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

Abstract

Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, restores 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 positive effect on steroidogenesis and spermatogenesis in men with metabolic disorders, thus MF treatment indicates prospective use for improvement of male reproductive functions and fertility. MF lacks teratogenic effects and has positive health effect in newborns. The review is focused on use of MF therapy for 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 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.

Keywords: diabetes mellitus; folliculogenesis; gestational diabetes mellitus; gonadotropin; in vitro fertilization; insulin; metformin; ovary; polycystic ovary syndrome; steroidogenesis; testes.

Figure 1

The cellular mechanisms of metformin action which 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.

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 effect 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. A reduced hyperinsulinemia and an increase in IGFB-1 levels lead to a decrease in the stimulating effect of insulin and IGF-1 on the 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 the 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.

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 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 the 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.