STUDIES OF THE METABOLISM OF WOMEN.

1. VARIATIONS IN THE FASTING BLOOD SUGAR LEVEL AND IN SUGAR TOLERANCE IN RELATION TO THE

MENSTRUAL CYCLE.

BY RUTH OKEY AND ELDA I. ROBB.

(From the Laboratory of Household Science, University of California, Berkeley.)

(Received for publication, June 15, 1925.)

INTRODUCTION.

The literature on the general question of the significance of the menstrual phenomenon has, recently, been so well summarized by Corner (1) and by Marshall (2) that any attempt at further review seems out of place here. That the present state of our knowledge with regard to the biochemical and metabolic changes involved in the monthly cycle in women is eminently unsatisfactory must, however, be conceded. In fact, until we have realized the extent of the difficulties encountered by the investigator in a field SO

hedged about by social and religious conventions, we are tempted to conclude that almost nothing has been achieved toward a rational understanding of these aspects of the phenomenon.

It has been estimated that the time during which the average woman is menstruating aggregates a total of 7 years (3). For from 65 to 75 per cent of all civilized women, some part, at least, of this period, is marked by pain and a greater or lesser degree of incapacitation for work. It must appear, moreover, that the best prospect for the achievement of an ultimately satisfactory inter- pretation of this practically important phenomenon rests upon the accumulation of data from chemical and physiological as well as anatomical and histological measurements. The results of the series of studies reported in this paper and those which are to fol- low are therefore offered in the hope that they may be of some value, even if they serve only as temporary units in the building of a more satisfactory understanding of the cyclic changes in the life processes of women.

165

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166 Metabolism of Women. I

LITERATURE.

Carbohydrate Metabolim.

That the metabolism of carbohydrates may be affected, directly or indirectly, by the activities of organs of internal secretion other than the pancreas, is generally granted. The role of the individual glands and their influence, one upon the other is, how- ever, very imperfectly understood. Hypersecretion of the suprare- nals is supposed to lead to increased mobilization of glucose from the glycogen storehouses, with an accompanying high level of blood sugar, and, possibly, glycosuria.

Riddle and Honeywell (4, 5) have recently observed, in various types of pigeons, a suprarenal hypertrophy coincident with ovula- tion. There was an accompanying increase, reaching 20 per cent, in the blood sugar. This began approximately 108 hours after the ovulation of the first egg of a pair, was maintained at a maxi- mum level throughout the time of ovulation, and gradually decreased to the resting level within 108 hours after the ovulation of the last egg. These investigators noted that the curve of blood sugar values was essentially similar to that of suprarenal hypertrophy.

Their conception of a rhythmic variation in carbohydrate meta- bolism coincident with a like variation in sexual activity impresses the reader with its similarity to the idea of rhythmic variation in the nutritive processes of women expressed by Jacobi (3). The difficulty in making direct comparisons arises from the fact that while the probabilities are (1) that ovulation in women takes place from 10 days to 2 weeks before the onset of menstruation no definite time relationships between the two phenomena have, as yet, been established. Moreover, there is much evidence (6) that the activities of the ovary as a gland of internal secretion must be considered, not as a single entity, but as a complex, result- ing from the balanced effects of corpus luteum, follicles, inter- stitial cells, etc. To some extent, also, there is evidence (7) of antagonism between certain functions of the ovaries and of the suprarenals in that atrophy of the ovaries with hypertrophy of the suprarenals sometimes results in loss of secondary sexual charac- teristics in women.

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R. Okey and E. I. Robb 167

Very few efforts to correlate the human menstrual cycle with physiological variations in blood sugar, or in sugar tolerance, have been reported in the literature; but the reports which we do have are distinctly contradictory.

H. Kahler (8) observed a slight rise in blood sugar at the time of the onset of the menstruation, with normal values for the same individuals at the end of the period. His determinations were, however, made by the method of Bang, using finger blood, and the observed variations were so small as to fall within the limits of experimental error.

Ernst Hoffmann (9) decided, on the other hand, that values for sugar in the blood serum were lower, and that the tolerance toward galactose and levulose was increased during menstruation. He considered, on the basis of this evidence, that the influence of the ovarian hormone on carbohydrate metabolism was quite marked.

This investigator made two determinations of serum sugar for each of his subjects, 1 hour after the ingestion of a test meal; the first in the intermenstrual period, and the second during men- struation. He had fifteen cases, to four of whom he gave 100 gm. of levulose; to ten, 30 to 40 gm. of galactose; and to one, 80 gm. of lactose. Eleven showed a typical lowering of serum sugar (from 0.01 to 0.03 per cent). In two cases (one a thyroid, and one an arthritis patient), he observed no change, and in two cases (a girl of 14 listed as a “nosebleed” case, and a chlorosis patient), there were increases of 0.03 and 0.01 per cent respectively, in the serum sugar at the time of the menstrual period. It is interesting to note that eight of the eleven cases who reacted with a smaller increase in serum sugar at the time of menstruation were listed as “gesund,” while the others were suffering from a variety of disorders.

Hoffmann also found, in rabbits, and in three of the four women whom he treated with “Luteovar, Poehl,” a similarly decreased response to galactose ingestion as measured by serum sugar determinations.

The method which he used for sugar estimation was a modifica- tion of that of Bertrand, and involved the taking of a considerable amount of blood. The fact that galactose and lactose were used as the test carbohydrates leads us to wonder how far his conclu- sions might be modified by repetition and reinterpretation of this

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168 Metabolism of Women. I

work in the light of t.he recent cont,ributions of ITolin and Rerglund (lo), and of Ucrglund and X (11) to our knowledge of the mecha- nism of the metabolism of these sugars.

In sharp contrast to this work of Hoffmann stands that of Itosen- bloom (12)) who has reported a large decrease in the food tolerance of diabetic patients during menstruation. This was accompanied by glycosuria, acidosis, and a marked increase in the tendency to develop coma. One of the two patients observed died as a result of this menstrual break. The loss of food tolerance was explained as due to an increase in the size, and, presumably, in the functional capacity of thyroids, suprarenal cortex, and pituitary glands, and some alteration in the functioning of the gonads which resulted in a temporary lack of correlation of endocrine activity.

Harrop and Mosenthal (13) have also reported a cast in which the sugar tolerance was markedly lessened during the menstrual period. They seem to believe that there is a possibility that menstruation in diabetic women is frequently coincident with terminal acidosis and coma.

EXPERIMENTAL.

The work reported here has been undertaken with the idea of determining, if possible, (a) whether or not there are any consistent variat,ions in the fasting blood sugar levels in women coincident with the different phases of the monthly cycle; and (b)whethcrthe response to the ingestion of a given amount of glucose in terms of rise in blood sugar level and urinary excretion of sugar is consis- tently different at different t,imes during the month in the same individual.

Subjects.

The subjects were young women, upper division and graduate students from the classes in Nutrition and preparatory Medicine, who volunteered for this work because of interest in it, and who were willing and able to give intelligent cooperation. All of them qualified as ‘5rormal” from a clinical point of view. Health records and records of physical examinations, etc., were obtained through the courtesy of the staff of the University of California Infirmary and supplemented by questioning the individual subjects.

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R. Okey and E. I. Robb 169

The three girls who constituted Group I were subjects for a detailed study of nitrogen metabolism in its relationship to the menstrual cycle, and were on weighed and analyzed diets’ which were kept constant for each individual for at least 1 month at a time. Group II consisted of subjects who were on the ordinary diets at their respective boarding clubs. They were, however, instructed to refrain from any large variations in their usual rou- tine of living while the experimental period lasted and, as far as could be ascertained, followed instructions. Group III, the detailed figures for which arc not included in the tables, consisted of students originally espected to be in Group II, who became ill during the experimental period or whose Infirmary record did not seem to justify rating as “normal.” Their blood sugar values, however, show no very marked differences from those of the other groups. Data for two men observed as controls over periods of 1 month each is likewise not given in detail, since these periods included several shorter ones on experimental diets of rat her radical nature. Day to day variations in blood sugars were approxi- mately the same as those observed in women during the inter- menstrual period.

Every precaution possible with a group of student sul.jects was taken to eliminate the effect of disturbing factors such as escite- ment, fatigue, etc. It is fully recognized, however, that the life

1 A detailed description of these diets will be given in a later paper. They were planned wit,h the idea of studying nitrogen metabolism at tlifier- ent levels of protein intake.

Diet I represented the ordinary mixed diet,, well balanced, but containing a comparatively small amount of protein. Meat was included, but the total protein aggregated 50 gm., with 250 gm. of carbohydrate.

Die& II was likewise well balanced, but it represented a somewhat higher level of protein intake (70 gm. of protein and 300 gm. of carbohydrate), was meat-free and contained very little purine.

Diet III contained 150 gm. of protein and 250 gm. of carbohydrate, with as little purine as could be obtained without limiting the intake to purified foodstuffs, or excluding necessary sources of vitamin.

Diet IV was designated as “low protein, purine-free.” It contained approximately 20 gm. of protein, with very little purine or creatine. The protein was, however, OF good quality and the diet was otherwise entirely adequate. Calories were in each case adjusted to the needs of the indi- vidual, largely through variation of the fat intake. All ictiets were very well tolerated, with the possible except,ion of Diet III in one case.

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170 Metabolism of Women. I

of the present day college woman lacks most of the elements of regularity which we require in the routine of existence of our laboratory animals. It has seemed, however, that the more intel- ligent cooperation which we have received from our student sub- jects has more than balanced the better control of activities pos- sible with institutionalized patients, who are usually not only not normal, physically, but either unwilling or unable to follow instructions.

The iactor of excitement can probably be considered to have been ruled out, very successfully. The young women were accustomed to act as subjects for various types of experimental work, and blood samples included in the series were, as a rule, obtained with a minimum of difficulty. The work of Foster (14) indicates, moreover, that emotional hyperglycemia with this type of subject is practically negligible, even where the taking of the sample involves considerable pain.

The effect of exercise was not so easy to eliminate. Blood sam- ples were taken from the members of Group I immediately after the measurement of basal metabolism, consequentSly they repre- sent resting values. The members of Group II came to the labora- tory, however, from a greater or lesser distance, and because of class schedules, it was not usually possible to secure a rest period before taking the samples. In most cases, nevertheless, it has been impossible for us to demonstrate any appreciably greater degree of day to day variation in samples taken from the subjects immediately after coming to the laboratory than in those who had a rest period before bleeding. This is, perhaps, not so contradic- tory to the findings of Rakestraw (15) as it may at first appear. His increases in blood sugar level were found only after quite short periods of very violent exercise in no way comparable to the more moderate, longer sustained exertion involved in the morning procedure of dressing and coming to the laboratory. Moreover, he has shown that very little change in blood sugar level is produced by long continued exercise.

Methods.

The blood samples were taken from the median veins in the arm, mixed with powdered lithium oxalate, and the protein precipi-

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R. Okey and E. I. Robb 171

tated according to the method of Folin-Wu (16). Analyses for sugar were made within the first few hours thereafter, by the improved method of Folin-Wu (17). Fresh glucose standards containing benzoic acid were made up, each week, and the old standard was analyzed against the new to check against any pos- sible deterioration. Every care was taken, also, to eliminate day to day variations in the method of procedure.

The sugar tolerance determinations were made according to a modification of the technique of Killian (18). The glucose used was Merck’s c. P. It was given in doses of 1.75 gm. per kilo of body weight, in 50 per cent solution, and without any preliminary meal. The amount of water taken at this time and subsequently during the test (usually 100 ml. per hour) was carefully measured. The possibility of blood dilution was checked by determinations of hemoglobin carried out according to the method of Cohen- Smith (19) as modified by Robscheit (20). Determinations of urine sugar were made by the method of Folin-Berglund (21). Creatine and creatinine were determined in blood and urine of the first five subjects in the tolerance series, but these determinations were afterwards abandoned as time-consuming and giving no significant results.

DISCUSSION.

Inspection of the data given in Tables I and II must lead to the conclusion that, whatever the influence of the menstrual cycle on carbohydrate metabolism, it is impossible to state positively, on the basis of “before breakfast” blood sugar determinations, that there is a uniform and consistent variation in the fasting level of blood sugar at any one phase of the monthly cycle in women. An attempt to summarize the results of a series of determinations, such as that given in Table III leads, however, to a suspicion that the time of t.he menstrual period may be marked by a greater degree of susceptibility to variation of blood sugar level than any other part of the cycle. The average menstrual value is slightly higher than the average intermenstrual value. If, in computing the normal average for each individual, we exclude figures obtained within 3 days before and 5 days after the onset of menstruation, we find that the greatest deviation from this average takes place within the menstrual period. If, however, we take as a “normal”

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172 Metabolism of Women. I

TABLE I.

Before Breakfast Blood Sugar Data of Group I.

Date.

193s

Sept. 29 Oct. 2

I‘ 4 ‘I 6 “ 10 “ 17 ” 24

Nov. 1 “ ! ‘I :

2 2 -f: 2 !a -

Per senl

,081

.09: .09: .09! ,095 .08 ,023.

1.10 I.09 1.0s -

T -- C.. me 24 yrs.

Date.

2933

kt. 12 “ 16 “ 17 “ 19 “ 23

19.%

ept. 5 “ 8 “ 11 “ 12 “ 13 “ 15 “ 18 “ 22 “ 25 “ 29

M. 3

“ 30

Jov. 3 “ 5 “ 6 “ 7 “ 8 “ 10 “ 12

1933

vov. 12 “ 13 “ 15

- : ‘ . : 7 .i : : c

-50 -10

00

+20 +60

-60 -30

00 +10 +20 +40 +70 -110 -140 -18 0 -22 0

-50 -20

00 SlO +2a +3a +5c +7c

oc +1c +3i(

Per cenl

.O% .09: .10: . 101 .lo(

.lO! ,101

.09:

.09!

.091 .09: .09; .OQ! OQ( ,098 .OQ‘

1.09 1.09, 1.09 1.10 I.10 I.10 I.10 I.09

j.10 b.10 I.09

F., age 31 yrs.

Date.

1924

Sept. 16 “ 18 “ 22 “ 25 1‘ “Q d

3ct. 3 “ 6 “ 9 “ 10 “ 11 “ 13 “ 16 “ 18 “ 21 “ 25 ” 27 (( 28 “ 29 “ 31

Jan. 18 (‘ 20 “ 23

) i l.5 is !2 2 1:

f t: t: -I(

--I (

+: f‘ -I-: + ' -II -1’ -1 -’ - - - -

- -

-

I.093 I.092 1.09: I.094 1.097 1.091 I.091 I.096 1.09: l.O9( I. 1Ot ).09f ).OQt 1.09: ) .oa ).OQt 1.09: ).08! ) .OQ:

1.08: ).lo( 1.w -

Remarks.

Constant Diet I.

Mixed.

Constant Diet II.

Purine- low.

Constant Diet III.

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R. Okey and E. I. Robb 173

TABLE I-Concluded.

II., age 24 yrs. c., age 24 yrs. I F.. age 31 yrs.

Date.

Nov. 22 “ 26

Dec. 3 “ r “ i “ 8 “ 10 “ 12

2 F!

Date.

B 0 a

_____

Per cent 1923

I.091 Nov. 17 1‘ 30

“ 22

I.080 Nov. 26 I.092 Dec. 3 I.090 “ 7 1.092 ‘[ 9 I.097 “ 10 1.088 “ 12 I.094 “ 14 3.093 (‘ 15

+: j( +I 1(

-I -l( )(

- li L( -1 7(

< !( -1 ( I(

+I L( +t 3( +1 5( St St

I.089 Jan. 25 j.090 “ 26 I.090 “ 28

“ 30 Feb. 2

“ 4 “ 6

I.095 “ 8 I.098 “ 13 I.097 “ 18 I.096 “ 19 I.101 “ 21 1.094 “ 23 I.099 “ 27 1.100 Mar. 3

“ 6 “ 8 “ 12 (‘ 13 “ 15 “ 17 “ 21

Per cent

1.093

I.094 ,099 .1oa

1.09E 1.09E 1.086 /.09c 1.09; 1. lOi

I.094 I.106 I.101 1 09; 1.08c I.094 1.094 1.09:

I ,085 1.082

-

Remarks.

High protein.

Purine- low.

Constant Diet IV.

Low protein.

Purine- low.

* The numbers in this column indicate days before (-) and days after (+) the onset of menstruation. Values for bloods taken during menstrua- tion are printed in bold faced type.

level, the average of all determinations for the individual in any given month, we find the average menstrual deviations slightly smaller. This is because we have not only higher, but also, fre- quently, lower values during menstruation than at any other time. It must be stated, unfortunately, that a set of averages made up in this way can hardly be taken as entirely representative, because

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Before Breakfast Blood Sugar Data of Group 1I. -

-

-

1

I -

-

N., age 29 yrs. Nd., age 31 yrs. Eb., age 24 yrs.

192s per cent Yov. 15 +2 0.096

‘( 17 $4 0.060 “ 20 +7 0.089

Dec. 10 -2 0.093

19.24 per cent

?eb. 8 -8 0.091 “ 15 -1 0.104 “ 16 0 0.100 “ 18 $2 0.102 “ 20 +4 0.096 “ 27 +ll 0.100

Mar. 12 0.095

1923

act. 31 -2 Nov. 3 +2

(‘ 5 +4 “ 7 $6 “ 16 +16 19.e/

Mar. 5 -12 “ 13 -4 “ 18 +l “ 19 +2 “ 21 $4 “ 24 +7

per cent

0.091 0.091 0.091 0.098 0.089

0.105 0.099 0.106 0.102 0.102 0.092

Pe., age 20 yrs.

19dS

Nov.20 -13 0.087 Dec. 4 fl 0.081

“ 6 +3 0.092 “ 8 $5 0.085

Pt., age 23 yrs.

Mb., age 22 yrs. -

-

1924

Feb. 11 “ 17 “ 21 “ 25

Mar. 3 “ 12 “ 17 “ 19 “ 21 “ 24

-10 0.090 -4 0.102

0 0.092

$4 0.106

+11 0.104 -5 0.093

0 0.094

+2 0.096 $4 0.091

+7 0.091

Ij., age 20 yrs.

0.104 0.092 0.087 0.093 0.093 0.095

-12

19%3

Nov. 10 “ 20 “ 22 “ 24 “ 26

Dec. 10

193.4

Mar. 12 0 0.100 “ 19 +7 0.100 “ 21 $9 0.100 “ 24 +12 0.102

X., age 22 yrs.

19t4

Feb. 18 -3 0.107 “ 21 0 0.096 “ 23 $2 0.099 “ 25 +4 0.098

Mar. 3 +ll 0.101

Ib., age 22 yrs.

lW6

Mar. 25 (‘ 28

-2 0

+2 +4

$19

PI., age 30 yrs. Pv., age 19 yrs.

T

-10 -4 -1

0

fl +2 +3 +4 $9

+11

0.084 0.094 0.093 0.080 0.089 0.100 0.092 0.085 0.093 0.092

19iB

Nov. 15 -13 0.093 “ 28 0 0.102 “ 30 +2 0.098

Dec. 2 +4 0.091 “ 5 +7 0.089

Nk., age 21 yrs.

192s

Oct. 17 “ 23 “ 26 “ 27 “ 28 “ 29 “ 30 “ 31

Nov. 5 “ 7

Feb. ‘7 “ 9

- * The numbers in this column indicate days before (-) and days after

(+) the onset of menstruation. Values for bloods taken during menstru- ation are printed in bold faced type.

174

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R. Okey and E. I. Robb 175

TABLE II-Continued.

Nk.-Concluded. Ib.-Concluded. Kp., age 34 yrs.

0

+1 +3 +7

fl4 -10 $2

per cent

0.098 0.103 0.098 0.084 0.084 0.098 0.096

-

$5 +7

+14 -8 -3

0 +2

-

-8 -3 -1

+1 +4 +7

+11 +I6

- & cent 1984

0.104 Sept. 1 0.105 (‘ 2 0 094 “ 4 0.117 “ 8 0.107 “ 15 0.096 “ 23 0.107 act. 1

1944

Feb. 11 “ 13 “ 20 “ 27

Mar. 3 “ 6 “ 8

19%

Apr. 1 “ 6 “ 8 “ 10 “ 13 “ 16 “ 20 “ 25

per cent

0.090 0.096 0.097 0.096 0.099 0.100 0.098 0.094

Hs., age 27 yrs. Di., age 21 yrs. Fe., age 19 yrs.

-8 0.089 -1 0.084 +1 0.091 f4 0.092

$6 0.085 +11 0.089 fl5 0.088

19.94

Sept. 23 “ 25 “ 27 “ 29

Oct. 3 “ 8 “ 17

196.5

Apr. 2 “ 9 “ 11 “ 14 “ 16 “ 21 “ 25

-9 0.103 -4 0.093

0 0.087

+1 0.102 +3 0.100 +6 0.095

+13 0.106 -6 0.098

0 0.101

$3 0.109

+8 0.092

-2 0

+2 $4 +8

t13

19.94

Sept. 1 “ 6 “ 10 “ 11 (‘ 13 “ 16 “ 23

Oct. 7 “ 13 “ 16 “ 21

age 22 yrs. Db., age 23 yrs. E. W

19.24

act. 3 “ 8 “ 13 “ 15 “ 18 “ 22 “ 27

-10 0.096 -6 0.089 +1 0.091

+4 0.096 +s 0.090

+I2 0.091 -10 0.090

-5 6.092 $1 0.101

f3 0.096

+6 0.114

19.24

Sept. 30 Oct. 3

“ 10 “ 13 “ 17 “ 21 “ 25 “ 30

Nov. 6 ‘( 8 “ 11

-10 -5

0

+2 +5 +9

+14

0.079 0.092 0.090 0.086 0.037 0.098 0.097

N.O., age 36 yrs.

1966

Mar. 19 “ 24 “ 26

4pr. 2 “ 9 “ 16

-14 0.095 -9 0.097 -7 0.093

0 0.089

+7 0.096 $14 0.094

Sp., age 28 yrs.

19.&i

Sept. 1 “ 16 “ 25 “ 30

-19 -14

-5 0

0.096 0.099 0.097 0.097

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176 Metabolism of Women. I

TABLE II-Concluded.

Sp.-Concluded.

19,4

Oct. 2 “ 9 “ 11 “ 33

“ 25 “ 28 66 99

“ 31 Nov. 3

“ 5 “ I1 1925

Jan. 29 Feb. 6

“ 10 “ 14 “ 16 “ 20 “ 25 “ 26

Mar. 3 (‘ 4 “ 6 “ 9

+2 +9

+11 1;

0

+1 +3 +6 $8

+13

per cent

0.096 0.099 0.087 0.097 0.091 0.096 0.093 0.090 0.101 0.096 0 084

-8 0 091 0 0.096

+4 0.098 +g 0.099

+10 0.095

+14 0 090 -7 0.093 -6 0 090 -1 0.098

0 0.099

+2 0.097

+5 0 098

-

Cs., age 20 yrs. Cr., age 25 yrs.

192.5

Jan. 26 “ 29

Feb. 3 “ 6 “ 10 “ 13 “ 17 (‘ 20 “ 21 6‘ 24

“ 27 Mar. 3

per cent 1924

0.098 Nov. 12 0.099 “ 19 0.102 “ 26 0.099 Dec. 4 0.103 “ 8 0 097 1

I

-21 -14

-7 0

+4

- per cent

0.092 0.103 0.107 0.094 0.105

0.093 1 Mbe., age 19 yrs. 0.104 ~ 0.106

1945

o og7 Jan. 27 “ 0.096 30

o og5 Feb. 3 “ 6

Fs., age 33 yrs. “ 10 “ 13

IS%5

Jan. 28 -10 Feb. 3 -4

CL 7 0 “ 9 +2 “ 14 +7 “ 18 $11 Cc 25 -5 “ 27 -3

Mar. 3 -1 “ 6 -4

“ 17 0.103 (‘ 20 0.098 “ 27 0.089 Mar. 3 0.087 “ 5 0.089 ~ 0.093 0.088 0.091 0.097 0.094

-2 0.091

-I-l 0.089 +5 0.094 +8 0 093

+12 0.099 -18 0.096 -14 0.097 -11 0.090

-4 0.092 0 0.089

+2 0.096

the number of intermenstrual determinations for some of the subjects was not large enough.

The t.olerance tests (see Table IV and Figs. 1 to 3), on the other hand, seem to give more conclusive evidence of cyclic variation. Inspection of the tables will show that the lowest peak of the blood sugar curves following the ingestion of 1.75 gm. of glucose per kilo of body weight came during or immediately

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R. Okey and E. I. Robb 177

before the menstrual period. The highest blood sugar values obtained for each individual were in the tests made just before or just after this time. This would seem to indicate that the mechanism by which glucose is removed from t,he blood stream is, in some way, altered at the time of menstruation.

TABLE III.

Summary of Results of before Breakfast Blood Sugar Determinations in Normal* Individuals.

Total No. of determinations included. . . No. of menstrual periods included.

“ “ subjects studied. . Average fasting blood sugar value. . .

“ intermenstrual value, . “ ‘I

menstrual value. of highest menstrual values for each period

observed Average of highest intermenstrual values for each

period observed. . Average of lowest menstrual values for each period

observed Average of lowest intermenstrual values for each

period observed. Average of greatest menstrual deviations from inter-

menstrual average Average of greatest intermenstrual deviations from

intermenstrual average. _. Average of greatest menstrual deviations from general

average. _,., ,..._._,_.__._.____._.._._,__.__. Average of greatest intermenstrual deviations from

general average _. . .

- 315 49 26 0.0949 per cent. 0.0941 -(L 0.0958 “

0.099 “

0.098 “

0 092 “

0.090 “

0.0067 “

0.0049 “

0.0056 “

0.0060 “

“

‘I

‘I

‘I

“

“

“

“

“

L‘

* The results of determinations made on bloods from Group III are omitted in computing these averages because there is some reason to believe that the individuals composing this group were not to be considered as normal.

Perhaps the most interesting and significant thing to be observed from these curves, is, however, the tendency to extremely low blood sugar values in the period from 1 to 2 hours after the inges- tion of the test amount of glucose, during menstruation. Subject N.O. gave blood sugar values at this time which approach the lower limits of the range which is considered clinically safe after the giv- ing of insulin. This subject had, however, no abnormally low

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TABL

E IV

.

Suga

r To

leran

ce

Data

. $ 00

Bl

ood

suga

r. He

mog

lobin.

Ur

ine

suga

rs.

lelati

or

to

1ens

tru

ation

.

0 :

hr.

1 hr

. lf

hrs.

2

hrs.

21

hr

s

-19

-14 -5

0

$2

$9

-tll

---

---

perc

ent

per

cent

pe

r-cen

t pe

rcen

t pe

rcen

t

0.09

6 0.

129

0 09

7 0.

100

0.09

9 0.

099

0.11

8 0.

105

0.08

2 0.

086

0.09

7 0.

161

0.09

3 0.

081

0.07

9 0.

097

0.13

5 0.

091

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R. Okey and E. I. Robb 181

5% 140

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FIG. 1. Tolerance curves. Ingestion of 1.75 gm. of glucose per kilo of body weight.

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182 Metabolism of Women. I “/b

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FIG. 2. Tolerance curves. Ingestion of 1.75 gm. of glucose per kilo of body weight.

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183

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Metabolism of Women. I

values for fasting blood sugar, and gave no history of physical abnormality. She did, however, complain of extreme hunger dur- ing the latter part of each of these test periods. Subject FE., who also responded to the tolerance test with very low blood sugar values, stated that she was always ravenously hungry during her menstrual periods. Questioning of a number of other subjects has, moreover, led to the conclusion that, in cases where men- struation was not accompanied by nausea or cramps, this tendency to unusual hunger 2 or 3 hours after a meal was often observed during the period. The hunger may possibly be associated with increased tonicity of the smooth musculature as a whole, and, according to Sevringhaus (22) considered as an accompanying factor rather than a result of the hypoglycemia. There is, on the other hand, a possibility that this delayed relief from hypoglycemia during the menstrual period, with the unusually low blood sugar values following the ingestion of the test carbohydrate, may indi- cate that the pancreatic response is in some way altered at this time. Again, the fact that the lowest minima were obtained for the oldest subjects (N.O., aged 36 years; and Fs., aged 32 years) may possibly have some significance.

The types of curves obtained just before and just after the menstrual periods hardly correspond to those accepted as typical of hyperthyroidism, in that the return to the fasting level of blood sugar is too rapid. During menstruation, moreover, there is a tendency to develop lower minima as well as maxima.

The writers feel inclined to think that the seemingly contradic- tory results of the previous investigators quoted may, perhaps, be explained by the fact that no one of them has ever made a suffici- ently large series of determinations on any one subject. There is, however, a possibility that the reaction of the normal individual to sugar ingestion, if it does involve added production of insulin or the need for added insulin during the menstrual period, may be radically different from the response of the person whose capac- ity for producing insulin is curtailed by disease. It is hoped that it may be possible, at a future time, to study the effect of menstruation on the threshold of ketosis.

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R. Okey and E. I. Robb

SUMMARY AND CONCLUSIONS.

On the basis of a total of more than 300 determinations of “before breakfast” blood sugar, covering 49 menstrual periods in 26 normal women there seems to be no ground for conclusion that there is a consistent cyclic variation in the fasting blood sugar level in women. The average values observed during menstruation are slightly higher than those for the intermenstrual period. How- ever, there are a greater number, not only of high values, but also of low values, during the menstrual period than at any other time. Hence it is believed that, in making single determinations of blood sugar for purposes of clinicjl diagnosis, the time of the menstrual period should, in as far as possible, be avoided. This conclusion is borne out by a limited number (approximately 50) of additional observations on subjects not to be rated as strictly normal physically.

The ingestion of 1.75 gm. of glucose per kilo of body weight has, however, led in the ten cases observed, not only to smaller initial increases in blood sugar, but also to a greater degree of secondary hypoglycemia during the menstrual period than at any other time of the month. The effect noted immediately before and immc- diately after this time is jL-st the opposite, i.e. a lessened toler- ance, while the ingestion of glucose in the intermenstrual period has an intermediate effect. This smaller increase and greater decrease in blood sugar following glucose ingestion during men- struation suggesbs an altered functioning of the pancreas, coincid- ent with the time of menstruation. Speculation as to whether or not this is t’he result of an altered ovarian or suprarenal secretion seems hardly justified by the evidence at hand.

BIBLIOGRAPHY.

1. Corner, G. W., Physiol. Rev., 1923, iii, 457. 2. Marshall, F. H. A., Physiol. Rev., 1923, iii, 335. 3. Jacobi, M. P., Boylston prize essay, New York, 1876. 4. Riddle, O., and Honeywell, H. E., Am. J. Physiol., 1923, lxvi, 340. 5. Riddle, O., Am. J. Physiol., 1923, lxvi, 322. 6. Papanicolaou, G. N., Proc. Sot. Exp. Biol. and Med., 1924-25, xxii, 106. 7. Belfield, W. T., J. Am. Med. Assn., 1924, lxxxii, 1237. 8. Kahler, H., U’ien. klin. Woch., 1914, xxvii, 417. 9. Hoffmann, E., 2. Path. u. Therap., 1914, xvi, 337. exp.

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Metabolism of Women. I

10. Folin, O., and Berglund, H., J. Biol. Chem., 1922, li, 213. 11. Berglund, H., and Ni, T. G., J. Biol. Chem., 1925, lxiii, p. xlviii. 12. Rosenbloom, J., J. Am. Med. Assn., 1921, lxxvi, 1742. 13. Harrop, G. A., Jr., and Mosenthal, H. O., Bull. Johns Hopkins Hosp.,

1918, xxix, 161. 14. Foster, G. L., J. Biol. Chem., 1923, Iv, 303. 15. Rakestraw, N. W., J. Biol. Chem., 1921, xlvii, 565. 16. Folin, O., and Wu, H., J. Biol. Chem., 1919, xxxviii, 81. 17. Folin, O., and Wu, H., J. Biol. Chem., 1920, xli, 367. 18. Killian, J. A., Proc. Sot. Exp. Biol. and Med., 1919-20, xvii, 91. 19. Cohen, B., and Smith, A. H., J. Biol. Chem., 1919, xxxix, 489. 20. Robscheit, F. S., J. Biol. Chem., 1920, xii, 209. 21. Folin, O., and Berglund, H., J. Biol. Chem., 1922, li, 269. 22. Sevringhaus, E. L., J. Biol. Chem., 1925, lxiii, p. xlviii.

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Ruth Okey and Elda I. RobbTO THE MENSTRUAL CYCLE

IN SUGAR TOLERANCE IN RELATION FASTING BLOOD SUGAR LEVEL AND

WOMEN: I. VARIATIONS IN THE STUDIES OF THE METABOLISM OF

1925, 65:165-186.J. Biol. Chem. 

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