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