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THE MINIMUM QUANTITY OF ESTROGEN REQUIRED TO INDUCE ATYPICAL EPITHELIAL GROWTH OF THE UTERINE MUCOSA IN THE GUINEA-PIG ALEXANDER LIPSCHUTZ, M.D., LUIS VARGAS, JUN., M.D.. ARMANDO JEDLICKY, M.D., AND PEDRO BELLOLIO, M.D. (From the Department of Experimental Medicine, National Health Service, Republic of Chile, Santiago) It has been shown by many workers that a cystic glandular hyperplasia of the uterine mucosa can be induced in various species by prolonged admin- istration of follicular hormones. There may occur, also, a metaplasia of the epithelium of the endometrium, which becomes stratified in certain areas, while the glands may be transformed into solid epithelial cords. Under simi- lar experimental conditions metaplastic changes may occur also in the uterine cervix (for literature see Gardner, 1, and Loeb, 2). These observations are of special importance since the metaplastic changes, which sometimes assume a precancerous aspect, may persist even when administration of estrogens is suspended. In one case atypical growth of the uterine epithelium of precan- cerous aspect was observed in a castrated guinea-pig which had received sub- cutaneous injections of the monobenzoic ester of estradiol for a period of eight months, though the injections were suspended four months before the animal was sacrificed (Lipschutz, Iglesias and Vargas, 3). Allen and his associates (4) were successful in transplanting a cancerous cervical tumor occurring in a mouse treated with estrogens for ten months. It may be objected that in all these experiments an artificial condition is created and that no conclusions can be based upon them as to spontaneous tumorigenesis by endogenous estrogens, i.e. by estrogens secreted by the ovary in situ. On the other hand, it was shown by the senior writer some years ago that a similar atypical epithelial growth of the uterine mucosa may be induced in the guinea-pig without the injection of estrogens. If one ovary is removed completely and the second partially, so that only a small ovarian fragment remains in the body ('' complete ovarian fragmentation "), a considerable change in the sexual cycle occurs: the follicular phase is prolonged and the vaginal mucosa may remain cornified for many weeks (Lipschutz, 5). Under these conditions a cystic glandular hyperplasia of the endometrium may occur in the guinea-pig.' When such animals are kept under observation for sev- eral years there is found in almost all of those in which the ovarian fragment has remained intact, a penetration of uterine glands bgtween the muscular coats of the myometrium. There may also be a cornification of the upper part of the cervix, where normally only mucified epithelium occurs. In one instance the aspect of the cervix was frankly precancerous (Lipschutz, 7). 1 This work has been aided by grants from the Ella Sachs Plotz Foundation for the Advance- ment of Scientific Investigation, and from Mr. Adolfo Eastman in Limache, Chile. 2 Similar observations were made also in the rat (Burch, Wolfe and Cunningham, 6) 185 186 A. LIPSCHUTZ, L. VARGAS, A. JEDLICKY, AND P. BELLOLIO TABLE 1 : Efect of Eslradiol Injections on Uterine Weight - Estradiol hration o Body Weight (grn.) at Castration and at End of Experiment Ester Injections and Uterine Weight (day81 Per Injt-c tion (pg. Mono ben zoa te 85 0.1 3.7 385-660 600-820 795-950 . 1.2 1.o 3.4 Dipropionate 85 0.1 3.9 585-860 625-860 1.2 1.2 Benzoate- Bu t yra te 104 0.1 4.6 185-700 260-710 305-790 550-990 650-770 1.5 1.7 1.2 1.5 2.3 Monocaprylate 103 0.1 4.5 185650 260-790 305-800 560-830 770-890 1.4 1.9 2.1 1.2 4.2 __-___ -__ Benzoate 84 1 .o 37 440-585 4 7 5-680 490-580 575-670 595-670 2.5 2.3 2 .o 5 .O 2.3 Dipropionate 85 1 .o 3P 470-7 10 485-700 500-670 545-750 590-680 3.4 4.2 2.5 3.2 4.8 llenzoate-But yra te 97 1 .o 42 2 15-680 285-4310 3 10-660 570-980 620-920 3.0 2.5 2.0 4.5 3.7 Ca pryla te 96 1.o 41 235470 285-800 3 15-690 595-790 790-880 3.7 3.7 4.0 3.0 16.0 __ The ovarian fragment itself shows a pronounced tendency to form follicular cysts, sometimes with luteinization of the cyst wall. These results furnish convincing evidence that a prolonged follicular phase can cause atypical epithelial growth. The question remains, however, whether prolongation is of itself sufficient to produce this result or whether the quantity of estrogens produced in the unit of time must also increase, i.e. whether there must be in addition to prolongation of the folliculinemia a hyperfolliculinemia. Can atypical epithelial growth of the uterine mucosa be caused simply by a disturbance of the normal timing of the two endocrine phases of the ovary? This question is intimately bound up with another of considerable interest in experimental tumorigenesis. The carcinogenic substances, such as benz- pyrene, exert a tumor-producing action on or beneath the skin even when ap- plied in very small quantities. With the estrogens, on the contrary, large amounts seem to be necessary for a tumorigenic effect on the genital mucosa Can these two groups of substances, then, be aligned in respect to their tumor- producing properties? In the experiments to be described in this paper it is shown that a " tumori- genic " effect can be produced with only a few micrograms of estrogen provided certain conditions as to the timing of the application are observed. EXPERIMENTS Thirty-five castrated female guinea-pigs were treated with different doses of 4 esters of estradiol-monobenzoate, dipropionate, 17-benzoate-3-n-buty- rate, and monocaprylate (8). Three subcutaneous injections were given weekly for three to three and a half months, Fifteen animals received 0.1 IAg. of esterified estradiol per injection, and 20 animals 1.0 pg. per injection, in 0.1 ml. olive oil. The total dose of estradiol in the first group of experiments ATYPICAL EPITHELIAL GROWTH OF UTERINE MUCOSA IN GUINEA-PIG 187 was between 3.7 and 4.6 pg. per animal in 85 to 104 days, whereas in the second group the total was 37 to 42 pg. per animal in 84 to 97 days. Treat- ment was begun seven to eight weeks after castration so as to be sure that the uterus was in involution. The uterus of each animal was weighed and the genital tract was examined microscopically. A frontal section of the genital tract was made, showing the vagina and cervix and the uterine horns (Fig. 1). Cross-sections of both horns at a distance of about 1.5 cm. from the cervix were also made. The observations are summarized in Tables I and 11. As seen from Table I, repeated doses of 0.1 pg. of estradiol in the form of the monobenzoate or dipropionate will maintain the uterine weight for several months not far from the normal level, which is about 1 gm. in the adult virgin guinea-pig. The " useful hysterotrophic dose '' of these esters, or the quantity Transitional zone between cervix and uterus Individual cervix Common cervix Fornix ' Vaginal cervix Portio Vagina FIG. 1. SCIrEAlATlC DRAWINGOF FRONTAL SECTION OF BASEOF GUIXEA-PICUTERUS SHOWING VAGINA,CERVIX. AND BEGINNINGOF UTERINEHORNS of estradiol which when injected thrice weekly will maintain the uterine weight in the castrated guinea-pig on a normal level, is probably somewhat more than 0.1 pg.' In one of 5 animals the uterus weighed as much as 3.4 gm. Greater uterine weights were attained with 0.1 pg. of the benzoate-butyrate ester and especially with 0.1 pg. of the monocaprylate ester in experiments lasting about twenty days longer than those with the two esters first named. The maximum figures represent animals castrated after reaching adult life. Evidently, there- fore, the previous uterine history is of importance. With injections of 1 1J.g. the uterine weight is greatly increased, in general to about twice that observed in normal virgin animals. Exceptionally the in- crease is enormous, as in one animal of the monocaprylate group, with a uterus weighing 16.0 gm. The microscopic findings in the uterine mucosa corresponded with these observations on weight (Table 11). In the monobenzoate and dipropionate 3 In a new series of experiments with injections of 0.1 pg. a normal uterine weight was not always attained in the course of 82 days. 188 A. LIPSCHL~TZ, L. VARGAS, A. JEDLICKY, AND P. BELLOLIO TAHLEI I : IIislologic Effrcts of Estradiol Injections (Figures intlicatc number of animals) .-~ - Subniucosa With Metaplasis EY- of Uterus of Uterine Horn tra- Total (‘y6tic diol Nuni- Gland- - - With Metaplavia ~ __ Without Any per per ular between Cervix Metaplado In- of Hy- Abun- and IJterine With- of Uterine jec- Ani- dant Pig- llorn out With Horn tion mals pEa Vascu- Strati- lariza- nien Strati- fication (re.) tion fication __~- -__ _____~_ Monobenzoate 0.1 0 0 0 Ol 5 Dipropionate 0.1 ;] ;* 0 0 0 01 Benzoate-B ut yrate 0.1 52 0 2 3 3 1 Monocaprylate 0.1 5 4ap.‘ 2 3 4 3 0 -- - ____-- Monobenzoate 1 .o 54 3 2 4 2 0 Dipropionate 1.o 5 Sap. 4 3 4 3 0 Benzoate-Butyrate 1 .o 5 Sap. 5 2 3 4 1 Monocaprylate 1.o 5 5 ap. 3 1 5 4 0 ~ __ - * ap.
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