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BOR - Papers in Press, published online ahead of print June 15, 2005.
Biol Reprod 2005, 10.1095/biolreprod.105.042622
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BIOLOGY OF REPRODUCTION 73, 586–590 (2005)
DOI: 10.1095/biolreprod.105.042622
© 2005 by the Society for the Study of Reproduction, Inc.

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Carcinogenic Potential of Ovulatory Genotoxicity1

William J. Murdoch 2 

Department of Animal Science and Reproductive Biology Program, University of Wyoming, Laramie, Wyoming 82071


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RELATIONSHIP OF OVULATION TO...
 OXIDATIVE DAMAGE TO DNA...
 CONCLUSIONS AND ADDITIONAL...
 REFERENCES
 
Ovulation is a rate-limiting event for the perpetuation of a species; unfortunately, it imparts a cancer risk. Reactive oxidants generated during the mechanics of ovulatory follicular rupture damage the DNA of ovarian surface epithelial cells that are located within a limited diffusion radius. Those cells that survive the trauma of ovulation, along the margins of a ruptured follicle, proliferate and migrate to reconcile the discontinuity within the ovarian epithelium created at the site of oocyte release. It is conceivable that clonal expansion of an ovarian surface epithelial cell with unrepaired DNA, but not committed to death, could be an initiating factor in the etiology of common ovarian cancer. In fact, the majority of cancers of the ovary are derived from the surface epithelium; and circumstances that avert ovulation (oral contraceptive use, pregnancy/lactation) protect against ovarian adenocarcinoma. Not surprisingly, the genotoxic potential of ovulation is exacerbated by malfunctions in tumor suppressor/cell-cycle arrest and base-excision repair mechanisms. Recent experimental evidence indicates that vitamin E and progesterone protect against ovarian metaplasia by negating the oxidative stress of ovulation and by enhancing the repair capacity (genomic integrity) of the surface epithelium, respectively. Ovarian cancer of surface epithelial origin is a deadly insidious disease because it characteristically remains asymptomatic until it has metastasized throughout the abdominal cavity; therefore, prevention is a high priority.

epithelial ovarian cancer, ovulation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RELATIONSHIP OF OVULATION TO...
 OXIDATIVE DAMAGE TO DNA...
 CONCLUSIONS AND ADDITIONAL...
 REFERENCES
 
Ovaries are covered by a layer of epithelial cells that originate during embryonic development upon invagination of the coelomic mesothelium over the gonadal ridges [1]. Ovarian epithelia normally vary in type from simple squamous to cuboidal to low pseudostratified columnar. The surface epithelium is supported over the ovarian cortical interstitium (tunica albuginea) by a basement membrane and is held together by desmosomes and gap or tight junctional complexes. Surface cells are continuous at the ovarian hilum with the mesovarium and peritoneum. Preferential outgrowth of a follicle destined to ovulate brings it into close apposition with the ovarian surface [2].

The preponderance (>90%) of cancers of the human ovary originate from surface epithelial cells. Recognition of the predisposition of the ovarian surface epithelium to cancer was attributed to Sir Spencer Wells in 1872 [3]. The "incessant ovulation hypothesis" of ovarian cancer, based on emerging epidemiological reports suggesting a connection, was proposed by Fathalla nearly a century later [4]. Repeated ovulations, without long dormant periods, were reasoned to somehow cause transformation of the ovarian epithelium. It now is evident that ovarian surface epithelial cells in the vicinity of the site of follicular rupture are exposed to potential mutagens (inflammatory mediators and toxic oxidants) produced during the periovulatory period [2, 5, 6].

Ovulation creates a void along the ovarian surface that is mended by the migration of proliferative epithelial cells. A surface epithelial cell perturbed by ovulation and harboring a genomic defect might consequently be propagated during the wound-repair process [7]. Epithelial ovarian cancer is generally considered to be a unifocal disease ultimately arising by clonal expansion from a single cell [3].

According to the International Federation of Gynecology and Obstetrics, there are four basic stages of advancement in common ovarian cancer. Stage I is defined by the formation of a cyst that contains surface epithelial cells that have invaded (via matrix-degrading proteases released at ovulation [8] or by entrapment during luteal involution [9]) the ovarian cortex. Apparently the microenvironment of an inclusion cyst is conducive to metaplastic and dysplastic changes that precede tumorigenesis [7]. Transformed cells typically exhibit a Mullerian morphology akin to tubal, proliferative endometrial, gestational endometrial, or endocervical epithelia and form papillary serous (the most common subtype), endometroid, clear cell (the most lethal subtype), or mucinous tumors, respectively [3, 10]. Malignant cells are extruded into and seed the abdominal cavity when an inclusion cyst ruptures. Pelvic spread and generation of ascites fluid are the hallmarks of Stage II disease. Stage III is characterized by tumor implants involving the small bowel, mesentery, and superficial liver. Distant disseminate metastasis to the parenchymal liver and pleura occur in Stage IV [3]. Abdominal pain and swelling are the most frequent symptoms reported [11]. Death usually results from intestinal (e.g., bowel obstruction) or edematous (e.g., because of recurrent ascites and pleural effusion) complications [12].

Ovarian cancer is the fifth most frequent cancer in women (after breast, colorectal, lung, and endometrium); it carries a 1-in-70 lifetime risk. Diagnoses of epithelial ovarian cancer increase with age (average at initial presentation is 61). Most cases are sporadic; only 5–10% are familial. Risk among first-degree relatives (mother, sister, daughter) can be as great as 50%. Incidences are highest in the industrialized cultures of Europe and North America. Ovarian cancer ranks fourth in cancer-related deaths; it is the most common cause of fatality from a gynecologic malignancy. Less than 25% of patients with metastatic disease survive beyond five years [13].

The primary reason that ovarian cancer is so lethal is that it usually remains clinically silent until it has reached beyond the ovaries. Failure to detect localized/early-stage disease continues to be a major dilemma. Traditional diagnosis has consisted of a serum measurement of the shed differentiation/Mullerian cancer antigen CA-125 and transvaginal sonography. The crux of the problem is that the CA-125 test is insensitive and lacks specificity [14] and the positive predictive value of ultrasound screening is low [15]. Thus, the reality of the matter is that there is no combination of diagnostic tools available that have proven effective in reducing the mortality from ovarian cancer. Treatment of epithelial ovarian cancer generally entails cytoreductive surgery used in combination with platinum-containing drugs, alkylating agents, and/or taxol; notwithstanding, the majority of patients become refractory to chemotherapy and relapse [16].


   RELATIONSHIP OF OVULATION TO EPITHELIAL OVARIAN CANCER
TOP
 ABSTRACT
 INTRODUCTION
 RELATIONSHIP OF OVULATION TO...
OXIDATIVE DAMAGE TO DNA...
 CONCLUSIONS AND ADDITIONAL...
 REFERENCES
 
Humans

Conditions that stave off ovulation, namely pregnancy/ lactation and oral contraceptive use, protect against ovarian cancer by approximately 40% [13, 17–19]. Positive correlations clearly exist between increasing numbers of lifetime ovulations, ovarian precursor lesions, and carcinoma [20– 28]. In one study [26], there was an overall 6% increase in cancer risk with each ovulatory year. Ovulations in the 20– 29 yr age group were associated with the greatest liability. This begs the question: are ovulations at a peak reproductive stage of life more aggressive/damaging toward the ovarian epithelium? A recent report [28] indicates that the ovulatory factor may be more significant in premenopausal than postmenopausal onset ovarian cancer.

It follows that assisted reproductive programs that implement ovulation-inducing strategies would increase the risk for development of ovarian cancer. Yet results of surveys that have attempted to relate the use of fertility drugs to ovarian cancer have been inconclusive; some have deduced that women who do not become pregnant and those subjected to repeated treatments are at an elevated risk [29– 31], whereas others intimate weak or no significant correlations [32–36]. It appears that among nulligravid women, exposure to ovulation-stimulating hormones is associated with borderline serous tumors, but not with metastatic histologic subtypes [37, 38]. Furthermore, rates of ovarian cancer have remained relatively constant over recent decades despite the widespread application of ovulatory stimulants [39]. Nevertheless, because the prospective latency between initiation (i.e., at ovulation) and manifestation of established disease can be quite long (30–40 yr or more), it will be important to continue to monitor recipients of superovulation protocols.

Other Species

There are essentially no published data on spontaneous rates of epithelial ovarian cancer among nonhuman mammals. One would expect incidences to be very low because females of most species are either pregnant/lactating or seasonally anovulatory for the bulk of their reproductive lives. There is evidence in rodents that surface epithelial stratification and ovarian invaginations/cysts are related to total lifetime ovulations [40, 41] and cycles of ovulation induction [42]. Progression to cancer occurred in superovulated rats whose ovaries were exposed locally to an exogenous mutagen [43].

Ovarian peritoneal carcinomatas presumably of surface epithelial descent occur in intensive egg-laying domestic poultry, animals that ovulate nearly every day, at a relatively high frequency (4–40% depending on ovulation history and age) [44–46]. Moreover, inhibition of ovulation with a progestin protected hens from ovarian cancer [47].


   OXIDATIVE DAMAGE TO DNA OF OVARIAN SURFACE EPITHELIAL CELLS AFFECTED BY OVULATION: CARCINOGENIC IMPLICATION AND PROPHYLAXIS
TOP
 ABSTRACT
 INTRODUCTION
 RELATIONSHIP OF OVULATION TO...
 OXIDATIVE DAMAGE TO DNA...
CONCLUSIONS AND ADDITIONAL...
 REFERENCES
 
Base damages to DNA caused by reactive oxygen species are an inevitable by-product of physiological metabolism. To combat this predicament, animals have evolved elaborate enzymatic antioxidant defense mechanisms (superoxide dismutase, glutathione perioxidase, catalase); albeit, these are less than perfect, and some oxidants find their way to DNA targets [48]. Oxidative damage products in DNA are a significant contributor to the risk of cancer development [49–51]; I suggest that the ovulation link is a case in point.

Reactive oxidants are produced in excess during the mechanisms of ovulation and luteinization. It appears that the major source of free radicals is those liberated by leukocytes (respiratory burst) that infiltrate periovulatory follicles [6]. Another contributing factor could be the ischemia-reperfusion flux [52] that accompanies periovulatory tissue remodeling [53, 54].

Ovarian surface epithelial cells that overlie the formative ovulatory stigma suffer irreparable genomic damages and acutely become committed to apoptosis [55]. Bystander surface cells, circumjacent to the ovarian rupture site, are exposed to sublethal concentrations of reactive oxidants. Accordingly, the 8-oxoguanine contents of surface epithelial cells isolated from the perimeters of ovulated sheep, human, and hen follicles were elevated. Adducts in surface cells removed from unaffected ovarian areas, distanced from periovulatory follicles, were at a comparatively low/ baseline level [56–58]. Oxoguanine is arguably the most important mutagenic lesion in DNA; mispairing with adenine during replication can yield GC-to-TA transversions often detected in tumor cells [59–61]. A mutant/viable cell sloughed during the process of ovulation may account for cases of diffuse intraperitoneal disease in which the ovaries remain relatively uninvolved [3].

A defective tumor suppressor gene, such as those that overexpress competitive mutant forms of the growth-inhibitory BRCA1/2, TP53, DAB2, or DIRAS3, is a probable basis for developing ovarian neoplasia as a result of ovulation [62, 63]. Mutations in BRCA1/2 appear to be responsible for aggressive early-onset hereditary disease [64]. Oxidative damages to guanine persisted in ovine ovarian surface epithelial cells that were affected by ovulation in vivo and in which synthesis of TP53 was then negated in culture by an antisense oligonucleotide; this was related to discordant cellular growth rates and expression of CA-125 [65]. More than one-half of human ovarian adenocarcinomas have discernible mutations in TP53 [62] (though numbers of ovulatory cycles were not related to an increased mutation frequency [66]). Chromosomal anomalies and metaplasia have been detected in repetitive subcultures (to mimic recurrent ovulation-wound repair) of ovarian surface epithelial cells of rodents [67, 68].

Limiting ovulatory bouts, and hence diminishing oxidative stresses to the ovarian epithelium, is the presumptive first-line defense against ovarian cancer. Indeed, pharmacological agents (e.g., indomethacin) that cause a blockade of ovulation circumvented (as demonstrated in ewes) the accrual of 8-oxoguanine adducts in follicular-contiguous ovarian surface epithelial cells [56].

In the event of an ovulation, and to avoid accumulations of potentially harmful mutations, it is essential that accurate restoration or proficient removal of anomalous cells comes to fruition. Sublethal oxidative distresses to DNA typically are rectified by TP53-dependent cell-cycle arrest and polymerase ß-mediated base-excision repair mechanisms. The base-excision repair pathway is the principal contributor to the amendment of oxidative (e.g., 8-oxoguanine) corruptions in DNA [69]. Production of TP53 and polymerase ß by ovarian surface epithelial cells of ewes was enhanced by progesterone; the delay in proliferative responses invoked by TP53 allotted the time required for short-patch repairs and proof-readings, which were completed by the midluteal phase [56, 70]. Progesterone also upregulated poly(ADP-ribose) polymerase (PARP1) in sheep ovarian surface epithelial cells [71]. Poly(ADP-ribose) polymerase serves as an adjunct in DNA repair; binding of PARP1 and the synthesis of branched polymers of ADP-ribose in areas adjacent to a single-strand interruption functions as an antirecombinogenic element [72]. Progesterone inhibited proliferation [73] and induced apoptosis [74, 75] in cultures of ovarian surface epithelial cells of macaques. The ovarian epithelium bordering postovulatory follicles of hens (which do not form a corpus luteum) undergoes apoptosis and is resorbed during follicular regression/atresia [58]. Ovarian inclusion bodies of surface epithelium (Stage I disease) can evidently be eliminated via the Fas apoptotic system [76].

Because the prognosis for ovarian cancer patients with metastatic disease is so poor, and early detection has proven elusive, it is imperative that methods of chemoprevention be explored. DNA of ovarian surface epithelial cells associated with the ovulation stigma of ewes was protected from oxidative base damage by pretreatment with d-{alpha}-tocopherol (natural-source vitamin E). Programmed death within the surface epithelium at the apex of the preovulatory follicle (mediated by tumor necrosis factor [TNF]), and correspondingly ovulation, were not altered by {alpha}-tocopherol [57]. Ischemia-reperfusion injury to grafts of ovarian tissues was reduced by vitamin E [77].

As far as is known, vitamin E is the most effective (by acting as a hydrogen donor at its 6-OH group) chain-breaking antioxidant in cellular membranes, and thereby contributes to membrane phospholipid stability and safeguards intracellular molecules against damage imposed by free radicals [78, 79]. Vitamin E also can act via mechanisms beyond its oxidant-quenching properties (e.g., by inhibition of protein kinase C and activation of phosphatase 2A and diacylglycerol kinase pathways). Nitric oxide production by endothelial cells and superoxide release by leukocytes was suppressed by vitamin E [80]. Nonredox modes of {alpha}-tocopherol action include inhibitory and stimulatory effects on rates of mitosis and removal of damaged DNA, respectively [81–84]. Therefore, vitamin E could act during the immediate postovulatory period to impede untoward proliferative responses of ovarian surface epithelial cells until repairs to DNA can be accomplished.

Supplemental vitamin E (e.g., at midcycle) could be of particular value in women designated at risk for the development of ovarian cancer (e.g., those with a genetic predisposition who are not using a contraceptive technique that inhibits ovulation). There is epidemiological evidence suggesting an inverse relationship between consumption of vitamin E and risk of ovarian carcinoma [85, 86]. Similar reports have advocated protective effects of vitamin E against cancers of the lung, colorectum, cervix, and prostate gland [87]. It appears that, in general, incidences of oxidative DNA lesions and susceptibility to cancer are potentiated by micronutrient (e.g., antioxidant vitamin) deficiencies [88]. Interestingly, the circulatory antioxidant status of ovarian cancer patients was reduced compared to age-matched controls; however, whether this condition preexisted during ovulation cycles was unknown [89].


   CONCLUSIONS AND ADDITIONAL CONSIDERATIONS
TOP
 ABSTRACT
 INTRODUCTION
 RELATIONSHIP OF OVULATION TO...
 OXIDATIVE DAMAGE TO DNA...
 CONCLUSIONS AND ADDITIONAL...
REFERENCES
 
The course of ovulation is extraordinary in that it (as a requisite of fertility) involves a self-inflicted injury to the ovary. Inauspiciously, the DNA of neighboring ovarian surface epithelial cells is compromised by oxyradicals; I propose that this constitutes a first step in the etiology of ovarian tumorigenesis. The level of danger escalates when a cell (as a prelude to mutation) escapes (e.g., because of a malfunctional tumor suppressor mechanism) repair or death. Perhaps the ovarian epithelium (notably of humans and laying hens) is vulnerable to genetic damages that are not reconciled because it has not been under a strong evolutionary pressure to respond to superfluous ovulations [90].

It remains uncertain why, in particular, the ovarian surface epithelium is so prone to neoplastic transformation; after all, it represents only a small fraction of the diverse cell types that populate the ovary. Susceptibility may hinge on the fact that normal ovarian surface epithelial cells are of an uncommitted phenotype. Unlike the Mullerian epithelia of the female reproductive tract, development of ovarian surface cells is arrested at an immature pluripotent/ stem stage [7].

The sequences of events that lead to common ovarian cancer are multifactorial. Several aberrant phases are undoubtedly required to yield a malignant phenotype with distinct growth and metastatic advantages. Ovarian cancer is generally considered to have some level of hormonal involvement; progestins are protective and gonadotropins, androgens, and estrogens are facilitative [91–95]. Paracrine-autocrine modulators can also influence ovarian cancer cell behaviors: epidermal growth factor, transforming growth factor (TGF) {alpha}, platelet-derived growth factor, basic fibroblast growth factor, hepatocyte growth factor, keratinocyte growth factor/kit ligand, insulin-like growth factor-I, macrophage colony-stimulating factor, interleukin-1 and -6, TNF, steroidogenesis-inducing protein, and lysophosphatidic acid promote loss of contact inhibition, cellular proliferation, and/or proteolytic enzyme secretion; TGFB1, interferons {alpha} and {gamma}, high-dose TNF, and gonadotropin-releasing hormone are negative effectors [7, 62, 96, 97]. Metastatic spread is protease-dependent; urokinase and downstream matrix metalloproteinases that digest basement membranes and interstitial connective tissues are of particular importance [98]. Vascular endothelial growth/permeability factor is secreted by ovarian cancer cells and has been related to ascites formation and metastasis [99].

It is important to emphasize in closing that a circumstantial association between ovulation and the initiation of common ovarian cancer as presented in this overview does not prove causal effect, and that a simplified/cumulative "ovulation model" is not absolute, and does not explain the genesis of all epithelial ovarian tumors. For example: protection is conferred by tubal ligation or hysterectomy in spite of uninterrupted ovulation; protection provided by one gestation with breast feeding or short-term oral contraceptive use is superior to the predicted benefits of those missed ovulations that would have occurred otherwise; reduced numbers of ovulatory cycles because of menstrual irregularities and infertility (e.g., polycystic ovarian syndrome) are independent risk factors for ovarian cancer; and in addition to ovulation, other inflammatory responses have been linked to ovarian cancer, including endometriosis and exposure of the ovarian surface to exogenous irritants (e.g., talc or viruses) [5, 38, 64, 100–103].


   FOOTNOTES
 
1 Supported in part by NIH CA-97796 and RR-016474. Back

2 Correspondence: William J. Murdoch, Department 3684, 1000 East University Ave., University of Wyoming, Laramie, WY 82071. FAX: 307 766 2355; wmurdoch{at}uwyo.edu Back

Received: 6 April 2005.

First decision: 25 April 2005.

Accepted: 9 June 2005.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 RELATIONSHIP OF OVULATION TO...
 OXIDATIVE DAMAGE TO DNA...
 CONCLUSIONS AND ADDITIONAL...
 REFERENCES
 

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