Part of “CHAPTER 109 – ENDOCRINOLOGY OF PARTURITION“

Myometrial activity is inhibited during pregnancy by a variety of substances, including progesterone, prostacyclin (PGI2), relaxin, parathyroid hormone–related protein (PTHrP), and nitric oxide. These substances act in different ways, although in general they increase the intracellular levels of cyclic nucleotides, which in turn inhibit release of calcium (Ca²⁺) from intracellular stores or reduce the activity of the enzyme myosin light-chain kinase (MLCK). Myometrial contractions depend on conformational changes in the actin and myosin filaments that allow these to slide over each other, a process that requires adenosine triphosphate. This, in turn, is generated by myosin after phosphorylation of the myosin light chains by MLCK. MLCK is activated by interaction with the calcium-binding protein calmodulin, which in turn requires four Ca²⁺ ions for its own activation. Thus, agents that inhibit release of calcium from intracellular stores or reduce the levels of MLCK result in reductions of uterine contractility.

Progesterone inhibits spontaneous myometrial contractility and reduces stimulated activity during pregnancy. In species in which the ovary continues as a major source of progesterone throughout pregnancy, ovariectomy results in increased myometrial contractility—an effect that can be reversed by administration of exogenous progesterone. In primates, however, including the human, little evidence is seen for systemic progesterone withdrawal prepartum, and local, intrauterine changes in progesterone production or action have been postulated to occur at the time of labor. In women, ovarian progesterone production predominates during the first 5 to 6 weeks of pregnancy, and ovariectomy or administration of a progesterone receptor antagonist, such as mifepristone (RU-486), during this time results in increased myometrial contractility. The placenta becomes the major site of progesterone production after the sixth week of gestation. A key enzyme is 3β-hydroxysteroid dehydrogenase (3β-HSD) type 2, expressed in syncytiotropho-blast and responsible for the conversion of pregnenolone to progesterone. Pregnenolone is derived from low-density lipoprotein from the maternal circulation, and the syncytiotropho-blast layer of the placental villi contains low-density lipoprotein receptors allowing uptake from the intervillous pool of blood. The chorion, one of the membranes surrounding the fetus inside the uterus, also produces progesterone from pregnenolone within trophoblast cells, and this may provide a local source of progesterone to regulate production of uterotonins within the fetal membranes.