oncogenic risks in art

ONCOGENIC RISKS IN ART

DR. K.U.KUNJIMOIDEENARMC IVF, KOZHIKODE, KERALABELHOUL HOSPITAL, DUBAI, UAEPREMIUM CLINICS, DOHA, QATAR

Contents• Introduction•Malignancies of:

– Ovary– Breast– Endometrium, – Thyroid gland – Melanoma

Global Scenario • Worldwide, no. of people with problems of infertility has increased since 1990– Resulting in consistent increase in use of

strategies to improve fertility & reproductive rate• Highest incidence of infertility was found in

western countries with increasing proportion of infertile women receiving fertility treatment

• Clinical use of fertility drugs & other reproductive strategies expected to for large no. of women– Who postpone pregnancy for economic & social

reasons

Trends• In past three decades follow-up studies & multiple

case reports have discussed safety of ovulation-inducing drugs & risks associated with their use

• Ovulation-inducing drugs widely used for ovarian follicular stimulation during in vitro fertilization (IVF) cycles

• IVF treatment programs initially designed to treat women with mechanical infertility & no evidence of ovulation disturbances

• Currently,

– IVF treatment programs used to treat all types of infertility

Trends• Dutch study estimated

– 14% & 16.5% of couples seek medical care for infertility problems during their reproductive life

• In USA 2.5 % of live births per year result from assisted reproductive technologies

• Indian Data not estimated

• In USA number of women treated annually with fertility drugs (FD) nearly doubled between 1973 and 1991

BEURSKENS, M.P., J.W. MAAS & J.L. EVERS. 1995. Subfertility in South Limburg: calculation of incidence and appeal for specialist care. Ned.

Tijdschr. Geneeskd. 139: 235–238

Association between ART & Cancer• Hormonal & reproductive factors known to be

involved in etiology of cancers of the female reproductive system,

• A stimulating effect of Fertility Drugs on risk of these cancers theoretically possible

• Precise mechanisms involved in pathogenesis of hormone-related cancers remain unclear

• Difficult to predict how and to which extent Fertility Drugs may affect risk of various cancers

Kanakas n, mantzavinos t. fertility drugs and gynecologic cancer ann. n.y. acad. sci. 1092: 265–278 (2006).

Cancer incidence following T/t for infertility• In past years, much attention has been focused on possible association between use of Fertility Drugs & development of malignancies of:– Ovary– Breast– Endometrium, – Thyroid gland – Melanoma

Ovarian Cancer & Fertility Drugs• Ovarian cancer fifth most common malignancy

in women in developed countries

– Accounts for approximately 4% of all malignancies in females

• 80–90% of ovarian malignancies originates from ovarian epithelium

• 4–6% of all ovarian neoplasms originate from ovarian stroma

– E.G. Non-epithelial tumors of ovary germ cell tumors, sex-cord tumors

Ovarian Cancer & Fertility Drugs• Five main hypotheses that explain epidemiology of

epithelial ovarian cancer• First hypothesis

– Ovarian cancer caused by repeated ovulations disrupting ovarian epithelium leading to malignant transformation of epithelial cells

• Second hypothesis:– Persistent stimulation of ovary by gonadotrophins

increases risk of malignant changesRISCH, H.A. 1998. Hormonal etiology of epithelial ovarian cancer, with a

hypothesis concerning the role of androgens and progesterone. J. Natl. Cancer Inst. 90: 1774–1786

Ovarian Cancer & Fertility Drugs• Third hypothesis:

– Proposes a carcinogenic role for exposure of ovarian epithelium to environmental agents (e.g. Talcum powder)

– Talcum powder may enter pelvic cavity through vaginal canal

• Forth (endometriosis) hypothesis:

– Endometriosis act to promote development of ovarian cancer if endometriotic implants cause irritation & subsequently an inflammatory reaction

COOK, L.S., M.L. KAMB & N.S. WEISS. 1997. Perineal powder exposure and the risk of ovarian cancer. Am. J. Epidemiol. 145: 459–465PAULSON, R.J. 1997. Fertility drugs and ovarian epithelial cancer: the endometriosis hypothesis. J. Assist. Reprod. Genet. 14: 228–230

Ovarian Cancer & Fertility Drugs•Fifth hypothesis:

– Ovarian cancer may be by factors associated with excess androgenic stimulation of ovarian epithelial cells

– May be decreased by factors related to greater progesterone stimulation

• Above hypotheses raise concern regarding effect of ovulation induction drugs on cancer risk – Clomiphene citrate & gonadotropins (M.C used)

for stimulating ovulation– These drugs also both estrogen & progesterone

levels leading to breast & gynecological cancers

Ovarian Cancer & Fertility Drugs•Number of investigations attempted to address long-term effects of ovulation-inducing drugs on cancer risk, but most have had shortcomings like:– Small number of study subjects– Short follow-up– Imprécise information on drug exposures– Indication’s for usage– Absence of information on other correlates of drug exposure

AKHMEDKHANOV, A., A. ZELENIUCH-JACQUOTTE & P. TONIOLO. 2001. Role of exogenous and endogenous hormones in endometrial cancer: reviewof the evidence and research perspectives.

Ann. N. Y. Acad. Sci. 943: 296–315

Fertility drugs & ovarian cancer (Cohort studies)

Tomao F et al. Fertility drugs, reproductive strategies and ovarian Tomao et al. Journal of Ovarian Research 2014, 7:51cancer risk

IVF and ovarian cancer (Cohort studies)

Tomao F et al. Fertility drugs, reproductive strategies and ovarian Tomao et al. Journal of Ovarian Research 2014, 7:51cancer risk

Ovarian Cancer & Fertility Drugs• Based on evidence to date, there is no conclusive

link between Fertility Drugs use and ovarian cancer

• Most of above studies had relatively small numbers and/or short follow-up

• Because of lack of large studies with sufficient follow-up time since Fertility Drugs use

– Discussion about a possible association mostly inspired by theories concerning the pathogenesis of ovarian cancer

Ovarian Cancer & Fertility Drugs• Multiple punctures needed for IVF

– May, through repeated ruptures of ovarian epithelium, cause Increased mitotic activity in ovary

• Etiology of ovarian cancer multifactorial with genetic, environmental & endocrinological factors interacting in various causal pathways

• Studies needed to define molecular mechanisms by which ovulation contributes to this process

UNKILA-KALLIO, L., A. LEMINEN, A. TIITINEN&O. YLIKORKALA. 1998. Nationwide data on falling incidence of ovarian granulose cell tumours concominant with increasing use of ovulation inducers. Hum. Reprod. 13:

2828–2830

Breast cancer• Relationship between menarche, menopause, &

breast cancer risk has been found in epidemiologic studies– This events influence a woman’s cumulative

exposure to ovarian hormones by changing no. of lifetime ovulatory cycles

– Inverse association between obesity & breast cancer risk in premenopausal women may be explained by ovulatory abnormalities

• Some researchers say that there may be a link between infertility due to anovulatory disorders and a decreased risk of breast cancerPrentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive

breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006; 295: 629

Breast cancer and Fertility Drugs• Delivering a baby in older age will increase risk of

developing breast cancer• Majority of such women seek infertility

management methods and use hormonal drugs that increase the risk of breast cancer

• Long time exposure to endogenous estrogen risk of breast cancer

• Estrogen subtypes such as estriol and estradiol control ovarian function

(using drugs for reduction of estrogen level decreases breast cancer risk )Rao Ch V, Li X, Manna SK, Lei ZM, et al. Human chorionic gonadotropin decreases

proliferation and invasion of breast cancer MCF-7 cells by inhibiting NF-kappaB and AP-1 activation. J. Biol. Chem. 2004; 279: 25503-25510

Breast cancer and Fertility Drugs• Serum estrogen increases with clomiphene citrate

and FSH/hCG during infertility treatment• Serum estrogen levels are greater during cycles in

which ovulation is induced than in natural cycle in women

• Ovulation of multiple follicles results in high progesterone levels, also increase breast cancer risk

• Clomiphene citrate acts by binding to estrogen receptor (ER)– Exerts a weak estrogenic effect while blocking

endogenous estrogen– Thus may have a role in pathogenesis of breast

cancer

Breast cancer and Fertility Drugs•hCG

– Exists in high levels in early pregnancy, both anti-invasive & anti-proliferative effects

– May be involved through breast epithelial LH/hCG receptor & downregulation of nuclear factor kappa B and activator protein-1 transcription factors in human breast cancer

– hCG has a major impact on reducing cell proliferation, irrespective of type of cell or hormone receptor status

Rao Ch V, Li X, Manna SK, Lei ZM, et al. Human chorionic gonadotropin decreases proliferation and invasion of breast cancer MCF-7 cells by inhibiting NF-kappaB and AP-1

activation. J. Biol. Chem. 2004; 279: 25503-25510

Breast cancer and Fertility Drugs•Gonadotrophins

– May raise estrogen levels during follicular phase of ovulation induction cycles, but do not have any direct influence on breast tissue

– Women who have been treated with IVF, have an increasing risk of having breast or uterine cancer in their early period after treatment especially the first year

• With conflicting results from various studies direct effect of infertility treatment agents on mammary epithelial and/or stromal tissue, independent of downstream estrogen elevation, is not knownZarchi MK. The Effect of Assisted Reproductive Technologies on

Gynecological Cancer: Report of Our Experiences and Literature Review. Int J Biomed Sci 2013; 9 (3): 129-134

Fertility Drugs & Breast Cancer (cohort studies)

Arakbi WA et al. In Vitro Fertilization and Breast Cancer Risk: A Review. Int J Fertil, 50(5), 2005 p. 01–10

Fertility Drugs & Breast Cancer (case control studies)

Arakbi WA et al. In Vitro Fertilization and Breast Cancer Risk: A Review. Int J Fertil, 50(5), 2005 p. 01–10

Clinical Trial

Fertility and Sterility 2012 Vol.3(2):0015-023

Clinical Trial •Objective of study was to examine incidence rate of breast cancer in a cohort of women:– Undergoing T/t for infertility, comparing rate in

women who had in vitro fertilization (IVF) with those who did not

•Results:– There was no overall increase in the rate of

breast cancer in women who had IVF (HR 1.10, 95% confidence interval [CI] 0.88–1.36)

– But there was an increased rate in women who commenced IVF at a young age

Baseline Parameters

Time from first infertility investigation to breast cancer diagnosis (years)

Stewart. In vitro fertilization and breast cancer. Fertil Steril 2012.

Age-specific estimates of effect of IVF on breast cancer rate

Conclusion:• Authors concluded that delivering their first child late in reproductive life, whether assisted by IVF or not, is associated with an increased risk of breast cancer Stewart. In vitro fertilization and breast cancer. Fertil

Steril 2012.

Endometrial cancer & Fertility Drugs• Recognized risk factors for endometrial cancer are :

– Nulliparity & late age menopause, – Obesity, polycystic ovary syndrome, and– Presence of estrogen-secreting malignancies• Anovulation, infrequent ovulations & various

progesterone deficiencies mostly characterize hormonal subfertility• Irregular menstrual cycles are often anovulatory or

have a prolonged follicular phase– Both features result in prolonged exposure to

estrogen or progesterone raise risk of endometrial cancer

Endometrial cancer & Fertility Drugs• Two types of endometrial cancer described:

– Type I associated with hyper-estrogenic states & expresses estrogen & progesterone receptors

– Type II not associated with hyper-estrogenic states and functional ERs are rarely expressed

• Theory behind hormone dependent endometrial cancer– Estrogen stimulates mitotic activity of

endometrium induces its differentiation• cell division increases probability of random

mutations, leading to cancerBENSHUSHAN, A., O. PALTIEL, A. BRZEZINSKI, et al. 2001. Ovulation induction and risk of endometrial cancer: a pilot study. Eur. J. Obstet. Gynecol. Reprod. Biol. 98: 53–57

Endometrial cancer & Fertility Drugs• Two large cohort studies raise some concern

regarding effects of ovulation-inducing agents on endometrium

• Modan et al. in Israeli cohorts found that:– 21 uterine cancers were diagnosed during an

average of more than 20 years of follow-up, a significant twofold increase in risk was associated with FD use

• Althuis et al in US cohort reported:– 39 cases of endometrial cancer among cohort

members, found clomiphene use associated with a nonsignificant increase in riskMODAN, B., E., et al. 1998. Cancer incidence in a cohort of infertile women. Am. J.

Epidemiol. 147: 1038–1042.

Endometrial cancer & Fertility Drugs• Ron et al. and Venn et al studied Use of Fertility

Drugs in relation to risk of endometrial cancer – they found:– After 12 years of follow-up no significant increase in risk

• In the study by Venn et al cancer of uterus was not associated with IVF treatment or any of the specific FD examined, but risk estimate was based on very small numbers (n = 5)

• Conclusion:–relation between Fertility Drugs use and endometrial cancer is suffering from short follow-up and lack of information on important confounders further research needed

Melanoma and Fertility Drugs• Potential role for hormones in the etiology of

melanomas raises question of possible effects of fertility medications• Several clinical trials & some epidemiological

studies have showed a positive correlation • Biological mechanism underlying an effect of

Fertility Drugs on development of cutaneous melanoma unclear• Some epidemiologic studies suggest a possible

increase in melanoma risk in relation to hormonal subfertility and/or its treatment


Melanoma and Fertility Drugs• Dutch IVF follow-up study by Klip et al reported:

– Total of 34 melanomas during follow-up, but there was no difference in risk between exposed and unexposed patients

• In Seattle study, no overall association was found with drug use, but:– Nonsignificant increase in melanoma risk was associated with 12 or more cycles of clomiphene and hCG

• An Australian study by Venn et al. found no overall risk associated with drug usage but would not evaluate effects of specific FD


Melanoma and Fertility Drugs•Young et al. (Australia) reported:

– On long term follow up on 3186 women attending infertility clinic 14 developed melanoma

– Possible relation between fertility drugs and Melanoma difficult to interpret

YOUNG, P., D. PURDIE, L. JACKMAN, et al. 2001. A study of infertile treatment and melanoma. Melanoma Res. 11: 535–541

Cervical cancer and Fertility Drugs• Although cervical cancer is not generally viewed as

a hormonally related tumor, – Supported relationships of disease with parity &

use of oral contraceptives have raised concerns regarding effects of other hormonal agents

• Seattle study reported 36 in situ and invasive cervical cancers– Risk among women who had taken clomiphene

was reduced in regard to nonusers BUT– There was no apparent relation according to

duration of use• Further assessment of hypothesis needed

MUNOZ, N., S. FRANCESCHI, C. BOSETTI, et al. 2002. Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet

359: 1093–1101

Thyroid cancer and Fertility Drugs•Higher incidence rates of thyroid cancer in females than in males suggest:– A possible role of hormonal factors •Studies published to date do not show convincing evidence of an association between thyroid cancer risk & subfertility (treatment)• In a pooled analysis of 13 case-control studies from North America, Asia, and Europe– Use of Fertility Drugs was found to be associated

with 60%increase in thyroid cancer riskKOLONEL, L.N., et al. 1990. An epidemiologic study of thyroid cancer in Hawaii. Cancer Causes Control 1: 223–234

Thyroid cancer and Fertility Drugs• One of above mentioned studies included in this meta-analysis:– Individually reported a significant fourfold excess

risk associated with the use of Fertility Drugs– It was not possible either in this study or the

meta-analysis to determine: If the treatment itself or other correlates of

infertility were responsible for observed risk

LA VECCHIA, C., et al. 1999. A pooled analysis of case control studies of thyroid cancer III, oral contraceptives, menopausal replacement therapy and other female hormones. Cancer

Causes Control 10: 157–166

Trophoblastic tumors & Fertility Drugs• Ovulation-inducing drugs cause ovulation of more

than one oocyte, – It has been questioned whether increase in

production of immature or anucleated oocytes

– Might increase risk of developing gestational trophoblastic tumors, particularly persistent ones

• Several instances of gestational trophoblastic tumors, often occurring with a coexisting fetus, have been found among women exposed to ovulation-inducing agents

PETIGNAT, P., et al.. 2002. Are fertility drugs a risk factor for persistent trophoblastic tumour? Hum. Reprod. 17: 1610–1615.

Trophoblastic tumors & Fertility Drugs• Hydatidiform moles were reported to occur at a

rate of 1/659 among 2,369 clomiphene induced pregnancies

– Rate is onsiderably higher than natural incidence of 0.5–1.1/1,000

• Recent comprehensive review of literature concluded that :

– Women having a singleton pregnancy after exposure to ovulation inducers had no additional risk of persistent trophoblastic tumors compared with those who conceive without drugsPETIGNAT, P., et al.. 2002. Are fertility drugs a risk factor for persistent trophoblastic tumour? Hum. Reprod.

17: 1610–1615

Study Details• Objective of study:

– To evaluate risk of cancer in women who give birth after assisted reproductive technologies compared with women who give birth without ART

• Study design, size, duration: (n =806 248)– Population-based cohort consisting of all women

registered in Medical Birth Registry of Norway from 1984 to 2010

– Cancers identified by linkage to Cancer Registry of Norway

– Subjects followed from start of first pregnancy during observational period until first cancer, death, emigration

Risk of cervical and ovarian cancer for ART women compared with non-ART women

Risk of cancer of CNS & cutaneous malignant melanoma for ART women

compared with non-ART women

Risk of colorectal and thyroid cancer for ART women compared with non-ART women

Hazard ratios for cancer by site for ART women compared with non-ART women

Conclusion• Most studies are reassuring in not showing a strong

association between use of these medications and risks of most cancers

• Consistent observation is increased risk of endometrial cancer for women with infertility due to hormonal disorders

• Nulliparous women with refractory infertility may harbor a particularly high risk of ovarian cancer, irrespective of their use of infertility drugs

• Little attention focused on long-term effects of ART, which often involve much higher exposures to gonadotropins than those received by women in previous eras

Conclusion• Most IVF protocols include luteal phase support for

several weeks with supplemental have been linked to increase in breast cancer risk

• Relationship between women at particularly high risk of cancer, including those with a genetic predisposition & whether fertility medications have any unusual risk of cancer development UNCLEAR

•From majority of literature data, it can be concluded that FD and IVF do not increase risk of breast and ovarian cancer– However, concern about the risk of endometrial cancer

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oncogenic risks in art

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