ABSTRACT

In adult healthy beagle dogs, plasma concentrations of ACTH, cortisol, α-MSH, GH, prolactin and arginine vasopressin (AVP) were measured after i.v. administration of [d-Ala²,N-Me-Phe⁴,Met-(O)⁵-ol]-enkephalin (DAMME) at doses of 0·1, 0·5, 1, 5 and 10 μg/kg body weight. Significant dose-dependent increases occurred for ACTH, cortisol and GH at dose rates of 0·5, 1, 5 and 10 μg/kg body weight. Increments in plasma concentrations of prolactin were significant only at 5 and 10 μg DAMME/kg, and there was no significant effect on plasma concentrations of α-MSH and AVP. Prior i.v. administration of the opiate antagonist naloxone (0·1 mg/kg) attenuated the DAMME (10 μg/kg)-stimulated release of ACTH and cortisol. The results demonstrate that the [Met]-enkephalin analogue DAMME stimulates the release of ACTH, cortisol, GH and prolactin in dogs, and that this stimulation is, at least in part, mediated by μ-opioid receptors. The observations for ACTH and cortisol are different from those in man, where DAMME lowers their basal concentrations.

Journal of Endocrinology (1990) 127, 265–271

Under the assumption that the impaired inhibitory effect of glucocorticoids on cell division is an important determinant in the progression of corticotrophic adenomas, it is postulated that the magnitude of proliferation and the resistance to glucocorticoids are correlated. To test this hypothesis, 67 dogs with pituitary-dependent hyperadrenocorticism were studied to determine whether a correlation could be demonstrated between the effect of dexamethasone administration on the activity of the pituitary–adrenocortical axis and the size of the pituitary gland as estimated by computed tomography.

The volumes of the pituitary glands as calculated from summations of subsequent images of pituitary areas, ranged from 11·8 to 3238·6 mm³. Among the three dimensions, the height of the pituitary was the most sensitive indicator of enlargement. Calculation of the pituitary height/brain area ratio (P/B ratio) allowed correction for the size of the dog. The P/B ratio had the highest discriminatory power in distinguishing enlarged (n=41) from non-enlarged (n=26) pituitaries.

The effects of dexamethasone (0·1 mg/kg) on the plasma concentrations of cortisol and ACTH and on the urinary corticoid/creatinine (C/C) ratios were expressed as percentage changes from the initial values. For ACTH, cortisol and C/C ratios these figures for resistance to dexamethasone were significantly correlated with the dimensions of the pituitary, particularly the height, volume and P/B ratio.

It is concluded that the magnitude of the expansion of pituitary corticotrophic adenomas is dependent upon the loss of restraint by glucocorticoids, i.e. the degree of insensitivity to glucocorticoid feedback.

Journal of Endocrinology (1997) 152, 387–394

SUMMARY

In the male rat injections of CaCl₂ and MgCl₂ stimulated mitosis in bone marrow and thymus tissue. The magnesium salt was also mitogenic in the normal female, but calcium only exerted its mitogenic effect after ovariectomy. Oestradiol, but not progesterone replacement therapy abolished calcium-induced mitosis in the ovariectomized rat. The inability of calcium to stimulate cell division was also apparent in the thyroparathyroidectomized female rat, suggesting the oestradiol blockade did not operate via some indirect action on the calcium homeostatic hormones calcitonin or parathyroid hormone.

When thymic lymphocytes derived from male or female rats were isolated and maintained in suspension, increased calcium or magnesium concentrations in the culture medium stimulated the entry of cells into mitosis. Addition of oestradiol to the culture medium abolished the mitogenic effect of increased calcium levels, but had no effect on magnesium-induced proliferation. These experiments suggested that oestradiol might act at the cell surface to prevent the influx of calcium but not magnesium ions into the interior of the cell and thus to block the sequence of biochemical events which lead to the initiation of DNA synthesis and culminate in mitosis.

ABSTRACT

Dogs with spontaneous pituitary-dependent hyperadrenocorticism were divided into two groups, one with normal plasma concentrations of α-MSH (normal α-MSH dogs, n = 26) and the other with high plasma concentrations of α-MSH (high α-MSH dogs, n= 14), on the presumption that high α-MSH concentrations indicated a parent cell of pars intermedia origin.

The urinary corticoid/creatinine ratios of the high α-MSH dogs were significantly higher than those of the normal α-MSH dogs. The percentage decrease of the corticoid/creatinine ratios following dexamethasone administration was significantly higher in the normal α-MSH dogs than in the high α-MSH dogs. Dexamethasone resistance occurred in both the normal α-MSH dogs (4 out of 26) and the high α-MSH dogs (7 out of 14), indicating a relative rather than an absolute difference.

The short-term effect of orally administered bromocriptine, at a dose (10 μg/kg body weight) known to be effective in lowering prolactin concentrations in dogs, was investigated by measuring concentrations of cortisol, ACTH and α-MSH in plasma at 4, 6 and 8 h after administration. Significant decreases were observed for cortisol in both groups and for α-MSH only in the high α-MSH dogs.

The effect of 5 days of bromocriptine administration (10 μg at 12-h intervals) was assessed by measurements of urinary corticoid/creatinine ratios. Considering both groups as a whole, only the corticoid/creatinine ratios of the high α-MSH dogs decreased significantly on the first day of treatment. In each group there was one dog in which bromocriptine administration lowered the corticoid/creatinine ratios for several days, but the values stayed above the reference range and the animals did not recover.

It is concluded that high α-MSH concentrations are not unambiguously associated with the theoretically expected characteristics of pars intermedia disease. The results indicate that the pituitary lesions causing hyperadrenocorticism may not maintain the regulation characteristics of the lobe of origin.

J. Endocr. (1988) 118, 271–277

Abstract

This study was performed to determine whether, in the dog, there is at any time pulsatile release of α-MSH and whether secretion of ACTH from the pars intermedia (PI) contributes to the circulating concentrations of ACTH.

The 24-h secretory profiles of α-MSH, ACTH, and cortisol were determined in eight dogs. Plasma samples were obtained at 10-min intervals via an indwelling jugular catheter during two 12-h periods. Pulsatile secretion of α-MSH was found in all dogs, with wide variations in peak height. Plasma α-MSH levels were usually low (mean 15 pmol/l), but brief, distinct periods of increased plasma α-MSH concentrations as high as 489 pmol/l were found. Analysis of pulse frequency revealed a mean of 4·75 significant α-MSH peaks/24 h. The highest α-MSH peaks were associated with definite changes in the plasma concentrations of ACTH.

In separate studies, the influence of dexamethasone on the 6-h secretory profiles and on the haloperidol-stimulated secretion of α-MSH, ACTH, and cortisol was investigated. In these two studies, plasma ACTH was measured by a highly sensitive immunoradiometric assay. Dexamethasone pretreatment significantly suppressed the plasma concentrations of ACTH, cortisol, and α-MSH to 10·3%, 3·9%, and 74·6% respectively. Dexamethasone pretreatment also significantly reduced the haloperidol-stimulated secretion of ACTH and cortisol, but had no influence on the haloperidol-stimulated secretion of α-MSH. After the administration of haloperidol to the dexamethasone-pretreated dogs, there were small increases in the plasma concentrations of ACTH and cortisol, the latter being significant.

These data demonstrate that α-MSH is secreted spontaneously in a pulsatile manner in the dog and suggest that the canine PI contributes to circulating ACTH concentrations.

Journal of Endocrinology (1997) 152, 113–121

The 6-h plasma profiles of adrenocorticotropic hormone (ACTH), cortisol, α-melanocyte-stimulating hormone (α-MSH), and GH were studied in 17 dogs with pituitary-dependent hyperadrenocorticism (PDH) before and after hypophysectomy. The aim of the study was to investigate the relation between the hormone profile characteristics and recurrence of PDH after surgery.

The hormones were secreted in a pulsatile fashion. The basal plasma cortisol concentration and area under the curve (AUC) for cortisol were significantly higher in the PDH cases than in eight controls. The characteristics of the plasma profiles of ACTH and α-MSH were not significantly different between the PDH cases and the controls. In the PDH cases, less GH was secreted in pulses than in the controls, but the difference was not significant. The basal plasma cortisol concentration, the AUC for ACTH and cortisol, and the pulse frequency of ACTH and cortisol decreased significantly after hypophysectomy for the group of PDH cases. The basal plasma concentrations of ACTH and α-MSH, the AUC for α-MSH, and the characteristics of the plasma GH profiles of the PDH cases remained unchanged after hypophysectomy. No pulses of α-MSH were observed after hypophysectomy. The co-occurrence between the ACTH and cortisol pulses decreased significantly with hypophysectomy. The postoperative pulse frequency of ACTH was the only characteristic with predictive value for the recurrence of PDH after hypophysectomy.

The results of this study demonstrate that ACTH, cortisol, α-MSH, and GH are secreted in a pulsatile fashion in dogs with PDH. Hypophysectomy effectively reduces the secretion of ACTH and cortisol. The presence of ACTH pulses after hypophysectomy is a risk factor for the recurrence of hyperadrenocorticism.

ABSTRACT

Adrenocortical function studies were performed in seven Dandie Dinmont terriers with pituitary-dependent hyperadrenocorticism. The ability of dexamethasone at a dose rate of 0·1 mg/kg body weight to suppress cortisol secretion was only moderate in four out of the six dogs tested. Concentrations of α-melanocyte-stimulating hormone in plasma were highly increased. Responses to stimulation with corticotrophin-releasing hormone and the dopamineantagonist haloperidol, examined in three animals, were moderate or absent. These results indicate that adrenocortical stimulation, i.e. hyperadrenocorticotrophism, was caused by pituitary lesions which were functioning autonomously.

In six of the seven animals there was a very close familial relationship and the coefficients of relationship and the coefficients of inbreeding were significantly higher than in a representative control population.

It was concluded that these seven related terriers with hyperadrenocorticotrophism had the biochemical characteristics of de-novo neoplasms of proopiomelanocortin-producing cells, and there was evidence for a genetic involvement in tumorigenesis.

Journal of Endocrinology (1992) 135, 535–542

Loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene cause an X-linked syndrome of central hypothyroidism, macroorchidism, variable prolactin and GH deficiency, delayed pubertal testosterone rise, and obesity. To understand the pathophysiology of this syndrome, knowledge on IGSF1's place in normal development is imperative. Therefore, we investigated spatial and temporal protein and mRNA expression of IGSF1 in rats using immunohistochemistry, real-time quantitative PCR (qPCR), and in situ hybridization. We observed high levels of IGSF1 expression in the brain, specifically the embryonic and adult choroid plexus and hypothalamus (principally in glial cells), and in the pituitary gland (PIT1-lineage of GH, TSH, and PRL-producing cells). IGSF1 is also expressed in the embryonic and adult zona glomerulosa of the adrenal gland, islets of Langerhans of the pancreas, and costameres of the heart and skeletal muscle. IGSF1 is highly expressed in fetal liver, but is absent shortly after birth. In the adult testis, IGSF1 is present in Sertoli cells (epithelial stages XIII–VI), and elongating spermatids (stages X–XII). Specificity of protein expression was corroborated with Igsf1 mRNA expression in all tissues. The expression patterns of IGSF1 in the pituitary gland and testis are consistent with the pituitary hormone deficiencies and macroorchidism observed in patients with IGSF1 deficiency. The expression in the brain, adrenal gland, pancreas, liver, and muscle suggest IGSF1's function in endocrine physiology might be more extensive than previously considered.