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)
3.
4.
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
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
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?)
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
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)
51.
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