Edinburgh Medical Journal February 1942 SOME ASPECTS OF (ESTROGENIC THERAPY * By W. F. T. HAULTAIN, O.B.E., M.C., B.A., M.B., F.R.C.S.Ed., F.R.C.O.G. I HAVE chosen the subject of cestrogenic therapy for this lectui e for several reasons. The first is that the discovery of the female sex hormones is of comparatively recent origin and, though no doubt there is still much to be discovered with regard to sexual physiology, the work on the natural and synthetic oestrogens has advanced rapidly, with the result that various preparations are even now of the greatest use to the clinician. Secondly, cestrogenic therapy has always been of particular interest to me, even long before I had heard of such a name, and in 1928 I 1 wrote a paper on the administration of ovarian extract for the artificial menopause, gleaned from work which I had been carrying out clinically for five years previously. Since that time I have continued my clinical observations with the various natural and synthetic oestrogenic products which have been introduced, and in this lecture I intend to include my further observations in their appropriate place. Thirdly, special work in the clinical use of has oestrogens been carried out during the last three years in my obstetrical and gynaecological wards. That being so, I intend to deal chiefly in this lecture with conditions with which I have had some clinical experience in regard to the value of oestrogens, and will do no more than refer to other conditions for which have oestrogens been recommended, of which I have no personal experience. My last reason in choosing this subject is on contingent my first, in so far as cestrogenic therapy is now comparatively and can cheap often be carried out by the general practitioner in his It practice. is therefore an eminently suitable subject for a post-graduate lecture, in which I can discuss the various conditions for which oestrogens are useful and the type of products which A Honyman Gillespie Lecture delivered 5th February 1942. W. F. T. Haultain can be best used. Some idea of the dosage required in the different conditions will be given and the benefit to be expected with such dosage. It must be remembered, however, that this therapy is still in its pioneer stage, and ideas regarding dosage may change materially in the ensuing years. Lastly, I would like to give some warnings regarding the dangers that must be avoided in some particular conditions before subjecting a patient to such a therapy or applying it for too long a period of time. Historical Account of Discovery of (Estrogens It may be of interest in the first place to give a short historical account of the discovery of the more common oestrogens, including short descriptive notes on the most important preparations which are us are a of used clinically ; to many of these just collection names, which are confused in our minds with the numerous trade names allotted to the same substance by the various manu- facturers. In my opinion it should be forbidden by law for any substance to be called by more than one name, as this heterogeneity of names for any important substance is an added load to the already overburdened doctor's brain, and in many cases allows proprietary drugs to be prescribed without any knowledge as to their true nature. Especially is this the case with regard to the medical student's knowledge of proprietary preparations. In 1896 Knauer demonstrated that ovarian transplantation following double oophorectomy prevented atrophy of the uterus, and thus showed that the ovary must produce an internal secretion which acted through the medium of the blood stream. It was not until 1912, however, that Adler added further contribution on the physiology and pathology of the ovarian function,2 and Frank and Rosenbloom contributed additional knowledge in a paper in 1915 on the physiological active substances contained in the corpus luteum and placenta.3 The war years prevented much further research on these lines, and it was not until 1923 that rapid 4 progress was made, owing to the discovery by Allen and Doisy of the vaginal smear reaction in detecting the presence of oestrogenic substances. After this Frank and his collaborators found a that definite ovarian hormone was present in circulating and menstrual blood, the quantity passing through a definite cycle corresponding to the menstrual cycle. They also found this hormone in the blood of pregnant women, in the placenta in large quantities, and even in the corpus luteum itself. In 74 A Some Aspects of (Estrogenic Therapy 1927 a further impetus was given to the research by the discovery of Aschheim and Zondek 5 that oestrogens were present in high concentration in the urine of pregnant women, and later of mares. At this time it was believed by the majority of observers one and it was not till that the ovary produced only hormone, 1928, when the first natural oestrogen was obtained by Doisy, was in Veler and Thayer0 from pregnancy urine and isolated 7 crystalline form by the same collaborators in I929> and at the same time Corner demonstrated a different hormone from the corpus luteum, that it was really definitely established that the ovary produced two entirely different hormones. Doisy named his crystalline substance theelin, but it is now universally recog- nised as oestrone, which is a hydroxyketone having the formula Ci8H2202. Later, two other common oestrogens were prepared these from pregnancy urine and also from the placenta, and were named oestriol (trihydroxyoestrin C18H2403) and cestradiol (dihydroxyoestrin C18H2402). It is interesting to note that in I932 a natural oestrogen equilenin was prepared from the urine of pregnant mares by 8 9 Girard, Sandulesco et alii ; in 1938 Bachmann synthesised equilenin, this being the first sex hormone to be entirely synthesised from simple materials. In 1932 Cook, Dodds and Hewett10 prepared the first oestro- genic substance synthetically (i-keto-i : 2 : 3 : 4 tetrahydrophen- anthrene), but this was of relatively low potency and at that time these investigators stated that there were grounds for believing that substances of much higher activity would be found before long ; their prophecy was certainly a correct one, for in five years substances were discovered, 300,000 times more active than the initial preparation. In 1936 Dodds and Lawson11 showed that the phenanthrene ring, which had been present in all the earlier synthetic oestrogens, was not necessary for oestrogenic activity and that numerous diphenyl derivatives had oestrogenic properties. Further simplification of the molecule led to the examination of anol (^-hydroxyprophenyl benzene), and the high 12 activity of this substance was found to be due to an impurity ; thus the oestrogenic value of the impurity must be of very high potency. Further investigation of this contaminant at the Courtauld Institute produced hexoestrol, whereas at about the same time stilboestrol (4-4 dihydroxy a-j3 diethylstilbene) was produced by the same workers collaborating with Professor Robinson and his co-workers at Oxford13' 14' ir\ These two W. F! T. Haultain substances were found to be highly cestrogenic by oral administra- tion and compared favourably with the activity of oestradiol by injection. 16 In 1937 Robson and Schonberg discovered another cestro- genic substance in triphenylchloroethylene, which was found to have a marked degree of activity and has been successfully used in the treatment of many of the conditions to be mentioned in this lecture. In further reference to this oestrogen in this paper the name will be abbreviated to T.P.E., and I am indebted to Dr A. I. S. Macpherson for all the work done in my wards with this substance. Assessment of Results It has been shown by Papanicolau and Schorr17 that the activity of the oestrogens in the human can be estimated by the > change in the vaginal smear, large flat squamous epithelial cells with pyknotic nuclei being in abundance with a characteristic and of the leucopenia cornification cells, but for practical purposes 18 it has been shown by Smith and others that alteration in the smears is usually preceded and always paralleled by the relief of symptoms. Smears have been taken in some of my cases to show the beneficial action of oestrogens, but I am afraid that in the majority of cases the efficiency of the oestrogen has been estimated by the relief of symptoms and by clinical cure of the condition. Effects of (Estrogens and their Dangers The effects of oestrogens can be summarised as follows :? (1) They increase the size and vascularity of the uterus and stimulate the proliferation of the endometrium in preparation for the action of progesterone. (2) Bleeding will occur from endometrium released from the influence of oestrogens?oestrin withdrawal bleeding. (3) They increase the spontaneous activity of the uterine and tubal muscle and also the reactivity of the myometrium to oxytocins. (4) They increase the vascularity of the vagina and vulva, and the cornification of the vaginal epithelium. (5) Inhibition of the activity of the anterior lobe of the pituitary. Some Aspects of (Estrogenic Therapy (6) Vasomotor, metabolic and psychical disturbances char- acteristic of the menopause may occur when the body is deprived of oestrogen. (7) In large doses they inhibit lactation, probably by depressing the action of the lactogenic secretion upon the breast. (8) They promote the growth of the nipple and the mammary gland. It is of the greatest importance before administering cestrogens to be sure that the therapy is based on a sound appreciation of the physiological principles involved. I hey should never be given in a haphazard fashion for conditions outwith the indications just given, otherwise much harm may result in the way of upset of menstrual and metabolic functions (irregular bleedings, etc.).