Fast PCOS Cure

The Natural Pcos Diet

The Natural Pcos Diet, By Jenny Blondel, A Leading Australian Naturopath In Response To Thousands Of Requests For Professional Information To Help Women Suffering From Pcos. Real Solutions To Naturally Overcome PCOS. Naturally balance your hormones Increase your chances of conceiving Help you lose weight and feel good Curb your cravings for sugary foods Turn your fatigue around Achieve clearer, glowing skin See improvements in your mood. Do You Feel PCOS Is. Ruling Your Life? At Last! The Natural PCOS Diet. A Naturopath’s Easy Step-by-Step Guide to Overcoming PCOS Is. Now Available! Read more here...

The Natural Pcos Diet Summary

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Identifying Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS) is responsible for abnormal menstrual function in 5 to 8 percent or more of women during their reproductive years. It tends to run in families. Women with this condition have trouble conceiving a child, and they have increased hair on their faces, arms, legs, and areas of the body that are not usually hairy in women. In addition, they experience acne and obesity. The surprise finding in PCOS is that these women are also resistant to insulin and have increased blood levels of insulin even when they are not obese. The greater the degree of obesity, however, the more frequent that the metabolic syndrome is present (see Chapter 5). In fact, women with PCOS who do get pregnant have a prevalence of gestational diabetes that is 2 to 3 times that of those women without PCOS. Another feature that women with PCOS have in common with metabolic syndrome is obstructive sleep apnea. This sleep apnea results in daytime sleepiness and high blood pressure. The name...

Clinical features of obese PCOS women Insulin resistanceimpaired icell function

PCOS is characterized by several metabolic abnormalities, which are strongly influenced by presence of obesity. Insulin resistance is a common co-morbidity in women with PCOS and is associated with increased risk for hypertension and cardiovascular disease (Figure 13.1). Studies have shown that 25-35 per cent of obese women with PCOS, by 30 years of age, will have either impaired glucose tolerance or type 2 diabetes (Ehrmann, 1997). The studies examining insulin resistance in obese and non-obese women with PCOS have shown that obese PCOS women had significantly lower insulin sensitivity than non-obese women with PCOS. On the other hand, non-obese women with PCOS may demonstrate insulin resistance in the presence of completely normal glucose tolerance. Nevertheless, both fasting and glucose-stimulated insulin concentrations are in fact significantly higher in obese than non-obese PCOS women (Morin-Papunen et al., 2000). Acanthosis nigricans (AN) is a common sign of severe insulin...

The Genetics of Polycystic Ovarian Syndrome

PCOS, like diabetes, is a multigenic disorder with clear evidence for familial aggregation (317). There is a 5-10 prevalence of this disorder in women of reproductive age (318). As insulin resistance and hyperinsulinemia are a cause of PCOS, it has been expected that there is some overlap between the genes implicated in PCOS and those for diabetes. However, to date, no DM2-associated genetic variation has been validated for PCOS association. This may not be surprising, as most of the known DM2 loci appear to affect insulin secretion rather than response. A study suggested that the PPARG Pro12Ala variant may be a modifier of insulin resistance in Caucasian women with PCOS (319), but controversy remains (165).

Polycystic Ovary Syndrome and Cardiovascular Risk

PCOS is associated with an increase in cardiovascular risk factors (189). In addition to obesity that is commonly present and independently associated with increased cardiovascular risk, women with PCOS have dyslipedemia, hypertension and elevated PAI-1 levels. Obesity is a prominent feature in women with PCOS as about half of the patients are obese. Also, obesity appears to confer an additive and synergistic effect on the mani Women with PCOS have higher serum triglycerides, total and LDL cholesterol and lower HDL cholesterol levels than weight-matched regularly menstruating women (190). These findings however, vary and depend on the weight, diet and ethnic background. In a large study of non-Hispanic white women, elevated LDL-C was the predominant lipid abnormality in women with PCOS (191). An additional parameter contributing to the elevated cardiovascular risk is hypertension. Obese women with PCOS have an increased incidence of hypertension and sustained hypertension is threefold...

Polycystic Ovary Syndrome Diabetes and Cardivascular Disease

PCOS is the most common endocrinopathy that affects women of reproductive age (177). Data on the exact prevalence are variable mostly because of the lack of well-accepted diagnostic criteria. At present, the diagnosis of PCOS is based on the presence of ovulatory dysfunction and clinical or biochemical evidence of hyperandrogenism. The diagnosis requires a complete evaluation for exclusion of other causes of hyperandrogenism such as nonclassic adrenal 21-hydroxylase deficiency and androgen secreting neoplasms. The presence of polycystic ovaries on ultrasound is not a criterion for diagnosis as this is commonly found in randomly selected women (178). Although PCOS is known to be associated with reproductive morbidity and increased risk for endometrial cancer, diagnosis is especially important because PCOS is now thought to increase metabolic and cardiovascular risks (179). These risks are strongly linked to insulin resistance which is present in both obese and lean women with PCOS.

Cardiovascular Risk in PCOS Women

PCOS is considered a pathological condition at high risk for CVDs. This is not only due to the presence of androgen excess, insulin resistance, obesity, DM2, and dyslipidemia, but also because of many other risk factors (120) (Table 2). These cardiovascular risk factors are often evident at an early age, suggesting that women with PCOS represent a large population at increased risk for developing Prevalence of Impaired Glucose Tolerance (IGT) and Type 2 Diabetes Mellitus (DM2) in Women with PCOS Living in Different Geographical Areas in the World Prevalence of Impaired Glucose Tolerance (IGT) and Type 2 Diabetes Mellitus (DM2) in Women with PCOS Living in Different Geographical Areas in the World Classic and Newer Risk Factors for Cardiovascular Diseases in PCOS early-onset CVD, even if this has not yet been confirmed in prospective studies (121). The risk of CHD and myocardial infarction has been reported to be increased in patients with PCOS compared with regularly cycling women...

Evidence For The Developmental Origins Of Pcos

Two sources of evidence in human beings and animals suggest that PCOS may originate in intrauterine life. The first is evidence from clinical observations and experimental animal research suggesting that fetal exposure to androgen excess may program in utero, the development of PCOS traits that are expressed in adulthood (24). Further evidence comes from longitudinal observations of girls with LBW that follow a path through postnatal catch-up weight gain, amplified adrenarche, and ovarian hyperandrogenism in adolescence (3). This pathway is strongly related to central adiposity and insulin resistance, and has been thought of as the hyperinsulinemic pathway to PCOS as opposed to the hyperandrogenic pathway suggested above. It is likely, however, that both pathways have a common origin in intrauterine life as discussed below.

Insulin Resistance in PCOS

Insulin resistance in women with PCOS appears even more common than in the general population (79, 83). It should, however, be emphasized that the majority of the studies have simply demonstrated that, in comparison to adequate control groups, insulin resistance, as measured by various techniques or methods, was more common in subjects with PCOS. There are no epidemiological studies focusing on the prevalence of insulin resistance in PCOS. In one study examining the characteristics of more than 1,000 consecutive women with androgen excess, Azziz et al. (84) found that 716 of them had PCOS and were characterized, as a group, by hyperinsulinemia and insulin resistance. Interestingly, 60 of them were obese, which indicates that obesity per se may be an amplifier of a cause of this metabolic derangement. Many other studies have in fact reported that insulin resistance is very common in the presence of obesity, particularly the abdominal phenotype (79-81). The common thought is that...

Glucose Intolerance and DM in PCOS

Worsening insulin resistance in the long term is an important factor in the development of glucose intolerance states in PCOS (109, 110). Clinical studies have in fact shown that glucose intolerance is present, at the first clinical examination, in as many as 30-40 of obese PCOS women in the United States (79), in Australia (111) and, probably, to a lesser extent in those living in Europe (88), while it is uncommon in their normal-weight counterparts (87, 88). In any case, the prevalence rate for impaired glucose tolerance in the population of obese PCOS subjects appears to be higher than that reported in population-based studies on the incidence of glucose intolerance in women of similar ages (112), although cross-sectional or longitudinal epidemiological studies are lacking. Obesity represents the major determinant of glucose tolerance in PCOS (79, 81). Although insulin resistance seems to play a determining role in the development of DM2, the presence of insulin resistance does not...

Pcos And The Metabolic Syndrome

Insulin resistance and hyperinsulinemia have been extensively studied in PCOS. While obese patients have a more pronounced phenotype, even lean PCOS patients have a reduced insulinmediated glucose disposal and elevated basal hepatic glucose production (38). The hyperinsulinemia first described by Burghen et al. (12) was subsequently confirmed, including studies showing higher fasting insulin levels resulting from a higher basal insulin secretion rate (39), higher insulin responses during an oral glucose tolerance test (OGTT) independently of body weight (40), defects in insulin secretion (41) and combined beta-cell dysfunction (42). In about half of the affected patients, insulin resistance can be correlated with an augmented serine rather than tyrosine phosphorylation of insulin receptor-substrate 1 (IRS-1), causing impaired insulin signaling (43). The resulting hyperinsulinemia in turn induces more serine phosphorylation, propagating a vicious circle that continues until...

Infertility Treatment In Pcos

Inducing ovulation in patients with PCOS can be accomplished through several approaches reducing insulin concentrations, follicle stimulating hormone (FSH) stimulation or reducing LH concentrations (6). Reducing insulin concentrations can be accomplished by either weight loss or insulin-sensitizing agents, like metformin. Clomiphene citrate or gonadotrophin therapies have traditionally

Effect of Insulin Resistance Treatment on Polycystic Ovary Syndrome Weight Loss

Weight reduction is of paramount importance and cornerstone of every therapeutic strategy in PCOS. Although obesity does not seem to be the primary insult in PCOS, many studies have demonstrated the beneficial impact of weight reduction on the manifestations of the syndrome and especially insulin sensitivity, risk for diabetes and adverse cardiovascular risk profile (199). The effect of weight reduction by a hypocaloric low-fat diet on the metabolic and endocrine variables was studied in obese women with PCOS In another study, the effect of dietary intervention on insulin sensitivity and lipids, fibrinolysis and coagulation was examined also in obese women with PCOS (201). Insulin sensitivity was assessed by the eyglycemic clamp technique before and after a very low-calorie, protein-rich diet for 4 weeks that was followed by a low-calorie, low-fat diet for 20 weeks. After the 24-week intervention, insulin sensitivity was significantly increased along with a significant reduction of...

Endothelial function in PCOS

Obesity and insulin resistance are associated with blunted endothelium-dependent but not endothelium-independent vasodilation (Arcaro et al., 1999), with failure of hyperinsulinaemia to augment endothelium-dependent vasodilation (Steinbergs et al., 1996). This indicates that obesity is associated with endothelial dysfunction and endothelial resistance to the enhancing effect of insulin on endothelium-dependent vasodilation. Endothelial dysfunction might therefore contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects, such as those with PCOS (Dunaif, 1997 Wild et al., 2000). Insulin resistance has been proposed as a central metabolic basis for the clustering of risk factors in the multiple cardiovascular risk syndrome (syndrome X). However, Pinkney et al. (1997) have argued that the central problem Central large-vessel endothelial dysfunction plays a major role in atherogen-esis. The presence of systemic endothelial dysfunction (large and small vessel)...

Population lessons from the pcos paradigm

The androgen balance is profoundly affected in the presence of metabolic disorders, particularly obesity and the metabolic syndrome (2). Androgens have an important impact on both glucose and lipid metabolism, and on fat homeostasis, therefore it is not unlikely that androgen imbalance may play a role in the pathophysiology of the metabolic syndrome. Although the few large prospective studies have not confirmed a significant association, cross-sectional studies have nonetheless provided some evidence for a linkage between low testosterone levels and CHD events, particularly in men (2). One reason for the failure to obtain conclusive information from clinical and epidemiological studies may be partly dependent on the sex-related different behavior of sex hormones in the presence of obesity. On the other hand, this hypothesis has attracted scientific concern since low testosterone in men and a condition of relative hyperandrogenism in women are associated with abdominal obesity,...

Prenatal Growth Restraint and PCOS

A putative developmental program linking LBW and precocious pubarche (PP) with functional ovarian hyperandrogenism in adolescence has been suggested by Ibanez et al., following a series of studies in a Spanish population of girls (45). Girls with PP associated with elevated dihydroepiandros-terone sulfate (DHEAS) or androstenedione levels were more likely to be small for gestational age (SGA). Thus, birth weight SD scores (mean SEM) of PP girls (-0.81 0.13 n 102) were lower (p < 0.0001) than those in control girls (0.38 0.08 n 83) (46). One French study also reported that birth weight in unselected girls with PP was lower than expected (47). However, no association between SGA and PP was found in another smaller Parisian cohort (48). In addition, postmenarcheal Spanish girls without PP who were born SGA had DHEAS levels higher than those with normal birth weight (49). In a smaller study, Italian girls who were SGA examined at 6.0-7.5 years of age were found to have 30 higher DHEAS...

Metformin Clomiphene Citrate or Both for Ovulation Induction in PCOS

Given the demonstrated efficacy of metformin as monotherapy in increasing ovulation, the question arises whether it might constitute first-line therapy in the treatment of the anovulatory infertility of PCOS. The literature on this issue is conflicting and controversial. Palombo et al. performed a prospective, randomized, double-blind trial of metformin compared with clomiphene 150 mg in 100 nonobese PCOS patients (40). While there was no difference in ovulation rates, the pregnancy rate was significantly higher in the metformin group (15.5 ) than in the clomiphene group (7.2 ) (p 0.009) (40). The cumulative pregnancy rate was 68.9 for the metformin group as compared with 34 for the clomiphene group (p < 0.001). Moll et al. performed a randomized, double-blind trial that examined the effects of metformin compared with placebo given with clomiphene in 228 women with PCOS and found no significant differences in ovulation or pregnancy rates between the two groups (64). In the largest...

Obesity and the Abdominal Phenotype in PCOS

This could be due to a depot-specific inhibition of the expression of hormone-sensitive lipase (HSL) by testosterone and or to a decrease in the amount of b2 adrenergic receptors. This could also be an important pathophysiological factor behind the insulin-resistant phenotype of the upper-body obesity in men and of the hyperandrogenic PCOS (104). In humans, it is demonstrated that testosterone increases visceral fat in women. Female-to-male transsexuals treated with testosterone do in fact have an increase in visceral fat only when oophorec-tomized and thus eliminating the protective effects of estrogens (105). In addition, administration of androgens in postmenopausal women has been documented to increase visceral fat while reducing subcutaneous fat (106). This indicates that an increase in the testosterone to estrogen ratio in women causes accumulation of visceral adipose tissue, consistent with the important role of testosterone in determining the...

The Metabolic Syndrome in PCOS

Due to the high prevalence of insulin resistance in PCOS, some recent studies used the NCEP ATP III criteria to assess the prevalence of the metabolic syndrome in PCOS women. Glueck et al. (95) studied 138 PCOS patients and found a prevalence rate of 46 , whereas, more recently, Apridonidze et al. (82) found a prevalence of 43 by retrospectively reviewing the medical charts of 106 PCOS women attending the Endocrine Clinic of Richmond, Virginia. Both these studies, therefore, described a prevalence of the metabolic syndrome in PCOS women nearly twofold higher than that reported in the general population investigated in the cited NHANES III report (96), matched for age and body weight. Apridonidze et al. (82) also described higher free testosterone and lower SHBG levels in those women with the metabolic syndrome compared with those without it, as well as a higher prevalence of acanthosis nigricans and a tendency toward a greater family history for PCOS. These results were in accordance...

Prenatal Androgenization and PCOS

The developmental origins hypothesis of PCOS emerged following astute clinical observations in women with congenital virilizing disorders and was further substantiated by experimental animal research. Examples of prenatally androgenized humans are women with classical congenital adrenal hyperplasia from 21-hydroxylase deficiency and rare cases of women with congenital adrenal virilizing tumors(25, 26). These women are exposed to excess adrenal androgens during intrauterine life and, despite the normalization of androgen excess with treatment, manifest a PCOS-like syndrome in adult life, including functional ovarian hyperandrogenism, LH hypersecretion, anovulatory cycles, and polycystic ovarian morphology as well as central adiposity and insulin resistance (25, 26). Similar PCOS traits have also been reported recently for girls with congenital P450 oxidoreductase deficiency who are exposed to excess adrenal androgens in prenatal life but not after birth (27). Additional experiments of...

The Clinical And Molecular Phenotype Of Pcos

PCOS is a common endocrine-metabolic disorder affecting 6-8 of women during their reproductive age. The endocrine abnormalities include hyperandrogenism of ovarian and or adrenal origin, with variable clinical expression, and arrested follicular development leading to oligo- or anovulation and manifesting with oligo- or amenorrhea. Often women with PCOS have augmented luteinizing hormone (LH) secretion that contributes to hyperandrogenemia (11, 12). The metabolic trait of PCOS is characterized by central adiposity with associated insulin resistance and hyperinsulinemia, which further exacerbates the hyperandrogenism and ovulatory dysfunction. These, together with other features of the metabolic syndrome, impose an increased risk for type 2 diabetes and cardiovascular disease (13, 14). A common feature of PCOS resulting from aberrant folliculogenesis is the accumulation of small follicles in the periphery of a thickened ovarian stroma, yielding the characteristic polycystic ovarian...

Gestational Hyperandrogenism of Maternal Origin

The possible role of PCOS itself as a cause for gestational hyperandrogenism was evaluated in a recent study by Sir-Petermann et al. (60). Pregnant PCOS women were found to have higher concentrations of androgens than normal pregnant women, thus potentially exposing their unborn daughters to elevated androgen levels in utero. The origin of the androgen excess during pregnancy in women with PCOS women is uncertain but it could be due to increase in androgen production by the maternal theca interstitial cells stimulated by hCG. In this respect, the same investigators also reported that after delivery, androstenedione levels and ovarian volume of patients with PCOS were increased, suggesting that their ovaries were persistently stimulated during pregnancy (61). In addition, while the human placenta lacks 17b-hydroxylase and 17, 20-lyase, it does express 17 -hydroxysteroid dehydrogenase (17 b-HSD) and aromatase as well as 3b-hydroxysteroid dexydrogenase (3b-HSD) (62). It can therefore...

Genetic basis of obesity in PCOS

Several studies have shown that PCOS is a familial disorder and various features of the syndrome may be differentially inherited (Franks et al., 1997). However, the genetic basis of the syndrome remains controversial. Since then, many studies have revealed that most women with PCOS, both obese and lean, have a degree of insulin resistance and compensatory hyperinsulinaemia, and genes involved in the secretion and action of insulin have been investigated. Molecular studies of the insulin receptor gene in women with PCOS have shown a large number of polymorphisms, which are common in normal subjects and do not lead to any disturbance of receptor function (Talbot et al., 1996). The observation that although insulin resistance is largely reversible by weight reduction in obese women with PCOS, an abnormality of first-phase insulin secretion from i-cells of pancreas still exists, led to investigation of the insulin gene in the pathogenesis of PCOS. Waterworth et al. reported an association...

Thiazolidinediones in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is characterized by menstrual irregularities, infertility, hyperandro-genism, obesity, and insulin resistance. In a study of rosiglitazone (4 mg twice daily for 2 months) with or without clomiphene in 25 women with PCOS who had not responded to clomiphene alone, ovulatory rates were higher in the combined versus monotherapy groups (77 and 33 , respectively) 53 . Pioglitazone has also been shown to improve ovulation rates and hyperadrogenism associated with PCOS. In a randomized controlled trial 54 , 40 women were assigned to receive 30 mg piogli-tazone versus placebo for 3 months. The results revealed that the pioglitazone group had a significant decrease in their free androgen index as well as higher ovulation rates (41 had normal ovulation in the pioglitazone group as compared with 5.6 in the placebo group). These results point to an exciting new treatment option for PCOS however, because of the effects of these agents on gene expression, there may...

The paradigm of pcos

PCOS is one of the most common causes of ovulatory infertility, affecting 4-7 of women. After the original description by Stein and Leventhal (76), this syndrome has been defined in different ways over the last 15 years. In 1990 the National Institutes of Health (NIH) established very simple new diagnostic criteria, which were based on the presence of hyperandrogenism (either clinical, such as hirsutism, etc., or biochemical) and chronic oligo-anovulation, with the exclusion of other causes of blood androgen excess, such as adult-onset congenital adrenal hyperplasia, Cushing's syndrome, androgen-secreting neoplasms, and others (77). More recently, a consensus conference held in Rotterdam, in 2003 (78), re-examined the 1990 criteria and admitted the appropriateness of including ultrasound morphology of the ovaries among the diagnostic criteria of the syndrome. It was also established that at least two of the proposed diagnostic criteria, i.e., oligo-anovulation, clinical and or...

Elevated acutephase markers in subjects at risk of type diabetes

There are now robust data showing elevated inflammatory markers in obese men and women and in obese children. In addition, several other groups at risk of diabetes -including women with polycystic ovarian syndrome (PCOS), men and women of South Asian origin, Pima Indians, women with a family history of type 2 diabetes, and sedentary individuals - exhibit elevated inflammatory levels and do so independently of total body mass index (Ziegler, 2005 Sattar, 2006a). Markers of inflammation correlate with insulin resistance and predict type 2 diabetes, independently of other risk factors in several different populations (ARIC, WOSCOPS) (Schmidt etal., 1999 Freeman etal., 2002). Hence, it is clear that inflammatory perturbations predate diabetes by several years, and as such are potentially relevant to accelerated atherogenesis. The source for higher cytokine and acute-phase protein levels in pre-diabetes and diabetes remains unclear but will include adipocytes, endothelial cells and immune...

Increased cardiovascular risk

Figure 13.1 Mechanisms of increased cardiovascular risk associated with obesity and PCOS. with the synergistic negative effect of obesity and PCOS on glucose tolerance (Dunaif, 1997). It has been reported that postmenopausal women with history of PCOS has a 15 per cent prevalence of type 2 diabetes which is much higher than in the general population (Dalhgren et al., 1992). In the presence of peripheral insulin resistance, pancreatic -cell insulin secretion increases but impaired glucose tolerance and type 2 diabetes mellitus develops when the compensatory increase in insulin secretion is no longer able to maintain euglycaemia. Ehrmann et al. (1999) recently documented that insulin secretory dysfunction in women with PCOS contributed significantly to the observed glucose intolerance with up to 40 per cent of women demonstrating either IGT or type 2 diabetes mellitus. Recently Norman et al. (2001) performed a follow-up study of women with PCOS seeking to establish the frequency of...

Neuroendocrine factors

Perturbations of gonadotropin secretion are one of the hallmarks of PCOS. The most commonly described abnormality is an elevated serum LH or an elevated LH FSH ratio, an increased LH pulse frequency and increased LH pulse amplitude, an exaggerated response of LH to GnRH, and altered diurnal LH pulse frequency (Morales et al., 1996 Taylor et al., 1997). However, serum LH levels may be normal in up to 40 per cent of women with PCOS (Conway et al., 1990). On the other hand, Lobo et al. reported that bioactive immunoreactive LH ratio is elevated in PCOS, which means that increased LH bioactivity may be responsible for enhanced androgen production in the ovary of women with the syndrome (Lobo et al., 2002). It is a matter of debate whether the increase of gonadotropins, when present, is a primary abnormality of hypotha-lamic-pituitary axis or the cause is dysregulation of the feedback signalling. Recent studies have revealed decreased sensitivity of the GnRH pulse generator to inhibition...

Insulininsulin resistance

The observation of insulin resistance and hyperinsulinaemia in a subset of women with PCOS has added a new dimension to the understanding of the pathogenesis of PCOS, as well as recognition that the syndrome has Table 13.1 Main Pathogenic Mechanisms in PCOS Table 13.1 Main Pathogenic Mechanisms in PCOS substantial metabolic as well as reproductive implications. Burghen et al. (1980) first reported the presence of hyperinsulinaemia in a group of obese PCOS subjects and showed significant correlation with raised serum testosterone, androstendione and insulin. Since then, there have been many reports confirming the presence of insulin resistance and consequent hyperinsulinaemia in obese and non-obese subjects with PCOS. Studies have demonstrated insulin resistance in PCOS unrelated to body weight and composition, though obese PCOS women have consistently been shown to have a greater degree of insulin resistance compared to weight-matched controls. Interestingly, euglycaemic glucose clamp...

In Vitro Fertilization

IVF represents a last resort for PCOS patients with infertility. A meta-analysis examining IVF outcomes in patients with PCOS compared with normal controls found an increased cycle cancellation rate and lower fertilization rates among patients with PCOS (111). However, they were also found to have more oocytes per retrieval and comparable pregnancy and live birth rates when compared with the control group. In vitro maturation of oocytes in which immature oocytes are retrieved without stimulation is being investigated for its utility in PCOS patients who have failed other treatments or couples who have additional causes of infertility. Studies so far have shown similar pregnancy, live birth and miscarriage rates to IVF, and the technique reduces the risk of OHSS compared with traditional IVF cycles (112-114).

Pathogenesis Of Infertility

Serum luteinizing hormone (LH) levels are elevated in many patients with PCOS, especially in those who are lean (7). Abnormal regulation of LH was previously implicated as the cause of chronic anovulation in patients with PCOS. Studies have shown that increased LH levels during the follicular phase in patients with PCOS have deleterious effects on conception rates (8) and may contribute to higher miscarriage rates (9) although the mechanism remains controversial. However, up to 50 of women with clinical and biochemical manifestations of PCOS have normal LH levels, rendering its measurement of limited diagnostic value (3). Hyperinsulinemia is present in about 80 of obese women with PCOS and 30-40 of normal weight women with PCOS (10). Disturbances of insulin secretion or action are more prominent in women with PCOS complicated by amenorrhea or anovulation than in equally hyperandrogenemic women with regular cycles (11, 12). Hyperinsulinemic insulin resistance plays a key role in the...

Recent Developments

2 States of insulin resistance, including PCOS, are associated with a number of risk factors for cardiovascular disease. This forms the basis for the current approach to treatment, but can provoke anxiety in generally healthy young women. It is not clear whether PCOS per se is actually associated with a marked increase in cardiovascular complications, and the risk profiles of PCOS patients may not differ substantially from age- and body weight-matched controls.4 3 Other drugs that improve insulin sensitivity may have a role in management of PCOS, although experience of using these drugs around the time of pregnancy is very limited at present. Both pioglitazone5 and rosiglitazone6 have recently been shown to have beneficial effects in insulin-resistant women with PCOS.

Impaired Glucose Tolerance And Type Diabetes

Obesity is a well-recognized risk-factor for development of type 2 diabetes, but alone is insufficient to cause glucose intolerance. Thus, while it is generally accepted that women with PCOS are predisposed to type 2 diabetes (13,14), the development of diabetes cannot be attributed solely to the obesity that typically accompanies PCOS. Initial studies placed the prevalence of diabetes in PCOS at approximately 20 (8). More recent data have established that the prevalence of impaired glu- -o cose tolerance and type 2 diabetes mellitus among women with PCOS is even higher, with consistency across populations of varied ethnic and racial backgrounds (14,15). In two recent, large prospective studies, the prevalence of IGT g was between 30 to 40 and that of type 2 diabetes between 5 to 10 (14,15). < j These prevalences approximate those in Pima Indians who have one of the highest Ji rates of diabetes in the world (16). Evidence for an enhanced rate of development J of diabetes is also...

Definition of the syndrome

Polycystic ovary syndrome (PCOS) is a commonly diagnosed female endo-crinopathy and it is the commonest cause of anovulatory infertility affecting 1-5 per cent of women in the reproductive age group. It is considered to be a syndrome not a disease that manifests with heterogeneous clinical features. The most common features of PCOS are irregular menstrual cycles (oligomenorrhea or amenorrhoea), signs of androgen excess (hirsutism, acne, alopecia), and often obesity. However, only 5-10 per cent of women with PCOS express all the typical clinical features of the syndrome (Balen, 1999 Franks, 1999). At present the diagnosis of PCOS is usually based on the criteria derived from 1990 NIH-NICHHD (National Institutes of Health-National Institutes of Child Health and Human Development) conference, which are ovulatory dysfunction, clinical evidence of hyperandrogenism and or hyperandrogenaemia and exclusion of related disorders such as congenital adrenal hyperplasia, hyperprolactinaemia, or...

Conclusions And Future Implications

Both experimental animal research and clinical observations have strongly indicated that fetal exposure to androgen excess may program the reproductive and metabolic manifestations of PCOS in adult women. Environmental and or genetic factors influencing the functional capacity of the fetopla-cental barrier, that normally protects the female fetus from androgen excess, are likely to contribute to prenatal androgenization in humans. It is hypothesized that androgens acting on the differentiating tissues of the female fetus may program the ontogenic development and phenotypic expression of sexually dimorphic traits toward a more masculine phenotype in adult life. The molecular mechanisms underlying the developmental programming of PCOS by androgen excess are not known but may be related to epigenetic changes in gene expression induced by androgens during fetal development. In addition, such epigenetic modifications may also promote the transgenerational transmission of the PCOS...

Impaired Glucose Tolerance and Diabetes Mellitus

IGT and overt T2DM occur when the pancreatic P-cell is unable to compensate insulin resistance with hyperinsulinemia. In the U.S., PCOS is associated with a prevalence of IGT in excess of 30 and of T2DM in excess of 8 , while 27 of female T2DM patients have PCOS (Fig. 2) (69-71). In Italy and Germany, IGT is found in < 15 and T2DM in < 4 of PCOS patients, most likely due to the lower mean BMI of European women (3,54,72,73). The Nurses' Health Study showed an increased risk of T2DMin women with oligomenorrhea, of whom about 80 were likely to have had PCOS (74). In a British study, 82 of T2DM women had PCO on ultrasound (75). A Swedish study found a high prevalence of PCO in women with previous gestational diabetes (76). A Spanish study reported a high prevalence of ovarian hyperandrogenism and PCOS among women with Type 1 DM (77), and suggested that it is not insulin resistance that is primarily responsible for the ovarian hyperandrogenism, but rather hyperinsulinemia (78). While...

Relationship to Insulin Resistance and Diabetes

Although the exact mechanisms that lead to the development of PCOS are not clear it has been shown that insulin resistance and compensatory hyperinsulinemia possess the central role in the pathophysiology of the syndrome. Women with PCOS have both basal and glucose-stimulated hyperinsulinemia compared with weight-matched women and the high levels of insulin are thought to mediate the development of hyperandrogenemia, anovulation, and infertility. At the same time, insulin resistance and compensatory hyperinsulinemia are responsible for the cardiovascular risk factors. The hyperinsulin-ism correlates with the hyperandrogenism and occurs independent of obesity (180,181). The insulin resistance in at least 50 of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor (182). This abnormality is caused by a factor extrinsic to the insulin receptor, which is presumably a serine threonine kinase. Serine phosphorylation appears to modulate the activity of...

Dyslipidaemia and vascular risk

Women with PCOS would be predicted to be at high risk for dyslipidaemia because they are often obese and have elevated androgen levels (Wild, 1995). Moreover, insulin resistance and hyperinsulinaemia tend to increase risks for dyslipidaemia associated with insulin resistance. A number of studies have shown that obese women with PCOS have lower high-density lipoprotein (HDL) and or HDL2 levels as well as higher levels of cholesterol, triglyceride, apoli-poprotein B and free fatty acids than their lean counterparts and BMI proved to be the best predictor of these alterations on multiple regression analysis (Robinson et al., 1996 Rajkhowa et al., 1997). Recently it has been reported that PCOS women have higher concentration and proportion of small, dense low-density lipoprotein (LDL III) cholesterol (Dejager et al., 2001 Pirwani et al., 2001). These findings indicate that women with PCOS accompanied by increased concentration of LDL III are at increased risk for cardiovascular morbidity...

Kelsey ES Salley and John E Nestler

Infertility Treatment in PCOS Polycystic ovary syndrome (PCOS) affects 5-10 of women of reproductive age. One of the hallmarks of the syndrome is chronic oligo- or anovulation, making it one of the most common causes of infertility. While infertile PCOS patients have traditionally undergone conventional fertility treatments, insulin-sensitizing agents are also being explored because of the hyperinsulinemic insulin resistance intrinsic to the syndrome. Once women with PCOS become pregnant they are at increased risk for complications including early pregnancy loss, gestational diabetes and pregnancy-induced hypertension. Because pregnancy is a state of heightened insulin resistance and compensatory hyperinsulinemia, insulin-sensitizing agents, particularly metformin, are being investigated for prevention of these complications. Key words Polycystic ovary syndrome Fertility Pregnancy Infertility Early pregnancy loss Gestational diabetes Pregnancy-induced hypertension.

Definition and Epidemiology

PCOS is a diagnosis of exclusion, requiring the elimination of other causes of androgen excess or related disorders (15). To facilitate better comparability of clinical studies, a 1990 NIH conference defined PCOS as the presence of both (1) hyperandrogenism and or hyperan-drogenemia and (2) oligo- or anovulation (16). As this definition did not include ovarian morphology, a 2003 conference in Rotterdam (re-)introduced PCO as a third criterion and defined PCOS as the presence of at least two of the three above features (17). These two definitions, usually referred to as the 1990 NIH and the 2003 Rotterdam criteria, have recently been challenged by a task force report from the Androgen Excess Society, requiring the presence of hyperandrogenism and or hyperandrogenemia as a condition sine qua non, and either oligo- anovulation or PCO or both, in addition to the exclusion of other disorders (18). In spite of the multitude of definitions and the resulting difficulty in ascertaining the...

Historical Perspective

With their eponymous paper of 1935, describing seven patients with polycystic ovaries (PCO), amenorrhea, hirsutism, and obesity, Stein and Leventhal are credited for defining the syndrome later to be known as PCOS (7), although others had reported case reports with similar ovarian pathology as early as 1721 (8-10). With a paper published in 1921, Achard and Thiers are considered to be the first to report on the association of hyperandrogenism and diabetes mellitus in a 71-year-old bearded obese woman (11). However, this disorder, which they called diabete des femmes a barbe, was likely to be caused by adrenocortical pathology, rather than representative of PCOS. In 1980, with the development of standardized methods to measure insulin, Burghen et al. (12) demonstrated a correlation of hyperandrogenism with hyperinsulinemia in PCOS. With the first report on the amelioration of PCOS symptoms with the insulin sensitizer metformin by Velazquez et al. (13) in 1994, insulin resistance and...

Obstructive Sleep Apnea

Obese women with PCOS are at increased risk for obstructive sleep apnea (OSA) (56). Based on the increased prevalence of OSA in men, and recent evidence that androgens may play a role in the male predominance, overnight polysomnog-raphy was performed in obese women with PCOS and age weight-matched con- -o trols (56). Women with PCOS had a significantly higher apnea-hypopnea index cessive daytime sleepiness are more frequent in women with PCOS than in pre-menopausal controls. Insulin resistance appeared to be a risk factor for SDB in J women with PCOS. Q morbidity and mortality is uncertain. However, recent evidence suggests that OSA may indirectly increase the risk of cardiovascular morbidity and mortality. The Wisconsin Sleep Cohort Study documented that an apnea index of five or more events per hour resulted in significantly higher systemic pressures than in snorers or normals (58). Lavie et al. (59) demonstrated a similar association between an increased apnea-hypopnea index and...

Insulinlowering medications

Agents that lower insulin levels by improving insulin sensitivity may provide a new therapeutic modality for obese PCOS women. Metformin acts mainly by suppressing hepatic glucose production, and its insulin-sensitizing actions are primarily mediated through the weight loss that frequently occurs during therapy. Velasquez et al. (1994) first demonstrated that metformin administration to obese PCOS women was not only able to significantly improve insulin levels, but also to decrease LH and testosterone concentrations, regardless of changes in body weight, with a significant improvement in menstrual abnormalities in most patients. Glueck et al. (1999) reported that following metformin treatment 91 per cent of previously amenorrhoeic women with PCOS resumed normal menses independently of metformin dose and duration of treatment. They also observed a significant decrease of BMI, fasting insulin, testosterone and increased oestradiol in metformin treated PCOS women. Another study has...

Plausible Biological Mechanisms

Fetal programming of PCOS by androgen excess may be related to the phenomenon of sexually dimorphic programming of tissues. Normally, sexually dimorphic traits are programmed during the early neonatal period by the burst of gonadotropin and sex-steroid secretion in both sexes (8). Such developmental programming in the female may occur in prenatal life, under the influence of Fig. 5. Fetal programming of neuroendocrine, reproductive and metabolic traits of polycystic ovary syndrome (PCOS) by androgen excess. Prenatal androgen excess Prenatal androgen excess PCOS phenotype androgen excess, and be directed toward a more masculine phenotype with regard to reproductive, neuroendocrine, and metabolic traits in the female (Fig. 5). In the reproductive context, a key trait of PCOS is the hyperandrogenic phenotype of the ovarian theca cells, as mentioned earlier in this chapter. It is likely, that the structural and functional phenotype of PCOS theca cells is programmed during differentiation...

Gonadotropin Releasing Hormone

Both GnRH agonists and antagonists are being investigated for their roles in ovulation induction in patients with PCOS. While GnRH agonists in conjunction with gonadotropins may increase pregnancy rates, reduce the risk of miscarriage, and may be of use in patients with high LH levels who have either failed gonadotropin therapy alone or who have had recurrent miscarriages, the concern for multiple follicle development has hampered their use in these patients (6, 107, 108). Only small studies have been completed using GnRH antagonist treatment in conjunction with gonadotropins in patients with PCOS, and randomized controlled trials are needed to further define their role (109). Finally, pulsatile GnRH treatment has also been explored but due to the small size and short duration of studies, it needs further investigation (110).

Weight reduction by lifestyle modification

There is long-standing clinical evidence concerning the efficacy of weight reduction on clinical and endocrinological features of obese women presenting with PCOS. It has been reported that weight loss may improve menstrual abnormalities and both ovulation and fertility rate. Moreover, it was confirmed that hirsutism and acanthosis nigricans were significantly improved in most patients following weight loss. Reduction of hyperandrogenaemia appears to be the key factor responsible for these effects, since peripheral testosterone, androsten-dione and dehydroepiandrostendione sulphate values were significantly reduced after weight loss in obese PCOS women (Pasquali et al., 1989). These findings were subsequently confirmed by Kiddy et al. (1992) in women who obtained even moderate weight loss after long-term calorie restriction. They reported an improvement in menstrual pattern, endocrine profile and fertility in obese women (BMI > 25) with PCOS if they lost more than 5 per cent of...

Procoagulant Activity

Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality in premenopausal women, and insulin resistance and compensatory hyperinsuli-nemia play a fundamental role in the etiology of this syndrome. This is another example of an organ, in this case the ovary, responding normally to hyperinsuli-nemia by increasing testosterone secretion in the face of muscle and adipose tissue insulin resistance. Indeed, in this instance, the ovary may be supersensitive to insulin stimulation. In any event, the primary clinical manifestations of PCOS (hirsutism, abnormal menstruation, and difficulty in conceiving) are secondary to increased insulin-stimulated testosterone secretion by the ovary. Women with PCOS are at increased risk to develop both type 2 diabetes and the dyslipidemia of syndrome X. Both of these changes suggest that insulin-resistant and hyperin-sulinemic women with PCOS will be at increased risk of CHD, and there is now evidence of enhanced atherogenesis in middle-aged...

Plausible Genetic Contribution to Prenatal Androgenization

Evidence is accumulating that genetic modifiers of placental barrier to androgens, such as polymorphisms of the SHBG and P450 aromatase (CYP19) genes, or genetic variants associated with increased androgen receptor (AR) sensitivity may also contribute to fetal programming of PCOS by androgen excess. 1. Maternal factors (PCOS) SHBG levels are often low in women with PCOS as well as in subjects with abdominal obesity and features of the metabolic syndrome (65, 79). Although this is thought to be the result of hyperinsulinemia and hyperandrogenemia or other nutritional factors, there is also evidence that SHBG production may be genetically determined (29, 97). We have recently shown, in a case-control study, an association between the (TAAAA) polymorphism of the SHBG gene and PCOS among Greek women (99). In particular, women with PCOS were more frequently carriers of longer (TAAAA) alleles, compared with control women. Furthermore, carriers of the longer allele genotypes had lower SHBG...

The Placental Barrier to Excess Androgens

The experimental animal research and the clinical observations cited above suggest a common prenatal etiology for the postnatal endocrine metabolic manifestations of PCOS. The potential sources of excess androgens during intrauterine life to account for fetal programming of PCOS in humans, however, are not clearly known and remain an issue for further research. Normally, the female fetus is protected from the effect of maternal or fetal adrenal androgens by a combination of high SHBG that binds androgens and a high level of placental aromatase activity that converts androgens to estrogens. In a similar way, the fetus is also protected from excess maternal glucocorticoids by the feto-placental 11b-hydroxysteroid dexydrogenase type 2 (11b-HSD2), which catalyzes the metabolism of active cortisol to inactive cortisone (59). Thus, the primary function of placental SHBG and aromatase is to maintain the androgen to estrogen balance and protect the female fetus from the high concentration of...

Improve Your Diet And Increase Exercise If you improve your diet and increase your level of exercise you may be able to

Other studies have shown that reducing weight and increasing exercise improves ovulation rates and reduces male hormone levels. There's no question that healthy diet, exercise and lifestyle habits will significantly improve PCOS-related health problems, as well as reduce the risk of diabetes and cardiovascular disease.

Glycemic Control What Do I Have to Do

Oral hypoglycemic medications, including sulfonylureas and thiazolidinediones, should be discontinued and insulin started in the preconception period. One may consider continuing metformin in women with PCOS as discussed in more detail in Chapter 10. Basal insulin can be supplied either through the use of NPH insulin or through CSII. Lispro and aspart have been studied in pregnancy and can be used for bolus therapy. Glargine has not been studied in randomized controlled trials in pregnancy (60). A large study of insulin detemir in pregnancy is underway. Results of this study have not been published at the time of submission of this chapter.

Effects In Nondiabetes Conditions

In addition to being present in the classic insulin responsive tissues and the vascular endothelium, PPAR-y is also found in other cell types. Several studies (in vitro and in vivo) have shown that the thiazolidinediones have beneficial effects in polycystic ovary syndrome (PCOS), HIV disease, various cancers and inflammatory diseases. Polycystic ovary syndrome is characterized by hyperandrogenism, chronic anovulation, and insulin resistance. Consistent with their role as insulin sensitizers, the thiazolidinediones have been shown to have both insulin-sensitizing and ovulation-inducing effects in women with PCOS (90-92). Highly active antiretroviral therapy (HAART) is associated with several metabolic complications including fat redistribution (lipodystrophy), insulin resistance, and increased incidence of diabetes mellitus, hyperlipidemia, and hypertension (93). In several studies, the thiazolidinediones have been shown to improve insulin sensitivity and body fat distribution in...

Risk Factors For Obesity

Various medical genetic causes of obesity must also be considered. Endocrine conditions associated with weight gain include hypothyroidism, Cushing's syndrome, hypogonadism in the male, polycystic ovary syndrome (PCOS) in the female and growth hormone deficiency (42). Rare genetic causes of obesity include Prader-Willi syndrome, Bardet-Biedl syndrome and Cohen's syndrome. Diabetes can be an obvious consequence of the severe obesity associated with such syndromes.

How The Definition Of The Metabolic Syndrome Oyerlaps That Of Insulin Resistance

There are several other considerations emphasizing why different definitions of the metabolic syndrome and of the insulin resistance may in some way represent different entities and they should not therefore be used synonymously (37). In fact, many studies indicate that relatively new indices related to both insulin resistance and CvD may also be useful predictive tools or useful additions to the definition of the metabolic syndrome. These indices include markers of low-grade inflammation, which is currently suggested to play a major role in atherogenesis development. In fact, recent studies have shown that a relationship exists between inflammatory markers and indices of insulin resistance, both in subjects with the metabolic syndrome and in those with DM2 and obesity reviewed in (37) , as well as in those with PCOS (see paragraph below) (43). It is now well established that there is a strong and consistent inverse association between adiponectin and both insulin resistance and...

The Biology Of Sex Difference In Health And Disease

In this chapter, we will focus on some of the very complex aspects of the relationship between androgens and metabolic dysfunction, particularly insulin resistance, obesity, type 2 diabetes mellitus (T2D), and cardiovascular risk factors in women, in the general female population and particularly in women with the polycystic ovary syndrome (PCOS).

The Insulin Resistance Syndrome

More recently, the polycystic ovary syndrome (PCOS) Ji pected in anyone who has a personal or a family history of obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, or premature cardiovascular disease. It should also be looked for in women with a history of gestational diabetes mellitus (GDM) or PCOS and members of various ethnic and racial groups that have increased risk for obesity and type 2 diabetes. One of the most common manifestations of insulin resistance syndrome is the combination of obesity and type 2 diabetes mellitus. In the United States, approximately 80 of people with type 2 diabetes mellitus are overweight, defined as a body mass index (BMI) > 27 kg m2, and the current rapid rate of increase in the prevalence of type 2 diabetes mellitus is closely linked to the increasing prevalence of obesity and physical inactivity in our society (26). It is estimated that there are now approximately 16 million people in the United States with...

What Strategy to Use to Prevent TDM in Subjects Genetically Predisposed to TDM Lifestyle Intervention Pharmacological

415), muscle (127), and vascular bed (341, 342) - and ameliorate the release of inflammatory adipok-ines from macrophages and adipose tissue linked to insulin resistance (66, 126) and atherogenesis (416). In addition to the prevention of T2DM, early use of pioglitazone may reverse common metabolic complications of patients with IGT and T2DM, such as NAFLD (64) or PCOS (417), and reduce subclinical inflammation ,418) and atherosclerosis ,419). Pioglitazone has also been reported to reduce the risk of stroke and recurrent myocardial infarction in subjects with established CVD (420-423), although for unclear reasons rosiglitazone paradoxically increases myocardial infarction in patients with T2DM (424, 425) , Clinical trials with thiazolidinediones also suggest that they are the most promising of the currently available pharmacological agents for the prevention of T2DM (408-411).

Diabetes and fibrinolysis

Decreased fibrinolytic system capacity is observed consistently in blood from patients with DM, particularly those with type 2 diabetes (93,94). It has been known for many years that obesity is associated with impaired fibrinolysis (95) that elevated blood triglycerides and other hallmarks of hyperinsulinemia are associated with increased activity of PAI-1 (96) and that elevated PAI-1 is a marker of increased risk of acute MI as judged from its presence in survivors compared with age-matched subjects who had not experienced any manifestations of overt CAD (97). We found that impaired fibrinolysis in subjects with type 2 DM, not only under baseline conditions but also in response to physiological challenge, was attributable to augmented concentrations in blood of circulating PAI-1. Furthermore, obese diabetic subjects exhibited threefold elevations of PAI-1 in blood compared with values in nondiabetic subjects despite tissue-type plasminogen activator (t-PA) values that were virtually...

The Nature Of Complications

Only recently have these ideas, developed so effectively by Dr. Reaven, become conventional wisdom. In fact, syndromes of insulin resistance are manifest by impaired responses to insulin in skeletal muscle, adipose tissue, and the liver, clusters of abnormality including dyslipidemia with high triglycerides, low HDL cholesterol, decreased LDL particle size, postprandial lipemia, increased susceptibility to oxidation of LDL, obesity, hypertension, impaired fibrinolysis, and perhaps of most importance to the patient at risk, accelerated coronary artery disease manifested by acute coronary syndromes. Some or all of these derangements are seen in patients with syndromes of insulin resistance even in the ab- -o sence of the derangements in intermediary metabolism typical of diabetes, including hyperglycemia. Thus, women with the polycystic ovarian syndrome who are insulin resistant have accelerated coronary disease as do normal subjects who are not diabetic but have elevated fasting...

P Michael Conn Series Editor

Weetman, 2008 Energy Metabolism and Obesity Research and Clinical Applications, edited by Patricia A. Donohoue, 2008 Polycystic Ovary Syndrome Current Clinical Treatment, and Underlying Mechanisms, edited by Barbara Caleen Hansen and George A. Bray, 2008 Genomics in Endocrinology DNA Microarray Analysis in Endocrine Health and Disease, edited by StuartHandwerger and Bruce Aronow, 2008 Controversies in Treating Diabetes Clinical and Research Aspects, edited by Derek LeRoith and Aaron I. Vinik, 2008 Endocrine-Disrupting Chemicals From Basic Research to Clinical Practice, edited by Andrea C. Gore, 2007 When Puberty is Precocious Scientific and Clinical Aspects, edited by Ora H. Pesovitz and Emily C. Walvoord, 2007 Insulin Resistance and Polycystic Ovarian Syndrome Pathogenesis, Evaluation and Treatment, edited by Evanthia Diamanti-Kandarakis, John E. Nestler, D. Pandis, and Renato Pasquali , 2007 Hypertension and Hormone Mechanisms, edited by Robert M. Carey, 2007 The...

Use of medication to aid weight loss in primary care

Overweight because of polycystic ovarian syndrome (PCO). Some practitioners have tried to use it in combination with orlistat or sibutramine. It does not have any specific licensing arrangements for the treatment of obesity and currently does not have a clearly defined role.

Prevention Or Delay Of Type Diabetes

Prevention efforts may start with promotion of healthy lifestyle and appropriate screening in those at higher risk individuals > 45 years of age and those with a BMI > 25 kg m2 (22). Screening should also be considered for people who are < 45 years of age and are overweight if they have another risk factor for diabetes physical inactivity, first-degree relative with diabetes, members of high-risk ethnic populations (e.g., African American, Latino, Native American, Asian American, Asian American, and Pacific Islander), women who delivered a baby weighing > 9 lb or were diagnosed with gestational diabetes, hypertension, low HDL cholesterol, high triglycerides, women with polycystic ovarian syndrome, IGT, or IFG on previous testing, other clinical conditions associated with insulin resistance (e.g., severe obesity and acanthosis nigricans), and history of cardiovascular disease (CVD). Repeat testing may be carried out at 3-year intervals.

Association Of Insulin Resistance With Other Cv Risk Factors

Impaired fibrinolysis is now recognized as being an important component of the IRS and probably contributes considerably to the increased risk of CV events (17). Plasma PAI 1 antigen and activity are elevated in a wide variety of insulin resistant subjects including obese subjects with and without diabetes and women with the polycystic ovarian syndrome. Immuno-histochemical analysis of coronary lesions from patients with coronary

Atherogenesis In The Prediabetic State

Particularly fertile ground for germination of vulnerable plaques. Thus, a focus on treatment in the prediabetic state is likely to be important in preventing cardiovascular events later in ultimately diabetic subjects. One example is women with the polycystic ovary syndrome. These subjects are insulin-resistant and often have postprandial hyperglycemia. They are also often hypertensive. They are at increased risk for coronary artery disease. Accordingly, therapy designed to ameliorate insulin resistance is under intense investigation.

Databased Classification of Early

Using medical records, and, when available, questionnaire responses, we were able to distinguish a group of probable Early 2 subjects from the body of registered cases using criteria as depicted in Figure 7C.2. On the medical records, those with any mention of obesity, 'possible Type 2' or 'atypical' diabetes, acanthosis nigricans, polycystic ovary syndrome, or those with a BMI > 27 Kg M2 at onset, were selected in addition, those who responded to specific questions during the interview were considered likely to be Type 2. These questions elicit information on cessation of insulin use after the 'honeymoon' period, as well as on current treatment with oral agents. Those who do not meet one or more of the above criteria were considered to have type I diabetes. Using these criteria, we we were able to begin to address the question of secular increases in Early 2.

Metabolic syndrome definitions

The guidelines of the American Association of Clinical Endocrinologists13 appear to be a hybrid between the ATP III and WHO definitions of metabolic syndrome, but no defined number of risk factors is specified. Diagnosis is left to clinical judgment. The criteria include obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure, elevated fasting glucose and other risk factors, including polycystic ovary syndrome, sedentary lifestyle, advancing age, belonging to an ethnic group at high risk for type 2 diabetes or cardiovascular disease, family history of type 2 diabetes, hypertension, and cardiovascular disease (Table 1.3).

Risk factors for diabetes

Other risk factors for type 2 diabetes mellitus include age of 45 years or older, family history of diabetes (parent or siblings), physical inactivity, ethnicity (eg, Afro-American, Hispanic, Native American, Asian American, or Pacific Islander), impaired glucose tolerance, history of gestational diabetes or delivery of a baby weighing more than 9 lbs, hypertension (blood pressure > 140 90 mm Hg in adults), high-density lipoprotein (HDL) cholesterol level below 35 mg dL and triglyceride level above 250 mg dL, polycystic ovary syndrome, and history of vascular disease 10 . Park and Edington 11 applied a prediction model using sequential multilayered perception neural network architecture. High BMI was the most significant risk factor other significant factors that predicted risk over time with variations in trajectory were elevated blood pressure, stress, elevated cholesterol levels, and fatty food intake.

Type Diabetes The Twentieth and Twenty FirstCentury Epidemic

Various factors contribute to insulin resistance being overweight, advancing age, a sedentary lifestyle, an inherited susceptibility, and certain hormonal conditions such as polycystic ovary syndrome. We don't completely understand why insulin resistance develops, and there is probably more than one explanation, but recent research suggests that fat cells produce chemicals that cause tissues to resist the effects of insulin. More fat cells, as in obesity, make more of these chemicals. As a result, sugar can't move into cells and begins to accumulate in the blood, especially after meals. The rising blood-sugar levels drive the beta cells to produce more and more insulin to help push the sugar into the cells where it is needed. And since rising blood-sugar levels also worsen insulin resistance, a vicious cycle begins.

Screening for Prediabetes

However, trials have not yet been performed to determine whether or not a screening programme per se can reduce the incidence of or complications from T2D, and there is still no clear consensus on who should be screened and how often. Furthermore, a screening programme must be cost-effective but it is not yet known if the costs of earlier identification and intervention will be offset by future reductions in healthcare costs resulting from reduced morbidity and mortality from T2D and CVD. The ADA Position Statement on 'Prevention or Delay of Type 2 Diabetes' published in 2004 (American Diabetes Association, 2004b) concludes that 'men and women > 45, particularly those with BMI > 25, are candidates for screening to detect pre-diabetes (IFG or IGT)'. In addition, it is also acknowledged that screening should be considered in younger individuals with BMI > 25 who have additional risk factors including first-degree relative with T2D, habitual physical inactivity, member of 'high...

Causes Of Insulin Resistance

Insulin resistance may be caused by rare genetic defects that alter insulin binding to its cellular receptors or cause defects in receptor or postreceptor signal trans-duction (1). Recently, defects in the nuclear receptor, PPARy, have also been linked to syndromes of severe insulin resistance (2). In addition, some endocrine-metabolic syndromes, such as Cushing's syndrome, acromegaly, and polycystic ovary syndrome, are associated with insulin resistance because of the hormonal imbalances associated with these conditions. However, in the most common forms of insulin resistance, single gene defects have not been identified and the development of insulin resistance represents a complex interaction among a poorly understood array of predisposing genetic factors and acquired environmental factors that modify insulin sensitivity. Among the latter, the most prominent are obesity (particularly intra-abdominal obesity), physical inactivity, and increasing age. It is also now well documented...

Rationale for defining metabolic syndrome

In addition to the appreciation that weight gain and obesity are increasing global problems and that the location of body fat has both prognostic and therapeutic importance is the recognition of atherogenic risk factor clustering. This concept was noted by Framingham investigators who found it was common in both men and women, worsened with weight gain, and appreciably increased the risk of CHD.7 The odds ratios for individuals with this risk factor clustering was more than two-fold for men and more than six-fold for women. Subsequent studies identified factors that can intensify these metabolic abnormalities. They include aging (higher prevalence at higher age), ethnic subgroups, endocrine dysfunction (increased prevalence in polycystic ovary syndrome), and physical inactivity.8 The distinction from those unaffected is not trivial. Characteristic clinical features of risk factor clustering identify individuals who are more likely to become diabetic and or experience a cardiac event....

Proposed Diagnostic Criteria For Early

Clinicians also have begun to address diagnostic criteria for Early 2. Using their clinical experience as well as other clinic-based reports, Arslanian and Danadian characterized 'youth-onset atypical diabetes' as having a preponderance of black children, onset 13.5 years and in mid-puberty, increased female male ratio, increased BMI, acanthosis nigricans, and a family history of Type 2 diabetes (96). Heather Dean distinguished 'NIDDM in Youth' from Type 1 diabetes in her Native American patient population using age (> 6 and usually > 9 years), obesity (> 120 ideal body-weight or BMI> 85 percentile), clinical criteria (no recent weight loss or acute hyperglycemic symptoms), and a family history of Type 2 diabetes (106). The American Diabetes Association consensus statement tentatively suggests the criteria of obesity at onset, a positive family history, and acanthosis nigricans. Severe symptoms of hyperglycemia, polycystic ovary syndrome in females, and lipid abnormalities may...

Sources of Estrogens in Women

In the circulation, estrogen binds to sex hormone binding globulin (SHBG) produced in the liver and, with less affinity, to albumin (11). Only about 2 -3 of estrogen is free. Changes in SHBG levels may influence the tissue availability of free estrogen and also free androgen because the latter also binds to SHBG. Estrogens themselves increase, whereas androgens and high insulin levels decrease SHBG levels. During the menopause, the drop of estradiol reduces SHBG levels, which in turn, results in decreased binding and an increased concentration of free androgens. Consequently, estrogens decrease to a greater extent than do androgens resulting in an increase of the androgen estrogen ratio and a relative androgen excess in postmenopausal women. Some of the signs and symptoms observed after menopause and, in particular, changes in body composition are caused by this altered balance between estrogens and androgens (12).

Reproductive Hormones

As discussed above hyperinsulinemia is usually accompanied by hyperandrogenism, which leads to hirsutism and PCO (48). Amenorrhea, oligomenorrhea, and or dysfunctional uterine bleeding are common among obese adolescent females. Some of these patients will also develop PCO syndrome (48-50). PCO is now recognized as a component of the IRS (Vol. 1 Chaps. 11 and 13). Insulin-lowering agents have become the norm in the management of PCO (51).

Failed Adaptation to Insulin Resistance and pCell Failure The Natural History of TD

Groups at increased risk of subsequently developing diabetes exhibit P-cell dysfunction well before they would be considered to have reduced glucose tolerance, in keeping with the idea of a pre-existing risk. Examples include women with a history of gestational diabetes or polycystic ovarian syndrome, older subjects, who frequently develop hyperglycemia as they continue to age, and individuals with impaired glucose tolerance 30 . First-degree relatives of individuals with T2D, who are genetically at increased risk, also have impaired P-cell function, even though they may still have normal glucose tolerance 42 . This has particularly been well studied in the Pima Indians, in whom the prevalence of diabetes is higher than almost any other group in the world, and also been confirmed for non-Hispanic whites, African-Americans and Hispanics participating in the Insulin Resistance Atherosclerosis Study (IRAS) reviewed in 30 .

Abnormalities of menstrual cycle and infertility

PCOS is the commonest cause (78 per cent) of anovulatory in infertility (Hull, 1987). It was demonstrated that menstrual abnormalities are more frequent in obese than non-obese PCOS women (Kiddy et al., 1990). In addition, it was shown that a reduced incidence of pregnancy and inadequate response to pharmacological treatments to induce ovulation may be more common in obese PCOS women (Galtier-Dereure et al., 1997). Insulin resistance and accompanying hyperinsulinaemia, which can increase amount of body fat, can be directly related to impaired ovulation in obese PCOS women since treatment with insulin-sensitizing agents leads to improvement of menstrual cycles. It has been found that obese PCOS women tend to have lower ovulation response to pulsatile GhRH analogue administration than non-obese counterparts (Filicori et al., 1994). In the recent studies of PCOS women conceiving after in vitro fertilization or intracytoplasmic sperm injection, it was observed that those with obesity had...

Etiology and Clinical Presentation

Pcos Diagnosis

The etiology of PCOS, most likely a combination of genetic disposition and environmental factors, is not completely understood (23,24). While familial clustering of PCOS has been well documented, even including a male factor with higher androgen levels in first degree relatives of affected patients (25,26), the search for candidate genes has not come up with obvious culprits (27,28). While not its cause, insulin resistance plays a pathogenic role in the development of PCOS. Hyperinsulinemia increases ovarian and adrenal steroid hormone production, alters luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release, and decreases hepatic sex hormone-binding globulin (SHBG) production, thus increasing free androgen and estrogen levels (Fig. 1) (29). The unopposed estrogens stimulate the proliferation of adipose tissue, which is a source of aromatase and thus vice versa converts androgens into estrogens, further increasing their serum levels and leading to inappropriate...

Pathophysiology Of Macrosomia

Pathophysiology Undernutrition

Ovarian Hyperandrogenism and Premature Adrenarche Polycystic ovarian syndrome (PCOS) is being increasingly recognized in adolescents, often as part of the metabolic or insulin resistance syndrome. The syndrome includes, in addition to obesity and hyperinsulinism, hypertension, hyperuricemia, PCOS, acanthosis nigricans, dyslipidemia, and elevated plasminogen activator inhibitor-1 (54). Adolescents with PCOS have an approximate 40 reduction in insulin stimulated glucose disposal in comparison to body composition matched nonhyperandrogenic control subjects (55,56). Girls with premature adrenarche are at increased risk for ovarian hyperandrogenism and PCOS (57). Case finding is justified if the condition tested for is sufficiently common to justify the investment and type 2 diabetes is sufficiently common in obese children and youth to justify testing such youngsters, especially those with high-risk ethnicity or family history. Another criterion for case finding is that the condition...

Contemporary Endocrinology

Donohoue, 2008 Polycystic Ovary Syndrome Current Controversies, from the Ovary to the Pancreas, edited by Andrea Dunaif, R. Jeffrey Chang, Stephen Franks, and Richard S. Legro, 2008 Insulin Resistance and Polycystic Ovarian Syndrome Daniel H. Bessesen, 2007 Androgen Excess Disorders in Women Polycystic Ovary

Renato Pasquali and Alessandra Gambineri

Of Insulin Resistance Diabetes and Cardiovascular Risk Factors in Women The Paradigm of PCOS Population Lessons From the PCOS Paradigm Summary and Conclusions References There are many differences between the sexes in the susceptibility and the development of chronic metabolic and cardiovascular diseases, which may be partly explained by the disparate alterations of androgen balance particularly in the presence of obesity. Notably, available studies support the concept that the prevalence of insulin resistance, the metabolic syndrome, type 2 diabetes, and cardiovascular pathologies is different between the sexes. With respect to women, it is particularly evident from a recent meta-analysis that those with the abdominal phenotype of excess weight or obesity, who are characterized by a condition of relative hyperandrogenic state, are at high risk for a specific morbidity for these diseases. The paradigm of PCOS is a good example for investigating the relationship between...

Agathocles Tsatsoulis

The Clinical and Molecular Phenotype of PCOS Evidence for the Developmental Origins of PCOS Potential Origin of Prenatal Androgen Excess in Humans Plausible Biological Mechanisms Conclusions and Future Implications References Polycystic ovary syndrome (PCOS) is a common endocrine metabolic disorder in women, characterized by hyperandrogenism, chronic anovulation, and or polycystic ovaries in association with android fat distribution and insulin resistance hyperinsulinism. The etiology of PCOS remains elusive but there is increasing evidence that the phenotypic traits of the syndrome may be programmed in utero by androgen excess. Thus, female primates, exposed to androgen excess during fetal life, exhibit the reproductive and metabolic features of PCOS in adulthood. Women with congenital 21-hydroxylase deficiency and congenital adrenal virilizing tumors develop features characteristic of PCOS during adult life, despite the normalization of androgen excess after birth. Rare cases of...

Laparoscopic Ovarian Drilling

Surgical ovarian wedge resection was the first surgical treatment for anovulatory PCOS but fell out of favor due to the risk of postsurgical adhesion formation (95-97). Alternatively, LOD involves cautery of the ovarian surface using electrocoagulation or laser, which can be done on an outpatient basis, results in fewer postoperative adhesions, and requires no ongoing monitoring (98-100). It has been used as an alternate therapy in patients who do not conceive with clomiphene or gonadotropin therapy or in women who hyperrespond to gonadotropins and are therefore at increased risk of developing OHSS (101). To induce ovulation, LOD appears to most benefit lean PCOS women with high LH concentrations A recent prospective randomized clinical trial by Youssef and Atallah found unilateral ovarian drilling to be as effective as bilateral LOD at lowering LH concentrations in patients with PCOS as well as similar ovulation and pregnancy rates, which could result in less time required for the...

Uwaifo Gi Fallon Em Diabetes Care 2002 25 2081-7

Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos hormonal and metabolic profile. J Clin Endocrinol Metab 1999 84 4006-11. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States a prospective study. J Clin Endocrinol Metab 1998 83 3078-82. Asuncion M, Calvo RM, San Millan JL, et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected caucasian women from Spain. J Clin Endocrinol Metab 2000 85 2434-8. Dunaif A, Segal KR, Futterweit W, et al. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989 38 1165-74. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999 22 141-6. Legro RS, Kunselman AR, Dodson WC, et al....

The interaction of insulin resistance and Bcell function

Type A insulin resistance Insulin resistance, acanthosis nigricans, and hyperandrogenism Polycystic ovary syndrome Polycystic ovarian syndrome is a reproductive disorder characterized by hyperandrogenism and chronic anovulation not caused by specific diseases of the ovaries, adrenals, and pituitary. It is one of the most common hormonal disorders in women, with a prevalence estimated between 5 and 10 53-55 . Women with the polycystic ovary syndrome are more insulin resistant than are controls 56 . In these women, insulin acts synergistically with luteinizing hormone to increase the androgen production by ovarian theca cells. Insulin also inhibits hepatic synthesis of sex hormone-binding globulin, the main carrier protein for testosterone, and increases the proportion of testosterone that circulates in the unbound, biologically available, or free, state. The sole presence of IR does not lead to diabetes and 30 to 40 of women with the polycystic ovary syndrome have impaired glucose...

Summary and conclusions

The paradigm of PCOS is a good example for investigating the relationship between hyperandro-genemia and insulin resistance and metabolic and cardiovascular disorders. In fact, approximately two-thirds of women with PCOS have some degree of insulin resistance, particularly in the presence of obesity. Several studies performed worldwide have also demonstrated that the prevalence of the metabolic syndrome and DM2 is higher in PCOS women than in the general population. PCOS is often associated with the presence of obesity, mostly the abdominal phenotype. On the other hand, there are several differences related to ethnicity and geographical areas, which suggest the possibility that still-undefined environmental (or genetic ) factors may be involved. Importantly, the onset of DM2 tends to develop earlier in women with PCOS than in the general population, which indicates the need for careful early diagnosis and, possibly, preventive intervention, particularly focused on obesity. Although...

Risk factors of youth type diabetes mellitus

Polycystic ovary syndrome Insulin resistance and hyperinsulinemia are major components of polycystic ovary syndrome (PCOS) in obese and lean adult women and in adolescent girls 101,102 . PCOS affects 5 to 10 of women in the reproductive age group and is characterized by hyperandrogenism and amenorrhea or oligomenorrhea secondary to chronic anovulation 102 . Thirty percent to 40 of women with PCOS have IGT, and 7.5 to 10 have T2DM by the fourth decade 103,104 . A recent study of screening PCOS adolescents with oral glucose tolerance test showed IGT in approximately 30 and diabetes in approximately 4 105 . Our studies revealed that insulin sensitivity is approximately 50 lower in obese adolescents who have PCOS versus matched controls 106 . Adolescents who have PCOS and IGT have 40 lower first-phase insulin secretion and lower glucose disposition index compared with adolescents with NGT 107 . The presence of this metabolic profile in the early course of PCOS significantly increases the...

Mechanisms responsible for the overexpression of pai in diabetes

Therapy designed to reduce insulin resistance, the resultant hyperinsulinemia, or both have been shown to reduce PAI-1 in blood as well. Thus, treatment of women with the polycystic ovarian syndrome with metformin or troglitazone decreased concentrations in blood of insulin and of PAI-1 (100,103). Changes in the concentrations of PAI-1 in blood correlated significantly with those of insulin (100). The concordance supports the view that insulin contributes to the increased PAI-1 expression seen in vivo. indicative of syndromes of insulin resistance such as high body mass index and waist to hip ratio in addition to advanced age and elevated concentrations of triglycerides, the association of PAI-1 activity with physical activity was no longer significant. This observation, particularly in combination with the results seen after therapy with troglitazone and metformin in women with the polycystic ovarian syndrome, demonstrates that interventions designed to attenuate insulin resistance...

Franks Et Al Hum Reprod 1997 12 2641-8

Int J Obes 23 936-42. Azziz R, Ehrmann D, Legro RS et al. (2001) O'Keefe M, Ghazzi MN. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86 1626-32. Balen A (1999). Pathogenesis of polycystic ovary syndrome - the enigma unravels Lancet 354 966-7. Barbieri RL, Makris A, Randall RW et al. (1986) Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained women with hyperandrogenism. J Clin Endocrinol Metab 62 904-9. Barner RB (1998) The pathogenesis of polycystic ovary syndrome lessons from ovarian Burghen GA, Givens JR and Kitabchi AE (1980) Correlation of hyperandrogenism with hyperinsulinism in polycystic ovary disease. J Clin Endocrinol Metab 50 113-16. Conway GS, Jacobs HS, Holly JM and Wass JA (1990) Effects of luteinizing hormone, insulin like growth factor, and insulin like growth factor small binding protein in polycystic...

Growth Puberty And Diabetes Insulin Deficiency And Resistance

The interaction among growth, puberty, and diabetes is complex, with studies reaching differing conclusions, both about the events themselves and about the mechanisms involved. If diabetes is diagnosed before puberty, linear growth prior to diagnosis has been variously described as being reduced, increased, or unchanged (8-11). Following diagnosis, linear growth prior to puberty may be impaired, especially if diabetic control is poor (5,11,12). This inverse relationship between growth and poor diabetic control is more marked during puberty, such that the pubertal growth spurt may be impaired as well as the onset of puberty and menarche being delayed (6,7,13-17). Following menarche, menstrual dysfunction is more common, including secondary amenorrhoea and irregular cycles, as well as polycystic ovary syndrome (15,18). Improved diabetic control, involving more adequate insulinization, often leads to restoration of linear growth (19) and restoration of regular menstrual cycles (18).

Pregnancy Induced Hypertension

Hyperinsulinemia may increase renal reabsorption of sodium and stimulate the sympathetic nervous system, both of which can increase the risk of developing hypertension (115). Furthermore, insulin resistance and or its associated factors have been shown to be associated with PIH even years after pregnancy (175-180). Insulin resistance or associated hyperglycemia may impair endothelial function, which may decrease prostacyclin production (39). The hyperinsulinemic insulin resistance intrinsic to PCOS may therefore increase the risk of PIH. PCOS and PIH Given the risk for PIH in those with insulin resistance, it is not surprising that studies have found an association between women with PCOS and PIH. Diamant et al. found that preeclampsia was 11 times more common in anovulatory patients with PCOS undergoing ovulation induction than in normal controls (186). PCOS women were also more likely to have preeclampsia than anovulatory women without PCOS. The study did not control for BMI....

Counseling and Preconception Care Recommendations to Reduce Maternal and Fetal Risks of Preexisting Diabetes What Are

Fertility in women with DM2 is an even more complex issue. Obesity and polycystic ovarian syndrome (PCOS), both known to effect fertility, often occur with DM2. One review found that Counsel on smoking cessation strategies and set this as a preconception goal, if applicable Obtain a baseline measure of urine albumin excretion Counsel on the risks of preeclampsia and preterm delivery Counsel on the risk of progressive renal disease Counsel on maternal fertility, and if applicable, PCOS Obtain baseline TSH, if no previous one available Subsequent hyperglycemic visits Evaluation of and counseling on insulin dosing to improve glycemic control MNT for improving glycemic control Reinforcement of smoking cessation if applicable Initial euglycemic visit Recommendation. Some women with preexisting diabetes may have trouble conceiving, but most will not. Clinicians should maintain a high index of suspicion for PCOS, and if clinical criteria are met, further investigation for PCOS and possibly,...

Which cutaneous manifestations occur in other endocrine and metabolic disorders that are related to DM

Acanthosis nigricans is characterized by hyperpigmentation of the skin in regions where this forms folds, as in the axillae, the neck and the groins (Figure 18.4). Generalized acanthosis nigricans is usually related to development of neoplasia, mainly of the gastrointestinal tract, whereas the more limited form is related to conditions of insulin resistance, such as obesity, Type 2 DM, the polycystic ovary syndrome and acromegaly. Other endocrine conditions that cause cutaneous manifestations and are related to the appearance of DM are glucagonoma (causes the characteristic migratory necrolytic erythema), haemochromatosis (dark pigmentation of the skin), Cushing syndrome (atrophy of skin, striae in the abdomen, hirsutism), acromegaly (thickness of skin), the polycystic ovary syndrome (hirsutism, acanthosis nigricans) and the lipodystrophy syndromes.

Trends in the Use of Antidiabetic Drugs

Use of drugs to prevent diabetes or to treat related diagnoses (e.g. polycystic ovary syndrome) may result in changes in prescription patterns in the future. Such changes may confound the interpretation of data on drug use. At present there is some evidence for the efficacy of metformin, troglita-zone (now withdrawn), orlistat, rosiglitazone and rimonabant 17-19 on delaying the development from impaired glucose tolerance to diabetes. However, use of these drugs to prevent diabetes is not currently recommended.

Insulin Resistance Hyperinsulinemia and the IRS

Pathogenesis of the abnormalities and clinical syndromes that make up the IRS. To begin with, type 2 diabetes is the only clinical syndrome listed in Table 3 that is not associated with a significant degree of hyperinsulinemia. Obviously, in this instance, it is the failure of the pancreatic P-cell to adequately compensate for the insulin resistance that is responsible for the development of the clinical syndrome 16 . In the case of the other abnormalities and clinical syndromes listed in Tables 2 and 3, it is the relationship between insulin resistance, compensatory hyperinsulinemia, and the individual tissue response to the chronically elevated plasma insulin concentrations that is responsible for the observed pathophysiology. In this context, it is necessary to address the question of differential tissue insulin sensitivity, for if this phenomenon did not exist, there would be no IRS. For example, the ability of insulin to stimulate muscle glucose uptake and inhibit free fatty acid...

Pharmacological Interventions

With which this term is applied to metformin, in the absence of weight loss, insulin-stimulated glucose disposal does not increase in metformin-treated individuals 59-61 . It is outside the province of this chapter to discuss the mechanism of action of met-formin, nor its use as an effective treatment of type 2 diabetes or PCOS, but the clinical utility of metformin does not seem to reside in its ability to enhance insulin-stimulated glucose uptake. In addition to their clinically useful metabolic benefits, TZD compounds are approved for treatment of type 2 diabetes, and have been shown to decrease hepatic steatosis in patients with nonalcoholic fatty liver disease 65 and result in pregnancy when given to women with PCOS 66 . In light of this appealing clinical profile, the possibility that these compounds might be particularly effective in reducing CVD, and preventing the development of type 2 diabetes in particularly susceptible individuals, that is, insulin resistant, but without...

Menopausal Status and the Androgen Milieu

Similarly, the potential associations among the circulating androgen milieu total and free testosterone, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), and A4-androstenedione (A4A) and SF in diabetic women have been scarcely analysed, especially when studies adequately segregating both the type of diabetes and the pre- vs. postmenopausal population are considered. In contrast, several studies have analysed the concept that endogenous sex hormones may have a role in sex-dependent aetiologies of DM2, such that hyperandrogenism may increase risk in women while decreasing risk in men (55-63). In their comprehensive review, Ding et al. (56) reported that cross-sectional studies indicated that testosterone level was significantly lower in DM2 men but higher in DM2 women than in controls (p < 0.001, for sex difference). Similarly, prospective studies showed that men with higher testosterone levels had a 42 lower risk of DM2 (RR 0.58 95 CI 0.39-0.87), while there was suggestion that...

What are the risk factors for the development of DM

For Type 2 DM, epidemiologic studies as well as data from its pathophysiology and natural history, have shown various factors that are related to an increased frequency of its appearance. These factors are age > 45 years, obesity (BMI > 25 kg m2), family history of DM, a sedentary life-style, certain racial groups and nationalities (African Americans or Hispanics, Native Americans, Pacific Islanders, etc.), history of gestational DM or birth of a child > 4 kg (8.8 lb), history of hypertension or dyslipidaemia and the polycystic ovary syndrome. Also, a low birth weight and cigarette smoking have been associated epidemiologically with the risk of developing DM. However, the most powerful association has been found with the presence of Impaired Fasting Glucose (IFG) and or Impaired Glucose Tolerance (IGT). IFG is defined as the presence of fasting plasma glucose levels between 110-125 mg dl 6.1-6.9 mmol L for Europe 100-125 mg dl 5.6-6.9 mmol L for America), and IGT is the presence...

Gynaecological

Polycystic ovarian syndrome (PCOS) involves a triad of symptoms obesity, menstrual irregularity and hirsutism. The precise aetiology of this complex disorder and whether obesity is a primary or secondary phenomenon is not known (Franks, 1995). However, hyperinsulinaemia, such as occurs during puberty, has been suggested as being a prerequisite for the development of PCOS (Utiger, 1996). Recognized therapeutic options exist making it an important condition to diagnose and treat (Iuorno and Nestler, 1999). Metformin is beneficial in improving menstrual irregularities although the data regarding the effects on weight loss or hirsutism are inconsistent.

Oral contraceptives

Over the years oral contraceptives have been used in women with PCOS in order to avoid the risk of developing endometrial hyperplasia. The progestagen component decreases the frequency of GnRH pulses and LH secretion, thus reducing ovarian androgen production, while oestrogen increases SHBG concentration. Investigating the long-term effects of oral contraceptive therapy on metabolism and body composition in women with PCOS Pasquali et al. (1999) have found a significant reduction of waist circumference and waist-hip ratio, as well as of basal insulin levels and an improvement of glucose tolerance in some patients. Although controversy still exists regarding benefits of oral contraceptive in treatment of obese PCOS women, these findings indicate a potential benefit in body composition and the glucose-insulin system in PCOS women.

Growth hormoneIGF

Abnormalities of growth hormone (GH) secretion and or altered IGF-I concentrations may play a pathogenetic role in PCOS as in vitro and in vivo evidence supports a stimulatory role of GH in early and later stages of folliculogenesis and ovulation (Hull and Harvey, 2001). Therefore, reduced GH secretion may contribute to impaired follicular development and anovulation in PCOS. Abdominal obesity, which can exacerbate insulin resistance and reproductive features of the PCOS is associated with profoundly reduced and disorderly GH secretion (Pijl et al., 2001). Plasma GH concentrations in PCOS have been reported as reduced, normal or increased (Katz et al., 1993). The majority of studies in PCOS have evaluated the status of the somatotropic axis on the basis of acute secretagogue-stimulated GH release and reported a blunted GH response in women with PCOS compared with weight-matched controls (Wu et al., 2000 Villa et al., 2001). Recently, a profound reduction of daily basal (62 per cent)...

Insulin Resistance

It is a common assumption that all women with PCOS are insulin resistant, although this can be demonstrated only in about 70 of them with available tests (64-66), the main reason being that no generally accepted method for the quantification of insulin resistance exists (67,68). Clinically, in PCOS as well as other patients suspected of suffering from insulin resistance, the standard 2-h OGTT measuring both insulin and glucose yields the highest amount of information for a reasonable cost and risk, providing an assessment of both the degrees of hyperinsulinemia and glucose tolerance (69). In addition to obesity and family history of diabetes, ethnicity adversely affects the prevalence of insulin resistance, and generally minority populations with PCOS tend to be more insulin-resistant than Caucasians (33).

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