Paper - Development of the human ovary from birth to sexual maturity
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Simkins CS. Development of the human ovary from birth to sexual maturity. (1932) Amer. J Anat. 51(2): 465-505.
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Development of the Human Ovary from Birth to Sexual Maturity
Cleveland Sylvester Simkins
Department of Anatomy, University of Tennessee Medical School, Memphis
Six Plates (Twenty-Nine figures) Aided by a grant from the National Research Council.
The present study of the maturation of the human ovary is the outgrowth of a former paper (Simkins, ’28) in which the development of the gonads was traced to the time of birth. There shall be a slight overlapping of this study and the former one, because birth itself has no discernible effect upon gonogenesis, or even upon the ovary as a whole. The important events in the history of the human ovary are: first, the origin of the ventromedian thickening on the mesonephric body in embryos of 7 mm. Secondly, the differentiation of the indifierent gonad into a testis or an ovary during the second month. Thirdly, the cessation of mitotic division of the gonocytes during the sixth fetal month. And, fourthly, the growth of the ovary from the sixth fetal month to sexual maturity, about the fourteenth year. The present paper shall be limited to that fourth phase.
The series of gonads upon which this study is based is made up of sixty ovaries from the fifth fetal month to birth; ten from birth to the end of the first year, two between birth and the first year, two at two years, one at three years, one at seven years, two at eight years, two at nine, one at thirteen, and three at fourteen. (A partial list, with measurements, is given in table 1.)
It was my hope to secure a series separated by yearly intervals, from the first to the fourteenth, but dependable material accumulated so slowly that it was decided to offer the conclusions without further delay. This seems to be justified by the conviction that the results would not have been materially changed by the pursual of a more completely graded series.
Most of the material was obtained from autopsies and fixed in 10 per cent formalin. Some was obtained from operations; thisis especially true of the adults. Cause of death could not at all times be told, though most of the infants whose age has been recorded as newborn were either born dead or lived but a short time after birth. The gonads from the fetuses were all obtained from stillbirths. The material for this study has been accumulating over a number of years—a process that was necessarily slow because of the rarity at which female children go to autopsy. In so many instances promising material turned out to be valueless, because of the great postmortem dissolution of the cells. As a consequence, much has been discarded, and the material used is the best that can be hoped for from autopsies. The ovaries of adults were removed at laparatomies and fixed at once.
The ovary at birth
The shape (fig. 22, 0-7:) of the human ovary at birth is quite variable, though it most commonly presents an elongated and symmetrical ovoid appearance. Departures from such a shape occur so frequently that one is at a loss to decide which may be the normal.. The surface is granular, and the granulations appear more pronounced in fetuses, but as childhood approaches the surface becomes smooth and glistening. The shape may be like that of an Indian club (fig. 22, b) or a gourd. Often one finds the ovaries of the newborn lobulated with frayed edges and leaflike parts. That such appendages are truly ovarian can be proved by section. In one instance I found the ovary tremendously elongated. The inferior end was rounded and reposed upon the broad ligament, but the tail-like part ascended as high as the kidney in a gradually diminishing amount until it finally ended. I have found but one ovary that was composed of more than one completely separated part. In one there were two distinct nodules, and the larger of the two was almost divided again (fig. 22, c). The presence of cysts greatly alter the shape of the ovary (fig. 22, i). Anomalous shapes of the ovary occur much more frequently in the newborn than in the adolescent. During the period of sexual maturation the uneven edges and the granular surface become smooth and the extra nodules become incorporated into the body of the gland. Congenital absence of one or both ovaries occurs infrequently, Sanders (’28), Rossle und Wallart (’30). Chiari (’04) reported the case of double ovaries. In my collection no specimens show any signs of abnormalities except the divided one. In this case the lobes of ovarian tissue were distributed along the broad ligament toward the pelvic brim posteriorly and upward in the direction of the kidney. At birth the ovary has, in most cases, descended into the pelvis and lies along the superior margin of the posterior fold of the broad ligament from the uterine horn laterally. But it frequently happens that such an advanced position is not reached, in which case the ovary may lie anywhere from the inferior border of the kidney to the broad ligament in the pelvic cavity. Inasmuch as the ovary arises over a more or less extensive area from the ventromedian surface of the mesonephric body, any interruption in its descent would account for its position from the kidney to the broad ligament.
The size of the ovary at birth is also subject to wide variations. Indeed, the size of the human ovary varies widely at any age. In general, the ovary at birth is about 15 mm. long, 3 mm. wide, and 2.5 mm. thick, but this varies greatly (table 1). The growth involves the thicknes and the width to a greater extent than the length, although the gland increases in length, too. At the onset of puberty, between the thirteenth and fourteenth years, the ovary has attained a size approximately equal to the adult, which in my series varies between 27 mm. in length toi41 and 15 to 24 in width, and 8.5 to 19:4 in thickness. Ovaries of the adults are much more thickened than those of immature females. The size is greatly increased by the presence of cysts, which increase thewidth and thickness to a much greater extent than the length. In my collection of sixty pairs of ovaries, three pairs were cystic, which is an indication that about 5 per cent of the ovaries at birth possess cystic enlargements. The sizelof the cysts varies from a fraction of a millimeter to as much as 7 mm. in diameter (fig. 22, g). Cysts may occur in the ovaries at any age and appear grossly, very much like greatly enlarged follicles, but they diﬂ’er from true follicles in that no ova can be found in them and the stratum granulosum is either "torn away and appears as strands or clumps in the ﬂuid of the cyst, or is so attenuated as to consist of a single epithelial layer (fig. 26). The cystic follicles of the newborn and sexually premature females are never found in the follicles of the cortex, but always occur in those follicles near the periphery of the medulla.
Tabular view of the measurements of a series of human ovaries. The measurements were taken after the tissue had been fixed for at least twenty-four hours in 10 per cent formalin. Length is the greatest length in millimeters. Width is the greatest width, even through cysts when such were present. Thickness was measured through the center of the gonad, notthrough cysts when such were present.
AGE LENGTH WIDTH THICKNESS REMARKS
6months , 15 4.1 1.5 Stillborn fetus, right
6 months 12.9 4.9 2 Left ovary
8 months 19 5.2 2 Club-shaped ovary, left, fetus Bmonths 15 5.3 3.4 Right ovary oval, fetus
Term 21 4 3.4 Stillborn at term
Term 20.4 ' 5.8 3
Term 16 ‘L 3.2 2.3
Term 12 ‘ 7.5 5 2 cysts in right
Term 12 6 3.5 1 cyst in left
Term 15 5.5 4
Term 10 4.7 3.3
Term 12.3 5.5 2
Term 12 3.8 3.6
Tenn 24 7.5 4 Lived ten days, 3 cysts
Term 31 4.6 4 10-day infant, 2 cysts
2 months 11.7 3.6 2.5 2-month infant, left ovary
2 months 13.5 5.5 2.5 2-month infant, right ovary 3months 10 | 3.6 2.5 3-month infant, left ovary
3 months 10 3.5 2.5 3-month infant, right ovary
3 months 11.5 9 4 3-month infant, 2 large cysts, left 3 months 17 9.5 4 3-month infant, 3 large cysts, right 6months 18.3 7.7 6.5 6-month infant, left ovary
6 months 21,8 7.5 6.5 6-month infant, right ovary
1 year 16.7 10.5 5.5 1-year infant, two large cysts, left
lyear 17,2 10,2 5 1-year infant, 2 large cysts, right lyear 14 6 5 1-year-9-month infant, left ovary 9 months 18 6 6 1-year-9-month infant, right ovary 2yea,1-5 25 17.6 7.3 Died of lymphosarcomatosis, left 2 years 19 10 6 Right ovary, same child
3 years 17.6 7 4 3.-year child, left ovary
3 years 17 7 4 3-year child, right ovary
7 years 21 8.2 5 Left ovary
8_ years 19.8 10.6 5.4 Left ovary, 8-year-old child
8 years 16.4 8.7 8 Right ovary, 8-year-old child 9years 20.1 12 8 Left ovary, 9-year-old girl 9-years 22.5 12.4 8.6 Right ovary, 9-year-old girl
13 years 24.6 11 7 Died of burns, right ovary
14 year 35 15.5 8.5 Left ovary
14 years 36.2 11.8 7.3 Right ovary
14 years 19 10 7 Left ovary
26 years 27 24 16 Removed surgically
28 years 31 28.7 19.4 Removed surgically
28 years 28 19 10 Removed surgically
29 years 36 29 12 Removed surgically
40 years 41 38 12 Removed surgically
62 years 22 15 11 Removed surgically, senile ovary
Minute structure of the ovary
There is very little change in the microscopic structure of the ovary from the sixth month of gestation to the sixth month after birth. Birth seems to be a passing event in the matter of ovarian structure in that no ‘noticeable changes take place. In a former paper (Simkins (’28), I have pointed out that the cellular elements entering into the construction of the gonads come from the germinal epithelium—a conclusion that has since been confirmed by Swezy and Evans ('30). At the end of the fifth month the ovary is composed of an outer cortical portion and an inner medullary portion, internal to which lies the rete ovarii (figs. 2, 21). Prior to this time there is an active proliferation of the oogonia which greatly increases the size of the gland. The process of ovogenesis begins with cells delivered from the germinal epithelium, and the cells so delivered continue to proliferate and form the large genatiloid cells until the beginning of the sixth month. This process has been divided into three periods 470 CLEVELAND snvnsrna SIMKINS
by Swezy and Evans (’30): the early, middle, and late embryonic periods. The early period is one of growth and multiplication, the middle is characterized by maturation phases, among which phases are interpolated cytological activities which do not appear at any other time in the history of ovogenesis. The late embryonic period is characterized by phases similar to those of the adult male germ cells. The fourth period is that of the adult. This paper concerns itself with the changes that take place in the ovary during this fourth period, although I am unable to find any evidence that germ-cell division takes place in ovaries older than the sixth month of gestation, except the maturation divisions that take place at ovulation.
I Wish to emphasize the difference between the cortical and medullary parts of the early human ovary, because the most important changes that take place have to do with these two portions. The cortex (figs. 2, 21) arises first by the mitotic proliferation of cells delivered from the germinal epithelium. It is not of uniform thickness, but it does present a uniform structure. In it are to be found the large genitaloid cells, which are surrounded by an inconstant and incomplete layer of small ellipsoidal cells. The gonocytes usually have the deutobroch nucleus (figs._24, lower, 27, 28, éeft). These types of follicles are found only in the cortex of the ovary of fetuses and early infants, Where they constitute the most conspicuous part of the gland. In order to distinguish these early types from the other, later, type I have called them the ‘primordial’ follicles (compare pls. 1 and 2).
The second type of follicle, which I have designated the ‘primary,’ is to be found only in the peripheral margin of the medullary zone (fig. 21). These types diﬂer significantly from the primordial follicles. They are larger, take a deeper stain, and are always surrounded by at least a single row of large, round, and regular nuclei (figs. 24, above, 23, and 29). These are the follicles that grow and develop into definitive structures while the primordial follicles disappear. MATURATION or HUMAN ovsnr 471
The number of primordial follicles in the cortex is subject to wide variations, in different regions of the same ovary as well as in different ovaries. The first estimates of their number, based upon counts of representative sections and then multiplied by the number of sections, varied from 140,000 to as many as 800,000. This number was later found to be entirely too high. The number of primordial follicles Within difierent low-power fields varies from 65 to 220. The striking variations are illustrated by the photomicrographs 1 to 8, inclusive. The variation in number of gonocytes in different ovaries that are not markedly different in shape renders such estimations of doubtful significance.
Tabular view of estimated number of eggs in the hu/man ovary at various ages. The first column represents the average nu-ivnber of mm in primordial follicles in the low-power field. The second column, the primary follicles in the same field, and the third colwnm, the ast1'/mated number of primordial follicles in one ovary.
AGE PRIIIORDIAL IOLLIOLIB PRIMARY TOLLIOLIS ESTIHATID NUMBER
IN 140W-POWER fiELD IN LOW-POWER IIIIAD IN ON‘ OVA3-Y At birth 115 ' 3 143,000 5 months pp. 78 [ 4 112,000 6 months pp. 48 3 86,000 3 years 41 l 4 79,000 7 years 16 l 4 48,000 8 years 18 : 3 23,760 9 years 9 4 18,000 14 years , 3 l 3 J 10,500
Because of the unreliability of the estimates arrived at by counting a representative number of gonocytes, the method was discarded in favor of another. In the second method one entire ovary was sectioned serially, in sections of 10 p. The number of primary and primordial follicles were counted in representative low-power fields at intervals of every five sections; the sum of such counts gave the number of 143,000 as the average in one ovary. The lowest estimates were 86,000 and the highest 180,000. The numbers at various ages arrived at by this method are tabulated in table 2. 472 CLEVELAND sxnvnsrnn smxms
The number of primordial follicles found in the low-power field shows a percentage decrease that keeps step closely with the estimates for the total ovary. If the number from the sixth fetal month to birth is taken as unity, or a hundred, the number has declined to about 78 per cent of this at five months postpartum. Six months after birth it has decreased to 48 per cent and eight months to 45 per cent. There is not much decline during the next two years, because at the third year the number is about 41 per cent of the number at birth. Following the third year, there is a gradual loss in the number of primordial follicles reaching 16 per cent at the seventh year. In the eighth year it has fallen to 12 per cent, and at nine to 9 per cent. At the fourteenth eyar, the onset of sexual maturity, the primordial gonocytes have fallen to 3 per cent (figs. 20, 27).
The primary follicles, on the other hand, maintain a more or less constant number throughout the course of development (table 2). These are to be found only in the peripheral margin of the medullary portion, and though they may reach a great size, compared to the primordial ones, their number is never numerous (figs. 3, 6). In the newborn the average per low—power field is three, at five months, four; at six months, three; at eight months, four; and at three years, four; seven years, four; eight years, three; and at fourteen years, three.
The primordial follicles of the cortical portion disappear under the advance of the peripheral portion of the medulla, which expands centrifugally and encroaches upon the cortex, gradually reducing it to a thinner and thinner layer, until at the onset of sexual maturity it has practically gone and the function of supplying ova is taken over by the peripheral margin of the old medulla which has now become the cortex, the new cortex, in contradistinction to the old, which remains only as a connective-tissue layer covered externally by an inactive epithelial layer (figs. 14, 19, 20). The old cortex is thickest at birth, and by the eighth year has become reduced to a narrow zone (fig. 19), while the expansion of the medullary portion with its contained primary follicles increases greatly. The oogonia in the medullary portion were originally delivered from the germinating epithelium before and during the fifth month of fetal life. After that time the growth of the follicles is concerned with the proliferation of gonocytes of that initial delivery and difierentiation of isolated cells with reproductive potencies that remain inactive for a longer or shorter time. Some of the primary follicles may be almost ready to rupture a few months after birth, and from the seventh year onward primary follicles, as well as greatly enlarged follicles, are to be met with. These graafian follicles encountered in ovaries of the seventh, eighth, and ninth years are normal in every respect, and are probably awaiting some stimulus to reach the point where they might rupture.
The gonocytes of an eight months’ fetus (fig. 12) are irregularly distributed and all the oogonia are not completely surrounded by the ellipsoidal nuclei so characteristic of the primordial follicle, but the medullary portion is well-defined and a few oogonia with large round cells encircling them are to be "encountered. At birth (figs. 1, 2, 5, 6, 7, 8) the connective tissue has increased greatly and large primary follicles occur (fig. 6). At two months postpartum there is still a further increase in the amount of connective tissue and the primary follicles become better difierentiated (fig. 3). At three months postpartum the primordial follicles (fig. 4) show unmistakable signs of "degeneration (compare figs. 23 and 24).
That the growth of the ovary is from the medullary part toward the cortical gains credence from the conditions observed in an ovary of second year that died from lymphosarcomatosis. In this case the lymphosarcomatous cells have completely invaded the region of the hilus and medulla and have encroached upon the cortex almost to its complete annihilation, although a very narrow "zone is left in which a few primordial follicle were observed more or less yet unaltered. It could be argued that such might very well be the route of invasion of pathologic cells, but not that of normal differentiation.
In an infant six months postpartum the cortex is relatively thin (fig. 9), while the medulla is relatively thicker and the same thing is seen to be true in an infant one year old (fig. 10).
During the second year the epithelium is reduced to a thin layer of single and attenuated cells from which I have been unable to find any strands that jut into the stroma of the gland in the form of egg tubes. Immediately under the epithelium there lies a varying number of elongated connective-tissue cells that interlace somewhat, yet maintain a general parallel course to the surface of the gland. Immediately within lies the cortical portion with remains of the primordial follicles and the layer in which the primary follicles are to be found. These conditions still obtain during the third year (fig. 11).
At the seventh year (fig. 18) the medulla increases by the augmentation of connective-tissue cells and the increase in size of the primary follicles accompanied by a decrease in the thickness of the embryonic cortex and further disappearance of the primordial follicles. In the eighth year (figs. 13, 19) the very small primordial follicles lie immediately outside the medullary part and show very little change from the conditions found in ovaries of the seventh year. At the ninth year (figs. 14, 16) appear small collections of round cells that are identical in size, shape, and staining afiinity with the granulosa cells and those of the primary follicles, but no oogonia are contained within them. The epithelium is much reduced and the subjacent layer has increased in thickness, internal to which are to be found a few degenerating follicles of the primordial type.
At the thirteenth year (fig. 15) there is a further reduction in the number of primordial types, a greater increase in the connective-tissue cells and medulla. Large follicles, with more than one layer of follicle cells are encountered, but such types are never numerous. At the fourteenth year (figs. 17, 20) most of the primordial types of follicles have disappeared and the types that arose from the periphery of the medulla predominate. The conditions shown in figure 20 are unusual in that it is very rare to find so many of the primordial type in one field. The ovary at the fourteenth year is essentially mature sexually and offers no great diiference from that of the adult ovary up to the fortieth year, except that the mature ovary is shot through with remains of involuting corpora lutea and corpora albacantia.
The number of oogonia, primordial eggs, or germ cells in the ovary at birth has been the bone of contention for a number of years. As yet there is no very close agreement even in the reports of recent investigators. Schréider (’30, S. 340-342) shows that the estimates vary from 36,000 to over 300,000, and Haggstrom (’21) estimates the number in the ovary of a healthy Woman of twenty-two years at 400,000 eggs. V. Hansemann (’12) gives the following estimates: second year, 46,174 eggs; eighth year, 25,665; tenth year, 20,862; fourteenth to sixteenth, 39,000. Hammar and Hellmann ( ’20) report that in the ovary of a child three years and eight months old there are 194,283 follicles ranging in diameter from 50 to 1500;: and all in good condition, but there are also 37,015 follicles showing the same variation in size that are degenerating.
Henle (’73) estimated the number in both ovaries of an eighteen-year-old woman at 72,000. He counted the number of follicles in one-sixth of a sagittal section and multiplied the estimated number in one section by the total number of sections. V
Heyse (’97) employed a similar method in determining the number of ova in a Woman seventeen years old, his number for both ovaries is 35,200.
Sappey (’79) counted the number of follicles in 1 square millimeter of the ovary of a girl three years old and reached the conclusion there Were 422,000 follicles in one ovary. By the same method he estimated the number to be 675,000 in an ovary of four years, 300,000 in another ovary of the same age, and 300,000 in the ovary of a woman eighteen years of age. These numbers seem to be very high.
The criticism that can be oﬂ"ered against the estimates submitted concerns itself with the technique of the method. One might ask if the estimates are based upon representative counts and just what deviation might be expected to be found. My own figures are estimates. The number of primordial follicles were counted in one entire section, and this number was multiplied by the total number of sections. This method was abandoned when it Was realized that the cortical area became progressively smaller toward either end of the gonad, henceforth representative sections at both ends were selected and these numbers were added to total counts of every fifth section. Even this method gave results that varied so greatly as to be of doubtful significance. These estimates are made upon the probable number within a single ovary. Table 2 gives the average number to be found in a single low-power field (table 2).
v. Hansemann estimates the number at 6.5 months as 30,339 and at one year and two months an increase up to 48,808, followed by a decline to 46,174 during the second year. The number then declines 25,665 to eight years; 20,862 at ten; 16,390 at fourteen, and 5000 to 7000 at seventeen and eighteen. The general conclusion from the figures of v. Hansemann is that the number of ova decrease from birth to exual maturity and, of course, this number is further decreased until at senility no more eggs are present, or no further stimulus is exerted to cause potential oogonia in the connective tissue to develop.
The work that has been done upon lower forms bears out the general conclusion arrived at above. Arai (’20), working upon the albino rat, discovered that the total number of ova in both ovaries decreases rapidly from 35,100 at birth to about 11,000 at twenty-three days. From twenty-three to sixty days the number is nearly constant (11,000 to 10,000). It then decreases rapidly again to 6600 at seventy days.
Arai thinks the decrease is due mainly to the degeneration of primitive ova and in part to definitive ova, too.
No one has heretofore called attention to the two different types of follicles in the ovary which I have endowed, either rightly or wrongly, with so much importance. It matters very little how many primordial follicles are present, since they all degenerate by the time the gonad becomes sexually mature. The primary follicles, on the other hand, slowly increase in size, but remain more or less constant in number from birth to the fourteenth year. In ovaries of the mature female, twenty-six to forty years, no primordial follicles are found at all. The primary follicles show a remarkable constancy in numbers from birth to the fourteenth year (table 2). They are most conspicuous in ovaries of the premature years, where they may reach a size out of all proportion to the ovary. In the newborn ovary, or even in ovaries at the sixth and seventh fetal months, some of them are so large as to be cystic. When they are first arising, however, and are surrounded with a single layer of follicle cells (fig. 24), their average diameter is 50 u; this I take to be the smallest. The average size of the primordial follicles is 28 u—about 20 p less than the primary.
By counting the number of primary follicles in every fifth section throughout the entire length of the ovary, a reliable estimate may be arrived at- I used every fifth section because my sections were 10;: in thickness and the average diameter of the primary follicles, excepting the large cystic ones, was 50 u, and therefore very little likelihood of counting the same follicle twice need be reckoned with. This estimate gives about 30,000 for the newborn ovary—a number that varies only slightly through the years to sexual maturity.
Schriider (’30) recognizes in the structure of the ovary an external or surface epithelium under which there lies the fibrous subepithelial layer, the white membrane or tunica albuginea, and a parenchymatous zone in which there are to be found the ovarian vesicles, primary follicles, and growing follicles, and finally an inner or vascular zone. Such a description fits the ovary of the adult, but is not at all the structure of the ovary of the fetus. The subepithelial layer of loose connective-tissue cells does not begin to form until several months after birth, and even then is not a true membrane, but merely a collection of connective—tissue cells uniting the disappearing cortical portion with the expanding medullary portion, which soon assumes the position of the fetal cortex and hence is the second or new cortex from which the new follicles arise and grow in size and encroach more and more upon the old cortex until they protrude from the surface as small blisters.
The great number of potential oogonia and follicles, too, that are brought into being and then degenerate has stimulated much speculation concerning the phenomenon. Aschner (’14) accepts the enormous number of 400,000, the estimate of Sappey, as the probable number and speculates upon the struggle for mastery wherein the best eggs survive and produce follicles that rupture. A sort of natural selection taking place within the ovary itself. ‘
There are a great many more potential gonocytes born than ever come to a stage even approaching maturity, but to infer that there is a struggle for existence seems to me to be a far-fetched implication; rather does it seem to be a matter of mutual advantage wherein the follicles that degenerate offer up, in the very act and consequence of degeneration, material, space, and formative stufi for the growth of follicles more happily stimulated. It is probable that the stimulation for the growth of the follicles resides in a hormone secreted by the anterior lobe of the hypophysis. The great variation in the number of primordial follicles in the newborn ovary suggests that this hormone may operate even before birth and the number of follicles so produced varies according to the concentration of the hormone that circulates in the maternal blood and, as a consequence, transmitted through the placenta into the fetal circulation.
Neumann ( ’30) has shown that the umbilical blood of the newborn infant contains relatively large amounts of the hormone of the anterior lobe, which is, however, lost by the eleventh day postpartum. This suggests a possible experimental approach, in that extracts of the anterior lobe could be injected into the maternal circulation with the view toward determining its efiect upon the gonads of the offspring at birth. Swezy and Evans (’31) report that the administration of placental and hypophyseal hormones into pregnant female rats showed no appreciable effects in the ovaries of the ofispring at birth or even a few days thereafter. Teel (’26) found that injections of hypophyseal ﬂuid into the pregnant rat invariably caused resorption or abortion of the young, the result depending upon the period of gestation in which the injections were made.
Role of the germinative epithelium
Online Editor - "germinative epithelium" is a misnomer, as the primordial germ cells (that will form oocytes) are now known to migrate prenatally into the genital ridge.
There is a wide difference of opinion concerning the role of the germinative epithelium in the phenomenon of gonogenesis. One view is that the germinative epithelium continues to deliver potential germ cells to the stroma of the ovary throughout the entire fertile life of the female. A second contention is that the epithelium exercises such a function early in gonogenesis and subsequently ceases to deliver germ cells at a relatively early date. The germ cells arising thereafter come from potential gonocytes that reside in a latent state in the stroma of the gland. In a former study (Simkins, ’28) it Was pointed out that the early delivery of cells from -the germinative epithelium resulted in the formation of the core of the gonad, and these cells when-once constituting the core underwent extensive proliferations in place. It was further observed that this delivery of cells from the epithelium probably ceased during the fifth month of fetal life, at which time the epithelium consisted -of a layer of cuboidal and columnar epithelial cells. At birth (fig. 6, e'th) the epithelium is well marked and difiers markedly from the cells immediately subjacent to it. Its nuclei are ellipsoidal and seem to be bounded externally and internally by a thin cellular membrane. This epithelial layer may be thrown into folds (fig. 7, e’th) or appear somewhat broken (fig. 8, e’th), but from i-t there can be seen no clear-cut cases of cells invading the subepithelial zone either in the form of egg tubes or irregular nests of cells. At six months postpartum (fig. 9), the cuboidal and columnar nature of the epithelial cells has disappeared and the cells composing the outermost layer are small, darkly staining units arranged in a single stratum. The subepithelial layer is much thicker and is composed of elongated nuclei that interlace, yet maintain a general parallel course with the tangential surface of the ovary.
During the years that follow the epithelium becomes thinner, until at the ninth year (fig. 14) it is an attenuated layer of endothelial cells and takes on the structure of a serous membrane. During the time that the epithelium is undergoing these changes the subepithelial layer of connective tissue increases in thickness. Its nuclei become separated by extracellular materials to a greater and greater distance.
At sexual maturity, or the fourteenth year (fig. 20) the epithelium is a single layer of small nuclei that invest the gonad everywhere and at irregular intervals dip down into pockets and folds of the external surface. But, at the bottom of the folds and pockets there is no break in the continuity of the epithelium, which is always separated from the folliclebearing part of the gonad by the subepithelial connectivetissue layer.
In the adult ovary, twenty-sixth to the fortieth year, the epithelial layer becomes further stretched, and in some cases is converted into a connective-tissue layer composed of hyperplastic fibers. It may then become quite thick and oﬂer a considerable hindrance to the rupture of follicles, if not suppressing the function altogether. As the years go by, the epithelium is gradually reduced to a more and more ineffective layer until it finally plays out as an epithelial membrane. But, long before it is reduced to a connective-tissue membrane it ceases its function of delivering germ cells into the stroma of the gonad. This cessation occurs at about the same time the proliferating gonocytes cease dividing mitotically; that is, by the end of the fifth fetal month.
The future delivery of germ cells and origin of follicles throughout the fertile life of the female comes from cells that reside in the parenchymatous part of the gonad. These cells can be found at all ages in small nests throughout the cortical zone Where some of them give rise to the granulosa cell tumors (Meyer, ’31), and others to functional follicles under the stimulus of the hormone of the anterior hypophysis.
As the ovary approaches senility, the follicles disappear before the small masses of granulosa cells, but these often grow to various sizes as tumors, which often never cause any discomfort and can be recognized only on section. The size of the ovary decreases during senility until it is often no larger than a buckshot. The specimen in my collection showed such degenerative changes. In it the epithelium was thin and the subepithelial connective tissue comprised more than half the thickness of the gland. .No strands of epithelium could be found penetrating this layer and no nests of epithelial cells could be found throughout the stroma.
Allen (’23) called attention to the transformation of somatic cells into germ cells throughout the period of sexual maturity. He was able to demonstrate a continuous transformation of cells from the germinative epithelium of the ovary of the rat into germ cells. Kingery ( ’17) found that the germ cells were derived from the germinative epithelium in the white mouse throughout maturity. From the germinative epithelium he found irregular nests of cells that invaded the stroma and there transformed into germ cells and follicle cells as Well. Hargitt (’30) finds the germ cells coming from the germinative epithelium throughout the period of sexual maturity. Most of the Workers on the rodents are in agreement that germ cells are continually formed in the ovary from cells derived recently from the germinative epithelium. There is not so much agreement among the Workers on the carnivores.
Waldeyer (’70) could not find the ingrowths from the epithelium in the ovary of the eat, but such ingrowths, containing ova, were observed by him in the dog. Kingsbury (’13) observes that in the ovary of the cat, the egg tubes of Pﬂiiger instead of being downgrowths, or ingrowths from the surface epithelium (germinative) more exactly represent cell trails left behind in the advancement of the surface as the organ increases in size. Regaud and Policard (’O1) reached the conclusion that such ingrowths had nothing to do with the formation of the eggs and follicles of the adult dog. WiniWarter and Sainmont ( ’08) recognized three distinct periods of proliferation of the germ cells from the germinative epithelium of the eat, all of which were over shortly before or at puberty and new ova that arose in the adult came from cells in the stroma.
Rao (’28) finds invaginations of the surface epithelium taking place throughout sexual maturity in the ovary of the loris. From the depths of these invaginations he finds certain cells breaking off and moving further into the stroma, where they give rise to germ cells. But the germinative epithelium is not the only source of germ cells, for other germ cells arise by the transformation of interstitial cells into gonocytes.
League and Hartman (’25) are of the opinion that new ova cannot be formed anew in the adult from the germinative epithelium or from any other source, but are developed from latent germ cells resident in the gonad from very early ontogeny. They recognize the ingrowths from the germinative epithelium in the ovary of the opossum, but contend that such cells contribute the follicle cells only. Follicle cells so formed when not inclosing a resident germ cell give rise to the anovular follicles. Papanicolaou (’24) followed the formation of germ cells from the germinative epithelium of the guinea-pig throughout life; it started in the embryo, continued throughout the period of puberty, decreased in maturity and almost ceased with old age. Butcher ( ’27) confirmed the results "of Papanicolaou upon the white rat. We reach the general conclusion, from the works on lower animals, that there is a continuous delivery of cells from the germinative epithelium, that swell the ranks of the germ cells, the interstitial cells, and the follicle cells, but when we approach the conditions in the human ovary agreements are by no means so general.
It must be kept clearly in mind, when comparing conditions in the ovary of rodents with those of the human, that important and marked diiferences in structure obtain. The germinative epithelium of the rat is composed of cuboidal cells, and these at certain times may assume a height that is relatively columnar. In the human ovary this type of epithelium is lost early. After the seventh year the epithelium is reduced to a single layer of ellipsoidal cells and in advanced age (sixty-two) the same layer often becomes fibrous and quite thick and joins with the subepithelial layer. The subepithelial layer in the ovary of the rat is always thin, loose, and relatively unimportant, but in the human ovary this layer, sometimes called the tunica albuginea, is very thick and is composed of closely knit cells. The connective tissue of-the human ovary is out of all proportions to the amount of the same material in the rat. In the rat the connective tissue is reduced to a minimum and the germ cells, with their associates, the follicle cells (granulosa cells) make up the greater bulk of the gland, while in the human the germ cells and follicle cells are relatively few. The conditions of the adult ovary of the rat are more correctly comparable to the human ovary at the sixth fetal month. As long ago as 1880 Van Beneden called attention to these same differences and emphasized the fact that some animals possessed a germinative epithelium that was composed of active cells of more than one layer which possibly were active throughout life, while other animals, including man, had a very thin and non-active germinative epithelium. However, Waldeyer (’70) found cords that seemed to grow inward from the germinal epithelium in a Woman of seventy-five years. But these ingrowths contained no ova. It is quite possible that such cells constitute“ -the granulosa cell rests of Meyer and may be pathological.- Amann (’99) observed a similar phenomenon of cellular ingrowth from the germinal epithelium of an ovary of a Woman sixty-three years old. He stated further that the phenomenon was comparable to that which took place in the embryonic ovary. Fellner (’09) observed much the same thing in the ovary of a woman forty-three years of age. With Amann, he agreed that these ingrowths from the germinal epithelium contained ova and follicle cells.
The figures of Waldeyer depicting the ingrowth from the germinative epithelium are too schematic to permit of an unbiased interpretation, and I have been unable to find conditions in the human ovary of any age except the very early embryonic stages that even remotely resemble his published figures. It very frequently happens that the external surface of the old ovary is folded and even pitted. From the bottom of these crypts and pits breaks occur which reach a short distance into the subepithelial tissue, but these have never a diameter of more than 6 to 8 p, while the smallest of the definitive oogonia are 40 n. It appears rather incongruous that new ova would continue to be delivered from the germinal epithelium long after the close of the fertile period with no hope or possible fate other than dissolution. I have been unable to find conclusive evidence that such a thing does occur; on the other hand, there is abundant evidence that in the human ovary this delivery ceases early.
There are some reports that the senile ovary, under repeated stimulations of injections of the gonad-stimulating hormone of the anterior lobe will respond and produce functional ova (Steinach and Kun, ’28). Hill and Parkes (’31), however, have failed in their attempts to promote the reformation of germ cells by the administration of the gonadstimulating hormone. The technique employed by them may be objected to as offering very slight, if any, hope. In the first place, they attempted to increase the percentage of ovarian regeneration in ovariectomized mice. No percentage increase was discernible. Again they attempted to cause the reformation of oocytes in the ovaries of mice sterilized by X-rays, with the same negative results. These experiments, however, do not preclude the possibility of causing the reformation of definitive ova in the sterile ovary, as Steinach and Kun have reported.
It naturally follows, then, that the source of the follicles should be considered. Two possible sources suggest themselves: first, are the follicles delivered to the stroma .over a relatively short time and there remain, stored, so to‘ speak, until they are needed, or, secondly, are they derived throughout the period of fertility from somatic cells? I am convinced that the second alternative is the most likely one, and I am equally convinced that the adult human ovary does not receive germ cells from the germinative epithelium.
Vilaseca '(’19), in his description of the stroma of the human ovary at birth, denied the presence of cord- or tube-like downgrowths from the surface epithelium into the stroma of the gland. He very aptly contends that the growth is in the other direction, that is, from the hilus toward the periphery and all building m-aterialsmust come in through the hilus or through multiplication of that which is already there. The stroma is, then, built up from products of the germinal epithelium which proliferate rapidly and difierentiate into the various types of cells constituting --the stroma, which are connective-tissue cells, follicle cells, and germ cells.
Kervily ('34) has called attention to a process of amitotic division among the gonocytes of the newborn ovary. I have searched diligently through a very large series of ovaries and have not yet discovered conclusive evidence that the oocytes divide at -all after the sixth month. Polyovular follicles are not produced by‘ the multiplication of the ovum, but by the simultaneous enlargement of two cells within thenest of follicle cells, two germ cells becoming involved in the same nest of granulosa cells. The connective-tissue cells of the stroma divide by direct division, and so do certain cells undergoing dissolution, but with every upbuilding process the cells divide mitotically. The egg cell remains inactive for a long time, probably from the sixth fetal month to ovulation. Allen et al ( ’30) have shown that the human ova is ovulated after extrusion of the first polar body while in the metaphase of the second meiotic division.
Shaw (’25) has traced the fate of those follicles that never rupture to release an ovum. Some of them produce the corpus atreticum, others the corpus candicans, fibrosum, or restiforme. Thus there are four possible types of ending for the great number of follicles that are stimulated to start their development, but doomed never to finish it. The process of degeneration as described by Shaw is concerned only with the follicles of the adult and does not refer at all to those follicles that I have called the primordial, these merely shrivel up and disappear. Foulis (’76) states that there are upward of 35,000 ova in the human ovary at birth, some of which reach maturity. These, he contends, are delivered to the stroma of the gland from the germ epithelium, a process that ceases about the age of two and one-half years. He cannot subscribe to the View that the eggs arise from ingrowing tubes from the surface, as Pﬂiiger (’63) described. At no agepwas he able to see tubes penetrating the stroma from the surface epithelium. He further states that _at the sixth year the epithelium is composed of small ﬂat ‘corpuscles’ and makes up a layer that can be stripped off with ease—a thing that could not be true if it delivered cords or tubes of germ cells to the ovarian stroma. At the twelfth year the epithelium is much the same, only the small size of the ‘corpuscles’ is remarkable.
I am in agreement with the above, with certain exceptions appertaining to the number of ova in the ovary at birth and the time when the delivery of germ cells to the stroma ceases. After the cessation of participation in the formation of germ cells by the germinal epithelium, those germ cells so produced differentiate along two lines. One line leads to the formation of the small follicles surrounded by ellipsoidal cells more or less incompletely, and the other li.ne leads to the larger follicles surrounded by round and proliferating follicle cells. The first line degenerates completely, the second line leads to the formation of mature follicles by gradually extending their territory toward the periphery of the gland and giving rise to the neogenic zone of Felix (’12). These follicles, the primary, along with solid masses of granulosa cells, do not grow at the same rate, but constitute a part of the ovarian stroma, more especially that part of the stroma con~ stituting the parenchymatous zone. In a position of quietude, indistinguishable from other cells, the potential germ cells remain, probably awaiting stimulation to go forth and produce follicles. These are always found enlarging from the deeper parts of the neomedullary region toward the periphery, that is, in the same direction» the proliferation assumed in the formation of the gland as a whole. When sufficient stimulation is no longer forthcoming, the ovary ceases. to function, the menopause results. There is no evidence to support the view that the eggs are all used up, that the supply is exhausted by ovulation, because the potential masses of cells are always in the ovary, until in very advanced age. There is a feeble attempt to stimulate these masses, which have the appearance of granulosa cells, but the stimulus is too weak to produce more than tumors. It is probable that this gonad stimulator is the hormonefrom the anterior lobe of the hypophysis.
Hoffman ( ’31), in a series of experiments upon white mice, reached some indicative conclusions. Old senile mice were used, those in which an oestrous cycle had not occurred for months. The left ovarywas removed and sectioned. The animals were then allowed to recover and a portion of the anterior lobe was grafted subcutaneously into the thigh of the senile rats. After a varying length of time, certain animals were sacrificed and the remaining gonad examined and sectioned. It was increased to ten times the size of the remaining ovary. Large ‘follicles were present and the ovary had been restored to fertile function. The senile ovary was dense, shot through with small follicles, and held in dense stroma. In other animals so stimulated oestrus was restored, mating and pregnancy followed. Potential follicle cells exist throughout the life of the individual ovary in small clusters or singly in the cortical zone of the ovary, where they constitute and take part in the formation of the ovarian stroma and never become anything else unless stimulated to do so by the gonad-stimulating hormone of the anterior lobe.
The most characteristic part of the human ovary is the comparatively enormous amount of connective tissue. In the lower forms, such as the rat, cat, rabbit, and guinea-pig, there is a very small amount of connective tissue. In the ovary of the dog there is a little more connective tissue and then throughout the series of Primates the amount gradually increases. In the newborn babe and even in the fetus (fig. 8) the connective tissue is about equal in amount to the follicles and the follicle cells. This relationship does not long obtain. The nuclei of the cells are always elongated and curl about the follicles in an endless variety of ways. By the sixth month after birth (fig. 9) one can notice a decided increase in the amount of connective tissue. This increases apace so that the relative amount of connective tissue and follicles is greatly altered, the connective tissue far outmatching the space occupied by the follicles (fig. 10). This extraordinary proliferation of "connective-tissue cells at the third year (fig. 11) so changes the relationships that connective tissue constitutes most of the gland. Through the years that follow there is a constant increase in the absolute amount of connective tissue, until in senile old age the absolute size sf the gland decreases and the connective tissue undergoes a sort of hyaline degeneration.
Mainland (’31) has shown that through age, health, and disease there is no correlation in the density of the nuclei of the connective-tissue cells. From the advent of sexual maturity the number of nuclei in any prescribed and circumscribed area is about the same.
- In the human ovary at birth there are two kinds of follicles. those within the cortex and inconstantly and incompletely surrounded by Hat and ellipsoidal cells, the primordial follicles; and follicles completely and constantly surrounded by rounded cells, primary follicles. The primordial follicles have a.n average diameter of 30;; or less and the primary follicles have an average diameter of 50 um.
- The number of primordial follicles in the ovary at birth is subject to such wide variation that estimates have no significance, the estimated number varying in a single ovary from sixty-five to over 143,000. The primary follicles are not so numerous and their number remains more or less constant from birth to sexual maturity, when their number begins to fall.
- The primordial follicles lie in the primordial cortex of the early ovary where they undergo gradual degeneration, the last of them dissolving at the onset of sexual maturity. The advancing medulla carrying the primary follicles encroaches upon the old cortex and establishes a neogenic zone or a neocortical area from which the definitive follicles enlarge toward the periphery until they finally produce mature ova.
- The oogonia cease to multiply by mitosis at the sixth fetal month, during which time the delivery of germ cells from the germinal epithelium ceases. There are no tubes or cords of cells from the epithelium ramifying into the stroma of the ovary carrying with them new gonocytes throughout the period of sexual fertility. New gonocytes arise from cells of the neogenic zone, which are not to be considered as stored germ cells, but somatic cells induced to grow into germ cells by the gonad-stimulating hormone of the anterior lobe of the hypophysis.
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EXPLANATION or fiGURES
1 Cross section of the newborn ovary. Photomicrograph. X 250. fol.p'r., primordial follicle.
2 From a section of the newborn ovary. Photomicrograph. X 250.
3 From a'sectiou of the ovary of an infant two months postpartum. Photomierograph. X 250. cl.foll., enlarged primary follicle.
4 From a section of the ovary of an infant three months postpartum. Photomicrograph. X 250.
PLATE 2 EXPLANATION or fiGURES
5 From a cross section of the newborn ovary. Photomicrograph. X 250.
6 From a cross section of the newborn ovary. Photomicrograph. X250. cl.fol., follicle cells, stratum granulosum; e’th., germinal epithelium; fol.pr., primordial follicle.
7 From a cross section of the newborn ovary. Advanced degeneration of primordial follicles. Photomicrograph. X 250. e'th., epithelium.
8 From a section of the newborn ovary. Photomicrograph. x 250. e'th.,
9 From a section of an ovary of an infant six months postpartum. Photomicrograph. X 250. 10 From the ovary of child one year old. Photomicrograph. X 250. 11 From the ovary of a child three years old. Photomicrograph. X 250. 12 From the ovary of an eight-mouth fetus. Photomicrograph. X 250.
EXPLANATION OF fiGURES
13 From a section of an ovary eight years of age. Photomicrograph. X 250. 14 From a section of an ovary nine years of age. Photomicrograph. X 250. 15 From the cortex of an ovary thirteen years of age. Photomicrograph.
X 250. 16 The cortex of an ovary at nine years of age. Photomicrograph. X 250.
mzfifiﬂm EE.mm>Awm nz<a..§K5o v ankqm E350 zfiabm mo Zoafidfibsdfi PLATE 5
EXPLANATION OF fiGURES
17 From the medulla of an ovary fourteen years old. Photomicrograph. X 250.
18 The cortex of an ovary seven years old. Photomicrograph. X 250.
19 Showing the cortex and medulla of an ovary eight years old. Photomicrograph. X 250. cl.fol., enlarged follicle of the medullary zone.
20 Cortex of an ovary fourteen years old, showing a few. primordial follicles. Photomicrograph. X 250. e’th., epithelium reduced to a single layer.
21 Cross section of the newborn ovary to how the relationship between the cortex and medulla. X 35.
22 Ten free-hand sketches of the diﬂerent shapes of the ovary at birth. X 3.
23 Primary follicle of the ovary at birth. X 340.
24 Two primordial follicles (below), and a primary follicle (above) at one month postpartum. X 340.
25 Wall of an advanced follicle from an ovary at the eighth year. Stratum granulosum, a; theca interna, b; theca externa, c. X 340.
26 Wall of small cyst from an ovary at the third month postpartum. Stratum granulosum, a ; theca interna, b; theca externa, 0. X 340.
27 Two degenerating primordial follicles from the ovary of the fourteenth year. X 340.
28 Granulosa cell masses and a degenerating primordial follicle at the ninth year. X 340.
29 Large primary follicle and portion of the wall of a large cyst (5 mm.) at birth. Stratum granulosum, a. The theca interna and theca externa cannot be recognized. X 340.
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