|Year : 2017 | Volume
| Issue : 1 | Page : 55-61
Estrogen Biosynthesis and Its Regulation in Endometriosis
Qiu-Ming Qi1, Sun-Wei Guo2, Xi-Shi Liu2
1 Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
2 Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, China
|Date of Web Publication||17-Jul-2017|
Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University Shanghai College of Medicine, 419 Fangxie Road, Shanghai 200011
Source of Support: None, Conflict of Interest: None
Endometriosis is a common benign gynecological disorder with an enigmatic etiology and pathogenesis. It affects approximately 10% women of reproductive age. Although its etiology and pathogenesis remain poorly understood, it is characterized by the elevated local production of estrogen in the endometriotic tissues. In this paper, we review the mechanisms of estrogen biosynthesis and its regulation in endometriosis.
Keywords: 17 beta-Hydroxysteroid Dehydrogenase Type 2; Aromatase; Endometriosis; Estrogen Biosynthesis; Steroidogenic Acute Regulatory Protein
|How to cite this article:|
Qi QM, Guo SW, Liu XS. Estrogen Biosynthesis and Its Regulation in Endometriosis. Reprod Dev Med 2017;1:55-61
| Introduction|| |
Endometriosis, defined to be the presence of endometrium-like tissues outside the uterine cavity, is a common benign gynecological disorder with an enigmatic etiology and pathogenesis. It affects approximately 10% women of reproductive age, causing dysmenorrhea, pelvic pain, and infertility. Since estrogen is the major proponent for the growth of ectopic endometrium, the main medical treatment for endometriosis has so far focused on the hormonal alteration of the menstrual cycle to create an acyclic, low-estrogenic environment in eutopic and ectopic endometrium, with a major goal to produce a pseudopregnancy, pseudomenopause, or chronic anovulation status. Typically, the treatment is carried out either by blocking ovarian estrogen secretion (with gonadotropin-releasing hormone agonists or antagonists), by inducing pseudopregnancy (with progestin), or by locally inhibition of estrogenic stimulation of the ectopic endometrium (with aromatase inhibitor). Since estrogen plays a vital role in the maintenance and progression of endometriosis, in this paper, we review the mechanism underlying the estrogen synthesis and its regulation in endometriosis.
| Estrogen Biosynthesis and Metabolism in Humans|| |
In women with endometriosis, estrogen in the endometriotic tissues arise from two major sources: blood circulation and tissues secretion in situ. The first and also the usual way of estrogen production in normal women is estrogens (estradiol [E2] and estrone [E1]), which are secreted by the ovary reaching the endometriotic tissues through the blood circulation. In the preovulatory ovarian follicle, E2 is produced by theca and granulosa. Moreover, during ovulation follicular rupture and large amounts of E2 spill directly into the pelvic implants. In addition, aromatase (P450arom) that resides in the tissues outside ovary, such as peripheral fat and skin tissues, catalyzes the conversion of circulating androstenedione to E1 that may also reach endometriotic lesions through blood circulation and is subsequently converted locally to E2. The second source of estrogens is cholesterol, which is converted directly to E2 on site by steroidogenic enzymes in endometriotic tissues. In contrast to circulating estrogens, steroidogenic proteins present within endometriotic tissues may give rise to local production of estrogen., Endometriotic tissues have the ability to synthesize E2de novo from cholesterol, because there is a full complete set of steroidogenic enzymes within endometriotic stromal cells.,,, First, cholesterol is facilitated into the mitochondrion by steroidogenic acute regulatory protein (StAR). In the mitochondrion, cholesterol is converted to pregnenolone by cytochrome P450 side-chain cleavage (P450scc), which is then converted to progesterone via 3-hydroxysteroid dehydrogenase type 2 (HSD3B2); after that, cytochrome P450 17α-hydroxylase/17, 20-lyase (P450c17) catalyzes progesterone to androstenedione, and then P450arom converts androstenedione to E1, which is further converted to E2 by 17 beta hydroxysteroid dehydrogenase type 1 (HSD17B1)., The E2 can be converted to E1 by 17 beta hydroxysteroid dehydrogenase type 1 (HSD17B2), the enzyme mostly expressed in the epithelial cell component., E2, an estrogen with potent biological activity, serves as a potent mitogen in accelerating cellular proliferation and inhibiting cellular apoptosis, and it may promote the development and maintenance of endometriosis.
In the serial enzymatic conversions in E2 synthesis, the rate-limiting steps include the facilitated entry of cholesterol into the mitochondrion by StAR and the conversion of precursor substance to E1 by P450arom. In contrast to endometriotic lesions, normal endometrium does not have the ability to synthesize estrogen due to the absence of StAR and P450arom expression. Moreover, it has been reported that STAR (the gene coding for StAR) and CYP19A1 (the gene coding for aromatase) mRNA presented only in stromal but not epithelial compartment of endometriotic lesions.,,, HSD17B2 is believed to be one of the most important estrogen-metabolizing enzymes in the endometrium. In the normal endometrium or eutopic endometrium of women with endometriosis, there is a high level of HSD17B2 mRNA expressed in the epithelial cell component., This enzyme could efficiently convert the biologically potent estrogen E2 to weakly estrogenic E1,,, which plays a role in the balance of the local estrogen levels and the protection of the endometrium. In ectopic endometrial tissues, the expression of HSD17B2 is absent in epithelial cells, which results in a defect of estrogen inactivation and an accumulation of estrogen with high bioactivity in endometriotic lesions., Both mechanisms, including increase E2 production in endometriotic stromal cells and defect E2 metabolism in endometriotic epithelial cells, contribute to the local estrogen accumulation in endometriosis.
| Prostaglandin E 2 and Estrogen Biosynthesis in Endometriosis|| |
Prostaglandin E2 (PGE2), known to be a potent stimulator in steroidogenesis, plays a key role in the estrogen biosynthetic pathway in endometriotic tissues. PGE2 can induce expression of all steroidogenic genes necessary for estrogen biosynthesis de novo from cholesterol, including StAR, aromatase, and other essential steroidogenic genes expressed in endometriotic stromal cells, giving rise to increased local estrogen production in endometriosis.,,, Of which, the most striking inductions stimulated by PGE2 are observed for STAR and CYP19A1.,, Both endometriotic and endometrial stromal cells express four PGE2 receptor subtypes, namely, EP1, EP2, EP3, and EP4., PGE2, through binding and subsequently activation of EP2 or EP4, can activate the protein kinase A (PKA) signaling pathway via raising the intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP),,, which could enhance the binding of steroidogenic factor-1 (SF-1) to promoters of these steroidogenic genes, and induce phosphorylation of the transcriptional activator cAMP-response element-binding protein (CREB), which acts as an initiator to unfold the DNA-histone binding and then provides space for CCAAT/ enhancer binding proteins (C/EBP) binding to the promoter of these steroidogenic genes. The binding of SF-1 and CREB to the promoters of steroidogenic genes is responsible for inducing the expression levels and activity of these enzymes, thus promoting the estrogen biosynthesis in endometriotic stromal cells.,,
Cyclooxygenase-2 (COX-2) is the rate-limiting enzyme that catalyzes the initial step in the synthesis of prostaglandins from arachidonic acid. COX-2, upregulated in endometriotic stromal cells but not in normal endometrium,,, is able to further increase the PGE2 production in endometriotic lesions. The overexpression of COX-2 gene leads to an elevation of PGE2 and steroid converting enzymes, and thus COX-2 expression is correlated with the expression of enzymes involved in the elevation of PGE2 and thus excessive estrogen synthesis in endometriosis. Many investigators have demonstrated that some pro-inflammatory mediators, such as nuclear factor-κB (NF-κB), interleukin-1β (IL-1β), vascular endothelial growth factor (VEGF), and hypoxia inducible factor-1α (HIF-1α), could induce COX-2 in endometriotic and endometrial stromal cells.,,, In addition, PGE2 itself and E2 in lesions could further increase COX-2 expression in endometriotic stromal cells. Thus, there is a positive-feedback loop between inflammation and estrogen production in endometriosis. The loop favors the overexpression of COX-2, which further lead to redundant PGE2 formation, overexpression of key steroidogenic genes, and the continuous production of local E2 from cholesterol in endometriotic tissues, as depicted in [Figure 1].
|Figure 1: A schematic demonstration depicted the estrogen biosynthesis and its regulation in endometriosis. A full complete set of steroidogenic enzymes expressed in endometriotic tissues. In the endometriotic stromal cells, cholesterol is de novo converted to E2 by six enzymes, namely StAR, P450scc, HSD3B2, P450c17, P450arom, and HSD17B1. The inflammatory substances can induce the expression of COX-2, which catalyzes AA to synthesis of PGE2 in endometriotic stromal cells. PGE2, through binding to and subsequently activation of EP2 or EP4, can activate the PKA signaling pathway via raising the intracellular levels of cAMP, which could enhance binding of SF-1 and CREB to promoters of steroidogenic genes to promote E2 synthesis in endometriotic stromal cells. High levels of local E2 (through ER-β) and PGE2 in turn to induce COX-2 expression, which results in overexpression of steroidogenic genes, overexpression of COX-2, and continuous local production of E2 and PGE2 in endometriotic tissue. HSD17B2, expressed in epithelial cells, is the main enzyme for metalizing E2 to E1 in endometriotic tissue. Progesterone induces the expression of epithelial HSD17B2 by activating stromal PR-B, which can mediate the formation of RA to bind to the promoter and thus activation of HSD17B2. In endometriotic tissue, the decreased PR-B levels in the stromal cell disrupt the paracrine action of progesterone. ER-β suppresses ER-α and PR-B, leading to progesterone resistance and deficient inactivation of E2 in endometriotic tissue.[6,28] AA: Arachidonic acid; PGE2: Prostaglandin E2; RA: Retinoic acid; COX-2: Cyclooxygenase-2; A: Androstenedione; E1: Estrone; E2: Estradiol; SF-1: Steroidogenic factor-1; CREB: cAMP-response element-binding protein; StAR: Steroidogenic acute regulatory; P450scc: Cytochrome P450 side-chain cleavage; HSD3B2: 3-hydroxysteroid dehydrogenase type 2; P450c17: Cytochrome P450 17a-hydroxylase/17, 20-lyase; HSD17B1: 17 beta-hydroxysteroid dehydrogenase type 1; HSD17B 2: 17 beta-hydroxysteroid dehydrogenase type 2; PKA: Protein kinase A; ER-α: Estrogen receptor-α; ER-β: Estrogen receptor-β.|
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| A Molecular Link between Inflammation and Estrogen Production|| |
Endometriosis is considered to be a disease characterized by inflammation, with overexpression of a large number of inflammatory cytokines, growth factors, and chemokines in the endometriotic tissues, which are likely to play important roles in the initiation, progression, and maintenance of endometriosis.,,,, An autoregulatory loop model reviewed by Bulun et al. demonstrates a molecular link between inflammation and estrogen production in endometriotic tissues that the inflammatory substances can induce steroidogenic enzymes activity via PGE2-dependent pathway in endometriosis [Figure 1], which results in overexpression of steroidogenic genes, overexpression of COX-2, and continuous local production of E2 and PGE2 in endometriotic tissue.,,,
As an inflammatory transcription factor, NF-κB is known to play a pivotal role in many chronic inflammatory diseases. It is also implicated in the pathogenesis of endometriosis that NF-κB is involved in inflammation, proliferation, apoptosis, and angiogenesis., NF-κB activation in endometriotic cells could stimulate inflammation, induce pro-inflammatory cytokines and chemokines production, and further favor the development and maintenance of endometriosis. It is reported to be more active in the endometrium of patients with endometriosis and other estrogen-dependent pathologies, responsible for the activation of genes involved in the inflammatory cascade, and to play a role in activation of steroidogenic genes expression in endometriosis. Some downstream molecules of NF-κB, such as COX-2, VEGF, and HIF-1α, have been reported to be overexpressed in endometriotic lesions., The activation of NF-κB would further increase the production of pro-inflammatory cytokines and chemokines by upregulating its downstream target genes,, such as COX-2, and in addition the increased aromatase activity. This constitutes a positive-feedback loop as described by Bulun, resulting in increased local estrogen production in endometriotic lesions. In addition, the production of pro-inflammatory cytokines could further promote NF-κB activation in turn. Therefore, the increased inflammation may reflect the increased production of estrogens in endometriosis that increases inflammation through COX-2 activation and NF-κB activation, yielding the end result of elevated levels of PGE2 and E2.
| Transcription Factors That Regulate Estradiol Biosynthesis in Endometriosis|| |
Estrogen overproduction in endometriosis is due to an elevated SF-1 expression and CREB activation, both of which play roles in inducing steroidogenic enzymes overexpression., The orphan nuclear receptor SF-1 is responsible for coordinately activating the full steroidogenic cascade of genes. In human endometriotic stromal cells, PGE2 regulate the production of enzymes in steroidogenesis by inducing SF-1. The absence of SF-1 expression in normal endometrial cells is one of the major causes of irresponsiveness of steroidogenic genes to PGE2. CREB plays a cooperative role with SF-1 in regulating steroidogenic genes transcription. It works as an initiator to unfold the DNA-histone binding, which then provides room for C/EBP binding to the promoter of steroidogenic genes stimulated by PGE2, via induced phosphorylation of the transcriptional activator, which causes CBP recruitment and histone H3 acetylation. It has been well documented that PGE2-dependent steroidogenesis in ectopic endometrial stromal cells is mediated by molecular mechanisms downstream of cAMP.,, PGE2 increases intracellular cAMP levels via the EP2 or EP4. PKA activation results in phosphorylation of CREB, which facilitates its binding to CREB-responsive element on the promoter region of the STAR gene, aromatase, or other steroidogenic genes.,, In addition, transcriptional inhibitors of steroidogenic gene promoters, such as chicken ovalbumin upstream promoter transcription factor, Wilms' tumor 1 transcription factor, and CCAAT/enhancer binding protein β, are responsible for the silencing of these steroidogenic genes., The expression levels of these repressors are much higher in normal endometrium than in endometriotic tissue, whereas in the absence of SF-1, a transcriptional complex composed of repressors binds the steroidogenic promoters and suppresses them in endometrial cells.
| Estrogen Metabolism and Progesterone Resistance in Endometriosis|| |
HSD17B2 is one of the most important estrogen metabolizing enzymes. The HSD17B2 enzyme activity and mRNA were found to be stimulated by progesterone, which is mediated via progesterone receptors in endometrial stromal cells to induce formation of paracrine factors (such as retinoic acid [RA]) that in turn stimulate neighboring epithelial cells to express the enzyme HSD17B2,, leading to the conversion of E2 to E1. In normal endometrium, the paracrine factor RA activates the expression of the receptors retinoid A receptor or retinoid X receptor, which would further bind to the specificity protein (Sp1 or Sp3) to form a transcriptional regulation complex that regulates HSD17B2. Progesterone exerts an antiestrogenic effect in endometrium. However, in endometriotic tissue, progesterone is incapable of inducing epithelial HSD17B2 expression due to a defect progesterone receptor (PR) expression, possibly due to promoter hypermethylation of PR isoform B (PR-B); hence, no paracrine factors are produced in stromal cells. This results in a deficiency of metabolism of E2 in endometriosis, giving rise to high local concentrations of this potent mitogen, which in turn promotes the growth of the endometriotic lesions. In addition, the defective PR expression may also cause the endometrial stromal cells unresponsive to progesterone, resulting in progesterone resistance in endometriotic tissues., Therefore, the expression of PR and the variation of the PR subtypes (the ratio between PR-A and PR-B) may have important effect on the paracrine factors such as RA or Sp1/Sp3., The transcriptional activation of the HSD17B2 promoter would be blocked, and result in decreased expression or acyclic expression of HSD17B2 in epithelial cells, causing an accumulation of estrogen with high bioactivity and progesterone resistance in endometriotic lesions.,
| Epigenetic Changes of Steroidogenic Genes in Ectopic Endometrium|| |
A large number of studies have shown that some key factors for estrogen synthesis and estrogen action are associated with the promoter methylation status of the relevant genes. Endometriotic lesions aberrantly overexpress the whole set of steroidogenic genes, including STAR, CYP11A1, CYP17A1, CYP19A1, and HSD17B1, resulting in increased local E2 synthesis that could support the growth of lesions independent of ovarian E2. Expression of the steroidogenic genes in endometriotic tissues is regulated by SF 1coded by short for NR5A1 (nuclear receptor subfamily 5, group A, member 1). The expression of SF-1 is absent in normal endometrium but its expression level in endometriotic tissue is reported to be more than 12,000 times higher. SF-1 in the endometrium is silenced by heavy promoter methylation; however, it is demethylated in the SF-1 promoter in endometriosis, causing its overexpression. In turn, de novo SF-1 activation is thought to regulate the expression of the steroidogenic enzymes and to play a pivotal role in sustained survival of endometrial tissue at the ectopic sites by promoting a high level estrogenic state. Aromatase is the key regulator in the estrogen production in endometriotic tissues, with a much higher expression of CYP19A1 mRNA in eutopic and ectopic endometrium of endometriosis., CYP19A1 is reported to be hypomethylated in endometriotic tissues., Estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β) are both transcription factors that play important roles in endometrium from both normal and endometriosis.ER-α is encoded by the ER-α gene and plays roles in estrogen action primarily in the stromal cells in normal endometrium. However, stromal cells derived from endometriotic tissues are found to display increased expression of ER-β, or about 140 times higher than that of normal endometrium, likely as a result of aberrant hypomethylation of the ER-β promoter, whereas ER-αlevels are 9 times higher in endometrium than that in normal endometrium.,ER-β in endometriotic stromal cells occupies the ER-α promoter and down-regulates its activity, thus favoring the suppression of ER-α levels. The altered ratio of ER-α to ER-β is thought to also disrupt PR expression, and the high ratio in endometriotic stromal cells in turn leads to increased ER-β binding to the PR promoter and mediates the downregulation of expression of PR. Epigenetic changes expression level of SF-1, CYP19A1, ER-α and ER-β, and PR in endometriosis are very different in endometriotic tissue than in normal endometrium. As a result of altered expression of the nuclear receptors and steroidogenic genes, hormone signaling and subsequently hormone actions are altered in endometriosis. Collectively, these aberrations are proposed to increase estrogen-dependent proliferation and progesterone resistance of endometriotic lesions.
| Possible Cause for the Aberration of Local Estrogen Production in Endometriotic Lesions|| |
Given the well-documented aberration of local estrogen production in endometriotic lesions, one question that remains unanswered is how this aberration occurs in the first place. Following the heels of the report that platelets play important roles in the development of endometriosis,, we wondered whether platelets have any effect on estrogen production in endometriotic stromal cells. Interestingly, we found that platelets play a role on estrogen production in endometriotic tissues that activated platelets could induce increased estrogen production through NF-κB and transforming growth factor (TGF)-β1/Smad3 pathways in human endometriotic stromal cells. Activated platelets activate NF-κB and TGF-β1/Smad3 pathways to induce inflammation and hypoxia in endometriotic stromal cells, which further increase the production of pro-inflammatory cytokines and chemokines, which, altogether, lead to increased E2 production in human endometriotic stromal cells by PGE2-cAMP-dependent steroidogenesis pathway (Qi et al., unpublished data). The results suggested that platelets may well play a critical role in the autoregulatory loop that is in favor of estrogen production, and antiplatelets therapy could disrupt the loop and is thus promising for the treatment of endometriosis.
| Summary|| |
Compared with normal endometrium, endometriotic lesions show increased estradiol biosynthesis and reduced estradiol transformation with aberrant expression of steroidogenic enzymes, especially increased expression of StAR and aromatase but reduced HSD17B2 expression. In endometriotic tissues, the expression of STAR, aromatase, and other steroidogenic genes is PGE2-cAMP-dependent, which is regulated by transcription factors such as SF-1 and CREB. The high local E2 status plays a critical role in the progression and maintenance of endometriosis, and, as such, appears to be a right target for intervention. Progesterone resistance in endometriosis is due to a defect of PR expression, leading to the failure to produce RA. These aberrations along with epigenetic aberrations in steroidogenic genes in ectopic endometrium are likely to be responsible for the observed phenotypic aberrations at estrogen levels and estrogen action in endometriosis. Emerging data seem to indicate that activated platelets, resulting from repeated bleeding and the ensuing tissue repair process, may be responsible for all these aberrations. Rectification of these aberrations is likely a promising therapeutics for treating endometriosis.
Financial support and sponsorship
This research was supported in part by grants 81471434 (SWG), 81530040 (SWG), 81370695 (XSL), and 81671436 (XSL) from the National Natural Science Foundation of China.
Conflicts of interest
There are no conflicts of interest.
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