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Microsoft word - pcos-when clomid doesn't work.doc

Hallie Bensinger, FNP
Raymond Ke, MD
Many women suffering from infertility fail to release an egg each month. This state of chronic anovulation is characterized by irregular menstrual cycles and may be accompanied by obesity or hirsutism (increased hair growth). The condition is known as polycystic ovarian syndrome (PCOS) and despite its’ name, has little to do with ovarian cysts. There are other hormonal imbalances, such as hypothyroidism, hyperprolactinemia, and hyperinsulinemia, associated with anovulation but PCOS is by far, the most common. In treating infertile couples suffering from PCOS, the first option is the use of an ovulation drug called clomiphene citrate. Clomiphene citrate can be taken by mouth and is initially started at 50 mg (1 tablet) a day and increased incrementally to at least a dose of 150 mg a day in an effort to induce ovulation. With standard clomiphene citrate treatment, 75% of patients suffering from PCOS will resume ovulation. The 25% of patients who do not ovulate with standard dosages of clomiphene citrate are usually referred to as “clomiphene - resistant”. The following discussion will outline the treatment options available for clomiphene - resistant patients. WEIGHT LOSS
Obesity is known to contribute to infertility
19 20 21 22 23 24 25 26 27 28 29 30 35 40
and may increase a pregnant woman’s risk for (kg/m2)
complications during pregnancy and delivery.
In addition, obesity can lead to high blood
pressure, high cholesterol, diabetes, cancer Height
Weight (lb.)
and heart disease. Women with PCOS often 91 96 100 105 110 115 119 124 129 134 138 143 167 191 Being overweight is defined by a body mass 94 99 104 109 114 119 124 128 133 138 143 148 173 198 index (BMI) over 25 kg/m2 while obesity is defined by a BMI over 30 kg/m2. The table 97 102 107 112 118 123 128 133 138 143 148 153 179 204 on this page can be used to calculate your 100 106 111 116 122 127 132 137 143 148 153 158 185 211 BMI. To use the table, find your height (in inches) in the left hand column, and then 104 109 115 120 126 131 136 142 147 153 158 164 191 218 107 113 118 124 130 135 141 146 152 158 163 169 197 225 pounds). The number at the top of the column is the BMI for your height and 110 116 122 128 134 140 145 151 157 163 169 174 204 232 114 120 126 132 138 144 150 156 162 168 174 180 210 240 It is vitally important for overweight women with PCOS to lose weight. There is simply 118 124 130 136 142 148 155 161 167 173 179 186 216 247 no other therapy that offers as much benefit 121 127 134 140 146 153 159 166 172 178 185 191 223 255 as sustained weight loss. While studies have demonstrated that women can resume regular 125 131 138 144 151 158 164 171 177 184 190 197 230 262 128 135 142 149 155 162 169 176 182 189 196 203 236 270 after losing as little as 5% of their starting body weight, most women, especially those 132 139 146 153 160 167 174 181 188 195 202 207 243 278 who have a BMI greater than 28, will need to set a goal of 10-15% weight loss. The weight goal must be maintained for at least 6 months in order to see an improvement in PCOS symptoms. Many programs are available to assist women in weight loss, including the Lifestyle class offered through Fertility Associates of Memphis. After hormonal causes of excess weight are ruled out, a daily evaluation of calorie intake and exercise output will assist in achieving the weight goal. C/ /Ke documents/ /PCOS-When Clomid doesn't work Rev. 4/13/05 INSULIN SENITIZERS
Women with PCOS demonstrate resistance to the action of the insulin hormone that aids the cells throughout the body to
take in glucose for nutrition. Therefore, the body has to make more insulin in order to nourish the cells and keep blood
glucose levels stable. If the body fails to produce enough insulin, then diabetes will develop. It is documented that PCOS
women have nearly a four-fold increase in risk of developing diabetes by age 40 then women who do not have PCOS.
A consequence of resistance to insulin action is a high level of insulin that constantly circulates throughout the body. At
the ovary, it is believed that high insulin is the primary reason why PCOS women fail to ovulate. It is reasonable to deduce
that if the body can be made to be more sensitive to insulin, then insulin levels could drop and ovulation would resume.
Recent studies have confirmed that treatment to raise insulin sensitivity and lower circulating insulin in PCOS patients
results in dramatically improved ovulation and pregnancy rates. Furthermore, insulin sensitization lowers the level of
androgens (male hormone), which is responsible for hirsutism and acne in many PCOS women. The most commonly used
medication is metformin (Glucophage) and is approved for the treatment of type II diabetes. Fertility Associates of
Memphis has recently published a trial in which another diabetes treatment, rosiglitazone (Avandia), was able to induce
ovulation in over 75% of women previously resistant to clomiphene alone.
Insulin sensitization therapy may not just offer the short-term benefit of ovulation induction. It appears that resistance to
insulin may not just be associated with PCOS and diabetes but also high cholesterol and heart disease. Recently, a large,
federally funded study demonstrated that long-term (more than 4 years) treatment with metformin in people at risk for
diabetes could lower their risk of actually developing diabetes by 40% as compared to placebo. It also drastically reduced
their cholesterol and risk of cardiovascular disease. Side effects vary from stomach upset and diarrhea with metformin to
swollen fingers and feet with rosiglitazone. Tests to monitor your liver and kidney function will be done while taking
insulin sensitizers. Your physician will review the individual risks with you.
Clomiphene works by blocking the estrogen receptors in the brain and causing it to induce ovulation in the ovary. The
same effect can be accomplished with aromatase inhibitors, a group of medications primarily indicated in the treatment of
breast cancer. Aromatase inhibitors do not block the estrogen receptors like clomiphene in the brain but inhibit overall
production of estrogen temporarily achieving the same effect. Because there is no blockage of the estrogen receptor, the
effect is much shorter in duration and there is less detrimental effect on the growth of the endometrial (uterine) lining and
the changes in the cervical mucus so common with clomiphene.
The aromatase inhibitor most commonly used is called letrozole (Femara). It is prescribed in a similar fashion as
clomiphene with a five-day course right after her menses. In one study, the investigators had good success with a one-time
dose. Ovulation is typically around day 14-16. Due to its mechanism of action, letrozole is a good choice for women with
an ovulatory response to clomiphene but is either not achieving pregnancy or is known to have endometrial or cervical
mucus development issues. Most people have very few side effects with letrozole. Mild nausea can be controlled by taking
the pill with food at night. Uncommonly, women experience tiredness, headaches, muscular aches, or hot flushes. You
should contact your physician if you have any side effects.
Gonadotropin therapy is typically the next step for clomiphene - resistant patients. This is medication given by injections
typically taken for 8-12 days. Gonadotropins induce the production of multiple eggs that are then released (ovulated) on a
specific schedule. Because we can time the moment of ovulation, gonadotropin therapy is often combined with intrauterine
insemination (IUI) using the husband’s sperm. Gonadotropins are very successful with as many as 90% of patients,
previously resistant to clomiphene, successfully ovulating. Careful monitoring of therapy using blood hormone tests and
vaginal ultrasounds is necessary. Risks of therapy include a high (1 in 4) probability of twins and a 1-2% chance of triplets
(or higher). Rarely, patients may be at risk for ovarian hyperstimulation syndrome (OHSS), which is a serious condition
that affects not only the ovaries, but the liver, kidneys and circulatory systems as well. Again, with proper monitoring, the
risk of OHSS is largely preventable. A complete description of the gonadotropin therapy, including the risks and cost
involved, is available as a separate handout.
Before 1970, the popular therapy for PCOS was described as ovarian wedge resection. This involved a major operation
with a large incision where approximately one quarter to one third of the ovary was taken out in a pie fashion and the ovary
was sewn closed. The theory involves the ovary as the source of increased androgen production that is inhibiting ovulation.
When a portion of the ovary is removed, many patients would begin to ovulate. However, the effect was temporary and the
anovulation would often return within months. Furthermore, the surgery often induced scar tissue that would damage the
C/ /Ke documents/ /PCOS-When Clomid doesn't work Rev. 4/13/05 nearby fallopian tubes. With the development of clomiphene citrate, the classic ovarian wedge resection was, for most purposes, abandoned. With the advent of laparoscopy and outpatient surgery, this concept has been revisited. The theory is essentially the same, which is destroying part of the ovarian tissue that is responsible for the increased androgens. However, today, it can be performed as an outpatient basis through the laparoscope, a lighted telescope inserted into the abdomen through one or two small incision sites in the lower abdomen. Numerous (usually 20 or more) ‘punctures’ are made in the ovary with the use of laser or electrical energy. With or without added clomiphene, ovulation resumes in approximately 20-50% of patients. As with the original procedure, the effect is temporary with anovulation returning after several months. However, surgery through the laparoscope was less likely to form dense scar tissue around the tubes and recovery time was much shorter than the larger operation. Still scar tissue can occur and ovarian drilling is considered only when other techniques have failed. CONCLUSIONS
Most infertile women with anovulation and PCOS will respond to clomiphene. For those that do not, there are several
treatment options available and all have their advantages as well as disadvantages. If you are overweight, then a plan to
achieve sustained weight loss is of paramount importance. Using one or more of the treatments reviewed above, most
clomiphene – resistant women will be able to ovulate and hopefully, conceive.
April 14, 2005
C/ /Ke documents/ /PCOS-When Clomid doesn't work Rev. 4/13/05


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