Overnight dexamethasone suppression of cortisol is associated with radiocholesterol uptake patterns in adrenal incidentalomas.
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Adenoma↗
Biomedical subjects
F Fallo
Publications and source records attributed to F Fallo.
Scintigraphic patterns of adrenocortical carcinoma: morpho-functional correlates.
OBJECTIVE: Adrenocortical scintigraphy has demonstrated clinical utility in the morpho-functional characterization of adrenal tumors. The aim of this study was to identify possible relationships between the scintigraphic pattern and endocrine and/or morphological data in a series of adrenocortical carcinomas. DESIGN AND METHODS: Twenty-one patients with adrenocortical carcinoma (11 nonfunctioning and 10 hormone-secreting) were investigated with 75Se-methyl-nor-cholesterol scintigraphy. Clinical, hormonal, radiological, and pathological data were analyzed. RESULTS: The adrenal mass showed no radiocholesterol uptake in 18 cases (11 nonfunctioning and 7 functioning lesions). Contralateral normal adrenal gland was visualized in all patients with nonfunctioning tumors, whereas classic bilateral nonvisualization was observed in the 7 cases with hyperfunctioning masses. Three patients with cortisol-producing carcinomas showed radiotracer uptake by the mass, without visualization of the contralateral gland. At histology, the tumors were shown to be undifferentiated adrenocortical carcinomas; they had an aggressive clinical behavior. CONCLUSIONS: Radiocholesterol scintigraphy has an important role in diagnosing adrenocortical carcinomas, which typically are not visualized. However, 30% of hypersecreting adrenocortical carcinomas show an atypical increased tracer uptake, not predictive of the biochemical and histological features of the tumor.
Adolescent↗
Multiple endocrine neoplasia type 1 and adrenal lesions.
PURPOSE: We investigated the relationship of long-term pancreatic hormone hypersecretion with adrenal lesions in patients with multiple endocrine neoplasia type 1 and in those with sporadic pancreatic endocrine tumors. MATERIALS AND METHODS: We assessed the prevalence of adrenal lesions in 20 patients with multiple endocrine neoplasia type 1 and in a control group of 12 with sporadic pancreatic endocrine tumors. We also performed genetic testing for germline mutations of MEN1, the multiple endocrine neoplasia type 1 gene. RESULTS: Adrenal lesions were common in multiple endocrine neoplasia type 1, accounting for 35% of cases. All adrenal lesions were nonfunctioning and benign. The relative risk of adrenal tumors was higher in patients with multiple endocrine neoplasia type 1 than in controls (p <0.05). No apparent relationship was observed of hormonal pattern or genotype with adrenal disease. CONCLUSIONS: Hormone hypersecretion by pancreatic endocrine tumors is not the primary cause of the development of adrenal lesions and the role of the MEN1 gene in adrenal tumorigenesis remains unclear. Adrenal lesions follow a benign course in most multiple endocrine neoplasia type 1 cases but careful morphological and functional followup is advisable.
Adolescent↗
Effect of the serotonin antagonists ritanserin and ketanserin in Cushing's disease.
Central serotonergic regulation could have a role in the course of pituitary-dependent Cushing's disease. We studied the effects of ritanserin and ketanserin, two related selective 5HT2 receptor antagonists, in 11 patients with Cushing's disease. Treatment lasted from 1 month to 1 year (up to 4 years in one patient). Daily doses were 10-15 mg for ritanserin, and 40-80 mg for ketanserin. Since the two drugs share the same mechanism of action and no qualitative or quantitative differences in response to their administration were observed, the results were pooled together. Patients were assessed by clinical and hormonal evaluation. Urinary cortisol and ACTH were considered the parameters of interest. Short-term response: after 1 month, there was a significant decrease of urinary cortisol from 781 (160) to 331 (215) nmol/d (P < 0.02) while ACTH was 9.8 (1.5) pmol/L baseline and again 8.8 (2.2) pmol/L at 1 month (P = NS). For 9 patients, hormonal parameters were available after 1 week of treatment. In this case, also ACTH levels were significantly decreased (from 9.6 (1.7) to 5.2 (1.3) pmol/L; P < 0.01) together with urinary cortisol (from 781 (194) to 372 (165) nmol/d; P < 0.01). Long-term response: in 3 patients, hormonal parameters failed to respond to serotonin receptor antagonists, which were thus discontinued. An improvement was recorded in the remaining 8 patients, that was prolonged in 3, and transient in 5. In 3 of these latter patients, a marked increase of ACTH was observed before treatment discontinuation. Ketanserin was given to 2 patients with Nelson's syndrome, with only transient ACTH decrease in one, and no changes in ACTH response to CRH after 1 month treatment in both cases. An inhibitory effect of ritanserin and ketanserin on ACTH and cortisol production in Cushing's disease appeared to be limited both in terms of duration of response and number of patients with a satisfactory outcome. However, the results may provide a better understanding of serotonergic modulation in Cushing's disease and lead to therapeutic developments.
Adolescent↗
CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism.
Primary aldosteronism is characterized by autonomous production of aldosterone and arterial hypertension, and it occurs in 2 principal forms: aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). APA can be cured through removal of the adenoma, whereas IHA leads to hypertension that must be treated with medication. The origin of the autonomous aldosterone production in IHA is poorly understood, but genetic factors may contribute to its cause. To test the hypothesis that variants of the aldosterone synthase gene may contribute to susceptibility to IHA, we compared genotypes at 3 polymorphic sites in the CYP11B2 gene in patients with IHA (n=90) with those found in patients with APA (n=38), in patients with essential hypertension (n=72), and in normotensive individuals (n=102). We observed significant linkage disequilibrium among the 3 polymorphisms with 2 frequent haplotypes in all groups studied. One haplotype (C2R) was found to be increased in frequency in the IHA group (47%) compared with the other groups, which had a similar haplotype frequency (36%). The 3 polymorphisms studied have been implicated in either essential hypertension or excess aldosterone production in previous studies. Because of the strong linkage disequilibrium, the observed results could be due to the action of any 1 of the 3 alleles or to another allele in linkage disequilibrium with them. Our results suggest that variations in the CYP11B2 gene may contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.
Alleles↗
Slow-release lanreotide treatment in acromegaly: effects on quality of life.
BACKGROUND: It is not known whether medical treatment to lower growth hormone (GH) and insulin-like growth factor (IGF)-1 levels may improve the compromised quality of life of patients with acromegaly. METHODS: We studied the effects on quality of life of the slow-release somatostatin analogue lanreotide, 30 mg i.m., every 14 days for 2 months in 10 patients with active acromegaly (8 females/2 males, mean age 57.3 +/- 11.4). Hormone measurements and psychometric evaluation by means of self-rating scales were carried out in baseline conditions and after 1 and 2 months. The Symptom Questionnaire (SQ), the Cognitive Scale of the Screening List for Psychosocial Problems by Kellner and the Social Situation Questionnaire by Marks were employed. RESULTS: Together with a significant decrease in GH and IGF-1, treatment with lanreotide significantly improved SQ psychological distress, SQ well-being and Social Situation Questionnaire social fears. CONCLUSION: Medical treatment with lanreotide may improve the quality of life of patients with acromegaly. Being an open trial, changes could be due to nonspecific effects. However, they did not fade at 2 months. Improvement involved fears of social situations that have been linked to GH abnormalities.
Acromegaly↗
Mutations in CYP11B1 gene converting 11beta-hydroxylase into an aldosterone-producing enzyme are not present in aldosterone-producing adenomas.
In the human adrenal cortex, cortisol and aldosterone are synthesized by the isozymes 11beta-hydroxylase and aldosterone synthase, respectively, encoded by the 93% identical CYP11B1 and CYP11B2 genes. In vitro mutagenesis of CYP11B1 complementary DNA, resulting in the replacement of CYP11B1 codons by those encoding the corresponding amino acid residues of CYP11B2 enzyme (exon 5, Ser288Gly; exon 6, Val320Ala), yields a complementary DNA encoding a mutant enzyme with an efficient aldosterone synthase activity. Identical somatic mutations in the CYP11B1 gene in vivo would produce a gene encoding an enzyme with C18 activity and that would preserve ACTH responsiveness due to the retained 5'-promoter in the mutated CYP11B1 gene. An ACTH-responsive aldosterone synthase activity of this type is commonly seen in patients with aldosterone-producing adenomas (APA). We examined the occurrence of mutations in exons 5 and 6 of the CYP11B1 gene in APA from 10 patients with primary aldosteronism. Patients were selected on preoperative evidence of a 50% or greater plasma aldosterone decrease after short term dexamethasone trial and no aldosterone response to upright posture. DNA from adenomas was amplified by PCR using two pairs of primers spanning the regions of CYP11B1 gene, i.e. exons 3-5 and exons 6-9, where mutations could be located. Targeted regions were screened for mutations by automated sequencing of PCR products. No point mutations of the CYP11B1 gene over the two regions examined were found in APA. This argues against involvement of mutations in the pathogenesis of ACTH-responsive APA.
Adenoma↗
Risk factors and long-term follow-up of adrenal incidentalomas.
The natural course of adrenal incidentalomas and the risk that such lesions evolve toward hormonal hypersecretion or malignancy are still under evaluation. Of 246 consecutive patients with adrenal incidentaloma studied at our institution in the last 15 yr, 91 underwent surgery. Of the remaining patients, a group of 75 (52 females and 23 males; median age, 56 yr; range, 19-77 yr) with incidentally discovered asymptomatic adrenal masses (60 unilateral and 15 bilateral; median diameter, 2.5 cm; range, 1.0-5.6) was enrolled in an endocrine and morphological follow-up of at least 2 yr after diagnosis (median, 4 yr; range, 2-10). During follow-up, no patients developed malignancy; 9 showed mass enlargement, with appearance of a new mass in the contralateral gland in 2; 3 developed adrenal hyperfunction (overt Cushing's syndrome in 2, nonclinical hypercortisolism in 1); and 3 showed adrenal mass enlargement associated with adrenal hyperfunction (nonclinical hypercortisolism in 2, pheochromocytoma in 1). The estimated cumulative risks to develop mass enlargement and hyperfunction were 8% and 4%, respectively, after 1 yr, 18% and 9.5% after 5 yr, and 22.8% and 9.5% after 10 yr. Nine risk factors for adrenal mass enlargement or hyperfunction were arbitrarily selected and evaluated: sex, age, presence of obesity, hypertension, diabetes, abnormal endocrine tests, mass size, mass location, and scintigraphic uptake pattern. Three of them attained statistical significance: mass size of 3 cm or more at diagnosis and exclusive radiocholesterol uptake by the mass at scintigraphy had relevance for the occurrence of adrenal hyperfunction, whereas the presence of endocrine test abnormalities at diagnosis had predictive value for mass enlargement. It is concluded that subtle hormonal abnormalities are risk factors for mass size increase, which is not a sign of malignant transformation. Both mass size of 3 cm or more at diagnosis and exclusive radiocholesterol uptake, indicating higher risks of hyperfunction, should be considered to plan a more thorough endocrine follow-up.
Adolescent↗
Comment--Is there a role for low doses of mitotane (o,p'-DDD) as adjuvant therapy in adrenocortical carcinoma?
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Adrenal Cortex Neoplasms↗
Inactivation of the p16 tumor suppressor gene in adrenocortical tumors.
The mechanisms of adrenocortical tumorigenesis are still unknown. Evidence that the majority of adrenocortical tumors are monoclonal in origin suggests that a progressive accumulation of genetic aberrations, due to activation of protooncogenes and/or inactivation of tumor suppressor genes, leads to abnormal cell proliferation through a multistep process. Inactivation of the p16 tumor suppressor gene (p16INK4A), which encodes the cell cycle protein p16, was investigated in a series of 14 adrenocortical tumors. Using 11 polymorphic microsatellite markers spanning the short arm of chromosome 9, we demonstrated that three of seven adrenocortical carcinomas and one of seven adrenocortical adenomas had loss of heterozygosity (LOH) within chromosome 9p21, the region containing p16NK4A. Immunohistochemistry showed the absence of p16 nuclear staining in all adrenocortical tumors with LOH within 9p21, and positive staining in all remaining tumors without LOH. In conclusion, LOH within 9p21 associated with lack of p16 expression occurs in a considerable proportion of adrenocortical malignant tumors, but is rare in adenomas. Inactivation of p16INK4A may contribute to the deregulation of cell proliferation in this neoplastic disease.
Adrenal Cortex Neoplasms↗
Regression of cardiac abnormalities after replacement therapy in Addison's disease.
OBJECTIVE: To evaluate by echocardiography the cardiac structure and function in patients with primary adrenocortical insufficiency. DESIGN AND METHODS: Two-dimensionally guided M-mode echocardiograms and spectral Doppler studies were performed in seven consecutive patients with newly diagnosed autoimmune primary adrenal failure before and 4-8 months after an adequate regimen of steroid substitution. Echocardiographic parameters were also studied in ten healthy controls. RESULTS: In the cases with untreated Addison's disease, both left ventricular end-systolic and end-diastolic dimensions were significantly reduced in comparison with those in controls (P<0.01). Four patients had echocardiographic signs of mitral valve prolapse (MVP) at the anterior leaflet, with no evidence of mitral regurgitation by Doppler echocardiography. Systolic clicks characteristic of MVP were present on auscultation in two of these cases. Left ventricular chamber size normalized, i.e. significantly increased (P<0.01), and both echocardiographic and physical signs of MVP resolved after steroid substitution in all patients. All other echocardiographic indices were normal before and after treatment. CONCLUSIONS: Patients with untreated Addison's disease have cardiac abnormalities which regress after steroid substitution. A valvular-ventricular disproportion due to the hypovolemic state could explain these findings.
Addison Disease↗
Effect of octreotide on 24-h blood pressure profile in acromegaly.
The aim of the study was to investigate the effect of octreotide, a somatostatin analog drug potentially able to inhibit growth hormone (GH), on the circadian blood pressure profile in a group of patients with acromegaly. Ten patients with GH-secreting pituitary adenoma were studied before and 6 months after treatment with subcutaneous octreotide 0.2 to 0.6 mg/day. Twenty-four hour blood pressure and heart rate were measured every 15 min at daytime (07:00 to 22:59) and every 30 min at nighttime (23:00 to 06:59) using a TM-2420 recorder. No correlation was found between GH levels and 24-h blood pressure in baseline conditions. Untreated patients had a significant nocturnal decrease of both systolic and diastolic blood pressure (P < .01), and all showed a circadian systolic or diastolic blood pressure rhythm. During octreotide treatment, 24 h as well as nighttime systolic and diastolic blood pressures significantly increased (P < .05), whereas daytime systolic and diastolic blood pressures did not change. Treated patients did not have a nocturnal decline in both systolic and diastolic blood pressures (P = NS), and eight lost their systolic or diastolic blood pressure rhythm. In conclusion, blood pressure circadian rhythm seems to be maintained in acromegaly. Octreotide treatment is associated with an increase of 24-h and nighttime blood pressure, and with loss of circadian blood pressure rhythm. Splanchnic vasoconstriction by this drug, shifting blood to peripheral vessels, may explain this phenomenon.
Acromegaly↗
Zona fasciculata-like histotype and aldosterone response to upright posture are not related in aldosterone-producing adenomas.
Two distinct subtypes of patients with primary aldosteronism due to aldosterone-producing adenomas (APA), based on different aldosterone responses to angiotensin, have been identified. We evaluated the relationship between adrenal zona fasciculata-like histotype and response of plasma aldosterone to upright posture in a series of patients with APA. Twenty-five patients were retrospectively divided in two groups according to aldosterone response to posture, i.e., a first group without postural change of aldosterone (n = 19) and a second group with at least 30% aldosterone increase after standing (n = 6). The percentage of zona fasciculata-like cells was calculated at histology in all adenoma tissues removed at adrenalectomy. The two groups of patients were similar in sex, age, systolic/diastolic blood pressure, supine/upright plasma renin activity, supine/upright aldosterone, tumor size. No differences between the two groups were observed as to zona fasciculata-like (84 +/- 3% vs 71 +/- 9%, P NS) and non-zona fasciculata-like cells percentage in adenoma tissues. No inverse correlation was found in either group between the percentage change from supine to upright aldosterone and the percentage of zona fasciculata-like cells. Aldosterone and cortisol responses to ACTH testing were similar in the two groups. Our results indicate that the two subtypes of primary aldosteronism based on different postural responses of aldosterone are not due to a different prevalence of zona fasciculata-like histotype in APA.
Adenoma↗
Incidentally discovered adrenal tumors: endocrine and scintigraphic correlates.
Hormonal and morphological data were investigated in 202 consecutive patients with adrenal incidentalomas (171 unilateral and 31 bilateral) in an attempt to assess subclinical hyperfunction or malignancy. In addition to the classical evaluation, scintiscan was carried out in a large number of these patients. In unilateral incidentalomas, 83% showed normal hormonal function, whereas 17% had biochemical signs of adrenal overactivity (hyperaldosteronism in 3, hypercortisolism in 17, medullary hyperfunction in 9). [75Se]Methylnorcholesterol scintigraphy depicted malignant, space-occupying lesions as decreased or absent radiotracer uptake by the mass, and cortical adenomas as increased or normal uptake. In cortical adenomas a relationship between radiocholesterol uptake and degree of functional autonomy was demonstrated. [123I]Metaiodobenzilguanidine scintiscan visualized 7 of 8 pheochromocytomas. In bilateral incidentalomas, abnormal adrenal function was more frequent, accounting for 29% of cases (hyperaldosteronism in 3, hypercortisolism in 3, adrenal insufficiency in 2, and congenital adrenal hyperplasia in 1). Malignant lesions were not scintigraphically visualized. [75Se]Methylnorcholesterol scan also provided functional information in the case of a cortisol-secreting adenoma and an aldosteronoma with a concomitant contralateral nonhypersecreting adenoma, showing the greatest uptake in the hyperfunctioning adenomas. In both unilateral and bilateral lesions, endocrine testing failed to differentiate benign from malignant tumors. Although hormonal assessment is mandatory to clarify the functional patterns, only morphofunctional examination by scintiscan seems to provide more data about the likelihood of malignancy.
17-alpha-Hydroxyprogesterone↗
Age-related changes in glucocorticoid fast feedback inhibition of adrenocorticotropin in man.
A decrease in hypothalamic-pituitary-adrenal axis sensitivity to glucocorticoid feedback suppression seems to occur with aging. To investigate possible abnormalities in the inhibitory effect of glucocorticoids on ACTH secretion in the elderly, we evaluated the endogenous ACTH response to hydrocortisone (25 mg as an i.v. bolus) in 15 healthy aged (65-88 yr) and 15 healthy young (18-26 yr) men. Blood samples for ACTH and cortisol determinations were collected at -15, 0, 2, 5, 10, 15, 30, 45, 60, 90, 120, and 180 min. Hydrocortisone injection produced a rapid increase in plasma cortisol levels within the first 2 min in both groups. In old men, in concomitance with the cortisol increase, ACTH levels showed only a slight and nonsignificant decrease within the first 15 min, followed by a pronounced and significant decline thereafter. In young subjects, in concomitance with the plasma cortisol increase, a marked decrease in ACTH levels was observed within the first 15 min, followed by a less pronounced decline thereafter. The response curve of ACTH inhibition could be arbitrarily divided in two parts. The first part (from 0-60 min) showed a significant difference between old and young men, whereas the remaining part of the curve (from 60-180 min) showed no differences between the two groups. The slower response in glucocorticoid feedback inhibition of ACTH in old men supports the concept of some alteration in the central regulation by steroids in aging. Age-related vascular factors affecting cortisol penetration through the blood-brain barrier more than hippocampus-hypothalamus receptor abnormalities could be involved in the fast component of hypothalamic-pituitary-adrenal axis feedback regulation.
Adolescent↗
Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene.
Aldosterone suppression by dexamethasone, and high 18-hydroxycortisol and 18-oxocortisol levels are used to differentiate glucocorticoid-remediable aldosteronism (GRA) from other forms of primary aldosteronism. These methods are time consuming, expensive, and impractical for large studies. Moreover, diagnosis of GRA requires a confirmatory genetic test. We evaluated 117 patients with primary aldosteronism referred to our centers by the use of a long PCR technique to reveal the chimeric gene of GRA. In 60 of 117 patients, the response of aldosterone to dexamethasone (2 mg/day for 4 days) was also assessed. None of our patients, including 2 pairs of siblings, was positive for the chimeric gene. The results of long PCR were confirmed by Southern blotting. Despite a negative genetic test, 6 patients (1 with aldosterone-producing adenoma and 5 with idiopathic hyperaldosteronism) had plasma aldosterone suppressed by dexamethasone (i.e. < or = 2 ng/dL). Of 117 patients, 43 were identified as having aldosterone-producing adenoma and 74 as having idiopathic hyperaldosteronism. In our experience, the long PCR technique is a reliable and simple test to at least exclude GRA in patients with primary aldosteronism. A short term dexamethasone suppression test of aldosterone can be misleading in identifying GRA. The prevalence of GRA in primary aldosteronism remains to be established.
Adult↗
Evidence for androgen receptor gene expression and growth inhibitory effect of dihydrotestosterone on human adrenocortical cells.
Evidence for the expression of the canonic androgen receptor (AR) in human adrenal cortex has not been provided so far. The aim of the present study was to demonstrate the expression of the AR gene in normal and neoplastic adrenocortical human tissues and in the human adrenocortical cancer cell line, NCI-H295, and then to evaluate the effect of dihydrotestosterone (DHT) on human adrenocortical cell growth. An AR cDNA fragment with the expected size of 262 bp was detected by using reverse transcription (RT)-PCR in normal and neoplastic adrenocortical human tissues and in the neoplastic cell line, demonstrating that the gene for AR is indeed expressed in human adrenal cells. In the human adrenocortical cancer cell line NCI-H295, DHT at physiological concentrations produced a significant reduction in cell proliferation and inhibition of colony formation in soft agar. The inhibitory effect on adrenocortical cell growth was evident after both 24 and 48 h of treatment. The antiandrogens, cyproterone acetate and hydroxyflutamide, were capable of reversing the effects exerted by DHT. The androgen-induced growth inhibitory effect was also detected in primary culture of three non-functioning adrenocortical adenomas. These findings show that the canonic AR is present in human adrenocortical cells and that androgens may have a role in the adrenal cortex by reducing cell proliferation.
Adrenal Cortex↗
Life events and neurocirculatory asthenia. A controlled study.
OBJECTIVES: The purpose of this study was to assess the occurrence of stressful life events in the year before the onset of neurocirculatory asthenia. DESIGN: Case-control retrospective study. SETTING: A university medical outpatient clinic. SUBJECTS: A consecutive series of 50 patients with neurocirculatory asthenia and a control group of 50 healthy subjects, matched for sociodemographic variables, were studied. MAIN OUTCOME MEASURES: Paykel's Interview for Recent Life Events (a semistructured research interview covering 64 life events) was administered to patients and controls. RESULTS: Patients with neurocirculatory asthenia reported significantly more stressful life events than the control group (P < 0.05) and had significantly more of the following: exits (P < 0.05), undesirable (P < 0.05) and uncontrolled (P < 0.01) events. More events that had an objective negative impact (P < 0.001) and more independent events (P = 0.07) were also reported. Ratings of impact and independence were carried out by a blind rater who was unaware whether the event had occurred in patients or controls. CONCLUSIONS: The results are suggestive of a strong relationship between stressful life events and neurocirculatory asthenia. This is in agreement with a multifactorial model of pathogenesis in neurocirculatory asthenia and with current understanding of the extensive links of behavioral responses to stress with neurophysiological and biochemical processes.
Adult↗