Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

Ao, Shpakov

doi:10.3390/ph14010042

Cited by 41 publications

(23 citation statements)

References 462 publications

(314 reference statements)

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“…The pharmacotherapy of polycystic ovary syndrome (PCOS) may include the use of metformin in some scenarios to treat co-existent prediabetes or type 2 diabetes, to manage menstrual irregularity, and to improve fertility. Insulin resistance and hyperandrogenism are believed to play a key role in the pathophysiology of PCOS [ 42 , 43 , 44 , 45 , 46 , 47 ]. To this end, metformin reduces insulin resistance and inhibits the ovarian androgen production [ 44 , 48 , 49 , 50 ].…”

Section: Therapeutic Effects Of Metforminmentioning

confidence: 99%

“…The mechanism by which a treatment with metformin can contribute to the reversal of the clinical manifestations of PCOS, include direct and indirect actions at different levels of the hypothalamic–pituitary–gonadal axis, and the metformin-induced effects on cellular bioenergetics may have a role [ 47 ].…”

Section: Molecular Mechanisms Underlying Metformin Actionsmentioning

confidence: 99%

“…Decreasing hyperinsulinemia with metformin administration can lead to a reduction of circulating androgen levels, an increase of SHBG levels, and inhibition of premature luteinization. Moreover, there is evidence that metformin can directly affect the steroidogenic activity in the ovarian cells, acting through AMPK-dependent signaling pathways [ 42 , 44 , 45 , 46 , 47 , 48 , 50 ].…”

Section: Molecular Mechanisms Underlying Metformin Actionsmentioning

confidence: 99%

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Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Tulipano

2021

IJMS

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Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed.

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Section: Therapeutic Effects Of Metforminmentioning

confidence: 99%

Section: Molecular Mechanisms Underlying Metformin Actionsmentioning

confidence: 99%

Section: Molecular Mechanisms Underlying Metformin Actionsmentioning

confidence: 99%

See 1 more Smart Citation

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Tulipano

2021

IJMS

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“…Diabetes mellitus is a chronic disease affecting over 22 million people worldwide and has metabolic, inflammatory, and pathological genetic mechanisms [1,2]. A first-line treatment in type 2 diabetes, 1,1-dimethyl biguanide hydrochloride (metformin), is a biguanide that reduces hyperglycemia, prevents inflammation, normalizes lipid and carbohydrate metabolism, and reduces adipose tissue [3,4].…”

Section: Introductionmentioning

confidence: 99%

Is Metformin a Possible Beneficial Treatment for Psoriasis? A Scoping Review

Stănescu

Simionescu

Florea

et al. 2021

JPM

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Psoriasis is a chronic inflammatory condition with genetic, immunological, and metabolic etiology. The link between psoriasis and diabetes mellitus has been shown in genetic predisposition, environmental influences, inflammatory pathways, and insulin resistance, resulting in end-organ damage in both conditions. Because comorbidities often accompany psoriasis, the therapeutic management of the disease must also take into consideration the comorbidities. Given that metformin’s therapeutic role in psoriasis is not yet fully elucidated, we raised the question of whether metformin is a viable alternative for the treatment of psoriasis. We conducted this scoping review by searching for evidence in PubMed, Cochrane, and Scopus databases, and we used an extension for scoping reviews (PRISMA-ScR). Current evidence suggests that metformin is safe to use in psoriasis. Studies have shown an excellent therapeutic response to metformin in patients with psoriasis and comorbidities such as diabetes, metabolic syndrome, and obesity. There is no clear evidence supporting metformin monotherapy in patients with psoriasis without comorbidities. There is a need to further evaluate metformin in larger clinical trials, as a therapy in psoriasis.

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“…Positive effects have been described in adult men with metabolic syndrome, with an improvement in fertility through an increase in testosterone production ( 23 , 24 ). In addition, metformin, alone or in combination with other drugs, has been shown to restore the ovarian function in women with PCOS and to improve foetal development, pregnancy outcomes and offspring health in gestational diabetes mellitus and type 2 diabetes mellitus cases ( 25 ). The foetal and prenatal periods are critical windows for development of the male and female reproductive tracts because they are sensitive to hormones and steroids ( 26 , 27 ).…”

Section: Introductionmentioning

confidence: 99%

In Utero Exposure to Metformin Reduces the Fertility of Male Offspring in Adulthood

et al. 2021

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Metformin is a drug used for the treatment of type 2 diabetes and disorders associated with insulin resistance. Metformin is also used in the treatment of pregnancy disorders such as gestational diabetes. However, the consequences of foetal exposure to metformin on the fertility of exposed offspring remain poorly documented. In this study, we investigated the effect of in utero metformin exposure on the fertility of female and male offspring. We observed that metformin is detectable in the blood of the mother and in amniotic fluid and blood of the umbilical cord. Metformin was not measurable in any tissues of the embryo, including the gonads. The effect of metformin exposure on offspring was sex specific. The adult females that had been exposed to metformin in utero presented no clear reduction in fertility. However, the adult males that had been exposed to metformin during foetal life exhibited a 30% reduction in litter size compared with controls. The lower fertility was not due to a change in sperm production or the motility of sperm. Rather, the phenotype was due to lower sperm head quality – significantly increased spermatozoa head abnormality with greater DNA damage – and hypermethylation of the genomic DNA in the spermatozoa associated with lower expression of the ten-eleven translocation methylcytosine dioxygenase 1 (TET1) protein. In conclusion, while foetal metformin exposure did not dramatically alter gonad development, these results suggest that metabolic modification by metformin during the foetal period could change the expression of epigenetic regulators such as Tet1 and perturb the genomic DNA in germ cells, changes that might contribute to a reduced fertility.

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Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

Cited by 41 publications

References 462 publications

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Is Metformin a Possible Beneficial Treatment for Psoriasis? A Scoping Review

In Utero Exposure to Metformin Reduces the Fertility of Male Offspring in Adulthood

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