Letrozole treatment of adult female mice results in a similar reproductive phenotype but distinct changes in metabolism and the gut microbiome compared to pubertal mice

Torres, Pedro J.; Skarra, Danalea V.; Ho, Brian; Sau, Lillian; Anvar, Arya R.; Kelley, Scott T.; Thackray, Varykina G.

doi:10.1186/s12866-019-1425-7

Cited by 41 publications

(32 citation statements)

References 107 publications

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“…Ten bacterial genera or family (if genera unknown) were identified as having differential relative abundances in letrozole-treated mice compared to placebo-treated mice during weeks 1-5 of treatment ( Fig 7A). Similar to previous studies [28,40,41], the relative abundance of Lactobacillus, Dorea, Lachnospiraceae spp., Ruminococcus, Roseburia, Sutterella, Bifidobacterium, Parabacteroides, and Blautia were altered in letrozole-treated mice compared to placebo mice. Interestingly, the number of bacterial genera that had a differential relative abundance in letrozole compared to placebo-treated mice decreased from 10 to 4 genera two months after pellet removal ( Fig 7B).…”

Section: Letrozole Removal Resulted In Fewer Differential Gut Bacterisupporting

confidence: 88%

Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome

Arroyo

et al. 2019

PLoS ONE

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Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo-or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty.

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Section: Letrozole Removal Resulted In Fewer Differential Gut Bacterisupporting

confidence: 88%

Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome

Arroyo

et al. 2019

PLoS ONE

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“…Letrozole treatment in adult female rats for 14 days resulted in reduced estradiol levels (39). Increased LH levels, as a main feature of PCOS women, has also been observed in adult rodent letrozole models (20,40,41). In the present study, serum LH levels at 1.25 mg/kg BW were increased compared with other groups.…”

Section: Discussionsupporting

confidence: 69%

Maternal aromatase inhibition via letrozole altered RFamide-related peptide-3 and gonadotropin releasing hormone expression in pubertal female rat

Shaaban¹,

Tamadon²,

Shirazi³

et al. 2021

Preprint

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Despite the prevalence of polycystic ovary syndrome (PCOS) among childbearing women and the development of many animal models for this syndrome, information on its etiology is still scarce. Intrauterine hyperandrogenic environment may underlie changes at the levels of hypothalamus, pituitary and ovary organization in female offspring, and PCOS later in life. Letrozole, has been shown to mimic reproductive and metabolic characteristics of PCOS in adult rodent models. Therefore, the aim of this research was to assess the condition in a prenatal letrozole-treated rat model. Twenty-eight female rats from dams receiving letrozole at certain doses during late pregnancy were used in the trial. Pregnant Sprague-Dawley rats (n = 21) received letrozole treatment on days 16–18 gestation at doses 1.25, 1.0, 0.75, 0.5, and 0.25 mg/kg body weight (BW). Prenatal letrozole-treatment delayed parturition time and reduced the litter size in pregnant dams (P < 0.0001). Late puberty onset, irregular ovarian cyclicity, increased anogenital distance (AGD), body weight gain, and serum testosterone concentration and reduced estradiol levels (P < 0.0001) were observed in the female offspring of dams receiving 1.25 and 1 mg/kg BW letrozole. Furthermore, Letrozole at 1.25 and 1 mg/kg BW showed increased Rfrp and decreased Gnrh mRNA expression (P < 0.0001). Letrozole treatment at doses 1 mg/kg BW and lower was not feto-toxic. It was concluded that 1 mg/kg BW letrozole may be suggested for prenatal PCOS induction.

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“…Letrozole treatment in adult female rats for 14 days resulted in reduced estradiol levels (18). Increased LH levels, as a main feature of PCOS women, has also been observed in adult rodent letrozole models (47)(48)(49). In the present study, serum LH levels at 1.25 mg/kg BW were increased compared with other groups.…”

Section: Discussionsupporting

confidence: 69%

Maternal Aromatase Inhibition Effects on RFamide-Related Peptide-3 and Gonadotropin Releasing Hormone in Adult Murine Offspring With Polycystic Ovary Syndrome

Shaaban¹,

Tamadon²,

Shirazi³

et al. 2020

Preprint

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Background: Despite the prevalence of polycystic ovary syndrome (PCOS) among childbearing women and the development of many animal models for this syndrome, information on its etiology is still scarce. Intrauterine hyperandrogenic environment may underlie changes at the levels of hypothalamus, pituitary and ovary organization in female offspring, and PCOS later in life. Letrozole, has been shown to mimic reproductive and metabolic characteristics of PCOS in adult rodent models. Therefore, the aim of this research was to assess the condition in a prenatal letrozole-treated rat model. Methods: Twenty-eight female rats from dams receiving letrozole at certain doses during late pregnancy were used in the trial. Pregnant Sprague-Dawley rats (n=21) received letrozole treatment on days 16-18 gestation at doses 1.25, 1.0, 0.75, 0.5, and 0.25 mg/kg body weight (BW).Results: Prenatal letrozole-treatment delayed parturition time and reduced the litter size in pregnant dams (P<0.0001). Late puberty onset, irregular ovarian cyclicity, increased anogenital distance (AGD), body weight gain, and serum testosterone concentration and reduced estradiol levels (P<0.0001) were observed in the female offspring of dams receiving 1.25 and 1 mg/kg BW letrozole. Furthermore, Letrozole at 1.25 and 1 mg/kg BW showed increased Rfrp and decreased Gnrh mRNA expression (P<0.0001). Conclusions: Letrozole treatment at doses 1 mg/kg BW and lower was not feto-toxic. It was concluded that 1 mg/kg BW letrozole may be suggested for prenatal PCOS induction.

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Letrozole treatment of adult female mice results in a similar reproductive phenotype but distinct changes in metabolism and the gut microbiome compared to pubertal mice

Cited by 41 publications

References 107 publications

Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome

Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome

Maternal aromatase inhibition via letrozole altered RFamide-related peptide-3 and gonadotropin releasing hormone expression in pubertal female rat

Maternal Aromatase Inhibition Effects on RFamide-Related Peptide-3 and Gonadotropin Releasing Hormone in Adult Murine Offspring With Polycystic Ovary Syndrome

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