Download Polycystic Ovary Syndrome (PCOS)

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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
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(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 12-15 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,
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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
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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.
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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 12-13 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
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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, GonalF, 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
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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
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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
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(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
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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 $1700.00, 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 $12,000.00 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”
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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