Juniper Publishers: The Role of Antioxidant Supplementation in Endometriosis Therapy
JUNIPER PUBLISHERS- JOURNAL OF GYNECOLOGY AND WOMEN’S
HEALTH
Journal of Gynecology and Women’s Health-Juniper
Publishers
Authored by Annika Sinha*
Abstract
Endometriosis is a benign, estrogen-dependent
disorder, characterized by the presence of ectopic lesions in
extra-uterine regions of body, including the ovaries, peritoneum, and
even the thoracic cavity. Though the pathophysiology of endometriosis is
relatively unknown, disease itself is characterized by cell survival,
oxidative stress, cellular proliferation, excessive adhesion,
inflammation, and angiogenesis [Matsuzaki]. Though endometriomas are not
malignant, this atypical tissue can spread throughout the female
reproductive tract, causing chronic pain, infertility, and abnormal
bleeding. Approximately 1 in 10 women suffer from endometriosis [1].
Despite the prevalence of endometriosis, current treatment methods
include surgery, oral contraceptives, gonadotropin-releasing hormone
agonist therapy (GnRH), anti-inflammatory medications, danazol, and
aromatase inhibitors [1].
While these treatment methods aim to resects preexisting ectopic
lesions, cause ovarian estrogen synthesis down regulation, and lessen
cytokine-mediated inflammatory pain. Despite these interventions,
endometriosis often can recur after cessation of therapy; therefore,
novel medical therapies, such as statins, metformin, and antioxidant
therapy, could have the potential to alleviate the symptoms and
progression of endometriosis. This article is a brief review of relevant
and novel antioxidant treatments for endometriosis and their
possibility to increase and improve treatment options.
Introduction
Endometriosis is a common benign disease
characterized by extra-uterine implantation of endometrial-like tissue
within the ovaries, peritoneum, rectum, pelvis, and thoracic cavity.
While some women remain asymptomatic, its symptoms and signs include
infertility, chronic pain, irregular bleeding, and dyspareunia in
approximately 8% of women of reproductive age and up to 50% of infertile
women [1,2].
While the pathophysiologic mechanism of endometriosis is still unclear,
the disease is characterized by abnormal cellular proliferation,
invasion, and inflammation due to presence of reactive oxidative stress.
These atypical processes underlie the signs and symptoms of this
disease; therefore, treatment for endometriosis is targeted to address
the various aspects of its pathogenesis.
The management of endometriosis is currently as recommended by the European Society of Human Reproduction (ESHRE) guidelines [2].
These guidelines for endometriosis therapy include oral contraceptive
medications, GnRH agonists, progestogens, analgesics, danazol,
anti-progestogens, aromatase inhibitors, and conservative or
non-conservative surgical approaches. The treatment approach for
patients is highly dependent on the severity of the patient’s symptoms.
Traditionally, surgical interventions, such as resection and nerve
transection, are considered in patients with confirmed endometriosis who
do not respond to medical therapy [ASRM]. Surgical methods aimed to
removed endometriosis are considered more effective than non-invasive
means [1].
Surgery has been shown to significantly reduce pain, a major symptom of
endometriosis [ASRM] and can offer improvements in fertility [1,3].
Though these interventions have been shown to be effective, the relapse
rate of endometriosis post-surgery, the most aggressive treatment, is
still roughly 22% at 2 years and 40-50% after five years [4].
Though the current therapeutic means offer benefits to patients, recent
literature on endometriosis treatment suggests that other novel medical
approaches, especially in antioxidant therapy, may be able to
supplement the established treatment guidelines [3].
The Role of Antioxidants
All Though the pathogenesis of endometriosis is still
not fully elucidated, the disease is associated with oxidative stress
and an abnormal increase in reactive oxidative species (ROS). ROS are
volatile molecules that interact with biological molecules to activate
apoptotic mechanisms and cell death [5]. ROS are typically neutralized by physiological means; however, patients with
endometriosis have an altered balance of prooxidant and antioxidant
molecules. For example, oxidative markers, such as Cu, ceruloplasmin,
8-hydroxyl-2-deoxyguanosine, and total oxidant status, may be elevated
in endometriosis patients [6]. Moreover, serum total antioxidant status and thiol levels were significantly lower (p<0.001) [7,8].
This evidence demonstratesthat the low antioxidant levels may be
integral to the etiopathogenesis of endometriosis. Previous literature
on antioxidant therapy suggests that the beneficial properties of
antioxidants may reduce endometriosis-related symptoms and oxidative
damage.
The Evidence for Antioxidant Therapy
Based on the role of oxidative stress in
endometriosis, antioxidant use has been studied as a means to improve
patient outcomes in endometriosis. Current research assesses the
antioxidant characteristics of vitamin E, vitamin C,
epigallocatechin-3-gallate (EGCG), resveratrol, melatonin, andcerum
oxide nanoparticles. Analysis of the antioxidative benefits of these
therapies were determined by outcomes both in animal and human studies,
such as symptomatic reduction, pain alleviation, lesion size reduction,
and number of lesions.
In order to determine the effect of vitamin E and C,
46 women with endometriosis-related pain were given a combination of
vitamin E (1200 IU) and vitamin C (1000mg) for two months. Vitamin E is a
fat-soluble antioxidant that prevents the formation of the vitamin E
radicals, and vitamin C was added to this regimen because it functions
to recycle the vitamin E radial to vitamin E. After this randomized
control trial, 43% of the patients reported a reduction in chronic
pelvic pain, suggesting that vitamin E and C may offer noticeable pain
reduction even in short time frames (P=0.0055). The patients in the
control group did not experience any decrease in pain [9]. While Santanam et al. [9]
attributed the effects of vitamin supplementation to its anti-oxidative
and anti-inflammatory properties, there was no clear physiologic
mechanism stated in the article. However, the work of Durak et al. [10],
may offer some insight. In a rat model, experimentally induces
endometriotic cysts were treated with differing doses of vitamin C
(0.5mg, 1.25mg, and 2.5mg) to determine if vitamin C supplementation
would alter the volume and weights of these lesions. The cysts from
group treated with 2.5mg of vitamin C were significantly reduced in
weight and volume [10]. This evidence suggests that antioxidants, such as vitamin C, may reduce endometriosis symptoms by reducing lesion size.
In addition to vitamins, epigallocatechin-3-gallate
(EGCG) may also impact the size of endometriomas as well as selectively
inhibit neovascularization in these lesions. EGCG is a commonly found
polyphenol in green tea. In other fields, it has been found to prevent
tumor formation through initiating apoptosis and cell cycle arrest [11]. Therefore, Matsuzaki et al. [12]
assessed its effect in endometriosis. Cell samples for 55 endometriosis
patients were treated with EGCG and analyzed via rt-PCR, cell
proliferation assays, in vitro migration and invasion assays. EGCG
significantly reduced proliferation, cell migration, and invasion of
endometriotic cells [12].
Though EGCG appears to offer benefits for endometriosis patients, its
low bioavailability through ingestion of pure EGCG or green tea
consumption limits its use as a drug.
Like EGCG, resveratrol, another natural therapy, may
also improve endometriosis symptoms. Resveratrol is known
anti-proliferative agent and antioxidant found in grapes and red wine.
Ricci et al. [13]
studied the effects of both EGCG and resveratrol on endometriosis as
potential natural therapies. They investigated in a mouse model, 56 mice
completed surgical induction of endometriosis and were treated with
either resveratrol and EGCG for four weeks. Both interventions reduced
the mean number and volume of established lesions (P<0.005). Though
both treatments were effective in decreasing cell proliferation,
reducing vascular density, and increasing apoptosis, results due to
resveratrol (p<0.01) were more significant than those due to EGCG
(p<0.05) [13]. While the mechanism of action associated with resveratrol is not completely understood, Amaya et al. [14]
studied its dose-dependent impact on endometrium. In addition to its
antioxidant properties, resveratrol functions as a phytoestrogen. It has
different estrogen action based on concentrations; in low
concentrations, it acts agonistically. However, in high concentrations,
it functions antagonistically. Because endometriosis is an
estrogen-dependent disease, high levels of resveratrol was shown to
reduce proliferation of xenografts of human endometrium in mice [14].
Another naturally produced substance, melatonin, is
also suggested to have potent effects on endometriotic lesions.
Melatonin has several properties, including free radical scavenging,
stimulation of antioxidants, and increasing the efficacy of electron
chain function [15,16]. In humans, it is produced in the pineal gland, and has been shown to decrease oxidative damage [15]. To understand the role of melatonin, Yilmaz et al. [16],
implanted endometriotic lesions in twenty rats and treated ten with
melatonin and ten with saline (control). The outcome measures of this
study were volume and weights of the lesions. In the experimental group,
the lesion volume (p<0.01) and weights were significantly decreased
(p<0.05), showing that melatonin causes lesion regression [16].
Another novel antioxidant therapy includes the use of
cerium oxide in order to impact the progression of endometriosis.
Cerium oxide has radical-scavenging characteristics that could offer
benefit to endometriosis patients. Chaudhury et al. [17]
utilized cerium oxide nanoparticles to improve endometriosis-related
effects in a mice model. Mice with endometriosis treated with cerium
oxide nanoceria were found to have lower levels of ROS and higher levels
of total antioxidant capacity (TAC). Cerium oxide not only has
antioxidant properties, but also has regenerative traits. This process
of regeneration makes one dose of cerium oxide more appealing than the
use of other antioxidants. While this study shows the effect of cerium
oxide nanoparticles in endometriosis, there is also a concern for toxicity when using these nanoceria.
Conclusion
Endometriosis is a chronic, estrogen-dependent
condition that affects nearly 10% of women of reproductive age, causing
pain, irregular bleeding, and infertility. This disease is treated by
various medications, which function to reduce estrogen levels and
inflammation, and surgery to remove the endometriotic lesions. However,
despite this wide array of therapy, there is still high rate of relapse
after surgery, the first line therapy for symptomatic patients [4].
Because of this phenomenon, there may be a need to improve outcomes for
endometriosis patients. The current and previous literature focuses on
the efficacy of antioxidant therapy in the treatment and mitigation of
endometriosis. Antioxidants function by removing the free radial
species, upregulating antioxidant enzymes, and reducing oxidative
damage. Relevant antioxidants include vitamin E and C, EGCG,
resveratrol, melatonin, and cerium oxide. These molecules have been
shown to reduce the symptoms and progression of endometriosis mainly in
experimental animal models. However the studies highlight the potential
of the antioxidants enlisted in the article for use in women with
endometriosis. There is a need for further well designed and adequately
powered studies to assess the newer antioxidants in women suffering from
this debilitating disease.
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