The Process

The ovaries are two small glands, each about one-and-one-half to two inches long and three-fourths to one inch wide, located in a woman's pelvic cavity (Figure 1). They are attached to the uterus (womb), one on each side, near the fimbriated (finger-like) openings of the fallopian tubes. About once a month, a mature egg is released by one of the ovaries. The fimbriae of the fallopian tubes sweep over the ovary and pick up the egg after it has been released from the follicle (the fluid-filled ovarian cyst containing the egg). If the egg is fertilized, which usually occurs in the tube, the resulting embryo (fertilized egg) continues to mature and increase its number of cells as it travels to the uterus and implants in the endometrium (uterine lining). The embryo's full journey through the tube takes four to five days.

Figure 1: Female Reproductive tract

Hormone Production

In addition to producing eggs, the ovaries also secrete hormones. Hormones are substances secreted from organs of the body, such as the pituitary gland. adrenal gland, or ovaries, which are carried by a bodily fluid such as blood to other organs or tissues where the substances exert a specific action. The cycle of ovarian hormone production has two main phases. In the first phase. known as the follicular phase, an egg matures inside the ovary. The egg is surrounded by a layer of hormone-producing cells and fluid. The maturing egg, the surrounding cells, and the fluid are collectively known as a follicle. The follicle grows to a diameter of about an inch, forming a cyst-like sac on the surface of the ovary, before the fluid and the egg are released at ovulation.  

In natural cycles, an ovary contains several developing follicles, but usually only one follicle reaches maturity each month and releases an egg.  This follicle, known as the dominant follicle, secretes a generous amount of the female hormone estradiol (estrogen) into the bloodstream during the first phase of the cycle. The estrogen circulates to the uterus where it stimulates the endometrial cells to reproduce rapidly and repeatedly, causing the uterine lining to thicken as ovulation approaches. The physician can usually see this thickening on an ultrasound exam.

The second phase of ovarian hormone production begins with ovulation. The dominant follicle ruptures, usually around day 14 in a 28-day cycle, and releases a mature egg onto the surface of the ovary near the fallopian tube. The empty follicle collapses and the remaining follicle cells develop a yellow color. Collectively these cells are known as the corpus luteum, literally a "yellow body." The corpus luteum secretes estrogen and large
quantities of progesterone throughout the second half of the cycle, known as the luteal phase, which lasts approximately two weeks.

Traveling through the bloodstream to the uterus, the combination of progesterone and estrogen causes the uterine lining to further mature and produce nourishment for an embryo. About a week after ovulation. The endometrium is in prime condition for an embryo to implant. An experienced physician can tell approximately how many days have passed since ovulation by examining a sample of the endometrium taken in a biopsy. If no embryo implants, the secretion of estrogen and progesterone declines about
two weeks after ovulation and, as a result, the endometrium is shed. This shedding of the endometrium is called menstruation.

The first day of menstruation is known as "cycle day one." The length of the menstrual cycle is determined by counting the number of days from cycle day one until the start of the next menstrual period. Although variability in cycle length is usually due to variability in the follicular phase, the luteal phase can also be variable in length. The luteal phase should last 11 to 16 days. If it is not sufficient in length because of inadequate progesterone production, fertility problems may result. Since ovulation usually precedes menstruation by two weeks, a woman with a 28-day menstrual cycle is most likely to ovulate on day 14. Similarly, a woman with a 32-day cycle is most
likely to ovulate on day 18.

Directives From the Brain

The hvpothalamus and pituitary gland orchestrate the events leading to ovulation. These organs communicate with the ovaries via hormonal messengers traveling in the bloodstream. The hypothalamus is a thumb-sized structure in the base of the brain that controls many bodily functions and regulates the pituitary gland. The pituitary gland, about the size of a finger tip, is located just beneath the hypothalamus. The hypothalamus releases the hormone gonadotropin releasing hormone (GnRH), a messenger that tells the pituitary gland to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH are both involved in maturing the follicle, but FSH primarily makes the follicle grow and produce increasing amounts of estrogen. As the follicle grows, the increasing estrogen in the bloodstream signals the pituitary to shut down FSH production. A surge of LH triggers ovulation. After ovulation, the corpus luteum primarily produces
progesterone, which prepares the endometrium for the implantation of a fertilized egg (Figure 2).
              
DIAGNOSIS

Detecting Ovulation

The key to diagnosing ovulatory problems is to detect and confirm  ovulation. This can be done in several ways. An evaluation of the menstrual  pattern provides some clues. A woman who menstruates every 25 to 35 days  is probably ovulating regularly. She can also assume that ovulation occurs  about 14 days before day one of each period. It is important to remember,  however, that a woman can have randomly occurring uterine bleeding even  though she never ovulates. Moreover, she can also have fairly regular cycles  and not ovulate. There are several ways to detect ovulation, including  commercially available ovulation prediction kits and basal body temperature  charts.       

TREATMENT: OVULATION MEDICATION

Who Needs Ovulation Medication?

Ovulation drugs are used to either control the time of ovulation or regulate  erratic ovulation patterns. These medications, when administered appropriately,  can stimulate ovulation in most individuals and can also correct post-ovulatory problems by encouraging more than one egg per cycle to reach maturity. If  the time of ovulation is known, the doctor can schedule an insemination, for example, during the woman's "fertile days" to maximize the chance of  pregnancy.

Ovulation drugs also may be prescribed to increase the reliability of monthly  ovulation in oligo-ovulatory women (women who ovulate infrequently) or to encourage ovulation in anovulatory women. Women may not ovulate because of high ovarian production of male-type hormones (polycystic ovarian syndrome [PCOS), insufficient production of LH and FSH by the pituitary, or ovaries that do not respond well to normal levels of LH and FSH. Ovulation drugs may be indicated in the treatment of women with amenorrhea (absence of menstruation) and may be used to temporarily correct a luteal phase defect.

A luteal phase defect occurs when progesterone production from the corpus luteum shuts down prematurely, produces an inadequate amount of progesterone to mature the uterine lining, or if the ovary did not actually release an egg at the normal time of ovulation. The interval of time between ovulation and the beginning of the next menstrual period is usually 11 to 16 days. If a luteal phase defect occurs, this time may be shortened and the endometrium won't be in the proper condition to receive and nourish an embryo; therefore implantation cannot occur. Ovulation drugs are used to correct a luteal phase defect by enhancing the production of progesterone from the corpus luteum after ovulation, thereby making the endometrium more optimal for embryo implantation. The endometrium also can be supported by the use of natural progesterone.

Ovulation drugs also can be used to encourage the ovaries to produce more than one egg per cycle. This is done in preparation for various forms of assisted reproduction such as intrauterine insemination or In vitro fertilisation (IVF). The intent is to develop several mature eggs in hopes that at least one egg will be fertilized and result in pregnancy.

An evaluation should be performed to look for hormonal imbalances before medication is administered to stimulate ovulation. Abnormal (inadequate) ovulation is sometimes caused by a hormonal imbalance resulting from other conditions, such as thyroid disease. Correction of imbalance may allow ovulation to resume spontaneously without the use of  fertility drugs.

Hormonal Chain of Command

Figure 2: Directives from the Brain

The most commonly prescribed ovulation drugs are clomiphene citrate. follicle stimulating hormone (FSH), human chorionic gonadotropin [hCG].and human menopausal gonadotropin (hMG). These and four others,. bromocriptine, cabergoline, gonadotropin releasing hormone (GnRH) and GnRH analogs, which have very specialized applications, are described below. A chart is provided listing these ovulation drugs and their side-effects (Figure 3) 

DRUGS USED FOR OVULATION INDUCTION 

Clomiphene Citrate

The generic name of the most commonly prescribed ovulation drug is  clomiphene citrate. Brand names include Clomid® and Serophene®. This  drug is most often used to stimulate ovulation in women who have in frequent periods and long cycles. The standard dosage is one to two tablets  (50 to 100 milligrams) per day for five consecutive days. The regimen  begins early in the cycle, usually on the second, third, fourth, or fifth day  after menstruation begins. If necessary, a menstrual period can be induced by  progestin tablets or by an injection of natural progesterone before clomiphene therapy is started. The physician may first do a pregnancy test before administering progestin or progesterone. Provera®, Cycrin®, and Amen® are forms of medroxyprogesterone acetate, the progestin most commonly used to bring on menstrual bleeding. Vaginal progesterone (Crinone™) or  progesterone pills (Prometrium®) also may be prescribed. These medications  should not be used unless the physician is sure that the woman is not
 pregnant.

Clomiphene works by blocking estrogen receptors in the hypothalamus,  causing it to "think" there is an estrogen deficiency in the bloodstream. As a  result, the hypothalamus orders the pituitary gland to secrete more FSH and  LH into the bloodstream. The high level of FSH spurs the development of a  follicle and its egg. As the follicle grows, it secretes estrogen into the  bloodstream. About a week after the last clomiphene tablet is taken, the  hypothalamus senses the increased estrogen level and signals the pituitary to
release a surge of LH. This LH surge causes the egg to be released from the mature follicle in a process called ovulation.  If treatment is successful, ovulation usually occurs about a week or so after the last clomiphene tablet has been taken (from day 12 through day 21 of the cycle). The total cycle may be as long as 35 days. Most doctors rely on the menstrual pattern, the basal body temperature (BBT) chart, ovulation prediction kits, or serum progesterone levels to monitor a patient's response to the standard dose of clomiphene. A BBT chart is a chart in which the patient's body temperature upon awakening is plotted every morning before she gets up. The readings help identify ovulation, which is indicated by a persistent temperature rise of four-tenths of one degree or more. If these ovulation tests are positive, generally no other drugs are needed. If there is doubt, however, measuring the progesterone level about 18 to 21 days after  the start of clomiphene, or using ultrasound monitoring, can help to determine if and when ovulation occurred. If ovulation does not occur, the clomiphene dose may be increased in the next few cycles. If the larger dose of clomiphene fails to cause ovulation, the physician may choose to prolong the duration of treatment. Occasionally the physician may choose to add  other medications to clomiphene if the drug is not successful in inducing ovulation.

Clomiphene can alter the quality of cervical mucus, making it a thick, dry, and an impassable barrier for sperm. Some physicians may recommend a postcoita! test during a cycle of clomiphene therapy. For this test, the couple is asked to have intercourse during the time ovulation is predicted to occur. Soon afterward (usually four to 12 hours), in the doctor's office, a sample of the woman's cervical mucus is removed and examined under a microscope to see if sperm are present and able to move in the mucus. If the test is unsatisfactory, the physician may prescribe treatment to restore the proper consistency of the cervical mucus, or may perform an intrauterine insemination to bypass the cervix. Sometimes a change in medication to hMG or FSH may be the most appropriate action.

Clomiphene can sometimes alter endometrial thickness, making it thin and unreceptive to implantation. If this occurs, the physician may prescribe medication to increase the thickness of the endometrium, or change the prescribed medication to hMG or FSH.

Many doctors prescribe clomiphene to treat luteal phase defects. However, a luteal phase defect is also a possible side effect of clomiphene therapy. This problem can usually be corrected by adjusting the dosage with each cycle or by supplementing it with progesterone after ovulation until adequate endometrial development is achieved.

The lowest dose of clomiphene sufficient to induce ovulation is usually used for at least four to six cycles to provide an adequate trial for most  patients. About 40 to 45 percent of couples receiving clomiphene citrate will become pregnant after six cycles. Most authorities suggest that clomiphene be given for no more than six cycles prior to considering alternatives. Women who have irregular or absent ovulation due to hypothalamic disorders or who have very low estrogen levels generally do not respond well to clomiphene.

Human Chorionic Gonadotropin

A.P.L.®, Pregnyl®, and Profasi® are brand names for human chorionic gonadotropin (hCG). Sometimes hCG is added to the clomiphene regimen. Like a woman's natural LH surge, hCG causes the dominant follicle to release its egg. Produced by the placenta during pregnancy and extracted from the urine of pregnant women, hCG is similar in chemical structure and function to LH. The physician may use ultrasound images and blood estrogen levels to determine the precise day on which to administer hCG. Ovulation will usually occur 36 to 72 hours after hCG is administered. An early pregnancy test may be falsely positive if performed less than 10 days  after hCG is administered. If the patient still does not ovulate after hCG. She may become a candidate for hMG or FSH.

Human Menopausal Gonadotropin

Humegon'^ Repronex™, and Pergonal® are brand names for human   menopausal gonadotropin (hMG), one of the most potent ovulation drugs   currently in use. It is given by injection and contains equal parts of FSH and LH (or hCG as an LH substitute), which are derived from the urine of  postmenopausal women. FSH and LH have a direct impact on the ovaries by  stimulating them to produce multiple eggs in one cycle.

The hMG is often prescribed for anovulatory women who have tried   clomiphene without success. It may also help women whose pituitary glands do not produce adequate amounts of FSH and LH and as a result do not have menstrual periods (amenorrhea). In addition, this drug is used for IVF and  other assisted reproductive technologies to help produce multiple eggs. Although younger women tend to produce more eggs than older women,  each woman will respond differently. Many physicians will obtain a blood  test for FSH on day two or three of the cycle in order to better predict how  the ovary will respond to hMG. If the FSH level on day two or three of the  cycle is elevated, then a poor response to these medications can be predicted. Under these circumstances, alternatives involving other methods of assisted  reproduction may be discussed.

HMG treatment involves a series of injections and careful monitoring during each treatment cycle. Because this may involve a certain amount of  risk, expense, and inconvenience, many physicians first recommend a complete infertility work up including a laparoscopy. With the use of hMG.  women who are anovulatory but have no other fertility problems may expect pregnancy rates approaching those of spontaneously ovulating women,  approximately 20 percent to 30 percent per treatment cycle.

Most physicians begin hMG treatment on day two or three of the  menstrual cycle. The usual starting dose is one or two ampules (75 to 150  units) injected daily. Injections are usually administered over a period of  seven to 12 days, but this period may be extended if the ovaries are slow to respond. The follicle size is monitored with ultrasound and the blood estrogen level may be measured frequently throughout treatment. If tests indicate that the ovaries are not responding to hMG, the dose may be increased. The goal is to achieve one or more mature follicles and an appropriate estrogen level, so that ovulation can be triggered by an hCG injection. If too many follicles develop or if the estrogen level is too hhh, the physician may decide to withhold the hCG injection rather than risk
ovarian hyperstimulation syndrome or a high-order multiple pregnancy.

Follicle Stimulating Hormone

Fertinex™, Gonal-F™, and Follistim™ are the brand names for FSH. FSH was initially purified from the urine of postmenopausal women. Fertinex ™, is derived from the urine of postmenopausal women. Fertinex™ can be given by a subcutaneous injection (immediately beneath the skin). Fertinex™ is similar to hMG except that almost all of the LH has been removed. Recently, purified synthetic FSH has been developed through sophisticated manufacturing techniques and is now sold under the brand names of Gonal-F™ and Follistim™. These products contain no LH at all. They're also administered via subcutaneous injection. Like hMG, these FSH medications bypass the hypothalamus and pituitary and directly stimulate follicular growth in the ovary.

Most women who try FSH have already used clomiphene therapy without success. Many of these women have an elevated LH level and a low to normal FSH level. This combination is characteristic of polycystic ovarian syndrome (PCOS), a common diagnosis in women with ovulation problems.

FSH is often added to hMG when the initial response to that drug is inadequate.

Bromocriptine and Cabergoline

Some women ovulate irregularly because their pituitary glands secrete too much prolactin, the hormone that stimulates breast milk production in new mothers. Increased blood levels of prolactin may stop the normal ovulatory cycle because prolactin inhibits the release of FSH and LH. This condition is often treated with the medication bromocriptine or cabergoline which reduces the amount of prolactin released by the pituitary. Parlodel® is the brand name for bromocriptine and Dostinex™ is the brand name for cabergoline.

There are several causes of elevated prolactin levels in nonpregnant women. Excess prolactin may result from a cluster of cells within the pituitary gland that form a type of benign (non-cancerous) pituitary tumor called an adenoma. Even very small adenomas can be detected and their size measured by modern imaging techniques such as the CAT scan (computed axial tomography) or MRI (magnetic resonance imaging). Bromocriptine
and cabergoline may shrink the adenoma and lower the blood level of prolactin to normal. Continued use of the drug, often only a small dose, is necessary to maintain a normal prolactin level in patients with adenomas.  The prolactin level is elevated in some women because the prolactin- producing cells in the pituitary are hyperactive. High prolactin levels can also result from the use of certain drugs such as tranquilizers, hallucinogens, painkillers, alcohol, and, in rare cases, oral contraceptives. Disease of the
 kidney or thyroid may also raise prolactin levels.    These medications suppress prolactin production, and the blood prolactin level returns to normal in more than 90 percent of cases. Bromocriptine is  orally taken as a tablet or capsule one to four times a day until the prolactin  level is normal. It can also be administered vaginally. Cabergoline is taken as  one to two tablets twice each week. Of the women treated, approximately 85  percent will ovulate and can become pregnant if no other causes of infertility  are present. Bromocriptine and cabergoline treatment are usually discontinued during pregnancy. Women who fail to ovulate even after their prolactin levels are normal may be given clomiphene or gonadotropins along with bromocriptine and cabergoline.

Gonadotropin-Releasing Hormone

Factrel® and Lutrepulse® are brand names of gonadotropin releasing hormone (GnRH). GnRH is released from the hypothalamus in small amounts about once every 90 minutes. The pulsatile release of GnRH from the hypothalamus into the blood stream stimulates the pituitary gland to secrete LH and FSH. If GnRH is not being released properly, it can be administered by a special drug delivery system that includes a belt holding a lightweight pump. At intervals of about 90 minutes, the pump delivers a small volume of fluid through a needle placed beneath the skin (usually in the abdomen) or into a blood vessel.

Gonadotropin-Releasing Hormone Analogs (Agonists and Antagonists)

GnRH analogs are synthetic hormones similar to GnRH. but they act in a very different manner. Several drugs of this type are currently available in the United States: Lupron® (leuprolide acetate), Synarel® (nafarelin acetate) and Zoladex® (goserelin acetate) are GnRH agonists. Antagon™ (ganirelix acetate), is a pure GnRH antagonist. Others are under study or in use in other countries. These drugs, which are ineffective when taken orally, are prescribed as a daily, monthly, or quarterly injection, or a nasal spray.

The rhythmic release of GnRH stimulates the pituitary gland to secrete LH and FSH. However, when a woman takes a GnRH agonist. her pituitary gland is exposed to a constant, rather than a pulsatile, pattern of synthetic GnRH. After an initial acceleration in LH and FSH production, the pituitary then stops releasing these two hormones. This halts the production of  ovarian hormones, ovulation is prevented, and estrogen levels are reduced. GnRH agonists are prescribed for some patients with abnormal ovulatory cycles to enable them to respond better to hMG. By preventing communication between the pituitary gland and the ovaries, GnRH agonists allow the gonadotropin injections to be the sole source of follicle stimulation. Some physicians use agonists to induce ovulation and prevent the pituitary from prematurely creating the LH surge. A premature LH surge often results in cancellation of a cycle of ovulation induction for IVF or GIFT. The GnRH antagonists cause LH and FSH to be immediately suppressed.

In IVF and GIFT programs, a GnRH agonist is often used to prevent spontaneous ovulation when gonadotropins are given. Both the GnRH agonist and antagonist can prevent the undesired secretion of LH, which can cause the follicles to release their eggs before they are harvested. Many infertility specialists believe that the addition of GnRH analogs during ovarian stimulation for IVF yields more mature eggs for fertilization and therefore more  embryos for transfer.GnRH agonists have also been shown to help stimulate ovulation when given at midcycle and the ovarian follicles are mature.

RISKS AND COMPLICATIONS OF OVULATION DRUGS

There are potential risks and complications associated with the use of ovulation drugs. Side-effects should be discussed prior to taking ovulation drugs.

Women taking clomiphene have up to a 10 percent chance of having twins. The likelihood of having more than two babies is less than 1 percent. There is a slightly increased risk of miscarriage in pregnancies conceived with clomiphene therapy. Ovarian cysts, which can cause pelvic discomfort, may form as a result of the drug's mild to moderate overstimulation of the ovaries. A pelvic exam or ultrasound may be performed to look for ovarian cysts before beginning another clomiphene treatment cycle. Other side
effects of clomiphene may include hot flashes and mood swings while taking the drug, followed by depression, nausea, and breast tenderness. Mood swings may be surprising, severe, and persist throughout a treatment cycle.  As previously mentioned, a luteal phase defect may also occur. Side-effects  are more frequent with higher doses. Severe headaches or visual problems,  which are rare, are signs to stop treatment immediately and call the physician.

Despite intensive monitoring, multiple pregnancies occur in approximately 25 percent of gonadotropin cycles. Of the multiple pregnancies,  about two-thirds are twins and one-third are triplets or more. Premature  delivery is a known risk for multiple pregnancies. The greater the number of  fetuses present in the uterus, the greater the risk of premature delivery.  Premature delivery subjects the newborn to many complications including  severe respiratory distress, intracranial hemorrhage, infection, cerebral palsy,  and death. Some patients pregnant with triplets or more choose to undergo a  procedure known as multifetal pregnancy reduction in an effort to decrease  these risks. Other potential side-effects of gonadotropin treatment include   breast tenderness, swelling or rash at the injection site, abdominal bloating. mood swings, and slight twinges of abdominal pain. The most serious side- effect is ovarian hyperstimitlation syndrome, in which the ovaries become  swollen and painful. In severe cases, fluid accumulates in the abdominal  cavity and chest. In about 2 percent of cases, hyperstimulation requires   hospitalization. Fortunately, hyperstimulation rarely occurs without ovulation. Because most gonadotropin-treated patients need an hCG injection to trigger ovulation, the physician may choose to withhold the injection to decrease the chance of severe hyperstimulation or multiple  births, if tests show that the patient's estrogen level is too high or if too  many follicles are present. Some women experience mood swings during gonadotropin therapy, although usually less severe than those that occur with  clomiphene. It is difficult to separate the emotional changes due to the  dramatic hormone shifts during gonadotropin therapy from the stress  associated with this treatment. Regardless of the cause, a change in mood  can be expected during gonadotropin therapy.

Possible side effects of bromocriptine and cabergoline include nasal  congestion, fatigue, drowsiness, headaches, nausea, vomiting, fainting,  dizziness, and decreased blood pressure. For most patients, these side-effects  can be eliminated by adjusting the dosage. Some physicians start their  patients on a very low dose and increase it gradually in an effort to prevent  side-effects. The risk of multiple pregnancies is not increased as a result of  bromocriptine or cabergoline therapy.

The risk and complications of GnRH. such as multiple births and ovarian  hyperstimulation syndrome, are quite small. The patient taking a GnRH  antagonist or agonist often has temporary symptoms of menopause, including hot flashes, mood swings, and vaginal dryness. In addition, headaches, insomnia, decreased breast size, pain during intercourse, and bone loss may occur. These side-effects are temporary, and the effect on the pituitary is completely reversible after GnRH agonists and GnRH antagonists arc discontinued.

LONG-TERM RISKS OF OVULATION DRUGS

After years of clinical use, physicians can confidently advise patients that ovulation drugs are not associated with an increased risk of birth defects. Recently, several studies have suggested that women taking ovulation inducing drugs such as clomiphene and gonadotropin may be at increased risk for ovarian cancer. Although the data suggest that infertile women, and in particular women who take infertility medications, have a higher risk of ovarian cancer, it is not known whether or not the drugs are the cause of the increased risk. In fact, in one well-known study, the achievement of  pregnancy with or without the use of infertility drugs was associated with  decreased ovarian cancer risk. Even though one study implicated long-term  clomiphene use in an increase in ovarian cancer rates, it is not completely  certain at this time which fertility drugs, if any, might increase the risks.  Most studies relative to gonadotropin use do not reveal any increased risk  for ovarian cancer. Clearly, more research needs to be conducted to address  these issues. In the meantime, it is important that women taking these  medications discuss the risks with their physicians. One must weigh the  unproven risks against the clear benefits of ovulation-inducing agents.

CONCLUSION

Not all infertile women are candidates for ovulation drugs. To determine  the need for ovulation drugs, physicians require patients to undergo a series  of tests to identify the presence and exact cause of the ovulation problem.  Once a diagnosis is made, it may take several cycles (months) to determine  the right medication and dosage to trigger ovulation. An anovulatory woman  should be prepared to visit her doctor frequently for ultrasound tests, blood tests, and other monitoring procedures. Sexual intercourse may have to be  carefully timed. The regulation of ovulation requires an investment of time,  money, energy, and emotion. While most cycles end with disappointment  because a pregnancy is not achieved, all the effort is justified for couples  because the majority ultimately give birth to a healthy baby.