Letrozole

Letrozole is a novel and potent type (II) aromatase inhibitor with IC50 of 11.5 nM. It belongs to the reversible non-steroidal compound family which can inhibit Arom. However, there is no evidence that it can affect the adrenal steroidogenesis.[1]

Normally, Type II inhibitors have a common feature of heterocyclic azole moiety, which can be binded to the heme–iron in aromatase. It contains a structure of 1,2,4-triazole moieties which can coordinate the heme–iron of cytochrome P450. Meanwhile, benzonitrile substituted letrozole can mimic a unique enzyme structure of the substrate androstenedione.[2]

Letrozole administration can reduce spine synapse and axon outgrowth and it also will decrease the expression of estrogen receptor  (ER). While, the synaptic proteins including GAP-43 can impaire the long-termpotentiation.[1] Letrozole is proved to promote FSH release from the hypothalamic pituitary axis by responding to decreased estrogen (E) feedback.[3]

References:
[1] Chen Bian, Yangang Zhao, Qiang Guo, Ying Xiong, Wenqin Cai, Jiqiang Zhang. Aromatase inhibitor letrozole downregulates steroid receptor coactivator-1 in specific brain regions that primarily related to memory, neuroendocrine and integration. The Journal of Steroid Biochemistry and Molecular Biology. May 2014. 141: 37-43.
[2] Hakki Türker Akçay, Riza Bayrak. Computational studies on the anastrozole and letrozole, effective chemotherapy drugs against breast cancer. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 25 March 2014. 122: 142-152.
[3] Lindsay Malloch, Alice Rhoton-Vlasak. An assessment of current clinical attitudes toward letrozole use in reproductive endocrinology practices. Fertility and Sterility. December 2013. 100(6): 1740-1744.

Comparing the Administration of Letrozole and Megestrol Acetate in the Treatment of Women with Simple Endometrial Hyperplasia without Atypia: A Randomized Clinical Trial.[Pubmed:28353144]

Adv Ther. 2017 May;34(5):1211-1220.

INTRODUCTION: The present study was conducted as a pilot to compare the therapeutic effects and the potential side effects of oral Megestrol acetate and Letrozole in the treatment of simple hyperplasia in perimenopausal women. METHODS: The participants of this randomized clinical trial consisted of two groups of 25 women aged 44-50 presenting with abnormal uterine bleeding diagnosed with simple endometrial hyperplasia without cytologic atypia confirmed by transvaginal ultrasonography and biopsy. The first group received 40-mg doses of Megestrol acetate for 2 weeks per month for a total period of 2 months. The second group received 2.5-mg daily doses of Letrozole for a total period of 2 months. The differences in terms of quantitative measurements were analyzed using the independent two-sample t test and the paired t test. To compare the two groups in terms of the distribution of the categorical variables, Pearson's Chi square and Fisher's Exact tests were used at the significance level of 0.05 by Stata-9.2. RESULTS: Although the intervention led to significant improvements in both groups (P < .001), there was no difference between the groups in terms of accomplishing resolution (P = .74) [seven (28%) patients in the Letrozole group and five (20%) in the Megestrol group], while two patients in the Letrozole group and nine in the Megestrol group suffered from side effects, suggesting significantly lower side effects in the Letrozole group (P = .02). CONCLUSION: Letrozole and Megestrol acetate seem to have similar effects on the treatment of simple endometrial hyperplasia, the only difference being that Letrozole presents fewer side effects than Megestrol acetate in patients with this condition. FUNDING: Abnormal Uterine Bleeding Research Center of Semnan University of Medical Sciences, Semnan, Iran. TRIAL REGISTRATION: IRCT2015031011504N5.

Exercise differentially affects metabolic functions and white adipose tissue in female letrozole- and dihydrotestosterone-induced mouse models of polycystic ovary syndrome.[Pubmed:28344042]

Mol Cell Endocrinol. 2017 Jun 15;448:66-76.

Here we hypothesized that exercise in dihydrotestosterone (DHT) or Letrozole (LET)-induced polycystic ovary syndrome mouse models improves impaired insulin and glucose metabolism, adipose tissue morphology, and expression of genes related to adipogenesis, lipid metabolism, Notch pathway and browning in inguinal and mesenteric fat. DHT-exposed mice had increased body weight, increased number of large mesenteric adipocytes. LET-exposed mice displayed increased body weight and fat mass, decreased insulin sensitivity, increased frequency of small adipocytes and increased expression of genes related to lipolysis in mesenteric fat. In both models, exercise decreased fat mass and inguinal and mesenteric adipose tissue expression of Notch pathway genes, and restored altered mesenteric adipocytes morphology. In conclusion, exercise restored mesenteric adipocytes morphology in DHT- and LET-exposed mice, and insulin sensitivity and mesenteric expression of lipolysis-related genes in LET-exposed mice. Benefits could be explained by downregulation of Notch, and modulation of browning and lipolysis pathways in the adipose tissue.

The effects of Nobiletin, Hesperetin, and Letrozole in a combination on the activity and expression of aromatase in breast cancer cells.[Pubmed:28364779]

Cell Mol Biol (Noisy-le-grand). 2017 Feb 28;63(2):9-13.

Nobiletin (NOB) and hesperetin (HES) are the citrus polymethoxyflavone and flavonone. Aromatase or cytochrome P450 (CYP19) enzyme is a key enzyme in estrogen biosynthesis. The objective of this study was to investigate the combinational effects of HES, NOB and Letrozole (LET) as aromatase inhibitors on the activity and expression of aromatase in MCF-7 cells. In this study, aromatase enzyme activity based on the conversion of androgen substrate testosterone to 17beta-Estradiol was determined. Estradiol concentrations were measured using an electrochemiluminescence immunoassay. CYP19 gene expression was determined by quantitative real-time PCR. Our findings demonstrated that none of combinations including LET+NOB, LET+HES, LET+NOB+HES, and NOB+HES had no significant effects on aromatase activity and expression. The present study showed for the first time that the combination of HES, NOB, and LET had no effects on activity and expression of aromatase in MCF-7 breast cancer cells.

The discovery and mechanism of action of letrozole.[Pubmed:17912633]

Breast Cancer Res Treat. 2007;105 Suppl 1:7-17.

Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of Letrozole (Femara) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, Letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of Letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that Letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of Letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.

Letrozole as a potent inhibitor of cell proliferation and expression of metalloproteinases (MMP-2 and MMP-9) by human epithelial breast cancer cells.[Pubmed:12569569]

Int J Cancer. 2003 Mar 20;104(2):155-60.

P450 aromatase catalyzes the conversion of androgens to estrogens and plays a key role in the cell growth of hormone-dependent breast cancer in postmenopausal women. On the other hand, matrix metalloproteinases (MMPs), which can degrade almost all components of the extracellular matrix, play a crucial role in tumor cell invasion and cancer metastasis. In the present study the effect of Letrozole on cell proliferation of estrogen receptor (ER)-positive MCF-7 human epithelial breast cancer and MCF-12A human mammary epithelial cells was studied. The effect of Letrozole on the in vitro release of MMPs, particularly type IV collagenases (MMP-2 and MMP-9), by the ER-positive MCF-7 cells was also investigated, using a solid-phase method of high sensitivity and accuracy. Using RNA isolates from cell lines MCF-7 and MCF-12A, reverse transcriptase-polymerase chain reaction analysis revealed that only MCF-7 cells express the P450 aromatase gene. Study of the effects of Letrozole alone and the hormones 17-beta-estradiol, testosterone and 4-androstene-3, 17-dione in the presence and absence of Letrozole on cell growth at the DNA synthesis level showed that Letrozole significantly suppressed the endogenous aromatase-induced proliferation of MCF-7 cells. The majority of MMPs secreted by MCF-7 cells were identified in their pro-forms, which was in accordance with the low metastatic potential determined for these cells. After treatment of cells with Letrozole (10 nM) for 24 and 48 h, significant inhibition of MMP levels was obtained. Furthermore, concurrent treatment of MCF-7 cells with 17-beta-estradiol in the presence of Letrozole significantly suppressed the estradiol-induced stimulation of MMP levels. The data obtained suggest that Letrozole is a potent in vitro inhibitor of cell proliferation and of type IV collagenases expressed by ER-positive MCF-7 cells and may be of value for suppressing breast tumor growth and invasiveness.

Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor.[Pubmed:2149502]

J Steroid Biochem Mol Biol. 1990 Dec 20;37(6):1021-7.

CGS 20267 is a new non-steroidal compound which potently inhibits aromatase in vitro (IC50 of 11.5 nM) and in vivo (ED50 of 1-3 micrograms/kg p.o.), CGS 20267 maximally inhibits estradiol production in vitro in LH-stimulated hamster ovarian tissue at 0.1 microM with an IC50 of 0.02 microM and does not significantly affect progesterone production up to 350 microM. In ACTH-stimulated rat adrenal tissue in vitro, aldosterone production was inhibited with an IC50 of 210 microM (10,000 times higher than the IC50 for estradiol production); no significant effect on corticosterone production was seen at 350 microM. In vivo, in ACTH-treated rats, CGS 20267 does not affect plasma levels of corticosterone or aldosterone at a dose of 4 mg/kg p.o. (1000 times higher than the ED50 for aromatase inhibition in vivo). In adult female rats, a 14-day treatment with 1 mg/kg p.o. daily, completely interrupts ovarian cyclicity and suppresses uterine weight to that seen 14 days after ovariectomy. In adult female rats bearing estrogen-dependent DMBA-induced mammary tumors, 0.1 mg/kg p.o. given daily for 42 days caused almost complete regression of tumors present at the start of treatment. Thus compared to each other, CGS 16949A and CGS 20267 are both highly potent in inhibiting estrogen biosynthesis in vitro and in vivo. The striking difference between them is that unlike CGS 16949A, CGS 20267 does not affect adrenal steroidogenesis in vitro or in vivo, at concentrations and doses several orders of magnitude higher than those required to inhibit estrogen biosynthesis.