Some women may have difficulty getting pregnant because their ovaries are unable to release (ovulate) eggs. Fertility specialists may use medications to stimulate ovulation to help these women get pregnant. These medications are usually used in two ways: (1) to induce ovulation in patients who are unable to ovulate regularly and (2) to induce multiple eggs to develop and be released at once.
Nearly 25% of infertile women have ovulation problems. These women may ovulate less frequently or not at all (cessation of ovulation). These medications can help women ovulate more regularly, thereby increasing their chances of conception. These medications, often called “ovulatory drugs,” can also improve the uterus or the lining of the uterus (endometrium). In some cases, these medications may be used to encourage multiple eggs to develop at once. This procedure is usually done when a woman undergoes supernumerary ovulation and intrauterine insemination (IUI), in vitro fertilization (IVF), donor eggs, or frozen eggs (ova or fertilized eggs [embryos]).
Normal reproductive anatomy
The ovaries consist of two small organs, each approximately 1?inch long and 3/4 inch wide, located in the female pelvis. The ovaries are attached to the sides of the uterus (uterus) and are usually located below the fallopian tubes. At birth, a woman has about one or two million eggs already formed in her two ovaries. Unlike males, who are capable of producing sperm throughout their lives, females are limited in the number of eggs they can produce at birth. As they age, most eggs die off naturally (just as hair and skin cells die off). By the time a girl reaches puberty (on average around 10-13 years old), she still has about 400,000 eggs left. After the girl’s periods begin to normalize (close to once a month), the eggs mature in the follicle (a fluid-filled sac in the ovary that contains the eggs). The egg is released from the follicle (ovulation) when hormone levels reach standard levels. The umbilical hairs (finger-like protrusions) of the fallopian tube brush the ovary and allow the released egg to enter the tube. If it meets a sperm, the egg is usually fertilized in the fallopian tube. The fertilized egg (now called an embryo) begins to divide and travels through the fallopian tube into the uterus, where it lays in the endometrium (the lining of the uterus).
Menstruation is divided into three phases: the follicular phase, ovulation and the luteal phase.
Follicular phase
The follicular phase lasts approximately 10 to 14 days, starting from the first day of menstruation and continuing until the peak of luteinizing hormone (LH). During the follicular phase, the hypothalamus (an organ located in the brain directly above the pituitary gland) releases gonadotropin-releasing hormone (GnRH). This hormone informs the pituitary gland to release follicle stimulating hormone (FSH), which enters the ovaries through the bloodstream. Each month, the brain releases FSH to stimulate the development of several follicles in the ovary, each containing one egg. Generally, only one follicle becomes the dominant follicle, containing a fully mature egg, while the other follicles stop developing and the eggs in them die (called atresia). The dominant follicle becomes larger in size and releases a hormone called estrogen into the bloodstream. Elevated estrogen levels cause the pituitary gland to slow down the production of FSH. Estrogen also causes the lining of the uterus (endometrium) to begin to prepare for a possible pregnancy.
Ovulation
Ovulation begins with the peak of LH and ends with ovulation (the release of the egg from the primary follicle). As ovulation approaches, estrogen levels rise and trigger a surge of LH from the pituitary gland. ovulation occurs approximately 32 to 40 hours after the onset of the LH plateau.
Luteal phase
The luteal phase begins after ovulation and usually lasts about 12 to 16 days. After the egg is released, the follicle that once contained the expelled egg but has now emptied becomes the corpus luteum. The corpus luteum produces a hormone called luteinizing hormone, which helps prepare the lining of the uterus for embryo implantation and pregnancy. The egg is released and picked up by the fallopian tube, where fertilization occurs. If the sperm fertilizes the egg, the embryo will be transported through the fallopian tube and reach the uterus 4 to 5 days after ovulation. Once in the uterus, the embryo begins to attach itself to the endometrium (the lining of the uterus) in a process called implantation. Approximately 11 to 13 days after ovulation, if implantation does not occur, the ovaries will gradually produce less progesterone and estrogen. This causes the endometrium to break down and begin to shed, which is how menstruation (also called menstruation) comes about. With the start of menstruation, a new ovulatory cycle begins and the pituitary gland produces increased levels of FSH, which stimulates the development of another set of follicles.
The female hormonal cycle of normal ovulation. The follicular phase is the stage when follicles develop and secrete estrogen. Ovulation is a 48-hour period characterized by a dramatic rise in LH and the release of eggs (ovulation). The luteal phase is characterized by the production of large amounts of progesterone and estrogen.
Women who have regular monthly periods are likely to ovulate every month as well, with ovulation occurring approximately 14 days before the first day of each period. It is important to remember, however, that even if a woman never ovulates, her uterus will still bleed. There are several ways to detect ovulation, including the use of a home ovulation predictor kit that measures the peak of LH before ovulation actually occurs. Basal body temperature (BBT) charts can be used to track the rise in temperature after ovulation. Other tests include measuring progesterone levels in the blood during the luteal phase, ultrasound monitoring of follicles, and endometrial biopsy to detect the effects of progesterone on the endometrium (this last test is rarely performed).
Treatment: Ovulation-promoting drugs
Who needs ovulation stimulants?
Women with irregular periods (hypovulation) or anovulation (amenorrhea or cessation of ovulation) may have abnormal ovarian function. These women may take medication to return ovulation to normal. Before prescribing medication, the doctor should try to determine the cause of the ovulation problem. Some potential causes of ovulation problems include polycystic ovary syndrome (PCOS), low levels of LH and FSH produced by the pituitary gland, failure of the ovaries to respond to normal levels of LH and FSH, thyroid disease, elevated prolactin levels (hyperprolactinemia), obesity, eating disorders or dramatic weight loss, and/or excessive exercise. Sometimes the cause may not be identified. Women with abnormal ovarian function are usually able to induce ovulation with ovulation-promoting drugs.
Ovulation induction by ovulatory drugs is also used in patients who do not have abnormal ovarian function. The goal is to stimulate the ovaries to produce more than one follicle per cycle, resulting in the release of multiple eggs with the aim of fertilizing at least one egg and achieving a successful pregnancy. This is called controlled ovarian stimulation (COS) or supernumerary ovulation and can be accomplished with oral or injectable medications.COS is used in combination with intercourse or intrauterine insemination (IUI) and is often the initial treatment for several types of infertility in women with patent fallopian tubes.COS is also an important part of most IVF treatments.
Before using ovulation stimulants for COS, it is recommended to make sure that the fallopian tubes are open and unobstructed. This can be confirmed by injecting a dye into the fallopian tubes (hysterosalpingogram HSG) or by using a telescope with a light source to look inside the lower abdomen (laparoscopy). Patients with tubal obstruction are unable to conceive with ovulation stimulants or may be at risk for ectopic pregnancy (pregnancy outside the uterus). Ovulation induction should not be performed in patients with tubal obstruction unless the purpose of the induction is to collect eggs for IVF.
Prior to initiating supernumerary ovulation induction, the male partner should undergo a semen analysis to help determine whether ovulation induction should be used in combination with intercourse, IUI or IVF.
Commonly prescribed medications
The most commonly prescribed ovulation-inducing drugs are clomiphene (CC), aromatase inhibitors (e.g. letrozole) and gonadotropins (FSH, LH, human postmenopausal gonadotropin (hMG), human chorionic gonadotropin (hCG)). Other drugs used to induce ovulation include bromoergot cyclopentin, capsaicin, GnRH, GnRH analogs, and insulin sensitizers.
Clomiphene (CC)
Clomiphene is the most commonly prescribed ovulation stimulating drug used to stimulate ovulation in women with hypovulation or amenorrhea. It is also used in conjunction with IUI to promote multiple follicle development, to treat unexplained infertility, and as therapy for patients who are unable or unwilling to take more aggressive treatment.
The standard dose of CC is 50-100 milligrams (mg) of clomiphene per day for five days. Treatment is initiated early in the cycle, usually on the second to fifth day after the onset of menstruation, and may be initiated in the absence of a menstrual cycle if the woman is not ovulating. If a woman does not have a menstrual cycle, oral progestin may be given for 5-12 days to induce menstruation.
Clomiphene works by causing the pituitary gland to produce more FSH. Higher levels of FSH stimulate the development of one or more follicles (each containing one egg). The follicle secretes estrogen into the bloodstream as it grows. About a week after the last dose of CC, higher levels of estrogen cause the pituitary gland to release an LH spike, which prompts the release of eggs from the dominant follicle. It is important to determine whether the dose of CC used will result in ovulation. This can be done using menstrual patterns, ovulation prediction kits, testing blood progesterone levels or basal temperature charts to monitor the patient’s response to a given dose of clomiphene.
If ovulation does not occur at a dose of 50 mg, increase the CC by 50 mg immediately or in subsequent cycles until ovulation occurs. More than 200 mg per day for five consecutive days is usually not very effective, and patients who do not ovulate despite taking 200 mg of clomiphene may do better with a different treatment, such as gonadotropin injections. Your doctor will determine the appropriate dose for you. If the medication does not induce ovulation, your doctor may sometimes add other medications to the CC regimen. For more information on testing after ovulation has occurred, please see the ASRM Patient Profile Overview entitled Ovulation Testing.
In contrast to the timing of ovulation, the cervical mucus helps sperm enter the uterus or acts as a barrier depending on the timing of the menstrual cycle. Before ovulation, the cervical mucus becomes both thin and malleable in response to estrogen, helping sperm enter the uterus. After ovulation, progesterone levels rise and the cervical mucus becomes thick and viscous; CC can thicken the mucus and IUI can be used in combination with CC to help with this problem; CC can sometimes change the thickness of the uterine lining, making it thinner and less receptive to implantation. Therefore, the lowest dose of CC is usually prescribed to induce ovulation in anovulatory women, and CC will induce ovulation in approximately 80% of selected patients. Once the dose of CC to induce ovulation is determined, most patients will receive three cycles of ovulatory CC and may last up to six cycles. However, studies have shown that CC should not be given for longer than six cycles because the chances of pregnancy are very low and other treatments should be considered.
CC is not usually effective in women with irregular or absent ovulation due to hypothalamic disorders (e.g., caused by dramatic weight loss) or low estrogen levels (e.g., caused by non-functioning ovaries). In addition, obese women are more likely to be successful after weight loss, and CC is generally well tolerated. Side effects are relatively common, but generally mild. Hot flashes occur in about 10% of women taking clomiphene, but usually disappear immediately after the last pill is taken. Mood swings, breast tenderness, and nausea are also common. Severe headaches or vision problems (such as blurred vision or double vision) are uncommon and usually resolve almost immediately. If any of these serious side effects occur, treatment must be stopped immediately and the patient should inform the doctor. If these occur, it is not recommended to try CC again.
Women who become pregnant after using CC have an approximately 5-8% chance of conceiving twins. The chance of conceiving triplets and higher order multiples is extremely low (<1%< span="">), but may occur. Ovarian cysts may form and cause discomfort, but usually disappear with time. A pelvic exam or ultrasound may be used if indicated to look for ovarian cysts before starting another CC treatment cycle. The higher the dose, the more frequently side effects occur.
Aromatase inhibitors
Aromatase inhibitors are used to temporarily lower estrogen levels and cause the pituitary gland to produce more FSH. letrozole and anastrozole are currently the two drugs approved by the FDA for the treatment of postmenopausal breast cancer, but they are also used to induce ovulation in women with ovulation problems. Treatment is started early in the cycle, usually the second to fifth day after the start of menstruation, or may be started without a menstrual cycle if the woman is not ovulating. The dose is usually 2.5-5 mg per day for five days. Studies have shown that pregnancy rates with aromatase inhibitors are similar to those with CC and may be better for some ovulation disorders, such as polycystic ovary syndrome (PCOS). Similar to CC, aromatase inhibitors can also be used to promote multiple follicle development in combination with supernumerary ovulation-IUI for infertility, with success rates similar to those of CC treatment in combination with IUI. Recent studies have not shown that women who use letrozole to treat infertility are at greater risk of delivering children with congenital defects.
Insulin sensitizing drugs
Insulin resistance and high insulin levels in the blood (hyperinsulinemia) are common symptoms in women with polycystic ovary syndrome (PCOS). Although most women with PCOS ovulate on clomiphene, some women still fail to ovulate (“clomiphene-resistant”) and eventually require replacement or other treatments. After 4-6 months of insulin sensitizers (e.g., metformin), women with PCOS return to regular menstrual cycles and ovulation. Insulin sensitizers are not currently approved by the FDA for this use; insulin sensitizers are approved to treat type 2 diabetes and improve the body’s sensitivity to insulin.
Some patients with PCOS do not ovulate on CC or metformin alone, but may benefit from using both drugs together. In a large study sponsored by the National Institute of Child Health and Human Development (NICHD), more people became pregnant with CC alone or with both CC and metformin than with metformin alone. This is in contrast to an Italian study that showed metformin to be more effective. However, in the United States, CC is usually the drug of choice. The most common side effects are gastrointestinal side effects, including nausea, vomiting and diarrhea. Liver function abnormalities are uncommon in infertile women treated with metformin, and severe cases of lactic acidosis are very rare. Regular blood tests should be performed to check liver and kidney function. Other drugs used to treat diabetes to improve insulin sensitivity (such as rosiglitazone and pioglitazone) may also be used for this purpose.
Gonadotropins
Gonadotropins are ovulation-promoting drugs that contain either FSH or LH (alone or together). Unlike CC, aromatase inhibitors and insulin sensitizers, gonadotropins are not taken orally, but are injected. Gonadotropins can be prescribed to women who are anovulatory but have tried CC and are still not pregnant. They can also be used to help women with inadequate FSH and LH secretion in the pituitary gland. Gonadotropins can be used to stimulate the growth of multiple follicles simultaneously to improve infertility treatment in conjunction with supernumerary ovulation – IUI and IVF. It is important to note that the use of gonadotropins does not “deplete” the number of eggs more than when the drug is not taken during menstruation. Gonadotropin treatment can save eggs that would normally die and also allow these eggs to mature and be taken up or conceived.
For non-IVF supernumerary ovulation cycles, gonadotropin therapy usually begins on the second or third day of menstruation and is typically given at a starting dose of 75 to 150 IU per day. 7 to 12 days of stimulation is usually sufficient, but may be extended if the ovaries are slow to respond. During the stimulation phase of treatment, follicle size is monitored by ultrasound and blood estrogen levels may be measured several times. If the blood estrogen level does not rise and the ultrasound shows that the ovaries are not responding to the gonadotropins, the dose may usually be increased or occasionally the stimulation session may have to be cancelled. This is done to obtain one or more mature follicles and to achieve the appropriate estrogen levels for hCG stimulation of ovulation to mimic the natural LH peak. If too many follicles are growing, or if estrogen levels are too high, the physician may decide to forgo hCG injections to avoid the risk of ovarian hyperstimulation syndrome (OHSS) or high-order (more than two) multiple pregnancies.
Human chorionic gonadotropin (hCG)
Human chorionic gonadotropin has a similar chemical structure and function to LH. Injected hCG mimics the natural LH peak and stimulates the release of eggs and ovulation from the dominant follicle. The physician may use ultrasound and blood estrogen levels to determine the timing of HCG delivery. Ovulation usually occurs about 36 hours after hCG is administered. hCG is usually coadministered with gonadotropins to stimulate ovulation and may also be used when CC or aromatase inhibitors are used to induce ovulation. It is important to remember that pregnancy tests are performed by testing for hCG; in a pregnant woman, hCG is produced by the implanted embryo and the developing placenta. if a pregnancy test (blood or urine) is performed less than 10 days after hCG is provided to stimulate ovulation, the test may be false positive because residual hCG is still present.
Side effects of gonadotropins
As with all drugs, there are potential risks and complications associated with gonadotropin use. Before taking these (and any other) drugs, their side effects should be discussed. One of the most common risks is carrying more than one child (multiple pregnancies). Up to 30% of pregnancies stimulated by gonadotropins are multiple. Of these multiple pregnancies, about two-thirds are twins and one-third are triplets or more. Multiple pregnancies pose a health risk for both mother and fetus. Preterm birth is more common in multiple pregnancies; the greater the number of fetuses in the uterus, the greater the risk. The serious health consequences associated with preterm birth include severe respiratory problems, intracerebral hemorrhage, cerebral palsy, infection and even death of the newborn. For women carrying more than two children (such as triplets, quadruplets or more), a procedure called multiple pregnancy reduction may be an option to help reduce the risk of problems associated with high-order multiple pregnancies.
In addition to the problems associated with high-order multiple pregnancies, another potentially serious side effect of gonadotropin treatment is ovarian hyperstimulation syndrome (OHSS). With OHSS, there is painful ovarian swelling. In severe cases, excess fluid can accumulate in the abdominal cavity (pneumoperitoneum) and occasionally in the chest cavity. Hyperstimulation occurs in up to 2% of women during the gonadotropin cycle and can be severe enough to require hospitalization. Careful monitoring with ultrasound, measuring serum estrogen levels and adjusting gonadotropin doses can help physicians identify risk factors and reduce the risk of severe OHSS. If serum estrogen levels rise rapidly, are too high, or have excessive follicular growth, one of several strategies can be used to reduce the chance or severity of OHSS. Stop gonadotropin stimulation and delay administration of hCG until estrogen levels remain stable or decline (“glide”). Alternatively, hCG should be stopped altogether to prevent ovulation. For women not on leuprolide acetate (Lupron), another strategy is to replace hCG with a GnRH booster to stimulate ovulation, thereby significantly reducing the risk of overstimulation.
Other possible side effects of gonadotropin therapy include breast tenderness, swelling or rash at the injection site, abdominal distention, mood swings, and mild abdominal pain. Some women experience mood swings during gonadotropin therapy, but they are usually less severe than those caused by CC. Based on the hormone levels observed during gonadotropin treatment, it is difficult to distinguish between the emotional changes during this treatment and the stress associated with infertility treatment. Regardless of the cause, emotional changes during gonadotropin treatment are not new.
Bromelukotide and Cartegolide
Some women experience irregular ovulation or anovulation as a result of excessive secretion of prolactin by their pituitary gland. Excessive concentrations of prolactin in the blood (hyperprolactinemia) inhibit the secretion of FSH and LH, which in turn disrupts the growth of the dominant follicle and disrupts ovulation. In some women, high prolactin levels are caused by benign tumors (made up of prolactin-producing cells called adenomas). High levels of prolactin may also be due to the use of certain drugs such as tranquilizers, hallucinogens, painkillers, alcohol, and oral contraceptives (which are rare). Prolactin levels may also be raised by kidney or thyroid disease.
Hyperprolactinemia is usually treated with bromelukotide or capsaicin, which works by reducing the amount of prolactin produced by the pituitary gland. 90% of patients’ blood prolactin levels normalize after taking these drugs. Bromelukotide is usually taken daily, while carprogoline is taken twice a week. In the absence of other causes of infertility, about 85% of treated women will ovulate and become pregnant. Treatment is usually discontinued after pregnancy. If a woman does not ovulate after her prolactin levels return to normal, CC or gonadotropins may also be started.
Possible side effects of bromelukotide or carte blanche include nasal congestion, fatigue, drowsiness, headache, nausea and vomiting, fainting, dizziness, and decreased blood pressure. For most patients, dose adjustments can minimize or eliminate these side effects. Some physicians will initially prescribe very low doses to patients and gradually increase the dose in an attempt to prevent side effects. Treatment with ergometrine bromide or capsaicin is not supplemented with other infertility drugs, so the risk of multiple pregnancies is not increased.
Gonadotropin-releasing hormone (GnRH)
The hypothalamus releases small amounts of GnRH approximately every 90 minutes, and the periodic (rhythmic) release of GnRH into the bloodstream stimulates the pituitary gland to secrete FSH and LH. If GnRH release is abnormal, the drug can be administered continuously through a special delivery system that includes a priming belt attached to a light pump. The risk of multiple births and OHSS is very low. For the time being, GnRH is not used for this purpose in the United States.
GnRH analogs (promoters and antagonists)
GnRH analogs (boosters) are synthetic hormones that are similar to natural GnRH, but function differently because of their altered chemical composition (which generally makes them longer lasting). Leuprolide acetate, nafarin acetate, and goserelin acetate are all GnRH boosters. Under normal conditions, the hypothalamus periodically and rhythmically releases GnRH into the bloodstream, stimulating the pituitary gland to secrete FSH and LH, but when a woman is administered a GnRH analogue, her pituitary gland is continuously (rather than periodically) exposed to synthetic GnRH. This steady exposure leads to an initial increase in FSH and LH production and a subsequent decrease in subsequent release, thus preventing spontaneous ovulation.
Both ganirelix acetate and cetrorelix acetate are GnRH antagonists, and unlike the promoters, which first cause an increase in FSH and LH production, the GnRH antagonists immediately inhibit the production of FSH and LH.
Both promoters and antagonists are ineffective when administered orally, and GnRH promoters and antagonists prevent spontaneous ovulation, thus allowing eggs to be retrieved from developing follicles and used in nearly all IVF cycles.
Patients who have been administered GnRH antagonists or boosters for a long time may experience temporary side effects of menopause, including hot flashes, mood swings and vaginal dryness. In addition, headache, insomnia, breast reduction, painful intercourse, and bone loss may occur with long-term use. These side effects are temporary and the effects of the drug on the pituitary gland can be reversed when the GnRH analogue is discontinued.
Long-term risks of ovulation drugs
After several years of clinical use, physicians can tell patients unequivocally that CC and gonadotropins do not increase the risk of congenital defects. After several years of study, it is also certain that women administering ovulatory drugs such as CC and gonadotropins do not have an increased risk of ovarian cancer. Data on the long-term use of aromatase inhibitors, which are currently being compiled, are also more promising.
Conclusion
Infertility due to ovulation disorders can usually be corrected with various fertility treatments that promote the growth and development of mature eggs capable of ovulation.
Many of the drugs used to induce ovulation can also be used in conjunction with other treatments (e.g., IUI and IVF) to grow multiple eggs simultaneously (supernumerary ovulation) to treat other types of infertility.