Evolution of PCO definitions

PCOS –is not a diseases entity .The last letter S implies Syndrome. But what is   a syndrome?? Name a disease which involves too any academic bodies /Associations and dozens of consensus opinions in medical science across the globe ?? It is  PCO . What do we mean by the term “Diagnostic criteria for a certain disease “syndrome ? “ : Ans ¨A syndrome is a set of medical  symptoms & signs which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". Well, Webster's Dictionary defines a syndrome as a group of signs and symptoms that occur together and characterize a particular abnormality or condition. Another definition is a set of concurrent things, such as emotions or actions, that form an identifiable pattern.: This implies features composed of a collection of symptoms and signs, as well as biochemical, genetic, imaging and pathological findings. Diagnostic criteria help to classify a disease as “present” or “”  and have several purposes. First, they aim to estimate the natural course of disease, which is important information for the person involved and making him or her aware of possibility of a diseases or syndrome . . Subsequently, and more importantly, when a diagnosis indicates that the natural course of a disease is expected to be suboptimal, diagnostic criteria can guide treatment decisions, which have to aim to modify this prognosis in a beneficial way, thus improving the outcomes for the patients.

Evolution of PCOS ??   It was  one decade before Dr Pal was born in 1945). First thought of PCO was in the minds of  Stein and Leventhal (1935) .They reported a series of seven women with polycystic ovaries and oligo/amenorrhoea, later to be known as PCOS. The chief complaints of these women were oligo/amenorrhoea with subfertility, hirsutism or lower abdominal pain. Out of the seven women in the report, five were infertile, three were obese and three had hirsutism. All the seven women in the report gained normal menstruation after wedge resection and two of them became pregnant (Stein and Leventhal, 1935). Thus, the initial diagnosis of polycystic ovaries was related to patients’ outcomes.

Stein and Leventhal (1935) diagnosed polycystic ovaries with pneumoroentgenography and laparotomy. These diagnostic methods were abandoned with the advent of hormonal assays in the 1970s (Yen et al., 1970; Rebar et al., 1976; Yen, 1980) and the introduction of high-resolution real-time ultrasonography in the 1980s (Swanson et al., 1981; Adams et al., 1985).

 Second phase of thought was initiated by Insler in 1966 ,later accepted by WHO .What is the advantage of WHO criteria or classification of PCO  over Rotterdam so far we gynaecologits are so familiar.  Unfortunately the Who classification is an excellent classification for treatment of PCO  though it concentrates pearly on anovulation only., It is true that not all PCO are anovulatory and now we know that such ovulatory PCO ,though excluded in WHO classification have long term metabolic consequences in the long run, That is te only setback of WHO criteria but honestly speaking most of us base out Treatment protocol on WHO  classification of  anovulatory disorders. Way back in 1973  , the World Health Organization (WHO) classified  anovulation disorder  in a  more pragmatic for guiding treatment selection.  This classification was based on a preliminary classification published in 1968 (Insler et al., 1968-Who had more interest on Cervical scoring and changes in Cx in menst cycle prior to USG ,) . The  WHO , accepted Inslee’s  classification  and  classified anovulation into  three main  groups (World Health Organisation, 1973) . Later this classification was also adapted by ESHRE (The ESHRE Capri Workshop Group, 1995):

The classification was like this:  (i) Group I: hypogonadotropic hypogonadal anovulation, (ii) Group II: normogonadotropic normoestrogenic anovulation and (iii) Group III: hypergonadotropic hypoestrogenic anovulation.

The WHO classification guides treatment The WHO classification guides treatment. Women with WHO I anovulation need pulsatile administration of gonadotrophin-releasing hormone or gonadotrophins with luteinizing hormone activity (National Institute for Health and Care Excellence, 2013). Women in WHO-II group are predominately women with PCOS, for which clomiphene citrate has been the long-standing first-line medical treatment (ESHRE Capri Workshop Group, 2012; , with metformin, a combination of the two (National Institute for Health and Care Excellence, 2013) or letrozole (Legro et al., 2013; NHMRC, 2015) as recent and probably superior alternatives.

 Gonadotropins and laparoscopic ovarian surgery are considered as second-line treatments (ESHRE Capri Workshop Group, 2012; National Institute for Health and Care Excellence, 2013; Teede et al., 2011). For women with WHO class III, it is not effective to apply any of the ovulation-inducing regimens (The ESHRE Capri Workshop Group, 1995) and oocyte donation is an established fertility treatment in women with premature ovarian insufficiency (ESHRE Guideline Group on POI et al., 2016).

Third kind of classification of PCO by NIH, 1990: After stein Leventhal & WHO then the discussions on anovulation didn’t stop .It was an headache to clinicians and researchers as meanwhile people came to know this syndrome not only affects fertility but also shortens life. So there was a long demand of a standard definition.  This was initiated as “First international conference of PCOS “which was held at National Institutes of Health in 1990. Sadly, in NIH criteria formulated present was  –“No research: No long term study” !!!! : It was something like political meeting  as it was based on  opinion based criteria and majority of opinions were  taken granted . !! 

As mentioned ,it was framed  on a consensus questionnaire of the attendees, rather than clinical research data and  the following diagnostic criteria were put forth: 1)  oligo-anovulation and 2) hyperandrogenism/hyperandrogenaemia both must be present  but in the absence of all other endocrinopathies. Therefore such a definition warrants all kinds of endocrine evaluation like Cortisol, DHEASO4 , PRL ,TSH , insulin FSH, LH etc. which is next to impossible in clinical practice .

Fourth classification was Rotterdam, 2003: Then came in the drams stage  the famous Rotterdam criteria, 2003 :  (Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group, 2004a) But what are the drawbacks  of Rotterdam Criteria ?? No research: No long term study: But opinion based criteria was set as was NIH, 1990 . ,Criteria was formulated on    closed session consensus amongst  attendees  and not on long term study  .Sadly , such  Criteria of PCOS was formulated  on collective personal experiences only  !!!  Unfortunately most of the   current criteria for PCOS are based on expert meetings; there is a plea   to revisit each item of PCO criteria based on the evidence in prognostic studies and RCTs. The Rotterdam criteria have been useful in guiding research and therefore a number of clinical studies have been published over the past decade, but they should be evaluated for both prognostic capacity and the capacity to guide treatment a patient suffering from so called PCO. . The strengths and limitations of the Rotterdam criteria in guiding treatment selections and predicting prognoses in women with infertility is a little bright but not the long term health risks.. While the Rotterdam criteria have shown their advantages in predicting reproductive prognosis, the next step is to evaluate whether they can guide treatment choices in infertility as well as other health aspects of the syndrome. Based on available data in clinical studies, we should be able to determine whether the Rotterdam criteria are evidence-based criteria.

As members are aware that in 2003, a group of experts expanded the diagnostic criteria to include polycystic ovaries seen at ultrasound as a third diagnostic marker and to allow for a diagnosis of PCOS in addition to oligo-anovulation and hyperandrogenism/hyperandrogenaemia in the absence of all other endocrinopathies . If two of the three criteria were met and the same endocrinopathies were excluded; these are known as the Rotterdam criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group, 2004a,b). Again, let me  remind you  , my dear members that the Rotterdam criteria were on the basis of closed session consensus among attendees.

Which associations accepted such consensus statements blindly without any research based or long term follow up ??  Unfortunately these new definitions of Rotterdam were  accepted by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004, Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004) .

Are there any limitations of Rotterdam criteria?? Yes. There are .There are three   limitations of Rotterdam criteria. The main limitations is that such diagnostic criteria are  framed  on a meeting and sadly no long term study were carried out before formulating such globally accepted  diagnostic criteria of PCO , as no other criteria were available at that time for clinicians except NIH .Who criteria was not very much aware to clinicians . However, sonologists were too happy  with Rotterdam criteria as  such includes imaging of ovaries which were not included in WHO group of anovulation nether  NIH criteria . But there are three shortcomings of Rotterdam criteria which are still unresolved,. First lacunae of consensus 1)  It is opinion based criteria and no long term study were carried out by any of the attendees. 2) Second lacunae is the diagnosis of PCOS according to the Rotterdam criteria does not guide treatments of oligo-anovulatory infertile women with PCOS.  3)  Third limitation of Rotterdam criteria it  not highlight the long term  metabolic aspects of the diseases . These are the three limitations of Rotterdam criteria ??

We are basically gynaecologits and naturally  we are  mostly interested in restoration of fertility whereas metabolic physicians are more interested in long term health aspects of PCO like midlife onset of DM, Dyslipidaemia, Cardio vascular events . The diagnosis of PCOS according to the Rotterdam criteria does not guide treatments of oligo-anovulatory infertile women with PCOS.

Do the Rotterdam Criteria Predict Ovulation ??

Predictive models for pregnancy outcomes in infertile women with WHO group II anovulation and PCOS have been reported In WHO-II anovulatory women treated with clomiphene, predicting factors for live birth include A)  free androgen index (FAI), B) BMI, C) oligomenorrhoea and D) age (Imani et al., 2002), But predictors for ovulation include 1) FAI, 2) BMI, 3) oligomenorrhoea and 4)  ovarian volume (Imani et al. , 1998, 2000).

What are the factors which predict miscarriage in PCO??  1) Serum insulin-like growth factor-I (IGF-I), 2) testosterone, 3) age  4) oligomenorrhoea, 5)  duration of infertility and 6) FAI. , All these can predict the chance of ongoing pregnancy in women treated with FSH. More recently, the predicting value of patient characteristics such as A) age, B) BMI, C) hirsutism score, D) FAI, E) insulin and F) duration of infertility on reproductive outcomes in women with PCOS have been further confirmed in the data of the PPCOSI and PPCOSII trials.

The predicting factors in these models consist of different baseline characteristics. Some of them, such as hirsutism score, FAI, ovarian volume and oligomenorrhoea are important components of the Rotterdam criteria.

It is the phenotype of PCO that matters most in Reproductive outcome??  Ans: Of all the prognostic factors the different phenotypes of PCOS and the different components of the Rotterdam criteria can help to predict the reproductive outcome , although other predictors (e.g. insulin) are not included in the Rotterdam criteria. These predicting factors need to be confirmed in different populations in future studies.

How helpful is biochemical tests of PCO say insulin, PPBS , androgen?? Do such tets guide us in treatment planning  or prognostication?? Existing biochemical tests for PCOS have poor sensitivity and specificity. Anti-Müllerian hormone (AMH), a hormone produced by granulosa cells of ovarian follicles during the early stages, is a promising biomaker for PCOS. AMH may be a good substitute for PCOM and also a useful initial diagnostic test for PCOS . However, AMH is not included in the Rotterdam criteria. These were not considered in Rotterdam criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group, 2004a,b). As I have mentioned time and again that  the Rotterdam criteria were on the basis of closed session consensus among attendees.

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Do the Rotterdam Criteria Guide Treatment Selections?

Oligo-anovulatory infertile women with PCOS are treated with lifestyle intervention, medical or surgical ovulation induction and eventually IVF (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008). Oligo-anovulation, with or without hyperandrogenism/hyperandrogenaemia or polycystic ovarian morphology (PCOM), will not affect clinical decision-making in ovulation induction treatment choices according to current guidelines (Legro et al., 2013; National Institute for Health and Care Excellence, 2013; Teede et al., 2011; Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008).

Limitations of  Rotterdam criteria ?? The diagnosis of PCOS according to the Rotterdam criteria does not guide treatments of oligo-anovulatory infertile women with PCOS.

In contrast, the World Health Organization (WHO) classification of anovulation is more pragmatic for guiding treatment selection. Based on a preliminary classification published in 1968 (Insler et al., 1968), the WHO classified anovulation   three groups (World Health Organisation, 1973) and this classification was also adapted by ESHRE (The ESHRE Capri Workshop Group, 1995): (i) Group I: hypogonadotropic hypogonadal anovulation, (ii) Group II: normogonadotropic normoestrogenic anovulation and (iii) Group III: hypergonadotropic hypoestrogenic anovulation.

The WHO classification guides treatment. Women with WHO I anovulation need pulsatile administration of gonadotrophin-releasing hormone or gonadotrophins with luteinizing hormone activity (National Institute for Health and Care Excellence, 2013). Women in WHO-II group are predominately women with PCOS, for which clomiphene citrate has been the long-standing first-line medical treatment (ESHRE Capri Workshop Group, 2012; Legro et al., 2013; National Institute for Health and Care Excellence, 2013; Teede et al., 2011), with metformin, a combination of the two (National Institute for Health and Care Excellence, 2013) or letrozole (Legro et al., 2013; NHMRC, 2015) as recent and probably superior alternatives. Gonadotropins and laparoscopic ovarian surgery are considered as second-line treatments (ESHRE Capri Workshop Group, 2012; National Institute for Health and Care Excellence, 2013; Teede et al., 2011). For women with WHO class III, it is not effective to apply any of the ovulation-inducing regimens (The ESHRE Capri Workshop Group, 1995) and oocyte donation is an established fertility treatment in women with premature ovarian insufficiency (ESHRE Guideline Group on POI et al., 2016).

Do the Rotterdam Criteria Predict Prognosis?

Predictive models for pregnancy outcomes in infertile women with WHO group II anovulation and PCOS have been reported (Imani et al. , 1998, 2000, 2002; Mulders et al., 2003; van Wely et al., 2005; Rausch et al., 2009; Kuang et al., 2015). In WHO-II anovulatory women treated with clomiphene, predicting factors for live birth include free androgen index (FAI), BMI, oligomenorrhoea and age (Imani et al., 2002), while predictors for ovulation include FAI, BMI, oligomenorrhoea and mean ovarian volume (Imani et al. , 1998, 2000). Serum insulin-like growth factor-I (IGF-I), testosterone, age (Mulders et al., 2003), oligomenorrhoea, duration of infertility and FAI (van Wely et al., 2005) can predict the chance of ongoing pregnancy in women treated with FSH. More recently, the predicting value of patient characteristics such as age, BMI, hirsutism score, FAI, insulin and duration of infertility on reproductive outcomes in women with PCOS have been further confirmed in the data of the PPCOSI and PPCOSII trials (Rausch et al., 2009; Kuang et al., 2015).

The predicting factors in these models consist of different baseline characteristics. Some of them, such as hirsutism score, FAI, ovarian volume and oligomenorrhoea are important components of the Rotterdam criteria. Therefore, the different phenotypes of PCOS and the different components of the Rotterdam criteria can help to predict the reproductive outcomes to some extent, although other predictors (e.g. insulin) are not included in the Rotterdam criteria. These predicting factors need to be confirmed in different populations in future studies.

Existing biochemical tests for PCOS have poor sensitivity and specificity (Iliodromiti et al., 2013). Anti-Müllerian hormone (AMH), a hormone produced by granulosa cells of ovarian follicles during the early stages (Broer et al., 2014), is a promising biomaker for PCOS. AMH may be a good substitute for PCOM (Dewailly et al., 2011; Eilertsen et al., 2012) and also a useful initial diagnostic test for PCOS (Iliodromiti et al., 2013). However, AMH is not included in the Rotterdam criteria.

Fifth  classification cane in scenario , in 2006 .The  Androgen Excess Society (AES) has proposed a new set of diagnostic criteria in 2006 (Azziz et al., 2006), they are still the most widely adopted criteria by different guidelines and are used by a wide range of obstetricians and gynecologists as well as other specialists. However subsequent to  AES classification  two further consensus workshops regarding infertility management were held .

Which consensus centered  on  Women's health aspects of PCOS??  The  various health aspects of PCOS  women were duly considered  and duly  published afterwards (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008; Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group, 2012). Although the Rotterdam criteria remained   controversial (Azziz, 2006; Franks, 2006) and possibly don’t apply in modern day medicine much. Fifth classification  in 2008 & again in 2012 : All are now concentrating on :   Health aspects of PCOS  was stressed  in  Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008; Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group, 2012 :: Criteria were on the basis of closed session consensus among attendees.

Sixth  classification “ Considered mainly if not only Health aspects of PCOS were published afterwards (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008; Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group, 2012.) and not research based. Apart from infertility, it is clear that women fulfilling the PCOS criteria are at increased risks of pregnancy complications, long-term cardiovascular disease and endometrial cancer (Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group, 2012).

However, it is unclear which component of the PCOS criteria are specifically related to these risks. As such, there is a need for more prognostic studies that indicate which of the PCOS criteria are predictive for these complications, as well as RCTs that evaluate which characteristics of PCOS women can be used as treatment selection markers. IPD meta-analyses on these aspects of PCOS are also necessary for future research, as these studies can guide researchers and clinicians to find target populations for different interventions and therefore provide evidence of personalized PCOS care.

Conclusion: We are gynaecologits but not a doctor in truest sense !!! We are gynecologists and our primary responsibility is treatment of Infertility which  is the  “Tip of the Iceberg in PCOS’ Who cares whether such PCO women dies of DM/ MI / Stroke in 4^th/5^th decade of life ??  My duty is finished as soon as baby is born by CS !!!  I as a gynaecologist has succeeded in Tr of subfertility and I shall wash off my hands!! How true is this philosophy which is existent in members mind ??

Which definition of PCO we the members should follow??  Ans: For couples with anovulatory infertility, the current WHO-based classification can help clinicians guide treatment. Many  believe that in a similar way it should be evaluated whether the criteria that are used to diagnose PCOS can be used to guide treatment choices. The Rotterdam criteria have shown their advantages in predicting reproductive outcomes in women PCOS but not the treatment design . For any diagnostic criteria diagnosis is not enough but  the next step is to discover whether the criteria can guide us the clinicians

In the  decision-making on treatment selections. With the introduction of individual participant data (IPD) meta-analysis to this area, it could be possible to solve this problem based on the IPD in previously published randomized controlled trials (RCTs). Additionally, this should also be the subject of future RCTs, in which not only a treatment effect is assessed in a dichotomous way, but there is also an evaluation of whether a treatment effect is dependent on baseline characteristics .