Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 20, No. 4, pp. 493e502, 2006

doi:10.1016/j.bpobgyn.2006.01.010
available online at http://www.sciencedirect.com

4
Adenomyosis: the pathophysiology
of an oestrogen-dependent disease
Jo Kitawaki*

MD, PhD

Associate Professor
Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School
of Medical Science, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan

Adenomyosis uteri is a common gynaecological disorder that is characterized by the presence of

ectopic endometrial glands and stroma in the myometrium. Although adenomyosis and endometriosis are different diseases, both of them grow and regress in an oestrogen-dependent fashion.
Polymorphisms in the oestrogen receptor a gene are associated with a risk of adenomyosis.
Adenomyotic tissue contains steroid receptors as well as aromatase and sulphatase enzymes.
Together with the circulating oestrogen, locally produced oestrogens stimulate the growth of
tissue mediated by the oestrogen receptors. Oestrogen metabolism, including the expression
pattern of aromatase and the regulation of 17b-hydroxysteroid dehydrogenase type 2 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. In addition to the
conventional hormonal treatment with gonadotropin-releasing hormone agonists and danazol,
the use of steroid-releasing intrauterine devices may be applicable to clinics.
Key words: adenomyosis; aromatase; endometriosis; endometrium; oestrogen; genetic polymorphism; 17b-hydroxysteroid dehydrogenase; steroid receptors.

Adenomyosis uteri is a common gynaecological disorder that is characterized by the

presence of ectopic endometrial glands and stroma in the myometrium. The prevalence
of adenomyosis reported in the literature ranges from 5 to 70%,1 and largely varies in
relation to the number of tissue sections analysed. Bird et al2 found adenomyosis in 30e
60% of hysterectomy specimens. Adenomyosis is most prevalent in women of late reproductive age between 35 and 50 years. Nearly all cases (90%) of adenomyosis occur
in multiparous women,3 and it has been suggested that patients with adenomyosis have
a high incidence of early miscarriage.4,5 About 35% of adenomyotic cases are

* Tel.: 81-75-251-5560; Fax: 81-75-212-1265.

E-mail address: kitawaki@koto.kpu-m.ac.jp.
1521-6934/$ - see front matter 2006 Elsevier Ltd. All rights reserved.

494 J. Kitawaki

asymptomatic.1 Symptomatic patients with isolated adenomyosis complain

of menorrhagia (40e50%), dysmenorrhoea (15e30%) and metrorrhagia (10e12%).6
About 7% of patients with adenomyosis also have dyspareunia.7 The frequency and
severity of symptoms correlate with the extent5,6,8 and depth5,9 of adenomyosis.
ADENOMYOSIS AND ENDOMETRIOSIS
It has been well accepted that adenomyosis is a disease that differs from endometriosis. Nevertheless, the pathogeneses of the two diseases have several features in common. Thus, both diseases are most prevalent in women of reproductive age and
regress after menopause. Considering the regression aspect of the lesions, ovariectomy is the most effective therapy among various surgical and endocrine options,
but suppression of oestrogen levels by danazol or gonadotropin-releasing hormone
(GnRH) agonists causes regression of the lesions. However, the recovery of oestrogen
levels after the discontinuation of these therapies causes a relapse of the lesions. Thus,
both adenomyosis and endometriosis grow and regress in an oestrogen-dependent
fashion. Indeed, adenomyotic uteri frequently contain pathological features that usually
are associated with other oestrogen-dependent diseases. Adenomyosis is associated
with 69%10 and 79%11 cases of endometriosis, whereas pelvic endometriosis is
observed in only 6e20% of women with adenomyosis.1 Adenomyosis is associated
with 52%10 and 35e55%1 of leiomyomata, while leiomyoma is associated with 64%
of cases of adenomyosis.12 Endometrial polyps (2.3%), hyperplasia without and with
atypia as well as adenocarcinoma appear more frequently in patients with adenomyosis
than in the general population.1 Adenomatous hyperplasia coexists in 35% of adenomyosis cases.12 Adenomyosis is present in 33%10 and 38%12 of women with endometrial carcinoma. Marcus13 noted that 60% of uteri with endometrial carcinoma
contained coexisting adenomyosis compared to 39% of control uteri.
GENETIC INVOLVEMENT OF OESTROGEN-RELATED
GENE POLYMORPHISMS
Since adenomyosis is more common in parous women, mechanical events at parturition have been believed to be the main pathogenesis of adenomyosis. However, Israel
and Woutersz14 reported that pregnancy had never occurred in 20% of their adenomyosis cases. Adenomyosis is significantly associated with peritoneal endometriosis15
and in baboons with lifelong infertility.16 These findings do not necessarily support the
notion of acquired trauma of the uterus as a causative factor. As it is the case in most
chronic diseases, both genetic and environmental factors are implicated in the pathogenesis of adenomyosis. An earlier report by Emge10 and Arnold et al17 noted hereditary occurrences of adenomyosis. However, while extensive genetic studies have been
performed on endometriosis, only a limited number of studies have been performed
on adenomyosis.
Pandis et al18 identified the clonal chromosome abnormality of del [7] [q21.2q31.2]
in all of three specimens of adenomyosis tissue that they analysed. This abnormality is
also frequently seen in leiomyomata. Goumenou et al19 analysed 31 cases of adenomyosis and determined the incidence of loss of heterozygosity on 2p22.3-p16.1,
3p24.2-p22 and 9p21 chromosomal regions as 19.4%, 9.7% and 6.5%, respectively.
However, Wang et al20 failed to detect any chromosomal gain or loss in 25 cases of
adenomyosis using comparative genomic hybridization.

Pathophysiology of adenomyosis 495

Recent genetic studies have revealed an association between the development

of endometriosis and the polymorphisms of tens of genes,21 including the genes related
to sex steroid actions.22e26 A single nucleotide polymorphism in intron 1 of the ERa
gene assessed by PvuII restriction fragment length polymorphism generates PP, Pp
and pp genotypes. Kitawaki et al23 reported that the PP genotype is less frequently observed in women with endometriosis and women with adenomyosis and/or leiomyomata compared to those in the disease-free group. In the endometriosis group, there
is no difference in the distribution of PvuII genotypes due to complicating diseases (adenomyosis and/or leiomyomata) or severity of the clinical stages. Although the potential
role of the anonymous intronic polymorphisms in influencing the protein function of
ERa remains to be determined, it is known that the PP genotype is associated with
a higher bone mineral density than are the Pp and pp genotypes,27 suggesting that
the local oestrogenic action is more potent in women with PP genotypes. However,
women carrying the PP genotype who are estimated to show more potent oestrogenic
activities, conversely have a lower risk for oestrogen-dependent uterine disease.
Oehler et al28 have identified somatic ERa gene mutations in three of 55 specimens
of adenomyosis tissue using polymerase chain reaction (PCR)/single-strand conformation polymorphism analysis. The mutations are located in different receptor
domains, ERa(P129R) in the N-terminal domain, ERa(K231R) in the DNA-binding
domain, and ERa(M427I/L429M) in H7 of the C-terminal ligand-binding domain. Functional characterization revealed that two of the mutant ERa proteins display severely
impaired DNA-binding and transactivation properties secondary to an altered response
to oestrogens or changes in epidermal growth factor-mediated ligand-independent
activation. Both of these two studies23,28 suggest that the aberrant expression of ER
may be partly involved in the onset or growth of adenomyosis and endometriosis.
Kado et al24 analyzed a 3-base-pair insertion (I)/deletion (D) polymorphism in intron 4 of the CYP19 gene encoding P450arom and found that the D/D genotype is
more frequently observed in the endometriosis group compared to the control group.
However, there is no such relationship in the adenomyosis group.
STEROID RECEPTORS AND OESTROGEN METABOLISM
Breast cancer, endometrial cancer, endometriosis, adenomyosis and leiomyomas are
diseases that develop in an oestrogen-dependent fashion. These tumours commonly
contain oestrogen receptors (ER), progesterone receptors (PR) and androgen receptors. Tamaya et al29 studied hormoneeligand binding in adenomyosis. They found that
there was always ER in adenomyotic tissue, but in a reduced quantity when compared
with corresponding normal myometrium. PR was not always present, and when present there were fewer than in normal endometrium. Androgen receptors have also
been detected in adenomyotic tissue. Van der Walt et al30 found lower ER and slightly
higher PR levels. The reduced expression of steroid receptors is similar in endometriosis. Studies of hormoneeligand binding assays and enzyme immunoassays showed
a consistent reduction in the content of ER and PR in endometriotic implants.29,31e33
Immunohistochemical studies have shown reduced levels of ER and PR in endometriotic implants compared to those found in the eutopic endometrium.34e36
Oestrogen-dependent diseases of the uterus e including endometrial cancer,37e39
endometriosis,40,41 adenomyosis,42,43 and leiomyomata44,45 e contain not only ER but
also aromatase, an enzyme that catalyses the conversion of androgens to oestrogens,
suggesting that local oestrogen production may increase the oestrogen concentration.

496 J. Kitawaki

The main precursor androgen, D4-androstenedione, is converted by aromatase to

oestrone. The other source of oestrogen is oestrone-3-sulphate, the most abundant
oestrogen in plasma. Oestrone sulphatase, an enzyme that catalyses the conversion of
oestrone-3-sulphate to oestrone, is localized in adenomyotic tissue.43,46 Oestrone is further converted to more potent 17b-oestradiol, raising the local oestrogen activity level.
Together with the circulating oestrogen, this stimulates the growth of tissue mediated
by the ER (Figure 1). The mRNA of aromatase cytochrome P450 (P450arom), the major
component of aromatase, is expressed in adenomyotic tissue homogenates. The
P450arom protein is immunolocalized in the glandular cells of adenomyotic tissues
(Figure 2A).41
OESTROGEN METABOLISM IN THE EUTOPIC ENDOMETRIUM
Evidence has been presented showing that the eutopic endometria of patients with adenomyosis and endometriosis are a source of oestrogen production. Takahashi et al47
measured oestradiol levels in peripheral and menstrual blood of patients with endometriosis or adenomyosis and women with normal menstrual cycles. They found no
significant differences in oestradiol levels in peripheral blood, whereas in the menstrual
blood oestradiol levels were highest in women with adenomyosis, followed by the
patients with endometriosis, and lowest in the patients with normal menstrual cycles,
suggesting local oestrogen production in the uteri of patients with these diseases.
P450arom transcripts are expressed in the eutopic endometria of patients with endometriosis, adenomyosis and/or leiomyomas (diseased endometrium),41 whereas
P450arom transcripts are not detected in the eutopic endometria of women with no
gynaecological disease.41,48 P450arom protein is immunolocalized in the cytoplasm of
glandular cells in diseased endometrium (Figure 2D,E),41 but is not detected in the
disease-free endometria of the proliferative (Figure 2F) or secretory phases (Figure 2G).41
P450arom detection in endometrial biopsy specimens can be used at outpatient infertility clinics as an initial screening procedure for oestrogen-dependent disease.49
Interconversion of oestradiol and oestrone occurs in the human eutopic endometrium, where an oxidative reaction that inactivates oestradiol by conversion to

Figure 1. Oestrogen-dependent growth mechanism of adenomyosis. Tissue contains oestrogen receptors

as well as aromatase and sulphatase. The local oestrogen production may increase the oestrogen concentration which, together with circulating oestrogen, stimulates the growth of tissue mediated by the oestrogen
receptors. 17bHSD1, 17b-hydroxysteroid dehydrogenase type 1.

Pathophysiology of adenomyosis 497

Figure 2. Immunohistochemical localization of aromatase cytochrome P450 (A), oestrogen receptors (B)
and progesterone receptors (C) in adenomyotic tissue. Immunostaining for aromatase cytochrome P450
in eutopic endometrium of a woman with adenomyosis (D and E) and eutopic endometrium of a woman
free of disease (F and G) obtained during the proliferative (D and F) and secretory (E and G) phases of
the menstrual cycle. Original magnification
100. Bar 30 mm. Modified from Kitawaki et al (1997, Biology
of Reproduction 57: 514e519) and Kitawaki et al (1999 Fertility and Sterility 72: 1100e1106) with permission.

oestrone by 17b-hydroxysteroid dehydrogenase type 2 (17bHSD2) is predominant.

During the proliferative phase, the abundance of mRNA and the activity of
17bHSD2 are comparable in both disease-free and diseased endometria. However,
during the secretory phase, while the abundance of mRNA and the activity of
17bHSD2 increased four-fold to six-fold in diseased endometria, the 17bHSD2 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
17bHSD2 simply resulted from increased mRNA transcription.50
Taken together, although eutopic endometria more or less resemble one another
histologically, the endometria of diseased patients are remarkably different from the
endometria of disease-free women with regard to oestrogen metabolism (Figure 3).51
HORMONAL TREATMENT
Hormonal treatment is one of the conservative options providing symptomatic relief.
GnRH agonists and danazol have been widely used for the treatment of adenomyosis.

498 J. Kitawaki

Proliferative phase
AD

Secretory phase
AD

Normal
endometrium
17HSD2
E1

17HSD2
E2

AD
Endometrium
with estrogendependent
disease

Aromatase
17HSD2
E1
E2

E1

E2

AD
Aromatase
17HSD2
E2
E1

P4

Figure 3. Altered oestrogen metabolism in the eutopic endometrium of patients with endometriosis,
adenomyosis and/or leiomyomas. In the normal endometrium, aromatase is not present and 17bHSD2
is not induced during the secretory phase. 17bHSD2, 17b-hydroxysteroid dehydrogenase type 2; AD,
D4-androstenedione; P4, progesterone.

Although they have been successful in the treatment of endometriosis and leiomyomata, their success rate in the treatment of adenomyosis is less well established.
GnRH agonists provide regression of lesions as a secondary effect after suppressing
the hypothalamusepituitary axis and providing a hypo-oestrogenic status. Successful
pregnancies following treatment with GnRH agonists for infertile women with adenomyosis have been reported.52e54 Danazol, a testosterone derivative, provides regression of lesions by its direct action in addition to any secondary effect of providing
a hypo-oestrogenic status after central suppression. Ishihara et al55 demonstrated
that P450arom expression was diminished in the eutopic endometrium of women
with endometriosis, adenomyosis, or leiomyomata treated with GnRH agonists or danazol. The expression of P450arom in a culture of endometrial explants treated with
a GnRH agonist did not change, whereas danazol reduced P450arom expression. The
authors conclude that endocrine therapy partly normalizes the impaired hormonal expression of the eutopic endometrium. GnRH agonists reduce P450arom expression
mainly by promoting a hypo-oestrogenic state, whereas danazol reduces P450arom
in part by direct action on the eutopic endometrium.
No evidence has been reported showing that continuous oral intake of contraceptive pills causes regression of adenomyosis. In contrast, Fedele et al56 treated 25
women with recurrent menorrhagia associated with adenomyosis using a synthetic
progestogen levonorgestrel-releasing intrauterine device. After 12 months of treatment, all of 15 patients with menorrhagia attained remission and 16 patients attained
regular menstrual flows. Anaemia was significantly improved and endometrial thickness was significantly decreased, while the uterine volume decreased slightly. However,
18 patients had irregular bleeding during the first 3 months of use. The levonorgestrelreleasing intrauterine device exhibits direct progestogenic effects on both adenomyotic tissue and endometrium.
Igarashi et al57 treated 14 symptomatic women with adenomyosis using a danazolloaded intrauterine device and obtained complete remission of hypermenorrhoea in
12 patients. After removal of the device, three of the four infertile patients successfully
conceived. While the device was inserted, serum danazol levels were undetectable and

Pathophysiology of adenomyosis 499

both menstrual and ovulatory functions were preserved. In addition to the mechanism
suppressing the hypothalamusepituitary axis, danazol directly inhibits the growth of
endometrial and endometriotic cells by inhibiting multiple steroidogenetic enzyme
activities, including cytochrome P450s, aromatase41,55 oestrone sulphatase,43 and
dehydrogenases.
Research agenda
 local oestrogen-dependent growth mechanism
 genetic susceptibility
 association with infertility

SUMMARY
Although adenomyosis is a different disease from endometriosis, the pathogeneses of
the two diseases have a number of features in common. Both grow and regress in an
oestrogen-dependent fashion. Polymorphisms in the ERa gene are associated with
a risk of adenomyosis. Adenomyotic tissue contains ER, PR and androgen receptors
as well as aromatase and sulphatase enzymes, which catalyse the conversion of androgens to oestrogens, and oestrone-3-sulphate to oestrone, respectively. Together with
the circulating oestrogens, locally produced oestrogens stimulate the growth of tissue
mediated by the ER. Oestrogen metabolism, including the expression pattern of aromatase and the regulation of 17b-hydroxysteroid dehydrogenase type 2 (an enzyme
responsible for the inactivation of oestradiol to oestrone) 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. Hormonal
treatment includes administration of GnRH agonists and danazol. In addition to the
conventional general administration of drugs, steroid-releasing intrauterine devices
will be applicable in the clinic. However, the pathophysiology and hormonal treatment
have been less well investigated in adenomyosis than in endometriosis. Such hormonal
and genetic studies would lead to a better understanding of the aetiology and pathophysiology of adenomyosis.
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