Assessing medication use patterns among patients with polycystic ovary syndrome at a tertiary care teaching hospital in South Korea: A retrospective study

The study observed PCOS treatment patterns in Korean women aged 13 and above at a tertiary hospital from July 2014 to September 2022. MPA alone and EE with drospirenone were the most prescribed medications. Over the study, 45 patients changed prescriptions, 50 were lost to follow-up, and 5 adults discontinued medications. Most shifts involved transitioning from MPA to OCs. OCs, primarily EE with drospirenone, were commonly prescribed for PCOS management, targeting menstrual irregularities and hirsutism. MPA mainly regulated irregular periods but had a limited impact on acne and hirsutism. Customized treatment for PCOS requires careful consideration since complex symptom management requires tailored approaches.

Polycystic ovary syndrome (PCOS) was first documented in medical literature by Stein and Leventhal in 1935, and it is a complex endocrine disorder characterized by excessive androgen secretion due to hormonal imbalances in the hypothalamus, pituitary gland, and ovaries. [ 1 , 2 ] It affects approximately 4% to 10% of women of childbearing age, making it one of the most prevalent endocrine disorders, and its incidence continues to rise. [ 3 ] According to data from the Health Insurance Review and Assessment Service in Korea, the number of patients visiting hospitals due to PCOS surged from 40,148 in 2017 to 62,653 in 2021, representing a 56% increase over the past 5 years. [ 4 ] The precise etiology of PCOS remains elusive, though it is closely associated with hormonal imbalances and lifestyle factors such as dietary habits. [ 5 ] Patients with PCOS exhibit elevated levels of blood androgens and luteinizing hormone (LH), as well as distinct ultrasound findings, including enlarged ovaries with more than 12 follicles measuring 2 to 9 mm in diameter. [ 6 , 7 ] These hallmark characteristics of PCOS often lead to ovulatory dysfunction, resulting in irregular menstrual cycles, oligomenorrhea, amenorrhea, infertility, hirsutism, acne, obesity, and insulin resistance. Prolonged ovulatory disturbances can escalate to endometrial hyperplasia (EH) or endometrial cancer. Additionally, 50% to 70% of patients with PCOS experience insulin resistance, which poses a heightened risk of complications such as hypertension, dyslipidemia, and diabetes. [ 8 , 9 ] Effective management of PCOS necessitates the control of androgen excess, safeguarding of the endometrium, and prevention of metabolic complications. Treatment approaches involve the use of oral contraceptives (OCs) or progesterone to regulate menstrual cycles and inhibit endometrial proliferation, as well as antilike spironolactone to manage excess androgens. Furthermore, insulin sensitizers such as metformin are employed to alleviate hyperinsulinemia and insulin resistance, factors which contribute to increased androgen secretion. [ 10 , 11 ] The efficacy of metformin varies among individuals and depends on factors like obesity and blood insulin levels. [ 12 ] PCOS represents not just a gynecological disorder associated with infertility but also a form of metabolic syndrome with a heightened risk of diabetes and cardiovascular disease, necessitating long-term treatment and management rather than a definitive cure. [ 13 ] While studies have explored the elevated risk of type 2 diabetes, hypertension, dyslipidemia, and atherosclerosis associated with PCOS, [ 14 , 15 ] research regarding medication use patterns for the treatment of PCOS remains limited. Consequently, this study was performed to retrospectively assess medication use patterns among Korean women with PCOS visiting a tertiary teaching hospital from July 2014 to September 2022.

Conceptualization: Ji Hye Yu, Young-Mo Yang. Data curation: Ji Hye Yu, Young-Mo Yang. Formal analysis: Ji Hye Yu. Investigation: Ji Hye Yu. Methodology: Ji Hye Yu, Young-Mo Yang. Writing – original draft: Ji Hye Yu. Resources: Mi Kyung Moon, Hyo Cho Ahn. Validation: Mi Kyung Moon, Hyo Cho Ahn. Writing – review & editing: Mi Kyung Moon, Hyo Cho Ahn, Young-Mo Yang. Funding acquisition: Young-Mo Yang. Project administration: Young-Mo Yang. Supervision: Young-Mo Yang.

The Institutional Review Board (IRB) of Chonbuk National University Hospital granted ethical approval for this study (CUH 2022-11-005-001). The requirement for obtaining informed consent from the patients was waived by the IRB since their data were deidentified and encoded anonymously prior to statistical analysis. This study was conducted on patients visiting Chonbuk National University Hospital between July 2014 and September 2022. The following inclusion criteria were employed: diagnosis of PCOS; age ≥ 13 years; and having received medications for PCOS at least once. The average age of menarche in Korea is 12.6 years [ 16 ] ; therefore, patients under 13 years were excluded from the study. A trained hospital pharmacist conducted a retrospective chart review of the electronic medical records of selected patients with PCOS and collected the following information: demographic characteristics (age, weight, height, body mass index, drinking, smoking, and marital status), blood pressure, age at PCOS diagnosis, previous treatment for PCOS, comorbidities, ultrasound findings of the ovaries, symptoms, and prescribed medications for PCOS. The selected patients were categorized according to age and whether they were prescribed medication. Patients 21 years old and below were designated as the adolescent group and patients 22 years old and over were designated as the adult group for statistical comparison. [ 17 ] The medications examined were all medications that are prescribed for PCOS among those recorded in the hospital pharmacy. If the medication was changed during follow-up, the reason for the change and the alternative medication were recorded. All the analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC). Mean and SD were used for continuous variables, whereas frequencies (n) and percentages (%) were used for categorical variables. An independent t test was performed to compare the differences between the means of the continuous variables, and the chi-square test or Fisher exact test was conducted to compare the differences between the proportions of the categorical variables. P values < .05 were considered statistically significant.

Among 328 patients diagnosed with PCOS during the study period, 212 were included in the final analyses (Fig. 1 ). The demographic information of the subjects is detailed in Table 1 . The average age of all patients was 22.9 ± 5.7 years, with adolescents averaging 18.3 ± 2.1 years and adults averaging 27.5 ± 4.3 years. The average BMI was 26.5 ± 6.6 kg/m 2 ; 39 (47.6%) adolescents and 29 (40.3%) adults were considered overweight or obese, defined as having a BMI ≥ 25 kg/m 2 . The average age at which PCOS was diagnosed was 21.7 ± 5.2 years. The most common comorbidity was ovarian cysts, found in 20 patients (9.4%), followed by endometriosis in 19 (9%). A total of 98 patients (46.2%) exhibited polycystic ovaries on ultrasound, and oligomenorrhea was the most frequent symptom, found in 91 patients (42.9%). Characteristics of the study patients. BMI = body mass index, BP = blood pressure, DM = diabetes mellitus, HTN = hypertension, PCOS = polycystic ovarian syndrome, SD = standard deviation. Flow chart of selecting the study patients. The medications used to treat PCOS during the study period are detailed in Table 2 . Medroxyprogesterone acetate (MPA) had the highest prescription frequency with 114 patients (53.8%). This was followed by OCs which were prescribed to 66 (31.1%), while 17 (8%) were prescribed both MPA and OCs. Among the OCs, ethinyl estradiol (EE) 0.02 mg + drospirenone was the most common regimen, prescribed to 39 patients (18.4%). Medications used in the study patients. CC = clomiphene citrate, EE = ethinyl estradiol, EH = estradiol hemihydrate, EV = estradiol valerate, MET = metformin, MPA = medroxyprogesterone acetate, OCs = oral contraceptives. Changes in medication prescriptions and discontinuations during the study period are documented in Table 3 . There were 45 patients (21.2%) whose prescriptions changed during the study period, with 10 changing due to medication side effects and 8 due to a lack of effectiveness. A total of 5 patients (2.4%) discontinued the medication. Three of them chose to stop taking the medication due to side effects such as headaches, breast tenderness, depression, and weight gain. One patient discontinued the medication because of persistent amenorrhea despite use, and another discontinued the medication due to pregnancy. Fifty patients (23.6%) who received a one-time prescription and did not revisit the hospital during the study period could not be followed up. Change patterns of drug treatments are also presented in Table 4 . Cases of medication change and discontinuation. Change patterns of drug treatments. CC = clomiphene citrate, EE = ethinyl estradiol, EH = estradiol hemihydrate, EV = estradiol valerate, MET = metformin, MPA = medroxyprogesterone acetate, OCs = oral contraceptives. Adverse drug events are described in Table 5 . A total of 15 individuals (7.1%) experienced adverse drug events, comprising 5 adolescents (4.8%) and 10 adults (9.3%). These included edema, lower abdominal discomfort, headache, facial flushing, abnormal bleeding, depression, nausea, weight gain, and breast tenderness. Nausea was most common, affecting 8 patients (3.8%), followed by breast tenderness which affected 6 (2.8%). List of adverse drug events. ADR = adverse drug reaction.

In this study, prescription patterns for the treatment of PCOS were assessed among Korean women aged ≥ 13 years who visited a tertiary care teaching hospital between July 2014 and September 2022. The major finding from this study was that the most frequently prescribed medication for PCOS was MPA alone, followed by a combination of EE and drospirenone. During the study period, 45 patients changed their prescriptions and 50 patients were lost to follow-up. Among adults, 5 patients discontinued their medications. Among patients changing prescriptions, the most common pattern was a switch from MPA to OCs. The combination of estrogen and progestin (i.e., OCs) were prescribed to approximately 40% of patients during the study period. The majority of OC formulations consist of EE and antiandrogens like cyproterone acetate, drospirenone, norgestimate, levonorgestrel, and desogestrel. [ 18 ] In this study, the OC formulation with EE and drospirenone was most frequently prescribed for the management of PCOS. OCs are the first-line treatment option for menstrual irregularities, hirsutism, and acne in women with PCOS. [ 19 ] The effects of OCs on the clinical features of PCOS may be explained by several potential mechanisms. OCs promote negative feedback on LH secretion, which lowers ovarian androgen production, thereby mitigating hyperandrogenism. OCs also elevate the levels of sex hormone-binding globulin produced by the liver while decreasing the concentration of free androgens in the bloodstream. Additionally, OCs prevent the peripheral conversion of testosterone to dihydrotestosterone (DHT) and the binding of DHT with androgen receptors, thereby reducing the release of adrenal androgens. [ 20 ] Interestingly, it was observed that oral MPA (53.8%) was the most frequently prescribed medication to manage PCOS symptoms. MPA is a synthetic steroid hormone progesterone which is usually prescribed to treat absent or irregular menstrual periods and abnormal uterine bleeding in patients with PCOS who are unable to conceive and are not at risk for becoming pregnant. [ 21 , 22 ] MPA has also been reported to enhance insulin sensitivity and lipid profile in patients with PCOS. [ 22 – 25 ] However, MPA alone does not improve acne and hirsutism, which are the major cutaneous manifestations of PCOS. [ 26 ] MPA works by inhibiting excessive endometrial growth and reducing the risk of EH. [ 21 ] Ushijima and colleagues reported that 82% and 18% of EH patients receiving MPA with a 25-month to 73-month follow-up achieved complete and partial responses, respectively. [ 27 ] In another study, a 54.8% remission in EH patients occurred after taking MPA. [ 28 ] MPA is usually prescribed at 10 mg/day orally and continuously for 6 weeks or cyclically for 2 weeks each month for 3 months. [ 21 ] The prescription patterns of medications for PCOS were also summarized according to the clinical features of PCOS (see Tables, Supplementary Digital Content 1, Supplemental Digital Content, http://links.lww.com/MD/N295 , which illustrates medications used in the study patients according to their clinical features; Supplementary Digital Content 2, Supplemental Digital Content, http://links.lww.com/MD/N296 , which illustrates medications used in the adolescent patients according to their clinical features; Supplementary Digital Content 3, Supplemental Digital Content, http://links.lww.com/MD/N297 , which illustrates medications used in the adult patients according to their clinical features). In the present study, acne or hirsutism was identified in 46 patients, representing 21.7% of the study population. Among these cases, 20 patients were prescribed OCs, 1 received metformin alone, and 25 were treated solely with MPA. As mentioned, OCs are used as the first-line treatment for acne and hirsutism in women with PCOS. [ 19 ] However, metformin can also improve the cutaneous manifestations of PCOS such as acne and hirsutism, although its effectiveness may vary from one patient to another. Acne and hirsutism are related to hormonal imbalances associated with PCOS. [ 29 ] Elevated androgen levels can worsen acne and hirsutism, and metformin can help alleviate these symptoms through reducing androgen levels. In addition, many PCOS patients exhibit insulin resistance, which can affect their metabolic processes and hormone levels. Metformin improves insulin sensitivity, thereby reducing insulin resistance, which can partially enhance cutaneous symptoms. [ 29 ] Since acne and hirsutism are cutaneous symptoms, these may induce varying levels of distress in patients. As a result, over 50% of the patients with these symptoms in this study may opt to concentrate on addressing other non-cutaneous symptoms by solely receiving MPA therapy. The changes in medication prescriptions and discontinuations among PCOS patients underscore the intricate landscape of managing this complex condition. This study found that 21.2% of patients experienced changes in their PCOS medication regimen. Pharmacists play a vital role in supporting medication adherence and optimizing treatment plans for patients with PCOS. By collaborating with physicians, pharmacists can contribute to improved patient care by identifying potential medication issues, communicating concerns to physicians, and providing recommendations for treatment optimization. Community pharmacists, being accessible and often in continuous contact with patients, can offer personalized counseling, addressing concerns and fostering medication adherence. The identification of patients (2.4%) discontinuing medication reveals a critical juncture where both hospital and community pharmacists can intervene. Hospital pharmacists can contribute to patient education regarding potential side effects, enabling proactive management to prevent discontinuations. Meanwhile, community pharmacists can serve as ongoing sources of support, implementing follow-up protocols for patients receiving one-time prescriptions to bridge the gap highlighted by the 23.6% of patients who did not revisit the hospital during the study period. This collaboration between hospital and community pharmacists is essential for establishing a seamless continuum of care, optimizing treatment outcomes, and addressing the unique challenges faced by PCOS patients in adhering to prescribed regimens. The pilot study, which was conducted for the management of drug-related problems among high-risk discharge patients in South Korea, reported that collaboration between hospital and community pharmacists could have positive effects on medication adherence and the safe use of drugs. [ 30 ] PCOS encompasses a multifaceted array of symptoms. Aside from hormone-based therapies, several non-medications play pivotal roles in managing specific aspects of this condition. Metformin, a cornerstone for type 2 diabetes, is commonly employed to address insulin resistance in PCOS, aiding in weight management and potentially restoring regular ovulation. [ 29 ] Its impact on insulin levels often leads to improved menstrual regularity and increased chances of conception for women struggling with infertility due to PCOS. [ 29 ] Inositol, available as myo-inositol or D-chiro-inositol supplements, also demonstrates promise in enhancing insulin sensitivity. [ 3 ] Antiandrogen medications like spironolactone serve to counteract the effects of heightened androgens in PCOS, helping reduce symptoms like acne, hirsutism, and hair loss. [ 3 , 22 , 31 ] Statins, usually prescribed to manage cholesterol, may play a role in mitigating the increased cardiovascular risk associated with PCOS due to altered lipid profiles. [ 3 , 22 ] Emphasizing lifestyle modifications encompassing dietary adjustments, exercise regimens, and weight control strategies remains fundamental in managing PCOS symptoms holistically. [ 32 , 33 ] However, the efficacy of these interventions can vary widely among individuals, highlighting the importance of tailored treatment plans that often encompass a blend of medications, lifestyle adaptations, and ongoing medical oversight to optimize the management of PCOS symptoms while considering the unique needs and responses of each individual. Spanning 8 years from July 2014 to September 2022, this study delved into the experiences of PCOS patients at a tertiary hospital in Korea with over 1100 beds. Tertiary care settings often witness inconsistent patient follow-up since most patients with PCOS, after receiving their diagnosis, opt to receive long-term care at primary care facilities. This setup posed challenges in yielding statistically significant data when scrutinizing PCOS drug treatments and their associated side effects over the study duration. Despite the study’s segmentation and analysis of both adolescent and adult groups, the intricate nature of PCOS calls for sustained treatment and monitoring across various life phases. Future extensive research endeavors should aspire to extensively explore tailored PCOS medication strategies attuned to distinct life stages – spanning adolescence, childbearing years, menopausal transitions, and postmenopause – and meticulously examine treatment efficacy and the prevalence of correlated complications such as metabolic irregularities and reproductive health concerns. These longitudinal explorations should aim to bridge gaps in understanding optimal treatment protocols for PCOS, catering to the diverse needs of individuals at different life junctures, and acknowledging the complexities of this condition.