ACTA ENDOCRINOLOGICA (BUC)

Endocrine disruptors (EDs) are considered to have an impact on the function of reproductive axis at different levels as well on reproductive organs in both sexes. Complexity of female reproductive system influenced with various stressors including EDs lead to morphological and functional alterations. This is resulting in modulation of neuroendocrine regulation with consequent developmental irregularities and derangements, causative infertility, endometriosis as well as premature ovarian insufficiency or polycystic ovary syndrome. A number of experimental clues was obtained on female animal models using various EDs such as synthetic estrogens and phytoestrogens, neurotransmitters, pesticides or various chemicals. These substances lead towards consequent derangement of the neuroendocrine control of reproduction from early phases of reproductive development towards different phases of adult reproductive period. This text will address some novel insights into the effects of EDs on neuroendocrine regulation of gonadal axis, effects on ovaries as well on endometrium during implantation period.

Context. Cardiovascular risk is increased in women with polycystic ovary syndrome (PCOS). Do insulin sensitizing agents such as metformin (MET) and myoinositol (MI) ameliorate biomarkers of cardiovascular risk? Objective. To compare the effects of MET and MI on blood pressure, lipid profile and high sensitive C-reactive protein (hs-CRP) in women with PCOS in respect to their body mass index (BMI). Design. Open label, parallel randomized, single center study. Subjects and Methods. Sixty six women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of hormones, lipid profile, oxidized LDL (ox-LDL), hs-CRP, blood pressure measurement and clinical assessment of BMI, waist circumference (WC) and Ferriman Gallwey score (FG score) were performed before and after treatment. Results. Thirty patients in each group completed the trial. Compared with MET, MI significantly decreased diastolic blood pressure (DBP) (p=0.036) and significantly increased serum hs-CRP (p=0.043). No differences between groups in total cholesterol (TC), HDL-cholesterol, LDLcholesterol, ox-LDL and triglycerides were reported after 6 months. Treatment with MI reduced BMI (p=0.037), WC (p=0.005), DBP (p=0.021) and TC (p=0.008). During MET treatment a significant decrease in BMI (p=0.005), WC (p=0.004), FG score (p=0.001), testosterone (p=0.013) and free androgen index (FAI) (p=0.006) was observed. Conclusions. Our study showed an advantage of MI in reduction of DBP and TC thus predicting favorable metabolic and cardiovascular outcomes in PCOS women. MET more effectively decrease indices of hyperandrogenism.

The recent discoveries on organelles autoregulation and their molecular mechanisms motivate a novel perspective on mitochondria involvement in cardiovascular dysfunctions related to diabetes mellitus and obesity. We present here an up-dated view on the latter topic along with a condensed perception on morphological details resultant from diabetes mellitus experimental models. This study is organized into sections covering the following topics: (i) mitochondrial stress/dysfunction, (ii) the “quality controller” role of mitochondria exerted by fusion, fission, and mitophagy events, (iii) the connection between mitochondria and metabolic diseases, and (iv) the perspectives of potential application of mitochondrial-targeted compounds in metabolic diseases. Critical analysis of the knowledge available so far on mitochondria-metabolic diseases relationship allows a two sides conclusion: a doubtful view, as the correlation between impaired mitochondrial function and insulin resistance is still unclear, even after 40 years since its first publication, and a hopeful view based on the novel traits of this organelle uncovered recently, such as plasticity, the “quality controller” role, the “retrograde signalling”, and the coordinate interaction with the nucleus, endoplasmic reticulum, Golgi apparatus and lysosomes. At the horizon, the essential issue of targeting mitochondria for the alleviation of diabetes/obesity complications remains to be resolved.

Context. There is a lack of evidence on thyroid hormonal status and the prevalence of thyroid autoimmune diseases\r\nin Montenegro.\r\nObjective. In order to get an idea about that we performed thyroid function tests on ambulatory patients from different\r\nareas of Montenegro.\r\nDesign. The study took place since November 2005 till March 2007 at the Clinical Center of Montenegro.\r\nSubjects and methods. The study included 277 subjects of both sexes, referred for serum thyroid-stimulating hormone\r\n(TSH), thyroxin (T4) and free thyroxin (FT4), thyroperoxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). Also a multi-step statistical analysis of the\r\nbiochemical data was performed.\r\nResults. An age-dependent increment in serum TSH was detected in both males (p = 0.001) and females (p = 0.034). In females significant changes of T4 with age were detected (p = 0.017), but not in males (p = 0.427). Neither in males nor in females changes in FT4 were found (p = 0.342 and p\r\n= 0.831, respectively). A univariate logistic model demonstrated an association between thyroid antibodies and TSH, indicating that TSH ≥ 7.15 mU/L was a better predictor of TPOAb (p = 0.001) than of TgAb (p = 0.01) presence . A multivariate model adjusted for both age and gender gave similar results. The highest TSH increment (86%) was\r\nfound in sera containing both antibodies, while 33% of antibodies negative persons had TSH above 7.16 mU/L.\r\nConclusion. The results demonstrate high percentage of subclinical thyroiditis among the investigated subjects.

Context. Insulin-like growth factor-1 (IGF-1) is main serum surrogate marker of growth hormone (GH) secretion, used in diagnostics and treatment of GH deficiency (GHD) and acromegaly. Regional, ethnic, racial or nutritional factors obscure cross-population applicability of IGF-1 reference values. Establishment of population- and assayspecific reference values requires sizable representative cohort of healthy subjects. Subjects and Methods. In representative sample of healthy adult population of Serbia (N=1200, 21-80 years, 1:1 male:female) serum IGF-1 was analyzed by Siemens Immulite 2000 assay under uniform laboratory conditions. Upper and lower limit of reference range (5th - 95th percentile) were calculated for each of the 12 quinquennial age intervals. IGF-1 distribution was normalized and standard deviation score (SDS) calculated by Logarithmic and LMS methods. Results. IGF-1 and age correlated significantly, with most prominent decline at 21-50 years, followed by a plateau up to age of 70. Gender differences were not significant overall. Plateau in age-related IGF-1 decline was less prominent in women. Correlations of IGF-1 with body mass index (BMI) or waist to hip ratio (WHR) were insignificant. Superior IGF-1 SDS transformation was achieved with LMS method, while logarithmic method was simpler to use. Conclusions. Normative age-specific serum IGF- 1 reference values were established on a representative cohort of healthy adults in Serbia. Our results support recommendations against necessity for gender-specific or BMI- and WHR-specific reference ranges. Populationbased data serve to generate IGF-1 SDS, which is valuable in rational application of consensus guidelines, proper longitudinal follow-up, advancement in efficacy and safety and personalization of treatment targets.

Background. The concept of NE differentiation in prostate carcinoma has two major aspects: prostate tumors with\r\nprimary NE differentiation and NE differentiation occurred during hormonal therapy for prostate adenocarcinoma, with\r\nthe extreme case of tumor dedifferentiation into a NE hormone resistant carcinoma.\r\nMaterial and method. The patient, 62 years old, with a history of poorly differentiated prostate adenocarcinoma,\r\nhormonally treated with the decrease and then constant maintenance of serum PSA level to 0.01 ng/mL was admitted in the hospital, 8 years after prostate tumor diagnosis, and 3 years after ceasing of hormone therapy, with multiple bone and liver metastases of unknown primary source.\r\nResults. The serum levels of CgA, NSE, CEA, CA19.9, serotonin were elevated. The histopathological examination\r\nof the needle biopsy fragment from a liver metastatic lesion revealed small cell neuroendocrine carcinoma. Despite the\r\nprompt chemotherapy, the disease has progressed, with the occurrence of brain metastases and the patient?s death\r\n6 months after detection of the metastatic disease.\r\nConclusions. The present case confirms the diagnostic difficulties in llymetastatic undifferentiated small cells\r\ntumors, and on the other hand, draws attention to the possibility of NE dedifferentiation as a result of hormone\r\ndeprivation in patients with prostate cancer.