300

THE PHARMACOLOGY OF CORTISONE,CORTISOL (HYDROCORTISONE) AND

THEIR NEW ANALOGUESBy OLIVER GARROD, M.D., M.R.C.P.

Physician, Barnet General Hospital; late Research Fellow, Middlesex Hospital

In man the essential functions of the adrenalcortex stem from at least two hormones, cortisol(hydrocortisone) and aldosterone, these differingin their quality of action, mode of secretoryregulation, and probable site of production withinthe gland. The adrenal sex hormones are of re-latively minor physiological importance and willnot be considered here.The new synthetic analogues of cortisol are best

assessed in relation to the essential duality offunction of the adrenal cortex as revealed by theactions of its two principal hormones. The firstfunction is concerned with a number of homoeo-static processes and with resistance to stress andis served by the secretion of cortisol. In the bodycortisol is reversibly interconvertible with corti-sone and is probably the active form of the hor-mone. Cortisol and cortisone, with their almostidentical actions, are called glucocorticoids fortheir effects on carbohydrate metabolism. ThoughIngle (1950) has likened use of the word gluco-corticoid for these steroids to describing anelephant by the shape of its tail, yet it remains auseful generic term to cover all those diverseactions of cortisol and its analogues which seem tobe inseparably linked with their carbohydrateeffects.The second or mineralocorticoid function of the

adrenal cortex is concerned with the regulation ofsodium and potassium balance, and dependslargely on the secretion of aldosterone. A similarbut less potent mineralocorticoid is desoxycorti-costerone (DOC) which, though easily synthesizedand used therapeutically as the acetate (DOCA), issecreted only in small amounts by the adrenalcortex. Further to their glucocorticoid properties,cortisol and cortisone also have a weak mineralo-corticoid activity, which assumes an increasingimportance when they are being produced inexcess as in Cushing's syndrome, or administeredin large doses

Intermediate in quality of action betweencortisolVand aldosterone, but much less potent, is

corticosterone (Compound.B). Though it is thepredominant glucocorticoid in a number ofmammalian species, in man it is of little importancefor only small amounts are secreted (about i mg.a day) (Migeon et al., 1956).

The Secretion and Metabolism of CortisolThe rate of cortisol secretion is governed by

the level of circulating corticotrophin. Underquiescent conditions the pituitary corticotrophinoutput varies inversely with the concentration ofcortisol in the blood, resulting in a fairly steadyrate of cortisol secretion from day to day. Over-riding this basal ' feedback' regulation is thestress reaction whereby additional corticotrophinis released, probably in response to stimulatingneurohormones emanating from the hypothalamusand reaching the adenohypophysis by portalvenous pathways. Under such extreme stimu-lation cortisol secretion may rise to about 250 mg.a day.The capacity to suppress corticotrophin secre-'

tion is common to all known glucocorticoids,natural and synthetic, when given in doses which'equal or exceed in equivalence the normal cortisolsecretion of about 20 mg. a day. By only partiallysuppressing corticotrophin secretion smaller dosesthan these merely replace an equivalent amount ofendogenous cortisol; hence they are usually in-effective therapeutically in patients with intactadrenal function. In effective doses they causereversible atrophy of the zona fasciculata, whencecortisol is mainly derived, which lasts formany days after treatment has been stopped;hence the importance of slowly tapering off thedose over one to several weeks according to theduration of the preceeding treatment. If thisprecaution be neglected the patient is exposed tothe risks of an acute adrenal crisis when facedduring this period with severe stress, such aspneumonia or surgical trauma.

Likewise, during even moderately intensiveglucocorticoid therapy the patient cannot step up

copyright. on F

ebruary 7, 2020 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. D

ownloaded from

GARROD: Pharmacology of Cortisone, Cortisol and their New Analogues

his cortisol secretion in emergency, and must thenbe protected by raising the dosage, if needs betothe equivalent of 200 mg. of cortisone a day.

Independent of corticotrophic control there arewide diurnal variations in the rate of cortisolsecretion which falls to low levels in the earlymorning hours before rising to a sustained peak ataround 5 or 6 a.m. Whether this phenomenonshould be allowed to influence the timing and dis-tribution of dosage when steroids are being givenin small amounts has yet to be decided.

Radioisotope studies have been of great value inelucidating the metabolism of cortisol (Migeon etal., 1956; Peterson and Wyngaarden, I955 and1956). Within the body the free steroid has ahalf life of about I.4 hours, and is reduced toderivatives such as tetrahydrocortisol, tetra-hydrocortisone, and allotetrahydrocortisol (Bushand Willoughby, 1957), which combine in theliver with glycuronic acid to form glucuronides.Together these metabolites account for about 36 percent. of the secreted hormone and are excreted in theurine where they can be measured as 17-hydroxy-corticoids (Reddy, I954), or, together with thecortol and cortolone derivatives, as I7-ketogenicsteroids (Norymberski et al., 1953). Only about4 per cent. of the metabolites of cortisol can beaccounted for as i7-ketosteroids, and about O.I5per cent. of the hormone is excreted in the freestate (Wade and Kellie, 1957). Impaired liverfunction and myxoedema retard the conjugation,and renal failure the excretion, of these meta-bolites, hyperthyroidism having the opposite effect(Peterson et al., 1955). By means of radio-isotopestudies it has been shown that the high plasmai7-hydroxycorticoid levels of late pregnancy aredue to delayed metabolism, and not increasedsecretion, of cortisol (Migeon et al., 1957).

Physiological and Pharmacological Actionsof Cortisol

Despite the protean activities of cortisol, little isknown about the biochemical processes whichmediate these effects within the cells, though thereis evidence that a number of enzyme systems areinvolved (Ingle, I950). To quote Ingle (I950):' The consequences of cortical hormone actionspread through the organism in a manner re-miniscent of the waves caused by the impact of astone in a pool of water, but the point of impact ofthe hormone remains unknown for the present.'In most instances cortisol would seem to assistrather than initiate the processes which it affects(Sayers, 1950). Except for the electrolyte effects,the actions of cortisol are common to all theknown glucocorticoids, whether natural or syn-thetic, varying in strength but not in quality fromone such compound to another.

Biochemically these steroids influence themetabolism of protein, fat, carbohydrate, purines,electrolytes and water, and exert a direct calori-genic action (Evans et al., 1957). In excess theyinhibit tissue healing and body growth, influencethe local and general response to infection, andraise the body's resistance to stress; they help inmaintaining normal functions of the brain, heartand circulation, and stimulate the gastricsecretions.

Metabolic EffectsGlucocorticoids stimulate protein katabolism,

thereby increasing nitrogen output and glucoseformation (gluconeogenesis). In excess this leadsto muscle wasting, weakening of connective andvascular tissue, osteoporosis and the formation ofwide purple striae. Aminoacid, creatine and uricacid excretion are increased. This last effect maybe useful when treating acute gout, if not neu-tralised by increased uric acid formation.The complex actions of glucocorticoids on car-

bohydrate metabolism can be only partly accountedfor by increased gluconeogenesis, for thesesteroids also antagonize insulin, promote glycogenstorage, and lower the renal glucose threshold(Fourman et al., 1950). Large doses diminishglucose tolerance and cause mild glycosuria.Frank diabetes seldom results (less than i per cent.treated cases), and when it does is usually un-accompanied by ketonuria (Brookman et al.,1953). Fat mobilization and ketone combustionare accelerated, and starvation ketosis inhibited(Kinsell et al., 195I). A centripetal redistributionof body fat contributes towards the Cushingoidhabitus which is a feature of steroid overdosage.

Water and ElectrolytesThe complicated actions of cortisol and corti-

sone on water and electrolyte metabolism, thoughmainly located within the kidney, are not confinedto this organ, for these steroids have been shown toincrease the extracellular fluid volume inde-pendently of changes in, external water andelectrolyte balance (Levitt and Bader, 195I). Theyalso diminish the sodium : potassium ratio insweat and saliva (Conn and Fajans, 1952).

Acting as weak mineralocorticoids, cortisol andcortisone increase the renal tubular reabsorptionof sodium, resulting in fluid retention. Often thiseffect is only transient and followed by diuresis;frank oedema seldom follows unless other factorsare present. Paradoxically, and notably inAddisonian patients receiving DOCA, thesesteroids may initially increase sodium excretion,probably by raising the glomerular filtration rate(Garrod et al., I955a). The basis for their

Yune 1958 301copyright.

on February 7, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.34.392.300 on 1 June 1958. Dow

nloaded from

POSTGRADUATE MEDICAL JOURNAL

sodium-diuretic action in cardiac, scirrhotic andnephrotic oedema, is not yet understood.

Potassium excretion is increased by a directrenal tubular action, augmented by potassium re-lease from''protein breakdown. As opposed topure mineralocorticoids such as aldosterone andDOC, glucoco'rticoids act specifically and per-missively on water diuresis and so protect againstWater intoxication. Without them there is greatdelay in excreting a water load, and when they aregiven in excess water diuresis is accelerated. Theunderlying osmotic mechanisms are only partlyunderstood but seem to involve a direct action onthe renal tubules.

Bone and Calcium MetabolismHere, again, the effects of glucocorticoids are

complex and obscure. Prolonged treatment re-sults in negative calcium, phosphorus andnitrogen balances and eventually osteoporosis.These steroids also antagonize the action' of vita-min D and its analogues (Dickel, ig i) and soneutralize the effects of antitetanic treatment inhypoparathyroidism (Moehlig and Steinbach,I954). By inhibiting excessive calcium absorp-tion from the gut, they correct the defect'Whichcauses hypercalcaemia in some cases of sarcoidosis(Hellman et al., 1956).

The CirculationThe actions of glucocorticoids on the circulation

are largely permissive. Without them the bloodpressure and glomerular filtration rate. fall sharply.Similarly hypertension can be corrected by bitlateral adrenalectomy followed by minimal corti-sone maintenance (Harrison et al., 1952); yet,provided renal function is good, hypertensionseldom follows the use of these steroids in man,despite their potentiating the pressor a'ction ofnoradrenaline (Kurland and Freedberg, I95 I).Large doses can raise the glomerular filtration rateto supernormal levels. Cerebral blood flow in-creases, but cerebral oxygen and glucose utilizationare not affected (Schieve et al., 195I).

Blood and Blood VesselsGlucocorticoids in excess cause e3sinopenia and

regression of lymphoid tissue, this last action ex-plaining their usefulness in the treatment' oflymphosarcoma and lymphatic leukaemia. Theystimulate neutrophil and red cell production.andcan induce a mild reversible polycythaemia. Theyhave no consistent effects on platelet formation,purpura being'suppressed because of their actionin depressing capillary fragility (Zweichach et, al.,r953).

Anti-inflammatory and Anti-allergic ActionsGlucocorticoids modify both general and local

responses to inflammatory agents. Under. theirsuppressive influence fever abates and there, is afall in the erythrocyte sedimentation rate whichcan be correlated with a decrease in -plasmafibrinogen and gamma-globulin concentrations(Fletcher et al., 1952); the plasma albumin tendsto rise.The local anti-inflammatory effects of these

steroids are related to several actions:-a lesseningof fibroblast-response and cellular reaction, a di-minution: in the number of mast cells and con-sequently in the amount of tissue hyaluronic acid,and an inhibition of specific antibody synthesis.Whilst these actions may be desirable in the treat-ment of collagen' diseases and of excessive con-nective tissue proliferation in other ,disorders, theypredispose to the spread of tuberculosis and otherbacterial infections unless appropriate antibioticcover is provided.The remarkable. antiallergic properties of the

glucocorticoids are probably related to theirmodifying action on antigen-antibody reactionsand on histamine release, and may be lifesaving insuch conditions as status asthmaticus and bene-ficial in many other disorders.

Central Nervous SystemGlucocorticoids increase cerebral excitability,

predisposing to fits arid, psychoses in susceptiblesubjects. Euphoria and insomnia are commonaccompaniments of steroid therapy and less oftenagitated depression. The electroencephalographshows characteristic changes in Addison's disease(Forsham et al., 1949) and in patients on largedoses of cortisone (Bolandd and Headley, .I949).The pain-relieving properties of these steroidsseem to be related to their local anti-inflammatoryaction rather -thanr to any' direct effects on thesensory nervous system.

Gastric SecretionsGlucocorticoids increase the concentrattons,of

pepsin. and hydrochloric acid in the stomach,; asreflected in a rise of uropepsin excretion (Eastcottet al., 1953). This action, which is independentof the route of steroid administration, predisposesto peptic ulceration in those susceptible and is oneof the major risks of steroid therapy.

Secondary Endocrie EffectsAlthough exerting a direct calorigenic action

glucocorticoids in high dosage also. suppressthyroid functior, as shown by diminished radio-iodine uptake (Berson and Yalow, 1952) and a fallin the plasma protein-bound iodine (Hill et ial.,I950). Gonadal function may also be; depressed.

3fune 1.958'302copyright.

on February 7, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.34.392.300 on 1 June 1958. Dow

nloaded from

GARROD: Pharmacology of Cortisone, Cortisol and their New Analogues

The androgenici side-effects of large doses, such asacne and hirsutism, may be due to i7-ketosteroidmetabolites of cortisone.

AldosteroneAldosterone, the other major adrenocortical

hormone, is the principal regulator of sodium andpotassium balance, and is secreted mainly by thezona glomerulosa (Ayres et al., I957). Althoughcortisol also contributes towards sodium retentionand in excess may even become the predominantmineralocorticoid, yet its rate of secretion is un-related to the changing requirements of sodiumand potassium balance.

By contrast with cortisol,-the secretion of aldo-sterone is geared to the needs of the extracellularfluid volume, or more precisely probably of thearterial side of the vascular compartment (Bartter,I956). The mechanisms which regulate thissecretion are unknown but seem to be largely in-dependent of pituitary control since they remainintact after hypophysectomy. The physiologicalstimuli for increased aldosterone secretion are aloss or deprivation from the body of sodium,water, or blood, and a high potassium intake.Conversely, a high sodium intake, pitressin-induced water intoxication, and potassium de-privation all inhibit the secretion (Bartter, 1956).

Prolonged oversecretion of aldosterone, as inPrimary Hyperaldosteronism, leads to severepotassium deficiency, alkalosis, and excessivesodium retention which, being mainly intracellular,seldom gives rise to oedema. Similar effects occurwith overdosage of DOCA or fluorohydrocortisone(vide infra), and can likewise be corrected byseverely restricting the sodium intake.

Synthetic Analogues of Cortisol and CortisoneBy effecting minor adjustments to the steroid

ring or its attachments the chemist has been ableto a remarkable degree to enhance and modify theactions of these steroid hormones. Qualitatively,however, these changes have only brought about ashift of balance between their glucocorticoid andmineralocorticoid potencies. So far only three ofthe many new compounds have found their wayinto general use: the two delta- i steroids, pred-nisolone and prednisone, and 9-alpha-fluorohydro-cortisone (fludrocortisone). Two other compoundshave recently been made available.*

The Delta-I Compounds: Prednisolone andPrednisoneThese compound', which are analogues of

These are triamcinolone (i6 hydroxy-9-alpha-fluoro-prednisolone) and 6-methyl prednisolone.

cortisol and cortisone respectively, were dis-covered in the laboratories of the Schering Cor-poration (Herzog et al., I955). The introductionof a double bond between the first two carbonatoms of the steroid ring increases the glucocorti-coid potencies of cortisol and cortisone by at least4 to 5 times, yet without enhancing their mineralo-corticoid activities. Thus, prednisolone andprednisone can be given in therapeutic dosagewithout fear of causing excessive sodium re-tention or potassium depletion. In all other waystheir actions resemble those of the parent steroids,but with 4 to 5 times the potency. Except whentreating adrenal failure, sodium retention andpotassium depletion are undesirable side-effects ofsteroid therapy, and especially in debilitated,hypertensive, oedematous or cardiac patients, orwhen the aim of treatment is to promote sodiumdiuresis. These new compounds are thereforerapidly replacing cortisone and cortisol in generaluse, thereby obviating the need for sodium re-striction and supplementary potassium unlessheroic doses are being used as in the treatment ofcertain blood dyscrasias.

Recent studies have shown that prednisone andprednisolone are largely excreted in unmetabolizedform, giving rise to fewer tetrahydro-derivitives(Slaunwhite and Sandberg, 1957; Vermeulen,1956). As with the natural steroids, prednisoloneand prednisone are freely interconvertible withinthe body (Gray et al., 1956).

9-alpha-fluorohydrocortisoneThe remarkable effects of adding a halogen atom

in the 9-alpha position to the cortisol moleculewere discovered by Fried and Sabo (I Ofthese derivatives only the chlorinated and fluori-nated compounds were found to exceed the naturalsteroid in potency. Whereas the glucocorticoidactivity of 9-alpha-fluorohydrocortisone (FHC) isabout io times that of cortisone, the mineralocori-coid activity exceeds that of the parent compoundby at least ioo times (Garrod et al., 1955b) and isslightly greater than that of aldosterone.

Despite its enhanced glucocorticoid potency theextreme electrolyte activities of FHC preclude itssystemic use as a substitute for cortisone (Ward etal., 1954). However, since it can be given bymouth, it is an ideal substitute for DOCA in treat-ing adrenal insufficiency at doses of about O. 1-0.2mg. a day. The cortisone-like action of suchamounts is very small, so cortisone must also begiven to achieve adequate replacement.

This contraindication applies less when thesteroid is used topically, as in skin disease, for itis little absorbed into the circulation. Excessivesodium retention has, however, been reported

June I 958 303copyright.

on February 7, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.34.392.300 on 1 June 1958. Dow

nloaded from

304 POSTGRADUATE MEDICAL JOURNAL June I958

following liberal use of FHC ointments in patientswith extensive ulcerated skin lesions.A third use of FHC, which takes advantage of

its enhanced glucocorticoid activity, is in tests todifferentiate adrenocortical tumours from adreno-cortical hyperplasia (Renold et al., 1955). Usingthis compound the metabolic end-products aresmall enough rot to disguise the falls in I7-ketosteroid and 17-hydroxysteroid excretion whichfollow the steroid-induced suppression of endo-genous corticotrophin in patients with adrenalhyperplasia.

Some More Recent Cortisol DerivativesBy the addition of a 6-methyl group to cortisol

or prednisolone or a i6-OH group to FHC or9-alpha fluoroprednisolone compounds can beobtained with even greater glucocorticoid potencythan prednisolone, and without excessive mineralo-corticoid activity (Spero et al., 1956; Bernsteinet al., I956). These compounds, which have notyet been subjected to full clinical trial, are un-likely to offer advantages over prednisolone asthey seem to have no important qualitative dif-ferences in their glucocorticoid actions.

Then, there are the 2-methyl derivatives ofcortisol and FHC, which are the most potentmineralocorticoids yet discovered (Liddle et al.,1956). The second of these two compounds isseveral thousand times as active as cortisol onelectrolyte metabolism, and a single oral dose iseffective for about 48 hours. Many more ana-logues of cortisol are being prepared and sub-jected to biological assay.

Modes of Administration of Steroid HormonesFor pharmacological use, cortisone and FHC

are prescribed as the acetate esters, prednisoneand prednisolone usually as the free compounds,and cortisol in either form. Orally, they act within2 to 3 hours and are effective for about I2 hours,depending on the dose. To maintain adequateblood levels with oral therapy large doses shouldbe given I2-hourly and small doses 8-hourly,though FHC can be given once a day.With intramuscular injection the rate of

absorption is far slower and the effects of a singledose may last, though feebly, for several days. Inthe case of cortisol the free compound is morerapidly absorbed than the less soluble acetate.This route of administration offers no real advan-tages over the oral route, and is rarely indicated.To obtain a rapid effect, as in the treatment of

acute adrenal crisis and status asthmaticus it isnecessary to use intravenous cortisol, either as thefree compound (alcohol) or preferably as 'thesodium succinate ester or intravenous predniso-lone-21i-phosphate. ioO mg. of cortisol are dis-

solved in 500 ml. of 5 per cent. dextrose, and actmaximally when infused at a rate of io to I2 mg.an hour. The sodium succinate ester is verysoluble in water; IOO mg. given intravenously,dissolved in 2 ml. of distilled water or saline,begins to act within about half an hour (Orret al., 1955). Prednisolone-2i-phosphate has theadvantage of being stable in solution and verysoluble.

For topical and intraarticular use, only cortisolor its analogues, prednisolone and FHC are effec-tive, their effective concentrations in suspensionor as ointments being roughly inversely propor-tional to their glucocorticoid potencies (videsupra). Cortisol and FHC are used in acetateform, prednisolone as the free compound oracetate.

BIBLIOGRAPHYAYRES, P. J., GARROD, O., PEARLMAN, W. H., TAIT,

S. A. S., TAIT, J. F., and WALKER, G. (I957), Ciba Found.Colloq. Endocrin., 'Hormones in Blood,' Churchill, London.

BARTTER, F. C. (I956), Metab., 5, 369.BERNSTEIN, S., et al. (1956), J. Amer. chem. Soc., 78, 5693.BERSON, S. A., and YALOW, R. S. (I952), J. clin. Endocr., 12, 407.BOLAND, E. W., and HEADLEY, N. E. (0949),J. Amer. med. Ass.,

141, 301.BROOKMAN, J. J., DRACKMAN, S. R., SCHAEFER, L. E.,

and ADLERSBURG, D. (I953), Diab., 2, I00.BUSH, I. E., and WILLOUGHBY, M. (19S7), Biochem.Y.., in press.CONN, J. W., and FAJANS, S. S. (I952), Ann. Rev. Physiol., x4,

453-DICKEL, H. (i5si), Minch. med. Wschr., 93, I.EASTCOTT, H. H. G., FAWCETT, J. K., and ROB, C. G. (1953),

Lancet, i, io68.EVANS, E. S., CONTROPOULOS, A. N., and SIMPSON, N. E.

(1957), Endocrin., 60, 403.FLETCHER, A. A., DAUPHINEE, J. A., and OGRYZLO, XI. A.

(1952), 7. clin. Invest., 3I, 56I.FORSHAM, P. H., BENNETT, L. L., ROCHE, M., REISS,

R. S., SLESSOR, A., FLINCK, E. B., and THORN, G. W.(I9495, . clin. Endocr., 9, 66o.

FOURMAN, P., BARTTER, F. C., ALBRIGHT, F., DEMPSEY,E., CARROLL, E., and ALEXANDER, J. A. (I950), Y. clin.Invest., 29, I462.

FRIED, J., and SABO, E. F. (1954), Y. Amer. chem. Soc., 76, I455.GARROD, O., DAVIES, S. A., and CAHILL, G., Jr. (x955a),

-7. clin. Invest., 34, 76I.GARROD, 0., NABARRO, J. D. N., PAWAN, G. L. S., and

WALKER, G. (I955b), Lancet, 2, 367.GRAY, C. H., GREEN, M. A. S., HOLNESS, N. J., and

LUNNON, J. B. (I956), Y. Rndocr., 4,146.GRAY, S. J., BENSON, J. A., REIFENSTEIN, R. W., and

SPIRO, H. M. (i9sI),.y. Amer. med. Ass., 147, I529.HARRISON, J. H., THORN, G. W., and CRISCITIELLO, M. G.

(I952), Y. Urol., 67, 405.HELLMAN, L., BRADLOW, H. L., FRAZELL, E. L., and

GALLAGHER, T. F. (I956),.7. clin. Invest., 35, 033.HENNEMAN, P. H., DEMPSEY, E. F., CARROLL, E. L., and

ALBRIGHT, F. (I956), Ibid., 35, 1229.HERZOG, H. L., NOBILE, A., TOLKSDORF, S., CHARNEY,

W., HERSHBERG, E. B., PERLMAN, P. L., and PECHET,M. M. (i955), Seience, 122, 176.

HILL, S. R., REISS, R. S., FORSHAM, P. H., and THORN,G. W. (I950), Y. clin. Endocr., I0, 1375.

INGLE, D. J. (I950), Ibid., to, 1312.KINSELL, L. W., MARGEN, S., MICHAELS, G. D., and

PARTRIDGE, J. (Ig5I), Proc. 2nd Clin. ACTH Conf., x, 308.KURLAND, G. S., and FREEDBERG, A. S. (I95I), Proc. Soc.

exp. Biol. (N. Y.), 78, 28.LEVITT, M. F., and BADER, M. E. (9si),J. clin. Invest., 30, 655.LIDDLE, G. W., RICHARDS, J. E., and TOMKINS, G. 1M.

(I956),J. cdn. Endocr., I6, 917.

Bibliography continued on page 309

copyright. on F

ebruary 7, 2020 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. D

ownloaded from

June 1958 BAYLISS: Cortisone and its Analogues in Endocrinology 309

cretion. A similar effect may also be observedwhen cortisone is given to a hypercalcaemic patientwith multiple bony metastases if the steroid in-hibits the growth of the neoplastic tissue. Inhyperparathyroidism, on the other hand, cortisonedoes not influence the hypercalcaemia.

BIBLIOGRAPHYANDERSON, J., DENT, C. E., HARPER, C., and PHILPOT,

G. R. (I9S4), Lancet, ii, 720.BARTTER, F. (x956), Metabolism, 5, 369.BAYLISS, R. I. S. (1957a), Proc. roy. Soc. Med. 50, 76I.BAYLISS, R. I. S. (1957b), in 'Moder Trends in Endocrinology,'

London, Butterworth.BECK, R. N., and MONTGOMERY, D. A. D. (I956), Brit. med.J.,

ii, 921.

COPE, C. L. (I956), Ibid., ii, I93.FOURMAN, P., and HORLER, A. R. (1954), Lancet, i, 334.

GURLING, K. J., GORE, M. B. R., and BARON, D. N. (1958),Y. Endocr. 16, 304.

JAILER, J. W.-, GOLD, J. J., and WALLACE, E. Z. (I954),Amer. Y. Med., I6, 340.

KUPPERMAN, H. S., BLATT, M. H. G., VESELL, M.,GAGLIANI, J., WEISBADER, H., and VOSBURGH, L.(I955), Y. clin. Endocr., x5, 9I I .

LANCET (I9S5), i, 6.LEITH, W., and BECK, J. C. (I957), Y. clin. Endocr., 17, 28o.LIDDLE, G. W., and RICHARDS, J. E. (I956), Science, 123, 324.NABARRO, J. D. N., and WALKER, G. (I957), Brit. med. J.,

ii, 17.OWEN, J. A., ENGEL, F. L., and WEBSTER, T. B. (1957),

Y. clin. Endocr., 17, 272.PRADER, A. (1953), Helv. paediat. Acta, 8, 386.SEGALOFF, A., GORDON, D., and HORWITT, B. N. (1955),

Y. Amer. med. Ass., x57, I479.SPENCE, A. W., JENKINS, J. S., and ROBINSON, A. M.

(I956), Brit. med. Y., ii, 1348.WERNER, S. C. (I9S3), Y. clin. Endocr., 13, 1332.WILKINS, L., LEWIS, R. A., KLEIN, R., GARDNER, L. I.,

CRIGLER, J. F., ROSENBERG, E., and MIGEON, C. J.(1951), Ibid., xII, I.

ANAESTHETICS(Postgraduate Medical Journal)

Price: 3s. lld. post free

THE MODERN VIEW OF ANAESTHESIA CHLORPROMAZINE AND ALLIEDG. S. W. Organe, M.D., D.A., F.F.A.R.C.S. SUBSTANCESE PRODUCTION OF John Beard, M.D., D.A., F.F.A.R.C.S.,UNCONSCIOUSNES D.C.H.B. G. B. Lucas, D.A., F.F.A.R.C.S. CONTROLLED HYPOTHERMIA

ANALGESIA E. J. Delorme, M.D., F.R.C.S.(C.)J. B. Wyman, M.B.E., D.A., F.F.A.R.C.S. MANAGEMENT OF T APNOEIC

MUSCLE RELAXATION IN SURGERY PATIENTAngus Smith, F.F.A.R.C.S. Ronald Woolmer, D.A., F.F.A.R.C.S.

CONTROL OF THE BLOOD PRESSURE THE USE OF ANTIDOTES INAND CONTROLLED HYPOTENSION ANAESTHESIAC. F. Scurr, M.V.O., D.A., F.F.A.R.C.S. B. A. Sellick, D.A., F.F.A.R.C.S.

Published by

THE FELLOWSHIP OF POSTGRADUATE MEDICINE60, Portland Place, London, W.1

Bibliography continued from page 304-Oliver Garrod, M.D., M.R.C.P.MIGEON, C. J., BERTRAND, J., WALL, P. E., STEMPFEL,

R. S., and PRYSTORSKY, H. ('957), Ciba Found. Colloq.Endocrin., 'Hormnones in Blood,' in press, Churchill, London,

MIGEON, C. J., SANDBERG, A. A., DECKER, H. A.,SMITH, D. F., PAUL, A. C., and SAMUELS, L. T. (I956),Y. clin. Endocr., I6, II 37 and 129I.

MOEHLIG, R. C., and STEINBACH, A. L. (I954), J. Amer. med.Ass., 154, 42.

ORR, R. H., DI RAIMONDO, V., FLANAGAN, M. E., andFORSHAM, P. H. (I955), Ibid., 3S, 763.

PETERSON, R. E., and WYNGAARDEN, J. B. (I955), J. clin.Invest., 34, 957.

PETERSON, R. E., and WYNGAARDEN, J. B. (1956), Ibid., 35,552.

PETERSON, R. E., WYNGAARDEN, J. B., GUERRA, S. L.,BRODIE, B. B., and BUNIM, J. J. (1955), Ibid., 34, 1779.

REDDY, W. J. (x9S4), Metab., 3,489.

RENOLD, A. E., HAYDER, N. A., REDDY, W. J., GOLDFIEN,A., ST. MARC, J. R., and LAIDLAW, J. C. (1955), Ann.N.Y. Acad. Sci., 6i, 582.

SAYERS, G. (1950), Physiol. Rev., 30,*241.SCHIEVE, J. F., SCHEINBURG, P., and WILSON, W. P. (i95i),J. clin. Invest., 30, 1527.SLAUNVVHITE, W. R., Jr., and SANDBERG, A. A. (1957),J. clin. Endocr., 17, 395.SPERO, G. B., THOMPSON, J. L., MAGERLEIN, B. J.,

HAUZE, A. R., MURRAY, H. C., SEBEK, 0. K., andHOGG, J. A. (1956), J. Amer. chem. Soc., 78, 6214.

VERMEULEN, A. (I956), Acta endocr., 23, I13.WADE, A. P., and KELLIE, A. E. (i957), personal communication.WARD, L. E., POLLEY, H. F., SLOCUMB, C. H., HENCHP. 5., MASON, H. L., MATTOX, V. R., and POWER, M. H.

(1954), PrOc. Mayo Clin., 29, 649.ZWEICHACH, B. W., SCHORR, E., and BLOCK, M. M. (1953),Ann. N. Y. Acad. Sci., s6, 626.

copyright. on F

ebruary 7, 2020 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. D

ownloaded from