Download PDF
Exp Clin Endocrinol Diabetes 2018; 126(10): 645-650
DOI: 10.1055/a-0584-0006
Article
© Georg Thieme Verlag KG Stuttgart · New York

The Effect of Metformin on Serum Gonadotropin Levels in Postmenopausal Women with Diabetes and Prediabetes: A Pilot Study

Robert Krysiak
1   Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
,
Witold Szkróbka
1   Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
,
Bogusław Okopień
1   Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
› Author Affiliations
Further Information

Publication History

received 21 December 2017
revised 22 February 2018

accepted 27 February 2018

Publication Date:
12 March 2018 (online)

Also available at
    Permissions and Reprints

Abstract

Background Metformin was found to decrease serum levels of prolactin and thyrotropin. The aim of this study was to investigate the effect of this drug on hypothalamic-pituitary-ovarian axis activity in postmenopausal women with recently diagnosed and untreated glucose metabolism abnormalities.

Methods The study included three matched groups of postmenopausal women: patients with type 2 diabetes (group A, n=16), women with prediabetes (group B, n=14), and individuals with normal glucose metabolism (group C, n=14). Women with diabetes were then treated with high-dose metformin (3 g daily), while women with prediabetes received moderate doses of this agent (1.7 g daily). Glucose homeostasis markers, as well as serum levels of FSH, LH, thyrotropin, prolactin, estradiol and creatinine were measured at baseline and after 16 weeks of metformin treatment.

Results In both groups of metformin-treated women, the drug improved glucose homeostasis. High-dose metformin treatment reduced circulating levels of FSH and tended to reduce serum levels of LH, and these effects correlated with an improvement in insulin sensitivity. No changes in gonadotropin levels were observed in prediabetic women receiving moderate doses of metformin. Serum levels of thyrotropin, prolactin and estradiol, as well as the estimated glomerular filtration rate remained at a similar level throughout the study.

Conclusions Our study shows that the effect of metformin on hypothalamic-pituitary-ovarian axis activity in postmenopausal women depends on its dose and the magnitude of insulin resistance.

Key words

FSH - LH - menopause - metformin
 

  • References

  • 1 American Diabetes Association . Standards of medical care in diabetes – 2017. Pharmacological approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 01) S64-S74
    PubMedGoogle Scholar
  • 2 Diabetes Prevention Program Research Group . Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403
    CrossrefPubMedGoogle Scholar
  • 3 Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res 2008; 5: 157-167
    CrossrefPubMedGoogle Scholar
  • 4 Vigersky RA, Filmore-Nassar A, Glass AR. Thyrotropin suppression by metformin. J Clin Endocrinol Metab 2006; 91: 225-227
    CrossrefPubMedGoogle Scholar
  • 5 Cappelli C, Rotondi M, Pirola I. et al. TSH-lowering effect of metformin in type 2 diabetic patients: Differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients. Diabetes Care 2009; 32: 1589-1590
    CrossrefPubMedGoogle Scholar
  • 6 Isidro ML, Penín MA, Nemiña R. et al. Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy. Endocrine 2007; 32: 79-82
    CrossrefPubMedGoogle Scholar
  • 7 Morteza Taghavi S, Rokni H, Fatemi S. Metformin decreases thyrotropin in overweight women with polycystic ovarian syndrome and hypothyroidism. Diab Vasc Dis Res 2011; 8: 47-48
    CrossrefPubMedGoogle Scholar
  • 8 Lupoli R, Di Minno A, Tortora A. et al. Effects of treatment with metformin on TSH levels: a meta-analysis of literature studies. J Clin Endocrinol Metab 2014; 99: E143-E148
    CrossrefPubMedGoogle Scholar
  • 9 Krysiak R, Okopień B. The effect of metformin on the hypothalamic-pituitary-thyroid axis in women with polycystic ovary syndrome and subclinical hypothyroidism. J Clin Pharmacol 2015; 55: 45-49
    CrossrefPubMedGoogle Scholar
  • 10 Krysiak R, Gilowska M, Szkróbka W. et al. The effect of metformin on the hypothalamic-pituitary-thyroid axis in patients with type 2 diabetes and amiodarone-induced hypothyroidism. Pharmacol Rep 2016; 68: 490-494
    CrossrefPubMedGoogle Scholar
  • 11 Krysiak R, Okopień B. Thyrotropin-lowering effect of metformin in a patient with resistance to thyroid hormone. Clin Endocrinol 2011; 75: 404-406
    CrossrefPubMedGoogle Scholar
  • 12 Krysiak R, Okrzesik J, Okopień B. The effect of short-term metformin treatment on plasma prolactin levels in bromocriptine-treated patients with hyperprolactinaemia and impaired glucose tolerance: a pilot study. Endocrine 2015; 49: 242-249
    CrossrefPubMedGoogle Scholar
  • 13 Krysiak R, Kowalcze K, Szkrobka W. et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia. Eur J Intern Med 2016; 30: 94-98
    CrossrefPubMedGoogle Scholar
  • 14 Krysiak R, Szkróbka W, Okopień B. A neutral effect of metformin treatment on macroprolactin content in women with macroprolactinemia. Exp Clin Endocrinol Diabetes 2017; 125: 223-228
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 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: 236-241
    CrossrefPubMedGoogle Scholar
  • 16 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: 114-119
    CrossrefPubMedGoogle Scholar
  • 17 Velija-Ašimi Z. Evaluation of endocrine changes in women with the polycystic ovary syndrome during metformin treatment. Bosn J Basic Med Sci 2013; 13: 180-185
    PubMedGoogle Scholar
  • 18 Billa E, Kapolla N, Nicopoulou SC. et al. Metformin administration was associated with a modification of LH, prolactin and insulin secretion dynamics in women with polycystic ovarian syndrome. Gynecol Endocrinol 2009; 25: 427-443
    CrossrefPubMedGoogle Scholar
  • 19 Oleandri SE, Maccario M, Rossetto R. et al. Three-month treatment with metformin or dexfenfluramine does not modify the effects of diet on anthropometric and endocrine-metabolic parameters in abdominal obesity. J Endocrinol Invest 1999; 22: 134-140
    CrossrefPubMedGoogle Scholar
  • 20 Labbuzek K, Suchy D, Gabryel B. et al. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 2010; 62: 956-965
    CrossrefPubMedGoogle Scholar
  • 21 Ueno M. Molecular anatomy of the brain endothelial barrier: An overview of the distributional features. Curr Med Chem 2007; 14: 1199-1206
    CrossrefPubMedGoogle Scholar
  • 22 Krysiak R, Szkróbka W, Okopień B. Sex-dependent effect of metformin on hypothalamic-pituitary-thyroid axis activity in patients with subclinical hypothyroidism. Pharmacol Rep 2016; 68: 1115-1119
    CrossrefPubMedGoogle Scholar
  • 23 National Collaborating Centre for Women's and Children's Health (UK) . Menopause: Full Guideline. London: National Institute for Health and Care Excellence (UK); 2015. Nov 12
    Google Scholar
  • 24 Ross LA, Polotsky AJ. Metabolic correlates of menopause: An update. Curr Opin Obstet Gynecol 2012; 24: 402-407
    CrossrefPubMedGoogle Scholar
  • 25 Krysiak R, Okopień B, Gdula-Dymek A. et al. Update on the management of polycystic ovary syndrome. Pharmacol Rep 2006; 58: 614-625
    PubMedGoogle Scholar
  • 26 Weigert J, Neumeier M, Wanninger J. et al. Adiponectin upregulates monocytic activin A but systemic levels are not altered in obesity or type 2 diabetes. Cytokine 2009; 45: 86-91
    CrossrefPubMedGoogle Scholar
  • 27 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: 351-362
    CrossrefPubMedGoogle Scholar
  • 28 Nascimento AD, Silva Lara LA, Japur de Sá Rosa-e-Silva AC. et al. Effects of metformin on serum insulin and anti-Mullerian hormone levels and on hyperandrogenism in patients with polycystic ovary syndrome. Gynecol Endocrinol 2013; 29: 246-249
    CrossrefPubMedGoogle Scholar
  • 29 Feyereisen E, Méndez Lozano DH, Taieb J. et al. Anti-Müllerian hormone: clinical insights into a promising biomarker of ovarian follicular status. Reprod Biomed Online 2006; 12: 695-703
    CrossrefPubMedGoogle Scholar
  • 30 Edman CD. The climacteric. Buchsbaum, ed. The menopause. New York: Springer-Verlag; 1983: 23-32
    CrossrefGoogle Scholar
  • 31 Patil M. Gonadotrophins: the future. J Hum Reprod Sci 2014; 7: 236-248
    CrossrefPubMedGoogle Scholar
  • 32 Simpson E, Rubin G, Clyne C. et al. Local estrogen biosynthesis in males and females. Endocr Relat Cancer 1999; 6: 131-137
    CrossrefPubMedGoogle Scholar
  • 33 Duntas LH, Orgiazzi J, Brabant G. The interface between thyroid and diabetes mellitus. Clin Endocrinol 2011; 75: 1-9
    CrossrefPubMedGoogle Scholar
  • 34 Chau-Van C, Gamba M, Salvi R. et al. Metformin inhibits adenosine 5′-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology 2007; 148: 507-511
    CrossrefPubMedGoogle Scholar
  • 35 López M, Nogueiras R, Tena-Sempere M. et al. Hypothalamic AMPK: A canonical regulator of whole-body energy balance. Nat Rev Endocrinol 2016; 12: 421-432
    CrossrefPubMedGoogle Scholar
  • 36 López M, Varela L, Vázquez MJ. et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010; 16: 1001-1008
    CrossrefPubMedGoogle Scholar
  • 37 McFadden SA, Menchella JA, Chalmers JA. et al. Glucose responsiveness in a novel adult-derived GnRH cell line, mHypoA-GnRH/GFP: Involvement of AMP-activated protein kinase. Mol Cell Endocrinol 2013; 377: 65-74
    CrossrefPubMedGoogle Scholar
  • 38 Aroda VR, Knowler WC, Crandall JP. et al. Metformin for diabetes prevention: Insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study. Diabetologia 2017; 60: 1601-1611
    CrossrefPubMedGoogle Scholar
  • 39 Genuth S. The UKPDS and its global impact. Diabet Med 2008; 25 (Suppl. 02) 57-62
    CrossrefPubMedGoogle Scholar