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Steroidogenesis in pregnancy
Composed of 3 compartments
FETAL
PLACENT AL
MATERNAL COMPONENT
Source of precursors, clearance of steroids
STEROIDOGENESIS
Steroidogenesis in pregnancy
Human trophoblasts produce steroid, protein and peptide hormones in enormous amounts Hyperestrogenic state of pregnancy has unique and obligatory relationship with fetal adrenal secretion of C-19 steroids, precursor of estrogen synthesis Human syncitiotrophoblast utilize LDLcholesterol from maternal plasma for progesterone biosynthesis
Aldosterone
Deoxycorticosterone Cortisol
0.05 0.1
0.05 0.5 10-30
0.250 0.600
1 12 10-20
2.
3. 4.
5.
6. 7. 8. 9.
10.
placental lactogen (hPL) chorionic gonadotropin (hCG) Adenocorticotropin (ACTH) Growth hormone variant (hGH-V) Parathyroid hormonerelated protein (PTH-rP) Calcitonin Relaxin Inhibins Activins Atrial natriuretic peptide
Thyrotropin releasing hormone (TRH) Gonadotropin releasing hormone (GnRH) Corticotropin-releasing hormone (CRH) Somatostatin Growth hormone-releasing hormone (GHRH)
Glycoprotein Has biological activity same with LH Produced Placenta Fetal kidney Also produced by malignant tumors Presence of hCG in blood and urine of reproductive age women is almost indicative of the presence of fetal trophoblasts either in pregnancy or in neoplastic disease
Has the highest carbohydrate content of any human hormone 30% Plasma half life: 36-hour Composed of 2 dissimilar subunits ( and ) Bioactivity which is binding to the LH receptor is only present if the two units are combined Isolated subunits cannot bind to the LH receptor, and therefore, are not bioactive Structurally identical to 3 other glycoprotein hormones: LH, FSH and TSH Amino acid sequences of the beta subunit of hCG is distinctively dissimilar from those of LH, FSH, and TSH
Biosynthesis of hCG
Rate limiting synthesis of the -subunit results in low to undetectable circulating levels of free -subunit throughout pregnancy Plasma levels of free -subunits increase steadily until the 36th week of pregnancy and then plateaus till the end of pregnancy Rate of secretion of the complete hCG molecule is maximal at 8 to 10 weeks of gestation Placental GnRH, produced in cytotrophoblast, acts in paracrine manner on syncitiotrophoblast to stimulate hCG production Other agents that believed to influence hCG secretion in trophoblast: Interleukin-6 Epidermal growth factor Cyclic AMP Activin stimulates and inhibin inhibits production of GnRH and hCG
< 5 weeks hCG is expressed in both syncytiotrophoblasts and cytotrophoblast cells At the peak of maternal levels later in gestation hCG is produced almost exclusively in the syncitiotrophoblast
multiple forms of hCG in maternal plasma and urine and vary enormously in bioactivity and immunoreactivity Some results from enzymatic degradation and others by modifications during molecular synthesis and processing Free B-subunits levels are low to undetectable throughout pregnancy
Intact hCG molecule is detectable in plasma of pregnant women about 7 to 9 days after the midcycle surge of LH that precedes ovulation hCG enters maternal blood at time of blastocyst implantation Blood levels increase rapidly, doubling every 2 days Maximal levels attained at about 8 to 10 weeks gestation Between the 60th and 80th days after the last menses - peak levels reach about 100,000 mIU/mL
When the hCG titers exceeds 1,000-1,500 IU/L, vaginal ultrasonography should identify an intrauterine gestation 10-12 weeks gestation maternal plasma levels begin to decline Nadir - about 20 weeks Plasma levels are maintained at this lower level for the rest of the pregnancy Fetal plasma levels same pattern as the mother but plasma levels are only 3 percent of those in maternal plasma Urine concentration of hCG follows the pattern of maternal plasma
pregnancy Erythrobalstosis fetalis Fetal hemolytic anemia GTD Fetus w/ Down Syndrome
30 percent through the kidneys the rest cleared by the liver and other pathways
progesterone producing life span of the corpus luteum of menstruation could be prolonged for 2 weeks by hCG administration about the 8th day after ovulation or 1 day after implantation- hCG takes over for the corpus luteum Continued survival of the corpus luteum is totally dependent on hCG
Survival of the pregnancy is dependent on corpus luteum progesterone until the 7th week of pregnancy Progesterone luteal synthesis begins to decline at about 6 weeks despite continued and increasing hCG production Down regulation of hCG-LH receptors in the corpus luteum when trophoblasts produce sufficient progesterone for pregnancy maintenance
cells LH-hCG receptor is expressed in the thyroid Possibly, hCG stimulates thyroid activity via the LH-hCG receptor and by the TSH receptor hCG has intrinsic thyroid activity and maybe the 2nd placental thyrotropic substance
lactogenic and growth hormone-like bioactivity immunochemical resemblance to human growth hormone
concentrated in the syncytiotrophoblast like hCG detected in the trophoblast as early as the 2nd or 3rd week after fertilization of the ovum
single nonglycosylated polypeptide chain that is structurally similar to human prolactin (hPRL) production rate of hPL near term - about 1 g/day
demonstrable in the placenta within 5 to 10 days after conception can be detected in maternal serum by 3 weeks post fertilization Maternal plasma concentration rises until about 34 to 36 weeks, with higher levels in late pregnancy secreted primarily into the maternal circulation with very little amounts in maternal urine and in fetal blood and urine role in pregnancy is mediated through maternal actions possibility that hPL serves select functions in fetal growth
Prolonged maternal starvation in the 1st half of pregnancy - increase in the plasma concentration of hPL Very high maternal levels multiple gestations
2.
3.
Maternal lipolysis and increase in the levels of circulating free fatty acids - providing a source of energy for maternal metabolism and fetal nutrition Anti-insulin or "diabetogenic" action increase in maternal insulin - favoring protein synthesis and provision of mobilizable amino acids for transport to the fetus Potent angiogenic hormone - may play an important role in the formation of fetal vasculature
Placental ACTH
secreted into the mother or fetus during pregnancy not under feedback regulation by glucocorticoid and explains the maternal partial resistance to dexamethasone suppression
Maternal ACTH - does not cross the placenta to the fetus ACTH produced within the placenta - not under feedback regulation by glucocorticoid, which has been proposed as the rationale for maternal partial resistance to dexamethasone suppression
Corticotropin-releasing hormone (CRH) produced within the placenta - stimulates the synthesis and release of chorionic ACTH placental production of CRH
positively
regulated by cortisol important for controlling fetal lung maturation and the timing of parturition
Chorionic thyrotropin
There is evidence that placenta produces chorionic thyrotropin No evidence that it has a significant biological role in pregnancy
Relaxin
Expressed in: human corpus luteum, decidua, and placenta structurally similar to insulin and insulin-like growth factor relaxin along with rising progesterone levels acts on myometrial smooth muscle to promote uterine relaxation and the quiescence observed in early pregnancy relaxin and relaxin-like factors in the placenta and fetal membranes may play an autocrineparacrine role in regulation of extracellular matrix degradation in the puerperium
Circulating levels of PTH-rP are significantly elevated in pregnancy within the maternal but not fetal circulation synthesis has been shown in adult myometrium, endometrium, corpus luteum, and lactating mammary tissue. not produced in the parathyroid glands of normal adults may have an important autocrineparacrine role within the fetalmaternal unit as well as on the adjacent myometrium In the placenta, it may activate receptors on the trophoblast to promote calcium transport for fetal bone growth and ossification
Placental hGH-V synthesized in the syncytium, present in maternal plasma by 21 to 26 weeks increases in concentration to about 36 weeks Plateaus in level thereafter Not regulated by placental GnRH but responds inversely to maternal glucose levels, protecting glucose availability for the fetus Likely a factor in mediating insulin resistance in pregnancy Can stimulate gluconeogenesis and lipolysis
GnRH, TRH, CRH, GHRH and somatostatin there is an analogous placenta hormone indicative of a hierarchy of control in the synthesis of chorionic trophic hormones
immunoreactive GnRH - present in cytotrophoblasts but not in the syncitiotrophoblast regulate trophoblastic production of hCG the cause of the elevation of maternal levels of circulating GnRH that are seen early in pregnancy
Trophoblast, amnionchorion, and deciduas express both CRH-R1 and CRH-R2 receptors, as well as several variant receptors CRH can increase trophoblast ACTH secretion indicating autocrine-paracrine role for these hormones Large amounts of trophoblast CRH enter the maternal blood, but are bound by CRH-binding proteins that make it biologically inactive
induction of smooth muscle relaxation in vascular and myometrial tissue immunosuppression rising levels of CRH seen near the end of gestation - induction of myometrial contractions CRH may be involved in the initiation of parturition Prostaglandin formation in the placenta, amnion, chorion laeve, and decidua is increased by treatment with CRH - potential role of CRH in the timing of parturition
Glucocorticoids
in the hypothalamus : inhibit CRH release in the trophoblast: stimulate CRH gene expression a positive feedback loop involves:
in the first-trimester trophoblast represents a potential regulator of placental growth hormone production or a paracrine regulator of differentiation
Leptin
normally secreted by adipocytes initially believed to be an anti-obesity hormone now regulates bone growth and immune function secreted by both cytotrophoblast cells and syncytiotrophoblast and maternal levels are significantly higher than in non pregnant women and that in the fetal circulation Fetal leptin levels
Neuropeptide Y
found in the brain, sympathetic neurons innervating the cardiovascular, respiratory, gastrointestinal, and genitourinary systems has been isolated from placental cytotrophoblasts Receptors have been demonstrated in the placenta treatment of placental cells with neuropeptide Y causes the release of CRH
Inhibin
glycoprotein hormone, inhibit pituitary FSH release produced by the testis, ovarian granulosa cells and the corpus luteum placenta produces inhibin alpha-, and beta A and beta B-subunits Inhibin A principal bioactive inhibin secreted during pregnancy Highest level is at term Placental inhibin production together with large amounts of placental sex steroids inhibit FSH secretion and preclude ovulation during pregnancy
Inhibin
by activin A stimulated by hCg, GnRH, epidermal growth factor, transforming growth factor-alpha and PGF 2 and PGE 2 may act via GnRH to regulate hCG synthesis and secretion in the placenta
Activin
closely related to inhibin enhances FSH synthesis and secretion and participates in the regulation of the menstrual cycle roles in cell proliferation, embryogenesis, osteogenesis, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair and endocrine function nerve cell survival factors has 3 forms: A, B and AB
Activin
Chorionic activin and inhibin - regulators within the placenta for the production of GnRH, hCG and steroids Inhibin inhibitory, Activin - stimulatory may serve functions in placental metabolic processes other than GnRH synthesis, but are still under study Placental and decidual inhibin and activin early in pregnancy indicate their possible roles in embryogenesis and local immune responses Activin levels actively decline after delivery
Progesterone
After 6 to 7 weeks of gestation ovarian progesterone production is minimal After about 8 weeks placenta replaces the ovary as the source of progesterone & continues to increase production throughout pregnancy end of pregnancy - maternal levels of progesterone are 10 to 5000 times those in nonpregnant women, depending on the stage of the ovarian cycle daily production rate is 250 mg In pregnancies with multiple fetuses, daily production rate maybe >6000 mg/day
Progesterone - synthesized from cholesterol in a two-step enzymatic reaction 1st cholesterol is converted to pregnenolone within the mitochondria, a reaction catalyzed by cytochrome P450 cholesterol side-chain cleavage enzyme. Pregnenolone leaves the mitochondria and converted to progesterone in the endoplasmic reticulum by 3hydroxysteroid dehydrogenase Progesterone is released immediately through a process of diffusion
limited capacity for the biosynthesis of cholesterol in trophoblast the placenta must rely on exogenous cholesterol for progesterone formation maternal plasma cholesterol was the principal precursor (90 %) of progesterone biosynthesis in the placenta trophoblast preferentially uses LDL cholesterol for progesterone biosynthesis rate of progesterone synthesis is largely dependent on the plasma membrane of the trophoblast and primarily independent of uteroplacental blood flow
LDL receptors are localized in coated pits on the microvillus membranes of syncitium Hydrolysis of LDL releases essential amino acids and cholesterol esters, which in turn yield fatty acids and cholesterol Essential amino acids and fatty acids are transported to the fetus and cholesterol is used for placental progesterone biosynthesis Fetus contributes essentially no precursor Pregnenolone sulfate may be the most important precursor for synthesis and metabolism of progesterone in human decidua and fetal membranes
No relationship between placental progesterone synthesis and fetal well being Progesterone biosynthesis may persist several weeks after fetal death
Same as in men and nonpregnant women During pregnancy - a disproportionate increase in the plasma concentration of 5-dihydroprogesterone as a result of synthesis in syncytiotrophoblast from both placenta-produced progesterone and fetal-derived precursor 5-reduced metabolite contributes to the resistance in pregnancy against the vasopressor action of angiotensis II Progesterone is also converted to the potent mineralocorticoid deoxycorticosterone in pregnant women and in the fetus, thus an increase in deoxycorticosterone in the maternal and fetal compartments
extra-adrenal formation of deoxycorticosterone from circulating progesterone accounts for the vast majority of its production in human pregnancy 30 to 40% of progesterone secreted as metabolites in the urine, bile, feces 5 -reduction of progesterone is the major pathway of progesterone metabolism Metabolites of 5 -dihyfroprogesterone are bioactive in the brain, facilitating the action of GABA (anxiolytic agent) With the delivery of the placenta, sudden drop in the metabolite may account for the development of puerperal depression in some women
Role of Progesterone
Prepares and maintains the endometrium to allow implantation Has a role in suppressing the maternal immunologic response to fetal antigens thereby preventing preventing maternal rejection of the trophoblast and has a role in parturition serves as a substrate for fetal adrenal gland production of glucocorticoids and mineralocorticoids
produces huge amounts of estrogens using blood-borne steroidal precursors from the maternal and fetal adrenal glands Normal human pregnancy is hyperestrogenic state, continually increasing as pregnancy progresses terminating abruptly after birth last few weeks of pregnancy - amount of estrogen produced each day by syncitiotrophoblast is equivalent to that produced in 1 day by the ovaries of no fewer than 1000 ovulatory women
first 2 to 4 weeks of pregnancy - rising levels of hCG maintain production of estradiol in the maternal corpus luteum seventh week of pregnancy maternal corpus luteum production of both progesterone and estrogen decreases significantly there is a lutealplacental transition by the seventh week, more than 50 percent of estrogen entering the maternal circulation is produced in the placenta transition of steroid milieu from one dependent on the maternal corpus luteum to one dependent on the developing placenta
pathways for estrogen synthesis in the human placenta differ from those in the ovary of non pregnant women production occurs in the follicular and luteal Ovarian theca cells synthesize androstenedione granulosa cells estradiol Androstenedione is produced de novo from acetate and cholesterol, catalyzed by aromatase 450 estrone, acted upon by estradiol dehydrogenase estradiol In human trophoblast, neither cholesterol nor progesterone can serve as precursor for estrogen biosynthesis It does not express steroid 17-hydroxylase/17,20-lyase (CYP17) , so the conversion of C 21-steroids to C 19-steroids which is the immediate and obligatory precursors of estrogen is not possible C 19 steroids, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) can also act as estrogen precursors
DHEA-S secreted in large amounts by the fetal adrenal glands is converted to 16 hydroxydehydroepiandrosterone sulfate (16 OHDHEA-S) in the fetal liver DHEAS and 16 OHDHEA-S are converted in the placenta to estrogens viz., 17 estradiol (E2) and estriol (E3) Near term, half of E2 is derived from fetal adrenal DHEA-S and half from maternal DHEA-S 90 % of E3 in the placenta arises from fetal 16 OHDHEA-S and only 10 % from other sources
fetal adrenal cortex - most important source of placental estrogen precursors in human pregnancy levels of urinary estrogens in women pregnant with an anencephalic fetus were only about one tenth those in urine of pregnant women with a normal fetus absence of the fetal zone of the adrenal cortex in anencephalic fetuses - glands might provide one or more substances that serve to promote placental estrogen formation high levels of DHEA-S in cord blood of normal newborns also suggest this
large amount of DHEA-S in plasma and its much longer half-life uniquely qualify it as the principal circulating precursor for placental estrogen biosynthesis Near term, about 50 % of the estradiol produced in the placenta arises from maternal and 50 % from fetal plasma DHEA-S Placental estradiol primary estrogen circulating at term
estriol and estetrol in the maternal circulation are increased particularly in late pregnancy hydroxylated estrogens are produced in the placenta using substrates from the fetal adrenal gland and liver fetal liver expresses high levels of the enzyme 16hydroxylase, which acts on adrenal derived steroids disproportionate increase in estriol synthesis during pregnancy is accounted for by placental synthesis of estriol principally from plasma-borne 16-OHDHEA-S Near term, the fetus is the source of 90 percent of the placental estriol and estetrol precursor in normal human pregnancy
Near term, the fetus is the source of 90 percent of the placental estriol and estetrol precursor in normal human pregnancy placenta secretes several estrogens: estradiol, estrone, estriol, and estetrol majority of estrogen produced in the placenta released into the maternal circulation the hemochorial nature of the human placenta, majority of these estrogens - released in to the maternal circulation Maternal estriol and estetrol - produced solely from fetal precursors, have low sensitivity and specificity as indicators of fetal well-being
Compared with adult organs, adrenal cortex is the largest organ of the fetus At term, fetal adrenal glands weigh the same as those of the adult More than 85 % of the fetal gland is the fetal zone, which is absent in adults Fetal zone begins involuting immediately after birth 100 to 200 mg/day - daily production of steroids by the fetal adrenal glands near term, compared to 30 to 40 mg/day in resting adults
The enormous size and very great capacity for steroid synthesis made investigators think that aside from ACTH, there are other stimuli for growth of the adrenal gland immunoreactive ACTH decreases in fetal plasma as pregnancy progresses and as the fetal adrenal glands are growing at a rapid rate ACTH is necessary for the rapid growth of the adrenal gland during the latter part of pregnancy the rate of growth of the fetal adrenal glands is influenced by factors secreted by the placenta
Adrenal Enzymes
adrenal fetal zone cells have a severe deficiency in 3- hydroxysteroid dehydrogenase, 5-4-isomerase (3HSD)thus limiting the conversion of pregnenolone to progesterone and of 17- hydroxyprogesterone, an obligatory step in corisol biosynthesis very active steroid sulfo-transferase activity in the fetal adrenal glands, thus its principal secretory products are pregnenolone sulfate and DHEA-S
precursor for fetal adrenal steroidogenesis is cholesterol fetal adrenal glands can synthesize cholesterol from acetate the rate of de novo cholesterol synthesis by fetal adrenal tissue is extremely high, but still insufficient to account for the steroids produced by these glands cholesterols (LDL, HDL and VLDL) must be assimilated from the fetal circulation fetal adrenal glands are highly dependent on circulating LDL as a source of cholesterol for optimum steroidogenesis
Fetal-Placental Sulfatase Deficiency no hydrolysis of C 19 steroids no precursor for estrogen biosynthesis an X-linked disorder that affects only males with icthyosis and associated with delayed onset labor Fetal-Placental Aromatase Deficiency androstenedione cannot be converted to estradiol with virilization of the mother and the female fetus males have delayed epiphyseal closure during puberty the affected men continue to grow during adulthood, becoming very tall and displaying deficient bone mineralization
inhibit maternal and fetal pituitary ACTH secretion resulting in decreased maternal and fetal adrenal secretion of DHEA-S
Seen in a virilized female fetus with a tumor that produces a non-aromatizable C19 steroid androgen or production of testosterone early in pregnancy that exceeds the capacity of placental
urinary levels of estriol in women with pyelonephritis is the consequence of diminished renal clearance
fetal adrenal sources of C19 steroids for estrogen synthesis estrogen is produced principally with maternal plasma C19 steroids as precursor
Estrogens synthesized in the syncytium preferentially enters the maternal circulation more than 90 percent of estradiol and estriol formed in syncytiotrophoblast enters maternal plasma 85 percent or more of placental progesterone enters maternal plasma, and very little maternal plasma and very little to the fetus major reason for directional movement towards the maternal circulation is the hemochorioendothelial form of placentation Steroids from syncytium do not enter fetal blood directly
steroids must traverse cytotrophoblasts connective tissue of the villous core traverse the wall of the fetal capillaries fetal blood
Steroids in the fetal capillaries can then reenter the connective tissue of the villous core to reenter the syncytium net result of this is substantially greater entry of steroids into the maternal circulation compared to the amount that enters the fetal blood