Use of progesterone as luteal phase support after fresh embryo transfer 

In ART cycles, embryo quality as well as the receptivity of the endometrium play crucial roles in clinical outcomes. Progesterone prepares the endometrium for pregnancy by stimulating proliferation of the lining of the uterus to prepare for implantation. This happens in response to human chorionic gonadotropin (hCG) produced by the corpus luteum in the luteal phase of the menstrual cycle. Progesterone is also essential in the maintenance of a pregnancy.^4,5,6  

In ART, luteal function may be compromised. It has been demonstrated that luteal phase deficiency occurs in a long GnRh-agonist protocol and that corpus luteum deficiency as a consequence of ART in general, is partially caused by aspiration of the granulosa cells and the use of hCG.⁷   

The severity of the deficiency seems to be in relation to the vigorousness and number of aspirations performed and therefore the number of granulosa cells that are dislodged from the membrane granulosa layer.⁷  

What is the optimal time to start and end luteal phase support? 

Low progesterone and/or hCG levels may result in a thin endometrium, which is associated with lower pregnancy rates. Luteal phase support with progesterone, hCG or gonadotropin‐releasing hormone (GnRH) are therefore required in ART to improve implantation and pregnancy rates.^4,8 

The optimal timing to start the luteal phase support (LPS) is between 24 and 72 hours after oocyte retrieval and should last at least until the pregnancy test is positive. Administration of progesterone is routine for LPS.⁵ 

Studies have shown that in normal pregnancies, the level of progesterone is 75% at the sixth week of pregnancy and further reduces to 50% and 25% at the 10th and 15th week of pregnancy, respectively. The production of progesterone by the placenta increases significantly after eight weeks of pregnancy, which is when the luteal-placental shift begins. Consequently, there is growing evidence that LPS can be discontinued by the 10th week of pregnancy in ART.⁵ 

Available administration routes of progesterone 

Progestins can be administered using various routes, either vaginally, intramuscularly (IM), rectally, orally, or subcutaneously, with differential impact on the pharmacokinetics of progestins.⁹ 

According to Blake and colleagues(2010), oral administration may be convenient, but progesterone is rapidly cleared by first-pass hepatic metabolism, which means systemic bioavailability of progesterone is significantly lower compared to progesterone via vaginal administration.¹⁰  

As a result of lower bioavailability, high doses of oral progesterone are needed, which are associated with side effects including drowsiness, flushing, and nausea.¹⁰  

Vaginal progesterone is associated with sustained plasma concentrations, greater bioavailability, and has been shown to provide significant levels of progesterone to the endometrial tissue, inducing secretory transformation.¹⁰ 

Furthermore, the pharmacokinetics of oral progesterone are influenced by food intake, which has been shown to limit efficacy in inducing an in-phase secretory endometrium, and less favourable ART outcomes.¹⁰ 

In 2007, the American Food and Drug Administration approved progesterone vaginal insert 100mg for use two or three times daily to support embryo implantation and early pregnancy as part of ART treatment for infertile women.¹¹ In South Africa, progesterone vaginal insert 100mg is approved for three times daily dosing. 

Pharmacokinetics of vaginal progesterone  

According to Blake and colleagues (2009), vaginal progesterone provides a more reliable delivery of progesterone than oral therapy.¹⁰ 

IM progesterone is rapidly absorbed and high plasma concentrations are generally achieved within two hours, and peak concentrations within eight hours. Daily injections for up to 12 weeks are needed – especially in patients with ovarian failure who lack any endogenous contributions - to maintain adequate progesterone levels.¹⁰ 

IM progesterone may lead to inflammatory reactions at the injection site, sterile abscesses, and possible infections. Although rare, severe complications may include haematomas and secondary nerve compression. According to Check, IM progesterone is therefore often not the patient's first choice.^9,10 

Vaginal progesterone avoids variable absorption and high first-pass hepatic metabolism, while also preventing the uncomfortable, often painful, IM injection.¹⁰  

Blake and colleagues (2010) conducted a randomised pharmacokinetic study to determine the profile of different daily dosage regimens of a micronised progesterone vaginal insert for luteal support in ART, compared to an intravaginal progesterone gel.¹⁰  

They found that progesterone serum concentrations increased rapidly following administration of the progesterone vaginal insert, producing higher peak concentrations (C_max), and clearing faster than the gel.¹⁰ 

Progesterone vaginal inserts reached steady state within the first two days (24–36 hours), much more rapidly than the gel, which had not reached steady state by five days. At five days, the progesterone vaginal treatments produced sustained progesterone concentrations exceeding 10mg/mL across 24 hours.¹⁰ 

How effective and safe are vaginal progesterone inserts? 

Doody and colleagues (2009) assessed the efficacy and safety of progesterone vaginal inserts for luteal support in ART. This was a multi-centre (24), randomised, open-label phase III clinical trial.¹² 

The day after oocyte retrieval, progesterone vaginal insert or gel was begun for luteal support and continued for up to 10 weeks of pregnancy. The primary outcome was biochemical, clinical, and ongoing pregnancy and live birth rates.¹² 

Their findings indicated that pregnancy rates were high, with biochemical rates exceeding 50%, clinical and ongoing rates 40%, and live birth rates at 35%–38%. The adverse event profiles were similar across groups.¹² 

What do women prefer?  

Beltsos and colleagues (2014) conducted a survey among women living with infertility who were given vaginal progesterone (100mg inserted vaginally two or three times daily, or progesterone in oil injections (50mg)) for luteal phase support during fresh IVF cycles, to determine which route they prefer.¹³ 

The questionnaire assessed the tolerability, convenience, and ease of use of the two routes. Most women commented on the convenience and ease of use of vaginal progesterone, while a majority of women who administered progesterone injections described experiencing pain.¹³  

Furthermore, their partners often indicated that they had experienced at least some anxiety regarding the administration of progesterone injections.¹³  

The most distinguishing difference between vaginal progesterone and progesterone injections in this study was the overall patient preference for vaginal progesterone. Despite the need to administer vaginal progesterone either twice a day or three times a day, 82.6% of the patients in the vaginal group found it ‘very’ or ‘somewhat convenient’ compared with 44.9% of women in the injections group.¹³ 

Beltsos and colleagues (2014) concluded that their survey support the findings of other similar reports that vaginal progesterone provides an easy-to-use and convenient method for providing the necessary luteal phase support for IVF cycles without the pain and inconvenience of daily progesterone injections. Moreover, ongoing pregnancy rates with vaginal progesterone were as good as the pregnancy rates with progesterone injections.¹³ 

References 

1. Critchley Moybin JA, Armstrong GM, Williams ARW. Physiology of the endometrium and regulation of menstruation. Physiological Reviews, 2020. 
2. Hazlina NHN, Morhayati MN, Arif NANM, et al. Worldwide prevalence, risk factors and psychological impact of infertility among women: a systematic review and meta-analysis. BMJ Open, 2022. 
3. Jain M, Singh M. Assisted Reproductive Technology (ART) Techniques. [Updated 2022 Jun 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. 
4. Van der Linde M, on behalf of the Cochrane Gynaecology and Fertility Group. Lutheal phase support for assisted reproduction cycles. The Cochrane Database of Systematic Reviews, 2015.  
5. Zhao J, Hao J, Li Y. Individualized luteal phase support after fresh embryo transfer: unanswered questions, a review. Reprod Health, 2022. 
6. Wanggren K, Granbom MD, Iliadis SI, et al. Progesterone supplementation in natural cycles improves live birth rates after embryo transfer of frozen-thawed embryos—a randomized controlled trial. Human Reproduction, 2022. 
7. Ghanem ME and Al-Boghdady LA. Luteal Phase Support in ART: An Update. Enhancing Success of Assisted Reproduction, 2012. https://www.intechopen.com/chapters/41085 
8. Eftekhar M, Mehrjardi SZ, Molaei B, et al. The correlation between endometrial thickness and pregnancy outcomes in fresh ART cycles with different age groups: a retrospective study. MEFSJ, 2020. 
9. Check JH. Luteal Phase Support in assisted reproductive technology treatment: focus on Endometrin® (progesterone) vaginal insert. Therapeutics and Clinical Risk Management, 2009. 
10. Blake EJ, Norris PM, Dorman SF, et al. Single and multidose pharmacokinetic study of a vaginal micronized progesterone insert (Endometrin) compared with vaginal gel in healthy reproductive aged female subjects. Fertility and Sterility, 2010. 
11. Press release. FDA Approves Ferring Pharmaceuticals' endometrin (R) for Luteal Phase Support in Assisted Reproductive Technology Treatment, 2007. https://www.biospace.com/article/releases/fda-approves-ferring-pharmaceuticals-endometrin-r-for-luteal-phase-support-in-assisted-reproductive-technology-treatment-/ 
12. Doody KJ, Schnell VL, Foulk RA, et al. Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertility and Sterility, 2009. 
13. Beltsos AN, Sanchez MD, Doodly KJ, et al. Patients’ administration preferences: progesterone vaginal insert (Endometrin®) compared to intramuscular progesterone for Luteal phase support. Reproductive Health, 2014.