Ex Parte Chatlapalli et alDownload PDFPatent Trial and Appeal BoardJan 22, 201311478400 (P.T.A.B. Jan. 22, 2013) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte RAMARAO S. CHATLAPALLI, ARWINDER S. NAGI, and LAWRENCE VAN PELT __________ Appeal 2011-004447 Application 11/478,400 Technology Center 1600 __________ Before ERIC GRIMES, FRANCISCO C. PRATS, and SHERIDAN K. SNEDDEN, Administrative Patent Judges. SNEDDEN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to pharmaceutical compositions. The Examiner has rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Appeal 2011-004447 Application 11/478,400 2 STATEMENT OF THE CASE Claims 1-50, 64, 73 and 74 are on appeal. Claim 1 is representative and reads as follows: 1. A pharmaceutical composition comprising a core and at least one coating; wherein the core comprises conjugated estrogens; and the coating comprises bazedoxifene, or a pharmaceutically acceptable salt thereof. The sole rejection before us for review is the Examiner’s rejection of claims 1-50, 64 and 73-74 under 35 U.S.C. § 103(a) as being unpatentable over Komm #1,1 Komm #2,2 Barcomb,3 and Miller.4 I. Issue The Examiner finds that bazedoxifene and medroxyprogesterone acetate (MPA) are functional equivalents as both compounds are known to antagonize the unwanted effects caused by the administration of estrogen, that is, the stimulation of uterus cell proliferation (Ans. 10). Specifically, the Examiner finds that Komm #1 discloses that “[bazedoxifene] was effective in counteracting the negative effects of the administration of [conjugated estrogens (Premarin®)] to the uterus” (Ans. 9). The Examiner finds that Miller discloses that “the hyperplastic (i.e. cell proliferation) action of estrogen on uterine tissue can be successfully opposed by the 1 Komm et. al., American Society for Bone and Mineral Research (2003) Abstract SU385. 2 Komm et al., US 2004/0063692 A1, published Apr. 1, 2004. 3 Barcomb, US 5,547,948, issued Aug. 20, 1996. 4 Miller et al., “Design, Synthesis, and Preclinical Characterization of Novel Highly Selective Indole Estrogens,” 44 J. MED. CHEM. 1654-1657 (2001). Appeal 2011-004447 Application 11/478,400 3 coadministration of progestin” (Ans. 10, citing Miller at p. 1654, left col.), and that Barcomb discloses “a compressed tablet, wherein the tablet core contains a unit does [sic] of Premarin and a coating of medroxyprogesterone acetate (MPA, a known progestin)” (Ans. 5). In reaching a conclusion of obviousness, the Examiner finds that it would have been prima facie obvious for a person of ordinary skill in the art to make a tablet formulation of the mixture taught by [Komm #1] (bazedoxifene and Premarin) since [Komm #2] and Barcomb already teach tablet formulations of bazedoxifene and Premarin respectively, and further Barcomb teaches a core with Premarin and a coating with MPA, and replace one functional equivalence (MPA) with another (bazedoxifene), since both: bazedoxifene and MPA are known to counteract the side effects of estrogens (like Premarin) against breast and uterine tissues, thus resulting in the practice of claims 1-3 with a reasonable expectation of success. (Ans. 5.) Appellants contend that “there is no suggestion in [Barcomb] that MPA is interchangeable, equivalent or could be substituted by bazedoxifene to achieve Appellants’ claimed composition” and thus, “based on the facts, that Office is incorrect in its reliance on the limited teaching of the Barcomb” (App. Br. 11). Appellants further contend that “[a]ny reading of the reference cited would not lead a person of ordinary skill in the art to substitute MPA for bazedoxifene” because the cited art “does not disclose or suggest that MPA is interchangeable, equivalent or could be substituted by bazedoxifene” (id. at 13.) Appeal 2011-004447 Application 11/478,400 4 The issue presented is: Does the evidence of record support the Examiner’s conclusion that the cited prior art renders claim 1 obvious? Findings of Fact The following findings of fact (“FF”) are supported by a preponderance of the evidence of record. FF1. Komm #1 discloses a combination of bazedoxifene acetate and Premarin® (conjugated estrogens) for the treatment and prevention of osteoporosis in order to provide “a balanced, acceptable ‘estogenic’ profile” (See Komm #1, Abst.). FF2. Komm #1 discloses that “CE [conjugated estrogens] was combined with BZA [bazedoxifene] to determine the efficacy of BZA to antagonize the CE stimulation of the uterus” (id.). Komm #1 discloses that the uteri from animals co-dosed with bazedoxifene and conjugated estrogens “were not different from . . . untreated controls” (id.). FF3. Miller discloses that the “hyperplastic action of estrogen on uterine tissue can be successfully opposed by the coadministration of a progestin” (Miller p. 1654, left col.). FF4. Barcomb teaches the controlled release of a hormonal steroid from the sugar coating of a tablet (Barcomb col. 1, l. 66, to col. 2, l. 35) and that “[e]xamples of hormonal steroids suitable for incorporation into the sugar coating formulations of this invention include, medroxyprogesterone acetate” (Barcomb, col. 2, ll. 38-40). FF5. Barcomb teaches a formulation of Premarin® (a naturally occurring conjugated estrogen) in a compressed tablet, where the tablet core Appeal 2011-004447 Application 11/478,400 5 contains a unit dose of Premarin®, and where the tablet has a sugar coat containing medroxyprogesterone acetate (MPA). (Barcomb col. 6, ll. 17- 29.) FF6. Kumasaka5 teaches that MPA is a progestin that provides “slight[] endometrial protection against the hyperplastic response” of the estrogen-primed, ovariectomized rat. (Kumasaka, Abst.) Principles of Law Substituting one art recognized equivalent for another is obvious. See KSR Int’l Co. v. Teleflex lnc, 550 U.S. 398, 416 (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results”); In re Fout, 675 F.2d 297, 301 (CCPA 1982). Analysis MPA was a known progestin at the time of filing of this application (FF6). The preponderance of evidence on this record supports the Examiner’s conclusion that bazedoxifene and progestins (such as MPA) are art recognized functional equivalents as both were known to oppose the stimulation of the uterus caused by the administration of estrogens (FF2 and FF3). This, in our view, presents strong evidence of obviousness in substituting MPA in the tablet disclosed by Barcomb with bazedoxifene to achieve the composition of claim 1. We are not persuaded by Appellants’ arguments to the contrary. 5 Kumasaka et al., “Effects of Various Forms of Progestin on the the Estrogen-Primed, Ovariectomized Rat,” 41 Endocrine J. 161-169 (1994). Appeal 2011-004447 Application 11/478,400 6 Although we agree that the prior art cited by the Examiner supports a prima facie case of obviousness, our reasoning further relies on Kumasaka to establish the fact that MPA is a progestin. For this reason we designate our decision a new ground of rejection to provide Appellants a full and fair opportunity to address this new evidence. Conclusion of Law The preponderance of the evidence of record supports the Examiner’s conclusion that the cited prior art renders claim 1 obvious. Claims 2-50, 64, 73 and 74 fall with claim 1. 37 C.F.R. § 41.37(c)(1)(vii). SUMMARY We affirm the rejection of claims 1- 50, 64 and 73-74 under 35 U.S.C. § 103(a) as being unpatentable over Komm #1, Komm #2, Barcomb, and Miller. As our analysis varies from that of the Examiner, we designate our decision in this appeal a new ground of rejection. TIME PERIOD FOR RESPONSE This decision contains a new ground of rejection pursuant to 37 C.F.R. § 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960 (August 12, 2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)). 37 C.F.R. § 41.50(b) provides “[a] new ground of rejection pursuant to this paragraph shall not be considered final for judicial review.” 37 C.F.R. § 41.50(b) also provides that Appellant, WITHIN TWO MONTHS FROM THE DATE OF THE DECISION, must exercise one of the following two options with respect to the new ground of rejection to avoid termination of the appeal as to the rejected claims: Appeal 2011-004447 Application 11/478,400 7 (1) Reopen prosecution. Submit an appropriate amendment of the claims so rejected or new evidence relating to the claims so rejected, or both, and have the matter reconsidered by the Examiner, in which event the proceeding will be remanded to the Examiner. . . . (2) Request rehearing. Request that the proceeding be reheard under § 41.52 by the Board upon the same record. AFFIRMED, 37 C.F.R § 41.50(b) lp Notice of References Cited Application/Control No. 11/478,400 Applicant(s)/Patent Under Reexamination CHATLAPALLI ET AL. Examiner MARCOS SZNAIDMAN Art Unit 1628 Page 1 of 1 U.S. PATENT DOCUMENTS * Document Number Country Code-Number-Kind Code Date MM-YYYY Name Classification A US- B US- C US- D US- E US- F US- G US- H US- I US- J US- K US- L US- M US- FOREIGN PATENT DOCUMENTS * Document Number Country Code-Number-Kind Code Date MM-YYYY Country Name Classification N O P Q R S T NON-PATENT DOCUMENTS * Include as applicable: Author, Title Date, Publisher, Edition or Volume, Pertinent Pages) U Kumasaka et al., “Effects of Various Forms of Progestin on the the Estrogen-Primed, Ovariectomized Rat,” 41 Endocrine J. 161- 169 (1994). V W X *A copy of this reference is not being furnished with this Office action. (See MPEP § 707.05(a).) Dates in MM-YYYY format are publication dates. Classifications may be US or foreign. U.S. Patent and Trademark Office PTO-892 (Rev. 01-2001) Notice of References Cited Part of Paper No. 20130122 i"tld" ,illt' Jnurl/{d 1994, 41 (2). 161 - 169 Effects of Various Forms of Progestin on the Endometrium of the Estrogen-Primed, Ovariectomized Rat I \~, 111.1<'1 I I i\1 \ ."1:\ 1" ,\ , Em.1I1 ITOII. HIU"-KI WATANABE, I "I--' /I()"i I! !I\O, .\ld'V\ YOSHI ' AKA A 0 OBUlllOE MASAWA * /1,, ' II, ,III' /11/1 ' /1' " / (1",/1'/ "n II 1I r1 (;Vllrt ology and •Il,( !"nl f )"/h1 1i 11/111/ of f'II/JIII /llb,),. /lokk)1I fini lll' lI/ly . T/lcltigi 321-f)2, jajlUlI Abstract. Progestin supplementation has been advocated in estrogen treatment for postmenopausal women 10 avoid proliferation of the endometrjum. In this study we investigated the morphologic and I iPC'hcmical dfecls o ( progeslins on the endometrium of cstrogen primed, ovariectomized rats. A: thc prngl..'Stin derivatives, AJlylestcnol (AE), Norethisterone (NE), Danazol (OZ), Dydrogesterone (DG), Medrl)xyprogesterone acetate (MPA) and Cyproterone acetate (CPA), and as a anti-estrogen com pound, Tamoxifen (TMX), were applied. To evaluate the effects of these differenl compounds on the l'ndolO('trium, histol gic studies and measurement of estrogen receptor concentrations were performed. When 19-nortestosterone groups, AE, DZ and NE, were orally administered to the conjugated uine L's!nlgen (CE) trea ted, ovariectomized rats, the histologic pallern of the endometTium revealed rather a m rkL'd inhibitiun uf hyperplasia induced by CE than a progestational response. Two of 3 of 17a hyJrll)(ypmgc,teronc groups, DG and MPA, provided slightly endometrial protection against the hyperplastic response, but another one, CPA, did not have any inhibitory effect on the estrogenic stimu I•• \tnn of the endometrium. TMX was not capable of suppressing the endometrial hyperplasia caused by (I'" 'ldminislra tion. I he av filgC plasma concentration of estradiol (E2) were 82.0 ± 27.0 pg/ml (Mean±SD) after CE o1dmin istTa tion and there were no significant differences among these groups. Estrogen receptor con '"l'ntr.JtiClns of endometrium of progestins or antiestrogen added groups were not changed, when com p,l rL-d wi th the CE alone group. There was also no relationship between the estrogen receptor concen tra tions .lnd the histologic findings in the endometrium. This discrepancy may be chiefly due to the low dOSL 01 the progestins as compared with the CE dose. In view of the morphOlogic findings for the mJomctrium, this study suggests that opposed estrogen treatment with 19-nortestosterone derivatives pm.. ides the most satisfactory endometrial protection against hyperplasia. t-l'1l ,{·ords: Opposed estrogen treatment, ProgesHn. (Endocrille }ournaI41: 161- 169, 1994) IT IS WELL KNOWN that posbnenopausaJ estro ).;,·n rt::pli1cement therapy alleviates climacteric !il 'mpt ms. Ilowcver, unopposed estrogen treat m nt Increases the ri k of endometrial cancer. '-rJllCl' progestm has been shown to prevent the de VI lopment of endometrial hyperplasia and cancer, /{\;(l'IVW : Apri l 7, 1993 ".tTI 'doDec 'mber 17, 1993 (('lTcspI1ndence 10: Dr. Takahiro KUMASAKA, Depart ment 01 Ob-;tct rics and Gynecology, Dokkyo University, r f.hu T,1 higi 321-02, Jllp.ln combined estrogen and progestin therapy is widely used for posbnenopausaJ complaints. De pending on the various forms of their derivatives, progestins have androgenic and/or antiestrogenic effects . The only common effect ascribed to all progestins is the ability to ind uce the secrelory phase in the estrogen-primed endometrium. How ever, the effect of progestins on the endometrium may be related to the qualitative difference in the metabolism of the progestin . This study is de signed to evaluate the potential progestagenic and 1hZ KUMASAKA el al. anti-est rogenic effects of some progestins on estro gen primed, ovariectomized rat endometrium. Materials and Methods As progestin of 19-nor-testosterone derivatives, Allylestenol (A E: Nihon Organon Tokyo), Norethisterone (N E: Shionogi Pharmac. Co. Osaka) ,mtl Danazol (OZ: Tokyo Tanabe Pharmac. Co. To "-yo,; as 17o.-hydroxyprogesterone derivatives, Dvdrogesterone (OC: Oaiichi-Seiyaku Co. Tokyo), Medroxyp roges tero ne ace tate (MPA : Nihon UpJLlhn Limit. Tokyo) and Cyproterone acetate (CrA : Nihon 5chering Co. Osaka); and as an anti l'strogen ic derivat ive, Ta moxifen (TMX: I.C.I . rharmac Co. Osaka) were all examined for their ",He. ts on ovariectomized and conjugated equine l";lrogen (CE: Nihon Wyeth Co. Tokyo) treated rat enuometri um, and estrogen receptor concentra lIons in the endometrium were measured. As the sll.'roid so lvent, Tween-SO (TW-80: Wako Pure Chemical Ind ustries Ltd, Tokyo) was used. Four weeks after the ovariectomies, the rats were ran domly div ided inlo 7 groups, each group being composed of fi ve rats. CE was dissolved at a ratio ot 50 ,ug/O.5 ml in distilled water. Progestins and ethil1yl estrad iol (EE: Wako Pure Chemical Indus tries Ltd Tokyo) were dissolved at a ratio of 2.0 pg/05 ml in TW-BO. As control groups, one group was given 50 JIg/day of CE orally for 4 weeks, and IJw other 2.0 JIg/day of EE in a similar way. As treated groups, the rats were to be given 50 JIg/ E Group OVI( rats 1 ,--- ~ day of CE for 2 weeks and 2.0 JIg/day of progestin or TMX with 50 JIg/ day of CE for 2 consecutive weeks (Fig. 1). The rats were sacrificed with an overdose of ether and a histological examination of the en dometrium was performed. Estradiol receptor con centrations in the endometTium were measured by radioligand assay. The method for histological investigation: AU the uteri of the rats in this study were fixed in 10% formalin immediately after resection. After suffi cient fixation, six or seven tissue blocks for histo logical sections were obtained from each uterus (including the contTol cases), embedded in paraf fin, and the sections were stained with hematoxy lin eosin. The method of estTogen receptor assay of the en dometrium: The concentrations of cytosol estrogen receptors in the endometrium of the rats were measured by radioligand assay with Dextran coated charcol [1]. The flowchart of estrogen recep tor analysis of the cytosolic estrogen receptor assay is shown in Fig. 2. The minimal amount of tissue required for the measurement of cytosoJic receptor was 20 mg. The minimum detectable dose was 8 fmol/mg protein. A five-point Scatchard assay was performed with a concentration range for the ra diolabelled estradiol (specific activity: 93 Ci! mrnoI) of 0.05 to 2 mmol!L. A 250 fold molar ex cess of unlabeled diethylstilbestrol was used in a parallel series of tubes to distinguish specific from total binding. The maximum binding concentration was ob sacrificed and examined orally ~ -fCDf-----, I o I 4w I 6W I Bw study week E/P Group E : conjugated equine estrogen P : Progestlns aliI( rllts orally V ,rrr-,r®--l 1 I I o 4w 6W 8w Fig. 1. Methods of CE and progestins treatment in ovariectomized rat. 163 EFFECTS OF PROCESTrNS ON ESTROGENIC CHANGES IN EM Tissue-we,ght Minced In TEO Buller •• Homogenized " Cenlrlfuged at 50.000G lor 60 min. " Supematant (cytosol) • Moasurement of prolein cOr>C8ntrut.ons (tho method of lowry)" IRadlol8bei receptor ..,.say I Cytosol 250 ~ I (2mglml) 'H-e/--! !_'H-e,+OES... 4'c Incubated overnight !_DCC .... 500~ 1 4'<: Shaken lor 30 min 4'C Cenlfl tuged (3OOOfpm) for 15 min. " Counted•(supernatant) Scatchard plot • F' r,. ::!. nlL' flm'ol(11.1rt (l( cyto~olic estrogen receptor assay. " TED buff,' r: (10 mrnol Tris-Hel, pH 7.4. 1.5 mmol I-DTA, 1.0 mmol Dilhiothreitol); " , 3H-estradiol: (93 Ci/mnwl NEN); •••• DES: Diethylstilbestrol; ••••• [X.L: Tris, Nurit A. Dextran T. 70. lalned by Scatchvious data are summarized in Table 1. a lone treated group, the OZ, AE, MPA and TMX l ~,to~oli(' estrogen receptor: groups had no significant change in concentra Fil"urt' 9 how the effect of progestin on estro- tions . . ]I I I II , oil ~~ .. I Fig. 8. Ovariectomized Tilt endometrium after CE and TMX treatment (staining and magnification are the same as Fig. 4). There is moderate proliferation of glands consisting f large and high c lumnar epithe.lium. r.l<'1 ~ 1. HI~tllt"Rical fi ndings of ovariectomized rat endometrium after CE and progeshns or an anhestrogen administration 19·NortcstostcTone 17a ·Hydroxyprogesterone AE+CE NE+CE DZ+CE DG+ E MPA+CE CPA+CE TMX+CE CE EE ",". J, . n'II""'("I.lsia / ± +-++ + + ++ + -+ I- +-+ rr. ,h tl' r.lt Ilm ! ,J"/lil lVl rrl.l<, f a ross-reaction between progester (lilt' Inti lW-80 in our ratlioimmunoassay system, th ml:JSlIrcmenl of plasma progesterone concen TW- 80 CE 00 AE • .. C£ CE P < O 0 5 E,-R Imol/ my 'P...::O .0 1 200 100 tralions was impossible. Discussion There are many reports which indicate an in crease in the incidence of hyperrlasia and endome trial carcinoma in women trea ted with a relatively large dose of conjugated equ ine estrogens. Gelfand et al. [2) reported that endometrial hyperp lasia was I'4 E Pl MPA TMl(.. ..• + CE CE CE CE Effecl of p rogestins o n es tradio l receptor concentrations of Ilvaril..'Ctomi 7:cd rat endometrium (N: 5 in each group). TW-80, Tween-80; CE, Conjugatt'd equine es trogen; DG, Dydrogeslerone; AE, Allylestrenol; NE. No re thi s te rone; OZ, Danazol; MPA, Medroxyprogesterone acetale; TMX, Tamoxifen. ESlJadiDi pg/ml CE : Conjugated equine ".II'OII"n AE : AlIvl ••tr.nol NE : NOfethlate,one 02 : O.n...ol MPA : Medroxyptog••terone eeet"te 1000 DO : Ovdrog ••t"rono CPA : Cyproterone aeetate TMX : T omoxifon • : ConlJol (undeteet"blo) ** :The mean valu. 500 Fig. 10. Plasma L'Slradiol concentrations in estrogens and progeslins treated ovariectomized filt (N: 5 in ('ilch group). \1 'I KUMASAKA rt at. \ \HlsiJ ·rably more frequent in patients who re L IVt'd cr or a placebo than in their counterparts tr._-al d ~ IIIl progesbn. This prompted the addition 01 thl' ('~Irog~n-antagonist progest in to the estro t, 'II wpli'lC"t'ment n'glmen 10 reduc the incidence I I l>dll h\ pLrF idsia and carcinoma of the en dllmelTillrn Although considerable information on progesti n h.15 been obtained, investigations are still "ping InrlU(' to seie t the optimal dose of appropri .1k progcstin ior a treatment regimen. Some "Ioglc"<;!ins h.w!:" estrogenic properties, and these propl'rtiC!:; c"nn t be properly evaluated by using hnrmol1~ responsive systems when the chosen ('I\UPOHlls 1ft' alsl,) sens itive to progestagenic activ II' . M.uklt'wi 'Z 1'111 1. (31. using his newly developed j,l '111,-" In '!hod, ft>porteJ that progesterone, MPA ,lIll 1)7 \ 'strogen because of its frequent use In cli nical treatment. Progestins which are usually adm inistered o ra lly are divided into 19 tlortestusterune and 17a-hydroxyprogesterone de ri.ltiv(;'5 ,lI'curding to their molecular structure. 'tllS study has sho wn that CE given without pr ~e-.tin is il very potent stimulator of rat 'II,JUJllt'loriuOt, , I!.> in humans. The regimen of 50 u):., doly (If t l-- for -t weeks was associated with I vrLl pl,lsiil 10 100% of the rat endometorium. .\Ithough it is uJlclear whether the concept and klluinolugy regarding the morphologic spectrum ,I 1,1t ~lId mnl.'lrial hyperplasia is the same as hu 1I1<1n ,·nd..mlClrium, it has been shown that CE or I-f. .',IVUl withuut prog~tin is a very potent stimu I.lh'r "f ellliom ·trium. None of the rats which re It'IVet.1 IY-nortestosterone derivatives (AE, NE, DZ) had hyperplasia, thi kness of stroma or prolifera tion ot v('s els . n the other hand the prevention of ,~ndl)metr i a l hyperplasia, angioectasia and thick "It <;<; Ilf s troma seems to be weak when 170. 11\'tlrnxyprogesterone derivatives (DG, MPA, CPA) Jrc u!ied. Both DC and CPA were found to cause enJom trial hyper trophy of both glands and "hllm.t. Inlerest ingly, the endometrium specimen of the CPA treated group showed more angioectasia, hyperplasia and thickened stroma than the other progestin treated groups. Because such findings were not reported in humans, this difference may therefore be attributable to the spe cies. Out of the progestin group in tbe 170. hydroxyprogesterone derivatives, MPA had a rather preventive effect on angioectasia, hyper plasia and thickness of stroma. Our observaLions were in agreement with those of previou - studies [2, 4, 5J, in which MPA was introd uced to prevent the development of hyperplasia caused by estro gen LTeatment. Brooks et aI, [6] reported that MFA and NE were the least successful in suppressing stroma thickness, proliferation of glands and vas cular dilatation, DZ worked better than th se progestins in perimenopausal bleeding women. This suggests that the characterislic prevention of endometrial hyperplasia is related to the original molecular s tructure of the progestin derivatives. As a nonsteroidal antiestrogen, TMX is well known, and is used for pre- and postmenopausal patients with breast cancer. Gal el aI, (7) reported that endometrial hyperplastic changes were found in 27% of patients who had received TMX therapy following a prospective study. In our study also, in the TMX group an estrogenic effect on rat en domeLTium failed to be prevented after CE treat ment. These results indicate that TMX has a hyperplastic effect or non anti-estrogeniC effect on the endometrium. In this study, we failed to dem onstrate a reduction in estrogen receptor in any progestin or anti-estrogen groups, Although tbe reason for this discrepancy is unclear, !toh III and Janne et al. [9} reported that there was no correla tion between serum estradiol/progesterone, LH and FSH levels and the endometrial estrogen/pro gesterone receptor concentrations in peri-meno pausal women. Gibbons et al. [8] and Ja'nne et al. [9] showed that MPA, regardless of the dosage, was successful in reducing estradiol receptor concen trations to pretreatment levels, when only a low dose of CE was used. [n this study, the regimen was performed as a single dose study. [t may be considered that there was a dose imbalance be tween estrogen and progesterone which was nec essary to reduce the endometrial estrogen receptor. This means that a higher dose of progestin could suppress the estrogen receptor to a low level. To summarize, although most progestins provided 169 EFFECl'S F PROGESTINS ON ESTROGENIC CHANGES IN EM l'ndnm 'trial protI'Cl ion against hyperplasia, the 19- trogen treatment. CPA and TMX do not seem to be n rtt'"luo;lerone group most sa ti sfactori ly pre useful for the prevention of endometr ial , 'ntl' I I II-' endom trial hyperplasia caused by es- hyperplasia. References 11,11 r: «(r in human endometrium 111..1 l'lldon1etri ,ll C,lrnnoma . J Jpll Soc Callcer TllI'r "'t;. f :.'.-82n (In l"ranf.'Sd, t;l'lf,md M, rl'r 'm:zy A (1989) Prospective 1-ycar ~tuJ} " ' l,.,lwg ...n and prog(:snn in postmenopausal v, om« n: Ei(pcto:; On th e endnmetrium. Obstet ';VIIl'Ul. 74 3Y8-102. !\t.lrhItWIl:·Z L, Hochberg RB, Gurpid E (1992) In tnn", : e:;trogl'nicity ()f '\Orne progestagenic drugs. J "t/nit! I1i(l, ·/u.'/1/ Mo l 8io/ 41: 53-58. oj I 'wn.:7.Y A, Gelfand M (1989) The biologic signi fi I,WH' nf \.:;tologi.: illypm in progestogcn-trea teJ ; r.dllml·lriJl h pcrplasia . Am J O&Stel Gynecol 160: 12(,.. 111 I IIId.:l i I , '\I m p, Fem(; M, Norgren A (1990) En d"n1l,tTlrll hyperpl"sia: A prospective randomized toJ, .. I hi~t\llngy, tl.%UI.' s teroid recep tors and pl.hrTI,' ~IPr"iJ~ LIfter "bra:.io, with or without high I"" . ht." tilgl'n h·(:,llmenl. I1I1/icIlI/af Rrscllrclr 10: n~ ?3tJ 6. Brooks P, Serden sr, Davos I (1991) Hormonal in hibition of the endometrium for resectoscopic en dometri1l1 ablalion. Am / Obstet Gynecoll64: 1601 1608. 7. Gal D, Kopel S, Bashevkin M, Lebowicz ), Lev R, Tancer ML (1 991 ) Oncogenic potential of tamoxifen on endometrial of postmenopausal women with breast cancer-preli minary report. Gy/lecol Oneal 42 : 120-125. 8. Gibbons WE, Moyer LO, Lobo RA, Roy S, Mich~l DR (1986) Biochemical and his tologic effects of se quen tia l c. trogen/ progestoge n therapy on en dometriu m of postmenopausal WOmen. Am JObslel Gyneco/l54:456--461 . 9. Jiinne 0 , Kauppila A, Kontula K, Sy~ala P, Vihko R (1979) Female sex steroid receptors in normal, hyperplastic and carcinomatous endometrium. The relationship to serum steroid hormones and gona dotropins and changes during medroxyprogester one acetate administration. 1111/ Callcer 24: 545-554. Copy with citationCopy as parenthetical citation