|
211. Responses of serum levels of testicular
steroid hormones to hCG stimulation in patients with prostatic
cancer and benign prostatic hypertrophy.
Isurugi K, Kanazawa M, Yanaihara T, Kambegawa A
Prostate Suppl 1981;1:19-26
Serum levels of testosterone (T), dihydrotestosterone
(DHT), androsterone (A), 5 alpha-androstane-3 alpha, 17
beta-diol (5 alpha-diol) and estradiol-17 beta (E2) were
measured by radioimmunoassay in the sera of 9 patients with
untreated prostatic cancer and in 11 with benign prostatic
hypertrophy (BPH). Basal levels and responses to hCG
stimulation were investigated. Although no specific changes in
steroid hormone levels in either disease group were found,
response patterns of serum T, DHT, and E2 were shown to be
those characteristic of male senescence, suggesting a relative
predominance of estrogens over androgens. Neither 5 alpha-diol
nor A exhibited appreciable responses to hCG stimulation in
our study.
212. Androgens in serum and the risk of prostate
cancer: a nested case-control study from the Janus serum bank
in Norway.
Vatten LJ, Ursin G, Ross RK, Stanczyk FZ, Lobo RA, Harvei S,
Jellum E
Department of Community Medicine and General Practice,
University Medical Center, Trondheim, Norway.
lars.vatten@medisin.ntnu.no
Cancer Epidemiol Biomarkers Prev 1997
Nov;6(11):967-9
We tested the hypothesis that serum levels of testosterone
(T), dihydrotestosterone (DHT), and the DHT metabolite 3
alpha,17 beta-androstanediol glucuronide are positively
associated with the risk of prostate cancer. This nested
case-control study was based on the cohort of men who donated
blood to the Janus serum bank at Oslo University Hospital
(Oslo, Norway) between 1973 and 1994. Cancer incidence was
ascertained through linkage with the Norwegian Cancer
Registry. The study included sera from 59 men who developed
prostate cancer (cases) subsequent to blood donation and 180
men who were free of any diagnosed cancer (controls) in 1994
and were of similar age (+/- 1 year) and had similar blood
storage time (+/- 6 months) to the cases. Neither T, DHT, nor
the ratio T:DHT was associated with risk of developing
prostate cancer. Compared to the bottom quartile, the odds
ratio (OR) associated with the top quartile of T was 0.83 [95%
confidence interval (CI), 0.36-1.93]; the OR for the top
(compared to the bottom) quartile of DHT was 0.83 (95% CI,
0.36-1.94), and the equivalent OR for T:DHT was 1.31 (95% CI,
0.58-2.97). Similarly, 3 alpha,17 beta-androstanediol
glucuronide showed no association with prostate cancer risk;
the OR for the top (compared to the bottom) quartile was 1.10
(95% CI, 0.41-2.90). These results showed no association,
positive or negative, between androgens measured in serum and
the subsequent risk of developing prostate cancer.
213. Serum androgens and prostate cancer.
Nomura AM, Stemmermann GN, Chyou PH, Henderson BE, Stanczyk
FZ
Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu
96817, USA.
Cancer Epidemiol Biomarkers Prev 1996
Aug;5(8):621-5
It is suspected that male hormones are associated with the
risk of prostate cancer. To test this hypothesis, we conducted
a nested case-control study in a cohort of 6860
Japanese-American men examined from 1971 to 1975. At the time
of examination, a single blood specimen was obtained, and the
serum was frozen. After a surveillance period of more than 20
years, 141 tissue-confirmed incident cases of prostate cancer
were identified, and their stored sera and those of 141
matched controls were assayed for total testosterone, free
testosterone, dihydrotestosterone, 3-alpha-androstanediol
glucuronide, androsterone glucuronide, and androstenedione.
Odds ratios for prostate cancer, based on quartiles of serum
hormone levels, were determined using conditional logistic
regression methods. The odds ratios for the highest quartiles
were 1.37 (95% confidence interval, 0.73-2.55) for
3-alpha-androstanediol glucuronide and 1.24 (95% confidence
interval, 0.62-2.47) for androstenedione, but none of the
differences was statistically significant. The results were
unremarkable for the other four hormonal measurements. In
addition, the patients and controls were compared by hormonal
ratios (i.e., total testosterone:dihydrotestosterone), but the
results were also unremarkable. The findings of this study
indicate that none of these androgens is strongly associated
with prostate cancer risk.
214. Prospective study of sex hormone levels and
risk of prostate cancer.
Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ
Department of Medicine, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA, USA.
J Natl Cancer Inst 1996 Aug 21;88(16):1118-26
BACKGROUND: Sex steroids, particularly androgens, have been
implicated in the pathogenesis of prostate cancer. Data from
previous studies comparing circulating hormone levels in men
with and without prostate cancer are difficult to interpret,
since the studies were limited in size, hormone levels were
analyzed in blood drawn after the diagnosis of cancer,
nonrepresentative control subjects were used, and hormone and
hormone-binding protein levels were not simultaneously
adjusted.
PURPOSE: We conducted a prospective, nested case-control
study to investigate whether plasma hormone and sex
hormone-binding globulin (SHBG) levels in healthy men were
related to the subsequent development of prostate cancer.
METHODS: Among participants in the Physicians' Health Study
who provided plasma samples in 1982, we identified 222 men who
developed prostate cancer by March 1992. Three hundred ninety
control subjects, matched to the case patients on the bases of
age, smoking status, and length of follow-up, were also
identified. Immunoassays were used to measure the levels of
total testosterone, dihydrotestosterone (DHT), 3
alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and
prolactin in the stored (at -82 degrees C) plasma samples.
Correlations between individual hormone levels and between
hormone levels and SHBG in the plasma of control subjects were
assessed by use of Spearman correlation coefficients (r). Odds
ratios (ORs) and 95% confidence intervals (CIs) specifying the
prostate cancer risk associated with quartile levels of
individual hormones, before and after adjustment for other
hormones and SHBG, were calculated by use of conditional
logistic regression modeling. Reported P values are
two-sided.
RESULTS: No clear associations were found between the
unadjusted levels of individual hormones or SHBG and the risk
of prostate cancer. However, a strong correlation was observed
between the levels of testosterone and SHBG (r = .55), and
weaker correlations were detected between the levels of
testosterone and the levels of both estradiol (r = .28) and
DHT (r = .32) (all P < .001). When hormone and SHBG levels
were adjusted simultaneously, a strong trend of increasing
prostate cancer risk was observed with increasing levels of
plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and
2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse
trend in risk was seen with increasing levels of SHBG (ORs by
quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P
for trend = .01), and a non-linear inverse association was
found with increasing levels of estradiol (ORs by quartile =
1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend =
.03). No associations were detected between the levels of DHT
or prolactin and prostate cancer risk; for AAG, a marker of 5
alpha-reductase activity, only suggestive evidence of a
positive association was found. The results were essentially
unchanged when case patients diagnosed within 4 years of
plasma collection, case patients diagnosed with localized
(i.e., nonaggressive) disease, or control subjects with
elevated prostate serum antigen levels (> 2.5 ng/mL) were
excluded from the analyses.
CONCLUSIONS: High levels of circulating testosterone and
low levels of SHBG-both within normal endogenous ranges-are
associated with increased risks of prostate cancer. Low levels
of circulating estradiol may represent an additional risk
factor. Circulating levels of DHT and AAG do not appear to be
strongly related to prostate cancer risk.
215. Estradiol and testosterone metabolism and
production in men with prostatic cancer.
Meikle AW, Smith JA, Stringham JD
Department of Internal Medicine, University of Utah School of
Medicine, Salt Lake City 84132.
J Steroid Biochem 1989 Jul;33(1):19-24
We recently observed a familial influence on the plasma
concentration of sex-steroids and the metabolic clearance in
men with prostatic cancer. We have now determined, by isotope
dilution techniques, the blood estradiol and testosterone
production and clearance rates in men with prostatic cancer
and in unrelated controls. Thirty-eight men had a diagnosis of
prostatic cancer before the age of 63, and 22 controls matched
for age were randomly selected from the general population.
None of the patients or controls had received endocrine
therapy. The plasma content of testosterone,
dihydrotestosterone, estrone, estradiol, 3
alpha-androstanediol glucuronide, dehydroepiandrosterone
sulfate, sex-hormone binding globulin, apparent free
testosterone concentration, follicle stimulating hormone and
luteinizing hormone were not significantly different between
the groups. The metabolic clearance and production rates of
testosterone were significantly (P = 0.008 and P = 0.013,
respectively) higher in patients [447 +/- 26 L/day/body
surface area(m2) and 2.21 +/- 0.17 mg/day/m2, n = 38] than in
controls [346 +/- 20 L/day/m2 and 1.70 +/- 0.11 mg/day/m2, n =
22]. The PR and MCR of estradiol were not significantly
different between patients with prostatic cancer (n = 19) and
controls (n = 12). These results indicate that men with
prostatic cancer have elevated clearance and production rates
of testosterone without an alteration of estradiol production
or clearance.
216. Serum androgens: associations with prostate
cancer risk and hair patterning.
Demark-Wahnefried W, Lesko SM, Conaway MR, Robertson CN,
Clark RV, Lobaugh B, Mathias BJ, Strigo TS, Paulson DF
Division of Urology, Duke University Medical Center, Durham,
North Carolina 27710, USA.
J Androl 1997 Sep-Oct;18(5):495-500
Cancer of the prostate is the leading cancer among American
men, yet few risk factors have been established. Hair growth
and development are influenced by androgens, and it has long
been suspected that prostate cancer also is responsive to
these hormones. A blinded, case-control study was undertaken
to determine if hair patterning is associated with risk of
prostate cancer, as well as specific hormonal profiles. The
study accrued 315 male subjects who were stratified with
regard to age, race, and case-control status (159 prostate
cancer cases/156 controls). Hair-patterning classification and
serum levels of total and free testosterone (T), sex hormone
binding globulin, and dihydrotestosterone (DHT) were
performed. Data indicate that hair patterning did not differ
between prostate cancer cases and controls; however,
significant hormonal differences were detected between the two
groups. Free T was greater among cases than in controls (16.4
+/- 6.1 vs. 14.9 +/- 4.8 pg/ml, P = 0.02). Conversely,
DHT-related ratios were greater among controls (P = 0.03 for
DHT/T and P = 0.01 for DHT/free T). Several strong
associations also were found between hormone levels and hair
patterning. Men with vertex and frontal baldness had higher
levels of free T (16.5 +/- 5.5 and 16.2 +/- 8.0 pg/ml,
respectively) when compared to men with either little or no
hair loss (14.8 +/- 4.7 pg/ml) (P = 0.01). Data suggest that
increased levels of free T may be a risk factor for prostatic
carcinoma. In addition, although no differences in hair
patterning were detected between cases and controls within
this older population, further research (i.e., prospective
trials or case-control studies among younger men) may be
necessary to determine if hair patterning serves as a viable
biomarker for this disease, especially given the strong
association between free T levels and baldness.
217. Dramatic rise in prostate-specific antigen
after androgen replacement in a hypogonadal man with occult
adenocarcinoma of the prostate.
Curran MJ, Bihrle W 3rd
Department of Urology, Lahey Clinic Medical Center,
Burlington, Massachusetts 01805, USA.
Urology 1999 Feb;53(2):423-4
We present the case of a hypogonadal patient in whom a
20-fold increase in prostate-specific antigen and a palpable
prostatic nodule developed 6 months into the administration of
intramuscular testosterone.
218. Androderm Testosterone Transdermal
System.
Smith Kline Beecham
U.S. Prescribing Information 1997
219. Androgen-behavior correlations in hypogonadal
men and eugonadal men. II. Cognitive abilities.
Alexander GM, Swerdloff RS, Wang C, Davidson T, McDonald V,
Steiner B, Hines M
Department of Psychology, University of New Orleans,
Louisiana 70148, USA.
gmaps@uno.edu
Horm Behav 1998 Apr;33(2):85-94
Sex-typed cognitive abilities were assessed in 33
hypogonadal men receiving testosterone replacement therapy, 10
eugonadal men receiving testosterone in a male contraceptive
clinical trial, and 19 eugonadal men not administered
testosterone. Prior to and following hormone administration,
men completed four tests measuring visuospatial ability, three
tests measuring verbal fluency, two tests measuring perceptual
speed, and a measure of verbal memory. Group differences in
testosterone levels were unrelated to performance on most
cognitive measures, including visuospatial ability. Relative
to other men, hypogonadal men were impaired in their verbal
fluency and showed improved verbal fluency following treatment
with testosterone. These data suggest that
testosterone may enhance verbal fluency in hypogonadal men and
support the general hypothesis that current levels of
testosterone may influence some aspects of cognitive
function.
220. Decreased serum testosterone in men with acute
ischemic stroke.
Jeppesen LL; Jorgensen HS; Nakayama H; Raaschou HO; Olsen TS;
Winther K
Department of Clinical Chemistry, Glostrup Hospital,
Copenhagen, Denmark.
Arterioscler Thromb Vasc Biol (United States) Jun 1996, 16
(6) p749-54
Serum levels of total and free testosterone and 17
beta-estradiol were determined in 144 men with acute ischemic
stroke and 47 healthy male control subjects. Blood samples
from patients were drawn a mean of 3 days after stroke onset
and also 6 months after admission in a subgroup of 45
patients. Initial stroke severity was assessed on the
Scandinavian Stroke Scale and infarct size by computed
tomographic scan. Mean total serum testosterone was 13.8 +/-
0.5 nmol/L in stroke patients and 16.5 +/- 0.7 nmol/L in
control subjects (P = .002); the respective values for free
serum testosterone were 40.8 +/- 1.3 and 51.0 +/- 2.2 pmol/L
(P = .0001). Both total and free testosterone were
significantly inversely associated with stroke severity and
6-month mortality, and total testosterone was significantly
inversely associated with infarct size. The
differences in total and free testosterone levels between
patients and control subjects could not be explained by 10
putative risk factors for stroke , including age, blood
pressure, diabetes, ischemic heart disease, smoking, and
atrial fibrillation. Total and free testosterone levels tended
to normalize 6 months after the stroke . There was no
difference between patients and control subjects in serum 17
beta-estradiol levels. These results support the idea
that testosterone affects the pathogenesis of ischemic stroke
in men.
221. Hyposomatomedinemia and hypogonadism in
hemiplegic men who live in nursing homes.
Abbasi A; Mattson DE; Cuisinier M; Schultz S; Rudman I;
Drinka P; Rudman D
Department of Medicine, Medical College of Wisconsin,
Milwaukee.
Arch Phys Med Rehabil (United States) May 1994, 75 (5)
p594-9
The purpose of this study was to determine the prevalence
of low serum insulin-like growth factor-I (IGF-I) and
testosterone in men with poststroke hemiplegia. Serum
concentrations of IGF-I, total testosterone , and free
testosterone were compared in healthy young men, healthy old
men, and old men with poststroke hemiplegia. A low IGF-I
level, below the lower 2.5 percentile of the healthy young
men, occurred in 85% of the healthy old men, and in
88% of the poststroke hemiplegic patients. When a low
IGF-I was defined as a value below the lower 2.5 percentile of
the healthy old men, the prevalence in the hemiplegic men was
5%. For total testosterone , a value below the lower 2.5
percentile in the healthy young men occurred in 78% of the
healthy old men and in 79% of the stroke survivors. Low total
testosterone , defined as a value below the lower 2.5
percentile of the healthy old men, occurred in 17% of the
hemiplegic men. The results with free testosterone were
similar. Compared with healthy young men, most healthy old men
have low serum IGF-I and testosterone levels. Old hemiplegic
men resemble healthy old men in their IGF-I levels, but they
have more cases of severe hypogonadism (total tostosterone
< 193ng/dL). Because correction of IGF-I and testosterone
deficiencies in younger adults improves muscle strength, work
capacity, and quality of life, treatment with human
growth hormone and testosterone may be a useful adjunct to
physical measures in the rehabilitation of selected
hemiplegic stroke survivors.
222. Hormonal changes in cerebral infarction in the
young and elderly.
Elwan O; Abdallah M; Issa I; Taher Y; el-Tamawy M
Neurology Department, Cairo University, Egypt.
J Neurol Sci (Netherlands) Sep 1990, 98 (2-3)
p235-43
Fifty-one patients with CCT verified cerebral infarction
were submitted to serum and CSF radioimmunoassay of FSH, LH,
estradiol (E2), progesterone, testosterone , cortisol and T4.
The results were compared to those of 82 matched
controls. Our findings suggest that (1) high serum E2
is a risk factor of stroke in males; (2) low serum T4 is a
risk factor in males; (3) serum testosterone is
reduced in acute stroke in males confirming that it is stress
sensitive; (4) serum LH was higher in hypertensive thrombotic
males when compared to normotensive ones, and (5) FSH, LH, E2
and T4 are undetectable in CSF of patients and controls.
223. Circulating testosterone in pure motor
stroke.
Dash RJ; Sethi BK; Nalini K; Singh S
Department of Endocrinology, Postgraduate Institute of
Medical Education and Research, Chandigarh, India.
Funct Neurol (Italy) Jan-Mar 1991, 6 (1) p29-34
Serum LH, FSH and testosterone were quantitated in 9
patients with pure motor stroke within 24-48 h of its reported
onset. High circulating LH with normal or low
testosterone was noted in 8 of them. In response to
an intravenous bolus of GnRH, the LH responses were
exaggerated in all, but the FSH responses in 7 of them were
comparable to those in eugonadal age matched controls. The
rise in testosterone following 2000U hCG daily for 3
consecutive days was insignificant in the patients group
compared to the controls. The data suggest normally operative
pituitary testicular feed-back but decreased Leydig cell
response in pure motor stroke .
224. Prognostic factors in survival free of
progression after androgen deprivation therapy for treatment
of prostate cancer.
Ishikawa S, Soloway MS, Van der Zwaag R, Todd B
Department of Urology, University of Tennessee,
Memphis.
J Urol 1989 May;141(5):1139-42
We analyzed 110 patients with metastatic
prostate cancer (stage D2) to determine the associations
between interval until progression and the pretreatment
testosterone level, extent of bone metastases, performance
status, race, age and pretreatment level of prostatic acid
phosphatase. The median followup was 21 months (4 to 89
months). All patients received androgen deprivation therapy
when metastases were identified. This multivariate
analysis demonstrated that the pretreatment serum testosterone
was the most significant variable (p less than 0.01)
associated with interval until progression and the extent of
bone metastases observed on the bone scan was the second most
important variable (p less than 0.05). Age, race and
prostatic acid phosphatase were not significantly correlated
with the interval free of progression. Performance status was
significantly correlated but it was nonsignificant in the
multivariate analysis if the model already included
testosterone level and extent of metastasis. Patients
with a pretreatment testosterone level of less than 300 ng.
per 100 ml. and more than 6 areas of increased uptake on the
bone scan had the most rapid progression. We conclude
that serum testosterone and extent of bone metastases are the
most important of the analyzed factors in terms of interval to
progression in patients with protate cancer following androgen
deprivation.
225. Low serum testosterone and a younger age
predict for a poor outcome in metastatic prostate
cancer.
Ribeiro M, Ruff P, Falkson G
Department of Medicine, University of the Witwatersrand,
Johannesburg, South Africa.
Am J Clin Oncol 1997 Dec;20(6):605-8
Carcinoma of the prostate gland is one of the most
common malignancies in males. This study was undertaken to
determine which factors predict the course and outcome of
patients treated with first line hormonal manipulation. A
total of 144 patients with Stage D2 prostate cancer who
received androgen deprivation therapy were studied.
Pretreatment parameters analyzed were age, performance status,
analgesia usage, concurrent disease, histologic
differentiation, hemoglobin, leukocyte and platelet count,
serum creatinine, alkaline phosphatase, lactate dehydrogenase,
prostate specific antigen, total and prostatic acid
phosphatase, serum testosterone, follicle stimulating and
luteinizing hormone levels, number of metastatic sites and
bone scan grade. Only initial serum testosterone (> 10
nmol/l) had a positive impact on response (p = 0.0304),
whereas age older than 60 years had a positive impact on time
to progression (16 vs. 11 months, p = 0.0414). Both serum
testosterone (26 vs. 20 months, p = 0.003), and age (28 vs. 17
months, p = 0.036) had a significant influence on overall
survival. Low testosterone, indicating androgen
independence, and a younger age, seem to result in a more
aggressive disease and a poorer prognosis in advanced prostate
cancer.
226. Prognostic factors in patients with advanced
prostate cancer.
Soloway MS, Ishikawa S, van der Zwaag R, Todd B
Department of Urology, University of Tennessee,
Memphis.
Urology 1989 May;33(5 Suppl):53-6
One hundred ten patients with metastatic prostate
cancer (Stage D2) were analyzed to determine the associations
among time until progression and the pretreatment testosterone
level, extent of bone metastases as indicated by a
semiquantitative grading scale for extent of disease,
performance status, race, age, and the pretreatment level of
prostatic acid phosphatase (PAP). The median follow-up period
was twenty-one months, with a range of four to eighty-nine
months. All patients received androgen deprivation at the time
metastases were identified. A multivariate analysis
demonstrated that pretreatment serum testosterone was the most
significant variable associated with time until progression (P
less than 0.01) and that the extent of bone metastases
observed on the bone scan was the second most important
variable (P less than 0.05). The following factors did
not significantly correlate with progression-free intervals:
age, race, and PAP. The performance status was significantly
correlated, but was nonsignificant in the multivariate
analysis when the model already included the testosterone
level and the extent of bone metastases. Patients with a
pretreatment testosterone level of less than 300 ng/dL and
with more than six areas of increased uptake on the bone scan
progressed more rapidly.
227. Serum testosterone as a prognostic factor in
patients with advanced prostatic carcinoma.
Iversen P, Rasmussen F, Christensen IJ
Department of Urology, Rigshospitalet, University of
Copenhagen, Denmark.
Scand J Urol Nephrol Suppl 1994;157:41-7
In 245 patients with previously untreated advanced
carcinoma of the prostate, serum concentrations of
testosterone have been measured before androgen deprivation
therapy, and patients were divided in quartiles according to
their serum concentration. Pretreatment level of serum
testosterone was confirmed as having significant prognostic
value on progression-free, overall, and cancer-specific
survival, and the hazard ratios of lower quartiles compared to
the upper quartile for these endpoints were 2.3, 2.1, and 2.0,
respectively. However, correlations with symptomatology and
other pretreatment parameters suggest that low serum
testosterone merely is a consequence of the advanced
malignancy rather than a causative factor in the pathogenesis
of prostatic cancer.
228. A prognostic index for the clinical management
of patients with advanced prostatic cancer: a British Prostate
Study Group investigation.
Wilson DW, Harper ME, Jensen HM, Ikeda RM, Richards G,
Peeling WB, Pierrepoint CG, Griffiths K
Prostate 1985;7(2):131-41
Patients with histologically proven carcinoma of
the prostate (n = 186) were initially assessed and followed up
according to the standardized protocol of the British Prostate
Study Group, urologists from which contributed patients to
this investigation. These patients were given either endocrine
therapy or orchidectomy as first line treatment; the ratio of
the number of patients receiving these two treatments was
similar in each group of subjects compared for survival.
Prognostic indices were derived for all patients and for those
classified according to the presence (M1) or absence (M0) of
metastases. The prognostic indices were derived from clinical
and hormone data obtained at initial presentation. Whereas the
degree of tumor differentiation and plasma testosterone
concentrations were significant prognostic factors in both M0
and M1 disease, growth hormone was only significant in M1
patients, where age was also of borderline significance;
elevated growth hormone, higher Gleason grade,
younger age, and lower testosterone indicated a poorer
prognosis in M1 patients. These findings indicated the
feasibility of selecting a poor prognostic group of patients
that may derive benefit from a more aggressive
therapy.
229. The importance of prognostic factors in
advanced prostate cancer.
Soloway MS
Department of Urology, University of Tennessee,
Memphis.
Cancer 1990 Sep 1;66(5 Suppl):1017-21
Three factors were identified in a multivariate
analysis of prognostic factors in men with metastatic prostate
cancer as significantly associated with their progression-free
survival: 1) extent of disease on the bone scan, 2)
pretreatment serum testosterone, and 3) performance
status. Men with less than six bone metastases, a
pretreatment testosterone greater than 300 ng/100 ml, and an
excellent performance status will have a progression-free
survival much longer than a man with more extensive bone
metastases, a low testosterone prior to androgen deprivation,
and a poor performance status. This information
should be used to ensure proper stratification in randomized
trials. It may also be helpful in identifying the patient
unlikely to be helped by our current treatment. Such patients
should be considered for alternative approaches with the aim
of improving survival.
230. Sex hormone-binding protein, hyperinsulinemia,
insulin resistance and noninsulin-dependent diabetes.
Haffner SM
Horm Res 1996;45(3-5):233-7
Possible data complicating sex hormones, especially
testosterone, in the etiology of cardiovascular disease and
noninsulin-dependent diabetes mellitus (NIDDM) comes from the
much higher rates of cardiovascular disease in men than in
women. Pharmacological administration of anabolic steroids to
both men and women increases glucose and insulin
concentrations and also insulin resistance. In vivo assessment
of sex hormones and binding proteins in both premenopausal and
postmenopausal women has suggested that increased free
testosterone and decreased sex hormone-binding globulin (SHBG)
is associated with higher glucose and insulin concentrations.
In a few studies, increased insulin resistance has been
associated with decreased SHBG levels. Some data suggests that
visceral fat mediated the associates of sex hormones with
insulin in women. Little prospective data is available on the
association of sex hormones to the development of NIDDM in
women but in two studies, low SHBG concentrations predicted
NIDDM in Gothenburg and San Antonio. Recently, attention has
focused on the role of sex hormones in relation to insulin in
men. Surprisingly, higher levels of testosterone have
been associated with improved cardiovascular risk factors
(such as high-density lipoprotein cholesterol) and lower
glucose and insulin levels. Total testosterone and
SHBG have been associated with defects in nonoxidative glucose
disposal and upper body adiposity in normoglycemic Finnish
men. The latter observation is of interest since specific
defects in nonoxidative glucose disposal are observed in
normoglycemic relatives of subjects with NIDDM. The temporal
relationship between sex hormones and insulin has been
controversial. The traditional view of sex hormones increasing
insulin resistance has been challenged in women by studies
showing that insulin stimulates androgen production in the
ovary. Recent data [JCEM 1995;80:654-658] suggests that
insulin stimulates testosterone production and suppresses SHBG
production in normal and obese men. On the other hand,
administration of testosterone to centrally obese hypogonadal
middle-aged men has improved insulin sensitivity.
231. Sex hormone levels in young Indian patients
with myocardial infarction.
Sewdarsen M, Jialal I, Vythilingum S, Desai R
Arteriosclerosis 1986 Jul-Aug;6(4):418-21
The finding of abnormal levels of sex hormones in men with
coronary artery disease has led to the hypothesis that
alterations in sex hormones may represent an important risk
factor for myocardial infarction. In this study, the sex
hormone profile of 28 young men (aged less than 40 years) with
myocardial infarction was compared with 28 age- and
weight-matched normal men. Although the mean total serum
estradiol levels and the free estradiol index of the patients
and controls were similar, the mean serum total
testosterone level and the free testosterone index were
significantly lowered in the patients with myocardial
infarction (p less than 0.01). The ratio of serum
estradiol to testosterone was significantly increased in the
patients (p = 0.0005) and correlated with serum cholesterol,
triglycerides, and plasma glucose. A significant inverse
correlation was also demonstrated between total testosterone
and serum cholesterol and triglycerides. Hence, the
results of this study support the hypothesis that low plasma
testosterone and an increased estradiol-to-testosterone ratio
may be important risk factors for myocardial
infarction.
232. Androgen receptors mediate hypertrophy in
cardiac myocytes.
Marsh JD; Lehmann MH; Ritchie RH; Gwathmey JK; Green GE;
Schiebinger RJ
Department of Medicine, Harper Hospital, Detroit, Mich,
USA.
marsh@cardiology.harper.wayne.edu.
Circulation 1998 Jul 21;98(3):256-61
BACKGROUND: The role of androgens in producing cardiac
hypertrophy by direct action on cardiac myocytes is uncertain.
Accordingly, we tested the hypothesis that cardiac myocytes in
adult men and women express an androgen receptor gene and that
myocytes respond to androgens by a hypertrophic response.
METHODS AND RESULTS: We used reverse
transcription-polymerase chain reaction methods to demonstrate
androgen receptor transcripts in multiple tissues and
[3H]phenylalanine incorporation and atrial natriuretic peptide
secretion as markers of hypertrophy in cultured rat myocytes.
Messenger RNA encoding androgen receptors was detected in
myocytes of male and female adult rats, neonatal rat myocytes,
rat heart, dog heart, and infant and adult human heart. Both
testosterone and dihydrotestosterone produced a robust
receptor-specific hypertrophic response in myocytes,
determined by indices of protein synthesis and atrial
natriuretic peptide secretion.
CONCLUSIONS: Androgen receptors are present in
cardiac myocytes from multiple species, including normal men
and women, in a context that permits androgens to modulate the
cardiac phenotype and produce hypertrophy by direct,
receptor-specific mechanisms. There are clinical implications
for therapeutic or illicit use of androgens in
humans.
233. The relationship of natural androgens to
coronary heart disease in males: a review.
Alexandersen P; Haarbo J; Christiansen C
Center for Clinical and Basic Research, Ballerup,
Denmark.
Atherosclerosis (Ireland) Aug 23 1996 , 125 (1)
p1-13
Published studies dealing with the relationship between
circulating levels of testosterone and dehydroepiandrosterone
(sulfate) (DHEA(S)) and coronary heart disease (CHD) in males,
as well as corresponding experimental animal studies are
reviewed. One randomized intervention study, eight prospective
and 30 cross-sectional studies have evaluated this
relationship. In the intervention study, testosterone
undecanoate given orally significantly improved angina
pectoris in 62 patients with CHD as compared to
placebo. No significant association between serum
testosterone and CHD was reported in the prospective studies,
whereas those studies concerning DHEAS found either no or an
inverse association with CHD. Of 30 cross-sectional studies,
18 reported reduced concentrations of testosterone
(primarily), and/or DHEA(S) in CHD patients as compared to
normals, 11 found similar circulating levels of these
androgens in controls and patients with CHD, and one study
found elevated levels of DHEA(S) in patients. Animal
studies (six male rabbits and one in male chicks) suggest an
anti-atherogenic effect of testosterone and DHEA. In
conclusion, one intervention, eight cohort and several
cross-sectional studies suggest either a neutral or a
favourable effect of testosterone and DHEA(S) on CHD in
males.
234. Induction of circadian rhythm of feeding
activity by testosterone implantations in arrhythmic Japanese
quail males.
Lumineau S; Guyomarc'h C; Boswell T; Richard JP; Leray
D
U.M.R. 6552, Ethologie Evolution Ecologie, Universite de
Rennes 1-C.N.R.S., Rennes, France.
J Biol Rhythms (United States) Aug 1998, 13 (4)
p278-87
Studies in vertebrates have shown that hormones can
influence circadian rhythms of behavior. We investigated
whether testosterone could induce rhythmicity in arrhythmic
Japanese quail, kept in DD. The animals used were 3
1/2-week-old castrated males from a line of quail selected for
the lack of the circadian rhythm of feeding activity. After 3
weeks in DD, 8 birds were implanted with an empty implant and
16 others with a testosterone implant. Two weeks later, the
operation was repeated. After implantation, we noticed that 15
out of 16 testosterone -treated birds showed a circadian
rhythm of feeding activity, in contrast to the control birds,
which remained arrhythmic. The clarity of this rhythm
increased significantly after each implantation. A
positive correlation was found between the indexes of clarity
of the rhythm (autocorrelation coefficient ratio and area of
the peak of spectrum) and the plasma testosterone
level. The period of the induced free-running rhythm
was identical to the specific value of the endogenous
circadian rhythm in immature quail. The circadian period
showed a significant lengthening with the second implantation.
This lengthening looks like the variation previously observed
in maturing rhythmic or implanted quail. So, it would appear
that testosterone can act on rhythmicity on at least two
levels: by inducing the circadian rhythm and increasing its
clarity and by modulating its period. To explain these
results, several hypotheses can be considered. First, the
observed arrhythmy may be the consequence of an internal
desynchronization of oscillators, responsible for generating
the circadian rhythm of feeding activity, and testosterone
could play a role in the coupling of these oscillators.
Alternatively, we suggest that testosterone could act
on the transcription of genes implicated in the control of the
rhythmicity or may regulate by rapid signals the cellular
rhythmic activity. The possible functional values of
the enhancing of circadian rhythmicity by testosterone at
different stages of the bird's life were discussed.
235. Androgen receptors in experimentally induced
colon carcinogenesis
Izbicki J.R.; Wambach G.; Hamilton S.R.; et al.
II Department of Surgery, University of Cologne, D-5000 Koln
91 Germany
Journal of Cancer Research and Clinical Oncology (Germany)
1986, 112/1 (39-46)
Sex hormones may play a role in colonic carcinogenesis, as
evidenced by epidemiologic and experimental data showing
different tumor rates in males and females. We investigated
the effects of hormonal manipulation on tumor development and
on androgen receptor binding in both colonic wall and
experimentally induced tumors in male rats. Five of six
groups, each with 40 animals, were given 10 weekly s.c.
injections of azoxymethane (AOM), 7.5 mg/kg body weight.
Group-I served as normal controls. Group-II received AOM only.
Group-III was castrated 2 weeks prior to carcinogen treatment.
Group-IV was castrated similarly and then hormone substituted
with testosterone propionate. Group-V was chemically castrated
with the anti androgen cyproterone acetate. Group-VI was
castrated and given hormone vehicle. Scatchard analysis for
androgen receptors in cytosol from normal colonic wall and
tumor was performed with sup 3H-methyltrienolone as the
ligand. Androgens were found to have an inhibitory
effect on carcinogenesis: chemical castration increased
colonic tumor development (P < 0.05 for multiplicity), and
testosterone administration produced a borderline
statistically significant reduction in tumor incidence in
surgically castrated rats (P < 0.053), particularly in the
right colon. Specific binding sites for androgen with high
affinity and low capacity were found in the colonic wall of
all groups. Receptor density was not altered by AOM
administration, but increased after surgical castration.
Receptor density was markedly lower in tumors than in normal
colonic wall. Receptor binding sites in tumors were not
altered by the various hormonal manipulations. Our study
demonstrated that although cytoplasmic androgen receptors are
present in colonic wall and in experimental tumors,
AOM-induced colonic carcinogenesis appears to be only mildly
affected by manipulation of androgens.
236. Effects of androgen manipulations on
chemically induced colonic tumours and on macroscopically
normal colonic mucosa in male Sprague-Dawley rats.
Izbicki JR, Hamilton SR, Wambach G, Harnisch E, Wilker DK,
Dornschneider G, Eibl-Eibesfeldt B, Schweiberer L
Dept of Surgery, University of Munich, FR Germany.
Circulation 1998 Jul 21;98(3):256-61
Epidemiological and experimental studies suggest that
androgens influence colonic carcinogenesis. We investigated
the effects of hormonal manipulations (surgical and chemical
castration, hormone substitution) on colonic tumour
development, tumour and mucosal histopathology, and epithelial
proliferation in macroscopically normal colonic mucosa in male
rats, after induction of chemical colon carcinogenesis by
subcutaneous injections of azoxymethane (AOM). Chemical
castration with cyproterone acetate, but not surgical
castration, resulted in increased colonic tumorigenesis, which
was accompanied by decreased crypt length, decreased number of
cells per crypt, and increased crypt epithelial mitotic index
in the right colon. Chemically castrated rats also had crypt
hyperplasia and increased numbers of dysplastic foci in the
left colon which were not seen with surgical castration. By
contrast, rats given testosterone after surgical castration
showed decreased colonic tumorigenesis with an increased
proportion of tumours in the left colon and lower percentage
of tumours with invasion. The grossly normal mucosa of the
testosterone-substituted castrated rats showed decreased crypt
length in the right colon similar to the other groups of
castrated rats, but no significant increase in mitotic index.
Our results suggest that the anti-androgenic progestin
cyproterone is a potent enhancer of colonic tumorigenesis and
epithelial proliferative abnormalities after AOM
administration. Exogenous testosterone after castration alters
tumour distribution and characteristics and suppresses
epithelial proliferative abnormalities. Finally,
androgen effects on the colonic mucosa are more prominent in
the right than in the left colon, suggesting different
influences of hormones on the epithelium of these anatomical
sites.
237. Androgens and abdominal obesity.
Marin P, Arver S
Department of Heart and Lung Diseases, Sahlgrenska University
Hospital, Gothenburg, Sweden.
Baillieres Clin Endocrinol Metab 1998
Oct;12(3):441-51
Central or visceral obesity is recognized as a main risk
factor for cardiovascular disease and type 2 diabetes
mellitus. The co-existence of visceral obesity, increased
blood lipid levels, hypertension and impaired glucose
tolerance defines the metabolic syndrome that today is widely
recognized as one of the prime factors behind cardiovascular
morbidity and mortality. Endocrine disorders such as
insulinoma, hypothyroidism and hypercortisolism are known to
cause obesity. However, it is only hypercortisolism
that is associated with increased abdominal fat accumulation.
Recently, new findings have shed light on subtle
endocrinopathies that are prevalent in individuals presenting
with the metabolic syndrome. Such derangements are of
borderline character and often fall within the normal
reference range. Intervention studies demonstrate
that correction of relative hypogonadism in men with visceral
obesity and other manifestations of the metabolic syndrome
seem to decrease the abdominal fat mass and reverse the
glucose intolerance, as well as lipoprotein abnormalities in
the serum. Further analysis of the underlying
mechanism has also disclosed a regulatory role for
testosterone in counteracting visceral fat
accumulation. Longitudinal epidemiological data
demonstrates that relatively low testosterone levels are a
risk factor for development of visceral obesity. The
primary event that triggers the initial development of
visceral obesity is not known, but it seems plausible that
increased activity in the hypothalamus-pituitary-adrenal axis
can be of major importance.
238. Increased estrogen production in obese
men
Schneider G; Kirschner M A; Berkowitz R; Ertel N H
Veterans Adm. Hosp., East Orange, N.J. 07019, USA.
J Clin Endocrinol Metab 48 (4). 1979. 633-638.
Serum estrone (E1) and 17.beta.-estradiol (E2) were noted
to be 2-fold elevated in a group of morbidly obese men.
Urinary E1 and E2 production rates were elevated in proportion
to the degree of obesity, with values as high as 127 and 157
.mu.g/day, respectively. Although serum testosterone (T)
concentrations were reduced in obese men, averaging 348 .+-.
35 vs. 519 .+-. 42 ng/dl in lean controls, the dialyzable T
fractions were elevated and, hence, the calculated free T
concentrations were normal in obese men. The obese men
exhibited normal serum LH [lutropin], FSH [follitropin] and T
responses to clomiphene citrate, indicating intact
hypothalamic-pituitary-Leydig cell axes. MCR
[metabolic clearance rate] of T and peripheral conversion of T
to E2 and androstenedione (.DELTA.) to E1 were all increased
in obese men in proportion to the percentage above ideal
weight. Although the obese men exhibited increased
blood levels and production rates of estrogens, there were no
signs of feminization, increased T-estrogen-binding globulin
levels, or suppressed basal gonadotropin levels, suggesting a
lack of biological effect. Obese men may exhibit
defective estrogen receptors, leadint to decreased
T-estrogen-binding globulin, increased clearance of androgenic
hormones and elevated estrogen production rates.
239. Lower endogenous androgens predict central
adiposity in men.
Khaw KT; Barrett-Connor E
Department of Clinical Gerontology, University of Cambridge,
School of Clinical Medicine, United Kingdom.
Ann Epidemiol (United States) Sep 1992, 2 (5)
p675-82,
Central adiposity, sometimes described as male pattern fat
distribution, is adversely related to cardiovascular risk and
mortality independent of other measures of obesity. In a
cohort of 511 men aged 30 to 79 years in 1972 to 1974,
levels of androstenedione, testosterone , and sex
hormone-binding globulin measured at baseline were inversely
related to subsequent central adiposity, estimated 12 years
later using the waist-hip circumference ratio. The
observed differences in waist-hip ratio between top and bottom
tertiles of these hormones and sex hormone-binding globulin
were similar to mean waist-hip ratio differences between men
with stroke or ischemic heart disease and those without in
another prospective study. These findings, consistent with
studies suggesting that testosterone seems to mobilize the
abdominal depot on males, suggest that "male pattern" fat
distribution may be a misleading description for central
adiposity, at least, in men. Degree of maleness as indicated
by total androgen levels is, in fact, negatively
associated with central adiposity. However, the role of sex
hormone-binding globulin in regulating androgenic activity
warrants further investigation.
240. Enhanced conversion of androstenedione to
estrogens in obese males.
Kley HK, Deselaers T, Peerenboom H, Kruskemper HL
J Clin Endocrinol Metab 1980 Nov;51(5):1128-32
In normal and obese young males [90--120% and > 160% of
ideal body weight (IBW); IBW = 100%], plasma concentrations of
testosterone, androstenedione, estrone, and estradiol were
measured. Metabolic clearance and production rates of
androstenedione and the conversion ratios of androstenedione
to testosterone, estrone, and estradiol were determined using
the constant infusion technique. In the obese subjects, IBW
was inversely correlated (P < 0.001) with plasma
concentrations of androstenedione (r = 0.81) and testosterone
(r = 0.87), while the levels of estrone (r = 0.92) and
estradiol (r = 0.95) increased with IBW (P < 0.001). Thus,
when normal and obese subjects were compared as groups, plasma
androstenedione decreased form 1.24 +/- 0.13 to 0.93 +/- 0.15
ng/ml (mean +/- SD) and plasma testosterone decreased from
5.89 +/- 0.82 to 3.29 +/- 0.92 ng/ml (P < 0.001), while
estrone increased from 28.2 +/- 3.4 to 60.0 +/- 9.4 pg/ml, and
estradiol increased from 21.7 +/- 3.5 to 43.9 +/- 5.3 pg/ml.
The testosterone to androstenedione and the estradiol to
estrone ratios were not different in obesity, but changes in
IBW were positively correlated (P < 0.001) with differences
in the estrone to androstenedione (r = 0.93) and estradiol to
testosterone ratios (r = 0.93), indicating that fat tissue may
aromatize androgens, whereas reduction of 17-oxo-steroid
appears to be of minor importance. As the MCR of
androstenedione increased with IBW (from 2156 to 2636
liters/day P < 0.05) while plasma levels decreased, the
apparent production rate of androstenedione was not influenced
by the degree of obesity. The conversion of
androstenedione to estrone (r = 0.89) and of androstenedione
to estradiol (r = 0.82) was enhanced in obese subjects (P <
0.001). We suggest that enhanced aromatization of
androstenedione due to an increased adipose tissue mass may
account for the high plasma estrogen levels observed in obese
men.
|