Metabolic Factors in PCOS
by Tim Hyatt, ND
One of the possible etiologies of polycystic ovary syndrome (PCOS) is metabolic dysregulation and thus it may be more appropriately called “metabolic reproductive syndrome”. This article will review some aspects of the current clinical and scientific understanding of PCOS and consider how metabolic factors affect the clinical picture of PCOS.
In an article titled Diagnoses, Syndromes, and Diseases: A Knowledge Representation Problem, Calvo et al describe a syndrome as follows, “a syndrome is a recognizable complex of symptoms and physical findings which indicate a specific condition for which a direct cause is not necessarily understood.” PCOS is a great example of a syndrome because there is a cluster of signs and symptoms, but the scientific and clinical communities have been unable to isolate a specific cause. Yet, this condition affects a great number of people, and many providers still don’t understand a highly effective approach to diagnosis and treatment.
Diagnostic Criteria of PCOS
The scientific and medical communities consider PCOS to be an ovarian disorder centered around reproductive manifestations. Diagnostic criteria have been established multiple times by the NIH in 1990, the Rotterdam Criteria in 2003, and the Androgen Excess Society in 2006. Each organization uses the clinical features of hyperandrogenism, oligo or amenorrhea, and the presence of polycystic ovaries, but there is no consensus on the combination of those clinical features used to establish this diagnosis.
Some of the barriers to agreement pertain to the observation of polycystic ovaries, which is influenced by the low availability of ultrasound equipment in medical offices, the lack of expertise in imaging techniques, and the lack of consensus for diagnosis and treatment within the scientific community.
Urine testing is not diagnostic for PCOS. However, high levels of androgen metabolites, including testosterone, 5a-DHT, 5a-androstenediol, and androsterone may be observed in patients with suspected PCOS. Elevated levels of alpha metabolites are the norm in patients who have previously been diagnosed with PCOS. Oligo or amenorrhea are easily observed by documenting the timing of cycles, and ultrasound of ovaries is recommended when hyperandrogenism and cycle abnormalities are found.
Manifestations of PCOS are metabolic dysregulation—including overweight and obesity, insulin resistance, increased lipids and elevated cardiovascular risks, diabetes, beta cell dysfunction, hair loss on the scalp, hirsutism, acne, nonalcoholic steatohepatitis and sleep apnea, mood disorders, and binge eating.
Incidence and Prevalence of PCOS
PCOS affects 5-13% of women of reproductive age, depending on the diagnostic criteria used. Obesity or overweight affects 38-88% of women with PCOS, and insulin resistance (IR) is also common among patients with PCOS, with a prevalence of 35%-80%. Other conditions associated with an increased prevalence of PCOS include oligo ovulatory infertility, types I, II, and/or gestational diabetes, premature adrenarche, a heritable component in first-degree relatives with PCOS, and the use of valproic acid.
The etiology of PCOS is unknown, and there are many factors that have a strong association with its prevalence in the US and around the world. Theories about its etiology and pathogenesis include:
- Alteration in gonadotropin secretion
- Ovarian and adrenal dysfunction leading to hyperandrogenism
- Hyperinsulinemia, disordered insulin action, and obesity
- Genetic predisposition
HPO Axis and Insulin Resistance
When evaluating the possible etiologies of PCOS, two sets of characteristics emerge as interdependent processes. The first set is the hypothalamic pituitary ovarian axis (HPO), and the second is the hyperandrogenism combined with disordered insulin response.
In the HPO axis, ovarian output is entirely dependent on gonadotropin signaling. Once signaling is initiated and the ovaries respond to the onset of menarche, the gonadotropins and ovaries operate as a single unit. This continues unless disrupted by pathological changes or exogenous influences until the onset of menopause. If the gonadotropin signaling is inadequate, development of the follicle and corpus luteum is altered. This ongoing cycle dysregulation involves elevated androgens and abnormal insulin response.
Women with PCOS frequently have insulin resistance and impaired insulin response, hyperandrogenism, HPO dysfunction, and ovarian cysts. Hyperandrogenism and insulin dysregulation are processes linked together in a self-perpetuating cycle. As each of them rise, the positive and negative feedback loops of the gonadotropins and the ovaries are impaired, and the menstrual cycle is disrupted because insulin causes theca cells and granulosa cells to generate and release androgens.
The ovaries seem to have the biggest influence in hyperandrogenism and PCOS, but androgen production is often increased in the adrenal gland due to genetic predisposition, disrupted signaling, and hyperinsulinemia. The altered signaling and hyperinsulinemia tend to increase hyperandrogenism unless treatments are used to disrupt the process.
In a small study, Arroyo et al showed that thin and obese patients diagnosed with PCOS had abnormal postprandial and fasting insulin response when compared with controls. Many women with PCOS have fasting and or meal-challenged hyperinsulinemia. Consequently, increased levels of insulin results in low circulating levels of sex hormone-binding globulin SHBG) and higher free testosterone levels. Some have suggested that low circulating SHBG levels may be a good marker for women with PCOS because elevated androgens can also suppress SHBG.
Kursad et al noted that, “not all signaling pathways and insulin-responsive tissues are equally affected, and some effects other than the metabolic actions of insulin are overexpressed. Ovaries and the adrenal glands are two examples of tissues remaining sensitive to insulin actions where insulin may contribute to increased androgen.”
Insulin resistance and hyperinsulinemia were also found to affect endometrial physiology as well as the ovaries. Lee et al found that the function of insulin receptors, insulin receptor substrate proteins, and glucose transporters are dysregulated in the endometrium of women with PCOS.
Another factor to consider is that hepatic insulin resistance (insulin resistance in liver cells resulting in impaired glycogen synthesis) fails to suppress glucose production, enhances lipogenesis, and increases the synthesis of proteins such as CRP. This is only seen in obese women with PCOS when compared to “healthy” women of equivalent body weight. Obesity and PCOS have a compounding negative effect on endogenous glucose production, which may play a role in the etiology of glucose intolerance.
In addition to androgen production in the ovaries, the adrenal glands produce roughly half of the androgens in the body; therefore, DHEA and androsterone will be increased in patients with adrenal PCOS. There appears to be a genetic component to adrenal PCOS and Khasar-Miller showed that familial clustering of elevated DHEA-S levels in PCOS families in both female and male relatives mark a heritable component to this trait.
Other factors to consider are genetics, basal metabolic rate (BMR), and premature adrenarche (PA). For patients who are insulin-resistant with PCOS, their BMR is around 1,116 calories compared to the average BMR of 1,868 calories in women without PCOS. This may be the most important factor for the lack of success in weight reduction, insulin resistance, and androgen output for patients with PCOS.
Premature adrenarche is associated with hyperinsulinemia and childhood overweight. In girls with premature adrenarche, anti-mullerian hormone (AMH) was elevated when compared with healthy controls with no history of PA. Additionally, this study found that maternal history of PCOS was related to even higher levels of AMH, often correlated with higher risk for PCOS.
PCOS is an incredibly complex syndrome with many clinical factors that are interconnected. Researchers are hard at work trying to find pharmacologic therapies that are helpful for symptom management, but from a functional standpoint, providers must look at this condition and identify factors they can modify to help patients move forward in their quest to be healthy. Arguably, the metabolic features of PCOS are tightly linked to reproductive processes and function, and clinical interventions should be directed toward those features for effective treatment.
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