ABSTRACT
Introduction
Endometriosis is an estrogen-dependent disease on the background of progesterone resistance. Increased estrogen production, low estrogen metabolization, and altered estrogen receptors (ERs) expression contribute to the hyperestrogenic milieu within endometriotic lesions. Since estrogens play a crucial role in the pathogenesis of the disease, inhibition of estrogen production is one of the main targets of available and emerging drugs.
Areas covered
Firstly, we described the molecular alterations responsible for estrogen dependence. Secondly, we reviewed available and emerging treatments that interfere, through central (gonadotropin-releasing hormone analogs (GnRH-a), GnRH antagonists) or local mechanisms (aromatase inhibitors (AIs), inhibitors of steroid sulfatase (STS) and hydroxysteroid dehydrogenase type 1 (17β-HSD1)), with estrogen dependence. Finally, we focused on emerging treatments targeting ERs (selective estrogen receptor modulators (SERMs), estrogen receptors agonists, and antagonists).
Expert opinion
Available treatments interfering with estrogen pathways exert a contraceptive effect, have hypoestrogenic side effects, and cannot prevent or definitively treat the disease. Preclinical and animal studies are focusing on emerging drugs targeting ERs in order to overcome limitations of available treatments. These treatments may represent a promising option, as they may produce a more specific inhibition of disease activity within endometriotic implants, avoiding prolonged hypoestrogenic status and limiting systemic side effects.
Article highlights
Endometriosis is an estrogen-dependent inflammatory disease, causing dysmenorrhea, dyspareunia, dyschezia, chronic pelvic pain and infertility.
The pathogenetic pathways are not fully understood yet; however, increased estrogen sensitivity and progesterone resistance play a crucial role.
Increased estrogen production, low estrogen inactivation, and altered estrogen receptors (ERs) expression contribute to the high estrogen levels within endometriotic lesions.
Drugs acting by reducing circulating levels of estrogens and commonly used in daily clinical practice may reduce symptoms, with the drawback of hypoestrogenic side effects.
New therapies targeting local estrogen biosynthesis or estrogen receptors within lesions could potentially relieve symptoms with less side effects.
Selective estrogen receptor modulators (SERMs), estrogen receptors agonists, and antagonists are emerging treatments for endometriosis. Along with their action on ERs, they also impair others pathogenetic pathways involved in the disease, including inflammation.
This box summarizes key points contained in the article.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Abbreviations
17HSD217-hydroxysteroid dehydrogenase type 2
17β-HSD1 17-hydroxysteroid dehydrogenase type 1
ABT Add-back therapy
AIs Aromatase inhibitors
ART Assisted reproductive technologies
BMD Bone Mass Density
BZA Bazedoxifene
CE Conjugated estrogens
CLI Chloroindazole
COCsCombined oral contraceptives
COX2 Cyclooxygenase 2
E2 estradiol
E2MATE Estradiol- 3-O-sulfamate
ERα Estrogen receptors alpha
ERβ Estrogen receptors beta
ERB-041 (2-(3-Fluoro-4-hydroxyphenyl)-7-vinyl-1,3 benzoxazol-5-ol)
ERs Estrogen receptors
ESHRE European Society of Human Reproduction and Embryology
ESR1 Estrogen receptor 1
ESR2 Estrogen receptor 2
FSH Follicle-stimulating hormone
GnRH Gonadotropin-releasing hormone
GnRH-aGonadotropin-releasing hormone analogs
GnRH antagonists Gonadotropin-releasing hormone antagonists
GPR30 Membrane receptor G protein-coupled receptor 30
iNOS inducible nitric oxide synthase
IL Interleukin
IUD Intrauterine device
IVR Intravaginal ring
LH Luteinizing hormone
LNG Levonorgestrel
NALP-3 NOD-, LRR- and pyrin domain-containing protein 3
NETA Norethisterone acetate
NF-kB Nuclear factor kappa light-chain-enhancer of activated B cells
NSAIDs Non-steroidal anti-inflammatory drug
OBHS Oxabicycloheptene sulfonate
PGs Prostaglandins
PGE2 Prostaglandin E2
PR Progesterone receptor
QoL Quality of life
RERG Ras-like estrogen regulated growth inhibitor
RES Resveratrol
RLX Raloxifene
SERMs Selective estrogen receptor modulators
SGK1 Serum and glucocorticoid-regulated kinase
StAR Steroidogenic acute regulatory protein
STS Steroid sulfatase
TNFα Tumor necrosis factor alpha
TSEC Tissue-specific estrogen complex