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Editorial |
Director, ANZAC Research Institute, Sydney, New South Wales 2139, Australia
Address all correspondence and requests for reprints to: Professor David J. Handelsman, Director, ANZAC Research Institute, Head, Andrology Department, Concord Hospital, University of Sydney, Sydney, New South Wales 2139, Australia. E-mail: djh{at}anzac.edu.au.
As the centenary of the 1906 Food and Drug Act approaches, the FDA has come to serve not just as the national drug regulatory agency of the United States but also the de facto reference agency for the developed world. Having saved America from thalidomide in the 1960s, the FDA has powers and prestige that have grown to where its decisions are painstakingly scrutinized, it is a place of pilgrimage for drug developers, and its whims and misadventures are gossiped about in industry, academia, and the informed public around the world. So for outsiders, it was an enigma as to how and why a decade ago a range of potent prosteroids, including androstenedione (A; street name "Andro"), somehow evaded expected FDA regulatory scrutiny, especially because this occurred soon after the Anabolic Steroid Control Act (1990) had made possession of specified androgens illegal without a valid doctor’s prescription. The "how", the 1994 Dietary Supplements Act, allowed many substances including dehydroepiandrosterone (DHEA), melatonin, and A to be classed as food supplements rather than drugs; the "why" remains inexplicable to medical researchers who mostly regard this as a colossal mistake. Fittingly for a food supplement, the only safety concern of that act was with contamination, inevitably ignoring any possibility of potent biological effects of such prosteroids. By definition, foods lie beyond the reach of drug regulatory scrutiny, a boundary under continual challenge by the creeping fraudulence of most nutraceutical claims. Ultimately, the Clinton-era 1994 act created a huge, unregulated over-the-counter marker for prosteroids like DHEA and Andro, with ample cash flows to ward off reregulation in an era when the FDA was under siege to shorten times to drug registration. The understandable dissatisfaction of the FDA with this anomaly was given strong, if tacit, support because deregulation of prosteroids was not emulated in any developed countries.
As a drug, A is less well studied than its better known congener DHEA. Both are best considered naturally occurring, orally active prosteroids that, without nature’s preemption, would have had to be invented. DHEA and A are not considered hormones because, although they circulate in the bloodstream, they have no known distinctive biological effects or specific receptors. The latter conclusion must remain tentative because so many orphans lacking an identified natural ligand remain within the nuclear steroid superfamily. Most sound clinical research on DHEA has focused on its putative effects for adrenal androgen replacement therapy and in aging, considered as a functional form of adrenal androgen deficiency. At replacement doses of 25–50 mg DHEA/d, blood testosterone (T) concentrations are increased in women (1, 2), with high doses (100 mg) producing supraphysiological blood T concentrations (3). In men, however, even massive DHEA doses (1600 mg/d) have no effect on blood T (4), although blood estradiol is markedly increased (5). In women with complete adrenal failure (bilateral adrenalectomy, Addison’s disease), some (6, 7) but not all studies (8) report that at replacement doses DHEA improves well-being and sexual function. However, these findings do not extend to men with adrenal insufficiency (7, 8) or older men or women with age-related decline in blood DHEA concentrations (9). Such careful clinical evidence appears not to hinder in the least the proliferation of websites brimming with wildly unreliable hype on DHEA as an antiaging and health tonic. The curious paucity of studies into DHEA for enhancing sports performance or body building may reflect a dichotomy between, on the one hand, slick exploitation of the antiaging market populated by gullible, wishful, and affluent consumers—the marketer’s dream triad—and, on the other, a more pragmatic world of professional elite athletes expecting to base investment decisions on sound evidence and risk-benefit calculation.
Andro use appears to have surged in the last decade and, by contrast with DHEA, almost exclusively focused on the sports performance market (10). Initially this capitalized on Andro’s nonbanned status on the International Olympics Committee (now World Anti-Doping Agency) list of prohibited substances, a loophole now closed. Previous studies of Andro using doses up to 300 mg/d for 1 month or less (10 studies) or 2–3 months (five studies) have shown only inconsistent increases in blood T concentrations (11). So the study by Jasuja et al. (12) in this issue makes an important contribution by reporting the first high-dose study, using 1500 mg Andro daily for 12 wk, that replicates more realistically street patterns of hormone abuse, typically in massive doses for 2- to 3-month cycles. In nine men with genuine androgen deficiency, they found that Andro produced a 10-fold increase in blood A concentrations as well as a 2-fold increase in blood T levels. This is consistent with relatively inefficient (
6%) conversion of A to T by 17-ketosteroid reductase within the body, whereas only 1.8% of an oral Andro dose is converted to blood T (13). So the oral dose used by Jasuja et al. (12), approximately 1000 times men’s daily endogenous A production rate (14), delivers the equivalent of four to six times endogenous daily production rate of T into the bloodstream. This corresponds roughly to the top dose of the same group’s definitive studies of high-dose T in young men (15). Yet, although Andro induced definite increases in muscle mass (2.1–2.6%) and strength (7.2–9.3%), these are lower than those produced by equivalent supraphysiological T doses. This discrepancy may reflect even lower oral A bioavailability than previously estimated or incomplete run-off from prior androgen replacement therapy, or it may show that Andro’s in vivo metabolites included some with antiandrogenic effects. In any case, although Jasuja et al. (12) confirm definite biological effects of this oral Andro regimen, they also support the view that Andro is a prosteroid, biologically active only after conversion to more potent natural androgens in vivo.
This issue was also tackled by Jasuja et al. (12) in evaluating evidence from three in vitro systems in which A can interact directly with the androgen receptor (AR). The first employs an in vitro binding assay that uses a novel system based on an AR peptide fragment, representing the ligand-binding domain sequence, with a fluorescent androgen analog. Although this synthetic system differs from the native AR and its natural ligand, presumably explaining the lower affinity of dihydrotestosterone (DHT) binding than in more natural systems using authentic AR, the approximately 65-fold lower affinity of A confirms that it is, at best, a very weak androgen in its own right. To put this into perspective, endogenous A circulates at approximately 10% of the blood concentration of T, about the same levels as DHT, so its direct contribution to endogenous androgen action in men would be negligible. Because binding studies cannot distinguish between agonists and antagonist, two additional pieces of cell culture evidence are used to show that A may exert direct androgen-like effects in a nuclear translocation and an ad hoc androgen bioassay at high enough concentrations. These cell biology studies, however, lack the clinching evidence that A effects would still occur if conversion to T or DHT was prevented in the culture system. The cameo appearance of female spotted hyenas in this paper reflects a speculation on the possible androgenic effects of A in its own right arising from nature’s eccentric experiment with this species. Striking female dominance, a reproductive role reversal reflecting prenatal and infantile virilization, has been attributed to higher blood A levels in females than males. However, this explanation remains inconclusive for the same reasons as the cell biology experiments in that it remains likely that virilization due to A might occur only after conversion to more potent natural androgens within tissues. Indeed, 2-fold higher female than male blood A concentrations are equally evident in normal humans. However interesting this biological arcania, such evidence reflects the limitations of observational as opposed to experimental science, a dichotomy between weak and strong science that would appeal to Popper. Nevertheless, in concert these findings provide persuasive evidence that Andro is a prosteroid and, to a minor degree, a bioactive steroid in its own right, although only at industrial doses.
In this study, Bhasin’s group (12) has again advanced the frontiers of clinical research into androgen action. In 1996, his group pioneered the careful clinical study of high-dose androgens, a minefield of ethical tripwires, by showing unequivocally that high-dose T increased muscle mass and strength even in eugonadal men (16). In painstakingly creating a seminal precedent that such clinical research could be done safely and ethically, Bhasin’s 1996 study overturned previous wisdom that anabolic steroids had no definite beneficial effects on muscle mass or strength. This was best embodied by a technically excellent metaanalysis summating as inconclusive all available previous studies (17). The fatal flaw for that metaanalysis was that all previous studies used low doses that systematically failed to replicate real world androgen abuse. This false belief cost responsible health authorities dearly in credibility with the community of androgen abusers, a significant impediment to educational initiatives against hormone abuse. Bhasin’s group went on to show a strong linear relationship between T dosage and muscle response extending from below to well above the physiological range (18). In rewriting our understanding of androgen action on human muscle, these studies explain the efficacy of androgens as sports doping agents and provide a basis for evaluating antifrailty applications in older men. So in this study, Bhasin’s group (12) has again pushed forward the frontier to study a realistic, real world regimen, rather than the less ethically challenging studies using lower doses that, although safer and easier to conduct, cannot answer the crucial questions. It is salient that androgens have no natural clinical overdosage syndrome, aside perhaps from the mistiming of precocious puberty or masculinity itself according to ultrafeminist ideology. It is hard to imagine another biologically active endogenous compound that could be taken so uneventfully in a clinical trial at approximately 1000 times the normal daily exposure.
Does Andro have other medical potential? Although significantly less well absorbed orally than DHEA, as a prosteroid it shares the fate of being converted in the body into more potent bioactive steroids including T, DHT, and estradiol. The magnitude, consistency, and regulation of these conversions and their biological consequences remain largely unknown, a significant obstacle for marketing. Other than via patentable derivatives, Andro does not appear to have any distinctive properties as a potentially new therapeutic agent compared with other steroidal and nonsteroidal androgens in development. In any case, there is no legitimate health or medical niche that would become neglected were Andro no longer available.
Wisely, The Endocrine Society and the Hormone Foundation joined the lobbying efforts to support the reregulation of Andro and related prosteroids, aiming to have them revert to the appropriate status for steroidal prodrugs, whether novel or natural. This lobbying recently culminated in the Anabolic Steroid Control Act (2004) to close the loopholes in specifying over 30 more androgens, including Andro and related metabolites and derivatives, effectively bringing prosteroids under FDA scrutiny and rendering them no longer legally available over the Internet or counter from 2005. Nevertheless, however successful this legislation might be in its objectives, preventing androgen abuse is likely to require ongoing surveillance. In exempting DHEA and progestins, for example, the 2004 act leaves open the door to new loopholes. The consequences of sustained increases of blood T in women and blood estradiol in men using DHEA, for example, remain to be determined. Similarly, most marketed progestins have androgenic side effects, reflecting their structural relationships with 19-nortestosterone and potential for conversion to unrecognized but potent designer androgens like nobolethone (19) and tetrahydrogestrinone (20), recently identified as illegally manufactured and marketed as undetectable sports doping agents (21). At least the policing of illegal drug manufacturing is likely to be more successful than are educational attempts to deter androgen abuse when the hormones are available over the counter.
Like the sanctioned monopolies of doctors on prescription writing and of companies on marketing drugs within patent, drug regulation is a major but essential restraint on the hypothetically free market for pharmaceuticals. Practical experience, mainly through scandal as the engine of progress, has taught that judicious regulation is a vital balance in the pragmatic mosaic of structures necessary for a civilized modern society to flourish embedded within free market democracy. Such antimarket devices must be used judiciously but, when called for, should be armed with decisive force to achieve their intended result, a form of Powell doctrine applied to the peacetime warfare of drug development, marketing, and regulation. Andro is a good case in point, and the proof by Jasuja et al. (12) that it has clear androgenic effects provides definitive justification, if any more were still needed, to highlight the wisdom of the welcome if overdue reregulation of Andro and prosteroids. It also underscores The Endocrine Society’s laudable public health policy stance and its leadership will need to be exercised in ongoing vigilance.
Footnotes
Abbreviations: A, Androstenedione; AR, androgen receptor; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; T, testosterone.
Received December 2, 2004.
Accepted December 3, 2004.
References
-4-Androstene-3,17-dione binds androgen receptor, promotes myogenesis in vitro, and increases serum testosterone levels, fat-free mass, and muscle strength in hypogonadal men. J Clin Endocrinol Metab 90:875–883
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