Adrenalectomized Patients Research Articles

The metabolic phenotype of patients with primary aldosteronism: impact of subtype and sex - a multicenter-study of 3566 Caucasian and Asian subjects.

Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics. We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed. As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients. Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

Feasibility of Imaging-Guided Adrenalectomy in Young Patients With Primary Aldosteronism.

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

Abstract P142: Factors Associated With Persistent Cardiac Organ Damage In Primary Aldosteronism After One Year Of Treatment

Introduction: Adrenalectomy and medical treatment of primary aldosteronism (PA) both induce regression of left ventricle (LV) hypertrophy, while the effects on LV myocardial function are less investigated. Hypothesis: We hypothesized that persistent cardiac organ damage was more prevalent in medically treated PA patients. Methods: Eighty-four patients (57±11 years, 27% female) with PA underwent echocardiography at time of diagnosis and after 1 year of treatment (49% adrenalectomized, 51% medically treated). Persistent cardiac organ damage was identified as LV hypertrophy or low LV systolic function by midwall shortening or global longitudinal strain (GLS), both at baseline and at follow-up. LV diastolic function was assessed by left atrial enlargement and estimated LV filling pressure (E/e’). Results from logistic regression analyses are reported as odds ratio (OR) with 95% confidence intervals (CI). Results: After 1 year, a significant regression of LV hypertrophy was observed in adrenalectomized patients (44% vs. 22%, p=0.038), but not in medically treated patients (59% vs. 50%, p=0.206). Midwall shortening, E/e’ and prevalence of enlarged left atrium improved significantly in both treatment groups (all p<0.001), while GLS remained unchanged. In multivariable logistic regression analysis, receiving medical treatment for PA (OR 4.98 [95% CI 1.26-18.88] was a strong predictor of persistent LV hypertrophy independent of higher body mass index (OR 1.20 [95% CI 1.04-1.38]) and presence of diabetes (OR 6.48 [95% CI 1.20-34.83], all p<0.05). Important covariables of persistently low midwall shortening were persistent LV hypertrophy (OR 3.50 [95% CI 1.12-10.96]) and suppression of plasma renin activity after 1 year of treatment (OR 4.31 [1.15-16.12], both p<0.05). The strongest predictor of persistently low GLS was higher HbA 1c (OR 2.37[95% CI 1.12-5.02], p=0.024). Conclusions: In PA, LV hypertrophy regression was more common in adrenalectomized patients. Persistent LV hypertrophy and impaired glucose metabolism were the major factors associated with persistent LV myocardial dysfunction independent of treatment.

Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors.

ContextTesticular adrenal rest tumors (TART) are a common complication in males with classic 21-hydroxylase deficiency (21OHD). TART are likely to contribute to the androgen excess in 21OHD patients, but a direct quantification of steroidogenesis from these tumors has not been yet done.ObjectiveWe aimed to define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART.MethodsUsing liquid chromatography-tandem mass spectrometry, steroids were measured in left (n = 7) and right (n = 4) spermatic vein and simultaneously drawn peripheral blood (n = 7) samples from 7 men with 21OHD and TART. For comparison, we also measured the peripheral steroid concentrations in 5 adrenalectomized patients and 12 age- and BMI-matched controls. Additionally, steroids were quantified in TART cell– and adrenal cell–conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation.ResultsCompared with peripheral blood from 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11β-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11β-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cells produced higher levels of testosterone and lower levels of A4 and 11OHA4 after ACTH stimulation compared with adrenal cells, indicating ACTH-induced production of testosterone in TART.ConclusionIn patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic vs peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in vitro results indicate that this metabolism is ACTH-sensitive.

Can Extra Adrenal Cortisol Secretion Occur in an Adrenalectomized Patient?

Abstract Background: Established medical practice is that adrenalectomized patients require lifelong steroid replacement. We report a case which challenges that assumption. Clinical Case: A 38 year old female underwent transsphenoidal resection of a proven ACTH secreting pituitary adenoma. Post operatively her pituitary function was preserved, but due to residual tumour activity and the desire to preserve fertility, she had a bilateral adrenalectomy one year later and commenced hydrocortisone replacement. Subsequent pituitary imaging did not show recurrence of the tumour and her visual fields were stable, however her ACTH remained elevated at 100 and 130ng/L (09:00 <50 ng/L) despite steroid replacement.14 years after adrenalectomy she noticed weight gain and increased body hair. She also reported sometimes missing her hydrocortisone due to her busy job without ill effects. Her 9 am cortisol pre-hydrocortisone was elevated at 333 nmol/L (9am: 140–690 nmol/L) with ACTH of 203.0 ng/L (09:00 <50ng/L) She was able to suppress cortisol normally after a Dexamethasone suppression test. CT of her adrenals found no adrenal tissue. By now she had weaned herself off hydrocortisone, keeping an emergency supply. SST showed a cortisol of 320 nmol/L at 30 minutes, 360 nmol/L at 60 minutes with an elevated ACTH of 140 ng/L (09:00 <50 ng/L). Her weight gain and body hair growth stabilised. Discussion: We have demonstrated that this adrenalectomized patient has ACTH driven endogenous cortisol secretion which may be due to residual adrenal tissue due to seeding after surgery or the presence of steroid synthesis elsewhere. Extra adrenal sources for glucocorticoid production are known such as skin, gonads and thymus. However, the levels are insufficient to mount a significant stress response. There is evidence of adrenal regeneration in adrenalectomized animals. The regeneration is primarily of the adrenal cortex and does not involve the medulla. There has been one case report in literature of a 11 year old German boy who had adrenal regeneration detected on adrenal scintigraphy (Bilateral normal adrenal glands with normal activity) 13 years after adrenalectomy for Cushing’s disease.

The Impact of Glucocorticoid Co-Secretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease.

Excess aldosterone is associated with the increased risk of cardio-/cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects. The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation. Ninety-seven PA patients (43 unilateral, 54 with bilateral PA) from the database of the German Conn’s Registry were included. Anti-TPO and anti-TG levels were measured pre and 6–12 months post therapeutic intervention. Patients were assessed for ACS according to their 24- hour urinary cortisol excretion, late night salivary cortisol and low-dose dexamethasone suppression test. Abnormal test results in line with ACS were identified in 74.2% of patients with PA. Following adrenalectomy, significant increases in anti-TPO levels were observed in patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy (MRA). Our data are in line with an immunosuppressive effect of mild glucocorticoid excess in PA on thyroid autoantibody titers. This effect is uncovered by adrenalectomy, but not by MRA treatment.

SAT-LB76 Impact of Glucocorticoid Cosecretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease

Context: Excess aldosterone is associated with the increased risk of cardio- and cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects.The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation.Patients and Methods: 97 PA patients (43 with unilateral, 54 with bilateral PA) from the database of the German Conn’s Registry were included. Anti-TPO and anti-TG levels were measured pre and 6 to 12 months post therapeutic intervention. Patients were assessed for ACS according to their 24h urinary cortisol excretion, late night salivary cortisol and low-dose dexamethason suppression test.Results: Abnormal test results in line with ACS were identified in 74.2% of patients. Significant increases in anti-TPO levels were observed in adrenalectomized patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy.Conclusion: ACS appears to be a relevant factor in PA affecting thyroid autoimmune disease. The biochemical and clinical course maybe be exacerbated after resolution of hypercortisolism by adrenalectomy in PA.

Quality of Life in Primary Aldosteronism: A Comparative Effectiveness Study of Adrenalectomy and Medical Treatment.

In primary aldosteronism (PA), two subtypes are distinguished: aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). In general, these are treated by adrenalectomy (ADX) and mineralocorticoid receptor antagonists (MRA), respectively. To compare the effects of surgical treatment and medical treatment on quality of life (QoL). Post hoc comparative effectiveness study within the Subtyping Primary Aldosteronism: A Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan (SPARTACUS) trial. Twelve Dutch hospitals and one Polish hospital. Patients with PA (n = 184). ADX or MRAs. At baseline and 6-month and 1-year follow-up, we assessed QoL by two validated questionnaires: RAND 36-Item Health Survey 1.0 (RAND SF-36) and European Quality of Life-5 Dimensions (EQ-5D). At baseline, seven of eight RAND SF-36 subscales and both summary scores, as well as three of five EQ-5D dimensions and the visual analog scale, were lower in patients with PA compared with the general population, especially in women. The beneficial effects of ADX were larger than for MRAs for seven RAND SF-36 subscales, both summary scores, and health change. For the EQ-5D, we detected a difference in favor of ADX in two dimensions and the visual analog scale. Most differences in QoL between both treatments exceeded the minimally clinically important difference. After 1 year, almost all QoL measures had normalized for adrenalectomized patients. For patients on medical treatment, most QoL measures had improved but not all to the level of the general population. Both treatments improve QoL in PA, underscoring the importance of identifying these patients. QoL improved more after ADX for suspected APA than after initiation of medical treatment for suspected BAH.

Abstract 19331: The Adrenal Vein Sampling International Study-2: Results in 1636 Primary Aldosteronism Patients

Background: Guidelines recommend Adrenal vein sampling (AVS) for the subtyping of primary aldosteronism (PA), the most common curable cause of arterial hypertension. How this recommendation is implemented in practice remains uncertain. Hence, in 2011 upon completion of the AVIS-1 Study we launched the AVIS-2 Study to determine: 1) the success rate of the AVS studies performed in major referral centers worldwide; 2) the impact of AVS results on the clinical decision making and on outcome of the patients at follow-up. Methods: All the AVIS-1 Study centers were invited to join the AVIS-2 by entering the individual PA patients AVS and clinical data in an ad hoc predefined web-based database. Data were analyzed according to use of cosyntropin unstimulated or -stimulated protocols. Results and Conclusions: Sixteen centers in Europe, North America and Asia recruited a total of 1656 PA patients (age 50 years ± 10; 39.5% females). The AVS success rate was examined as a function of the Selectivity Index (SI) cutoffs. Among unstimulated AVS (n = 1307), the rate of bilaterally selective tests fell from 86% to 53% and 45% with cut off values of 1.10, 2.00 and 3.00, respectively; for adrenalectomized patients (49% of total), the decision was based on bilateral selective AVS in 71%, 56% and 43% of cases, respectively. Among cosyntropin-stimulated AVS, 85%, 80%, 76% and 72% were bilaterally selective, with a cut-off of 2.00, 3.00, 4.00, and 5.00, respectively; the rate of adrenalectomy based on AVS data fell from 47% with a cut-off = 2.00 to 40% with a cut-off = 5.00. The lateralization index value did not improve by comparing those with SI bilaterally > 2.0 (baseline) and > 5.0 after cosyntropin (3.8 [median, 1.6-12.7 IQR] vs 3.7 [1.5-14.0]). Conclusions: Only a minority of PA submitted to AVS have bilaterally selective studies if high cutoffs for the SI are used. Moreover, in even less patients AVS eventually led to adrenalectomy. These intriguing results from the largest dataset of AVS studies provide compelling evidence for the need of further prospective studies in this field.

Long-Term Control of Arterial Hypertension and Regression of Left Ventricular Hypertrophy With Treatment of Primary Aldosteronism

Primary aldosteronism (PA), a common cause of high blood pressure (BP), induces left ventricular (LV) hypertrophy and an excess rate of cardiovascular events. Whether its treatment provides long-term cure of hypertension and regression of cardiovascular damage remains uncertain. To the aim of assessing the effect of treatment of PA on BP and LV changes, we prospectively recruited 323 patients in a long-term follow-up study entailing serial echocardiography evaluations. Of them, 180 had PA and were assigned to either adrenalectomy (n=110) or medical therapy (n=70) on the basis of the adrenal vein sampling. The remaining 143 were consecutive optimally treated primary hypertensive patients. At baseline, the PA patients had more inappropriate LV mass than PH patients (27.1% versus 16.2%; P=0.020), despite similar BP values. At a median follow-up of 36 months (range, 6-225), BP was lowered (P<0.0001 versus baseline) to similar values in adrenalectomized (135±15/83±9 mm Hg), medically treated PA (133±11/83±7 mm Hg), and PH (139±15/86±9 mm Hg) patients. To this end, the adrenalectomized patients required significantly less drugs than the other groups. In PA patients, the LV mass index and the rate of LV hypertrophy fell through LV inward remodeling to the level of optimally treated PH patients, indicating that the LV work markedly decreased. Findings were similar when long-term (≥5 and ≥10 years) data were examined. Thus, an early diagnosis and a specific treatment of PA warrant normalization of BP and reversal of detrimental LV changes at long term.

TREATMENT OF PRIMARY ALDOSTERONISM: SHORT AND MIDDLE-TERM EFFECTS OF MEDICAL AND SURGICAL THERAPY IN PRIMARY HYPERALDOSTERONISM. EXPERIENCE ON 45 CASES: PP.18.187

Primary Hyperaldosteronism (PA), the most common causes of secondary hypertension, may be associated with hypokaliemia, cardiac and renal damage. Recommended treatment in unilateral PA is adrenalectomy, while medical treatment with mineralocorticoid receptor antagonists (MRA) is indicated bilateral adrenal diseases. We present our recent experience in a series of patients with PA. Aim of our study was to evaluate short and middle-term effects of medical and surgical treatment on hypertensive state, hormonal parameters and cardiac function in 45 patients with PA referred to our centre between 2005 and 2008. In all patients after confirmation of PA, ECG and echocardiography were performed at baseline and after treatment with adrenalectomy (n = 22) or MRA (n = 23) every 12 months with a median follow-up of 36 months. At baseline 82% presented moderate or severe hypertension, 66% hypokaliemia. Echocardiography measurement shows left ventricular hypertrophy in 69% of patients, 93% with concentric geometry; 40% presents reduced diastolic function and 4% reduced systolic function. After treatment both groups presented various degrees of blood pressure reduction (60% normalization after adrenalectomy, 82% on medical treatment) and 100% normokaliemia. In adrenalectomized patients there was a significant reduction of plasma aldosterone concentration (PAC) and normalization of ARR ratio. In medically treated patients we observed significant normalization of plasma renin activity (PRA) and consequently normalization of ARR. In both there was a significant reduction of LVMI, greater in the 1 year period in adrenalectomized patients, reduction of RWT only in adrenalectomized patients. Prevalence of hypertrophy decreased in both groups, diastolic parameters had no significant improvement. Changes of LVMI were significantly correlated with changes in diastolic blood pressure in both and with PAC reduction only in adrenalectomized patients. Thus, in the short-middle term, both Treatments are effective in normalization of plasma potassium, reduction of BP and ARR. Adrenalectomy seems to be more effective in the short-term in reduction of LVM and RWT, while both treatments are less effective in improving systolic and diastolic function.

An audit of nephroureterectomy for upper tract urothelial carcinoma

Background The boundary of nephroureterctomy has been revisited and lymph node dissection has been recommended recently. We investigated the role of synchronous ipsilateral adrenalectomy in treating patients with upper tract urothelial carcinoma. Methods 110 patients with clinically localized upper tract urothelial carcinoma treated by nephroureterectomy and bladder cuff resection were retrospectively evaluated. 70 patients underwent nephroureterectomy without concomitant ipsilateral adrenalectomy, whereas nephroureterectomy and ipsilateral adrenalectomy was performed in other 40 patients. Cancer specific, metastasis and local recurrence free survival during a follow-up of median 46 months were analyzed. Results No patient had adrenal metastasis among the 40 adrenalectomized patients. A total of 4 patients developed local recurrences; including 1 of the 70 adrenalectomy-sparing and 3 of the 40 adrenalectomized patients ( p = 0.102, chi-square test). Five patients with adrenalectomy and four without adrenalectomy had distant metastases ( p = 0.212, chi-square test). The five-year local recurrence free survival ( p = 0.09, log-rank test), metastasis-free survival ( p = 0.292, log-rank test), and cancer-specific survival ( p = 0.117, log-rank test) did not have significant difference between both groups. Conclusions This is the only study in recent 2 decades to evaluate the necessity of synchronous adrenalectomy in treating localized upper tract urothelial carcinoma. Adrenal-sparing nephroureterectomy seems justified for clinically localized upper tract urothelial carcinoma.

Abstract 4889: Long-term Changes Of Left Ventricular (lv) Structure And Function After Adrenalectomy Or Medical Treatment For Primary Aldosteronism

Objectives: to evaluate the structural and functional LV outcome of surgically or medically treated patients with documented primary aldosteronism (PA). Methods: after a cross-sectional Doppler echocardiography assessment of LV wall thickness and dimensions and transmitral LV filling flow velocity indexes, 55 PA patients entered a prospective follow-up study lasting 6.4 years (range: 4.5 to 8 years) after adrenalectomy (n=41) or medical treatment (n=14). The diagnosis of aldosterone producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) was based on adrenal vein sampling, pathology, and on follow-up data. Results: by the PAPY Study criteria 47 patients had APA and 8 IHA. Excess LV hypertrophy (LVH) and concentric remodelling rate was observed at baseline in both groups; atrial contribution to LF filling (ACLVF) was higher in the 14 (6 APA and 8 IHA) medically treated than in the 41 adrenalectomized patients. At follow-up blood pressure (p&lt;0.001) and the rate of LVH decreased (p&lt;0.001): LV mass index (MI) fell (from 115±22 to 106±18 in adrenalectomized patients and from, 118±26 to 103±21 in medically treated patients). This LVMI reduction and an increase of relative wall thickness (from 0.43±0.07 to 0.46±0.06 in adrenalectomized patients and from 0.41±0.06 to 0.45±0.05 in medically treated patients) attained statistical significance only in the former. By contrast, the reduction of ACLVF was significant only in the latter (p=0.002), thus indicating a normalization of the LV diastolic filling indexes (but only in the medically-treated patients which showed an impaired diastolic function at baseline). Conclusion: 1) Both treatments reduce BP, LV mass index and the prevalence of LVH; 2) With a similar fall of blood pressure and despite a greater reduction of antihypertensive drugs, these changes were more prominent in adrenalectomized patients; 3) An improvement of LV diastolic filling occurs also in the medically-treated PA patients when it is altered at baseline.

Long-Term Cardiac Effects of Adrenalectomy or Mineralocorticoid Antagonists in Patients With Primary Aldosteronism

Exposure to excess aldosterone results in cardiac damage in hypertensive states. We evaluated the long-term cardiac structural and functional evolution in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with primary aldosteronism were enrolled in a prospective study and were followed for a mean of 6.4 years after treatment with adrenalectomy (n=24) or spironolactone (n=30). At baseline, echocardiographic measurements of patients with primary aldosteronism were compared with those of 274 patients with essential hypertension. Patients with primary aldosteronism had greater left ventricular mass, more prevalent left ventricular hypertrophy, lower early:late-wave diastolic filling velocities ratio, and longer deceleration time than patients with essential hypertension but no differences in relative wall thickness and systolic function. During follow-up, average blood pressure was 135/82 and 137/82 mm Hg in patients treated with adrenalectomy and spironolactone, respectively. In the initial 1-year period, left ventricular mass decreased significantly only in adrenalectomized patients. Subsequent changes in left ventricular mass were greater in patients treated with spironolactone, with an overall change from baseline to the end of follow-up that was comparable in the 2 groups. Prevalence of hypertrophy decreased in both treatment groups, whereas diastolic parameters had only mild and nonsignificant improvement. Changes in blood pressure and pretreatment plasma aldosterone were independent predictors of left ventricular mass decrease in both treatment groups. Thus, in the long-term, both adrenalectomy and spironolactone are effective in reducing left ventricular mass in patients with primary aldosteronism, with effects that are partially independent of blood pressure changes.

Thymus hyperplasia after resolution of hypercortisolism in ACTH-dependent Cushing’s syndrome: the importance of thymic vein catheterization

Thymic hyperplasia has been described after the resolution of hypercortisolism from several etiologies, causing great diagnostic dilemmas. We describe a case where the catheterization of the thymic vein was essential for the differential diagnosis of a thymic enlargement in an adrenalectomized patient with ACTH-dependent Cushing's syndrome. The patient was a 48-year-old female with clinical and laboratorial data suggesting Cushing's disease. She underwent a transsphenoidal surgery with no tumor visualization and no remission of the syndrome. Histopathological studies disclosed a normal pituitary. She underwent a bilateral adrenalectomy and 8 months later a chest CT showed an increase of left thymic lobe, which was previously non-existent. After a negative (111)In-pentetreotide scintigraphy, the patient underwent simultaneous and bilateral catheterism of the petrosus sinuses and catheterization of the thymic and inominate veins and no ACTH gradient was shown among the sites of collection. She did not undergo thoracotomy and a follow-up was established. During the evolution, there was a spontaneous regression of the thymic lesion 38 months after the diagnosis. The ACTH gradient during the catheterization of thymic vein was essential for the differential diagnosis of the thymic enlargement tumor after hypercortisolism resolution in ACTH-dependent Cushing's syndrome, especially in this case, where the ACTH source was occult, thus avoiding an invasive surgical procedure for a benign entity with spontaneous resolution.

Expression of telomerase (hTERT) in aldosterone-producing adrenocortical tumors

Telomerase was found in cancers and immortalized cell lines, but only occasionally in normal tissues, thus suggesting that measurement of its hTERT subunit might help distinguishing benign from malignant tumors. Data on hTERT expression in adrenocortical tumors are scant and mostly confined to non-functioning tumors. Therefore, we investigated whether hTERT expression may predict malignancy in aldosterone producing adrenocortical tumors. We measured hTERT mRNA with a real-time one-step reverse transcription (RT) polymerase chain reaction (PCR) method, based on the use of hTERT-specific fluorescence resonance energy transfer (FRET) probes, in 19 adrenalectomized patients with aldosterone-producing adenomas (APAs), in whom long-term follow-up (median 7 years, range 5-14 years) data were available. We also studied two rare aldosterone-producing carcinomas (APCs), eight adrenocortical carcinomas (ACs), twelve normal adrenal cortexes, and two malignant cell lines (NCI-295H and SW-13). Telomerase activity and hTERT immunoreactivity were also investigated. Of interest, we detected hTERT mRNA in 58% of APAs at levels similar to those of malignant tumors, which all consistently showed hTERT expression. In hTERT expressing tumors, immunocytochemistry showed the nuclear expression of hTERT. No hTERT expression was found in the normal adrenocortical tissue. No histopathology differences were observed between hTERT-positive and -negative APAs; however, a patient originally held to have an hTERT-positive APA was retrospectively classified as APC because of metastatic spread. In conclusion, RT-PCR measurement of hTERT mRNA is a hallmark of malignant adrenocortical tumors, but identifies also a subset of hTERT-expressing APAs that might show metastatic spread at long-term follow-up.

The aetiology of hypertension after renal transplantation in man.

Abstract The renin-angiotensin-aldosterone system was studied in renal allograft patients, 70 per cent of whom were hypertensive. Plasma-renin levels were found to be normal, and a normal increase was observed when patients were changed from the supine to the erect posture (P&amp;lt;0.01). However, aldosterone-secretion rates were found to be approximately four times normal, and a positive correlation between these values and diastolic blood-pressure was observed (r = 0-5, P = 0-05). In patients with intact kidneys a highly significant correlation between plasma-renin activity and aldosterone-secretion rate was observed (r = 0.8, P&amp;gt;0.05), but this normal correlation was not apparent in the patients with transplanted kidneys (r = 0.1, P&amp;gt;0.5). Thus the aldosterone-secretion rates in these patients was not under the control of the renin-angiotensin system. Concurrent studies in adrenalectomized patients showed that they also had elevated aldosteronesecretion rates, and the injection of 14C-labelled cortisone acetate showed that they were capable of converting this steroid into aldosterone or an aldosterone-like metabolite. It is suggested that the hypertension seen after renal transplantation is related to the conversion of prednisone to a mineralocorticoid. Further support for this hypothesis was obtained from studies in patients who had their therapy changed from daily prednisone to alternate-day methylprednisolone. They were found to secrete less aldosterone and all the patients became normotensive following this régime (P &amp;gt;0.1). In addition, patients treated with an aldosterone antagonist, spironolactone, showed a prompt decrease in blood-pressure. It is concluded that the denervated transplanted kidney is able to maintain normal blood-pressure homeostasis in man, and that hypertension Seen after renal allografting is largely due to the therapy with immunosuppressive steroids.

Chromogranin 'A' in normal subjects, essential hypertensives and adrenalectomized patients.

Chromogranin A (CgA) is an acidic glycoprotein co-stored in vesicles and co-released with catecholamines. Although currently used as a humoral marker of endocrine tumours, several aspects of CgA secretion still need to be clarified in humans. Fifty-four controls, 83 essential hypertensive and six adrenalectomized patients were studied. In the controls and hypertensive patients, CgA and catecholamines were measured before (supine position) and after changes in posture (2' upright position), insulin-induced hypoglycaemia (0.15 IU/kg i.v.) and glucagon injection (1 mg i.v.). In addition, blood samples were taken in the morning (0800 h) and in the afternoon (1800 h), and every 5 h for 24 h. In the adrenalectomized patients, blood samples were obtained in the morning and in the afternoon. CgA was measured by an immunoradiometric assay, and noradrenaline and adrenaline by high-performance liquid chromatography. In controls, posture slightly increased plasma catecholamines without affecting CgA levels. Hypoglycaemia evoked a rise in noradrenaline (P < 0.04), adrenaline (P < 0.01) and CgA (79.6 +/- 11.8 vs. 46.1 +/- 10.1 microg/l, P < 0.03). Glucagon injection increased plasma adrenaline (P < 0.01) but not noradrenaline or CgA levels. At variance with blood pressure and catecholamines, CgA increased significantly in the afternoon (51.1 +/- 4.0 vs. 45.0 +/- 3.9 microg/l, P < 0.05); it also had a circadian rhythm, with peak values during the night (at 2300 h, 65.4 +/- 9.0 microg/l) and a nadir in the morning (at 0800 h, 43.1 +/- 6.6 microg/l). In hypertensives, basal and stimulated CgA levels as well as diurnal/circadian variations of this peptide were similar to those in normal subjects. In adrenalectomized patients plasma CgA in the morning (34.3 +/- 6.5 microg/l) was lower (P < 0.03) than in all controls and hypertensives studied, but also showed an afternoon increment (46.4 +/- 6.6 microg/l, P < 0.003). No correlation was found between CgA and catecholamines or blood pressure in all subjects or in the subgroups. In normal humans, chromogranin A and catecholamines are not always co-secreted, and co-secretion occurs only for marked exocytotic adrenergic stimuli, such as hypoglycaemic stress. In addition, chromogranin A has a circadian rhythm unrelated to plasma catecholamines. Basal plasma concentrations and the secretory pattern of chromogranin A in hypertensives do not differ from the findings in controls. Finally, the adrenal glands contribute partially to circulating chromogranin A and are not involved in the circadian rhythm of this peptide in humans.

Body composition determined by six different methods in women bilaterally adrenalectomized for treatment of Cushing's disease.

In 14 women, aged 47.2 +/- 10.5 yr, bilaterally adrenalectomized for Cushing's disease 13.6 +/- 7.7 yr before, all receiving conventional doses of glucocorticoid and mineralocorticoid substitution, body composition was studied with regard to body fat, body fat distribution, fat-free mass, and bone mineral density. The data were compared with those of 14 healthy women of similar age, body mass index, and menopausal state. Five different body composition measurement methods were compared, i.e. body densitometry by underwater weighing (UWW), total body water measurement by deuterium dilution (D2O dilution), dual energy x-ray absorptiometry (DXA), bioelectrical impedance spectrometry (BIS), and skinfold measurements, using a four-component model (4C-model) as the reference method. In the patients the percent body fat was significantly higher than that in the controls as determined by all methods, whereas fat-free mass was significantly lower when measured with the 4C-model, UWW, D2O dilution, DXA, or BIS. Measured by DXA, the percent trunk fat, estimated as [fat mass of the trunk (g)/total fat mass (g)] x 100%, was significantly higher in the patients than in the controls (39.3 +/- 6.4% and 29.9 +/- 7.8%, respectively; P < 0.001). Measured by DXA, there was no difference in total bone mineral density between the groups. Differences between the 4C-model, UWW, D2O dilution, and DXA for determination of percent body fat were rather small. Skinfold measurements and BIS results, however, deviated substantially from those obtained using the 4C-model. The study indicates that adrenalectomized patients receiving conventional glucocorticoid substitution have increased body fat percentages with a centripetal fat distribution and lowered fat-free mass, but normal bone mineral density. Furthermore, the study indicates that for clinical practice, DXA, D2O dilution, UWW, and the 4C-model can be used for determination of body composition in this patient group, whereas the more convenient bedside methods, BIS and skinfold measurements, did not give reliable results. We suppose that glucocorticoid overreplacement in adrenalectomized patients might be the cause of their abnormal body composition, although GH deficiency after pituitary surgery could have played a contributory role in some of the patients.

Endogenous Digitalis-Like Factor and Ouabain Immunoreactivity in Adrenalectomized Patients and Normal Subjects After Acute and Prolonged Salt Loading

The aim of our study was to evaluate whether adrenals are involved in the secretion of endogenous digitalis-like factor(s) with polarity similar to (or less than) that of ouabain (EDLF-1), and whether acute plasma volume expansion is a physiological releasing stimulus for this factor(s) in humans. For this purpose, we measured the concentration of this substance(s) by a human placenta radioreceptor assay (RRA) and by the Du-Pont-NEN ouabain-EIA (immunoreactive ouabain, I-Oua) in plasma C18-extracts of eight normotensives and six patients with bilateral adrenalectomy before and after acute salt loading (2 lt 0.9% NaCl/2 h). The study was repeated after 2 weeks of increased sodium intake (200 mEq/day). Under basal conditions, EDLF-1 by RRA and I-Oua were similar in adrenalectomized patients and in controls and were not significantly modified by saline infusion. After 15 days of high sodium intake, basal plasma EDLF-1 and I-Oua were not significantly different from prediet levels, both in adrenalectomized patients and controls and were likewise unaffected by saline loading. Saline infusion, by contrast, significantly ( P ≤ .05) suppressed hematocrit and PRA and increased ANP both in controls and in patients, either before or after prolonged high dietary sodium. Plasma aldosterone (ALD) was similarly reduced ( P < .001) in controls and, as expected, was undetectable in adrenalectomized patients. Our data indicate that in adrenalectomized patients circulating levels of EDLF-1 and I-Oua are similar to those of controls and that, in both groups, acute saline loading before and after sodium repletion does not influence circulating levels of these compounds. These findings suggest that, at least in humans, adrenals are not the main source of endogenous digitalis-like factor(s) with polarity similar to (or less than) that of ouabain, and that plasma volume expansion may be not a sufficient stimulus for the release of this factor(s).