naloxone and Cushing-Syndrome

Substantial evidence now exists to indicate that the endogenous hypothalamic opioidergic mechanism(s) represents one of the important controlling systems for release of gonadotropin-releasing hormone. Modulations of frequency and amplitude of the secretory activity of gonadotropin-releasing hormone appears to be mediated through an inhibitory action of endogenous opioids, and the functional coupling of the opioidergic and gonadotropin-releasing hormone systems is an ovarian steroid-dependent event. There is also evidence to implicate suprahypothalamic mechanism(s) that enhance endogenous opioid inhibition of secretion of gonadotropin-releasing hormone. Although exogenous opioid peptides and their synthetic analogs consistently induce the secretion of prolactin, blockade of opioid receptors in humans by naloxone failed to elicit a decrement in the levels of prolactin under a variety of conditions. On the contrary, naloxone induced a remarkable increment in the secretion of prolactin via an increased frequency of pulsatile release which is synchronized with pulses of luteinizing hormone. These observations suggest that a common neuroendocrine mechanism is involved in the opioidergic control of the secretion of both luteinizing hormone and prolactin in women.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Cushing Syndrome; DNA, Recombinant; Endorphins; Enkephalin, Leucine; Enkephalin, Methionine; Female; Gonadotropins; Humans; Hypothalamus; Luteinizing Hormone; Menstrual Cycle; Naloxone; Ovary; Pituitary Hormone-Releasing Hormones; Prolactin; Receptors, Opioid

The effect of a high (5.4 mg/h) and a low (0.8 mg/h) dose of naloxone (i.v. over a period of 90 min) on ACTH secretion was compared with placebo in patients with Addison's disease, congenital adrenal hyperplasia, Cushing's disease or Nelson's syndrome. In seven patients with primary adrenal insufficiency the high dose of naloxone provoked a significant increase of plasma ACTH concentrations (P less than 0.02) whereas the low dose of naloxone failed to influence ACTH secretion. In six patients with ACTH dependent Cushing's disease or Nelson's syndrome both doses failed to alter plasma ACTH levels. These results support the concept of inhibitory delta- or kappa-opiate receptors in the regulation of ACTH secretion. In patients with Cushing's disease or Nelson's syndrome ACTH secretion is insensitive to naloxone, presumably because of an autonomous pituitary adenoma or hypothalamic derangement.

Topics: Adrenal Gland Diseases; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Naloxone; Nelson Syndrome

Topics: Adult; beta-Endorphin; Cognition; Cushing Syndrome; Emotions; Endorphins; Humans; Middle Aged; Naloxone; Nelson Syndrome; Nociceptors

1. Petrosal sinus sampling has been used to establish the source of adrenocorticotropin (ACTH) in ACTH-dependent Cushing's syndrome. Naloxone, an opioid antagonist, stimulates ACTH secretion, probably via release of endogenous hypothalamic corticotropin releasing hormone (CRH). 2. Three patients with hypercortisolism were studied. Two showed suppressed (> 50%) urinary-free cortisol excretion with high-dose dexamethasone treatment (2 mg every 6 h for 2 days), one did not suppress. The patients were subjected to bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with simultaneous peripheral venous (forearm) samples. Basal (unstimulated) samples were taken and naloxone (125 micrograms/kg bodyweight) was given intravenously with subsequent simultaneous sampling. Plasma ACTH was measured by radio-immunoassay (RIA). 3. All cases exhibited a marked rise in immunoreactive (IR)-ACTH levels (pmol/L) after naloxone injection, basal to peak: case 1, left 11.5-22.1, right 9.8 with no rise, peripheral 9.1-9.5; case 2, left 456-863, right 125-501, peripheral 59-82; case 3, left 12.7-13.0, right 277-431, peripheral 12.1-11.7. All results indicate pituitary Cushing's syndrome, with a central to peripheral ratio > 2.3:1. Pituitary Cushing's syndrome was confirmed on the results of trans-sphenoidal pituitary surgery in cases 1 and 3. 4. It is suggested that naloxone injection during petrosal sinus sampling in Cushing's syndrome may assist in the diagnosis of ACTH source, by enhancing ACTH release from a pituitary micro-adenoma.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Corticotropin-Releasing Hormone; Cranial Sinuses; Cushing Syndrome; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Naloxone

Bilateral, selective, and simultaneous catheterization of the inferior petrosal sinus is not only a valuable tool in the differential diagnosis of Cushing's syndrome, but may also provide new insights into paracrine interactions at the pituitary level. We have investigated whether CRH (1 microgram/kg BW) has any effect on the release of PRL, GH, TSH, or the alpha-subunit of hCG during this procedure. Sixteen patients under evaluation for Cushing's syndrome (Cushing's disease, n = 12; ectopic ACTH syndrome, n = 2; glucocorticoid resistance, n = 1; hormonally inactive adenoma, n = 1) were catheterized. Two of the patients with Cushing's disease received 4.0 mg naloxone iv 15 min before stimulation with CRH. Patients with Cushing's disease demonstrated a central/peripheral gradient and an intersinus gradient not only for ACTH, but also for PRL, alpha-subunit, GH, and TSH, provided that the latter two hormones were not completely suppressed by the glucocorticoid excess. Moreover, all hormones increased in response to CRH on the side with the highest ACTH concentration; PRL rose from 31.2 +/- 6.4 to 61.6 +/- 12.4 micrograms/L (P less than 0.01), and alpha-subunit from 2.6 +/- 0.6 to 6.4 +/- 1.7 micrograms/L, (P less than 0.01). Naloxone was unable to abolish the PRL or alpha-subunit increase in response to CRH. A multihormonal response to CRH in inferior petrosal sinus blood was also observed in the patient with glucocorticoid resistance and in the patient with the hormonally inactive tumor, but not in the patients with ectopic ACTH secretion. The multihormonal response to CRH could be explained by cosecretion of other hormones together with ACTH from corticotroph adenoma, by an effect of CRH on pituitary blood flow, or by a paracrine action of pituitary corticotrophs on adjacent normal pituitary cells. Our results do not support the concept that such a paracrine action is mediated by beta-endorphin. However, a higher dose of naloxone may be required to antagonize the action of pituitary beta-endorphin.

Topics: Adrenocorticotropic Hormone; Adult; Blood Specimen Collection; Catheterization; Corticotropin-Releasing Hormone; Cushing Syndrome; Female; Glycoprotein Hormones, alpha Subunit; Growth Hormone; Humans; Male; Naloxone; Prolactin; Thyrotropin

The ACTH, cortisol and LH responses to low dose (0.8 mg/h) naloxone 90 min infusion were investigated in seven patients with untreated Cushing's disease, six patients with Addison's disease and four control subjects. Naloxone had no effects on ACTH hypersecretion or normal ACTH levels. These data confirm that naloxone cannot provide additional diagnostic or therapeutic approaches in ACTH hypersecretion syndromes, mainly in Cushing's disease. The mean percentage LH levels did not significantly change during low dose naloxone in controls or patients with Cushing's and Addison's diseases. This suggests that increased endogenous opioid peptides in these diseases may not modify the LH responses to low dose of naloxone. However, since three of five adults with Cushing's disease had increased LH levels during naloxone, further studies may be indicated.

Topics: Addison Disease; Adolescent; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Humans; Hydrocortisone; Luteinizing Hormone; Male; Middle Aged; Naloxone

The purpose of this study was to evaluate the effect of clonidine--an alpha 2-adrenergic agonist--and naloxone--an opiate antagonist--on pituitary hormone release. The study involved 43 women: 20 menopausal women, 9 untreated women with ACTH-dependent Cushing's disease, and 14 healthy women. Serum GH, ACTH, LH, FSH, TSH, cortisol, and plasma beta-endorphin concentrations were measured with RIA methods. A significant increase in GH and a significant decrease in ACTH and in cortisol was observed after clonidine injection in healthy women. Clonidine caused a significant decrease in LH concentration in the luteal phase of the menstrual cycle. However, naloxone induced the opposite effect on pituitary hormone release. In Cushing's disease, ACTH significantly decreased in response to clonidine. In postmenopausal women with hypertension a decrease in blood pressure, a marked decrease in the number of hot flashes, as well as a diminution in amplitude and frequency of LH pulsatility was found. Conclusions are as follows: (1) Clonidine may be useful in the treatment of hypertensive menopausal women; and (2) a diminution in ACTH, beta-endorphin, and cortisol release in response to clonidine was observed in Cushing's disease.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; Clonidine; Cushing Syndrome; Female; Growth Hormone; Humans; Hydrocortisone; Hypertension; Luteinizing Hormone; Menopause; Middle Aged; Naloxone; Pituitary Gland, Anterior; Pituitary Hormones, Anterior

Topics: Addison Disease; Adrenalectomy; Adrenocorticotropic Hormone; Adult; beta-Endorphin; Cushing Syndrome; Female; Humans; Injections, Intravenous; Male; Middle Aged; Naloxone; Radioimmunoassay

Topics: Cushing Syndrome; Humans; Naloxone; Pituitary Diseases; Pituitary Function Tests; Pituitary Hormones, Anterior

Young and mature, genetically obese and non-obese, spontaneously hypertensive rats (SHR) were injected with saline (controls) or naloxone for 12 weeks. Naloxone stilled the hyperphagia to a normal intake in the obese SHR (Obese/SHR) so that young Obese/SHR did not develop their usual massive obesity and mature Obese/SHR that had become massively obese were reduced to leanness. The naloxone-treated young, obese and non-obese SHR (controls) exhibited marked reduction of the weight of their pituitary and adrenal glands, whereas the pituitary and adrenal glands of naloxone-treated mature, obese and non-obese/SHR were greatly increased in weight. The elevated systolic blood pressure of the obese and non-obese rats was reduced after chronic treatment with naloxone. Naloxone treatment caused reduction of blood ACTH, corticosterone, and beta endorphin levels but elevated growth hormone levels. The characteristic hyperinsulinemia, hyperlipidemia, hyperglycemia, elevated BUN levels, and the Cushingoid spectrum of degenerative changes found in Obese/SHR did not appear in naloxone-treated rats.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Blood Pressure; Body Weight; Corticosterone; Cushing Syndrome; Disease Models, Animal; Endorphins; Female; Growth Hormone; Male; Naloxone; Obesity; Organ Size; Pituitary Gland; Rats; Rats, Inbred SHR; Rats, Inbred Strains

Endogenous opiates may be important in the control of ACTH secretion in men. The effect of opiate receptor blockade by naloxone on ACTH, beta-endorphin-like substance and cortisol release was studied in healthy women and in 9 patients with Cushing's disease. In the healthy subjects, ACTH, beta-endorphin and cortisol levels were increased in response to naloxone. However, in 3 our of the 9 patients with Cushing's disease, a paradoxical decrease in serum ACTH, cortisol and beta-endorphin concentrations was observed after naloxone administration. In the patients with a paradoxical response to naloxone, transsphenoidal microadenomectomy was ineffective.

Topics: 17-Hydroxycorticosteroids; Adrenocorticotropic Hormone; Adult; beta-Endorphin; Cushing Syndrome; Endorphins; Female; Humans; Hydrocortisone; Naloxone; Receptors, Opioid

Systemic administration of the enkephalin analog FK 33.824 was previously shown to inhibit ACTH secretion in man. In this study, the direct action of this analog on cortisol release was studied. The enkephalin analog (1 microM and 10 microM) did not influence basal or ACTH-stimulated cortisol production by cultured isolated adrenocortical cells prepared from the hyperplastic adrenal glands from three patients with Cushing's disease. Naloxone (10 microM) had also no direct effect on cortisol release. It is concluded that the met-enkephalin analog used in this study and naloxone do affect the hypothalamo-pituitary-adrenal axis via a central effect.

Topics: Adenoma; Adrenal Cortex; Adrenal Gland Neoplasms; Cells, Cultured; Cosyntropin; Cushing Syndrome; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Enkephalin, Methionine; Growth Hormone-Releasing Hormone; Hormones; Humans; Hydrocortisone; Naloxone

The effect of D-Ala2, MePhe4, Met-(0)enkephalinol (Sandoz FK 33-824; 0.5 mg, im) on pituitary hormone secretion was studied in 11 patients with Addison's disease and 11 patients with ACTH-dependent Cushing's disease. In patients with Addison's disease, a pronounced fall of plasma ACTH levels was observed (P less than 0.005). The ACTH response to FK 33--824 was partially reversed by naloxone (4 mg, iv). In patients with Cushing's disease, no unequivocal decrease in either ACTH or cortisol was seen. Moreover, FK 33--824 failed to influence the vasopressin-induced ACTH increase in 5 patients with Cushing's disease. In patients with cortisol deficiency due to either Addison's disease or bilateral adrenalectomy for Cushing's disease, FK 33--824 led to increases in PRL and GH similar to those described in normal subjects. However, in the presence of longstanding hypercortisolism, the PRL increase was significantly diminished, and the GH response to FK 33--824 was completely abolished. Our results suggest that in Addison's disease ACTH release is influenced by inhibitory opiate receptors. In patients with Cushing's disease, ACTH secretion is insensitive to FK 33-284, presumably because of an autonomous pituitary adenoma or hypothalamic derangement. The impairment of the PRL and GH responses to FK 33--824 in Cushing's syndrome seems to reflect a direct action of the elevated cortisol level, for it is not seen after bilateral adrenalectomy.

Topics: Addison Disease; Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Cushing Syndrome; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Endorphins; Enkephalins; Female; Follicle Stimulating Hormone; Growth Hormone; Humans; Hydrocortisone; Luteinizing Hormone; Male; Middle Aged; Naloxone; Prolactin

Thirteen patients with either Addison's disease, or Cushing's disease treated by bilateral adrenalectomy, were infused with the long-acting met-enkephalin analogue DAMME. In patients with Addison's disease significant and pronounced falls in ACTH and N- and C-terminal beta-LPH were seen; chromatography suggested that beta-endorphin fell concomitantly. Three out of four patients with Cushing's disease who had not received pituitary irradiation, also showed a decrease in plasma ACTH and N- and C-terminal beta-LPH; however, no change was seen in any of the irradiated patients. The changes were naloxone reversible. The levels of plasma met-enkephalin were normal and did not change after DAMME in any group of patients. These results are interpreted as suggesting that there are inhibitory opiate receptors controlling the release of ACTH, beta-LPH, and beta-endorphin.

Topics: Addison Disease; Adrenalectomy; Adrenocorticotropic Hormone; Adult; beta-Endorphin; beta-Lipotropin; Cushing Syndrome; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Endorphins; Enkephalin, Methionine; Enkephalins; Female; Hormones; Humans; Male; Middle Aged; Naloxone

Two patients with Nelson's syndrome and one patient after bilateral adrenalectomy for Cushing's disease, without any evidence of Nelson's syndrome, were studied with respect to the effect of hydrocortisone, naloxone and valproic acid (a GABA transaminase inhibitor) on ACTH secretion. Hydrocortisone suppressed plasma ACTH concentrations to normal in the patient without Nelson's syndrome, but failed to do so in the two patients with Nelson's syndrome. Naloxone and valproic acid caused a decline in plasma ACTH concentrations in the patients with Nelson's syndrome, but produced no change in the patient without Nelson's syndrome. Secretion of ACTH may thus be influenced by both opiate peptide and by gamma aminobutyric acid, as well as by the cortisol concentration, these agents may act at different sites to inhibit ACTH release by the tumour.

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Humans; Hydrocortisone; Middle Aged; Naloxone; Nelson Syndrome; Pituitary Neoplasms; Valproic Acid