Best Practice & Research Clinical Endocrinology & Metabolism
3Animal models of endometriosis: Replicating the aetiology and symptoms of the human disorder
Introduction
Endometriosis is an incurable disorder that is estimated to have an impact on the health and wellbeing of ∼1 in 10 women of reproductive age [1]. The defining characteristic of the disorder is the presence of tissue fragments (lesions) that contain stromal, epithelial and inflammatory cells mimicking the appearance of uterine (eutopic) endometrium. The time to diagnosis is estimated to be 7 years from the time the symptoms first appear [2] and definitive diagnosis is only achieved by a surgical laparoscopy. Depending upon the number, location and appearance of the lesions, three broad subtypes have been postulated; peritoneal, ovarian and deep infiltrating. These phenotypes are further classified, according to the criteria set by the American Society for Reproductive Medicine into stage 1 (minimal), stage 2 (mild), stage 3 (moderate) or stage 4 (severe) [3].
One of the most debilitating symptoms of endometriosis is chronic pain that may be constant or associated with fluctuations in the menstrual cycle. In their 2007 study, Vercellini et al. [4] analysed the association between patient clinical characteristics, lesion type, disease stage and severity of pain symptoms in a cohort of 1054 women having surgery for endometriosis and concluded that ‘the association between endometriosis stage and severity of pelvic symptoms was marginal and inconsistent’, a finding that has been replicated in other reports on smaller groups of women with endometriosis [5]. Landmark studies by Berkley and Stratton have redefined the relationship between lesions and pain symptoms by considering the evidence that endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the CNS [reviewed in [6]]. Asante and Taylor coined the term ‘neuroangiogenesis’ to describe the extensive cross-talk between nerves and blood vessels by which lesions develop a unique local neuronal and vascular supply [7]. It is also notable that recent studies have reported that in addition to physical pain symptoms, psychological factors such as stress, anxiety and depressive symptoms all have a negative impact on the health-related quality of life of women living with endometriosis [8]. These findings have stimulated a greater focus on the mechanisms that might alter pain perception in women with endometriosis and prompted an increase in the efforts to develop relevant preclinical models to investigate mechanisms and test potential therapies [6] (see Studies using Animal Models to Investigate Mechanisms and Treatments for Pain).
The incidence of endometriosis may be as high as 50% in women presenting at infertility clinics and a recent paper reported that the chance of having a baby even with IVF or ICSI was significantly reduced in women with endometriosis compared to women without the condition [9].
Why women develop symptomatic endometriosis remains something that is the subject of intense research interest. Whilst the most widely accepted theory for the formation of lesions is that of ‘retrograde menstruation’ that was proposed by Sampson 90 years ago [10], numerous commentators have concluded that this cannot explain why some, but not all, women develop symptomatic lesions and factors including the peritoneal environment, reduced immune surveillance, persistence of stem cells and oestrogenic stimulation are all being considered [1], [11], [12], [13]. Currently there is an increased interest in using genome wide association studies to better understand the risks/aetiology of endometriosis. A concerted international effort is underway using many thousands of samples [14]. The hope is that these studies may help identify targets to improve diagnosis.
The World Endometriosis Society [WES, http://endometriosis.org/] has brought together many of the key stakeholders interested in advancing understanding of endometriosis and its treatments. It works closely with WERF (the World Endometriosis Research Foundation, http://endometriosis.ca/research/werf/), which was formed in response to the need to accelerate research activities related to improving understanding of the aetiology of the disease and foster development of new therapies. These groups have brought together researchers and clinicians and published a series of papers detailing protocols for collection of tissues and fluids for research as well as research priorities [15]. Of note, many of the research priorities include recommendations building on the use of animal models. A recent exercise in priority setting that sought the views of patients, their supporters, researchers, as well as those involved in their care (clinicians and allied health professionals) has published a ‘Top 10’ of research priorities [16]. Tools to address these challenges include extensive use of human tissue resources (recently reviewed in [17]), as well as a range of animal models which are reviewed below.
Section snippets
Methodology
A search was conducted on Medline (Pubmed) using the search terms ‘animal model’ and ‘endometriosis’ on 15/8/17. All abstracts were read to verify the mention of an animal model and 747 papers were identified for further interrogation. Notably, there were a number of papers published in 2016/7 consistent with the recent identification of research priorities related to the aetiology of the disorder as well as the evaluation of drugs and other agents in preclinical studies. A further search on
Animal models of endometriosis
In a milestone review, Ruth Grummer highlighted the range of species used during the 1980's and 1990's in animal models for endometriosis research, identifying a number of small laboratory animals including rats, mice, rabbits and hamsters [18]: readers are referred to that paper for a historical perspective. For the purposes of this review we have focused on models that have been shown to recapitulate key features of the human disorder highlighting recent adaptations which appear to offer
Immune cells and inflammation
The peritoneal fluid of women with endometriosis contains higher concentrations of pro-inflammatory cytokines and prostaglandins and changes in immune cell complement (reviewed in [12]). There is also evidence that proinflammatory molecules, including prostaglandins (e.g. PGF2α, PGE2) that are produced by macrophages and other endometrial cells, act via their cognate receptors (FP, EP1-4) within endometrial lesions. In a xenograft model (nude mice, human tissue fragments), treatment with the FP
Studies using animal models to investigate mechanisms and treatments for pain
Pain associated with endometriosis has a significant impact on the quality of life of patients and development of new and effective therapies is a research priority that requires the development of appropriate pre-clinical models of endometriosis. Measurement of ‘pain’ in animal models depends upon the evaluation of behavioural responses which may be stimulus-dependent (e.g. von Frey, hotplate, vaginal distension) or spontaneous (e.g. grooming, burrowing) with the latter being accepted as a key
Studies using animal models to investigate mechanisms and treatments for infertility
A number of factors have been cited to explain the raised incidence of sub/in-fertility in women with endometriosis which were summarized by the Practise Committee of the American Society for Reproductive Medicine (ASRM) in 2012 [85]. These included changes in ovarian and endometrial (eutopic) tissue function, as well as changes in the concentrations of pro-inflammatory mediators in peritoneal fluid [12], [13]. Fertility can only be assessed in females where both ovaries and lesions are present
Future directions and priorities
A number of models of endometriosis have been developed and their application has informed our understanding of genetic factors, regulatory molecules and mechanisms that underpin symptoms, including pain and infertility. There are clear advantages to using primates, such as the Baboon, in endometriosis research as they have menstrual cycles and their size allows for repeated sampling of eutopic endometrium and lesions. However, their use is very tightly regulated and testing of compounds
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