Beruflich Dokumente
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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
494 J. Kitawaki
496 J. Kitawaki
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.
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
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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