Placental & Fetal Physiology PDF Notes - August 2023

August 29, 2023 PHYS: Placental & Fetal Physiology Page 1 of 10 Placental & Fetal Physiology Instructor: Nanette Tomicek, PhD ([email protected]) Block 5: Urology/Endocrine/Reproduction Thread: Physiology Conflicts of Interest: Dr. Tomicek has no conflicts of interest to disclose. Le...

August 29, 2023 PHYS: Placental & Fetal Physiology Page 1 of 10 Placental & Fetal Physiology Instructor: Nanette Tomicek, PhD ([email protected]) Block 5: Urology/Endocrine/Reproduction Thread: Physiology Conflicts of Interest: Dr. Tomicek has no conflicts of interest to disclose. Learning Objectives By exam time, you should be able to: 1. Describe the development and timing of transport of the blastocyst to the uterine wall. 2. Explain the roles of progesterone and estrogen in the preparation of the oviduct and uterus for receiving the developing embryo during a normal menstrual cycle. 3. Describe the process of implantation and formation of syncytiotrophoblast from the embryonic trophoblast and functional layer of the endometrium. 4. Evaluate the importance of human chorionic gonadotropin (hCG), and describe the role hCG in the maintenance of the corpus luteum in early pregnancy. 5. Outline the steps required in the development of the placenta including extraembryonic membranes. 6. Identify the fetal and maternal sources estrogens and progesterone across trimesters and describe the cooperation between the maternal compartment and fetoplacental unit. Study Questions 1. What is the syncytiotrophoblast, and how does it interact with the uterus and corpus luteum to coordinate hormone signaling pathways needed to maintain early pregnancy (1st trimester)? 2. How is it possible for fetal and maternal blood to make gas, nutrient, and waste exchange, but never mix whole blood during pregnancy? 3. How does the maternal-placental-fetal unit work together to synthesize progesterone, and estrogens needed for pregnancy maintenance without masculinizing or feminizing the fetus during development? Placenta Formation Begins with Implantation  Fertilization occurs in the uterine tube. o Rapid cell division yields morula by day 3 August 29, 2023 PHYS: Placental & Fetal Physiology Page 2 of 10 o Blastocyst forms by day 6 o Trophoblast (nourishment generator)- single layer of flattened cells  Major contribution to chorion • Embryo’s half of placenta o Embryoblast- inner cell mass  Generates embryonic disc • o  Embryo plus extraembryonic membranes “Hatching” from zona pellucida Implantation occurs at day 7. Implantation Timing Requires Coordination with Uterine Cycle • Day 21 of menstrual cycle o Mid-luteal phase of ovarian cycle o Secretory phase of uterine cycle  Predecidualization • • Marked by tortuous endometrial glands Stromal cells surrounding spiral arteries enlarge o Marked by high E2 and P4  Progesterone produced by corpus luteum for first 3 mo of pregnancy (1st trimester) • Implantation takes 5 days, day 26 of menstrual cycle o If failure menses at 28 days→ new cycle starts Implantation & Differentiation of Trophoblast layers • Apposition-loose connection o Paracellular cytokine communication • Adhesion o CAMs on uterine surface bind trophoblast August 29, 2023 PHYS: Placental & Fetal Physiology Page 3 of 10 o Pinopodes (finger like projections) appear  2-3 day window, endocytose uterine fluid, facilitate implantation o Inner cell mass faces uterus and burrows inward • Invasion (complete by day 11) o Trophoblast digests endometrial surface and releases growth factors o Cytotrophoblast- inner cell layer o Syncytiotrophoblast- outer layer; one big multinucleate mass  digests uterus with hyaluronidase Decidua is the Specialized endometrium of pregnancy • Uterine inflammatory response & decidualization o Lymphocytes, NKs, and M accumulate o Vessels become permeable, leaky and a pool of blood forms around site o Stromal cells complete differentiation into decidual cells  Secrete laminin, fibronectin, heparin sulphate, and type IV collagen matrix  Generates superficial layer zona compacta of endometrium, and a deep Zona spongiosa maintains glands. Edema distinguishes layers • Decidualization is most prominent during the first trimester, but elements persist even after placenta forms • Decidua basalis – portion deep to embryo • Decidua capsularis – portion overlying embryo o Zona compacta is encapsulating embryo by day 11 • Decidua parietalis – portion covering sides of uterus Human Chorionic Gonadotropin Maintains Corpus Luteum & Progesterone Levels o Syncytiotrophoblast secrets human chorionic gonadotropin (hCG) o Functions similar to pituitary LH, but not subject to H-P-O axis control August 29, 2023 PHYS: Placental & Fetal Physiology Page 4 of 10 o Target organ corpus luteum (CL) continues to secrete progesterone and estrogens if “rescued” by hCG o hCG also contributes to immunosuppression of mother. o hCG detectable in immunoassay 2 days post implantation ~ Day 14*  Levels rise for 2 months, peak, drop by 3 months • CL degrades, and placenta must be functional at that point to support pregnancy or miscarriage will result. *Be aware of conventions. Day 14 here is day 14 of the embryo’s life. In medicine it is common to count from the last menstrual period (LMP) so a practicing physician would consider this day 28 or the 4 weeks into pregnancy. Extraembryonic Membranes o Day 14 embryo is now encapsulated by endometrium o Extraembryonic membranes start to form  Yolk sac (vestigial)- Early food source  Amnion- shock absorber  Allantois -mostly vestigial/umbilical cord/bladder  Chorion- Forms behind syncytiotrophoblast & creates villi for blood flow/second step in creating placenta Formation of the Placenta & Extra Embryonic Membranes o Embryo and Endometrium both contribute o Embryo contribution  inner cell mass generates layer of extraembryonic mesoderm and migrates deep to cytotrophoblast o Maternal Contribution  Endometrial vessels • • Lacunae form in Syncytiotrophoblast Cytotrophoblast cells invade endometrial veins then spiral arteries • • Form primary chorionic villi Direct communication formed • Blood pool will supply fetus August 29, 2023 PHYS: Placental & Fetal Physiology Page 5 of 10 o By 15 days primary chorionic villi formed o Trophoblast invasion of endometrium o Secondary chorionic villi form o Extraembryonic mesoderm invasion o By 20 days tertiary chorionic villi form o mesoderm forms fetal vessels de novo o Meanwhile embryo is gastrulating! o Chorion formation complete with mature villi o Superficial surface of villus→ deep  Thin layer of syncytiotrophoblast with brush border facing maternal blood pool (intervillous space)  Sparse cytotrophoblasts  Mesenchymal cells (from mesoderm)  Fetal vessels • Migrate to form chorionic plate (forest of vessels) at basalis contact point o Final result is a VERY thin layer separating maternal and fetal blood. o Placenta (basalis plus plate) formation complete at 3 months (end of 1st trimester) o Timed with loss of CL o By 4th month o Placenta has expanded to fill uterus o Capsularis meets paritalis o Fetus is enclosed in both chorion and underlying amnion  Amnion- protects from mechanical shock  5-10 mL at 8 weeks, expands as fetus grows to 1-1.5 L o Allantois  Gives rise to umbilical cord then later urinary bladder Chorionic Villus Sampling (CVS) o A method of sampling fetal cells o Invasive, samples extracted from chorion  catheter inserted through the vagina or abdominal wall into the uterus August 29, 2023 PHYS: Placental & Fetal Physiology o Advantage, early sampling  performed as early as 8th week of pregnancy Amniocentesis o Usually performed in the 16th week of pregnancy o Less invasive than CVS, but can’t be done until enough amniotic fluid exists o Tests sloughed of fetal cells suspended in amnion Placental Complications o Abruption -Placental early detachment o Fetus may be undernourished o Hemorrhage for mother o Placental previa, cervix is covered Blood Flow o Maternal flow o ~120 spiral arteries discharge into intervillous space o Flow is pulsatile  Velocity dissipates as blood enters “pools” surrounding villi  Note no capillary bed here, intervillous space is the capillary o Venous blood drain from plate →placental veins → uterine & pelvic veins o Uterine contractions can impede flow o Fetal flow o Fetal blood (deoxygenated) originates from 2 umbilical arteries  Branch at amnion → penetrate chorionic plate→ villi o Fetal blood (oxygenated) returns via umbilical vein The Maternal-Placental-Fetal Unit o Joint effort needed for steroid biosynthesis o Progesterone is critical for maintaining pregnancy, estrogens also needed. o CL- not sufficient for late pregnancy Page 6 of 10 August 29, 2023  PHYS: Placental & Fetal Physiology Page 7 of 10 Replaced by placenta at 2-3 months o Placenta-lacks key enzymes needed for steroid biosynthesis  Mother & Fetus both assist with pathway  Products needed: • • • • Progesterone Estradiol (E2) Estriol (E3) Estrone (E1) o Mother o Source of cholesterol precursor o Placenta o Source of progesterone o Sink for androgens  Prevents masculinization of fetus o Fetal Adrenal Gland o Source of enzymes in Estrogen pathways o Fetal adrenals are larger than adult at term o Regulation! o Fetus cannot make estrogens alone  Does not have enzymes need to finish pathway •  Stops at DHEA step Fetal exposure to high estrogen can dangerously disrupt development • Conjugates intermediates with sulfate lowering bioactivity o The Maternal-Placental-Fetal Unit Steroidogenesis Pathways o See PowerPoint slides for diagrams/Review notes from steroidogenesis lectures Hormones and Preparing for Parturition o What is the trigger? The Placental Clock. o Countdown to estrogen dominance! August 29, 2023  PHYS: Placental & Fetal Physiology Page 8 of 10 Placental Progesterone is high for the duration of pregnancy • • Uterus is quiescent (Relaxin may also contribute) If estrogen concentration > progesterone → myometrium of uterus is activated for labor (increasing number of oxytocin receptors) o Hormones interacting/ controlling the clock come from both the fetus and placenta  Fetal ACTH also thought to signal  Prostaglandins stimulate uterine contractions, thought to initiate! August 29, 2023 PHYS: Placental & Fetal Physiology Page 9 of 10 Answers to Study Questions These answers are not meant to be all encompassing; rather they are examples of the types of thought processes needed for application of the material. 1. What is the syncytiotrophoblast, and how does it interact with the uterus and corpus luteum to coordinate hormone signaling pathways needed to maintain early pregnancy (1st trimester)? The syncytiotrophoblast is the structure responsible for digesting and invading uterine tissue to securely implant the embryo within the uterus. This creates areas of decidualization in the uterus including basalis which is the site of implantation deep to the embryo, and the decidua capsularis which forms by uterine tissues enveloping around the free wall of the embryo. The syncytiotrophoblast also secretes hCG which signals to directly to the CL and maintains its presence. The CL in turn continues to produce progesterone and estrogen to maintain the pregnancy. The CL will degrade after 3months, but this is generally enough time to form a placenta to take over hormone production for the remainder of pregnancy. hCG is commonly used in pregnancy assays and can be detected at 2 weeks after conception, or 4 weeks from the last menstrual period. 2. How is it possible for fetal and maternal blood to make gas, nutrient, and waste exchange, but never mix whole blood during pregnancy? The placenta is a shared structure made from both material and embryonic tissues. Fetal chorionic villi are generated from the invading cytotrophoblast. Maternal vessels are broken down by the syncytiotrophoblast and form pools of blood within lacunae and eventually become the intervillous space. A thin layer of syncytiotrophoblast, cytotrophoblast, and mesenchyme maintain separation between the maternal pool and the newly generated fetal vessels. This layer is thin enough to promote exchange of gases, wastes and nutrients, but not exchange of larger structures found in whole blood. 3. How does the maternal-placental-fetal unit work together to synthesize progesterone, and estrogens needed for pregnancy maintenance without masculinizing or feminizing the fetus during development? The maternal-placental fetal unit work together to make progesterone and estrogen needed for pregnancy, however no one organ has all elements needed (precursor, enzymes or products). The mother provides the precursor for steroidogenesis, cholesterol. The placenta has aromatase, which can convert androgens to estrogens (this can’t be done in the fetus as it can feminize structures and disrupt development), the fetus has hormones to make intermediates in the estrogen pathways but cannot finish the pathway as the without the help of the placenta and aromatase. Much of the DHEA intermediate the fetus makes is conjugated with sulfate to lower its bioactivity and prevent the fetus from over exposure to androgens and masculinization. See table on following page for summary. August 29, 2023 PHYS: Placental & Fetal Physiology Page 10 of 10 Further Reading Boron WF, Boulpaep EL. Medical Physiology a Cellular and Molecular Approach. 2nd ed., updated. Saunders Elsevier; 2012. (Available online to students via the Scott Library)