Effects of progestins on local estradiol biosynthesis and action in the Z-12 endometriotic epithelial cell line

Beranič, Nataša; Rižner, Tea Lanišnik

doi:10.1016/j.jsbmb.2012.07.004

Cited by 12 publications

(4 citation statements)

References 34 publications

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“…Although the HSD17b1 gene lacks a P 4 -responsive element in its promoter region, progestins including DNG downregulated HSD17b1 and upregulated HSD17b2 expression in immortalized endometriotic epithelial cells (Beranic & Rizner 2012). DNG inhibits the DNA-binding activity of NFkB, a key regulator of various pathological and inflammatory responses in endometriosis such as interleukin-8 production in human OESCs (Horie et al 2005, Yamanaka et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Dienogest reduces HSD17β1 expression and activity in endometriosis

Mori¹,

Ito²,

Miyata³

et al. 2015

Journal of Endocrinology

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Endometriosis is an estrogen-dependent disease. Abnormally biosynthesized estrogens in endometriotic tissues induce the growth of the lesion and worsen endometriosis-associated pelvic pain. Dienogest (DNG), a selective progesterone receptor agonist, is widely used to treat endometriosis and efficiently relieves the symptoms. However, its pharmacological action remains unknown. In this study, we elucidated the effect of DNG on enzymes involved in local estrogen metabolism in endometriosis. Surgically obtained specimens of 23 ovarian endometriomas (OE) and their homologous endometrium (EE), ten OE treated with DNG (OE w/D), and 19 normal endometria without endometriosis (NE) were analyzed. Spheroid cultures of stromal cells (SCs) were treated with DNG and progesterone. The expression of aromatase, 17b-hydroxysteroid dehydrogenase 1 (HSD17b1), HSD17b2, HSD17b7, HSD17b12, steroid sulfatase (STS), and estrogen sulfotransferase (EST) was evaluated by real-time quantitative PCR. The activity and protein level of HSD17b1 were measured with an enzyme assay using radiolabeled estrogens and immunohistochemistry respectively. OESCs showed increased expression of aromatase, HSD17b1, STS, and EST, along with decreased HSD17b2 expression, when compared with stromal cells from normal endometria without endometriosis (NESCs) (P!0.01) or stromal cells from homologous endometrium (EESCs) (P!0.01). In OESCs, DNG inhibited HSD17b1 expression and enzyme activity at 10 K7 M (P!0.01). Results of immunohistochemical analysis displayed reduced HSD17b1 staining intensity in OE w/D (P!0.05). In conclusion, DNG exerts comprehensive inhibition of abnormal estrogen production through inhibition of aromatase and HSD17b1, contributing to a therapeutic effect of DNG on endometriosis.

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Section: Discussionmentioning

confidence: 99%

Dienogest reduces HSD17β1 expression and activity in endometriosis

Mori¹,

Ito²,

Miyata³

et al. 2015

Journal of Endocrinology

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“…We tested different cell numbers (100, 200, 500 and 750 × 10 3 ) and different incubation times (24, 48 and 72 h), but the E1 into E2 conversion rates were very low, variable and less than 7%. For example, only 4% transformation was observed, despite the use of 200 × 10 3 Z-12 cells and an incubation time of 24 h. Thus, although Z-12 cells express the 17β-HSD1 mRNA [ 39 , 40 ], this does not seem to translate into E2 formation. Intrigued by this surprising result, we also tested the activity of aromatase, another steroidogenesis enzyme whose mRNA is expressed in Z-12 cells [ 39 , 40 , 41 ].…”

Section: Resultsmentioning

confidence: 99%

“…For example, only 4% transformation was observed, despite the use of 200 × 10 3 Z-12 cells and an incubation time of 24 h. Thus, although Z-12 cells express the 17β-HSD1 mRNA [ 39 , 40 ], this does not seem to translate into E2 formation. Intrigued by this surprising result, we also tested the activity of aromatase, another steroidogenesis enzyme whose mRNA is expressed in Z-12 cells [ 39 , 40 , 41 ]. By incubating 5, 10, 25, 50, 100, 300 and 600 × 10 3 Z-12 cells in the presence of [1β- 3 H]-4-androstene-3,17-dione (60 nM) for 1, 4 and 24 h, we did not observe a significant release of tritiated water, which would be representative of the aromatization of the A-ring of the natural aromatase substrate 4-DIONE to form E1 ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

et al. 2023

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Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting approach for the treatment of these two estrogen-dependent diseases. In order to obtain new inhibitors of 17β-HSD1, the impact of a m-carbamoylphenyloxy group at position three of an estrane nucleus was evaluated by preparing three derivatives of estrone (E1) and E2 using a microwave-assisted synthesis of diaryl ethers. Their inhibitory activity was addressed on two cell lines (T-47D and Z-12) representative of breast cancer and endometriosis, respectively, but unlike T-47D cells, Z-12 cells were not found suitable for testing potential 17β-HSD1 inhibitors. Thus, the addition of the m-carbamoylphenyl group at C3 of E1 (compound 5) did not increase the inhibition of E1 to E2 transformation by 17β-HSD1 present in T-47D cells (IC50 = 0.31 and 0.21 μM for 5 and E1, respectively), and this negative effect was more obvious for E2 derivatives 6 and 10 (IC50 = 1.2 and 1.3 μM, respectively). Molecular docking allowed us to identify key interactions with 17β-HSD1 and to highlight these new inhibitors’ actions through an opposite orientation than natural enzyme substrate E1′s classical one. Furthermore, molecular modeling experiments explain the better inhibitory activity of E1-ether derivative 5, as opposed to the E2-ether derivatives 6 and 10. Finally, when tested on T-47D and Z-12 cells, compounds 5, 6 and 10 did not stimulate the proliferation of these two estrogen-dependent cell lines. In fact, they reduced it.

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“…Данный эффект подтверждается тем, что под влиянием прогестагенов наблюдается снижение экспрессии множества маркеров и индукторов пролиферации и ангиогенеза (Ki-67, TNF, NFkB, сигнальные пути PI3K/AKT/mTOR, Wnt), нейрогенеза (NGF) и воспаления (CD31, IL-1β, Е2, IL-6, IL-8) [25][26][27][28][29][30][31][32]. Важным механизмом действия является также то, что прогестагены оказывают гипоэстрогенный эффект за счет подавления выработки ферментов ароматазы, 17β-гидроксистероиддегидрогеназы, регулирующих локальный синтез эстрогенов в эпителиальных клетках [33,34]. Кроме того, прогестагены по механизму отрицательной обратной связи подавляют пульсаторную секрецию гонадотропин-рилизинггормона (ГнРГ), что приводит к супрессии выработки фолликулостимулирующего (ФСГ) и лютеинизирующего гормона (ЛГ), вызывая нарушения фолликулогенеза, овуляции и снижение синтеза эстрогенов [17].…”

Section: механизм действия гормональной терапииunclassified

The issues of endometriosis hormonal treatment in reproductive age women

Ivanov

2022

Medicinskij sovet

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Endometriosis is one of the most common gynecological diseases associated with severe pelvic pain, uterine bleeding, and infertility. Current treatment patterns include endometriosis excision and medical management. Since endometriosis is a chronic disease with a recurrent clinical course, the crucial role holds a long-term suppressive therapy. It should be characterized by high efficacy, tolerability, a favorable safety profile, as well providing sustained remission and improving the quality of life. The current review summarizes the modern data on conservative management, mechanisms of hormonal therapeutic effects. The national recommendations of Russian and international obstetrics and gynecology societies were analyzed, taking into account the results of systematic reviews, meta-analyses and randomized clinical trials. Combined oral contraceptives and progestogens are considered as first-line hormone therapy. Choosing the proper medication is a controversial issue that requires a comprehensive understanding of its effect on various forms of endometriosis. The review analyzes comparative data on the effectiveness, safety, side effects, impact on the quality of life, the frequency of relapse during various progestogens monotherapy and oral contraceptives, including different dosage regimens. This data allows making an optimal choice of long-term management, with high compliance and efficiency, associated with low recurrence rate.

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Effects of progestins on local estradiol biosynthesis and action in the Z-12 endometriotic epithelial cell line

Cited by 12 publications

References 34 publications

Dienogest reduces HSD17β1 expression and activity in endometriosis

Dienogest reduces HSD17β1 expression and activity in endometriosis

Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

The issues of endometriosis hormonal treatment in reproductive age women

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