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91. Anemia of Androgen Deprivation (AAD) in
patients receiving combination hormonal blockade response to
erythropoietin
Stephen B. Strum
Culver City, & Whittier, California
Over 75% of patients with prostate cancer receiving
combination hormonal blockade (CHB) with an LHRH agonist +
Eulexin develop a moderate anemia with hematocrits ranging
from 30-36%. In patients with underlying heart disease, in
physically active patients or in those travelling to areas of
high altitude, this anemia may become clinically significant.
Hematologic findings in these patients are those of a
normochromic and normocytic anemia that are not related to
bone metastases nor to renal insufficiency. The anemia is
temporally related to the administration of CHB and is
apparent 3 months after the start of CHB and disappears within
2 to 3 months after the termination of CHB. In a pilot study,
Epogen was administered at a dose of 4000 units sq 3 times per
week. Within 2 months hematocrits returned to normal. Most
patients were titrated down to doses of 2000 units sq twice
each week while maintaining hematocrits slightly lower, in the
38-40% range. In those patients in whom the Epogen was
stopped, the hematocrits dropped to pretreatment
values(30-36%) within 2 months. No patients had evidence of
phlebitis or thrombosis after starting Epogen. We
conclude that the anemia of androgen deprivation is: 1] a
common finding in patients receiving CHB & 2] highly
responsive to low dose erythropoietin. Studies have
begun to evaluate erythropoietin levels obtained prior to CHB,
during CHB and during CHB + exogenous erythropoietin.
92. Anaemia associated with androgen deprivation in
patients with prostate cancer receiving combined hormone
blockade.
Strum SB; McDermed JE; Scholz MC; Johnson H; Tisman G
Daniel Freeman Marina Medical Centre, Marina del Rey,
California, USA.
Br J Urol (ENGLAND) Jun 1997 , 79 (6) p933-41
OBJECTIVE: To describe the incidence, time to onset and
extent of anaemia occurring in patients with prostate cancer
receiving combined hormone blockade (CHB) and the timing and
extent of recovery from anaemia in those patients where CHB
was discontinued.
PATIENTS AND METHODS: Patients with prostate cancer were
evaluated prospectively by physical examination and laboratory
tests at baseline and at routine intervals while receiving
CHB. Of 142 patients who received CHB, 133 were evaluable for
the assessment of anaemia; CHB was discontinued in 76
patients, of whom 64 were assessable for recovery from their
anaemia.
RESULTS: Haemoglobin levels declined significantly in all
patients from a mean baseline of 149 g/L to means of 139 g/L,
132 g/L and 131 g/L at 1, 2 and 3 months, respectively.
Haemoglobin levels continued to decline during CHB to a mean
nadir of 123 g/L at a mean of 5.6 months of CHB, representing
a mean absolute haemoglobin decline at nadir of 25.4 g/L. In
120 of the 133 (90%) patients, the relative decline in
haemoglobin at nadir was > or = 10% and was > or = 25%
in 17 (13%) others, representing a mean absolute haemoglobin
decline in this subset of 42.7 g/L. Significant symptoms
related to anaemia occurred in 17 patients (13%). Anaemia and
symptoms in these patients were easily corrected with the
subcutaneous administration of recombinant human
erythropoietin.
CONCLUSIONS: The anaemia associated with androgen
deprivation is significant and occurs routinely in men
receiving CHB. It is normochromic, normocytic,
temporally-related to the initiation of androgen blockade and
usually resolves after CHB is discontinued. We suggest that
patients receiving CHB undergo haematological testing at
baseline, 1-2 months after initiating CHB and periodically
thereafter. Patients developing anaemia should be questioned
about symptoms reflecting physiological compromise (e.g.
angina , dyspnoea on exertion). In the absence of other
causes, CHB should be suspected in the development of anaemia
in patients receiving this treatment.
93. [No title available].
[Article in Polish]
Rabijewski M, Adamkiewicz M, Zgliczynski S
Klinika Endokrynologii Centrum Medycznego Ksztalcenia
Podyplomowego, Szpital Bielanski.
Pol Arch Med Wewn 1998 Sep;100(3):212-21
The aim of this study was to determine the influence of
testosterone replacement therapy in elderly men on mood, bone
mineral density, and lipids. We investigated thirty men (mean
+/- SD; age 61.1 +/- 5.6 yr) with testosterone concentrations
(mean +/- SEM) 2.1 +/- 0.2 ng/ml. Testosterone deficiency was
replacement by intramuscular injections of testosterone
enanthate 200 mg every second week from 1.5 to 6 yr. (mean +/-
SD; 3.35 +/- 1.6 yr.). During the treatment serum testosterone
increased reaching normal levels (mean +/- SEM; 6.6 +/- 0.2
ng/ml). This was associated with significant increase
in positive mood parameters and a decrease in negative mood
parameters. Also self assessment of libido, potence
and dream were improved. Bone mineral density (BMD) of
lumbar spine increased. We noticed significant
decrease in total cholesterol, and LDL-cholesterol.
Hematocrit was increased. Prostate-specific
antigen concentration statistically increased from 0.65 +/-
0.1 to 1.35 +/- 0.1 ng/ml (mean +/- SEM), but in the cases of
its levels were in normal range. Patients with coronary heart
disease demonstrated decreasing symptoms of angina pectoris
and nitrate requirement. In summary, long-term
testosterone replacement therapy in elderly men may have
beneficial effects on well-being, libido, potence, dream, bone
mineral density, lipids, blood cell count and body mass (BMI).
This therapy appears to be safe and there is no adverse
effection on prostate.
94. Testosterone and depression in aging men.
Seidman SN, Walsh BT
Department of Psychiatry, College of Physicians and Surgeons
of Columbia University, New York, NY 10032, USA.
Am J Geriatr Psychiatry 1999 Winter;7(1):18-33
In men, testosterone secretion affects neurobehavioral
functions such as sexual arousal, aggression, emotional tone,
and cognition. Beginning at approximately age 50, men
secrete progressively lower amounts of testosterone; about 20%
of men over age 60 have lower-than-normal levels. The
psychiatric sequelae are poorly understood, yet there is
evidence of an association with depressive symptoms. The
authors reviewed 1) the physiology of the
hypothalamic-pituitary-gonadal axis and its changes with age
in men; and 2) the evidence linking testosterone level and
major depression in men. Data on this relationship are derived
from two types of studies: observational studies comparing
testosterone levels and secretory patterns in depressed and
non-depressed men, and treatment studies using exogenous
androgens for male depression. The data suggest that
some depressed older men may have state-dependent low
testosterone levels and that some depressed men may improve
with androgen treatment.
95. Bioavailable testosterone and depressed mood in
older men: the Rancho Bernardo Study.
Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D
Department of Family and Preventive Medicine, School of
Medicine, University of California, San Diego, La Jolla
92093-0607, USA.
J Clin Endocrinol Metab 1999 Feb;84(2):573-7
A cross-sectional population-based study examined the
association between endogenous sex hormones and depressed mood
in community-dwelling older men. Participants included 856
men, ages 50-89 yr, who attended a clinic visit between
1984-87. Total and bioavailable testosterone, total and
bioavailable estradiol, and dihydrotestosterone levels were
measured by radioimmunoassay in an endocrinology research
laboratory. Depressed mood was assessed with the Beck
Depression Inventory (BDI). Levels of bioavailable
testosterone and bioavailable estradiol decreased with age,
but total testosterone, dihydrotestosterone, and total
estradiol did not. BDI scores increased with age. Low
bioavailable testosterone levels and high BDI scores were
associated with weight loss and lack of physical activity, but
not with cigarette smoking or alcohol intake. By linear
regression or quartile analysis the BDI score was
significantly and inversely associated with bioavailable
testosterone (both Ps = 0.007), independent of age, weight
change, and physical activity; similar associations were seen
for dihydrotestosterone (P = 0.048 and P = 0.09,
respectively). Bioavailable testosterone levels were 17% lower
for the 25 men with categorically defined depression than
levels observed in all other men (P = 0.01). Neither total nor
bioavailable estradiol was associated with depressed mood.
These results suggest that testosterone treatment might
improve depressed mood in older men who have low levels of
bioavailable testosterone. A clinical trial is necessary to
test this hypothesis.
96. Testosterone, gonadotropin, and cortisol
secretion in male patients with major depression.
Schweiger U, Deuschle M, Weber B, Korner A, Lammers CH,
Schmider J, Gotthardt U, Heuser I
Max-Planck-Institute of Psychiatry, Clinical Institute,
Munich, Germany.
schweiger.u@psychiatry.mu-Luebeck.de
Psychosom Med 1999 May-Jun;61(3):292-6
OBJECTIVE: Previous studies of sex hormone concentrations
in depression yielded inconsistent results. However, the
activation of the hypothalamic-pituitary-adrenal system seen
in depression may negatively affect gonadal function at every
level of regulation. The objective of this study was to
explore whether major depressive episodes are indeed
associated with an alteration of gonadal function. METHODS:
Testosterone, pulsatile LH secretion, FSH, and cortisol were
assessed using frequent sampling during a 24-hour period in 15
male inpatients with major depression of moderate to high
severity and in 22 healthy comparison subjects (age range
22-85 years).
RESULTS: An analysis of covariance model showed that after
adjustment for age only, daytime testosterone (p < .01),
nighttime testosterone (p < .05), and 24-hour mean
testosterone secretion (p < .01) were significantly lower
in the depressed male inpatients. There was also a trend for a
decreased LH pulse frequency in the depressed patients (p <
.08).
CONCLUSIONS: Gonadal function may be disturbed in
men with a depressive episode of moderate to high
severity.
97. Testosterone therapy for human immunodeficiency
virus-positive men with and without hypogonadism.
Rabkin JG; Wagner GJ; Rabkin R
New York State Psychiatric Institute and Department of
Psychiatry, College of Physicians and Surgeons, Columbia
University, New York 10032, USA.
jgr1@columbia.edu
J Clin Psychopharmacol (UNITED STATES) Feb 1999, 19 (1)
p19-27
This study was designed to evaluate the safety and
effectiveness of testosterone therapy for clinical symptoms of
hypogonadism (low libido, low mood, low energy, loss of
appetite/weight) in human immunodeficiency virus-positive men
with CD4 cell counts less than 400 cells/mm3 and deficient or
low normal serum testosterone levels. The trial consisted
of 8 weeks of open treatment with 400 mg of intramuscular
testosterone cypionate biweekly. Responders were
maintained at this dosage for another 4 weeks and then were
randomized in a double-blind, placebo-controlled, 6-week
discontinuation trial. Of the 112 men who completed at
least 8 weeks of treatment, 102 (91%) were rated as responders
on a global assessment of sexual desire/function. Of
the 34 study completers with major depressive disorder and/or
dysthymia, 79% reported significant improvement in mood at
week 8. Average weight change was a gain of 3.7 pounds, with
45% gaining more than 5 pounds. Eighty-four men entered and 77
completed the double-blind phase; of these, 78% of completers
randomized to testosterone and 13% randomized to placebo
maintained their response. No significant medical or
immunologic adverse effects were identified.
Testosterone therapy was well tolerated and effective
in ameliorating symptoms of clinical hypogonadism, and equally
so for men with and without testosterone deficiency. For
patients with major depression and/or dysthymia, improvement
was equal to that achieved with standard
antidepressants.
98. Biological actions of androgens.
Mooradian AD, Morley JE, Korenman SG
Endocr Rev 1987 Feb;8(1):1-28
Though unnecessary for life itself, androgens are essential
for the propagation of the species and for establishment and
maintenance of the quality of life of males through their
support of sexual behavior and function, muscle strength, and
sense of well-being. In carrying out its many
functions, T acts both as hormone and prohormone. It
is an outstanding example of the diverse evolutionary
utilization of a primitive informational molecule both among
and within species. Not only does T act through the
androgen receptor both unchanged and via 5 alpha-reduction,
but it acts in tissues with a high aromatase level as an
estrogen via the estrogen receptor. Furthermore, DHT,
binding to the estrogen receptor, can act as an inhibitor of
estrogen action. The products of androgen metabolism may also
play active regulatory roles in hematopoiesis and in the
regulation of certain hepatic enzymes. Table 3 summarizes the
actions of secreted T in males indicating the probable
effector hormone. While gross hypogonadism is
uncommon, mild androgen insufficiency may be much more
frequent, especially in older men, and in those receiving
treatment for chronic medical conditions. It is quite possible
that such individuals would benefit from appropriate androgen
therapy were it available, but the current forms of
replacement therapy are not very satisfactory. Better
approaches are required. With the exception of a small number
of secreted proteins, the products of transcription induced by
androgens are not, as yet, known. When the androgen receptor
gene is cloned it will be possible to identify
androgen-regulated genes and their products. It will then be
possible to design agents selectively producing specific
desired androgenic effects.
99. The effects of exogenous testosterone on
sexuality and mood of normal men.
Anderson RA, Bancroft J, Wu FC
Medical Research Council Reproductive Biology Unit, Centre
for Reproductive Biology, Edinburgh, Scotland.
J Clin Endocrinol Metab 1992 Dec;75(6):1503-7
The effects of supraphysiological levels of testosterone,
used for male contraception, on sexual behavior and mood were
studied in a single-blind, placebo-controlled manner in a
group of 31 normal men. After 4 weeks of baseline
observations, the men were randomized into two groups: one
group received 200 mg testosterone enanthate (TE) weekly by im
injection for 8 weeks (Testosterone Only group), the other
received placebo injections once weekly for the first 4 weeks
followed by TE 200 mg weekly for the following 4 weeks
(Placebo/Testosterone group). The testosterone
administration increased trough plasma testosterone levels by
80%, compatible with peak testosterone levels 400-500% above
baseline. Various aspects of sexuality were assessed using
sexuality experience scales (SES) questionnaires at the end of
each 4-week period while sexual activity and mood states were
recorded by daily dairies and self-rating scales. In
both groups there was a significant increase in scores in the
Psychosexual Stimulation Scale of the SES (i.e. SES 2)
following testosterone administration, but not with
placebo. There were no changes in SES 3, which
measures aspects of sexual interaction with the partner. In
both groups there were no changes in frequency of sexual
intercourse, masturbation, or penile erection on waking nor in
any of the moods reported. The Placebo/Testosterone
group showed an increase in self-reported interest in sex
during testosterone treatment but not with placebo. The SES 2
results suggest that sexual awareness and arousability can be
increased by supraphysiological levels of
testosterone. However, these changes are not
reflected in modifications of overt sexual behavior, which in
eugonadal men may be more determined by sexual relationship
factors. This contrasts with hypogonadal men, in whom
testosterone replacement clearly stimulates sexual
behavior. There was no evidence to suggest an
alteration in any of the mood states studied, in particular
those associated with increased aggression. We
conclude that supraphysiological levels of testosterone
maintained for up to 2 months can promote some aspects of
sexual arousability without stimulating sexual activity in
eugonadal men within stable heterosexual
relationships. Raising testosterone does not increase
self-reported ratings of aggressive feelings.
100. Hormonal replacement and sexuality in
men.
Davidson JM, Kwan M, Greenleaf WJ
Clin Endocrinol Metab 1982 Nov;11(3):599-623
Only in the last few years has the scientific study of
hormonal replacement therapy for hyposexuality begun in
earnest with the advent of appropriately controlled experiment
studies. Dose-response relationships can be demonstrated
between testosterone (T) and sexual measures, but these have
not yet been investigated in detail. Some aspects of sexual
function are maintained in the presence of androgen levels
well below the normal range, but preliminary evidence suggests
that within a normal population high levels of T are
correlated with more vigorous responses to visual erotic
stimuli. Though T (and to a greater extent free T)
declines with aging in parallel with the decline of sexual
function, these hormonal changes contribute only to a minor
extent to the behavioural change. Some non-aromatizable
androgens may be less effective in stimulating sexual
behaviour than T, but initial data on effects of
dihydrotestosterone suggests that the capacity of an androgen
to be aromatized (converted to oestrogen) is not a requirement
for its sexual action. While T apparently increases
the incidence of all types of male sexual activity, recent
data contradict the belief that it directly facilitates the
erectile mechanism in men, even though erection frequency is
greatly reduced in untreated hypogonadal men. At the
present juncture, it appears that the initial action of T may
be on libido factors which lead in turn to the stimulation of
other aspects of sexuality. Specifically, we propose
that androgen acts through stimulating genital sensations
and/or other pleasurable awareness of sexual response rather
than directly through cognitive processes such as sexual
imagery.
101. Male hormone replacement therapy including
'andropause'
Tenover J.L.
Dr. J.L. Tenover, Wesley Woods Geriatric Hospital, 1821
Clifton Road NE, Atlanta, GA 30329-5102 United States
Endocrinology and Metabolism Clinics of North America (United
States) 1998, 27/4 (969-987)
Adult onset male hypogonadism and the testosterone
deficiency of the aging male often are under-recognized
entities. The etiologies, presentation, and diagnosis of
hypogonadism and andropause in the adult male are presented.
The expected therapeutic goals, potential treatment risks, and
management of androgen replacement therapy for the adult man
are reviewed. The advantages and disadvantages of the various
androgen delivery systems currently available and under
investigation are discussed.
102. Transdermal testosterone therapy in the
treatment of male hypogonadism.
Ahmed SR, Boucher AE, Manni A, Santen RJ, Bartholomew M,
Demers LM
Department of Medicine, Milton S. Hershey Medical Center,
Pennsylvania State University, Hershey 17033.
J Clin Endocrinol Metab 1988 Mar;66(3):546-51
Five hypogonadal men were treated with transdermal
testosterone therapy, using a testosterone patch applied to
the scrotal skin. Daily application of the patch, which
contained 10 mg testosterone, produced an increase in serum
testosterone concentrations from a pretreatment value of 45
+/- 12 (+/- SE; 1.5 +/- 0.4) to 436 +/- 80 ng/dL (15.1 +/- 2.8
nmol/L; P less than 0.001) after 4 weeks of treatment. Normal
serum testosterone concentrations were achieved in all men
after 6-8 weeks of therapy and were maintained during
continued long term therapy for 9-12 months with a patch
containing 15 mg testosterone. All men reported a
subjective increase in libido and sexual function during
therapy, and three men preferred it to testosterone
injections. The serum testosterone and estradiol
levels did not rise above the normal adult male range at any
time during therapy. However, elevated serum
dihydrotestosterone (DHT) concentrations occurred during
treatment; the pretreatment DHT concentration was 95 +/- 3
ng/dL (3.3 +/- 0.1 nmol/L), and it increased to 228 +/- 40
ng/dL (7.8 +/- 1.4 nmol/L) after 4 weeks of treatment and
remained elevated thereafter. The individual mean DHT to
testosterone ratio increased from a pretreatment value of 0.2
(range, 0.1-0.3) to 0.6 (range, 0.4-0.7) after 2 weeks of
therapy and remained high thereafter. Comparison of the serum
DHT levels in patients during therapy with those in normal men
who had similar testosterone concentrations [531 +/- 62 vs.
566 +/- 72 ng/dL (18.4 +/- 2.1 vs. 19.6 +/- 2.5 nmol/L); P
greater than 0.05] revealed that the mean serum DHT
concentration was significantly higher in the patients [315
+/- 69 vs. 87 +/- 6 ng/dL (10.8 +/- 2.4 vs. 2.9 +/- 0.2
nmol/L); P less than 0.001], as was the mean DHT to
testosterone ratio [0.6 (range, 0.25- 1.1) vs. 0.16 (range,
0.09- 0.24); P less than 0.001]. The high serum DHT levels
presumably were due to increased metabolism of testosterone to
DHT by the 5 alpha-reductase in the scrotal skin. Serum 3
alpha-androstanediol glucuronide levels were not elevated in
the patients. We conclude that transdermal testosterone
therapy is an effective long term treatment for hypogonadism
in men. It is, however, associated with high serum DHT levels,
whose potential long term effects on the prostate and other
tissues need to be investigated.
103. Evidence for hyperestrogenemia as the link
between diabetes mellitus and myocardial infarction.
Phillips GB
Am J Med 1984 Jun;76(6):1041-8
The previous findings of hyperestrogenemia in men
with myocardial infarction and of a correlation between the
ratio of serum estradiol to testosterone and the
glucose-insulin-lipid defect have led to the hypothesis that
hyperestrogenemia may be responsible for the increased
incidence of atherosclerosis and its complications in patients
with diabetes. The hypothesis predicts that the mean
serum level of estradiol and the ratio of serum estradiol to
testosterone are elevated in patients with diabetes. To test
this hypothesis, the serum levels of estradiol and
testosterone were measured in 21 nonobese men with diabetes
and in 19 apparently healthy men of similar age and weight. A
higher mean serum estradiol level (p less than 0.001) and
estradiol-to-testosterone ratio (p less than 0.005) were
observed in the patients with diabetes, whereas the mean serum
testosterone level was not significantly different.
The findings are consistent with the
hypothesis.
104. Abnormalities in sex hormones are a risk
factor for premature manifestation of coronary artery disease
in South African Indian men.
Sewdarsen M, Vythilingum S, Jialal I, Desai RK, Becker
P
Department of Medicine, R.K. Khan Hospital, Durban, South
Africa.
Atherosclerosis 1990 Aug;83(2-3):111-7
The relation between sex hormone levels and myocardial
infarction was studied in a case-control study among 117
Indian men with myocardial infarction aged 30-60 years and in
107 healthy Indian male controls. The patients and controls
were further divided into subsets defined by age in decades.
In the total patient population, testosterone concentration
was significantly lower than in the controls (P less than
0.01), whilst oestradiol (P less than 0.0005) and the
oestradiol to testosterone ratio (P less than 0.0005) were
significantly higher. Multivariate stepwise logistic
regression analyses demonstrated that free testosterone index,
the free oestradiol index, and the oestradiol to testosterone
ratio were significantly associated with myocardial
infarction, and that this association was independent of age,
body mass index, smoking and serum lipids. Further
analyses according to age subsets revealed that compared to
respective control groups, patients in the 4th decade had both
significant hypotestosteronaemia and hyperoestrogenaemia,
whereas in patients of the 5th decade significant differences
in total and in the calculated free oestradiol index were
noted, and in the 6th decade a significant difference was
detected only in the free oestradiol index. Hence, we conclude
that aberrations in endogenous sex hormones are significantly
associated with myocardial infarction, and that this
association appears to be strongest in young men and
diminishes with age, suggesting that these disturbances in sex
hormones may be associated with premature manifestation of
coronary artery disease.
105. Relationship between serum sex hormones and
glucose, insulin and lipid abnormalities in men with
myocardial infarction.
Phillips GB
Proc Natl Acad Sci U S A 1977 Apr;74(4):1729-33
Fifteen patients who had had a myocardial infarction before
the age of 43 were compared with thirteen age-matched normal
subjects. Twelve of the patients and three of the controls had
a delayed glucose and insulin peak in the glucose and insulin
areas than normal curves. When the measurements of the four
patients with the largest areas under the glucose tolerance
curve were separated, significant correlations were observed
in the remaining patients and controls. The ratio in
serum of the concentrations of estradiol-17beta to
testosterone (E/T) correlated with serum glucose area
(r equals + 0.69, P is less than 0.001), insulin area (r
equals + 0.80, P is less than 0.001), and the ratio of insulin
area to glucose area (I/G) (r equals + 0.64, P is less than
0.005) in the glucose tolerance test. Serum
cholesterol concentration correlated with E/T,
insulin area, and I/G, and serum triglyceride concentration
correlated with glucose area, I/G, and serum cholesterol
concentration. The hypothesis is presented (i) that in men who
have had a myocardial infarction, an abnormality in glucose
tolerance and insulin response and elevation in serum
cholesterol and triglyceride concentrations are all part of
the same defect (glucose-insulin-lipid defect), (ii) that this
glucose-insulin-lipid defect when glucose intolerance is
present is the "mild diabetes" commonly associated with
myocardial infarction but is based on a mechanism different
from that of classical diabetes, (iii) that this
glucose-insulin-lipid defect is secondary to an elevation in
E/T, and (iv) that an alteration in the sex hormone
milieu is the major predisposing factor for myocardial
infarction.
106. Relationship between sex hormones, myocardial
infarction, and occlusive coronary disease.
Luria MH, Johnson MW, Pego R, Seuc CA, Manubens SJ, Wieland
MR, Wieland RG
Arch Intern Med 1982 Jan;142(1):42-4
An alteration in sex hormones has been considered a risk
factor for myocardial infarction. In this study, estradiol
(E2) and testosterone (T) levels were evaluated in healthy
firefighters, patients with myocardial infarction acutely and
during their convalescence, patients with no evidence of
occlusive coronary artery disease on arteriography, and
patients with chronic angina pectoris in whom there was at
least one vessel that indicated 50% occlusive coronary artery
disease. Although T levels were similar in all groups,
E2 levels were substantially higher in patients with
myocardial infarction and in patients with chronic angina
pectoris. These results support the hypothesis that
elevated estrogen levels may be a risk factor for myocardial
infarction and coronary artery disease, possibly by promoting
clotting or coronary spasm.
107. Estradiol, testosterone, apolipoproteins,
lipoprotein cholesterol, and lipolytic enzymes in men with
premature myocardial infarction and angiographically assessed
coronary occlusion.
Mendoza SG, Zerpa A, Carrasco H, Colmenares O, Rangel A,
Gartside PS, Kashyap ML
Artery 1983;12(1):1-23
A series of thirty-three Venezuelan men with premature
myocardial infarction (mean age (M +/- SEM) 45 +/- 1.5 yrs)
and with greater than 50% occlusion of at least 2 coronary
arteries, and 19 weight matched control men (age 44 +/- 2 yrs)
with normal coronary arteries on coronary angiography were
studied. The percentages of significantly abnormal (greater
than +/- 2 S.D. of controls) serum or plasma concentrations of
various measurements (in decreasing order) were:
estradiol (33%), total apolipoprotein (apo)B
(24%), estradiol/testosterone ratio (21%), low density
lipoprotein (LDL) apo B (19%), apo AI (17%), apo AI/total
plasma apo B ratio (17%), total cholesterol (17%), and
LDL-cholesterol (LDL-C) (11%). In addition, a
multivariate discriminant function analysis showed that only
estradiol, apo AI, LDL-C, estradiol/testosterone ratio and
total cholesterol were statistically significant independent
markers of myocardial infarction with occlusive coronary
disease in these patients. Both serum estradiol
and estradiol/testosterone ratio correlated positively with
plasma apo B and LDL apo B, and inversely with apo AI;
serum testosterone correlated inversely with plasma apo B (p
less than 0.05). The data suggest that circulating sex
hormones (estrogens, testosterone) are not only independent
markers of coronary disease but may be pathogenetically linked
to apo B and apo AI metabolism.
108. The association of hypotestosteronemia with
coronary artery disease in men.
Phillips GB, Pinkernell BH, Jing TY
Department of Medicine, Columbia University College of
Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center,
New York, NY.
Arterioscler Thromb 1994 May;14(5):701-6
Hyperestrogenemia and hypotestosteronemia have been
observed in association with myocardial infarction (MI) and
its risk factors. To determine whether these abnormalities may
be prospective for MI, estradiol and testosterone, as well as
risk factors for MI, were measured in 55 men undergoing
angiography who had not previously had an MI. Testosterone (r
= -.36, P = .008) and free testosterone (r = -.49, P <
.001) correlated negatively with the degree of coronary artery
disease after controlling for age and body mass index. When
the patient group was successively reduced to a final study
group of 34 men by excluding the patients with other major
disorders, the testosterone and free testosterone correlations
persisted (r = -.43, P < .02 and r = -.62, P < .001,
respectively). Neither estradiol nor the risk factors, except
for high-density lipoprotein cholesterol, correlated with the
degree of coronary artery disease in the final group.
Testosterone correlated negatively with the risk factors
fibrinogen, plasminogen activator inhibitor-1, and insulin and
positively with high-density lipoprotein cholesterol.
The correlations found in this study between
testosterone and the degree of coronary artery disease and
between testosterone and other risk factors for MI raise the
possibility that in men hypotestosteronemia may be a risk
factor for coronary atherosclerosis.
109. Testosterone induces dilation of canine
coronary conductance and resistance arteries in vivo.
Chou TM, Sudhir K, Hutchison SJ, Ko E, Amidon TM, Collins P,
Chatterjee K
Cardiovascular Research Institute, University of California
at San Francisco 94143-0124, USA.
chou@cardio.ucsf.edu
Circulation 1996 Nov 15;94(10):2614-9
BACKGROUND: Although estrogens have been shown to be
vasoactive hormones, the vascular effects of testosterone are
not well defined. Like estrogen, testosterone causes
relaxation of isolated rabbit coronary arterial segments. We
examined the vasodilator effects of testosterone in vivo in
the coronary circulation and the potential mechanisms of its
actions.
METHODS AND RESULTS: Using simultaneous intravascular
two-dimensional and Doppler ultrasound, we examined the effect
of intracoronary testosterone in coronary conductance and
resistance arteries in 10 anesthetized dogs (5 male, 5
female). We also assessed the contribution of NO,
prostaglandins, ATP-sensitive K+ channels, and classic
estrogen receptors to testosterone-induced vasodilation.
Testosterone induced a significant increase in cross-sectional
area, average coronary peak flow velocity, and calculated
volumetric coronary blood flow at the 0.1 and 1 mumol/L
concentrations. This effect was independent of sex.
Pretreatment with N omega-nitro-L-arginine methyl ester to
block NO synthesis decreased testosterone-induced increase in
cross-sectional area, average coronary peak flow velocity, and
coronary blood flow. Pretreatment with glybenclamide to assess
the role of ATP-sensitive K+ channels did not influence
testosterone-induced dilation in epicardial arteries but did
attenuate its effect in the microcirculation. Pretreatment
with indomethacin or the classic estrogen-receptor antagonist
ICI 182,780 did not alter testosterone-induced changes.
CONCLUSIONS: Short-term administration of testosterone
induces a sex-independent vasodilation in coronary conductance
and resistance arteries in vivo. Acute testosterone-induced
coronary vasodilation of epicardial and resistance vessels is
mediated in part by endothelium-derived NO. ATP-sensitive K+
channels appear to play a role in the vasodilatory effect of
testosterone in resistance arteries.
110. Testosterone causes direct relaxation of rat
thoracic aorta.
Costarella CE, Stallone JN, Rutecki GW, Whittier FC
Department of Physiology, Northeastern Ohio Universities
College of Medicine, Rootstown, USA.
J Pharmacol Exp Ther 1996 Apr;277(1):34-9
Several recent studies have provided evidence that gonadal
steroid hormones can exert acute (nongenomic) effects on both
neural and vascular tissues. This study examines the acute
effects of testosterone (T) on vascular reactivity of the rat
thoracic aorta. Aortic rings from male Sprague-Dawley (SD)
rats with (+ENDO) and without (-ENDO) endothelium were
prepared for isometric tension recording. In (+ENDO) male
aortae precontracted with phenylephrine (PE), T produced
dose-dependent relaxation from 25 microM (30.3 +/- 7.1%) to
300 microM (99.4 +/- 0.4%), whereas T vehicle (< or = 0.5%
ethanol) had no effect. Pretreatment of (+ENDO) aortae with T
(50 microM; 10 min) attenuated subsequent contractile
responses to PE. Both maximal contraction and sensitivity to
PE were reduced by T. Pretreatment of (+ENDO) aortae with both
T and N omega-nitro-L-arginine methyl ester (250 microM)
reversed in part the attenuating effects of T alone; however,
both maximal response and sensitivity to PE were still reduced
compared to control rings (without T or N
omega-nitro-L-arginine methyl ester). Pretreatment of (-ENDO)
aortae with T reduced sensitivity to PE, but had no effect on
maximal contraction. T pretreatment (50 microM; 10 min) of
both (+ENDO) female SD aortae and (+ENDO) male
testicular-feminized rat aortae reduced maximal contraction
and sensitivity to PE in both groups to a similar extent as in
(+ENDO) male SD aortae. These data suggest that T has a direct
vasodilating effect on the rat aorta, which involves
endothelium-dependent (enhanced NO release) and Bindependent
mechanisms and is gender- and intracellular androgen
receptor-independent.
111. Testosterone relaxes rabbit coronary arteries
and aorta.
Yue P, Chatterjee K, Beale C, Poole-Wilson PA, Collins
P
Department of Cardiac Medicine, National Heart and Lung
Institute, London, UK.
Circulation 1995 Feb 15;91(4):1154-60
BACKGROUND: Until menopause, women appear to be protected
from coronary heart disease. Evidence suggests that estrogen
may play a role in the protection of the cardiovascular system
by exerting a beneficial effect on risk factors such as
cholesterol metabolism and by a direct effect on the coronary
arteries. To date there has been no evidence linking
testosterone with the occurrence of coronary heart disease.
Testosterone may affect the cardiovascular system
directly, thus partially explaining the difference in the
incidence of coronary artery disease in men and premenopausal
women. The purpose of this study was to assess the
direct effect of testosterone and a number of testosterone
analogues on rabbit coronary arteries and aorta in vitro.
METHODS AND RESULTS: Rings of coronary artery and aorta of
adult male or nonpregnant female New Zealand White rabbits
were suspended in organ baths containing Krebs solution;
isometric tension then was measured. The response to
testosterone was investigated in prostaglandin F2 alpha (PGF 2
alpha)- and KCl-contracted rings. The effects of endothelium
and nitric oxide synthase, prostaglandin synthetase, and
guanylate cyclase inhibition on testosterone-induced
relaxation were investigated. The effects of ATP-sensitive
potassium channels and potassium conductance were also
assessed. Relaxing responses in the presence of aromatase
inhibition and testosterone receptor blockade were performed.
The relaxing responses to the testosterone analogues
etiocholan-3 beta-ol-17-one, epiandrosterone, 17
beta-hydroxy-5 alpha-androst-1-en-3-one, androst-16-en-3-ol,
and testosterone enanthanate were measured.
Testosterone relaxed rabbit coronary arteries and
aorta. There was no significant difference between
the relaxation effect of testosterone with or without
endothelium. Similar results were obtained from male and
nonpregnant female rabbits. The relaxing response of
testosterone in the coronary artery was significantly greater
than in the aorta. The relaxing response of
testosterone in the coronary artery was significantly reduced
by the potassium channel inhibitor barium chloride but not by
the ATP-sensitive potassium channel inhibitor glibenclamide.
The relaxing response to testosterone was greater in PGF 2
alpha-contracted rings compared with KCl-contracted rings.
Inhibitors of nitric oxide synthase, prostaglandin synthetase,
and guanylate cyclase did not affect relaxation induced by
testosterone. Inhibition of aromatase and testosterone
receptors did not affect relaxation. Testosterone did not
shift the rabbit coronary arterial calcium
concentration-dependent contraction curves, whereas verapamil
did. There were, however, significant differences in the
relaxing response to testosterone compared with testosterone
analogues. Testosterone was the most potent relaxing
agent, suggesting that there may be a structure-function
relation in the relaxing response. CONCLUSIONS:
Testosterone induces endothelium-independent relaxation in
isolated rabbit coronary artery and aorta, which is neither
mediated by prostaglandin I2 or cyclic GMP. Potassium
conductance and potassium channels but not ATP-sensitive
potassium channels may be involved partially in the mechanism
of testosterone-induced relaxation. The in vitro
relaxation is independent of sex and of a classic
receptor. The coronary artery is significantly more
sensitive to relaxation by testosterone than the aorta.
Testosterone is a more potent relaxing agent of rabbit
coronary artery than other testosterone
analogues.
112. Effect of acute testosterone on myocardial
ischemia in men with coronary artery disease.
Webb CM, Adamson DL, de Zeigler D, Collins P
Cardiac Medicine, National Heart & Lung Institute,
Imperial College School of Medicine, and Royal Brompton
Hospital, London, United Kingdom.
Am J Cardiol 1999 Feb 1;83(3):437-9, A9
The effect of acute testosterone administration on
exercise-induced myocardial ischemia was assessed in 14 men
with coronary artery disease and low plasma testosterone
concentrations in a study of randomized, double-blind,
crossover design. Testosterone increased time to 1-mm
ST-segment depression compared with placebo by 66 (15 to 117)
seconds (p = 0.016), suggesting a beneficial effect of
testosterone on myocardial ischemia in these
patients.
113. Acute anti-ischemic effect of testosterone in
men with coronary artery disease.
Rosano GM, Leonardo F, Pagnotta P, Pelliccia F, Panina G,
Cerquetani E, della Monica PL, Bonfigli B, Volpe M, Chierchia
SL
Department of Cardiology, Istituto H. San Raffaele, Roma and
Milano, Italy.
rosanog@roma.hsr.it
Circulation 1999 Apr 6;99(13):1666-70
BACKGROUND: The role of testosterone on the development of
coronary artery disease in men is controversial. The evidence
that men have a greater incidence of coronary artery disease
than women of a similar age suggests a possible causal role of
testosterone. Conversely, recent studies have shown
that the hormone improves endothelium-dependent relaxation of
coronary arteries in men. Accordingly, the aim of the
present study was to evaluate the effect of acute
administration of testosterone on exercise-induced myocardial
ischemia in men.
METHODS AND RESULTS: After withdrawal of antianginal
therapy, 14 men (mean age, 58+/-4 years) with coronary
artery disease underwent 3 exercise tests according to the
modified Bruce protocol on 3 different days (baseline and
either testosterone or placebo given in a random order). The
exercise tests were performed 30 minutes after administration
of testosterone (2.5 mg IV in 5 minutes) or placebo. All
patients showed at least 1-mm ST-segment depression during the
baseline exercise test and after placebo, whereas only 10
patients had a positive exercise test after testosterone.
Chest pain during exercise was reported by 12 patients during
baseline and placebo exercise tests and by 8 patients after
testosterone. Compared with placebo, testosterone increased
time to 1-mm ST-segment depression (579+/-204 versus 471+/-210
seconds; P<0. 01) and total exercise time (631+/-180 versus
541+/-204 seconds; P<0. 01). Testosterone significantly
increased heart rate at the onset of 1-mm ST-segment
depression (135+/-12 versus 123+/-14 bpm; P<0.01) and at
peak exercise (140+/-12 versus 132+/-12 bpm; P<0.01) and
the rate-pressure product at the onset of 1-mm ST-segment
depression (24 213+/-3750 versus 21 619+/-3542 mm Hgxbpm;
P<0.05) and at peak exercise (26 746+/-3109 versus 22
527+/-5443 mm Hgxbpm; P<0.05).
CONCLUSIONS: Short-term administration of
testosterone induces a beneficial effect on exercise-induced
myocardial ischemia in men with coronary artery disease. This
effect may be related to a direct coronary-relaxing
effect.
114. Effect of testosterone replacement therapy on
lipids and lipoproteins in hypogonadal and elderly men.
Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska
A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M,
Sadowski Z
Department of Endocrinology, Bielanski Hospital, Warszawa,
Poland.
Atherosclerosis 1996 Mar;121(1):35-43
We investigated the effects of long-term testosterone
replacement in hypogonadal and elderly men on lipids and
lipoproteins. Twenty-two men with initial serum testosterone
concentrations below 3.5 ng/ml took part in the study: 11 with
hypopituitarism (1st group) and 11 otherwise healthy elderly
men with low testosterone levels (2nd group). Testosterone
deficiency was replaced by intramuscular injections of
testosterone enanthate 200 mg every second week. Plasma levels
of sex hormones, gonadotropins, SHBG, lipids and lipoproteins
were determined before the treatment and after 3, 6 and 12
months of treatment. During the treatment serum testosterone
and estradiol increased significantly, reaching normal levels.
This was associated with a decrease in total cholesterol (from
225 +/- 16.9 mg/dl to 202 +/- 13.6 mg/dl after 6 months and
198 +/- 12.8 mg/dl after 1 year of testosterone
administration, P < 0.0001 in men with hypoandrogenism
associated with aging and from 255 +/- 12.1 mg/dl to 214 +/-
10.6 mg/dl after 6 months and 206 +/- 9 mg/dl after 1 year of
treatment, P < 0.0001 in men with hypopituitarism) and
LDL-cholesterol concentrations (from 139 +/- 12.5 mg/dl to 126
+/- 10.7 mg/dl after 6 months and 118 +/- 9.8 mg/dl after 1
year of testosterone administration, P < 0.0001 in men with
hypoandrogenism associated with aging and from 178 +/- 10.3
mg/dl to 149 +/- 10.2 mg/dl after 6 months and 140 +/- 7.3
mg/dl after 1 year of treatment, P < 0.001 in men with
hypopituitarism). However, no significant decrease in
HDL-cholesterol levels or HDL2- and HDL3-cholesterol
subfractions was observed. The effects of testosterone
replacement therapy on lipids and lipoproteins were similar in
both groups with different aetiology of hypogonadism. No side
effects on the prostate were observed. The results of
this study indicate that testosterone replacement therapy in
hypogonadal and elderly men may have a beneficial effect on
lipid metabolism through decreasing total cholesterol and
atherogenic fraction of LDL-cholesterol without significant
alterations in HDL-cholesterol levels or its subfractions
HDL2-C and HDL3-C.
115. Regulation of atrial natriuretic peptide,
thromboxane and prostaglandin production by androgen in
elderly men with coronary heart disease.
Wu S, Weng X
Beijing Red Cross Chaoyang Hospital.
Chin Med Sci J 1993 Dec;8(4):207-9
Several recent observations suggest that atrial natriuretic
peptides (ANP) can modulate steroidogenesis in isolated rat
Leydig cells and in young men. Other observations suggest that
catechol estrogen can inhibit prostaglandin (PGI2) release in
the endothelium, and we had found that androgen can
relieve angina pectoris and improve myocardial ischemia in
elderly men with coronary heart disease (CHD), possibly
through relieving coronary artery smooth muscle
spasm. Because ANP and PGI2 are vasoactive peptides
which regulate vasomotion, there must be an interaction
between steroidogenesis hormones and vasoactive peptides. We
evaluated the effects of androgen (Sustanon 250)
administration on plasma ANP, PGI2 and thromboxane (TXA2)
levels in elderly men with CHD. Thirty 60-75-year-old men with
CHD received 250 mg (1 ml) Sustanon 250 injection, and 30 age-
and sex-matched CHD patients received 1 ml saline. Plasma ANP,
PGI2, TXA2, estradiol (E2) and testosterone (T) were
determined before injection and 3 weeks thereafter. The
results showed that Sustanon 250 administration increased
plasma ANP levels, decreased TXA2 and increased PGI2 levels
significantly, and thereby improved the TXA2/PGI2 imbalance in
CHD patients (all P < 0.01). Meanwhile, serum T levels rose
(P < 0.01), but E2 levels remained unchanged, and thus the
E2/T ratio decreased (P < 0.05). Our findings
demonstrate that androgen exerts its regulatory role by
altering plasma ANP levels and the TXA2/PGI2
ratio.
116. [Antianginal and lipid lowering effects of
oral androgenic preparation (Andriol) on elderly male patients
with coronary heart disease].
[Article in Chinese]
Wu SZ, Weng XZ, Yao XX
Department of Internal Medicine, Beijing Red-Cross Chaoyang
Hospital.
Chung Hua Nei Ko Tsa Chih 1993 Mar;32(4):235-8
Sixty-two elderly men with coronary heart disease (CHD), 54
of them also suffering from hyperlipidemia, were treated with
a new oral androgenic preparation (Andriol) through crossover
study. The results showed that after oral Andriol
administration for one month, serum estradiol/testosterone
(E2/T) ratio was reduced, (P < 0.05) symptom of angina
pectoris was relieved (total effective rate, 77.4%), signs of
myocardial ischemia in ECG and Holter monitoring were improved
(total effective rate, 68.8% and 75% respectively), serum
total cholesterol (TC) and triglyceride (TG) levels were
reduced dramatically (both P < 0.001) and the
serum level of high density lipoprotein cholesterol (HDL-ch)
was increased (P < 0.05), but the blood levels of
apolipoprotein-AI (APO-AI) and B (APO-B) remained unchanged.
No significant side effect of Andriol was observed.
117. Aromatization of androstenedione to estrogen
by benign prostatic hyperplasia, prostate cancer and expressed
prostatic secretions.
Stone NN, Laudone VP, Fair WR, Fishman J
Urol Res 1987;15(3):165-7
Human prostatic tissue and expressed prostatic secretions
(EPS) from patients with benign prostatic hyperplasia (BPH)
and prostate cancer were incubated with (1 beta 3H)
androstenedione. The extent of aromatization was determined by
measuring the transfer of 3H from the 1 beta position into
water. The amount of 3H2O recovered corresponds to the
estrogens formed. Tissue from 5 patients with BPH
yielded 2.13 (+/- 1.05) pmol/mg protein/h while the EPS from
the same patients yielded 727 fmol/mg protein/h. In
patients with prostate cancer the mean formation of estrogens
was 388 fmol/mg protein/h (+/- 75). 4-hydroxy-androstenedione,
an aromatase inhibitor, successfully inhibited aromatization
in BPH and prostate cancer 53-98%.
118. Endocrine therapy for benign prostatic
hyperplasia in the 90's.
Ekman P
Department of Urology, Karolinska Hospital, Stockholm,
Sweden.
J Urol (Paris) 1995;101(1):22-5
Endocrine therapy by means of castration for benign
prostatic hyperplasia was introduced already in the middle of
the 19th century. The technique was never popularized and was
abandoned following the introduction of safe surgical
techniques. In the second half of this century, small series
of various endocrine treatments have been reported, mainly
using progestational agents. The hormone dependency of the
prostate is unique, since testosterone itself is not very
active on the prostate cells but has to be converted to 5
alpha-dihydrotestosterone, which is almost ten times as
effective an androgen in the prostate cell. By blocking this
conversion, highly specific antiandrogenic effect will be
obtained in the prostate but not in other organs of the body.
The first 5 alpha-reductase inhibitor, finasteride, has proven
effective in reducing prostate DHT. In large clinical trials,
it has shown to reduce prostate size, improve urinary flow and
reduce symptom score, statistically significantly better than
placebo. The effect is sustained over at least 3 years. In a
double-blind, randomized, placebo-controlled study over 2
years, patients were similarly improved in the finasteride
group, whereas they deteriorated in the placebo group. This
indicates that finasteride is able to halt the progression of
the natural course of benign prostatic hyperplasia.
Benign prostatic hyperplasia, generally believed to be
a stromal disease, is potentially dependent on estrogens for
its development. By blocking aromatization of
testosterone to estrogen in the prostate cells, a hypothetical
beneficial effect on the disease process should be
gained. Results from phase II-studies have been
promising. However, in placebo-controlled studies, aromatase
inhibitors did not perform better than placebo.
119. [Physiopathological aspects of the treatment
of benign prostatic hypertrophy. Role of prostatic stroma and
estrogens].
[Article in French]
Sole-Balcells F
Instituto de Urologia, Nefrologia y Andrologia, Fundacion
Puigvert Escuela de Post-Graduados, Universidad Autonoma de
Barcelona, Espagne.
J Urol (Paris) 1993;99(6):303-6
The hypothesis of the etiopathogenesis of Benign Prostatic
Hypertrophy (BPH) on the basis of stroma-epithelium
interaction is presented. The fetal prostate has its origin in
the urogenital sinus depending on the dehydrotestosterone
stimulating the stromal cells having androgenic receptors.
This stroma hyperplasia is considered to be the initial factor
in the BPH formation. The inequality in growth factors is also
relevant for its formation. Stimulating factors, especially
the epidermal growth factor (EGF) prevail on involution
factors. The stromal cell has estrogenic receptors.
The estrogens from the testosterone aromatization are the
first stimulus on the prostatic stroma on the transitional and
periurethral area stimulating the glandular epithelium causing
BPH. The knowledge of BPH etiopathogenesis will make
its rational medical treatment possible, and eventually slow
or stop its growth when therapy in its early evolutive stages
is prescribed.
120. Estrogen receptor-beta: implications for the
prostate gland.
Chang WY, Prins GS
Department of Urology, University of Illinois College of
Medicine, Chicago 60612, USA.
Prostate 1999 Jul 1;40(2):115-24
Estrogens can have profound effects on prostate growth and
differentiation. These effects were thought to be mediated by
the classical estrogen receptor; however, the discovery of a
second estrogen receptor has redefined the estrogen signaling
pathway and may have broad implications on estrogen-responsive
tissues, including the prostate. The new estrogen receptor,
named estrogen receptor-beta (ERbeta), is preferentially
expressed in the prostate and maintains some characteristics
that are different from ERalpha. Establishing the distribution
and function of ERbeta in the various estrogen-responsive
tissues is critical to defining its pharmacological and
physiological impact. Differential expression of ERbeta may
facilitate development of tissue-specific estrogen agonists
and antagonists, a goal in the treatment of diseases in
estrogen-sensitive tissues such as breast cancer. This article
reviews the current knowledge on ERbeta and its potential
impact on the prostate.
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