The Roadmap for PCOS: From diagnosis to Root Cause Treatment

Polycystic Ovarian Syndrome is a delicate interplay between metabolic and endocrine factors that can be appropriately addressed once the condition has been identified. A diagnosis of polycystic ovarian syndrome (PCOS) is often the most challenging and yet the most important step toward addressing underlying causes and developing meaningful treatment plans for women struggling with symptoms of irregular periods, infertility, and hyperandrogenism.  Because symptoms vary widely, women with PCOS may present very differently from one another. This lack of uniformity makes obtaining an accurate diagnosis one of the greatest challenges. In the largest international study, one-third of women reported searching for answers for more than two years and consulting over three practitioners before receiving a diagnosis.¹  Such delays not only increase patient frustration but also postpone appropriate treatment. The rising prevalence of PCOS over the past three decades is thought to reflect both improved awareness and refinement of diagnostic criteria.²–⁴  With an estimated 10–13% of reproductive-age women affected, understanding the diagnostic criteria is essential for any practitioner who treats women.⁵

Establishing the Diagnosis

The gold standard for diagnosing PCOS was established in 2003, known as the Rotterdam criteria.  However, the criteria was updated to the  2023 International Evidence-Based Guideline, which was developed by the National Health and Medical Research Council, the European Society for Endocrinology, the American Society for Reproductive Medicine, the European Society for Human Reproduction and Embryology, and The Endocrine Society.⁶ It’s important to remember that this criteria has an underlying assumption that other endocrine disorders have been ruled out, such as hyperprolactinemia and thyroid dysfunction.⁷

For adults, 2 out of the 3 criteria must be met:

1. Polycystic ovarian morphology confirmed using ultrasound OR elevated anti-mullerian hormone (AMH) confirmed via blood test (new as of 2023)
2. Dysfunction with ovulation, such as amenorrhea or oligomenorrhea
3. Clinical and/or biochemical hyperandrogenism (hirsutism, acne, androgenic alopecia, elevated testosterone or DHEA)

In adolescence, ovarian ultrasounds or blood draws to measure AMH are not recommended. Ovulatory dysfunction and hyperandrogenism are the only criteria that should be assessed, as AMH is unreliable for that age group and ultrasound may be too invasive and not appropriate.  

It’s important to think critically about how this would play out when evaluating a patient.  A patient with PCOS could present with regular cycles, but have signs of hyperandrogenism and a remarkable ultrasound.  Another patient could present with only abnormal labs of elevated testosterone and irregular cycles, with no obvious physical symptoms.  Confirming the PCOS diagnosis now presents the patterns at play that are causing the imbalance.  Research shows after a formal diagnosis, patients’ clinical outcomes improve with targeted treatment.

Understanding the drivers in PCOS

Hormone dysfunction

Central pathogenesis of PCOS is dysfunction of the hypothalamic-pituitary-ovarian axis where signaling to the ovaries increases androgen production by the theca cells.  The primary defect starts with gonadotropin-releasing hormone, which then impacts LH (lutenizing hormone) and FSH (follicular stimulating hormone) signaling.  LH increases and FSH  decreases, leading to underdeveloped ovarian follicles and anovulation, as well as excess androgen production.  This imbalance then cascades to a decrease in progesterone, which then impairs the feedback on gonadotropin-releasing hormone, creating a vicious cycle where hormones become increasingly out of balance.

Goals of treatment are to support normal follicle development, address hyperandrogenism, promote healthy progesterone levels, and regulate adrenal function.⁸

Insulin resistance

Insulin has a strong role in the dysfunction of hormones in PCOS.  Hyperinsulinemia exacerbates other hormone dysfunction by stimulating ovarian and adrenal androgen production by disrupting LH and FSH.  It reduces hepatic synthesis of sex hormone–binding globulin (SHBG) and leads to an increase in free testosterone levels.⁹

While excess adipose tissue and obesity amplify insulin resistance, it’s important to note that insulin resistance can occur in lean women as well.¹⁰  Independent of obesity, insulin resistance has been identified as a core metabolic defect in PCOS and should be addressed and monitored in every patient.¹¹ Additionally, insulin resistance associated with PCOS can put the patient at risk for other conditions like cardiovascular disease, hypertension, and type II diabetes, which should be closely monitored. 

The bidirectional interplay between hyperandrogenism and insulin resistance creates a self-perpetuating cycle, which will continue to feed the metabolic and reproductive manifestations.¹² Addressing insulin resistance with lifestyle medicine and other established therapies is a crucial aspect of the treatment plan for any patient with PCOS.

Body Composition

While not linked as a direct cause of PCOS, excess adiposity and obesity have been linked to an increase in the severity and complexity of the syndrome as well as the overall risk of developing PCOS.¹³ All patients should use dietary and lifestyle modification to help support balance with PCOS; however, those patients who are overweight or obese will strongly benefit from even a modest improvement of their symptoms.  One study suggested weight loss of even as little as 5-10% would improve symptoms of ovulatory function, hyperandrogenism, and metabolic risk.¹⁴ Improving and maintaining healthy body composition will help patients manage symptoms and associated comorbidities.

Oxidative Stress

An underappreciated aspect of PCOS is the existence of impaired antioxidant defenses and excess reactive oxidative species, both which have been observed to impact follicular development, oocyte quality, ovulatory dysfunction, as well as fertility and menstrual cycles.¹⁵ Independent of obesity, patients with PCOS were found to have elevated oxidative stress markers and reduced capacity for oxidative stress, which in turn could also exacerbate insulin resistance and increase risk for metabolic syndrome and type 2 diabetes.  Oxidative stress fuels the same dysfunctional cycles of endocrine and metabolism.  Beyond this innate imbalance in oxidative stress, it has been found that environmental factors, including heavy metals, may be associated with other PCOS manifestations.¹⁶ Targeting oxidative stress should be a component of treatment for any patient with PCOS.

There are so many therapeutic opportunities to address the underlying causes of PCOS, which is why it is so critical for patients to have a clear diagnosis.  It’s important to approach treatment by addressing all the underlying mechanisms to help patients see meaningful results.

Resources

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