Population variation in age-related decline in male salivary testosterone

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age-related declines in male testosterone are also associated ... Table I. Mean (pmol/l) salivary testosterone levels (T) from men in four populations, for total sample .... Christiansen, K.H. (1991b) Serum and saliva sex hormone levels in Kung.
Human Reproduction Vol.17, No.12 pp. 3251–3253, 2002

Population variation in age-related decline in male salivary testosterone Peter T.Ellison1,7, Richard G.Bribiescas2, Gillian R.Bentley3, Benjamin C.Campbell4, Susan F.Lipson1, Catherine Panter-Brick5 and Kim Hill6 1Department of Anthropology, Harvard University, Cambridge, MA, 2Department of Anthropology, Yale University, New Haven, CT, USA, 3Department of Anthropology, University College London, London, UK, 4Department of Anthropology, Boston University, Boston, MA, USA, 5Department of Anthropology, Durham University, Durham, UK and 6Department of Anthropology, University of New Mexico, Albuquerque, NM, USA 7To

whom correspondence should be addressed at: Department of Anthropology, Peabody Museum, Harvard University, 11 Divinity Avenue, Cambridge, MA 02138 USA. E-mail: [email protected]

BACKGROUND: Age-related declines in free and bioavailable testosterone are frequently reported for Western populations, but interpopulation variation in this pattern has not previously been investigated. METHODS: Salivary testosterone was measured using a consistently applied protocol on morning samples collected from men in four populations (USA, Congo, Nepal, and Paraguay) representing different geographical, ecological, and cultural settings. RESULTS: Mean testosterone levels varied significantly between the four populations. The mean testosterone differences between populations were greatest for young men (aged 15–30 years) and insignificant for older men (aged 45–60 years). The slope of age-related decline in testosterone was significant in the USA and Congolese participants, but not in the Nepalese or Paraguayan participants. CONCLUSIONS: Age patterns of testosterone decline vary between populations primarily as a result of variation in the peak levels attained in young adulthood. The potential consequences of this variation for other aspects of male health deserve investigation. Key words: ageing/population variation/salivary testosterone/testosterone

Introduction Although formerly controversial, an age-related decline in free and bioavailable testosterone in healthy males is now a frequently reported pattern in Western populations (Ferrini and Barrett-Connor, 1998; Vermeulen et al., 1999; Harman et al., 2001). Age-related declines in testosterone levels in males have been associated with changes in body composition, including increases in fat mass, decreases in muscle mass, and decreases in bone mineral density (Denti et al., 1999; Vermeulen et al., 1999; Kenny et al., 2000; van den Beld et al., 2000). Reflecting these linkages to body composition, age-related declines in male testosterone are also associated with elevated risk of type II diabetes (Stellato et al., 2000; Haffner et al., 1996), coronary heart disease (Simon et al., 1997; De Pergola et al., 1997), ischemic stroke (Jeppesen et al., 1996) and osteoporosis (Francis, 1999; Snyder et al., 1999a). Low testosterone levels in older men are also associated with low libido, erectile dysfunction, and depression (Barrett-Connor et al., 1999; Schweiger et al., 1999; Wang et al., 2000). On the other hand, high testosterone levels have been associated with elevated risk and progress of prostate cancer (Crawford, 1992; van Tinteren and Dasio, 1993). Testosterone supplementation of older men has been shown to result in increases in lean-body mass, decreases in fat mass, © European Society of Human Reproduction and Embryology

increases in bone mineral density, and improvements in mood and sexual function (Bhasin and Tenover, 1997; Snyder et al., 1999a,b; Winters, 1999). Despite evidence of its clinical importance, relatively little is known about population variation in age patterns of testosterone. This contrasts strikingly with the increasing awareness of population variation in female ovarian steroid profiles and its relationship to disease risk (Ellison et al., 1993; O’Rourke and Ellison, 1993; Ellison, 1999; Jasienska et al., 2000; Jasienska and Thune, 2001). There are scattered reports of male testosterone levels from non-Western, non-clinical populations, but the comparability of these data is limited by differences in sample collection, handling, and assay procedures (Guerra-Garcia et al., 1969; Smith et al., 1975; Christiansen, 1991a,b; Beall et al., 1992; Campbell, 1994). This report presents data on age variation in male salivary testosterone values from four populations spanning broad genetic, ecological, and life style differences. All the samples were collected using the same protocols and were assayed in the same laboratory using consistent methods. The data are used for a preliminary test of the hypothesis that significant population variation exists in the pattern of age-related decline in male testosterone. By analogy with findings for women (Ellison et al., 1993), we expect that non-Western males will 3251

P.T.Ellison et al.

Table I. Mean (pmol/l) salivary testosterone levels (T) from men in four populations, for total sample and for three age groups. Population

USA Congo Nepal Paraguay P-value

15 to ⬍30 years

All ages

30 to ⬍45 years

45–60 years

T (pmol)

SEM

n

T (pmol)

SEM

n

T (pmol)

SEM

n

T (pmol/l)

SE

n

259 268 240 192 0.0002

10 12 13 12

106 33 37 45

335 286 251 197 0.0001

20 15 18 25

24 17 22 15

288 250 224 187 0.0004

17 19 19 14

31 11 14 21

238 247 225 192 NS

14 34 0 36

26 5 1 8

P-value is given for one-way ANOVA; NS ⫽ not significant.

have lower levels of testosterone in adulthood and slower rates of decline in testosterone with increasing age.

Materials and methods Participants in this study represent males from four populations that are geographically, genetically, ecologically, and culturally distinct: Lese horticulturalists from the Ituri Forest, Democratic Republic of the Congo (formerly Zaı¨re), (Bentley et al., 1993; n ⫽ 33); Tamang agropastoralists from central Nepal (n ⫽ 39; Ellison and PanterBrick, 1996); Ache foragers from southern Paraguay (Bribiescas, 1996; n ⫽ 45) and residents of Massachusetts, USA (n ⫽ 106). Lese, Tamang, and Ache participants represent all available willing males in the corresponding study areas. The USA participants were recruited by public advertisement, thus the potential for self-selection bias should be noted. Age data were derived from detailed demographic interviews in the Congo, Nepal, and Paraguay and from self-report in the USA. In all cases participants provided between one and five morning saliva samples collected within 2 h of waking from 1–5 days according to established collection protocols which minimize the risk of contamination with serum or gingival fluid (Lipson and Ellison, 1989). The samples were preserved with sodium azide until they could be transferred to the laboratory and frozen at –20°C. Testosterone levels have been found to be stable under these collection and handling procedures for up to 6 months (Lipson and Ellison, 1989). Testosterone values were determined for each sample by a tritium-based radioimmunoassay according to published protocols (Ellison et al., 1989). The sample values for individual participants were averaged to provide mean values for each subject. The age pattern of testosterone within each population was analysed using simple linear regression. Sample sizes were too small to justify higher order curve fitting. Population variation in average testosterone values is assessed by analysis of variance and by multiple linear regression with age, population, and age multiplied by population interaction as independent variables. For the purposes of the multiple regression population was re-coded as a binary variable, USA and non-USA.

Results The mean salivary testosterone values for men in the four populations were significantly different (ANOVA, P ⫽ 0.0002, Table I) although they fall within the broad normal range (100–1000 pmol/l) for adult males in all cases. However, the differences are not consistent across age groups and show convergence with age. Population differences are greatest 3252

among men under the age of 30 years (ANOVA, P ⫽ 0.0001) and are non-significant for men 45–60 years. A linear regression of testosterone on age for the combined data from all four populations indicates a highly significant negative relationship (y ⫽ 332 – 2.0x, P ⫽ 0.0001). The individual population regressions of testosterone against age are significant in the USA (y ⫽ 418 – 3.4x, P ⫽ 0.0001) and Congo (y ⫽ 346 – 2.3x, P ⫽ 0.03), but not in Nepal (y ⫽ 286 – 1.5x, P ⫽ 0.39) or Paraguay (y ⫽ 218 – 0.7x, P ⫽ 0.50). A multiple linear regression model with age, population (recoded as USA and non-USA), and age⫻population interaction as independent variables indicates significant effects of all three variables (y ⫽ 549 – 5.2⫻Age – 131.5⫻Population ⫹ 1.7⫻Age⫻Population, multiple R ⫽ 0.47, P ⫽ 0.0001. Significance of individual variables: Age, P ⫽ 0.0001; Population, P ⫽ 0.0002; Age⫻Population, P ⫽ 0.05). Discussion The data presented here provide the first opportunity to consider population variation in the relationship of male testosterone to age. All the data were collected according to the same protocols and analysed with the same assay methods in the same laboratory. This common methodology helps to control for many of the sources of variation that may confound the comparison of results from different studies. The most important general observation from these data is that age-related decline in free testosterone, as represented by salivary levels, is not a uniform characteristic of all populations. In particular, the rate of decline with age varies significantly between populations and in some populations (i.e. Nepal and Paraguay) does not achieve statistical significance, although this may be due to the sample size limitations in this study. The testosterone levels of older men (⬎45 years) tend to converge for all the populations studied while the levels of younger men (⬍30 years) vary significantly. This suggests that variability in the pattern of testosterone decline with age, results from population variation in the reproductive physiology of young males rather than in population differences in the rate of reproductive senescence among older males. If so, research into the mechanisms underlying age patterns of male testosterone should focus on the determinants of young adult levels as well as the causes of age-related decline. Because population differences in age patterns of testosterone have not previously been appreciated, the implications of

Interpopulation salivary testosterone variation in males

such variation for patterns of health risk have not been considered. If, for example, set-points for muscle anabolism and bone mineral density are established relative to testosterone levels in young adulthood, a steeper decline in testosterone from higher young-adult levels might result in more rapid agerelated changes in male body composition, bone mineral density, and related health risks. Higher testosterone exposure throughout adulthood in populations with high young-adult levels may also lead to greater prostate cancer risk. These possibilities provide additional motivation for increased efforts to study global variation in male gonadal function to complement studies of Western populations.

References Barrett-Connor, E., Von Muhlen, D.G. and Kritz-Silverstein, D. (1999) Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J. Clin. Endocrinol. Metab., 84, 573–577. Beall, C.M., Worthman, C.M., Stallings, J., Strohl, K.P., Brittenham, G.M. and Barragan, M. (1992) Salivary testosterone concentration of Aymara men native to 3600 m. Ann. Hum. Biol., 19, 67–78. Bentley, G.R., Harrigan, A.M., Campbell, B.C. and Ellison, P.T. (1993) Seasonal effects on salivary testosterone levels among Lese males of the Ituri Forest, Zaı¨re. Am. J. Hum. Biol., 5, 711–717. Bhasin, S. and Tenover, J.S. (1997) Age-associated sarcopenia – issues in the use of testosterone as an anabolic agent in older men. J. Clin. Endocrinol. Metab., 82, 1659–1660. Bribiescas, R.G. (1996) Testosterone levels among Ache´ hunter-gatherer men: a functional interpretation of population variation among adult males. Hum. Nat., 7, 163–188. Campbell, K.L. (1994) Blood, urine, saliva, and dip-sticks: Experiences in Africa, New Guinea, and Boston. Ann. N. Y. Acad. Sci., 709, 312–330. Christiansen, K.H. (1991a) Sex hormone levels, diet and alcohol consumption in Namibian Kavango men. Homo, 42, 43–62. Christiansen, K.H. (1991b) Serum and saliva sex hormone levels in Kung San men. Am. J. Phys. Anthropol., 86, 37–44. Crawford, E.D. (1992) Challenges in the management of prostate cancer. Br. J. Urol., 70 (Suppl.), 33–38. Denti, L., Pasolini, G., Sanfelici, L., Benedetti, R., Cecchetti, A., Bruschieri, L., Ablondi, F. and Valenti, G. (1999) The contribution of androgen decline to the aging-related changes of body composition and lipoprotein in the healthy man. J. Endocrinol. Invest., 22 (Suppl.), 68–69. De Pergola, G., De Mitrio, V., Giorgino, F., Sciaraffia, M., Pannacciulli, N., Minenna, A., Giorgino, F., Petronelli, M., Laudagio, E. and Giorgino, R. (1997) Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men. Metabolism, 46, 1287–1293. Ellison, P.T. (1999) Reproductive ecology and reproductive cancers. In PanterBrick, C. and Worthman, C. (eds), Hormones and Human Health. Cambridge University Press, Cambridge, UK, pp. 184–209. Ellison, P.T. and Panter-Brick, C. (1996) Salivary testosterone levels among Tamang and Kami males of central Nepal. Hum. Biol., 68, 955–965. Ellison, P.T., Lipson, S. and Meredith, M. (1989) Salivary testosterone levels in males from the Ituri Forest, Zaı¨re. Am. J. Hum. Biol., 1, 21–24. Ellison, P.T., Panter-Brick, C., Lipson, S.F. and O’Rourke, M.T. (1993) The ecological context of human ovarian function. Hum. Reprod., 8, 2248–2258. Ferrini, R.L. and Barrett-Connor, E. (1998) Sex hormones and age: a crosssectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am. J. Epidemiol., 147, 750–754. Francis, R.M. (1999) The effects of testosterone on osteoporosis in men. Clin. Endocrinol., 50, 411–414. Guerra-Garcia, R., Velasquex, A. and Coyotupa, J. (1969) A test of endocrine gonadal function in men: urinary testosterone after the injection of hCG.

II. A different response of the high altitude native. J. Clin. Endocrinol. Metab., 29, 179–182. Haffner, S.M., Shaten, J., Stern, M.P., Smith, G.D. and Kuller, L. (1996) Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Am. J. Epidemiol., 143, 889–897. Harman, S.M., Miller, E.J., Tobin, J.D., Pearson, J. and Blackman, M.R. (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab., 86, 724–31. Jasienska, G. and Thune, I. (2001) Lifestyle, hormones, and risk of breast cancer. Br. Med. J., 322, 586–587. Jasienska, G., Thune, I. and Ellison, P.T. (2000) Energetic factors, ovarian steroids and the risk of breast cancer. Eur. J. Cancer Prev., 9, 231–239. Jeppesen, L.L., Jorgensen, H.S., Nakayama, H., Raaschou, H.O., Olsen, T.S. and Winther, K. (1996) Decreased serum testosterone in men with acute ischemic stroke. Arterioscler. Thromb. Vasc. Biol., 16, 749–754. Kenny, A.M., Prestwood, K.M., Marcello, K.M. and Raisz, L.G. (2000) Determinants of bone density in healthy older men with low testosterone levels. J. Gerontol. A. Biol. Sci. Med. Sci., 55, 492–497. Lipson, S.F. and Ellison, P.T. (1989) Development of protocols for the application of salivary steroid analyses to field conditions. Am. J. Hum. Biol., 1, 249–255. O’Rourke, M.T. and Ellison, P.T. (1993) Salivary estradiol levels decrease with age in healthy, regularly-cycling women. Endocr. J., 1, 487–494. Schweiger, U., Deuschle, M., Weber, B., Korner, A., Lammers, C.H., Schmider, J., Gotthardt, U. and Heuser, I. (1999) Testosterone, gonadotropin, and cortisol secretion in male patients with major depression. Psychosom. Med., 61, 292–296. Simon, D., Charles, M.A., Nahoul, K., Orssaud, G., Kremski, J., Hully, V., Joubert, E., Papoz, L., Eschwege, E. (1997) Association between plasma total testosterone and cardiovascular risk factors in healthy adult men: The Telcom Study. J. Clin. Endocrinol. Metab., 82, 682–685. Smith, S.R., Cherti, M.K., Johanson, J., Radfar, N. and Migeon, C.J. (1975) The pituitary-gonadal axis in men with protein-calorie malnutrition. J. Clin. Endocrinol. Metab., 41, 60–69. Snyder, P.J., Peachey, H., Hannoush, P., Berlin, J.A., Loh, L., Holmes, J.H., Dlewati, A., Staley, J., Santanna, J., Kapoor, S.C. et al. (1999a) Effect of testosterone treatment on bone mineral density in men over 65 years of age. J. Clin. Endocrinol. Metab., 84, 1966–1972. Snyder, P.J., Peachey, H., Berlin, J.A., Loh, L., Lenrow, D.A., Holmes, J.H., Dlewati, A., Santanna, J., Rosen, C.J. and Strom, B.L. (1999b) Effect of testosterone on body composition and muscle strength in men over 65 years of age. J. Clin. Endocrinol. Metab., 84, 2647–2653. Stellato, R.K., Feldman, H.A., Hamdy, O., Horton, E.S. and McKinlay, J.B. (2000) Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care, 23, 490–494. Van den Beld, A.W., de Jong, F.H., Grobbee, D.E., Pols, H.A. and Lamberts, S.W. (2000) 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., 85, 3276–3282. van Tinteren, H. and Dasio, O. (1993) Systematic overview (meta-analysis) of all randomized trials of treatment of prostate cancer. Cancer, 72, 3847–3850. Vermeulen, A., Kaufman, J.M. and Giagulli, V.A. (1996) Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males. J. Clin. Endocrinol. Metab., 81, 1821–1826. Vermeulen, A., Goemaere, S. and Kaufman, J.M. (1999) Testosterone, body composition and aging. J. Endocrinol. Invest., 22, (Suppl.), 110–116. Wang, C., Swerdloff, R.S., Iranmanesh, A., Dobs, A., Snyder, P.J., Cunningham, G., Matsumoto, A.M., Weber, T. and Berman, N. (2000) Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J. Clin. Endocrinol. Metab., 85, 2839–2853. Winters, S.J. (1999) Current status of testosterone replacement therapy in men. Arch. Fam. Med., 8, 257–263. Submitted on March 7, 2002; resubmitted on June 11, 2002; accepted on July 31, 2002

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