Paper - The development of the sex cords in the gonads of man and mammals
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Gruenwald P. The development of the sex cords in the gonads of man and mammals. (1942) Amer. J Anat. 359-396.
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- 1 The Development of the Sex Cords in the Gonads of Man and Mammals
- 1.1 Introduction
- 1.2 Material and Methods
- 1.3 Observations
- 1.4 Discussion and Conclusions
- 1.5 Summary
- 1.6 Literature Cited
- 1.7 Plates
The Development of the Sex Cords in the Gonads of Man and Mammals
Department of Anatomy, The Chicago Medical School, Illinois
Four Plates (Twenty Figures)
Of all parts of the developing gonads, the sex cords have received most attention from the embryologists. They appear as the most important constituents of the gonads because they contain the primordial sex cells, and their somatic cells serve a direct auxiliary function in the process of sex cell maturation. Other parts of the gonads, as for example, the surface epithelium or the rete, are‘ often discussed in their developmental or functional relations to the sex cords; thus we find many of the discussions of development or structure of the gonads centered upon a description of these cords and their derivatives. However, our knowledge of sex cord development itself is anything but perfect. There is still no agreement on such important questions as the origin of these cords or their homologgv in both sexes.
.‘/ontinued observations and the acquisition of more material has led to the discovery of many additional details not given in the author’s earlier papers (’34, ’36). As a consequence, a more complete and better founded account of sex cord development can now be given. In view of the large number of summarizing articles on the subject, no detailed review of the literature seems necessary; representative references will be mentioned tliroughout the report.
Gonads of cat and human embryos are described as representatives of two fa.ir1_v distinct types of sex cord development in the ovary. All other mammalian species investigated by the author up to the present time, conform to one or the other of these types in the formation of their sex cords; it is quite possible, however, that transitional forms of sex cord development exist in other mammals.
This report is concerned with the somatic cells of the sex cords, and all statements refer to those cells only, unless sex cells are specifically mentioned. However, the present investigation may turn out to refer indirectly to the sex cells if definite evidence of the origin of these cells from the mesodermal tissues of the gonad materializes.
Material and Methods
An adequate staining technic is of particular importance in investigations on gonad development, because in early stages the histological characteristics of these organs are less distinct than those of many other primordia. Azan stain proved to be the best for general information on the structure of the gonads and their early primordia, and also for many details. It combines a fairly good presentation of the cells themselves with a distinct stain of the collagenous connective tissue, and this is in many cases sufficient to demonstrate the arrangement of cells and define the boundaries of epithelial cell groups or layers. In other instances silver impregnation was used, showing the most delicate reticular connective—tissue fibrils in very clear pictures. It should, however, always be used in combination with azan stained sections of the sa.me tissue in order to make up for the unstained cells. All silver impregnations were done with Gomori’s (’37, ’39) method. Hematoxylin stain was not used except in a few instances when sections prepared earlier for other purposes were investigated. The embryos and organs listed below were fixed in various solutions, most of them in Bouin’s ﬂuid; the thickness of sections was 5 to 10 u. Embryos are characterized by their crown-rump length in millimeters, postnatal stages as newborn (nb), juvenile (j), or adult (a). Print in italics (as 12) indicates that the complete embryo or a large part of it, usually containing both gonads, was sectioned. With few exceptions serial sections were available.
Stages prior to risible sexual de]7”erentiat7on: Man: 2, 5, 7,5, .9, 9, 9,5, 10, 10, 10,5, 11, 1-5’, 13,5, 14, 14, 15, 15, 15, 15,5, 16‘, 16, 17, 17.
Dog: 8, 8, 8, 10,5, 15, 15.
Pig: 7, 7, 15, 16,5, 17, 18, 18,5.
Rat: 6,5, 9.
Rabbit: .9, 9, .9.
Ovaries: Man: 20, :31, .24, 3rd month, 42, 50, 55, 60, 62, 72, 80, 90, 92, 95, 100, 102, 105, 140, 142, 150, 155, 160, 160, 190, 200, 210, 240, 270, 280, nb.
Cat: 2.2, 48, 65, 70, 75, 77, 77, 87, 100, 110, 120, 3, a.
Dog: 85, 85, 95, 150, 150, 160, 111), several a.
Pig: 20, 26, 31, 33, 42,5, 64, '74, 96, 98, 102, 109, 160, a.
Mouse: 9, 9,5, 9,5, 10,5, 13, 14, 14,5, 15,5, 17, nb.
Rat: 17, 17,5, 19, 23, 24, 28, 11b.
Rabbit: several :1.
Guinea pig: nb, a.
’1'csIes : Man: 18, 20, 31, 21, 2:2, .25, 28, 30, 48, 51, 60, 105. Cat: 4?, 47, 54, 61, 61, 66, 69, 70, 70, 70, 75, 75, 76, 76, 83, 88, 90, 95, 95, 100, 100, 117, 120, 120, 120, 120, 130, 130, 130, 131'), nb, j, j, a.
Dog: 34, 43, 69, 85, 85, 95, 95, 140.
P-lg: 19, 24,5, 27, 30, 30, 30, 37, 42, 43, 48, 62, 96, 105.
Mouse: 9, 9,5, 11, 19,5.
Bat: 12, 15, 16, 23.
Rabbit: 50, 56, j, j.
Spermophilu8.' 18, 20,5, 29,5, 35, 38, 39.
Hedge hog: 13, 33, 36, 39.
A limited series of representative observations will be described here; detailed reports of the findings in all available specimens would greatly exceed the desirable limits of space without contributing essentially to the problem under consideration. As mentioned in the introduction, the development of the secondary sex cords in cat and man will be described as representing the two types observed. These species were chosen because sufficient material was at hand to give a complete description; furthermore, the formation of secondary sex cords in the testis was successfully studied in these two forms.
Early gonad development; the formation of the primary sex cards A satisfactory interpretation of early development of the gonad is possible only on the basis of thorough knowledge of structure and properties of its mother tissue. Therefore, the present investigation was begun with a study of the coelomic wall at a stage prior to the development of the gonad primordium from it.
Duringiearly development the coelomic cavities are clefts in the lateral mesoderm. It is well known that their lining is at first nothing but a layer of mesoderm which, because it bounds a cavity, differs from deeper layers in the arrangement of its cells. In all other respects, the superficial cells show the closest similarity to the deep ones; on their basal side they are provided with the processes characteristic of mesenchymal cells. When these cells divide, one of the daughter cells may sink deeper into the tissue and become an ordinary mesenchymal cell. In early stages mesenchyme formation from the lining of the coelomic cavity is so abundant in certain areas that one has to be careful to distinguish these streams of cells from the primordia of the adrenal cortex (fischel, ’1.3; Politzer, ’36). The coelomic lining can in these stages almost be regarded as the germinal layer for the underlying mesenchyme; there is, however, also multiplication of typical mesenchymal cells. During this period the layer lining the coelomic cavity and the underlying mesenchyme are to be considered as a common unit. The differentiation of the coelomic lining into a layer with all morphological characteristics of an epithelium pu.ts an end to this condition. This happens in different parts of the coelomic wall at dilferent stages, and is almost completed in human embryos of 8 mm. The last areas to acquire epithelial structure are found at the bottom of various grooves in the retroperitoneal region, as, for instance, those bounding the mesonephric ridges.
The gonads first appear immediately after the superficial lining of the genital ridge has transformed itself into an epithelium. However, when it comes to furnish a large number of cells for the gonad primordium, the coelomic wall once more acts as a common unit and the epithelium actively participates in the production of cells for the early gonad. This does not, as described by many investigators, happen by means of distinctly bounded epithelial buds and cords growing into the subjacent mesenchyme, but by abolishing the newly acquired separation from it. Thus the early condition is reestablished, enabling the superficial layer to contribute to the growth of the underlying tissue. The recently formed basal membrane is now found perforated (fig. 1) and the gonad blastema consists of a mass of cells in which no epithelium is present. Sections with silver impregnation of the reticulum give the clearest pictures of this condition (fig. 2). The formation of this gonad blastema was considered as a mingling of epithelial and mesenchymal cells by van Vloten (’27) and Higuchi (’32), which is misleading because it creates the impression that there is a mixture of cells of different properties and potencies. This, however, is not the case; microscopic study does not reveal difierences in the morphological characteristics of the cells, apart from the primordial germ cells which will not be considered here. There is, moreover, no reason to suspect potential differences in this tissue just because it had gone through a very short period of separation into meso thelium and mesenchyme. There are many indications of a permanent close similarity of potencies of these two (Maximow, ’27; Gruenwald, ’-12). We have to consider the gonad blastema as a potentially uniform part of the coelomic wall, produced by a cooperation of superficial and deep layers in the same way as much of the viceral and parietal mesenchyme had been formed during earlier stages.
The primary sex cords soon begin to differentiate in this blastema. Their formation will be described here as it occurs in human embryos because these represented the most complete series of stages available to the author. In embryos of about 13 to 15 mm. heavier layers of argyrophile fibers appear in the gonads, arranged perpendicularly to the surface of the organ. They divide most of the gonad into incompletely bounded cell cords (figs. 3, 4). In embryos of 15 to 17 mm., the first indication of sex differences appears as a slightly better limitation and more parallel arrangement of the cords in the testis (fig. 5). Gonads of the same age with thicker and less regular cords can with great probability be identified as ovaries (fig. 6). During this period, the sex cords in gonads of both sexes are particularly ill—defined at their ends, that is, near the surface of the organ and opposite to it, near the attachment of the gonad to the mesonephros. This condition prevails in testes as Well as in ovaries through a brief following period during which the sex of the gonad becomes clearly evident from the shape of the cords. This fact is well known as far as the ovary is concerned. Regarding the testis, however, many descriptions in the literature refer to stages too early to show a complete separtion of the sex cords from their surroundings. There is, after distinct differentiation into testis, a period during which the sex cords as Well as the superficial mesothelium are incompletely bounded and cannot be clearly differentiated from the tissue destined to become the tunica albuginea. This condition can be clearly demonstrated by azan stain as well as by impregnation of the argyrophile fibers (fig. 7). The tunica albuginea in the human testis is not clearly delimited until the embryo reaches a "length of about 25 mm. By this time, a clear—eut separation of the sex cords from the surrounding tissue exists throughout the testis. A comparison of stages before and after this separation shows that many cell groups attached to the sex cords in the earlier stages, will in all probability give rise to clusters of interstitial cells. This observation will be discussed later in this report (p. 380). The superficial mesothelium acquires a distinct basal boundary at about the same time as do the distal parts of the sex cords.
These observations cast suspicion on previous statements regarding the recognition of sex diiferences in early gonads. The author, in agreement with several other investigators, had previously assumed (’36 b) that testes can be recognized as such in human embryos of 13 mm. The present investigation shows, however, that the earliest stage which allows this decision with suﬂicient reliability, is reached in human embryos of about 17 mm.
All available mammalian testes of proper stages show essentially the same course of development. The primary sex cords arise from a uniform blastema formed by the coelomic wall in the region of the genital ridge. The mass of these cords then becomes separated from the superficial mesothelium by a. tunica albuginea soon after the gonad can be recognized as male.
In the ovary, a corresponding separation of the primary sex cords from the surface of the organ occurs only in part of the species as exemplified in the following chapter by the findings in the cat. In the ovaries of this species, the primary sex cords are thin and separated from each other by large amounts of connective tissue. Toward the surface of the organ the cords gradually decrease in number, and a zone near the surface lining is almost or entirely devoid of primary sex cords (fig. 8). In the other group of mammals including man, however, the primary cords form a dense mass with little mesenchyme between them, and no connective tissue layer comparable to a tunica albuginea separates them from the epithelium of the surface. Some of the primary cords remain connected with the epithelium until the formation of secondary sex cords begins. The secondary cords are in these species never as clearly distinguished from the primary ones as they are in the cat and its equals. This difference in the arrangement of the primary sex cords of the ovary will be brought out in the following chapters, together with a consecutive difference in the formation of the secondary cords. Both these differences are not essential ones, and it is not improbable that species with an intermediate form of development will be found.
The formation of the secondary sex cords in cat embryos It is not surprising that certain details of the formation of secondary sex cords were first described in a species with primary sex cords well separated from the surface lining of the ovary, as is the case in the pig (Gruenwald, ’34 b). The development of the ovary in the cat to be described here, has much in common with that in the pig. Both show, in contrast to the human ovary, a distinct separation of primary and secondary sex cords during a long period of embryonic life. The formation of the secondary sex cords can, therefore, more easily be seen and understood in these and similar forms than in man a11d other species belonging to the second group to be described later in this report.
It had been found in pig embryos that the first visible step in the development of the secondary sex cords is a change in the superficial epithelium of the ovary, transforming it into two distinctly separated layers. The basal layer, which in the pig ovary exceeds the superficial layer in height, gives origin to most of the secondary sex cords. In later stages this layer disappears, apparently being used up by sex cord formation, and the remaining epithelium (the former peripheral layer) seems to carry on sex cord formation to a lesser extent. \Vhen this was reported it was not known whether a Well developed basal layer of the surface epithelium of the embryonic ovary is a peculiarity of the pig, or a more common condition in mammal embryos. It is of interest, therefore, to point out that the embryonic cat ovaries at hand show stages of the same process even clearer than pig gonads.
The earliest stage available (22-mm. embryo) shows the epithelial surface lining of the ovary divided into two distinctly different layers (fig. 8). The basal layer is the taller one and contains, among others, very large cells which may be primordial sex cells. In this gonad secondary sex cords have not yet appeared. The primary cords are, as in most embryonic ovaries, indistinctly visible. They form in their entirety a denser inner zone of the organ, separated from the surface epithelium by a layer of loose mesenchyme free of sex cords.
In the older stages observed, up to and including the 87-mm. embryo, the two layers of the surface epithelium can constantly be seen. The basal layer is now continuous with secondary sex cords extending into the organ through the above mentioned outer layer of loose mesenchyme (fig. 9). In their structure, these cords and the basal layer of the surface epithelium are almost identical, so that the latter may be regarded as a continuous layer of sex cord tissue at the periphery of the organ, giving rise to the cords themselves.
The oldest embryonic cat ovaries available (100 to 120-mm. embryos) no longer show a basal layer of the surface epithelium. Here, too, as in the pig embryo, some of the secondary sex cords are now attached to the only remaining layer of surface epithelium (fig. 10), and it is probable that these cords receive contributions from the epithelium. Here, however, the structure of the surface epithelium is considerably different from that of the attached sex cords, and a gradual transition from the one to the other is noticeable within the peripheral portion of the cords. In this respect, too, the conditions found in the cat are clearly comparable to those previously described in the pig (see ’34 b, fig. 4), and the diagram of sex cord formation given in that report can be applied to the cat as well as to the pig embryo.
The observations made in the testes of cat embryos illustrate the occurrence of vestigial male secondary sex cords. It is generally assumed that the mammalian testis does not develop sex cords comparable to the secondary sex cords of the ovary. All seminiferous tubules are said to develop from the first and only generation of sex cords. This led to the Well known theory of the development of the mammalian gonads Worked out especially by Kohn (’20) who held that the ovary in its central part contains a vestigial testis, that is, the primary cords. The testis, according to this theory, contains no homologue of the essential part of the ovary; the secondary sex cords are said to be purely ovarian structures.
A serious objection to this theory arose when the author described secondary sex cords in the testes of several normal human embryos (’34 c). They did not form vestigial ovarian tissue but normal primordia. of seminiferous tubules of the same structure as the primary cords. At that time no secondary sex cords could be seen in testes of other mammal embryos. Only the structure of the surface epithelium in the testes of cat and pig embryos of certain stages was found to correspond to that preceding the formation of secondary sex cords in the ovary (’36 a). In the case of the pig, the study of older stages revealed no evidence of secondary sex cords developing from this peculiar epithelium. The further development in the cat could not be traced at that time for want of material of proper stages. With the specimens now at hand some more information can be obtained.
The peculiarities found in the testis of the 42—mm. cat embryo were briefly reported in a previous publication (’34 a), at a time when the above described method of formation of the secondary sex cords in the ovary was still unknown. In this testis a great part of the surface epithelium shows a well separated basal layer (fig. 11) similar to that seen in the ovary, though not as tall. In all other available stages up to the 95-mm. embryo this same peculiarity of the surface epithelium was found, with the basal layer slightly exceeding the superficial layer in height. From the 61-mm. stage on, the basal membrane of this epithelium is not plane as it is in the earlier stages, but more or less uneven due to projections of the basal epithelial layer toward the tunica albuginea. In several instances epithelial cell cords connected with the basal layer were found in the tunica albuginea (figs. 12, 13). This shows that in the embryonic cat testis the sex-cord forming basal layer of the surface epithelium does not disappear early without forming cords as in the pig, but persists for a longer time and gives rise to vestigial secondary sex cords.
From the 100-mm. stage on, neither the special basal layer of the surface epithelium nor vestigial secondary sex cords were seen in most of the testes. Only one finding may be vaguely related to secondary cords: interstitial cell cords can be seen in these testes of old embryos, peripheral to the larger blood vessels of the tunica albuginea. This is a location in which no interstitial cells, but the vestigial secondary sex cords were found in earlier stages. These interstitial cells may be related to secondary sex cords in two ways. They may have developed around the sex cords and persisted after the cords degenerated, or they may have originated from the sex cords themselves by transformation} Accumulations of cells with increased amounts of cytoplasm and spherical nuclei 11ear some of the vestigial secondary sex cords (fig. 13) suggest the presence of interstitial cells associated with these cords; their origin could not be determined with the material at hand. Whatever the fate of the secondary sex cords in the cat testis may be, the fact that they develop, at least as transitory structures, from the special basal layer of the surface epithelium cannot be doubted any longer.
As far as can be concluded from the material available, development of the sex cords proceeds in a very similar manner in embryonic ovaries of dog, pig, and cattle. Regarding secondary sex cords in the testes of these species, an ob servation in pig embryos published and illustrated in an earlier contribution (’36 a) was mentioned above: a well separated inner layer of the surface epithelium similar to that described here in embryonic cat testes, was found in pig embryos of about 30 mm. To the best of the author’s knowledge, this layer does not give rise to sex cords in the pig testis, but it is evidence of some potency of sex cord formation in the mesothelium of the pig testis. Moskoff (’30) made an observation in sheep testes that may also be related to secondary sex cords. He found seminiferous tubules in the tunica albuginea in a high percentage of embryos as well as young sheep. Moskoff found no connections with the surface epithelium, and suspected herniation of primary cords through weak points in the tunica albuginea. However, his findings must be kept in mind as possible secondary sex cords as long as no conclusive evidence to the contrary is presented.
- About the possibility of such transformation, see pages 380 to 382.
The formation of secondary sex cords in human embryos Earlier investigation of human ovaries (’34 b) revealed that a condition comparable to the special basal layer of the mesothelium in the cat and pig, also exists in the human embryo. Here, however, it is not nearly as distinct and widely distributed as in the species described in the previous section; this is easily understood if one remembers the different shape and distribution of the primary sex cords and the absence of a tunica albuginea in the human ovary at the beginning of formation of the secondary cords (see p. 365). \Vhen these cords begin to develop, the primary cords are still connected with the surface epithelium in many places, and even those separated from the epithelium are very close to its basal surface. There is no distinct difference between primary and secondary sex cords in the human ovary, neither in the time of their formation nor in their shape. Due to the continued connection of sex cords with the surface epithelium, a separate basal layer can only form in small areas, as shown earlier in two 20-mm. embryos by azan stain (’34.~ b, figs. 9 and 10). Secondary cords developing from the surface lining with or without preceding formation of a distinct basal layer, are from the very beginning continuous with the thick primary cords. In later stages, the cords nearest the surface which are doubtless secondary cords, by far exceed the more centrally located ones in diameter (fig. 14). There is, however, no conclusive evidence to indicate that the change in diameter coincides with the boundary between primary and secondary cords. As a matter of fact there is no time at which this boundary can be determined in human ovaries. Here, as in the cat and pig, the only layer of the surface epithelium left in late stages probably contributes to sex cord formation (Gruenwald, ’34 b).
Secondary sex cords in mammalian testes were first found in human embryos (Grruenwald, ’34: c). They were seen in large numbers in two embryos of 106 mm. and 171 mm. CHL, respectively. In both cases, groups of histologically younger cords were present between the surface epithelium and the tunica albuginea, in many points connected with the epithelium and in a few places perforating the tunica albuginea and continuous with primary cords. Single cords attached to the surface epithelium were seen in several additional embryos. Groups of large, pale cells in the superficial epithelium, bulging toward the tunica albuginea, were found to be common in embryonic human testes, and designated as probable early stages of sex cord formation, comparable to the poorly developed special basal layer of the epithelium in the human ovary. Since the publication of that report, the author has seen serially sectioned testes of only a few (probably less than six) human embryos old enough to show secondary sex cords. In two of these embryos such cords were found. One is a eo1n— plctely sectioned normal embryo of 48 mm. CRL (67 mm. CHL) ; two small groups of typical secondary cords are present in one testis (fig. 15). In the other case, only about onehalf of one testis present in serial sections of the pelvis of a 51-min. embryo (CRL) showed a larger group of similar cords (fig, 16). This latter case is particularly instructive because the cords in question had been completely overlooked until the sections, originally stained with hemalum and eosin, were restained with azan or silver impregnation. (The cords are, of course, not invisible with hemalum stain, but they easily escape attention particularly i11 areas with a thin and dense tnnica albuginea.) These additional observations indicate that secondary sex cords may not be as rare in male human embryos as was originally believed. The surface epithelium of the testis can, therefore, not be as inactive and incapable of sex cord formation as the customary description indicates. There is every indication that the secondary sex cords form normal and functional seminiferous tubules in the human testis. In most instances some of these cords are continuous with primary cords, and both have near their junction the same histological structure.
Sex cord formation similar to that just described in the human ovary occurs in embryonic ovaries of the rat and possibly also the mouse. In these forms, too, very little connective tissue separates the primary cords from each other and from the surface epithelium, and no large areas of that epithelium are provided with a continuous sex-cord forming basal layer (Gruenwald, ’34 b). Secondary sex cords were never seen in testes of these rddents; however, the number of observations on record is not large enough to allow a final statement.
Discussion and Conclusions
After a summarizing review of the findings described in the preceding sections, conclusions will be drawn concerning the relations of the sex cords of both sexes to each other and to other parts of the gonads. The question of the origin of the sex cells and their possible inﬂuence on sex cord formation will not be discussed since no new evidence was gained by the present investigation. A few observations concerning developmental relations of sex cords and the interstitial tissue will be brieﬂy reported in the respective part of the following discussion.
The formation of the sex cords
Every theoretically possible method of formation of the primary sex cords has been advocated in the literature. The majority of the investigators hold that cell cords grow into the early gonad primordium from its epithelial surface lining. The opposite opinion, that is, complete inactivity of the superficial epithelium and sex cord formation from the mesenchyme only, was advanced by fischel (’30). An intermediate opinion is that of van Vloten (’27) and Higuehi (’32), tracing the primary sex cords back to a mixture of epithelial and mesenchymal cells. The present account of early gonad development shows that epithelium and mesenchyme cannot be distinguished in the gonad at the time when differentiation of the primary cords begins. At this stage the earlier condition of the coelomic wall is reestablished for a limited period of time: superficial and deep layers form a morphologically and potentially uniform blastema, and the surface lining resumes its epithelial structure only when formation of the primary sex cords is well under way. Histological characteristics are very vague at this stage, and this accounts for the many divergent opinions on early gonad development.
When the secondary cords form, the conditions in the gonad are quite different. The surface epithelium as well as the deeper cells of the gonad are morphologically more highly specialized and the formation of a blastema like that in the early gonad does not occur. Previous investigators are almost unanimous in assuming that the secondary cords develop from buds which grow into the gonad from the surface epithelium. Only fischel opposes this view and holds that the surface lining of the ovary (secondary sex cords in the testes of mammals were unknown at that time) never participates in sex cord formation. His argument is that the sex cords are at all times well distinguished from the surface epithelium by the morphological characteristics of their cells, and that no transitional cell form can be seen. According to the author’s own observations (see also ’34 b), this is, at least partly, correct. Fluent transitions between the cells of the epithelium and those of the secondary cords are indeed not as common as one would expect, assuming that the cords developed by transformation and ingrowth of superficial cells. The presence in the epithelium of a special basal layer forming the sex cords, explains the lack of transitions between the cords and the superficial layer; the basal layer is almost invisible as such unless connective tissue stains are employed, and was not observed by previous investigators. This accounts foi fischel’s findings. The customary description of the development of the secondary cords of the ovary from the surface epithelium can be advocated according to the findings reported here, as far as it concerns the tissue from which the cords originate. However, new details of the mechanism of sex cord formation are described, including the formation of the special basal layer of the surface epithelium preceding the ingrowth of the sex cords proper. The superficial layer contributes to sex cord formation only in late stages when the basal layer is apparently used up.
Early stages in the formation of secondary sex cords in the male are, wherever observed, comparable to those in the female. In the pig and cat, a very distinct basal layer of the surface epithelium is seen in the ovary, and an equally distinct, though lower layer develops in the testis. In the pig it seems to disappear without forming sex cords, whereas in the cat vestigial and probably transitory cords are formed from it. In man where there is an indistinct and inconspicuous basal layer in the ovary, the only comparable structures in the testis are cell groups at the base of the surface epithelium as described previously (’36 a). Secondary sex cords may develop in great numbers and to a high perfection. They establish connections with primary cords (fig. 22) or directly with the rete (Grruenwald, ’34c) and finally can not be distinguished from primary cords. They form, in all probability, functional seminiferous tubules.
A distinction between two types of sex cord development was made here only for purposes of description. The process of formation of these cords is essentially the same in both types and the difference, as conspicuous as it may appear upon comparison of the specimens, is due only to different amounts of mesenchyme separating the primary cords from each other and from the surface epithelium. It is, therefore, quite probable that transitional forms exist in species not yet examined with satisfactory technic and the knowledge of the processes described here.
Many peculiarities of the surface epithelium of the gonads have been carefully investigated with regard to sex cord formation. Proliferations and thickenings of the epithelium of the embryonic testis were described in an attempt to show evidence of a vestigial formative capacity of that epithelium. Hett (’27, ’30, ’32) published extensive descriptions of such findings in various mammals, but failed to distinguish those related to sex cord formation from others of quite different significance. Hett did not see actual sex cord formation; many of the thickenings and proliferations of the surface epithelium described in his papers are of a very peculiar type which was later investigated by the present author (’34 a). It was found that these areas of increased activity of the epithelium are in their distribution closely related to the large blood vessels in the tunica albuginea. These proliferations are probably reactions of the mesothelium to some unknown inﬂuence of the underlying blood vessels, and were never seen to form anything resembling sex cords. Buds and stratifications of the surface mesothelium related to sex cord formation such as those described by the author in the testes of man, cat, and pig, are independent of the course of blood vessels, and differ in their structure essentially from the rest of the epithelium. Both types of proliferations were, up to the present time, never found in the same species.
In the ovary, the activity of the surface lining seems to continue well into postnatal life. According to several reports (for details and references see Swezy, ’33), follicles are formed in the ovaries of some mammalian species by periodic proliferation of the superficial epithelium during sexual maturity. N 0 adequate material was available to the author to verify these reports. Experiments on mice have revealed that after x—ray irradiation the epithelium on the surface of the ovary proliferates abundantly, as if attempting to regenerate the parenchyma destroyed by the experiment (Parkes, ’26; Geller, ’30). N 0 sex cells were found in these newly formed cell groups, but luteinization was reported. In the dog ovary, similar proliferations can regularly be observed under normal conditions (fig. 17). The “anovu1ar” follicles resulting from those ingrowths were thoroughly described by J onckheere (’30). It is tempting to regard these buds in the dog ovary as vestigial sex cords. Entirely different groups of 376 PETER GRUENVVALD mushroom—shaped projections were seen on the surface of the ovaries of adult rabbits. In this case, however, there is no reason to bring the outward directed proliferations lined with typical surface epithelium, in connection with sex cord formation. These various peculiarities were described here to show that formative activities of the gonad epithelium must be interpreted with great care; they may, but do not necessarily, indicate a remaining potency of sex cord production.
The homology of ovary and testis - the embryologieal basis of ovariotestis formation
The commonly held conception of homology of certain parts iii the ovary and testis is best represented by Kohn’s well known and much quoted article on the structural plan of the gonads (’20). Secondary sex cords in the testes of amniotes were unknown at that time and it was concluded that the ovary contains, in its primary sex cords, homologues to the sex cords of the testis; the testis, on the other hand, was said to contain no homologue to the essential parts of the ovary derived from secondary sex cords. Since the primary cords of the ovary were thought to be of no considerable importance and, moreover, since they developed in a manner similar to testicular cords in a few species, it was held by many authors that the ovary contains in its interior a vestigial testis represented by the primary cords. Kingsbury (’13) had opposed this view long ago, asserting that the primary cords of the ovary are typical ovarian in most species and cannot even be distinguished with certainty from secondary cords. The present report fully confirms Kingsbury’s opinion.
The discovery of secondary sex cords as normal constituents of the testis is incompatible with the just quoted conception of gonad homology. In reptiles, such cords have been found in normal testes by Simkins and Asana (’30), Risley (’33, ’34) and Forbes (’37, ’40), and in birds by Witschi (’35) and Unger (’36, ’37). In man and mammals, the author ’s present and previous reports are the only ones describing distinct cords as well as stages preparatory for sex cord formation and identical with those seen in the ovary. This leads to a new concept of homology of the gonads. Primary as well as secondary sex cords may be found in the gonads of both sexes. There can be no doubt that the primary cords are of greater importance in the testis, and the secondary cords in the ovary. The other generation of cords is vestigial in either sex. In some species the cords of both generations differentiate according to the sex of the embryo, Whereas in others the specificity of primary cords for testicular, and of secondary cords for ovarian differentiation seems to hold. Primary cords will then develop similar to testicular cords even in the ovary, and Vice versa. Only in these instances the primary cords may be considered as a vestigial testis in the ovary as is the case in the mole (Altmann, ’27). Similarly, secondary cords may form a vestigial ovary in the testis as described i11 part of the above quoted reports on Sauropsida. This, however, is by no means the general rule. It must now be assumed that the vestigial generation, that is the primary one in the female and the secondary one in the male, can differentiate either according to the sex of the bearer or in the opposite manner, that is, according to the sex in which it forms the essential parts of the ‘brgan. Under normal conditions only the first mentioned alternative affords a possibility for the cords of the vestigial generation to contribute to the generative part of the gonad.
The existence of a homology of the gonads more complete than it had been believed before the detection of secondary sex cords iii the testis, necessarily inﬂuences the interpretation of ovariotestes. Goldschmidt, in his standard Work on intersexuality (’31), rejects the possibility of transformation of a testis into an ovariotestis in man and mammals because of the early degeneration of the germinal epithelium, preventing the formation of secondary cords accessible to a transformation in late stages. It was pointed out in a previous report (Gruenwald, ’36) that this premise can no longer be considered correct and that embryonic gonads of both sexes can give origin to ovariotestes if sex reversal occurs for genetic or other reasons. This conception has been adopted since by Moszkowicz (’36). The potency of the surface epithelium of the testis to form secondary sex cords has been pI'0VeIl by numerous reports of experimental gonad trans— formation by injection of sex hormones. Dantchakoff and Kinderis (’38) and Forbes (’38) working on reptiles, and Dantchakoﬂ’ (’35 a, b), Wolff and Ginglinger ( ’35), and Domm (’39) using chick embryos reported formation of secondary cords in original testes after treatment with female sex l1or— mones. In these experiments gonads were transformed from testes into ovaries although under normal conditions their secondary sex cords would develop either not at all or not farther than in mammals. Previous and present findings in human a.nd mammalian testes, in conjunction with the results of hormone experiments, justify the assumption that testes as well as ovaries have the potency of forming ovariotestes under proper conditions. It should be understood that this statement only refers to the possibility of complete as well as partial transformation and in no way proves that spontaneous formation of ovariotestes actually occurs in genetic males as well as females. This question is to be answered by the geneticists.
Developmental relations of the sex cords to other parts of the gonads
The sex cords and their derivatives, being the bearers of the sex cells, may well be considered to be the principal parts of the gonad. These cords are the first specific differentiations to appear in the gonad during its early development, and it is advantageous to relate many developmental changes occurring in the gonad to the sex cords. A part of the gonad well comparable in its early development with the primary sex cords, is the rete. It appears as a group of cords near the hilus of the gonad at the time when the primary sex cords acquire distinct basal membranes on their entire surface. From their earliest stages on, the rete cords are connected with the sex cords; they form a network and the diameter of the individual cords is smaller than that of the sex cords. It cannot be decided whether or not the rete cords develop from the proximal parts of the cords appearing first in the gonad and called primary sex cords in the previous chapters. It was mentioned that these cords are at first ill—defined at their ends, and investigation of sections can, therefore, not reveal whether the rete cords develop from their proximal ends or from the mesenchyme with which they are continuous. The rete soon differentiates to high structural perfection. Its basal membrane is then heavier than that of the sex cords, and a lumen develops in the rete cords at a time when the cells are still irregularly distributed in the solid sex cords. In the ovaries of several mammalian species, rete cords or tubules may be found connected with the mesothelium of the mesovarium. A discussion of the hypothetical homology of these connections with nephrostomes is beyond the scope of the present report. In none of the species investigated by the author are these openings into the abdominal cavity sufficiently well developed to suggest the formation of considerable parts of the rete from the coelomic epithelium; most of the rete doubtless develops from the gonad blastema. The point to be emphasized here is the similarity in the early development of the rete and the primary sex cords; both differentiate from the same blastema and are continuous with each other from their earliest appearance.
Another specialized constituent of the gonad is the interstitial “gland”. It may also appear in the form of cell cords as, for instance, in the testes of cat embryos; in the testes of certain other mammals the arrangement is less regular and suggests clusters of cells rather than cords. T-he interstitial cells of the ovary are, according to the majority of the authors, represented by the theca interna of the follicles, or cells derived from the theca of atretic follicles. Only a few mammals seem to show interstitial cells in embryonic ovaries. With a few exceptions to be mentioned soon, little attention was paid to developmental relations of interstitial cells and sex cords. It seemed obvious that the interstitial cells develop in the embryonic testis by swelling of mesenchymal cells between the sex cords. However, careful examination reveals that the problem is far more complex. Very soon after the dilferentia tion of the sex cords, the testes of most mammals contain very" large amounts of interstitial tissue ; this can hardly be traced back to the scanty tissue separating the cords in earlier stages (see figs. 4, 5). Earlier in the present report it was brieﬂy mentioned that findings in human embryos suggest formation of interstitial cells from the cell cords of the early testis. In the stage represented by figure 7, the primary cords are well defined and clearly bounded by basal membranes in the central parts of the organ; peripherally, they are continuous with smaller cords of irregular shape. These are not incorporated in the sex cords when their peripheral parts delimit themselves from the surrounding tissues; however, the bulk of the interstitial cells can soon be found in their place. This makes it appear highly probable that interstitial cells form in the human testis from small peripheral extensions of the primary sex cords. It is unlikely that this is the only source of interstitial cells; the mesenchyme probably contributes essentially to their formation.
Several more observations were made, suggesting close deVelopmental relations of interstitial tissue and sex cords in the embryonic testis. Evidence gained from older cat embryos points in this direction. The testes of these embryos have a zone between the area of the sex cords and the tunica albuginea that contains only large numbers of interstitial cell cords arranged parallel to the surface of the organ, but no sex cords. (There are also interstitial cell cords in radial arrangement between the sex cords.) Only in a small area at the hilus is this layer of interstitial cell cords perforated by the rete which leads from the center of the testis to the epididymis. Here interstitial cell cords come in close contact with the rete tubules, and end—to-end junctions of both structures can be observed not infrequently (fig. 20). In this respect these interstitial cell cords behave exactly like sex cords. Another observation in the interstitial cell zone of these testes also shows close relations of these two types of cords. In this area otherwise free of sex cords, cell cords may be found which, in their structural characteristics, are intermediate between the two kinds of cords. One of these is shown in figures 18 and 19. In azan stained sections, these cords appear to have a structure very similar to that of young male sex cords. The long axes of their cells stand at right angles to the axis of the cords, and the basal membrane is well developed (fig. 18). In contrast, the typical interstitial cell cords consist of irregularly arranged cells and have indistinct basal membranes. However, the just described intermediate cords are continuous with interstitial cell cords and never with sex cords. Silver impregnation of the reticulum also shows the intermediate character of these cords (fig. 19). Unlike the interstitial cell cords, they show no trace of argyrophile fibers within the cords themselves; however, gradual transition into interstitial cell cords may also be seen in figure 19. It should be noted that these cords are found in a region of the cat testis corresponding to that in which, according to the present observations, cords connected with the sex cords are transformed into interstitial cell groups in human testes. Cat testes comparable in their developmental stage to these early human testes were not available for investigation.
These indications of close developmental and structural relations of sex cords and interstitial tissue in the testis are in agreement with several reports in the literature. Peyron and his cowo1'kers (’36) described interstitial cells developing from cells of well established sex cords in a normal testis of a 5—cm. horse embryo, after finding the same relation in gonad tumors. Unfortunately the report of these authors does not show sufficient proof of the facts stated, but in View of the tremendous masses of interstitial cells developing in the embryonic horse testis, it is not unlikely that a mode of formation of these cells otherwise restricted to earliest stages, continues on into later periods of development.
Pellegrini (’26) reported transition of Sertoli cells into interstitial cells after experimental mechanical lesion of the testicle i11 adult rats, guinea pigs and dogs. Ziegler (’30) similarly described formation of typical interstitial cells from the cells of seminiferous tubules in the adult guinea pig in cases of atrophy of the testicles following tuberculosis. Moreover, he described the reverse process if the organ recovered spontaneously or after therapy.
Due to the absence of distinct interstitial tissue from the ovaries of most mammal embryos, a comparison of the development of that tissue in both sexes is very diﬂicult. The most important contribution was made by investigations on the development of the ovary of the horse. In this species the embryonic ovary is distinguished by the presence in it of a great amount of interstitial tissue, and Kohn (’26) and Petten (’33) showed convincingly that this tissue develops by gradual but complete transformation of primary as well as secondary sex cords. Patzelt (’39) recently reported a similar transformation of primary and, to a lesser extent, secondary sex cords into interstitial cells in the ovaries of badger embryos. These observations indicate that the same close developmental relations of sex cords and interstitial tissue as described in the testis, also may prevail in the ovary.
There is evidence of interstitial cell formation from sex cords in birds, too. Nonidez (’22 a, b, ’24), Benoit (’23, ’27) and Fell (’23, ’24) described this process in developing avian gonads of both sexes. Benoit (’27) made experiments on cocks similar to those of Pellegrini on mammals and obtained corresponding results. Gray (’30) concluded from his experiments on the compensatory right gonad of the hen, that “a transformation of practically all the ‘fat-laden cells’ into typical medullary cells takes place within twenty-one to twenty-eight days following ovariotomy”. This again is parallel to Ziegler’s above quoted experiments on guinea pigs. Krediet (’37) described sex cords changing into clusters of interstitial cells in the gonads of an intersexual duck.
Finally, corpus luteum formation may be drawn into the sphere of these considerations. During this process the cells of the follicle, being derivatives of sex cords, and those of the theca representing the interstitial tissue, converge in their differentiation in such a degree that they can no longer be distinguished. In this instance, too, sex cord derivatives assume characteristics of the interstitial tissue.
Evidence was advanced in this section from my own observations and the literature, indicating much closer developmental relations and potential similarities of the tissues of the gonad than have been previously admitted. The rete and the interstitial tissue develop, at least partly, in closest association with the sex cords. In human embryos, of which the best series of stages was available for the present investigation, the early primary sex cords of the testis continue proximally into the rete cords and distally into cell groups which probably form interstitial tissue. This, however, cannot be regarded as the general scheme of gonad development in mammals. Only the rete can constantly be found in this relation to the sex cords; as to the interstitial tissue, no such general rules can be established. However, numerous observations up to those of regular transformation of sex cords into interstitial cells, are evidence of similarities in origin and potencies of both tissues. When attempting to further rationalize these results, one may, in a very diagrammatic way, trace sex cords, rete, and interstitial tissue back to cell cords which develop from the gonad blastema and soon diverge in their differentiation. It can then be said that these cords, for which the common term gonadic cords may be used, differentiate after the principle of division of labor (Gruenwald, ’39); most of the cords form sex cords whose derivatives are in their function directly auxiliary to the sex cells, others develop into the rete providing for drainage at least in the male, and a third portion gives rise to the interstitial tissue with probable endocrine function. The cord shape is not equally well established in all of these parts; male structures generally show it more distinctly than their female homologues. The interstitial tissue may develop from the original gonad blastema either by way of gonadic cords or from the mesenchymal stroma of the organ. This highly diagrammatic presentation should not be understood as covering the details of gonad development. However, it may prove to be Valuable because it emphasizes the similarities in origin and potencies of the constituents of the gonads. Work on structure, physiology and pathology of the gonads was greatly hampered because these similarities were not sufiiciently taken into account. They enable different parts of the gonad to undergo convergent diiferentiation, or transitions from one type of tissue to the other under various normal and abnormal conditions. Such changes are often reported with undue skepticism, or regarded as queer incidents rather than typical expressions of the peculiar potencies of the gonad tissues.
- During the initial phases of gonad development, the coelomic wall forms a uniform gonad blastema by contributions from mesothelium and mesenchyme. The basal membrane separating the two disappears and the superficial cells participate in the formation of the gonad blastema as they did in earlier stages in the production of the mesenchyme of the coelomic wall. No ingrowth of epithelial cell cords from the mesothelium occurs during early gonad development.
- The primary sex cords differentiate within the gonad blastema, and soon other cell cords connected with them form the rete and, in the testis, interstitial cells. In the testis, a tunica albuginea forms and separates the sex cords from the superficial cell layer which again acquires epithelial structure. In some species, as represented by the cat, a similar connective tissue layer also forms in the ovary; in others, as in man, this layer is practically absent in the ovary and the primary sex cords are not completely separated from the surface epithelium.
- The formation of secondary sex cords can easily be followed in ovaries with a connective tissue layer separating the primary sex cords from the surface epithelium. The epithelium splits into two distinct layers of which the basal one gives rise to the secondary cords until it is used up entirely. Then some of the cords are connected with the only remaining peripheral layer and receive contributions from it. The secondary cords grow through the connective tissue layer and may eventually fuse with the primary cords.
- In the absence of appreciable amounts of connective tissue below the surface epithelium, the process of formation of the secondary sex cords is difficult to analyze. Primary and secondary cords can never be sharply distinguished in these species; a special basal layer of the surface epithelium forms only in small areas and is never as well developed as in the first mentioned group. However, the process is essentially the same in both types and the difference is only due to the varying amount of connective tissue separating sex cords and epithelium in the ovary.
- Earlier reports of the occurrence of secondary sex cords iii the testes of human embryos are corroborated by new findings of the same sort. Previous descriptions of changes in the surface epithelium of pig and cat testes comparable to early stages of secondary sex cords in the ovary, are supplemented by observations of actual formation of secondary sex cords from this epithelium in male cat embryos. It can no longer be doubted that secondary sex cords may be formed in the testes of mammalian embryos.
- The primary cords of the ovary and the secondary cords of the testis may attain a highly variable degree of structural perfection, which is not surprising with regard to their vestigial character. In most species, these cords do not form vestigial gonads of the other sex, but differentiate according to the sex of their bearer.
- The existence of later developing secondary sex cords, or the potency of forming such cords in the testis affords a possibility of formation of ovariotestes from primarily male as well as female gonads if sex reversal is caused by genetic or hormonal disturbances.
- Details of the early development of sex cords, rete and interstitial tissue, along with findings of intermediate forms and reports of transitions between sex cords and interstitial tissue, disclose close similarities in the origin and poteneies of these constituents of the gonads. This suggests a uniform conception of gonad development according to which the just mentioned structures develop by “division of labor” from gonadic cords with very similar, if not identical, original properties and potencies.
The author is indebted to Dr. VV. S. Hammond of Cornell University for supplying part of the cat embryos used in this investigation.
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1 Gonad region of a 9-mm. rabbit embryo. Azan stain. The basal membrane of the coelomic epithelium is distinctly visible to both sides of the gonad; in the area of the gonad itself it has disappeared and a uniform blastcma takes the place of epithelium a11d mesenchyme.
2 Gonad region of a 9—mm. rabbit embryo. Silver impregnation of reticulum. The irregularly scattered reticulum in the gonad area suggests the disappearance of the separation into epithelium a11d mesenchyme.
3 Urogenital ridge of a 14-mm. human embryo. Silver impregnation of reticulum. The distribution of the reticulum in the gonad indicates the beginning arrangement of the cells in cords.
4 Gonad of a 15—mm. human embryo. Silver impregnation of reticulum. Co1'd formation is slightly farther advanced than in the 14-mm. embryo (fig. 3). The coelomic surface is still not lined by a distinct epithelium.
5 Gonad of a 17—mm. human embryo. Silver impregnation of reticulum. The sex cords are more distinct than in the previous stages, and connected with a surface lining which again begins to assume epithelial character. The sex cords are comparatively slender (compare fig. 6) and perpendicular to the surface; this suggests a testis.
6 Gonad of a 16-mm. human embryo. Silver impregnation of reticulum. Essentially similar to figure 5, but the cords are wider and irregularly arranged; probable ovary.
7 Testis of a. 23-mm. human embryo. Silver impregnation of reticulum. Sex cord diiferentiation has made further progress. However, connections still exist with adjacent smaller cell groups and the surface lining.
Development of the secondary sex cords in enibryonic eat ovaries 8 Twenty—two millimeter embryo. Azan stain. The primary cords are accumulated iii the central portions of the organ (right side of fig.). The surface epithelium shows a. characteristic separation into two layers, the taller basal one containing large cells, probably primordial sex cells.
9 Seventy—seven millimeter embryo. Azan stain. Secondary sex cor(ls connected with the basal layer of the surface epithelium reach through the underlying connective tissue layer and connect with primary cords.
10 0ne~hund1-ed a11d ten millimeter embryo. Azan stain. The surface epithelium no longer shows a distinct separation into two layers. It is connected with some of the large secondary sex cords previously attached to the basal layer. Primal-_v and secondary cords cannot be distinguished.
Development of the secondary sex cords i11 embryonic eat testes 11 Forty»two millimeter embryo. Azan stain. Two distinct layers of the surface epithelium are present, similar to those i11 the ovary (compare fig. 8).
12 Seventy~six millimeter embryo. Azan stain. The basal layer of the surface epithelium has disappeared, but a vestigial sex cord is shown between the epithelium and the tuniea albuginea.
13 One hundred and thirty millimeter embryo. Azan stain. Another secondary sex cord is shown attached to the surface epithelium. It is surrounded by cells with nuclei somewhat larger than those of the connective tissue cells. This may indicate early interstitial cell formation.
14 Ovary of a. human embryo of 50 n1m. CRL. Silver impregnation of reticulum. Large secondary sex cords are attached to the surface epithelium.
15 Testis of a human embryo of 48 mm. CRL. Silver inlpregliatioii of reticulum. A group of secondary sex cords bulges into the tunica albuginea from the surface epithelium. One of the cords reaches into the area of the primary cords.
16 Testis of a. human embryo of 51 mm. CRL. Silver impregnation of reticulum. Several secondary sex cords protrude from the surface epithelium toward the tuniea. albuginea.
17 Ovary of an adult dog. Azun stain. Numerous proliferations of the surface epithelium are present, resembling sex cord formation.
18 and 19 Testis of :1 100~mm. cut embryo. Azun stain and silver impregnation of reticulum, respectively. In the area otherwise occupied by interstitial cell cords, a. cord (X) is shown with chnrzicteristics intermediate between those of sex cords and interstitial eell cords.
20 Testis of a iiewborn cut. Aznn stain. End-to—end junction of an interstitial eell cord (X) and 21 rete tubule is shown on the left side of the figure.
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Gruenwald P. The development of the sex cords in the gonads of man and mammals. (1942) Amer. J Anat. 359-396.
Cite this page: Hill, M.A. (2019, February 18) Embryology Paper - The development of the sex cords in the gonads of man and mammals. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_The_development_of_the_sex_cords_in_the_gonads_of_man_and_mammals
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