Endocrinology of parturition.

To insure optimal survival of the neonate, the timing of parturition must be tightly controlled. Parturition before term dramatically increases the risk of the birth of a nonviable premature infant. At a time after the baby is mature, the intrauterine environment becomes hostile. Postdate fetuses have an increased incidence of intrauterine demise. To maximize infant survival, mechanisms have evolved to allow for uterine distention and reduced contractions during pregnancy and the timely initiation of labor. In women this process is only partially understood. The control of the timing of labor is complex and involves interactions of the mother, the fetus, and the placenta plus membranes. In women, invasive study of the intrauterine environment is limited for ethical reasons. However, the control of pregnancy and parturition is highly species specific. Although much more is known about the process of parturition in rodents and sheep than in humans, there are no good nonprimate models of human parturition. Even subhuman primates have significantly different endocrine environments and controls than humans. There is a complex schema of the initiation of labor in women, and there is no simple chain of events as there are in other species. For instance, there cannot be shown an acute rise in circulating estrogen, nor an abrupt decline in circulating progesterone levels to signal the onset of labor in all pregnancies. Evidence suggests that there are multiple paracrine/autocrine events, fetal hormonal changes, and overlapping maternal/fetal control mechanisms for the triggering of parturition in women. For parturition to occur, two changes must take place in a woman’s reproductive tract. First, the uterus must be converted from a quiescent structure with dyssynchronous contractions to an active coordinately contracting organ with complex interlaced muscular components. This requires the formation of gap junctions between myometrial cells to allow for transmission of the contractile signal. The second change is that the cervical connective tissue and smooth muscle must be capable of dilatation to allow the passage of the fetus from the uterus. In pregnancy there is a dynamic balance between the forces that cause uterine quiescence and the forces that produce coordinated uterine contractility. There is also a balance between the forces that keep the cervix closed to prevent uterine emptying and the forces that soften the cervix and allow it to dilate. For delivery to occur, both balances must be tipped in favor of active uterine emptying. Whereas there may be a final common pathway for the initiation of labor, which involves alterations in prostaglandin and calcium metabolism, there are multiple, sometimes complementary, initiating factors involved in the onset of labor (1). These are endocrine, paracrine, and autocrine. The “final common pathway” to delivery is likely to be multiple, parallel, interactive paths that tip the balance in favor of coordinated uterine contractility and cervical dilation. These mechanisms involve a shift from progesterone to estrogen dominance, increased sensitivity to oxytocin, gap junction formation, and increased prostaglandin activity. Decreased nitric oxide (NO) activity and increased influx of calcium into myocytes are both required for uterine contractibility (2, 3). Complementary changes in the cervix involving a decrease in progesterone dominance and the actions of prostaglandins and relaxin, via connective tissue alterations, collagenolysis, and a decrease in collagen stabilization through metalloproteinase inhibitors, leading to cervical softening and dilation (4). It is clear that the above mentioned pathways are not all inclusive. Other factors, such as endothelin, are involved in uterine changes conducive to increased blood flow and myometrial activity (5). It is also clear that with many overlapping mechanisms, decrease or absence of a single component can be compensated by changes in other paths. By way of analogy, in mice with specific gene knockouts, CRH and oxytocin are not necessary for normal delivery. Although knockouts of cyclooxygenase (COX)-1, COX-2, phospholipase A2, and relaxin do alter the timing of labor, they do not preclude uterus emptying and cervical dilation in all animals (6). Thus, complementary actions for the system must come into play. It is also quite likely that many of the causes of preterm parturition differ from the initiators at term. In fact, there seem to be multiple causes of preterm parturition. For example, infection may overwhelm one or more control mechanisms of normal labor. Or, more specifically, a deficiency of a choriodecidual enzyme (such as 15-hydroxy-PG-dehydrogenase) may alter the metabolism of prostaglandin E2 (PGE2) resulting in excess and, ultimately, onset of labor (7, 8). On the other hand, in a novel and as yet undetermined way, Received June 14, 2000. Revision received September 5, 2000. Accepted September 8, 2000. Address correspondence and requests for reprints to: Gerson Weiss, M.D., New Jersey Medical School, Department of Obstetrics, Gynecology and Women’s Health, 185 South Orange Avenue, Newark, New Jersey 07103-2714. E-mail: weissge@umdnj.edu. * Supported by NIH Grant HD22338. 0021-972X/00/$03.00/0 Vol. 85, No. 12 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2000 by The Endocrine Society