Paper - Cytological studies on the internal secretory functions in the human placenta and decidua (1921)
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Fujimura G. Cytological studies on the internal secretory functions in the human placenta and decidua. (1921) J Morphol. 35(3): 486-576.
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Cytological Studies on the Internal Secretory Functions in the Human Placenta and Decidua
Osaka Medical College, Osaka, Japan
Two Double Plates (Ninety-Six Figures) and One Text Figure
In recent times, along with an increase of knowledge on internal secretion, it has been imagined by many authors that in the placenta and the decidua there should exist such a function. According to the literature which I know, Lettule and Larrier (’01) are those whose attention was ﬁrst drawn to this subject. They detected in the syncytium layer a kind of granular body termed ‘Plasmoidale Kugeln.’ This body they took to be a secretion of the placenta. Subsequently, Veit (’O2) attempted to trace the cause of eclampsia, and Behm (’03) the cause of morning—sickness to the function of the syncytium, and Bouchacourt (’03) observed an increase of lactation by using some placental preparations. Further, Halban, supported by his plentiful clinical observations, stated that the swelling of the nipples noticeable in a newborn child, the congestion and hyperplasy of the uterus, the hypertrophy of the mammary glands of a pregnant mother, and hypertrichosis are all probably due to his so-called ‘Reizstoff,’ which is thought to be a product of the placenta. Among other things, it seemed he tried to deduce the existence of the closest functionary correlation between the placenta and the mammary glands. Since the result of Ha1ban’s studies was published, the functions of internal secretions likely to exist in the placenta drew general attention, and thereafter studies of this subject followed quickly one after the other. In the present essay I have refrained from chronologically relating all the results of these researches, but instead, with a view to giving only a general idea of what is known about this subject at present, I have conﬁned myself to the summing up of" all the points of the investigations made by the various authors up to now, and to dividing them intoa few large sections along the lines of experimentation, biological chemistry, and histology. ‘
Now, in the early experimental investigations, it was the ﬁrst attempt of the various authors to investigate chieﬂy the effect which the placenta has upon the mammary glands, and the methods employed were either to inject into the animal used as the subject of the experiment an extract of the placenta or to transplant the placenta, and the results in either case were for the most part positive (Feller, ’09; Lederer and ’Pribram, ’10; Aschner and Grigoriu, ’11; Cristea and Aschner, ’12; Basch, ’12; G. Kawaida, ’12; M. Dohi, ’l6). However, as it was incidentally discovered at the same time that the placenta had shown_ some strong special reaction upon the other organs, e.g., the Vascular organs (Schickele/12), the internal secretory glands (Fellner, ’13; Colle, ’13), and the uterus (Fellner, ’09; Okintschitz, ’14; Hermann, ’15), it naturally became difﬁcult to assert that the ingredients of the placenta have such properties as react upon the mammary glands alone. And, further, as it became known generally that such changes in the mammary glands as mentioned above were not only due to pregnancy or the placental ingredients, but were also caused by extracts of the various organs, such as the embryo (Mandle, ’05; Bayliss and Starling, ’06; Foa, ’10; Biedl and Konigstein, ’ 10 ; Aschner and Grigoriu, ’10), the ovary (Ott and Scott, ’10,' Aschner and Grigoriu, ’11; Frank and Unger, ’11; Hermann,’ 15; Y. Taniguchi, ’16), the pituitary body (Hofstatter, ’11), the pineal and thyreoid glands (Ott and Scott, ’1l),the uterus while in childbed and the mammary glands which are giving suck (Schoefer and Mackenzie, ’11), the intestines, the testicles, the spleen, and the thymus (Kehrer, ’15), the decidua (Gentili and Binaghi, ’17), as well as by a certain kind of chemical matter, such as ‘Lymphagoga’ (Aschner and Grigoriu), and albumin, too (Frank and Unger, ’11; Fraenkel, ’14), the theory of internal secretion in the placenta which had begun to be adopted generally for a time began to lose its value by degrees.
In the next place, along lines of biological chemistry, there are the researches made by such authors as Higuchi (’09), Hermann (’15), and Harada (’16). These authors extracted from the placenta various kinds of chemical matter as its principal ingredients and subjected them to close examination, but they never mentioned a ‘hormone,’ which is always existent in the placenta.
Thirdly, with regard to the histological studies of the placenta, many researches have been made in the subject from earlier times, but a great majority of these researches were conﬁned to the development or general construction of the placenta, and very few authors have given any special consideration to the internal secretion of this organ nor have they closely examined the minute construction of the tissue elements or cells of the placenta, Already Ahlfeld (’78) had noted the appearance of‘ -vacuoles in the syncytium layer, and subsequently many authors recognized it; however, regarding the thing itself and its physiological signiﬁcance, nothing definite has yet been stated. Gottschalk (’90) deemed it a pathological product; Kossrnan (’92) took it for a kind of degeneration, while Langhans C92) interpreted it as ‘Leichenerscheinung. ’ Further, regarding the globules of fat in the same layer, demonstrations had already been made by Pela-Leusden (’97) and Marschand (’98). Bonnet (’99) deemed it a nutritious matter taken up by the embryo, and in recent times authors have generally agreed in recognizing it as nutritious matter of the embryo taken from the mother’s blood. Others, among them Halfbauer CO5), Costa C04 and ’O5), and Bondi (’11), inferred that the appearance of this matter must be due to the active functions of the cells, by which it is assimilated and absorbed. On the other hand, however, Wolff (’13), as per Letulle and Larrier as mentioned above, on comparing the granular body of the syncytium layer with the secretory grains Within the ordinary gland—cells, stated that both of them were a similar production. This theory was subsequently supported by Fraenkel, who was close to the deduction that there might be existent a certain secretory relation in the granular body of the syncytium layer. ,In short, the histological studies of this subject up to now have been confined, as mentioned above, to the construction and, consequently, the functions of the syncytium layer only, and there are even many defects in the studies and some resultant weakness in the point of the arguments, and no one can say that the opinions agree. Although there are some authors who recognized the internal secretory functions of the placenta, yet, sinceitheir arguments are based on a single part of the organ, viz., the syncytium layer, it must be stated that on the whole the basis of histological arguments for internal secretion in the placenta is very feeble indeed, and much more is still to be done to accomplish a consummate investigation of this subject. It should none the less be added that Fraenkel (’14) was one of those who were strongly opposed to the various theories given above, and he denied the effects, which, it was believed, the placental functions have upon the mammary glands, on the ground that exactly the same phenomenon as takes place in the suckling of mammals was observed in the suckling of Monotremata and Marsupialia, neither of which has the placental formation. In addition to that, Fraenkel, going so far as to discuss the‘ changes which the internal secretory glands and other organs have to undergo in consequence of the placental extract as was witnessed in the experimentations of the afore-mentioned authors, concluded that such changes were attributable to several ingredients, his so-called ‘Gift,’ contained in the extract. According to Fraenkel, who contradicted the theory which generally is in favor of the existence of internal secretion in the placenta, the internal secretory glands first respond to this ‘Gift,’ and, as a result, the other physical changes follow. In short, it may be said with regard to the existence of internal secretion in the placenta that, in spite of the numerous researches made along the lines of experimentation, biological chemistry, and histology, as I have mentioned above, the Views expressed are so varied that no conclusionhas been reached, and, therefore, regarding the real situation of this subject, it is at present not yet an established theory. M Many authors have given their attention to the existence of an. internal secretory function in the decidua, and have tried to demonstrate it, Starling (’06), Sfameni, Gentili (’13 and ’ 14), Schottlander (’14), Aschheim (’15), Gentili and Binaghi (’17) being among the number. Starling conducted experiments on the rabbit to ﬁnd the effects which the juice extracted from the mucous membrane of the uterus While in pregnancy exerts upon the mammary glands, and the result was of a negative nature. Sfameni for many years past had held that in the decidual cells -there should be existent an internal secretory function, the basis of his arguments being the striking resemblance from the view—point of morphology, between the decidual cells and those of the other internal secretory glands. In order to demonstrate this, Gentili, in the same laboratory as Sfameni, carried out experiments by the use of ' the decidual juice on the dog, the rabbit, and the frog, and it was found that, similar to the luteal cells of the ovary, the decidual cells have a special action upon both the circulatory and generative organs. Schottlander also, by assuming that it may be possible for the secretion of the glandular cells in the spongious layer of the decidua in the first month of pregnancy perhaps to enter the mother’s blood directly, recognized seemingly that the uterine glands at times have the signiﬁcance of an internal secretory gland. Aschheim, in 1915, by discovering plenty of lipoid in the decidual cells, imagined the existence of a special function in these cells. Lastly, Gentili and Binaghi, by conducting a Inicrochemical experiment on the various tissue elements which form the decidua of a cow, demonstrated the existence of a kind of lipoid in the tissues, as reﬂexive of the correlation which it seems they believed existing between a certain function, particularly an internal secretion of the decidual cells, and the lipoid. On a close examination of the result of researches made by these authors, it must be stated that even in those whose view was in favor of an internal secretion in the decidua the basis of arguments presented is in general as feeble as in the case of an internal secretion of the placenta.
It is a long time since I began to feel interested in the secretory function of the placenta and the decidua. I was ever of the opinion that both the placenta and the decidua have a certain secretory function, and the experimental method I adopted in investigating this subject was entirely different from that employed by the foregoing authors. That is to say, I conducted a serological research into the effects which the alchoholic extract of the placenta and the decidua has upon the mother’s blood, and the result was the discovery in the serum during pregnancy of, not only the well-known Abderhalden’s ‘Abbauferment,’ but also of such an antibody as has a property of the ﬁxation of complement- with ingredients of the extract referred to. And, as in ordinary cases, the'antigen which represents the phenomenon of ﬁxation of complement is either a proteid‘ or some such like matter, whereas in my case it is a substance which is soluble in alcohol, the latter must be deemed to be qualitatively different from the former. It makes me feel as if it were in order for me to presume that the antigens in my case are due to the lipoid substances which are peculiar to (having some relation with the secretory process of) both the placenta and the decidua. Accordingly I have become convinced that, in spite of the various authors whose arguments I have enumerated above as denying the existence of an internal secretory function in both the organs concerned, the fact must be the reverse. Needless to say, however, this argument is only along lines of reasoning, and, therefore, it must be stated that the reason why I have applied at this juncture the modern cytological methods, thus planning out a close histological investigation of the principal tissues and cells, particularly the cell bodies of the placenta and the decidua, was because I was anxious to decide more clearly the right or wrong of this hypothesis. I have also, by adopting the same methods, examined the minute structure of the principal cells as indicative of the change which the uterine mucous membrane undergoes prior to menstruation, which, being compared with that during pregnancy, has enabled me to arrive at a certain conclusion, as will be noted later, respecting the physiological signiﬁcance of the menstrual changes of the uterine mucous membrane.
Materials and Methods
The materials for research were taken from a total of fortythree cases, of which twenty-ﬁve had to undergo artiﬁcial interruption during the first half of pregnancy because of the following diseases: 6 cases of morning—sickness of high degree, 12 cases of phthisis, 2 cases of laryngeal tuberculosis, 1 case each of consumption of the bowels, of peritoneal tuberculosis, and of a valvular disease of the heart, 2 cases of glucosuria.
Of the remaining 18 cases, 14 had to undergo artiﬁcial interruption during the second half of pregnancy because of the following diseases: 1 case of beriberi, 5 cases of nephritis, 2 cases of a valvular disease of the. heart, 1 case of albuminuric retinitis, 3 cases of eclampsia, 2 cases of placenta praevia.
And the remaining 4 cases had to receive a Porro’s operation because of the following diseases: 1 case of mislaid transverse position and 3 cases of the narrow pelvis.
And as to the time of pregnancy in these 43 cases, it should be noted that 4 cases were less than 1 month, 2 cases 1 month, 4 cases 2 months, 7 cases 3 months, 6 cases _4 months, 3 cases 5 months, 4 cases 6 months, 3 cases 7 months, 3 cases 8 months,
4 cases 9 months, and 3 cases 10 months. And diﬁicult as it was to accurately determine the exact time of pregnancy in each case, the method I adopted in determining those less than one month was to take into account the size of the egg and the degree of development of the embryo and villi, and in those one month and upward, to consider the time of menstruation, the size of the uterus, the length and weight of the embryo, the length of the navel string, and the weight of the placenta, thus arriving at the approximate time of pregnancy.
As regards the obtaining of the materials from the fetal placenta, it should be noted that in the early stage of pregnancy a few pieces of ordinary villi from the surface of the ovum were taken, while in a little more advanced a few small cuts of the chorion frondosum, and in a well-formed stage of the placenta a few small bits of the latter have been cut out. Now, as to the maternal part of the placenta, a part was taken from placenta already delivered and from that not grown up yet, in the former case, from the surface opposite the uterus of the placenta, and in the latter, the mucous membrane of the uterus concerned being scratched off quickly,ras during an operation it is quite easy for the operator to determine the insertion of the placenta. The tissues obtained in this Way have always shown“ microscopically, besides the proper decidual tissue, the existence in them of parts of villi, syncytium cells, and the deposit of ﬁbrinoid material (‘kanalisiertes Fibrin’ ofl Langhans), all of which were proof that they were the materials I desired. In this connection it must be added that the decidual materials were always taken from the decidua Vera only, at every stage of pregnancy, by means of scratching out. All these pieces of tissues were so taken that they should not exceed a cube 3 mm. in size, and immediately after cutting they were dipped in the newly prepared ﬁxing solutions. For the latter I have ‘used: 1, Altmann’s ﬂuid of potassium bichromate and osmium tetroxide; 2, Flemming’s solution modiﬁed by Benda; 3, F1emming’s solution modiﬁed by Meves; 4, Levi’s mixture of formol, osmic acid, potassium bichromate, and corosive sublimate; 5, Luna’s mixture of formal, potassium bichromate, and glacial acetic acid. Each of the pieces was then treated in the usual manner being imbedded in paraﬁin and cut in sections of 3 to 4 pt. And as a treatment prior to staining, Rubaschkin’s method has been applied in a great majority of cases. For staining I have employed: 1, Altmann’s method of acid fuchsin and picric acid; 2, Heidenhain’s iron-alumhaematoxylin, and, 3, Benda’s alizarin—crystal-violet method, etc. All the methods which I have adopted, the ﬁxation with Levi’s mixture, and the staining with iron—alum-haematoxylin have been found to be comparatively successful.
My Own Observations
The chorionic villi, which are a main component of the placenta consist of: 1) the syncytium cell-layer; 2) the Langhans’ cells’ and, 3) the ‘Stromazellen,’ being cells in the stroma of villi» while the components of the decidua serotina and the decidua Vera chieﬂy consist of, 4) the decidual cells and, 5) the epithelium of the uterine gland. In the present chapter I intend to give a detailed account, mainly from the histological standpoint, of these important tissue components, or cell groups, especially as they appear in the different stages of pregnancy. However, since the structure of all kinds of cells varies even in the same stage of pregnancy and in the same group of cells, it would be a difficult task indeed to explain clearly the correlations existing between the minute structural changes of these cells, or cellular groups, and their functional signiﬁcance. Therefore, I have selected and drawn those deemed the most representative of all the structural images of the afore-mentioned tissue-cells which have been widely and thoroughly examined, as will be seen from the series of ﬁgures on the plates the object being to give a general idea of the structural changes of these cells. The explanations of each of these ﬁgures will make the pith of this chapter, as by so doing I believe the description could be much simpliﬁed and its understanding facilitated as much as possible. Thus, I shall appreciate very much if the reader will constantly refer to those ﬁgures While reading.
(1). The syncytium cell-layer (figs. 1 to 12)
As is well known, the syncytium layer is the epithelium which covers the surface of the villi, and the lack of boundaries between the cells is a feature of this layer. And it is also well known that within this layer there are several kinds of nuclei, differing in size and form and scattered here and there, besides dark-colored granular bodies and a great number of vacuoles which occasionally appeared in it. Its surface is covered with a brush—like border. This layer is generally well developed in the early stages of pregnancy, but in the second half of pregnancy it becomes thinner and looks much like an endothelium, so that, when examining its minute structure, it will be necessary to do so before the fourth month of pregnancy. Figure 1 shows that part of the anchoring villi which extends deeply into the decidua, while all the other plates show the different parts of the surface of the ordinary villi.
In ﬁgure 1 the syncytium presents a homogeneous protoplasmic layer generally dark-colored and contains an extremely large quantity of plastosomes (mitochondria). They are of different shapes, but mostly are rod-shaped or bacteroid and of different lengths, the longer ones being slightly curved. They arrange themselves in groups rather than being equally distributed over the layer, and in some places some of them point in the same direction, while others point in Various directions, thus in general giving them something of a meshy arrangement. The nuclei are clear and have in themselves a more or less conspicuous nuclear network, with one or two nucleoli.
In figure 2 the syncytium layer closely resembles ﬁgure 1 in structure, though the plastosomes contained therein differ from one another in their shape, arrangement, and number. These two ﬁgures show the simplest structure of the syncytium layer.
In figure 3 the plastosomes are generally faint and quite scattered; in the protoplasm there are some dark-colored granular bodies of different sizes and a small number of vacuoles; the smaller granules are somewhat dark in color and are generally found very near the surface, viz., the brush-like border, whereas the larger ones are light-colored and are found in other parts of the layer. The vacuoles are found close to the Langhans’ layer. The nuclei are irregular in shape, and besides the nuclear network there are one or two nuceoli.
In ﬁgure 4 the plastosomes are generally found in the deeper layer, i.e., close to the Langhans’ layer, and they are comparatively small in number. On the contrary, however, plenty of dark or yellowish dark—colored granules occur conspicuously all over the layer, the deeper colored ones being generally superﬁcial. Undoubtedly, granular bodies of this kind have grown up from the dark-colored granules in a conspicuous manner such as I have shown in ﬁgure 3 above, and they are very frequently met with elsewhere in the other parts of the syncytium layer. And, moreover, granular bodies of a similar kind are found, as will be seen in the following statement, not only in the syncytium layer, but also commonly in other cell groups. These granular bodies are, of course, extremely varied in their size, quantity, and color; however, .since they have a common aﬂinity to certain chemical and coloring matter, e.g. osmic acid, iron-alum-haernatoxylin, and acid fuchsin, etc., I have followed, for the sake of brevity, the precedents of many histologists in including all these granular bodies under the name of ‘lipoid’ granules. In this ﬁgure there is, moreover, only one vacuole close to the brush-like border. The nuclei are less conspicuous in their network, the chromatin forming itself into a large number of lumps, each of nearly equal size.
In figure 5 there are no plastosomes to be found, but the lipoid granules occur in extremely large quantities, and their sizes are nearly the same. They are found more or less in groups and are distributed all over the layer. At the same time the vacuoles make their appearance in a conspicuous manner, sometimes on the surface, sometimes in the innermost part, and sometimes in the middle, and they are about the same size as the lipoid granules. As is well known, it is in general very difficult to stain the plastosomes every time, and, therefore, accurately to determine their existence and where they are entirely wanting, as in this ﬁgure, it would be a very difficult task indeed. I have paid the closest attention to this, and have always selected for it the most excellent preparations for staining, with a View of doing away with all the possible defects in the technique of staining. From the existence, in a very conspicuous manner, of plastosomes in the neighboring tissues, entirely in contrast to this ﬁgure, I was prompted to conclude that it was well nigh necessary for me to assert the absolute lack of plastosomes in this part of the syncytium layer. Further, I may add that, as will be noted below, the same amount of attention has been given all the other cells where there are no plastosomes to be found, and I, on this score, am convinced that my observations concerning them are not erroneous.
In figure 6, the surface is somewhat light-colored and is clear. In it there are found innumerable quantities of vacuoles which are nearly of the same size, besides a small number of Iipoid granules. The innermost part, however, is of a comparatively dark color, and it likewise contains innumerable quantities of minor lipoid granules of about the same size, with very few vacuoles which are generally of small size. Some of the nuclei are oval, while others are irregular in their shape, and there is to be found a great number of chromatin granules which make their appearance in lumps of different sizes; the nuclear networks are usually less conspicuous. There are absolutely no plastosomes to be found.
In figure 7 the syncytium layer is extremely thick, and it is difficult to demonstrate the plastosomes. Lipoid granules of extremely varied sizes are found in large quantities. These granules are irregularly arranged, and they tend more or less to occur in groups; certain lipoid granules make their appearance as contents of vacuoles, in which case the granules always have a clear halo around them, as if they constituted the nucleus of the vacuoles. Such images are frequently met with not only in the syncytium layer, but also in other cell groups and, since theylare worth recognizing as very clearly indicating the relations which exist between the lipoid granules and the formation of vacuoles, the reader’s special attention is hereby drawn to this point (vide the left-hand side of this ﬁgure). The vacuoles are abundant, and their sizes and shapes are quite irregular and, as will be seen in the middle part of this ﬁgure, a great number of them are joined together at some places without boundaries being noticeable between them. From the existence of such images I am led to infer that an extraordinarily large vacuole is in general the outcome of minor vacuoles being agglutinated and joined to one another. In this Way, it seems that the vacuoles which have grown up into tremendous sizes ﬁnally rupture toward the surface, as it will be seen in the present ﬁgure that such vacuoles open up and connect directly with the intervillous spaces, clearly supporting the interpretation that I have given above. In ﬁgure 8, it is in general extremely deﬁcient in its character istic dark-colored protoplasm, but then there are all over the layer numberless vacuoles of a very small size, which grow so close to one another that they have exactly the appearance of a beehive. Of these vacuoles some of the larger ones lie together close to the surface, while others, connected with one another,. mutually ﬁnd their outlets to the surface through comparatively large openings. Because of these openings the surface of the syncytium layer, which is naturally level, becomes very uneven and irregular. The lipoid granules are very few, and no plastosomes are to be found. The nuclei are not only few, but being shrunken are changed into homogeneous bodies of small size, the nucleoli alone making a prominent appearance (vide the right-hand side of the ﬁgure).
In figure 9 the syncytium layer is comparatively thin, and there are comparatively few plastosomes to be found, being scattered here and there, and mostly rod-shaped. The lipoid granules'are middle-sized and are not many in number, and a few of them stay at the center of the vacuoles as if they were the nuclei of the vacuoles. The vacuoles are pretty large, and they arrange themselves close to the Langhans’ cells. The nuclei have distinct borders and masses of chromatin arrange themselves in rows, usually close to the nuclear membrane.
In figure 10 the protoplasm is, as in a majority of cases, generally dark-colored, though not homogeneous altogether and, on a close examination, it is found that it contains a great number of vacuoles, which gives the protoplasm more or less a foamy appearance, though very indistinct as compared with other foamy structures. The plastosomes are mostly rod—shaped and are very distinctly stained. They appear generally in the upper layer, though some are noticeable in the innermost layer. There are no lipoid granules to be found and no nuclei of normal conditions are to be met with, but, on the contrary, there are some curious bodies, whose size is somewhat larger than the ordinary nuclei and which are irregular in shape. Some of them are homogeneous and are quite dark-colored, while others being non-homogeneous consist of different parts which are either dark or light or somewhat clear when stained. We come across such structures very often_in other parts of the syncytium layer, but so far I have not been able to ﬁnd out their original nature.
In figure 11 the protoplasm shows numberless vacuoles as its constituents. The vacuoles are somewhat varied in their size, and with the exception of some which are full and stained, a greater portion of them, particularly those which are found on the surface, are more or less loose and somewhat ﬂattened in shape. Between these vacuoles there are extremely large quantities of plastosomes, which are mostly rod— or granula shaped and equally deep—colored as these which are found in ﬁgure 10. There are few lipoid granules to be found, and they exist for the most part in the superﬁcial layer, scattered here and there. What is especially worth noting is that there are red blood corpuscles in the protoplasm between these vacuoles (vide the left—hand side of the ﬁgure). The nuclei are oval-shaped, and the chromatin is very peculiarly arranged, its outward appearance resembling the shape of a chrysanthemum. In the center there is a nucleolus, and it must be noted that a nuclear condition of this kind is generally very rare.
In figure 12 the protoplasm is glutted with numberless vacuoles, andit is for this reason remarkably foamy in appearance. The vacuoles are of two sizes, of which the smaller ones are mostly located in the deeper portion and make a somewhat continuous layer, though in other parts there are to be found some of these smaller-sized vacuoles also. The larger vacuoles are crowded together in the middle part of the layer, and some of them burst forth onto the surface, While others make their appearance in the innermost layer close to the Langhans’ cells. The plastosomes are quite uniform in shape with those illustrated in the preceding ﬁgure, and they are all found in the protoplasm between the vacuoles. The lipoid granules are nearly of the same size and are found at several places, some of them with the halos distinctly described. The nuclei appear to be somewhat smaller in size, but there are no remarkable change in their structure. . . These structural conditions in the syncytium layer which I have illustrated and described ‘above can be detected at almost any time and place at the different periods from the ﬁrst month of pregnancy to nearly the fourth, and, therefore, there is no doubt that these structural changes cannot be taken as a measure to tell the precise time of pregnancy. At no time after the fourth month of pregnancy can we detect the plastosomes. The lipoid granules and vacuoles reach their maximum growth from the second to third month of pregnancy, and after the fourth month they gradually begin to decrease, entirely disappearing after the seventh month. The syncytium layer comes in sight a remarkable manner on the seventeenth or eighteenth day after pregnancy, reaches the maximum of growth at the end of the ﬁrst month, and from the second to the third month it seems, although not very conspicuously, more or less reduced in thickness, but after the fourth month it suddenly becomes thinner, and simultaneously its structure becomes simpliﬁed, and in the seventh month it will altogether atrophy and remain simply in the form of a thin membrane like an endothelium. Moreover, in the last two months the layer will disappear in some places and will be noticeable only as a discontinuous thin cover. In other words, this layer, excepting in the early stage of pregnancy, always decays and goes out of existence in inverse proportion to the growth of the embryo, and this is the very point which should engage the careful consideration of those who are interested in the functions of this layer.
2. The Langhans’ cells (ﬁgs. 13 to 26)
The Langhans’ cells have in general distinctly clear bodies, and are distinctly bordered with a thin membrane (pericula?) on the surface. Their sizes, shapes, and structures are extremely varied; on examination of the smallest cells (ﬁgs. 13 to 16 and 7, 8 and 10) it will be found that they are either round like a ball or oval-shaped, with foamy nuclei of corresponding shapes inside. The structures of the cell bodies consist of quite structureless stroma and a large quantity of plastosomes, of which the latter are rod-shaped in several lengths, and are usually distributed all over the cells, though sometimes they crowd together on one side of the cells. There is occasionally a small ovalshaped body somewhat dark in color close to one side of the nucleus, which might possibly belong to Meves’ so-called ‘Centrotheca;’ it, however, lacks a centriole within (ﬁg. 13). Within the nuclei there are generally one or two conspicuous nucleoli, and in most of the cases it is difficult _to discern the nuclear network. In the large sized cell bodies (ﬁgs. 17 to 19 and 2, 3, 9, 11 and 12) we always ﬁnd either a small quantity of lipoid granules or vacuoles. The lipoid granules are nearly the same in size, and, though small in number, they are scattered everywhere (ﬁgs. 17 and 11). The vacuoles are extremely varied in their size, quantity, and arrangement, and it is for this reason that the structures of the cell bodies have so many special features (ﬁgs. 18, 2, 3, and9). In such vacuolar cells the rod-shaped plastosomes are for the most part short in length, and they are arranged either along the walls of the vacuoles or crowded together in the protoplasm between the vacuoles; however, sometimes it will be found that, as will be seen in ﬁgure 18, the vacuoles are chieﬂy placed in order on the outskirts of the cells, and the plastosomes accumulate in the center around the nucleus. Again, it will be found that, as in ﬁgures 19 and 12, both the lipoid granules and vacuoles of various sizes are simultaneously contained in the cellbodies, in which case the plastosomes are comparatively small in number and are scattered here and there in the protoplasm between the lipoid granules and vacuoles.
In the largest cells (figs. 20 and 21) the cell bodies are in general well ﬁlled with a great number of vacuoles of various sizes, and consequently the protoplasm is noticeable only around the nucleus and between the vacuoles. There are almost no lipoid granules, which, when present, are small and are very few in number; also the plastosomes decrease in quantity and are mostly found around the nucleus.
In short, the smaller-sized cells have in general only the plastosomes as their material components, while the largersized ones still contain a number of lipoid granules and vacuoles and in the largest ones the cell bodies are commonly vacuolated in a high degree and the protoplasm decreases considerably in quantity, the plastosomes in general gradually decreasing in number as the cells grow in size, though -it sometimes happens that it is very difficult to demonstrate them, regardless of the size of the cell bodies. Of ﬁgures 22 to 26 it will be observed that ﬁgure 22 shows the lipoid granules only, ﬁgure 23 chieﬂy the small vacuoles and a few lipoid granules; in ﬁgure 24 it is entirely the same as the former, however, with the distinctive feature that the vacuoles are remarkably large and have lipoid granules of various sizes within; in ﬁgure 25 and 26 the bodies are vacuolated to the highest degree, and it is perfectly plain that the vacuoles which are extremely varied in size and shape mix together and grow larger, thus giving the cell bodies the appearance of a honey comb in a striking manner. The large and highly vacuolated cells such as are-illustrated in ﬁgures 21, 25, and 26 are very frequently met with in the Langhans’ islets.
The various structural images in the Langhans’ cells that I have described above make their appearance in a most remarkable manner from the end of the ﬁrst month of pregnancy to the end of the third month ,and in the fourth month, though the plastosomes are still existent in a remarkable degree, the lipoid granules and vacuolar formations are no linger conspicuous, and in the‘ following months not only do the cells decrease suddenly, but also these materials component of the cell bodies disappear, though the cells in the Langhans’ islets retain those structures as long as they exist.
3. The stroma cells of villi (figs. 27 to 38)
The smallest of the stroma cells of villi, as is illustrated by ﬁgure 27, are mostly ball—shaped and have the nucleus of a similar shape within. In the cell bodies there are plastosomes, mostly rod-shaped. Figures 28 and 29 are nearly the same as ﬁgure 27 in their shape, though the one contains in the cell body a somewhat large quantity of lipoid granules of different sizes, while the other has a small quantity of extremely small lipoid granules and an equally small quantity of small vacuoles. Figures 30 to 38 illustrate the cells arranged in their approximate order of size and, though their shape and structure appear extremely varied at a glance, it will be ‘found on close examination that, with the exception of ﬁgure 34, there is a structure which is common to nearly all the rest, the only difference between them being principally the size and number of vacuoles contained in the cell bodies. Generally speaking, the larger sized-cells have vacuoles which are naturally large in size and number, and the fact that large vacuoles are built up to some extent from the fusion of the smaller vacuoles which are connected with one another can be often proved in these stroma cells (ﬁg. 38). The plastosomes are mostly rod-shaped and lie scattered in the protoplasm located between the vacuoles, though they sometimes crowd together in a somewhat larger number in certain places (ﬁgs. 31, 32, 36, and 38). The lipoid granules are generally few in number and are found between the vacuoles, though at times they are present‘ within the small vacuoles (ﬁg. 36). The smallest of these lipoid granules, at a glance, bears a close resemblance to the granular plastosomes; however, since they are mostly very distinctly bordered, besides being stained darker, it is easy to distinguish them from the former (ﬁgs. 36, 37, and 31). Figure 34 looks somewhat different from the various cells described above in that the cell is nearly spherical, with a remarkably large nucleus within, besides a small number of somewhat large vacuoles and plenty of lipoid granules in the cell body. These granules have Various sizes, but are in general of middle size and a few of them are distinctly included in the vacuoles. The plastosomes are extremely limited in number, and lie scattered in the protoplasm between the vacuoles. It is very seldom that this kind of cells makes its appearance, and a great majority of cells in the stroma, as are chieﬂy illustrated by ﬁgures 35 to 38, present a distinct vacuolar formation.
The plastosomes in the stroma cells have in general a very strong staining power, and are therefore more easily detected than other cell groups. It is, moreover, very rare that the cells which have no plastosomes are met with, but in stroma cells the lipoid granules seldom appear. The stroma cells appear distinctly and are therefore most easily found during the period from the second to sixth or seventh month of pregnancy. In the eighth month, usually, numberless capillary blood vessels suddenly grow and increase within the villi, so that it is impossible to examine the cells. With every possible method it was difficult to detect the cells, and, therefore, I am inclined to believe that the stroma cells suddenly cease to exist at this stage of pregnancy.
4. The decidual cells (ﬁgs. 39 to '71)
It is a generally well-known fact that decidual cells are divided into very many kinds according to shape, size, staining properties, and structure; however, it has not as yet been deﬁnitely decided whether or not these kinds of cells should be reckoned as one and the same sort. Marschand (’04) ﬁrst divided the decidual cells into two types according to the difference in size. Subsequently, Fraenkel (’14), too, who studied them chieﬂy from the staining standpoint, set up a similar theory, and tried to divide them into his so-called acid cells (Eckersche Form) and the neutral cells (of large type); however, he himself and others had no doubt that there was not only no distinct division between these two kinds of cells, but rather there was existent an intermediate type of cells between them.
Figures 39 to 69 illustrate the Various kinds of decidual cells placed in order. Of these, cells such as in ﬁgure 39 are the smallest and are spherical with a nucleus of a corresponding form. The protoplasm is, as compared with the interstitial cells at the time of non-pregnancy, remarkably large in quantity, and contains in it a' large number of rod-shaped plastosomes. Figures 40 and 41 are a little bit larger than the former, and the one is spherical while the other is oval, both having a nucleus of nearly corresponding shapes. The protoplasm becomes still more abundant and the plastosomes are somewhat longer rods. It is worth our noting that both cells have a kind of boraer membrane already on the superﬁcial layer of the cell bodies. Figure 42 demonstrates the ﬁrst appearance of a few lipoid granules of various sizes within the cell bodies. Figure 43 illustrates a pear-shaped cell, which holds in the body a somewhat large quantity of granules and a few vacuoles. A few plastosomes are to be found, and they make their appearance only on one side of the cell. Figure 44 resembles the former in shape somewhat, and contains in the cell body remarkably large lipoid granules, which, on a close examination, are found to have a more or less distinctly clear halo around each of them, as though they constituted the contents of vacuoles. The plastosomes are mostly rod-shaped, and they crowd together on one side of the nucleus, while on the other they appear in a remarkably long, granular string (Fadenkorner). In ﬁgures 45 to 48 the cells have exceedingly Varied shapes, and the nucleus trends toward one side of the cell close to its superﬁcial layer. The cell bodies are ﬁlled with numerous irregular-sized vacuoles, which present a more or less distinct foamy structure. The plastosomcs are mostly short and rod-shaped and they are to be found in the proplotasm between the vacuoles. Some of them are arranged in a long row along the walls of the vacuoles, While others are found in groups in a certain section. The lipoid granules are, in general, small in number, and their sizes are irregular, some of them ﬁnding themselves distinctly at the center of the vacuoles (e.g., ﬁg. 46).
In the various cells described above it will be observed that the nuclei are generally dark—colored, with indistinct nuclear network in most of the cases, though the nucleoli contained are conspicuous enough. Figure 49 is extremely different in its appearance from these cells. The cell body presents a vacuolar formation in high degree and the protoplasm proper can be demonstrated in a small amount only along the surface of the nucleus, at which place only a few rod-shaped plastosomes are found. The border membrane on the surface of the cell is very distinct and the nucleus is different from that in the various cells described previously in that it is clear and presents a large foamy body. The nuclear network is somewhat distinct, and, besides, there are conspicuous nucleoli. It must be generally stated that this kind of cell appears very seldom. In ﬁgure 50 the cell body presents an equally high vacuolar formation as in the former, and, in addition to that, the vacuolar walls entirely disappear in some places and so allow the inner spaces of the vacuoles to communicate with one another, thus clearly indicating the evidence of the vacuoles having been agglutinated. A few more plastosomes than in the former are found in groups in these cells, and, besides, there is a small quantity of lipoid granules, mostly within the vacuoles. What is especially peculiar about this cell is that at the center of the cell body there appears a black colored homogeneous star-shaped lump, from the surface of which are shot forth a number of processes, which run over directly to the protoplasm between the vacuoles. The proper nucleus is hardly detected. In ﬁgure 51 the cell is longish, and the overabundance of plastosomes which are distributed densely almost all over the cell body is the feature of this cell. Between there, is a somewhat large number of vacuoles of various sizes, and no lipoid granules at all are to ‘be found.
In ﬁgures 52 to 54 thevarious cells illustrated are gradually larger than those described above, the cell bodies are ﬁlled with a large number of vacuoles and granules. The latter are extremely irregular in size and density and are sometimes found as contents of the former. The plastosomes are mostly short rods, and especially in ﬁgure 52 they are somewhat abundant, and some are found massed along one side of the nucleus. In ﬁgures 53 and 54 they are comparatively fewer and lie scattered between the vacuoles. The thin layer on the surface of the cell is thicker and more distinct in this kind of cell, to such an extent that it almost reminds us of the ordinary cell membrane. In ﬁgure 53, as in ﬁgure 50, we notice a black—colored round—shaped lump at the location of the nucleus; however, in this case, the surface of the lump is smooth and has no process. Comparatively few cells have such a black—colored lump, and, as in these cells it is always difficult to tell the whereabouts of a nucleus of normal condition, I am quite at a loss to know whether or not the dark lump described above should be deemed a modiﬁcation of the nucleus or regarded as that part of the protoplasm which is just adjacent to the nucleus which has, by reason of its staining properties, obscured the nucleus. This question, along with the stained lumps in the syncytium layer as illustrated in ﬁgure 10, constitutes a puzzle, and I have mentioned it here for the sake of future investigations. However, in View of the fact that numerous plastosomes, which are the important elements of a living cell, are always demonstrated in the cells concerned, while at the same time they present no noticeable regressive phenomena. I am rather inclined to believe that it is possible to attribute a certain functional signiﬁcance to these unknown lumps.
The cells illustrated in ﬁgures 55 to 57 are already exceedingly large, and they are, at a glance, recognized as Marschand’s so—called large-type of decidual cells. On the surface there is a rather thick layer, which may be divided into two of which the inner one is thick and the outer thin, and they exactly remind us of the deﬁnite cell membrane. The cell bodies consist of plastosomes, lipoid granules, and structureless stroma. The plastosomes are mostly long rods or threads, some being more or less peculiarly curved and the quantity of plastosomes is variable. The lipoids differ also in point of size, density, quantity, etc. What is worth our noting is that there is no vacuolar formation to be found in these cells. The nuclei are large, clear, and foamy. The nuclear network is especially conspicuous in ﬁgures 56 and 57. Figures 58 to 61 show the deﬁnite form commonly belonging to the- so-called decidual cells of large type. In these cells the cell membrane is remarkably thick, and the distinction between the inner and outer layers is always clear.’ What deserves our special attention at this juncture is that the outer layer contains, in most cases, ‘a kind of granular body which is somewhat large and yet irregular in sizeland stained a dark color. The cell bodies consist of a large quantity of plastosomes and homogeneous stroma. The plastosomes are mostly long rods, and they sometimes appear extremely elongated in the shape of threads (ﬁg. 61). They are distributed equally all over the cell bodies, although they sometimes tend to appear more or less in groups. The plastosomes in these large cells have, in general, very slow staining properties, and, therefore, they are a very difficult subject to be dealt with from the technical point of view. The nuclei are foamy and dark—colored, and the nuclear networks are indistinct.
The cells illustrated in ﬁgures 62 to 69 differ from those described above, and they all lack the plastosomes. Even in the most excellent stained preparations these cells appear within the decidual tissues in small numbers, for the most part more or less in groups, scattered like islets, so that it is, as a matter of course, incomprehensible that here alone the plastosomes are hard to be demonstrated. However, as, in consideration of their structure and shape, it is premature yet to decide posi tively that there is a tendency for a retrogressive change, among all these cells, I will here suggest provisionally that such a phenomenon is a sign of a certain functional period in the cells concerned. Now, at ﬁrst, in ﬁgures 62 and 63 the cell bodies are comparatively dark, and within they contain a large quantity of vacuoles and lipoid granules of various colors; some of the vacuoles distinctly have a lipoid granule as their nucleus, while others, being placed in rows close to thecell membrane, present a peculiar image. The nuclei are clear and have a somewhat distinct nuclear network. In ﬁgure 64 the cell body is ﬁlled with numberless vacuoles of nearly the same size, and on one side of the nucleus accumulates a large quantity of protoplasm, and, besides, there are a few deep yellowish-brown lipoid granules. Figure 65 is of nearly the same type as the former, but the lipoid granules contained are by far greater in quantity than the vacuoles. The nucleus is as clear as the former, with conspicuous nuclear network. Figures 66 and 67 illustrate the cells whose bodies are ﬁlled with an exceedingly large quantity of vacuoles of various sizes, in consequence of which the protoplasm becomes comparatively scarce and faint and is mostly noticeable only around the nucleus. And, besides, there are some vacuoles which hold dark or deep yellowish-brown lipoid granules; also vacuoles and lipoids, Whose size, quantity, and distribution are as varied as will be seen illustrated in the respective ﬁgures. The nuclei are generally dark and show extremely delicate network formations.
Figures 42 to 48 and 51 may be compared, from their sizes and histological point of View, with that class of cells which is termed by many authors as ‘decidual cells of small type’ (or possibly Ecker’s type), While, on the contrary, ﬁgures 55 to 61 and 64 to 69 may be nothing but the so called ‘large-type’ or ordinary decidual cells (neutral cells). Further, the various cells illustrated by ﬁgures 49, 50, 52, 53, 54, 62, and 63, judged from their size and internal structure, should be deemed an intermediate type which may intervene between the former two, since it is a very diﬂicult task to determine to which one it should belong. Now, the result of my careful examination of the appearance and distribution of these cells as compared with the time of pregnancy has been that, in the material which was taken a fortnight after conception, this being the earliest I have on hand, the cellular ingredients of the decidua chieﬂy consist of the small-type cells described above. In a little more advanced stage (i.e., about 17 or 18 days after pregnancy) the decidua shows also the appearance of a large quantity of the ‘intermediate-type cells,’ while in the few days following (i.e., about 22 or 23 days after pregnancy) with the decidua already of deﬁnite growth, all kinds of cells, especially the large-type ones, can be detected in comparatively large quantities. One month after pregnancy the large and intermediate type cells appear as the principal ingredients of the decidua, while on the contrary the small-type cells retrograde gradually and are met with only in the interstitial tissue. Such condition is maintained until the end of. the last month of pregnancy. In short, I concludefrom the histological and histogenetical point of view, that the various kinds of cells described above all belong to one class, and consequently it follows that the division of decidual cells into large and small types, is faulty. In other words, the term ‘small-type decidual cells’ applies only to the cells which are still at the early stage of growth, while the ‘large~type cells’ are those'in the last stage of growth. The time taken in -such growth is, according to my observations at the earliest stage of ‘ pregnancy at least, comparatively small, thus the small-type cells being perfected into the ‘deﬁnite large-type cells’ in so short a time.
The appearance of lipoid. granules and vacuoles in the decidual cells is most remarkable from the end of ﬁrst month to the second month of pregnancy, and they gradually decrease in the months following, though very infrequently they can be demonstrated even at the end of pregnancy. The plastosomes could no longer be demonstrated in any of the decidual cells after the seventh month of pregnancy.
And, in the interstitium of the decidua, such extremely strangelooking productions as are illustrated by ﬁgure 70 may some times be detected. They are stained dark and consist mostly of a great number of granular bodies which are extremely varied in size. There are_ granular threads, which are the result of the granules being linked together, more or less curved large rod-shaped bodies of "different lengths, and sometimes threads which are very long and often curved like screws, besides a large number of material ingredients, which, being mixed up among them, have shapes similar to them and yet are unstained and noticeable only as a shadow. The former, which are susceptible to staining, are dyed deep red by Altmann’s method and deep black by iron-alum-haematoxylin. At a glance they look like plastosomes in their shape and staining, and yet in general excel the latter in size considerably. If aggregated, they may be quite easily detectedunder medium magniﬁcation. Moreover, the staining properties of the ingredients are much stronger than the plastosomes, and they bear a rather close resemblance to lipoids in their density and appearance. The product of this kind do not only possess exactly the same properties in shape and stain as the granular bodies in the cell membrane of large-type decidual cells to which I alluded above, but also indicate that there is often the closest relation between the two; i.e., within the cell membrane of the cells concerned there are, besides the granular bodies above referred to, often short granular threads or large rod-shaped bodies, both of which are similar to the substances in the interstitium described above. One end of the rod-shaped bodies sometimes enters deep into the cell membrane and swells into a club—like shape, while a greater part -of the other end juts out into the interstitium, thus giving itself the appearance of passing into the interstitial product. I am not able to explain the original nature and functional signiﬁcance of this kind of product, and yet, according to the afore-mentioned observations, I have no doubt Whatever that in the formation of the product the large cell, and especially its cell membrane, plays an important part and, since such interstitial substances are "demonstrated in large quantities in the adjacent blood vessels as are illustrated by. ﬁgure 71, it may be inferred that they are ultimately absorbed in the vascular organs. The products of this kind are for the ﬁrst time noticed at about the second month of pregnancy, appear most conspicuously from the end of the second month to the third, decreasing gradually after that, and, though the decrease is considerable after the ﬁfth month, they may yet be demonstrated until about the sixth month. Besides the above, there are detected in certain parts of the interstitium numberless ﬁlar productions which have various length, and are sometimes long like threads or ﬁbers, of which the smaller and shorter ones sometimes bear a close resemblance to the plastosomes, while the others usually gather in great number and often make a mass of ﬁbrous bundles. This kind of product, so far as staining is concerned, is entirely similar to the interstitial productions described above, and yet it differs from the latter in that its shape is not so varied, its thickness is nearly always even, and, besides there is no special relation which is noticeable as existing between the products and neighboring cells.
5. The epithelium of the uterine gland (figs. 72 to 83)
As is generally well known, the uterine gland undergoes a certain morphological change at the early stage of pregnancy, and in my previous treatise I have drawn attention especially to the fact that the glandular cells also show a morphological change at such a time. Here I will observe and describe more thoroughly the changes of the cells concerned.
Figure 72 shows -a glandular cell which is commonly noticed at the early stage of pregnancy and which is already remarkably thickened and somewhat round. The shape of the nucleus for the most part corresponds to that of the cell. On top of the cell there are traces of cilia. The cell -body contains many slender and rod-shaped plastosomes, which latter chieﬂy gather closely against and surround the nucleus. In ﬁgures 73 and 74 the cell grows larger, and the plastosomes are demonstrated only in the upper half, while in the lower half which contains the nucleus, none of them are found. At this section of the cell there are plenty of lipoid granules, which are of about equal size and are stained a bright yellowish-brown color, and on top of both cells there are still the traces of the cilia. In ﬁgure 75 the cell is remarkably elongated, and within are contained a great number of lipoid granules. The nucleus is oval with a nuclear network distinctly observed; from this period on no more traces of cilia are to be found. The various cells illustrated by ﬁgures 76 to 78 gradually increase in their size and, since their swelling is remarkable, especially in the upper half, it is usual that this partsof the cell naturally juts far out into the lumen, though‘ the lower half, being comparatively narrow, is closely united with the basement membrane. Within the cell body are contained a great number of both lipoid granules and vacuoles, of which the vacuoles in ﬁgure 76 are as yet small and few and they chieﬂy occupy positions in the upper half of the cell body, whereas in ﬁgures 77 and 78 the vacuoles enlarge tremendously and fully occupy the upper half, in consequence of which cell bodies have the appearance of a honey comb in a high degree, and the protoplasm remains only as a thin wall which separates the vacuoles. The lipoid granules in the latter two kinds of cells chieﬂy crowd together at the base of the cell bodies, and only a small portion of them are left behind as contents of the vacuoles. The afore-mentioned three cells each present conspicuous nuclear network and nucleoli. And in the various cells in ﬁgures 75 to 78 no plastosomes are to be detected.
Figure 79 illustrates a large oval-shaped cell, Which has a similar-shaped large alveolar nucleus. The cell body, because of the vacuolar formations of various sizes, presents the image of a conspicuous honey comb, while the plastosomes lie scattered somewhat plentifully in the interstice between the vacuoles. Though there are some extremely small vacuoles in jet black, no ordinary lipoid granules in coarse grains are to be found. The contents of the nucleus are nearly homogeneous, and the characteristic nuclear network is not found,’ but within the nucleus there are two nucleoli. Figure 80 is an extremely irregular-shaped cell, with the nucleus of a corresponding shape. The structure of the._cell body is nearly the same as that in the preceding ﬁgure, and the vacuoles are somewhat plentiful, but the plastosomes are very few, and, besides, there are but few yellowish lipoid granules. The nucleus has a conspicuous network. .
As the change of the glandular cells reaches a high degree, the cells leave the basement membrane in large numbers and are isolated in the glandular lumen. Such cells I call temporarily the ‘desquamated cells’ in contrast to the cells which continue to settle on the basement membrane or remain ﬁxed on the walls. Figures 81 to 83 illustrate my so-called desquamated cells, in the inside of whose cell bodies there are many vacuoles and a small number of extremely small lipoid granules which are stained in black. At a glance they look like the ‘wall-ﬁxed’ cells, and yet on a careful comparison we ﬁnd that there is a more or less remarkable difference between them. That is to say, in the desquamated cells the cell bodies are in general somewhat turbid, and also the vacuoles look somewhat withered and decayed. No plastosomes are to be found, and, besides, the change of the nucleus is remarkable, as will be seen in ﬁgure 81. Here it is converted into a darkcolored and homogeneous lump provided with a Very irregular contour, having within a few small nucleole-like bodies. In ﬁgure 82, as before, the nucleus is simply a homogeneous and dark-colored lump; in ﬁgure 83 it has swollen somewhat remarkably, and the nuclear network‘ is extraordinarily conspicuous. In short, the desquamated cells hav_e undoubtedly began a retrogressive degeneration already, andfrom the existence of many broken pieces of cells which are always found in the glandular lumen it can be simultaneously demonstrated that the desquamated cells are doomed to break up and perish at this section sooner or later. The various changes undergone by the glandular cells described above are seen in a remarkable degree already on about the seventeenth or eighteenth day of pregnancy in the decidua serotina, while in the decidua vera it is a little bit later and the changes are noticed to about the same degree as the former only toward the end of the ﬁrst month of pregnancy. Both reach the maximal changes at about the end of the ﬁrst month of of pregnancy, and on the days following they gradually pass into the so-called desquamated cells and break up and perish as such.
The series of changes described above have a more or less difference of time between the decidua serotina and the decidua Vera, viz., in the formerpthey may be followed up vigorously up to the end of the second month "of pregnancy, though in the third "month they suddenly decrease, whereas in the latter such changes may be demonstrated even one month later.
The Histological Structures and their Functional Significance (Some Reflections on Literature)
In the preceding chapter I have given a somewhat minute account of the delicate histological structures of the various important cell groups which exist in the placenta and the decidua vera at different periods of pregnancy. Now, on a perusal of the observations given therein, it will be found that as components which are common to the various cell groups there are 1) plastosomes, 2) lipoid granules, and 3) vacuoles. As a matter of course the degree of the appearance of the three kinds'of components and their distribution in which they are present vary inﬁnitely as the kind of cells differs or according to each individual cell. However, that which exercises the most important inﬂuence over the shape and formation of the cell is chieﬂy the lipoid granules and vacuoles, of which the latter often appear in a very great number and occupy the whole body of the cell, thus giving the cell a highly foamy appearance or a honey comb structure. The cell which has fallen into such highly vacuolar formations makes one feel, at a glance, that it has presented a phenomenon of collapse due to the regression of the cell concerned, as some observers ‘are apt to conclude quite hastily. However, as, on a careful examination of it, it is found that, in spite of the high degree of changes. shown by the cell, there are demonstrated for the most part within the cell body the plastosomes which are deemed an important active element in the functions, and also in consideration of the normal structure of the nucleus and of the fully stained conditions of the cell body, there is no doubt as to the cells being alive. And even if it should be conceded for a while that the cell having the fully stained vacuoles as described above is the indication of a kind of regression, who could explai11 the reason why this kind of ‘regressive’ cell actually appears in so high a degree within the tissues of the placenta ‘and the decidua at a certain period of pregnancy, and especially in the ﬁrst half of pregnancy when the tissues should grow in a most vigorous manner? Therefore, I am conﬁdent that not only is it wrong to deem such vacuolar formations a death phenomenon of the cell, but also they should rather be taken for a quite signiﬁcant phenomenon which shows a certain function of the cell concerned. And, as regards the actual existence of such a function, I am inclined to assert from their closest resemblance to the structures of many other glandular cells, as a result of my histological observations, that a secretory function is existent in these kinds of cells. However, as the problem is of such a provisional character I will, for the present, reject all hasty assertions, but instead will consult literature Widely and make generalreference to the previous interpretations of many authors on the structures and secretory processes of the various glandular cells in the organs in -which secretory functions are deﬁnitely known, so that the most deliberate considerations can be given my histological observations and their functional signiﬁcance, which, being compared and discussed under impartial criticism, it is hoped, will help toward making the original nature of the functions clear.
Since the relations between glandular histology and secretory functions were early dwelt upon by R. Heidenhain (’68, ’75, ’80) with his penetrating eyes, the subject has aroused the interest of many excellent physiologists and histologists, and the studies of’ the subject have since followed so quickly one after_ the other, that it would be difficult to enumerate them here. The following are the principal authors who have studied the subject, and the materials chosen by them for investigations were chieﬂy pancreas, salivary glands, gastric glands, lacrimal glands, skin glands, and pelvic glands, all of which are usually known as representative glands in many kinds of animals classed above the amphibians: Schultze, Fr. E., ’64 and ’67; Langhans, ’69; Pﬁiiger, ’7 1; Schwalbe, ’71 ; Ebner, ’73; Nussbaum, ’78 to ’82; Ebstein and Griitzner, ’74; Lavdowsky, ’76; Langley, ’7 9 to ’89; Mathews, ’80; Klein, ’82; Biedermann, ’82 and ’86; Flemming, ’82; Kiihne and Lea, ’82; Nicoglu, ’93; Altmann, ’94; Galeotti, ’95; Krause, ’95 and ’97; Muller, ’96 and ’98; Solger, ’96; Zimmermann, ’98; Held, ’99; Maximow, ’0l; Noll, ’01; Fleischer, ’O4; Heidenhain, ’07; Babkin, Rubaschkin, and Ssawitsch, ’09.
I will not go to the trouble of giving a detailed account of each of the results of these research works, but will conﬁnemyself to summarising the main points of their investigations respecting the structure and secretory phenomena of glandular cells, which are most essential to my studies, and refer to the original works for details.
In the ﬁrst place, the structure of the glandular cells having a duct, or externally secreting glands, greatly differs, as is generally well known, according as they are serous or mucous. The serous cells have an exceedingly large number» of granular bodies, and consequently their characteristic is that they are generally dark. Thesegranular bodies are generally known as Cl. Bernard’s secreting granules. The .relation which the latter has to secreting functions has been generally recognized by many an interesting research work since that of R. Heidenhain, and it will be noted that Heidenhain, having observed a kind of slender thread-like structure which exists close to the basement membrane, of the glandular cell of a dog’s pancreas, for the first time drew general attention to a peculiar sort of organic structure which is existent in the glandular cell. This kind of thread-like structure was demonstrated also in the salivary ducts and convoluted uriniferous tubules in after years, and it cannot be anything but M. Heidenhain’s so-called ‘Basalﬁlamente’ or our plastosomes.
Below I wish to give a general outline of the changes appearing in these organic tissue elements of .the glandular cells which will follow the secretory functions.
Now, at ﬁrst, it is universally agreed by every author that secretory granules increase or decrease according to secretory functions. According to the result of the close examination with respect to such correlation, conducted chieﬂy while in a fresh condition, of the pancreas of the rabbit, the oesophagus glands of the frog, and the gastric glands of the water lizard, by Langley (’79 and ’89), whose exposition of the correlation is best authenticated, it will be noted that during suspense of their functions glandular cells are generally glutted with secretory granules, whereas as secretion begins the granules gradually decrease and disappear, in consequence of which in each cell will appear a sharp demarcation between the homogeneous wide outer layer and the remaining granular inner layer. This observation of Langley has been repeatedly proved‘ by many other authors in many other glands, and its validity except in a small number of cases, has been recognized by nearly everybody.
For convenience, I defer to a later section a minute explanation of the functional signiﬁcance of the thread-like production which is found in the basal part of glandular cells.
Even in mucous cells it has been universally acknowledged by many authors since F. E. Schultze (’64) that there are granular bodies in large numbers at a ﬁxed period of secretion, and at the time when secretion is very high these granules gradually disappear asin the serous cells (Langley, ’7 9 ; Biedermann, ’82). It seems therefore that in the forms of secretion formation mucous cells agree, for the most part with the serous cells. However, the reason Why both differ Widely in their structure is that in the latter the secretion is, for the most part, speedily drained into the glandular lumen at the time of secretory function, whereas in the mucous cells it is formed withinthe cell bodies, besides being stored up there for a certain period, thus giving the cells a peculiar structure and a characteristic clearness.
In short, in the aforementioned two kinds of glandular cells, the large quantity of secretory granules always to be seen in both during suspense of secreting functions disappears, by degrees as the functioning begins. In View of this fact, we have no doubt whatever that, at the time of secretion, the granules always play an indispensable part as the mother-ground for the secretions and, since secretory granules are generally deemed a solid production, according to the investigations of many authors while the secretions are mostly ﬂuid, it follows that it would be no great error to take it that, viewed simply from the histological standpoint, the so—called secretion, after all, _means, the liquefaction of secretory granules. However, the modes of liquefaction are, according to my view, so varied that they should by no means be dealt with in one and the same manner, but rather there are, roughly speaking, several forms, such as are given below, according to the kinds of glandular cells, or according as the cause which prompts secretion differs.
First form. This is observed in certain mucous cells. The secretion is brought into being simply by the melting down and growth of secretory granules which have developed in a ﬁxed degree, and, different from many other glandular cells in which the secretory granules are mostly preproducts of secretion, the granules here in this case show the same reaction as secretion (that is, mucin) from the beginning of their appearance and ﬁnd themselves already identical with the secretion as early as they appear. This fact was demonstrated by M. Heidenhain in the goblet cells of the intestine of the salamander, and it is, in general, difficult to tell deﬁnitely the time of liquefaction in what is covered by this form.
Second form. This is observed in many mucous cells. The granules, while in the ﬁrst stage, appear as a certain preproduct (mucigen), and undergo a chemical change simultaneously as they have developed to. a certain degree, and are changed into the ordinary secretion (i.e., mucin). Mention has been made to this effect by Biedermann (the mucous cells of the frog); M. Heidenhain and Nicoglu, ’93 and ’98 (the skin glands of a salamander); Altmann, ’94 (the submaxillary glands of a cat); Maximow, ’01 (Glandula retrolingualis of a hedgehog).
Third form. This is often seen in ordinary serous cells. As the functions begin, the secretory granules begin to liquefy gradually on the periphery and, although it appears that the granules are imbedded for a certain period in the secretion already formed, they ﬁnally change thoroughly into secretion, and then appear as simple vacuoles within the cell bodies. The clear halos around the granules referred to by Langley ('34), Corlier (’96) and Maximow (’01) were it seems, deemed by these authors-an essential ingredient in the formation of glandular cells; however, M. Heidenhain with Nicolas (’92) attributed one part of them rather to artiﬁcial production, while the other was brought into being in the form it appears in, possibly becausethe granules were reduced in size in connection with secreting functions.‘ And in recent times the researches regarding pancreas cells, conducted by Babkin, Rubaschkin, and Ssawitsch CO9), have proved the above mentioned views of Heidenhain with more force and accuracy; that "is, in the opinions of these authors, clear halos around the granules are, after all, nothing else but secreted matter which appears as a liqueﬁed product of the granular substance. And that such an image should be a sign of an important period in secretion formation within the cell bodies will be clear in the statement made by the three authors mentioned above on the changes which zymogene granules undergo at the period of a pancreas secretion: “Wir erhalteh den Eindruck, als ob das (Zymogene) Kornchen sich allmahlich auflost, in dem es sich immer mehr und mehr Verkleinert und in em kleines verwandelt” (p. 92). Fourth form. According to the views of Babkin, Rubaschin, and Ssawitsch above referred to, this presents an appearance somewhat like a modiﬁcation of the third form. That is to say, many secretory granules together with the intergranular substance concerned form themselves into somewhat large masses, which latter slowly begin to liquefy from the periphery, and are then gradually changed entirely into secretion in rather large drops, to be drained out into the glandular lumen. Compared with the third form, in which each individual granule becomes liqueﬁed separately, this type differs from the former in that a number of granules coagulated together in lumps are transformed gradually into drops of secretion. This form is distinctly demonstrated at a time when the function of pancreas cells is very greatly increased, especially by means of stimulating the vagus nerves or of soap infusion in the duodenum, it being characteristic of the secretion at such a time that the latter is very dense, and is rich in albumen and ferments. And the three authors mentioned above are of the opinion that the several bodies which are revealed by this secreting form may be compared with the small bodies which are often known as ‘Nebenkerne,’ ‘parasome,’ ‘corpusculus paranuclaires,’ and ‘noyau accessoir’ in the pancreas cells of the lower vertebrates.
Fifth form. This points to a case in which the substance of secretory granules changes its quality at a certain period, becomes soluble, and is only dissolved in the watery part of the secretion alone, as was instanced by Babkin, Rubaschkin, and Ssawitsch, in the experiment of the pancreas secretion after pouring acid in the duodenum. As a proof thereof, the secretion always shows in this case the same coloring reaction as do the zymogene granules.
The three forms (the third to the ﬁfth) described above are together met with in the pancreas cells, and it deserves special attention that accordingas the cause differs for the rise of secretion, even in one and the same glandular organ, there is a difference in the forms of secretion, and consequently in the nature of the secretion produced.
Sixth form. Certain secretory granules sometimes have two extreme developments. As an instance, M. Heidenhain observed the skin glands of a salamander and he found that, as the development of the granule reaches a certain degree, one part of it is liqueﬁed and passes into a viscous secretion, while the other goes on growing in size, and is perfected into the characteristic poison grains.
Seventh form. A certain organic structure is presented in the secreting granules; at the beginning it is not different from ordinary cases, and yet as a certain development is accomplished, every granule is divided into a crescent—shaped section (Kapuze) which is stainable, and into an unstainable section (Trager) within the crescent-shaped section, thus forming the ‘Halbmondkoperchen’ so termed by M. Heidenhain. This latter as it grows in size is considerably enlarged, especially in the Trager, and consequently the Kapuze is ﬂattened gradually and is only stuck like a plate on its one side. Then the Trager is at last dissolved altogether and is changed into secretion, while at the same time the Kapuze is also condensed, and forms itself into secondary granules, later on to be drained out along with the secretion, thus bringing about an entirely granule free condition of the cells. This form of secretion was ﬁrst detected and examined closely by M. Heidenhain in the pelvic gland of a salamander and in the lacrimal gland. Subsequently, Nicolas (’92), in a man’s lacrimal gland, Held (’99), in a rabbit’s submaxillary gland, and Fleischer (’O4), in a coW’s lacrimal gland, observed and proved the appearance of the crescent-shaped small bodies described above.
The above does not cover all the forms of granular liqueﬁcation at the time of glandular secretion, and yet it will be quite clear how varied the modes of liqueﬁcation are. . "
Now, I will discuss a little further the origin, and therefore the manner in which supply is made of secretory granules, this problem being the second in importance with respect to glandular secretion.
With regard to the origin of secretory granules, the problem itself is a very difficult one indeed, but it should be noted that, along with the sudden increase of studies on plastosomes in recent years, many authors have attempted a solution of this troublesome question.
Below I give a general account of the result of these researches. Generally speaking, every author equally agrees in the argument that every glandular cell always has within the cell body plastesomes as constant ingredients and, though the quantity and arrangement of the latter are certainly varied, it is the usual condition that while the serous cells are in a state of rest the numerous plastosomes are chieﬂy arranged in rows along the long axis of the cells. These plastosomes, however, generally decrease in quantity considerably during the period of secretion, especially when the cells are ﬁlled, and they are then found largely, close to the basement membrane of the cell, while near the lumen, they are either entirely absent or, if they are found, they are between the granules in a very small number. And in mucous cells, in contrast to serous cells, the plastosomes are found largely near the nucleus, though some lie scattered in the protoplasm between the secretory granules, all being arranged in an irregular order. With regard to the functional signiﬁcance of the plastosomes contained in these glandular cells, there are various theories, such as the theory of secreting mechanism by Benda (’O3, p. 780), that of water-secreting apparatus by M. Heidenhain (’O7), and that of prop system by Bruntz (’08); however, these are either the historic ones, having been refuted experimentally by Meves and Regaud (’08) already, or mere assumptions.
What is believed by a great majority of authors at present is that plastosomes are very closely related to the formation of secretory granules. And the ﬁrst man who published his views with'regard to this was Altmann (’94), who’ thought that his so-called ‘vegetative Faden’~a greater part of which agrees with our plastosomes of to-day~being split up in small pieces are formed into granular bodies in large numbers and make the beginning of secretory granules. Quite recently the researches of Laguesse (’99 a, b, ’05, ’11), Regaud (’O9), Regaud and Mawas (’09), Hoven (’10, ’11,-’12), Champy (’11), Schultze (’11), have followed one after the other, and, though their observations may differ a little from one another, either in triﬂing points or in the form of description, they none the less fall entirely into line with Altmann’s View that the formation of secretory granules has its origin.in plastosomes. And, moreover, the fact that, as is generally acknowledged, the number of plastosomes in glandular cells always increases or decreases according to the changes of secreting functions is nothing if not forcibly proving the validity of such a theory. l
However, this very theory is not without objections. M.Heidenhain, Mislawsky (’11), and Levi (’12) are those who are opposed to it. Especially M. Heidenhain, taking his stand on the ‘Protomeren-Theorie’ which he set forth, states that secretory granules should have their origin in extremely faint and extraordinarily small bodies in the protoplasm which are beyond our sight; these bodies growing up and increasing should gradually develop into the ‘smallest granules-—his ‘Primargranula’—which are seen microscopically to gradually bring about the growth of deﬁnite secretory granules. Thus it seems he denies the-histogenetical correlation between plastosomes and secretory granules. His theory, though most dex-_ terously proposed on the most profound proofs, is after all a mere hypothesis. Besides, in consideration of the following quotation, it will be quite clear how he holds the views that his so-called ‘Primargranula’ have a close. relation with the genuine cytomicrosomes in their formation, and that the _latter do correspond to a section of his ‘Basalﬁlamente,’ and, further, that the ﬁlaments are identical with F1emming’s M.itom:
Ich bin daher mit Solger der Meinung, dass auch in den serosen Driisenzellen die Basalﬁlamente Teil eines Fadensystems sind, welches nach der Bezeichnungsweise Fle_mming’s dem sogennanten Cytomitom zugehoren wﬁrde. . . . . Nicht ganz ausschliessen darf manjedoch zur Zeit die Moglichkeit, dass die Drﬁsengranula evéntuell von den genuinen Plasmamikrosomen sich ableiten, welche nach unseren allgemeinsten Erfahrungen immer innerhalb der Protoplasmaﬁlamente liegen, also verdichtete Teile feiner Fadchen sind. . . . . Da nun die Korperchen beiderlei Art (Primialrgranu-lis und genuine Mikrosomen) morphologisch schwierig unterscheidbar sind, so kanneine verwandschaftliche Beziehung zwischenbeiden zur Zeit wenigstens nicht abgelehnt wervden, besonders da wir ﬁber die positive Bedeutung der genuinen Plasmamikrosomen noch sehr im Unklaren sind (p. 390).
And since it has already been clearly, proved by the researches of Meves (’07) that F1emming’s Cytomitom agrees with our plastosomes, it would appear that M. Heidenhain does not only maintain the View that his ‘Basalﬁlamente’ exists as a watersecreting apparatus as mentioned above, but at the same time also supports, instead of disproving, the argument which regards basal ﬁlaments as being the matrix forthe formation of secretory granules, as Altmann and others do. As regards Mislawsky’s view, it will be noted that he, in line with ‘Levi, takes the ground that as between plastosomes and secretory granules there were no conspicuous conditions to be detected in support of the existence of a formative relation between the two. However, anent Mislawsky, it will be noted that the invalidity of such a view has been exhaustively pointed out by a Belgian cytologist, Duesberg, in comments noted for their profundity and thoroughness. The following phrase is there employed by him: “Ein negatives Resultat beweist nichts gegen eine Reihe positiver Resultat und man kann nur schliessen, dass Mislawsky die Bilder nicht beobachtet hat, die seine Gegner unter Augen hatten” (p. 785). This should incidentally prove to be a pertinent comment on the theory of the excellent Italian author, Levi.
If we summarize the observations of the various authors respecting the structures and functions of the glandular cells described above, we may enumerate as constituents of the glanduar cells, 1) plastosomes, 2) secretory granules, and, 3) secretions (vacuoles), besides the protoplasmic stroma proper, and it would be superﬂuous to state that of these constituents secretory granules have a directly important relation to the glandular secreting functions. The secretions are nothing else than a liqueﬁcation or modiﬁed product of the latter and there is no alternative but to assume that the secretory granules, once lost at secretion, take their matrix mostly from the plastosomes, which latter, being split up and separated in small pieces, gradually meet the deﬁcit so caused. Thus, the real state of glandular secreting functions is already a thing which can be largely followed up and made clear by means of minute histological investigations to-day.
Also the histological studies of the ductless glands—~internally secreting cells—have become very active of late years, and, especially among those which have been carried on by the methods of plastosomic study, we may enumerate the thyreoid and parathyreoid glands, suprarenal capsules (chieﬂy its cortex), Langhans’ islets of thepancreas, and the ovary. Of these organs, the ovary has been used more often than the rest as the object of study, and consequently, comparatively speaking, much is known about it. I will therefore give a general summary of the observations of the various investigators respecting this organ, consider its structure and the relations of its internal secretory functions, and then glance at the structures of the other organs, thus contributing toward a histological account of internal secretion in general.
That the corpus luteum is a kind of internally secreting organ (from the histological point of view) was advocated by Prenanas early as 1898 and by Born in 1900. Subsequently, the argument has been advanced with more certainty by a close histological study conducted by Regaud and Policard (’01), Fr. Cohn (’O3), Mulon (’09), Athias (’l1), Van der Stricht (’ 12), Tsukaguchi (’12, ’13), and Levi (’13). And the main grofind of this argument lies in nothing but that the luteal cells contain as formative ingredients of the cell bodies plastosomes and lipoid granules, and often demonstrate a very large quantity of vacuoles which may be deemed their secreted matter, and also that the close correlation between these ingredients functionally is plainly apparent in the same manner as it is seen in external secretory cells. Of the various ingredients mentioned above, lipoid granules certainly have the most important signiﬁcance in internal secretion; however, since the latter is not only characteristic of luteal cells, but is also widespread among the other kinds of internal secreting cells, Tsukaguchi has already argued that it would be proper, in view of its functions, rather to compare them with the secreting granules of ordinary glandular cells. '
In the next place, Cohn ﬁrst regarded the vacuoles in a rabbit as a secreted matter of the luteal cell, and he saw them simply as a dissolved product of lipoids; subsequently Tsukaguchi also studied the same animal, and likewise deemed them a modiﬁed product of lipoids. However, vacuoles differ exceedingly in the degree of their development in all kinds of animals. For instance, Van der Stricht did not notice any vacuoles in the luteal cell of a bat, and subsequently Levi’s observations regarding the same animal nearly agreed with those of Van der Stricht. _ In the guinea-pig, however, Levi noticed a small number of vacuoles, which he attributed to a retrogressive phenomenon of the cell concerned, and he stated that this phenomenon, by means of a chemical change of lipoids following it, could cause possibly the substance of the latter to be dissolved by the benzol and xylol which had been used by him, as clearing media. In short, whenever the vacuoles appear, the lipoid granules ﬁrst make their appearance as their forerunners, and the former pass into the latter in succession, as has been entirely agreed upon by many observers.
With regard to the origin of lipoid granules, the Zoyas (’91) pointed out that there was a certain quantitative relation between granules and plastosomes, and this fact was acknowledged by Mulon, Athias, and Tsukaguchi, though Levi alone tried to deny it, as in the case of external secretory granules.
With regard to the secreting phenomena of luteal cells, Van der Stricht argued that in the order Chiroptera it was possible to divide them into two forms, viz., serous secretion and lipoid secretion. By serous secretion is meant that the follicular epithelium, being the antecedent of the luteal cells, secretes liquor folliculi, and, according to him, the Graaﬁan follicle, after rupturing, still keeps on secreting in this manner for a ﬁxed period, it being characteristic of this secretion that in the peripheral part of protoplasm of the young luteal cell some serous inﬁltration appears, and for that reason gives that part generally a somewhat transparent appearance. Already at this period a large quantity of small lipoid granules appears within the cell bodies; however, since these granules do not as yet per ‘form any functions, he called this stage the serous secreting period of the luteal cells; then, as the ovum settles,.the corpus luteum has already reached its highest degree of development, and he termed it the second stage of corpus luteum formation.
At this stage the cell body is already ﬁlled with numberless lipoid granules, which, undergoing a chemical change, cause the cell body to keep on discharging secreted matter until the end of pregnancy. This is what the lipoid secretion means. This theory seems to have been afterward accepted in the main also by Levi. However, the condition is entirely different in the Rodentia, and especially in the rabbit. According to the observations of Cohn and Tsukaguchi, lipoids chieﬂy appear in a high degree only in the early part of pregnancy, then disappear rather speedily. In the second half of pregnancy the lipoids change into vacuoles almost as transparent as water, the cell bodies present a highly distinctive vacuolar structure, such condition being still more conspicuous toward the last period of pregnancy. N ow comparing this with what is observed in the Chiroptera mentioned above, this period of lipoid secretion, so-called by Van der Stricht, in the rabbit passes away in a comparatively short time, and then slowly passes to the stage of the characteristic vacuolar image; thus, it appears, it presents a certain stage of secretion which is peculiar to itself. In short, it is interesting to note that, in consideration of the changes in the forms of secretion in external secretory cells, the structure, and therefore the form in the secreting functions even in the same luteal cells, differ according as the class of animals differs.
That the interstitial cells of the ovary possess the same internally secreting functions as luteal cells, by reasongof the close resemblance which they bear to the latter in shape and structure, has been universally acknowledged in the researches made, in various kinds of animals, including the Rodentia, Chiroptera, and Carnivora, by Regaud and Policard (’01), Limon (’02, ’03), Fr. Cohn (’03), Regaud and Dubreuil (’O6), Mulon (’11), Athias (’11, ’12), Van der Sticht (’12), Tsukaguchi (’12, ’13), Levi (’ 13) . Now, according to these observers, the interstitial cells also contain, as do the luteal cells and many other glandular cells, important constituents, such as plastosomes, lipoid granules, and vacuoles. The vacuoles are especially very plentiful, and they, for the most part, present a minute, delicate, and peculiar vacuolar image, the protoplasm proper being barely noticeable around the nucleus. The lipoid granules, as compared with the luteal cells, are generally small in quantity and, moverover, it is sometimes difficult to detect them. It is customary for the lipoid granules more or less to increase in quantity at the time of pregnancy. It has been equally acknowledged by many observers that the lipoids of the interstitial cells generally appear for a comparatively short period, commonly fade away in color and change in quality speedily, thus gradually passing into the vacuolar substance. And then, many authors, except Levi, have proved and recognized, even in this case, that plastosomes have a direct relation in the formation of lipoids.
Entering into details, Mulon stated that in the rabbit the plastosomes, granular in form at ﬁrst, change into minute siderophil granules, and then diffuse siderophil substance, and the lipoids will be formed from the latter. Athias (’12), who examined a newborn bat, also seconded the argument of Mulon for the most part, and argued that plastosomes produce the lipoid first at their center and accumulate it there, and in support of his argument he stated that occasionally the cortex, which has the same staining properties as plastosornes, could be detected around the lipoid granules. Tsukaguchi certiﬁed to an intermediate type of granules between the plastosomes and the lipoid in the young interstitial cells, thus arguing that the granular plastosomes develop and grow in size directly into the lipoid granules, as are seen in the case of the luteal cells. In short, the various investigators have not as yet come to an agreement in their views as to the correlations between the two, and yet it has been universally acknowledged by them that as the cells grow and increase and the lipoids or vacuoles appear plentifully, the plastosomes decrease in quantity in inverse ratio.
With regard to the organs other than the ovary, Mulon (’10 a, b) closely examined the suprarenal capsules of a guinea-pig and rabbit, and stated that by the conglutination of the granular plastosomes was produced directly a ‘substance (possibly our lipoids) which has affinity for osmic acid (osmophil) or ironalum-haematqxylin (siderophil), and is introductory to the formation of a vacuolar secreting matter to follow. Celestino da Costa (’07), Champy (’O9), and Colson (’10), also having experimented on the cortical cells of the suprarenal of a cat, guinea pig, toad (Bombinator) and bat, have proved the same fact as above. Bobeau (’11) also argued that when the parathyreoid glandular cells of a horse form a certain effective product the plastosomes should play an important part. And, besides, Engel (’09), Mawas (’11), and Schultze (’11), each demonstrated the plastosomes in the thyreoid and parathyreoid glands of a man, a rabbit, and a frog, and, according to Duesberg, it was stated that the plastosomes could be detected in the Langhans’ cells of the pancreas. It should none the less be stated that a majority of the facts enumerated above are merely preliminary. Many future investigations must be looked forward to for a further enlightenment of the secretion of these organs.
In summarizing the histological knowledge We have at present of the internal secretory cells described above, almost every cell has, as its constant ingredients, plastosomes, lipoids, and vacuoles. Now, the plastosomes are not regular either in their shape or‘ arrangement while the lipoids are not quite regular in their size, quantity, and color, but the smaller ones bear a resemblance to granular plastosomes, while the larger ones, agglutinating with one another, form larger fatty droplets. The contents of the vacuoles probably consist of watery, transparent droplets, which are separated from one another by a very thin partition wall. The cell body should present a more or less conspicuous alveolar structure in proportion to the quantity hf vacuoles contained. The quantitative correlation by which these formative ingredients are connected to one another is not free from considerable variations. Occasionally only one or two of them exist to the absolute exclusion of all the rest._ It must be very often the case that such phenomenon-may. be partly due to the difference in the order of animals chosen for the subject of study and partly to the functional relation of the cell concerned. In short, it may be said that the various formative ingredientsdescribed above as being seen_in internal secretory cells constitute equally necessary constant elements, the same as with external secretory cells, as has been minutely dwelt upon previously. Now, it is a marvelous sight indeed to compare, histologically these two kinds of cells, and to look at the perfect agreement, not only in their structures, but also in the various histological changes which follow their functions. On this score, I am convinced that should there be a structure like the two kinds, of cells described above, besides the functional changes which very nearly correspond to the above, it would be no error to bring such cells under the category of glandular cells, regardless of the existence of a duct in them. And, if we look at the various cells of the placenta and the decidua, we will ﬁnd that all of them are well furnished with various conditions which mark the glandular cells above referred to, and that naturally we should assert the existence of secretory processes in them , also. In the following section, I will give a detailed account of. the secretory phenomena of the various cell groups.
The Phenomena of Internal Secretion on Various Cells of the Placenta and Decidua
It is too plain to need argument that in-all cases the real state of the life processes of any cell cannot be made clear unless all the phenomena in the living condition of the cell concerned be followed up closely with the microscope. However, since it is certainly difficult to attain such an object by the histological method employed by us at the present time, by noting the phenomena of internal secretion it is possible to denote each of the extremely varied structural images obtained from the preparations ﬁxed and stained as indicating a certain period in the phenomena of secretion; to compare carefully and consider the correlations between the different periods, and thus to infer the whole of the process of secretion. Therefore, I must ask the reader to take this point into consideration.
1. The phenomena of «internal secretion in the syncytium layer
Now, at ﬁrst, in ﬁgures 1 and 2 only plastosomes are present, M and lipoid granules and vacuoles are entirely absent, so that we may conclude that this shows the early stage at which secretion is not yet in appearance or when secretion is at rest. In the next place,‘ in ﬁgures 3 and 4, more or less lipoids appear, and vacuoles are either barely found at one part or not formed as yet; the lipoids, in general ﬁrst appear on the superﬁcial layer, at which place they tend to grow up and increase gradu ally. The plastosomes have decreased considerably in quantity especially in ﬁgure 4. The last two ﬁgures may be taken as the early stage of secretion in the syncytium layer, and as it passed to the subsequent stage, a large number. of vacuoles, viz., secretions, appear besides the lipoids. The vacuoles later on keep increasing, while, on the contrary, the lipoids decrease in quantity, and, moreover, of these vacuoles those which are near one another unite into vacuoles of various sizes, and it will be seen that the surface vacuoles of the latter ultimately rupture and open upon the surface of the syncytium layer. The process of secretion described above may be followed in ﬁgures 5 to 7. Should this process continue and reach its highest degree, such structural images as are shown» in ﬁgure 8 would be probably brought about in the end! What is pecu— liar in these various stages when secretion is very high is that plastosomes are detected. In the next place, what is shown in ﬁgure 9 is taken, similarly to what is in ﬁgures 3 and 4, for a comparatively early stage of secretion. However, the former differs more or less from the latter in that already a somewhat large quantity of vacuoles is noticeable in it. And, especially, the vacuoles are chieﬂy arranged close to the Langhans’ cells. Figure 10 demonstrates on one side a large quantity of plastosomes and on the other a region where no plastosomes are to to be found. This region presents, as mention has been made already, a foamy structure which can be detected only by careful attention. Figures 11 and 12 each clearly demonstrate plastosomes, besides a large quantity of vacuoles and a small quantity of lipoids. That is to say, in ﬁgures 9 to 12 it is always easy to demonstrate plastosomes at different periods of secretion, and therefore the various periods of secretion shown therein may be differentiated from those given in ﬁgures 5 to 8, though it is not easy to decide what correlations these stages have periodically between themselves in point of secreting ‘functions. However, according to the various images described above, it is deemed practicable in the main to arrive at the following presumptions with respect to the phenomena of secretion of this cell layer:
a. At a time when function of secretion has not yet begun, the chief ingredient of this layer is plastosomes, whichare found in a very large quantity; however, as the function begins, they suddenly decrease in quantity, and at a certain period, especially when lipoid granules are exceedingly plentiful, they entirely disappear. . It has already been explained how this lack of plastosomes is not the result of the want of skill in the making of preparations.
b. As the function begins, lipoid granules ﬁrst appear conspicuously, especially at a place which is close to the superﬁcial layer, and then vacuoles appear. Sometimes both can appear simultaneously at a comparatively early stage (fig. 9).
c. The direct relations between the lipoid formation and plastosomes , could ‘not be ascertained in my preparations. However, the origin of lipoid. granules was found in an extremely small granular body, and on the other hand it is clear that there is a tendency for the plastosomes either to decrease more or less in quantity as function of secretion increases or to entirely disappear. , .
d. The transparent halos which are sometimes found around the lipoids give the latter anpappearance of being the contents of vacuoles, and by reason of such a condition we are led to believe that a certain intimate relation exists between lipoids and the vacuolar formation (ﬁgs. 7, 9, and 12).
e. However, we cannot as yet positively state whether or not all vacuoles without exception have an intimate relation with lipoid granules such as is described above. For instance, I cannot deﬁnitely declare whether the formation of the extremely delicate foamy image such_ as is seen in a part of ﬁgures 8, 10, and 12 has been the result of the lipoid granules while in the earliest stage of lipoid formation, that is, while as yet in a stage in which they are exceedingly small, having changed their quality, and caused such small vacuoles to grow in groups, or whether as Mulon quoted before, has observed withirespect to the ovarian interstitial cell, at the period of his ‘diﬂused siderophil substance’ (though it is still beyond my power to prove that such a period could appear in the syncytium layer), the substance has, instead of forming lipoids directly assumed a vacuolar formation. It is for future investigations to solve such a question.
f. All vacuoles gradually unite, and it appears that they possibly make a kind of canal system running irregularly and crosswise within the syncytium layer, and some of them distinctly open their mouths in various places on the surface of the syncytium layer, thus it is apparent ,that their contents, their secretions, are drained out into the maternal vessel of the intervillous spaces. And, as is seen in ﬁgure 11, the blood corpuscles which are noticeable within the syncytium layer may be rightly taken for the mother’s corpuscles which have accidentally gone into the canal system mentioned above, which would in turn prove the existence of the latter.
g. The secreting function is at work from the beginning of pregnancy to the end of the fourth month, though it is most active in the second and third months.
2. The phenomena of secretion of the Langhans’ cells
The protoplasm in the Langhans’ cells which are still small and should be deemed comparatively young contains plastosomes only (ﬁgs. 13 to 16); however, as the cells reach a certain size the lipoid granules appear (ﬁgs. 4, 11, 12, 17, and 22). The latter have developed from extremely small granular bodies such as are Visible in ﬁgures 9 and 21, and their number is not very large; the vacuoles appear in a very conspicuous manner, and it seems that these have also grown into what they are comparatively speedily from a very minute form, it being clear that the larger. of them have been brought into being by the agglutination and joining together of some of the vacuoles. And, while the secreting process is in progress, it seems that lipoids play a directly essential part; how they change their quality and liquefy from the periphery, and thus gradually pass into vacuoles as in the syncytium layer, can be very clearly seen in ﬁgures 12, 23, and 24. The loss of lipoids which keeps going incessantly by such vacuolation is made good by fresh formations elsewhere, and thus, the same process being repeated, the vacuoles go on growing in number and size simultaneously as the cell appears more and more to increase in its capacity, though the preparations I have are still very poor to prove this positively. However, the fact that, as mentioned above, lipoids have their origin in very small granular bodies and that plastosomes considerably decrease in quantity as the cell grows in size and therefore its functions are promoted (please refer to ﬁgs. 13 to 21), cannot but be taken for having proved that V plastosomes, owing to their quantitative relations, take part in the lipoid formation and, if this deduction be practicable. it would follow that the large group of plastosomes which makes its appearance in an especially limited section, as is seen in ﬁgures 3 and 9, should not be without signiﬁcance for the new growth and supply of lipoids. In short, the phenomena of secretion of Langhans’ cells, in general, are not very active and yet the cells in the Langhans’ islets are somewhat different, and it seems the functions are very active in this part, so much so as to make it a feature of these cells that they present a very large and highly vacuolar formation (ﬁgs. 21, 22, and 26). Since the Langhans’ cells always have on the surface a comparatively conspicuous border membrane, there is no alternative for the contents of vacuoles, viz., secretions, but to pass through this membrane and be drained into the villous tissues, and they are therefore possibly bound to be ultimately absorbed on the side of the embryo. However, since the part like the Langhans’ islets where the functions are necessarily very active is, as is Well known either mostly wrapped up in the decidual tissue or exists within the intervillous spaces, ﬂoating directly in the m1(:ther’1s blood, it is posisible that the secretions coming rom sue a p ace are absorbe on the mother’s side. Moreover, the large number of vacuoles which is found in a part where the Langhans’ cell layer comes in touch with the syncytium cell layer as in ﬁgures 9 and 12, judged from the position they occupy, has been temporarily denoted by me as forming secretions of the syncytium layer and so described in the previous paragraph; however, I am afraid nobody can say for certain that it is so. If we suppose that the secretions are brought forth by the Langhans’ cells, who may say they will not come out into the intervillous spaces together with those of the syncytium layer? In a word, since the Langhans’ layer is entirely closed against the mother’s body by the syncytium layer in the early stage of pregnancy, it would follow that the secretions are entirely in the service of the embryo, but after that it _is probable that a part of them are taken also by the mother’s body.
The function of secretion of the Langhans’ cells, just like the syncytium layer, is active in the main almost from the ﬁrst stage to the end of the fourth month of pregnancy, though in the second and third months it is very active, suddenly subsiding with the ﬁfth month. In the Langhans’ islet it continues still longer and commonly gradually subsides after the sixth or seventh month.
The epithelium of villi is located between the circulation of the mother’s body and that of the embryo. and it is for this reason presumed that it must be an organ which takes nutrition for the embryo, as has been commonly held in literature, but that such is a groundless assumption must be quite clear from my histological observations given above. And,_besides, there are some important reasons which prove the utter fallacy of this theory. It is in the first to third months of pregnancy that the growth of the epithelium of villi is most active. If the functions of the alimentary organ for the embryo be assigned to it, the. epithelium of the villi should go on developing most vigorously, but the fact is quite the reverse, and it retrogrades and becomes thin in the second half of pregnancy, and accordingly the decline of functions is brought about. This is one of the absurdities. And in the eighth month of pregnancy, when the embryo calls for a still greater increase in the supply of its nutrition the capillary blood vessels of villi increases suddenly, as was mentioned above, and early in this stage the epithelium of villi becomes remarkably regressive and falls into decay, so that the embryonal circulation -of the villi is separated from that of the mother only by a thin membrane like endothelium, undoubtedly it being quite easy for both to allow the interchange of materials between them. In other words, the particular organ which is needed for the absorption of nutrition for the embryo ﬁrst makes its appearance in a perfect condition only after the epithelium of villi retrogrades and becomes thin. on this score I am led to believe that the epithelium of villi is simply an organ of internal secretion, and that the ground is extremely weak for the argument, which treats it as an organ to take nutrition for the embryo, as has been generally conjec-. tured in the past.
3. The phenomena of internal secretion in the stroma cells of villi
The smallest of the. stroma cells of villi is simply a ballshaped cell which is comparatively rich in protoplasm, and within the cell body there is a large quantity of plastosomes (ﬁg. 27), but presently a somewhat large quantity of lipoid granules or vacuoles having various sizes appears within the cell body (ﬁgs. 28 and 29); and" subsequently, as the cell grows in size the chief ingredients of the cell body will be plastosomes and vacuoles, while the appearance of the lipoids is not very distinct. The image such as is seen in ﬁgure 34 is very seldom met with. On the contrary," however, the vacuoles may be deemed the almost constant ingredients of each cell, and especially as the cell developes and grows in size they increase the more in size and quantity, and present a highly foamy structure which is characteristic of this kind of cell. Now, if we consider the correlations between the different constituents mentioned above, it will be found first that in these cells the plastosomes are stained comparatively easily, and are therefore very distinctly detected in each cell; and as regards its quantitative relations, it will be noted that there is not the least tendency in the plastosomes to decrease in quantity, even though the functions increase and the cells enlarge, as was seen in the epithelium of villi described above. On the contrary, the plastosomescrowd together in large numbers in the various protoplasmic sections of cell bodies, and they present the appearance of a new growth and multiplication in the sections concerned (ﬁgs. 30, 31, 32, 33, 36, and 38). The only exception is that when the quantity of lipoids contained in the cell body is remarkably large, the plastosomes decrease more or less remarkably in quantity (ﬁgs. 28 and 34). The lipoid granules, as mentioned above, do not appear in very large numbers and, since they arise from very small granular bodies, it is very diﬂicult to clearly discriminat_e the latter from the ordinary granular plastosomes (ﬁgs. 28, 29, 31, 36, and 37). Therefore, in consideration of this fact and of the quantitative relations between lipoids and plastosomes as described above, I am inclined to trace the mother-ground of the lipoid formation in the plastosomes. Then, with regard to the vacuolar formation, we may infer from the conspicuous halos which often appear around the lipoids, or from a phenom_enon in which the lipoid often occupies the position of a nucleus within the vacuole (ﬁgs. 29, 34, and 36), as in the case of the epithelium of villi as described above, that the vacuole should of necessity be the liqueﬁed product of a lipoid. In short, it may be stated that the secreting phenomena of these cells, if looked at from the histological view-point, are very simple indeed, and plastosomes ﬁrst bring forth lipoids, which latter in turn change into vacuoles, and the reason why the lipoids are comparatively scant is that the period of their appearance is exceedingly short. And, while perhaps -on one hand the contents of vacuoles, viz., secretions, are gradually drained out of the cell body, on the other the protoplasm and therefore the plastosomes bring about a prospective new growth and multiplication, presumably to provide for the materials of the next secretion, and in this manner the afore-mentioned process, as simply it may be, is repeated and follows in succession. At different times and in diﬁerent places, to make a secondary or, tertiary secreting process within a cell all the time, the cell develops and grows in size gradually, and its structure therefore becomes extremely complicated, and in this way I_suppose that, even in one and the same cell body, the various periods of the phenomena of secretion make a simultaneous appearance according to the ingredients contained. This is a mere hypothesis of mine, and yet since it was early refuted by M. Heidenhain that the secretory granules of all kinds start their individual function separately as a small independent ‘organel’ within the cell, this hypothesis of mine should not be taken exception to. And moreover, the increase and mass of protoplasm or plastosomes and the lipoids at different phases, all of which could be demonstrated in every part of this cell at any time, if sought for an interpretation of their signiﬁcance, will each provide a material to substantiate the hypothesis mentioned above. In this manner, this cell, While promoting its secreting functions on one hand, grows in size more and more, and such like relaw tions could be recognized more or less even in the Langhans’ cell.
The functions of secretion in the stroma cells of villi begin at the end of the ﬁrst month of pregnancy and continue actively until about the seventh month, though they are most active from the second month to the sixth. And though in the eighth’ month it appears that they suddenly subside, it will be found at all times that it is difficult clearly to follow the destiny of each of the cells, since it is interfered with by the strong increase of the capillary blood vessels of villi at this stage, as mentioned already. Since no special duct was detected, it is difficult to tell how the secretions are removed, other than by attributing it to osmose, as in the case of the Langhans’ cells, and by predestining the secretions to be absorbed by the embryo.
4. The phenomena of internal secretion of decidual cells
If We ﬁrst look at the decidual cells of the smaller type (ﬁgs. 39 to 51), we ﬁnd that the chief components of the cell body in the youngest are plastosomes (ﬁgs. 39 to 41), next appear lipoid granules (ﬁgs. 42, 43, and 44), then follow vacuoles, it thus being customary for the great majority of decidual cells of smaller type to contain many vacuoles and more or less lipoids besides plastosomes. The plastosomes sometimes decrease more or less in quantity in inverse ratio to the lipoids or vacuoles (ﬁgs. 43 and 49), but more often is it difficult to discern such relation, and, besides, many are plastosomes Which‘ either form a conspicuous group in some part of the cell body or considerably increase in quantity (ﬁgs. 44, 48, 50, 51, and 52). The lipoid granules arise at the beginning in a very small granular body, whence they grow up to a certainldegree, when clear halos appear around them, and the manner in which they directly participate in the formation of vacuoles (ﬁgs. 44, 46, 52, and 53) is the same as what is observed in the epithelium and the stroma cells of villi. And sometimes it occurs that the vacuolar formation appears equally at a time within one and the same cell body, and as a result the foamy image of high degree, such as is illustrated by ﬁgure 49, is brought into being, but this is rather rare, and in most cases the vacuoles_ vary in their sizes. And, besides, it is customary for the vacuolar formation in most cases to contain at the same time groups of plastosomes or lipoids of different sizes. In short, the smaller-type decidual cells entirely agree with the stroma cells of villi in their structure, and, therefore, there is no need for argument that their secreting phenomena should be dealt with in the same manner as the latter. On this score, I will not go to the redundant trouble of touching upon the secreting process of the smaller type decidual cells here, but will conﬁne myself to the brief statement that the function is repeatedly performed by the same methods as in the stroma cells of villi.
If we take a glance at the ﬁgures in the plate, it will be quite clear that the smaller-typed decidual cells, repeatedly performing as they do the functions as described above, develop and increase in size more and more, and passing through the various intermediate types (ﬁgs. 52 to 54, 62 and 63) gradually, as I mentioned in the previous chapter, pass into the larger-type decidual cells to attain the height of their growth. Therefore, the demarcation between the large and small types in the decidual cells is, after all, due to the difference in the degree of growth of the same kind of cells, and the smallness of the cell should be taken for an indication of comparative infancy, while the largeness of the cell shows that it has attained the region of perfection in its growth.
The large—type decidual cells may be divided into two kinds with respect to structure. One represents the kind of cells whose body is protoplasmic, and commonly has a large number of plastosomes, besides more or less lipoids which are often discernible, though vacuoles are almost absent (ﬁgs. 55 to 61). The other represents those cells whose body -presents a highly vacuolar image, whereas the protoplasm considerably decreases except around the nucleus, while no plastosomes are to be found. The lipoids contained are irregular in their quantity, but more or less of them are always existent (ﬁgs. 64 to 69). A great majority of the commonly so-called decidual cells belong to the former, while a comparatively small number is represented by the latter. . In the former class the structure of the cell is entirely different from the small-type decidual cells and my ‘intermediate type,’ so that along lines of histology there is no indication of the existence of the process of secretion, and although lipoids exist in smallnumbers, their quantity quickly decreases and they go out of existence as the cell body grows up in size, so that it would be in order to_ denote the lipoids rather as persistent bodies bequeathed from a period of their growth, and consequently it follows that it would be no great error to conclude that at this perioda secretion, such as was noticeable at the period that preceded it, either considerably declines or entirely disappears. However, in the various cells which belong to the latter class, the afore-mentioned secretory functions are developed to the extreme throughout all their growth, and there is an appearance which points to the utter exhaustion of plastosomes‘ on account of these functions. From the scantiness of ‘materials, it is diﬂicult to determine the destiny of this kind of cells; whether the cell body ultimately breaks up and decays or is absorbed or whether after throwing out the secretions, the plastosomes again increase or are replenished, and thus it slowly passes into the former class of cells; however, I at least am conﬁdent that it would be prema ture to assert that the various periods illustrated stand for a direct indication of retrogression or decay. In short, in the larger-typed decidual cells, it is possible clearly to observe in a portion of them the same process of secretion as in the small type cells, whereas in the largest number there is almost no sign of such a function, which fact _is worth much attention.
The large-type decidual cells, as aforesaid,~ no longer present the ordinary phenomena of - secretion for the most part, and yet, at a certian period, dark-stained coarse granular bodies of ir regular sizes often make their appearance within the bordering membrane of the periphery (figs. 55, 59 to 61); various material products having the same staining properties are often detected within the interstitium (ﬁgs. 70 and 71), which makes one feel that there is a certain formative relation between the two. And, ‘besides, similar products often ﬁlling up the blood vessels around them, - give’ the appearance of being absorbed in the vascular organs (ﬁg. 71). Such peculiar products having been originally observed in the ﬁxed preparations, it follows that they might be an artiﬁcial product, a result of the ﬁxatives, and yet from the observations mentioned above it is not difficult to conclude that a certain material which corresponds to them is prepared, perhaps by some special function of the cell membrane of_the cell concerned, and is sent forth in the direction of the interstitium. And should this supposition prove correct, it would follow that these two kinds of large-type decidual cells are functionally quite independent of one another, though they are genetically of the same origin.
Looking on the whole of the functions of the decidual cells from the histological point of View given above, I am led to believe that they may be roughly divided into three periods, according to the course of their development. The ﬁrst period is seen in all the small-typed decidual cells, the intermediate type so termed by me, and in" a portion of the large—typed cells, here the secreting functions are distinctly performed in the same manner as in the stroma cells of villi. In the second period, possibly by the functions of the cell membrane, a certain product is prepared, to be sent forth in the direction of the interstitium. The third period begins after the sixth month of pregnancy, when the cell ‘body in general shrinks considerably, and no plastosomes are to _be discovered, besides no particular tissue structures from which inference may be made of the functions performed are to be recognized. And, moreover, cells at this period experience the rise of embryon al pressure (the inner pressure of the uterus) as the time of pregnancy elapses, in consequence of which they are remarkably ﬂattened and afterwards present the appearance of ﬂattened epithelium. And,’ as regards the destiny of decidual cells, it seems that it has been argued in the past that they retrograde and perish by fatty degenera tion or coagulative necrosis (Klein); however, as a matter of fact, I have not as yet discovered such a change. All kinds of decidual cells perfect their growth comparatively rapidly early in the beginning of pregnancy, viz., in about threeweeks after pregnancy, and after that only a quantitative increase or decrease of the various cells occurs. Consequently, the degree of growth of the cells cannot be the sole measure of the time of pregnancy.’ However, judging from their quantitative relations, it is not difﬁcult to arrive by Way of inference at the approximate period of pregnancy; that is to say, the small type cells appear from about the second week of pregnancy to the end of the ﬁrst month, and the intermediate-type cells from above the seventeenth or eighteenth day to the end of the second month, in both cases in exceedingly large numbers, while the large type cells appear throughout the whole remaining period beginning about the twenty-second or twenty-third day of pregnancy, and yet it will be noted that these large cells are at the height of their activity during the period from the end of the ﬁrst month to the end of the third month of pregnancy, and while in the fourth month the functions are still pretty high, they considerably decline in the months to follow, and in the seventh month and after it is very seldom that such functions are clearly noticeable.
The phenomena of secretion of cells in the decidua serotina in the ﬁrst half of pregnancy _are nearly the same as in the decidua vera as described above. "In the second half, especially after the eighth month, giant-cells grow in large numbers, and somewhat remarkable changes take place, even histologically in the ordinary sense of the term, and, therefore, I have examined the subject with an especially keen interest; however, the absence of good materials, coupled with the difficulty in staining them has hindered me in. making excellent preparations, and the functions of cells at this period are therefore set aside for future investigations.
5. The phenomena of secretion in the uterine glandular cells at the time of pregnancy
The epithelium of the uterine gland undergoes a remarkable change in the early part of pregnancy, Viz., on about the seventeenth or eighteenth day after conception (ﬁgs. 72 to 83). Now, if we consider its phenomena of secretion, we shall ﬁnd that, even in this cell, lipoid granules first appear, and then vacuoles are formed. In the stained preparations, lipoid granules appear assembled and are accumulated especially near the basal part of the cell body and show a remarkably clear yellowish-brown color (ﬁgs. 73 to 78). The latter often appearing as contents of vacuoles (ﬁgs. 77 and 78), it wouldprobably appear that the vacuoles are a modiﬁed product of the lipoids, just the same as in the other cases. In this way the lipoids gradually change into vacuoles, the cell grows in size and presents a highly honeycomb structure (ﬁgs. 77 to 80). The plastosomes either decrease in quantity or become very difficult to discover as the functions of secretion increase in activity. However, I have not been able to make clear the formative relations between the plastosomes and lipoid granules. Be that as it may, it happens that, with the increase of the function of secretion and the growth of the cells, the latter gradually move over toward the comparatively enlarged glandular lumen, and, at last, leaving the wall of the glandular tubule, are entirely free Within the glandular lumen. The characteristics of these desquamated cells are that either the cell body shows a highly vacuolar formation or that the vacuoles being somewhat reduced in quantity, theprotoplasm becomes dark and turbid, and no plastosomes are to be found. The condition of the nucleus is also exceedingly abnormal (ﬁgs. 81 to 83). How the various cells of this kind are broken up by degrees and added to the large quantity of fragments ﬁlling up the glandular lumen can be observed and followed with a great certainty. ' The various changes of the uterine glandular cells as described above have, as was mentioned in my own observations, a deﬁnite relation to the time of pregnancy, and accordingly the rise and’ fall of the functions of secretion of these cells also act upon it; that is to say that, in the ﬁrst month and the ﬁrst half of the second month of pregnancy, the functions are at the height of their activity, and they subside considerably from the beginning of the third month, the subsidence being by far the greater in the fourth month, and in the ﬁfth month they seem to come to a standstill, it being no longer possible to demonstrate the function of secretion in the months that follow, viz., in the second half of pregnancy. In the next place, the aforementioned functions of the glandular cells, as compared with the decidua vera, appear more speedily and in a still higher degree in the decidua serotina, and fail accordingly earlier than in the former, and everybody easily recognizes that the scoretions of the glandular cell and its broken-up matter both accumulate in the glandular lumen for a certain period, though some consideration should be given the question as to how they are removed or absorbed. It is said that, according to what has been written on this subject, the placental formation commences from the second month and is perfected in the fourth month and that the decidua reﬂexa and decidua Vera are agglutinated in the ﬁfth month. Should this opinion be true, it would follow that the secretions of the uterus, looked at from the periodic relations of secretion, are for the most part drained into the uterine cavity, and take a part in the forma ' tion of the so-called uterine milk. However, according to my own experience, it appears that the placental formation and the adhesion of the decidua reﬂexa take part in an earlier part of pregnancy. ,Therefore, I am inclined to believe that a part of the secretions and detritus of the uterine glands, at least in a little advanced period of pregnancy, are naturally absorbed by the mother on account of the closure of the ducts.
It is to be observed that the syncytium layer, Langhans’ cells, stroma cells of villi, decidual cells, and uterine glandular cells, all of which constitute the chief tissue elements of the placenta and decidua, each contained plastosomes as a constant ingredient of its protoplasm, and that a majority have at the same time a certain quantity of either lipoid granules or vacuoles, or of both, and, consequently the minutes histological structure of these cell groups bears a close resemblance to that of both the internally and externally secreting cells. And, moreover, these main components of protoplasm or cell body are, according to their functions, as closely correlated to one another as they are in the glandular cells. Now, taking a general survey of this correlation, it was found in my study that the plastosomes, being the ﬁrst constituent, appear for the most to be the matrix of lipoid granules from which the latter rise, and as ia proof of this argument, I will cite the stroma cells of villi, in which the correlation between the two is very closely shown. We can notice it somewhat in the Langhans’ and decidual cells, and if we closely examine the manner in which the lipoids appear in these cells, it will be found that they always rise from granular bodies which are ‘very small and strongly siderophil. I believe that these may be rightly compared with the so-called ‘Primargranulis’ which Heidenhain found in the common glandular cells, and even though they appear very small, they do appear as a perceptible body. There is no evidence to be found of their appearing as slowly growing and increasing, as Heidenhain assumes to be the case, from an inﬁnitely small body which is hardly seen microscopically until they enter the vision of a microscope. Rather is it found that some of them bear a close resemblance to the granular plastosomes in their size and staining properties, clearly indicative of images running over between the two (ﬁgs. 28, 29, 31, 36, and 42), which will account for my argument that plastosomes should be deemed the matrix of the lipoid formation. And, for the second rea -son, I will give the fact that the plastosomes, either being con siderably reduced in their quantity or having gone out of existence, as the lipoid forrnation progresses, are scarcely detected. Such is the fact which is often noticed in all the cell groups other than the stroma cells of villi, and a part or the whole of the plastosomes cannot but be seen as having been consumed or exhausted in the formation of lipoids. However, in the Langhans’ cells, the stroma cells of villi, and in the decidual cells sometimes, when the functions have advanced considerably, the plastosomes not only show no sign of their decrease, but also increase and present more or less conspicuous groups in a limited section of the cell body. This apparently contradicts the statement given above, but, practically, the reverse is the case. It is probable that the plastosomes consumed partly by the functions performed, are increased and replenished, providing for the repetition of secondary and tertiary functions; by such an assumption the signiﬁcance of the increase of plastosomes in these cases will be made naturally clear, so that the various images described above do support with more force, instead of contradicting, the theory mentioned above.
And then, the lipoid granules growing and enlarging, as they do, from the very small granular bodies described above, change more or less in quality at the same time, and their color becomes somewhat faint, and, moreover, in certain cells, as for instance in a part of the epithelium of the uterine gland and the largetype decidual cells, they sometimes appear as granules having a very clear yellowish-brown color. At any rate, when they reach a certain degree of development, these lipoid granules create more or less conspicuous halos around themselves, which gives them the appearance of the contents of vacuoles. Such appearances_ are very commonly noticed in all the cell groups I have examined, and I cannot help recalling to mind the observations made by Babkin, Rubaschkin, and Ssawitsch respecting pancreatic cells as- cited before. Therefore, I believe that this appearance has a very great signiﬁcance in the secretion formation, in the same way as the phenomena of secretion of the pancreas as interpreted by these three observers just referred to does. In other words, the lipoids may be compared with the secretory granules of ordinary cells, and they like the latter are slowly liqueﬁed, in accordance with the third one of the various forms of glandular secretion (liquefaction) described above, and pass over to the secretions of a vacuolar shape. Therefore, the vacuoles are, after all, nothing else but a modiﬁed product of lipoids, and the contents should possibly be secretions as transparent as water.
According to the arguments given above, the various cellgroups of the -placenta and decidua entirely agree with the observations of the glandular cells not only in their structure, but also in the histological changes that follow their functions, and, therefore, there is no room for doubt that secretion should be existent in them also. And it will be brieﬂy stated, concerning their secreting phenomena, that probably lipoid granules rise directly from plastosomes, and then the former, growing in size, slowly change to the vacuoles, viz., secretions, and are thus thrown out of the cell body at times. If looked at from the standpoint of their secretion formation these cells, for the most part, closely resemble the external secretory cells, but viewed with regard to their inner structure in which they keep secretions within their own bodies for a comparatively long period and thus for the most part present a more or less conspicuous foamy image, they should be rather compared with the various internal secretory cells, which are observed in the ovary and the cortex of suprarenals. The principles of the phenomena of secretion, as aforesaid, look very simple indeed, and yet these phenomena do not make their appearance in one and the same cell necessarily at the same time. On the contrary, it is customary that within different parts of the same cell body the various stages of phenomena appear, one after the other, in consequence of which the structure of each individual cell becomes comparatively complex and diverse. Each individual cell, while repeatedly performing its secreting functions in this manner, gradually increase in itssize, and it is customary for the cell to grow considerably as it reaches the height of secretion. Even the syncytium layer whose cell border is indistinct, is generally very thick at the height of secretion, and the gradual increase in the size of the cell along with the rise of its secreting functions in this manner may be partly due to the accumulated assemblage of the secretions, though at the same time it cannot be denied that the rise of secreting functions is attended by the increase of the protoplasm and the growth of the nucleus.
There is, of course, a certain limit to the growth of each cell, but there is something exceptional about the decidual cell. It rises from certain extraordinarily small spherical cells within the proper mucous membrane of uterus, and yet it grows so very rapidly and becomes enormous in size that the classiﬁcation between the large and small types in the ordinary decidual cells, if dealt with according to their genesis, shouldbe anything but signiﬁcant. For these two mutually run over to one another through the intervention of the intermediate type, and no sharp demarcation exists between them. Therefore, these two kinds, histogenetically, belong to exactly the same kind of cell, and they only differ in that one is still young in its growth while the other has already perfected its growth. However, it must be noted here particularly that the two present an entirely different appearance histologically, and, therefore, in all probability, along lines‘ of their physiological functions. In other words, the decidual cell entirely changes its structure and functions along with the perfection of its growth. That is to say, the decidual cellwhich has perfected its growth no more demonstrates within its body any important tissue ingredients, except plastosomes; however, it seems that probably, at this period, the cell prepares, by means of the special action of a very strongly developed cell membrane, certain secretions, and sends them forth into the interstitium. At any rate, the cell passing through this stage gradually withers and becomes smaller.
The secretions, while at the height of their formation, are conglutinated with one another, produce in abundance vacuoles of various sizes and shapes, and will show a high beehive structure. And the way of their removal and absorption, if in the syncytium layer, will be, undoubtedly, by rupture, sooner or later, toward the intervillous spaces, and thus they will be absorbed in the mother’s blood, while in the various other cells, there is no knowing but that the secretions are thrown out by osmosis, and the secretions of the Langhans’ cells and the stroma cells of villi should, as a matter of course, be absorbed on the side of embryo, with the exception of those, which, ﬁnding their outlets in the Langhans’ islets, are probably taken in by the mother’s body. Both the large and small types of decidual cells certainly belong to the mother’s side, and the secreted or brokenup matter of the uterine glandular cells is at ﬁrst probably drained into the uterine cavity, to be absorbed by the mother’s side. And, on comparing the relations between the secretion of these Various cells, and the time of pregnancy we ﬁnd that, in general, the secretion is at its height in the ﬁrst half of pregnancy, and especially in the early part of that period, whereas in the second half of pregnancy it generally declines considerably, it being possible to demonstrate it only for a certain period in the stroma cells of villi, the cells of Langhans’ islets, and in the decidual cells. Below I will give this correlation with a diagram.
In short, it may be deduced that all the important tissue elements of the placenta and decidua, if looked at from the histological View-point, perform secreting functions. Pending further investigations in all possible directions, it would be difficult to tell what signiﬁcance these secretions thrown out of the various cell groups have physiologically; however, since it is evident that almost all of their secretions are internally rejected and are taken in either by the mother’s or by the fetal side, it makes one feel that, either by the cooperation of certain ‘hormones’ Which should of necessity be contained in each kind of secretions or by their contending actions, both the mother and the fetus would enjoy an extremely delicate and special physiological action. If that is so, it follows that the placenta should contain a great variety of ‘hormones,’ and the kind and quantity of ‘hormones’ contained should naturally differ according to the period of pregnancy and the kind of tissues, it being quite clear from the following chart that, speaking generally, those that are found in the early part of pregnancy should be comparatively numerous in kind and in abundance. On the contrary, however, I could not ﬁnd any important secretions in the placenta which is Well ripened. This is the point to which I should like to call attention for the deliberate consideration of all observers who are interested in the placental poison.
The Minute Histological Structure and Phenomena of Internal Secretion in the Uterine Mucous Membrane Prior to Menses
1. My own observations
a. The changes of the interstitial cells (ﬁgs. 84 to 91). The one shown in ﬁgure 84 is an interstitial cell in normal condition, it is Very small and ball-shaped,_ and the cell body as compared With its nucleus exceedingly small, containing within a certain quantity of plastosomes which are largely rod—shaped.
The nucleus is extremely clear and contains a nuclear network and conspicuous nucleoli. Figure 85 is remarkably larger than the former and is oval. The protoplasm increases in quantity and so does the nucleus. Within the cell body there are no plastosomes to be found, but, on the contrary, there are, in large numbers, strongly black—stained and almost equally shaped lipoid granules. The cell illustrated by ﬁgure 86 is ﬁlled by large numbers of vacuoles Within the cell body, and Very little is protoplasm proper. The plastosomes, being rod-shaped, for the most part lie scattered in the partition walls between the vacuoles. ‘Besides, there are, in large numbers, strongly blackstained and almost equally shaped lipoid granules. The cell illustrated by ﬁgure 86 is ﬁlled with large numbers of vacuoles within the cell body, and there is little protoplasm proper. The plastosomes, being rod-shaped, for the most part lie scattered in the partition walls between the vacuoles. Besides, there are, in various parts of the cell body, a few extremely small lipoid granules, small in numbers. The nucleus is somewhat dark and the nuclear network is indistinct. In this cell and those that are enumerated below there is a somewhat distinct border membrane on the surface.
In ﬁgure 87 both the cell body and nucleus are oval and, though the structure of the cell body is similar in general to the former, the lipoid granules appear in a somewhat larger quantity, in some cases existing as the contents of a vacuole. Now, the vacuoles grow larger than in the former in general. The plastosomes are comparatively few. In ﬁgures 88 and 89 both the cell body and nucleus are somewhat dark in color. Within there are vacuoles which appear in comparatively small numbers. The plastosomes in the one are somewhat larger in quantity and are distributed all over, while in the other they are comparatively smaller in number and are conﬁned to a certain section. Both demonstrate more or less lipoid granules of various sizes. In ﬁgure 89 some of the lipoid granules contained are light-colored, and it is extremely remarkable to ﬁnd the manner in which they present themselves as contents of vacuoles. Figure 90 illustrates changes of a very high degree, and the cell body is ﬁlled up with remarkably large numbers of vacuoles of different sizes, while the plastosomes lie scattered, in somewhat large numbers, in the partition walls of the vacuoles. The lipoid granules are extremely few in number and are very small in size, while the nucleus» is grown in size considerably, is clear and has nuclear network and nucleole, both of which are distinct. Figure 91 also shows nearly the same structure as the former, and yet its vacuoles being agglutinated with one another in large numbers, form large and irregular—shaped cavities, in consequence of which the cell body appears as though it were on the verge of destruction. There are no plastesomes to be detected, though the nucleus appears in a still full and stained condition, and both the nuclear network and nucleoli are conspicuous.
b. The changes of the glandular cells (figs. .92 to .96). Figure 92 illustrates, for the:-sake of comparison, a normal glandular cell, the nucleus is remarkably long and occupies the middle part of the cell body, so that the celljfbody is divided into the upper and basal parts, each being ﬁlled up with numberless plastosomes. The cilia are somewhat short and thick and are not altogether normal. Figures 93 to 96 illustrate the changes which take place prior to menses. Figure 93, as compared with normal conditions, is remarkably larger and its nucleus, being relatively small, lies rather inclined to the base of the cell, while the plastosomes, being chieﬂy short and rodshaped, largely lie scattered between the nucleus and the top of the cell, it being a peculiarity of this cell that there are large numbers of yellowish-brown lipoid granules assembled at its basal part. Besides, there are in another part of the cell a few deep-back lipoid granules, and, again, in this cell there are extremely large numbers of vacuoles nearly of an equal size, crowding together close to the top, viz., the cilial layer of the cell body, though some vacuoles arrange themselves along the surface of the nucleus in the deeper part of the cell. In the cell illustrated by ﬁgure 94, the upper part of the cell is clear, in general, because of the particularly conspicuous vacuolar formations, whereas the common protoplasm is accumulated more or less in the basal two-thirds of the cell, viz., around the nucleus, in which part vacuoles are also detected, though they are for the most part very small. Besides, in this protoplasmic part there are extremely large numbers of plastosomes, which arrange themselves and crowd together in various directions. Again, yellowish-brown lipoid granules are found in comparatively small numbers in the basal part of the cell, while deep-black lipoid granules, small in size and numbers, lie scattered in the upper part of the cell. The nucleus is relatively clear, and its nuclear network is indistinct. It is easy to ﬁnd the traces of cilia in ﬁgures 93 and 94. In ﬁgure 95 there are absolutely no cilia to be found, and the upper third of the cell is remarkably clear and is formed by somewhat large numbers of vacuoles, whose partition walls, having disappeared in part, give them the form of very irregularly shaped inner spaces. The lower two—thirds of the cell consist of remarkably dark protoplasm, and has in the middle a somewhat large nucleus. Within the protoplasm there are numberless vacuoles of a small size and comparatively small numbers of plastosoines. Both the nuclear network and nucleoli are very conspicuous. And this kind of cell is to be noticed in greatest numbers during the changes of the glandular epithelium. The cell shown in ﬁgure 96 is very weak in staining properties, both in its cell body and nucleus, and its minute structure is by no means ascertained. This kind of cell is very seldom seen, and may probably belong to the regressive type.
2. The phenomena of internal secretion
The so—called menstrual decidual cells are extremely varied in their shape and size, and yet, if looked at from the minute histological structure of the cell body, it will be noted that plastosomes, lipoid granules, and vacuoles constitute their chief components. The manner in which the latter, probably following the functions of the cell, correlate with one another may be easily recognized as being in extreme agreement with what is in the small-type decidual cell during pregnancy, and consequently, there is no. room for doubt that the functions of the cells concerned are performed in the same manner as the latter. Therefore, not only am I inclined positively to assert the existence of internally secreting functions even in the menstrual decidual cells, but also I believe that the origin of these cells is found in the interstitial cells proper of the uterine mucous membrane, from which origin, gradually with the rise of the function of secretion, a remarkable development and increase of the nucleus and cell body such as is described above are brought about, the relation in this case being in exact coincidence with the growth of the pregnant decidual cells. These facts taken into consideration, I am convinced that the two kinds of decidual cells (menstrual and pregnant) described above have the same origin, and yet the cells being inﬂuenced by the physiological conditions sometimes develop into the menstrual decidual cells, and sometimes, being advanced further, run over to the pregnant decidual cells. _
And, on taking a glance at the epithelial changes of the uterine gland, we ﬁnd that, as in the ordinary glandular cells, plastosomes, lipoid granules, and a large number of vacuoles, which last may be deemed a modiﬁed product of lipoid granules, are contained therein. The vacuoles grow in size gradually and are ﬁnally fused and present a honeycomb structure, especially on the surface of the cell, and then after losing the cilia, the cells assume the appearance of goblet cells which have their secreted matter accumulated chieﬂy on the surface. Along with such changes, it will be noted, on the other hand, that plastosomes and lipoid granules gradually diminish and disappear, and it appears that part of those cells which show changes in a high degree die and perish. In short, these structural changes cannot but clearly indicate the fact that these cells perform functions which are similar to the ordinary glandularcells. And, on comparing these changes with those experienced in the glandular cells during pregnancy, we ﬁnd that the backward ness in the degree of the appearance of lipoid granules and vacuoles occurring in these cells makes one feel as though a decided difference would exist between the two, however true it may be that no radically great difference exists between them.
With regard to the periodic changes of the uterine mucous membrane, ‘there have been many researches, such as the investigations of Hitschman, Adler, and Schroder (’07). Though a universally well-known fact, and yet conﬁned chieﬂy to the shape of the glandular tubules and the epithelium, very few observers have so far paid attention to the functional signiﬁcance of the so-called ‘menstrual decidual cells which are produced by the evolution of the interstitial cells, with the exception of Asada, who has quite recently demonstrated the existence of fat within the cells concerned, and inferred only that this fat is not a degeneration product and must have some relation to the functions of the mucous membrane. However, according to my observations mentioned above, it is easy to clearly recognize that, according to their structure, these cells also have secreting functions as in the case of the ordinary decidual cells. And, looked at from the histological View-point, I do not hesitiate conclusively to pronounce that this function declines and terminates immediately upon the beginning of the menses. From want of suitable materials on hand, I am not able to make a deﬁnite statement as to what destiny should befall these cells; however, I quite agree with the observations of other investigators in that they suddenly diminish and perish with the arrival of the menses. And, since it is doubtless true that the secretions of these cells are absorbed in the mother’s body, it should be a matter of special interest to consider the several clinical symptoms which present themselves frequently at menstruation, in the light of this fact for ‘the explanation of their causative relations. On the contrary, the changes of the uterine glandular epithelium, if compared at the time of pregnancy are remarkably small, and as we can easily assert that its secretions are thrown out of the body, there is certainly no need for argument that it is impracticable to attach an internal secretory signiﬁcance to the glandular cells; therefore, I am inclined to believe that this sort of periodic changes of glandular epithelium should be recongized as a mere preliminary behavior which is antecedent to pregnancy, and that by far the greater signiﬁcance, rather theoretically than functionally, should be attached to it.
1. The epithelium and stroma cells of villi, decidual cells, and uterine glandular cells, all of which constitute the chief tissue elements of the placenta and decidua, if subjected to the closest cytological investigations, show within the cell bodies, and common to them all, the formative constituents, such as plastosomes, lipoid granules, and vacuoles. These constituents, along with the functions of the cells, mutually show the requisite correlation with which they are connected with one another. Speciﬁcally:
a. The plastosomes, though for the most part rod-shaped, are either long or short, but occasionally they are granular, chain-like, or ﬁlar in their shapes. Their quantity generally more or less diminishes along with the progress of the secreting functions.
b. The lipoid granules are extremely varied in their shape, quantity, and in color (in the stained preparations), according to cell or the group to which the cell belongs or perhaps in accordance with the difference in the period of functions. In the earliest stage of their -appearance they are always granularshaped of extremely small size, and sometimes it is difficult to distinguish them from the granular-shaped plastosomes (‘plastochondrin’), insomuch so that it _suggests that the plastosomes may exist in a direct formative participation as matrix of the lipoid granules. And this connection is most conspicuously demonstrated in the Langhans’ cells, the stroma cells of villi, and in the decidual cells, and even in other cells it is quite easy to recognize it, because the plastosomes tend to diminish more or less in inverse proportion to the increase in the quantity of the lipoids. ,
c. The vacuoles are probably nothing but the lipoids gradually liqueﬁed and increased into what they are. And, with the rise of functions, they keep increasing in numbers and, as a higher degree of activity is attained, the vacuoles grow in size, and part of them by degrees become agglutined with one another, so that at last the cell body presents in its entirety a highly foamy image, being composed of numberless vacuoles of various sizes.
The various cell groups mentioned above, if looked at from their minute structure as well as the changes in the formative components, which latter probably have an intimate connection with their functions, bear a close resemblance to the ordinary classical glandular cells (pancreas, salivary and lacrimal glands) and the important internal secretory cells (luteal and interstitial cells of ovary, the cortical cells of suprarenals), and there exists no radically great difference between the two. That is to say, suppose we now take lipoid granules for secretory granules and vacuoles for secretions, and naturally these cell groups in placenta and decidua should come under the same category as glandular cells, and there would be no doubt whatever that the former have certain secreting functions in themselves.
2. The secreting phenomena of placental and decidual cells, with only the exception of the large-type decidual cells, generally present themselves as in the case of the ordinary glandular cells, with the changes which commonly appear in the structure of the cell bodies and almost under the same form. Now, looked at from the histological viewpoint, the secretions prob ably rise from the ‘plastochondrin,’ and then ﬁrst passing through the period of minor granules which corresponds to Heidenhain’s ‘Primargranulis,’ they gradually grow in size and form into the ordinary lipoid granules, which latter, being liqueﬁed continuously, change directly to the secretions (vacuoles). And, in this matter, it seems that the series of histological changes ordinarily even in the same cell body take place at different times and in different regions, so that the changes make their appearance in repetition secondarily, thirdly, and so on, which fact is responsible for the intricacy of structure which sometimes occurs in certain cells.
3. The methods of discharging secretions, if in the syncytium layer, are that the vacuoles ﬁnally rupturing themselves in several parts of the superﬁcial layer cause their contents—secretions—to escape directly into the intervillous spaces in a striking manner, though in the other cell groups the secretions for the most part cannot but be recognized as passing out by ‘osmose.’ And, of all the secretions, it should be noted that those which come from the syncytium layer, decidual cells, uterine glandular cells (a part) and also probably from the Langhans’ islets are absorbed by the mother’s body, while those which pass from the ordinary Langhans’ cells and the stroma cells of villi are absorbed in the fetal side.
4. As regards the relation between the secreting functions and the time of pregnancy:
a. The secreting functions of the syncytium layer may be demonstrated from the beginning of pregnancy to about the end of the fourth month, and yet it is in the second and third months that they are most active. '
b. The secreting functions of the Langhans’cells are almost entirely the same as in the sycytium layer. It is in the Langhans’ islets alone that they last somewhat longer, it being possible to demonstrate cells which have secretions in them up to the ﬁfth or seventh month, and naturally it can be imagined that the functions continue up to that time.
c. The secreting functions of the stroma cells of villi begin at about the end of the ﬁrst month of pregnancy, and keep quite active up to about the seventh month, though from the second to the sixth month they are at their height. However, it should be noted with care that in the eighth month these cells suddenly diminish remarkably and perish, in consequence of which the functions also will drop promptly at this period-.
d. The decidual cells are entirely different in their appearance falling in the classiﬁcation into large and small types, as it is well known. That is to say, in the so-called small—type cells the secreting conditions pretty Well agree with those in the other cells. This kind of cells appears already quite active on about the seventeenth or eighteenth day after conception, and nearly at the end of the ﬁrst month of pregnancy its growth and, consequently, its functions reach their climax. Thereafter, as the large-type decidual cells appear, the small—type cells suddenly diminish in quantity, and in consequence it appears-that the functions also drop quickly, though even up to the seventh month of pregnancy it is able to clearly demonstrate the existence of the functions.
Then, in the so-called large-type decidual cells, for the most part few, are the structures of the cell body by which the existence of secreting functions may be proved; however, in its strongly developed cell membrane a certain substance is formed, probably by a peculiar faculty of its own, and in this manner there occurs a material formation which may be deemed a secreted matter which is excreted by the cell body.
The large—type decidual cells are remarkable in their appearance by the end of the ﬁrst month of pregnancy, though in the second month they appear to reach their climax, and in the following third or fourth months, they diminish in their size. And, the afore-mentioned secreting phenomenon which is peculiar to these cells, begins in the second month, appears most remarkably in the third month, and may be demonstrated up to about the sixth month, though in the seventh month and after it is no longer possible to observe it. In general, the large-type cells retrograde and decay remarkably in the second half of pregnancy, though at the end of pregnancy it is still able to ﬁnd them, and, moreover, at this period there are some few cells which do contain a small quantity of lipoids.
The functions of the glandular epithelium are most active at the end of the ﬁrst month of pregnancy, begin to drop considerably from the beginning of the third month, in the fourth month the decline is greater, and in the ﬁfth month, it appears, they almost come to a standstill. In general, the functions make their appearance somewhat earlier in the decidua serotina than in the decidua Vera, and accordingly they stop earlier in the former than in the latter. The secretions are thrown out into the uterine cavity probably only in the earliest period of pregnancy, and later as the openings of the glandular tubules are closed by the placental formation and by the adhesion of the decidua Vera and decidua -reﬂexa, the secretions, along with the detrital matters of the degenerated glandular cells are, of necessity, absorbed by the mother.
5. Since it is possible that the secretions of the various kinds of cell groups mentioned above are, for the most part, absorbed, either by the mother or by the fetus, as in the case of internal secretions, everybody will easily assent to the supposition that, like the secretions of many internal secretory glands, each of them contains a certain hormone, and should this be the case, it may be said that each of the two organs concerned is assuredly a producer of hormones of various sorts and kinds, and is also a reservoir for them; and the kinds of hormones and the proportion of their mixture as contents of these organs should have important bearings upon the time of pregnancy and the part of the organs concerned which is taken as material for investigation. And, in the ﬁrst half of pregnancy, it is possible to show quite a variety of hormones, whereas in a wellripe placenta it is almost impossible to demonstrate their existence. ,
6. It has been believed by several authors that the epithehum of villi probably serves as an organ by which nutrition is taken to the embryo; however, histologically it is impossible to ﬁnd any ground for such argument.
7. The various cells described above usually increase in size more and more as their secreting functions progress. This fact is most remarkably noticed in the decidual cells. The large-type cell is, after all, nothing but the small-type cell grown up; its growth being gradual along with the progress of its functions and with its largest size it has perfected its development. Therefore, though at a glance it would seem that these two kinds of cells are entirely different from one another, yet they have the same origin, and originally they are the cells of the same kind. However, the sharp demarcation which exists between the two functionally should deserve our attention; that is to say, the decidual cell performs the conversion of its functions along with the perfection of its growth.
8, The foregoing conclusions would, at a glance, seem to contradict the work conducted by several authors up to now whose conclusion it was almost entirely to deny the internal secreting functions of the placenta and decidua; but the main reason for this is the fact that the materials employed for investigation by these authors have been for the most part mature organs, for in these there is almost no proof of any secreting phenomena being existent, and they have been therefore taken at most unfavorable times as materials to help us attain our aim. Therefore, in the future, should anyone desire to try his hand in this sort of research, it would be necessary for him by all means to take materials while yet in the early part of pregnancy. And, even in this case secretions of several kinds, even if they come from cells of one and the same origin, would possibly be, by no means, similar in quality, but rather in the organ concerned, there would be existent various kinds of substances produced from the various cell groups Whichform the organ. And, in case that there is a certain hormone action in these substances, it would follow that, during a certain period of pregnancy, the hormones will act upon both the mother and the fetus in diverse and complex manners.
9. The histological changes which the interstitial cells of the uterine mucous membrane and glandular cells undergo prior to menses resemble, in general, the changes which take place at the beginning of pregnancy, though they are by far the weaker. Therefore, even in that case, these two kinds of cells, looked at from their histological structure, have in common to themselves, secreting functions, to whose existence we may positively assert. And, the secretions, if in the interstitial cells, are undoubtedly absorbed internally, as in the case of the small-type decidual cells while in pregnancy, and should thereby bring about the various clinical symptoms which are experienced during menses.
The glandular cells differ from the former, and the secretions have probably no endocrine nature and are immediately thrown out to the outside, viz., into the uterine cavity, so that it would be difﬁcult to attach to_ them an important physiological signﬁcance, such as hormone action. Rather, it would be ﬁt to interpret such periodical changes of these cells as preliminary phenomenon of the coming pregnancy.
10. The interstitial cells of the uterus, prior to menses, are developed into the so—called menstrual decidual cells, which in point of structure, distinctly reminds us of the decidual cells of pregnancy. For this reason, it would be in order for us to trace the origin of the latter, as of the former, to the interstitial cells of the uterus.
In conclusion, my whole-hearted gratitude goes to Prof. R. Tsukaguchi for the kind and sincere leadership and revision which he has given me at the present Work, and to Professor Ogata, chief of our gynecological department, for the valuable materials for research and for the immense assistance he has given me.
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Explanation of Plates
All the figures given on plates have been drawn at the height of the object stage, by Abbe’s apparatus, under the same magnifying power: Zeiss’ 1LpOCllI‘0lI12Ll3 homogene immersion 3 mm., compensations okular. 12, tube length 160 mm.
The Various ﬁgures have all been drawn from the preparations ﬁxed by Levi’s solution and stained by Heidenl1ain’s iron—alum-haematoxylin, with only the exception of ﬁgure 7, which has been reproduced from the preparations by Altmann’s method, after changing the color.
1 to 12 Illustrate the syncytium layer and a part of the Langhans’ cells.
13 to 26 Illustrate the Langhans’ cells.
27 to 38 The stroma cells in the chorion villi.
39 to 69 The decidual cells.
70 The peculiar-looking product which makes its appearance in the cell membrane and interstitium of the large-type decidual cells.
71 The above-mentioned product ﬁlling up the blood vessels.
72 to 83 The glandular epithelium during pregnancy.
84 to 91 The interstitial cells prior to menses.
92 to 96 The glandular epithelial cells prior to menses
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