Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

Why don't corticotroph tumors always produce Cushing's disease?

OBJECTIVE: Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing's disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors. DESIGN: We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors. METHODS: We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM. RESULTS: We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones. CONCLUSIONS: By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.

Prognostic implications of telomerase expression in pituitary adenomas. / Implicación pronóstica de la expresión de telomerasa en adenomas hipofisarios.

OBJECTIVES: To analyse the prognostic value of telomerase expression in patients with pituitary adenomas (PAs) followed-up for at least 8 years. PATIENTS AND METHODS: A retrospective study was conducted of samples from 51 PAs (40 typical and 11 atypical) from patients who underwent transsphenoidal surgery between 2006 and 2008 and from 10 normal pituitary glands obtained by autopsy. Telomerase expression was assessed by immunohistochemistry, correlating the expression with that of Ki-67 and p53. RESULTS: We observed telomerase expression in 43 PAs (84.3%, 32 of the 40 typical PAs and in the 11 atypical PAs), which was higher in the clinically nonfunctioning cases (P=.0034) and very rare in the patients with acromegaly (P=.0001). There was a significant association between the percentage of tumour cells (>10%) and the recurrence of the adenoma (P=.039). There was no correlation with the expression of Ki-67 and p53 (P=.4986), and there were no differences according to age, sex, tumour size and invasiveness. CONCLUSIONS: A telomerase expression rate greater than 10% in the pituitary tumour tissue was associated with recurrence or progression of the PA, especially in the nonfunctioning cases.

Atypical pituitary adenomas: 10 years of experience in a reference centre in Portugal.

INTRODUCTION: Primary pituitary tumours are classified by the World Health Organization as typical adenoma, atypical adenoma, or carcinoma. Information on the incidence and prevalence of these pituitary tumours is limited, and these data in Portugal are scarce, obsolete, or non-existent. Our study evaluates pituitary adenomas (PA) in the population of Lisbon, and it aims to describe the prevalence of all subgroups in order to revise the incidence of the 'atypical' histological type and its correlation to tumour subtype, invasion, and recurrence. PATIENTS AND METHODS: A retrospective, descriptive analysis of patients with PA diagnosed between 2004 and 2013 was performed at Santa Maria University Hospital, a national reference centre. RESULTS: Of the 220 PA cases diagnosed, 28 (12.7%) fulfilled criteria for atypical lesions, and within that group, 23 were macroadenomas (82.1%) and 13 showed radiological evidence of invasion (46.4%). Ages ranged from 29 and 81 years (mean, 53.4 years). Eleven patients (39.3%) had functional tumours. Sixteen of the 28 patients (57.1%) experienced tumour recurrences; in the 100 adenomas monitored for more than 5 years, the recurrence rate in atypical PA was 7 times higher than in typical PA. Immunohistochemically, 28.6% of the tumours stained positively for ACTH, 25% for gonadotrophins, and 17.9% for prolactin. The proliferation index (Ki67) ranged from 3% and 25% (mean, 6.4%). CONCLUSIONS: Atypical PAs make up 12.7% of all surgically treated PA cases, and they tend to be invasive and recurrent macroadenomas. We found no differences in metastatic potential between typical and atypical PA.

Disease-specific quality of life evaluation and its determinants in Cushing's syndrome: what have we learnt?

Cushing's syndrome (CS) has a considerable negative impact on patient health-related quality of life (HRQoL). Two disease-specific instruments (the CushingQoL and the Tuebingen CD-25 questionnaire) are now available to assess the impact of the disease and its treatment on HRQoL. The purpose of this review was to summarize the characteristics of the studies which have used these two instruments to date and summarize their findings regarding (a) the determinants of disease-specific HRQoL in patients with CS and (b) the impact of treatment for CS on disease-specific HRQoL. A total of 7 studies were identified, 5 with the CushingQoL and 2 with the Tuebingen CD-25. Most were observational studies, though the CushingQoL had been used in one randomized clinical trial. In terms of clinical factors, there was some evidence for an association between UFC levels and disease-specific HRQoL, though the presence and strength of the association varied between studies. There was also some evidence that a more recent diagnosis of CS could lead to poorer HRQoL, and that length of time with adrenal insufficiency may also affect HRQoL. There was no evidence for an impact on disease-specific HRQoL of etiology or of the clinical signs and symptoms associated with CS, such as bruising, rubor, and fat deposits. One factor which did have a significant negative effect on HRQoL was the presence of depression. No clear picture emerged as to the effect of demographic variables such as age and gender on HRQoL scores, though there was some evidence for poorer HRQoL in female patients. As regards treatment, the two interventions studied to date (transsphenoidal surgery and pasireotide) both showed significant gains in HRQoL, with moderate to large effect sizes. This type of review is useful in summarizing knowledge to date and suggesting future research directions.

Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing's disease.

Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism.

Body composition after endogenous (Cushing's syndrome) and exogenous (rheumatoid arthritis) exposure to glucocorticoids.

Exposure to chronic glucocorticoid (GC) excess determines changes in body composition. The aim of the study was to compare body composition in women exposed to endogenous hypercortisolism (Cushing's syndrome, CS), exogenous glucocorticoid treatment (rheumatoid arthritis, RA) and controls. Fifty-one CS women, 26 RA women treated with low-dose prednisone (5 mg/day or 10 mg/2 days), and 78 female controls were included. Fourteen CS patients were hypercortisolemic, 37 in remission (10 required hydrocortisone substitution after surgery). Body composition parameters were measured by dual-energy X-ray absorptiometry scanning (DEXA). RA patients had a greater waist-hip ratio (WHR) (p<0.01), less lean body mass (LBM) (p<0.01), and lumbar bone mineral density (BMD) (p<0.01) than controls. CS patients, globally and those with cured disease, had more total fat (both percentage and kg) and trunk fat percentage, and less whole body-BMD than RA patients (p<0.05, p<0.01, p<0.05, respectively). Active CS patients had less whole body-BMD and more LBM than RA patients (p<0.05, p=0.01, respectively). Cured CS patients not taking hydrocortisone had more total fat [both percentage (p<0.05) and kg (p<0.05)], trunk fat percentage (p<0.05), lumbar BMD (p<0.01) than RA patients. Cured CS patients requiring hydrocortisone only differed from RA patients by smaller WHR (p<0.01). All the differences in BMD disappeared when the data were reanalyzed including only the estrogen-deficient groups. Hypercortisoliof CS determines an irreversible increase in body fat, greater than in RA. Endogenous and exogenous exposure to GC negatively affects body composition by increasing the WHR. There appears to be no additional effect on BMD in estrogen-deficient women.

Measurements of quality of life in patients with growth hormone deficiency.

Decreased quality of life (QoL) is a common feature of adults with GH deficiency (GHD) and is an important measure of efficacy of treatment. A number of tools have been used to measure QoL in studies of GHD patients, including both generic [e.g. Nottingham Health Profile (NHP); Psychological General Well Being Scale (PGWB)] and disease-specific questionnaires [e.g. Questions on Life Satisfaction Hypopituitarism (QLS-H) and Adult Growth Hormone Deficiency Assessment (AGHDA)]. This paper reviews QoL data in GHD patients as measured by both generic and disease-specific questionnaires. Results using generic tools tend to show worse baseline scores than the general population; however, since they do not contemplate dimensions specifically affected in patients with adult GHD, results after replacement with GH do not always show a significant improvement. The results from disease-specific tools invariably report an improvement of QoL in GHD patients upon GH replacement therapy, if it was abnormal at baseline. QoL data from the HypoCCS study, measured using the QLS-H questionnaire, show that pre-treatment QoL is significantly lower in adults with GHD than in the general population, but on treatment with GH replacement therapy, improvements in QoL are observed and maintained long-term over several years.

Determinants of neurosurgical outcome in pituitary tumors.

OBJECTIVE: Neurosurgery is one of the main therapies for pituitary tumors; optimising outcome is highly desirable for the patient and the health system. We have analysed predictors of outcome in surgically treated pituitary adenomas operated in this centre. DESIGN AND PATIENTS: A total of 289 patients underwent neurosurgery for a pituitary tumor, by the same two neurosurgeons, between 1982 and 2001. Their records were examined to find predictors of post-surgical outcome. Thirty-eight percent were males, with a median age of 40.8 (8-82.7) yr; 51.9% had been operated since 1992, 92.2% by the transsphenoidal route. Most tumors (70.2%) were macroadenomas; 28.4% were non-functioning, 27.3% secreted PRL, 26.3% GH of which 14 (4.8%) also secreted PRL, 17.3% ACTH, 0.3% FSH and 0.3% TSH. RESULTS: A stepwise, forward logistic regression analysis revealed tumor size as the only significant predictor of radiological cure [odds ratio (OR) for macroadenoma 0.16 vs microadenoma, p=0.0005]. Hormonally, PRL-secretion by the tumor was a predictor of poor prognosis (OR 3.29 for cure of non-PRL-secreting tumors, p=0.005), as was tumor size (OR 0.45 for cure of macroadenomas, p=0.005). Considering simultaneous radiological and hormonal remission, tumor size (OR 0.35 for macroadenoma, p=0.0002), and operation date (OR 0.40 for up to 1991, p=0.0002) were the only significant predictors. CONCLUSIONS: PRL secretion, tumor size and operation date are the main predictors of neurosurgical outcome in pituitary tumors, the latter suggesting that neurosurgical experience plays an important role.

Decreased insulin requirements after LAR-octreotide but not after lanreotide in an acromegalic patient.

A diabetic acromegalic man, not cured after surgery and radiosurgery, received lanreotide i.m. with great clinical and biochemical improvement. He required NPH insulin (76 to 84 units/day) to control his diabetes mellitus. Thirty-six hours after changing to LAR-octreotide (20 mg i.m/month) he presented symptomatic hypoglycemia, repeated at 48 and 72 h (50 mg/dL), despite reducing insulin to 26 Units/day. Thereafter, he reduced insulin by 30 to 50% for the first week after each LAR-octreotide injection, and gradually increased it again over the next 3 weeks. This situation persists after every injection 3 years later; this consistent behavior supports a specific effect of LAR-octreotide, and not a by chance phenomenon. No marked changes in circulating GH, IGF-1, immunoreative insulin, C-peptide, testosterone and glucose were observed prior to, and 3, 7, 14, 21, and 28 days after LAR-octreotide; however, there was 28% fall in plasma glucagon after 7 days, which rose thereafter. C-peptide (< 1.8 ng/mL) was indicative of decreased beta-cell function. To our knowledge, this is the first report of such a distinct differential behaviour of blood glucose and insulin requirements with different somatostatin analogs, and is worth recalling when starting an insulin-treated diabetic patient on this treatment. It may be related to a preferential binding of LAR-octreotide to subtype 2 somatostatin receptors in the pancreas, while lanreotide preferentially binds to subtype 5, not expressed in this tissue; this would explain the fall in glucagon, in parallel to the decrease in insulin requirements after LAR-octreotide; however, a contribution of differences in the effect of both somatostatin analogues on postreceptor signalling systems and/or intestinal carbohydrate absorption cannot be entirely ruled out.

Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly.

BACKGROUND AND OBJECTIVE: The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin LAR, Novartis Pharma AG) and lanreotide SR (Somatuline, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS: A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS: The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values < or = 6.5 mU/l (2.5 microg/l) and < or = 2.6 mU/l (1.0 microg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION: Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly.

Transient pituitary hypothyroidism in a patient with ectopic adrenocorticotrophic hormone secretion.

We report the case of a 55-year-old woman who presented with hypercortisolism secondary to ectopic adrenocorticotrophic hormone secretion and severe non-thyroidal illness syndrome (NTIS) due to metastatic small cell lung carcinoma associated with severe infections. The patient initially showed hormonal profiles of pituitary hypothyroidism and gonadal hypofunction. After decrease in cortisol production following treatment with chemotherapy and metyrapone, serum thyroid hormones and thyroid-stimulating hormone (TSH) concentrations normalized. Study of the relative contributions of cortisol and pro-inflammatory cytokines (interleukin-6 and tumour necrosis factor alpha) to the overall variability in thyroid function tests disclosed a significant and independent effect of serum cortisol on serum TSH concentrations; the variability in free thyroid hormone concentration was explained only by changes in TSH concentration. These observations indicate that cortisol could be the major determinant of changes in serum TSH concentrations in clinical conditions accompanied by hypercortisolism, as occurs in NTIS.

Antiproliferative effect and cell cycle modulation by melatonin on GH(3) cells.

We have investigated the effect of melatonin on cell proliferation and modulation, in the GH(3) experimental rat pituitary cell line; the expression of oncogenes c-myc, c-jun and the tumor suppressor gene p53 were also analyzed basally and after exposure to melatonin (10(-6), 10(-8) and 10(-10) M). Melatonin exhibited an antiproliferative effect at all the doses tested, decreasing the proliferating index by 50%. After exposure to melatonin, a decrease in Ki67 and Proliferation cell nuclear antigen occurred acute- and transiently (at 2 h) after a single dose which recovered at 4 h, as well as chronically after repeated 12-hour doses which persisted at 48 h; a similar behavior was observed both acute- and chronically for c-myc and c-jun, while it was opposite for p53, rising acute- and transiently as well as after repeated exposure. These results demonstrate that melatonin modulates the proliferation mechanisms of the GH(3) cells.

Observational study in adult hypopituitary patients with untreated growth hormone deficiency (ODA study). Socio-economic impact and health status. Collaborative ODA (Observational GH Deficiency in Adults) Group.

OBJECTIVE: The aim of the present study was to assess the socio-economic impact at baseline and after one year of follow-up of clinical and health status characteristics and laboratory tests of adult-onset GH deficiency (AGHD), a well-known clinical entity, in a large group of Spanish hypopituitary patients with untreated AGHD. DESIGN AND METHODS: A total of 926 eligible patients with GHD (GH

Recovery of hypopituitarism after neurosurgical treatment of pituitary adenomas.

Surgery is the treatment of choice for many pituitary tumors; pituitary function may suffer after operation, but relief of pressure on the normal pituitary may also favor postoperative recovery of hypopituitarism. The aim of this study was to investigate the frequency of new appearance and recovery of hypopituitarism after neurosurgery and try to identify features associated with it. Pre- and postoperative anterior pituitary functions were investigated in 234 patients with pituitary adenomas (56 nonfunctioning, 71 PRL-secreting, 66 GH-secreting, 39 ACTH-secreting, 1 LH/FSH-secreting, and 1 TSH-secreting tumors). Eighty-eight new postoperative pituitary hypofunctions appeared in 52 patients (12 NF, 14 PRL-secreting, 15 GH-secreting, 10 ACTH-secreting, and 1 LH/FSH-secreting adenomas). They corresponded to 27% ACTH deficiencies (in 29 of the 107 patients with normal preoperative ACTH in whom postoperative evaluation was complete), 14.5% (15 of 103) new GH deficiencies, 10.5% (15 of 143; P < 0.0005, significantly less than ACTH deficiency) new TSH deficiencies, 16.5% (20 of 121) new gonadotropin deficiencies, and 13% (9 of 71) new PRL deficiencies. Preoperatively, 93 were deficient in at least 1 pituitary hormone; after surgery, 45 (48%) recovered between 1 and 3 hormones. The 2 patients with LH/FSH- and TSH-secreting macroadenomas did not recover pituitary function. Factors associated with a higher probability of postoperative pituitary function recovery were: no tumor rests on postoperative pituitary imaging (P = 0.001) and no neurosurgical (P = 0.001) or pathological evidence (P = 0.049) of an invasive nature. Tumor size did not differ significantly between those who did and those who did not recover pituitary function after surgery. Even if clear hypofunction is observed at initial work-up, patients should be reassessed after surgery without substitution therapy, because practically half the preoperative pituitary hormone deficiencies recover postoperatively, eliminating the need for life-long substitution therapy.

Biochemical liver abnormalities in Turner's syndrome.

BACKGROUND: Turner's syndrome is a chromosomal abnormality (45X0) which may be associated with various autoimmune disorders and disease conditions; however, association with liver pathology has rarely been reported. OBJECTIVES: The aim of this work was to assess liver function abnormalities in a group of adult patients with Turner's syndrome. DESIGN AND METHODS: Liver function tests were performed in 16 women with Turner's syndrome all of whom had been previously treated with oestrogens. Patients with liver abnormalities were further studied with hepatic ultrasonography, serological markers of viral hepatitis and autoantibody determinations. RESULTS: Seven women (43.7%) presented with asymptomatic liver cholestasis; these patients were older than those with normal biochemical values (33.4+/-5.2 vs 24.7+/-5.7 years, P<0.05). Liver function abnormalities appeared 7.8+/-4.9 years after starting oestrogen therapy; however, no improvement of liver function was observed 20+/-17.7 months after stopping treatment. All of these women were anti-HCV and HBsAg negative, and autoimmune hepatitis was ruled out in all cases. Liver ultrasound only disclosed homogeneous liver enlargement in one case and cholelithiasis without bile duct abnormalities in another. Four patients underwent a percutaneous liver biopsy of which two were normal and two showed minimal non-specific changes. CONCLUSIONS: The incidence of biochemical liver cholestasis in this group of patients with Turner's syndrome is high. Oestrogen therapy and autoimmune disorders do not seem to be the responsible causes. It appears that this is a benign condition which does not seem to reflect any substantial liver dysfunction. The aetiology remains uncertain.

Cost-effectiveness and accuracy of the tests used in the differential diagnosis of Cushing's syndrome.

AIM: Establish the minimal biochemical and radiological examinations necessary and their cost-effectiveness to accurately diagnose the etiology of Cushing's syndrome (CS). MATERIAL AND METHODS: In 71 patients with CS followed between 1982 and 1997 biochemical studies (basal ACTH, 8 mg dexamethasone suppression test-HDST-, metyrapone stimulation test-MST-, or inferior petrosal sinus catheterization-IPSC-) and radiological investigations (abdominal CT scan, pituitary CT scan or MRI) were performed. Once pathology confirmed the diagnosis (48 pituitary Cushing's disease-CD, 17 adrenal neoplasms, 2 bilateral macronodular hyperplasia-BMH-, and 4 ectopic ACTH syndrome-ES-), the sensitivity, specificity, positive and negative predictive value of the different studies was calculated to establish the most accurate and cost-effective diagnostic protocol. RESULTS: In ACTH-independent CS (ACTH < or = 9 pg/ml; normal 9 to 54) a unilateral tumor was identified on abdominal CT scanning in 17, and BMH in 1; the other BMH had detectable ACTH (43.2 pg/ml). In ACTH-dependent CS, ACTH was > 9 pg/ml and IPSC (performed in 22) correctly identified 20 patients with CD and differentiated them from 2 with an ES (100% specificity and sensitivity). Pituitary MRI or CT did not disclose an adenoma in 41.7% of patients with CD, and was reported to exhibit a microadenoma in 2 of the 4 patients with ES. HDST and MST were of no additional use in the differentiation between CD and ES. CONCLUSIONS: Once CS is diagnosed low ACTH and an abdominal CT scan correctly identified all patients of adrenal origin. In ACTH-dependent CS IPSC was the best predictive test to differentiate CD from ES. BMH may behave as ACTH-dependent or independent. The other biochemical and radiological studies performed are not cost-effective and may even be misleading, and should not be routinely performed.

Study of glucose tolerance in consecutive patients harbouring incidental adrenal tumours. Study Group of Incidental Adrenal Adenoma.

OBJECTIVE: Clinically silent cortisol hypersecretion has been frequently observed in recent series of adrenal 'incidentalomas'. A significant body of data indicates that a spectrum of cortisol excess exists. Up to 90% of patients with cortisol hypersecretion are glucose intolerant. The aim of this study was (1) to assess glucose tolerance in consecutive patients with 'nonfunctioning' adrenal adenomas, and (2) to study the influence of the status of the hypothalamo-pituitary-adrenal axis (HPAA) on carbohydrate tolerance. PATIENTS AND METHODS: Sixty-four consecutive patients with nonfunctioning adrenal adenomas (non-hypersecretory) diagnosed between September 1995 and July 1996 in five hospitals were included in the study. The prevalence of glucose intolerance or diabetes mellitus was determined with an oral glucose tolerance test (oGTT) according to the recommendations of the National Diabetes Data Group. Twenty-three consecutive unselected patients diagnosed with 'nonfunctioning' adrenal adenoma were enrolled in a study to determine the influence of HPAA status on carbohydrate tolerance. In these patients, in addition to basal and post-dexamethasone serum and urinary free cortisol concentrations, assessment of peripheral sensitivity to insulin (estimated during the oGTT according to a previously validated method) and adrenal sensitivity to ACTH (calculated from the CRH test) were performed. RESULTS: Twenty-five patients were considered to have normal glucose tolerance (95% confidence interval (95% CI) for the mean of 2 h glucose, 5.5-6.5 mmol/l); 17 showed glucose intolerance (95% CI 8.5-9.3 mmol/l); and 22 were classified as having diabetes mellitus (95% CI 12.1-14.6 mmol/l), including six patients with previously known diabetes mellitus. These three groups were comparable in age, sex, body mass index, waist-hip ratio and concomitant diseases. Thus, the prevalence of disturbed glucose tolerance was 39/64 (61%), well above the prevalence of NIDDM described in a population of similar age in our area. Among the 23 patients included in the study of HPAA status, the size of the tumour correlated with serum cortisol after dexamethasone (DXM) (r = 0.52, P < 0.01) and 24-h urinary free cortisol (UFC) after DXM (r = 0.55, P < 0.01), and negatively with DHEAs (r = -0.42, P = 0.04). The area under the curve for ACTH after hCRH (AUCacth) correlated negatively with both UFC (r = -0.40, P = 0.04) and serum cortisol after dexamethasone (r = -0.47, P = 0.02). The degree of peripheral sensitivity to insulin (SI) positively correlated with adrenal sensitivity (r = 0.56, P = 0.005). CONCLUSIONS: A high prevalence (61%) of disturbed glucose tolerance was found among consecutive patients harbouring incidental 'nonfunctional' adrenal adenomas. Therefore, patients with incidental adrenal tumours should be tested for glucose tolerance. The positive correlation between insulin sensitivity and adrenal sensitivity to ACTH suggests that, in these patients, insulin resistance hampers ACTH action at the level of the adrenal.