Irregular and Frequent Cortisol Secretory Episodes with Preserved Diurnal Rhythmicity in Primary Adrenal Cushing’s Syndrome

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing’s syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

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Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00317.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. E63-E70 ◽

Cited By ~ 6

Author(s):

Maarten O. van Aken ◽

Alberto M. Pereira ◽

Marijke Frölich ◽

Johannes A. Romijn ◽

Hanno Pijl ◽

...

Keyword(s):

Body Mass Index ◽

Growth Hormone ◽

Body Mass ◽

Approximate Entropy ◽

Cushing's Syndrome ◽

Control Group ◽

Cortisol Secretion ◽

Age And Gender ◽

Gh Secretion ◽

And Gender

To evaluate the impact on the somatotropic axis of endogenous cortisol excess in the absence of primary pituitary disease, we investigated spontaneous 24-h growth hormone (GH) secretion in 12 adult patients with ACTH-independent hypercortisolism. Plasma GH concentration profiles (10-min samples) were analyzed by deconvolution to reconstruct secretion and approximate entropy to quantitate orderliness of the release process. Comparisons were made with a body mass index (BMI)-, age-, and gender-matched control group and an age- and gender-matched lean control group. GH secretion rates did not differ from BMI-matched controls but were twofold lower compared with lean subjects, mainly due to a 2.5-fold attenuation of the mean secretory burst mass ( P = 0.001). In hypercortisolemic patients, GH secretion was negatively correlated with BMI ( R = −0.55, P = 0.005) but not cortisol secretion. Total serum IGF-I concentrations were similar in the three groups. Approximate entropy (ApEn) was increased in patients with Cushing's syndrome compared with both control groups (vs. BMI-matched, P = 0.04; vs. lean, P = 0.001), denoting more irregular GH secretion patterns. ApEn in patients correlated directly with cortisol secretion ( R = 0.77, P = 0.003). Synchrony between cortisol and GH concentration series was analyzed by cross-correlation, cross-ApEn, and copulsatility analyses. Patients showed loss of pattern synchrony compared with BMI-matched controls, but copulsatility was unchanged. We conclude that hyposomatotropism in primary adrenal hypercortisolism is only partly explained (∼30%) by increased body weight and that increased GH secretory irregularity and loss of synchrony suggest altered coordinate regulation of GH release.

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Food-Dependent Cushing’s Syndrome: Possible Involvement of Leptin in Cortisol Hypersecretion*

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.10.6068 ◽

1999 ◽

Vol 84 (10) ◽

pp. 3817-3822 ◽

Cited By ~ 1

Author(s):

François P. Pralong ◽

Fulgencio Gomez ◽

Louis Guillou ◽

François Mosimann ◽

Sebastiano Franscella ◽

...

Keyword(s):

Food Intake ◽

Cushing’S Syndrome ◽

Adrenal Adenoma ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Adrenal Cells ◽

Patient Reported ◽

Stimulation Of

Abstract Stimulation of cortisol secretion by food intake has been implicated in the pathogenesis of some cases of ACTH-independent Cushing’s syndrome, via an aberrant response of the adrenal glands to gastric inhibitory polypeptide (GIP). We report here a novel case of food-dependent Cushing’s syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as well as in vitro on dispersed tumor adrenal cells obtained at surgery. In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced cortisol secretion. By comparison, no such stimulation was observed in vitro in adrenal cells obtained from another patient with bilateral macronodular adrenal hyperplasia and Cushing’s syndrome that did not depend on food intake, in tumor cells obtained from a solitary cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells. These results demonstrate that as in previously described cases of food-dependent Cushing’s syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they indicate that such a paradoxical response probably represents the hallmark of this rare condition. In addition, they suggest that leptin, which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in other cases of food-dependent Cushing’s syndrome, however, will be necessary to better ascertain the pathophysiological significance of this finding.

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Aberrant Membrane Hormone Receptors in Incidentally Discovered Bilateral Macronodular Adrenal Hyperplasia with Subclinical Cushing’s Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.11.8062 ◽

2001 ◽

Vol 86 (11) ◽

pp. 5534-5540 ◽

Cited By ~ 2

Author(s):

Isabelle Bourdeau ◽

Pierre D’Amour ◽

Pavel Hamet ◽

Jean-Marie Boutin ◽

André Lacroix

Keyword(s):

Cushing’S Syndrome ◽

Plasma Cortisol ◽

Hormone Receptors ◽

Gastric Inhibitory Polypeptide ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Free Cortisol ◽

Cortisol Levels

Cortisol secretion in adrenal Cushing’s syndrome can be regulated by the aberrant adrenal expression of receptors for gastric inhibitory polypeptide, vasopressin, catecholamines, LH/human CG (LH/hCG), or serotonin. Four patients with incidentally discovered bilateral macronodular adrenal hyperplasia without clinical Cushing’s syndrome were evaluated for the possible presence of aberrant adrenocortical hormone receptors. Urinary free cortisol levels were within normal limits, but plasma cortisol levels were slightly elevated at nighttime and suppressed incompletely after dexamethasone administration. Plasma ACTH was partially suppressed basally but increased after administration of ovine CRH. A 51-yr-old woman had ACTH-independent increases of plasma cortisol after 10 IU AVP im (292%), 100 μg GnRH iv (184%), or 10 mg cisapride orally (310%); cortisol also increased after administration of NaCl (3%), hCG, human LH, and metoclopramide. In a 61-yr-old man, cortisol was increased by AVP (349%), GnRH (155%), hCG (252%), and metoclopramide (191%). Another 53-yr-old male increased plasma cortisol after AVP (171%) and cisapride (142%). Cortisol secretion was also stimulated by vasopressin in a 54-yr-old female. This study demonstrates that subclinical secretion of cortisol can be regulated via the aberrant function of at least V1-vasopressin, LH/hCG, or 5-HT4 receptors in incidentally identified bilateral macronodular adrenal hyperplasia.

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PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

Acta Endocrinologica ◽

10.1530/eje-14-1113 ◽

2015 ◽

Vol 172 (6) ◽

pp. 677-685 ◽

Cited By ~ 41

Author(s):

Anne Thiel ◽

Anna-Carinna Reis ◽

Matthias Haase ◽

Gerald Goh ◽

Matthias Schott ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Somatic Mutations ◽

Germline Mutations ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Genetic Studies ◽

Younger Age ◽

Single Center Study ◽

Autonomous Cortisol Secretion

ObjectiveCortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACAL206R mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone.Design, patients, and methodsIn this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.ResultsAmong cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1+GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACAL206R mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions.ConclusionsPRKACAL206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.

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Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing's syndrome: molecular, immunohistochemical and pharmacological correlates

Journal of Endocrinology ◽

10.1677/joe-07-0413 ◽

2007 ◽

Vol 196 (1) ◽

pp. 1-9 ◽

Cited By ~ 27

Author(s):

E Louiset ◽

V Contesse ◽

L Groussin ◽

D Cartier ◽

C Duparc ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Cultured Cells ◽

Cushing's Syndrome ◽

Receptor Protein ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Rt Pcr ◽

Vasopressin Receptors ◽

Cell Incubation ◽

Pharmacological Profiles

Cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome can be controlled by illegitimate receptors. The aim of the present study was to characterize the molecular, immunohistochemical, and pharmacological profiles of vasopressin receptors in cells derived from three patients with AIMAH (H1–H3), in order to evaluate the role of ectopic vasopressin receptors in the physiopathology of hypercortisolism. Expression of mRNAs encoding the vasopressin receptor types (V1a, V1b, and V2) were analyzed by RT-PCR in adrenal tissues. The presence of V1a and V2 receptors was studied by immunohistochemistry on adrenal sections. The pharmacological profiles of vasopressin receptors involved in the control of cortisol secretion were investigated using the V1a receptor antagonist SR49059 and the V2 receptor agonist [deamino-Cys1, Val4, d-Arg8]-vasopressin on cultured cells. The V1a receptor protein was present and functional in H1 and H3 tissues, whereas the V1b receptor was not expressed in any of the tissues. RT-PCR experiments revealed that V2 receptor mRNAs were detected in the three tissues. In contrast, immunohistochemical and cell incubation studies showed that the V2 receptor was involved in the stimulatory effect of AVP on cortisol secretion in H1 and H2, but not in H3 cells. Taken together, these data show that expression of functional ectopic V2 receptors and repression of eutopic V1a receptor can coexist in some hyperplastic corticosteroidogenic tissues. They also reveal that immunohistochemical and incubation studies are essential for the characterization of ectopic receptors actually involved in the control of cortisol secretion by AIMAHs.

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In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-1256 ◽

2005 ◽

Vol 90 (3) ◽

pp. 1302-1310 ◽

Cited By ~ 61

Author(s):

Jérôme Bertherat ◽

Vincent Contesse ◽

Estelle Louiset ◽

Gaëlle Barrande ◽

Céline Duparc ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Gastric Inhibitory Polypeptide ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Adrenocortical Cells ◽

Normal Cells ◽

H1 Cells

In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing’s syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1–H4) preoperatively underwent a series of pharmacological and/or physiological tests. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured cells, derived from hyperplastic tissues, to various membrane receptor ligands. The adrenal tissues of the two patients who responded in vivo to food intake (H2 and H4) were stimulated in vitro by gastric inhibitory polypeptide. GnRH and human chorionic gonadotropin, but not FSH, stimulated cortisol secretion in patients H2 and H4. In these two cases, human chorionic gonadotropin but not GnRH stimulated cortisol production from cultured adrenocortical cells. Cisapride induced a significant increase in cortisol levels in patient H1. In addition, serotonin (5-HT) was more efficient to stimulate cortisol production in H1 cells than in normal adrenocortical cells. Upright stimulation test provoked an increase in cortisol levels in patients H1, H2, and H3. H1 and H2 cells were more sensitive to the stimulatory action of angiotensin II than normal cells. Similarly, arginine vasopressin (AVP) more efficiently activated steroidogenesis in H1 cells than in normal cells. In H1 tissue, immunohistochemical studies revealed the presence of 5-HT- and AVP-like immunoreactivities within clusters of steroidogenic cells, suggesting that these two factors acted through an autocrine/paracrine mechanism to stimulate cortisol secretion. The present study provides the first demonstration of primary adrenal Cushing’s syndrome dependent on both gonadotropin and gastric inhibitory polypeptide. Our data also show a hyperresponsiveness of hyperplastic adrenal tissues to 5-HT, angiotensin II, and AVP. Finally, they reveal for the first time the presence of paracrine regulatory signals in adrenal hyperplasia tissues.

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Evaluation of procoagulant imbalance in Cushing’s syndrome after short- and long-term remission of disease

Journal of Endocrinological Investigation ◽

10.1007/s40618-021-01605-5 ◽

2021 ◽

Author(s):

E. Ferrante ◽

A. L. Serban ◽

M. Clerici ◽

R. Indirli ◽

E. Scalambrino ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Control Group ◽

Cortisol Secretion ◽

Thrombotic Risk ◽

Disease Remission ◽

Short Term Evaluation ◽

Short And Long Term ◽

And Gender

Abstract Objective Patients with Cushing’s syndrome (CS) are at high risk of venous thromboembolism related to a hypercoagulability due to procoagulant imbalance. However, whether these alterations are reversible after disease remission is still unclear. The endogenous thrombin potential (ETP) measured with and without the addition of thrombomodulin provides a global representation of coagulation and previous data confirmed hypercoagulable profile in patients with active hypercortisolism. Aim of this study was to assess the short- and long-term modification of ETP in patients with CS after disease remission. Design and methods Nineteen patients with CS for whom surgical remission was achieved, were prospectively evaluated for clinical characteristics, cortisol secretion profile and ETP at different time points: (i) before surgical intervention; (ii) after 6 months and (iii) 5 years from the time of persistent remission. Nineteen healthy subjects matched for age and gender were also evaluated as control group. Results Before surgery, patients showed higher ETP-ratio (with/without thrombomodulin) than controls (0.62 ± 0.09-vs-0.56 ± 0.09, p = 0.034). No significant correlation between ETP-ratio and cortisol secretion was found. 6 months after remission, ETP-ratio was still significantly increased compared to controls (0.64 ± 0.09-vs-0.56 ± 0.09, p = 0.01), but was similar to baseline (0.64 ± 0.09-vs-0.62 ± 0.09, p = 0.87). At 5 years, ETP-ratio showed a significant decrease (0.55 ± 0.14-vs-0.62 ± 0.09, p = 0.02) and was comparable to controls (0.55 ± 0.14-vs-0.56 ± 0.09, p = 0.7). Conclusions Plasma hypercoagulability detected in patients with active hypercortisolism persists at short-term evaluation and seems to be completely reversible after long-term remission of disease. These data, as part of a whole evaluation of thrombotic risk, can contribute to make appropriate therapeutic choice in these patients.

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QUANTITATIVE ESTIMATION OF URINARY PREGNANETRIOL, PREGNANETRIOLONE, TETRAHYDRO S AND Δ5-PREGNENETRIOL IN THE INVESTIGATION OF ADRENOCORTICAL FUNCTION

Acta Endocrinologica ◽

10.1530/acta.0.0600657 ◽

1969 ◽

Vol 60 (4) ◽

pp. 657-668 ◽

Cited By ~ 2

Author(s):

Frances J. Thomas ◽

A. W. Steinbeck

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Cushing’S Syndrome ◽

Adrenocortical Carcinoma ◽

Quantitative Estimation ◽

Cushing's Syndrome ◽

Adrenocortical Function ◽

Adrenal Hyperplasia ◽

Ectopic Acth ◽

Modified Method ◽

Idiopathic Hirsutism

ABSTRACT A modified method for the estimation of urinary pregnanetriol, pregnanetriol, pregnanetriolone, Δ5-pregnenetriol and tetrahydro S was investigated. The steroids, separated by chromatography, were measured quantitatively, tetrahydro S by reaction with blue tetrazolium and the other three as acetaldehydogenic substances. The excretion of these steroids was studied in suspected instances of adrenal and/or ovarian disease. Urinary pregnanetriol and tetrahydro S levels were normal in Cushing's syndrome, secondary adrenocortical carcinoma, the Stein-Leventhal syndrome, idiopathic hirsutism and hypertension. Tetrahydro S was doubtfully elevated in an instance of ectopic ACTH Cushing's syndrome. Pregnanetriol excretion was elevated in untreated cases of congenital adrenal hyperplasia and after treatment in some. Pregnanetriolone was found in all patients with congenital adrenal hyperplasia, including those receiving cortisone. Pregnanetriolone was also detected in Cushing's syndrome, secondary adrenocortical carcinoma, the Stein-Leventhal syndrome, ectopic ACTH Cushing's syndrome and suspected congenital adrenal hyperplasia. Δ5-pregnenetriol was present as a glucuronide in the Stein-Leventhal syndrome and idiopathic hirsutism. The diagnostic implications of these results are discussed.

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