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                                            P ROGR E S S
                                                                                                                 Progress, No. 52

                                            in Human Reproduction Research
Bank Special Programme of
                                            No. 52                                                                          1999
Research, Development and
Research Training in Human
Reproduction (HRP)
                                            Tackling the problem of endometrial
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       amenorrhoea—the complete absence
                                            use long-acting progestogen-only meth-      of menstrual bleeding—affects 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           dometrium—the 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.
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 women’s 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
                                      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       women’s 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 women—and their partners—to              traceptives after the study was over.
                                      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 women’s 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 6–12 months, and 15% said they        negative effect on a woman’s 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 body’s
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, 2:487–490.
      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-
                                            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, 48:205–216.
to find out their attitudes to injectable   theless, one-third of the women chose         5
                                                                                             Rutter W et al. Women’s 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.                            149:417–419.
                                                                                            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 women’s 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.        1:275–284.
menstrual history, previous contracep-      The natural process of menstruation           7
                                                                                            Gold MA, Coupey SM. Young women’s
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, 11:17–24.
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 women’s 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. Martin’s Press, 1983.               amenorrhea. Contraception, 1998, 57:23-
for doing so. However, a year later         2
                                              Loudon NB et al. Acceptability of an oral   28.
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 2–20% 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           women’s 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 women’s
                                           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 women’s 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.
Progress, No. 52                             Research is changing our beliefs about

                                                  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.
                                             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-      ence—or rather lack of it—of 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:          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-
                                                                                            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 trial—aims 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 Programme’s           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
Fax: 41-22-7914171                            abnormal blood vessels are present in         treatment but also provide an updated
E-mail:                the endometrium of women who use              basis towards effective counselling.

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