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Hormonal Regulation of Vaginal Mucosa
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
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 [en]
aromatase inhibitors, vaginal atrophy, estrogen, proliferation, steroid hormone receptors, cell differentiation, cell adhesion, aquaporin 3
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:uu:diva-246215ISBN: 978-91-554-9181-9 (print)OAI: oai:DiVA.org:uu-246215DiVA: diva2:792366
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
List of papers
1. Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients
Open this publication in new window or tab >>Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients
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2012 (English)In: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 15, no 5, 473-480 p.Article in journal (Refereed) Published
Abstract [en]

Objective

Vaginal estradiol is considered contraindicated in aromatase inhibitor (AI)-treated patients because of the risk of elevated estrogen levels. This leaves limited treatment options for patients experiencing gynecological symptoms. However, in clinical practice, no precise estimation has been performed of circulating estrogens and aromatase index in postmenopausal breast cancer patients on long-lasting AI or tamoxifen treatment. 

Methods

Steroid hormones were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) and extraction radioimmunoassay (RIA). Postmenopausal AI-treated patients (n =33) were compared with tamoxifen-treated patients (n =34) and controls without vaginal treatment (n =56), with vaginal estradiol (n =25), or with estriol (n =11) treatment. 

Results

By use of LC-MS/MS, median (range) estradiol plasma concentrations were 16.7 (2.4-162.6), 31.0 (13.4-77.1), 27.2 (7.8-115.8) and 33.3 (20.3-340.1) pmol/l in AI-treated breast cancer patients, tamoxifen-treated breast cancer patients, postmenopausal controls and postmenopausal controls on vaginal estradiol, respectively. The AI-treated group and subgroups had significantly lower estradiol and estrone concentrations than all other groups(p <0.05). There was extensive interindividual variation in estradiol concentration within the AI-treated group, measured using both LC-MS/MS (2.3-182.0 pmol/l) and extraction RIA (2.4-162.6 pmol/l). The AI-treated group had lower aromatase index compared to all other groups (p <0.05-0.001).  

Conclusion

Circulating estrogen levels may have been underestimated in previous longitudinal studies of AI-treated breast cancer patients. Additional studies are required to further evaluate the role of circulating estrogens in breast cancer patients suffering from gynecological symptoms.

Place, publisher, year, edition, pages
Informa Healthcare, 2012
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-176847 (URN)10.3109/13697137.2011.642427 (DOI)000308942500011 ()
Available from: 2012-06-26 Created: 2012-06-26 Last updated: 2017-12-07Bibliographically approved
2. Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors
Open this publication in new window or tab >>Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors
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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.

Keyword
Aromatase inhibitors, Steroid hormone receptors, Vaginal atrophy
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-214584 (URN)10.1097/GME.0b013e31829e41df (DOI)000336214200012 ()24080848 (PubMedID)
Funder
Swedish Cancer Society, CAN 2012/603
Available from: 2014-01-08 Created: 2014-01-08 Last updated: 2017-12-06Bibliographically approved
3. Vaginal gene expression during treatment with aromatase inhibitors
Open this publication in new window or tab >>Vaginal gene expression during treatment with aromatase inhibitors
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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.

Keyword
Estrogen; Genitourinary symptom of menopause; Microarray; Vagina; Vaginal atrophy
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-245413 (URN)10.1016/j.clbc.2015.06.012 (DOI)000365190800018 ()26283501 (PubMedID)
Funder
Swedish Cancer Society, CAN 2012/603
Available from: 2015-02-26 Created: 2015-02-26 Last updated: 2017-12-04Bibliographically approved
4. Estrogenic regulation of aquaporin 3 in vaginal mucosa
Open this publication in new window or tab >>Estrogenic regulation of aquaporin 3 in vaginal mucosa
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(English)Manuscript (preprint) (Other academic)
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-245569 (URN)
Available from: 2015-02-26 Created: 2015-02-26 Last updated: 2015-04-17

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