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Endometrial regeneration after curettage
Endometr al regeneration after curettage CHARLES Stanford,
E.
McLENNAN,
M.D.
California
The speed and completeness of endometrial regeneration were studied in 30 grossly normal uteri curetted at various times in the menstrual cycle and removed one to 18 days after curettage. Regeneration a$peared normal if curettage was done as early as the second cycle day, but when performed later in the proliferative phase of the cycle there was a lag of at least 2 to 3 days in the regenerative process and the restored mucosa appeared less fully developed (thinner) than normal. Regeneration of secretory endometrium in most instances appeared even more markedly delayed, but the eight specimens in this group were inadequately distributed as to cycle day and number of days postcurettage. A few proliferative or hyperplastic endometria from anovulatory women demonstrated excellent regenerative ability.
RECENT STUDIES of human endometrial shedding and regeneration at the time of menstruation*~ 2 suggested an examination of the regenerative process that follows curettage of the uterus. Though every gynecologic pathologist has examined many curetted uteri, apparently no systematic review of either the degree or rate of endometrial restoration has been published. To investigate this question thoroughly one should in theory examine at least a single uterus curetted on each of the customary 28 days of the menstrual cycle and excised from 1 to 1 + n days later. The value for n might be as great as 27, but perhaps it is reasonable to assume that any significant histologic changes would be apparent within a much shorter time. It is not a simple task to locate grossly normal uteri curetted thoroughly 1 to 28 days prior to their removal from women who have carefully documented menstrual histories. The current popularity of hysterec-
From the Department Obstetrics, Stanford of Medicine.
of Gynecology University School
tomy for carcinoma in situ of the cervix provides many specimens excised 1 to 48 hours after conization and curettage, but there is a notable scarcity of properly sectioned organs removed 3 to 10 or more days after endometrial debridement. This retrospective study of specimens from our departmental pathology laboratory falls far short of a complete overview of the situation, which I would take to be at least one uterus curetted on each of 28 cycle days and removed one to 27 days after curettage, or a theoretical minimum of 756 specimens. But even the small sample at hand provides the basis for a few generalizations about endometrial regeneration and thus seems to merit reporting. Material
and
methods
By matching names on chronologically filed pathology reports pertaining to hysterectomy specimens, 30 patients who had been curetted and later subjected to hysterectomy within one to 18 days were identified. Their records were reviewed for menstrual histories and other pertinent details. New sections were cut from the paraffin blocks for hematoxylin and eosin or Milligan’s trichrome staining whenever the initial preparations were faded or otherwise unsuitable for study and photomicrography. In all, 175 sections of
and
Aided by Grant No. HD 0014.5 from The National Institute of Child Health and Human Development. Presented at the Thirty-fifth Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Gleneden Beach, Oregon, Oct. 2-5, 1968.
185
186
May 15, 1969 Am. J. Ohst. Rr G)-ner
McLennan
curettings or endometrial-myometrial blocks were examined in detail by light microscopy and representative areas from each specimen were photographed at various magnifications to make approximately 150 color transparencies and 50 black and white negatives. Obviously, material of this sort is best demonstrated by microprojection of multiple slides from each organ, or by viewing numerous photomicrographs made at varying magnifications, but publishing practices 71s71ally limit one to the use of a rather small number of illustrations that show only thr most salient features of the story. A much more extensive array of photographic eridence was used in the oral presentation and
Table I. Endometrial subsequent
hysterectomy
1 2
3 4 5 6 7 8 9 In 11 12 13 14 15 16 17 18
3 2
9 A. ‘P 4 4 ? 7 7
Table II. Endometrial subsequent
Case No. 19 20 21 22 23 24
25 26
hysterectomy
i w;e;a;B”i
! (
Extent
_.-__
;zi;;
__._.-_-.-.-
regeneration
4 6 6 2 6 4 ‘2
None (endometritis) Normal Normal None; blood clot at surface Slightly subnormal proliferation Subnormal proliferation None; open basal glands Subnormal proliferation Subnormal proliferation Normal Normal None, or thin new surface Nonrl or thin new surface Early proliferation (Iike day 6-7) Thin new surface on basalis None; open basal glands Surface restored ; early secretion _--.-
8 5 4 C) s 4 2 ‘) 1
~_____-
and time until
1 Extent
17 18 20 22 22 23 2~7 24
of endometrial
Normal
regeneration related to cycle day of curettage in secretory endometria
/
and time until
2
8
7 8 9 I1 11 1” I9 Ii I5 ----_____
to rc-
Table I summarizes the findings in 18 women whose endometria were in the proliferative phase of the cycle at the moment of curettage. ‘Their uteri were removed anywhere from 2 days (6 specimens) to 8 days following currttement. Three of the 4 organs curetted on dny 2 and removed 2 to 6 days later showed essentially normal endometria (Fig. 1 j, except for one with acute endornctritis and complete lack of regenerativt activity 4 days after cervical conization (Case 21. Despite the inflammation, this patient’s
Days from curettage to hyfterectomy
curettage
wish
Observations
regeneration related to cycle day of curettage in proliferative endometria
Cycle day of Case No.
has been preserved for any who view the slides or photographs.
2 2 6 1 10 ?I 3 3
of endometrial
regeneration
Intermittent surface restoration None; open basal glands Intermittent surface restoration; premenstrual None; denuded basalis Delayed menstrual shedding (day 5) None; surface clot None; surface clot None; surface -_clot - ~..- --.-..__.---.____-.
changes
.~.__
Volume Number
104 2
clinical course was uncomplicated. All others removed 2 or 3 days postcurettement but later in the cycle showed either spotty new surface epithelization over a very thin, mainly basal, endometrium (Fig. 2)) or merely a denuded basalis covered irregularly by a serosanguineous exudate. Four of the 5 uteri removed 4 days after curettage had restored surfaces (e.g., Fig. 3, Case 15), but the entire mucosal layer ap-
Endometrial
regeneration
after
curettage
187
peared shallower than that usually found in uninjured endometria on corresponding cycle days. The curettings in Case 18 were characteristic of very advanced proliferation (cycle day 15, by history) ; the residual endometrium 4 days later had an intact surface and early secretory effects were fairly abundant in the spongiosa layer (Fig. 4). Two of the 4 organs removed 5 or 6 days after curettage had normal endometria, but
Fig. 1. Endometrium beginning to organize new surface 2 days after curettage on second day of menstruation. A considerable thickness of spongiosa has been retained between the basalis and the fragmentary new epithelial covering along the surface. (x40.)
Fig. 2. Thin proliferating endometrium with partially renewed surface epithelium 2 days after curettage on the eleventh cycle day, at which time the curettings showed advanced proliferation. (X40.)
188
Mclennan
Table III.
Endometrial regeneration and hyperplastic endometria
reiated
to time after
curettage
-__.~---.----.. I
/
Case No. 27 28 29 30
Histobgy
of curetted
t&e
Days. from curettage to hysterectomy
Anovulatory proliferation Anovulatory proliferation Cystic glandular hyperplasia Cystic glandular hyperplasia
2 10 4 18
-_---_.---__
Fig.
3. An undulating new proliferative This resembles endometria seen on day 1). (x40.)
Fig.
4. Early
secretory
endomctrium
teenth cycle day. The curettings
showed
in anovulatory
..- -. _.--..--~..-.-~
-..__..~ .-
-_
/ 1
Extent
of endometrial
regeneration
New proliferative surface throughout uterus Advanced proliferative surface throughout: uterus None; denuded basalis .4dvanced proliferative surface with foci of residual hyperplasia mediallv ~-_--. -2 ____ -.~----._-. ---~~~ ._..
surface 4 days after curettage 6 of normal menstrual cycle
on twelfth day of cycle. (like Fig. 19 in reference
with newly formed surface 4 days after curettage only late proliferation (Case 18). (x40.)
on fif-
Volume Number
104 2
Endometrial
Fig. 5. Normal proliferative endometrium 6 days following curettage on second day of menstruation (Case 3). There was no apparent delay in regeneration. (X40.)
Fig. 6. Endometrium ment but restoration tion. (x40.)
8 days after curettage of surface; no evidence
regeneration
after curettage
189
these had been curetted on cycle day 2, as already noted (see Fig. 5). The other two, surgically injured later in the cycle, were relatively less well regenerated. Two uteri that were excised 8 days following curettement on cycle day 7 (Cases 9 and 10) also showed some degree of delay in regeneration and thus diminished depth of the mucosal layer (Fig. 6). Table II summarizes the findings in 8 uteri with secretory endometria at various stages of advancement (cycle days 17 to 24)) removed one to IO days after curettage. Al1 of these were abnormal in one way or another. Five showed merely serosanguineous exudates overlying dormant basal glands (Figs. 7 and 8). Two displayed interrupted areas of new surface (Figs. 9 and lo), but the total development of the endometrial layers was clearly retarded. Table III includes 2 specimens that showed frank cystic endometrial hyperplasia and 2 examples of proliferative endometrium associated with a history of anovulation. The latter had reformed their surfaces 2 and 10 days, respectively, after curettage (Figs. 11 and 12). One of the patients with hyperplasia presented a rather thick new proliferating surface covering occasional small
on seventh day of cycle, showing retarded of secretion 15 days after beginning of
develop-
menstrua-
190
McLennan
Fig. 7. Endometrial postovulatory day
surface 24 hours 10). Basal glands
after curettage on cycle day 22 (curettings interpreted as are covered by a thin layer of fibrinous exudate. (x100.)
Fig. 8. Serosanguineous exudate covering the basalis 3 days after curettage on cycie day no evidence of endometrial regeneration anywhere in this uterine cavity (Cast 24). i .40.)
foci
of
curettage.
residual But
hyperplasia the
other
18 patient,
days who
after was
33
years old, para 4, had merely a denuded basalis 4 days after removal of the hyperplastic surface.
Comment It is difficult to draw firm conclusions from these 30 specimens because they are unevenly distributed with respect both to day of cycle
and
clapsed
time
from
curettage
23;
to hysterec-
tomy, Nevertheless, several tentative suggestions may be worth mentioning. Unlike the astonishingly rapid stromal proliferation previously noted at the end of normal menstruation,’ curettage in the main is followed by a dormant period of 2 to 3 days without noticeable cndometrial activity unless the curettage is performed as early as the second day of menstruation. In the latter instance it
Volume Number
104 2
Endometrial
Fig. 9. Irregular endometrial surface contour showing earliest re-epithelization over residual, hemorrhagic spongiosa 2 days after curettage on cycle day 17 (curettings dated as postovulatory, secretory, day 4). Removal of the secretory portion of the endometrium must have been less complete than in Case 24, Fig. 8. (x40.)
Fig. 10. Partial new epithelial on cycle day 20. (x40.)
surface
on residual
regeneration
after curettage
191
might be presumed that the curet merely augments the natural phenomenon of tissue loss on days 2 and 3, and that by day 4 or later the anticipated estrogenic growth spurt is in full operation and thus the endometrium appears “normal” for that moment of the cycle. For the most part, well-establishedproliferative endometria tend to heal their surfaces within 4 days after the disruptive effects of curettage, but the stroma usually appears lessthick than expected and the total volume of endometrial tissue probably remains subnormal throughout the remainder of the cycle. These findings seem compatible with chnical observations of 4 to 5 days of minor bleeding after the usual curettage and some degree of reduction in the volume of bleeding during the ensuing menstrual period. In uteri with secretory endometria, a similar or even more impressive postcurettage dormant state persisting at least 3 days was noted. Indeed, 5 out of 8 specimensshowed a denuded basaliscovered with varying thicknessesof organizing bIood clot, but absoIuteIy no restoration of stromal or glandular elements. One specimen (Case 21) had advanced to a late premenstrual or very early menstrual pattern within 6 days and another exhibited the typical histologic picture of ir-
thin
spongiosa
layer
6 days
after
curettement
192
Mclennan
Fig. 11. New epithelial surface just 2 days after a woman with an irregular, anovulatory pattern
Fig. 12. Superficial
portion of intact proliferating endometrial surface in a uterus removed 10 days after curettage. The patient had been bleeding for 3 weeks at time of curettage and history suggested anovulation for about 4 months. (x100.)
regular (delayed) shedding 10 days after curettage and 5 days after onset of what the patient thought was an anticipated menstrual period. In this latter instance, there was some doubt about the completeness of the curet-
curettage
of proliferative
endometrium
from
of bleeding for at least 6 months. (x100.)
tage (done elsewhere) that accompanied conization of the cervix. Though these crude observations may be difficult to evaluate, they are offered as another small fragment in the unsolved puzzle of endometrial anatomy and physiology. Neither a literature search nor inquiries sent to leading gynecologic pathologists3* 4y S led me to previous studies of endometrial regeneration in normal, nonpuerperal uteri. Hertig,3 however, suggested that the regenerative power of proliferative endometrium would exceed that of the secretory phase, since mitoses seldom occur during the latter. This study does not, unfortunately, clarify in any way the controversy about the role of stroma in regeneration of endornetrial epithelium, described by Baggish, Pauerstein, and Woodruff,” because virtually all the curetted uteri exhibited either complete epithelization or a totally denuded and inactive basalis. But a recent review oi our menstrual specimens described earlier’ demonstrates, at least in some instancf:s, the attractiveness of Baggish’s contention that hyperchromatic stromal cells participate in reepithelization by a process simulating rnetaplasia. It is also of interest to note that Reid, Singer, and Coppleson” favor an in situ origin for new cervical squamous cpi-
Volume
Number
104 2
Endometrial
regeneration
after curettage
193
thelium that replaces columnar epithelium destroyed by electrocautery coagulation. In
would like to think that the newer molecular biology, as exemplified by Hamilton’s’ dis-
their view, the contribution of marginal healthy squamous epithelium is very small. Clearly we need much further study of the basic mechanisms by which the development, shedding, and renewal of human endometrial tissue is accomplished. The simple disclosures of light microscopy are far too gross for most and electron microscopy has not purposes, yet provided the necessary answers. One
cussion of the control by estrogen of genetic transcription and translation, may lead us ultimately to appropriate explanations. But at the moment there would appear to be a huge hiatus between the metabolism of RNA and protein in the nuclear and cytoplasmic fractions of the rat uterus and the clinical control of aberrant uterine bleeding in women.
REFERENCES
1. McLennan, C. E., and Rydell, A. H.: Obst. Rr Gynec. 26: 605, 1965. 2. Baggish, M. S., Pauerstein, C. J., and Woodruff, J. D.: AK J. OBST. & GYNEC. 99: 459, 1967.
3. Hertig, A. H.: Personal communication.
Discussion
C. BENSON, Portland, Oregon. Dr. McLennan has modestly added more important details to our knowledge of uterine physiology. This contribution is all the more welcome because he has corrected certain faulty assumptions which have skewed our thinking for many years. Now, half a century after the first accurate description of the menstrual cycle, we are beginning to appreciate the true sequence of endometrial repair. The author has indicated that the proliferative phase is, in truth, one of generation (regeneration) not duplicated during other phases of the cycle. That healing might be retarded following injury (curettage) after the third day of the cycle seems likely from the evidence presented. The implication that estrogen is the hormone favorable to tissue regeneration is a shrewd postulation. Certainly, this is true for proliferative and endometrial hyperplasia where maturation is mediated by estrogen. This view is supported by observations in clinical gynecology. However, trial therapy should be given to prove that estrogen is an important factor in endometrial healing. Despite the initial presumed simplicity of this study, it is now obviously very complex. Dr. DR.
RALPH
4. Richart, R. M.: Personal communication. 5. Woodruff, J. D.: Personal communication. 6. Reid, B. L., Singer, A., and Coppleson, M.: Australia and New Zealand J. Obst. & Gynaec. 7: 125, 1967. 7. Hamilton, T. H.: Science 161: 649, 1968.
McLennan has mentioned certain critical features, such as the very large number of normal specimens needed to really prove his hypothesis, and the need to stimulate a scanning process to visualize the changes in progress of healing. Other problems occurred to me: how can one prove by random sections that (1) surface regeneration occurs to rather than jrom the mouths of endometrial glands (Fig. 2)-granted epithelial spread is likely from the spared surface “islands” and (2) that the second (posthysterectomy) section really is from a curetted area (Figs. 3 and 4) ? In any event, it appears likely that endometrial healing follows the general pattern which Dr. McLennan has described. Actually, -postcurettage symptomatology and certain complications of curettage may reflect delay in endometrial healing. Why the stroma lags in the regenerative process is a question still unanswered. DR. ROGER HOAG, Berkeley, California. One point that impressed me about these slides was the lack of any inflammatory effect in the healing phase following curettage. I had always thought that one would see hordes of polvmorphonuclear cells in the surface areas as an inflammatory membrane, or at least more than we saw here. I am also impressed that the
194
Mclennan
timing of hysterectomy following curettage may be less critical than I had heretofore thought. I had always felt that one should do a hysterectomy within 48 hours after dilatation and curettage or it should be postponed for a late1 time. It would seem from Dr. McLennan’s sections and from his lack of comment about any complications of hysterectomy at varying times following curettage, that this fear possibly may be laid to rest. DR. CHARLES KIMBALL, Seattle, Washington. It seems to me it would be worthwhile to look back to the original work done in 1935-1936 by Novak and by Broders and Hcrrell when the Novak curette and the Randall curette were used very extensively to study cndometrial changes. In 1937 Dr. Herrell was awarded the Essay Prize by the American Association of Obstetricians and Gynecologists for a study showing serial endometrial biopsies done every 2 or 3 days throughout the cycle. I wonder if revival of this technique would contribute information to Dr. McLennan’s study. DR. MCLENNAN (Closing). Dr. Benson has raised a valid question, that is, how may one be certain that the piece of endometrial surface at which he’s looking had been scraped firmly with a curettc prior to the removal of the uterus. I can only say that, in addition to the few examples I demonstrated today, I have reviewed hundreds of sections from the uteri in this study
Am
hlay 15, 1969 J. Ohst. & Gynec.
and can assure ~CJII they appeared to have /,ccn sampled thoroughly from top to bottom and side to side, judging from the curcttings and from descriptions of the gross specimens. On the other hand, it‘s obvious that intact iJitS of tbndometrium frequently remain in the corriual rccesses, but these arcas lverc carefully excluded from the sclt‘ction of samples usccl to show regenerative cff~2ts. Dr. Hoag mclltionctl the inter,*sting fact that none of the cndomctrial specimens sho\ved any inflammation st,veral days following curct tagc. Of the 31) specimens I have no’il’ esarnincd there was only one that sho\vctd inflammation; it \V~IS a day 4 spccimrsn, that is, removed 4 clay< aftt-r curettage, the latter having bern tlonc ill COW junction with ccr\?& conization, and for some reason this particular cndometrial surfa,.<, e’shihited a solid mass of infamnlatory ccllr. I reviewed tbc clinical record and found that nothing unusual had happened to this patic~~i. Regarding Dr. Kimball’s suggestion allou t the use of thr 1,iopsy curette to obtain serial specimens front the same uterus, I don’t think this would hc vclry applicable ICI ~hc s0r1 ot question I ~cas trying to answer, namely, \\hat is the d~~grcc of over-all regeneration, the mechanism of it, the speed with which it occurs. and so forth. I think for this information we’ll have to continue to rely on total hysterectomy specimens following curettage.
E.
McLENNAN,
M.D.
California
The speed and completeness of endometrial regeneration were studied in 30 grossly normal uteri curetted at various times in the menstrual cycle and removed one to 18 days after curettage. Regeneration a$peared normal if curettage was done as early as the second cycle day, but when performed later in the proliferative phase of the cycle there was a lag of at least 2 to 3 days in the regenerative process and the restored mucosa appeared less fully developed (thinner) than normal. Regeneration of secretory endometrium in most instances appeared even more markedly delayed, but the eight specimens in this group were inadequately distributed as to cycle day and number of days postcurettage. A few proliferative or hyperplastic endometria from anovulatory women demonstrated excellent regenerative ability.
RECENT STUDIES of human endometrial shedding and regeneration at the time of menstruation*~ 2 suggested an examination of the regenerative process that follows curettage of the uterus. Though every gynecologic pathologist has examined many curetted uteri, apparently no systematic review of either the degree or rate of endometrial restoration has been published. To investigate this question thoroughly one should in theory examine at least a single uterus curetted on each of the customary 28 days of the menstrual cycle and excised from 1 to 1 + n days later. The value for n might be as great as 27, but perhaps it is reasonable to assume that any significant histologic changes would be apparent within a much shorter time. It is not a simple task to locate grossly normal uteri curetted thoroughly 1 to 28 days prior to their removal from women who have carefully documented menstrual histories. The current popularity of hysterec-
From the Department Obstetrics, Stanford of Medicine.
of Gynecology University School
tomy for carcinoma in situ of the cervix provides many specimens excised 1 to 48 hours after conization and curettage, but there is a notable scarcity of properly sectioned organs removed 3 to 10 or more days after endometrial debridement. This retrospective study of specimens from our departmental pathology laboratory falls far short of a complete overview of the situation, which I would take to be at least one uterus curetted on each of 28 cycle days and removed one to 27 days after curettage, or a theoretical minimum of 756 specimens. But even the small sample at hand provides the basis for a few generalizations about endometrial regeneration and thus seems to merit reporting. Material
and
methods
By matching names on chronologically filed pathology reports pertaining to hysterectomy specimens, 30 patients who had been curetted and later subjected to hysterectomy within one to 18 days were identified. Their records were reviewed for menstrual histories and other pertinent details. New sections were cut from the paraffin blocks for hematoxylin and eosin or Milligan’s trichrome staining whenever the initial preparations were faded or otherwise unsuitable for study and photomicrography. In all, 175 sections of
and
Aided by Grant No. HD 0014.5 from The National Institute of Child Health and Human Development. Presented at the Thirty-fifth Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Gleneden Beach, Oregon, Oct. 2-5, 1968.
185
186
May 15, 1969 Am. J. Ohst. Rr G)-ner
McLennan
curettings or endometrial-myometrial blocks were examined in detail by light microscopy and representative areas from each specimen were photographed at various magnifications to make approximately 150 color transparencies and 50 black and white negatives. Obviously, material of this sort is best demonstrated by microprojection of multiple slides from each organ, or by viewing numerous photomicrographs made at varying magnifications, but publishing practices 71s71ally limit one to the use of a rather small number of illustrations that show only thr most salient features of the story. A much more extensive array of photographic eridence was used in the oral presentation and
Table I. Endometrial subsequent
hysterectomy
1 2
3 4 5 6 7 8 9 In 11 12 13 14 15 16 17 18
3 2
9 A. ‘P 4 4 ? 7 7
Table II. Endometrial subsequent
Case No. 19 20 21 22 23 24
25 26
hysterectomy
i w;e;a;B”i
! (
Extent
_.-__
;zi;;
__._.-_-.-.-
regeneration
4 6 6 2 6 4 ‘2
None (endometritis) Normal Normal None; blood clot at surface Slightly subnormal proliferation Subnormal proliferation None; open basal glands Subnormal proliferation Subnormal proliferation Normal Normal None, or thin new surface Nonrl or thin new surface Early proliferation (Iike day 6-7) Thin new surface on basalis None; open basal glands Surface restored ; early secretion _--.-
8 5 4 C) s 4 2 ‘) 1
~_____-
and time until
1 Extent
17 18 20 22 22 23 2~7 24
of endometrial
Normal
regeneration related to cycle day of curettage in secretory endometria
/
and time until
2
8
7 8 9 I1 11 1” I9 Ii I5 ----_____
to rc-
Table I summarizes the findings in 18 women whose endometria were in the proliferative phase of the cycle at the moment of curettage. ‘Their uteri were removed anywhere from 2 days (6 specimens) to 8 days following currttement. Three of the 4 organs curetted on dny 2 and removed 2 to 6 days later showed essentially normal endometria (Fig. 1 j, except for one with acute endornctritis and complete lack of regenerativt activity 4 days after cervical conization (Case 21. Despite the inflammation, this patient’s
Days from curettage to hyfterectomy
curettage
wish
Observations
regeneration related to cycle day of curettage in proliferative endometria
Cycle day of Case No.
has been preserved for any who view the slides or photographs.
2 2 6 1 10 ?I 3 3
of endometrial
regeneration
Intermittent surface restoration None; open basal glands Intermittent surface restoration; premenstrual None; denuded basalis Delayed menstrual shedding (day 5) None; surface clot None; surface clot None; surface -_clot - ~..- --.-..__.---.____-.
changes
.~.__
Volume Number
104 2
clinical course was uncomplicated. All others removed 2 or 3 days postcurettement but later in the cycle showed either spotty new surface epithelization over a very thin, mainly basal, endometrium (Fig. 2)) or merely a denuded basalis covered irregularly by a serosanguineous exudate. Four of the 5 uteri removed 4 days after curettage had restored surfaces (e.g., Fig. 3, Case 15), but the entire mucosal layer ap-
Endometrial
regeneration
after
curettage
187
peared shallower than that usually found in uninjured endometria on corresponding cycle days. The curettings in Case 18 were characteristic of very advanced proliferation (cycle day 15, by history) ; the residual endometrium 4 days later had an intact surface and early secretory effects were fairly abundant in the spongiosa layer (Fig. 4). Two of the 4 organs removed 5 or 6 days after curettage had normal endometria, but
Fig. 1. Endometrium beginning to organize new surface 2 days after curettage on second day of menstruation. A considerable thickness of spongiosa has been retained between the basalis and the fragmentary new epithelial covering along the surface. (x40.)
Fig. 2. Thin proliferating endometrium with partially renewed surface epithelium 2 days after curettage on the eleventh cycle day, at which time the curettings showed advanced proliferation. (X40.)
188
Mclennan
Table III.
Endometrial regeneration and hyperplastic endometria
reiated
to time after
curettage
-__.~---.----.. I
/
Case No. 27 28 29 30
Histobgy
of curetted
t&e
Days. from curettage to hysterectomy
Anovulatory proliferation Anovulatory proliferation Cystic glandular hyperplasia Cystic glandular hyperplasia
2 10 4 18
-_---_.---__
Fig.
3. An undulating new proliferative This resembles endometria seen on day 1). (x40.)
Fig.
4. Early
secretory
endomctrium
teenth cycle day. The curettings
showed
in anovulatory
..- -. _.--..--~..-.-~
-..__..~ .-
-_
/ 1
Extent
of endometrial
regeneration
New proliferative surface throughout uterus Advanced proliferative surface throughout: uterus None; denuded basalis .4dvanced proliferative surface with foci of residual hyperplasia mediallv ~-_--. -2 ____ -.~----._-. ---~~~ ._..
surface 4 days after curettage 6 of normal menstrual cycle
on twelfth day of cycle. (like Fig. 19 in reference
with newly formed surface 4 days after curettage only late proliferation (Case 18). (x40.)
on fif-
Volume Number
104 2
Endometrial
Fig. 5. Normal proliferative endometrium 6 days following curettage on second day of menstruation (Case 3). There was no apparent delay in regeneration. (X40.)
Fig. 6. Endometrium ment but restoration tion. (x40.)
8 days after curettage of surface; no evidence
regeneration
after curettage
189
these had been curetted on cycle day 2, as already noted (see Fig. 5). The other two, surgically injured later in the cycle, were relatively less well regenerated. Two uteri that were excised 8 days following curettement on cycle day 7 (Cases 9 and 10) also showed some degree of delay in regeneration and thus diminished depth of the mucosal layer (Fig. 6). Table II summarizes the findings in 8 uteri with secretory endometria at various stages of advancement (cycle days 17 to 24)) removed one to IO days after curettage. Al1 of these were abnormal in one way or another. Five showed merely serosanguineous exudates overlying dormant basal glands (Figs. 7 and 8). Two displayed interrupted areas of new surface (Figs. 9 and lo), but the total development of the endometrial layers was clearly retarded. Table III includes 2 specimens that showed frank cystic endometrial hyperplasia and 2 examples of proliferative endometrium associated with a history of anovulation. The latter had reformed their surfaces 2 and 10 days, respectively, after curettage (Figs. 11 and 12). One of the patients with hyperplasia presented a rather thick new proliferating surface covering occasional small
on seventh day of cycle, showing retarded of secretion 15 days after beginning of
develop-
menstrua-
190
McLennan
Fig. 7. Endometrial postovulatory day
surface 24 hours 10). Basal glands
after curettage on cycle day 22 (curettings interpreted as are covered by a thin layer of fibrinous exudate. (x100.)
Fig. 8. Serosanguineous exudate covering the basalis 3 days after curettage on cycie day no evidence of endometrial regeneration anywhere in this uterine cavity (Cast 24). i .40.)
foci
of
curettage.
residual But
hyperplasia the
other
18 patient,
days who
after was
33
years old, para 4, had merely a denuded basalis 4 days after removal of the hyperplastic surface.
Comment It is difficult to draw firm conclusions from these 30 specimens because they are unevenly distributed with respect both to day of cycle
and
clapsed
time
from
curettage
23;
to hysterec-
tomy, Nevertheless, several tentative suggestions may be worth mentioning. Unlike the astonishingly rapid stromal proliferation previously noted at the end of normal menstruation,’ curettage in the main is followed by a dormant period of 2 to 3 days without noticeable cndometrial activity unless the curettage is performed as early as the second day of menstruation. In the latter instance it
Volume Number
104 2
Endometrial
Fig. 9. Irregular endometrial surface contour showing earliest re-epithelization over residual, hemorrhagic spongiosa 2 days after curettage on cycle day 17 (curettings dated as postovulatory, secretory, day 4). Removal of the secretory portion of the endometrium must have been less complete than in Case 24, Fig. 8. (x40.)
Fig. 10. Partial new epithelial on cycle day 20. (x40.)
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might be presumed that the curet merely augments the natural phenomenon of tissue loss on days 2 and 3, and that by day 4 or later the anticipated estrogenic growth spurt is in full operation and thus the endometrium appears “normal” for that moment of the cycle. For the most part, well-establishedproliferative endometria tend to heal their surfaces within 4 days after the disruptive effects of curettage, but the stroma usually appears lessthick than expected and the total volume of endometrial tissue probably remains subnormal throughout the remainder of the cycle. These findings seem compatible with chnical observations of 4 to 5 days of minor bleeding after the usual curettage and some degree of reduction in the volume of bleeding during the ensuing menstrual period. In uteri with secretory endometria, a similar or even more impressive postcurettage dormant state persisting at least 3 days was noted. Indeed, 5 out of 8 specimensshowed a denuded basaliscovered with varying thicknessesof organizing bIood clot, but absoIuteIy no restoration of stromal or glandular elements. One specimen (Case 21) had advanced to a late premenstrual or very early menstrual pattern within 6 days and another exhibited the typical histologic picture of ir-
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Fig. 11. New epithelial surface just 2 days after a woman with an irregular, anovulatory pattern
Fig. 12. Superficial
portion of intact proliferating endometrial surface in a uterus removed 10 days after curettage. The patient had been bleeding for 3 weeks at time of curettage and history suggested anovulation for about 4 months. (x100.)
regular (delayed) shedding 10 days after curettage and 5 days after onset of what the patient thought was an anticipated menstrual period. In this latter instance, there was some doubt about the completeness of the curet-
curettage
of proliferative
endometrium
from
of bleeding for at least 6 months. (x100.)
tage (done elsewhere) that accompanied conization of the cervix. Though these crude observations may be difficult to evaluate, they are offered as another small fragment in the unsolved puzzle of endometrial anatomy and physiology. Neither a literature search nor inquiries sent to leading gynecologic pathologists3* 4y S led me to previous studies of endometrial regeneration in normal, nonpuerperal uteri. Hertig,3 however, suggested that the regenerative power of proliferative endometrium would exceed that of the secretory phase, since mitoses seldom occur during the latter. This study does not, unfortunately, clarify in any way the controversy about the role of stroma in regeneration of endornetrial epithelium, described by Baggish, Pauerstein, and Woodruff,” because virtually all the curetted uteri exhibited either complete epithelization or a totally denuded and inactive basalis. But a recent review oi our menstrual specimens described earlier’ demonstrates, at least in some instancf:s, the attractiveness of Baggish’s contention that hyperchromatic stromal cells participate in reepithelization by a process simulating rnetaplasia. It is also of interest to note that Reid, Singer, and Coppleson” favor an in situ origin for new cervical squamous cpi-
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thelium that replaces columnar epithelium destroyed by electrocautery coagulation. In
would like to think that the newer molecular biology, as exemplified by Hamilton’s’ dis-
their view, the contribution of marginal healthy squamous epithelium is very small. Clearly we need much further study of the basic mechanisms by which the development, shedding, and renewal of human endometrial tissue is accomplished. The simple disclosures of light microscopy are far too gross for most and electron microscopy has not purposes, yet provided the necessary answers. One
cussion of the control by estrogen of genetic transcription and translation, may lead us ultimately to appropriate explanations. But at the moment there would appear to be a huge hiatus between the metabolism of RNA and protein in the nuclear and cytoplasmic fractions of the rat uterus and the clinical control of aberrant uterine bleeding in women.
REFERENCES
1. McLennan, C. E., and Rydell, A. H.: Obst. Rr Gynec. 26: 605, 1965. 2. Baggish, M. S., Pauerstein, C. J., and Woodruff, J. D.: AK J. OBST. & GYNEC. 99: 459, 1967.
3. Hertig, A. H.: Personal communication.
Discussion
C. BENSON, Portland, Oregon. Dr. McLennan has modestly added more important details to our knowledge of uterine physiology. This contribution is all the more welcome because he has corrected certain faulty assumptions which have skewed our thinking for many years. Now, half a century after the first accurate description of the menstrual cycle, we are beginning to appreciate the true sequence of endometrial repair. The author has indicated that the proliferative phase is, in truth, one of generation (regeneration) not duplicated during other phases of the cycle. That healing might be retarded following injury (curettage) after the third day of the cycle seems likely from the evidence presented. The implication that estrogen is the hormone favorable to tissue regeneration is a shrewd postulation. Certainly, this is true for proliferative and endometrial hyperplasia where maturation is mediated by estrogen. This view is supported by observations in clinical gynecology. However, trial therapy should be given to prove that estrogen is an important factor in endometrial healing. Despite the initial presumed simplicity of this study, it is now obviously very complex. Dr. DR.
RALPH
4. Richart, R. M.: Personal communication. 5. Woodruff, J. D.: Personal communication. 6. Reid, B. L., Singer, A., and Coppleson, M.: Australia and New Zealand J. Obst. & Gynaec. 7: 125, 1967. 7. Hamilton, T. H.: Science 161: 649, 1968.
McLennan has mentioned certain critical features, such as the very large number of normal specimens needed to really prove his hypothesis, and the need to stimulate a scanning process to visualize the changes in progress of healing. Other problems occurred to me: how can one prove by random sections that (1) surface regeneration occurs to rather than jrom the mouths of endometrial glands (Fig. 2)-granted epithelial spread is likely from the spared surface “islands” and (2) that the second (posthysterectomy) section really is from a curetted area (Figs. 3 and 4) ? In any event, it appears likely that endometrial healing follows the general pattern which Dr. McLennan has described. Actually, -postcurettage symptomatology and certain complications of curettage may reflect delay in endometrial healing. Why the stroma lags in the regenerative process is a question still unanswered. DR. ROGER HOAG, Berkeley, California. One point that impressed me about these slides was the lack of any inflammatory effect in the healing phase following curettage. I had always thought that one would see hordes of polvmorphonuclear cells in the surface areas as an inflammatory membrane, or at least more than we saw here. I am also impressed that the
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timing of hysterectomy following curettage may be less critical than I had heretofore thought. I had always felt that one should do a hysterectomy within 48 hours after dilatation and curettage or it should be postponed for a late1 time. It would seem from Dr. McLennan’s sections and from his lack of comment about any complications of hysterectomy at varying times following curettage, that this fear possibly may be laid to rest. DR. CHARLES KIMBALL, Seattle, Washington. It seems to me it would be worthwhile to look back to the original work done in 1935-1936 by Novak and by Broders and Hcrrell when the Novak curette and the Randall curette were used very extensively to study cndometrial changes. In 1937 Dr. Herrell was awarded the Essay Prize by the American Association of Obstetricians and Gynecologists for a study showing serial endometrial biopsies done every 2 or 3 days throughout the cycle. I wonder if revival of this technique would contribute information to Dr. McLennan’s study. DR. MCLENNAN (Closing). Dr. Benson has raised a valid question, that is, how may one be certain that the piece of endometrial surface at which he’s looking had been scraped firmly with a curettc prior to the removal of the uterus. I can only say that, in addition to the few examples I demonstrated today, I have reviewed hundreds of sections from the uteri in this study
Am
hlay 15, 1969 J. Ohst. & Gynec.
and can assure ~CJII they appeared to have /,ccn sampled thoroughly from top to bottom and side to side, judging from the curcttings and from descriptions of the gross specimens. On the other hand, it‘s obvious that intact iJitS of tbndometrium frequently remain in the corriual rccesses, but these arcas lverc carefully excluded from the sclt‘ction of samples usccl to show regenerative cff~2ts. Dr. Hoag mclltionctl the inter,*sting fact that none of the cndomctrial specimens sho\ved any inflammation st,veral days following curct tagc. Of the 31) specimens I have no’il’ esarnincd there was only one that sho\vctd inflammation; it \V~IS a day 4 spccimrsn, that is, removed 4 clay< aftt-r curettage, the latter having bern tlonc ill COW junction with ccr\?& conization, and for some reason this particular cndometrial surfa,.<, e’shihited a solid mass of infamnlatory ccllr. I reviewed tbc clinical record and found that nothing unusual had happened to this patic~~i. Regarding Dr. Kimball’s suggestion allou t the use of thr 1,iopsy curette to obtain serial specimens front the same uterus, I don’t think this would hc vclry applicable ICI ~hc s0r1 ot question I ~cas trying to answer, namely, \\hat is the d~~grcc of over-all regeneration, the mechanism of it, the speed with which it occurs. and so forth. I think for this information we’ll have to continue to rely on total hysterectomy specimens following curettage.