Rectal progesterone administration secures a high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol: a prospective interventional study

STUDY QUESTION: Can supplementation with rectal administration of progesterone secure high ongoing pregnancy rates (OPRs) in patients with low serum progesterone (P4) on the day of blastocyst transfer (ET)? SUMMARY ANSWER: Rectally administered progesterone commencing on the ET day secures high OPRs in patients with serum P4 levels below 35 nmol/l (11 ng/ml). WHAT IS KNOWN ALREADY: Low serum P4 levels at peri-implantation in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) cycles impact reproductive outcomes negatively. However, studies have shown that patients with low P4 after a standard vaginal progesterone treatment can obtain live birth rates (LBRs) comparable to patients with optimal P4 levels if they receive additional subcutaneous progesterone, starting around the day of blastocyst transfer. In contrast, increasing vaginal progesterone supplementation in low serum P4 patients does not increase LBR. Another route of administration rarely used in ART is the rectal route, despite the fact that progesterone is well absorbed and serum P4 levels reach a maximum level after similar to 2h. STUDY DESIGN, SIZE, DURATION: This prospective interventional study included a cohort of 488 HRT-FET cycles, in which a total of 374 patients had serum P4 levels >= 35 nmol/l (11 ng/ml) at ET, and 114 patients had serum P4 levels <35 nmol/l (11 ng/ml). The study was conducted from January 2020 to November 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients underwent HRT-FET in a public Fertility Clinic, and endometrial preparation included oral oestradiol (6 mg/24 h), followed by vaginal micronized progesterone, 400 mg/12 h. Blastocyst transfer and P4 measurements were performed on the sixth day of progesterone administration. In patients with serum P4 <35 nmol/l (11 ng/ml), 'rescue' was performed by rectal administration of progesterone (400 mg/12 h) starting that same day. In pregnant patients, rectal administration continued until Week 8 of gestation, and oestradiol and vaginal progesterone treatment continued until Week 10 of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 488 HRT-FET single blastocyst transfers, the mean age of the patients at oocyte retrieval (OR) was 30.9 +/- 4.6 years and the mean BMI at ET 25.1 +/- 3.5 kg/m(2). The mean serum P4 level after vaginal progesterone administration on the day of ET was 48.9 +/- 21.0 nmol/l (15.4 +/- 6.6 ng/ml), and a total of 23% (114/488) of the patients had a serum P4 level lower than 35 nmol/l (11 ng/ml). The overall, positive hCG rate, clinical pregnancy rate, OPR week 12, and total pregnancy loss rate were 66% (320/488), 54% (265/488), 45% (221/488), and 31% (99/320), respectively. There was no significant difference in either OPR week 12 or total pregnancy loss rate between patients with P4 >= 35 nmol/l (11 ng/ml) and patients with P4 <35 nmol/l, who received rescue in terms of rectally administered progesterone, 45% versus 46%, P = 0.77 and 30% versus 34%, P = 0.53, respectively. OPR did not differ whether patients had initially low P4 and rectal rescue or were above the P4 cut-off. Logistic regression analysis showed that only age at OR and blastocyst scoring correlated with OPR week 12, independently of other factors like BMI and vitrification day of blastocysts (Day 5 or 6). LIMITATIONS, REASONS FOR CAUTION: In this study, vaginal micronized progesterone pessaries, a solid pessary with progesterone suspended in vegetable hard fat, were used vaginally as well as rectally. It is unknown whether other vaginal progesterone products, such as capsules, gel, or tablet, could be used rectally with the same rescue effect. WIDER IMPLICATIONS OF THE FINDINGS: A substantial part of HRT-FET patients receiving vaginal progesterone treatment has low serum P4. Adding rectally administered progesterone in these patients increases the reproductive outcome. Importantly, rectal progesterone administration is considered convenient, and progesterone pessaries are easy to administer rectally and of low cost.