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Studies on Squamous Metaplasia in Rat Bladder II . Effects of Estradiol and Estradiol Plus Hexestrol*T

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Studies on Squamous Metaplasia in Rat Bladder II . Effects of Estradiol and Estradiol Plus Hexestrol*T Studies on Squamous Metaplasia in Rat Bladder II . Effects of Estradiol and Estradiol plus Hexestrol*t A. ANGRIST, P. CAPURRO, AND B. MOUMGIS (Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, New York 61, N.Y.) SUMMARY The effects of estrogens were studied with and without foreign body (rough glass beads and paraffin pellets) on the metaplasia of the bladder of rats on stock main tenance diet and on a vitamin A-deficient diet. Estradiol increased the degree of metaplasia in the bladder of rats when combined with vitamin A deficiency and/or foreign body stimulation. Estradiol affected bladder epithelium already made squamous more effectively than it did the normal transitional uroepithelium. A high dose of hexestrol, when added to estradiol, showed no enhance ment of the degree of metaplasi.a by estradiol benzoate in the bladder of the rat. The combination of vitamin A deficiency, foreign body in situ, and estrogenadminis tration was an effective means of obtaining keratinizing squamous metaplasia in the urinary bladder for studies of its developmental and reversal changes. In a previous presentation (4) the relation of The animals were divided into the following different forms of foreign-body irritation and of groups (the number of rats surviving with tissue vitamin A deficiency to squamous metaplasia in for study and the total number in each group mi the bladders of rats was reported. It is also known tinily are given following each group): that estrogens will cause squamous metaplasia. I. Stock diet + estradiol (6 survivals/lI rats) The metaplasia following estrogen administration II. Stock diet, estradiol + hexestrol (4/9) has been described in various organs of the genito Ill. Stock diet, rough glass bead + estradiol urinary system in different species (SO). It has (@/4) been found in the uterus (@,17, 19), and the mets IV. Stock diet, paraffin pellet + estradiol (8/7) plastic effect of estrogens in the male has also been V. Stock diet, paraffin pellet, estradiol + described for the prostate (14). hexestrol (6/16) In this paper we are concerned with the effects VI. Vitamin A-deficient diet + estradiol of estradiol and the combination of estradiol and (11/15) the synthetic estrogen hexestrol with vitamin A VII. Vitamin A-deficient diet, estradiol + deficiency and irritative. foreign body stimulation hexestrol (18/@5) on metaplasia in the bladder. VIII. Vitamin A-deficient diet, rough glass bead + estradiol (13/19) MATERIALS AND METHODS IX. Vitamin A-deficient diet, rough glass Young rats of the Sprague-Dawley strain were bead, estradiol + hexestrol (10/17) used. Some of the rats were feJ regular stock x. Vitamin A-deficient diet, paraffin pellet + Rockland rat diet (complete) and the others were estradiol (4/8) fed a vitamin A-deficient diet and given a small XI. Vitamin A-deficient diet, paraffin pellet, vitamin A supplement to prevent early mortality estradiol + hexestrol (6/16) (4). The same procedure described earlier for in Injections of estrogenic agents were begun 1—@ sertion of foreign bodies in the bladder was used. weeks after the implantation of foreign bodies, * Presented before the 50th Annual Meeting of the Amen unless otherwise noted, in Groups Ill, IV, V. VIII, can Association for Cancer Research in Atlantic City, April IX, X, and XI. In groups without foreign bodies 19-12, 1959. (I, II, VI, and VII), the estrogen treatment was t This work has beensupportedby GrantNo. RG-4572 begun 8—4weeks after Groups VI and VII devel (C1-C2) from the U.S. Public Health Service. oped vitamin A deficiency. The dose in oil of es Received for publication December 7, 1959. tradiol benzoate (Progynon benzoate, Schering 568 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1960 American Association for Cancer Research. ANGRIST et ai.—Squamous Metaplasia in Rat Bladder 569 Corp.) was 0.05 mg. 3 times a week. The dose of 36 weeks on estradiol, and one after 38 weeks. The meso-3,4-di-(p-hydroxyphenyl)-in hexane (Hexes bladders of the males showed @+changes. A single trol, Wm. S. Merrell Co.) was 0.5 mg. S times a surviving female showed a 4+ change after 36 week. Injections were continued until sacrifice or weeks of estradiol. All showed prominent hyper death of the animals (see Charts 1 and @).The plasia of the epithelium, one with active mitosis. bladders were fixed in neutral calcium formol and In Group V, three males and three females were stained with hematoxylin and eosin, periodic acid examined between @5and 39 weeks after implan Schiff (PAS), and Alcian Blue (4). tation of the paraffin pellet and @3—37weeks of The changes in the bladders have been classified estrogen plus hexestrol administration. Three (two as before (4) : 1+, having loss of the PAS-positive males and one female) of the six showed only 1+ material in the superficial layer; @+, featuring modification of the bladder mucosa after such pro parakeratosis; 3+, showing mild epidermidaliza longed treatment with the combined estrogens, tion with no granular layer; and 4+, showing and three rats showed some minimal metaplastic marked whitish thickening, often with opaque alteration but less than 1+ change. Four of six keratinized papillary projections and the keratin showed epithelial hyperplasia, with one male layer with stratum granulosum histologically. showing some papillary hyperplastic mucosa. In Group VI there were five males and six RESULTS females on vitamin A-deficient diet plus estradiol. The mucosal changes are tabulated, with the groups subdivided by time periods of up to 7 REG. DIET weeks, 8—@0weeks, and @0—40+weeks after the GRAMS ESTRADIOL 450 + HEXESTROL beginning of estrogen treatment, in Table 1. 400 dl A high early mortality prevailed in Groups I 350 II, Ill, IV, V, X, and XI. In Group I, on estradiol vii: A DEF. 300 only, three animals were examined after 10 days, 4―EST. + HEXESt. 250 200 REG. DIET GRAMS REG DICT ESTRADIOL 150 400 1@ESTROGEN + HEXESTROL 350 I 00 300 V1TADEE REG.DIET 50 250 @FESTROGEN +EST. ,@:1II@ 0 IIII IIII 200 ?VIT.A DEE I 2 3 4 5 6 7 8 150 + ESTROGEN MONTHS 100 CHART 2.—Weight gain of animals on stock (reg.) and vita 50 mm-deficient diet with estradiol and hexestrol. 0 IIII 1 2 3 4 5 6 7 8 MONTHS Two females showed 3—4+ change after 10 weeks CHART 1.—Weight gain of animals on stock (reg.) and vita of vitamin deficiency and 1@and @4weeks of es mm-deficient diet with estradiol. tradiol (Fig. 5), respectively. Another female showed @+to 3+ change after 1@weeks of vita three after 9 months. No significant metaplasia mm deficiency and 8 weeks of estradiol (Fig. 1). was found, though one female showed hyperplastic A fourth female showed @+change after 16 weeks thickening of the mucosa and another female had of vitamin depletion and 1@weeks of estradiol. The some focal hyperplasia of the deeper layers of the remaining two females showed a 1+ grade of epithelium. metaplasia after 17@ weeks. Three male rats on In Group II, given estradiol and hexestrol in estradiol for 1@weeks, 3 weeks, and 5@weeks, re combination, four animals were examined after spectively, showed a 1 + change. One of the two @ @7—37weeks.The bladders showed no metaplastic remaining male rats received estradiol for weeks epithelial changes; one male showed some focal and showed minimal, i.e., less than 1+, change, hyperplasia. and the other showed @+to 8+ change after only In Group III, only two bladders were obtained 1@weeks of estradiol. for examination, both at 7 weeks after the glass In Group VII there were eight males and five @ bead was implanted but only weeks after estro females, vitamin-deficient, treated with both es gen administration began. Both showed no mets tradiol and hexestrol. Only one of four males on plastic alterations and only minimal focal epi the vitamin-deficient diet for 11 weeks, and 6 thelial hyperplasia. weeks of administration of estradiol and hexestrol, In Group IV, two animals were examined after showed a @+ change, three showing minimal Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1960 American Association for Cancer Research. @ c@ @@4@f .@ :@c@ .@ .@ @— FO 0 O@ .@.@:@+ .@+ -@ z (.5 @ 2 2 @. @ u 0 @ V 4? @ c@cJ@C C @.E.E z lIE @I cI@ z @ :: @ *@ .;Z -l-+++ ++++ @@@@ ©@@4r:@@ .:.: - 0 .@ +z @5 @ut-@@ * Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1960 American Association for Cancer Research. ANGRIST et al.—Squamous Metaplasia in Rat Bladder 571 changes (0—1+) (Fig. 6). One female, with 11 weeks. All six rats showed marked 4+ changes, weeks of both estrogens, showed a 8 + to 4+ alter one female as early as 7@weeks after administra ation in the bladder; another female showed a 3+ tion of the drugs, and the remaining female and @ change after weeks of such administration. two males after 16 weeks (Fig. 10). Maximal Both showed calculi in the bladder. Two males changes were present in all with invagination of showed 1+ change after 9 weeks and 15@ weeks epithelium and epidermoid cyst formation in two of combined estrogen, and two females showed females and one male. In this series a high mor this degree of change after 8@ and 11 weeks. The tality prevailed early. remainder of the group (two males and one fe A separate group of rats was studied with vita male) showed very minimal changes after periods mm A deficiency, with paraffin pellets in situ in of both estrogens varying from 9 to 17 weeks. the bladder, and with subcutaneous diethylstil Keratinization was found in the rats with calculi besterol pellets of 0.5 mg.
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