SpringerLink
Log in

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

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Changes in LH and FSH levels were evaluated before and after metformin administration. In all 25 patients, plasma LH levels were significantly reduced after 3 months of metformin administration (500–1,500 mg/day). When patients were classified into a PCOS group (n = 12) or a non-PCOS group (n = 13), the reduction in LH levels only remained significant in the PCOS group. Plasma FSH levels were unchanged following metformin treatment when all patients were considered collectively and when patients were classified based on PCOS. LH/FSH ratio was significantly reduced only in the PCOS group. To examine the direct effect of metformin on gonadotropin-secreting cells, gonadotroph cell line, LβT2 was used for in vitro studies. Treatment of LβT2 cells with metformin modified neither the LHβ nor the FSHβ subunit promoter activity. The GnRH-induced LHβ promoter activity was not modulated in the presence of metformin. In contrast, GnRH-induced FSHβ promoter activity was significantly potentiated in the presence of metformin. Our results suggest that metformin does indeed modulate the basal level of LH and the LH/FSH ratio, albeit indirectly, particularly in the patients with PCOS. Additionally our results suggest that metformin does directly regulate FSH gene expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Goodarzi MO, Azziz R (2006) Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab 20:193–205

    Article  CAS  PubMed  Google Scholar 

  2. Hughes E, Collins J, Vandekerckhove P (2000) Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. Cochrane Database Syst Rev 3:CD000056

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Santana LF, de Sa MF, Ferriani RA et al (2004) Effect of metformin on the clinical and metabolic assessment of women with polycystic ovary syndrome. Gynecol Endocrinol 19:88–96

    Article  CAS  PubMed  Google Scholar 

  5. Thierry van Dessel HJ, Lee PD, Faessen G, Fauser BC, Giudice LC (1999) Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome. J Clin Endocrinol Metab 84:3030–3035

    Article  CAS  PubMed  Google Scholar 

  6. Creanga AA, Bradley HM, McCormick C, Witkop CT (2008) Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol 111:959–968

    CAS  PubMed  Google Scholar 

  7. Nardo LG, Rai R (2001) Metformin therapy in the management of polycystic ovary syndrome: endocrine, metabolic and reproductive effects. Gynecol Endocrinol 15:373–380

    CAS  PubMed  Google Scholar 

  8. Barbieri RL, Makris A, Randall RW et al (1986) Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 62:904–910

    Article  CAS  PubMed  Google Scholar 

  9. DeFronzo RA, Goodman AM (1995) Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The multicenter metformin study group. N Engl J Med 333:541–549

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  11. Genazzani AD, Battaglia C, Malavasi B et al (2004) Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril 81:114–119

    Article  CAS  PubMed  Google Scholar 

  12. Kaiser UB, Sabbagh E, Katzenellenbogen RA, Conn PM, Chin WW (1995) A mechanism for the differential regulation of gonadotropin subunit gene expression by gonadotropin-releasing hormone. Proc Natl Acad Sci USA 92:12280–12284

    Article  CAS  PubMed  Google Scholar 

  13. Bedecarrats GY, Kaiser UB (2003) Differential regulation of gonadotropin subunit gene promoter activity by pulsatile gonadotropin-releasing hormone (GnRH) in perifused L beta T2 cells: role of GnRH receptor concentration. Endocrinology 144:1802–1811

    Article  CAS  PubMed  Google Scholar 

  14. Adashi EY, Resnick CE, D’Ercole AJ, Svoboda ME, Van Wyk JJ (1985) Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev 6:400–420

    Article  CAS  PubMed  Google Scholar 

  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 72:83–89

    Article  CAS  PubMed  Google Scholar 

  16. Dunn CJ, Peters DH (1995) Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs 49:721–749

    Article  CAS  PubMed  Google Scholar 

  17. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ (1994) Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43:647–654

    Article  CAS  PubMed  Google Scholar 

  18. Moghetti P, Castello R, Negri C et al (2000) Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85:139–146

    Article  CAS  PubMed  Google Scholar 

  19. Alarid ET, Windle JJ, Whyte DB, Mellon PL (1996) Immortalization of pituitary cells at discrete stages of development by directed oncogenesis in transgenic mice. Development 122:3319–3329

    CAS  PubMed  Google Scholar 

  20. Harada T, Kanasaki H, Mutiara S, Oride A, Miyazaki K (2007) Cyclic adenosine 3′, 5′monophosphate/protein kinase A and mitogen-activated protein kinase 3/1 pathways are involved in adenylate cyclase-activating polypeptide 1-induced common alpha-glycoprotein subunit gene (Cga) expression in mouse pituitary gonadotroph LbetaT2 cells. Biol Reprod 77:707–716

    Article  CAS  PubMed  Google Scholar 

  21. Winters SJ, Moore JP (2007) Paracrine control of gonadotrophs. Semin Reprod Med 25:379–387

    Article  CAS  PubMed  Google Scholar 

  22. Rice S, Pellatt L, Ramanathan K, Whitehead SA, Mason HD (2009) Metformin inhibits aromatase via an ERK (extracellular signal-regulated kinase)—mediated pathway. Endocrinology 150:4794–4801

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Shimane University School of Medicine, 89-1 Enya Cho, Izumo, 693-8501, Shimane Prefecture, Japan

    Aki Oride, Haruhiko Kanasaki, Indri N. Purwana & Kohji Miyazaki

Authors
  1. Aki Oride
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haruhiko Kanasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Indri N. Purwana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kohji Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haruhiko Kanasaki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oride, A., Kanasaki, H., Purwana, I.N. 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 13, 236–241 (2010). https://doi.org/10.1007/s11102-010-0223-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-010-0223-x

Keywords

Search

Navigation