Advances in targeting estrogen synthesis and receptors in patients with endometriosis

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.

KEYWORDS:

• Endometriosis
• estrogens
• GnRH analogs
• GnRH antagonists
• aromatase inhibitors
• SERMs
• estrogen receptors

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

Additional information

Funding

This paper was not funded.