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Executive summary: indonesian guidelines on polycystic ovary syndrome management

Article information

Obstet Gynecol Sci. 2025;68(3):221-236
Publication date (electronic) : 2025 March 26
doi : https://doi.org/10.5468/ogs.24288
Mila Maidarti, MD, OG, PhD1,2,3, Achmad Kemal Harzif, MD, OG, PhD,1,2,3orcid_icon, Amalia Shadrina, MD, OG2,3, Nafi'atul Ummah, MD3, Wiryawan Permadi, MD, OG, PhD1,4, Polycystic Ovary Syndrome (PCOS) Guideline Collaboration Group5
1Indonesian Reproductive Endocrinology and Fertility Association, Indonesian Society of Obstetricians and Gynecologists Association, Jakarta, Indonesia
2Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine Universitas Indonesia, Jawa Barat, Indonesia
3Human Reproduction, Infertility, and Family Planning Cluster, Indonesia Reproductive Medicine Research and Training Center, Faculty of Medicine Universitas Indonesia, Jawa Barat, Indonesia
4Reproductive Fertility Endocrinology Division, Department of Obstetrics and Gynecology, Dr. Hasan Sadikin Hospital, Faculty of Medicine Universitas Padjajaran, Jawa Barat, Indonesia
5Members of the Polycystic Ovary Syndrome (PCOS) Guideline Collaboration Group, Indonesian Association of Reproductive Endocrinology and Fertility, Jakarta, Indonesia
Correspondence author: Achmad Kemal Harzif, MD, OG, PhD Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta 10430, Indonesia E-mail: kemal.achmad@gmail.com
Received 2024 September 10; Revised 2024 December 26; Accepted 2025 March 9.

Abstract

Objective

Polycystic ovary syndrome (PCOS) is a gynecological, endocrine condition characterized by ovulatory disorders, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology. PCOS has significant metabolic and reproductive implications that affect the quality of life of women. This PCOS guideline summary is based on the Indonesian Reproductive Endocrinology and Fertility Association guidelines for PCOS. This guideline is expected to guide the diagnosis and long-term management of PCOS.

Methods

We searched scientific evidence on the Cochrane and PubMed databases using the keyword “polycystic ovary syndrome”. This evidence was reviewed by experts in the field of obstetrics and gynecology, and recommendations were made based on scientific evidence while considering patient values, costs, and resources.

Results

A total of 127 recommendations and practice points were made regarding the diagnosis and management of PCOS. The levels of available health services and management algorithms for PCOS in Indonesia are also included.

Conclusion

The first-line treatment for managing hyperandrogenism and menstrual disorders in patients with PCOS is combined oral contraceptives. The first-line treatment for ovulation induction is letrozole, while clomiphene citrate, metformin, gonadotropins, and ovarian surgery serve as the second-line treatment. The third-line treatments included in vitro fertilization, with or without in vitro maturation.

Keywords: Polycystic ovary syndrome; Guideline; Consensus; Indonesia

Introduction

Polycystic ovary syndrome (PCOS) is a multifactorial complex endocrine condition. It is characterized by ovulatory disorders, hyperandrogenism (both clinical and biochemical), and polycystic ovary morphology. These findings are based on the Rotterdam criteria, which establish the diagnosis of PCOS if at least two of the three criteria are present [1].

PCOS is a gynecological condition that affects about 5-10% of women. According to a study conducted at a national referral hospital in Indonesia, PCOS is predominantly prevalent in women aged 26-30, affecting 45.7% of this age group, with menstrual abnormalities being the most commonly reported gynecological symptom [2].

PCOS is a condition that has significant metabolic and reproductive implications. Insulin resistance is the predominant metabolic condition observed in patients with PCOS, affecting approximately 71% of individuals. This syndrome can also lead to infertility owing to the absence of ovulation, a higher chance of miscarriage after natural conception or assisted reproductive technology, and a higher probability of developing ovarian hyperstimulation syndrome (OHSS) [3].

Women diagnosed with PCOS reported compromised quality of life [4]. However, the quality of life for women with PCOS can be enhanced through the management of the condition. Therefore, a comprehensive approach is necessary for diagnosing and managing PCOS. This PCOS guidelines summary is expected to provide guidance regarding the diagnosis and long-term management of PCOS based on scientific evidence.

Materials and methods

This executive summary was based on the Indonesian Reproductive Endocrinology and Infertility Association guidelines for PCOS. We searched scientific evidence on Cochrane and PubMed using the keyword "polycystic ovary syndrome". Our search encompassed guidelines, randomized controlled trials, clinical trials, systematic reviews, and meta-analyses. The scientific evidence was published in the last 13 years and written in English. This evidence was reviewed by experts in Obstetrics and Gynecology.

Based on the level of scientific evidence and considering patient values, costs, and resources, we formulated the following recommendations. 1) Strong recommendation. 2) Weak recommendation. And 3) good practice point.

Results

The recommendations of the Indonesian Reproductive Endocrinology and Infertility Association guideline for PCOS are presented in Table 1. The diagnosis and management of PCOS are performed in primary, secondary, and tertiary care centers, depending on the available facilities (Table 2). Women diagnosed with PCOS must undergo lifestyle modifications and receive first-line medical treatment of combined oral contraceptive pills. If the first-line therapy is ineffective, a second-line treatment can be administered (Fig. 1). Infertility is also frequently observed in patients with PCOS, and management includes medical treatment, lifestyle modifications, surgery, and in vitro fertilization (IVF) (Fig. 2).

Summary of PCOS guidelines recommendations [1,6,22]

Level of health services for PCOS [6]

Fig. 1.

Treatment of PCOS with menstrual disorders [6,7]. PCOS, polycystic ovary syndrome; SHBG, sex hormone-binding globulin.

Fig. 2.

Infertility Management in PCOS [6,7]. PCOS, polycystic ovary syndrome; IVF, in vitro fertilization; COC, combined oral contraceptive. *Medications used for PCOS, such as letrozole, COC, metformin, and gonadotropins, are considered off-label. This off-label practice is primarily supported by scientific data and is authorized in numerous countries. Healthcare practitioners must inform patients and discuss the advantages and disadvantages of treatment.

Medications used for PCOS, such as letrozole, combined oral contraceptive pills (COC), metformin, and gonadotropins, are considered off-label. This off-label practice is primarily supported by scientific data and has been authorized in numerous countries. Healthcare practitioners must inform patients of the advantages and disadvantages of treatment.

Discussion

1. Diagnosis of PCOS

To diagnose PCOS, at least two of the three Rotterdam criteria must be met. These criteria included ovulatory disorders, hyperandrogenism, and polycystic ovarian morphology. Approximately 95% of women with PCOS experience oligomenorrhea or amenorrhea and PCOS is diagnosed in 90% of these women with oligomenorrhea or amenorrhea [5].

The presence of hyperandrogenism in PCOS can be assessed through biochemical or clinical assessments. Clinical manifestations of hyperandrogenism include hirsutism, androgenic alopecia, and acne. These manifestations should be assessed during the diagnosis of PCOS. Hirsutism was evaluated by utilizing the Ferriman-Gallwey score. Biochemical hyperandrogenism is characterized by elevated levels of androgens, specifically testosterone, androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate. Free testosterone examination/free androgen index (FAI) is preferred for detecting hyperandrogenism because it is more sensitive than total testosterone examination. FAI is the ratio of total testosterone to sex hormone-binding globulin (SHBG) levels. An FAI value of >5% is an inclusive criterion for PCOS [6,7].

Polycystic ovary morphology was defined by finding more than 20 follicles in each ovary, or volume of each ovary >10 mL, or number of follicles per cross-section ≥10 [1]. Several researchers found that anti-mullerian hormone (AMH) levels may function as a diagnostic indicator for PCOS. However, serum AMH levels alone cannot be used to diagnose PCOS, particularly in adolescents.

2. PCOS diagnosis in adolescents

The diagnosis of PCOS in adolescents (under 18 years of age) should be cautiously approached because of the complex hormonal and reproductive changes that occur during the transitional phase. As a result, while some adolescents present with mature PCOS traits, others may show less suggestive symptoms. However, by the age of 18, most adolescents with PCOS show a clear phenotype. The diagnostic criteria for PCOS include two conditions: 1) evidence of hyperandrogenism (clinical and biochemical) and 2) chronic ovulation disorders [8].

Biochemical hyperandrogenism in adolescents can be assessed by measuring testosterone levels. The hyperandrogenism criteria for adults can also be applied to adolescents, that is an examination performed 2 years after menarche. Menstrual cycle abnormalities can occur in adolescents as part of reproductive maturation. Nevertheless, if a person experiences oligomenorrhea or amenorrhea for a minimum of 2 years after menarche or if they have primary amenorrhea by the age of 16 and other probable causes have been eliminated, these symptoms should be regarded as indicative of PCOS [8].

3. Insulin resistance in PCOS

Insulin resistance can manifest in obese and lean patients with PCOS, leading to hyperinsulinemia, increased androgen levels, and decreased SHBG synthesis. This limits the development of follicles and causes menstrual disorders [9]. Insulin resistance was clinically evaluated through the following methods: fasting blood glucose, oral glucose tolerance test, homeostatic model assessment (HOMA), and QUICKI calculations, and the hyperinsulinemic-euglycemic clamp procedure [10,11].

The euglycaemic clamp test is an established method for evaluating insulin sensitivity. However, its implementation in clinical practice is challenging. HOMA and QUICKI measurements can be used in PCOS; however, the results were based on the population average. Numerous studies have determined the HOMA and QUICKI cutoff values. According to a previous study, the cutoff value for the homeostatic model assessment of insulin resistance (HOMA-IR) assessment was 2 [10,11]. Wiweko and Mulya [12] found that fasting blood glucose and a fasting insulin ratio <10.1 IU/mL indicate insulin resistance and can be employed as a minor criterion for diagnosing PCOS. This cutoff had a sensitivity and specificity of 90.2% and 90.9%, respectively [12].

4. Psychological problems in PCOS

Women diagnosed with PCOS suffer a compromised quality of life. Symptoms experienced in PCOS, such as menstrual disorders, infertility, and hirsutism, are significantly correlated with an individual’s psychological well-being [4]. Moreover, women diagnosed with PCOS are at higher risk of displaying symptoms of depression, that are characterized by diminished interest, sleep disturbances, and fatigue. A previous meta-analysis found that individuals with PCOS exhibited higher scores, indicating the presence of depressive symptoms (44%), than the control group (17%) [7].

5. Non-pharmacological management

Women with PCOS should engage in physical activity and dietary modifications as an initial step in treatment. Increased physical activity and dietary changes can improve hormonal profile by reducing insulin resistance and restoring regular menstrual cycles. Furthermore, exercise can reduce body fat mass, particularly the visceral fat mass [13]. In women with PCOS, aerobic exercise improves insulin levels. During 3-month research, cycling for 30 minutes three times weekly with an intensity of 60-70% of the maximum rate of oxygen consumption (VO2 max) resulted in a substantial decrease in body mass index (BMI) (-4.5%) and improvement in insulin sensitivity [14].

Women with PCOS are encouraged to consume a low-glycemic diet. Up to 95% of women who followed a low-glycemic diet plan reported improvements in their menstrual cycles, resulting in increased insulin sensitivity and reduced testosterone levels [13]. Sørensen et al. [15] discovered that women with PCOS who followed a high protein diet (>40%) experienced a significantly greater decrease in body fat, waist circumference, body mass, and fasting blood glucose levels compared to the group consuming foods with regular protein content (<15%). Insulin sensitivity can be improved by altering the ratio of fatty acids consumed, specifically by increasing the consumption of monounsaturated fatty acids and reducing the consumption of saturated fatty acids [16]. Omega-3 supplementation significantly enhanced lipid profiles and lowered the total cholesterol/high density lipoprotein (HDL) and low density lipoprotein/HDL ratios [17].

Therefore, increased fiber consumption is recommended for patients with PCOS. Research has revealed that women with BMI >25 kg/m2 manifested a significant decrease in DHEA, estradiol, and testosterone levels following the implementation of a high-fiber diet compared to their baseline levels [18].

Previous studies have demonstrated a relationship between vitamin D levels and the occurrence and symptoms of PCOS. Vitamin D supplementation decreased blood androgen and AMH levels, leading to improved folliculogenesis and menstrual cycle. Furthermore, vitamin D supplementation improved insulin resistance and fat metabolism [19].

6. Management of PCOS with menstrual disorders

COC is the first-line treatment for PCOS to manage hyperandrogenism and menstrual cycle irregularities [1]. The combination of COC and metformin has been proven to be advantageous in high-risk populations, specifically in those with a predisposition to diabetes mellitus, impaired glucose tolerance, or belonging to high-risk ethnic groups. This combination could also regulate metabolic features if the first-line medication failed [7]. Anti-androgen therapy might be used as an alternative or additional therapy for conditions that other treatments are ineffective or if there are any contraindications [1]. Ozdemir et al. [20] revealed that treating PCOS with medroxyprogesterone acetate for 10 days a month for a period of 6 months improved the free androgen index, acne, and seborrhea scores, improved menstrual cycles, and reduced serum luteinizing hormone (LH) and testosterone levels. Anti-obesity medications might be considered according to the recommendations for the general population while considering their advantages and potential drawbacks [1].

7. Ovulation induction to treat infertility in PCOS

Letrozole is the first line of pharmacological treatment to induce ovulation in patients with PCOS. Clomiphene citrate and metformin combination is considered the second-line treatment, with gonadotropins or ovarian surgery [1]. Research has demonstrated that for ovulation induction, letrozole, compared to clomiphene citrate, leads to significantly increased live birth rates (odds ratio, 1.68; 95% confidence interval, 1.42-1.99) [21]. However, clomiphene citrate is associated with a higher risk of multiple pregnancies compared to letrozole [22].

A clomiphene citrate and metformin combination is preferred because of its ability to increase the incidence of clinical pregnancy compared to using only clomiphene citrate. There was a positive correlation between initial insulin levels and the impact of treatment (live births) in the clomiphene citrate and metformin groups compared to the clomiphene citrate group. This suggests that clomiphene citrate combined with metformin is more beneficial for patients with higher baseline insulin levels [23]. The addition of dexamethasone to clomiphene citrate increased the clinical pregnancy rate by a factor of six [24].

Additionally, gonadotropins can be utilized as ovulation induction agents. Gonadotropins exhibited superior efficacy compared with clomiphene citrate in terms of live births and ongoing pregnancy rates [24]. Begum et al. [25] revealed that a combination of gonadotropin and metformin effectively induced ovulation. The recombinant follicle-stimulating (rFSH)+metformin group showed significantly greater ovulation, pregnancy, and live birth rates compared to the metformin+clomiphene citrate and rFSH-only groups (P<0.05) [25]. Step-up gonadotropin treatment is preferred over the step-down regimen due to its higher rate of monofollicular development (68.2% vs. 32.0%, respectively). The step-up regimen resulted in a lower rate of ovarian hyperstimulation than the step-down regimen (2.25% vs. 11.0%, respectively) [26].

8. Use of insulin sensitizing agent

Hyperinsulinemia promoted androgen synthesis and decreased SHBG production, that resulted in an increase in free androgen levels. The overproduction of androgens in the ovaries, combined with high insulin levels, resulted in the early degeneration of ovarian follicles and anovulation [27]. Metformin is effective in facilitating ovulation and enhancing menstrual cycle frequency in women with PCOS. Pioglitazone also significantly improved menstrual patterns in women with PCOS [28].

A Cochrane systematic review comparing inositol with a placebo demonstrated an improvement in SHBG production. However, there were no significant differences in BMI, waist-to-hip ratio, ovulation rate, serum testosterone, fasting glucose, fasting insulin, triglycerides, or cholesterol levels [28]. DLBS-3233 can improve insulin resistance in PCOS. Previous research discovered that DLBS-3233 had greater efficacy in lowering insulin resistance than placebo, as evidenced by a decrease in HOMA-IR [29]. Administration of vitamin D can improve HOMA-IR and fasting plasma glucose levels in women with PCOS [30].

9. Bariatric surgery

A systematic review of 10 trials that included 587 patients with an average of 18.25 months follow-up revealed a higher pregnancy rate following bariatric surgery than the metformin group (34.9% vs. 17.1%, respectively). Furthermore, bariatric surgery resulted in greater improvement in menstrual regularity compared to the metformin group [31]. Bariatric surgery resulted in a significant decrease in blood glucose, serum insulin, triglyceride, total testosterone, DHEA levels, and increased SHBG levels [32]. Because the risk-to-benefit ratio of bariatric surgery as a treatment for infertility remains uncertain, we considered it an experimental treatment for women with PCOS.

10. Laparoscopic ovarian surgery

Indications for laparoscopic ovarian surgery included anovulatory PCOS and clomiphene citrate-resistant PCOS. This procedure may be recommended for individuals with LH hypersecretion. Laparoscopic ovarian drilling (LOD) can improve disturbances in the pituitary-ovarian feedback through several mechanisms. Ovarian follicle and stroma damage caused by LOD decreases inhibin and androgen levels, resulting in the elevation of FSH levels and the initiation of follicle maturation. Improvement in blood flow in the ovaries after the procedure also increases the delivery of gonadotropins. Another mechanism, the postoperative inflammatory process in the ovaries, stimulates the secretion of Insulin-like growth factor, which contributes to follicle development, ovulation, and enhanced insulin sensitivity [33,34].

11. IVF and in vitro maturation

If ovulation induction therapy failed in women with PCOS and there is no absolute indication for IVF, IVF could be considered a third-line option, possibly with in vitro maturation. Single-embryo transfer is the preferred method because of the potential for pregnancy complications in PCOS. In vitro oocyte maturation prevents ovarian hyperstimulation [1].

Women with PCOS undergoing IVF±intracytoplasmic sperm injection are particularly susceptible to ovarian hyperstimulation. Suppression of pituitary LH secretion with a GnRH antagonist lowers the likelihood of hyperstimulation [35]. A previous investigation revealed no statistically significant differences in fertilization rates, oocyte retrieval, and clinical pregnancy rates between the long-agonist and antagonist protocols. The agonist group exhibited an increased incidence of OHSS compared to the control group (22.2% vs. 0%, respectively) [36].

The administration of human chorionic gonadotropin (hCG) as a trigger can lead to the development of OHSS in individuals with PCOS undergoing IVF. Therefore, triggering with GnRH agonists offers a potential solution for the final oocyte maturation. While GnRH agonists were associated with a decreased live birth rate in IVF cycles with fresh embryo transfer compared to hCG, they had a lower occurrence of OHSS than hCG [37].

Notes

Conflict of interest

Authors declare no conflict of interest is associated with this study.

Ethical approval

Ethical approval is not required.

Patient consent

Patient consent is not applicable for this research.

Funding information

The authors receive no funding for this research.

Acknowledgement

The authors would like to thank the Indonesian Reproductive Endocrinology and Fertility Association, Indonesian Society of Obstetricians and Gynecologists Association for supporting the formulation of this guideline.

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Fig. 1.

Fig. 1.

Treatment of PCOS with menstrual disorders [6,7]. PCOS, polycystic ovary syndrome; SHBG, sex hormone-binding globulin.

Fig. 2.

Fig. 2.

Infertility Management in PCOS [6,7]. PCOS, polycystic ovary syndrome; IVF, in vitro fertilization; COC, combined oral contraceptive. *Medications used for PCOS, such as letrozole, COC, metformin, and gonadotropins, are considered off-label. This off-label practice is primarily supported by scientific data and is authorized in numerous countries. Healthcare practitioners must inform patients and discuss the advantages and disadvantages of treatment.

Table 1.

Summary of PCOS guidelines recommendations [1,6,22]

Recommendation Category
Diagnosis of PCOS
 Oligomenorrhea-amenorrhea and/anovulation
  The menstrual cycle is categorized as irregular if Good practice point
   1) Normal throughout the first year of menstruation
   2) One to 3 years after menarche: less than 21 or more than 45 days
   3) Three years from menarche until perimenopause: less than 21 days, greater than 45 days, or fewer than eight cycles yearly
   4) More than a year following menarche: a duration of over 90 days for a single cycle
   5) Primary amenorrhea occurring at an age greater than 15 years or if it has been more than 3 years following thelarche
  The optimal timing for the assessment and diagnosis of PCOS in adolescents with irregular menstrual cycles should be determined by a discussion with the patient and their parents, taking into cultural and psychosocial aspects Good practice point
  Adolescents displaying signs of PCOS but not meet the diagnostic criteria may be considered to have an elevated risk and should be reevaluated at or before they attain full reproductive maturity, which occurs 8 years following menarche Good practice point
  Ovulatory dysfunction may still manifest even in individuals with regular menstrual cycles. To confirm anovulation, midluteal progesterone levels can be tested Good practice point
 Hyperandrogenism (clinical and biochemical)
  The assessment of biochemical hyperandrogenism in PCOS is done by measuring free or total testosterone levels. The free androgen index can be used to estimate free testosterone levels Strong recommendation
  Androstenedione and dehydroepiandrosterone sulfate (DHEAS) examinations may be conducted if the testosterone levels are within the normal range. However, it has lower specificity and a decreased DHEAS associated with increasing age Strong recommendation
  For the precise determination of total or free testosterone, it is necessary to employ chromatography-mass spectrometry/mass spectrometry and extraction/chromatography immunoassays. It is not recommended to utilize radiometric or enzyme-linked free testosterone assays due to their poor sensitivity, accuracy and precision Strong recommendation
  In adults, the presence of hirsutism only should be regarded as a predictor of biochemical hyperandrogenism and PCOS. Without hirsutism, hair loss and acne are relatively poor biochemical indicators of hyperandrogenism Strong recommendation
  Testing for biochemical hyperandrogenism is difficult in women using hormonal contraception. If a biochemical evaluation of hyperandrogenism is required, the test should be conducted after discontinuing treatment for a period of 3 months or more, and the patient should be given non-hormonal replacement therapy Good practice point
  Biochemical assessment of hyperandrogenism is important to diagnose PCOS and the determination of the PCOS phenotype if clinical manifestations of hyperandrogenism (particularly hirsutism) are nonspecific or absent Good practice point
  Repeated androgen measurements have a limited role in establishing the diagnosis of PCOS in adults Good practice point
  Most adolescents achieve adult levels of androgen between the ages of 12 and 15 years old Good practice point
  In cases where androgen levels are higher than laboratory standard values, it is necessary to explore alternative causes of hyperandrogenemia besides PCOS Good practice point
 Polycystic ovary morphology
  Transvaginal ultrasound (US) examination is the most accurate ultrasound examination to diagnose PCOS Good practice point
  The findings of a transvaginal US indicative of PCOS are the presence of ≥20 follicles per ovary and/or ovarian volume ≥10 mL, or a follicle number per section ≥10, ensuring no corpus luteum, cyst, or dominant follicle Good practice point
Anti-müllerian hormone for PCOS diagnosis
 Anti-müllerian hormone (AMH) levels can be used to identify PCOM in adults. This examination cannot be utilized as a standalone assessment and is not suggested for adolescents Strong recommendation
 The evaluation of AMH levels should be carried out following the diagnostic algorithm, taking into consideration that AMH levels are not essential to diagnose PCOS in individuals with hyperandrogenism and irregular menstrual cycles Strong recommendation
 AMH levels or ultrasonography can be utilized to determine PCOM. It is advisable to avoid conducting both tests to prevent overdiagnosis Good practice point
 Healthcare professionals must be aware of factors that can influence AMH values, such as body mass index (BMI), age, menstrual cycle, use of hormonal contraception, and history of ovarian surgery Good practice point
Ferriman gallwey score
 The clinical symptoms of hyperandrogenism can be assessed through history taking and physical examination. Acne, androgenic alopecia, and hirsutism are symptoms of hyperandrogenism Good practice point
 Healthcare professionals are advised to Good practice point
  1) Utilize the modified ferriman gallwey score along with a photographic atlas to evaluate hirsutism
  2) Utilize the ludwig or olsen visual scale to evaluate hair loss in women
  3) Recognize that cosmetic interventions may have already addressed the physical signs of hyperandrogenism
  4) Assess the patient’s self-evaluation of their symptoms related to hyperandrogenism
  5) Monitor for clinical hyperandrogenism during therapy
Insulin resistance examination
 All women should undergo glycemic status examination during the diagnosis of PCOS Strong recommendation
 Regardless of BMI and age, women with PCOS should be examined for impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes Strong recommendation
 The recommended examination is the oral glucose tolerance test (OGTT) using a 75-g glucose. If OGTT examination is not available, examination of fasting plasma glucose (FPG) and/or HbA1c may be examined. Nevertheless, both FPG and HbA1c examinations exhibit reduced accuracy Strong recommendation
 Women who are seeking pregnancy or receiving infertility treatment should be offered the OGTT examination. If a preconception assessment is not conducted, the OGTT examination can be conducted during the initial antenatal visit and subsequently repeated between 24 and 28 weeks of gestation Strong recommendation
 Women with preexisting diabetes are more likely to develop PCOS; hence, screening should be considered Good practice point
 For the purpose of determining insulin resistance, the HOMA-IR assessment with a cutoff point greater than 2 or the Muharam score less than 10.1 can be utilized Good practice point
 The pathophysiology of PCOS is related to insulin resistance. However, insulin tests are not recommended for routine care due to their limited clinical relevance Good practice point
Early detection of decreased quality of life and psychological problems
 A compassionate approach is required while taking a patient’s medical history, and questionnaires can be utilized to evaluate the deterioration in quality of life Good practice point
 Assessment of psychosexual disorders in women with PCOS could be examined by using several questionnaires, such as the female sexual function index and Arizona sexual experience scale Good practice point
 Early diagnosis of eating disorders is essential due to the possible negative impact on lifestyle adjustment and dietary patterns advised in PCOS Good practice point
Risk of cardiovascular disease
 Women diagnosed with PCOS have an increased risk of developing cardiovascular disease. Thus, cardiovascular risk factors should be assessed Strong recommendation
 Irrespective of age or BMI, all women with PCOS require a lipid profile examination (triglycerides, cholesterol, LDL, and HDL) at diagnosis. Follow-up examinations are conducted depending on the overall risk of cardiovascular disease and the occurrence of hyperlipidemia Strong recommendation
 Annual blood pressure measurements are recommended for women with PCOS, particularly during the planning of pregnancy or the course of fertility treatment Strong recommendation
Endometrial hyperplasia and cancer risk
 Medical professionals must be aware of the fact that premenopausal women with PCOS are at a heightened risk of developing endometrial hyperplasia and cancer Strong recommendation
 It is important to educate women with PCOS of their increased susceptibility to developing endometrial hyperplasia and cancer. Given the minimal overall risk, it is not recommended to do regular screening for endometrial cancer Good practice point
 There are numerous factors that contribute to the elevated risk of endometrial hyperplasia and malignancy in women with PCOS, including prolonged and untreated amenorrhea, excessive body weight, type 2 diabetes, and constant endometrial thickening Good practice point
 To prevent endometrial hyperplasia and cancer in PCOS women, it is essential to maintain a healthy weight, regulate the menstrual cycle, and adhere to regular progesterone therapy Good practice point
 When significant endometrial thickness is observed, a biopsy with histological examination and withdrawal bleeding should be considered Good practice point
Non-pharmacological management
 Nutritional interventions and dietary patterns
  It is necessary to reduce the amount of calorie intake by 500-1,000 kcal/day, with a balanced nutritional composition and accompanied by an increase in fiber consumption Strong recommendation
  Overweight women should aim for a 30% energy deficit, equivalent to a daily calorie intake of 500-750 kcal (1,200-1,500 kcal/day) while considering their energy requirements, degree of physical activity, and body weight Good practice point
  To increase insulin sensitivity, individuals can consume small portions of food more frequently, accompanied by larger breakfast portions compared to dinner Weak recommendation
  A low glycemic index diet can reduce BMI, increase insulin sensitivity, and improve irregular menstrual cycles Weak recommendation
  Women with lean PCOS (BMI <23 kg/m2) are advised to increase their consumption of fruit and vegetables. Anti-inflammatory and antioxidant-rich diets like the Mediterranean diet may also be recommended Weak recommendation
  The primary management for lean PCOS, particularly in adolescents, is the prevention of weight gain and the promotion of a healthy lifestyle Good practice point
 Protein dietary recommendation
  A high protein and low carbohydrate diet can significantly reduce body mass, visceral fat and insulin levels Strong recommendation
  Diets high in protein can impact bone density and kidney function Strong recommendation
 Fat dietary recommendation
  Omega-3 consumption can reduce total cholesterol levels Strong recommendation
  Polyunsaturated fat consumption can enhance lipid and hormone profiles, therefore diminishing the likelihood of developing cardiovascular disease Strong recommendation
  Up to 30% of dietary intake should come from fatty acids comprising equal amounts of saturated, polyunsaturated, and monounsaturated fat Strong recommendation
 Fiber dietary recommendation
  A diet rich in fiber leads to decreased testosterone and DHEA levels Strong recommendation
  A high-fiber diet can improve the symptoms of hirsutism Strong recommendation
 Vitamin D
  PCOS women with low vitamin D levels have greater HOMA-IR, total cholesterol, LDL cholesterol, hyperglycemia, CRP, triglycerides, and reduced HDL cholesterol Strong recommendation
  Vitamin D preparations containing calcitriol (D3) are more effective than vitamin D2 preparations in increasing serum levels of 25-hydroxyvitamin D Strong recommendation
  Vitamin D and calcium supplementation have been proven to improve the menstrual cycle, follicle maturation, and weight loss in PCOS Weak recommendation
  Sunlight exposure and natural vitamin D consumption from fish oil have essential roles in vitamin D production Good practice point
 Physical activity
  Patients with PCOS should implement lifestyle changes to enhance their metabolic conditions, including lipid and anthropometric profiles, symptoms of hirsutism, and fasting insulin levels Strong recommendation
  Aerobic exercise can effectively decrease insulin resistance and improve lipid profile, BMI, abdominal circumference, and cardiorespiratory system (VO2 max) capacity in individuals with PCOS. High-intensity interval exercise and weight training are both beneficial in improving anthropometric measurements and insulin levels Weak recommendation
  The recommended weekly physical activity is 250 minutes moderate intensity, 150 minutes high intensity, or a balanced combination of both. It is recommended to incorporate muscle strengthening exercises that focus on major muscle groups on two non-consecutive days per week, and screen time should be minimized Good practice point
 Acupuncture therapy
  Acupuncture therapy, combined with pharmacotherapy and lifestyle changes, can improve fertility by improving pregnancy and ovulation rates, decreasing the LH/FSH ratio, lowering HOMA-IR, lowering BMI, improving menstrual cycles, and improving insulin resistance Weak recommendation
Management of PCOS with menstrual disorders
 Hormonal therapy
  The use of combined oral contraceptive (COC) is recommended for adult women with PCOS to manage menstrual cycle disorders and/or clinical hyperandrogenism Strong recommendation
  COC can be used for clinical hyperandrogenism and/or menstrual cycle disorders in adolescents at risk or diagnosed with PCOS Strong recommendation
  Administering large dosages of ethinyl estradiol (>30 μg) does not provide a significant difference in clinical benefit compared to low doses (<30 μg) for treating hirsutism in PCOS Strong recommendation
  The administration of cyproterone acetate and ethinyl estradiol 35 μg should be considered second-line therapy following COC Strong recommendation
  Administration of oral progestin given 10 days per month for 6-month course can improve irregular menstrual cycles and hormonal profiles associated with hyperandrogenism Strong recommendation
  Progestins can prevent endometrial hyperplasia, which lowers the likelihood of developing endometrial cancer in PCOS Weak recommendation
  The combination of both metformin and COC can be used to manage the metabolic status of women with PCOS Good practice point
PCOS and infertility
 Ovulation induction
 Aromatase inhibitor
  Letrozole should be the initial treatment for inducing ovulation in PCOS women who have anovulatory infertility and no other underlying causes of infertility Strong recommendation
  If letrozole is unavailable or its usage is prohibited, other ovulation induction agents can be used Good practice point
  Letrozole has a reduced likelihood of causing multiple pregnancies in comparison to clomiphene citrate Good practice point
 Clomiphene citrate with/without metformin
  Clomiphene citrate can be used in women with PCOS who have anovulatory cycles and no other underlying causes of infertility Strong recommendation
  Clomiphene citrate can be used as an ovulation induction agent in obese PCOS (BMI ≥30 kg/m2), infertility, anovulatory cycles and no other underlying causes of infertility Strong recommendation
  Clomiphene citrate may be administered in combination with metformin to manage PCOS- resistant clomiphene citrate, who have anovulatory infertility and no other underlying causes of infertility Strong recommendation
  Adding dexamethasone may enhance responsiveness in patients who do not respond to clomiphene citrate Strong recommendation
  Administering clomiphene citrate for ovarian stimulation carries a 5-7% chance of resulting multiple pregnancies. Therefore, ultrasound examination is required to evaluate the ovarian response Weak recommendation
  When aromatase inhibitors are not available, clomiphene citrate is preferred for inducing ovulation Good practice point
  The incidence of fetal malformations did not differ between the groups who received letrozole and clomiphene citrate Good practice point
 Gonadotropin
  Gonadotropins can be used as first-line treatment, with ultrasound monitoring and counseling related to the costs and risks of multiple pregnancies in women with PCOS who have anovulatory infertility and no other underlying causes of infertility Strong recommendation
  When accessible and affordable, gonadotropins are a viable alternative after clomiphene citrate+metformin to induce ovulation in women with PCOS who have anovulatory infertility and no other underlying causes of infertility Strong recommendation
  A combination of gonadotropin and metformin can be used instead of gonadotropins only in women with PCOS who have anovulatory infertility and no other underlying causes of infertility Strong recommendation
  Gonadotropins can be administered using either the step-up or the step-down regimens Good practice point
  The step-up regimen is preferable to the step-down regimen due to its enhanced safety and reduced likelihood of multiple pregnancies. Compared to the step-up regimen, the ovarian hyperstimulation rate was higher with the step-down regimen Strong recommendation
  Gonadotropins or laparoscopic ovarian drilling (LOD) may be employed in women with PCOS who have anovulatory infertility, resistance to clomiphene citrate and no other underlying causes of infertility. Patients must be informed about the benefits and drawbacks of their treatment Strong recommendation
  Consider the following when prescribing gonadotropins Good practice point
   1) The availability and cost of the intervention
   2) Expertise is necessary to implement the intervention
   3) Requires intensive ultrasound monitoring
   4) All accessible gonadotropin formulations have similar clinical effectiveness
   5) A low-dose step-up gonadotropin regimen is recommended to enhance the mono follicular development
   6) Risk of multiple pregnancies
  When gonadotropins are used for ovulation induction, the trigger is only administered when there are <3 mature follicles. If there are >2 mature follicles, the trigger must be discontinued, and patients are advised to avoid unprotected sexual intercourse Good practice point
 Anti-obesity medication
  The use of medications with anti-obesity effects is considered an experimental therapy for PCOS to enhance fertility. The available evidence is inadequate to support the recommendation of using this medication to improve fertility Weak recommendation
 Bariatric surgery
  For PCOS patients, bariatric surgery is considered as an experimental treatment. The available evidence is inadequate to support the recommendation of using this medication to improve fertility Weak recommendation
  Bariatric surgery may be considered in PCOS to improve weight loss, hirsutism, diabetes, hypertension, ovulation, menstrual cycle disorders, and pregnancy rates Weak recommendation
  It is necessary to consider the following Good practice point
   1) The cost of intervention
   2) Following surgery, weight management must be maintained
   3) The occurrence of perinatal risks such as small for gestational age, preterm labor, and perinatal mortality
   4) Can lower the risk of macrosomia and gestational diabetes
   5) It is recommended to refrain from getting pregnant while experiencing significant weight loss and to use contraception for 12 months post-bariatric surgery
  When pregnancy occurs, it is essential to consider the following factors
   1) Preventive management of nutritional deficiencies prior to and following surgery
   2) Multidisciplinary approach
   3) Monitoring fetal growth during pregnancy
 Pregnancy outcomes
  Compared to the general population, women with PCOS have an increased likelihood of achieving pregnancy. Pregnancy carries the potential for several risks, including gestational weight gain, gestational diabetes, miscarriage, small for gestational age, hypertension in pregnancy, preeclampsia, intrauterine growth restriction, low birth weight, preterm birth, and the necessity for a cesarean section. There was no evidence of an elevated risk associated with large for gestational age, macrosomia, or the need for instrumental assisted delivery among women with PCOS Strong recommendation
  Women diagnosed with PCOS are recommended to adopt lifestyle changes from the beginning of their pregnancy Good practice point
  Women diagnosed with PCOS who are considering pregnancy should have routine blood pressure evaluations due to the increased likelihood of hypertension and preeclampsia during pregnancy Good practice point
  Women with PCOS who are considering pregnancy are advised to undergo an OGTT examination due to the increased likelihood of hyperglycemia and complications during pregnancy Good practice point
 Use of insulin sensitizing agent
  Metformin
   Metformin can be given to women with PCOS who have a BMI of 25 kg/m2 or more in order to improve metabolic profiles such as glucose levels, insulin resistance, and lipid profile Strong recommendation
   Metformin can be used to enhance ovulation, pregnancy, and live birth rates in women with PCOS who have anovulatory infertility and no other underlying causes of infertility. However, patients should be provided with information regarding more efficacious medications for inducing ovulation Strong recommendation
   In obese PCOS (BMI ≥30 kg/m2) who have anovulatory infertility and no other underlying causes of infertility, the combination of clomiphene citrate and metformin has the potential to increase ovulation, pregnancy rates, and live births Strong recommendation
   During in vitro fertilization (IVF), metformin use can lower the risk of ovarian hyperstimulation syndrome (OHSS) in women with PCOS Strong recommendation
   Metformin is superior to a placebo in stimulating ovulation in women with PCOS, and the combination of metformin and clomiphene citrate is more effective than taking only clomiphene citrate Strong recommendation
   Metformin can be given to pregnant women to restrict excessive weight gain and lower the likelihood of preterm labor Strong recommendation
   Metformin combined with COC treatment may be given to women with PCOS and a BMI ≤30 kg/m2 after receiving COC or metformin only Strong recommendation
  Thiazolidinedione (pioglitazone)
   Pioglitazone therapy for PCOS can enhance ovulation. Discontinuation of treatment is advised if the patient desires pregnancy or becomes pregnant Good practice point
   The effective dose of pioglitazone is 30 mg per day Good practice point
  Inositol
   Inositol, whether administered alone or in conjunction with other treatments, is considered as an experimental therapy for PCOS with infertility. The available evidence is inadequate to support the recommendation of using this medication to improve fertility Strong recommendation
   It is recommended that women who use inositol and other complementary therapies seek the advice of a healthcare provider Good practice point
  DLBS-3233
   DLBS-3233 50 mg daily for 6 weeks can reduce fasting insulin levels and HOMA-IR Strong recommendation
   DLBS-3233 showed reduced adverse effects in comparison to metformin Strong recommendation
  Vitamin D
   For PCOS patients, low dosages of vitamin D (4,000 IU/day) can improve insulin resistance Good practice point
   Vitamin D supplementation in individuals with PCOS can enhance insulin sensitivity and lipid metabolism, decrease levels of free androgens, and enhance the response to ovulation induction Good practice point
Laparoscopic ovarian surgery
 LOD can be used as a second-line treatment for women with PCOS that does not respond to clomiphene citrate, who have anovulatory infertility and no other underlying causes of infertility Good practice point
 LOD exhibits comparable effectiveness to gonadotropins in instances of clomiphene citrate resistance and exhibits a reduced likelihood of ovarian hyperstimulation and multiple pregnancies Good practice point
IVF
 IVF is the treatment for PCOS with anovulation after the first or second-line ovulation induction medication has failed Good practice point
 IVF is effective in PCOS with anovulation, and single embryo transfer can minimize multiple pregnancies Good practice point
 PCOS patients undergoing IVF±ICSI should be provided with education regarding the following topics Good practice point
  1) The availability, cost, and convenience of the procedure
  2) Elevated risk of OHSS
  3) Strategies to lower the likelihood of OHSS
 In PCOS undergoing IVF±ICSI cycles with a GnRH agonist protocol, metformin can be given during or before stimulation to lower the likelihood of OHSS and improve clinical pregnancy Good practice point
 Gonadotropin stimulation protocol
  In women with PCOS undergoing IVF±ICSI cycles, the antagonist protocol has the potential to lower the occurrence of OHSS, the length of stimulation, and the total gonadotropin dose, in comparison to the long agonist protocol Strong recommendation
  In IVF/ICSI cycles for PCOS, trigger using low dose hCG can lower the risk of OHSS Good practice point
  In an IVF/ICSI cycle with a GnRH antagonist protocol, it is advisable to use a GnRH agonist as a trigger and freeze all viable embryos. This procedure is performed in cases where fresh embryo transfer is not planned or when there is an increased likelihood of OHSS Good practice point
  When undergoing IVF±ICSI cycles, frozen embryo transfer should be considered in women with PCOS Good practice point
  Trigger (trigger final oocyte maturation)
   GnRH agonists are preferred over hCG as triggers to prevent OHSS Strong recommendation
   Triggering with GnRH agonists leads to decreased pregnancy rates, especially in cases of fresh embryo transfer, however, this can be addressed in frozen embryo cycles Good practice point
  FSH and LH options
   Recombinant or urine-derived FSH may be administered to women with PCOS who are undergoing controlled ovarian stimulation in IVF±ICSI cycles. There is inadequate evidence to support a specific FSH preparation Good practice point
   In women with PCOS who are undergoing controlled ovarian stimulation for IVF±ICSI cycles, exogenous recombinant LH should not be administered in conjunction with FSH on a regular basis Good practice point
  Adjunct metformin
   Metformin can be given before or during ovarian stimulation in PCOS women undergoing IVF±ICSI cycles using a GnRH agonist protocol. The purpose is to decrease the likelihood of OHSS and improve the clinical pregnancy Strong recommendation
   There are several things to consider Good practice point
    1) Metformin administered at the beginning of the GnRH agonist protocol
    2) The recommended daily dose of metformin ranges from 1,000 mg to 2,550 mg
    3) During positive pregnancy tests or the resumption of regular menstruation, metformin is discontinued unless there is a medical necessity to continue metformin therapy
  It is important to inform patients that the use of metformin in conjunction with a GnRH antagonist treatment reduces the likelihood of OHSS Good practice point
In vitro maturation (IVM)
 An IVM entails the maturation of immature cumulus-oocyte complexes from stimulated and unstimulated antral follicles without a human gonadotropin trigger Good practice point
 With suitable facilities, IVM could be used to achieve pregnancy and live birth rates similar to IVF±ICSI without the risk of OHSS. This treatment involves the generation of an embryo, which is subsequently vitrified, thawed, and transferred in a subsequent cycle Good practice point

PCOS, polycystic ovary syndrome; PCOM, polycystic ovarian morphology; HOMA-IR, homeostatic model assessment of insulin resistance; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; LH/FSH, luteinizing hormone to follicle-stimulating hormone; ICSI, intracytoplasmic sperm injection; GnRH, gonadotropin releasing hormone; hCG, human chorionic gonadotropin.

Table 2.

Level of health services for PCOS [6]

Primary care Secondary care Tertiary care
Diagnosis of PCOS
 History taking √ √ √
 Physical examination √ √ √
 Clinical hyperandrogenism evaluation √ √ √
 Basic gynecological examination √ √ √
 Supporting examinations (US and laboratory exam) √ √
Management of PCOS with menstrual disorders
 Lifestyle changes √ √
 Combined oral contraceptive pills √ √
 Progestin √ √
Evaluation and management of PCOS with infertility
 Clomiphene citrate √ √
 Metformin √ √
 Thiazolidinediones √ √
 Inositol √ √
 DLBS-3233 √ √
 Aromatase inhibitor √ √

PCOS, polycystic ovary syndrome.