Conception Challenges: Insights into Infertility

A multitude of factors can contribute to infertility, but with the host of available treatment options, 85% to 95% of cases are treated with either medication or surgery.

Infertility is defined as unsuccessful conception after 12 months of attempting to conceive. In general, medical intervention is initiated after 12 months; however, if infertility is suspected based on medical history or if the woman is older than 35 years, an evaluation may be initiated earlier. ¹ According to the National Center for Health Statistics of the Centers for Disease Control and Prevention, an estimated 7.3 million women, or 12%, in the United States have difficulty getting pregnant or carrying a baby to term.^2-4

The most common causes of infertility in women include ovulation disorders, endometriosis, obstruction of or damage to the fallopian tubes, cervical factors, and polycystic ovarian syndrome (PCOS). In men, the most common cause of infertility is abnormal sperm production or function. ^1,3,4 Additional causes of infertility can be attributed to other medical conditions, as well as environmental or occupational factors. An estimated one third of infertility cases are due to female factors; another third are related to male factors; and the remaining third of infertility cases are caused by a combination of factors in both partners.^3,4 In an estimated 20% of cases, the factor contributing to infertility is not identifiable.^3,4

PHARMACOTHERAPY

Once a specific cause or contributing factor to infertility has been identified, a physician can determine the appropriate treatment to meet the specific needs of the patient. Eighty-five percent to 95% of infertility cases are treated with the use of medication and/or surgery.^3,4 The use of fertility drugs are the primary treatment for women with ovulatory problems who wish to conceive. Currently, numerous pharmacologic agents are approved for ovulation induction. In addition, other classes of agents are also used for the treatment of infertility. For example, although not approved by the FDA for the treatment of infertility, various studies have shown that metformin may restore ovulation or increase the chances of responding to therapy in women with PCOS or insulin resistance.^1,5 Other studies have shown that aromatase inhibitors, anastrozole (Arimidex) and letrozole (Femara), may be successful in ovulation induction.^4,5

CLOMIPHENE CITRATE

Clomiphene citrate (Clomid, Serophene) has been used since the early 1960s and was the first ovulation inductor. Today, it is still the most commonly used pharmacologic agent for ovulation induction.⁶ It is classified as a nonsteroidal compound with both estrogenic and antiestrogenic properties that are used to induce ovulation in anovulatory women.⁷ Although its exact mechanism of action is not well understood, this agent appears to stimulate the release of the pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which results in the development and maturation of the ovarian follicle, ovulation, and subsequent development and function of the corpus luteum.^6,7

Clomiphene citrate is used to induce ovulation in appropriately selected anovulatory women desiring pregnancy, such as those patients with oligomenorrhea, especially PCOS, and patients with slight menstrual irregularities.^5-7 Clomiphene citrate is ineffective in patients with primary pituitary or ovarian failure and is indicated only for patients in whom ovulatory dysfunction has been demonstrated. ^5-7 Clomiphene citrate is taken orally for 5 days starting on the third, fourth, or fifth day of the menstrual cycle, following either a spontaneous or induced bleeding with progesterone withdrawal.^5-7 If ovulation does not appear to occur after completion of the first course of therapy, the dose may be increased to 100 mg daily for 5 days. The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle.^6-9

Although clomiphene citrate regimens involving >100 mg daily for 5 days are not recommended by manufacturers, regimens of up to 150 or 200 mg daily for 5 days are widely used in patients.^7,9,10 The majority of patients who respond to therapy will do so after the first course of therapy.^6-9 If ovulation does not occur after 3 courses of therapy, therapy should be discontinued and the patient should be reevaluated.^7-9 Although about 75% to 80% of women treated with clomiphene citrate will ovulate, only about 40% to 50% become pregnant.^7,8

The most common adverse effects associated with the use of clomiphene citrate include ovarian enlargement or cyst formation and vasomotor symptoms, such as hot flashes, which are usually mild and disappear after clomiphene therapy is discontinued.^6-9Adverse visual symptoms, including transient blurring of vision, diplopia, and photophobia, have occurred and appear to be dose-related and usually disappear within a few days or weeks following discontinuation of the drug.^5-9

Other adverse effects of clomiphene citrate include nausea, vomiting, breast tenderness, and headache. Clomiphene citrate is contraindicated in patients with liver disease or in those with a history of liver dysfunction, and clinical evaluation of liver function should always precede therapy.^5,7,9 Clomiphene citrate is also contraindicated in patients with abnormal uterine bleeding of undetermined origin.^5,7,9

INJECTABLE GONADOTROPINS

Injectable gonadotropins are often utilized when clomiphene has been ineffective. These agents are indicated for the development of multiple follicles and ovulation induction following pituitary suppression.^5,10-13 Injectable gonadotropins contain FSH or LH alone or in combination.

A variety of gonadotropin formulations are available, which include human menopausal gonadotropin (hMG) products, such as menotropins for injection (Repronex, Humegon, and Menopur), all of which contain equal amounts of FSH and LH.^5,10-13 FSH-only products are also available, such as follitropin beta injection (Follistim), urofollitropin injection (Bravelle), and follitropin alfa injection (Gonal-F); also available is one recombinant LH product, lutropin alfa (Luveris), which is the first pure LH (recombinant human LH) for the treatment of female infertility.^5,10-13 Lutropin alfa is indicated for use in combination with follitropin alfa for injection for the stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency.¹¹

Treatment with gonadotropins involves a series of injections, and the use of these agents must be monitored closely to minimize the incidence of the adverse effects associated with these agents. Many of these products are available in prefilled, premixed pen delivery devices for ease of use and accuracy. Some injectable gonadotropins are administered intramuscularly and some are administered subcutaneously. Injections are usually administered over 7 to 12 days, but may be extended if the ovaries are slow to respond.^11-13 The size of the follicle is monitored via ultrasound and blood work, and the goal of therapy is to obtain one or more mature follicles and an appropriate estrogen level, in order for ovulation to be triggered by a human chorionic gonadotropin (hCG) injection.^11-13 When hCGs are used appropriately, more than 95% of women treated with them ovulate, but only 50% to 75% become pregnant.⁸ About 10% to 30% of pregnancies in women treated with hCGs involve more than one fetus, primarily twins.⁸

The most common adverse effects associated with injectable gonadotropins include breast tenderness, swelling or irritation at the injection site, mood swings, and abdominal bloating.⁵ The most serious adverse reaction associated with the use of injectable gonadotropins is ovarian hyperstimulation syndrome, in which the ovaries become swollen and painful.^5,10 In severe cases of ovarian hyperstimulation syndrome, fluid accumulates in the abdominal cavity and chest. In about 2% of gonadotropin cycles, hyperstimulation may be severe enough to require hospitalization.^5,10 If too many follicles develop, physicians may withhold the injection of hCG to prevent ovarian hyperstimulation or high-order multiple pregnancy. ^5,8-10 An estimated 10% to 20% of women treated with hCGs develop ovarian hyperstimulation. ⁸

GNRH ANALOGS

Gonadotropin-releasing hormone (GnRH) analogs can be classified as GnRH antagonists or agonists. Leuprolide acetate, nafarelin acetate, and goserelin acetate are classified as GnRH agonists.⁵ GnRH agonists are used to prevent premature release of eggs in in vitro fertilization. ^5,14 Leuprolide and goserelin are administered through subcutaneous injection, while nafarelin is administered as a nasal spray.

Ganirelix acetate and cetrorelix acetate are GnRH antagonists, which suppress the production of FSH and LH.⁵ These agents are indicated for inhibition of premature LH surge in controlled ovarian stimulation prior to assisted reproductive technologies (ARTs).¹⁵

Cetrorelix acetate is available in a 3-mg, single-dose regimen and a 0.25-mg daily dose given subcutaneously during earlyto- mid follicular phase.^14,15 In the singledose regimen, 3 mg of cetrorelix is administered when the serum estradiol level is indicative of an appropriate stimulation response, and is typically administered on stimulation day 7 (range, days 5-9). In the multiple-dose regimen, 0.25 mg of cetrorelix is administered on either stimulation day 5 or day 6 and given daily until the day of hCG administration.¹⁵ Cetrorelix acetate is contraindicated in women who are allergic to cetrorelix acetate, mannitol, or exogenous peptide hormones, and those with renal disease, known or suspected pregnancy, or lactation.¹⁵

Ganirelix acetate is administered as 250 mcg subcutaneously once a day during the mid-to-late follicular phase and should be continued daily until the day of hCG injection.¹⁶

The most common adverse effects associated with GnRH analogs include temporary symptoms of menopause, such as hot flashes, headache, insomnia, abdominal pain, and mood swings.^5,15,16

HCG HORMONE

HCG injections are 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 FSHs as part of an ART regimen.^5,17,18 Some are formulated for subcutaneous injection and some for intramuscular injection. They should not be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography.^5,17,18 The most adverse effects include pain at the injection site, headache, nausea, and gastrointestinal upset.

CONCLUSION

Today, many pharmacies specialize in infertility, and pharmacists can play an active role in assisting patients who face infertility. Pharmacists can ensure that these patients are adequately counseled on the proper administration of these medications by reiterating the information they received from their physician recommending that they discuss any concerns with their prescribing physicians. As the medical profession gains more insight into understanding the dynamics of infertility, there is continued hope for the millions of couples whose dreams to have a child may become realized.

Table

Examples of Pharmacologic Agents Used in Ovulation Induction

Class

Generic (Brand/Manufacturer)

Available Formulations

Common Adverse Effects

Estrogen agonist/antagonist

Clomiphene citrate (Clomid/ sanofi-aventis US)

Clomiphene citrate (Serophene/ EMD Serono)

50-mg tablets

Headaches, blurred vision, ovarian cysts, nausea and breast tenderness

Follicle-stimulating hormone (FSH)

Urinary-derived

• Urofollitropin injection (Bravelle/Ferring Fertility)

Recombinant DNA Technology

• Follitropin beta (Follistim/ Schering-Plough)
• Follitropin alpha (Gonal-F/ EMD Serono)

Injections

Increased incidence of multiple births, swelling or pain at the injection site, breast tenderness, mood swings, mild to severe hyperstimulation syndrome

Luteinizing hormone

Recombinant DNA

• Lutropin alfa (Luveris/EMD Serono)

Injection

Same as FSH

Human menopausal gonadotropins

Urinary-derived

• Menotropins (Repronex/Ferring Fertility; Menopur/Ferring Fertility)

Injection

Same as FSH

Gonadotropin-releasing hormone (GnRH) agonists

• Leuprolide acetate (Lupron Depot/Abbott;Eligard/sanofi-aventis)
• Nafarelin acetate (Synarel/Pfizer)
• Goserelin acetate (Zoladex/AstraZeneca)

Injection

Nasal spray

Injection

Headache, hot flashes, mood swings, insomnia, vaginal dryness

GnRH antagonists

• Ganirelix acetate (Schering-Plough)
• Cetrorelix acetate (Cetrotide/EMD Serono)

Injection

Same as GnRH agonists

Human chorionic gonadotropin

Urinary-derived

• Pregnyl (Organon)
• Novarel (Ferring Fertility)

Recombinant DNA technology

• Choriogonadtropin alpha (Ovidrel/EMD Serono)

Injection

Pain at the injection site, headaches, nausea

Adapted from references 5, 12-19.

Ms. Terrie is a clinical pharmacy writer based in Haymarket, Virginia.

References

1. Jose-Miller AB, Boyden JW, Frey KA. Infertility. Am Fam Physician.2007;75(6):849-856.

2. Infertility. United States Department of Health and Human Services National Women’s Health Information Center Web site. www.womenshealth.gov/faq/infertility.cfm. Accessed May 10, 2010.

3. Quick facts about infertility. American Society of Reproductive Medicine Web site. www.asrm.org/detail.aspx?id=2322. Accessed May 11, 2010.

4. Infertility Diagnosis. Resolve: The National Infertility Association Web site. www.resolve.org/diagnosis-management/infertility-diagnosis/. Accessed May 12, 2010.

5. Medications for inducing ovulation. American Society of Reproductive Medicine Web site. www.asrm.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ovulation_drugs.pdf. Accessed May 10, 2010.

6. Brassard M, AinMelk Y, Baillargeon JP. Basic infertility including polycystic ovary syndrome. Med Clin North Am.2008;92(5):1163-1192.

7. Monograph Clomid Oral. Medscape Web site. www.medscape.com/druginfo/monograph?cid=med&drugid=11204&drugname=Clomid+Oral&monotype=monograph&secid=6. Accessed May 10, 2010.

8. Problems with Ovulation. The Merck Manual Online Medical Library. Merck Web site. www.merck.com/mmhe/sec22/ch254/ch254c.html. Accessed May 11, 2010.

9. Clomid Prescribing Information. Sanofi-Aventis Web site. http://products.sanofi-aventis.us/clomid/clomid.pdf. Accessed May 10, 2010.

10. Phipps WR. Polycystic ovary syndrome and ovulation induction.Obstet Gynecol Clin North Am.2001;28(1):165-182.

11. Luveris Prescribing Information. EMD Serono Inc Web site. www.emdserono.com/cmg.emdserono_us/en/images/Luveris_tcm115_19351.pdf. Accessed May 12, 2010.

12. Bravelle Prescribing Information. Ferring Fertility Web site. www.ferringfertility.com/medications/bravelle/. Accessed May 12, 2010.

13. Repronex Prescribing Information. Ferring Fertility Web site. www.ferringfertility.com/medications/repronex/. Accessed May 10, 2010.

14. Gonadotropin Releasing Hormone Agonists. Resolve: The National Fertility Association Web site. www.resolveofohio.org/site/pageserver?pagename=lrn-wamo-fm-ago. Accessed May 10, 2010.

15. Cetrotide Prescribing Information. EMD Serono Inc Web site. www.emdserono.com/cmg.emdserono_us/en/images/Cetrotide_tcm115_19346.pdf. Accessed May 10, 2010.

16. Ganirelix Prescribing Information. Organon Web site. www.spfiles.com/piganirelix.pdf. Accessed May 10, 2010.

17. Ovidrel Prescribing Information. EMD Serono Inc Web site. www.emdserono.com/cmg.emdserono_us/en/images/ovidrel_prefilled_syringe_tcm115_19352.pdf. Accessed May 10, 2010.

18. Novarel Prescribing Information. Ferring Fertility Web site. www.ferringfertility.com/medications/novarel/. Accessed May 11, 2010.