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Biomedical subjects

A R Hermus

Publications and source records attributed to A R Hermus.

At least 91 records · Page 5Linked to original sources
PubMed1989

Effects of inhibition of cholesterol synthesis by simvastatin on the production of adrenocortical steroid hormones and ACTH.

Simvastatin, a derivative of lovastatin, is a potent inhibitor of cholesterol biosynthesis and may interfere with steroid hormone production, for which cholesterol is required. In a single-blind, placebo-controlled study, 24 patients with severe primary hypercholesterolaemia (mean serum cholesterol +/- SD = 10.74 +/- 1.59 mmol/l) were treated with simvastatin 40 mg per day for 8 weeks. Before and after treatment, the following parameters were evaluated: basal levels of ACTH, cortisol, androstenedione, dehydroepiandrosterone and 17-hydroxyprogesterone; urinary excretion of free cortisol; the cortisol response after short-term infusion of ACTH; the ACTH and cortisol response during insulin-induced hypoglycaemia. Total serum cholesterol decreased by 35.0 +/- 8.1% (P less than 0.001) and low-density lipoprotein (LDL) cholesterol by 39.8 +/- 9.8% (P less than 0.001); high-density lipoprotein (HDL) increased by 9.2 +/- 11.1% (P less than 0.001). Basal levels of ACTH were higher after simvastatin (2.9 +/- 1.9 pmol/l vs 4.1 +/- 2.9 pmol/l; P less than 0.05) whereas basal levels of steroid hormones were not significantly changed. The excretion of free cortisol was unaltered. The peak cortisol after ACTH infusion was lower after treatment (0.87 +/- 0.23 mumol/l vs 0.78 +/- 0.10 mumol/l; P less than 0.05), but was unaltered during insulin-induced hypoglycaemia. We conclude that simvastatin lowers serum cholesterol without clinically relevant effects on the adrenocortical steroid hormone secretion and the hypothalamic-pituitary-adrenal axis.

Adrenal Cortex Hormones↗
PubMed1989

Predictive factors for initial cure and relapse rate after pituitary surgery for Cushing's disease.

Twenty-seven patients with Cushing's disease underwent transsphenoidal pituitary surgery. After the operation 16 patients were cured, and 11 remained hypercortisolemic. In the cured patients a significantly lower incidence of paradoxical responsiveness to TRH or to LRH was found preoperatively (1 of 16) than in the failures (6 of 11; P less than 0.02, by Fisher's chi 2 test). Furthermore, responsiveness of cortisol to CRH administration was significantly lower in the failures [maximum, 0.30 +/- 0.10 mumol/L (10.8 +/- 3.6 micrograms/dL) vs. 0.50 +/- 0.07 mumol/L (18.1 +/- 2.5 micrograms/dL) in the cured patients; P less than 0.05]. There were no differences in basal plasma cortisol levels, ACTH levels, or suppressibility by dexamethasone between the 2 groups. In the 16 patients who were cured initially, 4 patients relapsed after a mean period of 4 yr. These 4 patients had significantly higher basal cortisol levels postoperatively than those who remained in remission [0.14 +/- 0.03 mumol/L (5.1 +/- 0.8 micrograms/dL) vs. 0.04 +/- 0.01 mumol/L (1.4 +/- 0.3 micrograms/dL); P less than 0.01]. Cortisol responses to CRH after the operation positively correlated with the basal cortisol levels at that time (P less than 0.05, by Spearman's rank correlation test; r = 0.64), thus, the relapsing patients had higher cortisol responses to CRH than patients who stayed in remission [maximum response, 0.31 +/- 0.07 (11.2 +/- 2.5 micrograms/dL) vs. 0.12 +/- 0.03 mumol/L (4.3 +/- 1.1 microgram/dL), respectively; P less than 0.05]. We conclude that 1) patients responding paradoxically to TRH and/or LRH have a lower chance of being cured after pituitary surgery; and 2) patients with higher cortisol levels (greater than 0.10 mumol/L; 3.6 micrograms/dL) after being cured initially have a higher chance of recurrence of their disease.

Adenoma↗
PubMed1989

Single-dose response study of the somatostatin analogue octreotide in acromegaly.

The recommended dosage schedules for intermittent sc therapy with the somatostatin analogue octreotide in acromegaly vary widely, from 100 to 1500 micrograms daily. As acute administration of octreotide has been shown to predict its long-term response, we performed a single-dose response study in 5 patients with active acromegaly using doses of 25, 50, 100, 200 and 400 micrograms octreotide as well as a placebo injection. Plasma GH of 2 patients did not normalize after any of the injections, but nadir plasma GH overall gradually decreased as doses were increased from 25 to 400 micrograms. The 400 micrograms octreotide dose was superior with regard to the duration of plasma GH suppression to below 5 micrograms/l or 25% of the basal GH level, the mean GH as a percentage of the basal level over the first 4 and 8 h, and the integrated reduction of plasma GH during the first 4 and 8 h. The postprandial integrated insulin secretion during the first 3 h after injection of the octapeptide was significantly lower after 50, 100 and 400 micrograms than after the placebo injection. The mean plasma glucose as a percentage of the basal level during the first 8 h was significantly higher after octreotide after the 200 and 400 micrograms injections. Minor adverse events were seen in 2 patients after injection of 200 and 400 micrograms octreotide. Within the limitations of this single-dose response study it was concluded that injection of 400 micrograms octreotide yields the best results with regard to suppression of GH secretion, whereas the 50, 100 and 200 micrograms doses are superior to 25 micrograms, but do not differ from each other.

Acromegaly↗
PubMed1987

Hypotensive effects of ovine and human corticotrophin-releasing factors in man.

The haemodynamic effects of i.v. bolus injections of 100 and 200 micrograms ovine CRF and human CRF in man have been compared. Neither ovine CRF 100 micrograms nor human CRF 100 micrograms caused a significant change in blood pressure, although the pulse rate was increased in all the subjects tested. The mean maximum increase in pulse rate after human CRF was almost twice that after ovine CRF (21 vs 12 beats X min-1; p less than 0.05). After 200 micrograms ovine CRF in all subjects the diastolic blood pressure declined gradually from 77 mm Hg to a nadir of 67 mm Hg at 22 min (p less than 0.002). After 200 micrograms human CRF diastolic blood pressure fell from 78 mm Hg to a nadir of 61 mm Hg at 6 min (p less than 0.002); the fall after human CRF was significantly greater than after ovine CRF (p less than 0.05). After 200 micrograms ovine CRF there was a slight increase in pulse rate lasting for 6 min, and after 200 micrograms human CRF there was a marked (reflex) tachycardia for 30 min. Only after the highest dose of human CRF did a slight increase in systolic blood pressure occur. The haemodynamic effects of both doses of human CRF were accompanied by significant increases in plasma noradrenaline concentrations, which were significantly greater after the higher dose.

Adolescent↗
PubMed1987

Enhancement of the ACTH response to human CRH by pretreatment with the antiglucocorticoid RU-486.

The response of ACTH to an i.v. bolus injection of 100 micrograms human CRH at 09.00 h was investigated in five healthy men with and without pretreatment with the antiglucocorticoid RU-486 100 mg given orally 7 h before the injection of CRH. In all five subjects the plasma cortisol level immediately before CRH administration at 09.00 h was significantly higher after pretreatment with the antiglucocorticoid (17.1 vs 11.1 micrograms/100 ml). Despite this higher baseline cortisol level, in all subjects the maximal CRH-induced ACTH increase was more pronounced after RU-486 loading (delta max ACTH 39 vs 26 pg/ml). This observation proves that in man physiological concentrations of cortisol determine the response of the pituitary to CRH. Furthermore, the findings suggest reduced circulating glucocorticoid activity after administration of 100 mg RU-486, not completely compensated by an increase in plasma cortisol.

Adrenocorticotropic Hormone↗
PubMed1987

Coexistence of hypothalamic and pituitary failure after successful pituitary surgery in Cushing's disease?

The type of secondary adrenal failure, which occurs after successful pituitary surgery in Cushing's disease was studied using CRH administration. Eight patients with Cushing's disease were studied in the immediate postoperative period (9-18 days) of successful pituitary surgery. The results in these patients were compared with those in 13 healthy subjects, 7 patients with secondary adrenal failure of the pituitary type and 9 patients with secondary adrenal failure of the hypothalamic type. In all postoperative patients with Cushing's disease, except one, clear ACTH and cortisol responses occurred after CRH, demonstrating hypothalamic adrenal failure in these patients. This demonstration of hypothalamic adrenal failure after neurosurgery strongly argues against a pivotal role for endogenous CRH in the pathogenesis of Cushing's disease in these patients. The mean ACTH response to CRH in the postoperative patients with Cushing's disease was significantly lower than that in patients with adrenal failure of the hypothalamic type. This suggests the presence of pituitary failure in the postadenomectomy patients. In conclusion, this study provides arguments that the secondary adrenal failure after adenomectomy in Cushing's disease is caused by both hypothalamic and pituitary failure.

Adrenal Insufficiency↗
PubMed1987

Reciprocal inhibition of the long-acting luteinizing hormone releasing hormone agonist Buserelin and human chorionic gonadotropin in stimulating Leydig cell steroidogenesis.

The interference between human chorionic gonadotropin (hCG, Pregnyl, Organon 1500 IU i.m.) and the long acting LHRH agonist Buserelin (500 micrograms s.c.) in stimulating Leydig cell steroidogenesis was studied in 6 eugonadal men. Simultaneous administration of a single injection of the agonist (LHRH alpha) and hCG blunted the plasma testosterone response observed 24 h after LHRH alpha alone, enhanced the secretion of oestradiol without affecting 17-hydroxy-progesterone and aggravated the late steroidogenic block at the 17,20-lyase locus. As compared to hCG alone, combined LHRH alpha and hCG administration also decreased the maximum and 48 h testosterone increments and the testosterone production reflected by the area under the curve, enhanced the production of oestradiol and again aggravated the 17,20-lyase lesion. The data show that the long acting agonist LHRH alpha and hCG reciprocally inhibit their stimulatory effect on Leydig cell testosterone secretion probably by a suppressive effect of oestrogens on the conversion of C21- to C19-steroids. The mechanism underlying this reciprocal inhibition remains to be elucidated.

17-alpha-Hydroxyprogesterone↗
PubMed1987

The higher the growth hormone response to growth hormone releasing hormone the lower the response to bromocriptine and thyrotrophin releasing hormone in acromegaly.

In acromegaly a direct relationship has been demonstrated between GH responsiveness to TRH and to the dopaminergic agent bromocriptine (Br). Recent data show an inverse relationship between GH responsiveness to Br and to GH releasing hormone (GHRH), but not between the GH responses to GHRH and TRH. Thirty-one acromegalic patients, 18 women and 13 men (age 46.2 +/- (SD) 13 years) were studied. Four patients had been treated, but all still had active disease. The GH responses to GHRH (hpGHRH1-44, Bachem 100 micrograms i.v. bolus), TRH (Thyroliberin, Hoechst 200 micrograms i.v. bolus) and Br (Parlodel 5 mg orally) were assessed in most of the patients. The GH responses to GHRH showed a wide interindividual variation (delta GH 1-995 ng/ml), which correlated significantly with the basal GH levels (r = +0.85, P less than 0.0001, n = 31). GH increments in response to GHRH were inversely related to the responses to Br, i.e. the lower the GH increase after GHRH the greater the GH decrease after Br (r = -0.49, P less than 0.01, n = 30). This decrease correlated with the basal PRL level (r = +0.45, P less than 0.02, n = 29) and also the GH response to TRH (r = +0.66, P less than 0.0001, n = 30). An inverse correlation was also found between the GH responses to TRH and to GHRH (r = -0.43, P less than 0.02, n = 29). The data are consistent with the existence of GH-secreting adenomas which are more sensitive to GHRH and less to Br and TRH (pure somatotroph adenomas) and of mixed (lactotroph-like adenomas) responsive to TRH and Br but less responsive to GHRH.

Acromegaly↗
PubMed1987

Escape from dexamethasone-induced ACTH and cortisol suppression by corticotrophin-releasing hormone: modulatory effect of basal dexamethasone levels.

The response of ACTH and cortisol to corticotrophin-releasing hormone (CRH) after pretreatment with various doses of dexamethasone was investigated in five healthy subjects. The five subjects participated in six experiments. In each experiment 200 micrograms ovine CRH was administered as an i.v. bolus injection at 0900 h after pretreatment with respectively: (A) 1 mg dexamethasone orally at 2300 h in the evening before CRH injection, (B) 2 mg dexamethasone orally at 2300 h in the evening before CRH injection, (C) 4 mg dexamethasone orally at 2300 h in the evening before CRH injection, (D) 2 mg dexamethasone orally at 2300 h in the evening before CRH injection, followed by 2 mg dexamethasone orally 1 h before CRH, (E) no dexamethasone and (F) 1 mg dexamethasone orally 1 h before CRH injection. In spite of overnight suppression with a single dose of dexamethasone CRH elicited cortisol rises in all individuals (experiments A-C). Dexamethasone pretreatment in experiment D abolished the CRH-induced stimulation of the pituitary-adrenal axis. There was a significant and negative correlation between the basal dexamethasone levels (i.e. the dexamethasone levels immediately before CRH administration) in the experiments A-D and the areas under the individual ACTH (R = -0.62; P less than 0.01 by Spearman's rank correlation test) and cortisol (R = -0.81; P less than 0.001 by Spearman's test) curves, i.e. the lower the basal dexamethasone levels, the greater the rise in ACTH and cortisol levels after CRH administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1987

Growth hormone responses to the releasing hormones GHRH and GnRH and the inhibitors somatostatin and bromocriptine in TRH-responsive and non-responsive acromegalics.

In acromegalics, the percent peak GH responses to TRH (pTRH) and bromocriptine (pBr) are inversely related with those to GHRH, favouring the hypothesis that in the adenomas of some patients there is a preponderance of GH-producing cells with lactotrope-like characteristics, whereas in others pure somatotropes predominate. The aim of the present study was to investigate whether patients responsive to TRH with allegedly lactotrope-like tumours differ from those patients not responding to TRH with more somatotrope-like adenomas in their answer to the GH inhibitors Br and SRIH and the releasing hormones GHRH and GnRH. The present study demonstrates that the observed reciprocal relations between the GH responses to GHRH, TRH and Br are only present in acromegalics paradoxically responding to TRH (pGHRH vs pTRH -0.73, pGHRH vs pBr -0.60, pTRH vs pBr +0.54, P less than 0.0002-P less than 0.02, N = 20), not in TRH-non-responders (N = 10). In contrast, in these latter patients, not in the former, close relations were found between the percent peak GH responses to GnRH (pGnRH) and pGHRH (r = +0.81, P less than 0.005) and between pGnRH and the percent maximum GH decrements in response to SRIH (pSRIH) (r = +0.64, P less than 0.05). Expectedly, the GH response to Br in the TRH-responders was significantly higher than in the non-responders (75 +/- 4% vs 54 +/- 3%, P less than 0.02), although it was also substantial in the latter. The GH response to SRIH was remarkedly similar in both groups (64 +/- 5 vs 57 +/- 9%, P greater than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1987

CRH as a diagnostic and heuristic tool in hypothalamic-pituitary diseases.

The value of CRH as a diagnostic and heuristic tool in hypothalamic-pituitary diseases is discussed. Biochemical and clinical data support the concept that a single bolus injection of CRH can divide patients with secondary adrenal failure into those with hypothalamic and those with pituitary disease. The results of CRH tests in patients with isolated ACTH deficiency suggest a pituitary defect in the majority of patients with this rare disorder. CRH administration in patients with acromegaly and macroprolactinoma demonstrates that the response of the pituitary to CRH is not modulated by high levels of growth hormone or prolactin. CRH can also be used to study the type of the secondary adrenal failure due to exogenous administration of glucocorticoids or endogenous overproduction of cortisol by an adrenal adenoma. The CRH-ACTH axis in man is a highly conserved system with unique characteristics which are a prerequisite to assure vitally important stress reactions.

Acromegaly↗
PubMed1986

The corticotropin-releasing-hormone test versus the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome.

The diagnostic accuracy of the corticotropin-releasing-hormone (CRH) test was compared with that of the oral high-dose dexamethasone suppression test in the differential diagnosis of Cushing's syndrome. A false-negative response to CRH was present in 9% (2 of 22) of patients with pituitary-dependent Cushing's disease and to high-dose dexamethasone in 11% (2 of 18). All 3 patients with Cushing's syndrome due to an adrenal adenoma were unresponsive to both CRH and dexamethasone. The only patient with ectopic corticotropin secretion had a false-positive response of corticotropin to dexamethasone and no response of corticotropin to CRH. Simultaneous failure of both tests to indicate the cause of Cushing's syndrome did not occur in this series, except in 1 patient with Cushing's disease and overt macronodular hyperplasia. It is concluded that the diagnostic accuracy of the CRH test in patients with Cushing's syndrome is comparable to that of the high-dose dexamethasone test and that the highest discriminatory score in the differential diagnosis of Cushing's syndrome is achieved by using both a CRH test and a high-dose dexamethasone test.

17-Hydroxycorticosteroids↗
PubMed1986

Responsivity of adrenocorticotropin to corticotropin-releasing hormone and lack of suppressibility by dexamethasone are related phenomena in Cushing's disease.

The ACTH and cortisol responses to 100 micrograms ovine corticotropin-releasing hormone (CRH) in 19 consecutive patients with Cushing's disease were compared with those in 13 normal subjects. In 2 patients with Cushing's disease, plasma ACTH and cortisol did not increase after CRH administration. Compared to the normal subjects, maximal ACTH increments [135 +/- 25 (+/- SEM) vs. 42 +/- 6 pg/ml; P less than 0.001, by Wilcoxon's two-sample test] and maximal cortisol increments (17.7 +/- 1.8 vs. 9.4 +/- 1.1 micrograms/100 ml; P less than 0.01 by Wilcoxon's test) after CRH were significantly higher in the 17 CRH-responsive patients with Cushing's disease. In the normal subjects, there was a significant negative correlation between the basal cortisol level and the maximal ACTH (r = -0.65; P less than 0.05, by Spearman's rank correlation test) and cortisol (r = -0.95; P less than 0.001, by Spearman's test) responses to CRH. In contrast, in the CRH-responsive Cushing patients, there was no significant correlation between the basal cortisol level and the maximal ACTH (r = 0.10; P greater than 0.10, by Spearman's test) and cortisol (r = 0.14; P greater than 0.10, by Spearman's test) increments after CRH treatment. In the normal subjects, there was no significant correlation between the basal ACTH level and the maximal ACTH increments after CRH administration (r = -0.24; P greater than 0.10, by Spearman's test). Again in contrast, in the CRH-responsive Cushing patients, maximal ACTH increments after CRH treatment correlated positively with basal ACTH levels (r = 0.69; P less than 0.005, by Spearman's test). Moreover, in these patients, the maximal ACTH increments after CRH were positively correlated with the ACTH levels after suppression with higher and lower doses of dexamethasone. We conclude that in Cushing's disease, unlike in normal subjects, circulating cortisol is not the major modulator of ACTH and cortisol responses to CRH, and that in these patients, responsivity of ACTH to CRH and lack of suppressibility by dexamethasone are related phenomena.

Adolescent↗
PubMed1985

ACTH and cortisol responses to ovine corticotrophin-releasing factor in patients with primary and secondary adrenal failure.

The ACTH and cortisol responses to an intravenous bolus injection of 100 micrograms ovine CRF were studied in 19 patients with adrenal failure. In all eight patients with primary adrenal failure, plasma ACTH levels increased from a mean basal level of 1494 +/- 431 (SEM) pg/ml to peak value of 2601 +/- 1220 pg/ml at 10 min. In comparison with healthy subjects absolute ACTH increments after ovine CRF were significantly augmented in the patients with Addison's disease (P* less than 0.001), and the absolute ACTH responses after ovine CRF were positively correlated with the basal plasma ACTH levels. The 11 patients with secondary adrenal insufficiency could be subdivided into two groups: (A) those having little or no ACTH and cortisol response to ovine CRF (five patients) and (B) those having prolonged and pronounced ACTH responses with a biphasic pattern and a delayed second peak (six patients), followed in all patients by a marked cortisol increase. These data demonstrate that the CRF-test can discriminate between hypothalamic and pituitary causes of secondary adrenal failure.

Addison Disease↗
PubMed1985

Aromatase inhibition by delta 1-testolactone does not relieve the gonadotropin-induced late steroidogenic block in normal men.

Aromatase inhibition by delta 1-testolactone [(17 oxa-D-homo 1,4 androstanediene-3,17 dione) 500 mg twice daily for 10 days] in nine normal men lowered circulating estradiol (E2) levels by about 25%, enhanced the secretion of FSH, 17-hydroxyprogesterone (17-OHP), and to a lesser degree testosterone (T), but did not affect serum LH levels. Despite E2 lowering there was greater accumulation of 17-OHP than of T after 7 days of treatment, suggesting 17,20-lyase inhibition. Unexpectedly, administration of delta 1-testolactone almost halved the T response to hCG (Pregnyl, 1500 IU), but did not affect the 17-OHP response. Thus, E2 lowering by testolactone aggravated the hCG-induced 17,20-lyase block present before testolactone administration. Although the present data might suggest that estrogens do not play a role in the genesis of the hCG-induced late steroidogenic block, the results suggest that testolactone per se, in addition to its reported antiestrogenic action, inhibits 17,20 lyase.

17-alpha-Hydroxyprogesterone↗