The molecular proponents of human parturition
Heidi Davis
December 22, 1998
Perhaps one ot the most amazing and necessary abilities of a species is that of procreation. Two single cells, egg and sperm, unite and form, through many cell divisions, another living being. A woman's body is capable of supporting that life and bringing it forth into the world. This process is apparently called labor, during which uterine muscles contract to dilate and efface the cervix thereby allowing a woman to push the fetus through the birth canal. Scientists have long been puzzled about the birth process: who decides the time to be born, how long the pregnancy will last, and, more importantly, how the birth process is controlled. As early as the 7th century BC Hippocrates believed the baby decides to be born--"when the child has grown big and the mother can no longer support him with food, (then) he struggles and breaks forth into the world" (Nathanielsz, 1996). This attributes decision-making capabilities to the fetus and tells us the result but does not explain what is truly happening. Many questions still remain unanswered. How big is big? And, if size is the deciding factor, why are some babies born prematurely? Research to determine the signals initiating human parturition is prolific, but, despite remarkable advances in the science and technology of reproduction, the mechanism of labor onset is still not completely understood.
In human parturition, the process has been theorized to occur via a hormonal feedback mechanism involving the fetus, mother and placenta, a structure made up of a maternal part (decidua) and a fetal part (chorion). The plancenta mediates the metabolic demands between the mother and fetus and is responsible for the production of hormones necessary in pregnancy and parturition. This collaboration provides back-up and failsafe mechanisms that may explain why most babies are born without a problem. Current evidence suggests that the steroid hormones namely progesterone, estrogens, oxytocin and cortisol, and paracrine molecules prostaglandins are all important to labor onset and maintenance. Therefore, investigation of their activity is necessary to more fully understand parturition.
Steroid hormones are lipid soluble and pass freely through the cell membrane into the cytoplasm. In the cytoplasm the hormone binds with an intracellular protein. An inhibitory protein is released from the receptor protein upon binding of the steroid hormone. The hormone receptor complex then travels through the cytoplasm into the nucleus where the complex binds to an enhancer region of DNA causing the transcription of mRNA. The mRNA then acts as a template for the specific protein that mediates the hormone's action. Because of this binding process it follows that the action of the steroid hormone would be directly dependent on hormone receptor concentration.
Progesterone: Progesterone is considered the hormone of pregnancy. Plasma progesterone concentrations increase throughout the pregnancy and are highest at term. At conception progesterone is produced by the corpus leuteum. At about three month's gestation production moves from the corpus leuteum to the placenta where it remains for the rest of pregnancy. Hormone receptors in the myometrium bind with progesterone, quieting the uterus. Because of this, high concentrations of plasma progesterone are credited with maintaining uterine quiescence and an unripe cervix, both necessary for pregnancy to continue.
Our first insights into the factors involved in labor came from observations of pregnant sheep. As pregnancy approaches term in sheep, plasma progesterone concentration declines and estradiol concentration surges. The decline in progesterone is attributed to its increased metabolism to a 17 hydroxylated product in the placenta. It is this decline that led Csapo, et al to postulate that the primary mechanism for labor onset is a withdrawal of progesterone. This hyposthesis was later expanded to include changes in the estrogen/progesterone ratio (Csapo, et al 1977)
In contrast with sheep, human plasma progesterone levels do not fall at labor onset (Boroditsky, 1978). However, the action of progesterone needs to be removed if the uterus is to be able to labor. This led researchers to look for a change in steroid hormone receptor concentrations as the mechanism for the uncoupling of progesterone's activity in the myometrium. High levels of receptors in the myometirum are thought to account for uterine quiescences. Efforts to determine it here is indeed a receptor concentration change have yielded inconsistent results. Researchers obtained myometrium
and placental tissue from term pregnant women who had cesarean prior to labor onset and who had normal labor onset but who had a cesarean because of fetal stress, herpes outbreak, or breech position. Analysis of the dicidua and the myometrium showed no change in the progesterone receptor concentration (Mashoumeh, 1997). Prior studies, however, showed a decrease in progesterone concentrations (How, 1995) Findings that the progesterone antagonist, RU 486, can induce labor supports the possibility that a decrease in myometrial progesterone receptor concentration may be required for labor onset (How, 1995)
Estrogen: Estrogen is produced in three forms: Estradiol, estrone and estriol. Experimental evidence had attributed an increase in maternal oxytocin production and an increase in oxytocin receptors on the myometrium to estrogen. Estrogen is also found to stimulate and increase in prostaglandin production and an increase in oxytocin receptors in the myometrium to estrogen. Estrogen is also found to simulate an increase in prostalandin production by the fetal membranes, the formation of gap junctions between the muscle cells of the myometrium, and cause rhythmic contractions (Adashi, ed. 1995).
Production occurs in the chorion and dicidua of the placenta. In sheep, estrogen can be directly synthesized from progesterone. The sheep placenta has a hydrolase available that converts progesterone to a 17 alpha, 20 alpha, dihydroxy Preg-4-en-3-one, and estrogen precursor. Prior to parturition in sheep estradiol plasma levels increase (Speroff, 1989). Unlike sheep, the human placenta does not have a hydrolase and, therefore, cannot directly synthesize estrogen. Estrogen production in humans is dependent on substrates provided by the fetus and the mother, namely estrone sulfate and dihydroepiandrosterone sulfate. (DHEAS) (Speroff, 1989). During the last month of pregnancy most estrogen comes from the fetal precursor, DHEAS (Adashi, 1995).
Oxytocin (OT): Like progesterone and estrogen, the steroid hormone oxytocin is involved in parturition. Oxytocin was considered the initiator of labor after uterine muscle from sheep was observed to contract after being treated with an extract from the pituitary . This extract was later found to be the hormone oxytocin. Released from the maternal pituitary during labor, OT's production is dependent upon estrogen concentration.
Oxytocin increases the frequency and strength of uterine contractions (Csapo, 1977) and is sometimes used to induce labor at term by intravenous administration. However, the role of oxytocin in natural labor initiation is controversial. In the initial stages of labor there is NO increase in maternal plasma oxytocin levels (Adashi, ed 1995). It is more likely that oxytocin's action is dependent on myometrial sensitivity. During pregnancy the concentration of oxytocin receptors in the myometrium steadily increases 80 fold from its pre-pregnancy state, and again doubles at labor onset (Speroff, 1989). This increase in oxytocin receptor concentrations in the myometrium lowers the OT threshold and thus activates the myometrium.
Cortisol: Observation of prolonged gestation in other species led to the conclusion that the fetal pituitary and adrenal gland are somehow involved in the parturition process. Sir Grant Mont Liggens performed and experiment where he surgically removed the pituitary from fetal lambs at 115 days gestation. A normal sheep pregnancy lasts 150 days. Sheep whose pituitary was removed remained in the womb well past the due date. When the pituitary and adrenal gland was removed pregnancy was also prolonged. By infusing these fetuses with cortisol, birth occurred in three days (Nathanielsz, 1996), The initiator for sheep parturition was determined to be connected to the pituitary/adrenal axis and namely dependent on the secretion of cortisol. Cortisol is a steroid hormone produced by the adrenal cortex. It belongs to a group of hormones known as gluccocorticoids. As a group, gluccocorticoids induce the synthesis of metabolic enzymes in their target tissues (Voet and Voet, 1995). Cortisol secretion increases ten days prior to parturition in normal sheep pregnancy. This is the beginning of a chain of events that leads to delivery. In the sheep placenta, cortisol increases the rate of metabolism of progesterone to estrogen via the precursor dihydroxyprogesterone.
In human's cortisol's role is a bit different. Maternal cortisol readily passes through the placenta to the fetus where it is thought inhibit the secretion of corticotropin from the anterior lobe of the fetal pituitary. This hormone stimulates the maturation of the fetal adrenal. The role of the fetal adrenal was first implicated when it was observed that pregnancy was prolonged in cases where the fetus's brain was deformed and the anterior portion failed to develop, a condition know and anencephaly (Nathaneilsz, 1996). This condition disturbs the fetal endocrine system and thus the secretion of corticotropin by the pituitary and the secretion of cortisol and the estrogen precursor DHEAS from the adrenal.
Prostaglandins (PG's): Prostaglandins anre carbon 20 compounds found in almost all mammalian cells. Hormone like in their effects,, they itracellularly mediated by cAMP. Unlike hormones, prostaglandins are local mediators and act in the same environment in which they are synthesized (Voet and Voet, 1995). Their production in the fetal membranes, placenta, uterine lining and myometrium is dependent on an increase in estrogen production and a decrease in progesterone. Progesterone inhibits the production of prostaglandins and keeps the myometrium from contraction. Evidence suggests that PG's play a key role in the mechanism of parturition--administration of PG's any time during gestation will induce labor (Adashi ed., 1995) In addition, PG's act directly on the cervix causing it to soften (Speroff, 1989). During labor there is a dramatic increase in the quantity of prostaglandins in amniotic fluid; however PG's in the amniotic fluid to not translocate across intact fetal membrane (McCoshen, et al 1990). Prostaglandins most implicated during labor are those synthesized by the aranchidonate pools in the fetal membranes. These PG's directly target the myometrium and stimulate contractions. A stimulant of PG synthase, the enzyme that catalyses PG production, had been found in urine. Urine collected from fetuses born via a normal vaginal delivery was more potent and and a greater stimulatory activity than urine collected from fetuses born via cesarean before labor onset. Thus, it is thought the amniotic fluid, which is mainly a product of fetal urination, may stimulate the production of PG by fetal membranes (Strickeland et al, 1983)
Although the exact trigger is not known it is obvious that parturition is a well-orchestrated event. Changes occur in the uroplacental environment that allow for expulsion of the fetus at the appropriate time. Although studies have not been able to pinpoint the very first change that occurs many of the components have fallen into place. Progesterone's quieting activity is offset by estrogen. The creation of an estrogen environment in the placenta increases the conversion of cortisol to cortisone so maternal cortisol no longer blocks the secretion of corticotropin from the fetal pituitary. Corticotropin, released form the fetal pituitary, matures the fetal adrenal. The fetal adrenal growns and increases its output of DHEAS. DHEAS is the estrogen precursor. More DHEAS available means more estrogen production. Estrogen increases prostaglandin production by the fetal membranes which increases contractions. Estrogen also increases oxytocin production, which increases contractions. Contractions are responsible for dilation and effacing the cervix. Dilation and effacement lead to pushing and pushing leads to birth. This chemical cascade is, in most cases, perfectly followed in normal pregnancy. Since pregnancy is necessary for parturition, it may be that the trigger for parturition is simply conception.
Works cited:
Adashi, E. et al, ed. Reproduction, endocrinology, surgery and technology..Lippencott-Raven publishers. Philadelphia, Penn. 1995.
Borodsky, R. et al. Maternal serum estrogen and progesterone concentrations preceding normal labor. Obstet & Gynecol 1978; 51:686-91
Csapo, A, et al. The See-Saw Theory of parturition in the Fetus and Birth. Ciba Foundation Symposium 47. New York, NY. 1977
How, H. Ela l. Myometiral estradiol and progesterone receptor changes in preterm and term pregnancies. Obstet & Gynecol. 1995; 86:936-40
Masoumehm R. et al. Sex steroid receptors and human parturition. Obset & Gynecol 1997; 89:918-24
Mitchell, B. F. et al Poregesterone synthesis by human amnion, chorion and decidua at term. Am J Obstet B\Gynecol 1987; 157:349-53
Nathanielsz, P. The timing of birth. American Scientist 1996; 84:562-69
Sperof, L et al. Clinical Gynecological Endocrinology and Infertility. 4th edition. Wilkin. Balsitmore, MD. 1989
Voet and Voet. Biochemistry. John Wiley and Sons Inc. New York, NY 1995
December 22, 1998
Perhaps one ot the most amazing and necessary abilities of a species is that of procreation. Two single cells, egg and sperm, unite and form, through many cell divisions, another living being. A woman's body is capable of supporting that life and bringing it forth into the world. This process is apparently called labor, during which uterine muscles contract to dilate and efface the cervix thereby allowing a woman to push the fetus through the birth canal. Scientists have long been puzzled about the birth process: who decides the time to be born, how long the pregnancy will last, and, more importantly, how the birth process is controlled. As early as the 7th century BC Hippocrates believed the baby decides to be born--"when the child has grown big and the mother can no longer support him with food, (then) he struggles and breaks forth into the world" (Nathanielsz, 1996). This attributes decision-making capabilities to the fetus and tells us the result but does not explain what is truly happening. Many questions still remain unanswered. How big is big? And, if size is the deciding factor, why are some babies born prematurely? Research to determine the signals initiating human parturition is prolific, but, despite remarkable advances in the science and technology of reproduction, the mechanism of labor onset is still not completely understood.
In human parturition, the process has been theorized to occur via a hormonal feedback mechanism involving the fetus, mother and placenta, a structure made up of a maternal part (decidua) and a fetal part (chorion). The plancenta mediates the metabolic demands between the mother and fetus and is responsible for the production of hormones necessary in pregnancy and parturition. This collaboration provides back-up and failsafe mechanisms that may explain why most babies are born without a problem. Current evidence suggests that the steroid hormones namely progesterone, estrogens, oxytocin and cortisol, and paracrine molecules prostaglandins are all important to labor onset and maintenance. Therefore, investigation of their activity is necessary to more fully understand parturition.
Steroid hormones are lipid soluble and pass freely through the cell membrane into the cytoplasm. In the cytoplasm the hormone binds with an intracellular protein. An inhibitory protein is released from the receptor protein upon binding of the steroid hormone. The hormone receptor complex then travels through the cytoplasm into the nucleus where the complex binds to an enhancer region of DNA causing the transcription of mRNA. The mRNA then acts as a template for the specific protein that mediates the hormone's action. Because of this binding process it follows that the action of the steroid hormone would be directly dependent on hormone receptor concentration.
Progesterone: Progesterone is considered the hormone of pregnancy. Plasma progesterone concentrations increase throughout the pregnancy and are highest at term. At conception progesterone is produced by the corpus leuteum. At about three month's gestation production moves from the corpus leuteum to the placenta where it remains for the rest of pregnancy. Hormone receptors in the myometrium bind with progesterone, quieting the uterus. Because of this, high concentrations of plasma progesterone are credited with maintaining uterine quiescence and an unripe cervix, both necessary for pregnancy to continue.
Our first insights into the factors involved in labor came from observations of pregnant sheep. As pregnancy approaches term in sheep, plasma progesterone concentration declines and estradiol concentration surges. The decline in progesterone is attributed to its increased metabolism to a 17 hydroxylated product in the placenta. It is this decline that led Csapo, et al to postulate that the primary mechanism for labor onset is a withdrawal of progesterone. This hyposthesis was later expanded to include changes in the estrogen/progesterone ratio (Csapo, et al 1977)
In contrast with sheep, human plasma progesterone levels do not fall at labor onset (Boroditsky, 1978). However, the action of progesterone needs to be removed if the uterus is to be able to labor. This led researchers to look for a change in steroid hormone receptor concentrations as the mechanism for the uncoupling of progesterone's activity in the myometrium. High levels of receptors in the myometirum are thought to account for uterine quiescences. Efforts to determine it here is indeed a receptor concentration change have yielded inconsistent results. Researchers obtained myometrium
and placental tissue from term pregnant women who had cesarean prior to labor onset and who had normal labor onset but who had a cesarean because of fetal stress, herpes outbreak, or breech position. Analysis of the dicidua and the myometrium showed no change in the progesterone receptor concentration (Mashoumeh, 1997). Prior studies, however, showed a decrease in progesterone concentrations (How, 1995) Findings that the progesterone antagonist, RU 486, can induce labor supports the possibility that a decrease in myometrial progesterone receptor concentration may be required for labor onset (How, 1995)
Estrogen: Estrogen is produced in three forms: Estradiol, estrone and estriol. Experimental evidence had attributed an increase in maternal oxytocin production and an increase in oxytocin receptors on the myometrium to estrogen. Estrogen is also found to stimulate and increase in prostaglandin production and an increase in oxytocin receptors in the myometrium to estrogen. Estrogen is also found to simulate an increase in prostalandin production by the fetal membranes, the formation of gap junctions between the muscle cells of the myometrium, and cause rhythmic contractions (Adashi, ed. 1995).
Production occurs in the chorion and dicidua of the placenta. In sheep, estrogen can be directly synthesized from progesterone. The sheep placenta has a hydrolase available that converts progesterone to a 17 alpha, 20 alpha, dihydroxy Preg-4-en-3-one, and estrogen precursor. Prior to parturition in sheep estradiol plasma levels increase (Speroff, 1989). Unlike sheep, the human placenta does not have a hydrolase and, therefore, cannot directly synthesize estrogen. Estrogen production in humans is dependent on substrates provided by the fetus and the mother, namely estrone sulfate and dihydroepiandrosterone sulfate. (DHEAS) (Speroff, 1989). During the last month of pregnancy most estrogen comes from the fetal precursor, DHEAS (Adashi, 1995).
Oxytocin (OT): Like progesterone and estrogen, the steroid hormone oxytocin is involved in parturition. Oxytocin was considered the initiator of labor after uterine muscle from sheep was observed to contract after being treated with an extract from the pituitary . This extract was later found to be the hormone oxytocin. Released from the maternal pituitary during labor, OT's production is dependent upon estrogen concentration.
Oxytocin increases the frequency and strength of uterine contractions (Csapo, 1977) and is sometimes used to induce labor at term by intravenous administration. However, the role of oxytocin in natural labor initiation is controversial. In the initial stages of labor there is NO increase in maternal plasma oxytocin levels (Adashi, ed 1995). It is more likely that oxytocin's action is dependent on myometrial sensitivity. During pregnancy the concentration of oxytocin receptors in the myometrium steadily increases 80 fold from its pre-pregnancy state, and again doubles at labor onset (Speroff, 1989). This increase in oxytocin receptor concentrations in the myometrium lowers the OT threshold and thus activates the myometrium.
Cortisol: Observation of prolonged gestation in other species led to the conclusion that the fetal pituitary and adrenal gland are somehow involved in the parturition process. Sir Grant Mont Liggens performed and experiment where he surgically removed the pituitary from fetal lambs at 115 days gestation. A normal sheep pregnancy lasts 150 days. Sheep whose pituitary was removed remained in the womb well past the due date. When the pituitary and adrenal gland was removed pregnancy was also prolonged. By infusing these fetuses with cortisol, birth occurred in three days (Nathanielsz, 1996), The initiator for sheep parturition was determined to be connected to the pituitary/adrenal axis and namely dependent on the secretion of cortisol. Cortisol is a steroid hormone produced by the adrenal cortex. It belongs to a group of hormones known as gluccocorticoids. As a group, gluccocorticoids induce the synthesis of metabolic enzymes in their target tissues (Voet and Voet, 1995). Cortisol secretion increases ten days prior to parturition in normal sheep pregnancy. This is the beginning of a chain of events that leads to delivery. In the sheep placenta, cortisol increases the rate of metabolism of progesterone to estrogen via the precursor dihydroxyprogesterone.
In human's cortisol's role is a bit different. Maternal cortisol readily passes through the placenta to the fetus where it is thought inhibit the secretion of corticotropin from the anterior lobe of the fetal pituitary. This hormone stimulates the maturation of the fetal adrenal. The role of the fetal adrenal was first implicated when it was observed that pregnancy was prolonged in cases where the fetus's brain was deformed and the anterior portion failed to develop, a condition know and anencephaly (Nathaneilsz, 1996). This condition disturbs the fetal endocrine system and thus the secretion of corticotropin by the pituitary and the secretion of cortisol and the estrogen precursor DHEAS from the adrenal.
Prostaglandins (PG's): Prostaglandins anre carbon 20 compounds found in almost all mammalian cells. Hormone like in their effects,, they itracellularly mediated by cAMP. Unlike hormones, prostaglandins are local mediators and act in the same environment in which they are synthesized (Voet and Voet, 1995). Their production in the fetal membranes, placenta, uterine lining and myometrium is dependent on an increase in estrogen production and a decrease in progesterone. Progesterone inhibits the production of prostaglandins and keeps the myometrium from contraction. Evidence suggests that PG's play a key role in the mechanism of parturition--administration of PG's any time during gestation will induce labor (Adashi ed., 1995) In addition, PG's act directly on the cervix causing it to soften (Speroff, 1989). During labor there is a dramatic increase in the quantity of prostaglandins in amniotic fluid; however PG's in the amniotic fluid to not translocate across intact fetal membrane (McCoshen, et al 1990). Prostaglandins most implicated during labor are those synthesized by the aranchidonate pools in the fetal membranes. These PG's directly target the myometrium and stimulate contractions. A stimulant of PG synthase, the enzyme that catalyses PG production, had been found in urine. Urine collected from fetuses born via a normal vaginal delivery was more potent and and a greater stimulatory activity than urine collected from fetuses born via cesarean before labor onset. Thus, it is thought the amniotic fluid, which is mainly a product of fetal urination, may stimulate the production of PG by fetal membranes (Strickeland et al, 1983)
Although the exact trigger is not known it is obvious that parturition is a well-orchestrated event. Changes occur in the uroplacental environment that allow for expulsion of the fetus at the appropriate time. Although studies have not been able to pinpoint the very first change that occurs many of the components have fallen into place. Progesterone's quieting activity is offset by estrogen. The creation of an estrogen environment in the placenta increases the conversion of cortisol to cortisone so maternal cortisol no longer blocks the secretion of corticotropin from the fetal pituitary. Corticotropin, released form the fetal pituitary, matures the fetal adrenal. The fetal adrenal growns and increases its output of DHEAS. DHEAS is the estrogen precursor. More DHEAS available means more estrogen production. Estrogen increases prostaglandin production by the fetal membranes which increases contractions. Estrogen also increases oxytocin production, which increases contractions. Contractions are responsible for dilation and effacing the cervix. Dilation and effacement lead to pushing and pushing leads to birth. This chemical cascade is, in most cases, perfectly followed in normal pregnancy. Since pregnancy is necessary for parturition, it may be that the trigger for parturition is simply conception.
Works cited:
Adashi, E. et al, ed. Reproduction, endocrinology, surgery and technology..Lippencott-Raven publishers. Philadelphia, Penn. 1995.
Borodsky, R. et al. Maternal serum estrogen and progesterone concentrations preceding normal labor. Obstet & Gynecol 1978; 51:686-91
Csapo, A, et al. The See-Saw Theory of parturition in the Fetus and Birth. Ciba Foundation Symposium 47. New York, NY. 1977
How, H. Ela l. Myometiral estradiol and progesterone receptor changes in preterm and term pregnancies. Obstet & Gynecol. 1995; 86:936-40
Masoumehm R. et al. Sex steroid receptors and human parturition. Obset & Gynecol 1997; 89:918-24
Mitchell, B. F. et al Poregesterone synthesis by human amnion, chorion and decidua at term. Am J Obstet B\Gynecol 1987; 157:349-53
Nathanielsz, P. The timing of birth. American Scientist 1996; 84:562-69
Sperof, L et al. Clinical Gynecological Endocrinology and Infertility. 4th edition. Wilkin. Balsitmore, MD. 1989
Voet and Voet. Biochemistry. John Wiley and Sons Inc. New York, NY 1995
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