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.

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.

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.

Diabetes mellitus and cancer.

Although an association between diabetes and cancer was found over 100 years ago, the issue underwent different interpretations over the subsequent decades, and only modern, prospective, epidemiological cohort and case-control studies conducted in several countries have provided reliable evidence of an increased cancer risk in diabetic patients, mainly in those with type 2 diabetes. This risk varies according to the tumor site: it is the greatest for primary liver cancer, moderately elevated for pancreatic cancer, and relatively low for colorectal, endometrial, breast, and renal cancers. The cause of the association is not clear and remains the subject of different hypotheses. The most frequently cited reason is the potential effect of insulin. Found in high concentrations, due to insulin resistance in most patients with type 2 diabetes, this hormone is believed to express a mitogenic effect. This hypothesis needs to be confirmed in appropriately programmed prospective studies, but it may already be helpful in choosing an adequate treatment for type 2 diabetes to achieve optimal metabolic control with a simultaneous reduction in hyperinsulinemia, such as diet, physical exercise, metformin, and acarbose.

Effect of oral antidiabetic agents on plasma amylin level in patients with non-insulin-dependent diabetes mellitus (type 2).

The purpose of the study was the comparison of the effect of the oral therapy of non-insulin-dependent diabetes mellitus (NIDDM) with either a sulphonylurea or biguanide derivative on plasma amylin level. In 10 healthy individuals the fasting plasma amylin level was 1.56 +/- 0.27 pmol/l (mean +/- SEM) and 6 min after i.v. injection of 1 mg glucagon a fourfold increase was observed. In 10 patients with NIDDM receiving glibenclamide (CAS 10238-21-8) the fasting plasma amylin level was twofold higher than in healthy control (2.72 +/- 0.38 pmol/l; p < 0.025) but following glucagon administration it increased only twofold. In 15 patients treated with metformin (CAS 657-24-9) the fasting plasma amylin level was similar to that in healthy individuals (1.64 +/- 0.25 pmol/l), but after glucagon stimulation the increment of plasma amylin was minimal and the relevant mean value was significantly lower when compared with those in healthy individuals and with NIDDM patients treated with glibenclamide. In 10 untreated obese patients with newly diagnosed NIDDM the administration of glibenclamide (14 days) resulted in the increase of basal (2.47 +/- 0.23 and 3.16 +/- 0.29 pmol/l; p < 0.1), and glucagon stimulated (3.34 +/- 0.39 and 4.56 +/- 0.38; p < 0.05) plasma amylin concentrations, whereas other 10 patients receiving metformin showed a decrease in fasting plasma level of this peptide before (2.64 +/- 0.59 and 1.28 +/- 0.38 pmol/l; p < 0.1), and after glucagon injection (5.02 +/- 0.55 and 2.83 +/- 0.65 pmol/l; p < 0.02). With the respect to the trophic effect of amyloid deposits in the pancreatic islets and to a hypothetic effect of amylin increasing insulin resistance, the present results emphasize the particular usefulness of metformin in the pharmacological treatment of NIDDM. All contraindications and side effects of metformin should be taken into account before drug administration.

[Risk factors of the incidence of late vascular complications of diabetes]. / Czynniki ryzyka zapadalnosci z powodu powiklan naczyniowych cukrzycy.

From the follow-up examination of 1329 out of 4420 type 2 (non-insulin-dependent) diabetes followed for 17 years, the incidence of micro and macrovascular complications (proteinuria and nephropathy, symptoms of leg vascular disease, ischemic heart disease, and cerebrovascular events, was estimated and related to the levels of baseline-risk variables using logistic regression. For new cases of proteinuria and heavy proteinuria, hyperglycemia was the common predictor (alongside diastolic hypertension, smoking and overweight); hyperglycemia and glycosuria were among significant predictors of leg vascular disease (with duration of diabetes, smoking, male sex, diastolic hypertension, and proteinuria). On the other hand, systolic hypertension and male sex prevailed among factors predicting both ischemic heart disease (with high cholesterol and overweight), and stroke. The data confirm the higher involvement of diabetic milieu in micro than macrovascular incidents, with diabetic foot disease placed in between.

[Mortality of diabetic patients in Warsaw--22 year prospective observation (1973/74-1995). I. Mortality of diabetic patients with type 2 diabetes (non-insulin-dependent-diabetes)]. / Umieralnosc chorych na cukrzyce w Warszawie--22-letnia obserwacja prospektywna (1973/74-1995). Czesc I. Umieralnosc chorych na cukrzyce typu 2 (insulinoniezalezna).

In the period 1973/74-1995 a prospective observation was carried out on 4420 diabetic patients (1990 males and 2430 females) aged 30-68 years, with type 2 (non-insulin dependent diabetes) of 1-10 years duration. During the 22-years period nearly 80% of initial cohort died. The risk of death were 2-times higher in diabetes than in the samples of general population observed at the same time. The death risk from cardiovascular disease were over 3-times higher than in general population. The relevant risk ratio has been found over 5-times higher for coronary heart disease, which were unlike to results from the differences in death ascertainment between diabetics and the city dwellers. The all-causes ratio of death and cardiovascular diseases were the same for women and men but it was selectively higher for females then males group for coronary heart disease and cerebrovascular diseases. Among diabetic cohort the risk of death was also higher for neoplasms, especially in women.

[Mortality of diabetic patients in Warsaw--22 year prospective observation (1973/74-1995). II. Mortality of patients with type I diabetes (insulin-dependent-diabetes)]. / Umieralnosc chorych na cukrzyce w Warszawie--22-letnia obserwacja prospektywna (1973/74-1995) czesc II. Umieralnosc chorych z cukrzyca typu 1 (insulinozalezna).

During the follow-up 1973/74-1995 years 171 subjects with type 1 (insulin dependent diabetes) (105 males and 66 females) aged 18-30 years died 31.6% (32.4% males and 30.3% females). The relative risk of mortality for all causes in the compared to the general population was 5.0 (3.5 for men and 7.5 for women). Almost 30% deaths were from renal disease, 17% from ischemic heart disease, and 3 death in women from carcinoma of breast.

Enhancement of alcohol-induced hypoglycaemia by H2-receptor antagonists.

The oral ethanol loading test (0.5 g/kg body mass) was carried out in 3 groups with 10 healthy male volunteers each before and after 7 days of administration of either cimetidine (CAS 51481-61-9), ranitidine (CAS 66357-59-3), or famotidine (CAS 76824-35-6). The parameters determined during 6 h comprised the blood levels of ethanol, acetaldehyde, glucose, lactate, pyruvate and bicarbonates, as well as blood pH, PCO2 and PO2. Only ranitidine significantly increased the mean blood ethanol concentration and none of the drugs modified the blood acetaldehyde concentration. Hypoglycaemia following alcohol ingestion was significantly enhanced by all H2-receptor antagonists, but was most pronounced after famotidine. The alcohol-induced rise in blood pyruvate and lactate rather had a tendency to decrease during the second test. The presented results suggest that the evident enhancement of alcohol-induced hypoglycaemia by H2-receptor antagonists is not dependent on the increase of ethanol absorption from the gastrointestinal tract, but represents rather a specific effect of these drugs on glucose metabolism.

[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.

Difference in the influence of maternal and paternal NIDDM on pancreatic beta-cell activity and blood lipids in normoglycaemic non-diabetic adult offspring.

The 75-g oral glucose tolerance test was performed in 38 normoglycaemic (World Health Organization criteria) non-diabetic volunteers, aged 31-40 years, of whom 20 had a non-insulin-dependent diabetic (NIDDM) mother and 18 had an NIDDM father. At the time of the study the offspring of NIDDM mothers had a somewhat higher body mass index (BMI) (males: 26.5 +/- 1.0 (mean +/- SEM), females: 27.5 +/- 1.5 kg/m2) than the offspring of NIDDM fathers (males: 23.4 +/- 0.9, females: 24.2 +/- 1.2 kg/m2). There was no difference in the time-course of glycaemia; however the serum concentrations of immunoreactive insulin (IRI), C-peptide and proinsulin were significantly higher in offspring of NIDDM mothers than in offspring of NIDDM fathers: area under the curve (AUC) serum IRI: 0.928 +/- 0.091 vs 0.757 +/- 0.056 nmol.l-1.h-1, p = 0.019; serum C-peptide: 6.379 +/- 0.450 vs 4.753 +/- 0.242 nmol.l-1.h-1, p = 0.004; serum proinsulin: 172 +/- 40 vs 51 +/- 7 pmol.l-1.h-1, p = 0.008). Serum IRI correlated with BMI, but C-peptide and proinsulin did not, and after accounting for BMI by covariance analysis they remained significantly higher in offspring of NIDDM mothers. In this group serum proinsulin was significantly higher in male than in female offspring (AUC serum proinsulin: 289 +/- 68 vs 77 +/- 27 pmol.l-1.h-1, P = 0.015). Male offspring of NIDDM mothers also had significantly higher serum triglyceride levels than females of the same group and than offspring of NIDDM fathers. The offspring (male and female) of NIDDM mothers had slightly lower serum apolipoprotein A-I levels than the offspring of NIDDM fathers. Significant correlations were found between serum triglycerides, HDL-cholesterol and apolipoprotein B, and serum concentrations of pancreatic beta-cell peptides, mostly in the offspring of NIDDM mothers; however, they did not display unequivocal association with gender within this group. The data are consistent with clinical observations of a greater risk of NIDDM transmission from the mother than from the father, and may suggest that male offspring are more exposed to this risk than female offspring.

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.

Alcohol tolerance in patients with non-insulin-dependent (type 2) diabetes treated with sulphonylurea derivatives.

The oral ethanol loading test (0.5 g/kg body mass given as 40% solution) was carried out in 5 groups, each of 10 out-patients with non-insulin-dependent (type 2) diabetes before and after 10 days of treatment with one of the following sulphonylurea derivatives: tolbutamide (CAS 64-77-7) 0.5 t.i.d., chlorpropamide (CAS 94-20-2) 0.5 once daily morning, glibornuride (CAS 26944-48-9) 0.025 t.i.d., glibenclamide (CAS 10238-21-8) 0.005 t.i.d. and glipizide (CAS 29094-61-9) 0.005 t.i.d. The response to alcohol (facial flush, heart rate, blood pressure) were compared, and blood concentrations of ethanol, acetaldehyde, pyruvate, lactate, hydrocarbonates as well as blood pH, pO2 and pCO2 were determined in fasting state and during 6 hours after alcohol ingestion. In all patients the family history of diabetes and the presence and degree of vascular complications were registered. Evident flushing phenomenon was observed in 6 patients treated with chlorpropamide, in 3 treated with tolbutamide, in 2 treated with glibenclamide, in one receiving glibornuride and in none treated with glipizide. All drugs caused a greater rise of blood ethanol and acetaldehyde levels in relation to the control tests, but the difference reached statistical significance only in the group receiving chlorpropamide. Moreover, patients (pooled) with positive thermographic response had also significantly higher blood levels of ethanol and acetaldehyde during the second test. The ratio of acetaldehyde to ethanol concentration in blood (mumol:mmol) was not significantly changed in any group indicating parallel impairment of both steps of ethanol metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)