US Pharm. 2024;49(9):17-22.

ABSTRACT: Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting about 10% of reproductive-age women as well as adolescents. Symptoms and signs related to excessive androgen production are prevalent in adolescents and young adults, with added metabolic complications occurring in adult women, so timely diagnosis and appropriate therapy are important. PCOS symptoms and signs include irregular menses, anovulation, infertility, acne, hirsutism, insulin resistance (IR), and weight gain. Nonpharmacologic and pharmacologic therapies address the signs and symptoms and reduce metabolic complications. The 2023 PCOS guideline recommends therapies including healthy-lifestyle interventions, combined oral contraceptives, metformin, eflornithine, letrozole, and clomiphene. Goals include regular menstrual cycles, fertility, and improvements in hirsutism, acne, IR, and weight. Pharmacists can play a key role in educating patients about PCOS and its treatment.

Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately 10% of reproductive-age adult women as well as adolescents.1-3 Upon diagnosis, nonpharmacologic and pharmacologic therapies are employed to manage dermatologic, menstrual, and metabolic features and complications and to address reproductive concerns.1 Treatment goals include blocking excessive androgen production, reducing insulin resistance (IR), maintaining a desirable weight, achieving regular menstrual cycles, correcting any infertility difficulties, and (if desired) preventing pregnancy.2,4-6

Although there is no cure for PCOS, appropriate therapy can improve the patient’s symptoms and quality of life. A comprehensive international guideline for the assessment and management of PCOS was published in October 2023.1 This review highlights recommendations from this guideline and includes information useful for the pharmacist in counseling patients about recommended nonpharmacologic and pharmacologic therapies. Most pharmacologic therapies prescribed for patients with PCOS are not specifically FDA approved for PCOS. The pharmacist can play a key role in educating and supporting patients regarding management strategies for controlling symptoms, preventing complications, and optimizing health.

Pathophysiology

The pathophysiology of PCOS involves excessive gonadotropin (Gn) secretion, IR, and increased androgen production.1,4,6 Increased pulse frequency of Gn-releasing hormone results in elevated luteinizing hormone (LH), leading to increased androgen production, anovulation, immature follicles, and the lack of a mature follicle.4,6 Some women develop numerous small ovarian cysts (fluid-filled sacs), hence the term “polycystic ovaries.” IR in adipose tissue and skeletal muscle results in hyperinsulinemia from increased insulin secretion, which leads to increased androgen levels from insulin action in the hypothalamus, pituitary, ovaries, and liver.4,6

Symptoms and signs of PCOS include irregular menstrual cycles and anovulation, acne, hirsutism, IR, and hyperinsulemia. Signs of clinical hyperandrogenism are the first to manifest in most patients (acne, hirsutism, and female-pattern hair loss in adults; severe acne and hirsutism in adolescents).1 If a combined oral contraceptive (COC) is not being taken for pregnancy prevention, irregular menses is quite common, and young women with fewer than four menstrual cycles per year—even without other significant PCOS symptoms—should see a healthcare provider (HCP). Metabolic complications include weight gain and obesity, type 2 diabetes (T2D), and cardiovascular (CV) disorders.1,2 Anovulatory infertility is more prevalent in patients with PCOS than in the general population, as are complications during pregnancy.6 Endometrial hyperplasia from irregular menses and anovulation increases the risk of endometrial cancer.1

Diagnosis

For both adolescents and adults, a thorough physical examination and history are needed, along with any additional screening and laboratory evaluation judged necessary by the patient’s HCP. A PCOS diagnosis per the revised Rotterdam criteria and current guidelines is based on documentation of irregular cycles and clinical hyperandrogenism.1 For adults, a diagnosis requires two of the following: irregular cycles, clinical hyperandrogenism, and either polycystic ovaries on ultrasound (US) or elevated anti-Müllerian hormone levels.1 In the absence of clinical hyperandrogenism, a test for biochemical hyperandrogenism using total and free testosterone is performed.1 If an adult has irregular menstrual cycles and clinical hyperandrogenism, it is not necessary to perform US or check anti-Müllerian hormone levels.1

In adolescents, a diagnosis is positive if the patient has irregular menstrual cycles and clinical hyperandrogenism (neither US nor anti-Müllerian hormone level testing is recommended for adolescents).1 An adolescent who does not meet the diagnostic criteria but has PCOS symptoms is considered to be at risk and should be rescreened within 8 years of menses onset. In some patients, it can be difficult to determine whether irregular menses, acne, and hirsutism are caused by PCOS or are part of normal maturation.1,7 Because PCOS in adolescence or young adulthood will continue through the reproductive years and impact fertility as well as cause other hyperandrogenic symptoms, timely diagnosis and appropriate therapy are important. In both adults and adolescents, other causes of clinical hyperandrogenism and irregular menses (e.g., adrenal tumors, Cushing syndrome, hypothyroidism, Gn deficiency, prolactin disorders) must be excluded.1,3

Treatment Overview

PCOS treatment is tailored to the patient’s specific signs and symptoms, whether dermatologic, reproductive, or metabolic.1 Goals include achieving regular menstrual cycles, maintaining fertility, lessening hirsutism and acne, and reducing IR. Patients are screened for hyperglycemia and existing CV risk factors on diagnosis and periodically thereafter, depending on the results of the baseline screening, to avoid T2D and CV complications.1 Patients who wish to become pregnant in the future should work with their obstetrician-gynecologist (OB-GYN) to develop a plan for improved fertility and a safer pregnancy.1 Because of the risk for depression and anxiety due to the presence of observable signs of PCOS (acne, hirsutism, and increased weight), screening for these conditions is suggested.1 Patients report dissatisfaction over delayed diagnosis, treatment, and counseling.1,3 The pharmacist can assist by educating patients about treatment modalities and reassuring them that although most therapies may take several months for beneficial effects, they are effective in most patients.

Nonpharmacologic Therapy

Lifestyle interventions are first-line therapy for PCOS and are imperative at all ages.1 Healthy lifestyle interventions include healthy eating and exercise to maintain weight, prevent weight gain, decrease PCOS symptoms, and increase well-being.5 Limiting intake of alcohol, sweetened drinks, and processed foods is recommended.1 Excess weight, especially in the abdominal area, increases hyperandrogenism and IR, thereby worsening PCOS. For patients who are not overweight, adopting a healthy lifestyle and preventing weight gain should be emphasized.1 For those who are overweight, it is important to avoid weight stigma and to encourage patience regarding weight loss. There is robust evidence that a modest weight reduction of 5% in overweight PCOS patients improves menstrual regularity, decreases metabolic complications, and increases a sense of well-being, and these points can be communicated to the patient in a caring manner.1,8

No specific eating plan has been proven more successful than others for improving PCOS-related metabolic, hormonal, or reproductive problems. Instead, the patient’s preference of diet with a varied micronutrient composition is recommended.1 The Mediterranean diet has shown benefit for addressing metabolic complications of PCOS.2 For overweight patients struggling with weight loss despite adopting a healthier diet with modest caloric restriction, the pharmacist can provide a referral to a dietitian for advice.

As with diet, no particular exercise program has been shown to be more effective than others for improving PCOS-related metabolic, hormonal, or reproductive problems.1 Patients should be encouraged to adopt an exercise program that they will adhere to. For adolescents, a goal is at least 60 minutes of moderate-to-vigorous physical activity each day.1 For adults aged 18 to 64 years, a goal is 250 minutes of moderate-intensity or 150 minutes of vigorous-intensity exercise per week. Both adolescents and adults should include muscle- and bone-strengthening exercises, with a goal of three times per week for adolescents and two times per week for adults.1

Healthy lifestyle interventions are also important for patients considering pregnancy. If the patient is unable to conceive, lifestyle changes for anovulation should be attempted prior to initiating pharmacologic therapy.6 A woman who wants to conceive should receive preconception-care screening and monitoring of weight, blood pressure (BP), diet, and nutrition, along with additional consideration of PCOS-related conception, pregnancy, and postpregnancy concerns.1 Pharmacists can counsel patients on the importance of a healthy diet and exercise program when trying to conceive and encourage them to work with their OB-GYN to develop a pregnancy plan. If a patient is taking medication for PCOS (a COC, for example), the timing of discontinuation should be discussed with the OB-GYN. Approximately 30% of patients with PCOS have few to no difficulties with conception or pregnancy.1,9 Others may achieve success via nonpharmacologic and pharmacologic therapy combined with additional screening and monitoring for conception and pregnancy concerns and complications.1,9 The first- and second-line pharmacologic agents utilized for anovulation infertility—letrozole and clomiphene citrate—are discussed later in this article.

Pharmacologic Therapy

Pharmacologic therapy for PCOS addresses nonfertility and fertility issues, and the therapy plan will incorporate the patient’s goals and consider patient-specific signs and symptoms. TABLE 1 summarizes aspects of selected PCOS pharmacologic therapies: COC pills (COCP), metformin, eflornithine, letrozole, and clomiphene citrate.1,4,10-18 Included in the table are each therapy’s use in PCOS, its adverse events (AEs), and its contraindications. Recommended use and important considerations for these pharmacologic therapies are discussed in the following sections.


COCP: Although not FDA approved specifically for PCOS, COCP containing an estrogen and progestin are recommended first-line, in addition to lifestyle interventions, for menstrual-cycle regulation and hyperandrogenism in adults with PCOS.1,11-13 COCP are also used in adolescents diagnosed with or considered at high risk for PCOS.1 COCP suppress LH and androgen secretion by the ovaries. The proven efficacy of COCP in regulating menses and decreasing hyperandrogenism in PCOS makes them the preferred hormonal contraceptive option.1,2 With more regular menses, endometrial hyperplasia and the risk of endometrial cancer are decreased. COCP also improve acne and hirsutism. Menstrual irregularities and acne typically improve before hirsutism does; hirsutism may need 6 months of COCP plus cosmetic therapies (e.g., laser therapy).1 Spironolactone, an antiandrogen, may be added off-label to COCP to lessen hirsutism, but it should be avoided in pregnancy due to the risk of male fetal feminization and risk of intrauterine growth restriction.4 COCP may have modest variable benefit in weight management, waist-to-hip ratio, and lipid profile.1

No single type of COCP is recommended as most effective for PCOS, but low-dose agents are preferred.1,8 COCP with the lowest effective estrogen component (e.g., ethinyl estradiol or equivalent at 20-30 mcg) are recommended, as higher-dose estrogen-component COCP are not more effective for PCOS and they have more AEs.1,3 For progestin, COCP containing the antiestrogen drospirenone or the low-androgen progestins desogestrel or norgestimate are preferred for controlling acne and hirsutism.4 However, hyperkalemia is a possible AE of drospirenone. A progestin-only product will treat menstrual irregularities and provide endometrial protection, but it does not supply the added benefits of COCP for PCOS.1

Pharmacists can discuss contraindications and possible common AEs of COCP with patients.1,4,10-18 Patients should be advised to report common AEs, if bothersome, and to monitor for and immediately report less common but serious AEs such as high BP, vision changes, migraine, blood clots, or jaundice.4,11-13 It is important to reassure patients that it may take several months for COCP to reduce target symptoms of PCOS.

Metformin: For PCOS, the use of metformin is recommended in addition to lifestyle interventions, as it has proven beneficial effects on blood glucose, weight, waist-to-hip ratio, testosterone, and triglycerides.1 Metformin, a biguanide, is used off-label for PCOS because it improves glucose tolerance, weight, irregular menses, and infertility.2,4 It is not recommended for treating hirsutism or acne. Metformin is less effective than COCP for menstrual irregularities, but it is an alternative for menstrual irregularities in PCOS patients who have contraindications to, cannot tolerate, or have failed COCP therapy.1 Metformin is recommended for PCOS in adults with a BMI >25 kg/m2, and it may be considered for adults with a BMI <25 kg/m2. It may also be used in adolescents with or at risk for PCOS who have irregular menses. If a patient has PCOS metabolic complications despite lifestyle interventions and COCP, metformin may be added; it is especially beneficial in those with higher BMI, impaired glucose tolerance, or high risk of T2D.1 Pharmacists should advise patients that they may experience gastrointestinal (GI) distress, most commonly diarrhea, upon initiating metformin.1,4,10-18 Patients should be reassured, however, that GI distress typically subsides with continued use and that taking metformin with a meal can lessen GI distress.15 Titrating the dose slowly to the effective dose for target PCOS symptoms and/or using the extended-released product will decrease GI AEs.8 For PCOS, the usual initial dosage of the immediate-release product is 500 mg two to three times daily, with a dose titration.4,15

Patients beginning metformin who are not taking COCP and do not wish to conceive will need to use another contraception method.8 Vitamin B12 deficiency can occur with long-term metformin use; checking B12 levels and taking an oral B12 supplement are recommended.1 Metformin is contraindicated in patients with an estimated glomerular filtration rate <30 mL/minute/1.73 m2, as there is an increased risk of the rare but serious AE of lactic acidosis with impaired renal function.15 Women taking metformin for PCOS who wish to conceive should discuss their metformin use with their OB-GYN. Because metformin crosses the placenta and the long-term health effects on fetal exposure are unclear, it is recommended that metformin be discontinued during pregnancy in PCOS patients.1,15

Eflornithine: Eflornithine is a 13.9% topical antiprotozoal cream approved for facial-hair reduction.16 This agent slows the growth of facial hair; however, it does not remove hair.10 Although COCP are considered first-line for PCOS hirsutism, eflornithine could be considered for facial hirsutism in patients not wanting to use COCP. Eflornithine, which is applied twice daily, improves facial hirsutism after 8 weeks, and approximately 50% of patients report improvement after 6 months.10 Mechanical laser and light therapies are more effective than eflornithine; eflornithine is useful as an adjunct to promote faster results.1,4 Pharmacists should discuss AEs and pregnancy concerns, as appropriate, with patients considering the use of eflornithine.1,4,10-18

Ovulation-Induction Medications: Many women with PCOS have fertility and pregnancy problems, including longer time to conceive and conception difficulties. Most PCOS-related infertility is treatable with lifestyle modifications and pharmacologic therapy. Some patients may experience an increased risk of pregnancy complications, which should be discussed in advance with the patient’s OB-GYN.1 The OB-GYN will work closely with the PCOS patient to develop and carry out a conception and pregnancy plan.

Letrozole and clomiphene citrate are the first- and second-line pharmacologic agents, respectively, recommended by the 2023 guideline for ovulation induction in anovulatory infertile women with PCOS who have no other fertility problems.1 These agents increase ovulation, pregnancy, and live birth rates.1 Letrozole, an aromatase inhibitor, helps stimulate production of a dominant follicle without adversely affecting endometrial thickness or cervical mucus, thereby improving conception and pregnancy outcomes.4 Letrozole is not FDA approved for ovulation induction in PCOS, but it is used off-label. For PCOS, the usual initial dosage is 2.5 mg by mouth daily for 5 days, beginning on cycle day 3, 4, or 5 following menses or a bleed induced by progestin.17 The dose may be increased to 5 mg in the next cycle, with a maximum dose of 7.5 mg.17 Letrozole is contraindicated in pregnancy, so it should not be used for ovulation induction if there is a possibility of a preexisting pregnancy (a negative pregnancy test is required).1,17 Pharmacists should counsel patients regarding the common letrozole AEs.1,4,10-18 Patients also should be advised to monitor for and immediately report less common but serious AEs, including high BP, abnormal vaginal bleeding, bone pain, and chest pain.17 Letrozole is associated with higher live birth rates and a lower risk of multiple fetuses with successful pregnancy than clomiphene, the recommended second-line agent for ovulation induction.1

Clomiphene citrate, a selective estrogen receptor modulator, is FDA approved for ovulatory dysfunction.18 A negative pregnancy test is required before therapy.18 For PCOS, clomiphene citrate at a dosage of 50 mg by mouth once daily for 5 days is begun on day 5 after menses. If ovulation does not occur, the dose may be increased on a subsequent course in 30 days.4,18 Ovulation typically occurs 5 to 10 days after the clomiphene course, and there is an increased risk of multiple births with successful pregnancy.4,18 The pharmacist should counsel patients on AEs as well as pregnancy and other contraindications to clomiphine use.1,4,10-18 The 2023 guideline recommends adding metformin to clomiphene therapy, as this combination is more effective than clomiphene used alone for ovulation; metformin should be discontinued during pregnancy.1

Other treatments for PCOS infertility, including laparoscopic surgery, in vitro fertilization, and parenteral Gn therapy, are beyond the scope of this article, but the interested reader can find more information in the 2023 PCOS guideline.1

The Pharmacist’s Role

Pharmacists can play a essential role in educating patients about PCOS and its therapies, and they should refer patients to an appropriate HCP to address PCOS-related signs and symptoms as well as potential complications. When counseling patients, pharmacists should emphasize that lifestyle interventions are first-line treatment for PCOS and should be continued after pharmacologic therapies are initiated. Additionally, patients should be reassured that although they may not initially see improvements in PCOS after beginning lifestyle inverventions and pharmocologic therapies, most patients will achieve benefits over time.

REFERENCES

1. Teede HJ, Tay CT, Laven JJE, et al; International PCOS Network. Recommendations from the 2023 International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023;108(10):2447-2469.
2. Francone NO, Ramirez T, Boots CE. Contemporary management of the patient with polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2023;50(4):695-705.
3. Pereira-Eshraghi CF, Vuguin PP. Polycystic ovary syndrome. Pediatr Rev. 2024;45(6):363-365.
4. Bartelme KM. Polycystic ovary syndrome. In: O’Connell MB, Smith JA, Borgelt LM, eds. Women’s Health Across the Lifespan: A Pharmacotherapeutic Approach. 3rd ed. New York, NY: McGraw Hill Education; 2024.
5. Huddleston HG, Dokras AD. Diagnosis and treatment of polycystic ovary syndrome. JAMA. 2022;327(3):274-275.
6. Shrivastava S, Conigliaro RL. Polycystic ovarian syndrome. Med Clin North Am. 2023;107(2):227-234.
7. Meczekalski B, Niwczyk O, Kostrzak A, et al. PCOS in adolescents—ongoing riddles in diagnosis and treatment. J Clin Med. 2023;12(3):1221.
8. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Gynecology. Polycystic ovary syndrome: ACOG Practice Bulletin, number 194. Obstet Gynecol. 2018;131(6):e157-e171.
9. Bahri Khomami M, Teede HJ, Joham AE, et al. Clinical management of pregnancy in women with polycystic ovary syndrome: an expert opinion. Clin Endocrinol (Oxf). 2022;97(2):227-236.
10. Managing polycystic ovary syndrome. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber’s Letter. February 2023 [390225].
11. Ethinyl estradiol and norgestimate. Lexi-Drugs. UpToDate Lexidrug. UpToDate Inc. https://online.lexi.com. Accessed June 17, 2024.
12. Ethinyl estradiol and desogestrel. Lexi-Drugs. UpToDate Lexidrug. UpToDate Inc. https://online.lexi.com. Accessed June 17, 2024.
13. Ethinyl estradiol and drospirenone. Lexi-Drugs. UpToDate Lexidrug. UpToDate Inc. https://online.lexi.com. Accessed June 17, 2024.
14. Contraceptive comparison table. Lexi-Drugs. UpToDate Lexidrug. UpToDate Inc. https://online.lexi.com. Accessed June 17, 2024.
15. Metformin. Lexi-Drugs. UpToDate Lexidrug. UpToDate Inc. https://online.lexi.com. Accessed June 17, 2024.
16. Eflornithine. Lexi-Drugs. UpToDate Lexidrug. UpToDate Inc. https://online.lexi.com. Accessed June 17, 2024.
17. Letrozole. Lexi-Drugs. UpToDate Lexidrug. UpToDate Inc. https://online.lexi.com. Accessed June 17, 2024.
18. Clomiphene citrate. Lexi-Drugs. UpToDate Lexidrug. UpToDate Inc. https://online.lexi.com. Accessed June 17, 2024.

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