Concomitant alterations of metabolic parameters, cardiovascular risk factors and altered cortisol secretion in patients with adrenal incidentalomas during prolonged follow-up.

OBJECTIVE: Adrenal incidentalomas (AI) are associated with metabolic and hormonal abnormalities, most commonly autonomous cortisol secretion (ACS). Data regarding alterations of insulin resistance (IR) and ACS after prolonged follow-up are limited. We investigated the evolution of IR, cortisol secretion and ACS development in patients with AI during prolonged follow-up. DESIGN: Prospective study in a tertiary hospital. PATIENTS AND MEASUREMENTS: Seventy-one patients with AI [51 nonfunctioning (NFAI) and 20 ACS] and 5·54 ± 1·7 years follow-up underwent testing for ACS and oral glucose tolerance test to determine IR indices and adrenal imaging. RESULTS: At follow-up, 16/51 (31%) NFAI patients converted to ACS, while two with previous ACS reverted to NFAI; 21% (7/33) of patients who did not covert to ACS exhibited high urinary-free cortisol (H-UFC) levels. All AI patients developed deterioration of IR irrespective of their cortisol secretory status. Eight patients developed newly diagnosed type 2 diabetes (9·8% NFAI and 15% ACS, respectively) and 14 IR (17·6% NFAI and 25% ACS, respectively). Adenoma size increased from 2·1 ± 0·8 to 2·3 ± 0·8 cm, whereas IR correlated with postdexamethasone cortisol level and adenoma size increase. IR showed an incremental continuum trend from normal UFC (Ν-UFC), to H-UFC, C-ACS and ACS patients. CONCLUSIONS: New-onset ACS developed in 31% patients with NFAI, whereas 21% of NFAI patients had H-UFC levels. All AI patients as a group and the subgroups of N-UFC, H-UFC, C-ACS and ACS patients developed deterioration of metabolic parameters during follow-up that was more prominent in ACS patients.

A new highly sensitive and specific overnight combined screening and diagnostic test for primary aldosteronism.

CONTEXT: Primary aldosteronism (PA) is the most common cause of endocrine hypertension that is diagnosed following a two-step process: an initial screening test, based on the serum aldosterone-to-renin ratio (ARR), followed by a relatively laborious and time-consuming confirmatory test to document autonomous aldosterone (ALD) secretion. OBJECTIVE: The aim of this study is to develop a simple overnight test for the early and definite diagnosis of PA. PATIENTS AND METHODS: Totally, 148 hypertensive patients underwent a fludrocortisone-dexamethasone suppression test (FDST) and the new overnight diagnostic test (DCVT) using pharmaceutical RAAS (renin-angiotensin-aldosterone system) blockade with dexamethasone, captopril and valsartan. RESULTS: Of the 148 patients, 45 were diagnosed as having PA and they all normalized their elevated blood pressure (BP) after administration of spironolactone or eplerenone. The remaining 103 patients were considered as having essential hypertension and served as controls. Using ROC analysis, the estimated sensitivity and specificity were 91 and 100%, respectively, for the post-FDST ARR, whereas 98% and 89% and 100% and 82% for the post-DCVT ARR and post-DCVT ALD, respectively, with selected cutoffs of 0.32ng/dL/µU/mL and 3ng/dL respectively. However, considering these cutoffs simultaneously, the estimated sensitivity and specificity were 98 and 100% respectively. Applying these cutoffs, the diagnosis of PA was confirmed in 44 (98%) of the 45 patients who were considered to have the disease. CONCLUSIONS: In this study, a highly sensitive and specific, low-cost, rapid, safe, and easy-to-perform diagnostic test (DCVT) for PA is described, which could be utilized on an outpatient basis potentially substituting conventional laborious testing.

Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension.

CONTEXT: Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA). OBJECTIVE: We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT). PATIENTS AND METHODS: One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-µg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs. RESULTS: Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group. CONCLUSIONS: A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.

Aggressive pituitary tumors.

Pituitary adenomas are common intracranial tumors that are mainly considered as benign. Rarely, these tumors can exhibit an aggressive behavior, characterized by gross invasion of the surrounding tissues, resistance to conventional treatment leading to early and frequent recurrences. Even more rarely, pituitary tumors can give rise to cerebrospinal or systemic metastases qualifying as pituitary carcinomas according to the latest WHO definition. In the same classification, a subset of tumors with relatively distinct histopathological features was identified and defined as atypical adenomas designated to follow a more aggressive clinical course. This classification, although clinically useful, does not provide an accurate correlation between histopathological findings and the clinical behavior of these tumors, neither is it adequate to convey the precise features of 'aggressive' tumors. Thus, 'aggressive' pituitary adenomas need to be properly defined with clinical, radiological, histological and molecular markers in order to identify patients at increased risk of early recurrence or subsequent tumor progression. At present, no single marker or classification system of pituitary tumor aggressiveness exists, and clinically useful information in the literature is insufficient to guide diagnostic and therapeutic decisions. Treatment of patients with aggressive pituitary tumors is challenging since conventional treatments often fail, necessitating multiple surgical procedures with additional radiotherapy. Although traditional chemotherapy applied in other neuroendocrine tumors has not been shown to be efficacious, newer agents, particularly temozolomide, have shown promising results and are currently used despite the lack of data from a randomized prospective trial. Molecular targeted therapies such as mTOR and epidermal growth factor inhibitors have also been applied and might prove to be useful in the management of these patients. In the present review, we provide information regarding the epidemiology and clinical, histopathological and molecular features of aggressive pituitary tumors using recent employed definitions. In addition, we review currently employed therapeutic means providing a therapeutic algorithm and highlight the need to identify more specific disease-related and prognostic markers and the necessity for central registration of these tumors.

Progress in aldosteronism: a review of the prevalence of primary aldosteronism in pre-hypertension and hypertension.

Primary aldosteronism (PA) secondary to excessive and/or autonomous aldosterone secretion from the renin-angiotensin system accounts for ∼10% of cases of hypertension and is primarily caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenomas (APAs). Although the diagnosis has traditionally been supported by low serum potassium levels, normokalaemic and even normotensive forms of PA have been identified expanding further the clinical phenotype. Moreover, recent evidence has shown that serum aldosterone correlates with increased blood pressure (BP) in the general population and even moderately raised aldosterone levels are linked to increased cardiovascular morbidity and mortality. In addition, aldosterone antagonists are effective in BP control even in patients without evidence of dysregulated aldosterone secretion. These findings indicate a higher prevalence of aldosterone excess among hypertensive patients than previously considered that could be attributed to disease heterogeneity, aldosterone level fluctuations related to an ACTH effect or inadequate sensitivity of current diagnostic means to identify apparent aldosterone excess. In addition, functioning aberrant receptors expressed in the adrenal tissue have been found in a subset of PA cases that could also be related to its pathogenesis. Recently a number of specific genetic alterations, mainly involving ion homeostasis across the membrane of zona glomerulosa, have been detected in ∼50% of patients with APAs. Although specific genotype/phenotype correlations have not been clearly identified, differential expression of these genetic alterations could also account for the wide clinical phenotype, variations in disease prevalence and performance of diagnostic tests. In the present review, we critically analyse the current means used to diagnose PA along with the role that ACTH, aberrant receptor expression and genetic alterations may exert, and provide evidence for an increased prevalence of aldosterone dysregulation in patients with essential hypertension and pre-hypertension.

Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion.

CONTEXT: Although adrenal incidentalomas (AIs) are associated with a high prevalence of cardiovascular risk (CVR) factors, it is not clear whether patients with nonfunctioning AI (NFAI) have increased CVR. OBJECTIVE: Our objective was to investigate CVR in patients with NFAI. DESIGN AND SETTING: This case-control study was performed in a tertiary general hospital. SUBJECTS: SUBJECTS included 60 normotensive euglycemic patients with AI and 32 healthy controls (C) with normal adrenal imaging. MAIN OUTCOME MEASURES: All participants underwent adrenal imaging, biochemical and hormonal evaluation, and the following investigations: 1) measurement of carotid intima-media thickness (IMT) and flow-mediated dilatation, 2) 2-hour 75-gram oral glucose tolerance test and calculation of insulin resistance indices (homeostasis model assessment, quantitative insulin sensitivity check, and Matsuda indices), 3) iv ACTH stimulation test, 4) low-dose dexamethasone suppression test, and 5) NaCl (0.9%) post-dexamethasone saline infusion test. RESULTS: Based on cutoffs obtained from controls, autonomous cortisol secretion was documented in 26 patients (cortisol-secreting AI [CSAI] group), whereas 34 exhibited adequate cortisol and aldosterone suppression (NFAI group). IMT measurements were higher and flow-mediated vasodilatation was lower in the CSAI group compared with both NFAI and C and in the NFAI group compared with C. The homeostasis model assessment index was higher and quantitative insulin sensitivity check index and Matsuda indices were lower in the CSAI and NFAI groups compared with C as well as in CSAI compared with the NFAI group. The area under the curve for cortisol after ACTH stimulation was higher in the CSAI group compared with the NFAI group and C and in the NFAI group compared with C. In the CSAI group, IMT correlated with cortisol, urinary free cortisol, and cortisol after a low-dose dexamethasone suppression test, whereas in the NFAI group, IMT correlated with area under the curve for cortisol after ACTH stimulation and urinary free cortisol. CONCLUSIONS: Patients with CSAI without hypertension, diabetes, and/or dyslipidemia exhibit adverse metabolic and CVR factors. In addition, NFAIs are apparently associated with increased insulin resistance and endothelial dysfunction that correlate with subtle but not autonomous cortisol excess.

Visceral adiposity index (VAI) is related to the severity of anovulation and other clinical features in women with polycystic ovary syndrome.

OBJECTIVE: The clinical phenotype of polycystic ovary syndrome (PCOS) includes reproductive and hormonal aberrations. Visceral adiposity index (VAI) is an indicator which could connect hyperandrogenism and anovulation. The objective was to evaluate the relationship between VAI, menstrual disorders and hormonal, biochemical and ultrasound parameters in women with PCOS. PATIENTS: One hundred and ninety-three women with PCOS diagnosed with Rotterdam criteria. MEASUREMENTS: We correlated VAI with metabolic and clinical features of the syndrome and with indices of inflammation and insulin sensitivity. In addition, we classified the patients into four groups according to the severity of menstrual disorders: Group A (n = 42), with severe menstrual disorders, Group B (n = 83), with mild menstrual disorders, Group C (n = 58), without menstrual disorders and Group D (n = 10) with women with sychnominorroia. RESULTS: In women with PCOS studied, VAI significantly positively correlated with body weight, fasting glucose, insulin, homeostasis model assessment (HOMA) score, white blood cells, platelets, uric acid, free testosterone, oestradiol, total cholesterol, γ-GT, SGPT. Furthermore, a significant inverse correlation between VAI and SHBG, Matsuda index and menstrual cycles per year was documented. From the comparison of the four groups, PCOS women with menstrual disorders had significantly higher VAI and HOMA indices when compared to PCOS without menstrual disorders. CONCLUSIONS: Visceral adiposity index is increased in patients with PCOS in concordance with the severity of anovulation, insulin resistance and inflammation. This index could be a very easy and helpful clinical tool in daily practice to predict insulin resistance in women with PCOS.

High prevalence of autonomous aldosterone secretion among patients with essential hypertension.

BACKGROUND: Previous studies based on standard endocrine testing have generally shown a low prevalence of primary aldosteronism, a form of autonomous aldosterone secretion (AAS), in hypertensive individuals. The purpose of this case-control study was to evaluate whether use of appropriately defined controls and combined testing reveal previously undetected AAS in hypertensives. MATERIALS AND METHODS: We investigated aldosterone secretion in 180 hypertensives with (n = 44) and without (n = 136) adrenal adenomas on computerized tomography (CT) and 72 matched nonhypertensive individuals with normal adrenal CT. Serum aldosterone and active renin were measured, and the aldosterone/active renin ratio was calculated before and after a modified fludrocortisone-suppression test (FST). In the latter, to eliminate any stimulatory effect of endogenous stress-induced adrenocorticotrophin hormone on aldosterone secretion, we administered 1 mg of dexamethasone on the last day of the classical FST fludrocortisone/dexamethasone suppression test (FDST). RESULTS: Using the 97·5 percentiles of serum aldosterone (74 pM L(-1)) and the aldosterone/renin ratio (32 pM L(-1) mU(-1) L(-1)) values obtained from the controls following the FDST, normal cut-off values indicative of adequate aldosterone suppression were established. Using the combination of these cut-offs, the estimated prevalence of AAS in patients with hypertension was 31%. Multiple linear regression analysis revealed a significant correlation between systolic and/or diastolic arterial blood pressure and the aldosterone value (P < 0·0001 and P < 0·01, respectively) and/or the aldosterone/renin ratio (P < 0·0001 and P < 0·01, respectively), which were obtained following the FDST. CONCLUSIONS: By applying new cut-offs obtained following modification of standard testing, AAS is quite prevalent in hypertensive individuals and correlates highly with arterial blood pressure. This may have relevance for both the aetiology of the hypertension and its optimal therapy.

The functional status of incidentally discovered bilateral adrenal lesions.

OBJECTIVE: To investigate autonomous cortisol and aldosterone secretion and insulin resistance (IR) indices, in patients with incidentally discovered bilateral adrenal lesions (BA). PATIENTS: Thirty-six patients with BA, 113 patients with unilateral adrenal incidentalomas (UA) and 89 healthy subjects (C) with normal adrenal imaging. MEASUREMENTS: All participants underwent adrenal imaging, baseline biochemical and hormonal measurements and the following investigations on consecutive days: (i) A 2-h oral glucose tolerance test (OGTT) (75 g) with glucose and insulin measurements every 30 min. (ii) An adrenocorticotrophin (ACTH) stimulation test with intravenous (i.v.) bolus administration of 250 µg of ACTH (1-24) and measurement of serum cortisol and aldosterone before and after 30 and 60 min. (iii) A low-dose dexamethasone suppression test (LDDST) (0·5 mg of dexamethasone every 6-h for 2 days) with cortisol measurement 6 h after the last dexamethasone dose and (iv) A NaCl (0·9%) postdexamethasone saline infusion test (PD-SIT) (2 l of NaCl 0·9% iv in 4 h) following the LDDST, with aldosterone measurement at the end of the test. RESULTS: Cortisol and aldosterone cut-offs based on the mean + 2 SD values obtained from the C group following the LDDST and PD-SITs were calculated (34·11 nm and 74·83 pm, respectively). Based on the above cut-offs, autonomous cortisol and aldosterone secretion was found in 42·5 and 15·9% of patients with UA, and in 41·7 and 19·4% of patients with BA, respectively. In addition, 17·7% of patients with UA and 19·4% of patients with BA had concomitant autonomous cortisol and aldosterone secretion. Cortisol and aldosterone levels following the LDDST and PD-SIT were significantly higher in the BA compared to the UA group, respectively. Furthermore, patients with BA had more pronounced glucose levels and insulin resistance (IR) indices compared to patients with UA. CONCLUSIONS: Patients with BA have more pronounced autonomous cortisol and aldosterone secretion and glucose metabolism alterations than patients with UA. Further studies are needed to evaluate the potential long-term consequences of these findings.

The clinical significance of adrenal incidentalomas.

BACKGROUND: The term adrenal incidentaloma (AI) indicates an adrenal mass lesion > 1 cm in diameter discovered during testing for conditions unrelated to adrenal disease. The overall prevalence of these lesions ranges between 3% and 10%. Their incidence increases with age, and it is clinically important to identify AI associated with hormonal activity and/or malignant potential. DESIGN: A detailed Medline search of all English language articles related to AI was carried out, and the clinical implications related to their hormonal activity and malignant potential are discussed. RESULTS: The subclinical hypercortisolism observed in a significant percentage of patients with AI is associated with some of the detrimental effects of continuous autonomous cortisol secretion, including a higher prevalence of hypertension, dyslipidaemia, impaired glucose tolerance or type 2 diabetes mellitus and an increased risk for osteoporotic fractures. However, it remains to be proven whether treatment to reverse subtle glucocorticoid excess is beneficial. Clinically silent phaeochromocytomas and primary adrenal cancer are conditions associated with significantly high morbidity and mortality and require urgent treatment, while the prevalence and clinical significance of autonomous mineralocorticoid secretion are less clearly defined. Size and radiological features are the main predictors of malignant potential. CONCLUSIONS: Patients harbouring AI should be evaluated for the possibility of malignancy and/or subclinical hypercortisolism which is associated with cardiovascular risk and bone loss. However, in the absence of prospective controlled studies correlating biochemical activity with end-organ complications, the long-term consequences of AI remain uncertain and their management remains largely pragmatic.

Optic neuropathy following radiotherapy for Cushing's disease: case report and literature review.

Radiation-induced optic neuropathy is a rare adverse effect of radiotherapy applied for the treatment of pituitary adenomas. We report a patient with a recurrent adrenocorticotrophin secreting pituitary adenoma who received external beam irradiation after failing surgical and medical therapy. Sixteen months after radiotherapy, the patient was presented with declining visual acuity, and radiation-induced optic neuropathy was diagnosed. Despite treatment with glucocorticoids and hyperbaric oxygen, her vision did not improve. The pathophysiology, prevention and treatment of radiation-induced optic neuropathy, including the efficacy of hyperbaric oxygen therapy are reviewed.

Paraneoplastic syndromes secondary to neuroendocrine tumours.

Neuroendocrine tumours may be either benign or malignant tumours, and have the ability to synthesise and secrete biologically active substances characteristic of the cell of origin that can cause distinct clinical syndromes. The term 'paraneoplastic syndromes' (PNSs) is used to denote syndromes secondary to substances secreted from tumours not related to their specific organ or tissue of origin and/or production of autoantibodies against tumour cells; such syndromes are mainly associated with hormonal and neurological symptoms. Appreciation of the presence of such syndromes is important as clinical presentation, if not identified, may delay the diagnosis of the underlying neoplasia. Conversely, early recognition can allow for more rapid diagnosis, particularly as the coexistence of a neoplasm with a clinical or biochemical marker offers an additional determinant of tumour status/progression. PNSs can complicate the patient's clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. Their diagnosis involves a multidisciplinary approach, and detailed endocrinological, neurological, radiological and histological studies are required. Correct diagnosis is essential as the treatment of choice will be different for each disorder, particularly in the case of malignant tumours; it is therefore important to develop appropriate means to correctly identify and localise these tumours. Clinical awareness and the incorporation into clinical practise of (111)In-octreotide scintigraphy, chromogranin A and other evolving biochemical marker measurement techniques have substantially contributed to the identification of patients harbouring such syndromes. Disease-specific medical therapies are mandatory in order to prevent recurrence and/or further tumour growth. Owing to their rarity, central registration of these syndromes is very helpful in order to be able to provide evidence-based diagnostic and therapeutic approaches.

Hepatic steatosis in young lean insulin resistant women with polycystic ovary syndrome.

OBJECTIVE: To investigate the presence of nonalcoholic fatty liver disease (NAFLD) in young lean women with polycystic ovary syndrome (PCOS) and insulin resistance (IR). DESIGN: Case control study. SETTING: Women with PCOS and healthy controls in a metabolic day ward. PATIENT(S): Seventeen young lean women with PCOS and 17 matched controls were studied prospectively. INTERVENTION(S): Fasting blood and a glucose tolerance test. Ovarian and liver ultrasonography, and computed tomography (CT) of the liver (women with PCOS only). MAIN OUTCOME MEASURE(S): Anthropometric variables, biochemical and hormonal parameters, and several IR indices were determined. Hepatic lipid content was assessed with ultrasonography and CT of the liver. RESULT(S): Women with PCOS had higher androgen levels, and the IR indices, glucose and insulin area under the curve, QUICKI, MATSUDA, and HOMA, compared to controls. In addition to IR, women with PCOS had normal aminotransferase levels, and higher, although within the normal range, alkaline phosphatase levels compared with controls. Women with PCOS had no evidence of NAFLD by either ultrasonography or CT of the liver. CONCLUSION(S): Young lean women with PCOS and IR do not have evidence of NAFLD. Because of the presence of IR, follow-up is required to determine whether they are at risk of developing NAFLD.

In overweight/obese but not in normal-weight women, polycystic ovary syndrome is associated with elevated liver enzymes compared to controls.

OBJECTIVE: To investigate liver enzymes in a cohort of women with Polycystic Ovary Syndrome (PCOS) and controls divided according to body mass index (BMI) and their association with features of the syndrome. DESIGN: Eighty-three PCOS women and 64 healthy women were studied. Patients and controls were subdivided into two groups, a lean subgroup (BMI <25kg/m(2)) and an overweight/obese subgroup (BMI >25kg/m(2)). Clinical history, height and weight were obtained and metabolic and hormonal parameters were determined. RESULTS: Serum fasting insulin, fasting glucose, HOMA-IR, triglycerides and total cholesterol were significantly higher (p<0.05) in women with PCOS compared to controls. No significant difference in serum liver enzymes levels between PCOS women and controls was detected. However, serum levels of alanine aminotransferase (ALT) (17.7 vs. 14.1 U/L, p<0.05) and gamma-glutamyl transpeptidase (gammaGT) (17.9 vs. 13.4 U/L, p<0.05) were significantly higher in overweight/obese PCOS women compared with overweight/obese controls. In overweight/obese PCOS patients and controls, ALT levels were positively correlated with free androgen index (FAI) (r=0.25 p<0.05) and total testosterone levels (r=0.33 p<0.01). CONCLUSIONS: The finding of elevated liver enzymes in overweight/obese PCOS women raises the question of screening for non-alcoholic fatty liver disease in this group.

High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas.

OBJECTIVES: Previous studies based on standard endocrine testing have shown a variable incidence of autonomous cortisol secretion (ACS) or autonomous aldosterone secretion (AAS) in patients with single adrenal adenomas (SAA). We tested whether the use of appropriate controls and modification of standard testing, aiming at eliminating interference from endogenous ACTH, reveals previously undetected subtle ACS and AAS by SAA. DESIGN: Case control study. Patients We investigated 151 patients with SAA and 72 matched controls with normal adrenal computerized tomography. MEASUREMENTS: All participants had arterial blood pressure recorded, and serum cortisol and aldosterone measured before and after intravenous administration of 250 mug of ACTH, and following dexamethasone administration. Eighty-three patients and all the controls had serum aldosterone and renin measured before and after saline infusion, and after a second saline infusion following dexamethasone administration. RESULTS: Using the mean + 2 SD values obtained from controls after dexamethasone administration and saline infusion following dexamethasone administration, normal cut-off values for cortisol (30.11 nM), aldosterone (67.59 pM), and aldosterone/renin ratio (9.74 pM/mU/l) were developed. Using these cut-off values, the estimated incidence of ACS and AAS in patients with SAA was 56.63% and 24.10%, respectively, whereas 12.05% had autonomous secretion of both cortisol and aldosterone. Systolic and diastolic arterial blood pressure correlated significantly with the aldosterone/renin ratio following AlphaCTH stimulation (P < 0.0002 and P < 0.001, respectively), and after saline infusion following dexamethasone administration (P < 0.003 and P < 0.002, respectively). CONCLUSIONS: By applying new cut-offs, ACS and AAS in patients with a SAA is very common, and aldosterone secretion correlates with arterial blood pressure.

Polycystic ovaries and the polycystic ovary syndrome phenotype in women with active acromegaly.

BACKGROUND: Previous retrospective studies have suggested that women with acromegaly may present with menstrual irregularity and symptoms/signs of hyperandogenism, a phenotype similar to that of the polycystic ovary syndrome (PCOS). OBJECTIVE: The aim of this study was to investigate prospectively the presence of the PCOS phenotype (PCOSP) and polycystic ovaries (PCO) on ultrasonography in women with active acromegaly. DESIGN: Women within the reproductive age range (21-43 years) with active acromegaly of recent onset and/or previous surgical and/or medical therapy were studied. MAIN OUTCOME MEASURES: Subjects underwent a physical examination; fasting bloods for androgens, pituitary hormones and metabolic parameters; an oral glucose tolerance test (OGTT) to estimate disease activity and insulin resistance; and a transvaginal ultrasound. RESULTS: Six women had newly diagnosed acromegaly, and eight still had active disease following previous surgical and/or medical treatment. Seven women were found to have PCO and six fulfilled the criteria for PCOSP; six of these women, five with PCOSP, had a pituitary macroadenoma. Women with PCOSP had significantly increased mean ovarian volumes and characteristic ovarian morphology compared to women without PCOSP (P < 0.05), higher levels of IGF-1 and testosterone and lower SHBG levels that did not reach statistical significance. A positive correlation between IGF-1 and mean ovarian volume was identified only in women with PCOSP (r = 0.851, P < 0.05). CONCLUSIONS: PCO and PCOSP are relatively common in women with acromegaly and may account for some of the symptoms related to gonadal dysfunction irrespective of the size of the pituitary tumour. It is likely that IGF-1 alone or in combination with GH and/or insulin resistance may be involved.

Bone remodeling.

The skeleton is a metabolically active organ that undergoes continuous remodeling throughout life. Bone remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized. The remodeling cycle consists of three consecutive phases: resorption, during which osteoclasts digest old bone; reversal, when mononuclear cells appear on the bone surface; and formation, when osteoblasts lay down new bone until the resorbed bone is completely replaced. Bone remodeling serves to adjust bone architecture to meet changing mechanical needs and it helps to repair microdamages in bone matrix preventing the accumulation of old bone. It also plays an important role in maintaining plasma calcium homeostasis. The regulation of bone remodeling is both systemic and local. The major systemic regulators include parathyroid hormone (PTH), calcitriol, and other hormones such as growth hormone, glucocorticoids, thyroid hormones, and sex hormones. Factors such as insulin-like growth factors (IGFs), prostaglandins, tumor growth factor-beta (TGF-beta), bone morphogenetic proteins (BMP), and cytokines are involved as well. As far as local regulation of bone remodeling is concerned, a large number of cytokines and growth factors that affect bone cell functions have been recently identified. Furthermore, through the RANK/receptor activator of NF-kappa B ligand (RANKL)/osteoprotegerin (OPG) system the processes of bone resorption and formation are tightly coupled allowing a wave of bone formation to follow each cycle of bone resorption, thus maintaining skeletal integrity.