Hum. Reprod. Advance Access published online on September 29, 2008
Human Reproduction, doi:10.1093/humrep/den358
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Ovarian epithelial dysplasia after ovulation induction: time and dose effects
1 Department of Oncology and Surgery, Centre Jean Perrin, Clermont-Ferrand, France 2 Department of Histopathology, Centre Jean Perrin, Clermont-Ferrand, France 3 Department of Histopathology, CHU of Clermont-Ferrand, Clermont-Ferrand, France 4 Department of Medical Information, CHU of Clermont-Ferrand, Clermont-Ferrand, France 5 Department of Obstetric, Gynecology and Reproductive Medicine, CHU of Clermont-Ferrand, Clermont-Ferrand, France
6 Correspondence address. Tel: +33-6-07-08-17-86; E-mail: chenegautier{at}yahoo.fr
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Abstract |
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BACKGROUND: Ovarian epithelial dysplasia was first described after prophylactic oophorectomies for genetic risk. Ovarian stimulation has been considered as a risk factor of ovarian cancer by Fathalla's incessant ovulation theory. In this study, we have investigated the risk of ovarian dysplasia after ovulation induction.
METHODS: We reviewed 99 oophorectomies or cystectomies between 1990 and 2005 divided them into two groups: previous in vitro fertilization (n = 37) and a panel of fertile controls (n = 62). Eleven epithelial cytological and architectural features were defined and an ovarian epithelial dysplasia score was calculated to quantify the degree of ovarian epithelial abnormalities.
RESULTS: All the ovaries were macroscopically non-cancerous except in two patients (one endometrioid cancer and one borderline tumour). The mean ovarian dysplasia score was significantly higher in the ovulation induction group than in the control group (7.64 versus 3.62, P = 0.0002). We also found a relationship between the number of ovulation-inducted cycles and the severity of ovarian dysplasia (‘dose-effect’) and a relationship between time after the end of ovulation induction (over 7 years) and the severity of ovarian dysplasia (‘time-effect’).
CONCLUSIONS: There is probably a relationship between ovarian epithelial dysplasia and either ovulation inducing drugs or infertility. By Fathalla’s incessant ovulation theory, ‘the dose effect and the time effect’ of ovarian stimulation may explain ovarian dysplasia formation.
Key words: female infertility/assisted reproduction/ovarian dysplasia/ovarian stimulation
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Introduction |
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Epithelial ovarian cancer is the most life-threatening gynaecological cancer, with a low 5 year survival rate estimated at 30–35% when all stages are taken together (Ahmed et al., 1996
). Its severity is due essentially to late diagnosis at an advanced stage (peritoneal carcinomatosis) in two-thirds of cases, which implies a poor prognosis with a survival rate lower than 20%.
On the other hand, the probability of remission is 
90%, if the cancer is diagnosed at an early stage (Stage IA) and 70% if diagnosed at Stage II (Brewer et al., 2003). However, the low specificity and low positive predictive value of the usual screening tests (ultrasonography and CA 125 antigen assay) (Sassone et al., 1991; Grove et al., 1992) combined with poor knowledge of ovarian carcinogenesis have made it impossible to identify a preclinical latency phase amenable to preventive surgery and to mass screening.
The most often cited risk factors for ovarian neoplasia are hereditary predisposition (5–10%) (Ford et al., 1994) and incessant ovulation (Fathalla, 1971) with for this second factor, a hypothetical implication for ovarian stimulation; the role of ovarian stimulation has been suggested (Harris et al., 1992; Whittemore et al., 1992), but is still controversial.
As the histological study of excised material from prophylactic ovariectomies indicated by genetic predisposition has shown frequent abnormalities interpreted as pre-cancerous ‘ovarian dysplasia’ lesions (Deligdisch et al., 1999), we sought similar lesions in material from oophorectomies carried out after ovarian stimulation during infertility treatment. This may determine the role of ovulation induction as a risk factor of ovarian carcinogenesis and thereby possibly define another group of women at risk.
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Materials and Methods |
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Population
Out of a total of 5500 adnexectomies and/or ovarian cystectomies performed between January 1990 and December 2005, we selected 97 patients, who were divided into two groups.
- Exposed group: 35 patients who had previously undergone in vitro fertilization (IVF) using ovulation induction, and in whom 37 ovarian adnexectomies and (or) cystectomies had been performed several years later for the indications given in Table II. Two patients underwent surgery twice. None of the patients in this group had presented an ovarian cyst in the ultrasonographic exploration carried out at the initial infertility consultations. This group of patients was obtained by crossing assisted reproduction treatment (ART) records (4500 patients) with surgical adnexectomy records [5500 adnexectomies and (or) ovarian cystectomies] over the period extending from January 1990 to December 2005. The 37 cases comprised 27 adnexectomies (12 unilateral and 15 bilateral) and 10 cystectomies.
- Control group: 62 fertile patients with no personal or family history of gynaecological neoplasia (breast, ovary or endometrium), who had undergone an adnexectomy and (or) a cystectomy for a benign disorder, and for whom a final histopathological examination showed their ovaries to be non-cancerous. We age-matched this group to the exposed group. To reduce the confounding and protective effect of oral contraceptive use, we selected patients for whom the duration of oral contraceptive use was short. Finally, to obtain a better statistical power, we took two randomly selected controls for one at-risk patient.
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Data collection
The following information was collected along with medical records: general characteristics and habits, gynaecological and obstetric data, and infertility-related variables, i.e. parity, use and duration of contraceptive methods, and use of fertility drugs (Table II). The information obtained was checked by telephone contact, if necessary.
Histopathological criteria
There is no consensual dysplasia scoring scheme, as the histopathological modifications characteristic of dysplasia are difficult to determine. The definition of dysplasia is thus based on cytological and architectural criteria, and several histopathological scoring scales have been designed based for ovarian dysplasia found in prophylactic oophorectomies for BRCA mutations (Salazar et al., 1996; Stratton et al., 1999; Barakat et al., 2000), in areas adjacent to Stage 1 ovarian carcinoma (Plaxe et al., 1990; Zheng et al., 1993), in the controlateral ovary of women with Stage 1 ovarian carcinoma (Mittal et al., 1993; Tressera et al., 1998), and in relation to ovulation induction (Nieto et al., 2001). We incorporated all these abnormalities (11 histopathological criteria) to obtain a complete, exhaustive dysplasia scoring system (Table I):
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- epithelial multilayering;
- tufting;
- surface papillomatosis;
- nuclear chromatin irregularity;
- nuclear contour irregularity;
- cellular pleomorphism;
- nuclear size enlargement;
- epithelial inclusion cysts;
- cortical invagination;
- psammoma;
- stromal hyperplasia: we used the semi-quantitative scale described by Boss et al. (1965), to score stromal hyperplasia, i.e. ovarian cortex wider than 1 mm with apparent cellular cortical stroma present in the medulla.
In each case, the abnormal areas were scored from 0 to 2 (0, normal; 1, moderately abnormal; and 2, severely abnormal). A dysplasia score for each patient was obtained simply by summing the scores of the 11 items (total range: 0–22).
All specimens were embedded in paraffin, sectioned at a thickness of 4–5 µm and stained with haematoxylin and eosin. The histopathology slides from the 37 exposed and 62 control patients were all read blindly by four pathologists who were specialists in oncogynaecology pathology in order to obtain an average score. For the cystectomies, the slides were read to confirm the histopathological diagnosis and inspect associated ovarian tissue to determine its dysplasia score. The average number of slides available for review from the two groups was 7.6 (5–11).
When several slides were available, the one with the highest dysplasia score was used. When there were major disagreements between pathologists, the slides were read again to reach a consensus.
Statistical analysis
Our main measure was the dysplasia score, with the hypothesis that the ovaries in the exposed group had a higher dysplasia score than in the control group. Comparison of means for the dysplasia scores of the two groups was carried out using Student's t-test. The groups were age-matched.
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Results |
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The exposed population numbered 35 patients of whom two underwent surgery twice, providing 37 samples of excised material. Epidemiological data (parity, duration of exposure to oral contraceptives, surgical indication and age at the time of adnexectomy) are given in Table II. Histopathological features of excised material from the exposed group were mainly benign cysts (35 cysts detected by ultrasonography), except in two patients (one endometrioid cancer and one borderline tumour) (Table III).
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Infertility was female in 60% of cases, with the following distribution: ovarian dysovulation 15%, tubal pathology 45% and endometriosis 40%. The cause of infertility was unknown in 26% of all cases (Table IV).
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The average number of stimulation cycles was three, with different protocols. We could not study the potential effects of treatment on the stimulation of ovulation owing to the large number of variables and the small sample size.
The histopathological abnormalities (Table I, Fig. 1) in the exposed group were almost always present and marked, occurring in 49%, except for psammoma (10%) and stromal hyperplasia (24.5%). The most frequently occurring abnormalities were epithelial multilayering (67.5%), tufting (65%), epithelial inclusion cysts (65%) and cellular pleiomorphism (62%). These abnormalities were usually less frequent in the controls, occurring in 25%, except for the epithelial inclusion cysts, which were found in 50% of cases.
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From these findings, a mean dysplasia score was calculated for the exposed group by averaging the scores of all the exposed patients. The average dysplasia score for the exposed patients was 7.64. The mean dysplasia score determined likewise for the controls was 3.62. This difference was highly statistically significant (P = 0.0002).
In addition, we found a statistically significant effect for the time interval between IVF and the adnexectomy or cystectomy. When this interval was <7 years, the mean dysplasia score was 1.28 compared with 11.52 after 7 years (>7 years) (P = 0.0001).
This ‘time effect’ (Fig. 2) is a new finding not described before: it seems that the dysplasia is installed gradually and becomes significant after a lag time evaluated here at 7 years. Once this time has elapsed, the dysplasia becomes permanent and can even worsen over time (Fig. 2).
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The number of stimulations is also appears to be important: one or two stimulations gave a mean dysplasia score of 3.4, whereas three or more stimulations raised the score to 10.7, with the difference being statistically significant (P = 0.0057).
The dysplasia also appeared to be more severe in refractory primary infertility, when stimulation failed, than when stimulations resulted in pregnancy. However, the difference was not statistically significant.
There was no statistical difference in the mean dysplasia score according to whether there was a positive or negative outcome of the ART (7.23 versus 9.42, P = 0.34).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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The Fathalla hypothesis (Fathalla, 1971
) regarded incessant ovulation as a risk factor of epithelial ovarian carcinoma. Each ovulation on the surface epithelium of the ovary could lead to a scar. During healing the invagination of the surface epithelium (Fig. 3A), cells in the stroma can form inclusion cysts (Fig. 3B) in a micro-environment in which the epithelial cells are subject to paracrine control, to the action of cytokines such as interleukins 1 and 6 and to the influence of growth factors stimulating cell proliferation (Berchuck et al., 1993; Wong et al., 1999; Wong and Auersperg, 2003). This hypothesis is consistent with the results of some experimental works and epidemiological studies (Harris et al., 1992; Whittemore et al., 1992).
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On the other hand, pregnancy, lactation and the oral contraceptive pill have a well-known protective effect due to the absence of ovulation (Wu et al., 1988
; Gross and Schlesselman, 1994). Hence ovarian stimulation was suspected to be a risk.
The first histopathological description of ovarian dysplasia was reported in the study of Gusberg and Deligdisch (1984), who examined prophylactic adnexectomy material from three females whose monozygotous twins had invasive cancers of the ovary (one endometrioid adenocarcinoma and two serous papillary adenocarcinomas, one grade II and the other grade III). In all three cases, the ovaries were macroscopically normal. However, microscopic inspection revealed various cytological and architectural anomalies: surface papillomatosis, epithelial inclusion cysts, nuclear pleiomorphism, epithelial multilayering and cortical invaginations. By analogy with the other pre-cancerous lesions of the genital tract, the association of these different abnormalities was termed ovarian dysplasia, or ovarian precancerous lesions (Resta et al., 1993).
Ovarian dysplasia is not a subjective impression related to the individual experience of the pathologist: it differs from normal ovarian tissue and from cancerous tissue, as was recently confirmed by Deligdisch in the work on morphometry and nuclear texture analysis (Deligdisch and Gil, 1989; Deligdisch et al., 1993, 1995).
Nieto et al. (2001) was the first to describe similar lesions after induced ovulation. We set out to confirm these abnormalities and adapted his score (designed for stimulated ovaries), adding further cytological criteria (epithelial inclusion cysts, cortical invaginations, psammomas and stromal hyperplasia) described in dysplastic lesions adjoining ovarian cancers. [Our exhaustive dysplasia score was also recently used on a cohort with ovarian dysplasia found in prophylactic oophorectomy for BRCA mutation (Chene et al., 2008a,b).]
The results of the present were comparable with those of Nieto et al. (2001), namely significant presence of dysplasia in stimulated ovaries (7.90 versus 5.7 P = 0.012 in Nieto study, 7.64 versus 3.62 P < 0.0002 in ours) (Fig. 4). Our findings thus corroborate those of Nieto, with an appreciable gain in statistical power from three times more patients in the exposed group.
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We also found evidence for two new effects.
The dose effect
The presence of histopathological abnormalities (and severity of dysplasia) seems to be linked to the intensity and number of hyperstimulations. The average number of stimulation cycles was three. There were 12 patients who had only one or two stimulations, whereas 23 had three or more; the dysplasia scores were, respectively, 3.4 and 10.7 (P = 0.0057).
This is consistent with the theory of Fathalla (1971): a cumulated dose at least above a certain threshold (i.e. a high number of induced ovulations) can generate dysplastic lesions, with the intensity of the response in terms of dysplasia being dose-related. Although there was a significant difference here between one or two stimulations and several stimulations, there was only a very weak correlation between dysplasia severity score and frequency of stimulation. The correlation coefficient between these two variables was 0.22475 (P = 0.1811) with R2 = 0.0505, i.e. only 5.1% of each variable was in correlation.
In contrast, when we took only those variables with a time interval of more than 7 years between the first stimulation and the adnexectomy (see below), the correlation coefficient was 0.6 (P = 0.0020) with R2 = 0.3878, i.e. nearly 40% correlation. In other words, in this subgroup, a greater the number of stimulations was associated with a worse dysplasia score. Animal experiments have led to the same conclusions. Thus, ovulation in rats has resulted in increased Ki67 expression and dysplastic features in the ovarian epithelial cells (Corakci et al., 2005). Celik et al. (2004) compared the rate of ovarian dysplasia in three groups of rats subjected, respectively, to one, three and six gonadotrophin cycles: there was a trend towards more severe dysplasia as the number of induced ovulation cycles increased.
Given our small sample size, we could not compare the different drug treatments. However, in the IVF group, 63% of the patients were stimulated by clomifene in association with FSH/HMG, which is an infrequent protocol for IVF stimulation, mainly used at the beginning of the IVF era. Clomifene has been shown to be the most harmful drug (Rossing et al., 1994).
The time effect
After confirmation of the presence of dysplasia lesions in stimulated ovaries, we observed a ‘time effect’ not hitherto reported in the literature, namely the existence of a time interval after ART treatment during which the ovaries are healthy and non-dysplastic and beyond which they appear abnormal and clearly dysplastic.
When the interval between stimulation and adnexectomy was 6 years or less, the dysplasia score was 1.28 compared with 11.52 (P < 0.0001) after an interval of 7 or more years: this difference was highly significant. This finding also held for longer times intervals (Fig. 2).
This empirical finding was not expected. At the beginning of the study, by analogy with the dysplasia found in prophylactic ovariectomy material excised for genetic risk, and based on the incessant ovulation hypothesis, we had simply postulated that stimulated ovaries could be the site of dysplastic lesions.
In the course of statistical analysis, we were surprised to find that recently stimulated ovaries were not dysplastic, unlike ovaries that had been first stimulated more than 7 years previously.
This time effect is unlikely to be mere coincidence. We were fortunate to have in our sample, two patients who had been operated on twice. One of these had a cystectomy in 2000, 5 years after stimulation, and then again in 2001, 6 years after stimulation: in both cases, the dysplasia score was nil. The other patient had a cystectomy in 1999, 5 years after stimulation, and then again in 2004, 11 years after stimulation. The first dysplasia score was nil, but the second was 10.
Combining these two effects, the dose effect and the time effect, we propose the following scheme for ovarian dysplasia formation (as distinct from cancer formation). One or two cycles of ovarian stimulation do not seem to induce any changes in epithelial ovarian surface. However, several cycles of ovarian stimulations seem to induce changes in histology of epithelial ovarian surface that remain latent for several years. These changes may be evaluative and lead to irreversible dysplastic lesions after 7 years or more. Evolution of dysplasia is uncertain in stimulated ovaries, although dysplasia in genetic ovaries (BRCA mutation) is a well-known risk factor of ovarian cancer: ART might be responsible for triggering a process of ovarian neoplastic formation, thereby putting these patients at risk.
Evidence of a time interval necessary for the appearance of these cytological and architectural modifications suggests that ovarian stimulation triggers a chain of cellular events culminating in a progressive biological process.
However, these findings must be interpreted with caution. We have no proof that these histopathological abnormalities are an early stage in the irreversible development of a malignancy. Ovarian cancer formation is a complex, stochastic, multifactorial process in which there is not necessarily a transition from a dysplasia to cancer. Our study is purely of observational value. We found that our sample of stimulated ovaries presented dysplastic lesions. We had no data concerning other stimulated patients, and so we do not know the true prevalence of ovarian dysplasia after stimulation. We had no way of knowing whether any of the cases of dysplasia would have subsequently developed into borderline lesions or cancer. In addition, these results do not imply that ovulation-inducing drugs are oncogenic, but the results would be compatible with the genetic theory whereby several mutations can induce both hypofertility and susceptibility to cancer of the ovary (in a similar way to which BRCA 1 and 2 mutations interact).
It should also be noted that we cannot know whether the ovarian epithelial dysplasia is directly associated with ovulation induction or whether there is a common link underlying infertility and ovarian dysplasia. Indeed, infertility is a well-known confounding effect because it is a risk factor for ovarian cancer, thus a common link underlying infertility itself and dysplasia is possible (Nieto et al., 1999). Another new study is planned to assess the exact responsibility of ovulation inducing drugs and infertility in ovarian dysplasia.
The frequent use of clomifene in these cases must also be taken into account as these drugs appear to increase the risk of borderline ovarian tumours (Parazzini et al., 1998; Sushan et al., 1999; Ness et al., 2002; Mahdavi et al., 2006).
On the other hand, among the 4500 patients undergoing IVF, the incidence of ovarian cysts was low and the ovarian cancer rate (one cancer and one borderline tumour) was low in comparison with the expected incidence and with the fact that five ovarian cancers or borderline tumours were found during the pre-IVF check-up during the same period.
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Conclusion |
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This study shows that more ovarian histopathological abnormalities are found after stimulation than in a control population, suggesting the responsibility of ovulation induction in the appearance of dysplastic lesions (Chene et al, 2008a
,b). Further works are necessary to study the link between infertility and ovarian dysplasia, to improve and validate our dysplasia scoring scheme in ovulation induction groups and to confirm the dose and time effects.
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References |
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Submitted on February 14, 2008; resubmitted on September 1, 2008; accepted on September 10, 2008.
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