Polycystic Ovary

SyndromeHEATHER BURKS, MD

OU PHYSICIANS REPRODUCTIVE MEDICINE

SEPTEMBER 21, 2018

Learning Objectives

At the conclusion of this lecture, learners should:

1) Know the various diagnostic criteria for polycystic ovary syndrome

2) Know the initial evaluation for a patient suspected to have

polycystic ovary syndrome

3) Understand the long-term health implications of polycystic ovary

syndrome

4) Understand key elements of the management of polycystic ovary

syndrome

Polycystic Ovary Syndrome (PCOS)

First described by Stein and Leventhal in 1935

Series of 7 patients with:

Amenorrhea

Hirsutism

Enlarged, multi-cystic ovaries

Am J Ob Gyn, 1935

•Male pattern hair growth

•Coarse terminal hair

•Male pattern hair growth

•Coarse terminal hair

PCOS: First series of 7 patients

Treated with ovarian wedge resection

All 7 resumed normal menses

2 of 7 became pregnant

Stein, Leventhal. Am J Ob Gyn, 1935

PCOS - Pathophysiology

“Cysts”

Actually follicles

Follicles arrested in development accumulate in the ovary

“PCOS women do not throw away their old follicles”

Normal ovulation: Selection of

dominant follicle

PCOS: Follicle arrest

Menstrual cycle changes: PCOS

Normal PCOS

PCOS: Definition

3 different sets of criteria created by 3 different meetings

National Institutes of Health 1990

Rotterdam ESHRE/ASRM Consensus 2003

Androgen Excess Society 2006

PCOS: Definition

NIH major criteria (all 3 required):

1. Chronic anovulation (oligo- or amenorrhea)

2. Clinical and/or biochemical evidence of hyperandrogenism

3. Exclusion of other causes of anovulation and

hyperandrogenism

Zawadsky JK, Dunaif A. , Blackwell Scientific 1992

PCOS: Definition

NIH minor criteria:

Insulin resistance

Perimenarchal onset of hirsutism and obesity

Elevated LH/FSH ratio

Ultrasonographic evidence of polycystic ovaries

Zawadsky JK, Dunaif A. , Blackwell Scientific 1992

PCOS: Definition

ACOG Practice Bulletin: PCOS 2018

R = required; NR = not required

So what IS PCOS??

A heterogeneous disorder of unclear etiology

An important cause of menstrual irregularity and androgen excess in

women

“Classic” PCOS

When fully expressed, manifestations include:

Ovulatory dysfunction

Androgen excess

Polycystic Ovaries

Obesity

PCOS: Prevalence

Affects 6-8% of reproductive age women

Most common cause of female infertility in the United States

Onset is likely pre-pubertal but difficult to detect until late

adolescence

Diagnostic tests

Anovulation: Menstrual history

⚫ < 9 menses/year or > 3 consecutive months without

menses

Hyperandrogenism:

Physical exam: Hirsutism, acne

Serum androgen levels:

Testosterone (T), Free T, DHEA-S

Pelvic Ultrasound

DIAGNOSIS OF EXCLUSION

Normal ovary Polycystic ovary

Controversy is due to high prevalence (up to 68%) of PCOM in normal young women

Pitfalls: ultrasound alone is not enough

Differential diagnosis

Androgen secreting tumor

Exogenous androgens

Cushing syndrome

Nonclassical congenital adrenal hyperplasia

Acromegaly

Genetic defects in insulin action

Primary hypothalamic amenorrhea

Primary ovarian failure

Thyroid disease

Prolactin disorders

Diagnostic tests of exclusion

▪ Pregnancy: HCG

▪ Congenital Adrenal Hyperplasia: 17-OH progesterone

▪ In high-risk populations

▪ Hyperprolactinemia: Prolactin

▪ Thyroid abnormalities: TSH

▪ Androgen secreting tumor: DHEAS, Testosterone

▪ Suspected if T > 200 ng/dL or DHEAS > 700 mcg/dL

▪ + Cushings syndrome: 24 hour urinary cortisol

Risk factors for PCOS in adolescents

Low birth weight: < 2500 g

Premature pubarche: Onset before 8yo

Family history (1st degree relative)

Obesity

Health implications

PCOS: Clinical Manifestations

Sam & Dunaif Trends Endocrinol Metab 2003.

Insulin sensitivity and obesity

Insulin resistance is a feature of PCOS in obese and non-obese women

Effects of Hyperinsulinemia

Activation of insulin receptor (IGF) in the ovary: augmented

thecal androgen response to LH

Suppression of hepatic SHBG production: increased free

androgen proportion

Direct stimulation of LH secretion by insulin

Sensitization of LH secreting cells to GnRH

Insulin Resistance

IR itself is not enough to cause PCOS

Only about 25% of reproductive-aged women with type 2

diabetes have PCOS

Screening for IR is indicated in patients with PCOS

PCOS and metabolic syndrome (MBS)

Associated with significant risk for early cardiovascular

disease

Criteria for diagnosis (3 of 5):

Abdominal obesity > 88 cm

Triglycerides > 150 mg/dl

HDL-C < 50 mg/dl

Blood pressure > 130/>85 mmHg

OGTT: 110-126 mg/dl and/or 140-199 mg/dl

Endometrial hyperplasia or

malignancy

Without regular ovulations:

Endometrium is exposed to estrogen from the ovaries and

adipose tissue

No or infrequent exposure to progesterone

Over time this can lead to endometrial hyperplasia or

even malignancy

Recommended workup

Physical examination

Blood pressure

Height/weight for BMI

Waist circumference

Signs of hyperandrogenism

Acne, hirsutism, alopecia

Signs of insulin resistance

Acanthosis nigricans

Laboratory evaluation

Document hyperandrogenemia: testosterone or free T

Exclude other causes

TSH

Prolactin

17-hydroxyprogesterone

Screen for other problems based on physical exam

(Cushing’s, acromegaly)

Additional evaluation

Ultrasound examination

FSH/LH levels

24-hour urinary free cortisol or overnight dexamethasone

suppression test if Cushing syndrome suspected

IGF-1 if acromegaly supsected

Screening for long term health

consequences

2 hour oral glucose tolerance test or Hemoglobin A1C

Fasting lipid profile

Blood pressure

Endometrial biopsy

Management of PCOS

Symptom-dependent treatment

Infertility

Skin manifestations, hirsutism

Dysfunctional uterine bleeding, endometrial cancer prevention

Obesity, diabetes prevention

Infertility treatment

Ovulation induction

WEIGHT LOSS: as little as 5% can resume ovulation

Clomiphene citrate

Approximately 50-80% ovulate with clomid alone

Aromatase inhibitors

Letrozole is now considered FIRST LINE by ACOG but remains an off-label use

Injectable gonadotropins

Laparoscopic ovarian drilling

Insulin-lowering medications - Metformin

Insulin sensitizers in PCOS

In women with PCOS:

Improves menstrual cyclicity, restores spontaneous

ovulation (up to 30% ovulate with metformin alone)

Improves symptoms of hyperandrogenism

May improve body composition (BMI, WHR) and lipid

profile

Symptoms

Increased terminal hair growth

Acne

Excess androgen production comes from the ovary

Increased theca cell volume

Increased expression of LH receptors on theca cells

Exaggerated androgen production occurs when LH binds

to receptors on the theca cells of the ovary

Hyperandrogenism

Skin manifestations, hirsutismtreatment

Oral contraceptives

Anti-androgens

Spironolactone

Flutamide

Finasteride

Topical eflornithine

Oral contraceptives

Currently considered first line therapy for those not currently

desiring fertility

Use low dose estrogen (20-30 mcg ethinyl estradiol) and

non-androgenic progestin (e.g. desogestrel or

drospirenone)

Oral contraceptives

Increases SHBG production in the liver

Decreases bio-available androgen

Decreases hirsutism, acne

Restores regular menstrual cycles if taken cyclically

Provides effective contraception

Anti-androgens

Effectively reduces biochemical and clinical

hyperandrogenism

May be more effective in treating hirsutism than metformin1

Improves menstrual cyclicity2

No improvement in metabolic abnormalities2

1 Ganie et al. JCEM 2004

2 Zulian et al. J Endocrinol Investig 2005

Dysfunctional uterus bleeding

Due to anovulation, which causes unopposed estrogen

exposure

Endometrial biopsy!! Rule out hyperplasia/malignancy

Combat with progestins

Oral contraceptives

Progestin only therapy

Oral (cyclic or continuous)

Intramuscular

Intrauterine device

Implantable contraception

Obesity, diabetes prevention

Obesity

Lifestyle management

Diet and exercise: Shown to effectively prevent diabetes in

high risk groups*

Effects:

Testosterone

Insulin levels

SHBG

Metformin

Lifestyle intervention and weight loss

Importance is emphasized, but difficult to achieve

Current recommendation is combination of lifestyle

modification with pharmacologic therapy

Refer for bariatric surgery evaluation if applicable and patient

is amenable

Would need to wait usually 12-18 months to try for pregnancy

Summary: PCOS

Initial evaluation:

H&P

Total T, DHEA-S, 17-hydroxyprogesterone, Prolactin, TSH,

LH, FSH

Pelvic ultrasound

Summary: PCOS

Periodic screening once diagnosis is established:

2 hour oral glucose tolerance test

Lipid profile

Blood pressure

+ Endometrial biopsy

Summary: PCOS

Treatment: Depends on symptoms and goals

Encourage healthy diet and exercise

Ovulation induction with clomid if pregnancy is desired

Oral contraceptive pills if pregnancy is not desired

Obese and IR patients: Metformin

Marked hirsutism refractory to OCPs: Consider spironolactone

Lifelong therapy may be necessary