PCOS: Targeting Treatments to Improve Reproductive Outcomes and Reduce CVD

Polycystic ovary syndrome (PCOS) is poorly understood and is 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 and cardiovascular events.  Unopposed estrogen may result in endometrial cancer. Once identified, women need to be counseled and treated appropriately to reduce their risk of these health problems.

CLINICAL ACTIONS:

Treatment for Menstrual Disorders

Women with PCOS who are 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
• Progestin-only contraceptives or progestin containing IUDs protect the endometrium but lead to abnormal bleeding patterns in over 50% of patients
• Insulin sensitizing agents, including biguanides (metformin) and thiazolidinediones (pioglitazone, rosiglitazone)
  • The use of insulin sensitizers are associated with decrease in androgen levels, improved ovulation, improved glucose tolerance
  • Important to discuss contraception
  • The insulin sensitizing agents are not currently approved by the FDA for the treatment of PCOS
    • Metformin, according to ACOG has the “safest risk-benefit ratio”
    • The International Guideline recommends metformin for those women with metabolic features of glucose intolerance/ insulin resistance

Treatment for Hirsutism

Women with PCOS can be treated with the following:

• Spironolactone, a diuretic, aldosterone antagonist, androgen receptor antagonist: 25-100 mg twice daily
  • May take up to 6 months to be effective
• Flutamide, an androgen-receptor antagonist 125-250 mg/day: Teratogenic
• Finasteride, a 5-alpha-reductase inhibitor, 1-5 mg/day: Teratogenic
• Topical eflornithine, an inhibitor of ornithine decarboxylase, twice daily application for facial hair
• Mechanical hair removal (electrolysis, laser vaporization, shaving, plucking, waxing, depilatory creams)

Treatment to Reduce Cardiovascular and Diabetes Risks

Women with PCOS who are 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
• Insulin sensitizing agents such as metformin can delay development of diabetes in those at risk
  • Data currently insufficient to recommend insulin-sensitizing agents prophylactically for women at higher risk of diabetes due to PCOS
• 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

Treatment for Women with PCOS Planning to Conceive

First-Line Interventions

• Letrozole
  • Letrozole (aromatase inhibitor) is considered a first-line treatment due to data demonstrating increased ovulation rates, clinical pregnancy rates and live-birth rate vs clomiphene citrate
  • Counsel patients that letrozole is not approved by the FDA for ovulation induction
  • 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
• Clomiphene Citrate
  • ‘Traditional’ first-line treatment with 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
• Both clomiphene citrate and letrozole are associated with increase in multiple births, preterm birth, and hypertensive disorders

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

Diabetes Assessment

Screening for Diabetes

• Assess glycemic status at baseline in all women at time of PCOS diagnosis and repeat every 1 to 3 years depending on other risk factors
• To assess glycemic status, use one of the following tests
  •  Oral glucose tolerance test (OGTT)
  • Fasting plasma glucose
  • HbA1c
• OGTT is recommended in women with PCOS and risk factors
  • BMI > 25 kg/m2
  • Asians > 23 kg/m2
  • History of impaired fasting glucose
  • Impaired glucose tolerance or gestational diabetes
  • Family history of diabetes mellitus type 2
  • Hypertension
  • High-risk ethnicity

Women considering fertility treatment or preconception planning 

• Prior to fertility treatment and/or preconception planning
  • Offer all women a 75-g OGTT
• In pregnancy
  • If not performed preconception, offer OGTT<20 weeks
  • Offer all pregnant women with PCOS an OGTT at 24-28 weeks gestation

SYNOPSIS:

Once diagnosed, treatment of PCOS should be tailored to patient’s risk factors and desires.  Lifestyle modifications including weight reduction and regular exercise have been shown to decrease the metabolic and hormonal effects of PCOS. Treatment regimens are based on protecting the endometrium from the effects of unopposed estrogen, reestablishing a regular menstrual cycle, preventing the metabolic syndrome and cardiovascular sequelae of PCOS, and providing support for ovulatory dysfunction in those anticipating pregnancy.

KEY POINTS:

• ACOG Practice Bulletin updated based on recent data that letrozole outperforms clomiphene citrate for ovulation induction
  • Higher live-birth rate: 27.5% vs 10.1% (P=0.007) with odds ratio of 1.64 (95% CI, 1.32-2.04)
  • Higher ovulation rate: 61.7% vs 48.3% (P<0.001)
  • Higher clinical pregnancy rate: Odds ratio of 1.40 (95% CI, 1.18-1.65)
• 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

Learn More – Primary Sources:

ACOG Practice Bulletin No. 194: Polycystic ovary syndrome

Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome

EJE: MANAGEMENT OF ENDOCRINE DISEASE: Morbidity in polycystic ovary syndrome

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME–PART 1

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME – PART 2