Patient education: Ovulation induction with clomiphene or letrozole (Beyond the Basics)

INTRODUCTION — Doctors use the term "infertility" when a couple is unable to become pregnant after one year of unprotected sex. In any given year, approximately 15 percent of couples in North America and Europe who are trying to conceive have infertility.

About once a month, an egg is released by one of the ovaries; this is called "ovulation." The egg travels down the fallopian tube, and if it is fertilized by a partner's sperm, pregnancy begins (figure 1). Some people have infertility because they do not ovulate regularly or at all. A common cause of this is polycystic ovary syndrome (PCOS). In other cases, the person does ovulate, but still has trouble getting pregnant. In either of these situations, treatment with hormones can stimulate the body to ovulate, which increases the chances of being able to conceive. Doctors call this "ovulation induction." (See "Patient education: Polycystic ovary syndrome (PCOS) (Beyond the Basics)", section on 'Treatment of infertility'.)

Before beginning any treatment for infertility, it's important that you and your partner both be evaluated in order to identify any potential causes and develop a treatment plan. This evaluation may include a complete history and physical examination, a semen analysis (for the male partner), blood testing, and other tests depending upon the individual situation. If it is determined that you are not ovulating, this means you will need medical intervention to get pregnant; treatment should be initiated soon after the initial consultation and evaluation. (See "Patient education: Evaluation of infertility in couples (Beyond the Basics)".)

This topic will discuss ovulation induction with oral medications (clomiphene or letrozole), including who should consider this option, how the treatment is given, side effects, and other procedures that may also be used to increase the chances of pregnancy. Other medications used to induce ovulation are discussed separately. (See "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)".)

WHAT ORAL MEDICATIONS CAN BE USED FOR OVULATION INDUCTION? — Health care providers can prescribe two different oral (pill) medications for ovulation induction: clomiphene and letrozole.

Clomiphene — Clomiphene (brand name: Clomid) is a weak estrogen-like hormone that acts on the hypothalamus, pituitary gland, and ovary to increase levels of certain hormones responsible for ovulation.

Letrozole — Letrozole (brand name: Femara) is a medication that is used in the treatment of breast cancer; however, it also works for inducing ovulation. Many health care providers recommend that people with PCOS try letrozole first, because studies have found it to be more effective. However, it is important to know that this drug has not yet been approved by the US Food and Drug Administration (FDA) for ovulation induction.

Before prescribing one of these medications, your provider will confirm that you are a candidate for ovulation induction (see 'Who should consider ovulation induction?' below). They will also do a physical exam and order tests to rule out other possible causes of infertility.

WHO SHOULD CONSIDER OVULATION INDUCTION? — There are two categories in which treatment with clomiphene or letrozole may be recommended:

●People who do not ovulate at all or who ovulate irregularly due to PCOS – The goal is to induce ovulation and increase the chances that the person will conceive a pregnancy.

●People who ovulate normally but are having trouble getting pregnant – In this group, clomiphene is usually tried first, along with intrauterine insemination (IUI). (See 'Intrauterine insemination' below.)

HOW DO I TAKE MEDICATION TO INDUCE OVULATION? — The exact protocol and schedule will depend on which medication your health care provider has prescribed as well as your individual situation.

Before starting medication — If you have polycystic ovary syndrome (PCOS) and have excess body weight or obesity, your provider may suggest trying to lose weight before taking medication to induce ovulation. Losing 5 to 10 percent of your body weight may lead to more regular periods and the return of ovulation without medication. Your provider can talk to you about your options for weight loss if this is something that could benefit you. (See "Patient education: Polycystic ovary syndrome (PCOS) (Beyond the Basics)", section on 'Weight gain and obesity' and "Patient education: Losing weight (Beyond the Basics)" and "Patient education: Weight loss surgery and procedures (Beyond the Basics)".)

Medication dosing and schedule — The dose will depend on which medication your health care provider prescribes. With both clomiphene and letrozole, the dose can be increased over time if ovulation induction does not result in pregnancy.

When you take the medication will depend on where you are in your menstrual cycle:

●The first day of menstrual bleeding is considered day 1 of the cycle. Some people who do not have regular menstrual cycles will take a hormone called progestin to help induce a period.

●Clomiphene is usually started on day 3, 4, or 5 of the cycle. Letrozole is started on day 3. In either case, you continue taking the medication once a day for five days.

●Ovulation usually occurs between cycle days 14 and 19. Most fertility specialists recommend using an ovulation predictor kit in order to know when your body is preparing to ovulate. These kits use a urine sample to measure hormone levels; they are available without a prescription in most pharmacies.

●You will be instructed to have sex on specific days to maximize your chances of getting pregnant. Many providers suggest having sex every other day for one week beginning five days after the last day of medication. Using an at-home ovulation predictor kit can also help you identify the optimal time to try to conceive. In some cases, the next step might be intrauterine insemination (IUI) instead of trying to conceive through sex. (See 'Intrauterine insemination' below.)

●Some health care providers recommend monitoring with pelvic (transvaginal) ultrasound. 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). Your provider might also order a blood test later in your cycle to confirm that ovulation has occurred.

Benefits — The benefit of these medications is that they are 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]). People using them do not absolutely require monitoring with ultrasound or blood hormone levels, although many health care providers do monitor with ultrasound. Clomiphene improves the chances of becoming pregnant for most people 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.

Risks — Risks of clomiphene therapy include a slightly increased rate of multiple pregnancies; approximately 6 percent of people 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.

Uncommon side effects of clomiphene include hot flashes, headaches, and mood changes. Visual symptoms such as blurring, double vision, or seeing spots occur in 1 to 2 percent of cases, and usually resolve when treatment stops.

Most studies do not show an increased risk of birth defects, pregnancy loss, or learning disability in children of women who took clomiphene or letrozole. There is no evidence of an increased risk of breast, uterine, or ovarian cancer.

IMPROVING CLOMIPHENE SUCCESS — Depending on your situation, your health care provider might suggest other things you can do to increase your chances of getting pregnant.

Lifestyle changes — People with infertility can sometimes make lifestyle changes to increase their chances of getting pregnant. These may include:

●Avoiding smoking and limiting alcohol and caffeine

●Losing weight, if you have weight gain related to polycystic ovary syndrome (PCOS) (see 'Before starting medication' above)

●Improving nutrition – This might also involve increasing calorie intake and gaining weight if you are underweight

Treatment with human chorionic gonadotropin — Some people do not have an increase in their luteinizing hormone (LH) level midcycle; this is one of the hormones involved in ovulation, and if the LH level does not rise, the ovary will not release an egg. In this situation, an injection of human chorionic gonadotropin (hCG) can trigger ovulation. hCG is known as "the pregnancy hormone"; its function is very similar to luteinizing hormone (LH).

Pelvic (transvaginal) ultrasound is used to determine when the follicle is ready, and you or your partner can give the injection at home. Ovulation occurs 36 to 44 hours later; you can then time sex accordingly or proceed to intrauterine insemination if that is your plan. (See 'Intrauterine insemination' below.)

Intrauterine insemination — Intrauterine insemination (IUI) is a simple procedure to place sperm directly into the uterus, which may increase the chances of getting pregnant. If you do not ovulate, your provider may recommend IUI in combination with ovulation induction. Some people do IUI because they do not have a male partner. IUI may also be recommended in situations where there is another known cause of infertility, such as a low sperm count, difficulty ejaculating, or a narrow cervical opening, or if the cause is not known.

WHEN OVULATION INDUCTION IS NOT SUCCESSFUL — If you do not get pregnant after several cycles of clomiphene or letrozole, your health care provider may suggest further testing before continuing with treatment. This will help them figure out whether other factors besides polycystic ovary syndrome (PCOS) might be contributing to infertility. Tests 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 you do not get pregnant after several cycles of ovulation induction with either clomiphene or letrozole, your health care provider will talk to you about your options. This will depend on your situation and which factors might be contributing to infertility.

Options might include:

●Treatment with gonadotropins – These are hormones that are given by injection and can also induce ovulation. (See "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)".)

●In vitro fertilization (IVF) – This involves fertilizing an egg in a lab and then transferring the embryo(s) directly into the uterus. (See "Patient education: In vitro fertilization (IVF) (Beyond the Basics)".)

It can be difficult to cope with the emotional highs and lows of infertility treatment. This is especially true if you have been trying to conceive for a long time, if treatment is not covered by insurance, and if you are dealing with other life stressors.

Many people find it helpful to connect with others who are going through infertility. Support groups and counseling services are available at many infertility treatment centers, as well as on the internet. To find a reputable group, talk to your health care provider. (See "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)", section on 'Where to get more information'.)

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
Female infertility: Treatments
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)