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Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden.
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2013 (English)In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 21, no 4, 383-390 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Women with breast cancer who are treated with aromatase inhibitors often experience vaginal atrophy symptoms and sexual dysfunction. This work aims to study proliferation and the presence and distribution of steroid hormone receptors in vaginal biopsies in relation to vaginal atrophy and vaginal pH in women with breast cancer who are on adjuvant endocrine treatment and in healthy postmenopausal women.

METHODS: This is a cross-sectional study that compares postmenopausal aromatase inhibitor-treated women with breast cancer (n = 15) with tamoxifen-treated women with breast cancer (n = 16) and age-matched postmenopausal women without treatment (n = 19) or with vaginal estrogen therapy (n = 16). Immunohistochemistry was used to study proliferation and steroid hormone receptor staining intensity. Data was correlated with estrogen and androgen levels, vaginal atrophy scores, and vaginal pH.

RESULTS: Aromatase inhibitor-treated women had a lower grade of proliferation, weaker progesterone receptor staining, and stronger androgen receptor staining, which correlated with plasma estrone levels, vaginal atrophy scores, and vaginal pH.

CONCLUSIONS: Women with aromatase inhibitor-treated breast cancer exhibit reduced proliferation and altered steroid hormone receptor staining intensity in the vagina, which are related to clinical signs of vaginal atrophy. Although these effects are most probably attributable to estrogen suppression, a possible local inhibition of aromatase cannot be ruled out.

Place, publisher, year, edition, pages
2013. Vol. 21, no 4, 383-390 p.
Keyword [en]
Aromatase inhibitors, Steroid hormone receptors, Vaginal atrophy
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:uu:diva-214584DOI: 10.1097/GME.0b013e31829e41dfISI: 000336214200012PubMedID: 24080848OAI: oai:DiVA.org:uu-214584DiVA: diva2:685106
Funder
Swedish Cancer Society, CAN 2012/603
Available from: 2014-01-08 Created: 2014-01-08 Last updated: 2017-12-06Bibliographically 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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Kallak, Theodora KunovacSundström Poromaa, IngerStavreus-Evers, Anneli

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Obstetrics, Gynecology and Reproductive Medicine

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