[en] Initially produced in Europe in 1958, metformin is still one of the most widely prescribed drugs to treat type II diabetes and other comorbidities associated with insulin resistance. Metformin has been shown to improve fertility outcomes in females with insulin resistance associated with polycystic ovary syndrome (PCOS) and in obese males with reduced fertility. Metformin treatment reinstates menstrual cyclicity, decreases the incidence of cesareans, and limits the number of premature births. Notably, metformin reduces steroid levels in conditions associated with hyperandrogenism (e.g., PCOS and precocious puberty) in females and improves fertility of adult men with metabolic syndrome through increased testosterone production. While the therapeutical use of metformin is considered to be safe, in the last 10 years some epidemiological studies have described phenotypic differences after prenatal exposure to metformin. The goals of this review are to briefly summarize the current knowledge on metformin focusing on its effects on the female and male reproductive organs, safety concerns, including the potential for modulating fetal imprinting via epigenetics.
Disciplines :
Animal production & animal husbandry
Author, co-author :
Faure, Mélanie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie de la différenciation sexuelle du cerveau ; Unité de Physiologie de la Reproduction et des Comportements, Centre Val de
Bertoldo, Michael J; Discipline of Obstetrics and Gynaecology, School of Women's and Children's
Khoueiry, Rita; Department of Development and Regeneration, Stem Cell Institute, KU Leuven,
Bongrani, Alice; Unité de Physiologie de la Reproduction et des Comportements, Centre Val de
Brion, François; INERIS, Direction des Risques Chroniques, Pole VIVA, Unite d'ecotoxicologie in
Giulivi, Cecilia; Department of Molecular Biosciences, School of Veterinary Medicine, University of ; Medical Investigations of Neurodevelopmental Disorders Institute, University of
Dupont, Joelle; Unité de Physiologie de la Reproduction et des Comportements, Centre Val de
Froment, Pascal; Unité de Physiologie de la Reproduction et des Comportements, Centre Val de
Simonet H Tanret G. Sur les propriétés hypoglycemiantes du sulfate de galegine. In: Bull Soc Chim Biol. Paris (1927). p. 908–27.
Passik C. Glucophage: 40 ans au Service de la Diabétologie. Paris (1997).
Rinaldi D. La Metformine, une Vieille Molécule Pleine d'espoir. Doctoral Diss Fac Pharm, Univ de Lorraine (2012).
Natali A Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia (2006) 49:434–41. 10.1007/s00125-006-0141-716477438
El-Mir M-Y Nogueira V Fontaine E Avéret N Rigoulet M Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. (2000) 275:223–8. 10.1074/jbc.275.1.22310617608
Owen MR Doran E Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. (2000) 614:607–14. 10.1042/bj3480607
Detaille D Guigas B Leverve X Wiernsperger N Devos P. Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function. Biochem Pharmacol. (2002) 63:1259–72. 10.1016/S0006-2952(02)00858-411960602
Guigas B Bertrand L Taleux N Foretz M Wiernsperger N Vertommen D et al. 5-Aminoimidazole-4-carboxamide-1-B-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase–independent effect on glucokinase translocation. Diabetes (2006) 55:865–74. 10.2337/diabetes.55.04.06.db05-1178
Cameron AR Logie L Patel K Erhardt S Bacon S Middleton P et al. Metformin selectively targets redox control of complex I energy transduction. Redox Biol. (2018) 14:187–97. 10.1016/j.redox.2017.08.01828942196
Wu C Qiu S Zhu X Lin H Li L. OCT1-mediated metformin uptake regulates pancreatic stellate cell activity. Cell Physiol Biochem. (2018) 47:1711–20. 10.1159/00049100329949790
Hardie DG Ross FA Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. (2012) 13:251–62. 10.1038/nrm331122436748
Nascimben L Ingwall JS Lorell BH Pinz I Schultz V Tornheim K et al. Mechanisms for increased glycolysis in the hypertrophied rat heart. Hypertension (2004) 44:662–7. 10.1161/01.HYP.0000144292.69599.0c15466668
Jager S Handschin C St-Pierre J Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1a. Proc Natl Acad Sci USA. (2007) 104:12017–22. 10.1073/pnas.0705070104
Coughlan KA Valentine RJ Ruderman NB Saha AK. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes. (2014) 7:241–53. 10.2147/DMSO.S4373125018645
Ke R Xu Q Li C Luo L Huang D. Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism. Cell Biol Int. (2004) 28:229–36. 10.1016/j.cellbi.2003.12.004
Gamble J Lopaschuk GD. Insulin Inhibition of 5′adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism (1997) 46:1270–4.
Hardie DG. Sensing of energy and nutrients by AMP-activated protein kinase 1–4. Am J Clin Nutr. (2011) 93:891S−6. 10.3945/ajcn.110.001925.1
Kukidome D Nishikawa T Sonoda K Imoto K Fujisawa K Yano M et al. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes (2006) 55:120–7. 10.2337/diabetes.55.01.06.db05-094316380484
Karnewar S Neeli PK Panuganti D Kotagiri S Mallappa S Jain N et al. Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: relevance in age-associated vascular dysfunction. Biochim Biophys Acta (2018) 1864:1115–28. 10.1016/j.bbadis.2018.01.01829366775
Foretz M Hébrard S Leclerc J Zarrinpashneh E Soty M Mithieux G et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. (2010) 120:2355–69. 10.1172/JCI40671DS120577053
Madiraju AK Erion DM Rahimi Y Zhang X-M Braddock DT Albright RA et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature (2014) 510:542–6. 10.1038/nature1327024847880
Madiraju AK Qiu Y Perry RJ Rahimi Y Zhang X-M Zhang D et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med. (2018) 24:1384–94. 10.1038/s41591-018-0125-430038219
Cuyàs E Verdura S Llorach-Pares L Fernández-Arroyo S Luciano-Mateo F Cabré N et al. Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Aging Cell (2018) 17:e12772. 10.1111/acel.12772
Wu H Esteve E Tremaroli V Khan MT Caesar R Mannerås-Holm L et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. (2017) 23:850–8. 10.1038/nm.434528530702
Bauer PV Duca FA Waise TMZ Rasmussen BA Abraham MA Dranse HJ et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. (2017) 27:101–17. 10.1016/j.cmet.2017.09.01929056513
Lablanche S Cottet-Rousselle C Lamarche F Benhamou PY Halimi S Leverve X et al. Protection of pancreatic INS-1 β-cells from glucose- and fructose-induced cell death by inhibiting mitochondrial permeability transition with cyclosporine A or metformin. Cell Death Dis. (2011) 2:e134–6. 10.1038/cddis.2011.15
El-Mir MY Detaille D R-Villanueva G Delgado-Esteban M Guigas B Attia S et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci. (2008) 34:77–87. 10.1007/s12031-007-9002-118040888
Royal Australian College of General Practitioners. Gestational diabetes mellitus. In: General Practice Management of Type 2 Diabetes: 2016–18. (2014). Available online at: www.racgp.org.au
Graham GG Punt J Arora M Day RO Doogue MP Duong JK et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. (2011) 50:81–98. 10.2165/11534750-000000000-0000021241070
Hou M Venier N Sugar L Musquera M Pollak M Kiss A et al. Protective effect of metformin in CD1 mice placed on a high carbohydrate-high fat diet. Biochem Biophys Res Commun. (2010) 397:537–42. 10.1016/j.bbrc.2010.05.15220573602
Gras V Bouffandeau B Montravers PH Lalau JD. Effect of metformin on survival rate in experimental sepsis. Diabetes Metab. (2006) 32:147–50. 10.1016/S1262-3636(07)70261-616735963
Gong L Goswami S Giacomini KM Altman RB Klein TE. Metformin pathways: pharmacokinetics and pharmacodynamics. Chemosphere (2012) 104:8897–901. 10.1097/FPC.0b013e3283559b22
Shu Y Brown C Castro RA Shi RJ Lin ET Owen RP et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. (2008) 83:273–80. 10.1038/sj.clpt.610027517609683
Fauser BCJM. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. (2004) 19:41–7. 10.1093/humrep/deh098
Cimino I Casoni F Liu X Messina A Parkash J Jamin SP et al. Novel role for anti-mullerian hormone in the regulation of GnRH neuron excitability and hormone secretion. Nat Commun. (2016) 7:1–12. 10.1038/ncomms1005526753790
Bertoldo MJ Faure M Dupont J Froment P. Impact of metformin on reproductive tissues: an overview from gametogenesis to gestation. Ann Transl Med. (2014) 2:1–13. 10.3978/j.issn.2305-5839.2014.06.0425333030
Vanlalhruaii Dasgupta R Ramachandran R Mathews JE Regi A Thomas N et al. How safe is metformin when initiated in early pregnancy? A retrospective 5-year study of pregnant women with gestational diabetes mellitus from India. Diabetes Res Clin Pract. (2018) 137:47–55. 10.1016/j.diabres.2018.01.00229325773
Brown J Grzeskowiak L Williamson K Downie Michelle R Crowther Caroline A. Insulin for the treatment of women with gestational diabetes. Cochrane Database Syst Rev. (2016). 11:1–294. 10.1002/14651858.CD01203729103210
New Zealand Ministry of Health,. Screening, Diagnosis Management of Gestational Diabetes in New Zealand: A Clinical Practice Guideline. (2014). Available online at: www.health.govt.nz
Network SIG. Management of Diabetes: A National Clinical Guideline (SIGN Publication o. 116.) (2008) SIGN. Available online at: www.sign.ac.uk/guidelines/fulltext/
National Institute for Health and Care Excellence (NICE). Diabetes in Pregnancy: Management From Preconception to the Postnatal Period (2015). Available online at: https://www.nice.org.uk/guidance/ng3
Association AD. Management of diabetes in pregnancy. Diabetes Care (2017) 40:S114–9. 10.2337/dc17-S016
Palomba S Pasquali R Orio F Jr., Nestler JE. Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis. Clin Endocrinol (Oxf). (2009) 70:311–21. 10.1111/j.1365-2265.2008.03369.x
Tang T Lord J Norman R Yasmin E Balen A. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) forwomenwith polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. (2012) 5–7:CD003053. 10.1002/14651858.CD003053.pub5
Petersen KB Pedersen NG Pedersen AT Lauritsen MP Freiesleben N la C. Mono-ovulation in women with polycystic ovary syndrome: a clinical review on ovulation induction. Reprod Biomed. (2016) 32:563–83. 10.1016/j.rbmo.2016.03.006
Misso ML Costello MF Garrubba M Wong J Hart R Rombauts L et al. Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. (2013) 19:2–11. 10.1093/humupd/dms03622956412
Tso LO Costello MF Albuquerque LET Andriolo RB Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev. (2009) 2:CD006105. 10.1002/14651858.CD006105.pub3
Tso LO Costello MF Albuquerque LET Andriolo RB Marjoribanks J MacEdo CR. Metformin treatment before and during in vitro fertilization or intracytoplasmic sperm injection in women with polycystic ovary syndrome: summary of a cochrane review. Fertil Steril. (2015) 104:542–4. 10.1016/j.fertnstert.2015.05.03826070519
Cassina M Dona M Di Gianantonio E Litta P Clementi M. First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis. Hum Reprod. (2014) 20:656–69. 10.1093/humupd/dmu02224861556
Yu Y Fang L Zhang R He J Xiong Y Guo X et al. Comparative effectiveness of 9 ovulation-induction therapies in patients with clomiphene citrate-resistant polycystic ovary syndrome: a network meta-analysis. Sci Rep. (2017) 7:1–12. 10.1038/s41598-017-03803-928630466
Mayes MA Laforest MF Guillemette C Gilchrist RB Richard FJ. Adenosine 5′-monophosphate kinase-activated protein kinase (PRKA) activators delay meiotic resumption in porcine oocytes. Biol Reprod. (2007) 76:589–97. 10.1095/biolreprod.106.05782817167165
Tosca L Uzbekova S Chabrolle C Dupont J. Possible role of 5′AMP-activated protein kinase in the metformin-mediated arrest of bovine oocytes at the germinal vesicle stage during in vitro maturation. Biol Reprod. (2007) 77:452–65. 10.1095/biolreprod.107.06084817567959
Huang Y Yu Y Gao J Li R Zhang C. Impaired oocyte quality induced by dehydroepiandrosterone is partially rescued by metformin treatment. PLoS ONE (2015) 10:e0122370. 10.1371/journal.pone.012237025811995
Bertoldo MJ Guibert E Faure M Ramé C Foretz M Viollet B et al. Specific deletion of AMP-activated protein kinase (α1AMPK) in murine oocytes alters junctional protein expression and mitochondrial physiology. PLoS ONE (2015) 10:e0119680. 10.1371/journal.pone.011968025767884
Calder MD Edwards NA Betts DH Watson AJ. Treatment with AICAR inhibits blastocyst development, trophectodermdifferentiation and tight junction formation and function in mice. Mol Hum Reprod. (2017) 23:771–85. 10.1093/MOLEHR/GAX05028962017
Louden ED Luzzo KM Jimenez PT Chi T Chi M Moley KH. TallyHO obese female mice experience poor reproductive outcomes and abnormal blastocyst metabolism which is reversed by metformin. Reprod Fertil Dev. (2014) 1:31–9. 10.1071/RD14339
Pikiou O Vasilaki A Leondaritis G Vamvakopoulos N Messinis IE. Effects of metformin on fertilisation of bovine oocytes and early embryo development: possible involvement of AMPK3-mediated TSC2 activation. Zygote (2014) 23:58–67. 10.1017/S096719941300030023870192
Sermondade N Dupont C Faure C Boubaya M Cédrin-Durnerin I Chavatte-Palmer P et al. Body mass index is not associated with sperm-zona pellucida binding ability in subfertile males. Asian J Androl. (2013) 15:626–9. 10.1038/aja.2013.10
Kort HI Massey JOEB Elsner CW Mitchell-leef D Shapiro DB Witt MA et al. Impact of body mass index values on sperm quantity and quality. J Androl. (2006) 27:1150–2. 10.2164/jandrol.0512416339454
Dupont C Faure C Sermondade N Boubaya M Eustache F Clément P et al. Obesity leads to higher risk of sperm DNA damage in infertile patients. Asian J Androl. (2013) 15:622–5. 10.1038/aja.2013.6523792341
Tartarin P Moison D Guibert E Dupont J Habert R Rouiller-Fabre V et al. Metformin exposure affects human and mouse fetal testicular cells. Hum Reprod. (2012) 27:3304–14. 10.1093/humrep/des26422811314
Riera MF Regueira M Galardo MN Pellizzari EH Meroni SB Cigorraga SB. Signal transduction pathways in FSH regulation of rat Sertoli cell proliferation. Am J Physiol Endocrinol Metab. (2012) 302:E914–23. 10.1152/ajpendo.00477.201122275758
Attia SM Helal GK Alhaider AA. Assessment of genomic instability in normal and diabetic rats treated with metformin. Chem Biol Interact. (2009) 180:296–304. 10.1016/j.cbi.2009.03.00119497428
Morgante G Tosti C Orvieto R Musacchio MC Piomboni P De Leo V. Metformin improves semen characteristics of oligo-terato-asthenozoospermic men with metabolic syndrome. Fertil Steril. (2011) 95:2150–2. 10.1016/j.fertnstert.2010.12.00921194687
Rabbani SI Devi K Khanam S. Role of pioglitazone with metformin or glimepiride on oxidative stress-induced nuclear damage and reproductive toxicity in diabetic rats. J Med Sci. (2010) 17:3–11. 22135519
Yan W Mu Y Yu N Yi T Zhang Y Pang X et al. Protective effects of metformin on reproductive function in obese male rats induced by high-fat diet. J Assist Reprod Genet. (2015) 32:1097–104. 10.1007/s10815-015-0506-226081124
Hurtado de Llera A Martin-Hidalgo D Gil MC Garcia-Marin LJ Bragado MJ. AMP-activated kinase AMPK is expressed in boar spermatozoa and regulates motility. PLoS ONE (2012) 7:e38840. 10.1371/journal.pone.003884022719961
Ghasemnejad-Berenji M Ghazi-Khansari M Yazdani I Nobakht M Abdollahi A Ghasemnejad-Berenji H et al. Effect of metformin on germ cell-specific apoptosis, oxidative stress and epididymal sperm quality after testicular torsion/detorsion in rats. Andrologia (2017) 50:1–8. 10.1111/and.1284628730645
Nasrolahi O Khaneshi F Rahmani F Razi M. Honey and metformin ameliorated diabetes-induced damages in testes of rat; correlation with hormonal changes. Iran J Reprod Med. (2013) 11:1013–20. 24639728
Ayuob NN Hussam ASM Soad SA. Impaired expression of sex hormone receptors in male reproductive organs of diabetic rat in response to oral antidiabetic drugs. Folia Histochem Cytobiol. (2015) 53:35–48. 10.5603/FHC.a2015.000525765091
Naglaa ZHE Hesham AM Fadil HA Motal ASM. Impact of metformin on immunity and male fertility in rabbits with alloxan-induced diabetes. J Am Sci. (2010) 6:417–26.
Nguyen TMD Alves S Grasseau I Métayer-Coustard S Praud C Froment P et al. Central role of 5′-AMP-activated protein kinase in chicken sperm functions. Biol Reprod. (2014) 91:1–15. 10.1095/biolreprod.114.12185525297543
Faure M Guibert E Alves S Pain B Ramé C Dupont J et al. The insulin sensitiser metformin regulates chicken Sertoli and germ cell populations. Reproduction (2016) 151:527–38. 10.1530/REP-15-056526917452
Córdova A Strobel P Vallejo A Valenzuela P Ulloa O Burgos RA et al. Cryobiology use of hypometabolic TRIS extenders and high cooling rate refrigeration for cryopreservation of stallion sperm: presence and sensitivity of 5 0 AMP-activated protein kinase (AMPK). Cry (2014) 69:473–81. 10.1016/j.cryobiol.2014.10.008
Tartarin P Guibert E Touré A Ouiste C Leclerc J Sanz N et al. Inactivation of AMPKα1 induces asthenozoospermia and alters spermatozoa morphology. Endocrinology (2012) 153:3468–81. 10.1210/en.2011-191122581459
Cheung PCF Salt IP Davies SP Hardie DG Carling D. Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding. Biochem (2000) 669:659–69. 10.1042/bj3460659
Alves MG Martins AD Vaz CV Correia S Moreira PI Oliveira PF et al. Metformin and male reproduction: effects on Sertoli cell metabolism. Br J Pharmacol. (2014) 171:1033–42. 10.1111/bph.1252224261663
Arlt W Auchus RJ Miller WL. Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3β-hydroxysteroid dehydrogenase. J Biol Chem. (2001) 276:16767–71. 10.1074/jbc.M100040200
Bailey C Puah JA. Effect of metformin on glucose metabolism in mouse soleus muscle. Diabete Metab. (1986) 12:212–8. 3770275
Lashen H. Review: role of metformin in the management of polycystic ovary syndrome. Ther Adv Endocrinol Metab. (2010) 1:117–28. 10.1177/2042018810380215
Velazquez EM Sosa F Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism (1994) 43:647–54. 10.1016/0026-0495(94)90209-78177055
Nestler JE Jakubowicz DJ. Lean women with polycystic ovary syndrome respond P450c17a activity and serum androgens. J Clin Endocrinol Metab. (1997) 82:4075–9.
Bailey C Turner R. Metformin. N Engl J Med. (1998) 334:574–9. 10.1056/NEJM1996022933409068569826
Harborne L Fleming R Lyall H Sattar N Norman J. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. (2003) 88:4116–23. 10.1210/jc.2003-03042412970273
Mansfield R Galea R Brincat M Hole D Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril. (2003) 79:956–62. 10.1016/S0015-0282(02)04925-712749437
Rice S Pellatt L Ramanathan K Whitehead SA Mason HD. Metformin inhibits aromatase via an extracellular signal-regulated kinase-mediated pathway. Endocrinology (2009) 150:4794–801. 10.1210/en.2009-054019574398
Fuhrmeister I Branchini G Pimentel A Ferreira G Capp E Brum I et al. Human granulosa cells: insulin and insulin-like growth factor-1 receptors and aromatase expression modulation by metformin. Gynecol Obs Invest. (2014) 77:156–62. 10.1159/00035882924603137
Richardson MC Ingamells S Simonis CD Cameron IT Sreekumar R Vijendren A et al. Stimulation of lactate production in human granulosa cells by metformin and potential involvement of adenosine 5 monophosphate-activated protein kinase. J Clin Endocrinol Metab. (2009) 94:670–7. 10.1210/jc.2008-202519001513
Pellatt LJ Rice S Mason HD. Phosphorylation and activation of AMP-activated protein kinase (AMPK) by metformin in the human ovary requires insulin. Reprod Dev. (2011) 152:1112–8. 10.1210/en.2009-142921209024
Attia GR Rainey WE Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertil Steril. (2001) 76:517–24. 10.1016/S0015-0282(01)01975-611532475
Svechnikov K Spatafora C Svechnikova I Tringali C Söder O. Effects of resveratrol analogs on steroidogenesis and mitochondrial function in rat Leydig cells in vitro. J Appl Toxicol. (2009) 29:673–80. 10.1002/jat.145619603415
Rone MB Midzak AS Martinez-arguelles DB Fan J Ye X Papadopoulos V. Steroidogenesis in MA-10 mouse leydig cells is altered via fatty acid import into the mitochondria. Biol Res Nurs. (2014) 91:1–14. 10.1095/biolreprod.114.12143425210128
Tosca L Froment P Solnais P Ferre P Foufelle F. Adenosine 5-monophosphate-activated protein kinase regulates progesterone secretion in rat granulosa cells. Endocrinology (2005) 146:4500–13. 10.1210/en.2005-030116020477
Tosca L Chabrolle C Uzbekova S Dupont J. Effects of metformin on bovine granulosa cells steroidogenesis: possible involvement of adenosine 5′ monophosphate-activated protein kinase (AMPK). Biol Reprod. (2007) 76:368–78. 10.1095/biolreprod.106.05574917123942
Mesbah F Moslem M Vojdani Z Mirkhani H. Does metformin improve in vitro maturation and ultrastructure of oocytes retrieved from estradiol valerate polycystic ovary syndrome-induced rats. J Ovarian Res. (2015) 8:1–10. 10.1186/s13048-015-0203-x26577050
Samarajeewa NU Ham S Yang F Simpson ER Brown KA. Promoter-specific effects of metformin on aromatase transcript expression. Steroids (2011) 76:768–71. 10.1016/j.steroids.2011.02.04121414336
Romero R Erez O Hüttemann M Maymon E Panaitescu B Conde-Agudelo A et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. (2017) 217:282–302. 10.1016/j.ajog.2017.06.00328619690
Tertti K Laine K Ekblad U Rinne V Ronnemaa T. The degree of fetal metformin exposure does not influence fetal outcome in gestational diabetes mellitus. Acta Diabetol. (2014) 51:731–8. 10.1007/s00592-014-0570-6
Vanky E Zahlsen K Spigset O Carlsen SM. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. (2005) 83:1575–8. 10.1016/j.fertnstert.2004.11.05115866611
Salomäki H Vähätalo LH Laurila K Jäppinen NT Penttinen A-M Ailanen L et al. Prenatal metformin exposure in mice programs the metabolic phenotype of the offspring during a high fat diet at adulthood. PLoS ONE (2013) 8:e56594. 10.1371/journal.pone.005659423457588
Wilcock C Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica (1994) 24:49–57. 10.3109/004982594090432208165821
Rowan JA Rush EC Obolonkin V Battin M Wouldes T Hague WM. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care (2011) 34:2279–84. 10.2337/dc11-066021949222
Ijäs H Vääräsmäki M Saarela T Keravuo R Raudaskoski T. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months. BJOG (2015) 122:994–1000. 10.1111/1471-0528.1296425039582
Hjorth-Hansen A Salvesen Ø Hanem LGE Eggebø T Salvesen KA Vanky E et al. Fetal growth and birth anthropometrics in metformin-exposed offspring born to mothers with PCOS. J Clin Endocrinol Metab. (2018) 103:740–7. 10.1210/jc.2017-0119129165598
Hanem LGE Stridsklev S Júlíusson PB Salvesen Ø Roelants M Carlsen SM et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age; follow-up of two RCTs. J Clin Endocrinol Metab. (2018) 103:1612–21. 10.1210/jc.2017-02419
Tertti K Toppari J Virtanen HE Sadov S Rönnemaa T. Metformin treatment does not affect testicular size in offspring born to mothers with gestational diabetes. Rev Diabet Stud. (2016) 13:59–65. 10.1900/RDS.2016.13.59
Ibáñez L López-Bermejo A Díaz M Marcos MV de Zegher F. Early metformin therapy (age 8-12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess, and oligomenorrhea in adolescence. J Clin Endocrinol Metab. (2011) 96:E1262–7. 10.1210/jc.2011-055521632811
Ibáñez L Ong K Valls C Marcos MV Dunger DB de Zegher F. Metformin treatment to prevent early puberty in girls with precocious pubarche. J Clin Endocrinol Metab. (2006) 91:2888–91. 10.1210/jc.2006-033616684823
Trautwein C Kümmerer K. Incomplete aerobic degradation of the antidiabetic drug Metformin and identification of the bacterial dead-end transformation product Guanylurea. Chemosphere (2011) 85:765–73. 10.1016/j.chemosphere.2011.06.05721752423
Khan U Nicell J. Human health relevance of pharmaceutically active compounds in drinking water. AAPS J. (2015) 17:558–85. 10.1208/s12248-015-9729-525739816
Blair BD Crago JP Hedman CJ Klaper RD. Pharmaceuticals and personal care products found in the Great Lakes above concentrations of environmental concern. Chemosphere (2013) 93:2116–23. 10.1016/j.chemosphere.2013.07.05723973285
Ter Laak T Baken K. The occurrence, fate and ecological and human health risks of metformin and guanylurea in the water cycle–a literature review. KWR (2014) 1–24.
Niemuth NJ Klaper RD. Emerging wastewater contaminant metformin causes intersex and reduced fecundity in fish. Chemosphere (2015) 135:38–45. 10.1016/j.chemosphere.2015.03.06025898388
Puscheck EE Bolnick A Awonuga A Yang Y Abdulhasan M Li Q et al. Why AMPK agonists not known to be stressors may surprisingly contribute to miscarriage or hinder IVF/ART. J Assist Reprod Genet. (2018) 35:1359–66. 10.1007/s10815-018-1213-629882092
Zhong T Men Y Lu L Geng T Zhou J Mitsuhashi A et al. Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene (2017) 36:2345–54. 10.1038/onc.2016.39127775072
Cuyàs E Fernández-Arroyo S Verdura S García RÁF Stursa J Werner L et al. Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism. Oncogene (2018) 37:963–70. 10.1038/onc.2017.36729059169
Zhang Q Li S Li L Li Q Ren K Sun X et al. Metformin treatment and homocysteine: a systematic review and meta-analysis of randomized controlled trials. Nutrients (2016) 8:E798: 10.3390/nu812079827941660
Bridgeman SC Ellison GC Melton PE Newsholme P Mamotte CDS. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes Metab. (2018) 20:1553–62. 10.1111/dom.1326229457866
Banerjee P Surendran H Chowdhury DR Prabhakar K Pal R. Metformin mediated reversal of epithelial to mesenchymal transition is triggered by epigenetic changes in E-cadherin promoter. J Mol Med. (2016) 94:1397–409. 10.1007/s00109-016-1455-727534967
Khan S Jena G. Sodium butyrate reduces insulin-resistance, fat accumulation and dyslipidemia in type-2 diabetic rat: a comparative study with metformin. Chem Biol Interact. (2016) 254:124–34. 10.1016/j.cbi.2016.06.00727270450
Bungard D Fuerth BJ Zeng P-Y Faubert B Maas NL Viollet B et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science (2010) 329:1201–5. 10.1126/science.119124120647423
Tang G Guo J Zhu Y Huang Z Liu T Cai J et al. Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation. Int J Oncol. (2018) 52:1899–911. 10.3892/ijo.2018.434329620187
Bertoldo MJ Guibert E Faure M Guillou F Ramé C Nadal-Desbarats L et al. Specific deletion of AMP-activated protein kinase (α1AMPK) in mouse Sertoli cells modifies germ cell quality. Mol Cell Endocrinol. (2016) 423:96–112. 10.1016/j.mce.2016.01.00126772142
Vigili de Kreutzenberg S Ceolotto G Cattelan A Pagnin E Mazzucato M Garagnani P et al. Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. Nutr Metab Cardiovasc Dis. (2015) 25:686–93. 10.1016/j.numecd.2015.03.00725921843
Caton PW Nayuni NK Kieswich J Khan NQ Yaqoob MM Corder R. Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. J Endocrinol. (2010) 205:97–106. 10.1677/JOE-09-034520093281
Zhang E Guo Q Gao H Xu R Teng S Wu Y. Metformin and resveratrol inhibited high glucose-induced metabolic memory of endothelial senescence through SIRT1/p300/p53/p21 pathway. PLoS ONE (2015) 10:e0143814. 10.1371/journal.pone.014381426629991
Lennox R Porter DW Flatt PR Holscher C Irwin N Gault VA. Comparison of the independent and combined effects of sub-chronic therapy with metformin and a stable GLP-1 receptor agonist on cognitive function, hippocampal synaptic plasticity and metabolic control in high-fat fed mice. Neuropharmacology (2014) 86:22–30. 10.1016/j.neuropharm.2014.06.02624998752
Bertoldo MJ Guibert E Tartarin P Guillory V Froment P. Effect of metformin on the fertilizing ability of mouse spermatozoa. Cryobiology (2014) 68:262–8. 10.1016/j.cryobiol.2014.02.00624556364
Adaramoye O Akanni O Adesanoye O Labo O. Evaluation of toxic effects of metformin hydrochloride and glibenclamide on some organs of male rats. Niger J Physiol Sci. (2012) 27:137–44. 23652227
