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Home , Adiponectin, Human placental lactogen, Insulin (medication)

SPECIAL FEATURE

Editorial

Placental and the Control of Fetal Growth

Michael Freemark

Robert C. and Veronica Atkins Professor of Pediatrics, Duke University School of Medicine, Durham, North Carolina 27701

he weight of a child at birth is a critical determinant acids, essential fatty acids, and for placental-fetal Downloaded from https://academic.oup.com/jcem/article/95/5/2054/2596527 by guest on 27 September 2021 T of neonatal morbidity and mortality and the risk of transport and fetal growth. metabolic disease throughout the life span: growth re- The metabolic adaptations of are orches- tarded [intrauterine growth retardation/small for ges- trated by hormones produced by the and mater- tational age (SGA)] infants are predisposed to hypogly- nal pituitary gland, which undergo dramatic changes dur- cemia, hypocalcemia, hypothermia, asphyxia, and ing gestation (4). After involution of ovarian sex steroid cognitive dysfunction; those who have rapid catch-up production by wk 6, placental and weight gain in early childhood are at increased risk for production increases exponentially to term. Concurrently, adult-onset type 2 , hypertension, preeclamp- there are progressive increases in (PRL), pro- sia, dyslipidemia, and ischemic disease (1). Like- duced by the maternal pituitary gland and decidua, and wise, large for gestational age (LGA) infants are pre- human chorionic somatomammotropin (CSH, also called disposed to childhood weight gain, , and human ), which has structural similar- the (2). ities to GH and PRL. CSH binds with high affinity to PRL receptors (Kd 0.1 nM) but with low affinity to human GH Despite a wealth of investigation, the molecular mech- receptors (Kd 770 nM), suggesting that it functions as a anisms controlling fetal weight gain and growth remain lactogen rather than as a somatogen during pregnancy. poorly understood. The paper by Mannick et al. (3) in this Interestingly, levels of pituitary GH (GH1) decline sharply month’s Journal provides new insight into the roles of during early and mid-pregnancy and are no longer de- placental hormones in the regulation of fetal growth in tected in maternal serum after 24 wk gestation. GH1 is normal and pathological . replaced by a variant GH [GH2 or placental GH (PGH)] The placenta controls fetal growth through delivery of produced by the syncytiotrophoblast. In contrast to pitu- , oxygen, and nutrients to the and clearance of itary GH, the variant GH is secreted tonically and in in- fetal waste products including carbon dioxide and urea. creasing amounts throughout the second half of gestation, The substrates for uteroplacental transport are derived reaching levels (20–40 ng/ml) comparable to those in acro- from maternal nutrient stores (4). In early and mid-ges- megaly. PGH binds with high affinity to GH receptors but tation, maternal food intake increases 10–15%, intestinal with low affinity to PRL receptors. Thus, the mother in mid- calcium absorption doubles, and there is a 60% rise in and late gestation is bathed in high levels of two lactogenic first-phase secretion. Because insulin sensitivity is hormones (PRL, peak 150–180 ng/ml; and CSH, peak preserved during the first half of pregnancy, the increase in 5000–7000 ng/ml) and a nearly pure somatogen (PGH). insulin secretion promotes lipogenesis and limits CSH is also secreted directly into the fetal circulation, reach- oxidation, facilitating maternal fat storage. In mid- and ing levels approximating 20–30 ng/ml, whereas fetal pitu- late gestation, maternal food intake and fat mass escalate, itary PRL levels can climb as high as 200–300 ng/ml; in con- but maternal is transformed by the emergence trast, PGH is detected only in maternal blood. of . This facilitates maternal utilization of Previous studies had found low maternal levels of PGH free fatty acids as an energy source, sparing , amino and CSH in pregnancies complicated by hypertension,

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BMI, Body mass index; CSH, chorionic somatomammotropin; LGA, large for Printed in U.S.A. gestational age; PGH, placental GH; PRL, prolactin; SGA, small for gestational age. Copyright © 2010 by The Endocrine Society doi: 10.1210/jc.2010-0517 Received March 3, 2010. Accepted March 19, 2010.

For article see page 2433

2054 jcem.endojournals.org J Clin Endocrinol Metab, May 2010, 95(5):2054–2057 J Clin Endocrinol Metab, May 2010, 95(5):2054–2057 jcem.endojournals.org 2055 preeclampsia, and intrauterine growth retardation (5, 6). to play important roles; mothers of SGA children had Mannick et al. (3) extend this work by exploring the re- lower prepregnancy body mass indices (BMIs) and less lation between PGH and CSH expression and pregnancy weight gain than mothers of appropriate for in normal term pregnancies. The expression of PGH and gestational age children; the converse was true of moth- CSH transcripts was assessed by a sophisticated fluores- ers of LGA children. In contrast to some other studies cent RT-PCR assay coupled with -specific restriction (1), the height of the mother and the height and weight analysis. Their study has a number of strengths. Most of the father had no relation to birth weight. In sum, important, the cohort was a homogeneous population these observations suggest that changes in fetal growth of healthy Caucasian women without known underly- associated with differential PGH and CSH gene expres- ing metabolic or pregnancy-related diseases. Mothers sion may be mediated or modulated by maternal nutri- with diabetes or toxemia and infants with fetal anom- tional status. Downloaded from https://academic.oup.com/jcem/article/95/5/2054/2596527 by guest on 27 September 2021 alies or genetic or infectious diseases were excluded. How do maternal nutritional status and placental hor- This design eliminates a number of major complicating mone expression interact to regulate fetal growth? One factors and may provide a window into the physiolog- hypothesis proposes that polymorphic or epigenetic reg- ical, rather than strictly pathological, role of PGH and ulation of PGH and CSH expression could alter the ex- CSH in fetal growth regulation. Five of the 15 women pression of other critical hormones or growth factors such in the SGA group were smokers, but the authors have as insulin or IGF-I, change the distribution and availability controlled for this confounder in their multiple regres- of maternal nutrients, and/or affect directly the replication sion analysis. and/or growth of fetal tissues. Because PGH is an insulin Their findings are novel. First, they show that half of antagonist and potent lipolytic that stimulates the PGH transcripts detected in term placenta encode IGF-I production during pregnancy (7, 10), a reduction in with C termini distinct from the major GH2 PGH expression would be expected to reduce and product (GH2-1); the functions of these alternative pro- circulating IGF-I levels. This in turn could reduce fetal teins are unknown, but they merit further scrutiny. Sec- weight by reducing maternal nutrient availability and lim- ond, the expression of GH2-1 is reduced in iting placental nutrient transfer (11). Conversely, in- from pregnancies of SGA babies but is normal in pla- creases in CSH expression have been postulated to induce centas of LGA pregnancies. Third, the predominant insulin resistance and lipolysis and to increase maternal CSH transcript (CSH1) is increased in placentas of LGA IGF-I expression (5); these in theory would increase ma- pregnancies but is unchanged in pregnancies of SGA ternal nutrient availability and placental transfer and pro- infants. mote fetal growth. These findings dovetail nicely with previous studies by But this hypothesis is problematic for several reasons. Caufriez et al. (7), who found high levels of CSH in the First, a reduction in lipolysis caused by PGH deficiency blood of pregnant mothers with and should be accompanied by an increase in maternal fat low levels of PGH in pregnant mothers giving birth to SGA stores; but many women who give birth to SGA infants, infants. Similar findings were recorded by Ursell et al. (8) like those in this and the McIntyre et al. study (9), have low and McIntyre et al. (9). Thus, the major placental syncy- BMIs. Second, the evidence that CSH is lipolytic and IGF- tiotrophoblast members of the GH/CSH hormone I-tropic is weak at best. Nearly all studies showing lipolytic family are regulated differentially, at least in late gestation. effects of CSH were performed using placental extracts How can the differential regulation of PGH and CSH be obtained before the discovery of PGH; more recent studies explained, and what is its pathophysiological signifi- using recombinant hormones show that the lactogens may cance? Some insight may be gleaned by consideration of inhibit lipolysis (12) and promote (13). Be- this study’s cohort. Auxological differences in the infants cause the molecular weights of CSH and PGH are nearly were asymmetric; birth weight (19.1–35%) and abdomi- identical, it is conceivable that CSH purified from human nal circumference (8.6–11.4%), reflecting fat deposition, placenta contained amounts of PGH sufficient to induce were affected to a far larger degree in the LGA and SGA lipolysis in vivo and in vitro. Moreover, mice with lacto- infants than birth length (5.9–7.9%) or head circumfer- gen resistance resulting from a knockout of the PRL re- ence (5.7–7.1%). Moreover, differences in placental ceptor, which binds placental lactogen as well as PRL, weight (19.6–30%) were comparable to differences in have normal insulin sensitivity and normal plasma IGF-I birth weight. These findings bespeak effects of PGH and and IGF binding protein-3 levels (14, 15). CSH on fetal weight gain during the last trimester, when An alternative or complementary hypothesis is grounded fetal fat stores and glycogen deposition increase in the idea that changes in PGH and/or CSH expression exponentially. Maternal weight and fat storage appear represent responses to, or effects of, underlying meta- 2056 Freemark Placental Hormones and Fetal Growth J Clin Endocrinol Metab, May 2010, 95(5):2054–2057 bolic or genetic disturbances that alter uteroplacental 203 g; range, 1270–3600 g), suggesting incomplete com- function. In this schema, PGH expression may decline pensation in some cases or the presence of other factors directly as a consequence of uteroplacental insuffi- that can maintain pregnancy and fetal development in the ciency resulting from an underlying disease like hyper- absence of CSH and/or PGH. tension or systemic lupus erythematosus or a generalized disorder of placental development. Alternatively, or in ad- dition, the fall in PGH may be an indirect consequence of Acknowledgments maternal undernutrition: decreased maternal weight or pregnancy weight gain would in theory increase maternal Address all correspondence and requests for reprints to: Dr. insulin sensitivity and plasma , which reduces Michael Freemark, Division of Pediatric Endocrinology and PGH expression in trophoblast cells in vitro (16). A fall in Diabetes, Box 102820, Duke University Medical Center, Downloaded from https://academic.oup.com/jcem/article/95/5/2054/2596527 by guest on 27 September 2021 Durham, North Carolina 27710. E-mail: FREEM001@ PGH expression might limit maternal lipolysis, thereby mc.duke.edu. compensating in part for a reduction in maternal fat stores. Disclosure Summary: The author has nothing to disclose. Both mechanisms could explain the reduction in PGH and the fall in maternal IGF-I in pregnancies associated with fetal growth retardation. Conversely, an increase in maternal BMI or gestational References weight gain would increase maternal fat stores and reduce 1. Murphy VE, Smith R, Giles WB, Clifton VL 2006 Endocrine regu- maternal insulin sensitivity, predisposing to glucose intol- lation of human fetal growth: the role of the mother, placenta, and erance in the pregnant state. The resulting relative or ab- fetus. Endocr Rev 27:141–169 2. Boney CM, Verma A, Tucker R, Vohr BR 2005 Metabolic syn- solute would increase placental weight, drome in childhood: association with birth weight, maternal , possibly through induction of IGF-II (11), and fetal and gestational diabetes mellitus. Pediatrics 115:e290–e296 weight, through induction of fetal (1, 3. Mannick J, Vaas P, Rull K, Teesalu P, Rebane T, Laan M 2010 Dif- ferential expression profile of /chorionic somatomam- 11). The increase in maternal fat would reduce plasma motropin (GH/CSH) in placenta of small- and large-for-gesta- adiponectin; this may increase CSH expression because tional-age newborns. J Clin Endocrinol Metab 95:2433–2442 adiponectin suppresses CSH as well as PGH (16). In- 4. Freemark M 2006 Regulation of maternal metabolism by pituitary and placental hormones: roles in fetal development and metabolic creases in CSH in the fetal circulation could promote hy- programming. Horm Res 65(Suppl 3):S41–S49 perinsulinemia by induction of ␤-cell replication (14, 17), 5. Handwerger S 2009 The growth hormone gene cluster: physiolog- thereby increasing fetal weight gain. Increases in maternal ical actions and regulation during pregnancy. Growth Genet Horm 25:1–8 CSH and induction of maternal ␤-cell replication and in- 6. Verhaeghe J 2008 Does the physiological acromegaly of pregnancy sulin production could serve to compensate for maternal benefit the fetus? Gynecol Obstet Invest 66:217–226 insulin resistance and defend against, or reduce the sever- 7. Caufriez A, Frankenne F, Hennen G, Copinschi G 1993 Regulation of maternal IGF-I by placental GH in normal and abnormal human ity of, gestational diabetes (14, 18, 19). pregnancies. Am J Physiol 265:E572–E577 Definitive evidence supporting these hypotheses is cur- 8. Ursell W, Brudenell M, Chard T 1973 Placental lactogen levels in rently lacking. Indeed, many have questioned the roles of diabetic pregnancy. Br Med J 2:80–82 9. McIntyre HD, Serek R, Crane DI, Veveris-Lowe T, Parry A, Johnson CSH and PGH in human physiology because some women S, Leung KC, Ho KK, Bougoussa M, Hennen G, Igout A, Chan FY, with deletions of the CSH and/or PGH genes have had Cowley D, Cotterill A, Barnard R 2000 Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal pregnancies and have given birth to children of normal, growth-retarded, and diabetic pregnancies: correlations normal birth weight (4). These findings suggest that nei- with fetal growth. J Clin Endocrinol Metab 85:1143–1150 ther CSH nor PGH per se is required for normal preg- 10. Barbour LA, Shao J, Qiao L, Pulawa LK, Jensen DR, Bartke A, Garrity M, Draznin B, Friedman JE 2002 Human placental growth nancy; however, it is possible that other hormones, such as hormone causes severe insulin resistance in transgenic mice. Am J pituitary GH and/or PRL, might compensate for the ab- Obstet Gynecol 186:512–517 sence of PGH or CSH. There are no clinical models of 11. Fowden AL, Forhead AJ 2009 Endocrine regulation of feto-placen- tal growth. Horm Res 72:257–265 combined deficiencies of lactogen and somatogen action 12. Brandebourg TD, Bown JL, Ben-Jonathan N 2007 Prolactin up- in pregnancy or postnatal life, but studies of a lactogen- regulates its receptors and inhibits lipolysis and release in resistant/GH-deficient mouse (15, 20) provide evidence male rat . Biochem Biophys Res Commun 357:408– 413 that the lactogens and somatogens act through overlap- 13. Freemark M, Fleenor D, Driscoll P, Binart N, Kelly P 2001 Body ping but distinct mechanisms to regulate metabolism and weight and fat deposition in prolactin -deficient mice. growth. It should also be noted that a review (4) of pub- Endocrinology 142:532–537 ϭ 14. Freemark M, Avril I, Fleenor D, Driscoll P, Petro A, Opara E, lished cases (n 11) of CSH and PGH deletions showed Kendall W, Oden J, Bridges S, Binart N, Breant B, Kelly PA 2002 variable fetal growth failure (mean birth weight, 2791 Ϯ Targeted deletion of the PRL receptor: effects on islet develop- J Clin Endocrinol Metab, May 2010, 95(5):2054–2057 jcem.endojournals.org 2057

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and insulin secretion in rat, mouse, and human islets: implication for receptors. Endocrine 32:182–191 Downloaded from https://academic.oup.com/jcem/article/95/5/2054/2596527 by guest on 27 September 2021

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