1. Polycystic ovarian syndrome (PCOS）
Wei Zhang
OB/GYN Hospital, Fudan University

2. Content OVERVIEW of PCOS PATHOPHYSIOLOGY SIGNS and SYMPTOMS
DIAGNOSTIC CRITERIA
TREATMENT

3. OVERVIEW

4. PCOS
1 st described by Stein and Leventhal as a triad of amenorrhea, obesity and hirsutism (1935)
The symptoms and severity of the syndrome vary greatly among affected women
It is one of the leading causes of female infertility

5. Definition & Abbreviations
Definition :Polycystic ovarian syndrome is a common endocrine disfunction typified by oligo-ovulation or anovulation, signs of androgen excess, and multiple small ovarian cysts
Abbreviations
PCOS = Polycystic Ovarian Syndrome
PCO= Polycystic Ovarian

6. Incidence PCOS is the most common disorder of reproductive-aged women
Affects approximately 4-12%
PCOS appears to equally affect all races and nationalities

7. . Etiology Genetic basis Aggregation of the syndrome within families
An increased prevalence has been noted between affected individuals and their sisters and mothers
The first-degree male relatives of women with PCOS have significantly higher circulating DHEAS levels .

8. Environment causes
Life style
Exercise
Diet
Androgen exposure, et. al

9. Interaction of Genetics and environment
PCOS may be a genetically determined ovarian disorder , the heterogeneity can be explained on the basis of interaction of the disorder with other genes and with the environment

10. PATHOPHYSIOLOGY

11. Reproductive cycle regulated by HPO axis
Hypothalamus
GnRH
Pituitary
FSH Gn LH
Ovary
Progesterone
Estradiol 内膜

13. Pathopysiologyz: What we think we know
Abnormal gonadotropin secretion
Excess LH and low, tonic FSH
Hypersecretion of androgens
Disrupts follicle maturation
Substrate for peripheral aromatization
Negative feedback on pituitary
Decreased FSH secreation
Insulin resistance, Elevated insulin levels
Vicious clycle of event, but why does it start?
See written physiology.

14. Disorder of H-P-O axis Increased GnRH from hypothalamus
Excessive LH secretion relative to FSH by pituitary gland
LH stimulates ovarian thecal cells to produce excessive androgen
Ineffective suppression of the LH pulse frequency by estradiol and progesterone
Androgen excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone

15. H-P-O axis Dysfunction in PCOS
GnRH
Estrogen
androgen
LH, FSH
Anovulation

16. Abnormal steroidogenesis
Intraovarian androgen excess results in excessive growth of small ovarian follicles
Follicular maturation is inhibited
Excess androgen causes thecal and stromal hyperplasia

17. PCO
These "cysts" are actually immature follicles. The follicles development stopped at an early antral stage due to the disturbed ovarian function
Polycystic is >12 follicles per ovary less than 10mm in diameter, ovary itself is enlarged

18. Metabolism disorder Hyperinsulinemia
Excess insulin production and insulin resistance
Hyperinsulinemia contributes to hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver
Hyperandrogenism vs. hyperinsulinemia: Which came first?
Dyslipidemia

19. Current theories of pathopysiology
Autosomal
Dominant Gene
Downstream
Signal Defect
GnRH E2 LH
Insulin Resistance
PCOS A
A proposed schema for the association of insulin resistance and PCOS. A single factor that causes serine phosphorylation of the insulin receptor and serine phosphorylation of P450c17, the key regulatory enzyme controlling androgen biosynthesis, could produce both the insulin resistance and the hyperandrogenism characteristic of PCOS. It is also possible that the insulin resistance and the reproductive abnormalities reflect separate genetic defects and that the insulin resistance unmasks the syndrome in genetically susceptible women. Recent studies suggest that insulin acting through its own receptor augments steroidogenesis and LH release. Androgens amplify the associated insulin resistance. [Figure is used with permission from A. Dunaif.]
The fact that insulin sensitizing agents treat this disease lends weight to this hypothesis.Why does the hyperinsulin state contribute? Remains to be seen… theory of abnormal phosphorylation of an insulin receptor, theory that elev insulin decr SHBG which is a stimulus to androgen production
This phenomenon of elev insulin causing elev androgen only seen in PCOS women
A=androgens, E2=estradiol

20. SIGNS and SYMPTOM

21. Clinical Features of PCOS
Hyperandrogenism
Hirsutism
Acne
Chronic anovulation (irregular menses)
Irregular menses
Infertility
Endocrine Dysfunction
Obesity
Insulin resistance
Acanthosis Nigricans
Impaired Glucose Tolerance and Type 2 Diabetes Mellitus
Dyslipidemia
Metabolic Syndrome and Cardiovascular Disease
Polycystic ovaries

22. Hyperandrogenism Hirsutism, acne, male pattern balding, alopecia
50-90% patients have elevated serum androgen levels
Rare: increased muscle mass, deepening voice,

23. Hirsutism:Ferriman-Gallwey Scoring System
Acne: 50%
Mild
moderate
severe

24. Facial Hirsutism in PCOS

25. Chronic anovulation/oligo-ovulation
Menstrual Dysfunction
Oligomenorrhea : %
Amenorrhea: 20 %
Regular cycles: 5-10 %
Infertility: 30-70%

26. Menstrual Dysfunction
Oligo or amenorrhea
Menstrual irregularity typically begins in the peripubertal period
Reduction in ovulatory events leads to deficient progesterone secretion
Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding
Increased risk for endometrial hyperplasia and/or endometrial CA

27. INFERTILITY Intermittent ovulation or anovulation
Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomid

28. Obesity Prevalence of obesity varies from 30-75%
2/3 of patients with PCOS who are not obese have excessive body fat and central adiposity
Obese patients can be hirsute and/or have menstrual irregularities without having PCOS

29. Insulin Resistance
> 80% are hyperinsulinemic and have insulin resistance (independent of obesity)

30. Acanthosis Nigricans Velvety plaques on nape of neck and
intertriginous
areas
Epidermal
hyperkeratosis
Associated with
insulin resistance

31. Ovarian Abnormalities
Thickened sclerotic cortex
Multiple follicles in peripheral location
80% of women with PCOS have classic cysts

33. Associated Medical Conditions
Increased risk of developing Type 2 Diabetes and Gestational diabetes
Low HDL and high triglycerides
Sleep apnea
Nonalcoholic steatohepatitis
Metabolic syndrome—43% of PCOS patients (2 fold higher than age-matched population)
Elevated heart disease
Advanced atherosclerosis

34. Consequences of PCOS Short-term consequences Long-term consequences
Irregular menses
Hirsutism/acne/androgenic alopecia  
Infertility
Obesity 
Metabolic disturbances : Abnormal lipid levels/glucose intolerance
Long-term consequences
Diabetes mellitus (DM)
Cardiovascular disease(CVD)
Endometrial cancer

35. Short-term consequences
Consequences of PCOS
Short-term consequences
Hirsutism, acne
Menstrual irregularity
hyperandrogen
infertility
Obesity
PCOS
hyperplasia/cancer
Long-term consequences
雄激素过多和胰岛素水平升高是引起PCOS远期危害的始发因素。同时雄激素过多和胰岛素水平升高也是相互促进，互为影响的。
CVD
Elevated insulin
Dyslipidemia
diabetes 35

36. DIAGNOSTIC CRITERIA

37. Difficult to diagnosis Changing criteria Varying symptoms over time
Not all women with PCOS have polycystic ovaries (PCO), nor do all women with ovarian cysts have PCOS
although a pelvic ultrasound is a major diagnostic tool, it is not the only one
The diagnosis is straightforward using the Rotterdam criteria

38. Menstrual irregularity due to anovulation or oligo-ovulation
NIH Criteria(1990)
Menstrual irregularity due to anovulation or oligo-ovulation
Evidence of clinical or biochemical hyperandrogenism
Hirsutism, acne, male pattern baldness
High serum androgen levels
Exclusion of other causes (CAH, tumors, hyperprolactinemia)

39. Menstrual irregularity due to anovulation oligo-ovulation
2003 Rotterdam Criteria (2 out of 3)
Menstrual irregularity due to anovulation oligo-ovulation
Evidence of clinical or biochemical hyperandrogenism
Polycystic ovaries by US
12 or more follicles measuring 2-9 mm in diameter
Increased ovarian volume (>10 cm 3 )
Exclusion of other causes (CAH, tumors, hyperprolactinemia)
In 2003 in Rotterdam, Netherlands, a consensus meeting between the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) redefined PCOS

40. Differential Diagnosis
Hyperprolactinemia
Prominent menstrual dysfunction
Little hyperandrogenism
2. Congenital Adrenal Hyperplasia
morning serum 17-hydroxyprogesterone concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis
confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL

41. 3. Ovarian and adrenal tumors
serum testosterone concentrations are always higher than 150 ng/dL
adrenal tumors: serum DHEA-S concentrations higher than 800 mcg/dL
LOW serum LH concentrations
4. Cushing’s syndrome
5. Drugs: danazol; OCPs with high androgenicity

42. Diagnostic Approaches
Clinical history (hair growth rate,
onset of symptoms)
Physical examination (hirsutism or
virilization, rounded facies, buffalo hump)
Laboratory testing (hormones)
Ultrasonography (ovary, endometrium)

43. Laboratory Testing Fasting glucose: elevated 2 hour OGTT: elevated
Fasting insulin: elevated
Free testosterone: elevated
DHEA-S: normal
17-hydroxyprogesterone: normal
Pelvic US
Lipids profile

44. Laboratory Evaluation
Total Testosterone (T)
DHEA-S (DS)
17-hyroxyprogesterone (17-OHP)
T Elevated
DS Elevated
T > 200 ng/dl
DS > 700 μg/dl
DS Elevated
Adrenal
Suspect Tumor
PCOS
T & DS Normal
17-OHP > 2 ng/ml
Idiopathic
Suspect CAH

45. TREATMENT

46. Treatment Goals of PCOS Treatment
Restoration a normal cycle and fertility
Lowering of insulin levels
Treatment of hirsutism, acne
Prenvention of endometrial cancer
Prevention of DM,CVD and metabolic syndrome

47. Treatment Option Lifestyle modification Anti-androgens
Insulin lowering agents
Induced ovulation-for pregnancy desired

48. Lifestyle modification
Weight loss:
Low-carbohydrate diets
sustained regular exercise
90% of anovulatory women restored to full ovulation despite relatively small amounts of weight loss following exercise and change of diet
BMI of 21 is ideal but the patient often respond to much less stringent body mass index

49. Anti-Androgen OCPs: first option when fertility is not desired
Decrease in LH secretion and decrease in androgen production
Increase in hepatic production of sex-hormone binding globulin(SHBG)
Decreased bioavailablity of testosterone
Decreased adrenal androgen secretion
Regular withdrawal bleeding
Prevention of endometrial hyperplasia

50. Spironolactone, 50-200 mg per day
Androgen receptor blockade
Steroid enzyme inhibition
Aldosterone antagonism
Lower blood pressure
Potassium sparing

51. Progestins progesterone withdrawal: every 1 to 3 months
Regular withdrawal bleeding
Prevention of endometrial hyperplasia and cancer
regimens include
MPA: 5 to 10 mg daily for days
Micronized progesterone: 200 mg each evening for days

52. Insulin-Sensitizing Agents
Induction of ovulation
Some reduced hair growth
Improved glucose utilization
Lowered serum insulin
Lipid lowering properties

53. Metformin Dosage: 1500-2550 mg per day
Clinically significant responses not regularly observed at doses less than 1000 mg per day
Treat with cyclic progestin to reduce endometrial hyperplasia if regular menses not attained
10 mg for 7 to 10 days every one to three months

54. Infertility will restore ovulation and menses in > 50% of patients
Weight loss—reduction in serum testosterone concentration and resumption of ovulation
Clomid: 80% will ovulate, 50% will conceive
Metformin
will restore ovulation and menses in > 50% of patients
added to clomid, improves ovulatory rates
CC/FSH/hCG
Laparoscopic surgery: wedge resections, laparoscopic ovarian laser electrocautery
IVF

55. Key points Pathophysiology Clinincal Features of PCOS
Diagnosis criteria
Treatment Option of PCOS

56. 丰有吉. 妇产科学，八年制本科教材，人民卫生出版社，2008
References
John O. Schorge . Williams Gynecology,2008 ISBN
丰有吉. 妇产科学，八年制本科教材，人民卫生出版社，2008
曹泽毅.中华妇产科学. 人民卫生出版社.2005

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