Paper - The ripe human Graafian follicle, together with some suggestions as to its mode of rupture

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Thomson A. The ripe human Graafian follicle, together with some suggestions as to its mode of rupture. (1919) J Anat. 54(1): 1-40. PMID 17103878

Online Editor  
Mark Hill.jpg
This 1919 historic paper by Thomson describes ovarian follicle development to Graafian follicle. The "discus proligerus" can refer to the attachment between cumulus oophrous and membrana granulosa.

See also by this author: Thomson A. The maturation of the human ovum. (1919) J Anat. 53(2-3): 172-208. PMID 17103860

Online Editor Notes  
  • discus proligerus is an historic term for granulosa cells surrounding the oocyte and forming the cumulus oophorus.
  • meiosis staging cannot be correct as described in text, as human oocyte completes meiosis I at ovulation and only completes meiosis II at fertilization.
  • See also paper by P N Odgers An Early Human Ovum (Thomson) in situ. J. Anat.: 1937, 71(Pt 2);161-168.3 PMID 17104634, describing an early embryo from Prof. Arthur Thomson
Nature Obituary 1935 - Prof. Arthur Thomson (1858 - 1935)
"ON his retirement in 1933, Prof. Arthur Thomson, whose death on February 7 will be widely regretted, had completed a somewhat unusual record of academic service. He was born on March 21, 1858, and for forty-eight years he represented human anatomy at the University of Oxford, first as University lecturer in human anatomy and afterwards as Dr. Lee’s professor of anatomy. After serving an apprenticeship in the famous school of anatomy at Edinburgh under Sir William Turner, Thomson went to Oxford in 1885. Unlike many of his later contemporaries, he did not enjoy the advantage of stepping into a department already equipped for teaching and research. On the contrary, the task fell to him of building up a new department from its very foundations. It will readily be appreciated that Thomson’s energies were fully employed for a number of years in developing the teaching side of his department to a level appropriate to the medical faculty of the University of Oxford, a task which was rendered very laborious at first by the criticism and opposition of some members of the University who were less ready to appreciate the importance of catering for an extensive and detailed medical curriculum."

Nature 135, 295-295 (23 February 1935) | doi:10.1038/135295a0

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1910 Fertilization | 1919 Human Ovum | 1921 The Ovum | 1927 First polar body | 1929 Oocyte Size | 1943 Fertilization | 1944 In vitro fertilization | 1948 In vitro fertilization

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The ripe human Graafian follicle, together with some suggestions as to its mode of rupture

Prof. Arthur Thomson

BY Arthur Thomson, Professor of Human Anatomy, University of Oxford

For the purposes of this paper the ripe Graafian follicle is defined as one which, from its superficial position, its size, and the thickness of the wall separating it from the ovarian surface, there is reason to believe is fast approaching the time at which rupture may take place. Added to this, must necessarily be considered the condition of the contained ovum. If evidence is forthcoming that the ovum is passing through, or has passed, the maturation stage, such is confirmatory proof that so far as the contents of the follicle are concerned they are ready for discharge. If, as not unfrequently happens, the ovum exhibits indications of degenerative changes, these must be taken into account in any estimate that may be formed regarding the normal appearance of the follicle.

Admitting that coincident with its approach to the surface of the ovary, the Graafian follicle enlarges, what are we to regard as the normal measures of its size? One can readily understand that there may be, and are, considerable variations in the dimensions of a follicle which in other respects fulfils the conditions which are to be regarded as indications of its ripeness.

Size of ripe Graafian Follicle. When reference is made to the various British and foreign text-books, it will be found that there is great disparity in the measures given. The dimensions recorded range from 2 mm. to 20 mm., the average size being about 15 mm. in diameter. In my experience this latter figure is much too high. In the specimens I have examined of follicles exceeding a diameter of 5 mm. I have either failed to find a contained ovum or when it was met with, it proved to be in a degenerated condition.

For these reasons a certain amount of caution is necessary before accepting the figures usually quoted, for mere naked eye inspection of the ovary, on section, may be misleading, since though the follicles exposed may be of considerable size, there is no proof that their contents are normal.

Nagel ((23), p. 44), to whom deference must be paid as a reliable observer, says that the follicle may attain a diameter of 10-20 mm. before it ruptures, and that no limits can be fixed to its growth within these figures; the test is whether the follicle contains a normal ovum. Testut ((31), p. 696), on the other hand, is much more conservative in his estimate; he describes the follicle as usually measuring between 2 and 8 mm. or more, occasionally as much as 9 mm. As will be noticed, his upper limit falls below the lower value given by Nagel.

If it be that the larger figures, viz. 15 to 20 mm., are of common occurrence, it follows that the ovary in which such a follicle is found must present a remarkable appearance, since the size of the ovary itself is usually recorded as about 30 mm. in length, so that the presence of so large a follicle in its substance would very materially affect the surrounding tissue, and would greatly alter the external appearance of the organ.

It is possible that immediately prior to its rupture the Graafian follicle may undergo a sudden and rapid increase in its size, but so far, in the material at my disposal, I have not come across any follicles of the larger dimensions given, which in other respects could be regarded as normal.

Possibly deductions as to the size of the ripe follicle prior to its rupture have been made from the appearance displayed by the presence of corpora lutea in different stages of development, but in regard to this it may be observed, that we are without information as to the rapidity and extent of the changes that may ensue within the follicle immediately after its rupture.

In the accompanying table the results are given, so far as the size of the follicle is concerned, as observed in the material at my disposal.

Table 1. - to be formatted

Table 1.  
Table I

Size of ripe Graafian Follicles containing Normal Ova The measures are given in millimetres.

Specimen Diameters Distance from Surface 453 À 35* 1:63 x 2-00 x 1-96 0-3 O1 122 4-53 x 3:14 x 4:90 0-3 453B 14* 2-62 x 1-56 x 2-54 0-34 02 106 0-79 x 0-80 x 0-62 0-36 01 95 4-59 x 3-16 x 4:82 0-56 U3 27 3-20 x 3-08 x 5-20 0-6 380 98** 1:47 x 1:84 x 2-80 0-88 L 453 À 3** 1:39 x 1-66 x 2-34 1:00 02 67 0-71 x 1-18 x 2-06 1-04 01 14 2-90 x 2-58 x 2-09 1:16 453F 34 0-98 x 0-56 x 1-20 1:28 453F 20 1:42 x 1:70 x 1-56 2-6 453F 30 1:37 x0-96x1-20 2-6

The specimens in this table are arranged in order of the thickness of the wall which separates the Graafian follicle from the surface of the ovary. Generally speaking, those with the thinnest wall are the larger follicles, though this is not an invariable rule, as may be seen from an inspection of the table. It would therefore appear that there is considerable variation in the size of the follicle independent of its proximity to the surface.

In specimens 453 B 14 and 453 A 85 (marked *) the contained ova, after examination, have been pronounced mature. In specimens 458 À 3 and 380 98 (marked **), the contained ova are in the process of maturation.

Apparently the healthy Graafian follicle tends to be spherical, as if well filled. In cases where it is irregular in shape and angular in form the contents are generally found to be in a degenerated condition.

If the examples given in the above table are to be regarded as ripe for rupture, their relatively small size suggests that they are in a more or less quiescent condition, and that prior to their rupture they will undergo a sudden and more or less rapid increase in their bulk when the appropriate occasion arises. This is a matter which will be dealt with later in the paper.

Position of Cumulus

Another point on which there is much conflict of opinion, in the published accounts, is the position within the Graafian follicle of the cumulus or discus proligerus surrounding the ovum.

Nagel ((23), p. 57) very definitely states that “in man, and, as it seems, in most mammals (Waldeyer, Frey, Henle) the cumulus always has this position on the medial wall of the follicle, somewhat more to one side or the other of the middle line, and consequently always opposite the stigma (the point where the follicle ruptures).” This view is acquiesced in and followed by Poirier (25), p. 695, vol. rrr.), Tigerstedt (32), and Piersol ((24),-p. 1989).

McMurrich ((18), p. 19) qualifies it somewhat by stating that the discus is found “at one point usually on the surface nearest the centre of the ovary.”

H. N. Martin ((20), p. 78) takes a diametrically opposite view, assigning a position to the cumulus usually corresponding to that “nearest the surface of the ovary.”

À. Flint ((9), p. 759) expresses the opinion that “the Situation of the discus proligerus is not invariable; sometimes it is in the most superficial and sometimes it is in the deepest part of the Graafian follicle.”

Most authors maintain à discreet silence on the point, whilst J. H. Raymond ((26), p. 627) accepts the view of Bôhm and Davidoff ((3), p. 352) to the effect that the discus proligerus with the contained ovum ultimately comes to lie free in the liquor folliculi, a change which is brought about by the softening of the cells forming the pedicle of the discus.

As the outcome of my own observations I feel justified in saying that the position of the cumulus or diseus proligerus is not always on the deep wall of the follicle opposite the stigma, as stated by Nagel and others, but that in fact it may. be frequently met with on the most superficial aspect of the follicle, i.e. that nearest the surface of the ovary, and consequently close to the stigma or point of rupture. Indeed, the position of the cumulus appears to be determined by no known law, and its occurrence on any part of the circumference of the follicle may be observed.

The view almost universally accepted, is that the discus proligerus remains throughout the growth of the follicle adherent to the cells of the stratum granulosum through the medium of a pedicle which may vary considerably in appearance, in some cases being long and attenuated, in others short and wide. The appearance represented under the microscope will vary much according to the plane of section, and any satisfactory elucidation of the subject is only possible after the careful examination and reconstruction of serial sections.

It frequently happens that a single section, or, it may be, a small series of sections, would give support to the view that the discus proligerus with the contained ovum lay free in the liquor folliculi. On more extensive examination, however, so far as my own experience goes, these specimens can always be traced so as to reveal a connexion with the cells of the stratum granulosum. Such an observation, however, does not necessarily contravert the view taken by Bôühm and Davidoff, for it is possible, as will be hereafter explained, that the cumulus and ovum may be found floating in the liquor folliculi, having acquired that position by a means other than that described by these authors, viz. the division of the pedicle.

The advantage of having thé ovum and diseus proligerus floating fairly free . in the liquor folliculi is at once apparent when we come to discuss the mode and manner of the discharge of the ovum when the Graafian follicle ruptures.

It is obvious that the position of the eumulus must stand in some distinct relation to the mechanism which determines the escape of the ovum from the follicle.

If one accepts the view that the cumulus is always situated on that side of the follicle which lies farthest from the surface of the ovary, it becomes at once difficult to explain how it is possible, by any increase of pressure in the fluid contained within the antrum folliculi, for the ovum to be expelled through an aperture which lies on the opposite side to that on which it is placed. It seems more probable that the fluid pressure being equally exerted in all directions, is rather likely to force the ovum more firmly against the wall on which it rests. Hence the obvious advantage of a more superficial position as claimed by Martin (Loc. cit.), for there the ovum resting on or in relation to the weakened wall of the follicle (stigma), where the rupture is about to take place, will naturally be expelled through the orifice made in the wall of the theca against which it lies, by the bursting pressure exerted by the liquor folliculi. Such an explanation seems feasible, and would be one way of explaining the escape of the ovum in those cases in which the cumulus is superficial in position. But the question naturally arises, is it the normal way?

In cysts which enlarge through the increasing amount of their fluid contents, there is a tendency towards the production of marked flattening of the cellular contents which line their more resisting envelopes. If this be the case, we would expect to find the cells of the stratum granulosum lining the interior of the follicle thinned and compressed, an appearance which we do not see; the absence of such a condition is probably to be accounted for on the supposition that these cells are really part and parcel of the liquor folliculi, forming as it were a superficial layer of cells bathed in and surrounding the liquor folliculi, overlying, but not intimately attached to, the “basal membrane” or “external limiting membrane” of some authors (see Robinson (27) pp. 811 and 819) which lines the inner surface of the internal theca. It is on this layer that the pressure exercised by the contents of the follicle is apparently exerted, else, were the cells of the stratum granulosum a constituent part of the wall : of the follicle, we would expect these cells, as already stated, to exhibit indications of the result of pressure. Reference will be made later to this basal membrane, meanwhile it will be sufficient to suggest that possibly there is a lymph space in association with it.

What holds good of the cells of the stratum granulosum must also apply equally to the cells of the eumulus. It would be natural to expect that in cases where the cumulus has a broad base and an absence of pedicle, the follicular cells of which it is composed would react to such pressure as may be exerted on them, were it not that they form a constituent part of the fluid and semifluid contents of the follicle. What is true of these cells would also apply to the ovum which they surround, consequently we are entitled to assume that ‘all the contents of the follicle within the basal membrane are subject to an equality of pressure, whatever that pressure may be. For the present the consideration of this subject is postponed until certain other details of the Graafian follicle have been considered. Meanwhile I here place on record my own observations as to the position of the cumulus within the follicle.

In 15 Graafian follicles which might be accounted as “ripe,”” and having normal contents, the cumulus or disceus proligerus was in seven cases situated superficially, that is towards the ovarian surface. In two instances it lay deep within the follicle, the term “deep” being here employed to indicate that the cumulus was placed on the -wall of the follicle farthest removed from the surface of the ovary. In six follicles the cumulus lay to one or other side of the follicle, intermediate in position between the superficial and deep positions above indicated.

In 10 Graafian follicles either containing degenerate contents, or not so advanced in growth, the cumulus was situated six times superficially, twice laterally, and in two cases deeply.

These records are too few from which to deduce any reliable data, but are sufficient to contravert Nagel’s statement, for out of 25 Graafian follicles the cumulus occupies a superficial position in 18 cases, or about 50 per cent. whereas it only occurs in the “deep” position, that accounted as normal by Nagel, in four instances or 16 per cent.

Liquor Folliculi

Concerning the manner of the production of the liquor folliculi there is much divergence of opinion. The question at issue is whether the liquor folliculi is of intercellular or intracellular origin.

Scattered among the follicular epithelium, contained within the follicle, are certain structures called the bodies of Call and Exner (4. These have been variously interpreted, by some as vacuolated cells (the “epithelial vacuoles ” of Flemming ((8), p. 878)), by others as intercellular collections.

The prevalent ideas with regard to the origin of the liquor folliculi may be briefly stated as follows. Nagel ((23), p. 54) regards it as formed partly by transudation from the vessels surrounding the follicle, partly by disintegration of the large follicular cells (the “ bodies of Call and Exner” or the “epithelial vacuoles” of Flemming), whose protoplasm swells, finally to be completely broken up, the nucleus at the same time crumbling away and finally breaking up.

On the other hand C. Honoré ((14), p. 587), from his researches on the rabbit, states that the stratum granulosum secretes the liquor folliculi just as the epithelium of the tubes of the kidney secretes urine. He explains the presence and appearance of the bodies of Call and Exner as follows. A certain number of the cells of the stratum granulosum group themselves radially and secrete a substance at first homogeneous. This central substance later becomes a reticulum, and increases in size with the growth of the follicle; the reticulum becomes finer, and a kind of peripheral membrane appears, at the same time the radial arrangement of the surrounding cells becomes less evident. The staining of these bodies in follicles of different sizes shews that their chemical constitution is modified by age.

My own observations on this subject may best be explained by a series of microphotographs, which I venture to think illustrate the successive stages of the process.

The feature which enables the observer to recognise them consists in the arrangement, in radial fashion, of the follicle cells disposed around them. This appearance is so characteristic that Call and Exner suggested that they were of the nature of ova, and that the arrangement of the cells surrounding them was comparable to the corona radiata encircling the ovum.

Within the area circumscribed by this radial formation of the follicular cells, in a typical example, there is a mass of variable size, often of a more or less clear, homogeneous matter, reacting to some stains in a selective way, but generally presenting appearances which correspond in tint and density with the reaction to the same stain of the coagulum in the antrum folliculi. The nature of the material occupying the centres of these radially arranged follicular cells has been variously interpreted. By some, these ‘‘ bodies ”” have been regarded as the product of the liquefaction of the protoplasm of the follicular cells (Nagel(2), p. 381; Waldeyer(3), p. 838). Bernhart considered them of a fatty nature, but this view was combated by Bischoff, who held that they failed to refract the light sufficiently to justify this assumption. Flemming describes them as vacuoles of epithelial origin. C. Honoré regards them as having an intercellular origin and as being due to the accumulation of the products of the special activity of the radially arranged follicular cells around them.

Fig. 1. Shewing bodies of Call and Exner (B. of C. and E.) surrounded by radial arrangement of follicular cells (Rad. foll. cells) in the stratum granulosum (str. gran.) of a human Graafian follicle. x 900 diameters. Antr. foll. antrum folliculi. Specimen 280 G. 5.

Fig. 2. Shewing a body of Call and Exner (B. of C. and E.) surrounded by radial arrangement of follicular cells (Rad. foll. cells) in the cumulus (cum.) of a human Graafian follicle. x 900. Ov. ovum.—Z. pell. zona pellucida.—-Cor. rad. corona radiata.—Antr. foll. antrum folliculi. Specimen 280 G. 4.

Fig. 3. Ovum within the stroma of the ovary surrounded by follicular cells. As yet there is no antrum folliculi. Near 1 of the watch dial there is a body of Call and Exner surrounded by a corons of follicular cells, within which the structure’ presents a homogeneous appearance. x 400. Specimen O. 2. 59. 4. Ovstr Int. theca.

Fig. 4. Section of a human Graafian follicle containing a maturing ovum. Ov. str. ovarian stroma; Int. theca, internal theca; ext. theca, external theca; sfr. gran. stratum granulosum; antr. fol. antrum folliculi; cum. cumulus, with bodies of Call and Exner therein; ov. ovum; surrounded by zona pellucida and corona radiata. B. of C. and E., Bodies of Call and Exner in the stratum granulosum. x 100. Specimen 280. G. 2.

In attempting an elucidation of these various views it will be necessary to draw attention first to the stage at which these bodies make their earliest appearance, and the manner of their distribution.

Fig. 8 represents the appearance of one of these bodies as seen in a Graafian follicle in which there is as yet no antrum folliculi. In the specimen shewn, the body of Call and Exner is of large size as contrasted with others which occur in the serial sections of the same follicle, and its contents react to the stain (iron haematoxylin and Van Giesen) in such a manner as to be coloured a deep orange. It may be noted that in follicles in which an antrum folliculi occurs, under the same staining reagents the enclosed coagulum is usually tinted yellow. The same relation is seen in specimens stained with Mallory’s connective tissue stain, both coagulum and “bodies” are coloured blue, the latter much more deeply. This cireumstance would suggest that the liquor folliculi is of the same or similar nature as the matter contained in the bodies of Call and Exner, though possibly more dilute.

The question of size, to which reference has been already made, is a matter of some importance, as will presently be noted, as having a bearing on the manner of formation of these bodies.

In regard to their distribution. As stated above, they occur in follicles prior to the formation of the antrum folliculi, and I have seen evidences of what I took to be their genesis in follicles as early as the double-layered stage of the follicular epithelium. Subsequent to the appearance of the antrum folliculi, they are met with equally amongst those parts of the follicular epithelium which are ultimately to become the stratum granulosum, and in the cumulus, as shewn in fig. 4.

When, however, by the increase in the size of the antrum folliculi, the stratum granulosum becomes much thinned, then we find their occurrence in that layer much less frequent, until in advanced stages of the growth of the follicle they cease to be met with in the stratum granulosum altogether.

Not so, however, in the region of the cumulus, for here, immediately around the ovum and towards the basal part of the cumulus, they may be seen in follicles which are to be regarded as near approaching rupture, to judge by the thinness of the superficial wall and the mature condition of the oocyte.

Meanwhile it may be noted that these so-called bodies of Call and Exner, in different stages of their development, exhibit very different appearances.

I am fortunate in being able to reproduce a microphotograph of the appearances displayed in the basal region of the cumulus where that structure becomes continuous with the stratum granulosum. Here within the same field certain appearances are to be noted which very definitely suggest that these bodies are the result of changes actually taking place in single follicular cells, or, it may be, in groups of such cells (fig. 5).

Fig. 6 is a view shewing in the centre of the field a follicular cell which is remarkable on account of its size and appearance.

Enclosed within a definite cell wall the cytoplasm appears uniformly granular, and stains somewhat more deeply than that of the surrounding cells; within this the nucleus shews up as a darker mass with no clearly defined nuclear membrane such as is so characteristic of the surrounding cells, and the chromatin granules are no longer isolated, but appear to be diffused through the nuclear protoplasm (käryoplasm) in such a way as to impart a darker tint to the whole nuclear substance, evidently a stage in the ultimate dissolution of that structure.

Fig. 5. Section through the base of the cumulus of a human Graafian follicle showing three bodies ot Call and Exner (a, a, b). Two of these (a, a) are seen to be formed from single follicular cells, whilst b exhibits their origin from a group of follicular cells. x 900. Specimen 280. 12. 5.

Fig. 6. Section through the follicular epithelium sbewing a an enlarged follicular cell prior to its being surrounded by a corona of contiguous follicular cells. At b a similar follicular cell is seen in process of being so surrounded. x900. Specimen 453 A. 4. 5.

In fig. 7 a further stage is exhibited. Here there is distinct evidence of a vacuolation of the cytoplasm taking place within the cell membrane, while the nucleus becomes less distinct and seems to be more diffuse. At the same time, as will be seen in the figure, the surrounding follicular cells, by the increasing expansion of the central cell undergoing these changes, arrange themselves in radial fashion, as would naturally be expected under the circumstances. In the same field another such body is seen enclosed in typical fashion by the characteristic radial formation of the surrounding follicular cells, though here a large vacuole occupies the major part of the cell and the nucleus has disappeared.

Fig. 7. Section shewing vacuolation of cells composing bodies of Call and Exner, a, a, a. At bthe nucleus of one of them is disappearing. x900. Specimen 280. 16. 5.

The occurrence of the vacuolation seems to vary in different examples; in many this phenomenon does not occur till after the nucleus is completely dissipated within the substance of the cell, so that the central mass produced would seem to form a more or less homogeneous, seemingly solid, clearly staining material, occupying the centre of the radial formation of the follicular cells. The change in the subsequent appearance of this substance is effected through the appearance either at the side of, or within it, of vacuoles of different sizes. In tbe first instance these spaces may be small and few, in which case the appearance presented is that of a coarse reticulum. In other cases the central mass may be transformed into a fine reticulum by the presence of a number of vacuoles which break it up in a more effective way, as seen in fig. 8.

Fig. 8. Section shewing the bodÿ of Call and Exner now reduced to the form of a reticulum by the vacuolation of its substance. Around the vesicle so formed the contiguous folkicular cells are grouped in coronal fashion. x900. Specimen 453 A. 4. 5.

Fig. 9. Section shewing how the bodies of Call and Exner (B. of C. and E.) may be compounded of a number of follicular cells. x900. Specimen 453 A, 4. 5.

Hitherto we have assumed that these appearances are the result of the changes induced in one follicular cell, but there is evidence that groups of cells may be agglutinated together, becoming, so to speak, encapsuled to form the centre of a radial formation, thereby greatly increasing the size of the socalled “body of Call and Exner.” Fig. 9 represents this appearance.

The individual cells of these groups appear to undergo the same changes as those noted in the single cells already referred to, resulting in the fusion of their products, and displaying this difference, that the size of the resulting body is considerably larger, and the reticulum more complex.

Fig. 10. Section of a body of Call and Exner vacuolated and shewing the disappearing nuclei, a, a, a, of some of the cells of which it is compounded. x 900. Specimen 280. 12.5.

A further proof of this is seen in fig. 10, where there is distinct evidence of the presence of nuclear structures within the resulting reticulum.

The microphotographs here reproduced make it clear that the bodies of Call and Exner can in no sense be regarded as due to the accumulation of the products of the special activity of the radially arranged follicular cells around them, as suggested by Honoré, but must be interpreted as the result of changes in a follicular cell or group of cells, whereby modifications are induced in their molecular structure, leading to the production of certain materials at different periods of their dissolution, and ultimately resulting in a liquefaction of the bulk of their contents, which, together with a residual stroma, contributes to the increase in the amount of the liquor folliculi.

In this respect my observations lead me to support the view advanced by Nagel and others. There can, I think, be little doubt but that the radial arrangement of the surrounding follicular cells is a purely mechanical result, and that the so-called bodies of Call and Exner are merely to be considered as foci of the processes which ultimately result in the breaking down of the primarily compact mass of follicular cells, coincident with the production of an antrum folliculi and the subsequent distension of that cavity with fluid.

In this way the major part of the follicular cells disappears. As to how they are replaced or multiply, we have the evidence of Flemming ((8), p. 376 and pl XIX, figs. 32-84), who describes the frequent occurrence of karyokinetic figures in the cells of the stratum granulosum of the cat and the rabbit, and of Harz (12) p. 374) who records mitosis in the follicular cells of the mouse, whilst Nagel ((22) p. 379, pl. XXI, fig. 14) refers to it as demonstrated in the human female.

In Professor A. Robinson’s memoir (21) I note the occurrence of mitotic division as exhibited in his beautiful series of microphotographs (see fig. 58, pl. X).

It follows that subsequent to the disappearance of the bulk of the follicular cells, only a thin layer of cells, often only a single row in thickness, is left lining the inner surface of the internal theca, and over-spreading the external limiting membrane: This much reduced layer constitutes the stratum granulosum.

The only other situation in which the follicular cells appear to persist is in the region of the cumulus, where in nearly all advanced Graafian follicles they remain as a stalk or pedicle to the mass of cells which contains the ovum.

In these situations the follicular cells which may subsequently undergo liquefaction, if this term may be employed, are not bedded in a compact mass of surrounding cells, but often lie in such a position that one part of their surface is only covered by a single layer of follicular cells, or may lie free in the wall of the antrum folliculi. The first of these conditions is represented in fig. 11, where in the stratum granulosum the body comparable to that of Call and Exner is represented by the cyst-like formation, the wall of which, directed to the antrum folliculi, is formed of a thinned and spread-out layer of follicular cells.

Fig. 12 shews the changes presented by a follicular cell superficially placed, i.e. one of the cells lining the antrum folliculi. Here, within a vacuole, the contained nucleus is exhibited undergoing evident dissolution. Similar changes are also represented in fig. 13, in which case the change in the appearance of the nucleus within the vacuole is less marked.

It would seem, in some cases, that the nuclear elements do not entirely disappear, a fact which would account for the presence in the liquor folliculi of the numerous nuclear-like bodies not unfrequently met with.

Fig. 11. Section of a body of Call and Exner in the stratum granulosum (str. gran.) separated from the antrum folliculi (antr. fon.) by but a single layer of follicular cells. x900. Specimen

Fig. 12. Section shewing a follicular cell, a, of the stratum granulosum (str. gran.) undergoing dissolution. The nucleus is seen in an altered condition surrounded by a vacuolated space which may either be an artefact of the nature of a retraction cavity or may contain fluid of a different chemical constitution from that contained within the antrum folliculi (antr. foll.\ which is seen in the form of a coagulum. x900. Specimen 280. 16. 6.

In considering the changes in the follicular epithelium coincident with the appearance and expansion of the antrum folliculi, a staining reaction which is by no means infrequent must be here referred to. This consists in a marked difference with which some of these follicular cells react to the same stain, or combination of stains. It is best seen in the specimens which have been subjected to the influence of some such reagent as Mallory’s connective tissue stain, whereby some of the cells become stained of a pink or a yellow colour, as contrasted with others (the majority) which exhibit a blue tint, an occurrence which would suggest that some of the cells were undergoing a change in their chemical constitution.

Fig. 13. Section shewing stratum granulosum (str. gran.) with a separated follicular cell (a) lying within a vacuolated space within the coagulum occupying the antrum folliculi (antr. foll.). The separated follicular cell (a) does not as yet present any appearance of undergoing er The vacuole around it may be an : artefact or due to the vital activity of the cell (a). Specimen 280. 14. 4.

It has been said that the cells of the stratum granulosum lining the interior of the follicle and resting on the membrana limitans externa which separates them from the inner surface of the internal theca, although often reduced to a single row of cubical cells, yet exhibit no appearance of flattening or compression, such as would be due to the result of pressure from within; for this reason these. cells must be regarded as a constituent part of the contained liquid contents of the follicle, the pressure exercised by which is supported by the internal theca overlain by the membrana limitans externa.

Another matter to which attention must be incidentally directed is the fact that the stratum granulosum is exceedingly prone to separate from the inner theca of the follicle. In this connexion the observations of Robinson ((27;, p. 320) on the ovarian follicles of the ferret are of interest. After pointing out that Wagener, Schottländer, and Limon regard the membrana limitans externa as a connective tissue structure, whilst Waldeyer and Nagel believe that it is formed by the follicular cells, the latter asserting that it is similar at first to the oôlemma, Robinson proceeds to point out that in the ferret, the membrana limitans externa does not react to stains in the same way as does the oôlemma (zona pellucida), and that when the follicular epithelium is detached from the internal theca by the action of the fixative reagents, the membrana limitans externa separates into two layers, as displayed in the figures he gives (figs. 58 and 60, pl. X). “The inner of the two layers,” continues the author, “is connected with the outer ends of the follicle cells, and is possibly formed by them in the same way that the external limiting membrane of the central nervous system is formed by the outer ends of the neuroglial cells. The outer layer is connected with the innermost flattened cells of the internal theca, and it reacts like other connective tissue structures to connective tissue stains.” He says further “ Its function is unknown, but its constant presence indicates utility, and it possibly regulates the passage of different materials in opposite directions to and from the follicle.” . ‘ In regard to the staining affinities of thé membrana limitans externa and the zona pellucida in human material, our own observations do not correspond with those of Robinson. In general, allowing for the difference in the density of the two structures —the membrana being exceedingly delicate as compared with the zona—the staining reaction appears to be very similar—both take up the plasma stain as distinct from the nuclear stain. The appearance of the membrana limitans externa is in every case very similar to that of the capillary walls, in fact of all vessels which possess no muscular coat.

In sections of the rabbit’s ovary, which were examined after being subjected to Mallory’s connective tissue stain (fixative: Flemming’s (strong) formula), both the zona and the membrane were tinted blue alike. It was noticeable that in the rabbit the membrane was a somewhat denser layer than is revealed in the human Graafian follicle.

Observations on the human material at my disposal confirm the view that the cells of the stratum granulosum are very prone to separate from the inner surface of the internal theca of the follicle, and when this separation takes place, the layer which intervenes, viz. the external limiting membrane, invariably remains attached to the connective tissue elements of the internal theca. The separated layer of the stratum granulosum exhibits little appearance on its outer surface of any but the feeblest connexion with this membrane, and in most cases shews little evidence of any connecting fibres. In some instances it would appear as if the union between the stratum granulosum and the membrana limitans externa was sufficiently intimate to lead to a tearing away of a layer of this latter structure, along with the cells of the stratum granulosum, so separating it into two layers, as described by Robinson, the inner being connected with the outer surface of the cells of the stratum granulosum, the outer still remaining adherent to the inner surface of the internal theca, though no difference in staining reaction such as is described by Robinson could be discerned. The accompanying figures (figs. 14 and 15) represent both conditions.

The fact that the ease with which the stratum granulosum appears to separate from the membrana limitans externa seems to vary with the ripening of the follicle, would suggest that this separation is a natural process, and not necessarily an artefact as frequently supposed. The fact, too, that the membrana limitans externa is at times prone to split into an external and an internal layer, where separation of the stratum granulosum takes place from the inner surface of the internal theca, inclines one to the view that possibly this intervening layer between these two mentioned structures may be in fact permeated by an irregular lymph space, which weakens the bond between the internal theca and the layer of the contained follicular cells, and so renders more easy the separation of the two structures. For apart from the evidence forthcoming in the examination of unruptured follicles, there is the circumstance that immediately after the bursting of the follicle and prior to the formation of a corpus luteum, the entire stratum granulosum is shed and disappears, leaving only the internal theca and the membrana limitans externa lining it. Moreover, through the courtesy of Professor Robinson I have been able to note the fact that in the ferret the ovuni after it has éscaped from the Graafian follicle is not only surrounded by the cells of the cumulus, but also has connected therewith a considerable amount of a layer corresponding to the stratum granulosum, thus proving that at the time of rupture the stratum granulosum was in part or in whole discharged. These observations seem to point to the separation of the stratum granulosum from the internal theca as a normal process, and not necessarily an artefact as so many hold it to be.

This matter will be again referred to when the mode of rupture of the follicle is discussed.

In concluding this section relating to the liquor folliculi, mention must be made of the varieties of coagulum met with in the follicle, even when subjected to the same fixing reagent. In many instances the coagulum exhibits the appearance of fine ground glass, in others the granulations are coarser. In some it takes on the form of an open meshwork. In all, as best seen at the edges, the reticulum varies much in appearance, in some it is fine, in others, coarse. These appearances, met with in what seem normal follicles, combined with the variety of tint displayed when subjected to the same staining reagent, suggest that the physical and chemical constitution of the liquor folliculi is not always constant, but is undergoing change, it may be by the addition or subtraction of constituents which affect its density or alter the character of its composition.

The Sheath of the Follicle

As usually described the specialised part of the ovarian stroma around the follicle consists of two not very clearly defined zones, the internal theca and the external theca. The internal theca is composed of a loose cellular stroma made up of round and spindle-shaped cells, and has a capillary net-work throughout its substance. To the outer side of this lies the external theca, in which zone, the tissue is denser, more fibrillar, and less vascular, though here the blood vessels are larger, and furnish the branches which supply the capillary plexus of the internal theca. In the theca externa there are also described a number of hollow spaces which are interpreted as enlarged lymph channels.

Fig. 14. Section shewing the appearance of the internal theca (int. theca) when the stratum granulosum has become separated from it. The membrana limitans externa (mem. lim. ext.) is seen adherent to the internal theca. B.vs. capillaries within the internal theca filled with blood corpuscles. x'700. Specimen O, 1. 103

Fig. 15. Section of the wall of a follicle shewing stratum granulosum (sfr. gran.) and internal theca (int. theca) lying in apposition, with the external limiting membrane (mem. lim. ext.) in between; at the point a this layer is seen to split, one layer (b) adheres to the internal theca, the other (c) clings to the stratum granulosum; the interspace between is probably a lymph space. B.vs. capillaries of internal theca: antr. foll. antrum folliculi. x 600. Specimen O. I. 20. 5.

A study of the appearance of the internal theca reveals the fact that this layer becomes richer in capillaries as the growth of the follicle proceeds (see Nagel, (23), p. 56); so also the round cells become larger and more numerous. In some instances I have reason to believe that the theca interna over the area which corresponds to the site of the cumulus is more vascular than in other parts of the circumference of the follicle, a fact which, as will presently appear, has some significance.

Not only does the internal theca appear to be richer in capillaries, but in several instances, one of which is here represented (fig. 16), the capillaries are not confined to the theca interna, but invade the substance of the follicular epithelium, where it forms the base of the cumulus or discus proligerus.

So far as I am aware, no mention of this condition has hitherto been made, and I was inclined to regard the first specimen I observed of this appearance as of the nature of a haemorrhage. The sections, which were stained with Mallorÿy’s connective tissue stain, revealed the blood corpuscles as tinted a brilliant scarlet, a feature which enabled us to trace with ease their disposition and arrangement. By adopting a method of reconstruction it was possible to prove the continuity of these collections of blood corpuscles, and to trace their connexion with the capillaries of the internal theca; there was also distinct evidence that around these collections of blood cells there was a delicate membrane, directly continuous with, and presenting the same appearance as, that enclosing the capillary channels of the internal theca. Obviously it was hazardous to base any conclusion regarding the nature of this condition on its occurrence in one particular specimen, consequently a search was made to see whether it occurred in other follicles. The-result was confirmatory, for in several other instances the presence of blood corpuscles similarly grouped and ensheathed was clearly demonstrated, though it must be admitted, that but for the differential staining produced by the employment of Mallory’s formula the occurrence of this particular arrangement might have been overlooked.

On reviewing the evidence, however, it was particularly noticeable that, with one exception, all the specimens exhibiting this feature were derived from the same source, a woman who died of heart disease, and regarding the post mortem of whom the report records the occurrence of “back pressure” changes in many of the viscera. This condition may naturally be regarded as answerable for the appearance displayed, and might be accepted as conclusive evidence that the arrangement of the capillaries represented is abnormal, were it not for the fact that a similar condition was met with in the ovary of a woman aged 85 who died of laudanum poisoning, in which case the ovum contained within the follicle was degenerate. It may be that the administration of this drug is alike responsible for the unusual appearance observed. Whatever be the cause, and whether or no we are to regard the incidence of

Fig. 16. Section through the cumulus or a human Graanan roule shewing ovum in situ surrounded by the zona pellucida and corona radiata. The base of the cumulus is invaded by capillaries containing blood cells. These are seen to be enclosed by distinct walls similar to those displayed by the capillaries of the internal theca (int. theca). The membrana limitans externa (seen at mem. lim. ext.) seems to disappear as a definite layer in the region corresponding to the base of the cumulus (cum.). Ext. theca, external theca: antr. foll. antrum folliculi, x 200. Specimen 453 F. 20. 4.

Exttheca. int. that. MerbiitLext this feature as normal or abnormal, its occurrence is worthy of record, since possibly, if normal, it may be the means of providing the ovum with an increased source of nutrition, whilst if abnormal, it may account for degenerative conditions which may arise in like or similar circumstances.

It is interesting to note that in the specimens taken from the woman who died of heart disease, the presence of this condition did not appear to have any deleterious effect on the ova, for in‘the sections examined these appeared to be normal. In the case of the woman who died from laudanum poisoning it is open to doubt whether the degenerated ovum was a direct result of the poison . or secondary to the vascular changes present.

There arises in this connexion the question of the relation of the membrana limitans externa (basal membrane) to these capillary invasions. It would appear from an examination of the specimens in which this peculiar distribution of the vessels occurs, that in the neighbourhood of their entry into the cumulus the menmbrana limitans externa has disappeared, and there seems no line of demarcation to separate the follicular cells from the connective tissue elements of the theca interna.

It must not be assumed that the cases I have recorded include all the instances of blood within the follicle. Not unfrequently undoubted cases of haemorrhage aré met with, occurring either as scattered masses of blood corpuscles within the substance of the follicular cell work, or else discharged in bulk into the antrum folliculi. These collections we generally found associated with molecular changes in the walls of the follicle, and also combined with marked degenerative changes in the ovum itself. It may be that the appearances I have noted, and here figured, are only an early stage of the process which ultimately results in a diffuse haemorrhage. If so, they may be of interest as shewing how this destructive process leading to the atresia of the follicle is induced.

Of the changes which take place in the structure of the internal theca at the point corresponding to the site of its ultimate rupture little need be said. As the covering wall of the follicle in this region becomes thinner its vascularity becomes reduced.

Already reference has been made to the membrana limitans externa (basal membrane). This, as has been said, intervenes between the inner surface of the theca interna and the peripheral cells of the follicular epithelium which lie within the follicle. It is shown in situ in fig. 17.

As already described, when separation occurs between these two constituents of the follicle, the bulk of the membrana limitans externa (basal membrane) remains adherent to the flattened cells forming the inner surface of the internal theca (see fig. 14). For this reason, the term ‘ basal membrane” as applied to it, suggesting its intimate connexion with the cubical cells of the stratum granulosum which overlie it, is misleading. Its behaviour and anatomical disposition are more in accord with the interpretation of the term ‘external limiting membrane” applied to it.

It should be noted that in many parts of the section of the wall-of the follicle this limiting membrane is the only layer which intervenes between the capillary stream and the contents of the follicle, and if so be, as has been suggested by its tendency to split into two layers, this limiting membrane contains a series of lymph channels within its substance, it may well be that it forms a structure of no little importance, not only in regard to the nutrition of the follicular contents, but also in conñexion with the process involving the rupture of the follicle itself.

The external theca. As already explained, there is no clear line of differentiation between this and the internal theca; it differs from the latter in the absence of a capillary network, and the greater density of its constituent layers, which are largely composed of fibrillar tissue, derived from the surrounding ovarian stroma, and concentrically arranged around the Graafian follicle. It is to the nature of this tissue that attention must first be directed.

Schäfer ( (29), p. 648) thus describes the ovary: “ Each ovary is formed of a solid mass of fibrous-looking tissue (stroma), which contains between its fibres very many elongated cells like those of embryonic fibrous tissue... .Along the line of attachment (hilum) blood vessels and nerves enter and leave the ovary, and accompanying these is a strand of fibrous tissue which contains plain muscle amongst its fibres.”

Fig. 17. Section through the wail of a human Graafian follicle shewing stratum granulosum (str. gran.),membrana limitans externa (mem. lim.ext.) and internal theca (int. theca) all in contact. B.vs. capillaries of internal theca containing blood. Antr. fol. antrum folliculi. x 700. Specimen 453 B. 27. 3.

Piersol ((24), p. 1987) says of the cortex of the ovary: “The stroma cells somewhat resemble the elements of involüntary muscular fibre in appearance,” and in reference to the medulla says it consists of fibro-elastic tissue and smooth muscle accompanying the larger vessels. In this connexion it may here be stated that in a specimen stained with Weigert’s elastic tissue stain the only situation in which elastic fibres were recognised was in relation to the walls of the vessels—neither in the general stroma of the organ nor in the follicular walls was there any evidence of the presence of elastic tissues.

Nagel ((25), p. 49) states that in the zona vasculosa there is “an extension from the muscular tissue of the broad ligament along the larger vessels, better marked in mammals than in‘man.” |

It would seem, therefore, that in the groundwork of the ovary we have to deal with fibrous and muscular elements, the differentiation of which is not always an easy matter.

Winiwarter ((35) and (36)) states that the distribution of the muscular element in the human ovary is identical with that exhibited in the cat, in which animal he describes it as entering into the formation of the external theca of the Graafian follicle. Before I was acquainted with his conclusions I was myself engaged in analysing the nature of the fibres of the external theca, and bad been led independently, through the staining reactions, to suppose that all the fibrils were not of a like nature,

Fig. 18. Section through the wall of a human Graafian follicle. a,coagulum within antrum tolliculi; b, retraction space between coagulum and stratum granulosum (str. gran.):; int. theca, internal theca with capillaries; ext. {heca, external theca with (c) bundles of smooth musculaï fibre. differentially stained with safranin and light green. x400. Specimen O 2. 52. 8.

My attention was first directed to this whilst examining some specimens stained with safranin and light green. With this reagent some of the concentric fibres of the external theca were stained a pronoünced pink, which stood out in contrast to the grayish green ‘tint of the surrounding stroma. Fig. 18 exhibits the appearance in a section through the follicular wall.

The coagulum within the antrum folliculi is stained a bright green in the original specimen, the membrana granulosa is purplish in tint. The theca interna is coloured a purplish gray, whilst in the theca externa there are elongated fibres which, staining a pronounced pink, stand out in marked contrast to the surrounding grayish green stroma. - Confirmatory evidence was also obtained from other specimens stained by Mallory’s method, wherein corresponding groups of fibres were stained distinctly purple in contrast with the surrounding bright blue colour; whilst in other sections of different follicles subjected to the influence of Congo red, the same tissue elements were revealed stained a dull violet, contrasted with the grayer colour of the tissue around. It is only fair to say that these results were not obtained in all the specimens examined, but so convinced was I of their significance that I employed other and more refined methods, with confirmatory results. Fearing lest my observations might be biassed, I handed over some unstained sections to my friend Mr H. M. Carleton, the Demonstrator in Histology, with the request that he would subject them to a careful examination. This he took great pains to do, and finally admitted that on histological grounds, no less than by reason of the staining reaction, the tissue undoubtedly contained smooth muscle fibre. From my own material F am enabled to furnish a figure of a highly magnified microphotograph which demonstrates these features (fig. 19).

Fig. 19. Higher magnification of a portion of the same follicular wall as that shewn in fig. 18. Str. gran. stratum granulosum; int. theca, internal theca; ext. theca, external theca, in which are seen the fibres, s.m.f., which have been identified as smooth muscle fibres. Mem. lim. ext. | membrans limitans externa, in this specimen not very clearly defined. x 600. Specimen O 2. 80. : S

Whilst there is thus undoubted evidence of the presence of smooth muscle in the external theca of the follicle, it is interesting to note that with certain reagents, we may obtain, under a low power, a general view of the distribution of this muscular element throughout the substance of the ovary as seen in section. This is best demonstrated in sections stained with safranin and light green; the colour differentiation effected is such as to indicate the presence of a tissue of a peculiar staining quality which invades the substance of the ovary along the line of the great vessels and follows them outwards as they reach the area of their distribution towards the cortex. The general arrangement of this particularly coloured zone conforms closely to the distribution of the blood vessels as indicated in the figure which Clark(6) has published in his account of the blood vessels of the ovary. As may there be seen, the smaller vessels are traced to the walls of the follicle, accompanied no doubt by the strands of smooth muscle, whose general course is indicated by their greater affinity for one of the constituents of the double stain. In the specimen examined the contrast between the differently stained areas was sufficiently pronounced to indicate the general distribution of the smooth muscle.

In the human ovary it thus appears that smooth muscle is present in considerable quantity, not so abundant as may be seen in lower forms, but still in such amount as to play a considerable part in the functioning of the organ.

According to Winiwarter ((36), p. 689), all attempts have hitherto failed to demonstrate the presence of this muscular element by experimental means. I therefore consulted my friend Dr Gunn, the Professor of Pharmacology here. who, after having had his interest enlisted in the question, determined to make a fresh attempt. He reports as follows: “The ovary (a rabbit’s) was suspended in a bath of oxygenated Locke’s solution at body temperature. Movements were recorded by a light-lever of high magnification, the method used being the same as has been widely employed for the isolated uterus and other organs. No spontaneous movements were shewn by the ovary. In one experiment the ovary of a full-grown virgin rabbit shewed on the addition of adrenaline to the Locke’s solution (in concentration of 1 in 200,000) a contraction of the ovary characteristic of smooth muscle. Adrenaline stimulates the sympathetic nerve ends in smooth musele. The sympathetic nerve is a motor nerve to the rabbit’s uterus. The experiment therefore indicated that the ovary contains smooth muscle, innervated by the sympathetic, and that the innervation of the ovary is qualitatively the same as of the uterus (in the rabbit). With high lever magnification the amplitude of excursion was very small, indicating a very small amount of contractile tissue.”

This experiment seems to set at rest all doubts as to the presence of functionally active muscular fibres within the stroma of the ovary, and as we have already seen that fibres answering to the histological details of smooth muscular fibres and reacting similarly to selective stains occur within the wall around the Graafñian follicle, it is evident that we have to hand a means which may play a not unimportant part in the rupture of the follicle.

Fig. 20. Section through a nearly ripe human Graeafian follicle; a, the surface of the ovary; here the follicular wall is only about -2 mm. thick: b, the cumulus containing the mature ovum, note that it lies on the superficial aspect of the follicle, immediately opposite and close to the thinnest part of the follicular wall. Both the cumulus (b) and the stratum granulosum (c) are separated from the internal theca in the upper hemisphere; d, the external and internal thecae combined, the magnification is not sufficiently high to differentiatethese layers. In the lower hemisphere of the follicle the cells composing the stratum granulosum are still adherent to the inner surface of the follicular wall, the membrana limitans externa alone intervening; the magnification is not sufficient to shew this layer; antr. foll. antrum folliculi. x 18. Specimen 453 A. 35. 4.

The Rupture of the Follicle

Having passed in review the various structures which enter into the formation of the Graafian follicle and its contents, it may now be possible to discuss the means by which the follicle ultimately ruptures and sheds its contents. Before, however, proceeding to consider this question, it may not be without advantage to reproduce a microphotograpli of a Graafian follicle which must have nearly reached the stage at which its rupture was imminent, to judge by the appearances displayed (fig. 20).

The estimated size of the follicle is 2-00 x 1:96 x 1:63 mm. As is readily seen, the superficial wall of the follicle, i.e. that separating its cavity from the surface of the ovary, is thin, only 0-2 mm. thick. The ovum contained within the follicle is judged to be mature, since there is present in it a divided first polar body, together with a second polar body, whilst the nucleus appears to have returned to the resting condition. A figure of this oôcyte has already been published in my previous paper on the maturation of the ovum(3#). For all these reasons, we are justified in supposing that the follicle is ripe, and has reached the stage in its existence when its collapse, and the liberation of its contents, cannot for long be delayed if the physiological necessity arises.

But an examination of the figure enables us to realise certain unusual features. First, we recognise that the ovum, surrounded by the cumulus, is so disposed that it lies superficially within the follicle, and' near, and in immediate correspondence with the line of the stigma—the site corresponding to the point of rupture. But secondly, it is obvious that throughout the superficia) hemisphere (i.e. that directed to the surface of the ovary) the stratum granulosum with the cumulus has become detached from the inner surface of the internal theca; elsewhere, over the inner surface of the posterior liemisphere, it still remains attached.

Obviously no better arrangement could be devised for the expulsion of the ovum than that shewn here, for if the rupture be due to an increase in internal pressure, the ovum would naturally, by the bursting pressure, be forced through the orifice made in the weakened wall when that gave way. Unfortunately, as we have already seen, the position of the ovum and the cumulus is not always superficial, but may be, and often is, situated in relation to the deep surface of the follicle, at a point opposite and farthest removed from the stigma, in which case it is difficult to understand how, when the rupture occurs, the discharge of the ovum is effected. Under these cireumstances the doubt arises in one’s mind, as to whether the ovum is not more likely to remain lodged in the bottom of the empty cup.

The detachment of the cells of the stratum granulosum from the inner surface of the internal theca is a matter which has already attracted a considerable amount of attention. The prevailing opinion is that the condition is to be regarded as an artefact—that it is due to the retraction induced by the coagulation of the liquor folliculi. Such an explanation seems feasible, and is possibly the one that comes readiest to hand; before accepting it, however, there are some other considerations that must be taken into account.

In the numerous examples of this condition which I have studied, I have been struck with the fact that there is not always such a correspondence in the contours and area of the retracted surfaces of the stratum granulosum and the internal theca as one might expect if the separation of the layers were effected by such mechanical means. It is not uncommon to find the stratum granulosum floated well into the centre of the follicle, and twisted and infolded in such a way as to suggest that these layers were afloat in the fluid contained within the follicle at a time prior to its coagulation. Further, they often exhibit appearances as if undergoing disintegration, and are frequently fragmented. In dealing with human material it is only fair to say that putrefactive processes must not be overlooked. Yet withal, I confess I am by no means assured that the condition is thus easily explained as being due to the effects of coagulation by fixation.

There are additional reasons for hesitating to accept this view. First, the case in which the eumulus is so disposed as to lie on the deep surface of the interior of the follicle, the site assigned to it by Nagel and others as normal. Under those circumstances it is difficult to see, as has just been observed, how by any pressure sufficient to burst the follicle the ovum could be expelled through an opening opposite in direction to the force to which it was being subjected. As has been said, a more reasonable supposition would be that it would be left in the bottom of the cup, and this, be it observed, is what is supposed to have happened in those cases of ovarian pregnancy which have been recorded, the explanation offered being that the ovum has failed to escape from the ruptured follicle and that the entering spermatozoôn has fertilised it in situ.

Second. Thanks to the kindness of Professor Robinson, I have had an opportunity of seeing, amongst his collection of ferret material, an ovum, just ‘ within the oviduct, apparently recently discharged from its follicle, which, besides being surrounded by the cells of the cumulus, had, attached to these, tags of tissue which could only be accounted for on the supposition that they were remains of the sheet of the surrounding stratum granulosum.

Third. In one case I had the opportunity of examining a human Graafian follicle which must have been quite recently ruptured. In this I failed to find any trace of follicular cells —all that remained was the enfolded and engorged internal theca, very definitely lined internally by the membrana limitans externa, without any trace, so far as I could see, of any follicular cells overlying it. Within what was left of the cavity of the follicle were a few scattered blood cells only1.

This raises of course the vexed question of the origin of the corpus luteum. Von Baer in 1827 propounded the view that the corpus luteum was derived from the theca interna. This conception has been supported by Valentine, His, Rokitansky, Kôlliker, Gegenbaur, Paladino, Nagel, Bonnet, Schottländer, Minot, Williams, Clark and others.

On the other hand Bischoff in 1842 expressed the opinion that the corpus luteum is derived from the follicular epithelium. This view has received support from Meckel, Pflüger, Luschka, Waldeyer, Sobotta, Honoré, Marshall, Van der Stricht, Heape, and Kries, amongst others.

Rabl in 1898 suggested a compromise, and concluded that the lutein cells have a double origin, arising both from the membrana granulosa and from the theca interna.

1 It is interesting to note that this specimen was obtained from the ovary of a woman whose uterus exhibited evidence of the onset of menstruation.

Into this controversy I am not at present prepared to enter; all I can say is that the human specimen I have here mentioned appears to confirm in every respect the original contention of Von Baer.

There can be little doubt but that the liquor folliculi serves two useful purposes: it acts as a source of nutrition for the ovum, as well as providing a means for its protection. The production of this fluid by the disintegration of the follicular cells through the agency of the so-called bodies of Call and Exner has been already discussed (see p. 14), and need not now be further alluded to. During this process of the dissipation of the follicular cells, with a concomitant increase in the size of the antrum folliculi, there also appears to be taking place a reproduction of these follicular cells to replace the wastage, as evidenced by the occurrence of mitotic division observed amongst them. To what extent this takes place it is difficult to say, but apparently there comes a time when this source of reinforcement is reduced to the thin single layer of cubical cells which represents all that is left of the stratum granulosum. In some instances, the conditions are such that this remaining layer may all but disappear, in fact in some cases I have failed to find evidence of it in parts of the circumference of the follicle.

Support is given to this view by the observations of Miss Lane-Claypon (6), p. 42) on the ripe Graafian follicle of the rabbit, in which she describes “almost complete disintegration of the membrana granulosa.”

A fact of some interest, be it noted, is that this condition is not necessarily met with in follicles which one would regard as fast approaching their rupture, as judged by their very superficial position and the thinness of their overlying wall. This activity on the part of the follicular cells is no doubt sustained by the nutrition derived from the fluids of the blood through the agency of the capillaries of the internal theca, and possibly the liquor folliculi itself may be increased in bulk by an admixture of constituents derived from both sources.

In this connexion, it is well to remember that interposed between the peripherally placed follicular cells and the capillary zone of the internal theca, there is the membrane which has been already alluded to as the membrana limitans externa (basal membrane). Now, as stated, there is considerable doubt as to the constitution of this membrane. We have seen that the union between this membrane and the follicular cells is generally speaking very feeble, and that the follicular cells are extremely liable to be detached therefrom, it may be by artificial means, or possibly as the result of a normal process. In the accompanying figure (fig. 21) there seems strong evidence for believing that the separation of the stratum granulosum and the internal theca is effected by the infusion of fluid between the two layers of the membrana externa, and not by the dragging away by retraction of the membrana externa from the intetnal theca, else how can we account for the appearance of distensions within these spaces and the concavity of their walls?

1 For the literature of this subject I am indebted to the papers of J. G. Clark (s) and F. H. Marshall (9).

As a consequence of this separation, whilst in the majority. of cases the bulk of the membrana limitans externa adheres to the inner surface of the internal theca, yet the evidence produced (see fig. 15) of the splitting of this layer so that one lamina adheres to the follicular cells, whilst the other remains in contact with the internal theca, suggests that the structure of-this layer is not so homogeneous as is usually described, but that sandwiched between its inner and outer strata there may be a weaker element, or, what is more probable, a series of lymph spaces in direct contact with the capillaries of the internal theca, as seen in the figure, on the one hand, and the bedded bases of . the follicular cells on the other.

Fig. 21. Section of human follicular wall shewing the commencement of the separation of the stratum granulosum (sir. gran.) from the internal theca (int. theca). This appears to involve the splitting of the mémbrana limitans externa through the distension of the lymph spaces in it, s0 that larger spaces (a, a, a) are produced, the walls ot which through their concave contours afford evidence of a pressure from within, due to the accumulation of fluid inside the spaces. Note the position of the capillaries (B.vs.) of the internal theca (int. theca) in relation to these spaces (a, a, a) the walls of which are formed by the split membrans limitans externa, one layer of which adheres to the internal theca, the other forming what looks like a basement membrane to the external layer of cells of the stratum gränulosum. Antr. foll. antrum folliculi filled with a reticulated coagulum. x400. Specimen 453 B. 30. 6.

This splitting of the external limiting membrane is a feature to which Robinson ((27), p. 820, plate X, figs. 58 and 67) has already called attention, though he attributes it to the use of fixatives. Granted that it is so, it may be the means of revealing potential spaces which at the time may not be distended, but this in no wise precludes the possibility of these being tissué fluid channels.

My reason for dwelling on these facts is that they may possibly afford an explanation of what happens when the follicle bursts. Various opinions have been expressed in regard to the mechanism which brings about this phenomenon. The generally accepted view is that by a gradual increase in the bulk of the contents of the follicle such a pressure is induced as will lead to the rupture of the gradually weakening wall in the region of the stigma.

On the other hand, some, in order to bring the details more into accord with the accepted facts, suggest that the rupture of the follicle is induced by a sudden increase in the follicular pressure.

Nagel ((23), p. 60) and his followers attribute the rupture to changes taking place in the tunica interna, whereby its vessels become highly developed, and its cells multiply enormously, every cell increasing in size by the growth of its protoplasm, at the same time the protoplasm becomes filled with a peculiar crumbling mass of which nothing more definite is known, from which the whole inner wall of the follicle (in the fresh condition even before its rupture) acquires a yellowish colour. The tunica interna thus altered has an undulating appearance, while its cells, which are now called lutein cells, and form a strong layer many rows thick, are arranged in the form of papillae, into every papilla runs a much-branched vessel. Through this growth of the lutein cells the contents of the follicle are pushed towards the thinnest part of the follicle (stigma) on the surface of the ovary, and thus the follicle is brought to its rupture.

In respect of this I can only say that my own observations have not enabled me to recognise these conditions in the still unruptured, though apparently ripe follicle. The appearances described are such as are readilÿ recognised in the freshly ruptured follicle, preliminary to the formation of a corpus luteum, though here unfortunately we are unable to form other than an approximate estimate of the time which may have elapsed between the rupture and the examination of the specimen.

Clark (6), in discussing the matter, in part attributes the dehiscence of the follicle to the peculiar arrangement of the vessels of the ovary, and was able to demonstrate the rupture of the follicle following the introduction of a carmine-gelatine injection. He also considers the occurrence of haemorrhage within the follicle more frequent than its absence.

Heape (13) considers that in the rabbit the rupture is induced by the stimulation of the erectile tissue, and not simply as a result of internal pressure . arising from increased vascularity, or a greater amount of liquor folliculi.

In a series of experiments Schochet ((30), p. 241) indicates that the liquor folliculi possesses a digestive enzyme that can be demonstrated by dialysis and other tests. As a tentative interpretation it is suggested that the rupture of a Graafñian follicleis due in part tothe digestion of the theca by the liquor folliculi.

Winiwarter ((86), pp. 640-41), in discussing the function of the smooth muscle met with in the ovary, reviews the suggestions previously made by Rouget (28), and Aeby (1), that the muscular tissue plays its part “by setting in action a complex mechanism subject to physiological conditions of which we are ignorant, and which simple galvanic stimulation cannot reproduce,” the conclusion being that ‘the ovary, together with all the internal genital tract, can undergo erection under the influence of a stimulus aroused, in the ovary, by the distension of the Graafian follicles; the increase of tension in the ovarian stroma brings on the rupture of the follicle, after which relaxation follows; it is therefore the muscular tissue of the mesovarium which plays the active part.” This hypothesis is also supported by Grohe (11).

Winiwarter’s own conclusion is that the muscular tissue in the mesovarium acts in part by controlling the venous return from the organ, thereby conferring on it an erectile power, probably associated with the period of rut, or, it may be, aroused by the stimulus of coitus, whilst he suggests that the presence of smooth muscle in the external theca of the Graafian follicle may be a determining cause of its rupture.

Furthermore, it has frequently been suggested that the congestions which occur within the pelvic organs at the menstrual periods, and the turgescence of the associated organs which may occur during coitus, may have something to do with the rupture of the follicles.

It is too complex a problem here to discuss the question of the relation of ovulation to menstruation, suffice it to say that the bulk of the evidence seems to point to the fact that there is an intimate association between the two phenomena, and that consequently those vascular changes which we associate with the one may be in part responsible for certain of the processes connected with the other.

As Eden puts it ((7, p. 6): “It is undoubtedly true that ovulation and menstruation are closely related to one another. Whether they are coincident or consecutive, and if consecutive, which precedes the other, we do not know with certainty.”

Barnes (2), p. 455), Dr Clelia Mosheral) and Helen MacMurchy (47), p- 909) quoting Giles ((10), p. 115) and Dr Mary Jacobi (15), are all agreed that there is normally a rise in blood pressure for a day or two prior to menstruation, and a fall immediately on the onset of the flow.

I am aware that the occurrence of apparently ripe Graafian follicles has been recorded in young children prior to menstruation, and even in some instances in the new-born child (Nagel (2), p. 418), but there is no evidence that these ever ruptured or that the ova therein contained were capable of fertilisation; it is much more probable that the follicles became atretic.

Considering the foregoing suggestions and the observations on which they are based, it would appear that well-nigh everything that could be said on the subject had been already stated. A little reflection, however will, I hope, induce the reader to believe that there are other ways of interpreting the phenomena, and so bringing them more in line with what experience would support.

I have endeavoured to suggest that the main function of the liquor folliculi is to nourish, conserve, and protect the delicate ovum as it lies within the follicle, Evidently a time arrives when, from the appearance presented, the further production of the liquor folliculi by the disintegration of the follicular cells is arrested, as evidenced by the reduction in number and change in character of the residual follicular cells. At this stage we may assume that the pressure within the follicle is stabilised, and may remain for unknown periods undisturbed. It is therefore hard to believe that the pressure within the follicle can be rapidly raised by any sudden increase in the amount of the fluid derived from the follicular cells.

We have around the follicular cyst, if such I may call the liquor folliculi enveloped by the stratum granulosum, a capillary plexus subject to all the controlling influences of the sympathetic nervous system.

We have already alluded to this capillary zone as essential to the nutrition of the follicular epithelium, though to what extent the liquid constituents of the blood may contribute to the fluid bulk of the liquor folliculi we have no information; but assuming that the liquor folliculi is in main the product of the follicular cells, it by no means follows that, since the source of that supply is no longer active, the fluid derived from the blood in the capillaries contributes no further to the increase in fluid contents of the follicular cyst; controlled as is this supply by the sympathetic, it must necessarily react to such stimuli as induce changes in the circulation directly concerned, or, it may be, in harmony with vascular changes induced in the tissue around.

Sexual thoughts, sexual desires, coitus, the congestion associated with menstruation, may all play a part, with what result?-—the immediate and sudden increase in pressure, involving, it may be, the transudation of a greater quantity of the fluids of the blood, and thus increasing the pressure contents of the follicle to its straining point. I suggest that in this process, when dealing with a follicle the contents of which are ripe for discharge but quiescent, the effusion of fluid poured out from the capillaries invades those lymph channels which, we have reason to believe, intervene between the cells of the stratum granulosum and the internal theca, thereby tending to separate the granular layer from the inner wall of the follicle, and thus leading to the release of the cumulus and its anchoring layers, so that it, with the contained ovum, lies free and floating within the cavity of the follicle in such a way that it must follow the stream of the fluid on its expulsion and release through the rupture.

In this way, possibly, is effected the liberation of the ovum and its associated follicular cells from the wall of the follicle, which Bôhm and Davidoff (3) have suggested as an initial stage in the escape of the ovum from the ruptured follicle. According to these authors the ovum and the cells of the surrounding cumulus, or discus proligerus, ultimately come to lie free and floating within the liquor folliculi, a process which in their opinion is effected by the softening of the cells of the pedicle of the cumulus, which thus leads to the separation of the cumulus and the contained ovum from the stratum granulosum. I do not deny the possibility of this happening, but I have not so seen it in any of the specimens I have examined, for in all the cases in which I have been able to follow, through a number of serial sections, the relations of an apparently free cumulus as displayed in some sections, on careful search I have been able invariably to trace its connexion with the stratum granulosum in other sections. For these reasons I suggest that the same end is accomplished by the stripping off of the entire follicular cyst from the inner wall of the internal theca by the rapid effusion of fluid derived from the capillaries, for in no other way can we account for the somewhat sudden increase in pressure which appears to be a necessary accompaniment of the process of ovulation.

Whilst admitting that this is a phenomenon which is dependent on effects primarily induced by the nervous mechanism controlling the circulation, we must not overlook the fact that there are other contributory causes that may play a part. We have hitherto assumed that the increase in internal pressure, effected as suggested, is the determining cause of the rupture of the follicle, for as soon as that pressure exceeds the resistance of the weakened wall of the follicle in the region of the macula or stigma, rupture must inevitably take place. On the other hand no regard has been paid to the possible influence of muscular contraction as the determining cause of the rupture of the follicle. The occurrence of smooth muscle fibre within the stroma of the ovary and mesovarium is generally admitted. Why is it there? Of what use may it be? Winiwarter ((35), p. 640) has already suggested that, by its contraction, the return of the flow of blood through the veins may be retarded, thus leading to a state of engorgement or erection of the organ, which will of course react on the capillary circulation and thus promote a more vigorous transfusion of the fluid constituents of the blood, thereby increasing the amount of lymph at certain selected and appropriate points; in this way, doubtless, assisting in increasing the bulk of the follicular contents. At the same time that author foreshadows the possibility of this smooth muscle acting as a potent factor in the rupture of the follicle, for he describes the disposition of this muscular tissue as not merely scattered throughout the stroma of the ovary, but also forming a definite layer in the external theca of the follicle.

After the demonstration which I have here given of the occurrence of a definite muscular layer in the wall of the human Graafian follicle (see figs. 18 and 19), it would seem that we are justified in assuming that this definite concentric layer fulfils some useful purpose. Its arrangement and disposition inevitably suggest that by its contraction a compressing effect, rapid and immediate, will be exercised on the contents of the follicle, thereby increasing the internal pressure and consequently determining the rupture of the follicle.

How are these facts in accord with the results of experience? Assuming that in the human female in the virgin condition there is a periodicity in ovulation coincident with that of menstruation, we have an explanation of this apparent association, because, at that period, we have reason to believe that the ovary shares in the general engorgement which occurs throughout the genital tract; under these circumstances the conditions are such as to lead to a slow and gradual increase in the amount of the fluid contents of the follicle as derived from the blood, and distinct from those which are the product of the follicular cells, which, be it noted, in a follicle fast approaching maturity, have no further reserve to call upon. The further increase in the fluid contents of the follicle is therefore dependent on conditions determined by the local circulation, and if this condition be steadily maintained, there is little difficulty in realising how the pressure may ultimately overcome the resistance, and so the rupture of the follicle may be effected without any necessary sexual disturbance other than that involved in the psychic and emotional changes induced by menstruation.

On the other hand, there is reason to believe that ovulation takes place at other times, and in other ways, than what may be termed the routine method. It is a matter beyond dispute that under the influence of intense sexual excitement, in coitu, women are occasionally cognisant of strange happenings, which they fail to describe, but by which they are deeply impressed. Is it unreasonable to suggest that these sudden, ill-defined and deep-seated sensations are the result of the rupture of a Graafian follicle? The facts seem to fit the case. Granted the presence of an all but ripe and superficially disposed Graafan follicle in what we may term a quiescent condition; if the action of the mechanism above suggested be accepted, we have all the means necessary to bring about rapid rupture. The exalted state of the circulation will assist in the rapid accumulation of fluid within the follicle, and its subsequent distension, whilst the instant response of the muscular element in the wall of the follicle to the call of the sympathetic will immediately result in a combination sufficiently effective to ensure the rupture of the follicle and the discharge of the ovum.

If, under these conditions, this explanation be accepted, it would seem to indicate that possibly the same may occur associated with minor degrees of sexual excitement, so that, whilst in the human female ovulation may, in the ordinary way, coincide with and be associated with the vascular changes concomitant with menstruation, yet there may be no bar to the rupture of a Graafñian follicle at any other time, provided such be ripe, in the sense that the ovum is mature, that the follicular cells have discharged their function by providing the necessary nutriment and affording the requisite protection, and assuming always that the follicle has acquired such a superficial position in the ovary as will permit of its rupture. There is reason to suspect that it may remain quiescent in this position until such conditions arise as may lead to increased vascular activity, or it may be the incidence of such stimuli as may react on the smooth muscle involved and so accelerate the process.

If it be doubted that the involuntary muscular fibre in the wall of the follicle can act in this way. I would urge that we have abundant evidence of its power of contraction in the appearance displayed in the wall of the follicle after rupture, for there seems little doubt that the infolded appearance of the engorged internal theca is in major part due to the compression exercised by this contracting element, for there is no evidence of the presence of elastic tissue'to bring about this result.


Briefly summarised the conclusions arrived at are as follows:

  1. There is reason to believe that the size of the ripe human Graafian follicle is usually very much overstated in the text-books. In the author’s experience it is doubtful if Graafian follicles over 5 mm. in diameter are normal.
  2. The position of the eumulus is not, as frequently stated, always situated in the deeper part of the follicle, i.e. that furthest from the surface of the ovary. It may occur in any position, but in the material available appears to occupy a superficial position in about 50 per cent. of cases.
  3. The so-called bodies of Call and Exner are follicular cells or groups of cells undergoing such changes as result in their ultimate liquefaction and disappearance to form the liquor folliculi.
  4. The radial arrangement of the follicular cells around these bodies is a purely mechanical result and is in no wise concerned with the elaboration of the material which they surround.
  5. The resulting liquor folliculi, primarily derived, as explained, from the follicular cells, is destined for the nutrition, conservation and protection of the ovum. It is doubtful whether it plays any active part in the subsequent rupture of the follicle, the necessary increase in the tension of the follicle being provided at the appropriate time by transudation of fluid from the blood circulating in the internal theca of the follicle.
  6. The stratum granulosum may be reduced to a single layer of cubical cells. In some instances there is reason to believe that even this layer disappears.
  7. In consequence of this reduction in the number of follicular cells, there comes a time when no further liquor folliculi of follicular origin is produced. When this stage is reached, there is reason to believe that the follicle may remain quiescent till other influences are brought into operation to determine its rupture.
  8. The cells of the stratum granulosum rest upon the membrana limitans externa, a delicate layer which separates these cells from the inner surface of the theca interna.
  9. It is noteworthy that the cells of the stratum granulosum strip off very readily from the membrana limitans externa. There is reason for suspecting that this under certain conditions is a normal process resulting in the liberation of the ovum so that it floats free in the liquor folliculi. 38 Arthur Thomson
  10. There is evidence for believing that the membrana limitans externa is not a simple single layer, but is permeated by potential lymph spaces, which on being distended lead to its splitting into two layers.
  11. On this assumption the cells of the stratum granulosum are therefore separated from the capillaries of the internal theca by a network of lymph channels into which the fluids of the blood may under certain conditions be speedily discharged.
  12. The rapid exudation of fluid in this situation has two consequences: it strips the cells of the stratum granulosum off the inner wall of the follicle and thus liberates the ovum and ceumulus, and at the same time rapidly increases the pressure within the follicle.
  13. It is noteworthy that.the vascularity of the internal theca increases as the age of the follicle advances, that it tends to be more pronounced in that part of the internal theca corresponding to the site of the cumulus, and in the later stages least in the position overlying the stigma.
  14. The amount of blood circulating in this capillary plexus will be determined by the conditions which control the surrounding circulation, either by increasing the flow, or, it may be, by retarding the venous return, the latter, as suggested by Winiwarter, being possibly due to the action of the smooth muscle constricting the veins and so leading to a turgescence of the tissue.
  15. Such vascular conditions may be associated with the congestion and increased arterial pressure which precedes the appearance of the menstrual flux, or may be the direct result of some excitatory stimulus of a sexual kind operating through the sympathetic.
  16. In either case the immediate result may be increased transudation of tissue fluid into the follicle with the results stated in paragraph 2.
  17. It is probable that under what we may regard as the normal condition of ovulation in the sexually inactive female, the vascular disturbance associated with menstruation is alone suficient to raise the intrafollicular pressure to the bursting point.
  18. In the sexually active female there is reason to suppose that the same effect may be independently induced by stimuli which react through the sympathetic nervous system, provided there is at the time a quiescent ripe follicle present in the ovary.
  19. In such cases no doubt the muscular element in the ovary plays an important part, more particularly that part of it which occurs in the external theca of the follicle, for this, by contracting on a follicle already undergoing distension owing to the exalted condition of the vascular supply, will naturally tend to increase the intrafollicular pressure and so lead to the rupture of the follicle.
  20. If these conclusions be true it would follow that ovulation is not necessarily limited to one particular period, but that under the influence of appropriate stimuli it may occasionally occur at other times as well.

In conclusion, I must express my thanks to my Laboratory Assistant, Mr W. Chesterman, and to Miss Beatrice Blackwood, for the assistance which has enabled me to carry out this research; they have both been untiring in their efforts to carry out my every wish, and I am deeply sensible of their help and co-operation.

To the Government Department of Scientific and Industrial Research, I am indebted for the services of Miss Blackwood, who was generously placed at my disposal as a research assistant.


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