Skip to main content

Advertisement

Log in

Estrogen and selective estrogen receptor modulators (SERMs) for the treatment of acromegaly: a meta-analysis of published observational studies

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Estrogen and selective estrogen receptor modulator (SERM) treatments for acromegaly have received limited attention since the development of newer pharmacologic therapies. There has been ongoing research evidence suggesting their utility in the biochemical control of acromegaly. Therefore, the aim of this meta-analysis was to synthesise current evidence with a view to determining to what extent and in which acromegalic patient subsets do estrogen and SERMs reduce IGF-1 levels. A literature search was conducted (finished December 2012), which included all studies pertaining to estrogen or SERM treatment and IGF-1. Seven patient subsets were identified from six published observational studies, and were pooled using meta-analytic methods. Overall, the pooled mean loss in IGF-1 was −29.09 nmol/L (95 % CI −37.23 to −20.95). A sensitivity analysis indicated that women receiving estrogen had a substantially greater reduction in IGF-1 levels compared with women receiving SERMs, with a weighted mean loss in IGF-1 of −38.12 nmol/L (95 % CI −46.78 to −29.45) compared with −22.91 nmol/L (95 % CI −32.73 to −13.09). There was a trend that did not reach statistical significance for men receiving SERM treatment at −11.41 nmol/L (95 % CI −30.14 to 7.31). It was concluded that estrogen and SERMs are a low cost and effective treatment to achieve control of IGF-1 levels in acromegalic women either as concomitant treatment for refractory disease, or where access to conventional therapy is restricted. Their use in men requires further study.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK (2011) American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly–2011 update. Endocr Pract 17(Suppl 4):1–44

    Article  PubMed  Google Scholar 

  2. Dekkers OM, Biermasz NR, Pereira AM, Romijn JA, Vandenbroucke JP (2008) Mortality in acromegaly: a metaanalysis. J Clin Endocrinol metab 93(1):61–67

    Article  CAS  PubMed  Google Scholar 

  3. Mestron A, Webb SM, Astorga R, Benito P, Catala M, Gaztambide S, Gomez JM, Halperin I, Lucas-Morante T, Moreno B, Obiols G, de Pablos P, Paramo C, Pico A, Torres E, Varela C, Vazquez JA, Zamora J, Albareda M, Gilabert M (2004) Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA). Eur J Endocrinol 151(4):439–446

    Article  CAS  PubMed  Google Scholar 

  4. Melmed S, Casanueva F, Cavagnini F, Chanson P, Frohman LA, Gaillard R, Ghigo E, Ho K, Jaquet P, Kleinberg D, Lamberts S, Laws E, Lombardi G, Sheppard MC, Thorner M, Vance ML, Wass JA, Giustina A (2005) Consensus statement: medical management of acromegaly. Eur J Endocrinol 153(6):737–740

    Article  CAS  PubMed  Google Scholar 

  5. Holdaway IM, Bolland MJ, Gamble GD (2008) A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol 159(2):89–95

    Article  CAS  PubMed  Google Scholar 

  6. Swearingen B, Barker FG 2nd, Katznelson L, Biller BM, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT (1998) Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J clin endocrinol metab 83(10):3419–3426

    CAS  PubMed  Google Scholar 

  7. Anagnostis P, Efstathiadou ZA, Polyzos SA, Adamidou F, Slavakis A, Sapranidis M, Litsas ID, Katergari S, Selalmatzidou D, Kita M (2011) Acromegaly: presentation, morbidity and treatment outcomes at a single centre. Int J Clin Pract 65(8):896–902

    Article  CAS  PubMed  Google Scholar 

  8. Fukuda I, Hizuka N, Murakami Y, Itoh E, Yasumoto K, Sata A, Takano K (2001) Clinical features and therapeutic outcomes of 65 patients with acromegaly at Tokyo Women’s Medical University. Intern Med 40(10):987–992

    Article  CAS  PubMed  Google Scholar 

  9. Minniti G, Jaffrain-Rea ML, Esposito V, Santoro A, Tamburrano G, Cantore G (2003) Evolving criteria for post-operative biochemical remission of acromegaly: can we achieve a definitive cure? An audit of surgical results on a large series and a review of the literature. Endocr Relat Cancer 10(4):611–619

    Article  CAS  PubMed  Google Scholar 

  10. Nomikos P, Buchfelder M, Fahlbusch R (2005) The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure’. Eur J Endocrinol 152(3):379–387

    Article  CAS  PubMed  Google Scholar 

  11. Reid TJ, Post KD, Bruce JN, Nabi Kanibir M, Reyes-Vidal CM, Freda PU (2010) Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed. Clin Endocrinol (Oxf) 72(2):203–208

    Article  Google Scholar 

  12. Trepp R, Stettler C, Zwahlen M, Seiler R, Diem P, Christ ER (2005) Treatment outcomes and mortality of 94 patients with acromegaly. Acta Neurochir (Wien) 147(3):243–251 discussion 250–241

    Article  CAS  Google Scholar 

  13. Melmed S, Colao A, Barkan A, Molitch M, Grossman AB, Kleinberg D, Clemmons D, Chanson P, Laws E, Schlechte J, Vance ML, Ho K, Giustina A (2009) Acromegaly Consensus, G.: guidelines for acromegaly management: an update. J Clin Endocrinol Metab 94(5):1509–1517

    Article  CAS  PubMed  Google Scholar 

  14. Melmed S (1993) Medical management of acromegaly–what and when? Acta Endocrinol (Copenh) 129(Suppl 1):13–17

    Google Scholar 

  15. Lacy CF, Armstrong LL, Goldman MP, Lance LL (2013) Drug information handbook, 22nd edn. Lexi-Comp, Inc., Hudson

    Google Scholar 

  16. Abs R, Verhelst J, Maiter D, Van Acker K, Nobels F, Coolens J-L, Mahler C, Beckers A (1998) Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab 83(2):374–378

    Article  CAS  PubMed  Google Scholar 

  17. Colao A, Ferone D, Marzullo P, Di Sarno A, Cerbone G, Sarnacchiaro F, Cirillo S, Merola B, Lombardi G (1997) Effect of different dopaminergic agents in the treatment of acromegaly. J Clin Endocrinol Metab 82(2):518–523

    Article  CAS  PubMed  Google Scholar 

  18. Cozzi R, Attanasio R, Barausse M, Dallabonzana D, Orlandi P, Da Re N, Branca V, Oppizzi G, Gelli D (1998) Cabergoline in acromegaly: a renewed role for dopamine agonist treatment? Eur J Endocrinol 139(5):516–521

    Article  CAS  PubMed  Google Scholar 

  19. Jackson SNJ, Fowler J, Howlett TA (1997) Cabergoline treatment of acromegaly: a preliminary dose finding study. Clin Endocrinol 46(6):745–749

    Article  CAS  Google Scholar 

  20. Mercado M, Borges F, Bouterfa H, Chang T.-C, Chervin A, Farrall AJ, Patocs A, Petersenn S, Podoba J, Safari M, Wardlaw J, on behalf of the, S. M. S. B. S. G. (2007) A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR® (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol 66(6):859–868

  21. Caron P, Beckers A, Cullen DR, Goth MI, Gutt B, Laurberg P, Pico AM, Valimaki M, Zgliczynski W (2002) Efficacy of the new long-acting formulation of lanreotide (Lanreotide Autogel) in the management of acromegaly. J Clin Endocrinol Metab 87(1):99–104

    Article  CAS  PubMed  Google Scholar 

  22. Caron P, Morange-Ramos I, Cogne M, Jaquet P (1997) Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J Clin Endocrinol Metab 82(1):18–22

    CAS  PubMed  Google Scholar 

  23. Maiza JC, Vezzosi D, Matta M, Donadille F, Loubes-Lacroix F, Cournot M, Bennet A, Caron P (2007) Long-term (up to 18 years) effects on GH/IGF-1 hypersecretion and tumour size of primary somatostatin analogue (SSTa) therapy in patients with GH-secreting pituitary adenoma responsive to SSTa. Clin Endocrinol 67(2):282–289

    Article  CAS  Google Scholar 

  24. Chanson P, Boerlin V, Ajzenberg C, Bachelot Y, Benito P, Bringer J, Caron P, Charbonnel B, Cortet C, Delemer B, Escobar-Jiménez F, Foubert L, Gaztambide S, Jockenhoevel F, Kuhn JM, Leclere J, Lorcy Y, Perlemuter L, Prestele H, Roger P, Rohmer V, Santen R, Sassolas G, Scherbaum WA, Schopohl J, Torres E, Varela C, Villamil F, Webb SM (2000) Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly. Clin Endocrinol 53(5):577–586

    Article  CAS  Google Scholar 

  25. van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, Klibanski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart PM, Friend KE, Clemmons DR, Johannsson G, Stavrou S, Cook DM, Phillips LS, Strasburger CJ, Hacker S, Zib KA, Davis RJ, Scarlett JA, Thorner MO (2001) Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. The Lancet 358(9295):1754–1759

    Article  Google Scholar 

  26. van der Lely AJ, Biller BM, Brue T, Buchfelder M, Ghigo E, Gomez R, Hey-Hadavi J, Lundgren F, Rajicic N, Strasburger CJ, Webb SM, Koltowska-Haggstrom M (2012) Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1,288 subjects in ACROSTUDY. J Clin Endocrinol Metab 97(5):1589–1597

    Article  PubMed  Google Scholar 

  27. Moore DJ, Adi Y, Connock MJ, Bayliss S (2009) Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation. BMC Endocr Disord 9:20

    Article  PubMed Central  PubMed  Google Scholar 

  28. Cozzi R, Attanasio R, Oppizzi G, Orlandi P, Giustina A, Lodrini S, Da Re N, Dallabonzana D (1997) Effects of tamoxifen on GH and IGF-I levels in acromegaly. J Endocrinol Invest 20(8):445–451

    Article  CAS  PubMed  Google Scholar 

  29. Cozzi R, Barausse M, Lodrini S, Lasio G, Attanasio R (2003) Estroprogestinic pill normalizes IGF-I levels in acromegalic women. J Endocrinol Invest 26(4):347–352

    Article  CAS  PubMed  Google Scholar 

  30. Attanasio R, Barausse M, Cozzi R (2003) Raloxifene lowers IGF-I levels in acromegalic women. Eur J Endocrinol 148(4):443–448

    Article  CAS  PubMed  Google Scholar 

  31. Dimaraki E, Symons K, Barkan A (2004) Raloxifene decreases serum IGF-I in male patients with active acromegaly. Eur J Endocrinol 150(4):481–487

    Article  CAS  PubMed  Google Scholar 

  32. Shimon I, Barkan A (2012) Estrogen treatment for acromegaly. Pituitary 15(4):601–607

    Article  CAS  PubMed  Google Scholar 

  33. Vallette S, Serri O (2010) Oral estroprogestin: an alternative low cost therapy for women with postoperative persistent acromegaly? Pituitary 13(4):311–314

    Article  CAS  PubMed  Google Scholar 

  34. Clemmons DR, Underwood LE, Ridgway EC, Kliman B, Kjellberg RN, Van Wyk JJ (1980) Estradiol treatment of acromegaly. Reduction of immunoreactive somatomedin-C and improvement in metabolic status. Am J Med 69(4):571–575

    Article  CAS  PubMed  Google Scholar 

  35. Duschek EJ, Gooren LJ, Netelenbos C (2005) Comparison of effects of the rise in serum testosterone by raloxifene and oral testosterone on serum insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Maturitas 51(3):286–293

    Article  CAS  PubMed  Google Scholar 

  36. Birzniece V, Sutanto S, Ho KK (2012) Gender difference in the neuroendocrine regulation of growth hormone axis by selective estrogen receptor modulators. J Clin Endocrinol Metab 97(4):E521–E527

    Article  CAS  PubMed  Google Scholar 

  37. Duschek EJ, Valk-de Roo GW, Gooren LJ, Netelenbos C (2004) Effects of conjugated equine estrogen vs. raloxifene on serum insulin-like growth factor-i and insulin-like growth factor binding protein-3: a 2-year, double-blind, placebo-controlled study. Fertil Steril 82(2):384–390

    Article  CAS  PubMed  Google Scholar 

  38. Weissberger AJ, Ho KK, Lazarus L (1991) Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 72(2):374–381

    Article  CAS  PubMed  Google Scholar 

  39. Helle SI, Holly JM, Tally M, Hall K, Vander Stappen J, Lonning PE (1996) Influence of treatment with tamoxifen and change in tumor burden on the IGF-system in breast cancer patients. Int J Cancer 69(4):335–339

    Article  CAS  PubMed  Google Scholar 

  40. da Silva BB, Moita DS, Pires CG, Sousa-Junior EC, dos Santos AR, Lopes-Costa PV (2007) Evaluation of insulin-like growth factor-I in postmenopausal women with breast cancer treated with raloxifene. Int Semin Surg Oncol 4:18

    Article  PubMed Central  PubMed  Google Scholar 

  41. Cakmak A, Posaci C, Dogan E, Caliskan S, Guclu S, Altunyurt S (2005) Raloxifene increases serum leptin levels in postmenopausal women: a prospective study. Am J Obstet Gynecol 193(2):347–351

    Article  CAS  PubMed  Google Scholar 

  42. Balogh A, Kauf E, Vollanth R, Graser G, Klinger G, Oettel M (2000) Effects of two oral contraceptives on plasma levels of insulin-like growth factor I (IGF-I) and growth hormone (hGH). Contraception 62(5):259–269

    Article  CAS  PubMed  Google Scholar 

  43. Gibney J, Johannsson G, Leung KC, Ho KK (2005) Comparison of the metabolic effects of raloxifene and oral estrogen in postmenopausal and growth hormone-deficient women. J Clin Endocrinol Metab 90(7):3897–3903

    Article  CAS  PubMed  Google Scholar 

  44. Stamatakis E, Weiler R, Ioannidis JP (2013) Undue industry influences that distort healthcare research, strategy, expenditure and practice: a review. Eur J Clin Invest 43(5):469–475

    Article  PubMed  Google Scholar 

  45. Waffenschmidt S, Janzen T, Hausner E, Kaiser T (2013) Simple search techniques in PubMed are potentially suitable for evaluating the completeness of systematic reviews. J Clin Epidemiol 66(6):660–665

    Article  PubMed  Google Scholar 

  46. Doi SA, Thalib L (2008) A quality-effects model for meta-analysis. Epidemiology 19(1):94–100

    Article  PubMed  Google Scholar 

  47. Clemmons DR (2011) Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays. Clin Chem 57(4):555–559

    Article  CAS  PubMed  Google Scholar 

  48. Doi SA, Barendregt JJ, Mozurkewich EL (2011) Meta-analysis of heterogeneous clinical trials: an empirical example. Contemp Clin Trials 32(2):288–298

    Article  PubMed  Google Scholar 

  49. Higgins JP, Deeks JJ (2008) Chapter 7: Selecting studies and collecting data. In: Higgins J, Green S (eds.) Cochrane Handbook for Systematic Reviews of Interventions V5.0.1 [updated Sept 2008]. The Cochrane Collaboration

  50. Takkouche B, Cadarso-Suarez C, Spiegelman D (1999) Evaluation of old and new tests of heterogeneity in epidemiologic meta-analysis. Am J Epidemiol 150(2):206–215

    Article  CAS  PubMed  Google Scholar 

  51. Onitilo AA, Doi SAR, Barendregt JJ (2013) Chapter 15: meta-analysis II Interpretation and use of outputs. In: Doi SA, Williams GM (eds) Methods Clin Epidemiol. Springer-Verlag, Berlin, pp 253–266

    Chapter  Google Scholar 

  52. Suikkari AM, Tiitinen A, Stenman UH, Seppala M, Laatikainen T (1991) Oral contraceptives increase insulin-like growth factor binding protein-1 concentration in women with polycystic ovarian disease. Fertil Steril 55(5):895–899

    CAS  PubMed  Google Scholar 

  53. Duursma SA, Bijlsma JW, Van Paassen HC, van Buul-Offers SC, Skottner-Lundin A (1984) Changes in serum somatomedin and growth hormone concentrations after 3 weeks oestrogen substitution in post-menopausal women; a pilot study. Acta Endocrinol (Copenh) 106(4):527–531

    CAS  Google Scholar 

  54. Dawson-Hughes B, Stern D, Goldman J, Reichlin S (1986) Regulation of growth hormone and somatomedin-C secretion in postmenopausal women: effect of physiological estrogen replacement. J Clin Endocrinol Metab 63(2):424–432

    Article  CAS  PubMed  Google Scholar 

  55. Bellantoni MF, Vittone J, Campfield AT, Bass KM, Harman SM, Blackman MR (1996) Effects of oral versus transdermal estrogen on the growth hormone/insulin-like growth factor I axis in younger and older postmenopausal women: a clinical research center study. J Clin Endocrinol Metab 81(8):2848–2853

    CAS  PubMed  Google Scholar 

  56. Leung KC, Johannsson G, Leong GM, Ho KK (2004) Estrogen regulation of growth hormone action. Endocr Rev 25(5):693–721

    Article  CAS  PubMed  Google Scholar 

  57. Leung KC, Doyle N, Ballesteros M, Sjogren K, Watts CK, Low TH, Leong GM, Ross RJ, Ho KK (2003) Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Proc Natl Acad Sci USA 100(3):1016–1021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Friend KE, Hartman ML, Pezzoli SS, Clasey JL, Thorner MO (1996) Both oral and transdermal estrogen increase growth hormone release in postmenopausal women–a clinical research center study. J Clin Endocrinol Metab 81(6):2250–2256

    CAS  PubMed  Google Scholar 

  59. Helle SI, Omsjo IH, Hughes SC, Botta L, Huls G, Holly JM, Lonning PE (1996) Effects of oral and transdermal oestrogen replacement therapy on plasma levels of insulin-like growth factors and IGF binding proteins 1 and 3: a cross-over study. Clin Endocrinol (Oxf) 45(6):727–732

    Article  CAS  Google Scholar 

  60. Birzniece V, Ho KK (2012) Growth and development: patching up a better pill for GH-deficient women. Nat Rev. Endocrinol 8(4):197–198

    Article  CAS  PubMed  Google Scholar 

  61. Riggs BL, Hartmann LC (2003) Selective estrogen-receptor modulators—mechanisms of action and application to clinical practice. N Engl J Med 348(7):618–629

    Article  CAS  PubMed  Google Scholar 

  62. Gibney J, Wolthers T, Johannsson G, Umpleby AM, Ho KK (2005) Growth hormone and testosterone interact positively to enhance protein and energy metabolism in hypopituitary men. Am J Physiol Endocrinol Metab 289(2):E266–E271

    Article  CAS  PubMed  Google Scholar 

  63. Nugent AG, Leung KC, Sullivan D, Reutens AT, Ho KK (2003) Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women. Clin Endocrinol (Oxf) 59(6):690–698

    Article  CAS  Google Scholar 

  64. Heald A, Selby PL, White A, Gibson JM (2000) Progestins abrogate estrogen-induced changes in the insulin-like growth factor axis. Am J Obstet Gynecol 183(3):593–600

    Article  CAS  PubMed  Google Scholar 

  65. Campagnoli C, Biglia N, Lanza MG, Lesca L, Peris C, Sismondi P (1994) Androgenic progestogens oppose the decrease of insulin-like growth factor I serum level induced by conjugated oestrogens in postmenopausal women. Prelim Rep. Maturitas 19(1):25–31

    Article  CAS  Google Scholar 

  66. Schreiber I, Buchfelder M, Droste M, Forssmann K, Mann K, Saller B, Strasburger CJ (2007) Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German pegvisomant observational study. Eur J Endocrinol 156(1):75–82

    Article  CAS  PubMed  Google Scholar 

  67. Grynberg M, Salenave S, Young J, Chanson P (2010) Female gonadal function before and after treatment of acromegaly. J Clin Endocrinol Metabol 95(10):4518–4525

    Article  CAS  Google Scholar 

  68. Landin-Wilhelmsen K, Tengborn L, Wilhelmsen L, Bengtsson BA (1997) Elevated fibrinogen levels decrease following treatment of acromegaly. Clin Endocrinol (Oxf) 46(1):69–74

    Article  CAS  Google Scholar 

  69. Schwartz E, Echemendia E, Schiffer M, Panariello VA (1969) Mechanism of estrogenic action in acromegaly. J Clin Invest 48(2):260–270

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Bijlsma JW, Duursma SA (1986) Serum concentrations of somatomedins and growth hormone in relation to bone metabolism in acromegaly and thyroid dysfunction. Clin Exp Rheumatol 4(2):105–110

    CAS  PubMed  Google Scholar 

  71. Deller JJ Jr, Di Raimondo VC, Grodsky GM, Forsham PH (1966) Acromegaly. The effects of various steroid hormones on the insulin-induced growth hormone response. Calif Med 104(1):1–5

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Ho KK, Valiontis E, Waters MJ, Rajkovic IA (1993) Regulation of growth hormone binding protein in man: comparison of gel chromatography and immunoprecipitation methods. J Clin Endocrinol Metab 76(2):302–308

    CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare no author-industry ties or other conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Suhail A. R. Doi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material (DOC 103 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stone, J.C., Clark, J., Cuneo, R. et al. Estrogen and selective estrogen receptor modulators (SERMs) for the treatment of acromegaly: a meta-analysis of published observational studies. Pituitary 17, 284–295 (2014). https://doi.org/10.1007/s11102-013-0504-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-013-0504-2

Keywords

Navigation