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Problems With Ovulation

By

Robert W. Rebar

, MD, Western Michigan University Homer Stryker M.D. School of Medicine

Last full review/revision Sep 2020| Content last modified Sep 2020
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The ovaries do not release an egg each month, as usually occurs during a menstrual cycle.

  • Ovulation problems can result from dysfunction of the part of the brain and the glands that control ovulation or from dysfunction of the ovaries.

  • Women can determine whether ovulation is occurring and estimate when it occurs by measuring body temperature or using home predictor kits.

  • Doctors use ultrasonography or blood or urine tests to evaluate ovulation problems.

  • Drugs, usually clomiphene or letrozole, can often stimulate ovulation, but pregnancy does not always follow.

A problem with ovulation is a common cause of infertility in women.

Causes

Reproduction is controlled by a system that includes the hypothalamus (an area of the brain), pituitary gland, ovaries, and other glands, such as the adrenal glands and thyroid gland. Problems with ovulation (release of an egg) result when one part of this system malfunctions. For example,

  • The hypothalamus may not secrete gonadotropin-releasing hormone, which stimulates the pituitary gland to produce the hormones that stimulate the ovaries and ovulation (luteinizing hormone and follicle-stimulating hormone).

  • The pituitary gland may produce too little luteinizing hormone or follicle-stimulating hormone.

  • The ovaries may produce too little estrogen.

  • The pituitary gland may produce too much prolactin, a hormone that stimulates milk production. High levels of prolactin (hyperprolactinemia) may result in low levels of the hormones that stimulate ovulation. Prolactin levels may be high because of a pituitary gland tumor (prolactinoma), which is almost always noncancerous.

  • Other glands may malfunction. For example, the adrenal glands may overproduce male hormones (such as testosterone), or the thyroid glands can overproduce or underproduce thyroid hormones. These hormones help keep the pituitary gland and ovaries in balance.

Ovulation problems may be due to many disorders. The most common cause is

  • Polycystic ovary syndrome, which is usually characterized by excess weight and excess production of male hormones by the ovaries

Other causes of ovulation problems include

  • Excessive exercise

  • Certain drugs (such as estrogens and progestins and antidepressants)

  • Weight loss

  • Psychologic stress

Rarely, the cause is early menopause—when the supply of eggs runs out early.

An ovulation problem is often the cause of infertility in women who have irregular periods or no periods (amenorrhea). Infrequently, an ovulation problem is the cause of infertility in women who have regular menstrual periods but do not have premenstrual symptoms, such as breast tenderness, lower abdominal swelling, and mood changes.

Changes During the Menstrual Cycle

Changes During the Menstrual Cycle

The menstrual cycle is regulated by the complex interaction of hormones: luteinizing hormone, follicle-stimulating hormone, and the female sex hormones estrogen and progesterone.

The menstrual cycle has three phases:

  • Follicular (before release of the egg)

  • Ovulatory (egg release)

  • Luteal (after egg release)

The menstrual cycle begins with menstrual bleeding (menstruation), which marks the first day of the follicular phase.

When the follicular phase begins, levels of estrogen and progesterone are low. As a result, the top layers of the thickened lining of the uterus (endometrium) break down and are shed, and menstrual bleeding occurs. About this time, the follicle-stimulating hormone level increases slightly, stimulating the development of several follicles in the ovaries. Each follicle contains an egg. Later in this phase, as the follicle-stimulating hormone level decreases, only one follicle continues to develop. This follicle produces estrogen.

The ovulatory phase begins with a surge in luteinizing hormone and follicle-stimulating hormone levels. Luteinizing hormone stimulates egg release (ovulation), which usually occurs 32 to 36 hours after the surge begins. The estrogen level peaks during the surge, and the progesterone level starts to increase.

During the luteal phase, luteinizing hormone and follicle-stimulating hormone levels decrease. The ruptured follicle closes after releasing the egg and forms a corpus luteum, which produces progesterone. During most of this phase, the estrogen level is high. Progesterone and estrogen cause the lining of the uterus to thicken more, to prepare for possible fertilization. If the egg is not fertilized, the corpus luteum degenerates and no longer produces progesterone, the estrogen level decreases, the top layers of the lining break down and are shed, and menstrual bleeding occurs (the start of a new menstrual cycle).

Diagnosis

  • A description of the woman's menstrual periods

  • Sometimes daily measurement of body temperature

  • A home ovulation predictor kit

  • Ultrasonography

  • Blood or urine tests

Doctors ask women to describe their menstrual periods (menstrual history). Based on this information, doctors may be able to determine whether women are ovulating.

To determine if or when ovulation is occurring, doctors may ask a woman to take her temperature at rest (basal body temperature) each day. If possible, she should use a basal body temperature thermometer designed for women who are trying to become pregnant or, if it is unavailable, a mercury thermometer. Electronic thermometers are the least accurate. Usually, the best time is immediately after awakening and before getting out of bed. A decrease 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 just occurred. However, this method is inconvenient or stressful for many women and is not reliable or precise.

A more accurate method is

  • An ovulation predictor kit for use at home

This kit detects an increase in luteinizing hormone in the urine 24 to 36 hours before ovulation. To provide a more accurate result, some kits also measure by-products of estrogen. Urine is tested on several consecutive days.

Doctors can accurately determine whether and when ovulation occurs. Methods include

  • Ultrasonography

  • Measurement of the level of progesterone in the blood or the level of one of its by-products in the urine

A marked increase in levels of progesterone or its by-products indicates that ovulation has occurred.

Doctors may do other tests to check for disorders that can cause ovulation problems. For example, they may measure testosterone levels in the blood to check for polycystic ovary syndrome.

Treatment

  • A drug to stimulate ovulation

A drug, such as clomiphene, letrozole (an aromatase inhibitor), or human gonadotropins, can usually stimulate ovulation. The particular drug is selected based on the specific problem. If the cause of infertility is early menopause, neither clomiphene nor human gonadotropins can stimulate ovulation.

Clomiphene

If ovulation has not occurred for a long time, clomiphene is usually preferred. A few days after menstrual bleeding begins, the woman takes clomiphene by mouth for 5 days. Before the drug is started, the woman usually needs to be given hormones to induce menstrual bleeding. Usually, she ovulates 5 to 10 days after clomiphene is stopped, and she has a menstrual 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 stimulates ovulation is determined, the woman takes that dose for up to four more treatment cycles. Most women who become pregnant do so by the fourth cycle in which ovulation occurs. Although about 75 to 80% of women treated with clomiphene ovulate, only about 40 to 50% of those who ovulate 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.

Ovarian hyperstimulation syndrome occurs in fewer than 1% of women treated with clomiphene. 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 stop the drug.

Clomiphene is used only after pregnancy has been ruled out because birth defects may result when it is used.

Letrozole

Letrozole is an aromatase inhibitor. Aromatase inhibitors block the production of estrogen. They are usually used to treat breast cancer in women who have gone through menopause. Letrozole may also be used to stimulate ovulation.

In women with polycystic ovary syndrome, letrozole may be more likely to stimulate ovulation than clomiphene. No evidence suggests that letrozole is more effective than clomiphene in women without polycystic ovary syndrome.

Like clomiphene, letrozole is started a few days after menstrual bleeding begins, and women take it by mouth for 5 days. If ovulation does not occur, a higher dose is used in each cycle until ovulation occurs or the maximum dose is reached.

Letrozole has fewer side effects than clomiphene. The most common side effects of letrozole are fatigue and dizziness.

Letrozole is used only after pregnancy has been ruled out because birth defects may result when it is used.

Human gonadotropins

If a woman does not ovulate or become pregnant during treatment with clomiphene or letrozole, hormone therapy with human gonadotropins, injected into a muscle or under the skin, can be tried. Human gonadotropins contain follicle-stimulating hormone and sometimes luteinizing hormone. These hormones stimulate the follicles of the ovaries to mature and thus make ovulation possible. Follicles are fluid-filled cavities, each of which contains an egg. Ultrasonography can detect when the follicles are mature.

When the follicles are mature, the woman is given an injection of a different hormone, human chorionic gonadotropin, to stimulate ovulation. Human chorionic gonadotropin is produced during pregnancy and is similar to luteinizing hormone, which is normally released in the middle of the menstrual cycle. Or, a gonadotropin-releasing hormone (GnRH) agonist can be used to stimulate ovulation, especially in women at high risk of ovarian hyperstimulation syndrome. GnRH agonists are synthetic forms of a hormone produced by the body (GnRH).

When human gonadotropins are used appropriately, more than 95% of women treated with them ovulate, but only 50 to 75% of those who ovulate become pregnant. About 10 to 30% of pregnancies in women treated with human gonadotropins involve more than one fetus, primarily twins.

Human gonadotropins are expensive and can have severe side effects, so doctors closely monitor the woman during treatment. About 10 to 20% of women treated with human gonadotropins develop moderate to severe ovarian hyperstimulation syndrome.

If a woman has a high risk of having more than one fetus or of developing ovarian hyperstimulation syndrome, it is safer not to use a drug to stimulate ovulation. However, if it is necessary to stimulate ovulation, using a gonadotropin-releasing agonist is safer than using human chorionic gonadotropin.

Other drugs

In some women with polycystic ovary syndrome, metformin (a drug used to treat people with diabetes) is sometimes used, usually with clomiphene, to stimulate ovulation. These women include those who are significantly overweight (with a body mass index of more than 35) and those who are diabetic or prediabetic (they have blood sugar levels that are high but not high enough to be labeled diabetes). However, even in these women, clomiphene is usually more effective than metformin and just as effective as metformin plus clomiphene for stimulating ovulation.

If the hypothalamus does not secrete gonadotropin-releasing hormone, a synthetic version of this hormone (called gonadorelin acetate), given intravenously, may be useful. This drug, like the natural hormone, stimulates the pituitary gland to produce the hormones that stimulate 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 to use 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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