186

MEDICAL SOCIETIES

ROYAL SOCIETY OF MEDICINE.

SECTION OF THERAPEUTICS ANDPHARMACOLOGY.

AT a meeting of this section on Jan. 12th, withDr. E. P. POULTON, the President, in the chair, ademonstration of several forms of apparatus for

administering oxygen and CO was followed by a Icontribution on the

Uses of Oxygen and Carbon Dioxide in II. Medicine

by Prof. J. S. HALDANE. He reminded his hearersthat in normal breathing of ordinary air the ventilationof the lung was so regulated that the partial pressureof CO2 in the mixed alveolar air was maintained at acertain level-a level which was characteristic foreach person, and usually corresponded to about5-5 per cent. of CO2 in the alveolar air reckoned asdry. If the supply of CO brought by the blood,or the percentage of CO in the inspired air, wasincreased, the breathing was increased correspondingly,

I

so as to keep the CO pressure in the alveolar airabout normal, if possible. The increase of breathingwas mainly in depth. The oxygen pressure was thus s

kept at about 14 per cent. of an atmosphere. Butthe pressure was not evenly distributed, even withnormal breathing, so that some alveoli had less Ioxygen, others more. The consequence was that,owing to the shape of the dissociation curve of Ioxyhsemoglobin, the higher oxygen content at someplaces did not compensate for the lower oxygen atothers. When breathing was shallow and rapid, Ieven though the volume breathed might be muchincreased, the deficiency in the mixed arterial oxygenpressure became much exaggerated, and easily caused Isymptoms of want of oxygen, as shown experi-mentally by Meakins, Priestley, and himself. Itwas also shown that the symptoms of shortage of.oxygen, such as Cheyne-Stokes breathing and generaldiscomfort, were relieved promptly by adding a littleoxygen to the inspired air. In such conditions as

Isevere pneumonia or shock, in which the breathingbecame very shallow, dangerous anoxaemia could beprevented by adding some oxygen continuously tothe inspired air, so that the available alveoli receivedenough. Prof. Haldane thought that in very manycases the immediate cause of death was oxygen-wantdue to shallow breathing, which was in turn the resultof weakening of the respiratory centre. However,it was only when the blood was insufficiently saturatedwith oxygen that a marked effect was produced byusing oxygen. A reduced pressure of oxygen in theinspired air, as in mountain sickness, or a reducedpercentage of oxygen, as in many industrial accidents,could cause insufficient saturation ; as also could athickening of alveolar walls or obstruction to thepassage of oxygen through them, as seen in phosgenepoisoning during the late war. All cases havinga markedly insufficient oxygen saturation were

dangerous, and the effects were cumulative on therespiratory centre itself, the higher nervous centres,the heart, and other organs. The one exception tothis rule was afforded by the chronic cases, in whichthe body seemed to have become acclimatised to

imperfect oxygenation of the blood, so that cyanosiswas unaccompanied by bad symptoms, and its dis-

Iappearance on giving oxygen did not bring relief.With insufficient saturation, breathing was at first

stimulated markedly; but the increase of breathingwashed out too much CO2, and this largely neutralisedthe stimulating effect. The breathing became shallowand frequent, because of enfeeblement of the respira-tory centre.The therapeutic administration of CO2 was a

more recent medical event than the giving of oxygen ;Yandell Henderson, in America, first used it tocounteract carbon monoxide poisoning, cases of thekind being relatively common in America. CO2was found a great aid in the expulsion of CO from thesystem ; even with air and CO2 the expulsion of COwas quicker than with pure oxygen. Prof. Haldanehad found that in an animal rendered helpless bybreathing a certain percentage of CO pure in air,the symptoms were much ameliorated when expiredair was substituted for the pure air, without varyingthe percentage of CO, or when about 5 per cent. ofCO2 was added to the pure air. Probably theamelioration was due to increased circulation throughthe brain. Henderson had recently stressed anotherinfluence of CO 3. When, after CO poisoning, or afterserious operations, breathing was feeble, a bronchialtube might become blocked. The result was thatthe air in the corresponding part of the lung wasabsorbed, and collapse ensued, which was apt tobe followed by local pneumonia. This tendency wasprevented by adding enough CO2 to the inspired airto maintain a normal depth of breathing. In new-born infants the expansion of the lungs was liableto be imperfect, resulting in local pneumonia, andCO2 seemed to be very useful in averting this. Itwas also instrumental in getting anaesthetics eitherinto or out of the body quickly.

Both oxygen and CO2 Prof. Haldane regarded aspowerful therapeutic agents, which ought alwaysto be available to members of the profession.

METHODS OF ADMINISTRATION.

Dr. G. P. CROWDEN demonstrated a chamber forthe reception of a patient for continuous artificialrespiration and administration of oxygen and CO2,if required, to tide him over critical pneumonia andsimilar illnesses.1 It had been proved, he said, of

great value for children with respiratory failure dueto poliomyelitis. Never previously had it been

possible to keep these cases alive while their respiratorymuscles were being restored to a condition of efficiency-a matter of weeks. While the patient was inhabit-ing this apparatus he could receive a blood transfusionthrough an aperture designed for the purpose.The PRESIDENT expressed his preference for the

simplest form of apparatus, namely, a mask andvalves-the ordinary gas mask with a big balloon.Recently he had a severe case of bronchitis and heartfailure, and pure oxygen given in this way for 15minutes sufficed to make the patient quiet, no moreoxygen being needed.

Dr. REGINALD HILTON said that the most frequentoccasion for the administration of oxygen was theanoxaemia of pneumonia. It had been shown thatwhen depth of breathing got below a certain point,anoxaemia resulted, but breathing had to be veryshallow before arterial anoxaemia resulted. He hadnot been successful in persuading patients with

pneumonia to wear a mask over their faces. Manypatients who had anoxaemia did not seem to bebreathing in a shallow way, and he did not now think

1 See Drinker, P., THE LANCET, 1931, i., 1186.

187

that shallow breathing, either in pneumonia or innormal respiration, was as important as he hadformerly believed. He had found that the pneumoniapatient breathed far more, in proportion, throughthe mouth than through the nose.

Dr. C. G. DOUGLAS, speaking as a physiologist,said he would like to see physicians studying thissubject seriously. The hopeful development had beenthe production of portable apparatus which allowedthe giving of oxygen for considerable periods. Bymeans of Prof. Haldane’s apparatus he had givenoxygen continuously for three days, during whichperiod the mask was off for only five minutes anhour, and not every hour. During the war this formof treatment proved particularly valuable in acutepulmonary oedema, largely brought on by phosgenepoisoning. To one patient who was very far gone,he had had to give 6 litres of oxygen per minute.Pneumonia patients he had not found very aversefrom the oxygen mask if one tried persuasion, andhelped them in the early stages. A nurse could betaught in three minutes how to use it. He thoughtevery practitioner, and certainly every hospital,ought to have an apparatus for the administration ofoxygen and of CO2,

Prof. M. S. PEMBREY said that though the claims ofoxygen and CO2 had been pressed on the presentoccasion he hoped no one would be misled into

thinking that pneumonia was purely a matter ofanoxaemia. He did not think the mortality-ratewas likely to be reduced by the early use of eitheroxygen or CO2, because of the pronounced cardiacand toxic effects. The value of those two agentslay pre-eminently in tiding patients over emergencies.If he were to suffer from pneumonia he would notlike to have CO2 or oxygen used from the beginning,for even slight resistance to breathing, as occasionedby the valve, was distressful in that disease.

Dr. G. MARSHALL remarked that during the warhe used the nasal catheter a great deal in treatingcases of gassing. The results there were so good thathe had been employing the nasal catheter ever since

I

when giving oxygen therapeutically. Dr. Marshallreferred to Dr. J. J. Coghlan’s paper (THE LANCET,Jan. 2nd, p. 13), pointing out the remarkable effectof inducing artificial pneumothorax in unilaterallobar pneumonia. It was definitely recognised, hesaid, that in unilateral pneumonia the conditionimproved and the respiration-rate fell if the pneumonicarea was thrown out of function by inducing pneumo-thorax.

Prof. HALDANE. in reply, agreed that in early stagesof lobar pneumonia there were no distinct indicationsof want of oxygen, and there seemed no reason forgiving it in those early stages. The special indicationfor it in that disease was when the lips began to getgrey ; it was then likely to tide the patient over i

the crisis. Probably oxygen did not shorten theperiod of the pneumonia. When he, Prof. Haldane,lay down in bed his breathing became slower anddeeper, but it was not so with all people. His

breathing-rate became reduced from 14 to 7 or I8 per minute. And he was amazed to find thathis breathing became periodic ; alternately it gotdeeper and shallower. Thus in his own personhe could produce Cheyne-Stokes breathing easily, Ibut it was difficult to produce in one of his colleagues.The Copenhagen school assumed that the alveolarair was of even composition and frequency all over, Ibut with that he did not agree. Admittedly when Ithe practitioner found that oxygen was required I

he should give it in the simplest way available, butif a cylinder was used the quantity given could bemeasured. ____

SECTION OF OBSTETRICS AND GYNAECOLOGY.

A MEETING of this section was held on Jan. 15thwith Mr. VICTOR BONNEY, the President, in thechair.

Recent Researches on Sex Hormones.

Prof. E. C. DoDDS read a paper on the Bearing ofRecent Research on the Sex Hormones on ClinicalObstetrics and Gynaecology. He said that thefirst step forward in our knowledge of the sex

hormones had occurred when Prof. Stockard haddemonstrated the changes in the vaginal epithe-lium during oestrus in rodents. Allen and Doisyhad shown that this change, which ceasedwhen both ovaries were removed, could bere-established by the injection of an alcoholic extractof ovary. The next step was the discovery that this.oestrus-producing substance could be also extractedfrom the placenta and from the urine of pregnantwomen. Following on this came the discoverythat transplants and extracts of the anterior lobe ofthe pituitary could cause premature puberty in rator mouse with the development of oestrus and theluteinisation of the ovaries. The demonstrationby Aschheim and Zondek of the presence of this

luteinising substance in the urine of pregnant womenlaid the foundation for a long series of observations,from purely chemical considerations of the hormoneon the one hand to the establishment of an accuratetest for the diagnosis of pregnancy on the other.

Finally, Corner had shown that an extract of corpusluteum could cause the changes characteristic ofearly pregnancy.

Prof. Dodds then gave a survey of the present-day views. It was believed that the anterior lobeof the pituitary controlled the ovarian periodicityby secretion of the hormone referred to as prolanby the Germans and as " Rho " factor by B. P.Wiesner. This was originally said to consist oftwo factors, one responsible for the follicle ripening.(prolan A) and the other responsible for luteinisation(prolan B). Although these two might be separateentities they had not yielded to physical separation.The stimulated ovary, with ripening follicles, secreted-cestrin, which caused enlargement of the uterus,,puberty, and cornification of the vagina characteristicof oestrus. The corpus luteum, in its turn, secretedanother hormone called by Corner " progestin,"and by Wiesner the " Beta " hormone, which

apparently was responsible for the development ofdecidual changes and was probably responsible for:the phenomenon of pseudopregnancy.

It was known that the removal of the ovaries caused.the production of castration cells in the anteriorlobe of the pituitary and that these cells could be madeto disappear by the administration of costrin. There

was, therefore, a complicated interaction and balanceof the whole system. Certain German authors had

put forward the following theory to explain the

periodicity of the sex cycle : the pituitary secretedprolan, which, after a time, caused the formationof a corpus luteum with its secretion progestin. The

progestin then reduced the secretion of prolan so thatthe corpus luteum retrogressed and so the process wenton. This theory would not explain the enormousproduction of oestrin and prolan during pregnancywhen presumably the corpus luteum was continuing.to secrete progestin.The standardisation of oestrin had presented.

188

considerable difficulties. Coward and Burn hadshown by using large numbers of animals that as theamount of oestrin injected was increased, an increasingnumber of rats or mice showed oestrus. It hadtherefore become necessary to carry out standardisa-tion on large numbers of animals and all previousquantitative work had been rendered useless. The

point where 50 animals showed oestrus and 50 didnot, had, by common consent among workers, becomethe standard for oestrin. Other variations in theeffectiveness of a dose were produced by the purityof the material and by the mode of administration.Very pure oestrin was excreted so rapidly that it wasgone before cestrus occurred; larger doses were

required for oral administration than for injection,and far fewer units were required for oral administra-tion of crude cestrin than of the pure material.Furthermore, the activity of a quantity dependedon the number of doses into which it was divided.Very little was known of the nature of the prolansexcept that they were complicated substancescontaining nitrogen.

Turning to the clinical application of this researchProf. Dodds said that oestrin had been recommendedfor every gynaecological condition-amenorrhoea,menorrhagia, haemophilia, and a host of other condi-tions. The prolans had been similarly recommended.The expense of progestin, due to the difficulty of obtain-ing corpora lutea, was an obstacle to its clinical use.

Probably all work in the past had been carried outwith grossly inadequate doses. He suggested thatwork should be confined to clear-cut cases about whichmuch is known and that large doses of cestrin shouldbe given. It should be possible to make preparationswhich would be slowly absorbed; large doses of

crystalline material appeared to be wasteful anduseless. The Aschheim-Zondek test for pregnancywas the only definite clinical aid that had so far comefrom this work. In conclusion, he offered a warningwith regard to the indiscriminate use of prolan.It was known that the ovary of an animal could beconverted into a solid mass of lutein tissue by theadministration of this material and it would beundesirable to run any risk of producing this effectin women.

UNITS OF DOSAGE.

Prof. A. S. PARKES said that standard units as

a measure of oestrus-producing hormone did not

exist, but it would be possible to standardise theoestrus-producing hormone within 10 per cent. bythe method of Coward and Burn. The test dependedon the cornification of the vagina of a mouse or rat ;in these animals the amount required to produce thecornification varied with the method of administra-tion, the time over which it was spread, and the numberof doses into which the material was split. Dis-

regarding for the moment these large variations, thelaboratory unit was a rat unit or a mouse unit.By keeping strictly to the same method with thesetwo animals Prof. Dodds and Mr. G. F. Marrian, D.Sc.,had shown that the dose required for rats was tentimes that for mice. Cornification was only one symp-tom of cestrus and the amount of hormone requiredto produce full oestrus, judged by distension of theuterus, was found to be very much greater. Marrianhad found that the necessary dose was about 200times greater in the mouse and it was likely that asimilar factor held for the rat. In larger animals thefigures were still more startling. To produce cestrusin the ovariectomised ferret or rabbit the figuresmounted rapidly into thousands and 100,000 mouseunits were required to produce full cestrus in a baboon

weighing 10 kg. The dosage was thus found to varystrictly on a weight for weight basis, and so continuingthe curve upwards the clinical dose became half amillion mouse units for a woman. Various reliable

preparations were on the market, one of which cost30s. for 2000 units. If half a million units were

necessary for a woman and this figure were multipliedby 12t, the factor for oral administration, the cost ofone effective dose would be ;E9000. The reasonable

dosage for clinical use was a very urgent problemand a revision of our ideas of the clinical applica-tion of the oestrus-producing hormone was urgentlyrequired.

CLINICAL TESTS.

Dr. H. GARDINER-HILL said that he had beenprovided by Prof. Dodds with standardised extractsof aestrin for four years. This material had beentried out on cases of amenorrhcea and of climactericphenomena. He had classified the cases into those of(1) primary amenorrhcea (normal individuals withdelayed development, wasting diseases, and glandulardefects), (2) primary menstrual irregularities, whichwere minor degrees of the first group, and (3)secondary amenorrhcea. None of group 1 ; one-

third of group 2 ; and in group 3 over half the casesof secondary amenorrhcea due to simple causes suchas climate, shock, or pregnancy had been affected.Secondary amenorrhcea due to glandular defect hadbeen unaffected. Two cases were striking; both

patients complained of amenorrhcea and sterility;both menstruated after injection of 180 and 200mouse units respectively, became pregnant and hadnormal children. Dr. Gardiner-Hill thought that

preparations of oestrin such as those provided byProf. Dodds were worth further clinical trial in care-fully selected straightforward cases of amenorrhoeaof the type he had discussed. He realised the

difficulty of assessing clinical results in these condi-tions, but nevertheless thought that it was difficultto account for the changes in his cases except on thesupposition that they had in some way resulted fromtreatment with oestrin. When the relative size of thehuman being and the experimental animals weretaken into consideration the effective dose certainlyseemed to be small, but the oestrus-producing effectin animals mentioned by Parkes appeared to be

quantitative. Could not the clinical results be

explained on the " trigger " hypothesis of W. Shaw-a small dose stimulating a sub-functioning follicularapparatus to produce active follicles and so initiatingthe cycle which ultimately resulted in the menstrualdischarge

. CHEMICAL CONSTITUTION.

Dr. Marrian said that in 1927 Aschheim and Zondekdiscovered the presence of oestrus-producing hormonein urine. The next step was in 1928 when Funkshowed that the oestrus-producing hormone had theacidic properties of a phenol. This gave the cluewhich led to the isolation by three independentworkers of a crystalline material with an empiricalformula of C18H2202. It proved to be a hydroxy-ketone. A little later Dr. Marrian himself hadisolated an oestrus-producing compound with theformula Ci$H2403 with three hydroxyl groups.Butenandt had then shown that both these substanceswere present in the urine of pregnant women, andthat one could be converted into the other bydistillation with potassium sulphate ; they were

therefore obviously related chemically. The firstof these (C18H2202) was more potent physiologicallythan the second, and a distinction should be made

189

between the substances when mention was made of Icestrus-producing hormone. The ketone gave itsmaximum response 24 hours after injection, whereasthe tritrodroxyl compound gave a longer latent

period and a much more prolonged response. Dr.Marrian suggested that further work should beconducted by using injections of the crystallinematerial only in order to obtain clear-cut results.

REACTIONS OF ENDOMETRIUM AND UTERINE

MUSCLE.

Dr. J. M. RoBSON said that it was important toknow something of the sex cycle in the human inorder to understand the action of these hormones.Under the influence of the corpus luteum hormone theendometrium was built up during the latter half ofthe menstrual cycle, to degenerate with the occurrenceof menstruation. There was also a change in theuterine muscle when under the influence of the I

corpora lutea, in that it would not respond to

pituitrin. Similarly the uterine muscle of a virginanimal which had been injected with corpus luteumextract did not respond to pituitrin ; nor did thepregnant uterus, but at term the corpus luteumsubsided. An observer who had inserted bagsconnected to manometers into the human uterushad shown that intravenous injection of pituitrincaused contraction during the first half only of thecycle. It was likely that the reactions in theendometrium and the muscle were independent andcould be dissociated ; dysmenorrhcea would resultwhen the pituitary acted on a uterus whose endo-metrium had not fully degenerated. Cases ofdysmenorrhoea, secondary amenorrhcea, and habitualabortion had all shown improvement after treatmentwith costrin ; those of primary amenorrhcea had not.

Mr. T. C. CLARE disputed the current interpretationof the fact that an ovary-stimulating substance wasfound during pregnancy in urine. This hormone,he argued, must be a chemical substance and as suchmust be fixed or absorbed by activity. When,therefore, it was being excreted unchanged it waseither being produced in excess of the body’s need,or else the demand had been reduced. This fixation

might be physiological or pathological. It .would be

interesting to know if the Aschheim-Zondek reactionwere positive in a young woman immediately afterhysterectomy. An appreciable proportion of cases

of malignant disease of the uterus had given a positivereaction ; this fact might be significant in the

aetiology of cancer. He suggested that it was merelydue to excess of hormone as the uterus was failing tofix the full quantity.

Dr. MAJRRiAN, in reply, said that Mr. Clare’s theorywas based on a false supposition that the presenceof the hormone in urine indicated failure of fixation.Nothing was known of the nature of the hormone ;if, as was possible, it acted like a catalyst, argu-ments based on quantitative fixation would fallto the ground.The PRESIDENT said that there was no doubt that

many claims in the past for the extracts had beenabsurd. The cause of the profusion was the confusion ofthe post and propter hoc ; it was so easy to forget theaction of chance. A girl of 20 was given an extractand afterwards started to menstruate ; although thechances might be ten to one that she would do so inany case, it was tempting to attribute falsely themenstruation to the treatment. He hoped thatwhen obstetricians or gynaecologists had clear-cutcases they would refer them to a biochemist whocould make good scientific use of the case. Surely

it should be easy to refer to the biochemist the

problem of how much use was the ovary after

hysterectomy.Prof. DODDS said that hysterectomy led to a cystic

condition of the ovaries which was abated by givingan extract of uterus.The j. RESIDENT suggested that as there was

luteinisation of the ovaries in vesicular mole it wouldbe interesting to examine the hormone content ofvesicular moles when suitably large ones were

available.Demonstration of Specimens.

Mr. T. G. STEVENS showed a rhabdomyosarcomaof the cervix removed from an unmarried woman,aged 23, who had had slight intermenstrual bleedingfor 12 months and recently a stabbing pain in theabdomen. The tumour which was attached to thecervix by only a thin pedicle was thought to be alarge mucous polypus and was removed in the out-patients’ department. Sections, however, showedsmall striated muscle-fibres, and also smooth muscle-fibres in a fibrous tissue stroma, and there was anincomplete covering of squamous epithelium. Afew glands but no cartilage were present. Mr.Stevens considered that in spite of the presence ofstriped muscle tissue, which was unusual, the tumourwas highly malignant; he therefore performedpanllysteroopllOrectomy..N 0 secondaries were seenin the abdomen, and the growth ceased abruptlywhere the pedicle joined the cervix. Deep X raytherapy was subsequently given. Judging by all

reported cases the prognosis was poor.-Dr. F. J.McCANN said that he had seen a few cases which hadcontained cartilage. There had been early recurrencein each case.-The PRESIDENT reported that he hadseen several cases of sarcoma during the last few-years, but none had contained striped muscle tissue.In two cases operation had not been followed byrecurrence. He doubted whether it was advisableto remove both ovaries, especially in so young a

patient, although X ray therapy was given. Hehad seen recurrence in an ovary.-Mr. STEVENS

replied that he held very strongly that ovaries afterthe removal of the uterus are of no use at all. He hadremoved both in this case because he wished to removeentire the whole lymph tract.

Mr. Louis C. RIVETT showed a foreign body whichhad been removed from the lumen of the smallintestine ten years after he had performed Caesareansection. Convalescence had been delayed, the patientstated that she had not felt well since then, but shehad only recently consulted her doctor. On examina-tion a mass was found in the upper abdomen. Atan exploratory operation the intestines were foundto be matted together and considerable anastomosis.had occurred. A foreign body found within thelumen of the matted intestines was removed througha hole which was sutured and drained. The patientmade a good recovery and afterwards only complainedof slight diarrhoea. The foreign body which Mr.Rivett had in his own keeping proved to be extensivefaecal concretions round a large gall-stone.

POST-GRADUATE WORK IN BERLIN.-Internationalmedical post-graduate courses are to be held in Berlinon the following subjects : internal medicine (Feb. 29thto March 5th) ; occupation and disease (March 7thto 14th) ; recent results of scientific research and theiremployment in obstetrics and gynaecology (March 14th to19th) ; surgery (April 4th to 9th) ; and practical progressin X ray diagnosis and treatment (April 10th to 17th).Particulars of these and of the regular courses may be hadfrom the information bureau of the Kaiserin Friedrich-Haus,Luisenplatz, 2, Berlin, N.W.6.