Effects Of Aromatase Inhibitors Research Articles

Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer.

While their negative impact on bone health is well established, the effects of aromatase inhibition (AI) on Wnt inhibitors and osteoprotegerin (OPG) are unknown. The aim of the study was to investigate the effects of AI on serum levels of sclerostin, DKK-1 and OPG, as well as their associations with PINP and CTX as markers of bone turnover and bone mineral density (BMD) assessed by DXA. We conducted a prospective longitudinal analysis of 70 postmenopausal women with hormone receptor-positive early breast cancer (BC) treated with anastrozole. All measurements were performed at baseline, 12 and 24 months of treatment. We measured the association of the investigated variables with circulating bone turnover markers, as well as with the BMD. After 24 months of AI therapy, sclerostin and OPG concentrations increased from 29.5 pmol/l (SD = 15.1) and 6.8 pmol/l (SD = 2.2) at baseline to 43.2 pmol/l (SD = 20.6) (p < 0.001) and 7.4 pmol/l (SD = 2.2) (p = 0.028), respectively. DKK-1 levels decreased from 34.3 pmol/l (SD = 13.5) at baseline to 29.7 pmol/l (SD = 12.3) at the 24-month visit (p = 0.005). Sclerostin levels significantly correlated with PTH, OPG and BMD of the lumbar spine, while DKK-1 correlated with the BMD of the femoral neck and of the total hip. The observed increase in sclerostin levels indicates a central role of osteocytes in bone turnover in women with BC.

Effects of aromatase inhibitors and body mass index on steroid hormone levels in women with early and advanced breast cancer

Aromatase inhibitors (AIs) are central to the management of oestrogen receptor-positive breast cancer in the adjuvant and metastatic setting. Levels of circulating steroid hormones (SHs) were measured in patients established on AIs to investigate: the influence of body mass index (BMI) in both the adjuvant and metastatic setting; the class of AI utilized in the adjuvant setting (steroidal versus non-steroidal); and differences in SH levels between women treated adjuvantly and those receiving a second-line AI for locally advanced/metastatic disease. Plasma levels of androstenedione, 5-androstene-3β,17β-diol, dehydroepiandrosterone, oestradiol and testosterone were measured by radioimmunoassay in women with breast cancer who were receiving AIs in either an adjuvant or a metastatic setting. Differences between mean SH levels by class of AI, BMI, and second-line versus adjuvant therapy were assessed. Sixty-four women were receiving AI therapy, 45 (70 per cent) in an adjuvant setting and 19 (30 per cent) were taking a second-line AI. There was no significant correlation between BMI and SH levels. However, BMI was significantly higher in the second-line AI cohort compared with the adjuvant cohort (29.8 versus 26.2 kg/m2 respectively; P = 0.026). In the adjuvant setting, patients receiving a steroidal AI had significantly higher levels of all five hormones (P < 0.050). In the second-line AI cohort, oestradiol levels were significantly higher than in the adjuvant cohort (4.5 versus 3.3 pg/ml respectively; P = 0.022). Multivariable analysis adjusted for BMI confirmed the higher residual oestradiol level in the second-line AI group (P = 0.063) and a significantly higher androstenedione level (P = 0.022). Residual levels of SH were not significantly influenced by BMI. However, the significant differences in residual SH levels between the second-line and adjuvant AI cohort is of relevance in the context of resistance to AI therapy, and warrants further investigation.

Effect of aromatase inhibitor on expression of &lt;I&gt;CYP19A, DMRT1&lt;/I&gt;, and gonadal sex differentiation in &lt;I&gt;Takifugu ob-scures&lt;/I&gt;

Effect of aromatase inhibitor on expression of &lt;I&gt;CYP19A, DMRT1&lt;/I&gt;, and gonadal sex differentiation in &lt;I&gt;Takifugu ob-scures&lt;/I&gt;

Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment

This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.

Effect of aromatase inhibitors on the ovarian development of stunted yearlings of rohu (Labeo rohita): a preliminary study

In India, many of the fish farmers stock 1-year-old stunted fishes (stunted yearlings) of Indian major carps (IMC) for enhancing fish production through compensatory growth, but many of them observed problems of early maturation in these fishes. Application of aromatase inhibitors for deceleration of ovarian maturation is one of the probable solutions to mitigate this issue. In the present study, a synthetic aromatase inhibitor letrozole [25 (L25) and 50 (L50) mg kg−1 feed] and a plant-derived aromatase inhibitor, grape seed extract [100 (G100) and 200 (G200) mg kg−1 feed], were fed to stunted yearlings of rohu (Labeo rohita) for 45 days well before the onset of breeding season. Maturation indices such as gonadosomatic index (GSI) and serum oestradiol (E) levels indicated a dose-dependent inhibition of ovarian development in the aromatase-inhibitor-treated fish. Higher dose of letrozole (GSI, 15.12 ± 0.18; E, 3.19 ± 0.42) and grape seed extract (GSI, 16.90 ± 0.40; E, 3.60 ± 0.75) were found to be more effective since control fish showed further advancement in maturation (GSI, 21.20 ± 1.10; E, 7.33 ± 0.74) during the peak breeding season (15th June). Histological observations also confirmed the results revealing a delayed initiation of ovarian development in the case of higher doses of letrozole and grape seed extracts. These results indicate the possible use of aromatase inhibitors in arresting the early maturation process in IMC.

Aromatase inhibitors with or without gonadotropin-releasing hormone analogue in metastatic male breast cancer: a case series

Background:Data regarding the safety and effectiveness of aromatase inhibitors (AIs) as monotherapy or combined with gonadotropin-releasing hormone (GnRH) analogue in male breast cancer are scarce.Methods:In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated.Results:Twenty-three men were included into this case series. Aromatase inhibitors in combination with or without a GnRH analogue were given as first-line therapy in 60.9% and as second-line therapy in 39.1% of patients, respectively. All patients had visceral metastases, whereas in five of them bone lesions coexisted. In all cases AIs were tolerated well, and no case of grade 3 and 4 adverse events was reported. A partial response was observed in 26.1% of patients and stable disease in 56.5%. Median overall survival (OS) was 39 months and median progression-free survival (PFS) was 13 months. Regarding OS and PFS, no significant effects of GnRH analogue co-administration or type of AI were noted.Conclusion:Our study shows that AIs with or without GnRH analogues may represent an effective and safe treatment option for hormone-receptor positive, pretreated, metastatic, male breast cancer patients.

Phase II chemoprevention trial: Anastrozole in DCIS and early invasive hormone-receptor (HR) positive breast cancer in postmenopausal women.

e11562 Background: Anastrozole, an aromatase inhibitor, decreases estrogen synthesis and is therefore, an effective treatment of (HR) positive breast cancer. We hypothesized that a short course of anastrozole can decrease levels of Ki-67, a surrogate measure of chemoprevention (the primary endpoint), and there may be correlation in Ki-67 reduction and decreased size of tumor on MRI (the secondary endpoint). Methods: In a single group phase II trial, 42 postmenopausal women with HR positive DCIS or early invasive breast cancer following diagnostic biopsy were enrolled. Patients were given 1 mg anastrozole for 2-4 weeks. Patients had an MRI before and after anastrozole, and then underwent surgery for measurement of change in Ki-67. The specimens were histologically graded on Ki-67, estrogen receptor (ER), progesterone receptor (PR), and Nottingham grade to compare pre and post-therapeutic effects of anastrozole. The two-sided Wilcoxon signed-rank test and Fisher’s exact test were utilized to analyze the data. Spearman correlation coefficients were obtained to assess the correlation between Ki-67 and MRI. Results: 34 patients were eligible. 15 out of 23 patients (65.2%) had decreased Ki-67, 5 (21.7%) had no change and 3 (13.0%) had increased Ki-67 levels. On average, there was a significant decrease in Ki-67 level of 4.9 from baseline (95% CI 1.8, 8.0; p-value=0.004). There was a significant decrease in grade of 0.3 (0.10, 0.49; p-value=0.016). Out of 34 patients, 5 patients (14.7%) showed a pathological complete response. In terms of HR, on average, there was a significant decrease in PR of 34.5 (8.98, 60.2; p-value=0.021). However, there was no significant change in ER (p-value=0.96). Among the 12 patients who had both Ki-67 and tumor size data available, there was low correlation between the change of Ki-67 level from baseline and the change of tumor size determined by MRI (R=0. 34). Conclusions: Anastrozole, as preoperative therapy for 2-4 weeks was effective in reducing Ki-67 in early invasive HR positive breast cancer. Thus the study met its primary endpoint, and therefore supports chemo preventive effects of aromatase inhibitors as shown in large chemoprevention trials. Clinical trial information: NCT00256217.

Mammographic Breast Density Response to Aromatase Inhibition

Mammographic breast density (MBD) is decreased by tamoxifen, but the effect of aromatase inhibitors is less clear. We enrolled early-stage postmenopausal patients with breast cancer initiating adjuvant aromatase inhibitor therapy and ascertained mammograms before and at an average 10 months of aromatase inhibitor therapy. We matched cases to healthy postmenopausal women (controls) from a large mammography screening cohort on age, baseline body mass index, baseline MBD, and interval between mammograms. We estimated change in MBD using a computer-assisted thresholding program (Cumulus) and compared differences between cases and matched controls. In predominantly White women (96%), we found 14% of the 387 eligible cases had a MBD reduction of at least 5% after an average of 10 months of aromatase inhibitor therapy. MBD reductions were associated with higher baseline MBD, aromatase inhibitor use for more than 12 months, and prior postmenopausal hormone use. Comparing each case with her matched control, there was no evidence of an association of change in MBD with aromatase inhibitor therapy [median case-control difference among 369 pairs was -0.1% (10th and 90th percentile: -5.9%, 5.2%) P = 0.51]. Case-control differences were similar by type of aromatase inhibitor (P's 0.41 and 0.56); prior use of postmenopausal hormones (P = 0.85); baseline MBD (P = 0.55); and length of aromatase inhibitor therapy (P = 0.08). In postmenopausal women treated with aromatase inhibitors, 14% of cases had a MBD reduction of more than 5%, but these decreases did not differ from matched controls. These data suggest that MBD is not a clinically useful biomarker for predicting the value of aromatase inhibitor therapy in White postmenopausal women.

Effect of Aromatase Inhibitors on Bone Mineral Density in a Japanese Breast Cancer Population

We retrospectively analyzed the bone mineral density (BMD) of postmenopausal Japanese women taking an aromatase inhibitor (AI), exemestane, anastrozole or letrozole, and calculated the decrease rate constant of BMD in each individual to compare the influence of the three AIs on BMD. We also aimed to evaluate the preventive effect of bisphosphonates (BPs) on the AI-induced decrease in BMD. The decrease rate constant of BMD (k(e)) in each individual was determined as a slope of linear regression of the relationship between time and logarithm of BMD value in each patient during the AI therapy. To compensate for the age-related change in BMD level, we estimated the age-related decrease rate constant of BMD (ke,0) in healthy Japanese postmenopausal women from the literature. AIs decreased BMD with a ke value of -0.0329 yr(-1), which was 4.7-fold larger than the k(e,₀) value of -0.00699 yr(-1). No significant difference was detected in the influence on BMD among AIs. Co-administration of BP ameliorated the ke value to -0.0117 yr(-1), a value similar to k(e,₀). The influence of AIs on BMD was quantitatively evaluated by using the decrease rate constant of BMD (k(e)). The present study also suggests that BPs may be useful to prevent the decrease in BMD induced by AIs.

Effects of Aromatase Inhibition on the Physical Activity Levels of Male Mice

Increasing activity levels in an inactive population can lead to associative increases in health and well-being. Both biologic and genetic factors have been identified that alter physical activity levels in humans and rodents with an extensive early literature regarding sex steroid effects on physical activity. Currently, it is suggested that the androgens require conversion to estrogens prior to eliciting any effects on activity patterns. Recent data contradicts this assertion; thus, the purpose of this study was to evaluate the necessity of the aromatase complex in activity regulation. Wheel running was assessed in male C57BL/6J mice under various sex steroid-disrupted and aromatase-inhibited conditions. Inhibition of the aromatase complex was achieved through administration of two different aromatase inhibiting substances-letrozole and exemestane. Wheel running was unaffected by aromatase inhibition in reproductively intact and sex steroid supplemented mice. Orchidectomy significantly reduced wheel running activity. Steroid replacement recovered wheel running to pre-surgical levels; however, aromatase inhibition did not further affect wheel running levels. The recovery of wheel running in mice with androgen supplementation and the further persistence of wheel running in mice with compromised aromatase function suggests that the androgens-testosterone in particular-may directly affect wheel running patterns in male mice.

Effects of aromatase inhibition and androgen activity on serotonin and behavior in male macaques.

Aggression in humans and animals has been linked to androgens and serotonin function. To further our understanding of the effect of androgens on serotonin and aggression in male macaques, we sought to manipulate circulating androgens and the activity of aromatase; and to then determine behavior and the endogenous availability of serotonin. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with (a) placebo; (b) testosterone (T); (c) T + Dutasteride (5a reductase inhibitor; AvodartTM); (d) T + Letrozole (nonsteroidal aromatase inhibitor; FemeraTM); (e) Flutamide + ATD (androgen antagonist plus steroidal aromatase inhibitor); or (f) dihydrotestosterone (DHT) + ATD (n = 5/group). Behavioral observations were made during treatments. At the end of the treatment period, each animal was sedated with propofol and administered a bolus of fenfluramine (5 mg/kg). Fenfluramine causes the release of serotonin proportional to endogenous availability and in turn, serotonin stimulates the secretion of prolactin. Therefore, serum prolactin concentrations reflect endogenous serotonin. Fenfluramine significantly increased serotonin/prolactin in all groups (p < .0001). Fenfluramine-induced serotonin/prolactin in the T-treated group was significantly higher than the other groups (p < .0001). Castration partially reduced the serotonin/prolactin response and Letrozole partially blocked the effect of T. Complete inhibition of aromatase with ATD, a noncompetitive inhibitor, significantly and similarly reduced the fenfluramine-induced serotonin/prolactin response in the presence or absence of DHT. Neither aggressive behavior nor yawning (indicators of androgen activity) correlated with serotonin/prolactin, but posited aromatase activity correlated significantly with prolactin (p < .0008; r² = 0.95). In summary, androgens induced aggressive behavior but they did not regulate serotonin. Altogether, the data suggest that aromatase activity supports serotonin production and that androgens increase aggression by another mechanism.

Supplemental Material for Effects of Aromatase Inhibition and Androgen Activity on Serotonin and Behavior in Male Macaques

Supplemental Material for Effects of Aromatase Inhibition and Androgen Activity on Serotonin and Behavior in Male Macaques

Abstract P2-13-10: Prospective randomized and multicentric evaluation of cognition in menopausal breast cancer patients receiving adjuvant hormonotherapy: a phase III study (Preliminary results)

Abstract Background: Cognitive impairment has been considered to be a possible adverse effect of aromatase inhibitors (AI). The aim of the study was to compare the impact of tamoxifen or AI on verbal memory (Rey auditory-verbal learning test) and other cognitive functions (memory, executive and attentional functions) after 6 months of treatment. Methods: In this randomized, open-label phase III study, menopausal patients treated with adjuvant hormonotherapy for early breast cancer were enrolled at the end of the radiotherapy. Patients over 70 years, with a history of cognitive disorder or with prior chemotherapy were excluded. Detailed neuropsychological assessments and quality of life evaluations were performed before the 1st administration of hormonotherapy and then 6 months later. Considering the usual norms of the auditivo-verbal Rey test, an alpha risk of 5% and a 95% power, 27 patients per arm had to be included. Statistical analyses included Chi2 test and Student tests when appropriate. Results: 62 consecutive evaluable patients were randomized in 2 arms between March 2009 and April 2011. Patients received tamoxifen in arm A (n = 31) and AI in arm B (letrozole n=17; anastrozole n=12; exemestane n= 2). Median age at inclusion was 61.4 years. The median time since menopause was 10 years. Characteristics of the breast tumor and initial neuropsychological evaluations did not differ significantly between the 2 arms. After 6 months, we observed a significant decline of the performance at the episodic memory test (immediate recall of the Rey auditory verbal learning test) (p = 0.0015) in arm A only and a significant improvement on executive measures (Trail Making Test and Stroop test) (respectively p = 0.03/p = 0.002) in arm B. Quality of life didn't differ after 6 months of treatment. Conclusions: These preliminary results do not support that AI have a worse adverse effect on cognitive functions than tamoxifen after 6 months of treatment. A confirmation is planned after one year of treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-10.

Comparison of Changes in the Lipid Profile of Postmenopausal Women With Early Stage Breast Cancer Treated With Exemestane or Letrozole

Effects of aromatase inhibitor (AI) therapy on the plasma lipid profile are not clear. Here the authors describe changes in fasting lipids (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides) before and after 3 months of exemestane or letrozole treatment. HDL was reduced in the entire cohort (P < .001) and in the exemestane group (P < .001) but unchanged in the letrozole group (P = .169). LDL was increased in the entire cohort (P = .005) and in the letrozole group (P = .002) but unchanged in the exemestane group (P = .361). This effect was at least partially attributable to washout of tamoxifen as only patients with prior use of tamoxifen experienced a significant increase in LDL. Baseline HDL was an independent predictor of the change in HDL (r(2) = -0.128, P < .001), and prior tamoxifen use was associated with greater increases in LDL (r(2) = 0.057, P < .001). Use of lipid-altering medications did not protect against the exemestane-induced drop in HDL or the increase in LDL observed in women with prior use of tamoxifen taking letrozole. In conclusion, AI treatment and/or washout of tamoxifen induced detrimental changes in the lipid profile of postmenopausal women with breast cancer.

Effectiveness of aromatase inhibitors and tamoxifen in reducing subsequent breast cancer.

Tamoxifen (TAM) has been prescribed for decades and aromatase inhibitors (AIs) have been used since the early 2000s in preventing subsequent breast cancer. However, outside of clinical trials, the effectiveness of AIs is not established. We examined the long-term risk of subsequent breast cancer among survivors treated with TAM and AIs in a large health plan. The study included 22,850 survivors, diagnosed with initial breast cancer (stages 0–IV) from 1996 to 2006, and followed 13 years maximum. We compared the risk of subsequent breast cancer in those who used TAM and/or AIs versus nonusers (the reference group). Hazard ratios (HR) adjusted for patient, tumor, treatment, and health-care characteristics were estimated using Cox models with time-dependent drug use status. Women who used TAM/AIs had a large reduction in risk of subsequent breast cancer compared with nonusers. While confidence intervals (CI) for all hormone treatment groups overlapped, women with high adherence (medication possession ratio ≥80%) who used AIs exclusively and had positive ER or PR receptor status had the greatest risk reduction (HR = 0.34, 95% CI: 0.28–0.41), followed by those who switched from TAM to AIs (HR = 0.39, 95% CI: 0.30–0.49), and those who used TAM exclusively (HR = 0.42, 95% CI: 0.36–0.47). Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly. Compared with nonusers, the reduction in subsequent breast cancer risk ranged from 58% to 66% across the hormone treatment groups and degree of adherence.

Effect of Aromatase Inhibitors on Background Parenchymal Enhancement and Amount of Fibroglandular Tissue at Breast MR Imaging

To evaluate whether treatment with an aromatase inhibitor (AI) influences background parenchymal enhancement (BPE) or amount of fibroglandular tissue (FGT) at breast magnetic resonance (MR) imaging in postmenopausal women with prior history of breast cancer. A waiver of authorization and patient consent was granted by the institutional review board for this HIPAA-compliant retrospective study. Postmenopausal women with breast cancer and MR imaging findings of the contralateral unaffected breast, before and during 6-12 months of AI treatment (anastrozole, letrozole, or exemestane), between August 1999 and June 2010 were retrospectively identified (n = 149). Two readers performed blinded side-by-side comparison of BPE and MR imaging-depicted FGT before and during treatment. BPE and FGT were classified as the same or greater on one of the two MR studies and by using categorical scales: minimal, mild, moderate, or marked for BPE and fatty, scattered, heterogeneously dense, or dense for FGT. Consensus was reached in cases of disagreement. The sign test was used to conduct a side-by-side comparison of BPE and FGT before and during AI treatment. A decrease in BPE occurred in 33.9% (37 of 109) of women during anastrozole treatment, while an increase occurred in only one (P < .0001); 28 of 37 decreases resulted in a category change of BPE. A decrease in MR imaging-depicted FGT occurred in 5.5% (six of 109) of women, while no increases occurred (P = .031). During letrozole treatment, a decrease in BPE occurred in 46% (15 of 33), while an increase occurred in one woman (P = .0003); a decrease in FGT occurred in only one woman, and no increases occurred. Similar results were seen when women also undergoing chemotherapy were excluded. Only seven women were treated with exemestane. Treatment with 6-12 months of anastrozole or letrozole was associated with decreases in BPE, which occurred in a greater proportion of women than decreases in FGT.

Does obesity change the effect of aromatase inhibitors (AIs) on estradiol, leptin, insulin, and IGF-1 serum levels in breast cancer patients?

e11008 Background: The complexity of the relationship between obesity and breast cancer reflects important contributions of obesity-related factors in the adjuvant therapy. The efficacy of adjuvant AIs compared to tamoxifen is lower in obese postmenopausal women. Therefore, we aimed to identify whether the effect of AIs on estradiol, leptin, insulin, and IGF-1 serum levels with respect to the status of the obesity in breast cancer patients. Methods: A total of 34 postmenopausal breast cancer patients treated with adjuvant AIs were enrolled in the study. Pretreatment and 3 months after treatment body weight, height, waist-to-hip (WHR) ratio and body mass index (BMI) were recorded. Blood samples for serum estradiol, leptin, insulin and IGF-1 were drawn after 12 hour starvation and stored in – 70o before and 3 months after the onset of AI treatment. Results: Median age and BMI were 61 years (range 49-84) and 31 (range 22-43), respectively. 18 (%52.9) patients were treated with letrozole and 16 (%47.1) patients were treated with anastrazole. There was no change in the 3 months period in weight, BMI and WHR. Estradiol levels were decreased significantly between the baseline and the 3rd month (p&lt;0.01). There was a slight increase in the leptin levels between the basal and 3rd month (p&gt;0.05). No significant change was detected in insulin and IGF-1 levels in the follow-up period. In the multivariate regression model, there was no difference between the effect of letrozole and anastrazole on estradiol levels. Pretreatment BMI did not alter the effect of AIs on estradiol levels. The only factor related with the effect of the AIs is the pretreatment estradiol levels. Conclusions: This study shows that the suppression of estrogen in obese breast cancer patients with AIs at the standard doses may not be different from non-obese patients. Further researches may show us other mechanisms for the obesity-related factors to improve outcome with aromatase inhibition in obese breast cancer patients.

Effect of aromatase inhibitor (letrozole) with long agonist protocol on the results of ICSI/ET in females with minimal and mild endometriosis

BackgroundICSI/ET in endometriosis patients has poor outcome by traditional protocols. The key enzyme in the biosynthesis of estradiol, aromatase, has been demonstrated within endometriosis. Combined administration of aromatase inhibitor and GnRH-agonist may efficiently suppress estrogen biosynthesis through a combined pituitary, ovarian and local factors in the implants. ObjectiveEvaluate the effect of using letrozole in improvement of the results of ICSI/ET in endometriosis women with long agonist protocol. PatientsSixty infertile women with minimal and mild endometriosis according to the revised American Fertility Society classification were scheduled for ICSI/ET. MethodsWomen were randomized into two groups. Group 1: using the traditional luteal long agonist protocol using triptorelin 0.1 and Group 2: using letrozole 5mg/day started 5days after the start of GnRH agonist for 5days. All patients were monitored with day 6 serum estradiol level and estradiol at day of HCG. The number of days of stimulation, number of retrieved oocytes, number of MII oocytes, cleavage rate, and pregnancy rate were studied in both groups. ResultsDays of stimulation were significantly higher in the treated group (p=0.019). Oocytes number was not affected (10.57±6.14) and (11.21±6.41) (p=0.516) in groups 1 and 2 respectively also, the number of embryos was not affected (p=0.955). Nine (32.1%) pregnant cases of 28 were in the first group while 8 from 27 in the second group (29.6%). ConclusionLetrozole significantly affected days of stimulation of ICSI cycle in endometriosis patients without affecting pregnancy rate.

Aromatase inhibitors for PCOS: a systematic review and meta-analysis

The effectiveness of aromatase inhibitors (AIs) in the treatment of anovulatory polycystic ovary syndrome (PCOS) remains unclear. The objective was to determine whether AIs are effective in improving fertility outcomes in women with PCOS. Databases were searched until July 2011. Inclusion criteria were women with PCOS, who are infertile, receiving any type, dose and frequency of AI compared with placebo, no other treatment or other infertility treatment. Outcomes were rates of: ovulation, pregnancy, live birth, multiple pregnancies, miscarriage and adverse events, as well as quality of life and cost effectiveness. Data were extracted and risk of bias was assessed. A random-effects model was used for the meta-analyses, using odds ratios (ORs) and rate ratios (RRs). The search returned 4981 articles, 78 articles addressed AIs and 13 randomized controlled trials (RCTs) met the inclusion criteria. No RCTs compared AIs versus placebo or no treatment, in therapy naïve women with PCOS. Meta-analyses of six RCTs comparing letrozole with clompihene citrate (CC) demonstrated that letrozole improved the ovulation rate per patient [OR 2.90 (95% confidence interval (CI) 1.72, 4.88), I(2) = 0%, P < 0.0001]; however, there was no statistical difference for the ovulation rate per cycle or the pregnancy, live birth, multiple pregnancy or miscarriage rates. Letrozole also did not improve pregnancy or live birth rates compared with placebo or with CC plus metoformin in women with CC-resistant PCOS. Results of comparisons of letrozole and anastrozole in women with CC-resistant PCOS were conflicting in terms of ovulation and pregnancy rates. In the absence of supportive high-quality evidence, AIs should not be recommended as the first-line pharmacological therapy for infertility in women with PCOS, and further research is needed.

P3-10-02: Gene Expression Changes in Methylnitrosourea (MNU)-Induced ER+ Mammary Cancers Following Short-Term Treatment of Rats with the Aromatase Inhibitor Vorozole.

Abstract Aromatase inhibitors have proven to be highly effective in both therapy and prevention of ER+ breast cancer. Vorozole (R83842), a high affinity competitive inhibitor of aromatase (similar to letrozole and anastrozole) showed strong activity in early clinical trials against ER+ breast cancer. Furthermore, vorozole was highly effective in the prevention and therapy of ER+ cancers in the MNU-mammary cancer model (Lubet, et al., Carcinogenesis 19, 1345, 1998). In the present study, rats bearing mammary cancers induced by MNU were exposed to vorozole (1.25 mg/kg BW/day) for 5 days. Global gene expression analysis showed that 162 genes were down-regulated and 180 genes up-regulated in cancers treated with vorozole (p &amp;lt; 0.05 and fold change &amp;gt; 1.5). The genes modulated by vorozole were compared with two additional sets of data. First, thirty-two genes and a number of pathways exhibited significantly concordant changes with aromatase inhibitors both in the animal model and in at least three of four published human data sets. In particular, differentially expressed genes enriched in the cell cycle pathway that were related to chromosome condensation in prometaphase [including Aurora-A, Aurora-B, Bub1B, non-SMC condensin I complex, subunit H (BRRN1), Condensin, CAP-G, CAP-G/G2, CAP-H/H2, CAP-D2/D3, CAP-E, TOP2, Cyclin A, Cyclin B, CDK1, Histone H1 and inner centromere protein (INCENP)] were downregulated after treatment with the aromatase inhibitor. These results appear to be in agreement with the strong anti-proliferative effects of aromatase inhibitors in both animal and clinical studies. A second comparison was with an in vitro study in which estrogen was removed from MCF-7 cells in culture. Decreases in genes related to the E2F1 transcription factor were observed. In our study, 13 modulated genes exhibited E2F-1 binding sites in their promoter regions, and 7 genes contained both ER binding and E2F binding sites. We were able to confirm modulation of the cell cycle related and E2F-related genes in a large independent set of human samples treated with anastrozole. The results on RNA changes for Bub 1B, Cyclin A and CDK-1 were verified by employing IHC analysis. In summary, gene changes observed in the rat closely paralleled gene changes associated with aromatase treatment and estrogen withdrawal in humans. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-10-02.