Insulin-like growth factor (IGF) system and hormonal-metabolic profile in women with polycystic ovary syndrome.

AIM of the study was to compare serum levels of IGF-1, IGF-2 and insulin­like growth factor­binding protein 3 (IGFBP-3) among non­obese and obese PCOS women, and to assess their relationship to metabolic and hormonal parameters.    METHODS: The study included 64 women diagnosed with PCOS (age 28.9 ± 5 years); 30 of them with BMI > 27 and 34 with BMI lower than 27. All subjects were examined for parameters of glucose and lipid metabolism, steroid hormones and serum IGF-1, IGF-2 and IGFBP-3 levels. RESULTS: No significant differences in serum IGFBP-3 (p=0.534), IGF-1 (p=0.29) and IGF-2 (p=0.56) between two groups have been detected. IGFBP-3 was in positive correlation with total cholesterol (p=0.026), LDL cholesterol (p=0.03) and triacylglycerols (p=0.022). IGF-1 were negatively correlated with insulin (p=0.022), HOMA IR (p=0.033), triacylglycerols (p=0.0196) and waist circumference (p=0.049). A positive correlation was detected between IGF-1 and HDL cholesterol (p=0.025). No significant relationship was observed between IGF-1 and steroid hormones. CONCLUSION: Serum levels of IGF-1, IGF-2 and IGFBP-3 in obese PCOS women do not differ from those detected in non­obese PCOS women. IGF-1 negatively correlated with metabolic parameters, indicating that lower IGF-1 may represent an important predictor of metabolic syndrome (MS) in PCOS women. All peptides seem to have little effect on ovarian steroidogenesis in PCOS (Tab. 1, Fig. 1, Ref. 30).

Is Apelin a new biomarker in patients with polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS) is associated with multiple risk factors for cardiovascular diseases, including insulin resistance, diabetes mellitus type 2, obesity, hypertension, and dyslipidaemia. Many studies have assessed the role of adipokines in the etiopathogenesis of PCOS, however, no single biomarker has been recognized to be in causal relation to the syndrome. Apelin has been identified as a new adipokine linked to obesity and insulin resistance. Some studies demonstrated that the apelin / apelin receptor could play a pivotal role in the pathogenesis of polycystic ovary syndrome, however the other yielded controversial results. Underlying mechanisms of possible involvement of apelin/apelin receptor complex are discussed.

Relationship between steroid hormones and metabolic profile in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is commonly associated with a higher cardiometabolic risk. The relationship between steroid hormones and cardiometabolic profile in PCOS has been evaluated, but no single hormonal predictor of this association has been identified to determine. To determine the relationship between steroid hormones and cardiometabolic risk factors in PCOS women. Study included 64 women diagnosed with PCOS. Fasting blood samples were analyzed for biochemical, metabolic parameters and sex steroid hormones. PCOS women with BMI>/-27 had significantly higher serum free testosterone (FT), free androgen index (FAI), estrone (E1) (p=0.014, p=0.02, p=0.01) than those with normal weight. In all subjects E1 positively correlated with BMI (p=0.0067), serum insulin (p=0.0046), HOMA-IR (p=0.0125) and negatively with HDL-cholesterol (p=0.009). FAI positively correlated with serum cholesterol (p=0.0457), triacylglycerols (TAG) (p=0.0001), HOMA-IR (p=0.037), and glycemia (p=0.0001), negatively with HDL-cholesterol (p=0.029). In multiple linear regression model E1 most significantly predicted HOMA-IR, whereas FT/FAI predicted HDL-cholesterol and BMI. We conclude that PCOS women with marked overweight or obesity have higher FT, FAI and E1 as compared with nonobese PCOS subjects. E1 and FT may predict worse cardiometabolic profile in PCOS.

Humoral predictors of ankle-brachial index in patients with peripheral arterial disease and controls.

INTRODUCTION: Peripheral arterial disease (PAD) is a common condition due to atherosclerosis with high prevalence in population over 55 years. Although its pathophysiology is well recognized, the role of inflammatory markers is still not fully known. OBJECTIVES: The aim of the study was to assess the relation of C-reactive protein (CRP), tumor necrosis factors-alpha (TNF-alpha) and interleukin-6 (IL-6) to ankle-brachial index (ABI) and metabolic variables in patients with PAD. The second aim was to find the most significant humoral predictor of ABI. PATIENTS AND METHODS: The study groups consisted of 55 patients (36 men and 19 women) diagnosed with PAD (age 63.65 ± 6.11 years) and 34 control subjects (7 men, 27 women) of average age 59.88 ± 6.10 years with ABI > 0.9. Blood samples were analyzed for glycaemia, lipid profile and inflammatory markers (CRP, TNF-alpha and IL-6). RESULTS: A significantly higher serum total cholesterol (p = 0.04), triglycerides (p = 0.005) and lower HDL cholesterol (p < 0.0001) were found in the PAD group as compared to controls. Patients with PAD had significantly higher serum glucose (p = 0.008), CRP (p = 0.0044), IL-6 (p < 0.0001) and TNF-α (p < 0.0001) in comparison to controls. In a multiple linear regression analysis among variables log IL-6 and log HDL cholesterol were most significantly related to ABI (LW 4.75 for log IL-6, LW 4.016 for log HDL cholesterol, respectively, p < 0.01) in all subjects. CONCLUSIONS: We conclude that among traditional and humoral risk factors IL-6 is the strongest predictor of ABI. HDL cholesterol is also significant and strong predictor of decreased ABI and could be a potential biomarker of PAD in patients using lipid lowering drugs (Tab. 1, Ref. 31).

The effect of alfacalcidiol and metformin on phenotype manifestations in women with polycystic ovary syndrome - a preliminary study.

Aim of this study was to evaluate the effect of vitamin D supplementation in obese, insulin resistant and vitamin D deficient PCOS women on biochemical and clinical hyperandrogenism and menstrual irregularity in comparison to effect of metformin or combined metformin plus vitamin D therapy. Thirty nine PCOS women were randomized into three groups and treated with alfacalcidiol (Group 1), combined alfacalcidiol and metformin therapy (Group 2) and metformin (Group 3) for 6 months. Serum TST, fTST, DHEAS, LH and LH/FSH were measured before and after six months of treatment. Menstrual cycle regularity, hirsutism, acne and pregnancy rate were assessed at the same time. There was a significant decrease in TST levels in the Group 2 and slight but not significant decrease in the Group 3. No significant changes in other parameters (fTST, DHEAS, LH, LH/FSH) have been found after 6 months therapy in all three groups. An improvement of menstrual cycle was detected in 78 % of patients in Group 1 (p<0.04), 80 % in the Group 2 (p<0.03) and in 90 % in the Group 3 (p<0.002), respectively. There was no significant improvement of acne and hirsutism in all three groups (all p not significant). Pregnancy rate was higher in the Group 3 as compared with Groups 1 and 2 (67 % vs. 0 % and 25 %, respectively), however without statistical significance. Vitamin D administration has no significant effect on androgen levels and clinical features of hyperandrogenism in obese vitamin D deficient PCOS women. However, it can potentiate effect of metformin on testosterone levels and LH/FSH ratio but not on clinical hyperandrogenism and pregnancy rate.

A missense variant in GLP1R gene is associated with the glycaemic response to treatment with gliptins.

Gliptins act by increasing endogenous incretin levels. Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic peptide receptor (GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed-up 6 months after initiation of gliptin treatment. GLP1R rs6923761 (Gly168Ser) and GIPR rs10423928 genotyping was performed using real-time PCR, with subsequent high-resolution melting analysis. The main study outcome was reduction in glycated haemoglobin (HbA1c) after treatment. GLP1R Gly168Ser variant was significantly associated with reduction in HbA1c in an additive model (ß = -0.33, p = 0.011). The mean reduction in HbA1c in Ser/Ser homozygotes was significantly lower compared with Gly-allele carriers [0.12 ± 0.23% vs. 0.80 ± 0.09% (1.3 ± 2.5 mmol/mol vs. 8.7 ± 1.0 mmol/mol); p = 0.008]. In conclusion, GLP1R missense variant was associated with a reduced response to gliptin treatment. The genotype-related effect size of ∼0.7% (8 mmol/mol) is equal to an average effect of gliptin treatment and makes this variant a candidate for use in precision medicine.

Nesidioblastosis in adults.

The persistent hyperinsulinemic hypoglycemia may be caused either by a solitary tumor of the pancreas secreting excessive amount of insulin, known as insulinoma or, rarely, by nesidioblastosis. Nesidioblastosis is a rare cause of persistent hyperinsulinemic hypoglycemia in adults. The incidence of nesidioblastosis in adults is unknown, but it is generally thought to be very low. The ß cell changes in adult nesidioblastosis suggest a dysregulation of the function of the cell. The cause of the functional dysregulation in adults is unknown. The pathogenesis of adult nesidioblastosis may be different from infantile congenital hyperinsulinism caused by a genetic effect. Histologically nesidioblastosis is almost always characterized by a proliferation of abnormal ß cells throughout the entire pancreas. Clinically and biochemically , it is not possible to distinguish between diffuse nesidioblastosis and insulinoma. If all highly selective noninvasive imaging techiques fail to identify a tumor, selective arterial calcium stimulation testing should be performed. The final diagnosis relies on the histopathologic evaluation. The treatment of adult nesidioblastosis is surgical resection of the pancreas.

[Is polycystic ovary syndrome associated with autoimmune thyroiditis?]. / Je syndróm polycystických ovárií asociovaný s autoimunitnou tyreoiditídou?

INTRODUCTION: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of fertile age and lately there is a discussion about its possible association with autoimmune diseases. The aim of the study was to examine incidence of autoimmune thyreoiditis (AIT) in PCOS women. PATIENTS AND METHODS: 64 PCOS patients were enrolled and 68 healthy menstruating women served as controls. All subjects were examined for thyrotropin (TSH), free thyroxin (fT4) and the presence as well as titers of antithyroid antibodies aTG (anti-thyreoglobulin) and aTPO (anti-thyreoperoxidase). RESULTS: There was no difference between PCOS and controls in average TSH levels (2.37 ± 1.46 mIU/l vs 2.37 ± 1.46 mIU/l) (p = 0.953), and fT4 levels (16.36 ± 5.34 pmol/l vs 16.49 ± 2.32 pmol/l) (p = 0.852). Autoantibodies titers were also non-significant aTG (53.09 ± 157.07 IU/ml vs 29.8 ± 100.77 IU/ml, p = 0.386) and aTPO (59.74 ± 149.03 IU/ml vs 45 ± 204.77 IU/ml, p = 0.805). However, PCOS women had significantly higher prevalence of aTPO (18.75 vs 7.35%, p = 0.045). On the other hand, the overall prevalence of AIT was similar in both groups. CONCLUSION: Our results show PCOS patients have slightly but significantly higher positivity of aTPO antibodies but the prevalence of AIT was insignificant.

[Epilepsy and disorders of reproduction]. / Epilepsia a reprodukcné poruchy.

Epilepsy in women is relatively often linked with reproductive disorders which include polycystic ovarian syndrome, hypothalamic amenorrhea and functional hyperprolactinaemia. These disorders have a significant share in a high incidence of infertility and premature menopause while the polycystic ovarian syndrome, also manifested by the metabolic syndrome, places the affected patients at risk of later consequences such as type 2 diabetes mellitus, cardiovascular diseases including arterial hypertension, gynaecological neoplasias (the breast and the endometrium), and in the case of pregnancy, a higher incidence of pregnancy induced hypertension. Apart from epilepsy as such, also antiepileptic treatment may have negative impact on the female's reproductive functions. In many cases, adverse effects of treatment complicate the patient's life more than the attacks alone. Medication induced weight gain might be responsible for different endocrine diseases (menstruation disorders, polycystic ovarian syndrome, hyperandrogenism). The article analyses the influence of side effects of the different antiepileptic drugs on the development of metabolic and endocrine anomalies. The role of antiepileptic drugs in the development of reproductive and endocrine disorders was first described by Isojarvim in 1993. A high incidence of polycystic ovarian syndrome and/or hyperandrogenism (43%) was observed in women taking valproat, which was clearly higher than in women taking other antiepileptics. Results reported in literature are rather controversial. The article gives an overview of current knowledge with respect to the influence of epilepsy and antiepileptics on the incidence ofpolycystic ovarian syndrome, which is considerably higher in women with epilepsy (10-25%) than in the unaffected population (4-7%), and of the related metabolic syndrome. The article concludes with recommendations for clinical practice in the treatment of epilepsy in women in reproductive age.

Adrenal incidentalomas and the metabolic syndrome--are there any differences between adenoma and hyperplasia?

Authors evaluated the prevalence of symptoms of the metabolic syndrome and insulin resistance in 25 patients with adrenal incidentalomas (10 men, 15 women) of the mean age 57.9+/-15 years. 15 patients had adrenal adenoma determined by CT or MR scan and 10 had unilateral or bilateral hyperplasia. The prevalence of obesity was 72%, arterial hypertension 60%, diabetes mellitus or impaired glucose tolerance 28%, hyperlipidemia 56% and hyperuricemia 20%, respectively, which is more frequent occurrence than that in normal human population. Patients with adrenal adenomas had mildly but significantly higher body mass index (BMI, p<0.05) and insulin resistance calculated as HOMA IR (p<0.05) and FIRI (p<0.05) and significantly higher values of serum ferritin (p<0.01). Plasma cortisol values were slightly but not significantly higher in the group with adrenal adenomas. Authors conclude that adrenal adenomas are probably more related to the metabolic syndrome than adrenal hyperplasia.

Metformin versus sibutramine in the treatment of hyperinsulinemia in chronically anovulating women.

Aim of this study was to compare the effects of metformin and a body weight reduction regimen using sibutramine on insulinemia, insulin sensitivity, and ovarian function in women with anovulatory cycles or infertility. 30 women with anovulatory cycles and hyperinsulinemia were treated with metformin and 15 anovulating women with obesity were treated with sibutramine in combination with a caloric restriction diet and physical exercise. In the metformin group there was a mild decrease of the body mass index (BMI), a decrease of fasting and stimulated insulinemia (I0, p < 0.05, I120, p < 0.01), a significant reduction of insulin resistance calculated as index FIRI (p < 0.05), serum LH (p < 0.05) and testosterone levels (p < 0.05). There was an improvement of menstrual cycles in 21 (70 %) of women, and 6 of them became pregnant. In the sibutramine group we found a significant decrease of BMI (p < 0.01), waist circumference (p < 0.01), fasting and stimulated insulinemia (p < 0.05, p < 0.01) and a significant improvement of insulin sensitivity (FIRI, p < 0.01). However, the levels of FSH, LH, and testosterone were not significantly changed. There was a significantly greater reduction of insulin levels and FIRI after sibutramine treatment compared with metformin treatment, while the changes of LH were not signifcantly different. Testosterone was changed more after metformin therapy. We conclude that although the body weight reduction using sibutramine has a more pronounced effect on insulinemia and insulin sensitivity, metformin may be more effective in the prompt restoration of ovarian function. (Tab. 3, Ref. 24.).

Obesity is the major factor determining an insulin sensitivity and androgen production in women with anovulary cycles.

Aim of this study was to test the hypothesis that obesity promotes the insulin-sensitivity and ovarian hyperandrogenism in anovulating women independently of the polycystic ovary syndrome (PCOS). We examined 80 women of reproductive age (19-38 years, mean 28.5 +/- 0.6 years) with anovulary cycles. 45 subjects had PCOS and 35 had chronic anovulation without hormonal and ultrasound criteria of PCOS. The control group consisted of 12 healthy females with normal ovulary menstrual cycle (age 26.4 +/- 0.6 years). We evaluated plasma insulin level baselines (I0); 120 min after oral administration of 75g of glucose (I120), we examined FSH, LH, prolactin, testosterone, 17 OH progesterone and DHEAS and calculated indexes of insulin sensitivity, i.e. FIRI and G/I. Women with anovulary cycles yielded a significant increase in I0 (p < 0.01), I120 (p < 0.01), FIRI (p < 0.01), FSH, LH (both p < 0.05) and testosterone (p < 0.01), and a significantly decrease in G/I (p < 0.01) in comparison to controls with normal weight. There was a significant correlation between BMI and insulin levels, BMI and FIRI, and between WHR or waist circumference and FIRI, or G/I. The highest levels of insulinemia and the highest degree of insulin resistance were found in obese women (BMI > 30 kg/m2). In the group of obese anovulating women we found a positive correlation between I0 and testosterone (p < 0.01). In PCOS group, we found a negative correlation between I0 and LH (p < 0.01), and FIRI and LH (p < 0.01). In the group of obese PCOS women there were significantly higher levels of plasma insulin, and lower insulin sensitivity as compared to lean PCOS patients. However, lean PCOS women were more hyperinsulinemic and insulin resistant than the control group of lean women. Our results indicate, that obesity is the important factor determinating the insulin sensitivity and hyperinsulinemia in PCOS women. Moreover, the body weight is the major determinant of insulinemia, insulin sensitivity and ovarian hyperandrogenism, independently of PCOS. (Tab. 5, Fig. 4, Ref. 23.).

[Obesity and disorders of the menstrual cycle]. / Obezita a poruchy menstruacného cyklu.

Obesity, the result of combined genetic and environmental factors, is in recent decades one of the most frequent diseases and is encountered mainly in Europe and North America. In women it is associated with the risk of several diseases, such as diabetes mellitus, osteoarthritis, cardiovascular diseases, sleep apnoea syndromee, breast cancer, cancer of the uterus and also with impairment of reproductive functions. Already during the last century some observations confirmed that a very low or very high body weight is more frequently associated with disorders of the menstrual cycle (MC), infertility and poor reproductive capacity. However only during the last decades the pathophysiological and molecular mechanisms of this relationship were gradually elucidated. The main factors which influences the menstrual cycle in obesity are: impaired estrogen metabolism, changes in the concentration of sex hormone binding globulin, hyperinsulinaemia, and probably also leptin levels.

[Hyperinsulinemia and disorders of the menstrual cycle]. / Hyperinzulinémia a poruchy menstruacného cyklu.

Hyperinsulinaemia and insulin resistance are usually associated phenomena of obesity and the polycystic ovary syndrome (PCO syndrome). On the other hand the PCO syndrome and obesity are often associated with disorders of the menstrual cycle and/or sterility. The authors examined 35 women aged 21 to 38 years (x = 27 +/- 4.4) with a history of anovulation cycles and/or sterility. 24 of them (68.6%) suffered from PCO syndrome. Their mean BMI was 28.95 kg/m2. 11 patients had a normal body weight, 6 were overweight and 18 were obese. The authors used the oral glucose tolerance test (oGTT) and during minute 0 and 120 blood samples were collected for assessment of the blood sugar and plasma insulin. Insulin levels in minute 0 (Io above 20 and in minute 120 (I120) above 65 uIU/ml were classified as hyperinsulinaemia. In the follicular stage of the anovulation cycle the authors assessed FSH, LH, testosterone, progesterone and prolactin. Hyperinsulinaemia ws recorded in 16 of 35 women. The mean insulin level at minute 0 was 11.9 +/- 1.3 and during minute 120 54.2 +/- 8.1 uIU/ml. The authors found significant differences in levels of I0 (6.4 +/- 1.2 vs. 16.1 +/- 1.9 uIU/ml, p < 0.01) and I120 (17.5 +/- 3 vs. 71.3 +/- 10.3 uIU/ml, p < 0.01) between obese and non-obese patients, Also in patients with the PCO there was a statistically significant difference in insulin levels of slim (BMI less than 25) as compared with obese women (BMI more than 30) (p < 0.01). A positive correlation was found between insulin levels and BMI (p < 0.01) and a liminal correlation between insulin and testosterone (p = 0.05). Patients with hyperinsulinaemia were treated with oral antidiabetics from the group of biguanides--metformin for a period of three months. During metformin treatment the insulin level declined and subsequently the menstrual cycle became normal in 11 of 16 patients with hyperinsulinaeia (68.7%), incl. two women who became pregnant. The results indicate a possible new indication of metformin in the treatment of ovarian hyperandrogenism in insulin resistant patients.