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From: ironjustice@aol.com on 8 Dec 2006 20:39
I suppose since increased red blood cell production leads to heart
failure in kidney patients .. the fact testosterone increases red blood
cell production .. gives credence to the .. **increased red blood cell
production** / increased hemoglobin .. INCREASING risk of .. **death**
...

Death is a .. bad .. sign .. TO BE .. used as a MARKER .. of **adverse
effects** ..

Turkish Journal of Endocrinology and Metabolism
2004, Volume 8, Number 4, Page(s) 143-145

Testosteron Replacement Therapy: Another Contributing Factor to Heart
Failure in β Thalassemia Major ?
Selçuk Dağdelen1, Ayşegül Atmaca1, Giray Kabakçı2, Tomris Erbaş1

1Department of Endocrinology and Metabolism, Hacettepe University,
School of Medicine, Ankara, Turkey
2Department of Cardiology, Hacettepe University, School of Medicine,
Ankara, Turkey
Keywords: Hypogonadism, beta-Thalassemia, heart failure, testosteron
enanthate
Introduction
Heart failure (HF) in beta-thalassemia major (BTM) has previously been
attributed almost only to iron-overload [1,2]. However predominantly
left-sided HF has been reported to develop in younger and less
hemosiderotic BTM patients in contrast to the involvement of elderly
and severely hemosiderotic cases by predominantly right-sided HF [3,4].
This is the reason why, Kremastinos et al. emphasized the importance of
other risk factors apart from iron-overload in the pathogenesis of HF
associated with BTM [5,6].
Androgenic anabolic steroids -including testosteronare known to be
associated with hypertension, ventricular remodelling, myocardial
ischemia, and sudden cardiac death, even in healthy men who are taking
these drugs to in crease athletic performance [7]. Testosteron is the
preferred ligand of the human androgen receptor in myocardium, and
modulates some cellular actions similar to those seen in HF and
cardiomyopathy [7]. In an experimental model, Zaugg et al., have
demonstrated for the first time that, androgenic anabolic steroids
–including testosteron- induced apoptotic cell death in rat myocytes
[8]. These findings were regarded as a molecular evidence to understand
the underlying pathogenesis of cardiac morbidity and mortality in case
of androgenic anabolic steroid abuse [8].

Beyond the heart as an organ to be damaged directly, fluid retention
and erythrocytosis are well known side effects of testostesteron
therapy which could precipitate pre-existing heart failure [9].

Despite the lack of comparative clinical evidences in human, searching
whether the testosteron therapy in physiologic- or supraphysiologic
regimens might have different cardiotoxic profiles, it seems reasonable
that at least for some instances, testosteron therapy is a potentially
cardiotoxic agent depending on host factors. Thus, here we report the
first betathalassemic case of the literature, in whom the role of
testosteron therapy has been discussed as a contributing factor to the
development of HF.

Case Presentation
A 16-year-old white male with BTM plus secondary hemochromatosis was
referred to the endocrinology department due to delayed puberty.
Following the physical examination, basal and dynamic hormonal
evaluations, and pituitary magnetic resonance imaging, he was diagnosed
on hypogonadotropic hypogonadism with pituitary hemochromatosis due to
diffuse reduction in pituitary signal intensity on T2-weighed images at
a background presence of hepatic hemochromatosis and concomitant high
levels of serum ferritin levels. Normal TSH and ACTH responses to TRH
and CRH stimulation tests were obtained respectively. GH axis was also
evaluated as normal (Table 1). Upon these findings, testosteron
replacement therapy –testosteron enanthate, 50 mg, IM, once in every
3 weeks- was started. Instead of hCG and/or hMG, testosteron was
preferred due to patients’ expectations of a less frequent injection.
On the 14th month of testosteron therapy, while he had no
cardiovascular sign or symptom, an echocardiography was obtained for
routine purposes to screen for probable complications, and suggested
diastolic dysfunction with completely normal systolic measurements.
Thereafter the dosage of testosteron was increased to 125 mg/month. On
the 5th month of dose increment, he admitted to the hospital with
palpitation and dyspnea on exertion, and his cardiopulmoner
auscultation revealed a systolic murmur over the cardiac base, Gallop
rythm and bibasal fine crackles. M-mode, 2-dimensional and Doppler
echocardiography was done, reported as the systolic dysfunction of the
left ventricle with second degree tricuspid insufficiency, and
confirmed the clinical diagnosis of congestive heart failure (Table 2).
Despite the compliance with desferrioxamine iron chelation therapy,
ferritin was measured as 1550 ng/ml at time of HF-diagnosis. With these
findings of heart failure, diuretics, digoxine, angiotension converting
enzyme inhibitors plus beta-blockers were administered, and testosteron
therapy was stopped. At the 18th month of his follow-ups, congestive
heart failure seemed to be stable on therapy with an ejection fraction
of 51%.
Table 1: Endocrine evaluation of the case before testosteron
replacement therapy.

Table 2: Echocardiographic findings of the case.
Top
Introduction
Case Presentation
Disscussion
References

Discussion
Despite intensive iron-chelation therapy, the survivals of BTM is still
limited by the occurrence of heart failure [6]. Myocardial iron
deposition alone does not affect left ventricular relaxation but
directly causes left ventricular myocardial restriction with an
elevation in pulmonary pressure, and thereafter causing predominantly
right-sided heart failure [4]. Left ventricular failure, which occurs
in younger, less hemosiderotic populations, seems to be multifactorial
in etiology [4]. Apart from iron loading, immunogenetic risk factor s
are claimed to trigger the mechanisms of left-sided heart failure
development in the context of dilated-type cardiomyopathy [4,6].
The clinical presentation of our case shows that there is a temporal
association between the initiation of testosteron replacement therapy
and HF-development. Interestingly the increase in the dosage of
testosteron is also followed by the precipitation of HF. Therefore
question of whether the testosteron might have played a triggering role
in the development of HF in our case, is raised on.

On the contrary, androgens are well known vasodilators in the coronary
[10], pulmonary [11], and peripheral vasculature [12]. In fact, it has
recently been shown that, testosteron therapy increased the cardiac
output acutely in elderly patients with HF via the reduction of left
ventricular afterload [13]. Additionally, gonadectomy of adult male
rats was shown to reduce the cardiac contractility which was then
reversed by gonadal replacement therapy [14]. On the other hand, Gao et
al. [15], and Li et al. [16], have reported that testosteron was a
cardiomyotoxic agent in the presence of a cardiomyopathic phenotype
(beta-2-adrenergic receptor overexpressed and guanylyl cyclase-A
knockout mice models, respectively). These controversies regarding the
cardio-toxicity, cardio-safety and even the cardiobenefits of
testosteron therapy definetly requires further explanations. However it
seems reasonable that, the cardiac effects of testosteron in case of an
established HF, can be ratherly different than in case of an otherwise
normal heart.

Consequently we propose that, testesteron replacement therapy could
contribute to the development and/or precipitation of HF, especially in
predisposed individuals like with BTM-associated hemochromatosis.
Regarding the underestimation of such an effect in the literature we
suggest that, further clinical evidences are required to document the
cardiac effects of gonadal status and gonadal replacement therapies on
the HF associated with BTM.
Top
Introduction
Case Presentation
Discussion
References

References
1) Bura M, Roberts W. Iron in the heart: etiology and clinical
significance. Am J Med 51: 209-221, 1971.

2) Schafer A, Cheron R, Dluhy R, Cooper B, Bunn F. Clinical
consequences of acquired transfusional iron overload in adults. N Engl
J Med 304: 319-324, 1981.

3) Kremastinos DT, Tiniakos G, Theodorakis GN, Katritsis DG, Toutouzas
PK. Myocarditis in β-Thalassemia Major: a cause of heart failure.
Circulation 91: 66-71, 1995.

4) Kremastinos DT. Heart failure in beta-thalassemia. Congest Heart
Fail 7: 312-314, 2001.

5) Kremastinos DT, Flevari P, Spyropolou M, Vrettou H, Tsiapras D,
Stavropolos-Giokas CG. Association of heart failure in homozygous
β-Thalassemia with the major histocompatibility complex. Circulation
100: 2074-2078, 1999.

6) Kremastinos DT, Tsetsos GA, Tsiapras D, Karavolias GK, Ladis VA,
Kattamis CA. Heart Failure in Beta- Thalassemia: a 5-year follow-up
study. Am J Med 111: 349-54, 2001.

7) Sullivan ML, Martinez CM, Gennis P, Gallagher EJ. The cardiac
toxicity of anabolic steroids. Prog Cardiovasc Dis 41: 1-15, 1998.

8) Zaugg M, Jamali NZ, Lucchinetti E, Xu W, Alam M, Shafiq SA, Siddiqui
MA. Anabolic-androgenic steroids induce apoptotic cell death in adult
rat ventricular myocytes. J Cell Physiol 187: 90-95, 2001.

9) Rhoden EL, Morgentaler A. Risks of testosteron-replacement therapy
and recommendations for monitoring. N Engl J Med 350: 482-492, 2004.

10) English KM, Jones RD, Jones TH, Morice AH, Channer KS. Testosteron
acts as a coronary vasodilator by calcium antagonistic action. J
Endocrinol Invest 25: 455-8, 2002.

11) Jones RD, English KM, Pugh PJ, Morice AH, Jones TH, Channer KS.
Pulmonary vasodilatory action of testosteron: evidence of a calcium
antagonistic action. J Cardiovasc Pharmacol 39: 814-823, 2002.

12) Perusquia M, Villalon CM. The vasodepressor effect of androgens in
pithed rats: potential role of calcium channels. Steroids 67: 1021-8,
2002.

13) Pugh PJ, Jones TH, Channer KS. Acute haemodynamic effects of
testosteron in men with chronic heart failure. Eur Heart J 24: 909-15,
2003.

14) Golden KL, Marsh JD, Jiang Y, Brown T, Moulden J. Gonadectomy of
adult male rats reduces contractility of isolated cardiac myocytes. Am
J Physiol Endocrinol Metab 285: E449-53, 2003.

15) Gao XM, Agrotis A, Autelitano DJ, et al. Sex hormones and
cardiomyopathic phenotype induced by cardiac beta 2-adrenergic receptor
overexpression. Endocrinology 144: 4097-4105, 2003.

16) Li Y, Kishimoto I, Saito Y, et al. Androgen contributes to
gender-related cardiac hypertrophy and fibrosis in mice lacking the
gene encoding guanylyl cyclase-A. Endocrinology 145(2): 951-8, 2004.


Who loves ya.
Tom


Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com


Man Is A Herbivore!
http://tinyurl.com/a3cc3


DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

From: James Michael Howard on 9 Dec 2006 11:34
On 8 Dec 2006 17:39:38 -0800, "ironjustice(a)aol.com" <ironjustice(a)aol.com>
wrote:

>I suppose since increased red blood cell production leads to heart
>failure in kidney patients .. the fact testosterone increases red blood
>cell production .. gives credence to the .. **increased red blood cell
>production** / increased hemoglobin .. INCREASING risk of .. **death**
>..
>
>Death is a .. bad .. sign .. TO BE .. used as a MARKER .. of **adverse
>effects** ..
>
>Turkish Journal of Endocrinology and Metabolism
>2004, Volume 8, Number 4, Page(s) 143-145
>
>Testosteron Replacement Therapy: Another Contributing Factor to Heart
>Failure in ? Thalassemia Major ?
>Sel�uk Da?delen1, Ay?eg�l Atmaca1, Giray Kabak�?2, Tomris Erba?1
>
>1Department of Endocrinology and Metabolism, Hacettepe University,
>School of Medicine, Ankara, Turkey
>2Department of Cardiology, Hacettepe University, School of Medicine,
>Ankara, Turkey
>Keywords: Hypogonadism, beta-Thalassemia, heart failure, testosteron
>enanthate
>Introduction
>Heart failure (HF) in beta-thalassemia major (BTM) has previously been
>attributed almost only to iron-overload [1,2]. However predominantly
>left-sided HF has been reported to develop in younger and less
>hemosiderotic BTM patients in contrast to the involvement of elderly
>and severely hemosiderotic cases by predominantly right-sided HF [3,4].
>This is the reason why, Kremastinos et al. emphasized the importance of
>other risk factors apart from iron-overload in the pathogenesis of HF
>associated with BTM [5,6].
>Androgenic anabolic steroids -including testosteronare known to be
>associated with hypertension, ventricular remodelling, myocardial
>ischemia, and sudden cardiac death, even in healthy men who are taking
>these drugs to in crease athletic performance [7]. Testosteron is the
>preferred ligand of the human androgen receptor in myocardium, and
>modulates some cellular actions similar to those seen in HF and
>cardiomyopathy [7]. In an experimental model, Zaugg et al., have
>demonstrated for the first time that, androgenic anabolic steroids
>�including testosteron- induced apoptotic cell death in rat myocytes
>[8]. These findings were regarded as a molecular evidence to understand
>the underlying pathogenesis of cardiac morbidity and mortality in case
>of androgenic anabolic steroid abuse [8].
>
>Beyond the heart as an organ to be damaged directly, fluid retention
>and erythrocytosis are well known side effects of testostesteron
>therapy which could precipitate pre-existing heart failure [9].
>
>Despite the lack of comparative clinical evidences in human, searching
>whether the testosteron therapy in physiologic- or supraphysiologic
>regimens might have different cardiotoxic profiles, it seems reasonable
>that at least for some instances, testosteron therapy is a potentially
>cardiotoxic agent depending on host factors. Thus, here we report the
>first betathalassemic case of the literature, in whom the role of
>testosteron therapy has been discussed as a contributing factor to the
>development of HF.
>
>Case Presentation
>A 16-year-old white male with BTM plus secondary hemochromatosis was
>referred to the endocrinology department due to delayed puberty.
>Following the physical examination, basal and dynamic hormonal
>evaluations, and pituitary magnetic resonance imaging, he was diagnosed
>on hypogonadotropic hypogonadism with pituitary hemochromatosis due to
>diffuse reduction in pituitary signal intensity on T2-weighed images at
>a background presence of hepatic hemochromatosis and concomitant high
>levels of serum ferritin levels. Normal TSH and ACTH responses to TRH
>and CRH stimulation tests were obtained respectively. GH axis was also
>evaluated as normal (Table 1). Upon these findings, testosteron
>replacement therapy �testosteron enanthate, 50 mg, IM, once in every
>3 weeks- was started. Instead of hCG and/or hMG, testosteron was
>preferred due to patients� expectations of a less frequent injection.
>On the 14th month of testosteron therapy, while he had no
>cardiovascular sign or symptom, an echocardiography was obtained for
>routine purposes to screen for probable complications, and suggested
>diastolic dysfunction with completely normal systolic measurements.
>Thereafter the dosage of testosteron was increased to 125 mg/month. On
>the 5th month of dose increment, he admitted to the hospital with
>palpitation and dyspnea on exertion, and his cardiopulmoner
>auscultation revealed a systolic murmur over the cardiac base, Gallop
>rythm and bibasal fine crackles. M-mode, 2-dimensional and Doppler
>echocardiography was done, reported as the systolic dysfunction of the
>left ventricle with second degree tricuspid insufficiency, and
>confirmed the clinical diagnosis of congestive heart failure (Table 2).
>Despite the compliance with desferrioxamine iron chelation therapy,
>ferritin was measured as 1550 ng/ml at time of HF-diagnosis. With these
>findings of heart failure, diuretics, digoxine, angiotension converting
>enzyme inhibitors plus beta-blockers were administered, and testosteron
>therapy was stopped. At the 18th month of his follow-ups, congestive
>heart failure seemed to be stable on therapy with an ejection fraction
>of 51%.
>Table 1: Endocrine evaluation of the case before testosteron
>replacement therapy.
>
>Table 2: Echocardiographic findings of the case.
> Top
>Introduction
>Case Presentation
>Disscussion
>References
>
>Discussion
>Despite intensive iron-chelation therapy, the survivals of BTM is still
>limited by the occurrence of heart failure [6]. Myocardial iron
>deposition alone does not affect left ventricular relaxation but
>directly causes left ventricular myocardial restriction with an
>elevation in pulmonary pressure, and thereafter causing predominantly
>right-sided heart failure [4]. Left ventricular failure, which occurs
>in younger, less hemosiderotic populations, seems to be multifactorial
>in etiology [4]. Apart from iron loading, immunogenetic risk factor s
>are claimed to trigger the mechanisms of left-sided heart failure
>development in the context of dilated-type cardiomyopathy [4,6].
>The clinical presentation of our case shows that there is a temporal
>association between the initiation of testosteron replacement therapy
>and HF-development. Interestingly the increase in the dosage of
>testosteron is also followed by the precipitation of HF. Therefore
>question of whether the testosteron might have played a triggering role
>in the development of HF in our case, is raised on.
>
>On the contrary, androgens are well known vasodilators in the coronary
>[10], pulmonary [11], and peripheral vasculature [12]. In fact, it has
>recently been shown that, testosteron therapy increased the cardiac
>output acutely in elderly patients with HF via the reduction of left
>ventricular afterload [13]. Additionally, gonadectomy of adult male
>rats was shown to reduce the cardiac contractility which was then
>reversed by gonadal replacement therapy [14]. On the other hand, Gao et
>al. [15], and Li et al. [16], have reported that testosteron was a
>cardiomyotoxic agent in the presence of a cardiomyopathic phenotype
>(beta-2-adrenergic receptor overexpressed and guanylyl cyclase-A
>knockout mice models, respectively). These controversies regarding the
>cardio-toxicity, cardio-safety and even the cardiobenefits of
>testosteron therapy definetly requires further explanations. However it
>seems reasonable that, the cardiac effects of testosteron in case of an
>established HF, can be ratherly different than in case of an otherwise
>normal heart.
>
>Consequently we propose that, testesteron replacement therapy could
>contribute to the development and/or precipitation of HF, especially in
>predisposed individuals like with BTM-associated hemochromatosis.
>Regarding the underestimation of such an effect in the literature we
>suggest that, further clinical evidences are required to document the
>cardiac effects of gonadal status and gonadal replacement therapies on
>the HF associated with BTM.
> Top
>Introduction
>Case Presentation
>Discussion
>References
>
>References
>1) Bura M, Roberts W. Iron in the heart: etiology and clinical
>significance. Am J Med 51: 209-221, 1971.
>
>2) Schafer A, Cheron R, Dluhy R, Cooper B, Bunn F. Clinical
>consequences of acquired transfusional iron overload in adults. N Engl
>J Med 304: 319-324, 1981.
>
>3) Kremastinos DT, Tiniakos G, Theodorakis GN, Katritsis DG, Toutouzas
>PK. Myocarditis in ?-Thalassemia Major: a cause of heart failure.
>Circulation 91: 66-71, 1995.
>
>4) Kremastinos DT. Heart failure in beta-thalassemia. Congest Heart
>Fail 7: 312-314, 2001.
>
>5) Kremastinos DT, Flevari P, Spyropolou M, Vrettou H, Tsiapras D,
>Stavropolos-Giokas CG. Association of heart failure in homozygous
>?-Thalassemia with the major histocompatibility complex. Circulation
>100: 2074-2078, 1999.
>
>6) Kremastinos DT, Tsetsos GA, Tsiapras D, Karavolias GK, Ladis VA,
>Kattamis CA. Heart Failure in Beta- Thalassemia: a 5-year follow-up
>study. Am J Med 111: 349-54, 2001.
>
>7) Sullivan ML, Martinez CM, Gennis P, Gallagher EJ. The cardiac
>toxicity of anabolic steroids. Prog Cardiovasc Dis 41: 1-15, 1998.
>
>8) Zaugg M, Jamali NZ, Lucchinetti E, Xu W, Alam M, Shafiq SA, Siddiqui
>MA. Anabolic-androgenic steroids induce apoptotic cell death in adult
>rat ventricular myocytes. J Cell Physiol 187: 90-95, 2001.
>
>9) Rhoden EL, Morgentaler A. Risks of testosteron-replacement therapy
>and recommendations for monitoring. N Engl J Med 350: 482-492, 2004.
>
>10) English KM, Jones RD, Jones TH, Morice AH, Channer KS. Testosteron
>acts as a coronary vasodilator by calcium antagonistic action. J
>Endocrinol Invest 25: 455-8, 2002.
>
>11) Jones RD, English KM, Pugh PJ, Morice AH, Jones TH, Channer KS.
>Pulmonary vasodilatory action of testosteron: evidence of a calcium
>antagonistic action. J Cardiovasc Pharmacol 39: 814-823, 2002.
>
>12) Perusquia M, Villalon CM. The vasodepressor effect of androgens in
>pithed rats: potential role of calcium channels. Steroids 67: 1021-8,
>2002.
>
>13) Pugh PJ, Jones TH, Channer KS. Acute haemodynamic effects of
>testosteron in men with chronic heart failure. Eur Heart J 24: 909-15,
>2003.
>
>14) Golden KL, Marsh JD, Jiang Y, Brown T, Moulden J. Gonadectomy of
>adult male rats reduces contractility of isolated cardiac myocytes. Am
>J Physiol Endocrinol Metab 285: E449-53, 2003.
>
>15) Gao XM, Agrotis A, Autelitano DJ, et al. Sex hormones and
>cardiomyopathic phenotype induced by cardiac beta 2-adrenergic receptor
>overexpression. Endocrinology 144: 4097-4105, 2003.
>
>16) Li Y, Kishimoto I, Saito Y, et al. Androgen contributes to
>gender-related cardiac hypertrophy and fibrosis in mice lacking the
>gene encoding guanylyl cyclase-A. Endocrinology 145(2): 951-8, 2004.
>
>
>Who loves ya.
>Tom


It is my hypothesis that when testosterone evolved, testosterone redirected
DHEA use ("Androgens in Human Evolution," Rivista di Biologia / Biology
Forum 2001; 94: 345-362). I have been able to use this hypothesis to
explain some things. For example, if one has sufficient DHEA and is
deficient in testosterone, treatment with testosterone will produce
beneficial effects. If one has low DHEA and low testosterone, then
supplementation with testosterone may cause problems as the increased
testosterone may direct DHEA use for some tissues and, therefore, deprive
other tissues of DHEA. I think this may explain why, sometimes,
testosterone helps individuals and sometimes produces negative results.

In the case you have presented here, beta-thalassemia major, I found one
report that found low DHEAS, the precursor of DHEA, to be low (Arch Fr
Pediatr. 1993 Oct;50(8):657-63). Therefore, based on my first paragraph, I
suggest that supplemental testosterone redirected already low DHEA to rbc
production with the result that a reduction in DHEA resulted in heart
problems.

James Michael Howard
From: Ed Friedman on 12 Dec 2006 18:18
Around 50 years ago, doctors studied the effects of testosterone (T) and
prostate cancer. Not one patient ever had the level of T in his blood
measured. All of the conclusions were based only on the amount of T given.

While this might be tolerated for 50 year old work, it is inconceivable
that anyone in modern times would have the audacity to publish an
article on the effects of giving T without actually measuring the level
of T in the blood.

Since T is essential in preventing prostate cancer, breast cancer, and
Alzheimer's disease, such articles as this are irresponsible. Clearly
there was a problem with T and BTM, but no greater condemnation of T can
be justified by their data, and without measuring the level of T in the
blood, the researchers are clueless as to what actually occurred in
their case study.

Ed Friedman
 | 
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