EndometriosisBMJ 2007; 334 doi: https://doi.org/10.1136/bmj.39073.736829.BE (Published 01 February 2007) Cite this as: BMJ 2007;334:249
All rapid responses
The oral contraceptives, progesterogens, gonadotraphin releasing
hormones agonists or surgery are the present treatment modalities for
Just like the way majority of cancers have an absolute requirement
for angiogenesis, the process by which new blood vessels are formed(1), in
endometriosis also the peritoneal implantation of endometrium requires
blood supply. The most potent angiogenic cytokine is vascular endothelial
growth factor (VEGF) and there has been substantial research into the
development of VEGF/VEGF receptor (VEGFR) antagonists1. Like cancers
increased VEGF expression was noticed in a mouse model2. Immunostaining
and gene expression of VEGF was examined in eutopic endometrium,
endometriotic lesions, and normal peritoneum2. In this study VEGF promoter
activity was evaluated in eutopic endometrium and endometriotic lesions. A
VEGF-targeted conditionally replicative adenovirus (Ad5VEGFE1) was
evaluated regarding specific viral replication in endometriosis cells and
induction of apoptosis. The results of study showed VEGF gene was highly
expressed in ectopic endometrium compared with eutopic endometrium and
normal peritoneum. The VEGF promoter was active in endometriotic cells.
Ad5VEGFE1 showed efficient viral replication and induction of apoptosis in
purified primary endometriotic cells and demonstrated a similar lower
targeting to the liver and the uterus in a mouse model.
Thus, Ad5VEGFE1 is a promising candidate for treating endometriosis
and holds potential for clinical testing2.
1. Hasan J, Jayson GC. VEGF antagonists. Expert Opin Biol Ther. 2001
2. Rein DT, Schmidt T, Bauerschmitz G, Hampl M, Beyer IM, Paupoo AA,
Curiel DT, Breidenbach MTreatment of endometriosis with a VEGF-targeted
conditionally replicative adenovirus. Fertil Steril. 2010 May
15;93(8):2687-94. Epub 2009 Jun 12.
Competing interests: No competing interests
Marie McDevitt (2007) poses an interesting question, namely “whether
any or sufficient research has been done to investigate whether physical
exercise or sport undertaken regularly or frequently at the time of
menstruation could be a risk factor for the development of endometriosis.”
She wonders whether vigorous exercise during the menstrual cycle would
promote retrograde endometrial material to travel up the fallopian tubes
and possibly enter the peritoneal cavity.
The existing research investigating exercise and endometriosis is
very limited, and therefore, one can say with certainty: no, not
sufficient research has been done. To address the “whether any research
has been done” part of her question, the answer is somewhat lengthier.
Most research on endometriosis and exercise is epidemiological; usually it
boils down to surveys that have been conducted on patients with
endometriosis regarding lifestyle indices, to enable deductive conclu-
sions as to possible predictors of endometriosis. Various such studies,
suggest that a decreased incidence of endometriosis in people who either
regularly exercised (Barbieri, 1990, Cramer, et al., 1986, Eskenazi, et
al., 1997, Signorello, et al., 1997), or … were heavy smokers (Cramer, et
al., 1986, Eskenazi, et al.).
I would hate to recommend to patients with endometriosis that they
should start smoking, and the perhaps somewhat surprising negative
correlation between smoking and endometriosis, is speculated to be
entirely on account of aromatase- and estrogen-reducing effects of
smoking. Rather, go exercise I would say, which unlike smoking, would also
improve cardiovascular health and reduce chances for getting colon cancer
and certain types of breast cancer.
That being said, some authors (Moen & Schei, 1997) have not been
able to confirm a relation-ship between smoking and any of the above
To the best of my knowledge, no more than half a dozen studies exist
that have actually experi-mentally examined the relationship exercise and
endometriosis, and mostly survey-based. Dhillon & Holt (2003) in a
case-control study involving 77 cases investigated the risk of endometriosis associated with recreational physical activity in women 18-39 years
old, and particularly looked at duration, frequency, and intensity of the
exercise. They found a reduction in incidence of endometriosis only in
women who reported frequent high-intensity exercise. This seems in line
with Signorello’s suggestion, that exercise exerts a protective effect
against endometriosis only if a certain threshold of intensity, duration
and frequency is attained. From the moment that the weekly amount of
exercise drops below 4 h/week a relationship between exercise and endometriosis could no longer be identified (Signorello, et al., 1997).
The other experimental study investigating exercise/endometriosis,
was performed by Carpenter and co-authors (1995). They found that
endometriosis patients treated with danazol have less side-effects when
simultaneously exercising. The reason is that the exercise (aerobic
exercise) lowers testosterone levels in women and thus androgenic side-effects.
With regard to Marie McDevitt’s concern that vigorous exercise during
menstruation might promote later development of endometriosis by
increasing the chances of retrograde menstruation, the only study that I
am aware of that argues along similar lines, was a Chinese study published
by Pan (1993) almost 25 years ago. This case-control study on 203 Chinese
women indeed claims that such a tendency would exist. However, in how far
this conclusion is actually supported by their data is somewhat unclear.
We should not forget that before the Los Angeles Olympics back in 1984 the
world was still debating whether women should be allowed to run marathons
… In any case, to the best of my knowledge, no study published during
the last 25 years has offered any evidence that exercise would increase
either endometriosis or retrograde menstruation. On the contrary, exercise
if anything at all, decreases the risk for endometriosis. The mechanism
through which exercise achieves this, is believed to involve a reduction
of both estrogen levels and possible endometrial aromatase activity
Barbieri RL. Etiology and epidemiology of endometriosis. Am J Obstet
Gynecol 1990; 16 (2): 565-7.
Carpenter SE. The effect of regular exercise on women receiving danazol
for treatment of endo-metriosis. Int J Gynaecol Obstet 1995; 49 (3): 299-
Cramer DW, Wilson E, Stillman RJ. The relation of endometriosis to
menstrual characteristics, smoking, and exercise. JAMA 1986; 255 (14):
Dhillon PK, Holt VL. Recreational physical activity and endometrioma risk.
Am J Epidemiol 2003; 13 (6): 392-393.
Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin
North Am 1997; 24 (2): 235-258.
McDevitt M. P.E./Sport and the aetiology of endometriosis (Rapid
responses). BMJ 2007; 334: 249-253.
Moen MH, Schei B. Epidemiology of endometriosis in a Norwegian county.
Acta Obstet Gynecol Scand 1997; 76 (6): 559-62.
Pan LY. Menstrual status as risk factors of endometriosis: a case-control
study [in Chinese]. Zhonghua Fu Chan Ke Za Zhi 1993; 28 (3): 147-149, 188.
Signorello LB, Harlow BL, Cramer DW. Epidemiological determinants of
endometriosis: a hospital-based case-control study. Ann Epidemiol 1997;
7 (4): 267-741.
Competing interests: No competing interests
ENDOMETRIOSIS IN AN EVOLUTIONARY PERSPECTIVE
Based on epidemiological evidence, Farquhar asserts that retrograde menstruation is the most probable pathogenetic mechanism for the development of endometriosis, a disease frequently associated with infertility 1. However, this interesting review does not address recent variations in reproductive habits that may cause a major increase in the number of retrograde menstruations and influence the likelihood of implantation of regurgitated endometrium,.
The reproductive patterns of women in today’s affluent Western nations differ greatly from those of our ancestors. Decrease in age at menarche, in number of pregnancies, in duration of breast feeding and increase in age at first birth all lead to an increase in the overall number of ovulations and menstruations a woman has within a reproductive lifespan (Table 1) 2-4. These changes impact even more dramatically during the decade at highest risk for endometriosis, i.e. between 25 and 35 years of age5. Data from the Nurses’ Health Study II demonstrated that all of the above factors are strongly associated with the risk of developing endometriosis 5. In Italy, the age at first birth has increased from 24.9 years in 1974 to 29.6 in 2004, whereas the mean number of children per woman has progressively decreased from 2.7 in 1964 to 1.3 in 2004. Mean duration of lactation was only 6.2 months in 2000 6.
A major rise in the number of spontaneous cycles may augment pelvic contamination by regurgitated endometrium. Missmer et al. calculated that in never users of oral contraceptives the risk of developing endometriosis increases six-fold in women who experience more than 291 ovulations, compared with those who experience less than 174 ovulations in their reproductive life 5. In fact, immediate postovulatory development of ovarian endometriotic cysts has been demonstrated during serial transvaginal tracking of ovarian follicles 7.
Monthly menstruation for decades on end is not the historical norm and current menstrual patterns are new and their health effects unproven 4. Specifically, the likelihood of developing a disease directly caused by menstruation, such as endometriosis, could be greater. In an evolutionary perspective, endometriosis could be viewed, at least in part, as a consequence of profound and rapid changes in human reproductive habits, and the scientific question may not be why the disease develops in some women but rather why it does not develop in all of them. Individual genetic and immunologic characteristics might lead to self-selection of “endometriosis-resistant” female subjects who would not be rendered infertile by the condition, thus assuring species continuity by adaptation to the current abnormal increase in menstrual contamination of the pelvis during reproductive age.
Competing interests: None
1. Farquhar C. Endometriosis. BMJ 2007; 334: 249-53.
2. Thomas EJ. Endometriosis. BMJ 1993; 306: 158-9.
3. Eaton SB, Pike MC, Short RV, Lee NC, Trussell J, Hatcher RA, Wood JW, Worthman CM, Jones NG, Konner MJ. Women’s reproductive cancers in evolutionary context. Q Rev Biol 1994; 69: 353-67.
4. Thomas SL, Ellertson C. Nuisance or natural and healthy: should monthly menstruation be optional for women? Lancet 2000; 355: 922-24.
5. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Malspeis S, Willett WC, Hunter DJ. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol 2004; 104: 965-74.
6. ISTAT Italian National Institute of Statistics. Tavole di Fecondità Regionale. Online publication, 15 February 2007 (http://demo.istat.it).
7. Jain S, Dalton ME. Chocolate cysts from ovarian follicles. Fertil Steril 1999; 72: 852-6.
Table 1. Variation in menstrual and reproductive patterns over the past century* Variable Foremothers Modern women Age at menarche (y) 16 12.5 Age at first birth (y) 19.5 24 Pregnancies (n) 6 2 Breast feeding Years Months Ovulations and menstruations 50-160 450 * Data from references 2-4
Competing interests: Table 1. Variation in menstrual and reproductive patterns over the past century* Variable Foremothers Modern women Age at menarche (y) 16 12.5Age at first birth (y) 19.5 24Pregnancies (n) 6 2Breast feeding Years MonthsOvulations and menstruations 50-160 450* Data from references 2-4
I welcome Dr. Farquhar's article on endometriosis. I wonder though,
in terms of aetiology whether any or sufficient research has been done to
investigate whether physical exercise or sport undertaken regularly or
frequently at the time of menstruation could be a risk factor for the
development of endometriosis? It would seem a biologically plausible
hypothesis, as the fallopian tubes are open-ended and retrograde
endometrial material could leave from them especially during vigorous
Competing interests: No competing interests
With an evidence based approach, Farquhar beautifully reviews the
most outstanding aspects of endometriosis (1). Nevertheless, we were left
with the impression that some important issues are in need of further
A systematic review has suggested an improvement in pregnancy rates
after laparoscopic treatment of endometriosis for women with infertility
(2), but is important to outline that, at the moment, this improvement
seems to be truth only for mild or minimal endometriosis and its effect on
more advanced stages remains uncertain (3,4). Further research is needed
before generalising this conclusion.
A recurrence of the endometriomata does not inevitably mean further
surgery. Quality of evidence supporting systematic surgery for
asymptomatic endometriomas is poor and it has been suggested that re-
operation is not always indicated for recurrent endometriomas.
Transvaginal aspiration might prove to be a reasonable alternative for
some patients in views to reduce impact on ovarian reserve as well as
other potential surgical complications associated with re-operation(3).
Although still under debate whether or not endometriosis affects
outcomes in the context of artificial reproductive techniques (3), what
has been proved in a recent systematic review is the fact that down-
regulation with GnRH agonists during three to six months prior to the
start of IVF increases the odds of clinical pregnancy by at least four-
Early referral to centres of excellence and early treatment of
infertility should always be considered in these patients (3).
1. Farquhar C. Endometriosis. BMJ 2007; 334: 249-53
2. Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C.
Laparoscopic surgery for subfertility associated with endometriosis.
Cochrane Database of Syst Rev 2002; (4): CD001398
3. Chavez-Badiola A, Drakeley A. Optimising in vitro fertilisation
(IVF) outcome in women with endometriosis. Reviews in Gynaecological and
Perinatal Practice 2006; 6 (3-4): 153-60.
4. Royal College of Obstetricians and Gynaecologists. RCOG Green-top
Guideline for the investigation and management of endometriosis 2006 (24).
5. Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary
down-regulation before in vitro fertilization (IVF)for women with
endometriosis. Cochrane Database of Syst Rev 2006; (1): CD004635.
Competing interests: No competing interests