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NJOG 2008 May-June; 3(1): 3 - 9 New concepts in pathogenesis and management
of polycystic ovarian syndrome:
Insulin resistance and role of insulin sensitizers
Rashmi Prasad Yadav National Academy of Medical Sciences, Bir Hospital. AbstractPolycystic ovarian syndrome (PCOS) is classically characterized by the clinical triad of androgen excess,anovulation infertility and obesity. Anovulation occurs due to functional ovarian and/or adrenalhyperandrogenism. The etiology and patho physiology of PCOS is unknown .Proposed theories includeexcess of gonadotropins; the effect of which is amplified by disturbances in intrinsic regulatory peptides, suchas inhibin or extrinsic regulatory peptides, such as insulin or insulin like growth factor ( IGF). For over 25years insulin resistance has been known to be associated with PCOS. Improvement in insulin resistance withthe use of insulin sensitizers, such as metformin and thiazoldinediones (TZDs) have been seen to be associatedwith better ovulation and reduced testosterone levels in patients with PCOS.
Aims: The aim of the present review is to discuss the new concepts in the pathogenesis of PCOS and to knowusefulness of insulin sensitizers in such patients.
Methods: Over 50 articles extending the span of more than 25 years have been reviewed and an attempthas been made to know the etiopathogenesis of PCOS and also to assess the validity for the uses of insulinsensitizers in patients of PCOS.
Results: With the advancement of knowledge regarding etiopathogenesis, the management of PCOS haschanged in recent years. In view of positive association between hyperinsulinemia and PCOS, improvementin insulin resistance through weight loss and use of insulin sensitizing drugs has been recommended.
Conclusions: Besides symptomatic treatment, recent studies recommend use of insulin sensitizers inmanagement in PCOS for better outcome in them.
ey words: Polycystic ovarian syndrome (PCOS), Insulin resistance (IR) Insulin sensitizers (IS).
associated with PCOS. The pathophysiolgy of PCOSis a complex and as yet not fully understood, so the Polycystic ovarian syndrome (PCOS), previously management of PCOS remains a challenge.
known as Stein –Leventhal syndrome, is classicallycharacterized by the clinical triad of androgen excess, Polycystic ovarian syndrome (PCOS) is characterized anovulation, infertility and obesity where anovulation clinically by persistent anovulation and is associated occurs due to functional ovarian hyperandrogenism with varied manifestations such as enlarged polycystic and / or functional adrenal hyperandrogenism. It is ovaries, secondary amenorrhea or oligomenorrhea and associated with manifestations such as enlarged infertility. According to an estimate by Dunaif 1et al 5- polycystic ovaries, secondary amenorrhea or 10% of women in the reproductive age have polycystic oligomenorrhea, hirsuitism and infertility. For over 25 ovarian syndrome. Besides, chronic anovulation and years insulin resistance has been known to be irregular bleeding, polycystic ovarian syndrome (PCOS) CorresspondenceDr Rashmi Prasad YadavAssociate Professor, Obstetrics and GynecologyC/o Dr Chandra Mohan Yadav, GPO 8975, EPC2189, Jwalakhel, Lalitpur; Kathmandu; Nepal.
E-mail: [email protected]; Mobile :+977-9841295567 Rashmi Prasad Yadav is characterized by hyperandrogenism which may be release and gonadotropin responses to multidose GnRH present in the absence of hyperandrogenemia in those were similar prior to and during a 12-h euglycemic – women in reproductive age who have enhanced tissue hyperinsulinemic clamp.9 It was thought that lack of sensitivity to androgens. According to the revised insulin effect may result in insulin resistance, which is guidelines of the Rotterdam PCOS Consensus a common feature of PCOS.10 However, it was later Workshop Group (2003), for diagnosing PCOS, a woman demonstrated that even after improvement of insulin must show two of the following three criteria:2 sensitivity with insulin sensitizers, like; pioglitazone Irregular menstruation or anovulation treatment , there was no difference in baseline LH values, Clinical and biochemical signs of LH pulsatility, or maximally stimulated percent of LH increment following GnRH with or without insulin Enlarged ovaries with a volume > 10 ml; 12 infusion in women with PCOS.11 Although a LH:FSH or more follicles in longitudinal and ratio of >2 was part of the diagnostic criteria for PCOS, anteroposterior diameter each. The multiple it was observed by Arroyo et al12 that obese women cysts measuring 2-9 mm cysts are arranged with PCOS do not necessarily have elevated LH levels.
Therefore, a normal LH level or LH:FSH ratio does notrule out a diagnosis of PCOS. Currently, the LH:FSH It is important to remember that polycystic ovaries are ratio is not included in the diagnostic criteria of the not a necessary feature of PCOS and also that many of these women with PCOS are not the ones withpolycystic ovaries. A chance finding of polycystic Under the influence of low but constant levels of FSH, ovary on ultrasound evaluation should not be multiple ovarian follicles are stimulated which do not considered as PCOS unless it is corroborated with achieve maturation. The life span of the follicles get clinical evidences. In a case of PCOS, androgen excess extended to several months, leading to multifollicular may be with or without skin manifestations.
cysts .These leutinised follicles are arrested in response Approximately, 50% women with PCOS are obese and to constant and relatively high levels of LH that provide tend to have an android pattern of obesity.3 a constant supply of steroids. Whereas an atretic follicledeficient in aromatase activity may become an Chronic anovulation may present as irregular androgenic follicle. Cultured follicular cells from the menstruation or amenorrhea. It is not essential to small follicles of polycystic ovaries produce small document anovulation by ultrasound or by hormonal amounts of estradiol but show a dramatic increase in assay, (progesterone measurements) in the presence estrogen production when stimulated by FSH or of clear clinical history. PCOS occurs in 85- 90% of Insulin-like growth-factor-1(IGF-1).13 FSH therapy women with oligomenorrhea and in 30-40% of women induces a larger number of follicles to develop in with amenorrhea.4 Anovulation in women with PCOS women with PCOS as compared with other women with is associated with steady state levels of hyper- infertility without PCOS.14 And hence, there is the gonadotrophic hyperestrogenemia. Constant exposure validity in proposition that a deficient in vivo ovarian of estrogen leads to proliferation and hyperplasia of response to FSH, possibly due to impaired interaction the endometrium and this can causes unpredictable between signaling pathways associated with FSH and episodes of vaginal bleeding. Unexposed estrogen IGF-1, may be a key event in the pathogenesis of exposure can be confirmed by progesterone withdrawal anovulation in PCOS.
test done after a negative urine pregnancy test.
The other problem hyperandrogenism is usually Gonadotropins, androgens, and ovarian
suggested by the presence of hirsuitism (occurring in steroids in PCOS
approximately 80% of PCOS sufferers) and it can bedocumented by measuring androgen levels in the Women with PCOS have higher mean concentrations blood. In PCOS, free testosterone is the most frequently of leutinizing hormone (LH), increased bioactivity of elevated steroid in the blood. Circulating levels of total LH and low –normal levels of follicle stimulating testosterone, androstenedione and dehydro- hormone.5 The precise mechanism(s) responsible for epiandrosterone (DHEA) are also elevated. In obese enhanced LH secretion in PCOS are not completely women with PCOS sex hormone binding globulin understood, although, studies have demonstrated a (SHBG) levels are decreased (the effect of obesity per potential influence of hypothalamic gonadotropin se) and this leads to an increase in free testosterone releasing hormone (GnRH) activity and ovarian steroid levels. Furthermore, insulin is a negative regulator of feedback.6 Although in in vitro studies, insulin has the production of SHBG by the liver, and SHBG levels been implicated as a potential regulator of LH secretion are decreased in hyperinsulinemic conditions such as in PCOS in dose dependent manner, the similar results the metabolic syndrome and visceral obesity.15 Besides have not been found in vivo studies.7, 8 Pulsatile LH the level of DHEA Sulfate is also elevated in blood and New concepts in pathogenesis and management of polycystic ovarian syndrome.
are exclusively secreted by the adrenal glands, the estimate about 20-40% of women with PCOS have mechanism of which remains elusive. However, insulin impaired glucose tolerance, which is approximately 7- and IGF-1 have been shown to upregulate adrenal 17- times higher than the rates seen in age and weight hydroxylase and 17, 20- lyase activity.16 matched control.10 In addition, the prevalence of type 2diabetes is increased in women with PCOS compared PCOS, insulin resistance inflammation,
with women without PCOS (15% v/s 2.3%)27. Lean and cardiovascular disease
women with PCOS have lower rates of carbohydrateintolerance. However, carbohydrate intolerance in lean Insulin resistance (IR) has been regarded as a silent women with PCOS have higher rates than weight- and condition which is known to be associated with an age - matched controls. Thus, PCOS is associated with increased incidence of cardiovascular disease (CVD) insulin resistance independently of total or fat-free body and atherosclerosis and now it is considered to be mass. Obese women with PCOS are more insulin inflammatory disorder.17 IR has been associated resistant than obese non –PCOS or non –obese women recently with increased levels of inflammatory with PCOS.10,28 Ehrmann29 et al showed pancreatic α- mediators in the blood.18 Therefore, studies have been cell dysfunction in a subset of women with PCOS. This conducted to review the levels of inflammation in subset of women is likely to have the highest risk of PCOS. Gonzalez19 et al. noted increased levels of tumor developing carbohydrate intolerance and type 2 necrosis factor –α, In cytokine that causes insulin diabetes. The Rotterdam Consensus Panel recommend resistance and is secreted by adipose tissue in women oral glucose tolerance tests for obese women with with PCOS compared with controls. Lean women with PCOS.2 In a study by Peppard30 et al (2001), among PCOS have higher TNF-α level than lean normal women women with type -2 diabetes, 8 were found to have while the levels were similar in obese women with PCOS and obese controls. Kelly et al. noted significantly The first step in the action of insulin involves binding increased levels of C-reactive proteins (CRP) and tissue to the cell surface receptor. Insulin resistance is plasminogen activators (tPA) in women with PCOS characterized by a post receptor defect in the action of compared with healthy weight matched controls.20 insulin, the cause of which is as yet uncertain.31 After However when adjusted for insulin sensitivity, CRP insulin binding the receptor undergoes auto- was no longer significantly different between groups phosphorylation on specific tyrosine residue but the difference in tPA levels remained. Women with (accomplished by Insulin Receptor Tyrosine Kinase PCOS have been shown to have higher plasminogen [IRTK]. The activated receptors then activates insulin activator inhibitor type-1(PAI-1); however, the levels receptor substrates (such as IRS-1,2,3) that in turn bind were not significantly different from controls.21 Besides, to signaling molecules such as phosphatidylinositol- in one study, PA-I levels were not significantly different 3) kinase and activate downstream signaling leading from controls when adjusted for body mass index to insulin- mediated glucose transfer.32 Abnormalities in both IRTK activity and in mediators distal to thereceptor are present in insulin resistant states. Serine While the different studies suggest that PCOS is phosphorylation of the insulin receptors decreases associated with a state of increased inflammation; as IRTK activity33. This is the probable mechanism of TNF- yet clinical studies have not shown increased rate of α induced insulin resistance, since serine cardiovascular disease in PCOS.23However, the phosphorylation of P450c17-á hydroxylase (the key beneficial effect of drugs thiazolidinediones and regulatory enzyme of androgen biosynthesis) increases metformin is considered partly due to the decrease in enzyme activity leading to androgen biosynthesis.34,35 the inflammatory response associated with their uses.
Serine phosphorylation has been noted to associate Troglitazone has been shown to reduce PAI-1 levels with decreased IRTK auto-phosphorylation. It is and improve endothelial – dependent vasodilation in possible that a single defect (serine phosphorylation) women with PCOS may be partly due to the decrease can produce both insulin resistance and hyper- in inflammation caused with its use.In addition, andogenism in a subgroup of PCOS women.36 In the metformin too, has been shown to decrease PAI-1 and study by Lin37 et al., insulin stimulated lactate CRP levels in PCOS patients.24,25 production in granulose-lutein cells was reduced inwomen with PCOS as compared to those women who Insulin Resistance and PCOS
were normal ovulatory. In vitro, human theca cellstudies have shown that insulin has direct stimulatory Burghen26 et al. in 1980 noted a significant positive effects on ovarian steroidogenesis.
association between insulin, androstenedione, andtestosterone levels among women with PCOS.
Similarly, Nestler37 et al. showed that insulin produced Subsequent studies confirmed insulin-resistance to be a greater increase in androgen production by theca the cause of hyperandrogenism. According to an cells isolates from women with PCOS compared with Rashmi Prasad Yadav subjects without PCOS, and that this effect was mediated specifically through the insulin receptor ratherthan through the IGF receptor cross- talk. There are The thiazolidinediones are the peroxisome proliferator- some data to suggest that insulin enhances the effect activated receptors (PPARs) agonists.The PPARs are of LH on pre-ovulatory ovarian follicles causing a subfamily of the 48-member nuclear –receptor premature activation and subsequent follicular superfamily and they regulate gene expressions in response to ligand binding.The putative ligandmediated activation of PPAR-γ2 by troglitazone(TZD) Hence, it is suggested, that the hyperinsulinemia (due impairs androgen and stimulates progesterone to insulin resistance) drives the LH effects on ovarian biosynthesis in primary cultures of porcine theca cells theca cells to cause androgen excesses that are by blocking the expressions of the cytochrome P450- intrinsically programmed to produce more androgen.39 17-α hydroxylase / C17-20 lyase gene and cytochrome Excess androgens are known to interfere with the P protein phosphorylation, which decreases the LH- process of follicular maturation, thus, inhibiting insulin driven theca cell androgen production.47,48 ovulation and adding to the population of arrestedfollicles.40 It has been postulated that PCOS ovaries In clinical studies, TZDs lower fasting and post prandial are more resistant to the metabolic effect of insulin glucose concentration.49 Insulin concentration than to the steroidogenic effects.1 decreases in most studies. Such changes indicate thatTZDs act as insulin sensitizers. Treatment with TZDs, It is known that insulin resistance has been associated like, troglitazone, for 3-6 months increases insulin with increased levels of inflammatory mediators in the stimulated glucose uptake in peripheral tissues.50,51 In blood.18 Recently; it has been shown that in response similar studies, TZDs increase hepatic sensitivity to to the hyperglycemia, the generation of reactive oxygen insulin i.e, ability of insulin to suppress endogeneous species from mononuclear cells (MNCs) is increased glucose production, and insulin sensitivity in adipose in PCOS independently of obesity40. In addition, tissue (measured from the ability of insulin to suppress intranuclear and inhibitory nuclear factor-κB increase free fatty acid concentrations.52 and decrease the number of MNCs respectively,independent of obesity41.This has been speculated to In women with PCOS, TZDs have been shown to be a cardinal inflammatory signal that contributes to improve androgen levels, ovulation rate and enhance the induction of insulin resistance and hyper- androgenism in PCOS. Although, further studies areneeded to clarify selective insulin resistance Conclusion and recommendation
As yet, etiopathogenesis of PCOS remains unsettled.
Role of insulin sensitizers in PCOS
Deregulation of steroidogenesis has been associatedwith insulin resistance, though; insulin resistance is not the part of the diagnostic criteria for PCOS. Weightloss is known to be helpful in the improving insulin Metformin is biguanide that is used to reduce plasma resistance, but it is difficult to achieve and retain.
glucose concentrations in type 2 diabetics. In these Besides, a large number of women with PCOS are lean patients, metformin does not lead to weight gain and but insulin resistant. Antiandrogen therapy in PCOS is can induce weight loss in some. Metformin primarily used for control of symptoms. Oral contraceptive works by reducing hepatic glucose production, and hormones are used for regularization of endometrial inhibiting gluconeogenesis both directly and indirectly shedding and protection. Induction of ovulation is (by decreasing free fatty acid concentrations).42,43 There offered to those who seek treatment for infertility.Role are some data to suggest that metformin has a favorable of insulin sensitizers are unique in PCOS due to the effect on body mass index, menstrual cyclicity and fact that they offer to the sufferer of PCOS both ovulation induction in women with PCOS. Studies have metabolic and gynaecologic benefits. And so, PCOS shown reductions in androgen levels and should be recognized as an indication for TZDs and improvements in ovulation when metformin was given metformin treatment, in view of insulin resistance in for a duration of 10-24 weeks. However, these effects were secondary to weight loss.44 In addition; metforminhas been found to reduce the high rates of gestationaldiabetes in those with PCOS.45 New concepts in pathogenesis and management of polycystic ovarian syndrome.
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