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INTRODUCTION — Infertility is defined as a couple's inability to become pregnant within 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.
Gonadotropins are hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) that can be given in an injection to stimulate a woman's ovaries to produce follicles, which contain an oocyte (egg). Gonadotropins are used for ovarian stimulation in three main settings:
●To induce ovulation in women who do not ovulate on their own (many of whom have already tried clomiphene citrate and/or letrozole)
●For women who do ovulate but who are having trouble conceiving (unexplained infertility)
●For women undergoing assisted reproductive technologies (ART) such as in vitro fertilization
This topic will review who should consider gonadotropins, how they are given, the side effects of treatment, and other procedures that may be used with gonadotropins to increase the chances of pregnancy. The use of other medications to induce ovulation and the evaluation of infertility are discussed separately. (See "Patient education: Ovulation induction with clomiphene (Beyond the Basics)" and "Patient education: Evaluation of infertility in couples (Beyond the Basics)".)
PREPARING FOR INFERTILITY TREATMENT — Before any infertility treatment begins, a woman and her partner should undergo an evaluation to determine the best course of 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. In women with amenorrhea due to anovulation (and no chance to become pregnant without medical intervention), infertility treatment should be initiated soon after the initial consultation and evaluation. (See "Patient education: Evaluation of infertility in couples (Beyond the Basics)" and "Evaluation and management of secondary amenorrhea", section on 'Initial evaluation'.)
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 (oocyte) and to release the egg from the ovary.
Most gonadotropin preparations used for infertility treatment are produced in a laboratory (called recombinant preparations) and must be injected under the skin to be effective. For most women, a preparation containing only FSH injections is recommended. Women who do not have regular menstrual periods and who have very low levels of LH and FSH require a preparation containing both LH and FSH.
WHO SHOULD CONSIDER INFERTILITY TREATMENT WITH GONADOTROPINS? — There are two categories of women who may benefit from treatment with gonadotropins:
●Women who do not ovulate at all or who ovulate irregularly (called anovulation and oligoovulation, respectively). Gonadotropins are given in this group with a goal of stimulating development of a single follicle and ovulation of a single egg. (See "Patient education: Absent or irregular periods (Beyond the Basics)".)
●Women who ovulate normally. Gonadotropins may improve the chances of becoming pregnant (with in vitro fertilization [IVF], intrauterine insemination [IUI], or by natural intercourse) by stimulating the ovaries to produce more than one follicle. Each of these approaches is associated with an increased risk of multiple pregnancies.
Depending upon the situation, one of several infertility treatments may be recommended. In women who do not ovulate, letrozole or clomiphene, rather than gonadotropins, is often recommended as an initial treatment (particularly in women with polycystic ovary syndrome [PCOS]) (see "Ovulation induction with letrozole"). The advantages of clomiphene or letrozole 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). (See "Patient education: Ovulation induction with clomiphene (Beyond the Basics)".)
If the woman has tried oral ovulation induction drugs (letrozole and/or clomiphene) without getting pregnant, the next step is often to try ovarian stimulation with injectable gonadotropins. Gonadotropins may also be used in women with regular menstrual cycles along with IUI or IVF. Another option that is sometimes considered for women with PCOS is laparoscopic minimal surgery of the ovaries. This may help restore ovulation.
GONADOTROPIN PROTOCOL — There are a number of protocols for the type, dosing, and timing of ovulation induction with gonadotropins [1]. The protocol used will depend on the woman's situation and the clinician's preferences. The protocol described below is an example and may differ from your instructions.
●The first day of menstrual bleeding is considered day 1 of the cycle (which can be a progestin-induced bleed for those with oligoovulation or anovulation). Most providers ask that you call 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 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.
Women vary considerably in their response to follicle-stimulating hormone (FSH) injections. Some women require only small doses of FSH to stimulate follicle growth. Other women 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 small doses of FSH are utilized, 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 can be given under the skin in most cases.
●After a few days of injections, you will be asked to have a pelvic ultrasound to measure follicle growth and possibly a blood test to measure hormone levels (serum estradiol). Depending upon the results of these tests, the gonadotropin dose may be maintained, increased, or decreased. Blood testing and pelvic ultrasound may be repeated three or more times during a cycle.
●For women who do not ovulate on their own, the goal is to have one follicle that is approximately 15 to 18 mm in size. If three or more follicles (greater than 15 mm each) are seen, the cycle may be cancelled due to the risk of becoming pregnant with twins, triplets, etc [2]. In some situations, the cycle may be converted to in vitro fertilization (IVF), so that the clinician can control the number of embryos that are placed in the uterus.
If the cycle is cancelled, you should stop the injections and follow-up with your health care provider.
●When blood testing and ultrasound measurements show that the follicle is "ready," you will be instructed to give an injection of hCG to trigger ovulation. The pregnancy hormone hCG is also called human chorionic gonadotropin and its function is very similar to luteinizing hormone (LH). hCG is usually injected under the skin in the evening.
●Some women will be instructed to have intercourse at a particular time the following day. In other cases, intrauterine insemination (IUI) will be recommended. (See 'Intrauterine insemination' below.)
Side effects of treatment — 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. The main risks of gonadotropin therapy are enlarged ovaries (causing abdominal discomfort), the development of ovarian hyperstimulation syndrome (OHSS) and conceiving a multiple pregnancy [1]. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)
Ovarian hyperstimulation syndrome — OHSS is a condition in which the ovaries become moderately to severely enlarged and multiple follicles develop on the ovaries. In severe cases, the woman may develop 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 women undergoing treatment with gonadotropins.
OHSS can be prevented most of the time 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. 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. (See "Prevention of ovarian hyperstimulation syndrome".)
INTRAUTERINE INSEMINATION — Intrauterine insemination (IUI) places sperm directly inside the woman's uterus, which may increase her chances of becoming pregnant. IUI, in combination with gonadotropins, may be recommended if the woman does not ovulate or when there is another known issue, such as a low sperm count, difficulty ejaculating, or a narrow cervical opening [1], or if the couple's infertility is unexplained [2]. IUI in combination with gonadotropins may increase overall pregnancy chances, but it also increases the chances for multiple pregnancy.
The male partner is usually instructed to obtain a semen sample by masturbating and ejaculating into a sterile container. The man 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. The process is similar if donor sperm is used.
Procedure — IUI is usually performed 12 to 36 hours after the woman injects human chorionic gonadotropin (hCG). During IUI, the woman lies on her back on an examination table and rests her feet in supports. A speculum is inserted in the vagina and a long, thin, flexible tube is used to insert the prepared sperm sample through the vagina and cervix inside the uterus. This takes less than five minutes.
The woman may feel some cramping during the procedure, although this usually resolves quickly. After the sperm sample is inserted and the tube is removed, the woman is usually asked to continue lying down for a few minutes. The woman may then resume her normal activities.
Postprocedure care — 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 a health care provider as soon as possible.
TESTING FOR PREGNANCY AFTER INFERTILITY TREATMENT
Blood testing — Approximately two weeks after intrauterine insemination (IUI) or intercourse, a blood or urine test for pregnancy (called human chorionic gonadotropin [hCG]) can be done. Home urine pregnancy testing is not as sensitive for detecting an early pregnancy as blood testing.
●If the first blood hCG level is <5 international units/L, the woman is 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 the hCG levels increase as expected, a pelvic ultrasound may be done three to four weeks after ovulation. 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 (image 1). 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. A heartbeat is usually visible by 5.5 to 6 weeks of pregnancy.
Pregnancy care — In most cases, prenatal care begins at 6 to 10 weeks of pregnancy. At this time, the woman will begin to see her clinician or nurse on a regular basis. These visits allow the provider to monitor the woman and baby's health and to answer any questions.
WHEN INFERTILITY TREATMENT IS NOT SUCCESSFUL — Ovarian stimulation using gonadotropins combined with intrauterine insemination (IUI) has a higher rate of success in most cases. However, more than one cycle of treatment is often necessary before pregnancy occurs. Some women will not become pregnant despite multiple attempts. Depending upon the situation, the next step may be to consider in vitro fertilization (IVF). (See "Patient education: In vitro fertilization (IVF) (Beyond the Basics)".)
It can be difficult to deal with the emotional highs and lows of infertility treatment. This is especially true if the woman (and her partner) have been trying to conceive for a long time, if treatment is not covered by insurance, and if there are any underlying problems in the couple's life (eg, medical, family or partner, job, financial).
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 [3].
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 (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
Long-term complications of pelvic inflammatory disease
Clinical manifestations and diagnosis of early pregnancy
Effects of advanced maternal age on pregnancy
In vitro fertilization: Overview of clinical issues and questions
Reproductive surgery for female infertility
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
●Resolve: The National Infertility Association
