PCOS new concepts and treatment

Peking University Third Hospital, P.R.China

Qiao Jie

The most common endocrine disorder Affecting about one in 15 reproductive age

women worldwide Heterogeneous presentation Features: clinical and/or biochemical

hyperandrogenism ovulatory dysfunction polycystic ovaries

PCOS

PCOS

Leading cause of androgen excess and ovulatory dysfunction

Causes 70–80% of hyperandrogenism Obesity LH/FSH ＞ 2 or 3 Insulin resistance (IR) Impaired glucose tolerance (IGT) Type 2 diabetes mellitus (DM) Dyslipidemia and cardiovascular disease

BRADLEY TRIVAX, MD CLINICAL BSTETRICS AND GYNECOLOGY Volume 50, Number 1, 168–177

PCOS symptoms and signsPCOS symptoms and signs

Robert J Norman, Lancet 2007; 370: 685–97

Saad A K Amer Obstet, Gynaecol Reprod Med 19:10

Criteria

The 1990 National Institutes of Health (NIH) criteria

Clinical hyperandrogenism and/or hyperandrogenemia

Oligo-ovulation or anovulation

Exclusion of related disorders

Zawadzki J Boston: Blackwell; 1992. pp. 377–384

Criteria

2003ESHRE/ASRM Rotterdam consensus meeting(Include 2 of the following)

Oligo- or anovulation

Clinical and/or biochemical signs of hyperandrogenism

Polycystic ovary morphology

Exclusion of related disorders

The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus WorkshopGroup. Fertil Steril 2004; 81:19–25

Phenotypes

2003 Rotterdam expanded the definition of PCOS, adding two additional phenotypes

1) polycystic ovaries and clinical and/or biochemical evidence of androgen excess

without ovulatory dysfunction

2) polycystic ovaries and ovulatory dysfunction without hyperandrogenemia and/or hirsutism (i.e. no

signs of androgen excess)

Controversy

Whether these two phenotypes actually represent PCOS ??

subtle endocrine and metabolic abnormalities

Conditions also present with polycystic-appearing ovaries and ovulatory dysfunction

Hypothalamicamenorrhea Hyperprolactinemia Pubertal development

Bradley Trivax, Cilinic Bstetrics Gynecol 50(1) 168–177

Controversy

Whether these two phenotypes actually represent PCOS ??

Carmina studied normal ovulation with PCO, hyperandrogenism women :

degrees of hyperinsulinism and hyperandrogenemia significantly less than NIH 1990 criteria PCOS

whether increased risk for developing metabolic complications, including type 2 DM, is not known

Carmina E Hum Reprod. 2009 Sep;24(9):2286

Phenotype (based on 2003Rotterdam criteria)

Robert J Norman, Lancet 2007; 370: 685–97

Phenotype (based on 2003Rotterdam criteria)

Robert J Norman, Lancet 2007; 370: 685–97

Criteria

AES 2006 (include all of the following)

Hyperandrogenism(hirsutism and/or

hyperandrogenemia)

Ovarian dysfunction(oligo-anovulation and/or polycystic

ovary)

Exclusion of related disorders

AES opinion: A principal conclusion was that PCOS should be first considered a disorder of androgen excess or hyperandrogenism

Ricardo AzzizThe Journal of Clinical Endocrinology & Metabolism 91(11):4237–4245

Prevalence Different in various race and ethnicity US: Blacks 8.0 % and Whites 4.8% Spain :6.5% Greek :6.8% Higher : Immigrant Indian subcontinent

Aboriginal heritage Australian

according to the definition of PCOS used the 2003 Rotterdam criteria is broader than 1990

NIH criteria: 1.5-fold higherRobert J Norman Lancet 2007; 370: 685–97

Hyperandrogenism

most important features of the syndrome classic PCOS phenotype : higher androgen

levels

clinical features ——hirsutism, acne, male-pattern alopecia

Biochemical ——testosterone ↑, DHEAS↑

androstenedioneor ↑, SHBG ↓

Hyperandrogenism

high circulating T concentrations: 60–80% high DHEAS concentrations: 25%

Mornitoring indicators ： serum total testosterone Bioavailabletestosterone (BioT) SHBG FAI other androgens

assays inconsistent among individual laboratories

Kumar A (PCOS). Clin Endocrinol 2005; 62: 644–49.

Hyperandrogenism

Do not allow monitor hormonal bioactivity

FAI (total testosterone/SHBGX100) correlates with BioT less overlap with normality

prostate-specific antigen —— promising marker of hyperandrogenism

strong positive correlation with testosterone and negative with SHBG levels

Clinical androgen excess

Hirsutism——70% Acne——30% Alopecia——8%

Hirsutism typically starts in the decade between 15 and 25 years and progresses slowly to become noticeable after 1 year from its onset

the prevalence of hirsutism in PCOS may vary according to race and ethnicity

Hirsutism Ferriman-Gallwey (mFG) score (individual variation in

hair growth may reflect ethnic differences) positive FG≥6

The characteristics of hyperandrogenism in Chinese Han community population

Peking University Third Hospital Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University West China Second University Hospital, Sichuan University First Affiliated Hospital of Medical College of Xi’an Jiaotong

University First Affiliated Hospital of Heilongjiang Chinese Medicine

University First Affiliated Hospital of Anhui Medical University Tianjin Medical University General Hospital Shengjing Hospital of China Medical University Second Xiangya Hospital of Central-South University Women’s Hospital of Fudan University Women’s Hospital School of Medicine Zhejiang University National center for chronic and noncomunicable disease control

and prevention (NCNCD)

Introduction

Hyperandrogenism or androgen excess is a common endocrine disorder of adult women, affecting between 5 and 10% of women of reproductive-age

Hyperandrogenism comprises a heterogeneous group of disorders

Patients with hyperandrogenism present with a variety of clinical manifestations, include hirsutism, acne, androgenic alopecia, and virilization

Biochemical derangements in ovarian, adrenal, and peripheral androgen production

At present, there isn’t a widely accepted criteria for the diagnosis of hyperandrogenism of Chinese women

Objectives

The objective of our research is trying to provide the clinical and biochemical diagnostic criteria for the hyperandrogenism of Chinese women, hoping that it will provide an insight into the hyperandrogenism of yellow race women.

Methods and Materials

From Oct, 2007 to Sept. 2009 A large-scale epidemiological investigation of

reproductive-age women, aged 19 to 45 years old, in 10 provinces of China

Approved by ten centers and National center for chronic and noncomunicable disease control and prevention (NCNCD)

A total number of 10120 women from rural and urban communities, rural and urban 1:1 and 80-120 residents per community

We trained 20 interviewers (10 senior and 10 junior gyneocologists and postgraduate students) from university hospitals

All the fieldworkers completed training in their region, including pilot interviews in non-sampled communities

During fieldwork, the principal investigator and supervisors monitored interviews on site

All the participants underwent a free medical evaluation, including a self-history and family history, physical and pelvic examination, transvaginal ultrasonography

Part of the participants contributed their blood samples for determination of biochemical indicators

The women who were suffering from chronic or acute diseases, menopausal (including natural and surgical menopause), pregnant at the time were excluded from our study

Hirsutism (F-G scoring system )

Acne (Reingold and Rosenfield, 1987)

The scoring of acne is based on the evaluation of the papules, pustules and nodules of acne on the cheeks, neck, chest and upper back

The severity of acne was graded according to the Consensus Conference on Acne Classification

According to these criteria, mild acne is defined by the presence of comedones, without significant inflammation and a few or no papules; moderate acne, by the presence of comedones, with marked inflammatory papules and pustules; and severe acne, by the presence of inflammatory nodules, in addition to comedones, papules, and pustules

Alopecia (Ludwig, 1977)

Blood samples

Sex hormone binding globulin (SHBG) Total testosterone (TT) Androstenedione (A) Immulite 1000 assay based on

chemiluminescence (DPC, USA) Free androgen index (FAI) was calculated

using the formula [TT (nmol/L) *100/SHBG (nmol/L)]

Result

General characteristics of the population investigated A total number of 10120 women between 19 and 45 years

old were entered into our study, and 3303 blood samples were collected

5 groups, 19-24 years old 1131 women (11.2%), 25-29 years old 1856 (18.3%), 30-34 years old 2165 (21.4%), 35-39 years old 2853 (28.6%) and 40-45 years old 2115 (20.9%)

84.3% of them have regular menstruation cycle 8631 women (85.3%) with normal cycles of 21-35 days,

1161 women (11.5%) with the duration of the cycle exceeds 35 days and 328 women (3.2%) with the cycles less than 21 days

376 women (3.7%) suffered from infertility

Hirsutism The F-G sore of the majority was 0(69.4%)

and 95.5% of the participants had an F-G score under 5. Meanwhile, there were 96.4% of the participants under 6, 97.0% under 7 and 97.5% under 8. According this, we divided the participants into hirsutism and non-hirsutism by 5 F-G score

According 5 F-G sore, General characteristics of hirsutism and non-hirsutism group

Hirsutism group

non-hirsutism group

T P

Age(year) 27.93±6.07 33.83±6.53 20.094 <0.001

Height(cm) 158.37±5.49 159.06±5.22 2.722 0.006

Weight(kg) 53.93±9.41 57.49±9.06 8.131 <0.001

BMI(kg/m2) 21.50±3.61 22.71±3.31 7.518 <0.001

Waist circumference (cm)

73.57±9.57 76.62±9.00 7.006 <0.001

Hip circumference (cm) 89.92±7.09 92.62±7.19 7.808 <0.001

W/H 0.82±0.07 0.83±0.06 3.248 0.001

TT(nmol/L) 1.87±0.96 1.51±0.81 -5.946 <0.001

TA(nmol/L) 12.17±4.93 9.79±4.37 -7.612 <0.001

FAI 4.85±0.31 3.33±0.06 -4.812 <0.001

Hair distribution in different age groups.

Age (year)

The percentage of hirsutism(%)

Main distribution area

Secondary distribution area

19-24 13.35%(151/1131) upper lip lower abdomen, thighs

25-29 7.76%(144/1856) upper lip chest, lower abdomen, thighs

30-34 3.97%(86/2165) upper lip chest, lower abdomen

35-39 1.54%(44/2853) upper lip chest, lower abdomen

40-45 1.23%(26/2115) upper lip

Contribution of different areas to hirsutism （ percentage ） upper lip > lower abdomen > chest > thighs > upper arms >

upper back > upper abdomen > chin > lower back

F-G score 0 1 2 3 4

upper lip 78.9 14.2 5.9 0.8 0.1

Chin 96.7 2.3 0.9 0 0

chest 92.1 6.1 1.1 0.1 0

Upper abdomen 95.4 3.1 0.9 0.1 0

lower abdomen 91.6 5.0 2.5 0.9 0.1

upper arms 93.6 4.2 0.9 0.3 0

thighs 92.7 3.9 2.7 0.6 0

upper back 94.8 4.0 1.1 0.1 0

lower back 97.2 2.0 0.6 0.1 0

Acne

The acne score of the women was mainly

0 (90.3%) , 1 (7.0%)

making up 97.3% of the women under the score of 2

ACNE: 2.7%

Alopecia

The incidence of alopecia was 1.3%,

only 129 participants involved 118 mild, 8 middle and 3 serious alopecia.

Hormonal hyperandrogenism characteristics of the population investigated

total testerone level 1.54±0.83nmol/L total androstenedione level 9.98±4.46 nmol/L free androgen index (FAI) 3.45±0.06()

Conclusion

Criteria of Clinical evaluation for hyperandrogenism in Chinese people

F-G score >=5 more significent position: upper lip, lower

abdomen and chest Different age women used different

hyperandrogenism evaluation system? Acne score >= 2 Fewer have alopecia

43

Study Participants

Invited projects 20000 women

Not start 3114 women

First participants16886 women

Questionnaire missing

1002 women

Questionnaire finished

15884 women

Others11134 women

Suspected PCOS cases

4750 women

Not performing ultrasound or detecting

peripheral blood 47 women

Only performing ultrasound

2046 women

Only detecting peripheral blood

25 women

Performing ultrasound and detecting

peripheral blood 2632 women

Performing ultrasound and detecting

peripheral blood2221 women

44

Materials and Methods

Study protocol Questionnaires, including ：

personal and family medical history

To define suspected PCOS cases Oligomenorrhea: ≥35 days Clinical hyperandrogenism: mF-G score≥6, or have

acne, or have premature alopecia, or have acanthosis nigricans

Polycystic ovary: either 12 or more follicles measuring 2–9 mm in diameter in at least one of the ovaries

45

Clinical examination To detect peripheral blood: INS, FPG, T, TSH,

TG, Cho, HDL, and LDL Transvaginal ultrasound

Defining PCOS ： the Rotterdam criteria, the presence of two or more of the following Oligomenorrhea Clinical and/or biochemical hyperandrogenism PCO

46

Healthy risk Metabolic syndrome

central obesity ： waist≥80cm At least two of the following

TG elevated ：≥ 1.7mmol/L HDL decreased ：＜ 1.29mmol/L BP increased ： SBP≥130mmHg or DBP ≥85mmHg FPG increased ： FPG≥5.6mmol/L

IR: HOMA-IR=FPG*fasting INS/22.5

Alberti KGMM et al. Metabolic syndrome-a new world-wide definition. A Consensus

Statement fom the International Diabetes Federation. 2006. Diabetes UK. Diabetic

Medicine, 23, 469-480.

47

Materials and Methods

At the same time, we choose hospital PCOS from the corresponding region hospital from 19-45 years old

A total of 959 diagnosed PCOS women were recruited (hospital PCOS)

48

Results Phenotype define

O+H, Oligomenorrhea and hyperandrogenism O+P, Oligomenorrhea and PCO H+P, Hyperandrogenism and PCO O+H+P, Oligomenorrhea and hyperandrogenism and PCO

49

Results

PCOS prevalence in China Biochemical Hyperandrogenism ： T ＞ 2.81nmol/L

Table 1: prevalence of PCOS in China (only with elevated T)

Phenotypes Total known PCOS Total + imputed polycystic ovariesa

O+H 223 (21.48%) 225 (20.16%)

O+P 240 (23.12%) 280 (25.05%)

H+P 341 (32.85%) 372 (33.23%)

O+H+P 234 (22.54%) 241 (21.57%)

Total 1038 (6.53%) 1118 (7.04%)

50

0. 0%

10. 0%

20. 0%

30. 0%

40. 0%

50. 0%

60. 0%

70. 0%

O+H O+P H+P O+H+P

PCOS phenotype

perc

enta

ge Hospi tal PCOS

Communi ty PCOS

Results To compare the distribution of PCOS subgroups between

community PCOS and hospital PCOS

51

To compare hospital PCOS and community PCOS

Community PCOS Hospital PCOS p values

n 894 959

Age 28.5±5.4 26.5±4.2 0.000

BMI 22.2±4.2 24.4±4.8 0.000

Weight 56.2±10.3 62.6±13.0 0.000

mF-G 3.33 4.5 0.000

TSH 2.34±3.72 2.77±3.2 0.022

T 2.12±1.17 2.47±1.30 0.000

SHBG 55.7±32.6 45.4±29.8 0.000

Glu 5.13±0.91 5.12±0.95 0.839

INS 6.56±8.96 13.3±10.5 0.000

TG 1.23±0.88 1.65±3.19 0.001

CHO 4.54±1.01 4.71±1.74 0.012

HDL 1.39±0.37 1.40±0.42 0.583

LDL 2.31±0.72 2.91±1.77 0.000

52

Results To compare normal control, community PCOS and

hospital PCOS

　Hospital

PCOS (n=959)

　Community PCOS （ n=8

94）　 normal control

(n=4008)

　 Cases rate 　 Cases rate 　 Cases rateMetabolic syndrome 155 16.2% 123 13.8% 428 10.7

%IR 427 44.6% 128 14.4% 283 7.1%

DM 183 19.1% 237 26.5% 769 19.2%

HBP 96 10.0% 120 13.4% 576 14.4%

Reduced HDL cholesterol

304 31.7% 152 17.0% 643 16.0%

ovary tumor 12 1.3% 33 3.6% 105 2.6%

family DM 141 14.7% 121 13.5% 456 11.4%

family HBP 307 32.0% 238 26.6% 1104 27.5%

family gynecology tumor

52 5.5% 58 6.5% 198 4.9%

family oligomenorrhea 118 12.3% 49 5.4% 70 1.7%

family infertility 36 3.8% 22 2.4% 38 0.9%

Family alopecia 105 10.9% 　 48 5.3% 　 184 4.6%

53

Results The distribution of PCOS subgroup in different

age groups

0. 00%

10. 00%

20. 00%

30. 00%

40. 00%

50. 00%

60. 00%

communi ty PCOS hospi tal PCOS

≤ 2526- 3536- 4041- 45

Treatment of infertility

with PCOS

DAVID S. GUZICK, Clin Obstet Gynecol2007 Mar;50(1):255-67

Laparoscopic ovarian diathermy

LOD may be offered to PCOS women with following conditions

experience CC-resistance or failure

markedly elevated LH

requiring laparoscopic assessment of their pelvis for other indications

Four punctures per ovaryaway from the ovarian hilum

electricity is activated for 5 sa monopolar coagulating current set at 30 w (150 joules)

Transvaginal hydrolaparoscopy

IVMan emerging technology that has promising potential

Advantages for PCOS patients Reduction of costs

Minimizing gonadotropin and GnRH analogue use

Elimination of ovarian hyperstimulation syndrome

Simplicity of protocol

Deficiency pregnancy rates lower: 30-35%

Implant rates 10-15%

2006-2008 IVM

　 　 IVM No.eggmature(

%)fertilization(%)

Good embryo

(%)

implantion(%

)

2006

COH 12 12.83 75.32 68.97 43.08 12.50

NC 21 15.14 60.06 60.73 49.30 6.38

　 33 14.30 65.04 63.84 47.34 9.86

2007

COH 11 18.91 74.52 49.68 52.38 9.09

NC 37 19.39 53.68 67.51 52.00 17.57

　 48 19.28 58.28 62.48 52.09 15.63

2008

COH 23 12.62 62.37 62.50 56.52 26.19

NC 43 16.85 48.05 60.00 55.62 38.75

　 66 15.68 52.70 60.96 55.97 34.43

2006-2008 IVM

　　

OR ET CP(%)Clinical pregnancy

　 No. single twin AT EP

2006

COH

12 11 18.18 2 1 1 0 0

NC 21 19 15.78 3 1 0 2 0

　 33 30 16.67 5 2 1 2 0

2007

COH

11 9 22.22 2 0 0 2 0

NC 37 33 33.33 11 7 1 3 0　 47 41 31.7 13 7 1 3 0

2008

COH

23 21 38.10 8 4 2 1 1

NC 43 38 55.26 21 10 7 3 1

　 66 5949.1

5 29 14 9 4 2

时间 IVF FET

1987 32 　

1988 45 　

1989 116 　

1990 76 　

1991 109 　

1992 118 　

1993 148 　

1994 157 1

1995 266 11

1996 229 9

1997 230 4

1998 223 15

1999 287 28

2000 397 74

2001 624 140

2002 960 384

2003 868 459

2004 1769115

5

2005 2352187

4

2006 3000151

0

2007 3496227

5

2008 4566257

8

2009 5565284

9

Peking University Third HospitalIVF － ET center

--- fresh IVF ---FET

0

1000

2000

3000

4000

5000

600019

8719

8819

8919

9019

9119

9219

9319

9419

9519

9619

9719

9819

9920

0020

0120

0220

0320

0420

0520

0620

0720

0820

09

新鲜周期数 解冻周期数

IVM pregnancy complications

Early pregnancy loss Gestational diabetes Pre-eclampsia Pregnancy hypertension Preterm labour

Higher perinatal mortality rate, unrelated to multiple pregnancy

Conclusions Polycystic ovary syndrome is a diverse and complex

female endocrine disorder Full of dabates from diagnosis to management.

Future priorities include development of evidence-based criteria for diagnosis and

treatment determination of the natural history cause long-term consequences prevention of the disorder

First international ASIA PACIFIC Meeting on PCOSJan, 2009 (Hong Kong 香港会议 )