Micronized progesterone is to-day the most widely used form of luteal support. Micronized progesterone can be administered orally, rectally or vaginally. However, the bioavailability of micronized progesterone following oral administration is variable as progesterone is metabolised in the liver to pregnenolone and pregnanediol and thereby inactivated. Hence, endometrial changes are inconsistent [54]. In addition, side effects such as nausea, abdominal bloatedness, drowsiness are common with oral administration. The rectal route is rarely used. The vaginal route of administration is widely used, due to ease of administration and high bioavailability as hepatic degradation is avoided. Intra-vaginal administration results in a high uterine concentration of progesterone with relatively low levels in the peripheral circulation. Vaginal micronised progesterone is available in both capsule and gel forms. The daily dose is 600–800 mg/day in 2–3 divided doses, although no dosage finding study has been performed; and 90 mg of gel (8 %) once daily. Pregnancy rates are similar with both forms of vaginal preparations [55, 56]. The disadvantages of vaginal micronized progesterone include local irritation in some women, discharge from the gel or capsule, and staining of the clothes. The divided dose may also be inconvenient, as daily routines need to be interrupted in the middle of the day. Additionally, vaginal administration is unacceptable in some societies.

When all progestogens were compared to placebo or no treatment in Van der Linden et al.’s [51] metaanalysis, progestogens were found to give a significantly better pregnancy rate than placebo or no treatment (OR = 1.83 95 % CI 1.29–2.61).

Progesterone in oil, 50–100 mg daily as an intramuscular injection is another form of luteal support. With the availability of vaginal progesterone, the intramuscular route is less often used than previously. Pain, rash and abscess at the injection site and the need for daily visits for intramuscular injection by trained staff, are important factors precluding routine use. Occasional occurrence of eosinophilic pneumonia has been reported in otherwise healthy women. However, if the vaginal route of administration is unacceptable or if there is severe local irritation, the i.m. route of administration may be preferred to the vaginal route. More recent evidence has found both routes to be equally effective [51, 57].

Luteal estradiol supplementation has been used in addition to progesterone support in an attempt to improve IVF outcomes, both in women with low luteal estrogen levels or electively in all treatment cycles. Transdermal estradiol patches delivering a dose of 100 μg/day or oral or vaginal estradiol 4–6 mg/day together with progesterone have all been used with variable results. The current evidence of benefit is limited to a higher implantation rate seen in one single study [58]. The addition of estradiol to progesterone support has not been shown to improve the pregnancy rate [51, 59].

Small bolus doses of GnRH have been used in an attempt to improve pregnancy rates in antagonist-treated cycles where GnRHa is used to trigger ovulation. Triptorelin 0.1 mg has been administered on the day of oocyte pick-up, embryo transfer and 3 days afterwards. The original reports suggested an improvement in both pregnancy and live birth rates [51, 60, 61]. GnRHa may support the CL by stimulating the secretion of LH by pituitary gonadotroph cells by acting directly on the endometrium through locally expressed GnRH receptors. Luteal-Phase GnRHa administration increases luteal phase serum hGC, estradiol and progesterone concentrations. The beneficial effect could possibly be due to a combination of effects on the embryo and the CL.

Dydrogesterone is a stereoisomer of progesterone, manufactured by conversion of progesterone with ultra violet light. It has been extensively used in over 90 million women, in 90 countries over 40 years and has been found safe for use in pregnancy [62]. Dydrogesterone has a 50 % higher affinity for the progesterone receptor than progesterone itself [63], and has no stimulatory or inhibitory effect on the androgen receptor. Chakravarty et al. [64], have compared oral dydrogesterone to micronised progesterone and found them to be equally effective. Two studies have reported dydrogesterone to have a superior effect to progesterone itself. Iwase et al. [65], has found dydrogesterone to be associated with a significantly higher Live Birth Rate. Patki and Pawar [66] have found a statistically significant increase in pregnancy rates with use of 30 mg dydrogesterone as compared to vaginal micronised progesterone in ART cycles. The Cochrane review of Van der Linden et al. [51] also found a significant effect in favour of dydrogesterone over progesterone itself in terms of pregnancy rates.

Dydrogesterone also has other advantages. It is available as an oral preparation. Although metabolised in the liver, the metabolite dihydrodydrogesterone, is active on the progesterone receptor, unlike the metabolites of progesterone itself.