Medications Used for In Vitro Fertilization

Anna K. Morin, PharmD

In vitro fertilization, or IVF, is a form of assisted reproductive technology, or ART, in which a woman’s reproductive system is stimulated to produce multiple oocytes, or eggs, which are extracted, fertilized in a laboratory and implanted in the uterus. (1) Since its introduction in the United States in 1981, 1.9% of all babies in the US are born through IVF and other ART. (2) IVF is the most effective option if natural or unassisted conception is not possible – i.e., either partner has received a diagnosis of unexplained infertility, fallopian tube damage or blockage, ovulation or uterine disorders, impaired sperm production or a genetic disorder. (1, 3) Protocols may differ depending on the woman’s diagnosis and individual IVF clinics, but IVF typically involves the following steps: oocyte production, oocyte retrieval, sperm retrieval, fertilization and embryo transfer. (1, 3) Oocyte production is a multistep process controlled by medications to replicate the different stages of ovarian stimulation and includes four main components: controlled ovarian hyperstimulation, suppression of ovulation, oocyte maturation and luteal phase support. (1, 3, 4) Each stage involves specific protocols and the most appropriate pharmacologic and therapeutic interventions are chosen after a thorough pretreatment evaluation. One full cycle of IVF takes approximately three to four weeks and begins with the use of medications on a precisely timed schedule to increase the number of mature follicles that develop in the ovaries and to control the time of ovulation. Many clinicians will prescribe a birth control pill for the woman to take for one or more weeks before beginning IVF to help prevent the release of hormones that could stimulate natural ovulation. (1, 3)

Day one of the menstrual cycle is defined as the first day of menstruation. A baseline visit is typically scheduled for cycle day three and includes a pelvic ultrasound to measure follicle growth and bloodwork to measure hormone levels. (1, 3) If appropriate, injectable follicle stimulating hormone, or FSH, mediations; such as follitropin (Gonal-F®, Follistim®) urofollitropin (Bravelle®) and menotropins (Menopur®, Repronex®), can be started to stimulate development of multiple follicles and eggs in the ovaries. (3, 4) FSH medications need to be subcutaneously self-injected at a consistent time daily, typically in the evening, over seven to 12 days until multiple mature size follicles have developed. (1, 3) FSH agents should not be used in patients with primary ovarian failure and are contraindicated in patients with overt thyroid or adrenal dysfunction, pituitary tumors, abnormal uterine bleeding on unknown origins, ovarian enlargement (not due to polycystic ovary syndrome) or previous hypersensitivity to any of these agents. (3, 4) Common adverse effects include soreness or mild bruising at the site of injection, abdominal bloating, abdominal cramping, headaches and breast tenderness. The goal of IVF ovarian stimulation is to produce approximately eight to 15 quality eggs (about 15-20 millimeters in diameter) for retrieval. (1, 3) Over stimulation of the ovaries can lead to significant discomfort and, in rare cases, ovarian hyperstimulation syndrome, or OHSS. (1, 3, 4) However, multiple eggs are often needed because some may not fertilize or develop normally following fertilization. Pelvic ultrasounds and blood testing is repeated every few days throughout the cycle and depending on the results of these tests, the dose of FSH may be adjusted up or down and other medications added as part of the IVF protocol.1,3

Pulsatile release of gonadotropin releasing hormone, known as GnRH, induces the production and release of luteinizing hormone, or LH, and FSH from the gonadotrophic cells of the anterior pituitary. (3, 4) At midcycle, a large increase in GnRH release results in an LH surge, that, in turn, induces the ovulation of the dominant follicle, resumption of oocyte meiosis and subsequently luteinization. GnRH agonist or GnRH antagonist products can be self-administered subcutaneously to suppress the pituitary gland’s ability to produce the LH surge needed for ovulation until the developing eggs are ready for retrieval. The GnRH agonist leuprolide Lupron® can be utilized to down regulate the pituitary gland’s ability to produce the LH surge. Referred to as the “long Lupron” or “luteal Lupron” protocol, leuprolide is usually started on day 21 of the menstrual cycle (about seven days before the next expected onset of menses), followed by the start of FSH medication within the first two to seven days after menses begins. (3) The leuprolide dose is often reduced when the FSH product is started. Instead of leuprolide, a GnRH antagonist such as cetrorelix (Cetrotide®) or ganirelix (Antagon®) can be used to prevent premature ovulation. (3) GnRH antagonists compete with native GnRH at pituitary binding sites, thus preventing the release of LH and FSH in a dose-dependent manner. Commonly administered subcutaneously, GnRH antagonists are started once the follicles have reached 14 millimeters, typically on or about the sixth day after initiation of FSH, and continued until human chorionic gonadotropin, or hCG, is started. (3) The effects of GnRH antagonists on LH and FSH are reversible after discontinuation of treatment. The “long Lupron” IVF protocol is commonly used, however, the GnRH antagonist protocols are now used more often. Success rates are similar with both protocols, and the use of ganirelix is associated with fewer injections during the stimulation cycle and lower risk for OHSS compared to the “long Lupron” protocol. (5)

Human chorionic gonadotropin, or hCG, available as the brand name products Novarel®, Ovidrel® and Pregnyl®, replicates the effect of an LH surge. (3, 4) Administered as a subcutaneous or intramuscular injection when the follicle measurements reach 15-20 millimeters in diameter and one day after the last dose of a, FSH medication, hCG produces final maturation of the eggs in preparation for ovulation. (1, 3, 4) Regardless of the stimulation protocol used, the egg retrieval procedure is planned for 34-36 hours after hCG injection and before ovulation. (1, 3) Adverse effects of hCG include nausea, vomiting, abdominal pain, tiredness, edema, headache and injection site reactions. After egg retrieval, women may experience cramping and feelings of fullness or pressure. On the day of egg retrieval, progesterone may be started to make the uterine lining more receptive to embryo implantation. (1, 3, 4) Administered intramuscularly or as a vaginal insert (gel or suppository), progesterone is continued for a minimum of 30 days after pregnancy has been confirmed. Progesterone is associated with headache, breast tenderness, irritation, slight bleeding and vaginal irritation.

Following egg retrieval and incubation, fertilization takes place using two common methods: conventional insemination, where healthy sperm and mature eggs are mixed and incubated overnight; or intracytoplasmic sperm injection, known as ICSI, where a single healthy sperm is injected directly into each mature egg. (1, 3) ICSI is preferred when sperm quality or number is low or if prior conventional fertilization attempts failed. One or more healthy fertilized eggs, now called embryos, can be implanted into the uterus three to five days after fertilization or may be frozen for use in a subsequent cycle. Prior to implantation, embryos can be tested to identify genetic or chromosomal defects. The success of an IVF cycle ending in a live birth depends on several factors, including the woman’s age, cause of infertility and treatment approach. (1, 2, 3) Chances of success increase when more than one cycle of IFV is done. The success rates of individual infertility clinics in the United States are published on the Assisted Reproductive Technology website – www.sart.org.

Women and couples considering IVF should discuss the risks and benefits with their health care provider. Although IVF has a high rate of success, it comes with some disadvantages as well, including potential adverse effects of multiple infertility medications and associated invasive procedures, as well as an increased rate of multiple births – i.e., twins or triplets. In addition, IVF can be financially, emotionally and physically stressful. According to the National Conference of State Legislatures, the average cost of an IVF cycle in the U.S. is $12,000 to $17,000, depending on which tests are required, the type and dose of medication(s) used, and the number of cycles required to become pregnant (https://www.ncsl.org/research/health/insurance-coverage-for-infertility-laws.aspx). Insurance policies cover the cost associated with IVF in some states, although this varies depending on location and individual insurance policy. +

References:

1. In vitro fertilization (IVF). Mayo Clinic. Updated 9/10/21. Available at: https://www.mayoclinic.org/ tests-procedures/in-vitro-fertilization/about/pac- 20384716. Accessed: November 19, 2021.

2. CDC, Assisted Reproductive Technology Surveillance – US, 2017. MMWR 2020;69(9):1- 20. Available at: https://www.cdc.gov/mmwr/ volumes/69/ss/ss6909a1.htm.

3. Advanced Fertility center of Chicago. Details about injectable medications for in vitro fertilization, IVF. Available at: https://advancedfertility.com/ ivf-in-detail/injectables-ivf-treatment/. Accessed: November 19, 2021.

4. Panesar K. Medications used for in vitro fertilization. US Pharm 2016;41(9):HS8-HS11.

5. Fluker M, Grifo S, Leader A, Levy M. Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertility and Sterility 2021; 75(1):38-45.

Anna K. Morin, PharmD Associate provost – Worcester/Manchester Massachusetts College of Pharmacy and Health Sciences