Effectiveness of progesterone supplementation in women presenting low progesterone levels on the day of frozen embryo transfer: a randomised controlled trial | BMJ Open

Introduction

Progesterone is an essential hormone in the process of implantation and pregnancy maintenance. Its crucial roles include luteal phase support, modulation of maternal immune response, suppression of inflammatory response, reduction of uterine contractility and improvement of uteroplacental circulation.1 Progesterone is a steroid produced primarily by the corpus luteum and the placenta. An investigation conducted by Csapo et al2 showed that luteectomy in early pregnancies induced abortion. Progesterone is necessary to obtain a secretory phase transformation of the endometrium. During the luteal phase, it prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin (hCG).3 During conditions of insufficient progesterone, which is defined as a luteal phase defect, progesterone may not maintain normal secretory endometrium and may prevent normal embryo implantation and growth.4 A mid-luteal serum progesterone <10 ng/mL was established to predict a luteal phase defect.5

Nowadays, frozen-thawed embryo transfer (FET) is being performed worldwide due to several factors, including implementation of vitrification with an extremely high survival rate, prevention of ovarian hyperstimulation syndrome and avoiding the negative effect of late follicular elevating progesterone on embryo implantation.6 With regard to endometrium preparation in the FET cycles, no protocol is definitely better than the others.7 8 Hormonal replacement therapy (HRT) is a commonly used protocol8 due to its flexibility and convenience9 in programming the embryo transfer day and excellent results.10 In this method, oestrogen is administered from the beginning of the menstrual cycle to inhibit follicle stimulating hormone (FSH) intercycle rise and follicular growth, resulting in the corpus luteum not being formed. Exogenous progesterone administration may begin 2, 3 or 5 days before the scheduled day of transfer depending on the stage of the frozen embryos.

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Accumulating evidence has supported the importance of the level of serum progesterone at the time of embryo transfer in HRT FET cycles and recommended the need for individualised luteal support. Labarta et al11 showed that the rate of ongoing pregnancy was significantly lowered in the group of women with serum progesterone level <9.2 ng/mL on the day of embryo transfer compared with women with progesterone level >9.2 ng/mL. In a retrospective cohort study of Gaggiotti-Marre et al,12 low serum progesterone level (≤10.64 ng/mL) 1 day before FET was associated with a lower rate of live births following FET of euploid embryos. Similarly, Cédrin-Durnerin et al showed that serum progesterone level <10 ng/mL was observed in 37% of FET cycles and was associated with significantly lower rates of pregnancy (34% vs 48%, p=0.04) and live births (17% vs 31%, p=0.01).10 Thereafter, some studies have assessed the benefit of progesterone supplementation in FET cycles when the progesterone level was below the cut-off. In two recent studies of Yarali et al and Álvarez et al,13 14 25 mg subcutaneous progesterone was added if progesterone level 1 day before embryo transfer was below the cut-off. The rates of ongoing pregnancy were comparable between the progesterone supplementation group and the control group whose progesterone level was above the cut-off. Until now, there have been no randomised control trials assessing the effect of adding progesterone on the day of embryo transfer.

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Progesterone is most commonly administered as vaginal suppositories. Vaginal progesterone, with the first uterine pass effect,15 is absorbed through the vagina and transmitted primarily to the uterus and therefore achieves higher tissue levels than the oral, subcutaneous or intramuscular route.16 Moreover, it is painless, self-administered and rarely induce allergic reactions.16 It is recommended that a low level of serum progesterone after vaginal administration may be rescued by an addition of another route of progesterone.10 Most of the recent authors used intramuscular progesterone in their studies.13 14

This randomised controlled trial is designed to evaluate the effect of progesterone supplementation in patients with low serum progesterone level on the day of embryo transfer. The primary outcome is the rate of ongoing pregnancy between two groups of women with progesterone level below 10 ng/mL on the day of frozen embryo transfer: the study group using 800 mg vaginal micronised progesterone supplemented with 50 mg progesterone intramuscular per day and the control group using only 800 mg vaginal micronised progesterone.

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