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R J Croughs

Publications and source records attributed to R J Croughs.

At least 19 recordsLinked to original sources
PubMed2000

GIP-dependent adrenal Cushing's syndrome with incomplete suppression of ACTH.

ACTH-independent Cushing's syndrome may be due to the development of ectopic hormone receptors in adrenal tissue. Thus, in food-dependent Cushing's syndrome the adrenals aberrantly express receptors for gastric inhibitory polypeptide (GIP). We present the case of a 60-year-old woman with food-dependent Cushing's syndrome whose cortisol levels increased after stimulation with CRH. In this patient with Cushing's syndrome the finding of low basal plasma cortisol levels in the late night and early morning as well as a paradoxical rise of plasma cortisol during a 7-h infusion with dexamethasone (carried out without any restriction in food intake), suggested that cortisol production was stimulated at times of food intake. Hourly measurements of plasma cortisol for 48 h revealed prominent meal-related peaks. A plasma cortisol response, elicited by oral glucose administration, could be prevented by octreotide. Plasma ACTH was low or undetectable. CRH administration was followed by a ACTH response from 3 to 16 ng/l and a plasma cortisol response from 230 to 680 nmol/l. Octreotide treatment for nearly five months induced a partial clinical and biochemical remission. Total bilateral adrenalectomy was performed. The left adrenal was grossly enlarged (7 x 5.5 x 4 cm) and the right adrenal was slightly enlarged (6 x 4 x 1.8 cm). Microscopy revealed bilateral nodular hyperplasia. Cell suspensions of adrenal tissue from the patient did respond in a dose-dependent fashion to stimulation with GIP and were very sensitive to stimulation with synthetic ACTH1-24. However, CRH had no significant effect on cortisol production in vitro. Using RT-PCR amplification and cDNA hybridization, GIP receptor was found to be overexpressed in the left and right adrenal tissues from this patient as compared to adrenal tissues from a normal individual or from non GIP-dependent adrenal Cushing's syndrome. There was no evidence of presence of adrenal CRH receptors. Thus, in this patient with food-dependent Cushing's syndrome, the CRH-induced plasma ACTH and cortisol response is probably mediated by an incomplete suppression of the HPA axis as a result of the intermittent food-dependent nature of Cushing's syndrome.

Adrenal Cortex↗
PubMed1998

Central diabetes insipidus and Cushing's syndrome due to ectopic ACTH production by disseminated small cell lung cancer: a case report.

The present case report describes the rare clinical presentation of diabetes insipidus in a patient with an ectopic ACTH syndrome (morning plasma cortisol 1.10 mumol/l, morning plasma ACTH 322 ng/l) due to disseminated small cell lung cancer including a metastasis in the posterior pituitary. The patient was treated by combination chemotherapy and at the same time received octreotide to control hypercortisolism and desmopressin (DDAVP) to control polyuria. Partial tumour remission was achieved resulting in decreased cortisol production and disappearance of the diabetes insipidus. Medical treatment could be discontinued. Several months later tumour regrowth occurred, with recurrence of hypercortisolism (mean morning plasma cortisol 0.74 mumol/l, mean morning plasma ACTH 112 ng/l) but without diabetes insipidus. Early treatment of hypercortisolism in patients with an ectopic ACTH syndrome and disseminated small cell lung cancer may prolong survival and improve the quality of life.

ACTH Syndrome, Ectopic↗
PubMed1998

Effects of corticotrophin-releasing hormone, vasopressin and insulin-like growth factor-I on proliferation of and adrenocorticotrophic hormone secretion by canine corticotrophic adenoma cells in vitro.

Extrinsic factors such as hypothalamic hormones or intrapituitary growth factors may stimulate clonal expansion of a genomically altered cell and therefore play a role in pituitary tumorigenesis. Here we report on the effects of the hypophysiotrophic hormones corticotrophin-releasing hormone (CRH) and vasopressin (AVP) and the intrapituitary growth factor insulin-like growth factor-I (IGF-I) on the proliferation of, as measured by the bromodeoxyuridine labelling index, and ACTH secretion by normal canine pituitary cells and corticotrophic adenoma cells of dogs with pituitary-dependent hyperadrenocorticism. The sensitivity to inhibition by cortisol was analysed under various conditions. Under basal conditions, no significant differences were found in the bromodeoxyuridine labelling indices between control cells and tumour cells. CRH, AVP, IGF-I and cortisol had no effect on the proliferation of canine pituitary cells or canine corticotrophic adenoma cells. In contrast with normal pituitary cells, the proliferation of corticotrophic adenoma cells was stimulated by fetal calf serum (FCS). This FCS-induced proliferation was not inhibited by cortisol. The CRH-induced ACTH secretion by corticotrophic adenoma cells was significantly (P < 0.05) lower than that by normal pituitary cells after 4 h incubation with CRH. Incubation with cortisol for 24 h resulted in reduced ACTH secretion under basal and AVP- or IGF-I-stimulated conditions. The relative inhibition was, however, significantly (P < 0.05) lower in ACTH-producing tumour cells than in normal pituitary cells. Cortisol did not inhibit the CRH-induced ACTH secretion in normal pituitary cells after 24 h. In conclusion, canine corticotrophic adenomas are less sensitive to stimulation by CRH and less sensitive to inhibition by glucocorticoids. These tumours have an aberrant sensitivity to a growth-promoting factor present in FCS. This factor may have an important role in the growth promotion of canine corticotrophic tumours.

Adenoma↗
PubMed1997

Molecular screening for somatic mutations in corticotropic adenomas of dogs with pituitary-dependent hyperadrenocorticism.

Pituitary tumorigenesis is now generally regarded as a multistep process of genomic damage leading to uncoupling of interdependent systems that control cell proliferation and differentiation. The alterations include mutations in genes encoding for proteins involved in signal transduction pathways, such as G-proteins and the p21 protein encoded for by the ras genes. Apart from their excessive secretion of ACTH, corticotropic adenomas are characterized by decreased sensitivity to inhibition by glucocorticoids. Therefore, mutations in the glucocorticoid receptor leading to decreased sensitivity to glucocorticoids may contribute to corticotropic tumor formation. In this study, 16 corticotropic adenomas of dogs with pituitary-dependent hyperadrenocorticism were screened for mutations in the Gs alpha, H-, K-, N-ras genes and the coding region of the DNA-binding domain of the glucocorticoid receptor. The cDNA fragment of the Gs alpha gene encompassed codons 159-240. The K-, and N-ras fragments spanned codons 1-71. The H-ras gene was only screened for mutations in codons 12/13 by direct sequencing of the PCR product. The cDNA fragment of the DNA-binding domain of the glucocorticoid receptor encompassed codons 410-500. The Gs alpha, K-ras, N-ras genes and the DNA-binding domain of the glucocorticoid receptor were screened by single-strand conformation polymorphism analysis. No mutations were found in the Gs alpha gene, the ras genes and the DNA-binding domain of the glucocorticoid receptor. It is concluded that mutations in the Gs alpha gene (codons 159-240), the K- and N-ras genes (codons 1-71), the H-ras gene (codons 12/13) and mutations in the DNA-binding domain of the glucocorticoid receptor do not play a role in the tumorigenesis of canine corticotropic adenomas.

Adenoma↗
PubMed1996

Melatonin and jet lag.

Jet lag is an ill-defined phenomenon resulting from rapid transmeridional flight and is considered to be due to desynchronization of circadian rhythms. The role of the pineal gland hormone, melatonin, in the synchronization of biological rhythms has raised interest in its use to alleviate jet lag. Indeed, recent studies support the use of this well-tolerated drug as a remedy for jet lag on long-haul flights.

Circadian Rhythm↗
PubMed1995

Proliferation of the murine corticotropic tumour cell line AtT20 is affected by hypophysiotrophic hormones, growth factors and glucocorticoids.

In pituitary-dependent hyperadrenocorticism (Cushing's disease), the disturbed regulation of ACTH secretion is associated with neoplastic transformation of corticotropic cells. As these two phenomena are almost indissolubly connected, it is of prime importance to elucidate the factor(s) that induce corticotropic cell proliferation. Here we report on the effects of hypophysiotrophic hormones and intrapituitary growth factors on the proliferation and hormone secretion of the murine corticotropic tumour cell line AtT20/D16v, as measured by DNA content, and ACTH concentration in culture media. In addition, sensitivity to the inhibitory effect of cortisol was assessed under various conditions. Corticotropin releasing hormone (CRH) and vasopressin (AVP) induced proliferation of AtT20-cells. In contrast to that caused by AVP, the CRH-induced proliferation was associated with increased ACTH secretion, which could be inhibited by cortisol. Insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) also stimulated the proliferation of AtT20-cells. The proliferation of AtT20-cells was significantly inhibited by cortisol in all tests. The IGF-I-induced proliferation was the least sensitive to inhibition by cortisol. The growth factors did not stimulate ACTH secretion but IGF-I differed in that it prevented the inhibition of basal ACTH secretion by cortisol. Additional experiments (Western ligand blot analysis) concerning the relative insensitivity of IGF-I induced proliferation to inhibition by cortisol revealed that IGF-I increased the concentration of a 29 kDa IGF binding protein (IGFBP) in the culture medium. The concentration of the 29 kDa IGFBP was slightly decreased by cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1995

Associated autoimmunity in Addison's disease.

As the last extensive series of patients with Addison's disease and coincident autoimmune phenomena were published approximately two decades ago, we studied the cause of the disease, the prevalence of autoimmune disorders and the frequency of occurrence of autoantibodies in 91 patients (31 men and 60 women, mean age 45.3-years-old, range 12-77) with Addison's disease. The cause of Addison's disease in six patients was tuberculosis (6.6%), and autoimmune adrenalitis was considered to be the cause in 83 patients (91.2%). In two patients (2.2%) other causes were responsible for Addison's disease. In 47% of the patients with autoimmune Addison's disease at least one other autoimmune disorder was present. Primary hypothyroidism had the highest prevalence (20.5%), followed by vitiligo (9.6%), non-toxic goiter (8.4%), premature menopause (7.3% of the women), Graves' disease (6%), pernicious anaemia (4.8%), Sjögren's disease (2.4%), hypoparathyroidism (1.2%), type 1 diabetes mellitus (1.2%) and coeliac disease (1.2%). The frequency of autoantibodies in the patients with autoimmune Addison's disease was: adrenal antibodies (82.7%), antibodies against microsomal antigens (58%), thyroglobulin antibodies (23.4%), parietal cell antibodies (19.8%), pancreatic islet cell antibodies (6.2%) and ovary antibodies (3.7% of the women). In comparison with other extensive series of patients with Addison's disease, we found the highest prevalence of autoimmune adrenalitis as the cause of Addison's disease, the highest prevalence of hypothyroidism and vitiligo as concomitant autoimmune disorders and the lowest prevalence of type 1 diabetes mellitus.

Addison Disease↗
PubMed1994

Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease.

OBJECTIVE: To study the influence of glucocorticoid replacement therapy on bone mineral density. DESIGN: Cross-sectional. SETTING: University hospital in the Netherlands. PATIENTS: 91 patients with Addison disease who had been receiving glucocorticoid replacement therapy for a mean of 10.6 years (range, 0.5 to 36.5 years). MEASUREMENTS: Bone mineral density of the lumbar spine and both femoral necks using a dual-energy x-ray absorptiometer and basal serum concentrations of adrenocorticotropin, gonadal hormones, and adrenal androgens. RESULTS: Decreased bone mineral density (less than 2 standard deviations [SD] of the mean value of an age-matched reference population) was found in 10 of 31 men (32%; 95% Cl, 17% to 51%) and in 4 of 60 women (7%; Cl, 2% to 16%). No statistically significant differences were found between men and women with regard to age, duration of glucocorticoid substitution, or glucocorticoid dose, either in absolute quantities or when expressed per kilogram of body weight. However, in men with decreased bone mineral density, the daily hydrocortisone dose per kilogram of body weight (0.43 +/- 0.08 mg/kg; mean +/- SD) was significantly (P = 0.032) higher than in men with normal bone mineral density (0.35 +/- 0.10 mg/kg). After correction for possible confounding variables, a significant linear correlation was found between hydrocortisone dose per kilogram of body weight and bone mineral density of the lumbar spine in the men (regression coefficient, -0.86; Cl, -1.60 to -0.13; P = 0.029) but not in the women. CONCLUSIONS: Long-term treatment with standard replacement doses of glucocorticoids may induce bone loss in men with Addison disease. Adjustment of glucocorticoid therapy to the lowest acceptable dose is mandatory in Addison disease, and regular measurement of bone mineral density may be helpful in identifying men at risk for the development of osteoporosis.

Addison Disease↗
PubMed1994

Responsiveness to corticotropin-releasing hormone and vasopressin in canine Cushing's syndrome.

Corticotropin-releasing hormone (CRH) and vasopressin are the most important hypothalamic factors regulating adrenocorticotropic hormone (ACTH) secretion. In this study we have investigated the responsiveness of the pituitary-adrenocortical axis to intravenous administration of CRH or lysine vasopressin (LVP) in 16 control dogs, 22 dogs with pituitary-dependent hyperadrenocorticism and five dogs with hyperadrenocorticism due to an adrenocortical tumor, using doses of CRH and LVP that caused equivalent ACTH responses in the control dogs. After CRH administration, the increment in plasma ACTH was significantly (p < 0.05) lower in dogs with pituitary-dependent hyperadrenocorticism (221 +/- 53 ng/l) than that in control dogs (279 +/- 41 ng/l). In the dogs with pituitary-dependent hyperadrenocorticism, the relative increases in ACTH after CRH were significantly (p < 0.05) lower than those after LVP. Despite the absence of an increase in ACTH following LVP administration in dogs with hyperadrenocorticism due to an adrenocortical tumor, there was a significant increase in plasma cortisol, the increment (790 +/- 238 nmol/l) being not statistically different from that in the control dogs (412 +/- 37 nmol/l). We conclude that in spite of the changes inherent to pituitary-dependent hyperadrenocorticism, i.e. neoplastic transformation of corticotropic cells and hypercortisolism, there is persistence of responsiveness to hypophysiotropic hormones. The ACTH secretion by corticotropic cells in pituitary-dependent hyperadrenocorticism was relatively less sensitive to stimulation with CRH than with LVP. Adrenocortical tumors develop an aberrant sensitivity to LVP.

Adrenal Cortex Neoplasms↗
PubMed1992

Pituitary tumors: diagnosis and treatment.

This article reviews the current general approach to the biochemical diagnosis and the treatment of pituitary tumors with special reference to medical treatment with dopamine agonists and somatostatin analogs. Dopamine agonists are the treatment of choice in patients with prolactin producing tumors. Octreotide is a major advance in the adjunctive treatment of growth hormone producing tumors. Trans-sphenoidal surgical decompression remains the primary treatment modality in gonadotrofinomas, clinically non-functioning pituitary tumors and thyroid stimulating hormone (TSH) producing tumors. Adrenocorticotrophin (ACTH) producing tumors are treated primarily by selective adenomectomy. The biochemical diagnosis of Cushing's syndrome is complex. Bilateral inferior petrosal sinus sampling for ACTH measurement is highly reliable in the differential diagnosis of ACTH dependent Cushing's syndrome, but needs expertise.

Animals↗
PubMed1992

Corticotropin-releasing hormone and adrenocorticotropic hormone concentrations in cerebrospinal fluid of dogs with pituitary-dependent hyperadrenocorticism.

There is still some controversy concerning the question of whether Cushing's disease in man is caused by a primary dysfunction of the pituitary or a hypothalamic disorder. In the latter option, excessive hypothalamic stimulation of pituitary corticotropes would cause or contribute to the genesis of POMC-secreting adenomas. In the present study cerebrospinal fluid (CSF) CRH levels and levels of ACTH and cortisol in CSF and plasma were measured in clinically healthy dogs, in dogs with pituitary-dependent hyperadrenocorticism (PDH), and in dogs with hyperadrenocorticism due to an adrenocortical tumor (ATH). In CSF from dogs with PDH, CRH concentrations (226.6 +/- 14.4 ng/liter) were significantly (P < 0.05) lower than those in control dogs (309.5 +/- 20.3 ng/liter). In the dogs with ATH, CSF CRH concentrations (211.0 +/- 40.3 ng/liter) were in the range of those in PDH dogs. In dogs with ATH, CSF ACTH levels (13.0 +/- 3.0 ng/liter) were significantly (P < 0.05) lower than those in control dogs (63.4 +/- 3.5 ng/liter), whereas in dogs with PDH, the levels (116.8 +/- 47.5 ng/liter) were not different from those in the control group. In control dogs, the concentrations of CSF CRH and plasma ACTH were significantly correlated (r = 0.635; P < 0.01). This functional dependency appeared to be disturbed in dogs with PDH, as in these dogs CSF CRH concentrations did not correlate with plasma ACTH concentrations. It is concluded that continuous hyperstimulation of pituitary corticotropes with hypothalamic CRH is probably not the cause of excessive ACTH secretion in dogs with pituitary-dependent hyperadrenocorticism.

Adrenal Cortex Neoplasms↗
PubMed1992

Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro.

We have studied seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary macroadenoma, four of whom received long term, high dose octreotide treatment. We have attempted to correlate the presence of somatostatin receptors (SS-R) in the adenomas and the outcome of octreotide treatment, as measured by tumor size, improvements in visual field defects, and hormonal response. The presence of SS-R in the pituitary adenomas was demonstrated in vivo using [111indium]octreotide scintigraphy and in vitro by autoradiography of tissue fragments obtained after transsphenoidal surgery. Adenomas from six of the seven subjects were SS-R positive. High dose (1200 micrograms, sc, daily) octreotide treatment was given to four subjects, three of whom were SS-R positive. Improvement of the visual field defects was observed in three of four patients (including the SS-R-negative subject), although no computed tomographic scan-assessed tumor size reduction was found. Two of four patients showed small but significant reductions in serum FSH concentrations (to 83% and 93% of initial values) with treatment. These in vivo responses to high dose octreotide treatment could not be predicted by pretreatment responses to 200 micrograms TRH or 100 micrograms octreotide. Tissue fragments for cell culture were obtained from six patients, and in vitro release of gonadotropins and/or alpha-subunit could be demonstrated in five cultures. In vitro, octreotide (10 nmol/L) significantly decreased gonadotropiin or subunit release in three of five cultures, whereas bromocriptine (10 nmol/L) significantly reduced the release in four of five cultures and to a significantly greater extent than octreotide. In conclusion, in six of seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary adenoma, SS-R were demonstrated in the tumor. In vitro incubation of adenoma cells with octreotide resulted in mild inhibition of gonadotropin or alpha-subunit release. Although in vivo long term treatment with high doses of octreotide did not result in substantial tumor size reduction, improvement of visual field defects was observed in three of four subjects.

Adenoma↗
PubMed1991

Absence of detectable immunoreactive alpha melanocyte stimulating hormone in plasma in various types of Cushing's disease.

We have measured alpha-MSH in plasma of normal subjects and subjects with various diseases of the pituitary-adrenocortical system using a radioimmunoassay with a sensitivity of 1.2 pmol/l. No alpha-MSH could be detected in plasma of normal subjects (n = 6), in plasma of patients with Addison's disease (n = 3), Nelson's syndrome (n = 2), bromocriptine responsive (n = 2) and unresponsive (n = 5) Cushing's disease and in plasma of psychiatric patients on chronic treatment with the dopamine antagonist haloperidol (n = 5). Plasma alpha-MSH remained undetectable in 2 patients with Cushing's disease after iv injection of 60 micrograms/kg haloperidol. In contrast, alpha-MSH was detectable in plasma of normal dogs (n = 2) and dogs with pituitary dependent hyperadrenocorticism (n = 2), whereas the iv injection of halo peridol was associated with a rise of plasma alpha-MSH. Thus we are unable to detect circulating alpha-MSH in man despite the use of a sensitive radioimmunoassay.

Addison Disease↗
PubMed1991

Withdrawal of bromocriptine after long-term therapy for macroprolactinomas; effect on plasma prolactin and tumour size.

The present study describes the effect on plasma prolactin values and tumour size of bromocriptine withdrawal in 12 patients who had been treated for macroprolactinomas for a period of 3.5-7 (mean 4.9) years. Pretreatment plasma prolactin values ranged from 12,000 to 210,000 (mean: 66,000) mU/l. Immediately before bromocriptine withdrawal plasma prolactin values were in the normal range (less than 350 mU/l for men; less than 450 mU/l for women). Bromocriptine treatment was associated with tumour reduction in all cases. The following observations were made upon withdrawal of bromocriptine: (1) In 11 patients hyperprolactinaemia redeveloped although plasma prolactin levels remained below 600 mU/l in two of these patients during a follow-up period of 1 year. In the other nine patients bromocriptine treatment was reinstituted after 4-12 weeks. (2) Hyperprolactinaemia was associated with tumour reexpansion in one case and increased density of the tumour in two cases. (3) In one patient plasma prolactin remained undetectable during a follow-up period of 1 year and no tumour re-expansion was found. It is concluded that tumour regrowth is uncommon and of small extent after cessation of long-term bromocriptine treatment for macroprolactinomas.

Adult↗
PubMed1990

Results of primary treatment with bromocriptine of prolactinomas with extrasellar extension.

Nineteen patients, seven women and twelve men, with macroprolactinomas characterized by extrasellar extension and basal prolactin levels above 6 U/l were treated with 10-20 mg bromocriptine daily in four divided doses for a mean period of 3.4 years (range 1.5-5.5 years). Plasma prolactin levels fell dramatically in all patients and values in the low normal range were obtained in sixteen patients. Tumor size was reduced by more than 75% in seventeen patients and by 50-75% in two patients. Tumor reduction was associated with the development of a partial empty sella in fourteen cases. In seventeen cases the pituitary became visible. Diminished visual acuity (six patients), bitemporal hemianopia (nine patients), unilateral and bilateral central scotomas (three patients) and oculomotor palsy (two patients) improved or normalized in all cases. Hypogonadism (all patients), hypothyroidism (nine patients) and hypocorticism (four patients) improved or normalized in most cases. It is concluded that in the medical treatment of macroprolactinomas 10-20 mg bromocriptine in four divided doses effectively reduces both plasma prolactin level and tumor size. The good results in this study may be related to the continued use of a fixed dose regimen of bromocriptine regardless of the plasma prolactin lowering effect.

Bromocriptine↗
PubMed1990

Treatment of macroprolactinomas with a new non-ergot, long-acting dopaminergic drug, CV 205-502.

Eleven patients with prolactin-producing pituitary adenomas were treated with the new non-ergot, long-acting dopamine agonist, CV 205-502, for a period of 2-18 months (mean 11 months). Tumour volumes ranged from 1.9 to 64 ml in seven patients who were newly diagnosed, and from 0.1 to 3.1 ml in four patients who had been treated for macroprolactinomas by oral bromocriptine or depot bromocriptine (Parlodel LAR). Plasma prolactin values ranged from 3.5 to 360 U/l before institution of CV 205-502 treatment in these 11 patients. The following observations were made: (1) plasma prolactin values fell dramatically in all patients, and values within the normal range were obtained in five patients at once-daily doses of CV 205-502 between 0.075 and 0.300 mg; (2) tumour size reduction was obtained in all patients with macroadenomas on pretreatment CT scans. Tumour reduction was associated with the development of a partial empty sella in five patients, and with visualization of the pituitary in six cases; (3) bitemporal hemianopia (five patients) disappeared in four patients and improved in one patient. Oculomotor palsy receded in one patient; (4) signs of anterior pituitary insufficiency improved or normalized in most cases affected; (5) mild nausea or dizziness during the first days of CV 205-502 treatment and/or during several days after a dose increase were observed in three patients. We conclude that CV 205-502 in a once daily dose is an effective and safe alternative in the long-term treatment of macroprolactinomas.

Administration, Oral↗
PubMed1990

Heterogeneity in Cushing's disease.

Some patients with Cushing's disease respond to neuropharmacological treatment, whereas others do not. This apparent heterogeneity has been attributed to the existence of a separate form of Cushing's disease of putative neurointermediate lobe origin as opposed to Cushing's disease of anterior pituitary origin. The present review summarizes recent observations in human and canine Cushing's disease which mitigate against this view. We propose that heterogeneity in Cushing's disease is related to heterogeneity of the normal anterior pituitary corticotroph. However, the most fundamental questions concerning the pathogenesis of Cushing's disease remain unanswered.

Cushing Syndrome↗