New markers of insulin resistance in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder in women of reproductive age. The diagnostic criteria include two out of three features: hyperandrogenism, polycystic ovaries on ultrasound and menstrual irregularities (Rotterdam Criteria 2003). PCOS patients are more vulnerable to develop diabetes, cardiovascular diseases and metabolic syndrome. Insulin resistance (IR) is prevalent in women with PCOS independently of obesity and is critically involved in reproductive and metabolic complications of the syndrome. Several tests have been developed to measure IR, some very reliable but complex like the hyperinsulinemic euglycemic glucose clamp and others less precise but easier and less invasive like HOMA-IR. New markers are needed to reach a more reliable assessment of insulin resistance. To date, several surrogate markers have been proposed in the literature to facilitate and improve the determination of IR. Many new proteins are strongly involved with PCOS physiopathology and IR, such as some adipocytokines (adiponectin, visfatin, vaspin and apelin), copeptin, irisin, PAI-1 and zonulin. Many other proteins have been proposed as potential new markers of IR in PCOS, such as resistin, leptin, RBP4, kisspetin and ghrelin, but their role is still controversial. In this review, we provide a short characterization of these new markers, recently studied as indicators of metabolic state.

Fertility in women of late reproductive age: the role of serum anti-Müllerian hormone (AMH) levels in its assessment.

INTRODUCTION: Fertility is referred to the capability for having offspring and can be evaluated by fertility rate. Women's fertility is strictly dependent on individual's age. The fertility peak occurs in the early 20s, and it starts to decline in the third and fourth decades of life (falling sharply after age 35). AIM: The aim of this work is to review the available data concerning fertility in women of late reproductive age, especially the role of serum anti-Müllerian hormone (AMH) levels. RESULTS: There are a lot of factors responsible for decrease of fertility in women of late reproductive age. These factors can be classified as oocyte-dependent (decrease in oocyte quantity and quality) and oocyte-independent (reproductive organs [uterus, oviducts] status and general health). Anti-Müllerian hormone (AMH) is a dimeric glycoprotein of the transforming growth factor-ß (TGF-ß) superfamily produced directly by the ovarian granulosa cells of secondary, preantral, and early antral follicles. It has been used as an ovarian reserve marker since 2002. Anti-Müllerian hormone seems to be the best endocrine marker for assessing the age-related decline of the ovarian pool in healthy women. Evaluation of AMH's predictive value in the naturally aging population is important for counseling women about reproductive planning as well as for treatment planning for women experiencing hormone-sensitive gynecological conditions such as endometriosis and fibroids. CONCLUSIONS: AMH can be considered as an indicator of fertility in late reproductive age women and pregnancy outcome in assisted reproductive technology cycles. AMH can strongly predict poor response in the controlled ovarian stimulation.

Premature ovarian insufficiency: the context of long-term effects.

PURPOSE: Premature ovarian insufficiency (POI) is defined as the cessation of the ovarian function before the age of 40 years. POI aetiology may be related to iatrogenic or endogenous factors and in many cases remains unclear. The aim of this review was to characterize the long-term consequences of POI. METHODS: The available literature regarding the long-term consequences of POI from MEDLINE has been reviewed. RESULTS: Lack of ovarian steroids synthesis has serious consequences for women's health. The short-term effects are similar to spontaneous menopause and refer mainly to the climacteric syndrome. In a longer perspective, POI affects a variety of aspects. It obviously and drastically reduces the chances for spontaneous pregnancies. Oestrogen loss leads also to urogenital atrophy. The most common urogenital symptoms include vaginal dryness, vaginal irritation and itching. The urogenital atrophy and hypoestrogenism interferes also with sexual functioning. Patients with POI are threatened by a decrease in bone mineral density (BMD). POI women also experience psychological distress and some studies have shown an increased risk of neurodegenerating diseases. Overall, POI women have a shortened life expectancy, mainly due to cardiovascular disease. Some studies have reported a reduced risk of breast cancer in this group of patients. CONCLUSIONS: In conclusion there are several well-characterized health risks in POI women. With every patient, an individualized approach is required to properly recognize and prevent these risks.

Study on the zona pellucida 4 (ZP4) gene sequence and its expression in the ovaries of patients with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder of unknown pathology, involving reproductive and metabolic abnormalities. Oocyte-specific genes are a group of genes expressed exclusively in ovarian tissue; therefore, they can play an important role in ovarian pathologies such as PCOS. The zona pellucida 4 (ZP4) gene encodes glycoprotein which is a part of the extracellular matrix of oocyte. MATERIALS AND METHODS: We analyzed 87 patients with PCOS, which were divided into four groups depending on their phenotype. In each patient, we performed profound clinical and biochemical analysis, including the measurement of serum androgens. The ovarian tissue samples were used to perform a real-time polymerase chain reaction and immunohistochemical staining using anti-ZP4 monoclonal antibodies. The ZP4 gene was sequenced from peripheral lymphocytes. RESULTS: The expression of ZP4 was present in early antral follicles and was stronger in mature follicles. The subgroup of patients with eumenorrhea and without hyperandrogenism presented the highest expression of ZP4 in ovarian tissue. In one case, we found a mutation of the ZP4 gene. No correlations were found between the ZP4 expression level and biochemical or clinical indices. CONCLUSIONS: Data from this and animal studies suggest a possible relationship between androgens and ZP4 expression. ZP4 expression is highest among patients with PCOS and a regular cycle, and this is a consequence of the presence of mature follicles in this group. In some patients with PCOS and infertility, ZP4 mutation can be found.

Functional hypothalamic amenorrhea and its influence on women's health.

INTRODUCTION: Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea. There are three types of FHA: weight loss-related, stress-related, and exercise-related amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). The final consequences are complex hormonal changes manifested by profound hypoestrogenism. Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 (IGF-1) and low total triiodothyronine. AIM: The aim of this work is to review the available data concerning the effects of FHA on different aspects of women's health. RESULTS: Functional hypothalamic amenorrhea is related to profound impairment of reproductive functions including anovulation and infertility. Women's health in this disorder is disturbed in several aspects including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of FHA. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. FHA patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects. CONCLUSIONS: FHA patients should be carefully diagnosed and properly managed to prevent both short- and long-term medical consequences.

Bone mineral density in women with polycystic ovary syndrome.

PURPOSE: PCOS is a complex disorder and various features of this disorder may have great importance for bone metabolism. The aim of the study was to determine the relationship between existing hormonal disorders, and bone mineral density (BMD) in young women with PCOS. METHODS: 69 reproductive-aged PCOS women and 30 age-matched healthy controls were enrolled to the study women. In each individual we assessed the body mass index (BMI). We evaluated the serum concentrations of: gonadotropins, prolactin (PRL), estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), testosterone (T), thyroid stimulating hormone (TSH), free thyroxine (fT4). We used the Homeostatic Model Assessment-Insulin Resistance Index (HOMA-IR) to diagnose insulin resistance. Bone mineral density in the lumbar spine was measured by dual-energy X-ray absorptiometry (DXA). RESULTS: The PCOS women had lower BMD values as compared to the controls (1.057 ± 0.1260 vs. 1.210 ± 0.1805 g/cm(2), p < 0.0002). In the analysis of PCOS patients according to BMI, only in the subgroup of the normal weight PCOS we find significantly lower BMD in comparison to controls (p = 0.0049). In patients with PCOS, BMD was positively correlated with insulin concentration and HOMA-IR. In the controls Z-score values were positively correlated with insulin concentration and HOMA-IR. CONCLUSIONS: The deleterious effect of estrogen deficiency on bones in PCOS is not balanced by androgen overproduction. Women with PCOS had significantly lower BMD of the lumbar spine compared to controls. Insulin seems to be one of the most important positive bone growth stimulators.

Is cigarette smoking more frequent among insulin-treated diabetics?

During epidemiologic investigations of vascular complications of diabetes in Warsaw the habit of cigarette smoking was analyzed in the subjects studied (4,530 diabetics). It was found that in the group of diabetics the number of ex-smokers was much greater (p less than 0.01) and that of present smokers lower (p less tan 0.01) than in a representative sample of the Warsaw population. Furthermore, it was observed that in the subgroup of insulin-treated diabetics the number of smokers was highest and the number of ex-smokers and nonsmokers was lowest in relations to other treatment subgroups.

Clinical course of myocardial infarction among diabetic patients.

The clinical course of myocardial infarction (MI) was compared between 154 known diabetic (Ds) and nondiabetic (NDs) MI patients matched for age, sex, and hospital ward. In both groups similar numbers of cases with cardiac rupture, shock, pulmonary edema, and clinically observed arrhythmias were found. In contrast, Ds patients had significantly more frequent A-V and intraventricular conduction disorders than NDs (P less than 0.02). Ds also died twice more often from MI (36%) than matched controls (18%). The excess case fatality rates from MI among Ds were limited to the period between the second and seventh day of hospitalization. The excessive fatality of Ds from MI resulted mainly from the high liability of insulin-dependent diabetic patients (IDDs), with the relative risk of over 4 in relation to NDs. Ds with arrhythmias and/or conduction disorders had a particularly poor prognosis for surviving, the relative risk exceeding 3. No ready explanation of this phenomenon is presently available.

The role of circulating glucose and triglyceride concentrations and their interactions with other "risk factors" as determinants of arterial disease in nine diabetic population samples from the WHO multinational study.

In 9 of the 14 national samples of diabetic patients assembled for the WHO Multinational Study of Vascular Disease in Diabetes additional laboratory data made it possible to relate manifestations of macrovascular disease to blood glucose concentrations as well as to diabetes duration and to other potential determinants. In five of the samples, serum triglyceride concentrations were also measured and were included in simple and multivariate analyses. Ischemic heart disease defined from Minnesota-coded EKGs and standardized WHO questionnaires was more strongly associated with serum triglyceride concentrations than with serum cholesterol concentrations, an association less notable in non-insulin-dependent diabetic patients. Ischemic heart disease was not related to the single fasting plasma glucose estimated for this study. Stroke and amputation were much more strongly related to the known duration of diabetes than was ischemic heart disease, and they were both related to blood glucose concentration measured at the time of study. Despite major variation in arterial disease prevalence rates between collaborating centers, risk for diabetic women appeared to equal that for diabetic men. The major variation in arterial disease prevalence between national groups could be accounted for only in part by the risk factors studied. Other factors, genetic or more likely environmental, are likely to contribute to the variation in arterial disease susceptibility and, if definable, may be potentially preventable.

Effect of nifedipine, captopril and prazosin on secretory function of pancreatic beta-cells in hypertensive patients with type-2 (non-insulin-dependent) diabetes and in hypertensive non-diabetics.

The aim of our study was to compare the effect of captopril--the angiotensin-converting enzyme inhibitor, nifedipine--the calcium antagonist, and prazosin--the alpha blocker, on the secretory function of pancreatic beta-cells in hypertensive patients with NIDDM and with normal glucose tolerance. The effect of a 2-week treatment with nifedipine, captopril and prazosin upon glycaemia, serum insulin (IRI) and C-peptide (CP) following oral and intravenous glucose load were investigated in three groups, each including 10 non-diabetic patients with essential hypertension (h) and 10 hypertensive type 2 (non-insulin-dependent) diabetics (h + d), aged 32-63 years. Nifedipine produced increase in glycaemia in the oral test in both groups. In the (h) group, but not in the (h + d) group, the drug caused reduction of the glucose-dependent increases in serum IRI and CP, more marked with respect to CP, as expressed by the decrease in the molar serum CP/IRI ratio. These results indicate that in non-diabetic patients, nifedipine reduces the early response of beta-cells to glucose, but this effect is partly compensated by a decreased insulin uptake by the liver. In patients with type 2 diabetes, this phenomenon does not become manifest because of absence or reduction in the early glucose-dependent insulin release. After captopril, lower values of glycaemia and serum IRI and CP were observed in both groups suggesting an improvement of insulin sensitivity. In conclusion, nifedipine has a small influence, and captopril and prazosin are devoided of any influence on the secretory function of pancreatic beta-cells. These drugs may be recommended for the treatment of hypertension in patients with type 2 (non-insulin-dependent) diabetes.

[Changes in secretion of cholecystokinin after cholecystectomy and the effect of these changes on biliary reflux and the state of the gastric mucosa]. / Zmiany w wydzielaniu cholecystokininy po cholecystektomii oraz wplyw tych zmian na wystepowanie refluksu zólciowego i stan blony sluzowej zoladka.

Cholecystokinin's role in regulations of gallbladder and gastric function was well documented. After cholecystectomy a secretion of cholecystokinin may be changed and observed symptoms are able to create a new clinical picture including biliary gastric reflux. In the study was noticed that in 12 patients after cholecystectomy the cholecystokinin secretion was increased in comparison to the period before operation. Observed increased levels of the enzyme were not in connection with biliary gastric reflux.

Hypoglycemia: a major problem in the management of diabetes in the elderly.

The aim of this study was to evaluate the incidence and causes of hypoglycemia requiring hospitalization of diabetic patients treated with insulin or oral antidiabetic agents. From 1975 to 1989, 20,978 patients were treated in the Department of Gastroenterology and Metabolic Diseases of the Warsaw Medical School; review of their records disclosed that severe hypoglycemia was the cause of admission in 236 cases (1.12%). Two hundred patients (74 older than 60 years) were treated with insulin and 36 (28 older than 60 years) with oral agents. The most frequent cause of hypoglycemia was dietetic error (123 cases), followed by excessive physical effort (55 cases), error in the dose of hypoglycemic drug (22 cases), and alcohol abuse (13 cases). Hypoglycemia was the cause of death in 13 patients (8 aged over 60 years). In another 24 patients (17 aged over 60 years), exacerbation of ischemic heart disease was observed. Serious injuries with bone fracture were experienced by 11 patients (7 aged over 60 years). We conclude that hypoglycemia is still a serious risk for the life and health of diabetic patients treated with insulin or oral agents, especially those in advanced age. For this latter group of patients, more liberal criteria of metabolic control seem to be justified.

[Immunogenicity of semisynthetic human insulin Novo--five year prospective studies]. / Immunogennosc insuliny ludzkiej pólsyntetycznej Novo--5-letnie badania prospektywne.

The aim of the study was to compare the immunogenicity of semisynthetic human and porcine monocomponent (MC) insulin Novo during--5-year observation. Thirty-one diabetic patients, never previously treated with insulin were randomly allocated to treatment with one of the two coded insulin preparations in a double blind trial. 15 patients aged 20-58 years (mean age--36 years) were treated with human insulin and 16 diabetics aged 19-61 years (mean age--34 years) with MC pork insulin. The insulin was injected twice a day (Actrapid plus Monotard). Serum insulin-binding antibodies were determined according to Christiansen (radioimmunoelectrophoretic method). The development of insulin-binding antibodies during the first year of observation was more rapid in patients treated with MC pork insulin but thereafter it was similar in the two studied groups. After 5 years of treatment with human insulin serum insulin-binding antibodies were found in 14 patients. The level of antibodies was very low (< 0.130 mU/ml) in 5 subjects, low (0.171-0.401 mU/ml) in 6 patients and relatively high (0.885; 1.186; 5, 162 mU/ml) in 3 patients. In the group of diabetics treated with MC pork insulin after 5 years of observation serum insulin-binding antibodies were found in 12 patients. The level of antibodies was low (0.131-0.576 mU/ml) in 9 subjects and relatively high (1.034; 3.954; 5.639 mU/ml) in 3 patients. The results obtained after 2-5 years of the study did not differ significantly (Wilcoxon's test, p > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)