Location of inclusion cysts in mouse ovaries in relation to age, pregnancy, and total ovulation number: implications for ovarian cancer?

Abstract

Benign ovarian cysts are thought to be precursor lesions that differentiate and transform into carcinoma. With the aim of testing the hypothesis that increased ovulation number increases the frequency or number of ovarian cysts, the development and appearance of ovarian cysts was investigated in mice of differing ages and total lifetime ovulation number. High total ovulation number was induced by keeping mice in cages divided by a screen, with a male on one side and two females on the other side. Significantly more cysts were observed in animals subjected to incessant ovulation for 8 months and in 12 month breeding mice than in 3-month virgin mice or 1-month prepubertal animals. These cysts had the appearance of benign serous inclusion cysts. When cystic ovaries were serial sectioned, 47% of cysts had a connection to the ovarian hilus and potentially to the tubules of the rete ovarii, 31% were adjacent to the hilus, and 22% had an intra-ovarian location. A significant increase in intra-ovarian cysts was observed in the 8-month incessant ovulation group, implying that high ovulation number leads to ovarian surface invagination and inclusion cyst formation. In conclusion, ovarian inclusion cysts may be derived from more than one epithelial source, but incessant ovulation may increase the proportion derived from the ovarian surface epithelium. Because the cysts observed resembled human serous inclusion cysts these results have possible implications for epithelial ovarian carcinoma.

Ovarian Epithelial Inclusion Cysts in Chronically Superovulated CD1 and Smad2 Dominant-Negative Mice

“…The formation of cysts has been reported previously to be location dependent after chronic ovulation (16). To confirm and extend these previous observations, the location of each cyst was determined as either located in the hilus (this did not include cysts that were on the oviduct side but not physically located within the hilus), perpendicular to the hilus at either edge, opposite the hilus, or in the middle of the ovary (Fig.…”

“…The wounding and healing process is necessary for oocyte release, but frequent rupture and repair also increases the chance for spontaneously developing mutations to accumulate in cellular DNA (13)(14)(15). Indeed, enhanced cyst formation and epithelial proliferation was observed in incessantly ovulating mice linking the process of ovulation with cyst formation (16,17). In addition, factors that increase ovulation increase the risk of developing ovarian cancers, whereas factors that reduce total lifetime ovulation reduce cancer risk (18 -25).…”

E-cadherin expression and bromodeoxyuridine incorporation during development of ovarian inclusion cysts in age-matched breeder and incessantly ovulated CD-1 mice

“…The dissection, fixation, and processing of the ovaries has been described previously, as has estimation of total lifetime ovulation number [1,2]. Female out-bred CD-1/Swiss Webster mice were housed in two groups in a temperature- and light-controlled facility; (1) in breeding pairs (BR group) with one female housed with a male Swiss Webster mouse and (2) in a cage divided by a perforated screen, with two females housed beside, but not in contact with a single male mouse, to induce incessant ovulation (IO group) and prevent breeding [1].…”

“…Our previous studies demonstrated that ovaries of CD-1/Swiss Webster mice subjected to incessant ovulation (IO) had changes suggestive of a precancerous state, such as an increased number of surface invaginations, stratification of the ovarian surface epithelium (OSE) and inclusion cyst formation [1,2]. Dilation of the rete ovarii tubules to form serous inclusion cysts also occurred with age in breeding females with a much lower total ovulation number [2].…”

“…Dilation of the rete ovarii tubules to form serous inclusion cysts also occurred with age in breeding females with a much lower total ovulation number [2]. However these studies compared ovaries from incessantly ovulated ovaries and breeders of different ages.…”