The Role of Cortisol in Prepa(1)

8/12/2019 The Role of Cortisol in Prepa(1)

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eview Reprod. Fertil. Dev., 1994, 6 , 141-50

The Role of Cortisol in Preparing the Fetus for BirthG. C. Liggins

Research Centre in Reproductive Medicine, University of Auckland,Auckland, New Zealand. Address for correspondence: Department of Obstetricsand Gynaecology, National Women s Hospital, Claude Road, Auckland.

Ab stract . The glucocorticoids, cortisol and corticosterone, have a unique function in the fetusin inducing a wide range of enzymes before birth that have little or no function during fetal lifebut on which survival after birth is dependent. The loss of the placenta a t birth deprives thefetus of a source of oxygen, glucose and heat (among many other things) for which alternativesmust be available immediately if survival is to be assured. In anticipation of these needs severalorgans undergo maturational changes in late pregnancy aimed at meeting these requirements.The lungs mature structurally and functionally, becoming distensible and capable of coping withhigh surface tension when air enters the alveoli with the first breath . In the liver, glycogenaccumulates and gluconeogenesis is initiated to meet the demands for glucose until feeding begins.There is an increase in the production of tri-iodothyronine and catecholamines in preparation forthe sharp increase in metabolic rate and thermogenesis associated with breathing and the coldenvironment. All these dramatic maturational events are regulated by cortisol as are numerousothers in most organ systems that contribute to neonatal well-being but on which survival is lessdependent. Pharmacological manipulation of these systems before birth has made a substantialcontribution to improving human health.

IntroductionJim Goding s life and mine ran remarkably parallelcourses over a decade or more. He was born 11 yearsbefore me but I caught up some of the difference when hespent some lost years as a prisoner of war. When I wasgraduating from Medical School, he was Superintendentof Prince Henry s Hospital. We were both late startersin research. Jim s fkst publication was in 1 956 at theage of 41 (Coats et al. 1956) and mine was in 1959at the age of 33 We both trained as surgeons andapplied those surgical skills to research; Jim adaptedhypophysectomy, adrenalectomy and transplantation ofthe ovary and uterus to the adult sheep whereas Iperformed hypophysectomy and adrenalectomy in fetalsheep. In 1967, we both reported our first results;experiments with autotransplanted uterus and ovaries(Goding et al. 1967) and fetal hypophysectomy (Ligginset al. 1967). Jim G oding s interest was to find thefactors regulating the end of the oestrous cycle, whereasmy interest was to find the factors regulating the end ofpregnancy. Our respective research in sheep inevitablyled us into the field of prostaglandins, culminating in197 1 when Jim and his colleagues described the luteolyticeffects of prostaglandin F a (PGFk) (McCracken et al.1971) and Susan Grieves and I described the uterinerelease of PGFk preceding parturition (Liggins andGrieves 1971). His early death in 1973 deprived Jim

of the opportunity of sharing in the discovery of ovinetrophoblastic protein, the prostaglandin-inhibitory proteinthat inhibits luteolysis, whereas I was fortunate to isolatgravidin, the prostaglandin-inhibitory protein that wthink inhibits parturition in women (Wilson et al. 1988)This review does not a ddress the initiation of parturitionbecause a recent James Goding Lecturer delivered thought-provoking paper on that subject (Thorburn 1991)My topic is a by-product of the initiation of parturitionwhich can be broadly described as preparation for birthPreceding parturition, fetal organs undergo acceleratedmaturation which facilitates the transition from intrauterinto extrauterine life. These changes are more or les(depending on species) tightly coupled to the mechanisminitiating parturition and the common factor is cortisolFor example, the foal is mature at birth over a widespan of gestation lengths provided that the onset oparturition is spontaneous (Silver et al. 1984). In thfetus, the well-known regulatory action of cortisol onenzyme activity in adults has a unique opportunity toinduce activity in enzymes that are dormant although therelevant genes have passed the programmed time whentranscription first becomes possible.At least in the fetal lung, the maturational responseto cortisol is enhanced by tri-iodothyronine (T3) anprolactin. Th is discussion w ill be largely confined tocortisol but the possibility of synergism of cortisol

The 1993 James R. Goding Lecture given at the 23rd Conference of the Australian Society for Reproductive Biology, University of OtagoDunedin, New Zealand.1031-3613/94/020141 05.0


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particularly with Tg and prolactin, in other organs shouldnot be overlooked.In most species investigated to date, late pregnancy ischaracterized by rising concentrations of cortisol in thefetal circulation; when the newborn is precocious and mustbe self-sufficient to survive (e.g. sheep) concentrationsrise sharply prepartum (Fig. 1) whereas slower increasesare characteristic of those species in which the newbornis immature and highly dependent on maternal care (e.g.rodents and human). The mechanism by which increasingactivity of cortisol is achieved also varies; in fetal sheep,the concentration of both total and free cortisol rises asa result of an increased rate of secretion (Fairclough andLiggins 1975) whereas in fetal rats, rising concentrationsof free cortisol are due mainly to falling concentrationsof cortisol-binding globulin (CBG). Nevertheless, thereis little evidence of species specificity in the spectrumof enzymes inducible by cortisol with the exception ofplacental 17~-hydroxylasewhich is inducible in somespecies (e.g. sheep) (Fig. 2 and absent or noninduciblein others (e.g. human). This exception is fundamental tospecies differences in the mechan ism initiating labour. Thepresence of a cortisol-inducible placental 1 7~ -h yd rox yla seperm its the fetal hypothalam ic-pituitary-adrenal system

a) Maternal jugular vein

26.0b)Fetal carotid artery

estational age days)Fig. 1 The first demonstration of a rise prepartum in fetalcorticosteroid levels. The concentration of total corticosteroids inplasma of fetal sheep in late pregnancy. Note that the rise occursalso in fetuses delivered prematurely. (Bassett and Thorburn 1969.)

to regulate placental steroid production (Flint et al 1975whereas its absence deprives the fetus of this formof control. Indeed, in the latter case, no alternativmechanism initiating parturition is known and currenhypotheses generally postulate a system in which thchorionic membrane and placenta interact in a paracrinefashion with the adjacent decidua, the contribution othe fetus being no more than permissive.

Fig. 2. Effect of infusion of dexamethasone for 45 h o n placentasteroid 17a-hydroxylase in fetal sheep. Western blot analysis ocytochrome P45Ol7 in microsomal preparations. Lane s 1-3, untreatecontrols; lanes 4-7 dexamethasone-treated. (France et al 1988.)

Interest in cortisol as the maturational horm one dateback to the origins of fetal physiology when Jost (1947reported his observations on the effects of decapitatinfetal rabbits. The role of cortisol in the small intestinwas acknowledged soon afterwards (Moog 1953). Thimpetus to investigate the hypothesis that cortisol haa general function in inducing fetal maturation camwith the discove ry of corticosteroid-induced maturationof the fetal lung (Liggins 1969; Kotas and Avery1971) which also drew attention to the potential fotherapeutic intervention with anteparturn corticosteroiadministration. The remainder of this paper revieworgan systems in which maturation effects of cortisohave been demonstrated.Thyroid

The thyroid is a good example of the way in whiccortisol converts a system in anticipation of birth from onmeeting the needs of fetal life to one meeting the needof extrauterine life. Autonomy of fetal thyroid functio


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advancement from gross immaturity to morphological andfunctional maturity approaching that at term (Liggins etal. 1987).Surfactant

Surfactant has a lipid component, disaturated phos-phatidylcholine, and a protein component consistingof at least four proteins-surfactant protein (SP) A(SP-A), SP-B, SP-C and SP-D. The synthesis of bothcomponents is stimulated by cortisol (Fig. 5 . Severalenzymes in the phosphatidylcholine biosynthetic pathwayincluding cholinephosphotransferase, phosphatidate phos-phatase, lysolecithin acyltransferase and phosphatidatecytidyltransferase have been reported inconsistently anddepending on species to be stimulated by glucocorticoids(see Rooney 1985). The rate-limiting enzyme that con-sistently responds to glucocorticoids is cholinephosphatecytidyltransferase, the activity of which correlates wellwith the rate of synthesis of phosphatidylcholine in fetallungs. The effect of glucocorticoid may be direct inpart but may also be mediated by fibroblast-pneumocytefactor secreted by fibroblasts adjacent to Type I1 cells(Smith and Post 1989) and by increased fatty acidsynthesis resulting from enhanced fatty acid synthaseactivity (Gonzales et al. 1990; Batenburg and Elfring1992).The mRNAs for the surfactant proteins SP-B and SP-C, which accelerate surfactant film formation, increaseduring exposure of human lung in vitro to glucocorticoids(Liley et al. 1989) (Fig. 6 . The mRNA for SP-A whichis probably concerned with the movement of surfactantinto and out of the alveolus has a biphasic responseto glucocorticoid, being inhibited at high concentrationsand stimulated at low concentrations (Liley et ale 1988).

SP E mRNASP CmRNA

I00

Cont E DHT

Fibroblast pneumocytefactorPhosphatidylcholine

SP-A SP-B SP-C\ /Surfactant p-Adrenergicstore

Distensibility surfactant

Fig 5. Diagram illustrating multiple points of action of cortisolon the biosynthetic pathway of pulmonary surfactant.

Structural MaturationExperimental evidence points increasingly to structuralchanges being at least as important as surfactant indetermining the compliance of the lung in the term

newborn or the pr erm corticosteroid-treated newborn(Schellenberg 1986). The lungs of fetal sheep, monkeysand rabbits that have become highly compliant aftertreatment with cortisol may contain little alveolar surfactantand are unstable (Beck et al. 1981; Liggins et al. 1984;Ikegami et al. 1987). The increase in collagen andelastin content of fetal lung that normally precedes birthis reproduced in immature fetuses by treatment withcortisol (Schellenberg et al. 1987) but it is likely thatthinning of septae and other architectural changes areequally important.Alveolar B-adrenoceptors

Two developmental responses necessary to prepare thefetal lung for its function as an organ of gas exchange, the

DexFig. 6 Effect of various steroids on mRNAs of the surfactant proteins, SP-B and SP-C inexplants of human lung. Cont, control; E2 17p-oestradiol; DHT, dihydrotestosterone; HP,17a-hydroxyprogesterone; F cortisol; E, cortisone; B, corticosterone; Dex, dexamethasone.P < 0.05 v control. Liley et al. 1989.)


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release of surfactant and reabsorption of alveolar wa-ter, can be stimulated by B-adrenergic agonists (Law-son et al. 1978; Olver et al. 1981). The sensitiv-ity of the responses increases greatly in late preg-nancy and can be induced prematurely by treatmentwith cortisol which specifically increases the concentra-tion of alveolar B-adrenergic receptors (Barnes et al.1984).Glycogenolysis

Unlike the liver, in which glucocorticoids promoteglycogen deposition, the response in the fetal lungis glycogenolysis (Bourbon and Jost 1982) (Fig. 7).Glycogen accumulation in the lung appears to beindependent of hormones and is unaffected by fetalhypophysectomy. The function of glycogenolysis probablyprovides substrate for phospholipid synthesis (Brehierand Rooney 1981).

Fig 7 Effect of dexamethasone Dex) treatment prepartum in miceon incorporation of choline into phosphatidylcholine in fetal lungslices and on lung glycogen. Choline incorporation in controls 0)and Dex-treated e); lycogen in controls A) and Dex-treated A).NB, newborn. Brehier and Rooney 1981.)

AntioxidantsFree-radical scavengers are not important in theprotected fetal environment but assume an importantfunction with the onset of air-breathing. Infusion ofcortisol into immature fetal sheep stimulates the activity ofsuperoxide dismutase, catalase and glutathione peroxidase(Walther et al. 1991).

Cortisol cortisone InterconversionIn fetuses of many species, cortisol is extensiveconverted to cortisone by 11B-hydroxysteroid dehydrgenase resulting in higher concentrations of cortisothan cortisol in fetal plasma (Murphy 1981). In tlung, however, the reaction is mainly reductive (Nicholand Lugg 1982). Although production of cortisol fro

cortisone in the lung is small compared with adrensecretion, local production could contribute to lung mauration. Glucocorticoids increase the activity of tenzyme suggesting a mechanism by which the effects rising plasma cortisol levels may be amplified in lutissue (Smith et al. 1982).mall ut

Although the fetus consumes large volumes of amnotic fluid, digestion is not required and waste materiaaccumulate in the large bowel as meconium. It seemlikely that cortisol-dependent maturation of the small goccurs before birth but most studies have been main suckling rats, rabbits or mice in which corticosterotreatment results in morphological maturation and indution of sucrase, alkaline phosphatase and Na /K+ATPase(Moog 1953; Guiraldes et al. 1981). Prenatal trement in rats elicits a precocious appearance of jejunsucrase (Celano et al. 1977) and alkaline phosphata(Ross and Goldsmith 1955). Alkaline phosphatase induced also in fetal rabbits (Lee et al. 1976). Aextensive morphological study in fetal sheep infused wphysiological amounts of cortisol at 0 . 7 of gestatifound advanced villus enterocyte kinetics (Trahair et 1987) suggesting that investigation of potential cortisinducible enzymes in tissues from this species may rewarding.

LiverReports of the effects of glucocorticoids on livenzymes are extensive but most relate to studies in viin suckling rats. Many of the numerous enzymes inducibafter birth are unresponsive before birth. Likewise, mostudies in fetuses are performed in vitro in rats (Tableand there is a paucity of research in vivo in specwith a longer gestation. The extent to which postnaresponses in rats can be extrapolated to prenatal respons

in species such as primates, sheep and guiea-pigs uncertain.The fetus receives an inexhaustible supply of glucoby transplacental passage from the mother. At birth, tfetus is suddenly deprived of this source of glucose andalternative source must become rapidly available; in thregard, the liver substitutes for the placenta in providifor the immediate needs for glucose from glycogen storand the longer-term needs from gluconeogenesis aincreased metabolism of fatty acids and amino aci


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Table 1 Enzymes induced by corticostemids in fetal liverEnzyme Species Study Reference

Tyrosine aminotransferase rat in vitro Wicks 1968; Coufalik and Monder 1974Argininosuccina te synth ase and argininosuccinate lyase rat in vitro Wicks 1968; Schwartz 1972Argininosuccinate lyase rat in vitro Husson et al 1986Fatty-acid synthase rabbit in vivo Gross et al 1975Glucuronosyltransferase rat in vivo Wishart and Dutton 1977Glucose-6-phosphatase sheep in vivo Fowden et al 1990Ornithine decarboxylase rat in vitro Hiramatsu et al 1985Carbon-dioxide-ammonia ligase rat in vivo Gautier et al 1985UDPg lucose-glycogen glucosyltransferase rat in vivo? Jacquot and Kretchmer 1964Monooxygenase human in vitro Mathis et al 1986

Rising prepartum concen trations of cortisol play a part inpromoting all these activities. The following discussionis drawn as far as possible from studies in species witha longer gestation.Glycogen Storage

In all species investigated to date, including rats Klepac1985), mice Tye and Burton 1980), monk eys and sheepBarnes et al. 1978), glucocorticoid administration causesa marked increase in the accumulation of liver glycogenJones and Rolph 1981 ). The prenatal rise in liverglycogen in fetal sheep Dawes and Shelley 1968) hasa close temporal relationship with the prenatal rise incortisol and it is prevented by fetal hypophysectomy oradrenalectomy Barnes et al. 1978). Glycogen depositionin response to cortisol is largely the result of activationof glycogen synthetase Schwartz and Rall 1973).Gluconeogenesis

Villee 1953) first demon strated gluconeoge nesis inslices of human fetal liver. Increased incorporation ofalanine into glucose and glycogen following exposureof human fetal liver to glucocorticoid was demonstratedsubsequently by Schwartz and Rall 1975). How-ever, experiments in vivo, particularly in rats, showedthat increased gluconeogenesis, whether spontaneous orglucocorticoid-induced, apparently occurs only after birthand is activated by factors associated with the transition toextrauterine life. This view was supported by a study ofsubstrate fluxes across the liver during infusion of labelledlactate in chronically cannulated sheep fetuses at 12 4 daysgestation; the cortisol-treated group showed no increasein glucose flux Rudolph et al. 1989). However, whenthe experiments were repeated at 137-140 days gestationthere was substantial gluconeogen esis Townsend et al.1991). Experiments are needed in other species to inves-tigate the possibility that gluconeogenesis is responsiveto glucocorticoids very close to term.

atecholaminesAlthough the fetal adrenal medulla releases cate-cholamines in response to various stresses such as

hypoxaemia and hypotension, its function becomes im-portant only with birth. The catecholamines then play amajor role in the adaptations to extrauterine life in severalorgans including lung surfactant secretion, lung waterresorption), vascular system increase in cardiac output,peripheral resistance and blood pressure), brain centralcontrol of breathing) and liver mobilization of energysubstrates) as well as the adaptation of brown fat forthermogenesis. These adrenergic responses occur partlyas a result of a surge in the release of catecholaminesduring labour and delivery Padbury et al. 1982) andthe cutting of the umbilical cord Padbury et al. 1981)and partly as the result of increased concentrations ofp-adrenergic receptors; glucocorticoids contribute to bothof these mechanisms.Phenylethanolamine N-methyltransferase PNMT)

The methylation of noradrenaline to form adrenaline iscatalysed by PNM T which is stimulated by glucocorticoidsWurtman and Axelrod 1966). Fetal adrenal medullarycells from sheep secrete increased amounts of adrenaline,but not noradrenaline or dopamine, when exposed toconcentrations of cortisol similar to that in the plasma ofthe term fetus Graham et al. 1986). It is possible thatthe medullary cells, through which the venous effluentis draining in the intact fetus, are exposed to highconcentrations of cortisol and that the activation of PN MTand the secretion of adrenaline are paracrine events. nadditional unidentified paracrine factor secreted by corticalcells which is synergistic with cortisol has been reportedCheung 1984). Although the plasma concentration ofcatecholamines does not rise be fore parturition, the risinglevels of cortisol prepare the adrenal medulla for themarked increase in activity observed during labour andafter delivery Eliot et al. 1981). As expected withenhanced PN MT activity, the predominant catecholaminereleased is adrenaline.

n the rat, the fetal lung con tains PNM T the ac tivity ofwhich increases on exposure to glucocorticoid Kenned yet al. 1990); this raises the possibility that adrenalinemay have a paracrine function in promoting surfactantsecretion and fluid reabsorption.


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The a ctivity of PN MT in the brain stem of the fetal ratis not enhanced by glucocorticoids (Bohn et al 1986),but in the neonatal rat this treatment is followed by asustained increase in activity (Turner et al 1979).b Adrenergic Receptors

Mech anisms leading to increased secretion of surfactantand decreased secretion of lung fluid become m ore sensitiveto adrenaline towards the end of gestation in fetal rabbits(Lawson et al 1978). This heightened sensitivity appearsto be the result of an increase in the concentration ofpulmonary /I-adrenergic receptors associated with risinglevels of cortisol. Receptor concentrations are increasedprecociously by treatment with glucocorticoid (Chenget al 1980) and autoradiography demonstrates that theresponse is specific to the alveoli (Barnes et al 1984).

drenalThe possibility that cortisol enhances the fetal adrenalresponse to adrenocorticotrophic hormone (ACTH) andthus contributes to the prepartum increase in cortisolsecretion has been investigated in fetal sheep. Theresponse in vivo to ACTH is enhanced by prior exposureto dexamethasone (Liggins et al 1977). Similarly,cortisol restores the responsiveness to ACTH of dispersedadrenal cells in which production of cortisol is blocked bytreatment in vivo with metyrapone (Challis et al 1985).The mechanism of action of cortisol remains unknownbut may involve enhanced production of CAM P ratherthan activation of 17 ~-h ydr oxy laseChallis et al 1986).

KidneyMaturation of fetal kidney function is acceleratedby treatment with corticosteroids. Prenatal treatmentof rats with dexamethasone stimulates the activity ofNa+ K+-ATPase in the cortical tubules (Dobrovik-Jenikand Milkovic 1988). Hill et al (1988) and Stonestreet et

al (1983) observed that the treatment of fetal sheep withcortisol increased the glom erular filtration rate and tubular

lacebo Rx

Fig 8 Glomerular filtration rates in control and betamethasone-treated fetal sheep . Means s.e.m. P 0.05 v. term fetuses. Valuesin parentheses are number of fetuses. (Stonestreet t al. 1983.

reabsorption of sodium (Fig. 8). Newborn infants whosmothers were treated with corticosteroids before preterdelivery showed no increase in creatinine clearance busodium fractional excretion was reduced as expected wienhanced activity of Na+ K+-AT Pase (Zanardo et a1990).

Haemopoietic and Lymphatic SystemsProgenitor cells of the erythropoietic system migrafrom the yolk sac to the liver in early embryonic lifThe liver remains the site of erythropoiesis throughoufetal life until shortly before birth when erythroid celenter the bone marrow and the erythropoeitic activity the liver rapidly subsides. This late switch appears to bcontrolled by cortisol. However, in hypophysectom izesheep and rats erythropoiesis persists in the liver and beyond term and treatment with glucocorticoid associated with normal regression of erythroid tissu(Liggins and Kennedy 19 68; Jacquot and Nagel 1 976The switch from fetal to adult haemoglobin is alsweakly dependent on cortisol. In adrenalectomized fetsheep, the onset of /I-globin synthesis is normal but thrate of synthesis is decreased unless cortisol is infuse(Wintour et al 1985). However, infusion of ACTH intact fetuses does not accelerate the rate of synthesof adult haemoglobin (Jansen et al 1982).Lymphoid tissue in the spleen and thymus regresslate in fetal life and is dependent on rising levels ocortisol. In fetal rabbits, this regression is prevented bhypophysectomy and restored by treatment with ACT(Beam 1961; Beam 1967).The regression of erythroid and lymphoid tissue neterm is a physiological response to cortisol and is distinfrom the well-known effects of pharmacological doses oglucocorticoids that cause retardation of fetal growth bpromoting differentiation at the expense of proliferatioBiphasic responses to glucocorticoids, in which dosbelow those causing growth retardation promote cortisosensitive systems and higher doses cause inhibitioare probably a common phenomenon; this emphasizethe need for care in selecting appropriate doses fstudies of cortisol-related events in the fetus (Bian et a1991).

BrainThere are numerous reports on the effects of glucocoticoids on brain development (reviewed by Meyer 1985However, almost invariably the experimental animal hbeen the suckling rat and the .doses used are massivcompared with those that induce enzyme activity in thfetus. As a consequence, the relevance of the results othese studies to the fetal rat or to the fetuses of another species is questionable.


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ConclusionThere is extensive evidence that the major role of

cortisol in the fetus is in the preparati on for the transitionfrom intrauterine to extrauterine life. In prococial speciescortisol-induced maturation occurs very rapidly close toterm and is tightly linked to the mechanism initiatingparturition; in contrast in altricial species it occursover a greater proportion of gestation extending intopostnatal life in some species and the relationship toparturition is ill-defined. In general cortisol promotescellular differentiation at th e expense of proliferation. Asa consequence glucocorticoids in pharmacological dosesare well known for their effects in retarding fetal bodyweight and organ growth. In physiological amountshowever glucocorticoids precociously activate a verywide range of enzymes that are necessary after birthalthough having little or no function in the fetus. Itis likely that a number of cortisol-sensitive enzymesremain to be identified particularly in view of therecent demonstration that cortisol may be dependent onsynergism with other hormones including T3 prolactinand adrenaline.

Not surprisingly because it is the organ on whichpostnatal survival most depends the fetal lun g is highlycortisol-dependent. This phenomenon has been effectivelyexploited to accelerate lung maturation in the humanfetus before preterm delivery.

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Manuscript received 20 August 1993; accepted 27 October 1993

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The Role of Cortisol in Prepa(1)