S. E. Oleandri

Relationships between dehydroepiandrosterone‐sulphate and anthropometric, metabolic and hormonal variables in a large cohort of obese women

The aim of the present study was to measure dehydroepiandrosterone‐sulphate (DHEA‐S) levels in obesity and assess the relationships between DHEA‐S and anthropometric, metabolic and hormonal variables.

Effects of acipimox, an antilipolytic drug, on the growth hormone (GH) response to GH-releasing hormone alone or combined with arginine in obesity.

Increased free fatty acid (FFA) levels of obese patients are likely involved in the pathogenesis of the growth hormone (GH) hyposecretion of obesity. To clarify their role, we studied the influence of inhibition of plasma FFA levels, induced by 500 mg oral acipimox (ACX), an antilipolytic drug, on the GH response to GH-releasing hormone (GHRH) alone or combined with arginine ([ARG] study A) in six normal women ([NS] aged 24 to 37 years; body mass index, 22.4 +/- 0.9 kg/m2) and six obese women ([OB] aged 21 to 40 years; body mass index 39.5 +/- 3.2 kg/m2). In a group of seven OB patients (aged 18 to 58 years; body mass index, 35.8 +/- 1.3 kg/m2), the effect of ACX on either GHRH- or GHRH+ARG-stimulated GH increase was also studied after a 4-day treatment with the same drug at 250 mg three times daily (study B). OB patients had baseline FFA levels higher than NS (0.77 +/- 0.06 v 0.44 +/- 0.09 mmol/L, P<.05). In study A, ACX reduced FFA levels to the same nadir in both groups (0.11 +/- 0.02 and 0.12 +/- 0.03 mmol/L, NS and OB subjects, respectively). In NS, ACX failed to significantly potentiate the GH response to either GHRH (1,371.9 +/- 425.2 v 1,001.8 +/- 229.0 micrograms/L x min) or GHRH+ARG (3558.4 +/- 1,513.7 v 3,045.9 +/- 441.8 micrograms/L x min), while in OB patients it increased the GH response to GHRH (797.6 +/- 277.3 v 353.8 +/- 136.7 micrograms/L x min, P<.01) and did not modify the response to ARG+GHRH (1,010.5 +/- 253.1 v 821.1 +/- 222.0 micrograms/L x min). In study B, ACX reduced FFA levels in OB patients (nadir, 0.09 +/- 0.04 mmol/L). This treatment strikingly increased the GH response to GHRH (1,734.0 +/- 725.4 v 271.5 +/- 112.8 micrograms/L x min, P<.01) and significantly potentiated that to ARG+GHRH (2,371.9 +/- 571.3 v 1,020.0 +/- 343.2 micrograms/L x min, P<.05). In conclusion, our present findings indicate that an acute reduction of plasma FFA levels in OB patients restores their somatotrope responsiveness, whereas it does not affect GH secretion in lean subjects. After prolonged treatment, ACX further improves GHRH-stimulated GH secretion in OB patients, suggesting that elevated FFA levels play a leading role in the GH hyposecretory state of obesity.

Assessment of GH/IGF-I axis in obesity by evaluation of IGF-I levels and the GH response to GHRH+arginine test

The GH response to provocative stimuli in obese is often as low as in panhypopituitaric patients with severe GHD; however, IGF-I levels are normal or slightly reduced. In 53 patients with simple obesity (11 M and 42 F, age: 40.3±1.6 yr, BMI: 39.1±1.0 Kg/m2), we evaluated the GH response to GHRH (1 μg/kg iv)+arginine (ARG, 0.5 g/kg iv), and total IGF-I levels. The mean (±SE) GH peak after GHRH+ARG was markedly lower (74% reduction, p<0.0001) in obese (16.8±2.0 μg/l) than in normal subjects (62.7±4.3 μg/l). IGF-I levels in obese patients (134.0±7.6 μg/l) were lower (33% reduction, p<0.001) than in normal subjects (200.8±5.7 μg/l). Taking into account the 3rd centile limit of normal response, the GH response to GHRH+ARG was reduced in 62.3% (33/53) of the obese patients, and 21.2% (7/33) of them had low IGF-I levels. Assuming the 1st centile limit, it was reduced in 33.9% (18/53) obese subjects, and 22% (4/18) of them had low IGF-I levels. Considering 3.0 μg/L as arbitrary cut-off, the GH response was reduced in 5.7% (3/53) of the obese patients, and still one of them had low IGF-I levels. Our findings: a) confirm that the secretory capacity of somatotroph cells is often deeply impaired in obesity; b) demonstrate that IGF-I assay generally rules out severe impairment of GH/IGF-I axis in obese patients with marked reduction of the GH secretion; c) indicate that the percentage of obese patients with concomitant reduction of GH secretion and IGF-I levels is not negligible. Thus, IGF-I assay should be routinely performed in obese patients; those presenting with low IGF-I levels should undergo further evaluation of their hypothalamo-pituitary function and morphology, particularly in the presence of empty sella.

Comparison among the effects of arginine, a nitric oxide precursor, isosorbide dinitrate and molsidomine, two nitric oxide donors, on hormonal secretions and blood pressure in man

Arginine has well-known stimulatory effects on GH, PRL and insulin secretion in man but the mechanisms underlying these effects are still unclear. More recently, it has been demonstrated that arginine is the precursor of nitric oxide (NO) which mediates its vasodilatator effect. Thus, it has been hypothesized that NO could also mediate the hormonal effects of arginine. To clarify this point, in seven normal young volunteers (7 normal male subjects, age 26–35 yr) we compared the effects of arginine hydrochloride (ARG, 0.5 g/kg iv over 30 min) on GH, PRL, insulin and glucose levels as well as on blood pressure, with those of isosorbide dinitrate (ISDN, 5 mg po) and molsidomine (MOLS, 4 mg po), two NO donors which possess well-known vasodilatatory effects. ARG infusion elicited a clear-cut GH increase (peak vs baseline 17.6±4.7 vs 2.7±0.8 (g/L, p<0.01), PRL (20.6±2.8 vs 6.9±0.5 (g/L, p<0.01) and insulin levels (31.4±5.7 vs 4.5±2.1 (U/L, p<0.01) while induced a biphasic variation of plasma glucose levels with early increase (p<0.01), followed by late decrease below basal values (p<0.01). On the other hand, blood pressure was decreased by ARG (nadir vs baseline; systolic: 103±6 vs 112±3, p<0.02 and diastolic 61 ±4 vs 72±2 mmHg, p<0.02, respectively). ISDN and MOLS did not modify basal GH, PRL and insulin as well as glucose levels while induced a clear reduction in blood pressure (ISDN: nadir vs baseline; systolic: 94±4 vs 112±2, p<0.02; diastolic 69±3 vs 80±2, p<0.02; MOLS: systolic: 94±3 vs 113±2 p<0.02; diastolic 63±4 vs 72±2, p<0.02). The lowering effect of both ISDN and MOLS on both systolic and diastolic blood pressure levels was higher than that induced by ARG. The effect of the latter was, in turn, significantly different from that of placebo on diastolic levels only. In conclusion, our present date are against the hypothesis that NO mediates the stimulatory effects of arginine on GH, PRL and insulin secretion. On the other hand, our findings agree with the hypothesis that ARG has NO-mediated vasodilatatory effect able to decrease blood pressure in man.

Short‐term fasting in obesity fails to restore the blunted GH responsiveness to GH‐releasing hormone alone or combined with arginine

OBJECTIVE Fasting is known to clearly increase both spontaneous and GHRH‐stimulated GH secretion in normal subjects and this effect is likely to be due to hypothalamic mechanism(s). Our aim was to clarify the effect of a 3 or 4‐day fast, on the GH response to GHRH alone or combined with arginine, an amino acid probably acting via inhibition of hypothalamic somatostatin release.

Adrenal responsiveness to high, low and very low ACTH 1–24 doses in obesity

To investigate adrenal activity in visceral obesity in which adrenal hyperactivity has been hypothesized. This could reflect hypothalamus–pituitary alterations leading to slight hyperfunction of the adrenal. Primary adrenal hypersensitivity to ACTH drive in obesity has also been suggested. However, it has also been reported that dehydroepiondrosterone (DHEA) levels in obesity are reduced and it has been hypothesized that this could play a role in the increased cardiovascular risk in obese patients.

Long-term re-evaluation of primary aldosteronism after medical treatment reveals high proportion of normal mineralocorticoid secretion.

OBJECTIVE In most cases of primary aldosteronism (PA), An adrenal aldosterone-secreting tumor cannot be reasonably proven, so these patients undergo medical treatment. Controversial data exist about the evolution of PA after medical therapy: long-term treatment with mineralocorticoid antagonists has been reported to normalize aldosterone levels but other authors failed to find remission of mineralocorticoid hypersecretion. Thus, we planned to retest aldosterone secretion in patients with medically treated PA diagnosed at least 3 years before. DESIGN Retrospective, cross-sectional study. METHODS The same workup for PA as at diagnosis (basal aldosterone to renin activity ratio (ARR) and aldosterone suppression test) was performed after stopping interfering drugs and low-salt diet, in 34 subjects with PA diagnosed between 3 and 15 years earlier, by case finding from subgroups of hypertensive patients at high risk for PA. Criteria for persistence of PA were the same as at diagnosis (ARR (pg/ml per ng per ml per h) >400, aldosterone >150 pg/ml basally, and >100 pg/ml after saline infusion) or less restrictive. RESULTS PA was not confirmed in 26 (76%) of the patients and also not in 20 (59%) using the least restrictive criteria suggested by international guidelines. Unconfirmed PA was positively associated with female sex, higher potassium levels, longer duration of hypertension, and follow-up, but not with adrenal mass, aldosterone levels at diagnosis, and treatment with mineralocorticoid antagonists. CONCLUSIONS This study suggests that mineralocorticoid hyperfunction in patients with PA after medical treatment may decline spontaneously. Higher potassium concentration and duration of treatment seem to increase the probability of this event.

Primary hyperaldosteronism is associated with derangement in the regulation of the hypothalamus-pituitary-adrenal axis in humans

Hippocampal mineralocorticoid receptors (MR) play a major role in the control of hypothalamus-pituitary-adrenal (HPA) axis. The functional profile of HPA axis and the impact of MR blockade under chronic exposure to mineralocorticoid excess are unknown. To clarify this issue, ACTH, cortisol, and aldosterone secretions were studied in 6 patients with primary hyperaldosteronism (HA) and 8 controls (IMS) during placebo, placebo+human CRH (hCRH) (2 μg/kg iv bolus at 22:00 h), potassium canrenoate (CAN, 200 mg iv bolus at 20:00 h followed by 200 mg infused over 4 h) or CAN+hCRH. During placebo, both aldosterone and ACTH levels were higher (p<0.01) in HA than in NS, while cortisol levels were not significantly different. Both HA and NS showed significant ACTH and cortisol responses to hCRH (p<0.004), although the hormonal responses in HA were higher (p<0.02) than in NS. CAN infusion did not modify aldosterone levels in both HA and NS. Under CAN infusion, ACTH showed progressive rise in NS (p<0.05) but not in HA, while cortisol levels showed a significant (p<0.05) but less marked and delayed increase in HA compared to NS. CAN enhanced hCRH-induced ACTH and cortisol responses in NS (p<0.05), but not in HA. In conclusion, in humans primary hyperaldosteronism is associated with deranged function of the HPA axis. In fact, hyperaldosteronemic patients show basal and hCRH-stimulated HPA hyperactivity that is, at least partially, refractory to further stimulation by mineralocorticoid blockade with canrenoate. Whether this hormonal alteration can influence the clinical feature of hypertensive patients with primary hyperaldosteronism needs to be clarified.

Effects of cholinergic blockade by pirenzepine on insulin and glucose response to oral and intravenous glucose and to arginine load in obesity

Parasympathetic nervous system is known to affect insulin secretion in animal and man and there is evidence that it is involved in the outcome of spontaneous and stimulated insulin hypersecretion observed in animal obesity. In human obesity, there are contradictory data. We studied the effect of 150 mg orally administered pirenzepine (PNZ), a muscarinic receptor antagonist, on the insulin response to glucose (75 g po or 0.33 g/kg i.b.w. iv) or arginine (0.5 g/kg infused in 30 min) in 18 obese subjects normotolerant to glucose. PNZ did not modify basal serum insulin and the hormone response to either intravenous glucose (AUC: 5221.6±1177.6 vs 5309.8±1534.8 mU/L.min) or arginine load (4257.9±832.7 vs 3952.8±549.3 mU/L.min). Calculated as AUC the insulin response to oral glucose load was unaffected by PNZ (6601.5±1218.6 vs 8614.3±1095.2 mU/L-min). Actually, the insulin rises at +30 min after oral glucose load was significantly blunted by PNZ (37.0±3.4 vs 81.6±16.9 mU/L; p<0.03). However, after statistical evaluation by ANCOVA assuming basal insulin and +30 min glucose levels as covariates, this significance disappeared. Our present data do not agree with the hypothesis that the cholinergic system plays a role in the exaggerated insulin secretion of obesity. Nevertheless, these findings confirm that acetylcholine positively influences insulin secretion in humans, likely via indirect mechanisms.

Effects of 3-month nifedipine treatment on endocrine-metabolic parameters in patients with abdominal obesity and mild hypertension

It is widely accepted that abdominal obesity presents with exaggerated insulin secretion, insulin resistance and a trend toward glucose intolerance. Hypertension is frequently associated to abdominal obesity, and hyperinsulinism could play a role in its pathogenesis. Some studies reported that Ca-antagonists positively influence insulin sensitivity and glucose tolerance in obese patients with normal or elevated blood pressure. However, other studies reported worsening of metabolic balance during treatment with Ca-antagonists in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients and in normal subjects. We studied 19 patients with abdominal obesity, mild hypertension and insulin resistance on balanced, mild hypocaloric diet (1400 Kcal), to verify the effects of the Ca-antagonist nifedipine on both basal and oral glucose tolerance test (OGTT)-induced glucose and insulin levels as well as on IGF-I basal and DHEA-S levels and fat mass (FM). To achieve this goal, 10 hypertensive obese subjects (HOB-NIFE, 3 males, 7 females, mean age±SD 44.6±1.7 yr; body mass index (BMI) 37.1±2.5 Kg/m2, WHR 0.95±0.02) received 3-month treatment with nifedipine (Adalat Crono 30 Bayer, 1 tab daily) while other 9 hypertensive obese (HOB, 3 males, 6 females, 42±2.4 yr, BMI 35.8±1.8 Kg/m2, WHR 0.91±0.03) were studied during diet only. The same parameters were studied also in 8 normotensive obese patients (OB: 3 males, 5 females, 48.1±2.1 yr, BMI 35.8±2.4 Kg/m2, WHR 0.90±0.03) on the same balanced hypocaloric diet. Basal systolic (SBP) and diastolic (DBP) blood pressure levels in HOB-NIFE and HOB were similar. At baseline, all groups had similar basal and OGTT-induced glucose, insulin and glucose insulin ratio (GIR) levels as well as IGF-I and DHEA-S levels. After 3 months BMI fell to the same extent in all groups (p<0.05 vs baseline) while WHR and FFM/FM ratio did not change. SBP and DBP decreased HOB-NIFE (p<0.02) but also during diet alone in both HOB and OB, though to a lesser extent (p<0.05). Both basal and OGTT-stimulated glucose and insulin levels as well as IGF-I and DHEA-S levels were not modified in HOB-NIFE as well as in HOB and OB. In conclusion, our data indicate that nifedipine treatment does not modify glucose tolerance as well as insulin secretion and sensitivity, IGF-I and DHEA-S levels in hypertensive abdominal obese patients. Thus, nifedipine treatment has no detrimental effects on endocrine-metabolic balance in hypertensive obese patients.