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Polycystic ovary syndrome (PCOS) is a frequent disease, characterized by disturbed ovarian function with hyperandrogenism. Anovulation is secondary to an absence of follicular dominance. Apart from a primary ovarian defect, insulin resistance is observed in PCOS women, even in the absence of overweight. This insulin resistance could be secondary to a defect in the insulin transduction pathway, mainly by a defect in receptor phosphorylation. It enhances hyperandrogenism as it increases ovarian androgen production. Therefore treating insulin resistance by weight loss or drugs reducing insulin resistance might improve fertility of PCOS women. Metformin has been shown to reduce ovarian production, enhance ovulatory cycles and in some cases increase fertility. However, there are few randomized studies on large numbers of patients to prove an effect on pregnancies as well as on the occurrence of early pregnancy loss. There are currently no recommendation on dose and duration of metformin treatment. It is noteworthy that metformin has no authorization in France to be prescribed apart from diabetic patients' care. Considering the medical care of PCOS women, the cardiovascular risk needs to be taken into account. Therefore hypertension, dyslipidemia and diabetes must be treated in those women who need to be followed carefully all over their life.
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PMID:[Insulin resistance and polycystic ovary syndrome]. 1271 82

The emerging epidemic of type 2 diabetes (T2DM) in young people reflects increasing rates of obesity and parallels the increasing frequency of T2DM in adults. As in adults, T2DM in children is part of the insulin resistance syndrome that includes hyperandrogenism seen as premature adrenarche and polycystic ovary syndrome, hypertension, dyslipidemia, and other atherosclerosis risk factors. Recent studies in children document risk factors for T2DM, and associated cardiovascular risk factors, including obesity, family history, diabetic gestation, and underweight or overweight for gestational age. Genetically determined insulin resistance or limited beta-cell reserve has been demonstrated in high-risk individuals, including first-degree relatives of girls with premature adrenarche. This genetic background, considered advantageous in a feast-and-famine existence (the thrifty genotype), is rendered detrimental with abundant food and physical inactivity, a lifestyle demonstrated to be typical of families of children with T2DM. The increasing incidence of T2DM in children and adolescents threatens to become a major public health problem. Risk factors for cardiovascular disease, hypertension, hyperlipidemia, and microalbuminuria are present at diagnosis of T2DM in Native American adolescents, indicating that insulin resistance has been present for some time before the diagnosis of diabetes was made. Case finding is likely to be beneficial in high-risk youths. Treatment is the same as that of adults. The only data on use of oral hypoglycemic agents in children have been with metformin. Community and governmental efforts to educate all children and their parents about the need for physical activity and dietary modification are essential to control this epidemic.
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PMID:Type 2 diabetes in children. 1276 53

Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6-18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7-87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.
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PMID:Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism. 1278 62

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 polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. It is a complex metabolic-endocrine disorder with severe long-term health consequences like type 2 diabetes. The increased risk for cardiovascular diseases in women with PCOS is due to diabetes, adipositas and dyslipidemia. Insulin resistance plays a key role in the pathophysiology of this syndrome. This makes the use of oral antidiabetic drugs most compelling. The majority of studies have shown amelioration of the typical symptoms like hyperandrogenism and cycle irregularities. Ovulation and pregnancy rates increased. Furthermore these drugs might be cardioprotective by improving insulin sensitivity and reduce the risk for type 2 diabetes. This article reviews the use of different oral antidiabetic drugs in the treatment of PCOS and their influence on fertility, the risk for type 2 diabetes and cardiovascular diseases.
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PMID:[The use of oral antidiabetic drugs in the treatment of polycystic ovary syndrome]. 1475 61

Seckel syndrome is a rare, recessively inherited disorder of severe growth retardation with low birth weight and distinct craniofacial, orodental and skeletal anomalies. In addition to these characteristics, some cardiovascular, hematopoietic, endocrine and central nervous system abnormalities have also been described. We report a patient with Seckel-like syndrome who has precocious puberty associated with non-classical congenital adrenal hyperplasia (NCCAH). She was admitted to our clinic three times. She was diagnosed as having Seckel-like syndrome and premature thelarche at the age of 8.9 years. At 10.9 years old she was admitted to our clinic with pubic hair and cliteromegaly. Hormonal findings revealed NCCAH and hydrocortisone therapy was offered but the patient was non-compliant. At 13.6 years she had acanthosis nigricans as an additional clinical finding and her pubertal stage was 4. She had irregular menses. On hormonal evaluation she had euglycemic hyperinsulinism accompanying mild hypertriglyceridemia and functional ovarian hyperandrogenism. Premature pubarche, hyper-insulinism, dyslipidemia, and hyperandrogenism, and some combinations of these, can be associated with reduced fetal growth. This is the first report of hyperinsulinism, and probably NCCAH, in association with Seckel syndrome.
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PMID:Seckel-like syndrome: a patient with precocious puberty associated with nonclassical congenital adrenal hyperplasia. 1496 29

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

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

Among girls with precocious pubarche (PP), those with low birth weight (LBW) are, even if nonobese, at risk for progression to polycystic ovary syndrome (PCOS) including hyperinsulinemic hyperandrogenism, dyslipidemia, dysadipocytokinemia, and central fat excess. Recently, we disclosed the efficacy of insulin sensitization with metformin to disrupt progression from PP to PCOS in formerly LBW girls who were postmenarche. In LBW-PP girls, we have now extended the exploration of early insulin sensitization therapy in two directions: 1) metformin therapy was started before puberty; and 2) we assessed the effects of metformin discontinuation in girls who had started metformin treatment after menarche. Prepubertal LBW-PP girls (n = 33; mean age, 8.0 yr; body mass index, 18.5 kg/m(2)) were randomly assigned to remain untreated or to receive metformin (425 mg/d) for 6 months. Postpubertal LBW-PP girls (n = 24; age, 12.4 yr; body mass index, 21.0 kg/m(2)) had been randomized (at -12 months) to remain untreated or to receive metformin (850 mg/d) for 12 months, at which time (0 month) a treatment cross-over was performed for 6 months. Fasting blood glucose and serum insulin, SHBG, dehydroepiandrosterone sulfate, androstenedione, testosterone, lipid profile, IL-6, and adiponectin were assessed at 0 and 6 months, as was body composition (by dual x-ray absorptiometry). In the prepubertal study (group A), comparisons of untreated vs. treated girls disclosed normalizing effects of metformin on SHBG, androstenedione, dehydroepiandrosterone sulfate, low and high density lipoprotein cholesterol, triglycerides, IL-6, adiponectin, total and abdominal fat mass, and lean body mass. In the postpubertal study (group B), treatment cross-over at 0 month was in each subgroup followed by a striking reversal in the course of the endocrine-metabolic state, adipocytokinemia, and body composition; all changes pointed to normalizing effects of metformin treatment. In conclusion, these two studies provide the first evidence that 1) prepubertal metformin therapy has normalizing effects on PCOS features in high risk girls with a combined history of LBW and PP; and 2) in adolescence, metformin's normalizing effects are reversed as soon as metformin therapy is discontinued.
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PMID:Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment. 1535 29

Emerging evidence indicates that prenatal growth relates to common disease in adulthood. Here, we review and embed a selection of advances within this field of research. Focus is on endocrine-metabolic and reproductive facets in girls and young women, who experienced a degree of prenatal growth restraint. Such early restraint has now been linked to variable constellations including the following: hyperinsulinemia; dyslipidemia; central adiposity; exaggerated adrenarche and precocious pubarche; early and rapidly progressive puberty; ovarian hyperandrogenism; elevated serum FSH and/or LH; small uterine and/or ovarian size; and oligo- or an-ovulation. Hyperinsulinemic insulin resistance is thought to be a prime pathogenetic factor. Accordingly, insulin sensitization is among the first therapeutic strategies explored, so far, with promising results.
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PMID:Novel insights into the endocrine-metabolic and reproductive consequences of prenatal growth restraint in girls. Girls-born-small become women-born-small. 1564 66


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