7 Incessant ovulation and ovarian cancer

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On Women's Health and Rights

Lectures, Speeches and Statements

Mahmoud F. Fathalla

Incessant ovulation and ovarian cancer

A swan song

8th Annual Conference of Obsterics and Gynaecology,

Luxor, Egypt

19-22 February, 2014

Incessant ovulation Incessant ovulation

and and

ovarian cancerovarian cancer

A swan songA swan song

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The Swan song is based on a popular belief that the swan, when it approaches the end of

life, makes a musical song. The relation of incessant ovulation to ovarian cancer has been

a subject that interested me for a long time. Considering age, this is probably the last time

I talk about it. This is why I labeled the talk as a swan song.

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Ovarian cancer is a silent killer.

Ovarian cancer is a silent killerOvarian cancer is a silent killer

■■ Most women have advanced disease at the time of Most women have advanced disease at the time of diagnosis. diagnosis.

■■ Intensive efforts have been directed towards developing Intensive efforts have been directed towards developing effective screening strategies. These efforts have not so effective screening strategies. These efforts have not so far met with success (Moyer, 2012far met with success (Moyer, 2012). ). Screening for Screening for ovarian cancer with the serum marker CAovarian cancer with the serum marker CA--125 and 125 and transtrans--vaginal ultrasound did not result in a decrease in vaginal ultrasound did not result in a decrease in ovarian cancer mortality, after a median followovarian cancer mortality, after a median follow--up of up of 12.4 years (National Cancer Institute, 2013)12.4 years (National Cancer Institute, 2013). .

■■ There is a need to reThere is a need to re--visit the potential of prevention visit the potential of prevention strategiesstrategies. .

Most women have advanced disease at the time of diagnosis. Intensive efforts have been

directed towards developing effective screening strategies. These efforts have not so far

met with success (Moyer, 2012). Screening for ovarian cancer with the serum marker

CA-125 and trans-vaginal ultrasound did not result in a decrease in ovarian cancer

mortality, after a median follow-up of 12.4 years (National Cancer Institute, 2013a).

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On World Cancer Day this year, the International Agency for Research on Cancer issues

a press release, highlighting that the global battle against cancer will not be won by

treatment alone, and that effective prevention strategies are urgently needed to prevent

cancer crisis.

Because ovarian cancer is a silent killer, prevention strategies are particularly important.

There is a need to re-visit the potential of prevention strategies. The incessant ovulation

hypothesis presents such opportunities for prevention.

In 1971, I submitted a hypothesis for a possible relationship between the repeated

involvement of the ovarian surface in the process of ovulation and the frequency of the

development of the common epithelial ovarian neoplasms. (Fathalla, 1971).

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This is a copy of the Lancet communication of 1971. I do not expect you to read it on the

screen. But I am showing it to make two points that may be of help to our younger

colleagues. As you can see, the paper is only one page, and it has been the most cited

paper of all my publications. Brevity is a virtue in scientific communication. A paper is

not judged by its length but by its message. The second point is to direct attention to the

phrasing of the title: Incessant ovulation: A factor in ovarian neoplasia? While the lay

press tries to attract readers by putting exciting exaggerated headlines, scientific

communication should be different. In this title, incessant ovulation is proposed as a

factor, not the factor or the cause, and it is put as a question not a statement.

The hypothesis was based on epidemiological data about reproductive risk factors in

ovarian cancer and on data from comparative oncology in animals with different

ovulation patterns. In the human female, ovulatory cycles are almost continuous from

menarche to the menopause. Social conditions of modern life not only render the majority

of ovulations purposeless, but also allow relatively infrequent non-ovulatory

physiological rest-periods of pregnancy and lactation. In other mammals, ovulations may

be limited to a breeding season, and the reproductive potential is generally exercised to

the full, allowing adequate physiological non-ovulatory rest-periods. Comparative

ovarian oncology shows the rarity of epithelial tumours in these animals. An exception is

the domestic fowl, with its frequent egg laying, in which adenocarcinoma of the ovary is

the commonest neoplasm. The plausibility of the hypothesis is supported by the unique

nature of the ovulatory process as a hormone induced injury involving processes of

trauma and repair, with possibilities for DNA damage.

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My aim in revisiting the incessant ovulation hypothesis with you today is to share with

you some recent data on the potential implications of the hypothesis for ovarian cancer

prevention, in the light of both current knowledge and future promising research. .

Incessant ovulation Incessant ovulation

and and


Implication for cancer prevention Implication for cancer prevention

I propose to discuss the potential implications under the above four main headings. Let us

start with prevention in the general population.

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Incessant ovulation and ovarian cancer Incessant ovulation and ovarian cancer

Implications for cancer preventionImplications for cancer prevention

■■ Prevention in the general populationPrevention in the general population

■■ Prevention in high risk groupsPrevention in high risk groups

■■ Opportunistic interventionsOpportunistic interventions

■■ New research frontiersNew research frontiers

Oral contraceptives (OCs) and ovarian cancer

Oral contraceptives (Oral contraceptives (OCsOCs) )

and and


The incessant ovulation hypothesis The incessant ovulation hypothesis

predicted in 1971 that suppression of predicted in 1971 that suppression of

ovulation by oral contraceptives will ovulation by oral contraceptives will

reduce ovarian cancer risk, a factor reduce ovarian cancer risk, a factor

that should then be considered when that should then be considered when

the pros and cons of the pros and cons of OCsOCs are are

evaluated (evaluated (FathallaFathalla, 1971). , 1971).

The incessant ovulation hypothesis predicted in 1971 that suppression of ovulation by

oral contraceptives will reduce ovarian cancer risk, a factor that should then be

considered when the pros and cons of OCs are evaluated (Fathalla, 1971). At the time,

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there were no epidemiologic studies about the topic. But many studies followed, and I

want to share with you some results from large studies.


and and


A 2008 collaborative reA 2008 collaborative re--analysis of data from 45 analysis of data from 45 epidemiological studies including epidemiological studies including

23 257 women with ovarian cancer and 23 257 women with ovarian cancer and

87 303 controls from 21 countries confirmed this 87 303 controls from 21 countries confirmed this risk reductionrisk reduction and, showed that the longer that and, showed that the longer that women had used oral contraceptives, the greater women had used oral contraceptives, the greater the reduction, and that the reduction persisted for the reduction, and that the reduction persisted for more than 30 years after oral contraceptive use had more than 30 years after oral contraceptive use had ceased, but became somewhat attenuated over ceased, but became somewhat attenuated over time (Collaborative Group on Epidemiological time (Collaborative Group on Epidemiological Studies of Ovarian Cancer, Studies of Ovarian Cancer, 20082008). ).

A 2008 collaborative re-analysis of data from 45 epidemiological studies including 23

257 women with ovarian cancer and 87 303 controls from 21 countries confirmed this

risk reduction, showed that the longer that women had used oral contraceptives, the

greater the reduction, and that the reduction persisted for more than 30 years after oral

contraceptive use had ceased, but became somewhat attenuated over time (Collaborative

Group on Epidemiological Studies of Ovarian Cancer, 2008).

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and and


More recently, a systematic review and metaMore recently, a systematic review and meta--analysis of 24 caseanalysis of 24 case--control and cohort studies control and cohort studies showed significant reduction in ovarian cancer showed significant reduction in ovarian cancer incidence in everincidence in ever--users compared with neverusers compared with never--users users and a significant durationand a significant duration--response relationship, response relationship, with with reduction in incidence of more than 50% reduction in incidence of more than 50% among women using among women using OCsOCs for 10 or more years for 10 or more years ((HavrileskyHavrilesky et al, et al, 20132013)). . The review concluded that The review concluded that the observed association between the observed association between OCsOCs use and use and reduced ovarian cancer risk fulfills many of the reduced ovarian cancer risk fulfills many of the classic criteria for causal inference in epidemiology, classic criteria for causal inference in epidemiology, including strength of association, consistency across including strength of association, consistency across studies, temporality, a biological gradient, biological studies, temporality, a biological gradient, biological plausibility, and coherence. plausibility, and coherence.

More recently, a systematic review and meta-analysis of 24 case-control and cohort

studies showed significant reduction in ovarian cancer incidence in ever-users compared

with never-users and a significant duration-response relationship, with reduction in

incidence of more than 50% among women using OCs for 10 or more years ( Havrilesky

et al, 2013). The review concluded that the observed association between OCs use and

reduced ovarian cancer risk fulfills many of the classic criteria for causal inference in

epidemiology, including strength of association, consistency across studies, temporality,

a biological gradient, biological plausibility, and coherence.

The use of Depot Medroxyprogesterone Acetate (DMPA) was also found to be associated

with a 39% reduction in the risk of epithelial ovarian cancer (Wilailak et al, 2012). A

significant risk reduction (83%) was observed when the duration of DMPA use was more

than 3 years. The protective effect of hormonal suppression of ovulation does not rule out

a possible additional hormonal modifying effect, whether by suppressing gonadotrophin

production or a direct effect of the hormonal drugs.

Reducing the risk of ovarian cancer in the general population

The prevalence of use of oral contraceptives can have an impact on the incidence of

ovarian cancer.

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OCsOCs and reducing the risk of and reducing the risk of

ovarian cancer in the general ovarian cancer in the general

populationpopulation

A report in 2008 estimated that oral contraceptives A report in 2008 estimated that oral contraceptives have already prevented some have already prevented some

200 000 ovarian cancers200 000 ovarian cancers and and 100 000 deaths100 000 deaths from from the disease, and that over the next few decades the disease, and that over the next few decades the number of cancers prevented will rise to at the number of cancers prevented will rise to at least 30 000 per year.least 30 000 per year.

(Collaborative Group on Epidemiological Studies of (Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and oral Ovarian Cancer. Ovarian cancer and oral contraceptives, 2008) contraceptives, 2008)

A report in 2008 estimated that oral contraceptives have already prevented some 200 000

ovarian cancers and 100 000 deaths from the disease, and that over the next few decades

the number of cancers prevented will rise to at least 30 000 per year (Collaborative Group

on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and oral contraceptives,

2008).

OCsOCs and reducing the risk of and reducing the risk of

ovarian cancer in the general ovarian cancer in the general

populationpopulation

A study of the A study of the decline in ovarian cancer incidence and mortality decline in ovarian cancer incidence and mortality among U.S. women age 35among U.S. women age 35––59 years during the period 197059 years during the period 1970––19951995, , a period during which parity has declined while oral contraceptia period during which parity has declined while oral contraceptive ve use has increased, reported that although the decline in parity use has increased, reported that although the decline in parity would be expected to increase ovarian cancer incidence, the would be expected to increase ovarian cancer incidence, the increasing prevalence and duration of oral contraceptive use wasincreasing prevalence and duration of oral contraceptive use wasprobably responsible for the overall decline in incidence. (probably responsible for the overall decline in incidence. (GnagyGnagy et et al, 2000)al, 2000). .

In another study, the observed In another study, the observed fall in incidence in Western Europe fall in incidence in Western Europe and a corresponding rise in and a corresponding rise in SSouthern and Eastern Europeouthern and Eastern Europe was was explained to be partly attributable to increasingly widespread uexplained to be partly attributable to increasingly widespread use of se of oral contraceptives in the former and to reduced fecundity in thoral contraceptives in the former and to reduced fecundity in the e latter (Bray et al, 2005). latter (Bray et al, 2005).

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A study of the decline in ovarian cancer incidence and mortality among U.S. women age

35–59 years during the period 1970–1995, a period during which parity has declined

while oral contraceptive use has increased, reported that although the decline in parity

would be expected to increase ovarian cancer incidence, the increasing prevalence and

duration of oral contraceptive use was probably responsible for the overall decline in

incidence. (Gnagy et al, 2000). In another study, the observed fall in incidence in

Western Europe and a corresponding rise in southern and Eastern Europe was

explained to be partly attributable to increasingly widespread use of oral

contraceptives in the former and to reduced fecundity in the latter (Bray et al,

2005).

OCsOCs prevalenceprevalence

According to a recent United Nations According to a recent United Nations estimate, oral contraceptives are being estimate, oral contraceptives are being used worldwide by used worldwide by 8.8 percent of 8.8 percent of women aged 15women aged 15--49 married or in 49 married or in unionunion, 18.4 percent in more developed , 18.4 percent in more developed regions, and 7.3 percent in less regions, and 7.3 percent in less developed regions. (United Nations developed regions. (United Nations Population Division, 2011).Population Division, 2011). World World users of oral contraceptives were thus users of oral contraceptives were thus estimated to be estimated to be more than 100 millionmore than 100 million. .

OCs are probably now the most widely used drug worldwide. According to a recent

United Nations estimate, oral contraceptives are being used worldwide by 8.8 percent of

women aged 15-49 married or in union, 18.4 percent in more developed regions, and 7.3

percent in less developed regions. (United Nations Population Division, 2011). World

users of oral contraceptives were thus estimated to be more than one hundred million (out

of 1,178, 863 000 women). Oral contraceptive use can be increased if women’s

contraceptive needs are met. According to the United Nations report, 11.2% of women

aged 15-49 married or in union who were fecund but not using contraception at the time

of the survey, reported not wanting any more children or wanted to delay the next child,

(11.4% in less developed regions, 24.2% in least developed regions). This translates to a

figure of more than 100 million women worldwide. Easing of prescription requirements

to allow over-the-counter access can be a move in the right direction (Grindlay et al,

2013).

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Should we increase OCs use to maximize its impact on prevention of ovarian cancer

worldwide? The answer has to be qualified. Other beneficial and adverse side effects of

OCs have to be taken into consideration when deciding on eligibility for use, and when

women make informed contraceptive choices. What we should do is to fulfill the

contraceptive unmet need. If this overall need is met, may more women who are

medically eligible will make an informed choice to us OCs to avoid an unwanted

pregnancy and benefit secondarily from the cancer protective effect.

Contraceptive unmet needContraceptive unmet need

11.2%11.2% of women aged 15of women aged 15--49 married or in union who were 49 married or in union who were

fecund but not using contraception at the time of the survey, fecund but not using contraception at the time of the survey,

reported not wanting any more children or wanted to delay reported not wanting any more children or wanted to delay

the next child, (the next child, (11.4% 11.4% in less developed regions, in less developed regions, 24.2%24.2% inin

least developed regions). This translates to a figure of least developed regions). This translates to a figure of

105,25,563 women105,25,563 women worldwide.worldwide.

Meeting the contraceptive unmet need will increase Meeting the contraceptive unmet need will increase OCsOCs use and can decrease ovarian cancer incidence use and can decrease ovarian cancer incidence

in the general population.in the general population.

Ovarian stimulating drugs and ovarian cancer: A still debated clinical challenge

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Ovarian stimulating drugs and ovarian Ovarian stimulating drugs and ovarian cancer: A still debated clinical challengecancer: A still debated clinical challenge

■■ Conflicting resultsConflicting results have been reported in small studies have been reported in small studies ((GadducciGadducci et al, 2013)et al, 2013)..

■■ A recent A recent Cochrane systemic reviewCochrane systemic review included a total of included a total of 182,972 women from 11 case182,972 women from 11 case--control studies and 14 control studies and 14 cohort studies (cohort studies (RizzutoRizzuto et al. 2013).et al. 2013). The review found The review found no convincing evidence of an increase in the risk of no convincing evidence of an increase in the risk of invasive ovarian invasive ovarian tumourstumours with fertility drug treatment, with fertility drug treatment, but that there may be an increased risk of borderline but that there may be an increased risk of borderline ovarian ovarian tumourstumours in in subfertilesubfertile women treated with IVF. women treated with IVF. Because of a high risk of bias in the studies Because of a high risk of bias in the studies analysedanalysed, , the review called for more studies at low risk of bias. the review called for more studies at low risk of bias.

The increasing use of ovarian stimulating drugs in the past few decades .to induce

multiple ovulations in the treatment of infertility and in assisted reproduction raised

concern about a possible long term effect on the development of epithelial ovarian

cancer. Conflicting results have been reported in small studies (Gadducci et al, 2013). A

recent Cochrane systemic review included a total of 182,972 women from 11 case-

control studies and 14 cohort studies (Rizzuto et al. 2013). The review found no

convincing evidence of an increase in the risk of invasive ovarian tumours with fertility

drug treatment, but that there may be an increased risk of borderline ovarian tumours in

subfertile women treated with IVF.

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Most of the studies have not confirmed a link between Most of the studies have not confirmed a link between these drugs and invasive ovarian cancers, although these drugs and invasive ovarian cancers, although some studies have suggested that the risk of borderline some studies have suggested that the risk of borderline ovarian tumors may be increased.ovarian tumors may be increased.

More large wellMore large well--designed studies are still needed to designed studies are still needed to further clarify the effects on cancer risk of these drugs further clarify the effects on cancer risk of these drugs and will allow more inand will allow more in--depth subgroup analysis based on depth subgroup analysis based on both patient and disease characteristics. both patient and disease characteristics.

H.N. H.N. SallamSallam HN, HN, AbdelAbdel--BakBak N, N, SallamSallam NH. Does ovulation NH. Does ovulation induction increase the risk of gynecological cancer? induction increase the risk of gynecological cancer?

FVV in FVV in ObGynObGyn, 2013, 5 (4): 265, 2013, 5 (4): 265--273.273.

Because of a high risk of bias in the studies analysed, the review called for more studies

at low risk of bias. Confounding variables, in reference to the incessant ovulation

hypothesis, include whether super-ovulation was followed by pregnancy, whether the

infertile patients treated were regularly ovulating or were anovulatory, and whether other

hormonal treatments, particularly progesterone, were administered in large doses after

ovulation.


While results so far are reWhile results so far are re--assuring, it is assuring, it is

clinically wise to follow the recent clinically wise to follow the recent

guidance to guidance to limit the use of ovulation limit the use of ovulation

induction or ovarian stimulation agents to induction or ovarian stimulation agents to

the lowest effective dose and duration of the lowest effective dose and duration of

useuse. .

((NICE clinical guideline, 2013)NICE clinical guideline, 2013)

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While results so far are re-assuring, it is clinically wise to follow the recent guidance to

limit the use of ovulation induction or ovarian stimulation agents to the lowest effective

dose and duration of use. (NICE clinical guideline, 2013). Simplified protocols for

infertility management are also to be encouraged (Ombelet, 2013).

We move next to prevention in high risk groups







These high risk groups fall in different categories.

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High risk groups:High risk groups:

-- Women with reproductive risk factors.Women with reproductive risk factors.-- Women with a family history and womenWomen with a family history and women who are BRCA1 and who are BRCA1 and BRCA2 mutation carriers.BRCA2 mutation carriers.

The same reproductive risk factors are associated with ovarian The same reproductive risk factors are associated with ovarian cancer risk in BRCA1 carriers to a similar relative extent as incancer risk in BRCA1 carriers to a similar relative extent as in the the general population (Antoniou et al, 2009)general population (Antoniou et al, 2009). .

■■ Women who need contraception Women who need contraception

■■ Women who do not need contraceptionWomen who do not need contraception

Let us start with women in high risk groups who need contraception. Women with

reproductive risk factors, women with a family history, and women who are BRCA1 and

BRCA2 mutation carriers who need contraception can benefit from the protective effect

of OCs if they conform to the eligibility criteria and make an informed choice. The same

reproductive risk factors are associated with ovarian cancer risk in BRCA1 carriers to a

similar relative extent as in the general population (Antoniou et al, 2009). The concern

about a long term increase risk of breast cancer is not based on solid evidence.

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Prevention in patients at a high risk Prevention in patients at a high risk

for developing ovarian cancerfor developing ovarian cancer

Women with risk factorsWomen with risk factors who need contraceptionwho need contraception can benefit can benefit from the protective effect of from the protective effect of OCsOCs if they conform to the if they conform to the eligibility criteria and make an informed choice.eligibility criteria and make an informed choice.

Based on solid evidence, current use of estrogen/ Based on solid evidence, current use of estrogen/ progestogenprogestogen OCsOCs is not associated with a longis not associated with a long--term increased term increased risk of breast cancer but may be associated with a shortrisk of breast cancer but may be associated with a short--term term increased risk while a woman is taking increased risk while a woman is taking OCsOCs (National Cancer (National Cancer Institute, 2013)Institute, 2013).. The risk of breast cancer declines with time The risk of breast cancer declines with time since last use. since last use.

But what about women with high risk factors who do not need contraception?

Women with reproductive risk factors, women with a family history, and women who are

BRCA1 and BRCA2 mutation carriers who need contraception can benefit from the

protective effect of OCs if they conform to the eligibility criteria and make an informed

choice. The same reproductive risk factors are associated with ovarian cancer risk in

BRCA1 carriers to a similar relative extent as in the general population (Antoniou et al,

2009). Based on solid evidence, current use of estrogen/progestogen OCs is not

associated with a long-term increased risk of breast cancer but may be associated with a

short-term increased risk while a woman is taking OCs (National Cancer Institute, 2013

b). The risk of breast cancer declines with time since last use. Women with risk factors

who have no need for contraception, either not being in sexual union or are infertile may

benefit from periodic suppression of ovulation.

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High risk groups:High risk groups:

Women with reproductive risk factors.Women with reproductive risk factors.

Women with a family history; womenWomen with a family history; women who who

are BRCA1 and BRCA2 mutation carriers.are BRCA1 and BRCA2 mutation carriers.

■■ Women who need contraceptionWomen who need contraception

■■ Women who do not need contraceptionWomen who do not need contraception

In a recent paper to the Lancet, a proposal was made that catholic nuns should have

access to OCs use.

Oral contraceptives for nuns??Oral contraceptives for nuns??

Today, the worldToday, the world’’s 94 790 nuns still pay a terrible price for their s 94 790 nuns still pay a terrible price for their chastity because they have a greatly increased risk of cancer: achastity because they have a greatly increased risk of cancer: a hazards hazards of their of their nulliparitynulliparity. . NulliparousNulliparous women have a higher number of women have a higher number of ovulatoryovulatory menstrual cycles than do menstrual cycles than do parousparous women because of the women because of the absence of pregnancy and lactation, and an increased number of cabsence of pregnancy and lactation, and an increased number of cycles ycles affects cancer risk.affects cancer risk.

If the Catholic Church could make the oral contraceptive pill frIf the Catholic Church could make the oral contraceptive pill freely eely available to all its nuns, it would reduce the risk of cancer, aavailable to all its nuns, it would reduce the risk of cancer, and give nd give nunsnuns’’ plight the recognition it deserves.plight the recognition it deserves.

Kara Britt, Roger Short. The plight of nuns: hazards of Kara Britt, Roger Short. The plight of nuns: hazards of nulliparitynulliparity. . Lancet Lancet VolVol 379 June 23, 2012379 June 23, 2012

It is true that women at high risk of ovarian cancer, who do not need contraception, may

benefit from periodic suppression of ovulation. But using the pill for this purpose is an

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“over-kill”. OCs are powerful hormonal drugs and their prolonged use is justified by their

contraceptive beneficial effect.

Can scientific research help? Mother nature says yes.



For women with risk factors who have no need for For women with risk factors who have no need for contraception, either not being in sexual union or are infertilecontraception, either not being in sexual union or are infertileand who may benefit from periodic suppression of ovulationand who may benefit from periodic suppression of ovulation

A research question:A research question:

Can we suppress only the process Can we suppress only the process of follicular rupture without of follicular rupture without inhibition of follicular growth and inhibition of follicular growth and without suppression of the without suppression of the development of corpus development of corpus luteumluteum??

Luteinized unruptured follicles in ovary are known to occur in mammals and

women.

van de Lagemaat R et al. Reproduction 2011;142:893-905

© 2011 Society for Reproduction and Fertility

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Red circle indicates the retained oocyte. Cumulus expansion and oocyte maturation

seemed to have been completed; however, the final follicle rupture did not take place.



For women with risk factors who have no need for For women with risk factors who have no need for contraception, either not being in sexual union or are infertilecontraception, either not being in sexual union or are infertileand who may benefit from periodic suppression of ovulationand who may benefit from periodic suppression of ovulation

A research question:A research question:

-- Can only the ovulation process be suppressed without Can only the ovulation process be suppressed without inhibition of follicular growth and development of corpus inhibition of follicular growth and development of corpus luteumluteum??

-- Can the process of follicular Can the process of follicular rupture be suppressed with rupture be suppressed with pharmacologic nonpharmacologic non--hormonal hormonal agents?agents?

The answer of recent advances in molecular biology is yes. We now have a much better

understanding of the process underlying follicular rupture.

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This picture is from a rare video shown on the television channel BBC.

Ovulation moment caught on cameraOvulation moment caught on camera

A human egg has been filmed in closeA human egg has been filmed in close--up emerging from the ovary for the up emerging from the ovary for the first time, captured by chance during a first time, captured by chance during a routine operation.routine operation.

GynaecologistGynaecologist Dr Jacques Dr Jacques DonnezDonnezspotted it in progress during a spotted it in progress during a hysterectomy.hysterectomy.

BBC Wednesday, 11 June 2008 18:00 BBC Wednesday, 11 June 2008 18:00 UKUK

The human egg has been caught, in close, emerging from the ovary. It does not give the

picture of a simple peaceful traumatic puncture of the ovarian surface epithelium.

The ovulation process

Ovulation is a unique process in that it constitutes a hormone-induced injury. Advances

in molecular biology provided better understanding of the mechanisms involved in a

complex process (Murdoch et al. 2010).

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The ovulation processThe ovulation process

The The ovulatoryovulatory surge of surge of gonadotropingonadotropin induces an induces an inflammatory reactioninflammatory reaction which brings the actual which brings the actual rupture of the ovarian surface epithelium. The rupture of the ovarian surface epithelium. The process is process is prostaglandin mediatedprostaglandin mediated. DNA. DNA--damaging damaging reactive oxygen species are generated by reactive oxygen species are generated by inflammatory cells attracted to the vicinity of the inflammatory cells attracted to the vicinity of the ovulatoryovulatory stigma. stigma. Potentially mutagenic lesionsPotentially mutagenic lesions in in DNA are normally countered andDNA are normally countered and reconciled by reconciled by TP53 tumor suppressorTP53 tumor suppressor--dependent celldependent cell--cycle arrest cycle arrest and base excision repair mechanisms. A link and base excision repair mechanisms. A link between incessant ovulation, inflammation and between incessant ovulation, inflammation and epithelial ovarian carcinogenesis is plausible epithelial ovarian carcinogenesis is plausible (Fleming et al, 2006)(Fleming et al, 2006)..

The ovulatory surge of gonadotropin induces an inflammatory reaction which brings the

actual rupture of the ovarian surface epithelium. The process is prostaglandin mediated.

DNA-damaging reactive oxygen species are generated by inflammatory cells attracted to

the vicinity of the ovulatory stigma. Potentially mutagenic lesions in DNA are normally

reconciled by TP53 tumor suppressor-dependent cell-cycle arrest and base excision repair

mechanisms. A link between incessant ovulation, inflammation and epithelial ovarian

carcinogenesis is plausible (Fleming et al, 2006).

Advances in the understanding of the process of ovulation threw more light on the

phenomenon of luteinized unruptured follicles (LUF), where the mature follicle does not

rupture, the oocyte is not released and the process of luteinization and hormonal

production proceeds as normal. Ovarian monitoring by ultrasound in women receiving

ovarian stimulation drugs showed a higher frequency of LUF (Qublan et al, 2006).

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PharmocologicPharmocologic production of production of

LuteinizedLuteinized UnrupturedUnruptured Follicle LUFFollicle LUF

The LH surge induces the expression of the The LH surge induces the expression of the prostaglandin prostaglandin synthasesynthase 2 gene (PGS2 gene (PGS--3) that codes for 3) that codes for an enzyme whose activity is essential for follicular an enzyme whose activity is essential for follicular rupture. If this enzyme were selectively inhibited, rupture. If this enzyme were selectively inhibited, ovulation would be eliminated without blocking ovulation would be eliminated without blocking luteinizationluteinization and synthesis of steroid hormones. and synthesis of steroid hormones.

The LH surge induces the expression of the prostaglandin synthase 2 gene (PGS-3) that

codes for an enzyme whose activity is essential for follicular rupture. If this enzyme were

selectively inhibited, ovulation would be eliminated without blocking luteinization and

synthesis of steroid hormones.

PharmocologicPharmocologic production of production of

LuteinizedLuteinized UnrupturedUnruptured Follicle LUFFollicle LUF

-- Oral administration of the cyclooxygenaseOral administration of the cyclooxygenase--2 (COX2 (COX--2) 2) inhibitor inhibitor meloxicammeloxicam was found to block the process of was found to block the process of ovulation in nonhuman primates when administered to ovulation in nonhuman primates when administered to simulate emergency contraceptionsimulate emergency contraception (Hester et al, 2010)(Hester et al, 2010)..

-- Pharmacologic production of Pharmacologic production of luteinizedluteinized unrupturedunrupturedfollicles by prostaglandin follicles by prostaglandin synthetasesynthetase inhibitors or other inhibitors or other drugs to prevent ovulation and simulate a normal nondrugs to prevent ovulation and simulate a normal non--conception cycle with unaltered steroid patterns and conception cycle with unaltered steroid patterns and levels and cycle length has been proposed as levels and cycle length has been proposed as a a promising lead for future contraceptionpromising lead for future contraception (US Institute of (US Institute of Medicine Report, 1996)Medicine Report, 1996)..

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Oral administration of the cyclooxygenase-2 (COX-2) inhibitor meloxicam was found to

block the process of ovulation in nonhuman primates when administered to simulate

emergency contraception (Hester et al, 2010). Pharmacologic production of luteinized

unruptured follicles by prostaglandin synthetase inhibitors or other drugs to prevent

ovulation and simulate a normal non-conception cycle with unaltered steroid patterns and

levels and cycle length has been proposed as a promising lead for future contraception

(Harrison and Rosenfield, 1996).



NonNon--hormonal pharmacologic suppression of hormonal pharmacologic suppression of ovulation, by prostaglandin ovulation, by prostaglandin synthetasesynthetase inhibitors or inhibitors or other drugs to prevent rupture of the ovarian other drugs to prevent rupture of the ovarian follicle, offers an attractive approach for periodic follicle, offers an attractive approach for periodic use by women in high risk groups who do not need use by women in high risk groups who do not need contraception but need protection from ovarian contraception but need protection from ovarian cancercancer. It will not require the level of effectiveness . It will not require the level of effectiveness of of OCsOCs. It will not necessitate prolonged regular . It will not necessitate prolonged regular use. It will also be free from hormonal adverse use. It will also be free from hormonal adverse effects. But further research is needed.effects. But further research is needed.

Although non-hormonal pharmacologic suppression of ovulation, by prostaglandin

synthetase inhibitors or other drugs to prevent rupture of the ovarian follicle, offers an

attractive approach for contraception, its periodic use by women in high risk groups who

do not need contraception but need protection from ovarian cancer, may be more feasible.

It will not require the level of effectiveness of OCs. It will not necessitate prolonged

regular use. It will also be free from hormonal adverse effects.

25



A recent metaA recent meta--analysis suggested that nonanalysis suggested that non--aspirin aspirin NSAIDsNSAIDs may be protective against may be protective against ovarian cancer, but recommended that ovarian cancer, but recommended that additional analyses, focusing on dose, additional analyses, focusing on dose, duration, and frequency of NSAID use and duration, and frequency of NSAID use and accounting for ovarian cancer heterogeneity accounting for ovarian cancer heterogeneity are necessary to further elucidate the are necessary to further elucidate the association (Murphy et al, 2012). association (Murphy et al, 2012).

A recent meta-analysis suggested that non-aspirin NSAIDs may be protective against

ovarian cancer, but recommended that additional analyses, focusing on dose,

duration, and frequency of NSAID use and accounting for ovarian cancer

heterogeneity are necessary to further elucidate the association. (Murphy et al,

2012).







26

Opportunistic intervention

Opportunistic interventionsOpportunistic interventions

When hysterectomy is performed on young women, When hysterectomy is performed on young women, removal of the ovaries will protect against the removal of the ovaries will protect against the development of ovarian cancer, but it may have its development of ovarian cancer, but it may have its negative effects. A report of over 24 years of negative effects. A report of over 24 years of followfollow--up, of 29,380 women participants of the up, of 29,380 women participants of the Nurses' Health Study, concluded that Nurses' Health Study, concluded that compared compared with ovarian conservation, bilateral with ovarian conservation, bilateral oophorectomyoophorectomyat the time of hysterectomy for benign disease was at the time of hysterectomy for benign disease was associated with a decreased risk of breast and associated with a decreased risk of breast and ovarian cancer but an increased risk of allovarian cancer but an increased risk of all--cause cause mortalitymortality (Parker et al. 2009(Parker et al. 2009;; 2013). In no analysis 2013). In no analysis or age group was or age group was oophorectomyoophorectomy associated with associated with increased survival. increased survival.

When hysterectomy is performed on young women, removal of the ovaries will protect

against the development of ovarian cancer, but it may have its negative effects. A report

of over 24 years of follow-up, of 29,380 women participants of the Nurses' Health Study,

concluded that compared with ovarian conservation, bilateral oophorectomy at the time

of hysterectomy for benign disease was associated with a decreased risk of breast and

ovarian cancer but an increased risk of all-cause mortality (Parker et al. 2009). In no

analysis or age group was oophorectomy associated with increased survival.

Can the incessant ovulation hypothesis suggest an alternative to oophorectomy for

ovarian cancer prevention? Yes, there is the promise of prophylactic salpingectomy.

27



The promise of prophylactic The promise of prophylactic salpingectomysalpingectomy

as an opportunistic intervention and an as an opportunistic intervention and an

alternative to alternative to oophorectomyoophorectomy

A Fallopian tube origin for epithelial ovarian cancer

Serous carcinomas of the ovary share many similarities and biochemical markers with the

Fallopian tube epithelium.

28

A Fallopian tube origin for A Fallopian tube origin for

epithelial ovarian cancerepithelial ovarian cancer

Serous carcinomas of the ovary share many Serous carcinomas of the ovary share many similarities and biochemical markers with similarities and biochemical markers with the Fallopian tube epithelium. While this can the Fallopian tube epithelium. While this can be explained by the common embryonic be explained by the common embryonic origin of the ovarian surface epithelium and origin of the ovarian surface epithelium and the the MullerianMullerian epithelium of the tube, it has epithelium of the tube, it has recently raised the possibility that the recently raised the possibility that the fimbrialfimbrial end of the Fallopian tube may be an end of the Fallopian tube may be an alternative source or main source of alternative source or main source of ovarian serous carcinoma (ovarian serous carcinoma (ZhengZheng and and FadareFadare, 2012), 2012)..

While this can be explained by the common embryonic origin of the ovarian surface

epithelium and the Mullerian epithelium of the tube, it has recently raised the possibility

that the fimbrial end of the Fallopian tube may be an alternative source or main source of

ovarian serous carcinoma (Zheng and Fadare, 2012). A tubal fimbrial origin can also be

explained by the incessant ovulation hypothesis. The impact of the ovulation process on

the tube should not be surprising in view of the close relationship of the tubal fimbria to

the ovary at the time of ovulation.

29

A Fallopian tube origin for A Fallopian tube origin for

epithelial ovarian cancerepithelial ovarian cancer

Ovulation has been shown to impact on Ovulation has been shown to impact on both the ovarian surface epithelium and the both the ovarian surface epithelium and the tubaltubal epithelial cellsepithelial cells (King et al., 2011)(King et al., 2011). . An An acute proacute pro--inflammatory environment is inflammatory environment is created following ovulation at the surface of created following ovulation at the surface of the ovary and within the distal fallopian the ovary and within the distal fallopian tube. With the release of an tube. With the release of an oocyteoocyte with its with its adherent cumulus adherent cumulus granulosagranulosa cells into the cells into the adjacent fallopian tube, both the ovarian adjacent fallopian tube, both the ovarian surface and the surface and the tubaltubal fimbriafimbria are bathed are bathed with follicular fluid containing inflammatory with follicular fluid containing inflammatory cytokines, reactive oxygen species, and cytokines, reactive oxygen species, and steroids (Tone et al., 2012)steroids (Tone et al., 2012)..

Ovulation has been shown to impact on both the ovarian surface epithelium and the tubal

epithelial cells (King et al. 2011). An acute pro-inflammatory environment is created

following ovulation at the surface of the ovary and within the distal fallopian tube. With

the release of an oocyte with its adherent cumulus granulosa cells into the adjacent

fallopian tube, both the ovarian surface and the tubal fimbria are bathed with follicular

30

fluid containing inflammatory cytokines, reactive oxygen species, and steroids (Tone et

al, 2012).

A tubal fimbrial origin of epithelial “ovarian” cancer, predisposed to by the repeated

process of ovulation and ovum pick up, has implications for research and for cancer

prevention. Routine careful examination of Fallopian tubes removed at the time of

hysterectomy may offer clues to early stages of cancer and pre-cancer (Vang et al. 2012).

Opportunistic interventionOpportunistic intervention

If the origin of serous cancer is mostly in the If the origin of serous cancer is mostly in the fimbrialfimbrial end of the Fallopian tube, end of the Fallopian tube, salpingectomysalpingectomyalone may be sufficient to reduce the risk of serous alone may be sufficient to reduce the risk of serous cancer and preserve ovarian function. While cancer and preserve ovarian function. While further research, in case control and longitudinal further research, in case control and longitudinal studies, is needed to verify the validity of this studies, is needed to verify the validity of this

protective effect, protective effect, salpingectomysalpingectomy can be can be recommended as a routine recommended as a routine procedure if one or both ovaries procedure if one or both ovaries are to be conserved at the time of are to be conserved at the time of hysterectomyhysterectomy. .

If the origin of cancer is mostly in the fimbrial end of the Fallopian tube, salpingectomy

alone may be sufficient to reduce the risk of cancer and preserve ovarian function. While

further research, in case control and longitudinal studies, is needed to verify the validity

of this protective effect, salpingectomy can be recommended as a routine procedure if

one or both ovaries are to be conserved at the time of hysterectomy.

Prophylactic oophorectomy is generally reserved for women who have a deleterious

mutation in a BRCA1 or BRCA2 gene. Salpingectomy alone may offer an attractive

alternative if ovarian conservation is desired (Kamran et al, 2013). A future pregnancy

may still be possible by assisted reproduction. Further research is needed to validate this

approach.

Tubal sterilization

Tubal sterilization has been reported to be associated with a reduced risk for ovarian

cancer (Cibula et al, 2011). The use of perineal talc has been incriminated as a possible

mechanism for ovarian cancer pathogenesis, which is prevented by tubal block. A

prospective analysis of perineal talc use and the risk of ovarian cancer based on the

Nurses' Health Study ( a prospective study of 121 700 female registered nurses in the

United States who were aged 30-55 years at enrollment in 1976), provided little support

31

for any substantial association between perineal talc use and ovarian cancer risk overall;

however, perineal talc use may modestly increase the risk of invasive serous ovarian

cancer (Gertig et al. 2000).

An alternative explanation for a protective effect of tubal sterilization, taking into

consideration a fimbrial origin of ovarian cancer and the role of ovulation, can be the

disturbed process of ovum pick-up due to the distancing of the tubal fimbria from the site

of ovulation after excision or cauterization of a part of the tube. Studies have suggested

the importance of the proximity of the fimbrial ovarian relation as an important factor in

ovum pick up and fertility (Roy et al, 2005).







The hen as an experimental model

32

Our hero for future research on the prevention of ovarian cancer is the incessant ovulating

egg laying hen.

The hen as an experimental modelThe hen as an experimental model

There are biological limitations for mammalian and There are biological limitations for mammalian and primate animal models for ovarian epithelial cancer primate animal models for ovarian epithelial cancer (Lu et al., 2009). (Lu et al., 2009). TheThe incessant incessant ovulatorovulator egg laying henegg laying hen, on the other , on the other hand, presented a near ideal experimental hand, presented a near ideal experimental model.(Leemodel.(Lee and Song, 2013)and Song, 2013). .

Clear advantages of the hen model include Clear advantages of the hen model include spontaneous tumor formation without the need for spontaneous tumor formation without the need for an exogenous carcinogen or genetic engineering. an exogenous carcinogen or genetic engineering. (Hakim et al., 2009)(Hakim et al., 2009)..

There are biological limitations for mammalian and primate animal models for ovarian

epithelial cancer (Lu et al. 2009). The incessant ovulator egg laying hen, on the other

hand, presented a near ideal experimental model.(Lee and Song, 2013). Clear advantages

33

of the hen model include spontaneous tumor formation without the need for an

exogenous carcinogen or genetic engineering.

The hen as an experimental modelThe hen as an experimental model

Approximately Approximately 83% of hens83% of hens develop ovarian epithelial cancer develop ovarian epithelial cancer after 3 to 4 years of continuous laying of eggs. after 3 to 4 years of continuous laying of eggs.

Hens and women share an incessant Hens and women share an incessant ovulatoryovulatory pattern, pattern, involving repetitive epithelial injury and repair with associatinvolving repetitive epithelial injury and repair with associated ed inflammatory factors in a hormonal milieu. inflammatory factors in a hormonal milieu. GenotoxicGenotoxic insults insults may target the ovarian surface epithelium or the may target the ovarian surface epithelium or the fimbrialfimbrialmucosa, both proposed sites of origin of epithelial ovarian mucosa, both proposed sites of origin of epithelial ovarian cancer. cancer. The 2The 2--yearyear--old hen would have ovulated about the same old hen would have ovulated about the same number of times as a woman who has reached menopause. number of times as a woman who has reached menopause.

There are unique similarities in the characteristics and There are unique similarities in the characteristics and biomarkers of human and chicken ovarian cancers. (Hakim et biomarkers of human and chicken ovarian cancers. (Hakim et al, 2009)al, 2009)..The incessant The incessant ovulatorovulator egg laying hen presents a near ideal egg laying hen presents a near ideal experimental model to develop new chemoprevention experimental model to develop new chemoprevention

strategiesstrategies..

Approximately 83% of hens develop ovarian epithelial cancer after 3 to 4 years of

continuous laying of eggs. Hens and women share an incessant ovulatory pattern,

involving repetitive epithelial injury and repair with associated inflammatory factors in a

hormonal milieu. Genotoxic insults may target the ovarian surface epithelium or the

fimbrial mucosa, both proposed sites of origin of epithelial ovarian cancer. The 2-year-

old hen would have ovulated about the same number of times as a woman who has

reached menopause. There are unique similarities in the characteristics and biomarkers of

human and chicken ovarian cancers. (Hakim et al, 2009). Recent research has shown that

oral contraceptives decrease the prevalence of ovarian cancer in the hen, as it does in

women. (Trevinol et al, 2012). The incessant ovulator domestic hen offers a model for

future studies on chemoprevention of epithelial ovarian cancer.

34



““Take homeTake home”” messagesmessages::■■ Meeting the contraceptive unmet need will Meeting the contraceptive unmet need will

increase increase OCsOCs use and can decrease ovarian use and can decrease ovarian

cancer incidence in the general population.cancer incidence in the general population.

■■ It is advisable to limit the use of ovulation It is advisable to limit the use of ovulation

induction or ovarian stimulation agents to the induction or ovarian stimulation agents to the

lowest effective dose and duration of use.lowest effective dose and duration of use.



““Take homeTake home”” messagesmessages (cont.)(cont.)::■■ Women with risk factorsWomen with risk factors who need contraceptionwho need contraceptioncan benefit from the protective effect of can benefit from the protective effect of OCsOCs if they if they

conform to the eligibility criteria and make an conform to the eligibility criteria and make an

informed choice. informed choice.

■■ Women with risk factors who have no need for Women with risk factors who have no need for

contraception, may benefit from periodic contraception, may benefit from periodic suppression of ovulation with suppression of ovulation with the the promise of promise of

pharmacologic nonpharmacologic non--hormonal suppression of hormonal suppression of

ovulation.ovulation.

35



““Take homeTake home”” messages (cont.)messages (cont.)::■■ SalpingectomySalpingectomy can be recommended as a routine procedure can be recommended as a routine procedure

if one or both ovaries are to be conserved at the time of if one or both ovaries are to be conserved at the time of hysterectomy.hysterectomy.

■■ The incessant The incessant ovulatorovulator egg laying hen presents a near ideal egg laying hen presents a near ideal experimental model to develop new chemoprevention experimental model to develop new chemoprevention strategies.strategies.

A final thought about incessant ovulation, the changing A final thought about incessant ovulation, the changing woman and the challenge to the Ob/woman and the challenge to the Ob/GynGyn professionprofession

Let me conclude with a final thought about incessant ovulation, the changing woman and

the challenge to our profession.

Women have incessant ovulation because they have changed socially but not

biologically.

From the hunter gatherer to From the hunter gatherer to

the modern womanthe modern woman

The modern woman in the postThe modern woman in the post--industrial society has to cope with industrial society has to cope with her new life while burdened with a reproductive system that has her new life while burdened with a reproductive system that has evolved to serve well the survival and reproductive success in hevolved to serve well the survival and reproductive success in her life er life in a hunterin a hunter--gatherer society.gatherer society.

36

From the hunter gatherer From the hunter gatherer

to the modern womanto the modern woman

A woman in a hunterA woman in a hunter--gatherer society will gatherer society will

get her first pregnancy soon after puberty, get her first pregnancy soon after puberty,

will lactate for three or four years, then will will lactate for three or four years, then will have other successive pregnancies and have other successive pregnancies and

breastfeeding periods. During her breastfeeding periods. During her

reproductive life span, she will probably reproductive life span, she will probably

have have no more than 50 ovulationsno more than 50 ovulations, spaced by , spaced by prolonged physiological prolonged physiological anovulatoryanovulatory rest rest

periods.periods.

Incessant ovulation is only one of the challenges which the changing woman continues to

present to our noble profession.

Where are women going, and where are they taking us in the future has been a topic of

science fiction, about women in a brave new world.

Quo Quo vadisvadis Ms Homo sapiensMs Homo sapiens??

The changing womanThe changing womanA continuing challenge to the Ob A continuing challenge to the Ob GynGyn professionprofession

■■ Reproduction: Reproduction: AA function of women, not function of women, not thethefunction of womenfunction of women

■■ The breast: from maternal to sexualThe breast: from maternal to sexual

�� Divorce of sex from reproduction:Divorce of sex from reproduction:

Sex without reproductionSex without reproduction

Reproduction without sexReproduction without sex

�� The vagina: from a birth canal to a pleasure canalThe vagina: from a birth canal to a pleasure canal

?? Women in a Brave New WorldWomen in a Brave New World

37

The novel:"Brave New world", predicts a new future for human reproduction.

Women in a Brave New WorldWomen in a Brave New World

The end of The end of viviparityviviparity

““Mustapha Mustapha MondMond leaned forward, leaned forward, shook a finger at them. shook a finger at them. ‘‘Just try to Just try to realize itrealize it’’, he said, and his voice sent a , he said, and his voice sent a strange thrill quivering along their strange thrill quivering along their diaphragms, diaphragms, ‘‘Try to realize what it Try to realize what it was like to have awas like to have a viviparous viviparous mothermother’’

AldousAldous Huxley. Brave new world, 1977Huxley. Brave new world, 1977

Not only will fertilization take place in vitro, but embryonic and foetal development will

also take place in vitro in special incubators or hatcheries. There will be an end to

pregnancy and delivery.

38

Will that mean the end for the noble profession of obstetrics?

Probably not.

Women in a Brave New WorldWomen in a Brave New World

The end of The end of viviparityviviparity

But not the end of obstetriciansBut not the end of obstetricians

““Dr WellsDr Wells advised me to have a advised me to have a

Pregnancy substitutePregnancy substitute..””

““But, my dear, youBut, my dear, you’’re only nineteen. The first re only nineteen. The first pregnancy substitute isnpregnancy substitute isn’’t compulsory till t compulsory till twentytwenty--one.one.””

‘‘I know, dear. ..I know, dear. ..Dr WellsDr Wells told me that told me that brunettes with wide pelvises, like me, ought brunettes with wide pelvises, like me, ought to have their first Pregnancy Substitute at to have their first Pregnancy Substitute at seventeen.seventeen.’’

AldousAldous Huxley. Brave new world. P. 39; P.41. Huxley. Brave new world. P. 39; P.41. Grafton books, London. 1977.Grafton books, London. 1977.

In this passage of the novel, obstetrician will be till in business and in demand to

administer “pregnancy substitutes”. The clever Dr Wells twists the rules to do more

business by informing his client how she needs the substitute earlier.

So, women may continue to change. But our profession will continue to be around, will

adapt, and will continue to do good business.

39

References

Antoniou AC, Rookus M, Andrieu N, et al. Reproductive and hormonal factors, and

ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: Results from the

international BRCA1/2 carrier cohort study. Cancer Epidemiol Biomarkers Prev

2009;18(2):601–10.

Behrens RF, Smith LA. Risk of ovarian cancer in women treated with ovarian stimulating

drugs for infertility. Cochrane Database Syst Rev. 2013 Aug 13;8:CD008215. doi:

10.1002/14651858.

Bray, F., Loos, A. H., Tognazzo, S. et al. Ovarian cancer in Europe: Cross-

sectional trends in incidence and mortality in 28 countries, 1953–2000. Int. J.

Cancer, 2005; 113: 977–990. doi: 10.1002/ijc.20649.

Britt K, Short R. The plight of nuns: hazards of nulliparity. Lancet 2012; 379: 2322-

2323.

Cibula D, Widschwendter M, Ma´jek O et al. Tubal ligation and the risk of ovarian

cancer: review and meta-analysis. Human Reproduction Update 2011;17: 55–67.

Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and

oral contraceptives: collaborative reanalysis of data from 45 epidemiological

studies including 23 257 women with ovarian cancer and 87 303 controls. Lancet

2008; 371:303-314.

Fathalla MF. Incessant ovulation-a factor in ovarian neoplasia? Lancet. 1971;

2(7716):163.

Fleming JS, Clare R. Beaugie CR, Haviv I, et al. Incessant ovulation, inflammation and

epithelial ovarian carcinogenesis: Revisiting old hypotheses. Molecular and

Cellular Endocrinology 2006; 247:4–21.

Gadducci A, Guerrieri ME, Genazzani AR. Fertility drug use and risk of ovarian tumors:

a debated clinical challenge. Gynecol Endocrinol. 2013; 29(1):30-5. doi:

10.3109/09513590.2012.705382.

Gertig DM, Hunter DJ, Cramer DW, et al.. Prospective study of talc use and ovarian

cancer. J Natl Cancer Inst. 2000; 92(3): 249-52.

Gnagy, S., Ming, E.1, Devesa, S, et al. Declining ovarian cancer rates in U.S. women

in relation to parity and oral contraceptive use. Epidemiology 2000; 11(2) 102-

105.

Grindlay K, Burns B, Grossman D. Prescription requirements and over-the-counter

access to oral contraceptives: a global review. Contraception 2013; 88 (1): 91-96.

Harrison PF, Rosenfield A., Editors, Committee on Contraceptive Research and

Development, Division of Health Sciences Policy, Institute of Medicine.

Contraceptive research and development- Looking to the future. National

Academy Press, Washington DC. 1996. p.134.

Hakim AA, Catherine P. Barry CP, Barnes J, et al. Ovarian adenocarcinomas in the

laying hen and women share similar alterations in p53, ras, and HER-2/neu.

Cancer Prev Res 2009;2 (2):114-121.

Havrilesky LJ, Moorman PG, Lowery WJ, et al. Oral contraceptive pills as primary

prevention for ovarian cancer: A systematic review and meta-analysis. Obstet

Gynecol. 2013;122(1):139-147.

Hester KE, Harper MJK, Duffy DM. Oral administration of the cyclooxygenase-2 (COX-

40

2) inhibitor meloxicam blocks ovulation in nonhuman primates when

administered to simulate emergency contraception. Human Reproduction, 2010;

25: 360–367.

Kamran MW, Vaughan, D. Crosby, N.A. et al. Opportunistic and interventional

salpingectomy in women at risk: a strategy for preventing pelvic serous cancer

(PSC). Eur J Obstet Gynecol Reprod Biol. 2013; 170(1):251-4. doi:

10.1016/j.ejogrb.2013.06.030.

King SM, Hilliard TS, Wu LY, et al. The impact of ovulation on Fallopian tube

epithelial cells: Evaluating three hypotheses connecting ovulation and serous

ovarian Cancer. Endocrine-Related Cancer 2011; 18: 627–642.

Lee J-Y, Song G. The Laying Hen: An Animal Model for Human Ovarian Cancer

Reprod Dev Biol 2013; 37(1): 41-49.

Lu KH, Yates MS, Mok SC. The Monkey, the Hen, and the Mouse: Models to

Advance Ovarian Cancer Chemoprevention. Cancer Prev Res 2009;2(9): 773-5.

doi: 10.1158/1940-6207

Moyer VA, U.S. Preventive Services Task Force. Screening for ovarian cancer: U.S.

Preventive Services Task Force reaffirmation recommendation statement. Ann

Intern Med 2012;157:900–4.

Murdoch WJ, Murphy CJ, Van Kirk EA, et al. Mechanisms and pathobiology of

ovulation. Soc Reprod Fertil Suppl. 2010;67:189-201.

Murphy MA, Trabert B, Yang HP, et al. Non-steroidal anti-inflammatory drug use and

ovarian cancer risk: findings from the NIH-AARP Diet and Health Study and

systematic review. Cancer Causes & Control 2012; 23 (11):1839-1852.

National Cancer Institute (a): PDQ® Ovarian Cancer Screening. Bethesda, MD: National

Cancer Institute. Date last modified 07/25/2013. Available at:

http://cancer.gov/cancertopics/pdq/screening/ovarian/HealthProfessional.

Accessed 16/09/2013.

National Cancer Institute (b): PDQ® Ovarian Cancer Prevention. Bethesda, MD:

National Cancer Institute. Date last modified 23-07-2010. Available at:

http://cancer.gov/cancertopics/pdq/prevention/ovarian/HealthProfessional.

Accessed 26/09/2013

NICE (National Institute for Health and Care Guidance). Clinical guideline 156.

: Assessment and treatment for people with fertility problems. Issued: February

2013. http://publications.nice.org.uk/fertility-cg156

Ombelet W. The Walking Egg Project: Universal access to infertility care –from dream to

reality. FVV in ObGyn, 2013, 5 (2): 161-175.

Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the time of hysterectomy

and long-term health outcomes in the nurses' health study. Obstet Gynecol. 2009;

113(5):1027-37. doi: 10.1097/AOG.0b013e3181a11c64.

Qublan H, Amarin Z, Nawasreh M, et al. Luteinized unruptured follicle syndrome:

incidence and recurrence rate in infertile women with unexplained infertility

undergoing intrauterine insemination. Hum Reprod. 2006; 21(8):2110-3. Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated with ovarian

stimulating drugs for infertility. Cochrane Database Syst Rev. 2013 Aug

13;8:CD008215. doi: 10.1002/14651858. Roy KK, Hegde P, Banerjee K, et al.. Fimbrio-ovarian relationship in unexplained

41

infertility. Gynecol Obstet Invest. 2005;60(3):128-32.

Tone AA, Virtanen C, Shaw P et al. Prolonged postovulatory pro-inflammatory signaling

in the Fallopian tube epithelium may be mediated through a BRCA1/DAB2 Axis.

Clin Cancer Res 2012;18: 4334-44. doi: 10.1158/1078-0432.

Trevino1 LS, Buckles EL, and Johnson PA. Oral contraceptives decrease the prevalence

of ovarian cancer in the hen. Cancer Prev Res 2012; 5 (2): 343-9. doi:

10.1158/1940-6207.

United Nations Population Division | Department of Economic and Social Affairs. World

contraceptive use 2011.

www.un.org/esa/population/publications/contraceptive2011/contraceptive2011.ht

m

Vang R, Shih IeM, Kurman RJ.. Fallopian tube precursors of ovarian low- and high

grade serous neoplasms. Histopathology. 2013;62 (1):44-58. doi:

10.1111/his.12046

Wilailak S, Vipupinyo C, Suraseranivong V, et al. Depot medroxyprogesterone acetate

and epithelial ovarian cancer: a multicentre case-control study. BJOG 2012;

119(6): 672-7. doi: 10.1111/j.1471-0528.2012.03298

Zheng W, Fadare O. Editorial Commentary: Fallopian tube as main source for ovarian

and pelvic (non-endometrial) serous carcinomas. Int J Clin Exp Pathol 2012;5

(3): 182-186.

An open access article based on the lecture: Fathalla MF.2013. Incessant ovulation and ovarian cancer – a hypothesis re-visited. Facts Views Vision Obgyn. 2013; 5(4): 292–297. PMCID: PMC3987381

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