Treatment of Infertility in Women Carriann Smith, Maureen Grimm, and Megan Schwegel

Reviews Reviews

Treatment of infertility in women Carriann Smith, Maureen Grimm, and Megan Schwegel

Received February 28, 2012, and in revised Abstract form April 12, 2012. Accepted for publication May 9, 2012. Carriann Smith, PharmD, is Associate Pro- Objectives: To review causes and risk factors associated with infertility, relevant fessor of Pharmacy Practice and Director of diagnostic procedures, and available pharmacologic and nonpharmacologic treat- Outreach, College of Pharmacy and Health ment options; to identify common dosing, administration, adverse effects, and key Sciences, Butler University, Indianapolis, IN. Maureen Grimm, PharmD, is a PGY-1 com- counseling points associated with infertility treatments; and to describe the role of munity practice resident, College of Phar- the pharmacist in caring for patients with infertility. macy, University of Georgia, Athens, and Data sources: Available clinical literature identified through searches of Med- College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN. Megan line and review of major textbooks in reproductive medicine. Schwegel is a student pharmacist, College Study selection: Studies were selected primarily to reflect current infertility of Pharmacy and Health Sciences, Butler treatment practices in the United States. The specific criteria evaluated included date University, Indianapolis, IN. of the study; date of publication; study population, including diagnosis, baseline char- Correspondence: Carriann Smith, PharmD, acteristics, and nationality; and number of participants. College of Pharmacy and Health Sciences, Butler University, 4600 Sunset Ave., India- Data synthesis: Treatment of infertility often involves the use of both pharmaco- napolis, IN 46208. Fax: 317-940-6172. E-mail: logic and nonpharmacologic therapy. This article provides an overview of these phar- [email protected] macologic treatments and provides two tables that outline the key administration and Disclosure: Dr. Smith has a retirement ac- safety concerns with these products. Nonpharmacologic procedures associated with count with Eli Lilly from previous employ- diagnosis and treatment also are outlined. ment that ended in 2003. The authors and APhA’s editorial staff declare no conflicts of Conclusion: Pharmacists are an excellent resource for patients suffering from interest or financial interests in any product infertility. First, pharmacists answer questions about administration and safety of or service mentioned in this article, including grants, employment, gifts, stock hold- these medications. Second, pharmacists discuss available treatment options and as- ings, or honoraria. Complete staff disclosure sist with referrals to specialists as needed. Third, pharmacists can provide emotional information is available at www.pharmacist. support for patients who may otherwise suffer in silence. com/education. Keywords: Infertility, pregnancy, reproduction, women’s health, pharmacy services. J Am Pharm Assoc. 2012;52:e27–e42. doi: 10.1331/JAPhA.2012.12044 Learning objectives At the conclusion of this knowledge- based activity, the pharmacist will be able to: ■■ Recognize the causes and risk factors associated with infertility. ■■ Describe the different diagnostic approaches used to determine infertility. Accreditation information ACPE number: 202-000-12-116-H01-P ■■ Compare the available pharmaco- Provider: American Pharmacists Association CPE credit hours: 2.0 hours (0.2 CEUs) logic and nonpharmacologic treat- Target audience: Pharmacists Fee: There is no fee associated with this activ- ment options for all the causes of Release date: June 15, 2012 ity for members of the American Pharmacists infertility. Expiration date: June 15, 2015 Association. There is a $15 fee for nonmem- ■■ Identify common dosing, adminis- Learning level: 2 bers. tration, adverse effects, and key counseling points associated with The American Pharmacists Association is accredited by the Accreditation Council infertility treatments. for Pharmacy Education as a provider of continuing pharmacy education (CPE). The ■■ Explain the role of the pharmacist ACPE Universal Activity Number assigned to this activity by the accredited provider in the treatment as well as the emo- is 202-000-12-116-H01-P. tional component of infertility.

e27 • JAPhA • 52:4 • J u l /A u g 2012 www.japha.org Journal of the American Pharmacists Association treating infertility Reviews

Role of the pharmacist diagnoses and reported prevalence ranges vary. This should not As infertility treatment continues to improve in the United be surprising because treatment plans are highly individualized by States, more couples are seeking medical care for infertility, patient; laboratory ranges are only a guide, and patients may have including pharmacotherapy treatments. According to the 2002 multiple factors. The prevalence ranges provided herein are adapt- National Survey of Family Growth, 12% (7.3 million) of repro- ed from multiple sources but most closely resemble those reported ductive-aged women (15–44 years) in the United States report- by Fritz and Speroff5 and other sources.6,7 ed use of infertility services.1,2 The websites of the Centers for Ovulation disorders include oligoovulation (infrequent ovu- Disease Control and Prevention and American Pregnancy As- lation) or anovulation (absence of ovulation). When women fail sociation indicate that approximately 6 million women aged 15 to ovulate regularly, fewer oocytes are available for fertiliza- to 44 years have difficulty getting or staying pregnant.3,4 tion. The World Health Organization lists the following three Because age is an important risk factor for infertility, the classifications for ovulatory disorders, and hyperprolactinemic criteria for an infertility diagnosis depends on the age of the pa- anovulation is considered a fourth category5: tient. For women aged 35 years or older, infertility is diagnosed ■■ WHO group I: Hypogonadotropic hypogonadal anovulation when pregnancy has not occurred within 6 months of frequent, represents 5% to 10% of anovulatory women with low serum unprotected intercourse. For women younger than 35 years, 1 estradiol levels and low to low-normal serum follicle-stimulat- year of frequent, unprotected intercourse without pregnancy is ing hormone (FSH) levels. These women have an abnormal re- considered to indicate infertility. Patients who meet this defi- sponse or a decreased production of gonadotropin-releasing nition of infertility should consult a physician, although most hormone (GnRH). patients delay seeking treatment until they have not become ■■ WHO group II: Eugonadotropic estrogenic anovulation repre- pregnant for 2 years or more.5 sents 75% to 85% of anovulatory women with normal estra- As the use of infertility medications increases, pharmacists diol and FSH levels. Patients with polycystic ovary syndrome need to provide patients with accurate information. Pharma- (PCOS) belong to this category. cists can assist patients by discussing their individual situa- ■■ WHO group III: Hypergonadotropic anovulation represents tions in a supportive atmosphere. To do so, pharmacists must 10% to 20% of anovulatory women and includes those with be educated on the causes, risk factors, and treatment options elevated serum FSH levels. Many of these women have amen- for infertility. orrhea resulting from premature ovarian failure. Women who have diminished ovarian reserve because of advanced age are managed similarly to those with premature ovarian failure. Active learning exercise: List two conditions/abnormalities among female patients that may cause infertility. ■■ Hyperprolactinemic Anovulation represents 5% to 10% of anovulatory women who do not ovulate as a result of hyperprolactinemia or thyroid disorders. Laboratory results may be Etiology similar to patients with hypogonadotropic hypogonadal anovu- Infertility may be related to factors in the man, woman, or both. lation. The two major causes of female infertility are ovulatory dysfunc- The primarily cause of tubal damage is pelvic inflammatory tion (20%–40%) and tubal and pelvic (including cervical) patholo- disease secondary to chlamydia or gonorrhea. Other causes of tub- gy (30%–40%). Some experts separate cervical and pelvic pathol- al damage are peritoneal or pelvic disorders, including endometri- ogy from tubal pathology. Because the treatment courses are simi- osis, adhesions from previous surgeries, appendicitis, inflammato- lar for tubal, pelvic, and cervical causes of infertility, the authors ry bowel disease, and pelvic tuberculosis. Laparoscopy allows the chose to group these together in Figure 1. Categorization of these practitioner to evaluate the damage to assist with determining the cause. The aforementioned conditions cause pelvic inflammation, and this impairs movement of both the oocyte and sperm through At a Glance the fallopian tube. Tubal damage also involves unexplained factors Synopsis: The literature was reviewed to provide an such as the possibility of congenital anomalies. In addition to tubal overview of pharmacologic treatments and nonpharma- damage, endometriosis can cause other disruptions to the female cologic procedures for diagnosing and treating infertility. reproductive system, including pelvic adhesions, direct damage to Pharmacists can be an excellent resource for patients ovarian tissue secondary to the growth and/or removal of excess dealing with infertility by answering medication ques- endometrial tissue, and production of substances that impair nor- tions, discussing treatment options, assisting with refer- mal hormone function. rals to specialists, and providing emotional support. Other causes (10%–20%) of infertility include unresolved Analysis: To support patients, pharmacists must be male factor infertility and chromosomal abnormalities. A discus- educated on the causes, risk factors, and treatment op- sion of other causes of infertility could include a variety of rare tions for infertility. The authors highlight conditions such conditions, as well as drug-induced infertility caused by cancer as ovulatory disorders, tubal and pelvic abnormalities, chemotherapy. We have chosen to highlight conditions such as and other causes of infertility. A diagnosis of unexplained uterine abnormalities, unresolved male factor, chromosomal ab- infertility suggests normal ovulatory function, a normal normalities, and unexplained infertility. Uterine and chromosomal uterine cavity, and bilateral tubal patency. abnormalities may cause early miscarriage that is interpreted

Journal of the American Pharmacists Association www.japha.org J u l /A u g 2012 • 52:4 • JAPhA • e28 Reviews treating infertility

Cause: Other causes Cause: Ovulatory Pelvic/tubal dysfunction blockage/damage Yes Cause known Chromosomal Endometriosis abnormalities No Yes Yes Yes WHO Group I WHO Group III No Unresolved Unexplained Pharmacologic Uterine male factor management Hyperprolactinemic factor with GnRH WHO Group II agonists Anovulation

IVF IVF with Many options;

Weight ICSI highest Cabergoline or Laparoscopy loss if success rate bromocriptine Address obese Surrogacy with IVF risk factors

IVF Metformin if Treatment with IVF with donor PCOS gonadotropins eggs and/or donor with or without sperm Pulsatile GnRH IUI or IVF Surgical repair agonist or gonadotropins or IVF IUI with clomiphene, with or without aromatase inhibitors, IUI or IVF or gonadotropins

IVF with gonadotropin antagonists has demonstrated some benefit in poor responders IVF with premature or diminished ovarian reserve

Figure 1. Common progression of female infertility management for single factors following diagnostic assessment Abbreviations used: GnRH, gonadotropin-releasing hormone; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; IVF, in vitro fertilization; PCOS, polycystic ovary syndrome; WHO, World Health Organization. IUI and IVF will involve the use of pharmacologic therapy and ovulation induction (usually as controlled ovarian hyperstimulation). The therapeutic selection will vary based on many factors, as mentioned in the text. Practitioners may also prescribe supportive treatments such as aspirin or progesterone therapy to patients receiving fertility treatments. as infertility. In a study published in 2005, infertile couples were and cigarette smoke causes premature aging of the ovaries, in turn found to have more chromosomal rearrangements than the gen- decreasing female fertility. eral population.8 If male factor infertility is not resolved, female Some researchers suggest that alcohol use is linked with in- patients will usually undergo in vitro fertilization (IVF) treatment fertility; however, this association remains contradictory.10 Stud- including intracytoplasmic sperm injection (ICSI). A diagnosis of ies have reported that moderate to heavy female drinkers take unexplained infertility suggests normal ovulatory function, a nor- longer to conceive. Other studies reported no adverse effect on mal uterine cavity, and bilateral tubal patency. ovulation or association with infertility in women who consumed varying amounts of alcohol. Risk factors Caffeine is another dietary factor that shows inconsistent ef- In a study conducted in the United Kingdom, increased female age fects on infertility.10,12 Studies linking caffeine use with infertility was found to be the single most important risk factor in cases of generally found the effect in those consuming 300 to 500 mg caf- 9 unexplained infertility. The study of 7,172 infertile couples who feine per day. Caffeine may increase estrogen production or de- attended the Aberdeen Fertility Centre in Scotland from 1993 to crease estrogen metabolism. A comprehensive review of human 2006 found that 26.6% of older women (35–39 years) were diag- studies of caffeine and reproductive health by Peck et al.12 indi- nosed with unexplained infertility compared with 21% of younger cated that the weight of evidence does not support a positive rela- women (<30 years). Various statistical analyses showed a signifi- tionship between caffeine consumption and infertility in women.12 cant association between female age and diagnosis of female infer- A patient’s weight can also affect infertility.13 Both under- tility. The diagnosis of unexplained infertility was more common in weight and overweight women are at increased risk of infertility, women older than 35 years. with effects found with body mass indexes (BMIs) of less than 17 or 10,11 Tobacco use has been associated with infertility. Most greater than 27 kg/m2, respectively. The decreased fertility found studies evaluating the association between tobacco use and fertil- with increased BMI is associated with insulin resistance. Excess ity have examined the effect of the amount of cigarettes smoked insulin can result in an androgen excess, leading to altered ovarian per day on fertility. Decreased rates of conception occur mostly physiology and a possible decreased ovulation.14 in women who smoke more than 10 cigarettes per day. In a study Decreased BMI specifically resulting from decreased caloric of 108 patients having IVF, active smoking induced significantly intake or increased exercise has been correlated with anovulation. more oxidative stress and could explain the impaired ability to This is thought to be a result of a decrease in GnRH, which leads form ova. This increased oxidative stress can lead to DNA damage, to a decrease in FSH and luteinizing hormone (LH), potentially in- e29 • JAPhA • 52:4 • J u l /A u g 2012 www.japha.org Journal of the American Pharmacists Association treating infertility Reviews

creasing the risk for infertility. Studies comparing infertility rates bleeding, or adverse effects from the anesthesia. Slight cramping and aerobic exercise have found that increased aerobic exercise or bleeding for 1 to 2 days is possible. (>7 hours vigorous exercise/week) has the ability to contribute to Transvaginal ultrasound involves inserting a sound wave–gen- increased infertility in women as a result of decreased FSH and LH erating probe into the vagina. These waves are reflected off of body levels leading to anovulation.15 structures and passed to a computer, which creates images. The Pharmacists should be aware of these risk factors and pre- probe is moved to allow visualization of pelvic organs. This proce- pared to discuss them with patients. Determining the patients’ ex- dure allows the physician to detect abnormalities of the ovaries, isting risk factor awareness and readiness for change will keep the uterus, vagina, and other pelvic structures and may help to identify lines of communication open, especially when addressing lifestyle pelvic inflammatory disease.18, 20 No known risks are associated changes such as weight loss. with administering transvaginal ultrasounds. Saline infusion sonohysterography is a procedure in which Diagnostic information saline is infused into the uterine cavity to enhance endometrial Identifying the underlying cause for an infertility diagnosis is an visualization during transvaginal ultrasound. Saline solution may important step toward treatment. This provides the practitioner help outline abnormal masses. Although, this procedure improves with the information necessary to establish an individual treat- the physicians’ ability to detect polyps, malignancy, adhesions, and ment plan. Considering the importance of increased female age as hyperplasia, it is not used alone for the diagnosis of infertility.20 No a risk factor in infertility, assessing ovarian reserve is fundamental known risks exist for this procedure, although patients may experi- to determining whether an aggressive treatment plan is needed. ence cramping after the procedure as a result of the infusion of The single most important test for assessing ovarian reserve is saline into the uterine cavity. anti-Müllerian hormone.5 Other hormones associated with assess- Laparoscopy is a procedure performed in the hospital or out- ing ovulatory disorders include progesterone, estradiol, FSH, and patient surgery center under general anesthesia that allows the inhibin B. Table 1 describes these and other laboratory tests used physician to directly visualize the contents of the pelvis. A small to diagnose the cause of infertility.16,17 Office procedures or out- incision is made below the patient’s umbilicus and a needle is in- patient surgery may be used to assess ovulatory disorders but are serted. Carbon dioxide gas is passed into the abdomen to allow for most useful in assessing tubal, pelvic, and uterine abnormalities. a bigger space so that the physician can see the area clearly. A lap- aroscope (small camera) is placed through the incision to enable the physician to see the inside of the patient’s pelvis and abdomen. Active learning exercise: Identify one laboratory test and one radio- logical test that are frequently used to assess fertility. Dye may or may not be injected to enable clearer visualization of the fallopian tubes. This allows the physician to visualize pelvic abnormalities that may lead to infertility such as endometriosis and These procedures include but are not limited to hysterosalpingog- peritubular adhesions. Therefore, laparoscopy is commonly used raphy, hysteroscopy, transvaginal ultrasound, saline infusion so- in women with pelvic/peritoneal abnormalities, unexplained infer- nohysterography, and laparoscopy. tility, and/or multiple risk factors for infertility before treatment is Hysterosalpingography (HSG) is a radiologic assessment of initiated.18 Laparoscopy is associated with general surgery risks. uterine cavity and fallopian tubal patency performed by injection Patients should rest and limit work for 2 to 3 days following the of contrast dye through the cervical canal to allow visualization of procedure. The gas used to inflate the abdomen may cause shoul- width of the cervical canal, contour of the uterine cavity, outline der pain after the procedure, and this pain can be treated with pre- of the lumen of fallopian tubes, presence or absence of spillage scription or over-the-counter pain relievers. of contrast from the fimbriated ends of the tubules, and outline of peritoneal structures. This allows the physician to detect fallopian Treatment tube damage or cervical/uterine structural abnormalities and en- Many treatment options are available for patients with infertility. dometrial polyps, if present.18,19 HSG is the most frequently used Pharmacotherapy may be used alone or in conjunction with as- radiologic procedure associated with assessment of fertility. HSG sisted reproductive technologies. With an increase in the number has little risk to the patient. Infection, iodine reaction, and faint- of patients seeking treatment, treatment commonalities exist for ing have occasionally been reported, and patients should report groups of patients based on etiology. Sample treatment progres- any fever, abdominal pain, and/or any lightheadedness following sions are outlined in Figure 1. An individual’s treatment plan may the test. be established based on factors such as diagnosis, prioritization Hysteroscopy is a procedure that inserts a hysteroscope into when multiple diagnoses are present, physician practice charac- the uterus to allow visualization of the endometrial cavity, includ- teristics, provider experience, patient risk factors, length of time ing the tubal ostia, endocervical canal, cervix, and vagina. The phy- couple has been trying, patient specific religious, and social and sician is able to evaluate the presence of lesions in the endometrial economic factors. cavity and may rule out uterine/cervical pathology. Of important Clinicians may define efficacy of pharmacologic treatments for note, this procedure is not sufficient for evaluating fallopian tubal infertility as producing the necessary effect, such as inducing ovu- damage and usually requires further testing to diagnose the cause lation. Patients, however, may consider the ultimate measure of ef- of infertility.18,20 Hysteroscopy also has little risk. Rarely, patients ficacy to be successful live birth. Researchers may argue, however, may experience injury to endometrial cavity, infection, heavy that additional factors, such as the quality of prenatal care, weak-

Journal of the American Pharmacists Association www.japha.org J u l /A u g 2012 • 52:4 • JAPhA • e30 Reviews treating infertility

Table 1. Laboratory tests used to diagnose the cause of infertility Laboratory test Description How performed Basal body Used to detect time of ovulation; test is inexpensive but difficult to Measure temperature under the tongue with basal body temperature interpret. Potential benefit in diagnosing and treating female infertility, thermometer every morning before getting out of bed, using although clinical utility is limited. the bathroom or eating/drinking anything. Progesterone Used to assess ovulation function. Low progesterone level indicates Serum test collected mid–luteal phase 1 week before ex- decreased or absent ovulation. pected menses. Anti-Müllerian Used to assess ovarian function; it is able to reliably detect declining Measured at any time during the menstrual cycle. hormone ovarian function early. Reflects the number of follicles, although no established threshold value. (Most insurers do not cover this test.) Estradiol Used to evaluate ovarian cyst or ovarian reserves. Higher levels may Measured on day 3 of menstrual cycle (day 1 being first day indicate a functional ovarian cyst or decreased ovarian reserve. of full menses). Thyroid-stimulat- Used to assess hypothyroidism (which can affect fertility). Elevated TSH Measured on day 3 of menstrual cycle (day 1 being first day ing hormone (TSH) plus low/normal T4 (free thyroxine) indicates hypothyroidism. of full menses). Follicle-stimulat- Used to evaluate presence ovarian follicles and oocytes. Measured on day 3 of menstrual cycle (day 1 being first day ing hormone of full menses). Prolactin Used to assess ovulation. High levels of prolactin may interfere with Measured on day 3 of menstrual cycle (day 1 being first day ovulation. of full menses). Inhibin B Used to evaluate reduced follicles and oocytes. Test is not widely avail- Measured on day 3 of menstrual cycle (day 1 being first day able outside of research laboratories. Low inhibin B levels indicate of full menses). decreased ovarian reserves. en the link between successful infertility treatment and live birth. tioned within the discussion of pharmacotherapy and are further A middle ground would be the number of successful pregnancies. defined in the following section. These procedures include intra- Regardless of the measurement desired, data linking individual uterine insemination (IUI), IVF, ICSI, and donor eggs. pharmacotherapy options with specific efficacy are insufficient. Pharmacists should be aware that treatments are intended to Other than initial treatment with clomiphene citrate or aromatase produce changes that are likely to cause normal or exaggerated inhibitors, rarely is a single pharmacologic treatment used without hormonal responses and subsequent undesirable reactions. These other interventions or therapies. reactions may be classified as adverse events but relate more to General and obstetrics/gynecology practitioners may feel hormonal changes than the medications themselves. The informa- comfortable ordering an initial fertility assessment and prescrib- tion provided in Tables 2 and 3 are derived from careful review of ing oral agents. If these efforts are unsuccessful, patients should information and references provided in three primary databases: seek the assistance of a reproductive endocrinologist. Pharma- cists have roles in supporting general practitioners and patients and in making suggestions for referral. The Society for Assisted Reproductive Technology (SART) provides data on its website documenting overall IVF success rates for SART member clinics and the results for specific clinics. The rapidly changing knowledge base and technical skills needed for these complex treatment regi- mens are best managed by reproductive endocrinologists. At this time, most pharmacists will not be involved in selecting therapeutic agents for infertility according to efficacy. Tables 2 and 3 outline key features associated with these pharmacologic treatments to support pharmacist interactions with patients. Pharma- cists should be aware of the different treatment options in order to answer questions about dosing, administration, and safety. Phar- macists may also discuss with patients the availability of different treatments and ways to reduce risk factors. Pharmacists who are aware of local clinic specifics can provide appropriate referrals for patients. Many patients may think that IVF is the only option for an infertility diagnosis. Community pharmacists should be aware that pharmacy computer systems may guide pharmacists to make confusing counseling statements. This is because pharmacy computer systems may Figure 2. Normal female reproductive cycle advise patients to not take these agents while pregnant. Careful Source: http://commons.wikimedia.org/wiki/File:MenstrualCycle2_en.svg. Attribution: consideration is needed to appropriately counsel patients receiv- By Isometrik (Own work) [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by- ing infertility treatment. Nonpharmacologic procedures are men- sa/3.0) or GFDL (www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons. e31 • JAPhA • 52:4 • J u l /A u g 2012 www.japha.org Journal of the American Pharmacists Association treating infertility Reviews

Table 2. Use, dosing, and administration of infertility medications Medication category, hor- Medication use Route of administration and dose Administration considerations mone (brand name—manufacturer) Selective estrogen receptor Treatment of ovulatory dis- 25–100 mg p.o. for 5 days. Not recom- Orally administered at same time each day. modulator, clomiphene citrate orders mended for more than six cycles or Complete fertility evaluation should be com- (Clomid—Sanofi-Aventis and doses >150 mg. pleted before initiation of therapy. Serophene—EMD Serono) Aromatase inhibitors, letrozole Off-label treatment of ovula- Letrozole: 2.5 mg p.o. daily starting on Orally administered; taken without regard to (Femara—Novartis), anastro- tory disorders and ovulation day 3 of menses and continued for 5 meals. zole (Arimidex—AstraZeneca) induction. days. Can be done for three cycles. Anastrozole: 1 mg p.o. daily starting on day 3 of menses and continued for 5 days. Can be done for three cycles. Gonadotropin-releasing hor- Depot form approved for the For endometriosis: 3.75 mg i.m. every Intramuscular depot should be administered mone (GnRH) agonist, leupro- use in endometriosis: tem- month or 11.25 mg i.m. once every 3 in physician office. Store unopened vials in lide for subcutaneous injection porarily shrinks endometrial months for a maximum of 6 months. refrigerator. Vials in use can be kept at room (Lupron—TAP), leuprolide lesions. Unapproved use with For infertility: dose varies; subcutane- temperature for several months with minimal depot (Lupron—Abbott) controlled ovarian hyperstimu- ous administration. loss of potency. lation: used to down regulate before initiating gonadotropins. GnRH agonist, goserelin Endometriosis: to temporarily Goserelin: 3.6 mg s.c. pellet every Goserelin: store at room temperature, protect (Zoladex—AstraZeneca), shrink the endometrial lesions 28 days. Nafarelin: nasal spray: one from light, and dispense in light-safe bag. Na- nafarelin (Synarel—Pfizer) spray in one nostril in morning and farelin: do not use topical nasal decongestants other nostril in evening. for at least 2 hours after nafarelin use. Avoid sneezing immediately after use. Gonadotropin/follitropin, Treatment of ovulatory disor- Subcutaneous injection various dos- Follitropin beta may be administered subcuta- follitropin alfa (Gonal-f—EMD ders in women ages depending on cycle and used neously or intramuscularly. Follitropin alfa is Serono), follitropin beta alone or with assisted reproductive available as powder for solution and follitropin (Follistim—Organon) technology beta as pen cartridge or powder for solution. Powder can be room temperature or refrigerator. Solution must be refrigerated after opening and should be used within 28 days. Protect from light. Assist patients with injection technique. When reconstituting powder, avoid shaking. Resulting solution should be clear. Gonadotropin/follitropin, Treatment of ovulatory dis- Subcutaneous or intramuscular injec- Subcutaneous or intramuscular injection fol- Urofollitropin (Bravelle— orders tion; various dosages depending on lowed by HCG. Instruct patient on injection Ferring) specific cycle. Starting dose usually technique. 150 to 225 IU daily for 5 days, with dose adjustment of no more than 150 IU daily. Maximum daily dose should not exceed 450 IU, and in most cases, use beyond 12 days is not recommended. Gonadotropin/luteinizing Hypogonadotropic hypogo- 75 IU daily until adequate follicular Solution should be clear and colorless. Any hormone, lutropin alfa nadism development is noted; maximum dura- unused portion after reconstitution should be (Luveris—EMD Serono) tion of treatment: 14 days. Should be discarded. Instruct patient on injection tech- administered with follitropin. nique. Administer around naval area. Gonadotropin/menotropins Stimulate the development Repronex: subcutaneous or intramus- Any unused reconstituted material should be (Menopur—Ferring and of multiple follicles, ovarian cular. Menopur: subcutaneous vari- discarded. The lower abdomen (alternating Repronex—Ferring) induction. ous dosages depending on specific sides) should be used. Solution should be clear cycle. and free from particulate matter before administering. Ovulation triggers, human Ovulation triggers HCG: 5,000-10,000 units i.m. 1 day after Instruct patient on administration technique. chorionic gonadotropin last dose of menotropin. Recombinant Patients should be instructed to administer (HCG) (Novarel—Ferring HCG: 250 mcg prefilled syringe given HCG injection at the specific time indicated by and Pregnyl—Organon). subcutaneously as one dose the day the reproductive endocrinologist. Recombinant HCG (Ovidrel— after finishing follicle-stimulating EMD Serono) hormone. GnRH antagonists, cetrorelix Suppress luteinizing hormone Cetrorelix or ganirelix 0.25 mg/day can Use subcutaneously only. Cetrorelix should be (Cetrotide—EMD Serono), production at the pituitary be administered during early to late reconstituted. Ganirelix provided as prefilled ganirelix level. follicular phase until HCG administra- syringes should only be used once. tion. Cetrorelix 3 mg given as a one time dose on any day during days 5–9.

Journal of the American Pharmacists Association www.japha.org J u l /A u g 2012 • 52:4 • JAPhA • e32 Reviews treating infertility

Table 2 continued Insulin sensitizers, metformin PCOS: decreases glucose pro- 500 mg p.o. daily up to 850 mg t.i.d. Administered orally with meals. (Glucophage—Bristol-Myers duction in the liver and uptake Squibb) of glucose in the intestine. Not FDA approved for off-label use. Micronized progesterone, Approved for use in treat- Capsules: 100–200 mg q.d. or t.i.d. Instruct patients on proper use of gel, supposi- oral capsule 100 or 200 mg ing secondary amenorrhea. inserted vaginally (off label), 4% or tories, vaginal inserts of suppositories. Instruct (Prometrium—Catalent; Off-label use to support em- 8% gel vaginally once or twice daily. partner in intramuscular injection or provide as Abbott), vaginal gel 4% or bryo implantation. May help Intramuscular: 12.5 mg q.d. at 2–11 a service. Before and after compounding, store 8% (Crinone—Watson), oil maintain pregnancy with or weeks’ gestation. Vaginal insert: 100 suppositories in refrigerator. Can keep for 90 for injection, vaginal insert without assisted reproductive mg q.d. to t.i.d. Compounded supposi- days after compounding. (Edometrin—Ferring), technologies. tory: 25–100 mg q.d. or b.i.d. suppository compounding kit (CurtisPharma) Dopamine agonist, Hyperprolactinemia Bromocriptine: initial dose: 1.25–2.5 Bromocriptine: take with food and monitor for bromocriptine (Parlodel— mg/day p.o.; may be increased by 2.5 adverse effect with dose increases. Cabergo- Novartis), cabergoline mg/day as tolerated every 2–7 days line: take without regard to meals. until optimal response. Cabergoline: initial dose, 0.25 mg p.o. twice per week; titrate by 0.25 mg/dose no more than every 4 weeks up to 1 mg p.o. twice per week. Antiplatelet, aspirin Low-dose aspirin is thought to 81 mg p.o. daily Take with food or drink to minimize gastrointes- help decrease the chance of tinal irritation. developing clots in the uterus and cutting off the blood supply to the baby. Abbreviation used: FDA, Food and Drug Administration; IU, International units; PCOS, polycystic ovary syndrome. Clinical Pharmacology, Lexi-Comp, and Facts and Comparisons ovary. Women with normal FSH levels and who produce adequate 4.0. When using tertiary databases to access information about estrogen are most likely to benefit from clomiphene citrate. Sev- adverse events for infertility patients, pharmacists must carefully eral studies have investigated the use of clomiphene in other popu- consider the primary source of the information. lations. Some studies have specifically shown that patients with Figure 2 provides an overview of the normal female menstrual PCOS may also benefit from initial treatment with clomiphene ci- cycle. The figure shows the changes in pituitary hormones (re- trate. Clomiphene citrate is often used as a first-line and last-resort ferred to as gonadotropins in the current work), ovarian hormone agent because it is the cheapest treatment. It is not recommended levels, and changes to the uterine lining, cervical mucus, and basal to be used for more than six cycles. Pharmacists may need to coun- body temperature. Several of the diagnostic tests outlined in Table sel patients with tubal or pelvic abnormalities who are repeatedly 1 corresponded to expected changes in hormone levels during the using this product to avoid more costly therapies. Pharmacists may normal cycle. also assist patients by referring them to a reproductive endocrinologist. Vasomotor symptoms are the most commonly seen adverse event, occurring in 10% or more of patients. Ovarian enlargement Pharmacotherapy treatment options is also common and should be monitored for resolution. Less than Ovulatory disorders and controlled ovarian 10% of patients are likely to experience adverse effects such as hyperstimulation abdominal discomfort, breast discomfort, and nausea. Less than Several medications can be used to induce ovulation in women 2% of patients may experience visual changes such as blurred vi- suffering from ovulatory disorders. These medications may also sion, flashes, or spots. If visual changes occur, the patient’s physi- be used in controlled ovarian hyperstimulation (COH) in patients cian should be contacted and the medication discontinued. As with without documented ovulatory disorders to improve the number most fertility treatments, there is a risk for multiple births. Patients of available oocytes for assisted reproductive technologies such who respond inadequately to clomiphene citrate may find a need as IUI or IVF. Additional oocytes will improve a patient’s chances for supplemental therapy to enhance their response. These other of achieving a pregnancy. COH involves inducing an exaggerated options include dexamethasone, human chorionic gonadotropin hormonal response to cause the maturation of multiple oocytes. (HCG), metformin, thiazolidinediones, and gonadotropins.23 The Clomiphene citrate use of adjunct therapy is more common in patients with PCOS. Clomiphene citrate (Clomid—Sanofi or Serophene—EMD Serano) Aromatase inhibitors: Letrozole and anastrozole is approved by the Food and Drug Administration (FDA) for treat- Aromatase inhibitors are increasingly being used for patients ing ovulatory dysfunction in female patients suffering from infer- with ovulatory disorders. Letrozole (Femera—Novartis) and an- tility.21 As a nonsteroidal selective estrogen receptor modulator, astrozole (Arimidex—AstraZeneca) may be used in patients with clomiphene citrate blocks and down regulates estrogen receptors. normal or elevated estrogen concentrations, irregular ovulation, This results in elevated levels of FSH and LH. This stimulates follic- or PCOS. Letrozole and anastrozole are nonsteroidal competitive ular growth and leads to ovulation without directly stimulating the e33 • JAPhA • 52:4 • J u l /A u g 2012 www.japha.org Journal of the American Pharmacists Association treating infertility Reviews

Table 3. Safety and counseling points for infertility medications Medication category, Adverse effects Contraindications/spe- Major drug interactions Key patient counseling points hormone, brand name cial considerations (manufacturer) Selective estrogen Ovarian enlargement, head- Response may be reduced None known May trigger symptoms similar to menopause. receptor modulator, ache, hot flashes, breast in patients with diabetes Ovulation is expected 5–10 days after last clomiphene citrate discomfort, abdominal or hyperinsulinemia. Preg- dose. Complete pregnancy test before re- (Clomid—Sanofi- discomfort/bloating, nausea nancy Category X. peat courses. Avoid driving a car or operat- Aventis and and vomiting, visual distur- ing machinery until patients know how the Serophene—EMD bances, multiple gestations medication will affect them. Vaginal dryness Serono) is possible and may be bothersome to patients attempting frequent intercourse. Aromatase inhibitors, Flushing, headache, dia- Contraindicated in preg- Strong inhibitor of CYP2A6 Because of off-label use, the patient may letrozole (Femara— phoresis, gastrointestinal nancy (Category X). Liver use caution with sub- need to sign a waiver. Blood count monitor- Novartis), anastrozole disorders/nausea, arthral- enzyme abnormalities strates. Minor interaction ing and glucocorticoid and mineral corticoid (Arimidex— gia, back ache, bone pain, with continued use. No with tamoxifen, tocilizum- replacement therapy are warranted while AstraZeneca) edema dose adjustment for mild ab, and conivaptan. on letrozole for an extended period, usually to moderate hepatic func- longer than duration used for infertility. Ad- tion; no studies in severe minister with or without food. hepatic insufficiency. Gonadotropin- Hot flashes, diaphoresis, Contraindicated during May diminish effects of Patients using depot for endometriosis releasing hormone headache, acne, gastroin- pregnancy (Category X) antidiabetes agents. should also use nonhormonal birth control. (GnRH) agonist, testinal disturbances/nau- Monitor bone mineral density in patient using leuprolide (Lupron— sea and vomiting, vaginitis, intramuscular treatment for endometriosis. Abbott) weight gain/loss, depres- Case reports of anaphylactic reactions. Note sion, dizziness, injection site that higher doses are reserved for other reactions, depletion of bone indications. density, ECG changes, emotional lability GnRH agonist, Headache, emotional labil- Pregnancy Category X May diminish effects of Monitor bone mineral density. Patients with goserelin, (Zoladex— ity, depression, insomnia, antidiabetes agents. diabetes patients should monitor blood glu- AstraZeneca), hot flashes, lethargy, re- cose carefully. Adverse effects may improve nafarelin (Synarel— duced libido, diaphoresis, over time. Vaginal bleeding/spotting may Pfizer) peripheral edema, depletion persist after 2 months of treatment. Adher- of bone density ence to schedule is very important. Gonadotropin/ Headache, ovarian cyst, ab- Follitropin alpha and None known High risk of multiple gestation and OHSS. follitropin, follitropin dominal cramps, OHSS, rare beta are both Pregnancy Patients should be instructed not to miss alfa (Gonal-f—EMD thromboembolic and/pulmo- Category X. Follitropin appointments or laboratory tests. Serono), follitropin nary conditions recorded in beta may contain trace beta (Follistim— patients on gonadotropins amounts of neomycin Organon) and/or streptomycin and should be used cautiously with hypersensitivity. Gonadotropin/ Headache, ovarian cyst/ Pregnancy Category X. None known High risk of multiple gestation and OHSS. follitropin, pain, abdominal cramps, Safety in renal and he- Educate patients on observation and man- urofollitropin vaginal bleeding, depres- patic insufficiency has not agement of mild allergic reaction. Assist (Bravelle—Ferring) sion, weight gain, OHSS, been studied. patients with injection technique. When emotional liability, injection reconstituting powder, avoid shaking. Do not site reactions, rare throm- use if reconstituted solution is not clear. Use boembolic and/pulmonary immediately after reconstitution. conditions recorded in patients on gonadotropins Gonadotropin/ Headache, fatigue, nausea, Pregnancy Category X None known Assist patients with injection technique. luteinizing hormone, diarrhea, constipation, rare When reconstituting powder, avoid shaking. lutropin alfa (Luveris— thromboembolic and/pulmo- Do not use if reconstituted solution is not MD Serono) nary conditions recorded in clear. Use immediately after reconstitution. patients on gonadotropins Gonadotropin/ Headache, abdominal pain, Has not been studied in None known High risk of multiple gestation and OHSS. menotropins, abdominal cramps, injec- renal or hepatic insuf- Educate patient on proper technique and (Menopur—Ferring tion site reactions, bloating, ficiency placement of injections. Powder may be and Repronex— nausea and vomiting, pain, stored at room temperature or refrigerated. Ferring) dizziness, tachycardia, Protect from light. After reconstitution, inject OHSS, rare thromboembolic immediately and discard unused portion. and/pulmonary conditions recorded in patients on gonadotropins

Journal of the American Pharmacists Association www.japha.org J u l /A u g 2012 • 52:4 • JAPhA • e34 Reviews treating infertility

Table 3 continued Ovulation triggers, Edema, injection site pain, Some formulations may None known Ovulation occurs approximately 36 hours human chorionic thromboembolic disorder, contain benzyl alcohol after first injection. Hormones will circulate gonadotropin (HCG; headache, irritability and should be avoided in in blood for days after injection—may result Novarel—Ferring and patients with hypersen- in a false-positive pregnancy test. Ovidrel is Pregnyl—Organon), sitivity. Contraindicated prefilled syringe. Inject into stomach area. recombinant HCG after conception (Preg- Store Ovidrel in refrigerator and protect (Ovidrel—EMD nancy Category X). Safety from light. Following reconstitution of oth- Serono) has not been established ers, solutions are stable for 30–60 days, in patients with hepatic or depending on the specific preparation. renal insufficiency. Keep all physician appointments and specific time schedule.

GnRH antagonists, Abdominal pain, hot flashes, Ganirelix syringe con- None known Instruct on injection technique. Patient cetrorelix headache, vaginal bleeding tains natural rubber and must follow specific timing provided by (Cetrotide—EMD or menstrual irregularity, could cause a reaction prescriber. Patient must keep all laboratory Serono), ganirelix injection site reactions, in patients with latex and prescriber appointments. Use immedi- nausea and vomiting, he- allergy. Pregnancy Cat- ately after mixing. patic impairment egory X. Insulin sensitizers, Diarrhea, nausea and vom- Avoided in patients Avoid/limit alcohol Counsel on symptoms of hypoglycemia and metformin iting, flatulence, headache, with hepatic and renal (increased risk of lactic how to deal with a hypoglycemic attack. (Glucophage— indigestion, hypoglycemia, disease. acidosis) Monitor for hematologic parameters and Bristol-Myers Squibb) vitamin B12 deficiency, renal function. Check vitamin B12 and folate weight loss, lactic acidosis if anemia is present. Take with food to decrease gastrointestinal upset. Take at same time every day. Lactic acidosis is rare but potentially severe consequence of therapy. Progesterone, oral Dizziness, abdominal pain/ No studies on use in Rivaroxaban, silodosin, Avoid activities that require mental alert- capsule 100 or 200 cramping, headache, hepatic and renal insuf- and topotecan. St. John’s ness until patients know whether it will mg (Prometrium— nausea, mood swings, irri- ficiency. Contains peanut wort may decrease pro- affect them. Discuss peanut allergy/warn- Catalent; Abbott), tability/depression, fatigue, oil and should not be used gesterone levels. ing with capsules and gel. Avoid using vaginal gel 4% or 8% breast tenderness, diar- by patients with peanut other vaginal drugs 6 hours before or after. (Crinone—Watson), rhea/constipation, disorien- allergy. If pregnancy occurs, may continue until oil for injection, tation, fluid retention placenta autonomy. Prepare patients for vaginal insert vaginal discharge for vaginally adminis- (Edometrin—Ferring), tered medications. compounding kit (CurtisPharma) Dopamine agonist, Nausea, headache, dizzi- The effect of renal and Major substrate of When taken with ethanol, an increase bromocriptine ness, fatigue, lightheaded- hepatic impairment has CYP3A4, ergot alkaloids, in gastrointestinal adverse effects or (Parlodel—Novartis) ness, vomiting, abdominal not been evaluated. alpha/beta agonists, ethanol intolerance may occur. Take at the cramps, constipation/ Caution should be used alpha1 agonists, anti- same time each day. Maintain adequate diarrhea, muscle weak- during pregnancy and psychotics, conivaptan, hydration. Discuss risks and benefits with ness, rhinitis, drowsiness/ postpartum and risks and cyclosporine, dasatinib, patients when used during pregnancy or somnolence benefits should be con- efavirenz, itraconazole, postpartum. sidered. Use cautiously in macrolide antibiotics, patients who are at risk of MAO inhibitors, meth- cardiovascular events or ylphenidate metoclo- psychosis. pramide, nitroglycerin, posaconazole, protease inhibitors, serotonin 5-HT 1D receptor agonists, serotonin modulators, tocilizumab, voriconazole Antiplatelet, aspirin Indigestion, nausea and Anticoagulants, other May have benefit during first and second vomiting, bleeding not antiplatelets, clot busters trimesters, but studies have not shown a common with low dose but definite advantage. serious Abbreviations used: CYP, cytochrome P450; ECG, electrocardiogram; HT, hydroxytryptamine; MAO, monoamine oxidase; OHSS, ovarian hyperstimulation syndrome. inhibitors of the aromatase enzyme, which synthesizes estrogens. metrium. This class is not FDA approved for these indications. The This inhibition stops the conversion of androgens to estrogen, re- primary concern regarding use of these agents is that they are clas- sulting in considerable reductions in plasma estrogen levels. This sified in Pregnancy Category X, with a risk of possible congenital in turns triggers the hypothalamus to increase secretion of LH and anomalies. A careful review of the adverse event profile suggests FSH.22–24 Unlike clomiphene citrate, these agents do not block es- that short-term use (i.e., 5 days) is not long enough to induce note- trogen receptors. This eliminates the negative impact on the endo- worthy adverse events. e35 • JAPhA • 52:4 • J u l /A u g 2012 www.japha.org Journal of the American Pharmacists Association treating infertility Reviews

Unfortunately, among women who respond poorly to attempts at Active learning exercise: Identify three key counseling points when COH, this suppression may be too great and excessively high go- dispensing gonadotropins. nadotropin doses may be needed as a result. In these patients, micro-doses of leuprolide may be used. This second feature of leu- Comparison of clomiphene citrate versus aromatase prolide uses lower doses. Before leuprolide produces suppression, inhibitors. Casper25 reviewed two studies demonstrating the ef- there is a surge of LH and FSH. If timing is correct, the presence ficacy of letrozole in women with PCOS. His conclusion was that of these hormones provides an additive effect to those provided by letrozole is at least as effective as clomiphene citrate for inducing the reproductive endocrinologist. Therefore, dosing of leuprolide ovulation and achieving pregnancy in patients with PCOS. Letro- is quite variable when used with COH. Although studies suggest zole is likely to produce less adverse effects and may require less that the first option produces higher success rates,22 it is unclear monitoring than clomiphene citrate. whether this is a result of the regimen itself or the fact that the Badawy et al.26 evaluated pregnancy outcome after the use second protocol focuses on those who respond poorly to gonado- of aromatase inhibitors or clomiphene citrate for unexplained in- tropins. fertility. Patients were randomized to three groups: anastrozole GnRH may be used alone in cases where overactive gonado- 1 mg daily for 5 days, 5 mg letrozole daily for 5 days, or 100 mg tropins are contributing to endometriosis. In addition to leuprolide, clomiphene citrate daily for 5 days. A control group of 200 women goserelin (Zoladex—AstraZeneca) and nafarelin (Synarel—Pfizer) were matched by age to women who conceived naturally during may be used for women with known endometriosis. Using GnRH the same 3.5 years of the trial. Clinical pregnancy occurred in 36 agonists for 6 months or less to treat endometriosis is recommend- (11.1%) patients receiving letrozole, 15 (10.5%) receiving anas- ed. Because of the increased chance for cyst formation with the trozole, and 77 (12.1%) receiving clomiphene citrate compared use of these agents, they should be started in the luteal phase if not with 21 (7.0%) patients in the control group. Deliveries occurred being used with COH.28 Patients requiring long-term therapy are in 30 (83%) patients receiving letrozole, 11 (73%) receiving anas- at risk for bone loss, but supplemental treatment with add-back trozole, and 65 (78%) receiving clomiphene citrate. Clomiphene estrogen and progesterone has limited this adverse effect.5 A de- citrate showed the highest pregnancy rate, although the difference tailed review of management of endometriosis is beyond the scope was not statistically significant. Letrozole was associated with a of the current work, but pharmacists interested in enhancing their higher delivery rate but was also not statistically significant. knowledge of infertility should examine this topic further. Regarding fetal safety, two infants born from the letrozole group had congenital anomalies and one had early neonatal death. Gonadotropins No other groups reported early neonatal death, but one infant in Exogenous gonadotropins are used to enhance ovarian function by the clomiphene citrate group had a congenital anomaly. Early re- providing additional FSH and/or LH activity. This enhanced func- ports suggest an increase of congenital cardiac and bone malfor- tion allows for the recruitment and development of multiple fol- mations in newborns of mothers using letrozole. In 2008, Elizur licles. Several exogenous gonadotropins are available for use by and Tulandi27 evaluated the literature to assess the fetal safety of injection: recombinant follitropin, including follitropin alfa (Gonal- drugs used for infertility. The results suggested that after several f—EMD Serano) and follitropin beta (Follistim AQ—Organon); cycles of clomiphene citrate, a slightly higher risk of neural tube urofollitropin (Bravelle—Ferring); lutropin (Luveris—EMD Se- defects and severe hypospadias is possible. A review of aromatase rano); and menotropins (Menopur—Ferring and Repronex—Fer- inhibitors shows flawed studies, and the use of aromatase inhibi- ring). IVF protocols using these treatments may start with low dos- tors with other agents makes it difficult to draw conclusions. Two es that step up. These protocols are likely more successful in limit- small studies referenced in the review indicated that the miscar- ing the occurrence of ovarian hyperstimulation syndrome (OHSS). riage rate and teratogenicity were not different for clomiphene These protocols typically start with doses of 50 to 75 International citrate and aromatase inhibitors and that miscarriage and terato- Units (IU) of FSH a day for 7 or more days, followed by regular dose genicity were generally unfounded for both treatments. Additional increases. Alternatively, a step-down approach begins with 150 data are needed to confirm or refute the rare possibility of congeni- IU or more of FSH followed by regular dose decreases. The start- tal anomalies with the use of clomiphene citrate and aromatase ing dose, frequency of dose change, and extent of dose change is inhibitors in infertility.27 specialized according to each provider/clinic. Vaginal ultrasounds In conclusion, data are not sufficient to support a clear rec- and serum estradiol levels are used to monitor the progression of ommendation of clomiphene citrate or aromatase inhibitors in all COH and may guide the reproductive endocrinologists on dosing 22 infertility patients. Additional studies in subpopulations are being decisions. released and suggest an increased use of aromatase inhibitors The most concerning adverse event related to the above medi- 29 when providers and patients are comfortable with the off-label use. cations used in ovulation induction/COH is OHSS. This adverse event is possible with any treatment used for the purpose of COH GnRH agonists and may not be dose dependent. It is characterized by cystic en- Leuprolide (Lupron—Abbott), a GnRH agonist, is most often used largement of the ovaries and rapid fluid shifts from the intravas- for infertility patients in conjunction with ovulation induction and cular compartment to the third space. Symptoms may be mild to COH. Leuprolide may be used in two ways.22 First, it may be used to severe and can include abdominal ascites, abdominal pain, sud- suppress the body’s natural cycle, allowing for reproductive endo- den weight gain, pain or swelling in extremities, persistent nausea, crinologists to control the cycle with exogenous hormones in COH. and/or vomiting. Patients with PCOS are more likely to experience

Journal of the American Pharmacists Association www.japha.org J u l /A u g 2012 • 52:4 • JAPhA • e36 Reviews treating infertility

OHSS. This condition is potentially life threatening, and women and pregnancy-related complications were the most common ad- presenting to a pharmacy should be directed to contact their phy- verse effects.34 Corifollitropin does not have proven efficacy over sician immediately or to visit the nearest emergency department. other forms of FSH. However, patients who are not at high risk of Maintenance of end-organ perfusion is critical and may require OHSS and would benefit considerably from a decreased number of the use of anticoagulants in the most severe cases. Gonadotropins injections (e.g., those who travel extensively for work) may prefer have similar adverse event profiles that may include headache, corifollitropin alfa. ovarian cysts, abdominal cramping, weight gain, nausea, vomiting, OHSS, and multiple gestations. Rare cases of thromboembolic Lutropin and pulmonary conditions have been recorded in patients using Lutropin alfa (Luveris—EMD Serano) is recombinant LH and is gonadotropins. Injection site reactions are possible but are most used only in patients with a rare condition of hypogonadotropic hy- 35 common with urine-derived products. pogonadism exhibiting profound LH deficiency. The mechanism of action is to stimulate the theca cells in the ovaries to stimulate Recombinant follitropin androgen secretion, which is converted to estradiol by aromatase Follitropin functions as FSH and is often referred to as recombi- enzymes. This subsequently can trigger follicular development. It nant FSH (rFSH). Both follitropin alfa (also alpha) and follitropin is approved for use with follitropin, and both medications are ad- beta consist of two linked alpha and beta glycoprotein chains that ministered subcutaneously.22 are conjoined by electrostatic and hydrophobic forces and structurally identical to endogenous FSH. The nomenclature does not Menotropins refer to the alpha and beta subunits but instead distinguishes one Menotropins (i.e., human menopausal gonadotropin [hMG]) were product from the other. Follitropin alfa was the first to market and, the first urine-derived preparation and were developed in the unlike follitropin beta, is purified by an immune-chromatographic 1960s. Menotropins are a one-to-one ratio of FSH and LH. Highly technique. Follitropin alfa and beta are indicated for ovulation in- purified menotropins (HP-hMG; Menopur—Ferring) and hMG duction in patients with ovulation disorders or for use in IVF proto- (Repronex—Ferring) are indicated for ovarian development in cols. Both are recombinant FSH expressed from Chinese hamster women who have received GnRH agonist or antagonist pituitary ovary cells. Unlike urofollitropin, rFSH is free of urinary proteins, suppression and who are enrolled in protocols for IVF or other as- which could be allergenic.22,30,31 sisted reproductive technology (ART). Menopur is extracted from the urine of postmenopausal women and purified. Each vial con- Urofollitropin tains 75 IU FSH activity and 75 IU LH activity in a sterile, lyophi- Similar to recombinant FSH, urofollitropin (Bravelle—Ferring) lized form intended for reconstitution with 0.9% Sodium Chloride also functions as FSH endogenously and is a highly purified form Injection. Repronex is a purified preparation of gonadotropins of urofollitropin. As with follitropin alfa and beta, when adminis- extracted from the urine of postmenopausal women. Each vial tered for 7 to 12 days, it stimulates the ovaries to produce multiple contains 75 or 150 IU FSH and 75 or 150 IU LH in a sterile, lyophi- follicles. Urofollitropin is administered by either intramuscular or lized form. Repronex is administered by subcutaneous or intra- subcutaneous injection. It is purified from the urine of menopausal muscular injection. Unlike follitropin, HCG, a naturally occurring women.32 Allergic response is possible, though rare, because of hormone in postmenopausal urine, is detected in this product.37,38 the source of the proteins. Menotropins versus follitropin. Several prospective and review studies have been conducted to evaluate whether recombi- Corifollitropin alfa nant menotropins or follitropin is preferred for COH. Studies have Similar to recombinant FSH and urofollitropin, corifollitropin alfa evaluated which therapy produces higher numbers and quality of functions as FSH in the body. It is not currently available in the follicles and higher number of live births, as well as cost consid- United States but has received approval for use in European Union erations. In 2008, Coomarasamy et al.39 selected seven studies states. Corifollitropin alfa is a hybrid molecule with a prolonged and found a significant increase in favor of menotropins for num- half-life. It consists of the FSH alpha subunit and a hybrid of the ber of live births. In 2009, Al-Inany et al.40 reviewed six studies FSH beta subunit and the C-terminal peptide of the HCG beta sub- of 2,371 patients to assess whether either treatment produced unit. This agent should be more patient friendly as a result of the better pregnancy rates. The authors concluded that menotropins reduced number of injections required to sustain multifollicular produced a better pregnancy rate in standard IVF cycles and bor- growth. Two strengths of corifollitropin (100 and 150 mcg) are derline improvement in patients not undergoing IVF. However, available outside of the United States based on patient weight the menotropins did not produce an improved pregnancy rate in 33,34 above or below 60 kg, retrospectively. patients having IVF with ICSI. The reason for this difference was Phase I trials reported no serious adverse events related to the unclear. drug and no changes in hematological or biological parameters. In 2010, Lehert et al.41 published a meta-analysis of 16 stud- Injection site reactions were mild and infrequent. Phase II and III ies and 4,040 patients to evaluate which therapy produces more trials both reported similar adverse event profiles. The Phase III oocytes with a lower total dose per cycle. This primary endpoint ENGAGE trial compared 150 mcg corifollitropin with 200 IU rFSH directly relates to the role of the product. The investigators be- and demonstrated similar serious adverse events between the two lieved that making comparisons regarding pregnancy was too dif- agents. The occurrence of severe OHSS was 1.9% versus 1.2% ficult for primary consideration because of multiple factors that for corifollitropin and rFSH, respectively. Headache, pelvic pain, varied among trials. Prospective randomized or quasirandomized e37 • JAPhA • 52:4 • J u l /A u g 2012 www.japha.org Journal of the American Pharmacists Association treating infertility Reviews

controlled trials were included, irrespective of concomitant use of caused by PCOS secondary to hyperinsulinemia. Although this is GnRH agonists or antagonists. Dosing and duration of treatment a commonly used therapy, it does not have FDA approval for this was not consistent among the included trials. Studies that includ- indication. Studies suggest that use of metformin in addition to ed patients with PCOS were excluded from the main analysis. Sec- clomiphene citrate in women with PCOS increases the frequency ondary endpoints included the total dose of gonadotropins, clini- of spontaneous ovulation, menstrual cyclicity, and ovulatory re- cal pregnancy rate, OHSS, and live birth rate, if available. Signifi- sponse to clomiphene citrate.7 Metformin improves insulin sen- cantly fewer oocytes were retrieved in the menotropins treatment sitivity by reducing absorption of glucose and reducing hepatic arm and the total dose of menotropins was higher. The difference glucose production. This leads to a reduction in hyperinsulinemia, in pregnancy rates and OHSS cases were not significant between which in turn reduces excess androgen production by the ovaries treatments.41 and reduces production of LH in the pituitary.45,46 Because of lack of control of baseline characteristics, vari- Dopamine agonists. Bromocriptine (Parlodel—Novartis) ability among treatment dose and duration, and postrandomiza- is approved by FDA to treat hyperprolactinemia associated with tion management, determining which treatment is more effective amenorrhea with or without galactorrhea, infertility, or hypogo- and cost effective in COH is difficult. Additional prospective tri- nadism. This medication should only be used in patients with el- als and subsequent analysis are needed to better evaluate which evated prolactin levels. Bromocriptine is used to reduce plasma treatment will produce the best results for specific populations. levels of prolactin, increase GnRH secretion, and induce ovulation, thereby restoring fertility.47,48 HCG Cabergoline (brand name no longer available), is a selective HCG (u-HCG; Novarel—Ferring and Pregnyl—Organon) and HCG dopamine receptor type 2 agonist also approved for treating hy- alfa (r-HCG; Ovidrel—EMD Serano) are approved by FDA for ovu- perprolactinemia. This treatment has fewer adverse effects and lation induction. Administration of HCG follows the use of gonado- greater potency than bromocriptine, suggesting that cabergo- tropins, aromatase inhibitors, or clomiphene citrate. It mirrors the line is a better treatment choice. However, longer term use may normal menstrual cycle and the normal LH surge occurring before increase the risk of hypertrophic valvular heart disease; there- ovulation. This completes the final steps of follicular development fore, bromocriptine may be considered the safer choice.5 23 and triggers ovulation. It also promotes the development of the Progesterone. Progesterone is commonly used to provide 35 corpus luteum and the production of testosterone. A single HCG luteal (postovulation) phase support. Progesterone provides is usually timed 36 hours before scheduled oocyte retrieval when many functions related to fertility, including preparing and main- used with IVF. One or more additional doses may also be ordered taining the uterine lining, and may prevent early miscarriage. for administration at specific times. Patients should be advised This may be especially important following other fertility agents, that this timing is very important and should notify their physician which may affect the body’s ability to produce progesterone. if they must deviate from the schedule. Urine-derived products It may also be used in patients whose ovaries do not produce (Novarel and Pregnyl) are supplied as 10,000 units and given in- enough progesterone or produce follicles that do not secrete tramuscularly. Recombinant HCG is supplied as 250 mcg and is enough progesterone. Patients with recurrent early pregnancy 42 administered subcutaneously. The formulations have compara- loss may especially benefit from the addition of progesterone. 23 ble efficacy. Recombinant HCG is preferred by patients because Progesterone is available in multiple dosage forms, includ- of the ability for subcutaneous administration. ing a vaginal gel (Crinone—Watson), vaginal suppository (compounding kit—CurtisPharma), vaginal inserts (Endometrin— GnRH antagonists Ferring), oral capsules inserted in the vagina (Prometrium— GnRH antagonists such as cetrorelix (Cetrotide—EMD Serano) Catalent; Abbott), and an oil-based solution injection. Studies and ganirelix (brand name off market) are used to suppress LH have examined the use of injectable formulations versus vaginal/ production at the pituitary level. This allows the LH surge to be oral formulations, as well as comparison of different vaginal managed by the fertility specialist. Cetrorelix or ganirelix 0.25 mg dosage forms. Most studies have not shown a conclusive best per day starting on day 7 until HCG administration may be admin- choice; however, vaginal treatments are preferred because of istered during early to late follicular phase until HCG administra- injection site reactions and patient adherence/tolerance.48,49 tion. In addition, a single dose of cetrorelix 3 mg on during days Oral administration of progesterone (Prometrium) is classified 5 through 9 can also be used.23,43,44 These protocols are primarily in Pregnancy Category B and is contraindicated in pregnancy used in patients who respond poorly to other treatment protocols because of the possibility of hypospadias and other possible con- involving GnRH agonists and gonadotropins alone. Studies have genital anomalies during pregnancy.50 Other forms of progester- demonstrated that antagonist trials may be especially useful in pa- one do not have this warning. Pharmacy computer systems may tients with OHSS risk because significantly fewer cases of OHSS alert the pharmacist to this contraindication. Pharmacists must have been reported in patients receiving GnRH antagonists than in ensure that patients understand these risks and benefits. those receiving GnRH agonists.30 Aspirin. Some physicians may start patients on aspirin Medications for purposes other than direct ovulation (81–325 mg) before treatment procedures. Published studies induction and COH show limited usefulness but have investigated a possible effect Metformin. Metformin (Glucophage—Bristol-Myers Squibb) on uterine blood flow and uterine clotting and in reducing OHSS. can be used as an adjunctive treatment in women with infertility Safety data also indicate that using aspirin during conception is

Journal of the American Pharmacists Association www.japha.org J u l /A u g 2012 • 52:4 • JAPhA • e38 Reviews treating infertility

not a pregnancy or fetus risk and that patients may need coun- Emotional component of infertility and seling to clarify the pregnancy warning with this medication.51 additional resources Infertility affects a patient’s health and her emotional well-be- Nonpharmacologic treatment methods ing. Infertility can greatly affect the relationship of the couple Ovulation induction/COH and relationships with friends and family. It can also cause a Ovulation induction includes the use of FSH, LH, or combination variety of emotions, such as feeling inadequate, embarrassed, treatment to induce maturation and release of follicles. Ovula- or disengaged. In a study conducted by GfK Roper on behalf of tion induction may be used with normal intercourse or with ART. Schering-Plough and Merck, 80% or more men and women said COH involves ovulation induction to produce multiple follicles they would have sought treatment sooner if they could do it over and increase the likelihood of success or allow cryopreservation again.53 Although the majority of couples felt that the struggle of embryos. No specific algorithm, standard, best practice, or to conceive had brought them closer together (58%) and more published guideline has been established. Before ovulation in- than 80% of women praised their partner for being supportive duction, the normal reproductive system is often down regulated throughout the process, 55% of couples reported that intimacy by the use of oral contraceptives or GnRH agonists. This allows became physically and emotionally anxious. Patients reported the reproductive endocrinologist greater hormonal regulation feeling “despair and loss that can’t be quantified,” “fear that and control. life will be eternally empty,” and not being able to “handle other people being emotionally invested.”53 Members of RESOLVE, a ARTs U.S. infertility association for patients, professionals, and me- IUI. IUI requires the insertion of sperm with a pipette into the dia, have criticized that attention to infertility often focuses on uterus to improve fertilization. The procedure is performed in success stories despite the fact that infertility treatment is not a regular exam room following ovulation induction. Before in- always a success. Although some patients will never be cured of semination, the sperm sample is cleaned and concentrated to infertility, discussing treatment failure is uncommon. Many pa- improve fertilization. Controversy exists regarding whether clo- tients have called for more recognition, funding, and support so miphene citrate, aromatase inhibitors, or gonadotropins are the that more couples experiencing infertility can get help. best pharmacologic treatment with IUI. Fully understanding what individual patients are experienc- IVF. IVF requires the surgical retrieval of mature eggs from ing when dealing with infertility and its treatments is difficult and a woman’s ovaries. Then, in the laboratory, the eggs are fertilized challenging. It is extremely important for pharmacists to provide with a man’s sperm. Typically, 3 to 5 days after fertilization, the appropriate medication counseling. Also, if patients are willing embryos are implanted into the uterus. IVF is usually recommend- to discuss the situation, listening and being empathic is critically ed in women with bilateral fallopian tube blockage. It is also used important. for other conditions causing infertility, including endometriosis, A variety of books, websites, and online communities are unexplained infertility, cervical factor infertility, male factor infer- available for information on infertility. In addition to its on- tility, and ovulation disorders. Women undergoing IVF have an in- line tools, the resolve network also has local meeting groups. creased likelihood of having multiple births. This is a risk because Pharmacists are encouraged to consult www.resolve.org to see multiple fertilized embryos are often implanted into the uterus to whether infertility support groups are available in the commu- increase the chance of conception. A variety of different treatment nity and, if so, to make this information available to patients. protocols are used by different clinics around the country. Patients are carefully monitored for an appropriate number of mature oo- References cytes and OHSS. Patients receiving treatments may have daily of- 1. Chandra A, Martinez GM, Mosher WD, et al. Fertility, family plan- fice visits as they approach retrieval, which may require regular ning, and reproductive health of U.S. women: data from the 2002 dose adjustment by a reproductive endocrinologist. National Survey of Family Growth. Accessed at www.cdc.gov/ ICSI. ICSI is a procedure in which a single sperm is injected nchs/data/series/sr_23/sr23_025.pdf, February 24, 2012. directly into an egg to achieve fertilization. Although this relates 2. Duwe KN, Reefhuis J, Honein MA, et al. Epidemiology of fertility more to male factor infertility, this technique is done in conjunction treatment use among U.S. women with liveborn infants, 1997- with the standard IVF procedures. It is especially useful in patients 2004. J Womens Health. 2010;19:407–16. who have previously failed conception with standard techniques. 3. Centers for Disease Control and Prevention. Reproductive health: Donor eggs and sperm. The use of egg donation is commonly infertility FAQs. Accessed at www.cdc.gov/reproductivehealth/In- used for women who are unable to conceive because of a decline fertility, February 25, 2012. in ovarian function. This usually occurs as a result of advancing 4. American Pregnancy Association. Statistics: pregnancy. Accessed age but may be independent of age. The woman donating the eggs at www.americanpregnancy.org/main/statistics.html, February undergoes ovarian stimulation, allowing her to produce multiple 25, 2012. eggs. A transvaginal ultrasound is used to monitor follicle growth. 5. Fritz MA, Speroff L. Clinical gynecologic endocrinology and infer- The eggs are removed through a small needle passing through the tility. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. vaginal wall. The woman receiving the donation has her cycle con- 6. National Infertility Association. Infertility diagnosis. Accessed at trolled using hormones, ensuring that her uterus is ready for im- www.resolve.org/diagnosis-management/infertility-diagnosis, plantation at the proper time.52 March 29, 2011.

e39 • JAPhA • 52:4 • J u l /A u g 2012 www.japha.org Journal of the American Pharmacists Association treating infertility Reviews

7. Healy DL, Trounson AO, Andersen AN. Female infertility: causes 29. Humaidan P, Quartarolo J, Papanikalaou EG. Preventing ovarian and treatment. Lancet. 1994;343:1539–44. hyperstimulation syndrome: guidance for the clinician. Fertil Steril. 8. Clementini E, Palka C, Iezzi I, et al. Prevalence of chromosomal ab- 2010;94:389–400. normalities in 2078 infertile couples referred for assisted reproduc- 30. Follistim AQ (follitropin beta injection) [package insert]. Whitehouse tive techniques. Hum Reprod. 2005;20:437–42. Station, NJ: Schering-Plough; 2010. 9. Maheshwari A, Hamilton M, Bhattacharya S. Effect of female age on 31. Gonal F (follitropin alfa for injection) [package insert]. Rockland, MA: the diagnostic categories of infertility. Hum Reprod. 2008;23:538–42. EMD Serono; 2009. 10. Kinney A, Kline J, Kelly A, et al. Smoking, alcohol and caffeine in re- 32. Bravelle (urofollitropin for injection) [package insert]. Parsippany, lation to ovarian age during the reproductive years. Hum Reprod. NJ: Ferring; 2008. 2007;22:1175–85. 33. Rombauts L, Talmor A. Corifollitropin alfa for female infertility. Ex- 11. Paszkowski T, Clarke RN, Hornstein MD. Smoking induces oxidative pert Opin Biol Ther. 2012;12:107–12. stress inside the Graafian follicle. Hum Reprod. 2002;17:921–5. 34. de Lartigue J. Corifollitropin alfa: a new option to treat female infer- 12. Peck JD, Leviton A, Cowan LD. A review of the epidemiologic evi- tility. Drugs Today (Barc). 2011;47:583–90. dence concerning the reproductive health effects of caffeine con- 35. Shoham Z, Smith H, Yeko T, et al. Recombinant LH (lutropin alfa) sumption: a 2000–2009 update. Food Chem Toxicol. 2010;48:2549– for the treatment of hypogonadotropic women with profound LH 76. deficiency: a randomized, double-blind, placebo-controlled, proof- 13. Grodstein F, Goldman MB, Cramer DW. Body mass index and ovu- of-efficacy study. Clin Endocrinol. 2008;69:471–8. latory infertility. Epidemiology. 1994;5:247–50. 36. Menopur (menotropins for injection) [package insert]. Tarrytown, 14. Pasquali R, Gambineri A. Metabolic effects of obesity on reproduc- NJ: Ferring; 2010. tion. Reprod Biomed Online. 2006;12:542–51. 37. Repronex (menotropins for injection) [package insert]. Tarrytown, 15. Green BB, Daling JR, Weiss NS, et al. Exercise as a risk factor NJ: Ferring; 2001. for infertility with ovulatory dysfunction. Am J Public Health. 38. Coomarasamy A, Afnan M, Cheema D, et al. Urinary hMG versus 1986;76:1432–6. recombinant FSH for COH following an agonist long down-regula- 16. National Infertility Association. Additional testing for females. Ac- tory protocol in IVF or ICSI treatment: a systematic review and meta- cessed at www.resolve.org/diagnosis-management/infertility-diag- analysis. Hum Reprod. 2008;23:310–5. nosis/additional-testing-for-females.html, January 4, 2012. 39. Al-Inany HG, Abou-setta AM, Aboulghar MA, et al. Highly purified 17. Jirge PR. Ovarian reserve tests. J Hum Reprod Sci. 2011;4:108–13. hMG achieves better pregnancy rates in IVF cycles but not ICSI 18. National Infertility Association. Evaluating your reproductive or- cycles compared with recombinant FSH: a meta-analysis. Gynecol gans. Accessed at www.resolve.org/diagnosis-management/infer- Endocrinol. 2009;25:372–8. tility-diagnosis/evaluating-your-reproductive-organs.html, January 40. Lehert P, Schertz JC, Ezcurra D. Recombinant human follicle-stimu- 4, 2012. lating hormone produces more oocytes with a lower total dose per 19. Kodaman PH, Arici A, Seli E. Evidence-based diagnosis and man- cycle in assisted reproductive technologies compared with highly agement of tubal factor infertility. Curr Opin Obstet Gynecol. purified human menopausal gonadotrophin: a meta-analysis. Re- 2004;16:221–9. prod Biol Endocrinol. 2010;8:112. 20. Grimbizis GF, Tsolakidis D, Anagnostou E, et al. A prospective com- 41. Ovidrel (choriogonadotropin alfa injection) [package insert]. Rock- parison of transvaginal ultrasound, saline infusion sonohysterogra- land, MA: EMD Serono; 2010. phy, and diagnostic hysteroscopy in the evaluation of endometrial 42. Devroey P, Abyholm T, Diedrich K, et al. A double-blind, random- pathology. Fertil Steril. 2010;94:2720–5. ized, dose-finding study to assess the efficacy of the gonadotropin 21. Clomid [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2006. releasing hormone antagonist ganirelix to prevent premature luteinizing hormone surges in women undergoing ovarian stimula- 22. Borglet LM, Calis KA, O’Connell MB, Smith JA. Infertility. In: Wom- tion with recombinant follicle stimulating hormone. Human Reprod. an’s health across the lifespan. Bethesda, MD: American Society of 1998;13:3023–31. Health-System Pharmacists; 2010:339–52. 43. Bakas P, Konidaris S, Liapis A, et al. Role of gonadotropin-releasing 23. Holzer H, Casper R, Tulandi T. A new era in ovulation induction. Fertil hormone antagonist in the management of subfertile couples with Steril.2006;85:277–84. intrauterine insemination and controlled ovarian stimulation. Fertil 24. Requena A, Herrero J, Landeras J, et al. Use of letrozole in assisted Steril. 2011;95:2024–8. reproduction: a systematic review and meta-analysis. Hum Reprod 44. Nestler JE, Jakubowicz DJ, Evans WS, et al. Effects of metformin on Update. 2008;14:571–82. spontaneous and clomiphene-induced ovulation in the polycystic 25. Casper R. Letrozole versus climiphene citrate: which is better for ovary syndrome. N Engl J Med. 1998;338:1876–80. ovulation induction? Fertil Steril. 2009;92:858–9. 45. Nestler JE. Metformin for the treatment of the polycystic ovary syn- 26. Badawy A, Shokeir T, Allam AF, Abdlhady H. Pregnancy outcome af- drome. N Engl J Med. 2008;358:47–54. ter ovulation induction with aromatase inhibitors or clomiphene ci- 46. Parlodel [package insert]. Suffern, NY: Novartis; 2006. trate in unexplained infertility. Acta Obstet Gynecol. 2009;88:187–91. 47. Xue T, Li SW, Wang Y. Effectiveness of bromocriptine monotherapy 27. Elizur SE, Tulandi T. Drugs in infertility and fetal safety. Fertil Steril. or combination treatment with clomiphene for infertility in women 2008;89:1595–602. with galactorrhea and normal prolactin: a systematic review and 28. Kiesel LA, Rody A, Greb RR, Szilagy A. Clinical use of GnRH ana- meta-analysis. Curr Ther Res Clin Exp. 2010;71(4):199–210. logues. Clin Endocrinol (Oxf). 2002;56:677–87.

Journal of the American Pharmacists Association www.japha.org J u l /A u g 2012 • 52:4 • JAPhA • e40 Reviews treating infertility

48. Kleinstein J, Luteal Phase Study Group. Efficacy and tolerability of 50. Prometrium [package insert]. North Chicago, IL: Abbott; 2011. vaginal progesterone capsules (Utrogest 200) compared with pro- 51. Hsieh YY, Tsai HD, Chang CC, et al. Low-dose aspirin for infertile gesterone gel (Crinone 8%) for luteal phase support during assisted women with thin endometrium receiving intrauterine insemina- reproduction. Fertil Steril. 2005;83:1641–9. tion: a prospective, randomized study. J Assist Reprod Genet. 49. Mitwally MF, Diamond MP, Abuzeid M. Vaginal micronized pro- 2000;17(3):174–7. gesterone versus intramuscular progesterone for luteal support in 52. National Infertility Association. Donor options. Accessed at www. women undergoing in vitro fertilization-embryo transfer. Fertil Ster- resolve.org/family-building-options/donor-options/donor-options. il. 2010;93:554–69. html, January 4, 2012. 53. Schering-Plough. GfK National survey complete results. Accessed at www.planforsomeday.com/survey.aspx, February 24, 2012. CPE assessment Instructions: This exam must be taken online; please see “CPE information” for further instructions. There is only one correct answer to each question. This CPE activity will be available online at www.pharmacist.com no later than June 15, 2012. 1. Which of the following is the least common diagno- 7. Progesterone is primarily used for which of the fol- sis in female infertility? lowing? a. Ovulatory disorders a. Inducing ovulation b. Tubal and pelvic disorders b. Luteal phase support c. Unexplained infertility c. Treatment of endometriosis d. Chromosomal abnormalities d. Treatment of hyperprolactinemia

2. Which of the following risk factors is related to the 8. Which of the following is a characteristic of ovarian determination that a patient should seek treatment hyperstimulation syndrome (OHSS)? for infertility? a. Its most common initial symptom is dizziness. a. Increased age b. It is less likely to occur in patients with polycystic b. Tobacco or alcohol use ovary syndrome (PCOS). c. Increase caffeine intake c. It is always dose dependent. d. Increased or decreased body weight d. It can be life threatening.

3. All of the following would be possible treatments 9. Which of the following is a symptom of OHSS? for a patient experiencing WHO (World Health Or- a. Hot flashes ganization) group I anovulation except: b. Swelling of extremities a. Clomiphene citrate. c. Mood swings b. Gonadotropin-releasing hormone (GnRH) agonist. d. Itching c. Gonadotropins. d. In vitro fertilization (IVF). 10. A patient who visits your pharmacy regularly con- fides that she has been trying to conceive for 2 4. Which of the following is a common adverse effect years. Which of the following actions would be ap- of clomiphene citrate? propriate for you to take? a. Headache a. Discuss available diagnostic testing and determine b. Tachycardia what tests have been completed. c. Hyperglycemia b. Inform the patient that she is likely facing treatment d. Bone pain with IVF and you can assist with selecting the best treatment. 5. Which of the following medications is used to trig- c. Inform the patient that she is unlikely to become ger ovulation? pregnant because of a specific risk factor. a. Clomiphene citrate d. Describe the adverse effects associated with fertil- b. Bromocriptine ity medications so the patient is prepared. c. Human chorionic gonadotropin d. Gonadotropins 11. Which of the following is true regarding the use of follitropin in female infertility? 6. When counseling patients on infertility treatments, a. Follitropin alfa is structurally different than follitro- it is important to: pin beta. a. Consider that the medication may be used outside b. Follitropin contains follicle-stimulating hormone its usual indication. (FSH) and luteinizing hormone (LH). b. Assure them that the medication will lead to suc- c. Follitropin is a GnRH antagonist. cess in conceiving. d. Follitropin is often referred to as recombinant FSH. c. Require them to discuss the details of their infertility issues. d. Suggest that they consider adoption. e41 • JAPhA • 52:4 • J u l /A u g 2012 www.japha.org Journal of the American Pharmacists Association treating infertility Reviews

12. GnRH antagonists are used to: 17. Which of the following is true regarding prepara- a. Suppress production of LH in the pituitary. tion of gonadotropins for injection? b. Shrink endometrial lesions. a. Reconstituted medications will still be cloudy after c. Support patients with PCOS. reconstitution. d. Treat hyperprolactinemia. b. Patients should prime prefilled pens before the first use. 13. Which of the following is a characteristic of meno- c. Powder should be shaken while reconstituting. tropins? d. Patients do not need to rotate the site of injection. a. They consist of a combination of LH and FSH. b. They are clearly more efficacious than follitropin in 18. Which of the following statements is correct re- controlled ovarian hyperstimulation. garding the use of progesterone in infertility treat- c. After reconstituting, they can be refrigerated and ment? used for multiple doses. a. If the fertility treatment is successful, progesterone d. They have a high rate of drug interactions when used treatment will usually continue into the first trimes- with other fertility drugs. ter of pregnancy. b. Oral administration of progesterone is the preferred 14. Which of the following is a correct statement about route for infertility treatment. fertility medications? c. Progesterone should not be given to patients with a. Most fertility medications can be given safely during an allergy to eggs. pregnancy because they are derived from naturally d. Progesterone may diminish the effects of antidiabe- occurring hormones. tes agents. b. HCG can be used to treat endometriosis, but this is considered an off-label use. 19. Which of the following statements is correct re- c. Patients should have a complete fertility evaluation garding clomiphene citrate? before initiating any medications. a. It is recommended for an indefinite number of cy- d. Patients receiving fertility treatment have a high cles. frequency of adverse effects. b. Concurrent use of St. John’s wort may decrease efficacy. 15. Which of the following statements is correct re- c. It results in increased levels of FSH and LH. garding the use of GnRH agonists? d. Doses are typically 5–10 mg daily. a. Depot forms are used for treating endometriosis. b. GnRH agonists produce a protective effect on bone 20. Which of the following is true of infertility? density. a. All patients follow a very similar course of pharma- c. Hot flashes are not commonly seen with GnRH ago- cotherapy and procedures. nists. b. Efficacy of a given pharmacologic agent is similar in d. Clomiphene citrate belongs to this medication class. all patients. c. Efficacy of a given pharmacologic agent is similar among all patients with the specific diagnosis such 16. Which of the following is used to assess ovarian re- as tubal factor. serves? d. All patients can benefit from having a pharmacist a. Anti-Müllerian hormone available who is willing to discuss treatment with- b. TSH out passing judgment. c. Basal body temperature d. Prolactin level

CPE information To obtain 2.0 contact hours of CPE credit (0.2 CEUs) for this activity, complete and submit the CPE exam online at www.pharmacist.com/education. A Statement of Credit will be awarded for a passing grade of 70% or better. You will have two opportunities to successfully complete the CPE exam. Pharmacists who successfully complete this activity before June 15, 2015, can receive credit. Your Statement of Credit will be available online immediately upon successful completion of the CPE exam. CPE instructions: Get your documentation of credit now! Posttests can be completed at www.pharmacist.com/education using these steps: 1. Go to Online CPE Quick List and click on the title of this activity. 2. Log in. APhA members enter your user name and password. Not an APhA member? Just click “Create one now” to open an account. No fee is required to register. 3. Go to www.pharmacist.com/CPEMonitor to provide APhA with your required NABP e-Profile ID. 4. Successfully complete the CPE exam and evaluation form to gain immediate access to your documentation of credit. Live step-by-step assistance is available Monday through Friday 8:30 am to 5:00 pm ET at APhA Member Services at 800-237-APhA (2742) or by e-mailing [email protected].

Journal of the American Pharmacists Association www.japha.org J u l /A u g 2012 • 52:4 • JAPhA • e42