WORCESTER MEDICINE
Infertility
Medications Used for In Vitro Fertilization Anna K. Morin, PharmD
I
n 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
12
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)
JANUARY / FEBRUARY 2022
