A pharmacotherapeutic review of treatment options for infertility in women

Abstract

The growing trend for women to wait later in life before having their first child has placed many women at a higher risk for difficult conception. There are numerous classes of medications available to assist women who have been diagnosed with infertility.Agents that are used in the treatment of infertility include: clomiphene citrate, aromatase inhibitors, gonadotropins, chorionic gonadotropins, gonadotropin-releasing hormone, gonadotropin-releasing hormone agonists, gonadotropin-releasing hormone antagonists, follitropins, and other miscellaneous agents. Medications chosen for a patient will vary depending on the identified cause of the infertility. Additionally, economic factors will play a role. It is important for healthcare professionals to be aware of treatment options and have a basic understanding of the role these medications play in the treatment of infertility. (Formulary. 2005;40:329–341.)

Many managed care organizations are impacted by the pharmaceutical costs associated with the treatment of infertility. No federal law exists that requires insurance coverage for infertility treatment. However, some states have mandated that insurers cover or offer to cover infertility treatment in insurance policies issued to employers.⁵

FEMALE REPRODUCTIVE CYCLE

The menstrual cycle is distinguished by changes throughout the month in the rates of secretion of female hormones and corresponding changes in the ovaries, sexual organs, and tissues. The duration of the menstrual cycle ranges from 20 to 45 days, with an average of 28 days. Abnormal cycle length is frequently associated with infertility.⁶

The menstrual cycle is a balance of hormonal relationships among the hypothalamus, pituitary, and ovaries. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) in pulsatile bursts every hour. In response to the secretions, the anterior pituitary secretes gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH).⁵

The purpose of the follicular phase is to develop a follicle capable of undergoing ovulation. At the beginning of the follicular phase there is a rise in FSH levels on the first day of the cycle, which prompts a reduction in progesterone and estrogen levels at the end of the previous cycle. This increase in FSH stimulates the growth of a group of follicles, ranging from 3 to 30. As FSH levels decline, one of the follicles is selected for ovulation. This dominant follicle develops and secretes increasing levels of estradiol, which exerts a negative feedback effect on hypothalamic secretion of GnRH and pituitary secretion of FSH. The result is that the remaining follicles cease development.⁷

In the second half of the menstrual cycle, the oocyte travels to the uterus through the fallopian tube. Meanwhile, progesterone levels increase and prepare the uterine lining for pregnancy.⁵ If the oocyte becomes fertilized by a sperm cell, the result is pregnancy. If pregnancy occurs, human chorionic gonadotropin (hCG) from the placenta prevents regression of the corpus luteum and maintains steroid (progesterone and estrogen) production to sustain the pregnancy. If the egg is not fertilized, it either dissolves or is absorbed into the body, causing a decline in estrogen and progesterone. This process leads to the shedding of the uterine lining of the uterus, which is presented as menstrual flow.¹⁰

CAUSES OF INFERTILITY

In approximately 90% of cases, the cause of infertility can be properly identified. Despite extensive testing, 10% of couples may never know the reason they cannot conceive.¹¹ Pelvic inflammatory disease (PID) is the major cause of infertility worldwide. PID comprises a variety of infections caused by different bacteria that block the fallopian tubes, a specific condition referred to as salpingitis. This condition may interfere with the egg and the sperm uniting, thus preventing fertilization. Another cause of infertility is endometriosis, which can cause rigid webs of scar tissue in the uterus, ovaries, and fallopian tubes, thereby preventing the transfer of the egg to the uterus.

Deficiencies or irregularities of gonadotropin-releasing hormone (GnRH) in this hormonal system can disrupt ovulation. This condition is medically referred to as hypogonadotropic hypogonadism. Some causes of hypogonadotropic hypogonadism include direct injuries to the hypothalamus or pituitary gland, medical conditions that disturb their regulation (kidney failure, cirrhosis, pituitary tumors), excessive exercise, and anorexia nervosa.^11,12

Polycystic ovarian syndrome (PCOS) results in ovarian production of high amounts of androgens, particularly testosterone. It appears to be an important cause of many menstrual disorders, which include amenorrhea or oligomenorrhea. In PCOS, increased androgen production results in high LH levels and low FSH levels, which prevents follicles from producing a mature egg.^13,14

Luteal phase defect is a general term that refers to inadequate production of progesterone, causing recurrent spontaneous abortion. Since progesterone is necessary for the thickening of the uterine lining, the ovum fails to successfully implant in the endometrium.

Benign fibroid tumors in the uterus are extremely common in women over age 30. They can cause infertility by interfering with the uterine cavity, blocking the fallopian tubes, or altering the position of the cervix and preventing sperm from reaching the uterus.

Asherman's syndrome, intrauterine adhesions/scarring often caused by dilatation and curettage (D&C) procedures, is another cause of infertility. The cervix can weaken and become unable to sustain a pregnancy. Scar tissue may form inside the uterine cavity, resulting in a closed uterus.

Other causes of infertility include ectopic pregnancy and medications such as antidepressants, hormones, antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen. These medications may reduce estrogen and LH levels.^11,12

TREATMENT OPTIONS

Treatment options for infertility include: clomiphene citrate, aromatase inhibitors, gonadotropins, chorionic gonadotropins, gonadotropin-releasing hormone, gonadotropin-releasing hormone agonists, gonadotropin-releasing hormone antagonists, follitropins, and other miscellaneous agents. Medications chosen for a patient will vary depending on the identified cause of the infertility. Additionally, economic factors will play a role.

CLOMIPHENE CITRATE

Clomiphene citrate (Clomid, Sanofi-Aventis) is considered a first-line agent for women with ovulatory dysfunction who are attempting to become pregnant. It is an oral agent categorized as a nonsteroidal estrogen receptor modulator that inhibits the negative feedback response on the hypothalamus by competing with estrogen for estrogen receptor-binding sites. This action leads to an increase in FSH and LH levels, promoting follicular growth and maturation, allowing ovulation to occur by increasing the number of eggs.^5,15

Patients who will generally receive the greatest benefits with clomiphene are those with PCOS, amenorrhea-galactorrhea syndrome, psychogenic amenorrhea, post oral-contraceptive amenorrhea, and certain cases of secondary amenorrhea of undetermined etiology. It is most effective in patients with normal FSH levels and adequate endogenous production of estrogen. Clomiphene is least effective in women with hypothalamic amenorrhea or an elevated basal FSH concentration.¹⁶ It should not be recommended for patients with ovarian cysts, abnormal vaginal bleeding, or abnormal liver function.¹⁵

To reduce the likelihood of multiple births, a gradual dose titration should occur. The recommended starting dosage is 50 mg daily (1 tablet) for 5 days, beginning on Day 5 of the menstrual cycle. This dose may be increased by increments of 50 mg in subsequent cycles to a maximum of 150 mg daily.^5,15 In practical settings, patients may take 50 to 250 mg daily for 5 days starting from Days 2 to 5 of induced or spontaneous bleeding. Administering the drug earlier in the cycle may avoid problems with implantation. Ovulation is expected to occur within 5 to 10 days after the last dose of the medication. If pregnancy does not occur within 3 to 6 consecutive ovulatory cycles of clomiphene therapy, alternative treatment should be considered.^5,14,15 Seventy-five percent of pregnancies achieved with clomiphene will occur within the first 3 cycles.¹⁴

Patients on clomiphene therapy may experience abdominal/pelvic pain or distention, visual symptoms, headache, hot flashes, mood alteration, pregnancy wastage, and birth anomalies.^5,12,15 Because clomiphene increases the number of ovulations, the chance of multiple pregnancies is greater. The risk of twins is 5% to 10%, and the risk of triplets and greater is <1%.¹⁷

AROMATASE INHIBITORS

Although not FDA-approved for use in infertility, aromatase inhibitors are sometimes used as alternatives to clomiphene. Letrozole (Femara, Novartis) is used most often for women with ovulatory dysfunction. Similar to clomiphene, it exerts its action by suppressing estrogen production. Letrozole is quickly cleared from the body and is only effective for the cycle in which it is taken. The advantage of letrozole is that it is less likely to adversely affect the uterine lining and cervical mucous, and it has a reduced rate of multiple pregnancy when compared with clomiphene.^14,18,19 Patients taking letrozole may experience hot flashes, gastrointestinal events such as nausea and vomiting, and leg cramps.¹⁹

GONADOTROPINS

When oral therapy proves to be unsuccessful for patients, gonadotropin agents can be used to produce ovulation for insemination or assisted reproductive techniques (ARTs). Women approved for treatment with gonadotropins must have ovaries that respond to FSH and LH stimulation. Gonadotropins are parenterally administered agents that require close monitoring in selected patients. They are more expensive than oral agents and are administered daily.

Human menopausal gonadotropin (hMG), commonly referred to as menotropins for injection (eg, Repronex, Ferring), is derived from the urine of postmenopausal women.⁵ Menotropins are administered to women for 7 to 12 days to produce ovarian follicular growth. Once sufficient follicular maturation occurs, human chorionic gonadotropin is given to induce ovulation. Menotropins should not be administered to women with primary ovarian failure.²⁰

Menotropins are available in varying quantities, 75 or 150 IU of FSH and LH. Each vial contains equal amounts of LH and FSH activity. In patients with oligo-anovulation who have received previous treatment with a GnRH agonist/antagonist, the recommended initial dose is 150 IU for the first 5 days up to a maximum daily dose of 450 IU not to exceed 12 days of therapy. Dosing adjustments may be made every 2 days at 75 to 150 IU per adjustment. If the patient responds appropriately, 5,000 to 10,000 USP units of hCG should be administered 1 day following the last dose of menotropins.

When using menotropins with ARTs for patients who have received prior GnRH treatment, the recommended starting dose is 225 IU, individually titrating up to 450 IU daily not to exceed 12 days. As with patients with oligo-anovulation, dosing adjustments can be made every 2 days at 75 to 150 IU per adjustment. If the patient responds appropriately, 5,000 to 10,000 USP units of hCG should be administered 1 day following the last dose of menotropins.

Women with hypothalamic anovulation and a baseline serum LH level below 0.5 IU/L have a deficiency in FSH and LH, and therefore should be treated with both. Women with hypothalamic amenorrhea and a baseline LH level greater than 0.5 IU/L can be treated with FSH alone.¹⁶

Adverse reactions with menotropins may include pulmonary and vascular complications, hemoperitoneum, mild- to-moderate ovarian enlargement, ovarian cysts, abdominal pain, various gastrointestinal symptoms, and pain and/or irritation at the site of injection.²⁰ Women using gonadotropins also have a significant chance of developing ovarian hyperstimulation syndrome (OHSS). This is a condition associated with altered permeability and leakage of protein-rich fluid from the small vessels of the ovary into the pelvic, abdominal, and possibly pleural cavities. One of the greatest threats with the use of gonadotropins is the risk of multiple gestation. The risk of twins is about 20%, and the risk of triplets is about 5%.¹⁷

CHORIONIC GONADOTROPINS

Chorionic gonadotropins include:

Human chorionic gonadotropin. Human chorionic gonadotropin (hCG) (Novarel, Ferring) is a polypeptide hormone that is produced by the human placenta. During the menstrual cycle, LH and FSH aid in the development of the ovarian follicle, and the mid-cycle LH surge triggers the release of the oocyte. Natural hCG comes from the urine of postmenopausal women and is administered after follicular maturation from ovarian stimulation. If the cause of ovarian failure is lack of a midcycle gonadotropin surge, treatment with exogenous hCG is given intramuscularly 3 to 4 days after the last dose of clomiphene. Human chorionic gonadotropin is indicated for induction of ovulation and pregnancy in women with anovulation secondary to primary ovarian failure. These women should be pretreated with human menotropins to force the release of the egg. To achieve ovulation, 5,000 to 10,000 IU 1 day following the last dose of menotropins is generally required.²¹

Choriogonadotropin alfa for injection. Choriogonadotropin alfa for injection (eg, Ovidrel, Serono; and Pregnyl, Organon) is a highly purified form of recombinant human chorionic gonadotropin (r-hCG). It is administered as a single 250-mcg subcutaneous injection following the stimulation phase of infertility treatment. Recombinant human chorionic gonadotropin results in egg maturation and triggers ovulation in patients following the follicular phase of fertility treatment. The activity of hCG is similar to the activity of LH, but hCG has a half-life of 24 hours as opposed to 1 hour with LH. Intercourse is advised 1 day following r-hCG administration and for the next 2 days.

Headache, irritability, restlessness, fatigue, edema, gynecomastia, and pain at the injection sites are the most common adverse effects reported for both the recombinant- and urine-derived products.²² No known risks during pregnancy have been reported when it is used appropriately.¹⁷

Recombinant hCG may be preferred over urine-derived hCG (u-hCG) due to its ability to be administered subcutaneously as opposed to intramuscularly, and due to a more predictable dose-response relationship during the dosing cycles.²³ Progesterone levels in the mid-luteal phase were found to be higher with the use of r-hCG compared with u-hCG.^24,25

GONADOTROPIN-RELEASING HORMONE

Gonadorelin acetate. Gonadorelin acetate (Factrel, Baxter) is a synthetic decapeptide that has the same amino acid sequence of endogenous GnRH. (Note: Gonadorelin has undergone changes in manufacturers and at press time it was unavailable for distribution in the United States.) The average starting dose is 5 mcg administered IV via a portable programmable mini-pump in intervals of 90 minutes for 21 days. The pulsatile administration of gonadorelin mimics the endogenous release of GnRH from the hypothalamus. Gonadorelin is indicated for the induction of ovulation in women with primary hypothalamic amenorrhea.

Gonadorelin is contraindicated in women with pituitary prolactinoma and in those with ovarian cysts.^5,26 Inflammation at the injection site, mild phlebitis, infection, and hematoma may result due to the intravenous administration of gonadorelin.⁵ There is a low risk for multiple pregnancies and OHSS. There should be no risk to the pregnancy with gonadorelin since it restores normal ovarian function and ovulation. If ovulation is delayed, however, the rate of miscarriage may be higher.¹⁷

GONADOTROPIN-RELEASING HORMONE AGONISTS

Gonadotropin-releasing hormone agonists cause a transient surge in circulating levels of LH, FSH, testosterone, and estradiol. After chronic administration (2–4 wk) of GnRH agonists, a sustained decrease in LH and FSH secretion and a marked reduction in ovarian steroidogenesis are observed. This reduction in LH decreases premature ovulation and suppresses the number of unviable oocytes to increase the likelihood of pregnancy. Adding a GnRH agonist to the treatment regimen for women with PCOS can potentially reduce the incidence of unsuccessful pregnancies.⁵ These agents are typically reserved for women with repeated premature ovulation and those who fail treatment with LH and FSH.

The side effects of GnRH agonists may include flushing, hot flashes, mood alteration, breast tenderness or pain, constipation, dizziness, headache, fatigue, irritation at the injection site, and vaginal dryness. These side effects are reversible upon discontinuation of these agents.²⁷

The GnRH agonists include:

Leuprolide acetate. Leuprolide acetate (eg, Lupron Depot, Tap Pharmaceutical) is a synthetic nonapeptide analog of naturally occurring GnRH. Although it is not FDA-approved for use in infertility, leuprolide is used in combination with other fertility agents for controlled ovarian hyperstimulation (COH) and endometriosis. Leuprolide possesses greater potency than the natural hormone. A 1-mg dose of leuprolide is administered by subcutaneous injection daily in patients with COH. It is most commonly used when a patient is undergoing a stimulation cycle with injectable fertility drugs by a down-regulation of the hormonal system.^27,28

Leuprolide is contraindicated in patients with abnormal vaginal bleeding and pregnancy. Patients should be monitored closely for weakness, paresthesias, and urinary tract obstruction in the first few weeks of treatment. Women who have a history of psychiatric illness should use this product with caution, as these patients can express an alteration in mood, memory impairment, and depression.²⁸

Nafarelin acetate. Nafarelin acetate (Synarel, GD Searle) is a potent synthetic decapeptide analog of GnRH that is used in the treatment of endometriosis. It is approximately 200 times more potent than endogenous GnRH in the pituitary release of LH and FSH. The length of administration determines the effects that nafarelin will have on the pituitary gland and sex hormones. Nafarelin is available as a nasal spray. The usual dose is 1 spray (200 mcg) in 1 nostril each morning, alternating the other nostril each evening, starting between Days 2 and 4 of the menstrual cycle for 6 months.

Symptoms such as shortness of breath, chest pain, urticaria, rash, and pruritus have been reported with nafarelin. The most frequently reported adverse reactions are hot flashes, changes in libido, vaginal dryness, headaches, acne, myalgia, decreased breast size, and irritation of the nasal mucosa.²⁹

Triptorelin pamoate. Triptorelin pamoate (Trelstar Depot, Watson Pharmaceuticals) is a synthetic decapeptide agonist analog of GnRH. Triptorelin is also more potent than GnRH. Triptorelin has been widely used in Europe since 1986 as part of in vitro fertilization protocols, but it is currently not FDA-approved for ovulation stimulation. When taken chronically, triptorelin acts as a potent inhibitor of gonadotropin secretion. Triptorelin pamoate suspension is administered by intramuscular depot injection as a single 3.75-mg IM dose 15 days prior to initiation of ovarian stimulation therapy.³⁰

Goserelin acetate. Goserelin acetate (Zoladex, AstraZeneca) is another synthetic form of endogenous GnRH that is used for the treatment of endometriosis and preparation of the pituitary gland prior to infertility treatment. The usual dosage is 3.6 mg subcutaneously every 28 days for a duration of 6 months.³¹

GONADOTROPIN-RELEASING HORMONE ANTAGONISTS

The GnRH antagonists include:

Ganirelix acetate. Ganirelix acetate (Antagon, Organon) is a third-generation GnRH analog (GnRHa) that has demonstrated high biologic potency with minimal histamine release. It can be administered subcutaneously and intranasally to improve patient compliance.³² It is indicated for the inhibition of premature surges of LH in women undergoing COH. It competitively blocks the GnRH receptors on the pituitary gonadotrophs and the subsequent signal transudation pathway. By doing so, ganirelix induces rapid reversible suppression of gonadotropin secretion.^33,34

Before administering ganirelix, FSH therapy should be initiated on Day 2 or 3 of the cycle. Ganrilex is then administered once daily during the mid- to late portion of the follicular phase, usually around cycle Day 8. This treatment should be continued until adequate follicle sizes are present and followed by hCG to enhance final maturation and induce ovulation. Human chorionic gonadotropin administration should be stopped in cases in which the ovaries are abnormally enlarged on the last day of FSH therapy to reduce the chance of OHSS.^17,32,33

Patients receiving ganirelix may experience abdominal pain, which may either be gynecological or gastrointestinal; headache; OHSS; vaginal bleeding; nausea; or injection-site reactions.³³

Two different dosages have been studied, multiple doses of 0.25 mg once daily and a single dose of 3 mg. Cetrorelix 0.25 mg may be given in the morning starting on Day 5 or 6 of ovarian stimulation with gonadotropins, or each evening starting on Day 5 of ovarian stimulation. This regimen is continued throughout gonadotropin treatment, including the day of ovulation induction. Cetrorelix 3 mg may be given once on Day 7 of ovarian stimulation with gonadotropins. If follicle growth does not allow ovulation induction on the fifth day after injection, cetrorelix 0.25 mg may be added once daily until ovulation induction occurs.

Cetrorelix is contraindicated in pregnancy and lactation, in postmenopausal women, in those with moderate-to-severe renal or hepatic impairment, and in those with hypersensitivity to cetrorelix. Some side effects may include headache, rash, nausea, hypotension, redness at the site of injection, pruritis, and cough.

The main advantages for women treated with cetrorelix are the avoidance of hormonal withdrawal side effects (eg, hot flashes) and the convenience of the dosage regimen, particularly the fact that no pre-treatment is required.^35,36

PROGESTERONE

Progesterone prepares the endometrial lining for implantation. Once the embryo has been implanted, progesterone helps maintain the pregnancy. There are various dosage forms available on the market; however, the non-oral routes are more favorable for the treatment of infertility. Vaginal gel (eg, Crinone, Serono; and Prochieve, Columbia Laboratories) is the only product FDA-approved for progesterone supplementation or replacement as part of an ART treatment for infertile women with progesterone deficiencies.^37,38 Although treatment may be somewhat painful, another effective method for patients is the use of progesterone intramuscularly. A progesterone injection (Progesterone in oil, Consolidated Midland Corp) is available and is suspended in an oil, commonly sesame or peanut, and is normally compounded by a specialty pharmacy.³⁹

Progesterone gel 8% (90 mg per dose) is given once daily for women who require progesterone supplementation and twice daily for those with partial or complete ovarian failure who require progesterone replacement. Treatment begins 2 days after ovulation and may continue for 10 to 12 weeks in women who become pregnant until placental autonomy is achieved.^38,40 Dosing for patients using IM progesterone ranges from 50 to 100 mg daily.⁵ Comparative studies have revealed that the vaginal gel is just as effective as the injection in producing successful pregnancy rates.⁴¹ Therefore, patients may prefer to use the gel to avoid injections.

Patients receiving progesterone may experience abdominal cramps and bloating, dizziness and headache, gastrointestinal symptoms, arthralgia, breast enlargement and pain, vaginal discharge, nocturia, and genital pruritis. It has also been documented that patients receiving once-daily dosing have been noted as experiencing some psychiatric symptoms, including depression, decreased libido, nervousness, and somnolence.³⁸ Outside of traditional progesterone side effects, patients receiving intramuscular injections may experience pain at the injection sites.

FOLLITROPINS

Follitropins. Follitropins are FDA-approved for the treatment of infertility when clomiphene therapy is inadequate. They are divided into 2 groups: human follicle-stimulating hormones (hFSH) or urofollitropins and recombinant human follicle-stimulating hormones (r-hFSH), which is subdivided as r-hFSH alpha and r-hFSH beta.⁴² Follitropins stimulate egg maturation in the ovary when administered. Their dosing is patient-specific, with the lowest dose being used to achieve the desired results. Therapy should not exceed 35 days.

Follitropins should be avoided in women who have high primary ovarian failure (indicated by high FSH levels), pituitary tumor, infertility not caused by anovulation, idiopathic abnormal bleeding, ovarian cysts not due to PCOS, and uncontrolled thyroid and adrenal dysfunction.^43,44

Patients on follitropins may experience ovarian enlargement, which is manifested as abdominal distention with or without pain, increased risk for OHSS, pelvic pain, nausea, vomiting, weight gain, oliguria, hypovolemia, hepatic dysfunctions and thromboembolic events.⁴² Patients also have similar risks for multiple gestations as with gonadotropins.¹⁷

Urofollitropins. The urofollitropins (Bravelle, Ferring Pharmaceuticals) are approved for both SC and IM injection. They contain purified hFSH extracted from the urine of postmenopausal women. They are used in conjunction with human chorionic gonadotropin (hCG) for ovulation induction in patients who have previously received pituitary suppression.^42,43

The recommended dose when using the urofollitropins is 150 IU daily for the first 5 days of treatment. Subsequent doses should be given based on patient response, with a maximum daily dose of 450 IU. Dosing beyond 12 days is not recommended.

Recombinant-hFSH. Recombinant-hFSH (Follistim AQ, Organon; and Gonal-F, Serono) is a preparation of recombinant DNA origin, which is essentially equivalent in its structure to endogenous FSH in the body.^12,44 There are 2 subunits, alpha and beta, which confer several differences. The alfa subunit has a lower pH than the beta subunit. Success rates are similar in terms of pregnancy outcomes when stratified by age. Recombinant-hFSH beta is available in SC and IM formulations, while r-hFSH alfa is available in a SC formulation only. Recombinant-hFSH is indicated for the induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure.^43,44 They are both used to develop multiple eggs in ovulatory patients participating in ARTs. They are also used to stimulate multi-follicular development during ovarian stimulation regimens for in vitro fertilization.¹⁴

When using r-hFSH, 75 IU is used for the first 7 days of treatment. Subsequent doses are based on patient response, with a maximum daily dose of 300 IU. Dosing beyond 35 days is not recommended. If there is an appropriate response to the follitropins, hCG (5,000–10,000 USP units) should be given the first day after the last dose of the follitropins to induce ovulation when sufficient follicular maturation has occurred.

MISCELLANEOUS AGENTS

Other agents include:

Metformin. Insulin resistance and hyperinsulinemia have been observed in patients with anovulation associated with PCOS.⁴⁵ These findings suggest that a reduction in insulin concentrations could potentially be significant for these patients. Metformin (eg, Glucophage, Bristol-Myers Squibb) is an oral biguanide that enhances insulin sensitivity in the liver by inhibiting hepatic glucose production. It also enhances insulin sensitivity in the muscle tissue to improve glucose uptake and use.

Patients receiving metformin may experience gastrointestinal symptoms such as nausea, vomiting, diarrhea, flatulence, abdominal discomfort, and indigestion. Other side effects may include asthenia and headache. Additionally, patients on metformin should be monitored for lactic acidosis. ^46,47

Dopamine agonists. The hypothalamic release of dopamine increases in patients with hyperprolactinemia, which inhibits anterior pituitary prolactin release and suppresses the hypothalamic secretion of GnRH.

Cabergoline (Dostinex, Pfizer) is long-acting with a high affinity for the dopamine-2 receptor. It is dosed as 0.5 to 3 mg orally twice daily. If pregnancy does not occur, the patient can stop taking the medication in the luteal phase and restart after the start of the next menses.⁵

Bromocriptine (Parlodel, Novartis) is a dopamine agonist that directly inhibits pituitary prolactin secretion. The recommended dose for bromocriptine is 1.25 mg orally daily, increasing to 2.5 mg daily after 2 weeks. It should be taken during the follicular phase once ovulation begins.

In a study of 64 women with constant hyperprolactinemia, 49 women who received bromocriptine achieved a total of 78 pregnancies. In the 15 patients who did not receive therapy, 25 pregnancies occurred. Seventy-two percent with therapy went to delivery, and 48% without treatment went to delivery.⁴⁸

It has also been published that a 60% to 80% pregnancy rate can be achieved using dopamine agonists if the only cause of infertility is chronic anovulation due to hyperprolactinemia.⁵

ECONOMIC CONSIDERATIONS

There is much ongoing debate regarding insurance coverage of infertility treatments. Proponents of coverage, such as Resolve: The National Infertility Association, endorse state and federal legislation that would require insurers to cover costs of appropriate treatment, and they believe the option to pursue infertility treatment must be available to all who desire it.⁵¹ However, the providers of insurance coverage are forced to make business decisions about ways to find a balance between treatment options they will cover and the economic impact on their organizations.

Cost-effectiveness analyses are often used to help determine what services and products should be offered by an organization. From the organizational perspective, direct medical costs should be considered. Direct medical costs include expenditures for medical products or services. These expenditures may include costs associated with hospitalization, drugs, physician fees, laboratory tests, and radiologic procedures. When determining coverage for infertility treatments, it is also important to consider the costs incurred from prematurely born multiple gestations resulting from some of these treatments.⁵² Limitations to conducting cost-effectiveness analyses in the area of infertility include the lack of standardized treatment protocols as well as the fact that success rates are often center-dependent.⁵

In 1996, a study concluded that IVF was more cost-effective than tubal repair by laparoscopy based on a cost-per-delivery of $23,718 for IVF versus $24,333 for tubal surgery and a 34% conception rate by IVF as compared with a 12.5% conception rate after tubal surgery.⁵² A study published in 1997 by Van Voorhis et al^52,53 reviewed the cost-effectiveness of intrauterine insemination (IUI), clomiphene administration and IUI (CC-IUI), and hMG-IUI. The study concluded that each treatment provided similar costs per delivery, yielding $8,674 for IUI, $7,808 for CC-IUI, and $10,282 hMG-IUI, and all treatments were more cost-effective than IVF ($43,138).

When the University of Iowa, a self-insured organization, conducted a study to determine the complete costs of infertility care over a 3-year period (January 1993–December 1995), it concluded that infertility healthcare costs accounted for a small portion of its total healthcare costs. Total healthcare costs were $86,445,642, while infertility-specific costs were $680,921.⁵²

CONCLUSION

There are numerous classes of medications available to assist women who have been diagnosed with infertility. Medications chosen for a patient will vary, depending on the cause of the infertility. Each class offers advantages and disadvantages (Table 2).

It is important for healthcare professionals to be aware of options and have a basic understanding of the role these medications play in the treatment of infertility. With the reported cases of infertility on the rise, the healthcare industry must be knowledgeable about treatment options and be prepared for the economic impact this can have.

Dr Moultry is assistant professor of pharmacy practice, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, and inpatient pharmacy operations manager, Harris County Hospital District, Houston. Dr Eaton is a drug information resident with Roche Pharmaceuticals, Nutley, NJ. She was a fourth professional year student in the College of Pharmacy and Health Sciences, Texas Southern University, when this manuscript was prepared. Dr Che is a staff pharmacist with Walgreens, Litchfield Park, Ariz. She was a fourth professional year student in the College of Pharmacy and Health Sciences, Texas Southern University, when this manuscript was prepared.

Disclosure: The authors report that no financial relationships exist between the authors and any of the manufacturers of products mentioned in this article.

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