Klotz Communications: Evolution of hormones during pregnancyEndocrinology of human parturitionLes hormones de l’accouchement
Introduction
Parturition is a coordinated process of transition from a quiescent myometrium to an active rhythmically contractile state requiring complex interplay between placental, fetal and maternal compartments. The precise mechanisms involved in initiation of labor are thought to involve functional progesterone withdrawal, increased estrogen bioavailability, corticotrophin releasing hormone (CRH) and neuroendocrine mediators and finally, increased responsiveness of the myometrium to prostaglandins and oxytocin [1]. Labor at term may be regarded best physiologically as a release from the inhibitory effects of pregnancy on the myometrium rather than as an active process mediated by uterine stimulants [2]. It involves an integrated set of changes within the maternal tissues of the uterus (myometrium, decidua, and uterine cervix), which occur gradually over a period of days to weeks. Such changes include an increase in prostaglandin synthesis and release within the uterus, an increase in the myometrial gap junction formation, and up-regulation of myometrial oxytocin receptors. Indeed, endocrine or paracrine-autocrine factors from the feto-placental unit bring about a switch in the pattern of myometrial activity [3]. In fact, human parturition is an inflammatory and endocrine event, where the two systems interact modulating labor onset and progression [4].
In the past, the placenta was believed to be a largely passive organ mainly responsible for delivering nutrients to the fetus. With progress in obstetric research, this concept has gradually shifted to one that recognizes the placenta as a transient endocrine organ and a central regulator of maternal–placental–fetal physiology. Thus, the placenta ensures appropriate physiologic milieus for normal growth and development of fetal, placental, and maternal tissues necessary for a successful pregnancy. Indeed, the placenta represents a very metabolically active organ during parturition. It is a source of a large number of “information” molecules that, when released, can exert their biologic effects on the placenta itself but can also enter the maternal and fetal circulation, thus acting as autocrine, paracrine, and endocrine factors [5], [6].
Placenta produces a large variety of molecules including steroid hormones, hypothalamic-pituitary hormones, neuropeptides, growth factors and cytokines, involved in parturition [7]. Steroid hormones include the common female gonadal steroid hormones, progesterone and estrogens. It is noteworthy that the placenta produces also hormones that are known to be produced by neuroendocrine organs, such as oxytocin, gonadotrophin-releasing hormone (GnRH), opioids and CRH.
However, the fetus itself plays a role in initiation of labor, through the secretion of neurohormones and other stimulators of prostaglandin synthesis [8].
Thus, inflammation, mechanical distension of the uterus at term and hormonal paracrine and autocrine signalling between the feto-placental unit and the mother seem to promote the initiation of human parturition through coordinated activation of stimulatory pathways and loss of uterine quiescence, which enables contractions to occur.
Section snippets
Phases of human parturition
Pregnancy may be considered as consisting of four parturitional phases (Fig. 1). During the first parturitional phase (phase 0 – quiescent phase) the uterus is kept in a quiescent state through the action of progesterone and other minor factors such as prostacyclin (PGI2), relaxin, parathyroid hormone-related peptide (PTHrP), calcitonin gene-related peptide, vasoactive intestinal peptide and nitric oxide (NO). All these agents act mediate an increased intracellular concentrations of cyclic
Estrogens
Estrogens are essential for uterine development and function, playing a key role in uterine contractility. Human pregnancy is characterized by a typical hyperestrogenic state. The placenta is the primary source of estrogens, and concentrations of estrogens increase in the maternal circulation with increasing gestational age [1]. Placental estrone and 17β-estradiol are derived primarily from maternal C19 androgens (testosterone and androstenedione), whereas estriol is derived almost exclusively
Conclusion
The mechanisms involved in human pregnancy maintenance and parturition are highly complex and involve mother, fetus and placenta. Despite extensive research, the integrated mechanisms underlying the onset of human parturition are not yet fully elucidated [73]. Inflammation is central in the process of labor, while prostaglandins, CRH, Ucns and oxytocin are key placental factors which mediate both endocrine (metabolism, immune function, cardiovascular changes) and paracrine (uterine
Disclosure of interest
The authors declare that they have no competing interest.
References (73)
- et al.
Endocrine immune interactions in human parturition
Mol Cell Endocrinol
(2011) - et al.
Placental endocrine function. Knobil and Neill's physiology of reproduction
(2006) Preterm labour. Biochemical and endocrinological preparation for parturition
Best Pract Res Clin Obstet Gynaecol
(2007)- et al.
Roles of glucocorticoids in human parturition: a controversial fact?
Placenta
(2014) - et al.
Endocrinology of parturition
Endocrinol Metab Clin North Am
(2006) - et al.
Progesterone withdrawal: key to parturition
Am J Obstet Gynecol
(2007) Regulation of progesterone signaling during pregnancy: implications for the use of progestins for the prevention of preterm birth
J Steroid Biochem Mol Biol
(2014)- et al.
Steroid hormone control of myometrial contractility and parturition
Semin Cell Dev Biol
(2007) - et al.
Changes in 17 beta, 20 alpha-hydroxysteroid dehydrogenase activity supporting an increase in the estrogen/progesterone ratio of human fetal membranes at parturition
Am J Obstet Gynecol
(1993) Progesterone receptors in the human uterus and their possible role in parturition
J Steroid Biochem Mol Biol
(2005)
Evidence for a local change in the progesterone/estrogen ratio in human parturition at term
Am J Obstet Gynecol
The role of oxytocin in parturition
BJOG
Mechanisms of labour – biochemical aspects
BJOG
Cytokines, prostaglandins and parturition – a review
Placenta
The expression of cyclooxygenase-2 (COX-2) in amnion and decidua following spontaneous labor
Prostaglandins
The initiation of parturition at term
Obstet Gynecol Clin N Am
Role of corticotropin-releasing hormone in onset of labour
Lancet
Neuroendocrinology of pregnancy and parturition
Handb Clin Neurol
Urocortins in human reproduction
Peptides
Endocrinology of parturition
J Clin Endocrinol Metab
Parturition: activation of stimulatory pathways or loss of uterine quiescence?
Adv Exp Med Biol
The control of labor
N Engl J Med
Peptide signaling in human placenta and membranes: autocrine, paracrine and endocrine mechanisms
Endocr Rev
Endocrine, paracrine, and autocrine placental mediators in labor
Hormones (Athens)
Factors implicated in the initiation of human parturition in term and preterm labor: a review
Gynecol Endocrinol
Endocrine and paracrine regulation of birth at term and preterm
Endocr Rev
Biochemical and biophysical predictors of the response to the induction of labor in nulliparous postterm pregnancy
Am J Obstet Gynecol
Parturition
N Engl J Med
The onset of human parturition
Arch Gynecol Obstet
Estrogen and progesterone metabolism in the cervix during pregnancy and parturition
J Clin Endocrinol Metab
Mechanisms of term and preterm birth
J Obstet Gynaecol
Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium
J Clin Endocrinol Metab
Progesterone receptors in the human pregnancy uterus: do they hold the key to birth timing?
Reprod Sci
A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition
Proc Natl Acad Sci U S A
Paracrine oxytocin and estradiol demonstrate a spatial increase in human intrauterine tissues with labor
J Clin Endocrinol Metab
Oxytocin is required for nursing but is not essential for parturition or reproductive behavior
Proc Natl Acad Sci U S A
Cited by (109)
Immune cells at the feto-maternal interface: Comprehensive characterization and insights into term labor
2024, Journal of Reproductive ImmunologyA global analysis of the determinants of maternal health and transitions in maternal mortality
2024, The Lancet Global HealthRelationship between cholestasis and altered progesterone metabolism in the placenta-maternal liver tandem
2024, Biochimica et Biophysica Acta - Molecular Basis of DiseaseAdverse pregnancy outcomes and pre-pregnancy mental health care
2023, The Lancet PsychiatryGestational cadmium exposure disrupts fetal liver development via repressing estrogen biosynthesis in placental trophoblasts
2023, Food and Chemical Toxicology