Drugs Used in the Treatment of Infertility

Medical Treatment of Ovulation Disorders

Since a woman's menstrual period generally occurs two weeks after ovulation in the absence of pregnancy, the frequency of ovulation (egg release) can usually be predicted by her bleeding pattern. Irregular or absent ovulation can occur for several reasons. Abnormalities in thyroid or prolactin hormone production, if present, can be treated with specific medication, resulting in more regular ovulation. When these hormone levels are normal, other medications are available to to stimulate egg production and release by the ovaries more directly and produce more regular ovulation in women who either do not ovulate at all, ovulate infrequently or ovulate on a very irregular basis. In selected cases of polycystic ovary syndrome (PCOS), when drug treatment is not effective or feasible, a surgical procedure called laparoscopic ovarian drilling may result in the resumption of monthly ovulation without the need for medical therapy.

Medical Treatment of Unexplained Infertility

Since it has long been recognized that pregnancy rates are generally higher when the ovaries are stimulated to produce multiple eggs, monthly treatment with Clomid or gonadotropins, in association with intrauterine insemination (IUI) or in vitro fertilization (IVF), can be used to enhance fertility potential for that month in women who already ovulate regularly on their own. A detailed discussion of the differences between IUI and IVF may be found here.

Clomid vs. Gonadotropins

Two different types of medications, Clomid and a group of drugs called gonadotropins, are FDA approved to stimulate egg production by the ovaries. Clomid and gonadotropins are quite different in their administration, success rates, side effect profiles and potential complications as discussed in more detail below. In brief, Clomid is a synthetic medication that is available in pill form. It is often used as first-line therapy for women who do not ovulate and exerts its effect on the ovaries indirectly by stimulating the body's own hormones, which generally leads to the production of only a small number of eggs and a low risk of multiple pregnancy. Clomid is also much less expensive than gonadotropins and usually requires less supervision of its use.

Gonadotropins are identical to the hormones produced by the pituitary gland in the brain that normally stimulate the ovaries, and thus provide a more direct stimulation effect on the ovaries. This generally leads to the production of more eggs than Clomid, a higher pregnancy rate, and an increased multiple pregnancy rate, especially when used with IUI. These drugs are also commonly used to stimulate the development of multiple eggs for IVF. Gonadotropins must be given by daily injection and closely supervised by a physician experienced in their use due to the potential for a serious complication known as ovarian hyperstimulation syndrome (OHSS).

Clomid (Clomiphene Citrate) with IUI

Clomid to Induce Ovulation in Anovulatory Women

Clomid (clomiphene citrate) is a synthetic drug that has a combination of estrogen and anti-estrogen properties in various parts of the body. It is available in pill form under the brand name Clomid and as generic clomiphene citrate. Although it has been called a "fertility drug," the primary use of Clomid is to stimulate ovulation in women who wish to become pregnant but do not ovulate on their own each month. Clomid can also be used to induce a more predictable pattern of ovulation for couples who find it hard to properly time intercourse due to very irregular periods. Generally up to 85 percent of women will begin to ovulate with the use of Clomid. About 50 percent of women treated with Clomid will become pregnant during the initial four to six months of ovulatory treatment cycles, assuming that there are no other factors contributing to their infertility.

Clomid for Ovulatory Women with Unexplained Infertility

While Clomid can be used as an initial treatment for infertile women who already ovulate normally on their own, pregnancy rates are only in the range of eight to 10 percent per cycle of treatment in this setting. This is likely a result of the limited increase in egg production that occurs with Clomid when compared with the injectable drugs described in the next section. In general, Clomid will stimulate only one to two eggs to grow in each cycle of treatment, comparable to what an ovulatory women will produce without treatment. Also, Clomid may have some potentially negative effects on fertility because the anti-estrogen properties of Clomid can prevent the formation of cervical mucous, which normally guides the passage of sperm into the uterus, and may also interfere with the maturation of the uterine lining, limiting the ability of the embryo to implant and grow within the uterus.

Clomid Administration

Clomid is started at a dose of one 50 mg pill daily for five days, beginning on day five of the menstrual period. This dose is increased as necessary to two pills (100 mg) or three pills (150 mg) per day for women who do not respond to the lower dose. The cost of Clomid ranges from about $15.00 per pill for the Clomid brand to approximately $3.00 per pill for the generic version, if not covered by insurance.

Once a consistent ovulation pattern has been established, an over-the-counter urine ovulation test can be used to determine the day of ovulation, at which time an intrauterine insemination (IUI) is performed in order to bypass the possible thick cervical mucus that may result from Clomid use. Alternatively, the progress of egg maturation following Clomid administration can be monitored with ultrasound and combined with an injection of human chorionic gonadotropin (hCG) to induce ovulation at the proper time. If pregnancy does not occur within four to six ovulatory cycles of Clomid treatment, consideration should be given to an alternative form of therapy as described below.

Clomid Side Effects

The side effects of Clomid are usually mild and short-lived, and may be dose related. They include hot flashes in 11 percent of treatment cycles; abdominal discomfort (7 percent); breast tenderness, visual symptoms, nausea, nervousness or insomnia (2 percent); and headache or dizziness (1 percent). Clomid may also induce the formation of an ovarian cyst in 14 percent of treatment cycles. Although the cyst will generally reabsorb, the following dose of medication should be withheld. About 10 percent of women who conceive with Clomid will have twins and a very small number of Clomid cycles may result in triplets.

Clomid with Metformin (Glucophage)

Metformin (Glucophage) is an insulin sensitizing drug that has been used for many years to treat diabetes and has also found use in the treatment of polycystic ovary syndrome (PCOS). By decreasing insulin levels, the use of Metformin alone may result in ovulation, but it appears to be less effective than Clomid for inducing ovulation and also for producing a successful pregnancy outcome. Metformin may be helpful in improving the response to Clomid when ovulation does not result from the use of Clomid alone.

Metformin is available as a pill that is taken two to three times daily. Its major side effect is intestinal discomfort and diarrhea, which may lead some women to discontinue its use within a short period of time.

Bravelle/Menopur/Gonal-F/Follistim with IUI or IVF

Bravelle, Menopur, Gonal-F and Follistim are members of a class of drugs called gonadotropins, which are among the hormones that both women and men normally produce in their pituitary glands. In men, these hormones stimulate the testes to produce sperm and testosterone and in women the hormones stimulate the ovaries to produce eggs and estrogen. There are two gonadotropins that are naturally produced: follicle stimulating hormone (FSH) and luteinizing hormone (LH). In women, although a small amount of LH is necessary, FSH is the primary hormone that drives egg production. Gonadotropins are generally used for women who fail to ovulate in response to Clomid therapy or who fail to conceive after four to six ovulatory Clomid treatment cycles. The drugs are also used to enhance the fertility of women who already ovulate on their own.

Gonadotropin Brands

Bravelle contains FSH that is extracted from the urine of menopausal women who produce this hormone in excess. Menopur is also extracted from the urine of menopausal women but contains a mixture of FSH and LH. Gonal-F and Follistim are both produced from the human gene for FSH that has been isolated and placed in cells that are grown in large volumes in the laboratory. Bravelle, Gonal-F and Follistim may be used alone or in combination with Menopur, to provide additional LH in selected cases. There does not appear to be any practical difference between Bravelle, Follistim, Gonal-F, or Menopur with regard to overall pregnancy rates or complication rates.

Gonadotropin Administration

The gonadotropins are given by a daily subcutaneous injection, using a short, thin needle attached to an insulin syringe, for approximately seven to 10 days, beginning on the third day of a menstrual period. The response to the medication is monitored by measurement of blood levels of estrogen and by ultrasound examination of the growth of the follicles, the small fluid-filled cysts within the ovaries that contain the eggs. Once satisfactory egg development has occurred, release of the eggs is induced with a single intramuscular injection of human chorionic gonadotropin (hCG; also available as Novarel and Pregnyl). For an IUI cycle, inseminations are scheduled on each of the two days following the hCG injection in anticipation of ovulation occurring approximately 40 hours after hCG administration. For an IVF cycle, the egg retrieval is scheduled to take place about 35 to 36 hours after the hCG is given.

The cost of the gonadotropin medication alone can range from $1,200 to $2,000 or more per treatment cycle, depending on the dose and duration of therapy required. This does not include the cost of the ultrasounds, estrogen levels, office visits, inseminations or IVF procedures that are also necessary.

Gonadotropin Success Rates with IUI vs. IVF

Although some couples may prefer to have intercourse during a gonadotropin stimulation cycle, the pregnancy rate of 10 percent that results following intercourse is significantly lower than the pregnancy rates of 20 percent and 50 percent that occur with IUI and IVF, respectively, in women under age 35. All of these success rates decrease progressively as women age into their later thirties and forties.

Gonadotropin Side Effects/Multiple Pregnancies

Since gonadotropins are identical to the natural hormones normally produced by women, there are minimal side effects attributable to the drugs themselves. Thus, the major practical complication of Bravelle, Menopur, Gonal-F or Follistim therapy, especially when used with IUI, is the risk of multiple pregnancy, which occurs in 25 to 30 percent of conceptions. Of the multiple pregnancies that occur, approximately 95 percent are twins, about five percent are triplets and about one percent consist of higher order multiples, such as quadruplets and quintuplets. It is important to understand that even the presence of twins represents a higher risk to the mother for several possible pregnancy complications and also to the babies for premature birth, compared with having one child at a time. The presence of higher-order multiple pregnancies of three or more represents a significant risk of early premature birth, which may impact the survival and later development of the babies. In this situation, selective embryo reduction may be considered by the couple in order to reduce the number of embryos down to two. IVF can help to limit the occurrence of high-order multiple pregnanciesby limiting the number of embryos that are placed in the uterus during an IVF treatment cycle.

Ovarian Hyperstimulation Syndrome (OHSS)

The other potential risk of gonadotropin use is ovarian hyperstimulation syndrome (OHSS). OHSS may occur following the hCG injection if too many follicles are stimulated within the ovaries and the estrogen levels become too high. OHSS may result in a spectrum of problems ranging from mild ovarian enlargement and discomfort to significant ovarian enlargement with fluid shifts into the abdominal and chest cavities that can result in decreased urine output, electrolyte imbalances and an increase in blood clot formation. Severe OHSS can generally be avoided by careful management and monitoring of the gonadotropin dose and by withholding the hCG injection if estrogen levels become too high. It is thus very important that the physician be experienced in the management of these medications.

Laparoscopic Ovarian Drilling

Although it is a surgical procedure, laparoscopic ovarian drilling may be a treatment consideration for women with polycystic ovary syndrome (PCOS) who fail to ovulate or conceive with Clomid and who either cannot afford gonadotropins or do not wish to risk the multiple pregnancies that can occur with these drugs. It has been shown that burning the surface cysts on the ovaries in women with PCOS can change the hormonal environment in such a way as to allow for spontaneous ovulation without the use of medication. This procedure can be accomplished as outpatient surgery through the laparoscope. However, the healing process does have the potential to cause scar tissue to form around the ovaries, which can prevent the eggs from escaping into the fallopian tubes to be fertilized with sperm. For this reason, ovarian drilling is generally recommended only in cases where drugs have not been effective or there are financial or other considerations that prevent their use. Pregnancy rates of up to 60 percent have been reported following laparoscopic ovarian drilling.

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