Vaginal progesterone treatment and circulating progesterone levels-an association yet to be determined.

Abstract

Sir, We read the study by Johnsson et al with great interest.1 The authors examined the associations between several plasma hormone concentrations including progesterone levels and preterm delivery in twin pregnancies, and the effect of vaginal progesterone treatment on plasma progesterone concentrations. For the purpose of that study, plasma samples were collected at inclusion at 18-24 weeks of gestation, and thereafter at 22-32 weeks of gestation in two groups, in a sub-study of a double-blinded, randomized placebo-controlled trial which originally investigated the effect of vaginal micronized progesterone on the prevention of preterm delivery among twins. Although the authors delineate their results with clarity, the conclusion made regarding the lack of influence of vaginally administered progesterone and progesterone serum levels needs further consideration. The authors state that vaginal progesterone treatment does not increase the circulating progesterone concentration and cite the seminal study by Cicinelli et al2 as a correlate for their conclusion. It is important to note that in the aforementioned study which assessed progesterone plasma levels among menopausal patients following vaginal administration of micronized progesterone, the mean progesterone serum levels were 5.12 ± 2.06 ng/mL, which is well above the normal menopausal reference level of .03-.3 ng/mL. Thus, the authors should use this study with caution in reaffirming their conclusion or at least stating the major differences between the study settings. Furthermore, the authors do not specify the timing of serum collection in relation to the administration of vaginal progesterone, hence exposing the results obtained to a potential bias or even misinterpretation, as it was previously shown in a pharmacokinetic analysis that serum progesterone levels peak 2-3 hours after vaginal administration of natural progesterone3 and levels measured at peak were similar to those obtained during ovulatory and luteal phases, a fact that is in contrary to the authors' conclusion. Yet another pharmacokinetic study of vaginal micronized progesterone4 found that mean peak plasma progesterone concentrations (Tmax) occurred after 6.1 hours, with a mean elimination half-life (T1/2) of 13.18 hours. Hence, it might be suggested that the correct setting for assuming a correlation between vaginal progesterone administration and its influence on serum progesterone level should differ from the one the author used.1 The aforementioned study's findings are in line with previous studies that demonstrated increased plasma progesterone levels after vaginal administration of progesterone.5, 6 As the main conclusion of the authors, namely, that progesterone, estradiol and unconjugated estriol concentrations are associated with neither cervical length nor preterm delivery has solid support from recent literature, we suggest that the authors rephrase their conclusion and discussion regarding the lack of effect of progesterone treatment on its circulating plasma concentration.