Pseudopregnancy and its Mechanism

Title:

Pseudopregnancy and its Mechanism

Date:

1929 January 1 Tuesday

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PSEUDOPREGNANCY AND ITS MECHANISM

read 13th February 1929.

By B. P. WIESNER, Ph.D. (By invitation.)

Menstruation has been a puzzling problem, not only to the laity but also to the physician and to the biologist. The nature of menstruation and, if one may say so, its biological meaning, have been quite obscure until a few years ago, but recent biological analyses, based upon and continuing Heape's and Marshall's fundamental work, revealed facts and relations which really provide an explanation, not only of menstruation and its biological meaning, but also of similar phenomena which have been wrongly reckoned to be equivalent to it. These new facts have been derived from observation and experiment, but to explain them it is probably necessary to become theoretical and to go a little deeper. So I must ask your permission to set forth some principles which seem to me rather important in their effect upon the structure of the sexual life of higher vertebrates.

In lower animals, for instance in most fishes, in the frog, etc., the sexual act consists of extrusion, both in the female and in the male. The female expels eggs; the male expels spermatozoa. One has every reason to suppose that the act of gamete-expulsion plays the same role in these animals as the sexual act does in higher forms. One can say, therefore, that the extrusion of gametes is both a sexual and a reproductive act.

It is now interesting to note that in all vertebrates, right up to the mammals, in the male sex, the reproductive and sexual function are represented by the same act, for in all species the male achieves the aim of its sexuality by ejaculating sperms.

But this holds true only for the male sex: because in the females of the higher vertebrates there is a distinct separation of the merely reproductive from the really sexual function. The laying of an egg in the fowl is not at all a sexual act, nor is ovulation. Quite apart from these reproductive functions there exists the definite sexual act. Since the gametes act no longer as sexual releasers (not being involved in the sexual act) they can be retained in the body after the sexual act, instead of being thrown out during it, and can undergo internal development. The separation of the sexual act from the beginning of the reproductive function is quite clearly expressed in the constitutional and in the functional characters of all mammals. In some species this is particularly clear: for instance, in the bat. There the sexual act appears in autumn, whereas ovulation does not occur till spring.

The separation of the sexual act from the reproductive function has some definite effect upon the structure of the sexual cycle; but as regards the latter there is another principle involved in the majority of the mammalian species. It is not so general, but nevertheless it plays an important part in the sexual life of most mammals. This principle is the restriction of sexual activity to certain times which are known as heat or oestrus. Most female mammals are inclined to mate only in these periods of oestrus. Before, during and after oestrus certain somatic changes occur. They have a definite purpose, to a certain extent, by making the sexual act possible (dilatation of the vagina and co-ordinating ovulation and insemination) and are quite significant and characteristic of this particular stage. These changes begin with the proliferation of the uterus as indicated by the rising branch of Diagram i.

Hyperæmia and epihelial activity begin and many special structures, such as cornification of the vaginal wall, appear. After heat has passed, and in some animals even before this stage, the proliferation is neutralised in a stage of destruction which is in some species marked by bleeding from the hyperaemic uterus. So the oestrus changes are regressing, but there follows, after a short interval, or even immediately, another development of the genital organs. In a new series of changes the uterus prepares to meet the demand of the egg, and when this necessity is fulfilled, when pregnancy has come to an end, the stage of rest is reached again. Thus the whole series of changes is completed after birth and forms a cycle in the real sense of the word : for the uterus and other organs return to the point where the changes began—i.e., the stage of rest which is interpolated between the functional cycles.

This cycle as a whole does not consist, accordingly, of simple development and regression but of two different phases. The cycle is diphasic, and we shall refer to the first and the second, or to the sexual and the reproductive phase. The oestrus phase or sexual phase is, as one sees quite obviously, only the first part of the cycle as a whole.

The contrast between the sexual and the reproductive phase is particularly clearly marked in the marsupials. We find in these animals two groups of organs: the first (mainly the vaginal channels) function only during the first phase (cestrus), whereas the second one functions during the reproductive phase. Insemination occurs through the vaginal channels: birth through a separate birth-way. In the higher mammals both functions are performed by the same organ?the vagina? through which the spermatozoa migrate and through which the fcetus is born. According to these two different phases the vagina undergoes change from one structure to another. Parallel changes occur in the uterus, which is of a different structure, during cestrus and pregnancy.

Here another principle comes in. We spoke about cestrus and the oestrus phase which is followed by a pregnancy with its typical structural changes in the genital system. Now it appears that these latter changes occur even if no fertilisation has taken place. In many animals they are not less intensive in the unmated than in the mated and fertilised female. For a long time it has been known that after sterile copulation, or when no mating was permitted, the bitch, nevertheless, shows all the changes in the endometrium which are typical of pregnancy. The mammary glands swell, the animal shows signs of labour at a date more or less normal for the termina- tion of pregnancy, and even goes so far as to carry bits of wood or the young of other animals to its sleeping place, where it tries to foster them. But although the degree and duration of the reproductive changes have been clearly marked in a few species, the general occurrence of the phenomenon has not been grasped, and one can easily understand that it has been regarded as something curious and strange. But pseudopregnancy, as one calls this phenomenon, is not at all absurd ; it is not something due to lack of internal adaptation or to a failure of Nature's ideas. Look at it from this point of view. If you had to construct a mammal yourself and you wanted to avoid the vain and unnecessary preparations for pregnancy, you would have to make these preparations dependent on the actual occurrence of fertilisation. Now, the only cell in the body which knows if fertilisation has occurred is the egg. The fertilised egg would have to warn the uterus that it should prepare for pregnancy, since the egg is, at the time of fertilisation, already floating through the tube: and it would have to elaborate and secrete a hormone which would incite pregnancy preparations. Such a task would mean a heavy burden for so tiny a cell. Moreover, it would mean that the germ plasm had to perform a somatic function. This would probably bring it in contact with, and under the influence of other endocrine glands, and would draw the germ plasm into the play of somatic happenings from which it must be kept apart.

But since the uterus prepares for pregnancy independent of fertilisation, the egg has nothing to do but to arrive in the uterus and settle down in the well-prepared mucosa. It is not in all mammals that pseudopregnancy is so clearly developed and so markedly expressed by the stage of the uterus and by the behaviour of the animal, but in all mammals it does appear. In all mammals the uterus prepares for pregnancy even in the absence of fertilisation, and these preparations go on for a couple of days at least till the uterus "finds out"?early in this species and late in that? that it has been working in vain.

Actually there is no mammal in which the preparation of the uterus for pregnancy would not occur in this independent way. That means that in unmated or sterile-mated females the oestrus phase is followed by pseudopregnancy. Let us neglect just now the fact that in some cases the occurrence of pseudopregnancy is restricted by certain mechanisms, though we will have to consider them later.

We have spoken of the biological importance of the mechanism which implies the independence of the pregnancy preparations from the egg. Its disadvantages are obvious, for in the absence of a fertilised egg those structures are wasted, and pseudopregnancy results. The duration of pseudo- pregnancy differs very much among various species. There are many details of minor importance, but it is the principle which counts, and it shows that the full cycle, as we have already pointed out, does not necessarily involve a pregnancy, but, on the other hand, does not consist only of an oestrus cycle. In the unmated or sterile-mated female oestrus is followed by pseudopregnancy instead of pregnancy, and as the term sexual cycle usually refers to the cycle in the non- pregnant female this is the more important case. Generalising our statements, we see that in those animals where oestrus occurs the sexual cycle consists of two phases, not only when pregnancy occurs but also in its absence, and in the latter case the reproductive phase takes the form of pseudo-pregnancy.

But this holds true only for those animals in which sexual activity of the female appears only periodically (as oestrus). It is one of the functions of the oestrus phase, towards the end of which the follicles burst, to co-ordinate insemination and ovulation, thus securing fertilisation; but there is another way to achieve this aim which one finds in the highest mammals, including man. Instead of correlating insemination and ovula- tion, sexual activity is unrestricted in these forms. Insemination occurs frequently, and therefore the probability of a meeting between sperm and egg can be as high as in mammals with restricted sex activity.

This difference has an important influence upon the structure of the sex cycle. The necessity to undergo periodic prepara- tions for a sexual act disappears together with the periodic reappearance of heat. Accordingly in the primates we do not find an oestrus phase. There is no particular preparation of the vagina for mating. But that other principle of which we spoke is valid as well since the preparation for pregnancy occurs also independently of mating or fertilisation. After every ovulation the monkey, or woman, shows preparation of the uterus for the reception of the egg which goes on for at least seven days, no influence of coition and no difference between very early pregnancy and the premenstrual structure of the uterus having been observed. These two stages have only quantitative differences, if any at all. The premenstruum is a short pseudopregnancy and menstruation is a pseudo- birth. As it comes to a very sudden end, its destruction being accompanied by bleeding, it has been compared with the destruction in which the oestrus proliferation ends and during which also bleeding occurs in many animals. But it has nothing in common with this phenomenon and can be compared only with the second phase of the diphasic cycle. As a whole, the cycle in human beings is monophasic?there are no oestrus changes which must be neutralised before the pregnancy preparations begin, but only an uninterrupted series of changes which are equivalent to the second phase. So it follows: whenever we want to study experimentally the mechanism of the menstrual cycle we must not draw conclusions from studies of the cEstrus cycle, but we must choose as our experimental object the infertile second phase of the diphasic cycle, the pseudopregnancy.

As we have said before, pseudopregnancy appears in every mammal, and we have given explanation of its biological role in some species. However, it does not appear after every ovulation. The economy of the sexual cycle, if I may use the term, is of a very different degree in the various species. It is quite obvious that the appearance of pseudopregnancy after every ovulation {i.e. even in the absence of mating) will lead, and actually does lead, to a waste of energy. The most uneconomic form of the cycle is exhibited by animals like the dog, where every ovulation is followed by a reproductive phase, irrespective of mating. Some animals show a mechanism which restricts pregnancy preparations, for instance the rat and mouse. In these animals the pregnancy preparations occur only after mating, so pseudopregnancy can occur only after a sterile coition. On the other hand, if the animal has failed to mate no second phase begins, but after a short interval an oestrus cycle appears again.

We may remark that this very interesting mechanism has led to a certain misapprehension of the sexual cycle in experiments on rats and mice. Since no second phase appears, in the absence of mating, female mice or rats can show a continuous periodicity of cestrus cycles, just as one menstrual cycle follows after another; this being one of the many reasons why the oestrus cycle has been compared to the menstrual cycle.

Certainly the rat and mouse already show a very economic form of the sexual cycle because only the sexual phase reappears spontaneously. But the most economic form of the sexual cycle is found in the rabbit, where not only is sexual activity unrestricted and mating can occur at any time, but where even the spontaneous periodicity of ovulation does not occur. In the rabbit it is only after mating that ovulation and the reproductive phase appear. The human sexual cycle, as regards its biological economy, is to be placed between the rat and the rabbit type, for sexual activity is not limited and no oestrus phase appears; but the periodicity of ovulation and pseudopregnancy, which is independent of the occurrence of coition, leads to a continuous series of cycles which are for the great part unnecessary and, from the individual's point of view, undesirable.

It may be more than a scientific claim to say that the structure of the human cycle should be changed, and it may sound very fictitious to say that perhaps in future medical interference in human beings will restrict pseudopregnancy and therefore its end (menstruation) to certain cases. This is even more than a vague idea as regards certain cases which are actually the subject of medical treatment. An investigation of the mechanism of the sexual cycle will show that it is at least not impossible to change the course of the sexual cycle, though it is a different question as to what degree that can be done as yet, and how far it is desirable.

So far we have only spoken about the "organisation" of the sexual cycle—its "phases" and the like. It is obvious that its mechanism has to be considered separately. First of all we have to remember that we have to choose pseudo- pregnancy for experimental purposes?not the oestrus cycle? if we want to draw any conclusion which will be valid for the menstrual cycle of human beings. To be quite accurate, we should not choose any experimental animal except the monkey; which is the only species in which the sexual cycle is directly comparable to that of human beings. However, this is not possible for an exhaustive investigation, and so we are forced to base our conclusions to a great extent upon our experiments with mice and rats.

Here we find that both the oestrus phase and the prepara- tions for pregnancy are dependent on the action of the ovary. We have only to remember that a few years ago American workers published their well-known experiments, in which they showed that injection of ovarian extracts can produce certain effects which are characteristic of the oestrus cycle (cornification of the vaginal epithelium and so on). A tremendous step forward was made when this substance was discovered, but the importance of that particular hormone has been greatly exaggerated. It is known under the name of oestrine, folliculine, menformone, and so on. Many authors even use the term "the" ovarian hormone for the cestrine preparations. Our experiments have shown, however, and since then other authors have come to the same conclusion, that the so-called cestrine does not produce the whole sexual cycle: it can only induce those changes in the uterus and the vagina which appear during the first phase. It may be remarked, also, that it does not even cause the full oestrus cycle to appear, no sexual activity and no rise of metabolism being caused by it: cestrine is only one factor of the oestrus hormone (the "alpha" factor).

But the main point is the inability of oestrine to produce the preparations for pregnancy. The discovery of this inability leads naturally to the conclusion that another hormone is formed in the ovary. This hypothetical hormone, of which I first found traces in blood, was named the beta factor. My colleague, Mr Patel, and I succeeded in extracting the beta hormone from corpora lutea by means of sulphosalicylic acid. Some time ago when this hormone was stated to exist it was also pointed out that the beta hormone which causes the second phase (pseudopregnancy or pregnancy) is not the only hormone which is necessary for the complete appearance of the pregnancy changes. It appears that the alpha factor plays a role in the second phase, though it is not able to produce it if no beta hormone is present, and moreover it even interrupts the second phase when given in large doses. Apparently its effect during the second phase is inverted so that it does not produce the full series of oestrus changes, but is used mainly as a hyperaemising and growth factor.

Turning to human beings again, we must remember that we have to compare the human cycle with the second phase of the cycle in mice or rats. Since we found that cestrine itself does not produce the second phase, we will not expect it to produce the premenstruum which is equivalent to the second phase. We found that injection of the alpha factor in various preparations and dosages was able to cause enlargement of the uterus of monkeys and even lead to bleeding, due to the strong hypersemia which it induced. But this bleeding cannot be compared with true menstruation, because the uterus of these animals did not show those changes of the premenstruum which are biologically really significant. In the preparation of the endometrium for the embedding of the egg no decidua can be formed by oestrine and the gland development never reaches the typical premenstrual degree. As no real premenstruum is formed one cannot call the bleeding actually observed a menstruation.

The beginning of the premenstruum, the formation of its typical structures, is therefore most probably due to a combined action of the alpha and beta hormones. On the other hand, we can conclude from experiments, to describe which would lead too far, that the end of pseudopregnancy in animals?and therefore most probably menstruation in human beings? appears when the supply of ovarian hormone ceases. One can prevent the end of pseudopregnancy (which is equivalent to menstruation) in experimental animals by injecting beta hormone. It should be possible, theoretically, to avoid menstruation, or to alter its date according to any necessity by injecting alpha and beta hormones.

There is another way to achieve the same result, though the experiments are not sufficiently advanced to permit definite conclusions and detailed statements.

We know that the ovary of the rat first produces first the alpha and then the beta hormone, and how accordingly the uterus first undergoes the changes of the first and then those of the second phase. There is a change of activity in the ovary which has been more closely investigated by Professor Crew and myself. Previous workers had found that the activity of the ovary, which induces the first phase, is incited by "a" pituitary hormone which is formed in the anterior lobe. The same mistake has been made (as regards this pituitary hormone) which we encountered in discussing the ovarian hormone. CEstrine (the alpha factor) has been called "the" ovarian hormone, but it has not been considered that the ovary produces various hormones and that one cannot speak about "the" ovarian activity since one has to consider the existence of various degrees and forms of ovarian endocrine activity. As to "the" pituitary hormone Professor Crew and I found that there are two factors involved which incite the first and second phase of ovarian activity respectively. Many details are still obscure, but we can neglect them in this discussion of principles.

So it appears that the ovary produces alpha hormone, or beta hormone, according to the particular pituitary hormone which is acting upon it. As regards the production of alpha hormone it cannot be made continuous, even if the particular pituitary hormone is continuously injected. Apparently there exists a periodicity which is independent of the pituitary (shown by American workers and unpublished experiments). As regards the beta factor it appears, however, that its production ceases normally because the supply of pituitary hormone is only limited. If one injects pituitary hormone in sufficient quantities the ovary goes on producing beta hormone, and therefore pseudopregnancy or pregnancy does not come to its normal end but is extended for some time (Teel: Parkes). Injections of pituitary hormone may lead, therefore, to dysmenorrhea, which is, however, not due to lack of hormones but to excessive supply. The first to mention this possibility were Zondek and Aschheim, and recent work has established the experimental proof for this assumption.

Many possibilities for the future are being derived from these findings. Two of them only which are of some interest to the clinician shall be discussed here. The first is the general attitude towards amenorrhcea. As long as menstruation was looked upon as the very sign of ovarian activity it was naturally desirable to produce it. But now we know that ovarian activity consists in the secretion of various hormones. I have spoken about the role of the alpha and beta hormone, and I now want to mention that there are most probably two, or even three more hormones, one of which has a certain influence upon metabolism, whereas the other seems to be the activating factor of sexuality. Menstruation is only a sign that pseudo- pregnancy has come to an end and it is by no means certain (it is even doubtful) if the other factors which do not produce pseudopregnancy but are of general influence on body health and normal psychical development are not much more important. It may be that in future amenorrhoea (the non-appearance of pseudopregnancy and the absence of menstruation) will not be regarded as trouble, but only the lack of these hormones which are important for the body as a whole. As soon as not only the medical man but also the average woman realises the nature of menstruation, the attitude towards its disturbances will change entirely. There is an even more important field to which these results are to be applied in my opinion. This is rejuvenation. During the last few years the prospects of reactivating the senile ovary have grown very much. The revival of the climacteric ovary is certainly an important task, as one could dispense with substitutive therapy; but it is also desirable to substitute it as long as the revival through pituitary hormone (which is possible) cannot be practised. If one wants to substitute the ovary one will have to remember that menstruation is not "the," and is not even the most important symptom for the action of ovarian extracts. If one succeeds in achieving the general effect of ovarian action upon the body one has done all that is desirable. But certainly much more work remains to be done.

Discussion.

Professor Johnstone congratulated Dr Wiesner on his address and on the courage with which he came to speak to the Society without notes, and in a language which was not his own and with which he had not long been familiar. They recognised in Dr Wiesner a very distinguished biologist, who had made a special study of sex physiology. He thought that Dr Wiesner had, with characteristic modesty, failed to make it clear that most of the work on which his remarks were based was actually his own. The address to which they had listened showed how advantageous it was for their Society to have a biologist come to speak to them occasionally, because it was only the man who was working in the calmer atmosphere of the biological laboratory who could extract anything like general principles out of the very complex question of the meaning and causation of menstruation. As clinicians, cumbered with much clinical work, they were unable to give the concentrated thought which a problem of the sort required.

He had been much interested in the clear way in which Dr Wiesner had shown the entire separation of the different phases of sexual activity?the sexual act and the reproductive act; and how this separation necessitated a cycle of changes in the female reproductive tract. The tract must be in a certain condition at the time of the sexual act, in order that the introduction of the spermatozoa into the uterus should be secured with reasonable certainty, and it must be in an entirely different condition in order to receive the fertilised ovum, and to further its development during gestation. In the case of animals, which have a definite oestrus period, the sexual act coincides more or less closely with ovulation, and the changes which immediately follow in the uterus in preparation for the nidation of the fertilised ovum secure a high degree of fertility in these animals. In the higher animals, where there was no definite oestrus period, and in which sexual activity is more or less continuous, another plan had to be adopted by Nature, in order to avoid infertility. There was no guarantee that the sexual act and ovulation would necessarily occur at or about the same time; therefore the uterus was prepared for the nidation of the fertilised ovum at regularly recurring intervals. Following on the brilliant pioneer work of Heape in earlier years, Dr Wiesner had shown how the premenstrual changes were really just a preparation of the uterus for the reception of the ovum, and that if the ovum remained unfertilised these preparations were "scrapped" in the form of menstruation, whereas if the ovum were fertilised, the changes in the uterus continued towards completion. Thus the difference between the premenstrual endometrium?the menstrual decidua, as it may be called?and the decidua of early pregnancy is quantitative only. In other words, at the moment before menstruation begins, the conditions in the interior of the uterus are qualitatively the same as those at the commencement of pregnancy, the only important thing missing being the fertilised ovum, and in order to emphasise this identity, the term pseudopregnancy had been adopted. Accepting this view, the disintegration of the endometrium during menstruation may, in a sense, be described as a pseudolabour terminating the pseudopregnancy, or as it has also been called, an infertile abortion.

Many interesting questions would doubtless arise out of this theory. For example, there was the question as to whether spasmodic dysmenorrhea might be regarded as analagous to the labour pains in this pseudolabour. If such a view sustained further examination, it would again illustrate the importance of knowing the different point of view which a biologist could give on matters with which, as clinicians, they were dealing every day. Similarly, this theory must have some bearing on questions such as the duration of pregnancy and the cause of the onset of labour.

He confessed that he found himself out of his depth when Dr Wiesner turned to the stimulation of the ovary by the so-called Rho factors from the pituitary. He could understand the direct working of a hormone, but when it came to the inverting of that hormonic action by the introduction of a second hormone, he found the question difficult to follow without having the facts in print. He would like to emphasise that it was Dr Wiesner himself and his fellow-workers who had discovered these Rho factors, and he understood that it was only within the preceding few days that they had actually discovered or isolated the beta hormone from the corpus luteum for which they had long been searching.

Dr Jamnes Young said he wished to associate himself with Pro- fessor Johnstone in what he said about the value of the interesting paper of Dr Wiesner. He agreed that many of the difficult problems with which clinicians were faced would no doubt find their solution as the result of the biological data which Dr Wiesner and his colleagues and others had discovered.

The idea of pseudopregnancy was an old one, and most biologists would admit that menstruation was to be considered as more in line with such phenomena as pseudopregnancy in lower animals than with pre-oestrum. It used to be a common view that menstruation and pre- oestrum were similar in their nature, but, as he understood it, that view had been forsaken for some time.

The points brought out about the actual mechanism which underlay the difference between oestrus and pseudopregnancy were revolutionary and were bound to throw light on those questions which were at present so puzzling. If there was one thing in the whole range of gynaecology which was hard to understand, it was the question of haemorrhage from the uterus. He believed that it was only along such lines as Dr Wiesner was following that solution would be found for such a question as this.

He had been interested in Dr Wiesner's reference to Corner's work. Corner's investigations were particularly interesting because he had taken up the same heterodox standpoint with regard to the question of periodicity. It used to be believed (and still was believed by many biologists) that periodicity was a thing determined by the ovarian function, more particularly by ovulation followed by a corpus luteum, which had a certain life, and when it matured and died menstruation came and the whole function went back to the beginning of the cycle. Corner, on the other hand, had discovered that this periodicity was in the tnacasus rhesus a function occurring in the body apart from this ovulation cycle. Dr Wiesner had considered the possibility that this function was determined by a series of phenomena which were bound up with the whole endocrine function. Dr Young found it a little difficult to follow the description of the various factors which underlay this curious mechanism, for example, the alpha and beta hormones and how they were affected by the pituitary, but he hoped to read Dr Wiesner's paper in the Transactions because it was only in that way that one could possibly undertake to follow in detail the argument of such a beautiful piece of scientific work.

Professor Hendry joined in the tribute to Dr Wiesner's powers as a scientist, linguist, and a clear expositor. The endocrine glands have always been something of a cross-word puzzle and Dr Wiesner has shown that there are still more lines to be fitted in. Professor Hendry instanced further cross effects among the endocrine glands. In pseudo- pregnancy in dogs, the mammary glands are frequently involved, resulting sometimes in acute discomfort to the animal. The intra- peritoneal injection in rabbits of tissue extracts from early human placenta induces the formation of enormous numbers of corpora lutea.

Dr Wiesner has referred to his extraction of ovarian hormones from the placenta in certain animals. Are these hormones actually produced in the placenta, or are they formed in the ovary and stored in the placenta? Dr Wiesner's demonstration of the intricate relationship of such glands, particularly of the pituitary and ovarian function, should prevent clinicians from attempting to treat all irregularities of uterine function as purely pelvic lesions. The whole ductless gland chain may require to be investigated in certain cases.

Dr Fahmy did not quite follow from Dr Wiesner's remarks just why pseudopregnancy ended. He wondered if the speaker had formed any ideas as to whether Professor Beckwith-Whitehouse was on the right lines in suggesting that menstruation in the human comes on as the result of the death of a non-fertilised ovum. His opinion was that in some way the death of the non-fertilised ovum leads to the breaking down of the endometrium and escape of blood and debris from the uterus.

The President desired to convey the thanks of the Society to Dr Wiesner for his most interesting paper, and before asking him to reply, he would like to know whether in the case he mentioned of pseudopregnancy in a bitch, he understood him to say that real placental tissue had been found in the uterus, or was it only decidua? He would also like to know if any difference had been observed between the decidual cells of a pseudopregnancy and those of an ordinary pregnancy.

He heartily congratulated Dr Wiesner on his excellent paper, and expressed his admiration for the way in which it had been presented.

Dr Wiesner (in reply) said it was rather difficult to answer such a general discussion, and he pointed out that his paper set forth merely a few facts and theories and a few explanations based, as he believed, on well-founded principles. One of these principles was that one had to compare right things with right things.

The recognition of menstruation as pseudopregnancy and pseudo- birth respectively was not as common as it should be, and was even less so when he first published a paper on the structure of the sexual cycle in 1925.

Regarding Rho factors: there were two phases of ovarian activity, the first, which produced alpha hormone and the egg: the second, which produced alpha and beta hormone. If the pituitary is removed no sex cycle occurs. It was possible to extract from the pituitary hormones which produced the first phase (which went on to make only alpha). But if a bit of a different extract from the pituitary was injected, that hormone did not stimulate the production of alpha alone, but alpha plus beta, and no eggs were shed.

There were two phenomena which he had been lucky enough to find: first, if one castrated a young female, then no puberty appeared, but at the time of puberty, castration phenomena occurred. At the time when an adult female became mature, the ovariotomised sister became fat, heavy and inactive. At this time apparently changes occurred which would make the presence of an ovary necessary. Secondly, if one transplanted the ovary from a senile animal to a young animal it would begin to function, and one could transplant it again, even after a year and a half.

With regard to the production of corpora lutea from placental Rho-factors. The pituitary stimulated the ovary; the ovary made the production of placental tissue possible by secreting alpha plus beta hormones. Thus the placenta was formed. But now, if the ovary were removed, the placenta was excluded and abortion took place. If, on the other hand, the placenta was removed, the corpora lutea at once degenerated. There must be some interrelation between the placenta and the ovary. If the pituitary were removed the ovary degenerated. If the ovary were removed the pituitary changed entirely. If the pituitary were removed abortion occurred. There were many glands which must interact in many situations. Assuming only five glands and five different conditions, one could calculate how many relation- ships must exist between them. Endocrinology certainly was a crazy task.

He had defined certain biological conditions and thereby had tried to find some principles.

The uterus of a week-old rat was inactive; but if cestrine were injected into this animal the uterus would become active. This maturity would occur in eight or twelve weeks. If the hormone were injected earlier, maturity would occur earlier, so that the change did not depend on the age of the uterus but on peripheral changes. It was the ovarian hormone which effected the change. The ovary began to work at a certain time. This could be proved by the fact that if the ovary of a very small rat were transplanted into an adult rat?even though it was ovariotomised?-the ovary began to function at once. It was the pituitary which began to act at a certain time. In most animals lactation occurred immediately after birth. Assuming that pseudopreg- nancy was complete, one should not be surprised if lactation appeared.

In answer to Dr Fahmy, he would point out that he was strongly opposed to the assumption that the egg played an active part in the early stages, because, though one destroyed all eggs, pseudopregnancy would still occur. Pseudopregnancy ended at a certain time whether a fertilised egg was present or whether there were no eggs at all. If there was any action on the part of the egg, why was it that in an animal whose ovaries were transplanted on to the kidneys, one found a perfectly normal pseudopregnancy.

In reply to Professor Hendry: Doisy first extracted cestrine from the placenta, and since then it had been found that in one kilogram of human placenta there was an average of 13,000 units of cestrine. It could hardly be assumed that this amount was just stored in, but not produced by, the placenta. It was extremely difficult to carry out experiments on this question because one had to remove the ovaries to make one's explorations, and then abortion was almost unavoidable.