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  • 1.
    Baumgart, Juliane
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Obstetrics and Gynecology.
    Nilsson, Kerstin
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
    Evers, A. Stavreus
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden .
    Kallak, T. Kunovac
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Kushnir, M. M.
    ARUP Institute for Clinical and Experimental Pathology, Salt Lake City UT, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, USA; Analytical Chemistry/Department of Chemistry, Biomedical Center and SciLife Laboratory, Uppsala University, Uppsala, Sweden.
    Bergquist, J.
    Department of Pathology, University of Utah School of Medicine, Salt Lake City UT, USA; Analytical Chemistry/Department of Chemistry, Biomedical Center and SciLife Laboratory, Uppsala University, Uppsala, Sweden.
    Poromaa, I. Sundström
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden .
    Androgen levels during adjuvant endocrine therapy in postmenopausal breast cancer patients2014In: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 17, no 1, p. 48-54Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate plasma steroid hormone levels in postmenopausal breast cancer patients with and without adjuvant endocrine therapy and in healthy postmenopausal women.

    Methods: Steroid hormone levels in postmenopausal breast cancer patients treated with aromatase inhibitors (n = 32) were compared with breast cancer patients treated with tamoxifen (n = 34), breast cancer patients without adjuvant endocrine therapy (n = 15), and healthy postmenopausal women (n = 56). Pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone (DHEA), androstenedione, total testosterone, dihydrotestosterone, estrone and estradiol were measured using liquid chromatography-tandem mass spectrometry. Sex hormone binding globulin was measured by solid-phase chemiluminescent immunometric assays, and the free androgen index was calculated.

    Results: Aromatase inhibitor users did not differ in dihydrotestosterone, total testosterone, androstenedione, DHEA, or free androgen index levels from healthy controls or untreated breast cancer patients. The highest total testosterone levels were found in tamoxifen-treated women, who had significantly higher plasma concentrations than both women treated with aromatase inhibitors and breast cancer patients without adjuvant treatment. Concentrations of cortisol and cortisone were significantly greater in aromatase inhibitor users as well as tamoxifen users, in comparison with healthy controls and untreated breast cancer patients. Aromatase inhibitor users had lower estrone and estradiol plasma concentrations than all other groups.

    Conclusion: Adjuvant treatment with aromatase inhibitors or tamoxifen was associated with increased cortisol and cortisone plasma concentrations as well as decreased estradiol concentrations. Androgen levels were elevated in tamoxifen-treated women but not in aromatase inhibitor users.

  • 2.
    Baumgart, Juliane
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Obstetrics and Gynecology.
    Nilsson, Kerstin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Obstetrics and Gynecology.
    Evers, Anneli Stavreus
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Kallak, Theodora Kunovac
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Poromaa, Inger Sundström
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Sexual dysfunction in women on adjuvant endocrine therapy after breast cancer2013In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 20, no 2, p. 162-168Article in journal (Refereed)
    Abstract [en]

    Objective: The goal of this study was to investigate sexual function in postmenopausal breast cancer patients treated with aromatase inhibitors.

    Methods: A population-based, cross-sectional study was conducted among postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched controls with and without estrogen treatment. Sexual function was assessed with a standardized questionnaire.

    Results: In all, 42.4% of aromatase inhibitor-treated breast cancer patients were dissatisfied with their sex life in general, and 50.0% reported low sexual interest; this was significantly more common than in tamoxifen-treated patients and controls (P < 0.05). Aromatase inhibitorYtreated patients reported insufficient lubrication in 73.9% and dyspareunia in 56.5% of cases, which were significantly more common than in controls, irrespective of hormonal use (P < 0.05). Tamoxifen-treated patients reported significantly more dyspareunia (31.3%; P < 0.05) but resembled controls in all other concerns.

    Conclusions: Our findings suggest that sexual dysfunction in aromatase inhibitorYtreated women is a greatly underestimated problem.

  • 3. Baumgart, Juliane
    et al.
    Nilsson, Kerstin
    Örebro University, School of Health and Medical Sciences.
    Stavreus-Evers, Anneli
    Kask, Kristiina
    Villman, Kenneth
    Lindman, Henrik
    Kallak, Theodora
    Sundström-Poromaa, Inger
    Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer2011In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 204, no 1, p. 26.e1-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the prevalence of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy. STUDY DESIGN: A population-based, cross-sectional study on postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched control subjects. Vaginal atrophy was assessed by gynecologic examination and atrophy-related symptoms by validated questionnaires. RESULTS: In all, 57.6% of aromatase inhibitor-treated and 32.4% of tamoxifen-treated breast cancer patients rated at least 1 vaginal atrophy symptom as moderate/severe, which was significantly more common than in control subjects ( P < .01). Aromatase inhibitor-treated patients more often had moderate or severe vaginal atrophy ( P < .05), a more atrophic cytohormonal evaluation, and significantly higher vaginal pH ( P < .05) than all control subjects, irrespective of hormonal use. CONCLUSION: Our findings indicate that the frequency of vaginal atrophy symptoms, particularly in aromatase inhibitor-treated women, might have been underestimated in previous clinical trials.

  • 4.
    Kallak, Theodora K.
    et al.
    Dept Womens & Childrens Health, Uppsala University, Uppsala, Sweden.
    Baumgart, Juliane
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Dept Obstetrics & Gynecology, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Kerstin
    Örebro University, School of Medicine, Örebro University, Sweden. Dept Obstetrics & Gynecology, Örebro University Hospital, Örebro, Sweden.
    Poromaa, Inger Sundstrom
    Dept Womens & Childrens Health, Uppsala University, Uppsala, Sweden.
    Evers, Anneli Stavreus
    Dept Womens & Childrens Health, Uppsala University, Uppsala, Sweden.
    Treatment with aromatase inhibitor acts indirectly through the estrogen receptor pathway causing decreased junction plakoglobin mRNA expression and vaginal atrophy2013In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 20, no 12, p. 1328-1328Article in journal (Other academic)
  • 5.
    Kallak, Theodora Kunovac
    et al.
    Dept Womens & Childrens Hlth, Uppsala Univ, Uppsala, Sweden.
    Baumgart, Juliane
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Obstet & Gynecol, Örebro University Hospital, Örebro, Sweden.
    Göransson, Emma
    Dept Womens & Childrens Hlth, Uppsala Univ, Uppsala, Sweden..
    Nilsson, Kerstin
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Dept Obstet & Gynecol, Örebro University Hospital, Örebro, Sweden.
    Poromaa, Inger Sundström
    Dept Womens & Childrens Hlth, Uppsala Univ, Uppsala, Sweden..
    Stavreus-Evers, Anneli
    Dept Womens & Childrens Hlth, Uppsala Univ, Uppsala, Sweden..
    Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors2014In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 21, no 4, p. 383-390Article in journal (Refereed)
    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.

  • 6.
    Kallak, Theodora Kunovac
    et al.
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Baumgart, Juliane
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Kerstin
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
    Åkerud, Helena
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Poromaa, Inger Sundström
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Stavreus-Evers, Anneli
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Vaginal Gene Expression During Treatment With Aromatase Inhibitors2015In: Clinical Breast Cancer, ISSN 1526-8209, E-ISSN 1938-0666, Vol. 15, no 6, p. 527-535.e2Article in journal (Refereed)
    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.

  • 7.
    Kunovac Kallak, T.
    et al.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Baumgart, Juliane
    Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
    Stavreus Evers, A.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Sundström Poromaa, I.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Moby, L.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Kask, K.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Norjavaara, E.
    Gothenburg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Kushnir, M. M.
    ARUP Institute for Clinical and Experimental Pathology, Salt Lake City UT, USA.
    Bergquist, J.
    Department of Physical and Analytical Chemistry, Analytical Chemistry, Uppsala University, Uppsala, Sweden.
    Nilsson, Kerstin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Obstetrics and Gynecology, Örebro University Hospital, Örebro, Sweden.
    Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients2012In: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 15, no 5, p. 473-480Article in journal (Refereed)
    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.

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