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The term intrauterine growth retardation (IUGR) is assigned to newborns born with a birth weight and/or birth length below the tenth percentile for their gestational age. Intrauterine growth retardation is usually due to maternal, fetal factors, or placental insufficiency, while endocrine factors represent just a small minority in its etiology. Main endocrine-related causes of IUGR are disorders in insulin or insulin-like growth factor-I (IGF-I) secretion or action. Newborns with IUGR are at increased risk to develop a metabolic syndrome later in life, namely obesity, arterial hypertension, hypercholesterolemia, cardiovascular disease, impaired glucose tolerance, or diabetes mellitus type 2. This association is the result of the adaptational changes of the fetal endocrine-metabolic mechanisms to the impaired intrauterine milieu to assure survival in the short term. The persistence of these changes after birth can be detrimental in adult life. Furthermore, premature adrenarche, as well as ovarian hyperandrogenism, seem to be associated with IUGR in girls, demonstrating that IUGR may have long-lasting effects on both somatic health and reproductive function. Finally, the intrauterine exposure of the fetus to stressors may affect the individual's ability to face stress in postnatal life. Therefore, if optimization of somatic and psychosocial well-being of the individual is the golden goal of medicine, special attention should be paid to maintain an optimal intrauterine milieu devoid of any stressors with adequate nutrient supply and to reserve ideal psychosocial support to the pregnant woman.
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PMID:Endocrine-related causes and consequences of intrauterine growth retardation. 1464 21

Approximately 50% to 70% of all women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and this hormone insensitivity probably contributes to the hyperandrogenism that is responsible for the signs and symptoms of PCOS. Although uncertainty exists, early detection and treatment of insulin resistance in this population could ultimately reduce the incidence or severity of diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. Even if that proves to be the case, there are still several problems with our current approach to insulin sensitivity assessment in PCOS, including the apparent lack of consensus on what defines PCOS and "normal" insulin sensitivity, ethnic and genetic variability, the presence of other factors contributing to insulin resistance such as obesity, stress, and aging, and concern about whether simplified models of insulin sensitivity have the precision to predict treatment needs, responses, and future morbidity. Although the hyperinsulinemic-euglycemic clamp technique is the gold standard for measuring insulin sensitivity, it is too expensive, time-consuming, and labor-intensive to be of practical use in an office setting. Homeostatic measurements (fasting glucose/insulin ratio or homeostatic model assessment [HOMA] value) and minimal model tests (particularly the oral glucose tolerance test [OGTT]) represent the easiest office-based assessments of insulin resistance in the PCOS patient. The OGTT is probably the best simple, office-based method to assess women with PCOS because it provides information about both insulin resistance and glucose intolerance. The diagnosis of glucose intolerance holds greater prognostic and treatment implications. All obese women with PCOS should be screened for the presence of insulin resistance by looking for other stigmata of the insulin resistance syndrome such as hypertension, dyslipidemia, central obesity, and glucose intolerance.
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PMID:Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. 1475 2

The issue of a possible relationship between type 2 diabetes and cancer is still debated. Such chronic diseases show a high incidence in the general population. In their pathophysiology both genetic and environmental factors are involved, inducing important modifications of metabolism. Diabetes is associated to profound metabolic alterations, such as hyperinsulinemia and insulin resistance, which are common in various diseases, i.e. obesity, hypertension, dyslipidemia and hyperuricemia. Those illnesses form the so-called metabolic syndrome. Insulin resistance, hyperestrinism and the associated hyperandrogenism may play a role in the onset of some malignancies, such as endometrium cancer, breast cancer and prostate cancer. Low plasma levels of IGF-1 are able to reduce the risk of cancer in type 2 diabetes patients. This goal can be obtained with preventive measures, as physical activity, diet and drugs that can reduce insulin resistance (metformin and thiazolidinediones).
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PMID:Evidence for a putative relationship between type 2 diabetes and neoplasia with particular reference to breast cancer: role of hormones, growth factors and specific receptors. 1503 27

We report a 5.5 year-old girl with a benign adrenocortical adenoma who presented with virilization and rapid growth. She did not have any clinical features of isosexual precocity or, except for hypertension, Cushing's syndrome. Measurement of hormones in adrenal vein blood obtained at surgery showed high concentrations of testosterone, cortisol, estradiol and intermediary substrates. Elevated levels of hormones detected in the peripheral blood were released directly from the tumor and were not the result of peripheral interconversion. Hyperandrogenism can obscure the clinical features of Cushing's syndrome and estrogen hypersecretion in patients with functional adrenal tumors.
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PMID:Cortisol and estradiol secretion by a benign virilizing adrenocortical tumor in a prepubertal girl. 1505 61

The insulin resistance syndrome (syndrome X, metabolic syndrome) has become the major health problem of our times. Associated obesity, dyslipidemia, atherosclerosis, hypertension, and type 2 diabetes conspire to shorten life spans, while hyperandrogenism with polycystic ovarian syndrome affect the quality of life and fertility of increasing numbers of women. Whereas a growing number of single genetic diseases affecting satiety or energy metabolism have been found to produce the clinical phenotype, strong familial occurrences, especially in racially prone groups such as those from the Indian subcontinent, or individuals of African, Hispanic, and American Indian descents, together with emerging genetic findings, are revealing the polygenetic nature of the syndrome. However, the strong lifestyle factors of excessive carbohydrate and fat consumption and lack of exercise are important keys to the phenotypic expression of the syndrome. The natural history includes small for gestational age birth weight, excessive weight gains during childhood, premature pubarche, an allergic diathesis, acanthosis nigricans, striae compounded by gynecomastia, hypertriglyceridemia, hepatic steatosis, premature atherosclerosis, hypertension, polycystic ovarian syndrome, and focal glomerulonephritis appearing increasingly through adolescence into adulthood. Type 2 diabetes, which develops because of an inherent and/or an acquired failure of an insulin compensatory response, is increasingly seen from early puberty onward, as is atheromatous disease leading to coronary heart disease and stroke. A predisposition to certain cancers and Alzheimer's disease is also now recognized. The looming tragedy from growing numbers of individuals affected by obesity/insulin resistance syndrome requires urgent public health approaches directed at their early identification and intervention during childhood. Such measures include educating the public on the topic, limiting the consumption of sucrose-containing drinks and foods with high carbohydrate and fat contents, and promoting exercise programs in our nation's homes and schools.
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PMID:Insulin resistance syndrome in children. 1518 Oct 20

Adrenal corticosteroids, i.e. glucocorticoids and mineralocorticoids, play important physiological roles in humans. Their actions are mediated by intracellular receptor molecules, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), which function as hormone-dependent transcription factors. Ligand-activated receptors modulate the transcription rates of responsive genes by interacting with responsive elements in the promoters of these genes or by influencing the activities of other transcription factors, via protein-protein interactions. Natural inactivating mutations of the GR or MR genes have been reported in humans with significant clinical phenotypes. The former causes sporadic or familial glucocorticoid resistance characterized by generalized partial insensitivity of tissues to glucocorticoids and subsequent activation of the hypothalamic/pituitary/adrenal axis with resultant hyperandrogenism in children and women and/or mineralocorticoid excess symptoms in both sexes. The latter develop pseudohypoaldosteronism type 1, i.e. hypotension and hyperkalaemic acidosis, as a result of reduced aldosterone actions in the kidney. An activating mutation in the MR gene causing early-onset, periodic hypertension was reported recently. The biological relevance of the GR and MR receptors was also addressed in mice whose GR or MR genes were inactivated or modified by gene targeting. The results were generally confirmatory of the concepts obtained by the human studies. Similarly, natural, compensated glucocorticoid and/or mineralocorticoid 'resistance' were described in several mammalian species, including non-human primates and rodents. Here we discuss the actions of GR and MR and the molecular defects of naturally occuring mutations in these receptors with associated pathophysiological changes.
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PMID:Glucocorticoid and mineralocorticoid receptors and associated diseases. 1524 44

During the neonatal period, increased stress due to infection or illness in low-birthweight infants may increase the importance of adequate adrenal cortisol secretion. Such low-birthweight infants often have transient cortisol insufficiency during the first few days of life, but then soon develop restored or even high cortisol levels. The pressure to enhance survival during this critical period could lead to either the programming of higher cortisol secretion, or the favorable selection of infants who are genetically predisposed to produce sufficient cortisol levels and activity. However, in long-term survivors of low birthweight, the maintenance of higher levels of cortisol secretion or action may contribute to increased hypertension and cardiovascular disease risk in later life. Similarly, low birthweight and subsequent rapid postnatal weight gain are associated with increased androgen secretion from the adrenal zona reticularis and this may contribute to disorders of hyperandrogenism and hyperinsulinemia before and after puberty. Precocious pubarche, the clinical manifestation of adrenal hyperandrogenism prepuberty, in girls is predictive of polycystic ovary syndrome, and is also associated with dyslipidemia, and increased central fat. In conclusion, long term consequences of low birthweight on both adrenal cortisol and adrenal androgen secretion could contribute to increased risks for the metabolic syndrome in later life.
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PMID:Adrenal function of low-birthweight children. 1572 16

Glucocorticoid resistance is a rare, familial or sporadic condition characterized by partial end-organ insensitivity to glucocorticoids. The clinical spectrum of the condition is broad, ranging from completely asymptomatic to severe hyperandrogenism and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance has been ascribed to mutations in the human glucocorticoid receptor-alpha (hGRalpha) gene, which impair one or more of the molecular mechanisms of GR action, thus altering tissue sensitivity to glucocorticoids. We identified a new case of generalized glucocorticoid resistance in a young woman who presented with a long-standing history of fatigue, anxiety, hyperandrogenism, and hypertension. The disease was caused by a novel, heterozygous mutation (T-->C) at nucleotide position 2318 (exon 9) of the hGRalpha gene, which resulted in substitution of leucine by proline at amino acid position 773 in the ligand-binding domain of the receptor. We systematically investigated the molecular mechanisms through which the natural hGRalphaL773P mutant impaired glucocorticoid signal transduction. Compared with the wild-type hGRalpha, hGRalphaL773P demonstrated a 2-fold reduction in the ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter, exerted a dominant negative effect on the wild-type receptor, had a 2.6-fold reduction in the affinity for ligand, showed delayed nuclear translocation (30 vs. 12 min), and, although it preserved its ability to bind to DNA, displayed an abnormal interaction with the GR-interacting protein 1 coactivator in vitro. We conclude that the carboxyl terminus of the ligand-binding domain of hGRalpha is extremely important in conferring transactivational activity by altering multiple functions of this composite transcription factor.
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PMID:A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: the importance of the C terminus of hGR LBD in conferring transactivational activity. 1576 88

Polycystic ovary syndrome (PCOS) affects mostly young women causing chronic anovulation, hyperandrogenism, hirsutism and obesity with android pattern. The prevalence of the metabolic syndrome (abnormal glucose metabolism, dyslipidemia, hypertension and increased waist circumference) in PCOS is not defined although both have a common etiologic factor: insulin resistance. This retrospective study from medical records examined the presence of obesity and features of the metabolic syndrome in women with PCOS. The metabolic syndrome was defined as presence of two or more of the following signs: abnormal glucose metabolism, hypertriglyceridemia, low HDL, and hypertension. Thirty nine records of patients with PCOS were reviewed. The mean age was 29.4 years and the body mass index was 36 kg/m2. Hypertriglyceridemia was present in 43%, low HDL in 71%, hypertension in 36%, impaired glucose tolerance in 10% and diabetes mellitus type 2 in 37%. The metabolic syndrome was identified in 44% of sampled women with PCOS. These findings indicate that women with PCOS are at increased risk of diabetes mellitus type 2 at a young age. PCOS patients have higher prevalence of the metabolic syndrome than the rest of the population and thus are at increased risk of cardiovascular disease even if they don't develop diabetes mellitus type 2.
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PMID:Association between the polycystic ovary syndrome and the metabolic syndrome in Puerto Rico. 1632 83

Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with many characteristic features, including hyperandrogenaemia, insulin resistance and obesity which may have significant implications for pregnancy outcomes and long-term health of the woman. This meta-analysis was conducted to evaluate the risk of pregnancy and neonatal complications in women with PCOS. Electronic databases were searched for the following MeSH headings: PCOS, hyperandrogenism, pregnancy outcome, pregnancy complications, diabetes mellitus, type II. A handsearch of human reproduction and fertility and sterility was also conducted. Studies in which pregnancy outcomes in women with PCOS were compared with controls were considered for inclusion in this meta-analysis. Fifteen of 525 identified studies were included, involving 720 women presenting with PCOS and 4505 controls. Women with PCOS demonstrated a significantly higher risk of developing gestational diabetes [odds ratio (OR) 2.94; 95% confidence interval (CI): 1.70-5.08], pregnancy-induced hypertension (OR 3.67; 95% CI: 1.98-6.81), pre-eclampsia (OR 3.47; 95% CI: 1.95-6.17) and preterm birth (OR 1.75; 95% CI: 1.16-2.62). Their babies had a significantly higher risk of admission to a neonatal intensive care unit (OR 2.31; 95% CI: 1.25-4.26) and a higher perinatal mortality (OR 3.07; 95% CI: 1.03-9.21), unrelated to multiple births. In conclusion, women with PCOS are at increased risk of pregnancy and neonatal complications. Pre-pregnancy, antenatal and intrapartum care should be aimed at reducing these risks.
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PMID:A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. 1689 Dec 96


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