Oral Administration Of Letrozole Research Articles

Metabolic Consequences of Polycystic Ovary Syndrome on Hepatic Function in High Fat Diet-Fed Rats: Potential Role of Exercise

Abstract Context Polycystic ovarian syndrome (PCOS) is the most common endocrine-metabolic disorder in reproductive-aged women. Since, The current study was designed to elucidate the metabolic comorbidities of polycystic ovarian syndrome, especially the hepatic effect, with or without high fat diet feeding, and to emphases the crucial role of exercise in managing such complications. Materials and Methods This study was carried out on 55 adult female albino Wistar rats, the study duration was 8 weeks. Rats included in the present study were randomly allocated into five equal groups, eleven rats each: Group I: Control group, Group II: Polycystic ovary syndrome (PCO) group, Group III: High fat diet fed polycystic ovary syndrome (HF-PCO) group, Group IV: Exercise-treated polycystic ovary syndrome (PCO-EX) group, Group V: High fat diet fed exercise-treated polycystic ovary syndrome (HF-PCO-EX) group. PCOS was induced in female wistar rats by oral administration of Letrozole (1mg/kg daily by oral gavage for 21 days in groups II, III, IV, V, high fat diet was supplemented to groups III and V. Rats of groups IV and V were subjected to 30 minutes swimming protocol 5 days/ week for 5 weeks after the period of induction. Results All measured values of the OGTT as well as area under the curve, serum fasting glucose (FG), insulin levels and HOMA-IR were all significantly increased in the PCO, HF-PCO when compared to control group. Compared to their corresponding non exercised groups, both PCO-EX and HFPCO-EX groups showed significant reductions in all parameters except for T90 in PCO-EX group. For the lipid profile, the serum level of TG, TC, LDL-C and AI were all significantly increased while HDL-C was significantly decreased in PCO and HF-PCO compared to control group as well as in HF-PCO group compared to PCO group. PCO-EX and HF-PCO-EX groups showed significant reductions in TG, TC, LDL-C and AI and a significant elevation in HDL-C when compared to their corresponding non- exercised groups. For liver enzymes serum level of ALT, AST and GGT were significantly increased in PCO and HF-PCO groups when compared with control group. Compared to their corresponding non exercised groups, both PCO-EX and HF-PCO-EX showed significant reductions in liver enzymes. As regard the hormonal profile, the serum level of estradiol, adiponectin and adiponectin/resistin ratio (A/R) were significantly decreased while serum level of testosterone, LH and resistin were significantly increased in PCO and HF-PCO groups compared to control group. PCO-EX and HF-PCO-EX groups induced significant increases in serum estradiol, adiponectin and A/R as well as significant decreases in serum testosterone, LH and resistin compared to their corresponding non exercised groups. Conclusion We could conclude that both moderate intensity exercise and avoiding high fat diet have beneficial therapeutic potentials in ameliorating the metabolic effects of PCO syndrome in rats especially the hepatic effects and the development of NAFLD.

Fisetin mitigates letrozole-induced polycystic ovarian syndrome in rats: crosstalk of AMPK/PI3K/AKT-mediated-Nrf2 antioxidant defense mechanism and the inflammasome NLRP3/NF-κB P65/IL-1β signaling pathways.

Polycystic ovarian syndrome (PCOS) is a highly prevalent condition affecting reproductive-aged women, causing insulin resistance, hyperandrogenism, weight gain, and menstrual problems. The present study intended to investigate the potential role of fisetin (FT) in letrozole (LZ)-induced PCOS inadult female rats and the possible mechanism underlying its action. PCOS was induced by oral administration of LZ (1mg/kg) for 21days. Treated rats received FT (1.25 or 2.5mg/kg) orally once daily for 14 consecutive days. Following the experimental duration, blood samples and ovary tissues were isolated and preserved for biochemical and histopathological examinations. The results revealed that LZ-induced PCOS led to significant abnormalities in sex hormones and metabolic parameters. Additionally, it initiated an inflammatory cascade, evidenced by activation of the NF-κB p65/IL-1β and AMPK/PI3K/AKT pathways, alongside downregulation of Nrf2 ovarian gene expression and NLRP3 inflammasome activity, which enhanced the production of proinflammatory cytokines. FT demonstrated its beneficial impacts by restoring hormonal disturbance and reversing the imbalanced metabolic parameters. Moreover, FT increased the mRNA of ovarian Nrf2 levels and suppressed the up-regulated inflammatory IL-1β/NF-κB p65 signaling pathway, consequently alleviating the elevated levels of ovarian NLRP3. The histopathological examination also confirmed that FT has a beneficial effect in ameliorating PCOS, consistent with the aforementioned parameters. Finally, the present results demonstrated that FT ameliorates LZ-induced PCOS through the intricate interplay between the AMPK/PI3K/AKT-mediated Nrf2 antioxidant defense mechanism and the regulation of the inflammasome NLRP3/NF-κB p65/IL-1β signaling pathways.

Apelin receptor modulation mitigates letrozole-induced polycystic ovarian pathogenesis in mice

AimsPolycystic ovarian syndrome (PCOS) is one of the most common (about 5–20%) reproductive disorders in women of reproductive age; it is characterized by polycystic ovaries, hyperandrogenism, and oligo/ anovulation. The levels and expression of ovarian adipokines are deregulated in the PCOS. Apelin is an adipokine that acts through its receptor (APJ) and is known to express in the various tissues including the ovary. It has also been suggested that apelin and APJ could be targeted as therapeutic adjuncts for the management of PCOS. However, no study has been conducted on the management of PCOS by targeting the apelin system. Thus, we aimed to evaluate its impact on combating PCOS-associated ovarian pathogenesis. MethodsThe current work employed a letrozole-induced-hyperandrogenism PCOS-like mice model to investigate the effects of apelin13 and APJ, antagonist ML221. The PCOS model was induced by oral administration of letrozole (1 mg/kg) for 21 days. A total of four experimental groups were made, control, PCOS control, PCOS + aplein13, and PCOS + ML221. The treatment of apelin13 and ML221 was given from day 22 for two weeks.Key findings: The letrozole-induced PCOS-like features such as hyperandrogenism, cystic follicle, decreased corpus luteum, elevated levels of LH/FSH ratio, and up-regulation of ovarian AR expression were ameliorated by apelin13 and ML221 treatment. However, the PCOS-augmented oxidative stress and apoptosis were suppressed by apelin 13 treatments only. ML221 treatment still showed elevated oxidative stress and stimulated apoptosis as reflected by decreased antioxidant enzymes and increased active caspase3 and Bax expression. The expression of ERs was elevated in all groups except control. Furthermore, the PCOS model showed elevated expression of APJ and apelin13 treatment down-regulated its own receptor. Overall, observing the ovarian histology, corpus luteum formation, and decreased androgen levels by both apelin13 and ML221 showed ameliorative effects on the cystic ovary. SignificanceDespite the similar morphological observation of ovarian histology, apelin13 and ML221 exhibited opposite effects on oxidative stress and apoptosis. Therefore, apelin13 (which down-regulates APJ) and ML221 (an APJ antagonist) may have suppressed APJ signalling, which would account for our findings on the mitigation of polycystic ovarian syndrome. In conclusion, both apelin13 and ML221 mediated mitigation have different mechanisms, which need further investigation.

Production of sterile mono-sex triploid yellow drum (Nibea albiflora): genotypic females and sex-reversed phenotypic males with emphasis on utilization as surrogate broodstock.

Production of sterile mono-sex fish is of great significance for sustainable aquaculture as well as germ cell transplantation. In this study, we aimed to produce mono-sex triploid yellow drum, including genotypic females (XXX female) and sex-reversed phenotypic males (XXX male). Firstly, the mono-female triploids were produced through cold-shock treatment on eggs fertilized with sperm from neo-males. Then, the mono-male triploids were produced by the sex reversal of mono-female triploids with oral administration of letrozole (LZ). We comparatively investigated the growth and gonadal development in the mono-sex triploids. The results showed that the triploids displayed similar growth performance to their diploids throughout their first year, but had impaired gonadosomatic index and gametogenesis. No mature gametes were produced in the triploids during their first spawning season. Meanwhile, we analyzed the process of gametogenesis in the both sex of triploids. Ultrastructure of gametogenesis showed that the germ cells arrested at abnormal metaphase 1 in females, while males had irregular meiotic divisions, variable-sized spermatid and degenerated cells. The expression levels of meiosis-related genes (i.e., sycp3 and rec8) confirmed the abnormal meiosis in the triploids. Furthermore, the gonadal development was also determined by the expression patterns of vasa, dmrt1 and cyp19a1a. Abnormal expression of vasa mRNA and protein were detected in triploids. High cyp19a1a expression levels suggested the sex steroid hormones production might be at least partially functional in triploid females. In addition, high dmrt1 expression levels confirmed the masculinization and testicular development of sex-reversed triploid males by LZ. Our findings provide an efficient protocol to produce sterile mono-sex triploid yellow drum and provide new insights into the mechanism of gonadal sterility of triploid fish.

Characterization of Early Gonadal Differentiation and Induction of Sex Reversal in the Rock Bream Oplegnathus fasciatus.

Rock bream (Oplegnathus fasciatus) is a typical fish that has a unique multiple sex chromosome system (♀X1X1X2X2/♂X1X2Y). We examined the early gonadal development in rock bream via continuous histological observations of the gonads at 40-120days post hatching (dph). The fish was identified as a typical gonochorist, and female gonads were found to differentiate earlier than male gonads. The ovarian cavity of the female was initially observed at 80 dph, whereas the efferent duct of the male was not observed until 100 dph. Immunofluorescence with the vasa-antibody revealed that germ cells were predominantly distributed around the ovarian cavity in females and on the edge of the gonad in males during the early stages of sex differentiation. Sex reversal was induced via the oral administration of letrozole (LTZ), 17α-methyltestosterone (MT), and 17β-estradiol (E2), respectively, during the labile period of gonadal development. LTZ and MT induced 100% masculinization of genotype-females, whereas E2 induced only 50-60% feminization of genotype-males. Such findings suggest that the fish retained high sexual plasticity despite the existence of the neo-Y chromosome. MT and E2 had negative effect on fish growth, whereas LTZ did not exert such side effect. LTZ and MT could accelerate gonadal development in sex-reversed genotype-males, whereas E2 inhibited gonadal development in genotype-females of rock bream. These findings provide a basis for further research on the mechanisms of sex determination and differentiation in fishes with X1X2Y sex chromosome system and provide a sex reversal protocol for rock bream.

Effect of Curcumin (Standard and Supplement) with Zinc on Reproductive Hormones in Polycystic Ovary Syndrome (PCOS) Rats

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous disorder that affects a large percentage of women worldwide. The pathophysiology is not fully explained. In recent years, complementary and alternative medicine has emerged as a viable treatment option. This study examined how curcumin and zinc affected on reproductive hormones in rats with polycystic ovary syndrome (PCOS). It was induced by oral administration of letrozole (1mg/kg/day) for 21 days. PCOS groups were treated over 14 days with curcumin standard 200 mg/kg, curcumin supplement 200 mg/kg, and zinc 30 mg /kg (separately or in combination with two forms of curcumin), and metformin 50 mg/kg as standard treatment. The blood biochemistry of these groups was compared to those of the groups of healthy, PCOS, and those who received metformin. The immunoassay ELISA technique was employed for measuring the concentration of reproductive hormones. The results manifested that the administration of letrozole resulted in a significant elevation (p≤0.05) of luteinizing hormone, follicle-stimulating hormone, testosterone, and prolactin associated with a significant decrease (p≤0.05) of estrogen and progesterone levels in the PCOS-designed model. The results of effect of curcumin supplement alone and with zinc showed a significant improvement in all parameters by reducing the luteinizing hormone, follicle-stimulating hormone, testosterone, and prolactin. Estrogen and progesterone elevated significantly for all groups, while the elevation was highly significant in both curcumin supplement alone and curcumin supplement with zinc. The treatment with curcumin supplement and their combination with zinc showed promising results in restoring reproductive hormones to the normal level.

Effect of Curcumin (Standard and Supplement) with Zinc on Reproductive Hormones in Polycystic Ovary Syndrome (PCOS) Rats

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous disorder that affects a large percentage of women worldwide. The pathophysiology is not fully explained. In recent years, complementary and alternative medicine has emerged as a viable treatment option. This study examined how curcumin and zinc affected on reproductive hormones in rats with polycystic ovary syndrome (PCOS). It was induced by oral administration of letrozole (1mg/kg/day) for 21 days. PCOS groups were treated over 14 days with curcumin standard 200 mg/kg, curcumin supplement 200 mg/kg, and zinc 30 mg /kg (separately or in combination with two forms of curcumin), and metformin 50 mg/kg as standard treatment. The blood biochemistry of these groups was compared to those of the groups of healthy, PCOS, and those who received metformin. The immunoassay ELISA technique was employed for measuring the concentration of reproductive hormones. The results manifested that the administration of letrozole resulted in a significant elevation (p≤0.05) of luteinizing hormone, follicle-stimulating hormone, testosterone, and prolactin associated with a significant decrease p≤0.05) of estrogen and progesterone levels in the PCOS-designed model. The results of effect of curcumin supplement alone and with zinc showed a significant improvement in all parameters by reducing the luteinizing hormone, follicle-stimulating hormone, testosterone, and prolactin. Estrogen and progesterone elevated significantly for all groups, while the elevation was highly significant in both curcumin supplement alone and curcumin supplement with zinc. The treatment with curcumin supplement and their combination with zinc showed promising results in restoring reproductive hormones to the normal level.

Letrozole, for the Management of Chronic Pelvic Pain Resulting from Endometriosis

Background: Letrozole, an aromatase inhibitor that inhibits the final step of the estrogen biosynthesis pathway to prevent estrogen synthesis, has been utilized in a variety of infertile scenarios. A common gynecological pain problem called endometriosis involves tissue that resembles the tissue that typically lines the inner layer of the uterus. It frequently results in fertility issues. According to the trials, the Letrozole medication continues to reduce the severity of persistent pelvic pain. According to reports, Letrozole therapy relieves pelvic pain brought on by endometriosis. Objective: In this study, we evaluated Letroszole's effectiveness in treating chronic pelvic discomfort associated with endometriosis. Study Design: A cross-sectional study Place and Duration: This study was conducted at Sandeman Provincial Hospital (SPH) / BMCH, Quetta Pakistan from December 2021 to December 2022. Methodology: A total of 60 patients with endometriosis were taken in this study. Patients with a past history of treatment for endometriosis with varying degrees of improvement were also included. Data was analyzed on SPSS version 24.0. Before starting the treatment, an initial diagnostic laparoscopy was used to diagnose and score endometriosis. Oral administration of Letrozole 2.5mg, celbex 200mg three times a day, calcium citrate 1000 mg, progestin norethisterone acetate 5 mg, and vitamin D (1000 IU) was given for 6 months Results: The mean age of the participants was30.9years. A total of 26 (43.3%) patients presented with dysmenorrhea. Out of 60 patients, 43 (71.6%) were nulliparous. The mean visual analogue scale which was 7.12 at the start of the therapy, dropped to 6.8 (p-value 0.02) in one month and dropped to 3.3 in six months of the therapy. Conclusion: Letrozole has been shown to be effective in treating pelvic pain related to endometriosis, with notable pain reduction and no recurrence of symptoms. Keywords: Letrozole, Endometriosis, pain score

Protective effect of astaxanthin and metformin in the liver of rats in which the polycystic ovary syndrome model was formed by giving letrozole.

In this study, the effects of astaxanthin on liver tissue in rats with polycystic ovary syndrome (PCOS) were evaluated. Fifty-four Spraque-Dawley rats were divided into 9 groups: Groups: Control, PCOS, PCOS+Metformin (Met), PCOS+ Astaxanthin (ASX)10, PCOS+ASX20, PCOS+ASX40, PCOS+Met+ASX10, PCOS+Met+ASX20, and PCOS+Met+ASX40. PCOS was induced in female rats by oral administration of letrozole (1 mg/kg) for 21 days. Rats were treated with ASX (10 mg/kg), ASX (20 mg/kg), ASX (40 mg/kg), and metformin (20 mg/kg) for 7 days after PCOS induction. At the end of the experiment, malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured in the liver tissue. The liver was stained with hematoxylin/eosin for histological examination. Additionally, NF-kB and caspase 3 were analyzed immunohistochemically. A remarkable abnormality was observed in the biochemical and histological parameters in the liver tissue of the PCOS model rats. Astaxanthin dose-dependently normalized the MDA level. Additionally, astaxanthin showed a protective effect by increasing the SOD level and increasing its antioxidant activities. We observed that administration of astaxanthin in addition to metformin applied in the standard was more effective. Caspase 3 and NF-kB immune positivity was lower in the groups given astaxanthin compared with PCOS. Histologically, it was observed that astaxanthin improved the deteriorated liver morphology in the letrozole-induced PCOS group. According to our results, it was observed that astaxanthin had antioxidant, anti-inflammatory and anti-apoptotic effects on PCOS in the treatment groups. Therefore, it was concluded that astaxanthin may have a protective effect against PCOS side effects.

Diacerein ameliorates letrozole-induced polycystic ovarian syndrome in rats

Polycystic ovary syndrome (PCOS) is the most common gynaecological endocrine disease that causes anovulatory infertility. The current study aimed to explore the possible role of diacerein (DIA), an IL-1β inhibitor, in treating letrozole-induced PCOS in rats that exhibit the metabolic and endocrinal criteria of PCOS patients. PCOS was induced in female Wistar rats by the oral administration of letrozole (1 mg/kg, per orally, p.o.) for 21 days. Rats were then treated with DIA (25 mg/kg/day, p.o.), DIA (50 mg/kg/day, p.o.), or metformin (2 mg/100 g/day, p.o.) for 14 days after the PCOS induction. PCOS resulted in a significantly higher body weight, ovarian weight, ovarian size, and cysts, as well as an elevation in serum testosterone, LH, insulin, glycemia, and lipid profile levels. All of these effects were significantly reduced by the DIA administration. Additionally, DIA remarkably inhibited the letrozole-induced oxidative stress in the ovaries, muscles, and liver by reducing the upraised levels of malondialdehyde and total nitrite and increasing the suppressed levels of superoxide dismutase and catalase. DIA enhanced the protective proteins Keap-1, Nrf2, and OH-1 levels. Finally, DIA inhibited the elevated mRNA levels of NLRP3 and caspase-1, the up-regulated inflammatory cytokines IL-6, TNF-α, and the IL-1β/NFκB signaling pathway. Our results proved that DIA ameliorates letrozole-induced PCOS through its antioxidant and anti-inflammatory properties.

The effectiveness of resveratrol in treatment of PCOS on the basis of experimental model in rats

Purpose of the study Polycystic ovary syndrome (PCOS) is a widespread endocrine disorder in women of reproductive age. Further research is required to justify new directions of effective targeted therapy of this condition. Resveratrol possesses anti-inflammatory, antioxidant and antidiabetic properties. The purpose of this study was to evaluate the potential effectiveness of resveratrol in PCOS based on the created model of this disease in Wistar rats. Materials and methods The PCOS model was created by oral administration of letrozole to female Wistar rats.. The animals received resveratrol at a dosage of 20 mg/kg and 30 mg/kg for the next 30 days. Then ovariectomy was performed for histological confirmation of the effectiveness of resveratrol in the treatment of PCOS. Regularity of estrous cycle, animal’s body mass and the level of soluble receptors for advanced glycation end products (sRAGE) in the blood of rats were also evaluated in dynamics. Results The study revealed that administration of resveratrol leads to dose-dependent restoration of normal morphology of ovarian tissue, normalizes regularity of estrous cycle and decreases body weight of rats with PCOS. Conclusion The results obtained in rats suggest that resveratrol may be a promising agent for the treatment of PCOS in women.

Retrospective analysis on pregnancy outcomes and fat-related factors of treatment of endomorph PCOS infertility patients by acupuncture of 8 acupoints around umbilicus

To assess the therapeutic effect of acupuncture of eight acupoints around the umbilicus in improving the metabolic level and reproductive function in endomorph polycystic ovary syndrome (PCOS) infertile patients. Retrospective analysis was performed on 96 cases of endomorph type PCOS infertility patients who were admitted to the clinic of the Reproductive Center of the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine from October 2015 to June 2018. Among them, fifty-six cases of the acupuncture group received treatment with acupuncture stimulation of eight acupoints (Shuifen ［CV9］, Yinjiao ［CV7］, Tianshu ［ST25］, Wailing ［ST26］, Huaroumen ［ST24］, etc.) around the umbilicus, and 40 cases of the control group were treated by oral administration of Letrozole. Acupuncture was performed once every other day, and Letrozole (2.5 mg/day) given once daily for 5 days, if no pregnancy got, the treatment procedure was repeated once again next menstruation cycle, continuously for 3 months. The pregnancy outcomes including the pregnancy rate, persistent pregnancy rate, ovulation rate and the first trimester abortion rate, and the levels of fat-related factors including body mass index (BMI), waist-to-hip ratio (WHR), homeostasis model of insulin resistance (HOMA-IR=fasting insulin x fasting blood glucose /22.5), leptin(LEP) and adiponectin(APN) of the two groups were compared. The ovulation rate (number of effective ovulation cycles/ number of observation cycles) x 100%, the first trimester abortion rate (number of spontaneous abortion within 12 weeks÷pregnancy cases) X100% were calculated. The fasting blood samples were taken for assaying serum LEP and APN contents using ELISA, blood glucose level using hexokinase assay, and serum insulin by using chemiluminescent microparticle immunoassay, separately. After the treatment, the pregnancy rate and the level of APN were significantly higher (P<0.05), and the BMI, WHR, HOMA-IR and LEP levels were all obviously lower in the acupuncture group than in the control group (P<0.05). There were no significant differences between the two groups in the persistent pregnancy rate, abortion rate and ovulation rate (P>0.05). Acupuncture at the eight points around the umbilicus can raise the pregnancy rate in obese type PCOS patients, which may be related to its effects in up-regulating serum APN and lowering BMI, WHR, HOMA-IR, and serum LEP levels.

Induction of sex reversal in blue drum ( Nibea mitsukurii ) and gynogenetic yellow drum ( Nibea albiflora ) by oral administration of letrozole

The objective of this study was to test the efficiency of an aromatase inhibitor, letrozole (LZ), to induce masculinization in blue drum (Nibea mitsukurii) and gynogenetic yellow drum (N. albiflora). Two experiments (Exp-1 and Exp-2) were performed to investigate the effect of LZ on the growth, sex ratio and gonad development in these two fishes. In Exp-1, blue drum were treated with oral administration of letrozole at different doses (0, 1, 10, 100 mg/kg). In Exp-2, gynogenetic yellow drum were orally administered different doses of LZ (0, 10, 100 mg/kg) and a dose of 10 mg/kg 17α-methyltestosterone (MT). The treatments in both experiments were performed from 25 to 85 days post hatch (dph). As a result, all the LZ-treated fish were phenotypic males despite of slower growth than the control during the treatment period. Free spermatozoa were observed from 150 dph onwards and the gonadosomatic index of the LZ-treated fish did not differ significantly from that in the control at maturity. However, the sex-reversed fish induced by MT exhibited a high proportion (33.4%) of testicular abnormalities. Our results showed that oral administration of LZ was efficient in inducing sex reversal in drums, and thereby facilitated their mono-sex culture.

GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile

BackgroundGnRH is the master molecule of reproduction that is influenced by several intrinsic and extrinsic factors such as neurotransmitters and neuropeptides. Any alteration in these regulatory loops may result in reproductive-endocrine dysfunction such as the polycystic ovarian syndrome (PCOS). Although low dopaminergic tone has been associated with PCOS, the role of neurotransmitters in PCOS remains unknown. The present study was therefore aimed at understanding the status of GnRH regulatory neurotransmitters to decipher the neuroendocrine pathology in PCOS.MethodsPCOS was induced in rats by oral administration of letrozole (aromatase inhibitor). Following PCOS validation, animals were assessed for gonadotropin levels and their mRNA expression. Neurotrasnmitter status was evaluated by estimating their levels, their metabolism and their receptor expression in hypothalamus, pituitary, hippocampus and frontal cortex of PCOS rat model.ResultsWe demonstrate that GnRH and LH inhibitory neurotransmitters – serotonin, dopamine, GABA and acetylcholine – are reduced while glutamate, a major stimulator of GnRH and LH release, is increased in the PCOS condition. Concomitant changes were observed for neurotransmitter metabolising enzymes and their receptors as well.ConclusionOur results reveal that increased GnRH and LH pulsatility in PCOS condition likely result from the cumulative effect of altered GnRH stimulatory and inhibitory neurotransmitters in hypothalamic-pituitary centre. This, we hypothesise, is responsible for the depression and anxiety-like mood disorders commonly seen in PCOS women.

Cellular and molecular mechanisms of pentoxifylline's beneficial effects in experimental polycystic ovary

Chronic low-grade inflammation and oxidative stress (OS) appear to be two main pathways involved in the pathogenesis of polycystic ovary (PCO) syndrome. Therefore, targeting these pathways by means of anticytokine and antioxidant agents might be a therapeutic alternative approach to the current treatments of PCO syndrome. In this study, we investigated the protective effects of pentoxifylline (PTX), a drug with antioxidant and anti–tumor necrosis factor alpha (TNF-α) properties, in hyperandrogenism-induced PCO rats. The inflammatory and OS responses and their connections with ovarian functionality in induced PCO rats were investigated through ovarian histopathologic examination and a series of biochemical measurements including serum estradiol, progesterone, testosterone, insulin, and TNF-α, ovarian and serum lipid peroxidation, total antioxidant power, and reactive oxygen species. Experimental PCO was induced in rats by oral administration of letrozole (1 mg/kg body weight) for 21 consecutive days. In a different group, PTX was administrated orally (50 mg/kg/d) for 21 days simultaneous with letrozole to assess its potential protective effects. The letrozole-induced PCOs were characterized by irregular cycles, high incidence of subcapsular ovarian cysts with diminished or scant granulosa cell layers, increased number of atretic preantral and antral follicles, and absence of CL. In addition, the letrozole-induced PCO rats exhibited notable increase in lipid peroxidation and reactive oxygen species of serum and ovary, serum testosterone, insulin, and TNF-α and significant decline in total antioxidant power, serum estradiol, and serum progesterone. Our results indicated that all the identified pathologic parameters and biochemical characteristics in letrozole-induced PCO rats in this study were preserved close to normal levels by simultaneous PTX treatments. Present results demonstrate that there is a direct connection between ovarian dysfunction and increased OS and inflammation in PCO. For the first time, the beneficial effects of PTX as a powerful antioxidant and TNF-α blocker in hyperandrogenism-induced PCO are reported.

Abstract 4241: Preclinical studies of brain/brain tumor disposition and antitumor efficacy of the aromatase inhibitor letrozole

Abstract In this study, we investigated the potential role of aromatase (CYP19) as a target for the treatment of CNS malignancies, as well as brain disposition and anti-tumor efficacy of letrozole, an aromatase inhibitor, in Sprague Dawley rats. Cytotoxicity and aromatase activity of letrozole against human glioma cell lines were measured using MTT assay and Enzyme Immunoassay respectively. For brain and brain tumor PK of letrozole, rats with and without orthotopic implantation of C6 glioma received letrozole (4 - 12 mg/kg; i.v. andor oral). Dual probe intracerebral microdialysis was performed to determine the unbound extracellular fluid (ECF) letrozole concentrations. Serial ECF and blood samples were simultaneously collected over 8 hrs. µPET/CT imaging was performed using 18F FDG to evaluate changes in active tumor volumes pre- and post-treatment of letrozole. Brain tissues were collected at the end of the experiment for histological evaluations. All glioma cell lines included in this study expressed CYP19 and letrozole exerted marked cytotoxicity against these cells ( IC50s 0.1 - 3.5 μM). The relative brain distribution coefficients, measured as the ratio of the observed AUC in ECF and AUC of unbound letrozole in plasma (AUCecf/AUCp,ub) ranged from 0.31 - 0.98. Furthermore, the tumoral ECF levels of letrozole was 1.5 - 2 fold higher relative to tumor-free region of the brain, resulting in tumoral ECF Cmax values that were 10 and 35-fold higher than the observed IC50 value of 0.1 µM against C6 gliomas cells in culture. µPET/CT imaging showed a marked reduction of active tumor volume (75-90%) after 8-10 days of letrozole treatment (N=7). Oral administration of letrozole showed similar brain disposition and efficacy of letrozole. Immunohistochemical analysis of aromatase demonstrated selectivelymarkedly higher aromatase expression in tumoral regions of the brain as well asand a clear considerable reduction in aromatase expression in letrozole the treated rats relative to the treatment group as compared to the control group. Thus, employing multifaceted and cutting edge in vitro and in vivo methods, we conclude: a) aromatase is abundantly expressed in glioma cell lines examined, b) letrozole exerts marked cytotoxicity in these cells presumably due to aromatase inhibition, c) letrozole has selectively higher accumulation in tumoral region of the brain and d) In vivo µPET/CT studies show marked efficacy of letrozole on C6 glioma in a preclinical rat model. Note: This abstract was not presented at the meeting. Citation Format: Nimita Dave, Pankaj B. Desai, Gary A. Gudelsky, Kathleen LaSance, Lionel M.L. Chow, Xiaoyang Qi. Preclinical studies of brain/brain tumor disposition and antitumor efficacy of the aromatase inhibitor letrozole. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4241. doi:10.1158/1538-7445.AM2014-4241

Efficacy of letrozole in treatment of endometriosis-related pain

To evaluate the efficacy of aromatase inhibitor (letrozole) in the treatment of endometriosis-related pain. A total of 20 women with Stage IV endometriosis presented with endometriosis-related pain refractory to previous treatment or recurrence after such treatment have been included in the study. All women were treated with oral administration of letrozole 2.5 mg in addition to elemental calcium 1000 mg and vitamin D 880 IU daily for a total treatment duration of 6 months. Baseline (pre-treatment), monthly during treatment, at end of treatment and 6 months after completion of treatment; all patients were evaluated for the presence and intensity of pain (including dysmenorrhea, deep dyspareunia and chronic pelvic pain) using a 100 mm visual analog scale (VAS). Mean age was 30.9 years with 80% of patients were NP. Half of patients presented with dysmenorrhea. Patients previously received oral contraceptives (50%), GnRH agonists (25%) and Medroxyprogesterone acetate (25%) or underwent laparotomy with ovarian cystectomy (20%) or exploration 30%). At the end of treatment (6 months after start treatment) mean VAS dropped from 7.65 at start of therapy to 6.1 ( p -value < 0.005). Six months later (12 months after start of therapy), further significant drop of mean VAS has been reported (from 6.1 to 4). Letrozole (aromatase inhibitor) has shown to be effective in the treatment of endometriosis-related pain with substantial improvement of pain with no recurrence of pain for 6 months after completion of treatment.

Combination of acupuncture and Chinese medicinal herbs in treating model rats with Polycystic Ovary Syndrome

We explored the effects of combination of acupuncture and Chinese medicinal herbs in treating model rats with polycystic ovarian syndrome (PCOS) and to explore whether acupuncture has positive effects on the absorption of salvianolic acid B in the extracts of a Chinese medicine formula when treating the model rats. 60 female Sprague-Dawley (SD) rats were randomly divided into Groups A, B, C, D, E and F, with ten rats in each group. Except Group F, all of the other rats were induced to PCOS with oral administration of letrozole. The rats in Group F served as normal controls. Group A was treated with acupuncture. Group B was treated with oral administration of the extracts of the Chinese medicine formula. Group C was treated with a combination of oral administration of the extracts of Chinese medicine and acupuncture. Group D received western medicine as positive controls. After treatment, the serum levels of follicle stimulating hormone (FSH), luteinizing hormone(LH) and testosterone (T) in each group were detected with the Enzyme-Linked ImmunoSorbent Assay (ELISA) and the serum concentration of salvianolic acid B were determined using High Performance Liquid Chromatography (HPLC). The serum levels of T and the ratio of LH/FSH in Group A, B. C, D, and F were significantly lower than those of Group E, indicating the model rats with PCOS were successfully established. Compared with Groups A, B, D and E, the serum levels of T and the ratio of LH/FSH in Group C were significantly lower respectively, indicating combination of acupuncture and Chinese medicinal herbs can significantly enhance curative effects in treating model rats with PCOS. The concentration of serum salvianolic acid Group C was significantly higher than Group B, indicating that acupuncture might improve the absorption of salvianolic acid B from the extracts of Salvia miltiorrhiza Bunge in the Chinese medicine formula. Combination of acupuncture and Chinese medicinal herbs significantly enhance curative effects in treating model rats with PCOS and acupuncture has positive effects in improving the absorption of salvianolic acid B in the extracts of the Chinese medicine formula when treating the model rats with PCOS.

Effects of Testosterone Undecanoate Administered Alone or in Combination with Letrozole or Dutasteride in Female to Male Transsexuals

Testosterone undecanoate (TU) has potential as androgen therapy for ovariectomized female to male (FtM) transsexual subjects; however, the long-term physiologic effects of TU treatment, the significance of testosterone (T), and the T metabolites dihydrotestosterone (DHT) and estradiol (E) on specific outcome parameters are currently unknown. The aim of this study was to investigate the long-term treatment of TU with regard to bone metabolism, body composition, and lipid profile in FtM subjects, and to evaluate the relationship between observed effects and circulating levels of T, E, and DHT. Circulating follicle-stimulating hormone, luteinizing hormone, T, E, DHT, and lipid concentrations were measured, as well as bone metabolism, body composition, and insulin resistance. This was a 1-year, randomized treatment, open-label, uncontrolled safety study. Fifteen ovariectomized FtM subjects from an outpatient clinic were divided into three groups to receive TU 1,000 mg alone or in combination with oral administration of letrozole (L) 2.5 mg/die or dutasteride (D) 0.5 mg/die for a period of 54 weeks. TU alone and TU + D treatments were successful in terms of hormone adjustment, did not result in any adverse effects, and were well-tolerated. Bone mineral density decreased by an average of 0.9 g/cm(2) in the TU + L group, and the addition of D resulted in a failure to gain lean mass. This study confirmed that TU is a successful and safe treatment for FtM subjects. These data indicate that E has an important role in bone metabolism and that DHT may play a role in muscle metabolism.

A Novel Tocolytic Agent: Effects of Letrozole on Gestational Length and Parturition Time

The purpose of this study was to determine whether letrozole, a potent aromatase inhibitor, could prolong gestation and/or delay parturition in rats. Seventy-five rats were divided into five groups of 15 rats each. Group I and group II rats were administered letrozole orally at doses of 0.002 and 0.02 mg/kg/day from days 15 through 21 of pregnancy, respectively. Rats in group IA were administered a concomitant estradiol cyclopentylpropionate (ECP) injection on day 15 and 0.002 mg/kg letrozole in that same manner as for group I. Rats in group IIA were administered concomitant ECP on day 15 and 0.02 mg/kg letrozole in the same manner as for group II. The control group received sterile saline only. Study and control groups were compared with respect to gestational length, parturition time, fetal mortality rate, stillbirth rate, and fetal body weight. Oral administration of letrozole both at daily doses of 0.002 mg/kg/day (group I) and 0.02 mg/kg/day (group II) consistently prolonged gestation and parturition time. The values of stillbirth rate, fetal mortality rate, and fetal body weight of group I were similar to those in the control group; conversely, fetal mortality rate and stillbirth rate of group II were higher than those values in the control group, and fetal body weight of group II was lower than in the control group. It was observed that concomitant injection of ECP effectively reversed the deleterious effects of letrozole on gestational length, parturition time, fetal mortality rate, stillbirth rate, and fetal body weight. The results of this study indicate that the aromatase inhibitor letrozole can prolong gestation and delays parturition in rats. Its deleterious effects on parturition can be reversed by ECP injection.