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

The aim of our study was to evaluate the activity of opioid receptors involved in the regulation of prolactin secretion in different kinds of hyperprolactinemic states (puerperal, idiopathic and tumoral subjects). Prolactin plasma level changes were measured after the acute administration of a met-enkephalin synthetic analogue. FK 33-824, and placebo. The prolactin-releasing effect of this drug, evident in control subjects, was blunted in patients affected by idiopathic hyperprolactinemia, and absent in puerperal and tumoral patients. These results indicate that hyperprolactinemia affects the activity of central opioid receptors, with the most evident effects in patients with highest prolactin plasma levels.

Topics: Adenoma; Adult; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Female; Humans; Pituitary Neoplasms; Pregnancy; Prolactin; Puerperal Disorders; Receptors, Opioid

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 function of the tuberoinfundibular dopaminergic (TIDA) neurons of 49 rats bearing oestradiol-valerate (EV)-induced prolactin (Prl) secreting tumours (prolactinomas) was evaluated in vivo, 7 months after discontinuation of EV-treatment, with neuroactive drugs acting via stimulation or inhibition of DA neurotransmission. Based on the size and morphologic appearance of the pituitary and on determination of plasma Prl levels, rats previously treated with EV could be divided into those bearing macro- (31/49) and those bearing micro-prolactinomas (18/49). Administration of the indirect DA agonist drug nomifensine (10 mg/kg iv) lowered plasma Prl levels in control rats, but failed to do so in rats bearing either macro- or microprolactinomas. Administration of the DA receptor antagonist domperidone (50 micrograms/kg ip) or the synthetic enkephalin analogue FK 33-824 (1 mg/kg ip) failed to induce a rise in plasma Prl in rats with macro-, but induced a clear-cut rise in plasma Prl in those with microprolactinomas. Prl unresponsiveness to all three neuroactive drugs indicates that long time after EV withdrawal TIDA neuronal function is still highly impaired in rats bearing EV-induced macroprolactinomas. The impairment of TIDA neuronal function would be of lesser extent in rats bearing microprolactinomas as revealed by a defective response to only one of the three applied neuroendocrine probes.

Topics: Adenoma; Animals; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Domperidone; Estradiol; Female; Hypothalamus; Neurons; Nomifensine; Pituitary Neoplasms; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Time Factors

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

D-Ala, Mephe, Met, enkephalin (Sandoz FK 33-824), 1.0 or 0.5 mg, was administered by i.v. infusion to normal subjects, patients with acromegaly and hyperprolactinemia due to pituitary adenoma and patients with pituitary dwarfism. FK 33-824 induced no significant change in plasma level of LH, FSH or TSH in any of the subjects studied. These results suggest a lesser role of opioid regulation in the release of above pituitary hormones compared with that in GH, PRL and cortisol.

Topics: Acromegaly; Adenoma; Adolescent; Adult; Child; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Dwarfism, Pituitary; Endorphins; Enkephalins; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Pituitary Diseases; Pituitary Neoplasms; Prolactin; Thyrotropin

ACTH excretion by cultured nonenzymatically dispersed pituitary tumor cells from a patient with Nelson's syndrome was studied. Hormone release was suppressed by 74 +/- 6% by the addition of 1 microM of the met-enkephalin analog FK 33824, while naloxone (1 microM) stimulated ACTH release by 70 +/- 5%. Somatostatin, dexamethasone, bromocriptine, and cyproheptadine in a concentration of 1 microM each inhibited ACTH release by 25 +/- 2%, 35 +/- 2%, 52 +/- 2%, and 61 +/- 4%, respectively, while lysine vasopressin (0.1 microM) and dibutyryl cAMP (5 mM) stimulated ACTH release by 112 +/- 8% and 220 +/- 4%, respectively. In conclusion, it was shown that the stimuli mentioned above directly affect ACTH secretion by the pituitary tumor cells. The inhibitory action of the met-enkephalin analog and the stimulatory action of naloxone on ACTH secretion make the presence of opiate receptors on this type of tumor likely.

Topics: Adenoma; Adrenocorticotropic Hormone; Adult; Cells, Cultured; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Endorphins; Enkephalins; Female; Hormones; Humans; Naloxone; Nelson Syndrome; Pituitary Neoplasms

D-Ala, Mephe, Met, enkephalin (Sandoz FK 33-824) is a stable long acting analog of methionine-enkephalin. FK 33-824 (0.5 or 1.0 mg), elicited plasma GH and PRL responses in normal subjects. In 23 patients with pituitary dwarfism, the response of plasma GH was markedly impaired, while PRL responded to a variable degree. In patients with acromegaly, there was little or no increase in GH and PRL after FK 33-824. Plasma GH increased to a variable degree after FK 33-824 in patients with hyperprolactinemia, with little change in plasma PRL. FK 33-824 decreased plasma cortisol in normal subjects and patients with pituitary disease. These results show that patients with acromegaly and hyperprolactinemia due to pituitary adenomas and patients with pituitary dwarfism do not respond well to FK 33-824, presumably because of hypothalamic or pituitary derangement.

Topics: Acromegaly; Adenoma; Adolescent; Adult; Child; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Dwarfism, Pituitary; Endorphins; Enkephalins; Female; Growth Hormone; Humans; Hydrocortisone; Hypothalamus; Kinetics; Male; Middle Aged; Pituitary Diseases; Pituitary Gland; Pituitary Neoplasms; Prolactin