Effect of letrozole in carcinogen-plus-estrogen-induced endometrial hyperplasia in mice.

PURPOSE To evaluate the effects of letrozole (Ltz) in carcinogen+estrogen-induced endometrial hyperplasia. METHODS BALB/c female mice were divided into four groups of 12 animals each receiving an intrauterine dose of N-ethyl-N-nitrosourea (ENU) and weekly subcutaneous injections of estradiol hexaidrobenzoate (EHB), except for group I(control). The groups were divided in I (control), II (ENU+EHB), III (ENU+EHB+MPA) and IV (ENU+EHB+Ltz). Group III also received intramuscular injections of MPA (medroxy progesterone acetate) every four weeks, while group IV received oral doses of Ltz daily. At the end of 16 weeks, the animals were sacrificed, and blood samples were collected for the measurement of serum estradiol and progesterone levels. Uterine histological sections were made to evaluate the presence of endometrial proliferative lesions. Differences between groups were evaluated with student's t test, ANOVA and chi-square test. RESULTS Groups ENU+EHB, ENU+EHB+MPA and ENU+EHB+Ltz showed varying degrees of endometrial hyperplasia. The incidence of hyperplasia in groups ENU+EHB and ENU+EHB+Ltz was higher and more severe than in group ENU+EHB+MPA. Control group showed lower levels of serum estradiol than the other groups. CONCLUSION There was no evidence that letrozole could act as an antiestrogenic drug in the development of endometrial proliferative lesions.

[1]  B. Mol,et al.  The accuracy of endometrial sampling in women with postmenopausal bleeding: a systematic review and meta-analysis. , 2016, European journal of obstetrics, gynecology, and reproductive biology.

[2]  Jae-Weon Kim,et al.  Gynecologic Cancer InterGroup (GCIG) Consensus Review for Clear Cell Carcinoma of the Uterine Corpus and Cervix , 2014, International Journal of Gynecologic Cancer.

[3]  M. Friedlander,et al.  Gynecologic Cancer InterGroup (GCIG) Consensus Review for Endometrial Stromal Sarcoma , 2014, International Journal of Gynecologic Cancer.

[4]  Q. Chu,et al.  Aromatase inhibition: a potential target for the management of recurrent or metastatic endometrial cancer by letrozole: more questions than answers? , 2011, Expert opinion on investigational drugs.

[5]  J. Geisler,et al.  Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole – of clinical importance? , 2011, British Journal of Cancer.

[6]  N. Cope,et al.  Endometrial hyperplasia: a clinician's review , 2010 .

[7]  N. Yaegashi,et al.  Prolonged long-term survival of low-grade endometrial stromal sarcoma patients with lung metastasis following treatment with medroxyprogesterone acetate , 2010, International Journal of Clinical Oncology.

[8]  T. Dahhan,et al.  The efficacy of hormonal treatment for residual or recurrent low-grade endometrial stromal sarcoma. A retrospective study. , 2009, European journal of obstetrics, gynecology, and reproductive biology.

[9]  L. Barker,et al.  Sustained effect of the aromatase inhibitors anastrozole and letrozole on endometrial thickness in patients with endometrial hyperplasia and endometrial carcinoma , 2009 .

[10]  Jens Einenkel,et al.  Histopathology of endometrial hyperplasia and endometrial carcinoma: an update. , 2007, Annals of diagnostic pathology.

[11]  S. Regauer,et al.  Hormonal therapy of endometrial stromal sarcoma , 2007, Current opinion in oncology.

[12]  Kiyoshi Ito,et al.  Hormone replacement therapy and cancers: the biological roles of estrogen and progestin in tumorigenesis are different between the endometrium and breast. , 2007, The Tohoku journal of experimental medicine.

[13]  V. Jordan Medroxyprogesterone acetate and metastases: of mice and (wo)men. , 2005, Journal of the National Cancer Institute.

[14]  J. Ragaz,et al.  Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model. , 2004, Journal of the National Cancer Institute.

[15]  E. Eisenhauer,et al.  The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers – a study of the National Cancer Institute of Canada Clinical Trials Group , 2004, International Journal of Gynecologic Cancer.

[16]  W. Yue,et al.  Intratumoral aromatase model: The effects of letrozole (CGS 20267) , 2004, Breast Cancer Research and Treatment.

[17]  Ş. Altaner,et al.  Comparison of the effects of letrozole and clomiphene citrate on ovarian follicles, endometrium, and hormone levels in the rat. , 2003, Fertility and sterility.

[18]  L. Horn,et al.  Risk of progression in complex and atypical endometrial hyperplasia: clinicopathologic analysis in cases with and without progestogen treatment , 2003, International Journal of Gynecologic Cancer.

[19]  M. Heineman,et al.  The postmenopausal ovary as an androgen-producing gland; hypothesis on the etiology of endometrial cancer. , 2002, Maturitas.

[20]  M. Dowsett,et al.  Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors , 2001, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  K. Miyajima,et al.  Time-dependent promotion activity of 17beta-estradiol on uterine carcinogenesis in mice initiated with N-ethyl-N-nitrosourea. , 2001, Cancer letters.

[22]  J. Liehr,et al.  Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens. , 2000, Cancer research.

[23]  R. Schenken,et al.  Outpatient diagnostic hysteroscopies. , 1996, Obstetrics and Gynecology.

[24]  A. Davies,et al.  2500 Outpatient Diagnostic Hysteroscopies , 1996, Obstetrics and Gynecology.

[25]  H. Mori,et al.  Chronological observation of mouse endometrial carcinogenesis induced by N-methyl-N-nitrosourea and 17 beta-estradiol. , 1996, Cancer letters.

[26]  K. Miyajima,et al.  Rapid and high yield induction of endometrial adenocarcinomas in CD-1 mice by a single intrauterine administration of N-ethyl-N-nitrosourea combined with chronic 17 beta-estradiol treatment. , 1996, Cancer letters.

[27]  Takuji Tanaka,et al.  Inhibitory Effects of Medroxyprogesterone Acetate on Mouse Endometrial Carcinogenesis , 1995, Japanese journal of cancer research : Gann.

[28]  G. Vittori,et al.  Outpatient hysteroscopy in the diagnosis of neoplastic and preneoplastic lesions of the endometrium. , 1988, European journal of gynaecological oncology.

[29]  M. L. Stone,et al.  Preliminary Studies of Aromatase in Human Neoplastic Endometrium , 1984, Obstetrics and gynecology.