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Diabetologia

Erschienen in:

03.08.2017 | Review

Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome

verfasst von: Susan Sam, David A. Ehrmann

Erschienen in: Diabetologia | Ausgabe 9/2017

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Abstract

Polycystic ovary syndrome (PCOS), the most common hormonal disorder among women of reproductive age, has various metabolic and reproductive consequences. Metformin was originally shown to lower testosterone levels in women with PCOS in the 1990s, an effect presumably related to its insulin sensitising actions. However, the precise mechanisms of metformin action in PCOS remain unclear and there is considerable heterogeneity in the clinical response to this therapy in women with PCOS. Recent evidence indicates that genetic factors may play a significant role in predicting response to metformin therapy in PCOS and future studies are needed to further identify women who are most likely to benefit from this therapy. At present, there is no clear evidence to support broad metformin use in PCOS. Well-designed prospective trials are needed to establish clear benefit for metformin use in the treatment of the reproductive and metabolic consequences associated with PCOS.

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Stein I, Leventhal M (1935) Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181–191CrossRef

Burghen GA, Givens JR, Kitabchi AE (1980) Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50:113–116CrossRefPubMed

Chang RJ, Nakamura RM, Judd HL, Kaplan SA (1983) Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 57:356–359CrossRefPubMed

Dunaif A, Segal KR, Futterweit W, Dobrjansky A (1989) Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174CrossRefPubMed

Legro RS, Kunselman AR, Dodson WC, Dunaif A (1999) Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 84:165–169PubMed

Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J (1999) Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22:141–146CrossRefPubMed

Apridonidze T, Essah PA, Iuorno MJ, Nestler JE (2005) Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:1929–1935CrossRefPubMed

Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN (2006) Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 91:48–53CrossRefPubMed

Legro RS, Kunselman AR, Dunaif A (2001) Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 111:607–613CrossRefPubMed

10.

Talbott E, Clerici A, Berga SL et al (1998) Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study. J Clin Epidemiol 51:415–422CrossRefPubMed

11.

Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T (1992) Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41:1257–1266CrossRefPubMed

12.

Dunaif A, Graf M (1989) Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 83:23–29CrossRefPubMedPubMedCentral

13.

Micic D, Popovic V, Nesovic M et al (1988) Androgen levels during sequential insulin euglycemic clamp studies in patients with polycystic ovary disease. J Steroid Biochem 31:995–999CrossRefPubMed

14.

Nestler JE, Barlascini CO, Matt DW et al (1989) Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 68:1027–1032CrossRefPubMed

15.

Nestler JE, Powers LP, Matt DW et al (1991) A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72:83–89CrossRefPubMed

16.

Nestler JE, Jakubowicz DJ (1996) Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617–623CrossRefPubMed

17.

Nestler JE, Jakubowicz DJ (1997) Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab 82:4075–4079PubMed

18.

Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH (2010) Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev, Issue 1, Art. no.:CD003053. DOI: 10.1002/14651858.CD003053.pub4

19.

Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH (2012) Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev, Issue 5, Art. no.:CD003053. DOI: 10.1002/14651858.CD003053.pub5

20.

Zhou K, Donnelly L, Yang J et al (2014) Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis. Lancet Diabetes Endocrinol 2:481–487CrossRefPubMedPubMedCentral

21.

Zhou K, Yee SW, Seiser EL et al (2016) Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet 48:1055–1059CrossRefPubMedPubMedCentral

22.

Jablonski KA, McAteer JB, de Bakker PI et al (2010) Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes 59:2672–2681CrossRefPubMedPubMedCentral

23.

Pau CT, Cheang KI, Modi BP et al (2016) The role of variants regulating metformin transport and action in women with polycystic ovary syndrome. Pharmacogenomics 17:1765–7173CrossRef

24.

Schweighofer N, Lerchbaum E, Trummer O, Schwetz V, Pieber T, Obermayer-Pietsch B (2014) Metformin resistance alleles in polycystic ovary syndrome: pattern and association with glucose metabolism. Pharmacogenomics 15:305–317CrossRefPubMed

25.

Gambineri A, Tomassoni F, Gasparini DI et al (2010) Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 95:E204–E208CrossRefPubMed

26.

Legro RS, Barnhart HX, Schlaff WD et al (2008) Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J Clin Endocrinol Metab 93:792–800CrossRefPubMed

27.

Diaz M, Lopez-Bermejo A, Sanchez-Infantes D, Bassols J, de Zegher F, Ibanez L (2011) Responsiveness to metformin in girls with androgen excess: collective influence of genetic polymorphisms. Fertil Steril 96:208–213CrossRefPubMed

28.

Shu Y, Brown C, Castro RA et al (2008) Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 83:273–280CrossRefPubMed

29.

El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228CrossRefPubMed

30.

Rena G, Hardie DG, Pearson ER (2017) The mechanisms of action of metformin. Diabetologia. DOI:10.1007/s00125-017-4342-z

31.

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ (2013) Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494:256–260CrossRefPubMedPubMedCentral

32.

Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN (2010) Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol 162:193–212CrossRefPubMed

33.

McCartney CR, Marshall JC (2016) Polycystic ovary syndrome. N Engl J Med 375:54–64CrossRefPubMedPubMedCentral

34.

Kurzthaler D, Hadziomerovic-Pekic D, Wildt L, Seeber BE (2014) Metformin induces a prompt decrease in LH-stimulated testosterone response in women with PCOS independent of its insulin-sensitizing effects. Reprod Biol Endocrinol 12:1–6CrossRef

35.

Hirsch A, Hahn D, Kempna P et al (2012) Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Endocrinology 153:4354–4366CrossRefPubMed

36.

Lee BH, Indran IR, Tan HM et al (2016) A dietary medium-chain fatty acid, decanoic acid, inhibits recruitment of Nur77 to the HSD3B2 promoter in vitro and reverses endocrine and metabolic abnormalities in a rat model of polycystic ovary syndrome. Endocrinology 157:382–394CrossRefPubMed

37.

Legro RS, Arslanian SA, Ehrmann DA et al (2013) Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 98:4565–4592CrossRefPubMedPubMedCentral

38.

Goodman NF, Cobin RH, Futterweit W et al (2015) American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome - part 1. Endocr Pract 21:1291–1300CrossRefPubMed

39.

Pirwany IR, Yates RW, Cameron IT, Fleming R (1999) Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum Reprod 14:2963–2968CrossRefPubMed

40.

Pau CT, Keefe C, Duran J, Welt CK (2014) Metformin improves glucose effectiveness, not insulin sensitivity: predicting treatment response in women with polycystic ovary syndrome in an open-label, interventional study. J Clin Endocrinol Metab 99:1870–1878CrossRefPubMedPubMedCentral

41.

Mansfield R, Galea R, Brincat M, Hole D, Mason H (2003) Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril 79:956–962CrossRefPubMed

42.

Attia GR, Rainey WE, Carr BR (2001) Metformin directly inhibits androgen production in human thecal cells. Fertil Steril 76:517–524CrossRefPubMed

43.

Cosma M, Swiglo BA, Flynn DN et al (2008) Clinical review: insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab 93:1135–1142CrossRefPubMed

44.

Martin KA, Chang RJ, Ehrmann DA et al (2008) Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1105–1120CrossRefPubMed

45.

Balen AH, Morley LC, Misso M et al (2016) The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update 22:687–708CrossRefPubMed

46.

Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A (1998) Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 138:269–274CrossRefPubMed

47.

Palomba S, Falbo A, Russo T et al (2007) Insulin sensitivity after metformin suspension in normal-weight women with polycystic ovary syndrome. J Clin Endocrinol Metab 92:3128–3135CrossRefPubMed

48.

Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS (1997) Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:524–530PubMed

49.

Naderpoor N, Shorakae S, de Courten B, Misso ML, Moran LJ, Teede HJ (2015) Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update 21:560–574CrossRefPubMed

50.

Costello MF, Shrestha B, Eden J, Johnson NP, Sjoblom P (2007) Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. Hum Reprod 22:1200–1299CrossRefPubMed

51.

Knowler WC, Barrett-Connor E, Fowler SE et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403CrossRefPubMed

52.

Pasquali R, Gambineri A, Biscotti D et al (2000) Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 85:2767–2774CrossRefPubMed

Titel: Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome
verfasst von: Susan Sam
David A. Ehrmann
Publikationsdatum: 03.08.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 9/2017
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-017-4306-3

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