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CLIMACTERIC 2011;14:339–344

Vaginal to overcome side-effects of aromatase inhibitors in cancer patients

G. Pfeiler, C. Glatz, R. Ko¨ nigsberg*, T. Geisendorfer{, A. Fink-Retter, E. Kubista**, C. F. Singer and M. Seifert

Department of Gynecology and Gynecological Oncology, Medical University of Vienna; *Applied Cancer Research – Institution for Translational Research Vienna (ACR-ITR VIEnna)/CEADDP, Vienna; {Chemical Analytics Seibersdorf Labor GmbH, Seibersdorf; **Department of Special Gynecology, Medical University of Vienna, Austria

Key words: , VAGINAL ESTRIOL, , VAGINAL DRYNESS,

ABSTRACT Objective Aromatase inhibitors are essential as endocrine treatment for hormone receptor-positive postmenopausal breast cancer patients. Menopausal symptoms are often aggravated during endocrine treatment. We investigated whether vaginal estriol is a safe therapeutic option to overcome the urogenital side- effects of aromatase inhibitors. Serum hormone levels were used as the surrogate parameter for safety. Methods Fasting serum hormone levels of ten postmenopausal breast cancer patients receiving aromatase inhibitors were prospectively measured by electro-chemiluminescence immunoassays and gas chromatography/ mass spectrometry before and 2 weeks after daily application of 0.5 mg vaginal estriol (Ovestin1 ovula), respectively. Results Two weeks of daily vaginal estriol treatment did not change serum or estriol levels. However, significant decreases in levels of serum follicle stimulating hormone (p ¼ 0.01) and (p ¼ 0.02) were observed. Five out of six breast cancer patients noticed an improvement in vaginal dryness and/or dyspareunia. Conclusions The significant decline in levels, indicating systemic effects, has to be kept in mind when offering vaginal estriol to breast cancer patients receiving an aromatase inhibitor.

INTRODUCTION sex , relieves menopausal symptoms in breast cancer survivors but increases the risk of recurrence of breast cancer. are clearly involved in the pathogenesis and It has been suggested that up to 70% of breast cancer progression of breast cancer. They exert strong pro-mitotic patients develop menopausal symptoms, either naturally or as effects on mammary and are a major proliferative a result of breast cancer-related treatment7. Chemotherapy stimulus for hormone-dependent tumors. Antiestrogenic and/or ovarian ablation can lead to premature ovarian failure therapy, either by blocking the receptor () and consequently to menopausal symptoms8,9. Endocrine or by estrogen deprivation (aromatase inhibitor), has become therapy of pre- and postmenopausal women enhances the most effective treatment for endocrine-responsive breast -related symptoms especially hot flushes and cancer1,2. These observations and, furthermore, a randomized vaginal dryness as well as dyspareunia2. With regard to trial regarding safety of (HT) after breast aromatase inhibitors, particularly high numbers of urogenital cancer (HABITS-trial)3 have lead to the recommendation that symptoms have been observed. The Arimidex, Tamoxifen, women with breast cancer should not receive or continue HT Alone or in Combination Trial (ATAC)10 reported vaginal even after a long period of initial therapy4,5. As shown by the dryness and dyspareunia in 18.5% and 17.3%, respectively, LIBERATE study group6, , a synthetic that is for patients randomized to anastrozol alone. Even more, re- pharmacologically and clinically different from conventional analysis of the Tamoxifen Exemestan Adjvant Multicenter

Correspondence: Dr G. Pfeiler, Department of Obstetrics and Gynecology, Medical University of Vienna, Wa¨hringer Gu¨rtel 18–20, 1090 Vienna, Austria

ORIGINAL ARTICLE Received 29-06-2010 ª 2011 International Menopause Society Revised 12-09-2010 DOI: 10.3109/13697137.2010.529967 Accepted 29-09-2010 Vaginal estriol in breast cancer patients Pfeiler et al. trial (TEAM)11 revealed vaginal dryness and decreased libido particular menopausal symptoms was completed. Menopausal in more than 40% of patients treated with . As symptoms were scored from 0, meaning not existent, to 10, aromatase inhibitors have become a mainstay of endocrine meaning worst affected. All participating patients agreed to breast cancer treatment, the amelioration of side-effects such insert vaginal estriol (Ovestin1, 0.5 mg) as instructed as local menopausal symptoms is a major issue in breast once daily in the evening for 14 days. cancer follow-up. In order to overcome those symptoms of estrogen deprivation, vaginal moisturizers or poorly absorbed Hormone measurements topical estrogens are used in daily clinical practice. Though non-hormonal vaginal moisturizers improve urogenital symp- Chemiluminescence immunoassay toms, their benefit is not statistically superior when compared to placebo and is significantly lower compared to vaginal After blood was allowed to clot for 1 h at room temperature, estrogens12,13. In contrast to oral HT, local application of serum was separated and aliquots were stored at 7808C. estrogens was expected to be safe in postmenopausal breast Estradiol, follicle stimulating hormone (FSH), luteinizing cancer patients14. Recently, the report of a small prospective hormone (LH) and SHBG were measured with kits for observation15 advised caution with the use of vaginal estradiol electro-chemiluminescence immunoassays purchased from in breast cancer patients receiving aromatase inhibitors, as an Roche Diagnostics (Germany) on a ‘Modular-170 5EEE4’ increase of serum estradiol levels was found that potentially auto-analyzer. Insulin and C-peptide were analyzed by an counteracts endocrine breast cancer treatment. According to Immulite 2000 system by chemiluminescence immunoassays the publication, practical guidelines for managing menopausal from Siemens-DPC, USA. The detection limit for estradiol was symptoms after breast cancer published in 200816 dissuaded as low as 10 pg/ml to detect even small increases in our group. from the use of vaginal estradiol in patients treated with aromatase inhibitors, but recommend the application of Gas chromatography-mass spectrometry vaginal estriol. However, safety data of vaginal estriol in breast cancer patients receiving aromatase inhibitors are In order to obtain results with high specificity and adequate missing. To throw more light on this issue, we prospectively sensitivity, serum levels of estriol and estradiol were measured investigated the safety of vaginal estriol in breast cancer by gas chromatography-mass spectrometry (GC-MS). patients receiving aromatase inhibitors by measuring serum hormone levels before and 2 weeks after daily use of vaginal Chemicals and reagents Disodium hydrogen phosphate, estriol tablets. potassium dihydrogen phosphate, methanol, ammonium iodide and ethyl acetate (analytical grade) were obtained from Merck (Darmstadt, Germany). Amberlite XAD-4 was METHODS purchased from Rohm and Haas (France). Ultrapure water was produced by a Milli-Q plus 185 water purification system We prospectively analyzed fasting serum hormone levels of with a Q-PAK 1 cartridge purchased from Millipore Corp. ten postmenopausal breast cancer patients receiving aroma- (Bedford, MA, USA). Reference compounds estriol and tase inhibitors before and 2 weeks after daily application of estradiol were obtained from Steraloids (Newport, USA). 0.5 mg vaginal estriol. This study was approved by the ethical The internal standard -d4 was purchased from committee of the Medical University of Vienna, Vienna, Ehrensdorfer (Augsburg, Germany). N-methyl-N-(trimethyl- Austria. silyl)trifluoroacetamide (MSTFA) was supplied from Mach- All patients included in this study were hormone receptor- ery-Nagel (Du¨ ren, Germany). Ethylthio-trimethylsilane was positive and received (Arimidex1) for breast purchased from Sigma-Aldrich (Vienna, Austria). A trimethyl- cancer treatment. Patients were excluded if they had an actual silyl iodide (TMSI) stock solution was prepared by adding or history of thromboembolic disease, postmenopausal uterine 5 ml MSTFA to 100 mg ammonium iodide and 300 ml bleeding, any hormonal, natural () or herbal ethylthio-trimethylsilane. The TMSI working solution was products for treatment of menopausal symptoms within at obtained by diluting 1 ml of TMSI stock solution with 9 ml least 1 year and respiratory, cardiac, or kidney MSTFA. insufficiencies. A full gynecological examination, including vaginal ultrasound and PAP smear, was performed at least 6 GC/MS analysis The GC-MS system consisted of a Trace GC months before the treatment period. The study design 2000 gas chromatograph coupled to a quadruple mass spectro- comprised a pretreatment visit (T1), a treatment period lasting meter Voyager (Thermo Quest Finigan, Manchester, UK) 14 days and a post-treatment visit (T2) exactly 15 days after operated in electron impact mode at 70 eV. The mass detector T1. At T1 and T2, blood was drawn at the outpatient clinic was operated in selected ion monitoring mode. Separation was between 07.00 and 08.00. Blood was taken after a fasting performed on a rtx-1 ms fused-silica capillary column, period of at least 8 h to rule out any interference of insulin and 15 m 6 0.25 mm internal diameter, 0.1 mm film thickness. sex hormone binding globulin (SHBG). At T2, blood was taken about 8–12 h after the last application of vaginal estriol. Sample preparation For the extraction of steroids, 1 ml serum A questionnaire concerning general medical history and in was used; 10 ml internal standard (ethinylestradiol-d4, con-

340 Climacteric Vaginal estriol in breast cancer patients Pfeiler et al. centration ¼ 4 mg/ml), 1 ml phosphate buffer and 1 ml XAD Hormone levels (ca. 1 g/ml) were added to the sample aliquot and shaken over night. After filtration and washing XAD with de- As indicated in Table 2, hormone serum levels measured by ionized water, the steroids were eluted with ethylacetate : radioimmunoassay and/or GC/MS were in the normal methanol in the ratio 1 : 1. The organic phase was brought to postmenopausal range and remained there after 2 weeks of dryness and derivatized with 100 ml MSTFA/TMSI. For daily vaginal estriol treatment. Before treatment with vaginal calibration, bovine serum was spiked in the range 0.2–10 estriol, no patient had a serum estriol level above 0.2 ng/ml or ng/ml. Male human serum was used as a blank sample. a serum estradiol level above 10 pg/ml. After 2 weeks of vaginal estriol use, no increase of serum estrogens could be demonstrated, either by use of radioimmunoassay or by GC/ Statistics MS. In all ten patients, serum levels of estriol and estradiol measured by GC/MS remained under the detection limits of A non-parametric Wilcoxon signed rank test was used to 0.2 ng/ml and 0.5 ng/ml, respectively, after 2 weeks of identify differences between mean hormone serum levels treatment with vaginal estriol. Comparing fasting serum levels before and after vaginal estriol treatment. For all analyses, a of LH and FSH before and after 2 weeks of treatment with p value 50.05 was considered statistically significant. SPSS vaginal estriol, a significant decrease in both version 17.0 statistical software system was used for all could be observed (LH -10.8%, p ¼ 0.02; FSH -12.8%, calculations. p ¼ 0.01) (Figure 1).

RESULTS Vaginal symptoms

The patient characteristics are shown in Table 1. All patients Six out of ten patients reported vaginal symptoms including received aromatase inhibitor therapy for at least 1 year vaginal dryness (6/10, 60%) and dyspareunia (5/10, 50%). (median 2.18 years, range 1.1–4 years). No patient stopped or Four patients (40%) did not indicate vaginal symptoms but modified therapy with the aromatase inhibitor or vaginal suffered from flushes and/or fatigue. Five out of six breast estriol during study participation. Gynecological examination cancer patients (83%) noticed a distinct improvement in of the patients, including vaginal ultrasound and PAP smear, vaginal dryness during the treatment period. Three out of five revealed no pathology (data not shown). Nine patients were patients (60%) with dyspareunia reported obvious relief after given breast-conserving surgery, and one patient had under- 2 weeks of daily vaginal estriol. No worsening of the gone mastectomy. Four lymph node-positive patients received complaints was reported. adjuvant chemotherapy before starting endocrine therapy.

DISCUSSION

Table 1 Patient demographics and characteristics Aromatase inhibitors have become the mainstay in the Patient characteristic Median Range n adjuvant treatment of endocrine-responsive postmenopausal breast cancer17. Any aromatase inhibitor-containing regimen Age (years) 65 50–77 Body mass index (kg/m2) 28.2 21–39 Age at menarche (years) 14 12–16 Age at menopause (years) 53.5 48–57 Tumor size (mm) Table 2 Fasting serum hormone levels before and after 2 weeks of 520 7 treatment with vaginal estriol 420 3 Timepoint 1 Timepoint 2 Nodal status p Positive 4 Mean Range Mean Range Value Negative 6 Estriol (ng/ml) 50.2 50.2 ER/PR status Estradiol (pg/ml) 510 510 ERþ/PR7 8 Progesterone (ng/ml) 0.40 0.10–0.97 0.35 0.1–0.67 0.14 ERþ/PR7 2 LH (mU/ml) 32.4 16.7–52.0 28.9 16.5–45.1 0.02 ER7/PRþ 0 FSH (mU/ml) 75.7 45.6–134.6 66.0 36.4–100.9 0.01 Grading SHBG (nmol/l) 48.0 25.4–103.5 46.0 20.8–100.8 0.08 Grade 1 0 Insulin (mU/l) 12.8 3.5–28.1 12.34 1.8–19.5 0.96 Grade 2 6 C-peptide (mg/l) 2.6 1.3–4.3 2.6 1.4–3.9 0.79 Grade 3 4 LH, luteinizing hormone; FSH, follicle stimulating hormone; SHBG, ER/PR, / receptor sex hormone binding globulin

Climacteric 341 Vaginal estriol in breast cancer patients Pfeiler et al.

Figure 1 Fasting serum levels of (a) luteinizing hormone (LH) and (b) follicle stimulating hormone (FSH) before and 2 weeks of treatment with vaginal estriol has demonstrated superior efficacy when compared to prospective trial, the majority of patients also reported distinct tamoxifen alone18. Hence, the vast majority of postmenopau- improvements in urogenital complaints. sal estrogen receptor-positive breast cancer patients will be However, changes in hormone serum levels due to vaginal offered an aromatase inhibitor as endocrine therapy except estriol application have been reported27–29; this implies those presenting with rare contraindications. Though aroma- systemic and not only local effects of this hormonal tase inhibitors are well tolerated, menopausal symptoms are therapy. Hence, the nearly total suppression of the level aggravated during endocrine treatment and thereby impair a of serum estrogen, which is warranted by use of an patient’s quality of life19,20. Two out of three most reported aromatase inhibitor, might be counteracted by vaginal menopausal symptoms, i.e. hot flushes, vaginal dryness, estriol. Our prospective study investigated serum hormone dyspareunia, could be overcome by the use of vaginal levels of breast cancer patients receiving aromatase inhibi- estrogens. Several studies21–23 have confirmed the efficacy of tors before and after 2 weeks of daily vaginal application of vaginal estradiol in showing significant improvement in 0.5 mg estriol. We observed no increase in levels of serum urogenital symptoms. But, since an increase in serum estradiol estriol and estradiol, by analyzing fasting serum 8–12 h following vaginal application in breast cancer patients after the last application of vaginal estriol. This is of receiving aromatase inhibitors has been reported15, this interest, since any increase in the level of serum estrogen therapy is contraindicated for those patients. Estriol is an would potentially be deleterious for breast cancer patients estrogen of low , which seems to exert anti-estrogenic on aromatase inhibitors. Several studies have reported a effects in an estradiol-rich environment and is not converted long-term increase in serum estradiol and levels in back to the highly potent estradiol24. In contrast to topical postmenopausal women after vaginal application of estra- estradiol, vaginal estriol does not contribute to endometrial diol. Estradiol serum levels increase between 4- and 20-fold stimulation25. In a meta-analysis of 214 women using vaginal after vaginal application and stay increased, indicating estriol cream26, a total of 337 biopsies generated at various that vaginal estradiol cannot be recommended for hormone stages of treatment revealed only atrophic . receptor-positive breast cancer patients receiving aromatase Vaginal estriol has been shown to be a potent and safe inhibitors15,30. As vaginal estriol is poorly absorbed and can- treatment for urogenital estrogen deficiency symptoms. In our not be converted to estradiol, several scientific communities

342 Climacteric Vaginal estriol in breast cancer patients Pfeiler et al. recommend this estrogen for amelioration of postmenopau- and LH. It is speculative and unlikely that the down- sal urogenital symptoms. This is underlined by our study. regulation of gonadotropins directly impacts on breast However, a short-term increase in serum estriol levels after cancer recurrence. vaginal application has been reported. Keller and co- Our study has several limitations. Our detection limit for workers27, as well as Mattsson and Cullberg31, demon- estriol was 0.2 ng/ml and for estradiol 10 pg/ml. We cannot strated peak levels of serum estriol 1–2 h after vaginal rule out significant increases of these hormones beyond these application of estriol, reaching pre-treatment levels after 8– detection limits, which might have caused our observed 24 h. No change in serum estradiol levels after application decline of gonadotropins after 2 weeks of vaginal estriol of vaginal estriol has been reported. We are not able to rule treatment. Second, desirable changes in the atrophic mucosa out a short-term increase in serum estriol between 1 and by vaginal estriol might lead to greater ability to absorb 8 h after vaginal application in our group, but we considerable amounts of hormone into the systemic circula- demonstrate here that serum estriol levels do not exceed tion, an effect which possibly occurs long after 2 weeks of our detection limit of 0.2 ng/ml 8–12 h after the last treatment. However, as the treatment dosage is routinely insertion. It is questionable whether a short-term increase in reduced from 0.5 mg vaginal estriol daily to once weekly after serum estriol for less than 8 h is able to impact on breast 2 weeks, this is unlikely, but cannot be ruled out entirely. cancer recurrence risk, but it cannot be ruled out entirely. Third, our results concerning the relief of urogenital com- Interestingly, we and others were able to demonstrate plaints are limited as this is not a controlled study and no significantly reduced FSH and LH levels after 2 weeks of standardized scales for the evaluation of symptoms were used. vaginal estriol treatment29. Schiff and co-workers reported a In conclusion, our prospective study investigating post- decline in FSH by 17% and in LH by 45% after vaginal menopausal breast cancer patients receiving aromatase estriol28, which could not be seen after orally administered inhibitors demonstrates that vaginal estriol does not lead to estriol. In their study, the decline of gonadotropins was a long-term elevation of serum estrogen levels. Nevertheless, paralleled by an increase in unconjugated estriol, thereby the significant decline in gonadotropins indicating systemic suggesting that serum estriol suppressed LH and FSH serum effects has to be kept in mind when offering vaginal estriol to levels. Likewise, Mattsson and Cullberg supposed a relation- breast cancer patients on aromatase inhibitors. ship between the decline of serum gondatropins and increased estriol serum levels31, as they observed a decrease Conflict of interest The authors report no conflict of of LH and FSH 6 h after vaginal estriol insertion. In our interest. The authors alone are responsible for the content and study, the significant decline in levels of gonadotropins, writing of the paper. 10.8% for LH and 12.8% for FSH, was not paralleled by increased serum estriol or even estradiol levels. Never- Source of funding This investigation was supported by a theless, a possible short-term increase in estriol 1–8 h after research grant from Privatstiftung fu¨ r Brustgesundheit, application could be stimulus enough to down-regulate FSH Vienna, Austria.

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