NEWS FROM REPRODUCTIVE PARTNERS

Polycystic Ovary Syndrome (PCOS):
An Update
by I. Lane Wong, M.D.

Chances are if you have irregular periods, you have heard of the term "Polycystic Ovary Syndrome (PCOS)."

The goals of this article are to define PCOS, describe how it causes infertility, and outline its treatment. PCOS is truly a syndrome because its specific cause is not well understood, known or agreed upon. In contrast to a specific disease, a syndrome is a group of symptoms and signs that are recognized to be associated with each other but without a common specific cause.

The most common symptoms and signs grouped with PCOS are irregular menses, infertility, hirsutism (excess hair growth), obesity, enlarged ovaries with numerous 2-8 mm cysts, elevated androgen (male-type) hormone levels, elevated luteinizing hormone to follicle stimulating hormone (LH/FSH) ratio, and hyperinsulinemia.

The most popular definition of PCOS in this country is hyperandrogenism + chronic oligo or anovulation (HA+COA) with the exclusion of known causes of HA+COA. Hyperandrogenism (HA) refers to a relative excess of androgens. Clinically, hyperandrogenism can show up as acne and hirsutism. Hormonally, hyperandrogenism manifests as elevated levels of androgens (testosterone, androstenedione, dehydroepiandrosterone sulfate [DHEAS]), and sometimes an elevated LH/FSH ratio. Chronic oligo or anovulation (COA) refers to irregular or absent ovulation over an extended time (usually many years). This will usually cause infertility.

The known causes of HA+COA that are usually ruled out by history, exam, or lab tests are prolactin disorders, thyroid disease, and sometimes an entity called late onset adrenal hyperplasia. (Late onset adrenal hyperplasia is screened for by checking a 17-hydroxyprogesterone blood level. It is much more prevalent in women of certain ethnic backgrounds [e.g. Eastern European Jewish] than others and needs to be checked in only certain cases.)

Another cause of HA+COA is hyperinsulinemia. Hyperinsulinemia refers to the state in which the body produces excess amounts of insulin. Insulin acts to lower glucose levels. If glucose levels are maintained within normal ranges, the person simply has hyperinsulinemia. If however, despite elevated insulin levels, the glucose levels are abnormally high, the person is frankly diabetic (Type II diabetes). 

In addition to HA+COA, hyperinsulinemia is often associated with central obesity (apple shaped as opposed to pear shaped adipose distribution), brown patchy areas of skin (acanthosis nigricans), and risk for hypertension and elevated cholesterol. In simplified terms, the relationship of hyperinsulinemia to PCOS, is that high insulin levels drive the ovaries to make excess androgens, which in turn cause anovulation. Even though one can argue that hyperinsulinemia is a known cause of HA+COA, and therefore by definition excluded from the definition of PCOS, most physicians simply regard hyperinsulinemia as a subset of PCOS. That is, among PCOS women it is recognized some will be hyperinsulinemic. Conversely, most but not all women with hyperinsulinemia qualify for the diagnosis of PCOS (HA+COA).

Unfortunately, there isn't a universally agreed upon way to screen for hyperinsulinemia. The research definition of hyperinsulinemia involves an IV, infusions, and multiple blood tests. It is impractical. The most popular clinical screen currently is a fasting glucose to insulin ratio. A glucose/insulin ratio <4.5 is consistent with hyperinsulinemia (Legro RS et al., J Clin Endocrinol Metab 1998;83:2694). Recently, 'insulin sensitizing' medications such as metformin (Glucophage) have been found to help induce ovulation in hyperinsulinemic PCOS women. 

If you have PCOS, it is likely that you are concerned about infertility or lack of ovulation. The usual first line of treatment is weight management, if you are overweight, and clomiphene. Clomiphene citrate (Clomid, Serophene) is usually given for 5 days, at doses ranging from 50 to 250 mg per day. In some women follicles may form but not ovulate. In such cases hCG can be injected when the follicle is of adequate size on ultrasound and ovulation will generally occur.

If conventional clomiphene administration is unsuccessful, extended clomiphene often works (e.g. 150 mg for ten days) (Lobo RA et. al., Fertil 
Steril 1982;37:762). Furthermore, the addition of dexamethasone (e.g. 0.5 mg at bedtime) (Trott EA, et al., Fertil Steril 1996;66:484) is often helpful, especially if the dehydroepiandrosterone sulfate (DHEAS) level is elevated. 

If clomiphene citrate still fails to cause ovulation the choice is between gonadotropin therapy with intercourse or intrauterine insemination (IUI), or as part of GIFT or IVF. If blood levels of androgens are elevated, then laparoscopic ovarian diathermy (Donesky BW, Adashi EY, Fertil Steril 1995;63:439) may be useful. If hyperinsulinemia is present, metformin with or without clomiphene (Nestler JE et. al., NEJM 1998;338:1876) can be considered.

PCOS is associated with a higher than normal miscarriage rate. Laparoscopic ovarian diathermy may decrease the miscarriage rate. Women with PCOS are at higher risk of ovarian hyperstimulation (producing an excess number of eggs) when given gonadotropins compared to the risk in normally ovulating women women. Interestingly, even normally ovulating women with isolated polycystic appearing ovaries demonstrate more responsive ovaries (Wong IL, et al. Human Reprod 1995;10:524). By giving gonadotropins starting at a low dose (e.g. 1 ampule per day) and increasing slowly (e.g. ½ amp every 4 to 7 days) the risks of multiple pregnancy and hyperstimulation are greatly reduced.

Ovulation induction in PCOS is virtually always possible, and therefore if this is your only infertility factor, you have every reason to be optimistic about your chance of conceiving. If you are not ovulating with clomiphene, the best next step will be based on the details of your specific condition. With PCOS, as with all conditions, our goal is to help you conceive with the greatest ease, economy and safety.
 

Fertility Drugs and Intrauterine Insemination
Help Couples with Unexplained Infertility and Endometriosis

A recent study (N Engl J Med. 1999;340: 177-183) showed that the combination of superovulation with injectable fertility drugs and intrauterine insemination (IUI) resulted in superior pregnancy rates compared to either procedure alone in patients with unexplained infertility. 

This randomized, controlled clinical trial consisted of 932 infertile couples in whom the women had no identifiable cause for their infertility and the men had motile sperm. The couples treated with injectable fertility drugs and IUI were three times as likely to become pregnant as the couples who only had inseminations into their cervix (ICI). There were twice as many pregnancies in the treatment group compared to those who received drugs and ICI, or IUI alone without drugs.

There was a higher miscarriage rate in the patients receiving drugs and IUI, but the authors of the study point out that there is nothing inherent about either fertility drugs or IUI that cause more miscarriages. Also no evidence exists that the combination of these two techniques work together to cause an increased chance of miscarriage.

In a previous study (Fertil Steril 1997; 68: 8-12) of patients with minimal or mild endometriosis, it was shown that treatment with superovulation and IUI was more than five times as likely to result in a live birth compared to couples who received no formal treatment.

At Reproductive Partners, we feel the combination of fertility drugs with IUI is appropriate for couples who have endometriosis, unexplained infertility, ovulation problems and mild male factor in whom less aggressive treatments have not worked. In general, we recommend that couples with these reasons for infertility have three cycles of superovulation with IUI before considering GIFT or IVF.
 

Using Low Dose Aspirin to Improve
Results with In Vitro Fertilization

In vitro fertilization (IVF) is one of the newest, high tech treatments to help infertile couples conceive. Aspirin, synthesized in 1897, is one of the oldest medications traditionally used for fever, pain and inflammation. In the last two decades the use of aspirin has broadened to include prevention and treatment of cardiovascular diseases, fetal growth retardation, preeclampsia and immunological causes of recurrent miscarriage. Now, one of the oldest treatments has been shown (Fertil Steril 1999;71: 825-829) to be useful in improving the results of IVF, one of the newest available.

In a randomized, controlled and double-blind placebo-controlled study, 149 patients went through IVF cycles with the only difference being the use of a single 100 mg aspirin (not available in the U. S.) a day in one group and placebo in the other. Patients in the aspirin group did much better than those on the placebo. They had statistically better numbers of eggs, higher estrogen levels, more uterine and ovarian blood flow, and almost double the implantation and pregnancy rates of the placebo group.

The authors conclude that one baby aspirin a day seems to be a useful and safe treatment for women who undergo assisted reproductive procedures. At Reproductive Partners, on the basis of early reports we began recommending in early 1998 that all of our IVF patients routinely take baby (81 mg.) aspirin. At present there is no evidence to suggest that this recommendation should be extended to women trying to conceive without assistance or using conventional fertility treatments.