April-June 198 Ind. J. Physiol. Phar easureof total pancreatic capacity to all the three enzymes in routine clinical I

EFFECT OF INTRAMUSCULAR ENANTHATE ON COMPENSATORY OVARIAN HYPERTROPHY IN THE RAT

wund. Diagnostic value of fecal eh . ;er. J. Diq. Dis.• 13 : 123-146. 1961.motryPSln UMESH K. SRIVASTAVA ew York. Paul B. Hoeber.• Inc. 1944. f pancreatic secretion via duod I Division of Endocrinotoqv. ers Company.Philadelphia. 1965~na Central Research Institute. Lucknow-226 007 of intestinal digestion and absorption in the

J.E. Scott and H V I Gut, 1 : 111- i2:: ~960~ Test of Pancreatic (Received on May 5. 1980) mal duodenal trypsin values . patientswith pancreatic d' In response to rsease, Gastroente- Summary : (N.E.) administered in repeated intramuscular doses was andelderlymales. Amer, J. Med. Sc.• 217 : found to bring about by and large a dose-related inhibition of compensatory ovarian hypertrophy nsof concentration of Serum lipase d (COH) which follows after the surgical removal of one ovary in adult rats. The relative inhibition eet. Mayo Clin.• 15 : 427 -433. 19:~. serum in the responsiveness of the remaining ovary to compensatory gonadotrophic stimulation leading f secretinas a clinical test of pancreatic function. to the COH was of the order of 14.2. 19.0. 26.3. 25.0 and 42.0% with 0.25. 0.50. 1.0. 2.0 and 4.0 mg doses of N.E.• respectively. The EDso was calculated to be of the order of 7.0 mg. ncreaticenzymesin human duodenal aspirate. There was no effect of the treatment on the weight of the pituitary at any dose. whatsoever. However. the treatment was found to induce a significant increase in the weight of the and the adrenals contents. Biochem. J., 53 : 274-277. 1953. at higher doses (2.0 and 4.0 mg). The possibility of delineating' the antigonadotrophic activity by meansof secretion Acta M d' . . e Ica Scand. of ·N.E: from its contraceptive potential. vis-a-vis the dose employed. is discussed. ntestinalcontent Scand J C'" • . IInc. and Lab. Key words : norethisterone enanthate intramuscular EDso on Occurringin patients with l '.. . compensatory ovarian hypertrophy (COH) anti-gonadotrophic aeruc s cirrhosIs.

aard. Diss. Gopenhagen 1935 F l . rom agerlof INTRODUCTION rostigminetest in h . c romc pancreaticopathies. Long-term contraception in women by depot intramuscular Norethisterone enanthate ies in cirrhosis of Arch I t . • n em. Med. (N. E.), a haptanoic acid ester of 19-nor- (norethisterone). has been found to be fairly effective (1.2) with its contraceptive effects being mediated via the inhibition .~~n~d s~~~~••nzymes and duodenal ~~~~~~r of pituitary gonadotrophic secretion (1.1.13.25). However. the incidence and intensity of Urnduringdigestion of standard meal. Scand. drug-induced side-effects attributed to the rather massive dosage schedule have limited its mass scale application. and there have been almost no attempts to investigate the possibility of delineating the contraceptive dose from the strong antigonadotrophic property of this long-acting synthetic progestin. The present study was an effort in that direction.

Although esterification and enol-etherification has been demonstrated to make the ts-nor-testosterone progestins many times more potent in their biological attributes as compared to their corresponding parent ketones (7.9). the structural manipulation of the

I 152 Srivertave /cturne 25 Ind. J. Number 2 molecule also abolished any predictable parallelism between antibonadotrophic with 0.25,0 anti-estrual and contraceptive activities of the parent progestin (8,12,22). In view of to be of the the fact that overall contraceptive effectiveness of any synthetic proqestin was a function of its partial (inherent) estrogenicity/progestational ratio, the dose employed by implication Effect of int becomes the most important single determinant of the nature and magnitude of its biological Weig effect. Since in the case of N.E. the partial estrogenic property has been demonstrated adrenals an to dominate over its progestational attributes (16,17) it was deemed of inte rest to invesu- of one ovar gate the relationship between its antigonadotrophic and uterine growth stimulating proper- pared to the ties in relation to the dose administered, and to determine if there was any parallelism a dose-depe~ between the two biological attributes. as absolute treatment on MATERIALS AND METHODS compared w statistically Adult female rats, body weight 110-165 g, of the Institute colony were used in the resulted in study. Only such animals which showed regular 4-5 day cycles were included in the the 0.5 mg study. Right ovary of each animal was surgically removed under light ether anaesthesia control leve and the treatment started immediately after the surgery according to the schedule of treatment: Intact control (Gr. I), Hemicastrated (H.C.) control (Gr. 11), Sham-Control Wei receiving plain olive oil (Gr. Ill>' H.C.+0.25 mg 'N.E:. (Gr. IV), H.C.+0.50 mg. 'N.E' basis of (Gr V), H.C.+2.0 mg 'N E: (Gr. V), and H.C.+4.0 mg 'N.E' (Gr. VII>. and a subsequent removal of addition of another group of five hemicastrated rats which were treated with 1.0 mg 't-J.E.')/ 4.0 mg dos d. Lest there was any variation due to the amount of vehicle injected, all animals received results sho 0.5 m! olive oil either with or without 'N.E: Each group had five rats. Animals were was, by an autopsied 24 hours after the last injection on day 10 along with a group of five intact pituitary eit animals which were not given any treatment (Gr. I). The remaining ovary was quickly decrease in removed, cleaned of adhering fat and tissue debris and weighed on a torsion balance to doses of ' nearest 0.2 rnq. Weights of uterus, adrenals and pituitary were also similarly recorded. All statistical analyses were done by employing the student -r test.

Determination of potency (EDso) : Co A dose-response curve was plotted on a semi logarithmic scale for the inhibition of COH against the corresponding dose of' N.E: employed. The effective dose of the rem 'N.E.' was at 50% level (EDso) was calcuated using the method of Litchfie!d and Wilcoxon (15), Iinear reiat RESULTS potent inhi many time Effect on compensetory ovarian hypertrophy (COH): in a unilat A significant inhibition of COH was observed at all the doses of 'N.E.' (P<0.05 and synthesis a 0.01). The relative inhibition of COH was of the order of 14.2, 19.0, 26.3, 25.0 and 42% double the

I April-June 1981 Vclume 25 Compensatorv Ovarian Hyoertrophy 153 lnd. J. Physiol. Phd'mac. ,'umber 2 I'sm ~€twe€n antibonadotrophic, with 0.25,0.50,1.0,2.0 and 4.0 mg doses of 'N.E.' respectively. The EDsfI was calculated progestin (8,72,22). In view of to be of the order of 7.0 mg. nthetic prog€$tin was a function the dose employed by implication Effect of intramuscular '.N.E.' on organ weights: re and magnitude of its biological Weights expressed on relative value basis: The results of im 'N.E: on the uterus, property has been demonstrated adrenals and pituitary have been presented in Table I. Consequent to surgical removal as deemed of interest to investi- of one ovary (hemicastration) there was a marked increase in the uterine weight as corn- terine growth stimulating proper- pared to the weight of the uterus in intact control animals. 'N.E: treatment further induced ne If there was any parallelism a dose-depended stimulation of uterine growth increase both in terms of its relative as well as absolute weight (P<0.05 and 0.01.). There was, however, just about no effect of the DS treatment on the weight af the pituitary except for an indication of slight stimulation (as compared with intact control, Gr. I) at the lowest dose of 0.25 mg, all the same it was nstitute colony were used in the statistically insignificant when compared with H.C. control. Gr. Ill. Hemicastration ay cycles were included in the resulted in a significant decrease in the weight of adrenals (p<0.02), however, except d under light ether anaesthesia the 0.5 mg dose, the progestin treatment was found to restore the adrenal weight to the according to the schedule of control levels. control (Gr. 11), Sham-Control (Gr. IV), H.C.+0.50 mg. 'N.E' Weights expressed on absolute value basis (mg!100 g). Calculated on the .E' (Gr. VII), and a sUbsequent basis of per 100 g body weight. the increase in uterine weight following surgical er~~reated with 1.0mg 'N.E.')/ removal of one ovary was further accentuated by 'N.E: treatment (P<0.01) at 2.0 and le Injected, al/ animals received 4.0 mg doses whereas the 0.25 and 0.50 mg doses had just about no effect. The had five rats. Animals ware results showed that the slight increase in the weight of pituitary following hemicastration g with a group of five intact was, by and large, maintained with no significant differences between the weights of e remaining ovary was quickly pituitary either among treatment groups or the controls. With regard to the adrenals the Ighed on a torsion balance to decrease in weight following removal of one ovary was restored with the 0.25 and 4.0 mg Y were also similarly recorded. doses of 'N.E.' (p<0.02, compared with sham-operated controls, Gr. Ill). T test.

DISCUSSION

ithmic scale for the percent Consequent to the surgical removal of one ovary, there was significant hypertroph employed. The effective dose of the remaining ovary (COH) in the adult rat. however, treatment with intramuscular (im field and Wi/coxon (15). NE.' was observed to inhibit COH at all doses investigated Showing, by and large, a dire linear relationship, In fact, 1.9-nortestosterone progestins in general are known to b potent inhibitors of pituitary gonadotrophic secretion with their esters or enol-ethers bein many times more effective (7,8,9,12,18). The increasing compensatory ovarian groW! in a unilaterally spayed ani mal has been attributed to a nearly two-fold increase In t e doses of 'N.E.' (P<0.05 and synthesis and release of gonadotro;.hins from the pituitary (5,6,14,19) providing near 4.2, 19.0, 26.3, 25.0 and 42% double the stimulation, both in terms of intensity as well as duration, to the remainrn 154 Srivesteva Volume Ind. J. Number ovary causing it to hypertro.phy. However, the identity of the gonadotrophin(s) involved I in the COH has not been clearly established, nonetheless, FSH is generally belfeved to I be the principal gonadotrophin responsible for COH (6,14,19,26). On the basis of the I available evidences it would seem that 'N.E.' inhibited any de novo synthesis and/or ~ I ~ I I release of FSH thereby depriving the rernaininq ovary of compensatory gonadotrophic Q) -;;; I stimulation, as was available in the absence of progestin treatment (Gr. 11 & Ill). The 1= :2 I generally unaltered weig.hts of the pituitary, by implication, lend reasonable credence to I "3 I this hypothesis. All the same, effects of 'N.E: on the ovary rendering it refractory! "0 '" I unresponsive to elevated peripheral gonadotrophic stimulation through a direct interacticn "0 I '" at the ovarian site (4,20) and/or via an impairment of its metabolic and biosynthetic integrity 'F" J 2 I (20, 23) can not be ruled out. In the rat 'N. E: has been demonstrated to exert effects () .~ C;; directly at the target tissues without the mediation of gonadotrophins, and the high anti' \ >'" t 0 co gonadotrophic effects have been attributed to its relatively high partial estropenicirs .£ I <:: '" progestational ratio (17). Because of this ratio only, atleast it would appear so, 'NE.' 1 !:> ~'" 0 I "- behaved like an 'impeded ' (shallow dose-response curve-slope) in so far as its .~ Q c I uterine growth stimulating property was concerned. Similar observations have been made :J I ~ "0 .~ with other closely related norethisterone esters such as norethisterone , and I .enc I ~ acetate (12).· As far as 'N.E.' is concerned it has been found to be so much I 'i'"s I estrogenic in rats as to induce implantation, an established estrogen-dependent phenomena- ~ i with its progestational property being exhibited through sustainance of subsequent c '" \ nidation (16). However, it is yet to be established whether this estrogenic activity wasa 0'" c I function of the progestin per se or its metabolite(s) (3). Further, it was noted that while Q I 8 I the ar-tiqonadotrophic EDso was comparatively very high (7 mg), maximurr. uterine stimula- -'"5 .tion was achieved with as little as 025 mg 'N.E:, there being no significant difference c c'" I between the increase in uterine weight obtained with 0.25, 2.0 and 4.0 mg. respectively. Q) I G> c I Thi~ would indicate that there was apparently no parallelism between the antigonadotrophlC 0 I and uterine growth stimulating property (dose) of 'N.E: In fact such a lack of parJllellsm .~~ ) s: I has been demonstrated to be an intrinsic property of esters and enolethers of narethisterone ;;:; 0 attributed to the substitution of a carboxylic acid or an alcohol side-chain at the 0:: or c )I ,a-unsaturated carbonyl position of 1:9-norprogestins (8). Further, accentuation of .!!! :J S, u "b' hemicastranon-induceo increase in uterine weight 'by 'N.E:. indicated a synergistic Q ':"J I I C!J interaction between 'N.E: and endogenous and such an effect may not E !:'"> ) be unlikely in the light of similar additive effects observed with c (10, 21). "0 ;:; I ~ I The effects of 'N.E.' in restoring the hemicastration-induced decrease in the adrenal w I §; weight were again typical of a weak estrogen. Although the results did not indicate any •Q... I 0) dose-response relationship either on the relative or absolute weight basis, yet corroborative UJ c: ~ I Cl) (IJ I :0 evidence (·12) substantiated the nature of response observed in the present study. « ;; !- I \ ~ --- -c:---,------=r-"-j ~ -, CD oJ ~ a. -J ~ 6· 0 O:J'~ -' --..Q)-J::::~"'-...... __ o c.. Lt Cb N ~. t~ •....••....•. 0 ID ~ 0 ~ 0 c.. 0 :::) <; :J CD" fTl .• ::::- (') .=l ~ 11 :::r ..,0c :T ~ •...•. :J~~:T~~"'00-0_ ~Cl>= ....•~ .-+ cC' Cl> Cl> o~cn~o~. Cl>~·i~0-..,cn~~:T03():T"< ~~o" :T:T ~•....'"C • Cl> •...~• a. :To ~-ocmO.>:J3~ ~,Cl>~~~ ~·"OoO.>a 5.3.@ g-~:r:rg ;:;0.. "0 0_ ::J :T ::J~~.~~~~00.>~~3·i~~~~~:T~~~ci .., ~ ~ ::J ':-' ~. ~ '" Cl> u.-+a...... •. .-+ X =tQ)"O---htn •...•. ~o =:- CQ....J m ~ o.Q o 0.> ()·~~~0.>:y~~.§·~0::J<1>0~6·0£"OY'~0_:Ti & ....•en 0 a. -. Cl> ro ::J ::0 ~ Y' 0.0.> s:- 0.>~()..,~<1>b~c~~()::Jc(3::J"OO"~0'><1>6·0.>~ "'----~~o~s. ?- :J "< ~ :T"'()O.> ::J::3 ::JCl>0.::J::J"'~ :::t.::J0..", ::J OG)o ::J::J-' ....• ~ ::J ro <1> 0. 0.> 0 A ::J 23 :::;;. ::J -. <1> a. <1>:y ~ 0.> a. "< a. ~ .CD...• ~·-'- -'"0 - •...0• ::J :::;. 0- _ "<:y 0.> :y ~ () _. ::J ..,<1> <1> Q) o ::J 0 ~. Q) •....•...Q•) -... 0 <;::J <1> zr s:- <1> _. o --~::J<1>==: '"0 cO::J •..• o ....• <1> OJ 0 - Q ..,::J ~ ~ () "0 ~ <1> '" Q) ~ <1> <1> <1> ~ •...<1>• 0"" ,,<::J o."'o.:y ::J ~""'ro ~<1>""'3' ~",:Y0-<1>0_0"'~ x~ :T» ~"O -c (3 ()' <1> <1> 3 -c C •...•~ ~ 0. ~ Cl.<1> ~ :::.C ~ <1> Q) <1> '" 0 zr ~ o .., QQ:l~~g-o-e '" r-v ~. . o-OJOJ ::J Q) :y ~ -. ~..... 0_ ~ •...<1>• - 0 ~ - .•..• .::J...•....<1>•.. a<1>. - •.•.'". en-. -<1> er ~ o ...•0. OJ III ..,<1> •..•<1> Vi' 2 0 <1> - '" Q) -c '" 0 ~ <1> ::J Q). <1>ro -. <1> -, :-L .., <1> .., -. .-..:::: q- ~ et ~. ,...... CD 3 .. -, ::J::r CD ~ -, Q) <1> .:::::0 '"CD" 3' c <1>'" -c to o n <1> <1> 0 - . .., 3 < ~ .a 3 3 Q) • _. ...,<1> Q) () ::J • ~ Q) 0 <; < '"0::0 OJ OJ <1> () ....• •..• ::J ~. ::J l"\ 0'" -'"0 < <1> C <; III C ~ en !2 o OJ Cii' ~ ....•0 o 0::J_ <1> 0 ~ct ~. ::J ::J Vi' zr Cl> ::J _ zr Cl) <1> ~ C OJ Q) . -.:J .., <1>..,-g..!2: •..•0..- -c ~ 0 -. 0 -.-()Q)~ < (§ e:. <1> •..• 0:J :J0()::JCl.~m~~~~ •..•<1> 3~ () "'<1>3()~(l), <1>Q) ....~•:ya.<1>en. _, "'''< g'~ - 0" ~ s Q ~ o a. f"cc'_

z< TABLE I [ff&ct of intramuscular nor&thisteronc onanthatc on organ weights of unilaterally ovarieGtomj,ed adult t~n'le rats. c: 0 3c 0"3 ___-r------"------~'" Weight of organs (mg) N Treatment group BodV ------~------N'" weight Left overv (mg) Pituiterv Adrenal (gm) Uterus ------~------Relative Absolute Relative Absolute R------elative Absolute Relative Absolute ------_ ..--_.- -_ ..------17·94± 36'8± 29·61± 21·60± 128.40±t 104-58± 6'5± 5·19± Intact 124±3.0t 3·13 2·11 2·99 2'~ 25·70 23·08 0-42 0·19 30-40± 25-46± 5·49± 31·2± 26·43± 215.00± 151'05±* 6'4± 4·8 H. C. 118±6.2 2·72 1·83 4·9 II 29-43 28·13 0·40 0·52 control 23·24±* 3020± 17-48± 8·0± fl·9± 32.8±* 116±4.9 164.40±* 141'69±* 3.14 III H. C. 0·91 1.85 088 5.62 27·90 22··12 1·90 +vehicle 16·10± 7.4±* 6·15±* 35'2±* 2939±* 19'80±* 121.0±4·3 20RAO±* 170'17±* IV H. C. 3·58 3·48 348 LA8 2696 19·02 0·24 0·3'3 +0·25 mg 5·69± 29·6± 24.99± 21.40±* 18'34± 1832J± 157·24± 6'8± V H. C. 119±7'3 2·29 1·70 2<:l1 2.&0 sz.so 31·28 0·72 0-44 +,}50 mg 32·4± 26·72± 22'80±* 18·75± () 25G'80±** 209·16±·· 7·2± 5·85± 0 H. C. 123±5·8 2-40 2·62 1·20 1-49 3 VI 0·61 "0 13·G3 R·58 0·87 + 2·0 mg ::0 '" 33·72±· 28·75±* 1HO±· 15·12± ., 246·36±** 227·66±** 6·8± 5·9± s VII H. C. 116±3'6 3·25 2·06 1'07 1·70 -< 28·99 16·26 0·5 0·28 +4·0 mg 0 < ------~------.------~-----..--~ ..--- '0;'" ::0 (t) Values are Mean ± S. E. of 5 animals In each group. :r: -c "0 * P

4. Callen-ins, M.R .. Lee Shlao·Lung and R.R. Humphrey. Action of progest;)gens on estrogen-induced Ovarian qrovvt+ Proc. Soc. Exp'l. Biot, Med .. 124 : 1001-1005. 1967. 5. Damassa. DA and J NI. Davidson. Effects of ovariectomy and constant light on responsiveness to estroger In the rat. Horm, & Beheviour, 4 : 269-281. 1973. 6. Edgren. RA. AF. Parlow. D.L. Peterson and R.C. Jones. On the mechanism of ovarian hypertrophy fOllOWing hernicastratron, Endocrtn%gy. 76 : 97 -102. 1965. 7 Ercoli. A. G Bruni. G. Falconi. R Gardi and A Meli, Broloqical activities of some sterold·ethers ; methy:tps:os terone enol-ethsrs. Endocrll)%gy. 67 : 521-525. 1960. 8 Falconr. G. and A Ereo/i Effect of enot-ethenficatron on anti-estrual and contraceptive activity of some ere- gesllns in rats. Proc. Soc. Exert. BioI. Med .• 108 : 3-6. 1961. 9 Falcoru, G. and G. Bruru. Studies on steroidat enol- ethers. Antioonadotrophtc activity of cyciopentyl denva. trves of some orally active propesnns. J. Endocr.n .. 25 : 169 173. 1962.

10. Folman. Y. and G.S. Pope. Effect of norethisterone acetate. drmetnvlstubestrol. genlstein and cournestro: 01 the uptake of (3H)-oestradlol by uterus. vagina and skeletal muscle of immature mice. J. Endocrtn .• 44 : 213-218. 1969. 11. Fotherby. K.• G. Howard. K. Shrimanker. M. Elder and P G.T. Bye. Occurrence of in women receiving Injectable contraceptive noretrusterone enanthate. Cornrecepuon, 18 : 530-542. J 978. 12. Gianruna. T.. B.G. Stemetz , C.L. Rassaert. EA. McDougal and A Melt. Biological Profile of Proc. Soc. Exptl, BioI. Med .. 131 : 781-789.1909. 13. Goebelsrnan, U.• Z. Frank. P. Stanczyk. F. Brenner. E. Ahcra, E.K. Goebelsman. E. Gentzschein and D.R. Mlsheli Jr Serum norethindrone (NET) concentrations following Intramuscular NET enanthate injections : effect upon serum IH, FSH. estradiol and proqesteone. Contraception. 19 : 2H3-313. 1979. 14. Johnson. D.C. and E. Witschl. Endocrinology of ovarian tumour formation in parabiotic rats. Can. Res .• 21 : 783-789. 1960. 15. Litchfteld, J.T. Jr. and F. Wilcoxon. A simplified method of evaulatinq dose-response effect experiments. J. Pharmacol. & Exptl. Therap .• 96 : 99-113. 1949. 16. Neumann. F.• Berswadt-Wallrabe. R-vow .. Vii. Eiger. K.J. Graf. S.H. Hasan. M. Mehring. Y .. Nishino and. H. Steinbeck. Special problems In toxrcity testing of long-acting depot-contraceptives. In;. PharmacologIcal Models m Contraceptive Development: Animel Toxicitv and SIde-effects tn Man' edited by E. Diczfalusy, Scrtptor. Copenhagen. 315-354 1973. 17. Nishino. Y. and F. Neumann. Ostroqens Partialwrrkunq von Gestagenen. speztell von Noreth isterononanthat. Arzneim=Forsch.l Druq Res -» 30 : 439 452. 1980. 18. Peterson, D.L.. R.A. Edgren and R.C. Jones. Steroid-induced block of ovarian compensatory hypertrophy in hemicastrated rats. J. Enaocrmolooy, 29 : 255-262. 1964. 19. Rarrurez. V.D. and C.H. Sawyer. The sex difference In the rat prturtarv FSH-response to unilateral gonadectomy as revealed III plasma radiotmmunoassav. Endocnnoloqv. 94 : 475-482. 1974.

I Ao,il June 1981 Compensatory Ovarian Hvpertroohv 157 Ind. J. Physiol. Pharmac.

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al and contraceptive activity of s ome pro.

onadotrophic activity of cye/opentyl d 173. 1962. enva· thy,stllbestrol. genistelll and e of Immature mice J End. on . . uocrm., 44 : r urr

auon in parabiotic rats. Can. Res., 21 : u/atlng dose-response effect expenments.

Hasan. M. Mehring. Y. Nishino and ot-contraM .ceptives.. In' . 'Phermeco rr og/•caH,' S In an edited by E. Olczfa/usy. Scriptor , enen. speziell von Noreth isterononanthat.

of ovarian compensatory hypertrophy in

FSH-responseto unilateral gonadectomy 82. 1974.

1