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PubMed2005

The aberrant expression of the gastric inhibitory polypeptide (GIP) receptor in adrenal hyperplasia: does chronic adrenocorticotropin exposure stimulate up-regulation of GIP receptors in Cushing's disease?

CONTEXT: Cortisol secretion is usually under the control of ACTH. However, cortisol secretion occurs in response to gastric inhibitory polypeptide (GIP) in rare cases of food-dependent Cushing's syndrome (CS). OBJECTIVE: We have investigated whether chronic ACTH stimulation or activation of the ACTH signaling pathway might be associated with GIP receptor (GIPR) expression. DESIGN: RT-PCR analysis and primary culture of hyperplastic adrenals. PATIENTS: All patients presented with CS: 20 unilateral adrenal adenomas, five Cushing's disease, one food-dependent CS. RESULTS: RT-PCR revealed GIPR expression in all hyperplastic adrenals studied. No RT-PCR product could be detected in two normal adrenals or 20 hyperfunctioning adrenal adenomas. Primary culture revealed a significant cAMP response to ACTH in all adrenals available for study (EC50, 8.1 x 10(-10) M in normals, 4.7 x 10(-10) M in Cushing's disease, and 4.4 x 10(-10) M in food-dependent disease). However, cultures taken from all four ACTH-dependent and the one food-dependent hyperplastic adrenals studied were also responsive to GIP (EC50 for cAMP, 1.3 x 10(-9) M in Cushing's disease and 4.1 x 10(-10) M in food-dependent disease). Fasting cortisol levels were low in the case of food-dependant Cushing's, rising postprandially as predicted. However, there was no trend toward low fasting or high postprandial cortisol in the other cases, suggesting that the presence of detectable GIPR alone, albeit with definite function in vitro, is not sufficient to cause clinically food-dependent CS. CONCLUSIONS: These data are consistent with the hypothesis that chronic ACTH stimulation or constitutive activation of the ACTH signaling pathway may be associated with aberrant GIPR expression, and suggest one mechanism for the pathogenesis of this phenomenon.

Adrenal Cortex↗

PubMed1992

[Role of adrenocortical scintigraphy in the exploration of incidentally discovered tumors].

To determine the utility of adrenocortical scintigraphy with I131-6 beta-iodomethyl-19-nor-cholesterol (NP59) in incidentally discovered adrenal masses, we studied 12 patients with a unilateral adrenal mass and without other primary tumors or signs of pheochromocytoma or hyperfunctioning adenoma. Ten patients had an adenoma (size: 12 to 35 mm), the diagnosis was made by surgery or by no change in size on repeated CT scans. The NP59 scintigraphy showed an increased uptake on the side of the tumor in 8 cases with a decreased uptake of contra-lateral gland in 7 cases. Hormonal investigations of glucocorticoid function suggested supranormal or fluctuant cortisol secretion in 5 cases as assessed by moderately elevated urinary free cortisol or by incomplete dexamethasone suppression test. These abnormalities disappeared after surgery. Two patients had normal bilateral uptake of NP59, the sizes of the tumors were 12 and 20 mm. Two patients had an extra-adrenal tumor. The NP59 scintigraphy showed a moderately decreased uptake on the side of the hematoma of one patient and a compression of the normal adrenal by ganglioneuroma of the other patient. Our results and those of other authors suggest that positive NP59 scintigraphy could confirm the cortical nature of an incidentally discovered adrenal mass, probably an adenoma that must be followed up morphologically and functionally. No uptake by a tumor greater than 2 cm suggests a primary malignancy or extra-adrenal origin which must be diagnosed by invasive methods.

Adenoma↗

PubMed1986

A comparison of adrenal cortical function in patients with depressive illness and Cushing's disease.

We measured total and free plasma cortisol, 24-hour urinary cortisol excretion, and corticosteroid-binding globulin in 21 normal subjects, 25 patients with depressive illness, and 6 patients with Cushing's disease. Patients with depression had mean 24-hour plasma (8.3 +/- 2.7 micrograms/dl) and urinary (36 +/- 33.55 micrograms/g creatinine) cortisol levels that did not differ from those of normal subjects (6.6 +/- 1.7 microgram/dl; 24.6 +/- 15.4 micrograms/g creatinine), but were significantly lower than those of patients with Cushing's disease (14.4 +/- 2.4 micrograms/dl; 215 +/- 101 micrograms/g creatinine). Not all patients with depression had hypercortisolemia, and the 1-mg dexamethasone suppression test identified some of those with adrenal hyperfunction. 17 of 25 patients had normal 8 a.m. and/or 4 p.m. plasma cortisol after dexamethasone (suppressors), while 8 patients had values greater than 5 micrograms/dl (nonsuppressor). Suppressors had normal total 24-hour plasma and urinary cortisol, while nonsuppressors had levels that were in the range seen in Cushing's disease. Patients with depression showed the expected circadian variation in total and free cortisol, but nonsuppressors had elevated levels in evening and early a.m. hours when levels in normal subjects were low. Patients with Cushing's disease had elevated levels throughout the day. The mean binding capacity of corticosteroid-binding globulin was not different in normal and depressed subjects (23.9 +/- 3.2 vs. 22.2 +/- 3.4 micrograms/dl), but was significantly decreased in patients with Cushing's disease (15.7 +/- 3.5 micrograms/dl). Although total cortisol levels were similar, nonsuppressors had significantly lower mean 24-hour plasma free cortisol (1.01 +/- 0.27 microgram/dl) than patients with Cushing's disease (2.4 +/- 0.54 microgram/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Function Tests↗

PubMed2002

[The management of thyrotoxicosis: a schematic approach].

Thyrotoxicosis is a well defined clinical entity, determined by an increase of plasma levels of thyroid hormones (T3 and T4). A number of causes of thyrotoxicosis are known, and it is therefore very important for the treatment to establish its etiology. In fact, metimazole or propylthiouracil are indicated for the thyrotoxic states caused by thyroid gland's hyperfunction (hyperthyroidism), but are not effective when thyrotoxicosis is determined by a follicular damage and disruption with leakage of preformed thyroid hormones, or in case of thyrotoxicosis factitia. Besides medical therapy, other two therapeutic options are available for the treatment of thyrotoxicosis: radioiodide administration (131I) and surgery. The physician can decide the best therapy on the basis of the following factors: etiology of thyrotoxicosis; patient's age and needs; presence/absence of concomitant diseases or pregnancy; presence of ophthalmopathy; goiter's size; advantages and disadvantages of each therapeutic option. A problem of particular regard is when and if to treat subclinical thyrotoxicosis (low TSH values, and normal plasma levels of thyroid hormones). On the basis of the natural history and of its consequences on the cardiovascular system and skeletal integrity, the authors propose to begin therapy whether subclinical thyrotoxicosis develop in the following four subgroups of subjects: patients with nodular goiter; women in post-menopause; patients with cardiac diseases; patients with osteoporosis.

Adenoma↗

PubMed1981

Isolated skeletal involvement in Cushing's syndrome: response to therapy.

A 38-yr-old male presented with severe symptomatic osteopenia secondary to adrenal hyperfunction without any clinical expression of Cushing's syndrome. The predominantly axial distribution of his osteopenia and the presence of rib fractures healing with abundant callus formation, despite insignificant elevations in serum alkaline phosphatase, were characteristic of glucocorticoid excess syndromes. The histological features of the pretreatment bone biopsy were typical of those associated with excess glucocorticoids, namely decreased quantities of nonmineralized bone matrix, reflecting sites of bone formation, and an increase in the number of osteoclasts, indicating enhanced bone resorption. Six weeks after adrenalectomy, repeat bone biopsy revealed a marked increase in bone matrix synthesis and a significant decrease in bone resorption. These observations suggest that stimulators of skeletal turnover, like sodium fluoride, may be inappropriate in the initial treatment of steroid-induced osteopenia after surgical cure and that vitamin D and calcium therapy offers a more rational approach. Furthermore, the importance of the routine evaluation of adrenal function in any patient presenting with osteopenia is stressed, as well as the fact that relatively isolated skeletal involvement, classically described in micronodular adrenal disease, is not necessarily peculiar to a specific subset of the syndrome but may potentially attend any cause of glucocorticoid excess.

Adrenal Cortex Function Tests↗

PubMed1995

[Nuclear medicine methods for the diagnosis of adrenal tumors].

Adrenal scintigraphy using 131I-6-beta-iodomethyl-19-norcholesterol or 6-methyl-75Se-methyl-19-norcholesterol is a function-dependent imaging method which, in association with high-resolution spatial imaging techniques, plays an essential role in the study of adrenocortical hyperfunction. It can distinguish between bilateral cortical hyperplasia and monolateral adenoma or carcinoma and can lateralise the adenoma. In patients with Cushing syndrome, in addition to allowing a distinction to be made between ACTH-dependent forms and independent forms, adrenocortical scintigraphy is particularly appropriate to identify non-common forms of adenomatous hyperplasia. Adrenocortical scintigraphy, performed during dexamethasone administration, is an accurate mean of differentiating bilateral adrenal hyperplasia from monolateral forms (adenoma or carcinoma) in patients with Conn's syndrome. Owing to the gradual spread of high-resolution spatial imaging techniques, the problem of the diagnostic classification of so-called "incidentalomas" (clinically silent masses discovered by chance) is a subject of considerable interest. Adreno-cortical scintigraphy appears to be able to provide an important contribution to identifying the functional behaviour of these tumours. Since the early 80s meta-iodobenzyl-guanidine (MIBG), marked with 131I or 123I, with a structure similar to norepinephrine and characterized by selective tropism for sympathetic and chromaffin tissue, has been used for the scintigraphic study of adrenal medulla. MIBG scintigraphy has been found to be particularly appropriate for the study of intra- and extra-adrenal, single and multiple, benign and malignant pheochromocytomas. This method has a high overall sensitivity and specificity. Lastly, MIBG scintigraphy is useful in the study of neuroblastoma.

3-Iodobenzylguanidine↗

PubMed2000

Adrenal responsiveness to high, low and very low ACTH 1-24 doses in obesity.

OBJECTIVE: To investigate adrenal activity in visceral obesity in which adrenal hyperactivity has been hypothesized. This could reflect hypothalamus-pituitary alterations leading to slight hyperfunction of the adrenal. Primary adrenal hypersensitivity to ACTH drive in obesity has also been suggested. However, it has also been reported that dehydroepiondrosterone (DHEA) levels in obesity are reduced and it has been hypothesized that this could play a role in the increased cardiovascular risk in obese patients. SUBJECTS: We have studied seven obese women with visceral adiposity (OB, age: 33.6+/-3.3 years, BMI: 33.8+/-1.3 kg/m2, WHR: 0.88+/-0.01). The results in OB were compared with those recorded in a group of age-matched normal women (NS, age: 30+/-1.3 years, BMI: 19.9+/-0.4 kg/m2, WHR: 0.76+/-0.02). METHODS: We have studied the cortisol (F), aldosterone (A) and DHEA responses to ACTH 1-24 administered at low (LD, 0.5 microg/m2) or very low (VLD, 0.125 microg/m2) dose followed by a second challenge with supramaximal dose (HD, 250 microg). RESULTS: Basal F, A and DHEA levels in OB were similar to those in NS. The peak F responses to ACTH were dose-related in both groups. At each dose the F peaks in OB (VLD: 495.6+/-43.9 nmol/l, HD: 722.3+/-67.7 nmol/l; LD: 519.2+/-46.0 nmol/l, HD: 729.6+/-44.7 nmol/l) were similar to those in NS (VLD: 556.7+/-45.9 nmol/l, HD: 704.8+/-20.7 nmol/l; LD: 511.8+/-22.8 nmol/l, HD: 726.7+/-26.5 nmol/l). The peak A responses to ACTH were dose-related in both groups. At each dose, the A peaks in OB (VLD: 0.55+/-0.03 pmol/l, HD: 0.79+/-0.09 pmol/l; LD: 0.63+/-0.04 pmol/l, HD: 0.78+/-0.09 pmol/l) were similar to those in NS (VLD: 0.8+/-0.10 pmol/l, HD: 0.86+/-0.09 pmol/l; LD: 0.8+/-0.10 pmol/l, HD: 0.95+/-0.12 pmol/l). The peak DHEA responses to ACTH were dose-related in both groups. At each dose the DHEA peaks in OB (VLD: 58.6+/-13.3 nmol/l, HD: 61.9+/-13.1 nmol/l; LD: 55.18+/-6.4 nmol/l, HD: 72.3+/-9.8 nmol/l) were similar to those in NS (VLD: 54.3+/-8.2 nmol/l, HD: 57.8+/-8.2 nmol/l; LD: 42.2+/-3.7 nmol/l, HD: 56.9+/-4.3 nmol/l). CONCLUSIONS: This study shows that the cortisol, aldosterone and dehydroepiondrosterone responses to high, low and very low ACTH doses in obese women overlap with those in age-matched lean controls; these findings suggest normal sensitivity of the different zones of the adrenal cortex to ACTH in obesity.

Adolescent↗

PubMed2000

Dietary protein restriction stress in the domestic chicken (Gallus gallus domesticus) induces remodeling of adrenal steroidogenic tissue that supports hyperfunction.

The stress of dietary protein restriction in the immature domestic turkey (Meleagris gallopavo) induces adrenal steroidogenic hypofunction that is associated with an alteration in the proportion of density-dependent subpopulations of steroidogenic cells within the adrenal gland. In contrast, when imposed on immature chickens, this nutritional stressor induces long-term enhancement of adrenal steroidogenic function. However, whether this alteration in function is accompanied by a remodeling of chicken adrenal steroidogenic tissue as in the turkey is not known. To address this question, immature cockerels (2 weeks old) were fed established isocaloric synthetic diets containing either 20% (control) or 8% (restriction) soy protein for 4 weeks. Adrenal glands were processed for the isolation of defined, density-separable, adrenal steroidogenic cell subpopulations: three low-density adrenal steroidogenic cell subpopulations [LDAC-1 (rho = 1.0285-1.0430 g/ml), LDAC-2 (rho = 1. 0430-1.0485 g/ml), and LDAC-3 (rho = 1.0485-1.0500 g/ml)] and one high-density subpopulation [HDAC (rho = 1.0510-1.0840 g/ml)]. The steroidogenic function of these cell subpopulations was assessed. Protein restriction consistently, but differentially, enhanced maximal ACTH-induced corticosterone production by the subpopulations: values of LDAC-1, -2, and -3 and HDAC from protein restricted birds were, respectively, 116, 43, 33, and 20% greater than those of corresponding cell subpopulations from control birds. However, it had contrasting influences on maximal ACTH-induced aldosterone production by the cell subpopulations. Whereas the value of LDAC-1 from protein-restricted birds was 70% greater than that from control birds, the values for LDAC-2 and -3 were not different from those of the control, and the value for HDAC was 22% less than that of the control. Protein restriction also altered the cell subpopulation composition of the adrenal gland: compared to control, it increased the proportion of LDAC-1 by 46% and decreased the proportion of LDAC-3 and HDAC by 34 and 20%, respectively. Thus, dietary protein restriction increased the proportion of cells (i.e., LDAC-1) having the greatest enhancement in corticosteroid production. This pattern of remodeling of chicken adrenal steroidogenic tissue in response to dietary protein restriction contrasts sharply with the pattern that occurs in another galliform species, the domestic turkey.

Adrenal Cortex Hormones↗

PubMed2003

Regulation of differential COUP-TF-coregulator interactions in adrenal cortical steroidogenesis.

Hyperfunctioning adrenocortical adenomas produce excessive amounts of various corticosteroids due to dysregulated expression of steroidogenic enzymes. Since no genetic mutations in steroidogenic enzyme genes have been identified as yet, the dysregulated expression at the transcription level may be crucial. Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) and steroidogenic factor-1 (SF-1) play key roles in the transcriptional regulation of steroidogenic P450 genes. Transfection studies showed that SF-1 activated and COUP-TFs repressed the transcription of bovine CYP17 gene promoter from the CRS2 element in a mutually exclusive manner in Y-1 cells. The results indicate that COUP-TFs negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic P450 genes. Expression of both COUP-TFI and COUP-TFII was significantly decreased in the cortisol-producing adenomas, in which CYP17 was drastically overexpressed, indicating that decreased expression of COUP-TFs play a key role in overexpression of CYP17 in this type of tumors. We then screened for COUP-TFI-interacting proteins from a cortisol-producing adenoma cDNA library using a yeast two-hybrid system and identified a novel RING finger-containing protein which can function as a coregulator for COUP-TFI. Notably, COUP-TFI activated rather than repressed several target genes including the human CYP11B2 gene promoter, the results of which were opposite to those of the CYP17 promoter. The bifunctional activities of COUP-TFI may be derived from the promoter context and our newly identified COUP-TFI coregulator.

Adrenal Cortex↗

PubMed2006

Hypothalamic-pituitary-adrenal activity in type 2 diabetes mellitus: role of autonomic imbalance.

Symptomatic diabetic neuropathy has been found to be associated with hypothalamus-pituitary-adrenal (HPA) axis hyperfunction, but no data are available about HPA activity in diabetic patients with asymptomatic autonomic imbalance. To evaluate HPA axis activity in patients with type 2 diabetes mellitus (T2DM) in relation to the presence or the absence of subclinical parasympathetic or sympathetic neuronal dysfunction, we performed an observational study on 59 consecutive type 2 diabetic patients without chronic complications and/or symptoms of neuropathy or hypercortisolism. The following were measured: serum cortisol at 08:00 am and at midnight (F8 and F24, respectively), post-dexamethasone suppression cortisol, 24-hour urinary free cortisol (UFC), and morning corticotropin (ACTH). Deep-breathing (DB) and LS (LS) autonomic tests were performed to assess the parasympathetic function; postural hypotension test was performed to evaluate sympathetic activity. Patients were subdivided into 4 groups: subjects with parasympathetic failure (group A), sympathetic failure (group B), both para- and sympathetic failure (group C), and without autonomic failure (group D). Hypothalamus-pituitary-adrenal activity was increased in group A compared with group D (UFC, 48.6 +/- 21.4 vs 21.6 +/- 9.8 microg/24 h, P < .0001; ACTH, 27.0 +/- 8.6 vs 15.7 +/- 5.7 pg/dL, P < .01; F8, 20.4 +/- 4.5 vs 13.6 +/- 3.8 microg/dL, P < .05; post-dexamethasone suppression cortisol, 1.2 +/- 0.4 vs 0.8 +/- 0.6 microg/dL, P < .05, respectively) and group B (UFC, 26.3 +/- 11.0 microg/24 h, P < .0001; ACTH, 19.9 +/- 8.0 pg/dL, P < .05). Regression analysis showed that UFC levels were significantly associated with the deep-breathing test (beta = -0.40, P = .004) and tended to be associated with the lying-to-standing test (beta = -0.26, P = .065), whereas body mass index, glycated hemoglobin, and duration of disease were not. Type 2 diabetic patients with asymptomatic parasympathetic derangement have increased activity of HPA axis, related to the degree of the neuronal dysfunction.

Adrenal Cortex Hormones↗

PubMed2001

Food-dependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing's syndrome: in vivo and in vitro studies.

Aberrant gastric inhibitory polypeptide (GIP) receptor expression in bilaterally hyperplastic adrenals or unilateral adrenal adenomas is a rare form of adrenal hyperfunction. So far, only few cases have been described. In all these cases, cortisol was the predominant steroid released in a food-dependent manner, leading to the development of non-ACTH-dependent Cushing's syndrome. In the present study, we describe a novel case of a GIP receptor-expressive adrenocortical adenomatous nodule, detected incidentally by computed tomography scanning in a 41-yr-old lady with hirsutism but no clinical signs of Cushing's syndrome, on physical examination. Hormonal investigations in morning fasting samples showed slightly elevated androgen levels, low-normal baseline cortisol, normal suppression of cortisol after dexamethasone administration, and ACTH levels that were not suppressed and did stimulate after CRH administration. The elevated urinary free cortisol excretion, in conjunction with an atypical cortisol diurnal rhythm, raised the possibility of an aberrant stimulation of cortisol production by the adrenal tumor. Further studies demonstrated food-dependent secretion of cortisol, which was abolished by prior octreotide administration. Notably, substantial amounts of adrenal androgens were also secreted after food consumption. Removal of the tumor resulted in undetectable cortisol and androgen levels that did not respond to food consumption. Histological examination of the excised tumor revealed an adrenocortical adenomatous nodule originating from the inner zona reticularis, consisting mainly of compact cells. A steroidogenic secretory pattern, indicating the concomitant release of adrenal androgens and cortisol, was also observed in vitro from tumor cells cultured in the presence of GIP. The in vitro secretory response to GIP was higher for the adrenal androgen DHEA, compared with cortisol. The expression of the GIP receptor in tumor cells, but not in the adjacent normal adrenal, was demonstrated by RT-PCR), using specific oligonucleotide probes for this receptor. In summary, we describe a patient with a GIP-expressive cortisol and androgen oversecreting adrenocortical nodule with the unusual presentation of hirsutism and not the typical clinical signs of Cushing's syndrome. It is of note that food intake in this patient provoked a substantial increase in both adrenal androgen and cortisol levels that, together with the histological appearance of this nodule, was compatible with a zona reticularis-derived tumor. Thus, aberrant expression of the GIP receptor does not exclusively involve cells of a zona fasciculata phenotype, as previously reported, but may also occur in other types of differentiated adrenocortical cells.

17-alpha-Hydroxyprogesterone↗