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.

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.

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.

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.

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.

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.

Inhibition of growth hormone release after the combined administration of GHRH and GHRP-6 in patients with Cushing's syndrome.

OBJECTIVE: In patients with Cushing's syndrome there is a blunted GH response to all types of stimuli. Although inferential data point towards a direct perturbation in the pituitary exerted by glucocorticoids, the basic mechanism is unknown. His-D-TRP-ALA-TRP-D-Phe-Lys-NH2 (GHRP-6) is a synthetic hexapeptide which releases GH by a direct pituitary effect through receptors other than GHRH receptors. Furthermore, the combined administration of GHRH and GHRP-6 is able to induce a large GH discharge even in some pathological states such as obesity, associated with GH blockade. To gain further insight into the disrupted mechanisms of GH secretion, Cushing's syndrome patients were challenged with either GHRH, GHRP-6 or GHRH together with GHRP-6. A group of normal subjects was included for control purposes. DESIGN: Three different tests were undertaken: (a) GHRH 100 micrograms i.v.; (b) GHRP-6 100 micrograms i.v. and (c) GHRH plus GHRP-6 100 micrograms i.v. of each; administered to each subject on different days, at least 4 days apart. PATIENTS: Ten patients (8 women, 2 men) with untreated Cushing's syndrome, 9 Cushing's disease and 1 adrenal adenoma. Five healthy volunteers (3 women, 2 men) of similar ages served as a control group. MEASUREMENTS: Plasma GH levels were measured by immunoradiometric assay. RESULTS: The areas under the curve (AUC) of GH secretion (mean +/- SEM in mU/I/120 min) in the control subjects after each test were: GHRH, 1420 +/- 330; GHRP-6, 2278 +/- 290 and GHRH plus GHRP-6, 7332 +/- 592 (P < 0.05 vs each compound alone). The AUCs for Cushing's syndrome patients were: GHRH, 248 +/- 165; GHRP-6 530 +/- 170 and for GHRH plus GHRP-6, 870 +/- 258 (P < 0.05 vs GHRH alone). After the combined stimulus only one out of the ten patients with hypercortisolism showed a GH peak over 20 mU/I, while all the controls had a peak over 84 mU/I. CONCLUSIONS: GHRP-6 induced GH secretion as well as the GH discharge elicited by GHRH and GHRP-6 are considerably reduced in Cushing's syndrome patients. This suggests that the main impairment of GH secretion in that pathological state resides at pituitary level.

[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.

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.

Regulation of growth hormone secretion by the growth hormone releasing hexapeptide (GHRP-6).

Growth hormone (GH) secretion is regulated by a complex system of central and peripheral signals. Recently, a new GH-releasing hexapeptide (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) called GHRP-6 which specifically releases GH has been studied. In the present work the mechanism of action of GHRP-6 has been addressed in experimental animal models as well as in obese subjects. GHRP-6 releases GH independently of the hypothalamic factors GHRH and somatostatin and is a powerful GH releaser in obesity.

Growth hormone releasing hormone priming increases growth hormone secretion in patients with Cushing's syndrome.

OBJECTIVE: In patients with Cushing's syndrome, decreased growth hormone (GH) secretion is observed though the basic mechanism is unknown. In states of chronic deficiency of hypothalamic growth hormone releasing hormone (GHRH) release, a blunted GH response to exogenous GHRH has been reported; such impairment can be partially normalized by repetitive GHRH administration (priming). In order to clarify whether a deficit in hypothalamic release of GHRH is the basis of the decreased GH secretion in patients with Cushing's syndrome, GHRH plus pyridostigmine tests were undertaken, both before and after GHRH priming. DESIGN: GHRH (200 micrograms/day as a single s.c. injection) was given daily over 7 days. Two pyridostigmine (120 mg p.o.) plus GHRH (100 micrograms i.v.) tests were performed before and after priming to assess GH response. PATIENTS: Eight patients (seven women, one man), with untreated Cushing's syndrome (six Cushing's disease, one autonomous bilateral adrenal hyperplasia, one adrenal adenoma), were studied. MEASUREMENTS: Plasma GH levels were measured by immunoradiometric assay. RESULTS: GHRH plus pyridostigmine-induced GH release was impaired in patients with untreated Cushing's syndrome (mean peak 5.2 +/- 1.4 mU/l, area under the curve (AUC) 472 +/- 96). Repetitive administration of GHRH over 7 days partially restored the GH response to the second pyridostigmine-GHRH test (mean peak 15.0 +/- 2.1 mU/l. AUC 1016 +/- 104), both P < 0.05. All of the eight Cushing's syndrome patients studied presented a higher GHRH plus pyridostigmine-induced GH secretion after priming. CONCLUSIONS: Repetitive administration of GHRH increases the pyridostigmine-GHRH-induced GH secretion in patients with Cushing's syndrome. This suggests that impaired hypothalamic release of GHRH is a contributing factor to the decreased GH secretion observed in chronic hypercortisolism.

[Results of trans-sphenoidal surgery for the treatment of acromegaly]. / Resultados de la cirugía transesfenoidal en el tratamiento de la acromegalia.

UNLABELLED: During the past 17 years (1972-89) 55 transsphenoidal surgery (TSS) interventions were performed in our Hospital in 53 cases of acromagaly (2 cases underwent surgery twice). RESULTS: 22 were cured (40%); 15 partial efficacy (27%) and 18 negative efficacy (33%). Mean GH values (ngr/ml) before surgery were: Cured cases 15.8 + 12.9 (p = 0.0015). Basal GH values above 40 ngr/ml obscure the prognosis of TSS in acromegaly. Cure was perfectly achieved in smaller size hypophysis adenomas (Hardy Grade land 11 in CT scan). The complications in the early post-surgery were rare and transient. Chronic sequelae due to TSS occurred in 7 cases (13.5%), as complete or partial anterior hypophysis failure. TSS is the treatment of choice of acromegaly in our environment, however a significant number of cases do not achieve cure and need to complete treatment with hypophyseal radiotherapy.

[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.

Evaluation of the pituitary-adrenal axis before, during and after pituitary adenomectomy. Is perioperative glucocorticoid therapy necessary?

Under the supposition that ACTH secretion will be compromised by surgical trauma, patients with pituitary adenomas undergoing transsphenoidal adenomectomy are frequently given corticoids, even though this therapy is controversial. We studied 10 patients with pituitary adenomas whose adrenocortical function was sufficient prior to surgery. The ACTH and cortisol levels rose significantly during surgery in all of these patients. Five patients completed a two-year postoperative follow-up period and their ACTH and cortisol values remained within normal limits. It may be that patients undergoing transsphenoidal surgery for pituitary adenomas do not need perioperative glucocorticoid treatment, since the hypophyseal-adrenal axis does retain its integrity.

In vitro effects of ketoconazole on corticotrope cell morphology and ACTH secretion of two pituitary adenomas removed from patients with Nelson's syndrome.

The direct effects of ketoconazole on the secretion of ACTH by human pituitary adenoma cells from 2 patient with Nelson's syndrome were studied in vitro. Stereologically quantified, intracellular changes affect the surface density of the endoplasmic reticulum (it decreased by 73%), the volume density of the secretion granules (it decreased by 49%), and the volume density of lysosomes (it decreased by 67%). The hormone released in the culture medium decreased depending on the doses of ketoconazole used; 10 mumol/l decreased ACTH levels by 31%. These data show that ketoconazole induce marked changes on corticotrope morphology and ACTH secretion in pituitary cells obtained from patients with Nelson's syndrome.

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.

Rapid improvement of visual defects with parenteral depot-bromocriptine in a patient with a non-functioning pituitary adenoma.

The management of non-functioning pituitary adenomas with bromocriptine is controversial, and surgical treatment is usually prescribed when the visual field is affected. Here we report, what we believe to be the first case of a patient with a non-functioning pituitary adenoma who experienced normalization of visual field defects and a substantial improvement in visual acuity after the parenteral administration of depot-bromocriptine. The patient's tolerance to the drug was excellent. The results of the immunohistochemical study of the surgically removed tumor were negative for PRL, GH, LH, FSH, TSH and ACTH. In our opinion, the use of depot-bromocriptine may represent an alternative to surgery in patients with non-functioning pituitary adenomas associated with visual lesions.

Contrasting features of insulin dependent diabetes mellitus associated with neuroectodermal defects and classical insulin dependent diabetes mellitus.

The Wolfram, or DIDMOAD, syndrome is a rare congenital disease that is associated with diabetes insipidus, insulin dependent diabetes mellitus of an early onset, bilateral optic atrophy and deafness. Urological disorders are usually present as well. We have studied nine patients belonging to five different families. All of the family members were HLA typed (including DR), and islet cell as well as antinuclear antibody determinations were carried out. Although individuals with insulin dependent diabetes mellitus are very prone to have either HLA-DR3 or -DR4 antigens, none of our patients had DR3 antigens and only one was DR4 positive. On the other hand, three of our patients were typed as HLA-DR2 positive. This antigen is uncommon in classical insulin dependent diabetes. In one of the families, the affected siblings did not share the same HLA haplotype. Islet cell and antinuclear antibodies were not found in any of the cases and six of the patients had a small, but significant, insulin secretory reserve. On the basis of some of the clinical features it was also possible to further distinguish between the DIDMOAD syndrome and the classical insulin dependent diabetes mellitus. The differences encountered between classical and DIDMOAD insulin dependent diabetes mellitus--the presence/absence of HLA linkage, HLA-DR2, -DR3 and -DR4 associations, islet cell or antinuclear antibodies, the tendency to ketosis and diabetic retinopathy--indicate that their etiopathogenies are triggered by distinct mechanisms.