1. Polycystic Ovarian Syndrome Refresher Course for the Family Physician
Lauren Coyne, MD
Clinical Assistant Professor
Department of Obstetrics and Gynecology

2. PCOS - Outline Background Incidence and Etiology
Clinical manifestations
Differential Diagnosis
Clinical Considerations

3. Background Endocrinopathy characterized by Future metabolic sequelae
Hyperandrogenism
Ovulatory dysfunction
Polycystic ovaries
Future metabolic sequelae
Cardiovascular disease
Diabetes

4. Definition Signs/Symptom NIH Criteria (Both required)
Rotterdam Criteria (2 of 3 required)
Androgen Excess Society
Hyperandrogenism R NR
Oligomenorrhea/ Amenorrhea
Polycystic ovaries by ultrasound -

5. Definition Signs/Symptom NIH Criteria (Both required)
Rotterdam Criteria (2 of 3 required)
Androgen Excess Society
Hyperandrogenism R NR
Oligomenorrhea/ Amenorrhea
Polycystic ovaries by ultrasound -

6. Hyperandrogenism Clinical findings Acne Hirsutism Androgenic alopecia
Acanthosis nigracans

7. Hyperandrogenism Laboratory findings
Total testosterone, SHBG
Bioavailable and free testosterone
Exclude other causes of hyperandrogenemia
TSH
Prolactin
17-hydroxyprogesterone
17-oh p to rule out nonclassical congenital adrenal hyperplasia due to 21 hydrozylase deficincy

8. Oligomenorrhea/Amenorrhea
Oligomenorrhea – Bleeding that occurs less frequently than every 35 days
Amenorrhea – Absence of menses for more than 3 cycles

9. Polycystic Ovaries Present in one or both ovaries
12 or more follicles measuring 2-9mm in diameter
Increase ovarian volume >10cc

10. Transvaginal sonography displays multiple small hypoechoic cysts
Transvaginal sonography displays multiple small hypoechoic cysts. (Used with permission from Dr. Elysia Moschos.)
Source: Polycystic Ovarian Syndrome and Hyperandrogenism, Williams Gynecology, 3e
Citation: Hoffman BL, Schorge JO, Bradshaw KD, Halvorson LM, Schaffer JI, Corton MM. Williams Gynecology, 3e; 2016 Available at: Accessed: February 14, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved

11. Exaggerated PCOS Ovarian Hyperthecosis HAIRAN Syndrome
Severe form of PCOS
Nest of luetinized theca cells throughout ovarian stroma
Severe hyperandrogenism and frank virilization
Greater degree of insulin resistance and acanthosis nigricans
HAIRAN Syndrome
Hyperandrogenic-insulin resistant acanthosis nigracans
Severe insulin resistance
PCOS variant vs genetic syndrome
Virilzation – Clitoromegaly, temporal balding, voice deepeing

12. Incidence/Etiology Affects 4-12% of female population
Equally affects all races and nationalities
Multifactorial and polygenic basis is suspected
Obesity may amplify the effects
Symptoms of androgens excess may affect different races/nationalities differently
Obesity is not a diagnostic criterion and 20% of patient are not obese

13. Pathophysiology Increased LH level
Increased degree of insulin resistance and compensatory hyperinsulinemia
Both insulin and LH stimulate androgen production by ovarian theca cells
Decreased levels of sex hormone binding globulin
Less circulating androgen is bound and more is therefore free to bind end organ receptors (more can be converted to estrone by aromatase in adipose)
Total testosterone can be in normal range, free testosterone levels elevated (clinically hyperandrogenic)
Anovulation
Altered GnRH pulsatility, inappropriate gonoadotropin secretion, insulin resistance (why metformin may benefit)

14. Consequences Short term Long Tern Obesity Infertility Depression
Sleep apnea
Irregular menses
Abnormal lipid levels
NASH
Hisutism/Acne/ Alopcia
Insulin resistance/acanthosis nigracans
Long Tern
Diabetes mellitus (2-5 fold increase)
Endometrial cancer
Cardiovascular disease

15. Clinical Manifestations
Menstrual dysfunction
Amenorrhea, oligomenorrhea, episodic menorrhagia (can result in iron deficiency anemia)
Hyperandrogenism
Hirsutism, acne, androgenic hirsutism
Infertility
Increased risk for ovarian hyperstimulation and multifetal pregnancy
Pregnancy complications
Insulin resistance
Obstructive sleep apnea
Metabolic syndrome/cardiovascular disease

16. Metabolic Syndrome Two or more criteria present
Elevated blood pressure
Greater or equal to 130/85
Increased waist circumference
>35 inches
Elevated fasting blood glucose
>100 mg/dL
Reduced HDL
Less than or equal to 50 mg/dL
Elevated triglyceride level
Greater than or equal to 150 mg/dL

17. Differential Diagnosis
Androgen secreting tumor
Exogenous androgens
Cushing syndrome
Screen only if coexisting signs of Cushing (moon facies, buffalo hump, abdominal striae, centripetal fat distribution, htn)
Nonclassical congenital adrenal hyperplasia
Acromegaly
Genetic defects in insulin action
Primary hypothalamic amenorrhea
Primary ovarian failure
Thyroid disease
Prolactin disorders

18. Non-classical CAH Late onsent
Adult presentation of anovulation and hirsutism
Genetic defect in 21 hydroxylase (CYP21)
Ashkenazi Jews, Hispanics, Yugoslavs, Native American Inuits in Alasaka, Italians
If in high risk groups screen with morning, fasting 17-hydrocyprogesterone level
If elevated, ACTH stimulation test (adrenocorticotropic)

19. Benefit of Weight loss? Lower circulating androgen levels
Resumption of menses
Improved pregnancy rates
Decreased hirsutism
Better glucose and lipid levels
See normalization of reproductive and metabolic abnormalities with as little as 5% loss of initial weight
Pharmacologic/surgical weight loss modalities may be beneficial
Unknown if helpful in normal weight patients

20. Type II Diabetes Screening
With diagnosis of PCOS
Fasting glucose level and 2 hour glucose challenge after 75g glucose load
Insulin level testing is of little utility

21. Cardiovascular disease screening
Dyslipidemia present in 70% of PCOS patients
Early onset of cardiovascular disease is suspected but not proven
Premenopausal PCOS patients have increased prevalence of subclinical atherosclerosis
Risk assess with BMI, fasting lipid and lipoprotein levels, and metabolic syndrome risk factors
Screen periodically
Regular exercise and weight control are best methods to reduce CV risk

22. How treat menstrual disorders?
Combination hormonal contraceptives
Suppress LH, suppress ovarian androgen secretion, increase SHBG
“Most effective” combination of hormonal contraception unknown
Progestin
Cyclic oral progesterone or progesterone containing IUD decrease endometrial cancer risk
Optimal regimen unknown
Insulin-sensitizing agents

23. How treat menstrual disorders?
Insulin – sensitizing agents
Metformin used most commonly
Tend to decrease weight
Improving insulin sensitivity is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance
Ovulation rates likely improve – discuss contraception!
No antidiabetic agent is FDA approved for PCOS related menstrual dysfunction
Unknown endometrial protective effects

24. Risk reducing medical therapy – Pregnancy not desired
Lifestyle modification
Increase exercise
Dietary changes – calorie restriction (no benefit of any other dietary modifications)
Insulin-sensitizing agents - Metformin
Beneficial if impaired glucose tolerance or metabolic syndrome is present
Used in conjunction with lifestyle changes
Commonly dosed 1500 – 2000 mg daily in divided doses

25. Risk reducing medical therapy – Pregnancy not desired
Statins
Increasing evidence of benefit of cardiovascular and endocrine benefit with PCOS
Long-term effects in preventing CV disease in young women with PCOS is unknown
Combined hormonal contraceptives and progestins
Dose dependent effects on insulin sensitivity of cOCP
Low-dose hormonal contraceptive is recommended
See increase in triglyceride and HDL
Consider additional cardiovascular risk factors such as hypertension, obesity, clotting history, cigarette use
Effect of progestins alone on metabolic risk factors vary and is not well understood

26. Ovulation Induction Associated with an increase in multiple birth
10% increased risk of twin gestation with use of clomiphene
Greater even with exogenous gonadotropins
May be higher with PCOS patients
Related obstetric and neonatal risks
Preterm birth
Hypertensive disorders
Gestational diabetes
Discordant growth
Fetal malpresentation

27. Ovulation Induction Clomiphene Citrate Gonadotropins First line
Live birth rates 20-40%
50% will conceive at starting dose (50mg)
20% will conceive at 100mg dose
Adding dexamethasone has been found to increase both rates of ovulation and pregnancy
Gonadotropins
Option if clomid fails
Low dose is optimal (higher rate of ovulation and monofollicular development with lower risk of ovarian hyperstim)

28. Ovulation Induction Ovarian drilling Aromatase inhibitors (Letrozole)
2nd line option
Beniefits may be temporary and medical induction may still be needed
Lower rate of multiples
Aromatase inhibitors (Letrozole)
Not FDA approved
Results similar to Clomid
May have lower multiple rates, higher implantation rates
Metformin
May increase pregnancy rates when used with clomid
No increase in pregnancy loss

29. Treating hirsutism Combined hormonal contraceptives Not FDA approved
Improvement has been noted
No optimal pill
Effects may be additive with usage of spironolactone

30. Treating hirsutism Antiandrogens
Teratogenic, best when combined with OCP
Spironolactone
Inhibits ovarian and adrenal steroidogenesis
Competes at androgen receptors in hair follicles
Inhibits 5 alpha reductase
Dose mg twice daily
May take 6 months for maximum effect
May see increased menstrual frequency
Flutamide
Androgen receptor agonist
Optimal use with lifestyle changes and metformin
Finasteride
Well tolerated

31. Treating hirsutism Insulin-sensitizing agents Elfornithin
Additional data needed
Elfornithin
Ornithine decarboxylase inhibitor
FDA approved
Cream applied twice daily

32. Cosmetic management of hirsutism
Mechanical removal
No evidence to support that shaving increases hair follicle number or size
Avoid folliculitis
Laser
Dark hair, light skin are best candidates
Repeat treatments may be necessary

33. Citations
Hoffman BL, Schorge JO, Bradshaw KD, Halvorson LM, Schaffer JI, Corton MM.Polycystic Ovarian Syndrome and Hyperandrogenism. In: Hoffman BL, Schorge JO, Bradshaw KD, Halvorson LM, Schaffer JI, Corton MM. eds. Williams Gynecology, 3e. New York, NY: McGraw-Hill; 2016.  February 15, 2017.
PB 108
PB 128