Luteal support

Luteal support is the administration of medication, generally progesterone, progestins, hCG or GnRH agonists, to increase the success rate of implantation and early embryogenesis, thereby complementing and/or supporting the function of the corpus luteum. It can be combined with for example in vitro fertilization and ovulation induction.

Progesterone appears to be the best method of providing luteal phase support, with a relatively higher live birth rate than placebo, and a lower risk of ovarian hyperstimulation syndrome (OHSS) than hCG.[1] Addition of other substances such as estrogen or hCG does not seem to improve outcomes.[1]

Progesterone and progestins

The live birth rate is significantly higher with progesterone for luteal support in IVF cycles with or without intracytoplasmic sperm injection (ICSI).[2][1] Co-treatment with GnRH agonists further improves outcomes,[1] by a live birth rate RD of +16% (95% confidence interval +10 to +22%).[3]

Routes and formulations

There is no evidence of any route of administration of progesterone or progestins being more beneficial than others for luteal support.[1] The main ones are:

Oral formulations for luteal support
Dydrogesterone10 mg 3 times daily,[4] or
20 mg twice daily.[5]
Progesterone200mg, 3-4 times daily[6]
Desogestrel450μg once per day.[7]
  • Oral administration of progesterone or progestin pills. Oral administration of progestins provides at least similar live birth rate than vaginal progesterone capsules when used for luteal support in embryo transfer, with no evidence of increased risk of miscarriage.[4][8]
  • Intravaginal administration of gel, tablets or other inserts, such as endometrin. This was the most commonly used medication for luteal support in an Israeli survey in 2013, used without adjunctive medication in 77% of cases, mainly as tablets.[9]
  • Intramuscular administration. Daily intramuscular injections of progesterone-in-oil (PIO) have been the standard route of administration,[6] but are not FDA-approved for use in pregnancy.

Time of initiation

The time for beginning luteal support can be put in relation to various events:

  • In IVF, generally somewhere between the evening of oocyte retrieval and day 3 after oocyte retrieval, with weak evidence indicating that 2 days after oocyte retrieval may be optimal.[10]
  • In artificial insemination, luteal support is generally started on the day of insemination, or the day after.[11]

Duration

Luteal support given for a shorter duration than 7 weeks results in an increased risk of miscarriage in women with a dysfunctional corpus luteum (as can be diagnosed by blood tests for endogenous progesterone).[12] In general, however, luteal support can safely be discontinued at the time of a positive pregnancy test (approximately 2 weeks after fertilization).[7]

Other substances tested in luteal phase

The addition of estrogen or hCG as adjunctives to progesterone do not appear to affect outcomes pregnancy rate and live birth rate in IVF.[1] In fact, luteal support with human chorionic gonadotropin (hCG) alone or as a supplement to progesterone has been associated with a higher risk of ovarian hyperstimulation syndrome (OHSS).[2] Low molecular weight heparin as luteal support may improve the live birth rate but has substantial side effects and has no reliable data on long-term effects.[1] Glucocorticoids such as cortisol has limited evidence of efficacy as luteal support.[1]

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References
  1. Farquhar, Cindy; Marjoribanks, Jane (2018). "Assisted reproductive technology: an overview of Cochrane Reviews". Cochrane Database of Systematic Reviews. 8: CD010537. doi:10.1002/14651858.CD010537.pub5. ISSN 1465-1858. PMC 6953328. PMID 30117155.
  2. Van Der Linden, M.; Buckingham, K.; Farquhar, C.; Kremer, J. A. M.; Metwally, M. (2012). "Luteal phase support in assisted reproduction cycles". Human Reproduction Update. 18 (5): 473. doi:10.1093/humupd/dms017.
  3. Kyrou, D.; Kolibianakis, E. M.; Fatemi, H. M.; Tarlatzi, T. B.; Devroey, P.; Tarlatzis, B. C. (2011). "Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: A systematic review and meta-analysis". Human Reproduction Update. 17 (6): 734–740. doi:10.1093/humupd/dmr029. PMID 21733980.
  4. Barbosa, Marina Wanderley Paes; Valadares, Natália Paes Barbosa; Barbosa, Antônio César Paes; Amaral, Adelino Silva; Iglesias, José Rubens; Nastri, Carolina Oliveira; Martins, Wellington de Paula; Nakagawa, Hitomi Miura (2018). "Oral dydrogesterone vs. vaginal progesterone capsules for luteal-phase support in women undergoing embryo transfer: a systematic review and meta-analysis". JBRA Assisted Reproduction. 22: 148–156. doi:10.5935/1518-0557.20180018. ISSN 1518-0557. PMC 5982562. PMID 29488367.
  5. Rashidi, Batool Hossein; Ghazizadeh, Mahya; Tehrani Nejad, Ensieh Shahrokh; Bagheri, Maryam; Gorginzadeh, Mansoureh (2016). "Oral dydrogesterone for luteal support in frozen-thawed embryo transfer artificial cycles: A pilot randomized controlled trial". Asian Pacific Journal of Reproduction. 5 (6): 490–494. doi:10.1016/j.apjr.2016.10.002. ISSN 2305-0500.
  6. Janelle Luk, MD; Pasquale Patrizio. "Luteal Phase Progesterone Support in ART/IVF". Medscape. Retrieved 2020-01-14.CS1 maint: multiple names: authors list (link)
  7. Wiweko, Budi (2016). "Luteal Phase Support in Controlled Ovarian Hyperstimulation". Springer: 135–144. doi:10.1007/978-81-322-1121-1_11.
  8. Griesinger, Georg; Blockeel, Christophe; T. Sukhikh, Gennady; Patki, Ameet; Dhorepatil, Bharati; Yang, Dong-Zi; Chen, Zi-Jiang; Kahler, Elke; Pexman-Fieth, Claire; Tournaye, Herman (2018). "Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial". Human Reproduction. doi:10.1093/humrep/dey306. ISSN 0268-1161.
  9. Vaisbuch, Edi; de Ziegler, Dominique; Leong, Milton; Weissman, Ariel; Shoham, Zeev (2014). "Luteal-phase support in assisted reproduction treatment: real-life practices reported worldwide by an updated website-based survey". Reproductive BioMedicine Online. 28 (3): 330–335. doi:10.1016/j.rbmo.2013.10.022. ISSN 1472-6483. PMID 24447959.
  10. Connell MT, Szatkowski JM, Terry N, DeCherney AH, Propst AM, Hill MJ (2015). "Timing luteal support in assisted reproductive technology: a systematic review". Fertil Steril. 103 (4): 939–946.e3. doi:10.1016/j.fertnstert.2014.12.125. PMC 4385437. PMID 25638420.
  11. Green, Katherine A.; Zolton, Jessica R.; Schermerhorn, Sophia M.V.; Lewis, Terrence D.; Healy, Mae W.; Terry, Nancy; DeCherney, Alan H.; Hill, Micah J. (2017). "Progesterone luteal support after ovulation induction and intrauterine insemination: an updated systematic review and meta-analysis". Fertility and Sterility. 107 (4): 924–933.e5. doi:10.1016/j.fertnstert.2017.01.011. ISSN 0015-0282.
  12. Lien, Y.R.; Jou, G.; Yang, P.; Chen, S. (2015). "The duration of luteal phase support by progesterone in fresh transfer cycles can be determined by corpus luteum rescue or not". Fertility and Sterility. 104 (3): e344–e345. doi:10.1016/j.fertnstert.2015.07.1074. ISSN 0015-0282.
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