PCOS: Targeting Treatments to Improve Reproductive Outcomes and Reduce CVD

SUMMARY:

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductive aged women, with a prevalence of 10-13%. It is a heterogeneous and poorly understood condition characterized by varying degrees of hyperandrogenism, ovarian dysfunction and polycystic ovaries.  Due to insulin resistance, women with PCOS are at increased risk for metabolic syndrome and consequent diabetes, cardiovascular events, and sleep disorders.  Unopposed estrogen from chronic anovulation may result in premenopausal endometrial cancer even though the absolute risk remains low. Once identified, women need to be counseled and treated appropriately to reduce their risk of these complications, while optimizing fertility, and reducing preconception risk factors throughout their lifetimes.

Treatment for Menstrual Disorders

Not Attempting to Conceive

• Combined oral contraceptives suppress luteinizing hormone secretion, ovarian androgen secretion and increase circulating sex hormone binding globulin (SHBG)
  • Recommended for primary treatment of menstrual disorders
  • May also be used to treat hirsutism
  • No clinical advantage of using high-dose ethinyl estradiol (≥30 μg) vs low-dose (<30 μg) when treating hirsutism
• Progestin-only contraceptives or progestin containing IUDs protect the endometrium but lead to abnormal bleeding patterns in over 50% of patients
• Metformin
  • Should be considered in adults with a BMI ≥25 kg/m2
  • Can be considered for adolescents
    • Starting at 500 mg increments with extended release may improve compliance
    • Maximum dose 2.5 grams in adults and 2 grams in adolescents
• Metformin can be used over OCP for metabolic indication
• OCP can be used over metformin for menstrual regulation and/or hirsutism
• Combination of metformin and OCP can be more effective than either medication alone
• Bariatric surgery
  • Should be considered to improve weight loss, ovulation, pregnancy rates, diabetes, hirsutism      
  • Given the rapid return of fertility, effective contraception is indicated prior to surgery

Note: Weight should be stable for a year prior to conception to decrease pregnancy and newborn complications

Treatment for Hirsutism

• Combined with effective contraception, anti-androgens could be considered to treat hirsutism if there is a suboptimal response after a minimum of 6 months of COCP and/or cosmetic therapy
• Spironolactone
  • Diuretic | Aldosterone antagonist | Androgen receptor antagonist
  • Dose: 25 to 100 mg twice daily
  • May take up to 6 months to be effective
• Flutamide
  • Androgen-receptor antagonist
  • Dose: 125 to 250 mg/day
  • Increased risk of severe liver toxicity
  • Teratogenic
• Finasteride
  • 5-alpha-reductase inhibitor
  • Dose: 1 to 5 mg/day
  • Increased risk of liver toxicity
  • Teratogenic
• Topical eflornithine
  • Inhibitor of ornithine decarboxylase
  • Twice daily application for facial hair
• Cyproterone acetate
  • antiandrogen and progestin medication
  • ≥10 mg is not advised due to risk for meningioma
• Mechanical hair removal
  • Electrolysis | Laser vaporization | Shaving | Plucking | Waxing | Depilatory creams

Treatment to Reduce Cardiovascular and Diabetes Risks

Not Attempting to Conceive

• Lifestyle modification (e.g. regular exercise and weight loss)
  • Weight loss is the primary therapy in PCOS
  • As little as 5% reduction in weight can restore regular menses and improve response to fertility medications
  • No advantage in any particular diet – caloric restriction is the key factor
  • Women should be informed that metformin and active lifestyle intervention have similar efficacy.
• Statins lower testosterone, total and LDL cholesterol levels but do not improve menses, hirsutism or acne
• No evidence that combined hormonal contraceptives or progestins will increase the risk of diabetes or CVD in women with PCOS
• All women with PCOS should have
  • A lipid profile at diagnosis and thereafter based on CVD risks, regardless of age and BMI
  • Blood pressure measured annually and when planning pregnancy or seeking fertility treatment

Treatment for Women with PCOS Planning to Conceive

First-Line Interventions

• Letrozole
  • Letrozole (aromatase inhibitor) is considered a first-line treatment for ovulation induction in infertile anovulatory women with PCOS, with no other infertility factors
• Letrozole starting dose is 2.5 mg/day for 5 days starting day 3, 4 or 5 of cycle and increase to 5 mg/day for 5 days with a maximum dosage of 7.5 mg/day if ovulation does not occur at lower, initial dose

• Letrozole should be used rather than clomiphene citrate in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, clinical pregnancy and live birth rates
• Clomiphene Citrate
  • Improved performance compared to metformin alone or placebo
  • Over 50% of those who conceive do so on 50 mg/day dose and 20% on 100 mg/day dose
  • Most pregnancies occur within 6 months
• Second-Line Interventions
• If clomiphene citrate or letrozole fails
  • Gonadotropins
  • Laparoscopy with ovarian drilling

Third-Line Intervention 

• The International Guideline considers IVF to be a third line intervention for PCOS

PCOS in Pregnancy

• PCOS women have higher risk pregnancies
• Women with PCOS are not at increased risk of large for gestational age babies, macrosomia, and instrumental delivery
• Assisted reproductive technology in women with PCOS will not add additional risk of miscarriage, preterm birth, impaired fetal growth, and caesarean section, over that observed in women without PCOS
• Metformin in pregnant women with PCOS has not been shown to prevent Gestational diabetes | Late miscarriage between 12 to 22 weeks | Hypertension in pregnancy | Preeclampsia | Macrosomia

Diabetes Assessment

Screening for Diabetes

• Assess glycemic status at baseline in all women with PCOS at time of diagnosis, when planning pregnancy or seeking fertility treatment and repeat every 1 to 3 years depending on other risk factors
• To assess glycemic status, use one of the following tests
  • 75-g Oral glucose tolerance test (OGTT)
  • If an OGTT cannot be performed then Fasting plasma glucose or HbA1C can be done, noting significantly reduced accuracy
  • OGTT is the most accurate test regardless BMI
• In pregnancy
  • If not performed preconception, offer OGTT at first prenatal visit
  • Offer all pregnant women with PCOS an OGTT at 24 to 28 weeks gestation

KEY POINTS:

• Letrozole outperforms clomiphene citrate for ovulation induction
  • Higher live-birth rate
  • Higher ovulation rate
  • Higher clinical pregnancy rate
• Before starting medical/surgical ovulation induction therapies, counsel about lifestyle modification including
  • Stop smoking
  • Reduce weight and increase exercise especially in setting of overweight/obesity
  • Reduce alcohol consumption
• Both letrozole and clomiphene citrate are contraindicated in pregnancy
• Management goals include
  • Protecting the endometrium from the effects of unopposed estrogen
  • Reestablishing a regular menstrual cycle
  • Preventing the metabolic syndrome and cardiovascular sequelae of PCOS
  • Providing support for ovulatory dysfunction for those anticipating pregnancy

Learn More – Primary Sources:

Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 

Monash University PCOS Program

ACOG Practice Bulletin No 194: Polycystic ovary syndrome

Screening and Diagnosis of Obstructive Sleep Apnea  – PcMED Project

CMAJ Review: Diagnosis and management of polycystic ovarian syndrome