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Vaginal gene expression during treatment with aromatase inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
Department of Obstetrics & Gynecology, School of Medicine, Faculty of Health and Medicine, Örebro University, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
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2015 (English)In: Clinical Breast Cancer, ISSN 1526-8209, E-ISSN 1938-0666, Vol. 15, no 6, 527-535 p.Article in journal (Refereed) Published
Abstract [en]

Vaginal gene expression in aromatase inhibitor-treated women was compared with postmenopausal control women treated with vaginal estrogen therapy. Vaginal tissue from aromatase inhibitor-treated women had low expression of genes involved in cell differentiation, proliferation, and cell adhesion, and associated with vaginal discomfort. The presence of vaginal aromatase suggests that this is the result of local and systemic aromatase inhibition. Background: Aromatase inhibitor (AI) treatment suppresses estrogen biosynthesis and causes genitourinary symptoms of menopause such as vaginal symptoms, ultimately affecting the quality of life for many postmenopausal women with breast cancer. Thus, the aim of this study was to examine vaginal gene expression in women during treatment with AIs compared with estrogen-treated women. The secondary aim was to study the presence and localization of vaginal aromatase. Patients and Methods: Vaginal biopsies were collected from postmenopausal women treated with AIs and from age-matched control women treated with vaginal estrogen therapy. Differential gene expression was studied with the Affymetrix Gene Chip Gene 1.0 ST Array (Affymetrix Inc, Santa Clara, CA) system, Ingenuity pathway analysis, quantitative real-time polymerase chain reaction, and immunohistochemistry. Results: The expression of 279 genes differed between the 2 groups; AI-treated women had low expression of genes involved in cell differentiation, proliferation, and cell adhesion. Some differentially expressed genes were found to interact indirectly with the estrogen receptor alpha. In addition, aromatase protein staining was evident in the basal and the intermediate vaginal epithelium layers, and also in stromal cells with a slightly stronger staining intensity found in AI-treated women. Conclusion: In this study, we demonstrated that genes involved in cell differentiation, proliferation, and cell adhesion are differentially expressed in AI-treated women. The expression of vaginal aromatase suggests that this could be the result of local and systemic inhibition of aromatase. Our results emphasize the role of estrogen for vaginal cell differentiation and proliferation and future drug candidates should be aimed at improving cell differentiation and proliferation. (C) 2015 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
2015. Vol. 15, no 6, 527-535 p.
Keyword [en]
Estrogen; Genitourinary symptom of menopause; Microarray; Vagina; Vaginal atrophy
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:uu:diva-245413DOI: 10.1016/j.clbc.2015.06.012ISI: 000365190800018PubMedID: 26283501OAI: oai:DiVA.org:uu-245413DiVA: diva2:791163
Funder
Swedish Cancer Society, CAN 2012/603
Available from: 2015-02-26 Created: 2015-02-26 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Hormonal Regulation of Vaginal Mucosa
Open this publication in new window or tab >>Hormonal Regulation of Vaginal Mucosa
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Vaginal atrophy symptoms such as dryness, irritation, and itching, are common after menopause. Vaginal estrogen therapy is the most effective treatment but not appropriate for all women. Women with estrogen-responsive breast cancer treated with aromatase inhibitor (AI) treatment, suppressing estrogen levels, often suffer from more pronounced vaginal atrophy symptoms. However, vaginal estrogen treatment is not recommended, leaving them without effective treatment options. The aim of this thesis was to study the effect of long-term anti-estrogen therapy on circulating estrogen levels and biochemical factors in vaginal mucosa in relation to morphological changes and clinical signs of vaginal atrophy.

Circulating estrogen levels were analyzed by use of mass spectrometry and radioimmunoassay. Immunohistochemistry was used to study vaginal proliferation and steroid hormone receptors in vaginal mucosa. Vaginal gene expression was studied by use of microarray technology and bioinformatic tools, and validated by use of quantitative real-time PCR and immunohistochemistry. An estrogenic regulation of aquaporins and a possible role in vaginal dryness was investigated in vaginal mucosa and in Vk2E6E7 cells.

Aromatase inhibitor-treated women had higher than expected estradiol and estrone levels but still significantly lower than other postmenopausal women. Aromatase was detected in vaginal tissue, the slightly stronger staining in vaginal mucosa from AI-treated women, suggest a local inhibition of vaginal aromatase in addition to the systemic suppression. Vaginal mucosa from AI-treated women had weak progesterone receptor, and strong androgen receptor staining intensity. Low estrogen levels lead to low expression of genes involved in cell adhesion, proliferation, and differentiation as well as weak aquaporin 3 protein immunostaining.

The higher than expected estrogen levels in AI-treated women suggest that estrogen levels might previously have been underestimated. Systemic estrogen suppression by treatment with AIs, and possibly also by local inhibition of vaginal aromatase, results in reduced cell adhesion, proliferation, differentiation, and weak aquaporin 3 protein staining. Low proliferation and poor differentiation leads to fewer and less differentiated superficial cells affecting epithelial function and possibly also causing vaginal symptoms. Aquaporin 3 with a possible role in vaginal dryness, cell proliferation, and differentiation should be further explored for the development of non-hormonal treatment options for vaginal symptoms.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1076
Keyword
aromatase inhibitors, vaginal atrophy, estrogen, proliferation, steroid hormone receptors, cell differentiation, cell adhesion, aquaporin 3
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-246215 (URN)978-91-554-9181-9 (ISBN)
Public defence
2015-04-24, Sal IX, Universitetshuset, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Cancer Society, CAN 2012/603
Available from: 2015-03-31 Created: 2015-03-03 Last updated: 2015-04-17

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Kunovac Kallak, TheodoraÅkerud, HelenaSundström Poromaa, IngerStaverus-Evers, Anneli

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