Utilizing novel animal models to assess endometriosis pathophysiology is not something new (86, 116). There has been extensive research using proposed animal models to assess etiology (117), diagnosis (118), resemblance (119), genetics (120), biomarkers (121) and therapeutics (122) for endometriosis disease. Sometimes these studies have reported promising results to encounter endometriosis as a multifactorial gynecological disease (123).
However, the need for handling this uncomfortable situation is still concerned. For example, despite many efforts, researchers could not propose noninvasive, definite and reliable approaches to diagnose endometriosis yet (124). Therefore, women with probable endometriosis existence still have to deal with pain and side effects of invasive procedure such as laparoscopy woefully.
There is a vast contribution of animal models to this disease in order to eliminate these difficulties. Due to lack of data, major trustworthy reviews like systematic reviews or meta-analysis were unable to address these issues (125). So it is required to look back and revise preclinical procedures like animal modeling to provide more authentic data by enhancing research qualities.
This review has provided new insight through the relation of hormones and endometriosis by gathering recent published data and analyzing it meticulously. The proposed scoring system is designed to compare novel animal models that are proposed through the past decade.
6.1 Scoring table rationale and evaluation
We used scoring tables for model assessment which was inspired from (126-128). We also utilized proven hormonal markers (ESR1. PGR, CYP17A1) and other genetic markers (BDNF, AGTR1, CCL2, C3, CD40, TIMP2, SERPINE1, CYP17A1, IGF1, IGF2, IL10, MMP1, MMP7 and MMP9) from study by (129) study to evaluate the models. The scoring was designed in a way that a contrast between suitability of available studies would be easily observable.
Our scoring rationale was considered as follows:
1. Non-human primate models gained higher scores than non-human mammals due to more resemblance to human physiologically and pathologically: (Non-human primate = 2, Non-human mammal = 1)
2. Spontaneous disease occurrence which is exclusive for Non-human primates gained highest scores, xenotransplantation models gained higher scores in comparison to autotransplantation / allotransplantation models due to utilizing cells or tissues from human which can be perceived as more closer to human pathological state:
(Spontaneous disease occurrence = 3, xenotransplantation = 2, autotransplantation / allotransplantation = 1)
3. Consistent pharmacological effects with humans by available verified drugs can be promising criteria for better future translational animal modeling:
(Consistent drug effects with human = +1, No pharmacological evaluation = 0, Non-consistent drug effects with human = -1)
4. Relevant life stage in animal models is a key factor for suitability due to occurrence of different outcomes with drug treatments in different stages of life:
(Identical life stage = +1, Not mentioned = 0, Non-identical life stage = -1)
5. Previous studies have suggested extensive hormonal dysregulations in endometriotic animal models, which can be in compliance with human photogenic state. The more similar the dysregulation, the better translational animal model would be:
(More than one similar hormonal marker regulation to human = +2, Single marker regulation similarity to human = +1, Not mentioned= 0, Non-consistent hormonal marker(s) regulation(s) with human = -1)
6. There are also numerous genes which get disrupted in the state of endometriosis. gene regulations can be consistent with human body dysregulations or not:
(More than one similar gene expression with human = +2, Single gene expression similarity with human = +1, No genetic evaluation = 0, Non-consistent gene(s) regulation(s) with human = -1)
7. One of the traditional ways of validating endometriosis existence is laparoscopy. The evaluation of engaged tissues by staining or observation of ectopic lesions is still the gold standard for diagnosis of the disease:
(Ectopic lesion(s) detection = +1, Not mentioned = 0, No ectopic lesion(s) detection = -1)
This table also provides novel insight for future studies to choose the most suitable model. It is worth mentioning despite achieving less score for non-human mammals in comparison to non-human primates, they benefit from wide availability, easy handling, cost effectiveness, faster growth and breeding. In non-human mammals segment, study by (130, 131) and (90) gained the highest score by providing key elements and resemblance to human endometriosis. (90) proposed their model in non-immunocompromised mice, which can be considered as an advantage for studies involving immunologic topics. While in humans endometriosis is an issue with adult women, most of other studies in this category neglected utilizing adult animals (102). This simple selection can produce inaccurate results for clinical trials and major analyzes. In spite of providing a considerable approach for xenotransplantation, (101) did not provide adequate animal modelling assessment. Although, the mouse model by (108, 109) gained a considerable grade, it is not recommended to use the outbred stock (CD-1) due to genetic variation and suitable availability of other inbred mice strains.
Transgenic animals for endometriosis studies are gaining increasing attention for further investigation of the disease. Some of this transgenic mice exhibit endometriosis features, while the others just facilitate the investigation of the disease and induction of endometriotic state is done by utilizing the previous developed methods. Transgenic animal models in this field can be one of the most promising tools to examine functions of various genes precisely.
Non-human primates are considered to be very similar to humans genetically and physiologically. In addition, they are able to develop spontaneous endometriosis, which can be a positive factor in research terms. In addition to similarities to human, endometriosis is confirmed more accurately considering hormonal assessment; therefore, they achieved higher scoring results. In this segment, (115) has proposed the best model scoring wise. Unlike other models of non-human primates, this model utilized anti progestin to develop endometriotic lesions in baboons. Therefore, can be proposed as best available animal model for hormone related endometriosis assessment.