Paper - Notes on the formation, structure and physiology of the corpus luteum of man, the pig, and the duck-billed platypus

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Solomons B. and Bronte Gatenby JW. Notes on the formation, structure and physiology of the corpus luteum of man, the pig, and the duck-billed platypus. (1924) BJOG : .

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Notes on the Formation, Structure and Physiology of the Corpus Luteum of Man, the Pig, and the Duck-Billed Platypus

By

Bethel Solomons, M.D. (Dubl.), F.R.C.P.I.,

Gymecologilst to Mercers Hospital, Dublin; and

J. W. Bronte Gatenby

M.A. (Dubl.), D.Sc. (Lond.), D.Phil. (Oxon.), M.R.I.A., Professor of Zoology, Trinity College, Dublin.

(From the School of Physic, Dublin University, and the Department of Embryology, University College, London).

Introduction

Since the discovery of the corpus luteum by Volcherus Coiter in the year 1573, the mammalian physiologist, and especially the gynaecologist have been striving to elucidate the interesting problems this organ presents. Moreover the histologists, and more latterly the cytologists, have entered into a lively discussion as to the precise manner in which the structure becomes formed.

In Belgium, Van der Stricht has studied the intimate structure of the corpus luteum in the bat (Vesperugo) «especially; in America, Corn-er has contributed two important papers on this subject in the pig, while in England, J. P. Hill'and O’Donoghue have given some account of the corpus luteum in Marsupialia.

Recently one of us published a paper on a human corpus luteum of ovulation, and in the present communication we propose to extend these observations, and to add some notes on our experiments on the liquor folliculi.

Our material consists of a collection of human, pig and rat

' corpora lutea. Moreover one of us has recently studied the forma tion of the corpus luteum of Ornithorhynchus, in conjunction with Professor 1. P. Hill, F.R.S,. who has seen some of the preparations of the pig and human corpora lutea which form the basis of the first part of the present paper. Formation, Structure, etc., of the Corpus Luteum 581

PART [. There are three views as to the Origin of the corpus luteum.

a. That it originates from the theca interna. The upholders of this view are:——von Baer, Valentin, His, Kolliker, Gegenbaur, Paradino, Nagel, Bonnet, Schottlander, Clark, Doering, Biihler, Jankowski, Heger.

b. That it originates from the granulosa or follicle epithelial layer:—Bischoff, Pflijger, Waldeyer, Call and Exner, Schulin, Sobotta, Honoré, Kreis, Sandes, Marshall, Vollker, O’Donoghue, Joka, Borell, P. Hill and Gatenby, Solomons, Togari.

c. That it originates both from theca interna and granulosa :—

Rabl, Van der Stricht, Seitz, Loeb, Cohn, Meyer, VVallart, Schroder, Marcotty, Reusch, Corner.

The whole question revolves around the fate of the cells "of the theca interna.

It can be said immediately that there can be no doubt that the upholders of the theca interna origin, whose names are quoted in paragraph a, are mistaken. The evidence brought forward by the observers named in paragraphs b, and c, is overwhelmingly against the view that the granulosa cells are lost at ovulation or subsequently. The fault lies in the fact that the theca interna theorists have not studied a perfect enough series of corpora lutea.

In all the common animals ordinarily at the disposal of European and American workers the cells of the theca interna and granulosa become much alike in size.

The only animal known to us in which cells of the granulosa and the theca] cells never approach each other in size, is Ornithorhynchus, the Australian duck-billed Platypus. In a paper, now in press, Gatenby and J. P. Hill have reported their observations on this form, and their findings will be referred to below.

VVe have another line of evidence to bring forward in this paper. One of us showed recently that the so-called silver nitrate techniques, for the Golgi apparatus, had the effect of blackening the theca interna of the human Graafian follicle. and that this argentophility persisted for some time in the corpus luteum of ovulation.

We have since procured more material and are able to add to these previous findings for the human.

Undoubtedly the most satisfactory material we have seen is that of Ornithorh_vnchus. The sections one of us has studied, in conjunction with Professor ]. P. Hill, F.R.S., at once settled the vexed question as to the fate of the theca interna, so far as 582 Journal of Obstetrics and Gynaecology

concerns this animal. In the duck-billed platypus the theca interna cells increase mitotically before and after ovulation, but do not hypertrophy like the granulosa cells, and take no part in luteincell formation.

It is just as well to be clear as to what we mean by this latter statement. There can be no doubt that in supporting or rejecting the mixed origin theory, certain observers have not been clear as to what were the criteria for stating that this or that theca interna cell had or had not become a lutein cell.

By the words “ lutein cell" most observers presumably mean a cell containing lutein granules. When, however, we press the question further and enquire w'hat is meant by the term “ lutein granule,” we find ourselves in clifficulties. lVIodern research seems to have shown that the so-called lutein cells of the corpus may or may not contain neutral and other fats, and that in some of them the lutein granules are merely swollen mitochondria. The Criteria for distinguishing by means of intra-cellular granulations between theca interna cells and granulosa cells of the corpus luteum of the larger mammals must at present he vague, because our understanding as to the nature of the lutein granules is itself inconsiderable.

In the duck-billed platypus neither size nor difficulties nor the questions originating from our ignorance of the cell inclusions present themselves; but in the larger mammals, not only do the theca interna cells resemble the granulosa or lutein cells in size, but also the former cells contain osmiophile granules and lutein like inclusions. '

In Plate II, fig. 12, we give a microphotograph of the newly ruptured follicle of the duck-billed platypus showing clearly the demarcation between the three layers. This photograph was taken in the Embryology "Department of the University College, London, under the direction of Professor J. P. Hill, F.R.S., from material collected, fixed and prepared by him. On the left we have the typical theca externa (T E) formed of connective tissue; at T I, are large groups of theca interna cells, and at M G, are the relatively enormous follicular epithelium, or granulosa cells. The clear space, C A F, is the empty follicle pr-eviously occupied by the egg.

At no time in the subsequent history of the corpus luteum of the duck billed platypus do the theca interna cells increase to the size of the granulosa (lutein) cells, so that in the platypus the true lutein cells are purely granulosa in origin.

The vacuoles in the cells of the theca interna noted by J. P. Hill, and previously described in the joint paper of Gatenhy and Hill, are well shown at T I, in the middle 9f the photograph. Formation, Structure, etc., of the Corpus Luteum 583

So far as the large mammals are concerned, the human, pig, cow, etc. there has been hitherto a real difficulty in following the fate of the theca interna cells. Corner traced the latter cells in the pig corpus, up to a certain stage, but considered thereafter these cells should be looked upon as theca-lutein cells, and consequently that the corpus of the pig was of mixed origin. We believe, nevertheltess, that there is a question as to whether this difficulty is due to the inadequacy of Corner’s technique. One of us has collected, and prepared pig corpora especially by the Da Fano silver method. In both the pig and the human there are elements in the formed corpus luteum which impregnate markedly with silver. In the human Graafian follicle there are similar argentophile elements, which are to be identified as the theca interna cells. In the pig, however, the same elements in the ripe Graafian follicle are not -especially argentophile, and the argentophility of the supposed theca interna elements of the formed corpus of the pig is of later development.

The wall of the human Graafian follicle, in material prepared by Da Fano’s method, exhibits four distinct cellular layers, Plate l, fig. 1. The innermost, lining the antrum folliculi, is the membrana granulosa or follicular epithelium, M G. Beneath it is the membrana propria M P, which is now recognized as being a definite cellular layer: it separates the follicular epithelium from the theca interna, which lies beneath the membrana propria. Finally beneath the theca interna lies the fibrous tunica externa, or theca externa.

In Plate 1, fig. I, is a diagram showing these layers. The follicle epithelium of the very large Graafian follicle from which this drawing was made, was found to be about six cells in thickness.

A fact not hitherto noted by previous observers, so far as we know, is that the uppermost layer of the human follicle epithelium is covered by a layer of squamous cells which appear at first sight to be something apart from the ordinary granulosa cells. These cells are shown in P1. l., fig. 1, at X, but we recognize that they may only be modified follicle epithelial cells.

The follicle cells at this period are somewhat elongated, on the average Iolu in diameter. The cells of the lowermost layer lying on the membrana propria, M P, are all definitely oriented: their nuclei lie towards the membrana propria, and their small Golgi apparatus away from the latter. This orientation does not apply to the overlying granulosa cells, which are oriented in various directions and not in any special manner. The earliest one-layered follicle epithelium of the young oocyte is arranged in a definitely orient-ed manner, as is the bottom layer of granulosa cells in the adult follicle. From our knowledge of the part taken by connective 584 Journal of Obstetrics and Gynaecology

tissues in the orientation of epithelia (A. Drew), we are led to believe that the definite orientation of the lower layer cells of the granulosa is governed by the underlying connective tissue elements.

The typical follicle epithelial cell is drawn in Pl. 1, fig. 5. The Golgi apparatus (G) is small and compact, and impregnat-es very densely in silver. Scattered mitochondria could be made out at M, but in none of our preparations did we discover true fat granules at this stage.

The theca interna layer, as before mentioned, impregnates densely in silver: this is shown in the microphotograph on Pl. II, fig. 10, at TI. In some of these black cells the eccentric nucleus may be distinguished.

In Pl. I, fig. 1, T1, the theca interna layer is shown: it is formed of irregularly stellate cells, generally with a markedly eccentric nucleus which is small for the large size of the cell. Not all the cells in this layer go quite black by Da Fano's method, some (ASX) are only golden brown, but these are generally among the smaller c-ells of this layer. .

It should be mentioned at this stage that in the large Graafian follicles of the pig, the theca interna cells are, compared with the other cells, much smaller, and in no case at this stage hav-e w'e managed to impregnate them blackly without at the same time blackening the membrane granulosa. It seems that the pig and human differ in the time of development of the characteristic fixing, impregnating and staining phenomena of the theca interna cells, and also in the relative number of theca interna elements. It is certain that in the pig the latter form a thicker layer and are smaller and more numerous.

Elsewhere one of us has given several microphotographs and a description of a human corpus luteum of ovulation, in which the argentophile theca interna cells were shown to keep their individuality, and on the whole were distinguishable from the true lutuein cells. A part of this corpus is drawn in Plate I, fig. 2, the theca interna cells being marked A S, the lutein (granulosa) cells, M G. For photographic confirmation of this argentophility of the theca interna cells of the adult human menstrual corpus, the reader is referred to Plate II, fig. II of this paper, T I, being stellate argentophile theca interna cells.

We were anxious to see how C0rner’s mat-erial——the pig, would show by Da Fano’s method. To our surprise we have been able to demonstrate that the pig’s corpus luteum contains a network of argentophile cells, Pl. II, fig. 8, apparently corresponding to the argentophile cells in the human corpus luteum.

In Pl. II, fig. 9, at a higher power, the same corpus is photographed, the stellate or theca interna cells, being quite black, the


Formation, Structure, etc., of the Corpus Luteum 585

interstices being occupied by the true luteal cells, unstained. At T E, are theca externa cells.

We suggest therefore that Corner is wrong. In reality, we consider, the theca interna cells keep separate from the lutein cells, and together with the theca externa columns, form the connective tissue matrix of the corpus luteum. These cells therefore are more connective than glandular.

One of us recently obtained a large human corpus luteum of menstruation, one centimetre in diameter. This interesting specimen proved to be regressing; a great development of secondary connective tissue had taken place as shown in _P1. 11, fig. I3, and in many places the luteal cells had collapsed completely, fig. 15. Here and there, however, there were less efifete regions, and in these we found groups of stellate argentophile cells, fig. 14, which resembled the theca interna cells of the ripe Graafian follicle, in size, shape, nuclear chromophility, and in cytoplasmic argentophility. Consequently we consider that the human theca interna cells keep their individuality up to the time of their final degeneration, and the subsequent formation, by theca externa elements, of the corpus albicans.

The very clear evidence obtained by J. P. Hill and Gatenby for Ornithorhynchus shows that the theca interna cells in this animal do not become glandular in the same sense as the lutein cells. It should be pointed out that the upholders of the mixed origin theory prefer to consider that even though the platypus theca interna cells did not swell visibly, the very presence of these cells not visibly changed and within the corpus proved the mixed origin.

In the platypus the theca interna cells do not take part in the formation of true connective tissue, nor could Hill and Gatenby prove that these cells contained visible rods or granules. Intracellular vacuoles, however, were present.

The idea of Sobotta that the theca interna cells become

converted into spindle-shaped cells, and form a connective tissue reticulum cannot be sustained for Ornithorhynchus. y The true connective tissue fibres of the adult platypus corpus, appear throughout to be of the theca externa origin, and there is no evidence that in_ter- or intra-cellular fibres originate from the theca interna.

Much the same position appears to hold for the larger mammals. The connective tissue proper, that is the true fibrous elements, we consider to be of purely theca externa origin. Corner's endothelial cell origin we doubt very much. This idea has not been sustained by the work of Hill and Gatenby, and is not supported by our ow'n observations on the pig——Corner’s material. Then also, the theca interna cells can be traced, as in the platypus, into the full grown

E 586 Journal of Obstetrics and Gynaecology

corpus, where they may form a stellate network, but no connective tissue fibres.

It seems to us that the discussions as to “mixed” or “ granulosa ” origins of the corpus luteum are rather idle. Certainly the theca interna cells take part in forming the corpus luteum : certainly in the larger mammals the stellate or interna cells form a network; certainly these cells may contain osmiophil granules; but we consider that in the human, the pig, and in the platypus. evidence that the theca interna cells produce inter- or intra-cellular fibres has yet to be pro-duce-d.

The discussions on the histology of this subject at the last resource come down to physiological function. The theca interna cells of the larger mammals contain osmiophile granules, but these appear to preserve their previous characteristics after corpus formation. The r-eal test as to the part played by the theca interna cells in the formation of the corpus luteum is whether they participate in the secretion of some hormone. It may be said at once that our technique does not permit us to answer this question. P. Hill, in the work carried out in conjunction with one of us, drew attention to the intracellular vacuoles of the theca interna cells of the platypus corpus luteum : here again it is difficult to say what this means. One might imagine that the theca interna cells could form some secretion at this period, and thereafter remain inactive, and that the subsequent activity of the corpus luteum might be

confined to the true lutein cells.

Finally, our view on this subject is that the theca interna cells -do not form true connective tissue fibres, and that proof that they participate in the production of a hormone has not been forthcoming.

One of the interesting facts that we have been able to bring out in this paper is the extraordinary change undergone b_v the Golgi apparatus during the metamorphosis of granular cell into luteal cell; shown in fig. 4 of Plate 1. The smaller upper drawing represents th-e apparatus of the granulosa cell, the lower, the fully grown apparatus of the luteal cell. This remarkable change is shown also in figs. 5 and 6, where the granulosa an-d luteal cells are drawn to the same scale.

In the later stages of the corpus luteum of pregnancy, and sometimes in that of menstruation, the Golgi apparatus loses its peri-nuclear eccentric position, passes around the nucleus (fig. 7). and" partially liquifies, or at least loses its regular arrangement as numerous well defined granules an-d rods. Formation, Structure, etc., of the Corpus Luteum 587

PART II.

If the hormone of liquor folliculi is destroy-ed by the digestive juices, one would expect the same to apply to the giving of corpus luteum extract. One of us has for years used the latter as a therapeutic agent by the mouth with success and without harm. VVe have recently tried bovine liquor folliculi on many women. It was used in the severe hzemorrhage which is often associated with puberty, in the ordinary menorrhagia (without tumour) of adult women, and in the haemorrhage of the menopause. It was also tried for menopausal symptoms. In all these the results were absolutely negative. The dose given varied from 1 to 2 ccs. and in some cases was repeated daily for 10 doses. It should be pointed out that the liquor folliculi was given by the mouth, and the active substance may have been destroyed within the alimentary canal. Later, we hope to try the effect of hypodermic administration.

Since glandular extracts became popular, one of us has tried them all. Corpus luteum extract may be used for the non-pregnant and the pregnant woman; in the former it has been prescribed for many conditions: menorrhagia, metrorrhagia; dysmenorrhoea, scanty or absent menstruation; sterility; menstrual epilepsy and the climacteric. For menorrhagia and metrorrhagia corpus luteum in common with other glandular prepartions has been found to have little effect. As this was thought to be reasonable in view of the fact that the retrogr-ession of the corpus luteum means the onset of menstrual bleeding as already stated, cases were tried with doses of bovine liquor folliculi which was collected by one of us, but in no case experimented on so far has there been reaction. In other words in our experience, ut-erine bleeding, even though it may be hormonic in origin, has not stopped by glandularextracts. Corpus luteum extract has been unsuccessful in most cases of dvsmenorrhoea. It was only given when there was no apparent "pathological condition present. VVhen successful, it seemed to us that the cases were definitely ovarian dysmenorrhoea, and that it acted probably by directly stimulating the ovary so that the Graafian follicles ruptured through the thickened cortex. It was pr-es‘-cribed in doses of 5 grains three times a day all through the month. Hypodermic administration both intermenstrually and at the time of menstruation has no different effect. For scanty or absent menstruation corpus luteum is a definite specific, and as these conditions are associated with sterility, we must consider them together.

Firstly. scanty menstruation in the unmarried : this is sometimes accompanied by obesity. \/Vhen the woman is not abnormally stout corpus luteum extract is prescribed. If stout, thyroid extract is given in addition. Moreover, attention to diet is necessary. In 588 Journal of Obstetrics and Gynaecology

this class of case hypodermic administration of corpus luteum 5 grs. daily for two weeks sometimes has great effect and is quicker in its action than when given by mouth.

Secondly, scanty menstruation in th-e married: this is almost invariably a-ccompanied by sterility, and in the absence of pelvic disease the results of the administration are startling, are definite, and compare so favourably with the results attained b_v the use of other glandular extracts that the latter have been discarded. At first sight it is strange to find that corpus luteum extract administered by the mouth should start menstruation, considering its supposed ordinary physiological action, but it is evident that we are dealing with not one but a series of primary and end effects which will only be cleared up after the physiologists have carried out more intensive investigations. Once menstruation is established properly, a short time only elapses until pregnancy occurs. This does not happen in all cases, but in 75 per cent. of those treated cases in which there was no pelvic or other lesion, and the patient followed out the treatment to the letter (and this must be done) pregnancy resulted. The procedure is as follows :—(‘orpus luteum (grs. 5 in capsule) is given by the mouth, twice a day for a week, then the dose is increased to one capsule three times a day. At the end of the month this is gradually increased to two, three times a day, z'.e., until the patient is getting thirty grains a day. The drug is taken the whole month, including the time of menstruation, and is continued for six months. As pregnancy occurs, or the menstrual flow increases in quality any time during this period, its effect is evidently cumulative. We have already” reported a case where a patient, who had never menstruated during three years of married life, commenced to do so after two months dosage. The menstruation continued for two months, then pregnancy oc-curred. Seven years later she consulted us, as she wished to conceive again. She had never menstruated since the birth of the child. A course of corpus luteum had then the same result, an-d a second child was born within a year after the re-commencement of its administration.

It is obvious, therefore, that in this type of case the drug is of immense service. The variety used has been manufactured by Parke, Davis and Co.

In the climacteric, when corpus luteum should theoretically be of immense service, we have found it, with few exceptions, of small avail. The old—time medical remedies must still be relied on. There is, however, now on the market a mixed gland preparation which is sometimes useful; it is.adreno-ovarian Co. of Harrower. and contains suprarenal gland gr. 1, ovarian substance with corpus luteum grs. 2%, and a little pituitary and thyroid extract. Although Formation, Structure, etc., of the Corpus Luteum 589

we do not as a rule advise pluri-glandular preparations, this is logical for patients whose symptoms point to affections of the glands mentioned.

There is one other class of case that must be considered. Sometimes young women suffer from fits during menstruation, and at no other time. We have tried corpus luteum in many such cases. Oral administration is useless. In 50 per cent. of our patients, when given hypodermically, cures resulted. It was given three times weekly during the month from the intermenstrual period, and daily during menstruation. The dose prescribed was grs. 3. Ashe has also published cures.

In pregnancy conditions corpus luteum has been found to be of great service, and its chief indication is in the prevention of abortion, miscarriage, and Ptemature birth. When a woman complains of any of these conditions, an exhaustive examination is made to exclude syphilis, etc. In the absence of anything definite, maldevelopment and early retrogression of the corpus luteum may be taken as very possible causes. The administration of 5 grs. daily has a satisfactory result in nearly all cases, provided that the woman takes the precautions which are usually advised in these cases. It is simple to understand why the corpus luteum acts so beneficially in the early cases, but why it should be of benefit in the last three months, i.e., for those who have been in the habit of bearing stillborn children, is more difficult to understand. But as mentioned above, w'e believe that this and parallel phenomena will be satisfactorily elucidated only after more intensive studies have been carried out on the lower mammals.

In the vomiting of pregnancy, both mild and severe, corpus luteum has been used most successfully in many instances, and while not being a specific, it is a very valuable remedy; 5 grs. three times daily is the dose which has been of most benefit. We have also used it hypodermically with good effect as advised by Hirst. Whitridge Williams“ and others believe that the effect is suggestive, whether or no it obtains cures. There are other vast possibilities open, and we hope later to try its effect in albuminuria, eclampsia and other toxaemias of pregnancy.

PART III.

In view of the results one of us had already obtained with corpus luteum in women, we decided to try the effect of giving liquor folliculi and corpus luteum to rats, and, as has been mentioned above, we tried the effect of bovine liquor folliculi on women.

Our experiments on rats were divided into two sections; in one, normal female rats were given doses of bovine liquor folliculi mixed in oats or condensed milk; in the other rats whose ovaries had been 590 Journal of Obstetrics and Gynaecology

removed were treated likewise. In both cases controls fed in the same way, but without the liquor folliculi, were used.

Fresh cow ovaries were brought to the laboratory and the liquor aspirated in a syringe. Some Graafian follicles contained as much as 10 cc. of liquor. The bovine liquor folliculi is a brownish straw colour, and when alcohol is added a dense precipitate is thrown down. In the case of th-e rats we gave the liquor folliculi fresh. It can be kept for a week without going bad by the addition of thymol water.

Our experiments were intended to run parallel with those of Allen and Doisy, only the latter workers had used the injection method, whereas we determined to try feeding experiments.

It should be mentioned that our experiments were carried out in the autumn and early winter, and that none of the rats had bred for two months. The previous summer had been poor, and the general health of the stock was not satisfactory. VVe do not propose to publish here a detailed account of our investigations: the sum total of our results was to show that in a small proportion of our spayed rats fed on raw liquor folliculi marked sexual feeling was aroused?‘ Such animals became excited when put with the male and behaved quite differently from the controls. In other cases the results were negative; possibly because the health of the animals was so poor.

Exactly parallel experiments with rats fed with raw corpus luteum gave less definite results, though in a small number of cases the rats became much excited when put with the male. Since our researches are not yet complete, we do not at present propose to lay too much stress on these experiments.

Allen and Doisy believe that corpus luteum injected into rats does not stimulate in the peculiarly marked manner of liquor folliculi applied in the same manner. It is hard to believe this on histological grounds; there is no good cytological evidence for differential secretory activity of the Graafian follicle and the corpus luteum at different periods. The one structure appears to drift smoothly into the other: there is no dropping out of cell areas, only the hypertrophy of pre-existing intracellular structures.

Yet we would wish that Seitz and Allen and Doisy were correct, because the isolation of two such ovarian hormones would be a discovery of great benefit to mankind.

Edgar All~en’s investigations especially appear to show that the primary cause of oestrus lies neither in the corpora lutea nor in the interstitial cells, but in the follicles.

Leo Loeb also believes that the first phase of the sexual cycle is

‘We also used the vaginal smear methods as well. Formation, Structure, etc., of the Corpus Luteum 591

dominated by the. maturing follicles, and the second by the corpus luteum. Loeb considers that the functions of the corpus luteum so far known are :~1, it sensitizes the uterine wall; 2, indirectly it probably facilitates the fixation of the ovum; 3, it evokes the growth processes of the mammary gland; 4, it helps to‘ regulate the sexual cycle.

Furthermore Loeb considers that the sexual cycle may be divided as follows: 1, the follicular phase, with pro-oestrus, and sometimes metoestrus; 2, ovulation; 3, the lutein phase, including the sensitizing of the uterus.

The climacteric or change of life period marks the termination of the reproductive cycle in a woman’s life. At this stage the ovary may be much diminished in size, and the larger Graafian follicles are said to be absent. In the majority of cases Graafian follicles of any size are difficult to discover: there is a marked preponderance of connective tissue and corpora albicantia, and corpora lutea no longer appear.

Thework cited in this paper leads us to believe that these changes associated with the menopause which often bring about difficult and dangerous psychic symptoms, might be prevented or at least alleviated by the proper administration of some ovarian hormone, for it is possibly the cutting off of the supply of some ovarian hormones previously derived from follicle or corpus luteum which bring about these physiological and psychological disturbances. This is a matter for the gynaecologist to investigate.

In connection with the possibility of a double set of secretory cells in the corpus luteum, it may be mentioned that the German worker Seitz claimed to have isolated from cow corpora lutea two active principles, one found in the early stages, which, injected subcutaneously, produces the menses in amenorrheic women, and which Seitz calls lipamin, the other a substance which is found in older corpora, called luteo-lipoid, and which acts as an inhibitor of the menstrual function. The first substance, lipamin, stimulates both the internal and external genitalia of mammals and recalls in its effect the liquor folliculi of Allen and Doisy. It might be suggested that the lipamin is found only in early corpora lutea because it is only in early stages that the antrum folliculi still contains the remains of the liquor folliculi, or because the character of the granulosa cells is still predominantly what it was in the Graafian follicle stage.

G. N. Papanicolou has shown that removal of the guinea-pig corpus luteum of ovulation accelerates the appearance of the next ovulation. or, more directly, the corpus luteum maintains or prolongs the interval of time between two ovulations or oestra.

This might be interpreted as experimental confirmation of Seitz’s 592 Journal of Obstetrics and Gynaecology

biochemical w'ork on the corpus luteum, in which he claimed to have isolated a substance, from old corpora lutea, luteo—lipoid, which acted as an inhibitor of the menstrual function.

Thus, in contradiction to Fraenkel’s claim, the corpus luteum probably regulates the inter-menstrual period, and does not bring about menstruation : it is the loss of power of the corpus luteum, marked cytologically by the inception of regression, that is the first sign of the next menstruation. If pregnancy supervened, the corpus luteum of ovulation becomes the corpus luteum of pregnancy, and goes on producing luteo—lipoid; therefore the embryo or placenta must be able t-o produce a substance which stirs up the corpus luteum to continued effort, and the production of such a substance by the embryo or placenta only stops some time before parturition. If we can isolate this substance from the embryo or placenta, it should be possible to prevent menstruation in the human female for any desired period.

The above remarks should be read in conjunction with Corner’s studies in the sow. Corner finds that during the sexual season there is a general overlapping in the duration of the corpora lutea, and, in any oestrus after the second, there are corpora lutea in an advanced state of degeneration, probably six weeks old, and others in a much more juvenile stage about three weeks old. It might be difficult in such a case to imagine a clear working of luteo—lipoid and lipamine, to use Seitz’s terms.

The latest work on the biochemistry of this subject, to which our attention was drawn by Dr. E. Werner, is that of Fraenkel and Mme. Maria Fonda (Bioch. Z., 1923, 141, 379-393). These authors claim to have isola.ted from the corpus luteum and the placenta, an active principle which promotes sexual development in young dogs. This principle was isolated by distillation in a high vacuum, as a viscous, light yellow syrup. Its formula is given as C,,H52O,. Such a_ substance would appear to resemble S-eitz’s lipamin.

The work done by Allen and Doisy seems to show that the liquor folliculi contains some hormone which produces a sexual stimulation. If the work- on the lower animals applied to human beings, conceive the train of events in the woman to be as follows: —rupture of the Graafian follicle releases the ovum, which is caught by the fimbriated opening, whereas the liquor folliculi is released into the abdominal cavity and absorbed into the blood, producing sexual feeling. Certain authors (e.g., Havelock Ellis*) have endeavoured to show that sex desire rhythm exists in women between the menstrual periods. VVhether this is true, and could

' Also M. Stopes. Formation, Structure, etc., of the Corpus Luteum 593

be made to fit in with the supposed time of abso-rption into the system of the liquor folliculi, we do not know, and at this stage it would be of little use to enter into the question.

It is a fact that in certain mammals ovulation pro-bably takes place after copulation, c.g., rabbit, and probably ferret and cat. If we assume that the breaking of the Graafian follicle, and the release of the hormone in the liquor folliculi are the causative agents of the desire for sexual union, the examples of the rabbit and domestic cat are difficult to explain away: the fact of the matter is that (estrus cycles of various mammals seem to differ fundamentally, and cannot all be explained under one scheme, as certain authors have tried to do.

CONCLUSIONS. _

1. Examination of the corpora lutea of the human, the pig, the rat. and the duck-billed platypus (Ornithorhynchus) shows that the lutein cells originate purely from the membrana granulosa.

2. The theca interna cells of the pig, human, and duck-billed platypus persist as such until regression sets in (P1. 11.. figs. 10, 11, 14).

3. By silver methods the theca interna cells impregnate blackly. The silver can be washed out with alum, and the theca interna cells will then stain blackly in heematoxylin (Pl. II., figs. 8, 9).

4. There is no evidence in the human, the pig, or theduck-billed platypus that the theca interna cells form inter- or intra-cellular fibres.

5. The growth of connective tissue in the aging corpus is not from endothelial cells, as suggested by Corner, but from theca externa elements. (Fig. 13).

6. The advisability of adopting the words theca-lutein cells is questioned.

7. The work of Gatenby and Hill on the duck-billed platypus shows that the theca interna cells never approach the granulosa (lutein) cells in size. (Fig. I2).

8. The cytology of the cytoplasmic inclusions of the human Graafian follicle wall, and corpus luteum is described.

9. The work of Allen and Doisy is noted, and parallel experiments with rats, fed, instead of injected, with liquor folliculi and corpus luteum, have been carried out. The results, still incomplete, support Allen and Doisy. '

IO. So far as the. experiments have been carried out, bovine liquor folliculi, given to women by the mouth, appears to have no effect on ailments peculiar to women.

II. Corpus luteum is useful when given by the mouth in the treatment of scanty and absent menstruation. It is a valuable aid 594 Journal of Obstetrics and Gynaecology

to the treatment of sterility, but of little service in th-e cases of menorrhagia and metrorrhagia. It is occasionally helpful in treating dysmenorrhoea. Menopausal symptoms are seldom relieved. It is successful in some cases of vomiting of pregnancy.

I2. Corpus luteum administered hypodermically has cured cases of severe vomiting of pregnancy, and of menstrual epilepsy.

13. It is difficult to understand why corpus luteum administered by mouth or hypodermically should cure amenorrhoea, considering its physiological action. This point requires intensive investigation by the physiologist in combination with the gynaecologist.

BIBLIOGRAPHY.

Corner. Contrib. Emb. Carizcg. Inst. lVash., 1915.

Corner. Amer. Jour. A2m.t., 1920.

Van der Stricht. Arch. de Biol., 1912.

Novak. “ Menstruation and its Dis0r(le)'.~.4.” Appleton, 1921. Allen. Amer. Jam-n. Anat. 1923.

Gatenby. Proc. Roy. Irish Amd., 1924.

— Bolles Lee’s Microtomists Vademecum, 1922. Churchill.

Gacenby and J. P. Hill. (iugnrcss).

Loeb, Leo. Amer. Jozmi. Anat., 1923.

Seibz. Quoted from Novak.

. Papanicolou. Amzt. Record, 1920.

Solomons. §\'ur_q. G]/')l{€60l. and Obste/., xxx, i, 173. \Villia.n1s. Obstetrics, 1923.

\—lb—'F#P'-‘ 9°F°"‘.°5°9°>‘.°’S"L"?~°!°’.“

PLATE I.

Fig. 1. Wall of ripe human Graafian follicle. LF, antrum folliculi, containing liquor. MG, niembrana granulosa; MP, membrana propria; TI, theca interna with stellate argentophil cells; AS and TE, theca externa.

Fig. 2. Part of menstrual corpus luteum, same scale, same method (Da Fano) to show lutein (granulosa cells, G) and theca interna cells, AS. (I-Iuman.) '

Fig. 3. Above, a membrana propria cell, below, a theca interna cell. (Human.)

Fig. 4. Above, Golgi apparatus of follicle (granulosa) cell, below, Golgi apparatus of lutein cell, now enormously swollen. (Da F ano.)

Fig. 5. Two granulosa cells, Fig. 6 a luteiu cell, and Fig. 7 a lutein cell of a regressing human corpus luteum. (Human, Da Fano.) .

PLATE II (Microphotographs).

Fig. 8. Pig corpus luteum, showing theca externa (T E). The larger elements are stellate theca interna cells.

Fig. 9. Same, high power. T E, externa, the dark elements are stellate argentophil interna elements. (Both Da Fano.)

Fig. 10. Ripe human Graafian follicle (compare with Fig. 1). (Da Fano.)

Fig. 11. Human menstrual corpus luteu111 (compare with Fig. 2).

Fig. 12. Photo by Dr. J. P. Hill of newly-ruptured follicle of plntypus showing elements clearly. C A F, follicle cavity; M G, granulosa; T I, theca interna; T E, theca externa.

Figs. 13, I5. Regressing human corpus luteum (menstrual), showing at Fig. 14 remains of stellate argentophil cells (theca interna). Da Fauo and iron haematoxylin.


Cite this page: Hill, M.A. (2019, August 23) Embryology Paper - Notes on the formation, structure and physiology of the corpus luteum of man, the pig, and the duck-billed platypus. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_Notes_on_the_formation,_structure_and_physiology_of_the_corpus_luteum_of_man,_the_pig,_and_the_duck-billed_platypus

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