Patient Information: Polycystic Ovary Syndrome Disease Process and Treatment

Transcription

1 1 William N. Burns, M. D. Associate Professor Department of Obstetrics & Gynecology Joan C. Edwards School of Medicine Marshall University Huntington, West Virginia, USA Patient Information: Polycystic Ovary Syndrome Disease Process and Treatment Polycystic ovary syndrome (PCOS) or polycystic ovary disease (PCOD), the association of multicystic ovaries with three cardinal physical manifestations, irregular or absent menstrual periods, increased body hair growth (hirsutism), and obesity, has been recognized at least since the 1930 s. The irregular or absent menstrual periods are due to infrequent or absent ovulation, which often causes the additional symptom of infertility. Drs. Stein and Leventhal were among the first physicians to describe and investigate the syndrome; thus PCOS/PCOD is also known as Stein-Leventhal Syndrome. Not all patients with PCOS or PCOD have all five findings (polycystic ovaries, erratic periods, hirsutism, obesity, and infertility), but most patients with PCOS have many (at least three or four) of them. Over the years there has been much debate and disagreement among doctors about how best to define PCOS. The debate over the true definition of PCOS led to debate and disagreement about how common a disease PCOS actually is. In recent years, acceptance of the concept that PCOS is a heterogeneous disorder (that is, capable of having somewhat different manifestations in different people), has grown. There is now general acceptance that PCOS is a very common disorder, the most common cause (80% or more of cases) of chronic menstrual irregularity in reproductive-aged women. Because chronic anovulation/menstrual irregularity is a common cause of infertility (responsible for 15-25% of cases of infertility), and PCOS is the most common cause of chronic anovulation/menstrual irregularity, PCOS is a very common problem among patients attending infertility clinics. The fundamental ovarian hormonal and functional abnormalities that accompany PCOS are infrequent or absent ovulation, infrequent or absent secretion of progesterone, increased secretion of male hormones, persistent (rather than cyclic) estrogen secretion, increased luteinizing hormone (LH) secretion, insulin resistance, and cystic ovaries

2 2 (though, again, not all patients necessarily have every single abnormality). Next we will discuss each of these components of the syndrome. Central to the disturbed physiology of PCOS is lack of ovulation and lack of production of the ovarian hormone progesterone. Ovulation and progesterone production are inseparably linked functions; ovulation (release of the egg from the ovary) reliably triggers the ovary to produce the hormone progesterone for the subsequent 12 to 15 days. It is exposure to a day period of progesterone at monthly intervals that makes a normally cycling woman get her period at regular monthly intervals. Because women with PCOS ovulate infrequently or not at all, they produce progesterone infrequently or not at all. Infrequent or absent production of progesterone causes the infrequent or absent menstrual periods of PCOS patients. Another cardinal hormonal abnormality of PCOS is increased androgen (male hormone) production by the ovary and occasionally by the adrenal gland also. If one looks hard enough with sensitive enough techniques (which sometimes actually is not necessary for standard patient care purposes), one can find evidence of increased androgen production in virtually all patients with PCOS. The increase in androgen production is usually not so severe that androgen levels approach those of a normal man, but it is enough to cause increased hair production and sometimes acne in women whose hair follicles and skin are sensitive to male hormones. Another important hormonal change in women with PCOS involves estrogen production. In a normally cycling woman, estrogen production characteristically varies, with predictable increases in secretion typically followed by equally predictable falls. In women with PCOS, estrogen levels are much less variable. The ovary, often working in concert with the fat cells of the body s fat deposits, produces estrogen, particularly a form of estrogen called estrone, at a steady, unrelenting pace. The steady production of estrogen is important for several reasons. One, it is important in the maintenance and perpetuation of the PCOS condition. Periodic drops in estrogen production are necessary to trigger the hormonal changes that lead to egg development and ovulation. When these periodic drops in estrogen do not occur, anovulation (lack of ovulation) ensues. The steady state production of estrogen in PCOS also has important effects on long-term general health. Steady, unrelenting exposure to estrogen, over many years time,

3 3 uninterrupted by drops in estrogen and exposure to progesterone increases the risk of cancer of the uterus and may also increase the risk of other cancers. Two other hormonal abnormalities critical in perpetuating the disturbed physiology of PCOS are very important to mention, increased luteinizing hormone (LH) and insulin resistance. Although some patients likely have both increased LH and insulin resistance, current thought is that in the majority of PCOS patients, one factor or the other is usually dominant in driving and sustaining the PCOS condition. Increased LH is the usual driving force for the condition in slender and normal body-weight women with PCOS. LH is a hormone produced and secreted by the pituitary gland, located in the head underneath the brain and behind the throat. When produced in excess, LH drives the steady, inappropriate ovarian secretion of estrogen and androgen described above. LH is often measured simultaneously with another important pituitary hormone, FSH. When measured concomitantly with FSH, women with increased LH secretion are found to have high LH levels relative to FSH, commonly expressed by the term elevated LH to FSH ratio. Insulin resistance is the usual driving force for the PCOS condition in overweight women with PCOS. Insulin is produced in the pancreas, a digestive organ located in the upper abdomen behind the stomach. Insulin is vitally important in the processing and assimilation of all the basic nutrients we ingest in our food, the sugars from the carbohydrates, the amino acids from the protein, and the fatty acids from the fats. One of its most important and well-known functions is to lower the blood sugar (blood glucose) level by driving glucose out of the blood and into body cells. It is a well-established fact that excess fat tissue often causes a person to become resistant to the action of insulin. Because of their condition, people who are insulin resistant must produce and secrete greater than usual amounts of insulin to keep their blood glucose at the normal, appropriate level. In some way, the elevated levels of insulin impact ovarian function, causing essentially the same alterations in ovarian function and hormone production that increased levels of LH do in women whose PCOS is LH driven. Several other important points should be made about the interrelationships of obesity, insulin resistance, and PCOS. Obesity is a risk factor that contributes very substantially to the causation of a number of important health conditions. Hardening of

4 4 the arteries leading to heart attack and stroke, high cholesterol, diabetes, high blood pressure, and gall stones are just some of the diseases of humans that to some significant extent are caused by being overweight. It is likely that in many overweight patients with PCOS, the PCOS is substantially or even exclusively caused by the obesity. In other words, it is likely that in some obese women with PCOS, all the symptoms and hormonal changes of PCOS are the direct result of being overweight. If this type of PCOS patient is ever successful in losing substantial amounts of weight, all the symptoms and hormonal changes of PCOS will revert to normal as the weight is lost. In addition, there is some thought that in some cases, the chain of causation may be reversed, that is, that the hormonal environment that typically exists in PCOS may cause fat deposition and weight gain. The clinical and scientific evidence in support of this suggestion is not extensive; nonetheless, this chain of events may be at work in some cases of PCOS. Before leaving the topic of ovarian hormonal and functional changes in PCOS, there is one more topic that should be discussed: the C of PCOS, the ovarian cysts. Recall that the original finding described by Stein and Leventhal was the association of the signs and symptoms of PCOS with multicystic, thick-walled ovaries. In medicine, the term cyst is used in two somewhat different, and potentially contradictory ways. In some contexts, the term cyst is used for a fluid-filled, abnormal growth or tumor, a growth that is not supposed to be present and therefore may need to be removed. In other contexts, the term cyst is applied to any body structure that is fluid-filled, even body structures that are normally present and normally fluid-filled and therefore do not need to be removed. The ovarian cysts of PCOS fall into this latter category. A woman s eggs are enclosed in compartments within the ovary called follicles. As the eggs mature and develop, the follicles that contain them accumulate fluid, i.e., they become cystic (again, in the latter sense of the word as described above). The overall ovarian hormonal environment of PCOS allows the initial development and fluid accumulation of the ovarian follicles, but inhibits the later stages of their development. Because of this, fluid-filled follicles containing underdeveloped or degenerating eggs accumulate in the ovary in PCOS, making them multicystic as described originally by Stein and Leventhal. The cysts in and of themselves are not a threat to the PCOS patient s health, and therefore they do not routinely need to be removed.

5 5 Treatment PCOS patients typically present to the fertility specialist wanting treatment for one or more of the three classic symptoms of PCOS, erratic and occasionally heavy periods, unwanted hair growth, or infertility. In some cases, it is difficult or impossible to treat all the symptoms simultaneously. In particular, some of the medications that are given to treat menstrual irregularity or hirsutism cannot or should not be given to women who want and are actively trying to become pregnant. Thus, the exact treatment that is best for any individual PCOS patient will depend to some extent on which symptoms of PCOS the individual patient most wants treated. For treatment of irregular periods, the mainstay of treatment is to provide the hormone that the PCOS patient lacks: progesterone. Patients most commonly accomplish this by taking standard birth control pills in the standard fashion. Standard birth control pills contain substantial amounts of progesterone, thereby providing what the PCOS patient is lacking. Another treatment option is to take the oral progesterone medication Prometrium or Provera for consecutive days every one to two months. Yet another treatment option is to use vaginally absorbed progesterone preparations. All of these treatment options are very effective in regulating menstrual bleeding in PCOS patients, and also are effective in protecting the patient from the adverse long-term effects of the uninterrupted estrogen secretion that accompanies PCOS. Hirsutism is also very effectively and most commonly treated with birth control pills, again standard birth control pills taken in standard fashion. Birth control pills work both by reducing ovarian androgen production and by blocking the action of androgen in the hair follicles and skin. Another very commonly used and effective medication is spironolactone, which probably works predominantly by blocking androgen action. Other newer (and therefore likely more expensive) androgen blocking agents are flutamide and finasteride. For the patient willing to take injections four to six times a year, regular injections of Depo-Provera (a form of progesterone) may be a good option. For treatment of facial hair, a new skin cream, Vaniqa, is now available and produces significant improvement for some patients. Finally, depending on blood-test results, the

6 6 hirsutism of a small minority of PCOS patients may need to be treated with drug combinations that include a glucocorticoid steroid medications such as Prednisone or Dexamethasone.. Any patient with hirsutism considering treatment should be well aware that in almost all cases, the above-described treatments do not make hair that is already present go away. The most that these treatments can accomplish generally is to prevent the continuing appearance of new hairs. For eradication of hair that is already present, electrolysis or perhaps laser treatment is almost always necessary. The goal of treatment for the PCOS patient suffering from infertility is straightforward: induce or stimulate the underperforming ovary to ovulate! For several decades, there were only four ways to accomplish this: weight loss, ovarian surgery, the oral drug clomiphene (brand names Clomid or Serophene), and daily injections of expensive gonadotropin drugs containing FSH (brand names Pergonal, Humegon, Gonal- F, and several others). In recent years, several adjunctive treatments that may enhance the effectiveness of clomiphene, and several wonderful new oral drugs that work by an entirely different mechanism from clomiphene, have been developed. These discoveries have given us a greater number of options for treating the PCOS patient, thereby improving overall treatment success rates. I will now try to succinctly and clearly describe the many options now available for the PCOS patient. Again, the four traditional therapies for inducing ovulation in the PCOS patient are weight loss, surgery, clomiphene, and gonadotropin injections. As regards weight loss, several important points should be made. First of all, weight loss obviously is appropriate only for the overweight PCOS patient, and is not indicated for the normal body weight or slender PCOS woman. However, for the overweight PCOS patient, weight loss can be of tremendous benefit. As regards infertility in the overweight PCOS woman, substantial weight loss alone will induce regular menstrual cycles, ovulation, and pregnancy in 50-60% or more of cases. And the benefits extend far beyond the cure of the infertility. The overweight PCOS patient who loses weight before becoming pregnant will have a safer and more likely successful pregnancy. Obesity increases the risk of many complications of pregnancy: high blood pressure (toxemia/pre-eclampsia), diabetes, and blood clots just to name a few. These complications can affect the health of

7 7 both the mother and the fetus. The overweight patient who loses weight before becoming pregnant lessens her risk of all these complications, thereby improving pregnancy outcome for both herself and the baby. Finally, the patient who loses weight and maintains her weight loss will diminish her long-term risk of all the obesity-related health risks described previously in this information sheet (see page 3). Although weight loss is of great benefit for the overweight PCOS patient, traditionally therapy directed at aiding weight loss has been managed primarily by dietician consultants or by physicians other than the infertility specialist. One exception to this is the relatively new drug metformin (see below), which is now routinely prescribed when appropriate by infertility specialist physicians. In current infertility practice, ovarian surgery for PCOS is not frequently recommended. The goal of ovarian surgery as traditionally performed has been to remove or destroy a portion of the ovarian tissue. This leads to a lowering of ovarian male hormone and estrone production, thereby creating a hormonal environment more conducive to egg-development and ovulation. Historically, surgical treatment has been only moderately effective. More importantly, surgery carries with it very serious fertility risks, risks that do not exist with non-surgical therapies. With ovarian surgery, the woman s egg supply is inevitably reduced (the eggs are in the ovarian tissue), which may impair the woman s very long-term fertility. Most importantly, ovarian surgery carries the risk of causing scar tissue formation that can profoundly impair tubal function, thereby creating a new, very serious fertility problem that the woman did not previously have. Because of these risks, and because of continued improvement in the effectiveness of non-surgical (pharmacological) treatment, ovarian surgery for PCOS is now infrequently indicated. Clomiphene is the traditional first-choice treatment for induction of ovulation in PCOS women, and is still a very successful and commonly utilized therapy. The medication comes as a pill and is taken once daily for five consecutive days beginning on the third, fourth, or fifth day of the menstrual cycle. Clomiphene is an anti-estrogen, an estrogen blocker. It tricks the woman s body into thinking that estrogen levels are low, and thereby triggers the chain reaction of hormonal events that lead to egg development and ovulation. The dosage can be increased two to five fold in step-wise fashion in

8 8 women who do not respond to the typical starting dose. Typically, 80% or more of PCOS patients ovulate in response to clomiphene, and 40-50% become pregnant. Ninety to ninety-two percent of viable clomiphene pregnancies are single pregnancies, eight to nine percent are twins, and one percent are triplets or more. Unpleasant side effects are common with clomiphene, but serious or life-threatening complications, fortunately, are very rare. The common side effects of clomiphene, many of which are due to its estrogen-blocking effects, are hot flashes, moodiness, headaches, bloating, and discomfort in the area of the ovaries due to ovarian enlargement. Patients who do not become pregnant with clomiphene fall into two categories, those that do not ovulate in response to clomiphene (i.e., clomiphene-resistant patients) and those who ovulate in response to clomiphene but do not become pregnant (i.e., clomiphene failure patients). Adjunctive treatments that enhance clomiphene s effectiveness are available for both categories of patients. Regarding clomipheneresistant patients, some such patients may become clomiphene-responsive if they take birth control pills for one to two months prior to taking the clomiphene. Some clomiphene-resistant patients, appropriately diagnosed by blood testing, may benefit from the addition of adrenal steroids such as Dexamethasone or Prednisone to their clomiphene. Finally, combining clomiphene with one of the wonderful new insulin sensitizing drugs, metformin (Glucophage) or rosiglitazone (Avandia), may convert the resistant patient to a responsive one. (The insulin-sensitizing drugs are described in more detail below.) For the clomiphene-failure patient, two main interventions to enhance clomiphene effectiveness should be considered. The addition of appropriately timed artificial insemination (intrauterine insemination) to the clomiphene treatment may convert a clomiphene failure to a clomiphene success, particularly in those clomiphene failures who have been identified as having poor cervical mucus. Serial monitoring with vaginal ultrasound may also be of benefit to the clomiphene failure patient. By performing vaginal ultrasound on two to four occasions around mid-cycle, more detailed information about egg development and ovulation can be obtained. Patients in whom an abnormality is detected with ultrasound may benefit from an adjustment of their clomiphene dose

9 9 (possibly either upward or downward), or from a single appropriately timed injection of an inexpensive hormonal preparation named human chorionic gonadotropin (hcg). As was mentioned briefly previously, several wonderful new drugs effective in stimulating egg development and ovulation have been discovered and marketed in recent years. These are the drugs metformin (brand name Glucophage), rosiglitazone (brand name Avandia) and pioglitazone (brand name Actos). All of these drugs act in some way to enhance the body s response to insulin they act as insulin sensitizers. Recall from our discussion of the hormonal changes that accompany PCOS the important role of insulin resistance, that insulin resistance appears to be the driving force that causes the ovarian functional and hormonal abnormalities in overweight PCOS women. Thus, these drugs are more likely to benefit the overweight PCOS patient than the slender PCOS patient, though they may be of some benefit in the slender PCOS patient also. The drugs come as pills that, of course, are taken orally and are effective in stimulating ovulation in 50% or more of appropriately chosen patients. They are effective when taken by themselves, and may for some patients be the appropriate initial therapy for their condition. They may also be helpful, as mentioned above, when used in combination with clomiphene and perhaps with other drugs. The precise mechanism of action of Glucophage is somewhat different from that of Avandia and Actos, and therefore the drugs have different side effects and (remotely possible) complications. The major and most common side effect of Glucophage is stomach upset and diarrhea. This side effect can be so severe that some patients simply cannot tolerate the medication. A pleasant side effect of Glucophage is that for a significant number of patients it in some way promotes weight loss. Thus, for the overweight PCOS patient who would like to lose weight before becoming pregnant, or who would like to use weight loss as her method of therapy, Glucophage, with or without concomitant diet and exercise modification, is often a particularly good therapeutic option. Avandia and Actos are generally well tolerated and do not cause stomach upset. Their most common side effect is fluid retention manifesting as leg swelling, which is usually mild. Unlike Glucophage, they do not promote weight loss if anything, they may promote slight weight gain because of the fluid retention. Nonetheless, they are about as effective as Glucophage in successfully stimulating ovulation. A favorable property of all the insulin-sensitizing agents is that

10 10 they do not appear to significantly promote multiple ovulation, and therefore do not appear to increase the risk of multiple pregnancy, as clomiphene and injections do. The fourth of the traditional therapies for stimulation of ovulation in PCOS is injection treatment. This treatment requires daily injections for seven to twenty days of drugs containing the powerful hormone named follicle stimulating hormone (FSH). Brand names of commonly used FSH-containing drugs are Gonal-F, Follistim, Pergonal, Repronex, Fertinex, and Humegon. During injection treatment, the patient must be seen three to eight times for vaginal ultrasound exam and for blood testing to assess her response. Because the drugs are expensive and taken daily, and because their safe use absolutely requires the above-described monitoring, injection treatment is expensive. The total cost per single cycle of treatment typically averages about $ , though in some cases the cost could be somewhat less (or, in other cases, unfortunately, somewhat more). The success of treatment ranges from ten to thirty percent per cycle, depending on the specifics of the couple s particular situation. Because injection treatment is so expensive and cumbersome, patients who take injections have almost always taken clomiphene and often other oral medications without success before embarking on injection treatment. With injection treatment, the risk of multiple pregnancy is higher than with other forms of treatment seventy to eighty percent of pregnancies are singletons, fifteen to twenty-five percent are twins, and five percent are triplets or more. The other major complication of injection treatment, besides multiple pregnancy, is a condition called ovarian hyperstimulation syndrome, which in rare cases can cause very serious sequelae such as stroke, blood clots, and even death. More details on the ovarian hyperstimulation syndrome will be provided in patient education materials that are specific for injection therapy. In vitro fertilization-embryo transfer (IVF-ET) is also effective in the treatment of infertility due to PCOS. Success rates range from twenty to fifty percent per cycle, depending primarily on the woman s age. Because of the high cost of IVF-ET (approximately $12, per cycle), it is generally performed only after simpler and much less expensive treatment measures have failed. Many treatment options for the PCOS patient with infertility have been described here in the final section of this communication. To help the patient grasp the full menu

11 11 of therapies, we will conclude with a complete list of all the treatment options discussed in the preceding pages. Hopefully this list and the explanations that preceded it will help the PCOS patient make the best and most fully informed decisions about her care: 1) Weight loss 2) Weight loss with adjunctive metformin (Glucophage) 3) Clomiphene 4) Clomiphene with artificial (intrauterine) insemination 5) Clomiphene with ultrasound monitoring 6) Clomiphene with single timed hcg injection 7) Clomiphene preceded by birth control pills 8) Clomiphene with Dexamethasone 9) Clomiphene together with metformin (Glucophage) or rosiglitazone (Avandia) 10) Metformin (Glucophage) 11) Rosiglitazone (Avandia) 12) Injections of FSH-containing medications 13) Surgery (not frequently strongly recommended) 14) In vitro fertilization-embryo transfer (IVF-ET) William N. Burns, M. D. Joan C. Edwards School of Medicine at Marshall University Copyright 2003