ARE THERE RELIABLE PREDICTORS FOR THE IMPAIRED QUALITY OF LIFE IN PATIENTS WITH CUSHING'S SYNDROME?

CONTEXT: Patients with Cushing's syndrome (CS) of any etiology experience a number of physical and psychological symptoms which impact negatively on health-related quality of life (HRQoL). SUBJECTS AND METHODS: HRQoL was measured using CushingQoL questionnaire. RESULTS: The first part of our study was a cross-sectional analysis of 141 patients with CS over a 10-year period. CushingQoL score was lower in pituitary CS compared to adrenal CS. Remission and older age were associated with better outcome on item 7 (physical appearance anxiety). In a multivariate regression analysis after adjustment for etiology, remission status, age, UFC, duration of hypercortisolism and presence of hypercortisolism-associated comorbidities the female gender was the only negative predictor associated with poorer outcome on each of the three scores. The presence of hypercortisolism-associated comorbidities independently predicted poorer outcome on the psychological and the global subscales.The second part of our research was a prospective study of 27 patients with adrenal adenoma. Achievement of remission independently predicted improvement of the total score of any patient. CONCLUSION: Studying in details and understanding the mechanisms of the impaired HRQoL in patients with CS is the only way to become aware of the problem and create methods that could help these patients.

Treatment outcome results from the Bulgarian Acromegaly Database: adjuvant dopamine agonist therapy is efficient in less than one fifth of non-irradiated patients.

OBJECTIVE: We described biochemical outcome in regards to different treatment modalities in patients with acromegaly in Bulgaria. PATIENTS AND METHODS: It was a retrospective analysis using data from the Bulgarian Acromegaly Database. Patients with eligible data on at least one treatment modality were included in the study. Disease control was assessed by both GH and IGF-1 values or by GH/IGF-1 alone in cases with one marker. Last follow-up was median 7.0 (range 0.5-51) years after diagnosis. RESULTS: We identified 534 patients with interpretable data, 65.4% of whom were females. Overall surgical cure rate was 28.8%. Adjuvant bromocriptine and cabergoline treatment was analyzed in 133 and 70 patients with disease control achieved in 18.8% and 31.4% respectively. Patients without prior radiotherapy had 16.3% and 18.2% control rates respectively. Predictors of response to dopamine agonist (DA) therapy were disease activity, radiotherapy and medication dose. Adjuvant somatostatin analog (SSA) treatment led to biochemical control in 38.6% of 70 patients. Combination of SSA and cabergoline led to remission in 25% of 20 patients. Growth hormone receptor antagonist (GHRA) alone or in combination resulted in remission in 61.5% of 13 patients. Approximately one third of the patients were cured median 10 years after irradiation. Overall disease control was observed in 51.4% of our patients increasing to 70.3% in the last 5 years of the study period. CONCLUSION: DAs are efficient in less than 20% of non-irradiated patients. They are a good cost-effective alternative for carefully selected patients.

Individual risk factors of the metabolic syndrome in adult patients with growth hormone deficiency--a cross-sectional case-control study.

OBJECTIVE: Growth hormone deficiency in adults (GHDA) is considered to be associated with increased cardiovascular risk, most commonly reflected by the prevalence of the metabolic syndrome (MS). However, there are still a limited number of studies comparing directly the MS prevalence in GHD patients to that in general population. The aim of this study was to investigate the individual risk factors of the MS in a cohort of GHD patients and to compare its prevalence with an age- and sex-matched control group. DESIGN: A cross-sectional case-control study. METHODS: In total, 54 adult patients with GHD (childhood onset GHD (COGHD): n=19, adult onset GHD (AOGHD): n=35) and 2 153 control subjects were studied. GHD was diagnosed according to the Endocrine Society Clinical Practice Guideline recommendations from 2011 and MS was scored by the NCEP-ATP III definition. RESULTS: The main metabolic abnormalities in GHD group were increased waist circumference (50.0%), low HDL-cholesterol (42.6%) and hypertriglyceridemia (40.7%) and their prevalence was significantly higher (p=0.013, p=0.019 and p=0.010, respectively) than in control group, where increased blood pressure prevailed (64.2%, p<0.0001). However, the difference in the MS prevalence between the 2 groups (29.6% vs. 24.9% in controls) failed to reach statistical significance (p=0.429). Patients with MS from both groups did not differ significantly in their metabolic profile (except for increased blood pressure), mean age and gender distribution. CONCLUSIONS: Although GHDA was associated with the development of visceral obesity and dyslipidemia, these adverse cardiovascular risk factors did not determine a higher prevalence of the MS in Bulgarian GHD patients compared to control subjects. Furthermore, the individual risk factors of the MS did not significantly differ between patients with MS from both groups.

Macroprolactinemia in patients with prolactinomas: prevalence and clinical significance.

BACKGROUND: Data on the prevalence of macroprolactinemia in patients with prolactinomas is quite limited as the presence of high-molecular prolactin forms is suspected mainly in subjects with mild hyperprolactinemia and negative pituitary imaging. OBJECTIVE: The main objective of this observational case-control study was to assess the prevalence and clinical significance of macroprolactinemia among patients with prolactinomas. METHODS: The study population consisted of 239 subjects: 131 prolactinoma patients and 108 sex-, age- and ethnicity- matched healthy controls. Macroprolactinemia was defined by a PRL recovery after PEG precipitation of<40%. RESULTS: The prevalence of macroprolactinemia among newly diagnosed prolactinoma patients did not differ statistically from the prevalence in the control group (3.5 vs. 3.7%; p=1.000) but was lower although non-significantly than the subgroup of patients treated with dopamine agonists (DA) (3.5 vs.10.8%; p=0.072). Significant association between disruptions of ovarian function and serum levels of the monomeric as well as high-molecular prolactin isoform was found. CONCLUSIONS: In few cases, the presence of typical hyperprolactinemia-related clinical symptoms and their disappearance after treatment with DA suggests biological activity of macroprolactin comparable with that of monomeric prolactin isoform. Decrease of macroprolactin levels after DA treatment could suggest tumoral origin of the high-molecular isoform in these rare cases. Although macroprolactinemia is considered a benign condition, pituitary imaging, DA treatment, and prolonged follow-up may be necessary in certain cases. An individualized approach to the management of patients with macroprolactinemia should be applied.

[Measurement of basal anti-Mullerian hormone level of healthy fertile women in Bulgaria].

OBJECTIVE: To establish mean and reference range of basal serum Anti-Mullerian hormona (AMH) levels in a group of healthy fertile Bulgarian women. METHODS: The present report covers the results of 9 month's period in which 72 healthy fertile Bulgarian women, aged 20-40 years were selected to determinate a reference group of healthy fertile women with normal values of AMH. Blood samples were collected on early follicular phase of menstrual cycle (2-4 days). AMH was analyzed in duplicate with the use of a double-antibody ELISA. RESULTS: We established mean values of AMH -1,46 +/- 0,93 in a group of healthy fertile Bulgarian women with mean 31,4 years of age. The values of AMH, which we obtained in the 10th percentile, 10th - 0,61 ng/ml and in the 90th percentile was 2.94 ng/ml. CONCLUSIONS: The measurement of AMH is a test easy for performance, with reference values for healthy fertile Bulgarian women -1,46 +/- 0,93 ng/ml.

Diurnal blood pressure pattern in patients with primary aldosteronism.

BACKGROUND: The aim of the study was to evaluate diurnal blood pressure (BP) profiles in patients with primary aldosteronism and to compare them to those in subjects with essential hypertension. The effects of specific therapy on the circadian BP profiles have been studied. MATERIALS AND METHODS: Sixty-four patients with primary aldosteronism were included in the study. Thirty of them revealed an aldosterone-producing adenoma (APA) and 34 had idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia. RESULTS: We did not find any significant differences in ambulatory BP monitoring (ABPM) between patients with APA and IHA. However, the circadian BP variation in the patients with primary hyperaldosteronism due to APA was preserved, while the patients with IHA showed lower nocturnal decline in comparison with patients with essential hypertension. There was a significant decline in office and ambulatory BP levels after treatment in the patients with both APA and IHA. The awake-sleep BP difference in patients with APA remained unchanged after surgical treatment, while in patients with IHA the night-time systolic and diastolic BP decline was significantly higher after spironolactone treatment. CONCLUSIONS: Primary hyperaldosteronism due to APA was associated with normal circadian BP variability and the surgical treatment led to highly significant decline in all BP parameters but had no influence on the extent of nocturnal BP variation. Spironolactone therapy restored normal nocturnal BP decline in patients with IHA. Reduction of night-time BP decline in patients with IHA is more likely to be related to the duration of the disease rather than to the aldosterone levels.

Markers of vascular function in hypertension due to Cushing's syndrome.

BACKGROUND: There are limited data regarding the role of vascular endothelial growth factor (VEGF) in arterial hypertension. The aim of the study was to determine some markers of vascular function, including VEGF, active renin and prostaglandin E (2) (PGE (2)) in patients with endocrine hypertension resulting from Cushing's syndrome. MATERIAL AND METHODS: The study comprised 32 patients with active Cushing's syndrome, 22 patients with essential hypertension, and 24 healthy volunteers. RESULTS: VEGF was significantly elevated in the groups of patients compared to controls. VEGF levels in the patients with Cushing's syndrome were significantly higher than in patients with essential hypertension. We did not find significant differences in VEGF levels between patients with Cushing's disease and Cushing's syndrome due to adrenal tumor. Active renin and PGE (2) levels did not differ significantly among groups. CONCLUSION: VEGF levels were significantly elevated in endocrine hypertension due to glucocorticoid excess. Higher VEGF levels were detected in patients with Cushing's syndrome compared to patients with essential hypertension. Based on our results, we could not judge the extent to which this VEGF elevation in the patients with Cushing's syndrome was due to the hypertension itself and/or to the presence of adrenal tumor/hyperplasia.

[Anti-Mullerian hormone: a gonadal hormone with multiple diagnostics resources].

Anti-Mullerian hormone (AMH) is a gonadal hormone synthesized by granulose cells of the ovary and Sertoli cells of the testis. Anti-Mullerian hormone is used to facilitate the evaluation of intersex disorders and as a marker in some ovarian tumors or ovarian reserve assessment in the infertility cases. Serum levels of AMH hold objective information, which is useful in the clinical practice. Therefore it is necessary to decimate the normal and the abnormal levels of AMH.

[Measurement of basal inhibin B level in Bulgarian women of the childbearing age]. / Opredeliane na bazalnite inhibin B niva pri zheni ot bulgarskata populatsiia vuv fertilna vuzrast.

OBJECTIVE: To establish mean and reference range of basal serum inhibin B levels in a group of healthy fertile Bulgarian women. METHODS: The present report covers the results of 9 month's period in which sixty-five healthy fertile Bulgarian women, aged 20-40 years were selected to determinate a reference group of healthy fertile women with normal values of inhibin B. Blood samples were collected on early follicular phase of menstrual cycle (2-4 days). Inhibin B was analyzed in duplicate with the use of a double-antibody ELISA. RESULTS: We established mean values of inhibin B 121.22 (+/- 45.04) pg/ml in a group of 65 healthy fertile Bulgarian women with mean 30.78 (+/- 3.94) years of age. The values of inhibin-B, which we obtained in the 5th percentile, was 33.15 pg/ml and in the 95th percentile was 190.75 pg/ml. CONCLUSIONS: The measurement of inhibin B is a test easy for performance, with reference values for healthy fertile Bulgarian women between 33.15 pg/ml and 190.75 pg/ml.

Vascular endothelial growth factor (VEGF), prostaglandin E2(PGE2) and active renin in hypertension of adrenal origin.

There are limited data regarding the role of vascular endothelial growth factor (VEGF) in arterial hypertension. The aim of the present study was to determine some markers of vascular function, including VEGF, active renin and prostaglandin E2 (PGE2) in patients with endocrine hypertension. The study comprised: 30 patients with primary aldosteronism; 32 patients with active Cushing's syndrome; 19 patients with pheochromocytoma; 22 patients with essential hypertension and 24 healthy volunteers. VEGF was significantly elevated in all groups of patients as compared to the controls. VEGF levels in patients with Cushing's syndrome were significantly higher than those in patients with essential hypertension and primary aldosteronism. We did not find significant differences in VEGF levels between patients with Conn adenomas and idiopathic aldosteronism as well as between patients with Cushing's disease and Cushing's syndrome. PGE2 levels were not significantly different among the groups. Active renin was significantly the lowest in patients with primary aldosteronism and significantly the highest in those with pheochromocytoma compared to controls. The level of active renin in patients with primary aldosteronism was significantly lower than in patients with Cushing's syndrome and pheochromocytoma. In conclusion, VEGF levels were significantly elevated in patients with endocrine hypertension due to glucocorticoid, mineralocorticoid and/or catecholamine excess. The highest VEGF levels were detected in patients with Cushing's syndrome. The latter is associated with accelerated development of atherosclerosis and increased cardiovascular risk. VEGF might contribute to the cardiovascular risk in this disease. This effect was not likely to be PGE2 mediated.

Circadian blood pressure profile in patients with Cushing's syndrome before and after treatment.

The aim of the study was to evaluate the circadian blood pressure (BP) profiles in patients with two forms of Cushing's syndrome, and to compare them to those in patients with essential hypertension. The study included 100 patients with Cushing's syndrome (80 with pituitary adenomas and 20 with adrenal adenomas) and 40 with essential hypertension. Twenty-four-h ambulatory BP monitoring was performed before and after therapy. All 3 groups had similar office-, 24-h-, awake-, and sleep BP mean values. The awake-sleep differences between the patients with two forms of Cushing's syndrome were similar. The night-time BP decline in the patients with Cushing's disease, as well as in those with adrenal adenomas, was significantly lower than that in the patients with essential hypertension. In the patients with both forms of Cushing's syndrome, there was a highly significant decline in the office and ambulatory BP levels after the treatment, and the awake-sleep systolic BP difference became significantly higher. The night-time diastolic BP decline was significantly higher after treatment in patients with adrenal adenomas and not-significantly higher in patients with Cushing's disease. In the patients with Cushing's disease, the duration of hypertension was greater, and lower percentage of normalized BP after treatment was observed in comparison with the patients with adrenal adenomas. The significant negative correlation between duration of the disease and extent of the night-time BP decline suggests that the 'non-dipping' profile is related not only to hypercortisolism itself but also to the severity of hypertension and duration of the disease.

Effect of transdermal estrogen therapy on some vasoactive humoral factors and 24-h ambulatory blood pressure in normotensive postmenopausal women.

BACKGROUND: Mechanisms of the vasoprotective effect of hormone replacement therapy (HRT) are not completely understood, and they may involve direct actions on blood vessels through modulation of endogenous vasoconstrictors and vasodilators. Most studies have focused on estrogen action on prostacyclin and nitric oxide, while insufficient data exist concerning the effect of estrogen replacement therapy (ERT) on vascular endothelial growth factor (VEGF) and prostaglandin E(2). OBJECTIVE: The aim of this study was to examine the effect of transdermal estrogen therapy on VEGF, prostaglandin E(2) and active renin in normotensive postmenopausal women. METHODS: Transdermal estrogen (Climara) (Schering): 50 microg 17beta-estradiol) was given for 3 months to normotensive women with a surgically induced menopause, and serum levels of VEGF, active renin and prostaglandin E(2) were measured before and after treatment. In addition, 24-h ambulatory blood pressure monitoring was carried out to determine the estrogen action on mean diurnal and nocturnal systolic and diastolic blood pressure levels. RESULTS: Estradiol treatment resulted in a significant increase in both VEGF and prostaglandin E(2). There was no significant change in active renin levels. However, out-patient monitoring showed a significant fall in systolic blood pressure (daytime, night-time and total 24-h). The stimulating action of ERT on VEGF and prostaglandin E(2) suggests that both factors can elicit estrogen vasodilatory effects. CONCLUSION: The estrogen-mediated increase in serum VEGF and prostaglandin E(2) concentrations may be a mechanism by which HRT benefits the cardiovascular system.

Effect of different hormone replacement therapy regimens on circadian blood pressure profile and active renin in postmenopausal women.

Hormone replacement therapy (HRT) was considered as main prevention of cardiovascular disease (CVD) in postmenopausal women. Mechanisms of vasoprotective effect of this treatment are complex. However, recent data give rise to some uncertainties about HRT benefits and risks. Little is known about the effects of oral and transdermal HRT regimens on the renin-angiotensin-aldosterone system (RAS) and blood pressure (BP). This 3-month study comprised 28 menopausal women (age range 45-55 years) divided into two groups: Group 1: 12 normotensive women with natural occurrence of menopause receiving oral treatment with Climen (Schering) containing estradiol valerate and cyproterone acetate; Group 2: 16 normotensive women with surgically induced menopause receiving transdermal application of Climara (Schering) containing 17beta-estradiol. There were no significant differences in office BP before and after treatment with Climara or Climen. However, ambulatory monitoring showed a significant fall in systolic BP (day-time, night-time and total 24-h) when estradiol alone was used. A similar trend towards lower values of systolic BP that was significant only for the night-time BP was observed after treatment with Climen. There were no significant changes in diastolic BP after both treatment regimens. Heart rate (day-time and 24-h) was significantly lower after transdermal estradiol treatment. There was no significant change in active renin after both treatment regimens. The present study showed that both treatment regimens resulted in lower ambulatory BP in normotensive postmenopausal women with more notable reduction in night-time BP. Increase in nocturnal dipping may account in part for the beneficial cardiovascular effects of HRT including decreased end-organ damage.

[Not Available]. / [The research work of the Bulgarian physicians during the period 1991 - 96]

The research study work is connected with certain for evaluation. Their knowledge is a precondition for a more qualitative and efficient work. The research study that took place gave us some notion to what extent the Bulgarian scientists in the field of medicine are aware of these criteria. What is the number of their scientific publications in Bulgarian and foreign magazines during the period 1991-96. The study gives an idea about how many of them have doctors

Aldosterone response to metoclopramide in patients with prolactinoma: effect of short-term bromocriptine treatment.

The acute effect of 10 mg metoclopramide i.v. on prolactin and aldosterone levels was studied in 8 women with prolactinoma and 8 normal women. The prolactin response to metoclopramide was blunted in hyperprolactinemic patients in comparison with controls. Metoclopramide induced similar aldosterone increases in patients and controls, but hyperprolactinemic women showed a more sustained aldosterone response. Bromocriptine treatment (10 mg daily p.o. for 5 days) in patients with prolactinoma completely suppressed the prolactin response to metoclopramide and the aldosterone response curve was very similar to that of controls. The results did not exclude some degree of suppression of aldosterone in response to bromocriptine.

Clinical and laboratory characteristics of type I (insulin dependent) diabetes mellitus at presentation among Bulgarian children.

Clinical and laboratory data of 1248 newly diagnosed diabetic children at the time of diagnosis were analysed. All children were admitted to the University Children's Hospital in Sofia, 45.9% before first their insulin injection. Symptoms preceding the diagnosis and laboratory data (plasma glucose and ketonuria) were analysed, respectively for 1100 and 1022 children. Blood pH (mainly arterialized) was available in 558 ketonuria positive children and in other 82 acidotic breathing was reported. Mother's education was noted in the 1226 hospital records. Among the children with known urinanalysis 13.5% were without ketonuria (148 patients), 12 of them with fasting blood glucose < or = 6.4 mmol/1 (115 mg/dl). Eighteen-point-two percent of all children were hospitalized in a state of severe ketoacidosis (blood pH < or = 7.2 or reported acidotic breathing). The average duration of thirst and polyuria was 28 +/- 33 days. Ketonuria negative children with plasma glucose < or = 6.4 mmol/l showed a significantly shorter period of symptoms, compared to those with plasma glucose > 6.4 mmol/1 (17 +/- 25 vs. 25 +/- 31 days; P = 0.0991). The cases with severe ketoacidosis, compared to those with mild ketoacidosis (blood pH 7.21 - 7.34) showed shorter period of symptoms too (P = 0.0658). Moderate positive relation existed between the age at diagnosis and duration of symptoms (chi 2 = 43.28, D.F. = 8, P = 0.0000). The percentage of severe ketoacidosis is higher in the younger age groups. Febrile illness, preceding the start of the symptoms was more common in the groups with shorter duration of symptoms (up to 1 month), but did not change the proportion of severe ketoacidosis. No significant difference was found between the level of mother's education and duration of the symptoms before diagnosis (P = 0.9782). We conclude that the level of metabolic disturbances at the diagnosis of IDDM among children was not influenced by the duration of the preceding symptoms. The severity of clinical picture was possibly dependent on the degree of insulinopenia, i.e. the rate of beta-cell destruction. Clinical heterogeneity was possibly dependent on genetical heterogeneity related to HLA class II genes.

Study on long-term biological variability of erythrocyte sedimentation rate.

The aim of the study was the estimation of long-term within-subject variability of ESR. ESR was measured in 52 healthy persons of both sexes, aged 20-50 years, twice a month during 6 consecutive months, after the method of Westergren. The within-run imprecision, expressed as CV was 13.2% (mean value, x = 3.9 mm h-1) and 3.8% (x = 16.0 mm h-1) respectively. The analytical day-to-day imprecision, calculated by duplicate measurements during 23 consecutive days. was s = 0.6 mm h-1. The medians from within-subject variances were 0.9 for men and 8.6 for women, respectively. The 90th percentiles were 11.3 for men and 40.6 for women, respectively. The critical differences based on the median value (dk50) were 3.1 mm h-1 (men) and 8.3 mm h-1 (women). The critical differences based on the 90th percentile (dk90) are 9.5 mm h-1 (men) and 17.7 mm h-1 (women).

Genetic heterogeneity of polycystic kidney disease in Bulgaria.

Linkage analysis was performed on 22 Bulgarian families with polycystic kidney disease (PKD) ascertained through the hemodialysis centers of two medical schools. A total of 128 affected and 59 unaffected individuals, and 54 spouses have been investigated using eight polymorphic markers linked to PKD1 and nine markers to PKD2. The results demonstrate locus heterogeneity with 0.67 as the maximum likelihood value of alpha, i.e., the proportion of families linked to PKD1. In five families, the results suggest linkage to PKD2 and observed recombinants place the gene between loci D4S1544 and D4S1542. In one family, two double recombinants for closely linked markers on chromosome 16 and on chromosome 4 give evidence for the lack of linkage to either PKD1 or PKD2, thus suggesting the involvement of a third locus. Analysis of clinical data in the PKD1 group versus the unlinked group shows no significant differences in the severity of the disease.

Bronchial dysplasia induced by radiation in miners exposed to 222Rn progeny.

OBJECTIVES: To investigate whether sputum cytology can be used to monitor epithelial cell changes in groups at high risk of lung cancer from exposure to radiation. METHODS: Dysplasia of bronchial cells was investigated by means of sputum cytology in a group of 434 underground miners. 100 of them were not exposed, and 334 were exposed to 222Rn progeny at cumulative exposures < 450 working level months. RESULTS: The frequency of dysplasia in the exposed group was significantly higher than that in the not exposed group (P < 0.0001), and an exposure-response relation was found. This relation was different for smokers and non-smokers. CONCLUSIONS: Possibly the frequencies of dysplasia could be used to assess past exposures of groups of miners. This approach could be applied to cases where data on radiation monitoring are not available or are very scarce.

Kraepelin revisited: a reassessment and statistical analysis of dementia praecox and manic-depressive insanity in 1908.

A meta-analysis was carried out on 53 cases of dementia praecox (DP) and 134 cases of manic-depressive insanity (MDI) originally diagnosed by Kraepelin or his collaborators in Munich in 1908. The original case material was coded in terms of Present State Examination syndromes and analysed statistically for internal consistency and discrimination between the two diagnostic entities. Kraepelin's DP and MDI were found to define homogeneous groups of disorders which could be clearly distinguished from one another. A CATEGO re-classification of the cases revealed an 80.2% concordance rate between Kraepelin's diagnoses and ICD-9. Cluster analysis of the original data reproduced closely Kraepelin's dichotomous classification of the psychoses but suggested that DP was a narrower concept than schizophrenia today, while MDI was a composite group including both 'typical' manic-depressive illnesses and schizoaffective disorders.