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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adrenal gland requires a continuous supply of cholesterol for the biosynthesis of adrenal corticosteroids, which can be supplied by low density lipoprotein receptor-mediated uptake or local synthesis. The present study examined whether hypolipidemic therapy with a potent HMG CoA reductase inhibitor, simvastatin, compromises the adrenal response to ACTH stimulation in adult patients with heterozygous familial hypercholesterolemia. The adrenal response to a 36-h continuous ACTH infusion was determined at baseline and after 2 months of simvastatin treatment (40 mg, twice daily) in eight patients. Simvastatin reduced total and low density lipoprotein cholesterol levels by 36% and 45%, respectively. The time course of the increase in serum cortisol concentrations with continuous ACTH infusion was the same before and during simvastatin therapy, as were the rates of urinary excretion of free cortisol, 17-hydroxycorticosteroids, and 17-ketosteroids. Urinary excretion of mevalonate, which correlates with rates of whole body cholesterol synthesis, decreased from 3.8 +/- 0.42 (+/- SEM) mu,ol/24 h at baseline to 2.75 +/- 0.56 on simvastatin; no significant changes were seen in the urinary mevalonate levels before and after simvastatin therapy during ACTH stimulation. We conclude that the hypolipidemic effects of simvastatin in patients with heterozygous familial hypercholesterolemia are paralleled by a decrease in urinary mevalonate, but that the drug does not adversely affect ACTH-stimulated adrenal corticosteroid production.
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PMID:The influence of simvastatin on adrenal corticosteroid production and urinary mevalonate during adrenocorticotropin stimulation in patients with heterozygous familial hypercholesterolemia. 184 5

To examine the relationship between corticotrophin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OXT) we have studied the responses of adenohypophyseal and neurohypophyseal hormones to CRH in eight patients (age 26-64 years, six female) with suspected pituitary-dependent Cushing's syndrome during bilateral, simultaneous inferior petrosal sinus catheterization. Blood samples were taken from both petrosal sinuses and a peripheral vein before, and at 5-min intervals for 15 min after, an intravenous injection of 100 micrograms human CRH1-41. CRH increased sinus AVP concentrations in all eight patients and OXT concentrations in four of five patients studied. Although AVP concentrations often increased in both sinuses, the side of maximal AVP rise was termed side(max-AVP). CRH did not affect peripheral or petrosal sinus mean concentrations of LH, FSH, GH or TSH. While there was no change in mean peripheral concentrations of AVP, OXT, ACTH, ACTH precursors or prolactin after CRH, sinus concentrations of OXT, ACTH and prolactin on side(max-AVP) were markedly elevated over contralateral values. CRH did not increase mean sinus concentrations of ACTH precursors. In seven patients with either no radiological abnormality or the pituitary fossa or a small adenoma the mean ACTH precursor/ACTH ratio in blood sampled from all sites was 2.1 +/- 0.16 (mean +/- SEM, n = 50). In a patient with a large, locally invasive tumour the mean ACTH precursor/ACTH molar ratio was 32.1 +/- 1.3 (n = 12; P less than 0.001), suggesting that alterations in this molar ratio may reflect the biological properties of the tumour. The source of CRH-stimulatable AVP and OXT remains uncertain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Corticotrophin releasing hormone (CRH1-41) stimulates the secretion of adrenocorticotrophin, vasopressin and oxytocin but not adrenocorticotrophin precursors: evidence from petrosal sinus sampling in man. 184 86

Acute activation of the hypothalamic-pituitary axis with CRH has been reported to suppress gonadotropin secretion in women of reproductive age. In this study we specifically examined the effects of increasing doses of human CRH (hCRH) on circulating concentrations of ACTH, cortisol, and gonadotropins in five agonadal women, aged 46-65 (mean, 51.2) yr. The subjects had undergone either natural menopause or surgical removal of their ovaries at least 1 yr before study. Each woman was studied on four separate occasions and received either saline or hCRH at a dose of 0.5, 1.0, or 2.0 micrograms/kg BW through an indwelling iv catheter in a randomized, single blind fashion. During each experiment, five sequential iv injections of the same dose of hCRH or saline were administered at 90-min intervals over an 8-h period, followed by a 10-micrograms iv bolus of GnRH to test for pituitary gonadotropin responsiveness. Blood samples for measurement of LH, FSH, PRL, ACTH, and cortisol were obtained at 15-min intervals through an indwelling iv in the contralateral arm. Episodic pulses of LH secretion were analyzed using the Cluster computer program. Transverse mean LH, FSH, and PRL levels did not change with increasing hCRH doses. Mean (+/- SEM) LH pulse frequency [saline, 5.2 +/- 0.4/8 h; hCRH, (0.5 micrograms/kg), 4.8 +/- 0.2; hCRH (1 microgram/kg), 5.2 +/- 0.2; hCRH (2 micrograms/kg), 5.4 +/- 0.2] and amplitude [saline, 14.4 +/- 4.2 IU/L; hCRH (0.5 microgram/kg), 14.0 +/- 2.4; hCRH (1 microgram/kg), 15.8 +/- 2.5; hCRH (2 micrograms/kg), 17.2 +/- 2.9] did not differ among groups. Although the transverse mean levels of ACTH [saline, 8.7 +/- 0.2 pmol/L; hCRH (0.5 microgram/kg), 12.4 +/- 0.3; hCRH (1 microgram/kg), 11.5 +/- 0.4; hCRH (2 micrograms/kg), 12.8 +/- 0.4] did not change with increasing doses of hCRH, the duration of cortisol peaks after hCRH was longer and accounted for the increased transverse mean at each dose [saline, 152.8 +/- 4.1 nmol/L; hCRH (0.5 microgram/kg), 265.4 +/- 10.5; hCRH (1 microgram/kg), 329.7 +/- 14.3; hCRH (2 micrograms/kg), 348.2 +/- 12.1]. These findings suggest that ever larger doses of pulsatile hCRH continue to increase adrenal output of cortisol secondary to more sustained ACTH responses. However, hCRH-induced acute hypercortisolism does not alter gonadotropin secretion in agonadal women.
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PMID:Dose-response effects of exogenous pulsatile human corticotropin-releasing hormone on adrenocorticotropin, cortisol, and gonadotropin concentrations in agonadal women. 185 Nov 83

Ipecacuanha syrup induces emesis by an early peripheral (gastric irritant) action and a later central effect at the chemoreceptor trigger zone (CTZ). We have studied the responses of plasma AVP, ACTH and ACTH-precursors to early and late ipecacuanha-induced nausea in nine healthy male subjects. Symptom severity was assessed using a linear analogue scale. All subjects reported 'early' nausea (N1) with a latency of 16 +/- 2 min (mean +/- SEM) and eight subjects vomited. Six subjects experienced recurrent nausea (N2) (latency 106 +/- 10.4 min) of whom five also vomited. The interval between the cessation of N1 and the onset of N2 was 55 +/- 10.8 min (range 25-80 min). The severity of nausea at the onset of N1 or N2 was similar but the AVP and ACTH responses were highly variable. Thus, while mean plasma AVP concentrations increased during both symptom periods, in three subjects during N1 and in three subjects during N2 plasma AVP concentrations did not rise above the normal range, despite marked symptoms. No clear pattern of AVP response to distinguish early peripheral from late central ipecacuanha-induced emesis was demonstrated. Whilst mean plasma ACTH concentrations increased during both N1 and N2 there were no changes in mean plasma ACTH-precursor concentrations. Analysis of pooled data for N1 and N2 demonstrated direct correlations between the nausea score and the peak incremental plasma responses of either AVP or ACTH and, despite the variability, peak incremental concentrations of AVP and of ACTH were also correlated. The data indicate that there is no difference in the AVP responses to peripherally or centrally stimulated ipecacuanha-induced nausea.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The responses of arginine vasopressin and adrenocorticotrophin to nausea induced by ipecacuanha. 198 63

In the ovine fetus, adrenalectomy at 90-120 days gestational age (dGA) results in a gradual increase in basal concentrations of fetal plasma ACTH beginning at approximately 122 dGA. Bilateral adrenalectomy at 116-119 dGA also results in an increase in POMC mRNA in the fetal pituitary. It is not known whether both the paraventricular nuclei (PVN) of the hypothalamus and the anterior pituitary of the ovine fetus are responsive in late gestation to the removal of cortisol negative feedback. The purpose of this study was to determine the subsequent effect of fetal adrenalectomy at 118-121 dGA on the CRH mRNA content in fetal PVN and on POMC mRNA in the fetal anterior pituitary at 134 dGA. Mature Rambouellet-Columbia cross-bred ewes (n = 10), bred on a single occasion only and carrying fetuses of known gestational ages, were used. Both fetal adrenal glands were exposed via a retroperitoneal approach and removed [adrenalectomized (ADX); n = 5]. In control fetuses (CONT; n = 5) adrenal glands were exposed and isolated, but not removed. At 134 dGA, fetal plasma cortisol concentrations were significantly greater in CONT fetuses (7.2 +/- 2.5 ng/ml) than in ADX fetuses (mean +/- SD, 1.97 +/- 0.9 ng/ml; P less than 0.025). At 134 dGA the fetal PVN was removed by micropunching, and the anterior pituitary was separated from neurointermediate and posterior lobes after necropsy. Total RNA was prepared by the guanidium isothiocyanate-cesium chloride method and subjected to Northern analysis using specific cDNA probes to CRH and POMC. After autoradiography, quantification of mRNA was performed by scanning densitometry. Quantities of specific hybridization signal for POMC and CRH were normalized to the content of actin mRNA in each individual sample. RNA prepared from PVN exhibited a single specifically hybridizing band for CRH of approximately 1300 nucleotides. RNA prepared from anterior pituitary exhibited a single specifically hybridizing band for POMC at approximately 1300 nucleotides. Anterior pituitary POMC mRNA was significantly increased (P less than 0.025) in ADX fetuses (236 +/- 32% of CONT). CRH mRNA in PVN was greater in ADX fetuses than in CONT fetuses (P less than 0.05; mean +/- SEM, 179 +/- 21% of CONT). Adrenalectomy in fetal sheep significantly increased expression of CRH and POMC. We conclude that the increased levels of mRNA for CRH and POMC indicate that both the fetal PVN (CRH) and the anterior pituitary (POMC) are responsive to removal of the primary source of circulating glucocorticoid at this gestational age.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of fetal adrenalectomy on messenger ribonucleic acid for proopiomelanocortin in the anterior pituitary and for corticotropin-releasing hormone in the paraventricular nucleus of the ovine fetus. 203 73

Primary cortisol resistance (PCR) is a rare cause of hypercortisolism and usually does not produce clinical manifestations. This report describes primary cortisol resistance in a boy with isosexual precocity. A 6 7/12-yr-old boy had Tanner stage 3 pubic hair, accelerated linear growth, and advanced bone age (10 yr), but normal (for age) tests. There were no features of glucocorticoid excess. Serum androstenedione and dehydroepiandrosterone concentrations were 4.7 +/- 0.3 nmol/L (mean +/- SEM of four measurements; normal less than 1.2) and 13.5 nmol/L (single measurement; normal, 1.0-2.2), respectively. The serum testosterone concentration was 0.9 nmol/L (normal, less than 0.7), and FSH and LH were normal. Serum cortisol concentrations were 1590 +/- 110 nmol/L (normal, 190-630) and 580 +/- 60 nmol/L (normal, 50-410) at 0800 and 2000 h, respectively. Serum cortisol responded normally to insulin-induced hypoglycemia. Glucocorticoids and adrenal androgens were resistant to suppression by dexamethasone. The Kd of [3H]dexamethasone binding to the glucocorticoid receptors of mononuclear leukocytes was increased (6.4 +/- 0.8 nM; mean +/- SEM of four determinations; normal, 1.4-3.4; P less than 0.001), but the binding capacity was normal. This patient with isosexual precocity has PCR, as indicated by functionally abnormal glucocorticoid receptors and hypercortisolism without other clinical or biochemical manifestations of Cushing's syndrome. Excessive adrenal stimulation by ACTH caused increased secretion of both cortisol and adrenal androgens, and the latter caused the clinical manifestations. PCR should be considered in other male children with isosexual precocity or female children with heterosexual precocity.
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PMID:Primary cortisol resistance presenting as isosexual precocity. 210 34

The role of a high CRH level in normal pregnancy remains unknown. Therefore we evaluated the concentrations of CRH and the related hormones in patients with pregnancy-induced hypertension. Fourteen women with pregnancy-induced hypertension, aged 20-39, at 30-39 gestational week, were investigated. The control group consisted of 20 healthy pregnant women matched according to gestational age. Plasma CRH beta-endorphin-like immunoreactivity, cortisol, and human placental lactogen were measured by radioimmunoassay, ACTH by an immunoradiometric method. It was found that in hypertensive patients the mean CRH concentration was significantly higher (4257 +/- 840 (SEM) ng/l) than that in healthy pregnant women (1083 +/- 227 ng/l, p less than 0.001). The concentration of ACTH, however, was only slightly higher 65.0 +/- 6.0 vs 50.7 +/- 2.5 ng/l p less than 0.025, whereas the differences in beta-endorphin, cortisol and human placental lactogen were not significant. In both groups there was no correlation between the CRH level and those of the related hormones. In healthy pregnant women the CRH level closely correlated with gestational age (r = 0.76, p less than 0.001), whereas in patients with hypertension no such correlation was present (r = 0.29). We assume that the marked enhancement of plasma CRH in pregnancy-induced hypertension is probably caused by its decreased breakdown in ischemic placental tissue, but its increased synthesis in the placenta and its indirect counterregulatory hypotensive role must also be considered.
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PMID:Enhancement of plasma corticotropin-releasing hormone in pregnancy-induced hypertension. 214 45

In a randomized, double-blind, placebo-controlled study, we assessed the efficacy of an ACTH(4-9) analogue, Org 2766, in the prevention of cisplatin neuropathy in 55 women with ovarian cancer. The analogue was given subcutaneously in a dose of 0.25 mg (low dose) or 1 mg (high dose) per square meter of body-surface area before and after treatment with cisplatin and cyclophosphamide (75 and 750 mg per square meter every three weeks). The threshold of vibration perception was used as the principal measure of neurotoxicity. After four cycles of chemotherapy, the mean (+/- SEM) threshold value for vibration perception in the placebo group increased from 0.67 +/- 0.12 to 1.61 +/- 0.43 microns of skin displacement (P less than 0.0001). In the high-dose treatment group, there was no increase in the threshold value after four cycles (from 0.54 +/- 0.12 to 0.50 +/- 0.06 micron). After six cycles of chemotherapy, the threshold value was 5.87 +/- 1.97 microns in the placebo group (more than an eight-fold increase from base line), as compared with 0.88 +/- 0.17 micron (less than a twofold increase) in the high-dose treatment group (P less than 0.005). In the high-dose group, fewer neurologic signs and symptoms were recorded than in the placebo group. With the lower dose of the analogue, these protective effects were less prominent. No side effects were seen after treatment with Org 2766. The rates of clinical response to chemotherapy were similar in all groups. These results suggest that Org 2766 can prevent or attenuate cisplatin neuropathy without adversely affecting the cytotoxic effect of the drug.
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PMID:Prevention of cisplatin neurotoxicity with an ACTH(4-9) analogue in patients with ovarian cancer. 215 70

These experiments test whether the rapid inhibition of ACTH responses in dogs fits the criterion for fast feedback. The ACTH response to hypoglycemia was measured after infusion of vehicle or cortisol at a rate of 9 or 18 micrograms/kg.min beginning at the time of injection of insulin or after infusion of 18 micrograms/kg.min beginning 20, 30, or 60 min later. Plasma ACTH was increased from 30-90 min after insulin treatment in all experiments. The ACTH responses to hypoglycemia were inhibited by cortisol infusions of 9 or 18 micrograms/kg.min beginning at 0 min [mean ACTH from 30-90 min: after vehicle, 557 +/- 57 (+/- SEM); after cortisol, 221 +/- 20 and 201 +/- 48 pg/ml, respectively], but the overall responses were not significantly reduced by infusions beginning 20, 30, or 60 min after the injection of insulin. The latency of the inhibition was 30 min after the infusions beginning at 0 min and 40-50 min after cortisol infusions beginning at later times. The infusion of cortisol also significantly reduced basal ACTH; however, this inhibition was not significant until 40 min. In further experiments the ACTH response to insulin-induced hypoglycemia was measured after infusing 45 micrograms/kg cortisol over 2, 5, or 15 min at rates of 22.5, 9, or 3 micrograms/kg.min. These infusions caused suppression of plasma ACTH by 30 min, but there was no significant difference in the degree of suppression (mean ACTH from 30-90 min: after vehicle, 532 +/- 34; cortisol for 2 min, 223 +/- 34; cortisol for 5 min, 197 +/- 18; cortisol for 15 min, 181 +/- 36 pg/ml). Thus, the inhibition of stimulated ACTH secretion in the dog is dependent on the feedback signal occurring at the initiation of the stimulus, but is not related to the rate of increase in plasma cortisol.
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PMID:Fast feedback control of canine corticotropin by cortisol. 215 73

To investigate the adrenostatic potential of a nonhypnotic low dose etomidate infusion, we administered 0.03 mg/kg etomidate in a bolus injection, followed by constant infusion of 0.3 mg/kg.h for 24 h to 6 patients with severe Cushing's syndrome. The dose-response relationship also was determined in 15 normal subjects. Three groups of 5 received, respectively, doses of 0.03, 0.1, and 0.3 mg/kg.h etomidate for 5 h after an initial bolus dose of 0.03 mg/kg. The response to exogenously administered ACTH [0.25 mg ACTH-(1-24)], injected after the etomidate or control infusion, was determined in all normal subjects. In the six hypercortisolemic patients, serum cortisol concentrations decreased from 1374 +/- 436 nmol/L (mean +/- SEM) to 188 +/- 91 nmol/L after 11 h of etomidate infusion and remained low until the end of the infusion. Cortisol levels returned to pretreatment concentrations by 24 h. Excretion of urinary free cortisol decreased from 1180 +/- 196 to 185 +/- 66 nmol/day. In the normal subjects, administration of etomidate led to a dose-dependent decrease in serum cortisol from about 550 to 83 nmol/L, while 11-deoxycortisol rose from low or undetectable levels up to 346 nmol/L. In response to ACTH, cortisol levels rose in inverse proportion to the etomidate dose. It was, however, significantly reduced compared to normal saline infusion even after the lowest dose. Changes in aldosterone and corticosterone concentrations were similar to those in cortisol, and 11-deoxycorticosterone changed in a pattern similar to that of 11-deoxycortisol. Two of five normal subjects reported tiredness during the highest etomidate infusion. No other side-effects were noted. We conclude that iv administered etomidate in a low nonhypnotic dose reduces serum cortisol concentrations in a dose-dependent manner in both hyper- and eucortisolemic subjects. This study suggests that etomidate at a dose of 0.1 mg/kg.h or lower may be an effective strategy for the control of severe hypercortisolemia.
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PMID:Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cushing's syndrome and dose-response relationship in normal subjects. 215 85


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