Effect of Intramuscular Progesterone Supplementation on Clinical and Ongoing Pregnancy Rates in Patients With Low Serum Progesterone Levels on the Day of Embryo Transfer in Artificial Frozen Cycles

Cryopreservation of frozen-thawed embryos has become a cardinal procedure in assisted reproductive therapies. This can be attributed to the development of the vitrification process and the improvement of embryo survival rates after thawing, leading to the progressive increase in the use of frozen embryo transfer (FET).

The need for FET has also increased greatly due to the implementation of a single embryo transfer policy in many areas of the world to reduce multiple pregnancies. This has led to an increase in surplus embryos derived from ovarian stimulation cycles. Moreover, although the 'freeze all' technique or elective embryo cryopreservation was mainly developed for patients with an increased risk of developing ovarian hyperstimulation syndrome, its use has now been extended to cover other indications, such as cycles involving pre-implantation genetic diagnosis, late-follicular progesterone elevation and embryo-endometrial asynchrony.

Despite this increased need for FET, there still exists debate over the best method to implement the practice. The two most common used treatment regimens to prepare the endometrium for embryo transfer are the so-called natural cycle (NC) and the hormone replacement therapy (HRT) cycle.

In a NC FET, there is no medical intervention apart from ultrasound monitoring during the proliferative phase, to schedule the transfer when the endometrium is synchronized to the developmental stage of the embryo. Although the advantage is the absence of estrogen supplementation, this protocol entails more frequent visits to the clinic and less cycle control. Despite this, there is still an ongoing debate whether frozen embryos transferred in a 'more physiologic' non-stimulated endometrium, may not only result in higher pregnancy rates, but also potentially decrease maternal and neonatal morbidity.

On the other hand, in the HRT cycle, also referred to as an artificial cycle, exogenous administration of estrogens and progesterone is used to mimic a natural cycle and therefore endometrial development. Although originally developed to allow embryo transfers in recipients of donated oocytes, the HRT protocol has proven to be successful in the general population as well.

The advantage of this protocol is the easy scheduling and minimal cycle monitoring. There are however, potential disadvantages associated with its widespread usage, including the increased expense and risks of estrogen supplementation such as thromboembolic events.

Generally speaking, in HRT cycles, progesterone supplementation begins once the proliferation of the endometrium with the administration of estrogens is considered sufficient. Progesterone is initiated to promote the final phase of endometrial preparation prior to embryo transfer, however, there is little agreement on the ideal route or dose of progesterone supplementation itself.

As regards the route of administration, when compared to intramuscular (IM) injections, patients seem to prefer the vaginal route owing to its quick, easy and painless administration. Despite this, there is limited data comparing IM versus vaginal progesterone administration, with some being in favour of the IM route and others showing no significant differences in terms of outcome.

However, the more recent focus on intramuscular rather than the traditional transvaginal progesterone supplementation, stems from newer mounting evidence that transvaginal supplementation not only increases vaginal discharge, but also has a limited effect in increasing serum progesterone levels.

Boynukalin et al., 2019 explored the idea of intramuscular progesterone supplementation in HRT FET cycles further, by substituting the traditional vaginal progesterone with 100mg of daily IM progesterone during endometrial preparation and thereafter till the 10th week of pregnancy. They found that the mean progesterone level on the day of ET was significantly higher in patients who later had an ongoing pregnancy (28 ng/ml) than those who did not have an ongoing pregnancy (16.4 ng/ml) with a p-value of 0.039. They did however conclude, that further investigation is needed for the individualization of intramuscular progesterone doses to reach optimal pregnancy rates.

Thus, more attention has been given recently to measuring serum progesterone during HRT FET cycles. Kofinas et al., 2015 suggested that progesterone levels >20 ng/ml (possibly due to an escape ovulation and subsequent embryo-endometrial asynchrony) on the day of transfer have been associated with decreased ongoing pregnancy and live birth rates. On the other hand, Yovich, et al., 2015 proposed an optimal mid-luteal progesterone range between 22 and 31 ng/ml.

Most recently, Labarta et al., 2017 investigated the relationship between serum progesterone levels on the day of embryo transfer (ET) and ongoing pregnancy rate (OPR). Their study recommended a minimum serum progesterone threshold (9.2 ng/ml) to optimize OPR in artificial cycles using transvaginal progesterone and this value could theoretically be used to decide if ET should be postponed or not.

Extrapolating from this data, we intend to investigate whether intramuscular progesterone supplementation can help improve OPR rates in the aforementioned patients with decreased serum progesterone on the day of ET. In other words, we intend to investigate further the concept of individualizing luteal phase support in HRT FET cycles.