Nestorone, a potent progestin, exhibits anti-inflammatory activity and prevents preterm birth in murine models of...

Preterm birth is the leading cause of neonatal and infant mortality worldwide. Vaginal progesterone reduces the rate of preterm birth by approximately 45% in women with a singleton gestation and a mid-trimester sonographically short cervix, but it is not effective in women with a prior spontaneous preterm birth who do not have cervical shortening. Whether a more potent, next-generation progestin could provide greater protection against preterm birth in high-risk populations has not been established. Experimental models of acute systemic and intrauterine inflammation are well-established and reproducible triggers of early and consequential preterm labor can provide a rigorous biologic context in which to compare progestational efficacy. Nestorone (segesterone acetate) is a highly potent and selective progestin approved by the US Food and Drug Administration for contraceptive use and widely used clinically.

To determine whether the highly potent progestin, Nestorone, administered at a substantially lower dose than progesterone can prevent preterm birth in established mouse models of inflammation-triggered parturition and to characterize its progestational and inflammation-modulating properties in preclinical systems.

Nestorone and comparator progestins were evaluated for transcriptional activation of human progesterone and glucocorticoid receptors in transfected cells. Inflammation-modulating effects were examined in endotoxin-stimulated human peripheral blood mononuclear cells, uterine smooth muscle cells, and lung epithelial cell lines using cytokine profiling and quantitative polymerase chain reaction. In vivo efficacy was assessed in timed-pregnant mice treated with Nestorone or progesterone (0.02 mg or 2 mg per mouse per day, respectively) on gestational days 15 and 16, followed by a systemic (intraperitoneal) or a local (intrauterine) endotoxin challenge to induce preterm labor.

(1) Nestorone exhibited the highest progesterone receptor-mediated transcriptional activity among the progestins tested, with only mild glucocorticoid receptor activity; (2) Nestorone attenuated endotoxin-induced expression of proinflammatory cytokines, including tumor necrosis factor α and interleukin-6, and increased expression of the anti-inflammatory cytokine interleukin-10 in human immune, uterine and lung cells; these effects were generally comparable to progesterone at matched concentrations; (3) Nestorone, at a substantially lower dose of 0.02 mg/day compared to 2 mg/day dose of progesterone, prevented preterm delivery, in murine models of both systemic and local intrauterine inflammation-induced preterm labor. For example, in a systemic inflammation model, preterm birth decreased from 100% (n=12/12) in endotoxin-treated controls to 8% (n=1/12) with the addition of Nestorone or progesterone (∼92% reduction). In addition, in an intrauterine inflammation model, preterm birth was reduced from 100% (n=11/11) to 0% for both Nestorone and progesterone (n=0/10; 100% reduction).

In established models of early and consequential preterm labor, Nestorone and progesterone both reduced preterm birth, with Nestorone achieving comparable efficacy at a substantially lower dose. These findings support the concept that the enhanced progestational potency of Nestorone may be beneficial in maintaining pregnancy under biologic stress conditions, justifying further translational investigation of Nestorone for preterm birth prevention.