Talk:Paper - The hormone of the corpus luteum
THE HORMONE OF THE CORPUS LUTEUM.*
By GEORGE W. CORNER
Professor of Anatomy, The University of Rochester, School of Medicine and Dentistry, Rochester, N.Y.
THE first really useful conjecture as to the function of the corpus luteum was made in 1898 by Prenant when he pointed out that its histological structure suggests that it is a gland of internal secretion. The same thought had evidently occurred to Gustav Born, for in the last days of his life the brilliant embryologist of Breslau suggested to his pupil and colleague, Ludwig Fraenkel, the idea that the corpus luteum serves by some endocrine action to facilitate or protect the implantation of early embryos. To Fraenkel fell the task of devising experiments with which to test the hypothesis he had received as a legacy from Born. The final results were reported in 1910. He chose to work with the rabbit and to make use of the fact that in this species the embryos spend eight days in the Fallopian tube and uterus before they become attached. During this time Fraenkel interfered with the natural course of events by such experimental procedures as removal of both ovaries or excision by knife or cautery of all the corpora lutea. When such operations were done before the embryos were attached, subsequent autopsy three or four weeks later invariably revealed that the embryos had disappeared from the reproductive tract. Presumably they had failed to survive because of the absence of some protective action of the corpora lutea ; but the exact nature of their fate and even the time at which they ceased to develop remained obscure.
At about the same time as Fraenkel’s latter experiments, and apparently without knowledge of his work, the French histologist Bouin and his embryological colleague Ancel (1910) had under way experiments which demonstrated another aspect of the activity of the corpus luteum. Taking advantage of the fact that in rabbits the ripening of eggs and the act of ovulation are induced by the stimulus of copulation, Ancel and Bouin took steps to produce corpora lutea by mating their does to vasectomised males. In such rabbits naturally pregnancy could not occur, but ovulation took place as usual, and the animals then differed from their condition of a few days before by reason of the presence in their ovaries of a crop of newly formed corpora lutea. In such animals Ancel and Bouin discovered a significant alteration in the histological structure of the uterus, which underwent a striking growth of the glandular and surface epithelium (since named pro- gestational proliferation) closely resembling the condition existing in early pregnancy. Figs. 1-3 will serve to show the nature of this change, although the photographs illustrate not the natural but experimentally produced alterations.
- Read at a Meeting of the Edinburgh Obstetrical Society,
15th December 1936.
In rabbits, which do not ovulate spontaneously, the effects of the corpus luteum are seen only after mating and are therefore almost inevitably associated with pregnancy; but in the human species and all other animals which undergo spontaneous cyclic ovulation, corpora lutea are formed in each cycle, and the uterus undergoes therefore at least a brief ‘‘ luteal phase.” In the human species this state of the uterus is the so-called premenstrual state.
Experiments of Loeb, published in 1907, had already revealed in still another way the existence of a special state of the endometrium caused by action of the corpus luteum. In the guinea-pig the placental tissue contains a large maternal element. Loeb showed that even in the non-pregnant animal the presence of the corpus luteum is sufficient to induce in the uterus a special state during which the endometrium may be stimulated, by mere mechanical irritation, to produce a decidual mass exactly as if the embryos had been there to call it forth by the stimulus of their implantation (see Fig. 4). To produce such an effect, it is merely necessary to open the abdominal cavity of a non-pregnant guinea-pig six or seven days after ovulation and to scratch the endometrium with a needle or to stitch a silk thread somewhat roughly through and through the uterus. A few days later the site of irritation is marked by the presence of a decidual tumour; but if the ovaries are removed at the time of the trauma no such deciduoma will form.
It will be seen that Fraenkel had demonstrated the dependence of implantation of the embryos upon the corpus luteum, while Ancel and Bouin by one experiment, and Loeb by another, had demonstrated the dependence of a definite functional state of the endometrium upon the same gland. It could scarcely be doubted that the two phenomena were related, and no doubt a demonstration of this relationship would have been given promptly had not the World War interfered for a time with such investigations.
It fell to the lot of the present writer (1928) to conduct experiments designed to tie together, if possible, the discoveries already cited. In a first group of rabbits, ovulation was induced by mating (to fertile males) and 14 to 18 hours thereafter both ovaries were removed. At the time of operation the ova were in the 2-cell stage and were on their way through the tube. Autopsy on the fifth, sixth or seventh day thereafter showed that progestational proliferation of the endometrium had not occurred. When the embryos were recovered for study, it was found that they had died zz utero, and from their size and stage of development it could be determined that they had ceased to grow early on the fourth day; that is to say, as soon as they had entered the uterus. In another group of control experiments, similar operations were done after removal of all of the ovarian tissue so that an equal amount of trauma was produced, but several corpora lutea survived. In these rabbits progestational proliferation of the uterus regularly occurred, and in six out of seven experiments normal embryos were found at the time of autopsy from the fifth to the eighth day. In a third group, experiments involving similar trauma were so conducted that all the corpora lutea were excised, but as much intact ovarian tissue was left as in the second group. In these, proliferation failed to occur and the embryos died. These experiments not only confirmed Fraenkel’s discovery of the dependence of the embryos upon the corpora lutea, and Ancel and Bouin’s discovery of the dependence of progestational proliferation upon the same gland, but they also proved that it is the proliferation which makes possible survival of the embryos. They indicated, moreover, that the uterine proliferation is necessary not only for implantation but also for the nutrition and protection of the free blastocysts during the time when they are lying free in the uterus.
These results emphasised the conjecture that there is an internal secretion produced in the corpora lutea which is able to effect the progestational change of the endometrium. The experiments just described could obviously be used as a test of extracts made in the effort to obtain the hypothetical substance. The writer was fortunate in having the collabora- tion, from this point on, of Dr Willard M. Allen, who brought to the task an excellent knowledge of biological chemistry. After a not unexpected period of preliminary exploration and uncertainty, we found (1929) that it was possible to extract from the corpora lutea of swine, by the use of hot alcohol, a crude oily material which when injected into experimental rabbits would substitute fully for their own corpora lutea. The experimental test, adapted from the experiments just recounted, consisted in mating a rabbit, followed the next day by removal of both ovaries and the daily administration for five days of the extract to be tested. Effective hormone- containing extract revealed itself by maintaining the embryos in good condition until autopsy on the sixth day, at which time the embryos were recovered and the endometrium found to be in a typical state of progestational proliferation (Figs. 1 to 3).
At the University of Wisconsin, at the same time, Hisaw and his associates, Meyer, Weichert and Fevold, were also engaged in the extraction of sows’ ovaries in the search for an active substance. Hisaw (1927) had been led to associate the corpus luteum with the remarkable relaxation of the symphysis pubis which occurs in certain rodents, notably the guinea-pig, as a phenomenon of pregnancy. It was through the quest for a corpus luteum hormone capable of producing this effect that Hisaw and his colleagues obtained and were the first (1928) to mention, although without exact definition, extracts having some of the properties now known definitely to be those of the corpus luteum hormone.
With one of their preparations, Weichert (1928) was able to demonstrate experimentally an effect of the corpus luteum which had been inevitably predicted by Loeb’s experiments on deciduoma formation, cited above; namely, that if, after he removes the ovaries of a guinea-pig the experimenter supplies corpus luteum hormone by injection of extracts, the ability to produce a deciduoma is retained (Fig. 4). Weichert’s work was confirmed in the author’s laboratory by Goldstein and Tatelbaum (1929).
Fig. 1. — Control section of rabbit’s uterus, 18 hours after mating. Animal castrated at this time. :
Fig. 2. — Uterus of same rabbit as in Fig. 1, after 5 days’ treatment with progestin. Typical effect.
Fig. 3. - Extreme corpus luteum effect.
Fig. 4. — Deciduoma in uterus of castrated guinea-pig induced by trauma under the influence of progestin. Preparation by Mr F. W. Lovejoy, Jr.
Fig. 5. — Graph showing inhibitory action of uterine motility in a rabbit, studied zm vivo by the fistula method. At mark 1 about 0-5 international unit of progestin was injected. Inhibition of motility in less than two hours. (From Allen and Reynolds, 1935.)
That corpus luteum extracts will maintain pregnancy in the rabbit not only for a few days, as in the original experiments, but even through the whole term of gestation, was demonstrated by the author with Willard Allen (1930), for we were able, as soon as we could prepare a sufficient quantity of the extract, to maintain pregnancy to full term in seven out of fourteen experiments.*
Although the experiments thus far quoted have been done upon the rabbit and guinea-pig, there is no doubt that similar effects are exerted in other species, including the primates. In 1930, Hisaw, Meyer and Fevold were able to produce premenstrual changes in the monkey’s uterus, a result since confirmed by P. E. Smith and by the writer. Kaufmann later reported (1932) production of premenstrual endometrium in a castrated human patient by the administration of large quantities of cestrin followed by moderate doses of corpus luteum extract.
Meanwhile my fellow-worker, Willard Allen, was making successful efforts to purify the extracts. Our crude extracts were already free of appreciable quantities of protein and of phospholipids. Allen (1930) carried the process further by the removal of cholesterol, cholesterol esters, neutral fats and fatty acids. Other workers (Fels and Slotta, 1931; Fevold and Hisaw, 1932; and Allen, 1932) ultimately obtained an almost pure crystalline substance of high potency. For his part of this work Allen received the Eli Lilly 1935 award of the American Chemical Society for the best work in bio- chemistry done by an American under 31 years of age. O. Wintersteiner of Columbia University, whose microanalytic skill was called into collaboration with Allen (1934), completed the purification and determined that the crystalline substance possesses the empirical formula C,,H3 902, and that both oxygen atoms are present in diketone linkage. The crystals
- Professor Crew’s remarks (see Discussion) refer to a half-serious remark
of the lecturer at this point, when he stated that the rabbits in question did not nurse their young, although lactation was well established, and suggested the possibility that even so poetic an attribute of maternity as the instinct to care for the young, may be in some respects dependent upon chemical factors.
occur in two forms, namely prisms (designated as the alpha form), melting at 128°, and needles (beta form), melting at 121°. Practically at the same time Slotta, Ruschig and Fels of Breslau (1934), and Butenandt and Westphal (19342) of Danzig also described ultimate purification of the crystalline preparations, and before long announced, as probably correct, the structural formula illustrated in the accompanying diagram :
Crs i CHs| WANN te oN
This Butenandt, with Westphal, Schmidt, and Kobler, after- ward confirmed (1934) by synthetic production of the same substance by chemical manipulation and rearrangement of two other more readily available sterols, namely stigmasterol and pregnandiol.
Progesterone may be regarded as a derivative of the steroid hydrocarbon pregnane. Its chemical relationship to the cestrogenic substances and the male hormone is indicated by the following diagrams, which illustrate respectively one of the cestrogenic substances, one of the male hormones, and progesterone, in comparison with the corresponding basic hydrocarbons.
When it became convenient to invent a name for the corpus luteum hormone we felt that we were justified by these experiments in coining the word ‘“‘ progestin,” that is to say, a substance which favours gestation. After the chemical identity of the hormone was determined, an international agreement among the workers interested established the name progesterone to indicate the pure substance, the word progestin being reserved as a family name for all chemically related substances having similar action, should others be discovered in the future, and also as a convenient word to cover partially purified extracts not definitely characterised by chemical analysis. Up to the present time this one chemical substance is the only one known which is strongly potent as
CH; Oestrane CHs CH; Androstane oH CHs CH, CH; iG regnane
tested upon the rabbit’s uterus, but progress of research and synthesis in the field of sterols has led to the discovery (Parkes, 1936) that several other similar compounds have at least a little progestational activity.
In 1935 a committee of experts, invited by the Permanent Commission of the League of Nations on _ Biological Standardisation, and acting under the chairmanship of Sir Henry Dale, agreed upon an international unit of pro- gesterone, namely the activity possessed by 1 mgrm. of the crystalline substance. During the period when only crude extracts were available, investigators were using various means of expressing the potency of their preparations. Corner and Allen, for example, used a rabbit unit defined as the amount of an extract necessary to produce in the adult rabbit in five days under certain specified conditions an alteration of the endometrium similar to that occurring in the pregnant rabbit on the eighth day. In practice, the state of the endometrium of the test rabbit was compared with a series of preparations indicating progressive changes designated by +, ++, +++ and ++-++, as illustrated in Allen’s paper of 1930(a). Other investigators adopted this convenient notation, but modified the test by using immature rabbits primed with cestrin. Such young animals are more sensitive than adults, and therefore the Clauberg unit and the McPhail unit refer to about half as much progesterone as a Corner-Allen unit, which is about equal to I international unit or a little less.
The corpus luteum is the only important natural source of progesterone. The sow’s ovaries contain (although it cannot all be recovered in pure form) about 20 milligrams per kilogram of fresh corpus luteum tissue. Kimura (1935) has found progestin in the cow’s corpora lutea, and Callow, Laurie and Parkes (1935) find it in the whale, which has become a commercial source. Apparently the human placenta contains a small amount of progestin (about 3 international units per kilo of fresh tissue) as first shown by Ehrhardt (1934) and Ehrhardt and Fischer-Wasels (1936), and confirmed by McGinty, McCullough and Walter (1936) and others. Callow and Parkes have recently made the remarkable observation, which can as yet scarcely be evaluated, that the adrenal cortex contains something capable of giving a positive test for progestin.
Knowledge of an effect of progestin upon uterine muscle came at first as a surprise. Knaus, who was working with rabbits during natural pregnancy, discovered (1927) that the pregnant rabbit’s uterus suspended zz wztro in physiological salt solution does not respond as does the non-pregnant organ to the application of pituitrin in the water bath. The suspicion that the corpus luteum is responsible for this state of the uterus he confirmed (1930) by making use of crude extracts such as those originally described by us; the uterus of a castrated rabbit which has been treated with progestin for five days becomes insensitive to the action of pituitrin zn vetro.
The question once arose as to whether this effect is actually due to progesterone or to some other hormone which might be present in the crude extracts, but a satisfactory demonstration that progesterone itself is responsible has been achieved by the use of natural and even synthetic crystalline progesterone, both of which repeat in every way the action of the crude extracts, when used in comparable dosage and provided that certain critical factors are observed as indicated in the paper of Makepeace, Corner and Allen (1936). It is, however, not impossible that other substances having the property of rendering the uterine muscle insensitive to pituitrin may exist, as is hinted indeed by certain of the results of Robson and Illingworth (1931).
Knaus’s work was followed by that of Reynolds, who made use of rabbits in which he had produced, by suitable operative preparation, uterine fistulas into which a small balloon could be inserted for the purpose of recording the uterine contractions zz vivo. In such preparations the contraction of the uterus is under the control of the ovarian hormones. After castration, the uterus becomes quiescent, but the administration of cestrin causes a return of spontaneous contractions. If then (Allen and Reynolds, 1935) the rabbit be given a small dose of progesterone by subcutaneous injection, within a few hours the uterine contractions begin to diminish and in about two hours the uterus has become entirely quiescent (Fig. 5).
It may be conjectured that this effect of the corpus luteum hormone serves a useful purpose by rendering the uterus quiescent during early pregnancy in order to protect the embryos from disturbance during the period of implantation, but it would be rash to accept such a generalisation until the observation upon which it is based has been extended to other species. At present there is a good deal of discrepancy between the results of various workers. With regard to the human species, Knaus (1929, 1933) and Krohn, Falls, and Lackner (1935) have published evidence that the effect exists, while the experiments of Chassar Moir (1934) and Robertson (1937) are in the negative. In view of the clinical results of Johnstone, Wilson and Elden, and Lubin and Clarke, cited below, the question is certainly still open.
The action of progesterone is in some respects dependent upon previous preparation of the uterus and other reproductive organs by cestrin. The progestational proliferation cannot be produced in young animals until they either have reached puberty or else their uteri have been brought artificially to the mature size and histological state by injections of cestrin. This fact was clearly shown by Allen (19300) following a hint from Hisaw’s work on another possible hormone of the corpus luteum (‘‘ relaxin”). In some other respects, however, the two hormones of the ovary are not supplementary but are antagonistic to each other. I have already mentioned the fact that contractions of the uterus zz széz are stimulated by cestrin but inhibited by progesterone. Another interesting example has to do with the phenomena of vaginal cornification on one hand and mucification during pregnancy on the other. The effect of cestrin upon the vaginal wall is to produce cornification of the surface epithelium, an effect which is used indeed in the standard test for cestrogenic potency. During pregnancy in the rat and mouse, the surface cells of the vagina change from the cornified state which it acquired at the cestrus at which the pregnancy began, into a state of extreme mucification. Administration to the non-pregnant animal of proper amounts of corpus luteum extract produces a similar mucification. This effect, at first thought to indicate the existence of a separate “‘ mucifying hormone,” has been explained by A. Allen and Meyer (1935) as due to an antagonism between the two hormones. Mucification can be produced by cestrin alone if given in very small dosage of the order of one-half the minimum cornifying dose. Administration simultaneously of a cornifying dose of cestrin and a suitable amount of progesterone also produces mucification, apparently because the progesterone cuts down the effective potency of the cestrin. The exact mechanism of these antagonistic relationships will require further study, but they should be kept in mind because they are very likely to be called upon at a later time in explanation of more complicated phenomena in which the hormones play a part, for example the menstrual cycle.
With regard to therapy with the corpus luteum hormone, I do not speak as a practitioner, and yet it may be worth while to point out the possible lines of treatment which seem from the standpoint of the laboratory to be worth trying. As I have shown, experimental study has revealed two chief potencies of the corpus luteum. In the first place it has the property of producing a special histological state of the endometrium, progestational proliferation, by which the nutrition and implantation of the early embryo is supported ; and in certain species in which the maternal tissues contribute largely to the placenta, or in which an elaborate decidua is developed, the corpus luteum stimulates this maternal response. The second action of the corpus luteum is exerted upon involuntary muscle in the uterus, which in some species at least is rendered insensitive to pituitrin and made quiescent. Rational therapy will depend, as far as we understand the situation at present, upon the use of these properties of the hormone and also possibly upon whatever power it has of antagonising cestrin.
If, for example, pathological study reveals the existence of abnormal conditions due to overaction of cestrin, the corpus luteum hormone may be called upon to exert any antagonistic property which it might have against the corresponding cestrogenic activity. Such a thought lies behind the use of progesterone for the relief of metrorrhagia accompanying cystic hyperplasia of the endometrium, for there is good experimental evidence that this condition of the uterus can be produced in laboratory animals by long-continued treatment with cestrin.
Those of us who have been working with corpus luteum extracts from the first, however, had primarily in mind, when we have considered the possibility of therapy, its power of maintaining pregnancy. If there are instances of disturbed gestation, of threatened abortion and of habitual abortion due to failure of the maternal corpus luteum, and if such cases can be recognised in time, it is possible that suitable treatment with progesterone may maintain the pregnancy. At first .we thought of this protective action from the histological standpoint, visualising such cases of abortion as due to retrogression of the progestational endometrium or of the decidua, and fore- seeing their relief by a successful reversal of the anatomical lesion. Such a happy result would be highly specific, since it would be attainable only in cases in which the corpus luteum is defective. The subsequent discovery, however, of the action of progesterone upon uterine muscle opens the possibility that a larger group of cases might be benefited, namely, those in which abortion is brought on by uterine spasm, no matter what the cause. In such cases the action of progesterone would not be specific but rather that of a sedative drug protecting the uterus from a tendency to spasm. We had better await, however, the clinical returns before speculating as to the mechanism of the therapeutic effect. From a number of clinics in various countries reports have been made indicating that administration of progesterone will indeed sometimes relieve the symptoms of threatened abortion, interrupting the bleeding and uterine pain; and that the normal course of gestation may be resumed. Up to the present, however, these reports have left something to be desired from a critical standpoint. The observations are difficult to control, for no two cases are exactly alike and no observer has had the courage to use the new therapy, for example, in alternate cases only, for the sake of comparison. It may be too much to ask that the obstetrician refrain, for scientific reasons, from the use of a possibly beneficial drug under circumstances of such importance to the patient ; but we may at least demand that the publication of results of progesterone therapy in threatened and habitual abortion be accompanied by reports of control cases, as nearly as possibly similar in number and character, treated before progesterone was available.
The striking quiescence of the uterus produced in some animals by progesterone has led, in spite of present uncertainty regarding the existence of the same phenomenon in the human species, to the use of progesterone for dysmenorrhea. We may cite in particular two reports coming respectively from the clinics of Professor Johnstone of Edinburgh (1936) and of my colleagues, Elden and Wilson of the University of Rochester (1936). These and other observers report that small doses of progesterone seem to relieve menstrual pain in about half the cases. Here again a control series is needed, and it should not be difficult to obtain the co-operation of a sufficient number of patients to secure a thoroughly scientific study by alternate application and omission of progesterone therapy in successive cycles.
Perhaps the best-defined clinical application of progesterone thus far is its use for the relief of puerperal after-pains as reported by Lubin and Clarke (1936), who find that a single injection of one unit of progesterone will relieve after-pains in almost go per cent. of the cases.
Allen, W. M., A2. Journ. Physiol., 1930@, xcii., 174.
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73 George W. Corner
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Professor Johnstone offered their guest the most cordial thanks of the Society for coming to address them. He thought it would interest the Fellows to know that Professor Corner’s primary purpose in coming to Britain was to give a series of lectures, not upon the sex hormones, but upon anatomical history. As a clinician he would not venture to discuss the scientific parts of Professor Corner’s paper further than to say that it had been profoundly interesting to be, so to speak, taken behind the scenes and to have revealed to them the actual steps and experiments by which Professor Corner’s discovery of the hormone of the corpus luteum was made. Two years ago they had had the privilege of welcoming to Edinburgh Professor Ludwig Fraenkel, and it was interesting to hear Professor Corner’s account of Fraenkel’s early work. Nobody but a chemist could pretend to discuss the chemical structure of these hormones, but Professor Corner came within their range when he discussed the effect of the progestin hormone on smooth muscles. Whether or not his argument proved to be ultimately correct, it had provided them with an interesting form of therapy, from which fairly satisfactory results seemed to be derived.
Professor Johnstone was much interested in the references to habitual and threatened abortion. His own experience in cases of habitual abortion began before progestin was available, and when luteinising doses of the gonadotropic hormones were used in the hope of stimulating the patient’s own corpus luteum to increased secretion. Whereas Professor Corner had some three ‘“ progestin babies,” he (Professor Johnstone) had on his record between twelve and twenty “‘ rhofactor babies ’’—the result of injection of the rhofactors (gonado- tropic hormones), which were then made by Dr Wiesner in Professor Crew’s laboratory. More recently all of them had been treating cases of threatened abortion with progestin; indeed it was almost a routine treatment, and in a number of cases seemed to be successful.
As regards glandular hyperplasia of the endometrium in metropathia hemorrhagica, he had had several successful cases in young women about the period of puberty, whom he had treated successfully with large doses of progestin. In older women, his experience had been much less, as the condition so commonly occurred near the menopause, and for economic and other reasons it was more satisfactory to treat them by intra-uterine radium, rather than to undertake the relatively expensive treatment by progestin.
With regard to dysmenorrhcea, Professor Corner probably knew that a number of years ago Professor Johnstone and Dr Young, Dr Haultain and Professor Hendry undertook a combined investigation into the treatment of spasmodic dysmenorrhcea by large luteinising doses of gonadotropic hormones. The results were much the same as those of Professor Wilson, to which Professor Corner had referred. They got successful results in rather less than half the cases, and even so, it was very difficult to know how far the element of suggestion could be ruled out in them. Dysmenorrhcea was very largely a psychological condition, and unless the treatment was under the most strict laboratory conditions, it was difficult to claim anything that one could call scientific results.
Professor Crew said that this was the second time to-day that Professor Corner had irritated him. This afternoon he stated that, though much was now known, yet still there remained much that was mysterious. Professor Crew objected to the use of this word in this connection: to them there could be no mystery, but only present ignorance. And now, Professor Corner seemed to be somewhat afraid of the possibilities that must follow the applications of his discovery. He appeared to entertain the view that beauty might be destroyed by advancements in knowledge. This was a timidity which could not be allowed to pass without comment. Professor Corner must always have known that in medicine there cannot be discovery without application. Moreover, he surely must know that though exact knowledge may shatter false concept by establishing truth, it created other and finer standards of what was really beautiful. Standards changed and knowledge was the tool that refashioned them. To Professor Crew, at least, there was no ugliness in the knowledge that the attributes of motherhood which had been given entirely false values by the chivalrous and sentimental, had chemical explanations. His palate had not been destroyed by recent advances in the knowledge of nutritional physiology: the sunset had not been ruined by the spectroscope. In Professor Corner himself there was conflict: scientist versus sentimentalist. He could only hope that the scientist would win.
Listening to Professor Corner one could not but be impressed by the scarcity of British names in the list of investigators who had made contributions to the knowledge of human _ reproductive physiology. Though it was true that scientific discovery soon became the common property of all, it was equally true that active research had a profound local effect, vitalising a school, inspiring both staff and students. In America there were very many brilliant scientists, but this was not the reason why so much of this work had been done in America and so little here. In America there was a desire to do such work, a demand for such work, and, moreover, there were facilities for doing it. Without primates as experimental material much of this work could not have been done. It could not have been done in Edinburgh, not necessarily because there were not the men, but principally because there were not the facilities.
He hoped that Professor Corner’s visit to Edinburgh might be the means of awakening among them not merely a greater admiration for the man and for his work, but a recognition of the urgent need of providing in this medical school greater opportunities for the carrying out of the kind of work that he had been doing. The medical school here was most ill-equipped in the matter of research facilities. Those who were attempting to carry out investigations that demanded experimental animal material were sadly handicapped. It was time that these things were changed. If Professor Corner was indirectly concerned with the improvement of our research facilities then he thought he would agree that his visit here had been most profitable.
Dr Robson said that Professor Corner’s paper formed a fascinating account of the recent developments in sex physiology. Some years ago the question arose as to whether the corpus luteum produced a separate hormone different from the cestrous hormone which was known to be secreted by the ovary. He remembered very well the classical paper of Corner and Allen which demonstrated that the corpus luteum produced a specific hormone with a definite effect on the endometrium of the rabbit’s uterus ; this reaction had formed the basis of all satisfactory methods of standardisation of progestin. Furthermore, he then showed it was possible to maintain pregnancy in the ovariectomised animal by the administration of a luteal extract. Dr Robson then referred to some recent observations of his own bearing on the development of this work.
It had been possible to maintain pregnancy in the hypophy- sectomised rabbit by the injection of progesterone, replacing the normal luteal secretion. Recently also the luteal activity had been maintained in hypophysectomised animals by the injection of small doses of gonadotropic hormone from pregnancy urine, thereby maintaining pregnancy. Thus it had been possible to replace experimentally not only the secretion of the corpus luteum, but also that of the pituitary.
It was possible that these experiments might explain the clinical results of Professor Johnstone. There was good evidence that it was very difficult to stimulate the ovary of primates by the administra- ° tion of gonadotropic hormone and to induce luteinisation; indeed very large doses of gonadotropic hormone might be necessary to be injected intravenously. But it was possible that the administration of small doses of pituitary hormone might be sufficient to maintain the activity of a corpus luteum already present in the ovary, even though they could not affect luteinisation. Such an effect might well account for the efficacy of gonadotropic hormone in the mainten- ance of pregnancy in cases of habitual abortion.
With regard to the action of progestin on the uterine muscle, two questions arose, namely (1) Was this action specific to the luteal hormone? (2) What was the significance of this action in the maintenance of pregnancy ?
With regard to the first question, there was no doubt that the synthetic hormone progesterone could inhibit the physiological activity of the uterine muscle; both the reactivity to oxytocin and the spontaneous rhythmic contractions recorded zz vivo could be inhibited. At the same time it was not impossible that other substances might have similar actions and this was indeed suggested by some of his experiments with different fractions of crude corpus luteum extracts. Some experiments now in progress with pure synthetics also gave some support for that point of view.
With regard to the second question it must be remembered that the inhibitory action of progestin had only been satisfactorily demonstrated in the rabbit. Experiments on the uterus of the mouse, the guinea-pig and the cat, had yielded negative results even when the movements were recorded zx sztu. The data of the human subject were by no means convincing and the later results did not support the view that the luteal hormone inhibited the physiological activity of the human uterine muscle. Further experi- mental work in primates appeared to be very desirable.
Dr Hain said that she was very interested in the relation between the endocrines and maternal instinct. In one of her experiments she had injected very large quantities of cestrin into the early lactating rat, and although the milk secretion was not inhibited—for she was able to withdraw quite large quantities of milk—the mother showed no interest in her young and eventually they died. Their death was caused by the lack of interest in the mother for her young and her refusal to nurse them.
Dr MacGregor said he wished to know how the corpus luteum hormone counteracted the effect of the cestrogenic hormone. In cases of metropathia hemorrhagica especially, administration of progesterone sometimes re-established a normal menstrual cycle. It was difficult to see how this acted unless the antagonistic action of progesterone was to hasten the excretion of cestrone.
He had started a clinical investigation on irregular uterine bleedings, especially those which occurred round about puberty. Progesterone therapy in some cases gave good results, while in others no effect was produced. These findings led to a more detailed investigation, when it was found that while in some cases progesterone gave relief, other cases, particularly those due to a hypoplasia of the uterus, could be treated more effectively with cestrone ; while another group of cases was associated with anovular bleedings and responded to anterior pituitary therapy.
Professor Corner said that progesterone in some cases of dysmenorrhoea gave really good results. If one considered his dictum that progesterone inhibited the reactivity of the uterine muscle, then this result was not surprising and a careful history into the type of pain complained of would show that in some cases the pain came on a few days before the onset of the period, with sometimes very severe pain during the period. The pain in this type was probably due to the increased sensitisation of the uterine muscle due to cestrone and might probably be relieved with progesterone. The other type of case was where the pain came on with the onset of the flow. These cases he believed were suitable for cestrone therapy, as the cause was probably an excess of progesterone or deficiency of cestrone producing an endometrium bordering on the pathological and requiring strong contractions not only for its expulsion but for its separation and that in a uterus which was not sufficiently sensitised.
- Dr MacGregor asked if Professor Corner thought there were
two hormones secreted by the anterior lobe of the pituitary, one stimulating follicular and the other corpus luteum development.
Dr Susanne Paterson said she thought there was another possible clinical application of progestin. That was the possible connection between lack of progestin and eclamptic and pre-eclamptic cases. Investigations along this line had been made in the last six months in the Elsie Inglis Hospital. The cases treated were only those who were suffering from severe albuminuria, cedema and high blood pressure and which gave the general clinical impression that eclampsia was imminent. In addition all the cases except two emergencies, which were admitted as such, had failed to improve under the routine conservative measures of treatment. They were proved as true pre-eclampsias by blood urea estimation and by urea concentration tests. This experiment lasted over six months and in all cases that were treated, the treatment was limited essentially to the administration of progesterone intra-muscularly. The first dose was 5 mgrms. given on the first day; this was repeated for the first three or four days according to symptoms and, over all, doses were given varying from 20 to roo mgrms. of progesterone over periods of between two and four weeks. The results were encouraging. In the first place none of these patients developed fits and all of them recovered. In the second place, improvement took place in the signs and symptoms of the cases from the commencement of treatment, occasionally with slight remissions ; and the result to the mother was complete recovery of kidney function in all cases, save one, where there was slight residual nephritis. It was impossible to devise a good control experiment for these results, but they were compared with similar cases occurring during the same six months of the preceding year.
In 1935 there were admitted to hospital and treated, 21 cases of pre-eclampsia, of which ten were judged severe. Of these, four developed fits and two died. In 1936, in the same months, 31 such cases were admitted to hospital, of which thirteen were severe, twelve of these were treated with corpus luteum and none developed fits and none died. Dr Paterson submitted these results because she thought they were suggestive and encouraging.
The President thanked Professor Corner cordially on behalf of the Society for a most interesting and instructive paper. In the clinical application of such work as Professor Corner had reported, a major difficulty with which one was confronted was that of dosage. This difficulty was largely due to the absence of a definite standard of ovarian function such as was available, for example, in disturbances of the thyroid or pancreas. If the extent to which the ovarian or anterior pituitary hormones were deficient could be determined precisely we should have a more rational basis than was now available on which to formulate treatment. A further difficulty was that of . expense. At present ovarian hormone therapy was costly, and unfortunately one could not assure the patient beforehand that it would necessarily be successful. In this connection Professor Corner’s remarks on the synthetic preparation of progestin had a special interest.
Professor Corner, in his reply, expressed great interest in the clinical experiences cited by Professor Johnstone and Dr Paterson. The question raised by Dr MacGregor as to how progesterone counteracts the effect of cestrone could not be answered at the present time. With regard to the question of the pituitary gonadotropic hormones, Professor Corner felt that current opinion favours the idea that there are two active substances. Referring to the concluding part of Professor Crew’s remarks, Professor Corner said that a visitor from overseas like himself would be very happy to think that he could return in some small part the encouragement and stimulation which the medical profession, and particularly that of his own country, had always received from the University and the physicians of Edinburgh.