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The Merck Manual of Medical Information--Home Edition
Section 22. Women's Health Issues
Chapter 240

Infertility

Infertility is the inability of a couple to achieve a pregnancy after repeated intercourse without contraception for 1 year.

Infertility affects about one of every five couples in the United States. It's increasingly common because people are marrying when they're older and are waiting longer to have a child. Nevertheless, up to 60 percent of the couples who haven't conceived after a year of trying eventually will conceive, with or without treatment. The goal of treatment is to reduce the time needed to conceive.

Causes of Infertility

Problem Area Percentage of Cases
Sperm 30 to 40
Ovulation 15 to 20
Fallopian tubes 25 to 40
Cervix 5
Unidentified factors 5 to 15

As a woman gets older, she is less likely to have a successful pregnancy. Particularly after age 35, a woman has a limited time to resolve infertility problems before menopause.

Major causes of infertility include problems with sperm, ovulation, the fallopian tubes, and the cervix as well as unidentified factors. The diagnosis and treatment of these problems require a thorough assessment of both partners.

Problems With Sperm

In an adult male, sperm are being formed continuously (spermatogenesis) in the testes. A nonspecialized cell requires about 72 to 74 days to develop into a mature sperm cell. From each testis, sperm move to the epididymis (a coiled tube located on top and down the back of the testis), where they are stored until ejaculation is about to occur. From the epididymis, sperm move through the vas deferens and the ejaculatory duct. In the ejaculatory duct, fluid produced by the seminal vesicles is added to the sperm to form semen, which moves through the urethra to be ejaculated. (see page 1056 in Chapter 228, Male Reproductive System)

To be fertile, a man must be able to deliver an adequate quantity of normal sperm to a woman's vagina. Various factors can interfere with this process, causing infertility.

An increase in the temperature of the testes from a prolonged fever or exposure to excessive heat can greatly reduce sperm count, decrease the vigor of sperm movement, and increase the number of abnormal sperm in semen. Sperm formation is most efficient at about 93.2° F., which is lower than normal body temperature. The testes, where sperm are formed, can be kept at this lower temperature because they are located in the scrotum, which is outside the body cavity.

Complete absence of sperm (azoospermia) results from a serious disorder within the testes or from blocked or missing vasa deferentia (on both sides). Semen that doesn't contain fructose, a sugar produced by the seminal vesicles, indicates that the vasa deferentia or seminal vesicles are missing or the ejaculatory ducts are blocked.

A varicocele, the most common anatomic abnormality in infertile men, is a mass of elongated, widened, snakelike veins in the scrotum, similar to varicose veins. It feels like a bag of worms. This abnormality may prevent proper drainage of blood from the testes, thus raising their temperature and reducing the rate of sperm formation.

More unusually, semen can travel in the wrong direction (retrograde ejaculation)--it backs up into the bladder instead of traveling down the penis. This disorder is more common in men who have had pelvic surgery, particularly prostate removal, and in men who have diabetes. Retrograde ejaculation can also result from abnormal nerve function.

Diagnosis

After obtaining a medical history and performing a physical examination, a doctor orders a semen analysis, the main screening test for male infertility. The man is asked not to ejaculate for 2 to 3 days before the analysis. For the analysis, he is asked to ejaculate, usually by masturbation, into a clean glass jar, preferably at the laboratory site. For men who have difficulty producing a semen sample this way, special condoms that have no lubricants or chemicals toxic to sperm can be used to collect semen during intercourse. An analysis based on two or three separate samples is more reliable.

If the semen sample is abnormal, the analysis may be repeated because samples from the same man normally vary greatly. If the semen still seems to be abnormal, the doctor seeks possible causes, such as mumps involving the testes (mumps orchitis), a sudden illness or prolonged fever in the previous 3 months, injury to the testes, exposure to industrial or environmental toxins, use of diethylstilbestrol or anabolic steroids, drug use, and alcohol intake. However, a low sperm count may indicate only that too little time had elapsed since the last ejaculation or that only some of the semen was deposited in the collection jar.

The doctor examines the man for physical abnormalities, such as undescended testes, and for signs of hereditary or hormonal disorders that might explain the infertility. Hormonal disorders that reduce testosterone production (hypogonadism) (see page 1298 in Chapter 268, Hormonal Disorders) can originate in the testes or other glands, such as the pituitary.

Infertility centers perform tests of sperm function and quality, often before medically assisted fertilization techniques are considered. One such test detects antibodies to sperm; another determines whether sperm membranes are intact. Still others can determine the sperm's ability to bind to the egg and penetrate it.

Treatment

Treatment depends on the cause of infertility.

Clomiphene, a drug used to induce ovulation in women, can be used to try to increase sperm counts in men. However, clomiphene doesn't seem to improve the sperm's ability to move or to reduce the number of abnormal sperm, and it hasn't been proved to increase fertility.

For men who have few normal sperm, artificial insemination may slightly enhance pregnancy rates because it uses the first portion of the ejaculated semen, which has the greatest concentration of sperm. A newer technique that selects only the most active sperm (washed sperm) is somewhat more successful. In vitro fertilization and gamete intrafallopian tube transfer (GIFT), which are much more complex and costly procedures, are successful in treating certain types of male infertility.

If a man produces no sperm, inseminating the woman with sperm from another man (a donor) can be considered. Because of the danger of contracting sexually transmitted diseases, including AIDS, fresh semen samples from donors are no longer used. Instead, frozen sperm samples should be obtained from a certified sperm bank, which has tested the donors for sexually transmitted diseases. However, pregnancy is less likely to result when frozen, rather than fresh, sperm samples are used.

Varicoceles can be treated with minor surgery. Studies suggest that pregnancy results in 30 to 50 percent of cases after the male partner has had varicocele surgery, but additional studies are needed for confirmation.

Problems With Ovulation

Ovulation is the release of an egg by the ovary.

A woman who has regular menstrual periods every 26 to 35 days, preceded by breast tenderness, lower abdominal swelling, and mood changes, usually releases one egg from a follicle (a fluid-filled cavity that contains an egg) in the ovary each month. A woman who has regular menstrual periods without these symptoms also may ovulate. If a woman has irregular periods or no periods (amenorrhea), (see page 1087 in Chapter 235, Absent or Abnormal Uterine Bleeding) the cause is determined before treatment to stimulate ovulation is started.

Monitoring Ovulation

Determining whether ovulation actually occurs is an important part of an infertility evaluation. Daily measurements of basal body temperature (temperature of the body at rest), usually taken immediately on awakening, may be used to determine if and when ovulation is occurring. A low point in basal body temperature suggests that ovulation is about to occur, whereas a slight, persistent rise of about 0.5° F. to 1° F. in temperature usually indicates that ovulation has occurred. However, basal body temperature is not a reliable or precise indicator of ovulation. At best, it predicts ovulation only within 2 days. More accurate techniques include ultrasound monitoring and ovulation predictor kits that detect an increase in luteinizing hormone (a hormone that induces ovulation), which peaks in the urine 24 to 36 hours before ovulation. Also, levels of the hormone progesterone in the blood or one of its breakdown products in the urine may be measured; a marked increase indicates that ovulation has occurred.

Whether ovulation occurs also can be determined by performing a biopsy: A small sample is removed from the lining of the uterus 10 to 12 days after ovulation is presumed to have occurred; the sample is examined under a microscope. If changes that normally occur in the uterine lining after ovulation are seen, ovulation has occurred. (see illustration, page 1076)

Treatment

A drug to induce ovulation is selected on the basis of the specific problem. For a woman who hasn't ovulated for a long time (chronic anovulation), clomiphene is usually preferred. First, a menstrual period is induced with another drug, medroxyprogesterone acetate. The woman then takes clomiphene for 5 days. Usually, she ovulates 5 to 10 days (average, 7 days) after clomiphene is stopped and has a period 14 to 16 days after ovulation.

If a woman doesn't have a period after treatment with clomiphene, she takes a pregnancy test. If she isn't pregnant, the treatment cycle is repeated with increasing doses of clomiphene until ovulation occurs or the maximum dose is reached. When the doctor determines the dose that induces ovulation, the woman takes that dose for at least six more treatment cycles. Most women who become pregnant do so by the sixth cycle in which ovulation occurs. Overall, about 75 to 80 percent of women treated with clomiphene ovulate, but only about 40 to 50 percent become pregnant. About 5 percent of pregnancies in women treated with clomiphene are multiple, primarily twins.

Because there is some concern that prolonged use of clomiphene may increase the risk of ovarian cancer, doctors take several precautions: They evaluate the woman before treatment, closely monitor her during treatment, and limit the number of treatment cycles.

Side effects of clomiphene include hot flashes, abdominal swelling, breast tenderness, nausea, vision problems, and headaches. About 5 percent of women treated with clomiphene develop ovarian hyperstimulation syndrome, in which the ovaries become greatly enlarged and a large amount of fluid shifts from the bloodstream to the abdominal cavity. To try to prevent this disorder, the doctor prescribes the lowest effective dose and withholds clomiphene if the ovaries enlarge.

If a woman doesn't ovulate or become pregnant during treatment with clomiphene, hormonal therapy with human menopausal gonadotropins can be tried. Currently, these hormones are extracted from the urine of postmenopausal women, but synthetic versions are being tested. Because human menopausal gonadotropins are expensive and have severe side effects, doctors don't recommend trying this form of therapy until they are sure that ovulation problems, not problems with sperm or fallopian tubes, are the cause of infertility. Even then, treatment cycles are closely supervised by doctors experienced in using these hormones.

Human menopausal gonadotropins, which are injected into the muscle, stimulate the ovarian follicles to mature. To monitor maturation, a doctor measures blood levels of the hormone estradiol and examines ultrasound scans of the pelvis. Doses are adjusted on the basis of the woman's response to the hormones. After the follicles are mature, the woman is given an injection of a different hormone, human chorionic gonadotropin, to trigger ovulation. Although more than 95 percent of the women treated with these hormones ovulate, only 50 to 75 percent become pregnant. In women treated with human menopausal gonadotropins, 10 to 30 percent of pregnancies are multiple, primarily twins.

A serious side effect of treatment with human menopausal gonadotropins is ovarian hyperstimulation syndrome, which develops in 10 to 20 percent of the women treated. This syndrome can be life threatening but usually can be avoided if the doctor closely monitors the treatment and withholds human chorionic gonadotropin when the woman's response becomes excessive. Human menopausal gonadotropins may increase the risk of ovarian cancer, but current evidence is insubstantial.

Sometimes, ovulation doesn't occur because the hypothalamus (the part of the brain that coordinates and controls hormonal activity) doesn't secrete gonadotropin-releasing hormone, which is necessary for ovulation. In these cases, a synthetic version of gonadotropin-releasing hormone may be used to induce ovulation. The risk of ovarian hyperstimulation is low with this treatment, so intensive monitoring isn't needed.

Problems With the Fallopian Tubes

The fallopian tubes may be abnormal in structure or function. The primary causes of problems are infection, endometriosis, and surgical closure of the fallopian tubes (tubal ligation) as a means of sterilization.

Causes of Fallopian Tube Problems

Congenital abnormalities
Pelvic inflammatory disease
Ectopic pregnancy
Ruptured appendix
Lower abdominal surgery
Endometriosis
Previous surgical closure (tubal ligation)

To determine if the fallopian tubes are open, a doctor orders a hysterosalpingogram (a special x-ray of the uterus and fallopian tubes) (see box, page 1073) shortly after the woman's menstrual period ends. This diagnostic test also shows congenital abnormalities (birth defects) of the uterus and fallopian tubes, fibrous masses in the uterus, and adhesions (fibrous bands that connect normally unconnected structures) in the uterus or pelvis. For reasons not clearly understood, fertility appears to be slightly enhanced after a normal hysterosalpingogram. Therefore, the doctor may wait to see if a woman becomes pregnant after this test has been performed before ordering additional tests of fallopian tube function.

If the hysterosalpingogram shows an abnormality such as adhesions in the uterus, the doctor examines the uterus with a hysteroscope (a viewing tube inserted through the cervix into the uterus). The hysteroscope may be manipulated to break adhesions during the procedure, thus increasing the likelihood that the woman will become pregnant. If more diagnostic information is needed, a laparoscope, a small viewing tube, is inserted in the pelvic cavity through a small incision in the abdominal wall. (see box, page 1073) This procedure, which is typically performed while the woman is under general anesthesia, enables the doctor to view the uterus, fallopian tubes, and ovaries. The laparoscope also may be used to remove abnormal tissue if the woman has endometriosis or to break adhesions in the pelvic cavity. Drugs can be used to treat endometriosis. For infections, antibiotics must be used. Surgery to repair a damaged fallopian tube, caused by an ectopic (tubal) pregnancy, a tubal ligation, or an infection, can be attempted, but it results in a low rate of normal pregnancies and a high rate of ectopic pregnancies. For these reasons, surgery isn't recommended often.

Problems With the Cervix

Mucus in the cervix (the lower part of the uterus that opens into the vagina) acts as a filter, preventing bacteria in the vagina from entering the uterus; the mucus also enhances sperm survival. This mucus is thick and impenetrable to sperm until the follicular phase of the menstrual cycle, when the egg and follicle are maturing in the ovary. During this phase, the levels of the hormone estradiol increase, making the cervical mucus clear and elastic, so that sperm can move through it into the uterus to the fallopian tubes, where fertilization can take place.

Diagnosis and Treatment

A postcoital test, performed between 2 and 8 hours after intercourse, can determine whether sperm can survive in the cervical mucus. The test is scheduled for the midpoint of the menstrual cycle, when the estradiol level is highest and the woman is ovulating. Normally, the mucus is clear and can be stretched to 3 to 4 inches without breaking. Under a microscope, the mucus has a fernlike appearance, and at the highest magnification, at least five active sperm are visible at one time. Abnormal results include overly thick mucus, no sperm, and sperm clumping together because the mucus contains antibodies to the sperm. However, abnormal results don't always indicate a problem with the mucus. Sperm may be absent only because they were not deposited into the vagina during intercourse, and the mucus may be overly thick only because the test wasn't performed at the proper time in the menstrual cycle. Although this test is widely used, it's not highly accurate.

Treatment of cervical mucus problems includes intrauterine insemination, in which semen is placed directly in the uterus to bypass the mucus, and drugs to thin the mucus, such as guaifenesin--a common ingredient of cough syrups. However, there is no proof that these measures increase the likelihood of pregnancy.

Unidentified Factors

Even when no cause of infertility can be identified, the couple may be able to conceive eventually. Treating the woman with clomiphene or human menopausal gonadotropins and placing washed sperm in her uterus may reduce the time needed to conceive. If the woman hasn't conceived after four to six menstrual cycles, special techniques, such as in vitro fertilization or gamete intrafallopian tube transfer, may need to be considered.

Fertilization Techniques

After all other treatments have failed to result in a pregnancy, more and more infertile couples turn to in vitro (test tube) fertilization. This procedure involves stimulating the ovaries, retrieving released eggs, fertilizing the eggs, growing the embryos in a laboratory, and then implanting the embryos in the woman's uterus.

Typically, a combination of clomiphene, human menopausal gonadotropins, and a gonadotropin-releasing hormone agonist (a drug that stimulates the release of gonadotropins from the pituitary gland) is used to stimulate the ovaries so that many eggs will mature. Guided by ultrasound scanning, a doctor inserts a needle through the vagina or abdomen into the ovary and removes several eggs from the follicles. In the laboratory, the eggs are placed in a culture dish and fertilized with washed sperm. After about 40 hours, three or four embryos are transferred from the culture dish into the mother's uterus through the vagina. Additional embryos can be frozen in liquid nitrogen to be used later if pregnancy doesn't occur. Despite the transfer of several embryos, the chances of producing one full-term baby are only about 18 to 25 percent each time eggs are placed in the uterus.

If a woman has unexplained infertility or endometriosis but normal fallopian tube function, gamete intrafallopian tube transfer (GIFT) can be performed. Eggs and washed sperm are obtained as for in vitro fertilization, but the eggs aren't fertilized with the sperm in the laboratory. Instead, the eggs and sperm are transferred to the far end of the woman's fallopian tube through the abdominal wall (using laparoscopy) or the vagina (guided by ultrasound scanning), so that the egg can be fertilized in the fallopian tube. At most infertility centers, the success rate for each transfer is about 20 to 30 percent.

Variations of in vitro fertilization and GIFT include the transfer of a more mature embryo (zygote intrafallopian tube transfer), use of donor eggs, and transfer of frozen embryos to a surrogate mother. These techniques raise moral and ethical issues, including questions about the disposal of stored embryos (especially in cases of death or divorce), legal parentage if a surrogate mother is involved, and selective reduction of the number of implanted embryos (similar to abortion) when more than three develop.

Psychologic Aspects

While a couple is undergoing infertility treatment, one or both partners may experience frustration, emotional stress, feelings of inadequacy, and guilt. Feeling isolated and unable to communicate, they may become angry at or resentful toward each other, family, friends, or the doctor. During each month of treatment, the couple may vacillate between hope and despair. The emotional stress can lead to tearfulness, fatigue, anxiety, sleep or eating disturbances, and an inability to concentrate. In addition, the financial burden and time commitment involved in diagnosis and treatment can cause marital strife.

These problems can be lessened if both partners are involved in and are given information about the treatment process, regardless of which one has the diagnosed problem. Knowing what the chances of success are as well as realizing that treatment may not be successful and can't continue indefinitely can help a couple cope with the stress. Information about when to end treatment, when to seek a second opinion, and when to consider adoption is also helpful.

Counseling and psychologic support can help. Support groups for infertile couples, such as RESOLVE, are available at local and national levels.

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