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

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 (sample brand names: 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 education: Evaluation of infertility in couples (Beyond the Basics)" and "Patient education: Treatment of male infertility (Beyond the Basics)".)

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

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 approximately 12 to 14 days before the next menstrual period (figure 1). A woman's best chance for becoming pregnant occurs when 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 with polycystic ovary syndrome (PCOS). Women who are unlikely to respond are those with absent periods and very low estrogen levels due to low body weight or exercise (called "hypothalamic amenorrhea"), or those with high follicle-stimulating hormone (FSH) levels, an indicator of ovarian aging (early menopause or "primary ovarian insufficiency"). (See "Patient education: Primary ovarian insufficiency (Beyond the Basics)".)

WHAT IS CLOMIPHENE? — Clomiphene is a weak estrogen-like hormone that acts on the hypothalamus, pituitary gland, and ovary to increase levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH, which is also important in the process of ovulation).

An increased level of FSH 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 education: Evaluation of infertility in couples (Beyond the Basics)".)

Dosing — Clomiphene is usually started on day 3, 4, or 5 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 1. If the woman does not have regular menstrual cycles (which is usually the situation), she may be given a course of progestin medication (medroxyprogesterone acetate [sample brand name: Provera]) to induce a period. However, a recent study suggests that this may not always be necessary. In a re-analysis of the study comparing clomiphene with metformin for ovulation induction, it was observed that the pregnancy rate was higher when clomiphene was started without inducing bleeding with medroxyprogesterone acetate [1]. By not waiting for medroxyprogesterone acetate-induced withdrawal bleeding, the time to ovulation is shorter.

Ovulation usually occurs between cycle days 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. Optimal timing of intercourse is on the day of the LH surge and the following day when ovulation occurs.

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). However, this requires that sperm survival in the upper genital tract is two or more days and, in some instances, this may not be the case.

Some health care 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/or blood testing to confirm whether ovulation occurred or not, which would affect the therapy recommendations for subsequent cycles. 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 is increased by 50 mg each month until ovulation occurs. There is no benefit of increasing the clomiphene dose if ovulation occurs, even if pregnancy does not occur. Nearly all pregnancies occur within the first six ovulatory cycles while using clomiphene, and there is little benefit of continuing clomiphene treatment after six unsuccessful ovulatory cycles. If this occurs it would suggest the need to evaluate other causes of infertility [2]. Failure to achieve pregnancy when ovulation is occurring is not a "clomid failure." It usually means that other fertility issues are present, such as tubal or male factor.

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, gonadotropin therapy, in vitro fertilization [IVF]). 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. In addition to anovulation, clomiphene is also administered in conjunction with intrauterine insemination in unexplained infertility. (See "Unexplained infertility".)

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 [OHSS]) 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 (a radiograph test showing the uterus and fallopian tubes), blood testing, and if not previously done, a semen analysis of the male partner. (See "Patient education: Evaluation of infertility in couples (Beyond the Basics)".)

If these tests are normal and the couple would like to continue with clomiphene treatment, other interventions, such as weight loss or gain, might be suggested.

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 25 kg/m². You can find your BMI using an online calculator (calculator 1 and calculator 2).

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 lifelong health benefits.

A combination of decreased calorie intake and exercise are recommended to achieve a 5 to 10 percent weight loss. (See "Patient education: Diet and health (Beyond the Basics)".)

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 and calculator 2), 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 luteinizing hormone (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 education: Infertility treatment with gonadotropins (Beyond the Basics)", section on 'Intrauterine insemination'.)

Metformin — Metformin (sample brand names: Glucophage, Glumetza, 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 when administered to women who have failed to ovulate on clomiphene alone, it may not improve pregnancy rates when compared with clomiphene-only treatment. Therefore, adding metformin to clomiphene is not recommended for women with PCOS unless they have "pre-diabetes" or type 2 diabetes [3]. Women should be attentive to the association of PCOS and insulin resistance, particularly when the response to clomiphene citrate is unsuccessful.

Letrozole — Letrozole is a medication that is used for women with breast cancer. Letrozole also works for ovulation induction in women with PCOS. In 2014, researchers reported that in women with PCOS, the use of letrozole to induce ovulation resulted in higher live birth rates (eg, more women became pregnant and carried to term) than clomiphene [4]. Some physicians have started using letrozole, but it is important to know that this drug has not yet been approved by the US Food and Drug Administration (FDA) for ovulation induction.

FAILURE TO CONCEIVE WITH OVULATORY CYCLES OF CLOMIPHENE — 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 education: Evaluation of infertility in couples (Beyond the Basics)".)

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 (IVF). (See "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)".)

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 United States 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 (http://www.asrm.org/).

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Female infertility (The Basics)
Patient education: Male infertility (The Basics)
Patient education: Infertility in couples (The Basics)
Patient education: Endometriosis (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Evaluation of infertility in couples (Beyond the Basics)
Patient education: Treatment of male infertility (Beyond the Basics)
Patient education: Infertility treatment with gonadotropins (Beyond the Basics)
Patient education: In vitro fertilization (IVF) (Beyond the Basics)
Patient education: Diet and health (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Diagnosis of polycystic ovary syndrome in adults
Recurrent pregnancy loss: Management
Metformin for treatment of the polycystic ovary syndrome
Overview of ovulation induction
Treatments for female infertility
Ovulation induction with clomiphene citrate
Endometriosis: Treatment of infertility in females
Unexplained infertility

The following organizations also provide reliable health information.

●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)