PROGESTERONE IN THE TREATMENT OF RHEUMATOID ARTHRITIS A CLINICAL TRIAL IN 5 CASES
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297 PROGESTERONE IN THE TREATMENT OF RHEUMATOID ARTHRITIS A CLINICAL TRIAL IN 5 CASES W. R. M. ALEXANDER M.B., B.Sc. Edin. NUFFIELD RESEARCH FELLOW J. J. R. DUTHIE M.B. Aberd., F.R.C.P.E. LECTURER IN THE RHEUMATIC DISEASES DEPARTMENT OF MEDICINE, UNIVERSITY OF EDINBURGH Rheumatic Unit, Northern General Hospital, Edinburgh Hench et al. (1949) reported dramatic remissions of symptoms in rheumatoid arthritis following the adminis- tration of ’ Cortisone ’ in large doses. In view of the technical difficulties and high cost of production of this hormone it seemed justifiable to attempt an assessment of the possible therapeutic value of progesterone, a steroid with a close structural relationship to cortisone, in a small series of cases in the active phase of rheumatoid arthritis. There is evidence of a great increase in progesterone production during pregnancy (Venning and Browne 1936, Browne et al. 1937, Venning et al. 1937), and the frequent occurrence of remissions of rheumatoid arthritis in patients becoming pregnant (Hench 1938) seemed to provide additional justification for this trial. Touw and Kuipers (1938) reported encouraging results in 2 cases of rheumatoid arthritis treated with com- paratively small doses of progesterone. In a larger series, Reich (1949) injected 12 male and 9 female patients with 50 mg. of progesterone daily for thirty days. Clinical improvement of various degrees was observed in 15 cases. CLINICAL MATERIAL AND METHOD The patients chosen for a trial of progesterone in high dosage were 4 women and 1 man. The female patients were selected from among those who had passed the menopause to avoid the possibility of excessive menstrual bleeding on withdrawal of the hormone. The diagnosis was based on the presence of a poly- arthritis of typical distribution, and radiological evidence of an arthritis of the rheumatoid type. All were in an active phase of the disease as indicated by persistent joint pain and swelling and mild or moderate hypo- chromic anaemia. With the exception of case 2, all had a raised erythrocyte-sedimentation rate (E.s.R.) on repeated estimation. All were inpatients in the Rheumatic Unit throughout the control and treatment periods. Clinical assessment was made by one observer (W. R. M. A.). Detailed charts of subjective symptoms and objective changes were kept, and the haemoglobin percentage and E.s.R. were recorded weekly or more frequently. From the time of admission the patients were put on a basic regime of treatment, the essentials of which were rest in bed, physiotherapy, and the application of rest splints to the painful joints. An ample well-balanced diet was supplemented with extra milk and vitamin concentrates except in case 4, where an 800-calorie diet was prescribed because of obesity. Patients remained on this regime for control periods of one to five weeks (see table) before injections were begun. Most cases of rheumatoid arthritis will improve initially in these circumstances, and the control period was thought to be essential to avoid the response to rest and physical treatment being attributed to progesterone. In the present 5 cases, signs of activity, as defined above, persisted and it was considered that an adequate base-line had been established in each case before progesterone was given. Preparation and Dosage.-Progesterone in oil-(B.D.H., 25 mg. per ml.) was administered intramuscularly in the doses indicated in the table. No toxic effects were noted, but in case 1 the affected joints became more painful and swollen during the administration of progesterone. RESULTS In no case was there any striking improvement during or after the administration of progesterone. The condi- tion of the joints improved in all cases, but not more so than would be expected from the non-specific measures used throughout. In 4 cases the E.S.R. remained rapid throughout the control period and during the period on progesterone. In case 2 the E.s.R. was normal on admis- sion in spite of considerable pain and limitation of move- ment in many joints ; during the administration of progesterone it increased, returning to normal before the patient’s discharge. In the 4 patients who were under- weight initially there was no significant gain in weight during or after treatment. In view of the fall in circulating eosinophils following the injection of adrenocorticotropic hormone (Thorn et al. 1948) and of cortisone (Thorn and Bayles 1949), eosinophils were counted hourly in case 1 after the injection of 100 mg. of progesterone. No fall had occurred at four hours, whereas an injection of 25 mg. of adreno- corticotropic hormone in this case produced a 90% fall. In 5 cases of ’rheumatoid arthritis not included in this series an injection of 100 mg. of progesterone produced no fall in 4 cases and a 37% fall in 1. DISCUSSION Spies and Stone (1949) found that steroids which had no effect on the circulating eosinophils did not produce an amelioration in rheumatoid arthritis comparable to SUMMARY OF CASES Case 1 received two courses of progesterone. Figures in parentheses indicate estimations carried out four weeks after end of treatment with progesterone. E.s.R. estimated in Westergren tube with oxalated venous blood (Wintrobe’s mixture). Haemoglobin estimated on oxalated venous blood with photo-electric colorimeter (100 %≡14.8 g. of Hb per 100 ml.). G2
Transcript of PROGESTERONE IN THE TREATMENT OF RHEUMATOID ARTHRITIS A CLINICAL TRIAL IN 5 CASES
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PROGESTERONE IN THE TREATMENT
OF RHEUMATOID ARTHRITISA CLINICAL TRIAL IN 5 CASES
W. R. M. ALEXANDERM.B., B.Sc. Edin.
NUFFIELD RESEARCH FELLOW
J. J. R. DUTHIEM.B. Aberd., F.R.C.P.E.
LECTURER IN THE RHEUMATIC DISEASES DEPARTMENT OF
MEDICINE, UNIVERSITY OF EDINBURGH
Rheumatic Unit, Northern General Hospital, EdinburghHench et al. (1949) reported dramatic remissions of
symptoms in rheumatoid arthritis following the adminis-tration of ’ Cortisone ’ in large doses. In view of thetechnical difficulties and high cost of production of thishormone it seemed justifiable to attempt an assessmentof the possible therapeutic value of progesterone, a steroidwith a close structural relationship to cortisone, in asmall series of cases in the active phase of rheumatoidarthritis.There is evidence of a great increase in progesterone
production during pregnancy (Venning and Browne1936, Browne et al. 1937, Venning et al. 1937), andthe frequent occurrence of remissions of rheumatoidarthritis in patients becoming pregnant (Hench 1938)seemed to provide additional justification for thistrial.Touw and Kuipers (1938) reported encouraging results
in 2 cases of rheumatoid arthritis treated with com-
paratively small doses of progesterone. In a larger series,Reich (1949) injected 12 male and 9 female patients with50 mg. of progesterone daily for thirty days. Clinicalimprovement of various degrees was observed in 15 cases.
CLINICAL MATERIAL AND METHOD
The patients chosen for a trial of progesterone in highdosage were 4 women and 1 man. The female patientswere selected from among those who had passed themenopause to avoid the possibility of excessive menstrualbleeding on withdrawal of the hormone.The diagnosis was based on the presence of a poly-
arthritis of typical distribution, and radiological evidenceof an arthritis of the rheumatoid type. All were in anactive phase of the disease as indicated by persistentjoint pain and swelling and mild or moderate hypo-chromic anaemia. With the exception of case 2, all hada raised erythrocyte-sedimentation rate (E.s.R.) on
repeated estimation. All were inpatients in theRheumatic Unit throughout the control and treatmentperiods.
Clinical assessment was made by one observer
(W. R. M. A.). Detailed charts of subjective symptoms
and objective changes were kept, and the haemoglobinpercentage and E.s.R. were recorded weekly or morefrequently. From the time of admission the patientswere put on a basic regime of treatment, the essentialsof which were rest in bed, physiotherapy, and theapplication of rest splints to the painful joints. An
ample well-balanced diet was supplemented with extramilk and vitamin concentrates except in case 4, wherean 800-calorie diet was prescribed because of obesity.Patients remained on this regime for control periods ofone to five weeks (see table) before injections werebegun.Most cases of rheumatoid arthritis will improve
initially in these circumstances, and the control periodwas thought to be essential to avoid the responseto rest and physical treatment being attributed toprogesterone. In the present 5 cases, signs of activity,as defined above, persisted and it was considered that anadequate base-line had been established in each casebefore progesterone was given.
Preparation and Dosage.-Progesterone in oil-(B.D.H.,25 mg. per ml.) was administered intramuscularly in thedoses indicated in the table. No toxic effects were noted,but in case 1 the affected joints became more painfuland swollen during the administration of progesterone.
RESULTS
In no case was there any striking improvement duringor after the administration of progesterone. The condi-tion of the joints improved in all cases, but not more sothan would be expected from the non-specific measuresused throughout. In 4 cases the E.S.R. remained rapidthroughout the control period and during the period onprogesterone. In case 2 the E.s.R. was normal on admis-sion in spite of considerable pain and limitation of move-ment in many joints ; during the administration ofprogesterone it increased, returning to normal before thepatient’s discharge. In the 4 patients who were under-weight initially there was no significant gain in weightduring or after treatment.
In view of the fall in circulating eosinophils followingthe injection of adrenocorticotropic hormone (Thorn etal. 1948) and of cortisone (Thorn and Bayles 1949),eosinophils were counted hourly in case 1 after the
injection of 100 mg. of progesterone. No fall had occurredat four hours, whereas an injection of 25 mg. of adreno-corticotropic hormone in this case produced a 90% fall.In 5 cases of ’rheumatoid arthritis not included in thisseries an injection of 100 mg. of progesterone produced nofall in 4 cases and a 37% fall in 1.
DISCUSSION
Spies and Stone (1949) found that steroids which hadno effect on the circulating eosinophils did not producean amelioration in rheumatoid arthritis comparable to
SUMMARY OF CASES
Case 1 received two courses of progesterone.Figures in parentheses indicate estimations carried out four weeks after end of treatment with progesterone.E.s.R. estimated in Westergren tube with oxalated venous blood (Wintrobe’s mixture).Haemoglobin estimated on oxalated venous blood with photo-electric colorimeter (100 %≡14.8 g. of Hb per 100 ml.).
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G2
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that reported with adrenocorticotropic hormone. Our
experience with progesterone confirms this.Venning (1946) reported a considerable rise in excretion
of corticoids in pregnancy. In the light of recent reportson the beneficial effect of cortisone it therefore seems
likely that remissions of rheumatoid arthritis occurringduring pregnancy are due to increased production notof progesterone but of steroids with a cortisone-likeaction. It is of interest, however, to note that the meta-bolism of progesterone in rheumatoid arthritis appearsto be abnormal. After the injection of progesterone thequantity of pregnanediol recoverable from the urine isgreater in patients with rheumatoid arthritis than innormal persons (Sommerville et al. 1950).
SUMMARY
Large doses of progesterone were administered to 5patients with rheumatoid arthritis.No evidence of therapeutic benefit was obtained.No fall in the number of circulating eosinophils was
noted after the injection of 100 mg. of progesterone.It is suggested that the remissions of rheumatoid
arthritis which occur during pregnancy are not due toprogesterone but may b’e attributable to increased
production of other steroids by the adrenal cortex.
We are indebted to Prof. L. S. P. Davidson for his helpfulcriticism and advice in the preparation of this report.
REFERENCES
Browne, J. S. L., Henry, J. S., Venning, E. H. (1937) J. clin. Invest.16, 678.
Hench, P. S. (1938) Proc. Mayo Clin. 13, 161.— Kendall, E. C., Slocumb, C. H., Polley, H. F. (1949) Ibid,
24, 181.Reich, N. E. (1949) Amer. Practitioner, 4, 1.Sommerville, I. F., Marrian, G. F., Duthie, J. J. R., Sinclair, R. J. G.
(1950) Lancet, Jan. 21, p. 116.Spies, T. D., Stone, R. E. (1949) Ibid, ii, 890.Thorn, G. W., Bayles, T. B. (1949) Practitioner, 163, 365.
— Forsham, P. H., Prunty, F. T. G., Hills, A. G. (1948) J. Amer.med. Ass. 137, 1005
Touw, J. F., Kuipers, R. K. W. (1938) Acta med. scand. 96, 501.Venning, E. H. (1946) Endocrinology, 39, 203.- Browne, J. S. L. (1936) Proc. Soc. exp. Biol., N.Y. 34, 792.- Henry, J. S., Browne, J. S. L. (1937) Canad. med. Ass. J.
36, 83.
EFFECTS OF SULPHONAMIDES ON SERUM-
PROTEIN, PLASMA VISCOSITY, ANDERYTHROCYTE-SEDIMENTATION RATE
JOHN HARKNESS
M.B., B.Sc. Glasg.CHEMICAL PATHOLOGIST, CENTRAL LABORATORY, PORTSMOUTH
THE effects of ordinary therapeutic doses of sul-
phanilamide and sulphapyridine on the serum-proteinlevels, plasma viscosity, and erythrocyte-sedimentationrate (E.s.R.) have been investigated in normal persons.
MATERIAL AND METHODS
The subjects of the experiments were apparentlynormal men, aged 20-63, but they were not physicallyexamined. Their lives were restricted to a routine ofwork, exercise, food, sleep, &c.. so as to reduce other
physiological stimuli to a minimum and to allow thesuccessive blood samples to be removed under almostidentical conditions. To reduce the emotional stimuli,the men were not told on which days blood would beremoved, and they were not likely to be mentallydisturbed by taking tablets.
Six men were given 2 g. of sulphanilamide by mouth,followed in 4 hours by another 2 g., and thereafter by 1 g.4-hourly until a total of 20 g. had been administered.
With another six men the same procedure was carriedout with sulphapyridine.Venous blood was drawn, with minimal stasis, from
the fasting men at the same hour of the day. Part ofthe blood was allowed to clot to produce serum, whichwas later separated by centrifuging ; and part was usedto make an accurate 4 : 1 mixture with 3-8% sodiumcitrate solution.
Clinical pathological estimations were made of (1)serum total protein, by the falling-drop specific-gravitytechnique of Barbour and Hamilton (1926) ; (2) plasmaviscosity by the technique of Houston et al. (1945);(3) serum viscosity by the same technique ; (4) packed-cell-volume (P.c.v.) by centrifuging citrated blood in
capillary hæmatocrit tubes for 1 hour at 3000 r.p.m. ;and (5) maximal corrected E.s.R. by the methoddescribed by Houston et al. (1945).
RESULTS
The effects of sulphanilamide and sulphapyridinewere identical, so only the sulphanilamide results arepresented. Figs. 1 and 2 show these results in graphicalform.The serum-protein, plasma viscosity, serum viscosity,
and E.s.R. had all increased within 48 hours of theadministration of the sulphanilamide. (The sulpha-pyridine tests were done at different time intervals, andtne increases
were evidentwithin 24hours of
giving that
drug.) Thatthese increasesare not dueto hæmocon-centration canbe ascertainedfrom the P.c.v.values, inwhich thevariation issmaller andinconstant,and by makingallowance forthis variationin calculatingthe changes inthese othervalues (as hasbeen done forthe serum-
protein onlyin fig. 1).No work
has previouslybeen publishedon the dailyvariations in
the plasma andserum viscosi-ties in responseto ordinaryphysiologicalstimuli, butmy experi-ence indicatesthat such vari-ations shouldbe less than
1% of the
original value.The changes
Fig. I-Variations in plasma viscosity, serum vis-cosity, packed cell volume, and serum-proteinon exhibition of sulphanilamide. Results are
expressed as percentages of values beforeadministration of sulphanilamide. The lines jointhe means of the experimental results.
