Review question
Many different interventions, dosages and administration routes of luteal phase support have been investigated. We made seven different comparisons to prepare a complete overview of this topic.
Background
After ovulation, the luteal phase of the menstrual cycle starts, and continues until the next menstruation. Remnants of the ovulated egg in the ovary are known as 'corpus luteum', or yellow body. The yellow body produces hormones, including progesterone. Progesterone stimulates proliferation of the lining of the uterus to prepare for implantation.
During assisted reproduction, the woman's pituitary gland is desensitised with medications so that the ovaries can be stimulated in a controlled manner. This results in more mature eggs, which can be harvested and fertilised outside the woman's body. Hyperstimulation of the ovaries causes a luteal phase defect, as the corpus luteum is unable to produce sufficient progesterone.
As a low progesterone level may lower the chance of implantation, the luteal phase needs to be supported. This may involve oral, vaginal or intramuscular progesterone, human chorionic gonadotropin (hCG) (which stimulates progesterone production) or gonadotropin-releasing hormone (GnRH) agonists. GnRH agonists stimulate the production of GnRH, a hormone responsible for follicle-stimulating hormone (FSH), and luteinising hormone (LH), which triggers ovulation and develops the yellow body. GnRH agonists are thought to restore LH levels and support the luteal phase naturally.
Study characteristics
We found 94 randomised controlled trials comparing different luteal phase support regimens in a total of 26,198 women. Our primary outcome was live birth or ongoing pregnancy. Other outcomes were clinical pregnancy, ovarian hyperstimulation syndrome (OHSS), miscarriage and multiple pregnancy. The evidence is current to August 2015.
Key results
hCG or progesterone given during the luteal phase may be associated with higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is not conclusive. The addition of GnRHa to progesterone appears to improve outcomes. hCG may increase the risk of OHSS compared to placebo. Moreover hCG, with or without progesterone, is associated with higher rates of OHSS than progesterone alone. Neither the addition of oestrogen nor the route of progesterone administration appears to be associated with an improvement in outcomes.
Quality of the evidence
Evidence for most comparisons was of low or very low quality. The main limitations in the evidence were poor reporting of study methods and imprecision due to small sample sizes.
hCG or progesterone given during the luteal phase may be associated with higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is not conclusive. The addition of GnRHa to progesterone appears to improve outcomes. hCG may increase the risk of OHSS compared to placebo. Moreover hCG, with or without progesterone, is associated with higher rates of OHSS than progesterone alone. Neither the addition of oestrogen nor the route of progesterone administration appears to be associated with an improvement in outcomes.
Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin (hCG) produced by the corpus luteum in the luteal phase of the menstrual cycle. In assisted reproduction techniques (ART), progesterone and/or hCG levels are low, so the luteal phase is supported with progesterone, hCG or gonadotropin-releasing hormone (GnRH) agonists to improve implantation and pregnancy rates.
To determine the relative effectiveness and safety of methods of luteal phase support provided to subfertile women undergoing assisted reproduction.
We searched databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and trial registers up to November 2014. Further searches were undertaken in August 2015.
Randomised controlled trials (RCTs) of luteal phase support using progesterone, hCG or GnRH agonist supplementation in ART cycles.
We used standard methodological procedures expected by Cochrane. Our primary outcome was live birth or ongoing pregnancy. The overall quality of the evidence was assessed using GRADE methods.
Ninety-four RCTs (26,198 women) were included. Most studies had unclear or high risk of bias in most domains. The main limitations in the evidence were poor reporting of study methods and imprecision due to small sample sizes.
1. hCG vs placebo/no treatment (five RCTs, 746 women)
Findings suggested benefit for the hCG group in live birth or ongoing pregnancy rates when data were analysed with a fixed-effect model (OR 1.76, 95% CI 1.08 to 2.86, three RCTs, 527 women, I2 = 24%, very low-quality evidence) but there was no clear evidence of a difference using a random-effects model (OR 1.67, 95% CI 0.90 to 3.12). hCG may increase ovarian hyperstimulation syndrome (OHSS) rates (OR 4.28, 95% CI 1.91 to 9.6, one RCT, 387 women, low-quality evidence).
2. Progesterone vs placebo/no treatment (eight RCTs, 875 women)
Findings suggested benefit for the progesterone group in live birth or ongoing pregnancy rates when data were analysed with a fixed-effect model (OR 1.77, 95% CI 1.09 to 2.86, five RCTs, 642 women, I2 = 35%, very low-quality evidence) but there was no clear evidence of a difference using a random-effects model (OR 1.77, 95% CI 0.96 to 3.26). OHSS was not reported.
3. Progesterone vs hCG regimens (16 RCTs, 2162 women)
hCG regimens included hCG alone and hCG with progesterone. There was no evidence of a difference between progesterone and hCG regimens in live birth or ongoing pregnancy rates (OR 0.95, 95% CI 0.65 to 1.38, five RCTs, 833 women, I2 = 0%, low-quality evidence). Progesterone was associated with lower OHSS rates than hCG regimens (OR 0.46, 95% CI 0.30 to 0.71, 5 RCTs, 1293 women , I2=48%).
4. Progesterone vs progesterone with oestrogen (16 RCTs, 2577 women)
There was no evidence of a difference between the groups in rates of live birth or ongoing pregnancy (OR 1.12, 95% CI 0.91 to 1.38, nine RCTs, 1651 women, I2 = 0%, low-quality evidence) or OHSS (OR 0.56, 95% CI 0.2 to 1.63, two RCTs, 461 women, I2 = 0%, low-quality evidence).
5. Progesterone vs progesterone + GnRH agonist (seven RCTs, 1708 women)
Live birth or ongoing pregnancy rates were lower in the progesterone-only group than the progesterone plus GnRH agonist group (OR 0.62, 95% CI 0.48 to 0.81, nine RCTs, 2861 women, I2 = 55%, random effects, low-quality evidence). Statistical heterogeneity was high but the direction of effect was consistent across studies. OHSS was reported in one study only; there was no evidence of a difference between the groups (OR 1.00, 95% CI 0.33 to 3.01, one RCT, 300 women, very low quality evidence).
6. Progesterone regimens (45 RCTs, 13,814 women)
There were nine different comparisons between progesterone regimens. Findings for live birth or ongoing pregnancy were as follows: intramuscular (IM) versus oral: OR 0.71, 95% CI 0.14 to 3.66 (one RCT, 40 women, very low-quality evidence); IM versus vaginal/rectal: OR 1.37, 95% CI 0.94 to 1.99 (seven RCTs, 2309 women, I2 = 71%, random effects, very low-quality evidence); vaginal/rectal versus oral: OR 1.19, 95% CI 0.83 to 1.69 (four RCTs, 857 women, I2 = 32%, low-quality evidence); low-dose versus high-dose vaginal: OR 0.97, 95% CI 0.84 to 1.11 (five RCTs, 3720 women, I2 = 0%, moderate-quality evidence); short versus long protocol: OR 1.04, 95% CI 0.79 to 1.36 (five RCTs, 1205 women, I2 = 0%, low-quality evidence); micronised versus synthetic: OR 0.9, 95% CI 0.53 to 1.55 (two RCTs, 470 women, I2 = 0%, low-quality evidence); vaginal ring versus gel: OR 1.09, 95% CI 0.88 to 1.36 (one RCT, 1271 women, low-quality evidence); subcutaneous versus vaginal gel: OR 0.92, 95% CI 0.74 to 1.14 (two RCTs, 1465 women, I2 = 0%, low-quality evidence); vaginal versus rectal: OR 1.28, 95% CI 0.64 to 2.54 (one RCT, 147 women, very low-quality evidence). OHSS rates were reported for only two comparisons: IM versus oral, and low versus high-dose vaginal; there was no evidence of a difference between the groups.
7. Progesterone and oestrogen regimens (two RCTs, 1195 women)
The included studies compared two different oestrogen protocols. There was no evidence of a difference in live birth or ongoing pregnancy rates between a short or long protocol (OR 1.08, 95% CI 0.81 to 1.43, one RCT, 910 women, low-quality evidence) or between a low or high dose of oestrogen (OR 0.65, 95% CI 0.37 to 1.13, one RCT, 285 women, very low-quality evidence). Neither study reported OHSS.