PCOS as a Metabolic syn-drome

Sang Ho Yoon

Division of Reproductive Endocrinology and Infertility

Department of Obstetrics and Gynecology

Dongguk University Graduate School of Medicine

Diagnostic criteria for Metabolic syn-drome : International Diabetes Federation (IDF)

Stein & Leventhal in the 1930s• Described the association between PCO mor-

phology, hirsutism, menstrual disturbances and obesity

The most common endocrine disorder in women

3 ~ 10 % of women of reproductive age 25 ~ 30% of infertility patients Major cause of anovulatory infertility

• 75% of PCOS: infertility d/t anovulation

Polycystic ovary syndrome (PCOS)

N Engl J Med , 2005

PCOS pathogenesis

Jayasena et al., Nat Rev Endocrinol, 2014

Clinical problem in PCOS

배란장애에 의한 불규칙한 월경 및 불임

남성호르몬 과다증세

당뇨 , 심혈관계 질환 위험도 증가Katsiki et al, Drugs, 2009

Lifelong complications

Norman et al., Lancet, 2007

Diagnostic criteria for PCOS

Jayasena et al., Nat Rev Endocrinol, 2014

Polycystic Ovary Definition

• TV USG• Follicular phase • 12 or more follicles measuring 2–9 mm in diam-

eter• Increased ovarian volume (>10 mL)

Serum anti-Műllerian hormone (AMH)• Secretion : granulosa cells of developing folli-

cles• Potential surrogate for USG• Correlate : AFC • If USG is inappropriate or unavailable

Rotterdam Criteria of PCOS

Polycystic Ovaries

Androgen Excess

Anovulation

2

1

3

Area 2 Hyperandrogenism

(clinical and/or biochemical)Polycystic ovaries

Regular cycles

Area 3Anovulation

Polycystic ovaries No evidence of androgen ex-

cess

Area 1NIH criteria 1990

Frank S, J Clin Endocrionol Metab, 2006

All possible phenotypes

Features

Hyperandrogenemia

Hirsutism

Oligoanovulation

Polycystic ovaries

NIH 1990 criteria

Rotterdam 2003 crite-ria

AES 2006 criteria

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Phenotypes

Azzizz et al, J Clin Endocrionol Metab, 2006

Hyperandrogenism

Nuremberg chronicle – Strange people – Hairy lady, 1493

Definition Clinical signs: hirsutism, acne, alopecia

(male-pattern balding) and frank viriliza-tion

Biochemical indicators• ↑total testosterone & androstenedione, • ↑free androgen index• However, these markers has proved markedly in-

consistent d/t problems with various assays

→ Reliable detection of this feature is not straightforward

The ESHRE/ASRM Rotterdam Consensus Meeting, 2003

Norman et al., Lancet, 2007

Clinical sign: Hirsutism

Being present in 65-75% of patients with PCOS defined by the NIH criteria

Rarely present in Asian women

Degrees vary greatly in different ethnic population

Modified FG score might underestimate clinical sign • Threshold of abnormality should be measured on

a population basis

Androgen Excess Society Guideline., JCEM, 2006Legro et al., JCEM, 2013

Carmina et al., AJOG, 1992DeUgarte et al., JCEM, 2006

Assessment of Hirsutism

95th percentile as upper normal limit in the white or black: 6-8

modified Ferri-man-Gallwey score

Ferriman D, Gallwey JD, JCEM. 1961

Escobar-Morreale., Hum Reprod Update, 2012

Clinical sign: androgenic alopecia

Ludwig., Brit J Derm, 1977

In Men In Women

Other clinical signs

Acne • Affects 14-25% of PCOS pts. • Unclear whether the prevalence of acne is signif-

icantly increased than general population Androgenic alopecia

• The prevalence in PCOS is unclear• Less frequent and presents later

Acne or androgenic alopecia could not be used reliably as clinical sign of hyperan-drogenism.

Androgen Excess Society Guideline., JCEM, 2006Norman et al., Lancet, 2007Legro et al., JCEM, 2013

Biochemical hyperandro-genism

Elevated circulating androgen levels• In 60-80% of PCOS pts.• The vast majority of abnormal value: free testos-

terone Low SHBG

• Excellent diagnostic accuracy for PCOS• Surrogate marker of insulin resistance and andro-

gen excess

However, between 20-40% of PCOS will have androgen levels within the normal range• Assays for androgens tend to be highly variable

and inaccurate• Some patients have normal levels of free T

Androgen Excess Society Guideline., JCEM, 2006Jayasena., Nat Rev Endorinol, 2014

Conway et al., Eur J Endocrinol, 2014

Biochemical assessment

Single most reliable indices of hyperandro-genism• Hirsutism & free T levels

Total testosterone is the first-line recom-mendation for assessing androgen excess in women• RIA to measure free T directly → been criticized for lack of accuracy, so should not

be used

FAI (Free androgen index) • By measurement serum total T and SHBG (T/

SHBG x 100)• Practical alternative to the measurement of free

T• Androstenedione, DHEAS → need in severe hirsu-

tim

Jayasena., Nat Rev Endorinol, 2014Conway et al., Eur J Endocrinol, 2014

Conway et al., Eur J Endocrinol, 2014

Norman et al., Lancet, 2007

Excessive ovarian androgen pro-duction

PCOS is the underlying factor in as many as 92% of women with hirsutism & 84% with persistent acne

PCOS should primarily be regarded as a disorder of excessive androgen biosynthe-sis, use or metabolism

Adams et al., BMJ, 1986Homburg., Hum Reprod, 1996

Androgen Excess Society Guideline., JCEM, 2006

Hyperandrogenism PCO

• Associated with hypersecretion of LH• Thickened theca cell layer• Theca cells secrete excessive androgens in basal

state or in response to LH stimulation

Both insulin and LH, alone and in combina-tion, exacerbate ovarian androgen produc-tion

Homburg., Best Pract Res Clin Obstet Gynecol, 2008Jayasena., Nat Rev Endorinol, 2014

Insulin resistance

Pathophysiology-hyperinsu-linemia

Speroff 8th ed., 2011

The role of hyperinsulinemia in the pathogenesis of PCOS

Homburg., Best Pract Res Clin Obstet Gynecol, 2008

Reported IR in PCOS

Legro et al., Obstet Gynecol Survey, 2004

Assessment of IR Still several problems…

• Apparent lack of consensus on “normal” insulin sensitivity

• Ethnic and genetic variability• Other factors contributing to IR such as obe-

sity, stress, and aging• Concern about whether simplified models of IR

have the precision to predict treatment needs, response, and future morbidity.

Assessment of insulin as a fasting hor-mone or as a surrogate of IR (HOMA…) is of little value although widely used for re-search studies. Norman et al., Lancet, 2007

Legro et al., Obstet Gynecol Survey, 2004

Consensus

No test of insulin resistance is needed ei-ther to make the diagnosis of or to select treatment for PCOS

Recommend the use of 75g OGTT to screen for IGT and T2DM in adolescent and adult women with PCOS

The ESHRE/ASRM Rotterdam Consensus Meeting, 2003

Legro et al., JCEM, 2013

Hyperinsulinemia Overall prevalence of IGT among US women

with PCOS was 30-35%, and 3-10% had T2DM• Non-obese PCOS: 10-15% prevalence of IGT and

1-2% prevalence of T2DM

A diagnosis of PCOS confers a 5-10-fold in-creased risk of developing T2DM

Key factor in the pathogenesis of anovula-tion and hyperandrogenism

Legro et al., JCEM, 2013

Cardiovascular events

Cardiovascular events in PCOS

Initial studies did not find an increased prevalence of nonfatal/fatal CVD in women with PCOS (Pierpoint et al., 1998; Wild et al., 2000)

Lifetime risk for CVD in PCOS women is high and mostly preventable, all PCOS women should be screened for CVD risk factors

Wild et al., JCEM, 2010

Incidence

Glucose intolerance: 30% of adolescents with PCOS

Dyslipidemia: 70 % of reproductive aged PCOS women

Non obese PCOS women: also may have

• Glucose intolerance

• Dyslipidemia

Syndrome X

Metabolic abnormalities: 외국 data

저자 국가 PCOS 대조군

제 2 형 당뇨

Ehrmann et al., 1999

USA 10% (13.5-40 years)

2.5% (NHANES II, 20-44 years)

이상지혈증 Legro et al., 2001 USA 70%

고혈압 Lo et al., 2006 USA 12% 4.9%

대사증후군 Apridonidze et al., 2005

USA 43%*

* Nearly 2-fold higher than age-matched general population

Metabolic abnormalities: 국내 data

Chae et al., 2008 (SNUH) Other Korean reports

제 2 형 당뇨 2.0% 1.0% (Lee et al., 2009)

이상지혈증 28.6% (14.1% in controls)

고혈압 (≥140/90mmHg)

13.6% (2.6% in controls)

대사증후군 23.3% (1.4% in controls)

14.5% (Park et al., 2007)

비만 (BMI≥25kg/m2) 25.2% 28.4% (Lee et al., 2009)

Chae et al, Hum Reprod, 2008

Age-related changes in the PCOS phenotype through-out lifespan

Reproductive abnormali-tiesClinical hyperandro-genismOverweight/obesity

Metabolic abnormalities (type 2 dia-betes)Postmenopausal hyperandrogenism (?)CVD (?)

Adolescence Adult fertile age Menopause Postmenopause

Pasquali et al., Ann N Y Acad Sci, 2006

Therapeutic goals in pt. with PCOS Restore menses and reduce the signs of

hyperandrogenism.

Prevention of endometrial cancer

Achieve successful pregnancy.

Avoidance of the long-term complication that are associated with obesity, insulin re-sistance, glucose intolerance, and type 2 DM.

The Amsterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, Hum Reprod 2012

Korean data

Prevalence of the PCOS sub-groups

Ethnics IM+HA+PCO IM+HA IM+PCO HA+PCO

Welt et al (2006-12)USA,

Iceland298 (71.3%) 7 (1.7%) 36 (8.6%) 77 (18.4%)

Dewailly et al (2006-10) France 246 (60.6%) 27 (6.7%) 66 (16.3%) 67 (16.5%)

Hsu et al (2007) Taiwan 88 (51.7%) 15 (8.8%) 31 (18.2%) 36 (21.1%)

Pehlivanov et al (2007) Bulgaria 41 (58.6%) 8 (11.4%) 7 (10.0%) 14 (20.0%)

Diamanti-Kandarakis (2007)

Greece 284 (46.4%) 251 (39.6%) 43 (6.8%) 46 (7.2%)

SNUH (2008) Korea 87 (52.4%) 23 (13.9%) 52 (31.3%) 4 (2.4%)

IM: Irregular menstruation (oligo-anovula-tion)

HA: Hyperandrogenism, PCO: Polycystic Ovary

No significant differ-ence in the prevalence of metabolic syndrome between women with O+P and control sub-jects, even in obese women

Shroff et al., Fertil Steril, 2007

PCOS phenotype in Korean cohort

Kim et al, Fertil Steril, 2014

PCOS phenotype in Korean cohort

Kim et al, Fertil Steril, 2014

PCOS phenotype in Korean cohort

Kim et al, Fertil Steril, 2014

Summary PCOS is the most common cause of hyper-

androgenic chronic anovulation and infertil-ity

Overproduction of androgens is at the heart of PCOS, often exacerbated by asso-ciated hyperinsulinemia

Obesity is common feature of PCOS but not a prerequisite for its development

Increased risk of developing type 2 dia-betes and cardiovascular disease

Summary PCOS without HA are common in Korea

and are less likely to have metabolic dys-function, insulin resistance and elevated BP

PCOS without HA may be a mild pheno-type of PCOS

PCOS in Korea could have a reduced like-lihood of having metabolic syndrome compared with other ethnicities

Needs Research…

Norman et al., Lancet, 2007Shroff et al., Fertil Steril, 2007Homburg., Best Pract Res Clin Obstet Gynecol, 2008

Risk of metabolic syndrome may vary among the phenotypes→ Individualization of treatment according to pheno-type