Factors contributing to variability in metformin concentration in polycystic ovary syndrome.

AIM: To investigate the factors affecting metformin concentrations after chronic administration in patients with polycystic ovary syndrome (PCOS), focusing on the pharmacokinetic variability and its implications for personalized therapy. METHODS: This study enrolled 53 PCOS patients undergoing long-term metformin treatment at the Clinic for Gynecology and Obstetrics in Nis, Serbia, from February to December 2019. Pharmacokinetic parameters were measured from blood samples, and metformin concentrations were determined with validated analytical techniques. RESULTS: There was a significant variability in metformin concentrations among PCOS patients, with body mass index (BMI) identified as a major influencing factor. Higher BMI was associated with lower plasma metformin levels, a finding suggesting an altered pharmacokinetic profile in obese patients. CONCLUSIONS: This study highlights the critical role of BMI in influencing metformin pharmacokinetics in PCOS patients and underscores the need for personalized treatment strategies in patients with PCOS.

Tobacco and alcohol as factors for male infertility-a public health approach.

BACKGROUND: The study of reproductive characteristics of 430 male subjects of different age, fertility status and educational level who were involved in the program of extracorporeal fertilization at the Clinic of Gynecology and Obstetrics, Clinical Centre Nis, examined their knowledge, attitudes and behavior regarding tobacco and alcohol consumption as lifestyle risk predictors of their partial or full infertility. METHODOLOGY: Consisted of the analyses of spermiograms to establish their fertility status and a survey of their attitudes towards smoking and alcohol use (behavior, knowledge of the general health and reproductive health consequences of such a lifestyle, and their determination to change it). RESULTS: The proportion with higher tobacco consumption and more severe forms of infertility increased significantly with ageing (P < 0.001); the highest daily consumption of alcohol and the incidence of intoxication was seen among azoospermic patients; the level of awareness of the harmful effects of tobacco was highest among normozoospermic subjects and the highest level of determination to quit smoking was statistically significantly present among azoospermic subjects. CONCLUSION: Appropriate use of health promotion activities in relation to alcohol and tobacco use is through specially designed programs.

Hematological and biochemical markers in determining the diagnosis and stage prediction of endometrial cancer.

OBJECTIVES: To establish whether there is a statistically significant difference in hematological and biochemical parameters between the patients with premalignant changes of the uterine mucosa and those with malignant changes. The aim is to establish whether hematological and biochemical parameters may be useful in predicting the stages of endometrial malignancy and in differentiating premalignant and malignant endometrial changes. MATERIAL AND METHODS: A retrospective study included 100 patients (70 with endometrial carcinoma diagnosis and 30 with atypical hyperplasia). We compared hematological and biochemical parameters in both groups. RESULTS: CRP, granulocytes, platelets, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) are statistically significantly higher in patients with malignant changes. Lymphocyte count is statistically significantly lower in patients with malignant changes. Platelet count is statistically significantly lower in patients with stages I and II in comparison to patients with higher disease stage. NLR and PLR have good discriminatory power for carcinoma presence. Patients with advanced changes have statistically significantly higher CRP values, higher granulocyte and platelet count, as well as higher values of NLR and PLR, and statistically significantly lower values of lymphocytes and MPV in comparison to benign changes. CONCLUSIONS: There is a possibility of using hematological and biochemical parameters in the assessment of endometrial changes as well as in the prediction of stages, in confirmed malignant changes of the endometrium.

Predictors of poor neonatal outcomes in fetuses diagnosed with congenital urinary tract anomalie.

OBJECTIVES: Urinary tract anomalies account for approximately one-quarter of all antenatally detected anomalies. The aim of this study was to identify factors associated with severe adverse neonatal outcomes of a prenatally diagnosed urinary tract anomaly. MATERIAL AND METHODS: A retrospective-prospective study included 101 pregnant women with prenatally diagnosed fetal urinary tract anomalies presented to the Council for Fetal Anomalies. Prenatal diagnoses were compared with autopsy findings in cases of terminated pregnancy or with clinical and operative findings of the infants. RESULTS: The mortality rate in the group of patients with fetal obstructive uropathy (60 patients) was 10% and in the group of patients with fetal multicystic dysplastic kidney (38 patients) 15.7%. Surgery was performed on 53.4% of the children, whereas more than half of the operations involved resolving associated urinary tract anomalies. Postoperative renal function deterioration occurred in 19% of the children. CONCLUSIONS: The prognosis of renal function in obstructive uropathies is excellent if oligoamnios does not develop prenatally and in case of timely provided surgical care is provided postnatally. The finding of the bilateral multicystic dysplastic kidney is associated with poor prognosis. The prognosis in fetal unilateral multicystic dysplastic kidney depends primarily on the condition of the contralateral kidney and the existence of associated anomalies.

Interaction of thrombophilic SNPs in patients with unexplained infertility-multifactor dimensionality reduction (MDR) model analysis.

PURPOSE: Our aim was to evaluate the frequency and SNP-SNP interactions between factor V Leiden (FVL) G1691A, prothrombin G20210A mutation, and C677T MTHFR and PAI-1 4G/5G gene polymorphisms in female IVF patients with unexplained infertility (UI) by using a multifactor dimensionality reduction (MDR) model analysis. METHODS: A total of 225 subjects were enrolled in the study. There were 105 females in UI group and 120 healthy controls. Designated SNPs were determined by using allele-specific PCR methods. The difference in thrombophilia prevalence was assessed by a chi-square test and logistic regression analysis. Four-locus SNP interaction model was tested using the MDR approach. A ten-fold cross-validation consistency (CVC) and permutation testing were performed. RESULTS: There was a significant difference of MTHFR C677T polymorphism frequency between the groups. Significantly less UI patients had MTHFR CC genotype (p = 0.005), while the risk allele T was more frequent (OR = 1.83, p = 0.0018). Logistic regression determined a significant association only for MTHFR C677T in our patients (TT genotype OR = 2.99). The MDR analysis confirmed the significance of a single-locus model for MTHFR C677T polymorphism (p = 0.015; OR = 2.93). However, the best, significant predictive model was the two-locus model comprising MTHFR C677T and FVL (CVC = 10/10, testing accuracy = 60.95%, p = 0.013; OR = 3.02). CONCLUSION: The MTHFR C677T polymorphism was significantly associated with UI, with minor allele T being more frequent. Additionally, there was a significantly increased presence of MTHFR C677T with FVL mutation in these patients. Therefore, MTHFR and its interaction with FVL should be recognized as contributing factors in the pathogenesis of infertility.

Short-term dexamethasone plus acetylsalicylic acid treatment during in vitro fertilization procedure.

OBJECTIVES: Embryo implantation represents the major limiting step during in vitro fertilization (IVF) procedure. Immu- nological and coagulation abnormalities were shown to have a substantial part in multifactorial etiology of IVF failure. We aimed to investigate the effect of short-term low-dose dexamethasone plus acetylsalicylic acid (ASA) treatment, starting at the time of embryo transfer, on the implantation and clinical pregnancy rates in general IVF population. MATERIAL AND METHODS: Out of 233 consecutive patients undergoing fresh IVF/intracytoplasmic sperm injection (ICSI) cycles 64 received an adjuvant treatment consisting of dexamethasone (0.5 mg/day) plus ASA (100 mg/day) (DA group), starting on the day of embryo transfer. Patients not receiving these medications comprised a control group. RESULTS: Significantly more patients in DA group had positive ß-hCG values than controls (59.38% vs. 37.67%, p = 0.004) (OR = 2.42, 95% CI: 1.33-4.41). Implantation rate was 26.53% in DA group and 15.92% in controls (p = 0.0294). Clinical preg- nancy rate per started cycle was higher in DA group (43.59%) than controls (28.92%), but the difference was not significant (p = 0.0879; OR = 1.99, 95% CI: 0.89-4.41). CONCLUSIONS: Our study shows a potential benefit of dexamethasone plus ASA adjuvant treatment in females undergoing IVF/ICSI procedure. As these results show improvement of IVF outcome, a greater number of patients undergoing this type and regime of adjuvant treatment should be investigated.

[Results of in vitro fertilization cycles at the Clinic for Gynecology and Obstetrics, Clinical Center of Nis].

INTRODUCTION: Infertility affects 15-17% of reproductive age couples in our country. In vitro fertilization brought revolution in treatment of this problem, bringing hope to many couples around the world for more than 3 decades. The aim of this paper was to present results and experiences of implementation of this method of treatment at the Clinic of Gynecology and Obstetrics in Nis. MATERIAL AND METHODS: The study included the first 402 women who had undergone in vitro fertilization program at the Clinical Center of Nis. The data were statistically analyzed by basic descriptive methods. The main outcome measures were demographic features, cause of infertility, duration of stimulation, average gonadothropine consumption, number of oocytes per aspiration and embryos transferred, mode of conception as well as clinical pregnancy and aspiration rate. RESULTS: The two main factors were the male infertility and tubal factor inferitily, being 51.61% and 48.39%, respectively The classical method of in vitro fertilization constituted 72.40% of all cycles, while intra cytoplasmic sperm injection method was used in 27.60% of all cycles. The average number of embryos transferred was 2.75. The cycle cancellation rate was 15.05%. The clinical pregnancy rate per ermbryo transfer was 35.44%; while the live birth rate per embryo transfer was 26.53%. DISCUSSION AND CONCLUSION: Our success rates are comparable with those in other European countries, where for in vitro fertilization the clinical pregnancy rates per aspiration and per transfer were 29.0 and 32.4%, respectively in the observed period. For intra cytoplasmic sperm injection, the corresponding rates were 29.9 and 33.0%. The main difference from the European average was the average number of transferred embryos and lower percentage rate of intra cytoplasmic sperm injection as a method of conception. Results

[Incidence of lip and palate clefts in children in Nis from 1990 to 2007].

INTRODUCTION: Cleft lip and palate is a complex congenital anomaly of the orofacial system in children. OBJECTIVE: The aim of this study was to determine the incidence of live-born children with cleft lip and/or palate compared to the total number of children born in the period from January 1, 1990 to December 31, 2007. METHODS: Epidemiological investigation was based on the records of live-born children at the Hospital of Gynaecology and Obstetrics of the Clinical Centre Nis. The study included 61,116 live-born children, i.e. 56,905 full-term babies. RESULTS: The total number of registered clefts during the investigation period was 43 (22 boys and 21 girls). The most frequent were the secondary palate clefts (44.2%); combined cleft were present in 34.9%, while primary palate clefts were reported in 20.9%. In respect to the season and order of birth, there was no statistically significant difference in the frequency of the primary, secondary and complete palate clefts. The age of mothers was not identified as a risk factor for the occurrence of cleft lip and palate. CONCLUSION: In the studied period, 43 children were born with the cleft lip and/or palate, equally in boys as in girls. The secondary palate clefts were most frequent. The season and order of birth had no statistical influence on the occurrence of this anomaly.

[Postpartum intra-abdominal haemorrhage--case report].

INTRODUCTION: The most frequent cause of gynaecological haemoperitoneum is ruptured ectopic pregnancy. Haemoperitoneum after a normal vaginal delivery is rare and it is associated with high maternal mortality. CASE REPORT: A 22-year-old primipara had a normal vaginal delivery. She experienced acute abdominal pain and hypovolemic shock ten hours after the delivery and was referred to our hospital twenty one hours after the delivery. An urgent ultrasound profile was done, which revealed free fluid in pelvis and in the whole abdomen. An immediate laparotomy was done and 2 litres of blood were found within the peritoneal cavity. The uterine wall was intact. We found a haematoma on the anterior wall of rectum and livid colours of broad ligament. The peritoneal cavity was cleaned and revised. Any injury of the spleen or liver was excluded. DISCUSSION AND CONCLUSION: Haematoperitoneum after a normal vaginal delivery is rare but life threatening to mothers. It is important to recognize this condition to avoid delay in diagnosis and treatment because of high maternal mortality. Our patient was bleeding from superficial rectal vessels. Only a few cases with undefined aetiologies have been reported in literature.

Development of c-kit immunopositive interstitial cells of Cajal in the human stomach.

Interstitial cells of Cajal (ICC) include several types of specialized cells within the musculature of the gastrointestinal tract (GIT). Some types of ICC act as pacemakers in the GIT musculature, whereas others are implicated in the modulation of enteric neurotransmission. Kit immunohistochemistry reliably identifies the location of these cells and provides information on changes in ICC distribution and density. Human stomach specimens were obtained from 7 embryos and 28 foetuses without gastrointestinal disorders. The specimens were 7-27 weeks of gestational age, and both sexes are represented in the sample. The specimens were exposed to anti-c-kit antibodies to investigate ICC differentiation. Enteric plexuses were immunohistochemically examined by using anti-neuron specific enolase and the differentiation of smooth muscle cells (SMC) was studied with anti-alpha smooth muscle actin and anti-desmin antibodies. By week 7, c-kit-immunopositive precursors formed a layer in the outer stomach wall around myenteric plexus elements. Between 9 and 11 weeks some of these precursors differentiated into ICC. ICC at the myenteric plexus level differentiated first, followed by those within the muscle layer: between SMC, at the circular and longitudinal layers, and within connective tissue septa enveloping muscle bundles. In the fourth month, all subtypes of c-kit-immunoreactivity ICC which are necessary for the generation of slow waves and their transfer to SMC have been developed. These results may help elucidate the origin of ICC and the aetiology and pathogenesis of stomach motility disorders in neonates and young children that are associated with absence or decreased number of these cells.

[Changes of the glomerular size during the human fetal kidney development].

INTRODUCTION: Newborns adaptation on postnatal conditions includes significant morphological and functional renal changes. Every kidney contains a constant number of nephrons, at the end of the nephrogenesis period, which extends from week 8 to 34 of gestation. Mature juxtamedullary nephrons possess higher filtration capacity than primitive superficial nephrons, which have insufficient vascularization. OBJECTIVE: The objective of the study was to calculate an average glomerular diameter in cortical zones of the kidney during development, to define periods of their most intensive growth, and to record differences of glomerular size between different cortical zones. METHOD: A total of 30 human fetal kidneys aged from IV to X lunar months were analyzed. Stereological methods were used for calculating the average glomerular diameter in superficial, intermediate and juxtamedullary zone of the kidney cortex. RESULTS: Glomeruli in the superficial cortical zone had the lowest average diameter. The average glomerular diameter continually increased from IV lunar month (0.057 +/- 0.004 mm) to X lunar month (0.082 +/- 0.004 mm), with highly significant correlation with gestational age (r=0.755; p<0.01). The average glomerular diameter in the intermediate zone increased from 0.081 +/- 0.004 mm (IV lunar month) to 0.096 +/- 0.004 mm (X lunar month) with low linear correlation with gestational age (r=0.161). Juxtamedullary glomeruli were the biggest ones. Their average diameter, during the IV LM ranged from 0.093 +/- 0.006 mm to 0.101 +/- 0.004 mm. In the newborns (X lunar month), juxtamedullary glomeruli had spherical structures with an average diameter of 0.103 +/- 0.004 mm, and low negative correlation (r=-0.032) with gestational age. In the IV and V lunar months of gestation, there was significant difference (p<0.01; p<0.05) between the average glomerular diameter in the different zones of the kidney cortex. CONCLUSION: Superficial glomeruli had the smallest diameter, while juxtamedullary glomeruli were the largest. The average glomerular diameter increased during intrauterine development in all zones, most intensive in the X lunar month. There was a significant difference of the glomeruli between different cortical zones in the young fetuses. Such significant difference receded as gestational age increased.

Quantitative analysis of the nephron during human fetal kidney development.

BACKGROUND: The development of human kidney is a complex process. The number, shape, size, and distribution of nephrons as functional units in a kidney, provide some important information about the organization of the kidney. The aim of this study was to extend the knowledge of the developing human kidney by studying nephrons in the kidney's cortex during gestation. METHODS: Kidney tissue specimens of 32 human fetuses, the gestational age from IV lunar month (LM IV) to LM X, were analysed. Specimens were divided in ten groups based on gestational age. Stereological methods were used at the light microscopic level to estimate the volume densities of the corpuscular and tubular components of the nephron in the cortex of the developing human kidney. RESULTS: Nephron polymorphism was the main characteristic of the human fetal kidney during development. In younger fetuses, just below the renal capsule, there was a wide nephrogenic zone. It contained the condensed mesenchyme and terminal ends of the ureteric bud. Nephrons, in the different stages of development, were located around the ureteric bud which branched in the cortical nephrogenic zone and induced nephrogenesis. More mature nephrons were located in the deeper part of the cortex, close to the juxta-medullary junction. During gestation, nephrogenesis continually advanced, and the number of nephrons increased. Glomeruli changed their size and shape, while the tubules changed their length and convolution. Renal cortex became wider and contained the more mature glomeruli and the more convoluted tubules. The volume density of the tubular component of the nephron increased continually from 10.53% (LM IVa) to 27.7% (LM X). Renal corpuscles changed their volume density irregularly during gestation, increasing from 13% (LM IVa) to 15.5% (LM IVb). During the increase of gestational age, the volume density of corpuscular component of the nephron decreased to 11.7% (LM VIII), then went on increasing until the end of the intrauterine development (LM X) when corpuscles occupied 16.73% of the cortical volume. The volume density of the developing nephrons (corpuscular and tubular portion) showed the significant positive correlation (r = 0.85; p<0.01) with gestational age. CONCLUSION: The present study was one of few quantitative studies of the human developing nephron. Knowledge about the normal development of the human kidney should be important for the future medical practice.