The Fibromatogenic Action of Specific Urinary Estro- Gens (Metahormones) in the Guinea Pig*T

The Fibromatogenic Action of Specific Urinary Estro- gens (Metahormones) in the Guinea Pig*t Alexander LipschCitz, M.D., 1Ren~ Thibaut, M.D., and Luis Vargas, Jr., M.D.

(From the Department o/ Experin',er~tal Medicine, National Health Service o/ the Republic o~ Chile, Santiago, Chile)

(Received for publication September i7, 194~)

Conversion of estradiol and estrone, or ortho- and the human placenta, as shown by Doisy (2) and Mar- parahorlnones, ~ into estriol, a specific urinary meta- rian (i9). Since both are present in the ovary (2), hormone of women, acquires a new interest since, in they can be considered as primary ovarian estrogens. guinea pigs, toxic phenomena, including tumorigenesis, Estriol and equilenin were used as representatives of are elicited by prolonged action of follicular hormones. urinary estrogens. The first is present also in the Further interest is added by the findings of Pincus placenta, but both are absent from the ovary. They can and Graubard (2o) who have reported that cancerous be considered as specific urinary estrogens. women appear to be unable to convert estrone into Pellets of crystalline hormones were prepared by estriol to any appreciable extent. It is generally as- compression in a suitable hand press as described in sumed that this conversion signifies inactivation; i.e., detail in the thesis of Thibaut (23). The weighed that substances of high estrogenic activity (estradiol pellets were implanted subcutaneously in castrated and estrone) are transformed into substances of low guinea pigs. After the death of the animals the pellets estrogenic activity (estriol in the urine of the pregnant were recovered and weighed again. The animals were woman; different urinary estrogens of the mare). One killed and autopsied at different intervals after im- may also assume, tentatively, that by means of this plantation of the pellet. The fibrous reaction was conversion the body protects itself against the toxic or classified in accordance with criteria specified in pre- tumorigenic action of follicular hormones. This as- vious papers by Lipschiitz and Vargas (i4) , and Lip- sumption was tested by making a quantitative com- schiitz, Bellolio, Chaume, and Vargas (io). The re- parison of the faculty of different ovarian and urinary sults with respect to absorption and total tumoral effect estrogens to elicit abdominal serosal fibroids in the as obtained in lI 4 animals are summarized in Table I guinea pig. and Fig. i.

MATERIALS AND METHODS COMPARATIVE FIBROI~'IATOGENIC ACTIVITY OF DIFFERENT ESTROGENS Alpha-estradiol and estrone were used as representatives of ovarian estrogens. Both are found also in the All of the four estrogens were tumorigenic. The urine, especially estrone, which can be extracted from localization of tumors was the same as in animals receiving estradiol and its esters, or artificial estrogens, * This investigation was aided by grants from Thc Jane Coffin as reported previously by Lipschiitz and Iglesias (io), Childs Memorial Fund for Medical Research, from The Rocke- feller Foundation, and from Mr. Adolfo Eastman of Limache, Iglesias (6), Lipschiitz, Iglesias, and Vargas (ii), and Chile. These grants were administered by Professor A. Lipschfitz. Szabo (22). However, there were considerable differ- Crystalline estradiol was supplied by Dr. Carl Miescher, of the ences as to the degree of the reaction. firm of Ciba in Basel. Estrone, estriol, and equilenin were supplied by Dr. Oliver Kamm, of Parke, Davis & Co. The first manifestations were found as early as 2~ j" The senior author is responsible for the interpretation of to 3 ~ days after implantation of pellets. These were results and preparation of the manuscript. small, barely visible, nodules on the spleen, the stom- i In recent years Lipschfitz (8) has used a new Spanish ach, and sometimes at the junction between the uterus terminology to indicate the physiological relationships of the and the parametrium. These primary manifestations different sex hormones. According to this terminology estradiol, progesterone, and testosterone are orthohormones; estriol and the of a fibrous reaction graded as o. 5 were present with specific urinary estrogens of the mare, pregnandiol, androsterone, all four estrogens. and dehydroandrosterone are metahormones. The term para- The tumoral reaction increased with time. At 8o hormones may be appropriate for those hormones whose physi- and ~2o days marked differences became evident be- ()logical activity is doubtful; for example, estrone. The term prehormone also may be useful. It must be left to others to tween estradiol and estrone on one hand, and estriol judge whether this terminology is convenient in English.-- and equilenin on the other. As noted in our previous Authors' note. reports (6, I~, I5) , individual variations were con- 45

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1942 American Association for Cancer Research. 46 Cancer Research siderable. Resistant animals were present in the groups it is known that estrone is absorbed more slowly than given each of the four estrogens. Nevertheless, it was estradiol. In our experiments, results of which are a striking finding that, in experiments continued for shown graphically in Figs. i and 2, we found that 5 ~ days or longer, 6 out of 33 animals treated with the absorption of estrone was considerably slower than estradiol and estrone developed high tumoral reactions, that of estriol or equilenin. Nevertheless, the tumori-

"FABLE l: TUNIORALEFFECT IN 71 CASTRATED FFMALE GUINEA Pros (2IO TO 53 ~ GM. WIIEN RECEIVING THE IhiPLANT) WITH SUBCUTANEOUSLYIMPLANTED PELLETs OF FOUR DIFFERENT ESTROGENS Number of animals with Average total tumoral Duration of absorption Total tumoral effect effect not experiment Number of per (lay c ~" , less than Estrogen in days animals #gm. Average Range grade 6 Estradiol ...... 5 ~ I o 75 2.7 o-9 I ] Estradiol ...... 80 5 I8 4.6 oq2 i[ 6 Estrone ...... 50 5 I3 3.2 o-5-8 I out of Estrone ...... 80 5 I I 3.9 o-5-6.5 I / 33 Estrone ...... I2O 8 5.5 4.6 1.5-I2 2j

Estriol ...... 50 4 44 ,.9 ,,-5 Estriol ...... 80 5 20 2. 4 0.5-4 Estriol ...... i2o 8 15 3.1 0-8 1 I out of Equilenin ...... 50 5 22 0.5 o-I.5 o| 38 Equilenin ...... 80 9 I9 0.7 0-4 o ] Equilenin ...... I 2o 7 15 o ....

- I o ,17 0 Estradiol l&l,5 i0 20 Es ~rone /~ 30 ~ I 40 t J -~ 1 ~ i ~ Equilenin 50 %-- / Estrio~ i #/ 60 . I ,. ~. Estriol 70 1 5 i 80 I ~iuilenin ]!8 90 2 Days IDO [Days L I 21 30 50 80 120 21 30 50 80 12( Fro. I.--Graphs showing degree of fibromatogcnic action of estradio], estrone, estriol, and cquilenin in i I4 castrated guinea pigs. The estrogens in pellets were implanted subcutaneously. Each point is the average of results in 4 to Io animals. The num- bers near each point indicate the average absorption in mgm. The fibromatogenic action of estriol and equilenin is considerably less than that produced by equal or smaller quantities of estrone or estradiol. For details see Table I and Thibaut (23). FIG. 2.--Graphs showing percentage absorption from subcutaneously implanted pellets of estradiol, estrone, estriol, and equilenin in 114 female guinea pigs. All pellets were of the same diameter, 1.6 ram., but not of the same length. The weights of the pellets varied between z.~ and 6.2 mgm. Rate of absorption of estrone was less than that of other estrogens. For details see Thibaut (23). not lower than grade 6, while among 38 animals genic action was enormously superior with estrone. treated with estriol and equilenin only one developed Our results show, therefore, that specific urinary estro- such a reaction, the tumoral reaction generally failing gens are less fibromatogenic than ovarian estrogens. to appear. This confirms the statement of Lacassagne (7) who The differences in the degree of tumoral reaction found equilenin to be less active than estrone in were not due to the differences in the quantities of eliciting mammary adenocarcinoma in mice, although hormones absorbed. From the work of Deanesly (1) no exact quantitative data on this point are available.

COMPARATIVE HYSTEROTROPIC ACTION the formation of polyps, may be obtained also with equilenin. Genital bleeding occurred with equilenin The question arises as to whether the lower fibro- as with other estrogens. matogenic action of certain estrogens is concomitant with a lesser estrogenic activity. According to general opinion this should be so because, in the Allen-Doisy COMPARATIVE FIBROMATOGENIC ACTION OF test, estriol and the urinary estrogens of the mare are FOLLICULAR HORMONES ABSORBED FROM less active than estradiol or estrone. The same results PELLETS AND INJECTIONS are obtained with the uterine tests. When rats are In previous experiments we (13 , 21) found that 38 injected once daily for 5 days with estrogens in oil, to 5 ~ injections of 75o to 2oo /,gm. of estradiol, or the highest uterine ratio (ratio of the weight of the ~5 o to 3o0 /,gin. of estrone, in oily solution; i.e., a uterus in mgm. to body weight in gm.) is obtained with estradiol. With estrone this ratio is somewhat less and with estriol and equilenin it is considerably below the value with estradiol, as shown by the work of Dorfman (3)- Similar statements concerning this ratio in the mouse were made by Evans, Varney, and Koch (5)- Emmens (4), however, discovered that the / Estrone differences in the degree of estrogenic effect exerted Estriol by the natural estrogens, as evidenced by cornification of the vaginal mucosa, depend in part upon the num- d ber of injections made into the same animal for pur- pose of assay. With two injections the approximate ~ Equilenin amounts of estradiol, estrone, and estriol in oily solution needed to produce 50 per cent of positive estrous vaginal responses are i:4:28o , whereas with four injections these amounts are only i:2.7:6. 4. ! These findings of Emmens raise the question as to whether there might be equality in certain actions of estrogens, hitherto different as judged by the results of r the Allen-Doisy test and the results of the short-term uterine test, provided a steady flow of hormone be maintained from a given source. Our results with pellets of estrogens appear to be in favor of such an 3 assumption. In our experiments with pellets there was 0 Days no considerable difference in uterine weights between estradiol, estrone, and estriol. Uterine weights were FI(3. 3.--Graphic summary of uterine weights in 93 castrated female guinea pigs treated with estradioI, estrone, estrioI, and inferior with equilenin, but the difference between equilenin. There was no difference between estradiol, estrone, equilenin and the other estrogens on this basis was and estriol. The averages were smaller with equilenin, but the not so remarkable as the differences between the fibro- differences in uterine weights were not as striking as the differ- matogenic actions, data on which are shown in Figs. ences in fibromatogenic effects. Compare with Fig. I. I and 3. It must be emphasized that, in experiments in total of 5.7 to i 1.4 mgm. given in the course of 3 to 4 which treatment with estrogens is prolonged, the months, did not elicit abdominal fibroids in female uterine weight does not depend entirely upon an guinea pigs. Only the first manifestations of a fibrous increase in the muscular coats. The increase depends reaction occurred in the form of tumoral seeds or to a large extent also upon the atypical proliferation fibrous strands at various places. Fibroids were pro- which the endometrium undergoes under these ex- duced only when 400/,gm. were injected thrice weekly; perimental conditions. In some instances adenomatous i.e., when a total of i6 to 20 mgm. were injected in the polyps may fill the uterine cavity and descend into course of 3 to 4 months. The results of the experiments the cervix and vagina (i8). Although we have not we are now reporting provided a basis for comparison yet made a comparative microscopical study of the of the fibromatogenic action of estrogens administered myometrial and endometrial reactions following im- on the one hand in repeated injections of oily solutions, plantation of pellets of different estrogens, we have and on the other by subcutaneous implantation of noted that atypical growth of the endometrium, with pellets. 4

In Table II we have summarized the results ob- assumed by Lipschfitz (9) that the estrogen level in tained in experiments with i8 guinea pigs killed 80 the blood will drop rapidly below the tumorigenic to I2o days after implantation of the pellet. These threshold unless enormous quantities are injected re- experiments are fully comparable as to duration of peatedly. On the contrary, when there is a continuous treatment with experiments on a group of 17 animals supply of estrogen from a subcutaneously implanted previously described in Tables I and II of the appendix pellet it is very likely that the level of concentration of the report by Rod6guez (i8), each animal in this of estrogen in the blood is maintained constant. The group having received 4 ~ to 5 ~ injections of i5o to height of this level will probably depend on the 300/,gin. of hormone in 95 to 123 days. As is shown quantity of estrogen absorbed in unit time; i.e., on in Table II, and Figs. 4 A, 4 B, and 4 C, considerable the surface area of the tablet or pellet, as indicated tmnorigcnesis was elicited with pellets when only by the studies of Lipschiitz and Vargas (15, i6). The 15 /,gm. of estradiol were absorbed daily in the course quantity sufficient to maintain the fibromatogenic of 8o days. threshold level of estrogens administered as pellets i.,

TABLE II: FIBROMATOGEN1C ACTION OF S~vlALL QUANTITIES OF F, STRADIOL OR ESTRONE ABSORBED ERO~\I SUBCUTANEOUSI.Y IMPLANTED TABLETS IN I8 CASTRATED FEJ~,IAI,E GUINEA PIGS Tumoral class Duration Quantity r /' of Weight absorbed Uterine experi- of Total subserous ])igestive Series XXVIII ment pellet Total Per day tumoral and para- Uterine tract and guinea pig No. in days rngm. mgm #gin. effect metrial apical parietal Splenic EstradioI 96 (Fig. 4, A-C) ...... 80 2.2 1.2 15 7[2.0 3 pm. 3 3 pr., ms. 3 97 ...... 80 3.3 1.2 15 5.0 o I 3 pr. 1 98 ...... 80 2. 4 1.4 18 o.o o o o o 102 ...... 80 3-4 2.2 28 3.0 2 ss. 0 0 I

95 ...... 8o 4.4 2.4 3 ~ 3.0 o 3 c, o Estrone 67 ...... 80 I. 9 0. 3 4 4 .0 o 3 0. 5 f., ms. 0. 5 f. 69 ...... 80 2.* o.3 4 o.5 o 0.5 f. o o 6o (Fig. 5) ...... 80 5.2 0.4 5 6.5 o 3 3 ms. 0.5 f. 24 ...... 80 3.3 I.i 14 4-5 i pm. 3 0. 5 f., ms. o 22 ...... 80 5.2 2.I 27 4.0 o 3 0.5 f., Ins. 0.5 s. 74 ...... 12o 2., o.2 1.7 2.o o o.5 f. o.5 f., ms. 1 86 ...... i2o 1.7 0.4 3.4 x.5 1 pro. 0. 5 f. o o 7 ~ (Fig. 6) ...... I2O 1.8 0. 5 4.2 3.o o 3 o o 71 ...... 12o 3.0 0. 5 4.2 2. 5 o 0. 5 f. o 2 85 ...... 120 1.7 0.6 5.6 3.0 I SS., pm. I o I 68 (Fig. 7, A and B) ..... 12o 1.9 0.9 7.5 4.0 2 ss., pm. I I int., ss. o 72 (Fig. 8) ...... 12o 2. 4 0.9 7"5 12.o 3 3 3 3 66 (Fig. 9, A-C) ...... 12o 3.8 1.3 lO.9 9.0 3 ss., pro. 3 I pr. 2 Abbreviations: f.=fibrous strands; s. tumoral seed; ss.=subserous tumors of uterus or intestine; pm.=parametrial tumors of uterus rns.-mesenteric tumors; int.--tumor on intestine.

With pellets of estrone, 5 to 7-5/~gm. per day were evidently much smaller than when these hormone: sufficient to produce large fibrous tumors in the course are administered by injection. of 8o to I2o days. The distribution and sizes of these These results provide new evidence that the estroger tumors are indicated in Figs. 5 to 9C. exerts fibromatogenic action when experimental con The comparative results obtained with implanted ditions provide for its continuous action on the effecto: pellets and with injections of oily solutions demonstrate tissues. Subcutaneous implantation of tablets or pellet: the fundamental importance of timing in tumorigenesis is the most effective method for obtaining this effect elicited by estrogens. Quantities as small as 15 t~gm. Lipschiitz and his associates (I7) have shown also of estradiol or 8 t*gm. of estrone, or less, absorbed that esterification, especially with caprylic acid in th. daily over a period of time, were equivalcnt in their 17- position, is another important means of securin~ fibromatogenic action to 4co ~gm. absorbed from an continuity of action. oily solution injected every second day. The following In contrast with the effects of 5 to 8/xgm. of estrone explanation is suggested: Estradiol and estrone when given by subcutaneous injections are rapidly absorbed absorbed from pellets, quantities of equilenin twio and partly inactivated in the liver. Hence injections or three times greater, administered in the same man every second day are not likely to maintain a stable ner, had no tumorigenic action or only an insignifican level of estrogen in the body. Accordingly, it has been effect (Table I).

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1942 American Association for Cancer Research. Fro. 4A.--Photograph showing multiple parametric tumors of both uterine horns, subserous uterine tumors of the left b.orn chiefly along the ventral muscular ridge, apical uterine tumors, large tumor at the hilum of the spleen, tumors oll the surface of the spleen, tumors of the epiploon. These developed in a castrated female guinea pig (Table II, No. 96) with a subcutaneously implanted pellet of 3.2 mgm. of estradiol. Absorption was at the rate of *5 #gm. daily, or 2.2 mgm. of estradiol in 8o days. Fro. 4B.--Photograph of the tumoral masses between the stomach and the spleen in the same animal as in Fig. 4A. FIr 4C.--Photograph of three turnors of the mesocolon and, at the left, a large tumor of the parietal serosa, inthe same animal as in Fig. 4 A. SU1VINIARY AND CONCLUSIONS The ovarian estrogens, estrone and estradiol, and the specific urinary estrogens, estriol and equilenin, were implanted subcutaneously, in the form of pellets, into castrated female guinea pigs. Observations were made upon the rates of absorption and the comparative effects of these estrogens upon uterine weights and their fibromatogenic activities. Specific urinary estrogens, such as estriol and equilenin, elicited abdominal serosal fibroids similar to those following subcutaneous implantation of pellets of estradiol and estrone. The fibromatogenic action of estriol was less than that of estradiol and estrone. The fibromatogenic action of equilenin was insignificant. The stronger action of estradiol and estrone as compared with that of the specific urinary estrogens was not due to absorption of larger quantities of the ovarian estrogens. On the contrary, estrone was absorbed more slowly and was more effective than twice FIG. 5.--Diagram showing tumors at the apices of the uterine horns and at other sites in the abdominal cavity in a castrated the quantities of absorbed estriol and equilenin. guinea pig (Table II, No. 60) treated by implantation of a pellet Estriol produced increase of uterine weight almost of 5.2 mgm. of estrone. Only o.4 lngm. was absorbed in 8o days, equal to that produced by estradiol and estrone; the or 5 /zgm. daily. 49

Fro. 6.--Photograph showing a large tumor at the apex of the left uterine horn in contact with the abdominal wall in a castrated guinea pig (Table II, No. 7 o) implanted subcutaneously with a pellet of 1.8 mgm. of estrone. Absorption was at the rate of 4.2/2gm. daily, or a total of o.5 mgm. in I2o days. Fro. 7A.--Photograph of several subserous uterine tumors, an apical tumor of the right uterine horn, and adhesions between the tumors and the omentum, in a castrated female guinea pig (Table II, No. 68) implanted with a pellet of 1.9 mgm. of estrone. Absorption was at the rate of 7-5 /zgm. daily, or a total of 0.9 mgm. in i2o days. Fro. 7B.--Photograph of a tumor of the mesocolon in contact with the serosa of the intestine, in the same animal as in Fig. 7A. FIG. 8.--Photograph of fibrous tumors in castrated female guinea pig (Table II, No. 72) implanted subcutaneously with a pellet of 2. 4 mgm. of estrone, showing tumors in the mesentery of the ileum and uterus embedded in large tumoral masses to which the colon is firmly adherent. Absorption was at the rate of 7.5 #gm. daily, or a total of o.9 mgm. in i2o days. Fro. 9A.---Photograph of the ventral surface of the uterus of a castrated female guinea pig (Table II, No. 66) implanted subcutaneously with a pellet of 3.8 mgm. of estrone, showing several subserous uterine tumors at typical locations. Absorption was at the rate of IZ ttgm. daily, or ~-3 mgm. in ~2o days. Fro. 9B.--Dorsal view of the uterus shown in Fig. 9 A, showing a chain of parametrial fibroids. Fro. 9C.--Tumor at the hilum of the spleen in the same animal as in Fig. 9A.

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1942 American Association for Cancer Research. Lipschiitz et al.--Fibromatogenic Action of Urinary Estrogens 5 ~ increase with equilenin was smaller. The differences lO. LIPS('IIUTZ, A., P. BELLOLIO, J. CHAUMrE, and L. VARGAS, JR. between the hysterotropic actions were less significant Comparative Conjunctive Tumorigenic Action of Three Different Estcrs of Estradiot. Proc. Soc. Exper. Biol. & than the differences between the fibromatogenic effects. Me(1., 46:164-i67 . 1941. When a steady flow of estrogen is established from a I 1. LIPSCHiJTZ, A., and R. IC~X.StAS. Multiples tumeurs ut&ines subcutaneously implanted pellet, abdominal fibroids et extrag4nitales provoqu6es par le benzoate d'oestradiol. can be elicited with about 5 /,gin. of cstrone absorbed Compt. rend. Soc. dc biol., I29:519-524 . I938. per day, as compared with 40o /,gm. injected thrice ~2. LiPsc~ii)'rz, A., R. IC.LESXAS, and L. VARC;AS JUN. Uterine and Extrauterine Localization of Experimental Fibroids wcekly in the course of 4 months. This difference is Induced in Guinea Pig by Prolongcd Administration of explained by the assumption that the tumorigenic Estrogcns. Proc. Soc. Exper. Biol. & Med., 45:788-792. faculty of estrogens is dependent upon a continuous 194o. action upon the effector tissues. 13. L1PSCII{]TZ, A., F. RODR~GUEZ, and L. VARGAS FILS. Dose Under the same experimental conditions which hystdrotrophe "utile" et dose "tumorig~ne" de l'ocstradiol et de l'oestrone libres. Compt. rend. Soc. de biol., I3o: provided for continuous action quantities of equilenin, 939-942 91939. two or three times as large as the effective amounts :14. LmSCHiSTZ, A., and L. VARCAS HLS. Etude quantitative de of estrone, had no fibromatogenic action or only an la tumorigent:se conjonctive clue 5 l'hormone folliculaire, insignificant effect. Compt. rend. Soc. de biol., I3I:27-3o. 1939. 15. Ln-scH0'rz, A., and L. VARGAS, Jv~,-. Experimental Tumori- REFERENCES genesis with Subcutaneous Tablets of Oestradiol. Lancet, I:t313q318. I939. I. DEANESLY, R. Depression of Hypophyseal Activity by the 16. LiPscHii'rz, A., and L. VAP,CaS, JUN. On the Comparative hnplantation of Tablets of Oestrone and Oestradiol. J. Rate of Absorption of Estradiol and its Estcrs from Sub- Endocrinol., I:36-48. 1939. cutancously Implanted Tablets in file Guinea Pig. In 2. DolsY, E. A. Biochemistry of the Estrogenic Compounds. press. Published in Sex and Internal Secretions. E. Allen et al., I7. LlpscH/5"rz, A., L. VARaAS, JR., H. BAZZA-RosALES, and H. 846-876. Baltimore, 1939. BAZzA-H.-;RRF.ma. Thc i7-Monocaprylic Ester of Estradiol 13. DORFMAN, R. I. Comparative Activity of Naturally Occur- --a Highly Active Tumorigenic Estrogen. Proc. Soc. ring Estrogens on the Infantile Rat Uterus and Vagina. Exper. Biol. & Med., 46:76-78. ~94I. Proc. Soc. Exper. Biol. & Med., 45:594-596. 194o. 18. L!PSCHiiTZ, A., L. VARGAS, JUN., A. JEI)I.ICK'i', and P. 4. EMMENS, C. W. Variables Affecting the Estimation of BEI.LOL10. The Minimum Quantity of Estrogen Required Androgenic and Oestrogenic Activity. Med. Research to Induce Atypical Epithelial Growth of the Uterine Council, London, Special Report Series No. 234, Reports Mucosa in the Guinea Pig. Am. J. Cancer, 39:185-198. on Biol. Standards, V:I-7I. 1939. ~94 o. 5- EVANS, J. S., R. F. and F. C. KocaI. The Mouse- VARNF.Y, T9. MARRIAN, G. g. The Chemistry of the Oestrogenic Hor-- Uterine Weight Method for the Assay of Estrogcns. moncs. Ergebn. d. Vitamin-u. Hormonforsch., 1:419-454. Endocrinology, 28:747-752. I941. I938. (i. IGLESIAS, R. Tumores experimentalcs utcrinos y extrageni- 20. P~Ncus, G., and M. GRAt:BAI~D. Estrogen Mctabolism in tales provocados por cl benzoato de estradiol. Public. Cancerous and Non-cancerous Women. Endocrinology, Med. Expcr. (Chile), I :i-32. ~938. 7. LACASSAGNE, A. Les rapports cntre les hormones sexuclles 26:427-432. I94 ~ . et la formation du cancer. Ergcbn. d. Vitamin-u. ttor- 2I. RonRiauez, F. Estudio experimental comparativo sobrc la dosis histerotr6fica 6til y la dosis tumorigena de las monforsch, :z:259-296. I939. 8. LIPSCHiJTZ, A. E1 complejo de las hormonas ovfiricas y hormonas foliculares libres (estradiol y estrona). Public. testiculares. Actualidad Mddica Peruana (Lima), 2:i6o- Med. Exper. (Chile), 8:1-32. I940. I75. 1936. 22. SZA~6, E. Accidn tumorlgena del estriol. Rev. chi!cna de 9- J~IPSCHiiTZ, A. Les grands probl~'mes de la tumorigen~se hig. y reed. prcv., 8:I27-I34. I94o. exp&imentale et les tumeurs conjonctives provoqu&s par 23. TI~I~AUT, R., La accidn tumorigena conjuntiva de las Otto, t'hormonc folliculaire. Livro de Homenagem Profcssores Para y Metahormonas foliculares. Public. Med. Exper. Ozorio de Almeida. Rio de Janeiro, 413-424 . I939. (Chile), 2:~-27. 1941.

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1942 American Association for Cancer Research. The Fibromatogenic Action of Specific Urinary Estrogens (Metahormones) in the Guinea Pig

Alexander Lipschütz, René Thibaut and Luis Vargas, Jr.

Cancer Res 1942;2:45-51.

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