Problems With Ovulation
In women, a common cause of infertility is an ovulation problem--that is, the ovaries do not release an egg each month (see Section 22, Chapter 241). Ovulation problems result when one part of the system that controls reproductive function malfunctions. This system includes the hypothalamus (an area of the brain), pituitary gland, adrenal glands, thyroid gland, and genital organs. For example, the ovaries may not produce enough progesterone, the female hormone that causes the lining of the uterus to thicken in preparation for a potential fetus. Ovulation may not occur because the hypothalamus does not secrete gonadotropin-releasing hormone, which stimulates the pituitary gland to produce the hormones that trigger ovulation (luteinizing hormone and follicle-stimulating hormone). High levels of prolactin (hyperprolactinemia), a hormone that stimulates milk production, may result in low levels of the hormones that trigger ovulation. Prolactin levels may be high because of a pituitary gland tumor (prolactinoma), which is almost always noncancerous. Ovulation problems may be due to polycystic ovary syndrome, thyroid gland disorders, adrenal gland disorders, excessive exercise, diabetes, weight loss, obesity, or psychologic stress. Sometimes the cause is early menopause--when the supply of eggs has run out early.
Ovulation is often the problem in women who have irregular periods or no periods (amenorrhea (see Section 22, Chapter 244)). It is sometimes the problem in women who have regular menstrual periods but do not have premenstrual symptoms, such as breast tenderness, lower abdominal swelling, and mood changes.
Diagnosis
To determine if or when ovulation is occurring, doctors may ask a woman to take her temperature at rest (basal body temperature) each day. Usually, the best time is immediately after awakening. A low point in basal body temperature suggests that ovulation is about to occur. An increase of more than 0.9° F (0.5° C) in temperature usually indicates that ovulation has occurred. However, basal body temperature does not reliably or precisely indicate when ovulation occurs. At best, it predicts ovulation only within 2 days. More accurate techniques include ultrasonography and ovulation predictor kits (which detect an increase in luteinizing hormone in the urine 24 to 36 hours before ovulation). These kits are used at home to test urine on several consecutive days. Also, the level of progesterone in the blood or saliva or the level of one of its by-products in the urine may be measured. A marked increase in these levels indicates that ovulation has occurred.
To determine whether ovulation is occurring normally, doctors may perform an endometrial biopsy. A small sample of tissue is removed from the lining of the uterus 10 to 12 days after ovulation is thought to have occurred. The sample is examined under a microscope. If changes that normally occur after ovulation are seen, ovulation has occurred normally. If the normal changes appear delayed, the problem may be inadequate production or inactivity of progesterone.
Treatment
A drug to trigger ovulation may be used. The particular drug is selected based on the specific problem. If ovulation has not occurred for a long time, clomiphene with medroxyprogesterone is usually preferred. First, the woman takes medroxyprogesterone, usually by mouth, to trigger a menstrual period. Then she takes clomiphene by mouth. Usually, she ovulates 5 to 10 days after clomiphene is discontinued and has a period 14 to 16 days after ovulation. Clomiphene is not effective for all causes of ovulation problems. It is most effective when the cause is polycystic ovary syndrome.
If a woman does not have a period after treatment with clomiphene, she takes a pregnancy test. If she is not pregnant, the treatment cycle is repeated. A higher dose of clomiphene is used in each cycle until ovulation occurs or the maximum dose is reached. When the dose that triggers ovulation is determined, the woman takes that dose for at least three to four more treatment cycles. Most women who become pregnant do so by the fourth cycle in which ovulation occurs. About 75 to 80% of women treated with clomiphene ovulate, but only about 40 to 50% become pregnant. About 5% of pregnancies in women treated with clomiphene involve more than one fetus, primarily twins.
Side effects of clomiphene include hot flashes, abdominal bloating, breast tenderness, nausea, vision problems, and headaches. About 5% of women treated with clomiphene develop ovarian hyperstimulation syndrome. In this syndrome, the ovaries enlarge greatly and a large amount of fluid moves out the bloodstream into the abdomen. This syndrome may be life threatening. To try to prevent it, doctors prescribe the lowest effective dose of clomiphene, and if the ovaries enlarge, they discontinue the drug.
If a woman does not ovulate or become pregnant during treatment with clomiphene, hormonal therapy with human gonadotropins, injected into a muscle or under the skin, can be tried. Human gonadotropins stimulate the follicles of the ovaries to mature. Follicles are fluid-filled cavities, each of which contain an egg (see Section 22, Chapter 241). Blood tests to measure estrogen levels and ultrasonography can detect when the follicles are mature. Then, the woman is given an injection of a different hormone, human chorionic gonadotropin, to trigger ovulation. When human gonadotropins are used appropriately, more than 95% of women treated with them ovulate, but only 50 to 75% become pregnant. About 10 to 30% of pregnancies in women treated with human gonadotropins involve more than one fetus, primarily twins.
Human gonadotropins can have severe side effects, so doctors closely monitor the woman during treatment. About 10 to 20% of women treated with human gonadotropins develop ovarian hyperstimulation syndrome (which can also occur with clomiphene). If hyperstimulation occurs (if the ovaries enlarge markedly or if estrogen levels increase too much), doctors do not give the woman human chorionic gonadotropin to trigger ovulation. Human gonadotropins are also expensive.
If the cause of infertility is early menopause, neither clomiphene nor human gonadotropins can stimulate ovulation.
If the hypothalamus does not secrete gonadotropin-releasing hormone, a synthetic version of this hormone, called gonadorelin, may be useful. This drug, like the natural hormone, stimulates the pituitary gland to produce the hormones that trigger ovulation. The risk of ovarian hyperstimulation is low with this treatment, so close monitoring is not needed. However, this drug is not available in the United States.
When the cause of infertility is high levels of the hormone prolactin, the best drug is one that acts like dopamine, called a dopamine agonist, such as bromocriptine or cabergoline. (Dopamine is a chemical messenger that generally inhibits the production of prolactin.)
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