Pregnancy & Parturition Lecture Notes 2024-25 PDF

Physiology: Pregnancy and Parturition Page 1 of 11 Dr. Jeyasuria Pancharatnam PREGNANCY AND PARTURITION Learning Objectives 1. Describe the process of fertilization 2. Illustrate the process of implantation 3. Outline the development of the pla...

Physiology: Pregnancy and Parturition Page 1 of 11 Dr. Jeyasuria Pancharatnam PREGNANCY AND PARTURITION Learning Objectives 1. Describe the process of fertilization 2. Illustrate the process of implantation 3. Outline the development of the placenta 4. Explain the major roles of the placenta and its hormones 5. Describe the concept of the maternal-placental-fetal unit 6. Describe the maternal response to pregnancy 7. Define the roles of estrogen, progesterone, oxytocin, relaxin, and prostaglandins in the initiation of parturition through its completion. 8. Describe the process of lactation 1. Describe the process of fertilization Post ovulation the cumulus oocyte is moved to the uterus by action of both smooth muscle as well as cilia in the fallopian tubes. Figure 1: Sperm penetration and fertilization of the Ovum Mature sperm head A man normally deposits 150 to 600 million sperm into the vagina of a woman at the time of ejaculation. A small number of sperm (50-100) reach the ampullary portion of the fallopian tube, where fertilization normally occurs. Physiolo ogy: Pregnan ncy and Parrturition Page 2 of 11 Dr. Jeya asuria Panch haratnam The sperm needs to o undergo capacitation (maturation) ( ) in the femaale genital trract to be abble to fertilizee an oocyte. Capacitated sperm m reach the egg e very qu uickly, withinn 5 minutees of ejaculaation, due to the combin nation of theeir swimming g motion an nd the forcefu ful contractioons of the utterus, cervixx, and fallopiaan tubes that occur during d femalee orgasm. Fertilization begins b as thhe sperm celll attaches tto the zona pellucida annd undergoees the acrosom mal reaction n and ends with w the fusio on of the maale and fem male pronucleei. The folloowing are the eight steps of o fertilizatio on Referr to Figure 1 above for steps1-8 off fertilization n Step 1. The T sperm heead weaves its i way past the folliculaar cells and aattaches to thhe zona pelluucida that surroounds the oo ocyte. The gllycoprotein that t mediatees this event is known ass zona pelluccida 3 (ZP3) Step 2. As a resultt of the speerm-ZP3 intteraction, thhe sperm ceell undergoees the acrossomal reaction, a prelude to o the migration of the speerm cell throough the muucus-like zonna pellucida. Step 3. Hydrolytic H enzymes e from m the acrossome reactioon dissolve the zona peellucida alloowing sperm peenetration thee zona pellucida. Step 4. The T cell mem mbranes of thet sperm an nd the oocytte fuse and the sperm ccontents enteer the oocyte. Step 5. The T oocyte undergoes u th he cortical reaction. r -T The rise in C Ca+ causes eexocytosis oof the cortical granules g ressulting in thhe hardeningg of the Zonna pellucidaa. This preveents more ssperm from pen netrating the oocyte term med polysperrmy. Step 6. The T rise in Ca+ C drives the t oocyte tot complete its second meiotic divvision (releaase of second polar body). Step 7. The T sperm nu ucleus decon ndenses and transforms t iinto the malee pronucleuss. Step 8. The T male and d female pron nuclei fuse, to form a neew cell, the zzygote 2. Illusttrate the pro ocess of imp plantation The zygote undergoes rapid Figure 2:: Transport off the conceptuus to the uteruus subseequent diviisions (~72 2 hours) resultting in thee formation n of the moruula (16 cells or o blastomerres). The T morulaa rapidly moves throu ugh the isth hmus to thee uterine cavityy, where it floats freelly in the lumen n of the uterus and traansforms into a blastocyst (Figure 2). The blastocyst consists of cells formiing an outer trophoblast layer, an innerr cell mass, and a flu uid-filled cavityy (Figure 3A A). Physiolo ogy: Pregnan ncy and Parrturition Page 3 of 11 Dr. Jeya asuria Panch haratnam Figu ure 3: Three sttages of implaantation and ccellular makeeup of the blasstocyst The outer layer of the blasttocyst forms the trophooblast. The trophoblast proliferatess and differrentiates into o the cytotroophoblast (innner layer) aand the synccytiotrophobblast (outer llayer) that invade the utterine wall too establish th he utero-placcental circullatory systemm (Figure 4).. The T inner cell mass is kno own as the embryoblast e t that consistts of a doublle-layered emmbryonic disk (epiblast and hypoblaast; Figure 3A). The T conceptu us floats freeely in the utterine cavityy for 72 hoours before it attaches tto the enndometrium m. Thus, imp plantation off the human blastocyst nnormally occcurs 6 to 7 days foollowing ovu ulation. Hormones H su uch as estroggen and prog gesterone as well as prosstaglandins aand cytokinees are reeleased to enhance e the transportatiion and devvelopment oof the embryyo and to ssignal mplantation in the endo im ometrium. Th he blastocysst also secreetes substancces that faciilitate im mplantation. A long-rangee signal th hat is secreted by the early blasstocyst is hhuman chorrionic gonadotropin n (hCG). hC CG is one of the moost importaant factors secreted byy the trrophoblast of the blastoccyst, both beefore and affter implantaation. hCG iis homologoous to LH L (luteinizin ng hormonee which is whyw it is ablee to maintainn the corpuss luteum, hC CG is allso an auto ocrine grow wth factor that promootes trophobblast growthh and placcental development.. hCG leveels are hig gh in the aarea where the trophooblast facess the enndometrium m. hCG may play a role in i the adhession of the trrophoblast too the epithellia of th he endometriium. Before B the in nitiation of implantation n, the zona pellucida thhat surroundds the blastocyst degenerates. This processs, known ass hatching oof the embryyo, occurs 6 to 7 days after ov vulation (Fig gure 3A). Physiolo ogy: Pregnan ncy and Parrturition Page 4 of 11 Dr. Jeya asuria Panch haratnam Immplantation occurs in thrree stages: (1) appositionn, (2) adhesiion, and (3) invasion. 1. Appossition is the earliest conttact betweenn the blastocyyst wall, thee trophoectodderm, an nd the endoometrial epith helium. This is a loose Figure 4 4: Developmentt of the placentta co onnection thhat usually occurs o in a crypt c in the en ndometriumm (Figure 3B)). 2. Adhession occurs when w the tro ophoblast ap ppears to atttach to the uterine u epitheelium using itts microvilli.. This processs is mediateed by ligand reeceptor interractions (e.g.. integrins) (Figure ( 3C). 3. Invasiion occurs when the blastocyst atttaches to the endom metrial epith helium, the trrophoblastic cells rapid dly proliferaate, and the trrophoblast differentiates d s into two layers: an in nner cytotrop phoblast lay yer and an outer syyncytiotrophhoblast layerr (Figure 3D)). 3. Outlinne the development of thet placenta a Shorttly after thee blastocyst has implan nted (6 to 7 days after fertiilization), th he syncytiootrophoblast invaddes the strom ma of the utterus (i.e., th he decidua) (Figu ure 4A). Within W the syncytiotroph s hoblast are lacunnae. The invading sy yncytiotrophhoblast break ks into the endom metrial veinns first, an nd then lateer into the arteriies, thus creating directd commmunication betweeen lacunae and matern nal vessels. In I addition, the proliferation p n of cytotro ophoblast ceells creates smalll mounds known k as primary p cho orionic villi (Figu ure 4B). The primary p choorionic villuss continues to grow wiith the prolifferation of ccytotrophoblastic Figuree 5: The Placcenta ccells. In adddition, mesennchyme from m the eextraembryoonic coelom m invades the vvillus, to foorm the secoondary chorrionic vvillus. Evenntually, thesse mesenchhymal ccells form feetal capillariies. The villlus is nnow known as a tertiaryy chorionic vvillus ((Figure 4C). The lacunaae also enlargge by mmerging withh one anotheer. Next, the lacunnae, filled with mmaternal bloood, eventuually merge with oone anotherr, to createe one masssive, iintercommunnicating inttervillous sspace ((Figure 5). Physiology: Pregnancy and Parturition Page 5 of 11 Dr. Jeyasuria Pancharatnam 4. Explain the major roles of the placenta and its hormones The placenta is the interface between the uterine wall and the embryo, and it has multiple functions assisting in the development of the fetus. For example: The placenta transfers required nutrients and oxygen from the mother to the fetus and transfers back the waste products and carbon dioxide. The placenta acts as a protective barrier to maternal immune cells, as the fetus can be regarded as a foreign allograft inside of the uterus. The placenta releases several proteins and steroid hormones in order to maintain the viability of the pregnancy (Figure 6). The most important placental peptide hormone is hCG. Early in the first trimester, hCG is manufactured by the syncytiotrophoblast. hCG maintains the corpus luteum, which is the major source of progesterone and estrogens. By itself, however, the corpus luteum is not adequate to generate the very Figure 6: Hormones during pregnancy high steroid levels characteristic of late pregnancy. Therefore, the placenta continues to produce large quantities of estrogens, progestins, and other hormones throughout gestation. Estriol, which is not important in non- pregnant women, is a major estrogen during pregnancy, and progesterone reduces uterine contractility and inhibits propagation of uterine contractions. 5. Describe the concept of the maternal-placental-fetal unit After 8 weeks of gestation, the placenta emerges as the major source of progesterone and estrogens; however, it cannot synthesize these hormones by itself. The luteal-placental shift (LPS) is a significant event in pregnancy when the placenta takes over progesterone production from the corpus luteum: The LPS marks the point where there is a shift from in endocrine control of pregnancy from the ovary to the placenta and occurs between week 7 and 9. Pregnancy from this point can continue after removal of the mothers ovaries. The placenta requires the assistance of both mother and fetus. This joint effort in steroid biosynthesis has led to the concept of the maternal-placental-fetal unit (Figure 7). Figure 7 illustrates the pathways used by the maternal-placental-fetal unit to synthesize progesterone and estrogens. Three reasons why the placenta is an imperfect endocrine organ: 1. The placenta cannot manufacture adequate cholesterol, the precursor of steroid synthesis. Physiology: Pregnancy and Parturition Page 6 of 11 Dr. Jeyasuria Pancharatnam 2. The placenta lacks two crucial enzymes (17α-Hydroxylase and 17, 20- Desmolase) that are needed for synthesizing estrone and estradiol. 3. The placenta lacks a third enzyme (16α-Hydroxylase) that is needed to synthesize estriol. The maternal-placental fetal unit overcomes these placental shortcomings in two ways: (1) the mother supplies most of the cholesterol as LDL particles and (2) the fetal adrenal gland and liver supply the three enzymes lacking in the placenta. The fetus does not synthesize estrogens without assistance, for two reasons: (1) it cannot because the fetus lacks the enzymes that catalyze the last two steps in the production of estrone, the precursor of estradiol, and (2) the fetus should not synthesize estrogens without assistance. If the fetus were to carry out the complete, classic biosynthesis of progesterone and estrogens, it would expose itself to dangerously high levels of hormones that would have adverse effects on the fetus. These levels of hormone would cause a deviation from normal sexual development. 6. Describe the maternal response to pregnancy During pregnancy, the mother experiences numerous and profound adaptive changes in her cardiovascular system, fluid volumes, respiration, fuel metabolism, and nutrition. Examples of changes: 1. Maternal blood volume increases by as much as 45% near term in singleton pregnancies and up to 75% to 100% in twin or triplet pregnancies. 2. Cardiac output increases appreciably during the first trimester of pregnancy (by 35% to 40%), but it increases only slightly during the second and third trimesters (~45% at term). Physiology: Pregnancy and Parturition Page 7 of 11 Dr. Jeyasuria Pancharatnam 3. Despite the large increase in plasma volume, mean arterial pressure (MAP) usually decreases during mid pregnancy and then rises during the third trimester. 4. Increased levels of progesterone during pregnancy increase alveolar ventilation. 5. Pregnancy increases the demand for dietary protein, iron, and folic acid. - During pregnancy, an additional 30 g of protein will be needed each day to meet the demand of the growing fetus, placenta, uterus, and breasts, as well as the increased maternal blood volume. - During pregnancy, the average required iron uptake rises to ~7 mg/day. In contrast, a non-pregnant woman of reproductive age needs to absorb ~1.5 mg/day of iron. - Maternal folate requirements increase significantly during pregnancy, in part reflecting an increased demand for producing blood cells. Folate deficiency may cause neural tube defects in the developing fetus, yet 400 to 800 μg/day of folic acid would almost certainly provide very effective prophylaxis. 6. Less than one third of the total maternal weight gain during pregnancy represents the fetus. The recommended weight gain during a singleton pregnancy for a woman with a normal ratio of weight to height is 11.5 to 16 kg. 7. Define the roles of estrogen, progesterone, oxytocin, relaxin, and prostaglandins in the initiation and maintenance of parturition. Throughout most of Figure 8: Three stages of Labor pregnancy, the uterus is maintained in a quiescent state through the actions of progesterone and relaxin. Eventually, a series of regular, rhythmic, and forceful contractions develops to facilitate thinning and dilation of the cervix— the obstetric definition of labor. Labor occurs in four stages: Stage 0. Uterine tranquility and refractoriness to contraction. Stage 1. Uterine awakening, initiation of parturition, extending to complete cervical dilation. (Figure 8) Stage 2. Active labor, from complete cervical dilation to delivery of the newborn (Figure 8). Stage 3. From delivery of the fetus to expulsion of the placenta and final uterine contraction. (Figure 8). Progesterone maintains uterine quiescence throughout pregnancy, decreasing the contractility of uterine smooth muscle. It should be noted that progesterone functions through the progesterone receptor (PR) which is in the family of nuclear receptors and although at labor the levels of progesterone are quite high there is a withdrawal of Physiology: Pregnancy and Parturition Page 8 of 11 Dr. Jeyasuria Pancharatnam progesterone function by both changes in the PR isoforms as well as coactivators at the transcription level. Estriol is a form of estrogen that is predominant during childbirth. Estriol inhibits the synthesis of progesterone by the placenta and prepares the smooth muscles of the uterus for labor. Estriol and other estrogens increase the number of oxytocin (OT) receptors in the myometrial and decidual tissue of pregnant women (Figure 9), increasing the sensitivity of smooth muscles in the uterine wall to undergo uterine contractions. Estrogen also increases the number of gap junctions. The gap junction protein in question is connexin 43. The increase in gap junctions allows communication and Ca++ flow between uterine muscle cells (myometrium) enabling synchronized contractions at labor. Another product of estrogen activity is the upregulation of the enzyme Co-oxygenase 2(Cox2) which is involve in the last step of prostaglandin production prior to labor. Progesterone and estrogen action tend to balance/shift the quiescent state to the contractile state of the myometrium respectively in pregnancy. Prostaglandins have three major effects: (1) to Figure 9: Positive feedback in Parturition strongly stimulate the contraction of uterine smooth muscle cells, (2) to potentiate the contractions induced by OT by promoting formation of gap junctions between uterine smooth muscle cells, and (3) to cause softening, dilation, and thinning of the cervix, which occurs early during labor. Once labor is initiated (stage 1), maternal OT is released in bursts, and the frequency of these bursts increases as labor progresses. The primary stimulus for the release of maternal OT appears to be distention of the cervix; this effect is known as the Ferguson reflex. OT is an important stimulator of myometrial contractions late in labor. During the second stage of labor, OT release may play a synergistic role in the expulsion of the fetus by virtue of its ability to stimulate prostaglandin release. Prostaglandins initiate uterine contractions, and both prostaglandins and oxytocin sustain labor. Relaxin may play a role in keeping the uterus in a quiet state during pregnancy. Production and release of relaxin increase during labor, when relaxin may soften and thus help to dilate the cervix. Positive feedback: Once labor is initiated, several positive feedback loops involving prostaglandins and OT help to sustain it. First, uterine contractions stimulate Physiology: Pregnancy and Parturition Page 9 of 11 Dr. Jeyasuria Pancharatnam prostaglandin release, which itself increases the intensity of uterine contractions. Second, uterine activity stretches the cervix, thus stimulating OT release through the Ferguson reflex. Because OT stimulates further uterine contractions, these contractions become self-perpetuating (Figure 9). Oxytocin also enhances milk ejection by stimulating the contraction of the network of myoepithelial cells surrounding the alveoli and ducts of the breast (galactokinetic effect). 8. Describe the process of lactation The fundamental secretory unit of the breast (Figure 10A) is the alveolus (Figure 10B and C), which is surrounded by contractile myoepithelial cells and adipose cells. These alveoli are organized into lobules, each of which drains into a ductule. Groups of 15 to 20 ductules drain into a duct, which widens at the ampulla—a small reservoir. The lactiferous duct carries the secretions to the outside. Figure 10: Sensory pathways stimulated by suckling that lead to the release of prolactin, Oxytocin and GnRH During puberty, breast development depends primarily on estrogens and progesterone. During pregnancy, gradual increases in levels of prolactin and human placental lactogen (hPL, also human chorionic somatomammotropin), as well as very high levels of estrogens and progesterone, lead to full development of the breasts. Physiology: Pregnancy and Parturition Page 10 of 11 Dr. Jeyasuria Pancharatnam The epithelial alveolar cells of the mammary gland secrete the complex mixture of sugars, proteins, lipids, and other substances that constitute milk. Milk is an emulsion of fats in an aqueous solution containing sugar (lactose), proteins (lactalbumin and casein), and several cations (K+, Ca2+, and Na+) and anions (Cl− and phosphate). The composition of human milk differs from that of human colostrum (the thin, yellowish, milk-like substance secreted during the first several days after parturition). The epithelial cells in the alveoli of the mammary gland secrete the complex mixture of constituents that make up milk by five major routes: 1. Secretory pathway. The milk proteins lactalbumin and casein are synthesized in the endoplasmic reticulum and are sorted to the Golgi apparatus, where lactose is synthetized by lactose synthetase. Water enters the secretory vesicle by osmosis and exocytosis discharges the contents of the vesicle into the lumen of the alveolus. 2. Transcellular endocytosis and exocytosis. The basolateral membrane takes up maternal immunoglobulins by receptor-mediated endocytosis. Following transcellular transport of these vesicles to the apical membrane, the cell secretes these immunoglobulins (primarily IgA) by exocytosis. The gastrointestinal tract of the infant takes up these immunoglobulins, which are important for conferring immunity before the infant's own immune system matures. 3. Lipid pathway. Epithelial cells synthesize short-chain fatty acids. However, the longer chain fatty acids (>16 carbons) that predominate in milk originate primarily from the diet or from fat stores. The fatty acids form into lipid droplets and move to the apical membrane. As the apical membrane surrounds the droplets and pinches off, it secretes the milk lipids into the lumen in a membrane-bound sac. 4. Transcellular salt and water transport. Various transport processes at the apical and basolateral membranes move small electrolytes from the interstitial fluid into the lumen of the alveolus. Water follows an osmotic gradient generated primarily by lactose and, to a lesser extent, by the electrolytes 5. Paracellular pathway. Salt and water can also move into the lumen of the alveolus through the tight junctions. In addition, cells, primarily leukocytes, squeeze between cells and enter the milk. PROLACTIN is essential for milk production, and suckling is a powerful stimulus for prolactin secretion. The actions of prolactin on the mammary glands include: 1. The promotion of mammary growth (mammogenic effect) 2. The initiation of milk secretion (lactogenic effect) 3. The maintenance of milk production once it has been established (galactopoietic effect). Initiating milk production requires prolactin but it also necessitates the abrupt fall in estrogens and progesterone that accompanies parturition. Prolactin is also the primary hormone responsible for maintaining milk production once it has been initiated. Prolactin receptors are present in tissues such as breast, ovary, and liver. Physiology: Pregnancy and Parturition Page 11 of 11 Dr. Jeyasuria Pancharatnam Prolactin stimulates transcription of the genes that encode several milk proteins, including lactalbumin and casein. Suckling is the most powerful physiological stimulus for prolactin release. Suckling has four effects (Figure 10): 1. It stimulates sensory nerves, which carry the signal from the breast to the spinal cord, where the nerves synapse with neurons that carry the signal to the brain. 2. In the arcuate nucleus of the hypothalamus, the afferent input from the nipple inhibits neurons that release dopamine. Dopamine normally travels through the hypothalamic-portal system to the anterior pituitary, where it inhibits prolactin release by lactotrophs. Dopamine is also called a prolactin-inhibitory factor (PIF). Thus, inhibition of dopamine release leads to an increase in prolactin release. 3. In the supraoptic and paraventricular nuclei of the hypothalamus, the afferent input from the nipple triggers the production and release of oxytocin in the posterior pituitary. 4. In the preoptic area and arcuate nucleus, the afferent input from the nipple inhibits GnRH release. GnRH normally travels through the hypothalamic-portal system to the anterior pituitary, where it stimulates the synthesis and release of FSH and LH. Thus, inhibiting GnRH release curbs FSH and LH release and thereby inhibits the ovarian cycle. Several factors act as prolactin-releasing factors (PRFs): thyrotropin-releasing hormone (TRH), angiotensin II, substance P, β endorphin, and vasopressin. During the first 3 weeks of the neonatal period, maternal prolactin levels remain tonically elevated. If the mother breast-feeds, increased prolactin secretion is maintained for as long as suckling continues. After the infant completes a session of nursing, prolactin levels return to their elevated baseline and remain there until the infant nurses again.