Therapeutic Management of Infertility:
A Pharmacist's Perspective

Release Date: September 1, 2015

Expiration Date: September 30, 2017

FACULTY:

Mia N. Barnes, PharmD, BCPS
Clinical Pharmacist
Medstar Southern Maryland Hospital Center
Clinton, Maryland

Dawn Wiemer, PharmD, BCPS
Clinical Pharmacist
Medstar Southern Maryland Hospital Center
Clinton, Maryland

FACULTY DISCLOSURE STATEMENTS:

Drs. Barnes and Wiemer have no actual or potential conflicts 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.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-15-048-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

FEE INFORMATION:

Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

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 provide participants with a review of infertility causes, currently available treatment options, and medication therapy used in the management of infertility.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Review the various phases and hormones involved in the menstrual cycle.
  2. Identify various causes of male and female infertility.
  3. Understand the various treatment strategies for infertility and describe medications used in the treatment of infertility.
  4. Acknowledge the role of the pharmacist in the management of infertility.

ABSTRACT: According to the CDC, nearly 1 in 8 couples (i.e., 12% of married women) has difficulty conceiving or sustaining a pregnancy. Furthermore, research has demonstrated a rising trend for women to delay childbearing, which has resulted in an increase in the number of women seeking additional reproductive therapies in order to conceive. Once the underlying cause of infertility—whether female-related factors, male-related factors, or both—has been identified, various treatment options may be used to improve the chances of conceiving. Medication options vary depending on the cause of infertility, as well as on the type of infertility treatment required. The pharmacist can serve as an important resource for patients dealing with infertility and its treatment.

According to the World Health Organization, infertility is defined as the inability to conceive after 12 months of unprotected intercourse, or 6 months if the woman is older than 35 years. The CDC reports that nearly 1 in 8 couples (i.e., 12% of married women) has difficulty conceiving or sustaining a pregnancy.1

In 2013, the National Vital Statistics Report showed that the preliminary birthrate for women aged 30 to 34 years was 98.7 births per 1,000 women, up 1% from the 2012 rate (97.3 births). The birthrate for women aged 35 to 39 years was 49.6 births per 1,000 women, up 3% from 2012, and the highest rate for this age group since 1963.2 In addition, the number of births to women in their late 30s increased 3% in 2013.2 As the trend of women pro longing their time to childbearing continues to increase, the number of women requiring additional reproductive therapies to conceive is also on the rise.

THE MENSTRUAL CYCLE

To understand the therapies for treating infertility, it is important to first be familiar with the natural processes of the female reproductive cycle (FIGURE 1). Numerous medications used in the management of infertility target various hormones and/or processes within the reproductive system.


The menstrual cycle is a series of natural changes a woman's body undergoes to prepare for a pregnancy. The length of this cycle is a median of 28 days, although it can range from 21 to 40 days.3,4 The menstrual cycle consists of three key phases: the follicular phase, ovulation, and the luteal phase.5 During the luteal phase, egg fertilization and implantation of the zygote may occur. The regulation of the menstrual cycle is influenced by a variety of hormones released by the hypothalamus, ovaries, and anterior pituitary (TABLE 1).5-7


Follicular Phase and Ovulation

The first day of menses marks the initiation of the follicular phase. Menstrual bleeding is caused by a decline in progesterone and estrogen levels that leads to the breakdown and shedding of the endometrium.3 The ultimate purpose of the follicular phase, however, is to ensure the selection and maturation of an ovarian follicle for ovulation.3,4,8 Following menses, an increase in follicle-stimulating hormone (FSH) occurs, which allows recruitment of the follicle intended for ovulation.4,8 As FSH levels decline, between 5 and 7 days prior to initiation of ovulation, a surge in midcycle luteinizing hormone (LH) occurs. The LH surge stimulates the final stages of follicular maturation and ovulation.8 LH stimulates the dominant follicle to bulge from the surface of the ovary and finally to rupture, releasing the oocyte.4,8

Luteal Phase

The luteal phase begins after ovulation and lasts about 14 days, ending just before the start of the next menses, unless fertilization occurs. In the luteal phase, the ruptured follicle closes and forms a structure called a corpus luteum, which produces increasing quantities of progesterone.4,8 The progesterone produced by the corpus luteum prepares the uterus for possible implantation of an embryo.4,8 If conception occurs, human chorionic gonadotropin (hCG) produced by the fertilized egg binds to LH receptors on the corpus luteum, maintaining steroid hormone production and preventing destruction of the corpus luteum, thereby sustaining the pregnancy.3,4,8 If fertilization and implantation do not occur, FSH levels start to rise, and follicular recruitment for the next cycle begins.3,4,8

CAUSES OF INFERTILITY

The causes of infertility may be multifactorial and may be attributed to one or both partners. Male-related factors have been found to be the cause of infertility in 25% of couples, whereas female-related factors are the cause in about 58% of couples; the cause is unknown in roughly 17%.3

Female factor infertility may be caused by a variety of disorders, including ovulatory-related dysfunction, abnormalities of the uterus or outflow tract, and tubal disease or dysfunction.3 Ovulatory dysfunction, which is reported in nearly 15% of all infertile couples and 40% of all infertile women, has a number of causes.9 Advanced age, obesity, hypothyroidism, hyperprolactinemia, polycystic ovarian syndrome (PCOS), eating disorders, and/or extremes of weight loss or exercise can result in ovulatory dysfunction.1,3

Tubal dysfunction, which is fallopian tube obstruction or epithelial dysfunction, can impair zygote motility, resulting in infertility.1,10 Endometriosis, pelvic inflammatory disease, previous use of an intrauterine device, appendicitis, pelvic adhesions, and previous ectopic pregnancy can all cause tubal dysfunction.3

Male factor infertility may be caused by hypogonadism, testicular disease, drug or toxin exposure (TABLE 2), defects in sperm transport, or erectile dysfunction.1,4,11,12


INFERTILITY TREATMENT OPTIONS

Once the cause of infertility has been identified, steps should be taken to correct the underlying problem, or therapeutic interventions (i.e., drug therapy, procedures, and/or surgery) should be initiated to assist conception.

Intrauterine insemination (IUI), also known as artificial insemination, is the most frequently performed procedure in couples diagnosed with mild-to-moderate male factor infertility or unexplained infertility.1,4 In IUI, prepared sperm are inserted into the woman's uterus just prior to the time of anticipated ovulation. In addition, medications such as clomiphene citrate (CC) and gonadotropins may be used to stimulate the ovaries (i.e., superovulation) prior to the procedure.1,4

Assisted reproductive technology (ART) has been used for more than 20 years.13 ART procedures are undertaken when other steps to correct underlying causes have been deemed ineffective or when clinical and laboratory interventions are necessary in order to achieve pregnancy.4 These techniques include, but are not limited to, in vitro fertilization (IVF), intracyto-plasmic sperm injection (ICSI), egg donation, gestational surrogacy, gamete intrafallopian transfer, and zygote intrafallopian transfer (TABLE 3).1,4 Some other ART procedures are egg and embryo cryopreservation, testicular sperm extraction, and in vitro maturation of oocytes.1


Indications for ART include male factor infertility, tubal disease (tubal and pelvic adhesions), absent or damaged fallopian tubes, endometriosis, preimplantation genetic diagnosis, need for third-party reproduction/donor eggs or gestational surrogate, unexplained infertility, age-related infertility, decreased ovarian reserve, and/or recurrent IUI failure.13

The use of ovulation-induction therapies varies depending on the specific ART procedure being used (FIGURE 2).6 The following therapy classes may be used alone or in combination with ART procedures: a combination of gonadotropins and gonadotropin-releasing hormone (GnRH) analogues, FSH products, LH agonists, and/or human menopausal gonadotropins.13 CC may also be indicated, but it is rarely used.13


MEDICATIONS USED TO TREAT INFERTILITY

In addition to the various ART options available, numerous medications are indicated for the management of infertility. Medication options vary depending on the cause of infertility, as well as on the type of infertility treatment that may be required.

Clomiphene Citrate

CC is FDA-approved and generally first-line therapy for treatment of infertility due to ovarian dysfunction.14 CC is a selective estrogen receptor modulator used for inducing ovulation. CC competitively inhibits estrogen receptors, resulting in elevated levels of FSH and LH.14 The increase of these hormones promotes follicle development and ovarian stimulation.4

The dosage of CC required to achieve ovulation should correlate with the patient's body weight.4 However, the recommended CC dosage is 50 mg daily, usually beginning on day 3 to 5 of a patient's cycle and continuing for 5 days.4 Ovulation most often occurs 6 to 12 days after therapy, so sexual intercourse should be timed accordingly.14 If ovulation does not occur, 100 mg daily should be given for a second cycle; this may be repeated two additional times. If ovulation occurs but does not result in pregnancy, CC may be administered for a maximum of six courses.

Adverse effects of CC are dose-dependent and are more severe at higher doses. Vasomotor flushes and ovarian enlargement are the most common adverse effects; however, ovarian hyperstimulation syndrome (OHSS), abdominal and breast discomfort, visual disturbance, and headache have also been reported. Patients should be made aware of the possibility of multiple births, since the incidence is increased when conception occurs during CC therapy.14

Gonadotropins

FSH and LH, which are gonadotropins, are necessary to stimulate the gonads throughout the reproductive process. Exogenous gonadotropins are used to induce ovulation in preparation for procedures such as IUI and ART cycles. Various gonadotropin preparations are available, with major differences between products in terms of source and presence or absence of LH activity (TABLE 4).4,15-22 In addition, continuous monitoring is required in patients using gonadotropin therapy, as ovarian response may vary greatly between women.


Some of the major concerns associated with gonadotropin therapy are multifetal gestations, multifetal births, and OHSS.4 These events have been reported with all gonadotropin therapies. In one clinical trial evaluating the use of Menopur (menotropins for injection) in IVF, multiple pregnancy as diagnosed by ultrasound occurred in 35.3% (n = 30) of 85 total pregnancies.15 However, a recent study reported that the rate of triplet and higher-order births has declined over the past decade owing to a reduction in the number of embryos transferred during IVF procedures.23 The benefits and risks of gonadotropin therapy should be discussed with the patient prior to initiation.

Menotropins: Extracted from the urine of postmenopausal women, Menopur is a highly purified menotropin that delivers LH and FSH in a 1:1 ratio. This agent is indicated for the development of multiple follicles and pregnancy in ovulatory women as part of an ART cycle.15 Following sufficient follicular maturation, hCG is then administered following menotropin use to induce ovulation. The standard dosing recommendation is 225 IU administered daily, with a maximum dosage not to exceed 450 IU per day.15 Following 5 days of treatment, dosing adjustments may be made based on the patient's ovarian response, as determined by serum estradiol levels and ultrasound evaluation of follicular growth.15 An open, phase III, randomized, controlled IVF study (n = 373) concluded that 26% of patients had clinical pregnancy, with 23% of them continuing pregnancy.15 The most common adverse effects are headache, stomach pain, upset stomach, and injection-site reactions.15

Repronex is a purified preparation of gonadotropins extracted from the urine of postmenopausal women.16 As with Menopur, Repronex directly stimulates the ovaries to induce ovulation. Repronex may be administered by SC or IM injection.16 The most common adverse effects associated with Repronex therapy include injection-site reactions and nausea. Adverse reactions associated with IM injection include abdominal cramps, vaginal hemorrhage, and nausea.16

Human FSH: Currently, three forms of purified FSH are available. One type is urofollitropin, a purified preparation of human FSH in which all LH activity has been removed.6 Two recombinant forms, follitropin alfa and follitropin beta, are also available.6 Recombinant FSH products have a shorter half-life than products derived from human urine; however, recombinant FSH preparations are considerably more expensive.6

Urofollitropin. Urofollitropin (Bravelle) is indicated for ovulation induction in women who have previously received pituitary suppression and for the development of multiple follicles as part of an ART cycle in ovulatory women who have previously received pituitary suppression.17

Extracted from the urine of postmenopausal women, urofollitropin is a highly purified preparation of FSH.17 In general, urofollitropin is administered for 7 to 12 days to stimulate egg maturation and multiple follicular development in women who have not been diagnosed with primary ovarian failure.17 The initial starting dose ranges from 150 IU to 450 IU per day, and urofollitropin may be administered by SC or IM injection.17 Following follicular maturation, hCG is administered to induce ovulation.17 An open-label, randomized, multicenter study conducted in 15 private and academic fertility clinics concluded that 69% (24/35) of patients receiving SC Bravelle and 70% (26/37) of patients receiving IM Bravelle achieved ovulation.17 With administration of Bravelle for ovulation induction, the most common adverse reactions (>5% incidence) included headache, hot flashes, OHSS, pain, and respiratory disorder. When Bravelle was used as part of an ART cycle, the most common adverse reactions (≥2% incidence) included abdominal cramps, abdominal fullness/ enlargement, headache, nausea, OHSS, pain, pelvic pain, and postretrieval pain.17

Recombinant FSH. As noted above, the two available recombinant forms of FSH are follitropin alfa (Gonal-f) and follitropin beta (Follistim). In both products, recombinant FSH production occurs in genetically modified Chinese hamster ovary cells. Gonal-f is indicated for the induction of ovulation and pregnancy in oligoanovulatory women in whom the cause of infertility is functional and not due to primary ovarian failure.18 It is also indicated for the development of multiple follicles in ovulatory women as part of an ART cycle.18 Gonal-f is available as a prefilled syringe and a multidose vial. Standard dosing ranges from 75 IU to 150 IU, but dosing should not exceed 450 IU per day.18 The most common adverse reactions (≥5%) in ovulation induction were headache, abdominal pain, and ovarian hyperstimulation.18 The most common adverse reactions (≥5%) in ART cycles were abdominal pain, nausea, abdominal enlargement, headache, and injection-site bruising.18

Follitropin beta is indicated for the treatment of infertility in both men and women.19 This product is indicated for the induction of ovulation and pregnancy in anovulatory infertile women in whom the cause of infertility is functional and not due to primary ovarian failure, and for pregnancy in normal ovulatory women undergoing controlled ovarian stimulation as part of an IVF or ICSI cycle.19 In men, urofollitropin beta is indicated for induction of spermatogenesis in patients with primary or secondary hypogonadotropic hypogonadism in which infertility is not due to primary testicular failure.19

The most commonly reported adverse reactions in women undergoing ovulation induction included ovarian cyst, OHSS, abdominal discomfort, abdominal pain, and lower abdominal pain.19 In women undergoing controlled ovarian stimulation as part of an IVF or ICSI cycle, the most commonly reported adverse reactions included pelvic discomfort, headache, OHSS, pelvic pain, nausea, and fatigue.19 In men using urofollitropin beta for induction of spermatogenesis, the most common (≥2%) adverse reactions were headache, acne, injection-site reaction, injection-site pain, gynecomastia, rash, and dermoid cyst.19

One study assessed the effect of follitropin alfa versus follitropin beta on pregnancy rates in women of various ages who were undergoing IVF.20 The retrospective study compared 365 IVF cycles, 233 using follitropin beta and 132 using follitropin alfa. It was concluded that there was no significant difference between the two groups in primary or secondary outcomes.20 However, pregnancy rates were significantly decreased with advancing age.20

Chorionic Gonadotropins: Produced by the placenta, hCG is a polypeptide hormone that may be used as a screening tool for pregnancy.4,21 The action of hCG in the body is nearly indistinguishable from that of LH, with a small degree of FSH activity.4 Throughout the menstrual cycle, LH is a key participant in ensuring the development and maturation of the ovarian follicle, and it is also responsible for triggering ovulation during the midcycle LH surge. Because of their similar receptor-binding capabilities, hCG may be substituted for LH to trigger ovulation in various infertility treatment options.4,21

Currently, there are three formulations of hCG. Choriogonadotropin alfa injection (Ovidrel), which is available as a prefilled syringe, is indicated for the induction of final follicular maturation and early luteinization in infertile women who have undergone pituitary desensitization and who have been appropriately pretreated with FSH as part of an ART program.22 Ovidrel is also indicated for the induction of ovulation and pregnancy in anovulatory infertile women in whom the cause of infertility is functional and not due to primary ovarian failure.22 Ovidrel is administered as an SC injection. Adverse reactions that occurred in more than 2% of the population included injection-site pain and bruising, gastrointestinal disorders, abdominal pain, nausea, and vomiting.22

Chorionic gonadotropin for injection, USP (Novarel), is indicated for prepubertal cryptorchidism in males that is not due to anatomical obstruction and for induction of ovulation and pregnancy in anovulatory infertile women in whom the cause of anovulation is secondary and not due to primary ovarian failure.21 Novarel should be used only in women who have been appropriately pretreated with human menotropins.21 Pregnyl is another currently available chorionic gonadotropin. There are no major differences between these two products. Each of these products should be administered as an IM injection. Adverse reactions may include headache, irritability, restlessness, depression, fatigue, edema, precocious puberty, gynecomastia, and/or injection-site pain.21

GnRH Agonist

Leuprolide acetate is a synthetic nonapeptide analogue of naturally occurring GnRH.4 Although leuprolide is not indicated for the treatment of infertility, it is used off-label for controlled ovarian stimulation and for the management of pain associated with endometriosis.4

GnRH Antagonists

GnRH antagonists competitively and reversibly bind to GnRH receptors in the pituitary gland, resulting in a decrease in LH production. Because LH production is suppressed, a premature LH surge is prevented, thereby permitting controlled ovarian stimulation.24,25 Currently, cetrorelix (Cetrotide) and ganirelix are the only GnRH antagonists approved for the treatment of infertility. These products are generally reserved for patients who respond poorly to treatment with GnRH agonists and gonadotropins alone. Treatment starts on day 6 or 7 of the induction cycle and continues until the day of hCG administration.25,26 GnRH antagonists are generally well tolerated. Research has shown that patients receiving these agents have a decreased incidence of cyst formation and hot flashes, compared with GnRH agonists and gonadotropins. GnRH antagonists also cause fewer cases of OHSS, which is advantageous for patients at risk for this syndrome.25,26

Alternative Therapies

Metformin: Metformin, a biguanide, is an antidiabetic agent that lowers glucose by decreasing hepatic gluconeogenesis, thereby reducing intestinal glucose absorption and improving insulin sensitivity. Although not FDA-approved for this use, metformin has also been administered as an adjunctive treatment for infertility in women with PCOS.27 It has been suggested that PCOS develops when the ovaries produce an excess of androgen, which may be attributed to an increased release of LH and insulin.28 Patients treated with metformin experience a decrease in insulin levels, which leads to a reduction of LH and androgen levels. This cascade of effects has proven beneficial in normalizing ovulation in PCOS patients.29

Aromatase Inhibitors: Aromatase inhibitors (AIs) block the aromatase enzyme responsible for converting androgen to estrogen. Although indicated for breast cancer treatment, AIs have been considered for infertility treatment.4 The mechanism by which these agents stimulate ovulation is the result of a negative feedback created by estrogen. The decrease in estrogen conversion results in an increase in LH and FSH, which leads to ovulation induction.4,30 Several studies have shown that AIs are at least as effective as CC for ovulation induction in patients with PCOS.31 When used for ovulation induction, letrozole (Femara) and anastrozole (Arimidex) are administered between days 3 and 7 of the menstrual cycle, for a total of 5 days.4 Owing to the short half-life and duration of therapy, adverse reactions of AIs are minimal. In addition, since estrogen receptor inhibition does not occur, adverse effects on the endometrium are limited.27

COMPLICATIONS AND RISKS OF TREATMENT

Ovarian Hyperstimulation Syndrome

OHSS is a complication of exogenous gonadotropin therapy that is associated with ovarian enlargement.7 OHSS, which may develop following oocyte retrieval and/or assisted ovulation, is characterized by ovarian enlargement caused by numerous ovarian cysts and a leakage of fluid into extravascular space.4,32 Generally, abdominal pain and bloating are the most prominent complaints of women experiencing OHSS, and supportive care is the most common treatment strategy.4,32 In extreme circumstances, surgical intervention may be required.

Ovarian Cancer

Various studies have been conducted to assess the increased risk of ovarian cancer in women exposed to ovulation-inducing medication. However, primary infertility and endometriosis are independent risk factors for ovarian cancer, thus making it difficult to adequately evaluate the risk.13 More research is needed to further classify and determine the association between ovarian cancer and infertility medications. Patient education on the potential adverse effects and risks of infertility medications should be addressed prior to therapy initiation.

THE PHARMACIST'S ROLE

The role of the pharmacist in infertility management has expanded over time, and it continues to evolve. The complexity of some infertility treatment regimens requires greater attention to detail by not only the pharmacist, but also the patient. The pharmacist can serve as an excellent resource to assist patients with infertility medication education, medication counseling, injection-technique training, and management of any adverse effects. The pharmacist also may assist with financial considerations (e.g., prior authorization, copay savings assistance) related to the high cost of many infertility therapies.

In addition, the diagnosis of infertility, along with the multifaceted treatment process, may cause an increased level of distress in the individual or couple undergoing treatment. Listening, showing empathy, and providing emotional support are important facets of the pharmacist's role in working with patients undergoing infertility treatment.

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