Effects of metformin on endocrine, metabolic milieus and endometrial expression of androgen receptor in patients with polycystic ovary syndrome

Ito-Yamaguchi, Akiko; Suganuma, Ryota; Kumagami, Atsuko; Hashimoto, Shigeatsu; Yoshida-Komiya, Hiromi; Fujimori, Keiya

doi:10.3109/09513590.2014.951321

Cited by 15 publications

(17 citation statements)

References 21 publications

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“…These findings are consistent with a recent study showing that chronic treatment with DHT increases AR-dependent epithelial cell proliferation in association with uterine gland formation in ovariectomized mice (Simitsidellis et al, 2016). Furthermore, the inhibitory effect of metformin on uterine AR expression in PCOS-like rats has confirmed its regulatory pattern as described previously in endometrial tissues collected from PCOS patients (Ito-Yamaguchi et al, 2015, Li et al, 2015a, Zhang and Liao, 2010). While activation of AR with DHT regulates epithelial growth factors and epithelial-stromal interactions in the mouse uterus (Simitsidellis et al, 2016), our current work has revealed that among the common regulatory genes metformin regulates DHT-induced alterations of Wnt7c and Vcl gene expression in the PCOS-like rat uterus.…”

Section: Discussionsupporting

confidence: 85%

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Zhang

Meng

et al. 2017

EBioMedicine

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Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial–stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K–Akt–NFκB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.

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Section: Discussionsupporting

confidence: 85%

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Zhang

Meng

et al. 2017

EBioMedicine

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“…In the uterus, AR expression peaks during the proliferative phase. AR is expressed in the nuclei of the luminal and glandular epithelium, stromal nuclei, and myometrial smooth muscle cells (Apparao, Lovely, Gui, Lininger, & Lessey, ; Horie et al, ; Ito et al, ; Ito‐Yamaguchi et al, ; Mertens, Heineman, Theunissen, de Jong, & Evers, ; Slayden et al, ). ARKO mice have impaired uterine growth and show reduced uterine diameter but implantation, fetal development, and parturition can take place (Walters et al, ).…”

Section: Introductionmentioning

confidence: 99%

How do elevated levels of testosterone affect the function of the human fallopian tube and fertility?—New insights

Dulohery

Trottmann

Bour

et al. 2019

Molecular Reproduction Devel

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Excess testosterone levels affect up to 20% of the female population worldwide and are a key component in the pathogenesis of polycystic ovary syndrome. However, little is known about how excess testosterone affects the function of the human fallopian tube-the site of gamete transport, fertilization, and early embryogenesis. Therefore, this study aimed to characterize alterations caused by long-term exposure to male testosterone levels. For this purpose, the Fallopian tubes of nine female-to-male transsexuals, who had been undergoing testosterone treatment for 1-3 years, were compared with the tubes of 19 cycling patients. In the ampulla, testosterone treatment resulted in extensive luminal accumulations of secretions and cell debris which caused ciliary clumping and luminal blockage. Additionally, the percentage of ciliated cells in the ampulla was significantly increased. Transsexual patients, who had had sexual intercourse before surgery, showed spermatozoa trapped in mucus. Finally, in the isthmus complete luminal collapse occurred. Our results imply that fertility in women with elevated levels of testosterone is altered by tubal luminal obstruction resulting in impaired gamete transport and survival.

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“…So far, the first line of treatment for women with PCOS and insulin resistance has been the administration of an antihyperglycemic agent called metformin. Numerous studies in adults have shown the favorable effect of metformin on glucose tolerance in type-2 diabetes, and other data also indicate that metformin is an effective agent in reducing insulin resistance and hyperandrogenism in adult women with PCOS [ 8 ]. However, it has been observed that metformin is also often poorly tolerated because of gastrointestinal side effects, such as nausea (61%), vomiting (30%), and diarrhea (65%) [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Vitamin D Oral Supplementation in Insulin Resistance in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

2018

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Objective: To evaluate the effect of vitamin D supplementation (alone or with co-supplementation) on insulin resistance in patients with polycystic ovary syndrome (PCOS). Methods: We performed a literature search of databases (Medline, Scopus, Web of Knowledge, Cochrane Library) and identified all reports of randomized controlled trials (RCTs) published prior to April 2018. We compared the effects of supplementation with vitamin D alone (dose from 1000 IU/d to 60,000 IU/week) or with co-supplements to the administration of placebos in women diagnosed with PCOS. The systematic review and meta-analysis protocol was registered in the International Prospective Register of Systematic Reviews (Prospero) as number CRD42018090572. Main results: Eleven of 345 identified studies were included in the analysis; these involved 601women diagnosed with PCOS. Vitamin D as a co-supplement was found to significantly decrease fasting glucose concentrations and the HOMA-IR value. HOMA-IR also declined significantly when vitamin D was supplemented with a dose lower than 4000 IU/d. Conclusions: Evidence from RCTs suggests that the supplementation of PCOS patients with continuous low doses of vitamin D (<4000 IU/d) or supplementation with vitamin D as a co-supplement may improve insulin sensitivity in terms of the fasting glucose concentration (supplementation with vitamin D in combination with other micronutrients) and HOMA-IR (supplementation with vitamin D in continuous low daily doses or as co-supplement).

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Effects of metformin on endocrine, metabolic milieus and endometrial expression of androgen receptor in patients with polycystic ovary syndrome

Abstract: Metformin was effective in decreasing HOMA-IR, LH, free testosterone and the relative expression levels of AR. Furthermore, metformin might improve the systemic and local environment of the uterus caused by hyperandrogenemia in PCOS patients with insulin resistance.

Cited by 15 publications

References 21 publications

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

How do elevated levels of testosterone affect the function of the human fallopian tube and fertility?—New insights

The Role of Vitamin D Oral Supplementation in Insulin Resistance in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

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