Relationship between serum progesterone (P) levels and pregnancy outcome: lessons from artificial cycles when using vaginal natural micronized progesterone

Luteal phase management during assisted reproduction is increasingly pursued for its potential to contribute to positive reproductive outcomes. Recent publications indicate that using vaginal natural micronized progesterone in artificial cycles leads to serum P levels in the mid luteal phase that are associated with pregnancy outcome after embryo transfer [1–5]. Two prospective clinical trials have been performed to date, including almost 1400 patients. These trials were blinded to the result of serum P on the day of embryo transfer, and accordingly, no changes in the dose of P for luteal phase support (LPS) were performed during the study period; thus, the association between serum P levels and ongoing and live birth rates could be analyzed [5, 6]. The critical threshold of serum P was around 9 ng/mL. Patients who exhibited lower levels showed a significantly lower ongoing pregnancy rate and higher miscarriage rate. These findings, combined with retrospective analyses [1–4], suggest that—regardless of uterine P levels—a minimum level of serum P is required to optimize clinical outcome.

In contrast, one recent study concluded that P levels do not influence outcomes, independent of a 10-ng/mL threshold [7]. An explanation for this finding is that patients who had low levels (< 8 ng/mL) received extra doses of progesterone. As such, the authors were carrying out an intervention to prevent low levels that may promote poor outcomes. These results demonstrate a critical point: if monitoring of serum P is conducted and LPS is modified accordingly, clinicians can overcome the problem of patients having inadequate levels of progesterone that are associated with poorer outcomes [8].

Notably, these results can be extrapolated only to artificial cycles and, most importantly, use of vaginal natural-like progesterone, as preferred by many clinicians worldwide [9]. Indeed, the pharmacokinetics and pharmacodynamics of vaginally administered P differ from those of the intramuscular, subcutaneous, or oral administration routes [10]. For this reason, studies examining the role of serum P on pregnancy outcome cannot be compared when using different routes of administration.

Vaginal delivery of P leads to higher uterine P levels due to the first uterine pass effect [11] and lower serum P levels when compared with parenteral administration. Importantly, the lower bioavailability with vaginal preparations does not seem to exert a reduced biologic effect [12, 13]. Whether there is a critical minimum threshold when using parenteral preparations needs to be further studied. Such a threshold might be expected to be higher when considering that the levels of serum P reached in steady state are three times higher with intramuscular versus vaginal administration. In addition, it is necessary to confirm that excessively high levels of P are not detrimental to pregnancy outcome [14].

Vaginal delivery is the preferred route of P administration in Europe; in the USA, intramuscular P is also frequently used. A recent study showed the superiority of intramuscular over vaginal P in artificial cycles, but the arm with vaginal P received a dose of half that used in Europe for artificial cycles (200 mg b.i.d. vs. 400 mg b.i.d.) [15]. This difference could explain discrepancies between centers in terms of success with different routes of P, as the doses administered are often clinician-determined.

The need to measure serum P is now apparent, but many questions remain. More research is needed to establish which is the best dose for each patient, according to the type of cycle, route of administration, and individual characteristics. According to our results, one out of three patients receiving vaginal P showed inadequate levels of serum P, and this led to an 18% lower ongoing pregnancy rate [6]. It is time to measure serum P levels and adapt the dose or the route according to the needs of the patient. Our experience reflects that this adjustment proves effective. Therefore, the era of individual luteal phase supplementation (iLPS) has begun.

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Conflict of interest

Dr. Labarta received a grant from Finox in 2016, has provided consultancy services for MSD and Ferring Pharmaceuticals, and is part of the Ferring Pharmaceuticals LIFE program.

During the past 12 months, she has received honoraria from Angelini/IBSA, Merck, MSD, and Ferring Pharmaceuticals for lecturing.