Patient information: Infertility treatment with clomiphene (Clomid® or Serophene®)

INFERTILITY TREATMENT OVERVIEW

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. If the woman is not ovulating regularly, one treatment option involves 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, are discussed separately. (See "Patient information: Evaluation of the infertile couple" and "Patient information: Treatment of infertility in men".)

Other articles about infertility treatment are also available. (See "Patient information: Infertility treatment with gonadotropins" and "Patient information: In vitro fertilization (IVF)".)

OVULATION

To understand why and how clomiphene is used, it is important to have a basic understanding of 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 (figure 1). A woman's best chances for becoming pregnant occurs around the day of ovulation and one to two days before ovulation. This would be approximately 12 to 14 days after the first day of a 28 day menstrual cycle (day 1 of the menstrual cycle is the first day of bleeding).

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

WHAT IS CLOMIPHENE?

Clomiphene is a estrogen-like 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 up to three cycles of clomiphene.

Pretreatment evaluation — Before any infertility treatment begins, a woman and her partner should undergo an infertility evaluation 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 (one pill) once daily for five days. The first day of bleeding is 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 (eg, Provera®, medroxyprogesterone acetate) to induce a period.

Ovulation usually occurs between cycle day 14 and 19. Most fertility specialists recommend the use of an ovulation predictor kit to plan intercourse. The kit uses a urine sample to predict when ovulation is about to occur by measuring the LH level; these are available without a prescription in most pharmacies. If an ovulation predictor kit is not used, the couple is advised to have intercourse every other day for one week, beginning around day 10 (10 days after the menstrual period starts).

Some healthcare providers recommend 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, although 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 while 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 it 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, headaches, abdominal bloating and pain, nausea and vomiting, mood changes, 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.

Most studies do not show an 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 are usually encouraged to have further testing before continuing with infertility treatment. This may include a hysterosalpingogram (an x-ray test showing the uterus and fallopian tubes), 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, use of other therapies (in addition to clomiphene) may improve success. Depending upon the individual, this may include weight loss or gain, or use of additional medications, such as 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. A BMI calculator is available here (calculator 1).

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 who 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 (calculator 1), increase calorie intake, and modify exercise habits to include less strenuous activities.

Treatment with human chorionic gonadotropin — Some women do not have an increase in their LH level midcycle and do not ovulate (figure 1), despite having a normally developed follicle (which contains an egg). These women often benefit from using an injection of human chorionic gonadotropin (hCG), which triggers 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. hCG may also be recommended for women who will have a procedure, such as intrauterine insemination. (See "Patient information: Infertility treatment with gonadotropins", in the section on intrauterine insemination).

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 in women with polycystic ovary syndrome (PCOS) and infertility if clomiphene treatment and weight loss are not successful.

Although metformin increases the chance of ovulating, it may not improve pregnancy rates when compared to clomiphene-only treatment. Therefore, adding metformin to clomiphene is not recommended for women with PCOS unless they have "pre-diabetes" or type 2 diabetes [1].

CLOMIPHENE FAILURE

If a woman with anovulation does not become pregnant despite ovulating during three cycles of clomiphene, there may be other causes of infertility (eg, endometriosis, adhesions, male factors). If a complete infertility evaluation has not been done, it should be done at this point. (See "Patient information: Evaluation of the infertile couple".)

Other infertility treatments may be recommended if clomiphene treatment is not successful; these include surgical treatment (to eliminate scar tissue or fibroids), ovulation induction with injectable gonadotropins, and/or in vitro fertilization. (See "Patient information: Infertility treatment with gonadotropins".)

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 states, although this varies by location and individual insurance policy. Less than half of the states within the US 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 people 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.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Evaluation of the infertile couple
Patient information: Treatment of infertility in men
Patient information: Infertility treatment with gonadotropins
Patient information: In vitro fertilization (IVF)
Patient information: Diet and health

Professional Level Information:
Diagnosis of polycystic ovary syndrome in adults
Laparoscopic surgery for ovulation induction in polycystic ovary syndrome
Management of couples with recurrent pregnancy loss
Metformin for treatment of the polycystic ovary syndrome
Overview of ovulation induction
Overview of treatment of female infertility
Ovulation induction with clomiphene citrate
Pathogenesis and treatment of infertility in women with endometriosis
Strategies for improving the efficacy of clomiphene induction of ovulation
Treatment of unexplained infertility

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)

Patient Support — There are a number of online forums where patients can find information and support from other people with similar conditions.

• About.com Infertility Conditions Forum

      (http://infertility.about.com/forum)

[2-5]