Causes of Polycystic Ovary Syndrome (PCOS): Key Factors

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in young women caused by a variety of overlapping factors that affect reproductive health and increase risk for aspects of cardiometabolic disease and general health across the life course. Other contributors to PCOS include genetic predisposition, degree of insulin resistance, androgen levels, low-grade inflammation, weight and body fat distribution, sleep and stress, and in-utero exposures that may predispose to development of PCOS. As clinicians, it is essential that we consider these factors in both diagnosis and treatment of PCOS and in the design of systems of care that are patient-centered and accessible to all women and girls with PCOS and their families.

Why It Matters

Polycystic ovary syndrome (PCOS) is more than just irregular periods or difficulty getting pregnant. It is a medical condition that can follow a woman into old age with ongoing connections between her reproductive symptoms and her metabolic risks. Women with PCOS have high levels of androgens (male hormones) that can cause problems with ovulation (release of an egg from the ovary). Androgen excess leads to symptoms like acne, hirsutism (excessive hair growth), and irregular menstrual cycles. Many women with PCOS are also at risk for insulin resistance, which can progress to prediabetes and even to diabetes type 2, as well as for dyslipidemia (abnormal amounts of lipids: cholesterol or triglycerides) and hypertension. The healthcare provider should be aware of these potential risks to her patient before puberty and continue to monitor her patient’s risk factors for these complications well into middle age.

PCOS Sticks in the past by treating PCOS in silos, when a comprehensive understanding of Gynecology, Endocrinology, Primary Care, Dermatology, Mental Health and Nutrtion are all required at the same time. PCOS challenges both the health care providers and their patients in terms of delays in diagnosis and treatment of related symptoms. Due to the inconsistencies in health screening of women with PCOS who are at risk for metabolic syndromes, patients and their health providers often face many barriers due to financial constraints and a lack of specialists to address weight management, mental health, and fertility care.

Beyond reproductive and metabolic features of PCOS, consideration of mental health and quality of life is critical. Anxiety and/or depression, body image concerns, sleep problems and feelings of stigma associated with PCOS symptoms such as acne, hirsutism or weight gain can add insult to injury. By addressing mood, sleep and stress, clinicians can help improve adherence to healthy lifestyle interventions, enhance quality of life and have a secondary benefit on reproductive and metabolic outcomes.

When treating a woman with hyperandrogenism and polycystic ovary syndrome (PCOS), consideration must be given to safety issues and potential trade-offs. For example, combined oral contraceptives may control bleeding and suppress androgen excess manifestations such as hirsutism or acne, but do not treat insulin resistance. In contrast, the insulin-sensitizing agents improve glucose and weight, but potential hazards to both mother and infant have been noted and thus must be given appropriate consideration. Ovulation induction agents can be very effective in increasing the chances of conception, but require close monitoring for the potential risk of multiple gestations as well as adequate ovarian response. Treatment choices need to be based on patients’ immediate reproductive goals and upon long-term goals and risks and should be reviewed periodically.

Why these factors matter for clinical decisions. It is useful at times to be reminded of the underlying reasons for PCOS, particularly when deciding management of individual patients at individual times. The genetics and family history clustering of PCOS is separate from the environmental and behavioural factors that determine whether an individual woman develops symptoms of PCOS. The point at which reproductive and metabolic features of PCOS intersect is insulin resistance, the key feature behind ovarian androgen excess in women with PCOS. While other factors such as low-grade inflammation and sleep disturbances can increase the severity of insulin resistance, psychosocial stress increases cortisol levels and poor health behaviours. Patient’s degree of insulin sensitivity, weight change, stress levels and sleep, as well as reproductive goals all need to be considered when planning care for women with PCOS.

Who It Affects

PCOS affects all women of reproductive age with ovaries. It can manifest differently across generations: in the young girl and adolescent with ovarian function, atypical pubertal development (and subsequently first menstrual bleeding) or early onset of severe acne that does not fit the typical pattern of puberty for age may be the first sign of PCOS. In contrast, adult women with PCOS may think of PCOS primarily as a cause of difficulties with subfertility, weight concerns or hirsutism. Importantly, women with PCOS must be aware that the risk for development of the metabolic syndromes is particularly increased during the transition to perimenopause. Recognition of the risks, and appropriate evaluation and management, are therefore important for women with PCOS.

The phenotypic expression of PCOS can vary between women and may be characterized by a range of reproductive and metabolic features. While many women with PCOS have been found to have high levels of central adiposity and insulin resistance, an increasing number of women are identified to have the ‘lean PCOS’ phenotype characterized by androgen excess and ovulation disturbance. Given this variability, diagnosis and management must be on an individual basis. In order to develop an appropriate management plan for a woman with PCOS, both reproductive and metabolic features of the syndrome need to be characterized, in addition to the woman’s personal preferences and goals. This information can be garnered from a reproductive history, assessment for hyperandrogenism and an evaluation of the main metabolic risk factors.

PCOS is not just a patient’s disease; it also affects families, communities, the health system and payers. Family members of women with PCOS need to learn how to support their loved ones in adopting healthy lifestyle habits that are sustainable over time. The health system and insurers need to determine how to cover services such as nutrition counseling, mental health care and state of the art weight management. Employers and policymakers need to understand the potential long-term impact of PCOS on worker productivity, absenteeism and healthcare costs. The impact of PCOS on these issues will depend on the time of diagnosis and how the disease is managed.

Achieving health equity is important. Health equity is about health and health care access, affordability, and cultural relevance. Many people in underserved populations do not have access to specialists, nutrition services or mental health and emotional wellness services. Cultural and societal messages about menstruation, fertility, and body image also affect when and how women and girls seek health care. ASHA aims to reduce health disparities by promoting accessible telehealth, community-based prevention and health promotion programs and services, and culturally competent counseling for women and girls.

What Changes

Diagnosis and early recognition

In evaluating a patient with PCOS, the clinician should consider the possibility of PCOS in any patient presenting with menstrual irregularity, hyperandrogenism (clinical or biochemical), or unexplained weight gain. A complete medical history (including both menstrual and symptom history), along with a physical examination to evaluate for signs of androgen excess (such as acne, hirsutism, male-pattern hair distribution, deep voice), will help to establish a diagnosis of PCOS and to rule out other disorders that may mimic PCOS, such as hypothyroidism, hyperprolactinemia and nonclassical congenital adrenal hyperplasia.

Many clinicians rely on established criteria for PCOS which include evidence of ovulatory dysfunction, hyperandrogenism (either clinical or biochemical), and ovarian hyperandrogenism (defined by ultrasound criteria). However, ultrasound findings can be unreliable in the adolescent. Early diagnosis of PCOS allows the clinician to counsel the patient about her lifestyle, future family planning options, and methods to reduce her risk of future cardiovascular disease. Furthermore, understanding the basic mechanisms that underlie PCOS will allow the clinician can assess for insulin resistance, a condition that affects a large number of women with PCOS and links the metabolic findings to ovarian dysfunction and androgen excess. In some women, their tissues do not respond adequately to insulin, resulting in elevated pancreatic production of this hormone. Increased levels of insulin can stimulate the production of androgens by the theca cells of the ovary.

In addition, insulin can decrease the levels of sex hormone binding globulin (SHBG) made by the liver, further increasing the levels of free androgens. Improving insulin resistance through diet and exercise, ensuring adequate sleep, and the use of medications such as metformin can help establish a regular menstrual cycle and improve metabolic health. While the genetic component to PCOS has long been recognized (PCOS can occur in a clustering of females within a family), current research seeks to better understand how genes and environment interact to produce the syndrome. Susceptibility to PCOS can manifest clinically to varying degrees depending upon diet, exercise, endocrine exposures and early life factors. Inflammatory exposures whether acute or chronic can significantly affect insulin sensitivity and ovarian function.

Women with PCOS often have elevated markers of low-grade inflammation and elevated metabolic risk scores, which predict future vascular complications. The criteria of weight status has been often used as a criterion for the diagnosis of PCOS; however, PCOS is clearly seen in women of varying weight. Furthermore, the distribution of body fat to the central sites often worsens insulin resistance and androgen excess; however, the majority of women with PCOS are actually lean. Therefore, each individual case must be evaluated uniquely and not generalised based on weight status alone. Stress and sleep problems can worsen hormonal and metabolic imbalances. Stress hormones, poor or inadequate sleep and sleep apnea can worsen insulin resistance and affect appetite regulation and mood. All of these factors can affect adherence to treatment. An integrated and individualised care Management plan is developed to address the person’s primary goals whether these be related to fertility, control of symptoms, reduction of metabolic risk, or emotional well-being. For those prioritising fertility, topics such as cycle tracking, ovulation induction and preconception counselling will be of importance.

For others focussed on symptom control, topics such as combined oral contraceptives, skin-directed therapies and anti-androgens with appropriate contraception will take precedence. Your metabolic goals can be reached by supporting the lifestyle, education and encouragement for healthy nutrition choices and increased activity, as well as support for adequate sleep and medication if necessary. This office screens for metabolic syndrome and its related risks. Initial screenings could include a fasting glucose (or oral glucose tolerance test if indicated by risk factors) and lipid profile, as well as blood pressure measurement, weight and waist circumference. In addition, we can screen for risk of sleep apnea and symptoms of anxiety and/or depression. Follow-up visits are crucial in re-evaluating as risk factors, symptoms and goals change.

Understanding all treatment options and their benefits and risks as well as their potential side effects. Lifestyle. Every woman benefits from healthy eating, muscle building exercise, and aerobic activity. While very thin women may not appear to benefit from these lifestyle interventions, even small amounts of weight loss can result in regular menstrual cycles and improved insulin sensitivity in overweight and obese women. A healthy diet is important for weight and glycemic control. A sustainable, culturally appropriate, and balanced diet that is high in fiber with lean protein and healthy fat is optimal for healthy weight regulation. Sleep and stress hygiene is also important for the regulation of appetite and metabolic signals to help maintain optimal weight.

When choosing hormonal therapies, it is important to individualize based on patient preferences and medical history to best control bleeding and androgen symptoms. Once bleeding and androgen symptoms are well-controlled, combined oral contraceptives can be used to improve acne and hirsutism over time. Additional improvement of hirsutism and acne can be achieved with anti-androgens (i.e., spironolactone). These medications must be used with reliable contraception due to fetal risk. Creating metabolic improvement is not required for ovulation induction and treatment, but in some individuals it will help increase ovulation and fertility, and in overweight women improve their cardiometabolic risk factors and decrease weight. A list of Insulinsensitizers has been compiled. Most of these medications, as well as many medications used for weight, are not indicated for use in pregnant women; therefore it is important to counsel patients clearly on the concept of pregnancyplanning, and for medications with a pregnancy contraindication, to stop or pause these medications before conception.

For the woman who desires children, fertility care begins with ovulation induction using first-line, evidence-based medications. For some women, ovulation induction medications with ovulation monitoring can help reduce the risk of multiple gestations while allowing for dose adjustment as indicated. Assisted reproductive techniques such as IUI and IVF must be considered for women for whom lifestyle and cycle tracking are not sufficient and family planning goals have not resulted in a pregnancy. System-level and access improvements to treatment of infertility. Comprehensive coverage of nutrition counseling services as well as behavioral health treatment for anxiety and other mental health conditions and/or evidence-based weight management programs. Equitable benefit designs to ensure early access to an appropriate multidisciplinary team of providers. Training and decision support tools for frontline clinicians to reduce delays and variability in diagnosis and treatment. Providing primary care teams with simple algorithms to quickly identify, assess and refer to appropriate specialists for children can result in shorter time to diagnosis and treatment.

Delivering care through a combination of telemedicine and community-based programs can reach underserved populations and provide busy families with easier access to care. Virtual nutrition visits and group coaching or other health education, and mobile apps for cycle tracking, activity/sleep tracking, and mood tracking are just a few examples of how health education and maintenance of care can continue throughout the year. Real-world challenges and considerations There are many real-world considerations that patients, their families and their healthcare providers consider when making therapeutic decisions. While providers may drive the choice of certain therapies, many treatment decisions are ultimately determined by patient preferences and factors such as available resources. A woman planning for pregnancy might choose to avoid any medications that require females to use contraception, while a woman interested in weight loss may choose to pursue costly weight loss options that her insurance does not cover.

There is a significant gap in access to quality mental health care and dermatology services. Future Care can be personalized with phenotype as a guide to selecting therapy, with adjustment for goals along the way. Future treatment could be refined by genetic and metabolic profiling. However, we are already seeing innovative solutions in Digital health, Shared-care models and Integrated clinics for improved coordination of care. Removing barriers to the implementation of evidence-based practice that incorporates nutrition, mental health and weight management will require policy changes. So what do providers and payers want to know? Start early, screen broadly and readjust your treatment goals at almost every visit.

Screen for risk for metabolic and mental health conditions, and match treatment goals to what’s most important at that moment in time. For example, start with a thorough history and targeted exam, then screen for metabolic risks. Use shared decision making to weigh the benefits, harms and costs of different treatments for reproductive symptoms in the context of a woman’s plans for pregnancy and her values.

Develop local connections to nutrition, mental health, dermatology and/or fertility care OR integrate these into your practice via telehealth.

Track meaningful outcomes: cycle regularity, symptoms, metabolic, mood and quality of life.

References:

https://www.nichd.nih.gov/health/topics/pcos/conditioninfo/causes https://pmc.ncbi.nlm.nih.gov/articles/PMC9964744/