Background: Progesterone, released by the corpus luteum, is essential to induce the secretory activity of the endometrium and facilitate embryo implantation. It is thought that low serum progesterone signals luteal phase deficiency, which has been linked with infertility and pregnancy loss. A recent systematic review suggested an association between serum progesterone levels and frozen embryo transfer (FET) treatment outcomes in patients undergoing assisted conception. However, most studies were retrospective and presented findings whose generalisability was limited.
Methods: ProFET was the largest multicentre prospective study to date investigating the association between serum progesterone and FET outcomes in an unselected population. Women undergoing FET were recruited from eight fertility clinics in the UK. Venepuncture was performed on the day of embryo transfer. Participants and personnel were blinded to progesterone levels. We conducted unadjusted and multivariable logistic regression analyses to investigate the association between serum progesterone levels and treatment outcomes. The primary outcome was the live birth rate per participant. The study was prospectively registered (NCT04170517).
Results: We recruited 402 women between January 2020 and February 2021. The mean (standard deviation) serum progesterone level was 14.9 (7.5) ng/ml. In comparison to women whose serum progesterone level was ≥7.8 ng/ml, those with lower progesterone (<7.8 ng/ml, 10th centile) experienced fewer live births (28.2% versus 40.0%, adjusted odds ratio [aOR] 0.44, 95% confidence interval [CI] 0.20 to 0.96, P = 0.04), lower odds of clinical pregnancy (30.8% versus 45.1%, aOR 0.41, 95% CI 0.19 to 0.89, P = 0.024) and a trend towards an increase in miscarriage rates (42.1% versus 28.7%, aOR 2.33, 95% CI 0.83 to 6.59, P = 0.11). The mean adjusted probability of live birth increased non-linearly from 36.3% (95% CI 28.8 to 43.9%) to 42.1% (95% CI 33.1 to 51.1%) as serum progesterone levels rose between the 10th and 90th deciles, although wide confidence intervals precluded the identification of an optimum range of progesterone levels associated with treatment success.
Conclusion: Our data showed that beyond a minimum critically important level, higher serum progesterone measurements were not confidently associated with a linear increase in the probability of live birth. Serum progesterone levels higher than the 90th centile may have been detrimental to treatment success, although this finding lacked statistical confidence. There is a need for high-quality interventional studies investigating whether additional progesterone supplementation in women with low serum progesterone results in non-inferior outcomes to those of women with normal serum progesterone.
