Table 1.
Summary of animal adenomyosis models by species, strain, induction method, duration of induction, and results.
| Pathogenesis | Species/Strain | Induction Method | Duration of Induction | Outcome | References | |
|---|---|---|---|---|---|---|
| Estrogen or estrogenic compounds | Estrogen | AB/Jena and DBA 2/Jena hybrid mouse | Pregnant F1 animals were orally given 1 mg/kg of 17β-phenylaminocarbonyloxyestra-1,3,5(10)-triene-3-methyl ether daily on days 12 to 16 post coitus | ≥10 months | Adenomyosis was found in 10 out of 27 virgin female offspring of estrogen-treated dams from 16 to 33 months of age | [66,67] |
| Rabbit | Stilbestrol (5 mg/mL) was injected i.m. | 2 years | Adenomyosis | [68] | ||
| Rhesus monkeys (Macaca mulatta) | S.c. implants containing 200 mg estradiol | 16 months | Adenomyosis | [69] | ||
| Transgenic mouse | Overexpressing human HSD17B1 | 5–12 months | Adenomyosis appeared at the age of 5.5 months and became more severe at 12 months | [70] | ||
| Sheep | Postnatal daily i.m. injections of estradiol-17β benzoate at a dose of either 0, 0.01, 0.1, 1, or 10 μg/kg body weight from PND 14–27 (period one) or PND 42–55 (period two) | PND 28, PND 56, PND 112 | Immediate responses to EB treatment included dose- and age-dependent increases in uterine wet weight, thickness of the endometrium, myometrium, and LE, but decreases in endometrial glands on PND 28 and 56. Transient exposure to EB decreased gland number and thickness of the endometrium and LE on PND 112 | [71] | ||
| Tamoxifen | CD-1 mouse | Tamoxifen, toremifene, and raloxifene dosed orally 2–5 days after birth consecutively |
42–90 days | Uterine adenomyosis was found in all (14 out of 14) mice dosed with tamoxifen and most mice (12 out of 14) treated with toremifene, in only one animal treated with raloxifene |
[72,73] | |
| C57 mouse | Female C57/BL6J pups (n = 20) were treated with oral tamoxifen (1 mg/kg) from age 1 to 5 days | 5, 10, 15, and 42 days of age | Causes disruption of myometrial development but not adenomyosis | [74] | ||
| Diethylstilbestrol | Balb/c or Balb/c and C3H inbred mouse | Pregnant mice were fed a diet containing 0.2 μg/g (of bodyweight) of DES continuously on the seventh day of pregnancy until the morning after delivery of the young | 18 months of age | Resembled adenomyosis occurred in Balb/c mice with the lesser frequency encountered in the hybrid strain | [75] | |
| CD-1 mouse | Pregnant outbred mice were treated s.c. with daily doses of DES ranging from 0.01 to 100 jug/kg on days 9 to 16 of gestation | 12 to 18 months of age | 1/22 adenomyosis in 5 ug/kg group |
[76] | ||
| Diarylpropionitrile (DPN) | ICR mouse | Mice in DPN group were dosed orally with 5 mg/kg DPN from day 2 to day 5 after birth | 3 months | Neonatal feeding of DPN resulted in adenomyosis in 50% of the mice, but the adenomyotic lesions were located exclusively near the serosa | [77] | |
| Bisphenol A (BPA) | CD-1 mouse | Outbred female CD-1 mice were treated on days 1–5 with subcutaneous injections of BPA (10, 100, or 1000 μg/kg/day) dissolved in corn oil or corn oil alone (Control) |
18 months | Adenomyosis occurred in all groups with an increasing trend in the two highest BPA groups (6% (1/18) Controls, 9% (2/23) BPA-10, 20% (4/20) BPA-100, and 19% (3/16) BPA-1000) | [78] | |
| Dioxin | C57 mouse | Pregnant mice (F0) were exposed to dioxin (10 μg/kg) in corn oil or vehicle alone by gavage on E15.5 (when organogenesis is complete) | 10–12 weeks | Adenomyosis was identified in most animals with a history of direct (F1–F2) or indirect (F3) dioxin exposure. However, although 70% (n = 10) of F1 animals exhibited deep adenomyosis, the incidence of advanced disease was slightly lower in F2 mice (63%; n = 11) and F3 animals (56%; n = 9) | [79] | |
| Ethinyl estradiol (EE2) | ICR mouse | Pregnant mice were exposed to 0.01 mg ethinyl estradiol (EE2)/kg per day or vehicle (olive oil) through oral intubation from day 11 to 17 of gestation. They delivered their offspring and raised them. When the experimental female F1 mice were at 8 weeks of age, they were not exposed to EE2 or to the same dose of EE2 or to vehicle twice a week until 20 weeks of age |
28 weeks | These findings indicate that adenomyosis is induced through either exposure to EE2 prenatally or after sexual maturity, but the highest frequency is seen through the combined exposures | [80] | |
| Progesterone | Balb/c mouse | S.c. implantation of pellets | 12–18 months | Present in almost all animals receiving 665 or 900 µg/day | [80,81] | |
| Prolactin | Pituitary grafts | SHN and SLN mouse | Ectopic (intrauterine and under the renal capsule) pituitary transplantation | 90 days | Incidence: 100% | [82,83] |
| Balb/c mouse | Anterior pituitary (AP) isografting at 8 weeks of age | 36 weeks | Increased the incidence of adenomyosis in mice | [84] | ||
| Wistar rat | Transplantation of a single anterior pituitary gland into the uterine lumen | 12 months | Adenomyosis was induced in six out of eight Wistar rats | [85] | ||
| Balb/c mouse, C3H mouse, or Balb/c and C3H F1 hybrids |
Transplantation of pituitary into the mammary tissue | 6 months | Lesions of adenomyosis were frequent in uteri of C3H and F1 hybrids but essentially absent from Balb/c animals | [86] | ||
| Balb/c, C57, C3H mouse | Pituitary was transplanted into the uterine cavity | 20 weeks | Adenomyosis had formed in the uteri of 22 (91.7%) mice out of 24 Balb/c mice after the transplantation of pituitary glands. Similar findings were obtained by experiments with C3H and C57 mice | [87] | ||
| Dopamine antagonists | SHN mouse | SHN female mice were subcutaneously injected with dopamine antagonists for 30 days or 50 days. | 70 or 90 days of age | The incidences of adenomyosis in the experimental groups of mice for 50 days rose up to over 70% | [88] | |
| Fluoxetine | Wistar rat | 2 mg/kg fluoxetine were given to rats by gavage | 98 days | Histological studies revealed 11 cases of adenomyosis in the noncastrated group receiving fluoxetine |
[89] | |
| Transgenic mouse | Dopamine D2 receptor (DRD2)-deficient mouse | Mice that are deficient in functional D2 receptors were generated | One year old | A large proportion of the female DRD2 deficient mice developed uterine adenomyosis, most commonly in mice greater than one year of age | [90] | |
| Endometrial–myometrial interface disruption (EMID) | Balb/c and C57 mouse | Mechanically induced EMID or thermally induced EMID | 8–12 weeks | Adenomyosis developed in the majority of mice in the EMID groups (83.3% in C57BL/6 mice, 100% in Balb/c mice); adenomyosis was found in 66.7% of the EMID mice 10 weeks later |
[91] | |
| Other transgenic models | Dicer | Dicer inactivated mutant mice | Dicer was inactivated in Müllerian duct mesenchyme-derived tissues of the reproductive tract of the mouse, using an Amhr2-Cre allele | >4 months of age | The glands were found within the myometrium. | [92] |
| FSHR | FSH receptor-haplo insufficient mice | The animals of the required genotype were produced by breeding 129T2/SV EmsJ Fshr−/− male and females of 3–5 months |
12 months of age | Some uteri showed endometrial glands deeply penetrating the myometrium | [93] | |
| Foxl2 | Foxl2 deleted mice | Conditional deletion of Foxl2 in the PN uterus using PR-Cre (Pgrcre/+) mice | PN15, PN25, adult | Myometrial disorder | [94] | |
| β-catenin | Conditionally stabilized β-catenin mouse | Mice that expressed a dominant stabilized β-catenin in the uterus were used by crossing PR-Cre mice with Ctnnb1f(ex3)/+ mice | 4 months of age | The incidence of 40% at 4 months of age and 80% at 6 months of age | [95] | |
| PGD2 | PGD2 synthesis impaired mice | PGD2 is not produced due to invalidation of both lipocalin hematopoietic type (L-PGDS and H-PGDS) genes | 6 months of age | HE staining showed the presence of focal adenomyosis in 35% (n = 9 from 28) of knockout mice | [96] | |
Abbreviations: DES—diethylstilbestrol; i.m.—intramuscular, intramuscularly; s.c.—subcutaneous; PN—postnatal; PND—postnatal day; PR—progesterone receptor; DPN—diarylpropionitrile.