Safety Of Aromatase Inhibitors Research Articles

Efficacy and safety of aromatase inhibitors in the management of idiopathic short stature: A meta-analysis

Efficacy and safety of aromatase inhibitors in the management of idiopathic short stature: A meta-analysis

Aromatase inhibitors: a useful additional therapeutic option for slowing down advanced bone age in boys with growth hormone deficiency.

Aromatase inhibitors (AIs) have been used to slow down estrogen-dependent skeletal maturation in pubertal boys with short stature. In the literature, few data evaluate the effectiveness and safety of AIs in boys with growth hormone deficiency (GHD). This study aimed to evaluate the auxologic effects and short-term laboratory profiles of combined AI and rhGH therapy for 1year in adolescent males with GHD. Male subjects between the ages of 10 and 16 with GHD from two different centers were included in the study. Patients were divided into two groups: (i) those who only used recombinant human growth hormone (rhGH) therapy (Group I; G-I) and (ii) those who also used AI therapy (anastrozole or letrozole) along with rhGH (Group II; G-II). Forty-one patients (G-I, 46%; G-II, 54%) were included in the study. All the subjects had isolated GHD. At the beginning of the treatment, the chronological ages (CAs) of the patients in the G-I and G-II groups were 11.8 (10.9-13.7) and 12.8 (12.0-14.3) years, respectively. The ratios of bone age (BA)/CA for the two groups were 0.8 (0.8-0.9) and 1.0 (0.9-1.1), respectively (p < 0.001). After the treatment, the height standard deviation (SD) scores and predicted adult height (PAH) significantly increased from baseline in all subjects in the G-I and G-II groups (p < 0.001; p < 0.001, respectively). There was no significant change in the ratio of BA/CA post-therapy in the G-I group (p = 0.1), while there was a significant decrease in the G-II group (p < 0.001). The growth velocities of the patients in the G-I and G-II groups were 9.1 (7.4-10.1) cm/year [1.5 (0.8-5.0) SD score] and 8.7 (7.5-9.9) cm/year [1.1 (0.3-3.1) SD score], respectively (p = 0.6). While post-therapy serum testosterone concentrations were seen to increase in the G-II group, none of the patients exhibited hematocrit above 50 percent, and the fasting glucose concentrations were normal. When used in addition to rhGH therapy in boys with GHD and advanced BA, AIs were observed to slow down the tempo of BA maturation after 1year, compared to those who received rhGH treatment alone. AI therapy was found to be safe during the 1-year observation period and thus could be considered for preserving growth potential in these patients.

Erkek İnfertilitesine Alternatif Farmakolojik Yaklaşım: Anti-Aromataz Bileşikler: Sistematik Derleme

Infertility is a reproductive system disease in which pregnancy does not occur despite long-term, regular and unprotected sexual intercourse. In the near future, it is estimated that approximately 15% of the world population will be affected by infertility and the majority of this will be male-induced infertility. In male infertility, 90% defective sperm production is effective and it is known that in infertile men, as a result of the increase in estrogen levels due to aromatase activity, the testosterone/estradiol ratio may decrease and spermatogenesis is impaired. Therefore, research on increasing intratesticular testosterone levels and improving impaired spermatogenesis has focused on aromatase inhibitors. However, since the efficacy and safety of aromatase inhibitors have not been clarified, it has been thought that anti-aromatase compounds with fewer side effects and stronger efficacy can be used as alternative therapeutic agents in the treatment of infertility. Phytoestrogens are estrogenic plant-derived compounds. Many have been shown to have aromatase inhibition, thereby increasing testosterone levels. In addition, it is known that there are different mechanisms that affect spermatogenesis apart from binding to estrogen receptors in their effects on the male reproductive system. Therefore, our aim is to review the latest developments and treatment approaches to natural polyphenolic compounds with anti-aromatase activity in male infertility. According to the literature, the most commonly used anti-aromatase compounds include resveratrol, quercetin, apigenin, and naringenin. All the compounds in this review were found to have positive effects on male infertility.

Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome.

Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome.

Phase I study combining pembrolizumab and aromatase inhibitor in patients with metastatic hormone receptor–positive breast cancer.

1053 Background: Aromatase inhibitor (AI) is standard of care for patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The current phase I trial was designed to test the safety and efficacy of AI and the immune checkpoint inhibitor pembrolizumab (NCT 02648477). Methods: Key eligibility criteria were HR+ HER2- MBC per ASCO/CAP; RECIST 1.1 measurable disease; adequate organ function; and ECOG 0-1. Eligible patients received 200 mg pembrolizumab IV every 3 weeks plus AI until progression or unacceptable toxicity. Primary objectives were to evaluate the safety and efficacy of this combination. This study employed a 3-at-risk design with a lead-in at the standard dosing of both AI and pembrolizumab with a targeted accrual of 20 patients. Results: A total of 20 patients were accrued between March 2016 and April 2017. Median age was 62 (range 34-79), with 75% white, 15% Asian and 10% unknown. Median lines of therapy were 3 (0, 9). All but one patient received aromatase inhibitor and/or fulvestrant prior to enrollment. The combination was well tolerated, and the most common adverse events were grade 2 fatigue (35%), rash (15%), and hot flashes (10%). Grade 3 adverse events were elevated AST/ALT (5%), rash (5%), and lymphopenia (5%). Responses were 10% partial response and 15% stable disease, resulting in a clinical benefit rate (CBR) of 20% at 6 months. Median follow-up time was 40.1 months (range 31.3 – 46.8 months). Median progression free survival was 1.8 months (95% CI 1.6, 2.6) and median overall survival was 17.2 months (95% CI 9.4, NA). 14 tumor specimens had programmed death ligand 1–positive (PD-L1) by 22C3 testing, including 3 PD-L1-positive and 11 PD-L1 negative. No association between PD-L1 and response was found. Conclusions: The combination of pembrolizumab and AI is well tolerated in patients with HR+ HER2- MBC who were not pre-selected for PD-L1. There was minimal overall clinical activity observed beyond what was to be expected with AI alone in this group of patients. Clinical trial information: NCT 02648477.

Efficacy and safety of letrozole or anastrozole in the treatment of male infertility with low testosterone-estradiol ratio: A meta-analysis and systematic review.

Aromatase inhibitors (AIs) have been used to treat male infertility for decades. However, due to the lack of large-scale randomized controlled studies and basic research, the efficacy and safety of AIs in the treatment of male infertility remain controversial. Therefore, it is necessary to conduct an evidence-based preliminary evaluation of the existing clinical trials of AIs in the treatment of male infertility. A comprehensive literature search was performed in the PubMed, Embase, Cochrane, CNKI, VIP, CBM, and Wanfang databases through August 2021 for all studies. We conducted a systematic review with a meta-analysis of all available studies reporting sperm conventional parameters, gonadotropin and testosterone levels, and/or the pregnancy rate. A total of 10 studies involving 666 patients were included. Letrozole (LE) or anastrozole (AZ) administration significantly increased sperm concentration, total sperm count, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T) levels, and the testosterone-to-estradiol ratio (T/E2), but E2 levels were significantly reduced compared with baseline values. Compared with the control group, which included selective estrogen receptor modulators (SEMRs) or human chorionic gonadotropin (HCG), LE, or AZ did not have any significant effect on sperm concentration, motility, and morphology, except that AIs had less effect on sperm motility than the control group (weighted mean difference [WMD]: -2.55; 95% CI: -4.11 to -1.00; p=0.001). AIs may be effective in the treatment of male infertility. For infertile male patients planning assisted reproduction, discontinuation of AIs for 2-7 days prior to sperm retrieval may increase the success rate of fertilization. Further studies with larger sample sizes are needed to validate these findings.

Clinical application of aromatase inhibitors to treat male infertility.

Infertility affects 15% of men and contributes to nearly half of all cases of infertility. Infertile men usually have impaired spermatogenesis, presenting as azoospermia or various degrees of asthenospermia and oligozoospermia. Spermatogenesis is a complex and coordinated process, which is under precise modulation by the hypothalamic-pituitary-gonadal (HPG) axis. An aberrant hormone profile, especially an imbalance between testosterone (T) and estradiol (E2), plays an essential role in male infertility. In the male, E2 is produced mainly from the conversion of T by the aromatase enzyme. Theoretically, reducing an abnormally elevated T:E2 ratio using aromatase inhibitors (AIs) could restore the balance between T and E2 and optimize the HPG axis to support spermatogenesis. For decades, AIs have been used to treat male infertility empirically. However, owing to the lack of large-scale randomized controlled studies and basic research, the treatment efficacy and safety of AIs in male infertility remain controversial. Therefore, there is a need to summarize the clinical trials and relevant basic research on the application of AIs in the treatment of male infertility. In this narrative review, we summarized the application of AIs in the treatment of male infertility, including the pharmacological mechanisms involved, clinical trials focused on patients with different types of infertility, factors affecting treatment efficacy and the side-effects. A literature search was performed using MEDLINE/PubMed and EMBASE, focusing on publications in the past four decades concerning the use of AIs for treating male infertility. The search terms included AI, male infertility, letrozole, anastrozole, testolactone, azoospermia, oligozoospermia, aromatase polymorphisms, obesity and antiestrogens, in various combinations. Clinical studies demonstrate that AIs, especially nonsteroidal letrozole and anastrozole, could significantly inhibit the production of E2 and its negative feedback on the HPG axis, resulting in increased T and FSH production as well as improved semen parameters in infertile men. Large-scale surveys suggest that obesity may result in symptoms of hypogonadism in both fertile and infertile males, such as decreased semen quality and attenuated sexual function, which can be improved by AIs treatment. Polymorphisms of the aromatase gene CYP19A1, including single nucleotide polymorphisms and tetranucleotide TTTA repeats polymorphism (TTTAn), also influence hormone profiles, semen quality and treatment efficacy of AIs in male hypogonadotropic hypogonadism and infertility. The side-effects of AIs in treating male infertility are various, but most are mild and well tolerated. The application of AIs in treating male infertility has been off-label and empirical for decades. This narrative review has summarized the target patients, dose, treatment duration and side-effects of AIs. Polymorphisms of CYP19A1 that may affect AIs treatment efficacy were also summarized, but a full understanding of the mechanisms involved in AIs action requires further study.

Role of medical treatment of endometriosis.

Endometriosis is a chronic benign disease that affects women of reproductive age. Medical therapy is often the first line of management for women with endometriosis in order to ameliorate symptoms or to prevent post-surgical disease recurrence. Currently, there are several medical options for the management of patients with endometriosis and long-term treatments should balance clinical efficacy (controlling pain symptoms and preventing recurrence of disease after surgery) with an acceptable safety-profile. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory conditions, being efficacious in relieving primary dysmenorrhea. Combined oral contraceptives and progestins, available for multiple routes of administration, are commonly administered as first-line hormonal therapies. Several studies demonstrated that they succeed in improving pain symptoms in the majority of patients; moreover, they are well tolerated and not expensive. Gonadotropin-releasing hormone-agonists are prescribed when first line therapies are ineffective, not tolerated or contraindicated. Even if these drugs are efficacious in treating women not responding to COCs or progestins, they are not orally available and have a less favorable tolerability profile (needing an appropriate add-back therapy). Because few data are available on long-term efficacy and safety of aromatase inhibitors they should be reserved only for women with symptoms who are refractory to other treatments only in a research environment. Almost all of the currently available treatment options for endometriosis suppress ovarian function and are not curative. For this reason, research into new drugs is unsurprisingly demanding. Amongst the drugs currently under investigation, gonadotropin-releasing hormone antagonists have shown most promise, currently in late-stage clinical development. There is a number of potential future therapies currently tested only in vitro, in animal models of endometriosis or in early clinical studies with a small sample size. Further studies are necessary to conclude whether these treatments would be of value for the treatment of endometriosis.

Ultrasensitive Serum Estradiol Measurement by Liquid Chromatography-Mass Spectrometry in Postmenopausal Women and Mice.

Accurate measurement of very low circulating estradiol (E2) (<5 pg/ml) in postmenopausal women and in mice is essential to investigating sex steroid action in target tissues. However, direct immunoassays are too inaccurate and conventional mass spectrometry-based measurement too insensitive at these serum E2 levels. We report application of an ultrasensitive method using a novel estrogen-selective derivatization in liquid chromatography-mass spectrometry to measure serum E2, with a detection limit of 0.25 pg/ml in small (0.2 ml) serum volumes that can quantify serum E2 in 98% and serum E1 in 100% of healthy postmenopausal women. Aromatase inhibitor (AI) treatment of postmenopausal women with breast cancer further reduces serum E2 by 85% and serum estrone (E1) by 80%. The wide scatter of circulating E2 in AI-treated women suggests that the degree of sustained E2 depletion, now quantifiable, may be an efficacy or safety biomarker of adjuvant AI treatment. This ultrasensitive method can also measure serum E2 in most (65%) female but not in any male mice. Further studies are warranted using this and comparable ultrasensitive liquid chromatography-mass spectrometry estrogen measurements to investigate the relationship of circulating E2 (and E1) in male, postmenopausal female, and childhood health where accurate quantification of serum estrogens was not previously feasible. This will focus on the direct impact of estrogens as well as the indirect effects of androgen aromatization on reproductive, bone, and brain tissues and, notably, the efficacy and safety of AIs in adjuvant breast cancer treatment.

Reconsideration of the third-generation non-steroidal aromatase inhibitors in pediatrics

Aromatase is the rate-limiting enzyme in estrogen biosynthesis. The third generation aromatase inhibitors (AIs), represented by letrozoleand and anastrozole, can combine with aromatase, effectively reducing the estrogen level in the body. Because of its high efficiency, selectivity and reversibility, it has been used in the treatment of McCune-Albright syndrome, familial male-limited precocious puberty, gynecomastia, and adolescent boy with short stature. The good efficacy and safety of AIs have been observed. However, so far the drug instructions of AIs usually do not show indications for children; there are risks of adverse reactions involving liver and kidney function, lipid metabolism, hyperandrogenemia and bone metabolism; especially the long-term effects on reproductive system and bone metabolism are still not clear. Therefore, it is necessary to prescribe it carefully and follow up closely. It was not recommended that AIs be routinely used to improve adult height of adolescent boy with short stature. And more clinical evidences are needed for the safety and effectiveness of AIs prescribed in pediatrics.

Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature

To assess the efficacy and safety of aromatase inhibitors (AIs) combined growth hormone in treatment of adolescent boys with short stature. One hundred and fifty-one short stature pubertal boys with age of 10-14 years and bone age of 13-15 years, who were admitted to the Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, were included in this trial. According to their own or parents' intention, the children were divided into recombinant human growth hormone (rhGH)+AI group ( n=108) and rhGH group ( n=43). All children were injected subcutaneously with rhGH 0.15-0.2 IU·kg -1·d -1, and those in rhGH+AI group were additionally given 2.5 mg/d letrozole or 1 mg/d anastrozole, orally for 12 months or longer. The children were followed-up every 3 months. During the follow-up visit, the predicted adult height (PAH), sex hormone level, glucose and lipid metabolism, and other indicators were measured, and adverse reactions were monitored. After intervention, there were significant differences in ΔBA(bone age)/ΔCA(chronological age), ΔHtSDS BA(height standard deviation score based on bone age)and ΔPAH between rhGH+AI group and the rhGH group( P &lt; 0.05 or P &lt; 0.01). During follow-up, 63.9%of the children in the rhGH+AI group had elevated uric acid and 51.9%had decreased high-density lipoprotein (HDL); 25.9%showed severe acne, excitement, hyperactivity and irritability, 11.1%had knee pain; 4.6%had fracture; 2.8%had mild renal dysfunction; 1.9%had inactivity, drowsiness, memory loss and performance decline; 1.9%showed mild abnormal liver function; 0.9%showed impaired fasting glucose; 0.9%showed granulocytopenia. In the rhGH group, 11.6%of the children presented with knee pain and 2.3%with impaired fasting glucose. AI combined with rhGH can delay the growth of BA and effectively improve the PAH of adolescent boys with larger bone age. However, the occurrence of adverse reactions of AI should be closely monitored during treatment.

Male Fertility: Review of the Publications of October – December 2019

The article provides an overview of the most influential papers on the topic of «male infertility». The main selection criteria were the practical significance of the article and the impact factor of the journal in which it was published, according to SCImago Journal Rank (SJR). As a result, we created the list of 10 papers published in the IV quarter (October − December) of 2019. The review included articles on the following issues: the effectiveness and prognostic factors of the effectiveness of microsurgical testicular sperm extraction (micro-TESE), the significance of sperm DNA fragmentation and «advanced paternal age» in the effectiveness of assisted reproduction technologies (ART) procedures, the role of latent chlamydial infection in azoospermia, management of adolescents with Kleinfelter syndrome, the effectiveness and safety of aromatase inhibitors in treatment of male infertility, sperm microbiome, the association between ART procedures and the cancer risk in children, follicle-stimulating hormone (FSH) treatment of male idiopathic infertility.

Abstract P5-13-02: Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25)

Abstract Background: Breast cancer (BC) patients (pts) with Oncotype Dx recurrence scores (RS) ≤ 25 represent a large fraction of BC cases. The TAILORx study demonstrated that these pts did not receive significant benefit from adjuvant chemotherapy. Despite their low to moderate risk and sensitivity to endocrine therapy, a number of BC pts may benefit from neoadjuvant therapy. The goal of this study is to assess tumor response, utilizing the preoperative endocrine prognostic index (PEPI), to a combination of the mTOR inhibitor everolimus and an aromatase inhibitor (AI) in this pt population. Methods: This is a phase II study evaluating the efficacy and safety of neoadjuvant AI and everolimus in postmenopausal pts with hormone receptor positive (HR+)/HER2 negative clinical stage II-III BC with low risk RS (≤ 25). Patient enrollment initiated in November 2014 at the Yale Cancer Center/Smilow Cancer Hospital and Care Centers. Key inclusion criteria are ECOG 0-2, adequate organ function, a fasting cholesterol ≤ 300 mg/dl and triglycerides ≤ 2.5 x IULN. Eligible pts received daily AI therapy (anastrozole 1 mg, letrozole 2.5 mg, or exemestane 25 mg) and everolimus 10 mg daily for up to a total of 26 weeks. The primary objective of the study was to determine the percent of postmenopausal pts with clinical stage II-III HR+/HER2- BC and a RS ≤ 25 who achieve a PEPI score of 0 following neoadjuvant AI and everolimus. The secondary objectives are to assess the tolerability and side effect profile, and to identify biologic markers predictive of a PEPI 0. Simon’s optimal two-stage design was utilized with a planned sample size of 27 eligible pts. First, 15 pts will be enrolled, if 5 or more of 15 eligible patients achieve a PEPI 0, the plan is to enroll another 12 pts. If 10 or more of the 27 eligible patients achieve a PEPI 0, we will conclude that the regimen warrants further study. This design has a power of 80% and a one-sided significance level of 0.1. Results: Of the 17 pts initially enrolled, 15 were evaluable for response; 4 of 15 (26%) had a PEPI scores of 0 which did not meet the primary endpoint; 4 (26%) had a path CR and 6 (40%) had PR. Grade 3 toxicities determined to be possibly/probably study related included anemia, anorexia, hypertension, maculopapular rash and hyperglycemia. One pt developed grade 3 atrial flutter and grade 4 QT prolongation which required a dose delay. One pt required hospitalization for pneumonia. Gene expression analysis by RNA seq was performed on 9 baseline (6 pts with CR/PR vs 3 non-responders); 13 post treatment (8 pts with CR/PR vs 5 non-responders) samples with 8 matched pairs (5 pts with CR/PR vs 3 non-responders). Baseline samples from pts who had CR/PR have significantly lower expression of MYC targets and oxidative phosphorylation genes, and significantly higher expression of genes associated with epithelial mesenchymal transition and interferon signaling, in comparison to non-responders. The expression of CYP19A1 gene, that codes aromatase, is significantly increased after therapy in samples from pts with CR/PR (logFC=1.33), but not in other pts. Expression of mTORC1 signaling pathway genes is increased after therapy only in samples from pts with CR/PR. Conclusion: Although this trial did not meet the set primary endpoint, 26% of pts achieved a PEPI 0. The combination of an AI and everolimus was overall well tolerated. Our study suggested that baseline expression levels of key pathways were associated with response to neoadjuvant AI plus everolimus. Citation Format: Maysa M Abu-Khalaf, Kimberly Aderhold, Michal Marczyk, Gina Chung, Erin Hofstatter, Tara Sanft, Andrea Silber, Michael DiGiovanna, Daniel Zelterman, Lajos Puzstai, Christos Hatzis. Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25) [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 P5-13-02.

Abstract P4-14-09: A nationwide data on the cardiovascular protective effect of tamoxifen and aromatase inhibitor in postmenopausal women with breast cancer

Abstract A large proportion of breast cancer patients receive hormonal therapy as their adjuvant treatment options. For postmenopausal women, the initial choice for the hormonal therapy is aromatase inhibitor (AI), and tamoxifen (TM) is reserved for women experiencing severe side effects against AI or having low bone density. An important but unresolved clinical question regarding the use of AI in postmenopausal women is the safety of AI regarding the risk cardiovascular events. Studies have shown inconsistent results over the cardiovascular safety of AI and TM. In this study, we investigated the risk of developing cardiovascular and cerebrovascular events in women with breast cancer who receive hormonal therapy using AI, TM, or both. To this end, we used the National Health Insurance Sharing Service in Korea which is provided by National Health Insurance Service. The database provides anonymized insurance data for research purposes after the approval of the review committee. In the database, we identified 47,569 women with the age older than 55 who were diagnosed with breast cancer. Patients were classified as no hormonal treatment group (n=18,807), AI group (n=19,584), TM group (n=7,081), or Switch group (n=2,097). The Switch group was defined as the women with history of both AI and TM prescriptions. During the studied period, a total of 2,032 cardiovascular or cerebrovascular events (CVE) were recorded. Overall, the women prescribed with TM had significantly less hazard ratio for developing CVE when compared to the women who did not receive any hormonal treatment (HR 0.809 95% C.I. 0.706-0.928). However, this protective effect of tamoxifen was not observed in either AI or Switch group (HR 0.917 95% C.I. 0.833-1.010, and HR 0.856 95% C.I. 0.695-1.053, respectively). The protective effect of TM was also similar in women older than 60 (HR 0.808 95% C.I. 0.696-0.938). The cardiovascular and cerebrovascular protective effects of tamoxifen was also substantial in high risk women defined by their family history of cardiovascular diseases and the diagnosis of hypertension or diabetes. Our results suggest that the use of TM is associated with a substantial protective effect against developing cardiovascular or cerebrovascular events in women with breast cancer. However, the protective effect was not observed for women receiving AI. Our data suggest the potential tailored approach in hormonal treatment in breast cancer patients who are at high risk of cardiovascular of cerebrovascular events. Citation Format: Moon H-G, Choi SH, Park Y, Jung JG, Ju YW, Kim KE, Kim Y, Lee E, Lee H-B, Han W, Noh D-Y, Yoon H-J. A nationwide data on the cardiovascular protective effect of tamoxifen and aromatase inhibitor in postmenopausal women with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-09.

Current and Emerging Therapeutics for the Management of Endometriosis.

Endometriosis is a chronic benign disease that affects women of reproductive age. Medical therapy is often the first line of management for women with endometriosis in order to ameliorate symptoms or to prevent post-surgical disease recurrence. Currently, there are several medical options for the management of patients with endometriosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory conditions, being efficacious in relieving primary dysmenorrhea. Combined oral contraceptives (COCs) and progestins, available for multiple routes of administration, are effective first-line hormonal options. In fact, several randomized controlled trials (RCTs) demonstrated that they succeed in improving pain symptoms in the majority of patients, are well tolerated and not expensive. Second-line therapy is represented by gonadotropin-releasing hormone (GnRH) agonists. Even if these drugs are efficacious in treating women not responding to COCs or progestins, they are not orally available and have a less favorable tolerability profile (needing an appropriate add-back therapy). The use of danazol is limited by the large availability of other better-tolerated hormonal drugs. Because few data are available on long-term efficacy and safety of aromatase inhibitors they should be administered only in women with symptoms refractory to other conventional therapies in a clinical research setting. Promising preliminary data have emerged from multicenter Phase III trials on elagolix, a new oral GnRH antagonist but non-inferiority RCT data are required to compare elagolix with first-line therapies for endometriosis.

The effect of aromatase inhibitors use on endothelial function among postmenopausal women with breast cancer.

e12064 Background: Data on long-term cardiovascular effects and safety of aromatase inhibitors (AI) are limited and conflicting. The purpose of the current study was to evaluate the effect of AI on vascular injury as assessed by peripheral endothelial function among women with breast cancer. Methods: This is an observational, prospective study of 96 postmenopausal women with breast cancer at initiation of treatment, with or without AI. All participants underwent baseline and 6-12 months follow up non-invasive peripheral endothelial function measurement. Reactive hyperemia index (RHI) was measured using the EndoPAT test. The primary endpoint was endothelial function deterioration of at least 20% between baseline and follow-up. Results: Mean age of the study population was 66±7 years. There was no statistical difference in demographic data between the groups. Compared with the control group, more women in the treatment group demonstrated worsening of RHI (53% vs. 42%, p = 0.207) between baseline and 6-12 month follow up measurement. There was no statistical difference between the groups at baseline. When RHI deterioration was evaluated as a dichotomous variable, with a 20% cutoff, women in the AI group demonstrated higher rates of RHI deterioration (28% vs. 8%, p=0.020). The risk of AIs for endothelial dysfunction was correlated with burden of cardiovascular (CV) risk, such that in women with &gt;3 CV risk factors, AIs were associated with increased risk of RHI deterioration (42% vs. 10%, p=0.016), whereas in women with &lt;2 CV risk factors, rates of RHI deterioration were similar in AI and control groups (20% vs. 7%, p = 0.232). Conclusions: This study suggests that AI therapy may be associated with vascular injury as detected by deterioration in endothelial function. The effect is more pronounced among women with higher baseline CV risk factor burden. The results of this study have potentially important implications for patients with breast cancer being treated with AI and for women at increased lifetime risk of breast cancer who may use AI for breast cancer risk reduction. Clinical trial information: NCT00719966.

Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials

Aromatase inhibitors (AIs) have been associated with cardiovascular disease in adjuvant randomized controlled trials (RCTs) comparing these drugs to tamoxifen. However, it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen. To address this question, we conducted a systematic review and meta-analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting. We searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to June 2016 for all RCTs comparing cardiovascular and cerebrovascular safety of AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. Relative risks (RRs) were pooled using DerSimonian and Laird random-effects models with analyses stratified by RCT design. A total of 19 RCTs were included in the meta-analysis (n = 62345). In the adjuvant setting, AIs were associated with a 19% (RR: 1.19, 95% confidence interval [CI]: 1.07-1.34) increased risk of cardiovascular events compared with tamoxifen. AIs were not associated with an increased risk compared with placebo in the extended-adjuvant setting (RR: 1.01, 95% CI: 0.85-1.20). In the adjuvant setting, tamoxifen was associated with a 33% (RR: 0.67, 95% CI: 0.45-0.98) decreased risk compared with placebo or no-treatment. The results from extended adjuvant RCTs comparing tamoxifen to placebo were inconclusive but suggestive of a small protective effect (RR: 0.91, 95% CI: 0.77-1.07). The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer.

Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature.

Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion. To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups. Randomized three-arm open-label comparator. Outpatient clinical research. Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)]. Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24-36 months. Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs. Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8) cm (P < .0006, analysis of covariance). Height SDS was: AI, -1.73 (0.12); GH, -1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, ∼97.6%] was: AI, -1.4 (0.1); GH, -1.4 (0.2); AI/GH, -1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, +22.5 (1.4) cm (P = .01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole. Combination therapy with AI/GH increases height potential in pubertal boys with ISS more than GH and AI alone treated for 24-36 months with a strong safety profile.

The cardiovascular safety of aromatase inhibitors and tamoxifen in post-menopausal women with breast cancer: A systematic review and meta-analysis of randomized controlled trials.

1573Background: The cardiovascular safety of aromatase inhibitors (AIs) in the treatment of breast cancer is controversial, with meta-analyses of randomized controlled trials (RCTs) reporting an in...

Potential role of aromatase inhibitors in the treatment of endometriosis.

Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%–10% of reproductive-age women, with a prevalence of 5%–50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs) are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis-associated infertility are needed to clarify its effect. The safety of AIs for ovulation induction or superovulation has generated a lively discussion. Data from recent retrospective and prospective studies have supported its safety.