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Polycystic Ovary Syndrome
R. Jeffrey Chang, M.D.
Department of Reproductive Medicine
University of California, San Diego
Commercial Disclosures (9.9.06)
Entity Activity
Wyeth Research fundingSerono Research supportTakeda Research supportBerlex Research support
Learning Objectives
• Integrate the altered endocrine-metabolic physiology with the clinical presentation
of polycystic ovary syndrome (PCOS) • Describe the evaluation and available treatment options for PCOS
Overview of PCOS
• In 5-10% of reproductive aged women
• Multi-system reproductive-metabolic disorder
• Hypothalamic-pituitary-ovarian axis
• Carbohydrate metabolism
• Obesity
Clinical Features of PCOS
• Androgen excess (hirsutism)
• Chronic anovulation (irregular menses)
• Insulin resistance (diabetes)
• Polycystic ovaries
Androgen Excess
• Hirsutism: Onset and distribution Growth rate
• Hyperandrogenemia: Total testosterone Free testosterone
• Virilization is rare
Facial Hirsutism in PCOS
Estimated Prevalence of Menstrual Patterns in PCOS
• Oligomenorrhea 70-75 %
• Amenorrhea 20 %
• Regular cycles 5-10 %
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Hormone Level
EstradiolProgesteroneFSHLH
Menstrual Cycle Day
Ovulation
Endometrial Thickness
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Normal Menstrual
Cycle
Hormone Level
EstradiolProgesterone
Endometrial Thickness
0 2 4 6 8 10 12 14 16 18 20
0 2 4 6 8 10 12 14 16 18 20 Weeks
Breakthrough
Withdrawal
Anovulatory Bleeding in
PCOS
Lower limit of normal
Ultrasound Description Of
Polycystic Ovaries
● Presence of 12 or more follicles in each ovary
● Increased ovarian volume (>10 ml)
● No consideration of stroma
Fertil Steril, 2003
Polycystic Ovaries Cystic Follicles
Uterus
Tube
Anatomic Features of the Polycystic Ovary
Ultrasound of the Polycystic Ovary
Insulin Sensitivity
Insulin
Liver Muscle
Pancreas
Hepatic Glucose Output
Glucose Utilization
Insulin Resistance
Insulin
Liver Muscle
Pancreas
Hepatic Glucose Output
Glucose Utilization
Increased
Glucose Intolerance in PCOS
n NGT IGT DM
Legro et al
(2005)
71 39 (55%) 25 (35%) 7 (10%)
Ehrmann et al (1999)
122 67 (55%) 43 (35%) 12 (10%)
Norman et al (2001)
67 54 (81%) 13 (19%) 0
16%/yr 2%/yr
9% 54%
6/11 4/14
Acanthosis Nigricans
• Velvety plaques on nape of neck and intertriginous areas
• Epidermal hyperkeratosis
• Associated with insulin resistance
Obesity in PCOS
• About 50% of PCOS
• Android distribution
• Associated with insulin resistance
• Lowers sex hormone binding globulin
• Adverse lipid profile
Other Historical Markers
• Peri- or postpubertal onset
• Familial occurrence
• Infertility
LH, FSH AndrogenEstrogen
GnRH
Anovulation
Hypothalamic-Pituitary-Ovarian Dysfunction in PCOS
0
2
4
6
8
10
12
0 20 40 60 80
0246
8101214
0 20 40 60 80
0 6 12 18 24
0 6 12 18 24
LH
mIU
/ml
LH
mIU
/ml
Normal
PCOS
* * * * * * * * *
* ** ** *** * * * ** **
24 Hour LH Pulse Secretion Pattern in Normal and PCOS
Adult Women
# pulses = 9
# pulses = 15
Normal ■ # pulses/22h = 9 ■ Orderly secretion
PCOS ■ # pulses/22h = 15 ■ Increased levels ■ Chaotic pattern
Patel K et al, Clin Endocrinol, 2004
5
4
3
2
1
0
5
4
3
2
1
00 100 200 300 400 500 Time (min)
Pla
sma
LH I
U/L
E2 : 67 pg/mlP : 0.4 ng/ml
E2 : 193 pg/mlP : 7.8 ng/ml
A
B
* * * * * * *
* *
A. Baseline: Pulse frequency in a normal woman studied on Day 8-10 of the cycle. Number of pulses = 7.
B. Treatment: Pulse frequency in the same woman studied 7 days later following daily E2 and P4.. Number of pulses = 2.
Effect of Steroid Feedback on LH Pulse Frequency in Normal
Women
Pastor et al, JCEM, 1998
A. Baseline: Pulse frequency in a PCOS woman. Number of pulses = 6.
B. Treatment: Pulse frequency in the same PCOS woman studied 7 days later following daily E2 and P4. Number of pulses = 5.
Effect of Steroid Feedback on LH Pulse
Frequency in PCOS Women
10
8
6
4
2
0
0 100 200 300 400 500 Time (min)
Pla
sma
LH I
U/L
E2 : 73 pg/mlP : 0.7 ng/ml
E2 : 205 pg/mlP : 8.4 ng/ml
A
B10
8
6
4
2
0
* * * * * *
* * * * *
Pastor et al, JCEM, 1998
Δ in
LH
pu
lses
/8 h
r
▲
▲▲▲
▲▲▲
▲
▲
▲
▲
▲
▲ ▲ ▲▲
▲▲▲
▲▲ ▲ ▲ ▲▲
▲
0 5 10 15 20 0 5 10 15 20Day 7 P (ng/ml) Day 7 P (ng/ml)
Controls PCOS
Change in LH Pulse Frequency After E2 + P Treatment
Pastor et al, JCEM, 1998
+2
0
-2
-4
-6
-8
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
Ch
ang
e i
n L
H p
uls
es/1
2 h
r
0 2 4 6 8 10
Day 7 P (ng/ml) Day 7 P (ng/ml)
Controls PCOS
Change in LH Pulse Frequency After E2 + P with Flutamide Treatment
0 2 4 6 8 10
●
● ● ●
●●
●
●
●
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
●
●
●
●
●●
●
●
●
● ●
●
●
●
Eagleson et al, JCEM, 2001
LH, FSH AndrogenEstrogen
GnRH
Anovulation
Hypothalamic-Pituitary-Ovarian Dysfunction in PCOS
▪ Female Rhesus monkeys, 6-13 yrs
▪ Testosterone subcutaneous pellets
- 4 mg/kg x 3 days - 0.4 mg/kg x 10 days
▪ Recombinant FSH treatment
Effect of Androgen Administration on the Ovary of Non-human Primates
Weil et al, JCEM, 1999
Effect of dose and duration of test- sterone treatment on ovarian size and follicle number
Testosterone effect on granulosa cell proliferation and apoptosis. Apoptosis index = # granulosa cell apoptotic nuclei per 100 cells
Vendola et al, JCI, 1998
Weil et al, JCEM, 1999
Co-localization of Androgen Receptor (AR) and FSH Receptor (FSHR) mRNA Expression
in Non-human Primate Ovary
FSH Receptor Gene Expression in Follicles from Testosterone Treated Monkeys
Weil et al, JCEM, 1999
• Increased ovarian size and follicle number
• Increased granulosa cell proliferation
• Decreased granulosa cell apoptosis
• May influence granulosa cell response
to FSH
Effect of Androgen Administration on the Ovary of Non-human Primates
LH, FSH AndrogenEstrogen
GnRH
Anovulation
Hypothalamic-Pituitary-Ovarian Dysfunction in PCOS
Causes of Hyperandrogenism
• Polycystic Ovary Syndrome
• Hyperthecosis
• Congenital adrenal hyperplasia
• Cushing’s syndrome
• Androgen producing tumor
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)
Total Testosterone (T)DHEA-S (DS)17-hyroxyprogesterone (17-OHP)
T > 200 ng/dlDS > 700 μg/dl
Suspect Tumor
17-OHP > 2 ng/ml
Suspect CAH
T Elevated ±DS Elevated
DS Elevated
T & DS Normal PCOS
Adrenal
Idiopathic
Laboratory Evaluation
Other Lab Considerations
• LH:FSH ratio
• Measure of insulin resistance
Treatment Options in PCOS
• Lifestyle modification
• Androgen suppression
• Anti-androgens
• Insulin lowering agents
The Fertility Fitness Progamme
• Discussed role of weight and body composition on reproductive health
• Agreement to seek lifestyle changes for 6 months
• Group meeting with partners for cooperation
• Weekly meetings for 2-5 hours with women
• Gentle aerobic exercise for 1 hr (walking, etc.)
• Lecture for 1 hr (eating, smoking, nutrition, etc) Modified from Norman RJ et al, Trends Endocrinol Metab, 2002
Results
• 15 obese (37 BMI) anovulatory PCOS women
• Mean weight loss was 2-5%
• Improvement in abdominal fat, psychological measures,
androgenicity, and insulin sensitivity
• 9 women resumed ovulation
• 2 pregnancies
Modified from Norman RJ et al, Trends Endocrinol Metab, 2002
Androgen Suppression
• Sex steroid administration
• GnRH agonist therapy
• Glucocorticoid administration
Oral Contraceptives
• Suppress ovarian androgen
• Increase SHBG
• Regular menstrual cyclicity
• Progestin opposition
• Contraception
Anti-androgens
• Spironolactone
• Flutamide
• Finasteride
Spironolactone
• Androgen receptor blockade
• Steroid enzyme inhibition
• Aldosterone antagonism–Lower blood pressure–Potassium sparing
• Dose: 100-200 mg/day
Flutamide
• Non-steroidal, selective anti-androgen
• Liver function tests
• Dose: 125-250 mg/day
Insulin Lowering Agents
• Metformin (Glucophage)- 1500-2000 mg/day
• Thiazolidinediones - Rosiglitazone (Avandia)
2-8 mg/day - Pioglitazone (Actos) 30-45 mg/day
Insulin Lowering Agents
• Induction of ovulation (30%)
• Some reduced hair growth
• Improved glucose utilization
• Lowered serum insulin
• Lipid lowering properties
Use of Insulin Lowering Drugs In Ovulation Induction
• Baseline hepatic and renal function tests
• Metformin (Category B)- Lactic acidosis- Iodine containing contrast dye
• Thiazolidinediones (Category C)- Monitor liver function - Edema