[en] Metformin is an oral anti-hyperglycemic drug that acts as an insulin sensitizer in the treatment of diabetes mellitus type 2. It has also been widely used in the treatment of polycystic ovary syndrome (PCOS) and gestational diabetes. This drug has been shown to activate a protein kinase called 5' AMP-activated protein kinase or AMPK. AMPK is present in many tissues making metformin's effect multi factorial. However as metformin crosses the placenta, its use during pregnancy raises concerns regarding potential adverse effects on the mother and fetus. The majority of reports suggest no significant adverse effects or teratogenicity. However, disconcerting reports of male mouse offspring that were exposed to metformin in utero that present with a reduction in testis size, seminiferous tubule size and in Sertoli cell number suggest that we do not understand the full suite of effects of metformin. In addition, recent molecular evidence is suggesting an epigenetic effect of metformin which could explain some of the long-term effects reported. Nevertheless, the data are still insufficient to completely confirm or disprove negative effects of metformin. The aims of this review are to provide a summary of the safety of metformin in various aspects of sexual reproduction, the use of metformin by gestating mothers, and its possible side-effects on offspring from women who are administered metformin during pregnancy.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Bertoldo, Michael J; Unité de Physiologie de la Reproduction et des Comportements, Institut National
Faure, Mélanie ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Neuroendocrinology ; Unité de Physiologie de la Reproduction et des Comportements, Institut National
Dupont, Joelle; Unité de Physiologie de la Reproduction et des Comportements, Institut National
Froment, Pascal; Unité de Physiologie de la Reproduction et des Comportements, Institut National
Language :
English
Title :
Impact of metformin on reproductive tissues: an overview from gametogenesis to gestation.
Simmons D. Metformin treatment for Type 2 diabetes in pregnancy? Best Pract Res Clin Endocrinol Metab 2010;24:625-34.
Hawthorne G. Metformin use and diabetic pregnancy-has its time come? Diabet Med 2006;23:223-7.
Wilcock C, Wyre ND, Bailey CJ. Subcellular distribution of metformin in rat liver. J Pharm Pharmacol 1991;43:442-4.
Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1994;24:49-57.
Detaille D, Guigas B, Levere X, et al. Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function. Biochem Pharmacol 2002;63:1259-72.
Shu Y, Sheardown SA, Brown C, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007;117:1422-31.
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;348 Pt 3:607-14.
Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-74.
Viollet B, Guigas B, Leclerc J, et al. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol (Oxf) 2009;196:81-98.
Hardie DG, MacKintosh RW. AMP-activated protein kinase-an archetypal protein kinase cascade? Bioessays 1992;14:699-704.
Rattan R, Giri S, Hartmann LC, et al. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med 2011;15:166-78.
Foretz M, Hebrard S, Leclerc J, 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.
Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010;11:390-401.
Nestler JE, Jakubowicz DJ, Evans WS, et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876-80.
Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001;75:310-5.
De Leo V, la Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation in women with poly-cystic ovary syndrome. Fertil Steril 1999;72:282-5.
Pal L, Chu HP, Shu J, et al. In vitro evidence of glucose-induced toxicity in GnRH secreting neurons: High glucose concentrations influence GnRH. Fertil Steril 2007;88:1143-9.
Gamba M, Pralong FP. Control of GnRH neuronal activity by metabolic factors: the role of leptin and insulin. Mol Cell Endocrinol 2006;254-255:133-9.
Coyral-Castel S, Tosca L, Ferreira G, et al. The effect of AMP-activated kinase activation on gonadotrophin-releasing hormone secretion in GT1-7 cell and its potential role in hypothalamic regulation of the oestrous cyclicity in rats. J Neuroendocrinol 2008;20:335-46.
Andersson U, Flilipsson K, Abbott CR, et al. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 2004;279:12005-8.
Han SM, Namkoong C, Jang PG, et al. Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats. Diabetologia 2005;48:2170-8.
Kim EK, Miller I, Aja S, et al. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 2004;279:19970-6.
Claret M, Smith MA, Batterham RL, et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 2007;117:2325-36.
Minokoshi Y, Alquier T, Furukawa N, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004;428:569-74.
Chau-Van C, Gamba M, Salvi R, et al. Merformin inhibits adenosine 5'-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology 2007;148:507-11.
Wen JP, Liu C, Bi WK, et al. Adiponectin inhibits KISS1 gene transcription through AMPK and specificity protein-1 in the hypothalamic GT1-7 neurons. J Endocrinol 2012;214:177-89.
Menassol JB, Tautou C, Collet A, et al. The effect of an intracerebroventricular injection of metformin or AICAR on the plasma concentrations of melatonin in the ewe: potential involvement of AMPK? BMC Neurosci 2011;12:76.
Tosca L, Froment P, Rame C, et al. Metformin decreases GnRH-and activin-induced gonadotropin secretion in rat pituitary cells: potential involvement of adenosine 5' monophosphate-activated protein kinase (PRKA). Biol Reprod 2011;84:351-62.
Oride A, Kanasaki H, Purwana IN, et al. Effects of metformin administration on plasma gonadotropin levels in women with infertility, with an in vitro study of the direct effects on the pituitary gonadotrophs. Pituitary 2010;13:236-41.
Billa E, Kapolla N, Nicopoulou SC, et al. Metformin administration was associated with a modification of LH, prolacting and insulin secretion dynanmics in women with polycystic ovarian syndrome. Gynecol Endocrinol 2009;25:427-34.
Genazzani AD, Battaglia C, Malavasi B, et al. Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril 2004;81:114-9.
Glueck CJ, Wang P, Fontaine R, et al. Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS). J Adolesc Health 2001;29:160-9.
Glueck CJ, Wang P, Fontaine R, et al. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 1999;48:511-9.
Lu M, Tang Q, Olefsky JM, et al. Adiponectinb activates adenosine monophosphate-activated kinase and decreases luteinizing hormone secretion in LbetaT2 gonadotropes. Mol Endocrinol 2008;22:760-71.
De Souza MJ, Arce JC, Pescatello LS, et al. Gonadal hormones and semen quality in male runners. A volume threshold effect of endurance training. Int J Sports Med 1994;15:383-91.
Hammoud AO, Wilde N, Gibson M, et al. Male obesity and alteration in sperm parameters. Fertil Steril 2008;90:2222-5.
Collier JG, Flower RJ, Stanton SL. Seminal prostaglandins in infertile men. Fertil Steril 1975;26:868-71.
Retterstøl K, Haugen TB, Tran TN, et al. Studies on the metabolism of essential fatty acids in isolated human testicular cells. Reproduction 2001;121:881-7.
Galardo MN, Riera MF, Pellizzari EH, et al. The AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-b-D-ribonucleoside, regulates lactate production in rat Sertoli cells. J Mol Endocrinol 2007;39:279-88.
Tosca L, Crochet S, Ferré P, et al. AMP-activated protein kinase activation moduclates progesteone secretion in granulosa cells from hen preovulatory follicles. J Endocrinol 2006;190:85-97.
Tosca L, Solnais P, Ferre P, et al. Metformin-induced stimulation of adenosine 5' monophosphate-activated protein kinase (PRKA) impairs progesterone secretion in rat granulosa cells. Biol Reprod 2006;75:342-51.
Tosca L, Chabrolle C, Uzbekova S, et al. Effects of metformin on bovine granulosa cells steroidogenesis: possible involvement of adenosine 5' monophosphate-activated protein kinase (AMPK). Biol Reprod 2007;76:368-78.
Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertil Steril 2001;76:517-24.
Will MA, Palaniappan M, Peegel H, et al. Metformin: Direct inhibition of rat ovarian theca-interstitial cell proliferation. Fertil Steril 2012;98:207-14.
Tosca L, Uzbekova S, Chabrolle C, et al. 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.
Kayampilly PP, Menon KMJ. AMPK activation by dihydrotestosterone reduces FSH-stimulated cell proliferation in rat granulosa cells by inhibiting ERK signaling pathway. Endocrinology 2012;153:2831-8.
Downs SM, Davis CC. Role of AMPK throughout meiotic maturation in the mouse oocyte: Evidence for promoation of polar body formation and supression of premature activation. Mol Reprod Dev 2010;77:888-99.
Tartarin P, Moison D, Guibert E, et al. Metformin exposure affects human and mouse fetal testicular cells. Hum Reprod 2012;27:3304-14.
Riera MF, Regueira M, Galardo MN, et al. Signal transduction pathways in FSH regulation of rat Sertoli cell proliferation. Am J Physiol Endocrinol Metab 2012;302:E914-23.
Bertoldo MJ, Guibert E, Tartarin P, et al. Effect of metformin on the fertilizing ability of mouse spermatozoa. Cryobiology 2014;68:262-8.
Naglaa ZHE, Hesham AM, Fadil HA, et al. Impact of metformin on immunity and male fertility in rabbits with alloxan-induced diabetes. Journal of American Science 2010;6:417-26.
Renner HW, Münzner R. Mutagenicity of sulphonylureas. Mutat Res 1980;77:349-55.
Bedir A, Aliyazicioglu Y, Kahraman H, et al. Genotoxicity in rats treated with the antidiabetic agent, rosiglitazone. Environ Mol Mutagen 2006;47:718-24.
Branco CS, Garcez ME, Pasqualotto FF, et al. Resveratrol and ascorbic acid prevent DNA damage induced by cryopreservation in human semen. Cryobiology 2010;60:235-7.
Collodel G, Federico MG, Geminiani M, et al. Effect of trans-resveratrol on induced oxidative stress in human sperm and in rat germinal cells. Reprod Toxicol 2011;31:239-46.
Garcez ME, dos Santos Branco C, Lara LV, et al. Effects of resveratrol supplementation on cryopreservation medium of human semen. Fertil Steril 2010;94:2118-21.
Rider MH, Hussain N, Horman S, et al. Stress-induced activation of the AMP-activated protein kinase in the freeze tolerant frog Rana sylvatica. Cryobiology 2006;53:297-309.
Storey KB. Reptile freeze tolerance: Metabolism and gene expression. Cryobiology 2006;52:1-16.
Hurtado de Llera A, martin-Hidago D, Gil MC, et al. The AMPK activator metformin inhibits one of the main functions of boar spermatozoa, motility. FEBS Journal 2012;279 Suppl 1:52-576.
Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774-800.
Misso ML, Costello MF, Garrubba M, et al. Metformin versus clomiphene citrate for infertility in non-obese women with polycyctic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2013;19:2-11.
Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;19:2474-83.
Rice S, Pellatt L, Ramanathan K, et al. Metformin inhibits aromatase via an extracellular signal-regulated kinase-mediated pathway. Endocrinology 2009;150:4794-801.
Ibáñez L, López-Bermejo A, Díaz M, et al. 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.
Palomba S, Falbo A, Russo T, et al. Systemic and local effects of metformin administration in patients with polycystic ovary syndrome (PCOS): relationship to the ovulatory response. Hum Reprod 2010;25:1005-13.
Kocak I, Ustün C. Effects of metformin on insulin resistance, androgen concentration, ovulation and pregnancy rates in women with polycystic ovary syndrome following laparoscopic ovarian drilling. J Obstet Gynaecol Res 2006;32:292-8.
Bouchard P. Treatment of infertility in women with polycystic ovary syndrome. Ann Endocrinol (Paris) 2010;71:225-7.
Mansfield R, Galea R, Brincat M, et al. Metformin has direct effect on human ovarian steroidogenesis. Fertil Steril 2003;79:956-62.
Richardson MC, Ingamells S, Simonis CD, 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.
Kayampilly PP, Menon KM. Follicle-stimulating hormone inhibits adenosine 5'-monophosphate-activated protein kinase activation and promotes cell proliferation of primary granulosa cells in culture through an Akt-dependent pathway. Endocrinology 2009;150:929-35.
Hou X, Arvisais EW, Davis JS. Luteinizing hormone stimulates mammalian target of rapamycin signaling in bovine luteal cells via pathways independent of AKT and mitogen-activated protein kinase: modulation of glycogen synthase kinase 3 and AMP-activated protein kinase. Endocrinology 2010;151:2846-57.
Reverchon M, Cornuau M, Cloix L, et al. Visfatin is expressed in human granulosa cells: regulation by metformin through AMPK/SIRT1 pathways and its role in steroidogenesis. Mol Hum Reprod 2013;19:313-26.
Mayes MA, Laforest MF, Guillemette C, et al. Adenosine 5'-monophosphate kinase-activated protein kinase (PRKA) activators delay meiotic resumption in porcine oocytes. Biol Reprod 2007;76:589-97.
Stricker SA. Potential upstream regulators and downstream targets of AMP-activated kinase signaling during oocyte maturation in a marine worm. Reproduction 2011;142:29-39.
Glueck CJ, Wang P, Goldenberg N, et al. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002;17:2858-64.
Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al. Effects of metformin on early pregnancy loss in the polucystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524-9.
Khattab S, Mohsen IA, Foutouh IA, et al. Metformin reduces abortion in pregnant women with polycystic ovary syndrome. Gynecol Endocrinol 2006;22:680-4.
Nawaz FH, Khalid R, Naru T, et al. Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with poycystic ovarian syndrome. J Obstet Gynaecol Res 2008;34:832-7.
De Leo V, Musacchio MC, Piomboni P, et al. The administration of metformin during pregnancy reduces polycystic ovary syndrome related gestational complications. Eur J Obstet Gynecol Reprod Biol 2011;157:63-6.
Glueck CJ, Goldenberg N, PranikoffJ, et al. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod 2004;19:1323-30.
Kovo M, Weissman A, Gur D, et al. Neonatal outcome in polycystic ovarian syndrome patients treated with metformin during pregnancy. J Matern Fetal Neonatal Med 2006;19:415-9.
Bolton S, Cleary B, Walsh J, et al. Continuation of metformin in the first trimester of women with polycystic ovarian syndrome is not associated with increased perinatal morbidity. Eur J Pediatr 2009;168:203-6.
Carlsen SM, Vanky E. Metformin influence on hormone levels at birth, in PCOS mothers and their newborns. Hum Reprod 2010;25:786-90.
Niromanesh S, Alavi A, Sharbaf FR, et al. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res Clin Pract 2012;98:422-9.
Gandhi P, Bustani R, Madhuvrata P, et al. Introduction of metformin for gestational diabetes mellitus in clinical practice: Has it had an impact? Eur J Obstet Gynecol Reprod Biol 2012;160:147-50.
Tertti K, Ekblad U, Vahlberg T, et al. Comparison of metformin and insulin in the treatment of gestational diabetes: a retrospective, case-control study. Rev Diabet Stud 2008;5:95-101.
Ijäs H, Vääräsmaki M, Morin-Papunen L, et al. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG 2011;118:880-5.
Carlsen SM, Martinussen MP, Vanky E. Metformin's effect on first-year weight gain: a follow-up study. Pediatrics 2012;130:e1222-6.
Kovo M, Haroutiunian S, Feldman N, et al. Determination of metformin transfer across the human placenta using a dually perfused ex vivo placental cotyledon model. Eur J Obstet Gynecol Reprod Biol 2008;136:29-33.
Vanky E, Zahlsen K, Spigset O, et al. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril 2005;83:1575-8.
Salomäki H, Vähätalo LH, Laurila K, 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.
Lautatzis M-E, Goulis DG, Vrontakis M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: A systematic review. Metabolism 2013;62:1522-34.
Charles B, Norris R, Xiao X, et al. Population pharmacokinetics of metformin in late pregnancy. Ther Drug Monit 2006;28:67-72.
Hughes RC, Gardiner SJ, Begg EJ, et al. Effect of pregnancy on the pharmacokinetics of metformin. Diabet Med 2006;23:323-6.
Eyal S, Easterling TR, Carr D, et al. Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos 2010;38:833-40.
Langer O, Yogev Y, Most O, et al. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol 2005;192:989-97.
Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477-86.
Gutzin SJ, Kozer E, Magee LA, et al. The safety of oral hypoglycemic agents in the first trimester of pregnancy: a meta-analysis. Can J Clin Pharmacol 2003;10:179-83.
Balani J, Hyer SL, Rodin DA, et al. Pregnancy outcomes in women with gestational diabetes with metformin or insulin: a case-control study. Diabet Med 2009;26:798-802.
Rowan JA, Hague W, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-15.
Rowan JA, Rush EC, Obolonkin V, et al. Metformin in gestational diaabetes: the offspring follow-up (MiG TOFU): body composition at 2 years. Diabetes Care 2011;34:2279-84.
Ekpebegh CO, Coetzee EJ, van de Merwe L, et al. A 10-year retrospective analysis of pregnancy outcome in pregestational Type 2 diabetes: comparison of insulin and oral glucose-lowering agents. Diabet Med 2007;24:253-8.
Harris EL. Adverse reactions to oral antidiabetic agents. BMJ 1971;3:29-30.
Habert R, Lejeune H, Saez JM. Origin, differentiation and regulation of fetal and adult Leydig cells. Mol Cell Endocrinol 2001;179:47-74.
Tapanainen J, Kellokumpu-Lehtinen P, Pelliniemi L, et al. Age-related changes in endogenous steroids of human fetal testis during early and midpregnancy. J Clin Endocrinol Metab 1981;52:98-102.
Lambrot R, Livera G, Coffigny H, et al. A new method for toxicity assays on human and mouse fetal testis. Biochimie 2006;88:1831-5.
Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16:972-8.
Rø TB, Ludvigsen HV, Carlsen SM, et al. Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. Scand J Clin Lab Invest 2012;72:570-5.
Vanky E, Carlsen SM. Androgens and antimullerian hormone in mothers with polycystic ovary syndrome and their newborns. Fertil Steril 2012;97:509-15.
Petersen C, Soder O. The sertoli cell-a hormonal target and 'super' nurse for germ cells that determines testicular size. Horm Res 2006;66:153-61.
Chen J, Hudson E, Chi MM, et al. AMPK regulation of mouse oocyte meiotic resumption in vitro. Dev Biol 2006;291:227-38.
Bungard D, Fuerth BJ, Zeng P-Y, et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 2010;329:1201-5.
Caton PW, Nayumi NK, Kieswich J, et al. Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. J Endocrinol 2010;205:97-106.
Choi E, Han C, Park I, et al. A Novel Germ Cell-specific Protein, SHIP1, Forms a Complex with Chromatin Remodeling Activity during Spermatogenesis. J Biol Chem 2008;283:35283-94.
Hazzouri M, Pivot-Pajot C, Faure A-K, et al. Regulated hyperacetylation of core histones during mouse spermatogenesis: involvement of histione-deacetylases. Eur J Cell Biol 2000;79:950-60.
Yan W, Si Y, Slaymaker S, et al. Zmynd15 encodes a histone deacetylase-dependent transcriptional repressor essential for spermiogenesis and male fertility. J Biol Chem 2010;285:31418-26.
Ghazeeri GS, Nassar AH, Younes Z, et al. Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview. Acta Obstet Gynecol Scand 2012;91:658-78.
Norman RJ, Wang JX, Hague W. Should we continue or stop insulin sensitizing drugs during pregnancy? Curr Opin Obstet Gynecol 2004;16:245-50.