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Original Studies |
Department of Obstetrics and Gynecology and Mid Sweden Research and Development Center, Sundsvall Hospital (M.D.); the Departments of Oncology (K.B.), Pathology (S.C., P.W.), and Obstetrics and Gynecology (T.B.), University of Umea, 901 85 Umea, Sweden
Address all correspondence and requests for reprints to: Prof. Torbjörn Bäckström, Department of Gynecology and Obstetrics, University Hospital of Northern Sweden, 901 85 Umea, Sweden. E-mail: torbjorn.backstrom{at}obstgyn.umu.se
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Apoptosis is a physiological mechanism to eliminate unwanted or dysfunctional cells (7) and is thereby an important regulator of cell homeostasis in many hormone-dependent organs (8, 9, 10, 11). Apoptosis has been induced in the uterine endometrium of hamster (12), rabbit (13, 14), and monkey (15) by withdrawal of steroid hormones. Apoptosis has been observed in human endometrium, mainly in the luteal phase (5, 16, 17, 18, 19, 20) and during menstruation, but also in the early proliferative phase (16, 21), but to our knowledge no detailed analysis of the changes before and during menstruation has been performed. Immunoreactivity for Ki-67 is only expressed in dividing cells (22). The number of cells expressing immunoreactivity for Ki-67 per 100 cells can therefore be used as a proliferation marker (22). Ki-67 is present in endometrial glands during the proliferative phase and during the first half of the secretory phase, but diminishes during the second part of the secretory phase (23, 24). The protooncogene bcl-2 (B cell lymphoma/leukemia-2) (25) functions to prolong the survival of healthy and pathological cells by blocking apoptosis (26). Endometrial epithelium is immunoreactive for Bcl-2 in the follicular phase (20, 23, 27), and its strictly cyclic appearance argues that Bcl-2 is under hormonal control. In this study, the number of apoptotic cells per 1000 cells was identified in endometrial samples representing a period from 4 days before the start of menstruation to the second menstrual day. The number of apoptotic cells per 1000 cells was used as a quantitative index for apoptosis. The apoptotic index was correlated to changes in serum levels of 17ß-estradiol and progesterone, cellular receptor levels for estrogen and progesterone, and proliferation of epithelial and stromal cells in superficial human endometrium during the perimenstrual period with the aim of correlating the changes in hormone concentrations with indicators of proliferation and apoptosis at the end of the cycle.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Endometrial microbiopsies were taken with a Pipell (Prodimed,
Neuilly-en-Thelie, France) or Endorette (Medscan, Malmö,
Sweden) instrument from 35 regularly menstruating healthy
women without any hormonal therapy during 37 menstrual cycles from 4
days before the onset of menstruation (day -4) until the second
menstrual day (day 1). The biopsies may represent any part of the
superficial corpus endometrium. Altogether, 75 biopsies were taken
representing 6 consecutive days, and the number of biopsies varied from
10–15 each day, as shown in Table 1
. One
biopsy per day and 1–3 biopsies/cycle were taken from individual
patients. In 2 cases, only a single biopsy was taken, paired biopsies
were taken in 29 cases, and 3 biopsies were taken in 5 cases. The
length of the menstrual cycle varied individually, but this study was
centered around the onset of bleeding. Informed consent was given by
all women, and the study was approved by the ethical committee of Umea
University.
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The biopsy material from corpus endometrium was obtained with an Endorett or Pipell instrument, fixed in 4% formaldehyde for 4–6 h, dehydrated, and embedded in paraffin according to routine procedures. Four-micron thick consecutive serial sections from all 75 biopsies were used for each procedure described below.
17ß-Estradiol receptor-
(ER), progesterone receptor (PR), and
Ki-67
ER, PR, and Ki-67 immunostaining was carried out as described previously (28). Briefly, the sections were deparaffinized, rehydrated, and incubated for 30 min with 3% H2O2 in methanol to block endogenous peroxidase activity. After a short rinse in buffer, the sections were boiled in a microwave oven (800 watts maximal effect) in citrate buffer. After cooling and rinsing in Tris-buffered saline, the application of normal horse serum was used for ER (1 D5, DAKO Corp., Glostrup, Denmark) and KI-67 (MIB 1, Immunotech, Marseille, France) antibodies, and goat serum was used for PR antibodies (PgR-ICA monoclonal, Abbott Laboratories, Chicago, IL) for 20 min to prevent nonspecific antibody binding. The sections were then incubated overnight at 4 C with monoclonal antibodies directed against ER, PR, and Ki-67. Localization of antigen-antibody complexes was performed with the avidin-biotin-peroxidase complex technique using the Vectastain ABC kit. Peroxidase activity was demonstrated by a 5-min incubation in 3,3'-diaminobenzidine tetrahydrochloride and H2O2 dissolved in citrate buffer. After rinsing, the sections were counterstained with Mayer’s hematoxylin. Controls were performed according to the antibody manufacturer’s recommendations. Sections from lymphoid tissue were used as positive controls. Normal serum substituted for primary antibody in negative controls.
ER and PR staining in surface and glandular epithelium as well as in stroma was evaluated in each section. Positive cells showed a brown reaction product in the nucleus, whereas the cytoplasm remained unstained. Staining was scored in four categories as follows: 0, cells were negative; 1, most cells were weakly stained or occasional cells were strongly stained; 2, most cells were moderately stained; and 3, most cells were strongly stained.
The Ki-67 index (the percentage of Ki-67-positive cells) was established by use of a standard light microscope and two different counting techniques. Any nuclear staining was regarded as positive, and no grading of staining intensity was made.
Technique 1
A grid was mounted in 1 eyepiece of the microscope, and a total of 500-1000 cells were counted in at least 10 representative fields, separately in glandular epithelium and stroma.
Technique 2
A Weibel 1 graticule was mounted in one eyepiece of the microscope and used according to stereological principles (29). The percentage of stained cells was determined by counting stained and unstained nuclei that crossed the graticule lines in 5–20 representative fields covering the whole section. In each biopsy, 300 cells/cell type were counted. There was no significant difference in results between these 2 techniques and the 2 observers (M.D. and S.C.; by Wilcoxon signed rank test, P = 0.56), but technique 1 took 2–3 times longer than technique 2.
Bcl-2
Sections from formalin-fixed tissues were processed as described previously (30). Sections were then incubated for 1 h at room temperature with a monoclonal antibody to human Bcl-2 (DAKO Corp., clone 124) and subsequently twice for 30 min each time with a rabbit antimouse antibody (DAKO Corp., Copenhagen, Denmark) and alkaline phosphatase complex (DAKO Corp., Carpinteria, CA). Slides were counterstained with Meyer’s hematoxylin and mounted. All washing steps were carried out with phosphate-buffered saline (PBS). Positive controls consisted of sections from human lymphoid tissue. In negative controls, the primary antibody was substituted with normal serum. The cytoplasm of positive cells stained purple. Infiltrating granulocytes were often seen in stroma and were used as internal controls.
Evaluation of Bcl-2 staining was performed semiquantitatively by scoring the intensity of staining as absent (0), weak (1), moderate (2), or strong (3) in surface epithelium, glandular epithelium, and stroma. The most intense staining was seen in some parts of the surface epithelium and was regarded as staining score 4. That kind of intense staining was not seen in glands or stroma during the study period, and even in surface epithelium the average image of staining never reached a score of 4. The evaluation was performed twice by the same analyzer (M.D.), and the median value was used in the statistical analysis.
In situ end labeling (ISEL)
ISEL of apoptotic cells was carried out as described previously (30). Tissue sections were deparaffinized and rehydrated in a standard manner, heated in 2 x SSC (0.3 mol/L NaCl and 30 mmol/L sodium citrate, pH 7) at 80 C for 20 min, and subsequently washed thoroughly in distilled water. To enable enzymatic incorporation of nucleotides, the sections were digested in 0.5% pepsin in HCl (pH 2) for 15 min under gentle shaking in a 37 C water bath. The digestion was stopped by washing several times in tap water and then in buffer A (50 mmol/L Tris-HCl, 5 mmol/L MgCl, 10 mmol/L ß-mercaptoethanol, and 0.005% BSA, pH 7.5) for 5 min. After drying, the sections were incubated for 1 h at 15 C in buffer A containing 0.01 mmol/L deoxy (d)-ATP, dCTP, dGTP, biotin-16-dUTP (Boehringer Mannheim Scandinavia, Stockholm, Sweden), and 5 U/mL DNA polymerase I (Sigma Chemical Co.). After blocking endogenous peroxidase for 5 min in 0.1% H2O2 in 0.01 mol/L PBS followed by 5-min washes twice in PBS, the sections were incubated in avidin dissolved 1:100 in PBS and 0.5% Tween-20 for 30 min at room temperature before developing with diaminobenzidine. For negative controls, DNA polymerase I was excluded from the nucleotide mix. Normal rat prostate from 3 days after castration was used as a positive control.
For quantification of apoptotic cells, a grid was mounted in one eyepiece of a standard light microscope. Cells inside the grid area in 20–40 randomly chosen fields (2000–8000 cells/section) were evaluated in hematoxylin/eosin- and ISEL-stained sections, and the apoptotic index (number of apoptotic cells per 1000 cells) was determined. The morphological criteria used for apoptotic cells were single rounded cells or fragments with densely aggregated chromatin and condensed cytoplasm, often lying in halos of extracellular space (31). In ISEL-stained sections, both morphological and staining criteria were required.
Blood samples
Blood samples were collected immediately before or after the endometrial biopsy. Samples were centrifuged, and serum was split into small portions that were frozen and stored at -20 C until analyzed in the same run by a TRFIA method (time-resolved fluoroimmunoassay, Wallac, Turku, Finland).
Duplicate analyses were performed, and the resulting mean value was used. All samples were assayed in the same run. The intraassay coefficient of variation was 2.0% for serum progesterone and 7.5% for serum estradiol analysis.
Statistical methods
To compare hematoxylin/eosin and ISEL methods for
detection of apoptosis, Spearman’s correlation coefficient (
) was
computed, and the regression line was fitted for the measurements.
One-way ANOVA was used to compare the levels of the indexes (or scores)
on the different study days. For the multiple comparisons, the least
significant difference (LSD) method was used. The Wilcoxon signed ranks
test was used to evaluate any possible systematic difference in the
evaluation of Ki-67 indexes for the two independent observers with
different methods. In all statistical tests used, P <
0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Apoptosis
In sections from endometrium taken 3–4 days before menstruation,
apoptotic cells were rare and scattered among ordinary cells in both n
glands and stroma. Two days before the onset of menstruation, an
increasing frequency of apoptotic cells was seen in glands
(P = 0.023), whereas apoptotic cells in stroma were
still relatively rare. The apoptotic index in epithelial endometrium
increased up to the day of the start of menstruation (P
< 0.001) and peaked the second day of menstruation (Fig. 1). Early in menstruation, apoptotic
cells were frequently seen in both glandular epithelium and stroma
(Fig. 2). The glands contained necrotic
remnants, blood, and apoptotic cells, and interstitial bleeding and
focal necrosis were seen in stroma. Necrotic cells showed ISEL staining
of low intensity in nucleus and cytoplasm and were seen in clusters.
Apoptotic cells could easily be separated from necrotic cells by their
typical morphology and more intense ISEL staining (32, 33).
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).
Comparisons between the indexes in hematoxylin/eosin- and ISEL-stained
sections were made in 23 sections. There was a strong correlation (
= 0.97; P < 0.01) between apoptotic indexes in these
methods.
Bcl-2
Glands were weakly stained during the first 2 study days, but the
staining score increased 2 days before the start of menstruation and
continued to increase until the first day of menstruation (from a score
of 0.5 to a score of 1.4; P < 0.001). The Bcl-2 score
in stroma decreased from weak or moderate staining at the beginning of
the study period until the onset of menstruation (from a score of 1.5
to a score of 1.0; P = 0.042; Fig. 1). The Bcl-2 score
in surface epithelium showed a significant increase to moderate
staining intensity 2 days before the start of menstruation (from a
score of 1.3 to a score of 2.0; P = 0.003) and stayed
at the same level during the rest of the study period. No surface
epithelium was found in two biopsies.
Ki-67
Staining of stroma was equally distributed in different areas
(Fig. 2), whereas staining of glands showed a marked heterogeneity.
During this study period, at the end of the menstrual cycle, some
superficial glands as well as surface epithelium could be strongly
positive, whereas in other superficial glands and deeper glands,
Ki-67-positive cells were rare. Apoptotic bodies did not show any Ki-67
staining. The mean Ki-67 index was about 10 in both epithelium and
stroma of endometrium at the beginning of the study period, 4
days before menstruation. It decreased in epithelial glands within 1
day (P = 0.004) and stayed at a very low level during
the rest of the study period (Fig. 1). In contrast, the Ki-67 index
increased in stroma until the first day of menstruation
(P < 0.001), but then rapidly decreased to the second
menstrual day (P < 0.001; Fig. 1).
17ß-Estradiol, progesterone, and their receptors
Serum 17ß-estradiol and progesterone concentrations fell from
luteal phase values 4 days before menstruation to minimal values during
menstruation (P < 0.001; Fig. 3).
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). The ER score in
stroma showed the opposite pattern, with increasing staining during the
first 2 study days (P = 0.017) and decreasing staining
from the day before the start of menstruation to the the second
menstrual day (Fig. 3). The surface epithelium showed little staining
of ER and PR throughout the study period without any obvious pattern of
change.
The PR score in glands decreased from day -4 and to day -3 (from a
score of 1.5 to a score of 1.0; P < 0.001) and stayed
at a low level until the second menstruation day. PR scores in stroma
were on a higher level 4 days before the start of menstruation and
still increased (from a score of 2.1 to a score of 2.8;
P = 0.016) during the first day of the study period
(Fig. 3), but decreased then until the second day of menstruation (to
score 1.8; P < 0.0001; Fig. 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Even ischemic necrosis is inevitable in the part of endometrium that is separated by interstitial bleedings (36), and we could observe necrotic areas in the endometrial stroma during the first 2 days of menstruation. Subsequently, both ischemia and hormonal withdrawal must be considered possible inductors of apoptosis in human endometrium. The capacity of hormonal withdrawal to give rise to apoptosis has been well documented in endometrium (14). It is more difficult to establish evidence for the possible relative ischemia during vasodilatation of the spiral arteries as a reason for apoptosis before menstrual bleeding starts. On the other hand, the vascular events at the onset of menstruation may be regarded as one event in the involution process after the fall in levels of 17ß-estrogen and progesterone hormones (2, 37). Apoptotic cells and bodies were seen close to the basal membrane and in the lumen of glands, indicating two possible elimination routes of the apoptotic bodies: 1) via lumen to the endometrial cavity together with other secretory products (20), and 2) via direct transport through the basal membrane to the stroma (16, 38). Tabizadeh has noted the same dyscohesion and suggests that the apoptotic cells in stroma are mainly derived from the epithelial cells (19). This might explain the stromal presence of apoptotic cells. However, we noted both stromal apoptotic cells and apoptotic bodies in the stroma, which indicates that apoptosis may occur in the stroma. Our results concur with the earlier studies on apoptosis in endometrium (19, 20, 21), but highlight the late secretory phase with strict dating of the biopsies according to the onset of the menstrual flow and not to the histological criteria of Noyes (39). However, in the study by Kokawa, apoptotic indexes were up to 50 times higher than our values (21). The reason for this discrepancy is unknown. The present material gives a more distinct increase in the apoptotic index in glandular epithelium 2 days before the start of menstruation.
A rapid increase in the apoptotic index was noted in both epithelium and stroma during the last days of the cycle, with a maximum index on the second day of menstruation. The apoptotic index was changed in parallel with low proliferation, as measured by the Ki-67 index in epithelium, which decreased at the beginning of the study period and stayed at a low level until the second day of menstruation. The stromal apoptotic index was lower than that in epithelium and increased on the day of onset of menstruation, i.e. 2 days later than in epithelium, and the maximal index was seen on the second menstrual day. The Ki-67 index increased in stroma and reached its maximum on the day of menstrual start, when about 30% of the stromal cells showed Ki-67 staining. These findings imply that in epithelium, the apoptotic and proliferation changes both promote a reduction in epithelial volume, whereas in stroma, the changes show a more rapid turnover of cells. These findings in epithelium are also similar to the findings in other hormone-dependent organs, such as breast and prostate (40), and suggest that apoptosis in endometrial epithelium is hormonally controlled and independent of menstrual bleeding. Our observation of the increasing Ki-67 index in stroma during the last luteal days and the highest index on the same day as the highest apoptotic index was observed, indicates a rapid cell turnover in stroma at the onset of menstruation. This stromal proliferation and cell turnover may indicate the renewal process of endometrium during menstruation. Bcl-2 immunoreactivity decreased to a minimum in glandular epithelium 3 days before the start of menstruation, but increased during the 2 days before the onset of menstruation, whereas in stroma it decreased at the beginning of the study period and was at a minimum when apoptotic index values peaked in the stroma. These changes in Bcl-2 staining in stroma are in concordance with the antiapoptotic effect of Bcl-2. The late reappearance of Bcl-2 in epithelium has been earlier observed by Gompel (23). It is interesting to note the rise in Bcl-2, whereas apoptosis increased in glands. The discrepancy between the behavior of glandular and stromal Bcl-2 staining during the induction of apoptosis may reflect the complex action of the Bcl-2 family and the role of local regulators. Interestingly, the temporal changes of apoptotic index and proliferation marker Ki-67 in stroma were close to the PR’s temporal changes and are in agreement with the studies showing the progesterone-induced second wave of proliferation in stroma late in the secretory phase (1). Apoptotic bodies showed no immunoreactivity for Ki-67, and this supported the observation by Coates that apoptotic cells and bodies were negative for Ki-67 immunoreactivity (41).
The progesterone concentration at the onset of bleeding was 6.4 nmol/L, and there had been an 81% decrease in progesterone concentration since day -4 before the day of onset of menstruation. The 17ß-estradiol concentration decreased from the normal luteal values to a minimum on the second day of menstruation. In addition, both ER and PR scores decreased in the epithelium at the time of the increase in the apoptotic index. The PR score remained low, whereas the ER score increased again at menstruation. Thus, progesterone effects on the glandular epithelium are decreased by progesterone withdrawal and potentiated by decreasing PR. The apoptotic index increased on days -3 to -2, i.e. 3–5 days after the midluteal progesterone peak, at the time when the progesterone effect on epithelium is very low. Against this background, it is possible that progesterone withdrawal is involved in the initiation of apoptosis in the glandular epithelium, and the initiation of apoptosis is similar to findings in other hormonal-dependent organs during hormonal withdrawal (40). A fall in serum 17ß-estradiol and progesterone values preceded the onset of apoptosis in both glands and stroma, but the increase in the apoptotic index in stroma is delayed 2 days compared with the increase in glands. The decrease in ER and PR scores in stroma was also delayed; in fact, the scores increased during 1–2 days at the beginning of the study period. This coincides in time with an increased stromal proliferation not seen in epithelium. One hypothesis could be that the increased receptor expression is part of the increased proliferation in the stroma. Local factors, such as receptors, may thus be part of the explanation for the difference in proliferative status between the stroma and the glandular epithelium and the delay in apoptosis in the stroma. Our results coincide with those of Bergeron, who has described a more rapid decrease in PR in the glandular epithelium than in the stroma (42).
Apoptosis in the glandular epithelium may be of importance for the menstrual involution process that is induced by hormonal withdrawal. Endometrial glandular hyperplasia may thus be induced by the absence of apoptosis in the conditions connected with the absence of hormonal withdrawal, such as amenorrhea. The high proliferation activity and the high cell turnover in stroma could indicate the stromal renewal process and the importance of stroma in endometrial repair. One clinical implication is that the stroma seems proliferatively sensitive during low hormonal influence. This might be of importance for, for example, tamoxifen-induced stromal hyperplasia.
Conclusions
Apoptotic activity in endometrial glandular epithelium increased during the withdrawal of 17ß-estradiol and progesterone and occurs during low proliferation as measured by the Ki-67 index. This process is very similar to the involution processes seen in other hormone-dependent organs in the human body and may argue for hormonal participation in the regulation of apoptosis in the endometrial epithelium. A complex situation is seen in the stromal cells during the period from a few days before until the second day of menstruation, with a high proliferative activity measured by Ki-67 index and decreasing Bcl-2 immunoreactivity. This indicates a high proliferative activity in stroma during the late luteal phase and a high cell turnover during menstruation and may imply the importance of stromal activity in the cellular renewal and repair of the endometrium. Both ER and PR showed later decrease in staining score in the stromal cells compared with the glandular cells. The later onset of apoptosis in stroma may point out the importance of receptors as local regulators of the effects of 17ß-estradiol and progesterone. The appearance of apoptotic cells close to the necrotic areas may indicate that even ischemia may be an inductor of apoptosis in the endometrial stroma.
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Acknowledgments |
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Footnotes |
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Received July 20, 1998.
Revised February 12, 1999.
Accepted February 16, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Endocr J. 2:87–95.
. J Pathol. 178:71–77.[CrossRef][Medline]
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