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A Review: Non-Human primate versus the Human Female Reproductive System Anatomy in the Context of their common uterine disorder; Endometriosis
Comparative anatomy between species offers an invaluable platform for studying and understanding developmental, reproductive, and pathological patterns in mammalian species. Due to a high level of similarity in the reproductive axis and the hormonal control system from the birth of the offspring through puberty to menopause, non-human primates continue to play a vital role in the research geared towards comprehending human’s reproductive patterns and disorders such as endometriosis. In this review, we seek to elaborate in detail the capacities of the female reproductive organs including similarities and differences of these organs in the non-human primates and humans. In addition, the significance of these anatomical structures in relation to understanding endometriosis using the baboon model is highlighted.
Anatomically similar systems may be used to model each other in biomedical research targeting diseases and their prevention. Such diseases of the human female reproductive system such as Pelvic Inflammatory Disease (PID) and endometriosis are associated with a significant morbidity. Indeed, PID has been implicated in the causation of infertility (Jason, 2011). Increased understanding of the diseases and interventions has been possible with nonhuman primates’ models. The baboon as a model for human disease is a relatively recent arrival at research and is of great interest due to the great phenotypic and genotypic similarity that is observed between the two species. The current paper seeks to review literature on the anatomical relevance of the baboon’s female reproductive system in modelling that of humans in the general sense and in the specific context of endometriosis research.
Background on the use nonhuman primates models for human pathophysiology
The baboon has been cited as the first animal whose genetic linkage map has been developed in the category of non-human primates. The baboon, as an animal model has provided an invaluable platform for genetic studies that assist in the comparison of baboon chromosomal structures with those of other species. By employing quantitative trait loci, researchers have been able to locate, within the genome, specific functional genes deemed relevant in particular phenotypic variations associated with human diseases (Tardif & VandeBerg, 2009).
On a wider perspective, nonhuman primates have played important roles in comparative biology aimed at better understanding of the human body and processes. Baboons, for instance, are large and have a reproductive system that is highly similar to that of humans, which qualifies them as ideal models for studying the human reproductive system, and the patterns, as well as disorders associated with it (Hooghe et al., 2009). Further, the baboon is very close to human species in the evolutionary phylogenetic context qualifying it as a suitable model candidate for human diseases research.
Notably, rodent models can be used for endometriosis research based on the many advantages like low cost, easy handling and possibility for easier genetic manipulations. However, they present big challenges when using them to conduct research especially in the line of female reproductive system disorders such as endometriosis. The challenges include but not limited to the big phylogenetic gap between rodents and humans, absence of a menstruation cycle, and major differences in the female reproductive system like the absence of the peritoneal fluid. In addition, the rodent models do not have the ability to spontaneous endometriosis and do not respond to non-physiological induction of endometriosis as is the case with humans and non- human primates (Jose et al., 1999). The huge difference in anatomical presentation of the reproductive organs makes a rodent model difficult to generate and unreliable.
Apart from phylogenetic relatedness, genetic anatomical similarities with the human primates, nonhuman primates are the most suitable models for research due to similarities in physiology and other biological features. Regardless, they pose some limitations that include complex and specialized infrastructure and logistics, as well as training for handling these animals. Furthermore, the animals are perceived to be ethically sensitive and expensive on the global research platform (D’Hooghe, 1997). The use of baboons, for instance, requires that high ethical measures are in place in the institutions that use them to carry out their research, which can be a costly affair (Hooghe et al., 2009). Nevertheless, the benefits of the baboon for modelling certain diseases surpass such limitations.
Regarding the baboons suitability as a model animal for human reproductive diseases research, the nonhuman primate presents with the opportunity to use a non-invasive cycle monitoring based on perineal changes. It is also big in size and quite strong hence capable of withstanding manipulations without much alterations to its anatomy. Further, the baboon is spontaneous in production of the peritoneal fluid, exhibits a continuous pattern of breeding, and there is a high cross-reactivity between baboons and humans (Hooghe et al., 2009). With cross-reactivity and the great semblance, ‘engineering’ the model without adverse biological ramifications to suit the purpose becomes convenient.
Having established the general pointers of similarity between the baboon and other nonhuman primates, the next step would be to look into the specific anatomy and biology of the reproductive organs side by side. The approach establishes similarities and differences, and can be used to highlight areas to observe when developing a model, and in the analysis research outcome. The comparison here is based on humans, the cynomolgus Monkey (Macaca fascicularis) and the baboon (papio species). Notably, female baboons exhibit both external and internal sex organs. The main internal genital organs in the baboon, just like in humans, are the ovaries, oviducts uterus and vagina. The external genitalia include the vaginal vestibule, clitoris, labia, perineum, and ischial callosities. Tardif et al. (2009), observes that the internal reproductive tract has a high degree of resemblance to that of humans.
The ovaries are paired in both cases but slightly larger in humans as compared to the Cynomolgus monkey. The mean weight (paired) in the monkey is indicated to be 0.42 g ± 0.14 g while in humans the ovaries weight range between 10 g and 16 g (Sch et al., 2008). On the other hand, the mean weight per single ovary would be 0.21 g and 5g to 8 g respectively (Sch et al., 2008). The total number of oocytes is more or less the same in both cases where at birth it ranges between 1 – 2 million. The foetal number is in the range of 5 – 7 million for the monkey while for humans it is at 6 – 7 million at 20 weeks (Sch et al., 2008). Both the monkey and the human display a mono-ovulatory cycle with a corpus luteum of 10 mm diameter in monkeys and 20 mm diameter in humans. In both cases the corpus luteum undergoes a lifespan of 14 ± 2 days with ovarian cysts as the common pathologic condition (Sch et al., 2008). Moreover, the ovaries of the baboon are slightly larger than in humans; in baboons, the ovary size is 14 mm by 9 mm and 10mm thick. One key observation and difference between human and baboon ovaries is that in baboons, the ovaries are loosely suspended in space, making them easily displaceable by other organs. Such a location explains why it is quite challenging to locate baboon ovaries by ultrasound during surgical procedures(Tardif et al., 2009). Notably, ovarian endometrioma is a complication that is common in human endometriosis. The ovarian cyst, in complication, may require great expertise to locate via ultrasound in baboon model.
Just like in humans, the baboons have paired fallopian tubes that arise from each side of the uterus with each tube approximated to be 55 mm long. Synonymous with humans’, the baboon fallopian tubes have three distinct regions namely isthmus (closest to the uterus), ampulla (middle region responsible for most fertilization events) and finally the infundibulum the region bordering the ovaries (Tardif et al., 2009). Consequently, any changes due to endometriosis affecting the oviduct are likely to be similar for both the baboon and the human. For instance, Wang et al. report on the case of oviduct progesterone resistance in both the baboon model and human endometriosis (2009). However, it should be noted that the baboon oviducts, for unknown reasons, is rarely involved in endometriosis (Olive, 2005, 176).
The uterus type in the both the Cynomolgus monkey and the humans is uterus simplex by anatomic classification although there are major differences in size. In the monkey, it measures 40 mm in length (including the cervix) by 20 mm while in humans it is 75 mm in length and 50mm in diameter at the upper part (Sch et al., 2008). The mean weight also varies significantly in both cases. The mean weight / weight range in the monkey is indicated as 7.42 ± 2.98 g (range: 2.83 – 16.37 g) while in humans it is shown to be 40 – 80 g (Sch et al., 2008).
The following disorders that afflict the uterus are common in the monkey and humans: Adenomyosis, endometriosis, endometrial polyps and Leiomyoma. Endometrium hyperplasia and endometrium carcinoma are typical to of human uterus only (Sch et al., 2008). In the baboon, uterine endometrioses can be either spontaneous or induced. The pouch of Douglas, the utero-sacral ligaments, uterovesical fold, and the uterine peritoneum, as well the uterine-omental regions of both the baboons and the human uterus are affected by endometriosis (Olive, 2005, 176).
The monkey’s cervix has been illustrated to be averagely 15 mm long and 18 mm in diameter while that of humans is about 25- 30 mm long and 20- 25 mm in diameter. The monkey’s cervix displays a sigmoid cervical canal shape, which is limiting to transvaginal endometrial biopsy, while that of human is relatively straight. In both humans and monkeys, the transformation zone in the cervix is indicated to be distinct. In the cynomolgus monkey, the common pathologic conditions of the cervix include squamous cell metaplasia and cervical intraepithelial neoplasia (papilloma virus (MPV-related) while in humans it is Reserve cell & squamous cell metaplasia and cervical intraepithelial neoplasia (human papilloma virus (HPV) (Sch et al., 2008).
The birth canal in the baboon is synonymous with that of humans displaying both internal genital and external genitalia. In both cases, it acts as a passage canal for the offspring as well as organ for sexual intercourse. The vagina in the baboon, is relatively larger compared to the uterus. It is illustrated that at the vestibule, it has a diameter ranging from 15 to 30 mm. On the other hand, in women, the average vaginal length is approximately 70–100 mm (Tardif et al., 2009)
The perineum structure is present in both humans and baboons. In baboons, it is connected to the base of the tail, the pelvic arch and the ischial callosities. The perineum in the baboon is distinctly different from that of humans by having a delicate covering skin that swells during the follicular phase of the menstrual cycle, indicating fertility (Tardif et al., 2009). The perineum in humans is generally less conspicuous regardless of the menstrual phase. It is important to note that endometrioses of the perineum are rare occurrences in both the baboon and humans, mostly occurring as a consequent of trauma (Hamdi et al., 2015). When it does occur, it is likely to be observed early in the baboon model.
The gynaecologic procedures used on non-human primates (baboons) are similarly applicable to humans owing to the closeness in the anatomic organization of the organs and their size. For instance, vaginal speculums and dilators used on petit women can also be used in baboons (Hooghe et al., 2009). However, the ovaries of the baboon as earlier noted are lateral to the midline simplex muscular uterus. The position makes it easier, and with some level of experience, for the trans-abdominal ultrasound, other than trans-vaginal, to identify them. It is also evident that the general orientation of the uterus in nonhuman primates is different from that in humans following an evolutionary adaptation to allow for different locomotive modes (Bauer, 2015). Regardless, when motion has been controlled for, similar procedures as used in humans can be optimised to suit the baboon.
Endometrioses Disease Burden
Endometriosis is illustrated as a chronic oestrogen-dependent disease with symptoms of chronic pelvic pain, especially during copulation. It is also a main cause of infertility in women (Budrys et al., 2012). Endometriosis poses challenges in treatment and diagnosis due to differences in presentation of disease symptoms and progression among different patients. Decreased quality of life, low productivity in work and an huge economic losses are attributable to the disease morbidity .The economic burden is estimated at a level equivalent to that of diabetes and rheumatoid arthritis (Klein et al., 2014). It has been illustrated that to date there is neither curative nor preventive therapies sufficiently effective against the disorder. Surgery is often a treatment option and can be performed to remove laparoscopic lesions from the pelvic area. However, the success rates are low since the symptoms appear to recur in approximately 40% of the women treated via surgery (Stouffer & Woodruff, 2017). Hormonal manipulations have been done in some cases in order to relieve pain but may be disastrous as they may impair fertility (Stouffer & Woodruff, 2017). Consequently, endometrioses is a disease of importance as far as health research is concerned.
Summary of the Baboon as a Model for Human Endometrioses
The high degree of similarity genetically and morphologically, as well as the relatedness phylogenetically, the baboon like other non-human primates has found continuous use as a model for human disease in research. Some disorders associated with the female reproductive system are common to both humans and non-human primates. Otherwise, some of these disorders can be successfully induced in the model animals. Endometriosis, a gynaecologic disorder depicted in approximately 10% of reproductive-age women is characterised by unusual development of endometrial cells outside the uterine cavity that results in infertility (Braundmeier & Fazleabas, 2008). Although the disease is widely studied with numerous publications, little is still known about its pathophysiology and pathogenesis. Some reasons for this shortcoming can be ineffective disease identification and inappropriate study approaches (Tardif et al., 2009). With the use of animal models to facilitate research for better disease identification and intervention, the baboon comes in handy for the research in endometriosis. There is a significant anatomical and physiological similarity between the female reproductive system of the baboon and that of the human primate. Moreover, endometriosis will affect similar sites in humans as in the baboon, with the exception the rarity of the disease occurrence in the baboon oviduct. The ability of endometriosis spread to skip the baboon oviduct is a mystery yet to be unravelled. It is one of the shortcomings in using the baboon to model endometrioses in humans. Otherwise, the endometriosis of the uterus-associated organs, the ovaries, cervix, vagina and the perineum occur at similar measures in both humans and the baboon. Further, similar gynaecologic procedures as are used in humans can be effectively adapted for the baboon and other nonhuman primates, which may help reduce the high cost of research associated with the use of nonhuman primates as research models.
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