Paper - A quantitative study of the hypophysis of the human anencephalic fetus

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Covell WP. A quantitative study of the hypophysis of the human anencephalic fetus. (1927) Am J Pathol. 3(1) :17-28. PMID 19969726

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This historic 1927 paper by Covell describes the hypophysis of the human anencephalic fetus.




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A Quantitative Study of the Hypophysis of the Human Anencephalic Fetus

W. P. Covell.

From the Department of Anatomy, University of M innesota, M innoapolis, Minn.

Introduction

The question of the presence or the absence of the hypophysis in the anencephalic fetus has been of special significance in connection with the subject of the function and interrelationship of the ductless glands. Some have even attributed this abnormality to a disturbance of the endocrine system. Previous to 1921 the general belief was that an hypophysis was frequently absent in anencephalics and when present was usually described as being diflerent from the normal gland. No quantitative methods have been applied, consequently the literature is based on qualitative observations only.

It is the purpose of this investigation to apply quantitative methods to these abnormal specimens and when the organ is present to compare it with that of the normal. In order to bring the subject to its present status the principal contributions are summarized below.

Review of the Literature

Ballantyne 1 has described forty-five anencephalic fetuses and states that “ the hypophysis rarely occurs.” Schwalbe 2 says the hypophysis is sometimes present and in a large number of cases there is accessory hypophyseal tissue. Haberfeld 3 examined three cases of anencephaly and reported an hypophysis as present in each. In one instance a pars nervosa was found in the upper part of the cralnio-.

pharyngeal canal. The glandular portions, in this instance,‘ extended through the canal and only a small polyp was present at either end. Brown 4 examined five specimens of anencephalic fetuses and failed to find the hypophysis. He concluded, therefore, that the condition

of apituitarism was normal for anencephaly. Mauksch 5 found an hypophysis in nine cases of this monstrosity. In five of these, he described a pharyngeal hypophysis with a par ‘ Received for publication September 28, 1926.

tially or totally patent craniopharyngeal canal which contained blood vessels and hypophyseal tissue. All three lobes were present in only two of the nine glands. When there was no posterior lobe (pars nervosa), he did not observe a pars intermedia and thus considered the hypophysis in such cases to consist of pars anterior only. In one instance he found the upper surface of the connective tissue capsule to contain a small neuroglial structure which was in contact neither with the brain tissue nor with the hypophysis. There was no intermediate glandular portion discernible. In two of the specimens the pars nervosa was found to be a small basophilic structure of neuroglial elements located on a concavity of the glandular part. He noticed a pars intermedia in contact with the latter but thought it appeared abnormal and incomplete. He found the pars anterior to be very vascular and the parenchyma in the form of cords surrounded by sinuses filled with blood.

Kohn 5 verified the report of Mauksch 5 as to the occurrence of the hypophysis. He investigated eleven cases of anencephaly and found an hypophysis in each. He likewise found the gland to be abnormal in structure. In only three of the specimens did he find a pars nervosa. He concluded that the pars intermedia and pars nervosa as well as the pars tuberalis are usually lacking. If the pars nervosa was not present, he thought the intermediate lobe was also absent. He reported that the cells of the pars anterior were normally differentiated. In addition he described a cell which he thought occurred but seldom in the normal fetal hypophysis. According to him, this latter mentioned type was present in large numbers in the anencephalic hypophysis. Such a cell type appeared to be larger than the chromophile cells and stained slightly basophilic or neutrophilic with Mallory’s triple connective tissue stain.

Wrete 7 found a hypophysis to be present in a case of encephalomyeloschisis totalis of an embryo of the seventh week. ‘

Material and Methods

The material used in this study consisted of thirty-two anencephalic fetuses which were obtained from the Department of Pathology, University of Minnesota. Most of the material had been previously preserved in IO per cent formalin in which it had remained for a year or more in some instances.

Twenty-seven of the thirty-two fetuses were females, the remaining five being males. They ranged in age from about the fifth fetal month to full term. The ages of the fetuses were determined by means of a formula used by Nafiagas 3 for conversion of the leg length (distance from the greater trochanter to the base of the heel) of the anencephalic fetus into total body length of a normal fetus. Then by applying to the result the formula of Scammon and Calkins 9 for converting the crown-heel measurement into terms of age in fetal months, the latter was determined. The formula given

by Nafiagas is as follows:

Crown-heel (cm.) = 3%: leg length (cm.) + 0.7

The formula developed by Scammon and Calkins gives the age in fetal months or “T” when “L” is the crown-heel measurement in centimeters.


The relative and absolute volumes of the parts of the gland were determined by the paper-weight method as described by Rasmussen and Herrick.” For a comparison of the abnormal with the normal gland, data available (Covell 11) on the hypophyses of sixty-two normal fetuses were used.

The relative amount of blood in the pars anterior of the hypophysis was approximated by projecting areas of sections 10 microns thick of this portion of the gland at a magnification of about 7 50 times. five fields were chosen on each of three different levels, two of the fields being near the periphery of the gland, one centrally located and the remaining two intermediate between the periphery and central parts. The vascular areas in each of the fields were outlined with a hard lead pencil. The relative amount of blood in the pars anterior was then ascertained by weighing the paper areas representing the blood and those representing the fibrous and glandular tissue, and dividing the weight of the vascular areas in paper by the total paper—weight.

For the normal gland, a section approximately one-half of the way through the gland was used and five fields were outlined on it. The relative volume of the blood was found to be very nearly identical withfthat determined by the use of the three levels and the fifteen fields.

General Description of the Hypophysis

Of the thirty-two specimens of the anencephalic fetus examined, an hypophysis was present in each instance. Such findings are in accordance with the more recent investigations on this monstrosity but in contradiction to the earlier work. It would appear that the earlier work was of a gross nature so that the small amount of hypophyseal tissue which lies on the malformed basis cranii may have been overlooked.

The hypophyseal fossa is usually lacking or at the most only feebly developed. No trace of the clinoid processes or dorsum sella is evident. Occasionally the anterior clinoid processes are slightly developed and so form a narrow fossa for the most anterior portion of the gland. A diaphragma sella is lacking, probably because of the absence of the clinoid processes.

The hypophysis may then be said, to lie on a flattened sella turcica covered over by membranes, vascular tissue and in some instances a small amount of brain tissue. Macroscopically it presents a flat triangular shape with the apex directed dorsally. The base of this mass is formed by two lateral spreading portions and the apex of one central mass. Such a shape no doubt is of embryologic significance because it is known that the glandular portion (pars anterior) grows in early fetal life by means of two lateral and one central buds from the ventral side of Rathke’s pouch. This form subsequently changes in the course of normal development because the gland soon approximates the shape of the fossa in which it is situated. Macroscopically, the neural elements (pars nervosa) of the gland, when present, appear as an irregularly shaped opaque mass on the dorso— posterior surface of the larger glandular portion. An infundibular stalk is lacking and only a thin cord of membrane remains to attach the gland to the overlying tissues. Microscopically, the hypophysis of the anencephalic fetus presents several striking differences when compared with the gland from the normal fetus. In the first place, the three lobes may not all be present. In only six of the seventeen specimens studied did the hypophysis consist of three lobes. In eleven instances there was no pars nervosa evident. In four of the latter a pars intermedia could be distinguished, whfle in the remaining seven the pars anterior appeared to comprise the total gland volume.

The extreme vascularity of the gland, particularly of the pars anterior, presents a marked difierence from that of the normal. Especially about the periphery of the anterior lobe the sinuses are dilated to such an extent that the parenchyma is reduced to narrow epithelial cords which appear to be surrounded by blood spaces. Toward the center of the pars anterior, the sinuses are usually less dilated with blood.

Trabeculae radiate through the pars anterior and contain numerous blood vessels. Occasionally there is a band of fibrous tissue separating the main bulk of the anterior lobe from the thin epithelial strip which borders the hypophyseal cavity. Likewise the pars intermedia may be separated from the pars nervosa by a thin band of fibrous tissue. The capsule of connective tissue about the gland is well developed and appears to be more extensive than in the normal hypophysis.

Relative and Absolute Volumes of the Gland and its Parts

A. Weight of the total gland. In Table I are given the absolute volumes of seventeen hypophyses and their lobes. It is evident that there is considerable individual variation in the total weight of the gland for fetuses of about the same age. The six observations for fetuses of the fifth to the sixth fetal months have a range of 29. 3 to 69.6 mg. and an average of 42. 3 mg. The range as observed from six specimens of the sixth to the seventh fetal months is 29.2 to 85.6 mg. with an average of 58.5 mg. Four hypophyses from fetuses of the seventh to the eighth fetal months show a range of 3 5.0 to 7 3.8 mg. and an average of 5 5.1 mg. The intervals from the eighth fetal month to birth are represented by only one observation. The age of the latter was calculated as 10.16 fetal months and the hypophysis weight was found to be 113.2 mg.

B. Weight of the pars anterior. Considerable variation is likewise evident in the weights of the pars anterior. For the fifth to the sixth months, the range is 29.3 to 65.4 mg. and the average is 40.9 mg. The weights of this lobe in specimens of the sixth to the seventh fetal months show a range of 28.9 to 85.6 mg. with an average of 57.8 mg. From the seventh to the eighth fetal months, the range is 34.6 to

TABLE 1

Absolute Volume of the Gland and its Parts in Seventeen Specimens of Anencephaly

Leg r£‘(’)‘tl:’l Age in Hygggh- a.I:1l:::l§0l' ncfrgssa Case number Sex length length fetal weight weight weight weight on computed months mg. mg. mg. mg. cm. c9 . . . . . . . . . . . . . . F 10.2 | 25.34 5.38 38.0 36.6 0.9 0.5

c2 . . . . . . . . . . . . . . M 10.7 26.51 5.56 41.6 40.8 0.8

CIO . . . . . . . . . . . . . F 11.0 27.20 5.66 37.3 37.3 . . . . . .

c4—17 . . . . . . . . . . . F 11.4 I 28.14 5.81 69.6 65.4 2.5 1.7

c23—184 . . . . . . . . . F 11.7 28.83 5.93 29.3 29.3 . . . . . .

c4 . . . . . . . . . . . . . . F 11.7 I 28.83 5.93 38.4 36.1 1.3 1.0

c23—183 . . . . . . . . . F 12.0 29.53 6.05 72.7 69.5 2.3 0.9

c7 . . . . . . . . . . . . . . F 12.7 | 31.16 6.32 50.4 50.4 . . .

c1 . . . . . . . . . . . . . . F 12.9 31.63 6.39 29.2 28.9 0.3

c6 . . . . . . . . . . . . . . M 13.1 32.09 6.47 41.2 40.3 0.9

c8 . . . . . . . . . . . . . F 13.2 32.33 6.51 85.6 85.6

cm . . . . . . . . . . . . . F 13.7 33.49 6.72 72.2 72.2

c15 . . . . . . . . . . . . . M 14.5 35.35 7.05 68.9 68.9 . . .

c3 . . . . . . . . . . . . . . F 14.6 35.58 7.08 35.0 34.6 0.4

c5 . . . . . . . . . . . . . . F 15.5 37.67 7.47 42.9 41.4 1.5 . . .

CI4 . . . . . . . . . . . . . F 16.6 40.23 7.95 73.8 71.4 2.0 0.4

c4—18 . . . . . . . . . . . F 21.2 50.93 10.16 113.2 106. 1.6 5.3 TABLE 2

Relative Volumes of the Lobes of the Anencephalic Hypophysis


Case number I 3 in Pars anterior Pars inter-media Pars nervosa etal months per cent per cent per cent c9 . . . . . . . . . . . . . . . . . . . . . . . 5 38 96.33 2 36 1 31

c2 . . . . . . . . . . . . . . . . . . . . . . . 5 56 98.08 1 92

c4—17 . . . . . . . . . . . . . . . . . . . . 5.81 93.97 3.59 2.44

c4 . . . . . . . . . . . . . . . . . . . . . . . 5.93 94.01 3.39 2.60

c23—183 . . . . . . . . . . . . . . . . . . 6 05 95.58 3 14 1.28

c1 . . . . . . . . . . . . . . . . . . . . . . . 6 39 98.97 1 03

c6 . . . . . . . . . . . . . . . . . . . . . . . 6 47 97.82 2 18

c3 . . . . . . . . . . . . . . . . . . . . . . . 7 08 98.86 1 14

c5 . . . . . . . . . . . . . . . . . . . . . . . 7.47 96.50 3 50 . .

c14 . . . . . . . . . . . . . . . . . . . . . . 7.95 96.75 2 71 0.54


71.4 mg. and the average is 54.1 mg. In the one gland of a fetus of 10.16 fetal months the weight of the pars anterior is 106.3 mg.

C. Weights of the partes intermedia and nervosa. The absolute volumes of the partes intermedia and nervosa are of very little significance because of the extreme variations. They are, however, of importance for a comparison with the normal Weights.

D. Relative volumes of the parts (lobes). The relative volumes of the various lobes of the hypophysis are given in Table 2. Because of the limited number of cases and the apparent irregularities in the partes intermedia and nervosa, the relative volumes will be con 3 sidered without respect to fetal age. The anterior lobe comprises about 93.9 to 1oo per cent of the total gland volume. In the eleven instances in which a pars intermedia was present, it is seen to comprise 1.14 to 3.59 per cent of the total gland Weight. The pars nervosa which occurs in only six of the seventeen cases varies in relative volume from 0.54 to 4.69 per cent. From the above percentage values it is evident that most of the hypophysis is pars anterior and only a small part is intermediate and posterior lobes. In only one instance does the pars nervosa exceed the pars intermedia in relative as well as absolute volume.

Volumetric Analysis of the Pars Anterior

A. Relative volume of the blood. Because of the engorged sinuses of the pars anterior and the prominent trabeculae, it was found necessary to determine the relative amounts of each. This was accomplished by means of the paper-weight method as already described. The results are tabulated in Table 3. The figures for the relative vascularity appear to vary from about 2 5 to 50 per cent for individual estimations. The average for the fifteen determinations is 38.98 per cent.


B. Relative volume of the trabeculae. The relative amounts of trabeculae present in the gland range from about o. 5 per cent to nearly 4 per cent. The average for the series is 1. 58 per cent. This figure represents only the larger masses of fibrous tissue in the pars anterior. The finer connective tissue framework is included with the percentage figure for the parenchyma, the average for which is 59.44 per cent of the volume of the pars anterior. The range is approximately 45 to 77 per cent.


It is thus obvious that considerable of the absolute volume of the anterior lobe is due to the presence of blood in the sinuses. From the relative averages cited above, it may be said that approximately two-fifths of this part of the gland is composed of vascular and fibrous stroma. The remaining three-fifths is comprised of parenchyma and finer fibrous stroma. Such an analysis is of value in determining the actual amount of glandular tissue which is present. The large amounts of blood apparently influence the volume of the anencephalic hypophysis to a marked degree.


TABLE 3

Volumetric Analysis of the Components of the Pars Anterior


Case number U Blood Trabeculae filll) (1_"g1b°:)Yu:“;;'§ga I fier cent per cent per cent c9 . . . . . . . . . . . . . . . . . .8 . . . . . . . . . . . . 38.18 3.98 57.84

c2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .' 40.37 V 0.49 59.14

c4—17 . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.81 2.02 54.17

c4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 37.83 1.12 61.05

c23—183 . . . . . . . . . . . . . . . . . . . . . . . . . 36.71 2.34 60.95

c7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34.48 1.03 64.49

c1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.56 1.40 77.04

c6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46.67 0.75 52.58

c8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.00 2.16 44.84

cm . . . . , . . . . . . . . . . . . . . . . . . . . . . . . 40.05 0.97 58.98

c15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37.81 1.59 60.60

c3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27.22 1.46 71.32

c5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.93 1.47 59.60

cm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36.63 2.00 61.37

c4-18 . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.46 0.97 47.57

Mean . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.98 1.58 59.44


Discussion

The shape of the anencephalic hypophysis is in contrast to the normally developed fetal hypophysis. Apparently the hypophyseal fossa plays an important role in determining the form and dimensions of the normal fetal gland. Since this fossa is lacking or at the most only feebly developed in anencephaly, the hypophysis is flattened and spreading. For this reason it is obvious that the flattened surface might permit the gland to keep its earlier fetal shape as it appears to do. The gland of the normal fetus is known to consist of three lobes and, in addition to the main body of the gland, a pars tuberalis. Likewise the. hypophysis of the anencephalic may be comprised of three lobes but not a pars tuberalis. It has been shown that a pars nervosa occurred in only six of the seventeen cases. The anterior lobe may then be said to form the main bulk of the hypophysis. The pars intermedia of this abnormal gland may or may not be present. The residual lumen (hypophyseal cavity) likewise is not always in evidence. The lobes of the hypophysis may appear qualitatively similar to the normal (with the exception of vascularity and fibrous tissue of the pars anterior) but vary considerably in quantity both relative and absolute.


TABLE 4

A Comparison of the Observed Average Values for the Weight of the Anencephalio H ypophysis with that of the Normal Fetal H ypophysis According to Age in

Fetal Months . Weight of the anen- . Weight of the normal Differences in Age 1“ fetal Num_ cephalic hypophysis . Num_ fetal hypophysis weight between m°nth5 be, of mg. be, of mg. anencephalic cases and normal fetal hypophyses Range Mean mg.

8 16.o— 41.3 30.1 +12.2 16 3o.2— 52.7 42.4 +16.1 12 42.4— 62.3 55.5 — 0.3 13 58.2-121.2 81.2 . . . 12 78.5—13o.1 95.6

1 112.6 112.6 + 0.6



Tables 4 and 5 illustrate by a comparison of observed averages the absolute volumes of the normal and abnormal gland. The total weight of the abnormal hypophysis for the fifth to the sixth fetal months exceeds the weight of the normal gland by 12.2 mg. When the average weight is corrected for blood in the pars anterior it checks with the corrected weight value for the normal. The average weight for the sixth to the seventh fetal months is greater than the normal by 16.1 mg. When these averages are corrected for vascularity, the anencephalic exceeds the normal weight by 0.65 mg. The absolute averages for the seventh to the eighth fetal months are about the same. The corrected values show the normal to be more than the anencephalic hypophysis in volume by 13.57 mg. Since there are no specimens between the age limits of the eighth and the tenth fetal months, a comparison is not justified. The weight of the postmature specimen is about the same when compared with a normal of the same age. After correction for vascularity the normal exceeds the total weight of the gland in anencephaly by 26.3 mg.



TABLE 5

A Comparison of the Average Total Weight of the Anencephalic H ypophysis with the Normal Fetal Hypophysis after each has been Corrected for Vascularity

Observed average


. . Qbserved av e Age in fetal weights of the a_ne1_1- weights of the normal Rggfggzsebigréiig m°nth5 Num- cephahc hypophysls Num- hypophysis as corrected for vasber of ’'‘3- ber of _r "'15- _ cularity of the anencases I cases cc hahc and normal Range Uncor- Corrected etal hypophyses rected mg. 5 to 6 . . . . . . 6 8 30.10 26.35 =*= 0.00 6 to 7 . . . . . . 6 16 42.4 35.45 + 0.65 7 to 8 . . . . . . 4 12 55.5 47.77 -13.57 8 to 9 . . . . . . 13 81.2 67.89 ... . 9 to 10 12 95.6 79.93 10.16 . . . . . . . 1 1 112.6 98.12 -26.32 TABLE 6

Relative Volume of the Blood in the Pars anterior of the Normal Fetal H ypophysis

L: 1— 4- 1

Relative volume

Necropsy number Total bcoiy length Rela.(§vtelc:r.0:(Eume o tgr?°:f . ,, W mu 24-165 . . . . . . . . . . . . . . . . . . . . . . . . . . 28.0 17.97 82.03

24-25 . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.0 12.15 87.85

24-24 . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.0 9.86 90.14

23-849 . . . . . . . . . . . . . . . . . . . . . . . . . . 39.0 26.87 73.12

22-323 . . . . . . . . . . . . . . . . . . . . . . . . . . 45.0 10.74 89.26

24-795 . . . . . . . . . . . . . . . . . . . . . . . . . . 45.5 18.82 81.18

24-72 . . . . . . . . . . . . . . . . . . . . . . . . . . . 46.0 16.71 83.29

23-224 . . . . . . . . . . . . . . . . . . . . . . . . . . ‘ 49.0 12.12 87.88

1746 . . . . . . . . . . . . . . . . . . . . . . . . . . .. 51.5 21.36 78.64

23-408 . . . . . . . . . . . . . . . . . . . . . . . . . . 55.0 16.41 83.59

23-535 . . . . . . . . . . . . . . . . . . . . . . . . . . 60.0 17.13 82.87

Mean . . . . . . . . . . . . . . . . . . . . . . . . . 16.40 83.60


It is obvious that if the amount of blood in the pars anterior be considered, the gland of the abnormal fetus usually is less in weight than the normal from a fetus of corresponding age. The same conclusion holds for the weights of the anterior lobes of normal and abnormal fetuses. The average relative amount of blood present in the normal fetal hypophysis is 16.4 per cent for eleven determinations. This figure is nearly two and one-half times less than the average for the pars anterior of the anencephalic gland.

Summary

The results obtained by this study may be summarized as follows:

1 . An hypophysis is present in anencephalic fetuses.

2. It is extremely variable in weight. If the weight is corrected for vascularity it is usually less than the weight of the normal fetal hypophysis which has also been corrected.

3. The pars nervosa is lacking in the majority of cases. When present its relative and absolute volumes are considerably less than those of the normal.

4. The pars intermedia is variable in both occurrence and volume. It may be present in a gland in which there is no pars nervosa in ‘evidence.

5. The pars anterior comprises most of the gland volume and apparently the total gland volume in some instances.

6. The average relative volume of blood present in the anterior lobe is about 39 per cent of the volume of that lobe.

The writer wishes to acknowledge his indebtedness to Professors R. E. Scammon and A. T. Rasmussen for their many valuable suggestions during the course of this study.

References

1. Ballantyne, A. Manual of ante-natal pathology. Edinburgh, 1902-04.

2. Schwalbe, E. Die Morphologie der Missbildungen des Menschen und der Tiere. Jena, 1909, iii, 108.

3. Haberfeld, W. Zur Pathologie des Canalis craniopharyngeus. Frankfurt. Ztschr. f. Path., 1910, iv, 96. 28

IO.

II.


Brown, F. J. The anencephalic syndrome in its relation to apituitarism. Edinburgh Med. J., 1920, N. S. xxv, 296.

Mauksch, H. Das Verhalten der Hypophyse und des Canalis craniopharyngeus in neun F iillen von Kranioschisis untersucht. Anat. Anz., 1921, liv, 248.

Kohn, A. Anencephalie und Nebenniere. Arch. f. milero. Anat. u. Entwcklngsmechm, I924, cii, 113.

Wrete, M. Ein Fall von Encephalo-Myeloschisis totalis bei einem menschlichem Embryo in der 7. Woche der Schwangerschaft. Ztschr. f. mikro. Anat. Forsch., I924, i, 563.

N afiagas, J: C. A comparison of the growth of the body dimensions of anencephalic human fetuses with normal fetal growth as determined by graphic analysis and empirical formulae. Am. J. Anat., I92 5-26, xxxv, 45 5. Scammon, R. E., and Calkins, L. A. Simple empirical formulae for expressing the lineal growth of the human fetus. Proc. Soc. Exper. Biol. and Med., 1922-23, xx, 353.

Rasmussen, A. T., and Herrick, R. A method for the volumetric study of the human hypophysis cerebri with illustrative results. Proc. Soc. Exper. Biol. and M ed., I921-22, xix, 416.

Covell, W. P. Quantitative studies on the human prenatalhypophysis and hypophyseal fossa. (Abstract.) Anat. Rec., 1926, xxxii, 23o.



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