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Curr Med Chem. Shao C, Dong W, Zhang H. Application of Guijiaosan Shenque acupoint paste can improve the scores of obesity, endocrine and TCM symptoms in treating obese polycystic ovary syndrome. Am J Transl Res. Download references. This work was supported by a grant from the National Natural Science Foundation of China Grant no.
You can also search for this author in PubMed Google Scholar. BH and HZ conceived the idea; HZ reviewed the literature; HZ designed the study and wrote the manuscript and designed the figures and tables; BH, JZ, XC, and XN critically revised the manuscript.
All authors participated in the revision the manuscript. All authors participated in the discussion of the analysis and interpretation of data in this article. The author s read and approved the final manuscript. Correspondence to Bing He.
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Reprints and permissions. Zhao, H. et al. Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment.
J Ovarian Res 16 , 9 Download citation. Received : 07 July Accepted : 26 December Published : 11 January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Methods An extensive literature search was performed up to July in PubMed, Google Scholar, Elsevier, and UpToDate databases. Pathogenesis of insulin resistance in polycystic ovary syndrome Genetics and foetal origin PCOS is an autosomal dominant genetic disease with various expression patterns that begins in early life, and metabolic changes precede reproductive abnormalities.
Insulin signal transduction pathway Insulin is a small peptide receptor-binding hormone released by pancreatic beta cells, which binds to cell surface receptors.
Hyperinsulinaemia and tissue insulin resistance IR in PCOS is caused by impaired insulin action in various target tissues, which is characterized by basal compensatory HI and a reduced insulin response to glucose overload.
Full size image. Treatment of insulin resistance in polycystic ovary syndrome Lifestyle change Guidelines recommend that once women are diagnosed with PCOS and have decreased insulin sensitivity, they should make lifestyle changes and start insulin sensitivity treatment immediately, even if there are no significant changes in glucose tolerance [ ].
Table 1 Common pharmacological approaches for reducing IR in women with PCOS Full size table. Conclusion In general, women with PCOS develop IR owing to abnormal insulin signalling and metabolic dysfunction in insulin-responsive tissues, with a high incidence of IR in PCOS and a significant negative impact on health.
Availability of data and materials All data generated or analysed during this study are included in this published article. Abbreviations IR: Insulin resistance PCOS: Polycystic ovary syndrome HI: Hyperinsulinaemia HA: Hyperandrogenism OA: Oligo-anovulation LH: Luteinizing hormone INSR: Insulin receptor PKB: Protein kinase B BMI: Body mass index FSIGT: Frequently sampled intravenous glucose tolerance HOMA-IR: Homoeostasis model assessment of insulin resistance TCM: Traditional Chinese medicine LIRKO: Liver-specific insulin receptor knockout NAFLD: Nonalcoholic fatty liver disease SHBG: Sex hormone-binding globulin GSK3: Glycogen synthase kinase 3 mTOR: Mammalian target of rapamycin GLUT4: Glucose transporter 4 MAPK-ERK: Mitogen-activated protein kinase-extracellular signal-regulated kinase PKC: Protein kinase C MI: Inositol DCI: D -chiral inositol.
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Article CAS Google Scholar Franks S, Gilling-Smith C, Watson H, Willis D. Do androgens cause insulin resistance? If glucose utilization is expressed as a function of muscle mass rather than total body mass, women do appear to be more insulin sensitive than men , Moreover, when isolated fat cells are compared, female adipocytes are more sensitive than male adipocytes to insulin-mediated glucose uptake These are subtle differences, however, and do not approach the degree of impairment in insulin sensitivity observed in PCOS 54 , Finally, in the rare syndromes of extreme insulin resistance and hyperandrogenism, specific molecular defects in insulin action have been clearly identified as the cause of insulin resistance 19 , It is possible, however, that androgens may produce mild insulin resistance.
Prolonged testosterone administration to female-to-male transsexuals, which produced circulating testosterone levels in the normal male range, resulted in significant decreases in insulin-mediated glucoses uptake in euglycemic clamp studies Studies in testosterone-treated castrated female rats have suggested that androgen-mediated insulin resistance may be the result of an increase in the number of less insulin-sensitive type II b skeletal muscle fibers and an inhibition of muscle glycogen synthase activity Hyperinsulinemic euglycemic clamp studies basally and during treatment with virilizing doses of testosterone in 13 female-to-male transsexuals.
Insulin-mediated glucose disposal decreased significantly at low and at high doses of insulin. Polderman et al. It has been more difficult to demonstrate that decreasing androgen levels improve insulin sensitivity in PCOS.
Diamanti-Kandarakis and colleagues reported that antiandrogen therapy did not alter insulin sensitivity in PCOS.
Other investigators have found modest improvements in insulin sensitivity in PCOS during androgen suppression or antiandrogen therapy , Fig. Such changes were apparent in less insulin-resistant, less obese, or nonobese PCOS women , Moreover, insulin resistance was improved but not abolished Fig.
It is of considerable interest that the effects of sex steroids on insulin sensitivity appear to be sexually dimorphic. Testosterone administration to obese males improves insulin sensitivity , and synthetic estrogen administration to male-to-female transsexuals produces insulin resistance Basal and insulin-mediated glucose disposal in 43 hyperandrogenic women and 12 control women.
The hyperandrogenic women were studied before and after 3—4 months of antiandrogen therapy with spironolactone, flutamide, or Buserelin.
Moghetti et al. Givens and colleagues have proposed that androgens have differential effects on insulin action, with testosterone worsening insulin sensitivity and the adrenal androgen, dehydroepiandrosterone DHEA , improving it. This hypothesis is based on differing correlations of these steroids with insulin-binding studies in blood cells and on their observation that women with elevated dehydroepiandrosterone sulfate DHEAS levels have normal insulin sensitivity Studies in which DHEA or DHEAS have been administered to humans have failed to support this hypothesis.
Administration of supraphysiological amounts of DHEA which also result in testosterone elevations since DHEA is a testosterone prehormone has produced mild hyperinsulinemia in women, but had no effects on insulin sensitivity in men, as would be expected given the sexually dimorphic effects of androgens on insulin action , Moreover, PCOS women with elevated DHEAS levels similar to those in ovulatory hyperandrogenic women are significantly more insulin resistant, arguing against an insulin-sensitizing action of DHEA 49 , In summary, the modest hyperandrogenism characteristic of PCOS may contribute to the associated insulin resistance.
Additional factors are necessary to explain the insulin resistance, since suppressing androgen levels does not completely restore normal insulin sensitivity , Further, androgen administration does not produce insulin resistance of the same magnitude as that seen in PCOS 54 , 55 , Finally, there are clearly defects in insulin action that persist in cultured PCOS skin fibroblasts removed from the hormonal milieu for generations see above Does hyperinsulinemia cause hyperandrogenism?
The syndromes of extreme insulin resistance are commonly associated with hyperandrogenism when they occur in premenopausal women 19 , 20 Table 1. Accordingly, it has been proposed that hyperinsulinemia causes hyperandrogenism. Insulin can be shown experimentally to have a variety of direct actions on steroidogenesis in humans 1 , 9 , Insulin can stimulate ovarian estrogen, androgen, and progesterone secretion in vitro 1 , 20 , Although some of these actions have been observed at physiological insulin concentrations, most actions have been observed at higher concentrations 1 , The presence of insulin receptors in crude ovarian membranes does not necessarily indicate a physiological role for insulin in the regulation of steroidogenesis since such receptors are widely distributed through the body 51 , Insulin is present in human follicular fluid but in concentrations most likely representing an ultrafiltrate of plasma rather than local production In contrast, IGF-I is produced by human ovarian tissue, and IGF-I receptors are present in the ovary , IGF-I and its receptor share considerable sequence, structural, and functional homology with insulin and its receptor, respectively The IGF-I receptor is a heterotetramer with twoα ,β-dimers assembled analogous to the insulin receptor 85 , 88 , — see above.
Insulin can bind to the ligand-binding domain of the IGF-I receptor and activate the tyrosine kinase activity of theβ -subunit and the intracellular events normally mediated by IGF-I 85 , 88 , , IGF-I can bind to and activate the insulin receptor, resulting in rapid effects on glucose metabolism 85 , 88 , In general, the affinity of the IGF-I receptor for insulin is considerably less than it is for IGF-I and vice versa However, this varies by tissue; thus data on receptor affinity cannot be extrapolated from one tissue to another.
α,β-Dimers of the insulin and IGF-I receptor can assemble together to form hybrid heterotetramers 11 , , , Insulin-like growth factor-binding proteins IGFBPs are major regulators of IGF action.
IGFBPs can specifically bind IGF-I and modulate its cellular actions by altering its bioavailability , Insulin decreases hepatic production of IGFBP-1 and may, thus, make IGF-I more biologically available Growth factor regulation of ovarian steroidogenesis appears to be primarily a paracrine system with locally produced IGF-I and IGFBPs acting on neighboring cells in concert with gonadotropins 1 , , , A number of other growth factors, including IGF-II, EGF, and transforming growth factor-α and -β, appear to have a role in the regulation both stimulatory and inhibitory of ovarian steroidogenesis 1 , , Insulin cannot interact directly with the receptors for these hormones 84 , 88 , , However, the receptors for some of these growth factors, such as the EGF receptor which binds both EGF and transforming growth factor-α , are also protein kinases 1 , 84 , For example, serine phosphorylation of the EGF receptor also decreases its tyrosine kinase activity , In rodents, hyperinsulinemia can result in up-regulation of ovarian IGF-I-binding sites, and this may provide yet another mechanism by which insulin can modulate growth factor action Insulin in high concentrations can mimic IGF-I actions by occupancy of the IGF-I receptor 1 , , , and this has been a proposed mechanism for insulin-mediated hyperandrogenism 8 — However, it has recently been shown that insulin has specific actions on steroidogenesis acting through its own receptor Moreover, these actions appear to be preserved in insulin-resistant states , , presumably because of differences in receptor sensitivity to this insulin action or because of differential regulation of the receptor in this tissue.
Our studies in cultured skin fibroblasts suggest that a mechanism for this may be selective defects in insulin action. Both insulin- and IGF-I-stimulated glycogen synthesis are significantly decreased in PCOS fibroblasts whereas thymidine incorporation is similar to control fibroblasts Fig.
Thus only the signaling pathways regulating carbohydrate metabolism may be impaired in PCOS, while those involved in steroidogenesis are preserved. This would explain the paradox of persistent insulin-stimulated androgen production in insulin-resistant PCOS women.
Insulin decreases hepatic IGFBP-1 production, the major circulating IGF-I-binding protein Thus, bioavailable IGF-I levels are increased in insulin-resistant PCOS women, and this may contribute to the ovarian steroidogenic abnormalities via activation of the IGF-I receptor In lean PCOS women, increases in GH release may also affect ovarian steroidogenesis There were no significant differences in thymidine incorporation in the PCOS fibroblasts right panel.
The dose-response curves for IGF-I were similar to those for insulin data not shown. Dunaif It has been more difficult to demonstrate insulin actions on steroidogenesis in humans in vivo because it is not feasible to administer insulin to nondiabetics for prolonged periods 1 , — However, these increases are minor and are not in the range seen in women with hyperandrogenism.
Furthermore, such transient meal-related increases in insulin do not result in increased androgen levels, whereas the more sustained increases produced by continuous insulin infusion can slightly increase androgen levels Studies in which insulin levels have been lowered for prolonged periods have been much more informative.
This has been accomplished for 7 days to 3 months with agents that either decrease insulin secretion, diazoxide or somatostatin , or that improve insulin sensitivity, metformin or troglitazone Circulating androgen levels have decreased significantly in women with PCOS in these studies.
Sex hormone binding globulin SHBG levels have increased , , compatible with a major role for insulin in regulating hepatic production of this protein , Abnormalities in apparent 17,lyase activity have improved in parallel with reduced circulating insulin levels consistent with insulin-mediated stimulation of this enzyme However, estrogen levels also decreased significantly, suggesting that insulin has diffuse effects on steroidogenesis Changes in estrogen levels were seen only when insulin levels were lowered with troglitazone and thus, alternatively, these changes might be the result of troglitazone-mediated increases in sex steroid metabolism, a recently reported action of this agent Rezulin Package Insert, Parke-Davis, Morris Plains, NJ.
It is also possible that troglitazone has direct effects on steroidogenesis. Indeed, the thiazolidinediones have been shown to have such effects on granulosa cell steroidogenesis Most of the reported actions of insulin on steroidogenesis are observed only in women with PCOS , and are greatly enhanced by the addition of gonadotropins when measured in in vitro experiments 1 , 20 , , , In the one study in normal women in which insulin levels were lowered by diazoxide administration, no significant changes in androgen levels were noted These observations suggest that, if insulin is to produce ovarian hyperandrogenism in women, polycystic ovarian changes e.
In normal women insulin does not appear to have any acute effects on ovarian function under physiological circumstances , , Although insulin has been shown to stimulate gonadotropin release in isolated rat pituitary cells , human studies of insulin action on gonadotropin release have yielded conflicting results.
Acute insulin infusion has not changed pulsatile LH or FSH release or gonadotrope sensitivity to GnRH in normal or in PCOS women, despite direct effects on gonadal steroidogenesis in PCOS women Long-term suppression of insulin levels with diazoxide, which resulted in decreases in circulating testosterone levels, did not alter circulating LH levels In contrast, decreases in LH levels were observed after 7 days of somatostatin-mediated insulin lowering , after metformin for 8 weeks , or after troglitazone for 3 months It is possible that insulin-mediated changes in gonadotropin release contribute to the changes of steroidogenesis produced by insulin in humans Fig.
Studies in which insulin levels have been lowered with the insulin-sensitizing agent, troglitazone, suggest that insulin is a general augmentor of steroidogenesis and LH release. Acute insulin infusions decrease DHEAS levels in men and women, suggesting that insulin is a negative modulator of adrenal androgen metabolism When insulin levels are chronically lowered, however, circulating DHEA and DHEAS levels rise in men but not in women, suggesting that this regulation of adrenal androgen metabolism is sexually dimorphic Lowering insulin levels with insulin-sensitizing agents, such as troglitazone, has resulted in decreases in DHEAS levels in PCOS women Fig.
The mechanism of this appears to be a direct action of insulin to increase adrenal sensitivity to ACTH in hyperandrogenic women Insulin can directly decrease hepatic SHBG production , explaining the frequently observed inverse correlation between peripheral insulin and SHBG levels Indeed, insulin rather than sex steroids appears to be the major regulator of SHBG production In summary, studies in which insulin levels have been lowered by a variety of modalities indicate that hyperinsulinemia augments androgen production in PCOS Fig.
Moreover, this action appears to be directly mediated by insulin acting through its cognate receptor rather than by spillover occupancy of the IGF-I receptor. Intrinsic abnormalities in steroidogenesis appear to be necessary for this insulin action to be manifested since lowering insulin levels does not affect circulating androgen levels in normal women.
Further, in many PCOS women, lowering insulin levels ameliorates but does not abolish hyperandrogenism. Family studies of PCOS.
Familial aggregation of PCOS suggesting a genetic etiology has been clearly established 1 , — Cooper et al. The proposed mechanism of inheritance was autosomal dominant with decreased penetrance. Givens and colleagues have reported multiple kindreds showing affected women in several generations and have examined some males in considerable detail 1 , Diagnostic criteria for PCOS were hirsutism and enlarged ovaries.
There was a high frequency of metabolic disorders, such as NIDDM and hyperlipidemia, in both male and female pedigree members. This would suggest inheritance in either an autosomal or X-linked dominant manner. Ferriman and Purdie studied women; affected status was assigned on the basis of hirsutism and enlarged ovaries assessed by gynecography.
The frequency of various abnormalities in relatives was determined by history provided by the proband; no relatives were examined. Oligomenorrhea and infertility were most common in women who had both hirsutism and enlarged ovaries. Forty-six percent of female relatives were reported to be similarly affected.
There was an increased incidence of baldness reported in male relatives. Similar results were found in a study of Norwegian PCOS probands identified by ovarian wedge resection Information on pedigree members was obtained by questionnaire.
Female first-degree relatives had a significantly increased frequency of PCOS symptoms i. There have been case reports of polyploidies and X-chromosome aneuploidies in PCOS , Larger studies, however, have found normal karyotypes Studies from the United Kingdom have phenotyped women on the basis of polycystic ovarian morphology detected by ultrasound The proportion of females affected in all sibships was However, not all women in each kindred were examined and, thus, an accurate ratio of affected to unaffected women could not be established for segregation analysis.
Further, the male phenotype was not sought. A more recent study prospectively examined the families of probands consecutively identified on the basis of polycystic ovarian morphology on ultrasound The first-degree relatives in 10 families were evaluated by history, measurement of physical indices, and hirsutism as well as serum levels of androgens, hydroxyprogesterone, gonadotropins, and PRL.
Transabdominal ultrasound was performed in female first-degree relatives. Glucose and insulin levels were assessed in obese but not lean probands. Twenty-two males were screened; eight had premature before age 30 yr fronto-parietal hair loss, 10 did not, and four were too young to assess.
Female affected status was assigned on the basis of ultrasound evidence of polycystic ovaries. If male affected status was considered to be premature balding, and a history of menstrual irregularity was used to assign postmenopausal affected status, the segregation ratio for affected families, excluding the proband, was Studies in monozygotic twins, however, have not found complete concordance of polycystic ovary morphology, arguing against this mode of inheritance The study contained only 19 pairs of monozygotic twins as well as a sample of 15 dizygotic twins.
This raises concern about the accuracy of the detection of polycystic ovaries. In several studies, PCOS affected status has been assigned on the basis of ovarian morphology rather than hormonal abnormalities. Only one study has proposed a male phenotype on the basis of examination of male relatives, and this study was constrained by a small sample size Nevertheless, these studies strongly suggest that PCOS has a genetic component, most likely with an autosomal dominant mode of transmission , If this is true, are there other phenotypes in affected kindreds?
The studies cited above have suggested that premature male balding may be a male phenotype , This finding could be an artifact, since it is also possible that bald men choose to marry hirsute women.
Recent studies in these families, however, suggesting linkage of this phenotype with a candidate gene in the steroidogenic enzyme pathway Ref. Our studies have suggested that insulin resistance may be an additional male phenotype as well as a prepubertal and postmenopausal female phenotype , Table 4.
This has been also reported recently in a series of Australian PCOS kindreds. In the small number of families that we have studied , , when women of reproductive age are insulin resistant, they usually have possessed the other endocrine features of PCOS.
The one insulin-resistant prepubertal girl was also hyperandrogenic and developed chronic anovulation after menarche consistent with the diagnosis of PCOS That insulin resistance and hyperandrogenism may be a prepubertal phenotype is supported by recent studies suggesting that PCOS develops in insulin-resistant girls with premature adrenarche 58 , , Table 4.
Our studies suggest that hyperandrogenism without insulin resistance is another phenotype in female PCOS kindred members of reproductive age Table 4. Finally, we have found postmenopausal hyperandrogenic female family members with normal insulin sensitivity, which may represent an additional postmenopausal phenotype Table 4.
This possibility is supported by the study of Dahlgren and colleagues 53 , which found that postmenopausal women with a history of PCOS had higher androgen levels than age-matched control women. We have found that hyperandrogenism and insulin resistance can segregate independently in PCOS kindreds It is not yet possible to determine whether this reflects separate genetic traits or variable penetrance of a single defect.
These studies also indicate that there is considerable phenotypic variation, even within kindreds. Candidate genes for PCOS. The biochemical reproductive phenotype in PCOS is characterized by increased LH secretion and acyclic FSH release 2 , The ovaries in response to LH and, often, the adrenals secrete excessive androgens, and there is decreased ovarian aromatization of androgens to estrogens The circulating androgens feed back on the hypothalamic-pituitary axis directly or via their extragonadal aromatization to estrogen to increase LH relative to FSH release, producing a self-sustaining syndrome 34 — 37 , The defect that initiates these reproductive disturbances in PCOS is unknown, but it can be shown experimentally that factors that increase either androgen secretion or LH release can reproduce these disturbances 1 , 2 , 12 , 38 , Indeed, polycystic ovaries and hyperandrogenism were present in a girl with an aromatase gene mutation leading to an inactive enzyme Transgenic mice overexpressing the LH β-subunit gene in their gonadotropes develop polycystic ovary morphology, androgen elevations, and LH hypersecretion The insulin resistance in PCOS is secondary to a postbinding defect in insulin receptor signaling, as discussed above When this enzyme is identified, it will make an excellent candidate gene for insulin resistance in PCOS.
This enzyme may also be responsible for altering Pc17 activity that results in hyperandrogenism and the PCOS reproductive phenotype Polymorphisms in the Pc17 gene itself were found not to cosegregate with the polycystic ovary-premature balding phenotypes in the families reported by Carey et al.
However, the polymorphism did affect the promoter region of the gene, and the frequency of the polymorphism was significantly increased in PCOS, suggesting that it might play a role in modifying the phenotype Further candidate gene searches in these families suggest a linkage with the steroid synthesis gene CYP11a, and an association study indicated a significant increase in a CYP11a polymorphism in hirsute PCOS women The polymorphism was also significantly associated with elevated testosterone levels.
These investigators have recently reported that an insulin gene VNTR-regulatory polymorphism was significantly associated with PCO in the same families Case-control studies suggested that the polymorphism was associated with anovulation and higher insulin levels , women who would be considered to have the endocrine syndrome.
This observation suggests that there may be a genetic basis for the finding of insulin resistance only in anovulatory women with hyperandrogenism or the PCO morphology. This insulin gene VNTR has been associated with decreased levels of islet cell insulin RNA and may thus result in decreased insulin secretion.
The mechanism by which this might cause hyperinsulinemia and insulin resistance is unknown. Polymorphisms in the dopamine and androgen receptors have not been significantly associated with PCOS , , There have been no mutations in the coding portions of the insulin receptor gene detected in PCOS 69 , , Extreme caution must be exercised, however, in the interpretation of both linkage and association studies.
Case-control association studies can give false-positive results because of subtle genetic differences between the populations This appears to have occurred in the association studies of the polymorphism in the Pc17 gene promoter with PCO Subsequent larger studies by these investigators failed to confirm the finding a.
Linkage studies of many candidate genes in the same families must have the level of significance for positive results adjusted for multiple tests. Thus log of odds scores greater than the traditional threshold of 3 must be used to prove linkage Such log of odds scores have not been achieved in the reported studies in PCOS , Does insulin resistance produce PCOS in women with PCO?
The polycystic ovary morphology detected by ultrasonography has been reported to be inherited as an autosomal dominant, if premature balding is used as the male phenotype see above. We have found that Caribbean Hispanic women have twice the prevalence of PCOS compared with other ethnic groups Brothers, as well as sisters, of PCOS women can be insulin resistant , The insulin-resistant sisters usually also have PCOS All of these observations support the hypothesis that there is a genetic component to PCOS and the insulin resistance associated with it.
Caribbean Hispanic women are also significantly more insulin resistant than non-Hispanic White women by euglycemic clamp determination of insulin-mediated glucose disposal PCOS independently further decreases insulin action.
Non-Hispanic White PCOS women have similar degrees of insulin resistance to Caribbean Hispanic normal ovulatory women These findings suggest that the increased prevalence of PCOS in this ethnic group may be secondary to an increased prevalence of insulin resistance.
Hyperinsulinemia resulting from a spectrum of defects in insulin action, at least some of which are genetic, may play a permissive role in the development of PCOS in genetically susceptible women Fig. This hypothesis is supported by the finding of the full-blown polycystic ovary syndrome hyperandrogenism and anovulation primarily in women with polycystic ovaries who are also hyperinsulinemic , A proposed schema for the association of insulin resistance and PCOS.
A single factor that causes serine phosphorylation of the insulin receptor and serine phosphorylation of Pc17, the key regulatory enzyme controlling androgen biosynthesis, could produce both the insulin resistance and the hyperandrogenism characteristic of PCOS.
It is also possible that the insulin resistance and the reproductive abnormalities reflect separate genetic defects and that the insulin resistance unmasks the syndrome in genetically susceptible women. Recent studies suggest that insulin acting through its own receptor augments steroidogenesis and LH release.
Androgens amplify the associated insulin resistance. Could PCOS and insulin resistance result from a single defect? An exciting recent finding by Miller and colleagues is the observation that serine phosphorylation of human Pc17, the key regulatory enzyme of both ovarian and adrenal androgen biosynthesis, increases its 17,20 lyase activity.
This would result in increased androgen secretion A modulation of steroidogenic enzyme activity by serine phosphorylation has been reported for 17β-hydroxysteroid dehydrogenase If the same factor that serine-phosphorylates the insulin receptor causing insulin resistance also serine-phosphorylates Pc17 causing hyperandrogenism, this could explain the association of PCOS and insulin resistance by a single genetic defect Fig.
Making a diagnosis of insulin resistance in an individual is problematic. Second, clinically available measures of insulin action, such as fasting or glucose-stimulated insulin values , do not correlate well with more detailed measurements of insulin sensitivity in research settings In view of these constraints, it is prudent to consider all PCOS women at risk for insulin resistance and the associated metabolic abnormalities of the insulin resistance syndrome: dyslipidemia, coronary artery disease, and hypertension.
Lipid and lipoprotein levels should be obtained on all PCOS women, and obese PCOS women should also have fasting and 2-h post g glucose load glucose levels as a screen for glucose intolerance.
Individual values for fasting and 2-h post g oral glucose load insulin levels are shown in PCOS and in weight-matched control women.
Although the means differ significantly, there is substantial overlap such that an individual value in a PCOS woman may not fall outside the normal range.
Dyslipidemia, dysfibrinolysis, and coronary artery disease. Women with PCOS would be predicted to be at high risk for dyslipidemia because they have elevated androgen levels and are frequently obese — Moreover, since they are also often hyperinsulinemic and insulin resistant, they would also be expected to be at increased risk for the dyslipidemia associated with insulin resistance Insulin, rather than androgen, levels correlate best with lipid abnormalities, and suppressing androgen levels does not alter lipid profiles in PCOS PCOS women also have impaired fibrinolytic activity with increased circulating levels of plasminogen activator inhibitor, PAI-1 , Elevated PAI-1 levels are associated with insulin resistance and are considered to be an independent cardiovascular risk factor by increasing the risk of intravascular thrombosis In PCOS, increased PAI-1 levels are also associated with insulin resistance, and these levels decrease with improvements in insulin sensitivity mediated by weight loss or insulin-sensitizing agents There are several intriguing cross-sectional studies that suggest that PCOS women may indeed be at increased risk for cardiovascular disease.
Women coming to cardiac catheterization who have a history of symptoms of hyperandrogenism have an increased prevalence of coronary artery disease Postmenopausal women with a history of ovarian wedge resection for PCOS have a significantly increased frequency of cardiovascular events compared with age-matched control women Women with PCO detected by ovarian ultrasound have more extensive coronary artery disease by angiography than women with sonographically normal ovaries The women with PCO also have higher free testosterone, triglyceride, and C-peptide levels and lower LDL levels than the women with normal ovaries, suggesting that they have both the endocrine and the metabolic derangements of PCOS Finally, increased carotid wall thickness measured by ultrasonography was found in PCOS women compared with case-controls The carotid wall thickness was significantly positively correlated with fasting insulin levels and body mass index, after adjustment for possible confounding variables However, since the PCOS women were significantly heavier than the controls, it was not possible to determine the independent impact of obesity on these findings As with studies of insulin action, studies of lipid metabolism in PCOS have been confounded by differences in body weight and ethnicity between patient and control groups.
Inconsistencies in diagnostic criteria, in particular, basing the diagnosis on ultrasound morphology rather than hormonal parameters, have resulted in heterogenous patient populations that have included women with regular ovulation and normal insulin sensitivity — Some investigators have found that LDL and HDL changes in PCOS can be accounted for by obesity and that only modest increases in total triglyceride levels appear secondary to PCOS-related insulin resistance , , A recent case control study does suggest that there are lipid abnormalities in PCOS after statistical adjustments for obesity However, Legro and colleagues found atherogenic alterations in lipoprotein levels in normal Hispanic women that did not differ further in Hispanic PCOS women.
Thus, there appear to be important additional genetic and environmental factors influencing lipid metabolism in PCOS. It has been suggested that insulin resistance causes hypertension; thus PCOS women would be expected to be hypertensive Significant increases in systolic blood pressure, albeit within the normal range, have been reported in obese PCOS women, but this study did not include a weight-matched control group Moreover, lean PCOS women in the study were not hypertensive, consistent with an effect of obesity rather than PCOS on blood pressure.
Careful studies of h blood pressures and left ventricular mass have failed to find evidence for hypertension in PCOS women in their second to fourth decades of life This has been confirmed in another recent study The studies discussed above in postmenopausal PCOS women, however, have found a significant increase in prevalence of hypertension It may be that hypertension is not manifested until later in life in PCOS women.
Conversely, it remains possible that the association between insulin resistance and hypertension does not exist in PCOS, analogous to observations in African Americans and in Pima Indians Gestational diabetes mellitus GDM.
Women with a history of GDM are insulin resistant, at increased risk to develop NIDDM, and have defects in the β-cell function that can be detected in the absence of glucose tolerance , PCOS women share these traits, and it would be expected that they would be at increased risk to develop GDM, if GDM is yet another manifestation of insulin resistance.
Two small studies of this have yielded conflicting results: one study found no increase in GDM while another detected an increased risk for GDM in PCOS women , A large prospective study in PCOS women containing appropriately matched control women is required to address this issue.
Until such a study has been completed, it is prudent to advise PCOS women contemplating pregnancy that they may be at increased risk to develop GDM. Leptin in PCOS.
Leptin, the recently identified product of the ob gene , has been investigated in PCOS. Since leptin is a fat cell product that acts on the hypothalamus , it could link the metabolic and neuroendocrine derangements characteristic of PCOS.
Leptin production is regulated by insulin and could be modulated in insulin-resistant PCOS women via this mechanism An initial report suggested that leptin levels were elevated in some PCOS women However, in this study the confounding effects of differences in body weight were not adjusted for appropriately.
Subsequent studies in PCOS that have contained appropriately weight- or fat mass-matched control women have not found significant differences in leptin levels in PCOS women. Agents that exacerbate insulin resistance should probably be avoided in PCOS, particularly in women who are also obese.
Oral contraceptives are widely used in PCOS to control menstrual irregularities and hyperandrogenism. Norethindrone-only containing contraceptives do not cause insulin resistance in normal women and, thus, may provide an alternative agent for PCOS women. Specific studies should be performed, however, to verify this hypothesis.
Glucocorticoids can exacerbate insulin resistance and should be avoided in PCOS. Fortunately, there are several therapeutic agents for hyperandrogenism that do not worsen and may even improve insulin sensitivity in PCOS Fig. These are spironolactone, GnRH analogs, and flutamide , Although medroxyprogesterone acetate does decrease insulin sensitivity in normal women , intermittent progestin withdrawal with this agent in the minimally effective dose i.
Weight loss is well known to decrease androgen levels and restore ovulation in PCOS It now appears that a reduction in circulating insulin levels is the mechanism for weight loss-associated reproductive benefits , , since lowering insulin levels by other modalities has similar results , , Indeed, agents that lower insulin levels by improving insulin sensitivity may provide a new therapeutic modality for PCOS.
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 — In two studies in PCOS, both from Venezuela, metformin therapy resulted in significant decreases in insulin and androgen levels , In one study this was also associated with weight loss, whereas in the other it was not Weight loss accounted for metformin effects on sex hormone levels in the study of Crave et al.
Metformin has not altered androgen levels or insulin action in PCOS in other studies. In contrast, the thiazolidenedione troglitazone improves insulin sensitivity without altering body weight and lowers circulating androgen, estrogen, and LH levels in PCOS Fig.
Further studies are in progress to determine the role for troglitazone as a therapeutic agent for PCOS. It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS.
Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women Table 3. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, Pc It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women Fig.
Recent studies strongly suggest that insulin is acting through its own receptor rather than the IGF-I receptor in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release.
There is no cure for PCOS, only lifestyle modifications and medications to manage symptoms. But, the good news is that lifestyle changes that help with PCOS also help with insulin resistance. Exercise causes the insulin receptors on our muscle cells to take in sugars without requiring extra insulin production.
Over time, this process makes the insulin receptors more sensitive to lower levels of insulin. That means the body responds by producing less insulin to process sugar. Lower insulin levels then leads to reduced androgen production, which helps with PCOS.
Healthy eating habits are also vital for women who have PCOS and insulin resistance, especially for those with a high BMI. The goal is sustained weight loss over time — keyword, sustained. Yo-yo dieting that causes us to lose and gain weight is very disruptive for our health and hormones.
To put it another way, weight loss can help the insulin receptors work better and allow the pancreas to lower insulin production.
This will reduce your levels of both insulin resistance and PCOS. It has been shown to help lower insulin resistance.
Stress hormones encourage the liver to release stored sugars, leading to spikes in blood sugar and insulin. You should do this at least once a year, as well as with any weight gain or loss of 10 pounds or more.
By knowing your level of insulin resistance, you can see if it gets better over time with diet changes and exercise. You can also see how insulin resistance and PCOS are related for you as an individual. PCOS and insulin resistance can have devastating effects, from infertility to vision damage to blood clots in the arteries.
But PCOS and insulin resistance exist on a spectrum - you can have low levels of disease and high levels. Knowing where you stand is the first step to taking control of your health.
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Clue is on a mission to desistance you Insulin resistance and PCOS your PCOSS, periods, ovulation, and so much more. Start tracking today. Under normal conditions, the hormone insulin rises briefly after eating. It stimulates the liver and muscles to take up sugar from the blood and convert it to energy. That then causes blood sugar to fall, and then insulin to fall.Insulin resistance and PCOS -
In these women, weight loss and blood sugar lowering medications or supplements will have no effect on their symptoms or their fertility. For women with PCOS type II, the cause of their symptoms tend to be a bit more complicated. For instance, disorders of the thyroid or adrenal gland may be to blame as well as nutrient deficiencies such as iodine, vitamin D and zinc.
In some women, environmental hormone disrupting toxins such as BPA, phthalates, and dioxins may be at the root cause of their symptoms. This results in a type of PCOS which is sometimes dubbed Inflammatory PCOS. These women often have other signs of inflammation such as headaches, acne, joint pain, autoimmune disease, or elevated CRP levels on blood testing.
If you have been diagnosed with PCOS, there are several important tests that I recommend to help determine an effective treatment strategy in your particular case. Your naturopath has access to in-depth thyroid and adrenal tests, testing for nutrient deficiencies, as well as environmental toxins levels.
These tests are crucial for the correct implementation of a treatment plan that is specific to your needs. Nicole Hartman is a naturopathic physician, a world traveler, a hiker, and a blogger.
She focuses her practice in digestion, women's health and weight loss and takes an integrative, evidence-based approach to healthcare. Get news, articles, and advice on fertility, women's health, and other areas of personal wellness delivered right to your inbox.
Nectar Naturopathic Clinic Enterprise Way Kelowna, BC V1Y 9S9. Click here to book an appointment. Close Search. The Five Faces of PCOS By Dr.
Nicole Hartman July 21, September 10th, Conditions , Fertility , Women's Health. No Comments. As a recap, a woman may be diagnosed with PCOS if two of the three following criteria are met:.
Oligo- or anovulation. This is characterized by a lack of ovulation, irregular menstrual cycles or an absence of a menstrual cycle.
Accurate screening for insulin resistance in PCOS women using fasting insulin concentrations. Gynecol Endocrinol. Amisi CA. Markers of Insulin Resistance in Polycystic Ovary Syndrome Women: An Update.
WorldJ Diabetes. Colberg SR, Sigal RJ, Fernhall B, et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement.
Diabetes Care. Bicer M,Alan M,Alarslan P,et al. Circulatinginsulin-like peptide 5 levels and its association with metabolic and hormonal parameters in women with polycystic ovary syndrome. J Endocrinol Invest.
doi: Mu L,Zhao YLai Y,Li R,Qiao J. Insulin resistanceand β-cell dysfunction and the relationship with cardio-metabolic disorders among women with polycystic ovary syndrome.
Clin Endocrinol Oxf. By Nicole Galan, RN Nicole Galan, RN, is a registered nurse and the author of "The Everything Fertility Book. Use limited data to select advertising. Create profiles for personalised advertising. Use profiles to select personalised advertising. Create profiles to personalise content.
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Living With. By Nicole Galan, RN. Medically reviewed by Renita White, MD. Table of Contents View All. Table of Contents. Consistently high levels of glucose in the blood can lead to pre-diabetes, and then to diabetes.
Insulin Resistance vs. Diabetes: Explaining the Differences. Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
If the above symptoms are familiar to you, schedule an appointment with your healthcare provider and request blood tests to determine how effectively your body is dealing with sugar. Bear in mind that testing for glucose levels often requires patients to fast beforehand, so be sure to check on the details with your doctor.
The first signs of Polycystic Ovary Syndrome PCOS typically include irregular or infrequent menstrual cycles and signs of high androgen levels , such as excess facial and body hair, severe acne, and male-pattern baldness. Additionally, many women with PCOS experience weight gain and may have difficulty conceiving.
Being diagnosed with insulin resistance or PCOS does not necessarily mean you will develop diabetes. Making healthy lifestyle changes and incorporating natural remedies can reduce insulin resistance symptoms to a manageable rate and prevent the necessity of medical treatment.
Reducing sugar intake, and replacing processed foods with whole grains, vegetables, and low-fat dairy products will help to lower blood sugar levels and decrease insulin resistance over time.
Regular exercise will help you to lose weight gained due to the slowed metabolism associated with the condition, as well as increase your energy levels and improve sleep. Concerning women with PCOS, researchers have found that a combination of Myo and D-Chiro Inositol in supplement form can promote hormonal balance and positively influence the use of insulin.
Inositol is a type of sugar naturally made in the body to balance moods, fertility, cholesterol, blood sugar, and metabolism. The added ashwagandha and vitamin D in the Myo and D Chiro Inositol Supplement from Intimate Rose also regulate brain hormones like serotonin and dopamine to relieve stress and feelings of depression associated with PCOS.
In addition, due to its effects on blood sugar and metabolism, the Myo and D Chiro Inositol supplement helps to reduce acne, hair loss, and weight gain. Medical treatment options for insulin resistance include mild doses of diabetes medication to lower blood sugar levels. If you have PCOS, health experts highly recommend scheduling an appointment with your doctor at your earliest convenience to get tested for insulin resistance.
Take control Insuln your health with FREE shipping resisrance our Insulin resistance and PCOS tests. Many people Insulin resistance and PCOS that insulin resistance Ibsulin also known as prediabetes and type Energy supplements for sustained energy diabetes — is anr to resisatnce and heart disease. Few realize that insulin resistance is also associated with a less-discussed health problem. By understanding the relationship between PCOS and insulin resistance, you can prevent the damage caused by both conditions. Women with PCOS produce higher-than-normal levels of male hormones, called androgens. The increase of androgens may cause some, or all, of the following symptoms:. PCOS is usually diagnosed based on blood tests that measure hormone levels. Journal of Ovarian Research volume 16Article number: 9 Cite this article. Metrics Organic ginseng. PCOS involves Acai berry brain health pathophysiological reskstance, and affected women usually have significant insulin Sweet potato gnocchi IR fesistance, which Sweet potato gnocchi Insulim major cause of PCOS. IR and compensatory hyperinsulinaemia have differing pathogeneses in various tissues, and IR varies among different PCOS phenotypes. Genetic and epigenetic changes, hyperandrogenaemia, and obesity aggravate IR. Insulin sensitization drugs are a new treatment modality for PCOS. We searched PubMed, Google Scholar, Elsevier, and UpToDate databases in this review, and focused on the pathogenesis of IR in women with PCOS and the pathophysiology of IR in various tissues.
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