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Journal of Steroid Biochemistry & Molecular Biology 83 (2003) 149155

Endometriosis: the pathophysiology as an estrogen-dependent disease

J. Kitawaki , N. Kado, H. Ishihara, H. Koshiba, Y. Kitaoka, H. Honjo
Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kamigyo-Ku, Kyoto 602-8566, Japan

Endometriosis, defined as the presence of endometrial glands and stroma outside of the uterine cavity, develops mostly in women of
reproductive age and regresses after menopause or ovariectomy, suggesting that the growth is estrogen-dependent. Indeed, the lesions
contain estrogen receptors (ER) as well as aromatase, an enzyme that catalyses the conversion of androgens to estrogens, suggesting that
local estrogen production may stimulate the growth of lesions. The expression patterns of ER and progesterone receptors in endometriotic
lesions are different from those in the eutopic endometrium. Moreover, estrogen metabolism, including the expression pattern of aromatase
and the regulation of 17-hydroxysteroid dehydrogenase type 2 (an enzyme responsible for the inactivation of estradiol to estrone), is altered
in the eutopic endometrium of women with endometriosis, adenomyosis, and/or leiomyomas compared to that in the eutopic endometrium
of women without disease. Immunostaining for P450arom in endometrial biopsy specimens diagnosed these diseases with sensitivity and
specificity of 91 and 100%, respectively. This is applicable to the clinical diagnosis of endometriosis. The polymorphisms in the ER-
gene, the CYP19 gene encoding aromatase, and several other genes are associated with the risk of endometriosis. Studies of these will lead
to better understandings of the etiology and pathophysiology of endometriosis.
2003 Elsevier Science Ltd. All rights reserved.
Keywords: Aromatase cytochrome P450; Endometriosis; Endometrium; 17-hydroxysteroid dehydrogenase; Steroid receptors

1. Background
Endometriosis is defined as the presence of endometrial
glands and stroma outside of the uterine cavity. Although
the exact prevalence is not clear, 510% of women of reproductive age are estimated to have endometriosis. Pains, including dysmenorrhea, deep dyspareunia and chronic pelvic
pains are associated with endometriosis, as well as infertility. It is pathohistologically a benign disease. However,
it is characterized by a malignant tumor-like nature in that
it grows, infiltrates and adheres to the surrounding tissues.
Although its exact etiology and pathogenesis are unclear,
two main theories for the pathogenesis have been proposed:
metastatic implantation after the reflux of endometrial cells
through the fallopian tubes [1], and metaplastic development
such as coelomic metaplasia [2].
Endometriosis is most prevalent in women of reproductive age and regresses after menopause. The occurrence of
endometriosis before menarche has not been reported. Considering the regression aspect of the lesions, ovariectomy is
Proceedings of the 15th International Symposium of the Journal of
Steroid Biochemistry and Molecular Biology, Recent Advances in Steroid
Biochemistry and Molecular Biology, Munich, Germany, 1720 May
Corresponding author. Tel.: +81-75-251-5560; fax: +81-75-212-1265.
E-mail address: (J. Kitawaki).

the most effective therapy among various surgical and endocrine therapies. Suppression of estrogen levels derived by
danazol or gonadotropin-releasing hormone agonists provide
the regression of the lesions. However, the recovery of estrogen levels after the discontinuation of the therapies causes
a relapse of the lesions. Endometriosis may relapse in postmenopausal women who have been treated with estrogen replacement therapy. These findings undoubtedly suggest that
endometriosis grows and regresses in an estrogen-dependent
fashion. In this study we focus on the pathophysiology of
endometriosis as an estrogen-dependent disease.
2. Steroid receptors
Breast cancer, endometrial cancer, endometriosis, adenomyosis and leiomyomas are diseases that grow in an
estrogen-dependent fashion. These tumors commonly contain estrogen receptors (ER), progesterone receptors (PR)
and androgen receptors. The expression patterns of steroid
receptors have been compared between endometriotic tissues and eutopic endometria. Electron microscopic analysis
has shown that one third of endometriotic implants are out of
phase with the menstrual cycle [3], and a light microscopic
study showed that only 13% of endometriotic implants were
synchronous with the corresponding eutopic endometria [4].
Studies of hormone-ligand binding assays and enzyme im-

0960-0760/03/$ see front matter 2003 Elsevier Science Ltd. All rights reserved.


J. Kitawaki et al. / Journal of Steroid Biochemistry & Molecular Biology 83 (2003) 149155

munoassays showed a consistent reduction in the content of

ER and PR in endometriotic implants [58]. Immunohistochemical studies have shown a reduced content of ER and
PR in endometriotic implants compared to that found in the
eutopic endometrium [911], while a study has shown an increased expression of ER in endometriotic implants [12]. Inconsistent findings have been reported on whether the steroid
receptors in endometriotic implants vary during the menstrual cycle. Howell et al. [13] showed heterogeneity in the
expression of steroid receptors between lesions of different
sites within the same patient. Nisolle et al. [14] showed that
the content of ER was comparable in red lesions but reduced
in black lesions, chocolate cysts and rectovaginal lesions.
They also noted that black and red lesions, but not chocolate cysts or rectovaginal lesions, showed a cyclic change in
ER, similar to eutopic endometria. In situ hybridization has
demonstrated the expression of ER- mRNA in endometriotic lesions [15].
A genetic study showed a reduced expression of exon 5
deleted splicing variant mRNA of ER- compared to that
in the eutopic endometrium [16]. While ER- contains domains AF, as does ER-, and binds at a similar affinity
to ligand estrogens, the tissue distributions of ER- and
ER- are different. Brandenberger et al. [17] estimated the
ER-:ER- mRNA ratio to be 15.5 and 5.2 in eutopic endometria and chocolate cysts, respectively. Matsuzaki et al.
[18] suggested a predominant expression of ER- in either
tissue, whereas Fujimoto et al. [19] showed a higher ratio
of ER-/ER- mRNA in chocolate cysts compared to that
in the eutopic endometrium.
Two PR isoforms, PR-A and PR-B, have been identified.
PR-A is a truncated form of PR-B that lacks the N-terminal
164 amino acids. These isoforms are produced from the
same gene and PR-A acts as a repressor of PR-B function.
Misao et al. [20] indicated a higher PR-B mRNA expression
in chocolate cysts, whereas Attia et al. [21] indicated the
absence of PR-B mRNA in endometriotic tissues.

3. Estrogen metabolism in endometriosis

Interestingly, estrogen-dependent diseases of the uterus,
including endometrial cancer [2224], endometriosis
[25,26], adenomyosis [27,28] and leiomyomas [29,30],
contain not only ER but also aromatase, an enzyme that catalyzes the conversion of androgens to estrogens, suggesting
that local estrogen production may increase the estrogen
concentration. Together with the circulating estrogen, this
stimulates the growth of tissue mediated by the ER. Because
of very low levels of aromatase activity and small tissue
volume, it had been difficult to detect aromatase activity in
endometriotic implants. Reverse transcription-polymerase
chain reactions enabled the detection of mRNA and the protein of aromatase cytochrome P450 (P450arom), the major
component of aromatase in such tissues [25,26] (Fig. 1).
Furthermore, immunohistochemistry showed that P450arom

Fig. 1. Reverse transcription-polymerase chain reaction-Southern blot analyses of aromatase cytochrome P450 (P450arom): (A) adenomyotic tissue
(AdT), endometriotic implant (EI), eutopic endometrium of woman without disease (N), and eutopic endometrium of woman with endometriosis
(EE); (B) endometrial biopsy specimens obtained from women with endometriosis (E), adenomyosis (Ad), leiomyomas (L) and free of disease

was exclusively localized in the cytoplasm of epithelial

glandular cells, but not in the stroma [26] (Fig. 2A). In
addition, endometriotic tissue contains 17-hydroxysteroid
dehydrogenase type 2 (17HSD2), an enzyme that converts
estrone (E1 ) to the more potent 17-estradiol (E2 ), whereas
they lack 17HSD type 1, an enzyme responsible for the
inactivation of E2 to E1 [31], raising the local estrogen
activity level (Fig. 3).

4. Estrogen metabolism in adenomyosis

Although adenomyosis is of a separate entity, P450arom
transcripts are also detected in adenomyotic tissue homogenates (Fig. 1) and the P450arom protein is immunolocalized in the glandular cells of adenomyotic tissues
(Fig. 2B) [26]. The aromatase activity in adenomyotic tissue homogenates is inhibited by the addition of a specific
monoclonal antibody to P450arom and some aromatase inhibitors, in a similar way to the response of the aromatase
activity in other human tissues [26]. This suggests that the
enzymatic property of aromatase in adenomyotic tissue is
similar to that found in other human tissues. Furthermore,
danazol, a testosterone derivative that is widely used in the
treatment of endometriosis, adenomyosis and leiomyomas,
provides regression of lesions as a secondary effect after
suppressing the hypothalamus-pituitary axis and providing
hypoestrogenic status. In addition to this mechanism, danazol directly inhibits multiple steroidogenetic enzyme activity
including cytochrome P450s and dehydrogenases. Danazol
inhibits the aromatase activity of the microsomal fraction of
the adenomyotic lesion dose-dependently at a minimal concentration of 108 M [26], less than the clinically available
concentration of 107 M. This suggests that danazol may

J. Kitawaki et al. / Journal of Steroid Biochemistry & Molecular Biology 83 (2003) 149155


Fig. 2. Immunohistochemical localization of aromatase cytochrome P450 in an endometriotic implant (A); adenomyotic tissue (B); eutopic endometrium
of woman with endometriosis (C), and eutopic endometrium of woman free of disease (D).

directly inhibit the growth of estrogen-dependent benign

uterine diseases.

5. Estrogen metabolism in the eutopic endometrium

There has been evidence that the eutopic endometria of patients with endometriosis is a source of estrogen production.

Fig. 3. Estrogen-dependent growth of endometriosis. Endometriotic tissue contains estrogen receptor as well as aromatase. The local estrogen
production may increase the estrogen concentration, which, together with
circulating estrogen, stimulates the growth of tissue mediated by the estrogen receptors.

Takahashi et al. [32] measured estradiol levels in peripheral

and menstrual blood of patients with endometriosis, adenomyosis, and women with normal menstrual cycles. They
found no significant differences in estradiol levels in peripheral blood, whereas in the menstrual blood, estradiol levels
were highest in women with adenomyosis, followed by the
patients with endometriosis, and lowest in the patients with
normal menstrual cycles, suggesting local estrogen production in the uterus with these diseases. RT-PCR-Southern blot
analyses have demonstrated that P450arom is expressed in
the eutopic endometria of patients with endometriosis, adenomyosis and/or leiomyomas (diseased endometrium) [26],
whereas P450arom transcripts are not detected in the eutopic endometria of women without any gynecological disease (Fig. 1) [26,33]. P450arom protein is immunolocalized
in the cytoplasm of glandular cells in diseased endometrium
[26] (Fig. 2C). Similarly, the P450arom protein is not detected in the disease-free endometria of the proliferative
(Fig. 2D) or secretory phase [26].
Interconversion of E2 and E1 occurs in the human eutopic
endometrium, where an oxidative reaction that inactivates
E2 to E1 by 17HSD2 is predominant. During the proliferative phase, the abundance of mRNA and the activity of
17HSD2 are comparable in both disease-free and diseased
endometria. However, during the secretory phase, while the
abundance of mRNA and the activity of 17HSD2 increased


J. Kitawaki et al. / Journal of Steroid Biochemistry & Molecular Biology 83 (2003) 149155

Fig. 4. Altered regulation of mRNA expression (A) and activity (B) of 17-hydroxysteroid dehydrogenase type 2, an enzyme responsible for the inactivation
of estradiol to estrone, in the endometrium of women with endometriosis, adenomyosis and leiomyomas (diseased) compared to the endometrium of
women free of disease (disease-free): P < 0.01 and P < 0.001 vs. the corresponding disease-free endometria in the secretory phase.

four- to six-fold in diseased endometria, the 17HSD2 remained unchanged in disease-free endometria. Kinetic studies showed that the Km is identical among the four groups
of endometria, suggesting that the elevation of 17HSD2
simply resulted from increased mRNA transcription (Fig. 4)
Taken together, although histologically eutopic endometria more or less resemble one another, the endometria of
diseased patients are remarkably different from the endometria of disease-free women in view of estrogen metabolism.
As a consequence, estrogen metabolism in the human endometrium should be re-evaluated (Fig. 5). In disease-free
endometria, during the secretory phase, the local E2 concentration may be higher than that in diseased endometria

because of the lower 17HSD2 activity, despite the fact that

the local E1 synthesized by aromatase is negligible. Progesterone is believed to weaken the local estrogen activity in the
endometrium by stimulating 17HSD2 activity. However,
this appears to be confined to diseased endometria but not to
disease-free endometria. The accumulation of information
on the distinction of pathologic endometria contributes to a
better understanding of estrogen-dependent diseases.

6. Application to a diagnostic test for endometriosis

The development of imaging diagnostic technologies,
including transvaginal ultrasound sonography and magnetic

Fig. 5. Altered estrogen metabolism in the eutopic endometrium of patients with endometriosis, adenomyosis and/or leiomyomas. In the normal
endometrium, aromatase is not present and 17-HSD2 is not induced during the secretory phase. 17-HSD2, 17-hydroxysteroid dehydrogenase type 2;
androstenedione (A); and progesterone (P).

J. Kitawaki et al. / Journal of Steroid Biochemistry & Molecular Biology 83 (2003) 149155
Table 1
Sensitivity, specificity, and positive and negative predictive values for
aromatase cytochrome P450 (P450arom) immunostaining in endometrial
biopsy specimens


P450arom positiveb
P450arom negativeb









Sensitivity = 91%; specificity = 100%; positive predictive value = 100%;

negative predictive value = 72%.
a Grouped category of endometriosis, adenomyosis, and leiomyomas.
b The cutoff value for the H-score was set at 20.

resonance imaging, have provided diagnostic tools for

diagnosing endometriosis. However, laparotomic or laparoscopic results are needed for conclusive diagnoses [35].
CA-125, a serological test, is useful for following the progression of endometriosis, but is limited in its use as an
initial diagnostic test because it is not sensitive enough to
diagnoses in the early stages of endometriosis [36]. The
development of an accurate and simpler diagnostic test for
endometriosis is necessary. The finding that P450arom is
expressed in diseased endometria but not in disease-free endometria [26] led us to evaluate the clinical utility of a test
that diagnoses the existence of endometriosis by detecting
P450arom in endometrial biopsy specimens. We collected
endometrial biopsy specimens from patients scheduled for
laparotomy or laparoscopy and immunostained the specimens for P450arom. The distribution and intensity of immunostaining was analyzed using a semiquantitative index
designated as the H-score (0300) [37]. Of 105 biopsied
specimens, the H-scores for P450arom in the endometria
obtained from patients with endometriosis, adenomyosis
and/or leiomyomas, varied widely. In contrast, all of the
H-scores for the 21 specimens from disease-free uteri were
below 20. The receiver-operating characteristic curve analysis showed a cutoff value of 20 with a sensitivity and
specificity of 91 and 100%, respectively (Table 1) [38]. This
technique may enable us to diagnose endometriosis more
easily and without laparoscopy or laparotomy when used
in combination with imaging diagnostic technologies, and
may be used as an initial screening at outpatient infertility


7. Endometriosis and estrogen-related gene

Although the exact etiology and pathogenesis is unclear,
both environmental and genetic factors have been implicated
in the disease. The role of genetic factors has been supported
by familial and twin studies [3941]. Recent genetic studies have revealed an association between the development
of endometriosis and the polymorphisms of several genes
[4249], including the genes related to estrogen metabolism
A single nucleotide polymorphism in intron 1 of the ER-
gene assessed by PvuII restriction fragment length polymorphism generates PP, Pp and pp genotypes. Among these
genotypes, the PP genotype has been reported to have a
higher bone mineral density than the Pp and pp genotypes
[50], suggesting that the local estrogenic action is more potent in those with PP genotypes than in those with Pp or
pp genotypes. The PP genotype is less frequently observed
in the endometriosis and adenomyosis/leiomyomas groups
compared to those in the disease-free group, suggesting that
the PvuII polymorphism of the ER- gene is associated
with the risk for endometriosis [44,45], adenomyosis, and
leiomyomas [45] (Table 2). However, these findings indicate
that women carrying the PP genotype who are estimated
to show more potent estrogenic activities, conversely have
a lower risk for estrogen-dependent uterine disease. Since
endometriotic implants and adenomyotic tissues express a
reduced amount of ER protein [1012], the aberrant expression of ER may be partly involved in the onset or growth of
estrogen-dependent benign uterine disease.
A 3-bp insertion (I)/deletion (D) polymorphism in intron
4 of the CYP19 gene encoding P450arom generates I/I,
I/D and D/D genotypes. Among these genotypes, the D/D
genotype is more frequently observed in the endometriosis
group compared to the control group, suggesting that the
3-bp I/D polymorphism of the CYP19 gene may be associated with the susceptibility of endometriosis [49] (Table 3).
While several studies failed to show an association between
the 3-bp I/D polymorphism and a risk of breast cancer,
Siegelmann-Danieli and Buetow [51] showed an increased
frequency of 3-bp I allele in patients with breast cancer
compared to controls. This again contradicts the findings in endometriosis. An aberrant transcription of CYP19

Table 2
Distribution of the PvuII genotypes of the ER- gene

PvuII genotypes (%)


Endometriosis (n = 109)
Adenomyosis and/or leiomyomas (n = 67)
Disease-free (n = 27)
Reference population (n = 179)







P-value vs. reference


P-value vs. disease-free

P = 0.022
P = 0.15
P = 0.016

P = 0.0005
P = 0.005

P = 0.016


J. Kitawaki et al. / Journal of Steroid Biochemistry & Molecular Biology 83 (2003) 149155

Table 3
The distribution of genotype and allele frequencies for the 3-bp insertion (I)/deletion (D) polymorphism of CYP19

CYP19: 3-bp I/D genotypes (%)



Endometriosis (n = 140)
With chocolate cysts (n = 103)
Without chocolate cysts (n = 37)
Re-AFS stage severe (n = 108)
Re-AFS stage light (n = 32)


Adenomyosis and/or leiomyomas (n = 67)

31 (46.3)

28 (41.8)

Control (n = 177)

86 (48.6)

80 (45.2)





P-value vs. controla


Pcb = 0.024
Pcb = 0.043
Puc = 0.041
Pcb = 0.035


8 (11.9)


11 (6.2)

P-values were evaluated by 2 test with 2 2 tables (I/I + I/D vs. D/D) in comparison with the group of control.
Pc = corrected P-values, Pc < 0.05 is considered significant.
c Pu = uncorrected P-values.

may be partly involved in the onset or growth of endometriosis.

It is unclear how the anonymous intronic polymorphisms influence their protein function. This remains to
be determined. Such genetic studies would lead to a better understanding of the etiology and pathophysiology of

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