There is evidence that medication used for ovarian stimulation and in vitro fertilization may be associated with ovarian cancer. In this review, we attempt to describe this relationship according to the most recent epidemiologic data and to present the possible mechanisms on the molecular level that could potentially explain this correlation.  Currently there is no proven relationship between any type of ovarian cancer and drugs used for infertility treatment. Overall, infertile women have increased risk for ovarian malignancies. Nulligravidas that received treatment are at increased risk for ovarian malignancy as compared to women that conceived after treatment. More studies with the appropriate statistical power and follow-up time, as well as with better adjustment for confounding factors, which
coexist in infertile patients, are required to evaluate accurately the long-term effects of these drugs and procedures.

Keywords: ovarian cancer; ovulation induction; in vitro fertilization; infertility

Introduction

The process in vitro fertilization (IVF) involves ovarian stimulation with a combination of drug, oocyte retrieval, fertilization of the mature oocytes in vitro, and finally, transfer of the embryos back into the endometrial cavity, which has been adequately prepared for implantation. It is obvious that the main concern regarding the association between IVF and ovarian cancer is tightly related to the use of fertility drugs for the purpose of stimulating the ovaries to produce multiple follicles, a process known as superovulation. To date, there have been several studies that have tried to resolve the question of long-term effects of drugs used in the treatment of infertility and their possible connection with gynecological cancer. However, the majority of them involve a small number of women, for a limited follow-up period and without a detailed description of their treatments. The most commonly used drugs for infertility problems are the gonadotropins (biological or recombinant), clomiphene citrate, human chorionic gonadotropin (hCG), GnRH analogs (agonists and antagonists), and progesterone. Out of these drugs, clomiphene citrate and gonadotropins cause excessive follicular development and multiple ovulation. In this paper, we perform a thorough review of the existing literature regarding the effects of fertility drugs on ovarian cancer risk.

Pathogenetic aspects of ovarian cancer

Several theories have been proposed to explain the association between ovarian cancer risk and fertility treatments. The theory of incessant ovulation, which implicates the repetitive damage and repair of the ovarian surface epithelium during ovulation in the pathogenesis of epithelial ovarian cancer, remains one of the most widely accepted.1 Increased exposure to gonadotrophins increases the frequency of ovulation and because gonadotropins are used to treat infertility, such treatment might, theoretically, put patients at risk for ovarian cancer.2 Finally, according to the follicle-depletion hypothesis, a diminished ovarian follicle reserve and advanced reproductive age often encountered in women suffering from infertility might increase the risk of developing ovarian cancer.3

Molecular and genetic aspects of ovarian cancer

Familiar predisposition, genetic instability, immunologic, angiogenetic, and hormonal factors are
related to the pathogenesis of ovarian cancer. Mechanisms that lead to ovarian cancer owing to genetic
instability include deactivation of one or two alleles of tumor-suppressive genes, changes of the enzymes
that act in DNA-repair, and increased oncogenic activity. The most commonly affected chromosome loci include 9p, 11q, and 22q.4 Mutations in the genes that encode metabolic and detoxification enzymes, such as GALT and GSTM, have been implicated in the development of ovarian cancer.5 Mutations in PTEN, a tumor-suppressive gene have been documented in certain histologic types of ovarian carcinomas.6 PTEN mutations as well as loss of heterozygosity (LOH) at locus 10q23.3 are quite common in ovarian endometriomas, as well as in endometrioid and clear cell ovarian cancers.7 K-ras is an oncogene that has been related to ovarian cancer. Mutations of K-ras are found in clear-cell ovarian carcinomas, especially in women with endometriosis. K-ras mutations were found in cancerous cells, but not in the neighboring cells with endometriosis or atypical endometriosis.8 According to those investigators, K-ras mutations are associated to malignant transformation of benign endometriosis to clear-cell carcinoma of the ovaries.8
In a rodent model, activation of the oncogenic Kras or conditional PTEN deletion within the ovarian
surface epithelium gave rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, genetic recombination of the two mutations in the same model lead to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas.9

Response of ovarian carcinomas to estrogen stimulation

Estrogens have been linked to the pathogenesis and growth of ovarian cancer. The key enzyme for estrogen biosynthesis or actually for the conversion of androgens to estrogens is aromatase. Tissue-specific aromatase expression is regulated by tissue-specific promoters located up-stream of a common coding region. Aromatase gene expression in malignant tumors of the ovary is primarily regulated by a promoter located in the 1.3/II region. These promoters are stimulated by PGE2 via a cAMP-PKA-dependent pathway. Thus, inflammatory substances such as PGE2 often encountered in chronic inflammatory processes such as endometriosis may play an important role in inducing local production of estrogens that promote tumor growth.10 Physiologically, estradiol is being metabolized to estrone, a weak estrogen, by the action of the enzyme 17--hydroxysteroid dehydrogenase (17-- HSD) type-2, which is being induced by progesterone in the endometrium. Seeger et al.11 concluded that estradiol and its derivatives may have a variable impact on the survival and growth of ovarian cell lines and the quantification of these derivatives may be of prognostic value of the risk women have for the development of ovarian cancer. O’Donnel et al.,12 have shown that the potential carcinogenic action of estrogen are mediated through estrogen receptors (ER-). In ovarian cancer cell lines, genes controlled through ER- mediated transcription had a three-fold increase in their expression, whereas there was no change in the expression of genes controlled by ER--mediated transcription.12 Growth factors such as TGF-a, TGF-b, and IGFI have also been implicated to the development of ovarian cancer.13 Menopausal and premenopausal women with high-IGF-I serum levels are at increased risk of developing ovarian and other gynecological cancers (e.g., cervical and endometrial).14

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