Transcript www.utd.org.tr

PCOS new concepts and
treatment
Peking University Third Hospital,
P.R.China
Qiao Jie
PCOS
 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
 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 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 Workshop
Group. 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 polycysticappearing 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
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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 higher
Robert J Norman Lancet 2007; 370: 685–97
Hyperandrogenism
 most important features of the syndrome
 classic PCOS phenotype : higher androgen
levels
 clinical features ——hirsutism, acne, malepattern alopecia
 Biochemical ——testosterone ↑, DHEAS↑
androstenedioneor ↑, SHBG ↓
Hyperandrogenism


high circulating T concentrations: 60–80%
high DHEAS concentrations: 25%

Mornitoring indicators：
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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
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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
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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%), 3539 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
Age(year)
27.93±6.07
33.83±6.53
Height(cm)
P
20.094
<0.001
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 Secondary distribution
area
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
 Study Participants
Invited projects
20000 women
Not start
3114 women
Questionnaire
missing
1002 women
First participants
16886 women
Questionnaire
finished
15884 women
Suspected PCOS
cases
4750 women
Others
11134 women
Performing ultrasound
and detecting
peripheral blood
2221 women
Not performing
ultrasound or detecting
peripheral blood
47 women
Only performing
ultrasound
2046 women
Performing ultrasound
and detecting
peripheral blood
2632 women
Only detecting
peripheral
43 blood
25 women
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
44
 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
45
 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
Alberti KGMM et al. Metabolic syndrome-a new
world-wide definition. A Consensus Statement fo
m the International Diabetes Federation. 2006. Di
abetes UK. Diabetic Medicine, 23, 469-480.

IR: HOMA-IR=FPG*fasting INS/22.5
46
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)
47
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
48
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%)
49
Results
 To compare the distribution of PCOS subgroups between
community PCOS and hospital PCOS
percentage
70.0%
60.0%
Hospital PCOS
Community PCOS
50.0%
40.0%
30.0%
20.0%
10.0%
PCOS phenotype
0.0%
O+H
O+P
H+P
O+H+P
50
 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
51
Results
 To compare normal control, community PCOS and
hospital PCOS
Metabolic syndrome
IR
DM
HBP
Reduced HDL cholesterol
ovary tumor
family DM
family HBP
family gynecology tumor
family oligomenorrhea
family infertility
Family alopecia
Hospital PCOS
(n=959)
Cases
rate
155
16.2%
427
44.6%
183
19.1%
96
10.0%
304
31.7%
12
1.3%
141
14.7%
307
32.0%
52
5.5%
Community
PCOS（n=894）
Cases rate
123
13.8%
128
14.4%
237
26.5%
120
13.4%
152
17.0%
33
3.6%
121
13.5%
238
26.6%
normal control
(n=4008)
Cases
rate
428
10.7%
283
7.1%
769
19.2%
576
14.4%
643
16.0%
105
2.6%
456
11.4%
1104
27.5%
58
6.5%
198
4.9%
118
12.3%
49
5.4%
70
1.7%
36
3.8%
22
48
2.4%
5.3%
38
184
52
105
10.9%
0.9%
4.6%
Results
 The distribution of PCOS subgroup in different
age groups
60.00%
≤25
26-35
36-40
41-45
50.00%
40.00%
30.00%
20.00%
10.00%
0.00%
community PCOS
hospital PCOS
53
Treatment of infertility
with PCOS
DAVID S. GUZICK,
Clin Obstet Gynecol
2007 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 ovary
away from the ovarian hilum
electricity is activated for 5 s
a monopolar coagulating current
set at 30 w (150 joules)
Transvaginal hydrolaparoscopy
IVM
an 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
2006
2007
2008
fertiliz
Good
ation(%) embryo(%)
implant
ion(%)
IVM
No.egg
mature(%)
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
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
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
2006
2007
2008
OR
ET
CP(%)
COH
12
11
NC
21
Clinical pregnancy
No.
single
twin
AT
EP
18.18
2
1
1
0
0
19
15.78
3
1
33
30
16.67
5
2
1
2
0
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
COH
23
21
38.10
8
4
2
1
1
NC
43
38
55.26
21
10
7
3
1
66
59
49.15
29
14
9
4
2
2
0
0
Peking University Third Hospital
IVF－ET center
6000
5000
4000
3000
2000
1000
新鲜周期数
--- fresh IVF
解冻周期数
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
0
FET
时间
IVF
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
1769
1155
2005
2352
1874
2006
3000
1510
2007
3496
2275
2008
4566
2578
2009
5565
2849
IVM pregnancy complications
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


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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 PCOS
Jan, 2009 (Hong Kong 香港会议)