Patient education: Infertility treatment with gonadotropins (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.

Approximately 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. 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."

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 infertility treatment with hormones called gonadotropins, 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: Ovulation induction with clomiphene or letrozole (Beyond the Basics)".)

WHAT ARE GONADOTROPINS? — Gonadotropins are two hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are normally produced by the pituitary gland. These hormones stimulate the ovaries to produce a "follicle," which contains an egg, and to release the egg from the ovary.

Gonadotropins can be used for treating infertility in people who do not ovulate on their own; they are often recommended for people who have already tried clomiphene citrate and/or letrozole, which are other treatments used for ovulation induction.

Gonadotropin therapy can also be used in people who do ovulate but are still having trouble conceiving, or for people undergoing intrauterine insemination (IUI) or in vitro fertilization (IVF).

Most gonadotropin preparations used for infertility treatment are made in a laboratory and must be injected under the skin to be effective. For most people, a preparation containing only FSH injections is recommended. People who do not have regular menstrual periods and have very low levels of LH and FSH require a preparation containing both LH and FSH.

WHO SHOULD CONSIDER INFERTILITY TREATMENT WITH GONADOTROPINS?

Candidates for gonadotropin therapy — There are two categories in which treatment with gonadotropins may be recommended:

●People who do not ovulate at all or who ovulate irregularly – In this group, gonadotropins are given as second-line treatment (after clomiphene citrate and/or letrozole) with a goal of stimulating the development of a single follicle and release of a single egg. (See "Patient education: Absent or irregular periods (Beyond the Basics)".)

●People who ovulate normally – Gonadotropins may improve the chances of becoming pregnant in people who ovulate normally by stimulating the ovaries to produce more than one follicle. However, this also increases the risk of having a multiple pregnancy (twins, triplets, or more). For this reason, many doctors recommend giving gonadotropins with in vitro fertilization (IVF) and transferring a single embryo, but gonadotropin therapy is often tried with intrauterine insemination (IUI) before moving to IVF. In this setting, it is important to be monitored closely with ultrasound to lower the risk of a multiple birth and associated pregnancy complications.

Other treatment options — In people who do not ovulate, particularly those with polycystic ovary syndrome (PCOS), letrozole or clomiphene, rather than gonadotropins, is used as initial treatment. The advantages of letrozole or clomiphene compared with gonadotropins include ease of oral administration, fewer side effects, lower cost (of the medication itself, as well as the monitoring), lower risk of multiple pregnancies, and reduced time commitment (related to monitoring during treatment). Another option that is occasionally considered for people with PCOS is laparoscopic minimal surgery of the ovaries. This may help restore ovulation. (See "Patient education: Polycystic ovary syndrome (PCOS) (Beyond the Basics)", section on 'Treatment of infertility' and "Patient education: Ovulation induction with clomiphene or letrozole (Beyond the Basics)".)

HOW IS GONADOTROPIN THERAPY GIVEN?

Timing and protocol — There are a number of protocols for the type, dosing, and timing of ovulation induction with gonadotropins. The protocol used will depend on your individual situation and your health care provider's preferences.

The schedule described below is an example; your provider will give you specific instructions. In general:

●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. You will most likely be asked to call your provider's office on the first day of bleeding to schedule an appointment for blood tests and an ultrasound.

●On days 3 to 5, you may be asked to have blood testing to measure hormone levels and a pelvic (transvaginal) ultrasound to be sure that there are no large preexisting cysts on the ovaries. You will be given instructions about the dose and timing of your first injection based upon the results of these tests.

●There is variability in how people's bodies respond to follicle-stimulating hormone (FSH) injections. Some people require only small doses of FSH to stimulate follicle growth. Others require larger doses of FSH to stimulate follicle growth. Most clinicians prefer to start with small doses of FSH to minimize the risk of the growth of many follicles. If your provider recommends small doses of FSH, extra days of injections may be required to stimulate follicle growth.

●In most cases, you will give an injection of gonadotropins once per day, in the evening (between 5 and 8 PM, for example). The injection is given under the skin, usually in either the belly or the thigh (figure 2). You can give the injections yourself or have a partner or another person give them.

●After a few days of injections, you will have a pelvic ultrasound to measure follicle growth. For people who do not ovulate on their own, the goal of ovulation induction is to have one follicle that is approximately 15 to 18 mm in size. You may also get blood tests to measure estrogen levels. Blood testing and pelvic ultrasound may be repeated three or more times during a cycle.

If multiple large follicles are seen on ultrasound, your provider may suggest canceling the cycle. (See 'Canceling a cycle' below.)

●When blood testing and ultrasound measurements show that the follicle is "ready," you will be instructed to give an injection of human chorionic gonadotropin or "hCG" to trigger ovulation. hCG is known as "the pregnancy hormone"; its function is very similar to luteinizing hormone (LH). hCG is injected under the skin in the evening.

●You might be instructed to have sex at a particular time the following day to maximize your chances of getting pregnant. In other cases, intrauterine insemination (IUI) is the next step. (See 'Intrauterine insemination' below.)

Canceling a cycle — If three or more large follicles develop, this is likely to increase the risk of getting pregnant with multiples (twins, triplets, etc). In this case, your provider may recommend either cancelling the cycle or performing another procedure, because having multiple enlarged follicles can also increase the risk of a problem called "ovarian hyperstimulation syndrome." (See 'Ovarian hyperstimulation syndrome' below.)

If a cycle is canceled, you should stop the injections and talk with your provider about what to do next. They may recommend moving to in vitro fertilization (IVF), since this allows for a single embryo to be transferred, mitigating the risk of pregnancy with multiples.

Risk and side effects — Gonadotropins usually do not cause side effects directly. However, the ovaries become somewhat enlarged during treatment, which can cause abdominal discomfort and, in more severe cases, nausea and vomiting.

Ovarian hyperstimulation syndrome — OHSS is a condition in which the ovaries become moderately to severely enlarged and multiple follicles develop. In severe cases, this can cause severe abdominal pain, vomiting, blood clots in the legs or lungs, and fluid imbalances in the blood. Moderate OHSS occurs in less than 6 percent of cases, and severe OHSS occurs in less than 2 percent of people undergoing treatment with gonadotropins when used with appropriate dosing and strict monitoring.

OHSS can usually be prevented by cancelling the cycle when blood estrogen levels are too high or there are too many follicles seen on ultrasound. If the cycle is cancelled, no more injections of gonadotropins are given and the hCG injection will not be given. (See 'Canceling a cycle' above.)

Depending upon how enlarged the ovaries become, other treatments may be necessary. The next cycle of treatment may be resumed when the ovaries have returned to their normal size.

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 gonadotropins. 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.

IUI in combination with gonadotropins may increase the likelihood of pregnancy, but it also increases the chances for multiple pregnancy.

Sperm collection — If you have a male partner, they are usually instructed to obtain a semen sample by masturbating and ejaculating into a sterile container. The male should avoid ejaculating two to three days before collecting the sample. The semen is then prepared in a laboratory to separate the active sperm from the inactive sperm and seminal fluid. Another option is to use donor sperm; the process for collecting and preparing it is similar in this case.

IUI process — IUI is usually performed 12 to 36 hours after you inject human chorionic gonadotropin (hCG). During IUI, you will lie on your back on an examination table with your feet in supports. The provider will use a speculum to hold your vagina open and use a long, thin, flexible tube to insert the prepared sperm sample through the vagina and cervix into your uterus. This takes less than five minutes.

You may feel some cramping during the IUI procedure, although this usually resolves quickly. After the sperm sample is inserted and the tube is removed, you will most likely be asked to continue lying down for a few minutes. After this, you can resume your normal activities.

Risks — Serious complications of IUI are uncommon. Common reactions include pelvic cramping, light bleeding, and vaginal discharge. If these problems are persistent or become severe, it is important to call your health care provider as soon as possible.

TESTING FOR PREGNANCY AFTER INFERTILITY TREATMENT

Blood testing — Approximately two weeks after trying to conceive (either through sex or with intrauterine insemination), a blood or urine test for pregnancy can be done. These tests measure human chorionic gonadotropin (hCG) levels. Your health care provider will tell you when to schedule this test.

Home pregnancy test kits are not as sensitive for detecting an early pregnancy as blood testing. For this reason, testing at home before your scheduled test is usually not recommended.

The results of your hCG blood test indicate whether or not you are pregnant:

●If the first blood hCG level is <5 international units/L, this means you are not pregnant.

●If the first hCG level is >10 international units/L, the test is usually repeated 48 hours later to confirm that the levels are increasing. The hCG level should double every 29 to 53 hours during the first 30 days.

●If the second hCG level does not double or decreases, the blood test may be repeated again 48 hours later. Depending upon the situation, there is a possibility that the pregnancy is not viable. hCG levels do not increase or begin to decline when the pregnancy is not progressing normally. (See 'When infertility treatment is not successful' below.)

Ultrasound — If your hCG levels increase as expected, a pelvic ultrasound may be done three to four weeks after ovulation to confirm pregnancy. At this time, it is usually possible to see a gestational sac inside the uterus. The gestational sac is a fluid-filled sac containing the embryo. At five to six weeks of pregnancy (four to five weeks after ovulation), the "yolk sac" is usually visible. The yolk sac provides nourishment to the embryo early in development. Fetal cardiac (heart) activity is usually visible by 5.5 to 6 weeks of pregnancy.

Prenatal care — In most cases, regular prenatal care begins at 6 to 10 weeks of pregnancy. At this time, you will begin to see your doctor, nurse, or midwife on a regular basis. These visits allow your provider to monitor your and your baby's health and answer any questions you have.

WHEN INFERTILITY TREATMENT IS NOT SUCCESSFUL — More than one cycle of treatment is often needed in order to get pregnant. However, some people will not become pregnant despite multiple attempts. If you have had several cycles of unsuccessful ovulation induction, your health care provider might consider in vitro fertilization (IVF). (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 treatment. Support groups and counseling services are available at many infertility treatment centers, as well as on the internet (see 'Where to get more information' below). To find a reputable group, talk to your health care provider.

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 cycles required 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 your state Insurance Commissioner's office. Information can also be found by visiting the website for Resolve, a national infertility organization.

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: Ovulation induction with clomiphene or letrozole (Beyond the Basics)
Patient education: Evaluation of infertility in couples (Beyond the Basics)
Patient education: Absent or irregular periods (Beyond the Basics)
Patient education: In vitro fertilization (IVF) (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.

Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations
Pelvic inflammatory disease: Long-term complications
Clinical manifestations and diagnosis of early pregnancy
Effects of advanced maternal age on pregnancy
In vitro fertilization: Overview of clinical issues and questions
Female infertility: Reproductive surgery
Recurrent pregnancy loss: Management
Overview of ovulation induction
Endometriosis: Treatment of infertility in females
The preconception office visit
Prevention of ovarian hyperstimulation syndrome
Procedure for intrauterine insemination (IUI) using processed sperm
Treatments for male infertility
Unexplained infertility
Use of assisted reproduction in HIV- and hepatitis-infected couples

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)