PCOS new concepts and treatment

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PCOS new concepts and treatment

• Peking University Third Hospital, P.R.China
• Qiao Jie

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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

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PCOS

• Leading cause of androgen excess and ovulatory
  dysfunction
• Causes 7080 of hyperandrogenism
• Obesity
• LH/FSHgt 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, 168177
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PCOS symptoms and signs
Robert J Norman, Lancet 2007 370 68597
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Saad A K Amer Obstet, Gynaecol Reprod Med 1910
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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. 377384
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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 811925
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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)

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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)
168177
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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 Sep24(9)2286
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Phenotype (based on 2003Rotterdam criteria)
Robert J Norman, Lancet 2007 370 68597
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Phenotype (based on 2003Rotterdam criteria)
Robert J Norman, Lancet 2007 370 68597
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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)42374245
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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 higher

Robert J Norman Lancet 2007 370 68597
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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 ?

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Hyperandrogenism

• high circulating T concentrations 6080
• 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 64449.
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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

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Clinical androgen excess

• Hirsutism70
• Acne30
• Alopecia8
• 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

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Hirsutism

• Ferriman-Gallwey (mFG) score (individual
  variation in hair growth may reflect ethnic
  differences)
• positive FG6

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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
  Xian 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
• Womens Hospital of Fudan University
• Womens Hospital School of Medicine Zhejiang
  University
• National center for chronic and noncomunicable
  disease control and prevention (NCNCD)

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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 isnt a widely accepted
  criteria for the diagnosis of hyperandrogenism
  of Chinese women

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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.

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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 11 and 80-120
  residents per community

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• 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

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• 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

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Hirsutism (F-G scoring system )
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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

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Alopecia (Ludwig, 1977)
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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)

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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

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• 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

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According 5 F-G sore, General characteristics of
hirsutism and non-hirsutism group
Hirsutism group non-hirsutism group T P
Age(year) 27.936.07 33.836.53 20.094 lt0.001
Height(cm) 158.375.49 159.065.22 2.722 0.006
Weight(kg) 53.939.41 57.499.06 8.131 lt0.001
BMI(kg/m2) 21.503.61 22.713.31 7.518 lt0.001
Waist circumference (cm) 73.579.57 76.629.00 7.006 lt0.001
Hip circumference (cm) 89.927.09 92.627.19 7.808 lt0.001
W/H 0.820.07 0.830.06 3.248 0.001
TT(nmol/L) 1.870.96 1.510.81 -5.946 lt0.001
TA(nmol/L) 12.174.93 9.794.37 -7.612 lt0.001
FAI 4.850.31 3.330.06 -4.812 lt0.001
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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
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Contribution of different areas to
hirsutism(percentage) upper lip gt lower abdomen
gt chest gt thighs gt upper arms gt upper back gt
upper abdomen gt chin gt 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
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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
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Alopecia

• The incidence of alopecia was 1.3,
• only 129 participants involved 118 mild, 8
  middle and 3 serious alopecia.

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• Hormonal hyperandrogenism characteristics of the
  population investigated
• total testerone level 1.540.83nmol/L
• total androstenedione level 9.984.46 nmol/L
• free androgen index (FAI) 3.450.06()

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Conclusion

• Criteria of Clinical evaluation for
  hyperandrogenism in Chinese people
• F-G score gt5
• more significent position upper lip, lower
  abdomen and chest
• Different age women used different
  hyperandrogenism evaluation system?
• Acne score gt 2
• Fewer have alopecia

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• Study Participants

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Materials and Methods

• Study protocol
• Questionnaires, including
• personal and family medical history
• To define suspected PCOS cases
• Oligomenorrhea 35 days
• Clinical hyperandrogenism mF-G score6, or have
  acne, or have premature alopecia, or have
  acanthosis nigricans
• Polycystic ovary either 12 or more follicles
  measuring 29 mm in diameter in at least one of
  the ovaries

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• Clinical examination
• To detect peripheral blood INS, FPG, T, TSH, TG,
  Cho, HDL, and LDL
• Transvaginal ultrasound
• Defining PCOSthe Rotterdam criteria, the
  presence of two or more of the following
• Oligomenorrhea
• Clinical and/or biochemical hyperandrogenism
• PCO

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• Healthy risk
• Metabolic syndrome
• central obesitywaist80cm
• At least two of the following
• TG elevated1.7mmol/L
• HDL decreasedlt1.29mmol/L
• BP increasedSBP130mmHg or DBP 85mmHg
• FPG increasedFPG5.6mmol/L
• IR HOMA-IRFPGfasting 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.
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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)

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Results

• Phenotype define
• OH, Oligomenorrhea and hyperandrogenism
• OP, Oligomenorrhea and PCO
• HP, Hyperandrogenism and PCO
• OHP, Oligomenorrhea and hyperandrogenism and PCO

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Results

• PCOS prevalence in China
• Biochemical HyperandrogenismTgt2.81nmol/L

Table 1 prevalence of PCOS in China (only with
elevated T)
Phenotypes Total known PCOS Total known PCOS Total imputed polycystic ovariesa Total imputed polycystic ovariesa
OH 223 (21.48) 225 (20.16)
OP 240 (23.12) 280 (25.05)
HP 341 (32.85) 372 (33.23)
OHP 234 (22.54) 241 (21.57)
Total 1038 (6.53) 1038 (6.53) 1118 (7.04) 1118 (7.04)
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Results

• To compare the distribution of PCOS subgroups
  between community PCOS and hospital PCOS

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• To compare hospital PCOS and community PCOS

Community PCOS Hospital PCOS p values
n 894 959
Age 28.55.4 26.54.2 0.000
BMI 22.24.2 24.44.8 0.000
Weight 56.210.3 62.613.0 0.000
mF-G 3.33 4.5 0.000
TSH 2.343.72 2.773.2 0.022
T 2.121.17 2.471.30 0.000
SHBG 55.732.6 45.429.8 0.000
Glu 5.130.91 5.120.95 0.839
INS 6.568.96 13.310.5 0.000
TG 1.230.88 1.653.19 0.001
CHO 4.541.01 4.711.74 0.012
HDL 1.390.37 1.400.42 0.583
LDL 2.310.72 2.911.77 0.000
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Results

• To compare normal control, community PCOS and
  hospital PCOS

Hospital PCOS (n959) Hospital PCOS (n959) Community PCOS(n894) Community PCOS(n894) normal control (n4008) normal control (n4008)
Cases rate Cases rate Cases rate
Metabolic 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
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Results

• The distribution of PCOS subgroup in different
  age groups

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Treatment of infertility with PCOS
DAVID S. GUZICK, Clin Obstet Gynecol 2007
Mar50(1)255-67
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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

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• 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)

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Transvaginal hydrolaparoscopy
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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

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2006-2008 IVM
IVM No.egg mature() fertilization() Good embryo() implantion()
2006 COH 12 12.83 75.32 68.97 43.08 12.50
2006 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
2007 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
2008 NC 43 16.85 48.05 60.00 55.62 38.75
66 15.68 52.70 60.96 55.97 34.43
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2006-2008 IVM
OR ET CP() Clinical pregnancy Clinical pregnancy Clinical pregnancy Clinical pregnancy Clinical pregnancy
OR ET CP() No. single twin AT EP
2006 COH 12 11 18.18 2 1 1 0 0
2006 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
2007 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
2008 NC 43 38 55.26 21 10 7 3 1
66 59 49.15 29 14 9 4 2
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?? 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 1769 1155
2005 2352 1874
2006 3000 1510
2007 3496 2275
2008 4566 2578
2009 5565 2849
Peking University Third Hospital IVF-ET center
--- fresh IVF ---FET
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IVM pregnancy complications

• Early pregnancy loss
• Gestational diabetes
• Pre-eclampsia
• Pregnancy hypertension
• Preterm labour
• Higher perinatal mortality rate, unrelated to
  multiple pregnancy

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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

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First international ASIA PACIFIC Meeting on
PCOSJan, 2009 (Hong Kong ????)
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