Adrenocortical Hyperplasia Research Articles

Expression and significance of super oxide dismutase and malondialdehyde in the serum of patients with adrenocortica diseases

Objective To investigate the expression and significance of super oxide dismutase activity and malondialdehyde concentration in the serum and adrenal grands of patients with adrenocortica diseases. Methods 12 patients with adrenal hyperplasia and 10 patients with adrenal adenoma which were carried out hospital surgery and confirmed by pathology, and 11 cases of normal as controls were selected.The serum level of Cu/Zn-SOD, Mn-SOD and MDA before operation, and Cu/Zn-SOD and Mn-SOD positive cells percentage of adrenal tissue were compared between three groups. Results Before adrenalectomy SOD activity was lower(P <0.05)and MDA concentration was higher in serum(P<0.05)than the control group.Cu/Zn-SOD positive cell was lower in adrenocortical adenoma tissue than that of adrenocorticohyperplasia and normal cortex(P <0.05).Mn-SOD positive cell had a significant difference among adrenocortical hyperplasia, adrenocortical adenoma and normal adrenal cortex tissue(P <0.05).Both SOD positive cell in adrenocortical adenoma tissue were the lowest of all.In addition,the expression of SOD in tissue had a significant positive correlation with serological expression in study group. Conclusion The superoxide dismutase activities and malondialdehyde concentration seemed to change with adrenocortica diseases.The detection of superoxide dismutase activities and malondialdehyde concentration in the serum and adrenal grands could be the potential methods for the diagnosis and differential diagnosis of adrenocortica diseases. Key words: Adrenal gland,adrenal cortex; Superoxide dismutase; Malondialdehyde

Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Prkar1a Knockout Mice

Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.

COMPLEX ANALYSIS OF GENETIC PREDISPOSITION TO DIFFERENT FORMS OF LOW-RENIN ARTERIAL HYPERTENSION: PP.21.338

Objective: Comparison of distribution of alleles and genotypes of polymorphic loci of RAAS genes: CYP11B2 (C-344T), REN (C-5434T, C-5312T, and A BglI G), CMA (G–1903A), ACE (I/D) and AT2R1 (A1166C) and their combinations in patients with low-renin forms of arterial hypertension (AH). Design and Method: 87 hypertensive pts aged 50 ± 13 years with low-renin forms of AH were studied. PAC and PRA were determined in the supine position and following 4-hour upright posture. Complex statistic analysis of differences in allele and genotype patterns distribution between different forms of low-renin AH was carried out by means of recently developed by our group software APSampler, which used a Bayesian Markov chain Monte Carlo-based method and provided an independent validation by means of Fisher's exact test. The differences were considered significant at p values < 0.05. RESULTS: According to clinical data and comparison with PAC, PRA and instrumental analysis pts were divided into 3 groups: group Ia (n = 41) with primary hyperaldosteronism (HA) associated with adenoma; group Ib (n = 18) with idiopathic HA -adrenocortical hyperplasia; combined group I included all 59 HA cases; and group II (n = 28) cases with low-renin essential hypertension with a normal PAC and the absence of structural adrenal changes. The analysis of carriership of allele and genotypes combinations showed significant differences between groups Ia, Ib and II. A comparison of groups II and Ia identified assemblage associated with predisposition only to primary HA: (–344T) CYP11B2 + BglI G REN + I ACE (p = 0.009, OR = 5.4 (95% CI 1.4 to 21.2)) and a comparison of groups II with group Ib identified assemblage as predisposing only to IHA: (–5312 T) REN + D ACE (p = 0.004, OR = 10.7 (95% CI 1.9 to 60.1)). Conclusions: Assemblage (–344T) CYP11B2 + BglI G REN + I ACE is factor of genetic predisposition only to PHA and assemblage (–5312 T) REN + D ACE - only to IHA, thereby indicating that these assemblages are risk factors for different forms of low-renin HA.

Improvement of hypercortisolism by β-blocker therapy in subclinical Cushing’s syndrome associated with ACTH-independent macronodular adrenocortical hyperplasia

A 61-year-old man with hypertension and diabetes was referred for the evaluation of multiple bilateral adrenal tumors. While Cushingoid features were not apparent, an elevated cortisol level in response to a low-dose dexamethasone suppression test (187.7nmol/l), an elevated urinary cortisol level (170.9nmol/day), and a weak response to a cosyntropin-releasing hormone (CRH) provocation test were observed. Furthermore, the serum cortisol level increased in response to a posture test or isoproterenol infusion. Accordingly, the patient was diagnosed as having ACTH-independent macronodular adrenal hyperplasia (AIMAH) with subclinical Cushing's syndrome associated with the aberrant expression of β-adrenergic receptors. After 2months of propranolol therapy, the serum cortisol responses to a posture test and isoproterenol infusion, the cortisol level in response to a low-dose dexamethasone suppression test (102.1nmol/l), and the urinary cortisol level (165.9nmol/day) all normalized. While the suppression of cortisol secretion was sustained for 24months, glucose metabolism and adrenal size were unaffected. To our knowledge, this is the first report of AIMAH accompanied by subclinical Cushing's syndrome associated with the aberrant expression of β-adrenergic receptors. Furthermore, propranolol inhibited cortisol hypersecretion in the present case. Additional cases or controlled studies are needed to determine the potential effect of propranolol on metabolic disorders and adrenal size in patients with AIMAH.

Cushing's disease

Cushing's syndrome refers to the clinical manifestations induced by chronic exposure to excess glucocorticoids. There are three pathological conditions that can result in the chronic overproduction of endogenous cortisol in man: the most frequent is Cushing's disease where adrenocorticotropic hormone (ACTH) is overproduced by a pituitary corticotroph adenoma, rarely ACTH can be produced in an 'ectopic' manner by a non-pituitary tumour, finally cortisol can be directly over-secreted by one or (rarely) the two adrenals that have become tumourous, either benign or malignant. The positive diagnosis of Cushing's syndrome requires that chronic hypercortisolism is unequivocally demonstrated biologically, using 24-h urinary cortisol, late-evening plasma or salivary cortisol, midnight 1-mg or the classic 48-h-low-dose dexamethasone suppression test, etc., all with essentially the same diagnosis potencies. The search for the responsible tumour then relies on the assessment of the corticotroph function, and imaging: suppressed ACTH plasma levels indicate an 'adrenal' Cushing, and the responsible unilateral adrenocortical tumour is always visible at computed tomography (CT) scan, whereas its benign or malignant nature may be difficult to diagnose before surgery. Imaging can suspect bilateral 'adrenal' Cushing, when the two adrenals are small, as in the primary pigmented nodular adrenal dysplasia associated with Carney complex, or enlarged, as in the ACTH-independent macronodular adrenocortical hyperplasia. Measurable or increased ACTH plasma levels indicate either Cushing's disease or the ectopic ACTH syndrome. When the dynamics of the corticotroph function (high-dose dexamethasone suppression test, the CRH test) are equivocal, and/or the imaging is non-contributive, it may be difficult to distinguish between the two. This is the situation where sampling ACTH plasma levels in the inferior petrosal sinus may be necessary. The best treatment option of Cushing's disease is when the responsible corticotroph adenoma can be entirely removed by the trans-sphenoidal approach, with sufficient skill to preserve the normal anterior pituitary function. When it fails, all other options directed towards the pituitary (radiation therapies), or the adrenals (medications or surgery), have numerous side effects. There is at present no recognised efficient medical treatment towards the corticotroph adenoma -still an orphan disease.

Hydrocortisone Inhibits the Basal and Angiotensin II-Stimulated Proliferation of Rat Adrenocortical cells in Organ Culture

The present study has been to test the effect of hydrocortisone (HC) on the mitotic incidence in adrenocortical cells of organ-cultured rat adrenal explants during a 24-hour incubation with or without angiotensin II (ANG). It was shown that HC significantly decreased the mean mitotic activity rate (MMAR) of adrenocortical cells in organ culture. That decrease concerned all the three cortical zone vs respective controls. In turn, ANG markedly increased the MMAR of the zona glomerulosa cells, when compared to the values recorded in controls, while there were no changes of the MMAR of the zona glomerulosa in the adrenal explants incubated with joint exposure to HC and ANG. The obtained results indicate that HC exhibits an inhibitory effect on the adrenocortical cell proliferation, which may suggest that arachidonic acid metabolites play an important role in the process of adrenocortical hyperplasia, their participation in the ANG-induced zona glomerulosa cell proliferation being strongly assumed.

American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

Laparoscopic Adrenalectomy for Large Adrenal Masses: Pushing the Envelope

To determine the role of laparoscopy for large adrenal tumors in terms of outcomes, pathology, operative time, and morbidity. A retrospective review of 24 patients who underwent laparoscopic adrenalectomy was performed to record the size of the lesions, surgical techniques used, operative times, estimated blood loss, duration of hospital stay, need for blood transfusion, conversion to open surgery, and complications. The laparoscopic adrenalectomy patients were divided into two groups based on tumor size: <8 cm (n = 16, group 1) and >or=8 cm (n = 8, group 2). Mean tumor size was 5.6 cm for group 1 and 12.1 cm for group 2. Mean operative times were 143.12 and 188.75 minutes for groups 1 and 2, respectively. Mean estimated blood loss was 89.69 mL for group 1 and 334.38 mL for group 2. Operative time and blood loss were significantly higher in group 2. Pathologic examination revealed eight adrenal cortical adenomas, five myolipomas, four pheochromocytomas, four cysts/pseudocysts, and three adrenocortical hyperplasias. No significant difference was found between groups concerning transfusion rates, duration of hospital stay, and conversion to open surgery. Laparoscopic adrenalectomy is a feasible procedure for large masses but results in longer operative times and higher total blood loss when compared with results for masses smaller than 8 cm. Our findings suggest, however, that laparoscopic adrenalectomy for masses larger than 8 cm can produce comparable results concerning hospital stay, conversion to open surgery rate, and pathologic outcome in comparison with results for adrenal masses smaller than 8 cm.

Adrenal incidentalomas and subclinical Cushing's syndrome: diagnosis and treatment

Adrenal incidentaloma has become a frequent clinical dilemma. Even in the absence of specific clinical features of Cushing's syndrome, adrenocortical incidentalomas may display steroid secretory activity at different degrees. The recognition of endocrine and metabolic dysfunctions associated with subclinical hypercortisolism leads to current awareness about its potential consequences. Different protocols and threshold values to define normal cortisol secretion and diagnosis of subclinical Cushing's syndrome have been proposed, including recent practice guidelines for the diagnosis of overt Cushing's syndrome. Follow-up studies have provided additional data about the natural course of the disease and related cardiovascular and metabolic consequences. The study of bilateral adrenocorticotropin-independent macronodular adrenocortical hyperplasia in some familial cases offers a new approach to understanding the spectrum of subclinical cortisol hypersecretion. The prevalence of subclinical hypercortisolism may be higher than previously reported as more sensitive diagnostic criteria are now recommended. The absence of a single gold standard test, the diversity of diagnostic criteria and the requirement of subsequent meticulous biochemical evaluations before a decision for treatment represent a challenge for the clinical management of this condition.

Diagnosis and surgical management of adrenocortical hyperplasia disease (report of 180 cases)

Objective To review the diagnosis and surgical therapeutic methods of adrenocorti-cal hyperplasia disease. Methods One hundred and eighty adrenocortical hyperplasia patients (74 males and 106 females with a mean age of 40 years) were retrospectively analyzed. The patients were divided into hypereortisolism (n=152) and aldosteronism (n=28) according to secretion. Data of clinical characteristic, endocrine and image examination were collected. All patients were treated by operation. Results Of these patients, 107 had Cushing disease (CD), 28 had adrenocorticotropin independent macronodular adrenal hyperplasia (AIMAH), 19 had ectopic adrenocorticotropin adrenal hyperplasia (EAAH), 4 had primary pigmented nodular adrenocortical hyperplasia (PPNAH), 28 had DOI: 10.3760/cma.j.issn. 1000-6702.2009.05.002idiopathic hyperaldosteronism (IHA). 24 h urinay free cortisol (24hUFC) excretion of CD, AIMAH, EAAH and PPNAH were 95.2-535.7 μg (mean, 287.6 μg), 24.8-808.2 μg (mean, 307.9 μg), 102.5-3127.0 μg (mean, 852.5 μg), 243.8-1124.6 μg (mean. 564.3 μg). The proportion loss of the serum cortisol circadian rhythm were 99% (102/103), 92% (11/12), 100% (17/17), 100% (4/ 4), respectively. Low- and high-dose dexamethasone suppression tests (DDST) failed to suppress cor-tisol secretion in AIMAH, PPNAH and EAAH groups, but HDDST was suppressed in CD group. Of the 28 IHA cases, 17 had hypokalemia and 15 had high urine kalium (>30 mmol/24 h). The results of plasma renin activity and serum aldosterone accorded with the diagnosis. Unilateral adrenalectomy were operated in 102 hypercortisolism cases, and 24hUFC of CD, AIMAH, EAAH and PPNAH were 56.2-233.5 μg (mean, 157.4 μg), 22.5-418.5 μg (mean, 117.9 μg), 116.5-1137.0 μg (mean, 756.7 μg), 124.6-422.6 μg (mean, 164.3 μg) 1 week after operation. The blood pressure was nor-mal in 8 paitents and droped in 13 patients for IHA after unilateral adrenalectomy. 24hUFC were nor-mal in 55 patients after bilateral adrenalectomy for hypercortisolism. One hundred and six patients were followed up for 4-158 months, the Cushing syndrome ameliorated and blood pressure dropped. Conclusions Unilateral adrenalectomy is the first choice for adrenocortical hyperplasia disease which needs operation. The operation mode of the contralateral adrenal gland is based on the hyperplasia types and clinical observation. Key words: Adrenocortical hyperplasia; Diagnosis; Surgical procedure, elective

Analysis of glucose-dependent insulinotropic peptide receptor (GIPR) and luteinizing hormone receptor (LHCGR) expression in human adrenocortical hyperplasia

To analyze the aberrant expression of the GIPR and LHCGR in different forms of adrenocortical hyperplasia: ACTH-independent macronodular adrenal hyperplasia (AIMAH), primary pigmented nodular adrenocortical disease (PPNAD) and diffuse adrenal hyperplasia secondary to Cushing's disease (DAHCD). We quantified GIPR and LHCGR expressions using real time PCR in 20 patients with adrenocortical hyperplasia (seven with AIMAH, five with PPNAD, and eight with DAHCD). Normal adrenals tissues were used as control and the relative expression was compared with beta-actin. GIPR and LHCGR expressions were demonstrated in all tissues studied. Median GIPR and LHCGR mRNA levels were 1.6; 0.4; 0.5 and 1.3; 0.9; 1.0 in adrenocortical tissues from AIMAH, PPNAD and DAHCD respectively. There were no differences between GIPR and LHCGR expressions in all tissues studied. GIPR and LHCGR overexpression were not identified in the studied cases, thus suggesting that this molecular mechanism is not involved in adrenocortical hyperplasia in our patients.

Autocrine/paracrine regulations of steroidogenesis in adrenocortical hyperplasias and tumors

Autocrine/paracrine regulations of steroidogenesis in adrenocortical hyperplasias and tumors

Transposition of pedicled adrenal gland for the treatment of adrenocortical and medullary hyperplasia

Objective To investigate the clinical efficacy of pedicled adrenal transposition for the treatment of adrenocortical and medullary hyperplasia, Methods Twenty cases of adrenal hyperpla-sia (6 men and 14 women; mean age,36 years ) had history of hypertension from 0.5 to 5 years. Of all cases, 15 had centripetal obesity and purple striae, 2 had weakness and polyuria, 3 had durative hypertension. Serum potassium and aldosterone were increased in 4 and 3 cases, respectively. Urinary 17-OH and 17-KS were increased in 15 cases. Epinepgrine, norepinephrine and dopamine increased in 3 cases, VMA increased in 4 cases. CT scan and MRI revealed adrenal diffuse enlargement with in-creased thickness or nodules in 18 and 3 cases, respectively, 131I-MIBG scan showed positive in 3 ca-ses. Preoperative diagnoses were Cushing's syndrome in 11 cases, hyperaldosteronism in 2 cases, pheochromocytoma in 1 case, adrenomedullary hyperplasia in 2 cases, Cushing's syndrome-cate-cholamine syndrome in 4 cases. All cases were treated with transposition of pedicled adrenal gland into the subcutaneous tissues. Results All operations were successful. The average operation time was 120 min, the average blood loss was 40 ml and the average hospital stay was 10 d. No obvious surgical complications occurred. Pathological studies of all the cases revealed the coexistence of adrenocortical and medullary hyperplasia. Seventeen cases were followed up for 0.5-8 years. Thirteen cases had no symptom and normal biochemical results. Four cases still had hypertension and abnormal biochemical results. They were recovered after adrenal operation of the ther side. Conclusion Transposition of pedicled adrenal gland could be an available option to treat patients with adrenocortical and medullary hyperplasia. Key words: Adrenocortical and medullary hyperplasia; Transposition, operation

Endothelial Dysfunction Is Related to Aldosterone Excess and Raised Blood Pressure

Primary aldosteronism (PA) is a secondary hypertension characterized by autonomous aldosterone hypersecretion from adrenocortical adenoma and/or hyperplasia. Recently it has been suggested that aldosterone excess is directly involved in the development of cardiovascular injury in PA independent of its hypertensive effect. The present study was designed to examine the relationship between aldosterone excess and endothelial dysfunction in PA patients. 25 PA patients were studied for vascular endothelial function by ultrasound measurement of flow-mediated vasodilation (FMD), and 10 PA patients were re-evaluated 3 months after surgical or medical treatment; 10 age-, gender-, and blood pressurematched hypertensive patients served as control subjects. Percent (%) FMD in PA patients (4.6+/-2.0%) was significantly (p < 0.0001) lower than that in the control subjects (7.9+/-2.0%). %FMD showed significant (p < 0.05) negative correlations with systolic blood pressure (SBP) (r=-0.48), brachial-ankle pulse wave velocity (r=-0.52), plasma aldosterone concentration (PAC) (r=-0.42), and aldosterone-renin ratio (ARR) (r=-0.42), while SBP showed a positive correlation with PAC (r=0.47). Percent FMD, SBP, PAC, and ARR significantly (p < 0.05) improved after surgical and medical treatment, although the changes of %FMD did not correlate with those of SBP, PAC or ARR. In conclusion, the present study has demonstrated that PA patients have endothelial dysfunction, which is related to aldosterone excess and raised blood pressure, and reversible after treatment, suggesting that aldosterone excess contributes to the development of endothelial dysfunction due to its hypertensive effect and/or its direct effect on the cardiovascular system.

Kinetic and structural studies of phosphodiesterase-8A and implication on the inhibitor selectivity.

Cyclic nucleotide phosphodiesterase-8 (PDE8) is a family of cAMP-specific enzymes and plays important roles in many biological processes, including T-cell activation, testosterone production, adrenocortical hyperplasia, and thyroid function. However, no PDE8 selective inhibitors are available for trial treatment of human diseases. Here we report kinetic properties of the highly active PDE8A1 catalytic domain prepared from refolding and its crystal structures in the unliganded and 3-isobutyl-1-methylxanthine (IBMX) bound forms at 1.9 and 2.1 A resolutions, respectively. The PDE8A1 catalytic domain has a K(M) of 1.8 microM, V(max) of 6.1 micromol/min/mg, a k(cat) of 4.0 s(-1) for cAMP, and a K(M) of 1.6 mM, V(max) of 2.5 micromol/min/mg, a k(cat) of 1.6 s(-1) for cGMP, thus indicating that the substrate specificity of PDE8 is dominated by K(M). The structure of the PDE8A1 catalytic domain has similar topology as those of other PDE families but contains two extra helices around Asn685-Thr710. Since this fragment is distant from the active site of the enzyme, its impact on the catalysis is unclear. The PDE8A1 catalytic domain is insensitive to the IBMX inhibition (IC(50) = 700 microM). The unfavorable interaction of IBMX in the PDE8A1-IBMX structure suggests an important role of Tyr748 in the inhibitor binding. Indeed, the mutation of Tyr748 to phenylalanine increases the PDE8A1 sensitivity to several nonselective or family selective PDE inhibitors. Thus, the structural and mutagenesis studies provide not only insight into the enzymatic properties but also guidelines for design of PDE8 selective inhibitors.

Hyper-responsiveness of adrenal gland to vasopressin resulting in enhanced plasma cortisol in patients with adrenal nodule(s)

Hyper-responsiveness of plasma cortisol to vasopressin has been demonstrated in ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) and some adrenal adenomas with Cushing's syndrome (CS). However, the clinical significance of hyper-responsiveness of plasma cortisol to vasopressin has not been investigated systematically in adrenal nodule(s). The aim of this study was to clarify the prevalence of hyper-responsiveness of plasma cortisol to vasopressin (vasopressin responder) and their clinical characteristics in terms of hormonal secretion using vasopressin-loading test in the patients with adrenal nodule(s) except pheochromocytomas. A vasopressin-loading test was performed on 61 consecutive patients with adrenal nodules (CS: 33, aldosterone-producing adenoma: 10, non-functional tumor: 18). Vasopressin responders were observed in 36.1% of adrenal nodule(s), 42.4% of CS and 28.5% of non-CS. In responders with CS, eight patients had bilateral nodules that were diagnosed as AIMAH, and the remaining six patients had a unilateral nodule. These patients had lower plasma cortisol than non-responders at both morning ( P < 0.01) and midnight ( P < 0.05), as well as the morning following overnight dexamethasone suppression at 1 mg ( P < 0.05) and 8 mg ( P < 0.05). Hyper-responsiveness of the adrenal gland to vasopressin resulting in enhanced plasma cortisol was frequently observed among patients with adrenal nodule(s). The vasopressin responders among the patients with adrenal nodule(s) frequently had CS with low autonomous cortisol secretion.

Phosphodiesterase 11A (PDE11A) and Genetic Predisposition to Adrenocortical Tumors

We have reported previously nonsense inactivating mutations of the phosphodiesterase 11A (PDE11A) gene in patients with micronodular adrenocortical hyperplasia and Cushing syndrome. The aim of this study is to investigate the presence of somatic or germ-line PDE11A mutations in various types of adrenocortical tumors: ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), adrenocortical adenoma (ACA), and adrenocortical cancer (ACC). PDE11A was sequenced in 117 adrenocortical tumors and 192 controls subjects; immunohistochemistry for PDE11A and tumor cyclic AMP levels were studied in a subgroup of adrenocortical tumors. One PDE11A inactivating mutation (R307X) was found in one ACA, 22 germ-line missense variants (18.8%) were found in adrenocortical tumors, and only 11 missense variants (5.7%) were found in controls. By comparing the common mutations, a higher frequency of mutations in adrenocortical tumors than in age/sex-matched controls were observed [16% versus 10% in ACC, 19% versus 10% in ACA, and 24% versus 9% in AIMAH; odds ratio (OR), 3.53; P = 0.05]. Somatic DNA from adrenocortical tumors with missense variants showed a wild-type allelic loss. A significant difference between ACC and controls was observed for a polymorphism in exon 6 (E421E; OR, 2.1; P = 0.03) and three associated polymorphisms located in intron 10-exon 11-intron 11 (OR, 0.5; P = 0.01). In AIMAH/ACA, cyclic AMP levels were higher than in normal adrenals and decreased PDE11A immunostaining was present in adrenocortical tumors with PDE11A variants. The present investigation of a large cohort of adrenocortical tumors suggests that PDE11A sequence defects predispose to a variety of lesions (beyond micronodular adrenocortical hyperplasia) and may contribute to the development of these tumors in the general population.

Phaeochromocytoma comb?ned with subclinical Cushing's syndrome and pituitary microadenoma

Phaeochromocytoma (PHEO) occasionally associates with pathological lesions of the adrenal cortex. The coexistence of PHEO and pre-clinical Cushing's syndrome (PCS) of the same adrenal gland has rarely been reported. We report a case of PHEO and PCS originating from the same adrenal gland and discuss the peculiar diagnostic aspects of this entity. A 64 yr old man was hospitalized to evaluate the right adrenal mass which was discovered incidentally by ultrasonography. He had a history of type 2 diabetes mellitus and hyperlipidemia. Blood pressure measurements were all normal during his hospital stay. Laboratory examination showed: urinary catecholamines were markedly increased. HbA1C of 14.3 %, midnight cortisol of 11(microg/dL), cortisol was not suppressed after the overnight 1 mg oral dexamethasone suppression test (DST): 3.42(microg/dL), 24 hr free cortisol in the urine : 213 microg/day (10-100), cortisol levels were suppressed more than 50% with 8 mg of dexamethasone. CT scan of the adrenal glands showed a 6 cm well encapsulated right adrenal mass together with a clearly normal left adrenal gland. MRI investigation of the sella turcica revealed a pituitary microadenoma on the right side of the adenohypophysis He was treated with alpha and subsequent beta blockers after the diagnosis of PHEO and PCS was made. Right adrenalectomy was performed. The pathology showed typical PHEO with adrenocortical hyperplasia. VMA, metanefrin and free cortisol levels were normalized one month after surgery. The present report is a rare case of PHEO combined with PCS in the same adrenal gland.

Unraveling the molecular basis of micronodular adrenal hyperplasia

The present review discusses the molecular basis of micronodular adrenal hyperplasia. It focuses on the role of genetic defects in cyclic-AMP (cAMP) signaling-related molecules, namely PRKAR1A, GNAS, PDE11A, and PDE8B in the predisposition to tumor formation. This review also discusses the involvement of cAMP signaling and related pathways and their impact on the adrenocortical tumor formation. Molecular abnormalities in the phosphodiesterases family are the most recently discovered genetic abnormalities that predispose individuals to various adrenocortical tumors. In contrast to GNAS and PRKAR1A, defects in phosphodiesterases are associated more frequently with incomplete penetrance. Recent findings indicate the importance of cAMP signaling for normal adrenocortical functioning and the sensitivity of the adrenal gland to subtle alterations in cAMP levels. The identification of low-penetrance mutations in more than one phosphodiesterase in patients with adrenocortical hyperplasia is suggestive for a complementary role of the different phosphodiesterases in adrenal gland abnormalities and possible involvement of other members of this pathway in adrenocortical tumor defects.

Phosphodiesterase 11A Expression in the Adrenal Cortex, Primary Pigmented Nodular Adrenocortical Disease, and other Corticotropin-independent Lesions

A variety of adrenal tumors and bilateral adrenocortical hyperplasias (BAH) leading to Cushing syndrome (CS) may be caused by aberrant cAMP signaling. We recently identified patients with a micronodular form of BAH that we have called "isolated micronodular adrenocortical disease" (iMAD) in whom CS was associated with inactivating mutations in phosphodiesterase (PDE) 11A ( PDE11A). In the present study, we examined PDE11A expression in normal adrenocortical tissue, sporadic tumors, and hyperplasias without PDE11A mutations, and primary pigmented nodular adrenocortical disease (PPNAD) and adenomas from patients with PRKAR1A and a single tumor with a GNAS mutation. The total number of the tumor samples that we studied was 22. Normal human tissues showed consistent PDE11A expression. There was variable expression of PDE11A in sporadic adrenocortical hyperplasia or adenomas; PPNAD tissues from patients with PRKAR1A mutations expressed consistently high levels of PDE11A in contrast to adenomas caused by GNAS mutations. Phosphorylated CREB was the highest in tissues from patients with iMAD compared to all other forms of BAH and normal adrenal tissue. We conclude that PDE11A is expressed widely in adrenal cortex. Its expression appears to be increased in PPNAD but varies widely among other adrenocortical tumors. PRKAR1A expression appears to be higher in tissues with PDE11A defects. Finally, sequencing defects in PDE11A are associated with a high state of CREB phosphorylation, just like PRKAR1A mutations. These preliminary data suggest that these two molecules are perhaps regulated in a reverse manner in their control of cAMP signaling in adrenocortical tissues.