Metformin therapy for restoration of female and male reproductive functions

madman

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Abstract: Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, restore the ovarian function in women with polycystic ovary syndrome (PCOS) and improves fetal development, pregnancy outcomes, and offspring health in gestational diabetes mellitus (GDM) and T2DM. MF treatment is demonstrated to improve the efficiency of in vitro fertilization and is considered a supplementary drug in assisted reproductive technologies. MF administration shows a positive effect on steroidogenesis and spermatogenesis in men with metabolic disorders, thus MF treatment indicates prospective use for the improvement of male reproductive functions and fertility. MF lacks teratogenic effects and has positive health effects in newborns. The review is focused on the use of MF therapy for the restoration of female and male reproductive functions and improvement of pregnancy outcomes in metabolic and endocrine disorders. The mechanisms of MF action are discussed, including the normalization of metabolic and hormonal status in PCOS, GDM, T2DM, and metabolic syndrome and restoration of functional activity and hormonal regulation of the gonadal axis.




1. Introduction

Metformin (1,1-dimethyl biguanide hydrochloride) (MF), an orally administered biguanide is the first-line drug for the treatment of type 2 diabetes mellitus (T2DM). It reduces the adipose tissue mass and increases the tissue sensitivity to insulin, thereby reducing hyperglycemia, normalizing carbohydrate, and lipid metabolism, and preventing inflammation and oxidative stress in the tissues [1,2]. MF is also used to treat non-alcoholic fatty liver disease [3], coronary artery disease [4,5], acute kidney injury, and chronic kidney disease [6], in patients with T2DM, metabolic syndrome (MetS), and obesity, and in patients without apparent symptoms of metabolic disorders [7]. There are numerous clinical and experimental studies indicating the effectiveness of MF as an anticancer drug, used to prevent the growth and metastasis in breast cancer [8,9], endometrial cancer [10–12], colorectal cancer [9,13], prostate cancer [14], and in a number of the other tumors [15,16].

Currently, there is a large body of evidence for the effectiveness of MF therapy in the restoration of reproductive functions and fertility in women with polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and T2DM, as well as to improve the effectiveness of the assisted reproductive technologies (ART), such as in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Important attributes of MF use in the treatment of pregnant women with PCOS and T2DM include its lack of teratogenic effect and established positive effect on fetal development, pregnancy outcomes, and newborn health. Moreover, convincing evidence has been obtained for the restorative effects of MF on steroidogenic and spermatogenic functions in men with diabetes mellitus (DM) and MetS. This review offers an overview of problems when utilizing MF therapy for the correction of reproductive dysfunctions in women and men and includes the analysis of possible mechanisms for positive effects of MF on reproduction. The review also includes only a brief description of the molecular mechanisms of MF action in target cells; these mechanisms are the focus of other review articles [17–24].




2. Summary of Cell Targets and Molecular Mechanisms of Action of Metformin


3. Metformin and Polycystic Ovary Syndrome


*3.1. Pathophysiology of Polycystic Ovary Syndrome

*3.2. The Use of Metformin in PCOS Women

*3.3. Combined Use of Metformin with Clomiphene Citrate, Letrozole, Liraglutide, Saxagliptin, or Oral Contraceptives

*3.4. The Mechanisms of Metformin Effects on Reproductive Functions in PCOS

3.4.1. Metformin-Induced Inhibition of Hyperandrogenism and Normalization of the Steroid Hormones Balance
3.4.2. Protective efFect of Metformin against Excess Androgens in PCOS
3.4.3. Effects of Metformin on FSH-Activated Signaling in the PCOS Ovaries
3.4.4. The Effect of Metformin on the Production of Anti-Müllerian Hormone in PCOS
3.4.5. Effect of Metformin on Metalloproteinases in PCOS
3.4.6. Influence of Metformin on Inflammation and Lipid Status in PCOS

*3.5. The Sensitivity of PCOS Women to Metformin Therapy


4. Metformin and Gestational Diabetes Mellitus

5. Metformin Treatment of Women with Diabetes Mellitus and Obesity


6. Metformin and the Male Reproduction

*6.1. Effects of Metformin on Male Reproduction in Metabolic Disorders
*6.2. The Clinical Studies of the Metformin Efficacy to Treat Reproductive Dysfunctions in Men

*6.3. The Experimental Studies of Metformin Effects on Male Reproductive Dysfunctions in Animal Models of Metabolic Diseases




7. Conclusions

The data presented in the review convincingly prove that MF has an improving effect on reproductive functions both in women with PCOS, GDM and T2DM, and in men with DM and MetS. At the same time, the effectiveness of MF therapy is due to a large number of different factors that must be taken into account when choosing this therapy and also when developing a strategy for using MF. Firstly, it is necessary to assess the efficiency of MF transport into the cell, which depends on the functional activity of the organic cation transporters and can be disrupted by inactivating mutations in their genes. The presence of certain mutations leads to a loss of responsiveness to MF and makes the use of MF therapy meaningless. Secondly, as demonstrated in women with PCOS, GDM, and T2DM, the MF therapy is more effective in the severely overweight and obese patients with IR, compensatory hyperinsulinemia, impaired glucose tolerance, as well as with dyslipidemia, which is due to a decrease in the blood levels of HDL-C. This is not surprising, since the clinical effect of MF therapy is due to an improvement in insulin sensitivity, a decrease in adipose tissue mass, and restoration of the glucose and lipid metabolism.

In addition, as demonstrated in a number of clinical studies in PCOS women, the effectiveness of MF is largely determined by the hormonal status of the ovaries and the functioning of the HPG axis. The MF therapy may be most effective in PCOS women who have: (1) severe HA, which may be due to hyperactivation of ovarian insulin/IGF1-regulated signaling pathways that stimulate androgen synthesis, as well as an increase in LH levels and the LH/FSH ratio and a decrease in the blood levels of IGFBP-1 and SHBG; (2) an increase in the AMH production; and (3) an increased aromatase expression and FSH-induced estrogen synthesis in the ovaries. There is reason to believe that various combinations of these factors, including those with IR and metabolic disorders, may become reliable indications for prescribing MF alone and in combinations with other drugs, diet or exercises to correct the reproductive functions in PCOS. This can be helpful when using MF to treat pregnant women with GDM and T2DM. Moreover, a systemic approach based on the analysis of the combination and severity of metabolic and hormonal dysfunctions may be useful to assess the efficacy of MF therapy for improving spermatogenesis and steroidogenesis in men with DM and MetS.

Since some of the MF targets overlap well with those of leptin, the assessment of leptin status in patients with reproductive disorders may also be important. As a result, leptin resistance, both systemic and in the ovaries/testes, as well as the changes in the hypothalamic leptin signaling pathways, negatively affecting the production of GnRH, can become factors that will determine the effectiveness of MF therapy. In this regard, it should be noted that the central mechanisms of action of MF, which easily penetrates the CNS and improves the metabolism of the neuronal and glial cells still remains underestimated. By acting on the CNS, MF restores the signaling networks of the hypothalamus and the other brain regions that are involved in the control of reproductive functions and undergo significantly compensatory and pathological changes in metabolic and endocrine disorders, including PCOS, GDM, T2DM, and MetS.

A unique feature of MF is the multiplicity of molecular mechanisms of its action on target cells, which include direct or indirect regulation of the AMPK-, calcium- and cAMP dependent signaling pathways, as well as the MAPK cascade and the IRS/PI 3-K/Akt pathway. As a result, MF controls not only energy and metabolic processes in the cell, but also the processes of growth, differentiation, apoptosis, inflammation, and ER stress. At the same time, most of the regulatory effects of MF are based largely on its modulating and normalizing influence on intracellular signaling cascades than on their prolonged stimulation or suppression. Depending on the functional state of the IRS/PI 3-K/Akt pathway, MF can either prevent its hyperactivation, which is especially important for its antitumor effect or, on the contrary, restore its reduced activity, improving the survival of target cells and their sensitivity to insulin and leptin. As expected, MF therapy affects the responsiveness of hypothalamic neurons, pituitary gonadotrophs, and testicular and ovarian cells to the hormones, growth factors, adipokines, and cytokines, but more studies are required for complete elucidation of all regulatory mechanisms involved.

The use of MF in combination with the other drugs has great potential. This is supported by the encouraging results of clinical trials of the combined therapy with MF and insulin in pregnant women with GDM and T2DM. In metabolic and endocrine disorders, the combined therapy not only allows to increase the efficiency and pattern of the effects of MF on the HPG axis, but also to reduce the pharmacological doses of drugs, including MF, thus avoiding possible side effects of high-dose drug administration, including the undesirable effect of MF on the functioning of the gastrointestinal tract.

The presented results indicate a significant and not yet fully understood the potential of MF therapy for the correction of reproductive dysfunctions in women and men. Significantly, of great importance are the absence of a teratogenic effect of MF and the low risks of MF therapy on the health of the mother and child. It should be taken into account that the unjustified use of MF for the treatment of patients lacking profoundly manifesting metabolic and endocrine disorders can lead to energy and metabolic imbalance and further deterioration of the functional state of their reproductive system.
 

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madman

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Figure 1. The cellular mechanisms of metformin action are carried out by activation of the AMP-activated protein kinase and inhibition of the mitochondrial electron transport chain complex I. Abbreviations: AC, adenylyl cyclase; ACC1/2, acetyl-CoA carboxylases 1 and 2; AMPD, AMP deaminase; AMPK, the heterotrimeric AMP-activated protein kinase consisting of the α1/2 (the target for activation phosphorylation at the Thr172), β1/2 and γ1/2/3 subunits; CREB, cAMP-activated transcription factor (cAMP response element-binding protein); ETC complex I, the mitochondrial NADH-dehydrogenase complex, the first complex of the respiratory electron transport chain; FA, fatty acids; LKB1, liver kinase B1; mG3PDH, mitochondrial glycerol-3-phosphate dehydrogenase; mTORC2, the mTOR complex 2; NFκB, nuclear factor κB; OCT1/2, the organic cations transporters 1 and 2; pCBP, the Ser436-phosphorylated form of CREB-binding protein with acetyltransferase activity, a co-activator of the factor CREB; PDE4B, cAMP-specific 3′,5′-cyclic phosphodiesterase 4B; PKA, cAMP-dependent protein kinase; PP2C, protein phosphatase 2C; ROS, reactive oxygen species
Screenshot (3238).png
 

madman

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Figure 2. The pathways involved in the inhibitory effect of metformin on hyperandrogenism in PCOS. Hyperinsulinemia and HA are among the key pathogenetic factors in the development of PCOS, which is why their attenuation by MF is the most important mechanism for improving the effectiveness of this drug on ovarian function in PCOS women. In PCOS, MF-induced increase in insulin sensitivity leads to a decrease in the HOMA-IR and a weakening of compensatory hyperinsulinemia. Another mechanism for lowering insulin levels may be an increase in the level of IGFBP-1, which specifically binds insulin and IGF-1. In PCOS, the expression of IGFBP-1 is generally reduced, and MF treatment may be one way to normalize it. Reduced hyperinsulinemia and an increase in IGFB-1 levels lead to a decrease in the stimulating effect of insulin and IGF-1 on ovarian steroidogenesis and a weakening of HA. Hyperinsulinemia leads to a decrease in the production of SHBG, which provokes HA in PCOS. MF-induced reduction of hyperinsulinemia leads to the normalization of the SHBG levels, thereby preventing excess androgen levels in the blood. By improving the functionality of the hypothalamic signaling network responsible for the pulsatile secretion of GnRH, treatment with MF leads to the normalization of blood LH levels and the LH/FSH ratio, both of which are increased in PCOS. A decrease in blood LH levels results in a weakening of gonadotropin-induced androgen production by the ovaries. A direct regulatory effect of MF on ovarian steroidogenesis was also established. By inhibiting the mitochondrial ETC complex I, stimulating the LKB1 activity and, as a result, increasing the AMPK activity, MF reduces the synthesis of androstenedione in the ovarian cells and prevents HA. It can be assumed that the prevalence of some mechanisms of the inhibitory effect of MF on HA is due to the characteristic features of PCOS pathogenesis and the metabolic and hormonal status of the ovaries. Details and bibliographic references are presented in Section 3.4. Abbreviations: AMPK, AMP-activated protein kinase; FSH, follicle-stimulating hormone; HA, hyperandrogenism; HOMA-IR, homeostasis model assessment of insulin resistance; IGF-1, insulin-like growth factor-1; IGFBP-1, insulin-like growth factor-binding protein-1; LH, luteinizing hormone; LKB1, liver kinase B1; SHBG, androgen, and sex hormone-binding globulin.
Screenshot (3240).png
 

madman

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Figure 3. Factors determining responsiveness to metformin and the effectiveness of metformin therapy in women with PCOS. Women with PCOS, as well as the patients with other pathologies, must have functionally active transporters of organic cations (OCT1, OCT2, and others) in order to respond to MF, since inactivating mutations and polymorphisms in the genes encoding these transporters lead to impairment of MF transport into the cell and make MF therapy ineffective. Since MF improves metabolic parameters and insulin sensitivity, its effectiveness in PCOS women with overweight or obesity, as well as with severe dyslipidemia and impaired glucose tolerance, is usually higher. There is evidence that MF therapy is most effective in PCOS women who have pronounced signs of hyperinsulinemia and hyperandrogenism, the increased LH levels and the LH/FSH ratio, the decreased levels of SHBG, IGFBP-1, and HDL-C, and the increased levels of AMH. It can also be assumed that MF will be more effective in patients with increased aromatase expression and ovarian hypersensitivity to FSH since one of the mechanisms of MF action is the normalization of the expression of genes encoding the FSH receptor and aromatase, as well as normalization in the response of ovarian cells to stimulation of FSH. Details and bibliographic references are presented in Section 3.5. Abbreviations: AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; HDL-C, high-density lipoprotein cholesterol; IGFBP-1, insulin-like growth factor-binding protein-1; LH, luteinizing hormone; OCT1 and OCT2, organic cation transporters-1 and 2; SHBG, androgen, and sex hormone-binding globulin.
Screenshot (3241).png
 

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