POLİKİSTİK OVER SENDROMU

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1 POLİKİSTİK OVER SENDROMU
Prof. Dr. Cem Fıçıcıoğlu Yeditepe Üniversitesi Tıp Fakültesi Kadın Hastalıkları ve Doğum A.D. Başkanı

2 PCOS PCOS hem adet düzensizliği hem de androjen fazlalığının önemli bir sebebidir. Hirsutizm İrregüler menstrüel siklus Obezite Klasik over morfoloji (USG ile) Klasik bulguların hepsi olmadığında spesifik tanı kriterleri oldukça tartışmalıdır.

3 PCOS Kadınlarda %6,5 - %8 oranda görülen en sık endokrinopatilerden biridir. ABD’de üreme çağındaki 5 milyon kadını etkilemektedir. Etiyoloji: multifaktöriyel (genetik komponent, epigenetik, çevresel faktörler) Ma X, Mol Hum Reprod, 2007 Azziz R, J Clin Endocrn Metab, 2005

4 Klinik Bulgular Menstrüel Disfonksiyon
Peripubertal periodda başlar ve menarş gecikebilir Oligomenore (yılda 9 menstrüel siklustan daha az) Amenore (≥3 ay menstrüel siklus olmaması) 40 yaşından sonra menstrüel sikluslar daha düzenlidir.

5 Klinik Bulgular Hiperandrojenizm Akne
Hirsutizm – Terminal vücut kullanmalarında erkek tipi artış. Etnik variabilite vardır, Asyalılarda daha az görülür. Erkek tipi saç dökülmesi Serum androjen seviyelerinde artış

6 Klinik Bulgular Polikistik overler
Bu görüntü nonspesifik olup normal adet gören kadınlarda da görülebilir.

7 Klinik Bulgular Metabolik sorunlar / kardiovasküler risk
Aşırı kilolu / obez (%40-85) İnsülin rezistansı (zayıflarda %30, şişmanlarda %70)

8 Klinik Bulgular Tip 2 diabet riski 2 kat Koroner arter hastalık riski
Nonalkolik steatohepatit

9 Klinik Bulgular Mood Depresyon Anksiyete Yeme bozuklukları
Yaşam kalitesi bozukluğu

10 Tanı Rotterdam Kriterleri
3 kriterden 2 tanesinin varlığı tanı koymak için yeterli Oligo ve/veya anovülasyon Klinik ve/veya biyokimyasal hiperandrojenemi bulguları Polikistik overler (USG) PCOS benzeri klinik durumu yapabilen tiroid hastalıkları, nonklasik konjenital adrenal hiperplazi, hiperprolaktinemi ve androjen üreten tümörler elimine edilmelidir.

11 Tanı

12 Tanı Birden çok klasifikasyon kriteri kullanımı klinisyen ve hasta açısından kafa karışıklığına yol açabilir. 2012 National Institutes of Health Evidence – based Methodology Workshop özet raporunda Rotterdam Kriterlerinin kullanımı önerilmiştir. Rutin olarak önerilmese de AMH kullanılabilir.

13 Tanı Polikistik overlerin USG tanısı ilk olarak 1986’da yapıldı.
2-9 mm çapında ≥ 12 folikül ve/veya ≥10mL over hacmi (0,5 x uzunluk x en x kalınlık) – tek overin uyması yeterli Daha önce önerilen folikül dağılımı, stromal ekojenite artışı ve artmış over volümü kriterlerinin elimine edilmesi önerilmiştir. Over volümü ve folikül sayısı yaşla azalmaktadır.

14 PKOS- Patofizyoloji Homburg R, Hum Reprod 2009

15 PCOS fenotipleri: Hiperandrojenizm
[1] type I classic PCOS Kronik anovulasyon Polikistik overler [2] type II classic PCOS Kronik anovulasyon Normal overler [3] ovulatory PCOS Ovulatuar sikluslar Normoandrojenizm [4] normoandrogenic PCOS Kronik anovulasyon For practical purposes, we will refer to phenotypes A and B as nonovulatory or classic PCOS. Phenotype C has also been referred to as ovulatory PCOS and as stated previously, phenotype D is the nonhyperandrogenic phenotype that has given rise to much of the controversy regarding the Rotterdam definition of PCOS. Androgen Excess and PCOS Society has suggested not including patients with normal androgen levels among the PCOS phenotypes (3). An expert committee of the Androgen Excess and PCOS Society (AEPCOS) suggested including only the first three phenotypes, excluding the fourth from the PCOS spectrum (3). arakis E, Escobar-Morreale HF, Futterweit W, et al. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin EndocrinolMetab 2006;91:4237–45. More recently, Dewailly and al. (4) reported that patients with chronic anovulation and polycystic ovaries but normal androgens have higher values of testosterone than controls, which suggests that these patients have a mild form of androgen excess. Welt et al. (5), studying a large heterogeneous group that included patients from New England and Iceland, concluded that ovulatory and normoandrogenic PCOS both represent a mild form of PCOS. polycystic ovaries need not be present to make the diagnosis (166),

16 Farklı PCOS fenotiplerinin rölatif prevalansları
Guastella et al, Fertil Steril 2010;

17 Farklı PCOS fenotiplerinin rölatif prevalansları
Abdominal obesite Artmış LH ve LH / FSH oranı Artmış androjenler Artmış insülin ve insülin direnci Type I classic PCOS represents the most common and severe form of PCOS. These patients presented as group with abdominal obesity, increased levels of LH and LH/FSH ratio, increased androgens, and elevated insulin and insulin resistance. In our setting, these patients represented almost 60% of all PCOS patients. Guastella et al, Fertil Steril 2010;

18 Farklı PCOS fenotiplerinin rölatif prevalansları
Klasik PCOS ve kontroller arasında BMI, bel çevresi, testosteron, insülin. LH genelde normal Ovulatory PCOS seems to be the mild form of classic PCOS. These patients presented with the most characteristics of PCOS but in a milder form. In fact, patients with ovulatory PCOS had intermediate values (between classic PCOS and controls) of BMI, waist circumference, testosterone, insulin, and QUICKI. Only the LH level was generally normal, and it represents the main difference from the other phenotypes of PCOS. On the other hand, it is well known that many patients with classic PCOS can attain ovulation by reducing their body weight (19). Therefore, we suggest that ovulatory PCOS may be the mild form of classic PCOS. Passage from classic to ovulatory PCOS and vice versa may be possible and related to sociocultural and environmental influences (20, 21). Guastella et al, Fertil Steril 2010;

19 Farklı PCOS fenotiplerinin rölatif prevalansları
Tip I’e göre önemli ölçüde düşük LH ve LH / FSH oranları Type II classic PCOS patients are very similar to other classic PCOS patients, but they are less common (only 8.4% of the total number of PCOS patients). The main difference between type I and type II classic PCOS is the LH levels and LH/FSH ratio. All patients with classic PCOS have increased LH and LH/ FSH ratios when compared with controls, but patients with polycystic ovaries have statistically significantly higher LH levels (and LH/FSH ratios) than patients with normal ovaries. This suggests that LH is important or in some way is related to the morphologic appearance of the ovaries. Guastella et al, Fertil Steril 2010;

20 Farklı PCOS fenotiplerinin rölatif prevalansları
Hafif testosteron yüksekliği (hala normal sınırlarda) FAI ve DHEAS normal Abdominal obesite yok Normal BMI Artmış LH ve LH / FSH oranı Normoandrogenic PCOS represents a unique group. We have confirmed the report by Dewailly et al. (4) that these patients have a mild testosterone excess (although within the normal range), but these patients do not present with hyperandrogenism— in fact, both their FAI and DHEAS levels are normal. Nor do these patients present with abdominal obesity—they have a normal BMI and normal waist circumference. From an endocrine point of view, this group of women is mainly characterized by increased LH and LH/FSH ratio, which is similar to classic PCOS and may be related in some way to their anovulation. In our opinion, normoandrogenic PCOS is part of the PCOS spectrum but may be a different disorder or have a different pathogenetic pathway. These women do not exhibit the two main components of PCOS: hyperandrogenism (at least, clinically relevant hyperandrogenism) and insulin resistance. Thus, we believe that it would be correct to keep these patients separated from other PCOS patients, as suggested by the Androgen Excess and PCOS Society committee (3). Guastella et al, Fertil Steril 2010;

21 Tanı 2013 Endocrine Society klinik pratik kılavuzunda, premenopozal kadınlarda PCOS tanısı için Rotterdam kriterleri önerilmiş. Postmenopozal kadınlarda durum daha karmaşık olsa da, iyi dökmante edilmiş uzun süreli oligomenore ve hiperandrojenizm hikayesi ile tanı konulabilir.

22 Ön Değerlendirme Hikaye ve Muayene - Rotterdam kriterlerine göre hikaye ve muayene ile birçok hasta PCOS tanısı alır. Adet düzensizliği tipik olarak ‘‘teenage’’ yıllarından başlar. 30 yaşından sonra oligomenore geliştiren kadınlarda PCOS olma olasılığı düşüktür. Serum Androjen Klinik – hirsutizm, akne (klinik hiperandrojenizm bulguları varsa biyokimyasal testlerin gerekliliği tartışmalı) Biyokimyasal – Total testosteron DHEAS (Hızlı ilerleyen hirsutizm) Serbest testosteron (sonuçlar güvenilir değil;total testesteron-SHBGüzerinden equilibrium dialysis ile hesaplanabilir)

23 Ayırıcı Tanı 1) Oligomenore 2) Polikistik Overler B-hCG
Prolaktin - hiperprolaktinemi TSH - tiroid hastalıkları FSH - over yetersizliği AMH LH gerekli değil, FSH/LH gerekli değil 2) Polikistik Overler USG bulgusu nonspesifik.

24 Ayırıcı Tanı 3) Hiperandrojenizm
Nonklasik Konjenital Adrenal Hiperplazi (21-hidroksilaz eksikliği) – elimine etmek için 17 OH progesteron bakılır. Etnik olarak Kuzey Avrupalı Yahudi, Hispanik, Slav, İtalyan kökenli kadınlarda prevalans yüksek (sırasıyla 1:27, 1:40, 1:50, 1:300) Sabah bakılan 17 OH progesteron > 200mg/dl (6nmol/L) Yüksek doz (250mcg) ACTH stimülasyon testi ile konfirme edilmelidir. ACTH sonrası serum 17 OH progesteron değeri 1000mg/dl (30nmol/L) < ise tanı dışlanır.

25 Ayırıcı Tanı Cushing Sendromu PCOS benzeri bulgular verebilir:
Oligomenore Hirsutizm Obezite İlave Bulgular: Hipertansiyon Supraklavikular yağlanma Hiperkortizolizm Strialar Proksimal kas zayıflığı

26 Androjen salgılayan tümörler
Androjen üreten over tümörü Adrenal tümör Ovarian hipertrikoz Serum testosteron > 150 ng/dl DHEA > 800 mcg/dL (adrenal tümör)

27 Tanı Sonrası Değerlendirme
Kardiometabolik risk değerlendirmesi Tip 2 Diabet, dislipidemi, koroner arter hastalığı açısından artmış risk Kan basıncı, BMI Açlık lipid profili 2 saatlik OGTT (açlık ve 2. saat glikoz) veya AKŞ + HbA1C Androjen Excess Society Normal Glukoz Seviyesi – Her 2 senede bir kontrol Bozulmuş glukoz tolerans testi – Yıllık takip İnsülin Rezistansı PCOS tanı ve tedavi seçimi için gerekli değil (validite edilen test yok)

28 Metabolic Syndrome: Kadında Tanısal Kriterler
30 yaş altında PCOS kadınlarda metabolic sendrom insidansı normal popülasyondan dört kat fazladır. (% 24) . WHO 1998 ve IDF 2005 de var. It is commonly diagnosed using the criteria suggested by Expert Panel on the Detection, Evaluation, and Treatment on High Blood Cholesterol in Adults (Adult Treatment Panel III or ATP III) (75),

29 Tanı Sonrası Değerlendirme
Depresyon ve Anksiyete PHQ-9 depresyon skalası GAD-7 anksiyete skalası

30 Tanı Sonrası Değerlendirme
Anovulatuvar Infertilite Intermenstruel interval 35 gün > ; oligoovulatuvar: Serum progesteron Düzenli sikluslarda 21.gün Düzenli değilse gelecek siklusun 7-10 gün öncesi

31 PKOS- Patofizyoloji Foliküle glukoz uptake azalır
İnsülin rezistansı Yüksek LH Foliküle glukoz uptake azalır Alternatif enerji pathway Glikolitik aneorobik pathway Bozulmuş foliküler mikroçevre Folikül içine glukoz girişi GLUT-4 aracılıghı ıle olur, ekspresyonu azalınca folikül içine glukoz girişi azaldığından Alternatif enerji pathwaylerinin kullanımı folikül mikrocevresini ve folikül içeriğini bozar ve oosit kalitesinin olumsuz etkiler

32 PKOS- Patofizyoloji Yüksek LH Azalmış VEGF Artmış RAS
Bozulmuş anjiogenezis Azalmış perifoliküler kan akımı Oksidatif stres, Artmış SOR Azalmış antioksidan kapasite SOR, serbest oksijen radikalleri, RAS renin-anjiyotensin sistemi

33 PKOS- shortterm ve Longterm sonuçlar

34 Farklı PCOS fenotiplerinde obstetrik ve neonatal sonuçlar
The cumulative rate of women with adverse obstetric or neonatal outcomes was significantly higher in the patients with PCOS than in the healthy controls (37/93 [39.8%] vs. 8/69 [11.6%], respectively; P= .0001) with an RR of 1.7 (95% CI 1.12–2.96). Recently, a meta-analysis (2) confirmed that the effects on reproductive function, which are due to PCOS, are not limited to infertility (oligoanovulation or anovulatory dysfunction), but also include pregnancy. A higher incidence of obstetric and neonatal complications has been detected in pregnant women with PCOS in comparison with controls (2). After categorizing patients with PCOS into the four ESHRE/ASRM phenotypes, significant differences between phenotypes were also found in the distribution of women with adverse obstetric or neonatal outcomes (13/14 [92.9%] vs. 6/7 [85.7%] vs. 3/5 [60.0%] vs. 15/67 [22.4%] for the full-blown, non-PCO, nonhyperandrogenic, and ovulatory phenotypes, respectively; P¼.003). The RRs for adverse obstetric or neonatal outcomes were 1.93 (95% CI 1.12–2.96), 2.23 (95% CI 1.21–3.15), 0.54 (95% CI 0.09– 1.63), and 0.48 (95% CI 0.31–0.78) for the full-blown, non-PCO, nonhyperandrogenic, and ovulatory phenotypes, respectively. The general linear model univariate procedure revealed a significant (P<.05) effect on the obstetric or neonatal outcomes if the patient had oligoamenorrhea and biochemical hyperandrogenism, whereas no significant effect was detected if clinical hyperandrogenism and PCO were present. First, we confirmed that pregnant women with PCOS had a higher incidence of obstetric or neonatal complications than healthy subjects (2). A higher prevalence of gestational diabetes mellitus was also observed, even if this risk was recently questioned in a systematic review of 16 studies, which included 2,263 women with PCOS and 92,933 controls (5). we found a higher RR for adverse outcomes in patients with the full-blown and non-PCO phenotypes than in those with the nonhyperandrogenic and ovulatory phenotypes. Our findings seem to demonstrate that ovarian dysfunction and biochemical hyperandrogenism affected obstetric or neonatal outcomes, increasing significantly (more than fourfold) the risk for obstetric or neonatal complication. Conversely, no significant effect was detected for clinical hyperandrogenism and PCO, which increased only slightly the risk for adverse outcomes. Ovarian dysfunction and biochemical hyperandrogenism seem to be related to hormonal and metabolic disruptions (9–11), which are probably linked not only to the long-term cardiovascular risks, as has already been demonstrated, but also to obstetric complications. On the other hand, there is some debate about the metabolic significance of PCO (12–14), whereas clinical hyperandrogenism seems to be related to the receptivity of terminal hair in sexual areas of the skin more than serum levels of androgens.

35 Tedavi amaçları Hiperandrojenemi semptomlarını yok et
Metabolik bozukluğu, tip 2 diabeti ve koroner kalp hastalığı riskini yönet Kronik anovülasyon sonrası oluşan endometrial hiperplazi ve endometrial ca riskini yönet Gebelik istemiyor; Hormonal Kontrasepsiyon – kilo verme Gebelik istiyor; Ovülasyon indüksiyonu – Kilo vermesi…

36 Sonuç PCOS heterojen bir endokrin bozukluğudur
Değişik fenotip spektrumu genel bir bozukluğun farklı derecelerinin ifadesi şeklindedir Bazı bilimsel kuruluşlar hiperandrojenemiyi hastalığın temel koşulu görmektedirler

37 teşekkürler

38 Tanı – Rotterdam kriterleri Polikistik overler (USG)
Özet Bazı bilimsel kuruluşlar hiperandrojenemiyi hastalığın temel koşulu görmektedirler Klinik Oligomenore Hiperandrojenemi; akne, hirsutizm Biyokimyasal – serum androjen artışı Tanı – Rotterdam kriterleri Oligomenore Hiperandrojenizm Polikistik overler (USG) 3/2

39 Bozulmuş foliküler mikroçevre
PKOS- Patofizyoloji İnsülin rezistansı Yüksek LH Hiperandrojenizm Bozulmuş foliküler mikroçevre Dislipidemi GDM riskinde artış Folikül sıvısının içeriği plazma ile korelasyon gösterir Increased ovarian androgen biosynthesis in the polycystic ovary syndrome results from abnormalities at all levels of the hypothalamic–pituitary– ovarian axis. The increased frequency of luteinizing hormone (LH) pulses in the polycystic ovary syndrome appears to result from an increased frequency of hypothalamic gonadotropin-releasing hormone (GnRH) pulses. The latter can result from an intrinsic abnormality in the hypothalamic GnRH pulse generator, favoring the production of luteinizing hormone over follicle-stimulating hormone (FSH) in patients with the polycysticovary syndrome, in whom the administration of progesterone can restrain the rapid pulse frequency. By whatever mechanism, the relative increase in pituitary secretion of luteinizing hormone leads to an increase in androgen production by ovarian theca cells. Increased efficiency in the conversion of androgenic precursors in theca cells leads to enhanced production of androstenedione, which is then converted by 17 b -hydroxysteroid dehydrogenase (17 ) to form testosterone or aromatized by the aromatase enzyme to form estrone. Within the granulosa cell, estrone is then converted into estradiol by 17 . Numerous autocrine, paracrine, and endocrine factors modulate the effects of both luteinizing hormone and insulin on the androgen production of theca cells; insulin acts synergistically with luteinizing hormone to enhance androgen production. Insulin also inhibits hepatic synthesis of sex hormone–binding globulin, the key circulating protein that binds to testosterone and thus increases the proportion of testosterone that circulates in the unbound, biologically available, or “free,” state. Testosterone inhibits and estrogen stimulates hepatic synthesis of sex hormone–binding globulin. The abbreviation scc denotes side-chain cleavage enzyme, StAR steroidogenic acute regulatory protein, and 3 -HSD 3 -hydroxysteroid dehydrogenase. Solid arrows denote a higher degree of stimulation than dashed arrows.

40 Özet Total testosteron, DHEA (Adrenal kaynaklı)
Oligoovulasyon ve hiperandrojenemiden sadece biri varsa USG ile polikistik over bakılır. Yoksa gerekli değil Prolaktin, TSH, FSH, AMH ek testler TA, BMI, AKŞ, 75gr OGTT

41 TEŞEKKÜRLER

42 PKOS Tanı- Fenotipleri Patofizyolojisi Semptomları
Short-term sonuçları Long-term sağlık riskleri Benzer semptomlara neden olan diğer durumlar

43 PKOS PKOS reprodüktif çağdaki kadınların yaklaşık %5-10’ nu etkiler
Kadınlarda en sık görülen endokrin bozukluktur Klinik olarak hormonal, reprodüktif, metabolik, fenotipik ve psikolojik problemlere neden olur Ma X, Mol Hum Reprod, 2007 Azziz R, J Clin Endocrn Metab, 2005

44 ANOVULASYON WHO sınıflaması
GRUP I: Hipotalamik-pitüiter yetmezlik (hipotalamik amenore) Stress ile indüklenen Anoreksia nervosa Kallmann Sendromu İzole gonadotropin eksikliği GRUP II: Hipotalamik-pitüiter disfonksiyon Normogodotropik, normoestrojenik, anovulatuar ve oligomenoreik kadınlar Bu grup klasik PCOS ‘ nu içine alır GRUP III: Ovaryen yetmezlik (Hipergonadotropik hipogonadanizm)

45 NIH – Rotterdam – AEPCOS criteria
We generally recognize four key features of PCOS: [i] ovulatory and menstrual dysfunction, [ii] hyperandrogenemia, [iii] clinical features of hyperandrogenism, and [iv] polycystic ovaries. L: Too few data are available to be able to predict whether women with regular ovulation and polycystic ovaries have an increased cardiovascular risk. There has been significant controversy regarding the diagnosis of PCOS, primarily owing to heterogeneous manifestations, which may change during a woman’s lifetime. An expert conference in 1990 sponsored by the National Institute of Child Health and Human Development (NICHD) was therefore convened to obtain consensus on the diagnostic criteria for PCOS. The following two criteria were considered central to the diagnosis of PCOS: 1) clinical and/or biochemical hyperandrogenemia; and 2) oligo- or anovulation, with exclusion of other known disorders such as congenital adrenal hyperplasia and androgen-producing tumors (3). Of note, the finding of polycystic ovaries on ultrasound (PCOUS), a clinical feature recognized to be associated with PCOS, was rejected at the NICHD conference as an essential component of the diagnostic criteria. In the decade following the implementation of the NICHD criteria, it was recognized that a broader spectrum of PCOS existed, extending beyond the diagnostic criteria put forth in 1990 Another expert conference was convened in Rotterdam, The Netherlands, May 1–3, 2003 sponsored in part by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine (14, 15). The meeting proceedings recommended that PCOS be defined when at least two of the following three features were present: [i] oligo and/or anovulation, [ii] clinical and/or biochemical signs of hyperandrogenism, and [iii] polycystic ovaries. These criteria also recognize that other androgen excess or related disorders should be excluded before assigning the diagnosis of PCOS. Molecular pathofizyoloji * genetic markers. Despite considerable phenotypic heterogeneity in PCOS, and overlap with the normal population, several metabolic and hormonal markers may prove helpful in future attempts to identify the PCOS genes. In addition to phenotypic heterogeneity, genetic heterogeneity likely exists. Phenotypic heterogeneity, inconsistent diagnostic criteria, temporal variation in symptoms, and incomplete penetrance plague ongoing research to identify the genes in other disorders as well. Considering the four features of ovulatory dysfunction, hirsutism, hyperandrogenemia, and polycystic ovaries, the Task Force identified nine phenotypes that could be considered as being PCOS considering current evidence (Fig. 1). However, the Task Force recognizes that clinical features may not be constant even in a single patient and can be modified by changes in body weight and lifestyle choices. In addition, the Task .

46 AE-PCOS PCOS is a hyperandrogenic disorder: the Task Force felt that PCOS was above all a disorder of androgen biosynthesis, utilization, and/or metabolism in women. As such, with currently available evidence the diagnosis of PCOS should not be established without evidence of either clinical or biochemical hyperandrogenism. Finally, the Task Force also recognized that although many patients with PCOS would have evidence of acne or androgenic alopecia, these could not be used reliably as clinical signs of hyperandrogenism. That the ovarian morphology should be considered when establishing the diagnosis, as polycystic ovaries are found in the majority, although not all, women with PCOS: That ovulatory dysfunction is a prominent, but not universal feature, of PCOS: the Task Force recognized that some patients with PCOS may demonstrate regular ovulation at the time of their evaluation, the so-called ‘‘ovulatory PCOS’’ (71, 108). However, the Task Force noted that patients with ‘‘ovulatory PCOS’’ constituted a minority of the PCOS population, and had less severe androgenic and metabolic features than anovulatory women with PCOS. The Task Force also recognized that there exists little data regarding the long-term maintenance of ovulation in women with ovulatory PCOS, whether these patients were intermittently anovulatory to a greater degree than normal, and that ovulatory function in PCOS often improved as patients neared the perimenopause. Recognition of associated abnormalities: the Task Force noted that the presence of obesity, insulin resistance, and hyperinsulinism, and increased LH levels or an LH/FSH ratio, while observed in a significant fraction of patients, should not be used as part of the definition of PCOS. Overall, at the present time, in the Task Force’s assessment, women with oligoamenorrhea and polycystic-appearing ovaries on ultrasonography but no evidence of hyperandrogenism may not have PCOS and should be considered as having a different disorder.

47 Rotterdam Criteria - 2003 Hiperandrojenizm Polikistik overler
Kronik anovulasyon The Rotterdam 2003 guidelines for diagnosis of PCOS included the sonographic finding of polycystic ovaries among the criteria. Rotterdam criteria (2) are more extensive, including patients with very different clinical appearances.the Rotterdam criteria may be useful for understanding the complexity and the heterogeneity of the syndrome, It is important to recognize that the new Rotterdam criteria have not nullified the NICHD criteria; rather, they have served to expand the diagnosis of PCOS to include the NICHD phenotype and other new phenotypes namely; 1) complete phenotype: oligo-/anovulation, hyperandrogenism, and PCO-US (OþHþP); 2) ovulatory phenotype: hyperandrogenemia and PCO-US (HþP); and 3) nonhyperandrogenic phenotype: oligo-/anovulation and PCO-US (OþP).

48 PKOS TANI ESHRE/ASRM 2003 Rotterdam kriterleri Oligo-anovulasyon
Klinik ve/veya biyokimyasal hiperandrojenizm USG de PCO görünümü

49 The two phenotypes of classic PCOS differed only in LH and LH/FSH ratios, which were statistically significantly higher in type I than in type II classic PCOS (see Table 2). Type I classic PCOS had statistically significantly higher values for LH levels and LH/FSH ratio than the controls and patients with ovulatory PCOS (see Table 2). Patients with type II classic PCOS had LH values that were similar to the controls and patients with ovulatory PCOS but a higher LH/FSH ratio than those two groups (see Table 2). Patients with ovulatory PCOS had LH and LH/FSH ratios similar to normal controls but lower than patients with classic or normoandrogenic PCOS Finally, patients with normoandrogenic PCOS had statistically significantly higher values for LH and the LH/FSH ratio than the controls (see Table 2). Also, although their testosterone values were in the normal range, their mean testosterone was statistically significantly higher compared with controls

50 Abdominal yağlanmanın önemi
Using Dual Energy X-ray Absorptiometry (DEXA), we found that although BMI and total fat were similar in the two groups (Table 1), there was more central distribution of fat in classic PCOS with a significantly higher percentage of trunk or abdominal fat, as well as an increased waist circumference (64). The ovulatory PCOS group had similar body composition compared to age and BMI- matched controls. Thus, it does appear from these data that ovulatory PCOS is a milder phenotype, with less prevalent features of insulin resistance and other metabolic and CV risk factors. Nonhyperandrogenic PCOS (phenotype D) It should be acknowledged that although this phenotype is considered part of the spectrum of PCOS according to the Rotterdam criteria, this is not universally accepted The prevalence of metabolic syndrome and insulin resistance was lower in this phenotype with normal androgens, compared with classic PCOS and ovulatory PCOS Therefore, this finding suggests to us that, although androgens appear to enhance the metabolic and CV risks in women with PCOS, the PCO may also be a contributor of this profile through unknown mechanisms.

51 PKOS- Patofizyoloji (Insulin Resistance and Hyperinsulinemia)
SHBG production Ovarian androgen production Disordered LH/FSH release Hyperandrogenism Anovulation Polycystic ovary syndrome

52 PCOS Oligo-Anovulation infertility Hirsutism Obesity
Cardiovascular diseases Insulin resistance Type-II DM Endometrial cancer

53 İnfertilite nedenleri
Speroff, Clinical Gynecologic Endocrinology and Infertility, Eighth Edition, 2011

54 Hangi kriterler hangi amaca yönelik ?
NIH 1990 AE-PCOS Society Uzun dönem metabolik veya CVS morbidite açısından Genetik temelin bulunması açısından Roterdam 2003 Anovulatuar infertilite / OHSS riskinin belirlenmesi açısından Thus, if the ultimate clinical or investigational concern were to be the long-term metabolic or cardiovascular morbidities of patients with PCOS, defining the disorder using the NIH 1990 or the AE-PCOS Society criteria would seem more appropriate. If the interest were to determine the genetics underlying this complex trait, then a more restrictive criteria, such as the NIH 1990, or even more limited to one or tow specific phenotypes (see Table 1) may be necessary to maximize homogeneity of the population. Alternatively, if the interest is determining the risk for anovulatory infertility and or hyperstimulation during ovulation induction, then broader criteria such as that proposed by Rotterdam 2003 may be appropriate (298).

55 PKOS – farklı fenotiplere göre KVS risk profili
there is little information about whether the risks pertain to all women with PCOS We conclude that in terms of CV and metabolic risks, not all women with PCOS should be considered alike. Metabolic syndrome is prevalent in women with PCOS, and it is known to be associated with a higher incidence of CV disease and DM. Metabolic syndrome evaluated in a group of white women with PCOS had an incidence of 46% compared with 23% in the general population (45). Even when matched by age and body mass index (BMI), the prevalence of metabolic syndrome was higher in the PCOS population, especially in those affected by the presence of acanthosis nigricans, indicating the importance of insulin resistance (46). Clearly, ethnicity and lifestyle differences between populations influence the prevalence of metabolic syndrome in PCOS. In one study, only 8.2% of patients met the Adult Treatment Panel III (ATP-III) criteria for metabolic syndrome in southern Italy (48). This much lower rate of metabolic syndrome in Italy compared with the United States is most likely influenced by the lower prevalence of obesity (only 30% of Italian women with PCOS are considered to be obese, compared with >50% in the United States) and lower incidence of dyslipidemia, particularly lower triglyceride levels For practical purposes, we will refer to phenotypes A and B as nonovulatory or classic PCOS. Phenotype C has also been referred to as ovulatory PCOS and as stated previously, phenotype D is the nonhyperandrogenic phenotype that has given rise to much of the controversy regarding the Rotterdam definition of PCOS. In a review by Dewailly et al. (55), the majority of women with PCOS (61%) could be retrospectively categorized into phenotype A. Phenotype C and D each represented approximately16% of the population. It should be understood that if routine ultrasound is used to attempt to aid in the diagnosis of PCOS in women who are only diagnosed clinically, only 5–7% will be found to have ‘‘normal’’ ovaries. The non-classical phenotypes are those referred to previously as phenotype C (ovulatory PCOS) and the non-hyperandrogenic phenotype D. We have also been able to assess the risk factor profiles of a number of women with unexplained or idiopathic hyperandrogenism (IH), who have normal menstrual function and normal ovaries. Although these women with IH are not considered to have PCOS, an assessment of this group allows us to determine the importance of the presence of polycystic ovaries or of hyperandrogenism on the various risk factors When examining the prevalence of finding at least one abnormal CV risk factor, it was 40% in classic PCOS and 20% in ovulatory PCOS, and it was found in only 5% of normal controls examined, which was similar to the prevalence in women with IH (Fig. 3). The fact that androgen levels were similar in women with IH and ovulatory PCOS, yet the CV risk factors were higher only in ovulatory PCOS, suggests the possibility that the existence of PCOs constitutes an independent risk factor, although this is merely a hypothesis.

56 PKOS- farklı fenotipler için metabolik komplikasyon riski
Evidence suggests that hyperinsulinemia plays a central role in the pathogenesis of PCOS.Women with PCOS demonstrate a significantly higher prevalence of impaired glucose tolerance and noninsulin dependent diabetes mellitus (NIDDM) compared with age- and weight-matched control subjects (5). More recently, we reported that the risk of metabolic syndrome is 11-fold higher in women with PCOS compared with age-matched controls (6). In addition, we found those women to have an increased risk for cardiovascular disease, as indicated by an elevated triglycerides (TG)/high-density lipoprotein (HDL) ratio (7). Other cardiovascular risk factors reported in this population include lipid abnormalities, hypertension, carotid and coronary atherosclerosis, and endothelial dysfunction (8–11). The majority of this data is based on studies defining women with PCOS by the NICHD criteria. There are limited data on metabolic complications in women belonging to the newer PCOS phenotypes as defined by the Rotterdam criteria, especially the nonhyperandrogenic phenotype (12). Participants were classified as having metabolic syndrome if they met three of the following five criteria: body mass index (BMI) >30, serum TG R150 mg/dL, serum HDL-cholesterol <50 mg/dL, blood pressure R130/85 mm Hg or on antihypertensive medication, and fasting blood glucose R100 mg/dL or the presence of NIDDM (14). A lower cut-off for glucose was used, based on recent guidelines (15). In PCOS subjects, insulin resistance (IR) was estimated using fasting insulin, homeostasis model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI). The HOMA-IR was calculated with the formula (fasting insulin [U/mL] x fasting glucose [mmol/dL])/22.5; percentage b-cell function ¼ (20 x insulin [mU/mL]/(glucose [mg/dL] x ) ; the QUICKI was derived by calculating the inverse of the sum of logarithmically expressed values of fasting insulin and glucose. The ageadjusted prevalence of metabolic syndrome was 36.1% for women with O+H+P (odds ratio [OR] 6.3 [95% confidence interval 2.1–18.9]), 41.3% for women with O+H (OR 7.8 [2.2–27.5]), and 42.3% for women with H+P (OR 8.2 [2.2–29.5]). For these three phenotypes, the prevalence of metabolic syndrome was significantly higher than the control subjects (8.3%; P<.001). The age-adjusted prevalence of metabolic syndrome in women with O+P (20.3%) was not statistically different compared with the control subjects To explore the role of BMI in the prevalence of metabolic syndrome, we examined women with obesity (BMI >30) separately. No women in any of the phenotype groups with a BMI <30 had metabolic syndrome. A higher proportion of PCOS women had NIDDM (3%–6%), except for the O+P phenotype, where no subjects had a fasting glucose level > 126 mg/dL (Fig. 2). The prevalence of impaired fasting glucose (IFG, fasting glucose 100–125 mg/dL) in women with O+H+P, O+H, and H+P (16%–17%, Fig. 2) was higher than in the phenotype O+P (6%), although this was not statistically significant. The mean fasting glucose level was not significantly lower in the control group (90.6 ± 12.5) compared with all 4 phenotype groups (Table 3). There was no significant difference in mean fasting glucose levels among the four phenotype groups after adjusting for age and BMI. The measures of insulin resistance QUICKI and ratio of fasting glucose to insulin (17) were not significantly different among the four PCOS subgroups (Table 3). The mean HOMA-IR levels in all four groups were not significantly different. The percentage of women with an abnormal HOMA-IR (>1.0 mol$mU/L2) (18) was similar in all groups (84.6%–94.1%). Beta-cell function was also similar in all four groups, and the percentage of subjects with abnormal HOMA b-cell (<100%) (18) were similar in all groups (18.8%–24.1%). We did not have fasting insulin levels in the control subjects to compare with the PCOS phenotypes. The complete phenotype (O+H+P), the hyperandrogenic phenotype (H+P), and the NICHD phenotype (O+H) all had a six- to eightfold increased risk of metabolic syndrome compared with the control group. The reported prevalence of metabolic syndrome in women with PCOS varies between 30% and 47% (6, 16, 20), depending on the criteria used for defining both PCOS and metabolic syndrome. but a lower risk in the nonhyperandrogenic PCOS phenotype (O+P, 20%). Although this lower prevalence was not significantly different from our geographically matched controls, In addition, the OþP phenotype had similar mean TG and HDL levels and TG/ HDL ratio compared with the control group. This suggests that OþP phenotype women may have fewer cardiovascular risk factors. These data collectively suggest that the nonhyperandrogenic phenotype (OþP), one of the new phenotypes created by the Rotterdam Criteria, may represent a form of PCOS associated with a milder metabolic profile. we did not find metabolic syndrome in any women with BMI <30, suggesting that in this young population obesity is an important determinant of metabolic syndrome. The risk of metabolic syndrome in women with PCOS is increased independentof BMI (17) An increased risk for impaired glucose tolerance and NIDDM in women with PCOS (NICHD criteria with biochemical hyperandrogenism) has been reported (5). The present study shows a trend toward a higher risk for IFG and NIDDMin all PCOS phenotypes, except women with nonhyperandrogenic phenotype (OþP), compared with control subjects We used different surrogate markers to examine insulin resistance in the four phenotypes and were unable to detect a significant difference. We found no significant difference in the prevalence of metabolic syndrome among the phenotypes that include women with hyperandrogenemia. In an Australian study, women with PCO-US only (n ¼ 15) had a similar metabolic profile as control subjects (12). In the same study, women with PCO-US and cycle irregularity (OþP; n ¼ 6) had evidence of hypertriglyceridemia and insulin resistance compared with control subjects. In contrast, we found the OþP group to have the lowest risk for metabolic syndrome, NIDDM, IFG, and lipid abnormalities, specifically the TG/HDL ratio. These findings suggest that the OþP phenotype may have an intermediate risk for metabolic complications compared with the other phenotypes and control subjects. Larger studies are needed to determine the precise metabolic risks in this specific phenotype to appropriately counsel this population. These findings suggest that the ovulatory PCOS subjects (HþP) have similar risks as the complete phenotype (HþOþP) and the NICHD phenotype (HþO). However, the nonhyperandrogenic (OþP) phenotype may represent a form of PCOS with an intermediate or milder metabolic risk profile.

57 Ayırıcı tanı PCOS is a hyperandrogenic disorder: the Task Force felt that PCOS was above all a disorder of androgen biosynthesis, utilization, and/or metabolism in women. As such, with currently available evidence the diagnosis of PCOS should not be established without evidence of either clinical or biochemical hyperandrogenism. Finally, the Task Force also recognized that although many patients with PCOS would have evidence of acne or androgenic alopecia, these could not be used reliably as clinical signs of hyperandrogenism. That the ovarian morphology should be considered when establishing the diagnosis, as polycystic ovaries are found in the majority, although not all, women with PCOS: That ovulatory dysfunction is a prominent, but not universal feature, of PCOS: the Task Force recognized that some patients with PCOS may demonstrate regular ovulation at the time of their evaluation, the so-called ‘‘ovulatory PCOS’’ (71, 108). However, the Task Force noted that patients with ‘‘ovulatory PCOS’’ constituted a minority of the PCOS population, and had less severe androgenic and metabolic features than anovulatory women with PCOS. The Task Force also recognized that there exists little data regarding the long-term maintenance of ovulation in women with ovulatory PCOS, whether these patients were intermittently anovulatory to a greater degree than normal, and that ovulatory function in PCOS often improved as patients neared the perimenopause. Recognition of associated abnormalities: the Task Force noted that the presence of obesity, insulin resistance, and hyperinsulinism, and increased LH levels or an LH/FSH ratio, while observed in a significant fraction of patients, should not be used as part of the definition of PCOS. Overall, at the present time, in the Task Force’s assessment, women with oligoamenorrhea and polycystic-appearing ovaries on ultrasonography but no evidence of hyperandrogenism may not have PCOS and should be considered as having a different disorder.

58 Tanı Sonrası Değerlendirme
Transvajinal USG’nin rolü Anovülasyon riski Anovülasyon yoksa infertilite riski belirsiz Gebe kalmak isteyen kadınlarda USG ile ovülasyon takibi