An abnormality of the growth hormone/insulin-like growth factor-I axis in women with polycystic ovary syndrome due to coexistent obesity.

In order to evaluate the GH/insulin-like growth factor-I (IGF-I) axis in the polycystic ovary syndrome (PCO), 21 women aged 18-38 yr were studied. The GH responses to the GH-releasing hormone (GHRH), and plasma concentrations of IGF-I were measured in seven obese women with PCO, seven obese healthy controls without PCO, and in seven nonobese subjects. Total GH secretion, as expressed by the integrated GH response to GHRH, in PCO obese women (617.4 +/- 150 micrograms/L.min) and in obese women without PCO (327.1 +/- 161.4 micrograms/L.min) were lower than that in nonobese healthy controls (3181.4 +/- 644.3 micrograms/L.min, P less than 0.001 and P less than 0.001, respectively). Plasma concentrations of IGF-I in obese PCO women (199.5 +/- 39.1 micrograms/L), and in obese women without PCO (192.4 +/- 36.8 micrograms/L) were similar to the IGF-I levels in nonobese controls (224.3 +/- 33.2 micrograms/L). In obese women with and without PCO, a negative correlation was found between the body mass index and the peak GH responses to GHRH (r = -0.639, P less than 0.02) and between age and IGF-I levels (r = -0.520, P less than 0.05). These findings suggest that an abnormality of the GH/IGF-I axis in PCO women may be due to coexistent obesity.

Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men.

We investigated the effects of long-term testosterone replacement in hypogonadal and elderly men on lipids and lipoproteins. Twenty-two men with initial serum testosterone concentrations below 3.5 ng/ml took part in the study: 11 with hypopituitarism (1st group) and 11 otherwise healthy elderly men with low testosterone levels (2nd group). Testosterone deficiency was replaced by intramuscular injections of testosterone enanthate 200 mg every second week. Plasma levels of sex hormones, gonadotropins, SHBG, lipids and lipoproteins were determined before the treatment and after 3, 6 and 12 months of treatment. During the treatment serum testosterone and estradiol increased significantly, reaching normal levels. This was associated with a decrease in total cholesterol (from 225 +/- 16.9 mg/dl to 202 +/- 13.6 mg/dl after 6 months and 198 +/- 12.8 mg/dl after 1 year of testosterone administration, P < 0.0001 in men with hypoandrogenism associated with aging and from 255 +/- 12.1 mg/dl to 214 +/- 10.6 mg/dl after 6 months and 206 +/- 9 mg/dl after 1 year of treatment, P < 0.0001 in men with hypopituitarism) and LDL-cholesterol concentrations (from 139 +/- 12.5 mg/dl to 126 +/- 10.7 mg/dl after 6 months and 118 +/- 9.8 mg/dl after 1 year of testosterone administration, P < 0.0001 in men with hypoandrogenism associated with aging and from 178 +/- 10.3 mg/dl to 149 +/- 10.2 mg/dl after 6 months and 140 +/- 7.3 mg/dl after 1 year of treatment, P < 0.001 in men with hypopituitarism). However, no significant decrease in HDL-cholesterol levels or HDL2- and HDL3-cholesterol subfractions was observed. The effects of testosterone replacement therapy on lipids and lipoproteins were similar in both groups with different aetiology of hypogonadism. No side effects on the prostate were observed. The results of this study indicate that testosterone replacement therapy in hypogonadal and elderly men may have a beneficial effect on lipid metabolism through decreasing total cholesterol and atherogenic fraction of LDL-cholesterol without significant alterations in HDL-cholesterol levels or its subfractions HDL2-C and HDL3-C.

Early diagnosis of Nelson's syndrome.

Nelson's syndrome is a specific form of Cushing's disease treated by bilateral adrenalectomy, presenting with a deep hyperpigmentation caused by a pituitary adenoma (corticotropinoma). These ACTH-secreting tumors are frequently aggressive, so early diagnosis is of prime importance. We have studied 33 patients with Nelson's syndrome, 28 women and 5 men, aged 14-56 yr at the time of adrenalectomy and 16-58 yr at the time of Nelson's syndrome diagnosis (observed for 5-32 yr). Methods of examination included simultaneous adrenocorticotropic hormone (ACTH) and cortisol measurements during routine hydrocortisone replacement therapy, computed tomography (CT), pituitary magnetic resonance imaging (MRI), and visual field examination. The results obtained in a group of six patients diagnosed in the last 3 yr were compared with those obtained in a group of 27 patients examined before 1992. High plasma ACTH levels accompanied by normal serum cortisol concentration were characteristic for a late stage of the disease. Absolute temporal scotomas were an early finding. MRI, especially with the gadolinium enhancement, was superior to CT in demonstrating pituitary microadenomas in Nelson's syndrome. Thus, MRI diagnosis allowed for an early neurosurgical treatment of the patients with Nelson's tumors.

Cellular aspects of folate and antifolate membrane transport.

Folates--one carbon carriers--take part in the metabolism of purine, thymidylate and some amino acids. Internalization of these compounds employs several mechanisms of transport systems. Reduced folate carriers and folate receptors play the most important role in this process. The physiological role of these molecules in normal and neoplastic cells is described regarding changes in transport activity and connection of transport systems with resistance to antifolates and cancer development.

Synergistic effect of 5-fluorodeoxyuridine and quinazoline antifolates on murine leukemia self-cultured in vitro.

The effect of thymidylate synthase inhibitors, fluorodeoxyuridine (FdUrd) and its two sulphonamide derivatives was examined in the culture of murine leukemia cells -- 5178Y (parental subline) and its fluorodeoxyuridine resistant subline 5178Y/F. A synergistic effect of the antimetabolites on cell survival was observed on exposure of the culture of either line to a slightly inhibitory concentration of FdUrd (1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphogluta mate or 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphoglyci ne. This effect was accompanied by a marked reduction, in both cell lines of intracellular concentration of 5,10-methylenetetrahydro-pteroyl-polyglutamate, although its concentration in the resistant subline was 3 times as high as in the parental line. The inhibitory effect of combined drugs on the cellular pool of folates in 5178Y line depended also on the sequence of drug addition, whereas in the FdUrd resistant line this sequence was without any effect. The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by antifolates is intensified by a prior use of FdUrd.

Effect of combined inhibitors of thymidylate synthase-5-fluorodeoxyuridine and quinazoline antifolates on murine leukemia cells cultured in vitro.

The synergistic effect of two different inhibitors of thymidylate synthase-FdUrd and sulphonamide derivatives on murine leukemia cells-5178Y (parental subline) and 5178Y/F (its fluorodeoxyuridine resistant subline) in culture was examined. Upon the exposure of cultures from both lines to a slightly inhibitory concentration of FdUrd (1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphogluta mine or -glycine a synergistic effect of antimetabolites on cell growth was observed. This was accompanied by a marked reduction in intracellular concentration in both cell lines of 5,10CH2H4PteGlu; the intracellular concentration of 5,10CH2H4PteGlu(n) in the resistant subline was 3 times higher than in parental line. The inhibitory effect of combined drugs on the cellular pool of 5178Y of the two antimetabolites also depends on the sequence of their addition; however in the FdUrd resistant cell-line the dependence on the sequence of the addition was not observed. The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by antifolates is intensified by proprior use of FdUrd.

[Efficacy and tolerance of trimetazidine, a metabolic antianginal, in combination with a hemodynamic antianginal in stable exertion angina. TRIMPOL I, a multicenter study]. / Efficacité et tolérance de la trimétazidine, antiangoreux métabolique, en association avec un antiangoreux hémodynamique dans l'angor d'effort stable. TRIMPOL I une étude multicentrique.

OBJECTIVE: Assess the antianginal and anti-ischemic effect of trimetazidine in patients with stable exercise-induced angina insufficiently controlled with conventional antianginal drugs. PATIENTS AND METHODS: The study population included patients with coronarographically documented stable exercise-induced angina and no other serious concomitant condition. For inclusion, patients had to have two comparably positive treadmill exercise tests. Conventional antiangina drugs (long-acting nitrate derivatives, beta-blockers or calcium antagonists) were continued as was any other therapy having no effect on the ECG ST segment. The patients were given a 4-week regimen of trimetazidine (20 mg t.i.d.) after the second positive treadmill test and final inclusion. At the end of this period, a final exercise test was performed. The study population included 700 patients (mean age 54 +/- 8.4 years, range 32-71 years, 615 men, 85 women) who completed the entire treatment protocol. RESULTS: The main findings observed after 4 weeks of treatment with trimetazidine were: significant lengthening of the total duration of exercise (486.6 s versus 443.7 s, p < 0.01)), increase in total work (10.6 METS versus 9.4 METS, p < 0.01), significant lengthening of delay to 1 mm ST depression (389.9 s versus 337.8 s, p < 0.01) and of the delay to onset of angina (450.3 s versus 251.7 s, p < 0.01). The other results were a significant reduction in the number of daily episodes of angina (2.47 versus 3.66, p < 0.01) and a reduction in mean use of complementary trinitrine (1.8 versus 2.94, p < 0.01). CONCLUSIONS: Four weeks of treatment with trimetazidine in combination with conventional antiangina drugs leads to a longer delay to development of 1 mm ST depression (ischemia threshold), significant lengthening of total duration of treadmill exercise, increased total work, and longer delay to angina theshold. Clinically, there was a reduction in the mean number of episodes of angina and a reduction in the use of trinitrine.

[Antiphospholipid syndrome in valvular heart diseases, ischemic heart disease and vascular thrombosis]. / Zespól przeciwcial antyfosfolipidowych a wady zastawkowe, choroba niedokrwienna serca i zakrzepica naczyniowa.

The antiphospholipid syndrome (APS) leads to venous and arterial thrombosis, cardiac diseases, neurological, gastroenterological and dermatological complications. The role of antiphospholipid antibodies in genesis of thrombi by interaction with plasma clotting factors is well known. There is no evidence of their influence on valvular heart diseases or atherogenesis. This paper presents views and opinions about APS and related cardiovascular complications.

[Superiority of magnetic resonance imaging (MRI) over computerized tomography (CT) in diagnosis of hypopituitarism]. / Wyzszosc rezonansu magnetycznego (MRI) nad tomografia komputerowa (CT) w ujawnianiu przyczyn niedoczynnosci przysadki.

Hypopituitarism can be a result of various lesions of hypothalamus, pituitary stalk, or of the pituitary gland itself. The aim of the study was to assess the value of CT and MRI examinations in determination of the cause of hypopituitarism. Seventeen patients with hypopituitarism (9 women and 8 men) aged 22 to 61 years have been examined. In three cases growth deficiency was observed, 4 women had galactorrhoea, 4 patients had diabetes insipidus, 16 patients had supra-adrenal insufficiency, 14 had signs of hypogonadism and 10 hypothyroidism. In each case plasma concentrations of LH, FSH, PRL, TSH, alpha-subunit, ACTH before and after appropriate stimulation with TRH, metoclopramid, LH-RH, GRF or metyrapon were determined with RIA. Every patient was examined both with CT and MRI (0.5 T Toshiba MRT 50a). All 17 patients had abnormal MR images of hypothalamo-pituitary area, while only 10 of them had abnormalities in their CT scans. In remaining 7 patients the MRI revealed: three cases of congenital malformation of hypophyseal stalk, two cases of empty sella, one posttraumatic lesion of the stalk and one case of granulomatous infiltration of the stalk. We found MRI superior to CT in establishing the case of hypopituitarism.

[A case of pituitary stalk tumor diagnosed with magnetic resonance (MRI)]. / Przypadek guza szypuly przysadki rozpoznany dzieki zastosowaniu rezonansu magnetycznego (MRI).

Authors present a case of 28-year old female with anterior hypopituitarism and diabetes insipidus, with properly functioning anterior pituitary cells as showed by means of measuring pituitary hormones in response to neurohormones i.v. injections. Magnetic resonance imaging revealed neoplastic tissue in the pituitary stalk destroying supraopticohypophysial and paraventriculohypophysial tracts, as well as portal blood system, thus preventing release of vasopressin and these hypothalamic neurohormones from accessing anterior pituitary.

[Primary hyperaldosteronism suppressed after glucocorticoid administration]. / Pierwotny hiperaldosteronizm hamowany podawaniem glikokortykoidów.

Authors present a case of glucocorticoid suppressible hyperaldosteronism in 18 year old female. Unmeasurable low plasma renin activity and marked increase in aldosterone concentration was established. After administration of dexamethasone, normalization of aldosterone concentration and blood pressure has been observed.

Peroxynitrite reversibly inhibits Ca(2+)-activated K(+) channels in rat cerebral artery smooth muscle cells.

Peroxynitrite (ONOO(-)) is a contractile agonist of rat middle cerebral arteries. To determine the mechanism responsible for this component of ONOO(-) bioactivity, the present study examined the effect of ONOO(-) on ionic current and channel activity in rat cerebral arteries. Whole cell recordings of voltage-clamped cells were made under conditions designed to optimize K(+) current. The effects of iberiotoxin, a selective inhibitor of large-conductance Ca(2+)-activated K(+) (BK) channels, and ONOO(-) (10-100 microM) were determined. At a pipette potential of +50 mV, ONOO(-) inhibited 39% of iberiotoxin-sensitive current. ONOO(-) was selective for iberiotoxin-sensitive current, whereas decomposed ONOO(-) had no effect. In excised, inside-out membrane patches, channel activity was recorded using symmetrical K(+) solutions. Unitary currents were sensitive to increases in internal Ca(2+) concentration, consistent with activity due to BK channels. Internal ONOO(-) dose dependently inhibited channel activity by decreasing open probability and mean open times. The inhibitory effect of ONOO(-) could be overcome by reduced glutathione. Glutathione, added after ONOO(-), restored whole cell current amplitude to control levels and reverted single-channel gating to control behavior. The inhibitory effect of ONOO(-) on membrane K(+) current is consistent with its contractile effects in isolated cerebral arteries and single myocytes. Taken together, our data suggest that ONOO(-) has the potential to alter cerebral vascular tone by inhibiting BK channel activity.

[Ventricular fibrillation as a symptom of prosthetic valve dysfunction that was caused by thrombosis on mitral valve. Surgery or thrombolytic treatment?]. / Migotanie komór jako objaw dysfunkcji sztucznej zastawki spowodowanej skrzeplina na sztucznej zastawce mitralnej. Leczenie operacyjne czy trombolityczne?

We discuss the case of 49 years old woman with recurrent thrombosis of prosthetic mitral valve with ventricular fibrillation as the complication. For the first time thrombotic prosthetic valve Carbo Medics 33 had been removed and the new valve--Medtronic Hall 31 mm was implanted in the mitral position. After diagnosis of the repeated thrombosis on the replaced prosthetic valve, the patient refused the subsequent operation. The fully effective thrombolytic therapy was then performed. The patient was discharged from the Department and was asymptomatic 4 month follow-up.

Peroxynitrite is a contractile agonist of cerebral artery smooth muscle cells.

On reperfusion of ischemic tissue, a prolonged phase of vasoconstriction occurs, the mechanism of which is poorly understood. However, it is known that peroxynitrite (ONOO-) is formed during reperfusion. In this study the contractile properties of ONOO- were investigated in Wistar rat middle cerebral arteries. The effects of ONOO- on vessel diameter were dose dependent. Low-dose ONOO- (10 microM) caused vessels to constrict by 15%. At an intermediate concentration of 25 microM, the effect of ONOO- was variable, whereas at the highest concentration (100 microM), vessels underwent persistent dilation and became insensitive to the endogenous vasoconstrictor 5-hydroxytryptamine. At the single cell level, ONOO- caused cerebral artery smooth muscle cells to contract. Reduced, but not oxidized, glutathione completely inhibited the contractile action of ONOO- on single cells. Vehicle and decomposed ONOO- each had minimal effect on cell length. These data show that ONOO- is a contractile agonist of middle cerebral arteries, at the single cell and whole vessel levels, suggesting that formation of ONOO- may contribute mechanistically to ischemic brain injury during stroke. Moreover, relatively high concentrations of ONOO- result in vascular paralysis.

Transdermal 17 beta-estradiol combined with oral progestogen increases plasma levels of insulin-like growth factor-I in postmenopausal women.

In order to evaluate the effect of postmenopausal estrogen replacement therapy on the plasma levels of the insulin-like growth factor-I (IGF-I) 12 postmenopausal women aged 44 to 59 years were studied. The control group consisted of 15 healthy premenopausal women aged 20-44 years. In the postmenopausal women the plasma levels of IGF-I, gonadotrophins and sex hormones were determined before and after 3 and 6 months cyclic replacement therapy with transdermal 17 beta-estradiol (E2 100 micrograms patches applied twice weekly) combined with oral chlormadinone acetate (2 mg daily for 7 days in each cycle). Basal levels of estradiol (E2), IGF-I, dehydroepiandrosterone sulphate (DHEA-S), testosterone and androstenedione were lower, but gonadotropin levels were higher in postmenopausal than in premenopausal women. In all the women studied age was inversely correlated with IGF-I levels (r = -0.793, p less than 0.001) and with DHEA-S concentrations (r = -0.435, p less than 0.02). In postmenopausal women transdermal estradiol administration restored the circulating E2 levels to the early follicular range and increased the IGF-I levels (from 76.4 +/- 9.2 micrograms/l to 141.8 +/- 20.8 micrograms/l; p less than 0.01). Transdermal estradiol decreased gonadotrophin levels without changes in concentration of DHEA-S, testosterone, androstenedione and SHBG. In postmenopausal women before and during replacement therapy a positive correlation was found between estradiol and IGF-I concentrations (r = -0.439, p less than 0.01). These results suggest that cyclic replacement therapy with transdermal 17 beta-estradiol in combination with chlormadinone acetate given orally increase the plasma levels of IGF-I in postmenopausal women.

MRI versus CT in the diagnosis of Nelson's syndrome.

The purpose of the study was to evaluate the utility of MRI and CT in the diagnosis of Nelson's syndrome, i. e. pituitary tumours in patients bilaterally adrenalectomized for Cushing's disease. Thirteen patients, followed up for 5-29 years after adrenalectomy, were studied. In 6 of them CT and MRI revealed no changes in the pituitary gland. In the remaining 7 patients only three CT scans were suggestive of a pituitary adenoma. MRI studies with administration of gadodiamide confirmed the CT diagnosis of Nelson's tumour in 3 patients and disclosed microadenomas in a further 4 patients. Neurosurgical treatment in 4 patients confirmed the MRI findings. Additionally CT and MRI examinations were performed in 5 patients suspected of a recurrent Nelson's tumour 3-11 years after neurosurgery. MRI visualized recurrent adenomas in 3 patients that were not well seen by CT scans. In our experience MRI was more effective than CT in the diagnosis of Nelson's syndrome.

Effects of transdermal 17 beta-oestradiol combined with oral progestogen on lipids and lipoproteins in hypercholesterolaemic postmenopausal women.

OBJECTIVES: The purpose of the study was to evaluate the effect of transdermal 17 beta-oestradiol with oral progestogen on the plasma levels of lipids, lipoproteins and apolipoproteins in hypercholesterolaemic postmenopausal women. DESIGN: During 6 months of replacement therapy with transdermal 17 beta-oestradiol combined with oral progestogen, plasma lipids, lipoproteins and apolipoproteins after 3 and 6 months were measured and compared with pretreatment values by Student's t-test. SETTING: From January 1992 until September 1992 patients were diagnosed and treated in an out-patient clinic of the Department of Endocrinology Medical Centre for Postgraduate Education, Warsaw. SUBJECTS: The patients studied were 11 non-obese postmenopausal women with hypercholesterolaemia based on the World Health Organization criteria. INTERVENTIONS: Venous blood samples were obtained before and 3 and 6 months after the beginning of cyclic replacement therapy with transdermal 17 beta-oestradiol (E2 100 micrograms day-1 combined with oral chlormadinone acetate (2 mg day-1 for 7 days in each cycle). MAIN OUTCOME MEASURES: The antiatherogenic effect of transdermal oestrogen replacement therapy exerted by increased levels of high-density lipoprotein subfraction 2 cholesterol (HDL2-C) leading to the decrease of the total cholesterol level was anticipated. RESULTS: After 6 months of the treatment the concentrations of HDL2 cholesterol (HDL2-C) increased from 0.45 +/- 0.07 mmol l-1 to 0.73 +/- 0.03 mol l-1 (P < 0.05) but the levels of HDL3 cholesterol (HDL3-C) decreased from 1.15 +/- 0.06 mmol l-1 to 0.89 +/- 0.07 mmol l-1 (P < 0.05). The concentrations of total cholesterol decreased from 6.9 +/- 0.13 mmol l-1 to 6.2 +/- 0.2 mmol l-1 (P < 0.05). No changes were observed in the plasma levels of total triglycerides, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, VLDL triglycerides, apolipoproteins A-I and B. CONCLUSIONS: In hypercholesterolaemic postmenopausal women, transdermally administered 17 beta-oestradiol 100 micrograms daily in combination with oral chlormadinone acetate has a beneficial effect through raising the level of the antiatherogenic HDL2-C subfraction and decreasing the level of total cholesterol.

Influence of oxy-LDL and interleukin-8 on the platelet/PMNs adhesion and on chemotaxis-mediated induction of iNOS in neutrophils.

Selectin-P expression on platelets stimulated with thrombin was measured in terms of formation of "rosettes" according to Jungi et al. [9]. Selectin-P-mediated platelet/PMNs adhesion was inhibited by iloprost (IC50 = 5.0 nM), sodium nitroprusside (NaNP, IC50 = 0.93 microM) and interleukin-8 (IL-8, IC50 = 88 ng/ml), but activated dose-dependently by oxy-LDL (3-15 micrograms/ml). Glycogen-induced peritonitis in rats up-regulated the iNOS activity measured by the 2,3-[3H]-citrulline formation by the abdominal cavity PMNs up to 6 h after insult. Pretreatment with IL-8 (3 micrograms/300 g iv) decreased the amount of PMNs in ascites as well as its iNOS activity. Chemotaxis mediated iNOS gene expression of PMNs were measured by Northern blot hybridization. IL-8 (100 ng/ml) did not influence the PMNs iNOS gene expression induced by chemotaxis. We conclude that the decrease in iNOS activity by IL-8 involves postranslational modification of the enzyme activity.

Hyperinsulinaemia and decreased plasma levels of dehydroepiandrosterone sulfate in premenopausal women with coronary heart disease.

OBJECTIVES: The purpose of the study was to establish plasma levels of insulin, ovarian sex hormones and dehydroepiandrosterone sulfate (DHEA-S) and to evaluate their correlations with lipids in premenopausal women with angiographically demonstrated coronary stenosis. DESIGN: Differences in plasma levels of insulin, ovarian sex hormones, DHEA-S and lipids between groups were compared by analysis of variance. SETTING: From January 1993 until December 1993 patients were diagnosed in the Outpatient Clinic of the Department of Endocrinology Medical Centre for Postgraduate Education, Warsaw. SUBJECTS: Premenopausal women with normal oral glucose tolerance test (OGTT) results, with and without coronary stenosis were studied: 21 women after acute myocardial infarction with angiographically demonstrated coronary stenosis (women with CHD), and 14 women with chest pain, a positive exercise test without significant changes of coronary arteries on coronarography (women with normal coronarography, NC). The control group consisted of nine, healthy women with no risk factors for CHD. MAIN OUTCOME MEASURES: In premenopausal women with CHD, the decreased plasma level of DHEA-S and hyperinsulinaemia were anticipated. RESULTS: In women with CHD, the plasma levels of DHEA-S (926.5 +/- 83 ng mL-1) were significantly lower than those in women with NC (1375.7 +/- 181 ng mL-1) and in healthy controls (1984 +/- 127 ng mL-1), P < 0.02 and P < 0.001, respectively. The fasting insulin and insulin response to an OGTT in women with CHD and with NC was higher than in healthy subjects. A significant decrease of high-density lipoprotein (HDL) cholesterol, HDL-2 cholesterol and apolipoprotein A-I, and an increase of total cholesterol, low-density lipoprotein cholesterol C and apolipoprotein B levels in women with CHD compared to healthy controls were observed. A negative correlation between fasting insulin and the plasma levels of DHEA-S was established. CONCLUSION: In premenopausal women, hyperinsulinaemia and decreased DHEA-S levels may contribute to the development of coronary atherosclerosis.