Polycystic Ovarian Syndrome (PCOS)

In 1935 Drs. Stein and Levinthal described a syndrome in which women suffered irregular, usually rare, periods, hirsutism (hair growth), and experienced varying degrees of infertility. Today we call it Polycystic Ovarian Syndrome(PCOS).

It's most general description is a syndrome in which there is too much male-type (androgen) hormone produced by the ovaries (and sometimes the adrenal glands) with associated disruption of the normal hormonal cycle. It's exact cause is unknown, but it seems to be hereditary. Almost one of twenty women of reproductive age have it, and it is one of the most common causes of infertility.

The most simplistic thinking about it in the past was the concept of ovulation failure: certain areas of the ovarian capsule, for some reason, had trouble releasing an egg; with this, the rest of the cycle got hung up with precursor hormones, like testosterone, building up. Ovarian wedge resection, a surgical procedure in which a portion of the ovarian capsule was cut out, was the standard treatment until the invention of birth control pills which overrode the entire hormonal cycle and with it, any abnormalities. Today, the entire cycle is overridden with birth control pills until a woman is ready for pregnancy. At that point, ovulation induction is carried out. Wedge resection is an outdated surgical treatment, but even now there are some researchers who are doing "ovarian drilling" via laparoscope to achieve the same results (resumption of ovulation). The jury is still out on this "surgery is the thing/surgery is not the thing/surgery might be the thing again" controversy. But even though laparoscopy is a low risk procedure with quick recovery, and even if it proves to improve ovulation, it won't do anything to help the effects of androgen excess.

Today treatment is based on whether pregnancy is sought or not: if so, induce ovulation with drugs like Clomid; if not, suppress the entire cycle artificially with birth control pills. More on this later.

But the plot thickens...

In 1980 research showed a connection between a weakening of the effects of insulin and too much testosterone in women with polycystic ovarian syndrome. So a modern understanding of PCOS has only come about in the last generation, with recent advances demonstrating other problems besides alterations in the menstrual cycle and ovulation. For one thing, there's a certain tendency toward diabetes with this insulin phenomenon, called "insulin resistance." It's not that there's too little insulin, but that the body isn't as sensitive to the insulin that's made.  Therefore, handling sugar is impaired. The body responds by having the pancreas make even more insulin, and the extra insulin tends to stimulate other tissues that normally aren't particularly responsive to insulin. One of the tissues is the ovary, which is stimulated to make extra androgen (testosterone).

The "bound up" testosterone is fairly unreactive. It's the free (unbound) testosterone that has the classical male hormone-like effects, like hair growth, acne, deepening of the voice, and disruption of the normal ovulation and cycling. In the ovary, instead of a dominant follicle on its way to firing off an egg at mid-cycle, there accumulates instead a collection of early follicles that don't go any further. (An ovary in such a state is, however, "loaded" such that there is an exaggerated response to induction of ovulation with a greater risk of twins and triplets from multiple simultaneous ovulations, should ovulation induction be used to treat PCOS--be careful what you wish for....)

The "full-blown typical" PCOS patient has a history of only occasional ovulations <6 per year) and prolonged cycles of greater than 35 days, male-like hair distribution or hair loss, obesity, multiple ovarian cysts, acne, and laboratory assessment demonstrating too much testosterone--and of course the absence of any other conditions which might cause the same signs and symptoms (like thyroid disease, adrenal disease, or too much prolactin). But there are varying degrees of PCOS, and many women with it have only few or isolated aspects of the disorder. On ultrasound, the ovary may have only a few small cysts, or it may be so loaded with follicles and cysts such that it resembles a honeycomb.  In fact, 20% of PCOS patients don't have multiple cysts; and to add to the confusion, 20% of normally ovulating women have small cysts present. In my practice, I've seen PCOS with only the testosterone elevations, mild elevations of testosterone with severely multicystic ovaries, or borderline ovarian involvement with significant elevations in testosterone. Sometimes the diagnostics can be so mild as to doubt the diagnosis.

And diagnostically, that can be a real problem!

So much so that organized medicine has yet to announce an official definition of PCOS.  
Enter the one test that is the standard for the diagnosis--the glucose/insulin ratio. Here's the logic--for so much sugar that's in your bloodstream, say, from that donut you just ate, there's a response from your pancreas to churn out insulin, which in turn does its job of driving sugar out of your blood stream and into your cells so that they can be acted upon chemically in all kinds of complex biochemical reactions that would bore even Mr. Data on Star Trek to death. The glucose/insulin ration, then, is the fraction of numbers that says for a certain value of glucose (sugar) in the blood, there's a certain value of insulin there to handle it. There are better tests, but these invlove torturous techniques involving multiple blood samples, IVs, dripping powerful chemicals into you, and other reasons that make the glucose/insulin plenty good enough.

Although insulin resistance is independent of weight, still being overweight can make it worse. Most patients with PCOS are advised to lose weight, but this is at best good advice, not a well-justified prescription. Insulin resistance may not even be a disease in some people, because age, weight, and ethnic origin have characteristic effects that are considered normal for such groups. Therefore, although insulin resistance is the standard of diagnosis for PCOS, not all people with insulin resistance have PCOS--take that one particular group called the pregnant! A drug used to treat insulin resistance, Metformin (an insulin "sensitizer"), doesn't always help PCOS...why?

Besides being a diagnostic marker to point out PCOS, the glucose/insulin ratio can also be useful in measuring the success of different treaments (Metformin, as mentioned above, weight loss, and other treatments). An improvement in the ration over time can help document improvement. Also, let's not forget the problem of diabetes, the Type II variety being just that--insulin resisitance. Whether PCOS or not, all insulin resistant folks have to be watched.

So...what's normal?

An abnormal glucose/insulin ration is about 4.5 to 1 or less (<4.5), and even lower in Hispanics. This means that when fasting, if your insulin level is over one fifth of what your your glucose level is, then that's way too much insulin for the amount of sugar, the fraction gets bottom-heavy, and that value's going to plunge.

(Example:  glucose/insulin = 100/20 = 5--normal; glucose/insulin = 100/40 = 2.5 --abnomral, indicating insulin resistance.) There are other tests used, some of them involving insulin drips, IVs, and so on, but this simple one-stick blood test seems the best tolerated in a private practice of needle-haters.

Other things besides PCOS can cause an increase in testosterone. Since this hormone is also produced in the adrenal gland, disorders (including cancer) of the adrenal need to be considered and/or ruled out.

So you have insulin resistance...so what? Really, what's the big deal?

Besides causing the ovary to make elevated amounts of testosterone, insulin, which normally behaves itself and respects other tissues, can bang up blood vessels, the liver, and cause damage by yet-to-be discovered assaults. For instance, other effects on other tissues include:

  • stimulation of the lining of blood vessels, causing hypertension;
  • effects on the liver and on cholesterol metabolism, contributing further to heart disease;
  • and a decrease in sex hormone-binding globulin (SHBG), which means less sex hormone is bound ("tied up," or stored within a bulky molecule) and therefore free to act. This is the way testosterone effects rise.

Therefore, care of a patient with PCOS includes testing for diabetes (fasting blood sugar, HbA1c), abnormal lipids (cholesterol, triglycerides, etc.), and keeping track of the amount of insulin resistance (with a glucose-to-insulin ratio).

Treatment goals are:

  • Reduce hair-growth problems and acne;
  • Manipulating the cycles hormonally to re-establish regular menstrual periods. (Too long stuck in the first part of the cycle can lead to overstimulation of the uterus by estrogen, possibly leading to uterine cancer.)
  • Re-establishing fertility by re-establishing ovulation (if pregnancy is desired).

These goals seem to ignore the main dangers, such as heart disease and cholesterol problems.  But the effects on other tissues is a study in its infancy, and the goals listed above are in fact a concern, especially to a young woman of child-bearing age.  As time goes by, we'll have a better understanding of PCOS and even a hierarchy of emphasis on things to worry about.

Treatment strategies include:

  • Birth control pills, to counteract the masculinizing effects of elevated testosterone and to hijack the functioning of the ovary so as to decrease testosterone production.
  • Insulin "sensitizers," like metformin, which some doctors think should be offered to all PCOS patients.
  • Anti-testosterone agents, such as spironolactone, which is actually a diuretic ("fluid pill"); such a drug competes with testosterone at the sites where testosterone acts on tissue. But this drug may mess up potassium and have other side effects, like other diuretics.

The regular gynecologist, fixated as he or she is on baby-making or baby-preventing, usually puts the emphasis on tailoring a treatment based on child-bearing plans: The Fork in the Road

If a woman with PCOS isn't seeking pregnancy, birth control pills will effectively create artificial cycles that will prevent irregular bleeding, prevent a tendency to uterine cancer, and decrease the amount of testosterone produced by the ovaries.  It can be assisted by metformin or other insulin "sensitizers."

If a woman seeks pregnancy, then ovulation inducers like Clomid (clomiphene) can be used.  Some infertility doctors also give the insulin-sensitizing agents (which can "resensitize" the insulin, another way to describe a lowering of insulin-resistance).

PCOS is not quite the disorder Drs. Stein and Levinthal thought it was in 1935. There seems to be a lot more to it than that, as the current wave of discovery which began in 1980 indicates. But they were a crucial beginning in helping women when they recognized the link between certain symptoms and an abnormal medical condition unique to women. The importance of this beginning is only now being appreciated inasmuch as we're beginning to see PCOS as it relates to heart disease, infertility, and diabetes.  We may be seeking the light at the end of the tunnel, but Drs. Stein and Levinthal found the right spot and dug that tunnel.

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