Paper - Observations on the growth of the suprarenal cortex (1930)
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Hill WC. Observations on the growth of the suprarenal cortex. (1930) J Anat. 64(4): 479-502. PMID 17104293
|adrenal growth in humans and other species.
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Observations on the Growth of the Suprarenal Cortex
By W. C. OSMAN HILL, M.D., Cu.B. (Birm.) Department of Anatomy, University of Birmingham
The relatively enormous size of the human suprarenal gland at the time of birth has long been a matter for remark. The exact time at which the fact became known is not certain, but mention is made of it by J. F. Meckel in 1812 and by Johannes P. Miiller in Hildebrandt’s Anatomie (1830-2). In the French translation of Meckel’s work are many interesting facts relating to the size of the suprarenals in Man. He quotes Bichat as stating that the suprarenal disappears entirely in old age; and he remarks that he himself has discovered enlarged suprarenals in those whom he has known to have been “addicted to the pleasures of love.” The foetal hypertrophy of the gland was evidently recognised even earlier than this, since Meckel (14) himself quotes G. B. Morgagni (1682-1781) as having discovered the suprarenals to be of small size in the anencephalic foetus, which indicates that the normal foetus was well known to have a large suprarenal.
The earliest detailed study of the development of the suprarenal was the work of M. Gottschau who published a number of papers on the suprarenals of Man and the rabbit (6) (1883). No reference is made in Gottschau’s writings to the zoning of the cortex. A closer investigation into the facts relating to the relative size of the suprarenals in the anencephalic and in other abnormal foetuses was made by R. Magnus (13) (1889). He found no case of anencephaly with a normally sized suprarenal, though he gives reference to cases where one large and one small gland had been found. He noted that the gland was-nermal in hydrocephaly.
The next step was the publication of R. Zander’s classical paper (20) on the suprarenals (1890). After alluding to Meckel’s remarks, he proceeded to give the weight of the suprarenals at various ages in Man relative to the weight of the kidney. He noted the fact that in other mammals (calf, sheep, cat and hedgehog) the gland is not so large in comparison with the kidney as in Man. Apart from the fleeting statement made by Meckel quoted above, Zander seems to have been the first to point out the close connection existing between the suprarenals and the sexual apparatus. He particularly noted that the suprarenals were larger in the Negro, thus correlating them with the larger sexual organs in that race. He made a further comparison by recording the weight of the suprarenals and the gonads in various foetal monsters. A reference was made to a case of anencephaly possessing normal suprarenals recorded by Klein.
The comparative anatomy of the suprarenals was very extensively studied by A. Pettit(15) (1896). No details were given of the evolution of the different parts of the cortex of the gland in the animals studied. This was, however, done later (1906) by H. Poll in Hertwig’s Handbuch(1s). In this account are to be found good figures of the appearances of the cortex in the foetal sheep and foetal pig. No mention is made here, however, of any transitory part of the cortex.. About the same time appeared the study by T. R. Elliot and I. Tuckett (4) on the suprarenal of the guinea-pig. They noted the small size of the gland at the time of birth, and the appearance of a relatively huge cortex during adolescence. In Cavia and Coelogenys, according to these authors, the cortex is larger in proportion to the rest of the gland than in any other mammal.
The actual reason for the large size of the human gland at birth was discovered almost simultaneously by S. Starkel and L. Wegrzynowsky (18) (1910), by T. R. Elliot and R. G. Armour (3) (1911), by H. Kern(i0) (1911) and by Erwin Thomas (19) (1911). All these workers mention the presence of a special zone of cortex lying between the true or adult cortex and the medulla. This has since come to be known as the “boundary zone” or “foetal cortex.” By Starkel and Wegrzynowsky it was referred to as “‘Markzone.” These authors drew attention to important vascular changes occurring in this layer of cortex after birth, whilst Elliot and Armour showed that the newly found zone underwent a process of involution after birth. The last-named writers also showed that the small size of the suprarenal of the anencephalus is due to an almost complete absence of the zone of cortex in question. Another important statement made by Elliot and Armour is that this “foetal cortex” is a structure peculiar to the human subject, not having been found by them in any other mammal, The only evidence for this seems to be a reference to the earlier paper by Elliot and Tuckett (4) on the suprarenal of the guinea-pig. They admit that apes were not examined. In Kern’s contribution(10) there is an accurate description of the process of involution of the “foetal cortex” after birth in Man and a mention of the vascular changes associated with this process. He also examined several other animals to ascertain if a similar process could be found among them and came to the conclusion that no such analogous condition was present. This seems not unreasonable when one reviews the age of some of the animals examined by him. These included guinea-pigs (2-3 weeks), rabbits (2-5 weeks), calf (4 weeks), ox (4 years), pig (6 months), sheep (6 months), rat (6 weeks) and horse (16 years). In the paper by Thomas attention is drawn for the first time to the naked-eye appearances observable in the gland during the process of involution of the foetal cortex in Man. He especially noted the pale peripheral zone corresponding to the true cortex and the darker bloodcontaining zone lying deep thereto.
E. E. Glynn) in 1912 published results of his work on the times at which the various changes occur in the evolution of the adult type of suprarenal cortex in Man. He pointed out that the three zones of the adult cortex are all recognisably present by the end of the second post-natal month. He also drew evidence to show an important connection between the cortex and the sexual apparatus. W. Dewitzsky (1) (1912) studied the histology of the gland in rats and other animals chiefly in reference to the growth of the medulla. He made references to the work of Kern and Thomas, but failed to find the “foetal cortex” in the animals he examined.
C. M. Jackson (8) (1913) made a study of the post-natal growth of various organs including the suprarenal in the albino rat. This was followed by a more detailed analysis of the suprarenal of the rat by the same author (9) (1919). He came to the following important results: (i) in normal post-natal development both cortex and medulla of the gland increase during the first year; after which the two structures grow at different rates; (ii) all three histologic cortical zones are present at birth; (iii) there is no definite cortico-medullary boundary in the earlier stages on account of the fact that islands of cortical tissue are found embedded in the medulla. These are absorbed later, thus giving the characteristic cortico-medullary boundary of the adult gland. Some of the islands remain isolated in the medulla for a considerable time after birth. The date of the occurrence of these changes is variable. Jackson made references to the previous work of Gottschau, Pfaundler and Soulié who had mentioned atrophic changes occurring in the deeper cortical zone in the rat and other animals. He came to the general conclusion that probably a zone of atrophic cortical tissue would be found in the young animal in the deeper parts of the cortex of the suprarenal and that it was probably due to the absorption of this tissue that the definite cortico-medullary boundary was produced.
Meanwhile in the same year J. C. Donaldson(2) had come to the opposite view. This writer had studied the relative volumes of cortex and medulla in the suprarenal of the rat. He discovered no degenerative phase in the growth of the suprarenal comparable with that occurring in the human gland.
The next step in the development of our knowledge of the cortex of the suprarenal was made by studying the lipoid content of the gland. Elliot and Armour(3) in their original description of the foetal cortex had been able to identify this structure chiefly on account of a conspicuous absence of fatty bodies, thus causing a contrast with the fasciculate zone of the true cortex with its cells heavily laden with lipoids.
M. F. Lucas Keene and E. E. Hewer (11) (1924) examined the lipoid content of all parts of the human gland at different stages of foetal life. They were able to show that the foetal cortex as well as the true cortex is capable of showing a reaction with Sudan III, though it does so happen that at the time of birth the foetal cortical zone is deficfent in fatty substances. Nevertheless at earlier stages they were able to show lipoid present in the foetal as well as in the true cortex, the staining being “very intense” by the 32nd week. They obtained this reaction also with anencephalic suprarenals. Moreover, it had been stated by Schafer (17) (1924) that the disappearance of the foetal cortex after birth was due to a fatty degeneration of its cells and therefore a reaction with Sudan III would be expected at this stage also. In a later paper (12) by Lucas Keene and Hewer (1927) the development of the human gland was reviewed in more detail, and a suggestion made that the problems connected therewith would probably find elucidation only on a study of the comparative development of the gland. In the same paper it is again stressed that lipoid can be seen in the foetal cortex by the 24th week and that this increases in amount more rapidly in the true than in the foetal cortex. They point out that the degeneration of the foetal cortex is associated with a diminution in the lipoid content.
Lastly E. Howard-Miller (1927) published results of a study of the suprarenal cortex of the young mouse. In this paper(7) a new zone of cortex having age and sex relationships is described as the X-zone, and a comparison is made with the foetal cortical zone of Man. The X-zone is a transitory zone situated at the cortico-medullary boundary. It is present in both sexes at birth, but disappears early in the male. In the female it is still growing at four weeks, and its degeneration is associated with the animal’s first pregnancy. The degeneration is said to be similar to that involving the human foetal cortex, but not to be at an analogous age period. Degeneration is associated with vacuolation of the cells and hyperaemic changes.
Summing up it may be said that the main trend of the more recent work on the foetal cortex points to the fact that some similar change might well be looked for among other mammals, in spite of the earlier findings of Elliot and Armour, Kern and Thomas and the isolated remarks of Donaldson. Accordingly in the present investigation the cortical structure of the suprarenal gland has been studied in the late foetal and early post-natal stages of a number of mammals. As all previous observations have been mainly confined to rodents, this order of mammals has not been investigated. Attention has therefore been directed to the lower Primates, the Carnivores and the Ungulates.
Material and Methods
The suprarenal glands of a number of lower Primates, Carnivores and Ungulates have been studied by means of dissections, sections and microscopical preparations.
With regard to shape and relations, the glands have been compared with that of Man, and the human gland at birth has been taken as a general standard of comparison in reference to size; but in most cases the gland has been compared in size with the kidney also. Measurements of the gland in its craniocaudal, side to side and antero-posterior directions have been recorded.
Sections have been taken in the sagittal and coronal planes and examined by the naked eye. For this purpose absolutely fresh material is of course essential. Under these circumstances it is generally possible to identify the chief zones, and in the case of sagittal sections, to see the way these are disposed around the central vein. Many important colour changes can also be recognised by this method.
For histological purposes the material was fixed in equal parts of Miiller’s fluid and Bouin’s aqueous picro-formol-acetic acid, or in equal parts Miiller and 4 percent. formalin. It is maintained that the cells of the cortex should be recognisable by their morphological characters alone; although it must be remembered that it was chiefly on account of the absence of lipoid in the cells of the foetal cortex that Elliot and Armour made their discovery of the presence of this zone in the human gland at birth. Later work, however, showed that the mere absence of lipoid is not sufficient to diagnose foetal cortex, since at certain stages this substance is present in the foetal as well as in the true cortex.
Accordingly the opinion is expressed that foetal cortical cells should be distinguished from true cortical cells by their larger size, swollen appearance, tendency to degeneration, vacuolated nuclei, and especially by their environmental vascular changes—engorgement of radial vessels and haemorrhage.
Therefore, although some sections have, for comparison with the human gland, been stained with Sudan III to show the presence of lipoid, most of the microscopic work has been done with sections stained with Mayer’s haemalum and counterstained with eosin. It is with eosin that the cells of the foetal cortex show their most characteristic reaction.
The suprarenal glands of the following Primates have been examined:
(i) Adult macaques of various species. (ii) Foetal macaques at full term.
(iii) Adult marmoset.
(iv) Foetal lemur at full term.
(v) Foetal Nycticebus at half term.
Some idea of the relative sizes of the suprarenals of a series of Primates is given in fig. 1.
The following measurements are of the suprarenal gland of a number of adult macaques:
Macacus cynomolgus, female, left 17mm. by 14mm. Macacus cynomolgus, female, right 17mm. by 10 mm. Macacus rhesus, male, left ... 15mm. by 9mm.
Macacus nemestrinus, male, right 15mm. by 138 mm.
In adults of this genus it is seen that the suprarenal gland is variable in size relative to the kidney; the variations being in relation to species, sex and age (cf. Schafer (17)). The gland is larger in the female than in the male, and section of the gland even to the naked eye proves that this increased size is due to cortex rather than to medulla. In the male the gland is small, flattened antero-posteriorly and its cortical rim is thin and pale. In a recently pregnant female the cortical rim was thick and more vascular than in the male. Microscopic sections showed the depth of the cortex in the female to be due to a thick layer of deep cortex corresponding to the human zona reticularis. In an older male M. rhesus the zona reticularis was found to be completely absent. This seems to have some bearing on the phenomena associated with the “*X-zone” described in the suprarenal of the mouse by Howard-Miller (7).
Fig. 1. Kidneys and suprarenals of a number of adult and foetal Primates all drawn to the same scale. A. Right kidney and suprarenal of adult male Macacus nemestrinus. B. Left kidney and suprarenal of foetal male Macacus hybrid. C. Left kidney and suprarenal of foetal male M. pileatus. D. Right kidney and suprarenal of foetal male Lemur niger. E. Left kidney and suprarenal of foetal male Nycticebus tardigradus. F. Left kidney and suprarenal of adult male Hapale jacchus.
Fig. 2. Coronal sections of the suprarenals of different Primates to show naked-eye appearances of the gland. All drawn to the same scale. A. Suprarenal of adult male Macacus rhesus. B. Suprarenal of adult female M. cynomolgus. C. Suprarenal of foetal male M. hybrid. ic. true cortex; r. reticular zone; f.c. foetal cortex; h. haemorrhagic zone of foetal cortex; m. medulla; v. central vein.
The size of the suprarenal gland in the full-term foetal macaque can be judged from fig. 1, B and C. The drawings were taken from a new-born male M. cynomolgus x M. pileatus, and a nearly full-term foetal M. pileatus. The gland is in each case almost as large as the kidney itself, so that in this respect it closely approaches in its relative size the human gland at the same stage of development. Measurements of the suprarenals of the above foetal macaques are as follows:
M. cynomolgus x M. pileatus (male) hybrid
Height 17-5 mm. Breadth 15-0 M. pileatus (male)
Left suprarenal Left kidney Height 10:0 mm. 16-0 mm. Breadth 10-5 10-5 Thickness 6-5 8-5
Right suprarenal Right kidney Height 9-0 mm. 16-0 mm. Breadth 12-0 » 11-0 Thickness 6-5 9-0
On section the suprarenal of foetal macaques presents to the naked eye the same appearances as the human foetal suprarenal (see fig. 2). Thus beneath the fibrous tissue sheath of the gland there is first a thin rim of pale yellowish or cream coloured cortex of firm consistence. This is succeeded by a thick zone of darker friable tissue which at first sight might be taken for medulla. The deepest parts of this friable zone may be darker than the rest on account of a greater vascularity or even from the presence of actual haemorrhage. In the middle of the gland the central vein is seen in section.
Microscopically the most striking fact is that the gland consists almost entirely of cortex as in the case of the human foetal suprarenal (see figs. 3 and 4). Medullary tissue is represented only by a few clumps of chromaffin cells around the central blood vessel and amongst the, deepest cells of the cortex.
The cortex of the suprarenal on the other hand shows a well-marked differentiation into two zones. The differentiation is clearly visible in sections stained both by the Sudan III method and by the haemalum and eosin method. The outermost part of the cortex consists of small cells with darkly haematoxylin-staining nuclei. These cells are more closely aggregated just beneath the capsule, but it cannot be said that they form a definite glomerular arrangement. The deeper layers of these small cells form columns descending into the depths of the gland substance even in the younger specimen. In sections of the suprarenal of the younger of the two specimens examined none of the cells of the outer part of the cortex show any lipoid reaction with Sudan III. There can be no doubt, however, that they represent the “true cortex” of the adult gland. The rest of the gland, i.e. the part corresponding to the friable zone described above, consists of totally different cells. These are large, pale and have large degenerate-looking nuclei. The boundary between this zone and the suprajacent one is not definite, for the cells of the “true cortex” are seen to be insinuating themselves between the uppermost strata of the zone under consideration. The more superficial cells look more degenerate than the deeper ones. They are pale and vacuolated and stain poorly. In sections stained by Sudan III the deepest cells of all are heavily loaded with lipoid. This proves conclusively that presence of lipoid cannot be used as a diagnostic sign ruling out the presence of “foetal cortex,” since there can be no possible doubt that these large pale-cells represent that structure (a) because of the comparative size of the gland, (b) because practically the whole gland consists of cortex, and (c) because of the obvious differentiation of the cortex into two morphological zones.
Fig. 3. Microscopic appearances of the suprarenal of foetal M. pileatua. capsule; t.c. true cortex; f.c. foetal cortex; m. medulla; v. central vein.
Fig. 4. Microscopic appearances of the suprarenal of an older foetal M. hybrid showing vascular changes. c. capsule; t.c. true cortex; f.c. foetal cortex; m. medulla; v. central vein.
In sections of the suprarenal of the older of the two foetal macaques stained by haemalum and eosin a further stage in development is seen (fig. 4). This consists of a massive engorgement of the radial blood vessels which spread outwards from the central vein into the cortical substance. In the specimen under consideration the vessels of the deeper half of the foetal cortex have undergone this engorgement. More superficially the vessels contain large masses of blood corpuscles, but not so many as those deeper in. Here and there appear one or two small areas of haemorrhage, where the engorgement has been so extreme as to cause actual rupture of the vessel wall. As would be expected the cells of the foetal cortex in this older specimen show a greater degree of degeneration than in the younger example.
Adult marmoset (Hapale)
In an adult male of this genus the suprarenal was found to be larger in comparison with the kidney than in Man (fig. 1). The gland hasaconical shape, being almost as thick at the base from before backwards as from side to side. The measurements are as follows:
Left suprarenal Left kidney Height ... see 7mm. 16 mm. Breadth at base 8 12 Thickness at base 5 8
The surface of the gland is wrinkled as in all adult Primates, suggesting removal of some deep tissue at an earlier stage. It is triangular in sagittal section. Microscopically it is made up of a central nodule of medulla which accounts for about one-third of the organ. Extensions of medulla into the cortex take place in the angles of the triangle. The cortex consists throughout of well-formed cells of which the outer third are small and show no lipoid reaction, whilst the remainder are arranged in columns radiating outwards from the medulla and which show a heavy lipoid reaction. There is no zona reticulata (cf. adult male Macacus).
The suprarenals have been examined in a Lemur niger at full term, and in a Nycticebus tardigradus at about mid term. The relative sizes of the glands and the kidneys can be judged and compared with those of other adult and foetal Primates from fig. 1. Measurements are as follows:
Lemur niger, full term, male
Left suprarenal Left kidney Height... | 9 mm. 11 mm. Breadth 7 7 Thickness 2 / 3
Nycticebus tardigradus, half term, male
Left suprarenal ' Left kidney Height ... 5-5 mm. 7mm. Breadth 55 4 Thickness 3-5 5
In each case therefore the suprarenal gland at the stage examined is shown to be almost as large as the kidney, and thus to agree with the human foetal gland.
In both cases section reveals the gland to consist, as in Macacus and Man, almost entirely of cortex. This cortex, moreover, is, even in the mid-term stage ' of Nycticebus, well differentiated into two very obvious zones; a peripheral zone of true cortex and a deep zone of “foetal cortex.”
In Nycticebus the true cortex consists of a very thin margin of tiny cells with very darkly staining nuclei. There is as yet no evidence of invasion of the “foetal” zone. The foetal cortex consists of large rounded cells arranged in columns radiating from the centre of the gland. Between the columns there: is loose reticular tissue containing vessels. The: vessels, however, are not engorged. The reticular tissue is more plentiful near the middle of the gland.
In both forms of Lemuroids examined the medulla is very sparse. On section no boundary can be seen between cortex and medulla since practically the whole gland consists of cortex. 490 W. C. Osman Hill
The suprarenals of the following Carnivores have been examined:
(i) New-born kittens of both sexes. (ii) New-born leopard cub.
(iii) New-born pups.
(iv) Pup, 4 days old.
(v) Young pups, 11 and 13 days old. (vi) New-born bear cub.
In none of the above, with the exception of the leopard cub, does the suprarenal at or about the time of birth exhibit such marked enlargement in comparison with the size of the kidney as in Primates (see fig. 5). In the leopard cub the gland was certainly relatively larger than in new-born kittens as is shown in fig. 5. On the contrary in the bear cub the gland was comparatively minute. It is therefore useless to draw conclusions from the size of the gland only. Moreover in the dog, in which the changes in the gland have been followed in most detail, there is no very obvious diminution in the relative size of the suprarenal during the time immediately after birth comparable with that seen in Primates. There is consequently no shrivelling of the surface of the gland; the adult gland having as smooth a surface as that of the full-term foetus.
The following are measurements in millimetres of the suprarenals and kidneys in a number of Carnivores:
Suprarenal Kidney Height Breadth Thickness Height Breadth Thickness
Kitten, full-term 3-5 6 2-0 18-0 14-5 9-5 male (left)
Kitten, full-term 4:0 8 2-5 15-0 13-0 5-5 female (left)
Leopard cub, 12-0 9 7-0 22-0 19-0 12-0 male (left)
Pup, full-term 4-0 7 2:5 18-0 10-0 8-0 male (right)
Pup, 4 days old 3-5 7 2-0 20-0 13-0 9-0 female (right)
Pup, 11 days old 5-0 10 — 30-0 20-25 15-0 female (left)
Bear cub, male 4:0 5 2-0 16-5 10-0 1:25 (right)
On section the suprarenal of any of the Carnivores examined shows to the naked eye that both medulla and cortex are present at the time of birth. Medulla, however, is less well developed than cortex. Microscopically the boundary between the cortex and medulla is not a definite line as in the adult gland. There are islets of cortex scattered irregularly in the substance of the medulla and masses of cortex projecting downwards from the main cortical layer into the medulla. As the animal grows older this arrangement is lost and a definite boundary comes to be formed between medulla and cortex. This arrangement is shown in the section taken from the suprarenal of an 11-dayold pup in fig. 6 and compared with a section of the gland of an adult dog. With regard to the details of cortical structure the following facts have been ascertained. Beneath a relatively thick capsule in the new-born pup’s suprarenal there is a well-formed zona glomerulosa of much greater relative dimensions than that seen in the suprarenal of any of the Primates. This zone consists of flask-shaped masses of tall columnar cells arranged side by side in a single layer. They show a definite lipoid reaction. The rest of the cortex consists of large ovoid cells arranged roughly in short columns radiating from the centre of the gland. Neighbouring columns intercommunicate and give a general reticular appearance (see fig. 6). These cells also show a lipoid reaction, the reaction being more intense as one approaches the medulla.
Fig. 5. Kidneys and suprarenals of a number of Carnivores. All natural size. A. Leopard cub, new-born male. Right kidney and suprarenal from in front. B. The same. Left kidney and suprarenal from the medial aspect to show the extent of the descent of the suprarenal over the upper pole of the kidney. C. Bear cub. Right kidney and suprarenal from behind. D. Kitten, new-born female. Left suprarenal and kidney from the front. E. Pup, new-born male. Right kidney and suprarenal from behind. F. Pup, 11 days old female. Left kidney and suprarenal from the front.
It is difficult to state what part of the suprarenal of young Primates corresponds to this deep zone of cells in the suprarenals of young Carnivores. The large size and general arrangement of the cells seems to point to their equivalence to the main mass of cortex of the young Primate suprarenal, i.e. to the so-called “foetal” cortex. It must be pointed out, however, that this layer of cortex does not entirely disappear in the Carnivores as it does in Primates, but persists deep to the glomerular zone as the zona fasciculata, though it is a moot point, according to the present investigation, whether the zona fasciculata of Primates, with its small cells growing in from the zona glomerulosa, is comparable with the zona fasciculata of Carnivores with its large cells present from the first and independent of the glomerular zone, which is in itself a more bulky stratum than in Primates.
It must be pointed out that the suprarenal of the adult dog differs from that of the pup in having a decided boundary between cortex and medulla. The medulla has grown of course in quantity and contains no islands of cortex. The cortex consists of a well-developed zona glomerulosa of even greater proportions than in the pup; succeeded by a zone of reticular arrangement of comparatively less depth than in the pup. It would appear that some absorption of cortical tissue at the cortico-medullary boundary occurs in the period immediately following birth as Jackson(9) suggested might be found. This absorption however is never so massive as is seen in Primates and never involves as much of the cortical tissues. Cortical tissue corresponding to the so-called ‘*foetal”’ cortex would appear to persist as the deep layer of the adult cortex.
The suprarenals of the following Ungulates have been examined:
(i) Lamb at birth (female).
(ii) Lamb, 2 days old (male). (iii) Lamb, 5 weeks old (male). (iv) Adult sheep.
(v) Pig at birth (both sexes). (vi) Pig, 24 hours old (both sexes). (vii) Pig, 5 days old (both sexes). (viii) Pig, 6 days old (male).
(ix) Adult pigs.
(x) Foetal hippopotami.
(xi) New-born goat.
, (xii) Foetal calves.
In all cases the suprarenal at the time of birth does not show any marked enlargement when compared with the adult gland in the same species (see fig. 7).
Measurements of various foetal glands are shown in the accompanying table, in millimetres.
The adult gland is always comparatively well developed when contrasted with.the gland of adult Primates. It never shows a wrinkled surface, so that, as in Carnivores, it can be assumed that there is never any gross removal of deep tissue during the evolution of the adult type of gland from the foetal organ. In most of the Ungulates examined the suprarenal is an elongated structure lying with its long axis transversely to the long axis of the kidney, but with one of its poles curving downwards and inwards towards the hilum of the corresponding kidney. The goat is an exception to this, for in this animal the suprarenal is a rounded organ, and in a new-born kid was about the size of a pea. In adult animals the suprarenal does not reach as far as the hilum of the kidney as it does in new-born animals, so that the gland becomes relatively shorter with age.
Fig 6. Microscopic appearances of the suprarenal of: A. Pup, 13 days old; B. Adult dog. c. capsule; g. glomerular zone; d.c. deep cortical zone; m. medulla; v. central vein.
Suprarenal Kidney Cc AW ~~ — a \ Height Breadth Thickness Height Breadth Thickness
Pig, 24 hours old female 5:5 15-0 4:5 44-5 20-0 16-0 (left)
Pig, 24 hours old male —_ — —_ 29-0 13-25 10-5 (right)
Pig, 5 days old female 5-0 13-0 6-5 35-25 16-0 13-5 (right)
Pig, 5 days old male 5-0 14-5 5:5 33-0 17-0 11-5 (right)
Pig, 6 days old male 4:0 17:0 5-5 37-0 18-5 6-0 (right)
Hippopotamus, 4-0 15-0 6-5 36-0 19-0 13-5 foetal male
Lamb, 2 days old male 7-0 17-5 6-0 34:0 26-0 16-0 (right)
Goat, 24 hours old male 6:5 6-0 4:0 23-0 19-0 12-0 (right)
Calf, mid-term male 8:5 11-0 — 42-0 25-0 — (left)
Sections of the suprarenal reveal to the naked eye the presence of cortex and medulla in all Ungulates at birth. In the adult there is a marked variation in the proportions of the cortex in different species. Thus in the sheep there is a very deep layer of cortex and but a small quantity of medulla, whereas in the adult pig there is a large amount of medulla and a thinnish rim of cortex around it. This difference is not so obvious in young suprarenals. Thus in newborn pigs there is little medulla and a deep cortical zone. The same is true of lambs and goats. In the pig the medulla comes to the surface at the hilum of the gland (sce fig. 8). Little can be made out of the details of cortical structure in naked-eyc sections of the gland, except that certain vascular changes are recognisable by the colour of the cut surface. There is a tendency in the young suprarenals of all the Ungulates examined at the time immediately after birth to show these vascular phenomena. They consist in engorgement of the cortex, with blood spreading out from the central vein along the radial vessels between the columns of cortical cells. In parts this engorgement is so great as tolead to rupture of the vessels with consequent extravasation of blood.
This is suggestive of the processes occurring in the Primate suprarenal at a corresponding age. To the naked eye these changes appear first as adistinct radial striation of the deeper parts of the cortex merging later into a general diffuse reddening of the whole cortex. These appearances were especially noted in the suprarenals of young lambs. Observations on the Growth of the Suprarenal Cortex 495
Fig. 7. Kidneys and suprarenals of a number of Ungulates. All drawn to the same scale. A. Pig, 24-hours-old male. Right kidney and suprarenal from behind. B. Pig, 6-days-old male. Right kidney and suprarenal from behind. C. Hippopotamus. Foetal male (mid-term). Left kidney and suprarenal from the front, D. Lamb, 2-days-old male. Right kidney and suprarenal from behind. E. Calf. Early foetus male. Left kidney and suprarenal from behind. F. Calf.
Mid-term foetus male. Left kidney and suprarenal from behind.
Fig. 8. Drawings of the naked-eye appearances of transverse sections of the suprarenals of a series of Ungulates. All drawn to the same scale. A. Lamb, 24 hoursold. B. Lamb, 2 days old. C. Lamb, 5 weeks old. D. Adult sheep. E. Adult pig. In A and B the radial striation of the deep parts of the cortex indicates the area of vascular infiltration. The dark spot in the centre of the gland is the central vein cut across. The drawings D and E were made after the material had been fixed for some hours in Miiller’s fluid, the medulla thus being darkly stained. 496 W. C. Osman Hill +
The microscopic appearances of the suprarenal structure are very variable in the different animals studied. It will therefore be necessary to describe the phases seen in (a) the pig, (b) the lamb, and (c) the goat separately.
In the pig at birth (sce fig. 9, A) the cortex is nearly homogeneous, consisting almost entirely of large cells with vesicular nuclei and eosinophil cytoplasm. These cells are arranged in columns radiating from the centre of the gland. At first they do not show a well-marked lipoid reaction, but in 5 or 6 days this reaction is well marked in all the cortical cells. In addition to this main mass of cells there are a few very small cells underneath the capsule of the gland. They form a very narrow strip in this situation, and are not arranged in any glomerular formation. In a 3-wecks-old pig these small cells have grown to produce a definite layer about twice as thick as at birth, but still do not show a definite glomerular arrangement. They stain deeply with haematoxylin in marked contrast to the deeper cells. Their nuclei are not vesicular and their cytoplasm not markedly cosinophil. The medulla of the suprarenal of young pigs is not present in great quantity though exceeding the amount in Primates. The cortico-medullary boundary is not well marked at birth, but becomes so by the age of 3 weeks.
Vascular changes occur in the meantime, but these are not so well marked as in the lamb described below. There is an engorgement of the vessels of the main mass of the cortex and this is still seen at the 3-weeks-old stage. There are no definite haemorrhages such as are seen in the lamb and the goat.
In the adult pig the main mass of the suprarenal still consists of cortex, though this is not so hyperplastic as in the sheep (sec fig. 8). The corticomedullary boundary is very definite; though there is one large mass of cortex almost completely surrounded by medulla on account of the folding of the gland surface. The main mass of cortex consists of large eosinophil cells with vesicular nuclei and arranged in columns extending from the medulla outwards to the layer of small cells lying beneath the capsule. This layer of small cells corresponding to the glomerular zone of higher forms is about four times as thick as in the new-born pig, and does not show any definite line of demarcation from the deeper zone. On the contrary there is a tendency for the small cells to grow down between the columns of the deep layer of cortex
fig. 9, B). (see fig. 9 B) (b) Lamb
The most striking phenomena associated with the growth of the suprarenal cortex of the sheep are the vascular changes which occur immediately after birth. These vascular changes are in well-marked contrast to the condition just described above in pigs.
In the new-born lamb the suprarenal cortex consists of two main types of cells as in the pig. Immediately beneath the capsule is a very thin stratum of tiny cells staining deeply with haematoxylin. The rest of the cortex is made up of large pale cells staining with eosin. The large cells have reticular nuclei. In the main they are arranged in columns at right angles to the gland surface, but deeper in they are more closely packed and arranged in a reticular formation. The cortico-medullary boundary is indefinite. Between the groups of cells constituting the deeper half of the cortex, the small vessels radiating into the gland tissue from the central vein are seen to be packed tightly with red blood corpuscles. The engorgement is less striking as the surface of the gland is approached.
In a lamb of 24 hours the vascular engorgement has increased and involves the whole cortex, thus giving it a radially striated appearance even to the naked eye. The engorgement is also more distinctly marked in the region where cortex and medulla come together. Here the vessels radiating outwards are seen to branch so as to allow for a twig to pass outwards between each cell column.
In a lamb of 2 days old the vascular engorgement has gone on to the extent of rupture of the vessel walls and consequent haemorrhage into the cortical tissues. In many parts the haemorrhage is extensive. There is, however, no apparent destruction of cortical tissue by this process. The cells of the main mass of cortex are still quite healthy. They have well-staining nuclei and a large bulk of cytoplasm as in the new-born lamb. The thin superficial stratum of small cells does not exhibit any change.
In a lamb of 5 weeks old all the vascular phenomena have subsided, but important cellular changes are to be seen in the cortex. The stratum of small cells under the capsule has grown to about twice its former thickness, and the cells in it have become more tightly packed, but there is no evidence of any glomerular arrangement. The main mass of cortex remains as in the previous stage, but from its deep aspect in parts of the gland a decided downgrowth of cortical cells has occurred into the medulla. These cells are arranged in reticular formation. They cause the cortico-medullary boundary to maintain its original indefiniteness.
In the adult sheep the cortex of the suprarenal is of enormous thickness. The medulla is merely a soft nodule of tissue embedded in its centre. Practically the whole of this mass of cortex consists of the large cells arranged in columns. The cortico-medullary boundary is very definite and the reticular zone has obviously disappeared.
In a new-born kid the microscopical characters of the suprarenal were very similar to those of the suprarenal of the lamb at the same age. Most of the gland consisted of cortex; but medulla was slightly more bulky than in the lamb. The division of the cortex into two zones was more definite than in the lamb. The superficial stratum of small cells was thicker and the cells more closely packed together, though showing no glomerular arrangement. The deeper cells forming the main mass of cortex were large, pale and eosinophil and were arranged in columns as in other forms. Between the columns the radial vessels were seen in parts to be in a state of engorgement. The engorgement has in places passed on to the stage of minute haemorrhages into the cortical tissues. These haemorrhages affect both zones of cortex, but are particularly prevalent at the junction between the deep and superficial zones.
Fig. 94. Microscopic appearances of the suprarenal of a pig, 6 days old. c. capsule; s.c. superficial cortical zone; d.c. deep cortical zone; m. medulla; v. central vein. Observations on the Growth of the Suprarenal Cortex 499
Fig. 98. Microscopic appearances of the suprarenal of an adult pig. c. capsule; s.c. superficial cortical zone; d.c. deep cortical zone; m. medulla.
Summary and Conclusions
1. The structure of the suprarenal gland is described in young animals of the three mammalian orders, Primates, Carnivora and Ungulata, with special reference to the cortex.
2. It is shown that in all the new-born Primates examined the suprarenal presents the same size relations to the kidney as in the new-born human child; and the enlargement is shown to be due to the same factor, namely a cortical hypertrophy. In all the specimens studied the hypertrophy affects the deeper cortical layer, and is therefore comparable to the “foetal” cortex of the human foetal suprarenal. Atrophy of this zone gives the adult gland a wrinkled surface.
83. The suggestion that the lipoid reaction is of no diagnostic value in the discrimination of “‘foetal” cortex is confirmed.
4, The zona reticulata of the adult gland like its predecessor, the “foetal” cortex, is shown to be a transient structure, at any rate, in male Primates.
5. In mammals lower than Primates there is at the time of birth no marked enlargement of the suprarenal gland; the adult gland has as smooth a surface as the young one. In most instances, however, the relative proportions between cortex and medulla are different from those seen in the adult gland. There is always more cortex than medulla at birth. Medulla may indeed be very scanty.
6. The cortico-medullary boundary in the suprarenal of young Carnivores and Ungulates is indefinite, suggesting that some process of modification is taking place there; either an absorption of the intra-medullary islands of cortex, or a downgrowth of cortex to meet these and fuse with them.
7. The structure of the suprarenal cortex in young Carnivores and Ungulates seems to indicate that the main mass of this part of the gland consists of cells morphologically similar to those of the “foetal” cortex of Primates. The rest of the cortex consists of a peripheral rim of small cells with no uniform arrangement, but morphologically similar to the “true” cortex of Man. There is, however, no indication of an extensive degenerative process affecting the main cortical mass; hence the absence of any relative decrease in size with consequent wrinkling of the gland surface during the later stages of growth. By virtue of these facts the zone of small cells immediately beneath the capsule never emerges from its pristine undifferentiated condition as it does in Primates. One important process, however, must not be lost sight of in giving an explanation of the microscopic appearances of the cortex in young animals, and that is the phenomenon of vascular engorgement and haemorrhage. A significant fact is that the vascular changes, even when ending in haemorrhage, do not cause the destruction of any gland tissue. This remark applies equally well to the Primate suprarenal, where the “foetal” cortex does eventually degenerate and disappear. The degeneration of foetal tissue in these forms must therefore be due to an entirely different process, and consequently another explanation - must be offered for the occurrence of engorgement and haemorrhage. : Possibly the increased vascularity is associated with the active growth or temporarily increased activity on the part of the main mass of the cortex. Extravasated blood in animals where haemorrhage occurs may act as pabulum for the actively growing cortical cells.
8. The zona reticulata, whenever it appears in mammals below the Primates, is shown to be a transient structure.
9. In all the animals examined the measurements show that the suprarenal is larger in female than in male animals at the time of birth.
In conclusion I wish to offer my thanks to Prof. J. C. Brash for his kindly help and criticism throughout my work; to Prof. Haswell Wilson for the use of apparatus in the Pathology Department; and to Mr H. G. Newth of the Zoology Department for one of the foetal macaques. The other foetal macaque and certain other material I have obtained through the kindness of the authorities of the Botanical Gardens, Edgbaston, Birmingham.
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