|
31. Endogenous testosterone, fibrinolysis, and
coronary heart disease risk in hyperlipidemic men.
Glueck CJ, Glueck HI, Stroop D, Speirs J, Hamer T, Tracy
T
Department of Pathology, University of Cincinnati College of
Medicine.
J Lab Clin Med 1993 Oct;122(4):412-20
To assess relationships of endogenous testosterone with
fibrinolysis and coronary heart disease risk factors in 55
newly referred hyperlipidemic men, we studied the
relationships of testosterone to basal fibrinolytic activity,
lipids, lipoproteins, and apolipoproteins. Testosterone
correlated positively with the major stimulator of
fibrinolysis, tissue plasminogen activator activity (r = 0.30;
p = 0.02) and correlated inversely with two independent
coronary heart disease risk factors, plasminogen activator
inhibitor activity, the major fibrinolysis inhibitor (r =
-0.33; p = 0.01), and fibrinogen (r = -0.39; p = 0.004).
Testosterone correlated inversely with plasma triglycerides (r
= -0.33; p = 0.01). Stepwise multiple regression was done with
fibrinolytic activities as the dependent variables, and age,
Quetelet Index (relative ponderosity), apolipoprotein A-I,
apolipoprotein B, triglyceride, testosterone, time of blood
sampling, and lipoprotein (a) as explanatory variables.
Testosterone was an inverse, independent predictor of
fibrinogen (p = 0.002); 53% of the variance of
fibrinogen could be accounted for by age and triglyceride
level (positive; p = 0.001, p = 0.01), and by apolipoprotein
A-I and testosterone (negative; p = 0.02, p = 0.002).
Testosterone was an independent inverse predictor of
tissue plasminogen activator antigen (p = 0.0008), with tissue
plasminogen activator antigen correlating inversely with
tissue plasminogen activator activity. Quetelet index
and apolipoprotein B wereindependent negative predictors of
tissue plasminogen activator activity (p =0.02, p = 0.03);
Quetelet index and triglycerides were independent positive
predictors of plasminogen activator inhibitor activity (p =
.0001, p = .0001) and alpha 2-antiplasmin (p = 0.0003, p =
0.009).
32. Effects of androgens on haemostasis.
Winkler UH
Zentrum fur Frauenheilkunde, Universitatsklinikum Essen,
Germany.
Maturitas 1996 Jul;24(3):147-55
Androgen deficiency is associated with an increased
incidence of cardiovascular disease. There is evidence
that thromboembolic disease as well as myocardial ifarction in
hypogonadic males are mediated by low baseline fibrinolytic
activity. Hypogonadism in males is associated with an
enhancement of fibrinolytic inhibition via increased synthesis
of the plasminogen activator inhibitor PAI 1. On the other
hand, stanozolol and danazol reduce PAI 1 and are associated
with increased fibrinolytic activity. However, in male abusers
of anabolic steroids the net effect on the haemostatic system
may change from anti- to prothrombotic; there appears to be an
individual threshold dose above which thrombogenic effects on
platelets and vasomotion may overcome the profibrinolytic
effects on PAI 1. There are numerous reports on weight-lifters
dying of atherothrombotic ischemic heart disease while abusing
anabolic steroids. Androgens are known to have profound
effects on carbohydrate and lipid metabolism. In fact, much of
the individual inconsistency of the effects of androgens on
fibrinolytic and haemostatic activity appears to be based on
the close interrelationship of these metabolic systems.
Androgens may have unfavourable effects on the HDL/LDL
cholesterol ratio, on triglyceride levels and on the
insulin/insulin-like growth factor 1 (IGF 1) system.
Hypertriglyceridemia as well as insulin resistance are both
associated with low fibrinolytic activity and increased PAI 1
levels. On the other hand, lipoprotein(a), a recently
acknowledged independent risk factor of CVD was shown to
respond favourable to androgen treatment, in men as well as in
women. In women, agonistic as well as antagonistic effects of
estrogens and progestins need to be taken into account. In
fact, estradiol may modulate testosterone effects on
haemostasis. Androgen medication in premenopausal women, such
asdanazol, was found to reduce PAI 1 suggesting an improvement
of the fibrinolytic activity. Also, in hormone replacement
therapy (HRT) androgenic progestins or complex compounds with
androgenic effects are associated with a marked reduction of
PAI 1 and an improvement of fibrinolytic activity. Further
improvement of fibrinolytic activity may be associated with
the marked decrease of lipoprotein (a) (Lp(a)) in women on
androgenic HRT. However, little is known on the
interrelationship of estrogens, 19-nortestosterone or
progesterone derivatives and testosterone. an
interrelationship that may have substantial impact on the
metabolic and particularly haemostatic net effects of a
preparation. In summary, information on the effects of
androgens on haemostasis is limited and may be particularly
incomplete due to the fact that interaction with other sex
steroids appears to be an important confounder. In any case,
there are numerous effects of synthetic androgens on the
synthesis and release of haemostatic factors, namely an
increase of the inhibitors of coagulation and a decrease of
the inhibitor of the fibrinolytic system. However, the use of
androgens in patients with congenital deficiencies of these
coagulation factors or previous events of cardiovascular
disease has yielded disappointing results. On the other hand,
particularly the reduction of fibrinolytic inhibition (PAI 1)
and Lp(a) were considered favourable effects of androgens with
regard to the risk of cardiovascular disease. Differences
between preparations withpronounced androgenic versus
antiandrogenic effects and the effect of combined preparations
need to be studied in much more detail. The
profibrinolytic effects of androgens may be of particular
interest with regard to favourable effects of HRT on
cardiovascular disease.
33. Plasminogen activator inhibitor in plasma is
related to testosterone in men.
Caron P, Bennet A, Camare R, Louvet JP, Boneu B, Sie P
Service d'Endocrinologie, Hopital Purpan, Toulouse,
France.
Metabolism 1989 Oct;38(10):1010-5
Low plasma testosterone and high levels of the rapid
inhibitor of plasminogen activator (PA-I) have been proposed
as risk factors for myocardial infarction. In this study,
the relationship between testosterone and PA-I activity levels
in middle-aged men without thrombotic antecedent was
investigated. In 54 normogonadic men (testosterone, 7.3 to
29.1 nmol/L), PA-I was related positively to body mass index
(BMI) and triglycerides and negatively to testosterone. When
these variables were controlled, the relation between PA-I and
testosterone remained significant (P less than .01). In the 41
normogonadic men with BMI less than 25, testosterone was the
only variable to influence PA-I. Fibrinolytic activity was
evaluated by the euglobulin lysis plate method and the
specific measurement of functional tissue plasminogen
activator. The basal fibrinolytic activity and the
response to venous occlusion were essentially controlled by
PA-I but were not significantly related to
testosterone. In 17 men with severe
hypogonadotrophinic hypogonadism (testosterone less than 3
nmol/L), PA-I was significantly increased (18.5 +/- 1.8 AU/mL,
mean +/- SE) compared with 9.5 +/- 0.8 AU/mL in 41
normogonadic men of normal weight (P less than .001). However,
14 hypogonadic men had a hypertriglyceridemia or a BMI greater
than 25, which could explain high PA-I levels. This
study shows that the level of the inhibitor of plasminogen
activator is partly dependent on hormonal status in men and
provides a link between independently established
epidemiologic data.
34. Testosterone increases human platelet
thromboxane A2 receptor density and aggregation
responses
Ajayi AA; Mathur R; Halushka PV
Department of Pharmacology, Medical University of South
Carolina, Charleston 29425-2251, USA.
Circulation (United States) Jun 1 1995, 91 (11)
p2742-7
BACKGROUND: The incidence of thrombotic cardiovascular
disease is greater in men than in premenopausal women.
Testosterone has been implicated as a significant risk
factor for cardiovascular disease and for acutemyocardial
infarctions and strokes in young male athletes who abuse
anabolic steroids. Thromboxane A2 (TXA2) is a
vasoconstrictor and platelet proaggregatory agent that has
been implicated in the pathogenesis of cardiovascular disease.
We therefore tested the hypothesis that testosterone regulates
the expression of human platelet TXA2 receptors.
METHODS AND RESULTS: In a double-blind, placebo-controlled,
randomized, parallel-group study, we determined the effects of
testosterone cypionate 200 mg IM given twice, 2 weeks apart,
or saline placebo in 16 healthy men. Platelet TXA2 receptor
density (Bmax) and dissociation constant (Kd) were measured by
use of the TXA2 mimetic 125I-BOP. Platelet aggregation
responses to I-BOP and to thrombin and plasma testosterone
concentrations were measured before treatment (pretreatment
phase), at 2 and 4 weeks (active phase), and again at 8 weeks
(recovery phase). Treatment with testosterone was
associated with an increase in the Bmax value from 0.95 +/-
0.13 to 2.10 +/- 0.4 pmol/mg protein (n = 9), with a peak
effect at 4 weeks (P = .001), returning to baseline by 8
weeks. There was no significant change in Bmax values in
the saline-treated group. The Kd values were unchanged.
Testosterone treatment was associated with a significant
increase in the maximum platelet aggregation response to I-BOP
(P < .001) at 4 weeks and returned to baseline at 8 weeks.
The EC50 values were not significantly changed. Platelet TXA2
receptor density was positively correlated (r = .56, P <
.001, n = 32 measurements) with pretreatment (endogenous)
plasma testosterone levels (range, 215 to 883 ng/dL) but not
Kd.
CONCLUSIONS: Testosterone regulates the expression
of platelet TXA2 receptors in humans. This may contribute to
the thrombogenicity of androgenic steroids.
35. Endocrine environment of benign prostatic
hyperplasia: prostate size and volume are correlated with
serum estrogen concentration.
Suzuki K, Ito K, Ichinose Y, Kurokawa K, Suzuki T, Imai K,
Yamanaka H, Honma S
Department of Urology, School of Medicine, Gunma University,
Japan.
Scand J Urol Nephrol 1995 Mar;29(1):65-8
Estrogen plays an important role in the development of
benign prostatic hyperplasia (BPH), as has been shown in both
experimental and clinical studies. T determine the endocrine
environment of BPH, serum total testosterone (Total-T), free
testosterone (Free-T), and estradiol (E2) conceptions were
measured, and the relationship between these levels and
prostate size and volume was analyzed. Blood samples were
collected from subjects who attended the mass screening for
prostate disease performed by our institute. No significant
correlations were found between Total-T levels, Free-T levels,
and prostate size, as determined by digital rectal
examination. However, E2 levels and the ratios for E2 levels
and the ratios for E2/Total-T and E2/Free-T were significantly
correlated with prostate size. To confirm these relationships,
prostate volume was calculated from transrectal
ultrasonographic images. E2 levels and these two
ratios were, indeed, highly correlated with prostate volume.
These results suggest that an estrogen-dominant environment
plays an important role in the development of
BPH.
36. A prospective study of plasma hormone levels,
nonhormonal factors, and development of benign prostatic
hyperplasia.
Gann PH, Hennekens CH, Longcope C, Verhoek-Oftedahl W,
Grodstein F, Stampfer MJ
Division of Preventive Medicine, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts.
Prostate 1995 Jan;26(1):40-9
We assessed the relation of plasma hormone levels and
nonhormonal factors with subsequent occurrence of surgical
treatment for benign prostatic hyperplasia (BPH) among
participants in the Physicians' Health Study. Frozen plasma
samples, collected at the study onset, were available for 320
men who developed surgically treated BPH up to 9 years later
and for 320 age-matched controls. Plasma testosterone (T),
dihydrotestosterone (DHT), androstenedione, estradiol (E2),
and estrone (E1) were measured for each case-control pair. In
unadjusted analyses, none of the hormones or hormone ratios
were associated with BPH; for example, for T and E2 the odds
ratios (OR) comparing the highest quintile (Q5) with the
lowest (Q1) were 0.74 (95% CI = 0.42, 1.30) and 1.07 (95% CI =
0.51, 2.22), respectively. However, in multivariate analyses
controlling diastolic blood pressure, exercise, alcohol, E1,
and DHT:T ratio, we observed a strong trend for increasing
risk across quintiles for E2 (Q5 vs. Q1 OR = 3.56, P trend =
0.009), and a weak inverse trend for E1 (Q5 vs Q1 OR = 0.51, P
trend = 0.07). The excess risk associated with E2 was confined
to men with relatively low androgen levels. Three nonhormonal
factors previously suspected as risk factors were
independently associated with surgical BPH in these data. The
OR for a 1-mm Hg difference in diastolic blood pressure was
1.04 (95% CI = 1.01, 1.07). Alcohol use and infrequent
exercise were inversely associated with risk of BPH surgery;
however, risk estimates were not consistent across categories
of exercise and alcohol frequency. Our results indicate that
normal variation in circulating androgen levels does not
influence development of BPH, but that variation in estrogen
levels might be important.
37. Estrogen formation in human prostatic tissue
from patients with and without benign prostatic
hyperplasia.
Stone NN, Fair WR, Fishman J
Prostate 1986;9(4):311-8
Prostatic tissue removed at the time of cystoprostatectomy
was separated into periurethral and peripheral zones.
Homogenized tissue was incubated with [1,2,6,7(3)H]
androstenedione in the presence or absence of an aromatase
inhibitor, 4-hydroxyandrostenedione (4-OHAD) and a 5
alpha-reductase inhibitor 4-MA
(N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane 17
beta-carboxamide). Estrogen formation was determined by
reverse isotope dilution of [3H] estrone and [3H] estradiol
and crystallization to constant specific activity. Control
incubations were carried out in parallel utilizing heated
prostatic tissue. Total estrogens produced in the periurethral
zone in patients with benign prostatic hyperplasia (BPH) was
223 fmol/mg protein/hr (SE +/- 57) compared to 102 fmol (SE
+/- 17) in patients without BPH. Estrogen formation in the
peripheral zone was 175 fmol (SE +/- 69) and 105 fmol (SE +/-
26) in patients with and without BPH, respectively. The
prostatic aromatase exhibits Michaelis-Menton kinetics with an
apparent Km of 90 nM. 4-OHAD inhibited aromatization in the
prostatic tissue by 57-93%. Aromatization was also strongly
inhibited by 4-MA, indicating that 4-MA is a potent aromatase
as well as a 5 alpha-reductase inhibitor in this tissue. These
results suggest that aromatization of androgens to estrogens
in the human prostate proceeds at a substantial rate and that
local estrogen formation could preexist and be a factor in the
etiology of BPH and prostatic cancer.
38. Expression of estrogen receptor in diseased
human prostate assessed by non-radioactive in situ
hybridization and immunohistochemistry.
Ehara H; Koji T; Deguchi T; Yoshii A; Nakano M; Nakane PK;
Kawada Y
Department of Urology, Gifu University School of Medicine,
Japan.
Prostate 1995 Dec;27(6):304-13
To understand the role of estrogen in the pathogenesis of
benign prostatic hyperplasia, expressions of estrogen receptor
(ER) mRNA and ER protein by in situ hybridization and by
immunohistochemistry, respectively, were investigated in human
prostatic tissues. In non-malignant region, ER mRNA and ER
protein were found in cytoplasm and nucleus, respectively, of
stromal cells, but not in glandular epithelial and basal
cells. In benign regions, ER mRNA/ER protein positive cells
were found in fibromyoadenomatous and myoadenomatous
hyperplasia, but not in adenomatous hyperplasia. A striking
feature was periacinar arrangement of ER mRNA/ER protein
positive stromal cells in all prostate carcinoma treated with
androgen withdrawal. The ER mRNA/ER protein positive cells
were immunohistochemically identified as fibroblasts,
myoblasts, and smooth muscle cells. These results
indicate that stromal cells are the primary target of estrogen
in prostate, and that androgen withdrawal upregulates the
expression of ER gene.
39. Roles of estrogen and SHBG in prostate
physiology.
Farnsworth WE
Department of Urology, Northwestern University Medical
School, Chicago, Illinois, USA.
Prostate 1996 Jan;28(1):17-23
Heretofore, the function of estrogen in the prostate, other
than as an antiandrogen, has been unclear. In this review of a
growing fund of knowledge about both estrogen and the plasma
protein, sex hormone-binding globulin (SHBG), or
testosterone-estradiol binding globulin (TeBG), the
hypothesis is proposed that estrogen, mediated by SHBG,
participates with androgen in setting the pace of prostatic
growth and function. It is suggested that the estrogen not
only directs stromal proliferation and secretion, but also,
through IGF-I, conditions the response of the epithelium to
androgen.
40. [The role of tissue steroids in benign
hyperplasia and prostate cancer].
[Article in German]
Voigt KD, Bartsch W
Universitatskrankenhaus Eppendorf, Abteilung fur klinische
Chemie, Hamburg.
Urologe [A] 1987 Nov;26(6):349-57
This paper presents a large body of data relating to benign
prostatic hyperplasia, which have been derived from
fundamental endocrinological research. For the urologist, the
data open up interesting aspects of the pathomorphology of
prostatic hyperplasia. The most interesting findings can be
summed up as follows: 1. Testosterone is the circulating
androgenic prohormone that mediates the intracellular message
leading to androgen secretion, though by way of its metabolite
dihydrotestosterone, which is really the active substance. 2.
This metabolic conversion is catalyzed by 5 alpha-reductase,
which is predominantly a stromal enzyme. 3. The
estrogen metabolism in the stromal cells of the prostate may
be associated with the abnormal growth of the
prostate. 4. In the presence of benign prostatic
hyperplasia dihydrotestosterone and 17 beta-estradiol
accumulate in the nuclei of the stromal cells. 5.
Adrenal androgens are also metabolized in the human prostate,
yielding some substances with androgenic and some with
estrogenic potency. 6. Changes in sex hormone binding
globulins (SHBG) are found with age whether benign prostatic
hyperplasia is present or not. It is therefore
questionable whether it has any influence on the development
of prostatic hyperplasia. 7. Although in some cases it
is not yet possible to determine whether the findings
presented in this paper have any causal significance, the data
can be used as a rational basis for hormonal treatment of
prostatic disease.
41. Estradiol causes the rapid accumulation of cAMP
in human prostate.
Nakhla AM; Khan MS; Romas NP; Rosner W
Department of Medicine, St. Luke's/Roosevelt Hospital Center,
New York, NY 10019.
Proc Natl Acad Sci U S A 1994 Jun
7;91(12):5402-5
Androgens are widely acknowledged to be central to the
pathogenesis of benign prostatic hypertrophy (BPH). However,
BPH increases in prevalence as men age, at precisely
the stage of life when plasma androgens are decreasing. The
decrease in total plasma androgens is amplified by an
age-related increase in plasma sex hormone-binding globulin
(SHBG) that results in a relatively greater decrease in free
androgens than in total androgens. In addition,
estrogens have long been suspected to be important in BPH, but
a direct effect on the human prostate has never been
demonstrated. We present data that are consistent with a role
for estradiol, and for a decrease in androgens and an increase
in SHBG, in the pathogenesis of BPH. We show that
estradiol, but not dihydrotestosterone, acts in concert with
SHBG to produce an 8-fold increase in intracellular cAMP in
human BPH tissue. This increase is not blocked by an
antiestrogen and is not provoked by an estrogen
(diethylstilbestrol) that does not bind to SHBG, thus
excluding the classic estrogen receptor as being operative in
these events. Conversely, dihydrotestosterone, which blocks
the binding of estradiol to SHBG, completely negates the
effect of estradiol. Finally, we demonstrate that the
SHBG-steroid-responsive second-messenger system is primarily
localized to the prostatic stromal cells and not to the
prostatic epithelial cells. Thus, we have shown a
cell-specific, powerful, nontranscriptional effect of
estradiol on the human prostate.
42. The effect of extracts of the roots of the
stinging nettle (Urtica dioica) on the interaction of SHBG
with its receptor on human prostatic membranes.
Hryb DJ, Khan MS, Romas NA, Rosner W
Department of Medicine, St. Luke's/Roosevelt Hospital Center,
New York, N.Y. 10019.
Planta Med 1995 Feb;61(1):31-2
Extracts from the roots of the stinging nettle (Urtica
dioica) are used in the treatment of benign prostatic
hyperplasia. The mechanisms underlying this treatment have not
been elucidated. We set out to determine whether specific
extracts from U. dioica had the ability to modulate the
binding of sex hormone-binding globulin to its receptor on
human prostatic membranes. Four substances contained in U.
dioica were examined: an aqueous extract; an alcoholic
extract; U. dioica agglutinin, and stigmasta-4-en-3-one. Of
these, only the aqueous extract was active. It inhibited the
binding of 125I-SHBG to its receptor. The inhibition was dose
related, starting at about 0.6 mg/ml and completely inhibited
binding at 10 mg/ml.
43. Effects of stinging nettle root extracts and
their steroidal components on the Na+,K(+)-ATPase of the
benign prostatic hyperplasia.
Hirano T, Homma M, Oka K
Department of Clinical Pharmacology, Tokyo College of
Pharmacy, Japan.
Planta Med 1994 Feb;60(1):30-3
The effects of organic-solvent extracts of Urtica dioica
(Urticaceae) on the Na+,K(+)-ATPase of the tissue of benign
prostatic hyperplasia (BPH) were investigated. The membrane
Na+,K(+)-ATPase fraction was prepared from a patient with BPH
by a differential centrifugation of the tissue homogenate. The
enzyme activity was inhibited by 10(-4)-10(-5) M of ouabain.
The hexane extract, the ether extract, the ethyl acetate
extract, and the butanol extract of the roots caused
27.6-81.5% inhibition of the enzyme activity at 0.1 mg/ml. In
addition, a column extraction of stinging nettle roots using
benzene as an eluent afforded efficient enzyme inhibiting
activity. Steroidal components in stinging nettle roots, such
as stigmast-4-en-3-one, stigmasterol, and campesterol
inhibited the enzyme activity by 23.0-67.0% at concentrations
ranging from 10(-3)-10(-6) M. These results suggest that some
hydrophobic constituents such as steroids in the stinging
nettle roots inhibited the membrane Na+,K(+)-ATPase activity
of the prostate, which may subsequently suppress prostate-cell
metabolism and growth.
44. The inhibiting effects of Urtica dioica root
extracts on experimentally induced prostatic hyperplasia in
the mouse.
Lichius JJ, Muth C
Institut fur Pharmazeutische Biologie, Philipps-Universitat,
Marburg, Germany.
Planta Med 1997 Aug;63(4):307-10
Extracts of stinging nettle roots (Urtica dioica L.
Urticaceae) are used in the treatment of benign prostatic
hyperplasia (BPH). We established a BPH-model by directly
implanting an urogenital sinus (UGS) into the ventral prostate
gland of an adult mouse. Five differently prepared stinging
nettle root extracts were tested in this model. The 20%
methanolic extract was the most effective with a 51.4%
inhibition of induced growth.
45. Severe sexual impairment produced by morbid
obesity. Report of a case.
Blum I; Marilus R; Barasch E; Sztern M; Bruhis S; Kaufman
H
Department of Medicine C, Rokach (Hadassah) Hospital,
Tel-Aviv, Israel.
Int J Obes (ENGLAND) 1988, 12 (3) p185-9
A 45-year-old man, was admitted for investigation of severe
sexual impairment. During 20 years of marriage, he had had no
normal sexual intercourse and the couple was childless.
Physical examination disclosed a severely obese man (weight
300 kg, height 1.75 m), with a relatively small and
invaginated penis and small (5 ml) soft testes. Laboratory
examinations disclosed the following: low serum testosterone
(1 ng/ml), with a reduced response to HCG (3.8 ng/ml). Sex
hormone binding globulin was at the lower limit of normal
(0.38 microgram/dl), serum free testosterone was low (0.98% of
total testosterone) as well as non-SHBG bound testosterone
(22% of total testosterone). Daily total urinary estrogen
excretion was increased (107 micrograms), the plasma estrone
(78 pg/ml) and estradiol (74 pg/ml) were elevated. The
gonadotropins were normal and responded adequately to LRH.
Plasma growth hormone was decreased, prolactin, T4 and adrenal
steroids were normal and responded normally to stimuli and
inhibitors. Chromosomal constitution was 46XY. Thus,
in this man the marked obesity produced a significant increase
in estrogens which subsequently induced a severe decrease in
testosterone and its free counterpart in excessive
impairment of sexual function.
46. The Testosterone Syndrome
Shippen and Fryer
1998 M. Evans and Company New York, NY
No abstract.
47. Endocrine aspects of ageing in the male.
Gooren LJ
Department of Endocrinology, Hospital of the Vrije
Universiteit, Amsterdam, The Netherlands.
lgooren@inter.nl.net
Mol Cell Endocrinol 1998 Oct 25;145(1-2):153-9
There is a statistical decline of testosterone levels in
ageing men, most manifest in free testosterone. While this
fall is only moderate, ageing men show clinical signs of
hypogonadism (loss of muscle mass/strength, reduction in bone
mass and an increase in visceral fat). This might represent
not only a fall but (also) an impairment of the biological
action of androgens in target organs. The first small scale
studies of androgen supplement administration in ageing men
were not disappointing. Anticipated risks lie with the
prostate and the cardiovascular system. The risks with regard
to prostate disease are often over-rated. The question remains
how the segment of the ageing male population possibly
benefiting from androgen supplements, can be identified. For
the treatment of postmenopausal women 'designer oestrogens'
are being developed; similarly, designer androgens retaining
beneficial anabolic effects with elimination of harmful
effects on the prostate and cardiovascular system, could be
devised.
48. [Sexual hormones in ageing males (author's
transl)]
Kley HK; Nieschlag E; Wiegelmann W; Kruskemper HL
Aktuelle Gerontol (Germany, West) Feb 1976, 6 (2)
p61-7
Alterations of sexual hormones in plasma of ageing males
occur between the 50th and 60th year of life with individual
variations: 1. Decreased values of testosterone in plasma and
a poor response to gonadotrophins demonstrate a diminished
synthesizing capacity of the testes in old men. 2. The
decreased testosterone plasma values are followed by an
increase in LH. The response of the anterior pituitary gland
to LH-RH stimulation in old men is normal. 3. Under
basal conditions estrone as well as estradiol plasma
concentrations increase significantly with age because of
increased conversion from androgens. 4. Parallel to
estrogen plasma values an increased concentration of the
sexual hormone binding globulin (SHBG) is found, resulting in
a steep decrease of the free (= active) testosterone fraction.
5. Decreased testosterone, which is more strongly
bound to SHBG and increased estrone and estradiol plasma
values result in an androgen/estrogen imbalance in old men.
(25 Refs.)
49. Direct effects of estrogens on the endocrine
function of the mammalian testis.
Moger WH
Can J Physiol Pharmacol 1980 Sep;58(9):1011-22
This article reviews literature relevant to the view that
estradiol (E2) synthesized in the testis acts locally to
modify testosterone secretion. Despite a lack of convincing
evidence from in vitro experiments, in vivo experiments with
intact and hypophysectomized animals have demonstrated that
estrogens can inhibit testosterone secretion by acting
directly on the testis. Reduced testosterone
production in estrogen-treated animals probably results from
reduced 17 alpha-hydroxylase and (or) C17-C20 lyase activity.
Estrogen-inhibited steroidogenesis may result from estrogen
binding to high affinity--low capacity estrogen receptors.
Besides being an estrogen target tissue, the testis produces
E2; the cellular site of testicular E2 synthesis remains
controversial. Recent studies indicate that E2 is synthesized
primarily in the Sertoli cells of neonatal rats and in the
Leydig cells of older rats. Follicle-stimulating hormone and
human chorionic gonadotropin (hCG) increase testicular
aromatase activity and E2 concentrations in neonatal and older
rats, respectively. An increase in testicular E2
concentrations, following hCG administration, may be one
mechanism by which testosterone synthesis becomes desensitized
to subsequent hCG stimulation. However, whether
gonadotropin-stimulated testicular E2 synthesis is part of a
physiologically relevant "short" feedback loop that
participates in the regulation of testosterone synthesis
remains to be determined.
50. Direct inhibitory effect of estrogen on the
human testis in vitro.
Namiki M, Kitamura M, Nonomura N, Sugao H, Nakamura M,
Okuyama A, Utsunomiya M, Itatani H, Matsumoto K, Sonoda
T
Department of Urology, Osaka University Medical School,
Japan.
Arch Androl 1988;20(2):131-5
The direct inhibitory effects of estrogens on human
testicular functions were investigated with a testicular organ
culture technique. 125I-labeled human chorionic gonadotropin
(125I-hCG) bindings in testes cultured in media containing
diethylstilbestrol diphosphate (DESDP) began to dose-relatedly
decrease a day after the start of the culture, and this
decrease remained relatively constant during the 5-day
culture. On the other hand, testosterone produced by the
cultured testes time-relatedly decreased during the 5-day
culture. From the above results it may be concluded
that the direct inhibitory effect of estrogens on human
testicular androgen production consists of not only the loss
of testicular hCG receptors but also of other mechanisms at a
distal step from hCG receptor activation.
51. The acute effect of estrogens on testosterone
production appears not to be mediated by testicular estrogen
receptors
Damber JE; Bergh A, Daehlin L, Ekholm C, Selstam G, Sodergard
R
Department of Physiology, University of Umea, 90187,
Umea.
Mol Cell Endocr 31 (1). 1983. 105-116.
Scatchard binding analysis was performed to measure the
cytoplasmic estrogen receptor in the testis of rats. After
treatment of rats with the antiestrogen tamoxifen no estrogen
receptor binding was found in testicular low speed supernatant
between 12 and 96 h after treatment. Such tamoxifen-treated
rats were used to study the acute effect of estrogens on
testosterone secretion, both in vivo and in vitro.
Injection of estradiol benzoate (50 .mu.g, 24 h prior
to experiment) resulted in a significant depression of basal
and LH[lutropin]-stimulated plasma testosterone levels in
control rats and this effect was unchanged in
tamoxifen-pretreated rats. In vitro,
estradiol-17.beta. also inhibited the LH-induced rise in
testosterone secretion by isolated testicular interstitial
cells. This inhibition was not affected if the rats had
been pretreated with tamoxifen. The inhibitory
effects of exogenous estrogens on testicular testosterone
production are probably not mediated by the estrogen
receptor.
52. The effect of testosterone aromatization on
high-density lipoprotein cholesterol level and postheparin
lipolytic activity.
Zmuda JM; Fahrenbach MC; Younkin BT; Bausserman LL; Terry RB;
Catlin DH; Thompson PD
Department of Medicine, Miriam Hospital, Providence,
RI.
Metabolism (United States) Apr 1993, 42 (4)
p446-50,
Stanozolol, an oral 17 alpha-alkylated androgen,
increases hepatic triglyceride lipase activity (HTGLA) and
decreases high-density lipoprotein cholesterol (HDL-C) levels,
whereas intramuscular testosterone has comparatively little
effect. In the present study, we tested the hypothesis that
aromatization of androgen to estrogen blunts the lipid and
lipase effects of exogenous testosterone. Fourteen male
weightlifters received testosterone enanthate (200 mg/wk
intramuscularly), the aromatase inhibitor testolactone (250 mg
four times per day), or both drugs together in a randomized
cross-over design. Serum testosterone level increased
during all three drug treatments, whereas estradiol level
increased only with testosterone alone (+47%, P < .05),
demonstrating that testolactone effectively inhibited
testosterone aromatization. Testosterone decreased HDL-C(-16%,
P < .05), HDL2-C(-23%, NS), and apoprotein (apo) A-I (-12%,
P < .05) levels, effects that were
consistently but not significantly greater with simultaneous
testosterone and testolactone administration (HDL-C, -20%;
HDL2-C, -30%; apo A-I, -15%; P < .05 for all). In contrast,
both testosterone regimens decreased HDL3-C levels by 13% (P
< .05 for both). HTGLA increased 21% during testosterone
treatment and 38% during combined testosterone and
testolactone treatment (P < .01 for both). Lipoprotein
lipase activity (LPLA) increased only during combined
testosterone and testolactone treatment (+31%, P < .01),
suggesting that estrogen production may counteract the
effects of testosterone on LPLA. Testolactone alone
had little effect on any lipid, lipoprotein, apoprotein, or
lipase concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
53. Effects of estradiol administration in vivo on
testosterone production in two populations of rat Leydig
cells
Keel B.A.; Abney T.O.
Dep. Endocrinol., Med. Coll. Georgia, Augusta, GA 30912
United States
Biochemical and Biophysical Research Communications (United
States) 1982, 107/4 (1340-1348)
The effects of in vivo administration of estradiol on
isolated rat testicular Leydig cells were investigated. Adult
intact rats were injected s.c. with 50 mug/100 g B.W. of
17beta-estradiol or vehicle twice daily for 2 days. Twelve
hours after the last injection, collagenase dispersed
interstitial cells were obtained and Leydig cells were
subsequently isolated on metrizamide gradients. Two distinct
peaks of specific sup 1sup 2sup 5I-hCG binding corresponding
to population I and II Leydig cells were observed. The hCG
binding profile was unaltered as a result of estradiol
treatment. Although twice as much testosterone was produced in
population II, the responsiveness of the two populations to
hCG or dbcAMP in vitro was identical (11- to 13-fold
increase). Estradiol administration in vivo resulted in a
33-48% decrease in basal and stimulated testosterone
production in both populations. These data indicate
for the first time that both population I and II Leydig cells
are sensitive to the direct inhibitory effects of estrogens on
testosterone production. This inhibitory effect was
not associated with an alternation in hCG binding capacity in
either population. Therefore, we conclude that no
functional difference exists between the two populations of
Leydig cells with respect to the action of
estrogens.
54. Tetrahydroisoquinoline alkaloids mimic direct
but not receptor-mediated inhibitory effects of estrogens and
phytoestrogens on testicular endocrine function. Possible
significance for Leydig cell insufficiency in alcohol
addiction.
Stammel W, Thomas H, Staib W, Kuhn-Velten WN
Abteilung Physiologische Chemie, Universitat Ulm, F.R.
Germany.
Life Sci 1991;49(18):1319-29
Possible effects of various tetrahydroisoquinolines (TIQs)
on rat testicular endocrine function were tested in vitro in
order to prove whether these compounds, some of which have
been claimed to accumulate in alcoholics, may be
mediators of the development of Leydig cell insufficiency, a
well-known side-effect of ethanol ingestion. TIQ
effects on different levels of regulation of testis function
were compared in vitro with estrogen effects, since both
classes of compounds have structural similarities.
Gonadotropin-stimulated testosterone production by testicular
Leydig cells was inhibited by tetrahydropapaveroline and
isosalsoline, the IC50 values (30 microM) being comparable to
those of estradiol (3 microM), 2-hydroxyestradiol (10 microM),
and the phytoestrogens, coumestrol (15 microM) and genistein
(7 microM); salsolinol (85 microM) and salsoline (240 microM)
were less effective, and salsolidine was ineffective. None of
these TIQs interacted significantly with testicular estrogen
receptor as analyzed by estradiol displacement.
However, tetrahydropapaveroline, isosalsoline and
salsolinol competitively inhibited (Ki 130-150
microM) substrate binding to cytochrome P450XVII, one
key enzyme of androgen biosynthesis, with similar
efficiency as the estrogens did (Ki 50-110 microM);
salsoline and salsolidine were again much less effective.
Since the efficient TIQ concentrations in this system are
identical with those reported to generate central-nervous
effects, it is concluded that certain TIQs may amplify
peripheral inhibitory effects of ethanol on testicular
endocrine function by their interaction with at least one
enzyme of the androgen biosynthetic pathway.
55. Levels of sex hormone-binding globulin and
corticosteroid-binding globulin mRNAs in corpus luteum of
human subjects: correlation with serum steroid hormone
levels.
Misao R, Nakanishi Y, Fujimoto J, Iwagaki S, Tamaya T
Department of Obstetrics and Gynecology, Gifu University
School of Medicine, Japan.
[Medline record in process]
Gynecol Endocrinol 1999 Apr;13(2):82-8
To understand regulation of the function of human ovarian
corpus luteum by sex steroid-binding proteins, the levels of
luteal intracellular sex hormone-binding globulin (SHBG) and
corticosteroid-binding globulin (CBG) mRNAs and serum steroid
hormones were simultaneously determined. The
expression of SHBG and CBG mRNAs was detected in all samples
analyzed. SHBG mRNA level was positively correlated with serum
estradiol-17 beta level (p < 0.05), but not with serum
progesterone level. There was a positive correlation
between SHBG mRNA level and serum estradiol-17
beta/progesterone ratio (p < 0.01). On the other hand, CBG
mRNA level was positively correlated with serum estradiol-17
beta and progesterone level (p < 0.01 and p < 0.01,
respectively). There was no correlation between CBG mRNA level
and serum estradiol-17 beta/progesterone ratio. SHBG and CBG
mRNA levels were not correlated with the levels of serum
testosterone, free testosterone or cortisol. These
findings suggest that the synthesis of luteal SHBG and CBG is
complexly regulated by estrogen and progesterone, and that
SHBG and CBG interact with estrogen and progesterone,
respectively, for luteal steroidal activity.
56. Effects of ethinyloestradiol on plasma levels
of pituitary gonadotrophins, testicular steroids and sex
hormone binding globulin in normal men.
Van Look PF, Frolich M
Clin Endocrinol (Oxf) 1981 Mar;14(3):237-43
Daily measurements of plasma FSH, LH, prolactin,
testosterone, 17 beta-oestradiol and sex hormone binding
globulin (SHBG) activity were made in eight healthy, normal
men during treatment with oral ethinyloestradiol (EE2) in a
dose of 30 micrograms/day for 5 days following a 5-day control
period. No significant changes in plasma levels of
FSH and prolactin during oestrogen treatment occurred. In
contrast, plasma concentrations of both LH and testosterone
showed a biphasic pattern. Following an initial suppression
during the first 3 days of oestrogen treatment both LH and
testosterone increased again to baseline values despite
continuation of oestrogen administration. The
secondary rise of both hormones was associated with (and
probably resulted from) a nearly 100% increase in the plasma
concentration of SHBG binding activity, and hence reduction of
free testosterone index (FTI). Unlike testosterone,
plasma 17 beta-oestradiol during EE2 administration did not
show a biphasic pattern, but a progressive decline that was
positively correlated with the fall in FTI. The
rapidity of onset and magnitude of the observed rise in SHBG
levels emphasizes the need for measurement of this binding
protein (or the free testosterone fraction) in studies on
feedback regulation of gonadotrophins employing exogenous EE2
in human males. The observed increase of SHBG to
supraphysiological values suggests that currently employed EE2
doses in such studies may be less 'physiologic' than is often
assumed.
57. Changes in testosterone muscle receptors:
effects of an androgen treatment on physically trained
rats.
Bricout VA; Germain PS; Serrurier BD; Guezennec CY
IMASSA-CERMA, Departement de Physiologie Systemique, Bretigny
sur Orge, France.
Cell Mol Biol (Noisy-le-grand) 1994
May;40(3):291-4
From results obtained in physiological investigations
carried out on various tissues sensitive to androgens, it
seems that the hormonal receptivity can reflect changes in the
endocrine status and specific response of a tissue.
The purpose of the present investigation was to test
whether an androgen treatment could modify the receptivity to
testosterone of the skeletal muscle and myocardium of
endurance trained rats. The experiment extended over
8 weeks, and animals received injections of delayed
testosterone heptylate every seven days. The myocardium and
two skeletal muscles with opposed functions and typology were
examined: the extensorum digitorum longus (EDL), and the
soleus (SOL). Results obtained using techniques based upon the
radio-competition principles provided information on the
testosterone-receptor binding. The binding curves were plotted
up to the saturating concentration of tritiated mibolerone, a
synthetic androgen specific of androgen receptors. The
quantity of receptors, calculated at the specific saturation
plateau is expressed in fmol/mg protein. Results show that
contractile muscular activity always increased the quantity of
receptors whereas the steroid treatment decreased it. Thus for
EDL and SOL of control trained rats the quantity of receptors
was 0.78 and 0.82 fmol/mg protein, respectively, compared to
0.23 and 0.43 fmol/mg protein for sedentary
testosterone-treated rats. The same "contractile activity"
effect was observed on the myocardium but enhanced with values
of 1.63 fmol/mg protein for control trained rats versus 0.30
fmol/mg protein for sedentary testosterone-treated rats.
The receptivity to testosterone of the skeletal muscle
and myocardium changes under the effect of an androgen
treatment.
58. Steroid hormones and neurotrophism:
relationship to nerve injury.
Jones KJ
Department of Biological Chemistry and Structure, University
of Health Sciences, Chicago Medical School, Illinois
60064.
Metab Brain Dis (United States) Mar 1988, 3 (1)
p1-18
Current data on the neurotrophic effects of steroid
hormones suggest that, in brain and spinal cord regions
containing receptor systems, steroids act at the
level of RNA and protein synthesis to effect metabolic changes
associated with nerve-cell survival, elaboration/maintenance
of dendritic and axonal processes, synaptogenesis, and
neurotransmission. While many of these effects appear to be
associated with the neuroanatomical systems involved in the
endocrine and behavioral aspects of reproduction, evidence
does exist for similar neurotrophic effects outside the
reproductive sphere. Both estrogens and androgens
appear to exert this stimulatory, growthlike effect on target
neurons. The effects of progesterone are not
discussed in this review because relatively little information
is available regarding the independent effects of progesterone
on the brain . We have just completed a study (Jones
et al., 1987b) which suggests that progesterone may act
independently in the brain to affect protein
synthesis. A number of conclusions concerning the
mechanism of steroid action in producing trophic effects on
neurons can be drawn. First, the time course of hormone action
is similar to that found in nonneural target tissue, such as
the uterus. Second, steroid hormones act on neurons through
receptor-mediated genomic activation. Third, this effect on
the genome appears to be at the level of both transcription
and translation. Fourth, there is brain -region specificity in
the gene products resulting from steroid hormone
administration. Finally, short-term exposure to
estrogens or androgens generally results in an anabolic
response within target neurons. The brain and spinal cord,
injured either by disease or by experimentally induced trauma
, is responsive in a reparative manner to exogenous and/or
endogenous gonadal steroid hormones. The mechanism
underlying this therapeutic role of steroids on damaged
neurons is not known but has been postulated to involve direct
action of steroid hormones or target neurons. It has
been hypothesized that two diseases, Alzheimer's and ALS, may
be related to steroid hormone/receptor deficiencies.
In this regard, Appel (1981) has suggested that putative
"neurotrophic hormones" acting at the synapse may be critical
in maintaining the neural networks affected in ALS,
Alzheimer's disease, and parkinsonism. Extending that
hypothesis to include direct action of such putative hormones
within the cell body and at the level of the genome, the
evidence presented in this discussion would argue that
possible candidates could be gonadal steroids.
59. Androgen deficiency and aging in men.
Swerdloff RS, Wang C
Department of Medicine, University of California, Los
Angeles, School of Medicine.
West J Med 1993 Nov;159(5):579-85
Androgen levels decrease with age in men. Androgen
deficiency in men older than 65 years leads to asthenia, a
decrease in muscle mass, osteoporosis, and a decrease in
sexual activity. Androgen deficiency has been reported
to cause changes in mood and cognitive function. The
combination of these factors results in impaired quality of
life in older men. Androgen replacement therapy in
hypogonadal men increases bone and muscle mass, enhances
muscle and cardiovascular function, and improves sexual
function and general well-being; whether elderly men
experience benefits of androgen replacement is not known.
These benefits have to be weighed against the possible adverse
effects of prostate and cardiovascular diseases. Careful
long-term studies are needed to assess the risk-to-reward
ratios of androgen or other hormone replacement therapy before
treatment strategies similar to estrogen therapy for
postmenopausal women are implemented.
60. Androgens and aging in men.
Swerdloff RS, Wang C
Division of Endocrinology, Harbor-UCLA Medical Center,
Torrance 90509.
Exp Gerontol 1993 Jul-Oct;28(4-5):435-46
Androgen levels decrease with aging in men.
Androgen deficiency in elderly men may lead to
asthenia, decrease in muscle mass, osteoporosis, decrease in
sexual activity, and, in some cases, changes in mood and
cognitive function. Combination of these factors may
result in impaired quality of life in the elderly male.
Androgen replacement therapy may increase bone and
muscle mass, enhance muscle and cardiovascular function, and
improve sexual function and general well-being. These
potential benefits of androgens have to be weighed against the
possible adverse effects on prostate and cardiovascular
diseases. Careful long-term studies will be required to assess
the risk-to-reward ratios of androgen or other hormone
replacement therapy before the development of treatment
strategies similar to estrogen and progestagen substitution
therapy for the postmenopausal female.
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