674

DISCUSSION

These observations show that small repeatedexposures to radiation lead to the regression oftumours without the intervention of a latent period.On the whole it appears that these diminutions insize are not due to destruction and disappearance oftumour cells, but rather to fluctuations in the blood-supply to the tumours, which form waves upon theslower regression due to disappearance of tumourcells. Secondly we have observed that, by applyingtreatment only during periods of growth, and with-holding it during periods of regression, tar warts havebeen cured in mice, and tumours in man benefited, withno more than trivial damage to the surrounding normaltissues, such as transient erythema or partial epilation.Both the tumour under treatment and the surround-

ing skin and normal tissues undoubtedly vary in radio-sensitivity, such variations being brought about bythe treatment itself. It follows that the ideal methodof treatment will be to choose for each repeated treat-ment a time when the tumour is relatively radio-sensitive and the skin radioresistant. Just as,in the treatment described, we have tried indirectlyto measure the radiosensitivity of the tumour, so,to obtain the best results, some measure of the radio-sensitivity of the skin and normal tissues is likewiserequired.We are indebted to Mr. Stanford Cade and to Mr.

Bernard Williams for permission to publish these twocases, arid to Dr. G. Cranston Fairchild, the radiologist,who was responsible for the X ray treatment administered.The radium used for the tar warts was on loan from theMedical Research Council.

REFERENCES

1. Mottram, J. C. : Brit. Jour. Radiol., 1924, xxix., 174.2. Mottram, J. C., and Eidinow, A.: Brit. Jour. Surg., 1932,

xix., 481.3. Mottram, J. C. : Brit. Jour. Radiol., 1927, xxxii., 61.4. " " : THE LANCET, 1928, ii., 966.5. " " : Brit. Jour. Radiol., 1932, v., 643.

INCREASING THE EFFECTIVENESS OF

TESTOSTERONE

BY A. S. PARKES, Sc.D., F.R.S.

(From the National Institute for Medical Research,London, N.W.)

THE effectiveness of testosterone in restoring theatrophic prostate and seminal vesicles of castratedrats can be much increased by adding x-substance 1or pure fatty acids 2 3 to the solution injected, oreven by augmenting the volume of oil used forinjection.3 This increased effectiveness is not obtainedif the fatty acid or additional oil is injected separately,so that it is almost certainly due to alteration of theconditions of absorption of the hormone at the siteof injection rather than to any synergism at the siteof action.2 3

These results recall the great increase in theeffectiveness of oestrone obtained by esterificationor by subdivision of the total dose into a series ofinjections. We have now further examined testo-sterone, and certain other male hormone compounds,in the light of this analogy, and by the kind ooöpera-tion of Dr. K. Miescher and Messrs. Ciba Ltd., wehave been able to investigate the behaviour of certainhighly effective esters of testosterone.

Technique.-The rats were castrated in batchesat 40 -60 g. body-weight and used for experimentnot less than one month later, when the rudimentaryprostate and seminal vesicles have an average total

weight of less than 25 mg. Five rats were used foreach test, and comparison is made only betweenexperiments carried out simultaneously on groupsfrom the same batch. All compounds were injectedin solution in arachis oil. Details of testing were aspreviously described.3 4

Subdivision of the daily dose.-It will be seen fromTable I. that subdivision of the daily dose into morningand evening injections increases the effectivenessof the two free hormones used. The increase, how.ever, is not so great as that obtained by increasingthe volume of oil or by adding palmitic acid.

TABLE I

Comparative Effectiveness of Free and Esterified HormonesGiven in Various Ways

Injections for 10 days; rats killed on the day after thelast injection.

The fact that palmitic acid increases the effective-ness of androstanedione,* an unesterifiable compound,shows that the action of the fatty acid is not depen-dent on actual chemical combination with the hormone.This observation is in keeping with the recent reportthat testosterone palmitate is inactive. 6 The increaseof effectiveness obtained by dividing the daily dosepoints clearly to retardation of absorption as themode of action of the additional oil or fatty acid.

Testosterone acetate and testosterone propionate.-Testosterone benzoate, the first ester to be made, isonly slightly active on capons.4 Miescher, Wettstein,and Tschopp,6 however, have recently given a pre-liminary account of the biological properties of awhole series of esters of testosterone with aliphatioacids, of which several, notably the acetate and

propionate, are highly active. A detailed paper bythese authors is to appear in the Biochemical Journal.

Our first experiment was to ascertain whetherthe various methods by which the effectiveness of thefree hormone can be altered are applicable to theesterified hormone. From Table 1. it will be seenthat subdivision of the daily dose, increase of oil, oraddition of palmitic acid all fail to alter appreciablythe response evoked by the two acetates used.Testosterone acetate, given alone in a small volumeof oil, is as effective as the free hormone givenwith palmitic acid and excess oil. As shown inTable II., the propionate is even more effective.

It seems therefore that, given as acetate or pro-pionate, the hormone becomes slowly but continuouslyavailable to the animal so that the loss by excretionand destruction is very much less than when freehormone alone is administered.

This finding that palmitic acid makes no differencewhen the availability of the hormone to the animal

* A saturated diketone corresponding to the hydroxyketoneandrosterone.

675

is already regulated by the slow breakdown of anester is further evidence that the acid acts by delayingabsorption. It may be emphasised that any"accessory substance " having a genuine synergismwith the hormone at the site of action should be aseffective when given with the ester as when givenwith the free hormone. In view of the uncertaintyas to the mode of action of the x-substance, experi-ments by the Amsterdam school on the addition ofx-substance to esterified testosterone will be awaitedwith interest.Duration of effect of a single injection.-The effect

of androsterone benzoate may be exerted long afterthe last injection, s We have therefore examined theduration of effect of certain esters in groups of ratskilled at various times after the injection of a singledose. A similar technique has been used by theBasle workers. Single injections of 5 mg. andro-stanediol acetate or androstanediol benzoate t pro-duced only a negligible response at 5, 10, or 15 daysafterwards. The meaning of this is not yet clear.A single injection of 2 mg. of testosterone as acetate tgiven in 1 c.cm. oil produces good growth of the

FIG. t.-Duration of response to a single injection of 2 ing.testosterone, x as acetate, O as propionate.

prostate and seminal vesicles 5 days later but thegrowth is not maintained and the organs are regress-ing at 10 days after injection. Following a singleinjection of 2 mg. testosterone as propionate, however,the prostate and seminal vesicles continue to growstrongly for 10 days or more, by which time theyreach a size similar to that produced by the same doseof free testosterone split up into twenty 12-hourlyinjections (Fig. 1). The response to a single injectionof testosterone is negligible.Frequency of injection necessary to maintain effective-

ness.-In view of the above results it was decided toexamine the two esters from the point of view of theminimum frequency of injection necessary to maintainmaximum effectiveness. The results are shown inTable II. and Fig. 2. From these it may beconcluded :—

(a) That even when given in a large volume of oil thefree hormone requires to be injected at least once dailyto show moderate effectiveness.

(b) That provided the total dose is constant, injectionsof both the propionate and acetate can be restricted totwice a week without loss of effectiveness and probablyeven to once a week without serious wastage.

(c) That of the two esters, the activity of the propionateis both more intense and more prolonged.

t Androstanediol 3-acetate and 3-benzoate.t All doses of testosterone esters are based on equivalents of

free hormone. Thus 1-2 mg. propionate == 1’15 mg. acetates1.0 mg. free hormone.

The average total weight of seminal vesicles andprostate in untreated castrated rats is less than25 mg. ; it will thus be seen that the growth pro-duced by the propionate in 10 days is really astonish-ing, the glands being nearly as large as those ofnormal adult males of similar body-weight. Onerat, given three doses of propionate over 10 days,

FIG..2.-Effectiveness of total dose of 2 mg. free testosterone,2 mg. testosterone as acetate, and 2 mg. testosterone as

propionate in relation to frequency of injection over a

10-day period.

had seminal vesicles alone of 690 mg. The suggestionthat the accessory glands of castrated rats cannot bemade to approach normal size in so short a time as10 days is thus refuted.These results indicate that the propionate of

testosterone is much the most active male hormonecompound so far known. It is, in fact, a mostremarkable substance, which should be invaluable

TABLE II

Comparative Effectiveness of Testosterone, TestosteroneAcetate, and Testosterone Propionate in Relation to

Frequency of Injection

Total dose in each case equivalent to 2 mg. testosterone.Duration of experiment, 10 days ; total oil, 5 c.cm.

for clinical purposes where daily administration isinconvenient or even impossible.

-

SUMMARY

Testosterone acetate and testosterone propionateare many times more effective than the free hormone,and their action is so prolonged that injection can berestricted to twice a week without loss of effectiveness.

676

Of the two compounds, the propionate has a moreintense and more prolonged action than the acetate.We are again greatly indebted to Dr. K. Miescher and

his colleagues, of Messrs. Ciba Ltd., for supplies of thecompounds and for early information about their results.

REFERENCES

1. David, K., Dingemanse, E., Freud, J., and Laqueur, E.:Zeits. f. physiol. Chem., 1935, ccxxxiii., 281 ; Freud, J.,Dingemanse, E. and Polak, J.: Acta brev. Neerl., 1935,v., 179.

2. Miescher, K., Wettstein, A., and Tschopp, E.: Chem. andInd., 1936, lv., 238; Schweiz. med. Woch., 1936,lxvi., 310.

3. Deanesly, R., and Parkes, A. S.: THE LANCET, 1936, i., 837.4. Same authors: Biochem. Jour., 1936, xxx., 291.5. Miescher, K., Wettstein, A., and Tschopp, E.: Schweiz.

med. Woch., 1936, lxvi., 763.6. Callow, R. K.: Jour. of Physiol., 1936, lxxxvi., 49 P.

VASCULAR TUMOUR SEATED IN

EXTENSOR HALLUCIS BREVIS MUSCLE

BY FRANK FORTY, M.B. Lond., F.R.C.S. Eng.RESIDENT SURGICAL OFFICER TO THE GENERAL HOSPITAL,

BIRMINGHAM

Campbell de Morgan, writing in -1864 on " Vascular

Tumours Seated in Muscle," expressed the opinionthat these growths must be extremely rare, since"it is very little likely that they should have beenoften found, but neither described nor preserved."He alluded to some 12 cases, which were all thathe could find to have been recorded up to that time.

CLASSIFICATION

From a survey of these together with a study ofseveral cases of his own, de Morgan classified vasculartumours arising in muscle as follows.

1. Tumours having the appearance of a varicose stateof the veins, unconnected with the muscular tissue inwhich they lie, but yet not isolated by any well-definedcovering of connective tissue.

2. Erectile tissue, forming in and encroaching on themuscular tissue, from which it is not separated by anydefined boundary.

3. Erectile tissue, forming a defined tumour, having aninvestment of connective tissue, not continuous with themuscular tissue in which it is embedded.

The term " erectile tissue " appears to have beenstarted on its career by Liston, who published thefirst description of this condition in 1843.1 Sincethen it has disputed the honours with a diversity ofother terms such as telangiectasis, cavernous

angioma, haemangioma, &c., which reflect the varietyof the histological appearances of these tumours.De Morgan preferred the terms erectile tumour orblood or vascular tumour to-the more lofty sounding one of "telangjectasis

" inasmuchas they are far more easy to read and write, and as theyconvey quite as correct a notion of the character of thedisease. The term " erectile " simply points to a factthat these tumours under certain circumstances becometurgid, and again empty themselves. It does not implythat they possess the peculiar nervous endowments andvascular arrangements of the normal erectile tissue.He considered that these were morbid growths, mostoften of congenital origin, though sometimes, as faras could be ascertained, they came in later life afteran injury.

PATHOLOGY

Histologically the tumours in de Morgan’s cases

showed a cavernous structure.This consisted of blood-containing cavities of various

sizes embedded in a connective tissue stroma containing

fatty tissue and a quantity of muscular tissue, par-ticularly near the outer surface of the tumour. Thesemuscular fibres were scattered and separated by adiposetissue, and from the indistinctness of their markings andtheir granular opacity were judged to be undergoing aprocess of atrophy. In the thicker portions between theneighbouring sinuses, yellow elastic tissue occurred plenti-fully. Mention is also made of the fact that some of thecavities " receive buds from the fibrous partitions or

meshwork: these have rounded ends, and appear to beoutgrowths. "With regard to the origin of these tumours,

de Morgan confesses that " the early condition of £vascular tumours has not yet been satisfactorilyinvestigated, and very little has hitherto been donetowards determining their mode of growth, or theirtrue structure." And again in the same connexion-

Nothing is known of the causes which determine theseat of the disease in one or other of the vascular tissues.Sometimes, it is said, the arterial portion of the vasculartissue is principally affected, sometimes, and perhapsmore usually in tumours, the venous, while probably inall cases, there is as well some affection of the capillaries.

This problem was especially investigated byH. Sutter,2 working in the surgical clinic of de Quer.vain. His researches, published in 1905, were basedupon a review of all the previously published cases,together with a study of 5 cases personally investi.gated. The fact that the total of published casessince Liston’s original description then numberedbut 40 bears witness to the rarity of the condition.From a histological study of his material, Sutteradvanced the theory that the primary event in thegenesis of these vascular tumours is a proliferationof the smooth muscle in the walls of the smallerblood-vessels.

This proliferation, which is accompanied by some

increase of elastic tissue, is at first concentric, but laterproceeds to a stage at which the smooth muscle-fibresderived from adjoining arterioles intermingle, resulting ina meshwork whose origin from the vessel walls is no

longer obvious. At this stage the histological picture isnot unlike that of small fibromyomata of the uterus, andSutter refers to the possibility that these tumours maylikewise arise primarily in a proliferation from the vesselwalls. He believes that the thin-walled cavernous bloodspaces, lined by a single layer of endothelium which occurto a greater or lesser extent in all these tumours, are dueto a dilatation of the capillaries of the perimysiumimprisoned within the meshwork of the proliferatedsmooth muscle. This dilatation of the capillaries wouldfollow a stasis of the blood stream due to a partial strangu-lation of the thin-walled vessels by the newly formedmuscle-fibres. In serial sections Sutter was able to tracethe thin-walled cavernous spaces back to the capillariesof the perimysium, whereas the arterioles in the growth,when followed to their terminal branches, lost themselvesamong the meshwork of connective tissue and plainmuscle forming the groundwork of the tumour, withoutestablishing any observable communication with thecavernous spaces. It was otherwise with the veins,which were occasionally found to open into the spaces.Sutter also mentions the presence, here and there,of clusters of proliferating capillaries which have theappearance of multiplying by a process of budding.De Morgan stated that vascular tumours seated

in muscle occurred most frequently in the lowerextremity, thus contrasting with cutaneous and sub.cutaneous naevi. Judging, however, from Sutter’slist of published cases, they appear to occur in anyof the skeletal muscles without showing preferencefor any particular regions of the body. The casehere reported seems to be the first on record tooccur in the extensor brevis hallucis, or indeed in

any of the small muscles of the foot.