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Biomedical subjects

D L Loriaux

Publications and source records attributed to D L Loriaux.

At least 199 records · Page 11Linked to original sources
PubMed1985

Central kappa- and mu-opiate receptors mediate ACTH-release in rats.

The control of ACTH secretion by opiates seems to involve stimulatory and inhibitory pathways, since opiate agonists and antagonists are capable of releasing ACTH in conscious rats. To elucidate the role of different opiate receptors in the control of ACTH release, rats were treated with receptor-selective opiate agonists and antagonists. The mu-opiate agonists, morphine and (D-Ala2, MePhe4, Gly5-ol)enkephalin, and the benzomorphan kappa-opiate agonists, MR 2034 and MRZ 2549, both stimulated ACTH release after central or peripheral injection. The effects of morphine, but not those of MR 2034, were blocked by a low dose of naloxone (50 micrograms/kg) and by the mu-receptor antagonist, beta-funaltrexamine. A 20 times higher dose of naloxone also blocked the effects of the kappa-agonist. Our data suggest that both mu- and kappa-opiate receptors are involved in the stimulation of ACTH release in rats.

Adrenocorticotropic Hormone↗
PubMed1985

Effects and pharmacokinetic properties of the rat/human corticotropin-releasing factor in rhesus monkeys.

The biological effects and pharmacokinetic properties of the recently sequenced rat/human corticotropin-releasing factor (r/hCRF) were evaluated in the rhesus monkey and compared to those of the previously studied ovine corticotropin-releasing factor (oCRF). An iv bolus of 0, 0.1, 1, 10, and 100 micrograms/kg r/hCRF and 1 microgram/kg oCRF were given to rhesus monkeys (four to five tests per dose). Serial blood samples were drawn before and up to 180 min after the injection for determination of plasma immunoreactive (IR) ACTH, cortisol, and IR-r/hCRF or IR-oCRF concentrations. Mean arterial blood pressure and heart rate were monitored. r/hCRF stimulated ACTH and cortisol secretion in a dose-dependent fashion. Its potency was similar to that of oCRF. r/hCRF, however, had a shorter half-life and a 3-fold higher MCR than oCRF. A dose-dependent decrease in the MCR of r/hCRF was observed, which may indicate a saturation of the clearance mechanisms. Significant decreases in mean arterial blood pressure, increases in heart rate, and a profound facial flush occurred at the dose of 100 micrograms/kg r/hCRF. We conclude that r/hCRF stimulates ACTH and cortisol secretion in a nonhuman primate with a potency similar to that of oCRF. The peptide has marked hypotensive effects at high doses and is cleared 3 times more rapidly than oCRF.

Adrenocorticotropic Hormone↗
PubMed1985

Morphine inhibits the pituitary-adrenal response to ovine corticotropin-releasing hormone in normal subjects.

To determine the locus of opiate modulation of ACTH secretion, 11 normal subjects were given ovine corticotropin-releasing hormone (CRH) 30 min after receiving either placebo or morphine sulfate. Plasma ACTH, cortisol, arginine vasopressin (AVP), epinephrine, norepinephrine, and CRH were measured 30 min before and up to 150 min after CRH administration. Morphine blunted the ACTH response for the first 60 min and cortisol response for the first 90 min after CRH administration. Morphine did not lower arginine vasopressin or catecholamine levels. To determine whether morphine's effect on ACTH and cortisol was due to a direct action on the corticotroph cell, dispersed rat pituitary cells were perifused with medium containing 1 microgram/ml morphine sulfate or medium alone. Morphine had no effect on the ACTH response of these cells to 10 nM CRH pulses. Similarly, morphine had no effect on ACTH production by dispersed rat pituitary cells in monolayer culture in response to 90- and 180-min incubations with 5 nM CRH. We conclude that morphine blunts the early response of the pituitary gland to CRH in vivo. Based on the lack of a direct effect of morphine on rat pituitary cells in vitro, we postulate that morphine given in vivo may modulate the pituitary ACTH response to CRH through other suprapituitary factors.

Adrenocorticotropic Hormone↗
PubMed1985

Pituitary-adrenal responsiveness to corticotropin-releasing hormone in patients receiving chronic, alternate day glucocorticoid therapy.

We examined the responsiveness of the pituitary-adrenal axis to ovine corticotropin-releasing hormone (oCRH) in 14 women with systemic lupus erythematosus receiving chronic, alternate day glucocorticoid therapy with prednisone. Testing was done twice and in a random order (at 2000 h) on the day when the steroid was taken (12 h after the last dose) and on the day when no glucocorticoid was administered (36 h after the last dose). Plasma ACTH and cortisol responses were markedly blunted on the day of treatment and mildly blunted on the day off treatment compared to those in normal subjects. Altered metabolic clearance of exogenous oCRF was not responsible for this difference, since the plasma disappearance curves of immunoreactive oCRH were similar on both days. The degree of suppression was dependent on the dose of prednisone, and the amount of cortisol secreted during the oCRH test was directly proportional to the logarithm of the concurrent plasma ACTH level. Thus, the cortisol response to ACTH was normal in all patients. These data suggest that the blunting of responsiveness to oCRH on both days of testing represents prednisolone suppression of the corticotroph cell. Despite this, the adrenal glands retain normal responsiveness to ACTH, suggesting that moderate decreases in daily ACTH secretion are compatible with sustaining normal adrenal function. Hence, the site of the mild suppression of the hypothalamic-pituitary-adrenal axis during chronic, alternate day treatment with glucocorticoids is central, whereas the adrenal glands appear to remain functionally unaffected.

Adolescent↗
PubMed1985

Growth hormone responses to continuous infusions of growth hormone-releasing hormone.

The pattern of GH secretion during a continuous 4-h iv infusion of 1 microgram/kg.h GH-releasing hormone (1-44)-NH2 (GHRH-44) or saline was examined in 15 adult men. There was prompt release of GH beginning within 20 min of starting the GHRH-44 infusions, reaching peak GH levels of 43 +/- 11 (+/- SE) ng/ml within 60-90 min. This is similar to the peak GH level reached in men after a single 1 microgram/kg GHRH iv bolus dose (34 +/- 8 ng/ml). GH levels then fell progressively, but did not return to baseline during the GHRH infusions. After GHRH infusions, the response (delta) to a 1 microgram/kg GHRH bolus dose was markedly attenuated (delta GH, 2.7 +/- 0.9 ng/ml) compared to the response (delta GH, 23 +/- 3 ng/ml) after saline infusion. Dispersed rat pituicytes perifused with medium containing 10 nM GHRH-44 responded with an initial rapid rise in GH secretion, followed by a progressive decline, and after 150 min of continuous GHRH exposure, the response to pulses of an equal or higher (100 nM) GHRH concentration was blunted. These results indicate that the peak response to GHRH infusions is similar to that of maximally effective bolus doses; during infusions, the GH response is not sustained; and immediately after GHRH infusions, the response to previously effective bolus doses is reduced. These phenomena could reflect either receptor-mediated desensitization, the depletion of rapidly releasable GH stores, or both. A counterregulatory rise in hypothalamic somatostatin secretion is not necessary to produce these effects, since the same phenomenon occurs in vitro and in vivo.

Adult↗
PubMed1985

Effects of pulsatile administration of growth hormone (GH)-releasing hormone on short term linear growth in children with GH deficiency.

To assess the efficacy of GH-releasing hormone (GHRH) in the treatment of GH deficiency, we measured the effects of pulsatile iv GHRH administration on GH secretion, plasma levels of somatomedin-C (SmC), and short term linear growth (as determined by lower leg measurements) in seven GH-deficient children in a placebo-controlled study. Either GHRH, at a dose of 1 microgram/kg (seven patients), or 0.9% saline (NS; four of these patients) was given iv every 3 h for 9-12 days; all patients also received GH for a similar period. Lower leg length was measured every 3 weeks before and after each treatment. GHRH was more effective than placebo in accelerating linear growth (P less than 0.05). The responses, however, were heterogeneous; four of the children responded with accelerated growth, and three did not. Two of the children who failed to grow had no increase in plasma GH or SmC during GHRH administration, and one had an attenuated GH response. The four children who grew had induction of pulsatile GH secretion [mean peak GH, 10.4 +/- 1.3 (+/- SEM) ng/ml after GHRH vs. 1.5 +/- 0.5 ng/ml after NS; P less than 0.05] and elevation in SmC levels (maximum, 0.5 +/- 0.1 U/ml during GHRH vs. 0.19 +/- 0.05 during NS; P less than 0.01). The lower leg growth velocity during GHRH treatment (2.8 +/- 0.2 mm/3 weeks) was greater than their own basal rate (0.6 +/- 0.2 mm/3 weeks; P less than 0.01) or their growth during placebo treatment (0.4 +/- 0.2 mm/3 weeks; P less than 0.01). Thus, repeated administration of GHRH stimulated increases in GH and SmC in some but not all GH-deficient children. The growth response appears to be related to the magnitude of the GHRH-stimulated rise in GH levels. GHRH increases short term linear growth in some children with GH deficiency and holds promise as an alternative to GH as a form of therapy in these patients.

Adolescent↗
PubMed1985

Sensitivity of cortisol and adrenal androgens to dexamethasone suppression in hirsute women.

To test the hypothesis that adrenal androgen secretion is more easily suppressed than is cortisol secretion by glucocorticoids, we examined the dose-response relationship for suppression of serum dehydroepiandrosterone (DHA), DHA sulfate (DHAS), testosterone, and cortisol by dexamethasone. Nine hirsute women received daily doses of dexamethasone, starting with 0.1 mg and increasing by 0.1-mg increments every 4 weeks, until the cortisol response to ACTH was reduced to 20% or less of the response before treatment. Serum hormone levels were measured at each dexamethasone dose before and after iv administration of 25 U synthetic ACTH. Although low doses of dexamethasone caused a similar suppression of basal cortisol, DHA, and DHAS levels, ACTH-stimulated DHA levels were suppressed to a greater extent than ACTH-stimulated cortisol levels. Higher dexamethasone doses did not result in a significant difference between the degree of cortisol and adrenal androgen suppression, as near-maximal suppression occurred for all three hormones. Maximal suppression of basal testosterone levels occurred at or below the dexamethasone dose of 0.3 mg. We conclude that the adrenal androgen secretory capacity is more sensitive to suppression by dexamethasone than is the adrenal cortisol secretory capacity. Furthermore, glucocorticoid therapy for hirsutism need not achieve complete cortisol suppression to effect a major reduction in adrenal androgen levels.

Adolescent↗
PubMed1985

Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486.

A patient with Cushing's syndrome due to ectopic ACTH secretion was treated successfully with the new glucocorticoid antagonist RU 486 [17 beta-hydroxy-11 beta-(4-dimethylamino phenyl) 17 alpha-(1-propynyl)estra-4,9-dien-3-one]. This compound is a 19-nor steroid with substitutions at positions C11 and C17 which antagonizes cortisol action competitively at the receptor level. Oral RU 486 was given in increasing doses of 5, 10, 15, and 20 mg/kg . day for a 9-week period. Treatment efficacy was monitored by assessment of clinical status and by measuring several glucocorticoid-sensitive variables, including fasting blood sugar, blood sugar 120 min after oral glucose administration, and plasma concentrations of TSH, corticosteroid-binding globulin, LH, testosterone-estradiol-binding globulin, and total and free testosterone. With therapy, the somatic features of Cushing's syndrome (buffalo hump, central obesity, and moon facies) ameliorated, mean arterial blood pressure normalized, suicidal depression resolved, and libido returned. All biochemical glucocorticoid-sensitive parameters normalized. No side-effects of drug toxicity were observed. We conclude that RU 486 may provide a safe, well tolerated, and effective medical treatment for hypercortisolism.

Adrenocorticotropic Hormone↗
PubMed1985

Adrenocorticotropin-stimulated adrenal androgen secretion in anorexia nervosa: impaired secretion at low weight with normalization after long-term weight recovery.

Adrenal androgen secretion is decreased in patients with anorexia nervosa. To assess the reversibility of the decreased secretion with recovery of body weight, we measured ACTH-stimulated adrenal androgen levels at different stages of recovery. Basal plasma GH and somatomedin-C levels also were measured, because both have been proposed as potential stimuli for adrenal androgen secretion. When studied at low body weight [58 +/- 3% (+/- SEM) ideal BW], women with anorexia nervosa had decreased ACTH-stimulated levels of dehydroepiandrosterone (DHA), DHA sulfate (DHAS), and androstenedione and decreased DHA to cortisol, DHAS to cortisol, and androstenedione to cortisol ratios compared to normal women. Women who had recently completed a refeeding program (within 2-4 weeks, 81 +/- 2% ideal BW) had an increased somatomedin-C level compared to low weight patients, but similar ACTH-stimulated adrenal androgen levels. Long term weight-recovered women (86 +/- 4% ideal BW, recovery for more than 6 months, with resumption of menses), however, had significant increases in ACTH-stimulated DHA and DHAS levels and DHA to cortisol and DHAS to cortisol ratios, and their hormone levels and ratios were not different from those in normal women. GH levels fell during weight recovery, although the values in the three patient groups did not differ significantly. We conclude that the recovery of adrenal androgen secretion while GH levels were falling provides evidence against a direct effect of GH as a stimulus for adrenal androgen secretion. The recovery of somatomedin-C before the recovery of adrenal androgens, however, and the positive correlation between plasma somatomedin-C and the integrated level of plasma DHAS (r = 0.50; P less than 0.02) are consistent with the hypothesis that somatomedin-C is a stimulus for adrenal androgen secretion.

Adrenal Glands↗
PubMed1985

Short term, low dose estradiol accelerates ulnar growth in boys.

We previously described a biphasic dose-response curve for ethinyl estradiol on short term growth in patients with Turner's syndrome. To investigate whether there is a similar phenomenon in boys, we measured the 3-week ulnar growth velocity (TUG) after administration of different doses of estradiol to five prepubertal or early pubertal boys. Basal TUG was determined initially. Subsequently, the boys received a 4-day iv infusion of estradiol at each of three doses (4, 20, and 90 micrograms/day) given double blind in a randomized sequence. TUG was determined before and after each infusion and was allowed to return to baseline before giving the second and third infusions. Mean TUG increased from 0.45 +/- 0.11 (+/- SEM) to 1.38 +/- 0.51 mm/3 weeks after the 4 micrograms/day infusion (P less than 0.05), from 0.49 +/- 0.11 to 1.0 +/- 0.4 mm/3 weeks after the 20 micrograms/day infusion (P = NS), and from 0.46 +/- 0.1 to 0.84 +/- 0.12 mm/3 weeks after the 90 micrograms/day infusion (P = NS). The mean serum estradiol level was 10 +/- 2.3 pg/ml during the 4 micrograms/day infusion, 16 +/- 2.3 pg/ml during the 20 micrograms/day infusion, and 96 +/- 12 pg/ml during the 90 micrograms/day infusion. Mean serum somatomedin-C levels were significantly higher only after the 20 and 90 micrograms/day estradiol infusions. We conclude that low dose estrogen can stimulate ulnar growth in boys and may play a role in the male pubertal growth spurt.

Adolescent↗
PubMed1985

Testolactone treatment of precocious puberty in McCune-Albright syndrome.

Current medical and surgical therapies of precocious puberty in McCune-Albright syndrome are often unsatisfactory. We used an aromatase inhibitor, testolactone, to treat precocious puberty in a girl with McCune-Albright syndrome. This child was unresponsive to 28 weeks of treatment with the long-acting agonist of LRH, D-trp6-pro9-NEt-LRH. During testolactone therapy, menses ceased, bone age advancement and height velocity diminished, and plasma oestradiol levels were suppressed. Serum gonadotrophin levels remained in the prepubertal range. Testolactone may be an effective therapy of precocious puberty in girls with McCune-Albright syndrome.

Androstenedione↗
PubMed1985

NIH conference. Clinical applications of corticotropin-releasing factor.

Ovine and human corticotropin-releasing factors (CRF) have similar potencies in causing adrenocorticotropic hormone (ACTH) and cortisol secretion in normal humans. Using long-acting ovine CRF (1 microgram/kg body weight as an intravenous bolus), we tested patients with Cushing's syndrome, adrenal insufficiency, and psychiatric conditions with mild hypercortisolism. Over 95% of hypercortisolemic patients with a pituitary adenoma responded with increases in plasma ACTH and cortisol concentrations; patients with the ectopic ACTH syndrome had no ACTH or cortisol responses; patients with ACTH-independent hypercortisolism of adrenal origin had low or undetectable plasma ACTH concentrations before and after CRF without any cortisol response. The differences in responses of patients with adrenal insufficiency of primary, pituitary, or suprapituitary type likewise suggest value of the CFR test in their differential diagnosis. The responses in the psychiatric patients should permit differentiation between Cushing's syndrome and hypercortisolism of psychiatric origin.

Adenoma↗
PubMed1984

The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushing's syndrome.

We investigated the effect of exogenous corticotropin-releasing factor on plasma levels of ACTH and cortisol in 13 patients with ACTH-secreting pituitary adenomas (Cushing's disease) and in 9 patients with other forms of Cushing's syndrome. In all patients with Cushing's disease, ovine corticotropin-releasing factor, given intravenously as a bolus injection (1 microgram per kilogram of body weight), caused a further increase in the already elevated levels of ACTH and cortisol. Successful transphenoidal adenomectomy was followed as early as one week after surgery by normalization or near-normalization of the ACTH and cortisol responses to corticotropin-releasing factor. On the other hand, patients with the ectopic ACTH syndrome, who also had high basal plasma concentrations of ACTH and cortisol, had no ACTH or cortisol responses to corticotropin-releasing factor. This difference in responsiveness between these two patient groups cannot be explained on the basis of different metabolic clearance rates of exogenous corticotropin-releasing factor, as shown by similar disappearance curves of immunoreactive corticotropin-releasing factor from plasma. Patients with Cushing's syndrome of adrenal origin who were hypercortisolemic during testing had undetectable plasma levels of ACTH and no ACTH or cortisol responses to corticotropin-releasing factor. We conclude that stimulation of the pituitary-adrenal axis with corticotropin-releasing factor may be useful in differentiating pituitary from ectopic causes of Cushing's syndrome.

ACTH Syndrome, Ectopic↗
PubMed1984

The effects of prolactin on rat ovarian function.

Hyperprolactinemia has been associated with several reproductive disorders. To investigate whether hyperprolactinemia directly affects rat ovarian function, we examined the ovarian histopathology and the activities of the four ovarian enzymes 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17-hydroxylase (17-OH), 17,20-desmolase (17,20-D) and aromatase in hyperprolactinemic rats and controls. Hypophysectomized, gonadotropin-treated Fisher rats were made hyperprolactinemic by isografting pituitary glands under the kidney capsule. The control animals received skeletal muscle. The ovaries were resected, pooled according to prolactin levels and microsomal enzyme activities were measured from each pool. Prolactin (PRL) levels were 344 +/- 23 ng/ml in the hyperprolactinemic rats and 18 +/- 5 ng/ml in the controls (p less than 0.001). Estradiol concentrations were 609 +/- 47 pg/ml in the hyperprolactinemic animals and 56 +/- 13 pg/ml in the controls (p less than 0.001). Ovarian and uterine weights were significantly higher in the hyperprolactinemic rats (p less than 0.02). Ovarian histopathology demonstrated benign polycystic transformation in the hyperprolactinemic animals. Hyperprolactinemia had no effect on 3 beta-HSD, but was associated with significant decreases in the 17-OH, 17,20-D and aromatase activities when compared to controls (p less than 0.001). We conclude that prolactin has a direct effect on rat ovarian function which appears to be independent of changes in gonadotropin secretion.

3-Hydroxysteroid Dehydrogenases↗
PubMed1984

Direct effect of the luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH on rat testicular steroidogenesis.

The luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH (LHRHa) inhibits rat testicular testosterone secretion. To determine whether LHRHa decreases serum testosterone concentrations solely by inhibiting gonadotropin secretion or, in addition, by influencing directly testicular testosterone biosynthesis, we examined the effects of LHRHa on the activities of 5 key testicular steroidogenic enzymes. Thirty hypophysectomized, hOG treated rats were given either LHRHa (1 micrograms sc/day) or saline during 7 days. The LHRHa treated animals exhibited a significant decrease of serum testosterone when compared to the control group (498 +/- 37 ng/dl vs 2044 +/- 105 ng/dl, mean +/- SEM, P less than 0.001). 17-Hydroxyprogesterone serum levels were also decreased in the LHRHa treated rats (61 +/- 6 ng/dl vs 93 +/- 7 ng/dl, P less than 0.005), while serum progesterone levels were similar in both groups of animals. These changes in steroid concentrations were associated with decreases in the microsomal enzyme activities of 17-hydroxylase (37 +/- 9 vs 654 +/- 41 pmol/mg protein/min, P less than 0.001), 17,20-desmolase (103 +/- 9 vs 522 +/- 47 pmol/mg protein/min, P less than 0.001), 3 beta-hydroxysteroid dehydrogenase (1.7 +/- 0.02 vs 4.1 +/- 0.1 nmol/mg protein/min, P less than 0.001), aromatase (95 +/- 7 vs 228 +/- 6 pmol/mg protein/min, P less than 0.001) and 17-ketosteroid reductase (167 +/- 9 vs 290 +/- 18 pmol/mg protein/min, P less than 0.01) in the LHRHa treated animals. These findings indicate that LHRHa can inhibit directly rat testicular testosterone biosynthesis.

17-alpha-Hydroxyprogesterone↗