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B. P. Meij, A. Rijnberk and J. A. Mol


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

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H S Kooistra, G Voorhout, J A Mol and A Rijnberk

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

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R. Stolp, R. J. M. Croughs and A. Rijnberk


Administration of cyproheptadine for 2 months to five dogs with pituitary-dependent hyperadrenocorticism (PDH) at a dose rate of 0·3 mg/kg per 24 h (group 1) and to four dogs with PDH at a dose rate of 1 mg/kg per 24 h (group 2) did not result in any clinical improvement. The hyperadrenocorticoid state, as indicated by the circulating cortisol levels, the urinary corticosteroid excretion and the response of the hypothalamo-pituitary-adrenal axis to lysine-vasopressin, thyrotrophin releasing hormone and dexamethasone did not change consistently, although there was a tendency to normalization of some parameters in the dogs of group 2. However, these changes were not found to be consistent for each individual dog but were limited to one parameter per dog. It is concluded that cyproheptadine is not suitable for the treatment of PDH in the dog.

J. Endocr. (1984) 101, 311–314

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Twenty-one dogs with spontaneous hyperadrenocorticism presented a clinical picture characterized by an insidious onset of abdominal enlargement, muscular weakness, obesity and alopecia. Slight diabetes mellitus was present in some. In the bitches usually there was absence of oestrus for a long time. In addition to polydipsia and polyphagia, features indicative of heat intolerance were observed frequently. The signs and symptoms found are compared to those of human Cushing's syndrome.

Determinations of the excretion of 17-hydroxycorticosteroids in 24-hr. urines were of great diagnostic significance. There was a considerable overlap of levels of plasma 11β-hydroxycorticosteroids in normal dogs and those with hyperadrenocorticism. Results of dexamethasone suppression tests are given.

In the sera of four exophthalmic animals and in one pituitary obtained by necropsy, elevated levels of exophthalmos-producing substance were found. Pathological findings have become available in a number of cases.

Preliminary results with hypophysectomy in four dogs are encouraging.

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BP Meij, JA Mol, MM Bevers and A Rijnberk

Pituitary function was assessed before and after transsphenoidal hypophysectomy in 39 dogs with pituitary-dependent hyperadrenocorticism (PDH). Anterior pituitary function was investigated using combined administration of four hypophysiotropic releasing hormones (corticotropin-releasing hormone (CRH), GHRH, GnRH, and TRH) with measurements of ACTH, cortisol, GH, LH, prolactin (PRL), and TSH Pars intermedia function was assessed by measurements of basal plasma alpha-MSH concentrations and adrenocortical function by baseline urinary corticoid/creatinine ratios. At eight weeks after hypophysectomy basal plasma ACTH, cortisol, GH, LH, PRL, and TSH concentrations were significantly lower than before surgery. In seven dogs with elevated alpha-MSH concentrations, the values returned to the normal level after surgery. In the combined anterior pituitary function test there were no plasma GH, LH, PRL, and TSH responses to stimulation, whereas plasma ACTH and cortisol responses were small but significant. Remission of hyperadrenocorticism was obtained in 35 dogs and recurrences occurred in 3 of these within 16 months postoperatively. At 8 weeks after hypophysectomy, these 3 dogs were not discernible, with respect to residual pituitary and adrenocortical function, from the 32 dogs with persisting remission. Urinary corticoid/creatinine ratios in the latter group of dogs did not increase during 22 months after hypophysectomy. In contrast to the presurgical findings, at 8 weeks after hypophysectomy there were significant positive correlations between baseline urinary corticoid/creatinine ratios and basal levels and responses for ACTH, indicating return to normal function of the pituitary-adrenocortical axis. It is concluded that among the adenohypophyseal cells present in the sella turcica after hypophysectomy, the corticotropes have a distinct behavior. Much more so than the other cell types, the unaffected corticotropes tend to remain functional, or a repressed reserve fraction of corticotropes may become functional. This may be due to the removal of the hypothalamic influence of a postulated corticotropin-release inhibiting factor or a diminished inhibitory influence of a postulated paracrine factor. The corticotropes may maintain normocorticism, but may also lead to mild recurrence after relatively long periods of remission.

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RP Favier, JA Mol, HS Kooistra and A Rijnberk

The main determinants of body size are GH and IGFs. The aim of this study was to investigate whether differences in adult body size of medium-sized and giant dog breeds can be explained by differences in GH release and/or in plasma IGF-I and IGF-II concentrations at a young age. The basal plasma concentrations of GH, IGF-I and IGF-II were determined once weekly in six Great Danes and six beagles from the age of 6 weeks until the age of 24 weeks. In addition, the 6 h secretory profile of GH was determined every 2 weeks. Basal plasma GH concentrations as well as the total area under the curve (AUC) and the AUC above the baseline for GH were significantly higher in Great Danes than in beagles of the same age. In contrast, plasma IGF-I and IGF-II concentrations did not differ significantly between the two breeds. Compared with values in adults, the basal plasma GH concentrations were high until the age of 7 weeks in the beagles, whereas in the Great Danes the basal plasma GH levels remained high during the entire observation period, albeit with a gradual decline. The mean frequency and the mean amplitude of GH pulses tended to be higher in Great Danes than in beagles, although a significant difference was only reached at the age of 19 and 23 weeks for the frequency and at the ages of 9, 11 and 13 weeks for the amplitude. An age-dependent decrease in pulse frequency occurred in the Great Danes. The results of this study demonstrate that differences in adult body size of medium-sized and giant dog breeds are preceded by differences in GH release and not by differences in circulating IGF-I or IGF-II concentrations. Both young Great Danes and young beagles experience a period of high GH release, but this period persists much longer in Great Danes. It is discussed that this difference may be due to delayed maturation of the inhibitory influences of somatostatin on pituitary GH release in the latter dogs.

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The median urinary excretion of 17-oxosteroids in 22 normal unanaesthetized dogs was 0·06 (range: 0·02–0·24) mg./kg. body weight/24 hr. 17-Oxosteroid excretion increased markedly after the administration of dehydroepiandrosterone and androstenedione, while testosterone caused only a very small increase.

The median urinary excretion of total 17-hydroxycorticosteroids (17-OHCS) in 21 dogs was 0·16 (range: 0·06–0·320 mg./kg. body weight/24 hr. This was calculated to amount to about 50–60% of the cortisol produced.

Stimulation with corticotrophin (ACTH) resulted in an increase of urinary 17-OHCS and of plasma 11β-OHCS levels, but 17-oxosteroid excretion was only slightly increased.

In 27 dogs the median plasma 11β-OHCS level was 4·0 (range: 1·3–9·7) μg./100 ml. at 8.00 hr. and 3·6 (range: 0·4–7·0) μg./100 ml. at 17.00 hr. In eight dogs 3-hourly plasma 11β-OHCS estimations were done; six of these animals showed a diurnal variation comparable to that in man.

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The response has been studied in nine dogs with hyperadrenocorticism due to adrenocortical tumours to the administration of dexamethasone, insulin, lysine-vasopressin and tetracosactide by measuring the changes in plasma cortisol concentration. Administration of dexamethasone did not produce a decrease in the plasma concentration of cortisol in any of these dogs. Administration of insulin caused slight increases in the plasma concentration of cortisol in four out of eight dogs. Lysine-vasopressin increased the plasma concentration of cortisol in eight out of nine dogs, three responded supranormally. Eight out of the nine dogs responded to tetracosactide administration, three responded supranormally. It is concluded that in the dog, in contrast to man, the lysine-vasopressin test cannot be used to differentiate between pituitary-dependent hyperadrenocorticism and hyperadrenocorticism due to an adrenocortical tumour. Apparently pituitary ACTH is not completely depleted in dogs with hyperfunctioning adrenocortical tumours.

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A. Rijnberk, J. A. Mol, M. M. Kwant and R. J. M. Croughs


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

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H S Kooistra, S H Greven, J A Mol and A Rijnberk


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