Ovulation Induction Ovulation induction is the process of stimulating the ovary to produce one or more eggs, which can be desirable in a number of clinical situations. There are a variety of medications, which we will discuss, capable of achieving this end. Following, we will discuss how the ovary functions, how certain medications work to stimulate the ovary and induce ovulation, as well as mention success rates and potential side effects.   Ovarian Physiology Females receive their lifetime allotment of eggs very early in their development – prior to their birth, in fact, with an average of seven million eggs being formed. These eggs are in a very immature state, incapable of being ovulated or fertilized as they rest deep in the tissue of the ovaries until puberty is reached. Now seven million eggs may seem like an ever-abundant supply, but most of these initial eggs will be reabsorbed by the body before ever maturing. In fact, this number is already reduced to a million eggs at the time of birth and down to about three hundred thousand by the time puberty is reached. Ouch! Well, three hundred thousand is nothing to scoff at – that should be more than enough, right? You’d think so, but the female body wastes eggs at an alarming rate. Here’s how: A typical woman will ovulate approximately 400 times in her life. Now, if the ovary could release just one egg per cycle from its resting state each month, a woman would have to live many thousands of years to use up all of her eggs. Each month, however, several dozen to several hundred of these immature eggs leave their resting state and resume growth, with usually only a single egg fully maturing and able to ovulate. The remaining eggs that had resumed growth are reabsorbed by the body never to be heard from again. The maturation and release of one egg from several hundred possible is a finely controlled process involving the hormones FSH (Follicle Stimulating Hormone) and LH (Luteinizing Hormone) which are produced in the pituitary gland. FSH stimulates the initial growth of the many egg-filled structures known as follicles. Follicles are a combination of an egg and surrounding cells that provide for the egg’s development. As follicles begin to grow in response to FSH, they begin producing their own hormone known as estrogen. Estrogen levels in the blood stream are detected by the pituitary gland and, when levels are low, FSH production is increased to stimulate further development of the follicles. As estrogen levels rise in response to the increasing levels of FSH, the pituitary gland responds by releasing less and less FSH. The body tries to keep the circulating FSH at the lowest possible level that can still sustain the growth of one dominant follicle so that only one mature egg will be released each month. Medications Used to Induce Ovulation Because the process of maturing a single egg requires such a delicate hormonal balance between the ovary and the pituitary gland, it only makes sense that some of the most common causes of infertility are a direct result of an imbalance in the hormones critical to egg development and ovulation. See Ovulatory Dysfunction in Diagnosing Infertility to learn about some of the more common ovulatory disorders affecting infertile women. Various medications can be effectively used to restore hormonal balance to the ovulatory cycle and/or increase the number of mature eggs available in a given cycle by "fooling" the pituitary gland. Here’s how some of them work. Clomiphene Citrate Clomiphene citrate (commonly known by the brand name Clomid) is the simplest and most common starting point for treating women with ovulatory disorders (see Ovulatory Dysfunction). This medication works as an anti-estrogen by blocking the effects of estrogen (or estradiol) throughout the body. As described above in Ovarian Physiology, rising estradiol causes the pituitary gland to decrease FSH output, thereby causing most of the egg-containing follicles to stop developing. Clomiphene citrate, however, essentially "hides" circulating estradiol from the pituitary gland, causing it to think there are still low levels of estradiol present in the body. As a result, the pituitary gland "thinks" that the ovarian follicles are not being stimulated enough and increases its output of FSH. This increased FSH, in turn, should allow for added stimulation of the follicles. One or more of the follicles will continue developing to maturity and eventually ovulate. This is a very important achievement in women who fail to ovulate normally due to the pituitary gland prematurely halting FSH production. Thus, the ultimate goal of clomiphene citrate is to indirectly cause the body to produce more of its own natural FSH in order to improve ovulatory function. The normal starting dose in women suffering from anovulation or oligoovulation is 50 mg (one pill taken orally) per day for 5 days. If ovulation fails to occur at this dosage, the level may be increased sequentially by one pill per day until the desired effect is achieved. Your physician may recommend the dosage be increased to as many as 5 pills per day. Generally, the medication is taken on days 5 through 9 of a menstrual cycle but the best timing can vary from patient to patient and will be precisely determined by your doctor. If successful, ovulation typically occurs about 5 to 9 days after completion of the medication. So how do we know if the Clomid therapy is working? There are several ways to determine this. Since the ultimate success of the therapy is ovulation, there are a couple of ways the patient can monitor herself for ovulation at home. One of these is the use of basal body temperature charts (BBTs) which require monitoring one’s temperature over the course of a cycle and recording the results. Evidence of ovulation is signaled by an increase in temperature level of 0.50 F for several days. The problem with BBTs, however, is the fact that the temperature increase occurs after ovulation and may not be detected until the following day due to the possibility of ovulating shortly after the last temperature for that day has been taken. Hence, you wouldn’t notice the temperature increase until you checked the next day. Although this isn’t critical if you just want to verify ovulation, it is a bit of a problem if you wish to optimize the timing of intercourse to become pregnant. Ovulation predictor kits are more advantageous than BBTs in that they inform the woman of ovulation before it happens. If you look at the menstrual cycle graphic, the body issues a surge of LH during mid cycle which actually triggers a follicle to release its egg. The ovulation predictor kits are used just like home pregnancy tests and turn positive when the LH surge is detected in urine. Since ovulation should be expected to occur sometime in the 24 to 48 hours following the surge, intercourse can be more effectively timed – usually we recommend couples have intercourse the day the predictor kit turns positive and again the following day. Back-to-back days of intercourse?! Just what you women wanted to hear – now he’s got a legitimate excuse to get some action, "Oh, I have a headache too, dear, but Doctor’s orders!" Cycle Monitoring Now the drawback with just using BBTs or ovulation predictor kits is that the woman must wait for ovulation to occur before she can determine if her therapy is working. If no sign of ovulation occurs, there’s no way to know what went wrong. That’s why close monitoring of the ovulatory cycle by your friendly neighborhood infertility specialist can be such a great benefit. With a few simple ultrasounds and blood tests, we are able to show you how your body is responding to the medication and make adjustments along the way. One of the most important tools in the cycle monitoring process is the follicular ultrasound. It is adept at detecting fluid-filled areas within the pelvis, which are basically what follicles are. From the very beginning of the cycle, it verifies that the ovaries are free of cysts – a prerequisite to administering any fertility medications. These cysts are not uncommon and are usually benign follicle-like growths on the ovary. If present, they can produce estrogen like a follicle and foul up a cycle before it even starts. They will usually resolve on their own given time and should be allowed to before resuming stimulation therapy. Once stimulation has begun, ultrasounds allow us to visualize and measure the size of any developing follicles on the ovaries. As the cycle progresses, we hope to see the follicle(s) grow in size from one day to the next until ovulation is imminent. Although the egg within the follicle is far too small to see with the ultrasound, the size of the follicle itself is a good indicator of how the egg is maturing – generally and up to a point, the larger the follicle, the more mature the egg. Finally at the end of the cycle, the ultrasound can be used to confirm that ovulation has taken place. Successful ovulation is indicated on ultrasound by the lack of a once present follicle(s) on the ovaries, presence of a corpus luteum, and/or free fluid in the pelvis as a result of the rupture of the follicle(s) at ovulation. Blood tests used in conjunction with follicular ultrasounds provide an even more complete picture of the quality of the ovulatory cycle. Estradiol, FSH, and progesterone are the hormones typically tested during an ovulation induction cycle (see Detecting Hormone Imbalances for descriptions of these hormones). Injectable Gonadotropins Some women will not ovulate following clomiphene citrate therapy and some women will ovulate but not become pregnant. There may be a number of reasons why, but a common one is simply that the FSH rise induced by the Clomid is insufficient to stimulate the ovary (see Clomiphene Citrate above). If this is the case, such a woman will respond better if higher levels of FSH can be attained over a longer period of time. These higher levels of FSH are achieved by injecting FSH directly into the body. And unlike Clomid, the use of injectable gonadotropins does not depend on the pituitary gland to decide how much FSH it wants to produce which may or may not be enough to provide proper ovarian stimulation. With injectables, your doctor controls your body’s FSH levels by replacing the dose normally provided by the pituitary gland with a series of controllable doses of the same hormone through direct injection. In this way, it is possible to attain levels of FSH which are sufficient to stimulate follicular development, oocyte maturation, and ovulation in a vast majority of patients. Your infertility doctor will determine the dosage and duration of the injectable medications depending on the goal of your treatment. In patients with anovulation or oligoovulation, the goal is to provide enough FSH to stimulate the development of a single follicle. For example, an anovulatory patient with a large number of small follicles may respond best to relatively low doses of medication given over prolonged periods of time (up to several weeks). Alternatively, other patients may require higher doses of medication to achieve an adequate response, but may take it for less time (say 7 to 12 days). In either case, it is not always possible to get a single follicle to develop. Often times, several follicles will respond to the medication by maturing and ovulating together, resulting in the release of more than one egg. This can result in a higher risk of having a multiple pregnancy. In cases of women who have normal ovulatory cycles with some other infertility indications, the goal of treatment may not be to produce a single egg, but instead produce multiple eggs. This process of intentionally stimulating the ovaries to produce multiple eggs is called superovulation and is particularly useful for increasing the probability of pregnancy in IUI and IVF cycles (see IUI and ART sections for details on these procedures). Because of the inevitable development of multiple eggs and the subsequent risk of multiple pregnancy when using injectable gonadotropins, it is very important to closely monitor these cycles as described above using ultrasounds and blood tests. If not properly supervised, you get women taking these medications at home, unknowingly producing and ovulating scads of eggs, having timed intercourse following a positive home ovulation predictor kit, then ending up pregnant with a litter of babies. Unfortunately, the media tends to glorify these kinds of pregnancies. But they are not only dangerous to the mother, but almost always lead to premature birth and subsequent health problems for the babies. And the media probably won’t give you the time of day for anything short of eight babies, anyway, so you may as well let us keep your pregnancy down to a safe one or two (preferably one) by allowing us to keep a close eye on you throughout your cycle. The goal of monitoring is to make sure that sufficient, but not excessive, stimulation is being provided to the developing follicles. In instances where a woman develops a number of follicles that puts her at high risk for multiples, we may urge her not to be inseminated (either through intercourse or IUI) and let the cycle run its course without the chance of pregnancy, or we may physically remove some or all of the eggs from the ovaries (see Egg Retrieval under ART) and proceed with IUI or IVF, thereby still allowing for pregnancy in the cycle. Our goal is to get our patients pregnant with a sound, manageable pregnancy – not get them pregnant at any cost. Historically, "fertility drugs" required direct injection into a muscle (intra muscular or IM injection) in order to work most efficiently. Although the medications work well, the injection kind of hurts. Thus, subcutaneous (just under the skin) injectable gonadotropins are all the rage today. Although not entirely painless, they are much more tolerable and are easier to give yourself. Don’t worry, every couple is given thorough injection training on how to administer the medication being prescribed and if still uncomfortable, our nurses will be glad to perform the injections in the office for you. These "fertility drugs" are better known by their various brand names: Pergonal, Lepori, and Menopur are all IM injectables that have been successfully used for years, while the newer subcutaneous injectables such as Gonal F and Follistim are becoming more and more prevalent. Because of their expense, it is not economical for us to keep a large enough supply of these medications on hand to serve all the patients using them on a daily basis, so they are purchased by the patients directly from a mail order pharmacy such as MDRx. And there lies the biggest shortcoming with treating patients with these medications – the cost. Depending on how your ovaries respond, a stimulation cycle can use up to $2000 - 3000 worth of these drugs. Some of the drug manufacturers have programs to assist couples in financial need. Check out their individual links to find out about eligibility and restrictions. HCG HCG is a "surrogate" LH that has the same stimulatory effects on the ovary that LH does and can be provided by injection to trigger ovulation at the optimal time in the cycle as determined by your doctor. HCG is given around the time of ovulation to nearly all patients undergoing infertility treatment in order to reinforce or replace a naturally weak or poorly timed LH surge. This is particularly important for women undergoing stimulated cycles, as most women doing so will not have a spontaneous LH surge. Since spontaneous LH surges can be unpredictable in terms of timing, it is actually desirable to eliminate the possibility of such a surge and optimize the timing of ovulation with HCG injections based on follicle size and estradiol levels (see GnRH agonists below for a discussion of how we can prevent LH surges). GnRH Stimulation Some women fail to ovulate because the hypothalamus fails to produce sufficient stimulation to the pituitary gland in the form of GnRH (Gonadotropin Releasing Hormone). This hormone is necessary to keep the pituitary functioning. During intervals of high physical or psychological stress, the hypothalamus may not secrete GnRH and the pituitary gland stops producing the gonadotropins FSH and LH which, we’re sure you know by now, are necessary for egg development and ovulation. In these instances, GnRH can be directly administered into the blood stream by injection with a high incidence of restoring pituitary function. GnRH Agonists Just the opposite of GnRH stimulation, mentioned above, is the use of GnRH agonists which prevent the secretion of GnRH from the hypothalamus, which subsequently turns off the secretion of FSH and LH from the pituitary gland. As touched on in other sections, this can be desirable for a couple of reasons. One is to prevent the onset of a premature LH surge which can halt the maturation of the still developing eggs and keep them from ovulating. Premature LH surges are not uncommon when performing ovarian stimulation because the pituitary gland can be easily fooled by the increase in estrogen produced by a number of developing follicles. Since the pituitary gland is only expecting to detect the estrogen from a single mature follicle, it may be fooled into thinking that the elevated estrogen level is coming from one follicle that’s ready to ovulate when, in fact, it is the cumulative effect of many developing, but still immature, follicles. Thus, the pituitary may send out an LH surge too soon in response to a misinterpretation of estrogen levels and sabotage the cycle. Thus, the use of a GnRH agonist allows your doctor to control the timing of ovulation by administering HCG when appropriate (see HCG above). Because the GnRH agonist effectively turns off the pituitary gland, all of the FSH for stimulating the follicles during such a cycle must come from injectable gonadotropins (see Injectable Gonadotropins above). GnRH agonists are given to a vast majority of our IVF patients specifically to prevent premature LH surges, since we’d hate to see a surge ruin a cycle in which a couple has made such a significant emotional and financial investment. A second reason why GnRH agonists are desirable is in the treatment of endometriosis (see Pelvic Factors under Diagnosing Infertility). Success Rates A large percentage of women stimulated with injectable gonadotropins will ovulate, but will not all conceive. Typically, most pregnancies occur in the first 3 to 6 treatment cycles. This is highly dependent on a number of factors, however. Patient age, pelvic factors, uterine factors, tubal factors, male factors, etc. can all influence pregnancy rates (see Diagnosing Infertility for detailed discussions of these factors). Patients who fail to get pregnant following the methods of ovulation induction described in this section may still be excellent candidates and attain high pregnancy rates with a more high tech procedure such as IVF (see ART section for detailed discussion of IVF). Risks and Side Effects of Using Injectable Gonadotropins As discussed above, the risk of multiple pregnancy is increased in women undergoing ovulation induction using injectable gonadotropins. As for side effects, patients may experience some soreness, redness, or discomfort at the site of the injection of the medication, but most tolerate the shots quite well. Some patients may feel bloated or full as their ovaries enlarge during the stimulation cycle, similar but stronger to what you might feel during the mid-cycle discomfort portion of a normal ovulatory cycle. Other less common side effects include nausea, fluid retention, and headaches. One side effect that deserves special attention is OHSS, or ovarian hyperstimulation syndrome, and is almost unique to ovulation induction cycles, particularly in women who develop a large number of follicles (usually 20 or more) in response to injectable gonadotropins. This fairly rare condition is characterized by significant enlargement of the ovaries, possible fluid retention in the abdomen, and general swelling throughout the body. The syndrome usually begins about a week after ovulation and is not unusual to occur in cycles where the woman winds up pregnant, as there may be some unidentified characteristic of pregnancy that helps to trigger the onset of OHSS. The syndrome usually resolves on its own, however, and may take a few days to a few weeks before the discomfort is gone. In severe cases of OHSS where there is nausea and substantial discomfort due to fluid retention, the patient may require closer supervision and/or treatment by the doctor. Careful monitoring and adjustments during the ovulation induction treatment by the physician keeps the likelihood of OHSS quite low.