Download Incessant ovulation and ovarian cancer

1
On Women's Health and Rights
Lectures, Speeches and Statements
Mahmoud F. Fathalla
Incessant ovulation and ovarian cancer
A swan song
th
8 Annual Conference of Obsterics and Gynaecology,
Luxor, Egypt
19-22 February, 2014
Incessant ovulation
and
ovarian cancer
A swan song
2
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.
3
Ovarian cancer is a silent killer.
Ovarian cancer is a silent killer
■ 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).
2012). Screening for
ovarian cancer with the serum marker CACA-125 and
transtrans- vaginal ultrasound did not result in a decrease in
ovarian cancer mortality, after a median followfollow-up of
12.4 years (National Cancer Institute, 2013).
2013).
■ There is a need to rere- visit the potential of prevention
strategies.
strategies.
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
and
ovarian cancer
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
Implications for cancer prevention
■ Prevention in the general population
■ Prevention in high risk groups
■ Opportunistic interventions
■ New research frontiers
Oral contraceptives (OCs) and ovarian cancer
Oral contraceptives (OCs
(OCs))
and
ovarian cancer
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
(Fathalla,, 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.
Oral contraceptives (OCs
(OCs))
and
ovarian cancer
A 2008 collaborative rere- 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 and, 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).
2008).
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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Oral contraceptives (OCs
(OCs))
and
ovarian cancer
More recently, a systematic review and metametaanalysis of 24 casecase- control and cohort studies
showed significant reduction in ovarian cancer
incidence in everever-users compared with nevernever-users
and a significant durationduration-response relationship,
with reduction in incidence of more than 50%
among women using OCs for 10 or more years
(Havrilesky et al, 2013)
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.
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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OCs and reducing the risk of
ovarian cancer in the general
population
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)
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).
OCs and reducing the risk of
ovarian cancer in the general
population
A study of the decline in ovarian cancer incidence and mortality
among U.S. women age 35–
35–59 years during the period 1970–
1970–1995,
1995,
a period during which parity has declined while oral contraceptive
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
(Gnagy et
al, 2000).
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
use of
oral contraceptives in the former and to reduced fecundity in the
the
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).
OCs prevalence
According to a recent United Nations
estimate, oral contraceptives are being
used worldwide by 8.8 percent of
women aged 1515-49 married or in
union,
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 100 million.
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 need
11.2% of women aged 1515-49 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%
(11.4% in less developed regions, 24.2% in
least developed regions). This translates to a figure of
105,25,563 women worldwide.
Meeting the contraceptive unmet need will increase
OCs use and can decrease ovarian cancer incidence
in the general population.
Ovarian stimulating drugs and ovarian cancer: A still debated clinical challenge
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Ovarian stimulating drugs and ovarian
cancer: A still debated clinical challenge
■ Conflicting results have been reported in small studies
(Gadducci et al, 2013).
2013).
■ A recent Cochrane systemic review included a total of
182,972 women from 11 casecase- control studies and 14
cohort studies (Rizzuto
(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.
Because of a high risk of bias in the studies analysed,
analysed,
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 casecontrol 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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Ovarian stimulating drugs and ovarian
cancer: A still debated clinical challenge
Most of the studies have not confirmed a link between
these drugs and invasive ovarian cancers, although
some studies have suggested that the risk of borderline
ovarian tumors may be increased.
More large wellwell-designed studies are still needed to
further clarify the effects on cancer risk of these drugs
and will allow more inin-depth subgroup analysis based on
both patient and disease characteristics.
H.N. Sallam HN, AbdelAbdel- Bak N, Sallam NH. Does ovulation
induction increase the risk of gynecological cancer?
FVV in ObGyn,
ObGyn, 2013, 5 (4): 265265- 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.
Ovarian stimulating drugs and ovarian
cancer: A still debated clinical challenge
While results so far are rere-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.
use.
(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
Incessant ovulation and ovarian cancer
Implications for cancer prevention
■ Prevention in the general population
■ Prevention in high risk groups
■ Opportunistic interventions
■ New research frontiers
These high risk groups fall in different categories.
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Incessant ovulation and ovarian cancer
Implications for cancer prevention
High risk groups:
- Women with reproductive risk factors.
- Women with a family history and women who are BRCA1 and
BRCA2 mutation carriers.
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).
2009).
■ Women who need contraception
■ Women 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
for developing ovarian cancer
Women with risk factors who need contraception can benefit
from the protective effect of OCs if they conform to the
eligibility criteria and make an informed choice.
Based on solid evidence, current use of estrogen/
progestogen OCs is not associated with a longlong-term increased
risk of breast cancer but may be associated with a shortshort-term
increased risk while a woman is taking OCs (National Cancer
Institute, 2013).
2013). The risk of breast cancer declines with time
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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Incessant ovulation and ovarian cancer
Implications for cancer prevention
High risk groups:
Women with reproductive risk factors.
Women with a family history; women who
are BRCA1 and BRCA2 mutation carriers.
■ Women who need contraception
■ Women 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??
Today, the world’
world’s 94 790 nuns still pay a terrible price for their
chastity because they have a greatly increased risk of cancer: a hazards
of their nulliparity.
nulliparity. Nulliparous women have a higher number of
ovulatory menstrual cycles than do parous women because of the
absence of pregnancy and lactation, and an increased number of cycles
cycles
affects cancer risk.
If the Catholic Church could make the oral contraceptive pill freely
freely
available to all its nuns, it would reduce the risk of cancer, and
and give
nuns’
nuns’ plight the recognition it deserves.
Kara Britt, Roger Short. The plight of nuns: hazards of nulliparity.
nulliparity.
Lancet Vol 379 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.
Prevention in patients at a high risk
for developing ovarian cancer
For women with risk factors who have no need for
contraception, either not being in sexual union or are infertile
and who may benefit from periodic suppression of ovulation
A research question:
Can we suppress only the process
of follicular rupture without
inhibition of follicular growth and
without suppression of the
development of corpus luteum?
Luteinized unruptured follicles in ovary are known to occur in mammals and
women.
van de Lage maat 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.
Prevention in patients at a high risk
for developing ovarian cancer
For women with risk factors who have no need for
contraception, either not being in sexual union or are infertile
and who may benefit from periodic suppression of ovulation
A research question:
- Can only the ovulation process be suppressed without
inhibition of follicular growth and development of corpus
luteum?
luteum?
Can the process of follicular
rupture be suppressed with
pharmacologic non-hormonal
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 camera
A human egg has been filmed in closecloseup emerging from the ovary for the
first time, captured by chance during a
routine operation.
Gynaecologist Dr Jacques Donnez
spotted it in progress during a
hysterectomy.
BBC Wednesday, 11 June 2008 18:00
UK
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 process
The ovulatory surge of gonadotropin induces an
inflammatory reaction which brings the actual
rupture of the ovarian surface epithelium. The
process is prostaglandin mediated.
mediated. DNADNA- damaging
reactive oxygen species are generated by
inflammatory cells attracted to the vicinity of the
ovulatory stigma. Potentially mutagenic lesions in
DNA are normally countered and reconciled by
TP53 tumor suppressorsuppressor-dependent cellcell-cycle arrest
and base excision repair mechanisms. A link
between incessant ovulation, inflammation and
epithelial ovarian carcinogenesis is plausible
(Fleming et al, 2006).
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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Pharmocologic production of
Luteinized Unruptured Follicle LUF
The LH surge induces the expression of the
prostaglandin synthase 2 gene (PGS(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.
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.
Pharmocologic production of
Luteinized Unruptured Follicle LUF
-
Oral administration of the cyclooxygenasecyclooxygenase-2 (COX(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).
2010).
- Pharmacologic production of luteinized unruptured
follicles by prostaglandin synthetase inhibitors or other
drugs to prevent ovulation and simulate a normal nonnonconception cycle with unaltered steroid patterns and
levels and cycle length has been proposed as a
promising lead for future contraception (US Institute of
Medicine Report, 1996).
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).
Prevention in patients at a high risk
for developing ovarian cancer
NonNon- hormonal pharmacologic suppression of
ovulation, by prostaglandin synthetase inhibitors or
other drugs to prevent rupture of the ovarian
follicle, offers an attractive approach for periodic
use by women in high risk groups who do not need
contraception but need protection from ovarian
cancer.
cancer. It will not require the level of effectiveness
of OCs.
OCs. It will not necessitate prolonged regular
use. It will also be free from hormonal adverse
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
Prevention in patients at a high risk
for developing ovarian cancer
A recent metameta-analysis suggested that nonnonaspirin 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).
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).
Incessant ovulation and ovarian cancer
Implications for cancer prevention
■ Prevention in the general population
■ Prevention in high risk groups
■ Opportunistic interventions
■ New research frontiers
26
Opportunistic intervention
Opportunistic interventions
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
followfollow-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 allall-cause
mortality (Parker et al. 2009;
2009; 2013). In no analysis
or age group was oophorectomy associated with
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
Incessant ovulation and ovarian cancer
Implications for cancer prevention
The promise of prophylactic salpingectomy
as an opportunistic intervention and an
alternative to oophorectomy
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
epithelial ovarian cancer
Serous carcinomas of the ovary share many
similarities and biochemical markers with
the Fallopian tube epithelium. 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
(Zheng and
Fadare,
Fadare, 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
epithelial ovarian cancer
Ovulation has been shown to impact on
both the ovarian surface epithelium and the
tubal epithelial cells (King et al., 2011).
2011). An
acute propro-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 fluid containing inflammatory
cytokines, reactive oxygen species, and
steroids (Tone et al., 2012).
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 intervention
If the origin of serous cancer is mostly in the
fimbrial end of the Fallopian tube, salpingectomy
alone may be sufficient to reduce the risk of serous
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.
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).
Incessant ovulation and ovarian cancer
Implications for cancer prevention
■ Prevention in the general population
■ Prevention in high risk groups
■ Opportunistic interventions
■ New research frontiers
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 model
There are biological limitations for mammalian and
primate animal models for ovarian epithelial cancer
(Lu et al., 2009).
The incessant ovulator egg laying hen,
hen, on the other
hand, presented a near ideal experimental
model.(Lee and Song, 2013).
2013).
Clear advantages of the hen model include
spontaneous tumor formation without the need for
an exogenous carcinogen or genetic engineering.
(Hakim et al., 2009).
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 model
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
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 22-yearyear-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).
2009).
The incessant ovulator egg laying hen presents a near ideal
experimental model to develop new chemoprevention
strategies.
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-yearold 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
Incessant ovulation and ovarian cancer
Implications for cancer prevention
“Take
home” messages:
■ Meeting the contraceptive unmet need will
increase OCs use and can decrease ovarian
cancer incidence in the general population.
■ It is advisable to limit the use of ovulation
induction or ovarian stimulation agents to the
lowest effective dose and duration of use.
Incessant ovulation and ovarian cancer
Implications for cancer prevention
“Take home” messages (cont.):
■ Women with risk factors who need contraception
can benefit from the protective effect of OCs if they
conform to the eligibility criteria and make an
informed choice.
■ Women with risk factors who have no need for
contraception, may benefit from periodic
suppression of ovulation with the promise of
pharmacologic nonnon-hormonal suppression of
ovulation.
35
Incessant ovulation and ovarian cancer
Implications for cancer prevention
“Take home” messages (cont.):
■ Salpingectomy can be recommended as a routine procedure
if one or both ovaries are to be conserved at the time of
hysterectomy.
■ The incessant ovulator egg laying hen presents a near ideal
experimental model to develop new chemoprevention
strategies.
A final thought about incessant ovulation, the changing
woman and the challenge to the Ob/Gyn
Ob/Gyn profession
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
the modern woman
The modern woman in the postpost-industrial society has to cope with
her new life while burdened with a reproductive system that has
evolved to serve well the survival and reproductive success in her
her life
in a hunterhunter-gatherer society.
36
From the hunter gatherer
to the modern woman
A woman in a hunterhunter-gatherer society will
get her first pregnancy soon after puberty,
will lactate for three or four years, then will
have other successive pregnancies and
breastfeeding periods. During her
reproductive life span, she will probably
have no more than 50 ovulations,
ovulations, spaced by
prolonged physiological anovulatory rest
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 vadis Ms Homo sapiens?
The changing woman
A continuing challenge to the Ob Gyn profession
■ Reproduction: A function of women, not the
function of women
■ The breast: from maternal to sexual
Divorce of sex from reproduction:
Sex without reproduction
Reproduction without sex
The vagina: from a birth canal to a pleasure canal
?
Women in a Brave New World
37
The novel:"Brave New world", predicts a new future for human reproduction.
Women in a Brave New World
The end of viviparity
“Mustapha Mond leaned forward,
shook a finger at them. ‘Just try to
realize it’
it’, he said, and his voice sent a
strange thrill quivering along their
diaphragms, ‘Try to realize what it
was like to have a viviparous
mother’
Aldous Huxley. 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 World
The end of viviparity
But not the end of obstetricians
“Dr Wells advised me to have a
Pregnancy substitute.”
“But, my dear, you’
you’re only nineteen. The first
pregnancy substitute isn’
isn’t compulsory till
twentytwenty-one.”
one.”
‘I know, dear. ..Dr
..Dr Wells told me that
brunettes with wide pelvises, like me, ought
to have their first Pregnancy Substitute at
seventeen.’
seventeen.’
Aldous Huxley. Brave new world. P. 39; P.41.
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: Crosssectional 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: 23222323.
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) 102105.
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