Sunday, October 14, 2007

Infertility treatment with clomiphene (Clomid® or Serophene®)

INTRODUCTION — Infertility is defined as a couple's inability to become pregnant after one year of unprotected intercourse. In any given year, about 15 percent of couples in North America and Europe who are trying to conceive are infertile.

The fertility of a couple depends upon several factors in both the male and female partner. Among all cases of infertility, about 20 percent can be traced to male factors, 38 percent can be traced to female factors, 27 percent can be traced to factors in both the male and female partners, and 15 percent cannot be traced to obvious factors in either partner.

When infertility occurs, the male and female partners are evaluated to determine the cause and best treatment options. For couples where the woman is not ovulating regularly, one treatment option involves the female partner taking an oral medication, clomiphene citrate (Clomid® or Serophene®).

This topic will review the use of clomiphene in the treatment of female infertility. The evaluation of the infertile couple, as well as the causes and treatment of male infertility, is discussed separately. (See "Patient information: Evaluation of the infertile couple" and see "Patient information: Treatment of infertility in men").

OVULATION — To understand why and how clomiphene is used, it is necessary to understand normal ovulation. Normally, a woman's ovaries produce one egg every 24 to 35 days. Ovulation usually occurs about 12 to 14 days before the next menstrual period (show figure 1). A woman's best chances for becoming pregnant occurs around the day of ovulation and two to four days before ovulation. This would be approximately 10 to 14 days after the first day of the menstrual cycle (day 1 of the menstrual cycle is the first day of bleeding).

A complex balance of hormones is required to stimulate ovulation, changes in hormone levels can cause ovulation to occur irregularly or to temporarily stop. A woman who has absent or irregular ovulation is said to have anovulation or oligoovulation.

There are several types of anovulation, as defined by the World Health Organization (WHO). These types are organized by the woman's blood level of follicle stimulating hormone (FSH) and estrogen (estradiol). FSH is a hormone produced by the pituitary (a gland within the brain) and estrogen is a hormone produced by the ovaries. The levels of these hormones change throughout the menstrual cycle, as shown in figure 1 (show figure 1).

Women who are most likely to respond to clomiphene include those who do not have an excessively elevated level of FSH (demonstrating a decrease in the number of eggs within the ovaries) and who have uterine bleeding when treated with a progestin (WHO class 2) (show table 1). This includes women with polycystic ovary syndrome.

WHAT IS CLOMIPHENE? — Clomiphene is a hormone that acts on the hypothalamus, pituitary gland, and ovary to increase levels of FSH and luteinizing hormone (LH, which is also important in the process of ovulation). An increased level of these hormones improves the chances of growing an ovarian follicle that can then trigger ovulation. In women who ovulate irregularly, approximately 80 percent who take clomiphene will ovulate, and 30 to 40 percent of all women who take clomiphene become pregnant. These numbers apply to women who have taken three cycles of clomiphene.

Pretreatment evaluation — Before any infertility treatment begins, a woman and her partner should be evaluated to be sure that clomiphene is the best treatment. This evaluation may include a complete history and physical examination, a semen analysis (for men), blood testing, and other tests depending upon the individual situation. (See "Patient information: Evaluation of the infertile couple").

Dosing — Clomiphene is usually started on day three, four, or five of the menstrual cycle at a dose of 50 mg once daily for five days. The first day of bleeding is arbitrarily called cycle day one. If the woman does not have regular menstrual cycles (which is usually the situation), she may be given a course of progestin medication to induce a period.

The couple is advised to have intercourse every other day for one week, beginning around day 10 of the clomiphene cycle. The couple may plan intercourse by using an ovulation predictor kit, which uses a urine sample to predict when ovulation is about to occur by measuring the LH level; these are available without a prescription. Most fertility specialists recommend the use of the ovulation predictor kit.

Some clinicians measure the blood level of progesterone one week before the expected menstrual period to determine if ovulation occurred; blood testing may be preferred to ovulation predictor kits because it provides reliable evidence that ovulation occurred (rather than a prediction that ovulation might occur).

Some healthcare providers recommend transvaginal ultrasound monitoring for women undergoing clomiphene treatment. This involves inserting a thin probe into the vagina and using sound waves to view the size and number of developing follicles (which contain an egg).

Use of an ovulation predictor kit, blood testing, and/or ultrasound are not required for women using clomiphene, and testing does not improve pregnancy rates significantly. However, almost all fertility specialists recommend use of an ovulation predictor kit and blood testing to confirm ovulation. Some recommend ultrasound, but this requires more office visits and increases the cost of treatment.

If ovulation does not occur during the first month, the clomiphene dose may be increased. There is no benefit of increasing the clomiphene dose if ovulation occurs, even if pregnancy does not occur. Most pregnancies occur within the first six cycles of using clomiphene, and there is little benefit of continuing clomiphene treatment after six unsuccessful cycles.

Benefits — The benefit of clomiphene is that it is relatively inexpensive and can be used before other, more expensive testing (such as hysterosalpingogram or laparoscopy) or infertility treatments (eg, in vitro fertilization). It does not require monitoring with ultrasound or blood hormone levels, although monitoring may be recommended in some cases. Clomiphene improves the chances of becoming pregnant for most women who ovulate irregularly, and carries a low risk of dangerous side effects.

Risks — Risks of clomiphene therapy include a slightly increased rate of multiple pregnancies; approximately 6 percent of women who use clomiphene have twins, while less than 0.5 percent have triplets or greater. There is a small risk of the ovaries becoming enlarged, although severe enlargement (known as ovarian hyperstimulation syndrome) is rare.

Common side effects of clomiphene include hot flashes, abdominal bloating and pain, nausea and vomiting, and breast tenderness. Visual symptoms such as blurring, double vision, or seeing spots occur in 1 to 2 percent of women, and usually resolve when treatment stops. Mood swings, depression, and headaches can occur, but are rarely serious enough to cause the woman to stop treatment.

There is no increased risk of birth defects, miscarriage, or learning disability in children of women who took clomiphene. There is no increased risk of breast cancer or uterine cancer. There may be a slightly increased risk of ovarian cancer if more than 12 cycles of clomiphene are used.

IMPROVING CLOMIPHENE SUCCESS — Women who do not become pregnant after three cycles of clomiphene may need further testing before continuing with treatment. This may include a hysterosalpingogram, blood testing, and if not previously done, a semen analysis of the male partner. (See "Patient information: Evaluation of the infertile couple").

If these tests are normal and the couple would like to continue with clomiphene treatment, additional interventions may improve success. Depending upon the individual, this may include weight loss or gain, or use of additional medications such as metformin or dexamethasone.

Weight loss — Women who are overweight or obese and who ovulate infrequently often benefit from weight loss as a treatment for their infertility. Overweight is defined as having a body mass index (BMI) greater than 27 kg/m2. To calculate BMI, divide weight in pounds by height in inches; then divide that number by height in inches and multiply by 703. A BMI table may also be used (show table 2A-2B).

Weight loss is an inexpensive and low-risk treatment with no side effects that has been proven to improve the chances of ovulation and pregnancy in women who are overweight. In addition, having a normal or near-normal weight can reduce the risk of complications during pregnancy. Furthermore, achieving and maintaining a weight in the normal range has life-long health benefits. A combination of decreased calorie intake and exercise are recommended to achieve a 5 to 10 percent weight loss. (See "Patient information: Diet and health").

Weight gain — Women who are underweight (defined as a BMI less than 17 kg/m2), have eating disorders (eg, bulimia or anorexia), or participate in strenuous exercise regimens may ovulate irregularly or not at all. These women may be advised to gain weight to a goal BMI of at least 19 kg/m2 (show table 2A-2B), increase calorie intake, and modify exercise habits to include less strenuous activities.

Treatment with human chorionic gonadotropin — Some women who do not have an increase in their LH level midcycle do not ovulate (show figure 1), despite having a normally developed follicle (which contains an egg). These women often benefit from an injection of human chorionic gonadotropin (hCG), which acts like LH to trigger ovulation. Transvaginal ultrasound is used to determine when the follicle is ready, and the woman or her partner can be taught to give the injection at home. Ovulation occurs 36 to 44 hours after the injection, and intercourse can be timed accordingly.

Treatment for insulin resistance — Women with polycystic ovary syndrome who have absent or irregular ovulation are often insulin resistant. Insulin is a hormone produced by the pancreas that functions to break down food into energy. Insulin resistance causes the body to produce excessive amounts of insulin, which leads to elevated levels of other hormones that interfere with ovulation. Treatment of insulin resistance can reduce these hormones, increase the chances of normal ovulation, and improve the chances of responding to clomiphene.

Metformin — Metformin (Glucophage®, Gumetza®, Riomet®, Fortamet®) is a medication that is used in the treatment of type 2 diabetes mellitus. It has also been used to treat insulin resistance in women with polycystic ovary syndrome and infertility if clomiphene treatment and/or weight loss is not successful. Some women who do not ovulate with clomiphene may ovulate with the combination of metformin plus clomiphene.

Metformin is thought to be safe to take while trying to become pregnant, but should be stopped once pregnancy is confirmed.

Glucocorticoid treatment — Women who are anovulatory WHO class 2 (show table 1) and have not ovulated in response to clomiphene treatment may benefit from treatment with clomiphene as well as a glucocorticoid (a type of steroid). Dexamethasone or prednisone are the glucorticoids most commonly used. One regimen is to use a glucocorticoid daily from the start of the treatment cycle through ovulation

CLOMIPHENE FAILURE — If a woman with anovulation does not become pregnant after three to six cycles of clomiphene, other infertility treatments may be considered. These include surgical treatments, ovulation induction with injectable medications and/or in vitro fertilization.

COSTS OF INFERTILITY TREATMENT — The costs of infertility treatments can be high depending upon what tests are required, the type and dose of medication(s) used, and the number of months that it takes to become pregnant. Insurance policies cover the costs of infertility treatment in some areas, although this varies by location and individual insurance policy. At this time, less than half of the states within the U.S. have laws requiring insurers to cover infertility treatment.

More information about a state's laws can be obtained by calling the state Insurance Commissioner's office. More information can also be found by visiting the website for the American Society of Reproductive Medicine (www.asrm.org/Patients/insur.html).

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
American Society for Reproductive Medicine

(www.asrm.org)
Resolve: The National Infertility Association

(www.resolve.org)
The International Council on Infertility Information Dissemination

(www.inciid.com)


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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Use of clomiphene citrate in women. Fertil Steril 2003; 80:1302.
2. Hughes, E, Collins, J, Vandekerckhove, P. Clomiphene citrate for unexplained subfertility in women (Cochrane review). Cochrane Database Syst Rev 2000; :CD000057.
3. Smith, YR, Randolph, JF Jr, Christman, GM, et al. Comparison of low-technology and high-technology monitoring of clomiphene citrate ovulation induction. Fertil Steril 1998; 70:165.
4. Barbieri, RL. Induction of ovulation in infertile women with hyperandrogenism and insulin resistance. Am J Obstet Gynecol 2000; 183:1412.

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