[HD 201] E01-T09-Placental Endocrinology_compressed

• Placental endocrinology involves the roles and production of hormones during pregnancy, focusing on the corpus luteum, placenta, and their interplay.
• The fetus controls maternal adaptations during pregnancy to ensure its survival.

Early Pregnancy

• After ovulation, the dominant follicle releases an oocyte that can be fertilized.
• The follicle's remnant transforms into the corpus luteum, producing estrogen and progesterone to prepare the endometrium for implantation.
• If fertilization occurs, the zygote transitions into a morula and then a blastocyst while moving towards the uterus.
• The corpus luteum becomes the Corpus Luteum of Pregnancy (CLP).
• If fertilization fails, the corpus luteum dies within ten days, causing progesterone levels to drop and leading to menstruation.
• After blastocyst implantation, the trophoblast differentiates into cytotrophoblast and syncytiotrophoblast around two weeks post-fertilization.
• Syncytiotrophoblast secretes human Chorionic Gonadotropin (hCG) to rescue the corpus luteum, indicating the embryo's viability.
• The corpus luteum of pregnancy produces necessary hormones before placental takeover, supported by the parents' blood.
• Without hCG (or if fertilization doesn't happen), the corpus luteum regresses, reducing progesterone, leading to endometrium shedding.

Corpus Luteum and the Placenta

• After ovulation, the remaining follicle becomes the corpus luteum.
• It secretes progesterone to prepare the endometrium for implantation through decidualization, along with estrogen, relaxin, and inhibin.
• The corpus luteum sustains the pregnancy until the placenta is fully developed, lasting about 10 weeks.
• The placenta produces progesterone exclusively around 7 weeks AOG.
• Progesterone, estradiol, and inhibin A inhibit pituitary gonadotropin (FSH) production, suppressing ovulation and causing amenorrhea during pregnancy.
• The placenta exclusively produces hormones after week 10.
• Certain procedures on pregnant individuals are delayed to coincide with when the placenta is supporting the pregnancy.
• The placenta starts producing progesterone around the 8th week of gestation.
• By the 10th week GA, the placenta will exclusively produce progesterone, known as the Luteal-Placental Shift.
• Removing the CLP before seven weeks GA leads to spontaneous abortion.

Corpus Luteum Characteristics

• The corpus luteum secretes progesterone, estrogen, relaxin, and inhibin.
• Until seven weeks of gestation, it exclusively produces progesterone.
• The placenta takes over progesterone production from eight weeks AOG.
• Placental takeover of progesterone secretion occurs as early as eight weeks AOG.
• Removal of the corpus luteum before seven weeks results in spontaneous abortion.

Roles of Hormones During Pregnancy

• hCG and the ovary primarily support pregnancy during the first trimester.
• The placenta progressively takes over during the second trimester.
• By the third trimester, the placenta fully supports pregnancy.
• Maturity of the developing baby's lungs, indicated by enhanced surfactant production, kicks off a signaling cascade that ends in parturition.
• The baby signals the mother when it can breathe air on its own.

Feto-Placental Unit

• The fetus influences its adaptations and growth via hormonal messages affecting metabolic processes, uteroplacental blood flow, and cellular differentiation.
• The fetus signals its desire to leave the uterus through hormones.
• The placenta is a hormone production site during pregnancy, forming the interface between maternal and fetal circulations.
• It facilitates maternal physiology adaptations and nutrient transfer while lacking innervation.
• The placenta has no innervations.
• Signaling molecules like secreted substances regulate through paracrine and autocrine action.

Production of Placental Hormones

• Placenta produces steroid and protein hormones at a greater amount and diversity than any other tissue.

Steroid Production Rate

• Estradiol-17B production increases from 0.1-0.6 mg/24hr (non-pregnant) to 15-20 mg/24hr (pregnant).
• Estriol production in pregnancy increases from 0.02-0.1 mg/24hr to 50-150 mg/24hr.
• Progesterone production rises from 0.1-40 mg/24hr to 250-600 mg/24hr during pregnancy.
• Aldosterone production increases from 0.05-0.1 mg/24hr to 0.250-0.600 mg/24hr.
• Deoxycorticosterone production increases from 0.05-0.5 mg/24hr to 1-12 mg/24hr in pregnancy.
• Cortisol production ranges from 10-30 mg/24hr in nonpregnant individuals, to 10-20mg/24hr during pregnancy.

Additional Steroid Hormone Production

• Aldosterone is produced by the maternal adrenal gland due to Angiotensin II stimulation.
• Deoxycorticosterone is produced in non-glandular tissues via 21-hydroxylation of plasma progesterone.
• Cortisol blood levels elevate during pregnancy due to reduced clearance from increased cortisol-binding globulin.
• Steroidogenesis results from interactions from organ systems.
• Fetal, maternal, and placental compartments are related in the final hormone levels.

Feto-Placental Unit Layers

• The trophoblast has two layers: an outer cytotrophoblast and an inner syncytiotrophoblast.
• The syncytiotrophoblast is on the fetal side of the intervillous space, facing the maternal side.
• The villus serves as a bridge between the maternal and fetal compartments.

Enzymes Associated with Steroidogenesis

• 17-Hydroxylase comes from the fetal compartment and transforms pregnenolone into 17-Hydroxypregnenolone and progesterone into 17-Hydroxyprogesterone, placenta lacks this enzyme.
• 3-beta Hydroxysteroid Dehydrogenase (3B-HSD) is produced in the placental compartment and transforms pregnenolone into progesterone and DHEA into androgens, the fetus cannot produce progesterone and corticosteroids on its own.
• Aromatase comes from the placental compartment and transforms androgens to estrogen.
• 21-Hydroxylase transforms progesterone into aldosterone and 17-Hydroxyprogesterone into cortisol.

Placental Steroid vs. Peptide Hormones

• Steroid hormones are cholesterol-derived, including progesterone, estrogens, and glucocorticoids.
• Peptide hormones include human chorionic gonadotropin (HCG), human placental lactogen, cytokines, growth hormones, insulin-like growth factors, corticotropin-releasing hormone, vascular endothelial growth factor and placental growth factor.

Placental Steroid Hormones - Progesterone

• Ovarian progesterone is minimal after the 6th to 7th week of AOG.
• Surgery to remove corpus luteum or both ovaries before the 7th week causes miscarriage, unless progestin is given.
• Around eight weeks AOG, the placenta is in charge of progesterone secretion throughout pregnancy.
• By the end, progesterone levels are 10-5000 times higher than in non-pregnant women.
• By term GA, progesterone levels are 100-200 ng/mL.
• Placenta produces about 250 mg/day but more in multifetal pregnancies at >600 mg/day
• Most progesterone produced by the placenta goes into the mother's blood.

Progesterone Levels during Pregnancy

• Progesterone is largely produced by the Corpus Luteum until about the 10th week GA.
• There is Luteal-Placental Shift from the 7th to 10th week GA during which the placenta emerges as the major provider of progesterone synthesis.
• Maternal circulating levels progressively increase.
• Progesterone concentration during the Luteinizing Hormone (LH) phase increase from 1-2 ng/mL to a plateau of 10-35 ng/mL over 7 days.

Progesterone Synthesis

• Involves a 2-step reaction with cholesterol in the mitochondria and endoplasmic reticulum.
• In the mitochondria; cholesterol converts to pregnenolone via cytochrome P450.
• In the endoplasmic reticulum; pregnenolone converts to progesterone via 3β-Hydroxysteroid Dehydrogenase.
• Maternal plasma cholesterol is the principal precursor of progesterone biosynthesis.

Progesterone Details

• Fetuses essentially do not contribute to the creation of progesterone.
• Trophoblasts use LDL-cholesterol
• Progesterone prepares the endometrium for implantation and suppresses the maternal immunologic response to fetal antigens, and has no relationship with fetal well-being, instead that is placental estrogen.
• Serves as a substrate for fetal adrenal gland production of both glucocorticoids and mineralocorticoids.
• There is a relationship between fetal well-being and placental estrogen production, and this is not the case for placental progesterone.
• The main pathway of progesterone metabolism is 5a reduction of progesterone which disproportionately raises plasma concentration of 5a-dihydroprogesterone.
• Progesterone is derived from maternal cholesterol, enters trophoblast from maternal blood, uses LDL cholesterol (enhanced by estrogen), where hydrolysis yields amino acids.

Progesterone Characteristics

• Is produced by the corpus luteum (before the 10th week) and placenta (after 10th week).
• It uses maternal LDL cholesterol.
• Is regulated by estrogen which increases LDL uptake, stimulates cholesterol production, and increases enzyme activity.
• Regulation prepares endometrium for implantation and causes decidualization.
• Promotes quiescent uterus during pregnancy.

Placental Steroid Hormones - Estrogen

• Estrogen in pregnancies is under the control of the fetus and how the fetus tells the body about the processes that affect fetal health.
• Estriol is the estrogen produced in the greatest quantity and increased by about a thousand fold.
• Estrone and estradiol are derived from both fetal and maternal precursors.
• Estradiol is higher than in the fetus but estriol is greater in the fetus.
• Divided into four types of estrogens: E1, E2, E3 and E4.
• Can cause a hypercoagulable state.

More Estrogen Details

• Estrogen during early stages of pregnancy maintain estradiol production from the corpus luteum.
• The major source of fetal adrenal DHEAS is LDL cholesterol circulating in the fetal blood.
• The minor source of fetal adrenal DHEAS is derived from pregnenolone secreted by the placenta
• Requires placental expression which are principally in syncytiotrophoblast.

Estrogen Production

• Requires steroid 17-hydroxylase/17,20-lyase (CYP17)
• Fetal adrenal glands are the most important source of placental estrogen precursors.

Estrogen Biosynthesis

• The pathways of estrogen made during pregnancy comes from ovaries.
• In the early months fetal androgen compounds derived from maternal bloodstream is used, but by the 20th week, the majority of maternal urine is derived from fetal androgens.

Estrogen Formation Details

• Estrogen gets transferred to placenta and converted via enzyme to get transferred to maternal.
• Near term, half of estradiol is from fetal adrenal, and half from maternal and is primary estrogen product at term.

Role of Estrogen

• Maternal cardiovascular adaptations regulated by estrogen.
• Blood volume is increased due to stimulation of maternal and trophoblastic renin-angiotensin.
• Functions involved in progesterone production, blood flow, mammary gland development, and regulates the adrenal glands.

Estrogen Production Issues

• Can lessen due to reduced trophic fetal influence
• Fetal can be anencephaly, or fetal adrenals can have hypoplasia.
• Reduction from X linked disorder, or autosomal recessive. Can increase from hyperstimulation with multiple gestations.

Estrogen Summary

• In short, produced by Luteum mostly, placenta, precursors or has roles and comes in various forms.

Placental Unit

• The placental villus is composed of trophoblast, mesenchymal cells, and fetal blood vessels.
• Note the two layers, Cytotrophoblast and Syncytiotrophoblast with the functions of each.

Human Chorionic Gonadotropin (hCG)

• Also known as the "pregnancy hormone"
• Glycoprotein used with biologic activity similar to luteinizing hormone (LH).
• Detection is an indicator of pregnancy.
• Has a long half life.

Human Chorionic Gonadotropin Structure

• Composed of 2 dissimilar subunits being α-92 amino acids and β-145 amino acids and are structurally related to 3 other glycoprotein related cells, the LH, FSH, and TSH.

Functions of HCG

• Both LH/hCG subunits are required to bind to receptors for both in corpus luteum and and fetal testis.
• Maximum testosterone secretion attained and acts as LH.
• Promotes sexual differentiation.
• Via the binding of hCG with some TSH receptors on thyrocytes.
• Stimulates the thyroid activity stimulates production and has other functions on targets.

HCG Levels

• Levels change during high and low based on if high multiple pregnancy.

Human Placental Lactogen

• Also called "human chorionic somatomammotropin" or "chorionic growth hormone"
• Secreted by the syncytiotrophoblast.
• HPL is used by most and its greatest of any known hormone in body.

Levels Details

• The hormone begins to rise in maternal plasma and it decreases when the fast turns to feed and it increases when fasting.

What It Does

• As well as the other hpl properties it serves as a potent angiogenic hormone and performs the process in pregnancy.

Summary of HPL

• Well made is a good structure simula that has properties and regulates functions.