PCOS: Possible Causes

We've been talking about PCOS (Polycystic Ovarian Syndrome), its definition and symptoms, how it presents, and its testing and diagnosis.

Today let's talk about the controversy over possible causes of PCOS.

Caveats

Determining the causes of things like PCOS can be incredibly complex.  Furthermore, as research develops, a better understanding of cause develops over time.  Therefore, insert many caveats to this information and remember that our understanding may change as further research is done.

What Causes PCOS?

Unfortunately, no one really understands why PCOS happens or what causes it.

Because of this, PCOS is a controversial diagnosis. Some doctors don't really believe it exists, some think it's merely a marker for Syndrome X ("metabolic syndrome") in females, some think it's all about hormones only, some think it's all about insulin resistance, some think it's caused by obesity, some think it causes obesity. 

Part of the problem is that PCOS is a syndrome and not a formal disease. One website clarifies the difference:

A syndrome refers to a group of symptoms, while a disease refers to an established condition.  A disease a condition that is marked by 3 basic factors. 

    1. An established biological cause behind the condition
    2. A defined group of symptoms
    3. Consistent change in anatomy due to the condition 

A syndrome does not have any of these features. Even the symptoms that are present are usually not consistent, and definitely not traceable to a single cause.

The reason behind most syndromes has still not been identified. For this reason, they are a type of medical mystery. In contrast, the reason or cause behind a disease can be identified very easily.

In other words, no one really knows why it happens or what causes it, and it presents with a wide variety of symptoms that make it difficult to classify.

Here's what we do know: In PCOS, an excess of androgens (male hormones) and  insulin resistance seem to be key parts of the syndrome. However, what causes this, which comes first, and which is more important is not clear.

Some researchers consider PCOS to be primarily a hormone imbalance disorder, and view insulin resistance as a side effect of the hormonal issues.

Other researchers consider insulin resistance (problems processing insulin) to be the real root of the issue, which then causes hormonal disturbances.

At this point, it's a bit of a chicken-or-the-egg question and no one has any definitive answers as to what causes PCOS.  All we have are educated guesses.

Hormones and Obesity and Insulin, Oh My

The most common suspects for a root cause of PCOS are hormones, obesity, and insulin resistance.  Each has arguments for and against it.

Hormonal Imbalance 

The prevailing view of PCOS suggests that it is primarily a hormonal disorder, and that an imbalance of hormones is the root cause of problems. Here is one common explanation, as given by one website:

A main underlying problem with PCOS is a hormonal imbalance. In women with PCOS, the ovaries make more androgens than normal. Androgens are male hormones that females also make. High levels of these hormones affect the development and release of eggs during ovulation...

The ovaries, where a woman’s eggs are produced, have tiny fluid-filled sacs called follicles or cysts. As the egg grows, the follicle builds up fluid. When the egg matures, the follicle breaks open, the egg is released, and the egg travels through the fallopian tube to the uterus (womb) for fertilization. This is called ovulation.

In women with PCOS, the ovary doesn't make all of the hormones it needs for an egg to fully mature. The follicles may start to grow and build up fluid but ovulation does not occur. Instead, some follicles may remain as cysts. For these reasons, ovulation does not occur and the hormone progesterone is not made. Without progesterone, a woman's menstrual cycle is irregular or absent. Plus, the ovaries make male hormones, which also prevent ovulation.

In this model, the immature follicles form cysts on the ovaries, and these cysts give off androgens ("male" hormones), and do not produce the progesterone that would normally be created if ovulation had occurred. The woman skips periods because she has not ovulated, and the endometrial lining builds up because it has not been shed and has been exposed to unopposed estrogen.

So the focus in this theory is on the ovaries, and the hormonal imbalances that cause ovarian cysts. However, the problem with this theory is that not all women with PCOS have cystic ovaries, yet clearly have symptoms of androgen excess. And some have cystic ovaries but no real signs of androgen excess.

Another model proposes that the basic problem is that the body does not produce or process androgens normally.

Women with polycystic ovarian syndrome (PCOS) have abnormalities in the metabolism of androgens and estrogen and in the control of androgen production...

...some evidence suggests that patients have a functional abnormality of cytochrome P450c17, the 17-hydroxylase, which is the rate-limiting enzyme in androgen biosynthesis.

Cytochrome P450c17 is active in the adrenals and ovaries, and excess activity of this enzyme could explain the increased androgen production from both sources in PCOS. 

Whatever the reason, the end result is that women with PCOS have too many androgens floating around, and that creates side effects in the body.

Women with PCOS also tend to be estrogen-dominant, meaning too much estrogen and not enough progesterone. This can make it difficult to sustain a pregnancy, even when one is achieved. For some women with PCOS, the key to maintaining a pregnancy seems to be treatment with supplemental progesterone before and during in the first trimester, although this treatment remains controversial to some.

The question is where the hormonal imbalance originates.  Some researchers theorize that PCOS originates with problems in the HPO (hypothalamic-pituitary-ovarian) axis.  This in turn affects many other glands (like the thyroid or the gonadotropic glands) and sets up a cascade of imbalances and negative effects.

If this is true, it means that many of the treatments we have today are simply "band-aid" approaches, addressing only the symptoms and not the real cause of issues.  But if a way to identify and treat HPO axis issues were to be found, perhaps PCOS could be prevented altogether.

Obesity 

Some doctors will tell you that "obesity" may cause PCOS, because fat stores produce extra estrogen and this in turn can alter other hormones.

However, it is more logical that perhaps the metabolic changes of PCOS cause the obesity instead.

In my opinion, this seems a much more likely explanation, especially since many women with PCOS report bouts of sudden, severe, unexplainable weight gains at various points in life, despite no changes in habits or intake.  And several studies report that the overall caloric intake of women with PCOS is similar to those without PCOS.  So there may be more to the story than the usual "eating too much" theory.

Because our society is so biased about "obesity" and weight issues, and because PCOS and obesity go hand in hand so often, it's very difficult to get researchers (and consumers) to view it objectively.  Many cannot disentangle their biases that obesity = gluttony long enough to consider the question of root causes of PCOS more objectively.

I certainly have heard from PCOS advocates who staunchly believe that their obesity is to blame for their PCOS status, and I've read materials from doctors theorizing that PCOS starts mostly in overweight teens because of their obesity which then triggers hyperandrogenism (in other words, there was a genetic predisposition there but it was the teens' overweight status that caused those genes to express, not the other way around).

However, this ignores the fact that average-sized women get PCOS too, and can have just as much androgen excess and insulin resistance as "obese" women with PCOS.  And not every fat woman has PCOS.

This view of obesity "causing" PCOS seems to be falling out of favor now, and most resources acknowledge that obesity does not cause PCOS, although it can exacerbate the symptoms.

The question is, does significant obesity amplify and worsen PCOS, or is significant obesity simply a symptom of a more severe manifestation of the syndrome?  Or do the two work synergistically in a negative feedback loop?

Insulin Resistance

It is clear that many women with PCOS have very strong insulin resistance (IR) issues, so it's been theorized that insulin resistance (and resulting hyperinsulinemia) causes both the tendency towards obesity, the hyperandrogenism, and the resulting PCOS symptoms. In other words, a problem with the insulin may be the root cause of everything else.

From http://www.fertilitycommunity.com/fertility/hyperinsulinemia-not-ovaries-at-core-of-pcos.html:

Polycystic ovary syndrome is in sore need of a new name, Dr. Barbara S. Apgar said at the annual meeting of the American Academy of Family Physicians.

Put aside the traditional notion that the primary defect in polycystic ovary syndrome (PCOS) involves the ovaries. Focus instead on hyperinsulinemia, which lies at the core of this common endocrinopathy, advised Dr. Apgar, a family physician at the University of Michigan, Ann Arbor.

Indeed, the finding of enlarged ovaries on palpation or polycystic ovaries on ultrasound in merely a sign of PCOS. Insulin abnormalities precede the elevated androgen levels that characterize PCOS. And switching off the ovaries via a GnRH agonist doesn't affect the hyperinsulinemia and insulin resistance, she noted...

In PCOS, hyperinsulinemia leads to hyperandrogenism, resulting in chronically elevated LH levels. The hair follicles are genetically sensitive to androgen stimulation, so acne and hirsutism are commonly part of the PCOS picture. Glucose intolerance, type 2 diabetes, and lipid abnormalities also are common. And 40%-60% of patients with PCOS are obese.

Treatment is not directed at the ovary. It's directed at the hair follicle level and also at the pancreatic level, where we see the insulin resistance, she explained.

Some doctors have hypothesized that perhaps women with PCOS have defective insulin receptors, so the body must overproduce insulin in order to get them to work properly.   Another theory is that, while insulin receptors are normal, there is a "post-binding defect in insulin signaling," as suggested here:

Insulin resistance in PCOS can be secondary to a postbinding defect in insulin receptor signaling pathways, and elevated insulin levels may have gonadotropin-augmenting effects on ovarian function.

Another theory put forth in the past was that perhaps women with PCOS produce insulin that is slightly defective in some way, so again the body would need to work harder and overproduce in order to help the insulin "unlock" the doors to the cells and get blood sugar into them.

Whatever the reason, it is thought that women with PCOS overproduce insulin, and all that excess insulin floating around the body then causes hormonal disturbances and imbalances, including the production of excess androgens. These excess androgens then interfere with ovulation, reproduction, and can cause hirsutism, acne, and other issues.

One argument against insulin resistance as a root cause in PCOS is that not all women with PCOS are documented as having IR.  Sources generally estimate that about 50-70% of women with PCOS have IR.  However, perhaps PCOS women without overt IR may simply have a more subtle presentation of it, one that is on the IR spectrum but does not quite reach "official" diagnostic levels.

Other Possible Causes

Some have suggested that PCOS may be an autoimmune condition.  However, it may simply be that autoimmune issues (like Hashimoto's hypothyroidism) are a side effect or coincidental co-morbidity of PCOS.  This is an area that deserves further research.

Research suggests that whatever the base cause, genetics plays a strong role in PCOS.

Because the symptoms of PCOS tend to run in families, the syndrome is probably caused, at least in part, by a change (or mutation) in one or more genes. However, because of the complex pattern of how PCOS symptoms change from one generation to the next, gene mutations are probably not the only cause of PCOS.

It is likely that PCOS results from a combination of factors, including genes and environmental features. Recent research conducted in animal models also suggests that, in some cases, the origins of PCOS may occur in the womb.

This idea that both genetic and environmental influences are needed for full expression of the syndrome is growing in acceptance, despite not knowing exactly which genes are involved:

Familial clustering of PCOS has been consistently reported suggesting that genetic factors play a role in the development of the syndrome although PCOS cases do not exhibit a clear pattern of Mendelian inheritance. It is now well established that PCOS represents a complex trait similar to type-2 diabetes and obesity, and that both inherited and environmental factors contribute to the PCOS pathogenesis.

Some researchers combine all the theories together, proposing that both genetics and environment play a role, and that the most severe cases of PCOS have both an insulin resistance source and an androgen production or metabolism problem.  From http://emedicine.medscape.com/article/256806-overview:

PCOS is, in some cases, a familial disorder, but the genetic basis of the syndrome remains unclear. Studies of family members with PCOS indicate that an autosomal dominant mode of inheritance, with premature male pattern baldness as the male phenotype, may occur. Full expression of the syndrome may require an insulin abnormality and a defect in androgen biosynthesis, but no gene (or genes) has been identified.

Conclusion 

What causes PCOS is a chicken-and-egg question at this point.  No one is sure what the underlying first cause is, and untangling that is a long and difficult process.

The two most likely candidates are a disturbance in androgen production/metabolism, or insulin resistance due to problems with insulin production, receptors, or signaling.

Another interesting possibility is an underlying disturbance in the HPO axis, which then creates the other disturbances commonly found with PCOS.

Familial clustering suggests a strong genetic component to PCOS, but some researchers believe that both genetic and environmental influences must combine for the full syndrome to express.  Other possibilities include autoimmune issues.

At this point, most of our treatments for PCOS are aimed at lessening the symptoms and hopefully mitigating future risk for complications.  In other words, they are "band-aid" approaches.

What we really need is to understand is the root cause of PCOS; only then can we begin to develop truly effective treatments.


References

*As always, trigger warning for many of these links and references.  Most contain lots of weight loss promotion or assumptions about the habits of people of size.

General Information on PCOS and Possible Causes

• http://emedicine.medscape.com/article/256806-overview - overview of PCOS, info on HPO axis issues, discussion of possible causes and treatments
• http://medical-dictionary.thefreedictionary.com/insulin+resistance - general information on insulin resistance
• http://www.nichd.nih.gov/publications/pubs/upload/PCOS_booklet.pdf - guide from the government with general information on PCOS, and some info on genetic links. Has a good explanation of the HPO axis and the hormonal cascade that results in ovulation
• http://humupd.oxfordjournals.org/content/11/4/357.full - a study, based on animal models, theorizing that excessive androgen exposure while in utero may pre-program the body to PCOS-like symptoms
• http://www.endocrine-abstracts.org/ea/0026/ea0026s28.1.htm - possible environmental influences on the development of PCOS
• http://jcem.endojournals.org/content/91/6/2100.full.pdf - Dutch twin study that found a strong genetic component in PCOS; "a polygenic multifactorial model involving multiple genes is most likely"

Articles on Insulin Resistance and PCOS

Am J Physiol Endocrinol Metab. 2001 Aug;281(2):E392-9. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E.  PMID: 11440917

Women with polycystic ovary syndrome (PCOS) are insulin resistant secondary to a postbinding defect in insulin signaling. Sequential euglycemic glucose clamp studies at 40 and 400 mU. m(-2). min(-1) insulin doses with serial skeletal muscle biopsies were performed in PCOS and age-, weight-, and ethnicity-matched control women...We conclude that there is a physiologically relevant defect in insulin receptor signaling in PCOS that is independent of obesity and type 2 diabetes mellitus.

Am J Physiol Endocrinol Metab. 2005 May;288(5):E1047-54.  Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, Dunaif A.  PMID: 15613682

Insulin resistance in polycystic ovary syndrome (PCOS) is due to a postbinding defect in signaling that persists in cultured skin fibroblasts and is associated with constitutive serine phosphorylation of the insulin receptor (IR). Cultured skeletal muscle from obese women with PCOS and age- and body mass index-matched control women (n = 10/group) was studied to determine whether signaling defects observed in this tissue in vivo were intrinsic or acquired...In summary, decreased insulin-stimulated glucose uptake in PCOS skeletal muscle in vivo is an acquired defect. Nevertheless, there are intrinsic abnormalities in glucose transport and insulin signaling in myotubes from affected women, including increased phosphorylation of IRS-1 Ser312, that may confer increased susceptibility to insulin resistance-inducing factors in the in vivo environment. These abnormalities differ from those reported in other insulin resistant states consistent with the hypothesis that PCOS is a genetically unique disorder conferring an increased risk for type 2 diabetes.

Diabet Med. 2011 Sep 26. doi: 10.1111/j.1464-5491.2011.03460.x. Current perspectives of insulin resistance and polycystic ovary syndrome. Pauli JM, Raja-Khan N, Wu X, Legro RS.  PMID: 21950959

"Insulin resistance likely plays a central pathogenic role in polycystic ovary syndrome and may explain the pleiotropic presentation and involvement of multiple organ systems. Insulin resistance in the skeletal muscle of women with polycystic ovary syndrome involves both intrinsic and acquired defects in insulin signalling. The cellular insulin resistance in polycystic ovary syndrome has been further shown to involve a novel post-binding defect in insulin signal transduction...Insulin resistance is linked to polycystic ovary syndrome. Further study of lifestyle and pharmacologic interventions that reduce insulin resistance, such as metformin, are needed to demonstrate that they are effective in reducing the risk of diabetes, endometrial abnormalities and cardiovascular disease events in women with polycystic ovary syndrome."