{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T02:18:44Z","timestamp":1767838724413,"version":"3.49.0"},"reference-count":23,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2015,10,28]],"date-time":"2015-10-28T00:00:00Z","timestamp":1445990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Symmetry"],"abstract":"<jats:p>We present a hypothesis for a mechanism involving self-organization of small functional units that leads to organ-level synchronization of uterine contractions in human labor. This view is in contrast to the long-held presumption that the synchronized behavior of the uterus is subject to well-defined internal organization (as is found in the heart) that exists prior to the onset of labor. The contractile units of the uterus are myocytes, which contract in response to both mechanical stretch and electrical stimulation. Throughout pregnancy progesterone maintains quiescence by suppression of \u201ccontraction-associated proteins\u201d (CAPs). At the end of pregnancy a functional withdrawal of progesterone and an increasingly estrogenic environment leads to an increase in the production of CAPs. One CAP of particular importance is connexin 43, which creates gap junctions between the myocytes that cause them to become electrically coupled. The electrical connectivity between myocytes, combined with an increase in intrauterine pressure at the end of pregnancy shifts the uterus towards an increasingly unstable critical point, characterized by irregular, uncoordinated contractions. We propose that synchronous, coordinated contractions emerge from this critical point through a process of self-organization, and that the search for a uterine pacemaker has been unfruitful for the sole reason that it is non-existent.<\/jats:p>","DOI":"10.3390\/sym7041981","type":"journal-article","created":{"date-parts":[[2015,10,28]],"date-time":"2015-10-28T13:43:01Z","timestamp":1446039781000},"page":"1981-1988","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Hypothesis for Self-Organization and Symmetry Reduction in the Synchronization of Organ-Level Contractions in the Human Uterus during Labor"],"prefix":"10.3390","volume":"7","author":[{"given":"David","family":"Banney","sequence":"first","affiliation":[{"name":"Mothers and Babies Research Centre, Hunter Medical Research Institute, The University of Newcastle, Newcastle NSW 2308, Australia"}]},{"given":"Roger","family":"Young","sequence":"additional","affiliation":[{"name":"Mothers and Babies Research Centre, Hunter Medical Research Institute, The University of Newcastle, Newcastle NSW 2308, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3064-6358","authenticated-orcid":false,"given":"Jonathan","family":"Paul","sequence":"additional","affiliation":[{"name":"Mothers and Babies Research Centre, Hunter Medical Research Institute, The University of Newcastle, Newcastle NSW 2308, Australia"}]},{"given":"Mohammad","family":"Imtiaz","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, 405 Liverpool St., Darlinghurst NSW 2010, Australia"}]},{"given":"Roger","family":"Smith","sequence":"additional","affiliation":[{"name":"Mothers and Babies Research Centre, Hunter Medical Research Institute, The University of Newcastle, Newcastle NSW 2308, Australia"}]}],"member":"1968","published-online":{"date-parts":[[2015,10,28]]},"reference":[{"key":"ref_1","unstructured":"Depolarization results from an influx of anions across the membrane, initiated by mechanisms including the hyperpolarization-activated inward current and the low-threshold T-type calcium ion (Ca2+) currents. With increasing depolarization, sodium currents are activated, causing further rapid depolarization, which in turn activates high-threshold L-type Ca2+ currents that sustain the plateau phase of the action potential. Subsequently voltage- and calcium-activated potassium currents, and the deactivation of depolarizing currents, drive the membrane potential towards resting potential and terminate the action potential."},{"key":"ref_2","unstructured":"Note: In this sequence, Ca2+ binds to Calmodulin, producing a complex that activates myosin light chains. This leads to phosphorylation of myosin light chains, which in turn enables interaction between myosin and actin heavy chains. It is this interaction between myosin and actin heavy chains that causes cell shortening [20]"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"C485","DOI":"10.1152\/ajpcell.00161.2012","article-title":"Role of serine-threonine phosphoprotein phosphatases in smooth muscle contractility","volume":"304","author":"Butler","year":"2013","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/S1071-5576(03)00089-3","article-title":"Calcium signaling and uterine contractility","volume":"10","author":"Wray","year":"2003","journal-title":"J. Soc. Gynecol. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1016\/S0002-9378(99)70390-X","article-title":"Contractile activity, membrane potential, and cytoplasmic calcium in human uterine smooth muscle in the third trimester of pregnancy and during labor","volume":"181","author":"Parkington","year":"1999","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/0002-9378(76)90100-9","article-title":"Quantitation of uterine activity in 100 primiparous patients","volume":"124","author":"Miller","year":"1976","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Young, R.C., and Barendse, P. (2014). Linking myometrial physiology to intrauterine pressure; how tissue-level contractions create uterine contractions of labor. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003850"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/aja.1000980206","article-title":"Progesterone \u201cblock\u201d","volume":"98","author":"Csapo","year":"1956","journal-title":"Am. J. Anat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1210\/jcem.87.6.8609","article-title":"Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium","volume":"87","author":"Mesiano","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1056\/NEJMra061360","article-title":"Parturition","volume":"356","author":"Smith","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_11","unstructured":"Two forms of estrogen are produced during pregnancy-estriol, produced in the placenta from fetal steroid precursors, and estradiol, produced from precursors made in the maternal adrenal gland. While both estriol and estradiol act on estrogen receptors, in eqimolar concentrations they form heterodimers which block estrogenic actions. Late in pregnancy, the growth of the fetal adrenal causes the rate of increase in estriol production to outstrip that of estradiol production, causing estriol to become dominant over estradiol, and through the production of estriol homodimers the uterine environment becomes increasingly estrogenic. An extraordinary consequence of this is that, while in a healthy pregnancy it is the maturation of the fetus that stimulates the estrogenic signals that lead to the emergence of labor, in the event that the baby dies, maternal estrogen becomes the signal, ensuring that the mother is not left with a dead fetus in-utero [23]."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1016\/S0002-9378(11)91699-8","article-title":"Studies of connexin 43 and cell-to-cell coupling in cultured human uterine smooth muscle","volume":"167","author":"Sakai","year":"1992","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1085\/jgp.80.3.353","article-title":"Improved electrical coupling in uterine smooth muscle is associated with increased numbers of gap junctions at parturition","volume":"80","author":"Sims","year":"1982","journal-title":"J. Gen. Physiol."},{"key":"ref_14","first-page":"463","article-title":"Control of myometrial contractility: Role and regulation of gap junctions","volume":"10","author":"Garfield","year":"1988","journal-title":"Oxf. Rev. Reprod. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e65110","DOI":"10.1371\/journal.pone.0065110","article-title":"Phasic oscillations of extracellular potassium (K(o)) in pregnant rat myometrium","volume":"8","author":"Young","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ramon, C., Preissl, H., Murphy, P., Wilson, J.D., Lowery, C., and Eswaran, H. (2005). Synchronization analysis of the uterine magnetic activity during contractions. Biomed. Eng. Online, 4.","DOI":"10.1186\/1475-925X-4-55"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1097\/00006254-197006000-00001","article-title":"The diagnostic significance of the intrauterine pressure. II. Clinical considerations and trials","volume":"25","author":"Csapo","year":"1970","journal-title":"Obstet. Gynecol. Surv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/S1701-2163(16)31044-1","article-title":"Mechanisms of term and preterm birth","volume":"24","author":"Gibb","year":"2002","journal-title":"J. Obstet. Gynaecol. Can."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Caglioti, G. (1992). The Dynamics of Ambiguity, Springer Verlag.","DOI":"10.1007\/978-3-642-58080-2"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/44416","article-title":"Symmetry in locomotor central pattern generators and animal gaits","volume":"401","author":"Golubitsky","year":"1999","journal-title":"Nature"},{"key":"ref_21","unstructured":"Stewart, I., and Golubitsky, M. (2011). Fearful Symmetry: Is God a Geometer?, Dover Publications."},{"key":"ref_22","unstructured":"Prigogine, I. (1997). The End of Certainty: Time, Chaos, and the New Laws of Nature, Free Press."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1210\/mend.11.12.0025","article-title":"Molecular and kinetic basis for the mixed agonist\/antagonist activity of estriol","volume":"11","author":"Melamed","year":"1997","journal-title":"Mol. Endocrinol. Baltim. Md."}],"container-title":["Symmetry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-8994\/7\/4\/1981\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:51:01Z","timestamp":1760215861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-8994\/7\/4\/1981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,28]]},"references-count":23,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["sym7041981"],"URL":"https:\/\/doi.org\/10.3390\/sym7041981","relation":{},"ISSN":["2073-8994"],"issn-type":[{"value":"2073-8994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,28]]}}}