Paper - The morphogenesis of the mammalian ovary (1913)

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Kingsbury BF. The morphogenesis of the mammalian ovary: Felis domestica. Amer. J Anat. 15(3): 345-387.

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This historic 1913 paper by Kingsbury describes mammalian ovary development in the cat model. Benjamin Freeman Kingsbury (1872-1946) was professor of Anatomy at Cornell University. Best known for his early description of mitochondria, but he also made significant contributions to embryology.


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The Morphogenesis Of The Mammalian Ovary: Felis Domestica

Benjamin Freeman Kingsbury (1872-1946)
Benjamin Freeman Kingsbury (1872-1946)


B. F. Kingsbury

Department of Histology and Embryology, Cornell University

Thirty-Two Figures


It is a striking peculiarity in the development of the reproductive system in man and mammals (not to consider other forms of the Vertebrata) that the duct system (modified in the female) is laid down double, the duct system of the Male disappearing in the Female or persisting as vestigial structures and vice versa, the organs of the female duct system and the mammary gland being vestigial in the male. The embryo in the course of development thus passes through an indifferent period during which the sex cannot be ascertained, followed by the period of sexual differentiation. In the double appearance of the reproductive fundaments development is protandrous — that is, the 'male' system appears earlier than the female — this rule applying also to the differential development of the ovary and the testis as well as the duct system. No fully satisfactory explanation has been given for this double development in the internal reproductive system. Three or four general explanations have been offered for this fundamental law. (1) The primitive vertebrate was hermaphroditic and that even in the higher forms the hermaphroditic tendency persists showing itself in the development of a double system, male and female, even causing the development in the male of a rudimentary mammary gland, in the female of a rudimentary prostate gland — organs which did not extend back in the line of vertebrate descent anywhere near the hypothetical hermaphroditic ancestral form. The occurrence of hermaphroditism among the ascidians and lower vertebrates (that is, Myxine) and the sporadic appearance of a true or false, complete or incomplete, hermaphroditism among the higher forms, up to and inckiding man, is regarded as supporting this contention. On this interpretation the indifferent period would be a potentially bisexual or hermaphroditic period in development. This interpretation is not necessarily opposed to the view that the sex-determining factors are already present in the egg at the time of its fertilization. (2) As a modification of the above view might be mentioned the interpretation that the early mammalian embryo during the indifferent period is truly bisexual, containing the potentialities of either sex whose subsequent determination leads to the arrest, atrophy and more or less complete disappearance of the organs of the opposite sex. These two views are related and also bear on the problem of sex determination whose cytological side is subsequently mentioned and briefly discussed. (3) It has been argued that the reason for the development of the Mullerian duct in the male is due to the fact that it was the original reproductive duct and that the utilization of the excretory duct system in the male as a reproductive duct was a secondary acquirement. This interpretation, supported by Waldeyer and Lenhossek, hardly suffices. The theory would fail to explain the appearance of the rudimentary mammary gland in the male, or the prostate and rete ovarii in the female. (4) The converse of this view might be suggested, namely, that the pronephric duct system (the male duct system) represented the ancestral system in the nephridia in pre-chordate forms, serving not only the nephric system but the reproductive system as well, and conveying both the male and female reproductive cells to the exterior. The shedding of the female reproductive cells into the coelomic cavity from the surface of the gonad and the development of a Mullerian duct in association therewith would thus be a secondary adaption.[1] (5) By no means exclusive of the preceding suggestions as to the meaning of the double character of the reproductive organs, since they deal with a distinct aspect of the problem, should be mentioned the attempts to analyse the mechanism of sex inheritance and development. Upon the cytological side we have the interpretations correlated with the large amount of work being done at the present time upon the determination of sex and the chromosome pattern of the germ cells. This is not the place in which to enter into a discussion of the complicated problem of the cytological basis in the determination of sex. The careful and detailed work on a number of forms, mainly invertebrate and chiefly insects has, as is of course well known, established the existence of an extra chromatin mass (heterochromosome) or chromosome complex whose presence is correlated with the development of the female sex.


Upon the basis of this fact theoretical considerations have led generally to the conclusion that the heterochromosome is the conveyor of 'femaleness', being an embodiment of 'determiners' of the female sexual characters, and that the female is homozj^gous as regards sex characters, the male being heterozygous. The presence of the heterochromosome in the higher vertebrates and its significance in the determination of sex are in a far from satisfactory condition at the present time. In the case of man, Guyer, Guthertz and Winiwarter have described heterochromosomes, but their descriptions do not mutually support one another and hence there is considerable uncertainty as to what the facts may be. Their observations, however, together with those of Jordan on the opossum and bat, Newman and Patterson on the armadillo, Stevens on the guinea pig, Vejowsky on the cat, indicate the presence in the male gametogenesisof an extra chromatin mass (heterochromosome). Jordan, however, states that it is absent in the spermatogenesis of mongoose, cat, squirrel, rabbit and pig. Winiwarter and Sainmont have observed in the oogenesis of the cat a body that they suggest may be a heterochromosome. The morphological basis of fact is therefore still very scant. The statement may be vouchsafed, furthermore, that the correlation of this individual chromatin mass with the development of female sexual characters or even with the determination of the female sex is unproven.


The assumption — to speak in Mendelian terms — that the female is homozygous (homogametic, Wilson; 9 9) as to sex, the male being heterozygous (digametic, Wilson cf), which appears to be the more generally accepted view, does not seem to afford a satisfactory hypothetical basis for the explanation of the double development of the reproductive duct system of higher vertebrates, the prostate and rete ovarii in the female, the mammary gland in the male. Nor does the converse furnish an interpretation much more satisfactory — that the male is homozygous as to sex ( cf cf ), the female being heterozygous { 9 d"). If it is believed to be of advantage to express sex in these terms, in so far as the explanation of the development of the primary sexual characters of vertebrates is concerned, it would seem necessary to consider both male and female heterozygous as to sex, the male characters being or becoming dominant in the male, the female characters recessive, and vice versa, in accordance with the early suggestion of Castle.


The only generalization that can be safely 'drawn, however, from the cytological conditions that have been described would appear to be that in the development of the female sex a greater amount of 'formative material' is required. This is in general accordance with the suggestions of Boveri, Goldschmidt and Wilson, and is supported by the experimental work of R. Hertwig and Kuschakewitsch, Miss King, and Riddle, indicating what has been termed a 'quantitative' rather than a qualitative factor in the determination of sex. It would seem as though on the cytological side little assistance were to be gained from the work upon the 'sex' chromosomes as carriers or determiners of sexual characters. In most of the work upon the 'x, ' 'sex' or heterochromosomes, the point of departure has been the correlation of chromosomes or parts of chromosomes with the appearance in development of definite morphological characters. The problem of the early development in vertebrates of the reproductive organs appears to be closely linked with hermaphroditism in the pattern, which I believe — admittedly by Wilson — presents difficulties from the standpoint of chromosomal sex determination. The problem is, I believe, broader and there is involved the choice between what I have termed a process interpretation and an ultimate particle interpretation of structure. Furthermore there are two aspects that may well be quite distinct so that the problem would be essentially doubled — the determination of sex on the one hand, and the origin and development of the sexual organs on the other.


From whatever point of view the development of the vertebrate reproductive system may be considered, interest must center in the essential organs — the ovary and testis — and the question as to whether or not they, as well as the duct system, exhibit the sexual dimorphism is particularly pertinent. Waldeyer ('70) suggested that the potentialities for the development of both ovary and testis existed in the same individual and that the male and female gonads developed from different portions of the germinal ridge. Van Beneden ( '80) from the conditions in the adult bat advanced the hypothesis that ovary and testis were homologous or at least analogous in their morphology, comparing the medullary cords (cordons pleins) to the tubuli contorti (seminiferentes) the medullar}^ tubes (cordons tubulaires) to the tubuli recti, the reticular body (corps reticule; that is, rete ovarii) to the rete testis (Halleri). Subsequent work on the development of the ovary by Mihalkowics ('85), Janosik ('85) ('88), Coert('90), Allen ( '04), and Winiwarter ( '00) particularly have seemed to justify the suggested homologization. It is the concensus of opinion of these later writers that the medullary cords are developed from the germinal epithelium, and are hence directly pf mesothelial origin, they being early formed and succeeded later by the growths that furnish the functional germ cells of the ovary, the frequently described Pfluger's egg tubes or cords. It should be stated, however, that the older interpretation of the origin of the medullary cords from the Wolffian body, as held by Waldeyer, Balfour, and Braun, is still adhered to by 0. Hertwig ('11) and Tourneux ('09), the latter regarding the tubuli contorti of the testis as developed from the same source, while the former derives them from the germinal epithelium (mesothelium).


The development of the rete ovarii (and the rete testis) seems unquestionably to demand further investigation to determine its mode of origin. Coert ('90), Mihalkowicz ('85), Janosik ('85), Allen ('04), and Felix ('11) have derived it from the mesothelium, while Sainmont ( '05) in his detailed study supports the older view of its origin from the Malpighian corpuscles of the mesonephros.


The most recent study of the development of the mammalian ovary, that of man, by Felix in the Keibel-Mall Handbook of human embryology" leaves undiscussed (apparently purposely) the question of the comparability of the medullary portion of the ovary with the testis, the presentation in the second volume contrasting in this respect with the brief statement in the first volume illustrated by means of an elaborate diagram supporting the testicular homology of the ovarian medulla. Felix, in fact, distinctly rejects this homologization, inferentially at least, by the form in which the development of the gonads in man is described. Briefly stated, in the indifferent stage, the gonad consists of an inner epithelial mass, separated from the covering epithelium by the (primitive) tunica albuginea. In the male this becomes the permanent T. albuginea and the inner epithelial mass speedily resolves itself into the spermatogenic tubules. In the case of the ovary however, the inner epithelial mass becomes again intimately associated with the mesothelial covering of the organ and a new peripheral zone closely blended with and probably derived from the inner epithelial mass becomes developed, termed by Felix the 'neogenic zone.' This is destined to form the definitive cortex of the mature ovary while the central portion of the inner epithelial nucleus or mass undergoes a progressive degeneration toward the periphery. The inner epithelial nucleus therefore furnishes the material for the functional structures in either ovary or testis, differentiation of the former proceeding peripherally, and more slowly whereas in the testis the differentiation is central and early. Any homolog of the seminal tubules of the testis is lacking in the human ovary, according to Felix.


It will be seen that the exposition of the development of the human ovary given by Felix is not in itself contrary to the acceptance of the ovarian medulla-testis homology, — previously mentioned — since the portion of the epithelial nucleus in the indifferent organ that forms the spermatogenic tubules of the male takes no part in the formation destined to furnish the ova and follicle cells of the fully developed ovaiy. The question of the double character of the ovary clearly hinges on the interpretation of the neogenic zone as well as that of the portion underlying it. It is evident however, that in any event the morphological comparison of the medulla of the ovary and the testis is not very close in man.


For the converse of the ovarian-testis homology — the representation of the ovary in the testis — but little has been said. There is nothing in the normal adult testis that can be construed as characteristically ovarian, as this would of necessity lie outside the tunica albuginea. Janosik ('85) has described a late formation of large cells in the surface epithelium of the testis in the human fetus as an attempt to form follicles. Biihler ('06) mentions the occurrence of germ cells in the surface epithelium of fetal testes, as apparently does Coert ('90). It is clear that any proliferative activity in the covering epithelium of the testis after the formation of the germinal cords is on any interpretation very slight.


The present investigation was undertaken to determine the origin of the interstitial cells- of the ovary, so abundant in that organ in the cat. While the monograph upon the development of the ovary of the cat by von Winiwarter and Sainmont ('08) has rendered unnecessary a detailed presentation of many aspects of ovarian morphogenesis in this animal, a somewhat differing interpretation and different point of view appear to justify a brief consideration by me.


The study in so far as presented is a purely morphological one based upon 60 series of sections of ovaries from relatively late fetal to adult life, the periods particularly considered being therefore those of the fetal, post natal, and pre-sexual development. While several methods of fixation and staining were employed, as indicated in the foot-note,^ depending upon what it was desired to bring out, the technique already described (Kingsbury - Published as a separate article.


'11) was found particularly useful because of the easy differentiation of the cells containing lipoid' and so-called 'mitochondria' (representing undoubtedly lipoid in masked form). The morphologieal differentiation obtained by this technique is particularly serviceable. The dark blue interstitial cells and the epithelial structures a lighter blue contrasting strikingly with the golden brown of the stromal tissue and thus permitting them to be readily distinguished without high power examination, while at the same time a good fixation of cytoplasmic and nuclear detail was obtained.


The ovaries upon which the study is based are as given below. Only a portion of the animals were reared in the laboratory, the greater number were procured from householders and hence the data as to age is not as exact as it would otherwise have been. My observations confirm those of Sainmont and v. Winiwarter that there is a large variation in ovaries of the same age. Age is therefore a poor indicator of stage of development, and the seriation may be easily determined from the internal structure of the ovary itself.


NO.


STAGE AND LENGTH


PLANE


FIXER


ST.«N


1


embryo 75 mm.


8m


Flemmings Fl.


iron hematox.



2


embryo 75 mm.


8 m T.


Flemmings Fl.


iron hematox.



.3


fetus 80 mm.


8 fj. Longi.


Flemmings Fl.


iron hematox.



4


fetus 80 mm.


8 M Trans.


Flemmings Fl.


iron hematox.



5


fetus 95 mm.


Trans.


Flemmings Fl.


iron hematox.



6


fetus 95 mm.



Flemmings Fl.


iron hematox.



7


fetus 95 mm.


Trans.


Flemmings Fl.


iron hematox.



8


fetus 95 mm.


Sag.


Flemmings El.


I. H. and Safr.



9


fetus 112 mm.


Long.


Zenker's Fl.


L H.; H. and E



10


3 to 4 day P.P.


Trans.


Zenker's Fl.


L H.



11


3 to 4 day P.P.


Sag.


Zenker's Fl.


I. H.; Safr.



12


6 days P.P.


Sag.


Zenker's Fl.


I. H; H. and E.



13


Ca. 10 davs P.P.


Trans.


Z(?)


H. and E.



14


8 days P.P.


Trans.


Z. + Mullera


Cu. H.



15


10 days P.P.


Trans.


Z.


I.H.



16


10 davs P.P.


Trans.


Z.


I.H.



17


12 days P.P.


Trans.


Z. + M.


Cu.H.



18


14 davs P.P.


Long.


Z. + M.


I.H.; Cu.H.



19


16 days P.P.


Trans.


Z. + M.


Cu.H.



20


Ca. 14 days


Trans.


Z.


I.H.



21


21 days P.P.


Trans.


Z.


I.H.



22


Ca. 4 wk.


Trans.


Flemmings Fl.


I.H.; Safr.



23


Ca. 4 wk.


Trans.


Flemmings Fl.


I.H.; .Safr.



24


33 days P.P.


Trans.


Zenker's + Mullers; Z. + M.


Cu.H.



25


Ca. 5 wk.


Sag.


Cu. dichr, etc.


H. and E.



26



Sag.


Z.


I.H.



27



Sag.


Z.


I.H.



28



Trans.


Fl.


I.H.; Safr.



29



Trans.


Fl.


I.H.; Safr.; no stain


30


7 wk. P.P.


Trans.


Z.


I.H.; Cu.H.



31


7 wk. P.P.


Trans.


Z. +M.


Cu.H.



32



Trans.


Fl.


Safr.



33


10 wk. P.P.


Trans.


Z. + M.


Cu.H.



34


Ca. 10 wk.


, Trans.


Z. + M.


Cu.H.



35


Ca. 3 mo.


Trans.


Fl.


I.H.; Safr.



36


Ca. 3 mo. (cystic)


Trans.


Fl.




37


Ca. 4 mo.


Trans.


Fl.


I.H.; Safr.



38


half grown



Fl.


I.H.; Safr.


39




Z.


Cu.H.



40


approaching sexual maturity



Hermann's Fl.


No stain ; Safr.



41



Trans.


Z. + M.; Benda's Fl.


Cu.H.; Benda's



42



Trans.


Z. + M.


Cu.H.; I.H.



43


young adult; virgin


Trans.


Picro-acetic


H. and orange



44


young adult; virgin


Trans.


Z.


I.H.



45


young adult; virgin


Trans.


Z.


H. and E.; H.

I.H. I.H.; H. and E.


and Pf.;


46


young adult; virgin


Trans.


z.



47 adult (young?) corp. lut.


Trans.


z.


II. and E.



48 adult (young) corp. lut.


Trans.


z.


H. and E.



49 adult


Trans.


Fl.


I.H.; Safr.



50 adult (injected)


Trans.


Ale.


H.



51 ' adult preg. ( » 132 a)


Trans.


Z. and M.


Cu.H.; I.H.



52 1 adult preg.(*E-l)


Trans.


z.


I.H.; Cu.H.; H.


and Pf.


53 1 adult preg. ( * 150 a)


Trans.


Z. + Pot. dichr.


H. andE.; I.H.


Cu.H.


54 i adult preg. (fetus *73)


Trans.


Z.Z.


H. and E.



55 adult preg. (fetu.s)


Trans.


Fl.


I.H.; Safr.



56 ' adult (preg. near term)


Trans.


HgC12.


I.H.;H. andPf.

E. H. and E.; H.P


H.and


57 adult nursing


Trans.


HgC12.


f.; I.H.;





Elastin St.



58 i adult (corp. lut.)


Trans.


Fl.


I.H.; Safr.



59 adult old (17 yr.)


Trans.


Fl.


Safr.; I.H.; no stain


60


(I ovary pathol.)


The study began with a fetus of 75 mm. total length, which corresponds closely with the forty-day fetus of Sainmont. At this stage the morphology of the testis is fully established, as is also the general morphology of the ovary, which consists of primitive medulla and primitive cortex both composed of cordlike groups of epithelial or epitheloid cells as the parenchyma, with strands of stroma cells interspersed. The parenchyma of the primitive cortex is in broad connection with the surface epithelium and consists largely of genitoid cells with but few indifferent cells discernible. The strands of stroma cells are small and relatively insignificant. The parenchyma of the primitive medulla is made up-of genitoid cells and indifferent cells the latter present in much greater amount as compared with the cortex. * The genitoid cells resemble those of the primitive cortex markedly. While some of them lie free in the stroma, the majority are surrounded by indifferent cells, some few possessing an evident follicular epithelium. Certain of these cells have taken on the character of 'egg cells.'


The parenchyma of the primitive medulla and primitive cortex are broadly confluent with each other, the separation of the two being largely indicated by a more marked accumulation of stromal tissue in the intermediate zone, in the form of a trabecular meshwork of strands of spindle-shaped stroma cells, and blood vessels which have a general longitudinal direction in this region. These blood-vessels form convenient landmarks. The primitive cortex (as well as the definitive cortex later) is strikingly free from larger vessels.


At the outset it may be said that it is obvious that in the morphogenesis of such an organ as the ovary, its increase in size must be kept constantly in mind, in the analysis. The ovary of the 75-mm. embryo or fetus in which the structural components — so-called medullary cords, egg cords, rete ovarii, and stroma — have already appeared, can nearly be contained in a single large Graafian follicle of the adult organ. An understanding of the moi'phological transformations that lead to the establishment of the adult organ is to be found only in a correct analysis of its growth. In the published descriptions of the development of the ovary the marked and rapid increase in size, it is felt by the writer, is frequently not adequately expressed or given due consideration. Thus, the so-called egg tubes of Pfliiger are spoken of as 'down-growths' of the surface (germinal) epithelium, whereas they more exactly represent cell trails left behind in the advancement of the surface as the organ increases in size. This does not apply apparently to the earliest proliferative growth of the germinal epithelium in the indifferent period, in which apparently there is an actual displacement of the underlying tissue (Felix '11 ).


The medullary cords in similar manner represent the earliest proliferations of the mesothelium whose immediate activity apparently largely determines the early growth. Whether or not the mesothelium loses its connection with these early formed masses, the stroma growing between as a tunica albuginea primitiva as described by Sainmont, I cannot of course consider, since the stages studied do not include the early development. In the 75-mm. fetus a sharp separation into primitive medulla and cortex by a distinct stromal layer does not exist.


In the further prenatal growth of the ovary, as illustrated in the stages examined, the ovary more than doubles its diameters. This size increase is due to the double activity of the epithelial elements (ova and indifferent or follicle cells) and of the stroma. The surface mesothelium retains throughout its connection with the epithelial masses to which the term egg cords may be applied and which early assumed a more elongated form due to their greater separation by strands of stroma and the increase in size of the ovary due to their growth and that of the stroma as well. The seat of proliferation lies mainly peripherally in the primitive cortex and the growing zone becomes more superficial as development proceeds. Cell divisions also occur frequently in the surface mesothelium, being apparently more abundant in the earlier stages in which the- egg cords are relatively more broadly connected with it. It but shares with the underlying egg cords a common growth activity and in no sense can it be regarded as the sole direct center of proliferation from which the latter are formed. Indeed, at birth the mitoses are more abundant in the outer portions of the egg cords than in the surface epithelium with which they are connected. The synizesis figure of the germ cells forms a convenient landmark which serves to mark the centrifugal march of differentiation within the egg cords. Mitoses continue to occur within the peripheral portion of the egg cords until about two weeks after birth.


von Winiwarter and Sainmont have described the divisions of the oogonia as practically ceasing at the time of birth, marked multiplication appearing again in the twenty-first-day ovary and becoming permanently arrested soon thereafter. I have seen no evidence of such a periodicity in the oogonial divisions in the material employed by me, which, it must be confessed, was not as abundant as that studied by these authors. The advance of the 'wave of synizesis' appeared a fairly steady centrifugal progression. In the thirty-three-day ovary the superficially located germ cells of the cords were in the synizesis stage, all the more deeply placed cells being postsynizetic. In all subsequent stages the ova were definite oocytes and in the seven-weeks' ovary the definitive cortex with its primary or resisting follicles was differentiating out of the primitive cortex.


In its development the ovary of the cat, as far as concerns the growth and differentiation of the cells that — according to the writer's interpretation — are to become the definitive ova of the period of sexual maturity, conforms to the plan described by Felix for the human o\'ary, the egg cords being less distinct in the human ovary and the neogenic zone described by Felix less developed as a distinct zone in the cat. The distinctness of the neogenic zone destined to furnish the ova of the mature period would appear to be likewise evident earlier than in the cat. The stroma by its growth evidently plays an important part in the breaking up of the egg cords and the formation of the primary follicles of the definitive cortex. In the deeper portions of the ovary marked growth activity of the stroma introduces a complexity not encountered in the typical zone of the primitive cortex. In the ovary before birth and for the first few days after birth the egg cords, project deeply into the ovary, occupying a position which subsequently will become medulla. The egg cords are typically branched, presenting the characteristic appearance well known from previous published descriptions by several workers (figs. 8-9) . In the deeper portions of the egg cords the ova are the most advanced in development and both types of cells — egg cell and follicle cell — may be recognized in this portion of the egg cord. The surrounding stroma is relatively denser in this middle zone of the ovary and the growth activity of the stroma appears particularly marked here. The strands of stroma cells run irregularly, some having a more radial, others a more tangential direction.


Because of the presence of egg cords in this zone, it is usually grouped as part of the primitive cortex. It might with equal propriety be regarded as part of the medulla, since medullary cords are also contained therein — that is, groupings of mainly indifferent cells with only an occasional definite ovum. This zone is in fact an intermediate zone and its peripheral portion persists as a boundary zone during the period of postnatal growth of the ovary.


In their deeper portions the egg cords become separated into cell groups containing one or more ova and in this way numerous follicles are formed. Then- number appears to be added to by continued 'cutting off' of egg cells from the egg cords in the intermediate zone. In this zone of the postnatal ovary great complexity exists. It seems to represent the main line of advancing stromal growth following upon the peripheral (and superficial) zone of epithelial proliferation, perhaps associated with the beginning follicular differentiation.


In illustration of the more general features of the morphogenesis, figures 8 to 15 may be consulted. The distinctness of the cortex becomes progressively more marked until it assumes its definitive structure. This applies as well to the other zones of the adult ovary What has been spoken of as the intermediate zona is most distinct in the growing ovary in the postpartum period (fig. 10), losing its identity in the adolescent and adult period (figs. 14 and 15) as part of the zona parenchymatosa. The zone vascularis, on the contrary, can hardly be said to exist as such in the fetal ovary, and becomes more distinct as maturity is approached. ^Marginal growth, along the line where ovary and ovarian ligament join (represented by the white line of the adult human ovary) appears to play an important part in the assumption of the adult morphology. In the marginal zone growth continues apparently as long as the increase in size continues in the presexual period (approxunately four months), the growth including the stroma as well as the parenchyma (elements of epithelial origin).


The zones of the ovary are but the expression of the mode of growth and type of blood supply, and hence possess no intrinsic or genetic significance such as the cortex and medulla of the suprarenal organ, for example, possess; but even so, the terminology of the regions of the mammalian ovary is not altogether satisfactory. The older terms, medulla and cortex, as well as the B.N.A. terms, zona vascularis and zona parenchymatosa are both employed and are both appHed to the mature organ. The latter terms may be very satisfactorily employed in the description of the adult ovary but they are not so applicable in the developing structure due to the mode of growth. The terms introduced by Sainmont ( '05) in his study of the development of the cat's ovary and subsequently adopted in the monograph by von Winiwarter and Sainmont ( '08) are quite serviceable and are those which will be used here, with two or three modifications which render them more serviceable as expressions of the present writer's conception of the morphogenesis. The primitive cortex becomes the definitive cortex during de^^elopment. This is a somewhat more restricted use of the term than that usually emplo3^ed. It represents therefore only the outer portion of the definitive cortex in the more usual use, or the zona parenchymatosa. It is, however, as employed by His ('65) in the cat's ovar3^ The outer portion of the nucleus epithelio-stromalis centralis (of Sainmont) is the intermediate zone described above. Into the composition of the zona parenchymatosa of the adult there goes, therefore, the definitive cortex, the intermediate zone and a portion of the epithehostromal nucleus. The zona vascularis is developed out of the basal nucleus (connective tissue) of the growing ovary extended at the expense of the epithelio-stromal nucleus, while the marginal growth of the ovary plays a part in establishing it. The primitive medulla would include the epithelio-stromal nucleus and the basal nucleus.


The developmental changes that take place in the deeper portions of the growing ovary, in the primitive medulla, are complex, and this is intensified by the desirability of determining, for theoretical reasons, the exact mode of growth and the morphological value at the different stages of the so-called medullary cords which have so frequently been regarded as the equivalents of the seminal tubules of the testis. The rete ovarii occupies a position in the cephalic portion of the medulla (fig. 9). Its tubules are, in the youngest embryo studied (75 mm.) easily distinguished, of definite cuboidal-columnar epithelium, with a distinct lumen. Subsequently, in older fetuses, the epitheliuni becomes more distinctly flattened and the rete character more accentuated (fig. 8). Whether the cell cords that form the structure are derived from the mesothelium at the cephalic end of the ovary, or are 'ingrowths' from the mesonephros, or are of double origin and nature, has not been made an object of investigation by me, and hence of course cannot be adequately considered at this time. The structure as observed in the growing organ suggests the last view. The rete furthermore undergoes a progressive change after birth and remains as a persistent structure in the adult ovary. It requires no very extensive study of the ovary of older fetal and new-born animals to determine that at least some of the medullary cords are connected with the rete ovarii, as has been described by others (von Winiwarter and Sainmont '08) and this requires therefore no extended description or comment at this point. Two other features of the medullary cords in the older embryos, the presence of fat-granules in the cells, and the occurrence of large cells within the cords, require brief discussion. Droplets of a fatty ('lipoid') nature were found in the medullary cords of the 95 mm. and 112 mm. fetus, three to four-day kitten, and still demonstrable in the six-day kitten. They may have been present in the earlier stages examined, but the technique was not of a nature to demonstrate their presence easily, von Winiwarter and Sainmont found the fat globules appearing about forty-five days p.c. (i.e., 70 mm. length, Sainmont), and no longer present three days p.p. They reject the interpretation of Allen ('04) in the pig, that the presence of fat is indicative of degeneration of the medullary cords. They emphasize on the contrary the presence of fat as evidence of profound metabolic change taking place in the medullary cords at this time. This, perhaps, could hardly be questioned. It might be added, however, that one can hardly speak of a "disappearance of lipoid from the medullary cords," since the application of what I may term a 'mitochondrial technique' adduces evidence of the presence of fat in abundance in masked form in all the epithelial cells within the ovary — so-called medullary cords, follicle cells and ova — at all stages of their later growth, at least, appearing as free hpoid globules in the last, in the process of their vitellogenesis. Hence the question resolves itself into the reason for the existence of droplets of free lipoid in the epithelial cells (medullary cords) in the deeper portions of the ovaries. Inasmuch as I find evidence of dwindling and disappearance of these cell cords in the deeper portions of the ovary at about this time (after birth) I incline to the interpretation offered by Allen.


The 'large cells' present in the medullary cords and the surface epithelium have not been specially studied by me. The}'- were encountered in the two youngest embryos and in the surface epithelium, particularly in the zone bordering the hilum, well along in postpartum stages. I have seen no reason for drawing a sharp line between these cells and obvious 'germ cells,' as I believe that all intergradations between them and the latter may be found. On the other hand, most of them, at least in the antepartum ovary, do not give rise to the definitive germ cells of the adult ovary, and hence are not primordial germ cells in the original sense ('Ureier,' of Waldeyer). It is unnecessary to introduce a discussion of their interpretation and significance. Reference is simply made to the excellent discussion of von Winiwarter and Sainmont (p. 67). 'Those investigators who accept a definite cell-lineage for the germ cells, strongly suggested by the observations of Allen ('11), Rubaschkin ('09, '11) Wood, Dodds, and others, may interpret them as unproductive side lines of the germ-track or as a more or less temporary hypertrophy, for unknown reasons of 'indifferent cells' cells, as accepted by von Winiwarter and Sainmont, who believe that they subsequently return to normal size. Upon a purely physiologic or process interpretation, however, these cells might still be grouped with the germ cells as an expression of the oogenetic processes at work in the developing ovary.


The period of the postpartum growth leading up to the appearance of medullary follicles and their growth is a critical one in the theoretical interpretation of the morphology. The primitive cortex and medulla become accentuated and extended. The ovary in the first five weeks quite doubles its diameter. The stroma ovarii continues its obvious growth activity. The increase in the epithelioid cords and their morphological transformations furnish the characteristic feature of this period. They increase in bulk and while very irregular in contour often assume a more tubular form. Their cells increase in size and by their arrangement assume a form more characteristically epithelial, as about a potential lumen. Their nuclei he more peripherally and the inner ends of the cells are more elongated, vacuolar and reticulate. Abundant 'mitochondrial' substance is present here. The structural appearance in such cases forces a comparison with the tubules of the testis, and the comparison becomes enhanced by the relation of the cell cords within the medulla of the ovary to the rete. The resemblance to the tubules of the undifferentiated embryonic testis, or more closely to the tubules of the cryptorchid is particularly striking, von Winiwarter and Sainmont ( '08) have called attention to this resemblance of the medullary cords to the tubules of the testis, as the former ('00) had previously done in his paper on the development of the rabbit's ovary, and as several have done in a comparison of the ovarian medulla with the testis. Such a comparison, to which the writer at first inclined, seems to him upon maturer consideration a superficial one. The elongated form, simulating a tubule is not the universal form of growth of these cell masses nor do they possess, when elongated, the morphology of the seminal tubules."* The form assumed is quite irregular and is obviously a factor of the growth of the epithelial cords and stromal strands in their mutual relation to one another in the growth of the ovary during this period.


The source of the cells that compose the cell cords and masses so prominent during the period of expansion is also important in this connection. Two modes of origin present themselves as possible: (1) A development by centrifugal growth of the primary medullary cords apparent in the embryo so that from them come all the epithelial cords inside the zone of the primitive cortex. This mode of growth would make the medullary structures a unit and strengthen the ovary-testis comparison. (2) That the cords and masses of epithelial cells within the medulla, while in many instances connected with the prunary medullary cords and quite possibly grown out from these cell groups, are nevertheless derived in part from the indifferent cells contained in the egg cords of the embryo. The differences of the epithelial cells would be purely a matter of position and relation and not intrinsic or morphological.


It is this last view that seems to me undoubtedly the correct one. Small groups of epithelial cells are to be found at all stages of the postpartum growth in the central nucleus, the intermediate zone and, especially later, in the inner portion of the primitive cortex. They are formed by the breaking up of the inner portions of the egg cords into primary follicles. Many of these primary follicles and epithelial cell groups without an ovum enclosed come to lie within the medulla, in the epithelio-stromal nucleus where they subsequently grow and play a part in the development of the medullary follicles, presently to be described.


Bremer, J. L. Amer. Jour. Anat., vol. 11, no. 4, May, 1911, pp. 393-416. Huber, G. Carl, and Curtis G. M. Anat. Rec, vol. 7, no. 6, June, 1913, pp. 207-220.


In connection with the comparison of the structures within the ovary to the testis tubules just considered, it may be said at this point that the cells are as strikingly follicle cells at this stage and place as subsequently in the development of the follicles of the adolescent and adult periods. This is particularly clearly shown in a comparison of such cells when a mitochondrial technique has been employed. The disposition of the mitochondrial granules in the inner ends of the cells in each instance serves to make the agreement more striking. The fact that these so-called medullary cords develop into follicles should leave no doubt of their ovarian character.

The medullary follicles. The development of the follicles within the medulla of the ovary of the kitten has been studied in detail by von Winiwarter and Sainmont, who apply the name of 'medullary follicles' and regard their appearance as marking a third stage in the development of the ovary. Their description, briefly stated, is as follows : At eight days postpartum the medullary cords are markedly elongated; at sixteen days they have increased in volume and the cells have hypertrophied and become more columnar in shape. This stage is the last one in which a connection of the medullary cords with Pfliiger's egg cords exists. 0\iiles exist within the medullary cords, generally smaller than those of the primitive cortex. Small medullary cords are described in the zone bounding the primitive cortex and containing o\ailes which belong to Pfliiger's egg cords. Such they interpret as ovules of Pfliiger's egg cords which have become isolated with a medullary cord. At twenty-three days p.p., primordial medullary follicles, both uni- and pluri-o\ailar, are beginning their development. At thirty-five days, the next described stage, the medullary follicles have become voluminous structures. These they group as follicles in process of growth and follicles fully formed, the latter possessing an antrum comparable to the antrum of the definitive Graafian follicles of the adult period. The medullary follicles now undergo a peculiar degeneration during the next two or three weeks, so that, at sixty to sixty-five days p.p., all remains of the medullary follicles have completely disappeared, this degeneration being accomplished or accompanied by an enucleation of the follicles by the ovarian stroma. The naked ova, so 'shelled out,' undergo a degeneration in the midst of the stroma. Not all ova degenerate through the destructive agency of the stroma, but undergo progressive degeneration within the medullary follicle. With the degeneration of the medullary follicles the indifferent cells and ova derived from the first proliferation of the germinal epithelium of the ovary entirely disappear.


An identical fate (i.e., degeneration) awaits the Graafian follicles deriived from the egg tubes of Pfluger, or the second proliferation of the germinal epithelium.^ Beginning about sixty to sixty-five days, Gi'aafian follicles develop from the deeper portions of the cortical zone, the first ones being nearly always pluri-ovular, containing two or three or more ova. Very large follicles are thus formed, so that, about three and one-half or four months' postpartum, the ovary attains a large size, becoming subsequently reduced in size with the degeneration of these follicles and their absorption. At this same time, the remaining resting or primary follicles formed from the second proliferation have practically disappeared. A third proliferation® then furnishes the ova and follicle cells destined to develop into the Graafian follicles of the period of sexual maturity.


5 von Winiwarter and Sainmont 1908, p. 85: "Nous nous proposons d'exposer dans le present chapitre qu'un sort identique est reserve a tons les ovules et follicules de de Graaf qui derivent des tubes de Pfliiger ou cordons corticaux (seconde proliferation). Cette decheance n'atteint pas tous les ovules au meme degre de developpement. Les uns, et ils sont majorite, ne depassent pas le stade de follicule primordial. Les autres se transform ent en folliclues de de Graaf plus ou moins volumineux. Neanmoins le resultat est le meme: leur ensemble est voue a la mort. Deplus, la degencrescence des foUicules de de Graaf suit une marche tres particuliere, etablissant une transition manifeste et graduelle entre I'atresie des follicules medullaires que rtous avons decrite et I'atresie typique, telle qu'elle a etc etudiee dans I'ovaire adulte. C'est pourquoi nous faisons suivre la description des cordons medullaires par celles de revolution des cordons corticaux, afin de faire ressortir combien le developpement de I'ovaire est continu et progressif."

"von Winiwarter and Sainmont, 1908, p. 89: "II arrive un moment (vers 3^ a 4 mois p. part.) ou, pratiquement, tous les follicules primordiaux ont disparu. On ne voit plus alors sous 1' epithelium de revetement qu'une serie de cordons epitheliaux, representant tout au moins en partie les anciennes cellules folliculeuses. Nous disons en partie, car, ainsi que nous le verrons ultcrieurement, tandis que ces phenomenes regressifs se deroulent, I'epithelium de revetement


I have sketched the general results of von Winiwarter and Sainmont because of the monographic character of the study made of the development of the ovary of the cat and the uniqueness of some of the results and interpretations offered.. It is therefore with some hesitancy that I venture, from a study of material inferior in amount to theirs, to offer interpretations that differ in certain fundamental respects.

In as far as concerns the medullary follicles, the difference of interpretation has three aspects. In the first place, as has been fully indicated in the discussion of the medullary cords in the foregoing paragraphs, the writer is unable to accept the sharp distinction between the products of a first and second proliferation, " a distinction that plays so important a part in the interpretations of von Winiwarter and Sainmont. The distinction of medullary cord and sex cord seems to the writer more a matter of differentiation, location, and convenience for descriptive purposes rather than a sharp distinction of materials of morphologically different values. The follicles that begin their development during this period are thus but the earliest follicles which from position may appropriately be termed medullary follicles, it is true, but only for descriptive and topographical reasons. Their development, peculiarities and fate are closely involved in- the growth processes taking place in the ovary at this time.

The second point of different interpretation involves the source of the ova and the early transformation of the inner portions of the 'egg cords.' As has been already stated, it has seemed to the writer clearly apparent from a comparison of the successive series of ovaries of advancing development, that going hand in hand with the peripheral growth of the egg cords there has been a central disassociation or breaking up of the egg cords in which the growth of the stroma has been largely instrumental. This leads to the isolation of the ova or groups of ova, and from these have come the ova which occur in the medullary follicles that begin their development in the third week after birth. In illustration of this interpretation there are submitted as text figures 1 to 6, six photographs of sections taken entirely at random and therefore not of illustrative value otherwise. In these the centrifugal oogenetic wave is indicated by the synizesis stage apparent in all save the first and last in which the ova are in the pre- and postsynizetic stages, respectively. From a comparison of these it will become apparent, I believe — if the growth of the ovary be kept in mind — that the large ova in the deeper portion which in the last two figures are in developing medullary follicles are derived from the progressive breaking up of the inner portions of the socalled egg-cords.


ne reste pas inactif. Une nouvelle proliferation (la troisieme), celle des invaginations epiiheliales , apparait et les colonnes cellulaires qui les composent, traversent I'albuginee et se melent aux amas des cellules, foUiculeuses. Comme ces deux formations sont constituees de cellules 6pitheliales ordinaires, il est impossible morphologiquement de distinguer ce qui revient aux unes et aux autres. Toujours est-il que c'est a leurs depens que se formeront la zone corticale definitive et les oeufs d^finitifs de I'adulte." (p. 260): "Ces invaginations, jointes aux cellules foUiculeuses de la zone corticale primitive, aboutissent a la formation de la zone corticale definitive de I'ovaire, a laquelle, seule, sera reservee la production des oeufs definitifs. Son histoire appartient a un chapitre ulterieur."


The third difference of interpretation of the medullary follicles concerns the meaning of the peculiarities of their foi-m. The view of von Winiwarter and Saimnont, that the great ii-regularity and peculiar form of the follicles encountered in the ovary of the cat at this stage is due to the destructive activity of the ovarian stroma by penetrating and enucleating the follicle, has been noted above. The striking peculiarity of the follicles developing during this period was observed by myself before I had become aware of the work of von Winiwarter and Sainmont and they had been interpreted in quite the reverse direction, namely, as progressive rather than regressive pictures. Further examination and consideraation has but confirmed me in the interpretation. The medullary follicles began their progressive development early in the third week after birth, although a close limitation of the time of their appearance cannot be given. The numerous ova in the ovary within the zone of the primitive cortex possess well-marked follicular epithelium. Some of them are definitely within so-called medullary cords of elongated form, others within moie irregular masses. A number lie free in the stroma, surrounded only by a single layer of folhcle cells which may vary from flattened to columnar in shape. Such ova are particularly found in the peripheral portion of the medulla and in the intermediate zone. Interspersed with these are cords or clusters of follicle cells whose connection with egg cells is not apparent. Some of these appear to come from the indifferent cells of the egg cord in its breaking up, or to have survived the degeneration of an egg cell which they once enveloped (fig. 16). Such epithelial structures with the surrounding stroma and the interstitial cells compose the epithelio-stromal nucleus of the two-week ovary. Marked growth of the masses and cords of follicular cells and of the stroma produces the ovary of two months. Very great irregularity is shown in the growth of the cords of follicle cells, and their relation to the ova is particularly interesting. A typical follicle formation of this period is shown in figures 24 and 25.



Fig. 1 80 mm. fetus. X 120. Fig. 4 Twenty-one day kitten. X 00.

Fig. 2 95 mm. fetus. X 110. Fig. 5 Thirty-three day kitten. X 60.

Fig. 3 Three to four day kitten. X 00. Fig. fi P^ive to six weeks kitten. X 60.


It is structures of this kind that have been interpreted by von Winiwarter and Sainmont as follicles in degeneration attended by penetration of the stroma and enucleatioti. Figures 16 to 25 are introduced in illustration of the reverse view. From the morphological relations there shown it would appear that the eggs are becoming enveloped by the growing follicle masses. Figure 16 shows two small egg cells of smaller size and close to each a cluster of follicle cells, doubtless derived from adjacent indifferent cells of the original egg cord. Each egg is invested by a laj^er of follicle cells of its own. By growth of the follicular cluster the ovum, in its epithelium, becomes partially surrounded (fig. 17, 18) and finally completely invested (figs. 19, 20) by the growing cell mass; and with the appearance of an antrum— indicated from the beginning — a Graafian follicle more or less irregular, is developed. Several ova may thus become included in a single follicle which may be of rather tubular form (fig. 23) . The layer of follicle cells belonging to the ovum and immediately surrounding it may be traced well into the complete investment. The investing mass fuses with it and its identity is finally lost. It is indicated in figures 17 to 21.

Whether the investing folUcular mass at the beginning is always or even usuall}^ distinct from the sheathing follicle cells is not easy to determine. In many instances, at least, it would appear that the investing mass is developed from one side of the primary follicle or medullary cord and in the process of growth simply becomes wrapped around, enclosing ovum and its follicular epithelium of the opposite pole, as well as some of the stroma.

In support of the above interpretation and as opposed to the reverse one of regressive change by a process of enucleation, may be advanced: (1) the fact that in general the smaller egg cells are less enclosed; (2) that they lie generally more peripherally; (3) that the line of fusion of the investing epithelium may often be detected (figs. 19, 20, 22); (4) that the free egg cells possess in most instances at least a sheathing simple follicular epithelium; (5) 'that degenerating egg cells lying free in the stroma are but seldom encountered.

Accepting the interpretation above set forth, it can hardly be doubted that these follicles owe their irregular form relations to a compounding of the growth of the stroma and that of the follicular elements. It may be suggested that their peculiarities are to some extent due to an attempt at follicle formation in an ovary during rapid growth; or, put differently, the growth of follicular elements and ovarian stroma in lines at variance with each other prevents the free expansion and uniform growth so characteristic of the adult ovary, so that the growing follicular cords must grow around the ovum and hence come to invest it (figs.^24 and 25). The reverse, from the same point of view, might easily be conceived to occur and the follicular cells be stripped off as a result of the pressures and tensions of the stromal growth, and thus the ovum be left naked in the midst of the stroma, producing thus the effect of enucleation without attributing to the ovarian stroma a specific activity in the process. Indeed, from the figures of von Winiwarter and Saimnont, as well as my own observations, this appears frequently to be the case. What chemical correlations may likewise be involved cannot be estimated. The follicular structures in the ovary at this period are of very varied form. In order to obtain a three-dimensional view of the relations, a model was made of a portion of an ovary (no. 26) in which folhcular cords, follicles and ova inside the primitive cortex are illustrated. The ova shown are in all cases immediately surrounded by their simple folhcular epithelium. Of two of the follicles so shown, enlarged drawings are given in figures 29 and 30; figure 29 may be compared to the sectional view shown in figure 23 and figure 30 may be similarly compared with figure 18. Within the larger masses an o\Tjm was contained completely enclosed. The picture that is afforded by the reconstruction supports, I believe, the evidence which the histology furnishes, namely, that in most instances the process illustrated by these peculiar follicle formations is one of inclusion rather than of exclusion of the ovum, in most instances at least.

Observations of these formations by earlier workers than von Winiwarter and Sainmont in the cat's ovary, or similar structures in the ovaries of other animals, appear to be lacking, von Kolliker, it is true, and Biihler in his earlier work, regarded the follicular epithehum as coming from the medullary cords and these in turn from the mesonephros, investing the egg cells (which were derived from the germinal epithelium) by growing around them, so that relations similar to those met with in the kitten's ovary may have been influential in forming their interpretations. But neither their description nor figures give us definite evidence.

The fate of these peculiar follicles is one of considerable importance in their interpretation. While many of these follicles evidently degenerate, the majority I believe remain as the large irregular, usually pluri-ovular follicles which are found in the ovaries of kittens before the onset of sexual maturity. Such follicles are shown in figure 13 and were figured by Sainmont (fig. 15) in his earlier paper, wherein they were not specifically discussed, although they were obviously thought of as derived from the egg tubes of Pfliiger. " In the later and larger work with von Winiwarter, so often referred to in this paper, these follicles were described and regarded as developed out of the material of the second proliferation (Pfliiger's egg tubes), succeeding as a second set the 'medullary follicles' formed from the medullary cords of the first proliferation which entirely degenerated. This interpretation is a necessary corollary to the interpretation given by them of the peculiar follicle formation with which we have just been dealing. Figures showing the irregularity and pluri-ovular character of these follicles are given (11 text figures, p. 90) but none showing their development, so that it is somewhat difficult to judge of the evidence — aside from the interpretation of the peculiar medullary follicles of younger ovaries — that lead them to regard these as quite distinct from the follicles of the earlier period. Sainmont's figures (4 to 9) appear to me far from convincing. In their description their resemblance to the medullary follicles is pointed out and the similarity in their mode of ' degeneration. ' They differ in the presence of a better developed theca and the relation and character of the interstitial cells.

As in their formative period — as I interpret it — -these follicles are characterised by their great irregularity and the numerous ova usually contained. This appears in figure 13 of a single section, and more so in a model made from a section of the same ovary. In between these follicles occur numerous cords of cells (which -were reproduced in part) and strands of interstitial cells(not shown in the model). The stroma forms a well defined theca for the follicle and it is there that the interstitial cells chiefly occur. Two of the uTegular pluri-ovular follicles are drawn separately (figs. 31 and 32). Their irregularity is clearly apparent from these. The cords of cells are apparently vanishing structures — small groups of follicle cells derived from the medullary cords or of cortical origin. In these follicles several ova are contained.

The approach of sexual maturity is attended by a profound degeneration of the Graafian follicles formed during the pre-sexual period. In ovaries of this stage nearly all the larger Graafian follicles are found to be in some stage of aresia, as illustrated in one of the figures in my paper on the interstitial cells. Eight ovaries of this period were examined. The conclusion of von Winiwarter and Sainmont that the degenerations of this period involve also the primary follicles as well and that the ova of the sexual maturity are derived from a third ' down-growth' from the surface epithelium, renders this period one of marked importance. As far as the material studied by me goes, it has afforded no evidence of such a new formation of ova; in nearly all cases an abundance of resting or primary follicles in the cortex was found to be present, and it is believed that the primary follicles found in the ovary during the adult period are formed in the differentiation of the cortical zone in the pre-sexual period. But one ovary (no. 39) was secured, clearly belonging to this period, in which the primary follicles had nearly completely disappeared, giving the picture described and figured by von Winiwarter and Sainmont. This was, however, regarded as a case of exceptionally profound degeneration, and showed no evidence of a renewed proliferation of oogonia from the surface epithelium. The margin of the ovary bordering the hilum long (up to three months, at least) remains a seat of proliferation and growth during the enlargement of the ovary in the pre-sexual period, and it is quite possible that in the second growth period (that immediately preceding sexual maturit}^) following the period of profound degeneration and corresponding diminution in volume, the marginal surface epithelium particularly resumes its proliferative activity with a resulting increase in the number of primary follicles. It is also quite possible that the profound degeneration and consequent third proliferation are related, and not constant but variable; only an extreme morphological interpretation would reject the possibility. The material, however, is insufficient for the settlement of these points. Neither the preliminary paper of von Winiwarter and Sainmont, nor the statements in their subsequent papers present the evidence in a form that seems to me fully convincing, and the promised chapter" upon the development of the third proliferation will be looked forward to with interest.

If it is a matter of deep-seated importance and not a mere expression of growth, a proUferation of ova just before sexual maturity will be found to occur in other mammals. It may be questioned, however, whether Rubaschkin ('12) is justified in regarding what he terms a Hhird proliferation' from the surface epithelium of the guinea pig ovary, occurring before birth, as homologous with a (third) profiferation of ova just preceding sexual maturity, such as von Winiwarter and Sainmont describe for the cat.


' See quotation, from p. 260, in footnote 0, p. 363.



As a result of the profound degenerations before the onset of sexual maturity there is left an ovary smaller but richer in stroma (fig. 14). The Graafian follicles that develop during the period of sexual maturity are almost always uni-ovular in the cat, are more regular and uniform in shape and the ova are characterized by a markedly different structural appearance as compared with the ova of the pre-sexual Graafian follicles as noted by von Winiwarter and Sainmont.

A very frequent accompaniment of the degeneration of the Graafian follicles of the pre-sexual period in kittens approaching sexual maturity, may be incidentally mentioned, namely, the occurrence of polar spindles, polar body formation and a form of degeneration of the ovum by fragmentation, simulating a parthenogenetic cleavage. It is unnecessary to consider here the question of their parthenogenetic nature. Similar conditions have been described in several forms. Bonnet has considered and rej ected their parthenogenetic character. In the ' ' Hertwig Handbuch, " Waldeyer has discussed them and pronounced against their parthenogenetic significance, while Hertwig regards them as essentially a beginning parthenogenesis. In the cat they occur most abundantly in old kittens (ca. four months) in the large Graafian follicles that have begun degeneration as atresia folliculi. While no particular search for them has been made, four polar spindles and several fragmenting ova (fig. 28) were encountered in a single ovary and were found to occur in four ovaries of this period. In illustration of the typical and 'normal' appearance, figures 26 and 27 are submitted, showing a first polar body and second polar spindle (?) in the same ovum. That there is not a factor peculiar to the period of adolescence which determines the introduction of maturation, is evinced by the occurrence of the polar spindle formation in a degenerating follicle of an adult ovary. That the phenomenon is not simply an indication that the growth period had been completed and the follicle essentially mature when it enters upon atresia, is also shown by the occurrence of a polar spindle in an obviously young Graafian follicle. In most instances, however, the follicles in which polar spindle formation occurs are of large size. The constant correlation is that with degeneration of the follicle. There appears to be, therefore, some factor connected with atresia folliculi that can, under certain unknown conditions, induce maturation.

In the period of sexual maturity the development of the Graafian follicles is quite variable and the morphology of the ovar}^ fluctuates correspondingly. Figure 15 shows a typical section of the zones of the adult ovary, the zona parench;yanatosa consisting of cortex and zone of Graafian ^follicles (epitheliostromal zone), and the zona vascularis.

General Conclusions

The results of this study of 60 series of cat ovaries may be summed up briefly at this point. From the stage with which the stud}' began, when the ovarian character of the organ is clearly established (75 mm. fetus) to sexual maturity, the ovary increases in diameter approximately five times. The growth zone appears to be mostly peripheral, in and beneath the mesothelial covering epithelium that is the source of the ova and folHcle cells. The greatest activity appears in the primitive cortex beneath the surface epithelium rather than in the latter, and growth continues here well into the postpartum period, as von Winiwarter and Saiimiont have shown. Up to approximately the third week postpartum the surface epitheUum and the underlying cell cords of mesothelial origin form a common mass, the latter being connected with the former. Subsequently (third week) they are separated by the appearance of a tunica albuginea.

At the margins of the ovary bordering the hilum the growth activity continues much longer (up to approximately three to four months) and along this bordering zone the surface epithelium retains its connection with the underlying egg and follicle cell groups.

The deeper masses of cells of mesothelial origin are the older and differentiation follows a centrifugal course save at the margin where younger stages in the oogenesis are to be encountered long after they have disappeared from t"he remainder of the ovary. In this growth the stroma plays an important part. The growth of the ovary may be said therefore to be mainly peripheral and marginal, and the differentiation centrifugal and marginal.


Accompanying the centrifugal wave of differentiation and growth there is a progressive advance in the state of development attained. Early in development (antepartum) large genitoid cells appear in the central portion mainly in the medullary cords. These disappear. The earliest follicles are central but do not attain large size of advanced development but degenerate. After birth (thii'd week), come the irregular medullary follicles which, however, degenerate. An irregular centrifugal wave of degeneration might therefore be said to follow after the wave of differentiation.

The wave of differentiation and growth does not run through to completion but in the periphery proceeds much more slowly, leading, therefore, to the establishment of a cortex in which the follicles remain long in a resting stage, as the well-known primary follicles.

Degenerations affecting follicles of all stages of development occur at all periods of the life history as well. The small and immature ovary of the anti- and postpartum periods is obviously 'unable' to provide adequate blood supply for the follicles beginning development during these periods and hence the suggestion at once arises that therein is to be found the reason for the profound degenerations occurring in the pre-sexual period and after sexual maturity; that the processes, which in the adult ovary lead to the formation of the mature Graafian follicle, are operative from the beginning but continually fail, due to the absence of the necessary conditions (nutritive or otherwise) reaching progressively more advanced stages as development and growth proceed. The lack of proper vascular and nutritive conditions is doubtless the cause of many of the degenerations^ (atresia folliculi; degenerations of primary follicles) particularly in the adult period. Inasmuch as it is extremely doubtful if the developmental factors are all intrinsic — that is, the growth and differentiation within the ovary independent of the rest of the organismit is equally improbable that all the degenerations of the growth period can be explained as due simply to the intrinsic conditions of growth.


Compare the conclusions of Clark, from the study of injected human ovaries, immature and adult. J. G. Clark. Johns Hopkins Hospital Reports, vol. 9, 1901 : pp. 593-676.


The relations of the zones that mark the morphogenesis of the cat's ovary may be illustrated by a series of schemata (text figure 7) wherein schema A indicates approximately the conditions in the 75 mm. fetus, schema D, the zones of the adult ovary. These schemata may also be directly compared with the photographs reproduced as figures 8 to 15. The nomenclature of the ovary has been briefly discussed (p. 357).



Fig. 7 Schema to illustrate the appearance of the zones in the morphogenesis of the cat's ovary. C.P., primitive cortex; C, cortex (definitive) ; N.E., epitheliostromal nucleus; N.B., nucleus basalis; Z.I., intermediate zone; Z.P., zona parenchymatosa; Z.V., zona vascularis.

In an attempted analysis of the morphogenesis of the mammalian ovary it would be necessary to compare the development in small, medium-sized and large animals in detail, in order thereby to eliminate the effects of size, and arrive if possible at the intrinsic aspects of the organogenesis. Such an analytical comparison of mammalian ovaries has hardly been done. The recent account of Felix of the development of the human ovary, as already sketched, indicates possibilities, and to it, along general lines, the development of the ovary of the cat appears to conform. The existence of 'medullary cords' and Pfliiger's 'egg tubes' must be regarded as of secondary significance as but variations in the mode of growth. The neogenic zone of Felix obviously compares with the primitive cortex of the ovary of the cat. It is to be regretted that the description did not include the important period of development during childhood.


The development of the cat's ovary, according to my interpretation, affords no support for the view that the ovary proper is superimposed as a distinct growth on a vestigial testis represented by the rete ovarii and the medullary cords. The latter, while they present a superficial resemblance, histologically, particularly to the tubules of a cryptorchid testis, are nevertheless obviously ovarian. Their apparent testicular character is due to their form of growth. They contain ova and form follicles, while their cells clearly agree with the follicle cells in structure, and this is also clearly due to the processes occurring within them, which are themselves in part a function of their relations. There remains the fact of the existence of a rete ovarii, the undoubted homolog of the rete testis, particularlj^ well developed in some animals, such as the cat, and connected with some of the so-called medullary cords which thus would appear clearly homologous with the tubuli contorti of the testis. The apparent dual structure of the ovary is but a part of the larger problem of the double development of the internal organs of reproduction in typical vertebrates, referred to at the beginning of the paper. The development of a rete and its connection with the parenchyma of the gonad in the female is but part of the tendency to develop the duct system of the male. The conclusions to which one is almost inevitable compelled is that of a deep-seated hermaphroditic tendency in the development of vertebrates, which finds expression in thfe double character of certain definite organs and structures. This but describes the morphogenetic pattern with a suggestion of its phylogenetic origin. Upon the analytical side, it might be affirmed that processes determining both male and female duct systems were present in development of each sex. If it were believed to put the problem on a better basis, it might be said that each sex is .heterozygous in this respect, the factors determining the development of the male duct system becoming dominant in the course of development of the male and vice versa. The development of the ovary indicates strongly that the development and double character of the reproductive system must be clearly differentiated from that of sex itself. The development of the reproductive system is double — has two aspects: the establishment of the fundamental plan of the system, and the underlying mode (metabolic attitude) that determines the direction taken — the determination of sex. " In the development of the human ovary and testis, for example, Felix has shown that in both sexes there is the same fundamental material which is worked over, so to speak, along one or the other lines of differentiation.

It was the suggestion, of Wilson I believe, that sex and the sexual characters might be differently determined, the latter by the heterochromosome. Suggesting in turn that the heterochromosome stands for the former; instead, it might be stated in closing as at the beginning of this paper, that the evidence indicates a quantitative rather than a qualitative sex difference, a different metabolic habit, degree or tendency that determines the result.

Summary

  1. In the development of the ovary of the cat, growth is mainly peripheral and marginal.
  2. Differentiation therefore follows centrifugally.
  3. The epithelial elements (parenchyma) occur in the form of cords.
  4. Medullary cords and egg cords are not to be sharply distinguished.
  5. The growth determines the appearance of fairly definite zones: (a) cortical, (b) intermediate, (c) epithelial stromal.
  6. Degenerations occur throughout the period of growth and in the adult period.
  7. In general, the degenerations follow a centrifugal course.
  8. The stroma obviously plays an active and important part in ovarian growth.
  9. The primitive cortex is interpreted as directly forming the definitive cortex containing the primary follicles.
  10. No evidence was found of a new formation of ova just prior to sexual maturity.
  11. Profound degeneration of the early formed Graafian follicles occurs, being most marked before the advent of sexual maturity.
  12. Polar spindles, polar body formation and fragmentation (abnormal cleavage?) occurs particularly in the atresia folliculi preceding sexual maturity.
  13. The Graafian follicles of the adult period are of a somewhat different type as compared with those of the growth period (presexual). Intergradation is, however, obvious.

Footnotes

  1. Cf. Felix, W. ; Theoretische Betrachtungen uber das Genitalsystem der Vertebraten. pp. 821-834, Handbuch der Entwicklungsgeschichte der Wirbeltiere, Vol. 3, 1, 1906.

Bibliography

An extensive list of literature references is not given. The ovary of the cat has been a favorite object of investigation: Pfliiger ('63), His ('65), Rouget ('79), Schulin ('81), Janosik ('85, '88), Giacomini ('87), Coert ('90), H. Rabl ('98), Ganfini ('07), Sainmont ('05), von Winiwarter and Sainmont ('08), have considered its structure and development. The last named, however, have so fully considered the literature upon the development of the mammalian ovary and that of the cat in particular, that a repetition here would be quite unnecessary. Only the titles of papers upon the mammalian ovary, referred to in the foregoing brief discussion, are therefore here included.

Allen, B. M. 1904 The embryonic development of the ovary and testis of the Mammalia. Amer. Jour. Anat., vol. 3, pp. 89-146.

1911 The origin of the sex-cells of Amia and Lepidoeteus. Jour. Morph., vol. 22, pp. 1-55.

VAN Beneden, E. 1880 Contribution a la connaisance de I'ovaire des mammiferes. Arch, de Biol., vol. 1.

BiJHLER, A. 1906 Geschlechtsdruse der Saugetiere, in Handbuch der Entwicklungsgeschichte der Wirbeltiere, herausgegeben von O. Hertwig. Vol. 3, 1. pp. 716-742. Jena.

Coert, H. J. 1890 Over de Ontwikkeling en den Bouw van de Geschlachtasklier bij de Zoogdieren meer in het bijzonder van den Eierstok. Diss. Inaug. Leiden. 1898

Felix, W. 1911 Chapter IX, in Handbuch der Entwicklungsgeschichte des Menschen, herausgegeben von F. Keibel und F. P. Mall, vol. 2, pp. 857-885. Leipzig.

Janosik, J. 1885 Histologisch-embryologische Untersuchungen liber des Urogenitalsystem. Sitzungsber. d. Kais. Akad. f. Wiss. Wien. Bd. 91, Abt, 3, pp. 97-199, Math-Naturw. Kl.

1888 Zur Histologic des Ovariums. Sitzungsber. d. Kais. Akad. d. Wiss. Vol. 96. Abt. 3, pp. 172-192. Math-Naturw. Kl. (December 1887).

Kingsbury, B. F. 1911 The histological demonstration of lipoids. Anat Rec, vol. 5, no. 6, June, pp. 314-318.


MiHALKOVics, V. von 1885 Untersuchungen fiber die Entwickelung des Harnu. Geschlechtsapparates der Amnioten, — I. Die Exoretionsapparate. — II. Die Geschlechtsgange. — III. Die Geschlecht.sdrii.sen. Internat. Monatschr. f. Anat. u. Histol., Bd. 2, pp. 41-106.

RuBA.scHKiN, W. 1909 Uber die Urgeschlechtszellen bei Sangetieren. Anat. Hefte. Bd. 39, pp. 605-652.

1912 Zur Lehre von der Keimbahn bei Sangetieren. Ueber die Entwickelung der Keimdrusen. Anat. Hefte, Bd. 46, pp. 345-411.

S.A.ix.\ioNT, G. 1905 Recherches relatives a I'organogenese du testicule et de I'ovaire chez le chat. Arch, de Biol., vol. 22, 1905-1907, pp. 71-162.

Waldeyeh, W. 1870 Eierstock und Ei. Leipzig.

vox Winiwarter, H. 1900 Recherches sur Tovogenese et I'organogene.se de I'ovaire des mammiferes (lapin et homme). Arch, de Biol., vol. 17, pp. 33-199.

vox Winiwarter, H., et S.\inmont, G. 1907 tJber die ausschlie.s.slich i)ostfotale Bildung der definitiven Eier bei der Katze. Anat. Anz., Bd. 32, pp. 613-616.

1908 Nouvelles recherches sur I'ovogenese et I'organogenesde I'ovaire des mammiferes (chat). Arch, de Biol., vol. 24, 1908-1909. pp. 1-142; 165-276; 373-431 ; 628-650.

Explanation of Figures

Plate 1

8 Transection of ovary, fetal kitten, 95 mm. (no. 5); rete ovarii, medullary cords (occupying central portion), egg cords, are shown. The 'synizetic wave' occupies approximately the middle of the zone of egg cords. Photograph. X 35.

9 Longisection of ovary, kitten 3 to 4 days, P. P. (no. 11). The position of the rete in the cephalic portion (at the right) is illustrated. There are shown the branched egg cords occupying the primitive cortex and extending down into the epithelio-stromal zone, the basal connective tissue nucleus. Medullary cords (in the epithelio-stromal zone) are not shown at this magnification. Photograph. X 15.

10 Transection of ovary, kitten 14 days, P. P. (no. 20). The zones of the ovary appear more definite. Medullary follicles beginning. Photograph. X 20.

11 Transection of ovary, kitten, Ca. 4 weeks (no. 22). The medullary follicles developing. In the primitive cortex, the primary follicles are forming. Photograph. X 20.

12 Transection of ovary, kitten, 5 to 6 weeks (no. 24). The peculiar medullary follicles whose development is illustrated in figures 16 to 25 are here shown developing. The cortical egg cords are now dissolved into primary follicles, the primitive cortex becoming the definitive cortex. Photograph. X 15.

13 Transection of ovary, kitten, 3 months (no. 35). The irregular, pluriovular medullary follicles are now large. Their irregularity and pluri-ovular character are indicated. Compare figures 31 and 32. The cortex is occupied by primary follicles. Two sections of rete ovarii are shown in the center. Photograph. X 12.


Plate 2

14 Transection of ovary, young virgin adult cat (no. 45). The Graafian follicles of the presexual period have practically disappeared and those of the adult period are developing. The zona parenchymatosa is well indicated by the ovarian stroma. Photograph. X 15.

15 Section of ovary, adult cat (no. 51). The surface of a corpus luteiim is cut. The zona parenchymatosa is occupied by the Graafian follicles in varying stages of development. The zone of primary follicles (cortex) is best indicated at the right and left. Photograph. X 12.

16 Two primary follicles with adjacent nests of follicle cells. From the intermediate zone of ovary no. 20 (14 day), showing 'stage 1' in the development of the irregular medullary follicles. Photograph. X 300.

17 Developing medullary follicles, 'stage 2.' Ovary no. 29. Photograph-. X 250.

18 Developing medullary follicle, 'stages.' Ovary no. 29. Photograph. X 250. A nodule of stroma is included between the investing and sheathing follicle cells. Two groups of interstitial cells are seen at the right, between them a small cluster of follicle cells.

19 Medullary follicle (young), 'stage 4.' The line of junction of the investing follicle mass is shown at the lower right hand corner (arrow). Photograph. X 250.

20 Similar to figure 19. The line of junction may be seen (j). Note also a nodule of included stroma (.s). Photograph. X 250.


Plate 3

21 Medullary follicle, illustrating the investment by the follicle mass. A group of stroma cells in the form of interstitial cells are being included (0- Photograph. X 250.

22 Irregular cumulus oophorus from a medullary follicle. The line of junction is still indicated {j). A small group of included stroma cells is also shown (s). Groups of interstitial cells lie external to the follicle (i). Photograph. X 250.

23 The development of medullary follicles. The elongated form of some of the follicle masses is illustrated. Four ova are related to the one shown, each with its peculiar sheathing follicular epithelium, two of them being cut through the nucleus. Photograph. X 60.

24 Two developing medullary follicles. Note the stromal investment of each. Groups of interstitial cells are shown interspersed. Photograph. X 100.

25 Two developing medullary follicles. Nodules of stroma are included between the investing and sheathing follicular epithelium. Photograph. X 100.

26 Mitotic spindle (polar spindle?) in a degenerating ovum. Ovary no. 39. Photograph. X 250.

27 Polar body. Degenerating ovum. From a section adjacent to that of figure 26. Photograph. X 250.

28 Ovum degenerating by fragmentation. A single nucleus is shown in tlie larger fragment. Two nuclei appear in the fragment immediately to the left of it. Photograph. X 250 (approx.).


Plate 4

29 Drawing of a single follicle grouping from a model of a segment of ovary no. 26. Two ova are shown each of which is within its own follicular epithelium. The irregularity of the 'investing' follicle mass is shown.

30 An ovum partially invested. From the model as in figure 29. A cordlike follicular mass lies adjacent to it.

31 Dniwing of a single irregular pluri-ovular follicle from a model of a segment of ovary no. 35.

32 As in figure 31. The marked irregularity and cordlike extensions are shown.




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