Induction of ovulation and ovarian cancer: A critical review of the literature

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Science, Mount Sinai School of Medicine, New York, New York, USA.
Fertility and sterility (Impact Factor: 4.59). 05/2006; 85(4):819-26. DOI: 10.1016/j.fertnstert.2005.08.061
Source: PubMed


To critically examine the possible association between ovulation-inducing drugs and ovarian cancer.
Medline literature review and cross-reference of published data.
The studies that have adjusted for the effects of confounding factors such as duration of oral contraceptive use and number of pregnancies have noted an increased risk of ovarian cancer among infertile women who remain childless despite long periods of unprotected intercourse. Whether such women are at risk due to the primary basis for their infertility or factors such as ovulation-inducing drugs, has been the subject of several studies. Overall, the findings on ovarian cancer (especially invasive epithelial and non-epithelial) risk associated with fertility drug treatment are reassuring. However, a stronger association between fertility drug use and borderline tumors of the ovary has been observed.
Despite the overall reassuring findings of the available studies, there is a need for well-designed clinical trials to understand the possible carcinogenic effects of the ovulation-inducing drugs.

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    • "Our previous studies confirmed these results (mean dysplasia score 7.64) and ovarian dysplasia seemed to be linked to the intensity and number of stimulations (dose-effect) and after a sufficient lapse of time (time-effect).13 However, the long term evolution is unknown.14,22 Animal experiments have given some interesting conclusions. "
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    ABSTRACT: Ovarian epithelial dysplasia was initially described in material from prophylactic oophorectomies for BReast CAncer gene (BRCA) mutation. Similar histopathological abnormalities have been revealed after ovulation stimulation. Given that tamoxifen (TAM) has a clomid-like effect and is sometimes used to induce ovulation, we studied the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in adnexectomies previously exposed to TAM for breast cancer. We blindly reviewed 173 histopathological slides of adnexectomies according to three groups – oophorectomies associated with TAM exposure (n=42), oophorectomies associated with clomiphene exposure (n=15) and a spontaneously fertile non cancerous control group (n=116). Morphological features (with an ovarian and tubal dysplasia scoring system) and immunohistochemical expression patterns of Ki-67, p53 and Aldehyde dehydrogenase 1 (ALDH1 is an enzyme significantly associated with earlystage ovarian cancer) were evaluated and correlated. Mean tubal dysplasia score was significantly higher in the TAM group and clomiphen group than in controls (respectively 7.8 vs 3.5, P<0.007 and 6.8 vs 3.5, P=0.008). There is no statistical difference for the ovarian score in TAM group in comparison with the control group whereas we found a significant score for clomiphen group (6.5, P=0.009). Increased ALDH1 expression was observed in the two exposed group whereas expression patterns of Ki67 and p53 were moderate. Interestingly, ALDH1 expression was low in non-dysplastic epithelium, high in dysplasia, and constantly low in the two carcinoma. Furthemore, we confirm our previous results showing that ALDH1 may be a useful tissue biomarker in the subtle histopathological diagnosis of tubo-ovarian dysplasia.
    European journal of histochemistry: EJH 04/2014; 58(2):2251. DOI:10.4081/ejh.2014.2251 · 2.04 Impact Factor
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    • "Moreover, the risk of cancer has been shown to be similar in children conceived by artificial reproductive therapies and those conceived naturally [27]. It should also be noted that, due to close medical surveillance, malignancies are overdiagnosed in the female population; this may also augment the early detection of cancers [28]. "
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    ABSTRACT: Although some studies have reported a potential connection between ovulation induction therapy (OIT) and malignant ovarian diseases, the results have been inconclusive. In the present study, we sought to determine whether women undergoing OIT at our in vitro fertilization (IVF) clinic, especially those with severe ovarian hyperstimulation syndrome (OHSS) and suspicious cytologic findings, were at risk for developing malignant ovarian tumours after treatment. Patients who underwent OIT at our IVF clinic were enrolled in this study and assessed for any evidence of malignant ovarian tumours. Patients who developed severe OHSS as a result of OIT were treated with a culdocentesis. Cells from the ascitic fluid were cytologically scored for abnormality and malignancy. Peripheral blood samples were obtained from patients with severe OHSS to determine serum levels of the tumour markers (CA-125 and HE4) that were used to calculate the Risk for Ovarian Malignancy Algorithm (ROMA) index. Follow-up data were available for 1,353 of the 1,587 patients (85%) who underwent OIT at our IVF clinic between January 2006 and December 2012. Twenty-three patients (1.4 %) were hospitalized with OHSS. Culdocentesis was performed 16 times in nine patients with severe OHSS (age range, 23--34 years; mean, 27.1 years). Although cytological examination of the ascitic cells of these patients suggested malignant ovarian neoplasia, over the course of the observation period, the ovarian volume gradually decreased and became normal. Subsequent cytological and histological examinations failed to find evidence of any malignant tumours in these nine patients. None of the 1,353 participants who underwent OIT developed any malignant ovarian tumours during the study period. Moreover, none of the 462 patients who were in our ovarian tumour registry were also participants in the IVF program. The presence of atypical cells in the ascitic fluid of women with severe OHSS does not likely indicate malignancy; therefore, radical surgical intervention is not justified. The risk of malignancy is minimal shortly after OIT. At our centre, OIT has not been associated with any cases of ovarian tumour.
    Reproductive Biology and Endocrinology 09/2013; 11(1):91. DOI:10.1186/1477-7827-11-91 · 2.23 Impact Factor
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    • "These abnormalities were increasingly severe (dose effects) and frequent (time effect) as the number of stimulation cycles raised. Nevertheless , the differing morphological and immunohistochemical profiles of these stimulated ovaries and those at genetic risk would indicate a different evolution at long term (towards cancer for ovaries in the presence of a BRCA mutation and perhaps towards borderline tumours in the case of ovaries stimulated during IVF protocols) [20] [21] [22] [23] [24]. -The physiopathological explanation (for both stimulated ovaries and those at genetic risk) appears to correspond with the incessant ovulation theory described by Fathalla [25]: during the ovulation scarring process, deep epithelial invaginations are often created. "
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    ABSTRACT: Our understanding of the early natural history of epithelial ovarian carcinoma is limited by the access to early lesions as the disease is very often diagnosed at advanced stages. The incessant ovulation theory from the last century that indicated the ovary as the site for the initiation of high-grade serous cancers is contrary to the newly emerging idea that ovarian cancer could arise from the distal fallopian tube. In view of the recent pathological and molecular studies, we propose to discuss the genesis of high-grade serous ovarian cancer.
    Critical reviews in oncology/hematology 03/2013; 88(1). DOI:10.1016/j.critrevonc.2013.03.004 · 4.03 Impact Factor
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