Effect of bariatric surgery on microvascular dysfunction associated to metabolic syndrome: a 12-month prospective study.

OBJECTIVE: To prospectively evaluate the effect of weight loss after bariatric surgery on microvascular function in morbidly obese patients with and without metabolic syndrome (MetS). METHODS: A cohort of morbidly obese patients with and without MetS was studied before surgery and after 12 months of surgery. Healthy lean controls were also examined. Microvascular function was assessed by postocclusive reactive hyperemia (PORH) at forearm skin evaluated by laser Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated from laser-Doppler skin blood flow and blood pressure. Regression analysis was performed to assess the contribution of different clinical, metabolic and biochemical parameters to microvascular function. RESULTS: Before surgery, 62 obese patients, 39 with MetS and 23 without MetS, and 30 lean control subjects were analyzed. The absolute area under the hyperemic curve (AUC(H)) CVC of PORH was significantly decreased in obese patients compared with lean control subjects. One year after surgery, AUC(H) CVC significantly increased in patients free of MetS, including patients that had MetS before surgery. In contrast, AUC(H) CVC did not significantly change in patients in whom MetS persisted after surgery. Stepwise multivariate regression analysis showed that only changes in HDL cholesterol (HDL-C) and oxidized LDL (oxLDL) independently predicted improvement of AUC(H) after surgery. These two variables together accounted for 40.9% of the variability of change in AUC(H) CVC after surgery. CONCLUSIONS: Bariatric surgery could significantly improve microvascular dysfunction in obese patients, but only in patients free of MetS after surgery. Improvement of microvascular dysfunction is strictly associated to postoperative increase in HDL-C levels and decrease in oxLDL levels.

Self-limited acute hepatotoxicity caused by pegvisomant.

We present a case of acute severe hepatitis in a patient with acromegaly receiving combination therapy with somatostatin analogs and pegvisomant. Hepatitis resolved completely 18 weeks after diagnosis of hypertransaminasemia without discontinuation of therapy and with a close clinical and biochemical follow-up. In this case, despite the severity of the hepatitis, therapy could be continued as hypertransaminasemia was gradually decreasing after the maximum peak. We also review the literature on toxic hepatitis associated to pegvisomant therapy analyzing the etiology, clinical predisposing factors and natural evolution.

Acute pharmacological reduction of plasma free fatty acids enhances the growth hormone (GH)-releasing hormone-mediated GH secretion in patients with Cushing's syndrome.

In Cushing's syndrome, GH secretion is blocked with all the stimuli tested. It has been reported that the acute pharmacological reduction of free fatty acids (FFA) leads to an enhancement of GH secretion in normal subjects and in pathological conditions associated with reduced GH secretion. To understand if the elevated FFA levels of hypercortisolism may be responsible for the altered GH secretion, 14 patients with active Cushing's syndrome underwent 2 paired tests with 100 micrograms i.v. of GHRH on 2 different occasions. In one test, they were pretreated with placebo and in the other one, with acipimox 250 mg p.o. 4 h before, and 250 mg p.o. 1 h before GHRH. The basal FFA levels (799 +/- 57 mmol/L) were reduced by acipimox throughout the whole test (values under 240 +/- 28 mmol/L). In the placebo pretreated group, GHRH-induced GH secretion was severely impeded, with a mean GH peak of 1.8 +/- 0.3 micrograms/L and area under the curve of 121.3 +/- 21.6 micrograms/L-120 min. All the patients showed a GHRH-mediated GH peak under 4 micrograms/L. Acute reduction of FFA by acipimox enhanced the GHRH action, with a mean GH peak of 11.1 +/- 1.8 micrograms/L and area under the curve of 652.9 +/- 110.3 micrograms/L-120 min (both P < 0.005). Individually analyzed after acipimox, all 14 subjects presented an enhancement in the GHRH-mediated GH peak, and 8 patients showed a response over 10 micrograms/L. In conclusion, acute FFA reduction by acipimox increased the GH secretion elicited by GHRH in chronic hypercortisolism. Elevated FFA may be a contributing factor to the deranged GH secretion observed in Cushing's syndrome.

The growth hormone (GH)-releasing hormone-GH-insulin-like growth factor-1 axis in patients with fibromyalgia syndrome.

Fibromyalgia (FM) is a painful syndrome of nonarticular origin, characterized by fatigue and widespread musculoskeletal pain, tiredness, and sleep disturbances, without any other objective findings on examination. Interestingly, some of the clinical features of FM resemble the ones described in the adult GH-deficiency syndrome. Furthermore, insulin-like growth factor (IGF)-1 levels are frequently reduced in patients with FM. To gain further insight into the mechanisms leading to dysregulation of the GH-IGF-1 axis in these patients, we assessed 24-h spontaneous GH secretion, GH responses to GHRH, and IGF-1 and IGF binding protein (BP)-3 levels before and after 4 days treatment with human (h)GH. We found that, in comparison with controls, patients with FM exhibited a marked decrease in spontaneous GH secretion as assessed by mean GH secretion (2.5 +/- 0.4 microg/L in controls vs. 1.2 +/- 0.1 microg/L in FM, P < 0.05), pulse height (4.7 +/- 0.8 microg/L in controls vs. 2.5 +/- 0.3 microg/L in FM, P < 0.05), and pulse area (4.7 +/- 1 min/mg x L in controls vs. 2.3 +/- 0.3 min/mg x L in FM, P < 0.05). In contrast, GH responses to GHRH (100 microg, i.v.) were similar in controls (mean peak, 13.5 +/- 2.5 microg/L) and in patients with FM (12.2 +/- 3 microg/L). Finally, treatment with hGH (2 IU, s.c. daily), over 4 days, led to a clear-cut increase in plasma IGF-1 and IGFBP-3 levels in patients with FM. In conclusion, our data show that patients with FM exhibited a marked decrease in spontaneous GH secretion, but normal pituitary responsiveness to exogenously administered GHRH, thus suggesting the existence of an alteration at the hypothalamic level in the neuroendocrine control of GH in these patients. Furthermore, our finding of increased IGF-1 and IGFBP-3 levels after GH treatment, over 4 days, opens up the possibility of testing the therapeutic potential of hGH in patients with FM.

Serum leptin levels in male marathon athletes before and after the marathon run.

Leptin is a hormone produced by the adipocytes to regulate food intake and energy expenditure at the hypothalamic level. It is commonly accepted that the main determinants of leptin secretion are the net amount of body fat and the mean size of adipocytes. On the contrary, important vectors of energy flux in the organism, such as food intake and energy expended on exercise, are not thought to be regulators of that secretion. To understand whether leptin is regulated by an acute energy expenditure such as strenuous exercise, 29 male athletes who had trained for marathon running were studied before and after a marathon run and compared with 22 nonobese, age-, sex-, and body mass index (BMI)-matched sedentary controls. Controls and marathon athletes showed no differences in BMI or fat-free mass. Marathon runners showed a strong reduction in total fat mass (6.2 +/- 0.4 kg; 9.1 +/- 0.5% of body fat) compared with controls (12.3 +/- 0.5 kg; 16.1 +/- 0.5% of body fat; P < 0.05). This difference in body composition was paralleled by a mean serum leptin level that in marathonians (2.9 +/- 0.2 micrograms/L) was significantly (P < 0.05) reduced compared with that in controls (5.1 +/- 0.6 micrograms/L). It is remarkable that the ratio of leptin per kg body fat, showed a very good agreement between the two groups, 0.40 +/- 0.04 microgram/L.kg for controls and 0.46 +/- 0.03 microgram/L.kg for marathonians. In the two groups, leptin was correlated with both body weight, BMI, and fat mass (P < 0.001). The marathon trajectory was the standard 42.195 km accomplished in an average time of 3 h, 17 min, 7 s, with a calculated energy expenditure of over 2800 Cal. After the marathon run, a water imbalance occurred, with a significant decrease in body weight and an increase in serum albumin. A significant (P < 0.05) reduction in leptin values was observed after the run (2.6 +/- 0.2 micrograms/L) compared with before (2.9 +/- 0.2 micrograms/L), which was more relevant considering the relative hemoconcentration. In conclusion, 1) compared with sedentary subjects, leptin levels are reduced in male marathon runners in parallel with the relevant reduction in total body fat; 2) expressed as a ratio of leptin per kg body fat, no differences were observed between marathonians and controls; and 3) after an energy expenditure of 2800 Cal in the marathon run, a reduction in leptin levels occurred. Strong changes in energy expenditure may regulate serum leptin levels in man.

Growth hormone (GH) responses to the combined administration of GH-releasing hormone plus GH-releasing peptide 6 in adults with GH deficiency.

In recent years the health problems of adults with growth hormone deficiency (GHD) and the benefits of GH replacement therapy have received considerable attention. However, the reliability of conventional GH tests in the assessment of pituitary GH reserve in this group of patients is still controversial. In this study, we assessed GH secretion after the combined administration of GH-releasing hormone (GHRH) (1 microgram/kg iv) and GH-releasing peptide 6 (GHRP-6, 1 microgram/kg iv) in adult patients diagnosed with GHD by conventional GH testing, and correlate this response with insulin-like growth factor I levels. Twenty-one subjects (13 male, 8 female) with long-standing diagnosis of GHD aged 21-54 years were studied. In 13 subjects GH responses to GHRH plus GHRP-6 were markedly reduced (peak GH response < 10 mU/l), whereas in the remaining eight the response was greater (range 11-100 mU/l). In conclusion, our data show that combined administration of GHRH plus GHRP-6 elicited a significant increase in plasma GH levels in about 40% of patients diagnosed with GHD by conventional GH testing.

In vitro short-term effects of SMS 201-995, bromocriptine and TRH on growth hormone cell morphology from human pituitary adenomas.

This study reports, by immunocytochemistry, ultrastructure and morphometry, the in vitro effects of SMS 201-995 (10 nM), bromocriptine (1 microM) and TRH (10 microM) on the morphology of cells from two acromegalic patient adenomas containing immunoreactive growth hormone (GH). By electron microscopy, one tumor presented numerous large secretory granules (densely granulated growth hormone cell adenoma) while they were scarce and small in the other (sparsely granulated growth hormone cell adenoma); fibrous bodies could be seen in the specimen and in vitro. In the sparsely granulated growth hormone cell adenoma, TRH produced an increase in endoplasmic reticulum surface density compared to the other cultures. Bromocriptine increased the number and decreased the secretory granule diameters, while SMS 201-995 produced no significant changes in the same time. In the densely granulated growth hormone cell adenoma, the three substances increased the number of granules. TRH increased the mitochondrial volume density and endoplasmic reticulum surface density (with respect to the other cultures). SMS 201-995 decreased the mitochondrial and lysosome volume densities and endoplasmic reticulum surface density. We conclude that 1) TRH produces in cultured cells of both adenoma types an increase in cellular activity. 2) In cultured sparsely granulated growth hormone adenoma cells, bromocriptine has a stronger inhibitory effect than SMS 201-995. In cultured densely granulated growth hormone cells adenoma, bromocriptine has smaller inhibitory effect than SMS 201-995.

Variability in the presence of the metabolic syndrome in Type 2 diabetic patients attending a diabetes clinic. Influences of age and gender.

In this study, we have assessed age and gender-related influences on the presence of the metabolic syndrome (MS) and closely related variables in Type 2 diabetic patients attending a diabetes clinic. For this purpose, we have taken retrospective clinical and biochemical data from consecutive Type 2 diabetic patients (n = 291) and we have classified them by gender, age (with 55 and 70 years as cut-off levels) and having or not having the MS (using both the WHO and NCEP-ATP III MS definitions). A higher prevalence of adiposity and hypertension was present in the females. Males were characterized by higher uric acid and lower HDL-cholesterol and apoA(1) levels (two-way ANOVA considering jointly age and gender as main effects, P < 0.05 in every case). Overall the prevalence of NCEP-ATP III-defined MS was less frequent than WHO-defined MS (63.2% versus 81.1%, respectively). This difference was greater for males (42.1% versus 77.6%, respectively) than for females (75.5% versus 83.2% respectively). The kappa-coefficient for the concordance between both MS definitions was 0.46 for males and 0.72 for females in the first age band, 0.29 for males and 0.48 for females in the second age band and 0.24 for males and 0.51 for females in the third age band. Thus, this study reveals relevant differences in the application of WHO and NCEP-ATP III MS definitions in a clinic-based Type 2 diabetic population from Southern Spain. In addition, the data suggest that gender confers a specific influence upon some MS-associated features in Type 2 diabetic patients attending a diabetes clinic irrespective of age band.

Clinical use of octreotide in unresectable meningiomas. A report of three cases.

Unresectable meningioma is the cause of a serious clinical problem, for whom no satisfactory mode of treatment is currently available. Meningiomas are known to have receptors for diverse hormones. In this sense, somatostatin receptors were found in every meningioma specimen studied in a recent report. In addition, somatostatin has been able to inhibit meningioma cell proliferation in vitro. A brief report of clinical use of somatostatin long-life analogue octreoctide upon three patients diagnosed of unresectable meningioma is here presented. Doses used were gradually increased up to 1000, 900 and 1500 micrograms/24 h during 16, 6 and 7 weeks, respectively. There was an almost perfect tolerance to the drug (in one case a mild and transient abdominal discomfort and diarrhea could be observed). An important alleviation of headaches in 2 cases, and a transient but objective improvement in ocular movements and signs in 1 case were noticed. No change (neither growth nor shrinkage) was observed by CT scan at the end of treatment course in the three cases studied. In 1 case a partial resection was performed and tissue specimen was found to contain somatostatin receptors. Although in our very limited experience no brilliant results are presented, duration of treatment or doses used could have been insufficient. Data herein presented seem to support recently reported findings in which no growth inhibition of meningioma cells cultured in vitro by adding octreoctide to the medium was observed. So, in our opinion, clinical use of octreoctide on unresectable meningioma deserves further experience, that must be carried out with great caution.

A rare cause of acromegaly: ectopic production of growth hormone-releasing factor by a bronchial carcinoid tumor.

Ectopic production of growth hormone-releasing factor (GRF) is a rare cause of acromegaly. In addition to its production by gangliocytomas, both hypothalamic and intrasellar, in rare cases various neuroendocrine neoplasms produce the substance, with resultant growth hormone cell hyperplasia of the pituitary and acromegaly. We report an endocrinologically well-documented case of a GRF-producing bronchial carcinoid tumor in which the associated acromegaly was cured by lobectomy.

Role of glucocorticoids in the neuroregulation of growth hormone secretion.

Elevated glucocorticoid (GC) levels produce a marked impairment in somatic growth in both rodents and primates. In addition, GC play an important role in the regulation of growth hormone (GH) synthesis and secretion. Blunted GH response to stimulation tests in conditions of chronic exposure to excessive cortisol secretion or administration are well documented. In contrast, acute administration of GC to normal human subjects induces a transient increase in plasma GH levels. This dual action of GC on GH secretion is probably due to the fact that they act at different loci; i.e. in the regulation of GH transcription and GHRH and somatostatin receptors at the pituitary level as well as GHRH, somatostatin and GH receptor gene expression at the hypothalamic level.

Growth hormone releasing hexapeptide-6 (GHRP-6) test in the diagnosis of GH-deficiency.

Pituitary GH reserve can be assessed by substances that act directly at the somatotroph, such as GHRH, or by a variety of metabolic and neuropharmacological tests acting at the hypothalamic level, such as hypoglycemia, clonidine or L-Dopa. In order to evaluate GHRP-6 as a test of pituitary GH reserve, we studied GH responses of i.v. administered GHRP-6 in a group of short-statured children, as well as in a group of adults diagnosed with growth hormone deficiency (GHD) by conventional GH testing. Although we found that the GH response to GHRP-6 was lower in patients with GHD than in normal children, on an individual basis a considerable degree of overlap was observed between the two groups. In contrast, we found an almost complete blockade of GH response to either GHRP-6 or GHRH plus GHRP-6 in patients with pituitary stalk transection, suggesting that this could be a cost-effective test for the diagnosis of this condition. A similar finding was also obtained in GH response to the combined administration of GHRH plus GHRP-6 in patients with GHD of adult onset; this test may well prove valuable in the diagnosis of this clinical entity.

Xanthomas of the Achilles tendon: report of a bilateral case and review of the literature.

We report a case of bilateral Achilles tendon xanthoma as the first clinical manifestation of familial hypercholesterolemia. We review the literature and stress the need for orthopaedic surgeons to be familiar with this disease. An early diagnosis of this metabolic disorder is important to institute medical therapy and to alter the course of the disease before the onset of coronary artery disease.

[Long-acting and repeatable dose bromocriptine in the prolonged treatment of prolactinoma]. / Bromocriptina de acción prolongada y de administración repetible en el tratamiento prolongado de los prolactinomas.

BACKGROUND: The presentations of intravenous or depot bromocriptine (bromocriptine LA or long acting, Pariodel LA and bromocriptine LAR or long acting repeatable, Pariodel LAR) have improved the efficacy and the tolerance of oral bromocriptine. In contrast to bromocriptine LA, bromocriptine LAR may be repeatedly administered intramuscularly. METHODS: Five patients with macroprolactinoma and 4 with microprolactinoma were included in the study. A 50 mg bottle of bromocriptine LAR was administered intramuscularly every month, over a minimum period of 6 months. PRL was determined prior to the study, 1, 3, 7, 14, and 28 days following the initial dose of bromocriptine and thereafter with monthly periodicity. RESULTS: The PRL values decreased in those patients with macroprolactinomas following the administration of bromocriptine LAR; in 2 patients the monthly doses of bromocriptine LAR was increased to 100 mg since the month after the initial dose PRL remained greater than 200 ng/ml with serum RPL normalizing in most of the patients at 6 months of treatment. In two of the three patients who presented visual changes a clear improvement was observed and in all the cases a reduction in the size of the macroprolactinoma was found upon CAT control at 6 months. The PRL values also decreased in the patients with microprolactinomas following administration of bromocriptine LAR, although the response was not as homogeneous as in the patients with macroprolactinomas due to that at 6 months 2 patients continued to have slightly elevated serum PRL levels. The microadenoma persisted in the control CAT at 6 months except in one case. Local and general tolerance to bromocriptine LAR was very good. CONCLUSIONS: This study indicates good tolerance to bromocriptine LAR, being a therapeutic option in the treatment of macroprolactinomas.

[Treatment of macroprolactinomas with delayed bromocriptine. Effectiveness of a single intramuscular injection]. / Tratamiento de macroprolactinomas con bromocriptina retardada. Eficacia de una sola inyección intramuscular.

The aim of the present study was to evaluate the effectiveness and tolerance of a new pharmaceutical preparation of long acting bromocryptine (bromocryptine depot of L.A.), characterized by the slow release of bromocryptine during 4 or 6 weeks after a deep intramuscular injection. It was administered to 9 patients with macroprolactinoma, 7 of which had visual abnormalities. The tolerance of the drug was excellent, and only one patient had nausea within the first 24 hours. In all cases, PRL values fell between 40% and 97%. All patients with visual abnormalities, including 2 patients with cranial nerve palsy (IIIth and VIIth pairs) returned to normal or improved. In the CT controls carried out after 4 weeks of therapy a reduction in tumor size was observed in 7 of 9 patients. Two patients were operated through the transesphenoidal route, PRL being demonstrated in the immunohistochemical study of the resected specimen. Subsequently, all patients received oral bromocryptine therapy with perfect tolerance. The results show that parenteral long acting bromocryptine is an effective, well tolerated and convenient way to start the therapy of macroprolactinoma, even when severe visual abnormalities are present.

Neuropharmacological assessment of growth hormone secretion.

The biochemical diagnosis of individuals who are either deficient in growth hormone (GH) or who have alterations in the normal pattern of GH secretion is difficult. The uncertainty surrounding diagnosis reflects the lack of a thorough understanding of the physiology of GH secretion and of the hypothalamic hormones involved. At least three hormones are implicated: GH-releasing hormone (GHRH), somatostatin and the endogenous ligand of the GH secretagogue receptor, although the role that each plays in the release of GH is not clear from the available experimental evidence. In such a situation, most of the dynamic tests of GH secretory capacity in humans need to undergo a 'trial and error' process before being validated. The search for the 'gold standard' test of GH secretion is ongoing, and the combination of GHRH plus GH secretagogues will probably play an important role in future clinical diagnosis.

Arterial hypertension as a complication of prolonged ketoconazole treatment.

Two of 14 patients with Cushing's syndrome treated on a long-term basis with ketoconazole developed sustained hypertension. In both cases normal plasma and urinary free cortisol levels had been achieved following ketoconazole therapy, yet continuous blood pressure monitoring demonstrated hypertension 31 (patient 1) and 52 weeks (patient 2) after treatment. In patient 1, plasma levels of deoxycorticosterone and 11-deoxycortisol were elevated. In patient 2, in addition to an increase in both deoxycorticosterone and 11-deoxycortisol levels, plasma aldosterone values were raised, with a concomitant suppression of renin levels. Our findings show that long-term treatment with high doses of ketoconazole may induce enzyme blockade leading to mineralocorticoid-related hypertension.

A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing disease patients: key role of AVPR1b receptor and potential therapeutic implications.

CONTEXT: Desmopressin is a synthetic agonist of vasopressin receptors (AVPRs). The desmopressin stimulation test is used in the diagnosis and postsurgery prognosis of Cushing disease (CD). However, the cellular and molecular mechanisms underlying the desmopressin-induced ACTH increase in patients with CD are poorly understood. OBJECTIVE: The objectives of this study were to determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release and to elucidate the cellular and molecular mechanisms involved in desmopressin-induced ACTH increase in CD. DESIGN: A total of 8 normal pituitaries (NPs), 23 corticotropinomas, 14 nonfunctioning pituitary adenomas, 17 somatotropinomas, and 3 prolactinomas were analyzed for AVPR expression by quantitative real-time RT-PCR. Primary cultures derived from corticotropinomas, nonfunctioning pituitary adenomas, somatotropinomas, prolactinomas, and NPs were treated with desmopressin, and ACTH secretion/expression, [Ca(2+)]i kinetics, and AVPR expression and/or proliferative response were evaluated. The relationship between AVPR expression and plasma adrenocorticotropin/cortisol levels obtained from desmopressin tests was assessed. RESULTS: Desmopressin affects all functional parameters evaluated in corticotropinoma cells but not in NPs or other pituitary adenomas cells. These effects might be due to the dramatic elevation of AVPR1b expression levels found in corticotropinomas. In line with this notion, the use of an AVPR1b antagonist completely blocked desmopressin stimulatory effects. Remarkably, only AVPR1b expression was positively correlated with elevated plasma adrenocorticotropin levels in corticotropinomas. CONCLUSIONS: The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and postsurgery prognosis of CD. Furthermore, our data indicate that AVPR1b is responsible for the direct/exclusive desmopressin stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b antagonists as potential therapeutic tools for CD treatment.