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