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Abstract

Endometrial stromal polyps (ESP) are a common spontaneous reproductive tract lesion in the female rat. However, there is limited information concerning the etiology, biology, and significance of these polyps as an end point in toxicology and carcinogenicity studies. This paper reviews relevant literature to address these aspects of ESP with respect to potential relevance to human uterine tumors. Endometrial stromal polyps in rodents appear as age-related lesions. There are only a few chemicals tested for carcinogenicity in rat and mouse cancer bioassays associated with increased incidence of ESP with no common characteristics or mechanism of action. Uterine endometrial polyps that occur in women and the uterine stromal polyps that occur in rodents have distinct characteristics, although both types of uterine lesions are common, benign, and noncancerous. Human endometrial polyps develop from both endometrial and stromal components, whereas rodent polyps develop from the stromal component of the uterus. Endometrial polyps in women are hormone sensitive, but there is no scientific or experimental evidence to date that suggests that uterine stromal polyps in rodents are hormone sensitive. Therefore, based on differences in their etiology and biology, endometrial stromal polyps observed in rodent toxicity and carcinogenicity studies appear to have limited relevance to human endometrial polyps occurring in women.

Keywords

toxicologic pathology uterine carcinogenesis rodent pathology safety assessment reproductive system endocrine disrupters.

Introduction

Scientists and regulators rely heavily on results of rodent toxicity and carcinogenicity studies to help identify and understand potential hazards to human health. Informed assessments are based on a thorough understanding of both the statistical and biological significance of findings. In this respect, our understanding is enhanced when bioassays show dose-related toxicities or proliferative lesions in both sexes in both rats and mice, when multiple organ systems are affected, when these target organs are similar in both species and both sexes, and when there is biological relevance between organ systems in rodents and humans. Interpretation of findings can be challenging when there are no dose-response relationships, when toxicities or proliferative lesions are few and limited to one organ system, and when biological relevance is unclear. This latter challenge is often the situation when assessing compounds that affect the rodent female reproductive tract. There are fundamental differences between reproductive physiology of rodents and women (for example, rodents have short, four-day estrous cycles; women have twenty-eight-day menstrual cycles), and there has been little work done in modeling or understanding the molecular and histological similarities between common lesions in the female rodent reproductive tract compared to that of women. Faced with these deficiencies, hazard identification and risk assessment are limited. In order to provide background for such issues, this paper focuses on endometrial stromal polyp, a common spontaneous female reproductive tract lesion observed in chronic carcinogenicity bioassays, with respect to its biology and etiology, and its relevance to risk assessment in women’s reproductive health.

Biology and Etiology of Endometrial Stromal Polyps in Rodents

Endometrial stromal polyp is the most common spontaneous reproductive tract lesion in aged nulliparous female rats (Brown and Leininger 1992; Dinse et al. 2010; Dixon et al. 1999; Eiben 2001; Engelhardt et al. 1993; Giknis and Clifford 2004; Leininger and Jokinen 1990). Uterine stromal polyps appear as single or, less commonly, multiple gelatinous sessile and pedunculated masses that expand into the lumen of the uterus. Histologically, endometrial stromal polyps are described as benign, sparsely cellular fibrous stromal masses covered by well-differentiated endometrium. Pathologists also observe that the endometrium may form glands within the superficial portion of the polyp or become trapped within the stromal proliferation. Polyps may be pedunculated and extend into the uterine lumen from slender stalks and distant from the basally located blood vessels. Such polyps appear predisposed to infarction and inflammation. Endometrial stromal polyps are classified as benign tumors, but pathologists have occasionally reported malignant transformation within stromal polyps, suggesting that they are sites for development of stromal sarcomas. However, stromal sarcomas arise within the endometrial stroma of the uterus as well (Dixon et al. 1999; Leininger and Jokinen 1990), and there is no evidence that polyps represent precancerous lesions.

Scientists in the National Toxicology Program (NTP) identified uterine stromal polyps as one of the most common spontaneous tumors in carcinogenicity bioassays (Brix et al. 2005). The average incidence of uterine stromal polyps was 16% in control Harlan Sprague-Dawley rats and 17% to 20% in control Fisher-344 rats (Brix et al. 2005; Dinse et al. 2010). Evaluation of historical control incidences of uterine stromal polyps in carcinogenicity studies conducted in the European Union and Japan suggests that the incidence of stromal polyps appears to increase over time in outbred strains such as the Wistar Han rat (Tennekes et al. 2004). This genetic drift in stromal polyp incidence also appeared in B6C3F1 mice in which an increased incidence of stromal polyps was observed over ten years with ranges from 0% to 14.3% (Eiben 2001).

Despite this high background incidence, little is known about the etiology, biology, and significance of uterine stromal polyps in rodents. The association of stromal polyps with age in rodents has led to an assumption that their growth is related to effects of unopposed estrogen during the process of reproductive aging, although there are no scientific studies to support this assumption. In fact, the hormonal processes during reproductive aging vary not only between rats and mice, but between different strains, as well (Davis et al. 2001). In rats, reproductive senescence is characterized by irregular and longer estrous cycles, states of unopposed estrogens and androgens, and stages of increased progesterone levels (repetitive pseudopregnancy) ending in anestrus (Vom Saal et al. 1994). Coincidentally, basal levels of the pituitary hormones FSH, LH, and prolactin are increased because of the interplay of endocrine feedback loops during this period. In contrast, mice generally do not have transitions of repetitive pseudopregnancy and can enter reproductive senescence after periods of persistent estrus or enter anestrus without any such prolonged transitions (Gosden et al. 1983). It should be noted that the reproductive lifespan varies considerably between mice and rats, between different strains, and certainly between different environmental conditions (including diets). For example, the average age of cycle cessation in the SD rat is ten to twelve months, that of the Fischer rat is sixteen to eighteen months, that of the C57Bl/6 mouse is sixteen to twenty months, and that of the C3HfC57Bl mouse is greater than seventeen months (Vom Saal et al. 1994). Given such variable influences, it is difficult to evaluate the relationship between the development of stromal polyps and the estrogen status of the animal by age without carefully controlled studies.

As rodents age, the uterine stroma appears more sensitive to progesterone (and androgen) influences than estrogen influences. During the transition phase in mice, average and peak serum estradiol levels are actually reduced compared to their normal cycle periods (reviewed in Vom Saal et al. 1994). In rats, the concentration of estrogen receptor and the overall estrogen-binding capacity in the uterus also significantly diminishes with increasing age (Gesell and Roth 1981). Endometrial mitotic activity, which clearly correlates with estrogen activity, decreases with increasing age, whereas uterine stromal mitotic activity, which correlates with progesterone activity, increases with increasing age in both rats and mice (Finn and Martin 1969; Krueger et al. 1975). Similarly, the collagen content of the uterus dramatically increases to a poorly vascularized sclerotic or hyalinized appearance as a function of age in both rats and mice (Leininger and Jokinen 1990; Vom Saal et al. 1994). Overall then, the development of stromal polyps is certainly linked with advancing age, but it is not clear whether stromal polyps are estrogen, androgen, progesterone, or prolactin dependent, or whether the interactions of age and hormonal changes simply create a uterine environment conducive to the development of stromal polyps.

Are They Considered Evidence of Carcinogenicity in Chronic Bioassays?

Because endometrial stromal polyps are one of the most common naturally occurring lesions in rodents, the significance of their appearance in chronic two-year carcinogenicity bioassays is often considered equivocal (uncertain), and increases in the incidence of stromal polyps alone have not been interpreted as clear evidence of carcinogenicity. Of over 400 studies conducted for carcinogenicity by the National Toxicology Program, only 4 (decalin; 1,2- dichloroethane; 1,5-naphthalenediamine; and 3,3'-dimethoxybenzidine-4,4'-diisocyanate) were reported to show increased incidence of uterine stromal tumors in mature treated female mice or rats.

In mice, two chemicals tested for carcinogenicity, decalin (NTP TR 513, 2005) and 1,2-dichloroethane (NCI-CG-TR55, 1978), showed marginally increased incidences of uterine stromal tumors when incidences of stromal polyps and stromal sarcomas were combined for statistical analysis. For decalin, stromal polyps occurred at incidences of 0/49, 0/50, 2/50, and 3/50 for control, low-, mid-, and high-dose groups, respectively, and combined stromal polyp or sarcoma incidences were 0/49, 0/50, 2/50, and 4/50 for control, low-, mid-, and high-dose groups, respectively (NTP TR 513, 2005). This finding was considered equivocal evidence of carcinogenicity because the incidences in the top dose group were not highly significantly increased compared to the controls, despite an overall positive trend. For 1,2-dichloroethane, endometrial stromal polyps were diagnosed in 3/49 (6%) low-dose females and 2/47 (4%) high-dose females, but in no controls. Uterine endometrial stromal sarcomas occurred in 2/49 (4%) of the low-dose and 3/47 (6%) high-dose females, but in no controls (0/60 pooled control or 0/60 matched vehicle control; NCI-CG-TR-55, 1978). The observations were significant when the incidence of stromal polyps and stromal sarcomas was combined, although neither incidence alone was significantly different compared to controls. The incidences of mammary adenocarcinomas and alveolar and bronchial adenomas were also significantly increased in test article–treated mice of both sexes compared to controls. The report concluded that 1,2-dichloroethane was found to be carcinogenic to B6C3F1 mice, based on mammary adenocarcinomas and endometrial tumors (stromal polyp and sarcoma combined) in female mice, and alveolar/bronchiolar adenomas in both sexes of mice.

There are a few studies of chemicals in which uterine polyps were increased in female mice but were not considered to be evidence of carcinogenicity. For example, inhalation studies of propylene conducted by the NTP showed a positive trend in the occurrence of uterine stromal polyps with exposure (p < .05; 0/47; 0/47; and 3/48 [6%]), but no statistical difference between the incidence in the high-dose group compared to the concurrent control group (NTP TR 272, 1985). The incidence of stromal polyps was also higher in the high-dose group female mice compared to the mean historical control rate (22 in 2,411 female mice, or 0.9%), but was within the range (0% to 6%) observed in studies throughout the NTP carcinogenesis program. The report concluded that occurrence of endometrial stromal polyps was not considered to be clearly related to exposure to propylene and there was no evidence of carcinogenicity in female B6C3F1 mice.

Results from a one-year neonatal mouse carcinogenicity study of quinacrine showed an increased incidence of endometrial hyperplasia and uterine stromal polyps at higher doses (Cancel et al. 2006). Quinacrine is used for nonsurgical female sterilization and is mutagenic and clastogenic in vitro. The carcinogenicity study was specifically designed to evaluate potential reproductive tract lesions as quinacrine was dosed during developmental windows of susceptibility (postpartum days 8 and 15), and mice were observed for fifty-two weeks. Uterine stromal polyps occurred at incidences of 0/23, 0/24, 4/23, and 3/22 in control, low, mid, and high doses, respectively, which was statistically significant in trend tests but not in pairwise comparisons. The authors concluded that quinacrine administered twice to neonatal mice may have enhanced or accelerated the development of endometrial hyperplasia and uterine stromal polyps at higher doses, but “because uterine stromal polyps are a commonly observed benign tumor in older mice, the significance of this finding is unclear and will require a weight of evidence evaluation for a conclusion on the carcinogenic potential of quinacrine.”

Similar to mice, few chemicals have been associated with induction of stromal polyps in rats as evidence of carcinogenicity. A study of 1,5-naphthalenediamine, conducted in 1978, was associated with increased uterine stromal polyps in female Fischer 344 rats with incidence levels of 2/24 (8%), 14/49 (29%), and 20/48 (42%) in control, low-dose, and high-dose groups, respectively (NCI-CG-TR-143). Several of these tumors showed a malignant phenotype within the stroma of the polyp and were classified as endometrial stromal sarcomas. The incidence of female rats having either clitoral gland adenoma or carcinoma was also statistically significant. Based on the pathology results, 1,5-naphthalenediamine was considered to be carcinogenic to female Fischer 344 rats and associated with adenomas and carcinomas of the clitoral gland. The report also concluded that 1,5-naphthalenediamine feeding appeared to be associated with increased incidences of thyroid and liver neoplasms and uterine polyps in female rats and liver neoplasms in male rats.

3,3'-Dimethoxybenzidine-4,4'-diisocyanate, a dimer of o-anisidine-4,4'-diisocyanate, was selected for bioassay by the National Cancer Institute because of the structural similarity of this compound to 3,3'-dimethoxybenzidine, a carcinogen in Fischer rats (NCI-CG-TR-128, 1979). For both sexes of rats, there was a significant positive association between dosage and the incidence of leukemia and malignant lymphoma and a significantly higher incidence of neoplasms of the skin in dosed male rats compared to control male rats. There was a significant positive association between the dosages administered and the incidences of endometrial stromal polyps in female rats (0/20, 5/48 [10%], and 10/48 [21%] in control, low-dose, and high-dose groups, respectively). The report concluded that under the conditions of the bioassay, 3,3'-dimethoxybenzidine-4,4'-diisocyanate was carcinogenic in Fischer 344 rats and associated with increased incidence of leukemia and malignant lymphoma in both sexes, skin neoplasms in male rats, and increased incidence of endometrial stromal polyps in female rats.

Uterine stromal polyps have increased in rats with the administration of other chemicals but were not considered evidence of carcinogenicity because they were not dose related. For example, female rats exposed to 2-amino-5-nitrothiazole had a higher incidence of uterine endometrial stromal polyps in the low-dose group than in controls (2/50, 9/49, and 3/50 for control, low-, and high-dose, respectively; NCI-CG-TR-53, 1978). Since only three high-dose animals had this tumor, the occurrence of uterine tumors in the low-dose group could not be clearly associated with administration of the test chemical. Similarly, female rats exposed to 1H-benzotriazole had a significantly higher incidence of endometrial stromal polyps in the low-dose group than that in the corresponding controls (2/48, 10/45, and 8/50 in control, low-, and high-dose groups, respectively; NCI-CG-TR-88, 1978). However, the incidence in the high-dose group was not significant, nor was there significance when the incidences of endometrial stromal polyps and stromal sarcomas were combined. The report concluded that endometrial stromal polyps were not associated with the administration of 1H-benzotriazole.

Steroidal estrogens and estrogenic or endocrine-disrupting chemicals have been tested for carcinogenicity in the NTP testing program without significant increases in rodent stromal polyp induction and without clear evidence of carcinogenic activity. Methoxychlor, a pesticide with estrogenic activity, showed no evidence of carcinogenicity in a chronic bioassay in Osborne-Mendel rats and B6C3/F1 mice; uterine stromal polyps were observed in 0/19, 1/34, and 4/35 in rats (NTP TR 35). In a multigeneration chronic bioassay, genistein, a naturally occurring isoflavone with estrogenic activity, was tested for carcinogenicity in a unique multigenerational exposure design to maximize potential effects on the reproductive tract in rats (NTP TR 545). In this testing regimen, genistein showed some evidence of carcinogenicity based on increased incidences of mammary gland adenoma and adenocarcinoma (combined) in the F1 generation (dosed from conception until termination at day 140) and the F3 generation (dosed from conception until weaning and terminated at day 140). Both uterine stromal polyps and uterine stromal sarcomas were observed in this genistein study without significance: uterine stromal polyps were observed in 4/54, 1/50, 3/50, and 1/49 in controls, 5, 100, and 500 ppm, respectively, and stromal sarcomas observed in 1/54, 0/50, 0/50, and 1/49 in controls, 5, 100, and 500 ppm, respectively (NTP TR 545). Recently, ethinyl estradiol (EE), a steroidal estrogen, was tested for carcinogenicity in a similar multigenerational exposure design (NTP TR 548, 2010). Multiple generations of NCTR Sprague-Dawley rats were continuously dosed with EE in feed from conception to two years (F1C), from conception to twenty weeks followed by control feed until termination at two years (F1T140), and exposing offspring of two prior generations of ethinyl estradiol-exposed rats to additional EE in feed from conception through weaning (postnatal day 21), followed by control feed through termination (F3T21). A marginally positive dose trend in the incidences of uterine stromal polyps occurred in F1T140 female rats: 2/51 (3.9%), 5/50 (10%), 6/50 (12%) and 7/50 (14%) in 0, 2, 10, and 50 ppm, respectively. A significantly increased incidence of uterine stromal polyps occurred in the low-dose, 2 ppm group, in F3T21 female rats: 1/52 (1.9%), 7/50 (14%), 2/50 (4%), and 5/50 (10%), respectively. The significance of increased incidence in uterine stromal polyps confined to the low-dose group was considered equivocal. Increased incidences of uterine non-neoplastic lesions in the F₁C females included atypical focal hyperplasia in all dosed groups, endometrial hyperplasia in the high-dose group, and squamous metaplasia in the 10 and 50 ppb groups. F₃T21 females had increased incidences of atypical focal hyperplasia in all exposed groups and an increased incidence of squamous metaplasia in the high-dose group. There was an increased incidence of eosinophilic focus in the liver of 50 ppb F₁C females and an increased incidence of basophilic focus of the liver in the 50 ppb group of F₁T140 females. The study report concluded that there was no evidence of carcinogenic activity of ethinyl estradiol in male or female Sprague-Dawley rats exposed continuously to 2, 10, or 50 ppb EE (F1); and equivocal evidence of carcinogenicity of EE based on marginally increased incidence of uterine stromal polyps in the F1T140 female rats (exposure to EE compound from conception through twenty weeks followed by control feed until termination).

In summary, there are only a few compounds in these various NTP-based carcinogenicity bioassays in which an increased incidence in uterine endometrial stromal polyps was considered significant. Of these few compounds, clear evidence of carcinogenicity had been determined based on the weight of evidence, which included the induction of neoplasms in both sexes and at multiple sites. There is no case in which a compound was determined to be carcinogenic based on a singular finding of increased uterine stromal polyp incidence in treated female animals. Based on review of the NTP carcinogenicity assays conducted since 1978, a treatment-related increase in uterine stromal polyps appears to be an uncommon event. Additionally, studies of endocrine-disrupting or estrogenic compounds show no clear evidence of stromal polyp induction, suggesting that polyps are not estrogen-dependent growths.

Consideration of the Relevance of Endometrial Stromal Polyps in the Uterus of Rodents and Women

A number of factors should be considered with respect to assessing the relevance of endometrial stromal polyps in rodents with respect to uterine tumors in women, including comparative morphology and molecular pathology, pathogenesis including exogenous/hormone dependence, and biological behavior and significance of tumors in women. As in rats, uterine endometrial polyps are common in women, with reported incidences ranging from 10% to 25% and peak incidence occurring in women aged forty to forty-nine years (Kurman 1994). Histologically, endometrial polyps in women are characterized as benign sessile or pedunculated masses of hyperplastic and cystically dilated endometrial glands in a fibrous stroma. Large vessels are located within the polyp. In women, polyps can have diverse patterns related to hormone status, and these lesions are classified morphologically according to the epithelial component (Mazur and Kurman 2005; Ramirez and Lawrence 2003). Because focal glandular proliferations are often identified at the base of the lesions, endometrial polyps are thought to arise from hyperplasia of the basalis layer (the endometrial layer that is not shed during menstruation) in women (Kurman 1994), although molecular studies have shown that karyotypically aberrant cells belong to the stromal component of endometrial polyps (Dal Cin et al. 1998). Endometrial stromal polyps in women are not precancerous lesions (Kurman 1994; Perry et al. 2010). Thus, in both rodents and women, these polyps are not considered precancerous, but malignant phenotypes may arise within them: in rats, it is a sarcomatous phenotype, and in women, it is a carcinomatous phenotype.

Although the etiology of uterine stromal tumors in rodents has not been identified, it is well documented that endometrial polyps in women are hormonally responsive. For example, treatment with tamoxifen has been shown to increase the incidence of endometrial polyps in women (reviewed in Deligdisch 2000). Indeed, tamoxifen treatment has a significant effect on the endometrium in women as a proliferative estrogen-agonist, which is in contrast to its use as an anti-estrogen in the treatment of breast cancer. The estrogen-agonist effect on the uterus is manifested by polypoid endometrial proliferation with glandular hyperplasia ranging from simple to complex and atypical. The stroma of these polyps is usually fibrotic. Long-term tamoxifen uses as well as unopposed estrogen use are also associated with the development of endometrial carcinomas (Cohen et al. 2001; Cohen 2004). In contrast, there is no clear evidence that estrogen or estrogen-like compounds are associated with endometrial polyp formation in adult rats. Tamoxifen given neonatally in the rat induces uterine adenocarcinoma and squamous cell carcinomas but has not been associated with endometrial polyp formation (Carthew et al. 2000).

Women also have a category of lesions defined as stromal nodules and stromal sarcomas. These lesions are uncommon but have histological similarities to rodent stromal polyps. The stromal tumors in women appear as sessile or polypoid masses covered by only a thin layer of endometrium, or they extend within the uterine stroma. Endometrial stromal nodules in women have a good prognosis, and surgery appears curative. Stromal sarcomas are rare gynecological tumors (0.2% of uterine tumors) with an indolent behavior, and they are often diagnosed after hysterectomy (Kondi-Pafiti et al. 2009; Vanni and Parodo 2004). They are progesterone-responsive malignancies, but their causes is unclear. They have a low malignant potential and a five-year survival rate of 60% to 80% (Dionigi et al. 2002). Endometrial stromal nodules and sarcomas are further distinguished from endometrial polyps at the genetic/molecular level in that stromal nodules are karyotypically heterogeneous, whereas endometrial polyps are monoclonal. Such molecular studies of rodent uterine stromal polyps are lacking.

Conclusions

Overall, there is no evidence that uterine endometrial polyps in women and uterine stromal polyps in rodents are morphologically or biologically comparable, except that they are both common benign lesions of the uterus. Among their distinctions, human endometrial polyps develop from both endometrial and stromal components, whereas rodent polyps develop from the stromal component of the uterus; importantly, endometrial polyps in women are hormone dependent, whereas there is no evidence suggesting that uterine stromal polyps in rodents are hormone dependent. There is no clear evidence that estrogen, estrogen-like compounds, tamoxifen, or endocrine-disrupting compounds are associated with endometrial polyp formation in adult rats. Indeed, the pathogenesis of rodent uterine stromal polyps is unclear. The few chemicals tested for carcinogenicity in rat and mouse cancer bioassays that have been associated with increased incidence of endometrial polyps in rodents appear to have no common characteristics or mechanism of action. Instead, uterine stromal polyps in rodents appear as common, age-related lesions and not as morphological counterparts with relevance to endometrial polyps in women.

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Endometrial Stromal Polyps in Rodents: Biology,Etiology,and Relevance to Disease in Women

Abstract

Keywords

Introduction

Biology and Etiology of Endometrial Stromal Polyps in Rodents

Are They Considered Evidence of Carcinogenicity in Chronic Bioassays?

Consideration of the Relevance of Endometrial Stromal Polyps in the Uterus of Rodents and Women

Conclusions

References