly raised all hormonal and haemodynamic parameters in the two groups. This increase was significantly higher in the normotensive offspring than in the controls. Naloxone did not modify any parameter in either group at rest, but it enhanced further the rise in plasma noradrenaline levels induced by exercise in both groups. A similar effect of naloxone during exercise was observed for plasma ANF levels in the normotensive offspring. Conclusions: Our findings show that plasma met-enkephalin, dynorphin B, ANF and noradrenaline levels at rest and during exercise are higher in normotensive offspring than in controls. The effects of naloxone indicate that in normotensive offspring at rest the opioid system does not affect ANF release, whereas during exercise it attenuates ANF hypersecretion, possibly by reducing noradrenaline release.

Pancreatic β-cell function in cirrhotic patients with and without overt diabetes. C-peptide response to glucagon and to meal☆☆☆

To study the role of pancreatic beta-cell function in glucose intolerance and frank diabetes that sometimes develops in cirrhosis, the C-peptide response to a bolus IV injection of 1 mg of glucagon was measured in nine controls and in two groups of patients with cirrhosis. The first group comprised nine subjects with normal or high-normal fasting plasma glucose and no glycosuria; five of them had impaired glucose tolerance. The second group consisted of eight cirrhotics in whom frank diabetes had developed six to 48 months after the diagnosis of cirrhosis. They were characterized by fasting plasma glucose greater than 140 mg/dL and permanent glycosuria. No differences in the degree of liver impairment or portal-systemic shunting were observed between the two groups. Plasma glucose response to glucagon was similarly reduced in cirrhotic subjects. Basal C-peptide was high normal in patients with cirrhosis, and significantly increased in nondiabetic subjects. By contrast peak C-peptide levels and total C-peptide responses to glucagon were low normal in cirrhotics and significantly reduced in patients with cirrhosis and diabetes. In 14 patients the C-peptide response to a standard meal was also measured. It was significantly reduced in patients with cirrhosis and diabetes (six cases), as compared to cirrhotic subjects without diabetes. Peak C-peptide after IV glucagon significantly correlated with peak C-peptide after the meal (r = .927), or total C-peptide response to meal (r = .871). Impaired insulin secretion may add to insulin resistance in patients with liver cirrhosis, leading to the development of frank diabetes, characterized by fasting hyperglycemia and glycosuria.

The Role of the Opioid Peptides in the Development of Hyperinsulinemia in Obese Women With Abdominal Body Fat Distribution

In this study, we investigated the hypothesis that increased opioid activity may be involved in the development of hyperinsulinemia in women with obesity and abdominal body fat distribution. Two groups of nine obese body (body mass index [BMI], 30 to 40 kg/m2) women with abdominal (A-ob) (waist to hip ratio [WHR] greater than 0.85) or gluteo-femoral (F-ob) (WHR greater than or equal to 0.80) fat distribution were examined and compared with eight normal-weight controls. Basal beta-endorphin levels were higher in the A-ob group than in the other groups. Each woman underwent two oral glucose tolerance tests (OGTT, 75 g glucose). A bolus of naloxone (0.8 mg) followed by a constant infusion of naloxone (0.04 mg/kg/h) or saline was also administered during the glucose challenge in random order, and blood samples for glucose, insulin, and C-peptide were collected at regular times after glucose administration. No difference was observed in basal or stimulated glucose concentrations between the three groups, nor between the saline or naloxone study. However, basal and stimulated insulin levels were significantly higher in obese women (particularly in the A-ob group) than in controls. Naloxone administration, however, did not significantly modify insulin and C-peptide glucose-stimulated concentrations in controls and in the F-ob group, whereas it significantly reduced (by approximately 47%) insulin levels in the A-ob group. Partial correlation coefficients showed a significant negative correlation between percent variation of glucose-stimulated insulin incremental areas during the naloxone study and the WHR in all women considered together (r = .544, P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)