Paper - Human ovum fifteen days old with reference to the vascular arrangements and morphology of the trophoblast
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A description of a human ovum fifteen days old with special reference to the vascular arrangements and to the morphology of the trophoblast. (1932) J. Obst. Gynaecol. 39(3): 471-506.
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- 1 A Description of a Human Ovum Fifteen Days Old with Special Reference to the Vascular Arrangements and to the Morphology of the Trophoblast
A Description of a Human Ovum Fifteen Days Old with Special Reference to the Vascular Arrangements and to the Morphology of the Trophoblast
By Ninian Mcintire Falkiner, M.B., B.Ch. (Dublin),
F.R.C.P.I., F.C.O.G., D.P.H., L.M.
Late Assistant to the Master, Rotunda Hospital, Dublin; Visiting Gynaecologist, Royal City of Dublin Hospital.
(From the Dejmrtment of Zoology, Trinity College, Dublin.) 1932
The study of human embryology and the study of the early stages of placentation have always been hampered by the difficulties of obtaining material.
Since the works of His and Keibel have made the later stages of human embryology more clear, an increased amount of attention has been paid to the study of early human ova, and very many specimens of the pre-somite stage of development have been described, both in Europe and America.
The number obtained in the British Isles is still very small, but includes the very famous specimens so fully described by Teacher and Bryce in 1908‘ and 1924“, and also the specimen described so long ago as 1837 by Thomas Wharton Jones.4 This last specimen should not be forgotten, as the description by Jones marked the commencement of the careful study of very young human ova.
In the absence of a very extensive literature on the subject of early human ova in the English language, I believe that the following description of an ovum, obtained by myself in curettings from the uterus, will be of value, not only in corroborating the works of others but in extending our present knowledge of the earlier stages of placentation. Before proceeding to describe the specimen it is necessary to allude to the descriptions of some of the well-known early ova.
The youngest human ovum hitherto described was obtained by Miller in 1913 and was described by him in that year. Streeter,5 however, has also described this unique specimen, and it is to his description that I owe the details that 1 am about to recount.
This ovum was discovered by chance in curettings, and only five sections were saved. Their value, however, was enhanced by their sequence and the excellent fixation and staining.
The clinical data show that the curetting was done about two days before the expected date of onset of menstruation, and Streeter calculates the age to be either 10 or 1 1 days. The greatest diameter, calculated from the most outlying trophoblast, is 0.9 millimetres; The internal diameter of the trophoblastic shell, or chorionic cavity, is 0.4 millimetres.
The trophoblast is represented by a layer of cytotrophoblast, i.e. Langhans’ layer, and this is a layer of uniform cubicidal cells. Its internal surface is lined by a mesoderm-like membrane, while from its surface there arises a luxuriant growth of epithelial syncytium.
The peculiarity of the syncytial layer is its tendency to wall off clear spaces, the sizes of which vary, those nearer the periphery being the larger.
Streeter discusses the origin of such spaces and their relation to the larger lacunae of later stages.
The outstanding point about the trophoblast is its capacity for eroding capillaries, and this phenomen is clearly seen in Miller’s specimen. The endometrium, or decidua, of the specimen is described as having the general characteristics of the pre-menstrual type. The compact layer, consisting of oedematous stroma, represents about one-eighth of the depth of the decidua.
The stroma cells do not show any decidual reaction except in the region immediately surrounding the ovum. Secretory activity in the glands is well marked, and is beautifully illustrated in the photographs accompanying Streeter’s article.
The ovum described by Teacher and Bryce,1 Ovum T.B. No. I, is older than Mi11er’s specimen. This specimen was obtained from an abortion. The decidual cast containing the ovum was ﬁxed 20 hours after it was aborted. The history of the case, the measurements of the ovum, and the state of development, botl1 as regards its chorionic and embryonic constituents, point to its being slightly older than Miller’s ovum, and the age attributed to the Ovum T.B. No. 1 by Streeter° is 12 days.
In the Miller ovum, none of the sections saved showed any gap in the decidua which could be identiﬁed as a point of entrance. Teacher, in his specimen, identified the point of entrance of the ovum as a narrow oriﬁce in the surface epithelium, which measured only 0.1 millimetre in diameter. This opening is sealed by a thrombus.
The description of the decidua suggests that degenerative change have taken place between the time of death of the ovum and the fixation of the specimen.
The diameters of the chorionic vesicle are distinctly greater than the corresponding measurements in Miller’s ovum. The greatest diameter -of the implantation cavity, presumably corresponding to the distance between the most out-lying trophoblast at opposite poles of the ovum, is 1.95 millimetres. The plasmidotrophoblast is described as forming an “extraordinarily spun-out investment” from the ovum. Its arrangement into strands which enclose spaces containing maternal blood is attributed to a process of vacuolation which has broken up solid masses into a sponge-work. Teacher stresses the fact that the primitive blood lacunae are, therefore, in the ﬁrst instance, entirely in the plasmido-trophoblast. There is marked erosion of the capillaries by the plasmodlo-trophoblast.
Peters’ ovum,’ described in 1899, was obtained at a post-mortem examination on a woman who committed suicide on the third day after the failure of the appearance of the menstrual flow. The specimen is well preserved, and Peters’ monograph must be regarded as a classic in the literature of early ova. The external diameters of the chorionic vesicle are 2.4 millimetres by 1.8 millimetres. The decidua is fully described and the differentiation of the spongy layer from the compact is indicated. The cytology of the compact layer is discussed at length, and the vascular changes are noted, particularly the formation of new capillaries in the region of the ovum.
Large cells are described by Peters as lying in the decidua near the implantation cavity, the nature of which, he states must remain doubtful.
In Peters’ ovum the point of entrance in the decidua is marked by a wide gap which is filled by a" closing coagulum, which not only fills the opening between the lips of the aperture in the decidua, but projects around the opening as a flat disc, assuming the shape of a mushroom cap. Peters names this closing coagulum the “Gewebspilz.”
The trophoblast of Peters’ ovum shows a more advanced state of development than is reached in Ovum T-LB. No. I, There are outgrowths from the cytotrophoblast which, although possessing the characteristic core of mesoderm, are not as yet branched. The plasmido-trophoblast is seen replacing the endothelial walls of maternal capillaries. Maternal blood bathes the ovum, and Peters describes and illustrates channels, narrow but definite, leading from the forming intervillous space into the maternal capillaries. These channels are lined by plasmido-trophoblast only. Peters‘ ovum is calculated by Streeter to be 13 days old.
Teacher and Bryce, in 1924, described the Ovum T.B. No. 22:3, which is an important ovum, not only on account of its good preservation but also on account of the comprehensive descriptions of the specimen; these incorporate the account of the operculum deciduae, a special structure developed from the trophoblast at that part which is in contact with the aperture of entrance after imbedding is completed. This structure closes, and welds together the lips of, the aperture.
It is interesting to note the absence of a Gewebspilz in this specimen, which is older than Peters’ ovum, being probably 14 or 15 days-old. Teacher satisfied himself that the operculum deciduae can be identified in the early ova described previously to 1924. There are no special features in the endometrium of this specimen. The chorionic vesicle is much larger than in the previously mentioned specimens, the external measurements being 4.5 millimetres by 3.75 millimetres. The villi are branched and have well-developed mesodermal cores.
The ovum Bi No. I, described by Florian,‘ in 1927, has :1 definite history, and the age is calculated to be 15 days. The description of the trophoblast shows it to be very similar in its appearance and stage of development to that of the present specimen.
These early ova have been mentioned in order to be able to contrast and compare features of the specimen to be described with conditions found in these specimens, both younger and of equal age. A glance at Plate I will show how the ages of these ova, as calculated by Streeter, compare with the present specimen.
History of the Specimen
The ovum to be described was recovered from curettings from the uterus, in the following circumstances :—
The patient, Mrs. M. G., attended the dispensary of the Royal City of Dublin Hospital, in March, 1931. She was aged 20 years and had been married three years. Her first pregnancy had resulted in a living baby, now aged two years. Since her conﬁnement the patient stated that she had had two abortions, the latter in February, 1931. This had been a six weeks’ abortion and had been accompanied by severe haemorrhage.
On examination I found Mrs. M. G. to be anaemic. (Hgb. 70 per cent). I found, on pelvic examination, that the cervix uteri was healthy but that the corpus was both retroﬂexed and retroverted. In addition, the uterus was sub-involuted.
I decided to treat the patient for anaemia and, later, to correct the displacement by operation, in addition to curetting the uterus. Accordingly, the patient attended the dispensary during the month following her first attendance, and received iron and arsenic by hypodermic injection.
She was admitted to hospital on the 15th April, having menstruated once since her abortion, the menstrual ﬂow starting on the 15th March. This menstrual ﬂow had been profuse and had lasted five days. The patient’s normal periodicity had always been 28 days. I did not suspect a pregnancy but attributed the irregularity to the anaemia and recent abortion.
Operation: 16th April, 1931.
General anaesthesia: Ether.
The cervix was dilated and the uterus curetted. The curetting from the posterior wall of the uterus consisted of a thick piece of endometium over half an inch in length. (Plate 2, Figs. A and B.). On its surface I noted a small, clear excrescence, two millimetres in diameter. It was globular in outline and projected markedly above the level of the mucous surface of the endometrium.
The possibility of this being an early ovum at once crossed my mind and I placed the curetting in normal saline and proceeded to open the abdomen. On opening the abdomen I found the uterus enlarged and retroverted, while there was a corpus luteum in the left ovary, which I carefully resected. I performed a Gilliam suspension and appendicectomy and closed the abdomen. The only observation made about the uterus was that it looked congested and felt rather soft.
The patient had a smooth convalescence, the uterine discharge remaining blood-stained for five days.
I questioned the patient regarding coitus and found that she was definite about coitus having taken place on the 23rd March and on the 1st April.
The specimens remained in saline for two hours, when I placed them in the hands of Professor Gatenby, who carried out the fixation and sectioning.
From saline, the specimen was transferred to Bouin’s fluid, without acetic acid, and left -overnight. It was then passed through 50 per cent, _7o per cent, and 90 per cent alcohol, and then into absolute alcohol. Clearing was carried out in cedar-wood oil overnight, and‘ then the specimen was transferred to xylol and embedded in paraffin wax. It was cut into sections of 10 micra in thickness, and no sections were lost. The microtome was re-orientated as the embryonic anlage was being neared so that an estimate of the measurements of the ovum as. a whole cannot be made from the number of sections.
Six sections were mounted on each slide and, showing the embryonic anlage are slides 26 to 36 inclusive. The first 12 sections, i.e, on slides 26 and 27, show only body stalk, and in slides 33, 34 and 3,5 the embryonic anlage, here represented only by a prolongation of the yolk sac, is missing, to reappear in all six sections on slide 36.
The staining of the various slides is as follows :—
Nos. 8 to 15. Iron Alum Haematoxylin, and Orange G.
No. 16. Mann’s Methyl Blue Eosin.
No. 17. Muchaematin.
Nos. 18 to 26. lron Alum Haematoxylin, Biebrich’s Scarlet.
Nos. 27 to 32. lirlich’s Hacmatoxylin, Orange G.
Nos. 33 to 37. Iron‘Alum Haematoxylin, Biebrich's Scarlet.
No. 38. Iron Alum Haematoxylin, Orange G.
No. 39. Iron Alum Haematoxylin, Biebrich’s Scarlet.
No. 40. Iron Alum Haematoxylin, Orange G.
Nos. 41 to 43. Iron Alum Haematoxylin, Biebrich’s Scarlet.
==Measurements of the Ovum==.
I calculated,the measurements of the ovum, after its fixation, from photograplis. V In each case the magniﬁcation was determined by photographing a_ millimetre scale with the micro-camera. The external measurements of the chorion were 2.05 by 1.80 millimetres. The diameters of the embryonic shield, amniotic cavity and yolk sac could be calculated by the number of sections showing these various structures. The other diameters I calculated from photographs.
Measurements of the embryonic shield : 0.23 mm. by 0.30 mm. by 0.06 mm.
Measurements of amniotic cavity : 0.23 mm. by 0.30 mm. by 0.13 mm.
Measurements of yolk sac : 0.24 mm. by 0.36 mm. by 0.52 mm.
In forming an estimate of the age of a given ovum, the history, both of menstruation and coitus, is the first consideration, and then the method by which the ovum has been obtained is of importance, since, in the case of an aborted specimen, development may have ceased some time before the expulsion of the ovum.
The measurements of the chorionic cavity and the individual villi and the measurements of the various component parts of the embryonic anlage are all of importance.
The most cogent evidence of age, I think, must be adduced from the state of development of the chorion, embryonic anlage and, particularly in this pre=somite period, the relation between the dimensions -of the amnion and yolk sac.
The Age and State of Development of the Ovum
Bryce“ has classified early ova into groups, as follows :——
Group A. The amnio-embryonic rudiment is still solid.
Group B. The ectodermic and entodermic vesicles are formed, the mesodermic villi are still undeveloped.
Group C. The ectodermic and entodermic vesicles become enlarged, the entodermic remaining smaller than the ectodermic. The villi are in the process of formation. There is not any sign of a primitive streak on the small rounded blastoderm.
Group D. The entodermic vesicle undergoes further enlargement and exceeds the ectodermic in dimensions, the villi begin to branch, the blastoderm becomes oval in shape. The primitive knot appears and the primitive streak shows in later embryos.
Group E. There is a fully developed primitive streak and a cloacal membrane deﬁned; a complete archcnteric or notochordal canal tunnels the elongated head process.
Group F. There is a notochordal plate and a neurenteric Canal patent or virtual; the neural plate and neural folds are formed and the foregut begins to close in.
Streeter“ terms the first group, those in which no primitive groove is present, and subdivides this group into three stages, which are differentiated by the stage of chorionic development, thus :—
Stage I. Before the appearance of villi.
Stage 2. Primitive villi present.
Stage 3. Branched villi present.
I have reproduced a table from Streeter,‘ with the addition of data of the present specimen, which shows its position with regard to age compared with other well-known early human ova. (Plate I.)
The specimen falls into Group D of Bryce’s classification, and into Stage 3 of Group 1 of Streeter’s.
The following features have led me to assign this position to the present specimen :—
1. The presence of branched villi with mesodermal cores.
2. The relative sizes of the yolk sac and the amniotic cavity; the former being the larger.
3. The fact that the clinical data, as I will proceed to show, point to the age of this ovum being either 14 or 15 days, which corresponds closely with the age of the other ova placed in these groups.
To estimate the age of the ovum in days it is necessary to consider the menstrual history, the dates of coitus, and the relation of the date of ovulation to the menstrual cycle. In addition, the length of time that the ovum may survive between ovulation and fertilization, and the length of time that the male germ cells will preserve their vitality after coitus must be considered. In this case the menstrual history is clear and the dates of coitus are known, but there is some doubt about the second date being as accurately remembered as the first.
The ovum was obtained 32 days after the first day of the previous period, 19 days after the calculated day of ovulation, and 15 days after the last coitus.
It does not seem feasible that the coitus of the 23rd of March could have been effective, as, even supposing that the spermatozoa Could have fertilized the ovum which would have left the Graaﬁan follicle about the 27th March, the age of the ovum at the date of curettage would have been about 19 days. This is the age attributed by Streeter° to the Mateer specimen, which is altogether more advanced than the present specimen.
Considering the latter date of coitus, namely 1st April, the age of the ovum appears to be 14 days. This age appears to me to be rather on the young side considering the state of development, and I believe that the date of coitus is wrong and that the ovum is 15 days old.
Description of the Specimen
The decidua presents a similar appearance to that of‘Peters’ specimen. The specimen described by R. W. Te Linde° (obtained at a curetting), although at a slightly later stage of development, is very suitable for comparison.
The decidua is very beautifully portrayed in Plate III, and it will be seen that the differentiation into a compact and spongy layer is well marked. The surface epithelium in this drawing is shown in its proper relation to the underlying compacta; actually, it had become stripped from its attachment in many places during the preparation of the sections.
A glance at Plate II, Fig. C, which illustrates the surface epithelium and compact layer, convinces one of the very marked cellular activity of the surface epithelium.
This is apparently a secretory activity, as there is to be seen at the apex of each cell a globular faintly staining body, either just or partially extruded from the cell body that has given it its origin. That this activity in the surface epithelium is short lived is suggested by the appearance of the nuclei of its individual cells, which are faintly staining and small compared to the nuclei of those contiguous cells which line the necks of the glands. The relation of the surface epithelium to the implantation cavity is remarkable in its similarity to the condition described and so fully illustrated by Peters.
As the surface epithelium passes from the decidua Vera to the decidua capsularis its character changes. It becomes more cubical than columnar and each cell has a broader and wider base, due, obviously, to the stretching of the underlying tissue by the growth of the implantation cavity.
As is clearly seen in Plate III, the epithelium does not cover the summit of the ovum, but the breach in its continuity is filled by the presence of the Gewebspilz (Peters’) or a fibrin plug shaped like the cap of a mushroom, in that it overhangs the edges as well as filling the space between them.
I cannot add to either the description or illustrations given in Peters’ monograph relating to the Gewebspilz, and I refer the reader to his original article.
The necks of the glands are separated in the compact layer by a stroma which I will describe later; I only wish to say here that the gland mouths are remarkably close to one another, the intervening distance being, in some cases, as little as 0.2 millimetre.
The more deeply lying parts of the glands show great cellular activity, characterized by the indentation of their walls by the proliferating epithelium. The epithelial cells are high, with basal nuclei which are deeply staining; the cytoplasm shows at its free edge a tendency to be irregular, and some of the cells approach in their appearance those cells of the surface epithelium that I have already described, but in no place is the same deﬁnite appearance of globular granules being extruded from the cells recognized.
The proximity to each other of the glands in the spongy ‘layer is Very remarkable, and only a single layer of stroma cells is to be seen between the most closely packed glands. At the same time there are, at regular intervals, passing up from“ the basal layer of the endometrium or decidua, strands of stroma tissue in which the arterioles can be seen, each cut many times as they pass up towards the surface. In the sections, as many as 10 glands may be seen packed closely together before the interposition of vascular and stroma tissue. At the same time, two vascular columns of stroma may be seen, with only one gland intervening.
The Contents of the glands vary to some degree, but, for the most pa.rt, the glands contain a faintly staining reticular material which seems to have retracted from the walls of the glands. It is more abundant in the deeper parts of the glands, but it is not in any sense restricted in its distribution through the lumina of the glands.
There is, in addition, a different type of material in some of the glands, and I use the words “in addition.” advisedly, meaning that some of the glands contain two different materials, i.e. two materials that differ in their microscopic appearances at least.
This latter material consists of globular. bodies that might be interpreted as cells in a state of degeneration. They are mostly larger than the epithelial cells of the walls of the glands, but some of them do appear to possess nuclei. It is interesting to note that they are in all cases grouped, that is, if one is to be seen in the ﬁeld, more are, on careful search, to be found in the same gland. They do not appear to be more numerous in those glands which approximate to the implantation cavity, nor is there any suggestion that the glands in which they appear have been the site of haemorrhage.
In those glands that lie immediately subjacent to the implantation cavity there is yet another type of substance to be seen. It is homogeneous and darkly stained, and completely distends the surrounding gland wall so that it contrasts with the walls -of the glands on either side by virtue of being quite free from indentations, and the individual cells are compressed.
Two possibilities as to the nature of this material present themselves: the first, that it is secretion penned up by the blocking of the gland ducts through the growing ovum compressing, surrounding or invading them; the second, that it is blood, due to invasion of the ducts by trophoblast, which, at the same time, has opened up an intercommunication between the gland-lumen and maternal vessels.
Both Peters’ and Frassi, quoted by Keibel,” describe haemorrhage into the uterine glands in the specimens they have described, and in my specimen I have found that in certain of the glands the material is, without any doubt, maternal blood. To sum up the appearance of the epithelial portion of the endometrium or decidua, there is great uniformity in its secretory activity, except in those glands just beneath the ovum, the secretory function -of which has ended, and if these glands have retained a function it is now mechanical.
In the consideration of the endometrium we have already recognized a distinct division of the early decidua into a compact and spongy layer. We must, therefore, describe separately the stroma Cells as seen in each of these two layers.
The most remarkable feature is the absence of decidual reaction. There is no marked inﬁltration with leucocytes or round cells. The individual stroma cells of the compact layer present marked variations, b-oth as regards size and form. (Plate 11, Fig. C.) The larger cells have relatively a larger amount of cytoplasm. The nuclei are deeply staining, and these larger cells may be seen in those parts of the decidua lying furthest from the implantation cavity. Some of these cells show two nuclei (a well-known characteristic of the typical decidual cell of later pregnancy).
I regard these cells as being intermediate between the ordinary stroma cells of the menstrual cycle and the true decidual cell. The majority of the cells are small, with a moderate amount of cytoplasm and deeply staining nuclei which are as large as the nuclei of the larger cells. The cells are not very closely packed, and appear to be separated by a faintly staining homogeneous materia1—-an appearance suggesting oedema. This is well illustrated in Plate 11, Fig. C.
1 can say, deﬁnitely, that proximity to the implantation Cavity does not inﬂuence the appearance of the stroma as regards decidual reaction. Where the oedema is marked the cells of the stroma assume a stellate appearance, clue to protoplasmic tendrils which interlace with similar processes of neighbouring cells. One of the most remarkable features of the decidua compacta is its vascularity, but it does not present free blood-cells’ as described by Streeter in Miller’s specimen.
That part of the stroma which lies between the glands presents a different picture. Such tracts of stroma are, in the main, extremely narrow and compressed, with the exception of those in" which an arteriole is threading its upward course from the basalis to the compacta. In this part the great majority of the cells are of the smaller type and markedly spindle shaped. Their long axes lie parallel to the general direction of the glands. Oedematous patches are to be seen, and groups of cells with interlacing processes are also present, as in the compact layer.
There is always a thick investment of stroma cells around the arterioles, and most of the cells are spindle shaped, their long axes are" parallel. to the free surface of the endometrium, as :1 rule, but their arrangement in circular whorls "round the arterioles is their main characteristic.
The description of the vascular structure naturally. falls under two headings, for, first, we have, in that part of the endometrium lying at some distance from the implantation cavity, vascular arrangements -consisting of supplying arterioles ending in capillary channels with venous channels leading back to the deeper parts, which hitherto have not been broken into by the advancing trophoblast; and, secondly, immediately in the neighbourhood of the ovum we have similar vascular arrangements, the structure of which has undergone most tremendous changes, the result of the invasion of the trophoblast.
Bartelmez“ has illustrated and described the vascular structure on the twenty—third day of the menstrual cycle. I believe that the general structure of the vascular fields in the present specimen is the same as he has described for the latter half of the menstrual cycle.
With the author’s kind permission I reproduce his reconstruction. (Plate V, Fig. A.)
The most interesting and remarkable feature in those vascular structures near the implantation cavity is the thick walls of the capillaries, thick by virtue of the close crowding of the endothelial cells. Where these capillaries are distended with blood the outstanding feature is the predominance of leucocytes. (Plate II, Fig. C). This feature becomes more noticeable as one nears the implantation cavity. On a general survey of the sections it is quite remarkable how such capillaries stand out on account of the deep staining of their endothelial walls. I believe that such a condition is not characteristic of pre-menstrual endometrium, and Peters also describes and illustrates the formation of proliferating capillaries in his specimen.
It may be remarked here that Heape (quoted by Marshall”) noted and discussed the predominance of leucocytes in the capillaries of the pre-menstrual mucosa of monkeys.
The great contrast presented by the vascular structure at the base of the ovum, where the capillary channels are invaded by the trophoblast, is well shown in Plate V, Fig. B. Tlhis plate represents a projection reconstruction, and was made to compare with Bartelmez’s illustration which I have reproduced. Plate V, Fig. B. has been reconstructed from slide 21 to slide 30 inclusive, which section would embody one-third of the basal decidua. Plate VI is a micro-photograph of section 3 o-n slide 24, which passes through the large sinus at the base of the implantation cavity. The position of this section is indicated on Plate V, Fig. B by two stars. The actual relation of section 3, slide 24, can be shown by holding a ruler between the two stars with its edge at right angles to the surface of the page.
What becomes apparent from a study of the reconstruction is that there is an uninterrupted circulation at the base of the ovum of a very special nature. We see a small supplying arteriole, the ultimate capillaries of which are divided into two types.
The first consists of capillaries which communicate directly with the large venous sinus at the base of the ovum. Such communications, of which there must be many, ensure a circulation, admittedly sluggish, for the diameter of the outgoing vessel is out of all proportion to that of the supplying arteriole.
The second type consists of the capillaries in the compacta, which are to be seen invaded by the trophoblast in differing degrees.
The stages just p-receding such vascular invasion may be seen in those vessels just outside the region of the ovum, which are not dilated but are as described above, i.e. with thick walls and loaded with leucocytes. (Plate II, Fig. C). The stage of actual invasion is seen near the implantation cavity, just outside the surrounding zone.
Here, as I will proceed to show, the vessels are being approached and invaded by special advance guard cells of the trophoblast; actually contiguous with the implantation cavity the capillaries are seen invaded, the breaches in their endothelial walls being filled by syncytial masses. We must assume that in this specimen there were vessels such as these, invaded in a similar way at an earlier stage of development.
The ultimate result of this advance of the chorionic vesicle is to produce an implantation cavity, the position of which occupies the previous position of the compact layer. Thus, eventually, the arterioles and venous channels of the spongy layer enter and drain the implantation cavity directly, without interposition of the capillaries of the destroyed compact layer.
The chief peculiarity of this particular stage of a developing placenta haemo-chorialis discoidalis olliformis is its temporary and changing structure, instanced particularly by the extreme lack of gross communication between the maternal vessels and the intervillous space which is being formed.
Peters illustrated the narrow forming channels in the syncytium ﬁlling the breaches of continuity in the maternal vessels, which channels, according t-o- Peters, allowed the blood to intercommunicate between intervillous space and the maternal vessels. Although the present specimen is not so favourable for similar observations, as the congestion, so marked in Peters’ specimen, is absent, nevertheless, the histological picture is altogether in support of Peters’ ﬁndings. Plate VI illustrates such channels as he mentions, leading between the large venous sinus and the implantation cavity.
The chorionic investment of the ovum has reached a state of development in which the villi not only possess a core of mesoderm, but are commencing to branch. I will deal with the structure of the mesoderm in an account of the embryonic anlage. In this section I wish to describe the attachment of the ovum to the surrounding maternal tissue, and particularly to elucidate vascular Connexions which exist at this period of development.
First of all, as in other early ova, Langhans’ layer can be seen, completely investing the blastocyst with the exception of a small area situated near the summit of the implantation cavity, where a curious adhesion is present between the trophoblast and the Gewebspilz. This fusion is Very distinct and can be traced through ﬁve sections. I believe that this adhesion represents the remains of the operculum deciduae. A full discussion of the operculum deciduae was given by Teacher2 in 1924.
Langhans’ layer is composed of individual cells with large, deeply staining nuclei. The cell boundaries are not well marked, but the nuclei are evenly spaced in marked distinction from the nuclear arrangement in the overlying syncytium. Where Langhans’ layer is not thrown into folds by the villous formation it is evenly clothed by a thin layer of syncytium which presents the characteristic striated border. The sides of the villi present a similar investment, but nearing the tips of the villi the syncytium increases in depth. A typical villus measures 0.36 millimetres in length, and as one approaches the distal end the arrangement of the trophoblast ceases to be diagrammatic. The reason for this is an immense proliferation of the cells of Langhans’ layer, which form solid masses without a mesodermal core. These cells do not completely resemble the regular cells of Langhans’ layer, but are larger a-nd more vacuolated, which characteristic becomes more marked at the periphery. It is not easy to be certain that such groups of cells are covered by syncytium, but an intervening layer of syncytium is usually seen between such cells and the forming intervillous spaces, and also between such groups of cells and the walls -of the implantation cavity. I believe that the inability to trace a complete investment of syncytium may be due to slight shrinkage during embedding and ﬁxation, producing spaces which are artefacts. This contention is supported by the ease of recognition of the syncytium bordering those spaces in which maternal blood cells are to be seen. I can recognize a layer of syncytium completely surrounding the implantation cavity, thus separating it from the enclosing zone.
In parts of the implantation cavity the structure of the syncytium is similar to the spun-out reticulum as described in the T.B. Ovum No. 1. This appearance is noted particularly towards the summit of the implantation cavity where, of course, villous formation is not so advanced or profuse.
In that part of the enclosing zone where maternal vessels are laid open, proliferation of the trophoblast is most marked,- and many endothelial channels present an endothelial wall towards the maternal tissues and a wall of trophoblast towards the implantation cavity. (Plate Ill). The appearance of such a vessel is well illustrated in Plate VI, where it is clearly seen that the trophoblast that has replaced the wall of the rmateral vessel is mainly syncytial and shows the process of canalization, described by Peters, by which are formed the early channels between the maternal circulation and the intervillous space.
In addition to a syncytium which clothes Langhans’ layer, one observes, distributed between the villi, large masses of syncytium which are less well stained and have nuclei with a faintly staining periphery and a well-stained nucleolus. I do not regard such masses as being essentially different from the rest of the syncytiotrophoblast, although at ﬁrst sight their appearance suggested to me the possibility of their being symplasmata (Grosser,“’ quoting Bonnet). My conclusion is based on being able to trace ‘a connexion between such masses and the more typical syncytium, and also on the recognition of the typical striated border to the protoplasm. The striated border of such masses of protoplasm is not so deﬁnite, or so easy to recognize, as in the syncytium bordering the villi.
This conclusion leads to the belief that there are no maternal cells other than blood cells to be seen in the area between the chorionic epithelium constituting Langhans’ layer and the flattened syncytial lining of the implantation cavity. We have’ therefore, in this area, an irregular network of young villi “equally distributed over the chorionic vesicle, with the exception of that part in relation to. the Gewebspilz, at the tips of which proliferation of the cells of Langhans’ layer has resulted in masses of cells which approach the enclosing zone. The villi and such cell masses are clothed by syncytium, but I find it difficult to decide whether these cellmasses, where they approach the enclosing zone, are actually in contact with the maternal tissues or whether a layer of syncytium has been interposed.
The syncytium encloses two types of space: (1) intervillous spaces, and (2) smaller spaces, apparently of earlier origin due to vacuolation in the syncytium. Narrow channels in the syncytium represent communications between these two types of spaces and the maternal blood-stream.
We have now to consider a further group of cells which lie peripheral to the syncytiotrophoblast and are intermingled with maternal tissue of the enclosing zone and, indeed, penetrate so widely that their trophoblastic origin might be questioned.
The enclosing zone is remarkable on account of its poorly staining constituents. Both glands and stroma share this characteristic, while the blood-vessels are, as a rule, dilated and their endothelial walls are well stained. The appearance of certain other well stained cells is more remarkable. (Pate VII, B). They may be seen distributed around the periphery of the ovum and sparsely even in the Gewebspilz. They are most numerous at the lateral poles of theimplantation cavity. Their characteristic is their large size, for they are many times larger than the stroma cells; in addition, the very deeply staining nuclei, which may almost fill the cell body, are remarkable.
There are two outstanding features in their arrangement: (I) They form fairly regular strands directed peripherally, and (2) they appear to be more numerous in the neighbourhood of dilated capillaries. Often such individual cells are surrounded by a clear area, suggesting histolytic properties. I am satisﬁed that they possess a deﬁnite cell membrane. I have followed them through successive sections in order to satisfy myself that the most outlying of these cells are continuous with strands of similar, more centrally placed cells. I attribute the origin of these cells, therefore, to the trophoblast, and shall proceed to bring forward further evidence of their nature, and also to show that similar cells were described in relation to the T.B. Ovum No. 1 and to Peters’ ovum, but the source of their origin was not decided.
Peters, in his monograph of 1899, mentioned large cells in the neighbourhood -of the ovum, the nature of which he discusses. His conclusions, however, are that these cells are not synqytial in origin, and he brings forth as evidence to support this view the identiﬁcation of their deﬁnite cell walls. He states that their origin must remain doubtful to him, but he is inclined to the belief that they represent the earlier stages of the well—known decidual cells. Merttens’ has also described them and has emphasized the similar appearance of these formations to those found by Strahl’ in the enclosing zone of the cat’s placenta, Strahl’ attributed their origin to the syncytium.
In Plate VI of Bryce and Teacher’s description of T.B. Ovum No. I, the necrotic zone of the decidua is shown illustrating a layer of large cells on its inner aspect, alluded to as large cells, probably maternal, in various stages of degeneration, some lying free within the implantation cavity, others imbedded in the necrotic tissue.
In Plate IX, Fig. 12 is shown a number of mono-nucleated cells-, with large cell bodies, scattered through the ovarian tissue in the zone of attachment of the villi of an ovarian pregnancy. The authors state that some of these are probably of foetal origin.
When Teacher” wrote his epoch—making work on chorionepithelioma, in 1903, he used the following words:
“The typical elements (of chorion-epithelioma) are:——
1. Small, well-deﬁned polyhedral cells, with large vesicular nuclei, closely packed together in masses without any connective tissue stroma between them.
2. Large multi-nucleated irregular masses of protoplasm, (plasmodia or syncytia), in which no deﬁnite cell boundaries are recognizable.
3. Large cells, sometimes rnono—nucleated, sometimes multinucleated, some of which present a resemblance to decidua cells, while others are identical in character with the multi-nucleated giant cells which occur in the decidua serotina. These are, in some parts, arranged in cell masses without intervening tissue stroma, in other parts they are inﬁltrating and destroying adjacent tissue after the manner of sarcoma.” (Plate VIII B and C).
From the foregoing it will be seen that at the periphery of early ova large cells have been noted,_the origin of which has been attributed to the decidua. Peters reasoned that syncytium could not give origin to cellular formations, but that the cells of Langhans’ layer could give origin to the syncytium seems to have been accepted by him. The reverse process does not seem to me to be inherently impossible.
While hesitating to disagree with Teacher’s interpretation of his specimen, it must be remembered that his first ovum came from an aborted decidual cast and that degenerative changes, which led him to believe that the cells he described were maternal, might be due to the interval that ‘had elapsed between their death and fixation.
It is interesting to note that Hubrecht” stated that he was very much struck by noticing that in a specimen fixed some hours after death the blastocyst (in the hedgehog) seemed very loosely attached to its surroundings; very much more so than he had ever noticed it in any blastocyst that was investigated when absolutely fresh.
The actual words in the 1908 monograph on the T.B. Ovum No. 1 are: “which are perhaps to be regarded as degenerating decidual cells.” Such phraseology indicates that the origin of these cells was not certain. Similar cells are seen in the case of ovarian pregnancy, and some of these are admittedly foetal in origin.
That the physiological prototype of chorion-epithelioma is the early chorionic investment of the ovum must be admitted. Teacher describes three types of constituent in the former. These three types of constituent are present in the specimen under consideration, namely, (1) the regular cells of Langhans’ layer and the aggregations of similar cells at the tips of the villi; (2) masses of syncytium, and (3) large mono—nucleated cells invading the maternal tissue.
Florian” has accurately described the trophoblast in the Ovum Bi. 1, and reproduces a photograph which may be compared with the drawing on Plate VII. He terms that part of the trophoblast invading the surrounding zone, proliferation plasmodium, in contra—distinction to the resorption plasmodium covering the villi.
The type of cell that is pictured in Plate VII and marked (a) is not distinguished by him, but I am of opinion that the peculiar position of such cells, with regard to the capillary wall and their size as well as their relation to the more centrally situated trophoblast, makes it certain that such cells belong to the trophoblast.
The specimen that I am considering presents an early stage in the formation of a placenta haemochorialis, and the clarity of the description as regards the foetal and maternal constituents is of great importance.
I have endeavoured to present an accurate description of the maternal vascular supply, both afferent and efferent, at this stage of development. Two types of syncytium are seen co-existing, the spun-out reticulum presenting remains of the first generation of syncytium as seen in Miller's ovum, while the second generation is the regular covering layer for the forming villi. These syncytial structures I regard as primarily the result of contact of the trophoblast with blood.
The function of syncytium, from a study of this specimen, could not be concluded to be erosive, as nowhere are there to be seen syncytial masses invading vessels, but wherever a vessel has been eroded, syncytium is always present in abundance. The function of syncytium would appear to be always to surround maternal blood as it escapes from the eroded vessels and thus to prevent the blood from coming into contact with maternal tissue other than endothelium. This is beautifully shown in Plate III, where a continuous layer of syncytium is indicated lying pressed up against the surrounding zone. Thus, the actual invasive property of syncytium may be doubted.
Where the advancing trophoblast has to deal with the marginal decidua it takes on the characteristics of strands of large cells which grow outwards, bringing about the histolysis of the immediate surrounding zone, and eroding capillaries in such a way that
steady and rapid encroachment of the decidua by the chorionic vesicle continues by virtue of two main factors:
1. The action of these advanced trophoblastic cells on the stroma and gland cells.
2. The result of their action on the vessels, which is ultimately to admit blood slowly into the implantation cavity. This keeps the syncytial layers pressed up against the enclosing zone, a fact which must, by virtue of mechanical reasons, hasten the dissolution of the maternal tissues.
When we recall what a very rapid encroachment is effected by the chorionic vesicle, it becomes apparent that the medium in which it grows is receptive. It would appear to me that the formation of a Gewebspilz, as described by Peters, is a normal occurrence in ova of about two weeks old, and that it is a very striking result of the rapid enlargement of the ovum without a corresponding and accommodating splitting of the compact layer of the decidua. But that later specimens, such as the ovum of Reichert, are completely covered by the cap-sularis seems to show that very soon the balance is adjusted. That the decidua capsularis must undergo considerable passive stretching, or, alternatively, active proliferation, would appear necessary. I am convinced that it must be 9. passive stretching.
To return to the picture presented in the present specimen at the roof of the implantation cavity, I believe it shows the remains of the o_perculum deciduae, in addition to the well-formed Gewebspilz. (Plate VIII A). 1 alluded to the adhesion of the blastocyst to the Gewebspilz: I do not think that the breach of continuity in Langhans’ layer is an artefact. If it is a normal occurrence for such a breach to occur it is possibly the result of the very ﬁrm adhesion of the operculum deciduae to the lips of the aperture by which the ovum became imbedded. If the growth of the ovum results in the margins of this aperture being drawn apart, the result would be either a break involving the maternal tissues on one or both sides, or a break in the chorionic vesicle. The appearance of my specimen suggests that the latter may have occurred, and if this is so the Gewebspilz may be formed as the result of the leakage from the chorionic Vesicle, a suggestion which hitherto has not been made. Thus, a ﬁrm covering for the ovum would be present while the lips of the decidua were still firmly attached by the operculum. Later, this attachment becomes increasingly difficult to identify because of the extreme attenuation of the decidua capsularis until the state of affairs in the present specimen is reached.
I was puzzled to explain that appearance of the camera lucida drawing (Plate II, Figs. A and B) of the fixed, but unsectioned, specimen, which shows a circular area at one side, near the summit of the ovum. It appeared to me, after having identified the Gewebspilz, that this could hardly represent the original point of entrance. It is clear to me now, however, that this circular area is due to the adhesion of the blastocyst to the Gewebspilz over that small area where the layer of Langhans’ cells is wanting.
Description of the Corpus Luteum
At operation, the corpus luteum, situated in the left ovary, presented a globular appearance. It was resected, without macroscopic trauma. After fixation its shape was that of a flattened sphere, the sections measuring 1.3 centimetres by 0.6 centimetre in their greatest diameters. (Plate IV, Fig. A).
The luteal tissue presents the usual folded appearance, while the centre of the structure is occupied by a cavity filled with very loose fibrous tissue. (Plate IV, Fig. C). The invasion of the luteal tissue by capillary vessels from the theca externa is very complete. These vessels reach the margins of the central space, and some capillary channels are to be recognized in the fibrous tissue of the central space. The endothelial cells of the capillaries are closely packed, suggesting continued proliferation. The luteal cells are, as a rule, round or polygonal, with deeply staining nuclei. The nuclei show a well-deﬁned nuclear membrane and a deeply staining nucleolus. In addition, some of the nuclei show chromatin granules. The cytoplasm of the cells shows varying degrees of vacuolation, while large clear spaces, bounded by what is, apparently, the cell membrane, are scattered profusely throughout the sections. Most of these clear spaces are larger than the surrounding luteal cells. It appears as if these clear spaces represent cells, the contents of which have been dissolved by the reagents used in preparation. In some places a nucleus with some surrounding cytoplasm is situated in one of these clear spaces. It is, therefore, inferred that these spaces represent active functioning cells, the structure of which has been completely disintegrated by the solution and the removal of a large part of their contents.
In those cells which do not show vacuolation the cytoplasm is moderately deeply staining and presents a ground glass appearance. The connective tissue forming the central core is continuous with strands of similar but more developed strands of connective tissue, which can be traced to their origin at the periphery. The capillary vessels can be identified in such strands. In the centre of this fibrous core, which is composed of widely separated young connective tissue cells, is enmeshed a moderate amount of blood. This blood is definitely in the nature of haemorrhage and is quite fresh, and I believe it to be the result of the handling of the specimen during removal. The luteal cells are bordered on their internal surface, which surrounds the central core by a deﬁnite internal lining of compressed connective tissue.
According to the classification of Franck, quoted by Graves,” this corpus luteum has reached a stage of maturity, in that it presents not only a picture of complete vascularization but also the luteal cells in their typical secreting stage. Some of the cells of the theca interna are notable for their large size, and are illustrated in Plate IV, Fig. B. These cells approach the luteal cells in size but their position differentiates them, for they are not intermingled with the luteal cells but are situated in the connective tissue strands which stretch inwards from the theca interna between the masses of luteal cells. They do not show vacuolation.
The question of whether or not degenerative change has already commenced to appear need hardly be considered in a corpus luteum of pregnancy which has developed from a follicle in which ovulation occurred about 19 days before the specimen was obtained. I regard the histological picture as evidencing continued activity, particularly on account of the vascularity of the whole structure. The very small haemorrhages in the central core are almost certainly the result of trauma during removal of the specimen.
Following the description of the decidua and that of the trophoblast, I feel that a consideration of the microscopic appearance of the specimen in relation to the present theories of the relation of ovulation to menstruation must be made.
First, the glandular structure demands attention. The picture of glandular activity presented in this specimen surpasses that of the pre-menstrual condition. 15 it to be concluded that such activity is merely a phylogenetic survival without function at this stage of pregnancy in the human female? It is clearly indicated by comparative studies that the human ovum for a period of some days, must remain in the lumen of the uterus before becoming imbedded. That its pabulum in such circumstances would be provided by the secretion of the uterine glands is a natural conclusion. It may be deduced that such a function in the present specimen, where the ovum has already been imbedded for about 10 days, is no longer necessary. My belief is that glandular activity is now of mechanical value; for as long as the glands are dilated and closely packed, the intervening strands of stroma are reduced to a minimum. This will militate against the invasion of the spongy layer by the trophoblast. The trophoblast has, apparently, a much greater affinity for the destruction of stroma cells than of glandular epithelium. This is remarkable, for the ﬁrst tissue to be attacked is the surface epithelium; but it is to be noted that, in this primary encroachment of the imbedding ovum, the ovum attacks the surface epithelium in the opposite direction to that which the subsequent attacks on the gland ducts are made. It may be remarked here that the condition of placenta accreta pre-supposes an ability of the trophoblast to invade the spongy layer. That such an invasion would be favoured by an absence of glandular activity, with increase of the intervening stroma, is obvious. In some forms of endometritis such a condition would occur, and this condition has been fully reported by various authors, including Tiemeyer."
I have noted the peculiar appearance of the glands immediately subjacent to the ovum. Their cavities are distended by what is, apparently, maternal blood or penned—up secretion. Glands distended with blood have been described both by Peters and Frassi as lying basal to the implantation cavity. In the present specimen the relation of these distended glands to the blood supply of the implantation cavity is suggestive. I conclude that their distended -condition influences the circulation at the base of the ovum: compression of the venous channels must result, but the compressive effect on the arterioles would not be so great. This would result in the slowing of the venous return and, subsequently, a dilatation of the veins, resulting in the production of the sinuslike vessel portrayed in Plate VI.
Thus, the glandular portion of the endometrium has other functions than the secretory function which must be regarded as the primary one. Apparently, in the menstrual cycle, the secretory function has to do with the solution of the menstrual clot. That the menstrual clot must undergo some change before its expulsion from the uterus, as the menstrual flow is a necessity if painful contractions of the uterus are to be avoided. At menstruation the compact layer and part of the spongy layer are thrown off, and thus the same line of cleavage is made use of at the “menstrual abortion” as at a full—time confinement.
The functions of the uterine glands might be summed up as follows :—
1. In the menstrual cycle.
(a) Secretory. To produce a ferment which facilitates the destruction of the menstrual clot.
(b) Mechanical. To form, at menstruation, a layer which is a natural line of separation, leaving behind closely packed fundi of the glands constituting an easily repaired surface.
2. During reproduction.
(a) Secretory. To produce embryotrophe for the period that the ovum remains in the uterine cavity before imbedding takes place.
(1) Formation of a layer impervious to the action of the trophoblast.
(2) The exertion of a definite effect on the blood—supply at the commencement of pregnancy, favouring the formation of a venous sinus.
(3) Provision of a natural line of cleavage.
(4.) Provision of a layer from which the regeneration of the mucous membrane takes place post-partum.
The stroma cells next command attention. I am conﬁdent that decidual reaction has only started to appear and is very far from complete. With regard to this observation it is very remarkable that on the last day of the menstrual cycle, decidual reaction is much more complete than in early pregnancy.“ Such a fact is surely hard to correlate with the accepted ideas on the production of decidual reaction.
That decidual reaction in the human female has nothing or little to do with immediate contact with the growing ovum is borne out by the occurrence of typical decidua in the uterus in ectopic pregnancy, and also by the occurrence, in normal pregnancy, of ectopic decidual cells, the distribution of which is, in particular, of great interest. It is also to be noted that the occurrence of large cells in the immediately surrounding zone -of early human ova has usually been attributed to decidual reaction. Such a conclusion, in my opinion, is erroneous, as I have shown in this specimen that the large cells are trophoblastic in origin. It will be remembered that Hubrecht“ at ﬁrst ascribed the origin of large cells in the hedgehog’s decidua to the maternal cells, but later he concluded that the origin of these so-called deciduofracts was trophoblastic.
My interpretation of the compact layer of the endometrium is that it provides a suitable medium, both vascularly and in its loose cellular formation for placentation. The compact layer is capable of yielding to the advance of the trophoblast in such a manner that the decidua capsularis is easily lifted to form a covering for the ovum, and that deeper invasion into the spongiosa is rendered unnecessary to accommodate the increasing bulk of the growing chorionic vesicle.
Next comes the consideration of the vascular supply of the decidua. The arterioles, as they ascend between the closely packed glands, are surrounded by a considerable stratum of stroma cells, and in the same stratum an efferent vein can usually be identified. The arteriole is extremely tortuous. The veins beneath the implantation cavity are dilated, but further away from the implantation cavity they are collapsed.
The capillaries, which are the only vascular components of the compact layer, are dilated in the immediate region of the implantation cavity and, further from it, are extremely remarkable on account of their proliferating endothelial walls and their increased leucocyte content. The former indicates cellular proliferation resulting in an increased resistance to the passage of blood-stream, which explains the presence of leucocytes which have the inherent characteristic of being more easily retarded in the capillary circulation than are the erythrocytes. Whether the presence of leucocytes is fortuitous or whether their presence is of importance during the process of placentation is a question I cannot answer. In the latter supposition, their function might either be to supply embryotrophe to the advancing trophoblast, or else to stem the advancing tide of foetal invasion. Under conditions in which placentation is of the epithelio-chorialic type the leucocytic infiltration is embryotrophic in function.
Heape” concluded that the presence of leucocytes in the premenstrual endometrium was evidence of a presence of a toxin. I am inclined to believe that their presence in this specimen is not of very great signiﬁcance, but is merely the mechanical result of the vascular formation necessary for the advance of the ovum.
The great hypertrophy of the walls of the endothelial channels of the -compact layer is a necessary preparation for the tremendous dilatation that is undergone after their invasion by the trophoblast. The factor that results in such hypertrophy, at present must remain uncertain.
The spiral structure of the arterioles is worthy of comment. Such arterioles are not seen elsewhere in the body. Their peculiar structure is well suited for the changes that they must undergo during the menstrual cycle and pregnancy. For instance, the structure would tend to minimize the loss at menstruation due to the low pressure in the capillaries that would result from the circuitous route offered to the blood by these tortuous vessels. The spiral arrangement protects the arteriole during the tissue loss of menstruation, as, when the integrity of the mucosa collapses at menstruation, accompanied as it is by involution, it can be readily imagined that such. corkscrew-shaped vessels would retract to an exaggerated degree, thus retracting to a deeper layer than that involved by tissue loss. In early pregnancy the spiral arterioles insure a low pressure in the capillaries, which minimizes the blood leakage when the invasion by trophoblast occurs. Possibly, in later pregnancy, the spiral arrangement allows of rapid increase in calibre, without increase in the distance traversed by the arteriole. The structure of the sinus at this period does not differ from capillary dilatation. It must be noted, however, that the venous channels as they advance towards the basal layer of the endometrium have an increasingly thicker investment of stroma cells, which are taking on the function of supporting the walls of the venous channels.
With regard to the circulation which takes place in the intervillous spaces, I would suggest that it is facilitated by the great dilatation of the venous channels at the base of the ovum. For if we have at the base of the implantation cavity, as a constant factor, an extremely dilated venous ‘channel, its constancy suggests a deﬁnite function. The pressure in such a dilated channel must necessarily be very much reduced. The capillaries supplying the blood to the intervillous space are not so markedly dilated. Thus, this condition of affairs is present: the pressure of the blood coming in at the lateral margins of the implantation cavity is higher than the pressure in the large veins at the base. This would result in the drainage of the blood from the implantation cavity, thus establishing, at this early stage, a “placental” circulation.
In attempting to correlate the conclusions which may be drawn from the study of the corpus luteum and decidua of the present specimen, with the theories of the inter-relationship between the corpus luteum and anterior pituitary on the one hand, and menstruation and pregnancy on the other, a consideration of the current views on the subject becomes necessary.
The views formulated by Beckwith Whitehouse,” in 1926, with regard to the activity of the C':0I'pUS luteum, and with regard to the effect of withdrawal of such activity, although providing a partial explanation of the menstrual cycle, did not explain certain aspects of the problem. The question of the relation of pro-oestral degeneration to menstrual bleeding was not explained, and the view that the death of an unfertilized ovum caused corpus luteum degeneration seemed somewhat inadequate.
The question of the relation of pro-oestral degeneration to menstruation can only be decided by making a definition of the term pro~oestrus and deciding its relation to ovulation. I believe -ovulation occurs about the middle of the menstrual cycle,”: 2°31 and that oestrus, or period of sexual desire in the human female, does not bear the same relation to ovulation as in the lower mammalia. Thus, the term pro-oestrus, if applied to a part of the cycle in the human female, cannot carry with it the same meaning as it does when ovulation and the period of oestrus nearly coincide.
I believe all deductions regarding the menstrual cycle must be made on a basis which takes into consideration the fact that ovulation is the all-important factor underlying the cyclic changes when those cyclic changes are concerned with reproduction. It ‘is a disregard of this basic fact, and also lack of evidence as to the time relation of ovulation to the menstrual ﬂow, that have led to the confusion of p-ro-oestral bleeding in the female dog with menstrual bleeding in the human female.
My belief is that normally there is no marked pro-oestral degeneration at the end of the pro-oestrus in the human female, although there may be slight retrogressive changes after the withdrawal of the stimulus from the follicle at the time of ovulation, which normally does not result in uterine bleeding; but these retrogressive changes are prevented from becoming marked on account of the stimulus, so soon after ovulation, that is derived from the corpus luteum. Hartman” has shown that very slight haemorrhage does occur in the middle of the cycle in monkeys, and I have noted the occurrence of uterine bleeding in pathological conditions of the endometrium in the human female. Such bleeding would occur with the same regularity as menstrual bleeding at about the thirteenth day of the cycle, and is particularly likely to occur in polypoid conditions of the endometrium.
Is it either logical or necessary to conclude that menstruation represents both pro-oestral and pseudo-pregnant degeneration? To my mind it appears illogical to prolong pro-oestrus after the occurrence of ovulation. Presumably, folliculin produces the necessary stimulus to produce the pro-oestral condition of the endometrium. The withdrawal of the stimulus arising in the follicle by excision of the follicle will result in uterine bleeding. This withdrawal of the follicle stimulus differs from what might be supposed to occur at ovuation. because in the latter case the secretion of progestin will shortly ensue on the rupture of the follicle. It is, therefore, evident, from the withdrawal (surgically) being followed by bleeding (presumably pro—oestral degeneration) that there is no efﬁcient mechanism outside the follicle to maintain pro-oestral conditions, which rather militates against the telescopic views of menstruation which postulate the continuance of pro—oestral conditions, plus pseudo-pregnancy, right up to the onset of menstruation.
Hartman“ states that the anterior pituitary elaborates a substance causing uterine bleeding. He produces evidence from experimental work in monkeys. If such a substance is secreted by the human pituitary, resulting in menstrual bleeding, its recognition would revolutionize the theories regarding the cycle and would remove the difficulty of having to accept the view that the onset of menstruation is due to the death of the unfertilized ovum. I am inclined to accept Hartman’s views.
The decidual picture I have attempted to describe represents the condition of affairs 32 days after the first day of the last menstrual period. It is pertinent to consider the very altered picture the endometrium would have presented on this day, had pregnancy not occurred. The endometrium, had such been the case, would have undergone the «collapse and destruction of menstruation and would already have been regenerated to a great degree.
To what factors must we ascribe the maintenance of the intact and secreting stru-cture of the young decidua? We have in the corpus luteum a picture of activity which suggests its complicity in maintaining the young decidua in a state of glandular activity.
How are we to explain the continuance of corpus luteum activity in pregnancy and its degeneration in the menstrual cycle? If we accept the view” that the follicular and lutein phase in the ovary is controlled by the internal secretions of the anterior pituitary, namely prolan A and prolan B, we must conclude that a rhythmic activity exists in the hypophysis. Hartman has introduced a new factor which, one presumes, is the elaboration of an active substance in the anterior pituitary capable of producing haernorrhage In the endometrium at a time synchronous with the withdrawal of prolan B. This substance is secreted only for a short time, when it is followed by the secretion of prolan A.
A study of a corpus luteum, removed on the second day of the menstrual cycle, is suggestive in this light for I noted that its interior, in sharp contrast to the corpus luteum of the present specimen, contained gross haemorrhage.
‘The question that I asked myself was: Is haemorrhage in the corpus luteum coincident with the onset of menstruation? If such should prove to be the case, Hartman’s ideas would receive further support, for coincident haemorrhages in the corpus luteum and the endometrium suggest an active haemorrhage-producing hormone.
To return to the consideration of the alternatives which are the result of pregnancy. It is reasonable to suppose that an imbedded ovum could exert a hormonic influence on the anterior pituitary body. Such hormonic influence apparently inhibits the production of the hormone that would bring about menstrual bleeding. We know that under the inﬂuence of pregnancy the «output of the hormones, prolan A and prolan B, is considerably increased and prolonged. Thus, we have an explanation of the absence of menstruation and of corpus luteum proliferation which results in the continued activity of the young decidua. In attributing a hormonic influence to the imbedded ovum which results in the inhibition of menstruation, I realize that I have not taken into account Teacher’s conclusion that imbedding might occur so late as the fourth day of an ensuing cycle. The weight of evidence appears to me to be against such a conclusion—a conclusion from which it would necessarily follow that the unimbedded ovum, when fertilized but lying free in the Fallopian tube or uterine lumen, could exercise some hormonic inﬂuence which results in the prevention of the onset of menstruation.
The functions of the corpus luteum“ may be enumerated as follows : I. To stimulate the pre-menstrual secretory activity of the endometrium.
2. To maintain a stimulus to the endometrium during pregnancy which results in continued activity of the endometrium, bringing about the changes that convert it to decidua.
3. To stimulate mammary changes which prepare the breasts for lactation.
4. To inhibit ovulation during pregnancy.
It is difficult to obtain evidence bearing on the length of time that the corpus luteum remains active during pregnancy. To what period is its activity prolonged? I have repeatedly observed that the ovaries at full time (in cases of Caesarean section) do not differ markedly from one another, and that there is not the same obvious corpus luteum that one expects to recognize both in the menstrual cycle and in the early months of pregnancy.
It is an accepted fact that the corpus luteum is not «essential for the continuance of pregnancy in the later months, and, recently, Corbet“ reported a case in which the corpus luteum was removed as early as the forty-fourth day after the first day of the last period and the patient proved to be pregnant and carried on to full time.
I had the «opportunity of studying the sections of this corpus luteum, and its general appearance was very similar to the corpus luteum from the present specimen.
At first sight such a result as Corbet reports seems surprising, but becomes more explicable when the phylogenetic signiﬁcance of the corpus luteum is reviewed.
In species in which placenta vepithelio—chorialis exists, the corpus luteum is of greater importance than in man, when placenta haemo-chorialis occurs. In other words the corpus luteum is essential during the whole of pregnancy in those species in which the uterine mucous membrane is responsible for the secretion of embryotrophe after the placenta has reached its fully developed condition.
Such a contention ﬁts in with the absolutely constant results obtained by Drummond and Asdell in their experimental work involving the removal of the corpus luteum from pregnant goats, at various periods of gestation. The result was always the termination of the pregnancy, even in the later weeks.
Now consider the result of the removal of the corpus luteum as early as a few days after the first missed period. The delicate structure of the still actively secreting decidua would presumably be rapidly altered by a sudden involution comparable to the changes that occur at menstruation. The as yet very small implantation cavity would be involved in a collapse of such an extent that haemorrhage and death of the ovum would result and abortion occur. It would seem that if removal of the corpus luteum was carried out after the decidua had reached its full development, say at the sixteenth week of pregnancy,“ no ill effects would be expected to follow.
The removal of the corpus luteum, however, after the fourth week of pregnancy, being unaccompanied by interruption of a pregnancy can be explained by the fact that any resulting retrogression in the secretory activity of the decidua at that time would be relatively small in its mechanical effects on the growing implantation cavity.
The conclusion formed is that the corpus luteum is necessary, before implantation, to stimulate the glands to secrete, and this secretory activity must be prolonged until imbedding is completed, and that, after imbedding is complete, the continuance of pregnancy does not depend directly on the activity of the corpus luteum, but that removal of the corpus luteum during the early months of pregnancy may be followed by abortion due to the changesthat would result in the young decidua.
That the corpus luteum is not essential in all cases after the fourth week is proved by Corbet’s case.
The relation of the corpus luteum to the decidual cell is very difficult to determine. I have suggested that the corpus luteum of menstruation may be the seat of haemorrhage at the time of the onset of the menstrual ﬂow. If such is the case its existence as a gland of internal secretion comes to a sudden end. It is likely that the corpus luteum during pregnancy gradually becomes more and more inactive. Now, in the menstrual cycle, it has been noted that the stroma cells are very like decidual cells in the few hours preceding the onset of the menstrual ﬂow. Again, it is to be noted that in many young pregnancies the absence of decidual reaction is noted. Evidently the presence of decidual cells becomes constant at about the fourth week of pregnancy.
These facts are suggestive. They lead one to the conclusion that decidual cells may make their appearance at the time when the corpus luteum has ceased to elaborate its hormone.
Wilfred Shaw” states that decidual cell production is controlled by the corpus luteum through a hormone circulating in the blood.
Is it possible that the decidual cell results from the stroma cell, which, having been stimulated by the corpus luteum, undergoes those changes that result in a decidual cell after or coincident with the withdrawal of the corpus luteum hormone?
1. That the features of the decidua at the ‘ﬁfteenth day of pregnancy do not altogether correspond with those found in premenstrual endometrium. These differences may be summarized as follows :
(a) The secretory activity of the glands and of the surface epithelium is more marked. (The changes in the glands produced by the mechanical effects of the growing ovum do not come under consideration.)
(b) The stroma cells do not so nearly approach the typical decidual cell in appearance as they do in the immediately pre-menstrual endometrium.
(c) The vascular condition in the compact layer is remarkable on account of the proliferation of the endothelial cells of the capillary walls and the marked preponderance of leucocytes.
2. That a reconstruction of the vascular arrangements at the base of the implantation cavity shows how the peculiar arrangement of the arterioles and veins of the pre-menstrual. end-ometrium (as reconstructed by Bartelmez) is modiﬁed by an early pregnancy.
The following is of particular interest :—
The capillaries of the uterine circulation communicate with the veins at two different levels in the endometrium, namely in the compact layer, and in the spongy layer. The effect of this arrangement is that when, during placentation, the compact layer undergoes almost complete destruction, there is an "underlying circulation uninterrupted in the spongy layer. This uninterrupted circulation reduces the liability to thrombosis, which would be likely to occur if all the capillaries of the arterioles were involved in trophoblastic invasion. Also, the maintenance of a circulation at the base of the ovum, independent of the forming placental circulation, and at the same time communicating with it, favours the ultimate establishment of a circulation in the implantation cavity.
The absence of blood in the implantation cavity of the present specimen, and in Frassi’s Ovum as compared with the congested state of the implantation cavity in Peters’ Ovum and Ovum T.B. No. 2, support the view that even as early as the second or third week, a deﬁnite circulation through the implantation cavity is effected.
3. The various types of trophoblast have been described and illustrated at this stage of pregnancy. The conclusions reached are as follows :— The trophoblast varies in the form that it assumes according to the nature of its surroundings. There are four differing types of structure in the trophoblast of this specimen : (1) Cells of Langhans‘ layer and similar cells forming solid masses connecting the typical villi with the margins of the implantation cavity. (2) The syncytial covering of the villi and similar masses of syncytium which lie free in the implantation cavity. (A more reticulated syncytium is also seen towards the summit of the ovum which is like the syncytium -of earlier specimens.) (3) Strands of cells which are situated in the necrotic surrounding zone and appear in places to approach syncytium in character as the protoplasm of neighbouring cells is intermingled. (4) Cells of somewhat similar appearance, which are situated in the, as yet, healthy decidua immediately outside the necrotic surrounding or enclosing zone.
These findings conﬁrm the descriptions of the trophoblast in Ovum Bi. No. I, by Florian, in which the first type of syncytium is’ termed resorption plasmodium and those cells in the surrounding zone are termed proliferating plasmodium.
I believe that the cells .that I have described in the healthy decidua outside the necrotic zone must belong to the trophoblast for reasons that I have enumerated.
An added reason to suppose these cells to be trophoblastic in origin is that it would be hard to imagine how the trophoblast could advance if its method of attack did not include the invasion of the, as yet, unaltered decidua.
4. That the changes that occur in the corpus luteum during the menstrual cycle and pregnancy are not fully understood, and that a study of a series of corpora lutea, recovered during menstruation, will possibly give support to Hartman‘s theories of the menstrual cycle.
In conclusion, I Wish to thank Professor Bronte Gatenby for the help he has given me. He carried out the sectioning of the specimen, and the drawings reproduced in Plate 11. In addition, he placed his department at my disposal to carry out the work incorporated in this communication, and at all times was ready with advice and helpful criticism.
Miss M. O’Brien, who is responsible for the remainder of the drawings, has «exercised the most meticulous Care in reproducing accurately the beauty of the individual sections. It is needless to stress the painstaking work that was necessary to produce the results that she has achieved in Plate III.
My thanks are also tendered to Professor A. Francis Dixon, who kindly placed at my disposal a great deal of literature which has been of great help. Doctor Robert Stump-f has always been ready to help me with the translations -of German literature.
1. Bryce, T. H., and J. H. Teacher. “Contributions to the Study of the Early Development and Iinbedding of the Human 0vun1.” Maclehose, Glasgow, 1908.
2. Teacher, J. H. “O11 the Implantation of the Human Ovum and the Early Development of the Trophoblast.” joiurn. Obstct. and Gyn. Brit. Emp., 1924, xxxi, 2.
3. Bryce, T. H. “Observations on the Early Development of the Human Embryo.” Trans. of the Roy. Soc. of Edin. I924, liii, Part 3 (No. 26).
4. Jones, T. W. Trans. Roy. Soc. London, 1837.
5. Streeter, G. L. “The Miller Ovum: the Youngest Normal Human Embryo thus far known.” Contributions to Embryology, No. 92.
6. Streeter, G. L. “A Human Embryo (Mateer) of the Pre-somite Period.” Contributions to Embryology, No. 43.
7. Peters, .H “Die Einbettung des Menschlichen Eies, etc.” Denticke, Wien, 1899.
8. Florian, J. “Uber zyvei junge Menschilichen Embryonen,” 1927. Vcrh. d. anat. Ges. (Anat. Anz. Erg-H. Bd. 63).
9. TeLinde, R. W. “A Study of the Very Early Decidua.” Amer. Ioum. of Obstct. and Gynecok, 193,0, xix, 6.
1o. Keibcl, F., and F. P. Mall. “Manuel of Human Embryology,” I,ipincott, Philadelphia, 1910.
PLATE 1. PI.A'rE 11(0) PLATE 1V(a). 1’1.A'1'1-: IV(l7). PLATE 1V(5)PI,A'1‘E V(a).
PLATE VIII(c). II.
15. Florian, J.
.Teacher, J. H.
. Hubrecht, A. W.
‘. Graves, W. P. . Tiemeyer, A. C.
. Beckwith Whitehouse.
. Shaw, W. . Corner, G. W. . Asdell, S. A.
.Hartmau, C. G.
. Graves, W. P.
. Whitridge Williams.
Bartelmez, G. W.. “The Human Uterine Mucous Membrane during Menstruation.” Amer. ]ourn_ Obstet. and Gynecol., 1931, xxi,
5. Marshall, F. H. A. “The Physiology of Reproduction.” Longnians, Green & Co., London, 1922. “On Chorion-epithelioina and the Occurrence of Chorion—epitheliomatous and Hydatidiforru Mole-like Structures in Teratomata. A Pathological and Clinical Study.” Iourn. Obstet. and Gynaecol. Brit. Emp., 1903, iv, I. “Studies in Mammalian Embryology.” Quart. lourn. Microsc. Sci., 1890, xxx. “Uber (las Syncytium im Trophoblast junger Menschlichen Embryonen,” 1928. I'crh. d. Anat. Ges. (Anat. Anz. Erg—H.). “Gynaecology,” Saunders, Philadelphia, 1928. “A case of Placenta Accreta.” Amer. Iourrz. of Obstet. and Gynecol, 1931. “The Inﬂuence of the Corpus Luteum upon Menstruation.” journ. of Obstet and Gynaecol_ Brit. Emp., 1926, Xxxiii,
3. “The Relation between Ovulation, Corpus Luteum Formation and Menstruation.” “Oestrns, Ovulation and Menstruation.” Phys. Rev., 1923, iii,
4. “Time of Conception and Ovulation in Relation to the Menstrual Cycle.” Journ. Amer. Med. Assoc., lxxxix. “The Corpus Luteum and the Menstrual Cycle together with the co-relation between Menstruation and Implantation.” Amer. fourn. of Obstet. and Gynecol., 1930, xix, 4. “Female Sex Hormonology.” Saunders, Philadelphia, 1931.
Hartman, C.(§., W. M. Firor, and E. M. G. (leilung, “Menstruation and the Anterior Pituitary.” Proc. Soc. Exper. Biol, Med., xxviii.
Drummond-Robinson, G., and S. A. Asdell. “The Relation between the Corpus Luteum and the Mammary Gland.” Iourn. Physiol., 1926, lxi, 4. “Obstetrics,” Appleton, New York, 1924. Corbet, R. M. Irish fourn. Med. Scz'., 1932.
Shaw, W. “The distribution and Signiﬁcance of Ectopic Decidual Cells. fourn. Obstet. and Gymzecol. Brit. Emp.,' 1927, xxxiv, 1‘. 504 Journal of Obstetrics and Gynaecology
Table of comparative ages of well—known early l1u111a11 ova adapted from Streeter with the addition of the data of the ovum B1 No. 1 described by Florian and the data of the present specimen.
In this table are shown the clinical data of the human embryos of Group I of the presomite period (Streeter) arranged from above downward in order of their development.
The data of the present specimen are illustrated by the ﬁrst and second lines of ﬁgures.
The ﬁrst line shows the actual dates of the month as compared with the days of the 1ne11strual cycle ﬁgured in the second line.
Camera Lucida drawing made by Professor‘ J. Bronte (latenby of the ﬁxed unsectioned specimen.
The scale is marked in millimetres. The lateral view shows the marked projection of the implantation cavity above the level of the surrounding mucosa.
(a) The specimen drawn fro111 above.
(b) The specimen drawn from the side.
(C) Drawing of the compact layer of the decidua magniﬁed by 680 diameters. Here is shown the very marked secretory activity of the surface epithelium. The stroma cells do not show a marked degree of decidual reaction. A capillary is seen with a very well marked wall of closely packed endothelial cells. In the lumen of the capillary the predominance of leucocytes is remarkable.
Drawing of Section 5 on slide 30; magniﬁed 70 diameters. Approximately the meridian section of the implantation cavity and ovum. A close study of this drawing reveals many interesting points: The decidua is plainly differentiated into a compact and a spongy layer. The surface epithelium and the epithelium of the glands are in a stage of active secretion. The surface epithelium cannot be traced over the summit of the ovum. The summit of the implantation cavity is roofed by a closing coagulu111 : the gewebspilz of Hubert Peters. The implantation cavity is situated in the compact layer and the subjacent spongy layer is modiﬁed by its presence. Beneath the ovum the glands of the spongy layer are dilated and contain a dense material which is either penned up secretion or maternal blood.
The relationship of the trophoblast to the surrou.nding compact layer is clearly shown, and the syncytial trophoblast forms a continuous lining for the implantation cavity. The villi show branching and they have wellmarked mesodermal cores. The magma cavity contains a faintly staining granular substance, while the embryonic anlage is represented by the yolk sac, the embryonic disc and amnion. The body stalk does not appear in this section. The dilated vessels in the decidua are well shown, and on A Description of a Human Ovum 505
tl1e right side of the implantation cavity a sinus of large proportions is seen whose wall adjacent to the ovum has been invaded and replaced by trophoblast.
The corpus luteum. (a) Drawing of the corpus luteum. Section magniﬁed by I8 diameters. This drawing shows the general structure and proportions of the corpus luteum. The central core is occupied by young ﬁbrous tissue showing a very loose reticular structure.
(b) The theca interna and the subjacent luteal cells magniﬁed by 340 diameters. The large proliferating cells of the theca interna are seen projecting in a wedge-shaped mass between the luteal cells on either side.
(0) Portion of the central core magniﬁed by 340 diameters showing the loose ﬁbrous tissue and some dilated capillaries.
(cs) The vascular arrangements in the pre-menstrual endoinetrium on the twenty-third day of the cycle. Reconstruction drawing reproduced with the kind permissio-n of Dr. Bartelmez.
(b) Reconstruction of the vascular arrangements at the base of the implantation activity. This drawing, reconstructed from slides 21 to 32‘ inclusive shows the ascending arteriole in black with its marked spiral course. One of its terminal capillaries is traced i11to a ve11o11s tributary of the large sinus at the base of the ovum. The remarkable distended veinous sinus are shown- in grey and offer a11 appearance suitable forcomparison with the veins in Bartelmez’ ﬁgure. The two stars indicate the position occupied by section 2 on slide 24, a photograph of which is ﬁgured in Plate VI.
(0) The same reconstruction to show the relationship of a uterine gland. The gland is seen to be somewhat dilated and its neck is constricted by pressure from the advancing trophoblast.
Microphotograph of the base of the implantation cavity, magniﬁcation 70 diameters.
This photograph shows very clearly the gap in the endothelial lining of the maternal sinus occupied by syncytial trophoblast. This syncytium presents narrow channels in its substance which form connecting passages between the intervillous spaces and the maternal blood stream. This picture is interesting to study in conjunction with the reconstruction Plate 6(b) as the positions of the various arterial channels and venous sinus can be identiﬁed in each.
Drawing of the trophoblast to show its relationship in detail to the decidua. Magniﬁcation 420 diameters.
This picture shows a typical villus at the lateral pole of the ovum. At the tip of the villus there is a mass of cells which are to be regarded as continuous with, and derived from Langhans’ layer. These cells are larger and more vacuolated than the regular cells of Langhans’ layer, clothing the chorionic vesicle and the villi. Covering the villi and the 506 Journal of Obstetrics and Gynaecology
chorionic vesicle there is a very deﬁnite layer of syncytium marked C. Similar but less readily discernible syncytium clothes the masses of cells at the tips of the villi. At the tip of the cell mass, where it is in contact with the necrotic zone of tl1e decidua the character of the trophoblast changes. Here it is represented by strands of cells which are marked B and whose protoplasm, in places, merges into that of the neighbouring cells. In the healthy marginal decidua the cells marked A are interpretated as being derived from the trophoblast one of these cells is seen projecting into the lumen of a maternal capillary.
(a) The adhesions between the roof of tl1e blastocyst and the gewebspilz. Micropliotograpli magniﬁcation 230 diameters. This photograph was taken by Mr. Pittock in the Department of Anatomy, University College, London, and is reproduced by the kind permission of Professor J. P. Hill.
(b) Microphotograph magniﬁed 35 diameters of a specimen of chorionepithelioma. Rotunda Hospital specimen reproduced with the kind permission of Dr. Bethel Solomons. This section shows a vei11 in the wall of the uterus with a mass of tumour cells lying free in the lume11 of the vein.
(C) The same section magniﬁed xos dianleters, sllowing the similarity in the tumour to the cellular structure of the trophoblast ﬁgured in Plate VII.
It is readily noted l1ow alike the cells of the tu111our mass lying free in the vein are to tl1e cell mass at the tip of the villus, both with the surrounding layer of syncytium. In that part of the tumour in the proximity of the vein, cells of the tumour are seen proliferating outwards into necrotic uterine tissue, which resemble in their structure and formation the cells of the trophoblast in the necrotic and marginal decidua.
Cite this page: Hill, M.A. (2019, October 17) Embryology Paper - Human ovum fifteen days old with reference to the vascular arrangements and morphology of the trophoblast. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_Human_ovum_fifteen_days_old_with_reference_to_the_vascular_arrangements_and_morphology_of_the_trophoblast
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