Mechanisms of relaxin-mediated premature birth.

In women, circulating relaxin is produced by the corpus luteum of pregnancy. The levels of relaxin are predominantly determined by the luteal mass, the number of corpora lutea present. Relaxin levels are highest after ovulation induction, which stimulates formation of many corpora lutea. Elevated relaxin levels in the first trimester of pregnancy are maintained throughout pregnancy and are linearly related to preterm birth. In an in vitro model of late human pregnancy cervix, relaxin increases MMP-1 and MMP-3 and decreases TIMP-1 levels, thus acting as a positive regulator of matrix metalloproteinases. In an in vivo rhesus monkey model of early pregnancy, relaxin decreases cervical collagen content, decreases cervical lumican levels, and stimulates MMP-7 levels. Early effects of relaxin in the uterus include increasing endometrial arteriole number and increasing the number of leukocytes, uterine natural killer cells, macrophages, and neutrophils. These cells release many cytokines which contribute to changes that stimulate and facilitate uterine contractility. If these changes persist in late pregnancy, relaxin may be a mediator of labor. Excess relaxin may produce these changes at an accelerated rate, causing preterm birth.