Paper - Anatomical evidence of prenatal function of the human parathyroid glands

Ref-Norris1946a

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Watt JC. Description of two young twin embryos with 17-19 paired somites. (1915) Contrib. Embryol., Carnegie Inst. Wash. 2: 15-54.

Online Editor Note

This historic 1946 paper by Norris is an early description of the development of thuman parathyroid glands. See also by same author: Norris EH. Anatomical evidence of prenatal function of the human parathyroid glands. Obstetrical and Gynecological Survey, April 1947, Vol.2(2), pp.145-146 Endocrine Links: Introduction | BGD Lecture | Science Lecture | Lecture Movie | pineal | hypothalamus‎ | pituitary | thyroid | parathyroid | thymus | pancreas | adrenal | endocrine gonad‎ | endocrine placenta | other tissues | Stage 22 | endocrine abnormalities | Hormones | Category:Endocrine Historic Embryology - Endocrine   1903 Islets of Langerhans | 1903 Pig Adrenal | 1904 interstitial Cells | 1908 Pancreas Different Species | 1908 Pituitary | 1908 Pituitary histology | 1911 Rathke's pouch | 1912 Suprarenal Bodies | 1914 Suprarenal Organs | 1915 Pharynx | 1916 Thyroid | 1918 Rabbit Hypophysis | 1920 Adrenal | 1935 Mammalian Hypophysis | 1926 Human Hypophysis | 1927 Adrenal | 1927 Hypophyseal fossa | 1930 Adrenal | 1932 Pineal Gland and Cysts | 1935 Hypophysis | 1935 Pineal | 1937 Pineal | 1935 Parathyroid | 1940 Adrenal | 1941 Thyroid | 1950 Thyroid Parathyroid Thymus | 1957 Adrenal

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Anatomical Evidence of Prenatal Function of the Human Parathyroid Glands

ANATOMICAL EVIDENCE OF PRENATAL FUNCTION OF THE HUMAN PARATHYROID GLANDS

EDGAR H. NORRIS

Department of Anatomy of the School of Medicine of Waslzington University, St. Louis, Missouri and ‘the Lynn Clinic, Detroit, Jlichvigan

NINE FIGURES

Probably more than any other scientist, the embryologist appreciates the fact that the individual begins his independent life long before birth. The embryologist knows that a man’s life commences with conception and that from the moment at which the ovum is fertilized there begins the long and everhazardous struggle to maintain life through necessary adjustments to ceaseless environmental change. During the intrauterine period the individual grows at an almost incomprehensible pace, in this epoch of 9 brief months increasing his weight by two billion times! During gestation not alone is mass remarkably multiplied, but structure is intricately differentiated, and functional adaptations directed toward the establishment of the indiVidual’s complete physiological independence are made. Sometime in the third week the embr_vonic heart begins to beat and the blood commences to circulate; before the end of the third month the skeletal muscles start to contract; and a little later the kidneys begin to secrete. In this paper I will submit anatomical evidence arguing strongly for the idea that the embryo may also begin the independent regulation of certain phases of its eliemistry at a very early date.

Some years ago I completed a study of 447 human parathyroid glands in 139 embryos, fetuses, and newborns (Norris, ’37).‘ The individuals in this series were rather evenly distributed throughout the gestational period and they provided bountiful material for my observations, which extended from a time prior to the appearance of the parathyroid glands to birth. At that time my observations led me to contend rather timorously for the early functionability of the parathyroid glands. Extensive studies since 1937, including my own analysis of function deduced from histologic structure and the correlation of structure with chemical. activity in pathologic states, have seemed to confirm that prior opinion. In the following paragraphs I will review the findings recorded in my communication of 1937 that seem pertinent to the present thesis. Undoubtedly there are several reasons Why the recognition of function by anatomic evidence in the endocrine tissues of the human embryo and fetus will be important. From the nature of things, however, it is not possible to experiment directly with_ the human embryo, and our knowledge of the intrauterine physiology of the individual must be built up from fragments that may be correlated with other processes and that may be tested by controlled experiments in animals.

The earliest recognizable indication of parathyroid tissue is found in the walls of the third and fourth endodermal gill pouches during the fifth week of gestation when the embryo is approximately 9 mm in length. Prior to the sudden appearance of the primordia of parathyroids III and IV, the endodermal cells lining the embryonic pharynx and its branchial pouches are quite the same in their microscopic characteristics. The earliest indication of the parathyroid is a localized differentiation of certain cells in the pouch wall (Weller, ’33). The cells multiply and as a result of the localized proliferation of histologically differentiated cells, a solid budlike nodule is produced. These cells of the early

‘The collection of embryos and fetuses of the Department of Einbryology, Carnegie Institution of Washington, Baltimore, supplemented by specimens from

the Departments of Pathology and Anatomy of the University of .\{inm>sntn was used. See Tabulation of Material, Norris, ’3T.

parathvroid priinordium, from the 1nome11t of their first appearance, are in all morphological respects quite the same as one of the cytological elements commonly found iii the parathyroids of postnatal life.

Even in the initial stage of the glancl’s development, the cells of the parathyroid are readily recognized, for they are large—10 to 1-1 microns in diameter, are relatively clear with sharply demarcated polygonal outlines and possess cytoplasm that is but lightly tinted by acid stains. They contrast strikingly with the smaller, dark, less well outlined cells of the pharyngeal endoderm. The nuclei, measuring 6 to 8 microns in diameter, are round, ovoidal, or somewhat angular centrally placed bodies containing several blocks of chromatin. At first the cells are packed closely together, but because of their less deeply staining cytoplasm, the structure of the developing parathyroid appears to be relatively less dense than that of other epithelial tissues in the same region (fig. 1, 2, 3 a11d 4). This primordial cell is characteristic and is the only parenchymal cytological element found in the parathyroid during the first half of the intrauterine period. It will be referred to in these pages as the primordial cell (fig. 2, 3 and 4).

A second type of cell is observed toward the latter part of the first half of the gestational period. This cell is characterized by greater or lesser degrees of vacuolization of its cytoplasm; therefore it is called the vesicular cell (figs. 5 and 6). In general, some enlargement of the cell tends to parallel the increasing amount of vacuolization; consequently vesicular cells are on the average somewhat larger than primordial cells. Evidence has accumulated to indicate that vesicular eells are associated with increased function of the parathyroids. Vesicular cells often predominate in the parenchyma of hyperfunctioning adenomas (Norris, ’-16) and in secondarily l1ype1'plastic glands (Castleman and Mallory, ’35).

A third cell type was observed earliest in the parathyroid of a fetus 115 mm long. A relatively large cell that measures 15 to 24 microns in diameter, that is outlined by a remarkably 132 EDGAR. H. NORRIS

distinct cell wall, and whose cytoplasm takes no tint——o1' only the faintest possible tint —-with acid stains, is present. The nucleus of this cell is eccentrically located, measures about (5 microns in diameter, and possesses a structure characterlstically more dense than that of the primordial cell. This is the clear cell (fig. 5). It has also been observed in the glands of several older fetuses. Clear cells tend to occur in groups although less commonly they may stand as isolated cells. It is apparent that there are transitional forms (Vesicular cells) between the primordial cell and the fully formed clear cell. VVl1en the fetus is in the mid-gestational period, another kind of transformation begins in certain of the primordial cells. Fine granules appear in the cytoplasm. At first the granules are few, but as they become more numerous in particular cells, their presence in the clear cytoplasm may give to the cell what suggests a vaeuolated structure. As the stainable cytoplasmic material increases in amount, a cell results

Fig. 1 Transverse section through fourth branchial complexes of 13 mm human embryo. The primordium of the right and left parathyroids IV are readily recognized by their clearer cells which contrast strikingly with the darker cells of the other endodermal structures in the section. X 50.

Fig.2 High power view of dorsal portion of fourth branehial complex of 13 mm human embryo. This View is taken from right side of same section as shown in figure 1. The parathyroid primordium is shown in upper part of figure (lateral aspect of fourth pouch) and the slit-like lumen of the pouch separates the parathyroid from the primordium of the lateral thyroid shown in the lower pnrt of the figure. X 375.

Fig.3 Transverse section of right third branchial complex of 16mm human embryo to show structure of and line of junction betireeu parathyroid and thymus. Only part of the thymus is shown at left: a complete section through the paratliyroid (center to right) in included. X 160.

Fig.4 ’1"ransversc section of left third branchial complex of 13 mm human embryo. Pharyngo-branchial duct in upper left. The large clear polygonal cells are those of the parathyroid primordium. X 160.

Fig. -3 High-power \’l€W from section of parathyroid III from a 163 mm human fetus to show a cluster of clear cells and the striking contrast they make with primordial, vesicular and dense cells. Dense cells predominate in this section. X 370.

Fig.0‘ High-power View from section of parathyroirl ITI from a 163 mm fetus to show primordial cells, vesicular cells, clear cells and dense cells. Primordial cells are least numerous; the other three types are present in approximately equal proportions. X 370. PRE.\'ATAL FUNCTION OF PARATHYHOIDS 133

that contrasts strikingly with the primordial cell and the clear cell. Because of the relatively large quantity of more deeply stained cytoplasmic material, this cell appears much denser than either a primordial or a clear cell. For this reason it is called the dense cell and in all other respects, except for the denser cytoplasm, this cell resembles a primordial or a vesicular cell.

Figures 1 to 6 134 EDGAR 11. NORRIS

In certain dense cells the condensation of the cytoplasm may progress still farther and this greater cytoplasmic condensation is paralleled by a decrease in the size and a change in the i'o1'm of the cell. Finally, by these alterations, a fifth cell type, the dark cell, is produced in the fetal gland. The fully formed dark cell has dense azurophilic cytoplasm, possesses an indistinct cell wall, and is indefinitely outlined.

-2 . AL .-~. .3». Fig. 7 High-power view from section of parathyroid IV from a. 115 mm fetus

to show the developing vascular elements and the resultant reticulation of the

parenchyma. Many primordial cells are present but the rnaljority are veicular and clear cells. X 325.

It tends to have a low columnar or cuboidal form, measures 8 to 10 microns in height by 5 or 6 microns in width, and is definitely smaller than the primordial cell. The nucleus of the dark cell measures about 5 microns, and its chrornatin is more compact and denser than that in the nucleus of a primorclial cell.

The formation of dense cells and dark cells may be observed througliout the latter half of intrauterine life. The formaPRENATAL FUNCTION OF PARATHYB-OIDS

tion of these Various kinds of cells, however, does not keep pace with the increasing length of the fetal body, and when sections from different fetuses of about the same length are compared, it is usual to observe great variability in the rela tive numbers of the distinctive cell types. Only rarely, however, are there marked Variations in the cytology of different glands from the same individual. At term (330 mm crownrump length) there is usually a predominance of primordial and vesicular cells with fewer dense cells and only occasional, irregularly scattered, dark cells or groups of these.

Thus we learn that, from the point of View of the glandules’ histogenesis, five cell types appear in the parenchyma of the parathyroid during the gestational period. These cell types

V are identical in all morphological respects with the cells found

associated with functional states of the parathyroid during postnatal life.

The average estimated volume of the parathyroids in the embryonic and fetal periods is recorded in table 1. The data of table 1 together with the field graph and growth curve shown in figures 8 and 9 demonstrate two points that may be applied in the study of our present problem and that lend support to the concept of the prenatal functionability of the parathyroids. In the first place, it appears that on the average the total parathyroid tissue of an individual grows at a rate that is quite different from the rate at which the body increases in length. Further, it is clear that the growth of the parathyroid manifests a periodicity having no correspondence with the rate of the body’s growth. During an initial period, while the body increases its length from 10 to 75 mm, the growth curve for the parathyroid rises so slowly that it nearly parallels the base line. This is true despite the fact that during the same period vascular elements begin to appear within the parenchymal mass.

A period of more rapid vascularization ( 75-100 mm) is apparently accompanied and followed by a stage of active parenchymal hyperplasia (fig. 7). VVhen the fetus is about 75 mm the rate of growth of the parathyroid changes remarkably 136 EDGAR H. NORRIS

and rather abruptly; during this second epoch the gland grows rapidly, and the growth curve rises precipitously. Therefore, in two periods of about equal duration (10 to 75 mm and 75 to 150 mm) We find the parathyroid tissue increasing at strikingly different rates.

TABLE 1

Tabulation of material‘ and data employed in the cvmstruction of the field graph shown in figure .9.

NUMBER OF NUMBER OF AVERAGE

15-19 H 56 0.00218 20-24 26 105 0.00233 25-29 17 68 0.00267 30-34 14 56 0.00333 35-39 7 26 0.00282 40-44 3 12 0.00425 45-49 4 16 0.00312 50-54 1 4 0.00242 55-59 1 4 0.00469 60-64 1 4 0.00274 65-69 2 8 0.00528 70-74 0 0 . . . . . . 75-79 1 4 0.00583 80-84 1 4 0.00511 85-89 1 4 0.01135 90-114 0 0 . . . . . .

115-119 1 2 0.05100

120-154 0 0 . . . . . .

155-159 1 1 0 25920 Totals 95 374

’ The complete details regarding individual cases are recorcled in the tables and

text of the paper by Norris, ’37.

Additional evidence to support our hypothesis may be obtained from a comparison of the growth rate of structures anatomically associated with that of the parathyroids. From the beginning parathyroid IV and the lateral thyroid are intimately associated. As shown by the field graphs and growth curves published in my earlier study (Norris, ’37; fig. 11) the lateral thyroid grows at a rate rather closely paralleling PRENATAL FUNCTION or PARATHYROIDS 137

that of the body’s length and at a rate quite diiferent from that of parathyroid IV.

When the cytology and histology of the parathyroid is compared With that of other endocrine structures such as the thyroid, the degree of differentiation is much more advanced at an early period in the case of the parathyroid. The first primary thyroid follicles appear in fetuses about 25 mm long

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MOVfl'RU?P LENGTH IN MILLIMETERS

Fig. 8 Field graph in which estimated volume in cubic millimeters of 374 para thyroids have been plotted againt body lengths in millimeters of the human embryos and fetuses.

(Nor1'is, ’16) and when the fetus is 65 mm long these primitive structures are still being generated from the epithelial plates, whereas we have noted the presence of cytologically differentiated elements in the parathyroids of embryos 9 mm in length.

We may now summarize and interpret the observations that are germane to the present thesis. 138 EDGAR H. NORRIS

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Fig. 9 Field graph and growth curve based upon the average estimated volume in cubic millimeters of the parathyroid tissue of 374 human embryos and fetuses plotted against body length in millimeters. The averages were determined for all of the individuals included within groups corresponding to an increase of 5 millimeters in body length. Data recorded in table 1. PRENATAL FUNCTION or PARATHYROIDS 139

1. The four parathyroids in a given individual make their sudden appearance simultaneously in the walls of the third and fourth branchial pouches and spring full-blown into being during the fifth gestational week, when the embryo is about 9 mm in length.

2. From their first appearance the primordial cells are morphologically quite like the cells that go by the same name and that are found in the glandules of individuals in the succeeding gestational months and throughout postnatal life (Norris, ’47).

3. Cell types other than primordial cells appear in the parathyroid only after there has been a period of multiplication of primordial cells as evidenced by growth of the glandule.

4. The five cytological types found in the fetal glands, the primordial cell, the vesicular cell, the clear cell, the dense cell, and the dark cell, are morphologically identical with the comparable types of cells found in the parathyroids during postnatal life.

5. Easily recognizable transitional vesicular cells are found in the fetal glands between the primordial cells and the clear cells.

6. Easily recognizable transitional dense cells are found in the fetal glands between the primordial cells and the dark cells.

7. Cell types that appear during; fetal life and that are characteristically associated with functional states in postnatal life must logically receive the same interpretation in both periods.

8. The parathyroid glands of the human embryo are cytologically well developed and differentiated and possess definitive primordial cells, which from the morphological point of View should be physiologically active, considerably earlier than do other endocrine glands.

9. Parathyroid IV and the lateral thyroid are derived from the endoderm of the fourth branchial pouch, and they remain in close anatomic association until long after the 140 EDGAR H. NORRIS

embryonic period has ended. Despite this common origin and this persistent anatomic relationship, the rates of growth of these two organs are strikingly different, and the time of cytological and structural differentiation in the two bodies contrasts even more conspicuously (Norris, ’37).

10. Although the growth of parathyroid III and of the endodermal thymus (the derivatives of the third pharyngeal pouch) have not been compared on the basis of actual measurements, it is evident from models that have_been made, that their growth rates are quite different and that differentiation in the two does not follow the same time schedule.

11. In accord with the tendency of cephalocaudal development the anlage of the median thyroid is recognizable in embryos about 2 mm in length (Norris, ’18) whereas the parathyroid primordia do not appear until the embryo has attained 9mm. However, even though the early primordial stage for the median thyroid (2 mm) considerably antedates the same stage for the parathyroids (9 mm), nevertheless an advanced state of differentiation of the parathyroids actually is accomplished much earlier (9 mm) than is the differentiation of the median thyroid (25 to 65 mm).

12. The periodicity of growth for the parathyroid is different from that of the body as a whole. While the embryo is increasing from 9 to 75 mm in length, the parathyroids are growing slowly. Apparently this minimal amount of parathyroid tissue is suflicient to meet the fetal demands through this considerable period. Starting with the 75 mm stage, the growth of the fetal parathyroid is very rapid.

13. The total volume of parathyroid tissue in a group of embryos of the same developmental stage tends to vary within wider limits than does the size of the four parathyroids of the same individual. This fact would seem to b'é§peak a close relationship between the total volume of parathyroid tissue and the economy of the particular individual.

Thirteen different morphological observations are enumerated that separately and collectively argue strongly in support of the thesis that the human parathyroid gland is physioPRENATAL FUNCTION or PARATHYROIDS 141

logically active during the embryonic and fetal periods. These observations not only demonstrate the early functional activity of the parathyroid but also suggest an independently regulated mineral metabolism within the organism of the developing individual. In a later study this conclusion may be further tested and related to such other correlated processes as skeletal differentiation and calcification.

LI TERA TURE CI TED

CASTLEMAN, B., AND T. B. l\z[ALLOR\' 1935 The pathology of the parathyroid gland in hyperparathyroidism. Amer. Jour. Path., vol. 11, pp. 1-72.

Noams. E. H. 1916 The morphogenesis of the follicles of the human thyroid gland. Amer. Jour. Anat., vol. 20, pp. 411-448.

— ————— —— 1918 The early morphogenesis of the human thyroid gland. .\1ner. Jour. Anat., vol. 24, pp. 443-465.

———-——*- 1937 The parathyroid glands and the lateral thyroid in man: their morphogenesis, histogenesis, topographic anatomy and prenatal growth. Carnegie Inst. Wash. Pub. no. 479, Contrib. Embi-yol., no. 159.

—»—-~— —— 1946 Primary Hyper-parathyroidism: A report of five cases that exemplify special features of this disease. Arch. Path. (in press).

—-—-~——— 1947 The parenchymal cytological elements of the human parathyroid glands. (In press.)

\V'ELLI:R, G. L. 1933 Development of the thyroid, parathyroid and thymus glands in man. Carnegie Inst. Wash. pub. 443, Contrib. Embryol., no. 141, vol. 24.

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