Polycystic Ovary Syndrome

Jennifer L. Phy, D.O. Reproductive Endocrinology & Infertility

Assistant Professor, TTUHSC Department of Obstetrics and Gynecology

Objectives
Review the importance and history of polycystic ovary syndrome (PCOS) Describe the features and diagnostic criteria of PCOS Identify serious health conditions related to or mimicking PCOS Review treatment options for PCOS (fertility and general health)

Why is Polycystic Ovary Syndrome (PCOS) Important To Me As A Future Physician?

A patient with PCOS may present to..
a gynecologist reporting irregular periods a primary care provider complaining of unexplained weight gain a dermatologist reporting acne, facial hair growth and loss of hair on the scalp an oncologist with diagnosis of uterine cancer a medical endocrinologist with diabetes a reproductive endocrinologist frustrated by infertility

History of PCOS
In 1935, two gynecologists, Irving F. Stein and Michael L. Leventhal, described a symptom complex associated with anovulation They described 7 patients (4 of whom were obese) with amenorrhea, hirsutism and enlarged polycystic ovaries They performed bilateral wedge resection, removing one-half to three-fourths of each ovary All 7 resumed normal menses and 2 became pregnant

count 10 bubbles = abnormal

Polycystic Ovary

Polycystic Ovary Syndrome

PCOS is common
Affects 4-6% of reproductive age women

Cause is unknown but autosomal-dominant mode of inheritance is suggested Characterized by cycle day 1 to cycle day 1
Oligoovulation (menses >35 day intervals) Hyperandrogenism (hirsutism, acne, alopecia or

elevated serum androgens) Typically, patients have polycystic-appearing ovaries by ultrasound Reproductive and metabolic abnormalities are very common

Diagnosis of PCOS Easy or Not Easy?

Combination of clinical and laboratory findings
Oligoovulation (menses >35 days apart) Hyperandrogenism (clinical or laboratory) Exclusion of other conditions that may have similar

clinical features such as

Abnormal thyroid function (Check TSH) Hyperprolactinemia (Check Prolactin) Congenital adrenal hyperplasia (Check 17-OHP) Cushings syndrome (24-hour urine cortisol when clinically indicated)

checking 21 OHase deficiency

Diagnostic Schemes for PCOS

National Institutes of Health Criteria, Signs & Symptoms 2013 (2 out of 3 are required) Hyperandrogenism Possible but not required Possible but not required Possible but not required Rotterdam Consensus Criteria, 2003 (2 out of 3 are required) Possible but not required Possible but not required Possible but not required Androgen Excess Society, 2006 (hyperandrogenism plus one are required) Required

Oligomenorrhea or Amenorrhea Polycystic ovaries by ultrasound diagnosis

Possible but not required Possible but not required

Oligoovulation
Menses >35 day intervals (from first day of menses from one cycle until the first day of menses of the next cycle) May be assessed by patient history A serum progesterone level does not need to be drawn to prove anovulation or oligoovulation Note that patients may have more frequent breakthrough bleeding, especially if endometrial lining is thickened (due to chronic estrogen exposure) can still bleed with oligoovulation

Hyperandrogenism
Hirsutism Acne Alopecia (male pattern hair loss) Elevated serum androgens
Total testosterone (*Most helpful androgen assay) Free testosterone (Usually recognized clinically) Dehydroepiandrosterone sulfate (DHEAS) not
unnecessary

usually performed because of significant assay variability

Hirsutism
Excessive facial and body hair growth caused by excess androgen production Usually associated with anovulatory ovaries and loss of cyclic menstrual function

Factors Influencing Hair Growth

changes in hair FOLLICLE

Dermal papilla Sexual hair Responds to sex steroids

Face, lower abdomen, anterior thighs, chest,

breasts

Androgenic Stimulation of the Hair Follicle

Requires conversion of testosterone to dihydrotestosterone (DHT) in the hair follicle The sensitivity of the hair follicle to androgens is determined by the local level of 5-reductase activity

5-Reductase Activity
Stimulated by insulin-like growth factor-I (IGF-I) IGF-I activity can intensify the hirsute response in anovulatory women with insulin resistance

IGF-1 sensitizes insulin receptor; insulin resistance > higher levels of IGF-1

Testosterone
80% of circulating testosterone is bound to a beta globulin - sex steroid hormonebinding globulin (SHBG) Normally, approximately 1% of testosterone remains unbound or free in women Testosterone is produced in excess by the ovarian theca cells in PCOS

Testosterone
Plasma testosterone levels (normal 20 80 ng/dL) are elevated in approximately 70% of women but still want to do it to rule out with anovulation and hirsutism ectopic testosterone Measurement may be inaccurate and costly If the testosterone level exceeds 200 ng/dL, an androgen-producing tumor must be suspected Note that testosterone levels may be significantly elevated in normal pregnancy (100 ng/dL in the first trimester and up to 800 ng/dL at term)

Testosterone Levels in Hirsute Women

SHBG depressed by excess androgens SHBG depressed by hyperinsulinemia (if present) Free testosterone elevated Metabolic clearance rate of testosterone is increased

Can a hirsute woman have a normal total testosterone concentration?

yes; metabolic clearance of testosterone. total testosterone test = rules out androgen secreting tumor but not PCOS.

Can a hirsute woman have a normal total testosterone concentration?

YES!
An elevated serum testosterone level is not mandatory for the diagnosis of PCOS if clinical features of hyperandrogenism are present. The purpose of the testosterone level is to screen for an androgen-secreting neoplasm.

Androgen-producing tumors
One of medicines vastly overrated problems Incredibly rare Functioning ovarian tumors are almost always PALPABLE (>5 cm) If a tumor is suspected but not palpable, catheterization procedures or surgical exploration with bivalving of the ovaries may be necessary

Androgen-producing tumors
Rapidity of development is important in your evaluation A woman who develops new onset of hirsutism after age 25 and demonstrates very rapid progression or masculinization over several months to a year usually has an androgen-producing tumor rather than PCOS (Favorite Board Question)
PCOS more gradual

this test is expensive; usually not recommended to order

DHEAS Level
Dehydroepiandrosterone sulfate (DHEAS) circulates in higher concentration than any other steroid and is derived almost exclusively from the adrenal gland Laboratory ranges vary Contributes to hirsutism by serving as a prehormone in hair follicles as a substrate for androgen synthesis Often mildly elevated in PCOS >700 ug/dL indicates abnormal adrenal function; however, this is so rare that its clinical use is questioned

17-hydroxyprogesterone (17-OHP) Level

Due to the relative frequency of late-onset adrenal hyperplasia, routine screening of 17-OHP in women who complain of hirsutism is recommended Baseline 17-OHP should be measured in the morning and should be < 200 ng/dL Levels between 200 and 800 ng/dL require Adrenocorticotropin hormone (ACTH) testing (levels >800 ng/dL are virtually diagnostic of 21hydroxylase deficiency)
Testing in the follicular phase of the menstrual cycle is best

don't need all the details but know principles of this; know normal values and outcomes of tests (next step)

ACTH Stimulation Test

If baseline 17-OHP is > 200 ng/dL, the ACTH stimulation test is recommended expensive Synthetic ACTH (Cortrosyn) 250ug is administered intravenously at 8:00 a.m. 17-OHP is measured at time 0 and at 1 hour The 1-hour values are plotted to determine whether the patient is normal, a heterozygote or has late onset congenital adrenal hyperplasia

Risk of Endometrial Cancer

Chronic anovulation (essentially a state of unopposed estrogen) increases risk of endometrial hyperplasia and endometrial cancer If prolonged amenorrhea or endometrial lining thickness is > 12mm, endometrial biopsy is recommended (after confirming a negative pregnancy test)

endometrial lining should be less than 10mm; this pt. is 40mm

Abnormal Endometrium

PCOS: constant estrogen bombardment so endometrium keeps getting thicker

Metabolic Disorders
Women with PCOS are at increased risk of hyperinsulinemia, hyperlipidemia and cardiovascular disease Anovulatory, hyperinsulinemic women are at a 5to 10-fold greater risk for noninsulin-dependent diabetes The age of onset of noninsulin-dependent diabetes is about 30 years earlier than in the general population

Assessing Insulin Secretion

Hyperandrogenism and hyperinsulinemia are commonly associated Hyperinsulinemia can directly augment theca cell androgen production in the ovary Hyperinsulinemia contributes to hyperandrogenism by inhibiting hepatic synthesis of SHBG and decreasing insulin-like growth factor binding protein-1 (ultimately increasing free testosterone levels)

Assessing Insulin Secretion

Anovulatory women who are hyperandrogenic may be assessed for glucose tolerance and insulin resistance gold standard with measurement of 2-hour glucose and insulin levels after a 75-g glucose load Annual assessment is appropriate in women who continue to be overweight

Assessing Insulin Secretion

75 gm 2-hour oral glucose tolerance test:
Normal glucose Impaired NIDDM
non-pregnant pts.

<140 mg/dL 140-199 mg/dL > or = 200 mg/dL

INS should never go over 100 in normal pts.

Insulin responses 2 hours after glucose load:

Insulin resistance likely Insulin resistance Severe insulin resistance

100-150 uU/mL 151-300 uU/mL > 300 uU/mL

Treatment of PCOS
Depends upon the goal of treatment
Menstrual cycle regulation Weight loss and health improvement Fertility

When is use of metformin appropriate for women with PCOS?

Metformin is an insulin-sensitizer commonly used to treat noninsulin-dependent diabetes Use of metformin is often used when insulin resistance is documented by glucose tolerance testing Use of metformin for ovulation induction or to improve response to clomiphene citrate (Clomid) is controversial

Pregnancy in Polycystic Ovary Syndrome (PPCOS) Study

Recent randomized, multicenter, doubleblind study to evaluate ovulation induction and live birth rates comparing
Metformin/placebo Clomiphene citrate/placebo Combination of metformin/Clomiphene citrate

In the treatment of women with PCOS

PPCOS Study
626 women with PCOS Age 18-39 years Randomized equally to the three treatment arms Treated for 6 cycles or for 6 months Frequent serum progesterone levels were obtained to determine ovulation Medications were discontinued when the patient had a positive pregnancy test

PPCOS Study Results

Live birth rate
Clomiphene citrate arm was 22.5% (47/209) Metformin arm was 7.2% (15/208) Clomiphene citrate/Metformin arm was 26.8%

(56/209) Stratifying by BMI did not alter results

PPCOS Study Results

There were no significant differences in spontaneous abortion rates between groups However, the spontaneous abortion rate was highest in the metformin group 5/24 (20.8%) compared to clomiphene citrate 5/60 (8.3%) and combined therapy 7/76 (9.2%)

PPCOS Study Conclusion

Clomiphine citrate is superior to metformin in achieving a live birth in infertile women with PCOS There is no statistically significant advantage to combined therapy in achieving live birth

Treatment of PCOS for menstrual cycle control and hirsutism

If conception is not desired, treatment is directed toward optimizing health and menstrual cycle control always before medication treatment Diet and exercise Metformin if indicated Oral contraceptive pills (OCPs) Spironolactone if hirsutism is significant or not improved with OCPs

Treatment of PCOS/Hirsutism
Initial treatment:
Low-dose oral contraceptives
Suppress ovulation and LH production Increase SHBG Progestins inhibit 5-reductase activity mimic natural hormone cycles Popular choices include triphasic preparations or those containing drospirenone Clinical improvement is slow Benefits may take 6 months to detect clinically

Treatment of Hirsutism
Electrolysis or laser hair removal is not recommended until hormonal treatment has been used at least 6 months synergistic with OCPs; always use with OCPs. Spironolactone (aldosterone antagonist diuretic) beginning 100mg daily
Inhibits adrenal and ovarian biosynthesis of androgens Competes for androgen receptors at the hair follicle Directly inhibits 5-reductase activity Use of contraception is important

Typical Case
26 yo G0 desires conception Menses occur every 2 to 6 months Hirsutism, acne, elevated BMI Normal pelvic exam (speculum, bimanual) Husband has previously fathered a pregnancy and has no health problems How would you evaluate?
total testosterone test, 17-OHP, TSH, prolactin.

Evaluation for PCOS

Detailed history and physical Quantitative beta-hCG TSH Prolactin Total testosterone 17-OHP Lipid panel 2-hour 75 gm glucose tolerance test
also ultrasound (>10 follicles); >12mm = biopsy it.

Case Results
Quantitative beta-hCG negative TSH and prolactin are normal Total testosterone elevated (80 ng/dL) 17-OHP normal (<200 ng/dL) Lipid panel (Cholesterol 200 mg/dL) 2-hour 75 gm glucose tolerance test is normal Hysterosalpingogram (HSG) shows patent fallopian tubes Pelvic ultrasound shows polycystic ovaries Husbands semen analysis is normal

Case
Diagnosis:
Polycystic ovary syndrome (PCOS)

Treatment
Preconception counseling Prenatal vitamins Emphasize importance of diet and exercise Good candidate for clomiphene citrate (Clomid) 50 mg daily, menstrual cycle days 3 7 Consider metformin (especially if abnormal 2 hour oral glucose tolerance test) Timed intercourse or insemination Consider checking ovulation predictor kit and cycle day 21 progesterone to confirm ovulation

Ovulation induction
Goal to achieve ovulation with lowest required dose of medication
Clomiphene citrate Letrozole (less common) Possibly in combination with metformin
can make them grumpy; headaches, visual changes

Well-tolerated Simple Inexpensive Multiple birth risk (reported 5-15%)

Clomiphene citrate (Clomid)

Use lowest dose possible to achieve ovulation (50 mg, 100 mg, 150 mg) Side effects include moodiness and rarely headaches and visual changes Monitor for ovulation via ovulation predictor kit or cycle day 21 progesterone (>3 ng/mL) Cyst formation is common anti-androgen that acts at hypothalamus Site of action: Hypothalamus Maximum of 12 cycles per lifetime is generally accepted
mimics low estrogen = FSH/LH surge

Summary
Proper evaluation and management of PCOS begins with a careful history and physical examination Laboratory evaluations are important to detect potentially serious medical conditions associated with hirsutism and anovulation Medical therapy requires patience Proper management of PCOS can be very rewarding and can restore a patients health, fertility, self-esteem and happiness

nuns high rate of PCOS because no OCPs. chickens ovulate every day = high risk of ovarian cancer. OCP decrease risk for ovarian cancer. pandas ovulate every 2 years = low risk

Questions?