The pharmacodynamics and safety of progesterone.

Abstract

Natural progesterone (P4) has a unique pharmacodynamic activity and safety profile compared to the synthetic progestins. As a result, a class effect does not exist for both P4 and synthetic progestins, in terms of both their efficacy and safety. Progestogens act at the genomic level by binding to the nuclear receptors and modulating the expression of some target-genes. P4 and the synthetic progestins have a hugely variable affinity for binding not only to the P4 receptors but also to other members of the steroid receptor family including glucocorticoid receptor, androgen receptor and mineralocorticoid receptor. This leads to different and specific pharmacokinetic profiles, clinical pharmacodynamics, safety and efficacy. P4 produced in the luteal phase of the menstrual cycle has several physiological effects regulating menses and, in the pregnant uterus, controlling the development of endometrial receptivity preparing the endometrium for implantation. P4 and its associated metabolites are powerful biological agents through genomic action by the progesterone nuclear receptor with a finely tuned regulatory role throughout pregnancy, from conception until delivery. Extra-nuclear, non-classical mechanisms of action have also been identified, including steroid interactions with some membrane receptors [oxytocin receptors and γ-aminobutyric acid (GABAA), and the induction of a direct relaxing effect on uterine contractility by blockage of calcium influx. The extent of activity of P4 on the central nervous system (CNS) is modulated by the route of administration: oral P4 is affected by the presence of bacteria and associated enzymes secreted in the gut, the intestinal wall and by the liver, whereas vaginal P4 is not. P4 and two important metabolites, namely, allopregnanolone (3a,5a-tetrahydroP4) and 3a,5a-tetrahydrodeoxycorticosterone, exert neuroprotective effects on neonates. They are also natural positive modulators of the neuronal GABAA receptor, providing a clear pathway to explain the rapid dose-dependent psychopharmacological actions including anxiolytic, antidepressant, anaesthetic, anticonvulsant and analgesic effects. Fundamental structural differences exist between P4 and the synthetic progestins, resulting in different safety profiles when they are used during the menstrual cycle, in early and late pregnancy and in the alleviation of peri- or postmenopausal symptoms.