1. Polycystic Ovarian
Syndrome
2012.04.03
임옥룡

2. Prevalence
 Most common female endocrinopathy
 5-10% of reproductive(3% in adolescent)
 90% with oligomenorrhea
 70% with hirsutism
 20% with polycystic ovary
 20-40% with persistent acne only
 10% with alopecia only
 75% of anovulatory infertility(M/C)

5. Rotterdam criteria(2003)
 Oligo-(>35days) or anovulation
 Hyperandrogenism(biochemical or clinical) :
hirsutism, testosterone
 Polycytic ovaries(US)
- ≥ 12 follicles in either ovary measuring
2-9mm in diameter
- >10mL ovarian volume

6. Pathogenesis

7. Pathophysiology
 Insulin resistance 20-50%
 Compensatory hyperinsulinemia
-65-70% of women with PCOS
-70-80% of obese
-30-40% of normal weight
 Hyperinsulinemia result in increased ovarian
theca androgen production and decreased
production of SHBG by liver
 Disorder of androgen excess or
hyperandrogenism

10. Manifestations
 Multiple manifestations
-cutaneous
-reproductive
-metabolic
 Peripubertal(12-13y) in onset

11. Cutaneous manifestations
 Hirsutism ; mFG ≥ 6
 Acne, persistent acne
 Baldness

15. Reproductive manifestations
 oligomenorrhea >35 days
 secondary amenorrhea
 anovulation
 infertility
 early pregnancy loss

16. Metabolic and endocrine
manifestations
 increased Testosterone(total,free)
 Androstenedione
 decreased SHBG
 increased Insulin
 increased LH/FSH ratio
 Dyslipidemia

18. lab
 Baseline blood sample ; LMP 3-7 day
 FSH, LH
 Prolactin, TSH, free thyroxine(FT4)
 Testosterone(total)
 Testosterone(free) ; gold standard
 FAI=100xTestosterone(ng/mLx3.467)/SHBG(nmol/L)
 Androstenedione >2.57ng/mL
 17-HP, DHEAS, SHBG
 75g OGTT, Insulin(fasting)
 TG(N<150mg/dL) HDL(N>50mg/dL)

22. Insulin resistance
 Insulin(fasting) >20mU/mL(10)
 Homeostasis model assessment of IR
(HOMA-IR) >2.5
fasting insulin(mIU/L) x glucose(mg/dL)/405
 C-peptide >4.6(2.5)

24. DDx
 Thyroid disease(hypo- or hyperTH) ; less
 Hyperprolactinemia ; 30% of secondary amenorrhea
 Ovarian failure
 Congenital adrenal hyperplasia ; 21-OH-deficient
nonclassic-CAH(M/C) 17-HP >2.0ng/mL(synacthen test)
 Cushing’s syndrome ; amenorrhea(80-
100%),hirsutism(60-100%), acne(40-50%)
 Androgen secreting tumor ; rare
 Severe insulin resistance and hyperinsulinemia
(fasting insulin 80uIU/mL, 2hr >300uIU/mL)
 Idiopathic hirsutism

25. General risk on PCOS
 Infertility
 Dysfunctional bleeding
 Endometrial carcinoma OR 2.7
 Obesity(50%)
 Type2 diabetes mellitus(T2DM)
 Dyslipidemia
 Hypertension
 Cardiovascular disease

26. Menopause on PCOS
 Improve many manifestations of PCOS(ovarian
size, morphology, T levels)
 Increased rates of obesity, insulin resistance,
hyperinsulinemia, T2DM, dyslipidemia,
cardiovascular events

27. Obstetric risk of PCOS
 Early pregnancy loss
 GDM 40-50% OR2.94
 Pregnancy-induced hypertension OR3.67
 Preeclampsia OR3.47
 Premature delivery OR1.75
 Increased perinatal mortality OR3.07
 SGA 10-15%
 Delivery by cesarean section

28. Risk of PCOS for female offspring
 Higher risk of developing PCOS
 Daughters of women with PCOS
-increased LH and testosterone
-hyperinsulinemia
-increased in ovarian size during puberty
 Genetic component, supported by strong
familial association
 Environmental component, including
programming from intrauterine
hyperandrogenemia

29. Risk of metabolic disorders for the
female offspring
 Timing of fetal androgen exposure seems to
be important factor in determining phenotypic
presentation of offspring
-Offspring of female monkeys that treated
early(gestational day 40) had impaired insulin
secretion
-offspring of late-treated(gestational day 100-
115) females show decrements insulin
sensitivity with increasing adiposity, but
preserved normal insulin secretory function

30. Risk of male offspring
 Increased body hair growth, premature male
balding, and insulin resistance
 Increased risk of coronary heart disease
 Mechanism not clear, but may involve insulin
resistance that develop because of exposure to
intrauterine hyperandrogenemia

31. Genetic counseling
 Strong familial clustering
 Lack of reliable association between genotype
and phenotype raises possibility that
inheritance of PCOS
 modified by environmental factors
 Multifactorial

32. Therapies
 No Treatment
 Weight loss
 Oral contraceptives
 Metformin
 Hirsutism
 Acne
 Anovulation and infertility

33. No treatment
 Spontaneous ovulation in PCOS occur, but
infrequently
 Although ovulation frequently increases as
PCOS women age, less likely to conceive and
deliver a baby

34. Weight loss
 Lifestyle changes(diet/exercise) effective
treatment
 500-1000kcal daily reduction
 Loss of 5-10% of body weight in 6 months
reduce hirsutism, acne, restore ovulation and
improve obstetric outcomes
 Fasting insulin, androstenedione,
dihydrotestosterone decreased. Although LH,
FSH, DHEA, DHEAS, testosterone, estrogen
level unchanged
 Protect T2DM and improve dyslipidemia

35. Oral contraceptives
 Reduce hyperandrogenism via suppression of LH
secretion and by stimulating SHBG production
 First-line therapy for hirsutism
 Yasmin(drospirenone ; antiandrogenic) after 3month,
efficacy assessed
 OCP continues until gynecologically mature
(5y post menarche)
 Progesterone only ; if estrogen contraindication or
periodic progestogen withdrawal requested(7-10d
every 3months often in four withdrawal bleeds
annually)

36. Metformin
 Metformin introduced in late 1950s
 In USA, metformin(insulin sensitizer) available in
1990s
 Reduce insulin resistance and insulin secretion by
reduction of ovarian androgen
 Inhibit hepatic glucose production
 Reduce plasma TG concentration
 Reduced weight and centripetal obesity
 Begin at 500mg daily/wk(1000-2500mg/d)
 Improve menstrual frequency and restore ovulation
 In PCOS, Protect against development of GDM and
reduce later development of T2DM

37. Factors affecting response to
metformin
 Higher BMI ; poor response
 <4wks metformin pretreatment suboptimal
 Insulin-resistant PCOS with low BMI ; good
response
 Higher insulin, low androstenedione, less
severe menstrual irregularity ; good response

38. Metformin on ovulation
 Combination of CC and metformin or
metformin alone
 After 6-8wks of metformin, letrozole plus
metformin
 Either 6wks before or at GnRH agonist long
protocol
 Ovarian drilling plus metformin
 CC resistant, Obese, Glucose intolerance

39. Metformin on cancer
 Because insulin promotes growth and has
mitogenic effects, suggested that metformin
might reduce risk of cancer in diabetic patients
 Evans et al. in T2DM patients, metformin had a
23% reduced risk of cancer compared to
patients on sulfonylureas
 Bowker et al. show that cancer-related mortality
rate significantly lower in metformin group
compared to sulfonylureas
 Decreased breast cancer
 Reduction in risk of pancreatic cancer OR0.38
 Lower risk of prostate cancer

40. Duration of metformin use
 Metformin for at least 8 weeks(PCOS)
-reduced weight, fasting glucose, triglycerides
and LDL by 4.5-5.6%
-fasting insulin by 14%
-calculated HOMA-IR by 22%
-reduced new onset diabetes by 40%
 In PCOS metformin for up to 6 months
reduced hirsutism and reduced androgen ,
with reductions in testosterone 25-50%

41. Metformin indication
 Metformin as a first line therapy
-T2DM(PCOS)
-IFG and IGT(PCOS)
-as it is in general population
-GDM(12wks, 32wks?, term?)

42. Hirsutism
 modified Ferriman-Gallwey ≥ 6
 Loss of 5-10% of weight improve hirsutism
within 6 months
 Prolonged(>6months) medical Tx

43. Hirsutism treatment
 Diane 35(cyproterone acetate ; block androgen
receptor 2mg/d)
-improve acne(3M), hirsutism(9M)
-add of CPA 10-100mg/d on first 10days
 Yasmin(drospirenone 3mg/d)
 Spironolacton(competitive inhibitor of androgen
receptor) 100mg/d
-widely used for hirsutism in USA where CPA not
available
-40% reduction after 6months
 Finasteride 1-5mg/d(inhibit 5a-reductase)
-30-60% reduction in hirsutism score

44. Acne
 Isotretinoin beneficial, in severe cases
 Eflornithine hydrochloride(inhibitor of
ornithine decarboxylase) topical apply

45. Anovulation and infertility
 Clomiphene citrate
 Metformin
 Tamoxifen
 Aromatase inhibitor(letrozole)
 Low-dose gonadotrophin therapy
 Glucagon like peptide-1(GLP-1)
 Laparoscopic ovarian drilling
 In-vitro fertilization

47. Clomiphene citrate
 Block estrogen receptor(hypothalamus). Induce
pulsatile release of GnRH and induce FSH from
anterior pituitary
 CC 50-150mg/d starting on Day 2, 3, 4 or 5
 Restore ovulation 49% and pregnancy
23%(PPCOS trial)
 Substitution of CC with tamoxifen(20mg for
every 50mg of CC) avoid anti-estrogenic effect
 CC resistance 20% of PCOS

48. CC and Metformin
 In PPCOS trial, ovulation 52% in first month
and 60% over 6 months
 Live birth rate over 6 months 27%
 Benefit of combined therapy on live birth
rates debated

49. Tamoxifen
 No anti-estrogenic effect
 Not licensed for ovulation
 Used in a similar way to CC(5 days in early
follicular phase) with starting daily dose of
20mg-40mg if ovulation not

50. Aromatase inhibitor
 Letrozole, anastrazole
 Block action of aromatase that convert
androstenedione and testosterone to
estrogen(no anti-estrogenic effect)
 Increased release of FSH
 Half life 2 days
 2.5-5mg/d for 5 days on Day2, 3, 4 or 5
 Questions of possible teratogenicity(locomotor
and heart)

52. Low dose gonadotrophin therapy
 Gonadotropin typically offered to not ovulated
with oral therapies
 Live birth rates over 6 cycles 60%
 Multiple pregnancy rates 16%
 Cancellation rate 16-40%
 Low dose gonadotropin 37.5 to 75 units

53. Glucagon like peptide-1 agonist
 Glucagon like peptide-1(GLP-1) ; incretin,
which enhances glucose-dependent insulin
secretion, delays gastric emptying, and
centrally controls appetite, therefore producing
weight loss
 GLP-1 agonist exenatide, metformin, and their
combination in obese patients with PCOS after
24wks of intervention, ovulation rates
improved by 50%, 29%, and 86%.
 Suggest that GLP-1 agonists may have a role
in therapy for PCOS

54. Adolescence(13-19y)
 All three of Rotterdam criteria make diagnosis
of PCOS
 85% anovulatory during the first year after
menarche
 59% still anovulatory during the third year
after menarche

55. In adolescent girls, Androgen Excess
Society(AES) 2006 criteria
 anovulation frequently occurs in the first 2 y
after menarche(physiologic anovulation)
 multifollicular ovaries can be a normal finding
in adolescence
 defining biochemical androgen excess in
adolescence girls difficult as normative ranges
fluctuate during puberty and acne and mild
hirsutism are common and obesity becoming
more prevalent

56. Adolescence treatment
 Many of pediatric colleagues have already
adopted metfomin as a standard treatment
in light of difficulties of maintaining diet and
life style restrictions in younger age group

57. conclusion
 Weight loss(diet, exercise)
 Oral contraceptives(yasmin, diane35)
 Metformin
 Clomiphen citrate
 Tamoxifen
 Letrozole
 Low dose gonadotrophin therapy
 Glucagon like peptide-1 agonist