Expression of Apoptosis-Related Proteins in Adenomyotic Uteri Treated with Danazol and GnRH Agonists

Abstract

The biologic properties of adenomyosis and the effects of therapeutic agents on adenomyosis were evaluated with immunohistochemistry, terminal deoxy-nucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, transmission electron microscopy, and analysis of genomic abnormality. In the adenomyotic endometrium, estrogen receptor (ER) expression was more intense than in the eutopic endometrium during the secretory phase, and bcl-2 was constantly expressed throughout the menstrual cycle. The expression of ER and bcl-2 was weaker in the adenomyotic endometrium treated with danazol than in that treated with gonadotro-pin-releasing hormone agonist (GnRHa), whereas bcl-2 phosphorylated on serine-87 was more intensely expressed in danazol-treated adenomyotic endometrium than in the GnRHa-treated one. The number of TUNEL-positive cells increased in the adenomyotic endometrium treated with danazol or GnRHa. Ultrastructurally, most of the adenomyotic endometrial cells treated with danazol underwent postapoptotic necrosis and formed a cluster of dead cells. In contrast, cells treated with GnRHa underwent typical apoptosis and were sparsely distributed in the adenomyotic endometrium. Analysis of several cancer-related genes showed no microsatellite instability or loss of heterozygosity in adenomyotic tissues. Therefore, we conclude that the occurrence of adenomyosis is correlated to bcl-2 expression regulated by estrogen and ER rather than genetic mutation.

Effect of pre-treatment with gonadotropin-releasing hormone analogue GnRH-α on high-intensity focussed ultrasound ablation for diffuse adenomyosis: a preliminary study

“…Until now, few reports have described HIFU ablation combined with GnRH-a pre-treatment for diffuse adenomyosis with a volume greater than 300 cm 3 and clinical follow-up after 12 months. Our study showed that after treatment with GnRH-a, the sizes of most uteri and lesions were clearly reduced and that vascular flow decreased, as observed in other studies [2,3]. The MR enhancement images or CEUS images showed that the non-perfused area indicated temporary ischaemic infarction in some lesions.…”

“…GnRH-a causes pituitary GnRH receptor desensitisation and leads to temporary amenorrhoea, which is also called reversible drug oophorectomy. GnRH-a may improve symptoms caused by adenomyosis by suppressing cell proliferation, inducing apoptosis and diminishing the volumes of the uterus and lesion [2,3]. Meanwhile, GnRH-a has an inhibitory effect on the ovaries and leads to similar complaints during menopause; moreover, the most worrisome outcome in women afflicted with adenomyosis is re-occurrence after withdrawal of the medicine.…”

Coexistence of adenomyosis and endometrioid endometrial cancer: Role in surgical guidance and prognosis estimation

“…Notably, these represent the same factors contributing to atypical hyperplasia and endometrial polyps through the creation of a hyper-estrogenic status. An overexpression of estrogen receptors in AM foci has been suggested as evidence of this possible association (8,29) supported by the fact that the concomitant EEC diagnosed was frequently of type I, typical of a hyper-estrogenic status and endometrial hyperplasia (3,30).…”

Functional Analyses of Endometriosis-Related Polymorphisms in the Estrogen Synthesis and Metabolism-Related Genes

“…First, danazol, an androgen analog used for treatment of endometriosis, directly binds to the AR of endometriotic tissue [58] and decreases the expression of Bcl-2 (a suppressor for apoptosis) [59], resulting in the cell death of endometriotic tissue. Second, an animal study has shown that danazol in vivo reduces AR, estrogen receptors, and progesterone receptors of the endometrium [60].…”