Endometriosis: Role of Aromatase and Recent Advances in the Disease Treatment

Kusum¹, Rai S² and Chaube R¹*

¹Department of Zoology, Institute of Science, India

²Department of Obstetrics & Gynecology, IMS, India

*Corresponding author: Radha Chaube, Department of Zoology, Assistant Professor, Institute of Science, Banaras Hindu University (BHU), Varanasi, India

Received: March 18, 2019;Accepted: April 17, 2019; Published: April 24, 2019

Abstract

Endometriosis is a disease condition where endometrial glands and tissues are present outside its uterine location mainly in pelvic peritoneum and on fallopian tubes and ovaries. It affects about 5-10% of women of reproductive phase and 20-50% of women who are suffering already with infertility. The aim of this study was the identification of causative factors, regulatory pathways, pathway related genes, factors leading to the cause or pathogenesis of endometriosis and recent advances in the field of its remedial measures. Overall updated literature survey showed that with the medicine, yoga, life style changes and ayurveda has more pronouncing effect on its treatment strategies.

Keywords: Endometriosis; Reproductive women; Remedies; Ayurvedic medicines; Yoga

Introduction

Endometriosis is presence of endometrial glands and stromal tissues outside the uterine endometrial region mostly in pelvic peritoneal region, on fallopian tubes and ovaries. It is an estrogen dependent gynecological disorder occurring in 5-10% of reproductive age women and 20-50% of women with infertility [1-4]. There are various factors which have been suggested to play an important role in the establishment and development of endometriosis. It includes sociodemographic characteristics, reproductive factors, environmental factors and personal habits [5]. All these factors have cumulative effect and help in development and progression of endometriosis.

Estrogen is the main hormone, which plays an important role in the pathogenesis of endometriosis and aromatase is the ratelimiting enzyme in its biosynthesis. For endometriosis there are many causative factors which are directly or indirectly involved in estrogen biosynthesis by affecting aromatase expression that regulates estrogen production in ovary, extra-ovarian sites and endometriotic implants. Most of the causative factors for endometriosis are related to steroidogenesis pathway, cAMP pathway or Hypothalamus- Pitutary-Gonadal Axis (HPG). These factors mainly affect genes of the pathways and thus there occurs excessive estrogen formation leading to growth and progression of endometriotic implants. However there are a number of medical therapies for endometriosis and all of these are mainly based on reduction or suppression of estrogen formation in endometrotic implants by regulating the aromatase expression (Figure 1).

Figure 1: Gene structure of human aromatase with exon, intron and promoter II regions.

    
    
    Figure 1: Gene structure of human aromatase with exon, intron and promoter II regions.

Estrogen and Aromatase

Estrogen biosynthesis occurs in a number of tissues that include ovarian granulose cells, corpus luteum of the ovary [6,7], testicular leydig cell [8], placental syncytiotrophoblast, adipose tissue [9], brain hypothalamus, amygdale and hippocampus regions [10,11].

Aromatase, the key enzyme for estrogen biosynthesis converts androstenedione into biologically active estrogen. Expression level of aromatase gene is highest in the ovarian granulosa cells in premenopausal women but later after menopause adipose tissue becomes the major aromatase gene expressing site [9]. It is immuno localized exclusively in the cytoplasm of glandular cells but immunoreactivity was not detected in the endometrial stroma [12]. It is present in the endoplasmic reticulum of cells and is composed of a specific form of cytochrome P450, called as aromatase cytochrome P450. Aromatase gene has marked homology to those of other members, notably a putative membrane-spanning region, I helix, ozoles and heme binding regions [13]. This enzyme utilizes molecular oxygen and reducing equivalents provided by a ubiquitous NADPHcytochrome P450 reductase to catalyze a series of three sequential hydroxylations that results in loss of the angular methyl group at carbon 19 and phenolization of the A ring of the steroid.

Aromatase (CYP19A1) spans about 135kb human genome with 503 amino acids sequence and is located at 15q 21.1 region of chromosome 15. This gene is very unique having 11 exons with 9 exons being translated, interrupted by 10 introns (about 80kb, exon 2a to exon 2) and consists of approximately 130kb pairs [5]. The unique sequences are present in the 5’-ends of the transcripts scattered over 100kb upstream of exon 2, whereas the translated coding sequences are present between exon 2-10 that lies about 35kb of the 3’-end of the gene [33,43]. Human aromatase gene includes multiple promoters and the aromatase transcript is tissue-specifically spliced from the multiple alternative exons available for exon 1. Presently nine unique alternative versions of exon 1 have been isolated. Each exon 1 is used in a tissue-specific manner; I.1 (1a) and I.2 (1e) in the placenta, I.3 (1c) and PII (1d) in the ovary and testis, I.4 (1b) in adipose tissue, I.5 in the fetal lung and intestine, I.6 in adipose and bone tissues, I.7 in adipose and vascular endothelial tissues, and 1f in the brain [26,44].

Aromatase Regulation in Endometriosis

In reproductive age women, Follicle Stimulating Hormone (FSH) binds to FSH receptor which is a G-protein-coupled receptor present on ovarian granulosa cell membrane that raises the intracellular cAMP levels and that further enhances the binding of two critical transcription factors. There are two most important transcription factors Steroidogenic Factor-1 (SF-1) and cAMP Response Element Binding Protein (CREB), both of these are located in proximal promoter II region of the aromatase gene (CYP19gene) [14]. These transcription factors in turn activate aromatase gene expression and consequently estrogen synthesis from the pre-ovulatory follicles [14,15]. In post menopausal women, expression of aromatase gene is regulated by the use of alternative promoter I.4 in adipose tissues and skin fibroblast by the similar regulatory cAMP pathway, which is activated by cytokines (IL-6, IL-11, TNFa) and glucocorticoides. It is proposed that aberrant aromatase expression is the only important molecular mechanism in the development and growth of pelvic endometriosis. In endometriotic implants aromatase activity was significantly stimulated by a cAMP analog, PGE2 or a combination of a glucocorticoid and a cytokines via cAMP pathway. PGE2 effect is mediated via the cAMP-inducing EP2 (receptor subtype). Estrogen increases PGE2 formation by stimulating Cyclo-Oxygenase type-2 (COX-2) enzyme in endometrotic implants. Thus a positive feedback loop for continuous local production of estrogen and prostaglandins, favouring the proliferation and inflammation in endometrotic implants is established. There may be other affecting molecular mechanisms that favour the development of endometriosis which includes abnormal expression of proteinase type enzymes that remodel tissues or their inhibitors [MMPs (Matrix Metalloproteinases), TIMPs (Tissue Inhibitor of Metalloproteinase-1)], certain cytokines (IL-6, RANTES) and Endometrial Growth Factors (EGF).

Genetical Studies Including Hormone Receptors, Steroids and Inflammatory Pathway Genes

Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors [16]. In view of this, genetic variants of genes that involves Estrogen Receptor Genes (ESRs), Progesterone Receptor genes (PRs), Steroidogenic Acute Regulatory gene (StAR), gonadotropin genes, steroid biosynthesis pathway genes mainly aromatase were extensively studied in recent years and a number of causative factors are yet to know.

It was found that both estrogen and progesterone receptors were present in endometriotic lesions. Immunocytochemical techniques demonstrated cyclic changes of Estradiol Receptors (ER) and Progesterone Receptors (PR) in human uterine tissues in several studies [17]. A differential regulation of the these receptors expression in the different uterine layers, such as the glandular epithelium and the stroma of the endometrium respectively reflects the differential functions with differential requirements of hormone effects of these tissues during different phases of the cycle [18-21]. It has been demonstrated that in normal endometrial tissue and endometriotic cysts estrogen molecule binds preferentially to ERa than to ERβ receptors [22]. Estrogen modulating enzymes in endometriotic lesions and cell lines has shown that, in contrast to normal endometrium of women without endometriosis, expression of cytochrome P450 or aromatase gene (CYP19) and 17β-Hydroxysteroid Dehydrogenase type 2 (17-HSD2) genes are present in the endometriotic lesions and uterine endometrium from patient [23,24]. But, in contrast to it, expression of 17β-Hydroxysteroid Dehydrogenase type 1 (17- HSD1) is deficient in these tissues which catalyzes the conversion of E1 (Estrone) to E2 (Estradiol) [25]. Estrogen produced by aromatase activity in the cytoplasm of leiomyoma smooth muscle cells or endometriotic stromal cells exert its effects by readily binding to its nuclear receptor within the same cell [23,26,27]. P450 aromatase is localized in the cytoplasm of glandular cells of adenomyotic tissues and eutopic endometrial obtained from patients with endometriosis [12] on the other hand disease-free endometrium and myometrium, lack its expression [27,28]. E2 and cytokines (IL-lβ, TNFa), which are increased in endometriosis induces Cyclo-Oxygenase-2 (COX- 2) gene giving rise to elevated concentrations of Prostaglandin E2 (PGE2) in these tissues. PGE2 is a most potent known stimulator of aromatase gene in endometriotic stromal cells [27] and a positive feedback loop get established in endometriosis patients causing a continuous estrogen formation leading to diseased condition (Figure 2).

Figure 2: Pathway of aromatase (CYP19) gene action for conversion of androstenedione into estrogen in ovary, extra-ovarian tissues and in endometriotic implants. Different treatment measures for endometriosis act at molecular level by endocrine regulatory pathways.

    
    
    Figure 2: Pathway of aromatase (CYP19) gene action for conversion of androstenedione into estrogen in ovary, extra-ovarian tissues and in endometriotic
implants. Different treatment measures for endometriosis act at molecular level by endocrine regulatory pathways.

Remedial Measures

All medical treatments for endometriosis are designed to decrease estrogen secretion by the ovaries, extra-ovarian tissues and in endometriotic implants (Table 1). Presently endometriosis is successfully suppressed by estrogen deprivation with antiandrogenic hormone treatments with danazol, Levonorgestrel-releasing intrauterine device (LNG-IUD), Gonadotropin Releasing Hormone (GnRH) analogues, Selective Estrogen Receptor Modulators (SERM), Selective Progesterone Receptor Modulators (SPRM), aromatase inhibitors, or induction of surgical menopause [29-32]. Current evidences suggest that about 50% of endometriosis patients with chronic pelvic pain are resistant to current available treatments that causes hypoestrogenic state [33-35]. Patient’s undergone surgery often recurs with pain remaining to repeated surgical attempts and immediate response to chronic pain in 50% cases of surgical menopause [36].

Table 1: Medical treatments of endometriosis.




  
    Hormonal
    
  
  
    GnRH    agonist
      Goserelin, Leuprolide,    Nafarelin, Buserelin, Triptorelin 
    Garner et al., 1994, Kitawaki    et al., 2008
  
  
    GnRH    antagonist
      Cetrorelix, Abarelix, Elagolix,    Danazol 
    Kupker et al., 2002, Altintas    et al., 2008, Taniguchi et al., 2013, Diamond et al., 2014
  
  
    Levonorgestrel-releasing    intrauterine device (LNG-IUD)
    Fedele et al., 2001
  
  
    Aromatase    Inhibitors (AIs)
      Anastrozole, Letrozole 
    Ferrero et al., 2011, Agarwal    et al., 2015
  
  
    Selective    Estrogen Receptor Modulators (SERMs)
      Raloxifene, Tamoxifen,    Bezedoxifene, Chloroindazole, Oxabicycloheptene 
    Yao et al., 2005, Yavuz et al.,    2007,Stratton et al., 2008, Atlintas et al., 2010, Kulak et al., 2011, Naqvi    et al., 2014, Lyu et al., 2015, Ezzat L, 2017
  
  
    Selective    Progesterone Receptor Modulators (SPRMs)
      Mifepristone (RU-486),    Onapristone, Asoprisnil, Mifepristone, Ulipristal acetate, Tanaproget
    Chawlisz et al., 2005, Zhang YX    , 2016, Hunaidi et al., 2013, Bruner –Tran et al., 2006
  
  
    Angiogenesis    inhibitors
      Letrozole, Anastrazole, TNP470    endostatin, Anginex, Rapamycin, Thalidomide, Statin, Rapamycin, Dopamine    cabergoline (Cb2), Quinagolide
    Verma and Konje, 2009, Bilotas    et al., 2010, Ferrero et al., 2011, Almassinokiani et al., 2014, Agarwal et    al., 2015
  
  
    Non    hormonal
    
  
  
    Immunomodulators
      Loxoribine, IFN-a 2β,    Etanercept, Lipoxin, Rapamycin, Infliximab, Pentoxifylline
    Badawy et al., 2001, Barrier et    al., 2004, Laschke et al., 2006, Koninckx et al., 2008, Kamencic and Thiel,    2008, Vlahos et al., 2010, Xu et al., 2012, Ingelmo et al., 2013, Kumar et    al., 2014, Ren et al., 2016, Ezzat L, 2017
  
  
    Antiantiangiogenics
      Caplostatin, Endostatin,    Angiostatin, Lovastatin, Atorvastatin, Simvastatin, Lodamin, Romidepsin,    Icon, Cabergoline, Bromocriptine, Quinagolide, Fenofibrate, Rosiglitazone,    Ciglitazone, Bentamapimod
    Dabrosin et al., 2002,Backer et    al., 2006, Jiang et al., 2007, Esfandiari et al., 2007, Lebovic et al., 2007,    Oktem et al., 2007, Bruner-Tran et al., 2009, Onalan et al., 2009,    Novella-Maestre et al., 2009, Sharma et al., 2010, Krikun et al., 2010, Becker    et al., 2011, Delgado-Rosas et al., 2011, Herington et al., 2011, Imesch et    al., 2011, Zhang et al., 2012, Almassinokiani et al., 2013, Lebovic et al.,    2004; 2013,Chang et al., 2013, Hamid et al., 2014, Ma and He, 2014, Ercan et    al., 2015, Hussein et al., 2016, Ezzat L, 2017



Table 1: Medical treatments of endometriosis.

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Citation: Kusum, Rai S and Chaube R. Endometriosis: Role of Aromatase and Recent Advances in the Disease Treatment. Austin J Obstet Gynecol. 2019; 6(2): 1137.

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Hormonal
GnRH agonist Goserelin, Leuprolide, Nafarelin, Buserelin, Triptorelin	Garner et al., 1994, Kitawaki et al., 2008
GnRH antagonist Cetrorelix, Abarelix, Elagolix, Danazol	Kupker et al., 2002, Altintas et al., 2008, Taniguchi et al., 2013, Diamond et al., 2014
Levonorgestrel-releasing intrauterine device (LNG-IUD)	Fedele et al., 2001
Aromatase Inhibitors (AIs) Anastrozole, Letrozole	Ferrero et al., 2011, Agarwal et al., 2015
Selective Estrogen Receptor Modulators (SERMs) Raloxifene, Tamoxifen, Bezedoxifene, Chloroindazole, Oxabicycloheptene	Yao et al., 2005, Yavuz et al., 2007,Stratton et al., 2008, Atlintas et al., 2010, Kulak et al., 2011, Naqvi et al., 2014, Lyu et al., 2015, Ezzat L, 2017
Selective Progesterone Receptor Modulators (SPRMs) Mifepristone (RU-486), Onapristone, Asoprisnil, Mifepristone, Ulipristal acetate, Tanaproget	Chawlisz et al., 2005, Zhang YX , 2016, Hunaidi et al., 2013, Bruner –Tran et al., 2006
Angiogenesis inhibitors Letrozole, Anastrazole, TNP470 endostatin, Anginex, Rapamycin, Thalidomide, Statin, Rapamycin, Dopamine cabergoline (Cb2), Quinagolide	Verma and Konje, 2009, Bilotas et al., 2010, Ferrero et al., 2011, Almassinokiani et al., 2014, Agarwal et al., 2015
Non hormonal
Immunomodulators Loxoribine, IFN-a 2β, Etanercept, Lipoxin, Rapamycin, Infliximab, Pentoxifylline	Badawy et al., 2001, Barrier et al., 2004, Laschke et al., 2006, Koninckx et al., 2008, Kamencic and Thiel, 2008, Vlahos et al., 2010, Xu et al., 2012, Ingelmo et al., 2013, Kumar et al., 2014, Ren et al., 2016, Ezzat L, 2017
Antiantiangiogenics Caplostatin, Endostatin, Angiostatin, Lovastatin, Atorvastatin, Simvastatin, Lodamin, Romidepsin, Icon, Cabergoline, Bromocriptine, Quinagolide, Fenofibrate, Rosiglitazone, Ciglitazone, Bentamapimod	Dabrosin et al., 2002,Backer et al., 2006, Jiang et al., 2007, Esfandiari et al., 2007, Lebovic et al., 2007, Oktem et al., 2007, Bruner-Tran et al., 2009, Onalan et al., 2009, Novella-Maestre et al., 2009, Sharma et al., 2010, Krikun et al., 2010, Becker et al., 2011, Delgado-Rosas et al., 2011, Herington et al., 2011, Imesch et al., 2011, Zhang et al., 2012, Almassinokiani et al., 2013, Lebovic et al., 2004; 2013,Chang et al., 2013, Hamid et al., 2014, Ma and He, 2014, Ercan et al., 2015, Hussein et al., 2016, Ezzat L, 2017

Cyperusrotundus, Corydalis yanhusuo, Lenonurus, Curcuma phaelculis, Salvia miltiorrhiza, Typhaangustifolia, Trogopterusxanthipes, Taraxacummongolicum, Cuscutachinensis and Sparganiumstoloniferum is commonly used as single herbs for endometriosis.	Tsai et al., 2017
Herbal combinations / formulations including Cyperusrotundus, Sparganiumstoloniferum, Corydalis yanhusuo, Typhaangustifolia, Curcuma phaelculis, Meilatoosendan with anti-inflammatory & anti-oxidative activity are used for endometriosis.	Tsai et al, 2017
A formulation of Polygonumbistorata, Acacia Arabica and Santalum album is useful in menorrhagia for having anti-haemorrhagic activity.	Jahan et al., 2016
Bamboo (B. vulgaris) leaves have wound healing and anti inflammatory potential and can be used for endometriosis.	Lodhi et al., 2016
Turmeric (Curcuma longa Linn) has been proven for its anti-inflammatory, antioxidant, anti-mutagenic, anti-diabetic, anti-bacterial and anti-cancerous pharmacological activities and can be used for endometriosis.	Krup et al., 2013
Cinnamon twig, Myrrh, Chinese angelica and Licorice root are used as alternatives for pain relief in endometriosis.	Suresh et al., 2012
A specific dose of mixture of Triphala, Kanchanarguggul & Chandraprabhavati has given a new hope for treatment of ovarian cyst.	Himanshu et al., 2011
QuyuJiedu Granules raises the ova quality by reducing TNF-alpha and IL-6 levels to improve the living micro-environment for the ova.	Lian et al., 2009