Oncogenic risks in ART

ONCOGENIC RISKS IN ART
DR. K.U.KUNJIMOIDEEN
ARMC IVF, KOZHIKODE, KERALA
BELHOUL HOSPITAL, DUBAI, UAE
PREMIUM 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

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–

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

• 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 changes
RISCH, 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

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

•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

•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

• 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

• 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 cancer
Prentice 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

• 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

•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

•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 known
Zarchi 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

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

• 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 cancer
BENSHUSHAN, 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

• 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 risk
MODAN, B., E., et al. 1998. Cancer incidence in a cohort of infertile women. Am. J. Epidemiol. 147: 1038–1042.

• 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

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

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

•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
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 risk
KOLONEL, 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 drugs
PETIGNAT, 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

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

Hazard ratios for cancer by site for ART

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

THANK YOU
drkmoideen@gmail.com
www.armcivf.com

Oncogenic risks in ART

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