Progestogens: natural or synthetic

Progestogens can be classified as natural or synthetic. Natural compounds are those with chemical structures similar to those produced by living organisms. In contrast, synthetic progestogens (or progestins) are compounds generated in the laboratory whose structures have been modified and do not correspond to a naturally occurring steroid. Progesterone is a natural progestogen; 17α-hydroxyprogesterone caproate (17-OHPC) is synthetic ( Table ).

Progesterone

Progesterone is a natural sex steroid produced by the corpus luteum and subsequently the placenta. The chemical structure is illustrated in the Figure . Csapo et al demonstrated that progesterone was key for the support of pregnancy in the first trimester. The findings of Csapo et al were buttressed by the observation that progesterone receptor blockade leads to early pregnancy loss (eg, RU-486 or mifepristone administration). Moreover, the administration of RU-486 to pregnant women in the third trimester results in cervical ripening and often the onset of labor.

Chemical structure of progesterone and 17 α-hydroxyprogesterone caproate

A, Chemical structure of progesterone; B, Chemical structure of 17α-hydroxyprogesterone caproate.

Romero. Progestogen and progestins: what is the difference? Am J Obstet Gynecol 2013.

Differences between progesterone and 17α-hydroxyprogesterone caproate

Progesterone and 17-OHPC have different physiologic properties and pharmacologic profiles. Moreover, there are different indications for their use in obstetrics.

Ruddock et al reported that progesterone suppresses myometrial contractility in strips that were obtained at the time of cesarean delivery; however, 17-OHPC did not have this effect and, at high concentrations, it stimulated myometrial contractility. Similar observations have been reported by Sexton et al and Anderson et al. Studies in pregnant mice indicate that progesterone (but not 17-OHPC) could prevent preterm delivery. However, the effects of the 2 compounds are complex and dependent on the route of administration, and the vehicle used.

Insofar as the effect of progesterone and 17-OHPC on the uterine cervix, a solid body of evidence derived from studies in pregnant women, animals, and in vitro experimentation show an important role for progesterone in the inhibition of cervical ripening and/or the molecular mechanisms implicated in this process. The effects of 17-OHPC on the uterine cervix in pregnant women, animals, and in the context of in vitro experiments have not been studied to the same extent as those of progesterone.

One study examined the effect of 17-OHPC on cervical length in patients with a history of ≥1 preterm births who were allocated to receive 17-OHPC vs an untreated control group. No difference in cervical length measurements over time was observed in women who received 17-OHPC. In contrast, vaginal progesterone reduced the rate of cervical shortening in patients with a history of preterm birth or premature cervical shortening.

Facchinetti et al reported that the risk of cervical shortening (defined as ≥4 mm) was lower in patients who received 17-OHPC than in a control group. These patients had been admitted with an episode of preterm labor, but did not deliver and were discharged. Thus, this population differs from that of the other two studies in which 17-OHPC and progesterone were being used to prevent preterm delivery before an episode of preterm labor.

A recent study comparing the effect of vaginal progesterone to 17-OHPC in pregnant mice showed that neither agent changed myometrial gene expression. In the cervix, 17-OHPC had no detectable effects on gene expression; however, vaginal progesterone up-regulated the expression of defensin-1 (a natural antimicrobial peptide). Tissues were harvested after only 6 hours of exposure to the agents. It is unclear if the mechanisms by which progesterone prevents preterm delivery in patients with a short cervix are related to the expression of defensin-1 or other pathways yet to be discovered.

Differences between progesterone and 17α-hydroxyprogesterone caproate

Progesterone and 17-OHPC have different physiologic properties and pharmacologic profiles. Moreover, there are different indications for their use in obstetrics.

Ruddock et al reported that progesterone suppresses myometrial contractility in strips that were obtained at the time of cesarean delivery; however, 17-OHPC did not have this effect and, at high concentrations, it stimulated myometrial contractility. Similar observations have been reported by Sexton et al and Anderson et al. Studies in pregnant mice indicate that progesterone (but not 17-OHPC) could prevent preterm delivery. However, the effects of the 2 compounds are complex and dependent on the route of administration, and the vehicle used.

Insofar as the effect of progesterone and 17-OHPC on the uterine cervix, a solid body of evidence derived from studies in pregnant women, animals, and in vitro experimentation show an important role for progesterone in the inhibition of cervical ripening and/or the molecular mechanisms implicated in this process. The effects of 17-OHPC on the uterine cervix in pregnant women, animals, and in the context of in vitro experiments have not been studied to the same extent as those of progesterone.

One study examined the effect of 17-OHPC on cervical length in patients with a history of ≥1 preterm births who were allocated to receive 17-OHPC vs an untreated control group. No difference in cervical length measurements over time was observed in women who received 17-OHPC. In contrast, vaginal progesterone reduced the rate of cervical shortening in patients with a history of preterm birth or premature cervical shortening.

Facchinetti et al reported that the risk of cervical shortening (defined as ≥4 mm) was lower in patients who received 17-OHPC than in a control group. These patients had been admitted with an episode of preterm labor, but did not deliver and were discharged. Thus, this population differs from that of the other two studies in which 17-OHPC and progesterone were being used to prevent preterm delivery before an episode of preterm labor.

A recent study comparing the effect of vaginal progesterone to 17-OHPC in pregnant mice showed that neither agent changed myometrial gene expression. In the cervix, 17-OHPC had no detectable effects on gene expression; however, vaginal progesterone up-regulated the expression of defensin-1 (a natural antimicrobial peptide). Tissues were harvested after only 6 hours of exposure to the agents. It is unclear if the mechanisms by which progesterone prevents preterm delivery in patients with a short cervix are related to the expression of defensin-1 or other pathways yet to be discovered.

Clinical indications for the administration of 17-OHPC

The use of 17-OHPC in patients with a history of preterm birth is largely based on the findings of the trial by Meis et al. 17-OHPC administration was associated with a significant reduction in the rate of preterm birth at <37 (36.3% in 17-OHPC group vs 54.9% in placebo group; relative risk [RR], 0.66; 95% confidence interval [CI], 0.54–0.81), <35 (20.6% vs 30.7%; RR, 0.67; 95% CI, 0.48–0.93), and <32 (11.4% vs 19.6%; RR, 0.58; 95% CI, 0.37–0.91) weeks of gestation (other studies had been performed before and summarized by an aggregate metaanalysis by Marc Kierse).

One of the questions raised during the review of the RCT by Meis et al was the high rate of preterm delivery in the placebo group of the trial, which was 54.9%. This has been considered as an unexpectedly high rate of preterm delivery for patients with a previous preterm delivery. This question was raised by the medical office of the Food and Drug Administration (FDA), based upon the first phase of this trial in which 17-OHPC was compared to placebo and the rate of preterm delivery in the placebo group was 36%. This first phase of the study was called, “17P-IF-001”; 150 subjects were randomized, 104 subjects had delivered, and there were 65 patients allocated to 17-OHPC and 39 to placebo. This first phase of the study had to be stopped because of problems with the manufacturing of 17-OHPC. The key question is why in the first phase of the study, the rate of preterm delivery in the placebo group was 36% and in the subsequent trial (Meis et al ) by the same investigators it was 54.9%. Iams has proposed that the high rate of preterm delivery in the placebo group can be attributed to the inclusion of a subset of women who were at particularly high risk for preterm delivery because of a history of early preterm birth, ethnic origin, or who were highly motivated to take a weekly injection of 17-OHPC. However, if the positive findings of the trial are due to the effect of 17-OHPC in this particular subgroup of patients, the external validity or generalizability to patients who do not have the same risk profile would be open to question. Specifically, should 17-OHPC be used in women with a history of preterm birth but who do not fit the “high risk profile” that has been invoked to justify the high rate of preterm delivery in the control group? The only way to resolve this question is to replicate the findings with another trial (see below).

The approval to market 17-OHPC to prevent preterm birth in women with a history of preterm birth is under Subpart H of the Code of Federal Regulations. This regulatory pathway is used when a decision is made to grant temporary approval on the basis of a surrogate endpoint (in this case, delivery at <37 weeks of gestation), and further studies are required. The FDA has requested that a second randomized clinical trial of 17-OHPC vs placebo be conducted before granting full marketing approval under the Food, Drug and Cosmetic Act 505(b). A randomized clinical trial of 17-OHPC vs placebo is currently in progress (ie, Confirmatory Study of 17P Versus Vehicle for the Prevention of Preterm Birth in Women with a Previous Singleton Spontaneous Preterm Delivery). Women with a history of preterm delivery are being allocated to receive placebo or 17-OHPC. The primary endpoint for this trial is delivery at <35 weeks of gestation; the original predicted date for conclusion has been moved from October 2013 to December 2016. Details about the trial are available on the following website: http://clinicaltrials.gov/ct2/show/NCT01004029?term=preterm+birth&rank=1 . The results of this trial will determine whether the efficacy of 17-OHPC in the prevention of preterm birth can be replicated.

Clinical indications for the administration of vaginal progesterone to prevent preterm birth

Two randomized clinical trials and an individual patient data metaanalysis have shown that vaginal progesterone reduces the rate of preterm birth in women with a short cervix in the midtrimester. Fonseca et al reported a randomized, double-blind, placebo-controlled trial in which women with a short cervix (defined as ≤15 mm by transvaginal ultrasound) between 20 and 25 weeks of gestation were allocated to receive either vaginal progesterone (200 mg of micronized progesterone) or placebo (safflower oil). The duration of treatment was from 24 to 34 weeks of gestation. Patients allocated to receive vaginal progesterone had a lower rate of spontaneous preterm delivery: <34 weeks of gestation than those in the placebo group (19.2% vs 34.4%; RR, 0.56; 95% CI, 0.36–0.86). The rate of adverse events was similar in both groups.

The PREGNANT trial, a multicenter, randomized, double-blind, placebo-controlled trial, included asymptomatic women with a singleton gestation and a sonographic short cervix (10-20 mm) at 19 weeks to 23 weeks 6 days of gestation. Patients were randomly allocated to receive vaginal progesterone gel (90 mg) or placebo daily, starting at 20 weeks to 23 weeks 6 days of gestation until 36 weeks 6 days of gestation, rupture of membranes, or delivery—whichever occurred first. Patients who received vaginal progesterone had a significantly lower rate of preterm birth at <33 weeks of gestation than those who received placebo (8.9% vs 16.1%; RR, 0.55; 95% CI, 0.33–0.92). Neonates born to mothers allocated to vaginal progesterone gel had a significantly lower frequency of respiratory distress syndrome (RDS) than those allocated to placebo (3.0% vs 7.6%; RR, 0.39; 95% CI, 0.17–0.92). The reduction in RDS remained significant after adjustment for pooled study site and a history of preterm birth (RR, 0.40; 95% CI, 0.17–0.94; P = .03). The frequency of adverse events was similar in patients who received progesterone and placebo, and there was no evidence of a potential safety signal.

An individual patient data metaanalysis is a specific type of systematic review in which the original data from each participant in randomized clinical trials are obtained directly from investigators in a trial. Such a metaanalysis was recently performed in which vaginal progesterone administration to asymptomatic women with a sonographic short cervix (defined as a cervical length of ≤25 mm) was associated with a significant reduction in the rate of preterm birth at <33, <35, and <28 weeks of gestation; RDS; composite neonatal morbidity and mortality; birthweight <1500 g; admission to the neonatal intensive care unit; and requirement for mechanical ventilation.

Collectively, the evidence suggests that vaginal progesterone prevents preterm delivery at <33 weeks of gestation in women with a short cervix and that this is associated with a reduction in neonatal morbidity/mortality. Importantly, this was observed in women either without or with a history of preterm birth. One trial that examined the efficacy of 17-OHPC in nulliparous women with a short cervix (defined as a cervical length of <30 mm) did not show evidence of efficacy for the prevention of preterm birth at any cervical length (based on a test of interaction).

A pharmaceutical company (Columbia Laboratories, Inc, Livingston, NJ) applied to the FDA for approval to market its preparation of vaginal progesterone for the prevention of preterm birth. The standard for FDA approval is 2 randomized clinical trials that show evidence of efficacy and safety. However, Columbia Laboratories, Inc, applied for marketing approval with data from only 1 trial (the PREGNANT study). The trial of the Fetal Medicine Foundation could not be considered for approval because it used a different preparation of vaginal progesterone (oil capsules rather than gel). The FDA did not approve the application of Columbia Laboratories, Inc, based on results of a subgroup analysis, and the company did not apply for a Subpart H approval, the pathway employed by the sponsor of 17-OHPC. Therefore, vaginal progesterone may be used off-label for the prevention of preterm birth in women with a short cervix.