Placenta
Volume 31, Supplement , Pages S33-S39, March 2010

Review: Sex and the Human Placenta: Mediating Differential Strategies of Fetal Growth and Survival

  • V.L. Clifton

      Affiliations

    • Corresponding Author InformationTel.: +61 8 8303 8321; fax: +61 8 8303 4099.

Robinson Institute, Department of Paediatrics and Reproductive Health, Faculty of Health Sciences, Medical North, Level 6, Frome Road, University of Adelaide, Adelaide, SA 5005, Australia

Accepted 23 November 2009. published online 11 December 2009.

Article Outline

Abstract 

There are known sex specific differences in fetal and neonatal morbidity and mortality. There are also known differences in birthweight centile with males generally being larger than females at birth. These differences are generally ignored when studying obstetric complications of pregnancy and the mechanisms that confer these differences between the sexes are unknown. Current evidence suggests sex specific adaptation of the placenta may be central to the differences in fetal growth and survival. Our research examining pregnancies complicated by asthma has reported sexually dimorphic differences in fetal growth and survival with males adapting placental function to allow for continued growth in an adverse maternal environment while females reduce growth in an attempt to survive further maternal insults. We have reported sex differences in placental cytokine expression, insulin-like growth factor pathways and the placental response to cortisol in relation to the complication of asthma during pregnancy. More recently we have identified sex specific alterations in placental function in pregnancies complicated by preterm delivery which were associated with neonatal outcome and survival. We propose the sexually dimorphic differences in growth and survival of the fetus are mediated by the sex specific function of the human placenta. This review will present evidence supporting this hypothesis and will argue that to ignore the sex of the placenta is no longer sound scientific practice.

Keywords: Placenta Sex, Pregnancy, Birthweight

 

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1. Introduction 

There are known sex specific differences in fetal growth and fetal and neonatal morbidity and mortality [1], [2], [3]. The earliest known English report of sex specific differences in fetal and neonatal outcomes was given by Josef Clarke in 1786 [4]. Dr Clarke examined birth outcomes at the Lying-in Hospital in Dublin from 1757 to 1784 recording the outcomes of more than 20,000 deliveries [4]. He observed greater mortality of males than females in both the number of stillbirths and neonatal deaths. The birthweight range of males and females was also different in that males were generally larger than females and females were more likely to be growth reduced. He also reported that the sex ratio was different in that more males were delivered than females rather than an expected 1:1 ratio [4]. These findings have been reported consistently in the literature to the present day [1], [2], [5], [6]. Even so, we still consider the fetus to be asexual in its response to a pathological condition of pregnancy. If that were the case, however, then males would not be 20% more likely to experience a poorer outcome in pregnancies complicated by pre-eclampsia, preterm delivery and intrauterine growth restriction (IUGR) [1]. To extend this concept further, the placenta, an important part of the fetus, which plays a central role in mediating growth and development, is also viewed as an asexual organ with most placental studies consistently pooling data derived from male and female placentae into one group. Sex differences in fetal growth are likely to be mediated by sex specific placental function. It is likely that not all mechanistic adjustments to a pathophysiology of pregnancy are sex specifically different [7] but in studying the placenta it is essential to at least consider the possibility that there may be a sex difference and to design experiments accordingly.

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2. Sex specific adaptations of the fetus 

Our studies of maternal asthma [8], [9], pre-eclampsia [10], [11] and preterm delivery [12], [13] indicate male and female fetuses and neonates institute different mechanisms to cope with an adverse environment or event. In the presence of maternal asthma, female fetal growth was reduced in the presence of mild maternal asthma and no inhaled steroid use during pregnancy [8]. When asthma was treated with inhaled steroids during pregnancy, female fetal growth was comparable to the non-asthmatic population [8]. These data suggest that the inflammatory effects of the disease affect mechanisms associated with female fetal growth. Conversely we have found the male fetus continues to grow normally in the presence of chronic, maternal asthma [8]. It is only when asthma worsens with an acute exacerbation that the male fetus shows signs of compromise which include IUGR, preterm delivery and stillbirth [9]. Very few retrospective epidemiological studies separate pregnancy outcomes by sex except for a recent report of the impact of maternal asthma during pregnancy on birthweight identified an increased incidence of IUGR males in pregnancies complicated by severe asthma [14]. Since we have shown that 55% of asthmatic women will experience at least one acute exacerbation during pregnancy [9], it is possible that the high rate of IUGR males in this retrospective analysis was a result of acute exacerbations [14]. We propose that together, these data indicate that males institute strategies that allow them to continue to grow normally in an adverse intrauterine environment which then places them at risk of compromise in the presence of a second stressful event such as an acute asthma exacerbation. Females adapt to a poor intrauterine environment of chronic maternal asthma by reducing their growth so they are smaller but not IUGR. This allows them to survive any further compromises in the intrauterine environment to nutrition or oxygen supply as the pregnancy progresses.

We have examined whether sex specific feto-placental adaptations also occur with other complications of pregnancy. Similar to our findings in pregnancies complicated by asthma, we identified sex specific differences in fetal growth of pregnancies complicated by mild pre-eclampsia. Pre-eclampsia was associated with normal growth trajectories of the male fetus and growth reduction in the female fetus [11]. These findings were associated with sex specific alterations in maternal peripheral microvascular function [10]. The presence of a male fetus was associated with a more vasoconstricted state in the maternal microvascular circulation of pre-eclamptic women. In women pregnant with a female fetus, maternal microvascular function was not significantly different between normotensive and hypertensive women. These data indicated that males and females institute different strategies to cope with the presence of pre-eclampsia with the male fetus attempting to grow normally and the female fetus reducing growth. One mechanism to ensure continued male growth in pre-eclamptic pregnancies may be the redirection of blood flow from the maternal peripheral circulation to the utero-placental circulation [10]. It must be noted that these studies were conducted in mild pre-eclamptic pregnancies that delivered at term and more severe forms of the disease are likely to be more complex in the mechanistic adaptations.

Adjustments in utero to an adverse environment by male and female fetuses also have relevance to the observed sex differences of survival of preterm neonates in the first 48h of postnatal life. Stark et al. [13] reported that extremely preterm male neonates (24–28weeks gestation) were born in a more vasodilated state than female neonates. The more dilated state of the peripheral microvasculature of the preterm male neonate was associated with lower systemic blood pressure, greater illness severity as measured by the clinical risk index for babies (CRIB II) score (a score ranging from 0 to 27 that accounts for sex, gestational age at delivery, body temperature and pH with the higher score being associated with a greater risk of death) and a greater risk of death in the first 72h of life [13]. Similar alterations in microvascular function in term neonates of pre-eclamptic pregnancies were also observed [11]. These findings have highlighted that the female neonate can more readily adapt to ex utero life even when delivered in a highly immature state at mid gestation and are possibly mediated by in utero adaptations to an adverse environment prior to delivery. More recent evidence by Stark et al. [15] would suggest that sex specific differences in placental function may in part influence early postnatal survival of the female preterm neonate relative to the male preterm neonate.

Other reports suggest there are sexually dimorphic differences in birthweight and survival for fetus and neonate. For example, the incidence of macrosomia associated with maternal glucose intolerance was greater in male fetuses than females fetuses [16]. Retrospective analyses of pre-existing diabetes during pregnancy identified male fetuses were more likely to be associated with a late gestation stillbirth than females [3]. Environmental pollution was associated with a greater risk of stillbirth for males than females [17]. Together these data indicate males and females are different in how they cope with a stress during pregnancy. It is likely this difference is mediated by the placenta and conferred by sex specific differences in the regulation and expression of placental genes, proteins, steroids and structure.

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3. The sexually dimorphic human placenta 

3.1. Sex chromosomes and the placenta 

The sex chromosomes are central to determining sex characteristics but also express genes involved in numerous other physiological functions [18]. The XY male receives one X chromosome from the maternal genome. Females inherit two X chromosomes at fertilization with one derived from the maternal genome and the other from the paternal genome. In females, one X chromosome is randomly inactivated early in embryogenesis as a dosage compensation allowing one copy of X-linked gene products to be transcribed. Once either the maternal or paternal X is inactivated, it remains inactivated from parent cell to daughter cells during cell division. The random inactivation means that some cells in an individual have the maternal X inactivated and other cells have the paternal X inactivated. The long-term silencing of the inactive X is mediated via methylation of cystine residues in clustered CpG dinucleotides. It has been proposed that non-random X inactivation can occur in the presence of genetic mutations in one X chromosome or for a selective advantage. Non-random X inactivation in an adverse environment may confer a survival advantage for females over males especially in relation to X-linked diseases [19].

From detailed mouse studies it has been demonstrated that the placenta preferentially inactivates the paternal X chromosome [19]. However humans are different from mice as Looijenga et al. (1999) and Zeng and Yankowitz (2003) have shown that both random and skewed patterns of X inactivation exist in the female human placenta [20], [21]. Furthermore the placenta is the only tissue known to be able to globally reactivate the inactive X chromosome in vitro at the specific gestational time points of early gestation and at term [22]. The ability to reactivate the inactive X chromosome in the placenta is due to it being in a hypomethylated state relative to the inactivated X chromosome in other somatic tissues [22]. These studies highlight the possibility that the human placenta of a female may be capable of inducing non-random X inactivation in an adverse intrauterine environment in the early stages of implantation.

3.2. Sex differences in global gene expression of the human placenta 

Global gene changes in the human placenta have been analysed by Sood et al. [23]. This research identified significant individual differences in placental gene expression which exemplifies the diversity of the human population and suggests that each individual placenta may therefore exhibit a unique molecular adaptation to the same maternal environment. The study clearly defined sex specific differences in placental gene expression not limited to just X and Y linked genes but also autosomal genes. Genes related to immune pathways including JAK1, IL2RB, Clusterin, LTBP, CXCL1 and IL1RL1 and TNF receptor were differentially expressed at higher levels in female placentae than male placentae [23]. The differences in immune gene expression may contribute to sex differences in the fetal response to infection or inflammation.

Preliminary microarray studies conducted between our laboratory and Professor Isabella Caniggia and Professor Igor Jurisica from the University of Toronto have identified 59 gene changes in the placentae of females and only six gene changes in placentae of males in pregnancies complicated by asthma (Clifton et al., 2006 A1 refer: http://www.med.monash.edu.au/anatomy/workshops/fnw-abstract-book-2006.pdf). The data collected from male and female placentae were entered into the OPHID database (http://ophid.utoronto.ca/navigator/) to identify downstream protein networks that were associated with the identified genes. This analysis identified hundreds of protein interactions altered in female placentae relative to male placentae in response to maternal asthma. These data show that female placentae institute multiple gene alterations that interconnect with numerous signalling networks to cope with the presence of maternal asthma some of which may contribute to reduced growth. The minimal placental gene alterations of the male placentae may be a mechanism that allows the male fetus to continue growing in an adverse environment. A general consideration from this data is that when experimental results from male and female placentae are pooled significant findings are lost in the analysis as male placentae are likely to have a different response from female placentae.

MicroRNAs (MiRs), a class of small non-coding RNAs involved in posttranscriptional regulation of protein coding mRNA, may also play a role in regulating sex specific gene expression. There are presently no published papers examining sex specific differences in placental MiRs but preliminary data presented by Dr Annette Osei-Kumah at the IFPA conference in Adelaide (2009) report female placentae of normal pregnancies have different mIR expression relative to male placentae [24]. While the sex of the placenta was not taken into consideration, other studies have identified differential MiR expression with pathophysiological pregnancies such as pre-eclampsia [25]. This study reported that seven MiRs were identified to increase in the presence of pre-eclampsia regardless of whether the fetus was SGA or not. Some of the target pathways for these increased MiRs included several different immune pathways. MiR expression was assessed in the fetal membranes in relation to labour, gestation and inflammation [26]. MiRs were significantly altered in the presence of chorioamnionitis and varied with gestational age but were not significantly altered by the process of labour. These studies open the way for new investigations into the mechanisms regulating placental gene transcription and expression and suggest the future of genomics will entail consideration of sex specific mRNA expression in conjunction with MiR expression.

3.3. Sex differences in fetal-placental protein expression 

Proteomic analysis of maternal plasma, umbilical cord plasma and placental protein extracts using surface enhanced laser desorption ionization-time of flight mass spectrometry (SELDI-TOF) was conducted on samples from asthmatic and non-asthmatic pregnant women [27], [28]. We identified 85 peaks that were significantly different between male and female fetuses from these studies with 14 protein peaks expressed in a sexually dimorphic manner in the placenta and cord plasma [27]. Limitations of the SELDI-TOF technique conferred by the type and number of different chips used to extract proteins from the samples suggest there may be many more sex specific proteins present in the placental extracts and cord blood that were not detected using this approach [29].

More sophisticated approaches conducted in the field of prenatal diagnosis will most certainly continue to identify fetally-derived sexually dimorphic proteins and nucleic acids in maternal plasma for the purpose of early diagnosis of fetal sex, chromosomal abnormalities and pregnancy complications [30], [31].

3.4. Sex specific placental immune function 

Immune function in adults is known to be sex specifically regulated. A recent review by Fish outlines the sex specific differences in adult immune function as determined by the differential effects of estrogen and testosterone [18]. Sex specific differences in immune function in the placenta are beginning to be published. Expression of cytokine mRNA including TNF-α, IL-1β, IL-6, IL-5 and IL-8 vary with asthma severity and fetal sex [32]. All cytokines were increased in female placentae of pregnancies complicated by asthma relative to female control placenta. The male fetus had no significant alterations in placental cytokine mRNA expression in the presence of maternal asthma [32]. We then assessed placental macrophages to determine whether the changes in female cytokine mRNA expression were related to increased resident placental macrophage numbers. CD68 positive macrophage numbers were higher in control males than females. Placental macrophage numbers did not differ significantly between females and males of pregnancies complicated by asthma suggesting any changes in mRNA expression were the result of upregulation of transcription rather than an alteration in the immune cell population [32].

Sex differences of the fetal-placental immune system have been investigated in relation to preterm delivery. Ghidini and Salafia (2005) reported that histological examination of placentae of males delivered less that 32weeks gestation, had more severe lesions of chronic inflammation than placentae from matched females [33]. The sites of chronic inflammation were areas of interaction between interstitial trophoblast and maternal decidua rather than within placental villi or membranes suggesting the maternal immune system induces an inflammatory response in the placenta via the decidua [33]. The Alabama Preterm Study examined differences in placental histology and markers of infection and inflammation in male and female preterm births at gestational ages less than 32weeks. Male neonates were more likely to have an infected placenta then female neonates with greater decidual lymphoplasmacytic cell infiltration [34]. More recently Yeganegi et al. (2009) [35] has reported that male placentae had higher toll-like receptor-4 (TLR-4) expression and a more enhanced endotoxin induced tumor necrosis factor (TNF)-α response relative to placentae from females. Since we have identified a greater population of placental macrophages in males relative to females of normal pregnancies, the enhanced TNF-α response may be derived from a sex difference in immune cell populations. They suggest this sex difference in cytokine production may contribute to the increased incidence of preterm delivery in males.

These data demonstrate that placental immune function is at least partially sex specific and suggests the placenta responds to maternal inflammatory status in a sex specific manner. These findings have implications for understanding the impact of maternal viral, bacterial and parasitic infections during pregnancy such as HIV, pneumonia and malaria on fetal growth and survival. It also has relevance to understanding the impact of maternal inflammatory states that can complicate pregnancy including obesity, rheumatoid arthritis, asthma and Crohn's disease. Pre-eclampsia has been identified as an inflammatory state and may also influence placental immune function in a sex specific manner. Since the placental immune system plays a role in regulating apoptosis, prostaglandin synthesis, vascular permeability and programming of the fetal immune system, it is possible that all these mechanisms are sexually dimorphic.

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4. Steroid pathways 

4.1. Fetal-placental steroid profile 

We used high pressure liquid chromatography (HPLC) to compare steroid profiles in cord blood collected from male and female neonates at the time of either spontaneous vaginal or elective Caesarean delivery [36]. The data demonstrated that steroid profiles from each individual could be identified by sex and by mode of delivery [36]. The known steroids identifiable in the HPLC profile, which included cortisol, cortisone, 17β-estradiol, estriol and progesterone, were not sex specifically different [36]. When the profiles were examined as an entire entity using principle component analysis it was found that four unknown steroids in the HPLC profile conferred a sex specific difference [36]. These data indicate there are sex specific differences in steroid production from the human fetal-placenta unit that may influence placental function.

While the HPLC steroid profile identified no differences in cortisol or testosterone between the sexes we have observed differences in placental pathways associated with these hormones and these will be discussed in detail.

4.2. Cortisol 

Both endogenous and synthetic glucocorticoids derived from the mother can reduce fetal growth [37], [38]. Multiple doses of betamethasone, a steroid that is not metabolised by the placenta, administered to women at risk of preterm delivery, resulted in a 9% reduction in neonatal birth weight and 4% reduction in neonatal head circumference [38]. In our study of asthma and pregnancy, there was a 12% reduction in female birth weight in the presence of maternal asthma when compared to female neonates from non-asthmatic mothers [8]. These alterations in growth were associated with increased circulating concentrations of cortisol, decreased placental cortisol metabolism by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) and reduced adrenal function in female fetuses of pregnancies complicated by asthma [8]. Conversely, the growth of the male fetus was normal in the presence of asthma despite exposure to comparable concentrations of cortisol observed in females of pregnancies complicated by asthma. These data suggest the male and female fetal-placental unit respond to cortisol in a differential manner. These findings have previously been reviewed [39].

More recent studies from our lab have shown a sexually dimorphic response of the preterm neonate to betamethasone exposure and placental cortisol metabolism [15]. Bioactive betamethasone exposure was associated with increased placental 11β-HSD2 activity in female placentae but not male placentae. Further, placental 11β-HSD2 activity was correlated with physiological stability in only the female neonate. We also reported increased cortisol concentrations in female cord blood and urine at 24h post-natally relative to males [15]. We suggest that these data indicate that the female placenta adjusts its glucocorticoid metabolic activity in the presence of high maternal glucocorticoid concentrations to possibly preserve female fetal adrenal function. These adjustments may be one mechanism that confers a survival advantage in preterm female neonates relative to preterm males but also highlights sex specific differences in the placental response to glucocorticoids.

Central to the regulation of cortisol activity is the presence of mineralocorticoid and glucocorticoid receptors, MR and GR, respectively, which are known to function in a sexually dimorphic manner in the brain and lung as demonstrated in a number of animal studies [40], [41], [42]. In the human placenta GR mRNA transcript variants and exon 1 promoter variants were recently examined [43]. GRα, beta, P and gamma mRNA and promoter regions 1A1, 1A2, 1A3, 1B and 1C were all detectable in the human placenta with GRα and promoter 1C having the highest expression. Promoter 1A3 expression was higher in male placentae versus female placentae which may be of significance in relation to GRα expression in presence of increasing concentrations of cortisol. 1A3 promoter is the only promoter that increases GR expression in the presence of glucocorticoids as demonstrated in a leukaemic cell line in vitro [44]. Preliminary data from our group would suggest GRα mRNA was reduced in female placentae and not male placentae in the presence of increased cortisol [39]. This difference in response may be conferred by differential expression of the GR exon 1A3 promoter region [43] but further studies need to be conducted.

More recently we have reported that cytokine mRNA expression in female placentae was correlated with cord blood cortisol concentrations [32] while there was no correlation between cortisol and cytokine mRNA expression in male placentae [32]. Cortisol was positively correlated with IGFBP-1, negatively correlated with IGFBP-3 and birth weight centile in females of normal pregnancies and pregnancies complicated by asthma [45]. No correlations between cortisol and IGF axis or birthweight centile were observed in males [45]. These findings suggest the fetal-placental response to glucocorticoid is sex specifically regulated possibly via differences in GR expression or function.

4.3. Testosterone 

The most obvious steroid that may control the sex specific differences observed in the human placenta would be testosterone because it is known to exert differential effects in males and females [18] and can alter glucocorticoid regulated pathways that profoundly affect the immune system [46] and hypothalamic-pituitary-adrenal axis [47]. In adult trauma models, haemorrhagic stress increased immune cell and myocardial cell p38 MAPK activity with subsequent increases in pro-inflammatory cytokine production in males only [48]. This effect on p38 MAPK was dependent upon the presence of testosterone during the trauma [48]. Activation of P38 MAPK is also known to inhibit GR function thus allowing for an increase in pro-inflammatory cytokine production [49]. These data suggest that activation of a stress response in the male results in the activation of testosterone dependent pathways which can inhibit glucocorticoid regulated pathways. This mechanism is thought to increase the risk of septic shock and death in male trauma patients [46]. This may also be the mechanism that determines sexual dimorphism in human fetal-placental glucocorticoid pathways and contribute to the increased morbidity and mortality in male babies.

Circulating testosterone concentrations vary with the sex of the fetus and are higher in the presence of a male fetus relative to a female fetus at delivery [50]. In the human placenta the androgen receptor (AR) is expressed in the decidua, syncytiotrophoblast and stromal cells [51], [52] suggesting testosterone may have a role in placental function in both male and female placentae. Interestingly the papers that reported AR localisation had not considered the influence of fetal sex even though AR is classically associated with male physiology. The human placenta also expresses two isoforms of 5α-reductase, the enzyme that converts testosterone to its bioactive form of dihydro-testosterone, which varies with gestational age and sex. Vu et al. (2009) identified that 5α-reductase protein expression was greater in female placentae at term [53]. This current data suggests the female placenta may be exposed to more bioactive concentrations of testosterone than the male placenta [53] but this work did not account for differences in testosterone concentrations between the sexes. Preliminary evidence presented by Stark et al. at the IFPA conference in Adelaide indicates testosterone is a more potent inhibitor of explant cytokine production from female placentae than male placentae [54]. These data suggest that testosterone may act in a sex specific manner in the human placenta and may be more potent in female placentae than males. The current data highlights a sexually dimorphic difference in placental function that may not be conferred by classical assumptions of sex steroid regulation. Further investigations into the role of testosterone in placental function are required.

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5. Growth factor pathways 

Insulin-like growth factor (IGF)-1 and IGF-2 are polypeptides with a sequence similar to that of insulin [55] which have mitogenic properties, inducing somatic cell growth and proliferation [56], [57]. Knockout and transgenic mice studies have demonstrated that IGF-1 and IGF-2 are required for optimal fetal and placental growth [58], [59], [60]. The actions of IGF-1 and IGF-2 are modulated by insulin-like growth factor binding proteins (IGFBP-1–6) [61]. The human placenta produces IGF-1 and IGF-2 which may act as local growth regulators [62] with IGF-2 more highly expressed [63]. The mechanisms which contribute to the different growth of male and female fetuses remain unclear but sex differences in growth regulation by the IGF axis may be involved. A study of 987 healthy singletons found that IGF-1 and IGFBP-3 concentrations in cord blood were higher in females than males [64]. Growth hormone concentrations were higher in males than females [64]. No difference in IGF-2 between male and female neonates was reported [64].

We examined fetal growth and the IGF axis in a prospective cohort of asthmatic and non-asthmatic women (n=145) which included cigarette users and non-smokers [45]. The birthweight centile of the female fetus steadily declined in the presence of maternal asthma alone and maternal asthma in combination with cigarette use. There was no significant decrease in birthweight centile of the male neonate in the presence of asthma or cigarette use. Cord plasma IGF-1 was the main component of the neonatal IGF axis altered by asthma and cigarette use. IGF-1 was increased in the presence of mild asthma and a male fetus and decreased in the presence of a female fetus and maternal asthma with cigarette use. IGFBP-3 was also decreased in the female fetuses of pregnancies complicated by asthma and cigarette use. The strongest overall predictor of female birth weight after accounting for asthma severity, inhaled glucocorticoid treatment and cigarette use was IGF-1. For males, the strongest predictor of birth weight was IGFBP-3. The data suggest male and female fetuses institute different strategies in response to adverse pregnancy conditions such as asthma and cigarette use. In particular the role of the IGF axis was regulated in a sexually dimorphic manner [45] and may be an important mechanism influencing fetal growth.

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6. Placental structure and function 

There is a lack of published evidence that suggests the placenta may be structurally or functionally different depending on the sex of the fetus but since gene, steroid and protein expression appear to be different, these differences may have downstream effects on structure and function.

Morphometric studies of the placentae of asthmatic pregnancies conducted in collaboration with Dr Terry Mayhew provided some evidence that the placenta may be structurally different in a sex specific manner [65]. From pregnancies complicated by asthma, most morphometric variables measured in the placenta declined, particularly in those pregnancies treated with inhaled glucocorticoids. The principal alterations in placental morphometry involved the feto-placental vasculature within peripheral villi. Compared to non-asthmatic controls, the overall length and volume of peripheral villi were perturbed in moderate/severe asthmatics and in those with high steroid use. Similar patterns of change were seen for fetal capillaries within those villi. These reductions were associated predominantly with male fetuses [65]. Since males continue to grow normally in pregnancies complicated by chronic maternal asthma and are significantly compromised in terms of growth and survival only after an acute exacerbation of asthma it may be possible that the morphometric changes in placental structure do not compromise growth unless there is a second stressful event. However these findings require more extensive investigation and its relevance to other complications of pregnancy have yet to be examined.

Functional differences in the placenta that result from structural changes that occur based on the sex of the fetus are yet to be examined but is an area that should be seriously considered in the future.

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7. Conclusion 

The data presented in this review provide evidence that the placenta functions in a sex specific manner. From a global perspective gene, protein and steroid pathways of the fetal-placental unit are sex specifically different and data published by our group and others support this statement. Specifically, the female placenta was shown to be responsive to changes in glucocorticoid concentration in both preterm and term pregnancies. An increase in cortisol was correlated with changes in female cortisol metabolism, cytokine mRNA expression, IGF axis, adrenal function and growth. The male placenta appears glucocorticoid resistant since pathways typically responsive to cortisol such as cytokine expression, the IGF axis, adrenal function and growth remained unaffected in the presence of increased cortisol. From these data, we propose males and females institute different strategies to cope with the same adverse maternal environment. As depicted in Fig. 1, the male strategy for responding to an adverse maternal environment is a minimalist approach with few gene, protein or functional changes instituted in the placenta which ultimately ensures continued growth in a less than optimal maternal environment. This male response is associated with a greater risk of either intrauterine growth restriction, preterm delivery or death in utero if another adverse event occurs during the pregnancy. The female placenta responds to an adverse maternal environment with multiple placental gene and protein changes that result in a decrease in growth without growth restriction (>10th centile). These female adjustments in placental function and growth ensure survival in the presence of another adverse event which may further compromise nutrient or oxygen supply. With these placental differences in mind, the pooling of placental tissues from males and females is no longer acceptable scientific practice and placental sex should be seriously considered in all experimental designs.

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Conflict of interest 

The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.

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Acknowledgements 

The work conducted in my laboratory was produced by a great number of enthusiastic post graduate students, post doctoral fellows and clinical collaborators including Dr Annette Osei-Kumah, Dr Vanessa Murphy, Dr Nicolette Hodyl, Dr Michael Stark, Dr Ian Wright, Ms Patricia Engel, Ms Philippa Talbot, Dr Renee Johnson, A/Professor Tamas Zakar, Professor Peter Gibson, Professor Roger Smith, Professor Warwick Giles, Ms Naomi Scott, Ms Erin Green, Ms Hayley Wyper, Ms Natascha Rennie, Ms Renee Crompton and Ms Lynda Deirkx. Thank you to all of you for your enthusiasm, support and continued contribution to the field. The work has been generously funded by the National Health and Medical Research Council, The Department of Health and Aging, Asthma NSW and Hunter Medical Research Institute.

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References 

  1. Vatten LJ, Skjaerven R. Offspring sex and pregnancy outcome by length of gestation. Early Hum Dev. 2004;76:47–54
  2. Di Renzo GC, Rosati A, Sarti RD, Cruciani L, Cutuli AM. Does fetal sex affect pregnancy outcome?. Gend Med. 2007;4:19–30
  3. Engel PJ, Smith R, Brinsmead MW, Bowe SJ, Clifton VL. Male sex and pre-existing diabetes are independent risk factors for stillbirth. Aust New Zealand J Obstet Gynaecol. 2008;48:375–383
  4. Clarke J. Observations on some causes of excess mortality of males above that of females. Philos Trans R Soc Lond. 1786;76:349–364
  5. Papageorgiou AN, Colle E, Farri-Kostopoulos E, Gelfand MM. Incidence of respiratory distress syndrome following antenatal betamethasone: role of sex, type of delivery, and prolonged rupture of membranes. Pediatrics. 1981;67:614–617
  6. Stevenson DK, Verter J, Fanaroff AA, Oh W, Ehrenkranz RA, Shankaran S, et al. Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage. Arch Dis Child Fetal Neonatal Ed. 2000;83:F182–F185
  7. Clifton VL, Vanderlelie J, Perkins AV. Increased anti-oxidant enzyme activity and biological oxidation in placentae of pregnancies complicated by maternal asthma. Placenta. 2005;26:773–779
  8. Murphy VE, Gibson PG, Giles WB, Zakar T, Smith R, Bisits AM, et al. Maternal asthma is associated with reduced female fetal growth. Am J Respir Crit Care Med. 2003;168:1317–1323
  9. Murphy VE, Gibson P, Talbot PI, Clifton VL. Severe asthma exacerbations during pregnancy. Obstet Gynecol. 2005;106:1046–1054
  10. Stark MJ, Dierkx L, Clifton VL, Wright IM. Alterations in the maternal peripheral microvascular response in pregnancies complicated by preeclampsia and the impact of fetal sex. J Soc Gynecol Investig. 2006;13:573–578
  11. Stark MJ, Clifton VL, Wright IM. Neonates born to mothers with preeclampsia exhibit sex-specific alterations in microvascular function. Pediatr Res. 2009;65:292–295
  12. Stark MJ, Clifton VL, Wright IM. Microvascular flow, clinical illness severity and cardiovascular function in the preterm infant. Arch Dis Child Fetal Neonatal Ed. 2008;93:F271–F274
  13. Stark MJ, Clifton VL, Wright IM. Sex-specific differences in peripheral microvascular blood flow in preterm infants. Pediatr Res. 2008;63:415–419
  14. Clark JM, Hulme E, Devendrakumar V, Turner MA, Baker PN, Sibley CP, et al. Effect of maternal asthma on birthweight and neonatal outcome in a British inner-city population. Paediatr Perinat Epidemiol. 2007;21:154–162
  15. Stark MJ, Wright IM, Clifton VL. Sex-specific alterations in placental 11beta-hydroxysteroid dehydrogenase 2 activity and early postnatal clinical course following antenatal betamethasone. Am J Physiol Regul Integr Comp Physiol. 2009;297:R510–R514
  16. Ricart W, Lopez J, Mozas J, Pericot A, Sancho MA, Gonzalez N, et al. Maternal glucose tolerance status influences the risk of macrosomia in male but not in female fetuses. J Epidemiol Community Health. 2009;63:64–68
  17. Sakamoto M, Nakano A, Akagi H. Declining Minamata male birth ratio associated with increased male fetal death due to heavy methylmercury pollution. Environ Res. 2001;87:92–98
  18. Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8:737–744
  19. Reik W, Lewis A. Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet. 2005;6:403–410
  20. Looijenga LH, Gillis AJ, Verkerk AJ, van Putten WL, Oosterhuis JW. Heterogeneous X inactivation in trophoblastic cells of human full-term female placentas. Am J Hum Genet. 1999;64:1445–1452
  21. Zeng SM, Yankowitz J. X-inactivation patterns in human embryonic and extra-embryonic tissues. Placenta. 2003;24:270–275
  22. Migeon BR, Axelman J, Jeppesen P. Differential X reactivation in human placental cells: implications for reversal of X inactivation. Am J Hum Genet. 2005;77:355–364
  23. Sood R, Zehnder JL, Druzin ML, Brown PO. Gene expression patterns in human placenta. Proc Natl Acad Sci U S A. 2006;103:5478–5483
  24. Osei-Kumah A, Hodyl N, Kong W-C, Owens J, Clifton VL. Sex specific differences in human placental micro RNA expression. In: Placenta  editors. International Federation of Placental Associations. SA, Australia: Elsevier Adelaide; 2009;p. A.103
  25. Pineles BL, Romero R, Montenegro D, Tarca AL, Han YM, Kim YM, et al. Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia. Am J Obstet Gynecol. 2007;196(261):e1–e6
  26. Montenegro D, Romero R, Pineles BL, Tarca AL, Kim YM, Draghici S, et al. Differential expression of microRNAs with progression of gestation and inflammation in the human chorioamniotic membranes. Am J Obstet Gynecol. 2007;197(289):e1–e6
  27. Murphy VE, Johnson RF, Wang YC, Akinsanya K, Gibson PG, Smith R, et al. The effect of maternal asthma on placental and cord blood protein profiles. J Soc Gynecol Investig. 2005;12:349–355
  28. Murphy VE, Johnson RF, Wang YC, Akinsanya K, Gibson PG, Smith R, et al. Proteomic study of plasma proteins in pregnant women with asthma. Respirology. 2006;11:41–48
  29. Osei-Kumah A, Hodyl N, Clifton VL. Proteomics in asthma. Expert Rev Clin Immunol. 2008;4:713–721
  30. Dennis Lo YM, Chiu RW. Prenatal diagnosis: progress through plasma nucleic acids. Nat Rev Genet. 2007;8:71–77
  31. Geifman-Holtzman O, Ober Berman J. Prenatal diagnosis: update on invasive versus noninvasive fetal diagnostic testing from maternal blood. Expert Rev Mol Diagn. 2008;8:727–751
  32. Scott NM, Hodyl NA, Murphy VE, Osei-Kumah A, Wyper H, Hodgson DM, et al. Placental cytokine expression covaries with maternal asthma severity and fetal sex. J Immunol. 2009;182:1411–1420
  33. Ghidini A, Salafia CM. Histologic placental lesions in women with recurrent preterm delivery. Acta Obstet Gynecol Scand. 2005;84:547–550
  34. Goldenberg RL, Andrews WW, Faye-Petersen OM, Goepfert AR, Cliver SP, Hauth JC. The Alabama Preterm Birth Study: intrauterine infection and placental histologic findings in preterm births of males and females less than 32weeks. Am J Obstet Gynecol. 2006;195:1533–1537
  35. Yeganegi M, Watson CS, Martins A, Kim SO, Reid G, Challis JR, et al. Effect of Lactobacillus rhamnosus GR-1 supernatant and fetal sex on lipopolysaccharide-induced cytokine and prostaglandin-regulating enzymes in human placental trophoblast cells: implications for treatment of bacterial vaginosis and prevention of preterm labor. Am J Obstet Gynecol. 2009;200(532):e1–e8
  36. Clifton VL, Bisits A, Zarzycki PK. Characterization of human fetal cord blood steroid profiles in relation to fetal sex and mode of delivery using temperature-dependent inclusion chromatography and principal component analysis (PCA). J Chromatogr B Analyt Technol Biomed Life Sci. 2007;855:249–254
  37. Fowden AL, Szemere J, Hughes P, Gilmour RS, Forhead AJ. The effects of cortisol on the growth rate of the sheep fetus during late gestation. J Endocrinol. 1996;151:97–105
  38. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol. 1999;180:114–121
  39. Clifton VL, Murphy VE. Maternal asthma as a model for examining fetal sex-specific effects on maternal physiology and placental mechanisms that regulate human fetal growth. Placenta. 2004;25(Suppl A):S45–S52
  40. Banjanin S, Kapoor A, Matthews SG. Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function and blood pressure in mature male guinea pigs. J Physiol. 2004;558:305–318
  41. Kovar J, Waddell BJ, Sly PD, Willet KE. Sex differences in response to steroids in preterm sheep lungs are not explained by glucocorticoid receptor number or binding affinity. Pediatr Pulmonol. 2001;32:8–13
  42. Owen D, Matthews SG. Glucocorticoids and sex-dependent development of brain glucocorticoid and mineralocorticoid receptors. Endocrinology. 2003;144:2775–2784
  43. Johnson RF, Rennie N, Murphy V, Zakar T, Clifton V, Smith R. Expression of glucocorticoid receptor messenger ribonucleic acid transcripts in the human placenta at term. J Clin Endocrinol Metab. 2008;93:4887–4893
  44. Breslin MB, Vedeckis WV. The human glucocorticoid receptor promoter upstream sequences contain binding sites for the ubiquitous transcription factor, Yin Yang 1. J Steroid Biochem Mol Biol. 1998;67:369–381
  45. Clifton VL, Hodyl NA, Murphy VE, Giles WB, Baxter RC, Smith R. Effect of maternal asthma, inhaled glucocorticoids and cigarette use during pregnancy on the newborn insulin-like growth factor axis. Growth Horm IGF Res. 2009;Aug 18 [E pub ahead of print]
  46. Angele MK, Schwacha MG, Ayala A, Chaudry IH. Effect of gender and sex hormones on immune responses following shock. Shock. 2000;14:81–90
  47. Rosmond R, Bjorntorp P. The interactions between hypothalamic-pituitary-adrenal axis activity, testosterone, insulin-like growth factor I and abdominal obesity with metabolism and blood pressure in men. Int J Obes Relat Metab Disord. 1998;22:1184–1196
  48. Angele MK, Nitsch S, Knoferl MW, Ayala A, Angele P, Schildberg FW, et al. Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol. Am J Physiol Endocrinol Metab. 2003;285:E189–E196
  49. Barnes PJ. Corticosteroid resistance in airway disease. Proc Am Thorac Soc. 2004;1:264–268
  50. Simmons D, France JT, Keelan JA, Song L, Knox BS. Sex differences in umbilical cord serum levels of inhibin, testosterone, oestradiol, dehydroepiandrosterone sulphate, and sex hormone-binding globulin in human term neonates. Biol Neonate. 1994;65:287–294
  51. Horie K, Takakura K, Fujiwara H, Suginami H, Liao S, Mori T. Immunohistochemical localization of androgen receptor in the human ovary throughout the menstrual cycle in relation to oestrogen and progesterone receptor expression. Hum Reprod. 1992;7:184–190
  52. Hsu TY, Lan KC, Tsai CC, Ou CY, Cheng BH, Tsai MY, et al. Expression of androgen receptor in human placentas from normal and preeclamptic pregnancies. Taiwan J Obstet Gynecol. 2009;48:262–267
  53. Vu TT, Hirst JJ, Stark M, Wright IM, Palliser HK, Hodyl N, et al. Changes in human placental 5alpha-reductase isoenzyme expression with advancing gestation: effects of fetal sex and glucocorticoid exposure. Reprod Fertil Dev. 2009;21:599–607
  54. Stark MJ, Hodyl N, Scott NM, Green E, Osei-Kumah A, Clifton VL. Effect of testosterone on placental cytokine production and p38 MAP Kinase. In: Placenta  editors. International Federation of Placental Associations. Adelaide, SA, Australia: Elsevier; 2009;p. A103
  55. Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem. 1978;253:2769–2776
  56. Zapf J, Rinderknecht E, Humbel RE, Froesch ER. Nonsuppressible insulin-like activity (NSILA) from human serum: recent accomplishments and their physiologic implications. Metabolism. 1978;27:1803–1828
  57. Ashton IK, Spencer EM. Effect of partially purified human somatomedin on human fetal and postnatal cartilage in vitro. Early Hum Dev. 1983;8:135–140
  58. DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature. 1990;345:78–80
  59. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993;75:73–82
  60. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 1993;75:59–72
  61. Lee PD, Conover CA, Powell DR. Regulation and function of insulin-like growth factor-binding protein-1. Proc Soc Exp Biol Med. 1993;204:4–29
  62. Fant M, Munro H, Moses AC. An autocrine/paracrine role for insulin-like growth factors in the regulation of human placental growth. J Clin Endocrinol Metab. 1986;63:499–505
  63. Han VK, Bassett N, Walton J, Challis JR. The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab. 1996;81:2680–2693
  64. Geary MP, Pringle PJ, Rodeck CH, Kingdom JC, Hindmarsh PC. Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth. J Clin Endocrinol Metab. 2003;88:3708–3714
  65. Mayhew TM, Jenkins H, Todd B, Clifton VL. Maternal asthma and placental morphometry: effects of severity, treatment and fetal sex. Placenta. 2008;29:366–373

PII: S0143-4004(09)00373-7

doi:10.1016/j.placenta.2009.11.010

Placenta
Volume 31, Supplement , Pages S33-S39, March 2010

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