Although naturally occurring cryptorchidism with its profound effects upon the testes

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1 SOME EFFECTS OF ARTIFICIAL CRYPTORCHIDISM ON THE ACCESSORY REPRODUCTIVE ORGANS OF THE RAT By E. J. CLEGG Department f Anatmy, University f Liverpl (Received 8 Octber 1959) SUMMARY Artificial cryptrchidism results in a shrt-lived increase in testicular hrmne prductin which is evidenced by changes in the accessry reprductive rgans. These changes include increases in rgan weight, in citric acid and fructse prductin, and in cell height. Subsequently, there is a fall in hrmne prductin, which cntinues at a fairly cnstant level. Althugh naturally ccurring cryptrchidism with its prfund effects upn the testes has been recgnized bth in man and the lwer mammals fr very many years, the changes which it prduces in the accessry reprductive system are less well knwn. Many wrkers cnsider that these rgans are but little affected [Hanes, 1911 ; Sand, 1921; Jeffries, 1931; Schltthauer & Bllman, 1942], but thers have fund changes f varying degree in artificially cryptrchid animals [Krenchevsky, 1930; Nelsn, 1934, 1937; Mre, 1945; Plagge, 1947], while Kudraschv & Ivanva [1931] fund that the accessry rgans f naturally cryptrchid rats are f immature appearance. Previus investigatrs have relied slely n the weights and histlgical appearances f the accessry rgans ; until recently their minute structure was the mst sensitive ' testis hrmne indicatr ' available [Mre, Hughes & Gallagher, 1930 a ; Mre, Price, & Gallagher, 19306]. Mre recently, hwever, the secretin f citric acid and fructse by the accessry reprductive rgans has cme t be regarded as a much mre sensitive index f testicular hrmne activity [Mann, Davies & Humphrey, 1949], and in the present investigatin an attempt has been made t determine the effect f cryptrchidism upn the secretin f these substances by the accessry rgans and hence upn the prductin f andrgenic hrmne by the testes. MATERIALS AND METHODS Fifty-five albin rats were used. These animals were f the same stck and were brn n the same day. They were cntained in ten litters, each f which was randmly divided int tw grups: ne was rendered cryptrchid, and the ther subjected t a sham peratin during which the testes were handled befre being returned t the scrtum. In the cryptrchid animals, the abdminal psitin f the testes was maintained by invaginatin f the prcessus vaginalis and clsure f the deep inguinal ring ; the testes were free t mve abut the peritneal cavity. This pera tin prved successful in all cases. The ages f the animals at peratin varied frm 63 t 72 days.

ARTIFICIAL CRYPTORCHIDISM IN THE RAT 211 At intervals f 5,10, 15, 21, 28 and 35 days after peratin animals were killed, and frm the cryptrchid and cntrl grups f each litter a seminal vesicle,

2 ARTIFICIAL CRYPTORCHIDISM IN THE RAT 211 At intervals f 5,10, 15, 21, 28 and 35 days after peratin animals were killed, and frm the cryptrchid and cntrl grups f each litter a seminal vesicle, cagulating gland and ventral prstate were remved and fixed in frml saline. Sectins 8 µ thick were cut and stained with haematxylin and esin. Cell heights were measured using a micrmeter eyepiece, the final figure in each case being a mean f ten bservatins. The seminal vesicles in each grup were squeezed free f secretin, which was pled and weighed. The tissues f the vesicles and cagulating glands were als weighed, and all three were dried at 63 C fr 24 hr. After re-weighing, the vesicle tissue and Citric acid in the vesicle and its secretin was cagulating glands were pled. measured by the methd f Saffran & Denstedt [1948], and fructse in the cagulating gland by Mann's [1951] mdificatin f the Seliwanff reactin. RESULTS AND DISCUSSION It will be mst cnvenient t cnsider the findings under the fllwing headings : (i) Organ weights. (ii) Citric acid levels in the seminal vesicle, (iii) Fructse levels in the cagulating gland, (iv) Cell heights and histlgical appearances. Organ weights (Tables 1-3; Figs. 1, 6) Figs. 1 and 6 shw the variatins in weight f the cryptrchid seminal vesicles and cagulating glands as a prprtin fthat f the cntrl rgans ver the experimental perid. In bth rgans the curves are similar, with an initial fall t 75-80% f the cntrl value at 5 days, and a rise t nrmal weight r slightly abve at days. This rise is apprximately the same in bth vesicle and gland, but ccurs sner in the latter rgan. There is a subsequent fall in weight, which is mst marked at the 28th pst-perative day. By the 35th day the weights f bth rgans are apprx. 90 % f thse f the cntrls. Fig. 1, which partitins the vesicle int tissue and secretin, shws that the peak level f secretin is reached by the 10th day, whereas that f the tissue ccurs 5 days later. This suggests that the effect f andrgen is first t stimulate secretin by the vesicle, and later t cause an increase in rgan weight. The return f the accessry rgans t nrmal r supernrmal weights des nt appear t have been previusly described. The subsequent decrease in weight has nly been held t ccur by Krenchevsky [1930], wh fund it in twenty ut f twenty-three litters. Plagge [1947] fund that althugh cryptrchidism resulted in decrease in size f the ventral prstate, the seminal vesicles and cagulating glands remained unaffected. Estimatins f the water cntent f the accessry rgans shwed that there were n significant differences between the cryptrchid and cntrl animals. Citric acid levels in the seminal vesicle (Tables 1.3; Figs. 2-5) Examinatin f the tables shws that there are similarities in the respnse f ttal vesicle weight and ttal vesicle citric acid t cryptrchidism, an initial lw level

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4 ARTIFICIAL CRYPTORCHIDISM IN THE RAT 213 being succeeded by a high level at 10 days. The subsequent fall is greater and mre rapid in the case f citric acid. After the 21st day the amunt f citric acid remains at abut 80% f the cntrl level, and its day-t-day variatins are similar t thse f the cntrls (Fig. 2). Table 3. Organ weight, citric acid and fructse cntent f seminal vesicles (s.v.) and cagulating glands (e.g.) f cryptrchid rats, expressed as percentages f nrmal cntrls S.v. tissue wt. Mean wt. (%) Wt./ 100 g bdy wt. (%) S.v. secretin wt. Secre tin/ rgan (%) Secre tin/ 100 g bdy wt. (%) S.v. tissue citric acid Citric acid/ 100 g bdy wt. (%) Citric acid/g rgan (%) S.v. secretin citric acid,-*-1 Citric Citric acid/ 100 g acid/ bdy g secrewt. (%) tin(%) Mean wt. (%) Cg. wt. Fruc- s tse/ Wt./lOOg 100 g bdy bdy wt. (%) wt. (%) Cg. fructse Fruc tse/ g rgan (%) Fig Pstperative days Weights f seminal vesicle tissue and secretin (cryptrchid as percentage f cntrls). When the partitin f citric acid between the tissue f the vesicle and its secretin is cnsidered, by cmparing Figs. 3 and 4, it is clear that in bth cryptrchid and cntrl animals the amunts f citric acid in the vesicle tissue are very similar, whereas the amunts in the secretin in the cryptrchid animals are much less than in the cntrls, althugh the frm f the tw curves is much the same. Thus it wuld appear that cryptrchidism des nt affect the frmatin f citric acid in the cells f the seminal vesicle, but it des t sme extent inhibit its secretin int the lumen f

5 214 E. J. CLEGG that rgan. This cnclusin is further illustrated in Fig. 5, where the cryptrchid value f citric acid is expressed as a percentage f the cntrl. The level f citric acid in the tissue remains relatively higher than that in the secretin during mst f the perid f the experiment Cryptrchid- Cntrl g-30. > OO 25 Ü M a J 2-5 i Fig Pstperative days Citric acid in seminal vesicle and fructse in cagulating gland. 35 Fig Pstperative days Cryptrchid animals: citric acid in seminal vesicle tissue and secretin.

6 ARTIFICIAL CRYPTORCHIDISM IN THE RAT 215 Since the shapes f the citric acid curves in the cryptrchid and cntrl tissue are basically similar, it may be cncluded that testicular hrmne utput is cntinuing, althugh at a reduced rate, after the 10th pstperative day. It wuld appear that the hrmne has a twfld effect upn the vesicle : t cause the frmatin f citric acid in the cells, and t stimulate its secretin int the lumen f the rgan Pstperative days Fig. 4. Cntrl animals : citric acid in seminal vesicle tissue and secretin Pstperative days Fig. 5. Citric acid in seminal vesicle tissue and secretin (cryptrchid as percentage f cntrls).

7 216 E. J. CLEGG Fructse levels in the cagulating gland (Tables 2, 3; Figs. 2, 6) Unfrtunately, it is difficult t separate the secretin frm the gland tissue, and the results treat nly f the ttal amunts f fructse in the rgan. Cmparisn f Figs. 5 and 6 shws that the fructse and citric acid curves are essentially similar. Hwever, in the case f fructse, the initial fall is greater, and the fall after 10 days is bth greater and mre rapid, a finding which crrespnds with that in respect f rgan weights. After 21 days the curves again shw a clse simi larity, fructse levels being generally prprtinately lwer than thse f citric acid. These findings cnfirm the view f Mann et al. [1949], that fructse respnds t a greater degree than citric acid t changes in the amunt f circulating testicular hrmne. Table 4. Cell height (µ) in accessry rgans f cryptrchid and cntrl rats (means ± s.e.m.) Cryptrchid Cryptrchid cells Cntrl cells as % f cntrls Cagu- Days after Seminal Cagulating Ventral Seminal Cagulating Ventral Seminal lating Ventral peratin vesicle gland prstate vesicle gland prstate vesicle gland prstate ± ± ± ± ±l ± ± ± ±l ± ± ± ± ± Cell heights and histlgical appearances (Table 4) In all three rgans examined, the changes in cell height in the cryptrchid animals, expressed as percentages f the cntrl value, are similar t thse in weight and fruc tse r citric acid cntent. In the seminal vesicle, the rise at 10 days is insignificant, and the subsequent fall is mre prlnged. In all three rgans the final level in the cryptrchid animals is between 85 and 90 % f that f the cntrls. Althugh these findings are f interest, they are much less marked than changes in rgan weight r citric acid r fructse cntent, and since it was impssible t detect (using simple staining methds) any histlgical differences between cryptrchid and cntrl accessry rgans, it must be cncluded that the use f histlgical criteria as 'testis hrmne indicatrs' [Mre et al. 1930, b] is much less satisfactry than citric acid r fructse determinatins. Mst authrs in the past have been unable t detect histlgical differences between the accessry rgans f nrmal and cryptrchid animals [Hanes, 1911; Sand, 1921; Jeffries, 1931; Schltthauer & Bllman, 1942], and the findings in the present investigatin are generally in agreement with these wrkers. Althugh Mre & Gallagher [1930] were unable t detect any abnrmality f histlgical appearance in guinea-pigs after 8 mnths' cryptrchidism, Mre [1945] fund that in rats there were histlgical changes suggestive f diminished andrgen utput up t 3 mnths after the establishment f cryptrchidism. The greatest drp in utput ccurred after 60 days' cryptrchidism, and there was a subsequent rise until by 100 days testicular hrmne utput appeared t be nrmal.

8 - - ARTIFICIAL CRYPTORCHIDISM IN THE RAT 217 Nelsn [1934, 1937], n the ther hand, was unable t detect any changes in the histlgy f the accessry rgans until 240 days after peratin, and the discrepancy between his and Mre's findings has nt been satisfactrily explained. The present investigatin shws that histlgical changes in the accessry rgans are small Fructse Organ weight Pstperative days Fig. 6. Weight and fructse cntent f cagulating gland (cryptrchid as percentage f cntrls). CONCLUSIONS All the particular features f the accessry reprductive rgans which were examined in the present investigatin rgan weight, citric acid and fructse cntent, and t a lesser extent cell height indicate that the establishment f a cryptrchid state is fllwed during the first 5 days by a diminished prductin f testicular hrmne. Subsequently there is an increase in utput t nrmal r supernrmal levels which in turn is succeeded by a decrease t a level which, in prprtin t the cntrl, is fairly cnstant within the time limits f the investigatin. This last finding is in agree ment with several ther authrs wh cnsider that testicular hrmne utput is diminished in cryptrchid animals. The wrks f Nelsn [1937] and Mre [1945] have already been referred t. Engberg [1949], using andrgen excretin in the urine as an index f its circulating level, came t similar cnclusins. The initial increase in testis hrmne utput des nt appear t have been pre viusly described, althugh Glver [1956] described a rise in the level f seminal fructse in rams, cnsequent upn scrtal insulatin ; the level remained high during the experiment, and gradually returned t nrmal after its terminatin. It was cn sidered that this increase was the result f an increased prductin f male sex hr mne. Althugh scrtal insulatin cannt be strictly cmpared with cryptrchidism, and althugh the experimental animals used differ greatly, it wuld seem that in crease in testicular temperature the feature cmmn t scrtal insulatin and cryptrchidism may under certain circumstances prduce a rise in the amunt f circulating andrgen. In cnsidering the way in which the results f this investigatin may have ccurred, it is necessary t describe the varius influences acting n the retained adult testis,

218 E. J. CLEGG and the effects they may prduce in it. These influences are heat, the capacity f the testis t react t gnadtrphins, and the gnadtrphin utput f the pituitary gland. Heat.

9 218 E. J. CLEGG and the effects they may prduce in it. These influences are heat, the capacity f the testis t react t gnadtrphins, and the gnadtrphin utput f the pituitary gland. Heat. It has been knwn fr many years that heat severely damages spermatgenic tissue [Mre & Chase, 1923; Mre, 1924, 1942], and it is the generally held view that the cause f the severe spermatgenic damage in the cryptrchid animal is the elevated envirnmental temperature f the testes [Crew, 1922; Mre & Quick, 1924; Mre, 1942]. Wrete [1942] shwed that in the muse this can damage t sme extent be prevented by the administratin f gnadtrphins. This authr als shwed that the Leydig cells are diminished in number by heat, and that gnadtrphins exert a similar prtective functin. Capacity t respnd t gnadtrphins. This will bviusly depend upn the cn ditin f the Leydig cells. A heat-damaged testis will be less capable f respnse than a nrmal ne, and this capacity will diminish the lnger the animal remains crypt rchid. Ultimately a stage will be reached where the testicular damage is maximal, and the respnse t gnadtrphins, in the shape f andrgen utput, will be cnstant. Gnadtrphic utput f the pituitary gland. Since a reciprcal relatinship exists between gnad and pituitary, a diminutin in testicular hrmne utput will result in an increased gnadtrphin utput by the pituitary, and vice versa. Hwever, in the cryptrchid animal the capacity f the testes t prduce hrmne will diminish with time, and ultimately a 'steady state' will be reached, when increased prduc tin f gnadtrphin prevents further testicular damage, but is insufficient t restre the testis t nrmal. Hence hrmne prductin will cntinue, althugh at a reduced level. The results f the present investigatin d nt shw whether this 'steady state' is permanent; Mre's [1945] experiments indicate that after 60 days, the utput f testicular hrmne may return t nrmal. The rise in rgan weights and citric acid and fructse levels seen between the 10th and 15th pstperative day may be explained in a similar way. During the first few days after peratin testicular damage is slight, and althugh hrmne pr ductin is initially decreased, the rgan can still respnd t the cnsequent rise in the prductin f gnadtrphins by an increased utput f andrgen. This capacity t respnd is sn lst, hwever, as the effects f heat becme prfund. I am grateful t Prf. R. G. Harrisn fr his interest and advice, t Mrs C. Mrley and Messrs P. Nicksn and R. Burbridge fr histlgical wrk, and t Mr D. J. Kidd and Miss M. Bawn fr the figures. REFERENCES Crew, F. A. E. [1922]. J. Anat., Lnd., 56, 98. Engberg, H. [1949]. Prc. R. Sc. Med. 42, 652. Glver, T. D. [1956]. J. Endcrin. 13, 235. Hanes, F. M. [1911]. J. exp. Med. 13, 338. Jeffries, M. E. [1931]. Anat. Ree. 48, 131. Krenchevsky, V. [1930]. J. Path. Bact. 33, 607. Kudraschv, B. A. & Ivanva, S.. [1931]. Endkrinlgie, 9, 413. Mann, T. [1951]. Prc. Sc. Study Fértil. 3, 50. Mann, T., Davies, D. V. & Humphrey, G. F. [1949]. J. Endcrin. 6, 75. Mre, C. R. [1924]. Amer. J. Anat. 34, 337. Mre, C. R. [1942]../. Cri. 47, 31.

ARTIFICIAL CRYPTORCHIDISM IN THE RAT 219 Mre, C. R. [1945]. Yale J. Bil. Med. 17, 203. Mre, C. R. & Chase, H. D. [1923]. Anat. Ree. 26, 344. Mre, C. R. & Gallagher, T. F. [1930]. Amer. J. Anat. 45, 39.

10 ARTIFICIAL CRYPTORCHIDISM IN THE RAT 219 Mre, C. R. [1945]. Yale J. Bil. Med. 17, 203. Mre, C. R. & Chase, H. D. [1923]. Anat. Ree. 26, 344. Mre, C. R. & Gallagher, T. F. [1930]. Amer. J. Anat. 45, 39. Mre, C. R., Hughes, W. & Gallagher, T. F. [1930a]. Amer. J. Anat. 45, 109. Mre, C. R., Price, D. & Gallagher, T. F. [19306]. Amer. J. Anat. 45, 71. Mre, C. R. & Quick, W. J. [1924]. Amer. J. Physil. 68, 70. Nelsn, W. O. [1934]. Prc. Sc. exp. Bil., N.Y., 31, Nelsn, W. O. [1937]. Cld. Spr. Harb. Symp. quant. Bil. 5, 123. Plagge, J. C. [1947]. Anat. Ree. 98, 597. Saffran, M. & Denstedt, O. F. [1948]. J. bil. Chem. 175, 849. Sand, K. [1921]. J. Physil. Path. gén. 19, 515. Schltthauer, C. F. & BUman, J. L. [1942]. Amer. J. vet. Res. 3, 202. Wrete, M. [1942]. Uppsala LäkFören. Förh. 49, 165.

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