Luteal phase support during assisted reproduction

In vitro fertilization

Progesterone supplementation is used for luteal support after in vitro fertilization (IVF).2 In this setting, progesterone is predominantly administered as a vaginal preparation, although preference differs by geographical region.2,13 A meta-analysis of RCTs found that neither the route of administration of progesterone (IM, vaginal, oral) nor progestogen type (micronised progesterone or synthetic) affected the outcome of luteal phase support for assisted reproduction techniques (ART), including IVF and intracytoplasmic sperm injection (ICSI), with respect to live birth/ongoing pregnancy, clinical pregnancy or miscarriage rates.14
The results of RCTs evaluating oral NMP after IVF have been mixed (Table 1 ). Supplementation with oral NMP after IVF significantly increased luteal phase serum progesterone levels and prolonged the duration of the luteal phase compared with no supplementation.15 Two studies comparing oral and vaginal NMP found similar rates of clinical pregnancy and ongoing pregnancy with either approach,16,17, although one study reported a significantly lower implantation rate with oral versus vaginal NMP.17 Likewise, a prospective randomised study which compared oral NMP and IM progesterone for luteal support in patients undergoing IVF found that, while the implantation rate was lower with oral NMP, the clinical pregnancy rate did not differ significantly.18 A case-control study reported that a combination of oral plus vaginal NMP provided a similar rate of ongoing pregnancy, but a lower abortion rate, to that seen with vaginal NMP alone.19

Intrauterine insemination

Intrauterine insemination (IUI) is used in the management of various types of infertility, including mild male infertility, mild endometriosis, and unexplained infertility.20 It is a relatively low-cost treatment and less invasive and psychologically demanding than IVF and ICSI procedures. IUI can be associated with pregnancy rates of 10–20% per cycle.21
Use of oral NMP in the IUI setting has been evaluated largely in observational studies (Table 1 ). A prospective observational analysis of 591 IUI cycles in which a single follicle was developed found that the clinical pregnancy rate was improved with oral NMP compared with no luteal support.22 A large retrospective analysis of 1779 patients found no significant difference in pregnancy outcomes (rates of clinical pregnancy, biochemical pregnancy, early miscarriage, and ectopic pregnancy) between recipients of oral NMP, dydrogesterone, or vaginal NMP.23
Two small, open-label, observational studies compared success rates in the first cycle of IUI with progesterone luteal support using NMP-SR or dydrogesterone in women with unexplained infertility (Table 1 ). Mean serum progesterone levels were maintained at ≥ 14 ng/mL during the mid-luteal phase in most patients in both treatment groups in both studies.12,20 First-cycle biochemically-confirmed pregnancy rates were 6.7% and 11% per study in patients treated with NMP-SR and 3.3% and 30% per study in patients treated with dydrogesterone. Possible reasons proposed by Gopinath and Desai for low pregnancy rates were monofollicular development in patients undergoing natural IUI cycles, a trend towards a low motility fraction, and evaluation of the first cycle only.20