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IT has long been known that simple watery or alcoholic extracts of various organs of the body produce a pronounced depressor action when injected intravenously, especially in the carnivora. Oliver and Schafer() observed such an action with an extract of thyroid gland, Mott and Halliburton(2) with extracts of brain and nervous tissues, Vincent and Sheen (3) with extracts from liver, muscle and various glandular organs, and other observers with a wide range of organs from different species. The suggestion that these effects were explained by the presence of choline in such extracts was shown to be inadequate by Vincent, with Osborne(4) and Sheen(3), who found that the action was but little affected by administration of atropine. Popielski(5) suggested that a common depressor agent, for which he suggested the name "vasodilatin," was present in such tissue extracts, and a hint appeared to be given as to its chemical nature when Dale and Laidlaw(6) found that the base now generally known as " histamine " produced the vascular and other characteristic effects of the hypothetical vaso-dilatin, when injected in relatively minute doses. Barger and Dale(7) soon afterwards succeeded in isolating from an extract of intestinal mucous membrane sufficient of this base for chemical as well as physiological identification. The quantity obtained, however, was small in relation to the total activity of this kind exhibited by the extract, and the nature of the raw material left it doubtful whether the histamine came from the living cells of the mucous membrane, or from the intestinal contents with which they had been in contact. For some years after this, though the correspondence in action, between the chief depressor constituent of various organ extracts and histamine, was widely recognised, the probability of their chemical identity seemed rather to be weakened. We may mention, for example, the observations of Stern and Rothlin(s), who extracted from the spleen a principle acting like histamine, but, finding that it was largely destroyed by heating with dilute alkali, concluded that it could 26-2 BEST, DALE, DUDLEY AND THORPE. not be histamine, which is stable to such treatment. We shall show later the need for caution in drawing such conclusions; but the balance of evidence and of opinion seemed to be unfavourable to the identification until Abel and Kubota published an important paper in 1919(9), in which they claimed to have made probable the presence of histamine itself, or of some substance closely related to it, as the essential depressor constituent of extracts from a number of organs and tissues, and of the products of partial hydrolysis of pure proteins. In some respects their evidence failed to be completely convincing. From two tissues onlythe pituitary gland and the gastro-intestinal mucous membrane-did they obtain pure salts, the picrate and chloroaurate, of histamine. The quantities so isolated were small in relation to the original depressor activity, the pituitary raw material was a commercial dried preparat...

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DIFFERENTIATrON OF SEX CHARACTERISTICS METDIHCABTRNAL a suprarenal cortex, and only occasionally to a malignant tumour. Not infrequently hyperplasia or neoplasia (adenoma) of the pars anterior of the pituitary also leads to virilism in women. With hyperplasia there is usually acromegaly. It is interesting to note that a marked change to virilism does not occur in women as the direct result of these lesions after the menopause, although, as we know, in many after that epoch certain masculine characteristics, such as hair on the face, are common. Similar changes may follow obphorectomy with the artificial menopause. With cortical suprarenal tumours the changes observed in women are remarkable. Many grow beards, and some appear in fairs as the well-known bearded women. They may have the voices of sergeant-majors, and be rough and aggressive in manner. When seen early, removal of the offending tumour may lead to retrogression of most of the masculine characteristics, but the altered larynx never reverts to its former shape and size. With acromegaly there is a limited change towards masculinity with amenorrhoea. The voice invariably deepens. In one case I found that the clitoris had become so greatly hypertrophied that it was causing the patient much distress. Acromegaly in men, as Harvey Cushing has shown, causes increased virilism, just as do suprarenal tumours. Feminism in Men A change in characteristics towards femininity is seen in men who have destructive lesions of the pars anterior of the pituitary, such as may be caused by cysts in that organ or by supraselfa tumours. In these circumstances the syndrome known as dystrophia adiposogenitalis is present. Hair disappears from the face and pubes, while the contour of the body and limbs assumes a feminine type. After castration, too, a certain degree of feminism develops. No doubt in all these circumstances the masculinity-maintaining mechanism is interrupted. SUMMARY The relation of the sex-directing factors of heredity and sex-chromosomal constitution have been discussed, and the continued sex differentiation in vertebrates through the sex-determining action of organs of internal secretion has been described, together with the nature of the later general sex characteristics brought into being by the endocrine genital system. Sex aberrations from biological, sociological, legal, and medical points of view have been considered.

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