Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

IJIR publishes special/guest-edited issues and topical collections. The peer review process for articles included in topical collections/special issues is the same as the peer review process of the journal in general. Additionally, if the Guest Editors author an article in their topical collection/special issue, they will not handle the peer review process.​

Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?

International Journal of Impotence Research volume 15, pages 156–165 (2003)Cite this article

Abstract

Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate, but with a modest effect on sexual function. We wondered if longer treatment would produce improved results. A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone (P<0.001) and free testosterone (P<0.001) occurred in all patients. Multivariable analysis showed that responses decreased significantly with aging (P<0.05). Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED. For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. Feldman HA et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54–61.

    Article  CAS  PubMed  Google Scholar 

  2. Laumann EO, Paik A, Rosen RC . Sexual dysfunction in the United States. Prevalence and predictors. JAMA 1999; 281: 537–544.

    Article  CAS  PubMed  Google Scholar 

  3. Gray A, Feldman HA, McKinlay JB, Longcope C . Age, disease and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991; 73: 1016–1025.

    Article  CAS  PubMed  Google Scholar 

  4. Deslypere JP, Vermeulen A . Leydig cell function in normal men: effect of age, lifestyle, residence, diet, and activity. J Clin Endocrinol Metab 1984; 59: 955–962.

    Article  CAS  PubMed  Google Scholar 

  5. Nankin HR, Calkins JH . Decreased bioavailable testosterone in aging normal and impotent men. J Clin Endocrinol Metab 1986; 63: 1418–1420.

    Article  CAS  PubMed  Google Scholar 

  6. Tenover JS, Matsumoto AM, Plymate SR, Bremner WJ . The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: response to clomiphene citrate. J Clin Endocrinol Metab 1987; 65: 1118–1126.

    Article  CAS  PubMed  Google Scholar 

  7. Blackman MR, Weintrau BD, Harman SM . Comparison of the effects of lung cancer, benign lung disease, and normal aging on pituitary–gonadal function in men. J Clin Endocrinol Metab 1988; 66: 88–95.

    Article  CAS  PubMed  Google Scholar 

  8. Woolf PD et al. Transient hypogonadotrophic hypogonadism after head trauma: effects on steroid precursors and correlation with sympathetic nervous system activity. Clin Endocrinol 1986; 25: 265–274.

    Article  CAS  Google Scholar 

  9. Woolf PD, McDonald JV, Lee LA, Kelly M . Hypogonadism of critical illness. J Clin Endocrinol Metab 1985; 60: 444–450.

    Article  CAS  PubMed  Google Scholar 

  10. Van den Berghe G, de Zeghert F, Lauwers P, Veldhuls JD . Luteinizing hormone secretion and hypoandrogenaemia in critically ill men: effect of dopamine. Clin Endocrinol 1994; 41: 563–569.

    Article  CAS  Google Scholar 

  11. Guay AT, Bansal S, Heatley GJ . Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab 1995; 80: 3546–3552.

    CAS  PubMed  Google Scholar 

  12. ACCE Clinical Practice Guidelines for the evaluation and treatment of hypogonadism in adult male patients. Endo Pract 2: 198–211.

  13. Bhasin S, Bremner WJ . 1997 Emerging issues in androgen replacement therapy. J Clin Endocrinol Metab 1996; 82: 3–8.

    Google Scholar 

  14. Kosasih JB, Abbasi AA, Rudman D . Serum insulin-like growth factor-1 and serum testosterone status of elderly men in an inpatient rehabilitation unit. Am J Med Sci 1996; 311: 169–173.

    CAS  PubMed  Google Scholar 

  15. Guay AT, Bansal S, Hodge MB . Possible hypothalamic impotence. Male counterpart to hypothalamic amenorrhea? Urology 1991; 38: 317–322.

    Article  CAS  PubMed  Google Scholar 

  16. Van den Bergeh G, de Zegher F, Bouillon R . Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998; 83: 1827–1834.

    Google Scholar 

  17. Giagulli VA, Kaufman JM, Vermeulen A . Pathogenesis of the decreased androgen levels in obese men. J Clin Endocrinol Metab 1994; 79: 997–1000.

    CAS  PubMed  Google Scholar 

  18. Govier FE, McClure RD, Kramer-Levien D . Endocrine screening for sexual dysfunction using free testosterone determinations. J Urol 1996; 156: 405–408.

    Article  CAS  PubMed  Google Scholar 

  19. LoGiudice F, Trimarchi F, Benvenga S . High prevalence of hypogonadism in impotence (Abstract). 10th International Congress of Endocrinology, San Francisco, 1996.

  20. Murray FT et al. Gonadal dysfunction in diabetic men with organic impotence. J Clin Endocrinol Metab 1987; 65: 127–135.

    Article  CAS  PubMed  Google Scholar 

  21. Spark RF, White RA, Connolly PB . Impotence is not always psychogenic. JAMA 1980; 243: 750–755.

    Article  CAS  PubMed  Google Scholar 

  22. Carroll JL, Ellis DJ, Bagley DH . Age-related changes in hormones in impotent men. Urology 1990; 36: 42–46.

    Article  CAS  PubMed  Google Scholar 

  23. Dobs AS, El-Deiry S, Wand G, Wiederkehr M . Central hypogonadism: distinguishing idiopathic low testosterone from pituitary tumors. Endo Pract 1998; 4: 355–359.

    Article  CAS  Google Scholar 

  24. Koreman SG et al. Secondary hypogonadism in older men: its relation to impotence. J Clin Endocrinol Metab 1990; 71: 963–969.

    Article  Google Scholar 

  25. Guay AT, Velasquez E, Perez JB . Characterization of patients in a medical endocrine-based center for male sexual dysfunction. Endo Pract 1999; 5: 314–321.

    Article  CAS  Google Scholar 

  26. Morales A, Johnston B, Heaton JPW, Lundie M . Testosterone supplementation for hypogonadal impotence: assessment of biochemical measures and therapeutic outcomes. J Urol 1997; 157: 849–854.

    Article  CAS  PubMed  Google Scholar 

  27. Burris AS et al. A long-term, prospective study of the physiologic and behavioral effects of hormone replacement in untreated hypogonadal men. J Androl 1992; 13: 297–304.

    CAS  PubMed  Google Scholar 

  28. Bagatell CJ, Heiman JR, Rivier JE, Bremner WJ . Effects of endogenous testosterone and estradiol on sexual behavior in normal young men. J Clin Endocrinol Metab 1994; 78: 711–716.

    CAS  PubMed  Google Scholar 

  29. Schiavi RC, White D, Mandeli J, Levine AC . Effect of testosterone administration on sexual behavior and mood in men with erectile dysfunction. Arch Sex Behav 1997; 26: 231–241.

    Article  CAS  PubMed  Google Scholar 

  30. Kwan M et al. The nature of androgen action on male sexuality: a combined laboratory-self-report study on hypogonadal men. J Clin Endocrinol Metab 1983; 57: 557–562.

    Article  CAS  PubMed  Google Scholar 

  31. Granata ARM et al. Relationship between sleep-related erections and testosterone levels in men. J Androl 1997; 18: 522–527.

    CAS  PubMed  Google Scholar 

  32. Davidson JM, Camargo CA, Smith ER . Effects of androgen on sexual behavior in hypogonadal men. J Clin Endocrinol Metab 1979; 48: 955–958.

    Article  CAS  PubMed  Google Scholar 

  33. Heaton JPW, Varrin SJ . Effects of castration and exogenous testosterone supplementation in an animal model of penile erection. J Urol 1994; 151: 797–800.

    Article  CAS  PubMed  Google Scholar 

  34. Mills TM, Reilly CM, Lewis RW . Androgens and penile erection: a review. J Androl 1996; 17: 633–638.

    CAS  PubMed  Google Scholar 

  35. Bivalacqua TJ et al. The influence of castration on pharmacologically induced penile erection in the cat. J Androl 1998; 19: 551–557.

    CAS  PubMed  Google Scholar 

  36. Reilly CM, Stopper VS, Mills TM . Androgens modulate the α-adrenergic responsiveness of vascular smooth muscle in the corpus cavernosum. J Androl 1997; 18: 26–31.

    CAS  PubMed  Google Scholar 

  37. Reilly CM, Lewis RW, Stopper VS, Mills TM . Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway. J Androl 1997; 18: 588–594.

    CAS  PubMed  Google Scholar 

  38. Traish AM, Kim NN, Goldstein I, Moreland RB . Alpha-adrenergic receptors in the penis: identification, characterization, and physiological function. J Androl 1999; 20: 671–682.

    CAS  PubMed  Google Scholar 

  39. Aversa A et al. Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction. Clin Endocrinol 2000; 53: 517–522.

    Article  CAS  Google Scholar 

  40. van der Poli T, Romijn JA, Endert E, Sauerwein HP . Effects of tumor necrosis factor on the hypothalmic–pituitary–testicular axis in healthy men. Metabolism 1993; 42: 303–307.

    Article  Google Scholar 

  41. Salchian B et al. Testicular pathologic changes and the pituitary–testicular axis during human immunodeficiency virus infection. Endo Pract 1999; 5: 1–9.

    Article  Google Scholar 

  42. Zwart AD, Iranmanesh A, Veldhuis JD . Disparate serum free testosterone concentrations and degrees of hypothalamo–pituitary–luteinizing hormone suppression are achieved by continuous versus pulsatile intravenous androgen replacement in men: a clinical experimental model of ketoconazole-induced reversible hypoandrogenemia with controlled testosterone add-back. J Clin Endocrinol Metab 1997; 82: 2062–2069.

    CAS  PubMed  Google Scholar 

  43. Danesi R et al. Clinical and experimental evidence of inhibition of testosterone production by suramin. J Clin Endocrinol Metab 1996; 81: 2238–2246.

    CAS  PubMed  Google Scholar 

  44. Donnelly P, White C . Testicular dysfunction in men with primary hypothyroidism; reversal of hypogonadotrophic hypogonadism with replacement thyroxine. Clin Endocrinol 2000; 52: 197–201.

    Article  CAS  Google Scholar 

  45. Mitchell R et al. Less acidic forms of luteinizing hormone are associated with lower testosterone secretion in men on haemodialysis treatment. Clin Endocrinol 1994; 1: 65–73.

    Article  Google Scholar 

  46. Hayami S, Sasagawa I, Nakada T . Influence of sex hormones on prostate volume in men on hemodialysis. J Androl 2000; 21: 258–261.

    CAS  PubMed  Google Scholar 

  47. Murialdo G et al. Sex hormones and pituitary function in male epileptic patients with altered or normal sexuality. Epilepsia 1995; 36: 360–365.

    Article  CAS  PubMed  Google Scholar 

  48. Wang C, Tso SC, Todd D . Hypogonadotropic hypogonadism in severe β-thalassemia: effect of chelation and pulsatile gonadotropin-releasing hormone therapy. J Clin Endocrinol Metab 1989; 68: 511–516.

    Article  CAS  PubMed  Google Scholar 

  49. Bergendahl M et al. Fasting suppresses pulsatile luteinizing hormone (LH) secretion and enhances orderliness of LH release in young but not older men. J Clin Endocrinol Metab 1998; 83: 1967–1975.

    CAS  PubMed  Google Scholar 

  50. Odell WD . Testosterone treatment of men treated with glucocorticoids. Arch Intern Med 1996; 156: 1133–1134.

    Article  CAS  PubMed  Google Scholar 

  51. Wang S-W et al. Effects of methanol extract of Chansu on hypothalamic–pituitary–testis function in rats. Metabolism 1998; 47: 1211–1216.

    Article  CAS  PubMed  Google Scholar 

  52. Reid IR, Wattie DJ, Evans MC, Stapleton JP . Testosterone therapy in glucocorticoid-treated men. Arch Intern Med 1996; 156: 1173–1176.

    Article  CAS  PubMed  Google Scholar 

  53. Rosmond R, Dallman MF, Bjorntorp P . Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab 1998; 83: 1853–1859

    CAS  PubMed  Google Scholar 

  54. Veldhuis JD . Recent insights into neuroendocrine mechanisms of aging of the human male hypothalmic–pituitary–gonadal axis. J Androl 20: 1–17.

  55. Hardy MP, Ganjam VK . 1997 Stress, 11β-HSD, and Leydig cell function. J Androl 1999; 18: 475–479.

    Google Scholar 

  56. Singh A et al. Differential hypothalamic-pituitary-adrenal axis reactivity to psychological and physical stress. J Clin Endocrinol Metab 1999; 84: 1944–1948.

    CAS  PubMed  Google Scholar 

  57. Chatterton RT Jr, Vogelsong KM, Lu Y-C, Hudgens GA . Hormonal responses to psychological stress in men preparing for skydiving. J Clin Endocrinol Metab 1997; 82: 2503–2509.

    CAS  PubMed  Google Scholar 

  58. Wang C et al. Testosterone replacement therapy improves mood in hypogonadal men—a clinical research center study. J Clin Endocrinol Metab 1996; 81: 3578–3583.

    CAS  PubMed  Google Scholar 

  59. Synder PJ et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999; 84: 1966–1972.

    Google Scholar 

  60. Spratt DI et al. Neuroendocrine-gonadal axis in men: frequent sampling of LH, FSH, and testosterone. Am J Physiol 1988; 17: E658–E666.

    Google Scholar 

  61. Jain P, Rademaker AW, McVary KT . Testosterone supplementation for erectile dysfunction: results of a meta-analysis. J Urol 2000; 164: 371–375.

    Article  CAS  PubMed  Google Scholar 

  62. Guay AT, Perez JB, Fitaihi WA, Vereb M . Testosterone treatment in hypogonal men: prostate-specific antigen level and risk of prostate cancer. Endo Pract 2000; 6: 132–138.

    Article  CAS  Google Scholar 

  63. Purvin VA . Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol 1995; 113: 482–484.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms Gail Macey for her work as research coordinator, and Ms Polly Zorolow and Ms Lynda Charters for their editorial assistance.

Author information

Authors and Affiliations

  1. Center for Sexual Function (Endocrinology), Peabody, Massachusetts, USA

    A T Guay, J B Perez, M B Hodge & E Velasquez

  2. Section of Medical Biostatistics, Lahey Clinic Northshore, Peabody, Massachusetts, USA

    J Jacobson

Authors
  1. A T Guay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J B Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M B Hodge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Velasquez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A T Guay.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Guay, A., Jacobson, J., Perez, J. et al. Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?. Int J Impot Res 15, 156–165 (2003). https://doi.org/10.1038/sj.ijir.3900981

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijir.3900981

Keywords

  • clomiphene citrate
  • erectile dysfunction
  • hypogonadotropic hypogonadism

This article is cited by

Search

Advanced search

Quick links