Age, Genetic, and Nongenetic FactorsInfluencing Variation in Serum Sex Steroids and

Zonal Volumes of the Prostate and BenignProstatic Hyperplasia in Twins

A. Wayne Meikle,1* Robert A. Stephenson,2 Cathryn M. Lewis,3Gail A. Wiebke,1 and Richard G. Middleton2

1Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah2Department of Urology, University of Utah School of Medicine, Salt Lake City, Utah

3Department of Medical Informatics, University of Utah School of Medicine,Salt Lake City, Utah

BACKGROUND. We have observed that hereditary and environmental factors have a sub-stantial influence on the plasma content of sex steroids in normal male twins and in men offamilies with prostatic disease.METHODS. The contribution of genetic and nongenetic familial factors on the variation ofplasma sex steroid concentrations and of the volume of zones of the prostate measured bytransrectal ultrasound (TRUS) has now been investigated in pairs of male monozygotic (MZ)and dizygotic (DZ) twin pairs between age 25–75 years. Bioelectric impedance permittedquantitation of body fat, lean body mass, and water. Morphometrics and testicular volumewere also determined.RESULTS. The intraclass correlation (rI) was >0.40 for the variation of the total volume (TV),the transition zone (TZ), the peripheral zone (PZ), and the ratio of TZ/PZ in both MZ and DZtwins, and heredity affected 22% of the variation of the PZ and TZ and 30% of the ratio ofTZ/PZ. None of the TV and environmental factors influenced the remainder of the variation.Heredity accounted for 25% or more of the variation of dihydrotestosterone (DHT), and theratios of DHT/testosterone (T), estradiol (E2)/T, androstanediol glucuronide, sex hormone-binding globulin (SHBG)-bound T, T/SHBG, luteinizing hormone (LH), follicle-stimulatinghormone (FSH), and dehydroepiandrosterone sulfate (DHEA-S). In MZ twin pairs the varia-tion of the volumes of the prostate became greater with age. In contrast, the variation of thesex hormone concentrations did not show greater variation with age. Heredity also affected>30% of the variation for waist measurement, weight, body fat, body mass, water and leanbody mass, body mass/fat, and testicular size.CONCLUSIONS. Our results indicated that both MZ and DZ twin pairs had zonal prostatevolumes more like their twin pair than like unrelated twins. However, nongenetic factorsexerted stronger influences than genetic factors on zonal volumes of the prostate. In contrast,hereditary factors had stronger influences on determining the variation of many sex hor-mones and morphometric characteristics than did nongenetic factors. Prostate 33:105–111,1997. © 1997 Wiley-Liss, Inc.

KEY WORDS: twins; genetic; hyperplasia; aging; androgens

Contract grant sponsor: NIH USPHS; Contract grant numbers: DK-45760, DK-43344, RR-00064.*Correspondence to: A. Wayne Meikle, M.D., Depts. of Medicineand Pathology, University of Utah School of Medicine, 50 NorthMedical Drive, Salt Lake City, UT 84132.Received 22 July 1996; Accepted 18 December 1996

The Prostate 33:105–111 (1997)

© 1997 Wiley-Liss, Inc.

INTRODUCTION

The prostate gland enlarges in response to andro-gens during and following puberty. However, pros-tate enlargement of the transition zone (TZ) leading tobenign prostatic hyperplasia (BPH) [1–5] occurs asmen age, when testosterone (T) concentrations declineand sex hormone-binding globulin (SHBG) concentra-tions rise, resulting in a decrease in the ratio ofT/SHBG and in free T [6–9]. This seeming paradox isunexplained, but could be influenced by hereditary orenvironmental factors. We are aware of no previousstudies examining the influence of genetic and nonge-netic factors on the decline of T with age, or determin-ing zonal volumes of the prostate. Prostate volumesdetermined by transrectal ultrasound (TRUS) haveshown good correlations with volumes measured afterradical prostatectomy, suggesting that TRUS is a sat-isfactory method for estimating prostate volume [10–13].

Twin studies have been used to determine the con-tribution of genetic and environmental factors on atrait of interest [14–18]. Since monozygotic (MZ) twinpairs are genetically identical, any variation betweenthem can be attributed to environmental differences.In contrast, dizygotic (DZ) twins are genetically re-lated as siblings and also may share common environ-mental influences. If differences in a trait becamegreater in MZ twin pairs with aging, then environ-mental influences might be an inferred explanation. Inthe current study, healthy male twins between age25–75 years were studied with morning serum sex ste-roid concentrations, and zones of the prostate weremeasured by TRUS. Our objectives were to determinewhether hereditary and environmental factors influ-enced the variation in serum sex hormone concentra-tions and volumes of the zones of the prostate. Weobserved that both hereditary and nongenetic factorsinfluenced the variation of serum sex steroid concen-trations and zonal volumes of the prostate in maletwin pairs.

MATERIALS AND METHODS

Subjects and Blood Collection

This study was performed to assess the influence ofhereditary and environmental factors on sex hor-mones and volumes of zones of the prostate and BPHin male twin-pairs between age 25–75 years. Morethan 1,500 potential participants were identified fromdata base registries, including a recent update of driv-er’s license information. This was accomplished bycoupling genealogy information, birth, death, anddriver’s license records. We report on data on 214

twins selected from 360 twins where all results wereavailable for both twin pairs, and neither twin hadhealth problems. One hundred twenty-six twins weremonozygotic (age 55 ± 12.5 years, mean ± SD, range30–77 years), and 88 were dizygotic (age 54.3 ± 11.9years, mean ± SD, range, 27–72 years). Men with pros-tate cancer or a history of treatment for BPH wereexcluded from analysis. Informed consent was ob-tained before entry into the study, conducted at theClinical Research Center of the University of Utah.None of the twins was receiving medication known toaffect sex steroid secretion. The American UrologicAssociation questionnaire was given to each twin, al-lowing calculation of the symptom score [19].

Between 0800–1030 hr, three blood samples for hor-mone and SHBG concentrations were obtained intubes by venipuncture at intervals of 15–20 min. Thesame volume from each specimen was pooled andstored at −20°C until assayed.

Hormonal Assays

Previously reported assays were used to determinethe concentrations of testosterone, dihydrotestoster-one (DHT), estradiol, estrone, free testosterone, bio-available testosterone (BioT), androstanediol glucuro-nide, dehydroeplandrosterone (DHEAS), luteinizinghormone (LH), and follicle-stimulating hormone(FSH) [1,20,21]. Intra- and interassay coefficients ofvariation were <12% [1,20,21]. Sex hormone-bindingglobulin (SHBG) was measured by an immunoradio-metric assay (Diagnostic Systems Laboratories, Inc.,Webster, TX). Zygosity testing was determined as de-scribed elsewhere [16].

Transrectal Ultrasound

A digital rectal examination preceded transrectalultrasound (TRUS) imaging, using a Bruel and Kjaer1846 instrument with a 7-mHz transducer (Bruel andKjaer, Billeria, CA). Total prostate measurement (TV,assuming 1 cc = 1 g) and the volumes of the transitionzone (TZ) were calculated by p/6 × width (maximaltransverse dimension), length (maximal anterior andposterior subregions), and height [1,22,23]. The pe-ripheral zone (PZ) volume (a central zone and fibrousarea were included in the peripheral zone calculation)was estimated by subtracting the TZ from the TV. Thecoefficient of variation for TV is 5%, and for TZ, 11%[1].

Morphometrics

Body weight, height and hip-to-abdominal girthmeasurements, and bioelectrical impedance (BIA)used a low-energy, high-frequency (50 kHz) electrical

106 Meikle et al.

current to determine body fat, lean body mass, andwater [24–26].

Statistical Analyses

The intraclass correlation (rMZ and rDZ for MZ andDZ twin pairs, respectively) is the correlation betweenthe members of the twin pair for a quantitative mea-surement. The intraclass correlation measures the ex-tent to which twin pairs are more alike than individu-als from the same population [27,28]. A higher corre-lation indicates that the twins are more like each otherthan persons from the general population. Heritability(h) or genetic influence was estimated from these cor-relations, and h = 2 (rMZ − rDZ) [27–30]. The proportionexplained by environmental factors is 1 − h.

RESULTS

Correlation in Twin Pairs

Prostate volume. As shown in Table I, the intraclasscorrelation (rI) for MZ was 0.64 for the variation of theTV (P # 0.0005), and 0.65 for DZ twins (P = 0.0002).For the TZ the rI was 0.55 and 0.44 for the MZ and DZtwin pairs, respectively (P = 0.0002). The PZ correla-tions were 0.58 and 0.44, respectively (MZ, P =0.00007; DZ, P < 0.00002). The results establish thatboth genetic and nongenetic factors influence about50% or more of the variation of the volume of the TV,TZ, and PZ in MZ twin pairs, but that a smaller per-centage was observed in DZ twin pairs.

Figure 1A–C shows the variation in prostate vol-umes between pairs of MZ twins at various ages, andFigure 2A–C shows the differences between pairs ofDZ twins. This shows the greater variation in volumesof zones of the prostate in both MZ and DZ twin pairsas they age.

Hormonal and morphometrics. In MZ twins, the rIwas 0.40 for the same physical characteristics includ-ing BMI, waist circumference, body fat, lean mass,weight, ratio of lean body mass to fat mass, and tes-ticular volume (Table I).

The rI in MZ twins pairs was 0.40 for the hormonalconcentration, except for SHBG-bound T. In DZ twinsonly testosterone, estradiol, estrone, DHEAS, SHBG-bound T, free T, weight, and height had an rI of 0.40 ormore. The variation in hormone and morphometriccharacteristics between MZ and DZ twin pairs did notbecome greater with age (data not shown).

Plasma hormone content. The plasma values for thevarious hormones, prostate volume, and morphomet-

ric measurements were similar in both groups of twins(data not shown), and they were matched for age.

Hereditary Influences on Variation of ProstateVolume and Hormone Values

Hereditary factors

Prostate zones. Hereditary accounted for 22% of thevariation for PZ and TZ, 30% for the TZ/PZ ratio, andnone for the TV, suggesting that the TZ and PZ areaffected more by heredity than is the TV (Table I).

TABLE I. Estimates of Correlations, Heritability, andEnvironmental Influences*

Twins MZ rI DZ rI

Heritability,(%)

Environ-mental,

(%)a

TV 0.64 0.65 0 100TZ 0.55 0.44 22 78PZ 0.55 0.44 22 78TZ/TV 0.61 0.56 6 94TZ/PZ 0.65 0.50 30 70T 0.48 0.4 16 84DHT 0.46 0.32 28 72Ratio DHT/T 0.51 0.31 40 60Estradiol (E2) 0.63 0.44 38 62Estrone 0.56 0.56 0 100Ratio E2/T 0.44 0.18 52 48AG 0.61 0.38 46 54BioT 0.59 0.30 58 42SHBG-bound T 0.53 0.39 28 72Free T 0.60 0.59 2 98T/SHBG 0.53 0.32 42 58LH 0.53 0.28 50 50FSH 0.85 0.17 100 0SHBG 0.57 0.26 62 38DHEAS 0.80 0.67 26 74BMI 0.64 0.19 90 10WHR 0.62 0.40 44 56Waist 0.67 0.32 70 30Height 0.82 0.72 20 80Body fat 0.54 0.16 82 18Body mass 0.53 0.14 68 32Body water 0.56 0.11 90 10Lean/fat 0.59 0.07 100 0Body weight 0.70 0.50 40 60Testicle 0.61 0.24 74 26

*rI, intraclass correlation; TV, total prostate volume; TZ, transi-tion zone; PZ, peripheral zone; T, testosterone; DHT, dihy-drotestosterone; DHEAS, dehydroepiandrosterone; FSH, fol-licle-stimulating hormone; LH, luteinizing hormone; AG, an-drostanediol glucuronide; BioT, bioavailable testosterone;SHBG, sex hormone-binding globulin; BMI, body mass index;WHR, waist/hip ratio.aTotal including common.

Age, Hormones, Prostate Zones, and Familial Factors 107

Hormones and morphometrics. The hereditary estimatewas 25% or more for the variation of BMI, waist cir-cumference, weight, body fat, ratio of lean body massto fat mass, and testicular volume (Table I).

Hereditary factors also accounted for 25% or moreof the variation in DHT, the ratio of DHT/T, estradiol,the ratio of estradiol/T, androstanediol glucuronide,SHBG-bound T, T/SHBG, LH, FSH, SHBG, andDHEAS (Table I). The hormonal concentrations thatshowed a similar rI in MZ compared to DZ twins pairsincluded T and free T. These hormones had a substan-tial correlation in both MZ and DZ twin pairs, sug-gesting that these measurements were influenced byboth hereditary and environmental factors.

Environmental Influences

Total environmental influences accounted for 70%or more of the variation of PV, TZ, TZ/TV, and TZ/PV.

More than 50% of the variation of T, DHT, DHT/T,E2, E1, BioT, SHBG-bound T, T/SHBG, free T, DHEA-S, body weight, and height was accounted for by en-vironmental factors (Table I).

DISCUSSION

Twin studies are widely used to understand thecontribution of genes and environmental factors on a

Fig. 1. Relationship of total prostate volume (A), peripheralzone (B), and transition zone (C) between MZ twin pairs and age.

Fig. 2. Relationship of total prostate volume (A), peripheralzone (B), and transition zone (C) between DZ twin pairs and age.

108 Meikle et al.

trait [28,31,32]. MZ twins are genetically identical, andany variation of a trait between MZ twins can be at-tributed to environmental differences. DZ male twinsare genetically related as siblings and are also affectedby similar environmental factors as they grow up witha sibling of exactly the same age and sex. Therefore,the variation of a trait between DZ twins is attribut-able to both genetic differences and environmental in-fluences. One assumption in twin studies is that theenvironmental correlation between MZ twin pairs isequal to the environmental correlation between DZtwin pairs, which then allows an estimate of geneticand environmental variances. These estimates allow acalculation of heritability that measures the propor-tion of phenotypic variances attributable to additivegenetic factors within this population and environ-mental factors. Twin studies are limited in that it is notpossible to interpret these heritability estimates interms of a mode of inheritance for a quantitative traitsuch as prostate volume or serum sex steroid concen-tration. Family studies more extensive than twin stud-ies are required for heritability estimates. Since theheritability calculation requires the assumption thatthe environmental factors are similar between MZ andDZ twins, any deviation from this assumption willaffect heritability estimates.

Although the heritability calculation is a simple de-scriptive statistic estimating the proportion of totalphenotypic variance due to genetic variation, highheritability does not imply that environmental factorsare unimportant. Rather, it indicates that within thepopulation, genetic factors are responsible for the ma-jority of the variation [33]. Despite these limitations, itis clear from our studies that both genetic and envi-ronmental factors exert a substantial influence onmany traits affecting variation in quantitative traits ofhormone concentrations and prostate volume. Furtherstudies will be required to ascertain the genetic or en-vironmental influences.

One prediction of the simple twin model is that thecorrelation between MZ twins should always be atleast as great as the correlation between DZ twins. Asampling effect of one or more of the assumptionsrelated to the twin model may violate the predictionand not fit the model. Such a discrepancy requiressampling from more extensive family pedigrees forresolution.

Our previous observations that nongenetic and he-reditary factors have substantial influence on theplasma content of androgens, estrogens, gonadotro-pins, and SHBG have been reconfirmed in normal men[14–18]. The new findings indicate that independent ofaging, both hereditary and environmental influencesmarkedly affect the variation of prostate volume. Wehave now shown that hereditary factors strongly in-

fluence the variation of SHBG, which contrasts withour previous observations [15–17]. In the currentstudy, SHBG was measured specifically by a radioim-munometric procedure rather than by a competitiveprotein binding technique, as reported before. The dif-ferences in assay technique and the broader age rangeof participants may account for this difference in re-sults.

It is well-known that the volume of the prostateenlarges with aging, and this has been assessed usingTRUS [34–40]. We recently observed a differential rateof growth of the PZ and TZ with aging. The majorenlargement of the gland before age 50 years is asso-ciated with growth of the PZ, and thereafter the rate ofgrowth of the TZ increases relative to the PZ. In thecurrent study, we found a high rI for MZ and DZ twinpairs on the volume of zones of the gland independentof aging. However, if genetic factors were the onlyinfluence on prostate volume, an intraclass correlationof >0.9 would be expected for MZ twins, with a lowintraclass correlation for the trait in DZ twin pairs. Theintraclass correlation is an estimate of both the geneticand nongenetic influences shared by twin pairs. Themathematical expression 1 − h is the total influence ofenvironmental or nongenetic factors on a trait. Lessthan 11% of this difference could be related to techni-cal measurement of the prostate volume. This meansthat for both hormonal and prostate volume measure-ments, nongenetic influences were substantial.

For prostate volume, the differences in measure-ments between MZ twins became greater as the twinsaged, but this divergence was not significantly differ-ent for age for hormonal concentrations. This is fur-ther confirmation for the influence of environmentalfactors on the divergence of prostate volume betweentwin pairs as they age. In contrast, although agingaffects hormonal concentrations in men, the aging in-fluences do not produce divergent effects on hor-monal concentrations. A portion of this difference canbe related to assay variation, which should be <10%on average. The genetic effect is a component of over-all influence, and for some hormones the hereditarycomponent was greater than the environmental influ-ence. For others, the nongenetic component exceededthe hereditary.

Partin et al. [41] conducted a study using a ques-tionnaire to assess the concordance of benign prostaticdisease in MZ and DZ twins. Of the 256 pairs withinformative data, 14% of the MZ twin pairs were con-cordant for benign prostatic disease, compared to 4.5%of the DZ pairs. These results provide preliminary evi-dence for the heritability of benign prostatic disease.

Sanda et al. [42] studied male relatives of probandswho were less than age 64 years at surgery for treat-ment of BPH and who had >37 g of tissue resected at

Age, Hormones, Prostate Zones, and Familial Factors 109

surgery. Male relatives of the probands had a 4-foldhigher lifetime risk of prostatectomy for BPH, andtheir brothers had a 6-fold increase in risk. This studyalso supports a hereditary predisposition or a com-mon environmental influence on the development ofclinical BPH. These studies were based on historicaldata and direct measurement of prostate volumes wasnot performed, and therefore those results contrastwith those of the current study, in which prostate vol-umes were quantitated.

Unless a genetic trait was present on Y chromo-somes, the high rI observed in both MZ and DZ twinpairs indicates that environmental influences affectthe trait. This appears to be the case for volumes ofzones of the prostate. A hereditary influence of 0%,22%, 22%, and 30% were observed respectively for theTV, TZ, PZ, and TZ/PZ volumes. In contrast, the en-vironmental influence was >69% for all zonal prostatevolumes or the ratios of the volumes. This means thatthe prostate enlargement that occurs in aging men ismainly affected by environmental and not hereditaryinfluences. The major growth of the PZ occurs beforeage 50 years, in contrast with the TZ, which enlargesmore after age 50 than the PZ. Further studies will berequired to determine what these environmental in-fluences might be. As reported elsewhere, men withlower androgen levels tend to have larger prostateglands as they age, suggesting that environmental fac-tors that lower a serum androgen concentration mayalso contribute to prostate enlargement [43].

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