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Case study presented by Valerie L. Baker, MD Medical Director Stanford Fertility & Reproductive Medicine Center, Stanford, CA

Progesterone use in assisted reproductive technology

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Supported by an educational grant from Solvay Pharmaceuticals, Inc.
Sponsored by the American Society for Reproductive Medicine.

When administering progesterone to support early pregnancy during in vitro fertilization (IVF), what protocols for initiating and continuing treatment should clinicians follow, in the absence of evidence?

Sarah is 39 years old, gravida 0, undergoing IVF for mild male factor infertility and diminished ovarian reserve. Three gonadotropin cycles with intrauterine insemination have failed. A recent saline infusion sonogram revealed a normal uterine cavity. Sarah has undergone an IVF cycle using a gonadotropin-releasing hormone (GnRH) antagonist, recombinant follicle-stimulating hormone (FSH), urinary human menopausal gonadotropin, and intramuscular (IM) progesterone. Unfortunately, no pregnancy occurred in this cycle, despite the transfer of 3 good-quality embryos.

Sarah found the IM progesterone shots administered by her husband very painful and stressful. She is concerned because her husband will be traveling frequently during their next cycle. However, she is willing to do whatever will give her the best chance of success.

Discussion

Q. What is the purpose of using progesterone during an IVF cycle?

A. Progesterone is required for the success of early pregnancy. If the corpus luteum is removed during the first 5 weeks after conception, the pregnancy will miscarry. By about 9 weeks’ gestation, the luteal-placental shift takes place: the trophoblast itself makes sufficient progesterone, and the pregnancy is no longer dependent on the corpus luteum.¹

There are several hypotheses explaining the need for progesterone administration during an IVF cycle. GnRH agonists and GnRH antagonists are commonly used to prevent ovulation. Either medication may suppress pituitary production of luteinizing hormone (LH), which is required for progesterone production. In addition, during oocyte retrieval, some of the granulosa cells lining the follicles are removed or disrupted, which may be another reason why luteal-phase supplementation is needed in an IVF cycle.

The most recent Cochrane review found higher ongoing pregnancy rates after embryo transfer with progesterone compared with placebo or no treatment,² and it is now routine to recommend luteal-phase support during an IVF cycle. Some clinicians also recommend progesterone supplementation during the natural cycle for women of more advanced age, like Sarah, but there are no solid data to support this practice.

Q.What is the “best” route for progesterone administration during an IVF cycle in terms of efficacy and side effect profile?

A. The “best” route of administration has not been clearly established. There are pros and cons associated with each route.

Oral preparations
Oral supplementation is not recommended because although some studies have not found a difference in efficacy between oral and other routes of administration, 2 randomized controlled trials found lower implantation rates, lower pregnancy rates, and/or higher miscarriage rates in women receiving oral compared with IM or vaginal progesterone.¹

Intramuscular progesterone
Preparations of IM progesterone are available using sesame oil, peanut oil, and more recently, ethyl oleate. The main downside of IM progesterone is local skin inflammation at the site of injection. At times, this reaction can be quite painful and can lead to induration that may persist for weeks after the injections are complete. There are also rare case reports of severe allergic reactions, including respiratory distress syndrome and pneumonitis, with the pneumonitis beginning 3 weeks after the first injection. Oil preparations containing progesterone have not been approved by the FDA for use as luteal-phase support for IVF cycles but have been widely used by IVF programs.

Vaginal preparations
Vaginal progesterone bypasses the initial metabolism in the liver and is therefore not associated with the sedating metabolites, which occur with oral preparations. Because the progesterone is first absorbed locally, intrauterine concentrations are high despite serum levels that are lower than with IM progesterone.

Vaginal progesterone may be administered using compounded suppositories, tablets containing micronized progesterone manufactured principally for oral use, 8% progesterone gel, or a micronized progesterone vaginal insert. Only the 8% gel and vaginal inserts are FDA-approved for luteal-phase support in IVF cycles. The micronized oral formulation available in Europe and the United States is used vaginally off-label during IVF cycles.

Data are limited regarding the optimal dose of progesterone for luteal-phase support. The usual doses for luteal-phase support are 200 to 600 mg/day with vaginal administration of the oral preparations. The FDA-approved doses for the vaginal preparations are 200 mg 2 to 3 times per day for the insert and 8% once daily for the vaginal gel. Less patient-to-patient variability in serum concentrations of progesterone was noted with the 3-times-per-day dosing.

The main side effects associated with vaginal preparations are vaginal irritation, discharge, and dyspareunia. The principal advantage of the vaginal preparations is that they are less painful than IM injections. IM injections may be difficult for a patient to administer herself, whereas vaginal preparations can be self-administered. However, vaginal preparations must be used 2 to 3 times per day, whereas IM progesterone is administered once daily when used for luteal-phase support.

Case study follow-up

Although Sarah had had local side effects from the IM progesterone, she chose it over a proposed vaginal preparation for her next cycle, based on her perception of potentially improved efficacy. However, when her husband began traveling for his job, she switched to a vaginal preparation and did achieve a pregnancy. Her physician told her she could safely discontinue progesterone at a gestation age of 8 weeks, but she chose to continue until the end of the first trimester.

This case underscores the fact that much of what we do with progesterone supplementation and assisted reproduction has evolved based on patient preferences and physician concerns, rather than on evidence.