Optimal Length of Progesterone Supplementation Before the Transfer of Cryopreserved(Frozen)-Thawed Embryos in an Artificial Cycle With Exogenous Estrogen and Progesterone.

Cryopreserved-thawed embryos are often replaced in an artificial cycle, in which the endometrium is prepared by exogenous estrogen and progesterone with or without the use of GnRH agonist downregulation. The correct duration for exposure to progesterone is still not well established. To date, there are no prospective randomized trials available, comparing different durations of progesterone supplementation before the date of transfer, with regard to treatment outcome (Nawroth).

The purpose is to transfer the embryo during the 'window of implantation', what is defined as the period during which the uterus is receptive for implantation of the free-lying blastocyst. This has been a subject of debate since many years (Bourgain et al, 2007).

Succesful implantation requires a co-ordinated series of events allowing a timely dialogue between a receptive endometrium and the intrusive blastocyst (Tabibzadeh, 1998). The period of receptivity is thought to be 3 days in human (Rogers et al, 1989; Yoshinaga, 1988; Psychoyos, 1993; Harper, 1992). It is suggested that blastocyst apposition begins about day LH+6 and is completed by day LH+10 (Lessey, 2000).

A number of structural and functional endometrial changes have been suggested to play a role in the implantation process: the formation of luminal epithelial pinopodes (Enders et al, 1973), expression of adhesion molecules and growth factors and cytokines (Lessey, 2000). Most of them are related directly or indirectly to progesterone secretion and influence on the endometrium.

In the Centre of Reproductive Medicine of the Brussels University Hospital, we start progesterone supplementation 7 days before the transfer of a day 5 embryo. In order to mimic the natural cycle, since progesterone starts to rise 2 to 3 days before ovulation, due to the LH-stimulated production by the peripheral granulosa cells (Speroff). In fresh IVF-cycles, progesterone is started from the day of oocyte retrieval. HCG administration in fresh cycles will lead to an increase in progesterone levels and therefore, endometrium will progress quickly, compared with frozen-thawed cycles which are hormone supplemented (Nawroth).

Our approach in artificial FrET cycles results in a pregnancy rate of 26%.

In other centres, progesterone supplementation is generally started 5 days before the embryo transfer. Recent studies show pregnancy rates up to 40.5% (Givens CR et al, 2009), using this approach.

In this trial, we want to determine the optimal duration of progesterone supplementation.

Inclusion criteria

• Artificial cycles, in which a frozen-thawed day 5 embryo is replaced.
• Signed informed consent.
• Normal transvaginal ultrasound at screening, without evidence of clinically significant abnormality consistent with finding adequate for ART with respect to uterus and adnexa.
• Embryos must be frozen by vitrification technique (cfr supra).
• Single or dual embryo transfer.
• Recipients of oocyte donation cycles may be included.

Exclusion criteria

• Known allergic reactions to progesterone products.
• Intake of experimental drug within 30 days prior to study start.
• Contraindication for pregnancy.
• Embryos of women above 39 years of age at the time of embryo freezing.