What does initiate parturition?
Several hormonal and other factors have been proposed to be involved in the initiation of parturition. However, definitive sequential events leading to initiation of parturition are still lacking. Conceptual evolution on the mechanism of initiation of parturition since 1891 has been briefed.
ERα, PR-A, cytokines, CRH, parturition
More than a century back, Spiegelberg  reported that parturition results from substances produced by the fetus. Later, it is suggested that some portion of the central nervous system and fetal adrenal are important . Experiments of Newton  and van Wagenen and Newton  have shown that following fetectomy, pregnancy continues and placental delivery occurs at or near to normal term in mice and monkeys. Liggins  however, reported that ACTH or cortisol infusion into pregnant lambs induces parturition on the 6th day of infusion. Conversely, Chatterjee et al.  have documented that the administration of glucocorticoid to pregnant rats close to term delays parturition. Liggins  later recorded that human fetuses with adrenal hypoplasia are born at or close to term. Administration of large doses of glucocorticoid to pregnant women  or sheep  before term also failed to induce premature labor.
Molokwu and Wagner  have proposed that an increased level of glucocorticoid at the time of parturition is due to the stress of labor but not a cause of parturition. On the other hand, Talbert et al.  could not detect any significant difference in cord plasma levels of cortisol in infants born after elective Caesarian section compared to those born after spontaneous onset of labor.
Based on 89 publications, the International Planned Parenthood Federation suggested that at term, fetal ACTH by stimulating fetal adrenal glucocorticoid induces a concomitant decrease in progesterone with a concurrent increase in estrogen. As a result, a spontaneous elevation of fetal and maternal prostaglandins and oxytocin leads to softening of the cervix and a simultaneous uterine myometrial contraction which consequently results in parturition . Cortisol, a progesterone agonist, has however been shown to exert a direct inhibitory effect on estrogen  and prostaglandin  synthesis.
Parturition is moreover claimed to be driven by a pulsatile pattern of oxytocin secretion [Parturition is moreover claimed to be driven by a pulsatile pattern of oxytocin secretion , but neither oxytocin antiserum  nor its antagonist [17,18] is found to prolong gestation or delay parturition. Circulating oxytocin therefore, does not seem to be essential for the initiation of parturition .], but neither oxytocin antiserum  nor its antagonist [17,18] is found to prolong gestation or delay parturition. Circulating oxytocin therefore, does not seem to be essential for the initiation of parturition .
Progesterone is known to support pregnancy and prevent parturition by promoting myometrial quiescence . In contrast, estrogen stimulates parturition by augmenting myometrial excitability and contractility  with a corresponding stimulation of prostaglandins and ripening of the cervix . Therefore to initiate parturition, transformation of myometrium from a quiescent to a contractile state requires a coordination of progesterone withdrawal and estrogen activation. However, in humans  and higher primates , maternal progesterone and estrogens levels are found to remain elevated during parturition.
RU 486, a progesterone antagonist and a potent abortifacient agent [18,25], not only increases myometrial estrogen receptor (ER) expression, it does also reduce progesterone concentration in several species including rats , monkeys  and humans . RU 486 also exerts a profound softening action on the cervix .
It is now hypothesized that functional progesterone withdrawal occurs by increased expression of progesterone receptor-A (PR-A) type which suppresses myometrial progesterone responsiveness .
Similarly, functional ERα activation is found to be linked with functional progesterone withdrawal . Progesterone withdrawal consequently stimulates prostaglandin synthesis by human endometrium , myometrium and cervix  and also by the rat myometrium . Released prostaglandin then induces gap junction formation between myometrial cells  which facilitates a synchronized propagated uterine contraction with a corresponding ripening of the cervix  and finally results in labor . Sugimoto et al  have shown that female mice lacking receptors for prostaglandin F2α do not deliver fetuses at term.
The expression of prostaglandin in the uterine tissue is increased by cytokines . IL-6 and IL-8 are the cytokines produced by human endometrium, myometrium, choriodecidua and cervices . Preterm labor due to uterine or intra-amniotic infection is being found to be associated with an increased synthesis and release of IL-6, IL-8  and prostaglandins . Progesterone and glucocorticoids, the well-established anti-inflammatory agents  cause a significant inhibition of IL-6 and IL-8  as well as prostaglandin synthesis . However, intraperitoneal infusion of proinflammatory cytokines does not cause activation of the pregnant rat uterus . The integrated role between the cytokines and prostaglandins in the initiation of labor therefore remains enigmatic.
Corticotropic-releasing hormone (CRH), a peptide highly expressed in human placenta at the end of gestation has also been implicated in the process of labor . An elevation of maternal serum CRH concentration has been documented as early as 18-week of gestation in patients who have subsequently aborted . Estrogen stimulates CRH through its action on prostaglandin synthesis. On the other hand, CRH is found to increase the synthesis and release of prostaglandins from the cells of amnion, chorion and deciduas [49,50].
In conclusion, the functional progesterone withdrawal with subsequent estrogen receptor activation possibly mediates the formation of prostaglandin which by interacting with cytokines and CRH may result in the initiation of parturition.
Constant encouragement of Professor Dr. Dato’ Khalid Yusoff, Dean Faculty of Medicine, Universiti Teknologi MARA is very much appreciated..
- Spiegelberg O. Die Dauer der Geburt, Lehrbuch der Geburtshilfe 1891. Marshall F, editor. The physiology of reproduction. London and New York: Longmans, Green and Co.; 1922.
- Millic AB, Adamsons KJ. The relationship between anencephaly and prolonged pregnancy. J Obstet Gynec Brit Common W 1969;76:102-11.
- Newton WH. ?Pseudoparturition? in the mouse and the relation of placental to Postpartum oestrus. J Physiol 1935;84:196-207.
- van Wagenen G, Newton WH. Pregnancy in the monkey after removal of the fetus. Surg Gynec Obstet 1943;77:539-43.
- Liggins GC. Premature parturition after infusion of corticotrophin or cortisol into foetal lambs. J Endocrinol 1968;42:323-9.
- Chatterjee A, Singh R, Chatterjee (Basu) R. Dexamethasone modulation of gestation length and parturition in rats. Pharmacol Res 1993;27:359-64.
- Liggins GC. The influence if foetal hypothalamus and pituitary on growth. In: Elliot K, Knight J, editors. Size at Birth, Ciba Foundation Symposium No. 27. Amster-dam: Elsevier Excerpta Medica; 1974.
- Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for Prevention of respiratory distress syndrome in premature infants. Pediatrics 1972;50:515-25.
- Bengtsson LP, Schofield BM. Progesterone and the accomplishment of parturition in the sheep. J Reprod Fert 1963;5:423-31.
- Molokwu ECI, Wagner WC. Endocrine physiology pf puerperal sow. J Anim Sci 1973;36:1158-63.
- Talbert LM, Esterling WE, Potter HD. Maternal and fetal plasma levels of adrenal corticoids in spontaneous vaginal delivery and caesarean section. Am J Obstet Gynec 1973;117:554-9.
- Findlay AL. The control of parturition. In: Edwards RG, editor. Research in Reprod. 1975.
- Schoonmaker JN, Erickson GF. Glucocorticoid modulation of follicle stimulating hormone-mediated granu-losa cell differentiation. Endocrinology 1983;113:1356-63.
- Pasmanik M, Izhar M, Zolti M, Shemesh M. Dexamethasone inhibition of prostaglandin production in human term placental cells is protein and ribonucleic acid synthesis dependent. Endocrinology 1991;128:2058-64.
- Antonijevic IA, Russell JA, Bicknell RJ, Leng G, Douglas AJ. Effect of progesterone on the activation of neurons of the su-praoptic nucleus during parturition. J Reprod Fert 2000;120:367-76.
- Kumaresan P, Kagan A, Glick SM. Oxytocin antibody and lactation and parturition in Rats. Nature (London) 1971;230:468-9.
- Chan WY, Chen DL. Myometrial oxytocin receptors and prostaglandin in the parturition process in the rat. Biol Reprod 1992;46:58-64.
- Chatterjee A, Ahmad A, Chatterjee R. How does RU 486 empty gravid uterus in rats? Biomed Res 1996;7:95-9.
- Phelan JP, Guay AT, Newman C. Diabetes insipidus in pregnancy: A case review. Am J Obstet Gynec 1978;130:365-6.
- Csapo AI. Progesterone ?block?. Am J Anat 1956;98:273-91.
- Fuchs F. Endocrinology of parturition. In: Fuchs F, Klopper A, editors. Endocrinology of Pregnancy.Philadelphia: Harper and Row; 1983. p. 247-70. 22. Basu R, Chatterjee A. Pregnant mare?s serum gonadotropin IV. Induction of premature labor by pregnant mare?s serum gonadotropin and its prevention by using clomiphene or indomethacin. Fetil Steril 1978;29:640-2.
- Yen S. Endocrine-metabolic adaptation in pregnancy. In: Yen S, Jaffe R, editors. Reproductive Endocrinology. Philadelphia: Saunders; 1991. p. 396-981.
- Walsh SW, Stanczyk FZ, Novy MJ. Daily hormonal changes in the maternal, fetal, and amniotic fluid compartments before parturition in a primate species. J Clin Endocrinol Metab 1984;58:629-39.
- Herrman W, Wyss A, Riondel A, Philibert D, Teutsch G, Sakiz E, et al. Effects d? un steroide antiprogesterone chez La femme: interruption du cycle menstruel et de la grossesse au debut. C R Seances Acad Sci III
- Tanaka K, Iwamasa J, Matsuura K, Okamura H. Effects of progesterone and antiprogesterone RU-486 on ovarian 3ß-hydroxysteroiddehydrogenase activity during ovulation in the gonadotropin-primed immature rats. J Reprod Fertil 1993;97:167-72.
- Puri CP, Katkam KR, D? Souza A, Elger WA, Patil RK. Effects of progesterone antagonist, Lilopristone (ZK 98,734) on induction of menstruation, inhibition of nidation and termination of pregnancy in bonnet monkeys. Biol Reprod 1990;43:437-43.
- Baulieu EE. Contragestion and other clinical applica-tions of RU 486, an Antiprogesterone at the receptor. Science 1989;245:1351-7.
- Critchley HO, Kelly RW, Lea RG, Drudy TA, Jones RL, Baird DT. Sex steroid regulation of leukocyte traffic in human deciduas. Hum Reprod 1996;11:2257-62.
- Mesiano S. Myometrial progesterone responsiveness and the control of human parturition. J Soc Gynecol Invest 2004;11:193-202.
- Mesiano S, Chan C, Fitter JT, Kwek K, Yeo G, SmithR. Progesterone with-drawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J Clin Endocrinol Metab 2002;87:2924-30.
- Kelly RW, Smith SK. Progesterone and antiprogestins: a comparison of their effects on prostaglandin production by human secretary phase endometrium and deci-duas. Prostaglandins Leukotrienes Med 987;29:181-6.
- Young A, Thomson AJ, Ledingham M, Jordan F, Greer IA, Norman JE. Immuno-localization of proinflammatory cytokines in myomet-rium, cervix and fetal membranes during human parturition at term. Biol Reprod 2002;66:445-9.
- Jeremy JY, Dandona P. RU 486 antagonizes the inhibitory action of progesterone on prostacyclin and thromboxane A2 synthesis in culture rat myometrial explants. Endocrinology 1986;119:655-60.
- Challis JR, Mitchell BF. Parturition. In: Serio M, Martini L, editors. Animal Models in Human Reproduction. New York: Raven Press; 1980. p. 391-408.
- Liggins GC. Ripening of the cervix. Semin Perinatal 1978;2:261-71.
- Sawdy R, Slater DM, Dennes WJ, Sullivan MH, Bennett PR. The roles of the cyclo-oxygenases types one and two in prostaglandin synthesis in human fetal membranes at term. Placenta 2000;21:54-7.
- Sugimoto Y, Yamasaki A, Segi E, Tsuboi K, Aze Y, Nishimura T, et al. Failure of par-turition in mice lacking the prostaglandin F receptor. Science 1997;277:681-3.
- Belt AR, Baldassare JJ, Molnár M, Romero R, Hertelendy F. The nuclear transcription factor NF-kappaB mediates interleukin-1bata-induced expression of cyclooxygenase-2 in hu-man myometrial cells. Am J Obstet Gynecol 1999;181:359-66.
- Mohan AR, Loudon JA, Bennett PR. Molecular and biochemical mechanisms of preterm labor. Semin Fetal Neonatal Med 2004;9:437-44.
- Romero R, Munoz H, Gomez R. Does infection cause premature labor delivery? Semin Reprod Endocrinol 1994;12:227-39.
- Gravett MG, Witkin SS, Haluska GJ, Edwards JL, Cook MJ, Novy MJ. An experi-mental model for intrauterine infection and preterm la-bor in rhesus monkeys. Am J Obstet Gymecol 1994;171:1660-7.
- De Bosscher K, Vanden Berghe W, Haegeman G. The interplay between the glucocortocoid receptor and nuc-lear factor-kappaB or activator protein-1: Molecular mechanisms for gene repression. Endocr Rev 2003;24:488-522.
- Lappas M, Permezel M, Georgiou HM, Rice GE. Nuclear factor kappaB regulation of proinflammatory cytokines in human gestational tissues in vitro. Biol Reprod 2002;67:668-73.
- O?Banion MK, Winn VD, Young DA. cDNA cloning and functional activity of a glucocorticoid regulated in-flammatory cyclooxygenase. Proc Natl Acad Sci 1992;89:4888-92.
- Mitchell BF, Zielnik B, Wong S, Roberts CD, Mitchell JM. Intraperitoneal infusion of proimflammatory cytokines does not cause activation of the rat uterus during late gestation. Am J Physiol Endocrinol Metab 2005;289:E658-64.
- Karalis K, Goodwin G, Majzoub JA. Cortisol blockade of progesterone: A possible molecular mechanism involved in the initiation of human labor. Nat Med 1996;2:556-60.
- McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R. A placental clock controlling the length of human pregnancy Nat Med 1995;1:460-3.
- Jones SA, Brooks AN, Challis JR. Steroids modulate corticotrophin-releasing hormone production in human fetal membrane and placenta. J Clin Endocrinol Metab 1989;68:825-30.
- Terzidou V. Biochemical and endocrinological preparation for parturition. Best Pract Res Clin Obstet Gynecol 2007;21:729-56.