Manuscript
Postmenopausal bleeding (PMB) occurs in about 10% of postmenopausal
women. The evaluation and management of PMB is a common and important
part of many health care providers’ daily practice (1,
2). Approximately 10% of women with PMB will end up with cancer(3-5). Consequently, 90% will be the result of benign
etiologies. The challenge in the workup and management of PMB is
therefore to detect all cancer cases without subjecting these women to
unnecessary invasive procedures. Many benign conditions are associated
with PMB: Endometrial and endo-cervical polyps, proliferative
endometrium, cervicitis and endometritis. Atrophic endometrium (AE) has
always been considered a dominant cause of PMB, with ranges between 30
to 50% (6-8). In fact
in 2018, the ACOG committee opinion stated that ”Postmenopausal vaginal
bleeding usually is caused by atrophic changes of the vagina or
endometrium.” (3). While bleeding from atrophic
vaginitis is quite common and easily diagnosed on routine speculum
examination, we questioned the atrophic endometrium part of the
statement as a cause of PMB. As there was no reference to the statement,
we reviewed the literature and made an effort to verify the source of
this important assumption and the histo-pathological data to support the
statement. Atrophic endometrium is defined as an endometrial lining
deprived of the functionalis layer and consisting exclusively of a thin
endometrial basalis layer with a few narrow tubular glands lined by
cuboidal epithelium. On pathology it does not show proliferative
endometrium, secretory endometrium or mixed activity(9).
The suggestion of AE as a cause for PMB can be traced back to the
article of Te Linde in 1940 (10). This was a pivotal
paper which first proclaimed that ”malignancy is responsible for the PMB
until unequivocally proved otherwise”. In this article Te Linde also
wrote: ”Endometritis occurring after the menopause may be responsible
for bleeding from the atrophic uterine mucosa”. To support his theory,
Te Linde reported that a combination of pus and adhesions can cause PMB.
There is no pathological confirmation or references to support the
statements in the article. The publication was written in a different
era and this was prior to newer technology including hysteroscopy,
ultrasound and immuno-histochemistry. It was also a time in which
“expert opinion” was sufficient for a theory to thrive and become a
fact. The notion that cancer and AE cause PMB persists to this day.
While cancer being a cause for PMB is well documented and proven, the
proof for AE being a cause of PMB is lacking and in our opinion
potentially misleading.
Review of the literature shows that cancer as a cause for PMB has
decreased over the years from as high as 50% to 10% with a reciprocal
increase in the percentage of benign causes for the
PMB(7-12). Postmenopausal women have not changed much
over the years although there has been an increase in obesity(13), patient longevity (14) and
probably a lower threshold for the workup of PMB. The shift in PMB
etiology is probably secondary to the introduction of new technologies
which have improved our ability to make an accurate diagnosis in women
with PMB. For example, polyps were rarely documented in the older
literature and now are being diagnosed frequently (7,
15). The fact that many patients with PMB had a histological diagnosis
of AE was a potential source for the different theories(16-19): Chronic congestion of the uterus, blood
dyscrasias, atherosclerosis and vitamin deficiency. In 1971, Meyer et
al’ (20) suggested three pathways for AE as a cause of
PMB: Uterine prolapse, myometrial atherosclerosis, and rupture of
atrophic endometrial cysts. While the association of uterine prolapse
and vaginal atrophy are clinically recognized (21),
the other two hypotheses did not hold true over the years. The most
recent pathophysiology of ”atrophy-related endometritis” causing PMB was
published in a review article by Ferenczy in 2003(22).
In this manuscript, Ferenczy hypothesized that the hypo-estrogenic
milieu causes endometrial atrophy and the absence of endometrial fluid
causes friction. This results in micro-erosions of the surface
epithelium and chronic inflammation which are prone to light bleeding.
The manuscript is an excellent review article, but we failed to find any
original article to support the hypothesis of ”atrophy-related
endometritis” causing PMB.
We examined many prominent medical textbooks and physician guidelines
(including Novak gynecology and ACOG Committee Opinion) and they all
affirm that AE is an important cause of PMB(3, 23-28).
In fact, in Novac Gynecology, AE is suggested as the cause of PMB in
60-80% of PMB. Up-to-date, a popular internet medical information
provider, was the only source that presented a reference, the Ferenczy
article, to support the proposal that AE is a cause PMB(24). The above examples affirm how the notion of AE
as a cause of PMB which was suggested by Te Linde, continues to persist
in the literature and became a medical “fact”. We didn’t find any
original article with scientific evidence for AE being a cause of PMB.
In fact we believe that AE is simply an incidental finding in the workup
of women with PMB. AE is associated with PMB simply because the
endometrial cavity of most postmenopausal women is atrophic. However,
that does not necessarily mean that AE is the cause of the PMB. We are
making a case against AE as a cause for PMB in general and specifically
against AE as the cause of endometritis.
Our supporting evidence:
1) Endometritis is not necessarily associated with uterine bleeding.
Intrauterine contraceptive device (IUCD) is known to cause an
inflammatory reaction of the endometrium (29).
However, postmenopausal women with an IUD are mostly asymptomatic(30-31).
2) Endometritis or active bleeding is rarely seen during hysteroscopy
for PMB.
Endometritis is a condition that can be diagnosed on hysteroscopy
(characterized by the visualization of edema, hyperemia, inflammation
and exudate formation).(32-33). Multiple studies were
published on hysteroscopy in PMB, but endometritis is rarely present
visually or histologically.
3) AE is a common pathological finding in PMB, but it is rarely seen
with endometritis (7, 11, 12, 19, 20, 33, 34).
Meyer et al’ (20), who studied AE in PMB, specifically
stated ”No atrophic endometritis was noted” in any histological
specimens. In our recent study of women 50 years and older (75% had
PMB) (34), there was only one case of endometritis out
of 560 biopsies. It will be fair to ask: How come we diagnose AE so
frequently, but we fail to see the endometritis, which is the ”etiology”
for the bleeding. Finally, in the Blaustein’s classical pathology text,
AE is not considered as a cause of endometrits8.
4) The incidence of PMB actually decreases with increasing age.
As a woman ages, the residual function of the ovary and the estrogen
milieu is decreasing. We would expect the endometrium to become more and
more atrophic as she gets older. If AE is really a cause of PMB, we
would expect to see an increase in the incidence of PMB as women get
older. However, the literature conclusively shows that the incidence of
PMB decreases with increasing age (35-37).
5) AE is ubiquitous in postmenopausal women, still over 90% of these
women will not have PMB.
There are about half a billion postmenopausal women worldwide(38). All those postmenopausal women are estrogen
deprived and harbor AE, but they rarely have PMB. Importantly, in the
10% of women who do have PMB, we often find pathology to explain it.
6) Pathological studies show that AE is actually associated with
amenorrhea and not with bleeding.
Magos (39) studied different regimens of hormonal
replacement therapy. Absolute amenorrhea of the women was always
associated with AE on histological examination.
7) Focal endometrial lesions are a common cause of PMB.
Endometrial pathology can be diffuse or focal. “Blind” endometrial
biopsies or dilatation and curettage are notorious for missing many
focal lesions such as polyps (40-41). When the
aspiration catheter is blindly sampling the endometrium, we might miss
the focal cavitary lesions and sample the AE which covers the entire
endometrial cavity (illustrated in Figure 1 and Video S1). When we
perform an endometrial aspiration, and get a pathology report of ”normal
endocervical tissue” - we interpret the result as failure to sample the
endometrial cavity. We do not attribute the endocervical tissue to be
the cause of the PMB. We believe that we should use the same logic when
we get a histological report of AE.
In our opinion, the above data support our assumption that AE is not a
cause of PMB. Defining AE as a cause of PMB may be potentially harmful
for the following reasons:
1) Accepting the AE result might give false reassurance to the patient
and her provider, while missing the real cause for the bleeding, such as
a polyp (40-41, 43
2) The stakes are much higher in cases of the mis-diagnosis of cancer
which starts as a focal lesions surrounded by AE(42).
Type 2 endometrial carcinoma is not related to unopposed estrogenic
stimulation and often arises in AE(42). Uterine
sarcoma is another cancer which is often missed on endometrial biopsy
and is likely to show AE (44).
3) The notion that AE is the cause of PMB has allowed some health care
providers to ”treat” the AE with estrogens. The concept of treating AE
is present in textbooks and guidelines for physicians and patients(45-49). We could not find any study that examined the
safety or outcome of this management.
We suggest the following as explanations for the high prevalence of AE
in PMB:
1) Missed focal lesions cause PMB more often than previously known. With
the development of newer diagnostic technologies, the recent literature
suggests that the incidence of missed focal lesions is higher than
previously reported: Nan Hanegem et al’ assessed 98 women who underwent
hysteroscopy and found that 59.3% had an endometrial polyp. 51%
identified in the initial workup and additional 8.3% were found during
follow up evaluation (43).
2) The source of the PMB might not be uterine. Rectal, vulvo-vaginal and
urological bleeding might be misinterpreted by the elderly woman as PMB.
3) A surge of estrogen followed by a withdrawal bleeding. The presence
of estrogen activity in the endometrium of older woman has been
documented by us and others (7, 34).
To avoid the misdiagnosis of cancer in cases of PMB with AE histology,
we propose a simple management: Evaluate the endometrium with
transvaginal sonogram. If the endometrial echo is thin, it is very
unlikely to miss any significant pathology. However, if endometrial
thickening is found (as seen in image 1), AE is unlikely to be the
diagnosis and further workup is needed. This simple management may avoid
unnecessary invasive procedures with their associated morbidity, cost
and discomfort.
Acknowledgements - non applicable.
Disclosure of interests - non applicable.
Contribution to authorship
Ohad D. Rotenberg MD - Development of the concept idea, writing,
literature research.
Gary L. Goldberg, MD - Guidelines of clinical perspective, editing.
Details of ethics approval - non applicable.
Funding - non applicable.