Current Topics Dry Blood Test for Typhus Fever By
P. N.
BARDHAN,
m.r.c.p.
(Edin.)
MAJOR, I.A.M.C.
N. TYAGI,
i.A.M.c.
and K.BOUTROS LIEUTENANT, R.A.M.C. (From the British Medical Journal, i, 19th February, 1944, p. 253) In 1942 Steuer utilized
a
slide-agglutination, method
for the rapid diagnosis of typhus fever. that 200 slides could be examined in 90
He claimed
minutes, and
that each individual slide could be read in from 5 to 10 minutes. We found his technique unnecessarily cumbersome, and it was therefore modified by us to for use. The workable essential make it more general difference between the two techniques was that, while measured of blood and Steuer used exactly quantities antigen suspension, we used approximate quantities. we is : The technique employ Method clean glass slide two drops of blood, obtained by pricking the finger or the ear lobe without squeezing, separated from each other by a grease-pencil line. Dry in air and mark the drops 1 and.2. Place a drop of concentrated suspension of OX 2 and OX 19 on blood drops 1 and 2 respectively. Leave for a minute, and then complete the mixing of the blood and the suspension by gently rocking the slide. (Mixing with a platinum loop or other foreign object tends to produce strings of fibrin, which cause coiifusion in reading the results.) Set aside for 5 minutes, taking Place
on
a
446
THE INDIAN MEDICAL GAZETTE
to avoid drying up of the slide and soiling by dust. Rock the slide occasionally. Results are read in from 5 to 10 minutes by the naked eye, and if necessary are confirmed by a handlens. The use of the low-power objective, as recommended by Steuer, is rarely necessary.
care
high enough for diagnosis. These observations suggest that negative cases may occasionally give positive results, but this is not of much import. The fact that every clinical typhus case which was proved positive by' the Weil-Felix reaction was spotted by the slide method is justification enough for urging the use of this simple technique as a preliminary to putting up a long series of tests by Dreyer's or Felix's method. It was decided to try out a number of slide-negative cases by Dreyer's method, to see whether the zone phenomenon or some other factor would produce positive results in slide-negative cases. Thirty-three such the highest dilution put up was sera were tested; 1 in 250 and the lowest 1 in 25. Of these, 25 were completely negative; the remaining 8 gave agglutinations as shown in table IV.
Results The tests were carried out on Egyptian labourers. Slides were taken in various camps under military control, were brought to the laboratory the same day, and were examined within the' next 24 hours. In all, 640 persons were examined; 11 of these gave 'slide' positive results against OX 19, and 2 were positive to OX 2 in addition. These 13 were then followed up for a complete Weil-Felix reaction, using Dreyer's technique. The results are summarized in table I.
Table IV
Table I Positive to OX 19
Negative
to OX 19
1944
[Sept.,
.
..
..
..
7*
..
..
..
6
Serial number
25
27
29
33
35
45
50
52
OX 2
0
25
0
50
25
25
0
25
OX 19
25
0
25
0
25
0
25
0
*
Of these 7 positives, 2 also showed agglutination in 1/50 against OX 2 : and these 2 were the same persons who were slide-positive for OX 19 and OX 2. The 7 ' slide- and Deryer-positive' cases were further studied by carrying out a series of Weil-Felix tests at 4-day to 7-day intervals. The results obtained are shown in table II.
None of these titres has any diagnostic value. Table
Serial number
1st test
2nd test
II
3rd test
3
OX 2
0 250
4
OX 2
50
50
50
50
125
500
OX 2
12
4th test
Remarks
Had typhus
50 250
a
month before first test.
Not traceable afterwards.
50 500
OX 2
19
?!
Had typhus 3 weeks
previously
Not traceable:
not
hospital.
0
500
history
in
available.
i
OX 2
20 21
0
0
1,280
2,560
OX 2 OX 2
22
0
0
250
1,800
0
0
250
250
Hospital
will thus be
seen
,
that all the clinical and Weil-Felixshowed 'slide agglutination' as
cases
Table III
0
Typhus with rash.
1,250
It is reasonable to conclude from. these results that slide-negative blood will not give a positive Dreyer reaction?certainly not of any diagnostic value. The low titres given in table IV have no significance beyond perhaps the possibility that the individuals had developed some immunity as a result of subclinical infection, or had suffered from the disease some time a
^
previously. Comment
Serial number
13*
15
17
25
:
'OX 2
0
0
0
0
0X19
0
0
0
50
*
0
1,250
well. The results of the 6 slide-positive and Deryer-negative cases (see table I) are detailed in table III.
U
diagnosed typhus-
Typhus with rash.
Nos. 4 and 19, despite of the history being unobtainable, should be considered. typhus cases in view of the high titre. The others were definite typhus cases. It
positive typhus
case:
Done twice, at five-day interval*
I
50
7
Except in 2 cases, there was no agglutination by Dreyer's method, and in neither of these was the titre
Having established that all positive cases can be detected by the slide method (of course to be confirmed by a complete agglutination test), and that the slide-negative cases will not give a positive result by Dreyer's method, it is. a reasonable assumption that a complete Weil-Felix test need not be done unless the slide test is positive. If this procedure is followed the obvious advantages will be : (a) economy in material and time; (b) avoidance of unnecessary bleeding of the patient; and (c) easier despatch of slides, as compared with that of blood or serum, to a laboratory situated at a distance from the hospital. Probably the test could be done on thick smears of blood, similar
CURRENT TOPICS
Sept., 1944]
to those used for the detection of malaria and taken at the same time.
of these constituents of the vitamin-B complex the finding that the protective actions of the various liver fractions is proportional to their contents of pantothenic acid. of
Summary
Egyptian civilians.
slideresult does not
cases
one
parasites,is considerably strengthened by
A dry blood test for typhus has been tried out among
It has been shown that all typhus positive result, though a
447
give
a
Bovine Serum (D.B.S.): A Substitute for Human Plasma
Despeciated
slide-positive By F. R. EDWARDS, mj)., ch.M., f.r.c.s. mean a positive case. Control tests show that a from the British Medical Journal, i, (Abstracted slide will not negative give a positive 15th January, 1944, p. 73) Weil-Felix reaction. The need for trying out this method on a more Substitutes for human plasma hitherto prepared extensive scale is urged, and the advantages to be have not fulfilled the three criteria : (a) retention in derived therefrom are discussed. the circulation and eventual metabolism; (b) exertion of an equivalent osmotic pressure; and (c) non-toxicity non-antigenicity, and freedom from antibodies. More Light on the B Complex Bovine serum can be made safe for man by destroy(From the British Medical Journal, i, ing the antibodies by heating to 72?C., while rendering 15th January, p. 85) the proteins uncoagulable with the addition of 0.2 per formalin and ammonia. Material so prepared In 1940 Van Etten and others found that the cent of to accord with the above precepts. administration of an ample supply of crystalline appears Clinical trial in 26 cases shows that it can be vitamin Bi did not and nerve prevent convulsions administered rapidly and in large amounts to man with degeneration in swine fed on autoclaved liver and whey. safety. ?f a Wintrobe cany the matter stage f fv, exPei!imen^s with an accurate description of symptomatology further, and pathology in A New Typhoid Vaccine for the Army pigs receiving all the known members of the B complex except Bi. The earliest clinical (From the Lancet, i, 4th March, 1944, p. 318) manifestations were failure of appetite and vomiting, The British Army authorities have decided to change followed by cyanosis, dyspnoea, and bradycardia, and ending with a severe degree of heart failure or sudden the well-tried T.A.B. vaccine, which was heat-killed and preserved in carbol-saline, for a new preparation of neuromuscular disturbance, dearth. No abnormality is killed by 75 per cent alcohol and preserved such as ataxic gait, was ever observed. Careful histol- which ogical examination of the nerve tissues, central and in 25 per cent alcohol. As before, great importance is peripheral, gave no evidence of degeneration or attached to the use of fully virulent strains and the the full complement of Vi antigen inflammation, but in practically every case local necroses vaccineis contains so important in producing a high level of fibres were present in both auricles which j my?tcardial^ and ventricles. Where the protection. Several points about the new alcoholized pathological condition had vaccine should be kept in mind. Bacteria suspended not advanced too far, administration of Bi led to in alcohol sediment more completely than in saline, recovery. Of particular interest are the biochemical findings. The concentration of carbonyl compounds and unless the bottle is thoroughly shaken the bacteria estimated as pyruvic acid was proportional to the sit tight and the syringe may not withdraw the proper degree of severity of the deficiency as judged by the dose of organisms. The doses of the new vaccine are smaller than those previously used. For men 0.25 c.cm. clinical manifestations. A sharp rise in blood pyruvic is followed after at least a fortnight by 0.5 c.cm., while of followed Quickly the progress rapid by +i? disease. ,r'as for women the doses are 0.2 c.cm. and 0.4 c.cm. the It was also found that a significant Annual reinoculation with 0.25 c.cm. is recommended increase m blood pyruvic acid after the administration for both. There was doubt at one time about the oi glucose always occurred in Bi-deficient animals but ability of 25 per cent alcohol to effect sterility if the not in the control group. As for urinary content of vaccine became contaminated during use, but this fear ?tii, it reflected?but by no means consistently?the dietary intake immediately before the collection of has been proved groundless. The chief advantage of the new vaccine is that alcohol preserves the integrity urme. Of more value in assessing the degree of Bi of the Vi antigen, as Felix has shown, and it also deficiency was the percentage retention of Bi after a probably induces a superior antibody response. Both given dose. This test, suggested by Najjar and Holt, local and general reactions are less severe than with gave results which can parallel with the clinical findings the old vaccine; Felix, Rainsford and Stokes and and the amount of Bi in the diet. workers of the Emergency Public Health Laboratory fr?m this the of work that 1,8 position near "f Service, point out that the average time lost through vitamin Bi as the antineuritic vitamin has been strongly reaction by those receiving TABC vaccine is likely to assailed, supporting the sceptical view put forward by be considerably less with an alcoholized than with a Meiklejohn in 1940. He concluded his review with product. Even so, the new vaccine the statement that phenolized is a multiple deficiency probably produces an initial stinging pain on injection and some responsible for nutritional neuritis but that there is still a possibility that the true antineuritic vitamin has people still get a local reaction and a slight rise of In future it may be possible to produce temperature. .vet to be discovered. of the use. crystalline By The question of even more inoffensive TAB vaccines. vitamins Wintrobe and his colleagues have shown that adding a representative of the paratyphosum C group neither riboflavin nor nicotinic acid has effect in any of organisms was considered, but infections of this maintaining the integrity of nervous tissue. It was kind in the Army were so few that this procedure was tnen found that the ataxic and the degenerative gait not adopted. Meanwhile there are sound reasons for nerve lesions brought about by a dietary deficiency the resignation of TAB from the active list and for the oi the vitamin-B are complex completely prevented seconding of TAB Ale. to take its place. whole oy desiccated The liver. anti-perniciousI anaemia fraction was found to be the most potent of the individual liver The Uses and Abuses of the Female Sex none of which are as fractions, etflcacious as whole liver, even when given Hormones parenterally, resu"s suSgest that there is a need for passage a? By T. N. MACGREGOR, mj>., p.B.c.s.Ed., m.r.c.o.g. f!e nerve-protection factor through the gastrointestinal tract. Finally, it has been shown that the (Abstracted from the Edinburgh Medical Journal Vol. LI, January, p. 39) dietary deficiency of either pyridoxine or pantothenic acid leads to an ataxic gait in swine and degeneration hormones most closely related to female sex The oi sensory neurones which could invariably be prevented physiology are the gonadotrophs hormone secreted by by the administration of these substances. The claim necessarily
_
?
,
*
.
THE INDIAN MEDICAL GAZETTE
448
pituitary
gonadotrophic hormone
anterior pituitary gland through its gonadotrophs hormono controls the development of the Graafian follicle, ovulation and corpus luteum formation. At the present time there is no reliable anterior pituitary preparation available for use which can simulate the actions of the naturally occurring gonadotrophs hormone; there are, however, two preparations which are of considerable therapeutic value, namely, serum gonadotrophs hormone prepared from pregnant mare's serum, and urine or chorionic gonadotrophic hormone extracted from pregnancy urine. The former stimulates follicular development; the latter causes corpus luteum formation. A combination of these two preparations forms a useful therapeutic agent indicated in conditions directly or indirectly associated with defective action of the anterior pituitary gland. The
The ovarian
orally. Anhydro-oxy-progesterone is a synthetic preparation of progesterone which is also active when given by mouth, but the effective dosage given orally is six times that given by injection. The uses of the sex hormones may conveniently be considered in two groups : gynaecological disorders and obstetrical conditions. Gynecological
(A) Before
disorders
puberty
only assume full function at thus few indications for the use of the sex hormones before this time. There is one condition, however, namely, vulvo-vaginitis, which can be effectively treated by cestrogenic hormone in the form of vaginal pessaries or by oral administration. The oestrogens stimulate the growth of the vaginal epithelium, and with the resulting increased glycogen content of the cells additional lactic acid is available so that not only is the infection controlled by the shedding of the epithelial squames, but the increased acidity of the vaginal flora proves inimical to the causative organism. It should be noted that the sulphonamides, especially sulphathiazol and sulphadiazine, are also effective in this condition and have none of the minor disadvantages, such as enlargement of the breasts, which are sometimes associated with the administration of the As the
sex
puberty, there
glands are
cestrogens. (B) During
the period
of
reproductive life
(1) Disturbances of' menstrual rhythm (a) Metropathia hemorrhagica.??The most common of irregular uterine bleeding is ^metropathia hsemorrha'gica or cystic glandular hyperplasia. This condition may occur at any time, but is more common at the beginning and end of the period of reproductive cause
^
hsemorrhagica and, pending more potent anterior pituitary preparations, it is the one most likely to meet with success, but the dosage must be adequate and the treatment must be energetic if satisfactory results are to be obtained. The intramuscular injection of 5 to 10 mg. of progesterone daily until the bleeding is controlled has been found to be an effective dosage. The role of the (Estrogenic hormone in functional uterine bleeding has recently been investigated, and not unfavourable .results have been reported. The results obtained in cases of irregular' uterine bleeding treated by oestrogenic hormone, and later referred to me, have been uniformly unsatisfactory. (6) Ovular bleeding, liypomenorrhcea and oligo-
hormones
The ovarian hormones are cestradiol or cestrogenic hormone elaborated by the developing Graafian follicles, and progesterone secreted by the corpus luteum not only elaborates its specific hormone, progesterone, but it also secrets cestradiol. Progesterone and cestradiol are the true or naturally occurring hormones of the ovaries and are produced for the most part by the ovaries under the stimulus of the gonadotrophic hormone of the anterior pituitary; they, are also secreted in variable amounts by other internal secretory glands, such as the adrenals. Potent preparations of these hormones have been available for some time. Now we have available for clinical use synthetic preparations of cestrogenic hormone, such as diethyl hexcestrol and triphenylchloroethylene stilbcestrol, which, though not chemically related, simulate closely the actions of the naturally occurring hormones. They, have the added advantage of being active when given
1944
life. It is characterized by a long intermenstrual period, five to ten weeks, followed by excessive and prolonged menstrual loss. It is possible that a minor psychological disturbance, acting through the higher cerebral centres and interfering with anterior pituitary function, forms the predominant etiological factor in metropathia hsemorrhagica. The essential cause of the condition, however, is a failure of ovulation with concomitant excessive production of the (Estrogenic hormone. In the present state of our knowledge progesterone seems to be the most effective therapy for metropathia
the anterior pituitary gland, (Estradiol elaborated by the developing Graafian follicles of the ovary, and progesterone secreted by the corpus luteum. Anterior
[Sept.,
menorrhcea.?These
are
minor
disturbances
of
the
rhythm. Ovular bleedifig, as the term implies, is. the bleeding which is sometimes associated
menstrual
-
with ovulation. It is believed to be due to a transient diminution of the oestrogenic hormone concentration occurring between the time of ovulation and mobilization of the corpus luteum. The temporary drop in the amount of circulating oestrogenic hormone results in a diminished stimulation of the uterine endometrium, which partially breaks down and causes bleeding. In some the bleeding may be very slight and represented by only a few spots, whilst in others the amount of blood lost may be similar to that of the normal period. Owing to the danger of inhibiting directly the anterior pituitary and indirectly ovulation, cestrogenic hormone is contra-indicated in this condition. The stimulation of the endometrium can, however, be adequately maintained in such cases by giving 5 mg. progesterone intramuscularly the day before the expected bleeding and for two days thereafter. A course of therapy over three menstrual cycles is usually efficacious. Hypomenorrhcea, or scanty menstrual loss, is not common and in most cases it is of no serious significance, as in such cases there is usually no failure of ovulation. There are a few cases, nevertheless, iu which there is failure of ovulation, and in such the bleeding is associated with the proliferative phase of the endometrium?so-called anovular menstruation. The importance of this type of menstruation in sterility is evident. An effective therapy must promote follicular maturation and ovulation; this can only be done by administration of anterior pituitary hormone, particularly the serum gonadotroph^ hormone, given in doses of 200 international units every third day for five injections, starting at the onset of the menstrual
period. Oligomenorrhoea,
or delayed menstruation, is not It is a frequent precursor of functional amenorrhcea and is prone to occur at the beginning and end of the period of reproductive life. Towards the menopause the bleeding is frequently associated with a proliferative endometrium, but at other times for the most part it is associated with a secretory endometrium. Thus there is a long proliferative phase of the endometrium and a normal secretory phase. The therapy indicated is one which will accelerate follicular development and ovulation; accordingly, the treatment most likely to be effective is the administration of anterior pituitary in the form of serum gonadotrophs hormone (200 i.u.) alone or in combination with urine gonadotrophic hormone (100 i.u.) every third day for five injections at the onset of the period. These preparations should be. given over three menstrual cycles at the time corresponding to the pre-ovulatory uncommon.
phase.
Sept.,
1944 |
449
CURRENT TOPICS
of sterility are found only after thorough investigation, (2) Dysmenorrhea and the cestrogens are given in order to evoke a defiThere are many cases, in which no nite and known response. The 'danger of cestrogenic obyious pathology exists and, although there may be a psychologicaltherapy in sterility, however, is that of so depressing basis for the pain, hormone pituitary function as to inhibit ovulation, thus*preventtherapy is efficacious. It is reasonable to assume frequently ing the occurrence of conception and promoting a that the rhythmic interplay of the ovarian secretions, whichpregnancy complex. exert their influence on the uterus and uterine adnexa, (4) Amenorrhcea may be maladjusted and increased function of one is due in most cases to a amenorrhcea partially override the function of the other. It is Although known that the cestrogenic hormone sensitizes thephysiological or a pathological condition, there is, a uterine musculature, promotes the large number of cases in which no proliferative phasenevertheless, of the endometrium and the amenorrhcea is apparent. A study of the increases the vascularity ofcause for such cases, however, leads one to the concluthe pelvic structures; whereas progesterone inhibitshistory in uterine activity and stimulates the secretory phase 01sion that in the majority there is an exciting psychothe endometrium. The disturbance; in some it is trivial, whilst in important point to keep inlogical mind, however, is that the corpus luteum secretes bothothers it may be grave. hormones and that they act synergistically on the When potent preparations of the ovarian hormones available the outlook in the treatment of uterus. Primary dysmenorrhcea, in my experience, isbecame promising, but the results invariably associated with ovulation; women who do amenorrhcea appeared not ovulate do not have obtained have not fulfilled the earlier expectations of This is painful periods. this form of therapy. clearly demonstrated in cases of ovular
bleeding, cestrin-withdrawal bleeding and the bleeding associated (5) The menopause with metropathia this case there is In hsemorrhagica. An important factor in the production of an unopposed cestrogenic action, and consequently there is mental reaction is the fear of loss of no pain associated with the bleeding, Painiul unfavourable women believe that sexual life menstruation is not necessarily associated with uterine sexual function?many the allaying of this ceases at the menopause?and hypoplasia or hyperplasia per se. dread may frequently change the whole outlook. As a result of clinical one believes There appears to be no indication for the use of the that it is only when thereinvestigation, is a deviation from tne normal finely adjusted concentration of the two ovarian cestrogens in irregular bleeding occurring at the menothe bleeding may be assohormones that the uterine reactivity becomes dis- pause, for theanreason that excessive with secretion of the already ordered, giving rise to pain either before or during ciated and any effect can only be of a very menstruation. If this contention is correct, tnen hormone temporary nature. It should be emphasized that slight hormone therapy for the relief of should dysmenorrhcea in uterine women at the bleeding menopause only be given during the second half of the menstrual irregular of a pathological process, and the cj'cle. Premenstrual dysmenorrhcea, in the absence 01 may be symptomatic of cestrogenic hormone in these cases, administration pelvic pathology, is most frequently associated witn though it may temporarily arrest the haemorrhage, excessive oestrogen or deficient progesterone production, merely masks the serious condition and delays, not and can be controlled by progesterone therapy in doses without danger, operative or other appropriate treatof 5 mg. every second day, starting eight days beiore ment. It is astonishing, however, how frequently the the expected period. Conversely menstrual dysmenoi- cestrogens are abused in the treatment of women comrhoea may be associated with excessive progesterone 01 subnormal (Estrogenic hormone secretion, and can be plaining of menstrualareirregularities at the climacteric. The cestrogens pre-eminently effective in relieved by the administration of cestrogenic hormone controlling the subjective symptoms associated with the in doses of 5 mg. of synthetic preparation given twice of ovarian function. The hot flushes, irridaily for four days prior to the onset of the period. cessation tability, depression, etc., which are so common and The (Estrogenic hormone is frequently administere as already pointed out, are conditioned to a during the first half of the menstrual cycle in cases which, certain extent by the psychological status of the of dysmenorrhcea. and this form of therapy may be individual, can be completely relieved by cestrogenic temporarily effective, but it acts oa ilhormone therapy. For this reason a high dosage of lation and consequently there is by suppressing always, the danger o such as 5 the cestrogens, mg. synthetic cestrogen thrice producing an abnormal condition, the treatment 0 daily, should be given until all symptoms are relieved, which may be much more difficult than that 01 tne the then and dosage should be gradually diminished primary disturbance. over a period of six to eight weeks. Satisfactory results obtained been in the artificially induced menohave (3) Sterility the administration of small doses of the pause by It is important to understand the role of the female cestrogens given as a prophylactic measure before any sex hormones in the treatment of sterility, as tney untoward symptoms arise. are frequently misused in this condition. JNow, 11 It is important to recognize that occasionally the ovulation takes place, lollops formation luteum corpus menopausal phase may pass imperceptibly into the normally?this is confirmed if one obtains a typical abnormal and that some patients, complaining initially secretory endometrial pattern in the tissue remmed of mild depression, may become definitely psychotic. with the biopsy curette immediately before a period, The cestrogens are of value in such cases when used or if pregnandiol can be recovered from the imnf: in as an adjuvant to general psychiatric treatment. the post-ovulatory phase?and there would therelore (C) POST-MENOPAUSE appear to be an indication for hormone therapy, it repeated examinations?and one examination is not In cases of senile vaginitis and kraurosis vulvse the conclusive?show that ovulation is not occurring, tnen restoration of the tissues, by the administration an anterior of cestrogenic hormone, to the same state of developto stimulate ovulapituitary preparation tion is indicated. It has been shown that anterior ment as that found during reproductive life, supplies pituitary preparations, especially serum gonadotropnic the necessary resistance to overcome the infection. hormone, can promote ovulation. Green-Armytage There is increased vascularity of the tissues and contends that small doses of oestrogen, for example, of the epithelium, and, in senile regeneration vaginitis, i to 1 mg. hexcestrol, given the change in the vaginal flora makes it inimical to daily during the first nve days of the cycle, that is during menstruation, nave a the causative organism. Leucoplakia vulvse, if treated beneficial effect not only on the pH ?f the in the early phase, responds satisfactorily to this but also secretion, treatment but may prove refractory in the later stages. promote a healthier condition 01 tne mucous plug?conditions favourable to the The dosage of the cestrogens employed in these condispermatozoa. There is also convincing evidence that administration tions should be a large one, say 15 mg. daily, adminisof the oestrogens promotes canalization of the tered over a short period. fallopian tubes in proved cases of tubal occlusion. These causes .
~
THE INDIAN MEDICAL GAZETTE
450
of the cestrogena to elderlysubsequent to operation for genital prolapse promotes the vascularity and regeneration of the tissues, This therapy proves which ensure sound healing. particularly beneficial in those cases in which the vaginal tissues are unduly friable and atrophic. administration
The
women
Pruritis vulvse is not
pause, and in the
factor
can
be
ascertained.
however, in which
after
uncommon
majority of
cases a
There
the
meno-
specific etiological are
some
cases,
be found, and in these the condition may be associated with some irritative lesion of the nerve endings arising from the atrophy of the tissues. (Estrogenic hormone therapy is often eminently successful in these resistant and difficult cases. It may be necessary to give a very high dosage if no result is obtained with a moderate dose. It should be noted, however, that it is not advisable to give a high dosage over more than a short interval of time. One case treated did not react favourably until a dosage of 45 mg. of synthetic oestrogen was given daily for seven days. The pruritis of was completely relieved. This high dosage oestrogen, however, provoked such a marked hypertrophy of the vaginal epithelium as to form a plaque in the anterior wall. Cystoscopic examination suggested a malignant condition of the base of the bladder, but the vaginal mucosa eventually returned to its normal post-menopausal state. The patient remained free of irritation until a recurrence two weeks ago. The most common etiological factor responsible for post-menopausal bleeding is a malignant condition of the uterus or its adnexa. It cannot be emphasized too strongly that post-menopausal bleeding, per se, is never an indication for cestrogenic hormone therapy, yet one frequently finds it being given quite unjustifiably in this condition. Some women may have an uneventful climacteric but complain of subjective symptoms late in life similar to those experienced at the menopause. Such cases can be effectively treated with the cestrogens, but they usually require a small maintenance dose
given
over a
no
cause
can
prolonged period. Obstetrical
conditions
The corpus luteum hormone or progesterone has welldefined physiological actions in the initiation and continuation of pregnancy. It is responsible for the the of uterine reaction decidual endometrium, thus preparing the endometrium for the nidation of the fertilized ovum. Its sedative action on the uterine musculature promotes conditions favourable for the the early process of embedding of the ovum and development of the placenta, and its uninterrupted production is essential for the continuation of the pregnancy. Consideration of these facts suggests the usefulness of progesterone therapy in (1) repeated early miscarriage suspected when the period is a few days late, (2) threatened abortion, and (3) recurrent abortion.
(1) Early
miscarriage?This
frequently
occurs
without the patient's knowledge, or it may be suspected when the period is repeatedly but not continuously a few days late. Some women realize intuitively that conception has occurred. A continuation of the pregnancy in such cases can be brought about by-the administration of progesterone, 5 to 10 mg. twice weekly, begun during the second half of the menstrual cycle and continued until at least the fourth month is reached. (2) Threatened abortion.?Abortion most frequently occurs at the time of the suppressed period, and it reaches its highest incidence at the time of the third missed period. The explanation for the frequency of abortion at. the third month is not clear. The placenta, by the time this stage is reached, is fully developed. It is known that pregnancy can continue /when the corpus luteum of pregnancy is removed at an early stage. The assumption is, therefore, that the placenta secretes the necessary amount of progesterone required for the continuation of the pregnancy. The change over from corpus luteum to placental production of _
[Sept.,
1944
progesterone probably takes place at the third month. A lag in the change over,' resulting in a lowering of the progesterone threshold, would furnish an explanation of the frequency of abortion at this time. The administration of progesterone in large doses (10 to 20 mg. daily) at the very earliest stage of a threatened miscarriage is frequently effective in saving the pregnancy. If much placental separation has occurred, however, the abortion will become inevitable and progesterone therapy is then valueless. It should be noted that progesterone therapy alone in threatened miscarriage is not enough; rest must be enforced and anxiety allayed by the use of sedatives. of administration (3) Recurrent abortion.?The progesterone early in pregnancy has resulted in the
continuation of the pregnancy to term in many cases of recurrent abortion. An adequate dosage, such as 5 to 10 mg. twice weekly, must be given as soon as the pregnancy is diagnosed and continued until at least the end of the fourth month of pregnancy. It is advisable to supplement this therapy by the administration of vitamin E. The cestrogens, in virtue of their function of increasing the sensitivity of the uterine muscie, have been used in (a) missed abortion, (b) induction of labour, and (c) uterine inertia. (a) Missed abortion.?As is well known, a dead ovum may be retained in utero for intervals of time varying from weeks to months. The cause of the retention of the ovum is presumably the diminished sensitivity of the uterine muscle. This can be overcome by the administration of cestrogens, and this form of therapy is frequently very successful in missed abortion ?tfid premature death of the fcetus. As the cestrogens are fairly rapidly destroyed in the body, it is suggested that a high dosage should be given over a short interval of time. I have obtained satisfactory results with 10 mg.. of synthetic oestrogen given hourly for six to ten hours, supplemented in some cases by posterior pituitary extract. This high dosage is well tolerated. The more advanced the pregnancy the more successful is this form of treatment. (b) Induction of labour and -premature death of fcetus.?When giving alone the cestrogens are rarely effective in inducing labour but when employed as part of a scheme of induction they may be of value, although their usefulness in these cases is difficult to assess. They are, however, efficacious in the induction of labour in cases where the fcetus dies in utero near term, and also in some cases of premature rupture of the membranes associated with delay in the onset of labour. (c) Uterine inertia.?The cestrogens have been found to be effective in more than half of a series of cases of uterine inertia. In my experience the results of this form of therapy have been inconclusive, as it has not been found possible to induce increased uterine sensitivity in many 'cases in which the indications for its use appeared to be specific and in which a satis-
factory
response was
anticipated.
Suppression
op lactation
The development of the breasts during pregnancy in preparation for lactation is brought about by the actions of the (Estrogenic and corpus luteum hormone. The secretion of milk in the breasts on the third or fourth day of the puerperium is due to prolactin or mammotrophic hormone of the anterior pituitary gland, whilst the continuation of milk production is associated with the stimuli arising from the act of suckling. During pregnancy and for the first two or three days of the pueipierium the mammotrophic hormone of the anterior pituitary is probably inhibited by the high blood concentration of the cestrogenic hormone; the delivery of the placenta results in the release of this inhibition. The administration of cestrogens, however, either before or after lactation is established, can again bring about the inhibition of the anterior pituitary milk secreting hormone; the breast either does not secrete milk or its secretion quickly subsides with this therapy, provided suckling _
_
Sept., 1944]
REVIEWS
does not take place. As the administration of cestrogens to a nursing mother does not inhibit the secretion of milk, it would seem that the reflex act of suckling must stimulate the .increased secretion of prolactin.
The important part played by the act of suckling in hormone production, leading to milk secretion, suggests how readify the endocrine system is influenced by nervous stimuli. In cases where breast feeding is contra-indicated, oestrogen therapy should be started the day after delivery. It is advisable to give an effective dose initially?5 mg. thrice daily for four days, followed by 5 mg. daily for six days is usually effective?in order to produce .complete inhibition of the lactogenic hormone. Lactation can be inhibited in eveiy case provided the dosage is adequate; the puerperal patient can tolerate a high dosage of cestrogenic hormone. The chemist has provided us with potent preparations, and it behoves us as clinicians to realize that the indications for their use must be defined and limited, and that their misuse may be fraught with serious consequences. Intelligently and wisely used, they can be of inestimable value.
451
P. N.
BARDHAN,
m.r.c.p.
(Edin.)
MAJOR, I.A.M.C.
N. TYAGI,
i.A.M.c.
and K.BOUTROS LIEUTENANT, R.A.M.C. (From the British Medical Journal, i, 19th February, 1944, p. 253) In 1942 Steuer utilized
a
slide-agglutination, method
for the rapid diagnosis of typhus fever. that 200 slides could be examined in 90
He claimed
minutes, and
that each individual slide could be read in from 5 to 10 minutes. We found his technique unnecessarily cumbersome, and it was therefore modified by us to for use. The workable essential make it more general difference between the two techniques was that, while measured of blood and Steuer used exactly quantities antigen suspension, we used approximate quantities. we is : The technique employ Method clean glass slide two drops of blood, obtained by pricking the finger or the ear lobe without squeezing, separated from each other by a grease-pencil line. Dry in air and mark the drops 1 and.2. Place a drop of concentrated suspension of OX 2 and OX 19 on blood drops 1 and 2 respectively. Leave for a minute, and then complete the mixing of the blood and the suspension by gently rocking the slide. (Mixing with a platinum loop or other foreign object tends to produce strings of fibrin, which cause coiifusion in reading the results.) Set aside for 5 minutes, taking Place
on
a
446
THE INDIAN MEDICAL GAZETTE
to avoid drying up of the slide and soiling by dust. Rock the slide occasionally. Results are read in from 5 to 10 minutes by the naked eye, and if necessary are confirmed by a handlens. The use of the low-power objective, as recommended by Steuer, is rarely necessary.
care
high enough for diagnosis. These observations suggest that negative cases may occasionally give positive results, but this is not of much import. The fact that every clinical typhus case which was proved positive by' the Weil-Felix reaction was spotted by the slide method is justification enough for urging the use of this simple technique as a preliminary to putting up a long series of tests by Dreyer's or Felix's method. It was decided to try out a number of slide-negative cases by Dreyer's method, to see whether the zone phenomenon or some other factor would produce positive results in slide-negative cases. Thirty-three such the highest dilution put up was sera were tested; 1 in 250 and the lowest 1 in 25. Of these, 25 were completely negative; the remaining 8 gave agglutinations as shown in table IV.
Results The tests were carried out on Egyptian labourers. Slides were taken in various camps under military control, were brought to the laboratory the same day, and were examined within the' next 24 hours. In all, 640 persons were examined; 11 of these gave 'slide' positive results against OX 19, and 2 were positive to OX 2 in addition. These 13 were then followed up for a complete Weil-Felix reaction, using Dreyer's technique. The results are summarized in table I.
Table IV
Table I Positive to OX 19
Negative
to OX 19
1944
[Sept.,
.
..
..
..
7*
..
..
..
6
Serial number
25
27
29
33
35
45
50
52
OX 2
0
25
0
50
25
25
0
25
OX 19
25
0
25
0
25
0
25
0
*
Of these 7 positives, 2 also showed agglutination in 1/50 against OX 2 : and these 2 were the same persons who were slide-positive for OX 19 and OX 2. The 7 ' slide- and Deryer-positive' cases were further studied by carrying out a series of Weil-Felix tests at 4-day to 7-day intervals. The results obtained are shown in table II.
None of these titres has any diagnostic value. Table
Serial number
1st test
2nd test
II
3rd test
3
OX 2
0 250
4
OX 2
50
50
50
50
125
500
OX 2
12
4th test
Remarks
Had typhus
50 250
a
month before first test.
Not traceable afterwards.
50 500
OX 2
19
?!
Had typhus 3 weeks
previously
Not traceable:
not
hospital.
0
500
history
in
available.
i
OX 2
20 21
0
0
1,280
2,560
OX 2 OX 2
22
0
0
250
1,800
0
0
250
250
Hospital
will thus be
seen
,
that all the clinical and Weil-Felixshowed 'slide agglutination' as
cases
Table III
0
Typhus with rash.
1,250
It is reasonable to conclude from. these results that slide-negative blood will not give a positive Dreyer reaction?certainly not of any diagnostic value. The low titres given in table IV have no significance beyond perhaps the possibility that the individuals had developed some immunity as a result of subclinical infection, or had suffered from the disease some time a
^
previously. Comment
Serial number
13*
15
17
25
:
'OX 2
0
0
0
0
0X19
0
0
0
50
*
0
1,250
well. The results of the 6 slide-positive and Deryer-negative cases (see table I) are detailed in table III.
U
diagnosed typhus-
Typhus with rash.
Nos. 4 and 19, despite of the history being unobtainable, should be considered. typhus cases in view of the high titre. The others were definite typhus cases. It
positive typhus
case:
Done twice, at five-day interval*
I
50
7
Except in 2 cases, there was no agglutination by Dreyer's method, and in neither of these was the titre
Having established that all positive cases can be detected by the slide method (of course to be confirmed by a complete agglutination test), and that the slide-negative cases will not give a positive result by Dreyer's method, it is. a reasonable assumption that a complete Weil-Felix test need not be done unless the slide test is positive. If this procedure is followed the obvious advantages will be : (a) economy in material and time; (b) avoidance of unnecessary bleeding of the patient; and (c) easier despatch of slides, as compared with that of blood or serum, to a laboratory situated at a distance from the hospital. Probably the test could be done on thick smears of blood, similar
CURRENT TOPICS
Sept., 1944]
to those used for the detection of malaria and taken at the same time.
of these constituents of the vitamin-B complex the finding that the protective actions of the various liver fractions is proportional to their contents of pantothenic acid. of
Summary
Egyptian civilians.
slideresult does not
cases
one
parasites,is considerably strengthened by
A dry blood test for typhus has been tried out among
It has been shown that all typhus positive result, though a
447
give
a
Bovine Serum (D.B.S.): A Substitute for Human Plasma
Despeciated
slide-positive By F. R. EDWARDS, mj)., ch.M., f.r.c.s. mean a positive case. Control tests show that a from the British Medical Journal, i, (Abstracted slide will not negative give a positive 15th January, 1944, p. 73) Weil-Felix reaction. The need for trying out this method on a more Substitutes for human plasma hitherto prepared extensive scale is urged, and the advantages to be have not fulfilled the three criteria : (a) retention in derived therefrom are discussed. the circulation and eventual metabolism; (b) exertion of an equivalent osmotic pressure; and (c) non-toxicity non-antigenicity, and freedom from antibodies. More Light on the B Complex Bovine serum can be made safe for man by destroy(From the British Medical Journal, i, ing the antibodies by heating to 72?C., while rendering 15th January, p. 85) the proteins uncoagulable with the addition of 0.2 per formalin and ammonia. Material so prepared In 1940 Van Etten and others found that the cent of to accord with the above precepts. administration of an ample supply of crystalline appears Clinical trial in 26 cases shows that it can be vitamin Bi did not and nerve prevent convulsions administered rapidly and in large amounts to man with degeneration in swine fed on autoclaved liver and whey. safety. ?f a Wintrobe cany the matter stage f fv, exPei!imen^s with an accurate description of symptomatology further, and pathology in A New Typhoid Vaccine for the Army pigs receiving all the known members of the B complex except Bi. The earliest clinical (From the Lancet, i, 4th March, 1944, p. 318) manifestations were failure of appetite and vomiting, The British Army authorities have decided to change followed by cyanosis, dyspnoea, and bradycardia, and ending with a severe degree of heart failure or sudden the well-tried T.A.B. vaccine, which was heat-killed and preserved in carbol-saline, for a new preparation of neuromuscular disturbance, dearth. No abnormality is killed by 75 per cent alcohol and preserved such as ataxic gait, was ever observed. Careful histol- which ogical examination of the nerve tissues, central and in 25 per cent alcohol. As before, great importance is peripheral, gave no evidence of degeneration or attached to the use of fully virulent strains and the the full complement of Vi antigen inflammation, but in practically every case local necroses vaccineis contains so important in producing a high level of fibres were present in both auricles which j my?tcardial^ and ventricles. Where the protection. Several points about the new alcoholized pathological condition had vaccine should be kept in mind. Bacteria suspended not advanced too far, administration of Bi led to in alcohol sediment more completely than in saline, recovery. Of particular interest are the biochemical findings. The concentration of carbonyl compounds and unless the bottle is thoroughly shaken the bacteria estimated as pyruvic acid was proportional to the sit tight and the syringe may not withdraw the proper degree of severity of the deficiency as judged by the dose of organisms. The doses of the new vaccine are smaller than those previously used. For men 0.25 c.cm. clinical manifestations. A sharp rise in blood pyruvic is followed after at least a fortnight by 0.5 c.cm., while of followed Quickly the progress rapid by +i? disease. ,r'as for women the doses are 0.2 c.cm. and 0.4 c.cm. the It was also found that a significant Annual reinoculation with 0.25 c.cm. is recommended increase m blood pyruvic acid after the administration for both. There was doubt at one time about the oi glucose always occurred in Bi-deficient animals but ability of 25 per cent alcohol to effect sterility if the not in the control group. As for urinary content of vaccine became contaminated during use, but this fear ?tii, it reflected?but by no means consistently?the dietary intake immediately before the collection of has been proved groundless. The chief advantage of the new vaccine is that alcohol preserves the integrity urme. Of more value in assessing the degree of Bi of the Vi antigen, as Felix has shown, and it also deficiency was the percentage retention of Bi after a probably induces a superior antibody response. Both given dose. This test, suggested by Najjar and Holt, local and general reactions are less severe than with gave results which can parallel with the clinical findings the old vaccine; Felix, Rainsford and Stokes and and the amount of Bi in the diet. workers of the Emergency Public Health Laboratory fr?m this the of work that 1,8 position near "f Service, point out that the average time lost through vitamin Bi as the antineuritic vitamin has been strongly reaction by those receiving TABC vaccine is likely to assailed, supporting the sceptical view put forward by be considerably less with an alcoholized than with a Meiklejohn in 1940. He concluded his review with product. Even so, the new vaccine the statement that phenolized is a multiple deficiency probably produces an initial stinging pain on injection and some responsible for nutritional neuritis but that there is still a possibility that the true antineuritic vitamin has people still get a local reaction and a slight rise of In future it may be possible to produce temperature. .vet to be discovered. of the use. crystalline By The question of even more inoffensive TAB vaccines. vitamins Wintrobe and his colleagues have shown that adding a representative of the paratyphosum C group neither riboflavin nor nicotinic acid has effect in any of organisms was considered, but infections of this maintaining the integrity of nervous tissue. It was kind in the Army were so few that this procedure was tnen found that the ataxic and the degenerative gait not adopted. Meanwhile there are sound reasons for nerve lesions brought about by a dietary deficiency the resignation of TAB from the active list and for the oi the vitamin-B are complex completely prevented seconding of TAB Ale. to take its place. whole oy desiccated The liver. anti-perniciousI anaemia fraction was found to be the most potent of the individual liver The Uses and Abuses of the Female Sex none of which are as fractions, etflcacious as whole liver, even when given Hormones parenterally, resu"s suSgest that there is a need for passage a? By T. N. MACGREGOR, mj>., p.B.c.s.Ed., m.r.c.o.g. f!e nerve-protection factor through the gastrointestinal tract. Finally, it has been shown that the (Abstracted from the Edinburgh Medical Journal Vol. LI, January, p. 39) dietary deficiency of either pyridoxine or pantothenic acid leads to an ataxic gait in swine and degeneration hormones most closely related to female sex The oi sensory neurones which could invariably be prevented physiology are the gonadotrophs hormone secreted by by the administration of these substances. The claim necessarily
_
?
,
*
.
THE INDIAN MEDICAL GAZETTE
448
pituitary
gonadotrophic hormone
anterior pituitary gland through its gonadotrophs hormono controls the development of the Graafian follicle, ovulation and corpus luteum formation. At the present time there is no reliable anterior pituitary preparation available for use which can simulate the actions of the naturally occurring gonadotrophs hormone; there are, however, two preparations which are of considerable therapeutic value, namely, serum gonadotrophs hormone prepared from pregnant mare's serum, and urine or chorionic gonadotrophic hormone extracted from pregnancy urine. The former stimulates follicular development; the latter causes corpus luteum formation. A combination of these two preparations forms a useful therapeutic agent indicated in conditions directly or indirectly associated with defective action of the anterior pituitary gland. The
The ovarian
orally. Anhydro-oxy-progesterone is a synthetic preparation of progesterone which is also active when given by mouth, but the effective dosage given orally is six times that given by injection. The uses of the sex hormones may conveniently be considered in two groups : gynaecological disorders and obstetrical conditions. Gynecological
(A) Before
disorders
puberty
only assume full function at thus few indications for the use of the sex hormones before this time. There is one condition, however, namely, vulvo-vaginitis, which can be effectively treated by cestrogenic hormone in the form of vaginal pessaries or by oral administration. The oestrogens stimulate the growth of the vaginal epithelium, and with the resulting increased glycogen content of the cells additional lactic acid is available so that not only is the infection controlled by the shedding of the epithelial squames, but the increased acidity of the vaginal flora proves inimical to the causative organism. It should be noted that the sulphonamides, especially sulphathiazol and sulphadiazine, are also effective in this condition and have none of the minor disadvantages, such as enlargement of the breasts, which are sometimes associated with the administration of the As the
sex
puberty, there
glands are
cestrogens. (B) During
the period
of
reproductive life
(1) Disturbances of' menstrual rhythm (a) Metropathia hemorrhagica.??The most common of irregular uterine bleeding is ^metropathia hsemorrha'gica or cystic glandular hyperplasia. This condition may occur at any time, but is more common at the beginning and end of the period of reproductive cause
^
hsemorrhagica and, pending more potent anterior pituitary preparations, it is the one most likely to meet with success, but the dosage must be adequate and the treatment must be energetic if satisfactory results are to be obtained. The intramuscular injection of 5 to 10 mg. of progesterone daily until the bleeding is controlled has been found to be an effective dosage. The role of the (Estrogenic hormone in functional uterine bleeding has recently been investigated, and not unfavourable .results have been reported. The results obtained in cases of irregular' uterine bleeding treated by oestrogenic hormone, and later referred to me, have been uniformly unsatisfactory. (6) Ovular bleeding, liypomenorrhcea and oligo-
hormones
The ovarian hormones are cestradiol or cestrogenic hormone elaborated by the developing Graafian follicles, and progesterone secreted by the corpus luteum not only elaborates its specific hormone, progesterone, but it also secrets cestradiol. Progesterone and cestradiol are the true or naturally occurring hormones of the ovaries and are produced for the most part by the ovaries under the stimulus of the gonadotrophic hormone of the anterior pituitary; they, are also secreted in variable amounts by other internal secretory glands, such as the adrenals. Potent preparations of these hormones have been available for some time. Now we have available for clinical use synthetic preparations of cestrogenic hormone, such as diethyl hexcestrol and triphenylchloroethylene stilbcestrol, which, though not chemically related, simulate closely the actions of the naturally occurring hormones. They, have the added advantage of being active when given
1944
life. It is characterized by a long intermenstrual period, five to ten weeks, followed by excessive and prolonged menstrual loss. It is possible that a minor psychological disturbance, acting through the higher cerebral centres and interfering with anterior pituitary function, forms the predominant etiological factor in metropathia hsemorrhagica. The essential cause of the condition, however, is a failure of ovulation with concomitant excessive production of the (Estrogenic hormone. In the present state of our knowledge progesterone seems to be the most effective therapy for metropathia
the anterior pituitary gland, (Estradiol elaborated by the developing Graafian follicles of the ovary, and progesterone secreted by the corpus luteum. Anterior
[Sept.,
menorrhcea.?These
are
minor
disturbances
of
the
rhythm. Ovular bleedifig, as the term implies, is. the bleeding which is sometimes associated
menstrual
-
with ovulation. It is believed to be due to a transient diminution of the oestrogenic hormone concentration occurring between the time of ovulation and mobilization of the corpus luteum. The temporary drop in the amount of circulating oestrogenic hormone results in a diminished stimulation of the uterine endometrium, which partially breaks down and causes bleeding. In some the bleeding may be very slight and represented by only a few spots, whilst in others the amount of blood lost may be similar to that of the normal period. Owing to the danger of inhibiting directly the anterior pituitary and indirectly ovulation, cestrogenic hormone is contra-indicated in this condition. The stimulation of the endometrium can, however, be adequately maintained in such cases by giving 5 mg. progesterone intramuscularly the day before the expected bleeding and for two days thereafter. A course of therapy over three menstrual cycles is usually efficacious. Hypomenorrhcea, or scanty menstrual loss, is not common and in most cases it is of no serious significance, as in such cases there is usually no failure of ovulation. There are a few cases, nevertheless, iu which there is failure of ovulation, and in such the bleeding is associated with the proliferative phase of the endometrium?so-called anovular menstruation. The importance of this type of menstruation in sterility is evident. An effective therapy must promote follicular maturation and ovulation; this can only be done by administration of anterior pituitary hormone, particularly the serum gonadotroph^ hormone, given in doses of 200 international units every third day for five injections, starting at the onset of the menstrual
period. Oligomenorrhoea,
or delayed menstruation, is not It is a frequent precursor of functional amenorrhcea and is prone to occur at the beginning and end of the period of reproductive life. Towards the menopause the bleeding is frequently associated with a proliferative endometrium, but at other times for the most part it is associated with a secretory endometrium. Thus there is a long proliferative phase of the endometrium and a normal secretory phase. The therapy indicated is one which will accelerate follicular development and ovulation; accordingly, the treatment most likely to be effective is the administration of anterior pituitary in the form of serum gonadotrophs hormone (200 i.u.) alone or in combination with urine gonadotrophic hormone (100 i.u.) every third day for five injections at the onset of the period. These preparations should be. given over three menstrual cycles at the time corresponding to the pre-ovulatory uncommon.
phase.
Sept.,
1944 |
449
CURRENT TOPICS
of sterility are found only after thorough investigation, (2) Dysmenorrhea and the cestrogens are given in order to evoke a defiThere are many cases, in which no nite and known response. The 'danger of cestrogenic obyious pathology exists and, although there may be a psychologicaltherapy in sterility, however, is that of so depressing basis for the pain, hormone pituitary function as to inhibit ovulation, thus*preventtherapy is efficacious. It is reasonable to assume frequently ing the occurrence of conception and promoting a that the rhythmic interplay of the ovarian secretions, whichpregnancy complex. exert their influence on the uterus and uterine adnexa, (4) Amenorrhcea may be maladjusted and increased function of one is due in most cases to a amenorrhcea partially override the function of the other. It is Although known that the cestrogenic hormone sensitizes thephysiological or a pathological condition, there is, a uterine musculature, promotes the large number of cases in which no proliferative phasenevertheless, of the endometrium and the amenorrhcea is apparent. A study of the increases the vascularity ofcause for such cases, however, leads one to the concluthe pelvic structures; whereas progesterone inhibitshistory in uterine activity and stimulates the secretory phase 01sion that in the majority there is an exciting psychothe endometrium. The disturbance; in some it is trivial, whilst in important point to keep inlogical mind, however, is that the corpus luteum secretes bothothers it may be grave. hormones and that they act synergistically on the When potent preparations of the ovarian hormones available the outlook in the treatment of uterus. Primary dysmenorrhcea, in my experience, isbecame promising, but the results invariably associated with ovulation; women who do amenorrhcea appeared not ovulate do not have obtained have not fulfilled the earlier expectations of This is painful periods. this form of therapy. clearly demonstrated in cases of ovular
bleeding, cestrin-withdrawal bleeding and the bleeding associated (5) The menopause with metropathia this case there is In hsemorrhagica. An important factor in the production of an unopposed cestrogenic action, and consequently there is mental reaction is the fear of loss of no pain associated with the bleeding, Painiul unfavourable women believe that sexual life menstruation is not necessarily associated with uterine sexual function?many the allaying of this ceases at the menopause?and hypoplasia or hyperplasia per se. dread may frequently change the whole outlook. As a result of clinical one believes There appears to be no indication for the use of the that it is only when thereinvestigation, is a deviation from tne normal finely adjusted concentration of the two ovarian cestrogens in irregular bleeding occurring at the menothe bleeding may be assohormones that the uterine reactivity becomes dis- pause, for theanreason that excessive with secretion of the already ordered, giving rise to pain either before or during ciated and any effect can only be of a very menstruation. If this contention is correct, tnen hormone temporary nature. It should be emphasized that slight hormone therapy for the relief of should dysmenorrhcea in uterine women at the bleeding menopause only be given during the second half of the menstrual irregular of a pathological process, and the cj'cle. Premenstrual dysmenorrhcea, in the absence 01 may be symptomatic of cestrogenic hormone in these cases, administration pelvic pathology, is most frequently associated witn though it may temporarily arrest the haemorrhage, excessive oestrogen or deficient progesterone production, merely masks the serious condition and delays, not and can be controlled by progesterone therapy in doses without danger, operative or other appropriate treatof 5 mg. every second day, starting eight days beiore ment. It is astonishing, however, how frequently the the expected period. Conversely menstrual dysmenoi- cestrogens are abused in the treatment of women comrhoea may be associated with excessive progesterone 01 subnormal (Estrogenic hormone secretion, and can be plaining of menstrualareirregularities at the climacteric. The cestrogens pre-eminently effective in relieved by the administration of cestrogenic hormone controlling the subjective symptoms associated with the in doses of 5 mg. of synthetic preparation given twice of ovarian function. The hot flushes, irridaily for four days prior to the onset of the period. cessation tability, depression, etc., which are so common and The (Estrogenic hormone is frequently administere as already pointed out, are conditioned to a during the first half of the menstrual cycle in cases which, certain extent by the psychological status of the of dysmenorrhcea. and this form of therapy may be individual, can be completely relieved by cestrogenic temporarily effective, but it acts oa ilhormone therapy. For this reason a high dosage of lation and consequently there is by suppressing always, the danger o such as 5 the cestrogens, mg. synthetic cestrogen thrice producing an abnormal condition, the treatment 0 daily, should be given until all symptoms are relieved, which may be much more difficult than that 01 tne the then and dosage should be gradually diminished primary disturbance. over a period of six to eight weeks. Satisfactory results obtained been in the artificially induced menohave (3) Sterility the administration of small doses of the pause by It is important to understand the role of the female cestrogens given as a prophylactic measure before any sex hormones in the treatment of sterility, as tney untoward symptoms arise. are frequently misused in this condition. JNow, 11 It is important to recognize that occasionally the ovulation takes place, lollops formation luteum corpus menopausal phase may pass imperceptibly into the normally?this is confirmed if one obtains a typical abnormal and that some patients, complaining initially secretory endometrial pattern in the tissue remmed of mild depression, may become definitely psychotic. with the biopsy curette immediately before a period, The cestrogens are of value in such cases when used or if pregnandiol can be recovered from the imnf: in as an adjuvant to general psychiatric treatment. the post-ovulatory phase?and there would therelore (C) POST-MENOPAUSE appear to be an indication for hormone therapy, it repeated examinations?and one examination is not In cases of senile vaginitis and kraurosis vulvse the conclusive?show that ovulation is not occurring, tnen restoration of the tissues, by the administration an anterior of cestrogenic hormone, to the same state of developto stimulate ovulapituitary preparation tion is indicated. It has been shown that anterior ment as that found during reproductive life, supplies pituitary preparations, especially serum gonadotropnic the necessary resistance to overcome the infection. hormone, can promote ovulation. Green-Armytage There is increased vascularity of the tissues and contends that small doses of oestrogen, for example, of the epithelium, and, in senile regeneration vaginitis, i to 1 mg. hexcestrol, given the change in the vaginal flora makes it inimical to daily during the first nve days of the cycle, that is during menstruation, nave a the causative organism. Leucoplakia vulvse, if treated beneficial effect not only on the pH ?f the in the early phase, responds satisfactorily to this but also secretion, treatment but may prove refractory in the later stages. promote a healthier condition 01 tne mucous plug?conditions favourable to the The dosage of the cestrogens employed in these condispermatozoa. There is also convincing evidence that administration tions should be a large one, say 15 mg. daily, adminisof the oestrogens promotes canalization of the tered over a short period. fallopian tubes in proved cases of tubal occlusion. These causes .
~
THE INDIAN MEDICAL GAZETTE
450
of the cestrogena to elderlysubsequent to operation for genital prolapse promotes the vascularity and regeneration of the tissues, This therapy proves which ensure sound healing. particularly beneficial in those cases in which the vaginal tissues are unduly friable and atrophic. administration
The
women
Pruritis vulvse is not
pause, and in the
factor
can
be
ascertained.
however, in which
after
uncommon
majority of
cases a
There
the
meno-
specific etiological are
some
cases,
be found, and in these the condition may be associated with some irritative lesion of the nerve endings arising from the atrophy of the tissues. (Estrogenic hormone therapy is often eminently successful in these resistant and difficult cases. It may be necessary to give a very high dosage if no result is obtained with a moderate dose. It should be noted, however, that it is not advisable to give a high dosage over more than a short interval of time. One case treated did not react favourably until a dosage of 45 mg. of synthetic oestrogen was given daily for seven days. The pruritis of was completely relieved. This high dosage oestrogen, however, provoked such a marked hypertrophy of the vaginal epithelium as to form a plaque in the anterior wall. Cystoscopic examination suggested a malignant condition of the base of the bladder, but the vaginal mucosa eventually returned to its normal post-menopausal state. The patient remained free of irritation until a recurrence two weeks ago. The most common etiological factor responsible for post-menopausal bleeding is a malignant condition of the uterus or its adnexa. It cannot be emphasized too strongly that post-menopausal bleeding, per se, is never an indication for cestrogenic hormone therapy, yet one frequently finds it being given quite unjustifiably in this condition. Some women may have an uneventful climacteric but complain of subjective symptoms late in life similar to those experienced at the menopause. Such cases can be effectively treated with the cestrogens, but they usually require a small maintenance dose
given
over a
no
cause
can
prolonged period. Obstetrical
conditions
The corpus luteum hormone or progesterone has welldefined physiological actions in the initiation and continuation of pregnancy. It is responsible for the the of uterine reaction decidual endometrium, thus preparing the endometrium for the nidation of the fertilized ovum. Its sedative action on the uterine musculature promotes conditions favourable for the the early process of embedding of the ovum and development of the placenta, and its uninterrupted production is essential for the continuation of the pregnancy. Consideration of these facts suggests the usefulness of progesterone therapy in (1) repeated early miscarriage suspected when the period is a few days late, (2) threatened abortion, and (3) recurrent abortion.
(1) Early
miscarriage?This
frequently
occurs
without the patient's knowledge, or it may be suspected when the period is repeatedly but not continuously a few days late. Some women realize intuitively that conception has occurred. A continuation of the pregnancy in such cases can be brought about by-the administration of progesterone, 5 to 10 mg. twice weekly, begun during the second half of the menstrual cycle and continued until at least the fourth month is reached. (2) Threatened abortion.?Abortion most frequently occurs at the time of the suppressed period, and it reaches its highest incidence at the time of the third missed period. The explanation for the frequency of abortion at. the third month is not clear. The placenta, by the time this stage is reached, is fully developed. It is known that pregnancy can continue /when the corpus luteum of pregnancy is removed at an early stage. The assumption is, therefore, that the placenta secretes the necessary amount of progesterone required for the continuation of the pregnancy. The change over from corpus luteum to placental production of _
[Sept.,
1944
progesterone probably takes place at the third month. A lag in the change over,' resulting in a lowering of the progesterone threshold, would furnish an explanation of the frequency of abortion at this time. The administration of progesterone in large doses (10 to 20 mg. daily) at the very earliest stage of a threatened miscarriage is frequently effective in saving the pregnancy. If much placental separation has occurred, however, the abortion will become inevitable and progesterone therapy is then valueless. It should be noted that progesterone therapy alone in threatened miscarriage is not enough; rest must be enforced and anxiety allayed by the use of sedatives. of administration (3) Recurrent abortion.?The progesterone early in pregnancy has resulted in the
continuation of the pregnancy to term in many cases of recurrent abortion. An adequate dosage, such as 5 to 10 mg. twice weekly, must be given as soon as the pregnancy is diagnosed and continued until at least the end of the fourth month of pregnancy. It is advisable to supplement this therapy by the administration of vitamin E. The cestrogens, in virtue of their function of increasing the sensitivity of the uterine muscie, have been used in (a) missed abortion, (b) induction of labour, and (c) uterine inertia. (a) Missed abortion.?As is well known, a dead ovum may be retained in utero for intervals of time varying from weeks to months. The cause of the retention of the ovum is presumably the diminished sensitivity of the uterine muscle. This can be overcome by the administration of cestrogens, and this form of therapy is frequently very successful in missed abortion ?tfid premature death of the fcetus. As the cestrogens are fairly rapidly destroyed in the body, it is suggested that a high dosage should be given over a short interval of time. I have obtained satisfactory results with 10 mg.. of synthetic oestrogen given hourly for six to ten hours, supplemented in some cases by posterior pituitary extract. This high dosage is well tolerated. The more advanced the pregnancy the more successful is this form of treatment. (b) Induction of labour and -premature death of fcetus.?When giving alone the cestrogens are rarely effective in inducing labour but when employed as part of a scheme of induction they may be of value, although their usefulness in these cases is difficult to assess. They are, however, efficacious in the induction of labour in cases where the fcetus dies in utero near term, and also in some cases of premature rupture of the membranes associated with delay in the onset of labour. (c) Uterine inertia.?The cestrogens have been found to be effective in more than half of a series of cases of uterine inertia. In my experience the results of this form of therapy have been inconclusive, as it has not been found possible to induce increased uterine sensitivity in many 'cases in which the indications for its use appeared to be specific and in which a satis-
factory
response was
anticipated.
Suppression
op lactation
The development of the breasts during pregnancy in preparation for lactation is brought about by the actions of the (Estrogenic and corpus luteum hormone. The secretion of milk in the breasts on the third or fourth day of the puerperium is due to prolactin or mammotrophic hormone of the anterior pituitary gland, whilst the continuation of milk production is associated with the stimuli arising from the act of suckling. During pregnancy and for the first two or three days of the pueipierium the mammotrophic hormone of the anterior pituitary is probably inhibited by the high blood concentration of the cestrogenic hormone; the delivery of the placenta results in the release of this inhibition. The administration of cestrogens, however, either before or after lactation is established, can again bring about the inhibition of the anterior pituitary milk secreting hormone; the breast either does not secrete milk or its secretion quickly subsides with this therapy, provided suckling _
_
Sept., 1944]
REVIEWS
does not take place. As the administration of cestrogens to a nursing mother does not inhibit the secretion of milk, it would seem that the reflex act of suckling must stimulate the .increased secretion of prolactin.
The important part played by the act of suckling in hormone production, leading to milk secretion, suggests how readify the endocrine system is influenced by nervous stimuli. In cases where breast feeding is contra-indicated, oestrogen therapy should be started the day after delivery. It is advisable to give an effective dose initially?5 mg. thrice daily for four days, followed by 5 mg. daily for six days is usually effective?in order to produce .complete inhibition of the lactogenic hormone. Lactation can be inhibited in eveiy case provided the dosage is adequate; the puerperal patient can tolerate a high dosage of cestrogenic hormone. The chemist has provided us with potent preparations, and it behoves us as clinicians to realize that the indications for their use must be defined and limited, and that their misuse may be fraught with serious consequences. Intelligently and wisely used, they can be of inestimable value.
451
