Human Reproduction Update 1998, Vol. 4, No. 4 pp.
312–322  European Society for Human Reproduction and Embryology
Pathophysiology of adenomyosis
Alex Ferenczy
Department of Pathology, The Sir Mortimer B.Davis Jewish General Hospital, 3755 Côte Ste-Catherine Road, Montreal,
Quebec, Canada H3T 1E2
TABLE OF CONTENTS
Historical background and definition
Pathogenesis
Incidence/predisposing factors
Clinical features
Associated pathology
Adenomyosis and pregnancy
Diagnosis
Pathology
Treatment
References
Adenomyosis refers to endometrial glands and stroma
located haphazardly deep within the myometrium.
Similar histological alterations may be found in extra-
uterine locations such as the rectovaginal septum. The
aetiology and pathogenic mechanism(s) responsible
for adenomyosis are poorly understood. Both human
and experimental studies favour the theory of endo-
myometrial invagination of the endometrium, al-
though the de-novo development of adenomyosis from
Müllerian rests in an extrauterine location is a possi-
bility. The prerequisite for adenomyosis may be trig-
gered or facilitated by either a ‘weakness’ of the
smooth muscle tissue or an increased intrauterine
pressure or both. Relatively high oestrogen concentra-
tions and impaired immune-related growth control in
ectopic endometrium may be necessary for the main-
tenance of adenomyosis. Smooth muscle cell hyperpla-
sia and hypertrophy are a reflection of reactive change
secondary to ectopic endometrial proliferation.
Further studies are needed for insight into the precise
aetiology and pathogenesis of adenomyosis. Adeno-
myosis is a relatively frequent endomyometrial pa-
thology discovered in multiparous women between 40
and 50 years of age. About 2/3 of women are sympto-
matic with menorrhagia and dysmenorrhoea; 80% of
adenomyotic cases are associated with leiomyomata
1To whom correspondence should be addressed. Tel: (514) 340-7526; Fax: (514) 340-7542; E-mail: mdfe@musica.mcgill.ca
uteri; and in women with endometrial adenocarcino-
ma, adenomyosis is relatively often seen. Definite diag-
312 nosis is made on hysterectomy specimens, although
313 attempts are made at securing preoperative diagnosis
316 by magnetic resonance imaging and myometrial
316 biopsies. Definite treatment of symptomatic women is
317 hysterectomy.
317
317 Key words: adenomyosis/pathogenesis
318
320 Historical background and definition
321
It was Rokitansky (1860) who first alluded to the presence
of endometrial glands in the myometrium as ‘cystosarco-
ma adenoides uterinum’. In 1896, Von Recklinghausen
described the same phenomenon under the term ‘adeno-
myomata and cystadenomata of the uterus and tubal wall’.
Cullen (1908) distinguished between adenomyoma, an in-
tramyometrial tumour-like condition made of endometrial
glands and stroma, and diffuse adenomyoma, in which
both elements were distributed throughout the myome-
trium. The term ‘adenomyosis uteri’ was first used by
Frankl (1925). In 1972, Bird et al. defined adenomyosis as
‘the benign invasion of endometrium into the myome-
trium, producing a diffusely enlarged uterus which micro-
scopically exhibits ectopic, non-neoplastic, endometrial
glands and stroma surrounded by the hypertrophic and
hyperplastic myometrium’. This definition still prevails
today; however, we like to qualify it further as to the ‘pres-
ence of endometrial glands and stroma located haphazardly
and deep within the myometrium’. The issue of depth is
important because the normal endomyometrial junction is
often irregular, and adenomyosis must be distinguished
from minimally invaginated basalis surrounded by
myometrium (Figure 1). There are two ways to circumvene
this problem. The first is to determine whether there is
myometrial hypertrophy (‘collar’) around foci of adeno-
myosis. Such alteration is not seen at the endomyometrial
junction (Figure 2). The second is to measure the distance
between the endomyometrial junction and the closest ade-

Figure 1. Endomyometrial junction featuring basalis endometrium
invaginating into superficial myometrium. There is no evidence of
hypertrophy of the surrounding myometrium. Such findings should
not be considered as adenomyosis. Original magnification ×100.
nomyotic foci. This should be ~25% of the total thickness
of the myometrium. The latter approach is particularly rel-
evant in the postmenopausal and gravid uterus because
periadenomyotic muscular hypertrophy in these uteri is
generally absent (Hendrickson and Kempson, 1980). Al-
though many consider adenomyosis a variant of endome-
triosis, so-called internal endometriosis (Emge, 1956;
Israel and Woutersz, 1959), we like to define endometriosis
as endometrial glands and stroma located outside of the
myometrium, e.g. uterine serosa, posterior subperitoneal
surface of the corpus, etc.
Pathogenesis
The precise aetiology and the developmental events lead-
ing to adenomyosis are unknown. A number of theories
have been proposed in the past 50 years and these have
been reviewed in detail by Ridley (1968). Currently, the
most widely held opinion is that adenomyosis develops as a
result of down-growth and invagination of the basalis en-
dometrium into the myometrium. Indeed, one can often see
direct continuity between the basalis endometrium and the
underlying adenomyosis in the myometrium. In extrauter-
ine regions such as the rectovaginal septum, adenomyosis
Uterine and extra uterine adenomyosis 313
Figure 2. Deeply located endometrial glands and stroma surrounded
by hypertrophic myometrium. This is a focus of adenomyosis.
Original magnification ×100.
may develop de novo from embryologically misplaced
Müllerian remains.
The triggering mechanism of endometrial ‘invasion’ of
the myometrium in humans remains to be determined. Pro-
liferative changes such as mitotic activity, increased nu-
clear DNA synthesis and ciliogenesis are significantly
more pronounced in the functionalis than the basalis layer
of the endometrium (Ferenczy and Bergeron, 1991). The
biological rationale for the geographic variation in prolife-
rative indices may lie in the difference in physiological
functions of the functionalis compared to the basalis layer.
The former is the seat of blastocyst implantation, whereas
the latter provides the origin for the regenerative endome-
trium following menstrual degeneration of the functionalis
(Ferenczy, 1980). During periods of regeneration, epithe-
lial cells from the stump of basalis glands are in direct
contact with the spindle-shaped cells of the endometrial
stroma, and ultrastructurally contain intracellular microfi-
lamentous/trabecular systems and pseudopodial cyto-
plasmic projections. These features are consistent with
migration by amoeboid contraction and expansion (Fer-
enczy, 1980). Such morphological alterations have as yet
not been described in adenomyotic endometrial glandular
epithelium. Nevertheless, in-vitro studies showed that en-
dometriotic cells have invasive potential and their invasion
index is similar to that of metastatic bladder cell lines
314 A.Ferenczy

(Gaetje et al., 1995). Such invasive potential may facilitate
extension of the basalis endometrium into the myome-
trium. In MCF-7 breast cancer cells, production of tenascin
is stimulated by the hormonally regulated epidermal
growth factors (EGF) (Chiquet-Ehrismann et al., 1989).
The fact that endometrial stromal fibroblasts produce ten-
ascin, a fibronectin inhibitor which in turn facilitates epi-
thelial migration suggests a complex physico-chemical
interrelationship during the process of endometrial
ugrowth processes. Tenascin has been immunolocalized
around proliferative phase endometrial glands but not in
post-ovulatory phase endometrial glands (Vollmer et al.,
1990). It is possible that tenascin mediates epithelial–me-
senchymal interactions by inhibiting cell attachment to fi-
bronectin in adenomyotic type endometrium as it does in
its endometrial counterpart.
A recent study using in-situ hybridization and immuno-
histochemistry demonstrated that endometrial glands in
adenomyosis selectively express more human chorionic
gonadotrophin (HCG)/luteinizing hormone (LH) receptor
mRNA and immunoreactive receptor protein than the non-
invaginating glandular epithelium (Lei et al., 1993). In
normal endometrium, the glands fail to demonstrate geo-
graphic variation (as a function of their depth) in HCG/LH
receptor expression. It is thus possible although not proven
that the increased receptor expression of invaginating en-
dometrial epithelium may be related to the potential to
invaginate into the myometrium and form adenomyotic
foci. It is of interest that increased HCG/LH receptor ex-
pression was found in endometrial carcinomas compared
to normal endometrial glands (Lei et al., 1992) as well as in
invasive versus non-invasive trophoblasts in choriocarci-
nomas (Lin et al., 1994).
Earlier steroid receptor studies using cytosol prepara-
tions yielded inconsistent results; some found no proges-
terone receptors in 40% of the adenomyotic cases studied
(Tamaya et al., 1979), whereas others found higher proges-
terone than oestrogen receptor concentrations (van der
Walt et al., 1986). Using immunohistochemical tracing
techniques the author found relatively high concentrations
of both oestrogen and progesterone receptors in both the
basalis and adenomyotic endometrium (unpublished ob-
servations) (Table I). Oestrogen receptors are prerequisites
for oestrogen-mediated endometrial growth. Although
there is no clear-cut evidence of impaired hormonal envi-
ronment in most women with adenomyosis, hyperoes-
trogenaemia may play a role in the invagination process
since high frequency of endometrial hyperplasia is found in
women with adenomyosis. According to some researchers,
a relatively high oestrogen concentration is necessary for
the development and maintenance of adenomyosis as well
as endometriosis (Yamamoto et al., 1993). Supporting this
contention is the clinical observation that suppression of
oestrogenic environment by danazol induces involution of
the ectopic endometrium as well as the associated symp-
toms such as menorrhagia and dysmenorrhoea (Yamamoto
et al., 1993). Akin to uterine leiomyomata, oestrogen is
synthesized and secreted in adenomyotic tissues (Yama-
moto et al., 1993). These investigators demonstrated both
aromatase and oestrogen sulphatase activities by steroido-
biochemical analysis in the supernatant faction of myome-
trium containing foci of adenomyosis. Oestrogen
sulphatase and particularly aromatase activity was higher
(1 mg protein of tissue) than that observed in the normal
adjacent myometrium and leiomyomata and overlying en-
dometrium (P < 0.01–0.001). Moreover, endometrial
enzymatic activity was suppressed in vitro by up to 50%
after addition of 106 M danazol (Yamamoto et al., 1993).
Aromatase was also demonstrated by immunohistoche-
mistry in the cytoplasmic substance of gland lining cells
but not stromal cells in foci of adenomyosis in human uteri.

Table I. Immunohistochemical characteristics of uterine adenomyosis, endometriosis, basalis endometrium and leiomyoma

Antibodies Adenomyosis
Diffuse Focal Endometriosis Basalis Leiomyoma
(adenomyoma) endometrium
G S M G S M SE S G S
AE1/AE3 4+ – 1+ 2+ 2+ 1+ 4+ – 4+ – 1+
Vimentin 1+ 1+ – 1+ 1+ – 1+ 2+ 1+ 1+ –
ER 4+ 4+ 4+ 2+ 2+ 1+ 4+ 4+ 4+ 4+ 2+
PR 3+ 4+ 4+ 3+ 3+ 3+ 4+ 4+ 1 to 3+ 1 to 3+ 4+
(focal) (focal) (focal) (focal) (focal)
Actin – – 3+ – – 3+ – – – – 4+
Desmin – – 3+ – – 3+ – – – – 4+

AE1/AE3 = low and high molecular weight cytokeratin; ER/PR = oestrogen/progesterone receptor; G = glandular epithelium; S =
stromal cells; M = myometrium surrounding ectopic endometrium; SE = surface epithelium.

Oestrogen production by adenomyotic tissue is also sup-
ported by finding more women with high oestradiol con-
centration (≥30 pg/ml) in the menstrual blood in those with
adenomyosis than in those without adenomyosis and nor-
mal ovulatory cycles (Takahashi et al., 1989). The secre-
tory response of adenomyotic tissue to hormonal
stimulation is consistent with effective progestogenic in-
fluence on the ectopic endometrium. Progestogens en-
hance aromatase activity both in eutopic and adenomyotic
tissues (Urabe et al., 1989) contributing thereby to
oestrogen biosynthesis in adenomyotic foci.
It may be that bioavailability of sex steroids is not suffi-
cient alone to produce adenomyosis. It is possible that the
myometrium in cases of adenomyosis is either predisposed
to be invaded by the basalis endometrium, and that ‘benign
invasion’ of the endometrium occurs secondary to ‘weak-
ness’ of the myometrium, or that myometrial weakness is
caused by trauma, such as curettage, myomectomy and
Caesarean section. In this regard, adenomyosis can be pro-
duced in pregnant rabbits by curetting one horn and tube,
while retaining pregnancy in the opposite horn (Lewinski,
1931). It is possible, although not proven, that myometrial
invasion by the endometrial basalis is enhanced by in-
creased intrauterine pressure which, according to Cullen
(1908), could be produced by elevated concentrations of
circulating progesterone.
Increased expression of the major histocompatibility
complex class II antigen (HLA-DR) in the gland cells of
normal (eutopic) and ectopic endometrium (18 patients)
and adenomyosis (50 patients) was observed by immuno-
histochemistry (Ota and Igarashi, 1993). In addition, ma-
crophages in the myometrium of adenomyosis appear to be
increased; these may activate helper T cells and B cells to
produce antibodies. Autoantibodies against phospholipids
in endometriosis and adenomyosis as well as marked de-
position of immunoglobulin (Ig)S or complement compo-
nents have been observed (Weed and Arquembourg, 1980;
Kreiner et al., 1986). The precise significance of these
aberrant immune phenomena in adenomyosis or endome-
triosis is not understood at present.
Experiments in vitro showed that activated CD3+ T cells
in the endometrium and their secretory product
interferon-γ induce expression of HLA-DR immunoreac-
tivity in endometrial gland cells and inhibition of their
proliferation (Tabibzadeh et al., 1993). The closer the en-
dometrial cells are to activated T cells, the greater is their
growth-inhibition. It appears that lymphoid follicle-like
structures, mostly located in the endomyometrial junction,
are rich in activated T helper cells. Their location coincides
with maximal inhibition of endometrial growth observed
both morphologically (Ferenczy et al., 1979) and by prolif-
Uterine and extra uterine adenomyosis 315
eration marker studies (Tabibzadeh et al., 1993). Con-
versely, endometrial proliferation is at its maximum near
the endometrial surface far away from basalis-containing
lymphoid aggregates (Ferenczy et al., 1979; Tabibzadeh et
al., 1993). It is plausible, although not proven, that adeno-
myotic uteri are poor in activated T cells, thus the basalis
endometrium may have growth advantage over non-ade-
nomyotic, lymphoid-rich basalis endometria. Whether
such anomaly is necessarily associated with acquired
myometrial weakness or whether it is an independent pre-
requisite for the development of adenomyosis remains to
be determined.
The precise reason for myometrial hyperplasia/hyper-
trophy located around deep foci of endometrium is not
known but may indicate either an attempt at controlling
endometrial invagination of the myometrium or may sim-
ply represent smooth muscle bundles pushed aside by the
ingrowing endometrium. By immunohistochemistry, the
myometrium surrounding the ectopic endometrium,
whether diffuse (adenomyosis) or focal (adenomyoma),
contains no abnormalities. Indeed, smooth muscle cells in
adenomyotic foci, normal myometrium and leiomyomata
(coexistent or not with adenomyosis) are all rich in actin
and desmin (Table I).
There are several animal models for the study of pa-
thogenesis of adenomyosis. In one, intrauterine isografts of
anterior pituitary mice lead to the development of adeno-
myosis (Jeffcoate and Potter, 1934). Prolactin may amplify
this event, for the isograft-free horn contained compara-
tively less developed adenomyosis. Whereas ovariectomy
prevented, oestradiol benzoate stimulated, the develop-
ment of adenomyosis in this animal model. In another
model, mice treated prenatally with high doses of diethyls-
tilboestrol (DES) developed adenomyosis. It appears that
certain strains of mice are prone to develop adenomyosis in
response to high concentrations of prolactin, oestrogens
and progestogens. More recently, Ficicioglu et al. (1995)
induced adenomyosis in non-castrated rats with hyperpro-
lactinaemia. The authors suggested that high prolactin con-
centrations cause myometrial degeneration in the presence
of ovarian steroids which may result in myometrial weak-
ness and subsequent myometrial invasion by the endome-
trial basalis. Of interest were the observations of Mori and
Nagasawa (1983) in mice in which myometrial invasion by
stromal fibroblasts along the branches of blood vessels
preceded invagination of endometrial glands. In another
study, Sakamoto et al. (1992) induced a high rate of uterine
adenomyosis in mice by ectopic pituitary isografts. DNA-
synthesizing activities and related enzymes, i.e. thymidi-
late synthetase and thymidine kinase, were markedly
increased in adenomyosis compared to control uteri.
316 A.Ferenczy
In the same experimental animal model, the finding of
the small molecular weight matrix metalloproteinase was
suggested to play a role in the development of adenomyosis
at the level of gene transcription, activation and inhibition
(Mori et al., 1996). Certain experimental observations sug-
gested that some hereditary factors may be involved in the
pathogenesis of adenomyosis. For example, the uteri of
recombinant inbred SMXA mice develop spontaneously
histological changes similar to adenomyosis and contain
tenascin around adenomyotic glands (Kida, 1994). These
observations together with the biological property of tenas-
cin detailed earlier in this article are consistent with the
endometrial origin of adenomyosis and the intramyome-
trial invagination concept of a genetically predisposed
myometrium. Also, compared to SMXA mice, the uteri of
F1 mice, a strain between SMXA and NJL strains, contain
even more prominent spontaneous changes resembling
human adenomyosis. Whether heredity is an important fac-
tor in adenomyosis in the human remains to be determined.
The de-novo origin of adenomyosis from Müllerian re-
mains in extrauterine sites seems to be supported by the
observation of adenomyosis in the rectovaginal septum.
Endometrial glands and stroma associated with smooth
muscle cell hypertrophy may be found in this location
forming adenomyotic nodules (Nisolle and Donnez, 1997).
Although these nodules may develop as a result of invagi-
nating peritoneal endometriosis, the Müllerian remains ori-
gin is favoured by some. According to Nisolle and Donnez
(1997), in most cases adenomyotic nodules are located
deep in the septum and occasionally in the muscularis pro-
pria of the rectum far from the pelvic peritoneum. Coex-
pression of vimentin and cytokeratin in endometrium
whether lining the endometrial cavity or located within
adenomyotic foci is typical of Müllerian-derived tissue.
Morphologically and receptor content-wise, rectovaginal
adenomyosis is identical to its intramyometrial counter-
part, including poor or no response to postovulatory pro-
gestational stimuli. Despite large doses of exogenous
progestational agents given to women with rectovaginal
adenomyosis to produce secretory transformation, hor-
monal therapy is poor. Obtaining definite cure of recto-
vaginal lesion by surgery is suggestive also of a metaplastic
de-novo process from Müllerian remains in that location
rather than implantation/invagination of peritoneal en-
dometriosis.
Admittedly, there are many more questions than answers
with respect to the precise origin and pathogenic mechan-
ism(s) of adenomyosis. Experimental and human studies
are needed to shed light onto the pathophysiology of this
challenging condition of the female genital tract.
Incidence/predisposing factors
The frequency of adenomyosis reported in the literature
ranges from 5 to 70% (Azziz, 1989), and is largely depend-
ent on how thoroughly the uterus is sampled, the histologi-
cal criteria for making the diagnosis of adenomyosis and
the selection of specimens to be evaluated. The more sec-
tions taken from a given specimen, the higher the fre-
quency. For example, when three routine sections are
taken, 31% of hysterectomy specimens contained adeno-
myosis and at six sections the rate increased to 61% (Bird et
al., 1972). Using stringent diagnostic criteria, e.g. deeper
than 25% of myometrial thickness, yields lower adeno-
myotic rates than if more superficially located glands are
considered. Uteri removed because of symptoms contain
higher rates of adenomyosis than those without symptoms.
Even in the latter cases, the rates vary from 19% (Lee et al.,
1984) in hysterectomy specimens to 57% in uteri examined
at autopsy (Emge, 1962).
The vast majority of cases (80%) are reported in women
aged 40 and 50 years old (Bird et al., 1972) and are asso-
ciated with the most severe symptoms. The remainder of
cases are observed in women younger than 39 years with
relatively mild or no symptoms and in women older than 60
years of age (Benson and Sneeden, 1958).
Nearly all cases (90%) of adenomyotic uteri occur in
multiparous women (Lee et al., 1984); it is not clear
whether the condition is more prevalent in white than in
black women (Israel and Woutersz, 1959; Mathur et al.,
1962). Prior Caesarean section and obesity are not predis-
posing factors (Benson and Sneeden, 1958; Bird et al.,
1972; Harris et al., 1985).
Tamoxifen in treated postmenopausal women seems to
reactivate pre-existing adenomyosis, which leads to an in-
crease in myometrial volume and uterine size (Ugwumadu
et al., 1993; Cohen et al., 1995). Adenomyosis has been
reported in 60% of 14 postmenopausal women on chronic
tamoxifen therapy who eventually received hysterectomy
for unrelated indications (Cohen et al., 1995).
Clinical features
About 35% of adenomyotic cases are asymptomatic (Benson
and Sneeden, 1958); in the remaining cases, the most frequent
symptoms are menorrhagia (50%), dysmenorrhoea (30%)
and metrorrhagia (20%). Occasionally, dyspareunia may be
an additional complaint. The frequency and severity of
symptoms correlate with the extent (Benson and Sneeden,
1958) and depth (Nishida, 1991) of adenomyosis. The pre-
cise cause of menorrhagia in these patients is not known. It

may be due to poor contractibility of the adenomyotic
uterus and compression of the endometrium by submucous
adenomyomata or leiomyomata. Mefenamic acid adminis-
tration can reduce blood loss suggesting that prostaglan-
dins (F2α) may also play a role in the greater degree of
blood loss in women with adenomyosis (Azziz, 1989).
Other factors may be anovulation, hyperplasia and rarely
adenocarcinoma. Dysmenorrhoea is due to uterine irrita-
bility which in turn is secondary to increased amounts of
blood loss. Not all investigators have demonstrated adeno-
myosis-related symptoms. For example, in one study of
136 patients with histologically verified adenomyosis,
symptoms were variable, non-specific and according to the
investigators were related to the associated pathologies
such as leiomyomata, endometriosis, polyps, etc. rather
than adenomyosis (Nikkanen and Punnonen, 1980). In
another study carried out prospectively, there were no dif-
ferences in either the frequency or severity of dysmenorr-
hoea and pelvic pain between 28 women with adenomyosis
and 157 ‘controls’ (Kilkku et al., 1984). A study of 23
women with uterine adenomyosis found no qualitative dif-
ferences in the spontaneous mobility of isolated myome-
trial tissue throughout the menstrual cycle from normal
regenerative and leiomyomatous uteri (Martinez-Mir et
al., 1990). The mobility pattern was of low amplitude and
high frequency of spontaneous contractions during the pro-
liferative phase; both changes were amplified in the secre-
tory phase. Histamine-produced myometrial contractions
were similar in all myometrial tissues investigated
(Martinez-Mir et al., 1990)
Associated pathology
Up to 80% of adenomyotic uteri contain associated
pathology. The most frequent one is leiomyomata (Azziz,
1989). Endometrial polyps (2.3%), hyperplasia without and
with atypia as well as adenocarcinoma appear more frequent
in patients with adenomyosis than in the general population
(Table II). In one study, 60% of uteri with endometrial
carcinoma contained coexistent adenomyosis compared to
39% in control uteri (Marcus, 1961). However, the presence
of adenomyosis has no adverse (negative) influence on the
prognosis of endometrial carcinoma (Marcus, 1961; Hall et
al., 1984). Pelvic endometriosis is observed only in 6–20%
of women with adenomyosis and in all likelihood the former
is unrelated to the latter.
Adenomyosis and pregnancy
Although adenomyosis occurs relatively frequently in
pregnancy [27 of 151 (17%) of Caesarean hysterectomy
Uterine and extra uterine adenomyosis 317
specimens] it is not a major cause of obstetric or surgical
complications. A review of 80 years of literature yielded
only 29 reports of complications, mainly uterine rupture
and perforation associated with adenomyosis (Azziz,
1986).
Table II. Associated pathology and adenomyosis
Disease %
Leiomyoma 35–55
Pelvic endometriosis 6–20
Salpingitis isthmica nodosa 1.4–19.8
Endometrial polyps 2.3
Endometrial hyperplasia 7.0
(types not specified)
Endometrial hyperplasia with atypia 3.5
Adenocarcinoma 1.4
Diagnosis
The clinical diagnosis of adenomyosis is only suggestive at
best (50%) (Hayata and Kawashima, 1987) and most often
is either not made (75%) (Owalabi and Strickler, 1977;
Azziz, 1989) or overdiagnosed (35%) (Lee et al., 1984).
Menorrhagia and dysmenorrhoea in a multiparous woman
in her late 40s/early 50s are suggestive but not diagnostic of
adenomyosis. The uterus may be diffusely enlarged (12
weeks of gestational size), soft and tender on palpation.
Hysterosalpingography for diagnosing adenomyosis is
not recommended because it misses 75% of the cases
(Marshak and Eliasoph, 1955) and is expensive. Similarly,
ultrasonography is of questionable diagnostic value. Ex-
perience with endovaginal ultrasonography seems to indi-
cate a better diagnostic accuracy than grey-scale
ultrasound with a sensitivity of 87%, a specificity of 98%, a
positive predictive value of 74% and a negative predictive
value of 99% (Fedele et al., 1992). Adenomyosis in tamox-
ifen-treated women appears as irregularly distributed
microcysts beneath the endometrium and in the myome-
trium masquerading as increased endometrial thickness on
transvaginal ultrasonography (Goldstein, 1994; Perrot
et al., 1994) and leads to undue anxiety and unnecessary
endometrial biopsies. The best radiological means so far is
magnetic resonance imaging (MRI) although experience is
limited. Low signal intensity myometrium surrounds nor-
mal, high-signal intensity endometrium. In other cases,
irregular cystic spaces in the myometrium give a honey-
comb-type appearance of adenomyosis. Blood CA125 de-
terminations have provided inconsistent results so far
(Takahashi et al., 1985; Halila et al., 1987) have little, if
318 A.Ferenczy
Figure 3. Diffuse adenomyosis of anterior wall of uterus. Note coarsely
trabeculated, diffusely hypertrophied myometrium stippled with foci of
ectopic endometrium. Original magnification ×4.
any, diagnostic value. More recently, myometrial biopsies
of the posterior uterine wall were performed using biopsy
needle (Bohlman et al., 1987) or resectoscope (McCaus-
land, 1992). The upper third posterior myometrial wall
biopsy without important bleeding revealed adenomyosis
in five of 45 women (11%) aged 40 years or younger who
were undergoing laparoscopy or laparotomy for miscel-
laneous reasons (Pasquinucci et al., 1991). Alternatively,
hysteroscopy-aided biopsy of the posterior uterine wall
with a 5 mm loop electrode in 50 women with normal
uterine cavity demonstrated adenomyosis in 66% of the
cases (McCausland, 1992). Others found very low sensi-
tivity of myometrial needle biopsy performed in 68 surgi-
cally removed uteri. The rates ranged between 8 and
18.7%; however, specificity was 100% (Popp et al., 1993).
In two studies, MRI predicted adenomyosis in eight of
eight patients (Mark et al., 1987) and in eight of 16 patients
(Marshak and Eliasoph, 1955) whose disease was con-
firmed by histology. The principal diagnostic means for
adenomyosis is histology of hysterectomy specimens.
Pathology
The characteristic gross appearance of adenomyosis is due
to myometrial hypertrophy surrounding endometrial mu-
Figure 4. Adenomyoma (focal adenomyosis) made of cystically di-
lated endometrial glands and hypertrophied smooth muscle. Typical
of adenomyoma, its margin is indistinct from the surrounding nor-
mal myometrium. Original magnification ×40.
cosa. When the whole myometrium or one of the myome-
trial walls is diffusely involved, the uterus is enlarged and
globular. On cross-section, the haphazardly distributed
hypertrophied muscular trabeculae surrounding foci of
adenomyosis are apparent (Figure 3). The latter may on
occasion contain brown-staining ‘old blood’ correspon-
ding to hemolysed blood and haemosiderin pigment de-
posits (Azziz, 1989). The focally involved uterus with
adenomyosis resembles a leiomyoma; the term adenomyo-
ma is applied to this rather frequent presentation of adeno-
myosis (Figure 4). Since the process is not neoplastic, the
term focal adenomyosis is preferred by Hendrickson and
Kempson (1980). Since adenomyoma is often confused
clinically with leiomyoma, a benign but neoplastic condi-
tion, we believe that the use of the term adenomyoma is
acceptable. Typically, adenomyoma has poorly defined
margins because they merge with the surrounding normal
myometrium (Figure 5). In contrast, leiomyomata com-
press the surrounding myometrium and have clear-cut,
well-circumscribed margins (Figures 6 and 7). The latter
can be enucleated, whereas the former cannot.
Over the years, the author accumulated experience with
a relatively large number of cases of adenomyosis (n = 50),
endometriosis (n = 50) (unpublished data) and normal en-
dometrium (n = 200) (Bergeron et al., 1988a,b; Ferenczy

Figure 5. Detail of poorly defined margin of adenomyoma. Unlike
ordinary leiomyomata, such a lesion cannot be enucleated. Magnifi-
cation: ×400.
Figure 6. Leiomyomata uteri with well-circumscribed margins contrast
with adenomyoma shown in Figure 5. Original magnification ×4.
Uterine and extra uterine adenomyosis 319
and Bergeron, 1991; Ferenczy, 1994) in both ovulating and
postmenopausal women.
Histologically and by immunohistochemistry, both the
endometrial glands and stroma in foci of adenomyosis re-
semble the basalis endometrium (Figures 8 and 9 and Table
I). It seldom responds to hormonal stimuli, a phenomenon
which explains at least partly why one sees only oc-
casionally haemorrhagic or reparative morphological ev-
ents in foci of adenomyosis. The reason for an increased
tendency for focal haemorrhage in deeply located adeno-
myotic foci is not understood (Sandberg and Cohn, 1962).
In contrast, ectopic endometrium in foci of endometriosis
often undergo cyclic changes including degeneration,
bleeding and regeneration in all respects similar to the
functionalis layer of the endometrium. The different fre-
quency in menstrual-type changes between the two en-
dometria are likely due to the relatively poor
vascularization of the basalis-type adenomyotic endome-
trium compared to the richly vascularized functionalis-
type endometrium in endometriosis. However,
adenomyotic endometrium seems to retain its proliferative
potential, to be the seat of endometrial growth and to be
responsible for failure of providing amenorrhoea or hy-
pomenorrhoea following endometrial ablation (Haber and
Ferenczy, 1993). Secretory transformation including stro-
mal decidualization in foci of adenomyosis is seen mainly
Figure 7. Histology of sharply defined margin of ordinary leiomyo-
ma. Original magnification ×100.
320 A.Ferenczy

during gestation and exogenous progestational therapy, the

changes being mediated by oestrogen and progesterone
receptors (Table I). Progestational effect in non-gravid
uterus occurs between 30 and 50% of adenomyotic foci
(Mathur et al., 1962; Molitor, 1971). During intrauterine
pregnancy, 57% of the articles reviewed by Azziz (1986)
described decidualization. Others observed decidualiz-
ation during pregnancy only in deeply located foci (at
depth of two low power fields), whereas decidualization
was absent or inconspicuous in foci located less than two
low power fields from the basalis–myometrium junction
(Sandberg and Cohn, 1962). Also, it is not unusual to find
hyperplastic changes with or without atypia in adenomyo-
sis associated with similar conditions in the overlying en-
dometrium. Hyperplasia in adenomyotic foci may contain
metaplastic changes of the glandular epithelium such as
tubal metaplasia, squamous metaplasia (squamous mo-
rules) and mucinous metaplasia. Adenocarcinoma may
also involve foci of adenomyosis. When carcinoma is
limited to adenomyotic foci, it should be considered
intramucosal since it does not make the prognosis worse
Figure 8. Foci of adenomyosis surrounded by hypertrophied smooth
than the carcinoma for which the patient has had surgery.
muscle. Original magnification ×400.
Whether adenocarcinomas located in both the overlying
endometrium and foci of adenomyosis represent simulta-
neous primaries or extension of the former in adenomyotic
foci is not possible to determine by histology. The latter
hypothesis is preferable because adenocarcinoma in foci of
adenomyosis without surface component is an extremely
rare event (Colman and Rosenthal, 1959; Winkelman and
Robinson, 1966).

Treatment

Suppressive hormonal therapies using oral contraceptives

and progestational agents are of no value. GnRH agonist is
given for 6 months to relieve symptoms (dysmenorrhoea
and menorrhagia) and decreases uterine volume; however,
the symptoms reappear after discontinuation of leuprolide
acetate therapy (Grow and Filer, 1991). Some women with
superficial adenomyosis (<1 mm myometrial involve-
ment) may theoretically benefit from hysteroscopic resec-
tion (McCausland, 1992). It remains to be seen whether all
adenomyotic foci can be removed from these patients using
this technique; if not, residual adenomyosis-related symp-
toms and signs will remain. Admittedly, the definitive Figure 9. Detailed view of inactive, basalis-type endometrial glands
therapeutic technique is hysterectomy. and stroma in focus of adenomyosis. Original magnification ×200.

References
Azziz, R. (1986) Adenomyosis in pregnancy. A review. J. Reprod. Med.,
31, 224–227.
Azziz, R. (1989) Adenomyosis: current perspectives. Obstet. Gynecol.
Clin. North Am., 16, 221–235.
Benson, R.C. and Sneeden, V.D. (1958) Adenomyosis: a reappraisal of
symptomatology. Am. J. Obstet. Gynecol., 76, 1044–1061.
Bergeron, C., Ferenczy, A., Toft, D.O. et al. (1988a) Immunocytochemical
study of progesterone receptors in hyperplastic and neoplastic
endometrial tissues. Cancer Res., 48, 6132–6136.
Bergeron, C., Ferenczy, A., Toft, D.O. et al. (1988b) Immunocytochemical
study of progesterone receptors in the human endometrium during the
menstrual cycle. Lab. Invest., 59, 862–869.
Bird, C.C., McElin, T.W. and Manalo-Estrella, P. (1972) The elusive
adenomyosis of the uterus. Am. J. Obstet. Gynecol., 112, 583–593.
Bohlman, M.E., Ensor, R.E. and Sanders, R.C. (1987) Sonographic
findings in adenomyosis of the uterus. Am. J. Roentgenol., 148,
765–766.
Chiquet-Ehrismann, R., Kalla, P. and Pearson, C.A. (1989) Participation of
tenascin and TGF-beta in reciprocal epithelial-mesenchymal
interactions of MCF7 cells and fibroblasts. Cancer Res., 49,
4322–4325.
Cohen, I. Beyth, Y., Tepper, R. et al. (1995) Adenomyosis in
postmenopausal breast cancer patients treated with tamoxifen: a new
entity? Gynecol. Oncol., 58, 86–91.
Colman, H.I. and Rosenthal, A.H. (1959) Carcinoma developing in areas
of adenomyosis. Obstet. Gynecol., 14, 341–348.
Cullen, T.S. (1908) Adenomyoma of the Uterus. W.B.Saunders,
Philadelphia.
Emge, L.A. (1956) Problems in the diagnosis of adenomyosis uteri. West J.
Surg., 64, 291–305.
Emge, L.A. (1962) The elusive adenomyosis of the uterus. Am. J. Obstet.
Gynecol., 83, 1541–1563.
Fedele, L., Bianchi, S. Dorta, M. et al. (1992) Transvaginal
ultrasonography in the differential diagnosis of adenomyoma versus
leiomyoma. Am. J. Obstet. Gynecol., 167, 603–606.
Ferenczy, A. (1980) Regeneration of the human endometrium. In Fenoglio,
C.M. and Wolff, M. (eds), Progress in Surgical Pathology. Masson,
New York, Vol. 1, pp. 157–173.
Ferenczy, A. (1994) Anatomy and histology of the uterine corpus. In
Kurman, R.J. (ed.), Blaustein’s Pathology of the Female Genital Tract.
Springer-Verlag, New York, pp. 229–277.
Ferenczy, A. and Bergeron, C. (1991) Histology of the human
endometrium: from birth to senescence. In Bulletti, C. and Gurpide E.
(eds), The Primate Endometrium. Ann. NY Acad. Sci., 622, 6–27.
Ferenczy, A., Bertrand, G. and Gelfand, M.M. (1979) Proliferation kinetics
of human endometrium during the normal menstrual cycle. Am. J.
Obstet. Gynecol., 133, 859–867.
Ficicioglu, C., Tekin, H.I., Arioglu, P.F. et al. (1995) A murine model of
adenomyosis: the effects of hyperprolactinemia induced by fluoxetine
hydrochloride, a selective serotonin reuptake inhibitor, on
adenomyosis induction in Wistar albino rats. Acta Eur. Fertil., 26,
75–79.
Frankl, O. (1925) Adenomyosis uteri. Am. J. Obstet. Gynecol., 10,
680–684.
Gaetje, R., Kotzian, S., Hermann, G. et al. (1995) Invasiveness of
endometriotic cells in vitro. Lancet, 346, 1463–1464.
Goldstein, S.R. (1994) Unusual ultrasonographic appearance of the uterus
in patients receiving tamoxifen. Am. J. Obstet. Gynecol., 170,
447–451.
Grow, D.R. and Filer, R.B. (1991) Treatment of adenomyosis with
long-term GnRH analogues: a case report. Obstet. Gynecol., 78,
538–539.
Haber, G. and Ferenczy, A. (1993) Electrosurgical solutions to
gynecological problems. Contemp. Obstet. Gynecol. (Canada),
November/December, 25–36.
Halila, H., Suikkari, A.M. and Seppala, M. (1987) The effects of
hysterectomy on serum CA-125 levels in patients with adenomyosis
and uterine fibroids. Hum. Reprod., 2, 265–266.
Uterine and extra uterine adenomyosis 321
Hall, J.B., Young, R.H. and Nelson, J.H. Jr (1984) The prognostic
significance of adenomyosis in endometrial carcinoma. Gynecol.
Oncol., 17, 32–40.
Harris, W.J., Daniell, J.F. and Baxter, J.W. (1985) Prior cesarean section: a
risk factor for adenomyosis? J. Reprod. Med., 30, 173–175.
Hayata, T. and Kawashima, Y. (1987) Clinicopathologic study of eight
cases of uterine body cancers associated with endometriosis interna
(uterine adenomyosis). Am. J. Obstet. Gynecol., 156, 663–666.
Hendrickson, M.R. and Kempson, R.L. (1980) Non-neoplastic conditions
of the myometrium and uterine serosa. Surgical Pathology of the
Uterine Corpus. W.B.Saunders, Philadelphia, pp. 452–467.
Israel, S.L. and Woutersz, T.B. (1959) Adenomyosis: a neglected
diagnosis. Obstet. Gynecol., 14, 168–173.
Jeffcoate, T.N.A. and Potter, A.L. (1934) Endometriosis as a
manifestationof ovarian dysfunction. J. Obstet. Gynecol. Br. Cmwlth,
41, 684–707.
Kida, H. (1994) Histological analysis of spontaneous adenomyosis-like
changes in recombinant inbred mouse uterus (SMXZ mouse) – a novel
animal model for adenomyosis. Acta Obstet. Gynecol. Jpn, 46,
323–330.
Kilkku, P., Erkolla, R. and Gronroos, M. (1984) Nonspecificity of
symptoms related to adenomyosis: A prospective comparative survey.
Acta Obstet. Gynecol. Scand., 62, 229–231.
Kreiner, D., Fromowitz, F.B., Richardson, D.A. et al. (1986) Endometrial
immunofluorescence associated with endometriosis and pelvic
inflammatory disease. Fertil. Steril., 46, 243–246.
Lee, N.C., Dicker, R.C., Rubin, G.L. et al. (1984) Confirmation of the
preoperative diagnoses for hysterectomy. Am. J. Obstet. Gynecol.,
150, 283–287.
Lei, Z.M., Reshef, E. and Rao C.V. (1992) The expression of human
chorionic gonadotropin/luteinizing hormone receptors in human
endometrial and myometrial blood vessels. J. Clin. Endocrinol.
Metab., 75, 651–659.
Lin, J., Lei, Z.M., Lojun, S. et al. (1994) Increased expression of
luteinizing hormone/human chorionic gonadotrophin receptor gene in
human endometrial carcinomas. J. Clin. Endocrinol. Metab, 79,
1483–1491.
Lei, M., Rao, C.V., Lincoln, S.R. et al. (1993) Increased expression of
human chorionic gonadotropin/human leuteinizing hormone
receptors in adenomyosis. J. Clin. Endocrinol. Metab., 76, 763–768.
Lewinski, H. (1931) Beitrag zur frage der adenomyosis. Zentralbl.
Gynaekol., 55, 2163–2167.
Marcus, C.C. (1961) Relationship of adenomyosis uteri to endometrial
hyperplasia and endometrial carcinoma. Am. J. Obstet. Gynecol., 82,
408–416.
Mark, A.S., Hricak, H., Heinrichs, L.W. et al. (1987) Adenomyosis and
leiomyoma: differential diagnosis with MR imaging. Radiology, 163,
527–529.
Marshak, R.H. and Eliasoph, J. (1955) The roentgen findings in
adenomyosis. Radiology, 64, 846–851.
Mathur, B.B.I., Shah, R.S. and Bhende, Y.M. (1962) Adenomyosis uteri: a
pathologic study of 290 cases. Am. J. Obstet. Gynecol., 84,
1820–1829.
Martinez-Mir, I., Estañ, L., Morales-Olivas, F.J. et al. (1990) Studies of the
spontaneous motility and the effect of histamine on isolated
myometrial strips of the nonpregnant human uterus: the influence of
various uterine abnormalities. Am. J. Obstet. Gynecol., 163, 189–195.
McCausland, A.M. (1992) Hysteroscopic myometrial biopsy: its use in
diagnosing adenomyosis and its clinical application. Am. J. Obstet.
Gynecol., 166, 1619–1626.
Molitor, J.J. (1971) Adenomyosis: A clinical and pathologic appraisal. Am.
J. Obstet. Gynecol., 110, 275–284.
Mori, T. and Nagasawa, H. (1983) Mechanisms of development of
prolactin-induced adenomyosis in mice. Acta Anat., 116, 46–54.
Mori, S., Fujii, M. and Kudo, R. (1996) Expression of the small molecular
weight matrix metalloproteinase in ademyosis of the mouse uterus.
Acta Obstet. Gynecol. Jpn., 48, 386–392.
Nikkanen, V. and Punnonen, R. (1980) Clinical significance of
adenomyosis. Ann. Chir. Gynaecol., 69, 278–280.
322 A.Ferenczy
Nishida, M. (1991) Relationship between the onset of dysmenorrhea and
hsitologic findings in adenomyosis. Am. J. Obstet. Gynecol., 165,
229–231.
Nisolle, M. and Donnez, J. (1997) Peritoneal endometriosis, ovarian
endometriosis, and adenomyotic nodules of the rectovaginal septum
are three different entities. Fertil. Steril., 68, 585–596.
Ota, H. and Igarashi, S. (1993) Expression of major histocompatibility
complex class II antigen in endometriotic tissue in patients with
endometriosis and adenomyosis. Fertil. Steril., 60, 834–838.
Owolabi, T.O. and Strickler, R.C. (1977) Adenomyosis: a neglected
diagnosis. Obstet. Gynecol., 50, 424–427.
Pasquinucci, C., Pittino, R. Carcione, R. et al. (1991) Contributo allo
studio dell’adenomiosi: le biopsie transmiometriali. Ann. Ost. Gin.
Med. Perin., 112, 91–94.
Perrot, N., Guyot, B., Antoine, M. et al. (1994) The effects of tamoxifen on
the endometrium. Ultrasound Obstet. Gynecol., 4, 83–84.
Popp, L.W., Schwiedessen, J.P. and Gaetje, R. (1993) Myometrial biopsy
in the diagnosis of adenomyosis uteri. Am. J. Obstet. Gynecol., 169,
546–549.
Ridley, J.H. (1968) The histogenesis of endometriosis. A review of facts
and fancies. Obstet. Gynecol. Surv., 23, 1–35.
Rokitansky, K. (1860) Ueber uterusdruesen-neubildung. Z. Gesellschaft
Aerzte Wien, 16, 577–581.
Sakamoto, S., Mori, T., Singtripop, T. et al. (1992) Increase of DNA
synthesis in uterine adenomyosis in mice with ectopic pituitary
isograft. Acta Anat., 145, 162–166.
Sandberg, E.C. and Cohn, F. (1962) Adenomyosis in the gravid uterus at
term. Am. J. Obstet. Gynecol., 84, 1457–1465.
Tabibzadeh, S., Sun, X.Z., Kong, Q.F. et al. (1993) Induction of a polarized
micro-environment by human T cells and interferon-gamma in
three-dimensional spheroid cultures of human endometrial epithelial
cells. Hum. Reprod., 8, 182–192.
Takahashi, K., Kijima, S., Yoshino, K. et al. (1985) Differential diagnosis
between leiomyomata uteri and adenomyosis using CA-125 as a new
tumor marker of ovarian carcinoma. Acta Obstet. Gynaecol. Jpn., 37,
591–595.
Takahashi, K., Nagata, H. and Kitao, M. (1989) Clinical usefulness of
determination of estradiol level in the menstrual blood for patients
with endometriosis. Acta Obstet. Gynaecol. Jpn., 41, 1849–1850.
Tamaya, T., Motoyama, T., Ohono, Y. et al. (1979) Steroid receptor levels
and histology of endometriosis and adenomyosis. Fertil. Steril., 31,
396–400.
Ugwumadu, A.H.N., Bower, D. and Ho, P.K. (1993) Tamoxifen induced
adenomyosis and adenomyomatous endometrial polyp. Br. J. Obstet.
Gynaecol., 100, 386–388.
Urabe, M., Yamaamoto, T., Kitawaki, J. et al. (1989) Estrogen biosynthesis
in human uterine adenomyosis. Acta Endocrinol. (Copenh.), 121,
259–264.
van der Walt, L.A., Sanfilippo, J.S., Siegel, J.E. et al. (1986) Estrogen and
progestin receptors in human uterus: reference ranges of clinical
conditions. Clin. Physiol. Biochem., 4, 217–228.
Vollmer, G., Siegal, G.P., Chiquet-Ehrismann, R. et al. (1990) Tenascin
expression in the human endometrium and in endometrial
adenocarcinomas. Lab. Invest., 62, 725–730.
Von Recklinghausen, F. (1896) Die Adenomyomata und Cystadenomata
der Uterus und Tubenwandung: Ihre Abkunft von Resten des
Wolff ’schen Koerpers. August Hirschwald Verlag, Berlin.
Weed, J.C. and Arquembourg, P.C. (1980) Endometriosis: can it produce
an autoimmune response resulting in infertility? Clin. Obstet.
Gynecol., 23, 885–893.
Winkelman, J. and Robinson, R. (1966) Adenocarcinoma of endometrium
involving adenomyosis. Cancer, 19, 901–908.
Yamamoto, T., Noguchi, T., Tamura, T. et al. (1993) Evidence for estrogen
synthesis in adenomyotic tissue. Am. J. Obstet. Gynecol., 169,
734–738.
Received on January 27, 1998; accepted on June 30, 1998