Hum. Reprod. Advance Access published online on April 23, 2007
Human Reproduction, doi:10.1093/humrep/dem038
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Spontaneous adenomyosis in the chimpanzee (Pan troglodytes): a first report and review of the primate literature: Case Report
1 Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO 65212, USA 2 School of Medicine, University of Missouri, Columbia, MO 65212, USA 3 Veterinary Resources, Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX, USA 4 Department of Laboratory Animal Medicine, Southwest Foundation for Biomedical Research, San Antonio, TX, USA
5 Correspondence address. Tel: +1-573-882-1725; Fax: +1-573-882-9010; E-mail: barrierb{at}health.missouri.edu
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Abstract |
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Adenomyosis is a non-neoplastic condition characterized by the presence of ectopic endometrium in the myometrium with hyperplasia of adjacent smooth muscle. Common symptoms in women include debilitating pelvic pain and abnormal uterine bleeding, and the condition has been paradoxically associated with both multiparity and subfertility. Adenomyosis spontaneously occurs in humans and some non-human primates, including the baboon and macaque, where it has been associated with primary infertility and the presence of endometriosis. No cases of adenomyosis have been previously reported in Pongidae such as gorilla, orangutan or chimpanzee. We here describe two cases of naturally occurring adenomyosis in the chimpanzee (Pan troglodytes) and briefly review the literature regarding the presence of adenomyosis in non-human primate species.
Key words: adenomyosis/leiomyoma/non-human primate/chimpanzee
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Introduction |
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TopAbstractIntroductionCase 1Case 2DiscussionReferences |
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Adenomyosis is a non-neoplastic condition characterized by the presence of ectopic endometrium in the myometrium with hyperplasia of adjacent smooth muscle (Zaloudek and Norres, 1987
). In women, it can result in debilitating pelvic pain (both cyclical and non-cyclical), can cause abnormal uterine bleeding and has been paradoxically associated with both multiparity and infertility (Parazzini et al., 1997; Matalliotakis et al., 2005). This paradoxical correlation with both fertility and infertility punctuates our shallow understanding of the pathophysiology of adenomyosis.
Spontaneous adenomyosis has been reported in many non-human primate species, including macaques and baboons (Table 1). In baboons, adenomyosis has been associated with primary infertility, raising the possibility that it may be a cause of unexplained infertility in the human (Barrier et al., 2004). In Macaca mulatta, spontaneous adenomyosis has been reported in both free ranging and captive monkeys (DiGiacomo 1977) and in monkeys exposed to unopposed estrogen (Baskin et al., 2002). Adenomyosis has also been found in other monkeys of the family Cercopithidae, including the pigtail macaque (Macaca nemestrina) and the cynomolgous monkey (Macaca fascicularis) (Ami et al., 1993; Waterton et al., 1993; Obasanjo et al., 1998). No case of adenomyosis has been previously reported in the family Pongidae: gorilla, orangutan or chimpanzee. We report two cases of adenomyosis in chimpanzees (Pan troglodytes).
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Case 1 |
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The first animal was a 32-year-old captive-born female chimpanzee who had a history of hyperlipidaemia and atherosclerotic heart disease and expired from congestive heart failure. She had four previous live births, with no recorded Cesarean sections or abortions. There was no record of obvious menorrhagia or dysmenorrhea in the animal's medical history. At the time of necropsy, the uterus appeared five times the normal size with an atrophied endometrium lined by a highly vascular myometrium. On microscopic exam, the myometrium contained a single large focus of adenomyosis — an intra-myometrial collection of endometrial glandular epithelium lacking nuclear atypia and mitoses and surrounded by typical stromal cells (Fig. 1A and B). The lesion was found at least two high power fields from the endometrial cavity. This adenomyotic focus was associated with hyperplasia and increased vascularity of adjacent myometrium. The ovaries were irregularly nodular with multiple atretic follicles, oocytes and involuting corpora lutea. There was no evidence of coexisting peritoneal endometriosis.
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Case 2 |
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The second animal was a 41-year-old female chimpanzee who was found with unexplained paralysis of bilateral lower limbs. Gross inspection revealed that the spinal cord contained an unstable fracture at T7–8. The animal was euthanized and underwent necropsy that demonstrated severe degenerative spondylitis and osteomyelitis with fracture of the spinal column. Direct trauma to the spinal cord resulted in paralysis. At the time of necropsy, an incidental finding of an irregularly enlarged and nodular uterus was documented (Fig. 2). This dam had a history of five previous live births, with no recorded Cesarean sections or abortions. Similar to the previous dam, she had no record of obvious menorrhagia or dysmenorrhea in her medical history. Microscopic examination of the myometrium revealed the presence of multiple leiomyomata as well as multiple epithelial-lined cysts containing uniform columnar cells with no mitoses and oval nuclei, consistent with adenomyosis (Fig. 1C and D). The majority of these lesions were found at least two high power fields from the endometrial cavity. Most adenomyotic foci were surrounded by a reactive hyperplasia of myometrial cells, whereas the leiomyomata appeared to be separate and distinct from these adenomyotic foci. This animal also had no evidence of coexisting peritoneal endometriosis.
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Discussion |
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Adenomyosis is defined as the ectopic presence of endometrial glands within the uterine myometrium, accompanied by surrounding myometrial hyperplasia (Zaloudek and Norres, 1987
). Commonly used histological criteria require endometrial tissue to be present at locations greater than one high power field from the base of the uterine epithelium. Adenomyotic glands are responsive to reproductive steroid hormone exposure and can proliferate and bleed along with the physiologic endometrium. Proliferation and shedding of the ectopic glandular epithelium can be asymptomatic or can cause dysmenorrhea and menorrhagia. These symptoms can frequently be severe and debilitating. Management of adenomyosis in women is currently limited to symptomatic relief using analgesics and/or hormonal compounds. Many patients do not respond to medical intervention; these women can be treated using surgical excision, typically at the expense of their future fertility.
The clinical diagnosis of adenomyosis is frustratingly elusive since it is a disease confined within the myometrium and therefore not directly visible at the time of laparoscopy or hysteroscopy. Recent advances in the diagnosis of adenomyosis using ultrasound and magnetic resonance imaging (MRI) have provided much-needed non-invasive tools (reviewed in Devlieger et al., 2003). However, given the difficulty in establishing a definitive diagnosis, especially at early stages, adenomyosis research has been hampered and the pathogenesis of adenomyosis remains elusive. A natural animal model would aid the development of better diagnostic testing for this disease and bolster our understanding of its pathophysiology and treatment.
The presence of adenomyosis has been reported in non-primate species (reviewed in Greaves and White, 2006). Four canines have been described with adenomyosis, although the disorder appears to be rarely symptomatic and therefore rarely diagnosed or reported (Gelberg and McEntee, 1986; Stocklin-Gautschi et al., 2001; Tamada et al., 2005). It has also been described in two felines, but again is a rarely reported condition (Dow, 1962; Gelberg and McEntee, 1986). There are numerous reports of spontaneously occurring and experimentally induced adenomyosis in mice and to a lesser extent in rats (reviewed, Greaves and White, 2006). With a lack of published histological studies of normal uteri in most animal species, it is unclear whether cases of spontaneous adenomyosis commonly occur in other non-primates.
Monkeys belong to the suborder Anthropoidea, a group of 
150 species that includes apes and humans. Over 90% of the anthropods are monkeys, the remainder are apes and humans. It has been postulated that the order splits into two infra-orders 35–40 million years ago: the Platyrrhini, or new world primates, and the Catarrhini, or old world primates (Goodman et al., 1998). The latter includes the old world monkeys (baboon and rhesus), apes and humans.
As suggested by the names, the anthropod suborders can be distinguished by their nasal features. Old world primates have a small nasal septum and nostrils that project downward, opposable thumbs, fingernails and toenails and they spend time in trees or on flat terrain. They are found on the African and Asian continents. New world primates have wide nasal septums and side-facing nostrils and live solely in trees in Central and South America. Some new world monkeys do not possess opposable thumbs, and a few have an isolated nail on the largest toe. Old world primates (including chimpanzees, baboons and macaques) appear to more closely resemble one another than their new world counterparts. The chimpanzee represents the most humanoid of the old world primates, and therefore, the finding of histologically human-identical adenomyosis in this family is perhaps consistent with expectations.
Both the chimpanzees described in this report experienced uninterrupted menses for many years. The chimpanzee in Case 1 had been pregnant four times, the chimpanzee in Case 2 had been pregnant five times. Any association between fertility status and the development of adenomyosis in chimpanzees is speculative given the few identified cases and the common intentional limitation of chimpanzee fertility using a combination of hormonal contraception (Norplant device), intrauterine device placement and forced abstinence over the animal's lifetime per institutional protocol.
The use of the chimpanzee as an experimental model in research is limited by ethical and political constraints and by cost. Looking to less prohibitive models, there are many reported cases of spontaneous adenomyosis in baboons and rhesus monkeys, and although the prevalence in baboons is unknown, one study found the prevalence in rhesus macaques to be between 12 and 24% depending on whether the population is free-ranging or captive (DiGiacomo, 1977). Much is known about the endometrial physiology of baboons and macaques, which appears to be remarkably similar to that of the human (Slayden and Brenner, 2004; Fazleabas, 2006).
Although much more phylogenetically distant from humans than the chimpanzee, one or both of these old world monkeys may offer a reasonable model for the experimental study of adenomyosis. Of particular interest is the baboon, which is larger and stronger than the macaque, able to tolerate multiple blood draws and laparoscopic surgeries and is amenable to trans-cervical aspiration biopsy of the endometrium (D'Hooghe, 1997). This last feature is extremely important, because hysterotomy is at least weakly associated with development of adenomyosis in the baboon (Barrier et al., 2004). If the same is true across primates, then access to endometrium by hysterotomy for experimental purposes in the macaque could confound interpretation of results from the experimental induction of adenomyosis.
All of the primate species known to develop adenomyosis—including now the chimpanzee—undergo spontaneous monthly menses. It is not known whether adenomyosis in the non-human primate is associated with menorrhagia or dysmenorrhea. Adenomyosis is associated with infertility in the baboon, but this association has not been described in any other species (Barrier et al., 2004). A tabulation of numbers of reported cases for each primate species and associated symptoms is found in Table 1.
Future study of adenomyosis in non-human primates may provide an experimental model for deductive research. The use of non-invasive imaging modalities such as MRI and vaginal ultrasound may allow for enough sensitivity and specificity to recruit animals for study, follow the disease course and measure response to therapies. There is one extant report confirming the utility of MRI for diagnosing spontaneous adenomyosis and following it during treatment with an experimental pure anti-estrogen in a pigtail macaque (Waterton et al., 1993).
Other non-human primates, baboons in particular, might be particularly useful for invasive experimental studies, such as the induction of adenomyosis by trans-cervical aspiration and intra-myometrial injection of aspirant. Another possibility, contingent on identifying candidate genes involved in the pathogenesis of adenomyosis, would be to obtain endometrial basal and stromal cells by trans-cervical aspiration and to modify genes suspected to play a role in pathogenesis. Such genetically modified endometrial tissue might then be successfully transferred back into the uterine cavity and the animal followed by non-invasive imaging for the development of adenomyosis.
The cases reported here demonstrate for the first time that histologically human-identical adenomyosis occurs in the chimpanzee. This data complements existing reports of adenomyosis in the non-human primate.
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