d-ala(2)-mephe(4)-met(0)-ol-enkephalin and Addison-Disease

The responses of plasma immunoreactive (IR) proopiomelanocortin (POMC)-derived N-terminal peptide (Nt), IR-beta-endorphin (Ep), IR-beta-lipotropin (LPH) and IR-ACTH levels to ovine corticotropin-releasing hormone (CRF) and FK 33-824 (Met-Enkephalin analogue) were studied in nine patients with Addison's disease. The basal plasma levels (mean +/- SE) of IR-Nt, IR-Ep, IR-LPH and IR-ACTH were significantly higher in patients with Addison's disease (4459 +/- 975 pg/ml, 132 +/- 25 pg/ml, 4425 +/- 1030 pg/ml, 553 +/- 89 pg/ml, respectively) than in the normal controls (202 +/- 38 pg/ml, 7 +/- 2 pg/ml, 101 +/- 18 pfi/ml, 53 +/- 16 pg/ml, respectively). Ovine CRF produced rapid and concomitant increases in plasma levels of IR-Nt, IR-Ep, IR-LPH and IR-ACTH. Ep and ACTH levels reached a peak at 30 min. On the other hand, Nt and LPH levels reached a peak at 60 min and these levels gradually decreased up to 120 min. The molar concentrations of these IR-peptides in plasma were changed in close parallel fashion to one another. FK 33-824 produced a pronounced and concomitant fall in IR-Nt, IR-EP, IR-LPH, and IR-ACTH levels. These results support the theory that Nt, Ep, LPH and ACTH are produced simultaneously from POMC as a common precursor in the pituitary gland and are secreted concomitantly under various conditions such as stimulation by CRF and inhibition by FK 33-824 in patients with Addison's disease.

Topics: Addison Disease; Adrenocorticotropic Hormone; Adult; beta-Endorphin; beta-Lipotropin; Corticotropin-Releasing Hormone; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Endorphins; Female; Humans; Hydrocortisone; Male; Peptide Fragments; Pro-Opiomelanocortin

A 61 year old Japanese man with a diagnosis of Addison's disease was admitted to Kyushu University Hospital for further investigation of high ACTH levels and hyperpigmentation which 37.5 mg of cortisone acetate failed to alleviate. The basal level of plasma ACTH was 700-1000 pg/ml, and following 25-37.5 mg cortisone acetate or 1 mg dexamethasone the levels were 300-600 pg/ml. The general pigmentation showed little improvement with such medication. Radiographic studies revealed a double floor of the sella turcica and cisternal herniation. These observations suggested the existence of a pituitary ACTH-secreting tumour. Plasma ACTH showed a circadian rhythm ranging from 440 to 1570 pg/ml and it was not suppressed to a normal range by oral administration of dexamethasone, 8 mg/day or by continuous infusion of dexamethasone, 1.25 mg/h for 2 h. Plasma ACTH responses of 80% above basal level to lysine-vasopressin (LVP), and 12% above basal to synthetic ovine corticotrophin releasing factor (CRF) were observed. FK 33-824, a methionine-enkephalin analogue, suppressed plasma ACTH to 85% of basal level, while bromocriptine (CB-154) caused no significant change. These findings led to a diagnosis of pituitary ACTH-secreting adenoma (corticotropinoma) in association with Addison's disease. The persistent circadian rhythm of plasma ACTH suggested that this adenoma may not be completely free from regulation by the central nervous system. This case may be clinically significant for investigation of the pathogenesis of pituitary adenoma, particularly in Nelson's syndrome.

Topics: Addison Disease; Adenoma; Adrenocorticotropic Hormone; Bromocriptine; Circadian Rhythm; Corticotropin-Releasing Hormone; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Dexamethasone; Humans; Hydrocortisone; Lypressin; Male; Middle Aged; Pituitary Function Tests; Pituitary Neoplasms

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