REVIEW

From to Preeclampsia: A Key Role for

Nadia Berkane,1,2 Philippe Liere,2 Jean-Paul Oudinet,2 Alexandre Hertig,3,4,5 Guillaume Lefevre, ` 4,6 Nicola Pluchino,1 Michael Schumacher,2 and Nathalie Chabbert-Buffet4,7,8

1Department of Gynecology and Obstetrics of University Hospital of Geneva, 1205, Geneve, ` Switzerland; 2U1195, INSERM and University Paris Sud, 94276 Kremlin Bicetre,ˆ France; 3Department of Nephrology, Tenon Hospital, APHP, 75020 Paris, France; 4University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France; 5Unit´e Mixte de Recherche Scientifique 1155, F-75020 Paris, France; 6Department of Biochemistry and Hormonology, Tenon Hospital, APHP, F-75020 Paris, France; 7Department of Obstetrics, Gynecology and Reproductive Medicine, Tenon Hospital, APHP, F-75020 Paris, France; and 8INSERM, UMR-S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France

Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, is produced primarily in the placenta by conversion of precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE. (Endocrine Reviews 38: 123–144, 2017)

I. Introduction III. Estrogen Biosynthesis Pathway in Pregnancy: A True II. Implantation and Trophoblast Invasion During Nor- Maternofetal Unit mal Pregnancy and PE A. Overview A. Physiology of implantation B. Steroidogenesis in apes and humans B. Physiology of uterine vessel invasion IV. Estrogen Metabolism Pathways in Pregnancy C. Implantation and uterine vessel invasion during A. Two singular estrogens: E3 and E4 PE B. Catecholestrogen synthesis D. Characteristics of placental implantation and in- C. Methoxyestrogen synthesis vasion in primates D. Conjugated estrogen synthesis

ISSN Print 0163-769X ISSN Online 1945-7189 Abbreviations: 2-MED2, 2-methoxyestradiol; 2-OHE1, 2-hydroxyestrone 1; 2-OHE2, Printed in USA 2-hydroxyestrone 2; BP, blood pressure; COMT, catechol-O-methyltransferase; CT, Copyright © 2017 Endocrine Society cytotrophoblast cell; DHEA, ; DHEAS, sulfated form of dehy- Received 23 May 2016. Accepted 28 February 2017. droepiandrosterone; E1, ; E1S, sulfated E1; E2, estradiol; E3, ; E4, ; First Published Online 3 March 2017 ELISA, -linked immunosorbent assay; eNOS, endothelial nitric oxide synthase; ER, ; ERE, estrogen responsive element; ERE-LS, estrogen responsive ele- ment-like sequence; EVT, extravillous trophoblast cell; GC, gas chromatography; GDM, gestational diabetes mellitus; GPER, G protein–coupled estrogen receptor; HIF-1a, hypoxia inducible factor-1a; HSD, b-hydroxysteroid dehydrogenase; HSD17B1, 17- b-hydroxysteroid dehydrogenase type 1; HSD3B1, 3b-hydroxysteroid dehydrogenase/ D5D4isomerase; LC, liquid chromatography; miRNA, microRNA; mRNA, messenger RNA; MS, mass spectrometry; NO, nitric oxide; PE, preeclampsia; PlGF, placental growth factor; RIA, radioimmunoassay; sFlt1, soluble fms-like tyrosine kinase 1; ST, syncytiotrophoblast cell; SULT, sulfotransferase; TNF-a, tumor necrosis factor-a; UBF, uterine blood flow; USF, upstream stimulatory factor; VEGF, vascular endothelial growth factor; VEGFR-1, vascular endothelial growth factor receptor 1; VSM, vascular smooth muscle.

doi: 10.1210/er.2016-1065 Endocrine Reviews, April 2017, 38(2):123–144 https://academic.oup.com/edrv 123 124 Berkane et al Low Estrogen Levels and Preeclampsia Endocrine Reviews, April 2017, 38(2):123–144

2. HSD17B1 ESSENTIAL POINTS 3. COMT a. Expression and activity Humans and apes are the only mammals synthesizing estrogens exclusively in the in pregnancy. · placenta and developing spontaneous preeclampsia. b. COMT knockout mice and PE. Estrogens promote placental angiogenesis and uterine artery vasodilation during VI. Signaling and Biological Effects of · pregnancy. E2 and Its Metabolites in Preg- nancy: A Key Link Between Estro- Aromatase deficiency and estrogen dysregulation could play a key role in gen Deficiency and PE · preeclampsia symptoms. A. Signaling pathways of estro- gens in normal placenta and The close interaction between estrogens and angiogenic/antiangiogenic factors · in PE reinforces the "estrogen" hypothesis. 1. Genomic signaling The use of reliable analytical technology, such as liquid chromatography/mass pathways · spectrometry and gas chromatography/mass spectrometry, is now compulsory to 2. Nongenomic signaling evaluate profiles in pregnancy. pathways 3. ER expression in placental Assessments of estrogen levels could play a key role in predicting preeclampsia and and uterine cells · potentially lead to preventive treatments. a. Placenta expression of ERs. b. Uterine expression of ERs. V. PE and Estrogen Deficiency 4. ERs and PE A. Estrogen levels in PE B. Biological effects of estrogens in normal preg- 1. Estrogens: E1, E2, E3 nancy and PE: the link with angiogenesis and a. E2. maternal uterine and systemic vascular tone b. E1 and E3. 1. Estrogens and angiogenesis 2. Catecholestrogens and 2-ME2 2. Estrogens and uterine blood flow increase a. Catecholestrogens. 3. Estrogens and maternal BP regulation b. 2-ME2. 4. Estrogens and placental and uterine cell dif- 3. Other E2 metabolites ferentiation and proliferation 4. Estrogen precursors 5. Estrogens and regulation of estrogen precursor B. Placental expression of involved in estro- synthesis by fetal adrenals gen biosynthesis in PE VII. PE Risk Factors and Estrogen Synthesis/Signaling 1. Aromatase Deficiencies a. Expression and regulation in normal A. Obesity pregnancy. B. Diabetes b. Regulation by transcription factors and C. Chronic hypertension microRNA. D. Kidney transplantation c. Expression and activity in PE. VIII. Therapeutic Implications d. Congenital aromatase deficiency and PE. IX. Future Directions

I. Introduction PE (type II). The only known therapy for either type of PE is delivery. reeclampsia (PE) occurs in 3% to 7% of This multisystem disorder affects the maternal vas- P(1) and is one of the main causes of maternal and fetal/ cular endothelium and leads to ischemic and edematous neonatal morbidity and mortality (2, 3). Its most com- phenomena in many organs (e.g., brain, , and kid- mon feature is the association of high blood pressure ney). Biological abnormalities observed during PE are $ $ (BP) (systolic BP 140 mm Hg and/or diastolic BP activated coagulation (5), excessive inflammatory re- $ 90 mm Hg) together with proteinuria ( 0.3 g/24 hours), sponse (6, 7), and an imbalance between angiogenic and both occurring after 20 weeks of gestation. Other fea- antiangiogenic factors (8–14). tures include high BP without proteinuria associated It is now accepted that PE is a placental disease (15, with elevated liver enzyme activities, increased blood 16). Placental examination shows excess cell necrosis, creatinine, thrombocytopenia, seizures, or intrauterine fibrinoid deposits, vessel thrombosis, and acute atherosis growth retardation (4). Two types of PE have been in the vessel walls (17). described: early-onset PE (type I) with occurrence of Although the specific causes of PE remain a matter of clinical signs before 34 weeks of gestation and late-onset debate, several pathophysiologic mechanisms leading to doi: 10.1210/er.2016-1065 https://academic.oup.com/edrv 125 the clinical signs of PE have been identified, including cytotrophoblast cells (CTs) multiply and fuse to form an imbalance between angiogenic and antiangiogenic fac- external syncytiotrophoblastic layer after adhesion to the tors (8–14), nitric oxide (NO) synthesis deficiency (18), endometrium. These syncytiotrophoblast cells (STs) fa- increased plasma tumor necrosis factor-a(TNF-a)(19–21), cilitate penetration of the conceptus into the decidua and and impaired maternal vascular endothelial functions are involved in maternofetal exchanges (O2, nutrients) (21–23). and endocrine secretion (such as and es- , such as estradiol (E2), can modulate vascular trogens). Development of the trophoblast is marked by endothelium functions and synthesis of both angiogenic the emergence and development of villi, some of which and stress factors. E2 is synthesized by the placenta in are attached to maternal tissues (anchoring villi). The very large amounts during pregnancy and promotes distal parts of these villi are composed of CTs, which angiogenesis and vasodilation (24). Indeed, E2 increases proliferate to form CT shells and are in direct contact NO synthesis (25–27) and levels of angiogenic factors, with maternal uterine cells and vessels (Fig. 1). Extra- such as vascular endothelial growth factor (VEGF) villous trophoblast cells (EVTs) detach from the base- (28–30) and placental growth factor (PlGF) (31), and ment membrane, migrate, and spread into the decidua inhibits TNF-a macrophage synthesis (32). Although and the first third of the myometrium and are involved in previous research showed conflicting results regarding the remodeling process of the uterine arteries (Fig. 1) the link between low plasma estrogen levels and PE (45–47). (33–36), several recent studies performed with reliable assays, such as liquid chromatography (LC)/mass spec- B. Physiology of uterine vessel invasion trometry (MS) or gas chromatography (GC)/mass spec- CTs invade the uterine spiral arteries, initiating a trometry (MS), have consistently reported low plasma E2 major remodeling of the uterine arterial wall caused by levels in preeclamptic women (37, 38). The earlier con- apoptosis, dedifferentiation of the muscular layer, and tradictory results were probably a consequence of using replacement by EVTs and fibrinoid deposits (48, 49). nonspecific and less sensitive methods for E2 assays, such This results in a complete loss of vascular tone and in- as radioimmunoassay (RIA) and enzyme-linked immu- sensitivity to all vasoactive substances. Furthermore, nosorbent assay (ELISA). Mass spectrometry coupled during the first wave of trophoblast invasion, there is a with LC or GC, together with purification steps, has transient accumulation of EVT plugs in the spiral artery considerably improved the reliability for determining lumen, which is responsible for a hypoxic state in the estrogen concentrations (39). placenta and consequent high local overexpression of Spontaneous PE is a disease primarily restricted to hypoxia inducible factor-1a (HIF-1a), which stimulates humans, although a few primate cases have also been VEGF synthesis (50). These factors promote vasculo- reported in the patas monkey (40), the rhesus monkey genesis, angiogenesis, and placental development (51). (41), and baboons with twin pregnancies (42). In- The plugs disappear progressively before 14 weeks of terestingly, these mammals share specific placentation pregnancy (52). This return to a normoxic environment is and steroidogenesis patterns during pregnancy. In this essential for the continuation of fetal and placental review, we describe estrogen synthesis and metabolism development. during pregnancy, as well as the estrogen deficiency occurring during PE. We also address the crosstalk be- C. Implantation and uterine vessel invasion during PE tween estrogens and angiogenic/antiangiogenic factors in Although clinical signs of PE occur in the second part the pathogenesis of PE. Finally, we look into how some of pregnancy, preclinical abnormalities occur during the PE risk factors could negatively affect placental ste- trophoblast invasion phase, particularly for early-onset roidogenesis, thus strengthening the “estrogen deficiency PE. During PE, trophoblast cell migration and invasion hypothesis” as the common pathway to development of into the decidua, myometrium, and vessels are typically PE signs. incomplete, and the development of angiogenesis and trophoblast cell proliferation are consequently impaired (53). This “shallow invasion” induces placental ischemia II. Implantation and Trophoblast Invasion caused by insufficient uterine blood flow (UBF). Sub- During Normal Pregnancy and PE sequently, shedding of trophoblast debris (54, 55) and A. Physiology of implantation oversecretion of antiangiogenic soluble fms-like tyrosine Human implantation and trophoblast invasion [which kinase 1 (sFlt1) into the maternal circulation occur (9–14, are detailed elsewhere (43)] result in the attachment of the 56, 57). This participates in the dysfunction of the sys- trophectoderm onto the uterine endometrium on day 6 temic maternal vascular endothelium, leading to hyper- after fecundation (44). From the trophectoderm, the tension and glomerular nephropathy. Meanwhile, the 126 Berkane et al Low Estrogen Levels and Preeclampsia Endocrine Reviews, April 2017, 38(2):123–144

Figure 1.

Figure 1. Anchoring villi with localization of the required enzymes for estrogen biosynthesis. A single layer of CTs fuses to form a multinucleated layer of STs, which is in contact with maternal blood. The thin outer CT shells proliferate and split through the ST layer in direct contact with maternal cells. CTs called EVTs then detach from the basement membrane and migrate and spread into the decidua and the first third of the myometrium. During the migration to uterine vessels, some EVTs acquire an invasive phenotype to facilitate penetration into maternal vessels and express adhesion molecules (45–47). The decidual and myometrial invasion of EVTs occurs via two pathways: an endovascular pathway and an interstitial pathway. associated inflammation leads to an increase in vascular maternal natural killer cells. In contrast, in other primates permeability, particularly via TNF-a and interleukin- and mammals (with the exception of rats), the invasion is 6 (7, 58). mostly superficial. Although artery remodeling does E2, progesterone, and their metabolites participate in occur, invasion is preferentially endovascular, thereby angiogenesis, as well as in normal trophoblast develop- limiting the risk of abnormal maternal immune reaction ment and invasion, through an upregulation of cell (59). In addition, in apes the placenta is the main estrogen proliferation, differentiation, and migration of CTs (see provider during pregnancy, whereas in other mammals below). Low E2 levels are likely to lead to insufficient steroidogenesis takes place in the ovaries throughout trophoblast development and angiogenesis processes, gestation (60, 61). which in turn may further contribute to low E2 levels, promoting a vicious cycle between hormonal imbalance III. Estrogen Biosynthesis Pathway in and disrupted implantation. Pregnancy: A True Maternofetal Unit

D. Characteristics of placental implantation and invasion A. Overview in primates During normal pregnancy, maternal plasma E2 levels A comparison between trophoblast invasion during increase progressively starting from 367 pM (luteal implantation and placentation in primates may provide phase) up to between 11,000 and 37,000 pM at the end of clues for understanding why apes are the only other pregnancy (62, 63). At the very early stage of human mammals to experience spontaneous PE (59). Apes and pregnancy, estrogens are mainly synthesized by the humans share a common high UBF that involves con- corpus luteum. At approximately 9 weeks of gestation siderable remodeling of the uterine artery wall. This (60), a hormonal ovary-to-placenta shift occurs, resulting remodeling process preferentially involves interstitial in placental production of E2, whereas the gonadotrope trophoblasts and requires deep invasion of these cells that axis is blunted. STs then become the main source of es- depends on an efficient crosstalk between CTs and trogens (64). Besides STs, placental macrophages may doi: 10.1210/er.2016-1065 https://academic.oup.com/edrv 127 also contribute, albeit in a minor way, to placental es- Further conversion of DHEAS to E2 by the placenta trogen production (Hofbauer cells) (65, 66). requires four key enzymes (Fig. 2). These enzymes are cell To our knowledge, all but one recent study (67) agree specific (Fig. 1). Sulfatases expressed by STs convert that the human placenta is an incomplete steroidogenic DHEAS into DHEA (73). Type I 3b-hydroxysteroid organ that needs to interact with fetal and maternal dehydrogenase (HSD)/D5D4isomerase (HSD3B1), ex- steroidogenic organs because it lacks some of the required pressed by STs and invasive CTs, converts DHEA into enzymes (Fig. 2). For example, 17a-hydroxylase-17,20 D4-. Some authors have found that lyase is not expressed (68, 69). Consequently, the hu- plasma concentrations of this weak androgen increase man placenta is unable to convert and gradually throughout pregnancy and then particularly at progesterone into the estrogen precursors, dehydroepian- delivery (74), whereas others report an increase at de- drosterone (DHEA) and D4-androstenedione, respec- livery only (75). Aromatase is a further step that irre- tively (Fig. 2). Therefore, human placental estrogen versibly converts D4-androstenedione into estrone (E1). synthesis depends on DHEA and its sulfated form E1 can also be sulfated, resulting in E1S, a compound (DHEAS), produced both by maternal and fetal adrenal with a longer half-life (10 to 12 hours vs. 20 to 30 minutes glands. for E1). In addition, E1S is reversibly convertible to E1 DHEA is sulfated by sulfotransferase 2A1, an enzyme (76) and is thus a circulating source of E1 (77). Finally, E1 highly expressed in the maternal and fetal adrenal glands is converted into E2 by 17-b-HSD type 1 (HSD17B1). E2 and liver (70, 71) in order to obtain DHEAS. Plasma is delivered by the placental vessel cells to the maternal concentrations of DHEAS decrease from the beginning of circulation but can also be locally synthesized within the pregnancy until 38 weeks of gestation, after which a uterus because uterine artery smooth muscle cells express twofold increase is observed at delivery (72). aromatase (77, 78) and invasive CTs express HSD17B1

Figure 2.

Figure 2. Steroidogenesis in pregnancy. In the syncytiotrophoblasts, is converted into pregnenolone by cytochrome P450 steroid chain cleavage (CYP450scc), and then into progesterone by HSD3B1. E2 is synthetized by the placenta during pregnancy but requires DHEAS provided by maternal and fetal adrenal glands because there is no 17a-hydroxylase, 17,20 lyase (CYP17A1) in the placenta. E2 mainly results from aromatization of D4androstenedione, because placenta 17bHSD3 is lacking and aromatase has a higher affinity for D4androstenedione than for circulating (81). 128 Berkane et al Low Estrogen Levels and Preeclampsia Endocrine Reviews, April 2017, 38(2):123–144

(79) (Fig. 1). Aromatization of testosterone (80) is neg- 2-hydroxylation step occurs mainly through CYP1A1 ligible during pregnancy because of a much higher af- and CYP3A4 activities (99). finity of aromatase for D4-androstenedione (81). Some amounts of E2 can also be produced in maternal adipose C. Methoxyestrogen synthesis tissue (82). Catecholestrogens are converted by placental catechol- O-methyltransferase (COMT) into methoxyestrogens. B. Steroidogenesis in apes and humans One of the main methoxyestrogens is 2-methoxyestradiol Humans and apes, the only mammals that develop (2-ME2), which is produced by the placenta but also by spontaneous PE, share three common features of ste- local synthesis at the implantation site because maternal roidogenesis: first, a lack of placental 17-a hydroxylase, arterial endothelial and decidual cells express COMT leading to a dependence on maternal and fetal adrenal (97–100) (Fig. 1). glands (68, 69, 83); second, a luteo-placental shift that leads to a dependence on placental aromatase activity D. Conjugated estrogen synthesis (60, 61); and third, a conversion of E1 into E2 that takes Estrogens can also be further and reversibly metabo- place exclusively in the placenta, leading to a dependence lized into inactive hormones by sulfation, glucuronidation, on the presence of HSD17B1 in this tissue (84) (Fig. 1). or quinone synthase processes. These conjugated products are excreted into the bile and/or . IV. Estrogen Metabolism Pathways Conversion into sulfated estrogens is mediated by cy- in Pregnancy tosolic sulfotransferases (SULTs). This is part of a de- toxification pathway leading to water-soluble deactivated Once synthesized, E1 and E2 can be further catabolized products readily excreted in the urine. Sulfated estrogens into estriol (E3), estetrol (E4), catecholestrogens or have a high albumin-binding affinity, rendering them un- methoxyestrogens, and conjugated forms, following the able to bind to estrogen receptors (ERs) and are thus bio- main pathways described below. logically inactive hormones (101). One of the most A. Two singular estrogens: E3 and E4 important SULTs for estrogens is SULT1E1 (also called Although displaying a weak biological activity, E3 is EST), synthesized by STs, as well as in several maternal and synthesized in very large amounts during pregnancy (85). fetal tissues, including liver, adrenal glands, breast, and E3 is a marker of fetal liver function, because it is mainly gastrointestinal epithelial cells (102). SULT1E1 has a derived from 16a-hydroxylated DHEAS, a fetal liver strong affinity for E1 and E2 at nanomolar concentrations product. E3 can also be produced in the fetal liver by 16a- (i.e., in the physiologic range during pregnancy) (70). hydroxylation of E2 (86). Conversion of E2 into E3 (87) SULT1E1 knockout mice have an apparent reduced fer- is mainly considered irreversible, although Jobe et al. (38) tility due to an excess of fetal death (103). These deaths are suggested a possible interconversion via an intermediate related to placental thrombosis, a consequence of the excess 16 keto E2. of estrogen found in these mice, and can be prevented by E4 is the product of 15a/16a-hydroxylation of E2, or anticoagulant treatment (103). Sulfation which takes place in the fetal liver (88–90); its concen- is a reversible process because enzymes called sulfatases can tration is much higher in the fetal than in the maternal convert sulfated estrogens into desulfated active hormones. circulation (91). The 15a-hydroxylase enzyme is specific Estrogens can also be glucuronidated (104, 105) or con- to the fetal liver and is no longer expressed after birth. verted into quinones or semiquinones (106). Consequently, E4 is no longer synthesized after birth (90). The role of this particular estrogen remains un- V. PE and Estrogen Deficiency known but it probably acts as a selective estrogen re- A. Estrogen levels in PE ceptor modulator (92–94). Levels of estrogens, their precursors, and their byprod- B. Catecholestrogen synthesis ucts have been evaluated in small series of women with Catecholestrogens result from the hydroxylation of pregnancy-related hypertensive disease. Table 1 summa- carbon 2 or 4 of E1 and E2 in an irreversible manner. The rizes available data. resulting hydroxylated metabolites of estrogens (2-OH- 1. Estrogens: E1, E2, E3 E2, 4-OH-E2, 2-OH-E1, and 4-OH-E1) are active mol- ecules with genomic and nongenomic effects (95–98). a. E2. Extensive and reliable steroid profiling is now These hydroxylation processes are mediated by different possible with GC or LC/MS. Furthermore, enzyme ac- cytochrome P450 (CYP450) isoforms, which are mostly tivity can be assessed by calculating product/substrate expressed in the placenta and liver. In the placenta, the ratios. We performed whole GC/MS steroid profiling in doi: 10.1210/er.2016-1065 https://academic.oup.com/edrv 129

Table 1. Estrogens and Preeclampsia groups and that E1 and E3 are lower, or tend to be lower, as shown by sensitive assays (i.e., GC/MS and LC/MS). Steroid/ Tissue Levels Techniques References 2. Catecholestrogens and 2-ME2 E2 Plasma Decreased GC/MS 37 a. Catecholestrogens. To our knowledge, only one study LC/MS 38 has measured catecholestrogens in PE (38). The authors RIA 108, 109 found lower levels of 2-hydroxyestrone 1 (2-OHE1) and ELISA 107 Placenta Decreased ELISA 110 2-hydroxyestrone 2 (2-OHE2) in mild and severe PE E1 together with a high level of 4-OHE1 and 16-OHE1 in a Plasma Decreased GC or LC/MS 37, 38 severe and mild PE respectively, suggesting potential E3 Plasma Decreased GC or LC/MS 37a,38 CYP450 hydroxylase alterations during PE (38). No modification RIA 108 Placenta Decreased ELISA 110 b. 2-ME2. Kanasaki et al. (112) reported lower 2-ME2 levels a 2-ME2 Decreased GC/MS 37 in women with PE, assessed by the LC/MS/MS technique Plasma LC/MS 38 LC/MS/MS 111, 112 between 22 and 29 weeks of gestation, compared with ELISA 111, 114, 115 controls. Furthermore, 2-ME2 levels were assessed by LC/ tandem MS between 11 and 14 weeks of gestation in Increased ELISA 116 Chilean women who subsequently developed PE and DHEAS Plasma Decreased GC/MS 37 normal pregnancies (113). In this study, 2-ME2 levels were ELISA 35 lower in the PE group than the control group (113). No modification ELISA 117 Only one study assessed 2-ME2 concentrations at de- D4-Adione Plasma No modification GC/MS 37 livery with GC or LC/MS. Jobe et al. (38) observed lower Increased ELISA 117, 118 2-ME2 levels in women with severe PE compared with a controls. Similarly, we found a trend toward lower 2-ME2 Nonsignificant trend. levels in severe PE compared with mild PE and controls (37). MS/MS, tandem mass spectrometry. Furthermore, three studies (using ELISA) reported lower 2-ME2 levels in PE compared with controls (111, the plasma of women with PE and normal pregnancies, 114, 115). In these studies, blood samples were collected collected at delivery, and demonstrated a lower E2 levels at the time of diagnosis—close to 29 weeks (111)—and at in the PE group (37). Other recent studies reported similar different periods of gestation (114), respectively. Only conclusions using different assays, such as LC/MS (38), one study using ELISA found higher plasma 2-ME2 ELISA (107), or RIA (108, 109). Indeed, low plasma E2 concentrations at delivery (third trimester) in a late-onset concentrations have been observed in both severe (37, 38, PE group vs. control group (116). Overall, these data 108, 109) and mild (37, 38) PE, as well as in placental suggest that 2-ME2 synthesis is also impaired during PE. tissue from pregnancies with PE (110). Additionally, a recent study using an ELISA technique reported a trend 3. Other E2 metabolites toward low E2 levels in women with PE compared with One E2 metabolite, 16-ketoE2, has been earmarked healthy pregnant women (111). as a likely candidate for a potential PE biomarker (38). This metabolite, possibly the result of an interconversion b. E1 and E3. E1 and E3 concentrations have also been between E2 and E3, has been found in maternal blood at measured at delivery in PE and control groups (37, 38, high concentrations during severe PE (38). However, this 108). Whereas Jobe et al. (38) found lower plasma levels finding needs to be confirmed by further studies. Finally, of both E1 and E3 in severe PE, we only observed a trend low levels of E3 metabolites (16- and 17-epiE3) have been toward lower E1 concentrations in severe PE, as well as a reported in severe PE by the same authors (38). Because trend toward lower E3 concentrations in both mild and 16- and 17-epiE3 demonstrate anti-inflammatory effects, severe PE groups (37). Furthermore, E3 was significantly it has been suggested that their low levels could partly lower in PE placental tissue than in tissue from women contribute to the excessive inflammatory response en- with normal pregnancies (110). Only one recent study, countered during PE (38). using the RIA technique to compare plasma E3 levels in women with PE or HELLP syndrome, did not find any 4. Estrogen precursors differences with normal pregnancy (108). Estrogen precursors in PE have been understudied, Taken together, these recent studies suggest that at and reported results are mainly contradictory. At de- delivery, plasma E2 concentration is always lower in PE livery, we found very low DHEAS plasma concentrations 130 Berkane et al Low Estrogen Levels and Preeclampsia Endocrine Reviews, April 2017, 38(2):123–144 in mild and severe PE (37). In contrast, Rosing and 1. Aromatase Carlstrom ¨ (35) described an increased DHEA/DHEAS a. Expression and regulation in normal pregnancy. Among ratio in the PE vs. control group. Finally, another study, the steroidogenic enzymes involved in the estrogen syn- which used ELISA to assess DHEAS levels, did not find thesis pathway, aromatase (P450arom) is the rate- any difference (117). limiting enzyme. Aromatase, encoded by the CYP19 To our knowledge, our paper was the only one to gene, is expressed in numerous tissues (gonads, brain, report D4-androstenedione assay by GC/MS during PE to fetal liver, vascular smooth muscle [VSM] cells, endo- assess the aromatase activity. This estrogen precursor thelial cells, macrophages, adipocytes, and connective measured at delivery in women with mild and severe tissues) (119–121) and widely expressed in the placenta PE was not different from the control group (37). On (122). The placental promoter contains binding sites for the contrary, two studies using ELISA (117, 118) found both inhibitors and enhancers of CYP19 gene expression that mean D4-androstenedione levels were higher in (123). An autocrine loop stimulates placental aromatase women with pregnancy-related hypertension. Further- expression by E2 via ER-a (124). Placental aromatase is more, women with severe hypertension showed the expressed only by trophoblasts that have undergone highest D4-androstenedione levels (118). differentiation and fusion to become STs (Fig. 1) (125).

B. Placental expression of enzymes involved in estrogen b. Regulation by transcription factors and microRNA. Two biosynthesis in PE specific microRNAs (miRNAs), namely mir-19b and mir- Dysfunction of enzymes involved in estrogen bio- 106a, have been identified in CTs as transcriptional in- synthesis could be the cornerstone of low or high estrogen hibitors of aromatase gene expression (126). These two levels found in PE. Indeed, placental E2 biosynthesis de- miRNAs promote CT proliferation and inhibit CT dif- pends on a sufficient androgen supply (i.e., DHEAS), but ferentiation, and their expression has been found to also on downstream placental enzyme expression and/or decline in STs (126). activity (sulfatase, HSD3B1, aromatase, and HSD17B1). Other transcriptional factors, namely the upstream 2-ME2 is also dependent on placental COMT expression stimulatory factors (USFs) 1 (USF1) and 2 (USF2), have and/or activity. Table 2 summarizes the main data on been reported to decrease CT differentiation and aroma- enzymes involved in estrogen synthesis in PE. tase expression in a low-O2 environment via the binding of these two factors on two E-boxes located upstream and within the aromatase-specific exon I.1 of the CYP19 gene

Table 2. Estrogen-Synthesizing Enzymes and (127). On the contrary, an increase in O2 levels leads to Controlling miRNAs in Preeclampsia Relative to degradation of USF1 and USF2 by the proteasome and Normotensive Persons increases CT differentiation and aromatase expression, Enzymes Levels Techniques References thereby re-establishing estrogen synthesis (127). Aroma- Aromatase tase activity and/or expression also seems to be influenced Activity in Decreased GC/MS 37a by ethnicity, as demonstrated by Charles et al., who plasma LC/MS 38 reported a higher aromatase activity assessed by the E1/ RIA, WB, 132 D qRT-PCR 4-androstenedione ratio in Andean women compared Activity in Decreased RIA 129 with their European counterparts (ancestry), suggesting placenta the existence of potential polymorphisms in humans (128). HSD17B1 miRNA Increased HTS, real-time 126 c. Expression and activity in PE. A defect in aromatase is expression mir-19b PCR and 106a suspected to be the biggest culprit in PE pathophysiology. Plasma level Decreased ELISA 143, 144 This hypothesis is supported by in vitro radiometric miRNA Increased qRT-PCR 143 evaluation of aromatase using [19-3H ]androstenedione expression mir-210 Real-time 3 and 518c PCR in human placental microsomes from both normal and COMT hypertensive pregnancies (129) as well as by studies on Activity in Decreased RIA 155 CYP19 gene polymorphisms (130). placenta Expression in Not modified WB, RtPCR 156 As reported by Jobe et al., assessment of low E1 con- placenta WB 115, 116 centrations in PE suggests abnormal aromatase activity (38). We found a reduction of the E1/D4-A ratio in PE, Abbreviations: HTS, high-throughput screening; PCR, polymerase chain reaction; qRT-PCR: quantitative reverse transcription polymerase chain which was not statistically significant, possibly due to an reaction; WB, Western blot. insufficient sample size (37). On the contrary, Moon et al. aNonsignificant trend. did not find abnormal aromatase activity (131). However, doi: 10.1210/er.2016-1065 https://academic.oup.com/edrv 131 in this study a potential bias may have been premature female endothelial cells overexpressing androgen re- delivery in the control group, suggesting abnormal preg- ceptors. We hypothesize that low estrogen levels due to nancy (mean gestational age at delivery, 34.7 6 2.9 weeks). genetic aromatase deficiency might result in a high ex- Looking at mechanistic factors, Perez-Sepulveda et al. pression of androgen receptors and androgen levels (lack demonstrated that aromatase expression was lower in PE of physiologic estrogen downregulation), giving rise to placentas compared with controls and suggested that androgen-mediated angiogenesis. Moreover, during PE hypoxia could explain this decrease after they compared there is an imbalance between proangiogenic and anti- the aromatase expression pattern of the choriocarcinoma angiogenic estrogens, a situation different from genetic cell line JEG-3 cultured under hypoxic conditions (132). deficiency of aromatase, whereas it has been shown that These authors also demonstrated a lower placenta aro- different ratios between estrogen metabolites with pro- or matase expression in a pregnant-rabbit model of pla- antiangiogenic properties can modulate both VEGF cental ischemia (132). production and angiogenic activity (141). In contrast, Charles et al. showed that chronic hyp- X-linked placental steroid sulfatase deficiency gives oxia, due to residence at high altitudes, increases aro- rise to very low estrogen levels (142) (certainly including matase activity or expression in individuals of Andean as both proangiogenic and antiangiogenic estrogens) and well of European ancestry (128). However, placental normal or slightly increased testosterone levels and does hypoxia in women with PE occurs in the second part of not constitute an antiangiogenic condition, similar to pregnancy, whereas residents at high altitude are exposed genetic aromatase deficiency. to a hypoxic environment throughout the pregnancy. This suggests that increased aromatase activity may be 2. HSD17B1 beneficial for placental development in the first trimester HSD17B1 is another enzyme potentially involved in but not at later stages. Nevertheless, Charles and col- PE (143, 144). Mainly HSD17B1 (145) (but also the leagues’ data, which were obtained in a very specific isoforms 3, 5, 7, 12, and 13) exhibit an activity dependent population in term of genetics and environment, may not on reductase reduced form of adenine di- be extrapolated to other populations. A recent study nucleotide phosphate and are responsible for the con- clearly underscored the role of environment in extrap- version of E1 into E2, whereas isoforms 2, 4, 6, 8, 9, 10, lacental aromatase activity by demonstrating that the 11, and 14 exhibit mostly an oxidative nicotinamide – estrogen/estrogen metabolite ratio was three times higher adenine dinucleotide dependent activity leading to the in Asian postmenopausal women living in the United conversion of E2 into E1 (146). HSD17B1 is found in States compared with Asian postmenopausal women numerous cells, including STs, CTs, stromal cells of the living in Shanghai, China (133). intervillous space (145), and EVTs (79), allowing local E2 To further support the pathologic role of aromatase synthesis during trophoblastic invasion (Fig. 1). deficiency, some gene polymorphisms (up to 88 recorded) Significantly lower plasma HSD17B1 protein levels leading to impaired aromatase expression and activity have been found in women with PE compared with women (134) have been found to be associated with PE occur- with normal pregnancies (143, 144). HSD17B1 has been rence (130). Furthermore, Kumar et al. found higher described as being dysregulated posttranscriptionally by levels of mir-19b and mir-106a in the placenta of women mir-210 and mir-518c, which are highly expressed in PE with PE compared with the placenta from gestation- placentas (143). These overexpressions could be a con- matched normotensive women (126). sequence of placental hypoxia (143). However, we did not observe any difference in HSD17B1 activity, as reflected d. Congenital aromatase deficiency and PE. Paradoxically, by E2/E1 ratios, in women with mild or severe PE com- women with placental CYP19 mutations leading to a pared with controls (37). Further evidence of a potential complete aromatase expression deficiency do not display HSD17B1 dysregulation during PE is required. PE (135–138). The only complication that arises during 3. COMT these pregnancies is virilization of both the mother and the female fetus due to an excess of circulating a. Expression and activity in pregnancy. COMT is found in (137, 138). Under these conditions, the placenta fails to numerous tissues, including brain, placenta, and artery convert D4-androstenedione into E1, giving rise to high endothelial cells (uterus, aorta, coronary) (95). Although peripheral and placental concentrations of testosterone there is only one COMT gene, specific COMT transcripts (138). Even though androgens have been shown to reduce are expressed into two forms: soluble (S-COMT) and vascular relaxation and negatively regulate placenta bound to intracellular membranes (MB-COMT) (147). The oxygenation (139), they may also promote angiogenesis latter is predominantly expressed in the brain, whereas via VEGF, as demonstrated by Sieveking et al. (140) in S-COMT is predominantly found in peripheral tissues 132 Berkane et al Low Estrogen Levels and Preeclampsia Endocrine Reviews, April 2017, 38(2):123–144

(148). Placental S-COMT significantly increases through- (c) maternal BP decrease, (d) placental cell differentiation out pregnancy (115). and proliferation, and (e) biosynthesis of estrogen pre- Several COMT regulation pathways have been de- cursors in fetal adrenal glands. Estrogens are also in- scribed in endometrial stroma cells (149) or in cancer cells volved in lactation, uterus contraction/relaxation, and (150). The placental COMT regulation pathway remains fetal development, which will not be developed here. unknown to date, and polymorphisms of this gene could Table 3 summarizes the main available data on estrogen result in low or high COMT activity. effects on the uterus and placenta. Reports on the association between the COMT polymorphisms and PE occurrence vary depending on A. Signaling pathways of estrogens in normal placenta which polymorphisms are assessed, as well as the eth- and in PE – nicity of the studied cohort (113, 115, 116, 151 156). 1. Genomic signaling pathways The genomic signaling pathway in estrogen target tis- b. COMT knockout mice and PE. BecausePEisspecificto sues has been extensively reviewed elsewhere (158–167). humans, attempts to study the occurrence of this pathologic ERs interact with specific DNA sequences (estrogen re- condition using experimental animal models are extremely sponsive elements: EREs) (159, 161) or with specific ERE- scarce. Kanasaki et al. (112) were the first to suggest that like sequence (ERE-LS) that differs slightly from the COMT is involved in PE pathophysiology. These authors 2 2 consensus ERE (123, 168, 169). For example, the effects described COMT / mice as presenting a mild PE-like of the estradiol/ERa complex on aromatase expression is syndrome with acute atherosis and glomerular endothe- mediated by an ERE-LS in the promoter region of the liosis along with low 2-ME2 levels and high placental HIF- aromatase gene (124). 1a expression until the end of gestation. The authors However, many estrogen-target genes do not possess hypothesized that low 2-ME2 enhances shallow implan- ERE or ERE-LS. In such cases, an indirect association of ER tation and placental insufficiency, which in turn decrease with DNA through different transcription factors, such as estrogen synthesis. They also suggested that substantial Sp1 or c-Fos/c-Jun complex, also called activated protein 1, placental COMT deficiency is required to trigger the syn- 2 2 2 has been shown (170, 171). This mechanism, called drome because COMT / females crossed with COMT+/ "tethering," stabilizes the DNA binding of transcription males did not present with PE. Interestingly, 2-ME2 treat- factor and/or recruits coactivators to the complex (171). ments improved placenta weights and clinical signs Although all estrogens (mainly E1, E2, E3, E4, and (proteinuria and blood pressure), which are altered during PE. catecholestrogens) bind to ERs, they display different However, even if 2-ME2 is involved in PE physiopathology, a b 2 2 affinities for each ER subtype (ER and ER ) and their the model of COMT / mice described by Kanasaki et al. isoforms, as well as different kinetics of dissociation (112) does not fit with the epidemiology of PE. A genetic 2 2 (172). E2 is the most potent effector (161). However, cause, such as COMT / , would suggest repeated PE, some metabolites of E2, such as 2-catecholestrogens, whereas most women with a history of PE have no recurrence. should actually be considered as for E2- Kanasaki et al. (112) suggested that PE-like syndrome mediated cell proliferation (173, 174) because they is due to an impaired catabolism of catecholestrogens and show a very low affinity for ERa and ERb and are as- not catecholamines, because they found no difference in sociated with a rapid kinetic dissociation. These me- dopamine, adrenaline, and noradrenaline concentrations 2 2 tabolites are also converted by COMT into 2-ME2 (161, in pregnant COMT+/+ and COMT / mice. Moreover, 175), a potent antiproliferative molecule (176). administration of an inhibitor of monoamine oxydase (which also catabolizes catecholamines) to three pregnant 2. Nongenomic signaling pathways +/+ COMT mice did not result in an increase in BP despite Nongenomic pathways of estrogen effects are also an increase in noradrenaline and adrenaline concentra- involved in vasodilation via the phosphatidylinositol-3 tions. However, not only was the sample size small, but it kinase/protein kinase B pathway, leading to endothelial was also difficult to precisely measure catecholamines NO synthase (eNOS) phosphorylation and promoting (157), so this remains to be confirmed. NO release (25–27, 177, 178). Besides NO production, E2 promotes vasodilation by inducing a rapid (5 to 15 minutes) prostacyclin synthesis, as demonstrated in VI. Signaling and Biological Effects of E2 and Its Metabolites in Pregnancy: A Key Link Between human umbilical vein endothelial cells (179). Using uterine Estrogen Deficiency and PE artery endothelial cells, another study showed that estrogen metabolites also stimulate prostacyclin production in During pregnancy, E2 and some of its metabolites pro- an ER-independent manner presumably involving G mote (a) angiogenesis, (b) vasodilation and UBF increase, protein–coupled estrogen receptor (GPER) (180). doi: 10.1210/er.2016-1065 https://academic.oup.com/edrv 133

Table 3. Main Estrogen Effects in Placenta and Uterus

Estrogen Angiogenesis Uterine Arteries Trophoblast Cells References E2 ↑VEGF ↑Blood flow through vasodilation ↑Proliferation 24, 25, 27, 97, 177–180, ++ Endothelial cells ↑VEGF, NO, PgI2,Ca (endothelial cells) ↑Differentiation 199–201, 225, 228, 230 ↑Migration Activation K+ channels CTs into STs ↑Proliferation Membrane hyperpolarization E1 No data ↑Blood flow through vasodilation No data 24 E3 No data ↑Blood flow through vasodilation No data 232 2-ME2 Inhibitor ↑Blood flow through vasodilation ↑Invasive phenotype 97, 112, 180, 210, 212, ↑ NO, PgI2 237, 238 Wall remodeling 2-OHE2 ↑Proliferation ↑Blood flow through vasodilation No data 97, 172, 173, 180 (low levels) ↓Proliferation ↑PgI2 (high levels) 4-OHE2 ↑Proliferation ↑Blood flow through vasodilation No data 97, 98, 180 (low levels) ++ ↓Proliferation ↑PgI2, blockade of Ca channels (VSM) (high levels) 4-ME2 ↑Proliferation ↑Blood flow through vasodilation No data 97, 180 ↑PgI2 E4 No data Weak vasodilator No data 92, 93, 233, 234 SERM effects? No effect on eNOS or NO production SERM effects? SERM effects?

Abbreviations: PgI2: prostacyclin; SERM, selective estrogen . ↑, Increased.

3. ER expression in placental and uterine cells expressed ERs (182, 187, 190), mainly ERb (187), whereas others reported low levels of expression or no a. Placenta expression of ERs. Studies focusing on placental expression during pregnancy in the endometrium and expression of both nuclear ER isoforms (ERa and ERb) spiral arteries (182). The mRNA expression of both report conflicting results. Although some did not find any nuclear ERa and GPER has been observed in myome- ER expression within the placenta (181–185), others ob- trium from pregnant humans. However, the ERa protein served that E2 bound to this tissue (186–188). Bukovsky is largely undetectable because of a rapid turnover by et al. (186) showed that villous CTs as well as villous proteasomal processing (191). Finally, in all but one vascular pericytes and amniotic fibroblasts express ERa. study (182), uterine vascular cells expressed both ERa They also showed that CT differentiation leading to mul- and ERb (192, 193). tinucleated STs was associated with changes in ER ex- a pression depending on the differentiation state, from ER +/ 4. ERs and PE b2 a b a2 b ER CTs into ER +/ER + young and ER /ER + Although estrogen receptors are fundamental for es- b mature STs (187). In addition, they observed that ER was trogen effects, the literature describing ERs and PE is expressed by STs, villous endothelial cells, amniotic epi- limited. Studies evaluating the potential links between thelium, and EVTs (187). In contrast, Kumar et al. (124) two polymorphisms of the ERa gene (PvuII and XbaI), a showed that ER messenger RNA (mRNA) was expressed in potentially involved in vascular disease, have yielded b CTs and increased during differentiation, whereas ER was contradictory results. A positive association of ER expressed less and declined with differentiation. For some polymorphisms with severe PE was described in a case- authors, placental characteristics affect ER expression: al- control study that included only white women (194), a though normal placentas exhibit strong ER expression, whereas no association was described in a case-control abnormal placentas with signs of senescence and/or study that included only Chinese women (195). severe villous immaturity do not express this receptor (186). ER expression could be disrupted during PE as chronic placental hypoxia has been shown to decrease B. Biological effects of estrogens in normal pregnancy and PE: the link with angiogenesis and maternal uterine and ERa expression in ovine arteries (189). systemic vascular tone b. Uterine expression of ERs. ER expression in endometrial, 1. Estrogens and angiogenesis myometrial, and vascular uterine cells has also been Angiogenesis during pregnancy is mainly regulated by studied. Some authors observed that decidual cells the angiogenic factors VEGF and PlGF (196), and crosstalk 134 Berkane et al Low Estrogen Levels and Preeclampsia Endocrine Reviews, April 2017, 38(2):123–144 with estrogens has been reported (197, 198). Interestingly, The estrogen-mediated vasodilation of the uterine ar- E2 and VEGF/PlGF have been reported as having similar teries depends on NO and eNOS because NOS inhibitors biological effects during pregnancy. Indeed, E2 also pro- decrease estrogen-induced UBF (222). Increased expres- motes uterine angiogenesis, migration, and proliferation of sion of eNOS has also been shown to be associated with endothelial cells (199–201). Numerous studies emphasize an eNOS activation during pregnancy, in both ewes (223) that a crosstalk between estrogen and angiogenic factors and women (224). E2-mediated NO and prostacyclin occurs and is mainly responsible for regulating the an- upregulation could be partially mediated by VEGF giogenesis processes (197, 198, 202–204). upregulation (225). In turn, NO stimulates VEGF syn- VEGF and PlGF share similar signaling pathways with thesis by vascular endothelial cells (226). E2 may also E2 (i.e., phosphatidylinositol-3 kinase/protein kinase B) induce vasodilation through direct nongenomic actions and activation of c-Fos and c-Jun (202–205). Moreover, on membrane ion channels of VSM (227–231). Other the VEGF gene contains a variant ERE (197) and E2 estrogens, such as catecholestrogens, may also participate upregulates VEGF (30, 197, 198), which in turn upre- in UBF increase by inducing prostacyclin synthesis and gulates PlGF and VEGF receptor 1 (VEGFR-1) expres- modifying calcium channel activities in endothelial and sion (206). Additionally, E2 upregulates the VEGFR-1 VSM cells (98). E1 (24) and E3 (232) are likewise de- gene, which contains an ERE-LS (203) and might directly scribed as powerful inducers of increased UBF and, be- upregulate VEGFR-2 expression in endothelial cells via cause E3 is a fetal byproduct, it has been suggested that the ERa/Sp1 pathway (tethering) (204). Thus, estrogens fetal “well-being” and growth are self-regulated by the modulate placental vascular cell proliferation (199–201), fetus itself. Interestingly, E4 is a weak vasodilator with no which is essential to expand the maternofetal contact effect on eNOS or NO production (233, 234). surface and uterine myocyte proliferation via several 2-ME2, which is highly increased during pregnancy pathways (207–209). (235, 236), also promotes vasodilation and increased Therefore, low E2 levels as found in PE may slow down UBF via uterine artery wall remodeling. Indeed, as shown angiogenesis as well as vasculogenesis, leading to insufficient in cultured human CTs, under low oxygen supply, placental development and maternofetal exchanges. 2-ME2 enables differentiation of CTs into invasive CTs On the contrary, the E2 metabolite 2-ME2 is a potent (237). In addition, 2-ME2 also promotes prostacyclin antiangiogenic factor with no proliferative activity (97). and NO synthesis (238). 2-ME2 inhibits both VEGF synthesis and vascular tubule E2 and its metabolites are potent uterine vasodilators. formation and induces disruption of tubulin polymeri- Consequently, their low levels during PE lead to de- zation (210). It also decreases HIF-1a, a major tran- creased oxygen supply to the feto-placental unit and scription factor induced by hypoxia that promotes VEGF placental overexpression of sFlt1, negatively affecting synthesis (112, 210–212). Following 2-OHE2 or 4- UBF and worsening the clinical situation by decreasing OHE2 treatment, a biphasic concentration-dependent steroid biosynthesis. proliferation of uterine artery endothelial cells has been shown in vitro (97). 3. Estrogens and maternal BP regulation BP is decreased during a normal pregnancy except 2. Estrogens and uterine blood flow increase during the last month, when it returns to nonpregnant Transformation from a single cell to a healthy 3.5-kg levels. This can be explained by a decrease in PlGF baby in only 9 months requires a high input of nutrients coupled with an increase in the sFlt1/PlGF ratio (239). and oxygen to the fetal unit through a considerably in- As discussed above, during normal pregnancy, estrogens creased (approximately fourfold) UBF (213). UBF change lower maternal BP through arterial vasodilation but also is mediated by a nearly 50% increase in maternal cardiac through an upregulation of HSD11B2, which converts output (214, 215), together with an increase in uterine active into inactive (240). This results in a artery vasodilation. Vasodilation begins early in preg- decrease in the vasoconstrictive activity of nancy and involves multiple effectors. During pregnancy, through receptors (241). During PE, low the classic renin–angiotensin system is activated (215), as is E2 levels may downregulate HSD11B2 expression, leading the nonclassic renin–angiotensin system (216), resulting in to systemic vasoconstriction (242, 243). vasodilation and antiproliferative and antiangiogenic ef- fects through ang 1-7, a metabolite of angiotensin II (217). 4. Estrogens and placental and uterine cell differentiation Interestingly, plasma ang 1-7 levels are lower in women and proliferation with PE than in those with normal pregnancy (216). E2 contributes to trophoblast cell proliferation but Both estrogens and progesterone induce uterine (182, also stimulates villous CT differentiation into STs, which 218, 219) and systemic (220, 221) artery vasodilation. in turn synthesize estrogens and enhance both CT doi: 10.1210/er.2016-1065 https://academic.oup.com/edrv 135 proliferation and maturation (186, 187). A U-shaped Obese individuals display high levels of blood leptin and association with placental weight has been described in low levels of blood adiponectin (254). Excessive pro- late PE when both very small and large placentas are duction of TNF-a and interleukin-6 by adipose tissue- observed (244). Low E2 levels could lead to small pla- resident macrophages has been described in both obese centas found in early PE. pregnant and nonpregnant women (253, 255). These proinflammatory adipokines display paracrine effects 5. Estrogens and regulation of estrogen precursor (local increase of leptin synthesis) (253), promote insulin synthesis by fetal adrenals resistance, and participate in the systemic low-grade in- Estrogens modulate the fetal hypothalamic-pituitary- flammatory state (253, 255–258). adrenal axis through the upregulation of placental During PE, inconsistent leptin levels have been re- HSD11B2 (245), resulting in a decrease in fetal cortisol ported (259). Nevertheless, plasma leptin levels have been concentration (242, 246). These low fetal cortisol levels found to be higher in obese women with PE than in stimulate adrenocorticotropic hormone release from the controls (254). As shown by Palei et al., leptin infusion to fetal pituitary gland, which then increases DHEA syn- normal pregnant rats increases BP and placental TNF-a thesis by the fetal adrenal glands. However, fetal adrenal synthesis (260). Whereas TNF-a stimulates aromatase a b glands express ER and ER , and their activity is con- expression in adipose tissue stromal cells (261), leptin- trolled by estrogens (247). High estrogen levels inhibit the mediated TNF-a upregulation induces an excess of CT fetal adrenal gland response to adrenocorticotropic and ST apoptosis in the placenta (262–264), thus de- hormone (247, 248). Interestingly, a marked decrease in creasing placental steroid biosynthesis. Using cultured E2 levels leads to an increase in fetal adrenal gland size term placentas incubated with different leptin concen- and an upregulation of DHEA synthesis (249). All these trations, Coya et al. found a dose-dependent decrease in findings suggest a tight retroregulation of its own pre- E2 release (265). cursor synthesis (i.e., DHEA) by E2. Therefore, low E2 levels during PE may induce higher fetal cortisol levels, B. Diabetes thus decreasing DHEA, the fetal adrenal-derived E2 Insulin resistance is the hallmark of gestational di- precursor. abetes mellitus (GDM) and type 2 diabetes and also plays a role in type 1 diabetes (266, 267). Chronic low- VII. PE Risk Factors and Estrogen Synthesis/ grade inflammation promotes insulin resistance, mainly Signaling Deficiencies via TNF-a and interleukin-6 but also via other in- flammatory cytokines (268). Maternal as well as fetal We reviewed available data on potential links between reactive hyperinsulinemia affects placental cells (269). All well-established risk factors of PE and abnormal E2 but one study (270) indicate that pregnant women with synthesis and/or signaling in order to strengthen the GDM have decreased plasma estrogen levels and in- hypothesis that PE is associated with estrogen de- creased plasma androgen levels (271, 272). Nestler (273) ficiency. Maternal conditions, such as obesity, di- reported a decrease in aromatase expression due to an abetes, and chronic hypertension, are well-known risk inhibitory effect of insulin. Uzelac et al. (271) reported factors of PE (16). Similarly, the risk of PE is increased reduced aromatase protein concentrations but no change in women with renal transplantation (250). Although in placental mRNA levels in women with GDM com- these risk factors often coexist in patients, we arbi- pared with those without GDM. This result suggests a trarily describe the specific association of each afore- posttranscriptional event. Increases in insulin-like growth mentioned condition with estrogen biosynthesis and factor I and II, which share structural similarities with signaling. insulin (271, 273, 274), seem to be involved as well (274), although controversial results have been reported about A. Obesity insulin-like growth factor I and II plasma levels during Over two thirds of women of reproductive age are GDM or type 2 diabetes (275). overweight or obese in the United States (251) (i.e., with a body mass index .25 and .30 kg/m2, respectively). C. Chronic hypertension Central distribution of body fat (marker of visceral fat) is Chronic hypertension is estimated to be present in 3% the main risk factor for cardiovascular disease, including to 5% of pregnancies (276). Potential causes of chronic PE (252). Adipocytes/adipose tissue-resident macro- hypertension could be an excess of oxidative stress and phages produce estrogens by converting androgens chronic low-grade inflammation (277). On the basis of through CYP19 aromatization (119) and also synthesize the obesity model, we suggest that the low-grade in- leptin, adiponectin, and several other molecules (253). flammation present in chronic hypertension induces 136 Berkane et al Low Estrogen Levels and Preeclampsia Endocrine Reviews, April 2017, 38(2):123–144 endothelial dysfunction and placental inflammation and therefore its activity, is highly tissue specific. To our could enhance placental necrosis/apoptosis and insulin knowledge, placental aromatase regulation by resistance, thus contributing to E2 deficiency, which has not been evaluated yet. All in all, these data open up could lead to PE. an interesting potential therapeutic field with use of es- trogen itself or regulators of its synthesis and activities D. Kidney transplantation that deserves to be further explored. Women with a kidney transplant represent a paradigm of high vascular risk. These patients frequently gain IX. Future Directions weight early after transplantation, leading to overweight or obesity (278). They also commonly present with some Abnormal estrogen levels and dysregulation of the en- degree of chronic renal insufficiency and chronic hy- zymes involved in estrogen biosynthesis have been de- pertension. It has been suggested that in such women, scribed during PE. An increasing number of studies chronic hypertension is associated with subclinical ath- highlight a marked decrease of estrogens in maternal erosclerosis and inflammation (279). This pattern could circulation, especially E2, the most potent ER . be related to numerous factors, such as immune response However, published studies report conflicting results, to the grafted tissues and possibly disease-related renal possibly due to small sample sizes and mixed PE types impairment. As described above, chronic inflammation (early and late onset). Moreover, most of the studies could promote endothelial injury, placental apoptosis, focused only on specific targeted steroids rather than and insulin resistance and then facilitate the subsequent comprehensive steroid profiling and also failed to assess disruption of placental steroidogenesis. Finally, in addi- their bioactivity. The mechanisms of E2 deficiency may tion to kidney disease itself, drugs such as prednisone not include changes in the regulation of expression of the only induce diabetes (280) but also enhance placental main steroidogenic enzymes (aromatase, HSD17B1), vasoconstriction, induce fetal and placental growth re- possibly via miRNAs and transcription factors such as striction, and prevent normal vascularization in rat USF1 and 2. placenta via a reduction in VEGF expression (281). However, the major role of estrogens during physio- Similarly, cyclosporine (282) as well as tacrolimus can logic placental development and pregnancy supports the induce hypertension, and the latter increases the in- hypothesis that low estrogen levels may play a central role flammatory state (283). in PE physiopathology. Moreover, the close interaction Although all these risk factors of PE can promote between estrogens and angiogenic/antiangiogenic bal- direct systemic endothelial injury, they also have a neg- ance, which are known to contribute to the pathophys- ative effect on the placenta, including inflammation and iology of PE, reinforces the “estrogen hypothesis.” This excess of placental necrosis/apoptosis, as well as affecting includes both regulation of angiogenic/antiangiogenic aromatase production. They may thus induce an estrogen factors by E2 and the common molecular regulatory deficiency, which further strengthens arguments for the pathways of placental and vascular functions. role of estrogen in PE. Further studies are required to confirm previous findings and develop clinical applications. We would VIII. Therapeutic Implications encourage larger studies with comprehensive steroid profiling using only analytically reliable MS procedures. Attempts to prevent PE by estrogen supplementation Major pending issues for clinical applications include remain limited. Kanasaki et al. (112) successfully reverted the following: (a) determining whether estrogen de- PE features with a subcutaneous administration of 2- ficiency is a consequence of a hypoxic placenta or rather 2 2 ME2 in COMT / mice. Djordjevi´c et al. (284) showed the cause or one of the initial causes of PE, (b) evaluating that intramuscular short-term administration of E2 in potential useful biomarkers of estrogens for PE screening, women with PE reduced mean arterial BP. Furthermore, and (c) assessing whether natural estrogens and/or ER genistein, a with ERb selectivity as well as and/or selective estrogen receptor modulator are an affinity for GPER (285, 286), has also been assessed in potential treatment lines for PE. the prevention of PE (287). In a case-control study, Fernandez et al. showed that women with the lowest Acknowledgments genistein intake were four times more likely to develop PE than women with the highest genistein intake (287). We thank Dr. Jessica Vincent for her help in designing Fig. 1 and Felicity The mechanisms of action of genistein may include Neilson for English-language editing. GPER binding, SF1 activation, and aromatase modula- Address all correspondence and requests for reprints to: Nadia tion. The regulation of aromatase expression, and Berkane, MD, Department of Gynecology and Obstetrics, HUG, doi: 10.1210/er.2016-1065 https://academic.oup.com/edrv 137

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