|
181. Evaluation of men on finasteride.
Gormley GJ
Merck Research Laboratories, Rahway, NJ 07065, USA.
Semin Urol Oncol; 14(3):139-44 1996
Finasteride, an orally active type II 5 alpha-reductase (5
alpha R) inhibitor, blocks conversion of testosterone (T) to
dihydrotestosterone (DHT). The utility of finasteride in
effectively managing benign prostatic hyperplasia has been
documented. Use of the drug results in reduced prostate volume
and serum levels. Patients receiving finasteride should be
monitored with periodic digital-rectal examination (DRE) and
serum PSA measurement. Patients with a sustained increase in
serum PSA or an abnormal DRE require additional evaluation.
There is no evidence that use of finasteride has an adverse
effect on prostate cancer detection, if the drug's effect on
serum PSA is recognized and accounted for.
182. The effect of finasteride in men with benign
prostatic hyperplasia. The Finasteride Study Group
Gormley GJ; Stoner E; Bruskewitz RC; Imperato-McGinley J;
Walsh PC; McConnell JD; Andriole GL; Geller J; Bracken BR;
Tenover JS; et al
Merck Research Laboratories, Rahway, NJ 07065.
N Engl J Med; 327(17):1185-91 1992
BACKGROUND. Benign prostatic hyperplasia is a progressive,
androgen-dependent disease resulting in enlargement of the
prostate gland and urinary obstruction. Preventing the
conversion of testosterone to its tissue-active form,
dihydrotestosterone, by inhibiting the enzyme 5
alpha-reductase could decrease the action of androgens in
their target tissues; in the prostate the result might be a
decrease in prostatic hyperplasia and therefore in symptoms of
urinary obstruction.
METHODS. In a double-blind study, we evaluated the effect
of two doses of finasteride (1 mg and 5 mg) and placebo, each
given once daily for 12 months, in 895 men with prostatic
hyperplasia. Urinary symptoms, urinary flow, prostatic volume,
and serum concentrations of dihydrotestosterone and
prostate-specific antigen were determined periodically during
the treatment period.
RESULTS. As compared with the men in the placebo group, the
men treated with 5 mg of finasteride per day had a significant
decrease in total urinary-symptom scores (P less than 0.001),
an increase of 1.6 ml per second (22 percent, P less than
0.001) in the maximal urinary-flow rate, and a 19 percent
decrease in prostatic volume (P less than 0.001). The men
treated with 1 mg of finasteride per day did not have a
significant decrease in total urinary-symptom scores, but had
an increase of 1.4 ml per second (23 percent) in the maximal
urinary-flow rate, and an 18 percent decrease in prostatic
volume. The men given placebo had no changes in total
urinary-symptom scores, an increase of 0.2 ml per second (8
percent) in the maximal urinary-flow rate, and a 3 percent
decrease in prostatic volume. The frequency of adverse effects
in the three groups was similar, except for a higher incidence
of decreased libido, impotence, and ejaculatory disorders in
the finasteride-treated groups.
CONCLUSIONS. The treatment of benign prostatic
hyperplasia with 5 mg of finasteride per day results in a
significant decrease in symptoms of obstruction, an increase
in urinary flow, and a decrease in prostatic volume, but at a
slightly increased risk of sexual dysfunction.
182a. Estrogen suppression as a pharmacotherapeutic
strategy in the medical treatment of benign prostatic
hyperplasia: evidence for its efficacy from studies with
mepartricin.
Boehm S, Nirnberger G, Ferrari P
Department of Neuropharmacology, University of Vienna,
Austria.
Stefan.Boehm@univie.ac.at
Wien Klin Wochenschr 1998 Dec 11;110(23):817-23
Estrogen suppression has been introduced as a
pharmacotherapeutic strategy in the medical treatment of
benign prostatic hyperplasia. Recent negative results obtained
in placebo-controlled trials with the aromatase inhibitor
atamestane raised doubts about the efficacy of estrogen
reduction. However, inhibition of aromatase not only reduces
estrogens but also increases androgens which promote prostatic
growth. In order to reevaluate the therapeutic efficacy of
estrogen suppression, we summarize clinical trials
investigating the therapeutic effects of mepartricin in the
treatment of uncomplicated benign prostatic hyperplasia.
Mepartricin has been reported to lower the levels of
circulating estrogens without causing changes in other
hormones such as androgens. By applying stringent inclusion
criteria, 23 studies (including 7 placebo-controlled trials, 3
post-marketing surveillance studies, and 13 open trials)
published between 1982 and 1996 were selected to be included
in this report. In 79.9% of 4635 patients treated with
mepartricin, its therapeutic effect was rated "good" or
"excellent". In 6 out of 7 placebo-controlled trials, the
therapeutic efficacy of mepartricin was significantly superior
to that of placebo. Comparison of these data with results
obtained with alpha 1-adrenoceptor antagonists or with the 5
alpha-reductase inhibitor finasteride indicates that
mepartricin is as efficient as these widely accepted medical
treatments for benign prostatic hyperplasia. Since
mepartricin acts selectively upon estrogens, the present
results show that estrogen suppression may be considered an
efficient pharmacotherapeutic strategy in the medical
treatment of uncomplicated benign prostatic
hyperplasia.
183. Aromatase in hyperplasia and carcinoma of the
human prostate.
Hiramatsu M, Maehara I, Ozaki M, Harada N, Orikasa S, Sasano
H
Department of Pathology, Tohoku University School of
Medicine, Sendai, Japan.
Prostate 1997 May 1;31(2):118-24
The expression and activity of aromatase was evaluated in
19 individuals with benign prostatic hyperplasia (BPH) and 26
prostatic carcinoma (PC) patients to elucidate the possible
biological significance of in situ estrogen production in the
development of human prostatic disorders. Marked aromatase
immunoreactivity was observed in proliferative stromal cells,
especially those around hyperplastic glands in 18 (95%) BPH
patients and in stromal cells surrounding carcinomatous glands
in 18 (69%) PC patient specimens. The percentage of
aromatase-positive stromal cells did not differ between BPH
and PC. No significant correlation was apparent between the
percentage of aromatase-positive cells and either the extent
of carcinoma differentiation or surgical stage in the PC
patients. Quantitation of aromatase activity by the [3H] water
assay yielded values of 27.23 +/- 6.87 and 26.52 +/- 9.12
fmol/hr/mg of protein for BPH (nine patients) and PC (nine
patients), respectively. Reverse transcriptase and polymerase
chain reaction analysis revealed that the mean aromatase mRNA
content was 1.671 +/- 0.82 and 1.11 +/- 0.51 attomole/ng of
total RNA (tRNA) for BPH (seven patients) and PC (four
patients), respectively. There were no significant differences
in aromatase activity or aromatase mRNA concentration between
PC and BPH. The alternative use of multiple exons 1 of the
aromatase gene was also examined. Predominant aromatase gene
transcripts contained exon 1b in three of four of PC specimens
and two of three BPH specimens examined, in contrast to the
use of exon 1d previously described in normal prostate. Unlike
breast and endometrium, therefore, aromatase expression in
human prostate was not associated with malignancy.
However, overexpression of aromatase, possibly
attributable to abnormal gene regulation, may result in
estrogen production in situ and play a role in the induction
or development of human prostatic disorders.
184. Aromatase mRNA levels in benign prostatic
hyperplasia and prostate cancer.
Tsugaya M, Harada N, Tozawa K, Yamada Y, Hayashi Y, Tanaka S,
Maruyama K, Kohri K
Department of Urology, Nagoya City University, Medical
School, Japan.
Int J Urol 1996 Jul;3(4):292-6
BACKGROUND: Estrogens are suspected to play a role in the
pathogenesis of benign prostatic hyperplasia (BPH) and
prostate cancer. In this study, the expression of aromatase
messenger ribonucleic acid (mRNA) was determined, and these
levels were quantitated, in human prostatic tissues to
evaluate the role of estrogens in the pathogenesis of BPH and
prostate cancer.
METHODS: Prostatic tissues were obtained either by
retropubic prostatectomy, radical prostatectomy, or radical
cystectomy from patients with BPH, prostate cancer, and
bladder cancer. The expression of aromatase mRNA in the
prostatic tissues was studied by Southern blot analysis of the
reverse transcription and polymerase chain reaction technique
(RT-PCR) products. Aromatase mRNA levels were measured in
human prostatic tissues by the RT-PCR using a fluorescent
primer.
RESULTS: Aromatase mRNA was identified in all specimens by
Southern blot analysis of the RT-PCR products. The
concentrations of aromatase mRNA (mean +/- SD) which were
measured by fluorometric quantitation in 16 of 19 patients
with BPH and in 3 of 4 patients with prostate cancer, were
1.81 +/- 3.02, and 0.84 +/- 0.27, x 10(-3)
attomoles/micrograms of total RNA, respectively.
CONCLUSIONS: These results demonstrate local
formation of estrogen in the prostates of patients with BPH
and prostate cancer. Controlled studies will be
necessary to determine whether this may be a factor in the
development of BPH and prostate cancer.
185. Effect of exogenous testosterone replacement
on prostate-specific antigen and prostate-specific membrane
antigen levels in hypogonadal men.
Douglas TH, Connelly RR, McLeod DG, Erickson SJ, Barren R
3rd, Murphy GP
Department of Surgery, Walter Reed Army Medical Center,
Washington, D.C. 20307-5001, USA.
J Surg Oncol 1995 Aug;59(4):246-50
Previous studies have suggested that serum
prostate-specific antigen (PSA) levels are under androgenic
influence, especially in patients with adenocarcinoma of the
prostate. PSMA (prostate-specific membrane antigen) is thought
to reflect hormonal or clonal resistance or an independence
with respect to testosterone regulation. The influence of
testosterone on serum PSA expression in normal men is not
clear. We studied the effect of exogenous testosterone
administration on the serum levels of PSA and PSMA in
hypogonadal men. Serial serum PSA, serum PSMA by Western blot,
and serum total testosterone levels were obtained at intervals
of every 2-4 weeks in 10 hypogonadal men undergoing treatment
with exogenous testosterone, delivered as testosterone
enanthate injection or by testosterone patch. Linear and
quadratic orthogonal polynomial scores were calculated for
PSMA, PSA, and testosterone. A 2-tailed, paired t-test failed
to demonstrate a significant correlation between serum PSA
(linear P = 0.432, quadratic P = 0.290) or PSMA (linear P =
0.162, quadratic P = 0.973) and serum testosterone levels.
This study suggests that in hypogonadal men, neither PSMA nor
PSA expression is testosterone-dependent.
186. Longitudinal evaluation of serum androgen
levels in men with and without prostate cancer.
Carter HB, Pearson JD, Metter EJ, Chan DW, Andres R, Fozard
JL, Rosner W, Walsh PC
Department of Urology, Johns Hopkins University School of
Medicine, James Buchanan Brady Urological Institute, Johns
Hopkins Hospital, Baltimore, MD 21287-2101, USA.
Prostate 1995 Jul;27(1):25-31
Androgens are thought to play a role in the pathogenesis of
prostate cancer. We evaluated androgen levels in 3 age-matched
groups of men who were part of the Baltimore Longitudinal
Study of Aging: 1) 16 men with no prostatic disease by
urologic history and exam (control group); 2) 20 men with a
histologic diagnosis of benign prostatic hyperplasia (BPH) who
had undergone simple prostatectomy; and 3) 20 men with a
histologic diagnosis of prostate cancer (16 with
local/regional cancer, and 4 with metastatic cancer).
Luteinizing hormone (LH), total testosterone (T), and free T
were measured on stored AM sera by radioimmunoassay (RIA).
Free T was also calculated from the measured concentrations of
total T and sex hormone binding globulin (SHBG). The median
number of repeated sex steroid measurements ranged from 6-9
over a period from 7-25 years prior to the diagnosis of
prostate disease. There were no significant differences in
age-adjusted LH, total T, SHBG, or calculated free T levels
among the groups at 0-5, 5-10, and 10-15 years before
diagnosis. These data suggest that there are no measurable
differences in serum testosterone levels among men who are
destined to develop prostate cancer and those without the
disease.
187. The role of sex steroids in the pathogenesis
and maintenance of benign prostatic hyperplasia.
Levine AC, Kirschenbaum A, Gabrilove JL
Department of Medicine, Mount Sinai School of Medicine, New
York, NY 10029, USA.
J Androl 1989 May-Jun;10(3):240-7
BACKGROUND: It has long been suspected that sex steroids
play a key role in the pathogenesis of benign prostatic
hyperplasia (BPH). Prostatic diseases do not occur in males
castrated before puberty or in males with heritable disorders
of androgen production or action. Both estrogens and
androgens have been shown to induce BPH in experimental
animals.
METHODS: Clinical studies utilizing hormonal therapies to
treat BPH were reviewed. Studies that used total medical
castration therapy via the use of a long-acting
gonadotropin-releasing hormone (GnRH agonist), partial
androgen blockade via the use of the 5 alpha-reductase
inhibitor finasteride, and estrogen blockade (via the use of
aromatase inhibitors) were analyzed.
RESULTS AND CONCLUSIONS: Both the GnRH agonists and
finasteride result in prostatic size reduction and alleviate
symptoms in some patients. Both therapies are more effective
in men with larger prostates (> 40 cc). Finasteride is less
efficacious in terms of size reduction than the GnRH agonists
but also has fewer side effects. To date, clinical trials with
aromatase inhibitors have not yielded dramatic positive
results in the treatment of BPH.
188. Endogenous sex hormones and prostate cancer: a
quantitative review of prospective studies.
Eaton NE, Reeves GK, Appleby PN, Key TJ
Imperial Cancer Research Fund, Cancer Epidemiology Unit,
Radcliffe Infirmary, Oxford, UK.
Br J Cancer 1999 Jun;80(7):930-4
This paper presents a quantitative review of the data from
eight prospective epidemiological studies, comparing mean
serum concentrations of sex hormones in men who subsequently
developed prostate cancer with those in men who remained
cancer free. The hormones reviewed have been postulated to be
involved in the aetiology of prostate cancer: androgens and
their metabolites testosterone (T), non-SHBG-bound
testosterone (non-SHBG-bound T), di-hydrotestosterone (DHT),
androstanediol glucuronide (A-diol-g), androstenedione
(A-dione), dehydroepiandrosterone sulphate (DHEAS), sex
hormone binding globulin (SHBG), the oestrogens, oestrone and
oestradiol, luteinizing hormone (LH) and prolactin. The ratio
of the mean hormone concentration in prostate cancer cases to
that of controls (and its 95% confidence interval (CI)) was
calculated for each study, and the results summarized by
calculating the weighted average of the log ratios. No
differences in the average concentrations of the hormones were
found between prostate cancer cases and controls, with the
possible exception of A-diol-g which exhibited a 5% higher
mean serum concentration among cases relative to controls
(ratio 1.05, 95% CI 1.00-1.11), based on 644 cases and 1048
controls. These data suggest that there are no large
differences in circulating hormones between men who
subsequently go on to develop prostate cancer and those who
remain free of the disease. Further research is needed to
substantiate the small difference found in A-diol-g
concentrations between prostate cancer cases and controls.
189. Relationships of serum androgens and estrogens
to prostate cancer risk: results from a prospective study in
Finland.
Dorgan JF, Albanes D, Virtamo J, Heinonen OP, Chandler DW,
Galmarini M, McShane LM, Barrett MJ, Tangrea J, Taylor
PR
Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Bethesda, Maryland 20892-7374, USA.
jd7g@nih.gov
Cancer Epidemiol Biomarkers Prev 1998
Dec;7(12):1069-74
Several lines of evidence suggest that sex hormones may be
involved in the etiology of prostate cancer. We conducted a
prospective nested case-control study to evaluate the
relationships of serum androgens and estrogens to prostate
cancer using serum collected at baseline for the
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The
29,133 male smokers who participated in the trial were 50-69
years old at baseline. During 5-8 years of follow-up, 246 men
were diagnosed with prostate cancer, and 116 of these were
randomly selected for inclusion in the current study. For each
case, two controls matched on age, date of blood collection,
intervention group, and study center were selected. Hormones
were measured in serum by RIA using standard procedures. None
of the individual androgens or estrogens was significantly
related to prostate cancer. These findings were unaltered by
simultaneous evaluation of serum androgen and estrogen
concentrations in multivariate models. These results do not
support a strong relationship of serum androgens and estrogens
with prostate cancer in smokers. Within-person variation in
concentrations of some hormones may have contributed to the
lack of significant associations.
190. 5 alpha-reductase activity and prostate
cancer: a case-control study using stored sera.
Guess HA, Friedman GD, Sadler MC, Stanczyk FZ, Vogelman JH,
Imperato-McGinley J, Lobo RA, Orentreich N
Department of Epidemiology, School of Public Health,
University of North Carolina, Chapel Hill 27599-7400,
USA.
Cancer Epidemiol Biomarkers Prev 1997
Jan;6(1):21-4
We report a nested case-control study of serum biomarkers
of 5 alpha-reductase activity and the incidence of prostate
cancer. From a cohort of more than 125,000 members of the
Kaiser Permanente Medical Care Program who underwent
multiphasic health examinations during 1964-1971, we selected
106 incident prostate cancer cases. A control was pair matched
to each case on age, date of serum sampling, and clinic
location. Serum levels of total testosterone, free
testosterone, androsterone glucuronide, and 5
alpha-androstane-3 alpha,17 beta androstanediol glucuronide (3
alpha-diol G) were measured on the stored samples and scored
as quartiles. Potential confounders included alcohol, smoking,
and body mass index. The adjusted odds ratios and 95%
confidence intervals for a one quartile score increase were
1.00 (0.75-1.34) for total testosterone, 1.14 (0.86-1.50) for
free testosterone, 1.13 (0.84-1.53) for androsterone
glucuronide, and 1.16 (0.86-1.56) for 3 alpha-diol G. A
limitation of this study is that there are two different 5
alpha-reductase isoenzymes, only one of which is expressed in
high levels within the prostate, yet both of which may affect
serum biomarkers. Since the two isoenzymes are encoded on
different chromosomes, variation in one would act as an
independent source of measurement error in any analysis of
serum biomarker effects of the other. Consequently, the odds
ratios may be underestimated and the study, although negative,
cannot exclude the previously hypothesized possibility that a
positive relationship between intraprostatic 5 alpha-reductase
activity and prostate cancer may exist. A clinical trial to
test this hypothesis is under way.
191. Prediagnostic serum hormones and the risk of
prostate cancer.
Nomura A, Heilbrun LK, Stemmermann GN, Judd HL
Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu
96817.
Cancer Res 1988 Jun 15;48(12):3515-7
Serum samples were obtained from 6860 men during their
study examination from 1971 to 1975. After a surveillance
period of about 14 years, 98 incident cases of prostate cancer
were identified. Their stored sera and that of 98 matched
controls from the study population were tested for the
following: testosterone, dihydrotestosterone, estrone,
estradiol, and sex hormone globulin. There was a suggestion
that serum dihydrotestosterone levels were lower and the
testosterone/dihydrotestosterone ratios were higher in the
prostate cancer cases compared with their controls. However,
none of these associations or that of the other hormones was
strongly significant. Further work is needed to clarify the
relationship between sex hormones and prostate cancer
risk.
192. Physical characteristics and factors related
to sexual development and behaviour and the risk for prostatic
cancer.
Hayes RB, de Jong FH, Raatgever J, Bogdanovicz J, Schroeder
FH, van der Maas P, Oishi K, Yoshida O
Department of Urology, Erasmus University Rotterdam, The
Netherlands.
Eur J Cancer Prev 1992 Apr;1(3):239-45
A case-control study of prostatic cancer was carried out to
examine the association between selected physical
characteristics and factors related to sexual development and
behaviour and the risk for this disease. In consideration of
an endocrinologic mechanism for these putative risk factors,
the association between selected factors and serum hormone
level in a comparison group, free of prostate cancer, was also
examined. One-hundred cases and 113 controls were included for
study. An elevated risk for prostatic cancer was found for
those currently married (odds ratio (OR) = 4.0), those who had
been married once (OR = 2.8), and those who were currently
practising a religion (OR = 2.0). Compared to subjects with
one child, those with more than one child and those with no
children were more common among cases than controls. Prostatic
cancer risk was associated with large body size and, in
particular, with greater weight (p < 0.01). Early age at
attainment of adult height was also associated with prostatic
cancer risk (p < 0.01). Only moderate associations were
found between increased frequency of sexual intercourse and
prostatic cancer risk. The levels of testosterone (T),
dihydrotestosterone, salivary testosterone and T/SHBG (sex
hormone binding globulin) did not vary with age. Older men had
higher oestradiol levels. Further, little association between
hormone levels and risk factors was found, except for married
subjects having increased serum androgens (p < 0.05) and
heavy subjects having decreased serum androgens (not
significant).
193. Serum steroids in relation to prostate cancer
risk in a case-control study (Greece).
Signorello LB, Tzonou A, Mantzoros CS, Lipworth L, Lagiou P,
Hsieh C, Stampfer M, Trichopoulos D
Department of Epidemiology and Harvard Center for Cancer
Prevention, Harvard School of Public Health, Boston,
Massachusetts 02115, USA.
Cancer Causes Control 1997 Jul;8(4):632-6
Blood samples were collected from 52 incident cases of
histologically confirmed prostate cancer and 52 age- and town
of residence-matched healthy controls in Athens, Greece.
Samples were analyzed blindly in Boston, Massachusetts (USA)
for testosterone (T), estradiol (E2), sex hormone-binding
globulin (SHBG), and dihydrotestosterone (DHT). The data were
modeled using multiple logistic regression with adjustment for
age, height, body mass index (wt/ht2), years of schooling, and
mutually among hormones. DHT was associated inversely,
significantly, and strongly with the risk of prostate cancer,
whereas T was associated marginally positively, and E2 was
associated nonsignificantly inversely with the disease. No
association was observed in this study with respect to
SHBG.
194. Serological precursors of cancer: serum
hormones and risk of subsequent prostate cancer.
Hsing AW, Comstock GW
National Cancer Institute, Division of Cancer Etiology,
Bethesda, Maryland 20892.
Cancer Epidemiol Biomarkers Prev 1993
Jan-Feb;2(1):27-32
A population-based nested case-control study was conducted
to determine the relation of prediagnostic serum levels of
testosterone, dihydrotestosterone, prolactin,
follicle-stimulating hormone, luteinizing hormone, estrone,
and estradiol to the risk of subsequent prostate cancer. Serum
specimens of study subjects were available from a blood
collection campaign in Washington County, Maryland, in 1974.
Serum hormone levels of 98 histologically confirmed prostate
cancer cases diagnosed in the subsequent 13 years were
compared to those of 98 controls who were individually matched
to cases on the basis of age (within weeks), sex, and race.
There were no significant differences in levels of these
hormones between cases and controls, although elevated levels
of luteinizing hormone and of testosterone:dihydrotestosterone
ratios were associated with mild increased risks of prostate
cancer.
195. Peripheral hormone levels in controls and
patients with prostatic cancer or benign prostatic
hyperplasia: results from the Dutch-Japanese case-control
study.
de Jong FH, Oishi K, Hayes RB, Bogdanowicz JF, Raatgever JW,
van der Maas PJ, Yoshida O, Schroeder FH
Department of Endocrinology and Reproduction, Erasmus
University Rotterdam, The Netherlands.
Cancer Res 1991 Jul 1;51(13):3445-50
The possible relationship between changes in peripheral
hormone levels and the occurrence of prostatic pathology was
studied in a case-control study, involving estimation of
various plasma hormones in 368 Dutch and 258 Japanese men, who
were grouped as controls and patients with benign prostatic
hyperplasia, focal prostatic carcinoma, or clinically evident
prostatic carcinoma. Results of a number of previous, smaller
studies concerning interrelationships between hormone levels
in elderly men were confirmed within the Dutch and Japanese
groups. Plasma levels of testosterone and estradiol were
significantly lower in the Japanese men, when compared with
those in Dutch men. Probably as a result of this difference in
testosterone levels, the ratio between serum levels of
testosterone and sex hormone-binding globulin (SHBG) was
decreased in the Japanese men, while the ratio between the
concentrations of dihydrotestosterone and testosterone was
increased. These differences were also found when results from
Japanese subgroups (controls and patients with prostate
pathology) were compared with those from the Dutch subgroups.
There were no significant differences in plasma androgen
levels between Japanese or Dutch prostate cancer cases and
their respective control subgroups. These findings do not
support a correlation between the lower plasma testosterone
levels and a lower incidence of prostate cancer in the
Japanese men. Furthermore, no significant differences were
found between salivary levels of testosterone or the ratio
between testosterone and SHBG in the various Dutch subgroups.
In Japanese benign prostatic hyperplasia patients, the
testosterone to SHBG ratio was significantly increased. In
conclusion, the results of this retrospective, cross-sectional
study do not indicate that hormonal levels play a primary role
in the origin or promotion of prostatic abnormalities. The
finding of a lower plasma testosterone in the Japanese men,
however, remains suggestive, warranting a more extensive
prospective study.
196. Testicular and adrenocortical function in men
with prostatic cancer and in healthy age-matched
controls.
Carlstrom K, Stege R
Department of Obstetrics and Gynaecology, Karolinska
Institutet, Huddinge University Hospital, Sweden.
Br J Urol 1997 Mar;79(3):427-31
OBJECTIVE: To compare the endocrine status of patients with
prostate cancer with that of age-matched healthy controls.
PATIENTS, SUBJECTS AND METHODS: Basal serum concentrations
of sex steroids, sex hormone-binding globulin (SHBG) and
gonadotrophins, and the basal levels and response to
adreno-corticotropic hormone (ACTH) of adrenocortical
steroids, were measured before treatment in 72 patients with
prostate cancer and in 42 age-matched healthy controls.
RESULTS: Patients aged < 60 years with prostate cancer
had significantly elevated levels of total testosterone and
unconjugated (E1) and total (tE1) oestrone while patients aged
> or = 60 years had significantly elevated levels of total
and non-SHBG-bound testosterone (NST). 17
alpha-hydroxyprogesterone and tE1. Gonadotrophins, SHBG levels
and relationships between total testosterone and SHBG were
normal in both age groups of patients, as were basal levels
and ACTH-induced increments of adrenocortical steroids. The
patients had normal age-related variations in SHBG and NST and
in basal levels and ACTH-induced increments of adrenocortical
steroids. There was a significant age-related increase in
serum E1 in the control subjects but not in the patients.
Patients with metastatic disease had significantly lower tE1
levels than had patients without metastases.
CONCLUSIONS: The results suggest an increased sensitivity
of the testis to gonadotrophic stimulation, as well as an
increased peripheral oestrogen synthesis in patients with
prostate cancer, the latter being most pronounced in younger
subjects. Men developing prostate cancer may have been exposed
to a combination of elevated endogenous oestrogen and androgen
levels for a long time. These findings support the theory of a
synergism between oestrogens and androgens as an important
factor in the aetiology of prostate cancer.
197. Dihydrotestosterone and testosterone levels in
men screened for prostate cancer: a study of a randomized
population.
Gustafsson O, Norming U, Gustafsson S, Eneroth P, Astrom G,
Nyman CR
Department of Urology, Karolinska Institute at Stockholm
Soder Hospital, Sweden.
Br J Urol 1996 Mar;77(3):433-40
OBJECTIVE: To investigate the possible relationship between
serum levels of prostate specific antigen (PSA),
dihydrotestosterone (DHT), testosterone, sexual-hormone
binding globulin (SHBG) and tumour stage, grade and ploidy in
65 cases of prostate cancer diagnosed in a screening study
compared to 130 controls from the same population.
PATIENTS, SUBJECTS AND METHODS: From a population of 26,602
men between the ages of 55 and 70 years, 2400 were selected
randomly and invited to undergo screening for prostate cancer
using a digital rectal examination, transrectal
ultrasonography and PSA analysis. Among the 1782 attendees, 65
cases of prostate cancer were diagnosed. Each case was matched
with two control subjects of similar age and prostate volume
from the screening population. Frozen serum samples were
analysed for PSA, DHT, testosterone and SHBG, and compared to
the diagnosis and tumour stage, grade and ploidy. Comparisons
between these variables, and multivariate and regression
analyses were performed.
RESULTS: There were significant differences in PSA level
with all variables except tumour ploidy. DHT levels were
slightly lower in patients with prostate cancer but the
difference was not statistically significant. There was a
trend towards lower DHT values in more advanced tumours and
the difference for T-stages was close to statistical
significance (P = 0.059). Testosterone levels were lower in
patients with cancer than in the control group, but the
differences were not significant. There was no correlation
between testosterone levels, tumour stage and ploidy, but the
differences in testosterone level in tumours of a low grade of
differentiation compared to those with intermediate and high
grade was nearly significant (P = 0.058). The testosterone/DHT
ratio tended to be higher in patients with more advanced
tumours. SHBG levels were lower in patients with cancer than
in controls but the differences were not statistically
significant. There were no systematic variations of tumour
stage, grade and ploidy. Multivariate analysis showed that if
the PSA level was known, then DHT, testosterone or SHBG added
no further information concerning diagnosis, stage, grade or
ploidy. Regression analysis on T-stage, PSA level and DHT
showed an inverse linear relationship between PSA and DHT for
stage T-3 (P = 0.035), but there was no relationship between
PSA and testosterone.
CONCLUSION: PSA was of value in discriminating between
cases and controls and between various tumour stages and
grades, but no statistically significant correlation was found
for ploidy. If PSA level was known, no other variable added
information in individual cases. Within a group, DHT levels
tended to be lower among cases and in those with more advanced
tumours. There was an inverse relationship between tumour
volume, as defined by PSA level, and 5 alpha-reductase
activity, as defined by DHT level, and the testosterone/DHT
ratio. This trend was most obvious with T-stage. No systematic
variation were found in the levels of testosterone or
SHBG.
198. Familial factors affecting prostatic cancer
risk and plasma sex-steroid levels.
Meikle AW, Smith JA, West DW
Prostate 1985;6(2):121-8
Whether familial factors affect the frequency of prostatic
cancer and the plasma content of sex-steroids was
investigated. Brothers (n = 257) of probands (n = 150)
diagnosed with prostatic cancer before age 62 years had a
fourfold higher risk for developing the disease than men in
the general population in the State of Utah and their
brothers-in-law (n = 202). Familial factors markedly affected
the plasma content of sex steroids (testosterone,
dihydrotestosterone, the ratio of testosterone to DHT,
sex-hormone binding globulin, and the free fraction of
testosterone) in nonendocrinologically treated probands and
their brothers and sons and in normal men in the general
populations. Index cases and their brothers and sons had a
significantly lower mean plasma testosterone content than
controls of comparable age. Preliminary data suggest that the
metabolic clearance rate of testosterone and the conversion
ratio of testosterone to estradiol are relatively high in
probands. The observations indicate that familial factors are
potent risk factors for the development of prostatic cancer.
They also suggest that plasma androgen values in families with
prostatic cancer cluster in the lower range of normal and that
plasma sex-steroid content is more similar in each brothers
with or without prostatic cancer than among nonbrothers.
199. A prospective, population-based study of
androstenedione, estrogens, and prostatic cancer.
Barrett-Connor E, Garland C, McPhillips JB, Khaw KT, Wingard
DL
Department of Community and Family Medicine, University of
California San Diego, La Jolla 92093.
Cancer Res 1990 Jan 1;50(1):169-73
Endogenous androgens have been suggested as determinants of
risk of prostatic cancer. To examine this possibility,
baseline sex hormone levels were measured in 1008 men ages
40-79 years who had been followed for 14 years. There were 31
incident cases of prostatic cancer and 26 identified from
death certificates with unknown dates of diagnosis. In this
study, total testosterone, estrone, estradiol, and sex
hormone-binding globulin were not related to prostate cancer,
but plasma androstenedione showed a positive dose-response
gradient. Age-adjusted relative risks of prostatic cancer for
low (0-2.2 nM), middle (2.3-3.1 nM), and high (3.2+ nM)
tertiles of androstenedione were 1.00, 1.34, and 1.98,
respectively (P trend less than 0.05). The linear gradient of
risk persisted after adjustment for age and body mass index.
If confirmed, these data suggest that androstenedione might
increase the occurrence of clinically manifest prostatic
cancer.
200. Serum pituitary and sex steroid hormone levels
in the etiology of prostatic cancer--a population-based
case-control study.
Andersson SO, Adami HO, Bergstrom R, Wide L
Department of Urology, Orebro Medical Center Hospital,
Sweden.
Br J Cancer 1993 Jul;68(1):97-102
The hypothesis that serum concentrations of pituitary
hormones, sex steroid hormones, or sex hormone-binding
globulin (SHBG) affect the occurrence of prostatic cancer was
tested in a consecutive sample of 93 patients with newly
diagnosed, untreated cancer and in 98 population controls of
similar ages without the disease. Cases did not differ
significantly from controls regarding serum levels of
luteinising hormone (LH) or follicle stimulating hormone
(FSH). Remarkably close agreement was found for mean values of
total testosterone (15.8 nmol l-1 in cases and 16.0 in
controls), and free testosterone (0.295 and 0.293 nmol l-1,
respectively), with corresponding odds ratios for the highest
vs lowest tertile of 1.0 (95% confidence interval 0.5-1.9) for
testosterone and 1.2 (95% confidence interval 0.6-2.4) for
free testosterone. Similar close agreement between cases and
controls was found for serum concentrations of estradiol,
androstenedione and SHBG, although the mean estradiol level
was non-significantly (P = 0.30) lower among cases. Changes
secondary to the disease were unlikely to have affected the
results materially, since only LH and FSH were associated with
stage of disease and this relationship was weak. Our findings
suggest that further analyses of serum hormone levels at the
time of diagnosis are unlikely to improve our understanding of
the etiology of prostatic cancer.
201. Pretreatment plasma levels of testosterone and
sex hormone binding globulin binding capacity in relation to
clinical staging and survival in prostatic cancer
patients.
Haapiainen R, Rannikko S, Alfthan O, Adlercreutz H
Second Department of Surgery, Helsinki University Central
Hospital, Finland.
Prostate 1988;12(4):325-32
Pretreatment plasma concentrations of total testosterone
(T), sex hormone binding globulin binding capacity (SHBG).
T/SHBG ratio, and free testosterone (fT) were measured in 123
patients with prostatic cancer categorized into groups
according to the UICC classification. The patients were
randomized to orchiectomy or estrogen therapy and the mean
follow-up time was 48 months. The mean plasma levels of T were
higher in patients without metastases and with intracapsular
cancer, but the differences were not statistically
significant. The calculated ratio of T/SHBG was noticed to be
significantly higher (p less than 0.05) in the M0 category.
The prognostic significance of pretreatment T and, more
impressively, T/SHBG ratio and fT was confirmed. Low
pretreatment values indicated poorer prognosis. This study
supports the view that there are differences in the
pretreatment T and fT levels in prostatic cancer patients in
relation to the stage of tumor and that these hormone assays
could be used as prognostic factors.
202. Serum hormone levels among patients with
prostatic carcinoma or benign prostatic hyperplasia and clinic
controls.
Hulka BS, Hammond JE, DiFerdinando G, Mickey DD, Fried FA,
Checkoway H, Stumpf WE, Beckman WC Jr, Clark TD
Department of Epidemiology, School of Public Health,
University of North Carolina at Chapel Hill 27514.
Prostate 1987;11(2):171-82
This study sought to identify differences in serum hormone
levels between prostatic cancer (CaP) patients, benign
prostatic hyperplasia (BPH) patients, and clinic controls
(CC). Serum testosterone, estradiol, and prolactin values were
obtained from 35 CaP, 42 BPH, and 161 CC patients attending a
single medical center between January 1984 and April 1985.
Relative risk estimates adjusted for age and race were
calculated to compare hormone values between each case group
and the CC. The distributions of hormone values and the
testosterone to estradiol (T/E) ratios were grouped into
thirds with the lowest third forming the reference category.
The relative risk estimates for BPH in the middle and high
thirds of testosterone were greater than unity (1.26 and 2.10,
respectively), whereas the relative risk estimates in the
middle and high thirds of estradiol were less than unity (0.63
and 0.35, respectively). For the middle and high thirds of the
T/E ratio, the relative risk estimates for BPH showed
statistically significant three- to fourfold increases. Modest
depression of serum testosterone and estradiol was noted for
CaP patients compared to CC, although the differences were not
statistically significant. This depression was interpreted to
be a likely result of the malignant process rather than a
cause of it, whereas the development of clinically evident BPH
was felt to be a biologically plausible response to an
elevated T/E ratio.
203. Plasma estradiol, free testosterone, sex
hormone binding globulin binding capacity, and prolactin in
benign prostatic hyperplasia and prostatic cancer.
Rannikko S, Adlercreutz H
Prostate 1983;4(3):223-9
The nature of hormonal changes with age and the possible
role of these changes in the development of benign prostatic
hyperplasia (BPH) and prostatic cancer (PC) were studied by
assaying the plasma levels of total and free testosterone (T),
estradiol (E2), prolactin, and sex hormone binding globulin
binding capacity (SHBG) in 20 normal healthy men aged 40-59
years, in 30 patients with BPH aged 63-79 years, and in 30
patients with PC of similar height, weight, and age as the BPH
patients. The mean E2 was highly significantly (P less than
0.0005) lower in the PC patients and in the young controls
than in the BPH patients. The mean free T was significantly
higher in the young controls than in the BPH patients (P less
than 0.025) and PC patients (P less than 0.0005). The PC
patients had a slightly lower (P less than 0.05) mean free T
and mean E2/free T ratio than the BPH patients. The mean
E2/free T ratio was significantly higher in the BPH patients
(P less than 0.0005) and in the PC patients (P less than
0.0025) than in the young controls. It seems possible that the
observed age-dependent significant increase in plasma estrogen
concentration in the BPH patients may act as a protective
factor against prostatic cancer.
204. Familial prostatic cancer risk and low
testosterone.
Meikle AW, Stanish WM
J Clin Endocrinol Metab 1982 Jun;54(6):1104-8
We investigated whether familial factors influence 1) the
incidence of prostatic cancer and 2) the plasma content of sex
steroids. A 4-fold higher relative risk for the development of
prostatic cancer was observed for brothers (n = 257) of
prostatic cancer cases (n = 150) compared to their
brothers-in-law (n = 202) and males in the general population
of the state Utah. The intraclass correlation for plasma
testosterone content [intraclass correlation coefficient (r1)
= 0.51; P less than 0.01] and the apparent free testosterone
concentration (r1 = 0.54; P less than 0.01) were highly
significant in nonendocrinologically treated cases and their
brothers. Further, sons and their fathers had significant
intraclass correlations for both plasma dihydrotesterone (r1 =
0.83; P less than 0.01) and the ratio of testosterone to
dihydrotestosterone (r1 = 0.46; P less than 0.05). Probands
and their brothers, and sons of the patients with the disease
had significantly lower plasma testosterone levels than
controls of comparable age. This is the first documentation
indicating that familial (possibly genetic) factors are potent
risk factors for predisposing men to the development of
prostatic cancer and in regulating the plasma content of
androgens. Our results indicate that plasma androgen levels in
families with prostatic cancer are clustered in the lower
range of the normal population. They also suggest that plasma
androgen content is more similar within each family with the
cancer than among the families without cancer.
205. Carcinoma of the prostate: relationship of
pretreatment hormone levels to survival.
Harper ME, Pierrepoint CG, Griffiths K
Eur J Cancer Clin Oncol 1984 Apr;20(4):477-82
Pretreatment hormone levels were determined in 222 patients
with prostatic cancer and their prognostic value assessed. The
patients were grouped into yearly survival categories and only
those whose cause of death was due to the disease were
included in the study. Low concentrations of testosterone in
plasma at the time of diagnosis related to a poor prognosis.
Patients who died within 1 yr of diagnosis had the lowest mean
plasma levels of this steroid. The pretreatment mean plasma
testosterone concentrations were found to be higher as the
survival period of the various groups lengthened. This
relationship was observed both when the total data were
analysed and also when the patients were subgrouped depending
on clinical evidence of spread of the tumour beyond the
prostatic capsule (T3) or on the presence of metastases (M1).
High pretreatment plasma concentrations of luteinizing hormone
were also associated with poor survival. Follicle-stimulating
hormone, prolactin and growth hormone concentrations did not
correlate with survival time. The indications from this study
are that poor testicular function is associated with early
death from prostatic carcinoma and that the measurement of
blood levels of testosterone at diagnosis could provide a
prognosis of subsequent life-span.
206. Occult prostate cancer in men with low serum
testosterone levels.
Morgentaler A, Bruning CO 3rd, DeWolf WC
Division of Urology, Beth Israel Hospital, Harvard Medical
School, Boston, Mass. 02215, USA.
JAMA 1996 Dec 18;276(23):1904-6
OBJECTIVE: To determine the prevalence of occult prostate
cancer in men with low serum total testosterone or free
testosterone levels.
DESIGN: Retrospective analysis of a consecutive series of
men.
SETTING: Academic teaching hospital.
PATIENTS: Seventy-seven men with low total testosterone or
free testosterone levels, with normal results of digital
rectal examination and prostate-specific antigen (PSA) levels
of 4.0 ng/mL or less. The mean age was 58 years.
INTERVENTIONS: Sextant prostate needle biopsies with
ultrasound guidance.
MAIN OUTCOME MEASURES: Results of prostate needle biopsies,
transrectal ultrasound, prostate volume, PSA level, PSA
density, total and free testosterone levels.
RESULTS: Prostate cancer was identified in 14% (11/77) of
the entire group and in 10 men (29%) aged 60 years or older.
The median age for men with cancer was 64 years. Histologic
examination showed Gleason scores of 6 or 7 for all cancers.
No significant differences were noted between the cancer and
benign groups with regard to PSA level, PSA density, prostate
volume, total testosterone level, or free testosterone
level.
CONCLUSIONS: A high prevalence of biopsy-detectable
prostate cancer was identified in men with low total or free
testosterone levels despite normal PSA levels and results of
digital rectal examination. These data suggest that (1)
digital rectal examination and PSA levels are insensitive
indicators of prostate cancer in men with low total or free
testosterone levels, and (2) PSA levels may be altered by
naturally occurring reductions in serum androgen levels
207. Pretreatment hormone levels in prostatic
cancer.
Haapiainen R, Rannikko S, Alfthan O, Adlercreutz H
Second Department of Surgery, Helsinki University Central
Hospital, Finland.
Scand J Urol Nephrol Suppl 1988;110:137-43
Pretreatment plasma concentrations of total testosterone,
prolactin, and total estradiol-17 beta (E2) were measured in
123 prostatic cancer patients who were categorized into groups
according to the UICC classification. Patients with
intracapsular tumour without metastases had significantly
higher (p less than 0.05) pretreatment total estradiol levels
than those with more advanced disease. The patients were
treated either by orchiectomy or estrogens. The mean follow-up
time was 48 months. Higher pretreatment estradiol and
testosterone levels were associated with better survival.
Prolactin assays seemed to be of no value in this respect.
208. Results of a study to correlate serum prostate
specific antigen and reproductive hormone levels in patients
with localized prostate cancer.
Vijayakumar S, Quadri SF, Dong L, Ignacio L, Kathuria IN,
Sutton H, Halpern H
Department of Radiation Oncology, Michael Reese Hospital,
Center for Radiation Therapy, University of Chicago, Illinois,
USA.
J Natl Med Assoc 1995 Nov;87(11):813-9
This cross-sectional study was undertaken to determine
whether serum hormones (free testosterone, androstenedione,
luteinizing hormone, or prolactin) have any influence on serum
prostate specific antigen (PSA) levels in patients with stage
A-C prostate cancer. Blood samples were collected prior to any
treatment in 36 patients; in 19 (group 1), three blood samples
were collected 10 minutes apart between 9:00 AM and 9:30 AM
for each patient and pooled together to avoid diurnal and
episodic variation in serum testosterone values. In the
remaining patients, only one sample could be collected (group
2). Free testosterone, androstenedione, luteinizing hormone,
prolactin, and PSA levels were determined with appropriate
radioimmunoassay techniques. Statistical analyses were
performed separately for groups 1 and 2, and then with pooled
data. None of the hormones in any of the analyses showed any
association to serum PSA values except for prolactin for the
pooled data and for group 2. This statistical significance for
prolactin disappeared on multivariate analysis. There were 21
African-American men and 15 whites in the study; no racial
differences in hormonal levels were found except for lower
luteinizing hormone levels in African Americans in group 2 and
pooled data. No differences were found between group 1 and
group 2 in the mean serum prolactin and luteinizing hormone
values. Serum free testosterone, androstenedione, and
luteinizing hormone appeared to have no influence on serum PSA
values in nonmetastatic cancer patients. Serum prolactin
values were inversely associated with PSA values in univariate
analysis for the pooled data; this disappeared in multivariate
analysis. Unlike other studies that found higher serum
testosterone levels in African-American college students than
whites, no such differences were seen in this age group
209. Production, clearance, and metabolism of
testosterone in men with prostatic cancer.
Meikle AW, Smith JA, Stringham JD
Prostate 1987;10(1):25-31
It was previously unknown whether the production and
metabolism of testosterone was altered in men with prostatic
cancer. We recently observed a familial influence on the
plasma concentration of sex steroids in men with the cancer.
We have now determined, by isotope dilution techniques, the
blood testosterone production and clearance rates and
testosterone metabolism to potent androgen metabolites in men
with prostatic cancer, their brothers, and unrelated controls.
Nineteen men had a diagnosis of prostatic cancer before age 63
(probands), 23 were brothers of these index cases, and nine
controls matched for age were selected randomly from the
general population. None had received endocrine therapy. The
plasma content of testosterone, dihydrotestosterone, sex
hormone binding globulin, apparent free testosterone
concentration, follicle-stimulating hormone, and luteinizing
hormone were not significantly different between the groups.
The metabolic clearance rate of testosterone was significantly
(P = .04) higher in probands (458 liters/day/body surface
area, median) than in controls (306 liters/day/body surface
area). The conversion ratios of both testosterone (1.8%) and
dihydrotestosterone (16.9%) to 3 alpha-androstanediol were
significantly greater (P = .04 and P = .004, respectively) in
probands than in controls (0.95%, 7.8%). These results
indicate that men with prostatic cancer have elevated
clearance rates of testosterone and an increased conversion
ratio of testosterone to its potent 5 alpha-reduced
metabolites.
210. Endocrine profiles during administration of
the new non-steroidal anti-androgen Casodex in prostate
cancer.
Verhelst J, Denis L, Van Vliet P, Van Poppel H, Braeckman J,
Van Cangh P, Mattelaer J, D'Hulster D, Mahler C
Department of Endocrinology, A. Z. Middleheim, Antwerp,
Belgium.
Clin Endocrinol (Oxf) 1994 Oct;41(4):525-30
OBJECTIVE: Casodex (Zeneca) is a new potent, long-acting
non-steroidal anti-androgen, which produces androgen
deprivation by blocking the androgen receptor. We evaluated
the endocrine effects of Casodex 150 mg daily given in
monotherapy as primary treatment for patients with prostate
cancer.
DESIGN: As part of a large, multicentre study comparing the
therapeutic effects of surgical castration with 150 mg/day
Casodex in monotherapy for patients with prostate cancer, a
subgroup of 23 patients on Casodex were studied in detail for
changes in endocrine parameters. Serum levels of LH, FSH,
testosterone, DHT, oestradiol, prolactin, sex hormone binding
globulin and free testosterone were measured at the start of
therapy and after 1, 4, 8, 12 and 24 weeks. Effects on libido,
sexual activity and the appearance of hot flushes, breast pain
and gynaecomastia were recorded.
RESULTS: Administration of Casodex resulted in a rise in LH
levels in all patients with a mean increase after 24 weeks of
102% (P < 0.001). Mean FSH levels showed a limited increase
(7%) after 24 weeks, which was significant only after 1 week
(P < 0.001). As a result of the high LH levels, total
testosterone levels increased after 24 weeks by 66% (P <
0.001), free testosterone by 57% (P < 0.001) and
dihydrotestosterone by 24% (P = 0.0112). Parallel to
testosterone, oestradiol levels rose by a mean of 66% (P <
0.001). Mean sex hormone binding globulin and prolactin levels
rose by respectively 8% (P = NS) and 65% (P < 0.01).
Despite an increase in testosterone levels, excellent androgen
blockade was obtained, as shown by a decrease in prostate
specific antigen levels in 22/23 patients. Libido was
maintained in 8/11 patients, and sexual activity in 5/6. No
patient complained of hot flushes. However, mild gynaecomastia
and/or breast tenderness were seen in 48 and 30% of cases
respectively.
CONCLUSION: Casodex 150 mg/day monotherapy resembles
surgical castration in achieving androgen deprivation, despite
an increase in LH and testosterone levels. In contrast to
castration, libido and sexual activity are usually maintained
and hot flushes are rare. However, mild gynaecomastia and/or
breast tenderness were noted in 48 and 30% of patients.
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