Social Science & Medicine xxx (2014) 1e8

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Growth hormone, enhancement and the pharmaceuticalisation of short stature Michael Morrison Centre for Health, Law & Emerging Technologies (HeLEX), Nuffield Department of Population Health, University of Oxford, Room 120, Rosemary Rue Building, Old Road Campus, Headington, OX3 7LF Oxford, Oxon, UK

a r t i c l e i n f o

a b s t r a c t

Article history: Available online xxx

This paper takes the biological drug human Growth Hormone (hGH) as a case study to investigate processes of pharmaceuticalisation and medicalisation in configuring childhood short stature as a site for pharmaceutical intervention. Human growth hormone is considered to have legitimate applications in treating childhood growth hormone deficiency and short stature associated with other recognised conditions. It is also regarded by bioethicists and others as a form of human biomedical enhancement when applied to children with idiopathic or ‘normal’ short stature. The purpose of this study is not to evaluate whether treatment of idiopathic short stature is enhancement or not, but to evaluate how some applications of hGH in treating short stature have come to be accepted and stabilised as legitimate ‘therapies’ while others remain contested as ‘enhancements’. A comparative, historical approach is employed, drawing on approaches from medical sociology and Science and Technology Studies (STS) to set out a socio-technical history of hGH in the US and UK. Through this history the relative influence and interplay of drivers of pharmaceuticalisation, including industry marketing and networks of drug distribution, and processes of medicalisation will be employed to address this question and simultaneously query the value of enhancement as a sociological concept. © 2014 Elsevier Ltd. All rights reserved.

Keywords: USA UK Pharmaceuticalisation Medicalisation Human enhancement History Growth hormone STS

1. Pharmaceuticalisation, medicalisation and enhancement Pharmaceuticalisation describes a process whereby ‘human conditions, capabilities and capacities’ are (re)configured as sites for intervention with pharmaceutical drugs (Williams et al., 2011, p711). Sociological interest in pharmaceutical use has been increasing in recent years, at least partly in response to significant increases in sales and application of pharmaceuticals since the 1980s (Busfield, 2003; Williams et al., 2008). This interest has manifested through transformations in well-established sociological concepts such as medicalisation (Conrad, 2005) and also in the rise of work on pharmaceuticalisation. Pharmaceuticalisation theorists have argued that a separate theory, linked to but discrete from medicalisation, is required to adequately theorise increasing pharmaceutical use. One argument is that pharmaceuticalisation can occur without accompanying medicalisation e for example when non-pharmaceutical treatments for existing medical conditions are replaced by pharmaceutical interventions (Abraham, 2010). It is also argued that aspects of pharmaceuticalisation occur outside the boundaries of medicine and medical authority.

For Abraham (2010, p606) this involves making a distinction between ‘biomedicalist’ arguments that growth in drug treatment is driven by scientific progress in identifying new pharmaceutical treatments for disease, and alternative non-medical explanations for the expansion in drug use such as ‘commercial priorities, government agendas, and false expectations of doctors and patients’. While Williams et al. (2011, p711) present a more constructionist, STS-influenced version of pharmaceuticalisation to Abrahams' realist model, they articulate a similar sentiment, arguing that the processes of pharmaceuticalisation ‘extend far beyond the realms of the strictly medical or the medicalised to […] non-medical uses for lifestyle, augmentation or enhancement purposes’. It is this contention that there is a realm, however defined, outside medicine where medical drugs are bring employed for ‘non-medical’ uses that makes pharmaceuticalisation a relevant analytic tool for examining the phenomenon of human enhancement. Human biomedical enhancement involves the use of ‘drugs, surgery and other medical interventions aimed at improving mind, body or performance’ (Conrad and Potter, 2004, p185). Enhancement, by definition, involves an expansion of medical technologies, including pharmaceuticals, beyond the traditional medical role of therapeutic or palliative intervention (Juengst, 1998; Daniels,

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2000). As such, it has been analysed by social theorists through the lenses of medicalisation (Conrad and Potter, 2004; Conrad, 2005) and pharmaceuticalisation (Coveney et al., 2011; Williams et al., 2011; see also Bell and Figert, 2012). The relationship between pharmaceuticalisation and medicalisation theories is not an ‘either/ or’ dichotomy. Relations between processes of medicalisation and pharmaceuticalisation are complex and contextual, ranging from mutual reinforcement to opposition (Abraham, 2010; Williams et al., 2011). Both processes can also be partial and reversible. Given this, it seems more appropriate to investigate the interactions between processes of medicalisation and pharmaceuticalisation in analysing human enhancement, than to focus on pharmaceuticalisation alone. Another contemporary update to medicalisation theory is also relevant for theorising biomedical enhancement. The biomedicalisation thesis propounded by Clarke et al. (2003) argues that medicine is becoming ever more technological and orientated around bioscientific understandings of the body and of human conditions. The power of biomedicine renders the body pliable as ‘an object which can be manipulated, reconfigured, moulded, sculpted and transformed through technoscience’ (Coveney et al., 2011, p380). Where medicalisation, it is argued, deals primarily with issues of medical control and normalisation, biomedicalisation emphasises ideas of transformation, choice and opportunities for customisation and enhancement. Thus studies of human enhancement through medicalisation theory must also engage with the questions of whether particular cases of enhancement are better characterised as ‘traditional’ medicalisation or biomedicalisation, and whether this distinction is analytically useful to the case. The aim of this paper is to take an empirical case study of a pharmaceutical described as having enhancement uses as a site to investigate the utility of using pharmaceuticalisation (and medicalisation) to gain analytic purchase on enhancement phenomenon. The selected case study is the use of human Growth Hormone (hGH) as a pharmaceutical intervention to increase the adult height of children with short stature. 1.1. Why human growth hormone? The naturally occurring human growth hormone protein was first isolated from human pituitary glands by American biochemists in the late 1950s. The newly isolated molecule was almost immediately investigated as an experimental intervention for children with abnormally short stature. The first report of a measurable increase in growth rate and height in a short child produced by administration of hGH was reported in 1958 and stimulated efforts to produce and supply the hormone to US paediatric endocrinologists (Raben, 1958; Tattersall, 1996). Although the initial discovery was made in the US, many other countries soon followed suit and set up their own systems of pituitary collection and hormone extraction. Pituitary-derived hGH was primarily used to treat children classified as having severe growth hormone deficiency (GHD) until 1985, when supplies of pituitary hGH were found to have been to be contaminated with biological material causing neurodegenerative effects, and rapidly withdrawn from use. A biosynthetic version of hGH, produced through the newlydeveloped technology of recombinantly-engineered cells incorporating the human genetic sequence for the growth hormone protein was pushed through the final stages of regulatory approval and became available by the end of 1985 (Tattersall, 1996). The recombinant hGH was produced by the US firms Eli Lilly and Genentech and marked a transition of hGH into established networks of commercial pharmaceutical production, sales and marketing. In the years following this transition, the patient population for hGH

increased significantly, including through off-label use in a range of short statured conditions. For many commentators this expansion reached its zenith in 2003 when the US Food and Drug Administration (FDA) approved Eli Lilly's Humatrope brand growth hormone for the treatment of idiopathic short stature (ISS). Treating children with idiopathic short stature, or short stature with no discernable physiological causation, is regarded by many as human enhancement (Tauer, 1995; Daniels, 1992; Conrad and Potter, 2004). Growth hormone makes a good case study for investigating enhancement for a number of reasons. It is a regularly cited example of a drug that can be used for both normal therapeutic applications and as a form of human biomedical enhancement, providing an opportunity compare pharmaceuticalisation across a legitimated therapeutic use and a contested enhancement application. The story of hGH begins in the mid-twentieth century, meaning there is a relatively accessible record of academic medical articles and pharmaceutical and regulatory ‘grey’ literature through which to trace the history of ideas and applications of the drug by those most closely involved with it (Weiner, 1988). Additionally, hGH has only received regulatory approval for treating ISS in the US, offering potential for comparative studies of hGH in other regulatory domains. Conrad and Potter (2004) have also argued that the value of hGH as a case study lies in its multiple enhancement uses, as hGH is also used as an illegal performance enhancer by athletes and bodybuilders and is prescribed off-label as an anti-ageing drug in some private clinics. Although there is merit to this appraisal, this article will focus exclusively on the use of hGH in short stature in order to give this example the in-depth consideration that it warrants and that has, arguably, been lacking in previous social science accounts. 2. Methods Drawing on the recommendations of Coveney et al. (2011), this study combines perspectives from medical sociology and Science and Technology Studies (STS) to investigate pharmaceuticalisation in the case of hGH. Following an STS perspective, technologies, including hGH, do not appear fully-formed to present ethical dilemmas about their use, but are shaped over the history of their creation, regulation and deployment. Accordingly, this investigation takes the form of a socio-technical history of hGH, tracing its early development, initial application and subsequent expansion including its contested application in ISS children (c.f. Oudshoorn, 1994; Goodman and Walsh, 2001). This history can be traced using the academic medical and ‘grey’ literature from the appropriate time period. Such an approach avoids taking a teleological ‘biomedicalist’ perspective on drug development and instead looks at the changing networks, conceptual frameworks and social relations through which hGH became available as a pharmaceutical. In theorising these networks it is also helpful to adopt the concept of a ‘pharmaceutical regime’ e a particular, more-or-less stable set of networks, ideas and relations through which particular types of pharmaceutical, such as hormone drugs, are produced and supplied (Goodman and Walsh, 1993 cited in Williams et al., 2011). This particular socio-technical history focuses on the comparative development of hGH in the US and the UK. Against the charge of an excessive focus on ‘Western’ issues at the expense of the rest of the world (Bell and Figert, 2012), I argue that human enhancement, much more so than the pharmaceutical industry, is at present primarily a Western phenomenon. The concept of biomedical enhancement and many of the technological applications described as ‘enhancing’ originate in the US, making it an obvious component for investigating pharmaceuticalisation and enhancement, while the UK presents a useful and accessible counter-example, which

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has taken a distinctly different stance on the application of hGH in ISS. 2.1. Troubles with enhancement Most sociological commentators are quick to acknowledge the difficulty of establishing a clear boundary between therapeutic use of medicine and enhancement; [w]hat constitutes a disease or disorder worthy of treatment and where to draw the line between these forms of therapy and other forms of enhancement amongst healthy people is no simple matter (Williams et al., 2011, p718). Nonetheless, this type of stance remains problematic because it employs the category of ‘enhancement’ without adequately defining what it means or unpacking the provenance of the term. The concept of human biomedical enhancement was developed by, primarily North American, bioethicists in the late 1970s and early 1980s as a rhetorical tool, initially intended to gain moral purchase on the potential uses of human genetic engineering technology (Crigger, 1998; Scully and Rehmann-Sutter, 2001). Enhancement is understood as one part of a dichotomy with therapy, where therapy describes the (morally) appropriate domain of medicine and enhancement transgresses it. The distinction between therapy and enhancement relies on the model of an ahistorical, acultural ‘normal’ human body as a ‘fixed point’ for assessing the morality of biomedical technologies (Daniels, 2000). As, such it embodies a second dichotomy, that between the natural and the cultural, where the former is privileged as authoritative, scientific and factual and where the body, and knowledge about the body belongs exclusively to nature (Twine, 2005). One outcome of this way of thinking is that biomedical enhancement is presented as a problem for society, but a problem created by a biomedical science that deals only with objective nature and is not itself ‘contaminated’ by the social. This mainstream bioethical framing of enhancement is, or at least should be, highly problematic for approaches to medicalisation and pharmaceuticalisation drawing on constructivist strands of STS and medical sociology (see Pickersgill, 2012 for a discussion of similar issues in psychiatry). It is therefore troubling to see scholars such as Conrad and Potter (2004) acknowledge that ‘the definition of health is socially situated, flexible and may ultimately be a mirage’ (p185) but then conclude that ‘hGH is used as a biomedical solution to what are fundamentally social problems’ (p201 emphasis added). Similarly Williams et al. (2011) write about ‘non-medical uses for lifestyle, augmentation or enhancement purposes’ (p711 emphasis added) as if these are unproblematic categories. If medical problems are a particular subset of social problems and the remit of what counts as ‘medical’ varies across time and in different socio-cultural contexts (Foucault, 1973; Lupton, 2000), then the distinction between problems being fundamentally ‘medical’ or ‘social’ makes no sense. Taken to its logical extreme, medicalisation theory allows that one day all social problems could be addressed through medicine. If medicalisation and pharmaceuticalisation are ideally value neutral descriptive approaches, then even full medicalisation or full pharmaceuticalisation of society cannot be deemed a priori negative developments on the grounds that a ‘fundamental’ boundary has been transgressed between social and medical problems. Instead, the balance of positive and negative consequences would still have to be investigated on a case by case basis. Given this, it is recommend that social scientists should not employ the term ‘human enhancement’ as if it was a neutral descriptive term. It is important to remember that ‘enhancement’ is

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a label conferred on particular technologies, or applications of technologies, by bioethicists. A more appropriate topic for sociological inquiry is therefore to ask how certain technologies come to be labelled as ‘enhancements’ while others are legitimated as ‘therapies’ and whether there is any analytic value in this labelling, other than to identify cases for sociological investigation. I therefore reframe my earlier contention that pharmaceuticalisation and medicalisation are relevant tools for studying enhancement phenomena. Rather, they are relevant tools for investigating cases labelled as enhancement. The central research question of this paper is therefore to ask how some uses of a pharmaceutical intervention in childhood short stature came to be legitimated as therapy while others remain contested and labelled enhancement. The following socio-technical history will attempt to answer this question by tracing the development of hGH and its uses, using pharmaceuticalisation and medicalisation as analytic tools.

3. Pharmaceuticalisation, medicalisation and short stature 3.1. Making abnormal short stature In order to investigate how a medical intervention for amelioration of short stature emerged, it is first necessary to ask how stature itself became an object of medical scrutiny. Human height and weight first came under the authority of public health during the nineteenth century, through the application of the normal distribution curve (Tanner, 1981). The normal curve allows individual height or weight measurements to be compared against a population mean value. Following the statistical convention, values within two standard deviations (SD) of the mean value are considered normal (expected) while values more than 2SD above or below the average are considered abnormal. While surveillance of height and weight was initially applied to adult populations, once adjusted for age and gender the normal distribution curve provided a suitably scientific tool for identifying and classifying children as having normal, healthy growth or abnormally tall or short stature for their stage of development. By the beginning of the twentieth century such tools were in demand, as child health had become a significant focus of medical attention: The significance of the child was that it underwent growth and development: there was therefore a constant threat that the proper stages might not be negotiated that in turn justified close medical observation (Armstrong, 1995, p396). This concern manifested in national public health programmes, but was also reflected in the emergence of medical sub-specialities such as paediatrics, and later paediatric endocrinology, dedicated not merely to observing, but also to intervening in childhood disorders. Following Conrad's ‘definitional’ view of medicalisation, where the core element is ‘defining a problem in medical terms, usually as an illness or disorder, or using a medical intervention to treat it’ (2005, p3), it is not immediately obvious whether the public health surveillance of childhood development counts as an instance of medicalisation. Abnormal height was mainly considered a marker for the risk of an underlying pathology, not as a disease in itself. However, as Jutel (2011) has argued in the case of ‘overweight’, instruments of measurement play a key role in establishing medical authority over physical states by transforming qualitative descriptions into quantitative assessments. The basis of diagnosis, and thus medical authority, begins with the measurement and comparison of individuals against the group or population and the

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production of categories of normal and abnormal into which people can be divided. The emergent paediatric and paediatric endocrine specialists and clinics provided new sites where children identified as having abnormal short stature through public health surveillance could be channelled into regimes of medical care and, importantly, intervention. Well before hGH became available, there is evidence that the impulse to treat short stature was already present in these spaces. Hamilton (1986) and Hoberman (2005) report the trialling of other hormones including oestrogen, testosterone, and even crude pituitary extracts as experimental (and largely unsuccessful) growth boosting interventions in the 1930s and 40s. Jutel's work on overweight is again pertinent here, in discussing how the boundaries between what counts as a symptom, an index of measurement for classification, and a condition itself can become blurred: ‘Weight is not only the diagnosing tool, but when there is enough of it […] it becomes a disease in and of itself’ (Jutel, 2011, p43). This suggests that a ‘slippage’, more subtle than a crude therapy/ enhancement distinction, was already occurring in the medical framing of short stature well before the emergence of hGH.

3.2. hGH and the pharmaceutical regime of endocrine drugs A second pertinent question regarding the emergence of a pharmaceutical intervention for short stature is to ask how the isolation of a naturally-occurring protein became so rapidly (re) configured as a pharmaceutical intervention. Here the discussion will present three interlinked currents in the history of endocrinology that go some way toward answering this question. Early scientific investigations of the glands and their properties employed laboratory animals which had undergone surgery to remove the particular gland under study (Oudshoorn, 1994). These animals would then be examined to see if their symptoms resembled any human diseases that might then be attributable to glandular deficiency. The next step was to feed the surgically-modified animals with different extracts made from the removed glands to detect which components might restore the animals to a healthy, pre-surgery state and thus identify the ‘active component’ e the hormone e produced by the gland. This indicates that even basic research on hormones contained an orientation towards human health and a model of hormones as agents for intervention. Laboratory investigation of the glands also became closely linked to the enrolment of the newly isolated hormones as pharmaceutical products well before hGH was isolated. Animal models remained the main site of study and isolation of new hormones. Once isolated, the most efficient, and perhaps the only cost effective, way to manufacture newly discovered hormone molecules was to use the glands of livestock animals such as sheep, pigs and cows, which were already being processed on an industrial scale, as a source of raw material (Oudshoorn, 1994). Unlike individual researchers, pharmaceutical firms had the financial and infrastructural capabilities to access and process this raw material. The decades following the licensing of the ‘wonder drug’ insulin to Eli Lilly in 1922 saw a series of ‘races’ to isolate new hormones, including the oestrogens, progesterone and testosterone, carried out by academic laboratories in direct partnership with pharmaceutical companies (Rasmussen, 2002). The search for a growth hormone was also part of this phenomenon. By the 1940s, the first animal growth hormones had been successfully isolated and pharmaceutical companies were already making deals with meatpacking firms to access a supply if animal pituitaries (Tattersall, 1996). There was thus a commercially lucrative pharmaceutical regime already in place into which growth hormone was expected to be enrolled.

This does not, however, explain why growth hormone was so anticipated. As early as 1921 the renowned American neurosurgeon Harvey Cushing had speculated that the pituitary gland might secrete a ‘hormone of growth’. Rasmussen (2002) has described how hormones and hormone drugs came to be regarded as ‘life's master molecules’ during the early decades of the twentieth century. Subsequent laboratory research can then be seen as the search for the expected ‘master molecule’ for governing animal and human growth. Through the pharmaceutical regime that had become established around previous hormones, growth hormone also promised to provide the next ‘big’ hormone drug, one that would permit pharmaceutical control over the biochemical mechanisms of human growth. 3.3. Pituitary hGH Raben's 1958 report announced the long expected arrival of the new master molecule for controlling growth. However, hGH did not follow the expected pathway to deployment as a pharmaceutical. Unlike previous hormones, hGH had an unexpected species specificity, meaning only GH extracted from human pituitaries would produce a physiological response in human children. This material property had two significant, related effects: with obvious limitations on the procurement of human cadavers for pituitary extraction, the supply of growth hormone was limited, and the lack of a mass-production option meant that commercial companies in the US and UK did not become involved in the manufacture of hGH in any significant way. The initial deployment of the new drug was largely an American affair. With established commercial networks of production and supply unavailable, the deployment of pituitary growth hormone relied on the formation of new, initially informal networks of collaboration between pathologists, biochemists and endocrinologists. Pathologists could extract the raw material of human pituitary glands, but needed biochemists to perform the technically difficult extraction of hGH. Extracted hGH would then be sent to paediatric endocrinologists for application and study. In 1961 the US National Pituitary Agency (NPA) was founded to oversee pituitary collection and distribution (Frasier, 1997). The NPA can be seen as an attempt to give a formal structure and authority to the informal networks that had arisen around hGH. The agency brought together the principal biochemists with the skill to extract hGH from pituitary glands, representatives from the College of American Pathologists to ensure the co-operation of their members and the National Institute for Arthritis and Metabolic Diseases (NIAMD) to provide state-associated legitimacy and, after 1963, funding (Anon, 1963). In the UK the Medical Research Council (MRC) had previously taken a lead in developing insulin production in the UK, liaising with the University of Toronto and Eli Lilly and ultimately forming a committee of physicians to oversee clinical experimentation with insulin in the UK (Sinding, 2002). Following the early reports of hGH in the US, the MRC decided to adopt a similar approach, setting up a Pituitary Hormone Committee to design and run a clinical trial investigating the potential of pituitary hGH as a growth promoting agent for short children in the UK (Milner, 1979). Physicians were encouraged to refer short statured children to the hormone committee, which then assessed them for inclusion in the trial. While the UK response drew largely on established institutional forms (the MRC, the NHS) in contrast to the emergent new networks of the US, both approaches produced similar results. In both cases the application of hGH was regarded as experimental intervention where both the selection criteria for patients and the regime of application of hGH were largely the responsibility of physicians and academics and were not subject to

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oversight from national regulatory agencies. Both networks served to exclude the pharmaceutical industry from sourcing raw material or supplying hGH from other territories directly to clinicians. In the US, this occurred because the NIAMD, as part of the US National Institutes of Health (NIH), was limited to supporting medical and scientific research and could not fund routine healthcare. Endocrinologists in the US wishing to obtain pituitary hGH had to submit a research application to the NPA explaining what they wished to study (e.g. differences in growth responses between sexes or establishing dose response curves in children at different ages). As a result, access to hGH was largely restricted to those endocrinologists capable of writing applications and carrying out research e which effectively meant those based in universities and teaching hospitals. Both systems also meant that, where selected, patients were receiving hGH on a not-for-profit basis. At this time, there was no diagnostic category of GH deficiency to work with as there was no means to measure hGH levels in the blood. Instead, cases of pituitary damage (e.g. caused by tumours) were assumed to have lower hGH levels as a result of the damage. In both countries, there was considerable early enthusiasm about the potential of the new drug to act as a panacea for short stature. In the US, one of the co-founders of the NPA wrote: Certainly on a theoretical basis, pharmacological doses [of hGH] should be effective in most children before epiphyseal [bone] fusion (Blizzard and Hopkins, 1963, p439). Similarly, the MRC trial included short children with diagnoses of suspected GH deficiency due to pituitary damage, a variety of syndromes of growth retardation linked with chromosomal abnormalities including Turner syndrome (TS) and PradereWilli syndrome (PWS), children with poor growth associated with low birth-weight and other patients with uncertain (idiopathic) growth failure (Tanner et al., 1971). This early optimism was soon tempered by the results of the first wave of clinical research. HGH failed to produce an unequivocal growth response in many of the children to whom it was administered. The therapeutic agenda in the US and UK then shifted towards rationing the limited resource and prioritising the most responsive and the most needy patients (Ibid.). By this point a biochemical assay to measure the levels of circulating hGH in the blood had been developed by American biochemists. When the assay was applied, children with known pituitary damage and very short stature were found to demonstrate notably lower levels of circulating hGH compared to normal-statured subjects. This provided evidence of a link between stature and hGH levels in the blood, allowing the concept of growth hormone deficient (GHD) short stature to be realised. Significantly, these children also showed the clearest growth response to application of pituitary hGH. In order to select the most needy and most responsive patients, a combination of the biochemical (circulating hGH) and statistical measurements were combined. GHD children were defined as those having the lowest levels of circulating hGH and physical height at least two standard deviations (though often more) below the mean height on a normal distribution curve. The creation of the diagnostic category of GHD demonstrates a clear co-construction of drug and disease. It also extended the processes of medicalisation of stature that began with the statistical tools that made abnormal short stature visible as a phenotype. Combining statistical measurement with a second index of classification e a biochemical measurement eadds an underlying, biological explanation for the phenotype, making GHD a full disease category and something wholly under medical authority. This definition also produces the disease category of GH deficiency as a problem with an inbuilt solution e GH replacement.

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This initial experimental deployment of hGH and its emergence as a therapy for GH deficiency is also a clear example of pharmaceuticalisation, as short stature becomes understood for the first time as a human state that can be altered through pharmaceutical intervention. The alternative networks that emerged between pathologists, biochemists, endocrinologists and funders demonstrate that pharmaceuticalisation can proceed not only in concordance with medicalisation, but also without direct involvement from pharmaceutical companies. This suggests that academic medical experimentation and non-industry funded medical research are potentially important sites for the production of new knowledge about pharmaceuticals and drivers of pharmaceuticalisation. 3.4. Biosynthetic hGH Recombinant hGH, manufactured by Eli Lilly and Genentech, is for all practical purposes identical to the naturally occurring pituitary hGH. It received formal regulatory approval from the FDA and other national regulatory agencies at the end of 1985 as a licensed treatment for GHD. This transition into the more familiar pharmaceutical regime of national regulatory agencies, pharmaceutical companies and sales and marketing campaigns rendered the alternative networks of pituitary hGH obsolete and they had largely shut down by 1986. Under the new regime the size of the US patient population for hGH rose from an estimated 3000 in 1985 to around 20,000 by the mid-1990s (Neely and Rosenfeld, 1994). This did not only include children with GHD. HGH was also licensed as a treatment for short stature in a range of other conditions. The first such approval in the US was for the minor indication of boosting growth in children with renal insufficiency (1993), followed by Turner syndrome (1996), PradereWilli syndrome (2000), children born small for gestational age (2001) and finally, and most controversially, idiopathic short stature (ISS) in 2003. European regulatory approvals (including the UK) generally matched what was happening in the US with the notable exception of ISS, for which no European regulatory approval has been requested to date. To what extent can this expansion be explained in terms of Abraham (2010) ‘non-medical’ drivers of pharmaceuticalisation? Certainly there is evidence of industry drug promotion and marketing. In 1994 a series of hearings in the US heard evidence that Genentech and Eli Lilly had both been involved in illegally promoting their growth hormone products for off-label use, and that illegal payments to physicians had been made to boost prescription rates (Conrad and Potter, 2004). Both companies were known to form close alliances, including financial support, with patient groups for families of short statured children. Genentech was also investigated for its sponsorship of school-based height surveys, in which school children were statistically assessed for height and those notably below the mean height often recommended to seek medical appraisal (Weiss, 1994). In 1999 Genentech admitted that it had aggressively promoted hGH for off label use to endocrinologists and accepted a US$ 50 million fine from the FDA (Nordenberg, 1999). The power of industry promotion becomes ever more evident when the twenty thousand strong US patient population for hGH is compared with European countries where different, often more strict rules apply to pharmaceutical sales and marketing. Comparable figures are not available for the UK, but estimates suggest that the incidence of GHD in the UK is around one tenth that of the US, similar to other European countries such as France and Germany (Guyda, 1999). However, there are other factors to consider that suggest the growing pharmaceuticalisation of stature was not due to industry power alone. In the pituitary networks hGH use was limited to research by endocrinologists primarily in academic or teaching

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hospital positions. The regulatory approval of recombinant hGH for GHD meant that it could be marketed to all board-certified paediatricians and paediatric endocrinologists in North America, and accessed through the NHS by their counterparts in the UK. This represented a substantial increase in the number of people and centres able to see short statured children as patients and prescribe hGH. Furthermore, with the supply of hGH no longer restricted by the availability of human pituitaries, physicians were also able to prescribe hGH for longer and in higher doses. Similarly, the use of hGH to treat short stature in other, non GHdeficient conditions can be understood as the result of a confluence of academic and industrial interests. Members of the old pituitary networks were well aware of the development of recombinant form of the drug before its formal approval in 1985. From the outset, treating GHD was not the only benefit anticipated from having an ‘unlimited’ supply of the biosynthetic hormone. Anticipating this ‘new era’ both the US NPA and the UK's Health Service committee supported trials of pituitary GH in short children who did not meet the biochemical criteria for GH deficiency but who, based on experimental work from the 1970s, it was believed might still show a diminished but definite growth response to hGH (Hindmarsh and Brook, 1987). All of the later approvals of recombinant hGH for further categories of short stature, including idiopathic short stature, had already been investigated using pituitary growth hormone, whether in the original MRC trial, in small investigative studies supported by NPA/NIAMD or in these later investigations prompted by the immanent arrival of the biosynthetic product. This illustrates that ISS was not a mere marketing invention of the pharmaceutical industry. Instead more complex interaction between medical and pharmaceutical industry interests and between processes of medicalisation and pharmaceuticalisation are involved in the expansion of hGH use in short stature. Why then has ISS failed to attain legitimacy when other uses of hGH in non-GHD conditions have been largely non-contested? One explanation is that other conditions such as Turner syndrome or small-for gestational age births are pre-existing, already legitimised medical conditions for which growth retardation is one of the recognised symptoms. ISS by contrast is based on statistical assessment of abnormal stature alone and, by definition, has no detectable underlying pathological cause, making it an inherently less authoritative diagnostic category from a medical perspective (after Foucault, 1973). Some physicians regard it not as a ‘real’ diagnostic category, but as a ‘diagnosis of exclusion’ (Wit and Rekers-Mombarg, 2002, p604) e a classificatory ‘space’ for those patients for whom no pathological mechanism can be identified. Treating ISS is therefore contested among medical professionals because it does not wholly meet their criteria for a legitimate diagnostic category, and does not therefore carry an automatic entitlement to treatment. Another explanation is financial. The patient populations for GHD, TS, PWS and other categories are all comparatively small, whereas ISS theoretically includes all the children in a given population whose height is less than 2.25 SD below the average1 In the era of recombinant hGH supply is not truly ‘limitless’ as is sometimes claimed, but rather the limiting factor has switched from the availability of pituitary glands to the cost of providing treatment. ISS represents a significantly larger expansion of the licensed uses of hGH than any previous diagnostic category, presenting a much larger financial burden for healthcare providers, whether private insurers or state-funded agencies, making ISS economically and politically controversial.

1 This definition of short stature replaced the statistical cut-off of 2SD in Lilly's regulatory submission to the FDA for ISS.

While both of these explanations are pertinent, ISS is also controversial because it represents the high-watermark of a continuum of a rejection by paediatric endocrinologists of taking GH deficiency as the dominant way of understanding and defining short stature. GHD was the original diagnostic category for hGH and can also be seen as the ‘gateway’ through which industrially manufactured hGH entered the market of pharmaceutical interventions for short stature. It is perhaps ironic then that the very availability of recombinant hGH also served to destabilise the biochemical boundary of GHD as a diagnostic cut-off point. With the removal of the rationing mind-set of the pituitary GH era, much wider research into hGH, both as a therapeutic agent and as a physiologically active agent was possible. By the 1990s a growing body of experimental work was beginning to reveal that secretion of GH did not fall easily into two levels-the deficient and nondeficient, but rather there appeared to exist a continuum between the most severe deficiency and the levels seen in normal, healthy children (Johanson and Blizzard, 1990). At the same time trials of recombinant hGH were demonstrating that GHD was not a necessary precondition for children to be able to show an increase in growth rate and height. The rationale for using a particular cutoff point in GH levels began to look increasingly uncertain and as a result many paediatric endocrinologists fell back on physical and statistical characteristics as a practical basis for making treatment decisions (Neely and Rosenfeld, 1994). Given this context, the approval of ISS can be seen as part of a continuum of changing practice among endocrinologists, albeit with full support from industry, instead of a one-off ‘enhancement’ use. What ISS does, that the other approved categories of hGH use do not, is to raise the inconvenient question of why it is desirable to intervene in short stature at all. As noted, GHD, TS, PWS are all medically legitimised diagnostic categories. This appears to render the decision to use hGH as an intervention in these conditions impervious to questioning among many doctors, bioethicists and, perhaps more disappointingly, some medical sociologists as well. But this should not be the case. Stripped of an underlying pathological mechanism to hide behind, ISS forces the question of what is actually gained by making short children somewhat less short. The answer is, and can only be that short stature itself is often regarded as an inherently undesirable state. Moreover this is true in all but the most severe cases of GHD, as well as TS, PWS and is not limited to ISS alone. It was arguably present even before hGH was isolated, in the early attempts to treat short stature with other hormone drugs and even in the public health categorisation of being below a certain height as ‘abnormal’ short stature. This is challenging because the evidence for the negative effects of short stature per se is equivocal and contested (Allen and Frost, 1990; Sandberg and Colsman, 2005). ISS, in my analysis, is most controversial because it exposes an underlying rationale for both medicalisation and pharmaceuticalisation of short stature e that short stature requires amelioration e to wider scrutiny. This space of uncertainty also provides an opportunity for bioethicists to colonise the debate using the analytic tools of enhancement and therapy. 4. Conclusion This socio-technical history of hGH has demonstrated that the development and subsequent expansion in use of a pharmaceutical can be usefully understood as a series of complex interactions between heterogeneous processes of pharmaceuticalisation and medicalisation. There is no one simple driver of these processes, but rather different drivers interact with each other at different times and in different spaces. Medicalisation of stature, driven by public health concerns, brought short stature into focus as a quantified state that could be assessed and evaluated in comparison to others

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in a given population. Short stature also becomes problematised at this stage as ‘abnormal’ short stature suggests something that is both undesirable and that required redress. These public health efforts, however, did not directly contribute to the pharmaceuticalisation of stature. This required the development of a chemical means of intervention in stature, which was duly found in the form of hGH. Both the discovery of a molecule expected to govern human growth and its availability as a pharmaceutical were anticipated and planned for by the pharmaceutical regime of hormone-based drugs that preceded the isolation of hGH. I contend that hGH was not a drug ‘looking for a disease’; rather it was a drug with an expected application, which then found itself in need of a diagnostic category to regulate and ration a limited supply. The deployment of pituitary hGH demonstrated that pharmaceuticalisation could occur through medical experimentation (involving small scale trials that often did not correspond to the four stages of formal clinical trials) without any direct involvement of the pharmaceutical industry. It is also worth noting that the absence of national regulatory agencies in the pituitary networks allowed the experimenters a freedom to investigate the effects of hGH in diverse populations in ways that would probably not be possible for industry actors. The transition to a commercially available biosynthetic hGH illustrates the power of pharmaceutical marketing to increase sales (especially in the US), but the more interesting aspect of this period is the confluence between medical and pharmaceutical interests. Industry actors were certainly keen to expand the use of hGH into new indications, but they did so with the active co-operation of many academic paediatric endocrinologists. Indeed, neither Genentech nor Lilly promoted any ‘new’ uses of hGH in short stature that academic clinicians had not already investigated with pituitary hGH. This highlights the power of pharmaceuticals as practical and symbolic tools of both the pharmaceutical industry and the medical profession. As such they connect and bind industry and academic interests in the nexus of pharmaceuticalisation and medicalisation. It is also important to recognise the prestige associated with academic medical experimentation as something that drives exploratory new applications of existing drugs and therefore can also drive pharmaceuticalisation. Even during the most expansive phase of hGH use there is little to suggest that biomedicalisation theory has much to offer this case. HGH treatment brings very short children closer to average height. It does not make anyone taller than average. It is a fundamentally normalising intervention, rather than a vehicle for selfcustomisation or consumer choice. As a result, ISS is controversial not because it represents consumerist self-modification, but because it opens up assumptions about the need to treat short stature which underlie the pharmaceuticalisation-medicalisation nexus to scrutiny about their diagnostic, financial and therapeutic merit. ISS is thus a product of medicalepharmaceutical mutual interest and something which has come to challenge and potentially destabilise these interests. Throughout, this paper has tried to demonstrate that the case of hGH is not a simple matter of a divide between ‘legitimate’ treatment of GHD and dubious modification of children with ISS. This framing has been popularised by bioethicists because it maps neatly unto the therapy vs enhancement model. It also serves to exclude other approved uses of hGH from discussion and to obscure the history of hGH. In so simplifying the case, this approach also severely distorts it, securing GHD firmly in the unquestioned (and seemingly unquestionable) realm of nature and allowing ISS to be presented as the only application of hGH ‘contaminated’ by social factors. It is for exactly these reasons that it is argued that sociologists need to avoid using the term ‘enhancement’ uncritically and

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