Severe Cushing's syndrome from an ectopic adrenocorticotropic hormone-secreting neuroendocrine tumour treated by osilodrostat.

Summary: Severe Cushing's syndrome from an ectopic adrenocorticotropic hormone-producing tumour is rare but often demands rapid diagnostics and treatment of hypercortisolism with its comorbidities. Pharmacotherapy of hypercortisolism by ketoconazole, metyrapone and osilodrostat is currently available. If unsuccessful or insufficient a bilateral adrenalectomy is an option. We present a 28-year-old female with severe Cushing's syndrome caused by a bronchial metastatic neuroendocrine tumour (NET). Hypercortisolism was efficiently treated by osilodrostat with block-replace and then titration regimen. A once-daily dose was finally used with normalised cortisol levels. Androgen levels measured by liquid chromatography-mass spectrometry were slightly elevated during the treatment but without any symptoms. A simple once-daily use of osilodrostat with titration regimen led to normalised cortisol levels in a severe Cushing's syndrome patient with an uncurable bronchial NET. Transient hypocortisolism during treatment appeared but was easily treated by hydrocortisone. Learning points: Cushing's syndrome from an ectopic adrenocorticotropic hormone-producing tumour is rare. Cortisol upregulation is often severe and rapid, though clinical signs are not always fully pronounced. Rapid treatment is a key for preventing and reducing complications such as fractures, thromboembolism, bleeding, hyperglycaemia, and arterial hypertension. The novel potent steroidogenesis inhibitor osilodrostat can be used as first-line treatment for reducing hypercortisolism.

Karyotyping of Lymphocytes and Epithelial Cells of Distinct Embryonic Origin Does Not Help to Predict the Turner Syndrome Features.

BACKGROUND: In Turner syndrome (TS), fluorescent in situ hybridization (FISH) karyotyping offers an alternative to classical karyotyping. OBJECTIVE: We tested the added value of FISH karyotyping from lymphocytes (mesodermal origin), buccal cells (ectodermal origin), and a rear-tongue smear (endodermal origin) to determine the 45,X cell line fraction and its impact on patient phenotype. DESIGN AND PATIENTS: Classical karyotyping and three FISH assays were done in 153 girls and women previously diagnosed with TS in four university hospitals. The 45,X cell line fraction was determined for each method and correlated with the major phenotypic signs. RESULTS: Classical karyotyping identified 45,X/46,XX mosaicism in 77/153 subjects (50%), 45,X monosomy in 52/153 (34%), and other karyotypes in 24/153 (16%). FISH from lymphocytes verified 45,X in 47/52 original cases, whereas 4/52 had 45,X/46,XX and 1/52 45,X/47,XYY mosaicism. The 45,X cell line fraction was higher in FISH from lymphocytes compared to classical karyotyping (median 86.4% vs. 70.0%; p < 0.001), while there was no difference for FISH from buccal or rear-tongue smear cells. The mean 45,X cell line fraction was more abundant in patients with several of the characteristic phenotypic signs compared to patients without them (p < 0.01), but the predictive power was insufficient. CONCLUSION: FISH analysis confirmed the findings of classical karyotyping; only a few 45,X monosomy cases were reclassified as mosaics. The 45,X cell line fraction did not show clinically meaningful prediction of the phenotype. FISH analysis of buccal or rear-tongue epithelial cells may be a non-inferior, less invasive alternative to classical karyotyping.

Acromegaly: Clinical Care in Central and Eastern Europe, Israel, and Kazakhstan.

Acromegaly is a rare condition typically caused by benign pituitary adenomas, resulting in excessive production of growth hormone. Clinical manifestations of acromegaly are diverse, varying from the overgrowth of body tissue to cardiovascular, metabolic, and osteoarticular disorders. Symptoms may emerge slowly, overlapping with other diseases and often involve many different healthcare specialists. In the last decade, efforts to provide an accurate and timely diagnosis of acromegaly have improved disease management and clinical experience. Despite this progress, marked differences in the diagnosis, treatment, and management of acromegaly exist from country-to-country. To address these inconsistencies in the region comprising Central and Eastern Europe, Israel, and Kazakhstan, a panel of acromegaly experts from 13 of these countries was convened. Acromegaly experts from each country provided available information on the approaches from their country, including regional treatment centers and multidisciplinary teams, treatment access, reimbursement and availability, and physician education, disease awareness, and patient advocacy. Across several areas of acromegaly management, divergent approaches were identified and discussed, including the provision of multidisciplinary care, approved and available treatments, and disease awareness programs. These were recognized as areas of potential improvement in the management of acromegaly, in addition to participation in national and regional acromegaly registries. Further experience exchange will facilitate the identification of specific strategies that can be adapted in each country, and widespread participation in acromegaly registries will enable their evaluation. It is anticipated that this approach will support the optimization of acromegaly patient care across this region.

Haplotype analysis of the X chromosome in patients with Turner syndrome in order to verify the possible effect of imprinting on selected symptoms.

AIMS: Turner syndrome is the only chromosome monosomy that is postnatally compatible with life. The reported incidence of TS is 1 in 2500 liveborn girls. The phenotype of these girls is highly variable, with cardiac abnormalities being life-threatening defects. The aim of the study was to reveal the possible influence of the parental origin of the X chromosome in these patients on a selected phenotype that is associated with Turner syndrome. Selected symptoms and parameters were: a bicuspid aortic valve, aortic coarctation, lymphoedema, pterygium colli, coeliac disease, thyroiditis, otitis media, diabetes mellitus 2, renal abnormalities, spontaneous puberty, and IVF. METHODS: The X chromosome haplotype was determined for a group of 45,X patients verified by native FISH. A molecular diagnostic method based on the detection of different lengths of X chromosome-linked STR markers using the Argus X-12 QS kit was used to determine the X haplotype. RESULTS: Our results, analysed by Fisher's exact (factorial) test, suggest independence between the maternal/paternal origin of the inherited X chromosome and the presence of the anomalies that were studied (P=1 to P=0.34). CONCLUSION: In the group of 45,X patients, who were precisely selected by means of the native FISH method, no correlation was demonstrated with the parental origin of the X chromosome and the observed symptom.

Predictive and prognostic significance of tumour subtype, SSTR1-5 and e-cadherin expression in a well-defined cohort of patients with acromegaly.

In somatotroph pituitary tumours, somatostatin analogue (SSA) therapy outcomes vary throughout the studies. We performed an analysis of cohort of patients with acromegaly from the Czech registry to identify new prognostic and predictive factors. Clinical data of patients were collected, and complex immunohistochemical assessment of tumour samples was performed (SSTR1-5, dopamine D2 receptor, E-cadherin, AIP). The study included 110 patients. In 31, SSA treatment outcome was evaluated. Sparsely granulated tumours (SGST) differed from the other subtypes in expression of SSTR2A, SSTR3, SSTR5 and E-cadherin and occurred more often in young. No other clinical differences were observed. Trouillas grading system showed association with age, tumour size and SSTR2A expression. Factors significantly associated with SSA treatment outcome included age, IGF1 levels, tumour size and expression of E-cadherin and SSTR2A. In the group of SGST, poor SSA response was observed in younger patients with larger tumours, lower levels of SSTR2A and higher Ki67. We observed no relationship with expression of other proteins including AIP. No predictive value of E-cadherin was observed when tumour subtype was considered. Multiple additional factors apart from SSTR2A expression can predict treatment outcome in patients with acromegaly.

Multivariable Prediction Model for Biochemical Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

CONTEXT: First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. OBJECTIVE: To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. DESIGN: Retrospective multicenter study. SETTING: Eight participating European centers. METHODS: We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. RESULTS: Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72-0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98-0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19-1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43-4.29), P = .0013; insulin therapy OR = 2.65, (1.02-6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01-1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94-0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (ß = 0.90, standard error (SE) = 0.02, P ≤ .0001 and ß â€…= 0.002, SE = 0.001, P = .014, respectively). CONCLUSION: Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.

Pituitary Stalk Enlargement in Adults.

Pathologies involving the pituitary stalk (PS) are generally revealed by the presence of diabetes insipidus. The availability of MRI provides a major diagnostic contribution by enabling the visualization of the site of the culprit lesion, especially when it is small. However, when only an enlarged PS is found, the etiological workup may be difficult, particularly because the biopsy of the stalk is difficult, harmful and often not contributive. The pathological proof of the etiology thus needs to be obtained indirectly. The aim of this article was to provide an accurate review of the literature about PS enlargement in adults describing the differences between the numerous etiologies involved and consequent different diagnostic approaches. The etiological diagnostic procedure begins with the search for possible other lesions suggestive of histiocytosis, sarcoidosis, tuberculosis or other etiologies elsewhere in the body that could be more easily biopsied. We usually perform neck, thorax, abdomen, and pelvis CT scan; positron emission tomography scan; bone scan; or other imaging methods when we suspect generalized lesions. Measurement of serum markers such as human chorionic gonadotropin, alpha-fetoprotein, angiotensin converting enzyme, and IgG4 may also be helpful. Obviously, in the presence of an underlying carcinoma (particularly breast or bronchopulmonary), one must first consider a metastasis located in the PS. In the case of an isolated PS enlargement, simple monitoring, without histological proof, can be proposed (by repeating MRI at 3-6 months) with the hypothesis of a germinoma (particularly in a teenager or a young adult) that, by increasing in size, necessitates a biopsy. In contrast, a spontaneous diminution of the lesion is suggestive of infundibulo-neurohypophysitis. We prefer not to initiate steroid therapy to monitor the spontaneous course when a watch-and-see attitude is preferred. However, in many cases, the etiological diagnosis remains uncertain, requiring either close monitoring of the lesion or, in exceptional situations, trying to obtain definitive pathological evidence by a biopsy, which, unfortunately, is in most cases performed by the transcranial route. If a simple surveillance is chosen, it has to be very prolonged (annual surveillance). Indeed, progression of histiocytosis or germinoma may be delayed.

The relationship of mitochondrial dysfunction and the development of insulin resistance in Cushing's syndrome.

PURPOSE: Cushing's syndrome is characterized by metabolic disturbances including insulin resistance. Mitochondrial dysfunction is one pathogenic factor in the development of insulin resistance in patients with obesity. We explored whether mitochondrial dysfunction correlates with insulin resistance and other metabolic complications. PATIENTS AND METHODS: We investigated the changes of mRNA expression of genes encoding selected subunits of oxidative phosphorylation system (OXPHOS), pyruvate dehydrogenase (PDH) and citrate synthase (CS) in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) and mitochondrial enzyme activity in platelets of 24 patients with active Cushing's syndrome and in 9 of them after successful treatment and 22 healthy control subjects. RESULTS: Patients with active Cushing's syndrome had significantly increased body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and serum lipids relative to the control group. The expression of all investigated genes for selected mitochondrial proteins was decreased in SCAT in patients with active Cushing's syndrome and remained decreased after successful treatment. The expression of most tested genes in SCAT correlated inversely with BMI and HOMA-IR. The expression of genes encoding selected OXPHOS subunits and CS was increased in PM in patients with active Cushing's syndrome with a tendency to decrease toward normal levels after cure. Patients with active Cushing's syndrome showed increased enzyme activity of complex I (NQR) in platelets. CONCLUSION: Mitochondrial function in SCAT in patients with Cushing's syndrome is impaired and only slightly affected by its treatment which may reflect ongoing metabolic disturbances even after successful treatment of Cushing's syndrome.

Serum steroid profiling in Cushing's syndrome patients.

CONTEXT: Cushing's syndrome is caused by increased exposure to cortisol. Discrimination of different causes of endogenous hypercortisolism can make a diagnostic dilemma. PATIENTS AND METHODS: In serum samples from patients with Cushing's syndrome (47 with Cushing's disease, 6 with ectopic ACTH-dependent Cushing's syndrome, 16 with adrenal adenoma, 7 bilateral adrenal hyperplasia (BMAH) with overt Cushing's syndrome, 42 controls from the general population) using novel method based on gas chromatography-tandem mass spectrometry (GC-MS/MS) we measured 94 serum steroids to search for steroid fingerprint of each subtype. RESULTS: Patients with Cushing's disease and ectopic ACTH producing tumors showed elevated levels of androgens and their metabolites when compared with healthy controls. Mineralocorticoid precursors were also elevated in ectopic ACTH syndrome. The levels of androgens were decreased in adrenal adenomas and BMAH. ROC analysis showed 100% sensitivity and 93.6% specificity for 11ß-hydroxyepiandrosterone sulfate for discrimination of Cushing's disease from ectopic ACTH secretion. We didn't find any significant (p < 0.05) difference in steroids that would discriminate BMAH from unilateral adenomas causing Cushing's syndrome. CONCLUSION: Various causes of Cushing's syndrome show particular steroid fingerprints that can be used to discriminate and may help to achieve appropriate clinical diagnosis.

Adult growth hormone deficiency in CEE region: Heterogeneity of the patient pathway.

OBJECTIVES: Adult growth hormone deficiency (AGHD) is a rare disease characterised by abnormal body composition, reduced strength and exercise capacity and impaired psychological wellbeing. An advisory board of leading Central and Eastern European (CEE) endocrinologists was assembled to gain insights into the status of AGHD care in the CEE region. Topics of discussion included the position of adult hypopituitarism/AGHD in health system priorities, availability and affordability of treatments, awareness of AGHD, practice guidelines used in CEE countries and provisions for long-term care of patients. DESIGN: Prior to the meeting, the advisors were asked to summarise, using an itemised survey questionnaire, the usual standards of care for patients with AGHD in their country. At the meeting, the panel of experts discussed the findings and thereby elucidated similarities and differences among CEE countries; these were compared with international guideline-recommended practices for AGHD. RESULTS: All CEE countries involved reported having some type of infrastructure in place for care of patients with GHD transitioning from adolescence to adulthood. Most countries reported having at least one specialist centre for patients with AGHD. The main variations across the region included initial entry into healthcare systems, tests required to confirm AGHD diagnosis and medication reimbursement by health authorities. Most CEE countries relied on international society-led guidelines, while some countries have developed national guidelines. CONCLUSION: The CEE Adult Endocrinology Advisory Board meeting recognised considerable diversity in the care and patient pathways for AGHD across CEE countries. Additional work is needed to optimise care of patients with AGHD in the CEE region.

Role of gamma knife radiosurgery in the treatment of prolactinomas.

PURPOSE: Stereotactic radiosurgery is one of the treatment options for prolactinomas, the most commonly used being Gamma Knife Radiosurgery (GKRS). GKRS is indicated mainly in the treatment of dopamine agonist (DA)-resistant prolactinomas. In our study, we report on our experience in treating prolactinoma patients by GKRS. METHODS: Twenty-eight patients were followed-up after GKRS for 26-195 months (median 140 months). Prior to GKRS, patients were treated with DAs and 9 of them (32.1%) underwent previous neurosurgery. Cavernous sinus invasion was present in 16 (57.1%) patients. Indications for GKRS were (i) resistance to DA treatment (17 patients), (ii) drug intolerance (5 patients), or (iii) attempts to reduce the dosage and/or shorten the length of DA treatment (6 patients). RESULTS: After GKRS, normoprolactinaemia was achieved in 82.1% of patients, out of which hormonal remission (normoprolactinaemia after discontinuation of DAs) was achieved in 13 (46.4%), and hormonal control (normoprolactinaemia while taking DAs) in 10 (35.7%) patients. GKRS arrested adenoma growth or decreased adenoma size in all cases. Two patients (8.3%) developed hypopituitarism after GKRS. Prolactinoma cystic transformation with expansive behaviour, manifested by bilateral hemianopsia, was observed in one patient. CONCLUSIONS: GKRS represents an effective treatment option, particularly for DA-resistant prolactinomas. Normoprolactinaemia was achieved in the majority of patients, either after discontinuation of, or while continuing to take, DAs. Tumour growth was arrested in all cases. The risk of the development of hypopituitarism can be limited if the safe dose to the pituitary and infundibulum is maintained.

An isolated Xp deletion is linked to autoimmune diseases in Turner syndrome.

Background Females with Turner syndrome (TS) are prone to develop autoimmune diseases (AIDs). The X chromosome contains several immune-related genes. Growth hormone (GH) and estrogens modulate the immune system. We aimed to clarify whether the loss of a specific X chromosome gene locus and the administration of GH and estradiol facilitate the development of AIDs in TS females. Methods Retrospective data on clinical course, AIDs, karyotype and treatment were analyzed from a cohort of 286 Czech females with TS (current age 2.8-43.3 years; median age 18.7 years). The karyotypes were sorted using two different classification systems: a mosaicism-focused and an isochromosome (isoXq)-focused approach. Karyotype subgroups with a significantly higher prevalence of AIDs were further evaluated. Data of common therapies were correlated with the prevalence of AIDs. Results The most frequent AIDs were autoimmune thyroid disease (AITD; 37.4%; n = 107) and celiac disease (CD; 8.7%; n = 25). All karyotype subgroups were prone to develop AIDs. Females with an isolated Xp deletion had a significantly higher prevalence of AITD and CD compared to all other individuals with TS (AITD: 66.0% vs. 31.5%, p < 0.0001; CD: 17.4% vs. 7.2%; p = 0.04, respectively). We observed no link between the mean age at initiation as well as the duration of GH and/or estrogen administration and the occurrence of AIDs. Conclusions Isolated Xp deletion contributes to the development of AIDs in TS patients. The haploinsufficiency of genes located in Xpter-p11.2 may explain this observation. Common therapies used in TS do not modify the risk of AIDs.

Novel GC-MS/MS Technique Reveals a Complex Steroid Fingerprint of Subclinical Hypercortisolism in Adrenal Incidentalomas.

CONTEXT: Improvement of imaging methods has led to more incidental adrenal tumor findings, especially adenomas. Routine hormonal evaluation uses only a few steroids to evaluate possible hormonal hypersecretion of these adenomas, but a wide spectrum of serum steroid hormone changes has not been published. OBJECTIVE: To measure the serum levels of 83 steroids from patients with unilateral and bilateral adrenal incidentalomas to uncover full steroid profile changes in patients with subclinical hypercortisolism (SH). DESIGN: Cross-sectional study. SETTING: The study was conducted at a tertiary inpatient clinic. PATIENTS: Fifty-two patients with adrenal incidentalomas (unilateral, n = 29; bilateral, n = 23), including nonfunctioning (n = 11) vs SH (n = 41), and 26 age- and sex-matched controls from the general population were included. MAIN OUTCOME MEASURES: Eighty-three serum steroids were measured by gas chromatography-tandem mass spectrometry (GC-MS/MS) before and after 1 mg dexamethasone, ACTH, midnight serum cortisol, and urinary free cortisol/24 hour. RESULTS: Of 83 measured steroids, 10 were significantly decreased in patients with SH, including dehydroepiandrosterone sulfate (DHEAS), androsterone sulfate, epiandrosterone sulfate, androstenediol sulfate, conjugated 5α-androstane-3ß,17ß-diol, and conjugated 5α-androstane-3α,17ß-diol. This finding was observed even when unilateral, bilateral, male, and female subgroups were analyzed separately. When we compared routine clinical methods and GC-MS/MS‒measured steroids, the most discriminatory was DHEAS followed by midnight serum cortisol, epiandrosterone sulfate, androsterone sulfate, ACTH, and 16α-hydroxypregnenolone. CONCLUSIONS: SH was associated with decreased levels of adrenal androgens, their metabolites, and pregnenolone metabolite. GC-MS/MS is a powerful tool for measuring serum levels of these undescribed changes in steroid metabolism, which are characteristic of SH in adrenal incidentalomas.

[Male hypogonadism and its treatment]. / Hypogonadismus u muzu a jeho lécba.

Male hypogonadism can be of various etiology and that reflects its clinical manifestation, diagnostics and treatment. Male hypogonadism leads not only to decreased fertility, but influences the cardiovascular system, mood changes, bone fragility, lipids and other metabolic functions. Diagnosis of hypogonadism can be cumbersome, as well as the choice of optimal hormonal supplementation. The aim of this article is to summarize the basics from symptoms, diagnosis and treatment of male hypogonadism.

Acromegaly at diagnosis in 3173 patients from the Liège Acromegaly Survey (LAS) Database.

Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liège Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years; P < 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (P = 0.015). Ages at diagnosis and first symptoms increased significantly over time (P < 0.001). Tumors were larger in males than females (P < 0.001); tumor size and invasion were inversely related to patient age (P < 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (P < 0.001). GH was inversely related to age in both sexes (P < 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6-4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.

Magnetic resonance imaging and histology correlation in Cushing's disease.

INTRODUCTION: We continuously look for new techniques to improve the radicality of resection and to eliminate the negative effects of surgery. One of the methods that has been implemented in the perioperative management of Cushing's disease was the combination of three magnetic resonance imaging (MRI) sequences: SE, SPGR and fSPGR. MATERIAL AND METHODS: We enrolled 41 patients (11 males, 30 females) diagnosed with Cushing's disease. A 3D tumour model with a navigation console was developed using each SPGR, fSPGR and SE sequence. The largest model was then used. In all cases, a standard four-handed, bi-nostril endoscopic endonasal technique was used. Endocrinological follow-up evaluation using morning cortisol sampling was performed for 6-34 months in our study. RESULTS: In total, 36 patients (88%) were disease-free following surgery. Our results indicate we achieved 100% sensitivity of MR. Overall, the conformity of at least one donor site, as compared with the places designated on MR, was in 78% of patients. We searched the place of compliance in individual locations. There is a consensus in individual locations in 63 of the 123 cases (or 56%). The correlation gamma function at a 5% significance level was then 0.27. DISCUSSION: The combination of MR sequences (SE, SPGR, fSPGR), neuronavigation system and iMRI led to increased sensitivity of up to 100%. Specificity reached 56% in our study. CONCLUSION: We found a high success rate in surgical procedure in terms of the correlation between MR findings and histology, which leads to remission of Cushing's disease.

[Current and future therapy of acromegaly]. / Soucasnost a perspektivy lécby akromegalie.

Acromegaly is a rare disease caused by overproduction of growth hormone, which significantly worsens quality of life and increases morbidity and mortality of patients. Modern specialized surgery, radiosurgery, radiotherapy and pharmacotherapy substantially improved therapeutical possibilities and the perspective of patients. Current thera-peutic modalities enable to create individually tailored therapy for the specific patient and suppress the acromegalic activity. Novel forms of currently used active substances and even conceptually new forms of pharmacotherapy are under preparation and testing (eg. octreotide in capsules, CAM2029, Somatoprim, ATL1103).Key words: acromegaly - cabergoline - new drugs - pegvisomant - somatostatin analogs - therapy.

T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

The Response of C19 Δ5-steroids to ACTH Stimulation and Hypoglycemia in Insulin Tolerance Test for Adrenal Insufficiency.

Studies on the time course of ACTH- or insulin-induced hypoglycemia stimulating adrenal androgens are usually limited to dehydroepiandrosterone and/or its sulphate. Our data on dehydroepiandrosterone (DHEA) and its hydroxylated metabolites clearly show that measurements of DHEA and its sulphate (DHEAS) are valuable markers of the integrity of the HPA (hypothalamus-pituitary-adrenal) axis. Assessments of HPA function should rely on measurements of baseline and/or stimulated serum cortisol concentrations, and C19 Δ5-steroids may provide additional information. The art of stimulation of 7- and 16-hydroxylated metabolites of DHEA can help our understanding of the formation sequence of these compounds.

The role of early cortisol level in the assessment of the radicality of resection in central Cushing's disease.

INTRODUCTION: To increase radicality and avoid surgical complications new treatment options are under investigation. One of the promising possibilities is to assess early morning cortisol levels on the first and second postoperative day. MATERIAL AND METHODS: We enrolled 34 patients (9 males, 25 females) diagnosed with Cushing's disease. Blood samples to determine cortisol level were taken always at 06:00 and sent to the lab. The samples were taken on the first and second postoperative day. For all patients, standard four-handed, a bi-nostril endoscopic endonasal technique was used. Endocrinological follow-up (6-34 months) was performed using morning cortisol sampling. RESULTS: In total, 36 patients (88%) were disease-free post-surgery. In the group with early postoperative levels of morning cortisol of less than 463 nmol/L, only 2 of 29 patients (7%) exceeded the final morning level of cortisol at follow-up. In patients with early postoperative cortisol levels between 17 nmol/l and 234 nmol/l all subjects showed normal postoperative cortisol levels. DISCUSSION: In 30 of 34 patients (88%), the level of cortisol was within normal limits. The prediction importance of early measurement of cortisol is 93% for patients with early postoperative cortisol levels of less than 463 nmol/L. The prediction importance of early measurement of cortisol is 100% for patients with early postoperative cortisol levels from 17 to 234 nmol/L. CONCLUSION: The monitoring of early morning cortisol levels seems to be an important tool in the management of central Cushing's disease.