1 REVIEW Diamonds are forever: the cortisone legacy Stephen G Hillier, The Queen’s Medical Research Institute, Centre for Reproductive Biology, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK (Requests for offprints should be addressed to S G Hillier; Email: [email protected]) This article is based on the Jubilee Medal lecture delivered by Prof. Hillier in November 2006 celebrating the Diamond Jubilee of the Society for Endocrinology Abstract The year 1946 was not only the year that the Society for developments in endocrinology ever since. This article Endocrinology was founded, but also the year that Edward surveys the extraordinary cortisone timeline, from first Kendall’s compound E (cortisone) was first synthesised by synthesis until now. The concluding scientific message is Louis Sarett. By 1948, sufficient quantities of compound E that intracrine metabolism of cortisone to cortisol via were available for the rheumatologist Philip Hench to test it 11bhydroxysteroid dehydrogenase type 1 likely sustains local successfully for the first time in a patient with rheumatoid amplification of glucocorticoid action at sites of inflammation arthritis. It was immediately hailed as a ‘wonder drug’ and was throughout the body. The broader message is that the shown to be effective in a number of inflammation-associated discovery of compound E by Kendall (basic scientist), its conditions, most notably rheumatoid arthritis. The sub- large-scale synthesis by Sarett (industrial chemist) and its sequent development of endocrinology as a discipline is therapeutic application by Hench (rheumatologist) serves as a inextricably linked to the chemistry, biology and medicine of paradigm for modern translational medicine. It is concluded anti-inflammatory glucocorticoids. Sixty years after the first that endocrinology will remain a force in health and disease if chemical synthesis of cortisone, corticosteroids remain among it continues to evolve sans frontie`res at the basic/applied/cli- the top ten most commonly used prescription and over the nical science interface. A challenge for the Society for counter drugs. Basic and clinical studies of glucocorticoid Endocrinology is to ensure this happens. biosynthesis, metabolism and action have trail-blazed Journal of Endocrinology (2007) 195, 1–6 Introduction synthesis and therapeutic applications are celebrated as a paradigm for modern translational medicine. The Society for Endocrinology was founded in 1946 ‘to promote the advance of endocrinology by observational or clinical studies’. The year 1946 was also the year that Lewis The steroid rush Hastings Sarett, an organic chemist at Merck Research Labs in the USA, published the first synthesis of a recently discovered The bedrock of the Society for Endocrinology is steroid adrenal steroid hormone named ‘compound E’ (Sarett 1946). chemistry, which entered its heyday during the 1930s. Compound E had been crystallised from bovine adrenal Landmark developments around that time included elucida- glands 10 years earlier by Edward Calvin Kendall (Mason et al. tion of the signature perhydrocyclo-pentanophenanthrene 1936). Kendall’s compound E would eventually be known as steroid structure by Otto Rosenheim and Harold King in ‘cortisone’ (Kendall 1953) and become one of the wonder 1932 (Feiser & Feiser 1959) and introduction of the general drugs of the 20th century. Hence, 2006 was the diamond name ‘steroid’ in 1936 to cover all compounds with a sterol- jubilee year of both the UK Society of Endocrinology and the like skeleton (Klyne 1957). The sex steroids oestradiol, first synthesis of compound E. This brief review traces the testosterone and progesterone were discovered between 1929 impact of cortisone on the development of steroid and 1935, followed by the adrenocortical hormones, endocrinology from then until now. The concept is advanced cortisone and cortisol, in 1935–1938. By 1937, most of the that its intracrine activation to cortisol at sites of inflammation classic steroid hormones had been isolated and their structures supports both natural and therapeutic anti-inflammatory determined (Feiser & Feiser 1959). Following a hiatus during effects of cortisone. More broadly, cortisone’s discovery, WWII, the field was massively boosted in 1948 by the Journal of Endocrinology (2007) 195, 1–6 DOI: 10.1677/JOE-07-0309 0022–0795/07/0195–001 q 2007 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/27/2021 04:06:58PM via free access 2 S G HILLIER . Cortisone and inflammation announcement of the dramatic therapeutic effects of cortisone By January 1950, Kendall & Hench had named compound E (see below) and the race to synthesise more and more steroid as cortisone to avoid its confusion with vitamin E (Kendall analogues with beneficial therapeutic effects. By 1956, 10 1964). In the same year, Kendall & Hench shared the Nobel years after the Society was founded, the number of novel Prize for Physiology or Medicine ‘for research on the steroidal substances synthesised had risen to over 7000 (Klyne structure and biological effects of adrenal cortex hormones’ 1957). During this period, the mineralocorticoid aldosterone with Tadeus Reichstein who had independently discovered was also discovered (Simpson et al. 1953). The first Society for cortisone at around the same time as Kendall and named it Endocrinology Medal was awarded to the co-discoverer of substance Fa (Reichstein 1936). aldosterone, James F Tait, in 1968. Significantly, the obverse prominently displays the perhydrocyclo-pentanophenan- threne steroid nucleus. Diamond decades Ever since it was ‘launched’ as a pharmaceutical in 1950 Kendall’s compounds (Kendall 1964), cortisone and a succession of closely related synthetic analogues have remained among the most widely Compound E was first isolated in 1935 from bovine adrenal prescribed medications in the world. At the same time, the glands along with a series of structurally related steroids science of endocrinology – particularly steroid endocrinology (including cortisol, then named compound F) capable of – has advanced beyond recognition. Understanding how improving muscular strength when administered to adrenal- cortisone is formed, metabolised and acts in health and disease ectomised rats or dogs (Mason et al. 1936, Reichstein 1936). has been integral to this progress, as is now considered. Individual steroid yields were only between 85 and 500 mg cortisone per 100 lb adrenal glands (Feiser & Feiser 1959). 1950s: steroid chemistry Therefore it was initially agreed that their use should be confined to small animals and none should be employed for Kendall (1964) initially believed it, ‘.highly improbable that clinical medicine (Hench 1964). The impetus to develop any product will ever be found which can be used in place of synthetic methods for adrenocorticosteroids came from the cortisone and the closely related compound F’. Compound F US entry into WWII in 1941, initially fuelled by a rumour (hydrocortisone; cortisol) quickly became the first topically that Luftwaffe pilots were taking adrenal extracts to increase applied corticosteroid effective in a variety of inflammatory their resistance to oxygen deprivation at high altitudes. skin disorders (Sulzberger & Witten 1952, Ravis & Eaglstein Although this rumour was unfounded, it is said to have kick- 2007). Meanwhile, cortisone was being hailed as a panacea for started the all-out quest for a large-scale synthetic route to the treating various diseases of unknown cause but with an active adrenal hormone, which at the time was given higher inflammatory basis. However, with high dosage and long- strategic priority than penicillin and anti-malarials (Quirke term usage, the remarkable therapeutic effects of cortisone 2005). Of the six biologically active steroids that had been were countered by undesirable side effects, such as excessive isolated from adrenal glands, Kendall’s compound A (11- salt and water retention, increased gastric acidity and dehydrocorticosterone) was initially targeted for synthesis psychosis. Considerable effort was therefore directed at because it possessed the simplest structure (Kendall 1964). chemical and microbiological syntheses of new cortisone Although synthetic ‘A’ proved to be active in animals, it had derivatives with lessened toxicity and improved efficacy no beneficial effects in patients with Addison’s disease. (Feiser & Feiser 1959). Progress was aided by the arrival of Therefore, attention turned to the closely related ‘E’ conformational analysis, which allowed molecular structures (cortisone), eventually leading to the historic 37-step and stereochemical confirmations to be assigned on the basis synthesis from desoxycholic acid published by Sarett (1946). of quantitative physiochemical parameters (Barton & By summer 1948, sufficient compound E was available for Cookson 1956). Milestones included the discovery that Kendall’s long-time collaborator at the Mayo Clinic, Philip whereas 9a-fluorination increased anti-inflammatory Showalter Hench, to test clinically. A pilot trial of compound potency, it also caused excessive protein loss, potassium loss, E on a patient with Addison’s disease was ‘encouraging’ sodium retention and oedema. On the other hand, (Kendall 1964). Then, on 21 September 1948, the first i.m. introduction of a 1,2 double bond in the A ring (to create injection of an aqueous suspension of compound E (100 mg) prednisone from cortisone and prednisolone