A syndrome is not an infection, nor a specific illness, but a combination of pathologic signs or symptoms that appear in the aggregate in a single individual. Polycystic ovarian syndrome (PCOS), when it is diagnosed (and frequently it is not), usually becomes apparent at the onset of puberty in young women. Anatomically, it consists of small cysts on the tiny follicles that release egg cells at ovulation. The condition is hard to diagnose in part because the cysts are usually too small to be displayed by conventional imaging techniques, although they can sometimes be observed with transvaginal ultrasound.
The syndrome includes several menstrual characteristics that manifest more or less, depending upon the individual, such as amenorrhea (no periods whatsoever); irregular timing of periods; irregular flow during menstruation; or abnormally heavy menstrual flow. Some but not all affected individuals have hirsutism (excessive body hair)—for example, visible mustache hair that the doctor never notices because they bleach it; hair on their arms that they shave; hairy abdomen or breasts; and so on. They frequently, but not always, have a chunky, boxerlike, masculine build, but I’ve also seen some whose shapes are classically feminine.
Not a tremendous amount is known about the etiology or origins of PCOS. It is often a disorder of elevated levels of male sex hormones, which can cause insulin resistance in women. Usually this is caused somehow by excess serum insulin levels secondary to insulin resistance. So these people, if they’re nondiabetic, may have high serum insulin levels, which bring about the high levels of male sex hormones. The precise mechanism for this is murky. Many but certainly not all of these people become diabetic, probably by the same mechanism of beta cell burnout that we see in type 2 diabetes. Most but not all of these women have difficulty losing weight. For example, I have a teenage patient who is about five and a half feet tall and came to me weighing 160 pounds. She’s currently under treatment for PCOS. The best I’ve been able to do so far is get her weight down to about 150, but she’s eating only 7 ounces of protein and 24 grams of carbohydrate per day. Her weight seems to have leveled off, and although we’ve instituted other measures (which we will discuss), I don’t know whether she’ll be able to get any more weight off without severe caloric deprivation.
A serious consequence of this condition is infertility, which affects many but not all people with this syndrome. I have one patient who had children but had to have a total hysterectomy—and it was only then that her PCOS was discovered on microscopic examination of her ovaries.
As with many syndromes, there is no single test to determine if one has PCOS, unless it can be seen on transvaginal ultrasound. The diagnosis is made either on a discovery such as the one mentioned in the preceding paragraph, or on clinical grounds, based upon a combination of signs and symptoms. One of these, as noted, is insulin resistance. But how does one diagnose insulin resistance?
One way is to experimentally determine how much 1 unit of a rapid-acting insulin will lower a person’s blood sugar, assuming that the person is on a stable blood sugar control regimen and the blood sugars are not going to be dropping or increasing. For a 140-pound insulin-using type 1 diabetic, 1 unit of regular insulin would lower blood sugar about 40 mg/dl. So if you have a person of this weight and 1 unit of regular insulin lowers her blood sugar by only 20 mg/dl, that’s a good indicator of insulin resistance. If the person already has abdominal obesity or generalized increase in body fat, you don’t know how much of that insulin resistance is caused by the body fat and how much may be caused by the syndrome. So ultimately the diagnosis still depends upon inference from a combination of signs and symptoms.
Another way of diagnosing the syndrome is to observe the influence of the insulin-sensitizing agent Glucophage on insulin requirements and upon menses of these patients. If someone who has no periods finally starts to have periods when she’s put on metformin, there’s a good likelihood of a positive diagnosis. There are also some laboratory tests that can be performed to identify hormonal disturbances. The following abnormal blood tests can be costly but in combination are highly suggestive of this disorder: LH (luteinizing hormone) at least three times as high as FSH (follicle-stimulating hormone); 17-alpha-hydroxy progesterone, estronel, free estradiol, IGF-1 (insulin-like growth factor 1), and androstenodione. Perhaps the two most important hormonal indicators would be a low ratio of DHEA sulfate to free testosterone and low IGF-1 binding protein.
This condition does not necessarily lead to poor blood sugar control. One of my PCOS patients is a lovely young lady who has essentially normal blood sugars but cannot lose weight. She’s distressed by that circumstance and also distressed by her failure to ovulate and have periods, which means that unless we can improve things she will not be able to have children.
There are treatments for this condition. For many years, a diuretic called spironolactone was given for female hirsutism. It was quite effective and is still being used for this element of the syndrome. When using this medication, serum potassium levels should be checked regularly, as they might increase unduly. A number of years ago, I was treating a diabetic patient who had been trying to become pregnant for at least five years. She was not obese, but she did have slightly hairy arms and some dark hair in the mustache area. Although she had quite normal blood sugars, I noticed that she had to inject considerably more insulin than I would have anticipated for someone of her weight. I therefore decided to try her on the insulin-sensitizing agent metformin (Glucophage), which lowers insulin resistance in the liver. In a few months, she had become pregnant—after years of unsuccessful visits to infertility specialists. Furthermore, her insulin requirements dropped considerably.
Several years after I made this observation, the first papers on the use of metformin to treat this particular syndrome were published. Because these women—in my practice, mostly teenagers—are so distressed by their weight problems, and because of my anticipation of their infertility, I have tried them on every medication that lowers insulin resistance that I can think of. When I learn of a blood test that will focus on a substance that causes insulin resistance, such as tumor necrosis factor alpha (TNF-alpha), I test these patients, and indeed, I have seen very high levels of this substance in some—but again, not all—of them. When I find TNF-alpha elevated, I may prescribe several substances that have been shown to lower the blood levels or to reduce its action. Some TNF-alpha inhibitors that came up on an Internet search include the NSAID sulindac; EGCG, the main constituent of green tea; 1,25 dihydroxy vitamin D-3 (calcitriol), which is sold only by prescription and whose dosage must be carefully regulated to prevent hypercalcemia; quercetin, a widely marketed dietary supplement (most often made from the skins of onions and garlic); circumin; and Trental (pentoxifylline). This last medication has been used for many years, with only limited success, for intermittent claudication, a condition caused by poor circulation in the legs. I save Trental as something of a last resort, because it must be taken at the end of a meal, and if a person mistakenly takes it on an empty stomach, it can cause considerable gastric distress.
I refer likely PCOS patients to specialized physicians called reproductive endocrinologists for confirmation of my diagnosis and for prescription of sex hormone replacement therapy (birth control pills). I continue to address their blood sugar problems myself.
When treating PCOS, I usually begin with metformin, starting with timing to cover that time of day when basal insulin doses are greatest. For example, I may use the timed-release Glucophage XR at bedtime to help lower bedtime doses of Levemir insulin. I may also try Actos, an insulin-sensitizing agent that reduces the insulin resistance of fat and muscle cells.
Next I might add a medication called ramipril, which has also been shown to lower insulin resistance. Ramipril is used commonly to treat hypertension and diabetic kidney disease. It is an ACE inhibitor but differs from other such medications in that it affects more tissues. It can, however, cause a dry cough in some users that resolves when it is discontinued.
I also may use some of the supplements recommended in Chapter 15 for the amelioration of insulin resistance.
For several years I have been following the development of a medication that has been shown to ameliorate some of the consequences of PCOS. Its chemical name is d-chiro inositol. It has been shown to lower blood levels in women of the male sex hormone testosterone—both in the free and protein-bound forms. According to a study of PCOS patients published in the April 29, 1999, issue of the New England Journal of Medicine, its use increased the rate of ovulation from 27 percent in those taking a placebo to 86 percent in those taking the drug. As with other agents that lower insulin resistance, it lowered serum cholesterol and triglyceride levels as well as blood pressure. It also lowered serum DHEA sulfate, a precursor of male sex hormones. An appropriate dose would be 1,200 mg daily.
Since my patients suffering from PCOS are very distressed by their inability to lose weight, even after we have gotten them to ovulate, I searched the Internet for sources of d-chiro inositol. I found the product already being sold in the United States and manufactured in New Zealand. It is distributed through several retailers by Humanetics Corporation of Eden Prairie, Minnesota, under the brand name Inzitol. They can be found on the Web at www.humaneticsingredients.com. Internet sources for a version product called d-Pinitol 600 include www.rockwellnutrition.com and www.drhoffman.com.
I suspect that the problem of PCOS is more common than most physicians realize, simply because usually it can only be diagnosed inferentially.