PCOS Matters: Updates in the Diagnosis and Assessment of Polycystic Ovary Syndrome 

Katrina Rodriguez-Asuncion MD

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder affecting women of reproductive age, with a global prevalence ranging from 10% to 13%. In regions like South East Asia and the Eastern Mediterranean, this prevalence might be even higher. This syndrome is primarily characterized by irregular menstrual cycles, hyperandrogenism, and a distinct ovarian appearance. Those with a PCOS diagnosis also experience metabolic dysfunction, obesity, infertility, and an elevated risk of both pregnancy complications and long-term cardiovascular problems. Despite its prevalence, the exact causes and mechanisms of PCOS remain unclear, with the condition being seen as intricate and influenced by various factors. Consequently, diagnosing PCOS involves largely ruling out other known conditions that involve hyperandrogenism or impact ovulation. 

The complexity of PCOS has led to the development of multiple diagnostic criteria over time, causing confusion among healthcare professionals and women dealing with the condition. This has resulted in delays in diagnosis and management, leading to undesirable clinical outcomes for many individuals. Indeed, the creation of the 2023 International Evidence-Based Guideline for PCOS assessment and management is a significant step forward. The objective is to minimize global disparities in the existing clinical guidelines and to expand the approach to managing this condition. This involves implementing a comprehensive assessment program that covers all PCOS-related aspects. This approach aims to assist healthcare providers and women with PCOS in accurately diagnosing and effectively managing this prevalent yet insufficiently researched condition. 

Diagnostic Criteria for PCOS

In 1935, Stein and Leventhal initially described PCOS as a set of symptoms currently recognized as the  combination of hirsutism, obesity, amenorrhea, and bilaterally enlarged polycystic-appearing ovaries. Numerous diagnostic criteria have been proposed which variably include a combination of hyperandrogenism, oligo-amenorrhea,  and changes in ovarian morphology, as evaluated through pelvic ultrasonography. 

PCOS was defined by the National Institute of Child Health and Human Development in 1990 as the presence of both clinical and/or biochemical signs of hyperandrogenism and oligo- or chronic anovulation. Ultrasound findings of polycystic ovaries were noted to be suggestive of PCOS, but not necessarily diagnostic, which contradicted the prevalent approach in the United Kingdom and much of Europe at that time, which viewed this finding as the core feature of PCOS. This debate continued until 2003. Thus a joint consensus statement commonly known as the Rotterdam Criteria was created by  27 PCOS experts  at a conference sponsored by both the European Society of Human Reproduction (ESHRE) and American Society for Reproductive Medicine (ASRM) in Rotterdam, Netherlands. These criteria expanded the  phenotypic expression of PCOS to encompass any two out of the three key characteristics of PCOS: oligo-amenorrhea, hyperandrogenism, and an ultrasonographic finding of polycystic ovarian morphology. The new proposed criteria increased the prevalence of PCOS by approximately thrice as compared to its predecessor, the 1990 NIH criteria. Moreover, using these criteria allowed the diagnosis of PCOS without hyperandrogenism, which had been previously considered as the primary defect by the 1990 NIH criteria.

The Androgen Excess Society (AES) again made the criteria hyperandrogenism central to the diagnosis of PCOS again in 2006, while validating the significance of ovarian morphology in the diagnosis of this syndrome. The presence of hirsutism and/or biochemical hyperandrogenism, as well as either oligo-anovulation and/or polycystic-appearing ovarian morphology (PCOM) was required by AES guidelines for the diagnosis of PCOS.

The presence of various classification systems resulted in clinical confusion and was considered to delay scientific progress in the understanding of PCOS. Therefore, the NIH held an evidence-based methodology workshop on PCOS in 2012, in which experts recommended the use of the expanded 2003 Rotterdam criteria, while specifically identifying these sub-phenotypes: androgen excess and ovulatory dysfunction; androgen excess and PCOM; ovulatory dysfunction and PCOM; and androgen excess, ovulatory dysfunction, and PCOM. Updates and key recommendations specified that PCOS should be diagnosed using the 2018 International Evidence-based Guideline criteria, which is built upon the consensus-based 2003 Rotterdam criteria with the exclusion of other etiologies. The most recent 2023 International Evidence-Based Guideline for Assessment and Management of PCOS also followed the Rotterdam criteria but with the inclusion of the Anti-Müllerian Hormone as a surrogate marker for ovarian morphology in place of ultrasonography.

Biochemical Hyperandrogenism

In women, androgens normally function to support bone density, muscle mass, and sexual function. The majority of oligo-amenorrheic patients with PCOS also have biochemical hyperandrogenemia. The ovaries are the primary source of hyperandrogenism in patients with PCOS. Accordingly, testosterone, predominantly in the free form unbound to sex-hormone-binding globulin (SHBG), is most frequently elevated in these patients and is the most sensitive marker for diagnosis. This is because obesity and hyperinsulinemia are associated with reduced SHBG, and thus total testosterone levels are typically lower in patients with PCOS whereas the unbound form may be elevated. 

Biochemical hyperandrogenism should be defined by an elevated total or free testosterone. If the total or free testosterone is not elevated, testing the androstenedione and dehydroepiandrosterone sulfate could be considered. In patients who are already on combined oral contraceptive pills (OCP), the OCP should be withdrawn for a minimum of 3 months prior to testing for hyperandrogenism. Clinicians should also be aware that an elevated androgen level does not always equate to a diagnosis of PCOS. Other causes of hyperandrogenemia should also be ruled out, such as ovarian and adrenal neoplastic growths, congenital adrenal hyperplasia, Cushing’s syndrome, ovarian hyperthecosis (after menopause), iatrogenic causes, and/or syndromes of severe insulin resistance. Hence, a proper history and physical examination are crucial in assessing for an androgen-secreting tumor.

Clinical Hyperandrogenism

A comprehensive history and physical examination should be done, and symptoms and signs of clinical hyperandrogenism, including acne, female pattern hair loss and hirsutism in adults and severe acne and hirsutism in adolescents, should be sought. Among these symptoms, presence of hirsutism alone is already predictive of biochemical hyperandrogenism in PCOS, since 60-70% of patients suffers from this condition as opposed to female pattern hair loss and acne. Hirsutism is characterized as excessive terminal hair growth in a male pattern distribution. If left untreated, it can grow to lengths of up to more than 5 mm. The gold standard for assessing and quantifying the degree of hair growth is the Modified Ferriman–Gallwey (MFG) scoring system, in which terminal hair growth, on a scale from 0 to 4, at nine different anatomic sites, is scored. Subsequently, these scores are summed up and a MFG score of 4-6 is indicative of hirsutism. However, different factors  that can limit clinical assessment should also be taken into consideration such as ethnicity and hair removal treatments. The MFG and other clinical signs of hyperandrogenism are also used to monitor improvement or response to therapy. 

Irregular Cycles and Ovulatory Dysfunction

In adults, the average menstrual cycle is around 28 days, with a normal range of 21–35 days. The most recent guidelines emphasize irregular menstrual cycles, particularly oligo-amenorrhea (cycles more than 35 days apart or fewer than 8 cycles per year), as a marker for ovulatory dysfunction in PCOS. Polymenorrhea (less than 21 days apart) is also considered in the criteria, though it is less common. Ovulatory dysfunction can still occur with regular cycles, and if anovulation needs to be confirmed, serum progesterone levels can be measured. For adolescents, irregular cycles are normal in the first year post-menarche. After that, irregular menses should be defined as cycles less than 21 or more than 45 days apart, and more than 90 days for any single cycle. Additionally, primary amenorrhea by age 15 or more than 3 years post-thelarche is noteworthy. These variations in menstrual cycle patterns between adults and adolescents should be taken into account when diagnosing PCOS, ensuring a more accurate and appropriate assessment.

Ovarian Morphology

The classic description of Polycystic Ovarian Morphology (PCOM) included the appearance of an increased number of follicles ranging from 2 to 9 mm in size, arranged in a peripheral distribution around a bright echo-dense stroma. The 2003 Rotterdam criteria recommended PCOM to be defined as either 12 or more follicles measuring 2–9 mm in diameter or an ovarian volume of more than 10 cm3 for either ovary. Several other markers of PCOM have been previously described. The latest guidelines defines PCOM as either more than or equal to 20 follicles per ovary and/or an ovarian volume of 10 cm3 on either ovary, using transvaginal ultrasound twith a transducer frequency of 8 MHZ or more. As previously mentioned in other guidelines, the transvaginal approach remains the most accurate modality for the diagnosis of PCOM. If transvaginal ultrasound is not possible, transabdominal ultrasound may be utilized but due to the difficulty of assessing follicle counts throughout the ovary with this approach, a different cut-off points was utilized: ovarian volume (OV) with a threshold of more than or equal to 10 mL or follicle number per section (FNPS) more than or equal to 10 in either ovary in adults.

The Anti-Müllerian Hormone 

Anti-Müllerian Hormone (AMH), is a polypeptide secreted by granulosa cells of the ovarian follicles. Studies have shown that this hormone is significantly elevated in women with PCOS as compared to those without the condition. This finding led to a consensus that AMH can serve as a surrogate for ovarian morphology and potentially replace sonographic findings. However, it is important to emphasize that levels of AMH should be taken within the context of a comprehensive diagnostic algorithm. AMH alone cannot diagnose PCOS; rather, it should always be used in conjunction with other clinical and biochemical criteria. In cases where hyperandrogenism and irregular menstruation/anovulation are already present, the measurement of AMH level is not necessary for the diagnosis. 

Summary of the Diagnostic Criteria for PCOS 

Beyond PCOS

The updated 2023 International Evidence-Based Guideline for PCOS assessment and management takes a comprehensive approach by not only focusing on PCOS diagnosis but also addressing associated medical conditions. Research has shown that women with PCOS face an elevated risk of developing various health issues, including cardiovascular disease, impaired glucose tolerance/type 2 diabetes, obstructive sleep apnea, endometrial hyperplasia and cancer, mental health concerns, psychosexual dysfunction, body image distortion, and eating disorders.

By integrating the assessment of these conditions into the guideline, healthcare professionals can effectively identify and address these risks in a timely manner. This comprehensive approach leads to improved overall health outcomes and quality of life for women with PCOS, ensuring a more holistic and patient-centered approach to their care.

Cardiovascular Disease Risk

Women with PCOS are at an increased risk of cardiovascular disease, including potential cardiovascular mortality. It is recommended that all women with PCOS, regardless of age and BMI, should have a baseline lipid profile at the time of diagnosis. Additionally, monitoring blood pressure annually is crucial due to the elevated risk of developing hypertension in this population. 

Impaired Glucose Tolerance and Diabetes Mellitus Type 2 

PCOS increases the risk of impaired glucose metabolism and type 2 diabetes regardless of age and BMI. It’s recommended to assess glycemic status at diagnosis and periodically thereafter (every 1-3 years) based on individual risk factors. While a 75g oral glucose tolerance test (OGTT) is recommended for PCOS patients, fasting plasma glucose and/or HbA1c can also be utilized, though with perhaps slightly less sensitivity in detecting dysglycemia. 

For women with PCOS, especially those planning pregnancy or fertility treatment, undergoing an OGTT is important if they don’t have pre-existing diabetes. If this test is not done preconception, it is advisable to consider it during the first prenatal visit and if normal, to repeat the test at 24-28 weeks age of gestation. 

Obstructive Sleep Apnea 

The association between obstructive sleep apnea (OSA) and PCOS is significant, irrespective of BMI. Women with PCOS should be evaluated for potential symptoms of OSA, including snoring, daytime sleepiness, or unexplained fatigue. If these symptoms are present, screening with validated tools or referral to a specialist for assessment, is recommended. Utilizing simple obstructive sleep apnea screening questionnaires, such as the Berlin questionnaire (which is validated in the general population), can aid in identifying OSA in women with PCOS. It’s important to note that a formal sleep study is required for a definitive diagnosis of obstructive sleep apnea. 

Endometrial Hyperplasia and Cancer 

While routine screening for endometrial hyperplasia and endometrial cancer in premenopausal women with PCOS is not recommended due to its low probability, it is important to make women with PCOS aware of this risk. Addressing other risk factors such as untreated amenorrhea, overweight/obesity, type 2 diabetes, and a persistently thickened endometrium is crucial. Providing information about preventive strategies including weight management, cycle regulation, and regular progestogen therapy can help mitigate the increased risks effectively. 

Mental Health Issues

The emotional and psychological aspects of PCOS should be given serious consideration. Research has demonstrated a notable occurrence of moderate to severe depressive symptoms and outright depression among adult and adolescent individuals with PCOS. Screening patients with validated tools is essential to identify those at risk for depression, allowing for timely referrals or treatments. It is important to have conversations with women affected by PCOS to understand their symptom perception, concerns, priorities and ultimately the impact of PCOS on their quality of life. The severity of symptoms and potential diagnoses of depression or anxiety can then guide the management approach for better outcomes.

Psychosexual Dysfunction, Body Image Distortion and Eating Disorders

Polycystic ovary syndrome can have a profound impact on various aspects of a person’s well-being. Factors such as weight gain, acne, hirsutism/alopecia, mood disorders, infertility, and medication effects can contribute to psychosexual issues, body image concerns, and even eating disorders. It is crucial for healthcare professionals to have open discussions with their patients, and to provide them with the necessary support and corresponding management. This can significantly improve the overall quality of life for of individuals dealing with PCOS.

Conclusion

At present, Polycystic Ovary Syndrome is still diagnosed based on clinical evaluation. Using the modified Rotterdam criteria, it is recommended that PCOS be diagnosed if at least two of the following are present: clinical or biochemical hyperandrogenism, evidence of oligo-anovulation, polycystic appearing-ovarian morphology on ultrasonography (or an elevated anti-Mullerian Hormone as a surrogate) with exclusion of other relevant disorders. 

As clinicians, it is important not to a short-sighted view of PCOS. Instead, we should consistently strive for a comprehensive approach in both diagnosing and managing the condition, since women diagnosed with PCOS have been observed to have an increased susceptibility to developing cardiovascular, metabolic and pulmonary conditions, psychological or psychiatric disorders, cancer, and psychosexual dysfunction. In addition, educating the patient about her condition and enabling her to take an active involvement in her own management empowers her to take control of her overall health, leading to improved adherence to treatment and more favorable clinical outcomes. 

This way we can show that PCOS matters. Our patients matter.

References:

Christ, J.P.; Cedars, M.I. Current Guidelines for Diagnosing PCOS. Diagnostics 2023, 13, 1113. https://doi.org/10.3390/ diagnostics13061113 

Teede, H.J.; Tay, C.T.; Laven, J.J.; Dokras, A. et. Al., Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome, The Journal of Clinical Endocrinology & Metabolism, 2023;, dgad463, https://doi.org/10.1210/clinem/dgad463