AMERICAN JOURNAL OF EPIDEMIOLOGY Vol. 121, No.

1
Copyright © 1985 by The Johns Hopkins University School of Hygiene and Public Health Printed in U.SA.
All rights reserved

THE DEVELOPMENT OF BENIGN PROSTATIC HYPERPLASIA

AMONG VOLUNTEERS IN THE NORMATIVE AGING STUDY

ROBERT J. GLYNN,1 EDWARD W. CAMPION,*3 GLEN R. BOUCHARD1 AND

JEREMIAH E. SILBERT1-4

Glynn, R. J. (VA Outpatient Clinic, Boston, MA 02108), E. W. Campion, G. R.

Bouchard and J. E. Silbert The development of benign prostatic hyperplasia

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among volunteers in the Normative Aging Study. Am J Epidemiol 1985;121:78-90.
This study describes the development of benign prostatic hyperplasia among
2,036 volunteers in the Veterans Administration Normative Aging Study, a longi-
tudinal study of human aging situated in Boston. Men were followed from enroll-
ment in the study (between 1961 and 1970) until their last examination prior to
May 15, 1982. Two indications of benign prostatic hyperplasia were considered:
1) a clinical diagnosis made at a uniform physical examination, and 2) surgical
treatment Incidence rates for both a clinical diagnosis and surgery for benign
prostatic hyperplasia increased through the eighth decade. Life table analysis
estimated the lifetime probability of surgical treatment to be 0.29. Known risk
factors for cardiovascular disease and diabetes as well as marital and socioec-
onomic status, religion, cigarette smoking and alcohol and coffee consumption
were evaluated as risk factors. Controlling for age in proportional hazards models,
statistically significant predictors of surgery were prior clinical diagnosis, lower
socioeconomic status, Jewish religion, and not currently smoking cigarettes;
whereas only body mass index was a significant predictor of a clinical diagnosis.
Although a prior clinical diagnosis was an important predictor of surgery (adjusted
odds ratio 3.52, 95% confidence interval = 1.93-6.42), this diagnosis is neither
sensitive nor specific In its association with surgery.

hyperplasia; longitudinal studies; prostate

Operations on the prostate are the most
frequently performed surgical procedures in
men aged 65 years and over, and hyperpla-
sia of the prostate is the leading reason for
prostate surgery (1, 2). In American males
aged 65 and older there were 218,000 pros-
Received for publication January 16, 1984, and in
finalformApril 24,1984.
1
Normative Aging Study, Veterans Administration
Outpatient Clinic, 17 Court St, Boston, MA 02108.
(Reprint requests to Dr. Glynn.)
1
Geriatrics Unit, Massachusetts General Hospital,
Boston, MA.
3 slucue8
Division on Aging, Harvard Medical School, Bos-
ton,4 MA.
Department of Medicine, Harvard Medical
School, Boston, MA.
Supported by the Medical Research Service of the
Veterans Administration.
78
tate operations performed in 1979, giving a
rate of 22.6 per 1,000. Hyperplasia of the
prostate is the fourth leading discharge di-
agnosis from non-Federal short stay hos-
pitals for men 65 and older, with an annual
r a t e of 16.5 discharges per 1,000 population
(1). In spite of its clinical and economic
significance, there is remarkably Little in-
formation relating precursor variables to
t n e onget ^ j t n e surgical treatment of
. . . . 7 . .„ „. T
benign prostatic hyperplasia (2, 3). In par-
ticular, there have been no longitudinal
afiidipa
-
Previous case-control studies, examina-
tions of clinical series, and comparisons of
. , ., . ., , , r ,
worldwide incidence rates have found some
important characteristics of benign pros-
 DEVELOPMENT OF BENIGN PROSTATIC HYPERPLASIA
tatic hyperplasia. Benign prostatic hyper-
plasia is seldom found in men under age 40
but beginning at age 40 there is a very
strong age-related increase, estimated by
Moore (4) to reach a prevalence of 75 per
cent among men aged 80-90. Lytton et al.
(5) have calculated the probability of a 40-
year-old man requiring an operation for
benign prostatic hyperplasia, if he lives to
age 80, to be approximately 10 per cent.
The prevalence is low among Japanese and
Chinese men, high among whites, and as
high or higher among blacks (3, 6). Two
studies (2, 5) reported that Jewish men
have a higher incidence than non-Jewish
men. Thus, there are apparent differences
in rates of benign prostatic hyperplasia by
ethnicity and religion. No association has
been found for marital status (2, 7, 8).
Benign prostatic hyperplasia has been
found to be related to lifestyle variables;
coffee drinkers are reportedly at somewhat
greater risk than men who do not drink
coffee and smokers are at reduced risk com-
pared with nonsmokers (2, 7). Benign pros-
tatic hyperplasia is more prevalent in men
with hypertension, coronary heart disease,
and diabetes (9-11); but these may be spu-
rious relationships existing because of the
common association of all these diseases
with age. Other epidemiologic findings, in-
cluding comparison of international mor-
tality rates and possible relationships with
prostate cancer, have been described (3, 7,
8).
The present study examines prospec-
tively the development of benign prostatic
hyperplasia among male volunteers in the
Normative Aging Study. Two outcomes are
considered: 1) the diagnosis of benign pros-
tatic hyperplasia at a regularly scheduled
Normative Aging Study physical examina-
tion, and 2) surgery for benign prostatic
hyperplasia as reported by participants as
part of a medical history during the exam-
ination. We consider five specific questions
suggested by the findings summarized
above: 1) What are the age-specific inci-
dence rates determined by a clinical diag-
79
nosis and by surgery for benign prostatic
hyperplasia? 2) Are Jewish men at greater
risk than non-Jewish men? 3) Are marital
status, socioeconomic status, as well as cof-
fee, alcohol and cigarette consumption re-
lated to the development of benign pros-
tatic hyperplasia? 4) Are known risk factors
for coronary heart disease and diabetes also
risk factors for benign prostatic hyperpla-
sia? 5) What is the risk of surgery among
those men with a prior clinical diagnosis
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relative to the risk of men with no such
prior diagnosis?
MATERIALS AND METHODS
The Normative Aging Study is a longi-
tudinal study of human aging established
by the Veterans Administration in 1961.
Six thousand male volunteers from the
Greater Boston area were screened to pro-
vide an initially healthy population.
Screening was based on laboratory, clinical,
radiologic, and electrocardiographic crite-
ria. Men were disqualified from participa-
tion in the study if they had a history of
conditions such as heart disease, cancer,
gout, diabetes, cirrhosis, peptic ulcer, re-
current asthma, bronchitis or sinusitis.
Also disqualifying was either systolic
blood pressure greater than 140 mmHg or
diastolic blood pressure greater than 90
mmHg. Acceptable conditions included
childhood and other generally acute condi-
tions from which there were no sequelae.
No volunteer was excluded because of a
clinical diagnosis or prior surgical treat-
ment of benign prostatic hyperplasia.
With these criteria, 2,280 men were ac-
cepted into the Normative Aging Study,
ranging in age at entry from 21-81 with a
mean of 42 years. The educational level of
the population as of 1971 was as follows: 14
per cent less than high school, 25 per cent
high school graduates, 35 per cent beyond
high school and 26 per cent college gradu-
ates. By occupation, 52 per cent were
white-collar workers (professional, mana-
gerial, clerical and sales). Ethnically, the
population accorded fairly closely with the
80 GLYNN ET AL.
distribution found in the Boston area.
However, only 2 per cent of the volunteers
were black, which is lower than the 3.7 per
cent in the Boston metropolitan area (12).
Additional information about the popula-
tion and a description of early dropouts
from the study have been published (13,
14).
Screening and initial examination oc-
curred between 1961 and 1970. Subse-
quently, men under age 52 have reported
for examinations every five years; after age
52 they have reported every three years.
Each examination contains a uniform med-
ical history and physical examination, in
addition to blood and urine tests. In partic-
ular, at each examination the examining
physician inquires about symptoms of
lower urinary tract obstruction including
hesitancy in initiating voiding, decreased
urinary stream, and postvoiding dribbling.
Such obstructive symptoms are distin-
guished from irritative symptoms such as
dysuria, frequency or urgency (15). This
physician also performs a digital examina-
tion of the prostate. A clinical diagnosis of
benign prostatic hyperplasia is based upon
a physical finding of an enlarged or abnor-
mally firm prostate, or by a history of
symptoms if the symptoms can not be at-
tributed to another cause such as prostatitis
or cancer of the prostate.
Because most men over age 60 have some
evidence of prostatic enlargement there is
clearly a subjective component to this clin-
ical diagnosis. The need for surgery is a
more reliable indication of the presence of
significant benign prostatic hyperplasia. At
each examination participants report
whether they had surgery for benign pros-
tatic hyperplasia, either by transurethral
resection or by one of the open methods of
surgical treatment. Surgery for benign
prostatic hyperplasia is distinguished from
prostatectomy for prostate cancer.
Men eligible for the current study were
the 2,049 Normative Aging Study partici-
pants who had at least two examinations.
Thus, the 231 men who had only one ex-
amination were excluded. These excluded
men were younger at baseline (mean ±
standard deviation (SD) = 40.4 ± 10.7
years) than the included men (mean ± SD
= 41.9 ± 9.3 years). This slight but statis-
tically significant difference (p < 0.05) in-
dicates a tendency for younger men to dis-
continue participation in the study. In ex-
amining prospectively the development of
a clinical diagnosis of benign prostatic hy-
perplasia we further excluded the 101 men
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who had such a diagnosis at their first
examination. Not surprisingly, these 101
men were older (mean ± SD = 48.7 ± 11.0
years) than the included men. In examining
the risk of surgery for benign prostatic hy-
perplasia the 12 men who had such surgery
prior to entry into the Normative Aging
Study were excluded; however, men with a
prior clinical diagnosis were not excluded
from analyses of the risk of surgery. Since
the exact date of onset of a clinical diag-
nosis could not be determined, onset was
assumed to occur at the midpoint of the
interval between the examination of first
diagnosis and the prior examination. Par-
ticipants were followed from their initial
examination until the development of be-
nign prostatic hyperplasia or until their last
examination before May 15,1982. Age-spe-
cific incidence rates for both diagnosis and
surgery were estimated nonparametrically
using the Cutler-Ederer life table approach
(16).
Variables examined as possible predic-
tors of either a clinical diagnosis or surgery
for benign prostatic hyperplasia were: age,
systolic and diastolic blood pressure, serum
cholesterol, uric acid, fasting and two-hour
glucose, body mass index, religion, socio-
economic status, marital status, as well as
coffee, cigarette and alcohol consumption.
At each physical examination blood pres-
sure is measured by an examining physician
using a standard mercury sphygmomanom-
eter and a 14-cm cuff. With the subject
seated, systolic blood pressure and fifth-
phase diastolic blood pressure are measured
to the nearest 2 mmHg in each arm. Values
 DEVELOPMENT OF BENIGN PROSTATIC HYPERPLASIA
used for the current study are the average
systolic and diastolic levels for the two arms
at each examination. At each examination
subjects report to the study center at 8:00
A.M. after an overnight fast and abstinence
from smoking. Serum is collected by veni-
puncture and analyzed for cholesterol, uric
acid and fasting glucose. Two-hour glucose
level is measured following a 100 g glucose
load. Body mass index is the ratio of weight
in kilograms to the square of height in
meters. Details of measurement and the
relationship of these variables with cardio-
vascular disease in this population have
been described (17-19).
Cigarette smoking information and mar-
ital status have been assessed five times
during the course of the study. The level of
these variables at a given physical exami-
nation was taken to be the measure nearest
in time to that examination. The Duncan
Index of socioeconomic status (20) and the
usual number of cups of coffee and drinks
of alcoholic beverages per day were assessed
by mailed questionnaire in 1973. An indi-
vidual's levels of these variables were as-
sumed constant throughout the study.
Upon admission into the study men were
asked about their ethnicity and religious
background. All Jewish participants in the
study were of European ancestry.
Each individual's risk of a diagnosis or
of surgery for benign prostatic hyperplasia
was considered to depend on his most re-
cent assessment of these predictors. For
example, an individual's risk of having a
clinical diagnosis at his third Normative
Aging Study examination was considered
to depend upon his characteristics assessed
at his second examination. In analyses of
possible risk factors other than age, 291
men were excluded because of missing data,
which in almost all cases was due to non-
response to the socioeconomic status, al-
cohol and coffee consumption questions.
Among the 2,049 Normative Aging Study
participants with more than one examina-
tion, these 291 men with some incomplete
data had an age distribution (mean ± SD
81
= 41.9 ± 11.0 years) almost identical to the
age distribution of the remaining 1,758 par-
ticipants (mean ± SD = 41.9 ± 9.0 years).
There were no significant differences in the
rates of either clinical diagnosis or surgery
for benign prostatic hyperplasia between
the group of men with some missing data
and those with complete data.
Associations of putative risk factors with
both the diagnosis and surgery for benign
prostatic hyperplasia were estimated as-
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suming the proportional hazards model
stratified by age groups (21). In additional
unstratified models, age was considered as
a separate risk factor. Full models consid-
ering all putative risk factors as well as
stepwise models were estimated. Variables
entered the stepwise model if the p value
associated with their chi-square to enter
was less than 0.10 and remained in the
model if the p value associated with their
chi-square to remove was less than 0.15. By
considering each individual's most recent
risk factor levels, risk factors were time-
varying. Only the most recent levels of pu-
tative risk factors were considered in each
proportional hazards model. Parameters in
the proportional hazards model were esti-
mated by maximizing the partial likelihood
as implemented by the BMDP statistical
package (22). For all multivariate models
the alcohol, cigarette and coffee consump-
tion variables were transformed by log (1 +
daily consumption) to normalize their dis-
tributions.
RESULTS
Age-specific incidence rates for both a
clinical diagnosis and surgery for benign
prostatic hyperplasia are shown in tables 1
and 2. Each man was classified into an age
group according to his age at his previous
physical examination. Since most Norma-
tive Aging Study participants have had
three or four examinations, an individual
might contribute person-years of experi-
ence to several different age groups. The
incidence rates of both a clinical diagnosis
and surgery were markedly greater in sue-
82 GLYNN ET AL.

TABLE 1 O.OT

Incidence of benign prostatic hyperplasia. Clinical

diagnosis: 1,948 Normative Aging Study participants
with no clinical diagnosis of benign prostatic
hyperplasia at entry into the study, followed from
entry (between 1961 and 1970) until their last
examination prior to May 15, 1982
Age
(years)
at Man-years Cases Incidence
previous rate
examination
21-39 6,780.3 25 0.0037

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40-49 8,927.8 84 0.0094
50-59 4,977.1 156 0.0313
1.0 1.5 2.0 2.5 3.0 J.S H.O H.i 5.0 5.5
60-69 1,268.1 65 0.0513
70-87 219.6 13 0.0592 TERRS OF FOLLOH-UP
FIGURE 1. The cumulative probability of surgery
TABLE 2 for benign prostatic hyperplasia over an interval equal
Incidence of benign prostatic hyperplasia. Surgical to the time between examinations for men in the
treatment: 2,037 Normative Aging Study participants Normative Aging Study. Using the Cutler-Ederer life
with no surgical treatment for benign prostatic table method (16), estimates are based on 2,037 par-
hyperplasia prior to entry into the study, followed ticipants with no surgical treatment for benign proa-
from entry (between 1961 and 1970) until their last tatic hyperplasia prior to entry into the study, followed
examination prior to May 15, 1982 from entry into the study (between 1961 and 1970)
until their last examination prior to May 15, 1982.
Age
(years)
at Man-years Caws Incidence than 3.5 years. For men aged 70 or older
rate
previous there was a probability of 0.058 of having
examination surgery at some time during a 3.5-year in-
21-39 7,021.1 0 0 terval. The 3.5-year probabilities for men
40-49 9,767.1 2 0.00020 aged 60-69, 50-59 and 40-49 were 0.041,
50-59 6,135.7 25 0.00407
0.015 and 0.0005, respectively. Again, it is
60-69 1,904.1 23 0.01208
70-87 361.8 7 0.01935 clear that the risk was markedly greater
with each increasing decade of life. Using
cessively older age groups. The greatest these data, the probability that a 40-year-
increase between age groups in the inci- old man who lives to age 80 will have sur-
dence rate of a clinical diagnosis occurred gery for benign prostatic hyperplasia by age
at age 50. The per cent increase in diagnosis 80 is
among men older than 70 compared with
men 60-69 was 15 per cent. By contrast, 1 - (0.9995)2 (0.9796)2 (0.9591)3
the greatest increase in the incidence rate • (0.9425)3 = 0.292.
of surgery occurred at age 60 and the per
cent increase in men older than 70 com- A similar graph describing the probabil-
pared with men 60-69 was 60 per cent. ity of developing a clinical diagnosis of be-
The probability of having first-time sur- nign prostatic hyperplasia could not be
gery for benign prostatic hyperplasia, esti- drawn because the exact date of onset was
mated by the Cutler-Ederer method (16), is unknown. Assuming that the symptoms or
shown in figure 1. Estimates for men under physical finding developed at the midpoint
age 60 were based on 5.5 years of follow-up of the interval between examinations, the
because the great majority of men in this 3.5-year probability of a man initially aged
age group had intervals between examina- 70-87 having a first diagnosis of benign
tions of less than 5.5 years; for most men prostatic hyperplasia was 0.178. The 3.5-
over 60, examination intervals were less year probabilities for men aged 60-69, 50-
 DEVELOPMENT OF BENIGN PROSTATIC HYPERPLASIA 83
59 and 40-49 were 0.171, 0.110 and 0.042, nign prostatic hyperplasia are shown in
respectively. The cumulative probability table 5. In assessing the relationship of each
that a 40-year-old man who is initially free variable to surgery an individual's most
of benign prostatic hyperplasia and lives to recent previous measure of each variable
age 80 will develop symptoms or a physical was considered. Thus, for example, an in-
finding is 0.777. dividual's risk of having surgery for benign
Putative risk factors for benign prostatic prostatic hyperplasia between his second
hyperplasia other than age were first ex- and third examinations was considered to
amined categorically within age groups. depend on his age and other factors as
This was done because relationships might assessed at his second examination. Age
not be monotonic and might differ with was by far the most important predictor

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age. Incidence rates of surgery for benign of surgery. With age in the model, a prior
prostatic hyperplasia within categories of clinical diagnosis was an important inde-
putative risk factors and age are shown in pendent predictor of surgery. Controlling
table 3. Not shown are diastolic blood pres- for age and prior clinical diagnosis, three
sure and fasting glucose which gave results additional variables were significant inde-
similar to systolic blood pressure and two- pendent predictors and the signs of their
hour glucose, respectively. There were some estimated coefficients indicate the direc-
clear trends in incidence rates across cate- tion of their association with surgical treat-
gories. Men smoking one pack of cigarettes ment. Men of higher socioeconomic status
or more per day had markedly lower rates and cigarette smokers were less likely to
of surgery than both nonsmokers and for- have surgery whereas Jewish men were
mer smokers. Jewish men had higher rates more likely than non-Jews. Controlling for
of surgery than non-Jews, and men with a these variables, no other variable showed a
prior clinical diagnosis had much higher significant prospective association with
rates of surgery than men with no prior surgical treatment. In particular, married
diagnosis. Yet about half (26 out of 53) of men were no more likely to have surgery
the men having surgery had no prior clini- than unmarried men and none of the stan-
cal diagnosis at an examination within five dard risk factors for cardiovascular disease
years of their operation. None of the labo- and diabetes were positively associated
ratory or physical variables considered with surgery. For variables entering the
showed any clear association with surgery. stepwise model, estimated coefficients and
There were also no apparent associations standard errors from this model were quite
with marital status, coffee or alcoholic bev- similar to the estimates from the full model.
erage consumption. Estimated standard errors were slightly
In table 4 are shown incidence rates of a larger in the full model. To potentially con-
clinical diagnosis of benign prostatic hy- trol more effectively for the effects of age,
perplasia within categories of putative risk a proportional hazards model stratified
factors and age. There was a trend for men over four age groups (40-49, 50-59, 60-69
with lower cholesterol levels and lower body and 70-87 years) was considered. The es-
mass indices to have lower incidence rates timated coefficients and standard errors for
of a clinical diagnosis than men with higher variables other than age in this model were
levels of these variables. No other variables nearly identical to the coefficients in the
showed any marked associations with the unstratified model presented.
diagnosis. Not shown are diastolic blood The coefficients in Cox's proportional
pressure and fasting glucose which also hazards model can be interpreted in a man-
showed no association. ner analogous to the interpretation of coef-
Multivariate associations of putative risk ficients in a logistic regression model. For
factors other than age with surgery for be- instance, the estimated coefficient for age
84 GLYNN ET AL.

TABLE 3
Incidence of surgery for benign prostatic hyperplasia by age within specific categories of putative risk factors:
1,747 Normative Aging Study participants with no surgical treatment for benign prostatic hyperplasia prior to
entry into the study and with complete covariate information, followed from entry (between 1961 and 1970) until
their last examination prior to May 15, 1982

Age (years) at previous examination

4CM9 60-69 60-«9 70-87
No. No. No. No.
of IR* of IR of IR of IR
cases cases cases cases
Systolic blood pressure
<120 mmHg 2 0.5 6 2.9 7 13.3 1 10.4

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120-139 mmHg 0 0.0 13 5.0 10 12.8 4 33.6
£140 mmHg 0 0.0 4 4.6 4 10.6 2 25.2
Uric acid
<5.0 mg/100 ml 0 0.0 1 1.9 4 32.1 0 0.0
5.0-6.9 mg/100 ml 2 0.4 16 4.8 11 10.8 5 25.1
£7.0 mg/100 ml 0 0.0 6 3.6 6 11.2 2 38.4
Serum cholesterol
<200 mg/100 ml 1 0.3 12 7.5 5 10.2 1 10.5
200-249 mg/100 ml 0 0.0 8 3.5 8 12.2 3 24.4
£250 mg/100 ml 1 0.5 3 1.8 8 14.9 3 39.2
Two-hour glucose
<90 mg/100 ml 1 0.7 2 2.7 2 7.9 1 26.5
90-139 mg/100 ml 1 0.2 18 4.7 16 14.7 5 26.4
£140 mg/100 ml 0 0.0 3 3.1 3 8.8 1 14.9
Body mass index
<23 kg/m 2 0 0.0 2 2.7 6 16.2 0 0.0
23-27.9 kg/m 2 1 0.2 16 4.5 12 11.6 6 32.2
£ 2 8 kg/m 2 . 1 0.5 5 4.0 4 11.8 1 17.2
Alcoholic beverages
Nondrinker 0 0.0 0 6.0 2 11.1 3 45.7
1-729 drinks/year 2 0.4 21 5.4 14 12.5 4 22.6
£ 2 drinks/day 0 0.0 2 1.6 5 12.9 0 0.0
Coffee consumption
No coffee 0 0.0 2 3.4 2 8.7 0 0.0
< 3 cups/day 1 0.4 12 6.1 10 13.8 3 26.2
£ 3 cups/day 1 0.2 9 3.0 9 3.0 4 27.2
Cigarette smoking
Never 0 0.0 11 5.7 7 9.8 6 32.1
Former 2 0.6 9 3.7 12 16.4 1 11.1
< 1 pack/day 0 0.0 2 7.5 1 13.9 0 0.0
£ 1 pack/day 0 0.0 1 1.1 1 6.1 0 0.0
Marital status
Never married 0 O.O 0 0.0 2 36.5 1 90.2
Married 2 0.3 22 4.3 17 11.8 5 24.7
Other 0 0.0 1 3.7 2 10.8 1 12.4
Socioeconomic status
Duncan index <40 1 0.3 8 4.7 5 11.1 3 70.1
40 < Duncan <70 0 0.0 9 4.5 10 15.0 2 12.3
Duncan £ 7 0 1 0.4 6 3.2 6 10.5 2 22.5
Jewish religion
No 2 0.3 17 3.4 17 11.7 4 17.2
Yes 0 O.O 6 10.0 4 17.6 3 48.2
Clinical benign prostatic
hyperplasia
No 1 0.1 15 3.2 10 8.7 0 0.0
Yes 1 1.8 8 9.7 11 20.5 7 54.5
' Incidence rate x 103.
 DEVELOPMENT OF BENIGN PROSTATIC HYPERPLASIA 85
TABLE 4
Incidence of a clinical diagnosis of benign prostatic hyperplasia by age within specific categories of putative risk
factors: 1,702 Normative Aging Study participants with no clinical diagnosis of benign prostatic hyperplasia at
entry into the study and with complete covariate information, followed from entry (between 1961 and 1970) until
their last examination prior to May 15, 1982
Age (years) at previous examination
20-39 40-49 60-69 60-69 70-87
No. No, No. No No
of IR* of IR of IR of IR of IR
case* cases cases cases can s

Systolic blood pressure

<120 mmHg 9 3.9 28 8.2 53 30.8 19 55.9 2 56.7

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120-139 mmHg 12 3.9 36 9.4 68 32.3 32 59.5 5 62.6
£140 mmHg 1 2.8 8 13.9 22 32.0 6 23.9 2 29.0
Uric acid
<5.0 mg/100 ml 3 5.0 9 11.9 16 37.4 4 50.6 2 74.5
5.0-6.9 mg/100 ml 15 3.7 47 8.9 87 31.6 35 49.9 4 29.9
£7.0 mg/100 ml 4 3.8 16 8.9 40 29.9 18 51.7 3 128.3
Serum cholesterol
<200 mg/100 ml 13 4.8 28 9.9 42 31.5 18 50.2 5 117.7
200-249 mg/100 ml 7 3.3 29 9.1 60 32.1 27 67.7 2 21.5
£250 mg/100 ml 2 2.2 15 8.1 41 31.3 12 32.3 2 41.0
Two-hour glucose
<90 mg/100 ml 9 7.7 12 8.7 24 38.4 11 72.1 2 99.2
90-139 mg/100 ml 11 2.6 55 9.5 97 31.1 36 48.8 5 41.3
£140 mg/100 ml 2 5.6 5 7.1 22 28.5 10 42.1 2 46.6
Body mass index
<23kg/m' 3 3.5 9 9.4 24 41.5 11 56.2 3 146.8
23-27.9 kg/m 1 15 4.1 46 9.2 94 32.3 38 55.0 4 34.3
£28 kg/m2 4 3.3 17 9.0 25 24.4 8 33.2 2 42.6
Alcoholic beverages
Nondrinker 2 6.8 5 7.8 9 27.6 11 107.4 2 36.2
1-729 drinks/year 16 4.2 44 8.2 101 31.3 33 43.2 6 56.1
£2 drinks/day 4 2.5 23 12.3 33 34.2 13 49.8 1 45.8
Coffee consumption
No coffee 3 3.9 8 8.9 19 42.2 7 56.2 1 54.0
<3 cups/day 7 5.3 20 8.9 50 29.1 26 46.0 2 24.6
£3 cups/day 12 3.3 44 9.4 74 31.5 24 54.8 6 71.1
Cigarette smoking
Never 8 5.9 25 11.3 47 29.1 26 55.5 6 49.4
Former 7 4.0 33 10.6 63 31.9 23 44.1 3 58.9
<1 pack/day 1 1.6 1 1.8 8 35.9 1 20.8 0 0.0
£ l pack/day 6 3.0 13 6.6 25 35.7 7 77.4 0 0.0
Marital status
Never married 3 7.7 0 0.0 3 24.3 3 85.2 1 621.1
Married 18 3.5 71 9.6 135 32.4 47 48.0 5 38.0
Other 1 6.3 1 3.8 5 21.8 7 62.0 3 60.6
Socioeconomic status
Duncan index <40 8 4.2 24 8.1 40 28.1 16 47.4 2 59.7
40 s Duncan <70 6 2.9 24 9.3 56 34.1 23 48.9 3 32.4
Duncan £70 8 4.6 24 10.4 47 32.5 18 56.2 4 68.8
Jewish religion
No 22 4.0 67 9.1 122 30.2 47 47.6 8 53.3
Yes 0 0.0 5 10.7 21 44.3 10 71.5 1 29.3
* Incidence rate x 103.
86 GLYNN ET AL.

TABLE 5
Cox regression analysis of surgery for benign prostatic hyperplasia in relation to previous examination
assessments of putative risk factors: 1,747 Normative Aging Study participants with no surgical treatment for
benign prostatic hyperplasia prior to entry into the study and with complete covariate information, followed from
entry (between 1961 and 1970) until their last examination prior to May 15, 1982
St«pwise model Full model
Variable* Standard x'to Standard
Coefficient Coefficient
error enter error
Entering the stepwise model
Age 0.0880 0.0154 67.71 0.0888 0.0166
Prior diagnosis of benign prostatic 1.2582 0.3064 15.42 1.2644 0.3097
hyperplasia

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Socioeconomic status -0.0176 0.0066 4.50 -0.0169 0.0067
Jewish religion 0.7955 0.3438 5.13 0.7669 0.3625
Cigarette packs/day (log) -1.2153 0.6980 4.10 -1.2162 0.7039
Not entering the stepwise model
Diastolic blood pressuret 2.66
Uric acid 0.76 -0.1295 0.1281
Body mass index 0.39 0.0346 0.0490
Fasting glucose 0.30 0.0064 0.0114
Coffee cups/day (log) 0.15 0.0480 0.2577
Alcoholic drinks/day (log) 0.06 -0.0439 0.2962
Two-hour glucoset 0.05
Marital status 0.01 0.0638 0.4254
Systolic blood pressure 0.01 -0.0004 0.0088
Serum cholesterol 0.00 0.0001 0.0031
* Variables listed in order of entry into the stepwise model.
t Diastolic blood pressure and two-hour glucose were not considered in the full model because of high
correlations with systolic blood pressure and fasting glucose, respectively.

of 0.0880 means that, for two groups of men
differing in age by 10 years but identical in
all other important risk factors, older men
have an estimated incidence of surgery for
benign prostatic hyperplasia approximately
2.41 times the incidence of men 10 years
younger. The factor 2.41 is exp(0.880 X 10).
A 95 per cent confidence interval for this
estimate is 1.78-3.20. Similarly, the ad-
justed rate ratio for men with a prior clin-
ical diagnosis compared with men with no
prior diagnosis is 3.52 (95 per cent confi-
dence interval = 1.93-6.42). Other adjusted
rate ratios are: 0.70 for men 20 units higher
in socioeconomic status (on a 100 point
scale) compared with men at any specified
level (95 per cent confidence interval =
0.54-0.91); 2.22 for Jewish men compared
with non-Jews (95 per cent confidence in-
terval = 1.13-4.35); and 2.32 for men cur-
rently not smoking compared with current
smokers of one pack of cigarettes per day
(95 per cent confidence interval = 0.90-
5.99).
The results of a Cox regression analysis
considering predictors of a first clinical di-
agnosis of benign prostatic hyperplasia are
shown in table 6. The variables considered
as predictors were identical to the variables
in the previous regression with the excep-
tion of a prior clinical diagnosis. Although
four variables entered the stepwise model,
only two, age and body mass index, could
be considered statistically significant. Age
was by far the most important predictor.
Controlling for age, men with lower body
mass indices were somewhat more likely to
have a clinical diagnosis than heavier men.
Adjusted rate ratios from this model are:
1.99 for men 10 years older than men of
any specified age (95 per cent confidence
interval = 1.78-2.22); 0.82 for men 5 kg/m2
heavier than men with any specified body
mass index (95 per cent confidence interval
 DEVELOPMENT OF BENIGN PROSTATIC HYPERPLASIA 87
TABLE 6
Cox regression analysis of a clinical diagnosis of benign prostatic hyperplasia in relation to previous examination
assessments of putative risk factors: 1,702 Normative Aging Study participants with no clinical diagnosis of
benign prostatic hyperplasia at entry into the study and with complete covariate information, followed from
entry (between 1961 and 1970) until their last examination prior to May 15, 1982
Stepwise model Full model
Variable*
Coefficient Standard x1 to Coefficient Standard
error enter error
Entering the stepwise model
Age 0.0687 0.0057 145.05 0.0712 0.0063
Body mass index -0.0404 0.0202 4.47 -0.0410 0.0215
Serum cholesterol -0.0022 0.0013 2.77 -0.0023 0.0013

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Jewish religion 0.3011 0.1778 2.67 0.2689 0.1855
Not entering the stepwise model
Systolic blood pressure 2.19 -0.0058 0.0042
Uric acid 1.06 0.0688 0.0549
Two-hour glucoset 1.05
Fasting glucose 0.93 -0.0055 0.0053
Socioeconomic status 0.85 0.0022 0.0028
Diastolic blood pressuret 0.77
Cigarette packs/day (log) 0.44 -0.1253 0.1903
Married 0.35 0.1196 0.2045
Alcoholic drinks/day (log) 0.22 -0.0435 0.1143
Coffee cups/day (log) 0.00 0.0212 0.1010
* Variables listed in order of entry into the stepwise model.
t Diastolic blood pressure and two-hour glucose were not considered in the full model because of high
correlations with systolic blood pressure and fasting glucose, respectively.

= 0.67-1.00); 0.90 for men 50 mg/100 ml
higher in serum cholesterol than men with
any specified level (95 per cent confidence
interval = 0.79-1.02); and 1.35 for Jewish
men compared with non-Jews (95 per cent
confidence interval = 0.95-1.91). For vari-
ables entering the stepwise model, esti-
mated coefficients and standard errors
from this model were similar to the esti-
mates from the full model; estimated stan-
dard errors in the full model were slightly
larger. When the proportional hazards
analysis was stratified by age, identical re-
sults were obtained.
DISCUSSION
In spite of the increasing number of el-
derly men in the population, and the cost
to society of prostatic disorders, very little
is known about the epidemiology of benign
prostatic hyperplasia. Among volunteers in
the Normative Aging Study, rates of both
first diagnosis and first surgery for benign
prostatic hyperplasia increased with age up
to the eighth decade. The sharpest increase
in rate of first diagnosis occurred among
men in their fifties, whereas the sharpest
increase in rate of first surgery occurred
among men in their sixties. The probability
that a 40-year-old man who lives to age 80
will have surgery for benign prostatic hy-
perplasia at some time during his life is
estimated from this population to be about
0.29. This is almost three times the lifetime
estimate obtained by Lytton et al. (5) in
their survey of prostate surgery in New
Haven between 1953 and 1961.
No other risk factor could approach age
in the strength of its association with either
a clinical diagnosis or surgery for benign
prostatic hyperplasia. A prior clinical di-
agnosis was a strong predictor of surgery
but there were many men with clinically
diagnosed benign prostatic hyperplasia at
entry into the study who did not have sur-
gery during the approximately 15 years of
follow-up, while other men had surgery
with no prior clinical diagnosis. Of the 57
88 GLYNN ET AL.
men having surgery, 31 had a clinical di-
agnosis at a prior examination. However,
only nine of these 31 men had a clinical
diagnosis upon entry into the Normative
Aging Study. Other than these nine, there
were 92 men with a clinical diagnosis at
entry to the study who reported for at least
one subsequent examination and did not
have surgery during follow-up. This sub-
stantiates the variable clinical course of
benign prostatic hyperplasia, with some
men proceeding rapidly to a stage where
surgery is required and others able to tol-
erate the clinically apparent condition for
intervals over 10 years without surgical
treatment. However, the description of the
degree of variability in the progression of
benign prostatic hyperplasia is limited by
the reliability of the clinical diagnosis.
The limited reliability and validity of the
clinical diagnosis of benign prostatic hy-
perplasia have been described elsewhere.
Meyhoff and Hald (23) reported consider-
able interobserver variation in estimates of
preoperative prostatic weight. However,
they did find a significant correlation be-
tween estimated and actual prostatic
weight. Castro et al. (24) and Andersen et
al. (25) found no correlation between the
severity of symptoms and the degree of
infravesical obstruction as assessed urody-
namically. These studies did not consider
men in the general population. The corre-
lation between the size of the prostate as
palpated on rectal examination and the de-
gree of obstruction of the urinary tract may
be slight. The present finding of a clinical
diagnosis as a significant predictor of sub-
sequent surgery lends some support to the
validity of the clinical diagnosis. The limi-
tations of this diagnosis are also clear in
the Normative Aging Study data. There are
newer noninvasive techniques for assessing
postvoiding residual urine, and these
should lead to more reliable clinical diag-
noses (26).
In addition to age and a clinical diagno-
sis, Jewish men, nonsmokers and men of
lower socioeconomic status had an in-
creased risk of surgery for benign prostatic
hyperplasia. The adjusted relative rate for
Jewish men compared with non-Jews of 2.2
found in the current study is quite consis-
tent with the relative risks of 2.4 reported
by Morrison (2) and 2.5 reported by Lytton
et al. (5). The study by Armenian et al. (8)
reported identical percentages of Jewish
men in both their case and control series.
Lytton et al. noted the international differ-
ences in incidence rates of benign prostatic
Downloaded from http://aje.oxfordjournals.org/ at Pennsylvania State University on September 18, 2016
hyperplasia and speculated that the higher
rates among Jewish men might be because
the majority of Jewish men in their study
were foreign-born. Of the 13 Jewish men in
the Normative Aging Study who had sur-
gery for benign prostatic hyperplasia, only
one was born outside the United States.
Incidence rates of surgery among foreign-
born participants in the Normative Aging
Study were roughly comparable to the rates
among USA-born men, but could not be
accurately estimated because of small num-
bers (only four foreign-born men had sur-
gery for benign prostatic hyperplasia).
The adjusted relative risk for smokers of
one pack of cigarettes per day compared
with nonsmokers was 0.4. This is consistent
with the relative risk of 0.5 reported by
Morrison (2) and the finding by Greenwald
et al. (7) of a lower proportion of smokers
among men having surgery for benign pros-
tatic hyperplasia than among controls.
Rates of surgery for former smokers were
similar to rates for never smokers (table 3),
so these groups were combined in determin-
ing overall rates (table 5). Morrison re-
ported that former smokers had rates in-
termediate between current and never
smokers.
The finding in the current study of a
higher incidence of surgery among men of
lower socioeconomic status was unantici-
pated. Richardson (27) described social
class differences in several measures of be-
nign prostatic hyperplasia among Scottish
men in the early 1960s. Men of higher social
status were found to have higher rates of
mortality and surgery due to benign pros-
 DEVELOPMENT OF BENIGN PROSTATIC HYPERPLASIA
tatic hyperplasia. However, a higher per-
centage of men in the lower social classes
reported symptoms of nocturia, and among
all men admitted to the hospital for benign
prostatic hyperplasia, men of lower social
status were more likely to be in acute reten-
tion. Differences in rates of prostate sur-
gery between men of different social status
may be due to differences in health insur-
ance plans or medical care utilization pat-
terns. We are not encouraged to conclude
that the differences between men of differ-
ent social status in rates of surgery are due
to lifestyle differences which have a direct
biologic effect.
A clinical assessment of benign prostatic
hyperplasia remains a part of most stan-
dard physical examinations and so it is of
interest to compare the clinical diagnosis
with surgery for benign prostatic hyperpla-
sia. Risk factors for palpable enlargement
may not be the same as those for the hy-
pertrophied median lobe. Older age and
Jewish religion were predictive and had
similar effect estimates for both a clinical
diagnosis and surgery among men in the
Normative Aging Study. Men with lower
body mass indices and lower cholesterol
levels were more likely to have a clinical
diagnosis but were not more likely to have
surgery. This difference may be due to a
detection bias since a clinical diagnosis may
be more difficult to make in a heavier man.
In two case-control studies of men
undergoing surgery for benign prostatic hy-
perplasia, Bourke and Griffin (10, 11)
found strong positive relationships between
hypertension, diabetes mellitus and benign
prostatic hyperplasia. They concluded that
an age-related increase in estrogens was a
common link in all three diseases. However,
these studies assessed blood pressure and
glucose levels at the time of surgery and
thus did not control for the stress of the
operation. The current study found no dif-
ferences in the distributions of both fasting
and two-hour glucose between men devel-
oping benign prostatic hyperplasia and
those remaining free of the disorder. Addi-
89
tionally, there were no indications that any
of the major risk factors for cardiovascular
disease were predictive of benign prostatic
hyperplasia. Cigarette smokers had lower
rates of surgery than nonsmokers, and
heavier men as well as men with higher
cholesterol levels had lower rates of clinical
diagnosis. The directions of these relation-
ships are opposite to what would be ex-
pected under the hypothesis of an associa-
tion between cardiovascular disease and be-
Downloaded from http://aje.oxfordjournals.org/ at Pennsylvania State University on September 18, 2016
nign prostatic hyperplasia. The large num-
ber of man-years of follow-up gives
strength to these findings of no association.
Greenwald et al. (7) found equal numbers
of diabetics in their case and control series
as well as equal numbers of men using
antihypertensive medications. Morrison
(2) reported that cases were more likely to
be using rauwolfia (relative risk for rau-
wolfia use = 2.2). He found no strong as-
sociation with other antihypertensive med-
ications and concluded that the risk with
rauwolfia use is not secondary to a relation-
ship of benign prostatic hyperplasia to hy-
pertension.
There is currently considerable contro-
versy about the possible relationship of be-
nign prostatic hyperplasia to prostatic can-
cer (7, 8). Data from the Normative Aging
Study are too sparse to address this contro-
versy directly. As of May 15, 1982, 10 of
the volunteers in the Normative Aging
Study had developed prostatic cancer.
None of these men had prior surgery, but
six of the 10 had a prior clinical diagnosis
of benign prostatic hyperplasia. A compar-
ison of risk factors for prostatic cancer and
for benign prostatic hyperplasia shows
some similarities and some differences. Age
is the most important risk factor for both
diseases and for both the incidence in-
creases monotonically with age (28). In
contrast to their higher rates of benign
prostatic hyperplasia, Jewish men in both
Israel and New York are reported to have
lower rates of prostatic cancer (28). We
know of no evidence that cigarette smoking
is protective against prostatic cancer.
90 GLYNN ET AL.
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