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Published in: BMC Endocrine Disorders 1/2024

Open Access 01-12-2024 | Metformin | Research

Effect of metformin on anti-mullerian hormone levels in women with polycystic ovarian syndrome: a systematic review and meta-regression analysis of randomized controlled trials with

Authors: Mehdi Mehdinezhad Roshan, Mohammad Hassan Sohouli, Elma Izze da Silva Magalhães, Azita Hekmatdoost

Published in: BMC Endocrine Disorders | Issue 1/2024

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Abstract

Background

Several interventional studies have evaluated the potential anti-Mullerian hormone (AMH)-reduction effect of metformin. However, the results are still contradictory. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of metformin on AMH in the women with with polycystic ovarian syndrome (PCOS).

Methods

Scopus, PubMed/Medline, Web of Science, Cochrane, and Embase databases were searched using standard keywords to identify all controlled trials investigating the AMH levels following metformin administration. Pooled weighted mean difference and 95% confidence intervals were achieved by random-effects model analysis for the best estimation of outcomes.

Results

Sixteen studies with 484 participants’ were included in this article. The pooled findings showed that AMH levels in the single arm clinical trials were significantly reduced (pooled WMD of -3.06 ng/ml; 95% confidence interval [CI] -4.03 to -2.10; P < 0.001) after use of metformin. Furthermore, compared to the control group, in randomized clinical trials, a reduced significant effect on AMH levels was observed following use of metformin (pooled WMD of -3.47 ng/ml; 95% CI -7.14 to -0.19; P = 0.047). Furthermore, higher reduction in the AMH levels with a metformin dosage ≤ 1500 mg/day and duration of treatment ≤ 12 weeks when compared to higher dosages and duration of intervention, observed in this meta-analysis.

Conclusions

In conclusion, results this meta-analysis of clinical trials confirms the beneficial effect of the treatment with metformin in the reduction of the AMH levels in women.
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Literature
1.
go back to reference Grootegoed JA, Baarends WM, Themmen AP. Welcome to the family: the anti-müllerian hormone receptor. Mol Cell Endocrinol. 1994;100(1–2):29–34. PubMed PMID: 8056154. eng.CrossRefPubMed Grootegoed JA, Baarends WM, Themmen AP. Welcome to the family: the anti-müllerian hormone receptor. Mol Cell Endocrinol. 1994;100(1–2):29–34. PubMed PMID: 8056154. eng.CrossRefPubMed
2.
go back to reference Grynnerup AG, Lindhard A, Sørensen S. The role of anti-Müllerian hormone in female fertility and infertility - an overview. Acta Obstet Gynecol Scand. 2012;91(11):1252–60. PubMed PMID: 22646322. eng.CrossRefPubMed Grynnerup AG, Lindhard A, Sørensen S. The role of anti-Müllerian hormone in female fertility and infertility - an overview. Acta Obstet Gynecol Scand. 2012;91(11):1252–60. PubMed PMID: 22646322. eng.CrossRefPubMed
3.
go back to reference Dumont A, Robin G, Catteau-Jonard S, Dewailly D. Role of Anti-Müllerian hormone in pathophysiology, diagnosis and treatment of polycystic ovary syndrome: a review. Reprod Biol Endocrinol. 2015;13:137. PubMed PMID: 26691645. Pubmed Central PMCID: PMC4687350. Epub 20151221. eng.CrossRefPubMedPubMedCentral Dumont A, Robin G, Catteau-Jonard S, Dewailly D. Role of Anti-Müllerian hormone in pathophysiology, diagnosis and treatment of polycystic ovary syndrome: a review. Reprod Biol Endocrinol. 2015;13:137. PubMed PMID: 26691645. Pubmed Central PMCID: PMC4687350. Epub 20151221. eng.CrossRefPubMedPubMedCentral
4.
go back to reference Bhide P, Homburg R. Anti-Müllerian hormone and polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2016;37:38–45. PubMed PMID: 27103234. Epub 20160401. eng.CrossRefPubMed Bhide P, Homburg R. Anti-Müllerian hormone and polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2016;37:38–45. PubMed PMID: 27103234. Epub 20160401. eng.CrossRefPubMed
5.
go back to reference Chhabra N, Malik S. Effect of insulin sensitizers on raised serum anti-mullerian hormone levels in Infertile women with polycystic ovarian syndrome. J Hum Reprod Sci. 2018 Oct-Dec;11(4):348–52. PubMed PMID: 30787519. Pubmed Central PMCID: PMC6333035. eng. Chhabra N, Malik S. Effect of insulin sensitizers on raised serum anti-mullerian hormone levels in Infertile women with polycystic ovarian syndrome. J Hum Reprod Sci. 2018 Oct-Dec;11(4):348–52. PubMed PMID: 30787519. Pubmed Central PMCID: PMC6333035. eng.
6.
go back to reference Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. lippincott Williams & wilkins; 2005. Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. lippincott Williams & wilkins; 2005.
7.
go back to reference Dunaif A. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome—a reappraisal. Nat Clin Pract Endocrinol Metab. 2008;4(5):272–83.CrossRefPubMed Dunaif A. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome—a reappraisal. Nat Clin Pract Endocrinol Metab. 2008;4(5):272–83.CrossRefPubMed
8.
go back to reference Yin W-W, Huang C-C, Chen Y-R, Yu D-Q, Jin M, Feng C. The effect of medication on serum anti-müllerian hormone (AMH) levels in women of reproductive age: a meta-analysis. BMC Endocr Disorders. 2022;22(1):1–14.CrossRef Yin W-W, Huang C-C, Chen Y-R, Yu D-Q, Jin M, Feng C. The effect of medication on serum anti-müllerian hormone (AMH) levels in women of reproductive age: a meta-analysis. BMC Endocr Disorders. 2022;22(1):1–14.CrossRef
9.
go back to reference Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Reviews. 2015;4(1):1.CrossRef Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Reviews. 2015;4(1):1.CrossRef
10.
go back to reference Adams J, Polson D, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J (Clin Res Ed). 1986;293(6543):355–9.CrossRefPubMed Adams J, Polson D, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J (Clin Res Ed). 1986;293(6543):355–9.CrossRefPubMed
11.
go back to reference Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Assessing risk of bias in a randomized trial. Cochrane Handb Syst Reviews Interventions. 2019;205:28. Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Assessing risk of bias in a randomized trial. Cochrane Handb Syst Reviews Interventions. 2019;205:28.
12.
go back to reference Schwingshackl L, Knüppel S, Schwedhelm C, Hoffmann G, Missbach B, Stelmach-Mardas M, et al. Perspective: NutriGrade: a Scoring System to assess and judge the Meta-evidence of Randomized controlled trials and Cohort studies in Nutrition Research. Adv Nutr. 2016;7(6):994–1004. PubMed PMID: 28140319. eng.CrossRefPubMedPubMedCentral Schwingshackl L, Knüppel S, Schwedhelm C, Hoffmann G, Missbach B, Stelmach-Mardas M, et al. Perspective: NutriGrade: a Scoring System to assess and judge the Meta-evidence of Randomized controlled trials and Cohort studies in Nutrition Research. Adv Nutr. 2016;7(6):994–1004. PubMed PMID: 28140319. eng.CrossRefPubMedPubMedCentral
14.
17.
go back to reference Wiweko B, Susanto CA. The effect of metformin and cinnamon on serum anti-mullerian hormone in women having PCOS: a Double-blind, randomized, controlled trial. J Hum Reproductive Sci. 2017;10(1):31. Wiweko B, Susanto CA. The effect of metformin and cinnamon on serum anti-mullerian hormone in women having PCOS: a Double-blind, randomized, controlled trial. J Hum Reproductive Sci. 2017;10(1):31.
18.
go back to reference Foroozanfard F, Samimi M, Almadani KH, Sehat M. Effect of metformin on the anti-Müllerian hormone level in infertile women with polycystic ovarian syndrome. Electron Physician. 2017;9(12):5969.CrossRefPubMedPubMedCentral Foroozanfard F, Samimi M, Almadani KH, Sehat M. Effect of metformin on the anti-Müllerian hormone level in infertile women with polycystic ovarian syndrome. Electron Physician. 2017;9(12):5969.CrossRefPubMedPubMedCentral
19.
go back to reference Tagliaferri V, Romualdi D, Immediata V, De Cicco S, Di Florio C, Lanzone A, et al. Metformin vs myoinositol: which is better in obese polycystic ovary syndrome patients? A randomized controlled crossover study. Clin Endocrinol. 2017;86(5):725–30.CrossRef Tagliaferri V, Romualdi D, Immediata V, De Cicco S, Di Florio C, Lanzone A, et al. Metformin vs myoinositol: which is better in obese polycystic ovary syndrome patients? A randomized controlled crossover study. Clin Endocrinol. 2017;86(5):725–30.CrossRef
20.
go back to reference Tomova А, Deepinder F, Robeva R, Kirilov G, Mechandjiev Z, Kumanov P. Anti-Müllerian hormone in women with polycystic ovary syndrome before and after therapy with metformin. Horm Metab Res. 2011;43(10):723–7.CrossRefPubMed Tomova А, Deepinder F, Robeva R, Kirilov G, Mechandjiev Z, Kumanov P. Anti-Müllerian hormone in women with polycystic ovary syndrome before and after therapy with metformin. Horm Metab Res. 2011;43(10):723–7.CrossRefPubMed
21.
go back to reference Sauerbrun-Cutler M, Lederman M, Keltz M, Lee M, Stein D. Serum anti-müllerian hormone levels (AMH) decrease after metformin administration in women with both lean and overweight polycystic ovary syndrome (PCOS). Fertil Steril. 2012;98(3):S213.CrossRef Sauerbrun-Cutler M, Lederman M, Keltz M, Lee M, Stein D. Serum anti-müllerian hormone levels (AMH) decrease after metformin administration in women with both lean and overweight polycystic ovary syndrome (PCOS). Fertil Steril. 2012;98(3):S213.CrossRef
22.
go back to reference Nascimento AD, Lara LAS, Rosa-e-Silva ACJS, Ferriani RA, Reis RM. Effects of metformin on serum insulin and anti-mullerian hormone levels and on hyperandrogenism in patients with polycystic ovary syndrome. Gynecol Endocrinol. 2013;29(3):246–9.CrossRefPubMed Nascimento AD, Lara LAS, Rosa-e-Silva ACJS, Ferriani RA, Reis RM. Effects of metformin on serum insulin and anti-mullerian hormone levels and on hyperandrogenism in patients with polycystic ovary syndrome. Gynecol Endocrinol. 2013;29(3):246–9.CrossRefPubMed
23.
go back to reference Panidis D, Georgopoulos NA, Piouka A, Katsikis I, Saltamavros AD, Decavalas G, et al. The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia. Gynecol Endocrinol. 2011;27(8):587–92.CrossRefPubMed Panidis D, Georgopoulos NA, Piouka A, Katsikis I, Saltamavros AD, Decavalas G, et al. The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia. Gynecol Endocrinol. 2011;27(8):587–92.CrossRefPubMed
24.
go back to reference Neagu M, Cristescu C. Anti-Műllerian hormone–a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome. J Med Life. 2012;5(4):462.PubMedPubMedCentral Neagu M, Cristescu C. Anti-Műllerian hormone–a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome. J Med Life. 2012;5(4):462.PubMedPubMedCentral
25.
go back to reference Romualdi D, De Cicco S, Tagliaferri V, Proto C, Lanzone A, Guido M. The metabolic status modulates the effect of metformin on the antimullerian hormone-androgens-insulin interplay in obese women with polycystic ovary syndrome. J Clin Endocrinol Metabolism. 2011;96(5):E821–4.CrossRef Romualdi D, De Cicco S, Tagliaferri V, Proto C, Lanzone A, Guido M. The metabolic status modulates the effect of metformin on the antimullerian hormone-androgens-insulin interplay in obese women with polycystic ovary syndrome. J Clin Endocrinol Metabolism. 2011;96(5):E821–4.CrossRef
26.
go back to reference Piltonen T, Morin-Papunen L, Koivunen R, Perheentupa A, Ruokonen A, Tapanainen JS. Serum anti-Müllerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome. Hum Reprod. 2005;20(7):1820–6.CrossRefPubMed Piltonen T, Morin-Papunen L, Koivunen R, Perheentupa A, Ruokonen A, Tapanainen JS. Serum anti-Müllerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome. Hum Reprod. 2005;20(7):1820–6.CrossRefPubMed
27.
go back to reference Dursun F, Güven A, Yıldız M. Assessment of anti-Müllerian hormone level in management of adolescents with polycystic ovary syndrome. J Clin Res Pediatr Endocrinol. 2016;8(1):55.CrossRefPubMedPubMedCentral Dursun F, Güven A, Yıldız M. Assessment of anti-Müllerian hormone level in management of adolescents with polycystic ovary syndrome. J Clin Res Pediatr Endocrinol. 2016;8(1):55.CrossRefPubMedPubMedCentral
28.
go back to reference Madsen HN, Lauszus FF, Trolle B, Ingerslev HJ, Tørring N. Impact of metformin on anti-Müllerian hormone in women with polycystic ovary syndrome: a secondary analysis of a randomized controlled trial. Acta Obstet Gynecol Scand. 2015;94(5):547–51.CrossRefPubMed Madsen HN, Lauszus FF, Trolle B, Ingerslev HJ, Tørring N. Impact of metformin on anti-Müllerian hormone in women with polycystic ovary syndrome: a secondary analysis of a randomized controlled trial. Acta Obstet Gynecol Scand. 2015;94(5):547–51.CrossRefPubMed
29.
go back to reference Fleming R, Harborne L, MacLaughlin DT, Ling D, Norman J, Sattar N, et al. Metformin reduces serum müllerian-inhibiting substance levels in women with polycystic ovary syndrome after protracted treatment. Fertil Steril. 2005;83(1):130–6.CrossRefPubMed Fleming R, Harborne L, MacLaughlin DT, Ling D, Norman J, Sattar N, et al. Metformin reduces serum müllerian-inhibiting substance levels in women with polycystic ovary syndrome after protracted treatment. Fertil Steril. 2005;83(1):130–6.CrossRefPubMed
30.
go back to reference Fábregues F, Castelo-Branco C, Carmona F, Guimerá M, Casamitjana R, Balasch J. The effect of different hormone therapies on anti-müllerian hormone serum levels in anovulatory women of reproductive age. Gynecol Endocrinol. 2011;27(4):216–24.CrossRefPubMed Fábregues F, Castelo-Branco C, Carmona F, Guimerá M, Casamitjana R, Balasch J. The effect of different hormone therapies on anti-müllerian hormone serum levels in anovulatory women of reproductive age. Gynecol Endocrinol. 2011;27(4):216–24.CrossRefPubMed
31.
go back to reference Falbo A, Rocca M, Russo T, D’Ettore A, Tolino A, Zullo F, et al. Serum and follicular anti-mullerian hormone levels in women with polycystic ovary syndrome (PCOS) under metformin. J Ovarian Res. 2010;3(1):1–6.CrossRef Falbo A, Rocca M, Russo T, D’Ettore A, Tolino A, Zullo F, et al. Serum and follicular anti-mullerian hormone levels in women with polycystic ovary syndrome (PCOS) under metformin. J Ovarian Res. 2010;3(1):1–6.CrossRef
32.
go back to reference Campagnoli C, Berrino F, Venturelli E, Abbà C, Biglia N, Brucato T, et al. Metformin decreases circulating androgen and estrogen levels in nondiabetic women with breast cancer. Clin Breast Cancer. 2013;13(6):433–8.CrossRefPubMed Campagnoli C, Berrino F, Venturelli E, Abbà C, Biglia N, Brucato T, et al. Metformin decreases circulating androgen and estrogen levels in nondiabetic women with breast cancer. Clin Breast Cancer. 2013;13(6):433–8.CrossRefPubMed
33.
go back to reference Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin. 2004;20(4):565–72.CrossRefPubMed Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin. 2004;20(4):565–72.CrossRefPubMed
34.
go back to reference Pigny P, Merlen E, Robert Y, Cortet-Rudelli C, Decanter C, Jonard S, et al. Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metabolism. 2003;88(12):5957–62.CrossRef Pigny P, Merlen E, Robert Y, Cortet-Rudelli C, Decanter C, Jonard S, et al. Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metabolism. 2003;88(12):5957–62.CrossRef
35.
go back to reference Fallat ME, Siow Y, Marra M, Cook C, Carrillo A. Müllerian-inhibiting substance in follicular fluid and serum: a comparison of patients with tubal factor infertility, polycystic ovary syndrome, and endometriosis. Fertil Steril. 1997;67(5):962–5.CrossRefPubMed Fallat ME, Siow Y, Marra M, Cook C, Carrillo A. Müllerian-inhibiting substance in follicular fluid and serum: a comparison of patients with tubal factor infertility, polycystic ovary syndrome, and endometriosis. Fertil Steril. 1997;67(5):962–5.CrossRefPubMed
36.
go back to reference Laven JS, Mulders AG, Visser JA, Themmen AP, De Jong FH, Fauser BC. Anti-mullerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J Clin Endocrinol Metabolism. 2004;89(1):318–23.CrossRef Laven JS, Mulders AG, Visser JA, Themmen AP, De Jong FH, Fauser BC. Anti-mullerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J Clin Endocrinol Metabolism. 2004;89(1):318–23.CrossRef
37.
go back to reference Kezele PR, Nilsson EE, Skinner MK. Insulin but not insulin-like growth factor-1 promotes the primordial to primary follicle transition. Mol Cell Endocrinol. 2002;192(1–2):37–43.CrossRefPubMed Kezele PR, Nilsson EE, Skinner MK. Insulin but not insulin-like growth factor-1 promotes the primordial to primary follicle transition. Mol Cell Endocrinol. 2002;192(1–2):37–43.CrossRefPubMed
38.
go back to reference Gulyas BJ, Hodgen GD, Tullner WW, Ross GT. Effects of fetal or maternal hypophysectomy on endocrine organs and body weight in infant rhesus monkeys (Macaca mulatta): with particular emphasis on oogenesis. Biol Reprod. 1977;16(2):216–27.CrossRefPubMed Gulyas BJ, Hodgen GD, Tullner WW, Ross GT. Effects of fetal or maternal hypophysectomy on endocrine organs and body weight in infant rhesus monkeys (Macaca mulatta): with particular emphasis on oogenesis. Biol Reprod. 1977;16(2):216–27.CrossRefPubMed
39.
go back to reference Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18(6):774–800.PubMed Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18(6):774–800.PubMed
40.
go back to reference Knight PG, Glister C. TGF-β superfamily members and ovarian follicle development. Reproduction. 2006;132(2):191–206.CrossRefPubMed Knight PG, Glister C. TGF-β superfamily members and ovarian follicle development. Reproduction. 2006;132(2):191–206.CrossRefPubMed
Metadata
Title
Effect of metformin on anti-mullerian hormone levels in women with polycystic ovarian syndrome: a systematic review and meta-regression analysis of randomized controlled trials with
Authors
Mehdi Mehdinezhad Roshan
Mohammad Hassan Sohouli
Elma Izze da Silva Magalhães
Azita Hekmatdoost
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Endocrine Disorders / Issue 1/2024
Electronic ISSN: 1472-6823
DOI
https://doi.org/10.1186/s12902-024-01570-z

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