Introduction

Progesterone is essential for the female reproductive cycle, having roles in the menstrual cycle, blastocyst implantation and maintenance of pregnancy.1,2 During the luteal phase of the menstrual cycle after ovulation, progesterone is secreted by the corpus luteum and instigates secretory transformation of the endometrium into an implantation-receptive state.2 Progesterone continues to be produced during pregnancy, where it is involved in modulating the maternal immune response, reducing uterine contractility and regulating the utero-placental circulation, thus contributing to the maintenance of pregnancy.1
Insufficient exposure to progesterone to enable normal secretory transformation of the endometrium and implantation (luteal phase deficiency) is associated with infertility and early pregnancy loss.2,3 Luteal phase deficiency also occurs following controlled ovarian stimulation used in assisted reproduction, with potentially adverse effects on implantation in this setting.2 Later, in established pregnancy, a functional withdrawal of progesterone activity within the uterus is associated with onset of labour, whether at term or preterm.4
Exogenous progesterone is used to treat various obstetric conditions associated with reduced progesterone activity. Progestogens widely approved for use in pregnancy include natural progesterone, and the synthetic progestogens 17α-hydroxyprogesterone caproate (17OHP-C) and dydrogesterone. Synthetic progestins mimic some of the effects of progesterone, but have variable affinities for other steroid receptors (androgen, glucocorticoid, and mineralocorticoid receptors) which results in differential progestogen activity and safety profiles.5
The most common routes for delivery of progesterone in the obstetric field are intramuscular (IM), vaginal and oral.117OHP-C is administered by IM injection6 and dydrogesterone is administered orally.7 Since the early 1990s, natural progesterone for exogenous administration has been formulated in micronised particles to enhance its bioavailability after oral administration.8 Despite this improvement, oral natural micronised progesterone (oral NMP) requires multiple daily doses due to first-pass metabolism and is associated with adverse events (e.g. drowsiness and/or dizziness) due to active metabolites.8 A sustained-release formulation of NMP (NMP-SR) has been developed to overcome the limitations of oral NMP. NMP-SR has a better tolerability profile than conventional oral NMP and is more bioavailable, allowing for once-daily dosing.9
This narrative review examines available evidence from clinical studies investigating oral NMP and oral NMP-SR in the obstetric indications of luteal phase support during assisted reproduction; prevention of threatened miscarriage; prevention of preterm delivery; and high-risk pregnancy.