PCOS and Insulin Resistance: Part 3 What Causes PCOS?
In a previous post, I stated that PCOS is deemed a diagnosis by exclusion, and that the causes are unknown. It seems from my research that PCOS (Polycystic Ovary Syndrome) would best be defined as a complex, and poorly understood, reproductive and metabolic condition, which may have “…genetic, metabolic, fetal, and environmental factors…” all playing an intricate role in its etiology . In later blogs I will discuss the diagnosis and treatment of PCOS, including the complimentary approaches which I deem appropriate.
Instead of focusing on the “causes” of PCOS, let’s rather look at all these delicate and interactive factors, individually.
PCOS runs in families and certain genes have been linked to PCOS. There is a fair body of research, but all data I have read, emphasizes the need for more studies.
PCOS is an “…ancient evolutionary trait” with ethnic variations. We now know that it is a “…complex polygenic disease…”, in other words, it has a more complex inheritance pattern than the simple one-gene, autosomal dominant mode of inheritance that was earlier suggested. The challenges of genetic research are in part due to its heterogeneity, i.e. women present with diverse characteristics, as well as the various challenges of making a diagnosis (which I hope to discuss later), as well as very small sample sizes to date.
The evidence for a genetic component was identified in twin studies where it has been suggested that PCOS is “…not the result of a single autosomal genetic defect, but that environmental factors, perhaps both intrauterine and extrauterine, are involved in the pathogenesis of this disorder…”. What these studies did seem to show is that “…fasting insulin level, … and BMI did appear to be significantly influenced by genetics”. Other studies have observed “…familial clustering of PCOS, with sisters more likely to be affected with signs and symptoms of the disorder, and first-degree relatives having higher rates of metabolic abnormalities including insulin resistance, … dyslipidemia, and MetS (Metabolic Syndrome). … which suggests that it is a genetic trait… Male relatives of women with PCOS had increased prevalence rates of MetS and obesity compared to the general US male population… Some studies have also suggested increased rates of CVD (Cardiovascular Disease) events in parents of women with PCOS.” What most of these studies are eluding to is that the “…genetic susceptibility (is not just reserved) to PCOS (but also to)… its associated insulin resistance”, in other words, Insulin Resistance, is most likely a genetic trait that can be passed down, making individuals susceptible to Metabolic Syndrome given the “right” (or rather wrong) environment .
Knowing what we already know about PCOS, and how insulin and insulin resistance play a role in this condition, it is almost impossible to separate the metabolic from the reproductive actions of insulin. As such, here I will discuss both the Metabolic as well as the Reproductive factors associated with PCOS. There is much confidence in the evidence that women with PCOS, as well as their direct relatives, show a higher incidence of Metabolic Syndrome relative to the general population. Metabolic Syndrome expresses itself, among other things, as signs and symptoms of Obesity, increased waist:hip ratio, Hypertension, disrupted glucose metabolism and Insulin Resistance, Dyslipidemia and CVD as illustrated in the figure below (Figure 1).
Figure 1: Prevalence of different elements of metabolic syndrome in women with PCOS
In one of the discussions Dr. Jason Fung and I had on PCOS and Insulin Resistance, he sent me a one of many article, and about it, he said, and I quote, “What I like is the figure on pathophysiology - it shows very clearly how hyperinsulinemia is at the very centre of all the problems of PCOS.” As such, the figure below (Figure 2) illustrates how Hyperinsulinemia is associated with the Metabolic and Reproductive aspects of PCOS in a very interesting “feedback loop” mechanism, or a vicious cycle. If I were to translate this image into words, I would say that it shows the connection between adipose (fat) tissue, insulin, reproductive hormones and ovulation.
Figure 2: Pathophysiology of PCOS—a vicious circle. Several theories have been proposed to explain the pathogenesis of PCOS. One of these is that neuroendocrine defects lead to increased pulse frequency and amplitude of LH and relatively low FSH. This causes intrinsic defects in ovarian androgen production. Also, there may be an alteration in cortisol metabolism and excessive adrenal androgen production. Insulin resistance with compensatory hyperinsulinemia further increases ovarian androgen production both directly and indirectly via the inhibition of hepatic SHBG production. Obesity, insulin resistance, and high circulating androgens
As I mentioned a few times before, there is general consensus that women with PCOS have higher degrees of insulin resistance independent of obesity in relation to the general population. “Women with PCOS are at increased risk for the spectrum of disorders associated with insulin resistance, including metabolic syndrome, endothelial dysfunction, nonalcoholic fatty liver disease, gestational diabetes, and pregnancy-induced hypertension”, just to name a few.
What we now know is that insulin is involved in hormone production, and ovulation. Androgen (male hormone) excess is one of the hallmark signs in the diagnosis of PCOS. I shall discuss this in a later post. We can also see from this illustration (Figure 2) that hyperandrogenemia (androgen excess) is both impacted by, as well as it impacts, insulin resistance, which in turn has a direct and indirect effect on ovulation. It actually goes further than that. It shows that androgen excess also has a direct impact on adipose (fat) tissue, further increasing insulin resistance and hyperinsulinemia which further exacerbates hyperandrogenemia…and the cycle goes on and on.
As said above “Hyperandrogenemia is the biochemical hallmark of PCOS”. According to the same source, 80-90% of women with disrupted menstruation show elevated androgen levels. Polycystic ovaries, one of the other hallmark signs for the diagnosis of PCOS, produce Theca Cells. “Theca cells from PCO secrete more androgens…” and the vicious cycle continues…
“PCOS is the most common cause of normogonadotropic anovulation, accounting for 55–91% of the entire World Health Organization-II (WHO-II) cohort”. Making PCOS, and Insulin Resistance, always relevant in the discussion of infertility. Even still, this same source notes that glucose tolerance and insulin resistance was not systemically investigated in PCOS and infertility until very recently.
Also important to note here, is that “…regular menstrual cycles do not exclude chronic anovulation, especially in women with clinical signs of androgen excess. Twenty to 50% of women with clinical hyperandrogenism and apparent eumenorrhea may have anovulation .... Therefore, ovulation should be assessed...”. In other words, even if menstrual cycles appear to be normal, in 20-50% of these cases, women may not be ovulating.
“…There is incomplete understanding of the process of normal ovulation, it varies over lifetime, and it is often difficult to measure objectively... as many as 85% of women with PCOS have clinical evidence of menstrual irregularities.”
“Reducing insulin resistance can … restore ovulatory menstrual cycles.” This is the clincher! Even if we don’t fully understand ovulation, in a later blog, I will attempt to show, in much more detail, how medications, such as metformin, and/or lifestyle modifications such as a low carb diet and Intermittent Fasting can, very successfully, restore ovulation by lowering insulin resistance.
Obesity is a factor that should really be addressed independently of all the other metabolic factors. I have stated that not all obese women have PCOS and not all PCOS women are obese. I am an example of this. Having said that… 80% of women with PCOS, in the United States, are Obese.
“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to MetS”. Obese women with PCOS have been shown to have larger subcutaneous adipocytes (fat cells), and “higher free androgen levels”, this cause-effect relationship with insulin resistance was well-illustrated in the figure above (Figure 2). “It is now well accepted that obesity is associated with chronic low-grade inflammation, which may contribute to insulin resistance … high-sensitivity C-reactive protein, and IL, which suggest the presence of inflammation, have been reported in PCOS.”
“Massive weight loss in obese women with PCOS… has been shown to improve multiple reproductive and metabolic abnormalities in the syndrome”, it “…reduces circulating androgens and increases SHBG levels, reduces ovarian volume and follicle count, improves insulin sensitivity, reduces hyperinsulinemia, and improves menstrual cyclicity and fertility”.
As such, obesity is an important factor, if not one of the most important ones, and it should be highlighted. There will always be debate on “whether obesity per se can cause PCOS” as these two are so intricately connected and associated. It is almost certain that “…obesity may play a key role in promoting the development of PCOS in susceptible individuals”, susceptible either by genetics, environment or both. The obesity epidemic will likely further increase the metabolic and reproductive concerns of future generations. Having said all this, and putting the right amount of emphasis on the management of obesity in women with PCOS, lean women with PCOS must not be ignored, ovulation may still be affected and insulin resistance addressed.
Some studies have suggested that “…early exposure to androgens … may be a risk factor for developing PCOS … increased risk of developing metabolic syndrome (MetS) … and PCOS-like symptoms”. At least experimentally, it has been shown that excess fetal Testosterone in-utero may induce “…PCOS-like reproductive and metabolic traits in female mammals…”. If this is correct, and I believe that it is, it seems logical then that children, male and female, born to women with PCOS would have a higher incidence of Metabolic Syndrome, making the management of PCOS before pregnancy that much more important…TO BE CONTINUED… (as a mother, I know this to be important…no woman wants to, knowingly, pass on dangerous traits to her children.)
This is a very broad topic and clearly there isn’t nearly enough evidence, research or studies to fill this paragraph. When we talk about environmental factors, we could be talking about anything.
Diet, for one. To date, “Food intake has not been assessed in women with PCOS.” I could fill in the blanks here… but clearly this is an important factor when addressing Insulin Resistance, and any expression of it (like PCOS), and I will attempt to do so in a later blog.
Exercise (nowadays you can't talk about diet without mentioning exercise, it’s the old – and by old, I mean outdated - calorie-in, calorie-out theory), “…exercise alone is inadequate to improve symptoms relating to PCOS phenotype”, as such lack of exercise may also not explain anything about PCOS.
Chemicals or “Environmental agents can act as endocrine (hormonal) disrupters”. To date, it has been found that BPA (bisphenol-A) “an estrogen-mimicking compound, may contribute to the pathogenesis of PCOS”. Further interesting is the positive correlation between BPA and insulin resistance. At this point, many of us have heard a lot about BPA, so I won’t go into detail about it now, but if you don’t know what BPA is, you can always read more on what the Mayo clinic has to say about it, here.
There are other important factors associated with PCOS that I did not address here, but hope to be able to address at a later time. Among these factors, Cancer, and Psychosocial issues such as depression, anxiety and bipolar disorders, are at the top of my list.
In my next blog, I will talk about the Diagnosis of PCOS, and later, a more practical look at the Treatments of PCOS. Stay tuned!