Endocrine Adaptations in the Foal Over the Perinatal Period 2

7/27/2019 Endocrine Adaptations in the Foal Over the Perinatal Period 2

1/10

Endocrine adaptations in the foal over the perinatal period

A. L. FOWDEN*, A. J. FORHEAD and J. C. OUSEY

Departmentof Physiology, Development and Neuroscience, Universityof Cambridge, Cambridge, UKRossdale and Partners,Beaufort Cottage Stables, High Street, Newmarket, UK.

*Correspondenceemail: [email protected]; Received: 03.05.11; Accepted: 04.08.11

Summary

Inadaptingto life ex utero, the foalencounters a number of physiological challenges. It has to assume the nutritional, respiratory and excretory functionsoftheplacentaand activate full regulatorycontrol over its own internal environmentfor thefirst time. To achieve this, there must be structural andfunctionalchanges to a wide range of tissues including several endocrine glands. In most species, including the horse, these maturational changes begin in lategestationand continue intothe firstfew days of neonatal life.Consequently, during thisperinatalperiod,there are majorchangesin the sensitivity and/or setpoint of keyendocrine axes, which alterthe circulating hormone concentrationsin the foal.In turn,these endocrinechangesare responsible formany of theother physiological adaptations essential for neonatal survival. The perinatal alterations in the hypothalamic-pituitary-adrenal (HPA) axis are particularlyimportantin theseprocesses,althoughthe sympatho-adrenalmedullaryaxis andendocrine pancreasalso have keyrolesin ensuringhomeostasisduringthemultiplenovelstimuliexperiencedat birth. Abnormalities inthe perinatalendocrine profile caused by adverseconditions before or afterbirth may, therefore,lead to maladaptation or aid survival of the newborn foal depending on the specific circumstances. This review examines the perinatal changes inendocrinologyin normal and compromised foalsand the roleof theseendocrine changes in the physiologicaladaptations to extrauterine lifewith particularemphasison the HPA axis,adreno-medullary catecholamines and the endocrinepancreas.

Keywords: horse; hypothalamic-pituitary-adrenal axis; sympatho-adrenal axis;endocrine pancreas

Introduction

At birth,the foal faces a numberof physiological challenges in adapting tolife ex utero including assuming the nutritional, respiratory and excretoryfunctions of the placenta along with full regulatory control over its owninternal environment for the first time (Sangild et al. 2000). Many of thehomeostatic functions, such as thermo- and gluco-regulation, are notactive before birth but, like pulmonary respiration, are vital after delivery(Fowden et al. 1998). Specific tissues and organ systems of the foal must,therefore, be competent to carry out their new functions at or shortlyafter birth, if the neonate is to survive the passage from intra- to

extrauterine life. Consequently, preparations for this transition beginduring late gestation and involve maturational changes in the structureand functional capacity of key tissues essential for immediate neonatalsurvival (Silver 1990; Sangild et al. 2000). Longer-term adaptations inthese and other tissues then continue over the next few days of neonatallife in response to the novel stimuli of high pO 2, cold exposure, enteralnutrition, locomotion and behavioural interactions.

Endocrine glands are amongst the tissues adapting in function duringthe perinatal period. Changes in the sensitivity and/or set points ofseveral major endocrine axes have been observed both before and/orshortly after birth in a number of species including the horse (Berg et al.2007; Fowden and Forhead 2009). Indeed, these endocrine changes andthe ensuing alterations in circulating hormone concentrations are oftenresponsible for the maturational changes seen in other physiologicalsystems during the perinatal period. The glucocorticoids, in particular,have a wide range of maturational effects but many other hormones,

such as the catecholamines and pancreatic hormones, also haveimportant roles in maintaining homeostasis during the stress of adaptingto extrauterine life (Fowden et al. 1998; Fowden and Forhead 2009).In addition to the normal maturational processes, there are alsochanges in the intrauterine development and perinatal adaptationof the endocrine glands in response to adverse conditions that alterthe environment in utero, such as maternal ill health, nutrientdeprivation or placental dysfunction (Bertram and Hanson 2002; McMillenand Robinson 2005; Fowden et al. 2006). This review examines theperinatal changes in endocrinology in normal and compromisedfoals and the role of these changes in the physiological adaptationsto extrauterine life with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis, adreno-medullary catecholamines and theendocrine pancreas.

The hypothalmic-pituitary-adrenal axis

Activation of the hypothalmic-pituitary-adrenal (HPA) axis is important formany of the adaptive processes essential for life ex utero. In all speciesstudied to date, including the horse, there is an increase in the cortisolconcentration in the fetal circulation during the period immediately beforebirthas a result ofdevelopmentalchangesat alllevelsof theHPA axis (Fig 1)(Liggins 1994; Challis et al. 2000). This increase in fetal glucocorticoidavailabilityinducesstructuralandfunctionalchangesin a varietyof differenttissues, including the lungs, liver, kidneys and gastrointestinal tract (Silver1990; Sangild et al. 2000). It also activates many of the physiological

processes that arevital atbirthbuthave littleor nofunctionin fetallife, suchas pulmonary ventilation, glucogenesis and renal sodium conservation(Fowden et al. 1998). Inmany species,prepartumactivationofthefetalHPAaxis is also involved in the onset of labour. In man and other primates,parturition is facilitated by increased adrenal output of oestrogenprecursors,whereas in ruminants, it is the cortisol surge itselfthat induceslabour by actions on uteroplacental steroidogenesis and prostaglandinproduction (Wood and Cudd 1997; Challis et al. 2000). Consequently, insome species, adrenal glucocorticoids act to coordinate prepartummaturation of the fetus with the onset of uterine contractile activity, whichmaximises the chances of delivering viable young (Silver 1990). In horses,the signalfor the onset oflabouris not asclear asin otherspecies but mayinvolveincreasedadrenalsecretion of steroids(Silver1994).

The hypothalmic-pituitary-adrenal axis and

cortisol production

In the horse, activation of the HPA axis occurs late in gestation comparedwith other species (Rossdale et al. 1973; Fowden and Silver 1995; Woodand Cudd 1997). Fetal cortisol concentrations only begin to rise about 5days before birth and then escalate rapidly towards term in pony foals(Fig 1b).Thisis associatedwith a doublingof adrenalweightover thelast 5%of gestation, primarily due to increased growth of the zona fasciculata inthe adrenal cortex(Comlineand Silver 1971). Similar increments in adrenalweight and cortisol concentrations are observed in fetal sheep and pigsduring late gestation but these begin proportionately earlier in gestationand occur more slowly than in fetal horses (Wood and Cudd 1997). Ingeneral, plasma adrenocorticotropic hormone (ACTH) concentrations risein parallel with the cortisol concentrations in the fetus (Silver and Fowden1994; Cudd et al. 1995). Thus, in sheep, there is a progressive increase in

Equine Veterinary Journal ISSN 0425-1644

DOI: 10.1111/j.2042-3306.2011.00505.x

130 EquineVeterinary Journal 44, Suppl. 41(2012) 130139 2012 EVJLtd

danielahilda

paola

gas

emiliano


2/10


3/10

dysfunction syndrome, which suggests that adrenal exhaustion can occurwhenstressis prolonged (Hartet al. 2009b). Theseobservationsshow thattheabilityof theequine adrenal glandto secrete cortisol developsonlylatein gestation and is directly related to the viability of the foal. The cortisolresponse to ACTH administration, therefore, provides a useful clinical testof the maturity and health status of newborn foals (Rossdale et al. 1984;Wong et al. 2009).

The developmental profile of the adrenocortical response to stressfulstimuli, such as hypoglycaemia and hypotension, differs from that seen inresponse to exogenous administration of ACTH1-24 (Fig 2b) (Silver et al.1987; Silver and Fowden 1995; OConnor et al. 2005). The increment inplasma cortisol in response to insulin-induced hypoglycaemia is smallerand delayed relative to that evoked by direct administration of ACTH1-24 inboth near-term fetuses and neonates (Fig 2b). However, by 714 days,there is a rapid, sustained increase in plasma cortisol concentrations inresponse to both hypoglycaemia and hypotension (Silver et al. 1987;

OConnor et al. 2005). The cortisol response to hypoglycaemia, therefore,rises progressively with postnatal age in contrast to that seen in responseto exogenous ACTH administration (Fig 2a). This suggests that, during theperinatal period, there may be developmental changes occurring at thehypothalamic-pituitary level that determine the secretion of endogenous,bioactive ACTH.Certainly, there is little, if any, ACTH release in response toinsulin-induced hypoglycaemia in the fetus, even close to ter m, yet by 34days afterbirth thisresponseis briskand significantly greater in magnitudethan that seen prenatally (Fig 3a). However, despite the greater incrementin ACTH, adrenocorticalsensitivity to endogenousACTH appears to be less

34 days after birth than in newborn foals (Fig 3b), consistent with thefindings with exogenous ACTH1-24 administration (Fig 2a). Rapid rises inACTH and cortisol concentrations are also seen in 7-day-old foals inresponse to acute hypotension (OConnor et al. 2005). However, by 14days, the ACTH response to this physiologicalchallenge is significantly lessthan at 7 days, despite a similar cortisol increment (OConnor et al. 2005).There may, therefore, be changesin the bioactivity of pituitaryACTH duringthe neonatal period or, alternatively, other factors, such as adrenalinnervation, may act to increase adrenocortical sensitivity to endogenousACTH during stressful conditions in foals by age 14 days (Edwards 1997;Wood andCudd1997).

The cellular and molecular mechanisms responsible for the perinatalchanges in basal and stimulated HPA function in the foal remain largelyunknown. At the pituitary level, there is little evidence for changes in themorphology or density of the corticotrophs observed in the fetal ovinepituitary during theprepartum period (Fowden and Silver 1995). However,

the alterations in the pulsatile pattern of fetal ACTH concentrations withproximity to delivery suggest that there are prepartum changes inhypothalamic secretion of the ACTH releasing factors, corticotrophinreleasing hormone (CRH) and arginine vasopressin, and/or in theabundance of the receptorfor theseneuropeptides on the corticotrophs ofthe foal (Cudd et al. 1995). At the adrenal level, production of cortisoldepends on 3 key rate-limiting enzymes: cholesterol side chain cleavage(P450SCC), 3b-hydroxysteroiddehydrogenase (3bHSD)and17a-hydroxylase(P450C17). Cytochrome P450SCC, which converts cholesterol topregnenolone (P5) is present in the zona glomerulosa and putative zona

a)

P

lasmacortisolconcentrationng/ml

80

Response to ACTH124 b) Response to hypoglycaemia

70

60

50

40

30

20

10

0

0 15 30 45 60

Time (min)

Preterm fetus Term fetus Newborn Foal 35 days Foal 714+ days

Time (min)

90 120 0 15 30 45 60 90 120-10

Fig 2:Mean s.e.increment(change) in plasmacortisol concentrationfrom baseline(0 min)inresponseto (a)administrationof adrenocorticotropic

hormone (ACTH1-24 12 mg/kg bwti.v.)and (b)hypoglycaemia inducedby insulin (0.5 u/kg bwti.v.)inponyfetuses beforeterm (320 days of gestation,filledcircles) andin newbornpony foalsat


4/10

reticularis of the equine adrenal gland from as early as 150 days ofgestation and rises in abundance in these regions, and in the zonafasciculata, with increasing gestational age (Han et al. 1995). The enzyme3bHSD synthesises progesterone from P5 and increases in abundance,predominantly in the zona fasciculata, from about 280 days of gestationonwards,in association withultrastructural changes to thiszone indicativeof increasedsteroidsynthesis (Webb andStevens1981; Han et al. 1995).Incontrast, P450C17, required forcortisolproduction, is only detectable inthe

equine adrenalglandat lowconcentrations until veryclose to termwhen itsexpression increases in parallel with the prepartum rise in fetal cortisolconcentrations (Fig 1b). By birth, all 3 enzymes are abundant throughoutthe zona fasciculata of the neonatal adrenal gland and show little furtherchange in expression during thefirst fewweeks of post natal life (Han et al.1995). Theseperinatalchanges in cytoarchitecture and enzyme content ofthe equine adrenal gland are, therefore, consistent with the increasedresponsiveness to exogenous ACTH1-24 between late gestation and birth(Fig 2a), and with the positive correlation observed between the cortisolresponse to ACTH1-24 of thenewbornfoaland itsgestationalage at delivery(Ousey et al. 2011).Theyalsosupportthe suggestion that otherfactorsareinvolved in the subsequent post natal changes in adreno cortical ACTHresponsiveness (Fig 2a). These factors include adrenal blood flow, ACTHreceptor density, ACTH clearance and the release of adreno-medullarypeptides witheffects on the adrenal cortex(Fowden andSilver 1995;Woodand Cudd1997).

In rat dams, environmental challenges during pregnancy influenceHPA function in the newborn pups but little is known about the immediateneonatal consequences of suboptimal intrauterine conditions on thisaxis in more precocious species such as the horse (Lesage et al. 2001;Fowden et al. 2006). Dysphagia and chronic weight loss during TBpregnancy caused by infection with Streptococcus equi increases thebasal cortisol concentrations of their growth restrictedfoals 1524 h afterbirth but has little effect on the cortisol response to exogenous ACTH 1-24at this age, irrespective of the nutritional plane of the mother at the timeof infection (Ousey et al. 2008). Neonatal HPA function is also alteredwhen fetal growth is manipulated by embryo transfer between equinebreeds of different sizes (Allen et al. 2002; Giussani et al. 2003; Ouseyet al. 2004). Both intrauterine growth-restriction (IUGR) caused bytransferring a TB embryo into a pony uterus and fetal macrosomiainduced by the reciprocal transfer of a pony embryo into a TB mare altercortisol responses to ACTH and physiological stimuli in the newborn foal.

In TB foals growth restricted by embryo transfer into pony mares, basalcortisol concentrations are high 12 h after birth, despite normal ACTHconcentrations, although the cortisol response to exogenous ACTH1-24 issmall compared with that of normally grown TB foals during the first daypost partum (Ousey et al. 2004). However, 45 days later, the cortisolresponse to ACTH1-24 and HPA sensitivity to acute hypotension areno different in IUGR and normally grown TB foals (Giussani et al. 2003;Ousey et al. 2004). In contrast, overgrown pony foals delivered by TBmares have normal basal concentrations of cortisol and ACTH for 10 daysafter birth and a normal cortisol response to exogenous ACTH1-24 at 1 and5 days (Giussani et al. 2003; Ousey et al. 2004). However, theseovergrown pony foals had a reduced ACTH response to acutehypotension on Day 6, which was coupled with a cortisol response similarto that seen in normal pony foals with greater ACTH responses (Giussaniet al. 2003). Neonatal adrenocortical sensitivity to endogenous ACTH,therefore, appears to be enhanced during stressful conditions when

intrauterine growth is enhanced above the genetic norm by increasingthe surface area of the placenta (Allen et al. 2002; Giussani et al. 2003).Conditions during intrauterine development, therefore, appear to affectHPA function of the newborn foal in the 10-day period after birth,although the changes are subtle in some instances and may take severaldays to develop.

The hypothalmic-pituitary-adrenal (HPA) axis and

progestagen production

The fetal HPA axis may have a role in controlling the length of gestation inthe mare through adrenal production of pregnenolone, P5 (Silver 1994;Chavatte et al. 1997; Ousey 2004; Fowden et al. 2008). This steroid isbelieved to be the main precursor for uteroplacental production of the

progestagens that control uterine quiescence during the second half ofequine pregnancy (Silver 1994; Chavatte et al. 1997; Ousey et al. 2003).Although the specific progestagens involved in this process remainunknown (Ousey et al. 2000a; 2001), uteroplacental uptake of P5 from thefetal circulation and total maternal progestagen concentrations both riseduring late gestation in parallel with the structural and functionaldevelopments in the fetal adrenal (Ousey et al. 2003). Indeed, whendevelopment of the fetalHPA axisis impairedby fescue toxicosis,maternal

progestagen concentrations remain low throughout pregnancy andgestation is often prolonged (Brendemeuhl et al. 1995; Cross et al. 1995).Conversely, premature activationof the fetalHPAaxis by intrauterinestressfrom placentitis, interbreed embryo transfer, or by fetal CRH or ACTHinjection increases maternal progestagen concentrations and leads toearly delivery in some instances (Rossdale et al. 1992; Ousey et al. 1998;Allen et al. 2002;Ousey2004; Morris et al. 2007). Moreover, removalof thefetal gonad, another potential source of P5, has little effect on the normalprofile of maternal progestagen concentrations during late gestation(Pashen and Allen 1979). Collectively, these findings suggest that the fetalHPA axis is involvedin uteroplacental progestagen production and uterinequiescence in the mare.

Integrated hypothalmic-pituitary-adrenal (HPA)

function during the prepartum period

By combining the cortisol and progestagen data, a possible sequence ofmaturational changes can be described for the integrated function of thefetal HPA axis during the prepartum period as follows. Before 290 days ofgestation (>30 days from delivery), the fetal HPA axis has a basal levelof activity and is relatively unresponsive to stimuli. Circulatingconcentrations of ACTH are low and the adrenal appears to produce P 5primarily, due to a lack of P450C17 (Fig 4a). Much of the cortisol circulatingin the fetus at this time may be of maternal origin derived bytransplacental passage down the concentration gradient (Fowden et al.2008). After 300 days of gestation (255 days before delivery), activity ofthe HPA axis increases (Fig 4b). The adrenal cortex grows and developsmorphologically, possibly due to increased ACTH exposure caused bychanges in the pattern and bioactivity of the ACTH released by thepituitary (Comline and Silver 1971; Webb and Stevens 1981; Cudd et al.1995). With low P450C17 expression, this leads to increased adrenal P5production, which, in turn, enhances uteroplacental production of several

progestagens (Holtan et al. 1991; Rossdale et al. 1992; Ousey et al.2003). These steroids maintain uterine quiescence in the face ofincreasing uterine stretch and lead to rising total progestagenconcentrations in the mare during the last 2025 days of gestation(Fig 4b). Once the adrenal gland expresses sufficient P450 C17 in the last 5days or so of gestation, it appears to switch from P5 to cortisol productionwith the result that fetal cortisol concentrations rise and uteroplacentalsynthesis and maternal concentrations of total progestagens fall (Fig 4c).Withdrawal of the progestagenic block on uterine contractility is,therefore, coordinated with cortisol-stimulated maturation of the fetaltissues in the horse through this putative switch in adrenal steroidsynthesis. Certainly, when delivery occurs prematurely either naturally orby induction with oxytocin before 320 days, plasma P5 and otherprogestagen concentrations are high in the newborn foal in conjunctionwith low cortisol concentrations, consistent with a switch in adrenalsteroidogenesis very close to term (Holtan et al. 1991; Panzani et al.

2009). Thus, paradoxically, the fetal HPA axis appears to act sequentiallyfirst to prevent and then to facilitate the onset of labour in the mare(Fig 4).

The stimulus for the rise in adrenal P450 C17 expression so close to termremains unknown but may depend on removal of an inhibitor or onsufficient exposure to bioactive ACTH or to cortisol itself. The rising fetalcortisol concentrations may also have direct effects on uteroplacentalprogestagen production as administration of synthetic glucocorticoidsto either the mare or fetus increases total maternal progestagenconcentrationsand can induce earlydeliverydepending on the gestationalageat treatment(Alm et al. 1975;Rossdale et al. 1992; Ousey et al. 2011).However, the specific progestagen profile in the mare differs betweenmaternal and fetal treatment with ACTH or synthetic glucocorticoids,despite transplacental passage of natural and exogenous glucocorticoids

A. L. Fowden et al. Perinatal endocrineadaptations

133EquineVeterinary Journal 44, Suppl.41 (2012)130139 2012 EVJLtd


5/10

from the dam (Rossdale et al. 1992; Ousey et al. 1998, 2000b, 2011).Collectively, these findings suggest that maternal as well as fetal HPAfunction may influence the periparturient endocrine profiles, particularlyduring adverse conditions. The trigger for the final endocrine cascade thatleadsto parturition, therefore, appears to be multifactorialin the mare andnotsolely dependenton increasedcortisol production by thefetal adrenalgland as occurs in ruminants (Silver 1994; Wood and Cudd 1997; Challiset al. 2000).

Sympatho-adrenal medullary axis

The sympatho-adrenal medullary system secretes catecholamines and

several other neuropeptides with cardiovascular and metabolic effectsinto the circulation. It is, therefore, involved in regulating homeostasisand responds to a range of stresses common in newborn animals, suchas hypoglycaemia and hypotension (Silver 1990; Spurlock and Furr1990). Plasma concentrations of the catecholamines, adrenaline andnoradrenaline, increase towards term in normal pony foals to peak at orshortly after birth before returning to basal values within 1014 days ofbirth (Fig 1c). Noradrenaline concentrations were generally higher thanadrenaline concentrations throughout the perinatal period with theexception of the period immediately after birth (Fig 1c). Neitherconcentration appears to be affected by the breed of horse, at least 6days after birth (Giussani et al. 2003; Forhead et al. 2004). When deliveryis induced prematurely with oxytocin, noradrenaline concentrations arehigher and adrenaline lower in the 2 h after birth than that seen in full-term neonates (Silver et al. 1984). In stressed premature foals,noradrenaline concentrations may be as much as 5-fold higher than

normal, although adrenaline concentrations remain low (Silver et al.1984). However, induction of delivery within 2448 h of full-term has littleeffect on the temporal profile of catecholamine concentrations over thefirst 10 days after birth (Holdstock et al. 2011). At birth, totalcatecholamine concentrations are inversely related to the pH of umbilicalarterial blood in both premature and full-term foals (Silver et al. 1984).The sympatho-adrenal medullary axis, therefore, appears to be largelyresponsible for the marked perinatal surge in catecholamineconcentrations in the foal and is sensitive to stressful stimuli, at least bylate gestation.

Sympatho-adrenal medullary responses to asphyxia and insulin-induced hypoglycaemia have been studied in foals before and after birth(Comline and Silver 1971; Silver et al. 1987; Silver and Fowden 1995).These responses increase during late gestation and, again, between birth

and 2 weeks before resembling mature responses by about age 12 weeks(Comline and Silver 1971; Silver et al. 1987; Silver and Fowden 1995). Incontrast, there is no change in the catecholaminergic response to acutehypotension between 7 and 14 days of post natal life, despite theconcomitant changes in HPA sensitivity (OConnor et al. 2005). Studies onanaesthetised foals show a doubling of total catecholamine output by theadrenal gland between late gestation and 2 weeks after birth in responseto direct stimulation of the peripheral end of the cut splanchnic nerve(Comline and Silver 1971). Since there is no change in adrenalcatecholamine content over this period (Comline and Silver 1971), theseobservations suggest that splanchnic innervation to the equine adrenalmedulla becomes progressively more effective at releasingcatecholamines during the perinatal period. Indeed, increased adrenal

innervation by age 14 days may be responsible for the enhancedadrenocortical sensitivity to ACTH seen in response to acute hypotensionas splanchnic nerve stimulation and the release of adrenal neuropeptides,such as vasoactive intestinal peptide, have been shown to increaseadrenal cortisol output in response to exogenous ACTH in young, sucklingcalves (Edwards 1997). Indeed, earlier innervation of the adrenal gland inpony foals overgrown by development in a TB mare may explain theirenhanced adrenocortical response to acute hypotension relative tonormally grown pony foals delivered by pony mares (Giussani et al. 2003).Stressful stimuli that activate both the HPA and sympatho-adrenalmedullary axes may, therefore, cause greater cortisol secretion perunit ofACTH than seen in response to administration of ACTH alone. However,sectioning of the splanchnic nerve to the adrenal gland has little effect onthe catecholaminergic response to asphyxia, or anoxia, in either the fetusor the neonate until about 2 weeks after bir th of thefoal (Comline and Silver 1971). This suggests that, unlike the lamb,

adreno-medullary cells of the foal remain directly sensitive to pO 2 forsome time after birth, despite the increasing effectiveness of theinnervation (Comline et al. 1965; Comline and Silver 1971).

In late gestation, the sympatho-adrenal medullary response of the foalto hypoglycaemia is solely noradrenergic, whereas, by 714 days afterbirth, it is primarily adrenergic (Fig 5). At the nadir of the glucoseconcentrations in the older foals, there are significant increases in bothcatecholamine concentrations but the increment in plasma adrenaline is10-fold greater than the noradrenergic response (Silver et al. 1987; Silverand Fowden 1995). Similar developmental changes in the relative adrenaloutput of the 2 catecholamines are seen in response to asphyxia of thefoal (Comline and Silver 1971). There is also a perinatal switch fromnoradrenaline to adrenaline output by the adrenal gland in response todirect stimulation of the splanchnic nerve with adrenaline accounting for

a) >30 days from delivery

FETUS

MOTHER

UTERO-

PLACENTALTISSUES

ACTH ?

Cortisol P5 Progestagens

Progestagens

Basal progestagens

-95 -85 -75 -65 -55 -45Days from delivery

-35 -25 -5 Newborn-15

20

15

Totalprogestagen

concentration(ng/ml)

10

5

0

Rising progestagens Rapidly fal lingprogestagens

Progestagens Progestagens

Cortisol P5 Progestagens Cortisol P5 Progestagens

ACTH ACTHAdrenal

cortex

Adrenal

cortex

P450c17Adrenal

cortex

b) 255 days from delivery c) 30 days fromspontaneous delivery at full-term (


6/10

2030% of the total adrenal catecholamine output just before term butover 70% of the total two weeks after birth of the foal (Comline and Silver1971). In part, this may be due to perinatal activation of the HPA axis ascortisol is known to induce activity of phenyl-N-methyl-transferase, theenzyme responsible for adrenaline synthesis from noradrenaline, in theadrenal gland of fetal sheep near term (Comline et al. 1970; Coulter et al.1991). This suggestion is consistent with the lower adrenalineconcentrations seen in newborn foals delivered prematurely before thefinal prepartum cortisol surge (Silver et al. 1984). However, fetaladrenaline and cortisol concentrations are not correlated during lategestation and there is no change in the adrenaline content of the equineadrenal between late gestation and 2 weeks after birth (Comline andSilver 1971; Giussani et al. 2005). Consequently, factors other thancortisol, such as the improving innervation, may contribute to theincreasing adrenaline output of the adrenal gland during this period. In

neonates of other species, the pattern and frequency of discharge in thesplanchnic nerves is known to cause differential release of the variousadreno-medullary secretions (Edwards 1997).

Noradrenaline and adrenaline are known to affect cardiovascularfunctionin fetaland newbornfoals (Hollis et al.2006;OConnor et al. 2006).They raise bloodpressure by increasing both systemic vascular resistanceandheartrate at allages studied from midgestation to 14 days after birth,although they are more effective pressor agents after than before birth(OConnor et al. 2005, 2006; Hollis et al. 2006). Neonatal sensitivity tothe catecholamines and sympatho-adrenal medullary responses tohomeostatic challenges are affected by the conditions experiencedin utero. The overgrown pony foal produced by embryo transfer intoa TB mare has diminished plasma catecholamine responses to acutenitroprusside-induced hypotension 6 days after birth but a raisedbasal arterial blood pressure, despite similar basal catecholamineconcentrations to normally grown pony foals delivered by pony mares

(Giussani et al. 2003). These changes are coupled to an increasedbaroreflex threshold and reduced baroreflex sensitivity in the pony foaldelivered by a TB mare. Conversely, TB foals with IUGR resulting fromdevelopment in a pony mare have augmented sympatho-adrenalresponses to acute hypotension but no change inbasal blood pressure, baroreflex threshold or basal catecholamineconcentrations, although baroreflex sensitivity was increased relative tonormal TB foals delivered by TB mares (Giussani et al. 2003). Changes inthe secretion and action of the catecholamines during the perinatalperiod, therefore, have an essential role in the cardiovascular and otheradaptations to life ex utero. Administration of noradrenaline oradrenoreceptor agonists may, therefore, be a useful clinical treatment forthe neonatal hypotension frequently seen in premature and othercompromised foals(Hollis et al. 2006).

The endocrine pancreas

Before birth, fetal glucose concentrations are controlled primarily by thetransplacental passage of glucose from the mother and, hence, the mainrole of the endocrine pancreas in utero is not to regulate the glucoseconcentration butto matchthe rate of fetalglucoseutilisationto therateofplacental glucose supply (Fowden and Hill 2001; Fowden and Forhead2009). However, at birth, the endocrine pancreas must become directlyinvolved in gluco-regulation and maintain normoglycaemia in the face ofthe increased metabolic demands of the neonate and switch froma continuous to an intermittent supply of nutrients. Episodes ofhypoglycaemia are common in the foal during the neonatal period, whichsuggests that the mechanisms of glycaemic control are not always fullycompetentat birth inthis species (Spurlockand Furr 1990).

Pancreatic b cell function

Althoughbasalinsulin concentrationsin thefoaltendto behigherat age14days than earlier in pre- or post natal life (Fig 1e), there is little variation intheplasmainsulinconcentration from160 days of gestationto birthor fromDay1toDay10post partum innormal foals,eventhoughthere is a markedpostnatal increasein the glucose concentration(Fowden et al. 1980,1982;Holdstock et al. 2004). The mainincrease in plasma insulin concentrations,therefore, appears to occur over the first 8 h post partum in associationwith the onset of sucking (Fig 1e). The temporal profile of neonatal insulinconcentrations appears to be unaffected when labour is induced 2448 hbefore fullterm basedon pre-colostral electrolyte concentrations(Fowdenet al. 1984; Holdstock et al. 2012). There is also little evidence fordifferences in insulin concentrations between pony and TB foals duringearlyneonatallife (Fowdenet al. 1984;Forhead et al. 2004). Comparisonofthe relationships between the endogenous concentrations of insulin andglucose during the perinatal period shows that the set point for

glucose-stimulated insulin secretion in the foal shifts progressively tohigher glucose concentrationsfromlate gestationthroughto 2448 hafterbirth when the relationship resembles that in the mature horse (Fowdenet al. 1980).In keeping with this, there arechanges in thepancreatic b cellsensitivityto exogenous glucose during the perinatal period (Fowdenet al.1982,1984, 2005;Holdstock et al. 2004).

Exogenous administration of glucose to fetal horses does not evokeinsulin secretion before about 200 days of gestation (Fowden et al. 1980).Thereafter, there is a prompt increase in the fetal insulin concentration inresponseto exogenousglucose. Thisresponse increasesbetween260 and290+ days of gestational age and then, in late gestation (>300 days),increases with proximity to delivery as indicated by the prepartum rise incirculating cortisol concentrations (Fowden et al. 1980, 2005). In lategestation, the glucose-stimulated insulin increment was 3-fold greater in

a) Noradrenaline

2.5

2.0

No

radrenaline

conce

ntrationng/ml

1.5

1.0

0.5

0

b) Adrenaline

7

6

Adrenaline

concentrationng/ml

5

4

2

1

3

0

-30 0 30 60 -30 0

Time (min)

30 60 -30 0 30 60

Term fetus Newborn Foal 714 days

Fig 5:Mean s.e.plasmaconcentrationsof (a)noradrenaline and(b) adrenalinein responsetohypoglycaemia inducedby insulin administration

(0.5 u/kg bwti.v.)in ponyfoalsin lategestation(>315 days of gestation, filledcircles) andat


7/10

fetuses with cortisol concentrations >15 ng/ml than in those of the samegestational age withlower cortisol concentrations(Fowden et al. 2005).At2 h after birth, the pancreatic b cell response to glucose is low comparedwith that seen either in late gestation or at age 57 days (Fowden et al.1982, 1984). Since the pancreatic b cell response to glucose varies littlebetween 24 h and Day 9 post partum (Holdstock et al. 2004), thesuppressed response seen immediately after birth may be due to theelevated catecholamine concentrations (Fig 1c), as both adrenaline and

noradrenaline are known to inhibit insulin secretion in fetal and matureanimals (Fowdenand Hill 2001).In contrast, thepancreaticb cell responseto the amino acid, arginine,shows littlechange in magnitudeeither duringlate gestation or between Days 2 and 10 post partum, although theseresponses are smaller than those evoked by glucose at all ages studied(Fowden et al. 1984, 2005; Holdstock et al. 2004). Since arginine andglucose act through different pathways to stimulate insulin secretion(Fowden and Hill 2001), these observations suggest that the majorperinatal changes in b cell function may occur in the glucose signallingpathway, upstream of the mechanism of insulin vesicle release common toboth pathways.

Proinsulin is detectable in plasma from newborn foals and increases inconcentration over the first 2448 h post partum, although absoluteconcentrations are only 510% of those of insulin (Holdstock et al. 2004).Proinsulin concentrations also increase after administration of exogenousglucose and arginine but not in response to the smaller increments

in endogenous glucose seen after feeding (Holdstock et al. 2004).The proinsulin responses are also smaller and more prolonged thanthe corresponding insulin responses (Holdstock et al. 2004). Theseobservations suggest that there may be changes to the rate of proinsulincleavage within the insulin vesicles or in proinsulin clearance from thecirculation as the glucoregulatory demands on the b cells rise with theintermittent provision of nutrients after birth. Overall, the perinatalchanges in the sensitivity and set point of the pancreatic b cells toglycaemic changes,particularly between the immediateprepartum periodand 48 h after birth suggest that these cells are responsive to the otherendocrine changes occurring at delivery and/or to the release of gutpeptides andhormones after feeding forthe first time (Ousey et al. 1995).

In common with other species (Fowden and Forhead 2009), insulin actsto lower glucose concentrations in the foal both before and after birth(Silver et al. 1987; Silver and Fowden 1995; George et al. 2009). Thishypoglycaemic action of insulin appears to be less effective shortly after

birth, as glucose clearance is slower in response to exogenous glucoseadministration 1224 h after birth than in older foals, despite a normalinsulin response (Holdstock et al. 2004).This apparent tissue resistance toinsulin immediately after birth may be due to the higher concentrations ofcatecholamines and cortisol, which cause glucogenesis and insulinantagonism, respectively. In other species, there are also changes in theabundance of insulin receptors and proteins in the intracellular insulinsignalling pathways during late gestation, which may influence the actionof insulin perinatally (Fowden and Hill 2001; Muhlhauser et al. 2009).Whether similar developmentalchangesoccurin thesesignallingpathwaysin equine tissues remains unknown.

Insulin concentrations are low after birth in premature and ill foals(Fowden et al. 1984;Barsnicket al. 2011). Comparedwith thefull-termfoal,the pancreatic b cell responseto exogenousglucose is also decreased 2 hafter birth in foals delivered prematurely by induction before 320 days(Fowden et al. 1984).In part, thesefindingsmay reflect theinhibitoryeffect

of the higher thannormal noradrenaline concentrations in premature foals(Silver et al. 1984). Neonatal b cell responses to exogenous glucose arealso affected by induction of delivery closer to term and by adverseconditions in utero. Induction of delivery 2448 h before full term leads toan enhanced b cell sensitivity to glucose without any change in glucoseclearance, which suggests that the increased insulin secretion may be acompensatory response to greater insulin resistance caused by thehypercortisolaemia of these foals (Holdstock et al. 2012). An increased bcellresponse to glucose is alsoobservedin 2-day-oldpony foalsovergrownin utero by transferas embryos intoTB mares (Forheadet al.2004).Inthesecircumstances, the apparent increase in b cell sensitivity to glucose mayreflect b cell proliferation before birth in response to an increased fetalsupply of nutrients via the larger than normal placenta (Allen et al. 2002).However, as basal insulin concentrations were increased and glucose

clearancewas normal in theseovergrownfoals (Forhead et al. 2004),theremay also be a degree of tissue insulin resistance, although this wasnot associated with any change in basal cortisol or catecholaminesconcentrations or in the hypoglycaemic response to acute administrationof insulin (Giussani et al. 2003; Forhead et al. 2004; Ousey et al. 2004).Similarly, maternal undernutrition during mid to late gestation caused bymaternal infection with Streptococcus equi increased glucose-stimulatedinsulin secretion in 5-day-old foals when the mares were on a moderate

relative to a high plane of nutrition at the time of infection (Ousey et al.2008). This exaggerated insulin response was unlikely to reflect insulinresistance as there was no change in basal insulin concentrations or in thehypoglycaemic response of acute insulin administration (Ousey et al.2004). Similar improvements in b cell sensitivity to glucose have beenobserved in juvenile offspring of sheep and rats undernourished duringpregnancy (Ozanne and Hales 1999; Clarke et al. 2000). Conditions duringboth pre- and immediate post natal development, therefore, appear tohave an important role in determining pancreatic b cell function of thenewborn foal but the extent to which this reflects direct changes in theb cells or indirect responses to tissue insulin resistance remains tobe determined.

Pancreatic acell function

Much less is known about pancreatic a cell function in the foal. In contrastto insulin, glucagon concentrations increase during late gestation to peak

at birthand, then, decline progressively duringthe 10 daysafter birthof thefoal (Fig 1d). Basal glucagon concentrations show a similar temporalpattern in newborn foalsinducedto deliver 2448 h before full-term basedon milk parameters (Holdstock et al. 2012). Compared with normal12-day-old foals, glucagonconcentrations areraised 10 foldin septic foalsand2 fold inthosehospitalisedfor otherillnesses,suchas failure of passiveimmunity, limb deformities and encephalopathy (Barsnick et al. 2011).Equine pancreatica cells respond to arginine from late gestation onwardsbut appear to be relatively insensitive to changes in glycaemia, even at 10days afterbirth in bothinducedand spontaneouslydelivered foals(Fowdenet al. 1999;Holdstock et al. 2012).The responses to arginineappear to begreater in utero than neonatally but this may reflect, in part, the slowerclearance of arginine from the fetal circulation (Fowden et al. 1999;Holdstock et al. 2011). Glucagon secretion in response to arginineincreased over the first 10 days post partum in normal term foals andwas greater in foals induced to deliver 2448 h before term than in those

born spontaneously at term (Holdstock et al. 2012). Collectively, theseobservations suggest that glucagon functions as a stress hormone in thefoal during the perinatal period. This is consistent with its known action inactivatingfetal glucogenesis in otherspecies and withthe immediate needfor an endogenous source of glucose after the placenta is lost at birth(Fowden et al. 1998; Sangild et al. 2000). The pancreatica cells, therefore,act to ensure a glucose supply to insulin insensitive tissues, such as thebrain, during adverse conditions when glucose availability is limited, whilethe pancreatic b cells are involved in regulating glucose uptake by insulinsensitive tissues, such as skeletal muscle, during the normal variations inglucose availability associated with the intermittent patterns of feedingand exercise seen in newborn foals.

Other hormones

There are several other endocrine systems, such as the renin-angiotensinsystem, somatotrophic axis, adipokines and leptin and the thyroidhormones, that adapt perinatally and contribute to the physiologicaladjustments required to thrive ex utero (Fowden and Forhead 2009). Inkeeping with cold exposure for the first time, concentrations of thyroxineandtri-iodothyronine (T3) are highinthefoalforthefirst 48 h after birth andthen fall to stablevalues forthe following3 weeks (Murray andLuba1993).Concentrationsof T3, inparticular, increasein the2 h after birthof full-termpony foals in parallel with the rise in cortisol concentrations and are low inpremature foals with hypocortisolaemia (Silver et al. 1991). Cortisol may,therefore, stimulate formation of T3 from thyroxine by activation of tissuedeiodinases in the foal as occurs in the lamb during the prepartum period(Forhead et al. 2006). Cortisol may alsobe involvedin inducingangiotensinconverting enzyme (ACE) as pulmonary ACE activity increases during late

Perinatalendocrineadaptations A. L. Fowden et al.



8/10

gestationto peak at birth inlinewith thefetalcortisolconcentrationsin thefoal (OConnor et al. 2002). Angiotensin II is a known pressor agent in thefetalhorsenear termand concentrationsof itsprecursor, angiotensinogen,decline immediately after birth in full-term foals but are high and remainelevated after premature delivery, consistent with the potential action ofcortisol in activating pulmonary ACE (Broughton Pipkin et al. 1982;OConnor et al. 2005). Concentrations of insulin-like growth factor (IGF)-Iandleptinalso increase innewbornfoalsin thefirstfew days afterbirthand

thenstabilise at mature values by 23 weeks (Hess-Dudan et al. 1994;Berget al. 2007). The initial neonatal increase in these concentrations mayreflect, in part, gastrointestinal uptake of IGF-I and leptin directly from themilk before gut closure (Hess-Dudan et al. 1994; Sangild et al. 2000; Berget al. 2007). Neonatal leptin concentrations appear to be unaffected byeither sepsis or other illnesses but are lower in hospitalised foals thatsubsequently die thanin thosethat survive (Barsnick et al. 2011).

Conclusions

In summary, there are major adaptations in several endocrine systems ofthe foal during the perinatal period (Fig 1), which are influenced by theconditions it experiences in utero and by its maturity at birth. Theseendocrine changes are closely inter-related and critical for the structuraland functional adaptations in many of the other physiological systems

essential for neonatal survival. The perinatal alterations in HPA functionare particularly important in these processes, although the sympatho-adrenal medullary axis and endocrine pancreas also have key roles inensuring homeostasis during the novel challenges associated with life exutero. Changes in the functioning of the HPA axis begin before birth andlead to a switch in adrenal steroidogenesis, which results in prepartummaturation of the foal and, possibly, also in the onset of labour in themare. Changes in the HPA axis continue after birth and are associatedwith alterations in functioning of the pituitary and adrenal glands. In turn,the 5-fold increase in perinatal cortisol availability is influential in adaptingmany physiological systems to their new postnatal roles, including severalother endocrine axes. The sympatho-adrenal medullary axis becomesprogressively more sensitive to stimuli during the perinatal period, inpart, due to the increasing effectiveness of the splanchic innervation.Catecholamine concentrations increase 20-fold in the immediate neonatalperiod and have an important role in maintaining blood pressure and

glycaemia during the transition from intra- to extrauterine environments.Similarly, there are changes in the function of the pancreatic a and b cellsduring the perinatal period, which are important in the more long-termmetabolic adaptations to enteral nutrition. Although insulin and glucagonconcentrations change only 23-fold during the perinatal period, thesechanges are essential for maintaining a glucose supply and in establishinggood glycaemic control with the loss of parenteral nutrition viathe placenta.

Abnormalities in the perinatal endocrine profile caused by adverseconditions before or after birth may, therefore, lead to neonatalmaladaptation anda poor prognosisfor the foal.Alternatively, theymay bebeneficialand aidits survival, despite earlydeliveryand/orIUGR. In additionto the immediate neonatal effects, endocrine abnormalities during theperinatal period may have long-term consequences for the foal byprogramming the structure and function of its tissues more permanentlywith implications for its physiological phenotype later in life (Rossdale andOusey 2002; McMillen and Robinson 2005; Fowden et al. 2006). Indeed,recent studies suggest that overexposure of the foal to cortisol in theimmediate neonatal period can influence HPA function shortly thereafterand have metabolic effects many months later (Jellyman et al. 2012;Valenzuela et al. 2011). The endocrine profile of the newborn foal may,therefore, provide a good index of both the conditionsexperienced duringintrauterine development and the likelihood of physiologicalabnormalitiesarising later in life. Thus, closer monitoring of neonatal endocrine statusmay have potential benefits to equine clinical practice and to the horseracing industry moregenerally.

Authors declaration of interests

No conflicts of interest have beendeclared.

Source of funding

Weare also indebted to theHorserace Betting Levy Boardfor their financialsupport overmany years.

Acknowledgements

WewouldliketothankthemanymembersoftheDepartmentsofPhysiology,

Development and Neuroscience who helped with the experimental andbiochemical aspects of these studies. In particular, we would like to thankPeter Rossdale, without whose enthusiasm and expert training none ofthesestudieswouldhavebegunor progressed to completion.

References

Allen, W.R., Wilsher, S., Ousey, J.C., Rossdale, P.D. and Fowden, A.L. (2002) The

influence of maternal sizeon placental,fetaland postnatal growthin thehorse: II

endocrinologyof pregnancy.J. Endocrinol. 172, 237-246.

Alm, C.C., Sullivan, J.J. and First, N.L. (1975) The effect of a corticoid

(dexamethasone), progesterone, oestrogen and prostaglandin F2a on gestation

length in normal and ovariectomised mares. J. Reprod. Fertil., Suppl. 23,

637-640.

Bailey, C.S., Macpherson, M.M., Pozor, M.A., Troedsson, M.H.T., Benson, S.,

Giguere, S., Sanchez, L.C., LeBlanc, M.M. and Vickroy, T.W. (2010) Treatment

efficacy of trimethoprim sulfamethoxazole, pentoxifylline and altrenogest inexperimentallyinduced equineplacentitis. Theriogenology74, 402-412.

Barsnick, R.J.I.M., Hurcombe, S.D.A., Smoith, P.A., Slovis, N.M., Sprayberry, K.A.,

Saville, W.J.A. and Toribio, R.E. (2011) Insulin, glucagon and leptin in critically ill

foals.J. Vet. Intern. Med. 25, 123-131.

Berg, E.L., McNamara, D.L. and Keisler, D.H. (2007) Endocrine profiles of

periparturientmares and their foals.J. Anim. Sci. 85, 1660-1668.

Bertram, C.E. and Hanson, M.A. (2002) Prenatal programming of postnatal

endocrine responses by glucocorticoids. Reproduction 124, 459-467.

Brendemeuhl, J.P., Williams, M.A., Boosinger, T.R. and Ruffin, D.C. (1995) Plasma

progestagen, tri-iodothyromine and cortisol concentrations in postdate

gestation foals exposed in utero to the tall fescue endophyte Acremonium

coenophialum. Biol. Reprod. Monogr. 1, 53-59.

Broughton Pipkin, F., Rossdale, P.D. and Frauenfelder, H. (1982) Changes in the

renin-angiotensin system of the mare and foal at parturition. J. Reprod. Fertil.,

Suppl. 32, 555-561.

Challis,J.R.G.,Matthews,S.G., Gibb,W. and Lye,S.J. (2000)Endocrineand paracrineregulationof birth at termand preterm. Endocr. Rev.21, 515-550.

Chavatte, P., Holton, D., Ousey, J.C. and Rossdale, P.D. (1997) Biosynthesis and

possible biological roles of progestagens during equine pregnancy and in the

newborn foal. Equine Vet. J.,Suppl. 24, 89-95.

Clarke, L., Firth, K., Heasman, L., Juniper, D.J., Budge, H., Stephenson, T.

and Symonds, M.E. (2000) Influence of relative size at birth on growth and

glucose homeostasis in twin lambs during juvenile life. Reprod. Fertil. Dev. 12,

69-73.

Comline, R.S., Silver, I.A. and Silver, M. (1965) Factors responsible for the

stimulationof the adrenalmedulla during asphyxiaof the foetal lamb.J. Physiol.

178, 211-238.

Comline, R.S. and Silver, M. (1971) Catecholaminesecretionby the adrenal medulla

of thefoetal andnewborn foal.J. Physiol. 216, 659-682.

Comline, R.S., Silver, M. and Silver, I.A. (1970) Effect of foetal hypophysectomy on

catecholamine levels in the lamb during prolonged gestation. Nature 225,

739-740.

Coulter, C.L., Young, I.R., Browne, C.A. and McMillen, I.C. (1991) Different roles ofthepituitary andadrenal cortexin the control of enkephalinpeptide localization

and cortico-medullary interaction in the sheep adrenal during development.

Neuroendocrinology53, 281-286.

Cross, D.L.,Redmond,L.M. andStrickland,J.R. (1995) Equinefescuetoxicosis:signs

and solutions.J. Anim. Sci. 73, 899-903.

Cudd, T.A., Le Blanc, M., Silver, M., Norman, W., Madison, J., Keller-Wood, M. and

Wood, C.E. (1995) Ontogeny and ultradian rhythms in adrenocorticotropin and

cortisol in thelate gestation fetal horse.J. Endocrinol. 144, 271-283.

Edwards, A.V. (1997) Aspects of autonomic and neuroendocrine function. Equine

Vet. J.,Suppl. 24, 109-117.

Forhead, A.J., Curtis, K., Kapstein, E., Visser, T.J. and Fowden, A.L. (2006)

Developmental control of iodothyronine deiodinases by cortisol in the ovine

fetus andplacenta near term. Endocrinology147, 5988-5994.




9/10

Forhead, A.J., Ousey, J.C., Allen, W.W. and Fowden, A.L. (2004) Postnatal insulin

secretion andsensitivityaftermanipulationof fetalgrowth byembryotransfer in

the horse.J. Endocrinol. 181, 459-467.

Fowden, A.L., Barnes, R.J., Comline, R.S. and Silver, M. (1980) Pancreatic b cell

functionin thefetalfoal andmare.J. Endocrinol. 87, 293-301.

Fowden, A.L., Ellis, L. and Rossdale, P.D. (1982) Pancreatic b cell function in the

neonatalfoal.J. Reprod. Fertil., Suppl. 32, 529-535.

Fowden, A.L. and Forhead, A.J. (2009) Hormones as epigenetic signals in

developmental programming. Exp. Physiol.94, 607-625.Fowden, A.L., Forhead, A.J., Bloomfield, M., Taylor, P.M. and the late Silver, M.

(1999) Pancreatic a cell function in the fetal foal during late gestation.

Exp. Physiol. 84, 697-705.

Fowden, A.L., Forhead, A.J. and Ousey, J.C. (2008) The endocrinology of equine

parturition. Exp. Clin.Endocrinol.Diabetes 116, 393-403.

Fowden, A.L., Gardner, D.S., Ousey, J.C., Giussani, D.A. and Forhead, A.J. (2005)

Maturation of pancreatic beta cell function in the fetal horse during late

gestation.J. Endocrinol. 186, 467-473.

Fowden, A.L.,Giussani, D.A.and Forhead, A.J.(2006) Intrauterine programming of

physiologicalsystems: Causesand consequences. Physiology21, 29-37.

Fowden, A.L. and Hill, D.J. (2001) Intrauterine programming of the endocrine

pancreas. Br. Med.Bull. 60, 123-142.

Fowden, A.L., Li, J. and Forhead, A.J. (1998) Glucocorticoids and the preparation

for life after birth: are there long term consequences of the life insurance?

Proc.Nutr.Soc. 57, 113-122.

Fowden, A.L. and Silver, M. (1995) Comparative development of the

pituitary-adrenal axis in the fetal foal and lamb. Reprod. Domest. Anim. 30,170-177.

Fowden, A.L., Silver, M., Ellis, L., Ousey, J.C. and Rossdale, P.D. (1984) Insulin

secretion in the foal during the perinatal period. Equine Vet. J., Suppl. 16,

286-291.

George, L.A., Staniar, W.B., Treiber, K.H., Harris, P.A. and Geor, R.J. (2009) Insulin

sensitivity and glucose dynamics during pre-weaning foal development and in

response to maternal diet composition. Domest.Anim. Endocrinol. 37, 23-29.

Giussani, D.A., Forhead, A.J. and Fowden, A.L. (2005) Development of

cardiovascular function in the horsefetus.J. Physiol. 565, 1019-1030.

Giussani, D.A., Forhead, A.J., Gardner, D.S., Fletcher, A .J.W., Allen, W.R. and

Fowden,A .L. (2003) Postnatal cardiovascular function aftermanipulationof fetal

growthby embryotransferin thehorse.J. Physiol. 547, 67-76.

Gold, J.R., Diver, T.J., Barton, M.H., Lamb, S.V., Place, N.J., Mohammed,

H.O. and Bain, F.T. (2007) Plasma adrenocorticotropin, cortisol and

adrenocorticotropin/cortisol ratiosin septicand normal-termfoals.J. Vet. Intern.

Med. 21, 791-796.Han, X., Fowden, A.L., Silver, M., Holdstock, N., McGladdery, A., Ousey, J.,

Allen, W.R., Rossdale, P.D. and Challis, J.R.G. (1995) Immunohistochemical

localization of steroidogenic enzymes and phenylethalamine-N-methyl-

transferase(PNMT)inthe adrenal glandof thefetal andnewbornfoal. EquineVet.

J. 27, 140-146.

Hart, K.A., Heuser, G.L., Norton, N.A. and Barton, M.H. (2009a)

Hypothalamic-pituitary-adrenal axis assessment in healthy term neonatal foals

utilizing a paired low dose/high dose ACTH stimulation test. J. Vet. Intern. Med.

23, 344-351.

Hart, K.A., Slovis, N.M. and Barton, M.H. (2009b) Hypothalamic-pituitary-

adrenal axis dysfunction in hospitalized neonatal foals. J. Vet. Intern. Med. 23,

901-912.

Hess-Dudan, F., Vacher, P.Y., Bruckmaier, R.M., Weishaupt, M.A., Burger, D. and

Blum, J.W. (1994)Immunoreactiveinsulin-like growthfactor I andinsulinin blood

andmilk of mares andin blood plasma of foals. EquineVet.J. 26, 134-139.

Holdstock, N.B., Allen, V.L., Bloomfield, M.R., Hales, C.N. and Fowden, A.L. (2004)

Development of insulin and proinsulin secretion in newborn pony foals.J. Endocrinol. 181, 468-476.

Holdstock,N.B., Allen, V.L. and Fowden, A.L. (2012)Pancreatic endocrine function

innewbornponyfoalsafterinducedorspontaneousdeliveryatterm. EquineVet.

J. 44 (Suppl. 41), 30-37.

Hollis,A.R., Ousey, J.C., Plamer,L., Stephen,J.O.,Stoneham,S.J.,Boston, R.C.and

Corley, K.T. (2006) Effects of norepinephrine and combined norepinephrine and

fenoldopaminfusion on systemic hemodynamicsand indicesof renalfunction in

normotensiveneonatal foals.J. Vet. Intern. Med. 22, 1210-1215.

Holtan, D., Houghton, E., Silver, M., Fowden, A.L., Ousey, J. and Rossdale, P.D.

(1991)Plasmaprogestagen in themare, fetusand newborn foal.J. Reprod. Fertil.,

Suppl. 44, 517-528.

Hurcombe, S.D.A., Toribio, R.E., Slovis, N., Kohn, C.W., Refsal, K., Saville, W. and

Mudge, M.C. (2008) Blood arginine vasopressin, adrenocorticotropin hormone,

andcortisol concentrations at admission in septic andcriticallyill foals andtheir

association with survival.J. Vet. Intern. Med. 22, 639-647.

Jellyman, J.K., Allen, V.L., Forhead, A.J., Holdstock, N.B. and Fowden, A.L. (2011)

Hypothalamic-pituitary-adrenal axis function in pony foals after neonatal

glucocorticoid overexposure. EquineVet. J. 44 (Suppl. 41), 38-42.

Lesage, J., Blondeau, B., Grino, B., Breant, B. and Dupouy, J.P. (2001) Maternal

undernutrition during late gestation induces fetal overexposure to

glucocorticoids and intrauterine growth retardation and disturbs the

hypothalamic-pituitary-adrenal axis in the newborn rat. Endocrinology 142,1692-1702.

Liggins, G.C. (1994) The role of cortisol in preparing the fetus for birth. Reprod.

Fertil. Dev. 6, 141-150.

Lyle, S.K., Hague, M., Lopez, M.J., Beehan, D.P., Staempfli, S., Len, J., Eilts,

B.E. and Paccamonti, D.L. (2010) In vitro production of cortisol by equine

fetal adrenal cells in response to ACTH and IL-1B. Anim. Reprod. Sci. 121,

S322-323.

McMillen, I.C. and Robinson, J.S. (2005) Developmental origins of metabolic

syndrome: prediction,plasticity and programming. Physiol. Rev. 85, 571-633.

Morris, S., Kelleman, A.A., Stawicki, R.J., Hansen, P.J., Sheerin, P.C., Sheerin, B.R.,

Paccamonti, D.L. and LeBlanc, M.M. (2007) Transrectal ultrasonography and

plasma progestin profiles identifies feto-placental compromise in mares with

experimentallyinduced placentitis. Theriogenology67, 681-691.

Muhlhauser, B.S., Duffield,J.A., Ozanne,S.E.,Pilgrom, C.,Turner,N., Morrison,J.L.

and McMillen, I.C. (2009) The transition from fetal growth restriction to

accelerated postnatal growth: A potential role for insulin signaling in skeletal

muscle.J. Physiol. 587, 4199-4211.Murray, M.J. and Luba, N.K. (1993) Plasma gastrin and somatostatin and

serum thyroxine (T4), tri-iodothyronine (T3), reverse tri-iodothyronine (rT3) and

cortisol concentrations in foals from birth to 28 days of life. Equine Vet. J. 25,

237-239.

OConnor, S.J., Fowden, A.L., Holdstock, N., Giussani, D.A. and Forhead, A.J.

(2002) Developmental changes in pulmonary and renal angiotensin converting

enzyme concentration in fetal and neonatal horses. Reprod. Fertil. Dev. 14,

413-417.

OConnor, S.J., Gardner, D.S., Ousey, J.C., Holdstock, N., Rossdale, P.D., Edwards,

C.M.B., Fowden, A.L. and Giussani, D.A. (2005) Development of the baroreflex

and endocrine responses to hypotensive stress in the newborn foal and lamb.

Pflugers Arch. 450, 298-306.

OConnor, S.J., Ousey, J.C., Gardner, D.S., Fowden, A.L. and Giussani, D.A. (2006)

Development of baroreflex function and peripheral vascular reactivity in the

horsefetus.J. Physiol. 572, 155-164.

Ousey, J.C. (2004)Perinatal endocrinologyin themare andfetus. Reprod. Domest.Anim. 39, 222-231.

Ousey, J.C., Dudan, F. and Rossdale, P.D. (1984) Preliminary studies of mammary

secretions in the mare to assess foetal readiness for birth. Equine Vet. J. 16,

259-263.

Ousey, J.C., Forhead, A.J., Rossdale, P.D., Grainger, L., Houghton, E. and Fowden,

A.L. (2003) The ontogeny of uteroplacental progestagen production in pregnant

mares duringthe secondhalf of gestation. Biol. Reprod. 69, 540-548.

Ousey, J.C., Fowden, A.L., Rossdale, P.D., Grainger, L. and Houghton, E. (2001)

Plasma progestagens as markers of feto-placental health. Pferdeheilkunde 17,

574-578.

Ousey, J.C., Fowden, A.L.,Wilsher,S. andAllen,W.R. (2008)The effectsof maternal

health andbody condition on theendocrine responsesof neonatal foals. Equine

Vet. J. 40, 673-679.

Ousey, J.C.,Freestone, N.,Fowden,A.L.,Allen,W.R.and Rossdale, P.D.(2000a) The

effects of oxytocin and progestagens on myometrial contractility during equine

pregnancy.J. Reprod. Fertil., Suppl. 56, 681-691.

Ousey,J.C., Rossdale, P.D.,Palmer,L ., Grainger,L . and Houghton, E. (2000b) Effectsof maternally administeredDepot ACTH1-2a on fetal maturationand thetimingof

parturitionin themare. Equine Vet. J. 32, 489-496.

Ousey, J.C., Ghatei, M., Rossdale, P.D. and Bloom, S.R. (1995) Gut hormone

responsesto feedingin healthyponyfoalsaged07 days. Biol.Reprod. Mono. 1,

87-96.

Ousey,J.C., Klling,M., Kindahl,H. and Allen,W.R. (2011) Maternal dexamethasone

treatment in late gestation induces precocious fetal maturation and delivery in

healthyThoroughbred mare. Equine Vet. J. 43, 424-429.

Ousey, J.C., Rossdale, P.D., Dudan, F.E. and Fowden, A.L. (1998) The effects of

intra-fetal ACTH administration on the outcome of pregnancy in the mare.

Reprod. Fertil. Dev. 10, 359-367.

Ousey, J.C., Rossdale, P.D., Fowden, A.L., Palmer, L., Turnbull, C. and Allen, W.W.

(2004) The effects of manipulating intra-uterine growth on postnatal

Perinatalendocrineadaptations A. L. Fowden et al.



10/10

adrenocortical developmentand otherparameters of maturity in neonatal foals.

EquineVet.J. 36, 616-621.

Ozanne, S.E. and Hales, C.N. (1999) The long term consequences of intra-uterine

protein malnutrition for glucosemetabolism. Proc.Nutr.Soc. 58, 615-619.

Panzani, S.,Villani, M.,McGladdery, A., Magri,M., Kindahl, H.,Galeati, G.,Martino,

P.A. and Veronesi,M.C. (2009) Concentrations of 15-ketodihydro-PGF2a, cortisol

and progesterone in the plasma of healthy and pathaolgic newborn foals.

Theriogenology72, 1032-1040.

Pashen, R.L. and Allen, W.R. (1979) The role of the fetal gonads and placenta insteroid production, maintenance of pregnancy and parturition in the mare.

J. Reprod. Fertil., Suppl 27, 499-509.

Rossdale, P.D., McGladdery, A.J., Ousey, J.C., Holdstock, N., Grainger, L. and

Houghton, E. (1992)Increasein plasma progestagenconcentrations in themare

after foetalinjectionwith CRH,ACTH or betamethasone in lategestation. Equine

Vet. J. 24, 347-350.

Rossdale, P.D.and Ousey,J.C. (2002) Fetalprogrammingfor athleticperformancein

thehorse: potential effectsof IUGR. EquineVet. Educ. 14, 98-112.

Rossdale, P.D., Ousey, J.C., Cottril, C.M., Chavatte, P., Allen, W.R. and McGladdery,

A.J. (1991) Effects of placental pathology on maternal plasma progestagen and

mammary calcium concentrations and on neonatal adreno-cortical function in

the horse.J. Reprod. Fertil., Suppl. 44, 579-590.

Rossdale, P.D., Ousey, J.C., Silver, M. and Fowden, A.L. (1984) Studies on equine

prematurity VI: guidelines for assessment of foal maturity. Equine Vet. J. 16,

300-302.

Rossdale, P.D. and Silver, M. (1982) The concept of readiness for birth. J. Reprod.

Fertil., Suppl 32, 507-510.Rossdale, P.D., Silver, M., Comline, R.S., Hall, L.W. and Nathanielsz, P.W. (1973)

Plasma cortsiol in the foal during the late fetal and early neonatal period. Res.

Vet.Sci. 15, 395-397.

Rossdale, P.D., Silver, M., Ellis, L. and Frauenfelder, H. (1982) The response of the

adrenal cortex to tetracosactrin (ACTH1-24) in the premature and full term foal.

J. Reprod. Fertil., Suppl. 32, 545-553.

Sangild, P.T., Fowden, A.L. and Trahair, J.F. (2000) How does the fetal

gastrointestinal tract develop in preparation for enteral nutrition after birth?

Livest.Prod. Sci. 66, 141-150.

Silver, M. (1990) Prenatal maturation, the timing of birth and how it may be

regulated in domestic animals. Exp. Physiol. 75, 285-307.

Silver, M. (1994) Placental progestagens in the sheep and horse and the changes

leadingto parturition. Exp. Clin. Endocrinol. 102, 203-211.

Silver, M., Cash, R.S.G., Dudan, F., Fowden, A.L., Knox, J., Ousey, J.C. and

Rossdale, P.D. (1984) Postnatal adrenocortical activity in relation to plasma

ACTH and catecholamine levels in term and premature foals. Equine Vet. J. 16,

278-286.

Silver, M. and Fowden, A.L. (1994) Prepartum adrenocortical maturationin the fetal foal: responses to ACTH(1-24). J. Endocrinol. 142, 417-425.

Silver, M. and Fowden, A.L. (1995) Sympathoadrenal and other endocrine and

metabolic responsesto hypoglycaemiain thefetal foalduring lategestation. Exp.

Physiol. 80, 651-662.

Silver, M., Fowden, A.L., Knox, J., Ousey, J., Cash, R. and Rossdale,

P.D. (1991) Relationship between circulating tri-iodothyronine and cortisol

in the perinatal period of the foal. J. Reprod. Fertil., Suppl. 44,

619-626.

Silver, M., Fowden, A.L., Ousey, J.C., Knox, J., Franco, R. and Rossdale, P.D. (1987)

Sympathoadrenal responseto hypoglycaemiain thefoal.J. Reprod. Fertil., Suppl.

35, 607-614.

Spurlock, S.L. and Furr, M. (1990) Disorders of glucose metabolism. In: Equine

Clinical Neonatology, Ed: A.M. Koterba, W.H. Drummond and P.C. Kosch, Lea &

Febinger, Philadelphia. pp 684-686.

Valenzuela, O.A., Jellyman, J.K., Holdstock, N.B., Allen, V.L., Forhead, A.J.

and Fowden, A.L. (2011) Neonatal overexposure to natural glucocorticoids

programs insulin sensitivity in yearling foals. J. DoHaD. 2 (Suppl. 1), pIII-323.

Webb,P.D. andStevens,D.H. (1981)Developmentof theadrenal cortexin thefetal

foal:an ultrastructural study.J. Dev.Physi ol. 3, 59-73.

Wong, D.M.,Vo, D.T., Alcott,C.J., Stewart, A.J.,Peterson,A.D., Sponsellar, B.A. and

Hsu, W.H. (2009) Adrenocorticotropic hormone stimulation testsin healthyfoals

frombirth to12 weeks ofage. Can. J.Vet. Res. 73, 65-73.

Wood, C.E. and Cudd, T.A. (1997) Development of the hypothalamic-

pituitary-adrenal axisof theequine fetus:a comparativereview.EquineVet. J. 24,

74-82.



Endocrine Adaptations in the Foal Over the Perinatal Period 2

Documents

Transcript of Endocrine Adaptations in the Foal Over the Perinatal Period 2