The pathophysiology of polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of uncertain aetiology, which affects between 6 and 10% of women of the reproductive age. The heterogeneity of both the ovarian morphology and clinical findings in women with polycystic ovaries has been well recognized since Stein & Leventhal's (1935) first report and gradually led to the establishment of the term polycystic ovary syndrome. The many features of this syndrome can be broadly divided into three categories: clinical, endocrine and metabolic. The clinical features include menstrual abnormalities, hirsutism, acne, alopecia, anovulatory infertility and recurrent miscarriages. The endocrine features include elevated androgens, luteinizing hormone, oestrogen and prolactin levels. The metabolic aspects of this syndrome include insulin resistance, obesity, lipid abnormalities and an increased risk for impaired glucose tolerance and type 2 diabetes mellitus (type 2 DM). Controversy persists regarding the criteria used for PCOS diagnosis. Currently, the recommended diagnostic criteria for PCOS are hyperandrogenism and ovulatory dysfunction with the exclusion of specific disorders, such as nonclassic adrenal 21-hydroxylase deficiency, Cushing's syndrome, hyperprolactinaemia and androgen-producing tumours. This clinical definition reflects a 1990 National Institutes of Health–National Institute of Child Health and Development Consensus Conference (Zawadeski & Dunaif, 1992) in which there was poor agreement among the 58 specialists who completed a questionnaire on the diagnostic criteria for PCOS, with no single criterion endorsed as ‘definite or probable’ by more than 64% of respondents. Interestingly, the conclusion of this meeting was that the polycystic ovary morphology is consistent with, but not essential for, the diagnosis of the syndrome. Sonographic criteria for polycystic ovaries have been refined with advances in technology (Fox, 1999; Atiomo et al., 2000) and transvaginal ultrasound is currently the gold standard for diagnosing polycystic ovaries. Using the most conservative criteria based on transabdominal ultrasound, the presence of 10 or more cysts, 2–8 mm in diameter, arranged either peripherally around a dense core of stroma or scattered throughout an increased amount of stroma (Adams et al., 1985), up to 23% of normal volunteer women meet the sonographic criteria for polycystic ovaries (Clayton et al., 1992). On the other hand, many investigators have maintained that ovaries from women with PCOS may be sonographically normal (Hann et al., 1984; Timor-Tritsch & Rottem, 1998). Thus, the ovarian morphological changes must be distinguished from the endocrine syndrome of PCOS and be considered as a sign rather and not a disease. Despite being one of the most common endocrinopathies, a comprehensive explanation of pathophysiology is still lacking. The heterogeneity of PCOS may well reflect multiple pathophysiological mechanisms, but the definition of each contributing mechanism has been slow to emerge. Traditionally, it has been useful to consider the polycystic ovary syndrome as the result of a ‘vicious cycle’, which can be initiated at any one of many entry points. Altered function at any point in the cycle leads to the same result: ovarian androgen excess and anovulation. Several theories have been proposed to explain the pathogenesis of PCOS: A unique defect in insulin action and secretion that leads to hyperinsulinaemia and insulin resistance. A primary neuroendocrine defect leading to an exaggerated LH pulse frequency and amplitude. A defect of androgen synthesis that results in enhanced ovarian androgen production. An alteration in cortisol metabolism resulting in enhanced adrenal androgen production. It must be accepted, however, that each of these are artificial stating points to our understanding of the metabolic–ovarian–pituitary circuitry being closely interrelated. The first recognition of an association between glucose intolerance and hyperandrogenism was made by Achard & Thiers (1921) and was called ‘the diabetes of bearded women’. The association between increased insulin resistance and PCOS is now well recognized. Insulin resistance is defined as a reduced glucose response to a given amount of insulin. There are several mechanisms contributing to the state of insulin resistance: peripheral target tissue resistance, decreased hepatic clearance, or increased pancreatic sensitivity. Studies with the euglycaemic clamp technique indicate that insulin resistance is a common feature of the syndrome, and both obese and nonobese women with the syndrome are more insulin-resistant and than and normal women et al., et al., 1992). obese PCOS women decreased insulin with nonobese PCOS women et reduced insulin in PCOS with a in obese and a in obese PCOS, that is to insulin resistance to with the of insulin resistance, the of hyperinsulinaemia in PCOS women was being in response to these indicate that insulin resistance is a common in women with PCOS of and that insulin resistance in obese PCOS is of one unique to PCOS and the other however, have insulin resistance in PCOS an glucose tolerance et al., a glucose et al., 1992) or a euglycaemic clamp et al., normal insulin action in normal PCOS There are several for these which an any common in PCOS The of on diagnostic there is no standard definition and of insulin in in insulin and the of a of type 2 diabetes are into many with a of may type 2 to decreased insulin pancreatic dysfunction has been in PCOS et al., & The defect increased secretion of insulin and decreased secretion results in insulin secretion to for the of insulin resistance. The decreased in these the dysfunction of type 2 and are more in PCOS women who have a with type 2 an increased risk for glucose results in insulin resistance, but the defect et al., that it may be the primary in et have that polycystic ovaries type 2 not with a defect in the secretion of insulin. a in the insulin to decreased hepatic insulin has been to be for the in insulin by investigators et al., et al., Several have on mechanisms of insulin in to the pathogenesis of insulin resistance in Insulin action is a the insulin The insulin such as and and and the of insulin. A mechanism for insulin resistance in at of PCOS women to be to of insulin A to the insulin a of the insulin leading to of et al., Dunaif, It is that the defect in insulin action is to glucose other of insulin in are not Interestingly, of to be the mechanism of insulin resistance of & to the of the of androgen in both the adrenal and ovarian Thus, has been to and androgen synthesis et al., It is that a single defect both the insulin resistance and the hyperandrogenism in a of PCOS women leading to androgen excess in the defect in insulin action in PCOS, & the metabolic and of insulin and in from PCOS and there is a defect in insulin action in PCOS that affects but not that there is a defect in that insulin and synthesis by the same and that insulin by insulin and is to the that the metabolic defect is in or of this in PCOS The for the of a defect in insulin action in PCOS is consistent with of no in the insulin et al., et al., et al., The association between hyperinsulinaemia and Several have a between insulin and androgen et al., et al., the of hyperinsulinaemia with the of clinical of the syndrome et al., et al., hyperandrogenism results from the hyperinsulinaemia of insulin resistance, or has been since this was of the hyperinsulinaemia as the primary the in which the by et al., or the of a et al., et al., has not changes in the state in et have that not insulin in It is however, that may to to the insulin resistance of PCOS, as investigators have that insulin resistance was androgen et al., or et al., these findings indicate that not a in insulin resistance in women with PCOS and that insulin action the in It is that hyperinsulinaemia androgen in PCOS Insulin may as a LH of ovarian of insulin and by the of LH Despite that insulin ovarian androgen in PCOS, the mechanism on insulin with the in to insulin on the ovarian et al., was proposed as a mechanism of of the of in the androgen response to LH et al., of by insulin to increased androgen in insulin has been to the with an of than that of The of insulin with the is an at insulin The of and which of a of and of both have been et al., It is that these can insulin and with it has been proposed that insulin has specific on et al., 1985), a by in of both & et al., and et al., 1984; et al., Interestingly, & and not that insulin on in must be but both the or the as insulin that insulin the of LH but not frequency in obese women with PCOS & This is consistent with report by et that there is a of the of LH and that of insulin in these Studies in which insulin have been by that insulin to changes in ovarian androgen secretion at the An is that the reduced secretion of LH with these be to insulin have been in tissue et al., and insulin to in at in et al., et proposed of ovarian as an mechanism of insulin action in a of obese PCOS this a in insulin with by a of ovarian as by a in the response of to the of An report by et that hyperinsulinaemia may in tissue of women with PCOS the this There are other of insulin which to hyperandrogenism in PCOS: the of hepatic synthesis of which more androgen and oestrogen to be and the of hepatic of which an in of and 1999; et al., 1992). This is now to be the mechanism for the between peripheral insulin and levels. This is that are for insulin resistance, and reduced is a for the of type 2 et al., The clinical of these findings is that of hyperandrogenism in women with PCOS may be by that insulin and insulin levels. in women with PCOS the endocrine and ovarian dysfunction et al., et al., the with that either insulin et al., or et al., or that insulin et al., & et al., or et al., et al., have that a in insulin is with a of ovarian androgen secretion in The of androgen with with mechanism of an by in insulin a ovarian of the can not be changes of changes in for there still The and not insulin but the metabolic and endocrine androgens, increased decreased consistent with and decreased and more menstrual abnormalities and the reproductive in anovulatory PCOS women et al., et al., 1999; et al., 1999; et al., et al., are currently at a the that include of and many to the of that a response to the can is in and the of or diabetes in have that throughout in women with PCOS to et al., as well as the of diabetes et al., a et reduced of the of in women with these a of of throughout as no have been among women with it must be that are lacking. It be that are more than in hyperinsulinaemia from the in type 2 et al., insulin resistance and hyperinsulinaemia have an in PCOS, are not with hyperinsulinaemia many women with type 2 is it that ovaries to be in an insulin-resistant insulin a from glucose to et have that of women with type 2 polycystic ovaries in ultrasound, clinical of hyperandrogenism menstrual that hyperinsulinaemia is not for the of the syndrome. in a more of et that the of type 2 and polycystic ovaries on that these changes in insulin It is that the insulin resistance and the reproductive reflect and that insulin resistance the syndrome in that women with the endocrine syndrome of hyperandrogenism and to be insulin-resistant et al., et al., et al., women with hyperandrogenism or polycystic ovaries morphology in ultrasound are not intolerance and Insulin resistance and dysfunction are both to the of glucose intolerance and type 2 Thus, PCOS women be to be at an increased risk for type 2 et have that up to of obese PCOS women impaired glucose tolerance or type 2 the criteria are are than in a in women of by et al., a of et have that women with PCOS are at increased risk for glucose intolerance and type 2 to and of the reproductive that nonobese PCOS women may have glucose intolerance women with PCOS are more to diabetes et al., consistent with these a in women with a of PCOS a of type 2 et al., 1992). disease. Insulin resistance is considered to be a risk for as it is with impaired glucose tolerance and type 2 et al., and lipid et al., features of the syndrome that there is an association between PCOS and disease. et and women for the of in women and these women more to report hirsutism, diabetes and disease. et a ultrasound for polycystic ovary morphology on women no in the of polycystic ovaries in women with and normal women with PCOS more that there may be association between PCOS and the are a of and are not for and not have criteria for the et at a by ultrasound in women with The was increased in women with PCOS but there was no in the of women with changes have been in women with et and in PCOS than in a et a response to a which the on in women with et a response to as a in the in women with PCOS with women with normal ovaries. et a between function and in insulin-resistant women with PCOS, an association which was than that of insulin sensitivity. of these findings an in function in women with PCOS and are of changes in function in these the association between PCOS with risk a of women with PCOS et al., not an excess from disease. et no excess of or among women with a of PCOS, increased of several risk and from diabetes and risk of among women with The for the between of risk and of is It is to the of a of type 2 among women with PCOS with in this it has been that mechanisms may be in PCOS such as to oestrogen or elevated of increased have been in women with polycystic ovaries and PCOS et al., et al., risk a between insulin and has been in many et al., et al., et al., it is that this association not in PCOS: women with PCOS not to be to for have insulin resistance et al., et al., however, to be in women with PCOS than in of the of insulin resistance et al., in a of women with a of PCOS, et have a of to This may a of the an of or a of not in a with PCOS be to be at risk for to elevated androgen and insulin resistance. A of have that women with PCOS an by of elevated and reduced have that women with PCOS have an not by the abnormalities but by and of dense to et al., et al., an increased hepatic has been metabolic to be more closely to metabolism than to androgen levels. et that androgen not lipid in et have for the first that with a androgen the lipid and that this may be to of PCOS women have been to have increased of et al., are both to the insulin resistance state & 1992) and to increased risk of et al., being an risk for PCOS, these decreased with in insulin by et al., or et al., et al., et have elevated in women with PCOS, of the presence of It is that a may an sign of which that by of a between and was which is in with the findings by et to Interestingly, 6 of reduced in these that insulin may by the LH both and in response to is a of PCOS et al., et al., This has been considered to be the primary in PCOS and the of androgen It is that the elevated LH are to an increased of the to by an in LH pulse and but et al., et al., 1998). The LH and to normal can be to increased pulse frequency of secretion et al., to a in of the of & et al., It is that this increased is at both and This is consistent with an of LH secretion that has been both in with PCOS et al., and in with PCOS et al., with the LH in rather than at there is that LH is elevated in many with PCOS, in LH is normal et al., et al., 1992). et & have on of LH secretion as an of secretion of It is that a is to synthesis and it is the frequency and of that and secretion of LH and Thus, in ovulatory an in frequency LH synthesis to the LH slow to PCOS, are and LH and impaired et have that the of in anovulatory women with PCOS can slow pulse secretion and in a more the same of an of the pulse to by and in PCOS women et al., 1998). these that the increased LH and secretion in PCOS are not a of the of to but reflect an of the pulse to it was that such be a mechanism for the abnormalities in who to of PCOS & The mechanisms the reduced however, The of hyperinsulinaemia and in women with PCOS, in ovarian of pulse have to be an not be of LH in have that secretion of is an for normal function et al., and that the of is by ovarian on the Thus, of oestrogen LH and at the more than LH et al., of oestrogen a with the LH at of oestrogen to elevated LH secretion & of at the of the the LH response to and are for the at a the of the abnormalities in PCOS be to an on the or more to an of androgens, of to at the of the the has been the are that a primary of has a on LH secretion in PCOS, this must be et al., androgen in normal women et al., or women with the PCOS not the secretion of luteinizing An by et is that the of to in PCOS women to be the that of the neuroendocrine to excess of androgen may such by the neuroendocrine to LH at resulting in ovarian hyperandrogenism et al., This has been in by et who have that of to LH in many have been proposed for the of of of these the neuroendocrine that leads to exaggerated LH pulse On the other hand, it is that an elevated LH is not for ovarian et al., 1992). of LH in of women with PCOS et al., in nonobese et have a of with ultrasound of polycystic in which the ovarian response to with was to with a et not LH with in this of to with normal but that this any changes in levels. This that the primary in PCOS is in the with of LH to ovarian A of have proposed an of PCOS as a of ovarian hyperandrogenism in which the is an elevated androgen et al., et al., that women with PCOS have increased of and in response to LH et al., of of et al., a in a primary of et have a in both and in from polycystic ovaries to the response in normal the of response to LH was the of LH in not the that these be by the of to of LH in each type of the ovary the for the among the ovarian the is for the of and of ovary more than The of synthesis in is the which of to The of each are by each and of the and in the both and of the a to the both and The type is both in and adrenal a of the to to and to and have been and to in the of the A of the The that which is by each type include the of and the of and the of from the of and have that increased androgen is a of PCOS in the that the with PCOS results from an of ovarian et al., The that PCOS results from a primary of androgen by et who that the of the and but not This both and in both the ovarian and adrenal Thus, this may be as ovarian dysfunction as adrenal dysfunction or as both has that ovarian hyperandrogenism is a result of of the androgen-producing On the other hand, is consistent with of adrenal in of women et al., 1992). adrenal androgen may be elevated in women with PCOS, the of that in most the ovary is the to excess androgen of anovulatory women with polycystic ovaries has not in the or of the et al., an to the for the increased in PCOS et in of and from normal and PCOS ovaries. the in the of to and increased by more than and in PCOS with was that the increased synthesis of is the primary enhanced secretion in Interestingly, a of have proposed that is increased in PCOS, this that both and are increased in PCOS of and for a primary defect at the of the ovary from the polycystic ovary The presence of many with a androgen to oestrogen was first to a of the to be and to to et al., et al., The that of and is consistent with a of a the are to from androgen to oestrogen the that is essential for and A of ovarian and by and endocrine Thus, LH of androgen synthesis to be by such as and by such as and It has been that in et al., has the et al., has the to it was that increased of from the multiple be a in secretion et al., 1998). ovarian function is to be by and are in normal ovarian it is that ovarian and by and with LH to production. It is that the of of the of the in the from polycystic ovaries was to be the same as in consistent with of in PCOS & & 1992). may be to the and of and polycystic ovarian at in the of PCOS women in it is et al., on and are to be to of insulin et al., the from the with but has the menstrual in the of the with et al., changes a for in ovarian of such an a in menstrual in both obese and women and may a pathophysiological mechanism in women with PCOS & however, report that in women with PCOS not from normal of et al., there is no for of or in women with polycystic ovary syndrome et al., A for the of A for the multiple features in women with PCOS has been proposed by of to androgens, a for the and mechanism of multiple are by androgen leading to an to that in women with PCOS: LH et al., and impaired insulin secretion and action et al., 2000) are by hyperandrogenism and et al., 1998). to be the core disorder in both women with PCOS and et al., and hyperinsulinaemia this core disorder into anovulation. et have that androgen excess in in ovarian and adrenal which may both to it is that a of PCOS in is based on or androgen excess from the ovary or adrenal both of which are the of well explain many of the that as in the that abnormalities of PCOS are initiated in this has been in et in a of women at was in the of polycystic ovaries and the of and to at and the of that the common of PCOS have in women with polycystic ovaries have than normal ovarian secretion of that are with and obesity, the women with polycystic ovaries have of LH resulting from A association between polycystic ovaries and has been by et in a this there no in between women with polycystic ovaries and with features of the of the association between and polycystic is uncertain and with of in with and hyperandrogenism et al., An increased adrenal androgen in of PCOS women et al., et al., as a result of a or to ovarian secretion & A more proposed mechanism is an alteration in cortisol The of cortisol metabolism include by and in and with by in and to this increased peripheral cortisol metabolism either by increased and increased of cortisol et al., et al., 2000) or impaired and impaired of cortisol et al., results in of secretion a in the normal cortisol at the of adrenal androgen excess of this of cortisol to be in women with peripheral cortisol metabolism as a proposed mechanism for the of et first increased cortisol in the of PCOS women and to that the of to cortisol in PCOS than in enhanced This is for both of to in and cortisol to in it was that increased of both and enhanced hepatic cortisol in in have that is by et al., an that be by et al., a of this by prolactin has been as a mechanism clinical of in women & et have changes in the of androgen and in response to a alteration of the et for of in PCOS that the of to cortisol in PCOS women than in impaired of of the of cortisol to and is an in and for to cortisol of this is with increased metabolic of of and and tissue are of insulin that the of this be the result of that be to The mechanism of in women with PCOS is still more than of women with PCOS may be and may abnormalities of cortisol this mechanism for abnormalities of and in et increased in PCOS with of the in PCOS by et was in PCOS et have the increased of of in as a mechanism of cortisol metabolism in proposed mechanism is that oestrogen in PCOS, in the of in that oestrogen not have a on in et al., et al., the association between the of these with insulin resistance and hyperinsulinaemia in women with PCOS to be and explain the cortisol metabolism in these of that is the reproductive endocrine in of PCOS et al., et al., a of of women with PCOS, of the of have PCOS and have with menstrual The of is a by at an et al., Insulin resistance consistent with a A of PCOS women for both androgen and insulin et al., Interestingly, et have an association between insulin resistance and rather than menstrual in the of women with It was that of with PCOS on the of may to at risk for insulin resistance for the of Thus, insulin resistance and may reflect of a single or the of or more to et have an association between PCOS and at the of of the insulin that PCOS is in to an alteration in insulin production. a of the which for the as a in the of A the that is the primary for PCOS et al., the same however, a common of for at from the of was and was proposed to the increased to the to a the frequency of in women with PCOS not from the frequency in the et al., Using a et for the of in the of the results of both and association that the synthesis which for and the insulin are in the of PCOS and may explain the heterogeneity of the syndrome. PCOS to a in which a of in with to the clinical and heterogeneity et al., of of and in the pathophysiology of PCOS, PCOS for the et al., 1999; et al., the normal et for and association with PCOS or in from The for was with the for which increased with The results for but no that the is to to the of PCOS et al., An or insulin are currently The defect of PCOS and an of There is that the features include insulin resistance, androgen excess and A in a but the are to be There are between PCOS and obesity, and diabetes mellitus with both and the with PCOS are most women are not of these recognition and of the metabolic of PCOS be the of the a and are of has been used as an of PCOS and a in the of both and of this