Evaluation of male reproductive function after aromatase inhibitor treatment during adolescence: case series with literature review.

Background. Aromatase inhibitors (AIs) can significantly improve semen parameters in infertile men. In this study, we investigated the efficacy of AIs for azoospermia in a Chinese population with AZFc microdeletion. Aims. Patients with AZFc microdeletion who were treated with AIs were analyzed retrospectively by collecting clinical data, including their hormone profile and treatment outcome. Patients were divided into those with sperm in their semen after AI treatment (group A) and those without sperm in their semen after AI treatment (group B). Results. The rate of Y chromosome AZF microdeletions was 9.30% (313/3364) from March 2015 to March 2021, among which patients with complete AZFc microdeletion accounted for 63.2% (198/313), and of the 198 patients with AZFc microdeletion, 69.7% (138/198) showed azoospermia. Forty-six (33.3%) of the azoospermic patients had sperm in their semen after AI administration. Testosterone (T) and testosterone-to-estradiol ratio (T/E2) levels were higher in group A than those in group B after treatment, and the differences were significant (T, P = 0.038 ; T/E2, P = 0.004 ). Paired t -test demonstrated that the change of T levels before and after treatment was statistically significant ( P = 0.003 ). The increased E2 and T/E2 ratio levels before and after treatment were not statistically significant ( P = 0.057 and 0.080), but they were close to the threshold value ( P = 0.05 ). Conclusions. Patients with AZFc microdeletion accounted for the largest proportion of male infertility caused by Y chromosome microdeletions. AIs can promote spermatogenesis in azoospermic patients with AZFc microdeletion, and sperm could be found in the semen of some patients after AI administration. T and T/E2 levels after AI treatment could be used as biomarkers to distinguish azoospermic patients with AZFc microdeletion who responded better to AIs from those who did not respond well.

Decrement of endometrial thickness was recorded following short-term aromatase inhibitor treatment in breast cancer patients previously treated with tamoxifen. It is necessary to verify if long-term aromatase inhibitor treatment can maintain this phenomenon. Prospective long-term comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 64 postmenopausal breast cancer patients, with further repeated measurements, performed following administration of aromatase inhibitors. There was a significant decrement of endometrial thickness, following 36.5 +/- 15.7 months of tamoxifen treatment, from a mean value of 8.7 +/- 5.2 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.2 +/- 4.6 mm, measured following 5.3 +/- 4.8 months of aromatase inhibitor therapy (P < 0.001). Further ultrasonographic studies revealed the same significant trend. In the first ultrasonographic study performed during aromatase inhibitor treatment, five (7.8%) patients demonstrated a significant increase of endometrial thickness. Hysteroscopy revealed a benign endometrial polyp in three patients and atrophic endometrium in the other 2. In 35 patients (54.7%), endometrial thickness was reduced following the administration of aromatase inhibitors and in 24 patients (37.5%) there was no change in endometrial thickness. With longer duration of aromatase inhibitor therapy, more patients showed decrement of endometrial thickness. Reversal of endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients is maintained throughout long-term aromatase inhibitor treatment.

BackgroundThe Aromatase Inhibitors (AIs)-based therapy used in breast cancer patients to profoundly lower estrogen levels seems to enhance the loss of bone mineral density (BMD) and to increase the fragility...

Background: Estrogen receptors are over-expressed in around 70% of breast cancer cases. The genetic changes that occur during aromatase inhibitor (AI) treatment are not well understood and may differ depending upon the patient's response phenotype. Methods: We performed whole genome sequencing (WGS) of matched blood, pre-treatment, and post-treatment biopsy samples from 22 estrogen receptor positive breast cancer patients treated with neoadjuvant aromatase inhibitors. For 5 cases, we performed the whole genome sequencing (WGS) on patients’ matched normal, two pre AI-treatment, and two post AI-treatment DNA isolates from biopsy samples. We validated all putative coding and non-coding somatic mutations using deep sequencing. By comparing the validated somatic mutations from pre- and post- AI treatment biopsy samples, we were able to determine the alterations in the tumor genomes. In every case we defined the clonal architecture of each pair of pre-treatment and post-treatment biopsy samples by comparing the variant allele frequencies from thousands of validated somatic mutations. Results: Comparisons of the two pre AI-treatment biopsy samples from the same patient indicates that the variant allele frequencies of mutations showed high concordances in all 5 cases, 0.74 to 0.95 range of correlation coefficient. Only a small percentage of somatic mutations were detected in one pre-treatment sample and not the other (4.65% overall). In comparing the somatic variations between pre-treatment and matched post-treatment biopsy samples in 22 cases, we found that patients with good clinical response to AI treatment retained known driver mutations only in their pre-treatment tumors. Conversely, those patients with poor clinical response presented new driver mutations in their post-treatment samples. Furthermore, the variant allele frequency for most mutated genes decreased in post AI treatment samples for patients with good AI treatment response; on the contrary, the variant allele frequency increased for patients with poor clinical response. Conclusions: From WGS of matched normal, pre-treatment, and post-treatment biopsy samples, we identified new driver genes mutated in patients with poor clinical response, while patients with good clinical response had lost mutated driver genes in their post-treatment biopsy samples. The genetic landscape revealed by WGS of pre-treatment and post-treatment biopsy samples reveals mutational repertoires are remodeled by AI therapy. This finding suggests deep sequencing of AI treated samples will be necessary to reveal the complete complement of mutations present in a patient's tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-423. doi:1538-7445.AM2012-LB-423

Introduction: Aromatase Inhibitors (AI) are a mainstay of treatment for hormone receptor positive breast cancer (BC) in postmenopausal women. However, patients under AI treatment often suffer from Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness in hands, fingers, knees, hips and feet, which may limit treatment and subsequently increase BC mortality. The depletion of estrogen following AI initiation has been postulated to cause AIMSS. However, it has not yet been fully established about the clinical significance of AIMSS and its risk factors and the underlying mechanisms. The aim of this study is to identify epidemiologic risk factors associated with the development of AIMSS in BC patients on adjuvant AI therapy. Methods: We conducted a retrospective review of medical records among 111 stages 0-III hormone receptor positive BC patients who received adjuvant AI therapy, including anastrozole, letrozole or exemestane, between January 2009 and June 2017, at the University of Maryland Greenebaum Comprehensive Cancer Center. To be eligible, women had to be either postmenopausal or premenopausal, on a GnRH analog for at least 3 months, and report of no AIMSS before the AI initiation. We collected patients’ data on demographics, lifestyle factors, reproductive histories, tumor characteristics, types of AI and cancer treatment, co-morbidities, use of medications, length of AI therapy, and onset and severity of AIMSS. We defined severe AIMSS as AIMSS requiring the change of AI therapy or discontinuation of AI. The demographics and clinicopathological characteristics of patients on AI therapy and frequencies of AIMSS onset during AI treatment was characterized with means (SDs) or percentages. To estimate the association of severe AIMSS with epidemiologic risk factors, odds ratios (ORs) and 95% confidence intervals were calculated using multivariable-adjusted logistic regression. Results: This study included 111 BC patients with a mean age of 64 years. Their mean BMI at time of BC diagnosis was 30.8 kg/m2, and 41% of patients were White, 39% were Black, 4% were Asian/Pacific Islander, and 16% were other. Majority of patients (77%) had no prior experience of tamoxifen use and used letrozole as an initial AI therapy (70.3%); 15.3% used anastrozole, and 14.4% used exemestane. We found that 52.6% of patients experienced any degree of AIMSS while on AI therapy. In particular, 19.8% of patients required change or holding AI therapy, and 3.6% permanently discontinued AI because of AIMSS. We observed that older age at AI therapy initiation and higher levels of circulating vitamin D-25OH were significantly associated with lower odds of severe AIMSS. Multivariate ORs (95% Cis) comparing the highest to the lowest tertile of age and vitamin D levels at AI initiation were 0.18 (0.05-0.71) and 0.10 (0.02-0.49), respectively (all P-trend: ≤ 0.04). There were no significant association between race, body mass index, smoking, alcohol use, reproductive factors, type of AI therapy, and tamoxifen use prior to AI therapy. Conclusions: In our study, nearly 52.6% of BC patients on adjuvant AI therapy experienced AIMSS. Of those, 23.4% changed or discontinued AI regimen due to severe AIMSS. Older age and higher circulating levels of vitamin D-25OH at the initiation of adjuvant AI therapy were associated with lower risk of developing severe AIMSS. The study results support the clinical significance of AIMSS in BC patients leading to decreased adherence to AI therapy. The replication of our association with age and vitamin D levels in a larger study is warranted as it may provide a greater insight into etiologies of AIMSS. Citation Format: Yamin Sun, Simran Elder, Seungyoun Jung, Candace Mainor, Shruti Murali, Paula Rosenblatt, Katherine Tkaczuk. Factors associated with aromatase inhibitor associated musculoskeletal symptoms in early stage breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-13.

Short-statured midpubertal boys with predicted adult height (PAHt) below the third percentile are a therapeutic challenge. Aromatase inhibitors (AI) delay estrogen-driven epiphyseal fusion and possibly enhance adult height (AHt). To assess the efficacy of AI treatment on AHt in midpubertal boys with a short PAHt due to advanced bone age (BA) or idiopathic short stature (ISS). Retrospective study. Tertiary pediatric endocrine referral center. Two groups of midpubertal boys treated with AI were studied: 27 boys with fast puberty compared to matched untreated controls and 16 boys with ISS treated with GH and AI (GH&AI) compared to those treated with GH only. Anthropometric measurements, BA and PAHt, were tracked. AHt was compared across groups. Achieved AHt in AI-treated boys vs controls and the PAHt. The median duration of AI treatment was 2.8 years for the AI-only group and 2 years for the GH&AI group. Throughout treatment, AI-treated groups gained height similarly to controls and showed a decrease in BA SD score (AI only: P = .009; GH&AI: P = .029) and an improvement in PAHt (AI only: P = .003; GH&AI: P = .037). Compared to controls, AI-treated children achieved greater AHt (AI only: 166.6 ± 3.1 cm vs 163.4 ± 1.3 cm, P = .003; GH&AI: 167.3 ± 6.1 cm vs 164.9 ± 3.5 cm, P = .194). The difference between AHt and PAHt at baseline was more pronounced in the AI-treated groups (AI only: 3.8 ± 3.5 cm vs -0.3 ± 5.0 cm, P = .001; GH&AI: 7.5 ± 5.2 cm vs 4.3 ± 3.6 cm, P = .050). AI treatment extends the growth period, resulting in an AHt surpassing initial predictions. Our findings underscore the potential of AI treatment in midpubertal boys with a short PAHt due to advanced BA and in those treated with GH for ISS.

Cardiovascular disease (CVD) is one of the most common comorbidities in breast cancer survivors. Recently, the target population and treatment period for aromatase inhibitor (AI) treatment in breast cancer patients has been expanding. However, information on adverse CVD events from the long-term use of AI is still lacking. The aim of this study was to investigate the CVD side effects of AI treatment and to evaluate the changes in lipid profile during AI treatment. A systematic search of PubMed (Medline), EMBASE, and Cochrane Library databases reporting on cardiovascular outcomes or lipid profiles change in adult female breast cancer patients (>19 years old) with AI was performed. The pooled analysis of 25 studies showed that the prevalence rate of any type of cardiovascular disease was 6.08 per 100 persons (95% CI 2.91–10.31). Angina was the most common type of heart-related cardiovascular event accounting for 3.85 per 100 persons, followed by any type of stroke (3.34) and venous thromboembolism (2.95). Ischemic stroke (OR 1.39, 95% CI 1.07–1.81) and myocardial infarction (OR 1.30, 95% CI 0.88–1.93) were more common in AI compared with tamoxifen, whereas the prevalence of venous thromboembolism (OR 0.61, 95% CI 0.37–1) was significantly lower in the AI group. In addition, treatment with AI for 6–12 months showed a decrease in HDL-cholesterol and an increase in LDL-cholesterol and total cholesterol. Various CVDs can occur when using AI, and in particular, the risk of MI and ischemic stroke increases in comparison with the adverse effect of tamoxifen. The occurrence of CVD might be related to the deterioration of the lipid profile after AI treatment. Therefore, a customized individualization strategy considering each patient’s CV risk factors is needed during AI treatment.

1130 Background: Because male breast cancer (MBC) is rare, treatment recommendations are derived from results of trials in female patients (pts). Although, several studies have shown the superiority of third-generation aromatase inhibitors (AI) over tamoxifen in menopausal women with advanced breast cancer, the role of such molecules remains unknown in male pts. We report here the largest experience about the efficacy of AI in MBC pts with advanced disease and their impact on estradiol (E) levels. Methods: MBC pts were selected from the breast cancer database of the Centre Antoine-Lacassagne (Nice, France) as follows: Metastatic disease with at least one measurable or assessable non-measurable lesion, estrogen receptor (ER) and/or or progesterone receptor (PR) positive, availability of complete clinical and histological data, evidence of progressive disease at initiation of AI, receipt of at least one month of treatment with non steroidal (anastrozole, letrozole) or steroidal (exemestane) AI. Sex hormone levels were retrospectively assessed on serum samples from our institutional serum bank. Results: 15 pts entered the study. Median age was 68 (range 39–85). 7 pts received previous lines of hormonal therapy (median = 1) and 3 pts a previous line of chemotherapy before the introduction of AI. The best response was complete response in 2 pts (13%), partial response in 4 pts (27%), stable disease (SD) in 2 pts (13%) and progressive disease (PD) in 7 pts (47%). The median duration of objective response (OR) was 11.6 months (95% confidence interval [CI] 7.6–15.5). At the time of analysis, 8 pts (53%) had died and 7 (47%) were still alive. The median PFS and OS were 4.4 months (95% CI 0.1–8.6) and 33 months (95% CI 18.4–47.6) respectively. The 1-year PFS and OS rates were 20% (95% CI 9.7–30.3) and 84.6% (95% CI 74.6–94.6), respectively. 9 out of 11 pts with available samples had E levels less than the lower limit of the assay during AI treatment. Among the 9 pts with E level decrease, four had OR, one had SD, and four had PD. 1 pt had E levels higher than the upper limit of the assay during AI treatment. This pt showed disease progression. Further data on FSH and testosterone levels will be presented at the meeting. Conclusions: AI are active in MBC pts. This activity is correlated with a significant reduction in E levels. No significant financial relationships to disclose.

12018 Background: Aromatase inhibitors (AIs), such as anastrozole, letrozole, and exemestane, are commonly used in the treatment of women with early or advanced-stage breast cancer (BC). However, the potential cardiovascular risks associated with AI treatment, particularly the occurrence of cardiovascular events (CVEs) such as acute myocardial infarction and ischemic stroke, remain a concern. This meta-analysis aims to evaluate the impact of AI and tamoxifen treatment on the risk of CVEs in women with BC. Methods: A comprehensive search was performed across PubMed, Embase, and Cochrane databases for randomized controlled trials (RCTs) and cohort studies comparing cardiovascular outcomes in patients with BC receiving AIs (anastrozole, letrozole, or exemestane) versus those receiving tamoxifen. Data were analyzed using a random-effects model, and the odds ratios (OR) with 95% confidence intervals (CI) were calculated. P values &gt; 0.10 and I2 values &gt; 25% were considered to indicate significance for heterogeneity. Statistical analysis was performed using R, version 4.4.2. Results: Sixteen studies, involving 188,635 participants, were included in the analysis, of whom 124,473 (65.98%) received AI treatment. A statistically significant difference was observed in heart failure and cardiomyopathy, with the treatment showing an increased risk of these events (OR: 1.48; 95% CI [1.11 to 1.99]; p = 0.0079; I2: 79%). Similarly, myocardial infarction was also significantly more likely to occur in the AI group (OR 1.20; 95% CI [1.01 to 1.42]; p = 0.033; I2: 59%). Thromboembolic events were less frequent in the AI group compared to the Tamoxifen group (OR 0.75; 95% CI [0.56 to 0.99]; p = 0.044; I2: 82%). Arrhythmia was associated with a HR of 1.2306 (95% CI [0.8295 to 1.8255]; p = 0.302; I2: 89%). Cardiovascular death had a HR of 1.09 (95% CI [0.86 to 1.40]; p = 0.451; I2: 55%), and stroke had a HR of 1.0233 (95% CI [0.90 to 1.15]; p = 0.715; I2: 41%). Cardiovascular death in terms of OR was 1.26 (95% CI [0.94 to 1.69]; p = 0.128; I2: 84%), and the risk of cardiovascular events was associated with an OR of 1.38 (95% CI [0.99 to 1.92]; p = 0.054; I2: 64%). Heart failure and cardiomyopathy had a HR of 1.24 (95% CI [0.98 to 1.56]; p = 0.064; I2: 79%), while thromboembolic events had a HR of 1.02 (95% CI [0.88 to 1.17]; p = 0.774; I2: 0%). The HR for myocardial infarction was 1.12 (95% CI [0.93 to 1.36]; p = 0.214; I2: 59%). Hypertension was associated with an OR of 1.07 (95% CI [0.94 to 1.21]; p = 0.2866; I2: 40%), and stroke had an OR of 1.10 (95% CI [0.91 to 1.33]; p = 0.320; I2: 66%). Conclusions: This systematic review and meta-analysis indicate that AI treatment in BC patients is associated with an increased risk of heart failure, cardiomyopathy, and myocardial infarction. Notably, AI treatment demonstrated a protective effect against thromboembolic events.

Aromatase inhibitor (AI) treatment is first-line systemic treatment for the majority of postmenopausal breast cancer patients with estrogen receptor (ER)-positive primary tumor. Although many patients benefit from treatment, some will develop resistance, and models mimicking acquired resistance will be valuable tools to unravel the resistance mechanisms and to find new treatments and biomarkers. Cell culture models for acquired resistance to the three clinically relevant AIs letrozole, anastrozole and exemestane were developed by selection and expansion of colonies of MCF-7 breast cancer cells surviving long-term AI treatment under conditions where endogenous aromatase-mediated conversion of androgen to estrogen was required for growth. Four cell lines resistant to each of the AIs were established and characterized. Maintenance of ER expression and function was a general finding, but ER loss was seen in one of twelve cell lines. HER receptor expression was increased, in particular EGFR expression in letrozole-resistant cell lines. The AI-resistant cell lines had acquired ability to grow without aromatase-mediated conversion of testosterone to estradiol, but upon withdrawal of AI treatment, testosterone induced minor growth stimulation. Letrozole, exemestane and tamoxifen were able to abrogate the testosterone stimulation but could not reduce growth to below the level in standard growth medium with AI, demonstrating cross-resistance between letrozole, exemestane and tamoxifen. In contrast, fulvestrant totally blocked growth of the AI resistant cell lines both after withdrawal of AI and with AI treatment. These data show that ER is the main driver of growth of the AI-resistant cell lines and indicate ligand-independent activation of ER. Fulvestrant is an efficient treatment option for these AI-resistant breast cancer cells, and the cell lines will be useful tools to disclose the underlying molecular mechanism for resistance to the different AIs.

Could aromatase inhibitors (AI) be used to reduce risks of uterine endometrial cancer growth or recurrence during ovarian stimulation? In a xenograft mouse model of endometrial cancer, concomitant AI administration suppressed the growth of endometrial cancer during ovarian stimulation. Recurrence and mortality rates of estrogen receptor-positive early breast cancer are reduced by long-term AI administration. Concomitant AI use for ovarian stimulation in patients with breast cancer is recommended for reducing estrogen-related potential risks. However, the efficacy of concomitant AI use for estrogen receptor-positive endometrial cancer have not been demonstrated conclusively by clinical or experimental animal studies. Forty nude mice xenografted with uterine endometrial cancer cells were allocated to four groups. Group 1: no ovarian stimulation (control). Group 2: ovarian stimulation. Group 3: AI administration + ovarian stimulation. Group 4: ovariectomy and ovarian stimulation. Tumor growth was evaluated during the 6-week treatment period. Ishikawa 3-H-12 uterine endometrial cancer cells (estrogen and progesterone receptors-positive) were transplanted into 6-week-old BALB/cSlc-nu/nu nude mice, followed by interventions 2 weeks later. Compared to ovarian stimulation alone (Group 2), significant suppressions of tumor growth were observed in other three groups (Groups 1, 3 and 4, all at P < 0.05) and correlated with estrogen levels. AI administration had no apparent impact on embryo development. In this study, we examined the growth of endometrial cancer tumors using one endometrial cancer cell line. Clinical endometrial cancer or hyperplasia cells can have diverse origins and AI may not be effective against other cancer cell types. Concomitant AI use may provide a chance for safer childbirth by for patients with endometrial cancer or hyperplasia. This study was supported by the Graduate Student Aid from the St. Marianna University School of Medicine. The authors declare no competing interests.

Background: Post-menopausal breast cancer survivors are often prescribed aromatase inhibitors (AIs) to decrease the chance of cancer recurrence. Despite their efficacy, many survivors do not fully adhere to their AI regimen. To improve adherence rates, it is important to understand which patient factors are associated with adherence. Current research has mostly focused on demographic, cancer, and symptom variables, most of which cannot be modified. One relevant factor that may be modifiable is health beliefs, which include perceived susceptibility of cancer recurrence, perceived benefits of treatment, and perceived barriers to treatment. Among breast cancer patients, each of these has been found to be associated with adherence behaviors, such as mammography and tamoxifen adherence. In this study, we explored whether health beliefs also play a role in adherence to AIs. Objective: The purpose of this longitudinal study was to determine whether patients with lower perceived susceptibility to cancer recurrence, higher perceived barriers to taking AIs, and lower perceived benefits of AIs were more likely to non-adhere to their AI regimen. Method: Four hundred and thirty-seven breast cancer survivors who were currently on an AI completed a survey that included the Health Beliefs and Medication Adherence in Breast Cancer (HBMABC) scales (a measure adapted from the Champion Health Belief Model Scales (CHBMS) for Mammography Screening), as well as questions about their demographics and symptoms. Exploratory and confirmatory factor analysis of the HBMABC yielded a 3-factor solution: perceived susceptibility, perceived benefits, and perceived barriers. Adherence data, including drug holidays (taking breaks from AI treatment) and premature discontinuation (stopping AI treatment early), were collected from physicians' notes in patients' medical charts dating from the day they completed the survey through the end-date of their prescribed AI treatment. Bivariate analyses were conducted to determine variables that were predictive of non-adherence. Variables found to be associated with non-adherence were entered into multiple logistic regression analyses. Results: Eighty-five patients (20.6%) exhibited some form of non-adherence (premature discontinuation, drug holiday, or both). Joint pain severity and the number of years a patient was on an AI at the time of the survey were both associated with non-adherence. After adjusting for these covariates, perceived barriers to AI treatment was significantly associated with non-adherence (OR 1.76, 95% CI: 1.03 – 3.00, p = 0.04). No relationship was found between perceived susceptibility or perceived benefits, and AI adherence. Conclusions: Breast cancer patients on AIs who perceive greater barriers to AI treatment are more likely to non-adhere to their AI regimen. This finding suggests that clinicians can intervene to help modify patients' negative beliefs and ultimately help improve patients' adherence levels. Citation Format: Brier MJ, Stricker CT, Chambless DL, Chen J, Ahluwalia K, Mao JJ. Health beliefs predict adherence to aromatase inhibitors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD4-02.

Sleep oscillations related to memory consolidation during aromatases inhibitors for breast cancer

The third-generation aromatase inhibitors (AIs), letrozole, anastrozole and exemestane, are becoming the first choice endocrine drugs for post-menopausal women with breast cancer, since they present greater efficacy when compared with tamoxifen in both adjuvant and metastatic setting. In particular, several large and well designed trials have suggested an important role for AIs in the adjuvant treatment of postmenopausal women with estrogen-receptor positive breast cancer either in the upfront, sequential or extended adjuvant mode. Overall, AIs are associated with a small but significant improvement in disease free survival. The expanding use of AIs in the treatment of early breast cancer means that individual patients will be exposed to the agents for longer durations, making it increasingly important to establish their long-term safety. This review focused on the effects of AIs on bone metabolism, serum lipids and cardiovascular risk. AIs have adverse effects on bone turnover with a reduction of bone mineral density and an increase in the rate of fragility fractures. With respect to tamoxifen AIs present lower thrombotic risk and a less favorable impact on lipid profile, whereas the true effects on cardiovascular risk still remain to be clarified. An adequate monitoring of bone mineral density (BMD) and lipid profile could be recommended for post-menopausal women candidate to AIs.

Aromatase inhibitors (AIs) are a class of drugs that prevent conversion of androgens to estrogens, and that are approved in the United States as adjunctive treatment of estrogen receptor-positive breast cancer. Because ultimate fusion of the growth plates is estrogen-dependent in both boys and girls, AI administration may help to slow down epiphysial maturation and allow for greater height potential. Research trials in children with short stature have predominantly been done in Finland and Florida. Despite the apparent efficacy described by these groups, only ˜110 children worldwide have been treated with AIs in research protocols (and usually concomitant with other growth-promoting agents) as of the end of 2008 (and none to final height). That said, many children are being treated with AI’s in the United States outside of research protocols. Furthermore, little is known about the short- and long-term safety of AIs in children. Thus, it is imperative that there be well-designed, long-term studies of efficacy and safety of AI use in pediatric populations.Conflict of interest:None declared.