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Rat uterine tissue and cell responses to the presence of plain and indomenthacin-delivering IUDs.

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THE ANATOMICAL RECORD 208507-514 (1984)
Rat Uterine Tissue and Cell Responses to the Presence
of Plain and Indomethacin-DeliveringIUDs
C.C. PAGE, P.R. HURST, AND G.F.S. SPEARS
Departments of Anatomy, (C. C.E?, I!R. H.) and Social and Preuentiue
Medicine (G.RS.S.), Faculty of Medicine, University of Otago, Dunedin
New Zealand
ABSTRACT
Plain silastic intrauterine devices or those containing 270 pg
of indomethacin were inserted into the caudal portion of one uterine horn of
mature Wistar rats. After a 3-week period animals were fixed by perfusion on
the morning of day 2 after estrus. Segments of uterine tissue corresponding to
regions adjacent to and cranial to the devices as well as an equivalent portion
of the contralateral horn were embedded in glycol methacrylate. A group of
control animals without any form of device were treated in an identical manner. Sections cut from these segments were evaluated by grid-point stereology
to ascertain changes in tissue volumes and cell populations. It was found that
the presence of plain devices induced hypertrophy in the stroma and myometrium of the portion of the uterus adjacent to the device. The presence of
indomethacin in such devices prevented stromal hypertrophy.
No changes in populations of fibroblasts or areas of glandular or vascular
tissue were evident in any treatment group. Cell populations of neutrophils,
eosinophils, and mononuclear cells, however, were elevated in the superficial
stroma of the horns bearing either type of device; this feature was more
pronounced for neutrophils in the presence of the indomethacin devices. Neutrophils, rather than eosinophils, predominated in the epithelia of the uterus
bearing either type of IUD. Conversely, eosinophil populations were reduced
in the superficial tissues cranial to the devices delivering indomethacin. Neutrophils and mononuclear cells were also found to be elevated in the deep
stroma of tissues adjacent to both the plain and medicated device.
The accumulation of inflammatory cells in
the endometrium in response to the presence
of intrauterine devices (IUDs) as well as their
emigration into the uterine lumen has been
commonly observed in experimental animals
such as the rabbit (El Sahwi and Moyer,
19711, rat (Doyle and Margolis, 19631, and
rhesus monkey (Marston et al., 1971; Hurst
et al., 1977). This response is one of many
seen in the human uterus after insertion of
IUDs (Sheppard and Bonnar, 1980). The studies involving observations on uterine tissue
were, however, qualitative and, apart from
attempts at quantitations of changes to luminal cells (El Sahwi and Moyer, 1971) or
human endometrial vascularity (Shaw et al.,
1979), quantitative studies are lacking on
changes that might occur in total uterine
tissue as well as cell distributions in uteri
bearing IUDs.
The present study has therefore attempted
to quantify total tissue changes and patterns
0 1984 ALAN R. LISS, INC.
of cellular distribution within the rat uterus
and ascertain what changes occur after fitting rats with IUDs for 3 or 4 weeks. Two
types of device were selected, a rod-shaped
silastic device covered by a vinyl sleeve, and
a similar system loaded with indomethacin
which is designed to deliver low levels (4-5
pglday) of this anti-inflammatory drug (Peplow and Hurst, 1981). It is known that in
cyclic or late pregnant rats the population of
stromal macrophages, eosinophils, and neutrophils fluctuates considerably (Rytomaa,
1960; Ross and Klebanoff, 1966; Padykula,
1981).Thus uterine tissue was studied in control and IUD-fitted rats which were all selected on the morning of day 2 of metestrus.
Received June 10, 1983; accepted September 29, 1983.
Address reprint requests to Dr. P.R. Hurst, Anatomy Department, University of Otago, Dunedin, New Zealand.
508
C.C. PAGE, P.R. HURST, AND G.F.S. SPEARS
MATERIALS AND METHODS
Three groups of five or six Wistar rats, age
4 months, were used in this study. Group 1
animals served as controls and carried no
IUDs. Group 2 animals were fitted with plain
silastic IUDs, and group 3 were fitted with
IUDs containing 270 pg indomethacin a t laparotomy under pentobarbitone anaesthesia
on day 2 of metestrus (Peplow and Hurst,
1981). The IUDs measured 1.0 X 0.1 cm and
were inserted into the lower half of the left
uterine horn. The animals were then rested
for 23-29 days during which time daily vaginal smears were taken. Only those rats
showing consistent estrous cycles of 4 days’
duration were retained in the study.
On day 2 of metestrus following this rest
period the animals were anaesthetised and
the uterine tissue fixed in situ by aortic perfusion with saline (for about 1rnin), followed
by 10% phosphate-buffered formalin a t a
pressure of 100 mm Hg. The uterine horns
were divided into three regions (Fig. 1): A)
immediately rostra1 to the IUD; B) adjacent
to the IUD, the device being retained during
preparation; and C) from the contralateral
horn in a position corresponding to B.
In group 1 (animals without a n IUD) the
tissue was divided in a corresponding manner. Tissue from each of these regions, except
where B contained a n IUD (groups 2 and 31,
was divided into three segments before
embedding. The tissue was kept in 10% formalin until it was required.
To prepare sections for light microscopy
each piece of tissue was dehydrated through
70%, 95%, and absolute alcohol followed by
Fig. 1. Female rat reproductive system with silastic
IUD.
three changes of glycol methacrylate infiltrating solution before being embedded under vacuum in glycol methacrylate. Tissue
containing a n IUD required longer dehydrating and infiltrating periods. After embedding, tissue containing a n IUD was also cut
into three segments and reembedded. Therefore, for each animal there were nine blocks
of tissue: Al, A2, As, B1, B2, B3, C1, C Z ,
and Cs.
Sections (2 pm) were cut on a Sorvall JB/4
microtome and six slides, each containing
three consecutive sections, were prepared
from each of the nine segments. The six sets
of sections were made a t about 50 pm intervals along each region of the uterine horns.
Sections were stained for 20 sec in filtered
Lillie Mayer hematoxylin, washed for 5 min
in running water, and then stained for 60
min in fresh, filtered Wrights Blood stain
buffered to pH 4.8 with 0.1 M acetate buffer.
This particular staining procedure allows
clear distinction of neutrophils and eosinophils, with the latter being strongly eosinophilic at a pH of less than 5. The slides were
then dehydrated in three changes of absolute
alcohol (1-2 min each change), cleared in xylene, and mounted. Slides were coded so that
the observer did not know the origin of the
sections.
Grid-point stereology (Elias and Hyde,
19801, using a 100-point grid overlay on a
Reichert visopan projection microscope, was
employed to determine volume fractions of
stromal fibroblasts, eosinophils, neutrophils,
blood vessels including the lumen and wall
tissue of capillaries, glands, and leucocytes
in the epithelium, as well as total proportions of muscle, epithelium, stroma, lumen,
and total tissue. Eight random fields of endometrium were evaluated on each section,
four in a zone including a small part of the
epithelium (superficial stromal zone) and four
in a zone close to the muscle layer (deep
stromal zone). Using a lower power of magnification ( x 251, proportions of muscle, stroma, epithelium, and lumen were determined;
adventitia was disregarded. Volume fractions were determined by the formula Vv =
Pn/Pt, where Pn = number of grid points
overlying a specific tissue or cell, and Pt =
the total number of points on the grid. This
information was entered into a B5930 computer and analysed using a n analysis of variance programme from the Statistical
Package for the Social Sciences (Nie et al.,
1975)followed by a Scheffe analysis (Scheffe,
UTERINE RESPONSES TO IUDs IN RATS
1959)of group differences. This involved comparing the mean volume fraction for each
variable for each region (A, B, or C) of uterus
with other regions within the same groups of
animals and with the same region in the
other two groups of animals. Differences in
means were taken to be statistically significant a t a level of 1%or less.
RESULTS
The most significant findings are shown in
Figures 2 and 10 and summarised in the
corrresponding tables. For all groups the volume of tissue (Fig. 2) in region A was less
than the total tissue volume of region B and
region C because the uterine horns taper cranially (Fig. 1).The volume of region C remained constant among the three groups.
There was a significant increase in total tissue volume in region B of groups 2 and 3
(Table 1).In group 2 this increase was due to
elevated volumes of both stroma and muscle
whereas in group 3 it was due to a n increased
amount of muscle only; the proportion of
stroma remained similar to that of region B
in animals not fitted with IUDs (Figs. 3, 4;
Table 2).
Volumes of epithelium were also estimated, but these showed no significant
changes owing to the various treatments. The
presence of either type of IUD caused the
lumen to be distended. Fibroblasts were easily distinguished by their fine cytoplasmic
processes, large pale nuclei, and prominent,
dark-stainingnucleoli (Fig. lla); however, no
changes were found in the volume fractions
of these cells. Also, no alterations were evident in the volume fractions of blood vessels
and glands in the stroma of uteri bearing
either plain or indomethacin-loaded IUDs. In
group 1 (no IUD), there were no differences
in the distribution of polymorphonuclear or
mononuclear cells in any region or zone.
TABLE 1. Statistically significant differences at the 1%
level by a one-way analysis of variance followed by
Scheffk's test
Between regions within groups:
Stroma and muscle B > A = C
Group 2:
Total tissue B > A = C
Group 3:
Muscle B > A = C
Total tissue B > A = C
(Stroma B > A = C a t P = 0.02)
Between groups within regions:
Region A:
Stroma 2 > 1 = 3
Muscle 2 > 3 > 1
Muscle 2 > 3 > 1
Region B:
Total tissue 2 > 1
fig. 2
lZo
rTot.1
T
T
"
0
g 45
509
ABC ABC ABC
no plain ind
IUD IUD IUD
40
35
30
25
n
"
ABC ABC ABC
no plain ind
IUD IUD IUD
Figs. 2-4. Low-power magnification estimations (+
SEMI of total tissue (21, relative stromal volume (31, and
relative muscle volume (4)of uterine tissues of control
and IUD groups for the different regions A, B, and C as
depicted in Figure 1.
5 10
C.C. PAGE, P.R. HURST, AND G.F.S. SPEARS
TABLE 2. Mean proportion of stroma and muscle in total tissue volume (within groups)'
Region
Percent
stroma
Percent
muscle
A
No IUD (group 1)
B
C
Plain IUD (group 2)
A
B
C
I
A
Ind. IUD (group 3)
B
C
60.0
60.6
58.1
60.0
56.9
59.1
58.2
54.1
60.8
39.0
38.5
40.5
37.8
40.7
39.0
40.0
43.7
37.4
'Data derived from Figures 2-4
TABLE 3. Significant differences in proportional cell
volumes between regions A, B, and C within groups I ,
2, and 3
Superficial endometrial zone:
Group 1
No significant differences
Epithelial leucocytes
Group 2
Stromal neutrophils
Stromal eosinophils
Group 3
Epithelial leucocytes
Stromal neutrophils
Mononuclear cells
Deep endometrial zone:
All groups
No significant differences
B>C=A
A>B>C
A=B>C
B>A>C
B>A=C
A=B>C
In animals with IUDs, changes were observed in the leucocyte populations (Table 3)
as follows:
Epithelial Leucocytes (Figs. 5, 11)
More than 99% of these were neutrophils,
only a few eosinophils being sighted in the
epithelium of the hundreds of sections evaluated. There were increases in the occurrence of epithelial leucocytes in region B of
both groups carrying IUDs, and also in region A of the group with the indomethacinloaded IUD. In the contralateral uterine
horns (region C), there were no significant
differences in the proportion of epithelial leucocytes between any of the three groups. In
numerous sections of regions A and B leucocytes were observed in the lumen; these appeared to be predominately degenerated
neutrophils, but were not subject to quantitation. Eosinophils were also evident in the
lumen.
TABLE 4. Significant differences in proportional cell
volumes between groups 1, 2, and 3 within
Pegions A, B, and C
Superficial endometrial zone:
Region A
Epithelial
leucocytes
Stromal neutrophils
Stromal eosinophils
Mononuclear cells
Region B
Epithelial
leucocytes
Stromal neutrophils
Stromal eosinophils
Mononuclear cells
Region C
Stromal neutrophils
Mononuclear cells
Deep endometrial zone:
Stromal neutrophils
Region A
Mononuclear cells
Region B
Stromal neutrophils
Mononuclear cells
Reeion C
Mononuclear cells
3
2
2
3
>
=
>
>
1
3
1
2
= 2
> 1
= 3
> 1
2
3
2
3
=
>
=
>
3
2
3
1
>
>
>
=
1
1
1
2
3 > 1 = 2
3 > 1 = 2
2
2
2
3
3
=
=
=
>
>
3
3
3
1
1
>
>
>
=
=
1
1
1
2
2
in the region adjacent to the IUD only (Table
4; Fig. 6). No difference was seen between
any region of superficial stromal zone eosinophils of control animals (group 1)or the
contralateral horns of animals bearing either
type of IUD.
In the deeper zone of stroma adjacent to
the muscle there were no significant differences in eosinophil populations between regions of uterine tissue, or between any groups
of animals.
Neutrophils
Neutrophil populations were elevated in
the superficial stroma of the uterine horns
bearing either plain or indomethacin-loaded
Stromal Leucocytes
IUDs (Fig. 7). This increase was more marked
Eosinophils
in the areas directly adjacent to the IUDs
In the superficial zone of stroma a marked and in the region above the plain IUD (Table
increase in eosinophils was observed in both 4). In the deeper stroma neutrophils were
regions A and B of the uterine horns bearing again elevated by the presence of either type
plain IUDs (group 2). For the uteri bearing of IUD (Fig. 81, although their density was
an indomethacin-loadedIUD (group 31, eosin- less when compared with an equivalent volophil populations were significantly elevated ume of tissue in the superficial stroma.
511
UTERINE RESPONSES TO IUDs IN RATS
fig. 5
fig. 6
T
-
Stromal
ioninuphila
-
0.2
-s
c
fig.?
Stromal
1.2
fig.9
,-- fig.10
Stromal
Mononuclear
0.8
0.4
0
no plain
IUD IUD
ind
IUD
Figs. 5-10. High-power magnification estimations of
the mean volume fractions of various cell types in uterine tissues of the three groups. Fig. 5) Leucocytes in the
epithelium; 6) eosinophils in the superficial stroma; 7)
Mononuclear Cells (Figs. 9-11)
It was noted in both superficial and deep
stroma that there were isolated mononuclear
cells which were likely to be either lymphocytes, plasma cells, or macrophages. The
staining procedure adopted here was primarily used to demonstrate either neutrophils or
eosinophils, but unfortunately these mononuclear cells were not always specifically
identifiable as lymphocytes, macrophages, or
plasma cells. It was found that these cells
were elevated in horns bearing either type of
IUD, although this increase was more
marked by the presence of a n indomethacinloaded IUD in both zones of stroma studied.
There was a threefold increase of these cells
ABC A B C ABC
no plain ind
I U D IUD IUD
neutrophils in the superficial stroma; 8) neutrophils in
the deep stroma; 9) mononuclear cells in the superficial
stroma; 10)mononuclear cells in the deep stroma.
in the contralateral horn of the rats fitted
with a n indomethacin-loaded IUD when compared with the control group.
DISCUSSION
It has recently been reported that nonmedicated IUDs, made in a similar manner to
those used in the present study, caused a n
increase in uterine tissue weight and that
the incorporation of indomethacin diminishes this hypertrophy (Peplow-and Hurst,
1982). Evaluation of tissue areas, in the present study, confirms this finding, and furthermore has determined that both stroma and
muscle are increased by a plain IUD in the
rat. In a study of 14 cases, myometrial hypertrophy was also observed in 12 human IUD-
512
C.C. PAGE, P.R. HURST, AND G.F.S. SPEARS
Fig. 11. Superficial endometrium (a)from control animal and (b) adjacent to an indomethacin-loadedIUD. In
(b) a portion of the IUD is seen separated from the epithelium by a small area of lumen (L).Small arrows
indicate epithelial neutrophils; large arrows show neutrophils at the stromal/epithelial boundary. F = fibroblasts; M = mononuclear cells (see text). Magnification,
x860.
UTERINE RESPONSES TO IUDs IN RATS
bearing uteri (Honore, 1979). The finding
here that only the muscle component is elevated when such IUDs deliver 4-5 pg/drug/
day (Peplow and Hurst, 1981) suggests that
when delivered from a n intraluminal site,
low levels of the drug are capable of suppressing stromal hypertrophy. It remains to
be determined if higher doses can influence
the muscle layers that lie deeper to the source
of indomethacin.
The elevation of neutrophil numbers within
the epithelium of uterine horns fitted with
either type of IUD suggests a unidirectional
migration of these cells toward the IUD. This
finding supports many previous observations
on IUD action (reviewed in Duncan and
Wheeler, 1975; Moyer et al., 1976). It was
apparent that the increase in epithelial leucocytes was most predominant in the region
of tissue adjacent to the IUDs. Nonsteroidal
anti-inflammatory drugs are reportedly inhibitory to leucocyte migration (see below),
and yet higher numbers were seen in the
epithelium cranial to the indomethacin device than in the same area above the plain
IUD. Most of the epithelial leucocytes were
neutrophils, suggesting either that eosinophils do not predominate in the foreign body
reaction or their migration rate was submaximal at the time of sampling after the insertion of the devices. Similarly, Padykula and
Tansey (1979) showed that heterophils (neutrophils) and monocytes, rather than eosinophils, were elevated in the superficial
endometrium during late pregnancy in the
rat. It should be borne in mind, however, that
degranulation of eosinophils may have occurred during their passage through the
basal lamina and epithelium; if this had happened, the staining procedure used here
would have equivocally identified them only
in the stroma. It is known that eosinophils
can modulate inflammation by exocytosis of
their granule contents into extracellular
spaces (Beeson and Bass, 1977) and undergo
lysis in the stroma of rats during estrus (Ross
and Klebanoff, 1966). Further studies are
clearly needed, perhaps by a n ultrastructural analysis, in order to clarify this as well
as a determination of changes in the epithelial and luminal leucocyte population at various times after IUD insertion.
Concomitant with the increase in epithelial leucocytes, a marked rise in stromal neutrophils was a distinct feature of the tissue
response close to both forms of IUD. Almost
twice the volume of these cells was seen in
513
the uterine horns bearing the indomethacin
device. This increased accumulation might
represent a greater response by neutrophils
to indomethacin, in which case the drug
would not be preventing this part of a n
inflammatory reaction. Alternatively, a
slower migration was occurring once these
cells had left the vascular system, resulting
in a buildup of larger numbers to be observed
at the time of sampling. This latter possibility would be favoured if tissue neutrophil
chemotaxis is inhibited by nonsteroidal antiinflammatory drugs in the uterus as is reported for leucocytes in other tissues (Di
Rosa, 1979) or from in vitro studies (Spisani
et al., 1979).
Contrary to the finding of extensive numbers of neutrophils throughout the stroma in
response to the different IUDs, eosinophils
were increased only in the superficial zone of
the stroma, with indomethacin reducing this
feature cranial to the device. The similarity
of eosinophil volumes in the stroma close to
the muscle zone of all groups suggests again
that IUDs do not influence this cell type in
the deep endometrium, and that those that
were seen in increased frequency in the superficial stroma had emigrated from proximate vascular tissue.
Prostaglandins are important mediators of
increased vascular permeability, and it is
well established that indomethacin is a potent inhibitor of cyclo-oxygenase causing a
suppression of prostaglandin production
(Vane, 1971; Gryglewski, 1979). If IUDs are
causing increased vascular permeability
(Shaw et al., 19791, it might be expected that
a n indomethacin delivery system would reduce this and consequently edema would not
be so evident. If there had been edema there
would probably have been a reduction in the
volume fraction of fibroblasts, since the extracellular compartment would have been increased. This study showed a constancy of
fibroblast populations with respect to tissue
volume in all treatment groups, suggesting
that edema is not a major consequence of the
insertion of IUDs in rats.
Monocytes, macrophages, and plasma cells
have been shown to be elevated in the stroma
of postpartum rats (Padykula and Campbell,
1976), and monocytes were found in the epithelium and to accumulate at the stromalepithelial boundary during late pregnancy
(Padykula and Tansey, 1979). Macrophages
were clearly identified in monkey uterine luminal flushes from IUD-fitted animals (Hurst
514
C.C. PAGE, P.R. HURST, AND G.F.S. SPEARS
et al., 1977) and formed a substantial population on human IUDs (Myatt et al., 1975).
The study reported here tentatively suggests
that some or all of these cell types might also
be undergoing changes in the stroma, but it
must be emphasised that a further study is
required to ascertain more precisely if any
alteration t o the population of these cells is
occurring in response to the presence of plain
and medicated IUDs.
ACKNOWLEDGMENTS
This work was performed whilst one of us
(C.C.P.)held a summer research scholarship
from the Otago Medical Research Foundation. We are grateful to Vicki Gamble, Keith
Pickersgill, and Ken Turner for their technical assistance, and Margaret Scoular for typing the manuscript.
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