Milos Stojanovic

Nondiabetic patients with either subclinical Cushing's or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: clinical implications.

OBJECTIVE The aim of this study was to estimate insulin sensitivity (IS) in nondiabetic patients with adrenal incidentalomas (AI): nonfunctional adrenal incidentalomas (NAI) and patients with AI and subclinical Cushings syndrome (SCS). METHODS Based on the inclusion criteria (normal fasting glucose levels, no previous history of impaired fasting glucose and/or diabetes, and no medications or concomitant relevant diseases) and the exclusion criteria (pheochromocytoma, overt hypercortisolism, hyperaldosteronism, adrenal carcinoma, metastasis of extra-adrenal tumors, extra-adrenal malignancies), 142 subjects were drawn from a series of patients with AI. The subjects were age-, sex- and body mass index (BMI)-matched: 70 with NAI (50 women and 20 men), 37 with AI and SCS (31 women and 6 men) and 35 healthy control (HC) subjects (30 women and 5 men). The oral glucose tolerance test (OGTT) and several indices of insulin sensitivity (IS) were used: homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), triglycerides and glucose index (TyG), index of whole-body insulin sensitivity (ISI-composite) and glucose to insulin ratio (G/I). RESULTS There was a significant difference in IS between subjects with NAI and HC (HOMA, p=0.049; QUICKI, p=0.036; TyG, p=0.002; ISI-composite, p=0.024) and subjects with SCS and HC (AUC insulin, p=0.01; HOMA, p=0.003; QUICKI, p=0.042; TyG, p=0.008; ISI-composite, p=0.002). There was no difference in the tested indices of IS between subjects with NAI and SCS (p>0.05). However, subjects with SCS had a significantly higher prevalence of impaired glucose tolerance and higher area under the curve for glucose than subjects with NAI (p=0.0174). The linear regression analysis showed that 1 mg-DST cannot be used as a predictor of HOMA (R(2)=0.004, F=0.407, p=0.525). Significant relationship was found between 1 mg-DST and ISI-composite (R(2)=0.042, F=4.981, p=0.028) but this relationship was weak and standard error of estimate was high. The linear regression model also showed that ACTH cannot be used as a predictor of HOMA (R(2)=0.001, F=0.005, p=0.943) or ISI-composite (R(2)=0.015, F=1.819, p=0.187). CONCLUSIONS Insulin resistance is a major cardiovascular risk factor; therefore, the assessment of IS in patients with AI, even nonfunctional, has a valuable place in the endocrine workup of these patients.

Drospirenone in the treatment of severe premenstrual cerebral edema in a woman with antiphospholipid syndrome, lateral sinus thrombosis, situs inversus and epileptic seizures.

We report herein the case of 32-year-old woman with situs inversus, thrombophilia, antiphospholipid syndrome and severe premenstrual syndrome (PMS) with cerebral edema and epileptic seizures prior to menstruation. Seven days prior to regular menstruation she developed severe PMS, including headache, blurred vision, epileptic seizures, urinary incontinence, craving for food, depression and irritability. Papilledema was detected. Daily hormone analyses prior to and during menstruation confirmed an ovulatory cycle with extremely high progesterone, prolactin and insulin levels in the late luteal phase. From day 29 to day 31, progesterone and insulin decreased sharply and the estradiol/progesterone ratio changed, leading to epileptic seizures and the peak of her symptoms. Diuretic treatment was administered. All symptoms disappeared during the first few days of menstruation. A novel oral contraceptive, containing ethinyl estradiol and drospirenone, an antimineralocorticoid progestogen, was given during the next cycle and hormone analyses were repeated. All symptoms were reduced significantly and no cerebral edema and epileptic seizures occurred. This is the first report of a woman with severe PMS and cerebral edema being treated successfully with an oral contraceptive containing drospirenone.

Finger Length Ratios in Serbian Transsexuals

Atypical prenatal hormone exposure could be a factor in the development of transsexualism. There is evidence that the 2nd and 4th digit ratio (2D : 4D) associates negatively with prenatal testosterone and positively with estrogens. The aim was to assess the difference in 2D : 4D between female to male transsexuals (FMT) and male to female transsexuals (MFT) and controls. We examined 42 MFT, 38 FMT, and 45 control males and 48 control females. Precise measurements were made by X-rays at the ventral surface of both hands from the basal crease of the digit to the tip using vernier calliper. Control male and female patients had larger 2D : 4D of the right hand when compared to the left hand. Control males left hand ratio was lower than in control females left hand. There was no difference in 2D : 4D between MFT and control males. MFT showed similar 2D : 4D of the right hand with control women indicating possible influencing factor in embryogenesis and consequently finger length changes. FMT showed the lowest 2D : 4D of the left hand when compared to the control males and females. Results of our study go in favour of the biological aetiology of transsexualism.

Hot flush values of gonadotropins and estradiol in the menopause

* Accepted papers are articles in press that have gone through due peer review process and have been accepted for publication by the Editorial Board of the Serbian Archives of Medicine. They have not yet been copy edited and/or formatted in the publication house style, and the text may be changed before the final publication. Although accepted papers do not yet have all the accompanying bibliographic details available, they When the final article is assigned to volumes/issues of the journal, the Article in Press version will be removed and the final version will appear in the associated published volumes/issues of the journal. The date the article was made available online first will be carried over.

ALTERED HRT AND ABPM IN MENOPAUSAL WOMAN

Objective: A 49-year-old female, presents with a complaint of “haven’t sleep well for years”. For the last three years, she noticed higher BP (blood pressure) despite taking beta blocker (BB). She also noticed that some nights she wakes up sweating. She reports being more tired and with difficulty concentrating at work. MEDICAL HISTORY Hypertension. Tobacco: smoking 8 cigarettes/day for 26 years. EtOH: 2–3 glasses of wine/week. Last menstrual period 2 years ago. MEDICATION BB once/day for hypertension. PSYCHIATRIC HISTORY No. SOCIAL HISTORY Lives with a supportive husband. No pets. FAMILY HISTORY Mother 76 y.o. with history of hypertension. Design and method: PHYSICAL EXAM Height = 172 Weight = 63. Ambulatory blood pressure monitoring (Meditech ABPM05) find mean daytime 138/87 mmHg P 76/min. Mean night-time 122/73 mmHg P 62/min. LABORATORY FSH = 44 LH = 34 IU/L Estrogen = 40 pmol/L. Results: CLINICAL COURSE Trisequens (estradiol-norethisteron) was recommend to alleviate her menopause-related symptoms. Patient developed increased dysphoria during the second month of treatement. After three months Trisequens was discontinued. At the time the Trisequens was discontinued, ABPM was performed for a second time and find slightly lower blood pressure values. Mean daytime 137/86 mmHg P 76/min. Mean night-time 120/72 mmHg P 62/min. NEXT TRIAL includes estradiol and drospirenone combined therapy (Angelique). FOLLOW-UP After six months on Angelique she noticed significant improvement of her vasomotor symptoms and her sleeping pattern. ABPM was performed yet again and find significantly lower BP values when compared with the first ABPM done before she starts taking Trisequens. Mean daytime 133/82 mmHg P 76/min. Mean night-time 116/66 mmHg P 58/min. Conclusions: When adequate hormone replacement therapy is prescribed, ambulatory blood pressure monitoring cofirm good regulation of blood pressure.

Variability of HOMA and QUICKI insulin sensitivity indices

Abstract Assessment of insulin sensitivity based on a single measurement of insulin and glucose, is both easy to understand and simple to perform. The tests most often used are HOMA and QUICKI. The aim of this study was to assess the biological variability of estimates of insulin sensitivity using HOMA and QUICKI indices. After a 12-h fast, blood was sampled for insulin and glucose determination. Sampling lasted for 90 min with an intersample interval of 2 min. A total of 56 subjects were included in the study, and in nine subjects sampling was done before and after weight reduction, so total number of analyzed series was 65. To compute the reference value of the insulin sensitivity index, averages of all 46 insulin and glucose samples were used. We also computed point estimates (single value estimates) of the insulin sensitivity index based on the different number of insulin/glucose samples (1–45 consecutive samples). To compute the variability of point estimates a bootstrapping procedure was used using 1000 resamples for each series and for each number of samples used to average insulin and glucose. Using a single insulin/glucose sample HOMA variability was 26.18 ± 4.31%, and QUICKI variability was 3.30 ± 0.54%. For 10 samples variability was 11.99 ± 2.22% and 1.62 ± 0.31% respectively. Biological variability of insulin sensitivity indices is significant, and it can be reduced by increasing the number of samples. Oscillations of insulin concentration in plasma are the major cause of variability of insulin sensitivity indices.

Ambulatory blood pressure monitoring in patients with hyperthyroidism before the introduction of therapy and on therapy

The increased secretion of thyroid gland hormones affects the cardiovascular system by increasing heart rate and often by increasing systolic and diastolic blood pressure. We examined the influence of elevated thyroid hormone on blood pressure. Blood pressure monitoring was performed prior to the introduction of therapy in people with increased FT4 and on therapy when FT4 was in the normal range. We analyzed 32 people, of which 26 women had normal blood pressure values measured by blood pressure monitoring. Average age 45 and body mass index 27 kg / m. Blood pressure was measured by monitoring blood pressure for 24 hours. On average, before the introduction of the therapy, it was 133/83 mmHg P 96 / min. The blood pressure on average on therapy with tireosuppressive was 128/82 mmHg P 74 / min. The Wilcoxon-Mann-Whitney paired test showes a significant P <0.05 higher systolic blood pressure and pulse rate during the day and night before the treatment, when FT4 was higher, than the time when medication was taking, when the FT4 was in the normal range. No significant difference was found for diastolic blood pressure before the introduction of therapy and during therapy with tireosuppressives. When values of FT4 are increased, monitoring of blood pressure showes significantly higher values of systolic blood pressure and pulse during day and night compared to systolic blood pressure and pulse values when FT4 is in the normal range.

[PP.27.09] ROLE OF AMBULATORY BLOOD PRESSURE MONITORING IN SCREENING FOR SECONDARY HYPERTENSION

Objective: Since the development of ambulatory blood pressure monitoring (ABPM), various studies have shown to be a very useful method in cardiovascular risk assessment and remains the only method of diagnosing a non- dipping blood pressure profile. It has been suggested that all forms of secondary hypertension, including renal/renovascular, glucocorticoid and mineralocorticoid excess, phaeochromocytoma and toxaemia in pregnancy are associated with blunted, eliminated or reversed nocturnal blood pressure fall. Design and method: We analysed 1621 patients referred to the Clinic of Endocrinology to be examined for secondary etiology of hypertension. ABPM revealed 268 subjects with white coat hypertension (WCH) so we didn’t screened them for secondary hypertension. Meditech ABPM 05 device was used with appropriate cuff. We did all necessary analysis and tests in 1353 patients to see the aetiology of hypertension. The mean age was 42.6+/−10.8 years. There were 820 women and 533 men. Mean body mass index was 27 +/−8 kg/m2. Results: Screening for secondary hypertension revealed 68 patients with renovascular disease, 25 patients with all forms of hyperaldosteronism, 18 patients with pheochromocytoma including multiple endocrine neoplasia, 22 patients with glucocorticoid excess, 92 patients with obstructive sleep apnea. ABPM showed blunted or eliminated circadian blood pressure rhythm in 60 patients with renovascular disease or renal artery stenosis, 22 patients with all forms of hyperaldosteronism, 9 patients with pheochromocytoma including multiple endocrine neoplasia, 18 patients with glucocorticoid excess, every one of 92 patients with obstructive sleep apnea had blunted, eliminated or reversed nocturnal blood pressure fall. Conclusions: Results of our study indicate that nocturnal BP decrease was blunted or absent in a majority of patients with adrenal cause of hypertension. Nocturnal BP fall measured by ABPM may be very sensitive predictor of cardiovascular outcome and good method for screening for secondary hypertension.

[PP.17.22] PRIMARY ALDOSTERONISM AND TWIN PREGNANCY WITH INTRAUTERINE DEATH OF ONE FOETUS: A CASE REPORT

Objective: Primary aldosteronism (PA) appears in 7.4% of all cases with secondary hypertension during the reproductive age range. Still, only one hundred cases of pregnancy in PA have been reported. The cause is early termination of pregnancy in PA due to hypertension and hypokalaemia or an under diagnosis of PA in pregnancy. Pregnancy is a state of hyperreninemic hyperaldosteronism. High progesterone blocks mineralocorticoid receptor leading to a significant increase of aldosterone. Plasma renin activity (PRA) rises even more due to oestrogen stimulation. So, the aldosterone: PRA ratio in pregnant women with PA is falsely negative. We present the patient with PA and twin pregnancy complicated by single foetal intrauterine death. Design and method: A 30-year-old woman was investigated due to resistant hypertension and borderline hypokalaemia. PRA was 0.2 ng/ml/h, and the lowest level of aldosterone during the infusion test was 120 ng/l. Magnetic resonance scan revealed 12 mm adenoma of the left adrenal gland. Soon after the investigation twin pregnancy was revealed. Blood pressure was well controlled on Methyldopa 4 × 250 mg. At 26 weeks of pregnancy her blood pressure rose to 170/110 mmHg and proteinuria appeared. Pregnancy was complicated by single foetal intrauterine death. Results: At 37th week of gestation a dead foetus was delivered by caesarean section due to preeclampsia, and the other one died postpartum. She recovered completely and two years later decided for pre-conception surgery. The pre-treatment lowest level of aldosterone in the infusion test was 320 ng/l. Histopathology confirmed primary aldosteronism. The optimal management of PA during pregnancy requires an experienced team since there is a high risk of adverse outcomes. A reasonable approach is antihypertensives known to be safe in first trimester, considering amiloride in second and third trimester where hypertension or hypokalaemia is difficult to control. Twin pregnancy was the additional risk factor in this case, and a death of co-twin jeopardized maternal and neonatal outcome of the surviving foetus. Conclusions: Primary aldosteronism should be considered in all women with hypertension prior to conception or during pregnancy, especially where adrenal adenoma, hypokalaemia or proteinuria is present.

[PP.28.13] DIFFERENCES IN THE MONITORING AND DYSFUNCTION OF THE AUTONOMIC NERVOUS SYSTEM IN PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES

Objective: Dysfunction of the autonomic nervous system can be diagnosed by spectral analysis of variability of cardiac frequencies of consecutive RR interval using TASK FORCE monitor. Design and method: Methodology and results: Study was done using TASK FORCE monitor and software analysis of HRV Fourier transform algorithm. Testing at rest (20 min) and passive orthostasis (tilt table 90° for 6 minutes and parameters from ambulatory blood pressure monitoring (ABPM) device Meditech ABPM 05. Diagnostic procedures were done in 110 patients, of which 48 treated for type 1 diabetes, average age 37 years, of which 28 men and 20 women. The second group contained 62 patients with type 2 diabetes, average age 62 years of which 35 men and 27 women. Results: In groups with type 1 diabetes LF HF at rest X ∼ 1.745 ± 0.91 SD; LF HF orthostasis X ∼ 3.08 ± 2.65 SD; LF-DBP at rest 44.79 SD ± 16:52; LF DBP orthostasis X ∼ 51.91SD ± 11:41, HF RRI at rest 36.01 SD ± 14.65, HF RRI orthostasis X ∼ 25.98 SD ± 8.2; BRS at rest 10.1, ± SD 6.18. In the group with type 2 diabetes LF HF at rest X ∼ 4.01 The SD ± 7.02, LF / HF orthostasis X 4.7 ± 8.9, LF DBP at rest X ∼ 37.17 ± 14.85, LF DBP orthostasis X ∼ 37.32 ± 10.89, HF RRI at rest 43.51, SD ± 17:48, HF RRI orthostasis X 43.51 ± 23:30, BRS at rest SD 9.78 ± 6.50. Correlation between the groups showed highly significant difference for LF DBP in orthostasis (p < 0.00067). Conclusions: Conclusion: Significantly lower values of LF DBP were registered in the group with type 2 diabetes, which represents the FAILURE of SYMPHATETIC in orthostasis. Orthostasis has been shown in ABPM analysis as well. It is common that patients with diabetes have a dominant parasympathetic dysfunction.