Home Current Issue Previous Issues Collections Podcasts Blogs CME For Authors Journal Info
Skip Navigation LinksHome > September 2005 - Volume 98 - Issue 9 > Insulin Resistance in Polycystic Ovarian Disease
Southern Medical Journal:
doi: 10.1097/01.smj.0000177251.15366.85
CME Topic

Insulin Resistance in Polycystic Ovarian Disease

Bhatia, Vishal MBBS, MD

Free Access
Continued Medical Education
Article Outline
Collapse Box

Author Information

From the Department of Internal Medicine, Mercy Hospital of Buffalo, State University of New York, Buffalo, New York.

Dr. Bhatia has no disclosures to declare.

Reprint requests to Dr. Vishal Bhatia, Department of Internal Medicine, Mercy Hospital of Buffalo, State University of New York, 565, Abbott Road, Buffalo, NY 14220. Email: vbhatia@buffalo.edu

Accepted May 9, 2005.

Collapse Box

Abstract

The classic polycystic ovarian syndrome (PCOS) was originally described by Stein and Leventhal as the association of amenorrhea with polycystic ovaries and, variably, hirsutism and/or obesity. It is estimated that 5 to 10% of women of reproductive age have PCOS. Although insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance, independent of total or fat-free body mass. Postreceptor defects in the action of insulin have been described in PCOS that are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin, and thiazolidinediones (TZDs) improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that women who have PCOS have higher circulating levels of inflammatory mediators such as C-reactive protein, tumor necrosis factor, tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1). It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

Key Points

* Polycystic ovarian syndrome involves anovulation and hyperandrogenism.

* Polycystic ovarian syndrome is associated with insulin resistance.

* Insulin sensitizers are promising agents for polycystic ovarian syndrome.

* Insulin sensitizers have not been approved by the Food and Drug Administration for polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is characterized by chronic anovulation and hyperandrogenism (hyperandrogenism can exist in the absence of hyperandrogenemia, eg, enhanced tissue sensitivity to androgens) in premenopausal women. According to revised guidelines of the PCOS Consensus Workshop Group,1 two of the following three manifestations must be present for a diagnosis of PCOS: (1) irregular or absent ovulation, (2) elevated levels of androgenic hormones, and/or (3) enlarged ovaries containing at least 12 follicles each.1 Polycystic ovaries are defined as those found on ultrasound to contain 12 or more follicles measuring 2 to 9 mm in diameter and/or have an increased volume of 10 mL or greater. The presence of one ovary fulfilling these criteria is enough to meet the definition of polycystic ovaries. Other hyperandrogenic disorders such as nonclassic congenital adrenal hyperplasia and androgen-secreting tumors must be excluded before a diagnosis of PCOS can be made. It should be stressed that polycystic ovaries are not a necessary feature of PCOS and that many women with polycystic ovaries do not have PCOS. Women found to have polycystic ovaries on an incidental ultrasound should not be diagnosed with PCOS unless there is corroborating clinical evidence of the syndrome. Androgen excess may present with or without skin manifestations. It is estimated that 5 to 10% of women of reproductive age have PCOS.2 Around 50% of women with PCOS are obese and tend to have an android pattern of obesity.3 Chronic anovulation may present as irregular menstrual periods or amenorrhea. It is not necessary to document anovulation by ultrasonography or progesterone measurements in the presence of a clear clinical history. In fact, PCOS occurs in 85 to 90% of women with oligomenorrhea and in 30 to 40% of women with amenorrhea.4 Anovulation in PCOS is associated with steady levels of gonadotropins and ovarian steroids. Women with PCOS are thus in a “chronic estrous state.” Constant estrogen exposure leads to proliferation and hyperplasia of the endometrium, which can lead to unpredictable bleeding episodes. Unopposed estrogen exposure can be confirmed by a progesterone withdrawal test (medroxyprogesterone acetate 10 mg/d for 10 days), done after a negative urine pregnancy test.

Back to Top | Article Outline

Gonadotropins, androgens, and ovarian steroids in PCOS

Women with PCOS have higher mean concentrations of luteinizing hormone (LH), increased bioactivity of LH, and low to low-normal levels of follicle-stimulating hormone (FSH).5,6 The precise mechanism(s) responsible for enhanced LH secretion in PCOS are not completely understood, although past studies have demonstrated the potential influence of hypothalamic GnRH activity and ovarian steroid feedback.7–10 Insulin has also been implicated as a potential regulator of LH secretion in PCOS. In vitro studies have shown that cultured rat anterior pituitary cells exposed to insulin exhibited increased basal and GnRH-stimulated LH and FSH release in a dose-dependent manner.11–13 By comparison, in vivo studies involving indirect manipulation of serum insulin levels through administration of insulin-lowering drugs or dietary caloric restriction have not yielded consistent results as to the effect of insulin on gonadotropin secretion.14–18 It was observed recently by Mehta et al19 that increased LH secretion in women with PCOS as well as in women without PCOS was unaltered by prolonged insulin infusion. Pulsatile LH release and gonadotropin responses to multidose GnRH were similar before and during a 12-hour hyperinsulinemic, euglycemic clamp. It was thought that lack of insulin effect may have been the result of insulin resistance, which is a common feature of PCOS.20,21 Later, it was demonstrated that even after improvement of insulin sensitivity with pioglitazone treatment, there was no difference in baseline LH values, LH pulsatility, or maximally stimulated percent LH increment after GnRH with or without insulin infusion in women with PCOS.22 Previously, it was believed that an LH/FSH ratio of greater than 2 was part of the diagnostic criteria of PCOS. Obese women with PCOS, however, do not have elevated LH levels; therefore a normal LH level or normal LH/FSH ratio does not rule out PCOS. In fact, the LH/FSH ratio is no longer included in the diagnostic criteria for PCOS.23 Under the influence of low but constant levels of FSH, multiple follicles of the ovary are stimulated but do not achieve maturation. The lifespan of the follicles may extend over several months, leading to multiple follicular cysts. Luteinized in response to constant and relatively high LH levels, these “arrested” follicles provide a constant supply of steroids. The atretic follicle becomes an androgenic follicle by default because atretic follicles are deficient in aromatase activity. Cultured follicular cells from the small follicles of polycystic ovaries produce small amounts of estradiol but show a dramatic increase in estrogen production when stimulated by FSH or insulin-like growth factor (IGF)-1.24 FSH therapy induces a larger cohort of follicles to develop in women with PCOS when compared with other infertile women.25,26 A deficient in vivo ovarian response to FSH, possibly due to impaired interaction between signaling pathways associated with FSH and IGF-1, may be a key event in the pathogenesis of anovulation in PCOS. Hyperandrogenism is usually suggested by the presence of hirsutism (approximately 80% of women with PCOS) and can be documented by measuring androgen levels in the blood. Free testosterone is the most frequently elevated steroid in the blood in PCOS. Circulating levels of total testosterone, androstenedione, and dehydroepiandrosterone (DHEA) are also elevated. In obese women with PCOS, sex hormone binding globulin (SHBG) levels are decreased (a well-known effect of obesity), which leads to an increase in free testosterone levels. Furthermore, insulin is a negative regulator of SHBG production by the liver,27 and SHBG levels are decreased in hyperinsulinemic conditions such as metabolic syndrome and visceral obesity.28,29 Interestingly, concentrations of sulfated DHEA (DHEAS) are also increased in the blood. DHEAS is secreted exclusively by the adrenal glands. The mechanism of increased DHEAS production by the adrenals is not yet known, although insulin and IGF-1 have been shown to upregulate adrenal 17-hydroxylase and 17,20-lyase activity.30

Back to Top | Article Outline
PCOS, inflammation, and cardiovascular disease

Insulin resistance has been associated with an increased incidence of cardiovascular disease, and atherosclerosis is now considered to be an inflammatory disorder.31,32 Insulin resistance has recently been associated with increased levels of inflammatory mediators in the blood.33,34 Studies have therefore been conducted to look at inflammation in PCOS. Gonzalez et al35 noted increased levels of tumor necrosis factor (TNF)-α (the cytokine that causes insulin resistance and is secreted by the adipose tissue) in women with PCOS as compared with control subjects. Interestingly, lean women with PCOS had higher TNF-α levels than normal lean women, whereas the levels were similar in obese women with PCOS and obese control subjects. Kelly et al36,37 noted increased C-reactive protein levels and tissue plasminogen activator (t-PA) levels in women with PCOS as compared with healthy weight-matched control subjects. However, when adjusted for insulin sensitivity, C-reactive protein was no longer significantly different between groups, but t-PA levels remained significantly different. Women with PCOS also have higher PAI-1 activity and higher fibrinogen levels than control subjects.38 However, in another study, PAI-1 levels were not significantly different from control subjects when adjusted for body mass index (BMI).39 Glueck et al40 demonstrated that PAI-1 activity was an independent risk factor for miscarriages in PCOS. Although the above studies suggest that PCOS is associated with a state of increased inflammation, clinical studies have yet to definitively demonstrate an increased rate of cardiovascular disease in PCOS.41 Thiazolidinediones have been shown to decrease inflammation in obese and diabetic subjects.42–44 Thiazolidinediones (TZDs) have also been shown to reduce carotid intimal medial thickness, normalize vascular endothelial function, and improve fibrinolytic and coagulation parameters.45 Rosiglitazone therapy for 26 weeks reduced MMP-9 (a matrix metalloproteinase, implicated in atherosclerotic plaque rupture) and C-reactive protein levels in type 2 diabetics.46 In studies in PCOS women, troglitazone reduced PAI-1 levels47 and improved endothelium-dependent vasodilation.48 It is possible that the beneficial effect of TZDs in PCOS may be partly due to the decrease in inflammation. Metformin has also been shown to decrease PAI-1 and C-reactive protein levels in women with PCOS.49,50

Back to Top | Article Outline
Insulin resistance and PCOS

The association between hyperinsulinemia and PCOS was first noted by Burghen et al51 in 1980, when they discovered a significant positive correlation between insulin, androstenedione and testosterone levels among women with PCOS. Subsequent studies confirmed insulin resistance as the cause of hyperinsulinemia. It is estimated that 20 to 40% of women with PCOS have impaired glucose tolerance, a number approximately 7-fold higher than the rates in age and weight-matched women.21,52 Prevalence of type 2 diabetes mellitus is also increased in women with PCOS (15 vs 2.3% in women without PCOS).53 Lean women with PCOS have lower rates of carbohydrate intolerance than obese women with PCOS, but even lean women with PCOS have higher rates than age and weight-matched control subjects. Thus, PCOS is associated with insulin resistance independent of total or fat-free body mass. Obese women with PCOS are more insulin-resistant than obese non-PCOS or nonobese women with PCOS.21,54 Ehrmann et al55 demonstrated pancreatic beta cell secretory dysfunction in a subset of women with PCOS, and this subset probably has the highest risk of developing carbohydrate intolerance and type 2 diabetes.56 The Rotterdam consensus panel recommends oral glucose tolerance tests for obese patients with PCOS.1 Conversely, in a small study, Peppard et al57 found PCOS in 8 of 30 premenopausal women with type 2 diabetes. Insulin resistance is characterized by postreceptor defect in the action of insulin. The cause of this defect is still being elucidated. The first step in insulin action involves binding to the cell-surface receptor.58 Abnormalities in both insulin receptor tyrosine kinase (IRTK) activity and in mediators distal to the receptor are present in insulin resistance states.59 Serine phosphorylation of insulin receptor decreases IRTK activity.60,61 Studies in adipocytes from women with PCOS reveal adipocyte insensitivity to inhibition of lipolysis by insulin as well as a decrease in maximal rates of adipocyte glucose uptake.62,63 Although these defects are also present in obesity and type 2 diabetes, they can occur in PCOS in the absence of obesity. Dunaif et al64 reported decreased insulin receptor autophosphorylation in 50% of fibroblasts removed from women with PCOS, and this was due to increased receptor serine phosphorylation. Serine phosphorylation, as noted above, has been associated with decreased insulin receptor tyrosine autophosphorylation. In fact, this is the probable mechanism of TNF-α–induced insulin resistance.65 Since serine phosphorylation of P450c17 (the key regulatory enzyme of androgen biosynthesis) increases enzyme activity leading to androgen biosynthesis,66 it is possible that a single defect (serine phosphorylation) can produce both insulin resistance and hyperandrogenism in a subgroup of PCOS patients.67 Lin et al68 showed that reduced insulin stimulated lactate production in granulosa-lutein cells obtained from women with PCOS, whereas the same cells obtained from normal ovulatory subjects responded with increased lactate production after insulin exposure. In vitro human theca cell studies have shown that insulin has direct stimulatory effects on ovarian steroidogenesis.69–71 Nestler et al69 showed that insulin produced a greater increase in androgen production by theca cells isolated from women with PCOS than in cells obtained from subjects without PCOS and that this effect is mediated specifically through insulin receptors rather than through IGF (insulin-like growth factor) receptors “cross-talk.” There are some data to suggest that insulin enhances the effect of LH on preovulatory ovarian follicles, causing premature activation and subsequent follicle arrest.72 It is possible that hyperinsulinemia (due to insulin resistance) drives the LH effect on ovarian theca cells to cause androgen excesses, which are intrinsically programmed to produce more androgen.73 Excess androgens are known to interfere with the process of follicular maturation,74 thus inhibiting ovulation and producing more arrested follicles. It has been postulated that the PCOS ovaries are more resistant to the metabolic effects of insulin than to the steroidogenic effects of insulin.2 Further studies are needed to clarify the “selective insulin resistance” phenomenon.

Back to Top | Article Outline
Pharmacotherapy for PCOS
Spironolactone in PCOS.

Spironolactone, an antiandrogen, has been in use for the treatment of hyperandrogenism for nearly two decades. Its main benefit stems from blocking androgen receptors with a minor contribution from a decrease in androgen synthesis. Although experience with the drug in PCOS is limited, it has a good safety record at doses of 50 to 100 mg, both on a short- and a long-term basis.75–79 Ammini et al80 did a randomized, open-labeled study comparing the efficacy and safety of metformin (1,000 mg daily) and spironolactone (50 mg daily) in 69 subjects with PCOS. There was no significant effect on BMI, waist-to-hip ratio, blood pressure, oral glucose tolerance test parameters, and insulin sensitivity, although a significant fall was observed in 1- and 2-hour insulin levels. Both drugs showed significant improvement in menstrual cycle pattern, hirsutism score, and androgen levels, suggesting their efficacy in the treatment of PCOS. Spironolactone appears to be a better choice than metformin in view of better efficacy on hair growth and patient acceptance; however, metformin was superior in improving glucose tolerance and insulin sensitivity. Superior positive effects of metformin on insulin sensitivity, however, did not translate into proportionate clinical benefit in these PCOS subjects. This raises doubts about insulin resistance as the sole underlying factor.

Back to Top | Article Outline
Metformin in PCOS.

Metformin is a biguanide that reduces plasma glucose concentrations in patients with type 2 diabetes. Metformin in type 2 diabetics does not lead to weight gain and can induce weight loss in some patients. Metformin predominantly works by reducing hepatic glucose production and inhibiting gluconeogenesis both directly and indirectly (by decreasing free fatty acid concentrations).81,82 There are some data to suggest that it may slightly improve peripheral insulin sensitivity.83,84 Studies with metformin in PCOS revealed reductions in androgen levels and improvements in ovulation when metformin was given for a duration of 10 to 24 weeks (in various studies). However, only some of these studies revealed an effect independent of the weight loss induced by metformin.85–88 Metformin has also been found to reduce the high rates of gestational diabetes in PCOS.89

Back to Top | Article Outline
Thiazolidinediones.

The peroxisome-proliferator–activated receptors (PPARs) are a subfamily of the 48-member nuclear receptor superfamily90 and regulate gene expression in response to ligand binding.91,92 Three PPARs, designated PPAR-α, PPAR-δ, (also known as PPAR-β), and PPAR-γ, have been identified to date. PPAR-α is expressed predominantly in the liver, heart, and muscle and in the vascular wall. Fibrates such as fenofibrate, bezafibrate, ciprofibrate, and gemfibrozil act as full or partial PPAR-α agonists. In general, PPAR activation enhances free fatty acid oxidation, controls expression of multiple genes regulating lipoprotein concentrations, and has anti-inflammatory effects. PPAR-α agonists prevent or retard atherosclerosis in mice and human beings.93–95 PPAR-δ is expressed in many tissues, with the highest expression in the skin, brain, and adipose tissue. PPAR-γ is expressed most abundantly in adipose tissue but is also found in pancreatic β-cells, vascular endothelium, and macrophages.96,97 In January 1997, the first thiazolidinedione, troglitazone, was approved as a glucose-lowering therapy for patients in the United States with type 2 diabetes. Troglitazone was subsequently withdrawn from the market in March 2000 because of hepatotoxicity. The two currently available PPAR agonists, rosiglitazone and pioglitazone, were approved in the United States in 1999. Thiazolidinediones consistently lower fasting and postprandial glucose concentrations as well as free fatty acid concentrations in clinical studies.98–100 Insulin concentrations also decrease in most studies.98–100 Such changes indicate that thiazolidinediones act as insulin sensitizers, which has been confirmed by direct measurements in in vivo studies in human beings. For example, treatment of nondiabetic subjects or those with type 2 diabetes for 3 to 6 months with troglitazone, rosiglitazone, or pioglitazone increases insulin-stimulated glucose uptake in peripheral tissues.98,100–103 In similar studies, thiazolidinediones increase hepatic insulin sensitivity (the ability of insulin to suppress endogenous glucose production) and insulin sensitivity in adipose tissue (measured from the ability of insulin to suppress free fatty acid concentrations).100 Studies with TZD in subjects with PCOS have shown an improvement of the androgen levels and ovulation rate and enhanced insulin sensitivity without any reduction in the weight of subjects.16,17,47 Studies have now been done with rosiglitazone showing a decrease in testosterone, androstenedione, and DHEA levels and an increase in SHBG (thereby causing a decrease in free testosterone levels), along with an improvement in insulin sensitivity.104,105 Troglitazone has recently been shown to have independent effects on ovarian steroidogenesis106 and thus a direct effect of TZD apart from improvement of insulin resistance cannot be ruled out. In a recent study done by Ortega-Gonzalez et al107 involving head-to-head comparison of pioglitazone, 52 women with PCOS were randomly allocated to receive either pioglitazone (30 mg a day, n = 25) or metformin (850 mg 3 times daily, n = 27) and were assessed before and after 6 months. This study showed that a 6-month administration of pioglitazone in obese women with PCOS and severe insulin resistance was as effective as metformin in decreasing fasting blood serum insulin concentration and the insulin levels during a 2-hour oral glucose tolerance test without significantly changing fasting blood glucose concentration. Similarly, pioglitazone and metformin caused significant decreases in hirsutism and serum concentrations of free testosterone and androstenedione. This study selected only markedly obese women with PCOS with acanthosis nigricans and the most advanced degree of insulin resistance; hence results may not apply strictly to all women with PCOS. However, pioglitazone seemed to be more effective in improving insulin sensitivity, because fasting serum insulin concentrations were significantly lower after pioglitazone than after metformin treatment. These favorable effects of pioglitazone occurred despite a significant increase in body weight, BMI, and the waist-to-hip ratio associated with the use of pioglitazone but not with metformin. These paradoxical results can be explained by the beneficial shift from abdominal to subcutaneous fat simultaneous with the improvement in insulin sensitivity induced by TZD.108–110 The same group of investigators recently reported an increase in metoclopramide-stimulated prolactin release in obese women with PCOS after pioglitazone administration for 24 weeks.111 Therefore, it was suggested that long-term pioglitazone administration may lead to increased hypothalamic dopaminergic tone, and this can be the mechanism of amelioration of insulin resistance in obese insulin-resistant patients. Rosiglitazone therapy has also been shown to improve ovulation rates in PCOS with clomiphene citrate therapy.112 Pioglitazone may improve hyperandrogenism through a mechanism similar to troglitazone. The putative ligand-mediated activation of PPAR-γ2 by troglitazone impairs androgen and stimulates progesterone biosynthesis in primary cultures of porcine theca cells113 by blocking the expression of the cytochrome P450-17-α hydroxylase/C17–20 lyase gene and CYP protein phosphorylation, which decreases the LH insulin-driven theca cell androgen production.114

Back to Top | Article Outline

Conclusion

Although insulin resistance is not a part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. The treatment of PCOS in the past has largely centered on antiandrogen therapy for symptomatic control, cyclic hormones for regular menses, and ovulation induction for infertility. Although weight loss is helpful in the therapy of PCOS, it may be difficult to achieve. Furthermore, a significant percentage of women with PCOS are lean but insulin-resistant. Insulin sensitizers are unique in PCOS because they offer both metabolic and gynecologic benefit. Although the use of insulin sensitizers in PCOS has not been approved by the Food and Drug Administration, it is probable that PCOS will be a recognized indication for TZDs and metformin in future.

Back to Top | Article Outline

References

1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensuson diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2003;81:19–25.

2. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774–800.

3. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853–861.

4. Franks S, White DM. Prevalence of and etiological factors in polycystic ovarian syndrome. Ann N Y Acad Sci 1993;687:112–114.

5. Venturoli S, Porcu E, Fabbri R, et al. Episodic pulsatile secretion of FSH, LH, prolactin, oestradiol, oestrone, and LH circadian variations in polycystic ovary syndrome. Clin Endocrinol (Oxf) 1988;28:93–107.

6. Kletzky OA, Davajan V, Nakamura RM, et al. Clinical categorization of patients with secondary amenorrhea using progesterone-induced uterine bleeding and measurement of serum gonadotropin levels. Am J Obstet Gynecol 1975;121:695–703.

7. Rebar R, Judd HL, Yen SS, et al. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 1976;57:1320–1329.

8. Waldstreicher J, Santoro NF, Hall JE, et al. Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 1988;66:165–172.

9. Chang RJ, Mandel FP, Lu JK, Judd HL. Enhanced disparity of gonadotropin secretion by estrone in women with polycystic ovarian disease. J Clin Endocrinol Metab 1982;54:490–494.

10. Eagleson CA, Gingrich MB, Pastor CL, et al. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 2000;85:4047–4052.

11. Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 1981;108:1441–1449.

12. Soldani R, Cagnacci A, Yen SS. Insulin, insulin-like growth factor I (IGF-I) and IGF-II enhance basal and gonadotrophin-releasing hormone-stimulated luteinizing hormone release from rat anterior pituitary cells in vitro. Eur J Endocrinol 1994;131:641–645.

13. Soldani R, Cagnacci A, Paoletti AM, et al. Modulation of anterior pituitary luteinizing hormone response to gonadotropin-releasing hormone by insulin-like growth factor I in vitro. Fertil Steril 1995;64:634–637.

14. Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 1989;83:23–29.

15. Nestler JE, Clore JN, Strauss 3rd JF, Blackard WG. The effects of hyperinsulinemia on serum testosterone, progesterone, dehydroepiandrosterone sulfate, and cortisol levels in normal women and in a woman with hyperandrogenism, insulin resistance, and acanthosis nigricans. J Clin Endocrinol Metab 1987;64:180–184.

16. Dunaif A, Scott D, Finegood D, et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:3299–3306.

17. Hasegawa I, Murakawa H, Suzuki M, et al. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril 1999;71:323–327.

18. Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392–395.

19. Patel K, Coffler MS, Dahan MH, et al. Increased luteinizing hormone secretion in women with polycystic ovary syndrome is unaltered by prolonged insulin infusion. J Clin Endocrinol Metab 2003;88:5456–5461.

20. Pasquali R, Casimirri F, Venturoli S, et al. Insulin resistance in patients with polycystic ovaries: its relationship to body weight and androgen levels. Acta Endocrinol (Copenh) 1983;104:110–116.

21. Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65:499–507.

22. Mehta RV, Patel KS, Coffler MS, et al. Luteinizing hormone secretion is not influenced by insulin infusion in women with polycystic ovary syndrome despite improved insulin sensitivity during pioglitazone treatment. J Clin Endocrinol Metab 2005;90:2136–2141.

23. Arroyo A, Laughlin GA, Morales AJ, Yen SS. Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. J Clin Endocrinol Metab 1997;82:3728–3733.

24. Mason HD, Margara R, Winston RM, et al. Insulin-like growth factor-I (IGF-I) inhibits production of IGF-binding protein-1 while stimulating estradiol secretion in granulosa cells from normal and polycystic human ovaries. J Clin Endocrinol Metab 1993;76:1275–1279.

25. Homburg R, Eshel A, Kilborn J, et al. Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries. Hum Reprod 1990;5:32–35.

26. Scheele F, Hompes PG, van der Meer M, et al. The effects of a gonadotrophin-releasing hormone agonist on treatment with low dose follicle stimulating hormone in polycystic ovary syndrome. Hum Reprod 1993;8:699–704.

27. Yki-Jarvinen H, Makimattila S, Utriainen T, Rutanen EM. Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein 1 in vivo. J Clin Endocrinol Metab 1995;80:3227–3232.

28. Haffner SM, Karhapaa P, Mykkanen L, Laakso M. Insulin resistance, body fat distribution, and sex hormones in men. Diabetes 1994;43:212–219.

29. Laaksonen DE, Niskanen L, Punnonen K, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 2003;149:601–608.

30. l’Allemand D, Penhoat A, Lebrethon MC, et al. Insulin-like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells. J Clin Endocrinol Metab 1996;81:3892–3897.

31. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999;340:115–126.

32. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–143.

33. Festa A, D’Agostino R Jr, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000;102:42–47.

34. Haffner SM, Mykkanen L, Festa A, et al. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state. Circulation 2000;101:975–980.

35. Gonzalez F, Thusu K, Abdel-Rahman E, et al. Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. Metabolism 1999;48:437–441.

36. Kelly CC, Lyall H, Petrie JR, et al. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001;86:2453–2455.

37. Kelly CJ, Lyall H, Petrie JR, et al. A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2002;87:3287–3290.

38. Atiomo WU, Bates SA, Condon JE, et al. The plasminogen activator system in women with polycystic ovary syndrome. Fertil Steril 1998;69:236–241.

39. Atiomo WU, Fox R, Condon JE, et al. Raised plasminogen activator inhibitor-1 (PAI-1) is not an independent risk factor in the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2000;52:487–492.

40. Glueck CJ, Wang P, Fontaine RN, et al. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism 1999;48:1589–1595.

41. Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol (Oxf) 2000;52:595–600.

42. Aljada A, Garg R, Ghanim H, et al. Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? J Clin Endocrinol Metab 2001;86:3250–3256.

43. Ghanim H, Garg R, Aljada A, et al. Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. J Clin Endocrinol Metab 2001;86:1306–1312.

44. Garg R, Kumbkarni Y, Aljada A, et al. Troglitazone reduces reactive oxygen species generation by leukocytes and lipid peroxidation and improves flow-mediated vasodilatation in obese subjects. Hypertension 2000;36:430–435.

45. Parulkar AA, Pendergrass ML, Granda-Ayala R, et al. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001;134:61–71.

46. Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002;106:679–684.

47. Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:2108–2116.

48. Paradisi G, Steinberg HO, Shepard MK, et al. Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:576–580.

49. Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:4649–4654.

50. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997;46:454–457.

51. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980;50:113–116.

52. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165–169.

53. Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992;57:505–513.

54. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165–1174.

55. Ehrmann DA, Sturis J, Byrne MM, et al. Insulin secretory defects in polycystic ovary syndrome: Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 1995;96:520–527.

56. Dunaif A, Finegood DT. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:942–947.

57. Peppard HR, Marfori J, Iuorno MJ, Nestler JE. Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes. Diabetes Care 2001;24:1050–1052.

58. White MF, Kahn CR. The insulin signaling system. J Biol Chem 1994;269:1–4.

59. Caro JF, Ittoop O, Pories WJ, et al. Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes: Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest 1986;78:249–258.

60. Considine RV, Caro JF. Protein kinase C: mediator or inhibitor of insulin action? J Cell Biochem 1993;52:8–13.

61. Kruszynska YT, Olefsky JM. Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus. J Investig Med 1996;44:413–428.

62. Ek I, Arner P, Bergqvist A, et al. Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance? J Clin Endocrinol Metab 1997;82:1147–1153.

63. Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 1993;264:E197–E202.

64. Dunaif A, Xia J, Book CB, et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995;96:801–810.

65. Hotamisligil GS. Mechanisms of TNF-alpha-induced insulin resistance. Exp Clin Endocrinol Diabetes 1999;107:119–125.

66. Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci U S A 1995;92:10619–10623.

67. Tsilchorozidou T, Overton C, Conway GS. The pathophysiology of polycystic ovary syndrome. Clin Endocrinol (Oxf) 2004;60:1–17.

68. Lin Y, Fridstrom M, Hillensjo T. Insulin stimulation of lactate accumulation in isolated human granulosa-luteal cells: a comparison between normal and polycystic ovaries. Hum Reprod 1997;12:2469–2472.

69. Nestler JE, Jakubowicz DJ, de Vargas AF, et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998;83:2001–2005.

70. Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab 1996;81:302–309.

71. Barbieri RL, Makris A, Randall RW, et al. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986;62:904–910.

72. Franks S, Robinson S, Willis DS. Nutrition, insulin and polycystic ovary syndrome. Rev Reprod 1996;1:47–53.

73. Gilling-Smith C, Willis DS, Beard RW, Franks S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab 1994;79:1158–1165.

74. Hillier SG, Tetsuka M. Role of androgens in follicle maturation and atresia. Baillieres Clin Obstet Gynaecol 1997;11:249–260.

75. Stripp B, Taylor AA, Bartter FC, et al. Effect of spironolactone on sex hormones in man. J Clin Endocrinol Metab 1975;41:777–781.

76. Lee O, Farquhar C, Toomath R, Jepson R. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database Syst Rev 2000;CD000194.

77. Milewicz A, Silber D, Kirschner MA. Therapeutic effects of spironolactone in polycystic ovary syndrome. Obstet Gynecol 1983;61:429–432.

78. Shaw JC, White LE. Long-term safety of spironolactone in acne: results of an 8-year followup study. J Cutan Med Surg 2002;6:541–545.

79. Spritzer PM, Lisboa KO, Mattiello S, Lhullier F. Spironolactone as a single agent for long-term therapy of hirsute patients. Clin Endocrinol (Oxf) 2000;52:587–594.

80. Ganie MA, Khurana ML, Eunice M, et al. Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. J Clin Endocrinol Metab 2004;89:2756–2762.

81. Wu MS, Johnston P, Sheu WH, et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990;13:1–8.

82. Perriello G, Misericordia P, Volpi E, et al. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 1994;43:920–928.

83. Fantus IG, Brosseau R. Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo. J Clin Endocrinol Metab 1986;63:898–905.

84. Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998;338:867–872.

85. Velazquez EM, Mendoza S, Hamer T, et al. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647–654.

86. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617–623.

87. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab 1997;82:4075–4079.

88. Haas DA, Carr BR, Attia GR. Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil Steril 2003;79:469–481.

89. Glueck CJ, Wang P, Kobayashi S, et al. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 2002;77:520–525.

90. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science 2001;294:1866–1870.

91. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53:409–435.

92. Barbier O, Torra IP, Duguay Y, et al. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 2002;22:717–726.

93. Duez H, Chao YS, Hernandez M, et al. Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice. J Biol Chem 2002;277:48051–48057.

94. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410–418.

95. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study: a randomised study. Lancet 2001;357:905–910.

96. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001;70:341–367.

97. Dubois M, Pattou F, Kerr-Conte J, et al. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in normal human pancreatic islet cells. Diabetologia 2000;43:1165–1169.

98. Nolan JJ, Ludvik B, Beerdsen P, et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994;331:1188–1193.

99. Suter SL, Nolan JJ, Wallace P, et al. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 1992;15:193–203.

100. Miyazaki Y, Glass L, Triplitt C, et al. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients. Diabetologia 2001;44:2210–2219.

101. Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002;87:2784–2791.

102. Miyazaki Y, Mahankali A, Matsuda M, et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001;24:710–719.

103. Tack CJ, Ong MK, Lutterman JA, Smits P. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance: Effects of troglitazone. Diabetologia 1998;41:569–576.

104. Ghazeeri G, Kutteh WH, Bryer-Ash M, et al. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 2003;79:562–566.

105. Zheng Z, Li M, Lin Y, Ma Y. [Effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome]. Zhonghua Fu Chan Ke Za Zhi 2002;37:271–273.

106. Mitwally MF, Witchel SF, Casper RF. Troglitazone: a possible modulator of ovarian steroidogenesis. J Soc Gynecol Investig 2002;9:163–167.

107. Ortega-Gonzalez C, Luna S, Hernandez L, et al. Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;90:1360–1365.

108. Kelly IE, Han TS, Walsh K, Lean ME. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999;22:288–293.

109. Akazawa S, Sun F, Ito M, et al. Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care 2000;23:1067–1071.

110. Fonseca V, Grunberger G, Gupta S, et al. Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control. Diabetes Care 2003;26:1685–1690.

111. Ortega-Gonzalez C, Cardoza L, Coutino B, et al. Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome. J Endocrinol 2005;184:233–239.

112. Lv L, Liu Y. Effect of rosiglitazone on endocrine, metabolism and ovulatory performance in patients with polycystic ovary syndrome and insulin resistance. J Huazhong Univ Sci Technolog Med Sci 2004;24:480–482.

113. Schoppee PD, Garmey JC, Veldhuis JD. Putative activation of the peroxisome proliferator-activated receptor gamma impairs androgen and enhances progesterone biosynthesis in primary cultures of porcine theca cells. Biol Reprod 2002;66:190–198.

114. Veldhuis JD, Zhang G, Garmey JC. Troglitazone, an insulin-sensitizing thiazolidinedione, represses combined stimulation by LH and insulin of de novo androgen biosynthesis by thecal cells in vitro. J Clin Endocrinol Metab 2002;87:1129–1133.

There is no security on this earth, there is only opportunity. - —General Douglas MacArthur

Cited By:

This article has been cited 4 time(s).

Acta Endocrinologica-Bucharest
Fatty liver amplifies testosterone levels in patients with polycystic ovary syndrome
Serpoi, G; Cucu, C
Acta Endocrinologica-Bucharest, 3(3): 277-290.

Current Pharmaceutical Design
Effects of Thiazolidinediones Beyond Glycaemic Control
Kalaitzidis, RG; Sarafidis, PA; Bakris, GL
Current Pharmaceutical Design, 15(5): 529-536.

Fundamental & Clinical Pharmacology
Thiazolidinedione derivatives in diabetes and cardiovascular disease: an pdate
Sarafidis, PA
Fundamental & Clinical Pharmacology, 22(3): 247-264.
10.1111/j.1472-8206.2008.00568.x
CrossRef
Gynecological Endocrinology
Pseudotumor cerebri from sinus venous thrombosis, associated with polycystic ovary syndrome and hereditary hypercoagulability
Finsterer, J; Kuntscher, D; Brunner, S; Kruluger, W
Gynecological Endocrinology, 23(3): 179-182.
10.1080/09513590701237290
CrossRef
Back to Top | Article Outline
Keywords:

polycystic ovarian syndrome; insulin; resistance; sensitizers; thiazolidinediones

© 2005 Southern Medical Association

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.