The effect of aromatase inhibitor letrozole incorporated in gonadotrophin-releasing hormone antagonist multiple dose protocol in poor responders undergoing in vitro fertilization

( Kyung Hee Lee ),( Chung Hoon Kim ),( Hye Jin Suk ),( You Jeong Lee ),( Su Kyung Kwon ),( Sung Hoon Kim ),( Hee Dong Chae ),( Byung Moon Kang ) 대한산부인과학회 2014 Obstetrics & Gynecology Science Vol.57 No.3

Objective To evaluate whether letrozole incorporated in a gonadotrophin-releasing hormone (GnRH) antagonist multiple dose protocol (MDP) improved controlled ovarian stimulation (COS) and in vitro fertilization (IVF) results in poor responders who underwent IVF treatment. Methods In this retrospective cohort study, a total of 103 consecutive IVF cycles that were performed during either the letrozole/GnRH antagonist MDP cycles (letrozole group, n=46) or the standard GnRH antagonist MDP cycles (control group, n=57) were included in 103 poor responders. COS results and IVF outcomes were compared between the two groups. Results Total dose and days of recombinant human follicle stimulating hormone (rhFSH) administered were significantly fewer in the letrozole group than in the control group. Duration of GnRH antagonist administered was also shorter in the letrozole group. The number of oocytes retrieved was significantly higher in the letrozole group. However, clinical pregnancy rate per cycle initiated, clinical pregnancy rate per embryo transfer, embryo implantation rate and miscarriage rate were similar in the two groups. Conclusion The letrozole incorporated in GnRH antagonist MDP may be more effective because it results comparable pregnancy outcomes with shorter duration and smaller dose of rhFSH, when compared with the standard GnRH antagonist MDP.

Kinetics, Isotherm and Adsorption Mechanism Studies of Letrozole Loaded Modified and Biosynthesized Silver Nanoparticles as a Drug Delivery System: Comparison of Nonlinear and Linear Analysis

( Mahsa Pourshaban ),( Elham Moniri ),( Raheleh Safaeijavan ),( Homayon Ahmad Panahi ) 한국화학공학회 2021 Korean Chemical Engineering Research(HWAHAK KONGHA Vol.59 No.4

We prepared and investigated a biosynthesized nanoparticulate system with high adsorption and release capacity of letrozole. Silver nanoparticles (AgNPs) were biosynthesized using olive leaf extract. Cysteine was capped AgNPs to increase the adsorption capacity and suitable interaction between nanoparticles and drug. Morphology and size of nanoparticles were confirmed using transmission electron microscopy (TEM). Nanoparticles were spherical with an average diameter of less than 100 nm. Cysteine capping was successfully confirmed by Fourier transform infrared resonance (FTIR) spectroscopy and elemental analysis (CHN). Also, the factors of letrozole adsorption were optimized and the linear and non-linear forms of isotherms and kinetics were studied. Confirmation of the adsorption data of letrozole by cysteine capped nanoparticles in the Langmuir isotherm model indicated the homogeneous binding site of modified nanoparticles surface. Furthermore, the adsorption rate was kinetically adjusted to the pseudo-second-order model, and a high adsorption rate was observed, indicating that cysteine coated nanoparticles are a promising adsorbent for letrozole delivery. Finally, the kinetic release profile of letrozole loaded modified nanoparticles in simulated gastric and intestinal buffers was studied. Nearly 40% of letrozole was released in simulated gastric fluid with pH 1.2, in 30 min and the rest of it (60%) was released in simulated intestinal fluid with pH 7.4 in 10 h. These results indicate the efficiency of the cysteine capped AgNPs for adsorption and release of drug letrozole for breast cancer therapy.

Upregulation of PITX2 Promotes Letrozole Resistance Via Transcriptional Activation of IFITM1 Signaling in Breast Cancer Cells

Ying-ying Xu,Hai-ru Yu,Jia-yi Sun,Zhao Zhao,Shuang Li,Xin-feng Zhang,Zhi-xuan Liao,Ming-ke Cui,Juan Li,Chan Li,Qiang Zhang 대한암학회 2019 Cancer Research and Treatment Vol.51 No.2

Purpose Although the interferon  (IFN) signaling and the paired-like homeodomain transcription factor 2 (PITX2) have both been implicated in the progression of breast cancer (BCa), it remains obscure whether these two pathways act in a coordinated manner. We therefore aimed to elucidate the expression and function of PITX2 during the pathogenesis of endocrine resistance in BCa. Materials and Methods PITX2 expression was assessed in BCa tissues using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry and in experimentally induced letrozole-resistant BCa cells using RT-qPCR and immunoblotting. Effects of PITX2 deregulation on BCa progression was determined by assessing MTT, apoptosis and xenograft model. Finally, using multiple assays, the transcriptional regulation of interferon-inducible transmembrane protein 1 (IFITM1) by PITX2 was studied at both molecular and functional levels. Results PITX2 expression was induced in letrozole-resistant BCa tissues and cells, and PITX2 induction by IFN signaling powerfully protected BCa cells against letrozole insult and potentiated letrozole-resistance. Mechanistically, PITX2 enhanced IFN-induced AKT activation by transactivating the transcription of IFITM1, thus rendering BCa cells unresponsive to letrozoleelicited cell death. Additionally, ablation of IFITM1 expression using siRNA substantially abolished IFN-elicited AKT phosphorylation, even in the presence of PITX2 overexpression, thus sensitizing BCa cells to letrozole treatment. Conclusion These results demonstrate that constitutive upregulation of PITX2/IFITM1 cascade is an intrinsic adaptive mechanism during the pathogenesis of letrozole-resistance, and modulation of PITX2/IFITM1 level using different genetic and pharmacological means would thus have a novel therapeutic potential against letrozole resistance in BCa.

Licorice ethanol extract improves symptoms of polycytic ovary syndrome in Letrozole-induced female rats

Hyun Yang,Hye Jin Kim,Bo-Jeong Pyun,이혜원 한국한의학연구원 2018 Integrative Medicine Research Vol.7 No.3

Background: Licorice (Glycyrrhizae radix et rhizome, GRR) has long been used as an ingredient in Korean traditional medicinal herbal formulas for various metabolic and reproductive diseases. Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women. In the present study, we examined the effects of GRR extract on PCOS-like symptoms in female rats. Methods: Symptoms of PCOS were induced by Letrozole treatment for 4 weeks in 6-week-old female SD rats, after which the effects of GRR extract on recovery of normal hormonal levels and polycystic ovaries were assessed. Serum levels of luteinizing hormone (LH), follicular-stimulating hormone (FSH), LH/FSH ratio, and follicular cysts were evaluated, followed by the expression levels of known follicular phase markers such as Kitl, Cyp11a1, and Ptgs2. Results: The serum level of FSH was reduced only in the Lestrozole treatment group (PCOS), whereas significant recovery of FSH level was observed in the Letrozole and GRR co-treatment group (PCOS + GRR). Serum LH levels were not altered in any of the groups. Furthermore, the LH/FSH ratio (known biomarker for PCOS) was elevated only in the Letrozole treatment group (PCOS), whereas it was significantly reduced in the Letrozole and GRR co-treatment group (PCOS + GRR). For histological changes, follicular cysts, antral follicles, and increased thickness of the theca- and granulosa layers were observed in the PCOS group, whereas these alterations were remarkably reversed by GRR treatment. Conclusion: These results suggest that GRR extract inhibits the symptoms of PCOS by regulating imbalanced hormonal levels and irregular ovarian follicles.

Letrozole에 반응을 보인 다발성 폐전이를 동반한 저도 자궁내막 기저육종 1례

이남수,원종호,박희숙 순천향의학연구소 2004 Journal of Soonchunhyang Medical Science Vol.10 No.2

Low-grade endometrial stromal sarcoma is generally an indolent tumor rich in estrogen and progesterone receptors. Objective responses to hormonal therapy, most commonly with megestrol acetate, have been reported. The patient is a 50-year-old woman who presented with low-grade endometrial stromal sarcoma confined to the vagina in 1992 and was treated with local excision. Approximately 4 years later, the patient had recurrent right ovarian and ileal mass treated with right oophorectomy and segmental resection of ileum. In 2002, multiple lung metastatic lesions were discovered and treated with megestrol acetate. But megestrol acetate showed no response during the period. Letrozole was then given at a daily dose of 2.5 ㎎ with partial response for a duration of 10 months. Letrozole at a daily dose of 2.5 ㎎ may be effective in low-grade endometrial stromal sarcoma.

Estradiol valerate와 Letrozole에 의해 유발되는 다낭성난소증후군의 난소변화 비교

임성철 ( Sung Chul Lim ),정문진 ( Moon Jin Jeong ),김세은 ( Se Eun Kim ),김승현 ( Seung Hyun Kim ),김삼철 ( Sam Cheol Kim ),서승용 ( Seung Yong Seo ),김탁 ( Tak Kim ),강성수 ( Seong Soo Kang ),배춘식 ( Chun Sik Bae ) 대한산부인과학회 2011 Obstetrics & Gynecology Science Vol.54 No.6

목적: 다낭성난소증후군(polycystic ovary syndrome, PCOS)을 estradiol valerate (EV)와 letrozole (LE)로 유발할 수 있는데 인간의 다낭성난소증후군과 가장 유사한 질환동물 모델이 무엇인가를 알아보고자 하였다. 연구방법: EV와 LE를 각각 랫드에 처리하여 PCOS를 유발시킨 후 희생시켜 난소를 적출하였다. 난소를 조직학적으로 관찰하여 다낭성 난소 변화 유발유무, 난소의 크기, 난포낭의 크기 및 수를 측정하고 난포 및 간질세포의 황체화 등을 비교 관찰하였다. 결과: LE처리군은 EV처리군에 비하여 난소의 크기 및 난포낭의 수가 유의하게 증가하고 난포막세포의 황체화가 뚜렷하여 인간의 PCOS와 더유사한 소견을 보였다. 결론: 랫드에서 LE처리에 의한 PCOS는 PCOS질환유발 동물 모델로 더 적합한 것으로 평가된다. Objective: To compare ovarian morphology of the estradiol valerate (EV)-and the letrozole (LE)-induced polycystic ovary syndrome (PCOS) in rat models. Methods: EV were injected (IM) to 10 Sprague-Dawley rats and LE were administered (PO) to the other 10 Sprague-Dawley rats for 21 days. Sixty days after single injection of EV and 21 days after LE administration, the animals were sacrifi ced and the ovaries were sectioned, measured and analyzed histopathologically. Results: LE-treated group showed larger ovary bearing more abundant cystic follicles with luteinized theca cells. These fi ndings were more similar to human PCOS ovarian morphology. Conclusion: LE-induced PCOS model is recommended to conduct PCOS-related animal experiments.

Beneficial effects of Teucrium polium hydroalcoholic extract on letrozole-induced polycystic ovary syndrome in rat model

Zeynab Khosrowpour,Shirin Fahimi,Fateme Jafari,Mojgan Tansaz,Shamim Sahranavard,Mehrdad Faizi 대한산부인과학회 2023 Obstetrics & Gynecology Science Vol.66 No.2

ObjectivePolycystic ovary syndrome (PCOS) is an endocrine disorder that disrupts the menstrual cycle and causes infertility. Considering the increasing use of medicinal plants, the present study aimed to evaluate the effects of Teucrium polium L. on letrozole-induced PCOS in female rats. MethodsSix groups of rats (n=7 each) were evaluated. The control group received 1% carboxy methyl cellulose as vehicle, while the five other groups received letrozole 1 mg/kg orally for 21 days. After PCOS induction, the rats were orally administered T. polium extract (50, 100, and 200 mg/kg) or metformin (200 mg/kg) for 28 days. Subsequently, body and ovarian weights and serum levels of follicle stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, and testosterone were measured. Finally, the ovarian tissues were isolated for histological examination. ResultsThere were no significant changes in weekly body weight in any group. After 21 days of letrozole administration, PCOS induction was confirmed by estrous cycle irregularities and increased LH and testosterone levels. After treatment with the hydroalcoholic extract of T. polium, testosterone and LH levels were significantly reduced in all groups (P<0.05). Histological studies of ovaries in the metformin and T. polium groups exhibited normal follicular development with fewer and smaller cystic follicles than those in the PCOS group. ConclusionThe hydroalcoholic extract of T. polium improves serum levels of sex hormones, restores ovarian morphology in PCOS-induced rats, and is a good candidate for further clinical trials.

Functional Investigation on Aromatase in Endometrial Hyperplasia in Polycystic Ovary Syndrome Cases

Zhao, Pan-Lin,Zhang, Qiu-Fang,Yan, Li-Ying,Huang, Shuo,Chen, Yuan,Qiao, Jie Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.20

Objective: To explore the possible significance of aromatase P450 in endometrial hyperplasia with a background of polycystic ovary syndrome (PCOS). Methods: Immunohistochemistry was used to determine the expression of aromatase P450 in endometrium of PCOS patients. Semiquantitative analysis of aromatase P450 expression of mRNA and protein level wasalso carried out by real-time quantitative RT-PCR method. After endometrial cells were stimulated by testosterone and letrozole in vitro, the estradiol ($E_2$) level was determined, and the expression of cell aromatase P450 mRNA was assessed. Results: The aromatase P450 mRNA level was increased in endometria of PCOS patients. When endometrial cells were cultured with $10^{-6}M$ testosterone, the $E_2$ level in the culture medium increased. An inhibitory effect on $E_2$ generation and expression of aromatase P450 mRNA was observed when the endometrial cells were treated with $10^{-5}M$ letrozole. Conclusions: There is an increased expression of aromatase P450 in PCOS patient endometrium. Androgen stimulation could enhance the synthesis of aromatase P450 mRNA and the production of $E_2$ in endometrial cells in vitro while letrozole could do the reverse.

Traditional Medicine (Mahuang-Tang) Improves Ovarian Dysfunction and the Regulation of Steroidogenic Genes in Letrozole-Induced PCOS Rats

Yang, Hyun,Lee, Young Ho,Lee, Sang R.,Kaya, Pelin,Hong, Eui-Ju,Lee, Hye Won Elsevier 2020 Journal of Ethnopharmacology Vol.248 No.-

<P><B>Abstract</B></P> <P><B>Ethnopharmacological relevance</B></P> <P>Mahuang-Tang (MHT) has traditionally been used in Asia to treat a variety of diseases, such as fever without sweating, joint pain, lower back pain, asthma, and gynecological conditions. Polycystic ovary syndrome (PCOS) is a kind of gynecological disease that causes amenorrhea, infertility, and menopausal and urogenital disorders that could benefit from MHT treatment.</P> <P><B>Aim of the study</B></P> <P>In this study, we examined the effects of MHT on ovarian hormones and steroidogenic enzymes in female PCOS rats.</P> <P><B>Methods and results</B></P> <P>The PCOS rat model was induced by Letrozole, and an <I>in vivo</I> evaluation of whether the dietary consumption of MHT improved the PCOS-like symptoms was conducted. The luteinizing hormone (LH) level and luteinizing hormone/follicular-stimulating hormone (LH/FSH) ratio increased in PCOS rats but decreased following MHT treatment. In the PCOS rats, the reduced estrogen level was restored to that of normal controls with MHT treatment in serum. The transcription level(s) of gonadotropin receptors (<I>Fshr</I> and <I>Lhr</I>), steroid receptors (<I>Pgr</I>, and <I>Esr1</I>) and steroidogenic enzymes (<I>Cyp19a1</I>, <I>Hsd3b1</I>, <I>Hsd17a1</I>, and <I>Cyp11a1</I>) changed under the PCOS condition, and were regulated by MHT treatment in the ovaries of PCOS rats. The reproductive tissues of Letrozole-induced PCOS rats were restored into estrogenic condition from androgen environments.</P> <P><B>Conclusion</B></P> <P>These results suggest that MHT ameliorates the symptoms of PCOS by improving the dysregulation of ovarian steroids and steroidogenic enzymes in PCOS rats.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Drug Use Evaluation of Letrozole in Breast Cancer Patients at Regional Cancer Hospitals in Thailand

Ketkaew, Chaninun,Kiatying-Angsulee, Niyada Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.14

Background: Medication policy development in Thailand is continually promoting rational drug use. Letrozole, an endocrine therapy drug, is usually prescribed for post-menopausal status early and advanced stage breast cancer. After Ministry of Public Health announced Letrozole as compulsory licensed drug in 2009, more breast cancer patients can access to this drug at low cost especially those within universal coverage schemes. To ensure that Letrozole is rationally prescribed, the drug utilization study was conducted. Objectives: The aim of this study was to describe the appropriate use of Letrozole in breast cancer and the relationship between appropriate use and health benefit schemes. Materials and Methods: A retrospective study to evaluate use of Letrozole in breast cancer patients was performed for six months between January - June 2010 in seven regional cancer hospitals, Thailand. All prescriptions of Letrozole were identified from pharmacy dispensing databases and prescription papers. A medical record review was also performed to evaluate appropriate use referring to the drug use evaluation criteria. The approved criterion of this study was referred from the guideline of Thai National Formulary version 2010. Results: There were 681 prescriptions of Letrozole for 254 breast cancer patients with an average age of $58.6{\pm}10.0years$. The patients in universal coverage scheme (UCS), civil servant medication benefit scheme (CSMBS) and social security scheme (SSS) were 77.7%, 18.5% and 8.7% respectively. 10.6% were prescribed Letrozole for the first time. Letrozole were prescribed by oncologists (82.8%). The average number of tablets per prescription was $58{\pm}10$. Calcium supplements were prescribed concomitant with Letrozole for 19.4%. To assess drug use evaluation criteria, 45 prescriptions were excluded because of uncompleted clinical data, 636 prescriptions were evaluated. The study showed 86 prescriptions (13.5%) with inappropriate use including 6 (0.9%) not prescribed for estrogen receptor (ER) and/or progesterone receptor (PR) positive, 31 (4.9%) not prescribed for post-menopausal and 49 (7.7%) not prescribed for an appropriate duration. Appropriate use percentages in different health benefit schemes were similar, 85.7% of CSMBS, 86.4% of SSS and 86.7% of UCS. The relationship between health benefit scheme and appropriate use of Letrozole was not significantly different, ${\chi}^2$ (2, N = 636) = 0.081, p > 0.05. Conclusions: The study showed inappropriate use in breast cancer patients because of non-compliance with duration, menopausal status and hormone receptor requirements. To prescribe appropriate indication did not referred to the appropriate practice along the treatment. Drug use evaluation proved very useful for detecting the sign of inappropriate use and allows immediate feedback to the stakeholder for developing medication policy in the future. Importantly, there was no significantly difference in appropriate use of Letrozole across health benefit schemes.