An e-newsletter focusing on challenging case studies

Progesterone use
in assisted reproductive
technology

Read the following case study and earn

Case study presented by

FREE 0.5 CME/CE CREDIT Valerie L. Baker, MD
Medical Director
Expiration date: July 31, 2009 Stanford Fertility & Reproductive
Medicine Center, Stanford, CA
Estimated time to complete activity: 0.5 hour
Target: Physicians and nurse practitioners
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.

Researchers found higher

Discussion ongoing pregnancy rates
after embryo transfer with
Q. What is the purpose of using progesterone during an IVF cycle? progesterone compared
with placebo or no
A. Progesterone is required for the success of early pregnancy. If the corpus treatment
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 When oral progesterone is
not found a difference in efficacy between oral and other routes of administration, used vaginally, usual doses
2 randomized controlled trials found lower implantation rates, lower pregnancy
for luteal phase support are
rates, and/or higher miscarriage rates in women receiving oral compared with IM
or vaginal progesterone.1 200 to 600 mg/day
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 Vaginal progesterone is
used vaginally off-label during IVF cycles. easier to use
than IM preparations, but
Data are limited regarding the optimal dose of progesterone for luteal-phase the doses are more
support. The usual doses for luteal-phase support are 200 to 600 mg/day with frequent
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.

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References
1. Practice Committee of the American Society for Reproductive Medicine. Progesterone
supplementation during the luteal phase and in early pregnancy in the treatment of infertility: an
educational bulletin. Fertil Steril 2008;89:789-92.

2. Daya S, Gunby J. Luteal phase support in assisted reproduction cycles [review]. Cochrane
Database Syst Rev 2004;(3):CD004830.

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