Vaginal versus Intramuscular Progesterone

Written by: Katherine Moran, MD, MBA

Indications for Progesterone during IVF

• Progesterone supplementation is needed to prepare the endometrium for embryo transfer and for support of the pregnancy following embryo transfer.

• Progesterone is usually continued throughout the first trimester of pregnancy - up to 8 to 10 weeks. [1,2]

Types of Progesterone Supplements by Type of Embryo Transfer

• Fresh Embryo Transfer [3]

  • Option 1: vaginal progesterone suppository 100 mg two times a day (Endometrin)

  • Option 2: vaginal progesterone gel 90 mg once daily (Crinone)

• Frozen Embryo Transfer [4,5]

  • Option 1: Intramuscular (IM) progesterone 50-100mg daily

  • Option 2: IM progesterone 50-100mg every 3 days plus 200mg vaginal progesterone suppository twice daily

  • Option 3: 100mg vaginal progesterone suppository three times daily or 200mg twice daily

  • Option 4: vaginal progesterone gel 90 mg twice daily

Studies Assessing Luteal Phase Support for Fresh Embryo Transfers

• A 2022 review article determined progesterone is essential to successful IVF for fresh cycles using hCG trigger to protect against luteal phase deficiency. Most providers use vaginal progesterone, given its ease of use, but IM progesterone is also used by some. [6]

• A study performed in 2015 supports the use of estrogen in addition to progesterone for patients receiving a dual trigger (Lupron and hCG) [7]

Studies Comparing Vaginal versus Intramuscular Progesterone for Luteal Phase Support

• Luteal phase support refers to hormonal support with progesterone for implantation

• Luteal support for Fresh Embryo Transfers [8]

  • hCG trigger alone: only vaginal progesterone is needed

  • Lupron + hCG trigger: both progesterone and estrogen are used [7]

  • Fresh transfer is not performed after Lupron-only trigger as this does not offer enough luteal support and is associated with lower pregnancy rates. [9,10,11]

• Luteal support for Programmed FET

  • In a 2012 retrospective cohort study, pregnancy and live birth rates were higher with IM progesterone versus vaginal progesterone (Crinone) for day 3 FET. [12]

  • In a 2014 retrospective study, pregnancy and live birth rates were similar for IM and vaginal progesterone for day 5 FET. [13]

  • A 2021 randomized control trial compared daily IM progesterone versus IM injections every 3 days with vaginal progesterone twice daily versus vaginal progesterone alone twice daily. They found higher live birth rates and lower miscarriage rates for both IM progesterone groups compared to vaginal progesterone. [14]

• Luteal support for natural FET

  • Vaginal progesterone has been determined to be sufficient for natural FET cycles. [15]

Side Effects

• IM Progesterone

  • Most common concern with IM use is discomfort and pain with administration. Some ways to minimize discomfort include [16]:

    • Applying heat the area prior to injection

    • Warming the progesterone in oil using a warm pack

    • Massaging the injection site after injection

    • Typically associated with less vaginal bleeding compared to vaginal progesterone [4]

• Vaginal Progesterone

  • Perineal irritation and/or vaginal discharge [17]

  • Some patients can have some vaginal spotting due to irritation of the vagina or cervix.

Summary

In summary there have been many studies comparing vaginal versus IM progesterone in addition to combinations of the two methods of delivery. Vaginal progesterone is sufficient for luteal support following fresh embryo transfer. IM progesterone injections may be associated with more discomfort during administration; however, this method typically has been shown to be superior to vaginal progesterone when used for frozen embryo transfer either daily or every third day with vaginal progesterone daily.