Abnormal steroidogenesis and aromatase activity in preeclampsia
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
References (56)
- et al.
WHO analysis of causes of maternal death: a systematic review
Lancet
(2006) - et al.
Placental production of estradiol and progesterone after oocyte donation in patients with primary ovarian failure
Am. J. Obstet. Gynecol.
(1990) - et al.
Hormones in human pregnancy. IV. Plasma progesterone
Am. J. Obstet. Gynecol.
(1975) - et al.
Progestins activate vascular endothelial growth factor gene transcription in endometrial adenocarcinoma cells
Fertil. Steril.
(2003) - et al.
Estrogen augments the vasodilatory effects of vascular endothelial growth factor in the uterine circulation of the rat
Am. J. Obstet. Gynecol.
(2000) Définitions et conséquences des hypertensions artérielles de la grossesse
Ann. Fr. Anesth. Reanim.
(2010)- et al.
2-Methoxyestradiol deficiency is strongly related to hypertension in early onset severe pre-eclampsia
Pregnancy Hypertens
(2014) - et al.
Enzyme-mediated protection of the mineralocorticoid receptor against progesterone in the human kidney
Mol. Cell. Endocrinol.
(2001) - et al.
Hypertensive disorders and severe obstetric morbidity in the United States
Obstet. Gynecol.
(2009) Angiogenic factors in preeclampsia: from diagnosis to therapy
Hypertension
(2016)
Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice
Ultrasound Obstet. Gynecol.
New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia
Hypertension
Serum levels of progesterone in patients with preeclampsia
Wien Klin. Wochenschr.
Angiogenic factors in diagnosis, management, and research in preeclampsia
Hypertension
Steroid profiling in preeclamptic women: evidence for aromatase deficiency
Am. J. Obstet. Gynecol.
Aberrant synthesis, metabolism, and plasma accumulation of circulating estrogens and estrogen metabolites in preeclampsia implications for vascular dysfunction
Hypertension
From pregnancy to preeclampsia: a key role for estrogens
Endocr. Rev.
Studies on the metabolism of C-21 steroids in the human feto-placental unit.I. Formation of a beta-unsaturated 3-ketones in midterm placentas perfused in situ with pregnenolone and 17-alphahydroxypregnenolone
Acta Endocrinol.
Placental estrogen biosynthesis during human pregnancy
J. Clin. Endocrinol. Metab.
Estrogens in pregnancy
Vitam. Horm.
Pregnancy and laboratory studies: a reference table for clinicians
Obstet. Gynecol.
Vascular effects of 17 beta-estradiol in male Sprague-Dawley rats
Am. J. Physiol.
Sex steroids modulate uterine-placental vasculature: implications for Obstetrics and neonatal outcomes
Front. Physiol.
Placental expression of estrogen receptor beta and its hormone binding variant–comparison with estrogen receptor alpha and a role for estrogen receptors in asymmetric division and differentiation of estrogen-dependent cells
Reprod. Biol. Endocrinol.
Expression and localization of estrogen receptor-alpha protein in normal and abnormal term placentae and stimulation of trophoblast differentiation by estradiol
Reprod. Biol. Endocrinol.
Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model
Circulation
Estrogen and angiogenesis: a review
Arterioscler. Thromb. Vasc. Biol.
The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis
Nat. Commun.
Cited by (35)
Comparative steroid profiling of newborn hair and umbilical cord serum highlights the role of fetal adrenals, placenta, and pregnancy outcomes in fetal steroid metabolism
2023, Journal of Steroid Biochemistry and Molecular BiologyHuman HAND1 inhibits the conversion of cholesterol to steroids in trophoblasts
2022, Journal of Genetics and GenomicsCitation Excerpt :To gain an insight into the pathophysiological relevance of HAND1 in P4 and E2 production, we thereby further took advantage of pre-eclamptic and normal placental tissues and examined HAND1 expression as well as the expression of Aromatase, P450scc, and 3β-HSD1. Notably, HAND1 mRNA expression was obviously increased in the pre-eclamptic group (Fig. S1F), whereas Aromatase mRNA expression was significantly reduced by almost 75%, compared with the normal group (Fig. S1F), which is consistent with a previous report showing aromatase expression is decreased in pre-eclamptic placentas (Berkane et al., 2018). Likewise, the mRNA expression of 3β-HSD1 was apparently declined by nearly 50% in pre-eclamptic placental tissues (Fig. S1F).
Prenatal exposure to pesticides and risk of preeclampsia among pregnant women: Results from the ELFE cohort
2021, Environmental ResearchCitation Excerpt :Interestingly, PAI-1 levels increased in women with early-onset preeclampsia (24–32 gestational weeks) compared with the control group, but not in late-onset preeclampsia (35–42 gestational weeks) (Ye et al., 2017), a finding consistent with the association between prochloraz exposure and early preeclampsia. Second, prochloraz inhibits aromatase activity in placental cells (Laville et al., 2006; Sanderson et al., 2002; Vinggaard et al., 2000), and both the expression and function of placental aromatase are known to be diminished in pregnancies complicated by preeclampsia (Berkane et al., 2018; Perez-Sepulveda et al., 2015). Our results on residential proximity to agricultural applications are similar to those of Shaw et al. (2018), who observed a statistically significant inverse association between pyrethroids (chemical family including cypermethrin) and preeclampsia (OR = 0.79; 95% CI: 0.66, 0.94).
Apoptotic endocrinal toxic effects of perchlorate in human placental cells
2021, Toxicology ReportsCitation Excerpt :CYP19 A1 is one of the multiple enzymes involved in placental steroid biosynthesis and its endocrine function. Its alteration had been detected in pre-eclamptic and intrauterine growth retardation placentas [26,27]. We investigated the placental activity of CYP19A1.
Placental production of progestins is fully effective in villous cytotrophoblasts and increases with the syncytiotrophoblast formation
2020, Molecular and Cellular EndocrinologyCitation Excerpt :Further investigations would be required as these pathways can be altered in pathological pregnancies or by endocrine disruptors (Byrns, 2014; Berkane et al., 2018; Shan et al., 2019).
Placental progesterone and its receptor in HIV-infected pre-eclamptic women
2024, Histochemistry and Cell Biology
- 1
These authors contributed equally to this work.
- 2
Present address: Department of Gynecology and Obstetrics, University of Geneva Hospitals (HUG), Geneva, Switzerland.