Dataset Information

Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase mRNA and Protein Abundance in the Ovaries of Female Sprague Dawley Rats.

ABSTRACT:

Background

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive-aged women and leads to hyperandrogenism, anovulation, and infertility. PCOS has been associated with elevated serum homocysteine as well as altered methylation status; however, characterization of one-carbon metabolism (OCM) in PCOS remains incomplete.

Objectives

The aim of our research was to assess OCM in a letrozole-induced Sprague Dawley rat model of PCOS.

Methods

Five-week-old female rats (n = 36) were randomly assigned to letrozole [0.9 mg/kg body weight (BW)] treatment or vehicle (carboxymethylcellulose) control that was administered via subcutaneously implanted slow-release pellets every 30 d. For both treatment groups, 12 rats were randomly assigned to be euthanized during proestrus at one of the following time points: 8, 16, or 24 wk of age. Daily BW was measured and estrous cyclicity was monitored during the last 30 d of the experimental period. Ovaries were collected to assess mRNA and protein abundance of OCM enzymes.

Results

Letrozole-induced rats exhibited 1.9-fold higher cumulative BW gain compared with control rats across all age groups (P < 0.0001). Letrozole reduced the time spent at proestrus (P = 0.0001) and increased time in metestrus (P < 0.0001) of the estrous cycle. Cystathionine β-synthase (Cbs) mRNA abundance was reduced in the letrozole-induced rats at 16 (59%; P < 0.05) and 24 (77%; P < 0.01) wk of age. In addition, CBS protein abundance was 32% lower in 8-wk-old letrozole-induced rats (P = 0.02). Interestingly, betaine-homocysteine S-methyltransferase mRNA abundance increased as a function of age in letrozole-induced rats (P = 0.03).

Conclusion

These data demonstrate that letrozole-induced PCOS Sprague Dawley rats temporally decrease the ovarian abundance of Cbs mRNA and protein in the early stages of PCOS.

SUBMITTER: Bries AE

PROVIDER: S-EPMC8169814 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase mRNA and Protein Abundance in the Ovaries of Female Sprague Dawley Rats.

Bries Amanda E AE Webb Joseph L JL Vogel Brooke B Carrillo Claudia C Keating Aileen F AF Pritchard Samantha K SK Roslan Gina G Miller Joshua W JW Schalinske Kevin L KL

The Journal of nutrition 20210601 6

<h4>Background</h4>Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive-aged women and leads to hyperandrogenism, anovulation, and infertility. PCOS has been associated with elevated serum homocysteine as well as altered methylation status; however, characterization of one-carbon metabolism (OCM) in PCOS remains incomplete.<h4>Objectives</h4>The aim of our research was to assess OCM in a letrozole-induced Sprague Dawley rat model of PCOS.<h4>Methods</h4>Five ...[more]

PMID: 33758914

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Project description:BackgroundClomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes.MethodsIn this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period.ResultsWomen who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups.ConclusionsAs compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).

Project description:Background: Progestin is an alternative to gonadotropin-releasing hormone (GnRH) analogues in the follicular phase to suppress the premature luteinizing hormone (LH) surge in women with polycystic ovary syndrome (PCOS). However, progestin-primed ovarian stimulation (PPOS) is always accompanied by increased pituitary suppression and gonadotropin consumption. Previous studies suggested that letrozole appeared to have the potential to reduce the total gonadotropin dose required for ovarian stimulation. A retrospective cohort study was performed to evaluate the efficacy of PPOS with or without letrozole in infertile women with PCOS. Methods: This retrospective cohort study included 448 women with PCOS who underwent controlled ovarian stimulation (COS) with human menopausal gonadotropin (hMG) and medroxyprogesterone acetate (MPA) (n = 224) or hMG and MPA cotreatment with LE (n = 224) from January 2018 to March 2021 after propensity-score matching. The primary outcome measure was the hMG dose. The secondary outcomes were the durations of ovarian stimulation, the implantation rate, the number of oocytes retrieved and viable embryos, oocyte maturity and fertilization rates, the percentage of women with profound pituitary suppression (luteinizing hormone [LH] <1.0 IU/L on the trigger day). Results: The hMG doses (1949.89 ± 725.03 IU vs 2017.41 ± 653.32 IU, p > 0.05) and durations of ovarian stimulation (9.03 ± 1.79 days vs 9.21 ± 2.18 days, p > 0.05) were similar between the two groups. The implantation rate was significantly higher in the study group (MPA + hMG + LE) than in the control group (MPA + hMG) (42.22 vs 34.69%, p < 0.05). The numbers of oocytes and embryos retrieved were similar between the two groups. Interestingly, letrozole cotreatment was associated with decreased oocyte maturity and fertilization rates in comparison with standard PPOS protocols even though mature and fertilized oocyte yields were comparable. Compared with those in the control group, the LH values on the trigger day were significantly higher in the study group, together with significantly reduced pituitary suppression. Conclusion: Letrozole combined with PPOS cannot reduce hMG consumption in PCOS patients undergoing IVF treatment and shows no beneficial effect on cycle characteristics of COS. However, letrozole supplementation manifests as a superior implantation rate to that of the standard PPOS protocol in women with PCOS.

Project description:BackgroundTraditional Chinese medicine (TCM) usually involves syndrome differentiation and treatment. Acupuncture, one form of TCM, requires the selection of appropriate acupoints and needling techniques, but many clinical trials on acupuncture have used fixed acupuncture protocols without accounting for individual patient differences. We have designed a multicenter randomized controlled trial (RCT) to evaluate whether personalized or fixed acupuncture increases the likelihood of live births in infertile women with polycystic ovary syndrome (PCOS) compared with letrozole or placebo letrozole. We hypothesize that letrozole is more effective than personalized acupuncture, which in turn is more effective than fixed acupuncture, and that placebo letrozole is the least effective intervention. Moreover, we hypothesize that personalized acupuncture is more likely to reduce the miscarriage rate and the risk of pregnancy complications compared with letrozole.Methods/designThe study is designed as an assessor-blinded RCT. A total of 1100 infertile women with PCOS will be recruited from 28 hospitals and randomly allocated to 4 groups: personalized acupuncture, fixed acupuncture, letrozole, or placebo letrozole. They will receive treatment for 16 weeks, and the primary outcome is live birth. Secondary outcomes include ovulation rate, conception rate, pregnancy rate, pregnancy loss rate, changes in hormonal and metabolic parameters, and changes in quality of life scores. Adverse events will be recorded throughout the trial. All statistical analyses will be performed using IBM SPSS Statistics version 21.0 software (IBM Corp., Armonk, NY, USA), and a P value < 0.05 will be considered statistically significant.DiscussionThis study will be the first multicenter RCT to compare the effect of personalized or fixed acupuncture with letrozole or placebo letrozole on live birth in infertile women with PCOS. The findings will inform whether personalized acupuncture therapy can be considered an alternative treatment to improve the live birth rate in infertile women with PCOS.Trial registrationClinicalTrials.gov, NCT03625531. Registered on July 13, 2018. Chinese Clinical Trial Registry, ChiCTR1800017304. Registered on July 23, 2018.

Dataset Information

Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase mRNA and Protein Abundance in the Ovaries of Female Sprague Dawley Rats.

Background

Objectives

Methods

Results

Conclusion

Publications

Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase mRNA and Protein Abundance in the Ovaries of Female Sprague Dawley Rats.

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