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July 31, 2009
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Target: Physicians, physician assistants and nurse practitioners
Supported by an educational grant from Solvay Pharmaceuticals,
Sponsored by the American Society for Reproductive Medicine.
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.
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
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 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
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
have not been approved by the FDA for use as luteal-phase support for IVF cycles
but have been widely used by IVF programs.
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
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.
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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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.
Case study presented by
Valerie L. Baker, MD
Stanford Fertility & Reproductive Medicine Center, Stanford, CA
found higher ongoing pregnancy rates
after embryo transfer with progesterone compared with placebo or no treatment
progesterone is used vaginally, usual doses for luteal phase support are
200 to 600 mg/day
Vaginal progesterone is easier to use
than IM preparations, but the doses are more frequent