1. PLACENTAL HORMONES
Liza A. Tarca – Cruz, MD
Department of Obstetrics & Gynecology
Emilio Aguinaldo College of Medicine – Medical Center Manila
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3. Pre Test
1 – 3. Give 3 functions of the human placenta.
4 – 6. Give 3 hormones produced by the human placenta.
7. True or False – Placenta acts as an endocrine organ
during pregnancy
8. What is the hormone of pregnancy?
9. At what age of gestation does the placenta takes over in
the production of important pregnancy hormones
10. How many important enzymes are in the conversion of
DHEAS to Estradiol?
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4. Objectives
• To discuss in passing the functions of the
placenta
• To be able to discuss the different
placental hormones
– Properties
– Role in Pregnancy
– Associated Medical Condition
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20. Human Placental
Gonadotropin (hPL)
• Detectable:
– Serum: 2nd - 3rd week after
fertilization
– Placenta: 5 – 10 days after
conception
• Max: near term (34 – 36 weeks)
•
– ½ life: 10 – 30 mins
– 5 – 15 μg/mL (serum, late
pregnancy)
Placental Mass
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32. Pre Test Answers
1 – 3. Give 3 functions of the human placenta.
latcruzmd2013
33. Pre Test Answers
4 – 6. Give 3 hormones produced by the human placenta.
latcruzmd2013
34. Pre Test Answers
7. True or False – Placenta acts as an endocrine organ
during pregnancy
During pregnancy, the placenta acts as a temporary
endocrine tissue that secretes important placental
hormones needed to sustain pregnancy. The human
trophoblasts produces a great amounts of steroids and
protein hormones than any other endocrine tissue.
latcruzmd2013
35. Pre Test Answers
8. What is the hormone of pregnancy?
Human chorionic gonadotropin or hCG is a glycoprotein
that is known to be the pregnancy hormone thus its
presence in blood or urine is almost always indicative of
pregnancy.
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36. Pre Test Answers
9. At what age of gestation does the placenta takes over in
the production of important pregnancy hormones
7th week Age of Gestation
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37. Pre Test Answers
10. How many important enzymes are in the conversion of
DHEAS to Estradiol?
4 key enzymes DHEA-S Estradiol
1.High level of Steroid Sulfatase (STS)
DHEAS DHEA
2.3β Hydroxysteroid Dehydrogenase Type 1 (3βHSD)
DHEA Androstenedione
3.Cytochrome p450 Aromatase (CYP19)
Androstenedione Estrone
4.17β Hydroxysteroid Dehydrogenase (17βHSD1)
Estrone Estradiol
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Editor's Notes
Transfer of Gas
Diffusion of oxygen and carbon dioxide through placental membrame (similar to diffusion that occurs in the lungs)
Dissolve oxygen in maternal blood passes through placenta into fetal blood
Takes place as result of increase in partial pressure of oxygen in mother’s blood compared to fetus
Fetal carbon dioxide pressure accumulates a low pressure gradient of carbon dioxide develops across placental membrane
Carbon dioxide diffuses from fetal blood to maternal blood
Transport of Nutrients
Other metabolic substrate that fetus needs diffuse into blood in the same manner as oxygen
Glucose in fetal blood about 20 to 30% lower than materna blood
Results in rapid diffusion of glucose to fetus
Transport other substrate, fatty acids, potassium, sodium and chloride
Actively absorbs some nutrients from maternal blood
Excretion of Wastes
Diffuse from fetal blood to maternal blood
Urea, uric acid and creatinine
Excreted with waste products of the mother
Transfer from fetal circulation to maternal circulation moving osmotically from higher concentration to lower concentration as carbon dioxide
Formation of Barrier
-Placenta forms some barrier against some harmful substances in mother’s circulation
-Partially selective and does not fully protects fetus
-Medications that crosses the placenta (steroids, narcotics, anesthetics, antibiotics)
Hormone Production
- Placenta becomes a temporary endocrine gland which secretes estrogen and progesterone
During pregnancy, the placenta acts as a temporary endocrine tissue that secretes important placental hormones needed to sustain pregnancy. The human trophoblasts produces a great amounts of steroids and protein hormones than any other endocrine tissue.
The human placenta synthesizes enormous amount of protein and peptide hormones as well as hypothalamic like releasing and inhibiting hormones as seen in the slide.
The table in this slide is lifted from williams obstetrics 23rd edition section 2 in the topic maternal and fetal anatomy and physiology in the chapter of implantation, embryogenesis and placental development (page 62).
Estrogens and progesterone are produced by the placenta, while aldosterone are from maternal adrenal in response to the angiotensis II stimulus. The deoxycortisone are from extraglandular tissues thru 21-hydroxylation of plasma progesterone.
Human chorionic gonadotropin or hCG is a glycoprotein that is known to be the pregnancy hormone thus its presence in blood or urine is almost always indicative of pregnancy.
Its biological activity similar to leutenizing hormone (LH) wherein both act in the plasma membrane LH-hCG receptor.
hCG is almost exclusively produced in the placenta however the fetal kidney was found to synthesize the hormone as well. There is a little amount of hCG seen in the tissues of men and nonpregnant women which is believed to be from the production in the anterior pituitary gland.
High levels of hCG is said to be related to various malignant tumor such as trophoblastic neoplasm thus used as a tumor marker in gynecology. (seminoma, choriocarcinoma, germ cell tumors, h. mole, teratoma, islet cell tumors, testicular ca)
hCG has the highest carbohydrate content in any human hormone which accounts to 30%. The carbohydrate component specially the terminal sialic acid protects it from catabolism.
The plasma half life of hCG is 36 hours (LH 2 hours)
It is composed of 2 dissimilar subunit which are the alpha subunit containing 92 amino acids with all its glycoprotein contents are identical and the beta subunit containing 145 amino acids and has distinctly different amino acid sequence sharing only certain similarities.
Both alpha and beta chain synthesis are regulated separately. A single gene located on chromosome 6 encodes the alpha subunit for hCG, LH, FSH and TSH. There are 7 genes on chromosome 19 that codes 6 genes for beta hCG and 1 for beta LH.
Circulating free beta subunit levels are low to undetectable throughout pregnancy. While the free alpha subunit are seen in the placental tissue and maternal plasma which gradually and steadily increases until it plateau at 36 weeks. The alpha hCG secretion corresponds to the placental mass.
**Complete hCG (alpha and beta) is maximal at 8 to 10 weeks.
Before 5 weeks hCG is expressed in both cytotrophoblast and syncytiotrophoblast but later on, as the maternal serum level peaks, hCG is solely produced by syncitiotrophoblast.
**syncytiotrophoblast – epithelial covering of the highly vascular embryonic placental villi which imvades the wall of the uterus to establish nutrient circulation between the embryo and the mother. [roduces progesterone, hCG and hPL.
**cytotrophoblast – layer of langhans is the inner layer of trophoblast
**trophoblast – cells forming the outer layer of the blastocyst which provides nutrients to the embryo anddevelop into a large part of the placenta
The GnRH from the maternal pituitary and placental GnRH are involved in the regulation of hCG production in the placenta (which are expressed in both syncitio and cytotrophoblast). Activin and Inhibin produced from the maternal pituitary regulates the release of GnRH which stimulates the syncititrophoblast to secrete the hCG and later on hCG circulates and metabolized in the maternal liver and kidney.
Renal clearance accounts for 30% of its metabolic clearance and the remainer (70%) by the liver.
Intact hCG level is detectable in plasma of pregnant women 7 to 9 days after the midcycle LH surge that precedes ovulation and enters the maternal blood at the time of blastocyst formation with doubling time every 2 hours and maximal during 8 to 10 weeks then starts to decline at 10 to 12 weeks followed by nadir at 16 weeks and remains throughout pregnancy.
Pattern of hCG appearance in fetus is similar to that of the mother but the fetal plasma level is only 3% of their mother.
Amniotic fluid level is same as the mother during early pregnancy, declines as pregnancy progresses and near term is about 20% level of the maternal plasma.
The best known biological function of hCG is the so called rescue and maintenance of function of the corpus luteum which is continued progesterone production (by about two weeks). Another is by promoting relaxin secretion by the corpus luteum which was believe to promote uterine vascular vasodilatation and myometrial smooth muscle relaxation.
hCG also stimulates fetal testicular testosterone (as seen from the previous slide) which is maximum approximately when peak levels of hCG are attained and believed to be a critical time for sexual differentiation of the male fetus.
Since there is no vascularization at the fetal anterior pituitary from the hypothalamus there is only little LH secretion thus hCG act as LH surrogate to stimulate leydig cell replication and testosterone synthesis.
Development of hyperthyroidimsm in cases of high hCG level such us in GTD was attributed in the formation of chorionic thyrotropins by neoplastic throphoblast and some hCg binds with the TSH receptors in thyrocytes as well as the stimulation of the LH-hCG receptors which are also present in the thyrocytes.
Very high levels of hCG are seen on the following:
Multifetal pregnancy – more trophoblast, more hCG secreted
Erythroblastosis fetalis + fetal hemolytic anemia – enlargement of liver and spleen with accumulation of hCG (70% of hCG are metabolized in the liver)
GTD – cancer cells secretes beta subunit of hCG. Trophoblast but without villi secretes hCG
Down syndrome – 5x more than normal level of pregnancy, unexplained physiology
While low levels predicts early pregnancy wastage and ectopic pregnancy. As mentioned hCG maintains the function of corpus luteum for progesterone production to sustain pregnancy therefore low hCG means low progesterone then inability to hold pregnancy.
Due to its potent lactogenic and growth hormone like bioactivity as well as immunochemical similarity to human growth hormone it was called human placental lactogen or chronic growth hormone.
It has also been referred to as chorionic somatomammotropin
Also similar to hCG, it is demonstrated in both cyto and syncitiotrophoblast before 6 weeks but remains to be concentrated in the syncitiotrophoblast thereafter.
It is detected as early as 2nd to 3rd week post fertilization.
hPL is a single non glycosylated polypeptide chain (with molecular weight of 22,279Da) that contains 191 amino acids (hCG 188) with 96% sequence homology.
It is said to be structurally similar to prolactin.
There are 5 genes located at chromosome 17 .
The production of hPL near term is about 1 gram/day is by far the greatest known hormone in human
hPL is demontrable in the serum as early as 2nd to 3rd week after fertilization and in the placenta within 5 to 10 days after conception.
Maternal plasma concentration is linked to placental mass (like hCG) and may reach up to 5-15micrograms/mL in the serum during late pregnancy (which is higher than any other protein hormone)
**There is very little hPL detected in fetal blood or in urine of both fetus and mother and the amniotic fluid levels are somewhat lower than the plasma because it is secreted primarily into the maternal circulation.
hPL has putative actions in number of important metabolic processes such as maternal lipolysis where hPL aids in increasing the free fatty acid in the circulation so it can be a source of energy both for maternal metabolism and fetal nutrition.
hPL also has anti-insulin or diabetogenic effect which leads to increase maternal insulin level favoring protein synthesis and provides ready source of amino acids for the fetus. (also hPL is the hormone expected to rise during 24th to 28th weeks age of gestation, since it has anti-insulin effect, the maternal blood should have high level of blood sugar)
**hPL decreases maternal insulin sensitivity, and, therefore, raises maternal blood glucose levels, whilst decreasing maternal glucose utilization, which helps ensure adequate fetal nutrition (the mother responds by pancreatic endocrine upregulation).
And it has potent angiogenic property that play an important role in the formation of fetal vasculature.
ACTH, lipotropin and beta endorphin are all proteolytic products of proopiomelanocortin recovered from placental extracts. Actually, the physiologic role of ACTH is unclear however it is believed to be controlling fetal lung maturition and the timing of parturition. ACTH level increases during pregnancy thru the regulation of the CRH or corticotropin releasing hormone which I will tackle in a little while. Remember that ACTH is secreted into both maternal and fetal circulation however the maternal ACTH is not transported to the fetus.
Relaxin expression has been demonstrated in the Corpus Luteum ( 2 out of 3 – H2 & h3 others – h1 & h2), Decidua, and Placenta and is said to be structurally similar to insulin & Insulin Like Growth Factor. The rise in the maternal circulation in early pregnancy is attributed to the secretion in the corpus luteum which parallels the hCG production. It peaks at 14 weeks and during delivery. It is believed that relaxin alongside with progesterone acts on the myometrium to promote Relaxation & Quiescence to keep pregnancy during the early trimester. Relaxin also plays an important autocrine and paracrine role in the postpartum regulation of extracellular matrix degradation.
**mediate hemodynamic changes in pregnancy (increase cardiac output, renal blood flow and compliance of arteries. Relaxes pelvic ligaments and softens pubic symphysis.
Circulating levels of PTH-rP are significantly elevated in pregnancy within the maternal but not fetal circulation. Synthesis are seen in the Myometrium, Endometrium, Corpus Luteum & Lactating Mammary Tissues which plays important autocrine paracrine role to activate trophoblast receptors to promote calcium transport for fetal bone growth and ossification.
The placenta expresses a growth hormone variant which is not expressed in the pituitary also known as placental growth hormone. The gene is located in hGH-hPL at chromosome 17 and synthesis is located at the syncitium. This variant is detected in the maternal plasma at 21 to 26 weeks and increases until 36 weeks and plateau thereafter. The fact that hGH-V level in maternal plasma inhibits glucose in dose dependent manner arrived in the conclusion that hGH-V causes severe insulin resistance during pregnancy. (like hPL)
The hypothalamic like releasing or inhibiting hormones have analogous counterparts produced by the placental hormones.
GnRh is found in the cytotrophoblast but not in the syncitiotrophoblast and its function is to regulate the trophoblast hCG production hence the observation that GnRH levels are higher in early pregnancy.
**pituitary GnRH controls level of FSH and LH but once pregnancy sets in, its activity is not established.
CRH produced in nonpregnant is low at 5 -1 0pmol/L as compared to pregnancy which increases up to 500pmol/L specially during the last 5 to 6 weeks of conception. The biologic function of CRH is synthesized in the Placenta, Adrenal Glands, Sympathetic Ganglia, Lymphocytes, GIT, Pancreas, Gonads & Myometrium. CRH as discussed earlier increases ACTH level supporting the autocrine paracrine role and involved in the parturition initiation (CRH is a marker that determines the length of gestation and the timing of parturition and delivery). A rapid increase in circulating levels of CRH occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, CRH may act as a trigger for parturition. Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition: Increases levels of dehydroepiandrosterone (DHEA) directly by action on the fetal adrenal gland, and indirectly via the mother's pituitary gland. DHEA has a role in preparing for and stimulating cervical contractions.
Increases prostaglandin availability in uteroplacental tissues. Prostaglandins activate cervical contractions.
Prior to parturition it may have a role inhibiting contractions, through increasing cAMP levels in the myometrium.
It is also important to remember that the glucocorticoids released in the hypothalamus inhibits CRH release but in the contrary, glucocorticoids released by placental trohoblast stimulates CRH expression.
The role of placental derived GHRH is unknown but another regulator of hGH secretion known as ghrelin peaks during midpregnancy which regulates the production of hGH-V.
Leptin is a placental peptide hormone secreted normally by adipocytes and are synthesized in both Cytotrophoblast and Syncitiotrophoblast. It functions as an anti-obesity hormone by decreasing food intake through the hypothalamic receptor. It is also believe to regulate bone growth and immune function as well as the hormone believed to be correlated with fetal development and growth thus the fetal leptin level is correlated with fetal birthweight. The principle behind this is the inhibition of apoptosis and promotion of trophoblast proliferation.
Neuropeptide Y is widely distributed in the brain specifically the sympathetic neurons that innervates the cardiovascular, respiratory, gastrointestinal and genitourinary systems. It was isolated in the cytotrophoblast of the placenta and its role is to promote CRH release.
Inhibin is a glycoprotein hormone produced in the human testis and ovarian granulosa cells which includes corpus luteum that acts by inhibiting FSH release thereby inhibiting ovulation during pregnancy and released by the maternal pituitary to act on the GnRH to regulate placental hCG synthesis.
Activin is closely related with inhibin possesing 2 beta subunits and are expressed in the placenta and amnion which acts on GnRH synthesis. Before labor it is undected but as labor ensues it becomes detectable at the umbilical cord and declines steadily after delivery.
After 6 to 7 weeks gestation, very little progesterone is produced in the ovary that’s the reason why surgical removal of the corpus luteum or having a bilateral oophorectomy after the 7th week does not cause a decrease in excretion of urinary pregnanediol the principal urinary metabolite of progesterone. So if the surgery occurs before the 7th week then it will cause miscarriage unless an exogenous progestin is given.
After approximately 8 weeks, the placenta assumes the progesterone secretion and continuous to increase its level as evident in the maternal serum level throughout pregnancy.
The daily production of progesterone in the late, normal, singleton pregnancy is about 250mg while in multifetal pregnancy the rate may exceed 600mg/day
Progesterone is synthesized from cholesterol in a 2 step enzymatic reaction. first, cholesterol is converted to pregnenolone within the mitochondria in a reaction catalyzed by cytochrome p450 cholesterol side chain cleavage enzyme. Pregnenolone leaves the mitochondria and is converted into progesterone in the endoplasmic reticulum by 3beta hydroxysteroid dehydrogenase and released via diffusion.
The rate limiting step enzyme in cholesterol biosynthesis is the 3hydroxy 3 methylglutaryl coenzyme A (HMG CoA) reductase hence the placenta rely on exogenous cholesterol for progesterone formation and uses LDL for the progesterone biosynthesis
Progesterone metabolic clearance in pregnant is similar to men and non pregnant which is important in the initiation of parturition thru conversion to mineralocorticoid deoxycorticosterone.
During the 1st 2 to 4 weeks of pregnancy, the rising hCG levels maintain the production of estradiol in the maternal corpus luteum.
And like progesterone, at 7th week ovarian secretion of estrogen declines significantly. By the 7th week, more than half of estrogen entering the maternal circulation is produced in the placenta
The placenta then produces huge amount of estrogen using the blood borne steroidal precursors from the maternal and fetal adrenal glands. Near term, normal human pregnancy is a hyperestrogenic state and the syncytiotrophoblast produces estrogen equivalent to that produced in 1 day by the ovaries of no fewer than 1000 ovulatory women. The hyperstrogenic state terminates abruptly after delivery.
Placental estrogen synthesis differs from that of the ovary. Estrogen production in the ovary takes place during the follicular and luteal phase thru the interaction of theca and granulosa cells. Specifically, androstenedione us synthesized in the ovarian theca and then trasnferred to adjacent granulosa cells for estradiol synthesis.
In the trophoblast cholesterol nor progesterone cannot be a precursor for estrogen synthesis because the crucial enzyme for sex steroid synthesis the 17 alpha hydroxylase is absent in the placenta.
The c19 steroids dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) or the adrenal androgen serves as precursor for estrogen placental synthesis.
The conversion of DHEAS to Estradiol requires 4 key enzmes (discuss)
Fetal demise, ligation of umbilical cord with fetus, placenta remains in situ and anencephaly are all conditions associated with low maternal plasma and urinary excretion of estrogen but no concomitant decrease in progesterone since the placental endocrine function including biosynthesis of hCG and progesterone may persist for weeks after fetal demise without compromising it circulating level.
The reason behind low level of estrogen is that the fetal adrenal glands provides substances used by the placenta for estrogen formation. In cases of anencephaly wherein the level is only 10% as compared to normal pregnancy estrogen level because the adrenal glands of anencephalic fetus are atrophied due to absence of hypothalamic-pituitary function which in term stimulates ACTH production.
Even if the maternal adrenal gland produces dheas, the estrogen precursor, it is not enough to sustain the pregnancy thus the fetal adrenal gland remains to be the most important source of placental estrogen precursor in human pregnancy.
