Skip to main content
Download PDF
  • Déficit Androgénique Lié à l’Âge
  • Published:

Le déficit androgénique lié à l’âge: du diagnostic biologique au traitement substitutif

Androgen deficiency in aging male (ADAM). From biological evaluation to hormone replacement therapy

Andrologie volume 12, pages 138–148 (2002)Cite this article

Résumé

Le déficit androgénique lié à l’âge (DALA) suscite un intérêt croissant étant donné l’allongement de la vie dans les pays développés et la possibilité d’un traitement substitutif supposé protéger les hommes âgés contre les effets de la carence en testostérone. Plusieurs études épidémiologiques ont établi que les paramètres hormonaux les mieux corrélés avec la densité minérale osseuse, la masse musculaire et la force musculaire étaient le taux de la testostérone libre ou de la testostérone biodisponible, ainsi que le taux de l’estradiol biodisponible, c’est-à-dire non lié à la testostérone-estradiol binding globulin (TeBG). En effet la diminution avec l’âge de la sécrétion testiculaire est masquée par l’augmentation du taux de la TeBG si l’on se contente de mesurer la testostérone totale. Une autre difficulté pour le diagnostic biologique du DALA est l’incertitude quant aux seuils à prendre en considération. Certes, par consensus tacite, la plupart des investigateurs considèrent que sont déficitaires les hommes dont le taux de testostérone biodisponible est au-dessous de la limite inférieure des hommes adultes jeunes, généralement le cinquième percentile. En réalité, cette attitude empirique n’est pas totalement validée scientifiquement, d’autant que l’on ignore tout de l’évolution avec l’âge de la sensibilité des récepteurs androgéniques. Mais cette prise de position permet d’identifier les hommes âgés candidats à un traitement hormonal substitutif. Actuellement plusieurs formulations de testostérone sont disponibles, permettant son administration par voie orale, intra0musculaire, ou transdermique. L’undécanoate de testostérone (Pantestone®) pris par la bouche est en principe transporté par la voie du canal thoracique, court-circuitant partiellement le métabolisme hépatique.

L’énanthate de testostérone (Androtardyl®) et l’heptylate de testostérone (Testostérone Heptylate®) sont des préparations huileuses retards actives 2 ou 3 semaines. Mais les taux obtenus peuvent être supra-physiologiques dans les jours suivant l’injection. Les formulations transdermiques sont d’apparition plus récente. Le dispositif Androderm® est un patch d’application quotidienne, dont la cinétique d’absorption mime le rythme circadien de la testostérone, mais les taux de dihydrotestostérone (DHT) peuvent être supra-physiologiques. La testostérone en gel (Androgel®) produit, par une seule application quotidienne, des taux stables de testostérone, DHT et estradiol. Le choix entre ces différentes formulations dépend des besoins du patient, de ses demandes et de sa compliance pour un mode d’administration donné.

Abstract

There is increasing interest in the assessment of testicular function in aging men, probably because of an increasing number of males above 60 years and because of the emerging gap in the medical management of aging between men and women. In the last three decades, the endocrinological problems of menopause have been thoroughly taken into consideration, while the decline in testis activity in the so called andropause was only recently recognized to deserve a similar interest. In fact, testis endocrine function is not so easy to evaluate in elderly men: total testosterone (tT) level declines very slowly and it is a fallacious index of testis function because of the increase in testosterone/estradiol binding globulin (TeBG) levels in aging males. Free testosterone level is an accurate index when measured by reference techniques, while routine direct assays using testosterone analogues have been proven to be unreliable diagnostic tools. The measurement of bioavailable testosterone (bT) after ammonium sulfate precipitation of TeBG-bound testosterone is currently considered as the method of choice for diagnosing ADAM syndrome. Indeed, in aging males, bT levels are more closely correlated than tT with bone mineral density, muscle strength and muscle mass. Bioavailable estradiol is also a reliable index of testis aging in elderly males and is strongly correlated with bone mineral density. Unfortunately a serious expertise is needed for accurate measurement of bioavailable estradiol levels. Another difficulty in the diagnosis of ADAM syndrome in the uncertainty in the bT threshold to be taken into account. The 5th percentile of bT levels in young adult men can be arbitrarily choosen; however, there is no definite proof that such a threshold is totally appropriate, since no data are available regarding the evolution with years of androgen receptor sensitivity. Nevertheless, identifying androgen deficiency by means of bT measurement may lead to hormone replacement therapy, at least as a therapeutic test. Several formulations of testosterone are currently available using oral, intra-muscular and transdermal routes. Testosterone undecanoate (Pantestone®) is given orally and is supposed to reach the blood stream via the lymph thoracic channel. Intra-muscular testosterone in oil (Androtardyl® and Testosterone Heptylate®) can maintain high testosterone levels for two to three weeks, but can also induce supra-physiological levels of testosterone and dihydrotestosterone (DHT) within the first week after injection. Transdermal formulations have been recently proposed as non-invasive ways to administer testosterone while by-passing liver metabolism. Permeation enhanced transdermal system (Androderm®) can mimic the testosterone circadian rythm, but testosterone levels may be supra-physiological for several hours. DHT levels however are generally maintained whithin physiological values. Testosterone gel (Androgel®) can induce stable and physiological levels of testosterone, DHT and estradiol. Care should be taken to avoid contamination of the familial environment by testosterone after its application. The choice between these formulations depends obviously on the patient’s needs, the patient’s requests, and the patient’s compliance with a particular formulation.

Références

  1. ATKINSON L.E., CHANG Y.L., SNYDER P.J.: Long-term experience with testosterone replacement through scrotal skin. In: Nieschlag E., Behre H.M., eds. Testosterone, Action, Deficiency, Substitution. Berlin, Springer, 1998: 365–388.

    Google Scholar 

  2. BAULIEU E.E., THOMAS G., LEGRAIN S. et al.: Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge study to a sociobiomedical issue. Proc. Natl. Acad. Sci. USA, 2000, 97: 4279–4284.

    Article  PubMed  CAS  Google Scholar 

  3. BEHRE H.M., NIESCHLAG E.: Comparative pharmacokinetics of testosterone esters. In: Nieschlag E., Behre H.M. eds. Testosterone, Action, Deficiency, Substitution, Berlin, Springer, 1998: 329–348.

    Google Scholar 

  4. BEHRE H.M., ABSHAGEN K., OETTEL M. et al.: Intramuscular injction of testosterone undecanoate for the treatment of male hypogondism: phase I studies. Eur. J. Endocrinol., 1999, 140: 414–419.

    Article  PubMed  CAS  Google Scholar 

  5. BEHRE H.M., VON ECKARDSTEIN S., KLIESCH S. et al.: Long-term substitution therapy of hypogonadal men with transcrotal testosterone over 7–10 years. Clin. Endocrinol., 1999, 50: 629–635.

    Article  CAS  Google Scholar 

  6. DECHAUD H., LEJEUNE H., GAROSCIO-CHOLET M. et al.: Radioimmunoassay of testosterone not bound to sex-steroid binding protein in plasma. Clin. Chem., 1989, 35: 1059–1014.

    Google Scholar 

  7. DOBS A.S., LOOVER D.R., CHEN M.C. et al.: Pharmacokinetic characteristics, efficacy, and safety of buccal testosterone in hypogonadal males: a pilot study. J. Clin. Endocrinol. Metab., 1998, 83: 33–39.

    Article  PubMed  CAS  Google Scholar 

  8. DOBS A.S., MEIKLE A.W., ARVER S. et al.: Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J. Clin. Endocrinol. Metab., 1999, 84: 3469–3478.

    Article  PubMed  CAS  Google Scholar 

  9. DOBS A.S., BACHORIK P.S., ARVER S. et al.: Interelationship among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone trandermal system. J. Clin. Endocrinol. Metab., 2001, 86: 1026–1033.

    Article  PubMed  CAS  Google Scholar 

  10. ENGLISH K.M., PUGH P.J., PARRY H. et al.: Effect of cigarette smoking on levels of bioavailable testosterone in healthy men. Clin. Science, 2001, 100: 661–665.

    Article  CAS  Google Scholar 

  11. FERRINI R.L., BARRETT-CONNOR E.: Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am. J. Epidemiol., 1998, 147: 750–754.

    PubMed  CAS  Google Scholar 

  12. HAJI M., TANAKA S., NISHI Y. et al.: Sertoli cell function declines earlier than Leydig cell function in Japanese men. Maturitas, 1994, 18: 143–153.

    Article  PubMed  CAS  Google Scholar 

  13. HARMAN S.M., METTER E.J., TOBIN J.D. et al.: Longitudinal effect of aging on serum total and free testosterone levels in healthy men. J. Clin. Endocrinol. Metab., 2001, 86: 724–731.

    Article  PubMed  CAS  Google Scholar 

  14. KAUFMAN J.M., VERMEULEN A.: Androgens in male senescence. In: Nieschlag E., Behre H.M., eds. Testosterone, Action, Deficiency, Substitution. Berlin, Springer, 1998, 437–471.

    Google Scholar 

  15. KENNY A.M., GALLAGHER J.C., PRESTWOOD K.M. et al.: Bone density, bone turnover, and hormone levels in men over age 75. J. Gerontol. Med. Sci., 1998, 53A: M419-M425.

    CAS  Google Scholar 

  16. KENNY A.M., PRESTWOOD K.M., MARCELLO K.M. et al.: Determinants of bone density in healthy older men with low testosterone levels. J. Gerontol. Med. Sci., 2000, 55A: M492-M497.

    CAS  Google Scholar 

  17. KHOSLA S., MELTON L.J. 3rd, ATKINSON E.J. et al.: Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J. Clin. Endocrinol. Metab., 1998, 83: 2266–2274.

    Article  PubMed  CAS  Google Scholar 

  18. LEIFKE E., GORENOI V., WICHERS C. et al.: Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort. Clin. Endocrinol., 2000, 53: 689–695.

    Article  CAS  Google Scholar 

  19. LEJEUNE H.: Andropause ou vieillissement? Rev. Prat. Gynecol. Obstet., 1998, 26: 35–39.

    Google Scholar 

  20. MAZER N.A.: New clinical applications of transdermal testosterone delivery in men and women. J. Controlled Release, 2000, 65: 3003–3015.

    Article  Google Scholar 

  21. MEIKLE A.W.: A permeation-enhanced non-scrotal testosterone transdermal system for the treatment of male hypogondism. In: Nieschlag E., Behre H.M., eds. Testosterone, Action. Deficiency, Substitution. Berlin, Springer, 1998: 390–422.

    Google Scholar 

  22. MORLEY J.E., KAISER F.E., PERRY H.M. 3rd et al.: Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism, 1997, 46: 410–413.

    Article  PubMed  CAS  Google Scholar 

  23. MORLEY J.E., KAISER F.E., RAUM W.J. et al.: Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc. Natl. Acad. Sci. USA, 1997, 94: 7537–7542.

    Article  PubMed  CAS  Google Scholar 

  24. MORLEY J.E.: Androgens and aging. Maturitas, 2001, 38: 61–73.

    Article  PubMed  CAS  Google Scholar 

  25. NAHOUL K, ROGER M.: Dosages hormonaux. In: Papiernik E., Rozenbaum H., Belaïsch-Allart J. eds. Gynécologie. Paris, Flammarion Médecine-Sciences, 1990: 201–221.

    Google Scholar 

  26. NAHOUL K., ROGER M.: Age-related decline of plasma bioavailable testosterone in adult men. J. Steroid Biochem., 1990, 35: 293–299.

    Article  PubMed  CAS  Google Scholar 

  27. NAHOUL K., ADELINE J., ROGER M.: Evolution en fonction de l’âge du glucuronide d’androstanediol plasmatique chez l’homme. Pathol. Biol. (Paris), 1990, 37: 593–598.

    Google Scholar 

  28. Report of the National Institute on Aging Adisory Panel on testosterone replacement in men. J. Clin. Endocrinol. Metab., 2001, 86: 4611–4614.

    Google Scholar 

  29. ROSNER W.: Errors in the measurement of plasma free testosterone. J. Clin. Endocrinol. Metab., 1997, 82: 2014–2015.

    PubMed  CAS  Google Scholar 

  30. SZULC P., MUNOZ F., CLAUSTRAT B. et al.: Bioavailable estradiol may be an important determinant of osteoporosis in men. J. Clin. Endocrinol. Metab., 2001, 86: 192–199.

    Article  PubMed  CAS  Google Scholar 

  31. SWERDLOFF R.S., WANG C., CUNNINGHAM G. et al.: Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J. Clin. Endocrinol. Metab., 2000, 85: 4500–4510.

    Article  PubMed  CAS  Google Scholar 

  32. TENOVER J.S., MATSUMOTO A.M., PLYMATE S.R. et al.: The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: reponse to clomiphene citrate. J. Clin. Endocrinol. Metab., 1987, 65: 1118–1126.

    Article  PubMed  CAS  Google Scholar 

  33. TREMBLAY R.R., DUBE J.Y.: Plasma concentrations of free and non-TeBG bound testosterone in women on oral contraceptives. Contraception, 1974, 10: 599–605.

    Article  PubMed  CAS  Google Scholar 

  34. TREMBLAY R.R., MORALES A.: Canadian practice recommendations for screening, monitoring and treating men affected by andropause or partial androgen deficiency. Aging Male, 1998, 1: 213–218.

    Article  Google Scholar 

  35. VAN DEN BELD A.W., DE JONG F.H., GROBBEE D.E. et al.: Measures of bioavailable serum testosterone and estradiol and their relationship with muscle strength, bone density, and body composition in elderly men. J. Clin. Endocrinol. Metab., 2000, 85: 3276–3282.

    Article  PubMed  Google Scholar 

  36. VELDHUIS J.D., IRANMANESH A., MULLIGAN T. et al.: Disruption of the young-adult synchrony between luteinizing hormone release and oscillations in follicle-stimulating hormone, prolactin, and nocturnal penile tumescence (NPT) in healthy older men. J. Clin. Endocrinol. Metab., 1999, 84: 3498–3505.

    Article  PubMed  CAS  Google Scholar 

  37. VELDHUIS J.D., ZWART A., MULLIGAN T. et al.: Muting of androgen negative feedback unveils impoverished gonadotropinreleasing hormone/luteinizing hormone secretory reactivity in healthy older men. J. Clin. Endocinol. Metab., 2001, 86: 529–535.

    Article  CAS  Google Scholar 

  38. VERMEULEN A., VERDONCK L., KAUFMAN J.M.: A critical evaluation of simple methods for the estimation of free testosterone in serum. J. Clin. Endocrinol. Metab., 1999, 84: 3666–3672.

    Article  PubMed  CAS  Google Scholar 

  39. VERMEULEN A.: Andropause. Maturitas, 2000, 34: 5–15.

    Article  PubMed  CAS  Google Scholar 

  40. VERMEULEN A.: Androgen replacement therapy in the aging male—A critical evaluation. J. Clin. Endocrinol. Metab., 2001, 86: 2380–2390.

    Article  PubMed  CAS  Google Scholar 

  41. WINTERS S.J., KELLEY D.E., GOODPASTER B.: The analog free testosterone assay: are the results in men clinically useful? Clin. Chem., 1998, 44: 2178–2182.

    PubMed  CAS  Google Scholar 

  42. World Health Organization Ageing and Health Program: Men, ageing and health. Aging Male, 2003, 3: 3–36.

    Google Scholar 

  43. ZITZMANN M., NIESCHLAG E.: Hormone substitution in male hypogonadism. Mol. Cell. Endocrinol., 2000, 161: 73–88.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Najiba Lahlou

    Present address: Laboratoire de Biologie Hormonale, Hôpital Saint-Vincent-de-Paul, 82, avenue Denfert-Rochereau, 75014, Paris

Authors and Affiliations

  1. Laboratoire de Biologie Hormonale, Hôpital Saint-Vincent-de-Paul, 82, avenue Denfert-Rochereau, 75014, Paris

    Marc Roger

Authors
  1. Marc Roger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Najiba Lahlou
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roger, M., Lahlou, N. Le déficit androgénique lié à l’âge: du diagnostic biologique au traitement substitutif. Androl. 12, 138–148 (2002). https://doi.org/10.1007/BF03034960

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03034960

Mots-clés

Key words

Basic and Clinical Andrology

ISSN: 2051-4190