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P ROGR E S S
Progress, No. 52
in Human Reproduction Research
UNDP/UNFPA/WHO/World
Bank Special Programme of
No. 52 1999
Research, Development and
Research Training in Human
Reproduction (HRP)
Tackling the problem of endometrial
bleeding
Department of Reproductive
Health and Research, Long-acting progestogen-only con- cal event. The way that women react to
World Health Organization traceptives are safe and very effective. unpredictable bleeding, or indeed to
Geneva Currently, more than 20 million women amenorrhoeathe complete absence
use long-acting progestogen-only meth- of menstrual bleedingaffects their
Launched by the World Health ods such as depot-medroxyproges- attitude to the contraceptive method
Organization in 1972, the UNDP/ terone acetate (DMPA) and Norplant. that causes it. Service providers and
UNFPA/WHO/World Bank Special However, one drawback of these con- researchers need to be aware of the
Programme of Research, traceptives is that they cause unpre- perceptions that women, and the
Development and Research dictable vaginal bleeding (from the en- communities they belong to, have of
Training in Human Reproduction is dometriumthe inner lining of the menstruation and of non-menstrual
a global programme of technical uterus) in a majority of women. For bleeding.
cooperation. It promotes, many, the bleeding is slight (with no
coordinates, supports, conducts, risk of it causing anaemia), but its Even when we look at the specific
and evaluates research on prolonged duration and unpredictability event of endometrial bleeding induced
reproductive health, with particular deter many women from using or con- by progestogen, much more knowl-
reference to the needs of tinuing to use these contraceptives. edge is needed on how it actually
developing countries. happens. Endometrial bleeding induced
Effective counselling of a potential by progestogens is not menstruation,
user of a progestogen-only method although there are some similarities
can help in preparing her both for the between the two processes, so it is
absence of menstruation and for the important to see precisely what hap-
possibility of irregular endometrial pens to an endometrium that is ex-
bleeding. Research shows that women posed to progestogens and that be-
who are given information about what gins to bleed as a result. At the same
will happen and are reassured that it is time, our knowledge of what happens
a common side-effect are much more during menstruation is also progress-
likely to continue using the method. ing, and research in this area is helping
Indeed, with some progestogen-only with the development of contraceptive
methods they find that bleeding distur- methods that do not cause women
bances tend to decline after a year or undue inconvenience.
more of use.
INSIDE In May 1999 the Programme and
Endometrial bleeding that is induced the US National Institute of Child Health
How women perceive by the use of progestogens can be and Human Development (NICHD) co-
menstruation and their treated, but current treatments are of sponsored a meeting entitled "Ster-
menstrual patterns .................. 2 limited effectiveness. Thus there is oids and endometrial breakthrough
considerable interest in finding both a bleeding" at Monash University, Clay-
How does progestogen cause
treatment that works and a way to ton, Australia. Participants in the meet-
endometrial bleeding ............... 4
avoid the bleeding in the first place. To ing were leading scientists in this field.
Progestogen-only contraceptives do this, a much better understanding is The proceedings of this meeting are to
and vaginal bleeding ................. 5 needed of the biological mechanisms be published as a supplement of the
that cause bleeding from the en- journal Human reproduction in 2000.
Research is changing our dometrium. This issue of Progress presents some
beliefs about menstruation ..... 6
of the recent advances in the area of
Ongoing and planned studies .. 7 Dealing with the issue of endome- endometrial bleeding discussed at this
trial bleeding in connection with the meeting and gives an insight into the
New publications ...................... 8 use of a contraceptive method involves mechanisms of both natural menstrua-
far more than dealing with a physiologi- tion and progestogen-induced bleeding.
2
Progress, No. 52 How women perceive menstruation and
their menstrual patterns
Women the world over are very ological process; it becomes an event
aware of their pattern of menstruation that has social, cultural and psycho-
and how it affects their lives. Research logical implications. A woman has
that was carried out in 10 countries two two perceptions of bleeding: one from
decades ago led to a comparison of her actual experience and the other
Progress menstrual patterns and womens per-
ceptions of menstruation.1 That re-
from her position as a member of soci-
ety which has attached certain mean-
in Human Reproduction
search showed how women generally ings to menstruation, according to the
Research
seem to focus more on the number of authors of the 10-country study. The
days when they are bleeding than on interaction of these two elements de-
Issued quarterly by the UNDP/
the number of days when they are not. termines her attitude to menstrual
UNFPA/WHO/World Bank
It also showed that many women con- bleeding.
Special Programme of Re-
sider that an increase or decrease in
search, Development and
the number of days of bleeding is more Various studies have examined
Research Training in Human
important than a change in the number womens preferences for different pat-
Reproduction, World Health
of days without bleeding. Women tend terns of vaginal bleeding, particularly
Organization, 1211 Geneva 27,
to link the amount of their menstrual with regard to the use of oral contra-
Switzerland. For a free sub-
bleeding with the length of their men- ceptives. As early as 1977, for in-
scription, please write to the
struation, the research showed. More stance, research investigated the ac-
above address.
than two-thirds of the women in the ceptability to 196 women in Scotland,
study said they preferred to have one United Kingdom, of a long period with-
Editor: Jitendra Khanna
monthly bleed. In the 10 countries, out menstruation followed by a with-
most women (ranging from 53% in the drawal bleed. The women were given a
This newsletter is not a formal
United Kingdom to 91% in India) said combined oral contraceptive for peri-
publication of the World Health
that they did not wish to use methods ods of 84 days followed by 6 days
Organization (WHO), and all
that induced amenorrhoea. without the pill.2 Most of the women
rights are reserved by the
(82%) said that they preferred having
Organization. The document
Perceptions of menstruation vary in less frequent periods, and 91% of those
may, however, be freely re-
different cultures. These perceptions who completed the year of follow-up
viewed, abstracted, reproduced
may be positive or negative, but service liked the three-monthly regimen so
or translated, in part or in whole,
providers need to remember that these much that they refused to return to the
but not for sale or for use in
perceptions will influence the attitudes standard monthly regimen of oral con-
conjunction with commercial
of womenand their partnersto traceptives after the study was over.
purposes.
changes in bleeding patterns resulting However, 45% of the women withdrew
from the use of hormonal contracep- from the study early, chiefly for medi-
tives. Thus, just how acceptable hor- cal reasons.
monal contraceptives are often depends
on how much change in menstrual A study3 published in 1987 tested
bleeding a woman experiences and just how acceptable a seven-week cycle
what her perception of menstruation is. of pill use was to 100 women. In this
case, the authors of the study con-
Menstruation may be viewed either cluded that the seven-week cycle was
positively or negatively. For instance, not viable since the majority of volun-
menstruation may be perceived as a teers preferred the inconvenience of a
sign of femininity, fertility, youth, or monthly withdrawal bleeding. In con-
purification of the body, yet at the trast, a similar study reported in 1993
same time it is also linked with vulner- that when 198 Swedish women used
ability and pollution, and with attitudes an even longer cycle (nine weeks of
of disgust and shame. In some socie- taking the pill followed by one week
ties, these negative perceptions are without it), 63% preferred having a
the basis for restricting womens reli- withdrawal bleed every three months.4
gious, social and domestic activities This was despite some breakthrough
while they are menstruating. It is be- bleeding and spotting early in the cy-
cause of religious and social traditions cle. Some 26% of women in this Swed-
or taboos that menstruation may be ish study preferred monthly bleeding.
looked on as more than just a physi-
When 158 women were interviewed significantly more women who had re- 3
about oral contraceptive use and men- ceived intensive counselling were still Progress, No. 52
strual bleeding in an Australian study,5 using DMPA than were those who
83% said it was necessary to bleed received routine counselling only (42%
monthly when taking an oral contra- versus 11%).
ceptive. However, when they were given
a choice of how often to menstruate, Recent research in Thailand9 found
54% said they preferred to bleed that amenorrhoea was seen in a very
monthly, 27% preferred to bleed every negative light; it was considered not
three months, 4% preferred to bleed only to be unhealthy but also to have a
every 612 months, and 15% said they negative effect on a womans appear-
preferred not to bleed at all. ance. This perception was held regard- Menstruation has taken on
less of age or education. Health care such sociocultural, religious
A large European study on patterns providers in Thailand have experienced and psychological signifi-
of bleeding, which was reported in the same perception, and this prompted cance that many women
1996, involved interviews with women a group of Thai researchers to offer
refuse to tolerate distur-
in France, Germany and the United DMPA users complaining of amenor-
Kingdom.6 The 1201 women who were rhoea the option to switch to the com- bances to their pattern of vagi-
interviewed were asked to rank their bined monthly injectable Cyclofem in nal bleeding as a result of
preferences for bleeding every month, order to enable them to menstruate. using contraceptives.
every three months, every six months, Since Cyclofem contains 25 mg MPA
or not at all. The most preferred pattern and 5 mg estradiol cypionate, this
of bleeding was every three months option does not increase the bodys
and the least preferred pattern was not burden of synthetic steroid yet offers contraceptive that reduces the frequency
at all. continuation with a similar form of con- of menstruation: the tri-cycle pill regimen.
traception. This was tested in a con- British medical journal, 1977, 2:487490.
Few studies have researched atti- trolled clinical trial that involved 100 3
Hamerlynck JV, et al. Postponement of
tudes to menstruation and patterns of women who were DMPA users and withdrawal bleeding in women using low-
bleeding among women who were us-
10
had amenorrhoea. In this trial, 82% of dose combined oral contraceptives. Con-
traception, 1987, 35(3)199-205.
ing injectable or implanted contracep- women who switched to Cyclofem ex- 4
Cachrimanidou A-C et al. Long-interval
tives. However, one study involved in- perienced some vaginal bleeding within treatment regimen with a desogestrel-
terviews with 328 young women at six months but almost all of them containing oral contraceptive. Contracep-
three different clinical sites in the USA reported hormonal side-effects. Never- tion, 1993, 48:205216.
to find out their attitudes to injectable theless, one-third of the women chose 5
Rutter W et al. Womens attitudes to
or implanted contraceptives.7 Asked to continue using Cyclofem at the end withdrawal bleeding and their knowledge
about possible menstrual changes, of the trial, despite the fact that it and beliefs about the oral contraceptive
74% of the young women said that required a more demanding schedule pill. Medical journal of Australia, 1988,
they would stop using a contraceptive of administration. 149:417419.
6
Fuchs N, Prinz H, Koch U. Attitudes to
method if it caused irregular bleeding
current oral contraceptive use and future
and 66% said they would stop using it It is clear that many women world- developments: the womens perspec-
if it stopped them bleeding altogether. wide see their pattern of menstruation tive. European journal of contraception
The responses of the interviewees were as a sign both of their reproductive and reproductive health care, 1996,
not related to education, sexual or health and of their health in general. 1:275284.
menstrual history, previous contracep- The natural process of menstruation 7
Gold MA, Coupey SM. Young womens
tive use, and history of pregnancy or of has taken on such sociocultural, reli- attitudes toward injectable and
sexually transmitted diseases. Two- gious and psychological significance implantable contraceptives. Journal of
thirds of the young women interviewed that many women refuse to tolerate pediatrics, adolescence and gynecology,
1998, 11:1724.
said that they would prefer a contra- disturbances to their pattern of vaginal 8
Lei ZW et al. Effect of pretreatment coun-
ceptive method that would reduce their bleeding as a result of using hormonal selling on discontinuation rates in Chi-
menstrual flow. contraceptives. If their needs are to be nese women given depot
met adequately, we need to have a medroxyprogesterone acetate for con-
In China, a study confirmed the better understanding of the mecha- traception. Contraception, 1996, 53:357
importance of counselling on contra- nisms that underlie vaginal bleeding 361.
ceptive use and menstrual change.8 Of and of womens attitudes to menstrual 9
Supanee J-A. The effects of perceived
421 users of depot-medroxyproges- disturbances. Only then can effective change in the menstrual pattern on the
terone acetate (DMPA), half were given and acceptable solutions be found. acceptability of fertility regulating meth-
ods. D.Ph. thesis, University of Exeter,
detailed counselling both before and
United Kingdom, 1998.
during treatment while half received References 10
Manee P-A et al. Effectiveness of
only routine counselling. In both groups, 1
Snowden R, Christian B, eds. Patterns Cyclofem in the treatment of depot
women who stopped using DMPA cited and perceptions of menstruation. New medroxyprogesterone acetate-induced
menstrual change as the main reason York, St. Martins Press, 1983. amenorrhea. Contraception, 1998, 57:23-
for doing so. However, a year later 2
Loudon NB et al. Acceptability of an oral 28.
4
Progress, No. 52 How does progestogen cause
endometrial bleeding
Bleeding of the endometrium, when dopeptidase immunostaining, and el-
induced by progestogen, is known as evated levels of angiotensin.
breakthrough bleeding. This kind of
bleeding is not menstruation. Indeed, it The endometrium exposed to pro-
differs from normal menstruation in gestogen-only contraception shows
Progestogen-induced break- several ways. normal-looking capillaries next to highly
congested vessels and large thin-
through bleeding usually oc-
Menstruation takes place when the walled vascular spaces. Hysteroscopy
curs from the smaller capillar- endometrium in its secretory phase is has revealed evidence of patchy vessel
ies and veins. It starts and subjected to falling levels of ovarian rupture with intra-endometrial haemor-
stops irregularly and unpre- steroids. Most of the menstrual blood rhage. Research has shown evidence
dictably, coming from an en- loss occurs through the spiral arterioles, of increased fragility of blood vessels,
together with the collapse and shed- which probably results from distur-
dometrium that shows none
ding of most of the functionalis. Pro- bance of angiogenesis (the process of
of the cyclical changes of the gestogen-induced breakthrough bleed- development of blood vessels).
normal endometrium. ing, on the other hand, usually occurs
from the smaller capillaries and veins. Another local mechanism that may
Breakthrough bleeding starts and stops be related to progestogen-induced en-
irregularly and unpredictably, coming dometrial bleeding is an increase in the
from an endometrium that shows none number of leukocytes, including T cells,
of the cyclical changes of the normal macrophages and endometrial granu-
endometrium. lated lymphocytes. These cells can
release free radicals or other destruc-
Of course, different women respond tive agents that cause localized vessel
differently to the use of progestogen- damage and bleeding. (However, while
only contraceptive methods. Changes some research supports this increase
may also vary according to the type of in the number of leukocytes, other
progestogen and the dose. With research suggests that certain
Norplant use, prolonged and irregular leukocytes are actually reduced in
breakthrough bleeding is usually at its women using Norplant.) In addition,
worst during the first 12 months of use, tissue repair may be impaired, includ-
becoming more regular thereafter. With ing the clotting mechanism that would
DMPA, users also start by experienc- normally restrict bleeding. The endome-
ing prolonged and irregular bleeding, trial epithelium often appears dam-
but later on this pattern is replaced by aged in women using progestogens,
increasing periods of amenorrhoea. whether they have breakthrough bleed-
However, it is currently unclear just ing or not, which suggests that the
what causes this to happen. epithelium may act as a barrier that
limits breakthrough bleeding even
In women using Norplant, the en- though intra-endometrial bleeding may
dometrium may be only 220% of the occur.
thickness of mid-secretory en-
dometrium. At the same time, in con- What makes the problem of break-
trast to the reduction in the volume of through bleeding so mysterious is that
the endometrium, there is often an womens reactions to progestogen-
increase in vascular density with, some- only contraceptives vary from almost
times, reduced arteriole development continuous bleeding to no bleeding
and the appearance of large thin-walled whatsoever during the first year of
venules. Other typical endometrial Norplant use. Thus, one of the main
changes induced by the use of pro- focuses of research into breakthrough
gestogen-only contraceptives include: bleeding has been to look for endome-
elevated progesterone receptor and trial differences between women who
reduced estrogen receptor levels, el- bleed and those who do not. In an
evated levels of vascular endothelial analysis of successful versus unsuc-
growth factor (VEGF), reduced cessful endometrial biopsy procedures
endothelin and increased neutral en- involving women receiving Norplant,
women from whom tissue was col- dometrium that is exposed to pro- 5
lected had higher circulating estrogen gestogen exhibits changes in com- Progress, No. 52
levels and more bleeding days prior to parison with a normal endometrium, it
biopsy. This indicates that women with is unclear whether breakthrough bleed-
an endometrium that is too atrophic to ing is due to increased susceptibility,
sample have less circulating estrogen increased breakdown and damage, or
and reduced breakthrough bleeding. reduced repair and clotting. Whatever
However, the finding is uncertain. Some the reason, experience shows the im-
research, for instance, showed that portance of good counselling. If a
estrogen treatment for breakthrough woman is informed of the side-effects
bleeding reduced the length of the and understands them before she starts
episodes of bleeding but not the number. to use a progestogen-only contracep- What makes the problem of
Other studies have found little evidence tive, this will increase her acceptance
breakthrough bleeding so
that estrogen brings any benefit. of subsequent breakthrough bleeding.
mysterious is that womens
Source: Rogers AW. Mechanisms of pro- reactions to progestogen-
There is no clear consensus on the
gestogen-induced endometrial bleed-
best treatment for progestogen-induced ing. Gynaecology forum, 1999, 4(3):17 only contraceptives vary from
breakthrough bleeding. While the en- 21. almost continuous bleeding
to no bleeding whatsoever
during the first year of
Norplant use.
Progestogen-only contraceptives and vaginal bleeding
More than 20 million women worldwide use to irregular, frequent and prolonged bleeding.
progestogen-only methods of contraception.
The most widely used method among them is Women normally accept that use of a con-
the injectable depot-medroxyprogesterone ac- traceptive method may involve making a trade-
etate (DMPA) with some 13 million users. The off between benefits and disadvantages. How-
only other progestogen-only injectable, ever, many women are not prepared to tolerate
norethisterone enantate, has fewer than one unpredictable, irregular or prolonged bleeding.
million users.
A wide range of treatments have been tried
Other progestogen-only methods of contra- in order to overcome disturbances to the bleed-
ception include the implantable Norplant, which ing patterns of women who use progestin-only
is currently used by about six million women, methods. Surveys in the 1980s and 1990s show
and the intrauterine system Mirena which has that treatment regimens have included estrogens,
about one million users. Both these methods combined oral contraceptives, nonsteroidal anti-
release levonorgestrel. Other methods are be- inflammatory agents, vitamins, iron and
coming available such as Implanon, the single- anxiolytics. The use of a combined oral contra-
rod implantable system delivering etonogestrel ceptive may help to regularize the bleeding of
(first registered in Indonesia in 1998), and other Norplant users, but women may doubt the
injectable and implantable systems are under advantage of using two contraceptive methods
development. at the same time and the use of a method
containing estrogen negates the advantage of
Progestogen-only injectable and implantable an estrogen-free progestogen method.
methods have several features in common. On
the positive side they are very effective, and the Clearly, alternative more effective ways need
fact that they are long-lasting makes them easy to be found to meet womens concerns over
to use. On the other hand, they cause distur- disturbance of their bleeding patterns. Amenor-
bances in the normal bleeding pattern. For rhoea may be a more feasible goal than regular
instance, after one year of use it was found that bleeding for the users of progestogen-only meth-
less than 10% of women who used DMPA and ods. However, in view of the concern of many
Mirena, and only 25% of users of Norplant, women to have regular menstruation, further
experienced regular monthly bleeding. Other research will be needed to find out whether
users reported various patterns of bleeding rang- amenorrhoea would be an acceptable goal for
ing from no bleeding through infrequent bleeds women of different sociocultural backgrounds.
6
Progress, No. 52 Research is changing our beliefs about
menstruation
The past decade has seen a major phase of the cycle could be directly
shift in our understanding of how men- responsible for the sudden steep rise
struation occurs. The focus of interest in the production of MMPs at men-
has moved from the concept of men- struation.
struation as a process generated pri-
Research has changed our marily by vascular events to one in Research has pointed to the close
which tissue destruction is a key fea- temporal relationship between MMPs
understanding of the concept production and activation and cells of
ture. Although the onset of bleeding is
of menstruation from a proc- the first outward sign of menstruation, the immune system. Since the mid-
ess generated primarily by it is clearly not the first important event 1980s it has been argued that men-
vascular events to one in in the process. During the late luteal struation could be regarded as a proc-
which tissue destruction is a phase of the cycle, there is widespread ess of inflammation, and various stud-
degeneration of the basal lamina that ies have reported the dramatic increase
key feature. in lymphomyeloid cells (specifically
support the decidualized endometrial
cells and the endothelium of blood eosinophils, neutrophils and
vessels. Electron microscopy has re- macrophages) in the endometrium
10th Postgraguate Course vealed small lesions in the luminal immediately before menstruation. Al-
in Reproductive Medicine epithelium on the 28th day of the nor- though mast cells do not increase in
mal cycle and has shown that these number during the cycle there is a
and Reproductive Biology
are followed by very rapid, although sharp rise in mast cell activation before
incomplete, degeneration of the and during menstruation. Studies indi-
WHO Collaborating Center in cate numerous cellular interactions
functionalis layer, exposing open blood
Human Reproduction vessels and glands. Thus, it can be between these cells and the endome-
Clinic for Infertility and argued that the primary event that ini- trial stromal and epithelial cells that
Gynecologic Endocrinology, tiates menstruation is the destruction may be relevant to the expression of
Department of Obstetrics of tissue. MMPs and the degradation of tissue at
and Gynecology, menstruation. Each of these leukocytes
Geneva University Hospital If menstruation begins with tissue produces a range of regulatory mol-
destruction, how is this destruction ecules, including cytokines and
This course provides trainees the caused? Recent research has exam- proteases which are known to regulate
basic knowledge they need to initi- ined the actions of a group of enzymes, MMPs. Many of these regulatory mol-
ate, or participate in, research work in known as matrix metalloproteinases ecules are released only when the cell
reproductive health in their home or MMPs, in the endometrium. These is activated.
countries.
enzymes are stimulated as the result
of a process of inflammation, which in Research indicates that the pres-
Course dates:
1 September- 15 October 2000 turn is a response to the withdrawal of ence of large numbers of leukocytes in
progesterone. A number of the MMPs perimenstrual tissue is due to the influ-
Deadline for application: are capable of degrading both the inter- enceor rather lack of itof ovarian
31 March 2000 stitial matrix and basement membrane steroids. Experiments with animal en-
components, leading fairly rapidly to dometrium show that the numbers of
For more information contact: the bleeding that is characteristic of leukocytes are regulated negatively by
menstruation. They have been local- progesterone, and the influx of cells
Mme Sophie Fluckiger into the human endometrium coincides
ized to the endometrium immediately
Administration officer
before and during menstruation and with the fall in progesterone. Steroid
Clinic for Infertility and Gynecologic
Endocrinology they appear to be locally produced and hormones could control the influx of
Department of Obstetrics and activated. Indeed, the pattern of ex- migratory cells via their influence on
Gynecology pression of MMPs during the normal chemokines (chemoattractive mol-
Geneva University Hospital menstrual cycle seems to indicate ecules) which attract cells. In the uterus,
Boulevard de la Cluse 32 that they play an important role in the chemokines exist that are known to
CH - 1205 Geneva process. They are, for instance, found attract neutrophils and eosinophils and
Switzerland specifically at points where tissue de- that increase in the late secretory phase
struction occurs. Progesterone has of the cycle.
Tel: ++ 41-22-382-4322
Fax : ++41-22-382-4313
long been recognized as capable of
e-mail: sophie.fluckiger@hcuge.ch regulating the activity of collagenase Steroid hormones may also affect
(MMP-1), and the falling levels of pro- the differentiation and activation of
gesterone and estrogen during the late leukocytes in the human uterus. Both
estrogen and progesterone are known While a complete detailed explana- 7
to have a strong influence on uterine tion of how menstruation occurs is not Progress, No. 52
leukocytes in a number of species, yet available, it is clear that research
particularly with regard to their produc- into the actions of MMPs is leading the
tion of certain pro-inflammatory mol- scientific community towards a fuller
ecules. In mast cells in the mouse understanding of the physiological proc-
uterus, for example, estrogen promotes esses that are involved in this event
and progesterone inhibits certain sub- that affects women monthly during
stances (nitric oxide synthase, for in- much of their lives. This fuller under-
stance), while experiments on standing will contribute not only to a
macrophages in the rodent uterus show clearer picture of how steroid hormone
that estrogen has no effect but proges- contraception works, but will help re- Research supported by the
terone inhibits the same substances. searchers to devise methods of mak-
Programme and other institu-
Since neither estrogen receptors nor ing these contraceptives more accept-
progesterone receptors have been able to their users.
tions has changed our defini-
found in leukocytes in the human en- tion of menstruation. Today it
Source: Salamonsen LA. Current concepts
dometrium, the effects of estrogen and
of the mechanisms of menstruation: a
is seen less as a vascular
progesterone on leukocytes may be event and more as an inflam-
normal process of tissue destruction. Trends
indirect. in endocrinology and metabolism, 1998, matory response to the with-
9(8):305-309.
drawal of progesterone.
Ongoing and planned studies
Breakthrough bleeding remains the A study in Belgium compared the
chief reason why women discontinue endometrium of Norplant users at two
using long-acting progestogen-only points in time: at the onset of an
contraceptive methods. Since none of episode of vaginal bleeding and when
the treatments available are fully satis- they were not bleeding. The analysis of
factory,1 it is clear that there is a need paired biopsies from 23 volunteers sug-
to understand better the mechanisms gested that abnormal endometrial
of menstruation and how these are bleeding is associated with focal stro-
affected by contraceptive steroids, mal breakdown, the expression and
particularly progestogens. Counselling activation of certain MMPs, and the
is extremely valuable in helping women decreased expression of tissue inhibi-
prepare for side-effects such as break- tors of metalloproteinases (TIMPs)
through bleeding, but only further re- which inhibit the action of MMPs.
search can provide the necessary
knowledge to formulate new treatments Research in Australia looked at the
and develop new methods that dispel possible role of one specific MMP
the side-effects completely. (MMP-9 or gelatinase B) in triggering
endometrial bleeding. The
Research supported by the Pro- immunolocalization of MMP-9 and mi-
gramme and other institutions has led gratory cells was compared in Norplant
to changes in our definition of men- users and normal controls. MMP-9
struation, enabling us to see it being positive cells were identified as
triggered less by a vascular event and neutrophils, eosinophils, CD3+ T-cells
more by an inflammatory response to and macrophages, and MMP-9
the withdrawal of progesterone whereby immunostaining was also seen close
cells of the immune system invade the to these cells. These cells were seen
endometrium and release molecules in greater numbers both in normal con-
that increase the production and activ- trols at menstruation and in Norplant
ity of MMPs. Previous studies yielded users with endometrial bleeding. How-
evidence of vascular fragility, abnormal ever, there was no correlation between 1
Taking estrogens is moderately benefi-
angiogenesis, and disturbed mecha- the number of MMP-9 positive cells cial but estrogens negate some of the
nisms of menstruation associated with and the number of bleeding days prior benefits of a progestogen-only method.
progestogen treatment. Further sup- to the biopsy. Further investigations Nonsteroidal anti-inflammatory drugs
port for these events has been provided are continuing, comparing the effects have some positive effects but are often
by a number of recent findings from of different progestogens and examin- too expensive or in short supply in devel-
research supported by the Programme. ing their effects on different mecha- oping countries.
8 nisms, including the balance of MMPs long-acting progestogen-only methods
Progress, No. 52 and TIMPs. and have breakthrough bleeding. While
various processes are involved in ang-
Two studies have begun to assess iogenesis, experiments have shown
the effects of different treatments on that both the A and B progesterone
prolonged bleeding induced by receptors are present in endothelial
progestogens. A double-blind placebo- cells in the human endometrium. This
controlled trial in Chile is testing the observation emphasizes the need for
efficacy of mifepristone in improving further studies to define the direct role
the pattern of vaginal bleeding in of steroids on endothelial cell function.
Norplant users. After the Norplant de- In addition, research is needed to ex-
A multicentre, double-blind vice is inserted, users receive 100 mg amine why only certain areas of the
placebo-controlled trial is test- of mifepristone on two consecutive days endometrium show endothelial cell
at intervals of 30 days over a period of destruction with bleeding while other
ing the efficacy of vitamin E six months, and they are followed for a areas do not.
and low-dose aspirin in im- total of 13 months. The other study
proving the pattern of vaginal a double-blind, randomized, placebo- With regard to the endometrial en-
bleeding in Norplant users. controlled clinical trialaims to test vironment, the meeting considered the
the effect of vitamin E as an antioxidant role of anti-progestogens which have
and of low-dose aspirin as an anti- been found to reduce breakthrough
inflammatory agent, both alone and in bleeding in women using progestogen-
New Publications combination. The subjects, who are
currently being recruited, are Norplant
only methods. Progesterone antago-
nism is determined by the binding of
users in Chile, China, Dominican Re- anti-progestogens to the progestogen
public, Indonesia and Tunisia. receptor PR-A which is expressed in
Integrating STI management the endometrial epithelial cells and in
into family planning Directions for future research the stroma in the late luteal phase. The
services: what are the ben- meeting concluded that further studies
efits? A meeting on Steroids and en- using low-dose anti-progestogens are
Occasional Paper Series dometrial breakthrough bleeding, needed. It was also recommended that
WHO/RHR/99.10 cosponsored by the Programme and the role of selective estrogen receptor
NICHD, was held at Monash Univer- modulators (SERMs) should be ex-
This review documents the available ex- sity, Australia, in May 1999. The meet- plored in view of the presumed influ-
perience in the integration of manage- ing brought together experts in the field ence of raised estrogen on break-
ment of sexually transmitted infections to review the state of knowledge and through bleeding.
into family planning services. It clarifies
plan future research in this area. It was
the public health benefits of this integra-
tion, highlighting operational changes. felt that the importance of the problem The meeting agreed that the
has been emphasized by two develop- immuno-competent cells have a key
ments, namely the increasing use of role in regulating endometrial events
HIV in pregnancy: a review
hormone replacement therapy in de- and that they are likely to play a part in
Occasional Paper Series
WHO/RHR/99.15 veloped countries throughout the world, tissue breakdown. Large numbers of
and the introduction in Europe of the these cells appear to be present in the
Presents what is known about HIV in levonorgestrel intra-uterine system, endometrium of women using the
pregnancy, transmission of HIV from both of which also affect vaginal bleed- levonorgestrel intrauterine system. It
mother to child, and interventions to pre- ing patterns. While the Programmes was concluded that further studies are
vent such transmission. It includes sug- primary concern is fertility regulation, it required in this area.
gestions on the appropriate manage- was recognized that a wider scientific
ment of HIV-positive women during preg- community would now become con- Finally, the participants recognized
nancy and during and after delivery. A set
cerned with the problem. that the views of the progestogen users
of guidelines are also included on infec-
tion control and safe working conditions themselves were too frequently ignored.
for the management of HIV in pregnancy. The meeting identified several new In the 1970s, the Programme sup-
leads that may be fruitful avenues for ported a major cross-cultural study on
To request a copy please write to: future research. These can be broadly the patterns and perceptions of men-
classified as studies on the endome- struation. The meeting agreed that new
The Editor, Progress trial vasculature, studies on the en- data should be obtained on the views of
Special Programme of Research, dometrial environment, and studies of women from a variety of sociocultural
Development and Research Training the immuno-competent cells of the backgrounds on their acceptance of
in Human Reproduction endometrium. disturbed bleeding patterns and of
World Health Organization amenorrhoea. This would not only guide
1211 Geneva 27
Several studies have confirmed that researchers in refining the goals of
Switzerland
Fax: 41-22-7914171 abnormal blood vessels are present in treatment but also provide an updated
E-mail: rhrpublications@who.ch the endometrium of women who use basis towards effective counselling.
