Exp Clin Endocrinol Diabetes 2021; 129(01): 22-28
DOI: 10.1055/a-0921-6420
Article

The Impact of Ethinyl Estradiol on Metformin Action on Prolactin Levels in Women with Hyperprolactinemia

Robert Krysiak
1   Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland
,
Witold Szkróbka
1   Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland
,
Bogusław Okopień
1   Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland
› Author Affiliations

Abstract

Background Metformin reduced prolactin levels only in women with hyperprolactinemia.

Objective The purpose of this case-control study was to compare metformin action on lactoctrope function between women receiving oral contraceptive pills and women not using hormonal contraception.

Methods The study included two groups of matched women with elevated prolactin levels and new-onset prediabetes or diabetes. The first group consisted of 20 women using oral contraceptive pills for at least 12 months before entering the study, while the second group included 20 patients not using any hormonal contraception. Over the whole study period, all women were treated with metformin (1.7–3 g daily). Circulating levels of glucose, insulin, prolactin, thyrotropin, free thyroid hormones, adrenocorticotropic hormone, gonadotropins and insulin-like growth factor-1 were measured at the beginning and at the end of the study (16 weeks later).

Results Thirty-eight patients completed the study. Metformin reduced plasma glucose levels and improved insulin sensitivity but the latter effect was stronger in women receiving oral contraceptive pills than in women not using any contraception. Although metformin treatment decreased plasma prolactin levels in both study groups, this effect was stronger in women taking oral contraceptive pills. Only in this group of women, metformin increased plasma luteinizing hormone levels. The changes in plasma prolactin correlated with their baseline insulin sensitivity and the effect of metformin on insulin sensitivity. Metformin did not affect plasma levels of thyrotropin, free thyroxine, free triiodothyronine, follicle-stimulating hormone, adrenocorticotropic hormone and insulin-like growth factor-1.

Conclusions The obtained results suggest that the effect of metformin on overactive lactotropes depends on estrogen levels.



Publication History

Received: 13 April 2019
Received: 11 May 2019

Accepted: 15 May 2019

Article published online:
24 June 2019

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  • References

  • 1 Wróbel MP, Marek B, Kajdaniuk D. et al. Metformin – A new old drug. Endokrynol Pol 2017; 68: 482-496
  • 2 Wang YW, He SJ, Feng X. et al. Metformin: A review of its potential indications. Drug Des Devel Ther 2017; 11: 2421-2429
  • 3 Fujita Y, Inagaki N. Metformin: New preparations and nonglycemic benefits. Curr Diab Rep 2017; 17: 5
  • 4 Ueno M. Molecular anatomy of the brain endothelial barrier: An overview of the distributional features. Curr Med Chem 2007; 14: 1199-1206
  • 5 Labuzek 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
  • 6 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
  • 7 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
  • 8 Krysiak R, Szkróbka W, Okopień B. The effect of metformin on serum gonadotropin levels in postmenopausal women with diabetes and prediabetes: A pilot study. Exp Clin Endocrinol Diabetes 2018; 126: 645-650
  • 9 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
  • 10 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
  • 11 Banaszewska B, Pawelczyk L, Spaczynski RZ. et al. Effects of simvastatin and metformin on polycystic ovary syndrome after six months of treatment. J Clin Endocrinol Metab 2011; 96: 3493-3501
  • 12 Wu RR, Jin H, Gao K. et al. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with worst-episode schizophrenia: A double-blind, randomized, placebo-controlled study. Am J Psychiatry 2012; 169: 813-821
  • 13 Bo QJ, Wang ZM, Li XB. et al. Adjunctive metformin for antipsychotic- induced hyperprolactinemia: A systematic review. Psychiatry Res 2016; 237: 257-263
  • 14 Krysiak R, Kowalcze K, Szkróbka W. et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia. Eur J Intern Med 2016; 30: 94-98
  • 15 Zheng W, Yang XH, Cai DB. et al. Adjunctive metformin for antipsychotic-related hyperprolactinemia: A meta-analysis of randomized controlled trials. J Psychopharmacol 2017; 31: 625-631
  • 16 Krysiak R, Szkróbka W, Okopień B. A neutral effect of metformin treatment on macroprolactin content in women with macroprolactinemia. Exp Clin Endocrinol Diabetes 2016; 125: 223-228
  • 17 Krysiak R, Szkróbka W, Okopień B. Alternative treatment strategies in women poorly tolerating moderate doses of bromocriptine. Exp Clin Endocrinol Diabetes 2017; 125: 360-364
  • 18 Krysiak R, Szkróbka W, Okopień B. Sex-dependent effect of metformin on serum prolactin levels in hyperprolactinemic patients with type 2 diabetes: A pilot study. Exp Clin Endocrinol Diabetes 2018; 126: 342-348
  • 19 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
  • 20 Kars M, Souverein PC, Herings RM. et al. Estimated age- and sex-specific incidence and prevalence of dopamine agonist-treated hyperprolactinemia. J Clin Endocrinol Metab 2009; 94: 2729-2734
  • 21 Colao A, Sarno AD, Cappabianca P. et al. Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia. Eur J Endocrinol 2003; 148: 325-331
  • 22 Cosma M, Bailey J, Miles JM. et al. Pituitary and/or peripheral estrogen-receptor alpha regulates follicle- stimulating hormone secretion, whereas central estrogenic pathways direct growth hormone and prolactin secretion in postmenopausal women. J Clin Endocrinol Metab 2008; 93: 951-958
  • 23 Kalleinen N, Polo-Kantola P, Irjala K. et al. 24-h serum levels of growth hormone, prolactin, and cortisol in pre- and postmenopausal women: The effect of combined estrogen and progestin treatment. J Clin Endocrinol Metab 2008; 93: 1655-1661
  • 24 Ho KY, Thorner MO, Krieg Jr RJ. et al. Effects of gonadal steroids on somatotroph function in the rat: Analysis by the reverse hemolytic plaque assay. Endocrinology 1988; 123: 1405-1411
  • 25 Sitruk-Ware R, Nath A. Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills. Best Pract Res Clin Endocrinol Metab 2013; 27: 13-24
  • 26 Gourdy P. Diabetes and oral contraception. Best Pract Res Clin Endocrinol Metab 2013; 27: 67-76
  • 27 Marnach ML, Long ME, Casey PM. Current issues in contraception. Mayo Clin Proc 2013; 88: 295-259
  • 28 Sprangers SA, Brenner RM, Bethea CL. Estrogen and progestin receptor immunocytochemistry in lactotropes versus gonadotropes of monkey pituitary cell cultures. Endocrinology 1989; 124: 1462-1470
  • 29 Day EA, Ford RJ, Steinberg GR. AMPK as a therapeutic target for treating metabolic diseases. Trends Endocrinol Metab 2017; 28: 545-560
  • 30 Holt RI, Barnett AH, Bailey CJ. Bromocriptine: Old drug, new formulation and new indication. Diabetes Obes Metab 2010; 12: 1048-1057
  • 31 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
  • 32 Martínez de Morentin PB, González-García I, Martins L. et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab 2014; 20: 41-53
  • 33 Hardie DG, Ashford ML. AMPK: Regulating energy balance at the cellular and whole body levels. Physiology (Bethesda) 2014; 29: 99-107
  • 34 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: 351-162
  • 35 Tsai YC, Lee YM, Lam KK. et al. The role of hypothalamic AMP-activated protein kinase in ovariectomy-induced obesity in rats. Menopause 2010; 17: 1194-1200
  • 36 Ortega-González C, Cardoza L, Coutiño B. et al. Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome. J Endocrinol 2005; 184: 233-239
  • 37 Christian BT, Vandehey NT, Fox AS. et al. The distribution of D2/D3 receptor binding in the adolescent rhesus monkey using small animal PET imaging. Neuroimage 2009; 44: 1334-1344
  • 38 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
  • 39 Krysiak R, Okrzesik J, Okopień B. Different effects of metformin on the hypothalamic-pituitary-thyroid axis in bromocriptine- and cabergoline-treated patients with Hashimoto’s thyroiditis and glucose metabolism abnormalities. Exp Clin Endocrinol Diabetes 2015; 123: 561-566
  • 40 De Maria JE, Livingstone JD, Freeman ME. Ovarian steroids influence the activity of neuroendocrine dopaminergic neurons. Brain Res 2000; 879: 139-147
  • 41 Narayanan RP, Bujawansa S, Qureshi Z. et al. Hypogonadism secondary to hyperprolactinaemia: successful treatment but adverse consequences. Exp Clin Endocrinol Diabetes 2012; 120: 311-313
  • 42 Sondheimer SJ. Oral contraceptives: Mechanism of action, dosing, safety, and efficacy. Cutis 2008; 81 (1 Suppl) 19-22