A case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldosterone secretion?

OBJECTIVE: The mechanisms inducing steroidogenesis in primary aldosteronism (PA) remain poorly defined. It was recently demonstrated that some G-protein-coupled receptors are abnormally expressed in aldosterone-producing adenomas (APA). We evaluated the potential role of LH and GNRH receptors (LHR (or LHCGR) and GNRHR) in regulating aldosterone secretion in a patient with APA arising during pregnancy (index case) and in a subset of other patients with PA. PATIENTS AND METHODS: GNRH test was performed in the index case, 11 other PA, and 5 controls. GNRHR and LHR expressions were examined in 23 APA and 6 normal tissues. RESULTS: Aldosterone response increased significantly (114%) in the index case after GNRH test was performed preoperatively, while it was blunted after adrenalectomy. Aldosterone also increased after human chorionic gonadotropin and triptorelin stimulation. A partial aldosterone response to GNRH was observed in other 7/11 PA, while a significant response was observed in two patients. Controls did not respond to GNRH test. GNRHR was overexpressed and LHR expression was moderate in the APA tissue from the index case. Moreover, LHR was found in normal adrenals and overexpressed in 6/22 APA. GNRHR was overexpressed in 6/22 APA, 2 of them with a 95- and 109-fold higher expression than normal. A correlation between the clinical and molecular findings was observed in five out of seven patients. CONCLUSION: We describe a case of PA diagnosed during pregnancy, which appeared to correlate with aberrant LHR and GNRHR expression. Our findings suggest that a subset of patients with PA has aberrant LHR and GNRHR expression, which could modulate aldosterone secretion.

Somatostatin receptor expression in adrenocortical tumors and effect of a new somatostatin analog SOM230 on hormone secretion in vitro and in ex vivo adrenal cells.

BACKGROUND: Somatostatin is a widely distributed polypeptide that modulates endocrine and exocrine secretion, cell proliferation, and apoptosis by 5 somatostatin receptors (SSTR1-5). The inhibitory effects of somatostatin on tumor growth may be the result of its suppressing the synthesis and/or secretion of growth factors and growth-promoting hormones. AIM: Very little information is available on the effect of somatostatin analogs on adrenal tumors, so we examined SSTR expression in adrenocortical tumors and studied the effect of a somatostatin analog (SOM230) on hormone secretion and cell viability in adrenal cells. MATERIAL/SUBJECTS AND METHODS: SSTR expression was analyzed by real-time PCR in 13 adrenocortical carcinomas (ACC), 24 aldosterone-producing adenomas (APA), 11 cortisol-producing adenomas (CPA), and 7 normal adrenals (NA), and verified by immunohistochemistry (IHC) in 14 samples. The effect of SOM230 on cortisol or aldosterone secretion in H295R and primary cell cultures was determined by radioimmunoassay, and its effect on viability in H295R and SW13 using the MTT test. RESULTS: SSTR1 and SSTR2 mRNA was expressed in 100% of adrenal tumors. Compared to NA, ACC revealed an increase in almost all SSTR, while only some APA over-expressed SSTR3 and SSTR1. CPA expressed SSTR similar to NA. IHC confirmed the mRNA expression data. At nanomolar concentrations, SOM230 inhibited hormone secretion in primary adrenal cultures and H295R cells, but had no evident effect on cell viability. CONCLUSIONS: The evidence of SSTR over-expression (particularly in ACC) and of hormone secretion being inhibited by SOM230 suggests a potential therapeutic role for this broad-spectrum somatostatin analog in adrenal tumors.

Genetics of adrenal tumors.

The impact of genetics and genomics on clinical medicine is becoming more and more important. Endocrinology pioneered the development of molecular medicine, but also the study of adrenal tumors had a great impact in this field. Particularly important was the detection of genetics of tumors derived from the adrenal medulla, as well as that of those derived from the sympathetic and parasympathetic paraganglia. The identification of mutations in one of the several pheochromocytoma/paraganglioma susceptibility genes may indicate a specific clinical management drive. Less well understood is the genetics of adrenal cortex tumors, in particular adrenocortical carcinoma, a rare and particularly aggressive disease. There are only a few examples of hereditary transmission of adrenocortical carcinoma, but the analysis of low penetrance genes by genome wide association study may enable us to discover new genetic mechanisms responsible for adrenocortical-derived tumors.

Food-dependent Cushing's syndrome: from molecular characterization to therapeutical results.

OBJECTIVE: Cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) may be regulated by the aberrant expression of several G-protein-coupled receptors. Bilateral adrenalectomy is the treatment of choice in most cases. We searched for aberrant receptor expression in a patient with AIMAH and evaluated the response to medical and surgical treatment. PATIENT: A 35-year-old woman with amenorrhea, hirsutism, and hypertension presented ACTH-independent cortisol secretion with high androgen levels. Abdominal computed tomography showed bilateral adrenal macronodules (4.5 cm right and 1.0 cm left). Scintigraphy with I(131)-norcholesterol showed bilateral uptake, prevalent on the right side. Several in vivo stimulation tests were assessed before and after treatment and in vitro studies were performed after unilateral adrenalectomy. RESULTS: Plasma cortisol increased after a standard meal test (60%) and oral glucose loading (147%), and the response was blunted by pretreatment with 100 microg s.c. octreotide. The therapy with long-acting release octreotide (octreotide-LAR) showed an improvement in urinary free cortisol (UFC) levels. Unilateral adrenalectomy was performed and histopathology revealed macronodular AIMAH. Cortisol and androgens increased after perifusion of tumoral tissue with glucose-dependent insulinotropic polypeptide (GIP), and GIP and LH-receptor overexpression was found in both the adrenal nodules and the adjacent cortex. After surgery, UFC and androgen levels normalized followed by clinical improvement. CONCLUSIONS: GIP and LH-receptor expression may coexist in AIMAH, influencing the functional and morphological phenotype. Aberrant hormone receptor expression enables specific pharmacological treatment, but long-term studies are needed to evaluate its real efficacy. Unilateral adrenalectomy may be a safe initial option, particularly for asymmetric bilateral adrenal enlargements.

Cardiovascular risk factors and ultrasound evaluation of intima-media thickness at common carotids, carotid bulbs, and femoral and abdominal aorta arteries in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a tendency for obesity, high insulin, and high 24-h blood pressure levels has been reported in children and adolescents. Increased intima-media thickness (IMT) is considered a measure of subclinical atherosclerosis and a predictor of myocardial infarction and stroke. OBJECTIVE: The objective of the study was to evaluate glucose metabolism, lipid profile, IMT of the abdominal aorta, right and left common carotids, carotid bulbs, and common femoral arteries in adult CAH patients. SUBJECTS: Nineteen (10 females, nine males; 28 +/- 3.5 yr) patients (12 salt wasting and seven simple virilizing) and 19 (10 females, nine males) healthy subjects matched for anthropometric parameters (age, sex, body mass index, smoking habit, waist to hip ratio, and blood pressure). METHODS: Glucose metabolism was studied using the oral glucose tolerance test and the homeostasis model assessment-insulin resistance. The echo-Doppler was used for arterial ultrasound. 17-Hydroxyprogesterone, androstenedione, testosterone, ACTH, plasma renin activity, total and high-density lipoprotein cholesterol, and triglycerides were measured. RESULTS: CAH patients had significantly higher fasting plasma insulin (11.6 +/- 6.20 microU/ml vs 5.18 +/- 2.4 microU/ml; P < 0.0001) and homeostasis model assessment-insulin resistance than controls (2.46 +/- 1.92 vs 1.12 +/- 0.58; P = 0.0033). IMT of the studied arteries was higher in CAH patients than controls. There was no correlation between IMT and cumulative glucocorticoid doses and androgen levels. CONCLUSION: A reduced insulin sensitivity and increased IMT were demonstrated in adults with CAH, who consequently need a follow-up for cardiovascular risk.

X-linked adrenoleukodystrophy with olivopontocerebellar atrophy.

X-linked adrenoleukodystrophy (X-ALD) is a rare neurological disorder characterized by adrenal, gonadal and nervous system dysfunction. Patients usually develop spinal cord degeneration with involvement of the cerebral white matter. While a spinocerebellar variant has been described, the selective involvement of cerebellar white matter is very rare. We report the case of a patient affected by X-ALD whose clinical and magnetic resonance imaging (MRI) results resembled olivopontocerebellar atrophy. He was a 29-year-old mentally retarded man, who began to complain of slowly progressive gait ataxia after an 8-year history of Addison's disease. Serial MRI revealed marked cerebellar atrophy involving the inferior cerebellar vermis and brainstem, but sparing the supratentorial white matter. The diagnosis of X-ALD was confirmed by elevated levels of very long-chain fatty acids in the serum. After 2 years follow-up, the patient developed spastic paraparesis. The patient represents an unusual clinical presentation of X-ALD, as further confirmed by the MRI results. Consequently, cerebellar symptoms should be considered as a clinical presentation of X-ALD. Early recognition of this rare disorder would be useful for genetic counselling and therapy.

Comparison of circulating and local adipose tissue renin-angiotensin system in normotensive and hypertensive obese subjects.

The renin-angiotensin-aldosterone system (RAAS) plays a well-recognized role in the regulation of BP and in salt and water balance. Since hypertension affects a considerable proportion of obese patients, circulating RAAS has been studied in obese subjects with and without hypertension, albeit with conflicting results. Furthermore, attention has recently focused on the expression of the components of the Renin-angiotensin system (RAS) in some organs, including adipose tissue where it seems to be involved in the regulation of growth and differentiation. The aim of our study was to investigate circulating RAAS and adipose tissue RAS in obese patients with and without hypertension and in matched controls. PRA, and plasma and urinary aldosterone levels were measured in 35 obese, 30 hypertensive obese patients and in 20 controls. In addition, the expression of angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1) genes was studied in sc adipose tissue from 8 obese, 6 hypertensive obese and 6 healthy subjects. As previously demonstrated in other studies, there were no significant differences in the levels of circulating RAAS components in the 3 groups. As regards local RAS, interestingly, we found that AT1 gene was significantly more expressed in sc adipose tissue from obese patients with hypertension than in those without hypertension and controls. By contrast, AGT levels were similar in the 3 groups. Our data do not support the hypothesis of an involvement of circulating RAAS in the development of obesity-related hypertension. On the other hand, local RAS seems to be differently regulated in sc adipose tissue from obese patients with hypertension with respect to normotensive obese patients and controls.

Gene expression of angiotensinogen in adipose tissue of obese patients.

Recently, the genes of components of the renin-angiotensin system (RAS), namely angiotensinogen (AGT), angiotensin converting enzyme and angiotensin II receptor have been described in adipose tissue. In animal models the angiotensinogen in adipose tissue has been implicated in the pathogenesis of metabolic alterations and hypertension associated with obesity. The aim of our study was to evaluate the AGT gene expression both in visceral and subcutaneous adipose tissue in obese patients and lean subjects. AGT mRNA levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR) using specific primers. AGT mRNA was expressed at variable levels in obese patients. It was significantly greater in visceral than in subcutaneous adipose tissue. Positive and significant correlation was found between the expression of AGT in visceral adipose tissue and BMI. These data suggest that angiotensinogen may be determinant of fat distribution and may be involved in the plurimetabolic syndrome of central obesity.