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
Condition: Serum Progesterone Levels; Progesterone Supplementation; Frozen Embryo Transfer; Clinical Pregnancy Rates; Ongoing Pregnancy Rates
Study type: Interventional

Summary: 
      The aim of this study is to investigate whether intramuscular progesterone supplementation
      will improve clinical pregnancy rates and ongoing pregnancy rates in patients with decreased
      serum progesterone levels on the day of embryo transfer in artificial frozen cycles.
    

Detailed description: 
      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.
    

Intervention name(s): Twice-daily transvaginal progesterone supplementation; Twice-weekly intramuscular + Twice-daily transvaginal progesterone supplementation
Intervention type(s): Drug; Drug
Intervention description(s): Patients with serum progesterone levels >9.2 ng/ml on the day of embryo transfer in artificial frozen cycles will receive the traditional twice-daily vaginal progesterone supplementation till 12 weeks gestation.; Patients with serum progesterone levels <9.2 ng/ml on the day of embryo transfer in artificial frozen cycles will receive the twice-daily vaginal progesterone in addition to twice-weekly intramuscular progesterone supplementation till 12 weeks gestation.
Intervention MeSH terms: Progesterone
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients undergoing frozen cycles following ICSI will receive artificial endometrial preparation from day 2/3 of their cycle in the form of 2mg Estradiol Valerate pills thrice daily for 7-10 days. After confirming endometrial thickness > 7mm via TVS, progesterone supplementation will start via Prontogest® 400mg vaginal pessaries twice daily for 5 days, ending with the day of embryo transfer (ET).
On the morning of ET, serum progesterone will be measured and if the value is over 9.2ng/ml, only the traditional twice daily vaginal progesterone will be resumed until 12 weeks gestation. If the value is under 9.2 ng/ml, intramuscular progesterone supplementation with Prontogest® 100mg will be added in twice-weekly doses (every 3 days) to the vaginal supplementation.
Quantitative β-hcg 2 weeks after ET to detect chemical pregnancies. Ultrasound 4 weeks after ET to detect clinical pregnancies. Ultrasound repeated at 12 weeks to confirm ongoing pregnancy rates.
Masking: None (Open Label)
Primary purpose: Other