By Morley, John E
Abstract The diagnosis of late life hypogonadism is controversial. For the purposes of discussion, it is suggested that treatment of late life hypogonodism requires the presence of symptoms, a low level of circulating free or bioavailable testosterone level and a positive response to treatment. While this may appear to be a radical proposal, we believe it represents the most rigorous scientific approach to the diagnosis of late life hypogonadism at the present time.
Keywords: Hypogonadism, testosterone, ADAM, aging male survey, androgen deficiency
Few areas have created as much controversy as the diagnosis of late life hypogonadism and its management. So while the condition was first mentioned in the Chinese Text of Internal Medicine and had a major, though controversial, role in the medicine of the late nineteenth and firsthalf of the twentieth century , it was considered an invention of the pharmaceutical industry in the beginning of the twenty-first century . Over time it has had many names including male menopause (a truly inappropriate name), male climacteric, adrenopause, androgen deficiency of the aging male (ADAM), partial androgen deficiency of the aging male (PADAM) and late-onset hypogonadism. Recendy, a number of guidelines have been published in an attempt to define the condition and provide treatment guidelines [3,4], Despite this, much confusion still exists regarding the appropriate approach to diagnosing late life hypogonadism.
There would appear to be some consensus that the appropriate diagnosis of late life hypogonadism requires a complex of symptoms as well as an arbitrary testosterone level. The first problem arises in determining which constellation of symptoms determines that a male has late life hypogonadism. Part of the problem is many of the symptoms of late life hypogonadism are similar to those of depression, protein energy undernutrition, fatigue and frailty [5- 8] and some, such as muscle weakness (sarcopenia), are considered by some to be a characteristic of the aging process . While attempts to create symptom complexes as questionnaires, such as the Saint Louis University Androgen Deficiency in Aging Males (ADAM) questionnaire and the Aging Male Survey are highly sensitive, they have suboptimal specificity [10-16]. There is also a pervasive viewpoint that a careful history and examination by a clinician would in some magical way perform better than either of these two questionnaires . This viewpoint has not been tested, though an attempt to look at a variety of other symptoms failed to enhance the specificity [13, and unpublished observations].
A problem with symptoms is that recent studies have shown that there is marked inter-individual variation of the testosterone level at which symptoms occur, though within an individual the level appears to be relatively constant [18,19]. Using a single symptom, namely libido, as the gold standard for the diagnosis has also proved to be poorly associated with a given level of total or calculated bioavailable testosterone . An attempt to improve the discriminate value of libido by using CAG repeats as a determinant of testosterone receptor efficacy also proved not to be successful . Thus, while there is ample evidence that a low libido in the presence of some level of ‘low testosterone’ can be reversed by testosterone therapy , a low libido by itself is insufficient to allow the diagnosis of hypogonadism. Similar problems exist with determining the role of testosterone in producing poor quality erectile function [22-25]. There is even less ability to use other symptoms classically associated with hypogonadism as diagnostic markers. At a minimum it would appear that prior to using symptoms as a partial component of the diagnosis of late life hypogonadism, both depression and hypothyroidism should be excluded. Another conundrum is that many of the symptoms associated with hypogonadism are commonly seen in persons with illness and many of these diseases can produce low testosterone levels .
If symptoms perform poorly to diagnose late life hypogonadism then perhaps a biochemical measurement would be a better diagnostic tool? It is now well recognized that total testosterone, free testosterone and bioavailable testosterone all decline with aging [27-30]. Thus, a reasonable approach would be to create a normal range for young persons and use values below the normal range to make the diagnosis. This has stood endocrinologists in other conditions, e.g. hypothyroidism, in good stead over the years. Unfortunately, there are young persons with perfectiy normal libido and sexual function, who spend a significant portion of the day with testosterone levels well below any arbitrary normal range . While, in part, this is due to the circadian rhythm, in some individuals these ultra low levels occur at times when testosterone levels would be expected to be well within the normal range [31- 33]. In addition, a significant week to week variation in testosterone levels occurs [34,35]. Further, classical testosterone measurements have been shown to be highly variable from assay to assay and often it appears that normal values for the assays have not been appropriately calculated [36-38]. Because most late-onset hypogonadism is due predominandy to hypothalamic-pituitary dysfunction, measurement of luteinizing hormone is not useful in aiding in the determination of gonadal status [39,40].
A second controversy in the measurement of testosterone in the diagnosis of hypogonadism revolves around whether total testosterone is sufficient or if some measure of unbound (free) or loosely bound (bioavailable) testosterone is a more appropriate measure [34,38,41- 44]. Endocrinology has championed the measurement of free hormones and it seems strange that this principle is not championed when it comes to testosterone. While there are sex hormone binding globulin (SHBG) receptors and in some cases cellular effects may be due to testosterone bound to SHBG, this would appear to be a limited situation . When it has been looked at, bioavailable testosterone appears to correlate better with potential hypogonadal symptoms than does total testosterone . Salivary testosterone, a proxy for unbound testosterone, may also perform better than total testosterone [46-48]. Because of the increase in SHBG with aging and a possible alteration in binding kinetics, men with total testosterone as high as 17 nmol/L may have low bioavailable testosterone levels [42, and unpublished observations].
Since the original studies by Tenover , Morley et al.  and Sih et al.  demonstrating positive effects of testosterone replacement in older males with biochemical hypogonadism a number of other placebo controlled studies have been published. While numbers are not large, there is sufficient data to allow rigorous meta- analyses to demonstrate positive effects of testosterone replacement on sexuality and muscle mass and strength [21,52-54]. In addition, a well conducted three year study showed that testosterone increased function in older men . It should be recognized that there is a significant placebo effect, and replacement doses of testosterone may need to be relatively elevated to produce a measurable effect . Finally, evidence for serious side effects in carefully monitored males is minimal [57-59].
Based on the above, we would like to suggest that a combination of symptoms and testosterone measurement is inadequate to make the diagnosis of late life hypogonadism. An appropriate diagnosis of hypogonadism can only be made when an older person has symptoms of low testosterone (or possibly sarcopenia or osteopenia), for which other common causes have been excluded and has a relatively low testosterone (
1. Morley JE, Perry HM III. Androgen deficiency in aging men: role of testosterone replacement therapy. J Lab Clin Med 2000;135:370-378.
2. Groopman J. Hormones for Men (public awareness campaign launched to help in recognition of symptoms of male menopause or andropause). New Yorker, July 29, 2002.
3. Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legras JJ, Lunenfeld B, Morley JE, Schulman C, Wang C, Weidner W, Wu FC. Investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male 2005;8:56-58.
4. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91:1995-2010. 5. Shores MM, Moceri VM, Sloan KL, Matsumoto AM, Kivlahan DR. Low testosterone levels predict incident depressive illness in older men: effects of age and medical morbidity. J Clin Pyschiatry 2005;66:7-14.
6. Morley JE, Kim MJ, Haren MT, Kevorkian R, Banks WA. Frailty and the aging male. Aging Male 2005;8:135-140.
7. Lunenfeld B, Saad F, Hoesl CE. ISA, ISSAM and EAU recommendations for the investigation, treatment and monitoring of late-onset hypogonadism in males: scientific background and rationale. Aging Male 2005;8:59-74.
8. Morales A, Tenover JL. Androgen deficiency in the aging male: when, who, and how to investigate and treat. Urol Clin North Am 2002;29:975-982.
9. Morley JE, Baumgartner RN, RoubenoffR, Mayer J, Nair KS. Sarcopenia. J Lab Clin Med 2001;137:231-243.
10. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, Perry HM III. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000;49:1239- 1242.
11. Lin YC, Hwang TI, Chiang HS, Yang CR, Wu HC, Wu TL, Huang SP. Correlations of androgen deficiency with clinical symptoms in Taiwanese males. Int J Impot Res 2006; 18:343347.
12. Tancredi A, Reginster JY, Schleich F, Pire G, Maassen P, Luyckx F, Legros JJ. Interest of the androgen deficiency in aging males (ADAM) questionnaire for the identification of hypogonadism in elderly community-dwelling male volunteers. Eur J Endocrinol 2004;151:355-360.
13. Morley JE, Perry HM III, Kevorkian RT, Patrick P. Comparison of screening questionnaires for the diagnosis of hypogonadism. Maturitas 2006;53:424-429.
14. Miwa Y, Kaneda T, Yokoyama O. Correlation between the Aging Males’ Symptoms Scale and sex steroids, gonadotropins, dehydroepiandrosterone sulfate, and growth hormone levels in ambulatory men. J Sex Med 2006;3:723-726.
15. Heinemann LA, Saad F, Heinemann K, Thai DM. Can results of the Aging Males’ Symptoms (AMS) scale predict those of screening scales for androgen deficiency? Aging Male 2004;7:211-218.
16. Myon E, Martin N, Taieb C, Heinemann LA. Experiences with the French Aging Males’ Symptoms (AMS) scale. Aging Male 2005;8:184- 189.
17. Handelsman DJ. Testosterone: use, misuse and abuse. Med J Aust 2006;185:436-439.
18. Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab 2004;89:3813-3817.
19. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006;91:4335^1343.
20. Travison TG, Morley JE, Araujo AB, O’Donnell AB, McKinlay JB. The relationship between libido and testosterone levels in aging men. J Clin Endocrinol Metab 2006;91:2509-2513.
21. Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A, Isidori A, Febbri A, Lenzi A. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol 2005;63:601-602.
22. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol 2004;172:658-663.
23. Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, Chen J. Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed? J Urol 2005;173:530-532.
24. Shabsigh R. Testosterone therapy in erectile dysfunction. Aging Male 2004;7:312-318.
25. Tariq SH, Haleem U, Omran ML, Kaiser FE, Perry HM III, Morley JE. Erectile dysfunction: etiology and treatment in young and old patients. Clin Geriatr Med 2003;19:539-551.
26. Morley JE, Melmed S. Gonadal dysfunction in systematic disorders. Metabolism 1979;28:1051-1073.
27. Morley JE, Kaiser FE, Perry HM III, Patrick P, Morley PM, Stauber PM, Vellas B, Baumgartner RN, Garry PJ. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46:410-413.
28. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol 1997;146:609-617.
29. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724-731.
30. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middleaged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2002;87:589-598.
31. Spratt DI, O’Dea LS, Schoenfeld D, Butler J, Rao PN, Crowley WF Jr. Neuroendocrine-gonadal axis in men: frequent sampling of LH, FSH, and testosterone. Am J Physiol 1988;254:E658-E666.
32. Diver MJ, Imtiaz KE, Ahmad AM, Vora JP, Fraser WD. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol 2003;58:710-717.
33. Plymate SR, Tenover JS, Bremner WJ. Circadian variation in testosterone, sex hormone-binding globulin, and calculate non-sex hormone-binding globulin bound testosterone in health young and elderly men. J Androl 1989;10:366-371.
34. Morley JE, Patrick P, Perry HM III. Evaluation of assays available to measure free testosterone. Metabolism 2002; 51:554- 559.
35. Vermeulen A, Verdonck G. Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men. J Clin Endocrinol Metab 1992;74:939-942.
36. Lazarou S, Reyes-Vallejo L, Morgentaler A. Wide variability in laboratory reference values for serum testosterone. J Sex Med 2006;3:1085-1089.
37. Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2004;89:634-643.
38. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 2007;92:405-413.
39. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sei Med Sci 2002;57:M76-M99.
40. Morley JE. Androgens and aging. Marmitas 2001;38:61-71.
41 Nankin HR, Calkins JH. Decreased bioavailable testosterone in aging normal and impotent men. J Clin Endocrinol Metab 1986;63:1418- 1420.
42. Vermeulin A, Kaufman JM. Diagnosis of hypogonadism in the aging male. Aging Male 2002;5:170-176.
43. Christ-Crain M, Meier C, Huber P, Zimmerli L, Trummler M, Muller B. Comparison of different methods for the measurement of serum testosterone in the aging male. Swiss Med WkIy 2004;134:193- 197.
44. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666-3672.
45. van den BeId AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 2000;85:3276- 3282.
46. Wang C, Plymate S, Nieschlag E, Paulsen CA. Salivary testosterone in men: further evidence of a direct correlation with free serum testosterone. J Clin Endocrinol Metab 1981;53:1021-1024.
47. Morley JE, Perry HM III, Patrick P, Dollbaum CM, Kells JM. Validation of salivary testosterone as a screening test for male hypogonadism. Aging Male 2006;9:165-169.
48. Gonacharov N, Katsya G, Dobracheva A, Nizhnik A, Kolesnikova G, Herbst V, Westermann J. Diagnostic significance of free salivary testosterone measurement using a direct luminescence immunoassay in healthy men and in patients with disorders of androgenic status. Aging Male 2006;9:111-122.
49. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;75:1092-1098.
50. Morley JE, Perry HM III, Kaiser FE, Kraenzle D, Jensen J, Houston K, Mattammal M, Perry HM III. Effects of testosterone replacement therapy in old hypogonadal males: re preliminary study. J Am Geriatr Soc 1993;41:149-152.
51. Sih R, Morley JE, Kaiser FE, Perry HM III, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997;82:1661- 1667.
52. Bolona ER, Uraga MV, Haddad RM, Tracz MJ, Sideras K, Kennedy CC, Capies SM, Erwin PJ, Montori VM. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007;82:20-28.
53. Ottenbacher KJ, Ottenbacher ME, Ottenbacher AJ, Acha AA, Ostir GV. Androgen treatment and muscle strength in elderly men: a meta-analysis. J Am Geriatr Soc 2006;54:1666-1673.
54. Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol 2005; 63:280-293.
55. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005;90:1502-1510.
56. Haren MT, Witten GA, Chapman IM, Coates P, Morley JE. Effect of oral testosterone undecanoatc on visuospatial cognition, mood and quality of life in elderly men with low-normal gonadal status. Maturitas 2005;50:124-133. 57. Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: retrospective analysis. J Clin Endocrinol Metab 1997;82:3793- 3796.
58. Haddad RM, Kennedy CC, Capies SM, Tracz MJ, Bolona ER, Sideras K, Uraga MV, Erwin PJ, Montori VM. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007;82:29-39.
59. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo- controlled trials. J Gerontol A Biol Sei Med Sci 2005;60:1451-1457.
60. Stein DJ, Baldwin DS, Dolberg OT, Despiegel N, Bandelow B. Which factors predict placebo response in anxiety disorders and major depression? An analysis of placebo-controlled studies of escitalopram. J Clin Psychiatry 2006;67:1741-1746.
61. Haren MT, Kim MJ, Tariq SH, Wittert GA, Morley JE. Andropause: a quality-of-life issue in older males. Med Clin North Am 2006;90:1005-1023.
JOHN E. MORLEY
Division of Geriatric Medicine, Saint Louis University Medical Center, and VA Medical Center (GRECC), Saint Louis,
(Received 21 September 2007)
Correspondence: John E. Morley, MB, BCh, Division of Geriatric Medicine, Saint Louis University Medical Center, 1402 South Grand Boulevard, M238, Saint Louis, MO 63104, USA. Tel: (314) 977-8462. Fax: (314) 771-8575. E-mail: [email protected]
Copyright Taylor & Francis Ltd. Dec 2007
(c) 2007 Aging Male. Provided by ProQuest Information and Learning. All rights Reserved.