If you want to start a family, I’ve got good news: Your likelihood of conceiving and having a healthy baby, in spite of PCOS, is very high. I start this chapter with this encouraging message because it is so easily lost in a discussion of the complicated forces at work in PCOS. It’s possible you’ll become pregnant without doing anything for your health. But if you lose some weight, your chances of conceiving are much greater. If you’re carrying extra pounds, weight loss is healthy and a good idea, in any case. It’s certainly the best way to start. If weight loss doesn’t work, fertility drugs very likely will. We will look at two frequently prescribed drugs in this chapter, one of which I recommend over the other, although there are times when I suggest using them in combination.
Carrying your unborn child inside your body puts extra physical stress on your biological systems. Any system already out of balance may be made more so by this added stress. It makes sense, therefore, to have your body in the best working order possible before becoming pregnant. A woman with PCOS, besides often having trouble in conceiving, has more difficulty in getting her body into a reasonably healthy condition. Although taking steps to improve your health before a pregnancy may not be easy to achieve, it can make a big difference in your future well-being and your child’s.
If you have been diagnosed with PCOS and want to conceive, I strongly recommend:
• Losing about 10 percent of your body weight and engaging in brisk activity for at least half an hour each day. The weight loss and exercise will help lower high blood pressure and high insulin and male hormone levels.
• Having a complete physical checkup, including a full array of lab tests. Discuss any abnormal lab test results with your doctor in light of your plans for bearing a child.
• Discussing with your doctor your impaired glucose tolerance or type 2 diabetes status. I’ll address this in the type 2 diabetes section in chapter 10.
• Taking prenatal vitamins prescribed by your gynecologist.
Once you are pregnant, your obstetrician may decide to supplement you with progesterone if your hormone levels are short of what’s needed to maintain a healthy pregnancy.
There is a relatively short time in each menstrual cycle when an egg can be fertilized by sperm. Normal women with regular cycles often have trouble conceiving simply because of poor timing and are usually advised to keep trying. For women with irregular cycles, timing is even more problematic. But fertility problems are more than a matter of timing for many women with PCOS, because even when they have regular menstrual cycles, they often do not ovulate.
When they do ovulate, women with PCOS can conceive without any medical assistance, and often do. (About a quarter of women with PCOS have regular cycles, and some conceive without medication.) Individuals vary greatly in their symptoms— there are women with regular cycles who may or may not ovulate, those with irregular cycles who may ovulate on occasion, and those who almost never have a cycle or ovulate.
Don’t jump to the conclusion that PCOS is responsible for your fertility problem. Adhesions, endometriosis, uterine fibroids, fallopian tube problems, or cervical mucus disturbances could present physical obstacles to conception. A number of systemic or hormonal disturbances, such as thyroid disease, prolactin secreting disorders, excessive weight, pituitary and adrenal disorders, genito-urinary disease, or infections (for example, pelvic inflammatory disease) may be the primary cause of the infertility. And, of course, your partner may have issues of his own.
Before settling on PCOS as the cause of infertility, the other possible causes have to be eliminated. Once that is done, if you have irregular or infrequent periods, with sometimes heavy bleeding, PCOS is likely to be responsible, although this is not a diagnosis you can make yourself. A competent gynecologist is important in excluding local gynecological diseases or barriers to achieving pregnancy. An ultrasound of your ovaries and uterus is one of many tests that will help identify the problem.
Clearly you cannot become pregnant unless you ovulate. For a woman with PCOS, having menstrual cycles is no guarantee that she is ovulating. The following three ovulation tests are popular. I recommend using more than one for reasons I’ll explain below. Home kits. Home kits do not measure ovulation itself but the luteinizing hormone (LH) surge that precedes the release of the egg from the follicle. The over-the-counter kits usually consist of five test sticks to measure the LH level in your urine. If a test line on the stick becomes darker than a control line, you are having an LH surge. If the test line stays lighter than the control line, you are not—and should try again the next day with a new test stick.
For a woman with regular cycles, the arrival of an LH surge means that she is likely to ovulate in the next twenty-four hours. Unfortunately, things are not so simple for women with PCOS, whose high levels of LH are not necessarily a precursor to ovulation. Either way, though, this is the best time to try to conceive—it can’t hurt!
Basal body temperature. Ovulation causes your body temperature to rise by 0.3 to 0.5 degrees Fahrenheit (0.2 degrees Centigrade) or higher, due to a higher progesterone level. Your body remains at this slightly higher temperature until your next period. The challenge is to detect this small temperature rise.
One of the best ways of doing so is to take your temperature at the same time each morning, preferably before you get out of bed. For reliability, you really do need to take the reading at the same time each day. A difference of even a half hour can affect the reading. Stress, lack of sleep, an extra glass of wine consumed the night before, a cold, or medication can also affect your temperature reading.
Most women take their own temperature by mouth, with either a mercury or digital thermometer. Taking an oral temperature with a digital thermometer is the most convenient. You can get a special chart from your doctor on which to record your daily temperature readings.
By the time you capture the increase in your body temperature on paper, it may be too late for you to conceive in this cycle. But for most women with PCOS, the fact that ovulation took place at all is good news in itself.
Progesterone blood level. This lab test on a blood sample taken in your doctor’s office during days 21 to 23 of your cycle measures your progesterone level. If you ovulated, your progesterone level will be elevated. The result of this test is a more reliable indicator of ovulation than a positive home kit test result or a rise in basal body temperatures.
Although pelvic pain is not often mentioned in medical journal articles as a common PCOS symptom, my experience suggests that at least one in ten women with PCOS suffers from it. Ovarian discomfort and small follicle cyst ruptures, sometimes after sexual activity, are probably responsible. These occur more dramatically in women prone to cystic ovarian adenomas, dermoid cysts, and recurrent large follicular or corpus luteum cysts. In rare instances, major bleeding emergencies can occur, requiring instant medical attention and surgery. Suppressive therapy with an oral contraceptive is indicated, and such a woman’s progress needs to be followed by an experienced gynecologist, with frequent examinations and ultrasound follow-ups.
Weight loss alone is sufficient to enable some women with PCOS to ovulate and subsequently become pregnant. Before resorting to medications, first try a weight loss program. The one I recommend to my patients is described in detail in chapters 6 and 7. In any case, it’s a good idea to establish healthy eating and exercise habits. Truly that may be all you need.
If that doesn’t work, two drugs have been very successful in enabling women with PCOS to ovulate: metformin and clomiphene citrate. Let’s look at both.
Metformin (brand name Glucophage) was approved by the FDA in 1994 for use in the management of type 2 diabetes. It lowers your blood sugar level by slowing the liver’s release of stored glucose and lowers insulin resistance in muscle tissue. Metformin also helps lower LDL cholesterol levels somewhat and does not cause hypoglycemia, because it does not increase insulin secretion. It also frequently reduces testosterone levels and may result in weight loss. Metformin is the most widely used oral agent in the treatment of adults with type 2 diabetes. Millions of Americans take it, and most physicians are familiar with it.
Metformin can trigger a series of events that lead to more regular menstrual cycles and ovulation. Having PCOS, however, does not automatically mean you should be using this drug. Some prominent experts prefer other treatment strategies. For example, metformin may not be the initial drug of choice for women suffering from PCOS-related skin and hair symptoms but who are not obese and have regular ovulatory cycles.
The side effects of metformin can appear early, but frequently diminish after six to eight weeks of use. They include bloating, nausea, vomiting, flatulence, and diarrhea. Every person taking the drug reacts differently. Some women (in my experience, fewer than 5 percent) are unable to tolerate it at all, while others have few if any side effects.
Before starting metformin treatment, you need a pelvic ultrasound examination, and your doctor will probably prescribe progestin to initiate a menstrual cycle—often 10 mg Provera daily for seven to ten days, or a 200 mg Prometrium capsule in the evening for seven to ten days. You may have heavy bleeding following this.
I then start patients on a 500 mg tablet of metformin taken with dinner for ten to fourteen days. If there are minimal or no side effects, we add a second 500 mg tablet at breakfast time. Side effects become less frequent as your body becomes accustomed to the drug, and the dosage is gradually increased, depending on symptoms, to 2,000 mg daily, split between breakfast and dinner doses. A new oral liquid form of metformin has been useful in some cases. An overly rapid increase in dosage is a major cause of women being unable to tolerate metformin, so be patient.
After two to three months of treatment, you may notice more regular cycles. You can also test whether you have ovulated with home test kits, basal body temperature curves, and, most useful, your progesterone blood level on days 21 to 23 of your cycle.
If tests indicate that you did not ovulate on a divided dosage of 2,000 mg of metformin a day over three to six months, your next step is to add clomiphene citrate on days 5 to 9 of your next cycle. Most women with PCOS ovulate on this regimen and often become pregnant during the next few months. Metformin and clomiphene citrate together help 75 to 80 percent of women with PCOS ovulate, which is greater than using metformin alone. It’s your gynecologist’s responsibility to evaluate you during clomiphene treatment, since on occasion it may cause significant enlargement of the ovaries and pelvic pain. An increase in multiple births has been reported with clomiphene citrate, but this has not been reported with metformin alone.
Although metformin has been shown not to affect the fetus, I recommend that you stop the drug once your pregnancy is confirmed.
Metformin reduces insulin resistance, decreases fatty liver formation, reduces risk factors for cardiovascular disease and clotting, and improves to some extent blood lipid levels. Metformin may protect the heart, reduce high blood pressure, and lower male hormone levels. It probably delays the development of type 2 diabetes. It helps both overweight and normal-weight women with PCOS to achieve ovulation. Some experts believe that many of the benefits attributed to metformin may in fact be due to the weight loss that occurs in a number of women taking the drug. To some extent, this may be true. What is known, however, is that the beneficial effects occur in most studies, despite an absence of weight loss during administration of the drug.
I usually make the following recommendations to my patients who take metformin:
To avoid hypoglycemia, you should eat a somewhat reduced carbohydrate diet consisting of six small meals a day. Hypoglycemia is not caused by metformin, but perhaps by an overly strict low-carbohydrate diet. The mid-afternoon hours are times when insulin-resistant women with PCOS may feel uncomfortable, fatigued, and less able to concentrate, so plan to snack on a combination of complex sugars and proteins. I often recommend a snack of a green apple with low-carb peanut butter.
Avoid alcohol. I highly recommend that you avoid alcohol while on metformin therapy.
Cautions. If, for some reason, you need a CT scan—more specifically, an intravenous iodine contrast diagnostic CT scan—
Diet and exercise are difficult to adhere to. When women with PCOS cannot achieve a 5 to 7 percent loss of body weight through diet and exercise as their first course of treatment, their doctors may consider the use of insulin sensitizers, particularly for women with moderate to severe insulin resistance or features of the insulin resistance syndrome. The drugs Actos and Avandia, despite their ability to lessen insulin resistance, can promote weight gain and thus make PCOS symptoms worse. Metformin, a member of a different family of drugs, the biguanides, frequently promotes or “triggers” weight loss as well as reduces insulin resistance. It helps many women lose weight through loss of appetite, which is a great relief to women with PCOS who can suffer sugar cravings, an out-of-control appetite, and mood swings. Often, long before reaching the optimum daily 2,000 mg dosage, women often feel its ameliorating effects on their appetites. Some women lose weight notice a decrease in appetite and sugar cravings, and fewer hypoglycemic symptoms after eating at half that dose. These positive signs can indicate a reduction in insulin level and provide a substantial emotional and physiological boost.
stop taking metformin the day before, the day of the test, and the morning after. This prevents any possible hazardous elevation of the metformin blood level due to the effect of iodine on your kidneys and the very rare and serious complication of lactic acidosis.
Have your creatinine level checked at least every three to six months. Any increase is a warning that your kidneys are being overworked. If it approaches 1.4 mg percent, stop taking metformin. If you have any pre-existing kidney disease, you should use metformin with caution, if at all.
Clomiphene citrate (brand names Clomid and Serophene) can be used alone for infertility therapy or in combination with metformin, as discussed above. Clomiphene citrate is not a steroid hormone or an insulin sensitizer. It is a weak estrogen that binds to the hypothalamic and pituitary estrogen receptors, making them blind to the estrogens that are circulating in the blood. This allows the pituitary gland to secrete more LH and FSH, stimulating the ovaries and encouraging follicle development that leads to ovulation.
Your physician can use your pituitary FSH and LH blood levels as a guide to your chances of responding to clomiphene citrate. A minority of women with PCOS may have low levels of LH, FSH, and estradiol due to lack of menstrual bleeding, even after taking progestin for seven days. They may not respond to clomiphene citrate treatment. These women appear to have reduced activity of the hypothalamic and pituitary glands, a state that may be caused by a very lean BMI of 20 or less, malnutrition, eating disorders, excessive stress, or emotional problems. Obviously it’s important to address these issues, and professionals can help.
Before you start taking clomiphene citrate, you need a blood b-hCG test to make sure that you are not already pregnant. The standard starting dose of clomiphene citrate is 50 mg (1 tablet) a day for 5 days, from days 5 to 9 (occasionally days 3 to 7) of your menstrual cycle, after a natural or progestin-induced menstrual flow. The majority of women with PCOS need to take progestin to trigger a menstrual cycle. About 50 percent of patients conceive at the 50 mg dose, while another 20 percent achieve pregnancy with a 100 mg dose of clomiphene citrate. If no ovulation occurs at the 50 mg dosage, the daily dose can be upped progressively to a maximum of 200 to 250 mg for up to 3 months.
If a woman is responsive to clomiphene citrate, she is likely to be so within three or four cycles. The surge of ovulation usually occurs on cycle days 16 to 17, when clomiphene citrate is used from days 5 to 9 of the cycle. However, 5 to 12 days may pass after the last day of clomiphene citrate treatment before the ovulatory surge. Since the majority of patients who respond to clomiphene citrate get pregnant in the first three months, beyond that point you and your doctor should look for other causes of infertility.
Cautions. Often the length of your menstrual cycle will increase slightly with clomiphene citrate. The drug increases a woman’s chance of having twins by 8 to 10 percent, and of having triplets by about 1 percent. The drug sometimes causes increased cervical mucus that reduces your chances of conceiving—it can literally get in the way.
The potential for the development of ovarian cancer in women treated with clomiphene citrate and gonadotropins has been the focus of several studies. There are none as yet that confirm an increased incidence of ovarian cancer in a large number of such women. It is prudent, however, to limit treatment to no more than one year.
Because clomiphene citrate stays in the blood for at least three to four weeks, it can have a negative effect on the latter half (luteal phase) of the menstrual cycle. Your basal body temperature chart can indicate an absence or presence of ovulation and the length of the luteal phase. When your temperature elevation is less than eleven days, it may be due to what physicians call an “inadequate” luteal phase.
Significant enlargement of the ovaries occurs in approximately 5 percent of women a few days after completion of a course of treatment with clomiphene citrate tablets. The longer you’re on the drug, the more likely it is. If your ovaries become enlarged or you feel pelvic discomfort, avoid intercourse and physical activity. Your specialist may check you every clomiphene citrate treatment cycle, and also perform an ultrasound examination to look for cysts.
When you do not ovulate even at maximal levels of clomiphene citrate, your specialist may suggest an injection of human chorionic gonadotropin (hCG) at midcycle. This increases LH secretion and may also improve the luteal phase of the cycle. Timing of the hCG injection is important—it usually is given on the seventh day after the last clomiphene citrate tablet. An ultrasound of your ovaries at that time may show a follicle preparing to release an egg. Chances of conception are best on that night and for the following two days.
Most women who have side effects notice them when first taking a 50 mg tablet of the drug, though they are not dose related. Hot flashes—much like those seen in menopausal women—are the most common side effect, occurring in about 10 percent of women. Breast tenderness, bloating, tiredness, headaches, increased acne and hirsutism, depression, nausea, and dryness of scalp hair are less common. Visual symptoms, including blurring or visual spots and flashes, may occur in some women. The length of treatment and an increased dosage of the drug may be also associated with this side effect. Visual symptoms usually disappear within a few days after you stop taking the drug, but can last as long as several weeks. It is usually a good idea to stop treatment if you have this complication.
While there are cautions that patients and doctors should take seriously, there’s good news—very good news—too. Chances are you can get pregnant and have a healthy baby. With clomiphene citrate, you can expect the following:
1. The ovulation rate is 80 percent.
2. Approximately 40 percent of the ovulating women become pregnant.
3. The rate of pregnancies per induced ovulatory cycle is 20 to 25 percent.
4. The multiple pregnancy rate is 10 percent—mostly twins, and rarely triplets.
Assuming that the two fertility drugs metformin and clomiphene citrate are more or less equally effective, which is the drug of choice? I recommend metformin because its side effects are potentially less serious than those of clomiphene citrate.
POSSIBLE SIDE EFFECTS
5. The miscarriage rate is not increased.
6. There is no increase in birth defects, and the infant survival rate is normal.
7. If lack of ovulation is the only cause of a woman’s infertility, her chance of conceiving over six months is close to the normal rate of 60 to 75 percent.
Some women with PCOS are resistant to this drug, but less so when it’s taken in combination with metformin. Women using a combination therapy ovulate and get pregnant more often. In several studies of clomiphene citrate resistant women who were given metformin together with clomiphene citrate, their 10 to 27 percent ovulation rates rose to an average of 80 percent. They also had lower testosterone and insulin levels, a lower BMI, and improved cervical mucus. The addition of metformin to clomiphene citrate probably reduces elevated insulin levels, which are a major factor in the infertility of women with PCOS. This is more likely to occur in very obese women with PCOS and severe insulin resistance.
Three members of the thiazolidinedione family of drugs have been widely used to treat women with PCOS. In 2000, the FDA banned one of them, troglitazone (Rezulin), because of its potential for liver damage and failure. The other two, pioglitazone (Actos) and rosiglitazone (Avandia), were approved by the FDA in 1999 for the treatment of type 2 diabetes. These drugs operate as well as metformin in achieving ovulation and reducing insulin resistance and elevated testosterone levels. The average dosages of Avandia and Actos in PCOS vary, but often are 4 mg and 30 mg, respectively, taken once daily. Avandia and Actos possibly improve the function of the beta cells of the pancreas that produce insulin. Women may suffer weight gain with these insulin sensitizers, and they reduce insulin resistance even when no weight loss takes place. Before taking these drugs, you need a careful pretreatment evaluation of your liver function. While you are taking them, follow-up liver function studies should be done at three-month intervals for the first year of treatment.
Caution. The problem with these drugs as fertility aids is the open question of how they effect the fetus, since they have not as yet been widely used in women with PCOS. In contrast, most experts agree that metformin has no obvious fetal effects. I do not use these drugs to help women achieve pregnancies. Other strikes against Actos and Avandia are the possibilities of weight gain, headaches, tiredness, and the development of fluid in the legs. A potentially serious complication is that they may cause or worsen heart failure or liver disease. If you do take either drug, be sure to report any rapid increase in weight gain, leg swelling, or shortness of breath to your physician immediately. These drugs are not recommended for women with heart failure and active liver disease.
In otherwise healthy women with PCOS, either of these two drugs may serve as an alternative to those unable to tolerate metformin. Some women who don’t respond optimally to metformin alone have more regular menstrual cycles and lower insulin and testosterone levels when they take Actos or Avandia with metformin.
D-Chiro-inositol appears to effectively reduce insulin action in women with PCOS and is virtually free of side effects. There is evidence that it can improve ovulatory function and decrease male hormone levels This option is one to watch for—it’s not yet FDA approved or commercially available.
An elevated blood level of the male hormone DHEAS in a woman with PCOS is a reliable sign that her adrenal glands (in addition to her ovaries) are secreting increased amounts of male hormones. If your DHEAS level is quite high, and standard treatments for infertility do not work, a small dose of dexamethasone (0.25 mg) can be taken at bedtime with food. This should be used with caution, and only when your endocrinologist and gynecologist agree. It must be stopped as soon as you become pregnant, because there is no uniform consensus on its effect on fetal well-being. This dose can be added to metformin alone, a combination of metformin and clomiphene citrate, or clomiphene citrate alone.
If weight loss through a healthy diet and moderate exercise doesn’t work, and if metformin in combination with clomiphene citrate gets no ovarian response, you may need to look at other options. Over the last thirty years, however, only 3 to 4 percent of the infertile women in my practice of nearly 2,000 women with PCOS have needed to resort to in vitro fertilization or similar fertility techniques. The incidence may vary, however, depending on a specialist’s type of practice.
A number of techniques and procedures have been developed to solve fertility problems. The following three approaches may be of most interest to women with PCOS.
In vitro fertilization (IVF). A woman’s age is important in IVF. The rate of deliveries per egg retrieval is two to three times lower in women over forty than in younger women. As women become older, there is a drop in the number of eggs and they are more vulnerable to problems. Before a woman undergoes IVF, her reproductive endocrinologist usually tests her FSH and estradiol blood levels on day 3 of the menstrual cycle, and again in another cycle if the levels are abnormal, particularly in women over thirty-five. An increase in the FSH level (greater than 20 mIU/ml) and a high estradiol level (over 70 to 100 pg/ml) may indicate a poor likelihood of successful IVF treatment.
In IVF, a number of eggs are surgically removed from a woman’s ovaries and fertilized by sperm in vitro (in glass), that is, in a laboratory receptacle. A fertilized egg is implanted in her uterus in the hope that it will develop into a fetus in the natural way. Infants resulting from in vitro fertilization are popularly known as test tube babies. There are more than 1 million test tube babies alive today. The world’s first test tube baby, Louise Brown, was born in Britain on July 25, 1978.
Gamete intrafallopian transfer. As with the in vitro fertilization procedure, eggs and sperm are collected from the prospective parents. Instead of being fertilized in vitro, eggs and sperm are inserted by a physician, without surgery, into the woman’s uterus. The expectation is that an egg will be fertilized and become implanted in the uterus wall in a natural way.
I hope that throughout your journey you’ll remember what I wrote at the start of this chapter—chances are you can get pregnant and have a healthy baby. Sometimes the hardest part is managing expectations and disappointments, so try to keep the big picture in mind and enjoy the sensual pleasures of lovemaking along the way.