Paper - lnvolution of tissues in fetal life: Difference between revisions

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|[[File:Mark_Hill.jpg|50px|left]] This historic 1946 paper describes early human development.
|[[File:Mark_Hill.jpg|50px|left]] This historic 1946 paper describes early human development in relation to tissues that are lost during development. It includes several of the [[Carnegie Collection]] embryos in the figures.
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[[File:Arthur Hertig.jpg|thumb|200px|alt=Arthur T Hertig|link=Embryology History - Arthur Hertig|Arthur Tremain Hertig (1904-1990)]]
[[File:Arthur Hertig.jpg|thumb|200px|alt=Arthur T Hertig|link=Embryology History - Arthur Hertig|Arthur Tremain Hertig (1904-1990)]]


Dr. Arthur T. Hertig graduated from the
[[Embryology History - Arthur Hertig|Dr. Arthur T. Hertig]] graduated from the University of Minnesota in 1928 and received his M.D. degree from Harvard University in 1930. He has been assistant professor of pathology ‘at the Harvard Medical School since 1941. He is pathologist to the Boston Lying-in Hospital and to the Free Hospital for Women in Brookline. His work has been in pathology with relation to obstetrics and gynecology, and in the embryology and pathology of the early human ovum.
University of Minnesota in 1928 and received his M.D. degree from Harvard University in 1930. He has been assistant professor of pathology ‘at the Harvard Medical
School since 1941. He is pathologist to the
Boston Lying-in Hospital and to the Free
Hospital for Women in Brookline. His work
has been in pathology with relation to
obstetrics and gynecology, and in the embryology and pathology of the early human
ovum.


This paper is from the Pathological Laboratories of the Boston Lying-in Hospital, the
This paper is from the Pathological Laboratories of the Boston Lying-in Hospital, the Free Hospital for Women, Brookline, the Departments of Obstetrics and Pathology, Harvard Medical School, Boston, and the Department of Embryology, Carnegie Institution of Washington, Baltimore.
Free Hospital for Women, Brookline, the
Departments of Obstetrics and Pathology,
Harvard Medical School, Boston, and the
Department of Embryology, Carnegie Institution of Washington, Baltimore.


==Introduction==
==Introduction==
Certain organs and tissues run a complete life cycle during pregnancy,
Certain organs and tissues run a complete life cycle during pregnancy, appearing, fulfilling their function, aging, and disappearing within a short but variable period of time. The exocoelomic membrane, for example, is present in the human ovum from the ninth to the thirteenth day, reaches its peak at the twelfth day, then rapidly declines. The yolk sac has fulfilled its imperfectly known purpose by the end of the eighth week, while the placenta has a definite function lunar months, then is discarded at birth. Dr. Hertig discusses the process of aging in these organs and the relation of embryology to gerontology.
appearing, fulfilling their function,
aging, and disappearing within a short
but variable period of time. The
exocoelomic membrane, for example, is
present in the human ovum from the
ninth to the thirteenth day, reaches
its peak at the twelfth day, then
rapidly declines. The yolk sac has fulfilled its imperfectly known purpose
by the end of the eighth week, while
the placenta has a definite function
lunar months, then is discarded at birth. Dr. Hertig discusses
the process of aging in these organs
and the relation of embryology to
gerontology.


RDINARILY one does not associate the
O field of embryology with that of
gerontology since the beginning and ending
of life would seem, at first glance, to be diametrically opposed. If, however, one regards the fertilized human ovum as a
whole, whose origin begins in the respective
gonads of its parents and whose extrauterine life is largely a function of the
original vitality with which it is endowed,
then it becomes apparent that the problems of embryology and gerontology are
more closely‘ correlated. Such a point of
View is admirably expressed by the eminent
embryologist, George L. Streeter (1) who
says, “The importance of quality of the
egg, and of course I include both its maternal and paternal elements, is not limited to
uterine life. Whether the infant survives its
first year depends in considerable part on
the original quality of the egg. If they withstand the usual Wear and tear of life until
between fifty and sixty years they conform to the actuary’s expectation of life at


birth—and to the embryologists’ expectation of the performance of an egg of average quality. It is only the extraordinarily
Ordinarily one does not associate the field of embryology with that of gerontology since the beginning and ending of life would seem, at first glance, to be diametrically opposed. If, however, one regards the fertilized human ovum as a whole, whose origin begins in the respective gonads of its parents and whose extrauterine life is largely a function of the original vitality with which it is endowed, then it becomes apparent that the problems of embryology and gerontology are more closely correlated. Such a point of View is admirably expressed by the eminent embryologist, George L. Streeter (1) who says, “The importance of quality of the egg, and of course I include both its maternal and paternal elements, is not limited to uterine life. Whether the infant survives its first year depends in considerable part on the original quality of the egg. If they withstand the usual Wear and tear of life until between fifty and sixty years they conform to the actuary’s expectation of life at birth—and to the embryologists’ expectation of the performance of an egg of average quality. It is only the extraordinarily good egg that is still going strong at 80 years, and we see him (or her) do this in the absence of any exquisite hygienic regime or environmental favor.”
good egg that is still going strong at 80
years, and we see him (or her) do this in
the absence of any exquisite hygienic regime or environmental favor.”


Streeter further emphasizes that the
total quality of such an egg is made up of
the quality of the separate parts or organs
and that any one of the latter may wear
out or age prematurely and cause the individual’s death While the other organs are
still capable of continued function. Thus
this author goes on to state, “It is also
probable that degenerative diseases of the
heart and blood vessels are to be explained
as well by the constitution of the germ-_
plasm with which the individual started
life (that is, the inherited vulnerability of
his Vascular system) as by the much
blamed overwork, overeating, oversmoking
and overdrinking, which in other individuals do not result in a comparable
damage.”


One might infer from this point of view
Streeter further emphasizes that the total quality of such an egg is made up of the quality of the separate parts or organs and that any one of the latter may wear out or age prematurely and cause the individual’s death While the other organs are still capable of continued function. Thus this author goes on to state, “It is also probable that degenerative diseases of the heart and blood vessels are to be explained as well by the constitution of the germ-plasm with which the individual started life (that is, the inherited vulnerability of his Vascular system) as by the much blamed overwork, overeating, oversmoking and overdrinking, which in other individuals do not result in a comparable damage.
that the relation of embryology to gerontology lay entirely in the realm of quality
of germ-plasm and its effect on the extrauterine life of the individual. That such is
not the case is shown by the fact that many
fetal organs, or portions thereof, involute or
age during intra-uterine life.


Examples of such a process are seen in
the development and involution of the
pro- and mesonephros, both purely fetal
organs, which play a functional role in the
development of the embryo. That such a
structure probably functions, albeit temporarily, is predicted by Flexner’s (2) biochemical studies on the metanephros, (successor to mesonephros) of the fetal pig.
This author concluded that “1) In pre secretory stage, cytochrome oxidase is in
low concentration and equally distributed
between epithelium and stroma. In secretory stage, oxidase increases markedly in
epithelium and disappears from stroma. 2) -In pre-secretory stage, redox potentials of epithelium and stroma are alike. With onset
of secretion, the potential of epithelium rises and that of stroma falls so that a difference of 0.230 volt develops between
them.” Whether similar studies on the proand mesonephros would show similar results or not is impossible to say, but studies
such as the above do correlate biochemical
changes with morphologic evidence of
maturation and function. These biochemical techniques have also been applied by
Flexner, Flexner, and Strauss (3) to the developing cerebral cortex of the fetal pig
with results comparable to those obtained
on the metanephros.


One might infer from this point of view that the relation of embryology to gerontology lay entirely in the realm of quality of germ-plasm and its effect on the extrauterine life of the individual. That such is not the case is shown by the fact that many fetal organs, or portions thereof, involute or age during intra-uterine life.




Examples of such a process are seen in the development and involution of the pro- and mesonephros, both purely fetal organs, which play a functional role in the development of the embryo. That such a structure probably functions, albeit temporarily, is predicted by Flexner’s (2) biochemical studies on the metanephros, (successor to mesonephros) of the fetal pig. This author concluded that “1) In pre secretory stage, cytochrome oxidase is in low concentration and equally distributed between epithelium and stroma. In secretory stage, oxidase increases markedly in epithelium and disappears from stroma. 2) -In pre-secretory stage, redox potentials of epithelium and stroma are alike. With onset of secretion, the potential of epithelium rises and that of stroma falls so that a difference of 0.230 volt develops between them.” Whether similar studies on the proand mesonephros would show similar results or not is impossible to say, but studies such as the above do correlate biochemical changes with morphologic evidence of maturation and function. These biochemical techniques have also been applied by Flexner, Flexner, and Strauss (3) to the developing cerebral cortex of the fetal pig with results comparable to those obtained on the metanephros.




In discussing this matter with Louis B.
In discussing this matter with Louis B. ‘Flexner he defined aging as “the sum total of those processes in an individual which lead to death.” Furthermore, if one considers the rate of aging as including the rate at which morphologic, physiologic, and biochemical changes take place, it is apparent from the studies of Flexner and his coworkers that the individual ages most rapidly when he is the youngest, namely, during the embryonic stage.
‘Flexner he defined aging as “the sum total
of those processes in an individual which
lead to death.” Furthermore, if one considers the rate of aging as including the
rate at which morphologic, physiologic, and
biochemical changes take place, it is apparent from the studies of Flexner and his coworkers that the individual ages most rapidly when he is the youngest, namely,
during the embryonic stage.


The intra-embryonic coelomic tract is yet
another structure that has a temporary but
distinctly functional life span. Likewise, the
cells which form the lens vesicle of the eye
involute and are extruded once their function has been completed (Streeter, 4).
Were it not for this fact, it would be impossible for light to be transmitted through
the crystalline substance of the lens. Another temporary but probably functionally
useful structure is the neurenteric canal of
the late presomite embryo.


Such examples as the above are given
The intra-embryonic coelomic tract is yet another structure that has a temporary but distinctly functional life span. Likewise, the cells which form the lens vesicle of the eye involute and are extruded once their function has been completed (Streeter, 4). Were it not for this fact, it would be impossible for light to be transmitted through the crystalline substance of the lens. Another temporary but probably functionally useful structure is the neurenteric canal of the late presomite embryo.
merely to indicate that various structures
in the embryo itself have a temporary but
functional life span. None of these alterations are, however,/a/s striking as the involutionary processes which go on in the
placenta and its associated structures—an
organ whose entire life cycle takes place
during the intra-uterine life of the individual.‘ It is the purpose of this review to describe and, insofar as is possible, to interpret the major involutionary changes that
occur in the placenta and some of its associated structures. These will be considered
under the following headings: (1) the exocoelomic membrane, (2) the yolk-sac, (3)
physiologic aging, and (4) pathologic aging
in the placenta.


I wish to acknowledge with gratitude the
cooperation of my various colleagues in the
preparation of this review: to Drs. George
B. Wislocki, H. Stanley Bennett, and Edward W. Dempsey for allowing me to use
the original plates of their respective publications some of which are shown in sections
3 and 4, to Drs. George L. Streeter and
Louis B. Flexner for helpful discussion and
suggestions with respect to aging in the
fetal period, and to Chester Reather and
Richard W. St. Clair for making some of
the pictures here used. I am furthermore


1 For the benefit of l the non-embryologist who
Such examples as the above are given merely to indicate that various structures in the embryo itself have a temporary but functional life span. None of these alterations are, however,/a/s striking as the involutionary processes which go on in the placenta and its associated structures—an organ whose entire life cycle takes place during the intra-uterine life of the individual.<ref> For the benefit of the non-embryologist who may read this, it should be noted that the placenta, or after-birth, is just as much a part of the fertilized ovum as the fetus or baby even though it is a temporary organ and is cast off at birth.</ref> It is the purpose of this review to describe and, insofar as is possible, to interpret the major involutionary changes that occur in the placenta and some of its associated structures. These will be considered under the following headings: (1) the exocoelomic membrane, (2) the yolk-sac, (3) physiologic aging, and (4) pathologic aging in the placenta.
may read this, it should be noted that the placenta,
or after-birth, is just as much a part of the fertilized ovum as the fetus or baby even though it is a
temporary organ and is cast off at birth.




I wish to acknowledge with gratitude the cooperation of my various colleagues in the preparation of this review: to Drs. George B. Wislocki, H. Stanley Bennett, and Edward W. Dempsey for allowing me to use the original plates of their respective publications some of which are shown in sections 3 and 4, to Drs. George L. Streeter and Louis B. Flexner for helpful discussion and suggestions with respect to aging in the fetal period, and to Chester Reather and Richard W. St. Clair for making some of the pictures here used. I am furthermore greatly indebted to W. B. Saunders Company of Philadelphia and to Dr. Thomas S. Cullen for their permission to reproduce Figures 1, 2, 3, 4, 5, 8, 11, 31 and 32 from the latter author’s book "The Umbilicus and its Diseases.” To Dr. E. J. Farris of the Wistar Institute of Anatomy and Biology I am grateful for permission to reproduce some of the illustrations from the various publications of Wislocki, Bennett and Dempsey (see bibliography for references and figures for specific illustrations used).


FIG. 1. A human ovum of approximately 8-9
days of age. It is barely implanted within the
endometrium, the epithelium of which is attempting to repair the defect in its surface. The thick
trophoblastic shell contains lacunae into which
flows maternal blood. The central or chorionic
cavity contains a globular, bilaminar embryonic
disk to which is attached the recently developed
exocoelomic membrane. The latter thus surrounds
the small irregular exocoelom designated as EX.
Carnegie 8215, section 12-5-1, X200.


greatly indebted to W. B. Saunders Company of Philadelphia and to Dr. Thomas S.
[[File:Hertig1946b fig01.jpg|500px]]
Cullen for their permission to reproduce
Figures 1, 2, 3, 4, 5, 8, 11, 31 and 32 from the
latter author’s book "The Umbilicus and
its Diseases.” To Dr. E. J. Farris of the
Wistar Institute of Anatomy and Biology
I am grateful for permission to reproduce
some of the illustrations from the various
publications of Wislocki, Bennett and
Dempsey (see bibliography for references
and figures for specific illustrations used).


THE EXOCOELOMIC MEMBRANE


One of the most evanescent structures of
'''Fig. 1.''' A human ovum of approximately 8-9 days of age. It is barely implanted within the endometrium, the epithelium of which is attempting to repair the defect in its surface. The thick trophoblastic shell contains lacunae into which flows maternal blood. The central or chorionic cavity contains a globular, bilaminar embryonic disk to which is attached the recently developed exocoelomic membrane. The latter thus surrounds the small irregular exocoelom designated as EX. Carnegie {{CE8215}}, section 12-5-1, X200.
the developing chorion (placenta) is the
thin mesothelium-like membrane which is
present in the human ovum from the 9th
to the 13th days (Figures 1-3). This membrane lines the chorionic cavity (except
where the latter is bounded by the embryonic disk) during this period of development. Conversely it forms the boundary of
the exocoelomic cavity—hence its designation as the exocoelomic membrane. Its


presence in the developing primate ovum
==The Exocoelomic Membrane==
(macaque) was first described by Heuser
(5) in 1932 and more fully elaborated by
the same author in 1938 (6). Its presence in
the developing human ovum was first noted
by Stieve (7) in 1926 in describing the
“Werner” embryo although that author
interpreted the structure as a yolk-sac.
Hertig and Rock (8) in 1941 described two
previous human ova of about eleven and
twelve days of age, both of which showed
extensive development of this membranous
structure. In that paper, the authors discuss at some length the problem of whether
or not this membrane constitutes the early
phase of yolk-sac formation. In the opinion
of Hertig and Rock it does not although
Lewis (9) intimates that embryos of this
age should have a large yolk-sac. Actually
the human yolk-sac apparently does not
begin to develop until late in the thirteenth
or early in the fourteenth day as it does in
the macaque monkey as shown by Heuser
and Streeter (10) although the exact stage
or stages in man have not yet been ob


FIG. 2. A human ovum of approximately 11 day:
One of the most evanescent structures of the developing chorion (placenta) is the thin mesothelium-like membrane which is present in the human ovum from the 9th to the 13th days (Figures 1-3). This membrane lines the chorionic cavity (except where the latter is bounded by the embryonic disk) during this period of development. Conversely it forms the boundary of the exocoelomic cavity—hence its designation as the exocoelomic membrane. Its presence in the developing primate ovum (macaque) was first described by Heuser (5) in 1932 and more fully elaborated by the same author in 1938 (6). Its presence in the developing human ovum was first noted by Stieve (7) in 1926 in describing the “Werner” embryo although that author interpreted the structure as a yolk-sac. Hertig and Rock (8) in 1941 described two previous human ova of about eleven and twelve days of age, both of which showed extensive development of this membranous structure. In that paper, the authors discuss at some length the problem of whether or not this membrane constitutes the early phase of yolk-sac formation. In the opinion of Hertig and Rock it does not although Lewis (9) intimates that embryos of this age should have a large yolk-sac. Actually the human yolk-sac apparently does not begin to develop until late in the thirteenth or early in the fourteenth day as it does in the macaque monkey as shown by Heuser and Streeter (10) although the exact stage or stages in man have not yet been observed. Thus the yolk-sac appears to begin its development about the time the exocoelomic membrane has reached its zenith and is degenerating. For fuller discussion of this problem and the details of the membrane’s development see Hertig’s (11) recent paper.
of age. The endometrial epithelium has super‘
ficially repaired the defect made by the implanting
ovum. The exocoelom (EX) is now a much mom
definite space and is bounded below by the primitive entoderm of the bilaminar embryonic disk.
Elsewhere it is surrounded by the sharply delineated exocoelomic membrane. Note the multiple
gossamer attachments of the membrane by mesoblastic cells to the surrounding trophoblast from
which it originally arose. Carnegie 7699, 8-5-3,


X100.
[[File:Hertig1946b fig02.jpg|500px]]


'''Fig. 2.''' A human ovum of approximately 11 days of age. The endometrial epithelium has superficially repaired the defect made by the implanting ovum. The exocoelom (EX) is now a much more definite space and is bounded below by the primitive entoderm of the bilaminar embryonic disk. Elsewhere it is surrounded by the sharply delineated exocoelomic membrane. Note the multiple gossamer attachments of the membrane by mesoblastic cells to the surrounding trophoblast from which it originally arose. Carnegie {{CE7699}}, 8-5-3, X100.


served. Thus the yolk-sac appears to begin
its development about the time the exocoelomic membrane has reached its zenith and is degenerating. For fuller discussion of


this problem and the details of the membrane’s development see Hertig’s (11) recent paper.
For the purposes of this review the development and involution of the exocoelomic membrane may be treated very briefly. The first appearance of this structure is in ova of approximately 8 days of age or in their 9th day of development. Such a specimen is seen in Figure 1. It contains a thin, irregular and in places imperfect membrane within the central cavity (chorionic) of the ovum. Most of the cavity is occupied by the embryonic disk but to the edge of the latter is attached the exocoelomic membrane. It arises from primitive mesoblastic or mesenchymal cells which in turn delaminate in situ from the adjacent cytotrophoblast of the chorion. As the individual mesoblastic cells continue to differentiate, the older ones join with their fellows to form a membrane-like structure. This process tends to separate the central portion of the chorionic cavity—now called the exocoelom—from the remainder of the cavity. Since the exocoelomic membrane is never entirely perfect, the two portions of the cavity intercommunicate—especially in the earlier phases of the membrane’s existence.


For the purposes of this review the development and involution of the exocoelomic membrane may be treated very
briefly. The first appearance of this structure is in ova of approximately 8 days of age
or in their 9th day of development. Such a
specimen is seen in Figure 1. It contains a
thin, irregular and in places imperfect membrane within the central cavity (chorionic)
of the ovum. Most of the cavity is occupied
by the embryonic disk but to the edge of
the latter is attached the exocoelomic membrane. It arises from primitive mesoblastic
or mesenchymal cells which in turn delaminate in situ from the adjacent cytotrophoblast of the chorion. As the individual
mesoblastic cells continue to differentiate,
the older ones join with their fellows to
form a membrane-like structure. This
process tends to separate the central portion of the chorionic cavity——now called the
exocoelom—from the remainder of the cavity. Since the exocoelomic membrane is
never entirely perfect, the two portions of
the cavity intercommunicate—especially in
-the earlier phases of the membrane’s existence.


Figures 2 and 3, of an 11- and a 12-day
Figures 2 and 3, of an 11- and a 12-day human ovum respectively, show later and more readily recognized stages in the development of the exocoelomic membrane.
human ovum respectively, show later and more readily recognized stages in the de-velopment of the exocoelomic membrane.


These specimens have previously been described by Hertig and Rock (8). In the
eleven day stage the membrane is well developed and sharply delimits the exocoelom from the surrounding chorionic cavity although the former is relatively small
as compared to the latter. Even in this
early stage of development, however, there
appears to be a stainable difi"erence between the fluid in the exocoelom and that
in the intercellular spaces of the chorionic
mesoblast. Thus, the fluid within the exo


FIG. 3. A human ovum of approximately 12 days
These specimens have previously been described by Hertig and Rock (8). In the eleven day stage the membrane is well developed and sharply delimits the exocoelom from the surrounding chorionic cavity although the former is relatively small as compared to the latter. Even in this early stage of development, however, there appears to be a stainable difi"erence between the fluid in the exocoelom and that in the intercellular spaces of the chorionic mesoblast. Thus, the fluid within the exocoelom stains more darkly and with fewer precipitated granules—presumably of protein—than does the fluid outside. Whether this bespeaks a difference in function of the two fluids or not is impossible to say. However, the exocoelom is much more intimately associated with the embryonic disk—being bounded by the primitive entoderm of the latter—so that in all probability the exocoelomic fluid possesses some functional as well as structural significance.
of age. The exocoelom (EX) now fills amost the
entire chorionic cavity although its membranous
envelope is being stretched to near the breaking
point as a consequence of which it is becoming
thinned out and attenuated. This stage precedes
by some hours that of the 13% day ovum seen in
fig. 4 at which stage the exocoelomic membrane has
fragmented. Carnegie 7700, section 6-1-5, X100.


coelom stains more darkly and with fewer
[[File:Hertig1946b fig03.jpg|500px]]
precipitated granules—presumably of protein—than does the fluid outside. Whether
this bespeaks a difference in function of the
two fluids or not is impossible to say. However, the exocoelom is much more intimately associated with the embryonic
disk—being bounded by the primitive entoderm of the latter—so that in all probability the exocoelomic fluid possesses some
functional as well as structural significance.


The peak in the development of the
'''Fig. 3.''' A human ovum of approximately 12 days of age. The exocoelom (EX) now fills amost the entire chorionic cavity although its membranous envelope is being stretched to near the breaking point as a consequence of which it is becoming thinned out and attenuated. This stage precedes by some hours that of the 13% day ovum seen in fig. 4 at which stage the exocoelomic membrane has fragmented. Carnegie {{CE7700}}, section 6-1-5, X100.
exocoelomic membrane is seen in the 12-day
ovum (Figure 3). At this stage, the exocoelom is relatively enormous and occupies
most of the chorionic cavity. There is still a
stainable difference between the fluid within
the exocoelom and that outside. In this respect, the present stage resembles that of
the previous day (Figure 2). The exocoelomic membrane itself, however, begins
to appear thinner and more frayed-out as
though the growth of the ovum had
stretched it nearly to capacity. That this
could be the case is shown by the mesoblastic attachments of the membrane to the
surrounding chorion from which it origi100


FIG. 4. A. A human ovum of approximately 13%
days of age. The hemorrhagic closing cap is seen
above the ovum. The chorion possesses simple unbranched villi. The chorionic cavity contains an
eccentrically situated embryo (see fig. 4B for details of the latter) and the remnants of the exocoelomic membrane (EX. M). The endometrium
shows an early decidual reaction about the'ovum.
The gland below the ovum contains extravasated
blood. Note large sinusoid in the endometrium to
the left of the ovum. Carnegie 7801, section 12-1-1,
X35.


B. Section through embryo of 13% day human
The peak in the development of the exocoelomic membrane is seen in the 12-day ovum (Figure 3). At this stage, the exocoelom is relatively enormous and occupies most of the chorionic cavity. There is still a stainable difference between the fluid within the exocoelom and that outside. In this respect, the present stage resembles that of the previous day (Figure 2). The exocoelomic membrane itself, however, begins to appear thinner and more frayed-out as though the growth of the ovum had stretched it nearly to capacity. That this could be the case is shown by the mesoblastic attachments of the membrane to the surrounding chorion from which it originally arose. Hence, with continued growth of the ovum as a whole, more and more stress is put upon the gossamer exocoelomic membrane. Whatever the mechanical or functional forces are, the wall of the exocoelom soon bursts—a good deal as though it were a tiny balloon whose stress had ex ceeded its strain. Unfortunately, no speci mens are available, either to the author or in the literature, that depict this cataclysm, although the ova showing early yolk-sac development usually contain remnants of the now defunct membrane. An example of this stage in human development is seen in Figure 4, an ovum about 13% days of age or its 14th day of development.<ref>The age of these young specimens is given in terms of developmental or fertilization age rather than menstrual age since the material described up to now was recovered in uteri removed surgically prior to the first missed menstrual period. In older specimens, such as the 23 mm. embryo depicted in Figure 14, the age is expressed in weeks after the last menstrual period. Thus a 21-day ovum, developmental age, is equivalent to an ovum whose menstrual age is 5 weeks or 35 days, since embryonic development does not begin until the 14th day after the last menstrual period at which time ovulation usually occurs.</ref>
ovum. Note the single-layered yolk-sac (YS) to
the left of the embryonic disk and the amniotic
caivity (AC) to the right. Note early connective
tissue in base of simple chorionic villi. The blood
at-the right is within the intervillous space of the
early placenta. Carnegie 7801, section 12-1-3,
X100.


nally arose. Hence, with continued growth
{|
of the ovum as a whole, more and more
| [[File:Hertig1946b fig04a.jpg|400px]]
stress is put upon the gossamer exocoelomic
| [[File:Hertig1946b fig04b.jpg|400px]]
membrane. Whatever the mechanical or
|-
| '''Fig. 4.A.''' A human ovum of approximately 13.5 days of age. The hemorrhagic closing cap is seen above the ovum. The chorion possesses simple unbranched villi. The chorionic cavity contains an eccentrically situated embryo (see fig. 4B for details of the latter) and the remnants of the exocoelomic membrane (EX. M). The endometrium shows an early decidual reaction about the'ovum. The gland below the ovum contains extravasated blood. Note large sinusoid in the endometrium to the left of the ovum. Carnegie {{CE7801}}, section 12-1-1, X35.
| '''Fig. 4.b.'''  Section through embryo of 13.5 day human ovum. Note the single-layered yolk-sac (YS) to the left of the embryonic disk and the amniotic caivity (AC) to the right. Note early connective tissue in base of simple chorionic villi. The blood at-the right is within the intervillous space of the early placenta. Carnegie {{CE7801}}, section 12-1-3, X100.
|}


HERTIG
<br>
Thus does a temporarily useful structure develop, age, and die, all within a life span of 4 or 5 days. That it must perform some physiologic as well as structural function cannot be denied although its exact nature must await further study.


functional forces are, the wall of the exocoelom soon bursts—a good deal as though
==The Yolk-Sac==
it were a tiny balloon whose stress had ex
As indicated in the section on the exocoelomic membrane, the exact time at which the human yolk-sac begins to develop and the manner in which it arises are unknown. That it undoubtedly develops when the ovum is about 13 full days of age, or in its fourteenth day of development, is shown by the fact that it has not yet appeared in the 12-day specimen (Figure 3) although it is a definite entity in the 13%day specimen seen in Figure 4. As noted before, Heuser and Streeter (10) have shown that in the macaque monkey the yolk-sac begins to form in the 12-day stage when the exocoelomic membrane is still a well developed structure. Whether the human exocoelomic membrane, by its disruption, assists in the formation of the yolk-sac or whether it forms in an independent manner, similar to that of the monkey, must await the securing of specimens of the late 13th and early 14th day.
ceeded its strain. Unfortunately, no speci
mens are available, either to the author or
in the literature, that depict this cataclysm,
although the ova showing early yolk-sac
development usually contain remnants of
the now defunct membrane. An example
of this stage in human development is seen
in Figure 4, an ovum about 13% days of age
or its 14th day of development.


Thus does a temporarily useful structure
develop, age, and die, all within a life span


of 4 or 5 days. That it must perform some
The youngest human ovum to show a definitive yolk-sac is the famous specimen described by Linzenmeier (12) in 1914. Although this specimen is neither fixed nor stained as perfectly as some of the more recently acquired human ova, it still shows a tiny, cleft-like yolk-sac continuous with the ventral aspect of the primitive entoderm. Remnants of the exocoelomic membrane are present as they are in older speciments of 14-16 days of age. For a pictorial representation of early yolk-sac development the reader is referred to Hertig and Rock’s (8) paper on the 11~12 day human ova.


physiologic as well as structural function
cannot be denied although its exact nature
must await further study.


THE YoLK-SAC
Figures 4 and 5 represent sections from the only normal specimens containing an early yolk-sac which are available to me for study. Complete descriptions of these ova have recently (1945) appeared in the paper by Heuser, Rock and Hertig (13).


As indicated in the section on the exocoelomic membrane, the exact time at
which the human yolk-sac begins to develop and the manner in which it arises are
unknown. That it undoubtedly develops
when the ovum is about 13 full days of age,
or in its fourteenth day of development,
is shown by the fact that it has not yet appeared in the 12-day specimen (Figure 3)
although it is a definite entity in the 13%day specimen seen in Figure 4. As noted before, Heuser and Streeter (10) have shown
that in the macaque monkey the yolk-sac
begins to form in the 12-day stage when the
exocoelomic membrane is still a well developed structure. Whether the human exocoelomic membrane, by its disruption, assists in the formation of the yolk-sac or
whether it forms in an independent manner, similar to that of the monkey, must
await the securing of specimens of the
late 13th and early 14th day.


The age of these young specimens is given in
The yolk-sac of the 14th day (fig. 4) possesses a single mesothelial layer which in places is beginning to take on added support from the surrounding mesoblast. It resembles the exocoelomic membrane in that it is continuous with the primitive (gut) entoderm of the embryo although it does not possess multiple mesoblastic attachments to the surrounding chorion. This difference in itself would seem to indicate that the yolk-sac is not merely a much-reduced exocoelomic membrane but a new structure entirely.
terms of developmental or fertilization age rather
than menstrual age since the material described up
to now was recovered in uteri removed surgically
prior to the first missed menstrual period. In older
specimens, such as the 23 mm. embryo depicted in
Figure 14, the age is expressed in weeks after the
last menstrual period. Thus a 21-day ovum, developmental age, is equivalent to an ovum whose
menstrual age is 5 weeks or 35 days, since embryonic development does not begin until the 14th
day after the last menstrual period at which time
ovulation usually occurs.




By the 17th day, the yolk-sac has taken on a typical double-layered appearance (fig. 5). This stage, in general, is characterized by a variable degree of blood vessel formation, although angiogenesis in the chorion (placenta) is moderately well advanced by this time. The reader is referred to Hertig’s (14) paper published in 1935 for further details on angiogenesis in the early primate chorion and for a review of the literature on blood vessel formation in the yolk-sac.


The youngest human ovum to show a
{|
definitive yolk-sac is the famous specimen
| [[File:Hertig1946b fig05a.jpg|400px]]
described by Linzenmeier (12) in 1914.
| [[File:Hertig1946b fig05b.jpg|400px]]
Although this specimen is neither fixed nor
|-
| '''Fig. 5.A.''' A human ovum of approximately 16%days of age. The chorionic villi are still simple, unbranched structures. The chorionic cavity contains a normally-situated embryo, the details of which are seen in fig. 5B. No trace of the exocoelomic membrane remains. Carnegie {{CE7802}}, section 44-3-5, X30.
| '''Fig. 5.B.''' Section through embryo of 16%-day human ovum. Note double-layered yolk-sac (YS) above and amniotic cavity (AC) below the embryonic disk. The amnion is lightly attached by mesoblastic tissue to the chorionic membrane whose simple villi are continuous with their trophoblastic cell columns. The latter are continuous with the surrounding endometrium although this feature is not seen in this picture. Carnegie {{CE7802}}, section 44-3-5, X100.
|}
<br>


stained as perfectly as some of the more
By the end of the third week, embryos of 17 to 21 days of age (Figures 6 and 7) possess a very prominent yolk-sac whose ventral wall is studded with small isolated blood islands. These structures are composed of thin, capillary-like structures containing nucleated red blood cells. Such discontinuous vessels are in the process of forming a vascular system by coalescing with those in the embryo proper, its body stalk, and chorion (placenta). The superb picture by the late Max Brodel, drawn for Cullen’s classic work on the umbilicus (15) shows the general features of such embryos (Figure 6). Figure 7, representing a 1.6 mm. embryo from The Carnegie Embryological Collection, shows an actual specimen of this general age. It is probably about 21 days of age and represents the stage of development just before the blood begins to circulate. Reconstructions of the chorionic vascular system at this stage done by Hertig (14) Show that the blood vessel primordia are discontinuous, devoid of blood cells and hence not yet capable of normal circulation.


recently acquired human ova, it still shows
[[File:Hertig1946b fig06.jpg|500px]]
a tiny, cleft-like yolk-sac continuous with
the ventral aspect of the primitive entoderm. Remnants of the exocoelomic membrane are present as they are in older speciments of 14-16 days of age. For a pictorial
representation of early yolk-sac development the reader is referred to Hertig and
Rock’s (8) paper on the 11~12 day human
ova.


Figures 4 and 5 represent sections from
'''Fig. 6.''' A drawing of a 0.7 mm. human embryo, about 17 days of age taken from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company. This figure, depicting the right half of the embryonic mass shows the circulation in the yolksac, embryo, body‘stalk and chorion as anatomically complete although later studies show that such a state does not actually occur until about 3 days later. Note the relatively enormous size of the yolk-sac with respect to the embryo and its amnion. Only the portion of the chorion or outer shell of the ovum near the body stalk is represented, the entire chorion at this stage measuring about 8.0 mm. in diameter.
the only normal specimens containing an
early yolk-sac which are available to me
for study. Complete descriptions of these
ova have recently (1945) appeared in the
paper by Heuser, Rock and Hertig (13).


The yolk-sac of the 14th day (fig. 4) possesses a single mesothelial layer which in
places is beginning to take on added support from the surrounding mesoblast. It resembles the exocoelomic membrane in that
it is continuous with the primitive (gut)
entoderm of the embryo although it does
not possess multiple mesoblastic attachments to the surrounding chorion. This difference in itself would seem to indicate that
the yolk-sac is not merely a much-reduced
exocoelomic membrane but a new structure entirely.


By the 17th day, the yolk-sac has taken
on a typical double-layered appearance
(fig. 5). This stage, in general, is characterized by a variable degree of blood vessel
formation, although angiogenesis in the
chorion (placenta) is moderately well advanced by this time. The reader is referred
to Hertig’s (14) paper published in 1935 for
further details on angiogenesis in the early
primate chorion and for a review of the
literature on blood vessel formation in the
yolk-sac.


{|
| [[File:Hertig1946b fig07a.jpg|400px]]
| [[File:Hertig1946b fig07b.jpg|400px]]
|-
| '''Fig. 7.A.''' A human embryo of approximately 20 - 21 days of age, measuring 1.6 mm in length. Fig. A. represents the chorion embedded within the endometrium and opened in such a way as to reveal the entire embryo when viewed from its left side. The yolk-sac is the most prominent feature of the embryo and is seen as a balloon-like mass whose distal surface is covered with blood islands. The embryonic disk itself together with its amnion is the thickened opaque mass where the embryo is attached to the chorion. See fig. B. for morphologic details of the embryo. Carnegie {{CE7545}}, sequence 7, X5.
| '''Fig. B.''' A cross section through the middle of a 20 - 21 day embryo. Note the enormous size of the yolk-sac containing blood islands Within its doublelayered wall. The embryo proper is the trilaminar mass between the yolk-sac and amniotic cavity and consists, from within outward, of primitive or gut entoderm, mesoderm and ectoderm. A portion of the chorion is seen below. Carnegie {{CE7545}}, section 6-2-2, X60.
|}
<br>


According to Stieve and Strube (16), who studied the yolk-sac circulation by reconstructing two 17-somite embryos, the blood begins to circulate at about this stage of development, since one of their specimens showed a completed vascular system while one did not. Therefore, since Figure 8 represents a 1.7 mm. embryo possessing 7 somites, originally described by Dandy (17), it is clear that this specimen is just on the border line of possessing a functional circulation. Dandy was not able to show an anatomically complete set of blood vessels in the yolk-sac of his specimen,‘although it was complete in the embryo and chorion. It is generally agreed, during this phase of active vascularization of the yolk-sac the latter undergoes a complex process of growth and differentiation which results in a portion of its lining (the true gut entoderm—as contrasted to the yolk-sac entoderm) being transformed into the primitive embryonic gut. This series of events can best be followed in Figures 6-11. Figures 7 and 10, representing actual specimens, are best consulted to see the morphologic difference between gut entoderm, a portion of the original embryonic disk, and yolk-sac entoderm which lines the yolk-sac itself and is formed later.


FIG. 5. A. A human ovum of approximately 16%days of age. The chorionic vil_li are still simple, unbranched structures. The chorionic cavity contains
a normally-situated embryo, the details of which
are seen in fig. 5B. No trace of the exocoelomic
membrane remains. Carnegie 7802, section 44-3-5,


X30.
5 therefore, that in man the circulation begins to function when the embryo possesses from 7 to 17 pairs of somites sometime dur ing its 4th week of development (6th week menstrual age). Several additional examples of this important stage of development are seen in Figures 9—11.


B. Section through embryo of 16%-day human
[[File:Hertig1946b fig08.jpg|500px]]
ovum. Note double-layered yolk-sac (YS) above
and amniotic cavity (AC) below the embryonic
disk. The amnion is lightly attached by mesoblastic
tissue to the chorionic membrane whose simple
villi are continuous with their trophoblastic cell
columns. The latter are continuous with the surrounding endometrium although this feature is not
seen in this picture. Carnegie 7802, section 44-3-5,


X100.
'''Fig. 8.''' A drawing of the right half of a 7 somite (1.7 mm.) embryo of the 4th week of development. At this stage, the blood vessels in the embryo, body stalk and chorion are anatomically complete although not quite so in the yolk-sac. The yolk-sac at its junction with the embryo is beginning to eonstrict and is associated with the invagination of the gut entoderm to form the fore and hind gut. (Fig. 2 from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company.)


By the end of the third week, embryos of
17 to 21 days of age (Figures 6 and 7) possess a very prominent yolk-sac whose ventral wall is studded with small isolated
blood islands. These structures are composed of thin, capillary-like structures containing nucleated red blood cells. Such
discontinuous vessels are in the process of
forming a vascular system by coalescing
with those in the embryo proper, its body stalk, and chorion (placenta). The superb
picture by the late Max Brodel, drawn for
Cullen’s classic work on the umbilicus (15)
shows the general features of such embryos
(Figure 6). Figure 7, representing a 1.6 mm.
embryo from The Carnegie Embryological
Collection, shows an actual specimen of this
general age. It is probably about 21 days
of age and represents the stage of development just before the blood begins to circulate. Reconstructions of the chorionic vascular system at this stage done by Hertig
(14) Show that the blood vessel primordia
are discontinuous, devoid of blood cells and hence not yet capable of normal circulation.


{|
| [[File:Hertig1946b fig09a.jpg|400px]]
| [[File:Hertig1946b fig09b.jpg|400px]]
|-
| '''Fig. 9.A.''' A drawing of the right half of a 2.5 mm embryo representing a stage in the middle of the 4th week of development. The circulation is complete and the heart functions at this stage. Note the constriction of the yolk-sac to form the omphalomesenteric or vitelline duct as the digestive tract becomes more mature. The growth of the embryo and its surrounding amnion have resulted in the partial approximation of the body stalk and the vitelline duct so that these structures are being combined to form an early umbilical cord. (Fig. 3 from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company.)
| '''Fig. 9.b.'''  A 3.2 mm embryo with amnion removed as viewed from below and to the left showing the omphalo-mesenteric duct and its connection with yolk-sac and the primitive embryonic gut. Note the communication between the exocoelomic space around the yolk-sac and the coelom (body cavity) within the embryo. Carnegie {{CE6488}}, sequence 2, X15. 104
|}


<br>
{|
| [[File:Hertig1946b fig10a.jpg|400px]]
| [[File:Hertig1946b fig10b.jpg|400px]]
|-
| '''Fig. 10.A.''' A 3.5 mm. embryo possessing 13 somites and representing the middle part of the fourth week of development. The amnion has been removed so that the approximation of the bodystalk and omphalo-mesenteric duct are less evident than in [[:File:Hertig1946b fig11.jpg|Fig. 11]]. This embryo is apparently a little longer than its developmental age would allow because its natural curvature is less, perhaps from having had the amnion removed. Carnegie {{CE6344}}, sequence 4, X15.
| '''Fig. 10.B.'''  A cross section through approximately the middle of the embryo seen in [[:File:Hertig1946b fig10a.jpg|Fig. A]]. Note the blood islands and vessels in the wall of the yolk-sac and the communication of the latter with the primitive gut of the embryo. The large spaces on either side of the gut are those of the coelom or body-cavity of the embryo. Carnegie {{CE6344}}, section 3-7-11, X75.
|}
<br>


Accompanying the changes which result in the formation of the primitive gut are a series of changes resulting in the growth of the embryo, its assumption of embryonic form and the metamorphosis of the body stalk into a more definitive umbilical cord. The latter results in a gradual restriction and elongation of the connection between the yolk-sac and primitive gut known as the omphalo-mesenteric duct (Figures 9A11). With further "growth of the amnion, the omphalomesenteric duct is gradually incorporated into the early umbilical cord as shown in Figure 11.


FIG. 6. A drawing of a 0.7 mm. human embryo,
[[File:Hertig1946b fig11.jpg|500px]]
about 17 days of age taken from Cullen’s “The
Umbilicus and Its Diseases,” W. B. Saunders Company. This figure, depicting the right half of the
embryonic mass shows the circulation in the yolksac, embryo, body‘stalk and chorion as anatomically complete although later studies show that
such a state does not actually occur until about 3
days later. Note the relatively enormous size of the
yolk-sac with respect to the embryo and its amnion. Only the portion of the chorion or outer
shell of the ovum near the body stalk is represented, the entire chorion at this stage measuring
about 8.0 mm. in diameter.


'''Fig. 11.''' A drawing or a 6.9 mm embryo in its 4th week of development drawn somewhat diagrammatically—to show the further approximation of the omphalo-mesenteric duct and the bodystalk due to the expanding omnion. (Fig. 4 from Cullen’s "The Umbilicus and Its Diseases,” W. B. Saunders Company.) Note that the yolk-sac is now almost as large as the amnion, the former now approaching its period of maximum activity.


FIG. 7. A human embryo of approximately 20-21
days of age, measuring 1.6 mm. in length. Fig. A.
represents the chorion embedded within the endometrium and opened in such a way as to reveal the
entire embryo when viewed from its left side. The
yolk-sac is the most prominent feature of the
embryo and is seen as a balloon-like mass whose
distal surface is covered with blood islands. The
embryonic disk itself together with its amnion is
the thickened opaque mass where the embryo is
attached to the chorion. See fig. B. for morphologic
details of the embryo. Carnegie 7545, sequence 7,


X5.
In embryos of the late 4th, 5th and 6th weeks of development (6th to 8th weeks menstrual age), the yolk-sac is a prominent structure with an active circulation and a prominent epithelial lining. The latter gives rise to tubular and cystic structures which were investigated by Meyer (18) in 1904. These gland-like spaces, best seen in Figure 12 C, begin to appear in embryos of 2-3 mm. and occasionally in younger specimens. However, they are most prominent and are usually present in embryos of 10— 20 mm. (5th and 6th weeks of development), two examples of which are seen in Figures 13 and 14. Their function is not understood but, since they are present during the period when the yolk-sac is largest and most prominently vascularized, one must assume that they possess some function. It is probable that they present a much larger surface area of yolk-sac epithelium to the rich vascular plexus than would the epithelial fining by itself. Whether the secretion of the yolk-sac has any specific function or not is unknown, but it probably does because of this mechanism for in creased absorption during the period of greatest yolk-sac activity.


Fig. B. A cross section through the middle of a
205-21 day embryo. Note the enormous size of the
yolk-sac containing blood islands Within its doublelayered wall. The embryo proper is the trilaminar
mass between the yolk-sac and amniotic cavity and
consists, from within outward, of primitive or gut
entoderm, mesoderm and ectoderm. A portion of
the chorion is seen below. Carnegie 7545, section
6-2-2, X60.


[[File:Hertig1946b fig12.jpg|500px]]


'''Fig. 12.''' A. A drawing of a 5 mm. embryo (late 4th or early 5th week of development) showing further development of the umbilical cord. The yolk-sac is large, well vascularized and its wall contains numerous cystic and tubular spaces derived from the lining epithelium. (Fig. 5 from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company.)


B. A photograph of the yolk-sac of a 6.7 mm. embryo. Carnegie {{CE7522}}, seqtience 9, X8.


According to Stieve and Strube (16),
C. A higher power photograph of the same yolksac as seen in Fig. B. to show the numerous cystic and gland-like spaces in its wall. Carnegie {{CE7522}}, sequence 7, X22.
who studied the yolk-sac circulation by reconstructing two 17-somite embryos, the
<br>
blood begins to circulate at about this
<gallery>
stage of development, since one of their
File:Hertig1946b fig12a.jpg|12A
specimens showed a completed vascular
File:Hertig1946b fig12b.jpg|12B
system while one did not. Therefore, since
File:Hertig1946b fig12c.jpg|12C
Figure 8 represents a 1.7 mm. embryo possessing 7 somites, originally described by
<gallery>
Dandy (17), it is clear that this specimen
<br>
is just on the border line of possessing a
[[File:Hertig1946b fig13.jpg|500px]]
functional circulation. Dandy was not able
to show an anatomically complete set of
blood vessels in the yolk-sac of his specimen,‘although it was complete in the embryo and chorion. It is generally agreed,


'''Fig. 13.''' A drawing of a 10 mm. embryo (5th week of development) showing a more advanced stage in the formation of the umbilical cord and a corresponding attenuation of the stalk of the yolksac. The latter is apparently still an actively functioning structure although the stage is being set for its decline in the immediate future. (Fig. 8 from Cullen's “The Umbilicus and Its Diseases,” W. B. Saunders Company.)




5 therefore, that in man the circulation begins to function when the embryo possesses
After the 8th menstrual week the yolksac gradually becomes less vascular, its epithelium degenerates and its shrinking lumen is filled with granular calcified debris (fig. 15 B). Associated with this process is the gradual stretching and attenuation of its stalk (fig. 15 A). The latter may or may not remain attached to the base of the umbilical cord as is shown in Figure 16 A. Actually at term the tiny, opaque, fiattened body may be anywhere (Figure 16 B) upon the surface of the chorion—even out on the membranous portion thereof. However, since the yolk-sac always lies within the chorionic cavity—even though that space gradually becomes obliterated—it is universally found between the amnion and chorion.
<br>
{|
| [[File:Hertig1946b fig14a.jpg|400px]]
| [[File:Hertig1946b fig14b.jpg|400px]]
|-
| '''Fig. 14.A.''' A drawing of a 23 mm. embryo, late in the 6th week of development (menstrual age 8 weeks), showing its yolk-sac lying between the amnion and chorion. The stalk of the yolk-sac is becoming progressively more attenuated although it still contains functioning blood vessels. (Fig. 11 from Cullen’s "The Umbilicus and Its Diseases,” W. B. Saunders Company.)
| '''Fig. 14.B.''' A section of a yolk-sac whose age is comparable to that shown in fig. A. Note the thick epithelium lining the structure and the congested blood vessels within its walls. B. L-i. H., S-35-835, X 100.
|}


7 from 7 to 17 pairs of somites sometime dur
ing its 4th week of development (6th week
menstrual age). Several additional examples of this important stage of development are seen in Figures 9—11.


During this phase of active vascularization of the yolk-sac the latter undergoes a complex process of growth and differentiation which results in a portion of its lining
Thus passes another temporarily useful fetal organ whose functional life span stretches from the 3rd to perhaps the 8th or 9th week of development. What the exact functions of the yolk-sac are is beside the point; it illustrates the fundamental concept that all tissues begin to age at a variable time after they are formed —some even completing their life cycle before we begin our extra-uterine existence.
(the true gut entoderm—as contrasted to
the yolk-sac entoderm) being transformed into the primitive embryonic gut. This
series of events can best be followed in
Figures 6-11. Figures 7 and 10, representing actual specimens, are best consulted to
see the morphologic difference between gut
entoderm, a portion of the original embryonic disk, and yolk-sac entoderm which
lines the yolk-sac itself and is formed later.


<br>
FIG. 8. A drawing of the right half of a 7 somite
{|
(1.7 mm.) embryo of the 4th week of development. At this stage, the blood vessels in the embryo,
| [[File:Hertig1946b fig15a.jpg|400px]]
body stalk and chorion are anatomically complete
| [[File:Hertig1946b fig15b.jpg|400px]]
although not quite so in the yolk-sac. The yolk-sac
|-
at its junction with the embryo is beginning to
| '''Fig. 15.A.'''  A half-tone drawing, natural size, of a 55 mm. embryo (menstrual age 11% weeks), lying within its amniotic sac. The chorion and uterus have been opened so as to expose the innermost membrane. The degenerating yolk-sac is seen at the right as a vesicle attached to the base of the umbilical cord by an attenuated strand—the yolkstalk. (Fig. 31 from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company.)
eonstrict and is associated with the invagination of
| '''Fig. 15.B.'''  A section of a slightly older yolk-sac (menstrual age 14 weeks) to show the thick avascular fibrous tissue wall and the degenerated epithelial lining. The lumen contains granular or amorphous debris which is undergoing calcification. The over; lying membrane is the amnion. B. L-i. H., S-35649, X60.
the gut entoderm to form the fore and hind gut.
|}
(Fig. 2 from Cullen’s “The Umbilicus and Its
<br>
Diseases,” W. B. Saunders Company.)
[[File:Hertig1946b fig16.jpg|500px]]


'''Fig. 16.''' The yolk-sac at term. A. A drawing, about half-size, of a placenta and a portion of its attached amnion. The yolk-sac, lying between the amnion and chorion, is seen as a pyriform mass attached to the base of the umbilical cord by a thin stalk. (Fig. 32 from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company.)


FIG. 9. A. A drawing of the right half of a 2.5 mm. embryo representing a stage in the middle of the 4th week of development. The circulation is
B. A photograph of a portion of the fetal surface of a normal mature placenta showing the characteristic tiny yellow opaque yolk-sac. The latter may lie anywhere within the obliterated chorionic cavity although it often lies fairly near the umbilical cord as shown in Fig. A. Actually this specimen lay near the margin of the placenta—some distance from the cord’s insertion. B. L-i. H., Pathological Laboratory.
complete and the heart functions at this stage.
Note the constriction of the yolk-sac to form the
omphalomesenteric or vitelline duct as the digestive
tract becomes more mature. The growth of the
embryo and its surrounding amnion have resulted
in the partial approximation of the body stalk and
the vitelline duct so that these structures are being
combined to form an early umbilical cord. (Fig. 3
from Cullen’s “The Umbilicus and Its Diseases,”
W. B. Saunders Company.)


B. A 3.2 mm. embryo with amnion removed as
C. A section of yolk-sac at term showing the {characteristic calcified mass surrounded by dense (fibrous tissue and lying between the amnion ?(above) and the chorion (below). B. L-i. H., E Pathological Laboratory, X60.
viewed from below and to the left showing the
<br>
omphalo-mesenteric duct and its connection with
<gallery>
yolk-sac and the primitive embryonic gut. Note
File:Hertig1946b fig16ab.jpg|16AB
the communication between the exocoelomic space
File:Hertig1946b fig16b.jpg|16B
around the yolk-sac and the coelom (body cavity)
File:Hertig1946b fig16c.jpg|16C
within the embryo. Carnegie 6488, sequence 2,
</gallery>
X15.
<br>
104
[[File:Hertig1946b fig17.jpg|500px]]


FIG. 10. A. A 3.5 mm. embryo possessing 13
'''Fig. 17.''' A. A cytologic drawing of a section from a 30-day human chorionic villus (Fig. 4 from Wislocki and Bennett, American Journal of Anatomy). The thick syncytium is seen covering the actively growing Langhans epithelium..The loose immature connective tissue contains a thin-walled capillary within which are seen fetal blood cells. Note that the erythroblasts are frequently nucleated. Iron hematoxylin, X1600.
somites and representing the middle part of the
fourth week of development. The amnion has been
removed so that the approximation of the bodystalk and omphalo-mesenteric duct are less evident
than in Fig. 11. This embryo is apparently a little
longer than its developmental age would allow
because its natural curvature is less, perhaps from
having had the amnion removed. Carnegie 6344,
sequence 4, X15.


B. A cross section through approximately the
B. A histologic drawing of a mature human chorionic villus (Fig. 17 from Wislocki and Bennett, American Journal of Anatomy). The syncytium is now much thinner, especially overlying the dilated fetal capillaries. Langhans cells are absent in this section although mature villi still contain a few scattered ones. The stroma is dense, the capillaries numerous, the latter containing many non nucleated fetal erythroblasts. Mallory’s connective tissue stain, X1600.
middle of the embryo seen in Fig. A. Note the blood
islands and vessels in the wall of the yolk-sac and
tlfi communication of the latter with the primitive
gut of the embryo. The large spaces on either side
of the gut are those of the coelom or body-cavity of
the embryo. Carnegie 6344, section 3-7-11, X75.
 
 
 
Accompanying the changes which result
in the formation of the primitive gut are a
series of changes resulting in the growth of
the embryo, its assumption of embryonic
form and the metamorphosis of the body
stalk into a more definitive umbilical cord.
The latter results in a gradual restriction
and elongation of the connection between
the yolk-sac and primitive gut known as the
omphalo-mesenteric duct (Figures 9A11).
With further "growth of the amnion, the
omphalomesenteric duct is gradually incorporated into the early umbilical cord as
shown in Figure 11.
 
 
FIG. 11. A drawing or a 6.9 mm. embryo in its
4th week of developmentgdrawn somewhat diagrammatically—to show the further approximation of the omphalo-mesenteric duct and the bodystalk due to the expanding omnion. (Fig. 4 from
Cullen’s "The Umbilicus and Its Diseases,” W. B.
Saunders Company.) Note that the yolk-sac is now
almost as large as the amnion, the former now
approaching its period of maximum activity.
 
 
In embryos of the late 4th, 5th and 6th
weeks of development (6th to 8th weeks
menstrual age), the yolk-sac is a prominent
structure with an active circulation and a
prominent epithelial lining. The latter
gives rise to tubular and cystic structures
which were investigated by Meyer (18) in
1904. These gland-like spaces, best seen in
Figure 12 C, begin to appear in embryos of
 
FIG. 12. A. A drawing of a 5 mm. embryo (late
4th or early 5th week of development) showing
further development of the umbilical cord. The
yolk-sac is large, well vascularized and its wall
contains numerous cystic and tubular spaces
derived from the lining epithelium. (Fig. 5 from
Cullen’s “The Umbilicus and Its Diseases,” W. B.
Saunders Company.)
 
B. A photograph of the yolk-sac of a 6.7 mm.
embryo. Carnegie 7522, seqtience 9, X8.
 
C. A higher power photograph of the same yolksac as seen in Fig. B. to show the numerous cystic
and gland-like spaces in its wall. Carnegie 7522,
sequence 7, X22.
 
 
FIG. 13. A drawing of a 10 mm. embryo (5th
week of development) showing a more advanced
stage in the formation of the umbilical cord and a
corresponding attenuation of the stalk of the yolksac. The latter is apparently still an actively functioning structure although the stage is being set
for its decline in the immediate future. (Fig. 8
from Cullen's “The Umbilicus and Its Diseases,”
W. B. Saunders Company.)
 
2-3 mm. and occasionally in younger specimens. However, they are most prominent
and are usually present in embryos of 10—
20 mm. (5th and 6th weeks of development), two examples of which are seen in
Figures 13 and 14. Their function is not understood but, since they are present during
the period when the yolk-sac is largest and
most prominently vascularized, one must
assume that they possess some function. It
is probable that they present a much
 
larger surface area of yolk-sac epithelium
to the rich vascular plexus than would the
 
epithelial fining by itself. Whether the’
 
secretion of the yolk-sac has any specific
function or not is unknown, but it probably does because of this mechanism for in
creased absorption during the period of
greatest yolk-sac activity.
 
After the 8th menstrual week the yolksac gradually becomes less vascular, its
epithelium degenerates and its shrinking
lumen is filled with granular calcified debris (fig. 15 B). Associated with this process
is the gradual stretching and attenuation
of its stalk (fig. 15 A). The latter may or
may not remain attached to the base of the umbilical cord as is shown in Figure 16 A.
Actually at term the tiny, opaque, fiattened body may be anywhere (Figure 16 B)
upon the surface of the chorion—even out
on the membranous portion thereof. However, since the yolk-sac always lies within
the chorionic cavity—even though that
space gradually becomes obliterated—it is
universally found between the amnion and
chorion.
 
 
 
FIG. 14. A. A drawing of a 23 mm. embryo, late
in the 6th week of development (menstrual age 8
weeks), showing its yolk-sac lying between the
amnion and chorion. The stalk of the yolk-sac is
becoming progressively more attenuated although
it still contains functioning blood vessels. (Fig. 11
from Cullen’s "The Umbilicus and Its Diseases,”
W. B. Saunders Company.)
 
B. A section of a yolk-sac whose age is comparable to that shown in fig. A. Note the thick epithelium lining the structure and the congested
blood vessels within its walls. B. L-i. H., S-35-835,
 
X 100.
 
 
 
 
Thus passes another temporarily useful
fetal organ whose functional life span
stretches from the 3rd to perhaps the 8th
or 9th week of development. What the
exact functions of the yolk-sac are is beside the point; it illustrates the fundamental concept that all tissues begin to age at a variable time after they are formed
—some even completing their life cycle
before we begin our extra-uterine existence.
 
 
 
FIG. 15. A. A half-tone drawing, natural size, of
a 55 mm. embryo (menstrual age 11% weeks), lying
within its amniotic sac. The chorion and uterus
have been opened so as to expose the innermost
membrane. The degenerating yolk-sac is seen at
the right as a vesicle attached to the base of the
umbilical cord by an attenuated strand—the yolkstalk. (Fig. 31 from Cullen’s “The Umbilicus and
Its Diseases,” W. B. Saunders Company.)
 
B. A section of a slightly older yolk-sac (menstrual age 14 weeks) to show the thick avascular
fibrous tissue wall and the degenerated epithelial
lining. The lumen contains granular or amorphous
debris which is undergoing calcification. The over;
lying membrane is the amnion. B. L-i. H., S-35649, X60.
 
 
 
FIG. 16. The yolk-sac at term. A. A drawing,
about half-size, of a placenta and a portion of its
attached amnion. The yolk-sac, lying between the
amnion and chorion, is seen as a pyriform mass
attached to the base of the umbilical cord by a
thin stalk. (Fig. 32 from Cullen’s “The Umbilicus
and Its Diseases,” W. B. Saunders Company.)
 
B. A photograph of a portion of the fetal surface
 
of a normal mature placenta showing the characteristic tiny yellow opaque yolk-sac. The latter may
lie anywhere within the obliterated chorionic
cavity although it often lies fairly near the umbilical
cord as shown in Fig. A. Actually this specimen lay
near the margin of the placenta—some distance
from the cord’s insertion. B. L-i. H., Pathological
Laboratory.
 
C. A section of yolk-sac at term showing the
{characteristic calcified mass surrounded by dense
(fibrous tissue and lying between the amnion
?(above) and the chorion (below). B. L-i. H.,
EPatho1ogica1 Laboratory, X60.


<br>
<gallery>
File:Hertig1946b fig17a.jpg|17A
File:Hertig1946b fig17b.jpg|17B
</gallery>


 
==Physiologic Aging of the Placenta==


FIG. 17. A. A cytologic drawing of a section from
In any discussion of aging in a given tissue or organ, cognizance must necessarily be taken of the morphologic changes associated with normal maturation in the organ. Insofar as possible such changes should be correlated with function. The placenta lends itself to such studies and therefore the morphologic and function changes associated with physiologic aging of the placenta will be briefly considered.
a 30-day human chorionic villus (Fig. 4 from Wislocki and Bennett, American Journal of Anatomy).
The thick syncytium is seen covering the actively
growing Langhans epithelium..The loose immature
connective tissue contains a thin-walled capillary
within which are seen fetal blood cells. Note that
the erythroblasts are frequently nucleated. Iron
hematoxylin, X1600.


B. A histologic drawing of a mature human
[[File:Hertig1946b fig18.jpg|500px]]
chorionic villus (Fig. 17 from Wislocki and Bennett, American Journal of Anatomy). The syncytium is now much thinner, especially overlying the
dilated fetal capillaries. Langhans cells are absent
in this section although mature villi still contain a
few scattered ones. The stroma is dense, the capillaries numerous, the latter containing many non
nucleated fetal erythroblasts. Mallory’s connective tissue stain, X1600.


PHYSIOLOGIC AGING or THE PLACENTA
Fig. 18. Lipoid in the syncytium of human chorionic villi at various stages of development (figs. 9, 10 and 21 from Wislocki and Bennett, American Journal of Anatomy).


In any discussion of aging in a given
A. Villus at 30 days, fixed in Champy’s fluid but.otherwise unstained. Note large black lipoid droplets in the syncytium and their absence in the underlying Langhans cells. A vacuolated Hofbauer in the stroma is seen to the left. X1600.
tissue or organ, cognizance must necessarily
be taken of the morphologic changes associated with normal maturation in the organ.
Insofar as possible such changes should be
correlated with function. The placenta


 
B. Portion of chorionic villus from 13-weeks placenta fixed in Champy’s fluid but unstained. Note thinner syncytium, smaller ljpoid droplets and irregularly arranged Langhans cells. X1600.


FIG. 18. Lipoid in the syncytium of human
C. Villus at term, fixed in Champy’s fluid but unstained, showing-thinned-out syncytium which still contains. lipoid although in. reduced amounts. X 1600.
chorionic villi at various stages of development
(figs. 9, 10 and 21 from Wislocki and Bennett,
American Journal of Anatomy).


A1’, Villus at 30 days, fixed in Champy’s fluid
[[File:Hertig1946b fig19.jpg|500px]]
but.otherwise unstained. Note large black lipoid
droplets in the syncytium and their absence in the
underlying Langhans cells. A vacuolated Hofbauer
in the stroma is seen to the left. X1600.


B. Portion of chorionic villus from 13-weeks
Fig. 19. Syncytium from human placenta at various stages of gestation, stained by the Altmann-Kull method for mitochondria (figs. 13, 14 and 19, from Wislocki and Bennett, American Journal of Anatomy).
placenta fixed in Champy’s fluid but unstained.
Note thinner syncytium, smaller ljpoid droplets
and irregularly arranged Langhans cells. X1600.


C. Villus at term, fixed in Champy’s fluid but
A. Villus from 30-day placenta. Note the large numbers of rod-like mitochondria in the syncytium and the lesser numbers in the Langhans cells. X1600.
unstained, showing-thinned-out syncytium which


FIG. 19. Syncytium from human placenta at
B. Villus from 13-weeks placenta showing the continued abundance of smaller mitochondria in the thinner syncytium. X 1600.
various stages of gestation, stained by the Altmann-Kull method for mitochondria (figs. 13, 14
and 19, from Wislocki and Bennett, American
Journal of Anatomy).


A. Villus from 30-day placenta. Note the large
C. Villus at term showing continued presence of mitochondria even though the syncytium is very thin. Note fuzzy or “stubble-like” border on surface of villus. X1600.
numbers of rod-like mitochondria in the syncytium
and the lesser numbers in the Langhans cells.
X1600.


B. Villus from 13-weeks placenta showing the
continued abundance of smaller mitochondria in
the thinner syncytium. X 1600.


C. Villus at term showing continued presence of
mitochondria even though the syncytium is very
thin. Note fuzzy or “stubble-like” border on surface
of villus. X1600.


still contains. lipoid although in. reduced amounts.
The most recent and complete histologic and cytologic studies on the maturation of the placenta are reported in the classic paper by Wislocki and Bennett (19). They have kindly allowed me to use some of their original illustrations for the purpose of this review (Figures 17—20) .
X 1600,


lends itself to such studies and therefore
the morphologic and function changes associated with physiologic aging of the placenta will be briefly considered.


The most recent and complete histologic
As a generalizing statement, it may be said that as the placenta matures it forms a larger number of smaller and thinnerwalled units, the chorionic villi, by means of which the maternal blood is made more efliciently available to the fetal blood within the placenta. Stated differently, the maturing placenta, in proportion to its volume, presents more of its surface to the maternal blood. These changes are vividly contrasted in Figure 17 which shows the relative thickness of the various layers through which any given substance must go in passing from the maternal to the fetal circulation. Thus in a 30 day placenta (Figure 17 A) a thick layer of syncytium and Langhans epithelium covers a relatively large villus‘ whose capillaries are often at some distance from its surface; whereas at term the villus (Figure 17 B) is much smaller, thinner-walled, more richly vascularized and present in larger numbers.
and cytologic studies on the maturation of
the placenta are reported in the classic
paper by Wislocki and Bennett (19). They
have kindly allowed me to use some of
their original illustrations for the purpose
of this review (Figures 17—20) .


As a generalizing statement, it may be
said that as the placenta matures it forms
a larger number of smaller and thinnerwalled units, the chorionic villi, by means
of which the maternal blood is made more
efliciently available to the fetal blood
within the placenta. Stated differently, the
maturing placenta, in proportion to its
volume, presents more of its surface to the
maternal blood. These changes are vividly
contrasted in Figure 17 which shows the
relative thickness of the various layers
through which any given substance must go
in passing from the maternal to the fetal
circulation. Thus in a 30 day placenta
(Figure 17 A) a thick layer of syncytium
and Langhans epithelium covers a relatively large villus‘ whose capillaries are
often at some distance from its surface;
whereas at term the villus (Figure 17 B) is
much smaller, thinner-walled, more richly
vascularized and present in larger numbers.


Functional studies by Flexner and his
Functional studies by Flexner and his associates on placentas of different animals (20), as well as in the human (21), have borne out this concept of increasing efficiency as term approaches. Thus Flexner and Gellhorn (20) state, “The rate of transfer of sodium per gram of placenta increases in each animal as gestation proceeds until just before term, at which time there is a sharp decrease. The variation in rate of transfer across the placentas has been correlated with morphologic change in the placenta.”
associates on placentas of different animals
(20), as well as in the human (21), have
borne out this concept of increasing efficiency as term approaches. Thus Flexner
and Gellhorn (20) state, “The rate of transfer of sodium per gram of placenta increases
in each animal as gestation proceeds until
just before term, at which time there is a
sharp decrease. The variation in rate of
transfer across the placentas has been correlated with morphologic change in the
placenta.”


As gestation progresses, the syncytial
As gestation progresses, the syncytial covering of the villi becomes thinner and thinner, a fact long observed, although its cytological structure has not been fully studied until Wislocki and Bennett’s work (19). The syncytium throughout pregnancy contains lipoid droplets (Figure 18) although they become smaller and less numerous as this epithelial structure matures. Wislocki and Bennett (19) in their summary state, “The association in syncytium of fat droplets and birefringent substances soluble in acetone, and of acetone-soluble substances capable of reacting with phenylhydrazine to form yellow phenylhydrazones suggests that the syncytium is the site of formation of placental steroid hormones.” The latter include estrogen and progestin. The origin of the chorionic gonadotropic hormone, on the other hand, has been tentatively linked with the placental cytotrophoblast by these authors upon the basis of their own work and a review of the literature.
covering of the villi becomes thinner and
thinner, a fact long observed, although its
cytological structure has not been fully


FIG. 20. Cytotrophoblast from human placenta
[[File:Hertig1946b fig20.jpg|500px]]
(figs. 27, 40 and 42 from Wislocki and Bennett,
American Journal of Anatomy).


A. The cytotrophoblast from a cell column of a
Fig. 20. Cytotrophoblast from human placenta (figs. 27, 40 and 42 from Wislocki and Bennett, American Journal of Anatomy).
30-day placenta. Note close approximation of vacuolated cells with beginning formation of ground
substance between. Iron hematoxylin, X1600.


B. A panchromatic photograph of a colored
A. The cytotrophoblast from a cell column of a 30-day placenta. Note close approximation of vacuolated cells with beginning formation of ground substance between. Iron hematoxylin, X1600.
drawing made from a cell island of a 13-weeks
placenta stained with Azan. The ground substance
(originally blue) occupies most of the intercellular
space but fibrin (originally red) appears as smaller
darker masses throughout this substance. X1600.


C. A panchromatic photograph of a similar cell
B. A panchromatic photograph of a colored drawing made from a cell island of a 13-weeks placenta stained with Azan. The ground substance (originally blue) occupies most of the intercellular space but fibrin (originally red) appears as smaller darker masses throughout this substance. X1600.
island from a 13-weeks placenta also stained with
Azan. Note the lighter, larger homogeneous areas
of fibrin (originally stained red) and the denser
intercellular ground substance (originally stained
blue). X225. '


studied until Wislocki and Bennett’s work
C. A panchromatic photograph of a similar cell island from a 13-weeks placenta also stained with Azan. Note the lighter, larger homogeneous areas of fibrin (originally stained red) and the denser intercellular ground substance (originally stained blue). X225.
(19). The syncytium throughout pregnancy
contains lipoid droplets (Figure 18) although they become smaller and less numerous as this epithelial structure matures.
Wislocki and Bennett (19) in their summary state, “The association in syncytium
110


[[File:Hertig1946b fig21.jpg|500px]]


FIG. 21. Human chorionic villi of various ages
Fig. 21. Human chorionic villi of various ages showing the distribution of gradually increasing amounts of “fibrinoid” as the placenta ages. Note decreasing edema of villous stroma and size of villi as the placenta matures. All villi magnified 100 times.
showing the distribution of gradually increasing
amounts of “fibrinoid” as the placenta ages. Note
decreasing edema of villous stroma and size of villi
as the placenta matures. All villi magnified 100
times.


A. Chorionic membrane and villi of 19-day
A. Chorionic membrane and villi of 19-day ovum. Note the loose connective tissue stroma and double-layered epithelium. “Fibrinoid” is not yet present. Carnegie {{CE5960}}.
ovum. Note the loose connective tissue stroma and
double-layered epithelium. “Fibrinoid” is not yet
present. Carnegie 5960.


B. Chorionic membrane and villi of 11-weeks
B. Chorionic membrane and villi of 11-weeks placenta. Note beginning fibrinoid degeneration of trophoblast in large villus at right. (Figs. B. C. & D. from teaching collection at Free Hospital for Women.)
placenta. Note beginning fibrinoid degeneration of
trophoblast in large villus at right. (Figs. B. C.
& D. from teaching collection at Free Hospital for
Women.)


C. Villi from 16-weeks placenta. Note increasingly prominent dark masses of “fibrinoid” which
C. Villi from 16-weeks placenta. Note increasingly prominent dark masses of “fibrinoid” which project from the surface of villi in the upper portion of th picture.
project from the surface of villi in the upper portion
of th picture.


D.’ illi from term placenta showing the prominent dark masses of “fibrinoid” associated with the
D. Villi from term placenta showing the prominent dark masses of “fibrinoid” associated with the old villous branch running diagonally across the picture.
old villous branch running diagonally across the
picture. '


of fat droplets and birefringent substances
soluble in acetone, and of acetone-soluble
substances capable of reacting with phenylhydrazine to form yellow phenylhydrazones


suggests that the syncytium is the site of
There has been considerable discussion in the literature as to whether the placental barrier is a pure semipermeable membrane or whether the placenta also has selective ability to pass certain substances and retard or reject others. Wislocki and Bennett (19) review the pertinent literature and conclude from that as well as their own work that the placental barrier is “more than a simple semipermeable membrane operating solely by diffusion and osmosis.” In keeping with such a concept is the presence of mitochondria in all stages of syncytial development—even at term (Figure 19) when the syncytium overlying the dilated capillaries has been regarded by Bremer (22) (quoted by Wislocki and Bennett) as being physiologically inert.
formation of placental steroid hormones.”
The latter include estrogen and progestin.
The origin of the chorionic gonadotropic
hormone, on the other hand, has been tentatively linked with the placental cytotrophoblast by these authors upon the basis of
their own work and a review of the literature.


There has been considerable discussion
in the literature as to whether the placental
barrier is a pure semipermeable membrane
or whether the placenta also has selective
ability to pass certain substances and retard or reject others. Wislocki and Bennett (19) review the pertinent literature
and conclude from that as well as their own
work that the placental barrier is “more
than a simple semipermeable membrane
operating solely by diffusion and osmosis.”
In keeping with such a concept is the presence of mitochondria in all stages of syncytial development—even at term (Figure
19) when the syncytium overlying the
dilated capillaries has been regarded by
Bremer (22) (quoted by Wislocki and
Bennett) as being physiologically inert.


As the cytotrophoblast“ of the placenta
As the cytotrophoblast<ref>The cytotrophoblast is the germinal bed of chorionic epithelium from which develops the syncytium, connective tissue, blood vessels and amnion. It is represented at different stages of placental development by: the inner epithelial shell of pre-villous ova (Hertig, 8), the Langhan’s epithelium, cell columns and trophoblastic shell of early placentas and the cell columns, cell islands and trophoblastic shell of maturing placentas.</ref> of the placenta matures, certain invariable changes take place with the resultant formation of various amounts of "fibrinoid,” or ground substance and fibrin. Wislocki and Bennett (19) have discussed these changes fully, pertinentstages of which are seen in Figure 20. These authors believe that, “this ground substance is a protein-containing fluid of mixed origins, derived mainly from the decidua and maternal blood stream, but also substances released by the cellular trophoblast. This ground substance contains no argyrophile or collagenous fibers. Fibrin becomes variously deposited in it.”
matures, certain invariable changes take
place with the resultant formation of various amounts of "fibrinoid,” or ground substance and fibrin. Wislocki and Bennett
(19) have discussed these changes fully,
pertinentstages of which are seen in Figure
20. These authors believe that, “this ground
substance is a protein-containing fluid of
mixed origins, derived mainly from the
decidua and maternal blood stream, but
also substances released by the cellular
trophoblast. This ground substance contains no argyrophile or collagenous fibers.


“The cytotrophoblast is the germinal bed of
chorionic epithelium from which develops the syncytium, connective tissue, blood vessels and
amnion. It is represented at different stages of
placental development by: the inner epithelial shell
of pre-villous ova (Hertig, 8), the Langhan’s
epithelium, cell columns and trophoblastic shell of
early placentas and the cell columns, cell islands
and trophoblastic shell of maturing placentas.


Fibrin becomes variously deposited in it.
This progressive physiologic aging of the placenta is discussed, not only for its intrinsic importance with respect to placental function but also because of its relation to changes of pathologic significance which will be considered in the closing section of this review.


This progressive physiologic aging of the
==Pathologic Aging in the Placenta==
placenta is discussed, not only for its intrinsic importance with respect to placental function but also because of its relation to changes of pathologic significance
which will be considered in the closing section of this review.


PATHOLOGIC AGING IN THE PLACENTA
As was pointed out in the previous section, the development of “fibrinoid” or ground substance, together with the resultant deposition of fibrin, is a concomitance of physiologic aging of the placental cytotrophoblast. This substance occurs in the various places where such tissue either has been or persists throughout gestation. It occurs, for instance, as focal accumulations beneath the syncytium of older villi such as seen in Figure 21. Such a locus of deposition represents the site at which the Langhans epithelium had been present earlier, only to disappear with maturation of the villus. Hence, “fibrinoid” is usually found along the main villus stems or major branches thereof——the oldest part of the villus—but is much less common in the small terminal branches that continue to form throughout pregnancy.


As was pointed out in the previous section, the development of “fibrinoid” or
ground substance, together with the resultant deposition of fibrin, is a concomitance of physiologic aging of the placental
cytotrophoblast. This substance occurs in
the various places where such tissue either
has been or persists throughout gestation.
It occurs, for instance, as focal accumulations beneath the syncytium of older villi
such as seen in Figure 21. Such a locus of
deposition represents the site at which the
Langhans epithelium had been present
earlier, only to disappear with maturation
of the villus. Hence, “fibrinoid” is usually
found along the main villus stems or major
branches thereof——the oldest part of the
villus—but is much less common in the
small terminal branches that continue to
form throughout pregnancy.


Dempsey and Wislocki (23) have shown
Dempsey and Wislocki (23) have shown that as the placenta ages basophilia of the syncytium decreases whereas its alkaline phosphatase increases (Figure 22). Their studies prove that the basophilia is due to the presence of ribonucleic acid, and that such a substance (considered as a phos phoric ester) could be regarded as a possible substrate for phosphatase. These authors therefore suggested as a possibility, “-that an enzymatic hydrolysis of ribonucleic acid occurs in the syncytial trophoblast and that the decrease in basophilia as pregnancy advances is caused by its more rapid hydrolysis by the increased amount of phosphatase.”
that as the placenta ages basophilia of the
syncytium decreases whereas its alkaline
phosphatase increases (Figure 22). Their
studies prove that the basophilia is due to
the presence of ribonucleic acid, and that


‘such a substance (considered as a phos
phoric ester) could be regarded as a possible
substrate for phosphatase. These authors
therefore suggested as a possibility, “-that
an enzymatic hydrolysis of ribonucleic acid
occurs in the syncytial trophoblast and
that the decrease in basophilia as pregnancy advances is caused by its more rapid
hydrolysis by the increased amount of
phosphatase.”


Dempsey and Wislocki indicate further
Dempsey and Wislocki indicate further that phosphatase may play a subsidiary role in the calcification of certain portions of the placenta (Figure 23). Such areas follow closely the distribution of the “fibrinoid” deposits described above. Since such areas contain phosphatase as well as glycogen—the latter a readily available source for the production of glyco-phosphoric esters serving as a substrate for phosphatase in the calcifying process (Harris, 24) quoted — by Dempsey and Wislocki)—the basis is laid for calcification of placental “fibrinoid.”
that phosphatase may play a subsidiary
role in the calcification of certain portions
of the placenta (Figure 23). Such areas fol


[[File:Hertig1946b fig22.jpg|500px]]


 
Fig. 22. Chorionic villi from human placentas of various ages to show increasing amounts of alkaline phosphatase in the syncytium as the organ matures. (Figs. 10, 11 and 12 from Dempsey and Wislocki, American Journal of Anatomy.) All villi magnified 235 diameters.
 
FIG. 22. Chorionic villi from human placentas of
various ages to show increasing amounts of alkaline phosphatase in the syncytium as the organ
matures. (Figs. 10, 11 and 12 from Dempsey and
Wislocki, American Journal of Anatomy.) All villi
magnified 235 diameters.


A. Villi of 8 weeks. Note localization of phosphatase to outer portion of syncytium.
A. Villi of 8 weeks. Note localization of phosphatase to outer portion of syncytium.


B. Villi of 16 weeks. Note rather uniform distribution of phosphatase in syncytium although it is
B. Villi of 16 weeks. Note rather uniform distribution of phosphatase in syncytium although it is somewhat more dense in the outer portion of the latter.
somewhat more dense in the outer portion of the
latter.


C. Villi at term. Note that the phosphatase is
C. Villi at term. Note that the phosphatase is localized to the syncytium but tends to assume an inner and outer concentration even within that single layer of tissue.
localized to the syncytium but tends to assume an
inner and outer concentration even within that
single layer of tissue.


low closely the distribution of the “fibrinoid” deposits described above. Since such
[[File:Hertig1946b fig23.jpg|500px]]
areas contain phosphatase as well as glycogen—the latter a readily available source
for the production of glyco-phosphoric esters serving as a substrate for phosphatase


Fig. 23. Calcification in the mature human placenta. Material is from the Boston Lying-in Pathological Laboratory.


FIG. 23. Calcification in the mature human
A. A portion of the maternal surface of a placenta, photographed under water, to show the fine, lace-like pattern of calcification. About half natural size.
placenta. Material is from the Boston Lying-in
Pathological Laboratory.


A. A portion of the maternal surface of a placenta, photographed under water, to show the fine,
B. A photomicrograph of the entire thickness of a placenta to show distribution of dark calcified “fibrinoid” associated with the larger villous stems. Note that the calcification is present throughout the placenta although its presence adjacent to the maternal surface (lower portion in picture) enables it to be seen and felt in the intact specimen as in Fig. A. X5.
lace-like pattern of calcification. About half natural size.


B. A photomicrograph of the entire thickness of
C. A more highly magnified portion of the maternal surface from Fig. B to show the calcified fibrinoid. This picture represents the portion in Fig.3? enclosed in the small rectangle. X60.
a placenta to show distribution of dark calcified
“fibrinoid” associated with the larger villous stems.
Note that the calcification is present throughout
the placenta although its presence adjacent to the
maternal surface (lower portion in picture) enables
it to be seen and felt in the intact specimen as in
Fig. A. X5.


C. A more highly magnified portion of the maternal surface from Fig. B to show the calcified
fibrinoid. This picture represents the portion in
Fig.3?» enclosed in the small rectangle. X60.


in the calcifying process (Harris, 24) quoted — by Dempsey and Wislocki)—the basis is laid for calcification of placental “fibrinoid.”


Calcification is not a constant phenomenon in the placenta although its precursor —“fibronoid”—is always found, ‘albeit in
Calcification is not a constant phenomenon in the placenta although its precursor —“fibronoid”—is always found, ‘albeit in variable but increasing amounts from about the 10th week until term. Since it involves the cytotrophoblast and the older supporting elements of the villus, calcification has no observable effect upon the function of the placenta as the small villi are usually spared.
variable but increasing amounts from
about the 10th week until term. Since it
involves the cytotrophoblast and the older
supporting elements of the villus, calcifica
FIG. 24. A human placenta at term showing
“fibrinoid” degeneration which has resulted in
thrombosis of the intervillous space leading to
infarction of the placenta. B. L-i. H., S-32-7'4.  


A. The edge of a mature placenta—fetal surface
on top and maternal surface on bottom—~showing
a laminated fibrin thrombus which appears to have
been deposited as the result of “fibrinoid” degeneration of villi and trophoblast on maternal surface.
Surrounding the thrombus and spreading out in a
fan- or wedge-shaped area is an area of infarcted
placenta whose blood supply has been cut off by
the thrombosis of the intervillous space. Normal
placental tissue is seen beyond. X5.


B. A higher power detail of rectangular area
[[File:Hertig1946b fig24.jpg|500px]]
seen in A. Note “fibrinoid” degeneration in the
center, thrombus on the right, necrotic villi at top
left and normal villi bottom left. X60.


tion has no observable effect upon the function of the placenta as the small villi are
Fig. 24. A human placenta at term showing “fibrinoid” degeneration which has resulted in thrombosis of the intervillous space leading to infarction of the placenta. B. L-i. H., S-32-7'4.
usually spared.


There are, however, pathological sequelae attendant upon the presence of
A. The edge of a mature placenta—fetal surface on top and maternal surface on bottom—showing a laminated fibrin thrombus which appears to have been deposited as the result of “fibrinoid” degeneration of villi and trophoblast on maternal surface. Surrounding the thrombus and spreading out in a fan- or wedge-shaped area is an area of infarcted placenta whose blood supply has been cut off by the thrombosis of the intervillous space. Normal placental tissue is seen beyond. X5.
“fibrinoid” which is apparently the etiological factor in the breakdown of the overlying syncytium. When this occurs maternal
fibrin is deposited upon the denuded surface resulting in obliteration of that portion
of the intervillous space. This is of frequent
occurrence in term placentas although minimal in amount so thatno observable harm
is done the fetus. If the process is extensive, as it may be on occasion, widespread
infarction‘ of the placenta may occur because the circulation through the intervillous space is impaired. A localized example of this sequence of events is seen in Figure 24.


A variant of this process, usually of no
B. A higher power detail of rectangular area seen in A. Note “fibrinoid” degeneration in the center, thrombus on the right, necrotic villi at top left and normal villi bottom left. X60.
significance to the fetus, is the deposition
of maternal fibrin on the under surfaceof
the chorionic membrane (fig. 25). Such
fibrin plaques are grossly observable as yellow opaque areas of somewhat increased
density on the fetal surface of the placenta.
On rare occasions this fibrin deposition—
really a variety of mural thrombosis—is
progressive and obliterates a significant
portion of the intervillous space leading to
placental infarction and fetal death.


The appearance of cystic foci in the
There are, however, pathological sequelae attendant upon the presence of “fibrinoid” which is apparently the etiological factor in the breakdown of the overlying syncytium. When this occurs maternal fibrin is deposited upon the denuded surface resulting in obliteration of that portion of the intervillous space. This is of frequent occurrence in term placentas although minimal in amount so that no observable harm is done the fetus. If the process is extensive, as it may be on occasion, widespread infarction<ref>Such infarction, it must be emphasized, is not associated with the toxemias of pregnancy whose underlying pathologic anatomy lies in the precapillary arterioles throughout the body. Such involvement of the arteriolar sinusoids of the decidua leads to necrosis of the latter with attendant placental infarction of the toxemic variety. Toxic separation of the placenta is one variety of this pathologic picture.</ref> of the placenta may occur because the circulation through the intervillous space is impaired. A localized example of this sequence of events is seen in Figure 24.
“fibrinoid” of placental cytotrophoblast is
another senile change which may produce
lesions of pathologic significance. The placental septa, between adjacent cotyledons
or lobes of the placenta, are structures
composed of variable amounts of such degenerated trophoblast mixed with maternal
decidua. Large maternal sinusoids drain
the intervillous space of each cotyledon and are often situated at the margin of the
latter in the base of the septum. These
vascular structures have little intrinsic
strength in their own walls but rely upon
the surrounding decidua for their main support. Therefore, if a cystically degenerated
septum becomes further weakened, with.resultant rupture of the sinusoids, a hematoma results and a variety of placental separation follows (Figure 26). (This is an example of so-called “non-toxic” separation
of the placenta because it is based upon a
senile rather than toxemic basis.) With the
disruption of the blood supply to the involved cotyledon, the latter becomes infarcted. It is unusual for this process to become extensive enough to endanger either
the mother or fetus.




* Such infarction, it must be emphasized, is not
A variant of this process, usually of no significance to the fetus, is the deposition of maternal fibrin on the under surfaceof the chorionic membrane (fig. 25). Such fibrin plaques are grossly observable as yellow opaque areas of somewhat increased density on the fetal surface of the placenta. On rare occasions this fibrin deposition— really a variety of mural thrombosis—is progressive and obliterates a significant portion of the intervillous space leading to placental infarction and fetal death.
associated with the toxemias of pregnancy whose
underlying pathologic anatomy lies in the precapillary arterioles throughout the body. Such
involvement of the arteriolar sinusoids of the
decidua leads to necrosis of the latter with attendant
placental infarction of the toxemic variety. Toxic
separation of the placenta is one variety of this
pathologic picture.




FIG. 25. A human placenta at term to show
The appearance of cystic foci in the “fibrinoid” of placental cytotrophoblast is another senile change which may produce lesions of pathologic significance. The placental septa, between adjacent cotyledons or lobes of the placenta, are structures composed of variable amounts of such degenerated trophoblast mixed with maternal decidua. Large maternal sinusoids drain the intervillous space of each cotyledon and are often situated at the margin of the latter in the base of the septum. These vascular structures have little intrinsic strength in their own walls but rely upon the surrounding decidua for their main support. Therefore, if a cystically degenerated septum becomes further weakened, with resultant rupture of the sinusoids, a hematoma results and a variety of placental separation follows (Figure 26). (This is an example of so-called “non-toxic” separation of the placenta because it is based upon a senile rather than toxemic basis.) With the disruption of the blood supply to the involved cotyledon, the latter becomes infarcted. It is unusual for this process to become extensive enough to endanger either the mother or fetus.
diffuse and discrete thrombosis of intervillous
space. B. L.—i. H., S-32-217.


A. Laminated fibrin thrombus deposited on under surface of chorionic membrane at left of picture. Note septum running horizontally between
[[File:Hertig1946b fig25.jpg|500px]]
two adjacent cotyledons, the lower of which is
infarcted due to diffuse and discrete intervillous
thrombosis while the top one is normal. X5.


B. A more highly magnified view of rectangle
'''Fig. 25.''' A human placenta at term to show diffuse and discrete thrombosis of intervillous space. B. L.—i. H., S-32-217.
seen in A. The fibrous tissue of the chorionic membrane is at the top, beneath which is the cytotrophoblast whose “fibrinoid” degeneration has
caused the discrete mass of fibrin to be deposited
from the maternal blood. X60.


A. Laminated fibrin thrombus deposited on under surface of chorionic membrane at left of picture. Note septum running horizontally between two adjacent cotyledons, the lower of which is infarcted due to diffuse and discrete intervillous thrombosis while the top one is normal. X5.


FIG. 26. A human placenta at term to show the
B. A more highly magnified view of rectangle seen in A. The fibrous tissue of the chorionic membrane is at the top, beneath which is the cytotrophoblast whose “fibrinoid” degeneration has caused the discrete mass of fibrin to be deposited from the maternal blood. X60.
cystic degeneration occurring in the “fibrinoid"
of a septum separating two adjacent cotyledons.
B. L.-i. H., S-34-581.


A. A low power view of two cotyledons separated by a cytotrophoblastic septum whose "fibrinoid” has undergone cystic degeneration. The resultant hematoma at the base has disrupted the
<gallery>
blood supply of the cotyledon at the left and caused
Hertig1946b fig25a.jpg|25A
infarction but has spared the one to the right. X5.
Hertig1946b fig25b.jpg|25B
 
</gallery>
B. A higher powered view of the rectangular
<br>
area seen in A. Note degenerated septum with recent hemorrhage below. The villi at the left are
[[File:Hertig1946b fig26.jpg|500px]]
congested and undergoing early necrosis whereas
the ones at the right are normal. X60.
 
 
 
DISCUSSION
 
Having attempted to point out that the
placenta and various accessory portions
thereof show evidence of physiologic and
pathologic aging, it remains only to mention certain pathologic examples of delayed
and accentuated aging in that organ.
 
The disease, erythroblastosis fetalis,5 is
an example of delayed aging of the placenta. Presumably the mechanism by which
this occurs is the continued and abnormal
stimulation of the fetal erythropoietic centers as the result of increased blood destruction. The placenta is a blood-forming organ, and as a result of this urgent need for
fetal red cells the placenta continues, until
term, a function it ordinarily loses in the first trimester. The placenta of a fetus suffering from the severest form of the disease
—universal hydrops—is consequently
large, pale, edematous, and friable with
microscopic evidence of immaturity and
intravascular erythropoiesis (25).


An example of premature aging of the
'''Fig. 26.''' A human placenta at term to show the cystic degeneration occurring in the “fibrinoid" of a septum separating two adjacent cotyledons. B. L.-i. H., S-34-581.
placenta is found in the'hypertensive albuminuric toxemia of pregnancy—eclampsia. Tenny (26) called attention to the
syncytial degeneration which occurs in the
placenta of this disease. Since many of the
involved placentas are actually premature,
these syncytial changes might be considered as premature senility in that portion
of the placenta because the syncytium
tends normally to become thin and degenerate as it matures. In keeping with this
morphologic alteration of syncytium in
the eclamptic placenta are the studies by
Smith and Smith (27) of the hormonal
changes in this diseas . These authors concluded that their “results indicate that this
disease of late pregnancy is closely associated with a progressive deficiency of progestin, a concomitant decrease of estrogen and
a consequent changed metabolism of estrogen involving greater and more rapid
destruction.” It has only to be recalled
that Wislocki and Bennett (19) show the
origin of the steroid hormones (estrogen
and progestin) to be in the syncytium to
appreciate the reason for the relative decrease of these hormones in the toxemic
patient.


A. A low power view of two cotyledons separated by a cytotrophoblastic septum whose "fibrinoid” has undergone cystic degeneration. The resultant hematoma at the base has disrupted the blood supply of the cotyledon at the left and caused infarction but has spared the one to the right. X5.


B. A higher powered view of the rectangular area seen in A. Note degenerated septum with recent hemorrhage below. The villi at the left are congested and undergoing early necrosis whereas the ones at the right are normal. X60.


<gallery>
Hertig1946b fig26a.jpg|26A
Hertig1946b fig26b.jpg|26B
</gallery>


5 This results from the iso-immunization of the
==Discussion==
Rh negative mother by the Rh positive fetal red
cells and the consequent destruction of the latter
by the induced hemolytic antibody in the mother’s
blood.


Having attempted to point out that the placenta and various accessory portions thereof show evidence of physiologic and pathologic aging, it remains only to mention certain pathologic examples of delayed and accentuated aging in that organ.


The disease, erythroblastosis fetalis,<ref>This results from the iso-immunization of the Rh negative mother by the Rh positive fetal red cells and the consequent destruction of the latter by the induced hemolytic antibody in the mother’s blood.</ref> is an example of delayed aging of the placenta. Presumably the mechanism by which this occurs is the continued and abnormal stimulation of the fetal erythropoietic centers as the result of increased blood destruction. The placenta is a blood-forming organ, and as a result of this urgent need for fetal red cells the placenta continues, until term, a function it ordinarily loses in the first trimester. The placenta of a fetus suffering from the severest form of the disease —universal hydrops—is consequently large, pale, edematous, and friable with microscopic evidence of immaturity and intravascular erythropoiesis (25).


An example of premature aging of the placenta is found in the'hypertensive albuminuric toxemia of pregnancy—eclampsia. Tenny (26) called attention to the syncytial degeneration which occurs in the placenta of this disease. Since many of the involved placentas are actually premature, these syncytial changes might be considered as premature senility in that portion of the placenta because the syncytium tends normally to become thin and degenerate as it matures. In keeping with this morphologic alteration of syncytium in the eclamptic placenta are the studies by Smith and Smith (27) of the hormonal changes in this diseas . These authors concluded that their “results indicate that this disease of late pregnancy is closely associated with a progressive deficiency of progestin, a concomitant decrease of estrogen and a consequent changed metabolism of estrogen involving greater and more rapid destruction.” It has only to be recalled that Wislocki and Bennett (19) show the origin of the steroid hormones (estrogen and progestin) to be in the syncytium to appreciate the reason for the relative decrease of these hormones in the toxemic patient.


No discussion of placental aging would
No discussion of placental aging would be complete without some reference to that clinically important condition of postmaturity-the situation in which the patient fails to go into labor at the expected time. Rathbun (28) has recently reviewed the situation at the Boston Lying-in Hospital and finds upon analysis of 250 cases that post-mature fetuses continue to gain weight until the 20th day after the expected date of confinement. After that time they begin to lose weight, suggesting that the postmature placenta may not be as efficient as it once was. Experimental evidence for this is found in the earlier-quoted work of Flexner and Gellhorn (20) who showed that in animals the peak of placental efficiency with respect to the passage of sodium occurred just before term was reached. It is not surprising, in the light of these and other studies, that nature has created in the placenta an organ whose efliciency does not last long beyond the expected onset of labor.
be complete without some reference to that
clinically important condition of postmaturity-the situation in which the patient
fails to go into labor at the expected time.
Rathbun (28) has recently reviewed the
situation at the Boston Lying-in Hospital
and finds upon analysis of 250 cases that
post-mature fetuses continue to gain weight
until the 20th day after the expected date
of confinement. After that time they begin
to lose weight, suggesting that the postmature placenta may not be as efficient
as it once was. Experimental evidence for
this is found in the earlier-quoted work of
Flexner and Gellhorn (20) who showed that
in animals the peak of placental efficiency
with respect to the passage of sodium occurred just before term was reached. It is
not surprising, in the light of these and
other studies, that nature has created in
the placenta an organ whose efliciency does
not last long beyond the expected onset of
labor.


REFERENCES
==Footnotes==
<references/>


1. Streeter, George L., “Development of the Egg
==References==
as seen by the Embryologist,” Scient. Monthly,
32: 495-506, 1931.


2. Flexner, Louis B., “Biochemical Changes Associated with Onset of Secretory Activity in the
1. Streeter, George L., “Development of the Egg as seen by the Embryologist,” Scient. Monthly, 32: 495-506, 1931.
Metanephros of the Fetal Pig,” Anat. Rec.,
73, suppl. 2: 20, 1939.


3. Flexner, Josefa B., Louis B. Flexner and William L. Straus, Jr., “The Oxygen Consumption, Cytochrome and Cytochrome Oxidase
2. Flexner, Louis B., “Biochemical Changes Associated with Onset of Secretory Activity in the Metanephros of the Fetal Pig,” Anat. Rec., 73, suppl. 2: 20, 1939.
Activity and Histological Structure of the
Developing Cerebral Cortex of the Fetal Pig,”
J. Cell & Comp. Physiol., 18: 355-368, 1941.


4. Streeter, George L., “Developmental Horizons
3. Flexner, Josefa B., Louis B. Flexner and William L. Straus, Jr., “The Oxygen Consumption, Cytochrome and Cytochrome Oxidase Activity and Histological Structure of the Developing Cerebral Cortex of the Fetal Pig,” J. Cell & Comp. Physiol., 18: 355-368, 1941.
in Human Embryos, Carnegie Institution of
Washington,” Pub. 557, Contrib. Emb7yol., 31:
27-63, 1945.


5. Heuser, C. H., “An Intrachorionic Mesothelial
4. {{Ref-Streeter1945}}
Membrane in Young Stages of the Monkey


(Macacus Rhesus),” Anat. Rec. 52: suppl.
5. Heuser, C. H., “An Intrachorionic Mesothelial Membrane in Young Stages of the Monkey (Macacus Rhesus),” Anat. Rec. 52: suppl. pp. 15-16, 1932.
pp. 15-16, 1932.


Heuser, Chester H., “Early Development of
6. Heuser, Chester H., “Early Development of the Primitive Mesoblast in Embryos of the Rhesus Monkey,” Carnegie Institution of Washington, Pub. 501, Cooperation in Research: 383-387, 1938.
the Primitive Mesoblast in Embryos of the
Rhesus Monkey,” Carnegie Institution of Washington, Pub. 501, Cooperation in Research:
383-387, 1938.


Stieve, H., “Ein 13% Tage altes, in der Gebarmutter erhaltenes und durch Eingrifi‘ gewonnenes menschliches Ei,” Zeitschr. F. mikr-.
7. Stieve, H., “Ein 13.5 Tage altes, in der Gebarmutter erhaltenes und durch Eingrifi‘ gewonnenes menschliches Ei,” Zeitschr. F. mikr-. anat. Forsch., 7: 295-402, 1926.  
anat. Forsch., 7: 295-402, 1926. Hertig, Arthur T., and John Rock, “Two
Human Ova of the Pre-villous Stage, Having
an Ovulation Age of About Eleven and Twelve
Days Respectively,” Carnegie Institution of
Washington, Pub. 525, Contrib. Embr_yol., 29:
127-156, 1941.


Lewis, Frederic T., “The Minot Pre-somite
8. {{Ref-Hertig1941}}
Embryo and the Herzog Pre-allantoic Embryo
as Elucidating a Still Younger Stage of Human
Developments,” Anat. Rec., 73: suppl. #2, 3637, 1939.


Heuser, Chester H., and George L. Streeter,
9. Lewis, Frederic T., “The Minot Pre-somite Embryo and the Herzog Pre-allantoic Embryo as Elucidating a Still Younger Stage of Human Developments,” Anat. Rec., 73: suppl. #2, 3637, 1939.
“Development of the Macaque Embryo,” Carnegie Institution of Washington, Pub. 525,
Contrib. Embryol., 29: 15-55, 1941.


Hertig, Arthur T., “On the Development of
10. Heuser, Chester H., and George L. Streeter, “Development of the Macaque Embryo,” Carnegie Institution of Washington, Pub. 525, Contrib. Embryol., 29: 15-55, 1941.
the Amnion and Exocoelomic Membrane in the
Pre-villous Human Ovum,” Ferris Lecture,
Delivered May 2, 1945 at Yale University,
Yale J. Biol. & Med. In press.


Linzenmeier, G., “Ein junges menschliches Ei
11. Hertig, Arthur T., “On the Development of the Amnion and Exocoelomic Membrane in the Pre-villous Human Ovum,” Ferris Lecture, Delivered May 2, 1945 at Yale University, Yale J. Biol. & Med. In press.
in situ,” Arch. F. Gynak,. 102: 1-17, 1914.
Heuser, C. H., John Rock, and Arthur T.
Hertig, “Two Human Embryos Showing Early
Stages of the Definitive Yolk Sac,” Carnegie
Institution of Washington,’ Pub. 557, Contrib.
Embryol., 31: 85-99, 1945.


Hertig, Arthur T., “Angiogenesis in the Early
12. Linzenmeier, G., “Ein junges menschliches Ei in situ,” Arch. F. Gynak,. 102: 1-17, 1914.  
Human Chorion and in the Primary Placenta of
the Macaque Monkey,” Carnegie Institution
of Washington, Pub. 459, Contrib. Embryol.,
25: 37-81, 1935.


Cullen, Thomas S., Embryology, Anatomy, and
13. Heuser, C. H., John Rock, and Arthur T. Hertig, “Two Human Embryos Showing Early Stages of the Definitive Yolk Sac,” Carnegie Institution of Washington,’ Pub. 557, Contrib. Embryol., 31: 85-99, 1945.
Diseases of the Umbilicus Together with Diseases
of the Urachus, Philadelphia and London:
Saunders, 1916.


Stieve, H., and I. Strube, “Uber die Entwicklung des Dottersackresilaufes beim Menschen,”
14. Hertig, Arthur T., “Angiogenesis in the Early Human Chorion and in the Primary Placenta of the Macaque Monkey,” Carnegie Institution of Washington, Pub. 459, Contrib. Embryol., 25: 37-81, 1935.
Zeitschr. F. Mikr.-anat. Forsch., 32: 107-175,
1933.
Dandy, Walter E., “A Human Embryo with
Seven Pairs of Somites, Measuring about 2
mm. in length,” Am. J. Anat., 10: 85-108,
1910.


Meyer, Arthur W., “On the Structure of the
15. Cullen, Thomas S., Embryology, Anatomy, and Diseases of the Umbilicus Together with Diseases of the Urachus, Philadelphia and London: Saunders, 1916.
Human Umbilical Vesicle,” Am. J . Anat, 3:
155-166, 1904.


Wislocki, George B. and H. Stanley Bennett,
16. Stieve, H., and I. Strube, “Uber die Entwicklung des Dottersackresilaufes beim Menschen,” Zeitschr. F. Mikr.-anat. Forsch., 32: 107-175, 1933.
“The Histology and Cytology of the Human
116


Monkey Placenta, with Special Reference to
17. Dandy, Walter E., “A Human Embryo with Seven Pairs of Somites, Measuring about 2 mm. in length,” Am. J. Anat., 10: 85-108, 1910.
the Trophoblast,” Am. J. Anat., 73: 335-449,
1943.


20. Flexner, Louis B., and Alfred Gellhorn, “The
18. Meyer, Arthur W., “On the Structure of the Human Umbilical Vesicle,” Am. J . Anat, 3: 155-166, 1904.
Comparative Physiology of Placental Transfer,” Am. J. Obst. & Gynec., 43: 965-974, 1942.


21. Gellhorn, Alfred, Louis B. Flexner, and Louis
19. Wislocki, George B. and H. Stanley Bennett, “The Histology and Cytology of the Human and Monkey Placenta, with Special Reference to the Trophoblast,” Am. J. Anat., 73: 335-449, 1943.
M. Hellman, “The Transfer of Sodium Across
the Human Placenta,” Am. J. Obst. & G_ynec.,
46: 668-672, 1943.


22. Bremer, J. L., “The Interrelations of the Mesonephros, Kidney, and Placenta in Different
20. Flexner, Louis B., and Alfred Gellhorn, “The Comparative Physiology of Placental Transfer,” Am. J. Obst. & Gynec., 43: 965-974, 1942.
Classes of Animals,” Am. J. Anat., 19: 179209, 1916.


23. Dempsey, Edward W., and George B. Wislocki, “Histochemical Reactions Associated
21. Gellhorn, Alfred, Louis B. Flexner, and Louis M. Hellman, “The Transfer of Sodium Across the Human Placenta,” Am. J. Obst. & G_ynec., 46: 668-672, 1943.
with Basophilia and Acidophilia in the Placenta


22. Bremer, J. L., “The Interrelations of the Mesonephros, Kidney, and Placenta in Different Classes of Animals,” Am. J. Anat., 19: 179209, 1916.


HERTIG
23. Dempsey, Edward W., and George B. Wislocki, “Histochemical Reactions Associated with Basophilia and Acidophilia in the Placenta and Pituitary Gland,” Am. J. Anat., 76: 277301, 1945.  
 
and Pituitary Gland,” Am. J. Anat., 76: 277301, 1945. ‘ '


24. Harris, H. A., “Glycogen in Cartilage,” Nature, 130: 996-997, 1932.
24. Harris, H. A., “Glycogen in Cartilage,” Nature, 130: 996-997, 1932.


25. Hellman, Louis M., and Arthur T. Hertig,
25. Hellman, Louis M., and Arthur T. Hertig, “Pathological Changes in the Placenta Associated with Erythroblastosis of the Fetus, Am. J. Path., 14: 111-120, 1938.
“Pathological Changes in the Placenta Associated with Erythroblastosis of the Fetus,
Am. J. Path., 14: 111-120, 1938.
 
26. Tenney, Benjamin, “Syncytial Degeneration
in Normal and Pathological Placentas,” Am.
J. Obst. & G_yrLec., 31: 1024-1028, 1936.
 
27. Smith, George Van S. and O. Watkins Smith.
“Estrogen and Progestin Metabolism in Pregnancy,” J. Clin. Endocrin., 1: 470-476, 1941.
 
28. Rathbun, Lewis S., "An Analysis of 250 Cases
of Postmaturity,” Am. J. Obst. & Gynec., 46:
278-282, 1943.
 
l Submitted for publication November 5, 1945
 
The author’s address is:
 
DR. ARTHUR HERTIG
 
BOSTON LYING-IN HOSPITAL


221 LONGWOOD AVENUE
26. Tenney, Benjamin, “Syncytial Degeneration in Normal and Pathological Placentas,” Am. J. Obst. & G_yrLec., 31: 1024-1028, 1936.


BOSTON 15, MASSACHUSETTS
27. Smith, George Van S. and O. Watkins Smith. “Estrogen and Progestin Metabolism in Pregnancy,” J. Clin. Endocrin., 1: 470-476, 1941.


ABSTRACT
28. Rathbun, Lewis S., "An Analysis of 250 Cases of Postmaturity,” Am. J. Obst. & Gynec., 46: 278-282, 1943.


There are certain organs and tissues which run
a complete life cycle during fetal life. The exocoelomic membrane, for example, is present in the
human ovum from the ninth to the thirteenth day,
reaches a peak at the twelfth day, then rapidly
declines. The yolk sac appears from the twelfth to
the seventeenth day, assumes a definite structure, and by the end of the eighth week begins to degenerate until by the time of birth it is only a tiny
atrophic structure. The placenta, a highly specialized organ, has a function for ten lunar months,
then is discarded at birth. Pathologic aging in the


Submitted for publication November 5, 1945


placenta is observed when certain cytological
changes pass beyond the normal physiological
limits and lead to such phenomena as focal calcification and mural thrombosis of the intervillous
space, hematomas, and infarcts. Such diseases as
erythroblastosis fetalis lead to a continued immaturity of the placenta because of the continued
demand for its function as a blood forming organ.
On the other hand, certain toxemias of pregnancy
acting through the mechanism of premature senility of the placenta lead to deficiency of the steroid
hormone elaborated by this organ.




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Hertig AT. lnvolution of tissues in fetal life: a review. (1946) Anat. Rec. 94: 96-116.

Online Editor 
Mark Hill.jpg
This historic 1946 paper describes early human development in relation to tissues that are lost during development. It includes several of the Carnegie Collection embryos in the figures.


See also:
Hertig AT. and Rock J. Two human ova of the pre-villous stage, having a developmental age of about seven and nine days respectively. (1945) Contrib. Embryol., Carnegie Inst. Wash. Publ. 557, 31: 65-84.

Hertig AT. and Rock J. On a normal human ovum not over 7.5 days of age. (1945) Anat. Rec. 91: 281.

Hertig AT. and Rock J. On a normal ovum of approximately 9 to 10 days of age. (1945) Anat. Rec. 91: 281.

Hertig AT. and Rock J. On a human blastula recovered from the uterine cavity 4 days after ovulation. (1946) J Gerontol. 1(1): 96-117.

Links:

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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

lnvolution of Tissues in Fetal Life - A Review

Arthur T Hertig
Arthur Tremain Hertig (1904-1990)

Dr. Arthur T. Hertig graduated from the University of Minnesota in 1928 and received his M.D. degree from Harvard University in 1930. He has been assistant professor of pathology ‘at the Harvard Medical School since 1941. He is pathologist to the Boston Lying-in Hospital and to the Free Hospital for Women in Brookline. His work has been in pathology with relation to obstetrics and gynecology, and in the embryology and pathology of the early human ovum.

This paper is from the Pathological Laboratories of the Boston Lying-in Hospital, the Free Hospital for Women, Brookline, the Departments of Obstetrics and Pathology, Harvard Medical School, Boston, and the Department of Embryology, Carnegie Institution of Washington, Baltimore.

Introduction

Certain organs and tissues run a complete life cycle during pregnancy, appearing, fulfilling their function, aging, and disappearing within a short but variable period of time. The exocoelomic membrane, for example, is present in the human ovum from the ninth to the thirteenth day, reaches its peak at the twelfth day, then rapidly declines. The yolk sac has fulfilled its imperfectly known purpose by the end of the eighth week, while the placenta has a definite function lunar months, then is discarded at birth. Dr. Hertig discusses the process of aging in these organs and the relation of embryology to gerontology.


Ordinarily one does not associate the field of embryology with that of gerontology since the beginning and ending of life would seem, at first glance, to be diametrically opposed. If, however, one regards the fertilized human ovum as a whole, whose origin begins in the respective gonads of its parents and whose extrauterine life is largely a function of the original vitality with which it is endowed, then it becomes apparent that the problems of embryology and gerontology are more closely correlated. Such a point of View is admirably expressed by the eminent embryologist, George L. Streeter (1) who says, “The importance of quality of the egg, and of course I include both its maternal and paternal elements, is not limited to uterine life. Whether the infant survives its first year depends in considerable part on the original quality of the egg. If they withstand the usual Wear and tear of life until between fifty and sixty years they conform to the actuary’s expectation of life at birth—and to the embryologists’ expectation of the performance of an egg of average quality. It is only the extraordinarily good egg that is still going strong at 80 years, and we see him (or her) do this in the absence of any exquisite hygienic regime or environmental favor.”


Streeter further emphasizes that the total quality of such an egg is made up of the quality of the separate parts or organs and that any one of the latter may wear out or age prematurely and cause the individual’s death While the other organs are still capable of continued function. Thus this author goes on to state, “It is also probable that degenerative diseases of the heart and blood vessels are to be explained as well by the constitution of the germ-plasm with which the individual started life (that is, the inherited vulnerability of his Vascular system) as by the much blamed overwork, overeating, oversmoking and overdrinking, which in other individuals do not result in a comparable damage.”


One might infer from this point of view that the relation of embryology to gerontology lay entirely in the realm of quality of germ-plasm and its effect on the extrauterine life of the individual. That such is not the case is shown by the fact that many fetal organs, or portions thereof, involute or age during intra-uterine life.


Examples of such a process are seen in the development and involution of the pro- and mesonephros, both purely fetal organs, which play a functional role in the development of the embryo. That such a structure probably functions, albeit temporarily, is predicted by Flexner’s (2) biochemical studies on the metanephros, (successor to mesonephros) of the fetal pig. This author concluded that “1) In pre secretory stage, cytochrome oxidase is in low concentration and equally distributed between epithelium and stroma. In secretory stage, oxidase increases markedly in epithelium and disappears from stroma. 2) -In pre-secretory stage, redox potentials of epithelium and stroma are alike. With onset of secretion, the potential of epithelium rises and that of stroma falls so that a difference of 0.230 volt develops between them.” Whether similar studies on the proand mesonephros would show similar results or not is impossible to say, but studies such as the above do correlate biochemical changes with morphologic evidence of maturation and function. These biochemical techniques have also been applied by Flexner, Flexner, and Strauss (3) to the developing cerebral cortex of the fetal pig with results comparable to those obtained on the metanephros.


In discussing this matter with Louis B. ‘Flexner he defined aging as “the sum total of those processes in an individual which lead to death.” Furthermore, if one considers the rate of aging as including the rate at which morphologic, physiologic, and biochemical changes take place, it is apparent from the studies of Flexner and his coworkers that the individual ages most rapidly when he is the youngest, namely, during the embryonic stage.


The intra-embryonic coelomic tract is yet another structure that has a temporary but distinctly functional life span. Likewise, the cells which form the lens vesicle of the eye involute and are extruded once their function has been completed (Streeter, 4). Were it not for this fact, it would be impossible for light to be transmitted through the crystalline substance of the lens. Another temporary but probably functionally useful structure is the neurenteric canal of the late presomite embryo.


Such examples as the above are given merely to indicate that various structures in the embryo itself have a temporary but functional life span. None of these alterations are, however,/a/s striking as the involutionary processes which go on in the placenta and its associated structures—an organ whose entire life cycle takes place during the intra-uterine life of the individual.[1] It is the purpose of this review to describe and, insofar as is possible, to interpret the major involutionary changes that occur in the placenta and some of its associated structures. These will be considered under the following headings: (1) the exocoelomic membrane, (2) the yolk-sac, (3) physiologic aging, and (4) pathologic aging in the placenta.


I wish to acknowledge with gratitude the cooperation of my various colleagues in the preparation of this review: to Drs. George B. Wislocki, H. Stanley Bennett, and Edward W. Dempsey for allowing me to use the original plates of their respective publications some of which are shown in sections 3 and 4, to Drs. George L. Streeter and Louis B. Flexner for helpful discussion and suggestions with respect to aging in the fetal period, and to Chester Reather and Richard W. St. Clair for making some of the pictures here used. I am furthermore greatly indebted to W. B. Saunders Company of Philadelphia and to Dr. Thomas S. Cullen for their permission to reproduce Figures 1, 2, 3, 4, 5, 8, 11, 31 and 32 from the latter author’s book "The Umbilicus and its Diseases.” To Dr. E. J. Farris of the Wistar Institute of Anatomy and Biology I am grateful for permission to reproduce some of the illustrations from the various publications of Wislocki, Bennett and Dempsey (see bibliography for references and figures for specific illustrations used).


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Fig. 1. A human ovum of approximately 8-9 days of age. It is barely implanted within the endometrium, the epithelium of which is attempting to repair the defect in its surface. The thick trophoblastic shell contains lacunae into which flows maternal blood. The central or chorionic cavity contains a globular, bilaminar embryonic disk to which is attached the recently developed exocoelomic membrane. The latter thus surrounds the small irregular exocoelom designated as EX. Carnegie 8215, section 12-5-1, X200.

The Exocoelomic Membrane

One of the most evanescent structures of the developing chorion (placenta) is the thin mesothelium-like membrane which is present in the human ovum from the 9th to the 13th days (Figures 1-3). This membrane lines the chorionic cavity (except where the latter is bounded by the embryonic disk) during this period of development. Conversely it forms the boundary of the exocoelomic cavity—hence its designation as the exocoelomic membrane. Its presence in the developing primate ovum (macaque) was first described by Heuser (5) in 1932 and more fully elaborated by the same author in 1938 (6). Its presence in the developing human ovum was first noted by Stieve (7) in 1926 in describing the “Werner” embryo although that author interpreted the structure as a yolk-sac. Hertig and Rock (8) in 1941 described two previous human ova of about eleven and twelve days of age, both of which showed extensive development of this membranous structure. In that paper, the authors discuss at some length the problem of whether or not this membrane constitutes the early phase of yolk-sac formation. In the opinion of Hertig and Rock it does not although Lewis (9) intimates that embryos of this age should have a large yolk-sac. Actually the human yolk-sac apparently does not begin to develop until late in the thirteenth or early in the fourteenth day as it does in the macaque monkey as shown by Heuser and Streeter (10) although the exact stage or stages in man have not yet been observed. Thus the yolk-sac appears to begin its development about the time the exocoelomic membrane has reached its zenith and is degenerating. For fuller discussion of this problem and the details of the membrane’s development see Hertig’s (11) recent paper.

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Fig. 2. A human ovum of approximately 11 days of age. The endometrial epithelium has superficially repaired the defect made by the implanting ovum. The exocoelom (EX) is now a much more definite space and is bounded below by the primitive entoderm of the bilaminar embryonic disk. Elsewhere it is surrounded by the sharply delineated exocoelomic membrane. Note the multiple gossamer attachments of the membrane by mesoblastic cells to the surrounding trophoblast from which it originally arose. Carnegie 7699, 8-5-3, X100.


For the purposes of this review the development and involution of the exocoelomic membrane may be treated very briefly. The first appearance of this structure is in ova of approximately 8 days of age or in their 9th day of development. Such a specimen is seen in Figure 1. It contains a thin, irregular and in places imperfect membrane within the central cavity (chorionic) of the ovum. Most of the cavity is occupied by the embryonic disk but to the edge of the latter is attached the exocoelomic membrane. It arises from primitive mesoblastic or mesenchymal cells which in turn delaminate in situ from the adjacent cytotrophoblast of the chorion. As the individual mesoblastic cells continue to differentiate, the older ones join with their fellows to form a membrane-like structure. This process tends to separate the central portion of the chorionic cavity—now called the exocoelom—from the remainder of the cavity. Since the exocoelomic membrane is never entirely perfect, the two portions of the cavity intercommunicate—especially in the earlier phases of the membrane’s existence.


Figures 2 and 3, of an 11- and a 12-day human ovum respectively, show later and more readily recognized stages in the development of the exocoelomic membrane.


These specimens have previously been described by Hertig and Rock (8). In the eleven day stage the membrane is well developed and sharply delimits the exocoelom from the surrounding chorionic cavity although the former is relatively small as compared to the latter. Even in this early stage of development, however, there appears to be a stainable difi"erence between the fluid in the exocoelom and that in the intercellular spaces of the chorionic mesoblast. Thus, the fluid within the exocoelom stains more darkly and with fewer precipitated granules—presumably of protein—than does the fluid outside. Whether this bespeaks a difference in function of the two fluids or not is impossible to say. However, the exocoelom is much more intimately associated with the embryonic disk—being bounded by the primitive entoderm of the latter—so that in all probability the exocoelomic fluid possesses some functional as well as structural significance.

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Fig. 3. A human ovum of approximately 12 days of age. The exocoelom (EX) now fills amost the entire chorionic cavity although its membranous envelope is being stretched to near the breaking point as a consequence of which it is becoming thinned out and attenuated. This stage precedes by some hours that of the 13% day ovum seen in fig. 4 at which stage the exocoelomic membrane has fragmented. Carnegie 7700, section 6-1-5, X100.


The peak in the development of the exocoelomic membrane is seen in the 12-day ovum (Figure 3). At this stage, the exocoelom is relatively enormous and occupies most of the chorionic cavity. There is still a stainable difference between the fluid within the exocoelom and that outside. In this respect, the present stage resembles that of the previous day (Figure 2). The exocoelomic membrane itself, however, begins to appear thinner and more frayed-out as though the growth of the ovum had stretched it nearly to capacity. That this could be the case is shown by the mesoblastic attachments of the membrane to the surrounding chorion from which it originally arose. Hence, with continued growth of the ovum as a whole, more and more stress is put upon the gossamer exocoelomic membrane. Whatever the mechanical or functional forces are, the wall of the exocoelom soon bursts—a good deal as though it were a tiny balloon whose stress had ex ceeded its strain. Unfortunately, no speci mens are available, either to the author or in the literature, that depict this cataclysm, although the ova showing early yolk-sac development usually contain remnants of the now defunct membrane. An example of this stage in human development is seen in Figure 4, an ovum about 13% days of age or its 14th day of development.[2]

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Fig. 4.A. A human ovum of approximately 13.5 days of age. The hemorrhagic closing cap is seen above the ovum. The chorion possesses simple unbranched villi. The chorionic cavity contains an eccentrically situated embryo (see fig. 4B for details of the latter) and the remnants of the exocoelomic membrane (EX. M). The endometrium shows an early decidual reaction about the'ovum. The gland below the ovum contains extravasated blood. Note large sinusoid in the endometrium to the left of the ovum. Carnegie 7801, section 12-1-1, X35. Fig. 4.b. Section through embryo of 13.5 day human ovum. Note the single-layered yolk-sac (YS) to the left of the embryonic disk and the amniotic caivity (AC) to the right. Note early connective tissue in base of simple chorionic villi. The blood at-the right is within the intervillous space of the early placenta. Carnegie 7801, section 12-1-3, X100.


Thus does a temporarily useful structure develop, age, and die, all within a life span of 4 or 5 days. That it must perform some physiologic as well as structural function cannot be denied although its exact nature must await further study.

The Yolk-Sac

As indicated in the section on the exocoelomic membrane, the exact time at which the human yolk-sac begins to develop and the manner in which it arises are unknown. That it undoubtedly develops when the ovum is about 13 full days of age, or in its fourteenth day of development, is shown by the fact that it has not yet appeared in the 12-day specimen (Figure 3) although it is a definite entity in the 13%day specimen seen in Figure 4. As noted before, Heuser and Streeter (10) have shown that in the macaque monkey the yolk-sac begins to form in the 12-day stage when the exocoelomic membrane is still a well developed structure. Whether the human exocoelomic membrane, by its disruption, assists in the formation of the yolk-sac or whether it forms in an independent manner, similar to that of the monkey, must await the securing of specimens of the late 13th and early 14th day.


The youngest human ovum to show a definitive yolk-sac is the famous specimen described by Linzenmeier (12) in 1914. Although this specimen is neither fixed nor stained as perfectly as some of the more recently acquired human ova, it still shows a tiny, cleft-like yolk-sac continuous with the ventral aspect of the primitive entoderm. Remnants of the exocoelomic membrane are present as they are in older speciments of 14-16 days of age. For a pictorial representation of early yolk-sac development the reader is referred to Hertig and Rock’s (8) paper on the 11~12 day human ova.


Figures 4 and 5 represent sections from the only normal specimens containing an early yolk-sac which are available to me for study. Complete descriptions of these ova have recently (1945) appeared in the paper by Heuser, Rock and Hertig (13).


The yolk-sac of the 14th day (fig. 4) possesses a single mesothelial layer which in places is beginning to take on added support from the surrounding mesoblast. It resembles the exocoelomic membrane in that it is continuous with the primitive (gut) entoderm of the embryo although it does not possess multiple mesoblastic attachments to the surrounding chorion. This difference in itself would seem to indicate that the yolk-sac is not merely a much-reduced exocoelomic membrane but a new structure entirely.


By the 17th day, the yolk-sac has taken on a typical double-layered appearance (fig. 5). This stage, in general, is characterized by a variable degree of blood vessel formation, although angiogenesis in the chorion (placenta) is moderately well advanced by this time. The reader is referred to Hertig’s (14) paper published in 1935 for further details on angiogenesis in the early primate chorion and for a review of the literature on blood vessel formation in the yolk-sac.

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Fig. 5.A. A human ovum of approximately 16%days of age. The chorionic villi are still simple, unbranched structures. The chorionic cavity contains a normally-situated embryo, the details of which are seen in fig. 5B. No trace of the exocoelomic membrane remains. Carnegie 7802, section 44-3-5, X30. Fig. 5.B. Section through embryo of 16%-day human ovum. Note double-layered yolk-sac (YS) above and amniotic cavity (AC) below the embryonic disk. The amnion is lightly attached by mesoblastic tissue to the chorionic membrane whose simple villi are continuous with their trophoblastic cell columns. The latter are continuous with the surrounding endometrium although this feature is not seen in this picture. Carnegie 7802, section 44-3-5, X100.


By the end of the third week, embryos of 17 to 21 days of age (Figures 6 and 7) possess a very prominent yolk-sac whose ventral wall is studded with small isolated blood islands. These structures are composed of thin, capillary-like structures containing nucleated red blood cells. Such discontinuous vessels are in the process of forming a vascular system by coalescing with those in the embryo proper, its body stalk, and chorion (placenta). The superb picture by the late Max Brodel, drawn for Cullen’s classic work on the umbilicus (15) shows the general features of such embryos (Figure 6). Figure 7, representing a 1.6 mm. embryo from The Carnegie Embryological Collection, shows an actual specimen of this general age. It is probably about 21 days of age and represents the stage of development just before the blood begins to circulate. Reconstructions of the chorionic vascular system at this stage done by Hertig (14) Show that the blood vessel primordia are discontinuous, devoid of blood cells and hence not yet capable of normal circulation.

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Fig. 6. A drawing of a 0.7 mm. human embryo, about 17 days of age taken from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company. This figure, depicting the right half of the embryonic mass shows the circulation in the yolksac, embryo, body‘stalk and chorion as anatomically complete although later studies show that such a state does not actually occur until about 3 days later. Note the relatively enormous size of the yolk-sac with respect to the embryo and its amnion. Only the portion of the chorion or outer shell of the ovum near the body stalk is represented, the entire chorion at this stage measuring about 8.0 mm. in diameter.


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Fig. 7.A. A human embryo of approximately 20 - 21 days of age, measuring 1.6 mm in length. Fig. A. represents the chorion embedded within the endometrium and opened in such a way as to reveal the entire embryo when viewed from its left side. The yolk-sac is the most prominent feature of the embryo and is seen as a balloon-like mass whose distal surface is covered with blood islands. The embryonic disk itself together with its amnion is the thickened opaque mass where the embryo is attached to the chorion. See fig. B. for morphologic details of the embryo. Carnegie 7545, sequence 7, X5. Fig. B. A cross section through the middle of a 20 - 21 day embryo. Note the enormous size of the yolk-sac containing blood islands Within its doublelayered wall. The embryo proper is the trilaminar mass between the yolk-sac and amniotic cavity and consists, from within outward, of primitive or gut entoderm, mesoderm and ectoderm. A portion of the chorion is seen below. Carnegie 7545, section 6-2-2, X60.


According to Stieve and Strube (16), who studied the yolk-sac circulation by reconstructing two 17-somite embryos, the blood begins to circulate at about this stage of development, since one of their specimens showed a completed vascular system while one did not. Therefore, since Figure 8 represents a 1.7 mm. embryo possessing 7 somites, originally described by Dandy (17), it is clear that this specimen is just on the border line of possessing a functional circulation. Dandy was not able to show an anatomically complete set of blood vessels in the yolk-sac of his specimen,‘although it was complete in the embryo and chorion. It is generally agreed, during this phase of active vascularization of the yolk-sac the latter undergoes a complex process of growth and differentiation which results in a portion of its lining (the true gut entoderm—as contrasted to the yolk-sac entoderm) being transformed into the primitive embryonic gut. This series of events can best be followed in Figures 6-11. Figures 7 and 10, representing actual specimens, are best consulted to see the morphologic difference between gut entoderm, a portion of the original embryonic disk, and yolk-sac entoderm which lines the yolk-sac itself and is formed later.


5 therefore, that in man the circulation begins to function when the embryo possesses from 7 to 17 pairs of somites sometime dur ing its 4th week of development (6th week menstrual age). Several additional examples of this important stage of development are seen in Figures 9—11.

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Fig. 8. A drawing of the right half of a 7 somite (1.7 mm.) embryo of the 4th week of development. At this stage, the blood vessels in the embryo, body stalk and chorion are anatomically complete although not quite so in the yolk-sac. The yolk-sac at its junction with the embryo is beginning to eonstrict and is associated with the invagination of the gut entoderm to form the fore and hind gut. (Fig. 2 from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company.)


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Fig. 9.A. A drawing of the right half of a 2.5 mm embryo representing a stage in the middle of the 4th week of development. The circulation is complete and the heart functions at this stage. Note the constriction of the yolk-sac to form the omphalomesenteric or vitelline duct as the digestive tract becomes more mature. The growth of the embryo and its surrounding amnion have resulted in the partial approximation of the body stalk and the vitelline duct so that these structures are being combined to form an early umbilical cord. (Fig. 3 from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company.) Fig. 9.b. A 3.2 mm embryo with amnion removed as viewed from below and to the left showing the omphalo-mesenteric duct and its connection with yolk-sac and the primitive embryonic gut. Note the communication between the exocoelomic space around the yolk-sac and the coelom (body cavity) within the embryo. Carnegie 6488, sequence 2, X15. 104


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Fig. 10.A. A 3.5 mm. embryo possessing 13 somites and representing the middle part of the fourth week of development. The amnion has been removed so that the approximation of the bodystalk and omphalo-mesenteric duct are less evident than in Fig. 11. This embryo is apparently a little longer than its developmental age would allow because its natural curvature is less, perhaps from having had the amnion removed. Carnegie 6344, sequence 4, X15. Fig. 10.B. A cross section through approximately the middle of the embryo seen in Fig. A. Note the blood islands and vessels in the wall of the yolk-sac and the communication of the latter with the primitive gut of the embryo. The large spaces on either side of the gut are those of the coelom or body-cavity of the embryo. Carnegie 6344, section 3-7-11, X75.


Accompanying the changes which result in the formation of the primitive gut are a series of changes resulting in the growth of the embryo, its assumption of embryonic form and the metamorphosis of the body stalk into a more definitive umbilical cord. The latter results in a gradual restriction and elongation of the connection between the yolk-sac and primitive gut known as the omphalo-mesenteric duct (Figures 9A11). With further "growth of the amnion, the omphalomesenteric duct is gradually incorporated into the early umbilical cord as shown in Figure 11.

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Fig. 11. A drawing or a 6.9 mm embryo in its 4th week of development drawn somewhat diagrammatically—to show the further approximation of the omphalo-mesenteric duct and the bodystalk due to the expanding omnion. (Fig. 4 from Cullen’s "The Umbilicus and Its Diseases,” W. B. Saunders Company.) Note that the yolk-sac is now almost as large as the amnion, the former now approaching its period of maximum activity.


In embryos of the late 4th, 5th and 6th weeks of development (6th to 8th weeks menstrual age), the yolk-sac is a prominent structure with an active circulation and a prominent epithelial lining. The latter gives rise to tubular and cystic structures which were investigated by Meyer (18) in 1904. These gland-like spaces, best seen in Figure 12 C, begin to appear in embryos of 2-3 mm. and occasionally in younger specimens. However, they are most prominent and are usually present in embryos of 10— 20 mm. (5th and 6th weeks of development), two examples of which are seen in Figures 13 and 14. Their function is not understood but, since they are present during the period when the yolk-sac is largest and most prominently vascularized, one must assume that they possess some function. It is probable that they present a much larger surface area of yolk-sac epithelium to the rich vascular plexus than would the epithelial fining by itself. Whether the secretion of the yolk-sac has any specific function or not is unknown, but it probably does because of this mechanism for in creased absorption during the period of greatest yolk-sac activity.


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Fig. 12. A. A drawing of a 5 mm. embryo (late 4th or early 5th week of development) showing further development of the umbilical cord. The yolk-sac is large, well vascularized and its wall contains numerous cystic and tubular spaces derived from the lining epithelium. (Fig. 5 from Cullen’s “The Umbilicus and Its Diseases,” W. B. Saunders Company.)

B. A photograph of the yolk-sac of a 6.7 mm. embryo. Carnegie 7522, seqtience 9, X8.

C. A higher power photograph of the same yolksac as seen in Fig. B. to show the numerous cystic and gland-like spaces in its wall. Carnegie 7522, sequence 7, X22.


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Fig. 17. A. A cytologic drawing of a section from a 30-day human chorionic villus (Fig. 4 from Wislocki and Bennett, American Journal of Anatomy). The thick syncytium is seen covering the actively growing Langhans epithelium..The loose immature connective tissue contains a thin-walled capillary within which are seen fetal blood cells. Note that the erythroblasts are frequently nucleated. Iron hematoxylin, X1600.

B. A histologic drawing of a mature human chorionic villus (Fig. 17 from Wislocki and Bennett, American Journal of Anatomy). The syncytium is now much thinner, especially overlying the dilated fetal capillaries. Langhans cells are absent in this section although mature villi still contain a few scattered ones. The stroma is dense, the capillaries numerous, the latter containing many non nucleated fetal erythroblasts. Mallory’s connective tissue stain, X1600.


Physiologic Aging of the Placenta

In any discussion of aging in a given tissue or organ, cognizance must necessarily be taken of the morphologic changes associated with normal maturation in the organ. Insofar as possible such changes should be correlated with function. The placenta lends itself to such studies and therefore the morphologic and function changes associated with physiologic aging of the placenta will be briefly considered.

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Fig. 18. Lipoid in the syncytium of human chorionic villi at various stages of development (figs. 9, 10 and 21 from Wislocki and Bennett, American Journal of Anatomy).

A. Villus at 30 days, fixed in Champy’s fluid but.otherwise unstained. Note large black lipoid droplets in the syncytium and their absence in the underlying Langhans cells. A vacuolated Hofbauer in the stroma is seen to the left. X1600.

B. Portion of chorionic villus from 13-weeks placenta fixed in Champy’s fluid but unstained. Note thinner syncytium, smaller ljpoid droplets and irregularly arranged Langhans cells. X1600.

C. Villus at term, fixed in Champy’s fluid but unstained, showing-thinned-out syncytium which still contains. lipoid although in. reduced amounts. X 1600.

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Fig. 19. Syncytium from human placenta at various stages of gestation, stained by the Altmann-Kull method for mitochondria (figs. 13, 14 and 19, from Wislocki and Bennett, American Journal of Anatomy).

A. Villus from 30-day placenta. Note the large numbers of rod-like mitochondria in the syncytium and the lesser numbers in the Langhans cells. X1600.

B. Villus from 13-weeks placenta showing the continued abundance of smaller mitochondria in the thinner syncytium. X 1600.

C. Villus at term showing continued presence of mitochondria even though the syncytium is very thin. Note fuzzy or “stubble-like” border on surface of villus. X1600.


The most recent and complete histologic and cytologic studies on the maturation of the placenta are reported in the classic paper by Wislocki and Bennett (19). They have kindly allowed me to use some of their original illustrations for the purpose of this review (Figures 17—20) .


As a generalizing statement, it may be said that as the placenta matures it forms a larger number of smaller and thinnerwalled units, the chorionic villi, by means of which the maternal blood is made more efliciently available to the fetal blood within the placenta. Stated differently, the maturing placenta, in proportion to its volume, presents more of its surface to the maternal blood. These changes are vividly contrasted in Figure 17 which shows the relative thickness of the various layers through which any given substance must go in passing from the maternal to the fetal circulation. Thus in a 30 day placenta (Figure 17 A) a thick layer of syncytium and Langhans epithelium covers a relatively large villus‘ whose capillaries are often at some distance from its surface; whereas at term the villus (Figure 17 B) is much smaller, thinner-walled, more richly vascularized and present in larger numbers.


Functional studies by Flexner and his associates on placentas of different animals (20), as well as in the human (21), have borne out this concept of increasing efficiency as term approaches. Thus Flexner and Gellhorn (20) state, “The rate of transfer of sodium per gram of placenta increases in each animal as gestation proceeds until just before term, at which time there is a sharp decrease. The variation in rate of transfer across the placentas has been correlated with morphologic change in the placenta.”

As gestation progresses, the syncytial covering of the villi becomes thinner and thinner, a fact long observed, although its cytological structure has not been fully studied until Wislocki and Bennett’s work (19). The syncytium throughout pregnancy contains lipoid droplets (Figure 18) although they become smaller and less numerous as this epithelial structure matures. Wislocki and Bennett (19) in their summary state, “The association in syncytium of fat droplets and birefringent substances soluble in acetone, and of acetone-soluble substances capable of reacting with phenylhydrazine to form yellow phenylhydrazones suggests that the syncytium is the site of formation of placental steroid hormones.” The latter include estrogen and progestin. The origin of the chorionic gonadotropic hormone, on the other hand, has been tentatively linked with the placental cytotrophoblast by these authors upon the basis of their own work and a review of the literature.

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Fig. 20. Cytotrophoblast from human placenta (figs. 27, 40 and 42 from Wislocki and Bennett, American Journal of Anatomy).

A. The cytotrophoblast from a cell column of a 30-day placenta. Note close approximation of vacuolated cells with beginning formation of ground substance between. Iron hematoxylin, X1600.

B. A panchromatic photograph of a colored drawing made from a cell island of a 13-weeks placenta stained with Azan. The ground substance (originally blue) occupies most of the intercellular space but fibrin (originally red) appears as smaller darker masses throughout this substance. X1600.

C. A panchromatic photograph of a similar cell island from a 13-weeks placenta also stained with Azan. Note the lighter, larger homogeneous areas of fibrin (originally stained red) and the denser intercellular ground substance (originally stained blue). X225.

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Fig. 21. Human chorionic villi of various ages showing the distribution of gradually increasing amounts of “fibrinoid” as the placenta ages. Note decreasing edema of villous stroma and size of villi as the placenta matures. All villi magnified 100 times.

A. Chorionic membrane and villi of 19-day ovum. Note the loose connective tissue stroma and double-layered epithelium. “Fibrinoid” is not yet present. Carnegie 5960.

B. Chorionic membrane and villi of 11-weeks placenta. Note beginning fibrinoid degeneration of trophoblast in large villus at right. (Figs. B. C. & D. from teaching collection at Free Hospital for Women.)

C. Villi from 16-weeks placenta. Note increasingly prominent dark masses of “fibrinoid” which project from the surface of villi in the upper portion of th picture.

D. Villi from term placenta showing the prominent dark masses of “fibrinoid” associated with the old villous branch running diagonally across the picture.


There has been considerable discussion in the literature as to whether the placental barrier is a pure semipermeable membrane or whether the placenta also has selective ability to pass certain substances and retard or reject others. Wislocki and Bennett (19) review the pertinent literature and conclude from that as well as their own work that the placental barrier is “more than a simple semipermeable membrane operating solely by diffusion and osmosis.” In keeping with such a concept is the presence of mitochondria in all stages of syncytial development—even at term (Figure 19) when the syncytium overlying the dilated capillaries has been regarded by Bremer (22) (quoted by Wislocki and Bennett) as being physiologically inert.


As the cytotrophoblast[3] of the placenta matures, certain invariable changes take place with the resultant formation of various amounts of "fibrinoid,” or ground substance and fibrin. Wislocki and Bennett (19) have discussed these changes fully, pertinentstages of which are seen in Figure 20. These authors believe that, “this ground substance is a protein-containing fluid of mixed origins, derived mainly from the decidua and maternal blood stream, but also substances released by the cellular trophoblast. This ground substance contains no argyrophile or collagenous fibers. Fibrin becomes variously deposited in it.”


This progressive physiologic aging of the placenta is discussed, not only for its intrinsic importance with respect to placental function but also because of its relation to changes of pathologic significance which will be considered in the closing section of this review.

Pathologic Aging in the Placenta

As was pointed out in the previous section, the development of “fibrinoid” or ground substance, together with the resultant deposition of fibrin, is a concomitance of physiologic aging of the placental cytotrophoblast. This substance occurs in the various places where such tissue either has been or persists throughout gestation. It occurs, for instance, as focal accumulations beneath the syncytium of older villi such as seen in Figure 21. Such a locus of deposition represents the site at which the Langhans epithelium had been present earlier, only to disappear with maturation of the villus. Hence, “fibrinoid” is usually found along the main villus stems or major branches thereof——the oldest part of the villus—but is much less common in the small terminal branches that continue to form throughout pregnancy.


Dempsey and Wislocki (23) have shown that as the placenta ages basophilia of the syncytium decreases whereas its alkaline phosphatase increases (Figure 22). Their studies prove that the basophilia is due to the presence of ribonucleic acid, and that such a substance (considered as a phos phoric ester) could be regarded as a possible substrate for phosphatase. These authors therefore suggested as a possibility, “-that an enzymatic hydrolysis of ribonucleic acid occurs in the syncytial trophoblast and that the decrease in basophilia as pregnancy advances is caused by its more rapid hydrolysis by the increased amount of phosphatase.”


Dempsey and Wislocki indicate further that phosphatase may play a subsidiary role in the calcification of certain portions of the placenta (Figure 23). Such areas follow closely the distribution of the “fibrinoid” deposits described above. Since such areas contain phosphatase as well as glycogen—the latter a readily available source for the production of glyco-phosphoric esters serving as a substrate for phosphatase in the calcifying process (Harris, 24) quoted — by Dempsey and Wislocki)—the basis is laid for calcification of placental “fibrinoid.”

File:Hertig1946b fig22.jpg

Fig. 22. Chorionic villi from human placentas of various ages to show increasing amounts of alkaline phosphatase in the syncytium as the organ matures. (Figs. 10, 11 and 12 from Dempsey and Wislocki, American Journal of Anatomy.) All villi magnified 235 diameters.

A. Villi of 8 weeks. Note localization of phosphatase to outer portion of syncytium.

B. Villi of 16 weeks. Note rather uniform distribution of phosphatase in syncytium although it is somewhat more dense in the outer portion of the latter.

C. Villi at term. Note that the phosphatase is localized to the syncytium but tends to assume an inner and outer concentration even within that single layer of tissue.

File:Hertig1946b fig23.jpg

Fig. 23. Calcification in the mature human placenta. Material is from the Boston Lying-in Pathological Laboratory.

A. A portion of the maternal surface of a placenta, photographed under water, to show the fine, lace-like pattern of calcification. About half natural size.

B. A photomicrograph of the entire thickness of a placenta to show distribution of dark calcified “fibrinoid” associated with the larger villous stems. Note that the calcification is present throughout the placenta although its presence adjacent to the maternal surface (lower portion in picture) enables it to be seen and felt in the intact specimen as in Fig. A. X5.

C. A more highly magnified portion of the maternal surface from Fig. B to show the calcified fibrinoid. This picture represents the portion in Fig.3? enclosed in the small rectangle. X60.


Calcification is not a constant phenomenon in the placenta although its precursor —“fibronoid”—is always found, ‘albeit in variable but increasing amounts from about the 10th week until term. Since it involves the cytotrophoblast and the older supporting elements of the villus, calcification has no observable effect upon the function of the placenta as the small villi are usually spared.


File:Hertig1946b fig24.jpg

Fig. 24. A human placenta at term showing “fibrinoid” degeneration which has resulted in thrombosis of the intervillous space leading to infarction of the placenta. B. L-i. H., S-32-7'4.

A. The edge of a mature placenta—fetal surface on top and maternal surface on bottom—showing a laminated fibrin thrombus which appears to have been deposited as the result of “fibrinoid” degeneration of villi and trophoblast on maternal surface. Surrounding the thrombus and spreading out in a fan- or wedge-shaped area is an area of infarcted placenta whose blood supply has been cut off by the thrombosis of the intervillous space. Normal placental tissue is seen beyond. X5.

B. A higher power detail of rectangular area seen in A. Note “fibrinoid” degeneration in the center, thrombus on the right, necrotic villi at top left and normal villi bottom left. X60.

There are, however, pathological sequelae attendant upon the presence of “fibrinoid” which is apparently the etiological factor in the breakdown of the overlying syncytium. When this occurs maternal fibrin is deposited upon the denuded surface resulting in obliteration of that portion of the intervillous space. This is of frequent occurrence in term placentas although minimal in amount so that no observable harm is done the fetus. If the process is extensive, as it may be on occasion, widespread infarction[4] of the placenta may occur because the circulation through the intervillous space is impaired. A localized example of this sequence of events is seen in Figure 24.


A variant of this process, usually of no significance to the fetus, is the deposition of maternal fibrin on the under surfaceof the chorionic membrane (fig. 25). Such fibrin plaques are grossly observable as yellow opaque areas of somewhat increased density on the fetal surface of the placenta. On rare occasions this fibrin deposition— really a variety of mural thrombosis—is progressive and obliterates a significant portion of the intervillous space leading to placental infarction and fetal death.


The appearance of cystic foci in the “fibrinoid” of placental cytotrophoblast is another senile change which may produce lesions of pathologic significance. The placental septa, between adjacent cotyledons or lobes of the placenta, are structures composed of variable amounts of such degenerated trophoblast mixed with maternal decidua. Large maternal sinusoids drain the intervillous space of each cotyledon and are often situated at the margin of the latter in the base of the septum. These vascular structures have little intrinsic strength in their own walls but rely upon the surrounding decidua for their main support. Therefore, if a cystically degenerated septum becomes further weakened, with resultant rupture of the sinusoids, a hematoma results and a variety of placental separation follows (Figure 26). (This is an example of so-called “non-toxic” separation of the placenta because it is based upon a senile rather than toxemic basis.) With the disruption of the blood supply to the involved cotyledon, the latter becomes infarcted. It is unusual for this process to become extensive enough to endanger either the mother or fetus.

Hertig1946b fig25.jpg

Fig. 25. A human placenta at term to show diffuse and discrete thrombosis of intervillous space. B. L.—i. H., S-32-217.

A. Laminated fibrin thrombus deposited on under surface of chorionic membrane at left of picture. Note septum running horizontally between two adjacent cotyledons, the lower of which is infarcted due to diffuse and discrete intervillous thrombosis while the top one is normal. X5.

B. A more highly magnified view of rectangle seen in A. The fibrous tissue of the chorionic membrane is at the top, beneath which is the cytotrophoblast whose “fibrinoid” degeneration has caused the discrete mass of fibrin to be deposited from the maternal blood. X60.


Hertig1946b fig26.jpg

Fig. 26. A human placenta at term to show the cystic degeneration occurring in the “fibrinoid" of a septum separating two adjacent cotyledons. B. L.-i. H., S-34-581.

A. A low power view of two cotyledons separated by a cytotrophoblastic septum whose "fibrinoid” has undergone cystic degeneration. The resultant hematoma at the base has disrupted the blood supply of the cotyledon at the left and caused infarction but has spared the one to the right. X5.

B. A higher powered view of the rectangular area seen in A. Note degenerated septum with recent hemorrhage below. The villi at the left are congested and undergoing early necrosis whereas the ones at the right are normal. X60.

Discussion

Having attempted to point out that the placenta and various accessory portions thereof show evidence of physiologic and pathologic aging, it remains only to mention certain pathologic examples of delayed and accentuated aging in that organ.

The disease, erythroblastosis fetalis,[5] is an example of delayed aging of the placenta. Presumably the mechanism by which this occurs is the continued and abnormal stimulation of the fetal erythropoietic centers as the result of increased blood destruction. The placenta is a blood-forming organ, and as a result of this urgent need for fetal red cells the placenta continues, until term, a function it ordinarily loses in the first trimester. The placenta of a fetus suffering from the severest form of the disease —universal hydrops—is consequently large, pale, edematous, and friable with microscopic evidence of immaturity and intravascular erythropoiesis (25).

An example of premature aging of the placenta is found in the'hypertensive albuminuric toxemia of pregnancy—eclampsia. Tenny (26) called attention to the syncytial degeneration which occurs in the placenta of this disease. Since many of the involved placentas are actually premature, these syncytial changes might be considered as premature senility in that portion of the placenta because the syncytium tends normally to become thin and degenerate as it matures. In keeping with this morphologic alteration of syncytium in the eclamptic placenta are the studies by Smith and Smith (27) of the hormonal changes in this diseas . These authors concluded that their “results indicate that this disease of late pregnancy is closely associated with a progressive deficiency of progestin, a concomitant decrease of estrogen and a consequent changed metabolism of estrogen involving greater and more rapid destruction.” It has only to be recalled that Wislocki and Bennett (19) show the origin of the steroid hormones (estrogen and progestin) to be in the syncytium to appreciate the reason for the relative decrease of these hormones in the toxemic patient.

No discussion of placental aging would be complete without some reference to that clinically important condition of postmaturity-the situation in which the patient fails to go into labor at the expected time. Rathbun (28) has recently reviewed the situation at the Boston Lying-in Hospital and finds upon analysis of 250 cases that post-mature fetuses continue to gain weight until the 20th day after the expected date of confinement. After that time they begin to lose weight, suggesting that the postmature placenta may not be as efficient as it once was. Experimental evidence for this is found in the earlier-quoted work of Flexner and Gellhorn (20) who showed that in animals the peak of placental efficiency with respect to the passage of sodium occurred just before term was reached. It is not surprising, in the light of these and other studies, that nature has created in the placenta an organ whose efliciency does not last long beyond the expected onset of labor.

Footnotes

  1. For the benefit of the non-embryologist who may read this, it should be noted that the placenta, or after-birth, is just as much a part of the fertilized ovum as the fetus or baby even though it is a temporary organ and is cast off at birth.
  2. The age of these young specimens is given in terms of developmental or fertilization age rather than menstrual age since the material described up to now was recovered in uteri removed surgically prior to the first missed menstrual period. In older specimens, such as the 23 mm. embryo depicted in Figure 14, the age is expressed in weeks after the last menstrual period. Thus a 21-day ovum, developmental age, is equivalent to an ovum whose menstrual age is 5 weeks or 35 days, since embryonic development does not begin until the 14th day after the last menstrual period at which time ovulation usually occurs.
  3. The cytotrophoblast is the germinal bed of chorionic epithelium from which develops the syncytium, connective tissue, blood vessels and amnion. It is represented at different stages of placental development by: the inner epithelial shell of pre-villous ova (Hertig, 8), the Langhan’s epithelium, cell columns and trophoblastic shell of early placentas and the cell columns, cell islands and trophoblastic shell of maturing placentas.
  4. Such infarction, it must be emphasized, is not associated with the toxemias of pregnancy whose underlying pathologic anatomy lies in the precapillary arterioles throughout the body. Such involvement of the arteriolar sinusoids of the decidua leads to necrosis of the latter with attendant placental infarction of the toxemic variety. Toxic separation of the placenta is one variety of this pathologic picture.
  5. This results from the iso-immunization of the Rh negative mother by the Rh positive fetal red cells and the consequent destruction of the latter by the induced hemolytic antibody in the mother’s blood.

References

1. Streeter, George L., “Development of the Egg as seen by the Embryologist,” Scient. Monthly, 32: 495-506, 1931.

2. Flexner, Louis B., “Biochemical Changes Associated with Onset of Secretory Activity in the Metanephros of the Fetal Pig,” Anat. Rec., 73, suppl. 2: 20, 1939.

3. Flexner, Josefa B., Louis B. Flexner and William L. Straus, Jr., “The Oxygen Consumption, Cytochrome and Cytochrome Oxidase Activity and Histological Structure of the Developing Cerebral Cortex of the Fetal Pig,” J. Cell & Comp. Physiol., 18: 355-368, 1941.

4. Streeter GL. Developmental horizons in human embryos. Description of age group XIII, embryos about 4 or 5 millimeters long, and age group XIV, period of indentation of the lens vesicle. (1945) Carnegie Instn. Wash. Publ. 557, Contrib. Embryol., Carnegie Inst. Wash., 31: 27-63.

5. Heuser, C. H., “An Intrachorionic Mesothelial Membrane in Young Stages of the Monkey (Macacus Rhesus),” Anat. Rec. 52: suppl. pp. 15-16, 1932.

6. Heuser, Chester H., “Early Development of the Primitive Mesoblast in Embryos of the Rhesus Monkey,” Carnegie Institution of Washington, Pub. 501, Cooperation in Research: 383-387, 1938.

7. Stieve, H., “Ein 13.5 Tage altes, in der Gebarmutter erhaltenes und durch Eingrifi‘ gewonnenes menschliches Ei,” Zeitschr. F. mikr-. anat. Forsch., 7: 295-402, 1926.

8. Hertig AT. and Rock J. Two human ova of the pre-villous stage, having an ovulation age of about eleven and twelve days respectively. (1941) Carnegie Instn. Wash. Publ. 525, Contrib. Embryol., 29: 127-156.

9. Lewis, Frederic T., “The Minot Pre-somite Embryo and the Herzog Pre-allantoic Embryo as Elucidating a Still Younger Stage of Human Developments,” Anat. Rec., 73: suppl. #2, 3637, 1939.

10. Heuser, Chester H., and George L. Streeter, “Development of the Macaque Embryo,” Carnegie Institution of Washington, Pub. 525, Contrib. Embryol., 29: 15-55, 1941.

11. Hertig, Arthur T., “On the Development of the Amnion and Exocoelomic Membrane in the Pre-villous Human Ovum,” Ferris Lecture, Delivered May 2, 1945 at Yale University, Yale J. Biol. & Med. In press.

12. Linzenmeier, G., “Ein junges menschliches Ei in situ,” Arch. F. Gynak,. 102: 1-17, 1914.

13. Heuser, C. H., John Rock, and Arthur T. Hertig, “Two Human Embryos Showing Early Stages of the Definitive Yolk Sac,” Carnegie Institution of Washington,’ Pub. 557, Contrib. Embryol., 31: 85-99, 1945.

14. Hertig, Arthur T., “Angiogenesis in the Early Human Chorion and in the Primary Placenta of the Macaque Monkey,” Carnegie Institution of Washington, Pub. 459, Contrib. Embryol., 25: 37-81, 1935.

15. Cullen, Thomas S., Embryology, Anatomy, and Diseases of the Umbilicus Together with Diseases of the Urachus, Philadelphia and London: Saunders, 1916.

16. Stieve, H., and I. Strube, “Uber die Entwicklung des Dottersackresilaufes beim Menschen,” Zeitschr. F. Mikr.-anat. Forsch., 32: 107-175, 1933.

17. Dandy, Walter E., “A Human Embryo with Seven Pairs of Somites, Measuring about 2 mm. in length,” Am. J. Anat., 10: 85-108, 1910.

18. Meyer, Arthur W., “On the Structure of the Human Umbilical Vesicle,” Am. J . Anat, 3: 155-166, 1904.

19. Wislocki, George B. and H. Stanley Bennett, “The Histology and Cytology of the Human and Monkey Placenta, with Special Reference to the Trophoblast,” Am. J. Anat., 73: 335-449, 1943.

20. Flexner, Louis B., and Alfred Gellhorn, “The Comparative Physiology of Placental Transfer,” Am. J. Obst. & Gynec., 43: 965-974, 1942.

21. Gellhorn, Alfred, Louis B. Flexner, and Louis M. Hellman, “The Transfer of Sodium Across the Human Placenta,” Am. J. Obst. & G_ynec., 46: 668-672, 1943.

22. Bremer, J. L., “The Interrelations of the Mesonephros, Kidney, and Placenta in Different Classes of Animals,” Am. J. Anat., 19: 179209, 1916.

23. Dempsey, Edward W., and George B. Wislocki, “Histochemical Reactions Associated with Basophilia and Acidophilia in the Placenta and Pituitary Gland,” Am. J. Anat., 76: 277301, 1945.

24. Harris, H. A., “Glycogen in Cartilage,” Nature, 130: 996-997, 1932.

25. Hellman, Louis M., and Arthur T. Hertig, “Pathological Changes in the Placenta Associated with Erythroblastosis of the Fetus, Am. J. Path., 14: 111-120, 1938.

26. Tenney, Benjamin, “Syncytial Degeneration in Normal and Pathological Placentas,” Am. J. Obst. & G_yrLec., 31: 1024-1028, 1936.

27. Smith, George Van S. and O. Watkins Smith. “Estrogen and Progestin Metabolism in Pregnancy,” J. Clin. Endocrin., 1: 470-476, 1941.

28. Rathbun, Lewis S., "An Analysis of 250 Cases of Postmaturity,” Am. J. Obst. & Gynec., 46: 278-282, 1943.


Submitted for publication November 5, 1945



Cite this page: Hill, M.A. (2024, March 28) Embryology Paper - lnvolution of tissues in fetal life. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_lnvolution_of_tissues_in_fetal_life

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