What We Know – And Don’t Know – About PCOS
70% of women affected by PCOS remain undiagnosed worldwide.
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Polycystic ovary syndrome (PCOS) is the most common hormonal disorder in women of reproductive age. Despite affecting 8–13% of women, its diagnosis can prove challenging and typically requires a visit to 1 or more physicians over the course of at least 1 year. As a result, up to 70% of women remain undiagnosed worldwide according to the World Health Organization (WHO).
PCOS can cause unpleasant symptoms and is associated with morbidities such as fertility issues, metabolic syndromes and impaired glucose tolerance. Here, we explore what researchers know – and don’t know – about PCOS and fertility.
What is PCOS and how is it diagnosed?
PCOS is a condition that can be characterized by elevated levels of male sex hormones, called androgens, and/or the formation of small fluid-filled sacs (cysts) on one or both ovaries, which is where the name of the disorder originates from. Understanding the cause of PCOS and diagnosing it is complex; some women develop cysts (morphological symptoms), while others present with symptoms that are biochemical in origin.
The hormone imbalances present in women with PCOS affect ovulation, the process where the ovaries release an egg into the uterus. Infrequent or absent ovulation can manifest as irregular menstrual cycles or a complete lack of menstruation for some women. Individuals with PCOS are also at an increased risk of developing other health conditions, including but not limited to type 2 diabetes mellitus, high cholesterol, endometrial cancer and heart disease.
The process of diagnosing PCOS is one of exclusion, where all other potential causes for the following symptoms must be ruled out:
- Symptoms of high androgen levels – including the growth of unwanted facial or bodily hair, acne or elevated blood testosterone levels
- Menstrual periods that are irregular or absent
- Polycystic ovaries detected on an ultrasound scan
Current guidelines require that a diagnosis of PCOS must be based on the presence of at least two of the above criteria.
Is there a known cause of PCOS?
PCOS is an example of a multifactorial disease, which means it can be caused by a variety of factors that may or may not influence each other. Research has demonstrated that genetic and environmental factors can contribute to a person developing PCOS, but an exact cause for the condition is not yet known.
Insulin resistance and PCOS
Insulin resistance affects 50%–70% of women with PCOS, which has led to a body of research exploring whether insulin resistance might even be the root cause of the condition.1
Insulin is produced when blood glucose levels rise and helps our cells take in glucose so that it can be stored for energy. Insulin resistance occurs when the body does not respond to insulin efficiently. Over time, this means that a greater amount of insulin is required for our cells to take up the same amount of glucose. Excess insulin levels – or hyperinsulinemia – can drive excessive androgen production.2 Increased insulin levels can also contribute to other metabolic complications that are associated with PCOS. The issue is that not every woman with PCOS also has insulin resistance, so while there might be a connection, a causal relationship has not been established.
Genetic and epigenetic influences in PCOS
PCOS can run in families and has an estimated heritability of 70%, but how PCOS might be inherited is not well understood.3 Twin-, family- and population-based studies have identified genetic variants – some of which are implicated in the pathways of androgen biosynthesis – as being associated with the disorder. However, functional genomics studies that can explain the significance of identified genetic variants are currently lacking.4
Genetic research has also indicated that there might be several subtypes of PCOS, adding further complexity to the disorder’s pathophysiology. Dapas et al. analyzed the genes of ~900 women suffering from irregular menstrual periods.5 The women were categorized based on their body mass index (BMI), levels of glucose, insulin and reproductive hormones. The genetic analyses revealed two apparent subtypes of PCOS: a “reproductive group” and a “metabolic group”, with each subtype being associated with a specific group of gene variants.
In the reproductive group, ~23% of women had higher levels of luteinizing hormone (LH) and sex hormone binding globulin (SHBG), in addition to a lower BMI and insulin levels. Approximately 37% of the metabolic group had lower levels of SHBG and LH, a higher BMI and higher glucose and insulin levels. “Our study provides support for the hypothesis that PCOS is in fact a heterogeneous disorder with different underlying biological mechanisms,” the authors said. “As a consequence, grouping women with PCOS under a single diagnosis may be counterproductive because distinct disease subtypes will likely benefit from different interventions.”
Attention has also turned to the potential contribution of epigenetics, which regulates gene activity without causing changes to the underlying DNA sequence, in PCOS pathophysiology. In mice, excess prenatal exposure to anti-Müllerian hormone (AMH) leads to PCOS symptoms in the mother’s offspring. A 2021 study by Mimouni et al. suggests that such epigenetic mechanisms might ensure certain traits in affected mice are transmitted to future generations.6 Whether this transgenerational inheritance could occur in humans is not yet known.
PCOS and fertility – what’s the latest?
Research to date suggests that the complexity and heterogenic nature of PCOS rule out a likely single cause. A cure for the condition therefore does not exist, though pharmacological interventions – such as the contraceptive pill – and lifestyle changes can help to regulate the menstrual cycle and address other symptoms.
A major concern for couples affected by PCOS is fertility; an estimated ~90–95% of anovulatory women seeking infertility treatment have the condition.7 “One of the main symptoms of PCOS is anovulation, which means that women will ovulate irregularly or not at all. That can make it challenging to fall pregnant naturally,” Dr. Katrina Moss, a research fellow in the School of Public Health at the University of Queensland, explained.
Challenging, but not impossible; many people with PCOS do conceive naturally. For those who do not, there are several fertility treatment options available, which are typically prescribed in a stepped manner.
Though care guidelines differ across the world, oral drugs that are ovulation-inducing (OIs) are often the first-line treatment for anovulatory fertility in women that do not have other infertility factors.8 “Patients doing OI will take medication to encourage egg development and their specialist will monitor how many follicles are developing. Once the biggest follicle reaches the desired size, patients will have a trigger injection to mature the egg and release it from the follicle. The patient will have timed intercourse or insemination to complete the process,” Moss said.
Injectable gonadotropins, which also stimulate ovulation, have been used as a traditional next line of treatment. 8 Women might then choose to explore options including intrauterine insemination (IUI) and/or in vitro fertilization (IVF).
Moss recently explored the birth rates and outcomes of women with and without PCOS using data from the Australian Longitudinal Study on Women’s Health.9 “The Australian Longitudinal Study on Women’s Health has been collecting data from a dedicated sample of women since 1996, so it gives us a unique opportunity to understand the whole story when it comes to fertility treatment,” she explained.
The study analyzed the outcomes of women with PCOS using fertility treatments according to the clinical practice guidelines adopted in Australia. These guidelines recommend a treatment plan of OI, followed by IUI and IVF. “We studied 1109 women who were using fertility treatments and found no difference in births between the women with and without PCOS or between those on different treatment paths,” Moss said. The study also found that non-invasive treatments such as OI are effective for women with PCOS; fewer women with PCOS progressed to IVF after OI compared to those without the condition.
“OI is less invasive than IVF because everything happens in the patient’s body. It’s also more affordable because there is less medical intervention required. For people with PCOS where their only barrier to falling pregnant is that they are not ovulating, OI may be all they need,” said Moss. It’s important to note that age might be a key factor for success, as the study found more women with PCOS were likely to start fertility treatments earlier (age 31) than those without (age 34).
“However, if the partner also has fertility challenges, IUI or intracytoplasmic sperm injection might be needed. And patients with conditions such as endometriosis may be better off going straight to IVF as that treatment is more suited to their condition. The priority should be to get patients into the most suitable treatment for them as quickly as possible,” Moss added.
The study carries limitations in that it is retrospective and that the findings might not translate to other parts of the world beyond Australia. However, Moss hopes that the team’s findings are a source of comfort: “We think that women with PCOS can stress a bit less about fertility treatment. Most won’t have fertility problems and if they do it is highly treatable. Many women with PCOS start thinking about their fertility early, which is key factor in their high birth rates,” she said.
The landscape of PCOS research and funding
There are many unknowns surrounding PCOS, which presents challenges for patients, clinicians and researchers alike. Adequate funding for research is a critical factor in getting answers.
Brakta et al. estimated the National Institutes of Health (NIH) funding allocations for PCOS over a 10-year period (2006-2015).10 The study compared PCOS research funding to grants awarded for three disorders with similar degrees of morbidity and prevalence: rheumatoid arthritis (RA), tuberculosis (TB) and systemic lupus erythematosus (SLE). “PCOS, compared with RA, TB, and SLE, was relatively less funded (total mean 10-year funding was $215.12 million vs $454.39 million, $773.77 million and $609.52 million, respectively),” the authors concluded.
When discussing why PCOS research might be underfunded, Brakta et al. highlight the fact that generally, diseases of women are underfunded – though efforts are being made to address this. Additionally, the fact that PCOS is a metabolic disorder, which also carries reproductive consequences, might complicate the distribution of funding resources from different institutes; to which research area should funding be appropriately allocated?
A recent analysis of global trends in PCOS research suggests that the condition’s pathogenesis has become a “long-term forefront of research”. In more recent years, additional attention has been paid to health management in PCOS prevention and the potential long-term complications of the condition.
With growing evidence highlighting the condition’s impact on quality of life and wellbeing, PCOS research and drug development is clearly an area of unmet need. While existing treatments can provide symptom management and address fertility issues, mechanism-based treatments are sorely needed.
Dr. Katrina Moss was speaking to Molly Campbell, Senior Science Writer for Technology Networks.
About the interviewee
Dr. Katrina Moss is a postdoctoral research fellow at the Australian Women and Girls’ Health Research (AWaGHR) Centre at the University of Queensland. Here, her research interests lie in reproductive health and assisted reproductive technology, maternal predictors of child health and development, the consequences of injury and trauma and the developmental origins of health and disease.
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