Markedly reduced insulin-like growth factor-1 in the acute phase of myocardial infarction.

OBJECTIVES: We investigated whether insulin-like growth factor-1 (IGF-1) is reduced in the early phase of acute myocardial infarction (AMI) and whether such a decrease might influence prognosis. BACKGROUND: Insulin-like growth factor-1 protects against insulin resistance and apoptosis. Although insulin resistance has been reported in AMI, IGF-1 levels have not been investigated. METHODS: We measured serum IGF-1 in 23 patients with AMI within 24 h of symptom onset and in 11 matched controls. In the first 12 patients and controls, we also measured fasting insulin, diurnal growth hormone (GH) and insulin sensitivity (assessed as glucose disappearance or T/2 after an insulin bolus), and repeated IGF-1, insulin and GH after one year. In all patients, 90-day cardiovascular death, recurrent ischemia, reinfarction, revascularization and late malignant arrhythmias were assessed. RESULTS: The AMI patients versus controls showed markedly reduced IGF-1 (115 +/- 112 vs. 615 +/- 300 ng/ml, p < 0.0001) and slower T/2 (-0.98 +/- 1.5 vs. -2.57 +/- 1.0 mg/dl/min, p = 0.01). Low IGF-1 often preceded the rise of myocardial necrosis markers. Patients with 90-day events (n = 12) versus those without had lower IGF-1 (47 +/- 54 vs. 189 +/- 110 ng/ml, p < 0.0001). Acute phase GH and insulin concentrations did not differ significantly from controls. After one year, the patients' IGF-1 values had risen to 460 +/- 242 ng/ml (p = 0.1 vs. controls, p < 0.0005 vs. acute phase), whereas GH levels were lower (0.2 +/- 0.2 vs. 2.5 +/- 2.3 ng/ml, p = 0.01) and insulin levels higher (12.5 +/- 0.2 vs. 3.9 +/- 2.6 microU/ml, p < 0.0001) compared with controls. CONCLUSIONS: In the early phase of AMI, serum IGF-1 levels are markedly reduced and may contribute to adverse outcomes. Reduced IGF-1 preceding the rise of myocardial necrosis markers suggests a possible pathogenetic role. A compensatory increase in IGF-1 appears to occur by one year.

Serum prolactin response to thyrotropin-releasing hormone and metoclopramide in patients with prolactin-secreting tumors before and after transsphenoidal surgery.

Seven female patients with amenorrhea, galactorrhea, and hyperprolactinemia were examined before and after selective transsphenoidal removal of a PRL-secreting microadenoma. Before adenomectomy, metoclopramide (MCP; 10 mg orally) and TRH (200 micrograms iv) did not increase PRL blood levels in any of the seven patients. On the contrary, after oral administration of 10 mg MCP, a positive response was noted in a group of eight lactating women 3 days postpartum. After surgery, serum PRL level returned to normal in all patients. A positive PRL response to MCP and TRH was found in six of the seven patients 1 month after surgery. One patient, who had the lowest PRL level, failed to show a PRL increase after both stimuli. These findings indicate that hypothalamic pituitary function can be restored to normal after transsphenoidal removal of PRL-secreting pituitary tumors.

Postoperative evaluation of dopaminergic tone in prolactinoma patients. II. Plasma thyrotropin response to metoclopramide.

In 24 patients who had a PRL-secreting pituitary adenoma, diagnosed by pituitary dynamic function tests and CT scan, and confirmed at surgery, the TSH response to a dopamine (DA)-antagonist drug, metoclopramide (MCP), was studied pre- and postoperatively to elucidate whether altered DA tone was present and related to hyperprolactinemia. Preoperatively, a TSH response to MCP occurred in 18 patients. Plasma TSH levels did not increase after MCP in 5 patients who had a macroprolactinoma and in 1 patient with a microprolactinoma located just beneath the diaphragm of the sella turcica. Postoperatively, in all patients who had a prolonged clinical remission and normalization of PRL dynamic tests TSH did not respond to MCP (9 of 24 patients). In 4 patients who had normal or borderline PRL levels in the immediate postoperative period, the TSH response to MCP disappeared, but became evident later together with progressive elevation of PRL levels. TSH increases after MCP occurred in all patients who had abnormal PRL levels after surgery, except in 2 patients with a macroprolactinoma infiltrating the neighboring structures. In conclusion, these results confirm the existence of increased DA tone in patients with a prolactinoma. However, the presence of an increased TSH response to DA antagonist drugs could be masked in patients who had large tumors or tumors located just beneath the sellar diaphragm. The TSH test after MCP administration can readily detect increased DA tone in the postoperative period even when PRL levels remain slightly elevated or borderline.

Successful induction of ovulation and conception with combined gonadotropin-releasing hormone agonist plus highly purified follicle-stimulating hormone in patients with polycystic ovarian disease.

Five women (group A) with polycystic ovarian disease (PCOD) and sterility for at least 3 yr were treated for 1 cycle for ovulation induction with a combined regimen of GnRH agonist (GnRH-A) plus highly purified FSH. The patients received GnRH-A (Buserelin; 200 micrograms, sc, twice a day) for 6 weeks and then GnRH-A combined with FSH highly purified (2 ampules a day; 75 IU FSH and less than 0.11 IU LH in each ampule). Ovarian response was evaluated by plasma estradiol (E2) assay and ultrasound examination, performed daily. Furthermore, plasma FSH and LH levels were assayed 3 times a week. Once a follicle was considered sufficiently developed, the combined regimen was withheld, and 24-48 h later hCG (5000 IU, im) was given. The results are compared with those of 31 ovulatory cycles induced by im FSH highly purified (group B) in PCOD patients with the same FSH administration, clinical, and monitoring protocols. Ovulation was achieved in all cycles treated by GnRH-A plus FSH. Two singleton and a twin pregnancy resulted. Multiple follicular development occurred in all cycles. Plasma E2 levels were generally in the normal range. Echographic and endocrine features in the 2 groups were as follows. 1) basal ovarian volume and ovarian enlargement were similar. 2) Group A had a greater number of follicles than did group B (P less than 0.01), while E2 to number of follicles and E2 to ovarian volume ratios were greater (P less than 0.01) in group B. 3) The linear correlations between plasma E2 levels and ovarian volume were markedly different in groups A and B (P less than 0.01). The regression line for group B had a steeper slope than that for group A. This finding indicates that at a fixed ovarian volume plasma E2 levels were significantly lower in group A than in group B. We conclude that the combined GnRH-A and FSH regimen may constitute an alternative and promising tool for the induction of ovulation in patients with PCOD.

Insulin, C-peptide, androgens, and beta-endorphin response to oral glucose in patients with polycystic ovary syndrome.

We examined the effects of an oral glucose load on plasma insulin, androgens, and beta-endorphin (beta EP) concentrations in patients carefully selected as having polycystic ovary syndrome (PCOS) and normal glucose tolerance. Our aim was to verify whether insulin resistance is a common feature of PCOS and to differentiate the metabolic abnormalities related to PCOS from those associated with obesity. Plasma immunoreactive insulin (IRI), C-peptide (C-PR), testosterone, androstenedione, dehydroepiandrosterone sulfate, ACTH, and beta EP responses to a 3-h oral glucose tolerance test (OGTT) were evaluated in 10 obese (OB-PCOS) and 10 nonobese (NO-PCOS) patients with PCOS and in 7 obese and 7 nonobese ovulatory controls. OB-PCOS and NO-PCOS did not differ significantly from weight-matched controls in the IRI response, but had a significantly higher C-PR response in terms of mean postglucose load levels and mean incremental areas. During OGTT, mean plasma levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate declined in both PCOS groups as well as in controls, and no significant correlation between the plasma androgen and IRI or C-PR responses was found. The ACTH response in OB-PCOS and NO-PCOS was similar to that in controls, with a progressive decrease until 180 min. A similar decline in plasma beta EP was found in controls, whereas no change in plasma beta EP was observed in OB-PCOS and NO-PCOS. These findings indicate that independently of the presence of obesity, PCOS patients have enhanced insulin secretion in response to OGTT and show a peculiar pattern of changes in plasma beta EP.

Immune parameters in a population of institutionalized elderly subjects: influence of depressive disorders and endocrinological correlations.

Twenty-six institutionalized elderly subjects, selected as healthy according to the SENIEUR protocol, were compared to adult controls to establish correlations between affective disorders and immune abnormalities and to investigate underlying neuroendocrine mechanisms. After an extensive psychodiagnostic examination, 35% of the aged subjects were classified as depressed. Cutaneous delayed hypersensitivity tests showed reduced responses in the aged, but no correlation was found with the psychological status. Examination of the peripheral blood lymphocyte subsets revealed no imbalance in the percentages of CD3+, CD4+, CD8+ cells in the aged. A slight reduction in the CD4+/CD8+ cell ratio could however be detected in the non-depressed aged, as compared to adult controls. The CD4+/CD45R+ cell subset was reduced in non-depressed aged. The percentage of B lymphocytes was reduced in the aged, mostly in the non-depressed subjects. No changes were detected in the percent of OKDR+ cells. The percentage of CD16+ cells was found unchanged, while that of Leu7+ cells was significantly higher in the aged than in the adults and in the non-depressed than in the depressed aged. Leu7+ cell levels were negatively correlated with the depression score. On double labelling, the percent of CD16+/Leu7+ cells appears increased in the subgroup of depressed aged and positively correlated with age. Plasmatic and urinary cortisol levels were both positively correlated with depression score. Urinary cortisol level was higher in the depressed aged. These parameters, as well as plasmatic ACTH, beta-endorphin and urinary catecholamines, were not correlated with immune responses. Based on these findings, we recommend that the neuroendocrinological conditions should be taken into account when healthy subjects are examined in studies of immune senescence.

Impairment of lymphocyte activities in depressed aged subjects.

Lymphocyte activities were determined in a population of 26 institutionalized aged subjects, selected as healthy according to the SENIEUR protocol and previously reported to display immunological and endocrinological abnormalities correlated with depressive disorders. The lymphocyte mitotic response to PHA, which was reduced in aged as compared to adult subjects, was found to be significantly lower and negatively correlated with the depression score in the elderly subjects. In supernatants of PHA-stimulated lymphocyte culture from aged subjects, IL-2, IL-4 and gamma-IFN levels were very low and more severely affected in the depressed aged group. Each cytokine production was negatively correlated with age and depression score. NK activity was lower in the aged and it could be augmented by the addition of IL-2 or alpha-IFN, even though to a lesser extent than in the adult subjects. The nondepressed aged displayed higher levels of IL-2 inducible NK activity than the depressed aged subjects. IL-2 and alpha-IFN stimulated NK activities were negatively correlated with depression score. The present work indicates that the psychological status could affect lymphocyte reactivity in the aged. Given the relatively high frequency of affective disorders in these subjects, the psychological status should be considered in studies of immune senescence.

Platelet alpha 2-adrenoceptors and diurnal changes of platelet aggregability in hypertensive patients.

OBJECTIVE: To analyse whether platelets from hypertensive patients have an increased responsiveness to aggregating agents during morning hours and whether these changes might be related to concurrent changes in platelet membrane alpha 2-adrenoceptor characteristics, plasma catecholamine and cortisol levels, and blood pressure values. DESIGN AND METHODS: Blood samples from 14 mild-to-moderate essential hypertensive males were collected in the morning (0700-0900 h) and the evening (1900-2100 h) to determine platelet aggregability responses to adrenaline and ADP, platelet alpha 2-adrenoceptor number and binding affinity to [3H]-yohimbine, plasma catecholamines and cortisol. During the same day patients underwent 24-h ambulatory blood pressure monitoring. RESULTS: The lowest concentration of adrenaline required to induce biphasic aggregation was significantly lower in the morning than in the evening, indicating an increased morning platelet aggregability to adrenaline; the minimum ADP concentration inducing aggregation was similar in morning and evening samples. There were no significant differences between morning and evening samples in platelet alpha 2-adrenoceptor number and binding affinity. Plasma adrenaline, noradrenaline and cortisol levels were higher in the morning than in the evening, but no correlation was observed between hormonal changes and the morning increase in platelet sensitivity to adrenaline. Ambulatory blood pressure recording showed abrupt morning elevations in systolic and diastolic blood pressures over sleeping values. However, morning blood pressure readings were not significantly different from those recorded during the rest of the day and in the evening. The morning rise in mean arterial pressure displayed a significant inverse correlation with the increased platelet sensitivity to adrenaline that was observed during the same hours. CONCLUSIONS: The results indicate that the increased morning responsiveness to adrenaline that was observed in platelets obtained from hypertensive patients does not appear to be mediated by changes in the characteristics of platelet membrane alpha 2-adrenoceptors, but morning blood pressure elevations might play some role in inducing this platelet hyper-reactivity.

Serum levels and biochemical characterization of oestradiol-17 beta dehydrogenase in umbilical cord blood.

The properties of the enzyme oestradiol-17 beta dehydrogenase from human umbilical cord serum have beem compared with those of oestradiol-17 beta dehydrogenase present in the maternal peripheral blood. On the basis of studies on stability, specificity, optimum pH, rate of enzymic reaction and Km determinations it can be concluded that oestradiol-17 beta dehydrogenase in the umbilical cord arteries has an activity between 5 and 15 times higher than in the umbilical cord vein and about 65% of the activity of the enzyme present in the maternal peripheral blood. The present results strongly suggest that in pregnancy the enzyme oestradiol-17 beta dehydrogenase is elaborated not only by the placenta but also by the foetus.

Evidence that hydrogen sulphide can modulate hypothalamo-pituitary-adrenal axis function: in vitro and in vivo studies in the rat.

The gas hydrogen sulphide (H2S) is normally produced in large amounts in the central nervous system during the metabolism of sulphur-containing aminoacids. H2S was recently shown to influence long-term potentiation in the rat hippocampus; this finding suggested that the gas may act as a neuromodulator in the brain. We therefore tested the effect of the gas on the release of corticotropin-releasing hormone (CRH) from rat hypothalamic explants. CRH immunoreactivity in the incubation media was taken as a marker of peptide release. We found that the addition of NaHS to incubation media was consistently associated with a concentration-dependent decrease in KCl-stimulated CRH release, whereas basal secretion was unaffected. Increased endogenous H2S production may be also obtained using an indirect precursor of H2S formation, S-adenosyl-L-methionine (SAMe). The latter mimicked the effects of NaHS, since it reduced potassium-stimulated CRH release. In vivo, SAMe showed no effect on hypothalamo-pituitary-adrenal (HPA) function under resting conditions, but inhibited stress-related glucocorticoid increase.

Dopaminergic mechanisms regulating prolactin secretion in patients with prolactin-secreting pituitary adenoma. Long-term studies after selective transsphenoidal surgery.

Twenty-seven female patients with prolactin-secreting pituitary microadenoma, were studied at different intervals following selective transsphenoidal removal of the tumor. Postoperatively, all patients had normal prolactin (PRL) levels and regular menstrual cycles were restored. Sixteen of 27 patients showed positive responses to TRH and metoclopramide (MCP) within 1 mo after surgery. On the contrary, 9 patients showed evaluation of these patients demonstrated that normal neuroendocrine relationships were restored after several months since positive PRL responses to TRH and MCP could be elicited in such patients. The remaining 2 patients who showed basal PRL levels in the upper range of normal, exhibited negative responses to TRH and MCP. These patients had progressively to TRH and MCP exhibited 10-20 mo after surgery a normal decrease in PRL levels following administration of carbidopa plus L-Dopa. Negative responses to carbidopa plus L-Dopa were instead obtained in 6 postoperative patients with elevated PRL levels and negative responses to TRH and MCP. These results suggest that: 1) Hyperprolactinemia induced by "autonomous" pituitary adenomas increases hypothaLamic dopamine (DA) secretion, which in turn inhibits PRL secretion by nonadenomatous lactotropes. 2) Total selective removal of the microadenoma acutely decreases PRL concentration, but a functional inhibition of the normal lactotrope can persist for a period of few months following surgery in a certain number of patients. 3) Prolonged reduction of PRL concentration is accompanied to a normal DA tone with reestablishment of normal neuroendocrine relationships.

Enchancement of deficient pituitary response to luteinizing hormone releasing hormone in patients with primary amenorrhea.

Although the absence of pituitary response to the luteinizing hormone releasing hormone (LHRH) test has been considered proof of a lesion primarily localized at the pituitary level, the possibility exists that an absent pituitary response may represent only the effect of a chronic deficiency of hypothalamic secretion. To verify this hypothesis, 4 patients with primary amenorrhea, hypogonadotropic hypogonadism, and deficient or absent responses to a 25 mug LHRH rapid IV test were treated with 400 mug LHRH infused in 7 hours during each of 3 successive days. The finding that patients with deficient LH responses to a rapid LHRH test became normally responsive to a second equivalent test after a slow and prolonged treatment with the decapeptide suggests that, in these patients, besides a lesion at the pituitary level, a primary defect at the hypothalamic or higher centers may also be suspected.

Effect of estrogens on luteinizing hormone release in testicular feminization syndrome before and after gonadectomy.

The effect of exogenous estrogens on luteinizing hormone release was studied in three siblings with complete testicular feminization syndrome. Two subjects, 21 and 20 years old, were postpubertal. The third, 15 years old, was in the early pubertal stage. An estrogen provocation test was performed in which 20 mg of conjugated estrogens were administered intravenously and serum follicle-stimulating hormone and luteinizing hormone levels were assessed every 12 hours for 96 hours under basal conditions, on day 5 of an eight-day treatment with 0.2 mg/day ethinyl estradiol orally, and on day 5 of a subsequent eight-day treatment with 0.2 mg/day ethinyl estradiol and 120 mg/day cyproterone acetate orally. The first two tests were repeated one month after gonadectomy. During pregonadectomy treatments there was an overall luteinizing hormone fall. After gonadectomy, the two postpubertal subjects exhibited luteinizing hormone surges during ethinyl estradiol treatment -in one as a single peak and in the other as multiple peaks. A positive feedback effect was not induced in the youngest patient either before or after gonadectomy as in normal prepubertal and early pubertal females. The data suggest that testosterone or some other testicular factor inhibits estrogen induced positive feedback for luteinizing hormone. This inhibition mechanism acts independently of the testosterone cytosol receptor.

Four cases of pregnancy with low estrogen production due to placental enzymatic deficiency.

4 cases of normal pregnancies associated with low estriol excretion and resulting in healthy infants are described, in which by in vitro studies on the placentas a steroid 3-sulfatase deficiency was found in 3 cases and a lack of activity of the aromatizing system was found in the 4th case. A reduced activity of the aromatizing system was also shown in one of the cases affected by steroid 3-sulfatase defect. The placental 3 beta-hydroxysteroid dehydrogenase, delta 4,5-isomerase system was measured in 3 cases and results were normal. The repetition of the specific lack of steroid 3-sulfatase was observed in 2 successive pregnancies of the same patient (case T.C.). It is interesting to note that, at variance with other reports, this patient delivered 2 fetuses, both female.

[Male pseudohermaphroditism caused by 17-alpha-hydroxylase deficiency. Personal case reports and a review of the literature]. / Pseudoermafroiditsmo maschile da deficit di 17-alpha-idrossilasi. Casistica personale e revisione della letteratura.

Adrenal hyperplasia due to 17-alpha-hydroxylase deficiency is coupled with precocious hypogonadism, which causes pseudohermaphroditism in XY subjects and primary amenorrhea in XX subjects. The physiology of gluco- and mineral-corticoid adrenal activity, as well as the biosynthesis of gonadal steroids, is totally altered. We report two cases of XY subjects, identified as females, who came to our observation for primary amenorrhea and exhibited a hypertension with hypokaliemia. We also report a critical review of the literature, with a main attention to differential diagnosis and mineralcorticoid physiopathology, in order to contribute to the knowledge of normal adrenal function and of this enzymatic defect.

[Hyperandrogenism originating from the adrenal gland. Current observations on a clinical case]. / Iperandrogenismi di origine surrenalica. Recenti acquisizioni e descrizione di un caso clinico.

Recent reported data on hyperandrogenisms of suprarenal origin are presented and the case of a 26-year-old woman suffering from hirsutism and secondary amenorrhoea reported. Preoperative hormonal measurement showed very high Dehydroepiandrosterone (DHEA) levels (8,000 ng/ml) and a less dramatic increase in Androstenedione (A) and Testosterone (T), of 3.5 and 1.17 ng/ml respectively. Androgens were uniformly increased following administration of ACTH (250 micrograms for 3h for 2 days) and inhibited by intake of Desamethazone (8 mg/die for 3 days per os). ACTH values were low and failed to increase after insulin-induced hypoglycaemic stimulus. Pelvic echography and laparoscopy showed normal ovaries. A suprarenal scan revealed slight bilateral hyperplasia with irregular trace distribution on the left. CT showed a slight anomaly of the left gland which appeared spherical with convex margins. Unilateral suprarenectomy was carried out and the controlateral gland explored. The removed gland presented a histological picture of "micronodular focal hyperplasia". Treatment was begun with Prednisone and temporary remission of the clinical and biochemical pictures was achieved but one year after the operation androgen concentration was found again to be abnormally increased. The final diagnosis was "Bilateral suprarenal hyperplasia" with initial unilateral involvement. To conclude, this particular hyperandrogenism with ACTH levels at the lower limits of normal and with underlying primary suprarenal hyperplasia may be included among the better known suprarenal hyperplasia syndromes responsible for the Cushing and Conn syndromes.

Failure of bromocriptine to modify the response to metyrapone in normal subjects.

In order to study the role played by the dopaminergic system on the secretion of ACTH, we evaluated the influence of bromocriptine on the response to metyrapone. Levels of serum cortisol and 11-deoxycortisol and of urinary 17-OH-corticosteroids and 17-ketosteroids were measured both before and after stimulation with metyrapone in ten normal adults. This was followed by a week of administration with bromocriptine (5 mg/die) after which the above measurements were repeated. The results obtained did not differ significantly. Thus it may concluded that, under these conditions and at this dose, bromocriptine does not modify the response to metyrapone.