La pose d’un cathéter intraveineux associée à une période de repos est utile pour le dosage du cortisol mais ne l’est pas pour le dosage de la prolactine

Objective

The use of an intravenous catheter with a rest period has been recommended to avoid false-positive results for hyperprolactinaemia and false-negative results for hypocortisolaemia. We tested the relevance of this recommendation.

Design

Plasma cortisol and prolactin levels were determined before (T-15) and after a 15-min rest period (T0) in 119 patients, 38 males (M) and 81 females (F). 52 of the 119 patients were known (K; 30 females and 22 males) and 67 unknown (UK; 49 females and 18 males) to the unit.

Results

Prolactin was lower after rest in women (12.3 ± 22.7 ng/l vs 11.7 ± 22.5 ng/ml, P = 0.03), but not in men (6.2 ± 4.5 ng/ml at T-15 vs 5.8 ± 3.2 ng/ml at T0, P = 0.09), in the UK subgroup (10.6 ± 20.7 ng/ml at T-15 vs 10.1 ± 20.9 ng/ml at T0, P = 0.06) and in the K subgroup (10.1 ± 16.7 ng/ml at T-15 vs 9.7 ± 15.8 ng/ml at T0, P = 0.08). None of the patients with prolactin levels higher than 20 ng/ml at T-15 diminished its prolactin value below this cut-off value. Plasma cortisol levels were lower after rest in women (17.9 ± 5.9 μg/dl at T-15 vs 16.5 ± 6.1 μg/dl at T0, P < 0.0001), in the UK subgroup (18 ± 6.1 μg/dl at T-15 vs 16.6 ± 6.4 μg/dl at T0, P = 0.0003) but not in men (18 ± 4.4 μg/dl at T-15 vs 17.5 ± 5.8 μg/dl at T0, P = 0.47) and in the K subgroup (17.8 ± 4.6 μg/dl at T-15 vs 17 ± 5.4 μg/dl at T0, P = 0.13). At T0, 3.3% and 15% of patients presented values below the cut-off value of 10 μg/dl (276 nmol/l) and 17 μg/dl (470 nmol/l), respectively.

Conclusion

These results don’t justify intravenous catheterisation with a rest period for plasma prolactin determination in contrast with plasma cortisol determination.     

Central serotoninergic response to orthostatic challenge in patients with neurocardiogenic syncope.

AIMS: To determine whether central serotoninergic system activity is impaired by orthostatic challenge in patients with neurocardiogenic syncope (NCS). METHODS AND RESULTS: Thirty-five [mean age: 24 (SD): 6 years] patients with a clinical history of NCS and positive head-up tilt test and 35 age-matched healthy volunteers (CON = 25+/-5 years) with negative response were studied. Overnight dexamethasone suppression test (DST) (1.5 mg given at 11 p.m.) was performed to assess the sensitivity of the hypothalamic-pituitary-adrenal axis by measuring next day cortisol (microg/dL) at 8 a.m. and 4 p.m. Cardiac autonomic function, cortisol, and prolactin (ng/dL) were also determined at baseline supine (BAS) and after 5, 10, and 15 min of orthostatic stress (OS) at 60 degrees . No significant differences were observed in cortisol plasma levels after the DST: CON = 0.6+/-0.6 microg/dL vs. NCS = 0.6+/-0.5; P = 0.7. Cardiac autonomic function, cortisol, and prolactin responses were similar in both study groups (CON vs. NCS; P > 0.05) during BAS: cortisol = 8.6+/-4 vs.8.7+/-4 microg/dL and prolactin = 16.8+/-9 vs. 16.8+/-9 ng/dL; OS-5: cortisol = 8.7+/-5 vs. 8.5+/-4 microg/dL and prolactin = 16.9+/-9 vs. 15.8+/-9 ng/dL; OS-10: cortisol = 8.5+/-5 vs. 8.1+/-3 microg/dL; prolactin = 16.2+/-9 vs. 15.8+/-9 ng/dL, and OS-15: cortisol = 9.0+/-5 vs. 8.4+/-4 microg/dL; prolactin = 17.1+/-9 vs. 15.5+/-9 ng/dL. CONCLUSION: Central serotoninergic response during orthostatic challenge was not impaired in patients with recurrent NCS. These findings suggest that the activation of the hypothalamic-pituitary-adrenal axis is not altered in patients with recurrent NCS.     

Mechanisms of androgen deficiency in human immunodeficiency virus-infected women with the wasting syndrome

Although prior studies suggest reduced androgen levels in women with acquired immune deficiency syndrome wasting, little is known regarding the regulation of adrenal and ovarian androgen secretion in such patients. We investigated ovarian and adrenal function in 13 human immunodeficiency virus-infected women with acquired immune deficiency syndrome wasting and 21 age- and body mass index-matched healthy control subjects studied in the early follicular phase. Subjects received hCG (5000 U, im) on d 1 and Cosyntropin (0.25 mg, i.v.) on d 3 after dexamethasone (1 mg, orally, at 2400 h) pretreatment on d 2. At baseline, human immunodeficiency virus-infected subjects demonstrated significantly reduced T [18 +/- 2 vs. 25 +/- 2 ng/dl (0.6 +/- 0.1 vs. 0.9 +/- 0.1 nmol/liter); P = 0.02], free T [1.5 +/- 0.1 vs. 2.4 +/- 0.2 pg/ml (5.3 +/- 0.5 vs. 8.3 +/- 0.6 pmol/liter); P = 0.001], androstenedione [119 +/- 6 vs. 162 +/- 14 ng/dl (4.16 +/- 0.20 vs. 5.66 +/- 0.48 nmol/liter); P = 0.02], and dehydroepiandrosterone sulfate [0.96 +/- 0.17 vs. 1.55 +/- 0.19 microg/ml (2.6 +/- 0.5 vs. 4.2 +/- 0.5 micromol/liter); P = 0.047] levels compared with the control subjects. T [8 +/- 2 vs. 6 +/- 2 ng/dl (0.3 +/- 0.1 vs. 0.2 +/- 0.1 nmol/liter); P = 0.48], free T [0.5 +/- 0.2 vs. 0.4 +/- 0.1 pg/ml (1.7 +/- 0.7 vs. 1.5 +/- 0.5 pmol/liter); P = 0.85], 17 hydroxyprogesterone [0.5 +/- 0.2 vs. 0.7 +/- 0.2 microg/liter (1.6 +/- 0.6 vs. 2.0 +/- 0.6 nmol/liter); P = 0.63], and androstenedione [-1 +/- 12 vs. 8 +/- 11 ng/dl (-0.03 +/- 0.42 vs. 0.28 +/- 0.39 nmol/liter), P = 0.61] responses to hCG were not different between the groups. Cortisol responses were increased and dehydroepiandrosterone sulfate responses were decreased in the human immunodeficiency virus-infected vs. control subjects after ACTH stimulation. The ratio of DHEA to cortisol was significantly decreased at 60 (71 +/- 11 vs. 107 +/- 10; P = 0.02) and 90 (63 +/- 8 vs. 102 +/- 9; P = 0.004) min post-ACTH in the human immunodeficiency virus-infected patients compared with control subjects. Baseline urinary free cortisol levels were not different between the groups [36 +/- 9 vs. 36 +/- 5 microg/24 h (99 +/- 26 vs. 100 +/- 13 nmol/d)]. The DHEA to cortisol ratio correlated with the CD4 count (r = 0.67; P = 0.01). These data demonstrate significant shunting of adrenal steroid metabolism away from androgenic pathways and toward cortisol production in human immunodeficiency virus-infected women with the wasting syndrome. In contrast, our data suggest intact ovarian androgen responsivity to hCG stimulation. Further studies of the mechanism of adrenal steroid shunting and the efficacy of androgen replacement in human immunodeficiency virus-infected women are necessary.     

Adrenocortical function in hyperprolactinemic women.

To study the effects of prolactin (PRL) on adrenocortical function in humans, dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), androstenedione (delta) and testosterone (T) were measured in serum obtained from 35 hyperprolactinemic women with galactorrhea and amenorrhea before and after treatment with bromocriptine-induced fall in mean PRL levels from 82 +/- 8 (SE) to 14 +/- 2 ng/ml (n = 39, P less than 0.0005), DHAS fell from 322 +/- 21 to 237 +/- 21 microgram/dl (n = 39); P less than 0.0005), DHA fell from 492 +/- 47 to 378 +/- 30 ng/dl (n = 39; P less than 0.01) while T (n = 16) and delta (n = 13) levels were unchanges (44 +/- 4 vs. 49 +/- 4 ng/dl and 280 +/- 55 vs. 236 +/- 40 ng/dl, respectively). In addition, 4 women were infused iv with 25 microgram synthetic ACTH over 4 h and serial blood samples drawn while hyperprolactinemic, and again 2-4 months later following normalization of PRL levels by bromocriptine. Although pre-infusion levels of DHAS were lower when PRL levels were normalized, no significant differences in responses of circulating DHAS, DHA, T, cortisol and 17-hydroxyprogesterone concentrations were detected between the two infusions. Since DHAS is virtually an exclusive product of the adrenal cortex, and since high PRL levels appear to inhibit ovarian steroid production, the findings suggest that hyperprolactinemia selectively stimulates adrenocortical androgen production.     

Rapid decrease of leptin in middle-aged sedentary individuals after 20 minutes of vigorous exercise with early recovery after the termination of the test

This study investigated the leptin response to vigorous exercise. We examined 12 sedentary subjects (7 males and 5 females) aged 45-59 yr (53 +/- 6.3) with body mass index of 26.1 +/- 8 Kg/m2. The selection of the population was based on the absence of endocrine or any other pathological anomaly. Basal concentrations of leptin, cortisol, insulin and glucose were measured at 08:00 h after an overnight fast. After that the individuals were placed on a computer-controlled ergometer performing a 20-min run at 70% VO2 max under controlled environmental conditions. Blood samples were obtained immediately after the completion of the test. For the following hour, all subjects were placed in the supine position and blood samples were taken at the end of the time period. Statistical evaluation was performed using analysis of variance (ANOVA) for independent variables. Plasma leptin levels exhibited a statistically significant decrease at the end of the 20 min running period (1.5 +/- 0.1 ng/ml vs 3.2 +/- 0.4 ng/ml, p<0.005). Interestingly, after 1 h in the supine position, leptin levels reached the basal values (3.17 +/- 0.1 ng/ml). The concentration of insulin, glucose and cortisol were unaltered during the exercise test (9.8 +/- 1.3 vs 8.85 +/- 1.27 microIU/ml, 95.58 +/- 6.71 mg/dl vs 98.4 +/- 0.78 mg/dl and 10.35 +/- 0.74 microg/dl vs 9.5 +/- 0.7 microg/dl respectively). In conclusion, our data demonstrate a relationship between stressful physical activity and plasma leptin levels in middle-aged subjects.     

Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate

alpha-MSH antagonizes many of the immune and neuroendocrine effects induced by inflammatory cytokines. Studies have shown that alpha-MSH attenuates the stimulatory effect of IL-1 on the hypothalamic-pituitary-adrenal (HPA) axis and plays a physiological role in limiting the HPA response to IL-1. Recently an alpha-MSH antagonist, agouti-related protein (AGRP), has been identified in the hypothalamus, which stimulates food intake by antagonizing the effects of alpha-MSH at specific melanocortin receptors. It is unknown whether AGRP can also modulate neuroendocrine responses to inflammatory cytokines. We have therefore examined the effects of AGRP on the HPA axis and on prolactin (PRL) at baseline and in response to stimulation by IL-1 beta in nine ovariectomized rhesus monkeys. In the first study, the effects of intracerebroventricular (i.c.v) infusion of 20 microg (n = 6) and 50 micro g (n = 4) of human AGRP (83-132)-NH(2) were compared with icv saline infusion. There was a significant stimulatory effect of 20 microg AGRP on cortisol release over time (P < 0.001). The area under the hormone response curve (AUC) for cortisol increased by 29% after 20 microg AGRP vs. saline; the AUC for ACTH increased by 166% (P = 0.028); the AUC for PRL increased by 108% (P = 0.046). There was a significant stimulatory effect of 50 microg AGRP on ACTH (P < 0.001), cortisol (P < 0.001), and PRL (P < 0.001) release over time. The AUC for ACTH after 50 microg AGRP increased by 98%; the AUC for cortisol increased by 37%; the AUC for PRL increased by 161%. The effects of AGRP on ACTH, cortisol, and PRL release were prevented by alpha-MSH infusion. In the second study, animals received icv either 50 ng of human IL-1 beta or 20 microg of AGRP followed by 50 ng IL-1 beta. AGRP significantly enhanced the ACTH (P < 0.05) response to IL-1 beta. The peak ACTH response to IL-1 beta alone was 124 +/- 55 pg/ml vs. 430 +/- 198 pg/ml after IL-1 beta plus AGRP; the peak cortisol response was 70 +/- 8.2 microg/dl vs. 77 +/- 6.2 microg/dl, but this was not significantly different. In conclusion, AGRP stimulated ACTH, cortisol, and PRL release in the monkey and enhanced the ACTH response to IL-1 beta. These studies suggest that, in addition to its known orexigenic effects, AGRP may play a role in neuroendocrine regulation and specifically that AGRP may interact with alpha-MSH to modulate neuroendocrine responses to inflammation.     

Clinical review: Early morning cortisol levels as a predictor of remission after transsphenoidal surgery for Cushing's disease

INTRODUCTION: We describe the use of serum cortisol and ACTH levels on postoperative d 1 and 2 as remission predictors after transsphenoidal surgery for Cushing's disease (CD). METHODS: Morning cortisol and ACTH levels were drawn daily after surgery; glucocorticoids were withheld until evidence of hypocortisolemia. Early remission was defined retrospectively as a subnormal morning cortisol level [< or =140 nmol/liter (< or =5 microg/dl)] on postoperative d 1 or 2 and sustained remission as subsequent eucortisolemia. RESULTS: Of 40 consecutive adults with CD (mean age 39 yr), 80% achieved early remission. Of 39 patients with a minimum follow-up of 14 months (mean 33 months), 31 (79.5%) achieved sustained remission at a mean follow-up of 32 months, including 30 of 31 (97%) with early remission and one of eight (12%) without early remission (P < 0.0001). Sustained remission was achieved in 26 of 28 (93%) patients having their first operation, compared with five of 11 (45%) with a prior unsuccessful operation (P < 0.001). For the 32 patients in early remission vs. the eight in nonremission, mean nadir cortisol levels were 57.6 +/- 33.0 (2.05 +/- 1.2 microg/dl) vs. 631.1 +/- 352.2 nmol/liter (22.9 +/- 12.8 microg/dl) (P < 0.0001), and nadir ACTH levels were 11.9 +/- 6.5 vs. 64.1 +/- 54.6 ng/liter (P < 0.001). Of 31 patients with sustained remission, 100% had subnormal morning cortisol levels, whereas 31% had subnormal ACTH levels (P < 0.0001). CONCLUSIONS: Serum morning cortisol levels on postoperative d 1 and 2 without glucocorticoid replacement provide a safe, simple, and reliable measure of early remission for CD and are predictive of sustained remission. This method allows for consideration of a repeat operation during the same hospitalization in patients with persistent hypercortisolemia.     

Dynamics of serum cortisol levels after transsphenoidal surgery in a cohort of patients with Cushing's disease

Transsphenoidal pituitary surgery is the treatment of choice for Cushing's disease (CD). Despite the widespread acceptance of this procedure, there is no agreement regarding the definition of successful treatment. We prospectively studied postoperative serum cortisol dynamics in 41 patients with CD (including a total of 45 surgeries). The mean postoperative follow-up period was 4.8 yr. Remission was defined as clinical and laboratory signs of adrenal insufficiency, glucocorticoid dependence, and serum cortisol suppression on overnight oral 1-mg dexamethasone suppression test. Serum cortisol was measured preoperatively and postoperatively at 6, 12, and 24 h (28 surgeries) and at 10-12 d (45 surgeries). No statistical difference was detected in mean preoperative and 6-h postoperative cortisol levels between surgically induced remission patients [22.1 +/- 7.73 microg/dl (610 +/- 213.3 nmol/liter) and 25.2 +/- 19 microg/dl (695.2 +/- 524.4 nmol/liter)] and surgical failure patients [23.6 +/- 6.95 micro g/dl (651.4 +/- 161.8 nmol/liter) and 37.5 +/- 18.1 microg/dl (1035 +/- 499.6 nmol/liter); P = 0.50 and P = 0.17]. At 12 and 24 h after surgery, the difference was significant (P = 0.009 and P < 0.0001). Mean cortisol levels were 12.44 +/- 13.3 microg/dl (343.3 +/- 367.1 nmol/liter) and 4.72 +/- 6.72 microg/dl (130.3 +/- 185.5 nmol/liter) in the remission group and 26.3 +/- 7.06 microg/dl (725.9 +/- 194.8 nmol/liter) and 23.5 +/- 6.86 microg/dl (648.6 +/- 189.3 nmol/liter) in the failure group (P = 0.009; P < 0.0001). At 10-12 d after the procedure, the difference was also significant (P < 0.0001): cortisol levels were 2.52 +/- 3.32 microg/dl (69.5 +/- 91.6 nmol/liter) in the remission group and 24.9 +/- 13.3 microg/dl (687.2 +/- 367.1 nmol/liter) in the failure group. In conclusion, in the immediate postoperative period of transsphenoidal surgery, remission of CD is not necessarily defined by undetectable serum cortisol. During the first 10-12 d after surgery, cortisol nadir correctly classified the remission [cortisol, 7.0 microg/dl (193.2 nmol/liter) or less] and the failure groups [cortisol, 8.0 microg/dl (220.8 nmol/liter) or more]. Glucocorticoid should be administered only after laboratory and/or clinical evidence of adrenal insufficiency.     

Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism

Anorexia nervosa (AN) is associated with low bone density in adolescents and adults. Hypercortisolemia has been reported in adults with this disorder and has been hypothesized to be a factor in bone loss. However, the secretory dynamics of cortisol in adolescents with AN and the contribution of alterations in cortisol secretion to bone metabolism in AN have not been examined. We examined the dynamics of cortisol secretion by Cluster and deconvolutional analysis in 23 girls with AN and 21 healthy adolescents of comparable age and maturity. Cortisol sampling was performed every 30 min for 12 h overnight. Twenty-four-hour urinary free cortisol (UFC) and creatinine (cr) were obtained for all subjects. The surface area (SA) of the subjects was calculated. Markers of bone turnover (type 1 procollagen, osteocalcin, and N-telopeptide) were examined. Subjects with AN were prospectively followed over 1 yr, and those who recovered weight (defined as a 10% increase in body mass index) were again studied. On Cluster analysis, girls with AN had significantly higher mean cortisol (8.6 +/- 2.0 vs. 5.9 +/- 1.1 microg/dl; P < 0.0001), nadir cortisol (5.5 +/- 2.3 vs. 3.4 +/- 1.2 microg/dl; P = 0.0008), valley mean cortisol (7.0 +/- 2.7 vs. 4.7 +/- 1.5 microg/dl; P = 0.001), peak amplitude (12.6 +/- 4.4 vs. 7.8 +/- 3.0 microg/dl; P = 0.0004), peak area (652 +/- 501 vs. 340 +/- 238 microg/dl; P = 0.02), and total area under the curve (6112 +/- 1467 vs. 4117 +/- 802 microg/dl; P < 0.0001) than healthy adolescents. On deconvolutional analysis, the frequency of nocturnal secretory bursts (7.0 +/- 1.2 vs. 5.8 +/- 1.3 /12 h; P = 0.001), total nocturnal pulsatile cortisol secretion (69.3 +/- 14.7 vs. 53.9 +/- 11.1 microg/dl; P = 0.0003), and total cortisol secretion (89.6 +/- 18.8 vs. 71.2 +/- 17.6 microg/dl; P = 0.002) were significantly higher in girls with AN than in healthy controls. Cortisol half-life trended higher in girls with AN. However, basal cortisol secretion and approximate entropy did not differ between the groups. UFC/cr and UFC/cr.SA were significantly higher in girls with AN than in controls [0.050 +/- 0.028 vs. 0.036 +/- 0.017 (P = 0.04) and 0.035 +/- 0.020 vs. 0.023 +/- 0.012 (P = 0.03)]. Six of 23 girls with AN had UFC/cr.SA values that were more than 2 sd above those in healthy controls. An inverse correlation was noted between measures of cortisol concentration as well as pulsatile secretion and measures of nutritional status (body mass index, fat mass, leptin, insulin, and IGF-I). An oral glucose load suppressed cortisol levels in healthy adolescents, but not in AN patients. Weight recovery was associated with a significant decrease in the number of secretory bursts. In girls with AN, strong inverse correlations were noted between levels of cortisol (mean, nadir, and total area under the curve) and levels of markers of bone formation (C-terminal propeptide of type 1 procollagen and osteocalcin). Conversely, in healthy controls, cortisol values did not predict levels of markers of bone turnover. Adolescent girls with AN have significantly higher serum cortisol concentrations and UFC/cr.SA values than healthy adolescents. This increased cortisol concentration is a function of increased frequency of secretory bursts, resulting in increased pulsatile secretion. Hypercortisolemia appears to be a direct consequence of undernutrition and is associated with a decrease in markers of bone formation. Therefore, high cortisol values in AN may contribute to the low bone density observed in adolescents with this disorder by decreasing bone formation.     

Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients

The aim of the study was to evaluate the hypothalamus-pituitary-adrenal (HPA) axis in patients (nine males, three females; mean age +/- sem 51 +/- 2 yr) with adult-onset GH deficiency (GHD) due to surgically treated pituitary tumors with preserved HPA function and without evidence of tumor recurrence before and during recombinant human (rh) GH replacement therapy (duration 31 +/- 6 months). HPA function was assessed by urinary free cortisol and morning serum cortisol levels as well as cortisol responses to 1 mug ACTH test (n = 7 patients) or insulin tolerance test (n = 5 patients) before and during rhGH therapy, the cut-off for the diagnosis of hypoadrenalism being a cortisol peak less than 18 microg/dl (<500 nmol/liter) after stimulatory tests. Serum cortisol and urinary free cortisol levels were significantly lower on therapy than before [7.6 +/- 0.8 vs. 11.5 +/- 0.9 microg/dl (208 +/- 22 vs. 317 +/- 24 nmol/liter), P < 0.01, and 19.6 +/- 2.5 vs. 32.2 +/- 3.2 microg per 24 h (54 +/- 7 vs. 89 +/- 9 nmol per 24 h), P < 0.05, respectively], whereas no change in cortisol-binding globulin levels was observed. Cortisol peak after either ACTH test or insulin tolerance test was lower on rhGH therapy than before [15.9 +/- 1.5 vs. 20.2 +/- 1.1 microg/dl (437 +/- 43 vs. 557 +/- 31), P = 0.01, and 13.1 +/- 2.6 vs. 20.4 +/- 1.4 microg/dl (362 +/- 71 vs. 564 +/- 37 nmol/liter), P = 0.03, respectively]. Accordingly, central hypoadrenalism was detected in nine of 11 patients. In conclusion, low GH and IGF-I levels, likely enhancing the conversion of cortisone to cortisol, may mask a condition of central hypoadrenalism. Therefore, the reassessment of HPA function in GHD patients during rhGH therapy is mandatory.     

Relation between Helicobacter pylori infection, thyroid hormone levels and cardiovascular risk factors on blood donors

The aim of this study was to assess the relationship between Helicobacter pylori (Hp) infection, serum thyroid hormone levels and certain cardiovascular risk factors in normal volunteers. In 110 blood donors (85 men, 25 women, aged 35.6 +/- 9.76) the serum levels of IgG antibodies against Hp were estimated using a sensitive immunoassay. Serum estimation of T3, T4, TSH, FT3, FT4, thyroid (microsomial) autoantibodies, C-Reactive-Protein, a1-acid-glycoprotein, vitamin B12, folic acid, cholesterol, triglycerides, total lipids, HDL, LDL, and antibodies against hepatitis A, was also carried-out. In all subjects a number of clinicoepidemiological parameters including body mass index, smoking habits, educational level, number of siblings and presence of symptoms from the digestive system were carefully recorded. Statistical analyses were performed using the SPSS statistical package. Helicobacter pylori infection was found in 54 subjects (49.1%). On univariate analysis, significant differences between subjects positive and negative for Helicobacter pylori infection were found for FreeT3 (3.11 +/- 0.5 pmol/ vs. 3.42 +/- 0.8 pmol/l, P=0.025), FreeT4 (1.04 +/- 0.2 ng/dl vs. 1.17 +/- 0.3 ng/dl, P=0.025), and thyroid autoanti bodies (23.65 +/- 24 vs. 14.97 +/- 8, P=0.018). Significant differences were also found for Cholesterol (207.8 +/- 39 mg/dl vs. 193.3 +/- 40 md/dl, P=0.05), LDL (133.2 +/- 32 mg/dl vs. 119.6 +/- 40 mg/dl, P=0.05) and folic acid (7.66 +/- 3.7 ng/ml vs. 6.39 +/- 2.5 ng/ml, P=0.038). A significantly positive correlation of Hp infection with age and number of siblings and a negative one with educational level were noticed. No differences concerning the levels of acute phase proteins, vitamin B12, antibodies against hepatitis A, body mass index, and smoking habits were found. On logistic regression analysis, significant differences remained only for thyroid autoantibodies (Odds ratio for titer ?30: 7.8, P=0.012), age (Odds Ratio for those aged >40 years vs those aged <40 years: 3.8, P=0.022) and educational level (Odds ratio for elementary 8.7 and moderate 5.1 vs higher education, P=0.003 and P=0.011 respectively). It is concluded that a relationship exist between Hp infection and the presence of high titers of thyroid autoantibodies in blood donors. There are no indications of the existence of a relationship between Hp infection with thyroid hormone levels, lipid concentrations and other cardiovascular risk factors.     

Effects of pioglitazone and metformin on plasma adiponectin in newly detected type 2 diabetes mellitus

OBJECTIVE: This prospective study evaluates the effect of insulin sensitizers, pioglitazone (PGZ) and metformin (MET) on plasma adiponectin and leptin levels in subjects newly diagnosed with type 2 diabetes mellitus (T2DM). DESIGN: Double blind, randomized, active control, dose escalation study of 12 weeks treatment duration. PATIENTS: Thirty apparently healthy, treatment-naive T2DM patients diagnosed within the past 6 months. MEASUREMENTS: Plasma adiponectin and leptin levels were estimated by enzyme-linked immunosorbent assay (ELISA), and insulin resistance by the homeostasis model of assessment (HOMA-IR). RESULTS: Baseline plasma levels of adiponectin were lower in diabetic (n = 30) subjects than matched controls (n = 10, 6.6 +/- 1.1 vs 10.4 +/- 4.2 microg/ml, P = 0.021). The 12-week treatment with PGZ significantly increased adiponectin concentrations (6.6 +/- 1.1-17.9 +/- 7.4 microg/ml, P < 0.001) with no alteration in the MET treated group (6.8 +/- 1.5-6.7 +/- 2.8 microg/ml, P = 0.9). A significant decrease in plasma leptin levels was observed in the MET treated group (32.0 +/- 28.9-21.4 +/- 23.3 ng/ml, P = 0.024) but not in the PGZ treated group (23.9 +/- 24.1-22.4 +/- 25.4 ng/ml, P = 0.69). The alterations in plasma adiponectin and leptin levels were not associated with any change in body mass index (BMI). PGZ therapy improved insulin sensitivity to a greater degree (P = 0.007 and P = 0.001 for fasting plasma insulin (FPI) and HOMA-IR, respectively) than MET (P = 0.75 and P = 0.02 for FPI and HOMA-IR, respectively) but this improvement was not significantly different from that of MET at the end of 12 weeks (P = 0.146 and P = 0.09 for FPI and HOMA-IR, respectively). However, improvement in insulin sensitivity with PGZ was not commensurate with the increase in adiponectin. Better control of postbreakfast plasma glucose (PBPG) as well as decrease in serum triglycerides (TGs) were also seen with PGZ (PBPG, P < 0.001; TGs, P = 0.013). The rest of the parameters were comparable. Adverse reactions reported were minor and did not result in treatment discontinuation. CONCLUSIONS: Pioglitazone therapy appears to be better in achieving glycaemic control and increasing plasma adiponectin and insulin sensitivity in newly detected type 2 diabetics.     

Subnormal plasma adrenal androgen levels in men with uremia

The 24-h mean plasma concentrations of 8 hormones were measured in 11 men with chronic uremia and 32 normal men. Our findings confirm previous reports of subnormal levels of testosterone, T3, and T4 and elevated levels of LH, PRL, and cortisol. In addition, we observed a new finding: markedly subnormal levels of the adrenal androgens dehydroisoandrosterone (DHA) and DHA sulfate. The mean DHA level in the patients was 164 +/- 46 (SD) ng/dl, compared with 320 +/- 124 in age-matched controls (P < 0.0001); the geometric mean DHA sulfate level was 40 micrograms/dl (95% confidence limits, 11-113) in the patients and 76 micrograms/dl (95% confidence limits, 26-214) in age-matched controls (P = 0.005). The depression of adrenal androgen levels in the face of elevated cortisol levels suggests a biosynthetic block in the adrenal cortex at the step where the C-19 and C-21 pathways diverge, namely the removal of the 2-carbon side chain by C-17, 20-lyase. If a similar defect were present in the testes, it could account for the diminished synthesis of testosterone, which is a further metabolite of DHA in the testes.     

Thyrotropin-releasing hormone increases plasma atrial natriuretic peptide levels in human

The effect of thyrotropin-releasing hormone (TRH) on plasma atrial natriuretic peptide (ANP), TSH, prolactin, cortisol and aldosterone levels in 26 patients with normal pituitary and thyroid gland function was examined. Bolus iv injection of 200 micrograms TRH produced, between 0 and 60 min, a significant gradual rise of plasma ANP concentrations from 30.4 +/- 2.3 to 54.8 +/- 6.4 pg/ml (mean +/- SE). Plasma prolactin and TSH concentrations increased four- and six-fold of basal values with peak responses at 15 and 30 min, respectively, whereas plasma cortisol and aldosterone concentrations remained unchanged after the drug treatment. The patients had no significant changes in blood pressure or pulse rate. We conclude that there may be indirect mechanism(s) which result in increased ANP levels after TRH administration.     

Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels

As men age, serum testosterone levels decrease, a factor that may contribute to some aspects of age-related physiological deterioration. Although androgen replacement has been shown to have beneficial effects in frankly hypogonadal men, its use in elderly men with borderline hypogonadism is controversial. Furthermore, current testosterone replacement methods have important limitations. We investigated the ability of the orally administered aromatase inhibitor, anastrozole, to increase endogenous testosterone production in 37 elderly men (aged 62-74 yr) with screening serum testosterone levels less than 350 ng/dl. Subjects were randomized in a double-blind fashion to the following 12-wk oral regimens: group 1: anastrozole 1 mg daily (n = 12); group 2: anastrozole 1 mg twice weekly (n = 11); and group 3: placebo daily (n = 14). Hormone levels, quality of life (MOS Short-Form Health Survey), sexual function (International Index of Erectile Function), benign prostate hyperplasia severity (American Urological Association Symptom Index Score), prostate-specific antigen, and measures of safety were compared among groups. Mean +/- SD bioavailable testosterone increased from 99 +/- 31 to 207 +/- 65 ng/dl in group 1 and from 115 +/- 37 to 178 +/- 55 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.054 group 1 vs. group 2). Total testosterone levels increased from 343 +/- 61 to 572 +/- 139 ng/dl in group 1 and from 397 +/- 106 to 520 +/- 91 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.012 group 1 vs. group 2). Serum estradiol levels decreased from 26 +/- 8 to 17 +/- 6 pg/ml in group 1 and from 27 +/- 8 to 17 +/- 5 pg/ml in group 2 (P < 0.001 vs. placebo for both groups and P = NS group 1 vs. group 2). Serum LH levels increased from 5.1 +/- 4.8 to 7.9 +/- 6.5 U/liter and from 4.1 +/- 1.6 to 7.2 +/- 2.8 U/liter in groups 1 and 2, respectively (P = 0.007 group 1 vs. placebo, P = 0.003 group 2 vs. placebo, and P = NS group 1 vs. group 2). Scores for hematocrit, MOS Short-Form Health Survey, International Index of Erectile Function, and American Urological Association Symptom Index Score did not change. Serum prostate-specific antigen levels increased in group 2 only (1.7 +/- 1.0 to 2.2 +/- 1.5 ng/ml, P = 0.031, compared with placebo). These data demonstrate that aromatase inhibition increases serum bioavailable and total testosterone levels to the youthful normal range in older men with mild hypogonadism. Serum estradiol levels decrease modestly but remain within the normal male range. The physiological consequences of these changes remain to be determined.     

Novel interactions of adiponectin with the endocrine system and inflammatory parameters

Several markers of chronic immune activation have been found in association with obesity and insulin resistance. We aimed to study the interaction of adiponectin with chronic inflammation and known components of the insulin resistance syndrome. Insulin sensitivity (minimal model analysis) and plasma soluble fractions of TNF-alpha receptor 1 (sTNFR1) and 2 (sTNFR2), adrenal and thyroid function, and adiponectin were evaluated in 68 apparently healthy subjects. An additional group of type 2 diabetic patients (n = 19) similarly studied, except for insulin sensitivity, were also included in the analysis. As reported by others, serum adiponectin concentrations were higher in women than in men (13.55 +/- 9.79 vs. 8.64 +/- 7.83 mg/liter; P = 0.018). They were also higher in healthy subjects compared with diabetic patients (10.35 +/- 8.48 vs. 7.41 +/- 8.31 mg/liter; P = 0.021). As expected also, circulating adiponectin was significantly associated with waist to hip ratio (r = -0.28; P = 0.013), diastolic blood pressure (r = -0.25; P = 0.027), fasting plasma high-density lipoprotein cholesterol (r = 0.35; P = 0.001), triglycerides (r = -0.37; P = 0.001), and insulin sensitivity (r = 0.30; P = 0.011). Additionally, subjects in the higher quartile of circulating adiponectin had lower sTNFR2 concentrations (3.05 vs. 4.37 microg/liter; P = 0.012), a trend to lower sTNFR1 concentrations (1.76 vs. 2.20 microg/liter; P = 0.055), higher concentration of serum morning cortisol (16.86 vs. 13.52 microg/dl; P = 0.027), and higher serum free T(4) levels (1.31 vs. 1.20 ng/dl; P = 0.038). Multiple regression analysis models were constructed to predict adiponectin concentrations. Predictive variables in these models included insulin sensitivity, waist to hip ratio and free T(4), contributing to 17%, 10%, and 8% of adiponectin variance, respectively, These findings suggest that circulating adiponectin differentially modulates insulin action and that thyroid-axis, inflammatory cytokines, and the adrenal cortex might intervene in this modulation.     

Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma

OBJECTIVE: There is scant information on the morbidity associated with subclinical Cushing's syndrome in patients with a clinically inapparent adrenal adenoma. In the present study, we have determined the prevalence of alterations of the hypothalamic-pituitary-adrenal axis in such patients and examined whether any correlation between endocrine data and the clinical phenotype exists. DESIGN AND METHODS: A multi-institutional retrospective study was carried out on 210 patients (135 women and 75 men aged 19-81 years) with an adrenal adenoma detected serendipitously between 1996 and 2000 in four referral centers in Italy. RESULTS: Hypertension was observed in 53.8%, obesity in 21.4% and hyperglycemia in 22.4% of patients. The 47 patients with midnight serum cortisol >5.4 microg/dl, a value corresponding to the 97th centile of 100 controls, were older and displayed greater fasting glucose (120.4+/-52.2 mg/dl vs 105.1+/-39.2 mg/dl, P = 0.04) and systolic blood pressure (148.3+/-14.6 mmHg vs 136.4+/-16.2 mmHg, P = 0.0009) than the 113 patients with normal cortisol levels. The difference in systolic blood pressure remained statistically significant (P = 0.009) when age was used as a covariate. The percentage of hypertensive patients undergoing treatment was not different between the two groups (90.5 and 97.1%) but the percentage of patients with controlled hypertension was significantly lower among the hypercortisolemic patients (12.5 vs 32.4%, P = 0.04). Glycated haemoglobin (HbA1c) levels were higher in the hypercortisolemic diabetic patients (8.9+/-1.1% vs 7.1+/-1.3%, P = 0.005). CONCLUSIONS: Elevated midnight cortisol concentration is a reliable test to select a subgroup of patients with a clinically inapparent adrenal adenoma with an adverse cardiovascular risk profile.     

Increased plasma levels of soluble selectins in patients with unstable angina

BACKGROUND: Inflammation plays an important role in the pathogenesis of unstable angina. Adhesion molecules, such as selectins, mediate the interactions between leukocytes, platelets and endothelial cells during inflammation and thrombogenesis. HYPOTHESIS: The purpose of this study was to determine whether soluble E-selectin, P-selectin and L-selectin levels are increased in patients with unstable angina (UA). METHODS: Soluble E-, P- and L-selectin levels were measured by enzyme-linked immunoassay in the peripheral blood of 23 patients with UA, 26 patients with stable angina (SA) and 15 control patients with angiographically normal coronary arteries. RESULTS: Soluble E-selectin levels were significantly higher in patients with UA (45+/-11 ng/ml) than in controls (30+/-8 ng/ml, P<0.001), or patients with SA (34+/-8 ng/ml, P=0.001). Similarly, plasma levels of P- and L-selectin were significantly higher in patients with UA (427+/-144 and 772+/-160 ng/ml, respectively) than in patients with SA (278+/-79 and 643+/-94 ng/ml, respectively, P<0.005 vs. UA for both), or control patients (189+/-43 and 601+/-126 ng/ml, respectively, P=0.001 vs. UA for both). CONCLUSIONS: Plasma levels of soluble selectins were increased in patients with UA compared with patients with SA or patients without angiographically visible coronary artery disease. Measurements of these adhesion molecules may be helpful as non-invasive markers of coronary plaque destabilization in UA.     

Inhibition of cortisol biosynthesis decreases circulating leptin levels in obese humans

CONTEXT: Glucocorticoids increase both appetite and leptin secretion; the hyperleptinemic effect might be a counterregulatory response to the orexigenic effect of glucocorticoids. However, the effect of glucocorticoid inhibition on leptin production has not been reported. OBJECTIVE: We tested the hypothesis that if glucocorticoid-induced hyperleptinemia plays a physiological role, then inhibition of endogenous cortisol biosynthesis should decrease leptin secretion. DESIGN: A randomized, placebo-controlled, cross-over study design was used. SETTING: The study was carried out at a General Clinical Research Center. PARTICIPANTS: Eight obese subjects (four men, four women; mean age, 30.4 +/- 1.56 yr; mean body mass index, 42.0 +/- 1.33 kg/m2) participated in the study. Intervention: The subjects were treated with metyrapone (750 mg every 4 h) or placebo for 24 h during two overnight admissions, 2 wk apart. Blood sampling for measurement of cortisol, leptin glucose, insulin, and C-peptide was performed hourly for 6 h and every 2 h for 24 h. MAIN OUTCOME MEASURE: The change in plasma leptin from baseline during metyrapone vs. placebo treatment was measured. RESULTS: Metyrapone treatment was associated with a significant decrease in plasma cortisol level; the cortisol nadir was 4.84 +/- 1.22 microg/dl during placebo and 2.80 +/- 0.65 microg/dl during metyrapone treatment (P = 0.009). Compared with placebo, metyrapone treatment was associated with a significant reduction in circulating leptin levels and marked attenuation of the nocturnal rise in plasma leptin (+28.45 +/- 11.12% vs. +55.51 +/- 5.42%; P = 0.01). CONCLUSIONS: We conclude that metyrapone-induced inhibition of cortisol biosynthesis results in hypoleptinemia, which indicates that glucocorticoids may play an important role in the physiological regulation of leptin.     

Neuroendocrine consequences of fasting in adult male macaques: effects of recombinant rhesus macaque leptin infusion

Fasting inhibits the gonadotropic axis and stimulates the corticotropic and somatotropic axes. Since leptin is a product of fat cells that has been implicated in the control of both reproduction and metabolism, we hypothesized that the decrease in leptin observed during fasting was responsible for these effects on reproductive and metabolic hormones. Recombinant rhesus leptin (rrhLep) produced in our laboratory was infused (100 microgram/h) into fasted adult male rhesus macaques (6-9 kg) beginning at midnight after the first missed meal and continuing until the end of the study. Bioactive luteinizing hormone (LH), testosterone, cortisol and growth hormone (GH) were measured in plasma from samples collected at 15-min intervals for the last 15 h (42-57 h) of the fast. We analyzed pulsatile LH and GH secretion by deconvolution analysis and the orderliness of pulsatile LH and GH release by the approximate entropy (ApEn) statistic. There was no difference in LH pulse frequency between control and fasted groups, but there was a significant decrease in the mean concentration of LH released (7.6 +/- 1.4 ng/ml control vs. 2.7 +/- 0.65 ng/ml fasted) that was not relieved with rrhLep infusions (2.8 +/- 0.83 ng/ml). Model-free Cluster analysis confirmed these inferences and also indicated that the peak height was lower in the fasted (4.6 +/- 1.0 ng/ml) and the fasted + rrhLep (2.85 +/- 1.0 ng/ml) groups compared to controls (16. 3 +/- 1.4 ng/ml). Testosterone levels reflected those of LH. Fasting resulted in an increase in GH secretory pulse frequency (5.3 +/- 0. 95 pulses/15 h control vs. 12.8 +/- 1.4 pulses/15 h fasted) and this increase was not affected by rrhLep infusion (12.5 +/- 1.4 pulses/15 h). In addition, fasting also increased the ApEn (decreased the orderliness) of pulsatile GH secretion, and this characteristic was not relieved with rrhLep infusions. Cortisol levels in fasted animals were 2- to 3-fold higher than those observed in control studies, and this increase was particularly pronounced at the time when the animals expected their first meal of the day. The increase in circulating cortisol observed in fasted animals was not affected by rrhLep infusion. Glucose levels at the end of the sampling period were 80 mg/dl in controls, 48 mg/dl in fasted animals and 58 mg/dl in the fasted + rrhLep group. Circulating leptin levels averaged 1.2 +/- 0.37 ng/ml in control animals, 0.7 +/- 0.2 ng/ml in fasted animals and 10.1 +/- 5.6 ng/ml in fasted animals infused with rrhLep. These studies suggest that intravenous replacement with homologous leptin does not reverse the acute changes in GH, LH and cortisol secretion observed with fasting in the adult male macaque.