The Diffusely Enlarged Uterus - American Journal of Clinical

T H E DIFFUSELY ENLARGED UTERUS*
K. M. TRUEMNER, M.D., AND D. H. KAUMP, M.D.
From the Departments of Pathology, Providence Hospital, and Wayne University College of
Medicine, Detroit, Michigan
CLINICAL SUMMARY
For purposes of comparison we divided our 52 patients with enlarged uteri
into a group of 24 with a history of abnormally increased menstruation and a
group of 28 without abnormally increased menstruation. These groups are
referred to as menorrhagic and non-menorrhagic in the balance of this paper.
In each group there was one nulliparous patient with an enlarged uterus.
In both groups of patients, the average age (menorrhagic, 41 years; nonmenorrhagic, 42 years) and the incidence of such clinical symptoms as leukorrhea,
low back pain, pelvic pain and menstrual irregularity were similar. In spite of
the history of increased menstrual flow in the menorrhagic group it is notable
that only 5 patients had blood hemoglobin values below 11.5 Gm. per 100 ml.
of blood (Sanford-Sheard, sodium carbonate method) at the time of their admission to the hospital. The number of deliveries ranged from none to 7 in
each group.
* Abridgement of thesis submitted by K. M. Truemncr to the Faculty of the Graduate
School of Wayne University College of Medicine in partial fulfillment of the requirements
for the degree of Master of Science in Pathology.
Received for publication, September 27,1948.
544
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During the past century the clinical picture of abdominal pain, menorrhagia,
and leukorrhea associated with the pathologic picture of a diffusely enlarged
uterus has been attributed, either primarily or in combination, to subinvolution, 16 ' 1 9 ' 2 3 inflammation with fibrosis of the myometrium, 15 ' 24 ' 25 primary
vascular changes,6• 9 •'° muscular hypertrophy, 8 '"• 2 7 and endocrine dysfunction.1' 4
This study is based on the examination of 64 nontumor-bearing uteri of which
52 were diffusely enlarged, 6 were atrophic, 1 was obtained at necropsy from a
pregnant woman at term, and 5 were normal uteri which served as controls.- We
regarded uteri as enlarged if their dimensions, exclusive of the cervix,27 exceeded
a length of 5 cm., a width of 4.4 cm., and a thickness of 2.2 cm. and if the maximum thickness of the myometrium exceeded 1.5 cm.
Both clinical and pathologic surveys were made. On each patient from whom
a uterus was obtained a detailed clinical abstract was prepared which contained
information as to the age, number of deliveries, menstrual history, gynecologic
complaints, pertinent physical and laboratory findings, and associated medical
or surgical lesions. The pathologic abstracts included gross observations as to
the size of the uterus, microscopic findings, and maceration-extraction studies of
the myometrial wall.
DIFFUSELY ENLARGED UTERUS
545
GROSS PATHOLOGIC SUMMARY
MICROSCOPIC STUDY
For histologic studies we used formalin-fixed sections of full thickness blocks
of the uterine wall and of associated structures, stained with hematoxylin-eosin,
Masson's trichrome and Weigert-van Gieson stains. In the microscopic sections
the endometrium was studied for evidences of inflammation and of endocrine
imbalance. Extravascular collections of leukocytes were considered to be
evidence of inflammation, and cystic change, glomerular forms, sub-basilar
glands and diphasic changes were considered as evidence of endocrine imbalance.
The submucosal, vascular, and subserosal myometrial areas were examined for
the amount, type, and distribution of connective tissue and its relation to muscle
fibers. The connective tissue was recorded as normal, slightly increased, or
significantly increased. The arteries, veins, and lymphatics in each myometrial
layer were similarly analyzed. The muscle was studied for evidence of mitotic
activity.
The microscopic findings are summarized in Table 1.
Twenty-seven of the diffusely enlarged uteri in this series had an essentially
normal histologic architecture (Fig. 1) and 25 had a significant degree of connective tissue increase. The increase in connective tissue was chiefly of a fibrillar
form and had a perivascular distribution with radiating strands between and
separating the muscle bundles. This increase in connective tissue assumed two
fairly distinct forms of distribution, a diffuse subserosal interstitial increase
(Fig. 2; 21 cases) and a diffuse increase noted in all three layers of the myometrium (4 cases). The subserosal connective tissue increase was found in
association with inflammatory lesions of the pelvic viscera or in those patients
with clinical evidence of prolapse. In those found in association with chronic
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On cut section the color of the myometrium varied from pale yellow to yellowish pink. The consistency was uniformly increased and firm and in occasional
cases the vascular channels were prominent but characteristically the myometrium was smooth throughout. Significant degrees of edema and fibrosis of
the outer third of the myometrium were present equally in both groups and were
usually in association with chronic pelvis inflammatory disease, retroversion and
prolapse.
In considering the size of the uterus and the myometrial thickness in relation
to the age of the patients from both groups, the diffusely enlarged uteri, as examined in the laboratory, were found almost entirely in women between the
ages of 35 and 50 years. This is the period during which the menopause is
reached. Nineteen of the 24 patients with menorrhagia and 18 of the 28 patients without menorrhagia were in this age group.
Small endometrial polyps were found in 2 cases of the menorrhagic group
but otherwise the endometrium was grossly similar in both groups. Cortical
ovarian retention cysts, cystic cervicitis, and evidence of chronic inflammation in
the fallopian tubes were found equally in both groups. Simple serous cystomas
of the ovary were found in two instances.
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TRUEMNER AND KAUMP
TABLE 1
MICROSCOPIC F I N D I N G S IN D I F F U S E E N L A R G E M E N T O F T H E U T E R U S
MICROSCOPIC FINDINGS
Endometrial alterations
Chronic inflammation
Subserosal connective tissue i n c r e a s e . . . .
Diffuse connective tissue increase
M a r k e d changes resulting from pregnancy
M i t o t i c forms
MENORRIIAGIC
GROUP ( 2 4 CASES)
NONMENORRHAGIC
GROUP ( 2 8 CASES)
11
0
8
1
2
0
7
0
13
3
4
0
Consequently, we feel that the term "chronic metritis" has little if any place
in the nomenclature or in the description of the diffusely enlarged uterus. "Fibrosis" of the uterus may be a term worthy of retention if it is used in the restricted sense of implying a process secondary to adnexal inflammation, to
stasic change, or to the aging process.
The changes resulting from parity were best demonstrated by the Weigertvan Gieson stains. These changes consisted of an increase in elastic tissue
masses separating the medial muscle fibers and lying between the media and
adventitia (Fig. 4). From occasional adventitial masses there were delicate
elastic strands extending into the adjacent interstitial tissue. There was also
medial collagen deposition with increased adventitial collagen paralleling the
elastic tissue changes. There was no definite correlation between the number of
pregnancies and the histologic residuals except that there was a general tendency
F I G . 1. F r o m a diffusely enlarged u t e r u s with normal connective tissue and muscle proportions in a 49 year old multipara. Average diameter of muscle fibers 5.94 microns.
Masson's stain. X 40.
F I G . 2. Severe subserosal fibrosis and stasis changes in a 38 year old parous woman
with chronic suppurative salpingo-oophoritis. Masson's stain. X 40.
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suppurative salpingo-oophoritis, there were organized fibrous exudates on the
uterine serosa but in no case was there evidence of extension of any inflammatory
process into the inner portions of the myometrial wall. In those with clinical
evidences of prolapse and retroversion there was microscopic evidence of venous
and lymphatic dilatation (Fig. 3). In many sections large masses of collagen
surrounded these vascular structures and extended out into the interstitial tissue
of the myometrium. In the 4 uteri with diffuse fibrosis this change was
prominent in the outer third of the myometrium but with no evidence of either
associated adnexal inflammation or of vascular stasis. Baker has pointed out
that in the uterus an increase in age is characterized by replacement of muscle
with connective tissue, beginning with the serosa and progressing centrally.
In rats the aging process of the uterus is characterized by progressive deposition
and condensation of connective tissue.5,28,29 We considered that in these cases
an early aging process had begun. This concept was further supported by our
own studies of senile uteri (6 cases) in which there was progressive fibrosis beginning in the subserosal zone.
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548
TRUEMNER AND KAUMP
FIG. 3. Venous and lymphatic dilatation with moderate fibrosis in a 42 year old multipara with severe retroversion of the uterus. Masson's stain. X 40.
FIG. 4. Classical residual changes of pregnancy. Patient was a 57 year old, para 7.
Myometrium 2.5 cm. in thickness. Weigert-van Gieson stain. X 40.
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for the most marked changes to occur in those women who had had most pregnancies. Venous and lymphatic dilatation was prominent in occasional sections
and suggested the possibility that mechanical stasis may be a factor in the
failure of normal resolution.
The changes induced by pregnancy apparently have little relationship to
menorrhagia when we consider that they were more severe and frequent in the
uteri from nonmenorrhagic than from menorrhagic women. We do believe that
subinvolution is a pathologic term worthy of retention when it is applied to those
uteri in which special elastic stains reveal a definite exaggeration of residual
changes of pregnancy, as described in the preceding paragraph.
In the group of 52 uteri there were 8 in which there was severe vascular medial
and adventitial collagen deposition and varying degrees of subintimal thickening.
These 8 uteri came from patients with severe retroversion (2 cases), cardiac decompensation (1 case), prolapse of the uterus (4 cases), and previous radium insertion (1 case). There was no difference in the character and distribution of the
vascular changes in the menorrhagic and in the nonmenorrhagic groups. In no
case was the bulk of the vascular structures increased sufficiently to produce an
increase in the size of the uterus. We can attribute little importance to vascular
changes as a primary factor to either increased size of the uterus or to the
tendency to menorrhagia.
Quantitative estimation of connective tissue in the uterine wall was obtained
by determination of weight before and after extraction with sodium hydroxide.26
The amount was expressed as per cent of residual weight and represents the per
cent of connective tissue in a given portion of myometrium. This was controlled by rehydration of the tissue and microscopic study to demonstrate the
absence of all muscle tissue. Duplicate determinations were made in sufficient
numbers from the same uterus to demonstrate close agreement.
Our series of connective tissue extractions is of interest because of the general
agreement with the gross and microscopic observations. The percentage of
connective tissue extracted in this series is listed in Table 2.
From our connective tissue extraction studies Ave found the higher percentages
of connective tissue present in those uteri in which the basic architecture was
altered by an increase in collagenous connective tissue either on the basis of
adnexal inflammation or stasis.
The size of muscle fibers was measured in the following manner on Massonstained sections: Using a fixed rigid mounting, the sections were projected with
an oil-immersion lens onto a 45 degree angle plane mirror and reflected to the
surface of smooth bond paper. The measurements were set up with a 100micron micrometer scale. For measurement we selected only cells roughly
circular or ovoid in cross sections and in which the nucleus was central. Fibers
so selected represent the widest possible area and should be more accurate than
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550
TRUEMNER AND KAUMP
the cross sectional measurements of longitudinal cells previously reported. '"
At least 20 fibers from three different locations were traced, two diameters of
each cell were measured, averaged and the cross-sectional areas expressed as
square microns.
The results of cross sectional measurements of the muscle fibers are presented
in Table 3.
In this study we found an increase in the average muscle fiber diameter of a
sufficient degree to cause an actual increase in the size of the uterus. We found
no hyperplasia or undue mitotic activity in our cases although mitoses have
been reported.11 The increase in muscle diameter was apparent, not only in
TABLE 2
CONNECTIVE T I S S U E EXTRACTION
CASE
MENORRHAGIC GROUP
CASE
NONMENORRHAGIC GROUP
1
2
3
4
5
10
8.3
6.9
6.1
5.8
1
2
3
8.7
6.5
6.2
TABLE 3
MUSCLE DIAMETERS
(In Microns)
GROUP
Normal
Menorrhagic
Nonmenorrhagic
CASES
RANGE
AVERAGE
PER CENT ABOVE
NORMAL*
5
19
26
5.38-6.07
4.94-6.14
5.30
5.82
5.62
0
22
14
* Percentage above normal is based on computed cross-sectional areas.
cases with normal histologic architecture but also in those uteri in which there
were varying degrees of fibrosis due to the secondary factors already described.
Simple myometrial hypertrophy has been defined as a condition found only
in nulliparous uteri. 7,14 I t is our opinion that this is not the case and that
parous uteri also may have myometrial hypertrophy during the menopausal
period. We do not believe that this is on a work basis as previously suggested,
is. i9,20,21 inasmuch as in our series no significant incidence of truly hyperplastic
endometrium was encountered. We believe that there is a moderate but
definite muscle-fiber hypertrophy as the primary underlying mechanism of
uterine enlargement in the menopausal and premenopausal uterus.
There is some evidence which may explain the muscle-cell hypertrophy. In
our studies of the endometrium, evidence of endocrine dysfunction was present
in 18 instances consisting of cystic change, glomerular forms, sub-basilar glands,
and diphasic changes.
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(In per cent as residual weight)
DIFFUSELY ENLARGED UTERUS
551
CONCLUSIONS
There are no apparent histologic changes in the diffusely enlarged uteri of our
group to suggest a primary, uterine factor for the menorrhagia of women at the
menopausal and premenopausal periods. We believe that the basic cause of
enlargement of the uterus is a diffuse hypertrophy of muscle fibers, which is
probably secondary to abnormal endocrinal stimulation. The connective
tissue increase is proportional to this hypertrophy and the histologic architectui'e
is essentially normal.
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I t is quite well established that the basis of menopausal symptoms lies in
either a qualitative or quantitative alteration, in estrogen-progestin balance
and in the estrogen-androgen ratio. That the uterus is a receptor organ of
endocrine metabolism was reported by Heller who found that estrone and
estrogenic substance was increased twenty times in potency by incubation with
minced uterine tissue. Spleen, heart and lung, and kidney to a lesser extent,
affected an increase in potency. Heller suggested that these organs caused an
enzymatic reduction of the estrone to the more potent estradiol. I t was also
demonstrated that liver tissue, unless inhibited by sodium cyanide, has the
ability to destroy and inactivate estradiol. In this connection it is of interest
that administration of vitamin B complex plus crude liver to women, postpartum will accelerate and enhance the process of uterine involution.3 In rats,
liver is able to inactivate estrone even after exclusion of the reticulo-endothelial
system, thus indicating that the liver cell itself must contain the inactivating
factor.30
In castrated female rats a definite uterine hypertrophy with an increase in
length and diameter of the uterine body and cornuae follows prolonged administration of subcutaneous estrone. In addition to simple muscular hypertrophy
there is actual hyperplasia of muscle cells.2
The uterine size progressively increases during sexual life until true atrophy
begins with the completion of the menopause. This phenomenon, unrelated
to parity, is attributed to the periodic estrogenic stimulation of the menstrual
cycle.17 Relative or actual excess of estrogen is suggested by the slight difference in the degree of uterine-fiber hypertrophy as demonstrated by the slightly
increased cross-sectional area of fibers in menorrhagic women.
It is our opinion that there is a basic progressive enlargement of the uterus
in the premenopausal and menopausal age which arises from an absolute or
relative excess of estrogen and which may be augmented and modified by such
factors as subinvolution, adnexal inflammation, and congestive and stasic
changes with the production of varying degrees of fibrosis. At the conclusion
of the menopause and at the time of withdrawal of excessive estrogenic stimulation, true senile atrophy begins with a replacement of muscle by collagen,
beginning in the subserosal zone. We feel that further strong support would be
lent to this concept if it were possible to demonstrate an abnormal estrogenandrogen ratio either quantitatively or qualitatively in women of this age group
with enlargement of the uterus. If this could be demonstrated our concept of
enlargement of the uterus would rest on a complete and firm foundation.
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TRUEMNER AND KAUMP
In certain instances this basic histologic pattern is altered by fibrosis and by
the changes of subinvolution. Special stains are frequently necessary to
identify the character of these alterations and should be used in the study of this
type of uterus.
We suggest the term "menopausal myometrial hypertrophy" for those uteri
that have an essentially normal histologic architecture but may be modified
by the changes of subinvolution, of stasis, of adjacent inflammation and of
aging.
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