US Pharm. 2016;41(9):HS8-HS11.

ABSTRACT: In vitro fertilization (IVF) is a form of assisted reproductive technology in which a woman’s reproductive system is artificially stimulated to produce oocytes, which are extracted, fertilized in a laboratory, and then implanted in the uterus. This is a multistep process that needs to be carefully controlled with the use of medications. The four main components of IVF include pituitary downregulation, controlled ovarian hyperstimulation, induction of ovulation, and luteal-phase support. Because of the complex interplay of the various drugs used to replicate the different stages of the fertilization process, pharmacists should be an active part of the IVF healthcare team.

In vitro fertilization (IVF) is a type of assisted reproductive technology (ART) in which a woman’s reproductive system is artificially stimulated to produce oocytes, or eggs, which are extracted, fertilized in a laboratory, and implanted in the uterus. This procedure was developed for use in women with nonfunctional fallopian tubes, but it is now reserved for women in whom reproductive techniques have failed or in women whose infertility is due to male factors, endometriosis, immunologic factors, unexplained infertility, or other causes.1,2

Overview

The first successful transfer of an IVF human embryo was recorded by Steptoe and Edwards in 1976; the pregnancy was ectopic, however. Soon afterward, in 1978, the first IVF pregnancy was achieved, and the numbers of IVF centers and IVF procedures performed have substantially increased since then.3 This is due, in part, to the fact that IVF results in the highest pregnancy rate per cycle.4 The live birthrate per transfer is about 41% in women aged <35 years.5

IVF is a multistep process involving ovarian stimulation, ovulation induction, collection of oocytes, fertilization with sperm, and transfer of the fertilized oocytes to the uterus for implantation and maturation. Each stage must be carefully controlled via the administration of medications. At each stage, there are different protocols for the use of these drugs, and the most appropriate pharmacologic regimen and therapeutic intervention are chosen after a thorough pretreatment evaluation and an accurate diagnosis.1 Controlled ovarian stimulation is achieved with the use of gonadotropin-releasing hormone (GnRH) analogues and inhibitors of natural steroid hormones, such as clomiphene citrate, recombinant follicle-stimulating hormone (FSH), and luteinizing hormone (LH).

Generally, the induction stage requires daily monitoring of serum estradiol levels and periodic transvaginal ultrasonography.1 If the protocol involves the use of GnRH agonists for pituitary downregulation, these agents are initiated in the luteal phase of the cycle, prior to ovulation induction.1 With the flare protocol, the GnRH agonist is initiated when gonadotropin therapy begins. To stimulate the ovaries, clomiphene or gonadotropin is initiated after the onset of menses. Once the minimum criteria for an ovulation trigger are reached, ovulation is induced, usually with the use of human chorionic gonadotropin (hCG) or a GnRH agonist. For most programs, the minimum criteria to induce ovulation are the presence of three ovarian follicles that are 1.7 to 2 cm in diameter and an estradiol level of 500 ng/L. The number of ovarian follicles and the ovarian volume are monitored via ultrasonography. The oocytes are removed from the follicles by aspiration and incubated with sperm to enable fertilization. Between 48 and 72 hours later, cleaving embryos are transferred to the uterus, and luteal support—usually involving the use of progesterone—is initiated to promote successful embryonic implantation.1,2,4,6

Pituitary Downregulation

In the 1980s, the addition of GnRH agonists to stimulate the ovary and enable oocyte retrieval prior to the initiation of gonadotropin therapy resulted in increased pregnancy rates per cycle. This method has been improved over the years, with current pharmacologic regimens and retrieval techniques yielding large numbers of oocytes.1 GnRH agonists and, more recently, GnRH antagonists are used to initiate pituitary downregulation.

A GnRH agonist regimen may be long (2 weeks), short (8-10 days), or ultrashort (3 days). A Cochrane systematic review comparing long GnRH-agonist protocols with short GnRH-agonist protocols found no difference in live-birth and ongoing-pregnancy rates. However, there was moderate evidence of higher clinical-pregnancy rates in the long-protocol group.6

Controlled Ovarian Hyperstimulation

A number of different agents are used to achieve controlled ovarian hyperstimulation. These include clomiphene, GnRH analogues, menotropins, urofollitropin, highly purified FSH, and recombinant human FSH (rh-FSH).

Clomiphene: Clomiphene is a racemic mixture of the geometric isomers enclomiphene and zuclomiphene that binds to estrogen receptors and induces ovulation by increasing the output of pituitary gonadotropins. Clomiphene occupies estrogen receptors much longer than estrogen itself does, thereby lessening the number of available receptors, which the hypothalamus interprets as a drop in estrogen levels. Consequently, negative feedback of estrogen on GnRH release is inhibited, which promotes a rise in circulating levels of LH and FSH. LH and FSH stimulate the ovaries, leading to ovulation, maturation of the ovarian follicle, and the development and function of the corpus luteum.1

Clomiphene, which is readily absorbed from the gastrointestinal tract, is administered at 50 mg orally once daily for 5 days, starting on day 5 of the menstrual cycle.7 This regimen may be repeated for up to two more courses, each given 30 days apart, until the patient responds. If the patient does not respond to the first course, the dosage may be increased to 100 mg; however, it is important to note that adverse effects are dose-related, and therefore the lowest possible dosage should be maintained. Patients who do not respond after three courses should be reassessed. The onset of pharmacologic activity is seen in 5 to 10 days, and peak plasma concentrations are observed in about 6.5 hours. Clomiphene is enterohepatically circulated, and its metabolites are excreted primarily in the feces via biliary elimination.1 Roughly one-half of the drug is excreted within 5 days, but the drug remains detectable in the feces for up to 6 weeks.8

Although clomiphene limits the number of oocytes, it cannot be used alongside a GnRH analogue to avoid premature luteinization.1 Its use is contraindicated in liver disease, abnormal uterine bleeding of unknown cause, and pregnancy. Clomiphene should be used with caution in patients with polycystic ovary syndrome (PCOS) because of their increased sensitivity to normal doses of clomiphene and their risk for an exaggerated response.7,8

Pharmacists should caution patients who are taking clomiphene about the possibility of blurred vision and should advise them against driving if this occurs. Patients should be reassured that symptoms of visual disturbance will resolve upon discontinuation of the drug. Patients may also experience hot flushes and ovarian enlargement. In the latter case, patients should be advised to avoid any activities that may cause trauma to the ovaries, such as pelvic examinations, sexual intercourse, and physical exercise.1

GnRH Analogues: GnRH analogues include human menopausal gonadotropin (hMG; also known as menotropins), urofollitropin, highly purified FSH, rh-FSH, and genetically engineered FSH. These agents stimulate ovarian follicular production in women without primary ovarian failure and result in follicular growth and maturation. However, they have a narrow therapeutic window ranging from no effect to ovarian hyperstimulation syndrome (OHSS).1

GnRH analogues should not be used in patients with primary ovarian failure that can be detected by high levels of FSH. GnRH analogues are also contraindicated in patients with overt thyroid or adrenal dysfunction, pituitary tumors, abnormal uterine bleeding of unknown origins, ovarian enlargement (not caused by PCOS), or previous hypersensitivity to any of these agents.9 Patients should be warned that the use of GnRH analogues can lead to OHSS and multiple births. Since their use leads to an increased risk of multiple pregnancies and spontaneous abortions, GnRH analogues should be used with caution and by experienced providers.

The pharmacist should ascertain that the patient fully understands how to inject the medication correctly. Furthermore, to reduce injection-site irritation, the patient should be advised to rotate injection sites and to change needles after drawing up menotropins and before an injection. If the patient experiences irritation at the site of injection, she should be advised to apply moist heat to the area.1,9

Other common adverse effects include abdominal cramps, abdominal swelling, abdominal pain, and headache. Since there have been reports of hypercoagulability in cerebral infarction related to OHSS, caution should be exercised when using GnRH analogues in patients who are predisposed to coagulation disorders.1

Menotropins: Menotropins are a mixture of FSH and LH purified from the urine of menopausal donors. Menotropins are available as Repronex or Menopur, both of which are SC injections containing 75 IU each of FSH and LH per vial.10,11 Repronex may also be administered IM. Repronex is produced via a 24-step purification process, and the method for extracting Menopur is even more complex.12 Menotropins, in conjunction with hCG, are indicated for multiple follicular development (controlled ovarian stimulation) and ovulation induction in patients who have previously received pituitary suppression.10 A study that compared SC administration of the two drugs found that Menopur had a better safety and tolerability profile compared with Repronex.13

The initial dosage of Menopur is 225 IU daily; after 5 days, adjustments of no more than 150 IU per adjustment may be made.11 Repronex may be initiated at a dosage of 225 IU, and adjustments of 75 to 150 IU may be made every 2 days. The maximum daily dose of Repronex should not exceed 450 IU, and use beyond 12 days is not recommended.10

Urofollitropin: This agent, the second generation of GnRH analogues, contains a highly purified preparation of human FSH and a minimal amount of LH. It is used in conjunction with hCG to produce ovulation in women who have previously undergone pituitary suppression.12 Urofollitropin is also indicated for the development of multiple follicles as part of an ART cycle in ovulatory women who have previously undergone pituitary suppression. The available brand is Bravelle, which provides 75 IU per SC or IM injection.12 The recommended dosage is 225 IU daily for 5 days. Adjustments to the dosage may be made once every 2 days and should not exceed 75 to 150 IU per adjustment. The maximum daily dose is 450 IU per day.

Highly Purified FSH: Highly purified FSH is a third-generation agent that contains more FSH than urofollitropin. It is administered SC rather than IM and is as effective as follitropin in achieving ovulation induction and pregnancy.1 Fertinex (EMD Serono) is no longer marketed in the United States, but generic versions are still available.

rh-FSH: This fourth-generation agent, which is manufactured via recombinant DNA technology, consists of two noncovalently linked, nonidentical glycoproteins designated as the alpha- and  beta-subunits.14 rh-FSH is free of LH and offers better batch-to-batch consistency than older FSH products. It is marketed as Gonal-f RFF, a sterile, lyophilized powder for SC injection after reconstitution. Each Gonal-f RFF single-dose vial contains 82 IU (6 mcg) follitropin alfa and delivers 75 IU. The pharmacokinetics of rh-FSH is similar to that of urofollitropin. Gonal-f RFF should be initiated at 225 to 300 IU daily SC administered for 5 days. The dosage may be adjusted by 75 to 150 IU per day, every 3 to 5 days, up to a maximum of 450 IU/day.15 Since rh-FSH contains <1% of contaminant proteins, most patients experience little to no pain at the site of injection. However, rH FSH is associated with the potential for immunogenicity.1

Induction of Ovulation

In IVF, ovulation can be induced with use of hCG, a hormone that replicates the effect of an LH surge in the normal menstrual cycle. In the U.S., Novarel is the brand indicated for this purpose. It is administered by the patient as an IM injection 1 day after the last day of menotropins or any other gonadotropin analogue. Each vial of Novarel contains 10,000 IU, and the dosage ranges from 5,000 and 10,000 IU.15 Novarel is associated with nausea, vomiting, abdominal pain, tiredness, headache, injection-site reactions, irritability, depression, edema, restlessness, and gynecomastia. It also may result in OHSS.

Luteal-Phase Support

The luteal phase, which is the second half of the menstrual cycle, begins with the formation of the corpus luteum and ends with either pregnancy or menstruation. Progesterone is the primary hormone at this stage, and since the pituitary is downregulated earlier in the cycle during IVF treatment, support is required.16 Support is usually in the form of progesterone supplementation, which has been shown to improve implantation and pregnancy rates. hCG supplementation also may be employed; however, since it is associated with OHSS, hCG is not the first choice.16

Typically, progesterone is initiated on the evening following egg retrieval. It is usually given IM or as a vaginal insert since, if administered orally, it can be broken down in the gastrointestinal tract.16 Support is continued for a minimum of 30 days after laboratory evidence of pregnancy is confirmed. The vaginal insert has been shown to be just as efficacious as IM injection and is better tolerated by patients. Women taking progesterone may experience adverse effects such as headache, breast tenderness, and vaginal irritation, burning, and slight bleeding.16

Further Reading

Various stimulation protocols have been introduced for controlled ovarian hyperstimulation of patients undergoing IVF. Because the details of these protocols are beyond the scope of this article, the interested reader is referred to these useful reviews: 1) Shrestha D, La X, Feng HL. Comparison of different stimulation protocols used in in vitro fertilization: a review. Ann Transl Med. 2015;3:137; and 2) Pacchiarotti A, Selman H, Valeri C, et al. Ovarian stimulation protocol in IVF: an up-to-date review of the literature. Curr Pharm Biotechnol. 2016;17:303-315.

Conclusion

IVF has been used successfully over many years. Because IVF involves the interplay of a number of drugs that need to be carefully administered, clinical pharmacists should be included as an active part of the IVF healthcare team. The pharmacist can advise the healthcare team not only on the choice of drug, but also on appropriate dosing, reconstitution (where required), and administration, particularly for GnRH analogues that may be self-administered.

REFERENCES

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