A novel herbal combination ameliorates ovarian dysfunction and regulates altered biochemical parameters in rats with letrozole-induced polycystic ovary syndrome

Objective:To investigate the potential activity of novel herbal combination and novel herbal formulation(syrup)in female Sprague Dawley rats with letrozole-induced polycystic ovary syndrome(PCOS).Methods:Forty-two rats were randomly divided into seven groups with six rats in each group.Group 1 received 0.5%carboxy methylcellulose orally for 37 days and served as the normal control group.Group 2 was orally administered with letrozole of 1 mg/kg for 21 days and served as the PCOS induction group without treatment.Group 3 to 7 were administered with letrozole of 1 mg/kg for 21 days orally to induce PCOS,and then respectively received clomiphene citrate at 1 mg/kg,100 and 200 mg/kg of novel herbal combination,200 mg/kg of novel herbal formulation(syrup),and 400 mg/kg of marketed formulation of Pushyanuga churna,once daily for 15 days.Effects of the novel herbal combination and its syrup formulation were evaluated on the hormonal profile,the levels of antioxidants,the lipid profile and on the ovarian morphology,using letrozole-induced PCOS model in rats.Results:Letrozole caused alterations in hormonal levels and lipid levels similar to PCOS and ovarian histology showed presence of ovarian cysts confirming the induction of PCOS in rats.On treatment with the novel herbal combination and its syrup formulation in PCOS-induced rats,the altered hormonal and lipid profiles showed significant recovery to normal levels.Ovarian histology confirmed the restoration of folliculogenesis in the PCOS-induced rats.The treatment with the syrup formulation of novel herbal combination was found to be more effective than novel herbal combination and showed better recovery in various parameters evaluated.The results of the study,however,suggested that treatment with novel herbal combination and its syrup formulation provided minimal protection against oxidative stress caused due to the induction of PCOS.Conclusions:The integrated approach for management of PCOS is to counterbalance the limitations associated with modern therapy.Both the novel herbal combination and the syrup formulation of novel herbal combination show efficacy in the management of PCOS in rats and restore folliculogenesis in the ovary.The syrup formulation of novel herbal combination is most effective in the management of PCOS and shows potential to be developed as an adjuvant therapeutic agent.

Comparison of Letrozole and Aminoglutethimide in Treatment of 113 Cases of Postmenopausal Women with Advanced Breast Cancer

Objective: To compare the efficacy and tolerability of letrozole with aminoglutethimide (AG) in postmenopausal women with advanced breast cancer. Methods: The multicenter, randomized controlled clinical trial was conducted in 113 patients. They randomly received letrozole 2.5 mg once daily (letrozole group) or AG 250 mg 4 times daily (AG group) with hydrocortisone. Results: The OR in letrozole group was 23.73% (2 cases of CR and 12 cases of PR, ITT OR was 21.88%), which was higher than in AG group (the OR 11.11%, 1 CASE of CR and 5 cases of PR, ITT 10.17%), but there was no statistically significant difference (P>0.05). Adverse events (AE) and the treatment related AE (RAE) in letrozole group (n=59) was 18.54% and 13.56% respectively, significantly lower than those (42.11% and 33.33% respectively) in AG group (n=57, P=0.002). Conclusion: The OR of letrozole in the treatment of postmenopausal advanced breast cancer positive or unknown for hormonal receptor is 23.73%, showing no significant difference to that of AG. The AE of letrozole are significantly less than AG.

Multivariate analysis to predict letrozole efficacy in improving sperm count of non-obstructive azoospermic and cryptozoospermic patients： a pilot study

We tested the hypothesis that letrozole increases sperm count in non-obstructive azoospermic or cryptozoospermic patients with a testosterone （T）/17-beta-2-oestradiol （E2） ratio 〈 10. Forty-six patients with no chromosomal aberrations were randomized into two groups： 22 received letrozole 2.5 mg per day for 6 months （Group 1：6 azoospermic＋ 16 cryptozoospermic patients）, while 24 received a placebo （Group 2：5 azoospermic＋19 cryptozoospermic patients）. The following data were collected： two semen analyses, clinical history, scrotal Duplex scans, body mass index （BMI）, Y microdeletion, karyotype and cystic fibrosis screens and follicle-stimulating hormone （FSH）, luteinizing hormone （LH）, E2, T and prolactin levels. Both before and after letrozole or placebo administration, the patients underwent two semen analyses and hormonal assessments. The differences were evaluated using the Mann-Whitney Utest. The relationships between sperm concentration after letrozole administration with respect to FSH, TIE2 ratio, bilateral testicle volume and BMI before letrozole administration were assessed using multivariate analysis. The side effects were assessed using the chi-square test. Group 1 had sperm concentration （medians： 400-1.290× 10^6 ml^-1; P〈0.01） and motility （medians： class A from 2% to 15%; P〈0.01）, FSH, LH and T significantly increased, while Group 2 did not. E2 levels diminished significantly in Group 1, but not in Group 2. Eight patients in Group 1 demonstrated side effects, whereas no patient side effects were observed in Group 2. The sperm concentration after letrozole administration is inversely related to TIE2, FSH and BMI; a direct relationship emerged between sperm concentration and testicular volume.

Preliminary study of letrozole use for improving spermatogenesis in non-obstructive azoospermia patients with normal serum FSH

We investigated whether letrozole （2.5 mg day-1） improves sperm count in non-obstructive azoospermia （NOA） patients. Four men were included in this study, and they had folliculo-stimulating hormone and other hormone levels within the normal range and no varicoceles or chromosomal aberrations. These four patients were administered letrozole for 3 months. Sperm count, testicular volume, gonadotropin, testosterone （T） and estradiol （E2） blood levels were assessed before, during and 1 week after the suspension of treatment. All patients showed spermatozoa in their ejaculate, increased gonadotropin and T levels and lower E2 levels （P〈0.05 in all cases）, when letrozole was administered. This suggests that letrozole treatment might improve sperm count in an NOA sub-population; however, more studies, including the proper controls, are needed to confirm its efficacy.

Stability-indicating liquid chromatographic method for the determination of Letrozole in pharmaceutical formulations

A stability-indicating high-performance liquid chromatographic method was developed and validated for the determination of Letrozole in tablet dosage forms. Reversed-phase chromatography was performed on Shimadzu Model LC-Class-Vp with Lichrocart/Lichrosphere 100 C-18 (250 mm 4.6 mm, 5 mm particle size) column with methanol: tetra butyl ammonium hydrogen sulfate (80:20V/V) as mobile phase at a flow rate of 1 mL/min with UV detection at 240 nm. Linearity was observed in the concentration range of 0.5-150 mg/mL (R 2 0.9998) with regression equation y 102582xt43185. The limit of quantitation (LOQ) and limit of detection (LOD) were found to be 0.043 and 0.012 mg/mL respectively. The forced degradation studies were performed by using HCl, NaOH, H 2 O 2 , thermal and UV radiation. Letrozole is more sensitive towards alkaline conditions and very much resistant towards acidic, oxidative and photolytic degradations. The method was validated as per ICH guidelines. The RSD for intra-day (0.78-0.97) and inter-day (0.86-0.96) precision were found to be lesser than 1%. The percentage recovery was in good agreement with the labeled amount in the pharmaceutical formulations and the method is simple, specific, precise and accurate for the determination of Letrozole in pharmaceutical formulations.

Randomized controlled trial of Letrozole versus Clomiphene citrate for induction of ovulation in polycystic ovarian syndrome (PCOS): A Malaysian experience

Background: The purpose of this study was to compare the effectiveness of Letrozole versus Clomiphene citrate for ovulation induction in polycystic ovarian syndrome (PCOS) with infertility. Methods: This was a prospective randomized trial involving 150 women with PCOS attending the Infertility Clinic at three hospitals in Malaysia. During the initial visit, anthropometric measurements and baseline investigations were performed. Patients were randomized to 5.0 mg Letrozole daily (75 patients) or 100 mg Clomiphene citrate daily (75 patients) from the fifth until the ninth day of menstruation. Serial transvaginal scans were performed to see the dominant follicles, endometrial thickness and number of follicles. Transvaginal scans were performed serially to look for evidence of ovulation. Results: The subjects were homogenously distributed. The difference between Letrozole and Clomiphene citrate for ovulation rate was 59 (78.7%) versus 40 (53.3%). Patients taking Letrozole exhibited a mean endometrial thickness (ET) at mid cycle of menses (Day 11-D14) of9.2 mm(SD ± 2.3) versus8.4 mm(SD ± 2.2) for patients taking Clomiphene citrate, and these differences were statistically significant

Crystal Engineering of Co(Ⅱ) Metal-organic Frameworks Based on the Hydrolysis Product of Letrozole and Coligands

The cyanide groups of letrozole(1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole) were hydrolyzed into the carboxylic groups under alkaline conditions. Then the hydrolysis product(1-[bis(4-carboxylphenyl)methyl]-1,2,4-triazole, H2ltzda) reacted with Co(NO3)2·6H2O in the presence of different bipyridl-typed ligands under hydrothermal conditions. As a result, two new Co(Ⅱ) MOFs were obtained, formulated as [Co2(ltzda)2(bpp)2]n(1) and {[Co2(ltzda)2(bpy)]·4H2O}n(2)(bpp = 1,3-di(4-pyridyl)propane, bpy = 4,4’-bipyridine). Two MOFs have been characterized by single-crystal X-ray diffraction, thermogravimetric analysis and magnetic measure. 1 displays a 2D metal-organic framework containing wave layers and 2 shows a pillared-layer structure existing in a 2-fold interpenetrated mode.

Simultaneous Letrozole and Clomiphene Citrate versus Letrozole Alone in Clomiphene Citrate Resistant Polycystic Ovary Syndrome: A Randomised Controlled Trial

Background: Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. The therapeutic strategies for clomiphene citrate (CC)- resistant patients include the addition of corticosteroids, extended duration of clomiphene, gonadotrophin therapy, laparoscopic ovarian drilling, in vitro fertilization or the use of aromatase inhibitors recently. Letrozole decreases estrogen levels in the body, so it releases the hypothalamus and/or pituitary gland from the negative feedback of estrogen. This increases levels of gonadotrophins, which stimulates follicular growth. Objectives: To evaluate the role of letrozole alone and simultaneous use of letrozole and clomiphene citrate (CC) for ovulation induction in patients with clomiphene citrate-resistant PCOS (CCR-PCOS). Patients and Methods: This open-label randomised controlled study was conducted in the Department of Obstetrics and Gynecology, Faculty of Medicine, Zagazig University, Egypt during the period from February 2018 to June 2019. The study included 60 CCR-PCOS patients who were randomly allocated by independent personnel into two arms: group A (letrozole alone) or B (letrozole + CC). In either group, monitoring the mean follicular diameter and endometrial thickness in the days 10, 12, and 14 of the cycle by transvaginal ultrasound and Measurement of serum Progesterone (ng/ml) 7 days after the expected time of ovulation. Results: We investigated various clinical and sonographic factors that may predict the outcome of the method of induction of ovulation in CCR-PCOS with no significant affection for the results. There was a non-significant difference between the studied groups regarding ovulation and pregnancy per cycle or per patient. Conclusion: Letrozole alone or simultaneous use of letrozole and CC offers a good second-line option for induction of ovulation in CCR-PCOS patients. However, the combination of CC and letrozole did not add any benefit over the use of letrozole alone regards ovulation rate, follicular volume, endometrial thickness, pregnancy rate and live birth rate.

Short-term Femara (letrozole) treatment and suppression of Ki67 expression in postmenopausal endometrial carcinoma

Objective: To determine if short-term treatment with Femara (letrozole) induces measurable reduction in tumor Ki67 expression in postmenopausal women with FIGO grade 1 and 2 endometrial carcinoma. Methods: In this non-randomized prospective study, 12 patients were given Femara (letrozole) 2.5 mg daily for approximately 3 weeks prior to planned hysterectomy for FIGO grade 1 or 2 endometrial carcinoma. A group of 12 demographically similar patients were enrolled as no-treatment controls. Ki67 expression in tumor cells was quantitated by immunohistochemistry with mechanical scanning within the initial endometrial biopsy and compared to that in the hysterectomy specimen for each patient in the treatment and control groups. Results: The treatment and control groups were similar in age, tumor grade and FIGO stage. When “aromatase inhibitor responsiveness” was defined as proportionate decline in Ki67% stained tumor cells of at least 70% between the pre-treatment endometrial biopsy and post-treatment hysterectomy specimens, 5 of 12 patients were found to be “responsive” in the treatment group with none of the controls fulfilling these criteria. Conclusion: Femara (letrozole) 2.5 mg daily for approximately 3 weeks induced a significant reduction in tumor cell Ki67 expression among 5 of 12 (41%) postmenopausal women with FIGO grade 1 or 2 endometrial carcinoma. We postulate that Ki67 may be a useful marker during aromatase inhibitor medical treatment of patients with endometrial cancer who are not candidates for surgical treatment.

SPE-UPLC-MS/MS assay for determination of letrozole in human plasma and its application to bioequivalence study in healthy postmenopausal Indian women

A rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry（UPLC-MS/MS） method is described for determination of letrozole in human plasma.Following solid phase extraction（SPE） of letrozole and letrozole-d4 on Orochem DVB-LP cartridges,chromatography was performed on Acquity UPLC BEH C_（18）（50 mm × 2.1 mm.1.7 μm） column using methanol-0.1%formic acid in water（85：15,v/v） as the mobile phase.Detection was carried out on a triple quadrupole mass spectrometer with an electrospray source,operated under positive ionization mode.Quantitation of letrozole and letrozole-d4 was done using multiple reaction monitoring（MRM） following the transitions at m/z286.2→217.0 and m/z 290.2→221.0,respectively.The calibration plots were linear through the concentration range of 0.10-100 ng/mL（r^2 ≥ 0.9990） using 100 μL human plasma.The extraction recovery of letrozole ranged from 94.3%to 96.2%and the intra-batch and inter-batch precision was ≤ 5.2%.The method was successfully applied to a bioequivalence study of letrozole after oral administration of2.5 mg tablet formulation to 16 healthy postmenopausal Indian women.The assay reproducibility was also established through incurred sample reanalysis（ISR） of 74 subject samples.

Combined effects of Gymnema sylvestre and Pergularia daemia on letrozole-induced polycystic ovarian syndrome in rats

Objective:To investigate the combined therapeutic potential of Gymnema(G.)sylvestre and Pergularia(P.)daemia on letrozole-induced polycystic ovarian syndrome(PCOS)in rats.Methods:Thirty six healthy female Wistar rats with regular estrus cycles were randomly divided into six groups each of 6.GroupⅠreceived 1 mL of 0.5%carboxyl methyl cellulose orally and served as the vehicle control group,while groupsⅡtoⅥwere treated with letrozole(1 mg/kg body weight p.o.)for 21 days to induce PCOS.After induction of PCOS,groupⅡserved as the PCOS control group,without treatment;groupⅢreceived metformin(20 mg/kg body weight p.o.)as the standard group,and groupsⅣtoⅥreceived G.sylvestre(100 mg/kg body weight p.o.),P.daemia(300 mg/kg body weight p.o.),and the combination of G.sylvestre and P.daemia,respectively,for 28 days.Vaginal smears were collected from all rats daily throughout the study to determine the phases of the estrus cycle.After completing the treatment schedule,oral glucose tolerance test,serum lipid profile and reproductive hormonal analysis were carried out.Subsequently,the rats were sacrificed to collect ovary and uterus for histopathological examination.Results:The PCOS control rats showed a significant irregularity in the estrus cycle,hyperglycemia,and the altered serum lipid profile such as the increased low and very low density lipoprotein,triglyceride,and decreased high density lipoproteins.In addition,the PCOS control rats showed a significant increase in serum luteinizing hormone,testosterone,and estrogen,and decrease in follicle stimulating hormone and progesterone.These changes were significantly revoked in all the treatment groups.The test drugs also significantly reduced the gained ovary weight(P<0.001),and histopathology of the ovary showed almost normal ovary.Among the treatment groups,the group of combination treatment of G.sylvestre and P.daemia showed superior ameliorative results in PCOS parameters.Conclusions:Combination of G.sylvestre and P.daemia presents potent synergistic activity against hyperandrogenism,hyperinsulinemia,anovulation and follicular cysts in letrozole-induced PCOS rats.

Protective and therapeutic effect of protocatechuic acid in assessment of letrozole- induced polycystic ovary syndrome in rats

Objective:To investigate the potential activity of protocatechuic acid in female Wistar rats with letrozole-induced polycystic ovary syndrome(PCOS).Methods:Thirty rats were divided into five groups of six each.Group 1 received 0.5%carboxy methyl cellulose orally and served as the normal control group;group 2 was treated orally with 1 mg/kg of letrozole daily for 21 days and served as the PCOS induced group;group 3 was orally administered with letrozole of 1 mg/kg for 21 days and further administered with standard drug of clomiphene citrate at a dose of 1 mg/kg body weight in 0.5%carboxy methyl cellulose per oral and served as the standard group;groups 4 and 5 were administered with letrozole of 1 mg/kg for 21 days and further treated with protocatechuic acid orally at low dose of 5 mg/kg body weight and high dose of 15 mg/kg body weight respectively for 15 days.At the end of the study period,rats were subjected for the estimation of invasive blood pressure and heart rate,biochemical estimations and antioxidant assay.In addition,ovarian histomorphology was examined.Results:The PCOS was confirmed in the letrozole induced rats with increased concentration of androgen,abnormal lipid levels,glucose,glycosylated haemoglobin and also depletion of antioxidants.After protocatechuic acid treatment,the increased levels of testosterone due to induction of PCOS were restored to normal levels.Additionally,there was a consistent decrease in luteinizing hormone and follicle stimulating hormone levels in the treatment groups,followed by decrease in the number of cysts after treatment with protocatechuic acid.Histopathological observations showed a remarkable recovery of the ovarian tissue and the presence of normalized structure of antral follicle.Protocatechuic acid treatment restored all the parameters to normalcy and abolished cysts formation in ovaries of female rats.Conclusions:Protocatechuic acid shows potential protective effects in letrozole-induced PCOS rats.The protective effect is comparable to that of clomiphene citrate and thus shows its potential in the treatment of PCOS.

Letrozole versus Gonadotropin in Unexplained Infertile Couples Failed to Conceive with Clomiphene Citrate

Background:?Unexplained infertility represents about 15% - 20% of infertile couples. Usually, these cases need assistance. Clomiphene citrate is the most used drug for this problem but sometimes pregnancy failed to achieve it, so other options for assistance are gonadotrophin or letrezole. The objective of our study was to compare the pregnancy rate for letrezole and gonadotropin inunexplained infertile women’s who failed to conceive with clomiphene citrate. Methods: This prospective quasi-randomized trial was carried out in cytogenetic unite at obstetrics and gynecology department, Zagazig University Hospital. 140 infertile females were included, induction of ovulation by letrozole for half of them and by gonadotrophin for the other half. Results: There was statistically highly significant decrease in duration of stimulation, E2 levels and endometrial thickness at day of HCG in letrezole group, no significant difference between two groups as regard number of follicles and pregnancy rate per cycle, while the cumulative pregnancy rate and the cost of stimulation are significantly higher in gonadotrophin group. Conclusion: In patient with unexplained infertility who failed to conceive with clomiphene citrate, gonadotrophins have a higher pregnancy rate than letrezole. However, pregnancy rate was high enough with lower cost with letrezole to be acceptable and justified its use in this group of patients.

Best time for progesterone supplementation in aid ovulation induction cycles by letrozole

Objective:To explore the best time for progesterone supplementation in AID ovulation induction cycles by Letrozole.Methods: The data analysed in this study were collected from 509 patients who were performed AID (Artificial Insemination by Donor) administrated letrozole (LE) between 2014.8-2015.7. All patients were randomly divided into 4 groups by the time of progesterone administrated, including experimental group and the control group. The experimental group was divided into group 1-72 h after ovulation, group 2-48 h after ovulation, group 3-24 h after ovulation and control group—without administrated LE. The gestation and live birth rate were evaluated by monitoring vaginal ultrasound and HCG blood value 14 d after AID.Results: The pregnancy rate with administrated progesterone added 72 h after ovulation was 31.9%, which was significantly higher than those of other groups, the same situation as groups added progesterone was significantly higher than the control group. However, there was no significant difference in the numbers of abortions among the four groups. The LBR of group 4 was significantly lower than that of group 1.Conclutions: Progesterone administrated 72 h after ovulation can promoted the gestation rate, but did not affect the rate of miscarrage .

Letrozole可更有效地降低乳腺癌的复发风险

据近期出版的《新英格兰医学杂志》（NEJM）刊登的IBSCG研究结果显示，letrozole与它莫西芬相比可更有效地降低乳腺癌幸存者复发的风险。研究证实letrozole有助于阻止乳腺癌向身体其他部位的扩散，复发高危女性可从letrozole中获益。

Letrozole可改善体外受精的结果

据西班牙研究人员报道，对卵巢过度刺激反应较差的患者利用芳香酶抑制剂letrozole进行辅助治疗可增加体外受精（IVF）的成功率。

Impact of alcoholic extract from sea cucumber(Holothuria parva)on letrozole-induced polycystic ovary syndrome in adult female rats

Objective:To explore the potential therapeutic impact of an alcoholic extract derived from the sea cucumber(Holothuria parva)on letrozole-induced polycystic ovary syndrome(PCOS)in adult female Sprague-Dawley rats.Methods:Sixteen female rats,aged 8 to 10 weeks,with a mean weight of(200±20)g,were randomly assigned to four groups:the control,PCOS,and two treatment groups receiving sea cucumber extract and metformin,respectively.PCOS was induced by administering letrozole at a dose of 1 mg/kg to initiate the treatment period at 60 days of age.The study spanned four weeks,during which ovarian and uterine tissues were collected for histological examination,and blood samples were collected for hormonal levels.Results:Significant decreases in luteinizing hormone/follicle stimulating hormone(LH/FSH)and testosterone and increases progesterone levels among groups treated with sea cucumber extract were observed.While no significant differences were observed in follicle-stimulating hormone(FSH)and testosterone levels,the distinctive variations in key hormones suggested a potential role for sea cucumber alcoholic extract in ameliorating PCOS symptoms.Conclusions:This research highlights the moderate efficacy of sea cucumber extract as a therapeutic intervention for PCOS,providing a novel perspective in the search for effective remedies.The observed hormonal alterations,particularly in LH,estradiol,and progesterone,underscore the need for further exploration into the underlying mechanisms and for optimizing the application of sea cucumber extract in PCOS management.

Bioequivalence and safety study of letrozole tablet in healthy Chinese postmenopausal women volunteers

Letrozole is an orally active aromatase inhibitor for the treatment of postmenopausal women with breast cancer. A single-dose, randomized, open-label, two-way crossover study was designed to compare the bioequivalence and safety of two formulations of letrozole （2.5 mg/tablet）, including a newly developed generic formulation （test） and a branded formulation （reference） in a group of healthy Chinese postmenopausal women volunteers under fasting conditions. Blood samples were obtained before study drug administration and at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 144.00, 192.00 and 240.00 h after drug administration. Letrozole levels in plasma were analyzed using a liquid chromatography-tandem mass spectrometry （LC-MS/MS） method. The safety profile was evaluated by adverse events （AEs） record, and assessed by physical examination, vital signs, spontaneous reporting, and clinical laboratory results. A total of 30 healthy Chinese postmenopausal women were enrolled in this study however, only 29 subjects were included in bioequivalence assessments due to serious adverse events （SAEs） in 1 subject. The 90% CIs for the ln-transformed ratios of C max , AUC 0–t , and AUC 0–∞ were 99.55%–115.17%, 97.35%–103.50%, and 97.29%–103.96%, respectively. All values met the predetermined criteria for assuming bioequivalence. One subject （3.3%） experienced SAE who received the reference formulation and 10 subjects （33.3%） reported a total of 13 mild AEs （4 reported from 4 subjects who received the test formulation, and 9 reported from 6 subjects who received the reference formulation）. In this single-dose （2.5 mg） study, we found that the test and reference formulations of letrozole tablet met the regulatory definition for assuming bioequivalence in healthy Chinese postmenopausal women. Both formulations were generally well tolerated in the population studied. Chinese Clinical Trials registration number： ChiCTR-TRC-11001457.

Transdermal delivery of letrozole:effects of vehicles and organic acids on its permeation through rat skin

The purpose of this study was to investigate the effects of vehicles and organic acids on the in vitro permeation of letrozole across rat skin. Permeation experiments were carried out with 2-chamber diffusion cells through rat skin. The binary solvent mixture of ethanol and isopropyl myristate （IPM） could markedly enhance the cumulative penetrated amount of letrozole after 8 h （Qs） compared with IPM alone, especially the IPM system containing 20% （w/w） ethanol. Surprisingly, the use of complexation with organic acids facilitated skin permeation of letrozole in the IPM--ethanol （20%, w/w） system. Due to different structures of tested organic acids, their effects on the penetration of letrozole were different. This study showed that the addition of an organic acid in the IPM-cthanol （20%, w/w） system was a promising approach to enhance the skin permeability of letrozole.