CLIMACTERIC 2015;18:63–68
Effect of anastrozole on hormone levels in postmenopausal women with early breast cancer I. Kyvernitakis, U-S. Albert*, M. Kalder, A-S. Winarno, O. Hars* and P. Hadji* Department of Gynecology and Obstetrics, and *Department of Gynecological Endocrinology, Reproductive Medicine and Osteoporosis, Philipps-University of Marburg, Germany
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Key words: HORMONE LEVELS, BREAST CANCER, AROMATASE INHIBITOR, POSTMENOPAUSAL
ABSTRACT Objectives The aim of this study was to investigate the influence of anastrozole on serum hormone levels in postmenopausal women with hormone receptor-positive breast cancer. Methods We prospectively determined serum levels of estradiol, testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and luteinizing hormone (LH) at screening, as well as after 12 and 24 months of treatment and studied the associations with markers of bone turnover and bone mineral density (BMD). Results Altogether, a full set of hormone levels was available for 70 patients. Anastrozole treatment led to decreases of 92.1% for estradiol and 11.1% for LH over the observation period (p 0.001). Conversely, FSH, DHEAS and testosterone concentrations increased by 5.9%, 33.3% and 50%, respectively (p 0.001). SHBG levels remained stable during the 24 months of treatment (p 0.355). There were modest associations between FSH, SHBG, CrossLaps and N-terminal propeptide of human procollagen type I (p 0.05). Moreover, SHBG correlated positively with the BMD of femoral neck, total hip, total hip T-score, lumbar spine and the lumbar spine T-score, whereas FSH and estradiol correlated with the lumbar spine T-score (p 0.05). Conclusions During the 24 months of follow-up, treatment with anastrozole decreased the serum levels of estradiol and LH. Furthermore, we found notable increases of serum levels of FSH, DHEAS and testosterone in the first 12 months of treatment, stabilizing thereafter. Additionally, we were able to correlate hormone levels with markers of bone turnover and BMD for the first time in this regard.
INTRODUCTION Breast cancer is the most common malignancy in women, responsible for 39 620 breast cancer deaths among US women in 20131. Endocrine therapy is the pivotal treatment in the adjuvant setting for over 75% of breast cancer patients. International guidelines recommend endocrine therapy for long-term treatment of at least 5 years, in patients with hormone-receptor positive primary breast cancer2. Recently, adjuvant treatment of postmenopausal women with aromatase inhibitors (AI) has been proven to be superior to tamoxifen with regard to disease-free as well as overall survival3–5. Aromatase inhibitors, including anastrozole, letrozole and exemestane, inhibit the aromatase enzyme and prevent the
conversion of androgen precursors to estrogen6. According to their biochemical structure, AIs are classified as steroidal or non-steroidal, with exemestane classified as a steroidal AI, which binds irreversibly to aromatase enzyme, whereas letrozole and anastrozole are classified as non-steroidal AIs comprising a reversible binding characteristic7. As a result of their mechanism of action, AIs are responsible for frequently reported musculoskeletal adverse events as well as for an increased incidence of osteoporosis and fractures8–11. Sex steroids define an essential role in breast cancer development. Among postmenopausal women, circulating sex hormone concentrations are strongly associated with several established or suspected risk factors for breast cancer12. After menopause, adipose and muscle tissue are the major
Correspondence: Dr I. Kyvernitakis, Philipps University of Marburg, Department of Gynecological Endocrinology, Reproductive Medicine and Osteoporosis, Baldingerstrasse 1, 35033 Marburg, Germany; Email: [email protected] ORIGINAL ARTICLE © 2015 International Menopause Society DOI: 10.3109/13697137.2014.929105
Received 07-01-2014 Revised 02-05-2014 Accepted 22-05-2014
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Aromatase inhibitors on hormone levels sources of endogenous estrogen, and obese postmenopausal women have both higher levels of endogenous estrogen13 and a higher risk of breast cancer14. Long-term results on serum estradiol concentrations support that AIs significantly decrease serum estradiol levels independent of the patient’s body mass index13. Previous studies have investigated the effects of exemestane and tamoxifen on circulating hormone levels in pre- as well as in postmenopausal women with breast cancer, indicating significantly different effects on hormone levels, such as testosterone, sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and parathyroid hormoneintact15,16. However, available data assessing the effects of non-steroidal AIs, such as anastrozole, on hormone profiles have not yet been reported. Consequently, the aim of the present study was to investigate the impact of anastrozole on serum levels of estradiol, testosterone, dehydroepiandrosterone sulfate (DHEAS), SHBG, FSH and luteinizing hormone (LH) at screening, as well as after 12 and 24 months of treatment. Additionally, we investigated the association with markers of bone turnover as well as bone mineral density (BMD) for the first time in this regard.
Kyvernitakis et al. The primary endpoint of the analysis was to investigate the changes of serum hormone profiles from baseline to 24 months. Secondary endpoints included associations with mean changes in levels of bone turnover markers as well as changes of BMD at the lumbar spine, which have been described separately17. In the present analysis, we assessed changes in hormone levels, including estradiol, testosterone, DHEAS, SHBG, FSH and LH. Moreover, we evaluated the correlations between hormone levels and BMD or markers of bone turnover as predefined in the study protocol.
Assessment of hormones
The study protocol was approved by the local ethics committee of the Philipps-University of Marburg before the enrollment of patients. Informed consent was obtained prior to study start from all subjects in accordance with the German law and the Declaration of Helsinki.
After a medical interview, serum was obtained between 08.00 and 10.00 from all participants after an overnight fast; the serum was directly centrifuged and stored at -80°C until analyses. Hormone levels were assessed for estradiol (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay coefficient of variation (CV) 1.4–3%; interassay CV 2.2–4.9%; sensitivity 5 pg/ml), testosterone (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 2.1–14.8%; interassay CV 2.5–18.1%; sensitivity 0.025 ng/ml), DHEAS (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 2.3–3.2%; interassay CV 2.4–2.5%; sensitivity 0.1 μg/dl), SHBG (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 1.1–1.7%; interassay CV 1.8–4.0%; sensitivity 0.38 nmol/l), FSH (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 1.3–2.8%; interassay CV 3.6–4.5%; sensitivity 0.1 mIU/ml) and LH (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 0.9–1.2%; interassay CV 1.6–2.2%; sensitivity 0.1 mIU/ml).
Study population and design
Statistical analysis
We prospectively investigated the serum hormone profiles of 70 postmenopausal women with primary hormone-receptor positive breast cancer. All patients had been introduced to the local interdisciplinary Tumor Board after they received surgery radiation treatment and had been assigned to adjuvant endocrine therapy with 1 mg anastrozole/day. Our study was a single-center, partially blind, longitudinal comparison over a 24-month period. We conducted visits at baseline, as well as after 12 and 24 months of therapy. The diagnosis and treatment occurred independently of study participation in accordance with the current national guidelines for breast cancer at the time of recruitment. Women receiving any drug treatment at baseline, including steroids, vitamin D, calcium, calcitonin, bisphosphonates or suffering from any endocrine, renal or bone diseases known to affect hormone or bone metabolism were excluded from the study. Furthermore, patients receiving a bone-targeted therapy at any point in time during the observation period were excluded from the study. Detailed data regarding endocrine symptoms, medication and anthropometric variables were collected at each visit.
Statistical analysis was performed by SPSS (Chicago, IL, USA) for Windows version 20. A control for normal distribution was performed by the Kolmogorov–Smirnov test. We applied ANOVA analyses, including the Bonferroni adjustment in the post-hoc-analysis, which adjusts probabilities on the basis of numbers of tests performed for each analysis. The correlation was calculated according to Spearman. All tests were performed two-sided and statistical significance was achieved with a p value 0.05. The results of all parameters were expressed as mean and standard deviation (SD). The Wilcoxon test and Mann–Whitney U-test were used to evaluate group differences.
METHODS
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RESULTS A total of 70 patients were recruited in the study and were available for the analyses. All patients presented with a postmenopausal status, as well as with a primary hormone receptor-positive breast cancer. Baseline characteristics of the study population are depicted in Table 1.
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DHEAS,
Hormone levels following treatment with anastrozole Median circulating levels of the studied hormones at each time point during treatment are reported in Table 2, while percentage and absolute changes are shown in Table 3 and Figure 1. Patients receiving anastrozole showed significant decreases in serum estradiol and LH from baseline, while FSH, testosterone and DHEAS increased. We found significant decreases of 92.1% for estradiol (p 0.001) and 11.1% for LH (p 0.002) over the 24 months of follow-up, while FSH, DHEAS and testosterone concentrations showed significant increases of 5.9%, 33.3% and 50% (p 0.001), respectively. With regard to SHBG, we noticed a non-significant decrease of 5.1% (p 0.355) after 24 months of anastrozole treatment.
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20.0 14.3 1.9 64.6 35.8 12.0 0.001 0.002 0.355 0.001 0.001 0.001 3.63, 2.99, 0.92, 6.23, 4.74, 3.56, 0.913 0.384 0.106 0.001 0.517 0.472 0.11, 0.87, 1.61, 3.95, 0.65, 0.72, 4.34, 0.001 2.96, 0.384 0.57, 0.106 5.27, 0.001 5.16, 0.001 4.1, 0.001 71.7 28.8 58.2 18 2.61 0.52 72.3 26.7 30.3 11.0 62.9 35.7 18 20.6 2.88 1.79 0.62 0.49
FSH, follicle stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin; DHEAS, dehydroepiandrosterone sulfate; tv, statistical marker of Friedman test
tumors;
74.1 29.9 57.1 23.1 2.33 0.52
malignant
73.8 26.5 30.4 10.1 62.6 32.5 25.3 22.8 2.82 1.74 0.59 0.45
TNM, TNM classification of dehydroepiandrosterone sulfate
67.7 32.4 61.3 46.3 1.95 0.35
77.1% 22.9% 100%
65.6 28.0 33.1 13.5 63.8 34.0 60.9 76.0 2.36 1.71 0.42 0.35
54 16 70
FSH (IU/l) LH (IU/l) SHBG (nmol/l) Estradiol (pmol/l) DHEAS (μmol/l) Testosterone (nmol/l)
2.9% 21.4% 75.7% 100%
0 vs. 24 months
2 15 53 70
12 vs. 24 months
5.7% 94.3% 100%
0 vs. 12 months
4 66 70
Median
100% 100%
Mean SD
70 70
Median
98.6% 1.4% 100%
Mean SD
69 1 70
Median
58.6% 27.1% 8.6% 5.7% 100%
Mean SD
41 19 6 4 70
Wilcoxon test tv, p
77.1% 22.9% 100%
24 months
54 16 70
12 months
62.1 7.4 163.5 5.9 75.3 16.7 28.1 5.6
Baseline
70 70 70 70
Hormone levels at baseline, 12 and 24 months (n 70)
Age (years) Height (cm) Weight (kg) Body mass index (kg/cm2) TNM-T T1 T2 total TNM-N N0 N1 N2 N3 total TNM-M M0 M1 total Receptor status positive total Radiation therapy no yes total Chemotherapy other anthracycin no total Type of surgery breast conservation mastectomy total
Friedman test
Mean standard deviation or %
Table 2
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n
Overall tv
Table 1 Baseline patient characteristics
0.001 0.001 0.379 0.001 0.001 0.002
Kyvernitakis et al. Overall p
Aromatase inhibitors on hormone levels
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Aromatase inhibitors on hormone levels Table 3
Kyvernitakis et al.
Percentage and absolute changes in hormone levels at baseline, 12 and 24 months (n 70) Median value
FSH (IU/l) LH (IU/l) SHBG (nmol/l) Estradiol (pmol/l) DHEAS (μmol/l) Testosterone (nmol/l)
% change
Absolute change
Baseline
12 months
24 months
0–12 months
12–24 months
0–24 months
0–12 months
12–24 months
0–24 months
67.7 32.4 61.3 46.3 1.9 0.3
74.1 29.9 57.1 23.1 2.4 0.6
71.7 28.8 58.2 18 2.7 0.6
9.5 7.7 6.9 50.0 19.4 50.0
3.2 3.7 1.9 84.1 11.6 0.0
5.9 11.1 5.1 92.1 33.3 50.0
6.4 2.5 4.2 23.1 0.5 0.3
2.4 1.1 1.1 19.5 0.3 0.0
4.0 3.6 3.1 42.6 0.8 0.3
Estradiol concentrations not only significantly decreased in the first 12 months of treatment, but also showed a further decline until the study end (p 0.001). Interestingly, the increases in concentrations of FSH, DHEAS and testosterone reached statistical significance only from baseline to 12 months of treatment (p 0.001), stabilizing thereafter. Investigating the 12-month intervals individually, LH and SHBG levels remained stable, whereas a significant decrease was only noted in the levels of LH (p 0.002) over the 24-month period.
Relationship of BMD or markers of bone turnover to hormone levels There were modest associations between FSH, SHBG and the bone turnover markers CrossLaps and N-terminal propeptide of human procollagen type I (PINP) (r 0.361, p 0.001 and
% change of median from baseline
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FSH, follicle stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin; DHEAS, dehydroepiandrosterone sulfate
r 0.238, p 0.05 for FSH and r 0.333, p 0.01 and r 0.41, p 0.001 for SHBG, respectively). The percentage change in BMD (g/cm2) from baseline to month 24 was measured by dual-energy absorptiometry (DXA) imaging (I-DXA; GE/Lunar) showing decreases of -2.9% and -4.3% at the lumbar spine (L1–L4) and total hip (p 0.009 and p 0.001), respectively detected. The decline of BMD at the lumbar spine stabilized after 12 months of treatment, while it further decreased at the total hip. All measurements were conducted by the same operator according to the operating procedures of the manufacturer. Moreover, SHBG correlated positively with the BMD at the femoral neck (r 0.265, p 0.03), total hip (r 0.389, p 0.001), total hip T-score (r 0.355, p 0.001), lumbar spine (r 0.326, p 0.01) and the lumbar spine T-score (r 0.301, p 0.01), while FSH correlated negatively with the lumbar spine T-score (r 0.295, p 0.01). Estradiol was associated with testosterone
60 50 40 30 20 10 0 -10
-20 -30 -40 -50 -60 -70 -80 -90 -100
baseline FSH [mIU/ml]
12 month LH [mIU/ml]
SHBG [nmol/l]
E2 [pg/ml]
24 month DHEAS [µg/ml]
Testosterone [ng/ml]
Figure 1 Percentage changes from baseline of hormone levels of 70 postmenopausal patients with estrogen receptor-positive breast cancer treated with anastrozole. FSH, follicle stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin; E2, estradiol; DHEAS, dehydroepiandrosterone sulfate
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Aromatase inhibitors on hormone levels (r 0.394, p 0.001) and the BMD of the lumbar spine (r 0.255, p 0.03), as well as with lumbar spine T-score (r 0.275, p 0.02). Testosterone also presented associations with DHEAS (r 0.51, p 0.001). From a statistical point of view, the changes between estradiol and testosterone presented a positive correlation at baseline, 12 and 24 months. Analyzing these two hormonal parameters, we found that, when estradiol values increased or decreased to a certain measurement point, testosterone in parallel increased or decreased. However, because the changes of testosterone were small compared to the large changes of estradiol, it is unclear whether these findings include any clinical significance.
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DISCUSSION The results of the present study indicate that treatment with anastrozole leads to a significant and clinically important decrease in serum estradiol as well as serum LH levels. Additionally, we found increases in testosterone, DHEAS and FSH levels. Circulating SHBG levels remained stable during the observation period. With regard to their underlying mechanisms of action, AIs bind to the aromatase enzyme and prevent the conversion of androgen precursors to estrogen6. This increase in androgens, such as testosterone and DHEAS, could explain the detected decline in LH. In addition, through feedback at the pituitary level, estradiol depletion leads to an increase in serum FSH levels. Mitwally and colleagues18 indicated that an increase in testosterone levels might additionally stimulate FSH production. Moreover, we analyzed the total data set to investigate the clinically relevant correlation between hormone levels and bone turnover markers and BMD. Changes in hormone levels had clinically significant associations with bone metabolism and BMD. We observed associations between FSH, SHBG and markers of bone turnover and BMD. Of particular interest is the role of SHBG, as it correlates with BMD measurements at almost all sites, as well as with both CrossLaps and PINP. This is somewhat surprising as this correlation has not been detected and reported previously. SHBG has both enhancing and inhibiting hormonal influences. SHBG levels are decreased by androgens and increase with estrogenic states. It has been shown that high serum estradiol levels enhance SHBG production in the liver. Estrogen depletion, as in AI treatment, on the other hand would lead to a reduction of SHBG, further increasing free androgen levels such as testosterone19. Furthermore, estradiol comprised the expected associations with lumbar spine BMD. To the best of our knowledge, data on long-term effects of anastrozole on hormone levels have not yet been reported. Previous studies have examined the hormone levels during treatment with exemestane or letrozole in postmenopausal women with hormone receptor-positive breast cancer. Evans and colleagues20 evaluated the short-term effects of exemestane 25 mg on estradiol and studied the associations with LH, FSH and DHEAS. They concluded that exemestane resulted in a 28% suppression of estradiol values from baseline and showed no associations with LH, FSH and DHEAS. However,
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Kyvernitakis et al. blood sampling was performed 5 days after a single dose of exemestane, which may explain the discrepancies from our findings. Further investigations from a phase I trial showed that exemestane at higher doses ( 50 mg/day) may increase DHEAS and testosterone levels, while the common dose of 25 mg/day was not associated with changes in DHEAS, androstendione or testosterone levels21. In a recent analysis by the TEAM trial, Hadji and colleagues15 compared the effects of exemestane vs. tamoxifen on hormone levels over 12 months of treatment. They stated that exemestane treatment was associated with a decrease in SHBG and increases in testosterone, DHEAS and FSH levels, while treatment with tamoxifen resulted in increases in SHBG, whereas the levels of testosterone and FSH decreased. Similarly, Rossi and colleagues22 compared the endocrine effects of the non-steroidal AI letrozole with tamoxifen in the HOBOE trial, indicating significantly different changes in hormone profiles between the two compounds. The authors supported that the profound inhibition of estradiol secretion could explain the higher efficacy of letrozole against tamoxifen, but also the higher incidence of long-term side-effects, such as osteoporosis, arthralgia as well as alteration in lipid metabolism. Furthermore, a sub-analysis of the REBBeCA trial19, examining the impact of aromatase inhibition on gonadal hormone levels of chemotherapy-induced postmenopausal patients, reported that AI users had significantly higher levels of free testosterone and significantly lower levels of SHBG after 24 months. Our results indicated severe increases in FSH, DHEAS and testosterone in the first 12 months of treatment, but also the stabilization in the following 12 months. Corresponding to these hormonal changes, Kyvernitakis and colleagues8 investigated the long-term effects of anastrozole therapy in postmenopausal women with breast cancer on clinically relevant menopausal symptoms and showed that these increased in the first year but stabilized or even improved in the 2nd year of treatment. These findings may be associated with the stabilization of hormone levels in the 2nd year of treatment, which warrants further investigation. The main limitation of our study is the missing placebo group, which would indicate the true value of our findings. We believe that it would be unethical to withhold adjuvant treatment to women with endocrine-responsive breast cancer for the purpose of this study, especially in the light of the efficacy of these treatments with regard to the overall survival benefit. Additionally, we could have used tamoxifen as a comparator but, because of the superiority of anastrozole vs. tamoxifen shown in the ATAC study, our local Tumor Board preferably recommended the AI as the frontline treatment, with an opportunity to switch after 2–3 years5,23. A further limitation of our study is the variability in hormone levels in postmenopausal women. Low testosterone levels measured in non-testosteronetreated women are less reliable and widely variable16. Furthermore, considering that SHBG values did not significantly change during the study period, the observed associations between these and BMD or bone turnover markers should be interpreted with caution since further evidence is currently missing. Finally, a considerable limitation of our study is the
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Aromatase inhibitors on hormone levels
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high mean baseline value of estradiol, which indicates crossreactivity with estrone and a variety of estradiol conjugates. This result is frequently reported in commercial assays24. The main strength of our study is its prospective design and the use of rigorous selection criteria for recruitment as well as being a single-center study, ensuring a fast process and immediate storage of the serum samples. Additionally, the present analysis assessed long-term changes in hormone concentrations by high-sensitivity assays for the first time in this regard. In conclusion, our results indicate that adjuvant endocrine treatment with anastrozole leads to significant increases in circulating levels of FSH, DHEAS and testosterone in the first 12 months of treatment, whereas they stabilize thereafter. Additionally, we found notable decreases in the hormone profiles of estradiol and LH during the first 24 months of
Kyvernitakis et al. treatment. Our analysis indicates a possible relation of SHBG and bone metabolism, as it correlates with BMD measurements at almost all sites. Finally, we presented modest associations of FSH and SHBG with markers of bone turnover. Conflict of interest Dr Hadji has received honoraria, unrestricted educational grants, and research funding from the following companies: Amgen, Novartis, GlaxoSmithKline, Eli Lilly, AstraZeneca, Roche, and Pfi zer. All other authors report no confl icts of interest. The authors alone are responsible for the content and writing of the paper. Source of funding An unrestricted grant from AstraZeneca has sponsored this research. Registration number of the German registry of clinical studies: DRKS00004826.
References 1. Desantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin 2014;64:52–62 2. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010;28:3784–96 3. Coates AS, Keshaviah A, Thurlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007;25:486–92 4. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007;369:559–70 5. Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45–53 6. Brodie AH, Jelovac D, Long B. The intratumoral aromatase model: studies with aromatase inhibitors and antiestrogens. J Steroid Biochem Mol Biol 2003;86:283–8 7. Miller WR, Bartlett J, Brodie AM, et al. Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist 2008;13:829–37 8. Kyvernitakis I, Ziller V, Hars O, Bauer M, Kalder M, Hadji P. Prevalence of menopausal symptoms and their influence on adherence in women with breast cancer. Climacteric 2014;17:252–9 9. Hadji P. Menopausal symptoms and adjuvant therapy-associated adverse events. Endocr Relat Cancer 2008;15:73–90 10. Eastell R, Adams J, Clack G, et al. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol 2011;22:857–62 11. Rabaglio M, Sun Z, Price KN, et al. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol 2009;20:1489–98 12. Key TJ, Appleby PN, Reeves GK, et al. Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. Br J Cancer 2011;105:709–22 13. Kyvernitakis I, Knoll D, Struck M, Hars O, Bauer T, Hadji P. Impact of BMI on serum estradiol and bone turnover markers in postmenopausal women with hormone-sensitive early breast cancer treated with anastrozole. J Cancer Res Clin Oncol 2014;140:159–66
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14. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003;95:1218–26 15. Hadji P, Kauka A, Bauer T, Tams J, Hasenburg A, Kieback DG. Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German substudy. Climacteric 2012;15: 460–6 16. Johansson H, Bonanni B, Gandini S, et al. Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide. Breast Cancer Res Treat 2013;142:569–78 17. Kyvernitakis I, Rachner TD, Urbschat A, Hars O, Hofbauer LC, Hadji P. Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer. J Cancer Res Clin Oncol 2014 June 7. Epub ahead of print 18. Mitwally MF, Casper RF, Diamond MP. Oestrogen-selective modulation of FSH and LH secretion by pituitary gland. Br J Cancer 2005;92:416–17 19. van Londen GJ, Perera S, Vujevich K, et al. The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer. Breast Cancer Res Treat 2011;125:441–6 20. Evans TR, Di Salle E, Ornati G, et al. Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res 1992;52:5933–9 21. Johannessen DC, Engan T, Di Salle E, et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res 1997;3:1101–8 22. Rossi E, Morabito A, Di Rella F, et al. Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial. J Clin Oncol 2009;27:3192–7 23. Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365:60–2 24. Naessen T1, Sjogren U, Bergquist J, Larsson M, Lind L, Kushnir MM. Endogenous steroids measured by high-specificity liquid chromatography-tandem mass spectrometry and prevalent cardiovascular disease in 70-year-old men and women. J Clin Endocrinol Metab 2010;95:1889–97
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Effect of anastrozole on hormone levels in postmenopausal women with early breast cancer I. Kyvernitakis, U-S. Albert*, M. Kalder, A-S. Winarno, O. Hars* and P. Hadji* Department of Gynecology and Obstetrics, and *Department of Gynecological Endocrinology, Reproductive Medicine and Osteoporosis, Philipps-University of Marburg, Germany
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Key words: HORMONE LEVELS, BREAST CANCER, AROMATASE INHIBITOR, POSTMENOPAUSAL
ABSTRACT Objectives The aim of this study was to investigate the influence of anastrozole on serum hormone levels in postmenopausal women with hormone receptor-positive breast cancer. Methods We prospectively determined serum levels of estradiol, testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and luteinizing hormone (LH) at screening, as well as after 12 and 24 months of treatment and studied the associations with markers of bone turnover and bone mineral density (BMD). Results Altogether, a full set of hormone levels was available for 70 patients. Anastrozole treatment led to decreases of 92.1% for estradiol and 11.1% for LH over the observation period (p 0.001). Conversely, FSH, DHEAS and testosterone concentrations increased by 5.9%, 33.3% and 50%, respectively (p 0.001). SHBG levels remained stable during the 24 months of treatment (p 0.355). There were modest associations between FSH, SHBG, CrossLaps and N-terminal propeptide of human procollagen type I (p 0.05). Moreover, SHBG correlated positively with the BMD of femoral neck, total hip, total hip T-score, lumbar spine and the lumbar spine T-score, whereas FSH and estradiol correlated with the lumbar spine T-score (p 0.05). Conclusions During the 24 months of follow-up, treatment with anastrozole decreased the serum levels of estradiol and LH. Furthermore, we found notable increases of serum levels of FSH, DHEAS and testosterone in the first 12 months of treatment, stabilizing thereafter. Additionally, we were able to correlate hormone levels with markers of bone turnover and BMD for the first time in this regard.
INTRODUCTION Breast cancer is the most common malignancy in women, responsible for 39 620 breast cancer deaths among US women in 20131. Endocrine therapy is the pivotal treatment in the adjuvant setting for over 75% of breast cancer patients. International guidelines recommend endocrine therapy for long-term treatment of at least 5 years, in patients with hormone-receptor positive primary breast cancer2. Recently, adjuvant treatment of postmenopausal women with aromatase inhibitors (AI) has been proven to be superior to tamoxifen with regard to disease-free as well as overall survival3–5. Aromatase inhibitors, including anastrozole, letrozole and exemestane, inhibit the aromatase enzyme and prevent the
conversion of androgen precursors to estrogen6. According to their biochemical structure, AIs are classified as steroidal or non-steroidal, with exemestane classified as a steroidal AI, which binds irreversibly to aromatase enzyme, whereas letrozole and anastrozole are classified as non-steroidal AIs comprising a reversible binding characteristic7. As a result of their mechanism of action, AIs are responsible for frequently reported musculoskeletal adverse events as well as for an increased incidence of osteoporosis and fractures8–11. Sex steroids define an essential role in breast cancer development. Among postmenopausal women, circulating sex hormone concentrations are strongly associated with several established or suspected risk factors for breast cancer12. After menopause, adipose and muscle tissue are the major
Correspondence: Dr I. Kyvernitakis, Philipps University of Marburg, Department of Gynecological Endocrinology, Reproductive Medicine and Osteoporosis, Baldingerstrasse 1, 35033 Marburg, Germany; Email: [email protected] ORIGINAL ARTICLE © 2015 International Menopause Society DOI: 10.3109/13697137.2014.929105
Received 07-01-2014 Revised 02-05-2014 Accepted 22-05-2014
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Aromatase inhibitors on hormone levels sources of endogenous estrogen, and obese postmenopausal women have both higher levels of endogenous estrogen13 and a higher risk of breast cancer14. Long-term results on serum estradiol concentrations support that AIs significantly decrease serum estradiol levels independent of the patient’s body mass index13. Previous studies have investigated the effects of exemestane and tamoxifen on circulating hormone levels in pre- as well as in postmenopausal women with breast cancer, indicating significantly different effects on hormone levels, such as testosterone, sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and parathyroid hormoneintact15,16. However, available data assessing the effects of non-steroidal AIs, such as anastrozole, on hormone profiles have not yet been reported. Consequently, the aim of the present study was to investigate the impact of anastrozole on serum levels of estradiol, testosterone, dehydroepiandrosterone sulfate (DHEAS), SHBG, FSH and luteinizing hormone (LH) at screening, as well as after 12 and 24 months of treatment. Additionally, we investigated the association with markers of bone turnover as well as bone mineral density (BMD) for the first time in this regard.
Kyvernitakis et al. The primary endpoint of the analysis was to investigate the changes of serum hormone profiles from baseline to 24 months. Secondary endpoints included associations with mean changes in levels of bone turnover markers as well as changes of BMD at the lumbar spine, which have been described separately17. In the present analysis, we assessed changes in hormone levels, including estradiol, testosterone, DHEAS, SHBG, FSH and LH. Moreover, we evaluated the correlations between hormone levels and BMD or markers of bone turnover as predefined in the study protocol.
Assessment of hormones
The study protocol was approved by the local ethics committee of the Philipps-University of Marburg before the enrollment of patients. Informed consent was obtained prior to study start from all subjects in accordance with the German law and the Declaration of Helsinki.
After a medical interview, serum was obtained between 08.00 and 10.00 from all participants after an overnight fast; the serum was directly centrifuged and stored at -80°C until analyses. Hormone levels were assessed for estradiol (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay coefficient of variation (CV) 1.4–3%; interassay CV 2.2–4.9%; sensitivity 5 pg/ml), testosterone (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 2.1–14.8%; interassay CV 2.5–18.1%; sensitivity 0.025 ng/ml), DHEAS (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 2.3–3.2%; interassay CV 2.4–2.5%; sensitivity 0.1 μg/dl), SHBG (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 1.1–1.7%; interassay CV 1.8–4.0%; sensitivity 0.38 nmol/l), FSH (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 1.3–2.8%; interassay CV 3.6–4.5%; sensitivity 0.1 mIU/ml) and LH (Roche Diagnostics GmbH, ECLIA-Cobas 601; intra-assay CV 0.9–1.2%; interassay CV 1.6–2.2%; sensitivity 0.1 mIU/ml).
Study population and design
Statistical analysis
We prospectively investigated the serum hormone profiles of 70 postmenopausal women with primary hormone-receptor positive breast cancer. All patients had been introduced to the local interdisciplinary Tumor Board after they received surgery radiation treatment and had been assigned to adjuvant endocrine therapy with 1 mg anastrozole/day. Our study was a single-center, partially blind, longitudinal comparison over a 24-month period. We conducted visits at baseline, as well as after 12 and 24 months of therapy. The diagnosis and treatment occurred independently of study participation in accordance with the current national guidelines for breast cancer at the time of recruitment. Women receiving any drug treatment at baseline, including steroids, vitamin D, calcium, calcitonin, bisphosphonates or suffering from any endocrine, renal or bone diseases known to affect hormone or bone metabolism were excluded from the study. Furthermore, patients receiving a bone-targeted therapy at any point in time during the observation period were excluded from the study. Detailed data regarding endocrine symptoms, medication and anthropometric variables were collected at each visit.
Statistical analysis was performed by SPSS (Chicago, IL, USA) for Windows version 20. A control for normal distribution was performed by the Kolmogorov–Smirnov test. We applied ANOVA analyses, including the Bonferroni adjustment in the post-hoc-analysis, which adjusts probabilities on the basis of numbers of tests performed for each analysis. The correlation was calculated according to Spearman. All tests were performed two-sided and statistical significance was achieved with a p value 0.05. The results of all parameters were expressed as mean and standard deviation (SD). The Wilcoxon test and Mann–Whitney U-test were used to evaluate group differences.
METHODS
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RESULTS A total of 70 patients were recruited in the study and were available for the analyses. All patients presented with a postmenopausal status, as well as with a primary hormone receptor-positive breast cancer. Baseline characteristics of the study population are depicted in Table 1.
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DHEAS,
Hormone levels following treatment with anastrozole Median circulating levels of the studied hormones at each time point during treatment are reported in Table 2, while percentage and absolute changes are shown in Table 3 and Figure 1. Patients receiving anastrozole showed significant decreases in serum estradiol and LH from baseline, while FSH, testosterone and DHEAS increased. We found significant decreases of 92.1% for estradiol (p 0.001) and 11.1% for LH (p 0.002) over the 24 months of follow-up, while FSH, DHEAS and testosterone concentrations showed significant increases of 5.9%, 33.3% and 50% (p 0.001), respectively. With regard to SHBG, we noticed a non-significant decrease of 5.1% (p 0.355) after 24 months of anastrozole treatment.
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20.0 14.3 1.9 64.6 35.8 12.0 0.001 0.002 0.355 0.001 0.001 0.001 3.63, 2.99, 0.92, 6.23, 4.74, 3.56, 0.913 0.384 0.106 0.001 0.517 0.472 0.11, 0.87, 1.61, 3.95, 0.65, 0.72, 4.34, 0.001 2.96, 0.384 0.57, 0.106 5.27, 0.001 5.16, 0.001 4.1, 0.001 71.7 28.8 58.2 18 2.61 0.52 72.3 26.7 30.3 11.0 62.9 35.7 18 20.6 2.88 1.79 0.62 0.49
FSH, follicle stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin; DHEAS, dehydroepiandrosterone sulfate; tv, statistical marker of Friedman test
tumors;
74.1 29.9 57.1 23.1 2.33 0.52
malignant
73.8 26.5 30.4 10.1 62.6 32.5 25.3 22.8 2.82 1.74 0.59 0.45
TNM, TNM classification of dehydroepiandrosterone sulfate
67.7 32.4 61.3 46.3 1.95 0.35
77.1% 22.9% 100%
65.6 28.0 33.1 13.5 63.8 34.0 60.9 76.0 2.36 1.71 0.42 0.35
54 16 70
FSH (IU/l) LH (IU/l) SHBG (nmol/l) Estradiol (pmol/l) DHEAS (μmol/l) Testosterone (nmol/l)
2.9% 21.4% 75.7% 100%
0 vs. 24 months
2 15 53 70
12 vs. 24 months
5.7% 94.3% 100%
0 vs. 12 months
4 66 70
Median
100% 100%
Mean SD
70 70
Median
98.6% 1.4% 100%
Mean SD
69 1 70
Median
58.6% 27.1% 8.6% 5.7% 100%
Mean SD
41 19 6 4 70
Wilcoxon test tv, p
77.1% 22.9% 100%
24 months
54 16 70
12 months
62.1 7.4 163.5 5.9 75.3 16.7 28.1 5.6
Baseline
70 70 70 70
Hormone levels at baseline, 12 and 24 months (n 70)
Age (years) Height (cm) Weight (kg) Body mass index (kg/cm2) TNM-T T1 T2 total TNM-N N0 N1 N2 N3 total TNM-M M0 M1 total Receptor status positive total Radiation therapy no yes total Chemotherapy other anthracycin no total Type of surgery breast conservation mastectomy total
Friedman test
Mean standard deviation or %
Table 2
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n
Overall tv
Table 1 Baseline patient characteristics
0.001 0.001 0.379 0.001 0.001 0.002
Kyvernitakis et al. Overall p
Aromatase inhibitors on hormone levels
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Aromatase inhibitors on hormone levels Table 3
Kyvernitakis et al.
Percentage and absolute changes in hormone levels at baseline, 12 and 24 months (n 70) Median value
FSH (IU/l) LH (IU/l) SHBG (nmol/l) Estradiol (pmol/l) DHEAS (μmol/l) Testosterone (nmol/l)
% change
Absolute change
Baseline
12 months
24 months
0–12 months
12–24 months
0–24 months
0–12 months
12–24 months
0–24 months
67.7 32.4 61.3 46.3 1.9 0.3
74.1 29.9 57.1 23.1 2.4 0.6
71.7 28.8 58.2 18 2.7 0.6
9.5 7.7 6.9 50.0 19.4 50.0
3.2 3.7 1.9 84.1 11.6 0.0
5.9 11.1 5.1 92.1 33.3 50.0
6.4 2.5 4.2 23.1 0.5 0.3
2.4 1.1 1.1 19.5 0.3 0.0
4.0 3.6 3.1 42.6 0.8 0.3
Estradiol concentrations not only significantly decreased in the first 12 months of treatment, but also showed a further decline until the study end (p 0.001). Interestingly, the increases in concentrations of FSH, DHEAS and testosterone reached statistical significance only from baseline to 12 months of treatment (p 0.001), stabilizing thereafter. Investigating the 12-month intervals individually, LH and SHBG levels remained stable, whereas a significant decrease was only noted in the levels of LH (p 0.002) over the 24-month period.
Relationship of BMD or markers of bone turnover to hormone levels There were modest associations between FSH, SHBG and the bone turnover markers CrossLaps and N-terminal propeptide of human procollagen type I (PINP) (r 0.361, p 0.001 and
% change of median from baseline
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FSH, follicle stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin; DHEAS, dehydroepiandrosterone sulfate
r 0.238, p 0.05 for FSH and r 0.333, p 0.01 and r 0.41, p 0.001 for SHBG, respectively). The percentage change in BMD (g/cm2) from baseline to month 24 was measured by dual-energy absorptiometry (DXA) imaging (I-DXA; GE/Lunar) showing decreases of -2.9% and -4.3% at the lumbar spine (L1–L4) and total hip (p 0.009 and p 0.001), respectively detected. The decline of BMD at the lumbar spine stabilized after 12 months of treatment, while it further decreased at the total hip. All measurements were conducted by the same operator according to the operating procedures of the manufacturer. Moreover, SHBG correlated positively with the BMD at the femoral neck (r 0.265, p 0.03), total hip (r 0.389, p 0.001), total hip T-score (r 0.355, p 0.001), lumbar spine (r 0.326, p 0.01) and the lumbar spine T-score (r 0.301, p 0.01), while FSH correlated negatively with the lumbar spine T-score (r 0.295, p 0.01). Estradiol was associated with testosterone
60 50 40 30 20 10 0 -10
-20 -30 -40 -50 -60 -70 -80 -90 -100
baseline FSH [mIU/ml]
12 month LH [mIU/ml]
SHBG [nmol/l]
E2 [pg/ml]
24 month DHEAS [µg/ml]
Testosterone [ng/ml]
Figure 1 Percentage changes from baseline of hormone levels of 70 postmenopausal patients with estrogen receptor-positive breast cancer treated with anastrozole. FSH, follicle stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin; E2, estradiol; DHEAS, dehydroepiandrosterone sulfate
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Aromatase inhibitors on hormone levels (r 0.394, p 0.001) and the BMD of the lumbar spine (r 0.255, p 0.03), as well as with lumbar spine T-score (r 0.275, p 0.02). Testosterone also presented associations with DHEAS (r 0.51, p 0.001). From a statistical point of view, the changes between estradiol and testosterone presented a positive correlation at baseline, 12 and 24 months. Analyzing these two hormonal parameters, we found that, when estradiol values increased or decreased to a certain measurement point, testosterone in parallel increased or decreased. However, because the changes of testosterone were small compared to the large changes of estradiol, it is unclear whether these findings include any clinical significance.
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DISCUSSION The results of the present study indicate that treatment with anastrozole leads to a significant and clinically important decrease in serum estradiol as well as serum LH levels. Additionally, we found increases in testosterone, DHEAS and FSH levels. Circulating SHBG levels remained stable during the observation period. With regard to their underlying mechanisms of action, AIs bind to the aromatase enzyme and prevent the conversion of androgen precursors to estrogen6. This increase in androgens, such as testosterone and DHEAS, could explain the detected decline in LH. In addition, through feedback at the pituitary level, estradiol depletion leads to an increase in serum FSH levels. Mitwally and colleagues18 indicated that an increase in testosterone levels might additionally stimulate FSH production. Moreover, we analyzed the total data set to investigate the clinically relevant correlation between hormone levels and bone turnover markers and BMD. Changes in hormone levels had clinically significant associations with bone metabolism and BMD. We observed associations between FSH, SHBG and markers of bone turnover and BMD. Of particular interest is the role of SHBG, as it correlates with BMD measurements at almost all sites, as well as with both CrossLaps and PINP. This is somewhat surprising as this correlation has not been detected and reported previously. SHBG has both enhancing and inhibiting hormonal influences. SHBG levels are decreased by androgens and increase with estrogenic states. It has been shown that high serum estradiol levels enhance SHBG production in the liver. Estrogen depletion, as in AI treatment, on the other hand would lead to a reduction of SHBG, further increasing free androgen levels such as testosterone19. Furthermore, estradiol comprised the expected associations with lumbar spine BMD. To the best of our knowledge, data on long-term effects of anastrozole on hormone levels have not yet been reported. Previous studies have examined the hormone levels during treatment with exemestane or letrozole in postmenopausal women with hormone receptor-positive breast cancer. Evans and colleagues20 evaluated the short-term effects of exemestane 25 mg on estradiol and studied the associations with LH, FSH and DHEAS. They concluded that exemestane resulted in a 28% suppression of estradiol values from baseline and showed no associations with LH, FSH and DHEAS. However,
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Kyvernitakis et al. blood sampling was performed 5 days after a single dose of exemestane, which may explain the discrepancies from our findings. Further investigations from a phase I trial showed that exemestane at higher doses ( 50 mg/day) may increase DHEAS and testosterone levels, while the common dose of 25 mg/day was not associated with changes in DHEAS, androstendione or testosterone levels21. In a recent analysis by the TEAM trial, Hadji and colleagues15 compared the effects of exemestane vs. tamoxifen on hormone levels over 12 months of treatment. They stated that exemestane treatment was associated with a decrease in SHBG and increases in testosterone, DHEAS and FSH levels, while treatment with tamoxifen resulted in increases in SHBG, whereas the levels of testosterone and FSH decreased. Similarly, Rossi and colleagues22 compared the endocrine effects of the non-steroidal AI letrozole with tamoxifen in the HOBOE trial, indicating significantly different changes in hormone profiles between the two compounds. The authors supported that the profound inhibition of estradiol secretion could explain the higher efficacy of letrozole against tamoxifen, but also the higher incidence of long-term side-effects, such as osteoporosis, arthralgia as well as alteration in lipid metabolism. Furthermore, a sub-analysis of the REBBeCA trial19, examining the impact of aromatase inhibition on gonadal hormone levels of chemotherapy-induced postmenopausal patients, reported that AI users had significantly higher levels of free testosterone and significantly lower levels of SHBG after 24 months. Our results indicated severe increases in FSH, DHEAS and testosterone in the first 12 months of treatment, but also the stabilization in the following 12 months. Corresponding to these hormonal changes, Kyvernitakis and colleagues8 investigated the long-term effects of anastrozole therapy in postmenopausal women with breast cancer on clinically relevant menopausal symptoms and showed that these increased in the first year but stabilized or even improved in the 2nd year of treatment. These findings may be associated with the stabilization of hormone levels in the 2nd year of treatment, which warrants further investigation. The main limitation of our study is the missing placebo group, which would indicate the true value of our findings. We believe that it would be unethical to withhold adjuvant treatment to women with endocrine-responsive breast cancer for the purpose of this study, especially in the light of the efficacy of these treatments with regard to the overall survival benefit. Additionally, we could have used tamoxifen as a comparator but, because of the superiority of anastrozole vs. tamoxifen shown in the ATAC study, our local Tumor Board preferably recommended the AI as the frontline treatment, with an opportunity to switch after 2–3 years5,23. A further limitation of our study is the variability in hormone levels in postmenopausal women. Low testosterone levels measured in non-testosteronetreated women are less reliable and widely variable16. Furthermore, considering that SHBG values did not significantly change during the study period, the observed associations between these and BMD or bone turnover markers should be interpreted with caution since further evidence is currently missing. Finally, a considerable limitation of our study is the
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Aromatase inhibitors on hormone levels
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high mean baseline value of estradiol, which indicates crossreactivity with estrone and a variety of estradiol conjugates. This result is frequently reported in commercial assays24. The main strength of our study is its prospective design and the use of rigorous selection criteria for recruitment as well as being a single-center study, ensuring a fast process and immediate storage of the serum samples. Additionally, the present analysis assessed long-term changes in hormone concentrations by high-sensitivity assays for the first time in this regard. In conclusion, our results indicate that adjuvant endocrine treatment with anastrozole leads to significant increases in circulating levels of FSH, DHEAS and testosterone in the first 12 months of treatment, whereas they stabilize thereafter. Additionally, we found notable decreases in the hormone profiles of estradiol and LH during the first 24 months of
Kyvernitakis et al. treatment. Our analysis indicates a possible relation of SHBG and bone metabolism, as it correlates with BMD measurements at almost all sites. Finally, we presented modest associations of FSH and SHBG with markers of bone turnover. Conflict of interest Dr Hadji has received honoraria, unrestricted educational grants, and research funding from the following companies: Amgen, Novartis, GlaxoSmithKline, Eli Lilly, AstraZeneca, Roche, and Pfi zer. All other authors report no confl icts of interest. The authors alone are responsible for the content and writing of the paper. Source of funding An unrestricted grant from AstraZeneca has sponsored this research. Registration number of the German registry of clinical studies: DRKS00004826.
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14. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003;95:1218–26 15. Hadji P, Kauka A, Bauer T, Tams J, Hasenburg A, Kieback DG. Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German substudy. Climacteric 2012;15: 460–6 16. Johansson H, Bonanni B, Gandini S, et al. Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide. Breast Cancer Res Treat 2013;142:569–78 17. Kyvernitakis I, Rachner TD, Urbschat A, Hars O, Hofbauer LC, Hadji P. Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer. J Cancer Res Clin Oncol 2014 June 7. Epub ahead of print 18. Mitwally MF, Casper RF, Diamond MP. Oestrogen-selective modulation of FSH and LH secretion by pituitary gland. Br J Cancer 2005;92:416–17 19. van Londen GJ, Perera S, Vujevich K, et al. The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer. Breast Cancer Res Treat 2011;125:441–6 20. Evans TR, Di Salle E, Ornati G, et al. Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res 1992;52:5933–9 21. Johannessen DC, Engan T, Di Salle E, et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res 1997;3:1101–8 22. Rossi E, Morabito A, Di Rella F, et al. Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial. J Clin Oncol 2009;27:3192–7 23. Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365:60–2 24. Naessen T1, Sjogren U, Bergquist J, Larsson M, Lind L, Kushnir MM. Endogenous steroids measured by high-specificity liquid chromatography-tandem mass spectrometry and prevalent cardiovascular disease in 70-year-old men and women. J Clin Endocrinol Metab 2010;95:1889–97
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