Category:Corticosteroids

A corticosteroid is a steroid hormone of the adrenal cortex, or a synthetic analogue of one. The category includes the glucocorticoids, which suppress inflammation, modulate immune function, and regulate the metabolism of glucose and protein; and the mineralocorticoids, whose principal physiological role is the reabsorption of sodium and the excretion of potassium in the distal nephron. The two activities overlap in the natural hormones and have been progressively separated in the synthetic ones.

The clinical history of these medicines begins, indirectly, with the London physician Thomas Addison. In his 1855 monograph On the Constitutional and Local Effects of Disease of the Suprarenal Capsules he described a syndrome of weakness, weight loss, hypotension, and a peculiar bronze pigmentation of the skin in eleven patients, all of whom were found at autopsy to have destroyed adrenal glands.^[1] The condition that now carries his name was, until well into the twentieth century, uniformly fatal; the only treatments available were salt and bed rest. By the 1930s the adrenal cortex was known to contain a heterogeneous mixture of biologically active substances, and three laboratories were working to separate them: Edward Kendall's at the Mayo Clinic, Tadeus Reichstein's at the ETH in Zurich and later at Basel, and Oskar Wintersteiner's at Columbia. Within a few years Reichstein and Kendall, between them, had isolated, named, and partly characterised twenty-eight crystalline compounds from cortical extract; the most biologically active of these was Kendall's Compound E, which would later be renamed cortisone.^[2]

The compound was scarce. To produce enough cortisone for clinical trials, Merck assigned the problem to the organic chemist Lewis Sarett, who developed between 1944 and 1948 a thirty-two-step synthesis from deoxycholic acid, recovered from cattle bile. Each gram of the final product required the bile of forty cattle.^[3] On 21 September 1948 the rheumatologist Philip Hench, who had observed for years that rheumatoid arthritis remitted during pregnancy and in jaundice, asked Kendall for some of Sarett's material and gave a 100-milligram daily injection to a 29-year-old woman who had been bedridden with severe rheumatoid arthritis for five years. Within four days she was walking around her room; the change in the joints was so dramatic that the Mayo investigators ran their fourteen-patient case series in haste and presented it at the staff meetings in April 1949.^[4] The film of patients walking out of their wheelchairs travelled the world. Hench, Kendall, and Reichstein shared the Nobel Prize in Physiology or Medicine in 1950, a span of eighteen months from the first clinical injection that has no parallel in the history of the prize.

A medicine that required forty cattle per gram could not be a medicine. The synthesis problem was solved from two directions. The American chemist Russell Marker, working in Mexico in the early 1940s on the sapogenin diosgenin from the wild yam Dioscorea mexicana, had developed a five-step degradation that produced progesterone in good yield, and had founded the Mexico City firm Syntex on that discovery; Marker's successors, including Carl Djerassi, extended the route to cortisone in 1951.^[5] The decisive step came in 1952 from the Upjohn microbiologists Durey Peterson and Herbert Murray, who showed that the mould Rhizopus arrhizus could introduce a hydroxyl group at the 11α position of progesterone in a single fermentation step, replacing what had been the most laborious arc of any chemical synthesis to that point.^[6] The price of cortisone, $200 per gram in 1949, fell within four years to under $6.

The natural hormones had a problem the synthetic ones could be designed to fix. Cortisol, the principal endogenous glucocorticoid, has significant mineralocorticoid activity, and high-dose cortisone causes sodium retention, hypertension, and hypokalemia. In 1955 Arthur Nobile at the Schering research laboratories used the bacterium Corynebacterium simplex to introduce a 1,2-double bond into the cortisone skeleton; the resulting compound, prednisone (and its reduced form, prednisolone) had four times the anti-inflammatory potency of cortisone with substantially reduced mineralocorticoid effect.^[7] Within months of the prednisone announcement, Josef Fried at Squibb reported that introduction of a 9α-fluorine atom increased glucocorticoid potency further, and the fluorinated steroids (triamcinolone, dexamethasone, betamethasone) followed.^[8] A separate fluorination at C9 produced fludrocortisone, which retained the mineralocorticoid activity of aldosterone in oral form and became the standard replacement therapy for Addison's disease and salt-wasting congenital adrenal hyperplasia.

The systemic glucocorticoid is among the most widely useful medicines in the modern pharmacopoeia, and among the most damaging when taken for long. The catalogue of adverse effects of prolonged use was assembled within a decade of cortisone's introduction and has not been substantially extended since: weight gain and central adiposity, hypertension, hyperglycaemia and diabetes, osteoporosis with vertebral fracture, avascular necrosis of the femoral head, cataract, glaucoma, immunosuppression with opportunistic infection, hypothalamic-pituitary-adrenal axis suppression, growth retardation in children, and psychiatric disturbance ranging from euphoria and insomnia to frank psychosis. To preserve the anti-inflammatory benefit while limiting systemic exposure, two strategies were developed. The first was topical application: hydrocortisone cream entered dermatologic use in 1955, and the medicinal chemistry of high-potency topical steroids (clobetasol propionate, 1973) established the modern topical corticosteroid series. The second was inhalation: beclometasone dipropionate, introduced for asthma by Glaxo in 1972, was the first inhaled corticosteroid, a class that has since become the foundation of long-term asthma control and a significant component of COPD therapy.^[9]

The therapeutic role of the corticosteroid continues to be defined. In the 1980s, the antenatal use of a brief course of betamethasone or dexamethasone was shown to accelerate fetal lung maturation and substantially reduce the mortality of preterm birth.^[10] In 2020, in the RECOVERY trial, a six-milligram daily dose of dexamethasone became the first medicine of any class shown to reduce mortality from severe COVID-19, and that finding was carried into routine care within a week of publication.^[11] Cortisone, eighty-five years after Compound E was crystallised in Rochester, remains a medicine whose history is still being written.

By exposure route and indication:

• Systemic glucocorticoids (oral, parenteral): dexamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone
• Inhaled corticosteroids (asthma, COPD): budesonide, fluticasone, mometasone
• Topical corticosteroids (dermatologic): betamethasone, clobetasol, hydrocortisone
• Mineralocorticoids (replacement therapy): fludrocortisone

Several of the medicines above appear in more than one row because they are used by more than one route. Hydrocortisone is the systemic-replacement steroid of choice in adrenal insufficiency but is also the lowest-potency topical preparation; betamethasone is given systemically (including antenatally) and in high-potency topical and ophthalmic formulations.

The boundary of this category is "an adrenal steroid hormone of the natural or synthetic kind". The androgens (testosterone, the androgen modulators) and the estrogens are gonadal steroids, not adrenal, and are collected separately. The aldosterone antagonists (spironolactone, eplerenone) are receptor antagonists rather than agonists, and although they are functionally anti-mineralocorticoids they are collected under their own class. The anabolic-androgenic steroids used in performance enhancement are outside the scope of this clinical reference; they appear, where they appear at all, only in the safety discussion of their endocrine consequences.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.