Skip to main content
SpringerLink
Log in

Mechanism delineating differential effect of an antiestrogen, tamoxifen, on the serum LH and FSH in adult male rats

  • Original Articles
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Tamoxifen, a synthetic non-steroidal antiestrogen with residual estrogenic activity, administered to adult male rats reduces their fertility. A decrease in the circulating LH and testosterone levels with a transient rise or no change in circulating FSH levels was observed. The present study was carried out to delineate the mechanism causing the differential effect of tamoxifen on circulating gonadotropins by correlating it to changes in the hypothalamic LHRH, pituitary gonadotropins and testicular inhibin/activin. Hypothalamus, pituitary-hypothalamus complex (PHC) and intact pituitary (PI) from control and tamoxifen-treated male rats were superfused in vitro, and pulsatile release of LHRH by hypothalamus and that of LH and FSH by the PHC and PI were studied. Concomitantly, testicular immunoexpression of α and βB subunits of inhibin/activin were studied by immunohistochemistry and enzyme-linked immunosorbent assays (ELISA). At 0.4 mg/kg/day dose of tamoxifen a decrease in mean hypothalamic LHRH and LH pulse frequency from PHC construct was observed. FSH pulse frequency was not affected under the same experimental conditions. At the same dose of tamoxifen, testicular expression of both α and βB subunits of inhibin/activin was upregulated. The study demonstrated that reduced circulating LH levels were due to a decrease in hypothalamic LHRH concentration and in LH pulsatility following tamoxifen treatment. The lack of effect on circulating FSH under the same experimental conditions was likely due to its modulation by inhibin and activin.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Levine JE, Bauer-Dantoin AC, Besecke LM, et al. Neuroendocrine regulation of luteinizing hormone releasing hormone pulse generator in the rat. Recent Prog Horm Res 1991, 47: 97–151.

    CAS  PubMed  Google Scholar 

  2. Gharib SD, Wierman ME, Shupnik MA, Chin WW. Molecular biology of the pituitary gonadotropins. Endocr Rev 1990, 11: 177–99.

    Article  CAS  PubMed  Google Scholar 

  3. Besecke LM, Guender MJ, Schneyer AC, Bauer-Dantoin AC, Jameson JL, Weiss J. Gonadotropin-releasing hormone regulates follicle stimulating hormone-beta gene expression through an activin/follistatin autocrine or paracrine loop. Endocrinology 1996, 137: 3667–73.

    CAS  PubMed  Google Scholar 

  4. Shupnik MA, Schreihofer DA. Molecular aspects of steroid hormone action in the male reproductive axis. J Androl 1997, 18: 341–4.

    CAS  PubMed  Google Scholar 

  5. Marubayashi U, Yu WH, McCann SM. Median eminence lesions reveal separate hypothalamic control of pulsatile follicle stimulating hormone and luteinizing hormone release. Proc Soc Expt Biol Med 1999, 220: 139–46.

    Article  CAS  Google Scholar 

  6. Gill-Sharma MK, Gopalkrishnan K, Balasinor N, Parte P, Jayaraman S, Juneja HS. Effect of tamoxifen on fertility of male rats. J Reprod Fertil 1993, 99: 395–402.

    Article  CAS  PubMed  Google Scholar 

  7. Balasinor N, Parte P, Gill-Sharma MK, Juneja HS. Effect of tamoxifen on sperm fertilising ability and pre-implantation embryo development. Mol Cell Endocrinol 2001, 178: 199–206.

    Article  CAS  PubMed  Google Scholar 

  8. Gopalkrishnan K, Gill-Sharma MK, Balasinor N, et al. Tamoxifen induced light and electron microscopic changes in rat testicular morphology and serum hormone profile of reproductive hormones. Contraception 1998, 57: 261–9.

    Article  CAS  PubMed  Google Scholar 

  9. Swerdloff RS, Walsh PC. Testosterone and oestradiol suppression of LH and FSH in adult male rats: duration of castration, duration of treatment and combineed treatment. Acta Endocrinol (Copenh) 1973, 73: 11–2

    Google Scholar 

  10. Gill-Sharma MK, D’Souza S, Padwal V, et al. Antifertility effects of estradiol in adult male rats. J Endocrinol Invest 2001, 24: 598–607.

    Article  CAS  PubMed  Google Scholar 

  11. Kirk SE, Dalkin AC, Yasin M, Haisenleder DJ, Marshall JC. Gonadotropin releasing hormone pulse frequency regulates expression of pituitary follistatin messenger ribonucleic acid: a mechanism for differential gonadotrope function. Endocrinology 1994, 135: 876–80.

    CAS  PubMed  Google Scholar 

  12. Kaiser UB, Jakubwaik A, Steinberger A, Chin WW. Differential effects of gonadotropin-releasing hormone (GnRH) pulse frequency on gonadotropin subunit and GnRH receptor messenger ribonucleic acid levels in vitro. Endocrinology 1997, 138: 1224–31.

    CAS  PubMed  Google Scholar 

  13. Meredith JM, Turek FW, Levine JE. Effects of gonadotropin-releasing hormone pulse frequency modulation on the reproductive axis of photo inhibited male Siberian hamsters. Biol Reprod 1998, 59: 813–9.

    Article  CAS  PubMed  Google Scholar 

  14. Gill-Sharma MK, Karanth S, Dutt A, Juneja HS. Effect of castration and steroid treatment on the release of gonado-trophins by the rat pituitary-hypothalamus complex in vitro. Horm Metab Res 1985, 17: 141–6.

    Article  Google Scholar 

  15. Dutt A, Gill MK, Karanth S, Lehri N, Juneja HS. The choice of a model for studying the hypothalamus-pituitary interactions in vitro. Mol Cell Endocrinol 1986, 45: 21–6.

    Article  CAS  PubMed  Google Scholar 

  16. Hartter DE, Ramirez VD. Responsiveness of immature versus adult male rat hypothalamic to dibutyryl cyclic AMP and forskolin-induced LHRH release in vitro. Neuroendocrinology 1985, 40: 476–82.

    Article  CAS  PubMed  Google Scholar 

  17. Miller MR, Sharpe RM, Maguire SM, Saunders PTK. Cellular localisation of messenger RNAs in rat testis: application of digoxigenin labelled probes to embedded tissue. Cell Tissue Res 1993, 273: 269–77.

    Article  Google Scholar 

  18. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with folin phenol reagent. J Biol Chem 1951,193: 265–7

    Google Scholar 

  19. Saito S, Roche PC, McCormick DJ, Ryan RJ. Synthetic peptide segments of lnhibin α- and β-subunits: Preparation and Characterization of polyclonal antibodies. Endocrinology 1989, 125: 898–905.

    Article  CAS  PubMed  Google Scholar 

  20. Veldhius JD, Johnson M. Cluster analysis: a simple, versatile and robust algorithm for endocrine pulse detection. Am J Physiol 1986, 250: E486–93.

    Google Scholar 

  21. Clark IJ, Cummins JT. The significance of small pulses of GnRH. J Endocrinol 1987, 113: 413–8.

    Article  Google Scholar 

  22. Haisendeler DJ, Dalkin AC, Ortolone GH, Marshall JC, Shupnik MA. A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes, evidence for differential regulation of transcription by pulse frequency in vivo. Endocrinology 1990, 128: 509–17.

    Article  Google Scholar 

  23. Hayes FJ, Seminara SB, Decruz S, Beopple PA, Crowley WF Jr. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab 2000, 85: 3027–35.

    CAS  PubMed  Google Scholar 

  24. Tilbrook AJ, Clarke IJ. Negative feedback regulation of the secretion and actions of gonadotropin-releasing hormones in males. Biol Reprod 2001, 64: 735–42.

    Article  CAS  PubMed  Google Scholar 

  25. Winters SJ, Troen P. Evidence for a role of endogenous estrogen in the hypothalamic control of gonadotropin secretion in man. J Clin Endocrinol Metab 1985, 61: 842–5.

    Article  CAS  PubMed  Google Scholar 

  26. Matsumoto AM, Bremner WJ. Modulation of pulsatile gonadotropin secretion by testosterone in man. J Clin Endocrinol Metab 1984, 58: 609–14.

    Article  CAS  PubMed  Google Scholar 

  27. Krieg RJ Jr, Batson JM, Martha PM Jr, Matt DW, Salisbury RL, Evans WS. Gonadotropin-releasing hormone stimulating luteinizing hormone secretion by perifused pituitary cells from normal, gonadectomized and testicular feminized rats. Endocrinology 1990, 126: 3022–7.

    Article  CAS  PubMed  Google Scholar 

  28. Selmanoff MK, Brodkin LD, Weiner RI, Siiteri PK. Aromatization and 5 alpha-reduction of androgen in discrete hypothalamic and limbic region of the male and female rat. Endocrinology 1977, 101: 841–8.

    Article  CAS  PubMed  Google Scholar 

  29. Spratt DP, Herbison AE. Regulation of preoptic area gonadotropin-releasing hormone (GnRH) mRNA by gonadal steroids in the long term gonadectomized male rats. Brain Res Mol Brain Res 1997, 47: 125–33.

    Article  CAS  PubMed  Google Scholar 

  30. Ferland L, Marchetti B, Seguin C, Lefebvre FA, Reeves JJ, Labrie F. Dissociated changes of pituitary luteinizing hormone releasing hormone (LHRH) receptors and responsiveness to the neurohormone induced by 17β estradiol and LHRH in vivo in the rat. Endocrinology 1981, 109: 87–93.

    Article  CAS  PubMed  Google Scholar 

  31. Garcia A, Schiff M, Marshall JC. Regulation of pituitary gonadotropin-releasing hormone receptors by pulsatile gonadotropin-releasing hormone injections in male rats. Modulation by testosterone. J Clin Invest 1984, 74: 920–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Vale W, Rivier J, Vaughan J, et al. Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid. Nature 1986, 321: 776–9.

    Article  CAS  PubMed  Google Scholar 

  33. Ling N, Ying SY, Uena N, et al. FSH is released by a heterodimer of the beta subunits from the two forms of inhibin. Nature 1986, 321: 779–82.

    Article  CAS  PubMed  Google Scholar 

  34. Najmabadi H, Rosenberg LA, Yuan QX, et al. Transcriptional and post transcriptional regulation of inhibin α subunit gene expression in rat Sertoli cells by 8 bromo-3′,5′ cyclic adenosine monophosphate. Mol Endocrinol 1993, 7: 469–76.

    CAS  PubMed  Google Scholar 

  35. Najmabadi H, Rosenberg LA, Yuan QX, Reyaz G, Bhasin S. Transcriptional regulation of inhibin beta B messenger ribonucleic acid levels in TM4 or primary rat Sertoli cells by 8 bromo cyclic adenosine monophosphate. Mol Endocrinol 1993, 7: 561–9.

    CAS  PubMed  Google Scholar 

  36. Krummen LA, Toppari J, Kim WH, et al. Regulation of testicular inhibin subunit mRNA levels in vivo: effects of hypophysectomy and selective follicle stimulating hormone replacement. Endocrinology 1989, 125: 1630–7.

    Article  CAS  PubMed  Google Scholar 

  37. Tate S, Suganuma N, Furuhashi M, et al. Direct effects of estradiol and tamoxifen on gene expressions of inhibin α and βA subunits in rat granulosa cells in vitro. J Endocrinol 1996, 43: 621–8.

    CAS  Google Scholar 

  38. Klaij IA, Toebosch AMW, Themmen APN, Shimaski S, deJong FH, Grootegoed JA. Regulation of inhibin alpha and beta subunit mRNA levels in rat Sertoli cells. Mol Cell Endocrinol 1990, 68: 45–52.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroendocrinology, National Institute for Research in Reproductive Health, Parel, Mumbai, 400012, India

    N. Balasinor PhD, P. Parte PhD, M. K. Gill-Sharma, J. Kini & H. S. Juneja

Authors
  1. N. Balasinor PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Parte PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. K. Gill-Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Kini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. S. Juneja
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to N. Balasinor PhD or P. Parte PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Balasinor, N., Parte, P., Gill-Sharma, M.K. et al. Mechanism delineating differential effect of an antiestrogen, tamoxifen, on the serum LH and FSH in adult male rats. J Endocrinol Invest 29, 485–496 (2006). https://doi.org/10.1007/BF03344137

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03344137

En]Key-words

Search

Navigation