(Circulation. 1995;91:2694-2698.)
© 1995 American Heart Association, Inc.
Articles |
Testosterone and Thromboxane
Of Muscles, Mice, and Men
From the Center for Experimental Therapeutics, University of Pennsylvania (Philadelphia).
Correspondence to Dr G.A. FitzGerald, Center for Experimental Therapeutics, 909 Biomedical Research Building-1, University of Pennsylvania, 422 Curie Blvd, Philadelphia, PA 19104.
Key Words: genes • editorials • steroids • testosterone • thromboxane
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Introduction |
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 Top Introduction References |
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The age-dependent increase in death from cardiovascular disease is less pronounced in premenopausal women than in men, but this divergence of risk narrows after middle age.1 This results from a relative increase in the death rate in women after the menopause.2 It has been suggested that the immediate postmyocardial infarction death rate is higher in postmenopausal women than in men.3 4 5 6 However, standardization of the data for age and major risk factors, such as hypertension, diabetes, and hypercholesterolemia, accounts for most, but not all, of this difference. Such multivariate adjustment also suggests that mortality at 3 years among hospital survivors of an infarction actually is lower in women than in men.7 8 The reasons why in-hospital mortality may still be slightly higher in women than men remain open to question and have recently been reviewed.8 Reasons include the delay in seeking medical care for women with coronary symptoms,9 10 11 12 a higher prevalence of silent or unrecognized infarctions in women than in men,13 psychosocial disparities,14 15 and the tendency of women to experience more complications after a myocardial infarction than do men. Complications include cardiogenic shock,16 17 18 19 congestive heart failure,20 21 and cardiac rupture.22 Although it is tempting to attribute the changing incidence of cardiovascular events in women to alterations in sex steroid production at the time of the menopause, it remains to be established that such a causal link exists. If it does, the mechanism is obscure. Complex alterations in both male and female sex hormones occur in women at the time of the menopause. Serum estradiol levels tend to reduce by 50% from
50 to 60 pg/mL in the fourth decade and remain depressed
thereafter; estrone levels decline similarly at the time of the
menopause but rise again toward premenopausal levels in the eighth
decade of life.23
Circulating androgens also undergo dramatic changes. In studies of
cardiovascular risk, most attention has been focused on
dehydroepiandrosterone (DHEAS), the most abundant androgen produced by
the adrenal gland in both men and women, and on testosterone. Serum
DHEAS declines from premenopausal levels of 1000 to 3000 ng/mL
gradually from the fourth decade to 300 to 400 ng/mL by the sixth
decade. Levels are lower in women than in men at every
age.24 Adrenal production of DHEAS declines despite
largely sustained levels of cortisol.25 Serum (total)
testosterone, in contrast, is reduced 50% from 0.4 to 0.5 ng/mL
during the fourth decade but rises again from the sixth
decade.25 26 Serum free testosterone is 10 pg/mL
in
premenopausal women and undergoes a similar age-dependent pattern of
change. Hirsute and virilized women tend to have levels of these and
other androgens, such as androstenedione, as much as threefold higher
than age-matched, premenopausal healthy women.27 Studies
of sex steroid epidemiology are based on immunoassays. Recent data with
physicochemical approaches—such as are now used for the detection of
anabolic steroid use in athletics—may cause question of the
specificity of this approach in the case of some analytes but are
unlikely to undermine the broad relations of sex steroid production
with sex and age.
It is apparent from these observations that relating cardiovascular risk to altered hormonal status will be a complex task for the epidemiologist. Which particular variable is likely to bear a causal relation to risk? Is it rational to expect a relation with a single sex steroid in a setting where the interplay of male and female sex steroids may be more relevant than the concentrations of a single hormone or its metabolite? An example of the magnitude of the challenge is provided by an attempt to relate levels of DHEAS, the most abundant circulating sex steroid, to the prospective incidence of cardiovascular disease in a 19-year follow-up of 942 postmenopausal women.24 Although DHEAS tended to be higher in women who smoked, had hypertension or an elevated cholesterol level, or did not use estrogen replacement therapy, it was not shown to predict cardiovascular death after multivariate adjustment of the data.24
An alternative approach has been to examine the direct effects of sex hormone administration on traditional risk factors, function, or gene expression in the vasculature.28 Given the disparity of risk between the sexes, particular attention has focused on the possibility that androgens might modulate such risk factors for cardiovascular disease. Information has been broadly derived from observational studies of athletes who abuse anabolic steroids and from controlled evaluations of the effects of testosterone administration to volunteers. A distinction should be kept in mind between studies that involve "pharmacological" dosing (testosterone administration to healthy men) and those that involve supplementation of hypogonadal men with "physiological" amounts of testosterone. It is believed that androgen receptors are saturated at physiological concentrations and that if pharmacological effects are observed, they might involve other receptors.
The cardiovascular toxicity of anabolic steroids has been reviewed recently.29 Although all tissues appear to express the same androgen receptor,30 agonists may express a varied profile of androgenic and anabolic properties. These compounds also may cause varied side effects, perhaps due to their differential affinity for related receptors, including progesterone, estrogen, and glucocorticoid receptors, although this concept is largely speculative.29 The metabolic action of anabolic steroids is complex and ill understood. For example, testosterone and certain analogues can be aromatized to yield estradiol,31 which, at least in rat skeletal muscle, exhibits a permissive effect on androgen receptor stimulation. Although androgen receptors exist in cardiovascular tissues,32 some of the cardiovascular responses to these compounds may be indirect. Thus, testosterone potently inhibits extraneuronal uptake (type 2) of norepinephrine and inhibits 11-ß-hydroxylase activity.33 34 These actions might contribute to a rise in blood pressure via increased levels of catecholamines or 11-deoxycorticosterone, respectively, in athletes taking anabolic steroids.
Despite these observations, the few data available for athletes taking anabolic steroids report that resting, systemic blood pressure is altered minimally35 36 or not at all.37 38 These observations are borne out by controlled evaluation of the response to testosterone administration in healthy volunteers.39 40 However, the reported studies are anecdotal or of small sample size and do not exclude a modest but undetected effect of the steroids or a pronounced response in a subset of individuals. Virtually no information is available on the effects of anabolic steroids on blood pressure in women or how such medication might modify the hypertensive response to vigorous exercise.
The effects of anabolic and androgenic steroids on the lipid profile
are less controversial. A recent review indicated that the steroids
reduced HDL across a broad range of studies and, less impressive,
tended to increase LDL.41 For example, intramuscular
injections of testosterone enanthate (200 mg for 4 to 6 months)
decreased plasma HDL levels in 19 volunteers by an average of 13%,
with most of the suppression occurring in the first 4 weeks of
treatment. LDL cholesterol and triglyceride levels were not altered by
this particular regimen.42 Based on epidemiological
estimates relating the hazard ratio of coronary artery disease to a
decline in HDL, long-term suppression of HDL of this magnitude might be
expected to increase the incidence of coronary events by 20%.
However, no controlled prospective evaluations of the effects of
long-term androgen administration on coronary risk have been performed.
Interestingly, physiological levels of androgens appear to suppress HDL
production. Induction of experimental hypogonadism by injection of
the gonadotropin-releasing hormone antagonist Nal-Glu (100 mg/wk)
increased HDL by an average of 26% in 5 volunteers; this effect was
not observed when Nal-Glu was coadministered with testosterone
enanthate (100 mg weekly).43
Acute vascular occlusive syndromes, such as myocardial infarction and stroke, are believed to reflect platelet aggregation and attendant activation of the coagulation cascade, complicating vascular instability, most often, the rupture of an atherosclerotic plaque. Several factors released from activated platelets cause vasoconstriction, which also may contribute to tissue damage. Consistent with this hypothesis, biochemical indexes of platelet activation and thrombin generation have been elevated coincident with symptomatic episodes in syndromes of myocardial and cerebrovascular ischemia.44 Evidence for the persistent activation of the coagulation system, months after an acute event, has been noted in patients with a myocardial infarction.45 The implications of such a "procoagulant state" in apparently stable patients are less clearly understood than is the role of thrombosis in acute ischemia or infarction.
High estrogen levels have been associated with decreased levels of circulating fibrinogen46 47 and increased levels of plasminogen activator inhibitor–1 and tissue-type plasminogen activator antigen.48 Both female and male sex hormones have been reported to cause vasorelaxation,49 50 although the latter effect does not appear to be mediated via androgen receptors.50 Another way that sex steroids might influence the likelihood of thrombotic vascular occlusion would be to modify platelet function.
Thromboxane (TX) A2 is the major product of the enzyme
prostaglandin (PG) G/H synthase–I in human platelets. PGG/H synthase,
colloquially known as cyclooxygenase (COX), catalyzes the sequential
formation of PG endoperoxide intermediates (PGG2 and
PGH2) from arachidonic acid.
TXA2 is formed from PGH2 by the enzyme TX
synthase. TXA2 activates platelets via a membrane
receptor.51 It is also a vasoconstrictor. Although a
single receptor gene has been cloned,52 it is possible
that the existence of tissue-specific, alternative-splice variants of
the carboxyl terminus53 may explain the reported
pharmacological distinction between platelet and vascular responses to
TX agonists and antagonists.54 55 56 In
addition to
TXA2, the platelet receptor may be activated by
PGH257 or by 8-epi PGF2
.
The latter PGF2 isomer may be formed either by free
radical–catalyzed conversion of arachidonic acid or as
a COX product in human platelets and other
cells.58 59 It
presently is unclear whether 8-epi PGF2 acts as a
natural ligand for the receptor, as either a partial60 or
an inverse61 agonist, or if it acts at distinct but
related receptors.62
TXA2 derives its biological importance in platelet biology from its ability to function as an amplification signal for other, more potent agonists, such as thrombin and ADP.63 This probably explains the ability to detect an impact on TX inhibition by aspirin in clinical trials of cardiovascular disease64 65 66 despite the redundancy in the mechanisms by which platelets may be activated.
Observations by Ajayi and colleagues in the present issue of Circulation67 raise the possibility that differential responses to TX may contribute to sex-based disparities in the incidence of cardiovascular disease and to the cardiovascular toxicity of anabolic steroids. Sixteen healthy volunteers were injected with testosterone cypionate (200 mg) or saline placebo on two occasions (the injections were separated by 2 weeks), and their platelet function was assessed. Plasma testosterone rose from an average of 0.42 to 0.51 ng/mL in the actively treated group. The maximal platelet aggregation response to the TX analogue I-BOP ex vivo was increased compared with placebo and pretreatment levels 4 weeks after the first injection of testosterone and declined to pretreatment values by 8 weeks. Coincident with these changes, the number of receptor sites detected with radiolabeled I-BOP increased with testosterone treatment. Administration failed to alter either the affinity for the agonist in the binding assays or the EC50 for the agonist in the platelet aggregation assays. Pretreatment levels of testosterone correlate with TX receptor density.
Platelets are the anucleate fragments of megakaryocytes, and an effect of testosterone on TX receptor density would imply regulation of expression of this protein during megakaryopoiesis by the androgen. One of the two alternative promoters in the TX receptor gene contains a steroid response element,52 68 and dexamethasone has been shown to reverse the increase in TX receptor mRNA induced by the phorbol ester PMA.69 Animal models provide further support for the potential relevance of sex to platelet biology. Studies in the C3H mouse, a strain characterized by higher-than-average DNA, define the importance of genotype70 but also imply the importance of male sex hormones and genomic imprinting in platelet and megakaryocyte production. Thus, male mice had higher platelet counts, 35S incorporation into platelets, total circulating platelet counts, and total circulating platelet masses than female mice. Androgens have been shown to stimulate erythropoiesis.71 An interaction of male sex hormones and genotype was suggested by the inverse relation between platelet counts and the proportion of the C3H genotype in male but not female mice. Finally, the female parent had a significantly greater influence on the offspring's megakaryocyte DNA content (ploidy) and certain indexes of platelet function than the male parent-genomic imprinting.72 Interestingly, although megakaryocyte size was highly correlated with ploidy in these experiments, neither parameter correlated with platelet size, regardless of sex. Indeed, platelet size did not differ between male and female mice, implying that platelet size and count are under independent control.
Platelet size does not increase with platelet age in humans73 and, as in the mouse, appears to be regulated independently of platelet count.74 However, large platelets appear to be more reactive per unit volume than small platelets when exposed to agonists. Stimulation also results in greater release of serotonin, ß-thromboglobulin, and TXA2.75 76 Mean platelet volume was higher after a myocardial infarction in men who developed an additional ischemic event during 2 years of follow-up than in those who did not.77 A similar relation between cardiovascular risk and the tendency for platelets to aggregate spontaneously ex vivo has been reported.78 It is unknown whether these relations are modified by sex.
The work by Ajayi and colleagues was performed carefully and was the logical extrapolation of previous work by Halushka and colleagues indicating the effects of testosterone on TX receptors and TX-mediated responses in human erythroleukemia cells,79 rat vascular smooth muscle cells,80 and guinea pig coronary artery.81 The present study of the pharmacological effects of androgens is unlikely to relate directly to variations within the physiological range between sexes and across time within them. However, although the data are provocative, it perhaps would be premature to conclude that a mechanistic link between anabolic and/or androgenic steroids and cardiovascular risk has been established.
Platelet aggregation responses to agonists ex vivo have been useful in finding doses of drugs that act as platelet inhibitors, such as aspirin.82 Dose-dependent effects on this parameter are usually reflective of platelet inhibition in vivo. However, the use of this parameter as an index of platelet activation is somewhat more controversial. The signal—as in this study—usually is a small one, and the parameter is known to be influenced by many variables, eg, diet, exercise, and time of day. This may explain the confusion in the literature on the influence of gender on platelet aggregation.83 84 Furthermore, the assumption that ex vivo "hyperaggregation" will reflect in vivo platelet activation is far from obvious. Thus, the largest epidemiological study of platelet aggregation found that platelet reactivity to ADP ex vivo was depressed, not enhanced, in cigarette smokers.85 This is in contrast with several lines of evidence that indicate that platelets are activated in vivo by cigarette smoking.86 87 Perhaps exposure to increased amounts of agonist in vivo over an extended period will downregulate megakaryocyte receptor production, or consumption of the most "active" platelets in vivo will leave only less-responsive cells for harvest for the ex vivo studies. Nevertheless, these observations are provocative and might be followed up in several ways.
First, the mechanistic relation between androgens and TX receptors might be clarified. It would be important to know if the effects observed in platelets are specific for the TX receptor and not merely a reflection of a general effect on platelet proteins. Although platelet responsiveness to thrombin ex vivo was not modified to an extent that achieved statistical significance (P=.07), the original data are not presented and the level of significance suggests that this possibility not be totally excluded. Are platelet size and megakaryocyte ploidy influenced by testosterone administration? Although the platelet count was standardized before the aggregation studies, the influence of testosterone on platelet count is not reported.
If the effect of testosterone on TX receptors is specific, additional questions might be addressed. Is biosynthesis of TX modified in vivo by the administration of testosterone? This could occur through induction of either COX-1 or TX synthase. Androgens upregulate COX-1 expression in ram seminal vesicles.88 Might this be a mechanism by which receptor density is modulated? Is expression of TX receptors or response to TX agonists modified in models of androgen receptor deficiency, such as the testicular feminization syndrome or the mouse model of this condition? Previous studies in nucleated cells that exhibit plateletlike characteristics might be expanded by the study of the effects of testosterone on mRNA and protein of the tissue-specific TX receptor isoforms. Should such studies infer a role for testosterone on TX gene expression, its mechanism might be defined. Advantage might be taken of the C3H mouse strain to clarify the interplay of genotype and the effects of testosterone on TX receptors. Is the expression of thrombopoietin regulated by androgens, and if so, how does this translate into platelet function? The pending availability of TX receptor knockout mice will provide a useful reagent with which to study the effects of testosterone on megakarypoiesis and platelet function in vivo independent of its influence on the eicosanoid. Finally, the possibility that any effects of testosterone are modified by other sex steroids has not been addressed in any of these systems.
The study by Ajayi and colleagues is a nice example of mechanism-based clinical pharmacology. It draws attention to how little reliable information is available on either the potential benefits or the risks of anabolic steroids, despite their reportedly widespread clandestine usage. For example, a recent review29 cites reports of fewer than 30 life-threatening circulatory events linked to anabolic steroid use during the past 20 years. However, it is unknown how many events go unreported and the extent to which structural cardiac disease (eg, obstructive cardiomyopathy) might have confounded the incidence of reported cases. It is unknown how fitness, age, sex, and ethnicity might modify the response to these compounds. Given the approach of the Atlanta Olympics, perhaps it is timely for the human pharmacology of anabolic steroids to emerge from the locker room and be subjected to the objective scrutiny of clinical research.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association, Inc.
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References |
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