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The endocrine basis of toxemia of pregnancy
THE
ENDOCRINE
JEFFERSOK
BASIS
OF TOXEMIA
J. VORZIMER, M.D., ARTHUR LANGROCK, M.D., AND EMANUEL
OF PREGNANCY*
M.D., EDWIN M. RAPPAPORT, M.D., NEW YORK, N. Y.
(From the Jewish Maternity
Diz;ision
M.
of
FISHBERG,
the
Beth
Israel
G.
Hospital)
‘N THIS paper we desire to present evidence to support our belief that the so-called toxemia of pregnancy is a manifesta.tion of a disturbance of the endocrine glands. The observations here recorded have been carried out over a period of four years. They have led to the conclusion that in the large majority of instances toxemia of pregnancy occurs in women with a constitutional habitus, in itself a manifestation of an endocrine disturbance. I,
Our primary criterion for the diagnosis of toxemia of pregnancy was the development in the later months of pregnancy of abnormally high blood pressure, in women in whom there was no history or other evidence of preceding renal or hypertensive disease. It may well be that there are c,asesof toxemia of pregnancy in which hypertension is absent and the disorder is manifested solely by edema and albuminuria. But in order to deal with a criterion of the diseasewhich is practically universally acclepted, we have included only patients with high blood pressure. All our patients began pregnancy with normal blood pressure and’developed a systolic pressure exceeding 140 mm. and a diastolic pressure above 90 mm. Almost every patient had a blood pressure well over this level. The present study is based on 120 patients fulfilling this criterion. As ssntrols, we have used 100 consecutive patients having normal pregnancies. The evidence is presented under the following headings: (1) Body weight, (2). hair distribution, (3) stature, (4) facies, (5) form of pelvis, (6) basal metabolism, and (7) blood proteins. 1.
BODY
WEIGHT
The pregestational weight of women with toxemia of pregnancy averages much more than that of a similar number of normal pregnant women (Fig. 3). The average weight in the normal series was 126.2 pounds, as contrasted to the average weight in the toxemia series of 148 pounds. The high incidence of obesity in patients who develop this disease is thus demonstrated. Moreover, in a large proportion of these casesthere was a tendency to obesity from an early age. It is a wellknown fact that patients with toxemia of pregnancy gain weight excessively. Further evidence indicates that this obesity is of endocrine -*Read
at
a meeting
of the
New
York
Obstetrical 801
Society,
October
13.
1936.
802
AMjERlCaN
JOURNAL
03’
OBSTETRICS
AXD
GYNEOOLOGY
origin and not due to gluttony or lack of exercise. For, in the 6rst plade, there was nothing to suggest that the food intake or exercise of the patients with toxemia differed from that of the controls; indeed, many of our patients were obese in spite of strenuous dieting. Second, there was a very high incidence of other endocrine stigmas in the obese individuals. 2.
DISTRIBUTION
OF
HAIR
In the female, abnormalities in the distribution of hair resulting from endocrine disturbances are of two types : (1) An increase in the amount of hair, with a tendency to male distribution, that is on the legs, thighs, abdomen, chest, face, and occasionally around the nipples ; (2) Decrease in pubic and axillary hair so that it is scanty, very fine and silky, and sometimes almost absent. These two types of abnormality in hair disfribution due to endocrine disturbances were present, with almost equal frequency, in 74 per cent of the patients with toxemia, as compared to only 9 per cent of the normal controls. 3.
STATURE
Various observers have noticed that a high proportion of women with toxemia of pregnancy are of stocky build. The coincidence of short, thick-set framework and obesity gives many of these women a characteristic appearance. There are some patients, however, that have an unusually large bony framework (Fig. 1). Definite abnormalities of stature were present in 65.8 per cent of the toxemia patients as contrasted with 21.0 per cent of the normal patients. It was found that the average weight/height ratio of patients in the normal series was 2.08 pounds per inch and that of patients in the toxemia series 2.5 pounds per inch (Fig. 4). Such peculiarities of stature are generally regarded as due to aberrations in the function of the endocrine gla.nds.
An outstanding characteristic of most of our patients with toxemia of pregnancy was that they looked several years older than their chronologic age (Fig. 2). Some young women of twenty to twenty-five years appeared thirty to forty years of age. This appeared to be due to the combination of obesity, statural peculiarity, and change in facies. They had enlarged features of the acromegaloid type, which in many were of long standing, and in others had appeared during the antepartum course. The most common change in the features was enlargement of the nose. These facial changes were sometimes associated with enlargement of the hands and feet. Their development was almost always noted by the patient or her companions, and often progressed noticeably under clinical observation. It is true that in normal pregnancy there is some enlargement of the fea,tures, generally attributed to physiologic hyper-
VORZIMER
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E’NDOCRINE
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a.ctivity of the pituitary gland. This is rarely marked enough to become a. complaint, as it was in some of our cases of toxemia of pregnancy. It was found that 55 per cent of the latter had changes in facies, whereas such changes occurred in only 5 per cent of the normal patients. 5.
FORM
OF PELVIS”
In the course of evaluating pelvic x-rays one year ago, we were aroused by the infrequency of the true gynecoid pelvis in those women who deOf 23 pelves in toxemic women, only 2 veloped toxemia of pregnancy.
Fig.
1.
Fig. l.-Showing stocky with toxemia of pregnancy. 20 Pounds.) Fig. 2.-Facies of patient
Fig. build and (Photograph in
Fig.
girdle
2.
obesity in a woman of twenty-six taken two weeks postpartum after
years, loss of
1.
were gynecoid. Since this observation, we have x-rayed routinely all patients who developed toxemia to determine the correlation, if any, between their body habitus and pelvic architecture (Table I). The most striking feature of this survey is the low incidence of the gynecoid pelvis and the predominance of other types, especially the The table shows that the incidence of reversion to the male anthropoid. *We desire Schwartzchild
to for
express our sincere their aid with the
thanks to roentgenologic
Drs.
I. Seth aspects of
Hirsch and this study.
Myron
-4.
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and primitive type of pelvis in the toxemia series is very high. The r&e of the hormones in the evolution of pelvic types has been ably postulated by Caldwell, Moloy, and D ‘Esopo. 1 Since we find that women of extreme endocrine types in the great majority of cases have pelves that fall illto the android and anthropoid class, we may speculate that this reversion to the male and primitive type of pelvis is due to an inherent imbalance in the hormonal system.
4 Fig.
3.-Pregestational
Fig.
4.-Pregestational weight/height controls, demonstrating the
‘the
weight of preponderance
patients with of toxemia
high
ratio of incidence
toxemia among
patients of obesity
and normal the obese.
with
toxemia among the
controls.
and former.
Xote
normal
We must further comment on the unusual number of large pelves which appear to be more common than in our normal series. Some border on giantism, with dimensions far out of proportion to the stature of the patient (Fig. 5). We wish to report a final observation relative to the sepration of the symphysis during the antepartum period. Although the average separation, as seen stereoscopically, is not greater in the toxemia group than in the normal, in 7 eases this physiologic relaxation of the joint was by far
VORZIMER
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wider than any of a series of 150 normals (Fig. 6). In view of the accepted work of Abramson and coworkers,2 this may indicate an abnormal endocrine function in these patients, although further observation on a larger series is necessary for verification.
Fig. 5.-X-ray of pubic arch sweep of pubic arch and rami. symphysis (not demonstrable in with marked endocrine stigmas.
Fig.
B.-X-ray partum
symphysis separation
Of
of
of a large platypelloid pelvis. Note tremendous Bis-ischial diameter 16.0 cm. Wide separation of this view) also present. Case of recurrent toxemia
in case of symphysis.
patient Patient
with of
toxemia, extreme
showing endocrine
marked type.
ante-
The observations on the form of pelvis thus add very strong evidence to the impression that toxemia of pregnancy occurs in a woman of definite constitutional habitus, due probably to dysfunction of the endocrine system.
A number of investigators3-7 have shown that in uncomplicated pregnancy the basal metabolic rate is increased 10 to 30 per cent above normal. This is especially true in the later months of pregnancy. It TAELE ~~ .~
I.
SHOWING
PELVIC I 1
TTI'E
NUMBER OF CASES
I
-__~~_--
TYPES
Ix
THIS
SERIES
PER
I i
CENT
gggf
1 r
___-
Anthropoid Gynecoid with anthropoid Anthropoid with gyneeoid Android Android with gynecoid Android wit.11 anthropoid Platypelloid Platypelloid with gynecoid Gynecoid Gynecoid with narrow forepelvis
25 13 9 1: j
s” !I ii
1
2
PER CENT FOUND BY R(;;;y:;; D'ESOPO
30.1 15.7 2.6 16.6
11.6 4.6 6.5 11.6
i::
i::
6.0'
0.9
7.2 4.8
39.5 11.1
should further be borne in mind, in this connection, that all our patients bad high blood pressure, and it is well known to internists that in socalled essential hypertension there is a tendency to elevation of the metabolic rate. Hence, in hypertensive toxemia of pregnancy one would anticipate, a priori, a high basal metabolic rate by virtue of two factors, It is, therefore, of interest. and undoubtpregnancy and hypertension. edly significant that in 35 patients with toxemia of pregnancy, in whom repeated observations of the basal metabolic rate were made, we found that 68 per cent had bnsal metabolic r&es below plus 10 per c&tit, which is the accepted zoww limit of nomud during pregncLncy (Table II). TABLE
II.
SIIO~YING
CASE
PRIMIPARA
1
tl9 t30 - ,? 4-4 i-3
2 3 4 c i ; 9 10 11 12 13 11 15 16 17
tl3 -4 - 5 +I2 -10 t16 -11 t19 -3 +a -2 $- 3
BASAL
METABOLIC
CASE 18 19
20 21 22 23 34 25 26 27 28 a9 30 31 32 33 34 35
Ra!txs
IN CASES
XCLTIPARA t13 +15
-.I5 -4 -5 +I5 -9 +2 +15 $18 -9 -8 -4 +5 - 1 -2 -3 +2
WITH
,-
TUEMIA PER CENT BELOW tlo%
Primipara
65% Multipara 72% Total
68%
VORZIMER
ET
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OF
807
PREGNANCY
Since the main control of the metabolic rate rests in the endocrine glands, such a relatively low metabolic rate is indicative of an endocrine disturbance. In two instances, we had the opportunity of observing the development of toxemia of pregnancy, in patients following the fall in metabolic rate that took place, in the one instance “artificially” as a result of thyroidectomy, in the other spontaneously. The first patient was a primipara who had had a thyroidectomy for Graves’ disease in the fourth month of pregnancy. Following this procedure, the basal metabolic rate, which had previously been high, fell to minus 20 per cent. This patient, who had had a normal blood pressure and urine, subsequently developed copious albuminuria and hypertension. The second case was also a primipara who had had a basal metabolic rate of plus 20 to 26 per cent on several occasions for two years prior to her pregnancy. Instead of increasing during the pregnancy, as it normally does, the basal metabolic rate fell to minus 3 per cent a.nd she developed hypertension of 150/100 mm. 7.
PLASMA
PROTEINS
Chemical studies of the blood in the toxemias of pregnancy have revealed a fairly constant abnormality in the concentrations of the plasma proteins. It has been definitely shown by many authorsa, g that the plasma proteins are diminished in these cases, and that this diminution is absolute and not due to dilution.1° We corroborate these findings. In 15 of the 17 patients in whom this determination was made (Table III) the plasma protein concentration was depressed to between 4.07 and TABLE
III.
SHOWING PLASMA PROTEIN DETERUINATIONS IN 17 CASES OF TOXEMIA, WHICH 1 TO 7 ARE PRIMIPARAS, THE REMAINDER MTJLTIPARAS
= CASE
2 3 4 5 6 7
8 9 10 11 12 13 14 15 16 17
=zZ
TOT. PROT.
5.51 4.07 4.68 4.93 5.20 4.25 4.68 5.06 5.20
1
5.91 5.51
-
OF
6.25 5.51 5.85 4.93 4.93 6.25
ALBUMIN
3.05 2.61 2.25 2.39 2.50 2.81 2.34 2.51 3.75 3.51 3.12 3.95 2.73 3.12 3.21 2.34 3.12
-
-
GLOBULIN
2.46 1.46 2.43 2.54 2.70 1.44 2.34 2.25 1.45 2.50 2.39 2.30 2.75 2.73 1.72 2.59 3.13
5.91 gm. per cent as contrasted with normal limits There was also inversion of t,he albumin/globulin tendency toward inversion in 6 others. It is well ties of the endoerines sometimes affect the level
-
A/G
RATIO
1.2 1.7 0.92 0.9 0.92 1.9 1.0 1.2 2.5 1.4 1.2 1.7 0.98 1.2 1.2 0.9 -
1.0
of 6 to 8 gm. per cent. ratio in 6 cases and a known that abnormaliof the blood protein.
808
AMERICAN
JCK7BNAL
OF
OBSTETRICS
AND
GYNECOLOGY
Since the depression in the protein content of the blood in some cases occurred without significant albuminuria or dietary deficiency, it seems probable that it was a manifestation of an endocrine disturbance. TOXEMIA
OF PREGNANCY
AKD
RENAL
FUNCTION
Parenthetically, we would like to interpolate a. few words regarding the relation of toxem.ia of pregnancy to impairment of renal function. 1% not one of 120 patids with toxemia of pregnancy was there sigk&ant impairment of ,renal function. Of course, patients who entered pregnancy with glomerulonephritis are not included in the category of toxemia, of pregnancy. Renal function was studied by the eoncentration test and by the determination of the nonprotein nitrogen of the blood. All the patients were able to elaborate urine of specific gravity 1.020 or more, which rules out significant impairment of renal function (see Fishberg) .I1 The nonprotein nitrogen of the blood was also within normal limits. In the light of these facts, theories regarding impairment of renal function as a factor in the pathogenesis of the toxemias of pregnancy are, as has been realized by most recent students, to be discarded. Moreover, impairment of renal function need not be taken into consideration in the treatment of the toxemia of pregnancy. In the natural history of this disease,impairment of renal function does not appear during the pregnancy. It. may appear after many years as a secondary consequenceof the hypertension, just as it may result from long years of essential hypertension. DISCUSSION
Summarizing the data just presented, it is found that 98 per cent of our patients with toxemia of pregnancy revealed evidence of one or more of the endocrine stigmas under consideration, and in a large majority there were two or more. The significance of these endocrine stigmas in women with toxemia of pregnancy is all the more evident on comparison with the normal controls. Only 15 per cent of the latter presented any endocrine stigmas and only 3 per cent had more than one stigma. The fact that 15 per cent of our normal controls presented endocrine sti,gmas does not militate against their significance in the toxemic cases. Our conception is that these stigmas are merely evidences of an endocrine disturbance, often constitutional in nature, which predisposes to the development of what is known as toxemia of pregnancy. That the actual disorder does not become clinically manifest in every individual with the underlying endocrine disturbance is not surprising, in fact would be anticipated, and has many analogies in clinical medicine. Of several sons of parents with diabetes and obesity, only some may actually develop glycosuria even though all are obese and show diminished sugar tolerance. The individuals with the endocrine st.igmas described are al-
VORZIMER
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ENDOCRINE
BASIS
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809
ways to be considered as potential victims of toxemia, which may devel.op only in one of their later pregnancies. This statement is borne out by the well-known fact that multiparas may develop toxemia despite previous normal pregnancies. The evidence here presented adds support to the theory that toxemia of pregnancy is a condition developing on the basis of a disturbance of internal secretion. ‘We do not feel that the observations here recorded throw any light on the precise nature of the endocrine disturbance which produces the toxemia of pregnancy. All the endocrine glands are interrelated and The available evithle function of all of them is affected in pregnancy. dence does not permit a decision as to which of the endocrine glands is primarily at fault in the production of the toxemia of pregnancy, The work of AnseImino and Hoffmann,13 purporting to show that the blood of patients with toxemia of pregnancy contains an excess of a pressor and antidiuretic principle secreted by the pituitary gland, has failed of confirmation.13 On the other hand, the recent work of Smith and Smith,14 revealing the presence of an excess of prolan in the toxemia of pregnancy, is carefully controlled and to be accepted ; it may well prove the starting point of more intimate knowledge of the nature of the endocrine disturbance underlying the toxemia of pregnancy, but does not as yet show how this disturbance is initiated. THERAPEUTIC
AND
PROPHYLACTIC
IMPLICATIONS
Since the large majority of cases of toxemia of pregnancy develop in women who present detectable evidences of endocrine dysfunction, one has a basis in the antepartum clinic for the segregation of those women who are most likely to develop toxemia. Our observations indicate that about 30 per cent of women presenting the endocrine stigmas described above (stocky framework, obesity, abnormal distribution of hair, etc.) will develop toxemia of pregnancy. In the past six months we have observed 34 women with such endocrine stigmas but no evidences of toxemia develop definite toxemia of pregnancy. We feel that if women with endocrine stigmas are segregated in antepartum clinics and carefully watched, one will observe the inception of the vast majority of c,ases of toxemia of pregnancy. This will afford the opportunity not only to undertake appropriate measures of therapy at the time when they are most useful, but also to study the pathogenesis of this disease. The following may be said regarding the therapeutic implications of the fact that the toxemia of pregnancy is a result of endocrine dysfunction. While the precise nature of the endocrine disturbance is unknown, it is manifested by water retention in the organism. This water retention not only produces palpable edema, but it also may go on to the edema of the brain which is concerned in the production of the eclamptic
810
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seizure. In our Sands the most efficient treatment of the toxemia of pregnancy has been a regimen which tends to dehydrate the organism. The patient is put on a salt poor diet and the fluid intake is restricted to 1,000 CC. or less. What is especially to be emphasized is that protein intake is not limited; in fact, especially in patients with considerable albuminuria, we give as much as 100 gm. of protein daily. It should be remembered that the plasma proteins are generally low in the toxemia of pregnancy, and this favors the formation of edema; ample protein intake is essential to combat the lowering of the plasma proteins and thus tend to avert or remove edema. There need be no fear of nitrogen retention because of the high protein intake; renal function is not significantly impa,ired. Other dehydrating mea,sures which we employ are the frequent a,dministration of magnesium sulphate by mouth with resultant abundant watery stools and the use of thyroid extract in those cases having a low basal metabolic rate. The latter is indicated not only by the tendency to water retention, which it combats, but by the relatively low basal metabolism. The usual bed rest, and mild sedation with chloral and bromides or phenobarbital are also employed. In patients with great hypertension in whom convulsions or other cerebral symptoms seemed to impend, or with actual eclamptic convulsions, we have found the intravenous administration of magnesium sulphate of great value in addition to the other usual routine procedures. Using the “dehydrating regime” just described, we have obtained splendid results in the large majority of patients with so-called preeelampsia, with c1earin.g up of edema and fall in blood pressure. In the past four years convulsions did not develop in any patient with preeelampsia treated by this regime in our service at the Jewish 3laternit.y Hospital. However, we should like to emphasize the fact that. we do not believe that patient,s should be “carried along” on a medical regime for a long time. Onr findings corroborate the important studies of Harris,l” Peckham,16 Corwin and Herrick,l? and Herriek and Tillman,1Y who have shown that a high proportion of patients with toxemia later develop hypertensive disease with resultant shortening of life. There is some reason to believe that the chances of developing hypertension in later life are augmented by allowing the toxemia to persist for too long a. period. For the sake of the mother later in life, she should not be allowed to remain in a toxemic state a,ny longer than necessary. CONCLUSIONS
Evidence is presented which, we believe, indicates that toxemia of pregnancy is an endocrine disturbance evolving in women with a preexistent constitutional abnormality of the endocrine glands. The evidence consists in the following:.
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1. The average prepregnancy weight of patients that developed toxemia is 21.8 pounds more than that of patients in the normal series. The incidence of obesity in this type is great. 2. A high percentage of women with toxemia have abnormal distribution of hair. 3. Sixty-five and eight-tenths per cent of patients with toxemia have abnormalities of stature as contrasted with 21 per cent of controls. The average weight/height ratio of the normal series was 2.08 as compared to that of 2.5 for the toxemia series. 4. Fifty-five per cent of women with toxemia had changes in facies of the “acromegaloid” type as contrasted with 5 per cent of the controls. 5. Eighty-eight per cent of our cases with toxemia showed reversion to the male and primitive type of pelves. Giant pelves were unusually frequent. 6. Basal metabolic ratesin toxemia of pregnancy averages definitely less than in normal pregnancy. 7. As has previously been demonstrated by. others, the plasma proteins in. toxemia of pregnancy are depressed below those in normal pregnancy. 8. In. 98 per cent of our patients with (toxemia .of pregnancy there were one or more endocrine stigmas, and in a large majority there were two or more. Only 15 per cent of the normal controls presented any endocrine stigmas and only 3 per cent had more than one stigma. 9. In not one of our series of 120 cases of toxemia of pregnancy was there significant impairment of renal function as demonstrated by the concentration test and by the determination of the nonprotein nitrogen of the blood. 10. All pregnant women ha.ving endocrine stigmas should be eonsj.dered as potential victims of toxemia. It is advised that they be segnegated for investigation and proper therapy. The latter consists mainly in a regime of dehydration. 11. In “carrying along” a patient with toxemia of pregnancy, the fact should be seriously considered that a high proportion of patients later develop hypertensive disease with resultant shortening of life. REFERENCES
(I) Caldwell, Moloy, and D’Esopo: AM. J. OBST. & GYNEC. 28: 482, 1934. (2) Abramson, Roberts, aad Wilson: Burg. Gynec. Obst. 58: 595, 1934. (3) Bar: AM. J. OBST. & GYNEC. 2: 249, 1921. (4) Corn&: Surg. Gynec. Obst. 36: 53, 1923. ( 5) Sandiford and Wheeler: Bull. Johns Hopkins Hosp. 38: 227, 1926. (6) Daly ana Strozlse: J. A. M. A. 96: 1656, 1931. (7) Pardy: J. Iowa M. Sot. 25: 493, 1935. (8) Plass and Bogert: Bull. Johns Hopkins Hosp. 35: 361, 1934. (9) Plass and Mathew: Ax J. OBST. & GYNEC. 12: 346, 1926. (10) Oar-d and Peters : J. Biol. Chem. 81: 9, 1929. (11) Fishberg: Hypertension and Nephritis, ed. 3, Philadelphia, 1934, Lea & Febiger. (12) Bnselmino and Hoffmnnn: Edinburgh 16. J. 39: 376, 1932. (13) Potter: J. Obst. & Gynaec. Brit. Emp. 35: 743, 1928. (14) Smith and Smith: Surg. Gynec. Obst. 61: 175, 1935. (15) Harris: Bull. Johns Hopkins Hosp. 35: 103, 1924. (16) Peckham: AM. J. OBST. & GYNEC. 23: 386, 1932. (17) Corwin and Herrick: J. A. M. A. 88: 457, 1927. (18) Herrick and Tillman : Arch. Int. Med. 55: 643, 1935.
DISCUSSION DR. RAPHAEL KURZROK.-The whole subject of the interrelationship between the endocrine glands and toxemia of pregnancy was, I believe, first noted about twenty years ago, by Mofbauer. He, at that time, postulated the theory that the pituitary gland and the adrenals in association with a placental factor, the so-called biogenous nmines, substances of high pharmacologic potency, were interrelated with the toxemia of pregnancy. Only the first part of his theory has been taken up and investigated. Among the symptoms of toxemia, hypertension and edema are notable, as the result of a hyperproduction of one or possibly two of the hormones of the posterior pituitary gland. In the posterior pituitary gland we have a group of hormones, one of which, oxgtocin, has to do niith the contraction of the uterus, and has no bearing on the problem at hand. The other has a combination of activities, probably residing in two molecular groups: the first raises the blood pressure, the second inhibits diuresis. Another substance, possibly arising from the middle portion or the pars intermedia of the pituitary gland, has an edect on the melanophore groups of certain species. Anselmino and Hoffmann stated that the retention of water and the hypertension can very well be due to an overproduction of the hormone which produces exactly these two phenomena and whose origin is in the posterior pituitary gland. Unfortunately, they worked with the rabbit, which is notoriously unreliable, especially so far as this particular type of testing is concerned. The next important advance in this field was made by Gushing, who not.ed, in six cases of eclampsia, that there was direct invasion on the part of basophilic cells from the anterior pituitary gland and pars intermedia into the posterior pituitary gland, and that in the invasion of the posterior pituitary gland these cells underwent a process of degeneration and formed the amyloid substances or Herring bodies. He postulated, in addition, that the substanc.e, vasopressin, arises from the anterior pituitary gland, because histologically, the posterior hypophysis does not appear like a secreting tissue. This view is of importance, because the anterior pituitary is that portion which enlarges during pregnancy. Gushing’s concept has, however, recently been attacked in the work of Geiling and Lewis, and others. They have demonstrated that pure tissue cultures from the anterior pituitary gland contain neither the substance that raises blood pressure nor the substance that inhibits diuresis, nor the melanophore-expanding hormone. On the contrary, pure tissue cultures, arising from the posterior pituitary gland, produced both vasopressin and the melanophore-expanding substance. The other work which has been amazingly interesting in this field has been that of Smith and Smith of Boston, who demonstrated that in true toxemia of pregnancy there is a marked increase in the amount of prolan and a lowering in the amount of estrin of both the blood and the urine. At the present time we do not know whether the increase in prolan is a cause, or the result, of toxemia. It is very interesting to note that the lowering of the plasma of proteins is a usual conc,omitant of a lowered basal metabolic rate which has been found to accompany most of these cases of toxemia of pregnancy. More recently the adrenal has been drawn into the picture of toxemia of pregnancy by Fauvet. The adrenal is one of the glands of internal secretion that markedly enlarges during pregnancy. In toxemia of pregnancy and especially in eclampsia, however, there is a distinct diminution in the size of the cortex of the adrenal, and possibly some cases of death from toxemia of pregnancy unassociated with convulsions, may be due to a failure on the part of the adrenal. The general concept that offers the most potent possibilities is perhaps one comparable to, but opposite in effect to, our view of the menopause. The menopause is due to a derangement of the glands of internal secretion because of the permanent
GLASS-ROSENTHAL
:
STUDY
OF’
DER’MOID
813
CYSTS
loss: of one of these glands (the ovary). On the other hand, in pregnancy, a new gland of internal secretion in form of the placenta has been added. A re-arrangement must tak#e place, the nature of which depends a great deal upon the individual’s constitutjonal make-up, and endocrine equilibrium. Hence, the derangement thus induced in the pregnant woman will vary from patient to patient. In one it may be an overstimulation of the posterior pituitary gland, in another a failure of the adrena cortex (hyperemesis?), in a third hyperthyroidism, in a fourth a tachycardia due to disturbance of the autonomic nervous system, etc. :DR. ROBERT T. FRANK-No one can take exception to the extremely interesting clinical type presented this evening. The numerical preponderance of this group may be of significance, although the stigmas presented are very common. That they should appear in such numbers in this group proves at least that these individuals are more easily affected by disturbances, the nature of which I am unwilling to attempt to analyze, than other groups. If these gentlemen will take the time and the trouble, because much is involved, to study this group further, it would If this be important to note’whether they are equally subject to other disturbances. were true, it would merely mean that these individuals are more readily affected by many kinds of trauma, including eclamptie poisoning, if you wish to call it tha,t. The speakers have wisely refrained from attempting to state what is the basic cause of eclampsia. All you can say is that this group certainly shows what the Germans call ‘ ‘ Minderwertigkeit, ’ ’ a weakness, a vulnerability to the disturbance. DR. ARTHUR W. BINGHAM.-Dr. Langroek has described cases of patients who are, as we all know, more likely to become toxic, and who are poor risks medically and surgically as well as for maternity. That does not explain, however, the case of the average healthy young woman who eats too much, sits around, and does not exereme, gains too much weight, and develops a disturbance in her metabolism, endocrine glands and water balance. The question is how to prevent toxemia in the average healthy young woman.
A STUDY MomIs (From
OF DERMOID CYSTS WITH A SUGGESTION THE USE OF X-RAY IN DIAGNOSIS” GLASS, M.D., F.A.C.S., AND ALEXANDER M.D., BROOKLYN, N. Y. the Gynecological
Service
of the Long
H.
Island
ROSENTHAL,
College
AS TO M.A.,
Hospital)
1EVENTY-NINE patients with dermoid cysts of the ovary were ad)I5 mitted to the Long Island College Hospital from October, 1923, to May, 1936. Analysis of these cases emphasizes certain features which have considerable clinical significance. The youngest patient was fifteen years of age and the oldest fifty-eight. Sixty-five, or 82 per cent, were observed between the third and fourth decades of life. Among 500 consecutive ovarian neoplasms removed during this period, dermoid tumors ranked second to the serous cystomas whieh constituted one-third of our material and, surprisingly, they were more common than the pseudomucinous cysts which were noted in only 9.2 per cent of the cases. -10,
*Presented lY36.
(by
invitation)
before
the
New
York
Obstetrical
Society.
November
ENDOCRINE
JEFFERSOK
BASIS
OF TOXEMIA
J. VORZIMER, M.D., ARTHUR LANGROCK, M.D., AND EMANUEL
OF PREGNANCY*
M.D., EDWIN M. RAPPAPORT, M.D., NEW YORK, N. Y.
(From the Jewish Maternity
Diz;ision
M.
of
FISHBERG,
the
Beth
Israel
G.
Hospital)
‘N THIS paper we desire to present evidence to support our belief that the so-called toxemia of pregnancy is a manifesta.tion of a disturbance of the endocrine glands. The observations here recorded have been carried out over a period of four years. They have led to the conclusion that in the large majority of instances toxemia of pregnancy occurs in women with a constitutional habitus, in itself a manifestation of an endocrine disturbance. I,
Our primary criterion for the diagnosis of toxemia of pregnancy was the development in the later months of pregnancy of abnormally high blood pressure, in women in whom there was no history or other evidence of preceding renal or hypertensive disease. It may well be that there are c,asesof toxemia of pregnancy in which hypertension is absent and the disorder is manifested solely by edema and albuminuria. But in order to deal with a criterion of the diseasewhich is practically universally acclepted, we have included only patients with high blood pressure. All our patients began pregnancy with normal blood pressure and’developed a systolic pressure exceeding 140 mm. and a diastolic pressure above 90 mm. Almost every patient had a blood pressure well over this level. The present study is based on 120 patients fulfilling this criterion. As ssntrols, we have used 100 consecutive patients having normal pregnancies. The evidence is presented under the following headings: (1) Body weight, (2). hair distribution, (3) stature, (4) facies, (5) form of pelvis, (6) basal metabolism, and (7) blood proteins. 1.
BODY
WEIGHT
The pregestational weight of women with toxemia of pregnancy averages much more than that of a similar number of normal pregnant women (Fig. 3). The average weight in the normal series was 126.2 pounds, as contrasted to the average weight in the toxemia series of 148 pounds. The high incidence of obesity in patients who develop this disease is thus demonstrated. Moreover, in a large proportion of these casesthere was a tendency to obesity from an early age. It is a wellknown fact that patients with toxemia of pregnancy gain weight excessively. Further evidence indicates that this obesity is of endocrine -*Read
at
a meeting
of the
New
York
Obstetrical 801
Society,
October
13.
1936.
802
AMjERlCaN
JOURNAL
03’
OBSTETRICS
AXD
GYNEOOLOGY
origin and not due to gluttony or lack of exercise. For, in the 6rst plade, there was nothing to suggest that the food intake or exercise of the patients with toxemia differed from that of the controls; indeed, many of our patients were obese in spite of strenuous dieting. Second, there was a very high incidence of other endocrine stigmas in the obese individuals. 2.
DISTRIBUTION
OF
HAIR
In the female, abnormalities in the distribution of hair resulting from endocrine disturbances are of two types : (1) An increase in the amount of hair, with a tendency to male distribution, that is on the legs, thighs, abdomen, chest, face, and occasionally around the nipples ; (2) Decrease in pubic and axillary hair so that it is scanty, very fine and silky, and sometimes almost absent. These two types of abnormality in hair disfribution due to endocrine disturbances were present, with almost equal frequency, in 74 per cent of the patients with toxemia, as compared to only 9 per cent of the normal controls. 3.
STATURE
Various observers have noticed that a high proportion of women with toxemia of pregnancy are of stocky build. The coincidence of short, thick-set framework and obesity gives many of these women a characteristic appearance. There are some patients, however, that have an unusually large bony framework (Fig. 1). Definite abnormalities of stature were present in 65.8 per cent of the toxemia patients as contrasted with 21.0 per cent of the normal patients. It was found that the average weight/height ratio of patients in the normal series was 2.08 pounds per inch and that of patients in the toxemia series 2.5 pounds per inch (Fig. 4). Such peculiarities of stature are generally regarded as due to aberrations in the function of the endocrine gla.nds.
An outstanding characteristic of most of our patients with toxemia of pregnancy was that they looked several years older than their chronologic age (Fig. 2). Some young women of twenty to twenty-five years appeared thirty to forty years of age. This appeared to be due to the combination of obesity, statural peculiarity, and change in facies. They had enlarged features of the acromegaloid type, which in many were of long standing, and in others had appeared during the antepartum course. The most common change in the features was enlargement of the nose. These facial changes were sometimes associated with enlargement of the hands and feet. Their development was almost always noted by the patient or her companions, and often progressed noticeably under clinical observation. It is true that in normal pregnancy there is some enlargement of the fea,tures, generally attributed to physiologic hyper-
VORZIMER
ET
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E’NDOCRINE
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803
PR$,GNANCY
a.ctivity of the pituitary gland. This is rarely marked enough to become a. complaint, as it was in some of our cases of toxemia of pregnancy. It was found that 55 per cent of the latter had changes in facies, whereas such changes occurred in only 5 per cent of the normal patients. 5.
FORM
OF PELVIS”
In the course of evaluating pelvic x-rays one year ago, we were aroused by the infrequency of the true gynecoid pelvis in those women who deOf 23 pelves in toxemic women, only 2 veloped toxemia of pregnancy.
Fig.
1.
Fig. l.-Showing stocky with toxemia of pregnancy. 20 Pounds.) Fig. 2.-Facies of patient
Fig. build and (Photograph in
Fig.
girdle
2.
obesity in a woman of twenty-six taken two weeks postpartum after
years, loss of
1.
were gynecoid. Since this observation, we have x-rayed routinely all patients who developed toxemia to determine the correlation, if any, between their body habitus and pelvic architecture (Table I). The most striking feature of this survey is the low incidence of the gynecoid pelvis and the predominance of other types, especially the The table shows that the incidence of reversion to the male anthropoid. *We desire Schwartzchild
to for
express our sincere their aid with the
thanks to roentgenologic
Drs.
I. Seth aspects of
Hirsch and this study.
Myron
-4.
804
AMERICAN
JOURNALI
OF
OBSTETRICS
AND
GYNE,COLOGY
and primitive type of pelvis in the toxemia series is very high. The r&e of the hormones in the evolution of pelvic types has been ably postulated by Caldwell, Moloy, and D ‘Esopo. 1 Since we find that women of extreme endocrine types in the great majority of cases have pelves that fall illto the android and anthropoid class, we may speculate that this reversion to the male and primitive type of pelvis is due to an inherent imbalance in the hormonal system.
4 Fig.
3.-Pregestational
Fig.
4.-Pregestational weight/height controls, demonstrating the
‘the
weight of preponderance
patients with of toxemia
high
ratio of incidence
toxemia among
patients of obesity
and normal the obese.
with
toxemia among the
controls.
and former.
Xote
normal
We must further comment on the unusual number of large pelves which appear to be more common than in our normal series. Some border on giantism, with dimensions far out of proportion to the stature of the patient (Fig. 5). We wish to report a final observation relative to the sepration of the symphysis during the antepartum period. Although the average separation, as seen stereoscopically, is not greater in the toxemia group than in the normal, in 7 eases this physiologic relaxation of the joint was by far
VORZIMER
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ENDOCR.INE
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TOXEBMIA
OF
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805
wider than any of a series of 150 normals (Fig. 6). In view of the accepted work of Abramson and coworkers,2 this may indicate an abnormal endocrine function in these patients, although further observation on a larger series is necessary for verification.
Fig. 5.-X-ray of pubic arch sweep of pubic arch and rami. symphysis (not demonstrable in with marked endocrine stigmas.
Fig.
B.-X-ray partum
symphysis separation
Of
of
of a large platypelloid pelvis. Note tremendous Bis-ischial diameter 16.0 cm. Wide separation of this view) also present. Case of recurrent toxemia
in case of symphysis.
patient Patient
with of
toxemia, extreme
showing endocrine
marked type.
ante-
The observations on the form of pelvis thus add very strong evidence to the impression that toxemia of pregnancy occurs in a woman of definite constitutional habitus, due probably to dysfunction of the endocrine system.
A number of investigators3-7 have shown that in uncomplicated pregnancy the basal metabolic rate is increased 10 to 30 per cent above normal. This is especially true in the later months of pregnancy. It TAELE ~~ .~
I.
SHOWING
PELVIC I 1
TTI'E
NUMBER OF CASES
I
-__~~_--
TYPES
Ix
THIS
SERIES
PER
I i
CENT
gggf
1 r
___-
Anthropoid Gynecoid with anthropoid Anthropoid with gyneeoid Android Android with gynecoid Android wit.11 anthropoid Platypelloid Platypelloid with gynecoid Gynecoid Gynecoid with narrow forepelvis
25 13 9 1: j
s” !I ii
1
2
PER CENT FOUND BY R(;;;y:;; D'ESOPO
30.1 15.7 2.6 16.6
11.6 4.6 6.5 11.6
i::
i::
6.0'
0.9
7.2 4.8
39.5 11.1
should further be borne in mind, in this connection, that all our patients bad high blood pressure, and it is well known to internists that in socalled essential hypertension there is a tendency to elevation of the metabolic rate. Hence, in hypertensive toxemia of pregnancy one would anticipate, a priori, a high basal metabolic rate by virtue of two factors, It is, therefore, of interest. and undoubtpregnancy and hypertension. edly significant that in 35 patients with toxemia of pregnancy, in whom repeated observations of the basal metabolic rate were made, we found that 68 per cent had bnsal metabolic r&es below plus 10 per c&tit, which is the accepted zoww limit of nomud during pregncLncy (Table II). TABLE
II.
SIIO~YING
CASE
PRIMIPARA
1
tl9 t30 - ,? 4-4 i-3
2 3 4 c i ; 9 10 11 12 13 11 15 16 17
tl3 -4 - 5 +I2 -10 t16 -11 t19 -3 +a -2 $- 3
BASAL
METABOLIC
CASE 18 19
20 21 22 23 34 25 26 27 28 a9 30 31 32 33 34 35
Ra!txs
IN CASES
XCLTIPARA t13 +15
-.I5 -4 -5 +I5 -9 +2 +15 $18 -9 -8 -4 +5 - 1 -2 -3 +2
WITH
,-
TUEMIA PER CENT BELOW tlo%
Primipara
65% Multipara 72% Total
68%
VORZIMER
ET
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ENDOCRINE
BASIS
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TOXEmiWIA
OF
807
PREGNANCY
Since the main control of the metabolic rate rests in the endocrine glands, such a relatively low metabolic rate is indicative of an endocrine disturbance. In two instances, we had the opportunity of observing the development of toxemia of pregnancy, in patients following the fall in metabolic rate that took place, in the one instance “artificially” as a result of thyroidectomy, in the other spontaneously. The first patient was a primipara who had had a thyroidectomy for Graves’ disease in the fourth month of pregnancy. Following this procedure, the basal metabolic rate, which had previously been high, fell to minus 20 per cent. This patient, who had had a normal blood pressure and urine, subsequently developed copious albuminuria and hypertension. The second case was also a primipara who had had a basal metabolic rate of plus 20 to 26 per cent on several occasions for two years prior to her pregnancy. Instead of increasing during the pregnancy, as it normally does, the basal metabolic rate fell to minus 3 per cent a.nd she developed hypertension of 150/100 mm. 7.
PLASMA
PROTEINS
Chemical studies of the blood in the toxemias of pregnancy have revealed a fairly constant abnormality in the concentrations of the plasma proteins. It has been definitely shown by many authorsa, g that the plasma proteins are diminished in these cases, and that this diminution is absolute and not due to dilution.1° We corroborate these findings. In 15 of the 17 patients in whom this determination was made (Table III) the plasma protein concentration was depressed to between 4.07 and TABLE
III.
SHOWING PLASMA PROTEIN DETERUINATIONS IN 17 CASES OF TOXEMIA, WHICH 1 TO 7 ARE PRIMIPARAS, THE REMAINDER MTJLTIPARAS
= CASE
2 3 4 5 6 7
8 9 10 11 12 13 14 15 16 17
=zZ
TOT. PROT.
5.51 4.07 4.68 4.93 5.20 4.25 4.68 5.06 5.20
1
5.91 5.51
-
OF
6.25 5.51 5.85 4.93 4.93 6.25
ALBUMIN
3.05 2.61 2.25 2.39 2.50 2.81 2.34 2.51 3.75 3.51 3.12 3.95 2.73 3.12 3.21 2.34 3.12
-
-
GLOBULIN
2.46 1.46 2.43 2.54 2.70 1.44 2.34 2.25 1.45 2.50 2.39 2.30 2.75 2.73 1.72 2.59 3.13
5.91 gm. per cent as contrasted with normal limits There was also inversion of t,he albumin/globulin tendency toward inversion in 6 others. It is well ties of the endoerines sometimes affect the level
-
A/G
RATIO
1.2 1.7 0.92 0.9 0.92 1.9 1.0 1.2 2.5 1.4 1.2 1.7 0.98 1.2 1.2 0.9 -
1.0
of 6 to 8 gm. per cent. ratio in 6 cases and a known that abnormaliof the blood protein.
808
AMERICAN
JCK7BNAL
OF
OBSTETRICS
AND
GYNECOLOGY
Since the depression in the protein content of the blood in some cases occurred without significant albuminuria or dietary deficiency, it seems probable that it was a manifestation of an endocrine disturbance. TOXEMIA
OF PREGNANCY
AKD
RENAL
FUNCTION
Parenthetically, we would like to interpolate a. few words regarding the relation of toxem.ia of pregnancy to impairment of renal function. 1% not one of 120 patids with toxemia of pregnancy was there sigk&ant impairment of ,renal function. Of course, patients who entered pregnancy with glomerulonephritis are not included in the category of toxemia, of pregnancy. Renal function was studied by the eoncentration test and by the determination of the nonprotein nitrogen of the blood. All the patients were able to elaborate urine of specific gravity 1.020 or more, which rules out significant impairment of renal function (see Fishberg) .I1 The nonprotein nitrogen of the blood was also within normal limits. In the light of these facts, theories regarding impairment of renal function as a factor in the pathogenesis of the toxemias of pregnancy are, as has been realized by most recent students, to be discarded. Moreover, impairment of renal function need not be taken into consideration in the treatment of the toxemia of pregnancy. In the natural history of this disease,impairment of renal function does not appear during the pregnancy. It. may appear after many years as a secondary consequenceof the hypertension, just as it may result from long years of essential hypertension. DISCUSSION
Summarizing the data just presented, it is found that 98 per cent of our patients with toxemia of pregnancy revealed evidence of one or more of the endocrine stigmas under consideration, and in a large majority there were two or more. The significance of these endocrine stigmas in women with toxemia of pregnancy is all the more evident on comparison with the normal controls. Only 15 per cent of the latter presented any endocrine stigmas and only 3 per cent had more than one stigma. The fact that 15 per cent of our normal controls presented endocrine sti,gmas does not militate against their significance in the toxemic cases. Our conception is that these stigmas are merely evidences of an endocrine disturbance, often constitutional in nature, which predisposes to the development of what is known as toxemia of pregnancy. That the actual disorder does not become clinically manifest in every individual with the underlying endocrine disturbance is not surprising, in fact would be anticipated, and has many analogies in clinical medicine. Of several sons of parents with diabetes and obesity, only some may actually develop glycosuria even though all are obese and show diminished sugar tolerance. The individuals with the endocrine st.igmas described are al-
VORZIMER
ET
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:
ENDOCRINE
BASIS
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PREGNANCY
809
ways to be considered as potential victims of toxemia, which may devel.op only in one of their later pregnancies. This statement is borne out by the well-known fact that multiparas may develop toxemia despite previous normal pregnancies. The evidence here presented adds support to the theory that toxemia of pregnancy is a condition developing on the basis of a disturbance of internal secretion. ‘We do not feel that the observations here recorded throw any light on the precise nature of the endocrine disturbance which produces the toxemia of pregnancy. All the endocrine glands are interrelated and The available evithle function of all of them is affected in pregnancy. dence does not permit a decision as to which of the endocrine glands is primarily at fault in the production of the toxemia of pregnancy, The work of AnseImino and Hoffmann,13 purporting to show that the blood of patients with toxemia of pregnancy contains an excess of a pressor and antidiuretic principle secreted by the pituitary gland, has failed of confirmation.13 On the other hand, the recent work of Smith and Smith,14 revealing the presence of an excess of prolan in the toxemia of pregnancy, is carefully controlled and to be accepted ; it may well prove the starting point of more intimate knowledge of the nature of the endocrine disturbance underlying the toxemia of pregnancy, but does not as yet show how this disturbance is initiated. THERAPEUTIC
AND
PROPHYLACTIC
IMPLICATIONS
Since the large majority of cases of toxemia of pregnancy develop in women who present detectable evidences of endocrine dysfunction, one has a basis in the antepartum clinic for the segregation of those women who are most likely to develop toxemia. Our observations indicate that about 30 per cent of women presenting the endocrine stigmas described above (stocky framework, obesity, abnormal distribution of hair, etc.) will develop toxemia of pregnancy. In the past six months we have observed 34 women with such endocrine stigmas but no evidences of toxemia develop definite toxemia of pregnancy. We feel that if women with endocrine stigmas are segregated in antepartum clinics and carefully watched, one will observe the inception of the vast majority of c,ases of toxemia of pregnancy. This will afford the opportunity not only to undertake appropriate measures of therapy at the time when they are most useful, but also to study the pathogenesis of this disease. The following may be said regarding the therapeutic implications of the fact that the toxemia of pregnancy is a result of endocrine dysfunction. While the precise nature of the endocrine disturbance is unknown, it is manifested by water retention in the organism. This water retention not only produces palpable edema, but it also may go on to the edema of the brain which is concerned in the production of the eclamptic
810
AMFAICAN
JQURNAL
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OBSTETRICS
bND
GYNECOLOGY
seizure. In our Sands the most efficient treatment of the toxemia of pregnancy has been a regimen which tends to dehydrate the organism. The patient is put on a salt poor diet and the fluid intake is restricted to 1,000 CC. or less. What is especially to be emphasized is that protein intake is not limited; in fact, especially in patients with considerable albuminuria, we give as much as 100 gm. of protein daily. It should be remembered that the plasma proteins are generally low in the toxemia of pregnancy, and this favors the formation of edema; ample protein intake is essential to combat the lowering of the plasma proteins and thus tend to avert or remove edema. There need be no fear of nitrogen retention because of the high protein intake; renal function is not significantly impa,ired. Other dehydrating mea,sures which we employ are the frequent a,dministration of magnesium sulphate by mouth with resultant abundant watery stools and the use of thyroid extract in those cases having a low basal metabolic rate. The latter is indicated not only by the tendency to water retention, which it combats, but by the relatively low basal metabolism. The usual bed rest, and mild sedation with chloral and bromides or phenobarbital are also employed. In patients with great hypertension in whom convulsions or other cerebral symptoms seemed to impend, or with actual eclamptic convulsions, we have found the intravenous administration of magnesium sulphate of great value in addition to the other usual routine procedures. Using the “dehydrating regime” just described, we have obtained splendid results in the large majority of patients with so-called preeelampsia, with c1earin.g up of edema and fall in blood pressure. In the past four years convulsions did not develop in any patient with preeelampsia treated by this regime in our service at the Jewish 3laternit.y Hospital. However, we should like to emphasize the fact that. we do not believe that patient,s should be “carried along” on a medical regime for a long time. Onr findings corroborate the important studies of Harris,l” Peckham,16 Corwin and Herrick,l? and Herriek and Tillman,1Y who have shown that a high proportion of patients with toxemia later develop hypertensive disease with resultant shortening of life. There is some reason to believe that the chances of developing hypertension in later life are augmented by allowing the toxemia to persist for too long a. period. For the sake of the mother later in life, she should not be allowed to remain in a toxemic state a,ny longer than necessary. CONCLUSIONS
Evidence is presented which, we believe, indicates that toxemia of pregnancy is an endocrine disturbance evolving in women with a preexistent constitutional abnormality of the endocrine glands. The evidence consists in the following:.
‘VORZIMEB
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811
1. The average prepregnancy weight of patients that developed toxemia is 21.8 pounds more than that of patients in the normal series. The incidence of obesity in this type is great. 2. A high percentage of women with toxemia have abnormal distribution of hair. 3. Sixty-five and eight-tenths per cent of patients with toxemia have abnormalities of stature as contrasted with 21 per cent of controls. The average weight/height ratio of the normal series was 2.08 as compared to that of 2.5 for the toxemia series. 4. Fifty-five per cent of women with toxemia had changes in facies of the “acromegaloid” type as contrasted with 5 per cent of the controls. 5. Eighty-eight per cent of our cases with toxemia showed reversion to the male and primitive type of pelves. Giant pelves were unusually frequent. 6. Basal metabolic ratesin toxemia of pregnancy averages definitely less than in normal pregnancy. 7. As has previously been demonstrated by. others, the plasma proteins in. toxemia of pregnancy are depressed below those in normal pregnancy. 8. In. 98 per cent of our patients with (toxemia .of pregnancy there were one or more endocrine stigmas, and in a large majority there were two or more. Only 15 per cent of the normal controls presented any endocrine stigmas and only 3 per cent had more than one stigma. 9. In not one of our series of 120 cases of toxemia of pregnancy was there significant impairment of renal function as demonstrated by the concentration test and by the determination of the nonprotein nitrogen of the blood. 10. All pregnant women ha.ving endocrine stigmas should be eonsj.dered as potential victims of toxemia. It is advised that they be segnegated for investigation and proper therapy. The latter consists mainly in a regime of dehydration. 11. In “carrying along” a patient with toxemia of pregnancy, the fact should be seriously considered that a high proportion of patients later develop hypertensive disease with resultant shortening of life. REFERENCES
(I) Caldwell, Moloy, and D’Esopo: AM. J. OBST. & GYNEC. 28: 482, 1934. (2) Abramson, Roberts, aad Wilson: Burg. Gynec. Obst. 58: 595, 1934. (3) Bar: AM. J. OBST. & GYNEC. 2: 249, 1921. (4) Corn&: Surg. Gynec. Obst. 36: 53, 1923. ( 5) Sandiford and Wheeler: Bull. Johns Hopkins Hosp. 38: 227, 1926. (6) Daly ana Strozlse: J. A. M. A. 96: 1656, 1931. (7) Pardy: J. Iowa M. Sot. 25: 493, 1935. (8) Plass and Bogert: Bull. Johns Hopkins Hosp. 35: 361, 1934. (9) Plass and Mathew: Ax J. OBST. & GYNEC. 12: 346, 1926. (10) Oar-d and Peters : J. Biol. Chem. 81: 9, 1929. (11) Fishberg: Hypertension and Nephritis, ed. 3, Philadelphia, 1934, Lea & Febiger. (12) Bnselmino and Hoffmnnn: Edinburgh 16. J. 39: 376, 1932. (13) Potter: J. Obst. & Gynaec. Brit. Emp. 35: 743, 1928. (14) Smith and Smith: Surg. Gynec. Obst. 61: 175, 1935. (15) Harris: Bull. Johns Hopkins Hosp. 35: 103, 1924. (16) Peckham: AM. J. OBST. & GYNEC. 23: 386, 1932. (17) Corwin and Herrick: J. A. M. A. 88: 457, 1927. (18) Herrick and Tillman : Arch. Int. Med. 55: 643, 1935.
DISCUSSION DR. RAPHAEL KURZROK.-The whole subject of the interrelationship between the endocrine glands and toxemia of pregnancy was, I believe, first noted about twenty years ago, by Mofbauer. He, at that time, postulated the theory that the pituitary gland and the adrenals in association with a placental factor, the so-called biogenous nmines, substances of high pharmacologic potency, were interrelated with the toxemia of pregnancy. Only the first part of his theory has been taken up and investigated. Among the symptoms of toxemia, hypertension and edema are notable, as the result of a hyperproduction of one or possibly two of the hormones of the posterior pituitary gland. In the posterior pituitary gland we have a group of hormones, one of which, oxgtocin, has to do niith the contraction of the uterus, and has no bearing on the problem at hand. The other has a combination of activities, probably residing in two molecular groups: the first raises the blood pressure, the second inhibits diuresis. Another substance, possibly arising from the middle portion or the pars intermedia of the pituitary gland, has an edect on the melanophore groups of certain species. Anselmino and Hoffmann stated that the retention of water and the hypertension can very well be due to an overproduction of the hormone which produces exactly these two phenomena and whose origin is in the posterior pituitary gland. Unfortunately, they worked with the rabbit, which is notoriously unreliable, especially so far as this particular type of testing is concerned. The next important advance in this field was made by Gushing, who not.ed, in six cases of eclampsia, that there was direct invasion on the part of basophilic cells from the anterior pituitary gland and pars intermedia into the posterior pituitary gland, and that in the invasion of the posterior pituitary gland these cells underwent a process of degeneration and formed the amyloid substances or Herring bodies. He postulated, in addition, that the substanc.e, vasopressin, arises from the anterior pituitary gland, because histologically, the posterior hypophysis does not appear like a secreting tissue. This view is of importance, because the anterior pituitary is that portion which enlarges during pregnancy. Gushing’s concept has, however, recently been attacked in the work of Geiling and Lewis, and others. They have demonstrated that pure tissue cultures from the anterior pituitary gland contain neither the substance that raises blood pressure nor the substance that inhibits diuresis, nor the melanophore-expanding hormone. On the contrary, pure tissue cultures, arising from the posterior pituitary gland, produced both vasopressin and the melanophore-expanding substance. The other work which has been amazingly interesting in this field has been that of Smith and Smith of Boston, who demonstrated that in true toxemia of pregnancy there is a marked increase in the amount of prolan and a lowering in the amount of estrin of both the blood and the urine. At the present time we do not know whether the increase in prolan is a cause, or the result, of toxemia. It is very interesting to note that the lowering of the plasma of proteins is a usual conc,omitant of a lowered basal metabolic rate which has been found to accompany most of these cases of toxemia of pregnancy. More recently the adrenal has been drawn into the picture of toxemia of pregnancy by Fauvet. The adrenal is one of the glands of internal secretion that markedly enlarges during pregnancy. In toxemia of pregnancy and especially in eclampsia, however, there is a distinct diminution in the size of the cortex of the adrenal, and possibly some cases of death from toxemia of pregnancy unassociated with convulsions, may be due to a failure on the part of the adrenal. The general concept that offers the most potent possibilities is perhaps one comparable to, but opposite in effect to, our view of the menopause. The menopause is due to a derangement of the glands of internal secretion because of the permanent
GLASS-ROSENTHAL
:
STUDY
OF’
DER’MOID
813
CYSTS
loss: of one of these glands (the ovary). On the other hand, in pregnancy, a new gland of internal secretion in form of the placenta has been added. A re-arrangement must tak#e place, the nature of which depends a great deal upon the individual’s constitutjonal make-up, and endocrine equilibrium. Hence, the derangement thus induced in the pregnant woman will vary from patient to patient. In one it may be an overstimulation of the posterior pituitary gland, in another a failure of the adrena cortex (hyperemesis?), in a third hyperthyroidism, in a fourth a tachycardia due to disturbance of the autonomic nervous system, etc. :DR. ROBERT T. FRANK-No one can take exception to the extremely interesting clinical type presented this evening. The numerical preponderance of this group may be of significance, although the stigmas presented are very common. That they should appear in such numbers in this group proves at least that these individuals are more easily affected by disturbances, the nature of which I am unwilling to attempt to analyze, than other groups. If these gentlemen will take the time and the trouble, because much is involved, to study this group further, it would If this be important to note’whether they are equally subject to other disturbances. were true, it would merely mean that these individuals are more readily affected by many kinds of trauma, including eclamptie poisoning, if you wish to call it tha,t. The speakers have wisely refrained from attempting to state what is the basic cause of eclampsia. All you can say is that this group certainly shows what the Germans call ‘ ‘ Minderwertigkeit, ’ ’ a weakness, a vulnerability to the disturbance. DR. ARTHUR W. BINGHAM.-Dr. Langroek has described cases of patients who are, as we all know, more likely to become toxic, and who are poor risks medically and surgically as well as for maternity. That does not explain, however, the case of the average healthy young woman who eats too much, sits around, and does not exereme, gains too much weight, and develops a disturbance in her metabolism, endocrine glands and water balance. The question is how to prevent toxemia in the average healthy young woman.
A STUDY MomIs (From
OF DERMOID CYSTS WITH A SUGGESTION THE USE OF X-RAY IN DIAGNOSIS” GLASS, M.D., F.A.C.S., AND ALEXANDER M.D., BROOKLYN, N. Y. the Gynecological
Service
of the Long
H.
Island
ROSENTHAL,
College
AS TO M.A.,
Hospital)
1EVENTY-NINE patients with dermoid cysts of the ovary were ad)I5 mitted to the Long Island College Hospital from October, 1923, to May, 1936. Analysis of these cases emphasizes certain features which have considerable clinical significance. The youngest patient was fifteen years of age and the oldest fifty-eight. Sixty-five, or 82 per cent, were observed between the third and fourth decades of life. Among 500 consecutive ovarian neoplasms removed during this period, dermoid tumors ranked second to the serous cystomas whieh constituted one-third of our material and, surprisingly, they were more common than the pseudomucinous cysts which were noted in only 9.2 per cent of the cases. -10,
*Presented lY36.
(by
invitation)
before
the
New
York
Obstetrical
Society.
November