Parturition. Lactation. Endocrine function of placenta - hCG • Human chorionic gonadotropin • First marker of trophoblast differentiation, first measurable product (blood plasma, 8 days after fertilization) • Similarity with TSH, FSH, LH • Functions: • Survival of the embryo • Progesterone secretion maintenance by the corpus luteum hCG - functions Endocrine function of placenta - hPL • Human placental lactogen (somatomammotropin) • From 4 – 5 gestational weeks • Similarity with GH and PRL • Diabetogenic and lactogenic functions • Minimal growth-promoting activity • Secretion: • Prolonged fasting • HDL • Inzulin-induced hypoglycemia • Functions: • Maternal glucose metabolism (hyperglycemia) • Mobilization of FFA • Stimulation of inzulin secretion • Peripheral inzulin rezistance Endocrine function of placenta – placental growth hormone • Detectable at 15–20 gestation weeks • Highest during third semester • Secretion: • Hypoglycemia (+) • Leptin, insulin, cortisol (-) • Functions: • GHR and PRLR • Enhancement of maternal IGF-1 synthesis • Metabolic regulations – promotion of gluconeogenesis, lipolysis and anabolism, increasing the nutrient availability for fetal nourishment • Interconversions of steroids delivered from maternal or fetal precursors! • Maternal cholesterol • Establishment and maintenance of pregnancy • Attachement and implantation of embryo • Blocking effect on pro-proliferative estrogens • Immunologic tolerance • Inhibition of myometrium contractility • Preparation of mammary gland to lactation • Antagonization of PRL Endocrine function of placenta - progesterone Endocrine function of placenta - estrogens • Hyperestrogenic state during pregnancy • Depends on circulating precursors – predominantly from fetal androgens (DHEA), regulatory function of CRH • Estriol, estrone and estradiol • First synthesis by corpus luteum, then placenta • Increase the uteroplacental blood flow (estriol) • Stimulation of endometrial growth and differentiation, angiogenesis and vasodilatation (estradiol) • Stimulation of contraction of myometrial cells by increasing connexin-43 expression and OTR (estriol, estradiol) Parturition • Parturition = coordinated proces of transition from a quiescent myometrium to an active rhythmically contractile state requiring complex interplay between placental, fetal and maternal compartments • Functional progesterone withdrawal, increased estrogen availability, CRH, increased responsiveness of the myometrium to oxytocin Estrogens, progesterone, oxytocin, PGS, relaxin, CRH Parturition • Uterus conversion from quiescent structure with dyssynchronous contractions to an active co-ordinately contracting organ • Capability of cervical connective tissue and smooth muscle of dilatation to allow the passage of the fetus from the uterus • formation of gap junctions between myometrial cells • shift from progesterone to estrogen dominance • increased responsiveness to oxytocin by means of up regulation of myometrial oxytocin receptor • increased PG synthesis in uterus • increased myometrial gap junction formation • decreased nitric oxide (NO) activity • increased influx of calcium into myocytes • increased endothelin leading to augmented uterine blood flow and myometrial aktivity • activation of the fetal HPA axis • collagenolysis, and a decrease in collagen stabilization through metalloproteinase inhibitors = cervical softening and dilation Phases of human parturition PTHrP CGRP VIP Increased cAMP/cGMP = inhibition of calcium ions release Mechanicalstretch CAPs Connexin43 OTR Inflammatoryreaction cytokines Labour induction • CRH/cortisol (inflammation – PGs) • Mechanoreceptors (mechanical distension) • Inflammation, mechanical distension of the uterus in term of paracrine and autocrine signalling between feto-planental unit and mother promote initiation of parturition. Estrogens and parturition • Increase in the number of prostaglandin receptors, oxytocin receptors, and upregulating the enzymes responsible for muscle contractions (myosin light chain kinase, calmodulin) • Increase connexin 43 synthesis and gap junction formation in the myometrium • Cervical ripening (rearrangement and realignment of collagen, elastin, and glycosaminoglycans, mediated by the induction of collagenase and elastase) Progesterone and parturition • Stimulation of the uterine NO synthetase • Inhibition of myometrial gap junctions • (-) prostaglandin production • (-) development of calcium channels • (-) OTR • (-) collagenolysis • Note – switch of ballance between estrogens and progesterone • Change in the activities of enzymes involved in synthesis (17,20 hydroxysteroid dehydrogenase ) • Decrease in progesterone receptors expression • Local metabolism of progesterone Progesterone and parturition Oxytocin and parturition • Increased OT production (pulses) • Increased number of OTR at the end of pregnancy (estrogens, (-) progesterone) CRH, urocortins and parturition • CRH synthesis is stimulated by the produced fetal cortisol (positive feedback mechanism). • Very rapid rise of CRH in late pregnancy – connection with estriol surge and critically altered P/E3 and estriol/estradiol (E3/E2) ratios = estrogenic environment • Modulation of PGF production • Vasodilation of feto-placental circulation (NOS) • Stimulation of fetal DHEAS = fetal lung maturation and adaptive mechanisms in response to the stress of parturition • CRH increases corticotropin production and, consequently, the synthesis of cortisol by the fetal adrenal gland and maturation of the fetal lungs Relaxin and PGS and parturition • PGS • Increased levels before and during labor in the uterus and membranes • Central role in parturition • Stimulation of myometrial contractility • Ripening the cervix • Endpoint of the CRH cascade • Relaxin • Endometrial vascularization and remodelling of connective tissue • loosening of joints and tendons as well as softening of the cervix in preparation for birth • Corpus luteum, placenta, decidua Endocrinology of the puerperium – uterine changes • Progressive involution (500 g/week) • Palpable abdominally until about 2 weeks postpartum • Nonpregnant size (60 – 70 g) after 6 weeks postpartum • Mechanism: decrease of volume of myometrial cells • Rapid regeneration • 7th day = complete restoration of surface epithelium • Longer regenerative changes – area of placental implantation Endocrinology of the puerperium – endocrine changes • Nonlactating women • Rapid fall over 7 to 14 days • Normal cyclic functions and ovulation within 3 months • Initial ovulation – 9-10 weeks postpartum • Lactating women • PRL – anovulation, inhibition of GnRH secretion • Steroids • Rapid decrease (half-lives of minutes) • Progesterone • 24 h to luteal plase levels • Several days to follicular phase levels • Estradiol • 1-3 days to follicular phase levels • Pituitary hormones • FSH and LH • suppression in early weeks of puerperium • normal levels by the 4th postpartum week • deacreased sensitivity to GnRH • Prolactin • PRL rises during pregnancy • Fall with the onset of labor • Delivery = rapid surge in PRL Lactation • Mammogenesis • Estrogen, progesterone, PRL, GH and glucocorticoids, hPL • Lactation – enlargement of lobules, synthesis of milk constituents • PRL, insulin, adrenal steroids • PRL • High levels during third semester • Blocking effect of estrogens • Oxytocin • Milk ejection • Contractile response of smooth muscle cells • Visual, psychologic or physical stimuli) • Suckling • Activation of neural arch Lactation - overview