INTRODUCTION

Ovulation induction involves stimulating the ovary to produce one or more eggs. It may be accomplished with a number of different medications and may be helpful in a wide variety of clinical settings. A thorough understanding of the nature of ovulation induction may be very helpful for patients1 and requires knowledge of the basics of ovarian function, the indications for ovulation induction, how the medications work to induce ovulation, the anticipated benefits and pregnancy rates, and the potential side effects.

Ovarian Physiology
A woman receives her entire life time supply of eggs very early in her own development. This entire process is completed prior to birth with an average of seven million eggs being formed. The eggs are immediately surrounded by a special layer of supporting cells and enter a resting state where they will remain until they resume growth. The resting state may last for as little as a few days or as long as 50 years. From this point forward, no new eggs are produced. As the eggs leave the resting state and resume development, there is a steady decline in the number of eggs which remain in reserve within the ovaries. The number of eggs declines to approximately one million by the time of birth and further declines to about three hundred thousand by the time a woman enters puberty. The gradual decline continues throughout her reproductive life. Eventually the woman will exhaust her supply of eggs, cease having spontaneous menstrual cycles, and enter menopause (Figure 1).

Figure 1. Women receive their entire lifetime supply of eggs prior to their birth and soon begin the steady process of losing them. Starting from a maximum number of 7 million eggs, women hove approximately three hundred thousand when going through puberty and may hove only a few thousand remaining by their late thirties.

A typical woman will ovulate approximately 400 times in her life (i.e., 1 3 cycles per year, between puberty and menopause). Thus, there is an enormous discrepancy in the number of eggs potentially available and the number which actually develop to maturity and are released. To direct this process, the body has a simple and elegant mechanism which controls the number of eggs that mature completely in a given cycle. In brief, eggs rest in the ovary and are surrounded by special cells responsible for supporting the developing egg and for making the various hormones associated with ovulatory cycles. The combination of the egg and its special supporting cells is called a follicle. Once these follicles leave this resting state, they must either mature and release the egg or stop growing and be reabsorbed by the body. A large number of follicles leave the resting state each month (range varies from 50 to several hundred). As they grow, they become dependent on the stimulation of hormones from the pituitary gland (FSH - follicle-stimulating hormone and LH - luteinizing hormone) to continue their development. At the same time they begin producing their own hormones such as estrogen (principally the estrogen named estradiol). The pituitary gland, located at the base of the brain, senses the level of estrogen and other hormones in the blood stream. When levels are low, the amount of FSH released by the pituitary is increased to stimulate greater hormonal response. In contrast, as estrogen (and other hormone) levels rise throughout a cycle, the pituitary gland is inhibited and less FSH is released. The relationship between the hormone production of the developing follicles growing in the ovary and the stimulating hormones from the pituitary gland provides the body a precise mechanism for controlling the number of follicles (and thus eggs) which complete the maturation process in a given cycle. By keeping FSH levels at the lowest possible level which can sustain the growth of the most advanced follicle, only a single egg will mature completely and be released each month.

In brief, most women have several dozen to several hundred eggs resume growth and development during any given cycle. However, the stimulation from their pituitary is finely controlled and generally allows only one to mature completely and be released (Figure 2).

Figure 2. A large number of egg containing follicles resume growth each cycle. Precise control of circulating levels of follicle stimulating hormone (FSH) allow only one of the follicles to develop to maturity. This is why women typically become pregnant with one baby at a time.

Women Who Do Not Ovulate Regularly - Anovulation and Oligoovulation
The failure to have any ovulatory cycles (anovulation) or to have only very irregular ovulatory cycles (oligoovulation) are among the most common causes of infertility. The causes of these types of ovulatory disorders are quite diverse, and may include problems with the central nervous system or pituitary gland, problems within the developing follicles or ovary, or both.

Hypothalamic-Pituitary Problems
Some women fail to ovulate because there is liftle or no stimulation coming from their pituitary glands. This can result from a problem with their hypothalamus (the part of the central nervous system which communicates with the pituitary gland) and is common in women who exercise vigorously, are under a lot of stress, or who have anorexia or related eating disorders. These women do not produce sufficient LH and FSH to stimulate any of the follicles in the ovaries to maturity. Treatment consists of either stimulating the pituitary to release LH and FSH (see GnRH stimulation), or to simply replace the missing [H and FSH by administering it directly (see injectable gonadotropins).

Premature Ovarian Failure
Other women fail to ovulate simply because they have very few or no eggs remaining in their ovaries. When this happens prior to the age of 40, it is termed "premature ovarian failure" or "premature menopause". There are a number of reasons why women deplete their supply of eggs at a very young age, including prior chemotherapy or radiation therapy while treating a malignancy, prior removal of the ovaries, and various genetic abnormalities. However, there is usually no obvious explanation and these women are believed to have simply exhausted their supply of eggs at a very young age. These women have no viable eggs remaining and thus are not candidates for ovulation induction.

Polycystic Ovarian Disease, Chronic Anovulation, and Related Syndromes
The vast majority of women who fail to ovulate regularly have a pituitary gland which is functional and have plenty of egg containing follicles remaining in their ovaries. The problem appears to be in the relationship between the stimulatory effects of the [H and FSH released from the pituitary and the ensuing response of the follicles. While the specific source of the problem may vary widely and is not known for most patients, many of these women will have the clinical signs of polycystic ovarian disease which include multiple small follicles within the ovary which are visible on ultrasound, and abnormal levels of [H and FSH in their blood stream (Figure 3). Although the cause of the disorder and the clinical symptoms which the patients have may vary, a common finding is that these women lack sufficient FSH stimulation to keep their follicles developing to maturity.

Figure 3. Clomiphene therapy is initiated at dosage of 50 mg daily for 5 days starting an day 3 to 5 of the menstrual cycle. The dosage of drug is increased to 700 mg, if ovulation is not achieved in the very first cycle of treatment. If normal luteal phase and ovulation are not achieved in any cycle, dosage is usually increased in a stepwise fashion by 50 increments to a maximum of 200-250 mg daily for 5 days. Clomiphene citrate results in an increase in FSH levels and may allow a follicle to complete development and ovulate a healthy egg. (Adapted from Speroff, ed. "Clinical Gynecologic Endocrinology and Infertility" 6th Ed. Phila: Lippencott Williams & Wilkins, 1999 p. 1103, with permission.)

Most of the approaches to treatment focus on raising FSH levels to the point where follicular growth and development resumes, ultimately resulting in the release of a healthy mature egg (ovulation).

OVULATION INDUCTION IN WOMEN WITH ANOVULATION AND OLIGOOVULATION

Clomiphene Citrate
Clomiphene citrate is the simplest, and thus the most common, starting point for treating women with either anovulation or oligoovulation. The medication is classified as an anti~strogen, which means that it blocks the effects of estrogen throughout the body. This blockage means that the pituitary gland perceives that only low levels of estrogen are present in the circulation. The pituitary's response to low estrogen levels is to secrete more FSH and [H which induce follicular recruitment and ovarian estradiol production. This rise in FSH is very important since these patients have a relative lack of FSH stimulation. In most cases the rise in FSH is sufficient to stimulate the follicles to resume growth, complete maturation, and eventually ovulate.

The normal starting dose in women who are either anovulatory or oligoovulatory is one pill (50 mg) per day for 5 days (Figure 3). If ovulation fails to occur at this level, the dosage may be sequentially increased by one pill per day until the effective dose is determined. Occasionally, the dose may need to be increased to as many as 5 pills per day. The medications are generally taken on days 5 through 9 of a menstrual cycle but the best timing may vary from patient to patient. In properly selected patients, 80% can be expected to ovulate and approximately 40% become pregnant. Ovulation generally occurs between 14 and 19 days of the cycle.

Once a woman begins clomiphene citrate therapy, it is important to determine if the treatment has been successful in inducing ovulation. Monitoring for ovulation can be accomplished in a number of ways. Basal body temperature charts (BBT's) which show an elevation in basal temperature levels of 0.5°F for several days indicate ovulation has occurred. Infertile couples should keep in mind that the rise in temperature occurs after ovulation and thus at times may not be detected until the day after ovulation (i.e. the temperature rise at the time of ovulation may occur later on the day of ovulation than the time the basal temperature is taken), and thus BBT's are an inefficient way to time intercourse for becoming pregnant.Ovulation predictor kits which detect the midcycle surge of LH also provide presumptive evidence of ovulation. They have the added advantage of turning positive prior to the time of ovulation which allows effective timing of intercourse. Many physicians recommend that the couples have intercourse the day the predictor kit turns positive and again the following day. Blood tests and ultrasounds may also be used to determine the ovulation in more complex cases where more precise monitoring of the time of ovulation is required.

Finally, a progesterone level checked 5 to 10 days following the presumed date of ovulation may reaffirm that ovulation took place and that hormonal support during the second half of the cycle is adequate.Unfortunately, not all women who ovulate will become pregnant. The majority of pregnancies occur in the first three ovulatory treatment cycles. Very few pregnancies are achieved in patients who do not conceive in the first six ovulatory cycles. The cumulative pregnancy rates after several ovulatory cycles on clomiphene citrate are less than 50% (Figure 4). Significantly, five to ten percent of the pregnancies will be twins.

Figure 4. Cumulative pregnancy rates attained with multiple cycles of clomiphene citrate therapy in women who do not ovulate regularly.

Relatively few side effects are generally associated with clomiphene citrate. An occasional side effect is the blockage of estrogen's favorable effect on mucus production by the cervix. In some patients, cervical mucus may become "hostile" and inhibit the ability of the sperm to swim from the vagina through the uterus and into the fallopian tubes where fertilization normally occurs. The absence of this side effect may be confirmed by a simple post coital test (an evaluation of the nature of the cervical mucus and the number and viability of any sperm swimming there) once the effective dose of clomiphene citrate has been determined. Other reported side effects include hot flushes, an upset stomach or bowels, headaches, sensitivity to bright light, visual disturbances, mood swings, and breast tenderness.

Injectable Gonadotropins (LH and FSH)
Some women will not ovulate following clomiphene citrate therapy and others will ovulate but not become pregnant. While there are a number of possible reasons, in many cases the FSH rise which is attainable with clomiphene citrate is either too low or does not last long enough to provide sufficient FSH stimulation to correct the underlying problem. In many of these cases, the women will respond better if higher levels of FSH can be attained over longer periods of time. These higher levels of FSH are achieved by directly injecting FSH in the form of injectable gonadotropins.

There are two types of injectable gonadotropin preparations available. One contains both FSH and LH activities, (hMG; Human Menopausal Gonadotropin), while the other contains FSH only, (Follistim® follitropin beta for injection). LH and FSH are the hormones which the pituitary would normally produce and release to stimulate the follicles developing within the ovary. The use of injectable gonadotropins gives the physician control over the amount and duration of the FSH stimulation being provided to the developing follicles. Thus, it is possible to attain levels which are sufficient to stimulate follicular development, oocyte maturation, and ovulation in a vast majority of patients.

In patients with anovulation or oligoovulation, the goal is to provide enough FSH to stimulate the development of a single follicle. To this end, a number of different stimulation regimens have been described. Some patients, especially the anovulatory patient with a very large number of small follicles (e.g. PCO patients) may respond best to relatively low doses of medications given over prolonged periods of time (up to several weeks). These are the so called "low and slow" protocols (Figure 5). In contrast, other patients may require higher doses of injectable gonadotropins to achieve adequate ovarian responsiveness, but will typically require the medication for less time (approximately 7 to 12 days). In either case it is not always possible to achieve the goal of having a single follicle develop and at times these patients may have several follicles mature and release several eggs. The release of several eggs leads to the high incidence of multiple pregnancies encountered in these cycles.

Figure 5. Women with polycystic ovarian disease do not ovulate regularly, but do have a number of partially matured follicles present at any given time (A). The administration of relatively small amounts of exogeneous gonadotropins provides additional stimulation and allows a single follicle to develop to maturity (B). These treatments may be particularly effective in women who do not have spontaneous ovulatory cycles and who fail to respond to clomiphene citrate therapy.

Women who have normal ovulatory cycles and are undergoing superovulation are also generally stimulated with injectable gonadotropins. While the medications are the same as those used in the treatment of anovulatory women, the goals of treatment are quite different. The goal of superovulation is not to provide a "normal" ovulatory cycle with the release of a single oocyte but rather to provide an environment with proportionally elevated FSH stimulation to result in the release of multiple eggs (Figure 6). Women undergoing superovulation typically receive higher doses of injectable gonadotropins.

Figure 6. The development of multiple follicles may be obtained by giving relatively large quantities of gonadotropins and maintaining elevated levels of FSH for a period of several days. This type of ovulation induction cycle is used commonly during insemination cycles and is an important part of many of the assisted reproductive technologies.

Monitoring
Careful monitoring of treatment cycles using injectable gonadotropins is very important. This is because the normal control relationships between the follicles developing in the ovary and the pituitary gland are bypassed when gonadotropins are given directly. The goal of monitoring is to make sure that sufficient, but not excessive, stimulation is being provided to the developing group of follicles. Most cycles are monitored with a combination of ultrasounds, to determine the number and size of the developing follicles, and blood work to measure the estrogen being produced (Figure 7). The results of the monitoring along with knowledge about the duration of the stimulation and the woman's individual history allow the physician to optimize the dosage of the medications being administered. It can then be determined when the follicles are mature and ready to ovulate.

Figure 7. Ovulation induction cycles with injectable gonadotropins require close monitoring with serial ultrasound examinations of the developing follicles and measurement of serum estradiol levels. hCG is administered to induce actual ovulation when the follicles are judged to be mature. A pregnancy test may be performed approximately 2 weeks later to determine if the woman is pregnant.

A mid-cycle LH surge is required to induce the final maturational changes in the egg, to release the egg from the wall of the follicle, and to stimulate the actual release of the egg from the follicle. Most women will not have a spontaneous LH surge during stimulated cycles. A "surrogate" LH surge may be provided by the injection of hCG, a hormone which is generally produced after a women becomes pregnant. It has the same stimulatory effects on the ovary that LH does, but is less expensive and has a longer duration of action which makes it more practical and effective.

Success Rates
The vast majority of women stimulated with injectable gonadotropins will ovulate, but not all will conceive. Most pregnancies occur in the first three to six treatment cycles. A number of factors influence pregnancy rates including the age of the patient, the presence or absence of endometriosis or adhesions in the woman's pelvis, any problems with tubal function, abnormalities of the lining of the uterus where implantation should occur, and the quality of the partner's sperm. Patients who fail to become pregnant following ovulation induction with injectable gonadotropins may still be excellent candidates and attain high pregnancy rates with some of the assisted reproductive technologies.

Figure 8. Distribution of singleton and multiple pregnancies in women undergoing ovulation induction with injectable gonadotropins.

Multiple Pregnancies
The nature of ovulation induction in women with anovulation or oligoovulation and superovulation in ovulatory women means that there may be multiple eggs released in a given cycle. These patients are then at risk for having multiple pregnancies. Most of multiple pregnancies are twins (Figure 8), but high multiple pregnancies with three or more implantations may occur.

Side Effects
As the name indicates, injectable gonadotropins must be administered by shots. Some soreness, discomfort, and occasional redness or bruising may appear at the injection site. Most patients have very little, if any, trouble with the injections. However, some patients may feel full or even bloated as their ovaries enlarge as they go through their stimulation cycle. This sensation is caused by the expansion of the ovary as multiple follicles are developing into the latter stages of maturity. The discomfort is similar in nature (although somewhat greater in magnitude) to the midcycle discomfort which many women have during normal ovulatory cycles. Other less common side effects include fluid retention1 mild nausea, and headaches.

A rare but serious side effect which is almost unique to ovulation induction cycles is ovarian hyperstimulation syndrome (OHSS). This syndrome is characterized by significant enlargement of the ovaries, possible fluid retention in the abdomen, and rarely generalized swelling throughout the body. The syndrome typically begins approximately one week after ovulation. The syndrome is most common in cycles where the woman is pregnant but may occur in any cycle. Although the process is self limited and usually resolves on its own, it may take a few days to a few weeks to go away. In severe cases these women may have nausea, substantial weight gain from fluid retention, and may require close monitoring and treatment by their physician. Careful monitoring and adjustments in the ovulation induction treatment regimen by the physician prior to ovulation may markedly reduce (but not eliminate) the risk of OHSS. Fortunately, the severe forms of OHSS occur in less than 1 % of treatment cycles when the recommended doses are administered.

Gonadotropin Releasing Hormone (GnRH)
Some women fail to ovulate because the hypothalamus (part of the central nervous system) fails to provide sufficient stimulation to the pituitary gland. Specifically, the hypothalamus normally secretes a small molecule named GnRH which is required to keep the pituitary functioning. During intervals of high physical or psychological stress, the hypothalamus may not secrete GnRH and the pituitary will simply quit producing and releasing LH or FSH.

The missing stimulation to the pituitary can be replaced by the direct administration of GnRH. The medication has to be given in intermittent pulses approximately every 60 to 1 20 minutes to work correctly. Precise timing is generally provided by having a small medication pump inject the medication beneath the skin or directly into a vein. The pump is worn 24 hours a day and a typical treatment cycle lasts for approximately 2 weeks.

Pregnancy rates obtained with GnRH replacement are excellent and may be equivalent to those obtained with injectable gonadotropins in these women. Side effects are uncommon with the exception of a reaction or soreness at the site of injection. Multiple pregnancies are also uncommon but may still occur.

ADJUNCTS TO OVULATION INDUCTION

Treatment of Prolactin and Thyroid Disorders
Some patients have related medical conditions which either impact their ability to ovulate or alter their response to treatment during ovulation induction. Women with high levels of prolactin, a hormone secreted from the pituitary and which is normally at low levels in non-pregnant women, may become anovulatory. After evaluation, lowering of the prolactin level with a medication such as bromocriptine may allow the patient to resume normal ovulatory cycles, or have enhanced responses to other forms of ovulation induction. Other women may have problems with their thyroid gland which impacts their ability to ovulate. Appropriate replacement of thyroid hormone will generally correct any related problems. Many anovulatory and oligoovulatory women are screened for abnormal prolactin or thyroid levels during their initial evaluation.

Elevated Androgens (male type hormones)
Other women may have very high levels of androgens (the "male type" sex hormone) being produced in their adrenal glands. After a thorough evaluation to rule out more serious adrenal problems, these women may be given medications such as dexamethasone to lower their adrenal androgen production. The lower androgen levels will allow some patients to begin having spontaneous ovulatory cycles while others will have improved responses to other forms of ovulation induction. Women with symptoms of excess androgen production (unusual masculine type hair growth, acne, etc.) may be screened to see if they might benefit from this type of adjunctive treatment.

GnRH Analogs (Gonadotropin Releasing Hormones Agonists and Antagonists)
Some patients undergoing ovulation induction with injectable gonadotropins will have a spontaneous midcycle hormonal surge prior to the time the developing follicles are mature. When that happens, most of the eggs will fail to mature appropriately and will not ovulate. These premature surges may be prevented by the use of medications such as GnRH agonists or GnRH antagonists, which turn off the secretion of LH and FSH from the pituitary. With GnRH agonists, no stimulation is coming from the pituitary and all of the FSH for stimulating the follicles during the cycle comes from the injectable gonadotropins. In contrast, with the GnRH antagonists there is considerable pituitary contribution to the early phase of the stimulation. The GnRH antagonist is only administered when there is a risk of premature LH surge.


SUMMARY
Ovulation induction is a safe and effective means of restoring fertility in many women who do not ovulate or who ovulate rarely. Additionally, it may be used to induce the development and release of multiple eggs in ovulatory women undergoing various other infertility treatments. Careful selection of treatment regimens combined with appropriate levels of monitoring may result in excellent pregnancy rates.


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