Reply: Vaginal progesterone treatment and circulating progesterone levels-An association yet to be determined.

Abstract

This is a reply to the comment by Levin & Rottenstreich1 on our recently published study Plasma progesterone, estradiol, and unconjugated estriol concentrations in twin pregnancies: Relation to cervical length and preterm delivery.2 We would like to thank the authors for showing interest in our research. Our study examined the association between plasma hormone concentrations, cervical length and preterm delivery in twin pregnancies. We also investigated the effect of vaginal progesterone treatment on plasma hormone concentrations. The main conclusion of our study was that progesterone, estradiol and unconjugated estriol concentrations are associated with neither cervical length nor preterm delivery, and we did not find evidence of increased plasma hormone concentrations after 4-8 weeks of treatment with progesterone compared with the placebo group in this substudy of a double-blinded, randomized placebo-controlled trial investigating the effect of vaginal progesterone for prevention of preterm delivery in twin pregnancies. Levin & Rottenstreich's first comment regards the reference by Cicinelli et al.3 The authors mention that the study assessed plasma progesterone concentrations among menopausal women and that the mean plasma progesterone concentration was 5.12 ± 2.06 ng/mL following vaginal administration of micronized progesterone, which is higher than the normal menopausal reference level of <0.3 ng/mL. This is an interesting point but, nevertheless, the plasma concentrations of progesterone were significantly higher in the uterine artery compared with the radial artery (9.75 ± 3.21 ng/mL) in the study by Cicinelli et al. We do not reject that progesterone treatment may increase peripheral progesterone concentrations, but state that we did not find evidence of such an effect and suggest that peripheral concentrations do not increase proportionally to uterine concentrations with vaginal progesterone administration due to the first uterine pass effect.4 This is also in line with a later study by Ficicioglu et al5 suggesting that although plasma progesterone concentrations were lower in patients treated with vaginal progesterone compared with intramuscular progesterone, the endometrial tissue concentration of progesterone was higher in patients treated with vaginal progesterone. Levin & Rottenstreich mention that we do not specify the timing of blood sample collection in relation to the administration of vaginal progesterone pessaries. In the PREDICT study, participants were advised to insert the vaginal pessaries before going to bed at night, and blood samples were collected during the day in relation to outpatient visits. We do not have records of the exact timing between application of pessaries and blood sample collection. However, our study does not investigate concentrations after one single application, but instead examines the concentrations after 4-8 weeks of treatment, that is, during steady state. In this context, it is important also to consider the endogenous progesterone production and the likely relative increase in plasma progesterone concentration in twin pregnancies. Since the progesterone concentrations in twin pregnancies are very high, the small difference in circulating concentrations reported by Cicinelli et al would be hard to detect as a signal against the high background concentrations and is of doubtful biological significance. Nevertheless, we agree with the authors that this subject needs further investigation.