Understanding Female Infertility: Causes and Treatments

Release Date:  September 1, 2010

Expiration Date: September 30, 2012

FACULTY:

Jennifer L. Gibson, PharmD
Medical Writer and Editor
Marietta, Georgia

FACULTY DISCLOSURE STATEMENTS:

Dr. Gibson has no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

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Pharmacists

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Type of Activity: Knowledge

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This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To increase understanding of female infertility and review available treatment options.

OBJECTIVES: 

After completing this activity, participants should be able to:

  1. Review the anatomy and physiology of reproduction.
  2. Identify factors that influence female fertility.
  3. Discuss the causes of infertility.
  4. Describe pharmacologic and nonpharmacologic treatment options for female infertility.

Infertility is the involuntary inability of a couple to conceive.1 In general, infertility is defined as the reduced ability to conceive compared with the ability of the general population.2 In contrast, sterility is the complete inability to conceive.1 For most couples, the term “subfertility” is more appropriate, as achieving pregnancy is difficult but not impossible.2 In normal fertile couples, the monthly conception rate, or fecundity, is 20% to 25%.2-4 That is, among couples who have sexual intercourse the week prior to ovulation, 1 in every 4 to 5 couples will conceive each month.

Among reproductive-aged couples in the United States, approximately 10% to 15% experience infertility.3-6 Females reach peak fertility by the age of 25 years,1,4 and fertility declines slightly after the age of 30.2 After age 40, fertility in females declines rapidly.4

Infertility affects approximately 2.1 million married couples in the U.S.7 Half of the couples who seek treatment will eventually conceive while the other half will remain infertile.5 Among reproductive-aged females attempting to conceive, approximately 50% will become pregnant within 3 months, 75% within 6 months, and 90% within 12 months.2

REQUIREMENTS FOR CONCEPTION

There are many criteria that must be met in order for conception to occur. First, the female must ovulate, releasing an egg from her ovary. The egg must then travel through the fallopian tube. The male must produce and ejaculate an adequate number of normal, motile sperm. The sperm must travel through an unobstructed female reproductive tract, through the uterus to the fallopian tube, where fertilization occurs. The fertilized egg must then travel down the fallopian tube to the uterus and implant into the endometrium.1,8 A problem at any stage of the reproductive process results in infertility.1

Female hormone production is essential to adequate reproductive capability. During the follicular phase of the menstrual cycle, lasting for approximately the first half of the cycle, the hypothalamus releases gonadotropin-releasing hormone (GnRH). GnRH stimulates the anterior pituitary to release follicle-stimulating hormone (FSH), which controls the growth of a follicle containing an immature ovum or egg.7 After the follicle has matured, a surge of luteinizing hormone (LH) from the pituitary gland induces the release of the egg through ovulation and signifies the start of the luteal phase that will last for the remainder of the menstrual cycle.7,8 The ruptured follicle forms the corpus luteum, which produces progesterone that supports the endometrium for implantation. If a sperm fertilizes the egg, implantation in the endometrium of the uterus occurs 5 to 7 days after ovulation. The trophoblast cells surrounding the newly fertilized egg produce human chorionic gonadotropin (hCG) to maintain the corpus luteum. In the absence of hCG, the corpus luteum involutes and estrogen and progesterone decrease, resulting in menses. Corpus luteal hormone production is essential to the first 8 weeks of gestation; without it, pregnancy cannot be maintained.7

In most women, normal menstrual cycles range from 24 to 28 days, and menses occurs for the first 3 to 7 days. In women under age 35, a history of regular menstrual cycles is highly correlated with ovulation. A long cycle is often associated with anovulation (absence of ovulation). A short cycle may be associated with ovulation, but also with an inadequate follicular phase leading to poor endometrial development or a luteal phase deficiency leading to the inability to maintain pregnancy.7

FACTORS THAT INFLUENCE CONCEPTION

The rate of conception is influenced by the ages of both partners, the frequency of sexual intercourse, and the length of time the couple has been trying to conceive.1 Female age is the single most important determinant of conception success, and the increasing number of women delaying childbearing is leading to a rise in the number of women experiencing infertility. Primarily, age has a negative effect on ovarian reserve. Older women also have a higher body mass index (BMI) compared to younger women, as well as increased life stress and decreased frequency of sexual intercourse, all of which contribute to the decreased ability to conceive.9

Age also affects the type of infertility that women experience. Women over age 35 are less likely to present with ovulatory dysfunction than younger women. They are also twice as likely to be diagnosed with unexplained infertility or a tubal factor contributing to infertility.9

Lifestyle factors also influence fertility, including alcohol intake, caffeine consumption, drugs, and BMI.4 Among these, obesity is one of the most significant factors, affecting approximately half of the general population.10 Obesity is associated with many medical conditions, as well as social and psychologic disorders, and links between obesity and fertility-related disorders have recently been recognized.11

Obese women have a higher rate of infertility than lean peers.10 Female obesity is related to anovulation or oligoovulation (infrequent or irregular ovulation). Female obesity is also associated with at least 30% of cases of polycystic ovary syndrome (PCOS), a major cause of infertility.11 Weight gain and obesity worsen the menstrual irregularities associated with PCOS, while weight loss improves these symptoms.12 Adipose tissue also stores lipid-soluble steroids, including androgens, resulting in greater-than-normal steroid concentrations compared to those of normal-weight individuals. Further, fat cells are a site of sex hormone metabolism resulting from steroidogenic enzymes, such as 3-betadehydrogenase, 17-beta-hydroxydehydrogenase, and aromatase. Estradiol levels from increased aromatization of androgens have a negative effect on the hypothalamus, altering the release of GnRH and reducing LH and FSH at the pituitary, resulting in anovulation.11

CAUSES OF INFERTILITY

Infertility may be caused by male factors, female factors, or a combination of both. The major causes of infertility are summarized in TABLE 1.2,4,6 In approximately one-third of couples, more than one cause contributes to infertility.1 Ovulatory disorders, including anovulation, cause 10% to 15% of infertility in the U.S.2,4 Ovulatory dysfunction is usually manifested by oligomenorrhea (8 or fewer menstrual periods per year) or amenorrhea (the absence of menstrual bleeding). Ovulatory dysfunction may result from endocrine or metabolic disorders, including hypogonadism, the abnormal decrease in the functioning of the gonads. Hypogonadism may be of gonadal origin (hypogonadal), or pituitary or hypothalamic origin (hypergonadal).4

tbl1

Hypogonadal hypogonadism can be caused by genetic syndromes, amenorrhea owing to eating disorders, intense exercise, stress from systemic disease, pituitary surgery, cranial radiation, tumors of the central nervous system, and hyperprolactinemia.4 Certain drugs also lead to hypogonadism. These include opioids, phenothiazines, and risperidone, which block prolactin-inhibiting dopamine release,8 and anabolic androgenic steroids, which cause hyperandrogenism and menstrual irregularities.4

Hypergonadal hypogonadism includes premature ovarian failure (POF), in which a deficiency of sex steroids, elevated gonadotropins, and amenorrhea are present in women under the age of 40 years. POF may be caused by chromosomal or genetic abnormalities, autoimmune disease, viral infections, pelvic surgery, chemotherapy, and radiotherapy. In women suffering from hypergonadotropic hypogonadism, hormone replacement therapy is indicated to induce menstruation and decrease the risk of osteoporosis, but the effectiveness of hormone replacement on improving fertility has not been established.4

PCOS is a common endocrine problem associated with infertility, and infertility therapy is often needed for women with PCOS to achieve pregnancy.12,13 PCOS is defined as the presence of two or more of the following factors: menstrual irregularity, clinical or biochemical hyperandrogenism, and polycystic ovaries, after excluding other causes of hyperandrogenism.4 PCOS is the most prevalent endocrine disorder among young women, affecting 6% to 10% of women of childbearing age. PCOS accounts for 70% of anovulatory subfertility and is the most common cause of medically treatable infertility. The diagnosis of PCOS is important, not only for fertility issues, but for long-term consequences of insulin resistance and metabolic syndrome.4

Pelvic disease causes 30% to 40% of infertility in the U.S., 2,4 with tubal disease accounting for approximately 20% of infertility.4 Pelvic infections, especially gonorrhea and chlamydia, may irreversibly damage the fallopian tubes. Any pelvic inflammatory condition can result in the formation of adhesions that affect tubal integrity.4,7 The incidence of tubal disease is 10% after one episode of pelvic inflammatory disease, and up to 75% after 3 episodes, owing to anatomical abnormalities in the tubes that affect the union of sperm and egg.4 Additionally, severe dysmenorrhea is associated with uterine or anatomical abnormalities, such as fibroids or outflow tract obstruction.7

Endometriosis is implicated as an independent cause of infertility,6 although a causal link between endometriosis and infertility has not been identified.4 Severe endometriosis can cause pelvic adhesions and distort pelvic anatomy.7 Milder cases of endometriosis can alter the peritoneal fluid owing to the presence of inflammatory factors including macrophages, cytokines, and growth factors.4,7 This leads to luteal dysfunction, poor embryonic development, and implantation failure.7 Mild and minimal endometriosis may also lead to endocrine and ovulatory abnormalities that affect fertility.4

Fecundity in women with endometriosis is 2% to 3%.4 Overall, 5% to 6% of infertile women have endometriosis,9 and there is a higher incidence of endometriosis among infertile women (25%-48%) compared with the rest of reproductive-aged women.4,7

Male factors also affect fertility. Abnormal semen production causes 30% to 40% of infertility in the U.S.,2,4 and abnormal sperm transport through the cervical canal causes 10% to 15% of infertility.2 The remaining 10% to 20% of cases of infertility in the U.S. are due to unexplained causes.2 Uterine and cervical factors relating to infertility are uncommon, and are usually categorized as “unexplained infertility.”4 Uterine abnormalities include congenital malformations, leiomyomas, intrauterine adhesions, and endometrial polyps; these abnormalities usually affect pregnancy outcome more than the ability to conceive. Cervical factors affecting reproduction include changes in the quantity or quality of cervical mucus that can be caused by smoking or tobacco use,4,6 as well as by vaginal lubricants.8 Investigation into the causes of infertility is usually initiated after 1 year of unprotected intercourse during which pregnancy has not occurred.6,14 Earlier investigation may be warranted by significant past medical history such as previous pelvic inflammatory disease, amenorrhea, or female age over 35 years.6

EVALUATION AND DIAGNOSIS OF INFERTILITY

The initial evaluation of the female partner in infertility investigations includes a detailed assessment of past medical history, coital practices, medications, menstrual history, exposure to sexually transmitted diseases, previous fertility, substance use, surgical history, and toxin exposure, as well as a full physical examination and laboratory evaluation.6

The primary diagnostic tests for infertility in females include documentation of ovulation and a hysterosalpingogram (HSG) to evaluate tubal patency.2,9 Tracking basal body temperature (BBT) is a simple test to ascertain ovulation. The BBT increases when circulating progesterone increases; therefore, a sustained increase in BBT indicates that ovulation has occurred. Serum progesterone levels can also be measured to evaluate ovulation. An increased serum progesterone level of >5 ng/mL is presumptive evidence of ovulation; a midluteal phase serum progesterone level above 10 ng/mL indicates adequate hormone function.2

HSG involves imaging the uterine cavity to evaluate the internal pelvic anatomy and patency of the fallopian tubes. Laparoscopy can also be used to evaluate pelvic anatomy, adhesions, and endometriosis.4 Other diagnostic tests include measuring serum prolactin and thyroid-stimulating hormone in ovulatory women, a late-luteal phase endometrial biopsy, immunologic tests to detect sperm antibodies, and bacterial culture of cervical mucus and semen.2

TREATMENT OPTIONS FOR INFERTILITY

The goal of infertility treatment is to conceive a pregnancy that will result in the birth of a healthy infant. Additionally, treatment should minimize cost, stress, and physical discomfort as much as possible. The choice of infertility treatment should be based on age, cause of infertility, risk factors, and cost-effectiveness of therapy.8

Obesity-Related Infertility

Weight loss is the cornerstone of treatment of obesityrelated infertility in women11 and is the most costeffective infertility treatment for obese women.10 Anovulation caused by obesity is often effectively treated by weight loss in women with or without PCOS.4,10,11

Weight loss and lifestyle changes should be initiated prior to fertility treatments or conception.11 Weight loss is considered first-line therapy, before ovulation induction or assisted reproductive technology (ART), in obese women.4,10 Pharmacologic therapy should be considered if lifestyle modifications fail to induce ovulation in 3 to 6 months.4

Ovulation Induction

Ovulation induction is the treatment of choice for patients with ovulation disorders or unexplained infertility.7 Induction of ovulation should never be attempted until serious disorders preventing pregnancy have been ruled out, such as thyroid disorders.1,6 Treatment options include selective estrogen receptor modulators (SERMs), aromatase inhibitors, and gonadotropin-based therapy.7 Dopamine agonists can treat anovulation in women with hyperprolactinemia.1

Selective Estrogen Receptor Modulators: Clomiphene citrate (CC) is the most common and most effective agent used for inducing ovulation.4,6,7 CC can be used in women with or without PCOS.6 CC should also be used in women without hyperprolactinemia who have the ability to release LH and FSH.1 CC is 80% effective in inducing ovulation.6,15

CC is a SERM and is a competitive antagonist of estradiol at the cytoplasmic nuclear receptor complex.4,7 CC acts as an antiestrogen by binding to estrogen receptors in the hypothalamus and stimulates gonadotropin secretion by the pituitary gland to initiate the development of a follicle.1,4,7,15 Endogenous production of FSH is altered and ovarian hyperstimulation occurs.4,7,15 Controlled ovarian hyperstimulation (COH) exposes the ovaries to supraphysiologic levels of gonadotropins, resulting in multiple follicular development.16

The typical course of CC is initiated on day 3 to 5 after spontaneous or induced uterine bleeding, with an initial dose of 50 mg by mouth daily for 5 days.1,4,6,15 A surge of LH occurs 5 to 12 days after the last dose of CC, and couples are advised to have intercourse every other day during this time.1,4 If no pregnancy is achieved, menses should occur about 3 weeks after the last dose of CC.1

If ovulation is not achieved in the first cycle, the dose of CC is increased to 100 mg daily for 5 days.1,4,6 This dose should be sustained for 3 to 6 months before the patient is considered unresponsive to CC.1,15 The highest dose approved by the FDA is 100 mg daily,6 but doses of 150 mg daily and higher have been used with minimal success rates.17

When ovulation is induced with CC and no other causes of infertility are present, the conception rate is similar to normal fertile couples over time.2 When conception is achieved following treatment with CC, the incidence of multiple gestation is approximately 8%, nearly all being twins. The incidences of spontaneous abortion, ectopic gestation, intrauterine fetal death, and congenital malformation are not increased.1,2

In general, the side effects of CC are uncommon and not serious, and are related to the decreased perception of estrogen in the brain—vasomotor flushes, abdominal discomfort, breast tenderness, nausea and vomiting, visual symptoms, and headache.1,7,17 Ovarian hyperstimulation syndrome (OHSS) is the most significant side effect associated with CC, and includes gross ovarian enlargement, ascites, dyspnea, oliguria, and pleural effusion. CC should not be used in women who are pregnant, have ovarian cysts (other than women with PCOS), experience abnormal vaginal bleeding, or have abnormal liver function.17

There is concern that CC increases the risk of epithelial ovarian cancer, but new evidence indicates that this is not the case.1 Though findings associating fertility treatments and ovarian cancer are not definitive, the results are reassuring that fertility treatments do not cause cancer.16

Overall, 5% to 10% of women treated with CC fail to ovulate after individualized, graduated, sequential regimens.2 Metformin, an insulin-sensitizing drug, has been used alone and in combination with CC to increase pregnancy rates in both obese and nonobese women with PCOS.13 Metformin is a biguanide that reduces hepatic gluconeogenesis, ultimately leading to a reduction in insulin levels.4 Metformin reduces androgen and LH levels and improves insulin sensitivity; it may also improve embryo quality and endometrial receptivity.13 Metformin has a modest impact on ovulation rates, but it is most effective in normal-weight women without central adiposity.11 Recently, metformin was shown to be inferior to clomiphene in a prospective trial,11 and metformin has not been shown to improve pregnancy outcomes in women with PCOS, either alone or in combination with CC.18 The results achieved with metformin suggest that hyperinsulinemia is not the only metabolic pathway involved in ovulation dysfunction, but metformin may still be beneficial in obese patients with PCOS and glucose intolerance.11 Metformin is administered at a dose of 1,500 to 2,550 mg daily in the treatment of PCOS-related infertility.18,19 Metformin is not approved by the FDA for the treatment of infertility.6

Aromatase Inhibitors: Letrozole and anastrozole, which are primarily used for treating breast cancer in postmenopausal women, have also been used to induce ovulation in women who are resistant to CC.4,7,15 These third-generation nonsteroidal aromatase inhibitors are competitive irreversible inhibitors of testosterone aromatization15 and decrease circulating estrogen by more than 97%.7 The decreased estrogen alters the negative feedback in the hypothalamus and induces release of FSH, resulting in ovulation.7,15

In clinical trials, aromatase inhibitors were orally administered on days 3 to 7 of a menstrual cycle; the dose of letrozole ranged from 2.5 to 7.5 mg daily and the dose of anastrozole was 1 mg daily.15,20 The success rate of aromatase inhibitors at achieving pregnancy was 15% to 20% per cycle.15

Concerns regarding the risk of birth defects with aromatase inhibitors have been examined, but these drugs are not present during organogenesis owing to their short half-life of 45 hours. A recent multicenter analysis did not report an increased risk of birth defects in a cohort of 514 children born after administration of an aromatase inhibitor to induce ovulation.7,21 However, aromatase inhibitors should be discontinued as soon as pregnancy is suspected. The side effects of aromatase inhibitors are generally mild and include hot flashes, nausea, and vomiting.4 The risk of ovarian hyperstimulation is low with aromatase inhibitors, as is the risk for multiple gestations.15,20 Aromatase inhibitors are only FDA-approved for use in postmenopausal women and not for treatment of ovulatory disorders.17,22

Gonadotropin-Based Therapy: Women who fail therapy with CC and aromatase inhibitors may respond to exogenous gonadotropins and hCG or pulsatile GnRH to induce ovulation. Due to the expense and complications associated with gonadotropin-based therapy, a thorough evaluation to rule out other causes of infertility should be carried out prior to beginning therapy.1

Exogenous gonadotropins are effective at stimulating ovulation in cases of anovulation. They may also be administered as part of in vitro fertilization (IVF) regimens or intrauterine insemination (IUI).23 Starting doses of gonadotropin range from 75 to 225 IU daily subcutaneously for 5 to 12 days, depending on patient age, indication, and prior stimulation history.7,17 Obese women require higher doses of gonadotropin to achieve the same pregnancy rate as normal-weight controls.11 The patient should be monitored frequently with ultrasound and estradiol levels to assess follicular development and maturity. The dose of gonadotropin should be adjusted to avoid ovarian hyperstimulation.7 When two to four follicles measure approximately 18 mm in diameter, ovulation is induced with 5,000 to 10,000 IU of intramuscular hCG.1,7

Treatment of anovulation with gonadotropins results in a 100% ovulatory rate,1,2 but the overall pregnancy rate is 50% to 70%.1 The pregnancy rate per cycle with gonadotropins is 22%.2 The incidence of multiple pregnancies with exogenous gonadotropins is 30%, with 5% being triplets or more.1 The incidence of spontaneous abortion after gonadotropin therapy is 25% to 35%.2 The risk of congenital abnormalities with exogenous gonadotropins is not increased.1

Ovarian hyperstimulation is a significant side effect of gonadotropin therapy and may be life-threatening.1 Ovarian enlargement occurs in 5% to 10% of gonadotropin treatment cycles.2 Additionally, multiple follicle cysts develop, as well as stromal edema and multiple corpora lutea. Fluid shifts from the intravascular space into the abdominal cavity and results in hypovolemia and hemoconcentration. The exact cause of the ascites is unknown, but conservative treatment is indicated, including intense monitoring of fluid and electrolyte status. Pelvic examinations should not be performed, owing to the risk of ovarian rupture. Ovarian hyperstimulation usually resolves within 7 days, but lasts longer if pregnancy is achieved. Recent data do not support the claims that exogenous gonadotropins increase the risk of ovarian epithelial cancer.1

GnRH can induce ovulation in women with intact pituitary glands.1 If GnRH is used to treat anovulation, it must be administered in a pulsatile manner at 1- to 2-hour intervals.2 GnRH is most effectively administered intravenously, but may be administered subcutaneously. GnRH is administered through an infusion pump at doses of 5 to 20 mcg every 60 to 120 minutes.1 GnRH is administered for 7 days, and the cycle may be repeated every 21 days.17 Pregnancy rates with GnRH are no better than pregnancy rates achieved with gonadotropin and hCG therapy.1

Dopamine Agonists: These agents, including bromocriptine and cabergoline, are effective at inducing ovulation in hyperprolactinemic women. No adverse effects of dopamine therapy on fetuses or pregnancies have been reported, but drug therapy should be stopped when pregnancy is confirmed owing to the risk of possible birth defects.1,8 Concerns that large doses of dopamine agonists may increase the risk of cardiac valve regurgitation have not been confirmed in women treated for hyperprolactinemia.1

Treatment doses of bromocriptine range from 2.5 to 15 mg by mouth daily, and treatment doses of cabergoline range from 1 to 2 mg by mouth weekly, in 1 or 2 doses. When fertility is the goal of hyperprolactinemia treatment, bromocriptine is the treatment of choice owing to limited safety data regarding the use of cabergoline during conception and pregnancy.8 Overall, ovulatory menses and pregnancy are achieved in approximately 80% of women with galactorrhea and hyperprolactinemia.1 Most women with prolactin-secreting pituitary tumors remain asymptomatic during pregnancy.1,8

Surgical Techniques

Tubal reconstruction procedures (salpingostomy or fimbrioplasty) are debated in infertility literature owing to the low success rates of tubal reparative surgery and the increased risk of ectopic pregnancy.6 The effectiveness of such procedures depends on patient age, unilateral versus bilateral tubal disease, the density of adhesions, and the thickness of the tubal wall.7

The overall conception rate following tubal reconstruction is 30%, with 14% to 25% being tubal pregnancies.2,7 IVF is a successful option in cases of obstruction of the fallopian tubes causing infertility.1,4 With the success of IVF increasing, the value of surgical interventions may be dimished.7

Intrauterine Insemination

IUI is a simple and relatively lowcost treatment for infertility. However, age is a significant predictor of success in IUI, and success rates are particularly low in women over age 40.3 In women with unexplained causes of infertility, COH plus IUI achieves a 10% to 15% monthly pregnancy rate,2,3 and a cumulative pregnancy rate of 30% to 45%.3

The largest risk associated with IUI is high-order multiple gestation.3 COH and IUI should be considered first-line therapy in women who ovulate, who have no tubal abnormalities, and whose male partner has adequate motile sperm.2,3

Assisted Reproductive Technology

ART is used in couples with tubal disease, endometriosis, disorders of sperm production or transport, and unexplained infertility.1 The use of ART, in which both the sperm and egg are handled outside the body, doubled between 1996 and 2004.24

The success rate of ART for women who used fresh embryos from their own eggs is 35% to 45% overall. The success varies with age, with 42% of women aged less than 35 years achieving a successful pregnancy resulting in a live birth and only 7% of women over age 42 achieving the same.25

Indications for IVF, a type of ART, include tubal factor infertility, endometriosis, male factor infertility, unexplained infertility, ovarian failure, and diminished ovarian reserve.4 IVF is an alternative to IUI but requires closer monitoring, more medications and laboratory tests, and more invasive procedures, as well as significantly higher costs.3 Fewer than 10% of infertile couples attempt IVF due to the high costs.4

Age is a strong predictor of success in IVF.3,26 In women under age 35, 37% of IVF cycles resulted in live births; the live-birth rate is 30% in women aged 35 to 37 years, 20% in women aged 38 to 40 years, and 11% in women aged 40 to 41 years.4

IVF usually involves COH, oocyte retrieval, fertilization, embryo culture, and embryo transfer. COH may involve SERM- or gonadotropin-based therapy. After growth of the follicle, hCG is administered to induce final maturation of the follicle. The oocytes are retrieved, inseminated in vitro with sperm, cultured, and then transferred to the uterine cavity.1

The rate of pregnancy in IVF is directly related to the number of embryos implanted in the uterus,2 and the greatest risk with IVF is the large number of multiple pregnancies that result.1 The average term-pregnancy rate is 20% to 25% per cycle.1 The cumulative pregnancy rate for 6 cycles of IVF is approximately 60%. The spontaneous abortion rate following IVF is high (30%).2

Corifollitropin alfa, a long-acting FSH preparation, was approved by the European Commission in 2010 for COH in combination with a GnRH antagonist for the development of multiple follicles in women participating in an ART program.27 Corifollitropin alfa is an FSH receptor agonist28 and lacks LH activity.29 It is a hybrid molecule of recombinant FSH and the carboxy-terminal of the hCG molecule.28,29 The hybrid molecule has a 2.5-fold increase in half-life compared to recombinant FSH alone.28-30 One dose of corifollitropin alfa is effective for 7 days, reducing the number of injections required as part of IVF therapy.29

In initial studies, the pregnancy rate achieved with corifollitropin alfa was similar to daily treatment with recombinant FSH.29,30 Corifollitropin alfa is an injectable formulation administered at a dose of 100 mcg for women weighing less than 60 kg or 150 mcg for women weighing more than 60 kg.30,31 The most common side effects of corifollitropin alfa are related to COH—headache, nausea, fatigue, pelvic pain, and breast discomfort.29,30 Corifollitropin alfa is not approved for use in the U.S.22

Treatment for Endometriosis

Overall, 65% of women with endometriosis will conceive with no treatment.2 No medical treatment for endometriosis has been proven to increase the conception rate.2,4 Most data do not report an advantage to surgically treating endometriosis before initiating fertility treatment.7

Laparoscopic surgery is the surgical treatment of choice for endometriosis,7 and surgical ablation of endometriosis is beneficial in infertility.4,6,7 Following surgical treatment , 50% to 60% of women with moderate endometriosis will conceive, and 30% to 40% with severe endometriosis will conceive.2 For women with endometriosis that does not respond to surgery or suppressive drugs, ART may be considered.1

Treatment of Unexplained Infertility

The treatment of unexplained infertility is empiric, and includes COH, IUI, gonadotropins, and IVF as a last resort.4 Treatment options for infertility are summarized in TABLE 2.

tbl2

PROGNOSIS OF INFERTILITY TREATMENTS

The overall success rate of infertility treatments is 50%, but varies with age, medical history, and duration of infertility.6 Ovulatory dysfunction and unexplained infertility have the best prognosis.4 Infertility associated with anovulation has a success rate of approximately 50%. Infertility related to tubal factors has the least likelihood of achieving pregnancy, with only 17% success. A shorter duration of infertility and previous fertility increase the chance of achieving pregnancy, as well as female age under 30 years.6,32

Infertile couples who achieve pregnancy do not have higher rates of spontaneous abortion or perinatal mortality than age-matched control couples. If an infertile couple does not conceive after 2 years of treatment, the chance of conception is unlikely.2

CONSEQUENCES OF UNTREATED INFERTILITY

The inability to reproduce causes anger, guilt, and depression,1 and the stress of infertility has been compared to the loss of a loved one.5 Childbearing is a socially expected outcome of most marriages,5 and infertility-related stress leads to marital conflict, decreased sexual self-esteem, and decreased frequency of sexual intercourse.5,24 Infertility and related treatments place psychological, physical, and financial challenges on the couple,5 and caregivers should be mindful of approaching infertility treatments with honesty, respect, and sensitivity.24

Most pharmacist-patient interactions during the course of infertility treatments take place in the outpatient setting. Pharmacists can provide invaluable support for women undergoing infertility treatment by encouraging healthy lifestyle choices that can enhance fertility and by reviewing medication profiles for drugs that may be affecting fertility. Pharmacists can also ensure the safe and effective use of infertility medications and devices and offer strategies to recognize and reduce the adverse effects associated with some treatments. Pharmacists are a source of information for patients undergoing infertility treatments and are well placed to monitor patients for the signs and symptoms of psychological stress that often accompany infertility treatments.8

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