[PDF] Estrogen Production by Sertoli Cell Tumors of the Testis*

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Estrogen Production by Sertoli Cell

Tumors of the Testis*

Charles Huggins, M.D., and Peter Vincent Moulder, M.D. (From the Department o/ Surgery, The University .o[ Chicago, Chicago 37, Illinois) (Received for' publication March 23, 1945)

There is a group of tumors of the testis in dog

and man that cause feminization as a result of estrogen production. In this paper we shall demonstrate that these are neoplasms of the sustentacular cells of Ser- toli which, in the dog at least, contain large amounts of estrogen.

Feminizing testicular tumors.--The syndrome of testicular tumors in dogs producing estrogenic effects

was described by Greulich and Burford (13). The dogs are sexually attractive to other males (13, 33, 34), the tun'mrs ,are often in cryptorchid testes (13, 19), the mammary glands are enlarged (13, 33), and generalized alopecia with increased pigmentation of the abdominal skin and swelling of the penile sheath are sometimes present. Squamous metaplasia of the epithelium of the prostate and posterior urethra is usual (11, 34). The tumors often present similar cytologic charac- teristics. In the cases of Greulich and Burford they consisted of tubular structures of microscopic size. Innes (19) classified the growths as tubular adenomas (Sertoli cell tumors), and stated that some were of a strictly tubular variety while in others the tumor cells had transgressed the confines of the tubule to form irregular lobular masses. Zuckerman and McKeown (34) classified these neoplasms as adenocar- cinoma, and considered that "essentially they repre- sent a malignant development of all the cells of the seminiferous tubules, including the cells of Sertoli." The occurrence of tubular adenomas has been recog- nized, apart from the association with feminized males, for some time; thus Peyron (25) gave a histologic description of Sertoliform tumors of the testis in dogs more than 20 years ago.

Pick (26) described yellow nodular formations of

cylindrical neoplastic cells arranged in tubules in the ovary and in the cryptorchid testis of man, which he called adenoma tubulare ovarii testiculare; the cells were about 15t* in height and consisted of clear

* This investigation was aided by grants from the Committee for Research in Endocrinology, The National Research Council; and from the Albert and Mary

Lasker Foundation, Inc. and the Sidney and Frances Brody Foundation. cytoplasm with basal nuclei. Confirmatory studies of the pathology of these nodules by several workers have been reviewed by Kriickmann (20).

Neoplasms of the human testis associated with

growth of the breast have been reported frequently; commonest among them is the chorionic epithelioma (reviewed by Gilbert, 12). Three examples of testicu- lar tumors with accompanying mammary hyperplasia have been interpreted as interstitial cell growths; the tumor cells were not arranged in tubular form. The

case of Monaschkin (23) concerns a tumor of round, vacuolated neoplastic cells, which were stated to re-

semble the interstitial cells of Leydig. Hunt and Budd (4, 18) reported a man with symptoms of impotence and enlarged painful breasts, which subsided after removal of the associated testicular tumor. The growth was yellow and lobulated; the cells were ovoid in shape with eccentrically placed nuclei containing one or more large, basophilic nucleoli. Nation, Edmondson, and Hammack (24) described a man with mastopathy that did not disappear following removal of a testicu- lar tumor. The cells of this neoplasm contained oval

nuclei with one or more large, eccentric nucleoli; many fine droplets of fat were visible in the cytoplasm.

Estrogen production by the testis.--It is well known that the testis produces estrogen. Thus Fellner (11) observed that lipoid extracts of bull testis injected into castrate guinea pigs caused growth of the uterus. Qualitative studies indicating the presence of es- trogen in this gland have been reported by others, also, for the bull (3, 8, 9, 21), and by still others for the deer (7). Zondek (32) found that the urine

of stallions contained, on the average, 170,000 mouse units' of estrogen per liter, while the urine of colts

and geldings had about 0.3 per cent of this amount. Furthermore, the testis of the stallion contained 23,100 mouse units of estrogen in 350 grams, but less than

0.09 per cent of this amount was extracted from bull

testis. From horse testes Beall (1) isolated a-estradiol (0.21 mgm. per kgm.) as its di-a-naphthoate, and estrone (0.36 mgm. per kgm.) as its 3,5-dinitro- benzoate; these are higher than the estrogenic values reported for any other tissue.

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HugginsandMoulder-SertoliCellTumorsof the Testis511

METHODS

Five dogs withfeminizingtesticulartumorsof spon

taneousoriginwere available for study. Unless lacta tion was present,prolactin,15mgm.daily for 3 days, was injectedsubcutaneously.At autopsy thepituitary, thyroids,adrenals,testes, andprostate were weighed, and histologicpreparationsmadeof these tissues and of the breast.

Thetissues, and alsonormaltestis from

manand the dog, werestainedfor fatwithSudan, using frozen sections and the gelatin

1technic of

Heringaand tenBerge(14).Waterand total fat

contentof the testes weredeterminedas previously described(16).

Formalin-fixedtesticulartumorsof 2 dogs and, as

a control, follicle-containing ovaries of 5 dogs were ex tracted for estrogen with fat solvents as follows:About

13 to 70 gm. of the tissues were minced, weighed,

andextractedin a Soxhlet flask for 24 hours respec tivelywith95 per centethanol,ethyl ether, and again

95 per centethanol.

Thefat solvents were combined

andevaporatedto dryness.

Theresidue was dissolved

in ethyl ether, washed 4 timeswithdistilled water, andevaporatedto dryness.

Theresidue was again

takenup in 95 per centethanol,dilutedwithwater to reduce theconcentrationof alcohol to 70 per cent, andextractedtwicewithpetroleumetherin a separa toryfunnel;petroleumetherwas discarded and the ethanolfractionevaporatedto dryness.

Theresidue

was dissolved in sesame oil.

Bioassay was done onimmaturefemale albino mice,

21 days of age andweighing6 to 8 gm., by the

methodof Evans, Varney, and Koch (10).Five mice were used for each assay level, and 10 for the controls..

RESULTS

Anatomicstatus.-Theanimalswere stray dogs of

mongreltype andweighedbetween 9.3 and 13.6kgm.

Theages wereunknown,but4 of the animals were

old since they had dense cataracts and worn incisors;

1 dog withbilaterallycryptorchidtestes was consid

erablyyounger,for it hadnormaleyes and teeth.

Thedogs were sexuallyattractivetoothermales.

All hadhypertrophyof themammarypapillae(Fig.

1);1 dog lactatedspontaneously,2 lactated after pro

lactin injections, and in 2 dogslactationwas not in duced. In the dogsthatlactated 0.5 to 1.0 cc. of lipid-rich milk was expressed from each of the papillae.

Theprostateglandweighed from 6 to 38 gm.

Squamousmetaplasiaof the prostaticepitheliumwas

1We areindebtedto Professor P. P. H. De Bruyn for assis

tance in thepreparationof thegelatinsections, and to Dr. WilliamW. Scott for aid in the estrogen assays. Dr.Erwin lactin and estradiol. present in all cases. In the smallestglandtheacrm wereatrophic,and thekeratinizedepitheliumcharac teristic of estrogendominancewas present only in the prostaticurethra;in theotherglandsmetaplasia waspresentthroughoutthe acini also.

Constantchanges were not observed in the supra

renalglands;theweightof a singleglandvaried from 0.334 to 2.0 gm. In 2 dogs thesuprarenalswere small and there wasatrophyof the cortexwith"brown degeneration,"a lipoid band in the cortexencircling themedullaas described byCramerand

Horning

(5, 6) in certain strains of mice. In 2 dogs the supra renals werenormaland in 1, whosesuprarenals weighed 1.48 and 2.0 gm., small cortical adenomas were present.

Thepituitariesweighed from 35 to

73.5mgm.;neitherthey nor the thyroids were re

markable.One of the dogs had asquamouscarcinoma of the anus withretroperitonealmetastasis in lymph nodes.

Thetesticular tumors were 7 innumber,unilateral

in 3 dogs and bilateral in 2; 3 of thegrowthswere in cryptorchidtestes, bilateral in 1animal.Metastases were not present.

Thenontumoroustesticulartissue

showedmoderateto severeatrophyof thegerminal epitheliumin all the dogs.

Thefeminizingneoplasms

of the dog testiscorrespondto thelobulatedtumors with high fatcontentofHugginsandEichelberger (16);in the gross they are firm, white in color, and are bossed incontradistinctionto the soft orange yellowinterstitialcelltumors,which usually occur as single discrete masses.

In 3 of thegrowthsthe cells werearrangedin

tubules; in 2 the cells were diffuse(Fig.2) and tubu lararrangementwas notapparent,while in 2 others poorly formed,distortedtubules were observed. In thetubulartypes there weremanycells lying free in thelumina;the nuclei were basal in cells at the peripheryof the tubules.

Thenuclei in thetubular

typescontainedmuchchromatin,which was not so extensive in the diffuse types. In all cases large nucleoli wereprominentin the cells.

Thetumorlipids.-Innormaladultdog andhuman

testis stained forsudanophilicmaterial(fat),large quantitiesof lipid were found in theinterstitialcells of Leydig and in the Sertoli cells.

Thegerminalepi

theliumwas practically fat-free. All the estrogen-pro material,usually in a single large globule; in the cells ofinterstitialcelltumorsit wasdistributeddiffusely in many small droplets.

Thetotal lipidcontentof the

tumorswas 35.7 to 75.1 gm. per kgm. 'of fresh tissue; the average value fornormalcanine testis is 20.3 gm. per kgm.(16).

Tumorestrogens.-Twoof the testiculartumors

fromfeminizeddogs wereextractedfor estrogen and

values of 3.4 and 70pgm.per kgm. expressed in termsDownloaded from http://aacrjournals.org/cancerres/article-pdf/5/9/510/2439614/crs0050090510.pdf by guest on 26 July 2023

512

Cancer Research

FIG.2.-Sertolitumorofdiffusetypefromthetestisofafeminizeddog.Mag.X475.Downloaded from http://aacrjournals.org/cancerres/article-pdf/5/9/510/2439614/crs0050090510.pdf by guest on 26 July 2023

could notbeextractedfromaSertolicelltumorthat had notcausedfeminization.Combinedovariesweigh ing13.7 gm.from5 dogs atestrus(vaginalbleeding) containedtheestrogenequivalentof 34 tigm.perkgm.

DISCUSSION

Thesite ofestrogenproductionin the testis has

theliumof the glandiscertainlynotitssource:The do not causesquamousmetaplasiaof theprostate (17), andfemalenessoccurredin amaledogwithbilateral cryptorchism withassociatedtesticulartumorsin the presentseries.

Whileit isreadilyfeasible toeliminate

thegerminalcells bycryptorchismoradministration ofcertainsteroids (androgenorestrogen)no experi mentalapproachhas been devised toeliminateselec tively theinterstitialapparatusor theSertolicells.

Theovergrowthof aspecializedcell in atumorous

processprovidesanopportunitytostudythe physi ologic effect ofovergrowthof a singlecellulartype.

Evidenceadvancedpreviouslyregardingthe testicu

laroriginofestrogenisinconclusive;both Sertoli andLeydigcells have beenimplicated,buttheevidence has beeninferentialrather thansubstantive. In a humanhermaphroditewithbreasthypertrophy

WitschiandMengert

(31)foundanabundanceof Sertolicells inabdominaltestes, towhichtheyascribed theurine anditdisappearedaftercastration.In this testis clusters of theinterstitialcells ofLeydigwere present, thoughthey were smallanddid"notgive theimpressionof muchactivity."Theseauthorspoint andsustentacularcells of the testis,statingthatboth arisefromthe follicle cells of theprimordialgonia.

Evidence

thattheLeydigcellproducesestrogenis derivedfromtheassumption thatcertaintumorsof the humantestis associatedwithmammaryhyperplasia areinterstitialcellgrowths(18, 23,24).

Thisin

terpretationdoes not fit inwithothercaseswhere of the male sexhormones.Inchildrenseveral tu mors of the testes thatcytologicallyresembledinter stitialcellgrowthsof the dog have beendescribed (27,

29);they effected precociousgrowthof the sexual

organs andmusculardevelopment-clearevidenceof androgenproduction.

Anadultdescribedby Masson

anextremely hightiterofurinaryandrogenbutno gynecomastia;extractsof theurineof this mancon tained980 to 1,040 mgm.of17-ketosteroidsperdiem (30)in theketonicfraction.

ItISnow possible to provethattheestrogen-pro-

2 ducingtumorsof the testis arederivedfromSertoli cells; the evidence is based onhistochemicalstudy of thelipids andonestrogenextractionandassay.

Sertoli

(28),in hisdescriptionof thesustentacular cells of thetubulesof the testis,stated thatthey con tainfat. Byhistologicalmethodsthe lipids (11)of the testis werefoundpresentnormallyin 2locations: thesustentacularand theinterstitialcells. The nalepitheliumisnearlyfat-free.

All thetesticulartumorsoffeminizeddogs con

tainedlargeamountsoflipid;from75 to 370 per centmore fat thannormalcaninetestis. In 3 the neoplasticcells werearrangedin tubularformation whilein 2others tubularformationwaspresent,but thetubuleswereabortiveandtransitionstages were tracedbetweenstrictlytubular anddiffusepatterns of the samegrowth.Bydefinitionthe cells of the ularcells.

Theestrogencontentof theselipid-richneoplasms

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