Elsevier

Placenta

Volume 69, September 2018, Pages 40-49
Placenta

Abnormal steroidogenesis and aromatase activity in preeclampsia

https://doi.org/10.1016/j.placenta.2018.07.004Get rights and content

Highlights

  • Abnormal steroidogenesis occurs long before clinical signs of preeclampsia (PE).

  • Preeclamptic women had a specific aromatase defect at 24–29 weeks of gestation.

  • Preeclamptic women had lower placental aromatase expression at delivery.

  • Pregnancies with PE and “placental” SGA had increased 20α-dihydroprogesterone levels.

  • Pregnancies with “placental” SGA are associated with low estriol levels.

Abstract

Introduction

Estrogens and progesterone play critical roles in angiogenesis and vasodilation. Moreover, placental aromatase deficiency is detected in women with preeclampsia (PE) at delivery. We hypothesized that abnormal steroidogenesis occurs much earlier than typical PE diagnosis. Thus, we investigated whether the circulating steroid profile was already disturbed at 24–29 weeks of gestation in women with subsequent PE, and compared the profile with that of women with “placental” small gestational age (SGA) without PE.

Methods

We selected nulliparous women (n = 90) from the MOMA trial, including women with PE (n = 25), SGA (n = 25), and controls (NP; n = 40), for plasma steroid profiling by gas chromatography/mass spectrometry and to measure placental growth factor and soluble fms-like tyrosine kinase-1. Placental aromatase expression was evaluated in a new set of women.

Results

Compared with that of controls, the women with PE had a significantly lower estrone/androstenedione ratio, and exhibited a decreasing trend for estradiol and estrone levels. Lower estriol levels were observed in the SGA group compared to the NP group. Compared with that of controls, the women with PE and SGA had significantly higher levels of 20α-dihydroprogesterone (20α-DHP) and 20α-DHP/progesterone ratios. Pregnenolone sulfate levels were lower in the PE group than in the NP and SGA groups. Decreased expression of aromatase was observed in the PE group compared to the control group.

Discussion

Preeclampsia appears to be characterized by specific steroidogenesis dysregulation long before PE diagnosis, highlighting potential new biomarkers of PE.

Introduction

Preeclampsia (PE) is a placental disorder that causes maternal and fetal mortality worldwide [1,2]. Preeclampsia is mainly characterized by an imbalance between angiogenic and anti-angiogenic factors [3]. Although the contribution of these factors, such as placental growth factor (PlGF) and soluble vascular endothelial growth factor receptor 1 (VEGFR1, also known as soluble fms-like tyrosine kinase-1 [sFlt1]), to the initial placental defect is debatable, their measurement in maternal blood has a potential for routine use in PE diagnosis [[4], [5], [6], [7]].

Abnormal placental steroidogenesis has also been reported in women with PE [[8], [9], [10]]. In human and some non-human primate pregnancies, steroidogenesis takes place in the placenta and is characterized by a luteo-placental shift, which is complete before 9 weeks of gestation [11]. However, the human placenta lacks 17,20 lyase, which converts progesterone (P4) and pregnenolone into the estrogen precursors androstenedione (Δ4-ADIONE) and dehydroepiandrosterone (DHEA), respectively [12,13]. Therefore, estrogen synthesis relies on DHEA sulfate (DHEAS) produced in the fetal and maternal adrenal glands (Supplemental Figure 1) [12,13]. At the end of pregnancy, maternal blood concentrations of the most active estrogen, estradiol (E2), are 100-fold higher compared with those of non-pregnant women, reaching 30 nmol/L [14,15], whereas P4 levels are almost 100-fold higher than those during the luteal phase, reaching approximately 300 nmol/L at delivery [10,16].

Estrogens and P4 reduce systemic and uterine maternal blood pressure and increase uterine blood flow [[17], [18], [19]]. E2 also stimulates trophoblast proliferation and the differentiation of cytotrophoblasts into syncytiotrophoblasts [10,20,21]. Moreover, E2 and most of its metabolites, along with P4, promote uterine angiogenesis and endothelial cell migration and proliferation [10,19,22,23]. Interestingly, both E2 and P4 have pathways in common with VEGF and PlGF and directly or indirectly up-regulate VEGF, PlGF, and VEGFR-1 syntheses [10,18,24]. Some authors have postulated that E2 and P4 act through these angiogenic factors [25]. Aromatase (CYP19A) is a rate-limiting enzyme for estrogen biosynthesis, which converts Δ4-ADIONE into E1 in the placenta. Early blockade of estrogen synthesis by letrozole, a specific aromatase inhibitor, impairs new endometrial blood vessel growth in mice and represses numerous angiogenesis-related genes [26].

By gas chromatography/mass spectrometry (GC/MS), we previously identified impaired placental aromatization of androgens in women with PE at delivery, and a 50–70% decrease in serum E2, which correlated with disease severity [8]. These findings were independently confirmed by Jobe et al. [(9)] by liquid chromatography/mass spectrometry [8,9]. Recently, reduced placental aromatase expression and functionality were also detected in pregnancy with PE [27].

This background suggests that aromatase deficiency, leading to low estrogen levels, might modify both the angiogenic/anti-angiogenic balance and the uterine vasculature properties, thereby promoting the clinical features of PE. Accordingly, we hypothesized that PE is associated with specific steroidogenesis dysregulation, including an aromatase defect that could occur long before typical clinical signs leading to diagnosis. To test this hypothesis, in this study, we investigated (1) whether the maternal circulating steroid profile was already disturbed at 24–29 weeks of gestation in women with subsequent PE and (2) if this profile was specific to PE by comparing with that of a group with “placental” small for gestational age (SGA) without PE. Indeed, these conditions share common histopathologic placental findings but different clinical features [28]. For this purpose, we performed GC/MS-based steroid profiling in the plasma of three groups of women at 24–29 weeks of gestation classified by diagnosis at delivery: normal pregnancy (NP), PE, and SGA. The archived plasma from women included in the MOrbiMortality Amelioration in preeclamptic nulliparas (MOMA) trial (NCT00763672, unpublished data) was used. The blood sampling period, i.e., 24–29 weeks of gestation, was chosen for the MOMA trial to allow the identification of both early (<34 weeks of gestation) [29] and late PE, while still early enough to propose interventions as necessary. In addition, protein and RNA levels of aromatase in the placenta were analyzed in a distinct set of two groups of women with or without PE.

Section snippets

Study population

The study population consisted of the first 90 consecutive women included in the MOMA trial with completed files and final diagnoses (postpartum) of PE, SGA, or NP. No women presented with signs of PE during plasma sampling.

The MOMA trial was a randomized, controlled trial (NCT00763672) conducted from April 6, 2008 to April 20, 2011 to evaluate the effects of close monitoring of women identified to be at high risk of PE for maternal and fetal mortality and/or severe morbidity related to

Population study

Ninety women—40 NP, 25 with PE, and 25 with SGA—were included in this study. Baseline characteristics of the population and infant outcomes are presented in Table 1, Table 2. None of the pregnant women received corticosteroids before blood sampling, which occurred at a mean of 186 days of gestation in all three groups. Per the inclusion criteria, birth weight differed among the three groups. Diabetes and abnormal uterine artery Doppler were more frequent in the PE group, and tobacco use was

Discussion

Our data suggest a specific decrease in aromatase activity at 24–29 weeks gestation in women who subsequently presented with PE. Conversely, low E3 levels were found in the group of women who presented with SGA without PE. Moreover, both the PE and SGA groups were characterized by abnormal P4 metabolism with excess of 20α-reduced metabolites. We also found that the PlGF and sFlt1 levels correlated with steroid concentrations. Perez-Sepulveda et al. [27] demonstrated that a low E1/Δ4-ADIONE

Conflicts of interest

None.

Disclosure

The authors report no conflict of interest.

Acknowledgments

The MOMA trial was supported by grants from the Contrat de Recherche Clinique, French Ministry of Health (CRC05143-P051060); the sponsor was Assistance Publique des Hôpitaux de Paris (APHP). The GC/MS analysis was supported by a 2012 grant from the Conseil Regional d’Île-de-France (CORDDIM, grant #cod120162). Alexandre Hertig is the recipient of an Interface contract with the French National Institute of Health and Medical Research (INSERM). The study sponsors were not involved in the study

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    1

    These authors contributed equally to this work.

    2

    Present address: Department of Gynecology and Obstetrics, University of Geneva Hospitals (HUG), Geneva, Switzerland.

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