Fertility Drugs

and

Ovarian CancerDr. Saad Ghazal-Aswad, MD

Consultant Gynaecological OncologistChair O&G Department

Tawam Hospital

Arabian

Objectives of the presentation:• What are the risk factors for developing Ovarian

Cancer?• Fertility drugs and ovarian cancer: historical

background• Fertility drugs and ovarian cancer: recent literature

review• Cochrane data base• Conclusions.

PREVENTION Concept originated from China since

2600 BC• Superior doctors PREVENT the disease;• Mediocre doctors treat the disease

BEFORE clinical evidence;• Inferior doctors treat the disease AFTER clinical

evidence

Introduction:

Case sharing: 34 YO G0, married for 8 years with primary infertility

presented with large pelvo-abdominal mass about 24 cm in diameter.

In her PMH she had been treated for infertility with clomid tab for > one year and after that she had IOO with injection for more than 12 cycles.

US & Abdominal CAT scan suggested large endometrioma arising from the Rt ovary.

Laparatomy & Rt SO performed with peritoneal washing.

Histology confirmed WD enometroid adenocarcinoma. Is this due to Infertility treatment or developed on the

back ground of the endometriosis?

What are the risk factors for ovarian cancer?

A risk factor is anything that changes your chance of getting a disease like cancer. Different cancers have different risk factors. For example, unprotected exposure to strong sunlight is a risk factor for skin cancer. Smoking is a risk factor for a number of cancers.

But risk factors don't tell us everything. Having a risk factor, or even several risk factors, does not mean that you will get the disease. And many people who get the disease may not have had any known risk factors. Even if a woman with ovarian cancer has a risk factor, it is very hard to know how much that risk factor may have contributed to the cancer. Researchers have discovered several specific factors that change a woman's likelihood of developing epithelial ovarian cancer. These risk factors don’t apply to other less common types of ovarian cancer like germ cell tumors and stromal tumors.epidemiological study

Risk factors for ovarian cancer? Age: rare <40 but >50% aged 63 and above Obesity: BMI > 30 Reproductive history: pregnant and carried it to term before age 26 have a lower

risk. The risk goes down with each full-term pregnancy. Women who have their first full-term pregnancy after age 35 or who never carried a pregnancy to term have a higher risk of ovarian cancer.

Breastfeeding may lower the risk even further. Birth control: The lower risk is seen after only 3 to 6 months of using the pill, and

the risk is lower the longer the pills are used. This lower risk continues for many years after the pill is stopped. MPA usage had a lower risk of ovarian cancer. The risk was even lower if the women had used it for 3 or more years.

Gynecologic surgery: Tubal ligation may reduce the chance of developing ovarian cancer by up to two-thirds. A hysterectomy also seems to reduce the risk of getting ovarian cancer by about one-third.

Androgens: Androgens are male hormones. Danazol, a drug that increases androgen levels, was linked to an increased risk of ovarian cancer and women who took androgens were found to have a higher risk of ovarian cancer. Further studies of the role of androgens in ovarian cancer are needed.

Estrogen therapy and hormone therapy: recent studies suggest women using estrogens after menopause have an increased risk of developing ovarian cancer (esp. in women taking estrogen alone without progesterone) for many years (at least 5 or 10).

Risk factors for ovarian cancer? Family history of ovarian cancer, breast cancer, or colorectal cancer Family cancer syndromes: About 5 to 10% of ovarian cancers are a part of family

cancer syndromes resulting from inherited changes (mutations) in certain genes. Hereditary breast and ovarian cancer syndrome: BRCA1 and BRCA2, as well as

possibly some other genes that have not yet been identified. This syndrome is linked to a high risk of breast cancer as well as ovarian, fallopian tube, and primary peritoneal cancers. The risk of some other cancers, such as pancreatic cancer and prostate cancer, are also increased. The lifetime ovarian cancer risk for women with a BRCA1 mutation is estimated to be between 35% and 70%. For women with BRCA2 mutations the risk has been estimated to be between 10% and 30% by age 70. In comparison, the ovarian cancer lifetime risk for the women in the general population is less than 2%.

PTEN tumor hamartoma syndrome Hereditary nonpolyposis colon cancer Peutz-Jeghers syndrome MUTYH-associated polyposis Personal history of breast cancer Talcum powder Diet Analgesics: aspirin and acetaminophen reduce the risk of ovarian cancer. Smoking and alcohol use

Fertility drugs

Do they cause Ovarian cancer?

The risk of ovarian cancer after treatment for infertility.

Bristow RE1, Karlan BY; Curr Opin Obstet Gynecol. 1996 Feb;8(1):32-7. Recently, much attention in both the medical and lay communities has

been focused on a possible association between fertility drug use and invasive ovarian cancer, and ovarian tumors of low malignant potential. A causal relationship, if shown to exist, has important implications. In the past year, several large case-control and cohort studies have attempted to address this issue. However, interpretation of the available data has been hampered by a number of factors. Retrospective study designs, small numbers of ovarian cancer cases, and inconsistent reporting of fertility drug use and type of infertility have all been common methodological shortcomings. The known ovarian cancer risk factors of low parity and infertility have been particularly difficult to separate from any effect of ovulation induction. The current epidemiologic data are insufficient to implicate conclusively specific fertility medications in ovarian carcinogenesis. The data do suggest that women with refractory infertility may constitute a high-risk population for developing ovarian cancer, independent of fertility drug use. Until the relationship between ovulation induction and ovarian cancer risk is defined more accurately, a high index of clinical suspicion for ovarian neoplasms is indicated before, during, and after treating women for infertility.

Ovulation induction for infertility is it safe or not?

Anderson SM1, Dimitrievich E. S D J Med. 1996 Nov;49(11):419-21.

Case reports of ovarian tumors in women undergoing fertility treatment have raised questions about the potential neoplastic effects of ovulation-induction agents used in the treatment of infertility.

This has been the subject of much debate, media coverage and patient alarm. An increased risk of malignant epithelial ovarian cancer, borderline epithelial ovarian tumors, and nonepithelial ovarian cancer have been reported in association with the use of fertility drugs.

Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertilityIvana Rizzuto, Renee Behrens, Lesley A Smith. Cochrane Gynaecological Cancer Group; 13 AUG 2013

Background:The use of assisted reproductive techniques is increasing, but the possible link between fertility drugs and ovarian cancer remains controversial.

Objectives: To evaluate the risk of ovarian cancer in women treated with ovulation stimulating drugs for subfertility.

Search methods: We searched for published and unpublished observational studies from 1990 to February 2013. The following databases were used: the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 1, MEDLINE (to February week 4 2013), EMBASE (to 2013 week 09) and databases of conference abstracts. We also scanned reference lists of retrieved articles. The search was not restricted by language of publication.

Selection criteria: We searched for randomised controlled trials (RCTs) and non-randomised studies, and case series including more than 30 participants, reporting on women with exposure to ovarian stimulating drugs for treatment of subfertility and histologically confirmed borderline or invasive ovarian cancer.

Data collection and analysis: At least two review authors independently conducted eligibility and 'Risk of bias' assessment, and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We expressed findings as adjusted odds ratio (OR), risk ratio (RR), hazard ratio (HR) or crude OR if adjusted values were not reported and standardised incidence ratio (SIR) where reported. We conducted no meta-analyses due to expected methodological and clinical heterogeneity.

Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertilityIvana Rizzuto, Renee Behrens, Lesley A Smith. Cochrane Gynaecological Cancer Group; 13 AUG 2013

Main results We included 11 case-control studies and 14 cohort studies, which included a total of 182,972

women. Seven cohort studies showed no evidence of an increased risk of invasive ovarian cancer in

subfertile women treated with any drug compared with untreated subfertile women. Seven case-control studies showed no evidence of an increased risk, compared with control women of a similar age. Two cohort studies reported an increased incidence of invasive ovarian cancer in subfertile women treated with any fertility drug compared with the general population. One of these reported a SIR of 5.0 (95% confidence interval (CI) 1.0 to 15), based on three cancer cases, and a decreased risk when cancer cases diagnosed within one year of treatment were excluded from the analysis(SIR 1.67, 95% CI 0.02 to 9.27). The other cohort study reported an OR of 2.09 (95% CI 1.39 to 3.12), based on 26 cases.

For borderline ovarian tumours, exposure to any fertility drug was associated with a two to three-fold increased risk in two case-control studies. One case-control study reported an OR of 28 (95% CI 1.5 to 516), which was based on only four cases. In one cohort study, there was more than a two-fold increase in the incidence of borderline tumours compared with the general population (SIR 2.6, 95% CI 1.4 to 4.6) and in another the risk of a borderline ovarian tumour was HR 4.23 (95% CI 1.25 to 14.33) for subfertile women treated with in vitro fertilisation (IVF) compared with a non-IVF treated group with more than one year of follow-up.

There was no evidence of an increased risk in women exposed to clomiphene alone or clomiphene plus gonadotrophin, compared with unexposed women. One case-control study reported an increased risk in users of human menopausal gonadotrophin (HMG)(OR 9.4, 95% CI 1.7 to 52). However, this estimate is based on only six cases with a history of HMG use.

Introduction of Cervical Cancer Screening in AD 2013

CONCLUSIONS

Is there an increased risk of ovarian cancer in women treated with drugs for subfertility?

Drugs to stimulate ovulation have been widely used for various types of subfertility since the early 1960s and their use has increased in recent years.

Subfertile women are commonly exposed to these agents, which may be administered at high doses for long periods of time during treatment for subfertility. There is uncertainty about the safety of these drugs and the potential risk of causing cancers associated with their use.

Overall, based on 25 studies, which included a total of 182,972 women, we found no evidence that the risk of ovarian cancer was increased in women treated with fertility drugs, compared with subfertile women untreated with fertility drugs, or women in the general population.

Five of the 25 studies showed an increase in the risk of ovarian cancer, but these studies were of low methodological quality and therefore the results are too unreliable to conclude that there is a definitive risk of cancer while on treatment for subfertility.

More research studies, which are of high quality, are needed to determine whether there is an increased risk of ovarian cancer in women treated with fertility drugs.

Authors' Conclusions We found no convincing evidence of an

increase in the risk of invasive ovarian tumours with fertility drug treatment.

There may be an increased risk of borderline ovarian tumours in subfertile women treated with IVF.

Studies showing an increase in the risk of ovarian cancer had a high overall risk of bias, due to retrospective study design, lack of accounting for potential confounding and estimates based on a small number of cases. More studies at low risk of bias are needed.

Thank you !