Sex Hormones and Age: A Cross-sectional Study of Testosterone and Estradioi and Their Bioavailable Fractions in Community-dwelling Men

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1 American Jurnal f Epidemilgy Cpyright O 1998 by The Jhns Hpkins Unlveretty Schl f Hygiene and Public Health All rights reserved Vl. 147, N. 8 Printed In USA. Sex Hrmnes and Age: A Crss-sectinal Study f Teststerne and Estradii and Their Biavailable Fractins in Cmmunity-dwelling Men Rebecca L Ferrini 1 and Elizabeth Barrett-Cnnr 2 The rle f endgenus sex hrmnes in many diseases makes understanding factrs that influence levels f these hrmnes increasingly imprtant. This study examined age-assciated variatins in ttal and biavailable teststerne and estradii levels amng cmmunity-dwelling Caucasian men in Ranch Bernard, Califrnia. Plasma samples btained frm 810 men aged years in were analyzed in 1993 using radiimmunassay. Analyses f age-hrmne assciatins, adjusting fr weight, bdy mass index, alchl Ingestin, smking, physical activity, caffeine intake, specimen strage time, and disease status, were undertaken. Biavailable teststerne and biavailable estradii levels decreased significantly with age independently f cvariates. Ttal teststerne and estradii levels decreased with age nly when analyses were cntrlled fr cnfunders. The imprtance f the age-assciated decline in endgenus sex hrmne levels, particularly levels f biavailable teststerne and biavailable estradii, and their relatin t disease and functin in men deserve further research. Am J Epidemil 1998; 147: aging; estradii; hrmnes; men; teststerne Diseases as diverse as cardivascular disease (1,2), hypertensin (3), cancer (4-6), steprsis (7), strke (8), and diabetes mellitus (9, 10) have been linked t levels f endgenus sex hrmnes. It is therefre imprtant t understand the effects f age, besity, and behavir n circulating levels f biavailable sex sterids. Studies f the assciatin between age and endgenus sex sterids in men have yielded incnsistent results (11-14), pssibly reflecting sample selectin, time f day f bld sampling, type f hrmnal assay, r failure t cntrl fr cnfunding factrs (15, 16). Mst studies have measured ttal hrmne levels rather than their biavailable fractins, and t ur knwledge n previus reprt has measured biavailable estradii in men. This study was unique because f its 1) large, gegraphically defined sample f men, 2) ability t evaluate the effect f age independently f numerus majr variables (including bdy mass index, waist: hip rati, alchl use, cigarette smking, exercise intensity, caffeine intake, and chrnic disease) that may Received fr publicatin February 10, 1997, and in final frm September 12, General Preventive Medicine Residency Prgram, University f Califrnia, San Dieg and Califrnia State University, San Dieg, CA. 2 Department f Family and Preventive Medicine, Schl f Medicine, University f Califrnia, San Dieg, CA. Reprint requests t Dr. Elizabeth Barrett-Cnnr, Department f Family and Preventive Medicine, Schl f Medicine, University f Califrnia, San Dieg, 9500 Gilman Drive, La Jlla, CA cvary with age and alter endgenus hrmne levels, and 3) measurement f bth ttal and biavailable estradii and teststerne. MATERIALS AND METHODS Eighty-ne percent f surviving men frm the Ranch Bernard Study, an nging cmmunitybased study f lifestyle and aging amng middle- and upper middle-class Caucasian adults, participated in a fllw-up evaluatin in invlving a clinic visit and administratin f a standardized questinnaire n physical activity, smking, caffeine intake, and alchl cnsumptin in the 2 weeks prir t the interview. Apprximately half f the sample als cmpleted a questinnaire adapted frm the 1985 Health Interview Survey (17, 18) that assessed participatin in 15 leisure-time activities during the preceding 2 weeks, which were classified using intensity cdes established and validated by the Minnesta Heart Survey (19). Height, weight, and waist and hip girth were measured with participants wearing light clthing withut shes; bdy mass index (weight (kg)/ height 2 (m 2 )) and waist: hip rati were then calculated. Diabetes mellitus was defined by medical histry and the results f an ral glucse tlerance test, using Wrld Health Organizatin criteria (20). Plasma glucse was measured in a hspital diagnstic labratry using a hexkinase methd fr true glucse. Crnary heart disease was defined by medical histry 750 Dwnladed frm n 24 January 2018

2 Sex Hrmnes and Age in Older Men 751 and the presence f majr Q waves n an electrcardigram. Medical recrd review f a 30 percent sample cnfirmed the reprted diagnsis in 85 percent (diabetes) t 95 percent (heart attack) f cases. Venipuncture was perfrmed between 7:00 am. and 10:00 a.m. after a 12-hur fast Plasma was stred in plyprpylene tubes at 70 C until they were first thawed fr sex hrmne determinatins in 1993 (mean strage time = mnths (standard deviatin 8.7 mnths)). Ttal teststerne and ttal estradil levels were determined by radiimmunassay (21); biavailable teststerne and estradil levels were determined by an experienced labratry technician using the methd f Tremblay and Dube (22) in a University f Califrnia, San Dieg, endcrinlgy research labratry. Less than 1 percent f men had hrmne levels belw the level f assay sensitivity; values fr undetectable levels were cnverted t values slightly belw the assay sensitivity level fr analysis. Eleven men with teststerne levels mre than three standard deviatins abve the mean were included after medical recrd review revealed n explanatry medical cnditin. Intra- and interassay cefficients f variatin and sensitivity were as fllws: fr teststerne, 4.00 percent, 6.78 percent, and 37 pg/ml, respectively; fr estradil, 5.87 percent, 7.44 percent, and 6 pg/ml; fr biavailable teststerne, 5.80 percent, 7.61 percent, and 37 pg/ml X percent free; and fr biavailable estradil, 3.70 percent, 5.18 percent, and 6 pg/ml X percent free. Hrmne data were available fr 914 men. The present analysis includes the 810 men fr whm we had cmplete data n bdy mass index, waist: hip rati, current smking, current alchl use, caffeine intake, and specimen strage time. These men did nt differ significantly by age r hrmne level frm thse excluded. The distributin f hrmne values was nrmal. Additinal analyses that cntrlled fr exercise intensity were cmpleted in 391 men. Because specimen strage time was inversely crrelated with levels f biavailable teststerne (r = -0.20) and biavailable estradil (r = 0.08) (but nt with ttal teststerne r estradil), analyses were adjusted fr specimen strage time. Pearsn tw-tailed crrelatins were used t determine the crss-sectinal assciatins between age and individual hrmne levels. Partial crrelatins were used t cntrl fr bdy mass index, waist: hip rati, alchl use, smking, caffeine intake, mnths f strage, and exercise intensity. Agespecific hrmne levels were adjusted fr bdy mass index and ther cvariates using multiple analysis f variance. Tw-way analysis f variance, cntrlling fr age and bdy mass index, was used t test fr an interactin between chrnic disease (crnary heart TABLE 1. Tw-tailed Pearsn crrelatin* between behaviral cvariatm and level* f endgenus sex hrmne* (pg/ml) In 810 men aged years, Ranch Bernard, Califrnia, Cvartate Weight (kg) Bdy mass tndext WaistNp rati Alchl Intake (g/week) Cigarette smking (cigarettes/day) Caffeine Make (g/mnth) p < 0.01; ***p< t Weight (kgvhelghii (m*). Teststerne -O2A -O2A*** -0.13*** Estradtl Blavalabte teststerne Btavailable estraw 0.18"* 0.18«« disease, diabetes, r cancer) and age. Linear regressin was used t estimate the magnitude f hrmnal change with age. All analyses were perfrmed using the Statistical Package fr the Scial Sciences (SPSS, Inc., Chicag, Illinis). Given the multiple cmparisns, statistical significance was defined as p < RESULTS The men were aged years (mean = 69.6 years (standard deviatin 10.9 years)) in The assciatin f hrmne levels with majr cvariates is shwn in table 1. As shwn, bdy size measures were inversely crrelated with ttal teststerne but nt biavailable teststerne and with biavailable estradil but nt ttal estradil. Caffeine intake was psitively assciated with biavailable teststerne. There was a strng inverse linear assciatin between age and biavailable teststerne and biavailable estradil in the men (table 2). This assciatin was nt TABLE 2. Tw-tailed Pearsn crrelatins between levels f endgenus sex hrmnes (pg/ml) and age, and partial crrelatins cntrlled fr bdy mass Index and ther cvariatas, m 810 men aged years, Ranch Bernard, Califrnia, Hrmne Teststerne Ttal Bfavaflabte Estradl Ttal Btavaflabte f *** -0.28*** Partial crrelatin, cntrled fr bdy mass Indext *** *** Partial crrelatin. cntrled tr mutlpte cvartatesf -0.12** -0.53*** -0.09** -0.27*** * p<0.01 ;***p< t Weight (kg)/hejght> (m»). t Cvariates included bdy mass index, waisthip rati, alchl intake (g/week), smking (cigarettes/day), sample strage time (mnths), and caffeine intake (g/mnth). Am J Epidemil Vl. 147, N. 8, 1998 Dwnladed frm n 24 January 2018

3 752 Ferrini and Barrett-Cnnr materially changed after adjustment fr bdy mass index, waist: hip rati, alchl cnsumptin, cigarette smking, caffeine intake, and specimen strage time. Significant negative assciatins were als fund between age and ttal estradil and ttal teststerne, but nly after adjustment fr cvariates (table 2). These assciatins were unchanged in a separate analysis that adjusted fr exercise intensity (data nt shwn). Results were similar in men with and withut crnary heart disease, cancer, r diabetes. Figures 1 and 2 shw the multiply adjusted hrmne levels stratified by 5-year age grup. There was a stepwise Linear decrease in biavailable teststerne and estradil levels which persisted after adjustment fr all cvariates. Based n the beta cefficients frm linear regressin analysis, ttal teststerne cncentratins declined by apprximately 1.9 pg/ml fr each year f age, while biavailable teststerne levels declined by 18.5 pg/ml per year f age. Ttal estradil cncentratins declined by 0.03 pg/ml fr each year f age; biavailable estradil levels declined by 0.12 pg/ml per year f age. DISCUSSION This study fund a significant decline in biavailable estradil and teststerne with age amng men, and a much smaller, thugh still significant, negative assciatin f ttal teststerne and estradil with age ntrati 0) c O X ra E t (0 when data were adjusted fr cvariates. Age-related decrements were independent f bdy mass index, waist: hip rati, cigarette smking, alchl ingestin, caffeine intake, physical activity, and specimen strage time. Negative assciatins f ttal teststerne with age in men have been nted in sme crsssectinal studies (11-13, 23-26) but nt in thers (27-29). In 1,408 healthy men aged years, Simn et al. (11) reprted a stepwise age-assciated decrease in ttal teststerne (r = 0.25) with age that was independent f bdy mass index, subscapular skinfld thickness, and tbacc and alchl cnsumptin. Similarly, a study f 243 men in the Multiple Risk Factr Interventin Trial (30) reprted a negative crrelatin between age and ttal teststerne (r = 0.23). The Massachusetts Male Aging Study, a study f 1,241 men, shwed a weaker inverse assciatin between ttal teststerne and age (r = 0.10) (16), reprting annual declines f 0.4 percent in ttal teststerne levels amng bth healthy and ill men (14). A recent meta-analysis f 88 published studies shwed a significant inverse assciatin between age and ttal teststerne levels in men (15). Age-assciated declines in free teststerne (i.e., teststerne that is nt bund t sex hrmne-binding glbulin r albumin) have been reprted frm nly tw study centers, and neither grup reprted levels f ttal biavailable teststerne (which includes unui/6d) Teststerne - Biavailable Teststerne < >84 (n=27) (n=56) (n=81) (n=84) (n=109) (n=98) (n=219) (n=102) (n=34) Age Grup FIGURE 1. Levels f endgenus ttal and biavailable teststerne in 810 men aged years, by 5-year age grup, Ranch Bernard, Califrnia, Data were adjusted fr multiple cvariates, including bdy mass index (weight (kgyheight 2 (rrr*)), waist: hip rati, alchl Intake (g/week), smking (cigarettes/day), sample strage time (mnths), and caffeine intake (g/mnth). Am J Epidemil Vl. 147, N. 8, 1998 Dwnladed frm n 24 January 2018

4 Sex Hrmnes and Age in Older Men 753 E 1 25 n t C0 a a < (n=27) (n=56) (n=81) (n=84) (n=109) (n=98) - Estradil - Biavailable Estradil >84 (n=219) (n=102) (n=34) Age Grup RQURE 2. Levels f endgenus ttal and Wavailable estradil In 810 men aged years, by 5-year age grup, Ranch Bernard, Califrnia, Data were adjusted fr multiple cvariates, Including bdy rnass index (weight (kgj/heignt 2 (m 2 )), waist: hip rati, alchl intake (g/week), smking (cigarettes/day), sample strage time (mnths), and caffeine intake (g/mnth). bund as well as albumin-bund hrmne). The Massachusetts Male Aging Study reprted inverse assciatins f bth free (r = 0.22) and albuminbund (r = 0.21) teststerne with age in bth ill and healthy men (16). Thse investigatrs estimated annual declines f 1.2 percent in free teststerne and 1.0 percent in albumin-bund teststerne (14). The Multiple Risk Factr Interventin Trial (30) measured nly free teststerne levels, which decreased with age independently f bdy mass index. The present study shwed a weaker assciatin f ttal teststerne (r = 0.13) than f biavailable teststerne (r = -0.52) with age. The latter is the strngest reprted independent age-hrmne assciatin in the literature. T ur knwledge, n previus study has reprted n the relatin between ttal biavailable teststerne and estradil levels and age in a ppulatin-based study. Teststerne that is nt bund t sex hrmne is thught t be the bilgically active cmpnent, because teststerne is nly weakly bund t albumin. Bth decreased prductin and increased cnversin and metablic clearance f teststerne may explain the age-assciated decrease in ttal teststerne, while a previusly reprted age-assciated increase in sex hrmne binding capacity may explain the greater reductin in biavailable teststerne (31,32). In Ranch Bernard men, the decline in ttal estradil with age was small, and it achieved statistical significance nly after adjustment fr cvariates. Previus studies f the relatin between aging and estradil levels have prduced mixed results; sme reprted n age assciatin with estradil (12, 14, 26, 27) r free estradil (23); thers fund higher estradil levels with age (23, 24); and still thers nted reduced levels (r = 0.10) with advancing age (11). In cntrast t the weak assciatin between age and ttal estradil, there was a strng assciatin f biavailable estradil with age. T ur knwledge, this assciatin has nt been studied previusly. The ageassciated decrease in biavailable estradil amng these men may be partially explained by decreasing levels f teststerne, the primary substrate fr male estradil prductin, cupled with the higher levels f sex hrmne-binding glbulin in lder adults (16). The accuracy f sterid hrmne measurements made in stred plasma samples has been questined (33). Hrmne levels in the present study were smewhat lwer than levels reprted in Massachusetts (15), pssibly reflecting the lder age f ur chrt, the high sensitivity f ur assay, r the use f plyprpylene tubes fr strage (which may attenuate hrmne cncentratins). Plyprpylene tubes culd theretically bind sterid mlecules. This wuld nt alter the rdinal assciatins f hrmne levels with age r ther cvariates unless there was bias such that lder subjects had lnger sample strage times. We cntrlled fr the Am J Epidemil Vl. 147, N. 8, 1998 Dwnladed frm n 24 January 2018

5 754 Ferrini and Barrett-Cnnr latter pssibility by adjusting statistically fr strage time. There is sme evidence that the biavailable fractin f teststerne increases ver time, which is cmpatible with the prgressive deteriratin f the steridprtein cmplex (34). Again, this wuld nt be expected t alter the rdinal assciatins fr the bserved levels. In summary, biavailable teststerne and estradil decreased dramatically with age in these cmmunitydwelling men, independently f bdy size, health behavir, and chrnic disease. The relatins between this decline in endgenus sex hrmne levels and fragility, impaired functining, and chrnic diseases (such as steprsis, diabetes, cancer, and heart disease) shuld be the fcus f future research. ACKNOWLEDGMENTS This research was supprted by grant DK31801 frm the Natinal Institute f Diabetes and Digestive and Kidney Diseases and grant AG07181 frm the Natinal Institute f Aging. 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