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In this brief review, we discuss our efforts to validate nanoplatforms for imaging and treatment of endometriosis. We specifically highlight our use of nonhuman primates and primate tissues in this effort. Endometriosis is a painful disorder of women and nonhuman primates where endometrium-like tissue exists outside of the uterus. There are no reliable, specific, and noninvasive diagnostic tests for endometriosis. Laparoscopic imaging remains the gold standard for identifying small endometriotic lesions in both women and monkeys. Visualizing and surgically removing microscopic lesions remains a clinical challenge. To address this challenge, we have created nanoparticle reagents that, when administered intravenously, enter endometriotic lesions both passively and by targeting endometriotic cells. The particles can carry payloads, including near-infrared fluorescent dyes and magnetic nanoparticles. These agents can be used for imaging and thermal ablation of diseased tissues. We evaluated this approach on macaque endometriotic cells, human and macaque endometrium engrafted into immunodeficient mice, in endometrium subcutaneously autografted in macaques, and in rhesus monkeys with spontaneous endometriosis. Employing these models, we report that nanoplatform-based reagents can improve imaging and provide thermal ablation of endometriotic tissues., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)

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.

The baboon is an established model for endometriosis research. This report describes the occurrence of spontaneous endometriosis involving the ileocaecal junction and associated regional lymph nodes in the baboon. All endometriotic foci lacked the nuclear atypia, abnormal mitotic activity and altered nuclear-to-cytoplasmic ratio typical of malignancy. These findings are identical to reports in the human in which ileocaecal and colonic endometriosis is associated with endometriosis in pericolonic and mesenteric lymph nodes. The similarity between baboon and human colonic endometriosis in both location and pathology is striking and lends further evidence supporting the validity of the baboon as a model for human endometriosis.

Background: Endometriosis is one of the most common causes of infertility and pelvic pain. A baboon model has recently been developed whereby the intrapelvic injection of menstrual endometrium results in the induction of endometriotic lesions. We have used this model to investigate changes in ultrastructure and glycosylation of endometria from normal and diseased baboons., Methods: Endometriosis was induced in eight female baboons; endometrial tissue and endometriotic lesions were removed on days 9-11 post ovulation between 3 and 16 months of disease and compared with endometrium from 17 control animals, using electron microscopy and lectin histochemistry., Results: Ultrastructurally, diseased endometrial glands showed abnormalities in secretory vacuoles and an intracellular accumulation of glycogen; in later stages of the disease, glands resembled those of the late secretory phase endometrium. The abnormalities were mirrored by changes in glycan expression. In early disease, there was an increased binding of lectin from Dolichos biflorus agglutinin (DBA) to fucosylated N-acetylglucosamine residues, whereas in later stages, this binding generally decreased in association with the appearance of a late secretory phenotype., Conclusions: Endometriosis is accompanied by progressive changes in the gland architecture and biochemistry resulting in dyssynchrony within the window of uterine receptivity, which may result in the reduced fertility associated with this disease.

Background: Endometriosis occurs in several non-human primate species that have menstrual cycles. This study investigated the prevalence and familial aggregation of endometriosis in one of those species, the rhesus macaque., Methods: Between 1978 and 2001, 142 animals with endometriosis were identified from necropsy and surgical records and through the use of magnetic resonance imaging (MRI) at the Wisconsin National Primate Research Center, Madison, USA. All cases were used to build one large multigenerational pedigree and nine nuclear families comprising 1602 females in total. By 2002, the pedigrees contained 124 cases diagnosed at necropsy; 17 at surgery and three at MRI. Female animals that had died aged > or = 10 years without endometriosis, had both ovaries until at least 1 year prior to death, and had a full necropsy, were considered unaffected., Results: The prevalence of endometriosis among necropsied animals aged > or = 10 years in the colony was 31.4% [95% confidence interval (CI) 26.9-35.9%]; prevalence increased with rising age and calendar age at death. Familial aggregation of endometriosis was strongly suggested by a significantly higher average kinship coefficient among affecteds compared with unaffecteds (P < 0.001) and a higher recurrence risk for full sibs (0.75; 95% CI 0.45-1.0) compared with maternal half sibs (0.26; 95% CI 0.10-0.41) and paternal half sibs (0.18; 95% CI 0.02-0.34). The segregation ratio among affected mothers (44.2%) was not significantly higher compared with unaffected mothers (36.6%)., Conclusions: The results support familial aggregation of endometriosis in the rhesus macaque, and indicate that this is a promising animal model for the investigation of mode of inheritance, the location of potential genetic susceptibility loci and the influence of environmental factors.

This study was done to test the hypothesis that the incidence and recurrence of retrograde menstruation is higher in baboons with spontaneous endometriosis than in those without. A total of 399 laparoscopies was performed on 113 female baboons. Group 1 consisted of 84 animals with a normal pelvis (including 23 that later underwent induction of endometriosis and were assigned to group 4), group 2 comprised nine baboons with spontaneous endometriosis acquired during the last 2 years of the study, group 3 had 18 baboons with long-term spontaneous disease, and group 4 comprised 25 animals with induced endometriosis. Retrograde menstruation was defined by the presence of blood-stained peritoneal fluid (red or dark brown) during menses. Recurrence of retrograde menstruation was analysed during the first two laparoscopies in 13 baboons. Peritoneal fluid was 10 times more frequently blood-stained during menses (62%) than during non-menstrual phases (6%). Retrograde menstruation was observed more frequently in animals with spontaneous disease (groups 2 and 3, 83%) than in animals with a normal pelvis (group 1, 51%). Recurrence of retrograde menstruation was observed more frequently in baboons with spontaneous endometriosis (5/5) than in those without (3/8). The results of this study demonstrate that retrograde menstruation is common in baboons, with a higher prevalence and recurrence in animals with spontaneous endometriosis than in those without.

The use of a GnRH agonist or a progestational steroid (levonorgestrel) for the treatment of endometriosis in monkeys was compared. Four monkeys with spontaneous endometriosis were treated for 6 months with a continuous infusion of a GnRH agonist (25 micrograms/day). Five animals with surgically induced endometriosis were treated with the same agonist for 3 months. An additional group of five monkeys with surgically induced endometriosis was treated orally with levonorgestrel (1 mg/kg X day), while a final group of four monkeys served as untreated controls. During agonist treatment, the four monkeys with spontaneous endometriosis gained body weight and had a greater than 80% decline in cyst size (representing a decline in secretory activity). Monkeys with surgically induced endometriosis had almost total resolution of endometrial lesions during agonist treatment, which was maintained throughout a 4-month posttreatment period. After initial stimulation at the onset of the GnRH agonist infusion, serum LH, FSH, estradiol, and progesterone levels decreased to near the levels of detection, where they remained until treatment was terminated. In comparison, levonorgestrel reduced endometrial lesion size, but the monkeys did not resume normal cycles as early as those treated with the agonist. Levonorgestrel-treated monkeys had normal serum LH and FSH levels, but low serum estradiol and progesterone levels. The results of this study indicate that either continuous infusion of a GnRH agonist or administration of levonorgestrel is effective for treating endometriosis in monkeys. The hormonal data suggest that the GnRH agonist acts at the level of the hypothalamus and pituitary, whereas levonorgestrel acts at the ovarian level.