aging men spermatogenesis

8/13/2019 Aging Men Spermatogenesis

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33 1

REV IEW ART IC LE

Spermatogenes i s a n d Ag in g in th e H u ma nLA RR Y JO H N SO N

F rom the D epartm en t o f C e ll B io lo g y andAna tom y , th e U n ive rs ity o f T e xas H ea lthS c ie n ce C en te r a t D a lla s ,

D alla s , T e xas

K ey wo rd s : ag ing , h u ma n , spermatogenesis , sp erm pro-du c tio n , ge rm ce ll degene ratio n .J A nd ro l 1 98 6; 7 :3 31 -3 54 .

The e ffect o f ag e on hum an o rg an s is becom in gm o re im po rtan t a s a h ig he r pe rcen tage of peop le livelon ge r. T he produ ctio n o f su ff ic ien t fe rtile spe rm a t-ozo a by the te stis o f ag ing m en is in c rea sing ly im po r-tan t as co up le s w a it un til la ter in life to have ch ild renand as m ore ag ing m en a re ava ilab le to b ecom e p ar-en ts . F u rthe rm ore , kn ow led ge o f te sticu la r fu nc tionin ag in g m en m ay be im portan t in d iso rd ers such asben ign prosta tic hy pe rp lasia and im po tence .

R ep rin t re que sts : Lar r y Jo hn so n, P h.D ., D ep artm en t of C ellB io log y , th e U n iv ers ity o f T ex as H ea lth C en ter , 53 23 H ar r yH in es B ou lev ard , D a llas , T exas 7 5235 .

Mo s t of ou r orig ina l s tud ies rev iew ed here w er e suppo rted inpart by NI H Gran ts A G 2260 (W . B . N ea ve s, P. . ) and H D 1 6 7 7 3(L . Johnson , P. ,) and United S ta tes Ai r Fo rce co n tract C -0 616 (R .M . L eb ov it z, P. . ) .

Subm itted fo r p ub lica tion A pril 2 , 19 86 ; accep ted fo r pu b lica -tio n M ay 20 , 1986 .

T he co nsensu s o f reports on the endo crine func -tio n of th e te stis in o ld e r m en is tha t te sto ste roneprodu ctio n is red uced w ith age (H o rton e t a l, 1975;Ish im ara et a l, 1 977 ; H arm an and T sitou ra s, 198 0 ;S p arrow e t al, 1 980 ; D a i e t a l, 19 81 ; H arm an et a l,1 982 ; Y osh ida e t al, 19 82 ; W in te rs an d T roen , 1 982 ;B rem ner e t al, 198 3 ; D av idso n et al, 198 3 ; Joh nso n e tal, 1 984 c; N eaves e t a l, 19 84 ; W arne r e t a l, 1 985 ). In asum m ary of 14 recen t p ap ers based on 417 o ld and384 young adu lt m en , N eav es et a l (19 84) fou nd tha tse rum tes to ste ro ne co ncen tra tio n w as 1 4% low er fo rthe o lde r m en . F u rth erm ore , m any resea rch e rs(H arm an and T sitou ra s, 19 80 ; N ank in et al, 19 81 ;H arm an e t a l, 198 2 ; M u rono e t at, 19 82 ; W in te rs an dT roen , 19 82) ag ree tha t the te stis has a redu cedab ility to sec re te testo ste ro ne in re spon se to gon ad o-tro p in stim u la tion in aged m en . A lthou gh th e tes tisin o ld e r m en h as b een s tud ied (B lum , 1 936 ; M acLeodand G old , 195 3 ; M o lna r, 1 965 ; S asano and Ich ijo ,1 969 ; B ish op , 1 970 ; H om onn ai e t al, 1982 ; Niesch lage t al, 1 982 ), on ly recen tly h av e the qu an titativ easpec ts o f spe rm ato genesis , exp res sed in te rm s ofspe rm prod uc tion ra tes , b een ev alu ated in ag ing m en(A m ann , 198 1 ; Jo hnson e t a l, 198 4b , 19 84c , 19 84d ;198 6b ; N eaves e t al, 1 984 ).

T he q uan tita tive stu d ie s revea led th at d aily spe rmprod uc tion is sig n if ican tly low er in o lde r (50 -80yea rs) than in y ounge r (20 -48 yea rs) m en w ith sim -ila r te sticu la r w e igh ts (John son e t a l, 1 98 4b) o r low er


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33 2 Jou rna l o f A ndro lo gy . N ovem ber/D ecem ber 1986 V ol. 7

F ig . 1 . S c an n in g e lec tron m ic rog rap h o f te s tic u la r p a re nc hy m a in the s ta l lion . S e m in ife ro us tu bu les (S T ) an d ta i ls o f d ev e lo p in gs pe rm a tids (T S ) a re e v id en t. B a r le ng th is e qu a l to 5 0 m . (J oh ns on e t a l, 1 97 8 ) .

te sticu la r w e igh ts (N eav es, et al, 1 984 ; Joh nso n e t al,19 84c ) . M oreo ve r, u sing nove l tech n iqu es, Joh nsone t a l (19 81 , 19 83) d e term ined th e s tep s in sp erm a to -genesis w h e re the age -re la ted reduc tion in da ilyspe rm p ro duc tion occu rs (Jo hnso n et al, 19 84b ,1 984 c; John son and N eav es , 198 6) . L ikew ise, age -re lated d iffe rences in ch aracte r is tic s o f sem in ife ro ustu bu le s (Jo hnso n e t a l, 1 986 b), L ey d ig cells (K a le r andN eaves, 197 8 ; N eav es e t a l, 19 84) , no n-L eyd ig in ter-s titial ce lls (N eaves e t a l, 1 985 ), m yo id ce lls (Joh nsone t a l, 19 86b ) an d S e rto li ce lls (Jo hnson et a l, 198 4d)have b een d e tec ted . A ge -re lated changes in spe rm a to -genesis a lso occur in b u lls (M ilk M ark e tin g B oard ,1 95 0 , 19 67), rab b its (Ew ing et a l, 197 2) , m ice (G osd ene t a l, 19 82) , ra ts (P urv is e t al, 19 80 ; John son andN eaves, 19 83) , an d h orse s (Joh nso n and N eaves,1981 ; Joh nso n an d T hom pson , 19 83).

Eva lu atio n of Spe rm atogen esisin the H um an T estisT he Journa l o f A ndro log y pub lished an ex cellen t

rev iew on the eva lua tion of spe rm ato genesis b ased

o n sem ina l ch a rac ter is tic s (A m ann , 19 81). To p re -v en t d up lica tion , th is rev iew consid ers on ly ev a lua -tion o f spe rm ato genesis by exam in a tion of testicu la rt issue.

H um an spe rm a togenesis has been ev alu a ted b yth e gene ral app ea ran ce o f sem in ife rous tu bu le s (B as-co rn and O sterud , 19 25 ; N e lson , 195 3 ; M ann ion an dCottrel l , 1961; Joh nsen , 1 970 ; A gge r and Joh nsen ,19 78). T he gen era l ap pea rance o f sem in ife ro us tu -bu le s , even as o bse rv ed b y scann in g e lectron m icros-copy (John son et a l, 197 8) , can p red ic t on ly anim pres sion o f the ac tiv ity o f spe rm a togen esis (F ig . 1 ) .L ikew ise , the gene ral appea ran ce o f tubu les w ill no ta llow d e tec tion of m inor chang es in spe rm ato gene -sis .

D ifferen tia l cell coun ts have b een em plo yed toq uan tita tive ly eva lua te spe rm ato genesis in hum ans(R oo sen -R ung e, 1 95 6 ; M anc in i e t a l, 19 65) . D iffe ren -tia l ce ll coun ts have b een exp re ssed as th e num ber o fge rm cells p er un it leng th o f sem in ife ro us tu bu la rcircum fe rence (S te inb e rge r and T jio e, 1 968 ; Zuke r-m an e t a l, 197 8) , num ber o f ge rm ce lls p er S erto li ce ll


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No.6 SPE R M A T O G E N E S IS A N D A G IN G IN T H E H U M A N S Johnson 33 3

(R ow ley an d H e ller , 1 971 ; S kakk eb aek an d H e ller ,19 73 ; Z uke rm an et a t, 19 78) , o r num ber o f ge rm ce llsp er tubu le c ro ss sec tion (S ilbe r an d R odrigu ez -R igau ,19 81 ; S ilbe r, 19 84) . R esu lts ob ta in ed b y each of th eseapp ro aches w ere p ositive ly co rrela ted w ith th e co n-cen tratio n of spe rm ato zo a in e jacu la ted sem en(Zuke rm an e t at, 1 978 ; S ilbe r , 198 4) . C oun tin g thenum ber o f sp erm a tid s w ith elo ng ated n uc lei pe r tu -b u la r cross sec tion in te sticu la r b iop sies is pa rticu -la r ly su ited fo r the c lin ica l se tting , w he re ease o f cellreco gn itio n , low tim e requ irem en t, and good co rrela -tion s w ith spe rm con cen tra tion in th e e jacu la te a reim portan t (S ilb er , 19 84 ).

H um an sp erm a tog en esis a lso has been exp re ssedin te rm s of da ily sp erm p ro duc tion . D aily spe rm pro -d uc tion , a quan tita tive expre ssion of spe rm a togene -s is , is the to ta l n um ber o f sp erm a tozoa produ ced pe rd ay (K enn e lly and Foo te, 196 4 ; A m ann 1970a ). D a ilyspe rm p rod uc tion can be m easu red by cannu latio n ofth e re te te stis (L ino an d B ard en , 1972 ; A m ann e t al,197 4) o r ca lcu la ted from the num ber o f te sticu la rg erm ce lls o f a g iv en typ e corrected fo r the theo re ti-ca l y ie ld an d life span o f the ce ll ty pes cou n ted(A m ann , 1 970 a) .

C lerm on t (19 63) desc rib ed the ce llu la r a ssoc ia tionso f ge rm cells co nstitu tin g th e six d iffe ren t stages o fth e cyc le o f the sem in ife rou s ep ith elium in hum an s.T h is c lass ifica tion schem e still is u sed tod ay . Th ek ine tics o f spe rm a togenesis in h um ans w ere rev ea ledb y au to rad iog raph ic stu d ie s in w h ich th e du ra tion ofth e cy cle o f th e sem in ife rou s ep ith elium w as de te r-m ined (H e lle r an d C le rm on t, 19 64 ). B y add ing the

IDaily spe rm produc t i on is th e to ta l nu m b er o f s pe rm a to z o a p ro -d uc ed by p a ired tes te s e ac h da y . T h is is u s ua lly c a lc u la te d f romth e n um be r o f s p e rm a t ids in th e te s tis or th e n um be r o f s pe rm a-tozoa lea v in g th e tes tis (Amann , 1970a) .

Potent ial da i ly spe rm product ion is th e po te n tia l to ta l n um be r o fs pe rm a to z o a p rod uc e d b y pa ire d te s te s e ac h d ay , a s s u m ing nos ign ific an t d eg ene ra tion s u bs eq ue n t to the s p ec ific c e l l ty pe be ingc ou n ted . S pe c if ic c e ll ty p es c ou n te d m ay in c lu de ty pe B s p e rm a to -gon ia , p rim ary s p e rm a toc y te s , o r s ec o nd a ry s pe rm a to c y tes (J oh n -s on e t a l, 1 98 3 ).

Eff ic iency of spe rmat ogene s i s is a re la tiv e m e as u re o f e f fic ien c y o fs pe rm pro du c tion ob ta ine d b y d iv id ing da ily s pe rm pro du c tion o rp o te n t ia l d a ily s p e rm p rod uc tio n by the p a ired p a re nc hy m a lw e igh t . T h is v a lue fa c il ita tes c om pa ris on s a m ong s p ec ies tha th av e v a ried te s t ic u la r w e ig h ts (A m an n , 1 970 a ) an d a llow s c om -p a r is o ns o f s pe rm pro du c tio n ra tes a t d iffe ren t m a trra tio na ls tep s du rin g s p e rm a tog ene s is (J o hns on e t a l, 1 98 3 , 19 84a ; J oh n -s on , 19 85 ).

Da ily spe rm ou lpu l is the to ta l nu m b er o f s p e rm a toz o a re lea s e dda ily b y pa ired tes tes . T h is c an be es t im a te d by the nu m b er o fs pe rm a to z o a o b ta in ed b y c a nn u la tio n o f the ex c u rre n t d uc ts o fthe tes tis , s pe rm a to z o a rec ov e re d from the u r ine o r th e e jac u la te(A m an n , 19 70 a ). D a ily s pe rm o u tp u t h as b ee n re ev a lu a te d inhum a ns fo llo w in g s tab iliz a tion o f ex tra gon ad a l s p e rm res e rv es( J ohns on , 1982) .

du ra tion s o f each stage o f the cyc le in w h ich a g ivence ll type occurs , th e life sp an o f tha t ce ll type can b ede te rm ined . G iv en the life span and th eo re tical y ie ldo f spec ific ce ll ty pes, sp e rm p rod uc tion ra te ob tain edby co un tin g num bers o f ge rm ce lls in bo th te ste s canbe exp re ssed o n a da ily basis (K enne lly an d Foo te ,1 964 ; Sw ie rstra , 19 67 ; A m ann and L am biase , 1 969 ;A m ann , 1 970 a) . T he th eo re tical y ie ld is ca lcu lated by2, w here n equ a ls th e n um ber o f ce ll d iv is ionsbe tw een a sp ec if ic ce ll ty pe and spe rm a tozoa . If thetheo retica l y ie ld is ab ov e one (the v alu e fo r spe rm a-tid s) , the exp re ssio n o f spe rm produ ctio n is ca lledpo ten tia l d a ily sp erm p ro duc tion (Jo hnso n et a l,1983) .

I t is o n ly recen tly th at d aily spe rm prod uc tion orpo ten tia l da ily spe rm pro duc tion h as been estim a tedfo r hum an s (A m ann and H ow ard s, 198 0 ; John son etal, 1 980 a, 1 980b ; 198 1 , 1 98 3 , 19 84b , 198 4c , 1 984d ;1 986b ; A m ann , 1 981 ; N eaves e t a t, 1 984 ; Jo hnsonan d N eav es , 19 86) . C alcu la tin g da ily sp erm p rod uc -tion pe r g decapsu la ted tes ticu lar p arenchym a fac ili-tate s com parisons am ong spec ies as it is a m easu re o feffic iency of sp erm a tog en es is (o f sp erm produ c tio n )rega rd le ss o f te sticu lar size (A m ann , 19 70a ; A m annet a l, 197 6) . H um ans (A m ann , 198 1 ; Jo hn son e t a t,1 981 ) have a low er e ff ic ien cy (6 X 106/g) o f s pe rm ato -genesis th an o the r sp ec ie s inc lud in g n on-hum anprim a tes (23 X 106/g) , ra ts (20 -24 X 106/g) , rabb i ts(26 -28 X 106/g) and ho rse s (1 9 X 106 /g ) (A m ann ,1 970 a ; 19 81 ; A m ann et a t, 19 76 ; R obb e t a l, 1 978 ;Jo hnson e t a t, 1 980 a , 198 4a ; Jo hnson and N eaves,1 983 ; John son and Thom p son , 19 83 ; L ebov itz an dJo hnson , 1 983 ; Jo hnson , 1 985 a) .

T he lon g dura tion of sp erm a tog enesis (74 days) inhum an s (H elle r and C le rm on t, 196 4) an d a low ernum ber o f g erm ce lls p er un it v o lum e of pa ren chym a(density ) com pared w ith o th er m o re effic ien t sp ec ie s(F igs. 2 and 3) con tr ibu te to the low effic iency o fspe rm a to genesis in hum ans. The hum an te stis alsohas low er pe rcen tages o f sem in iferous tubu le, sem -in ife ro us ep ith elium , and ge rm ce ll nu cle i than thete stis from ra ts o r ho rse s (F ig . 2 ) . U sin g spe rm atid sw ith a sph erical n uc leus (ro und spe rm atid s) to d ep ic tth e d en sity o f ge rm cells in the stage o f the cy cle inw h ich spe rm iatio n occurs , the h um an te stis is com -pa red w ith the rat and horse testis (F ig . 3 ). T hereduced dens ity o f spe rm atid s w ith a sphe rica l nu -cleus in th e h um an te stis com pared w ith o the r spe -cie s can be seen in reg ions o f tub u le s w here thesege rm ce lls a re rela tive ly ab und an t. U n like sem in ife r-o us tu bu le s from ra ts o r ho rse s, tubu les in h um ansa re no t consis ten t in th e abundance of g erm cells


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F ig . 2 . C o m p ar is o n o f th e re la tiv e pe rc e n ta ge o f tes tic u la r pa ren c h y m a oc c up ie d by s em in ife rous tub u le s , s e m in ife ro us ep ith e liu m , a nds ph e ric a l nuc le i o f roun d s pe rm a tid s (G o lg i a nd c a p p ha s e s ) in ra ts , h o rs es , a nd h um an s . (J oh ns o n e t a l, 1 98 0 ; J oh ns o n , 19 85a ).

w ith in a sp ecif ic stage o f th e cyc le . F igu re 4 illu strate sthe re lativ e pau city o f spe rm a tid s w ith a sp he rica lnu cleus in seve ral sem in iferou s tu bu le s at the sam estage o f the cyc le ( tha t o f spe rm ia tion ) in the sam ehum an te stis as in F ig u re 3 . O th e r stages o f th e cyc leo ften h ave m is sing gene ratio ns o f ge rm ce lls cha rac -te ris tic o f th at sp ec if ic stage . L ow num bers and thelack of a ll gen era tions o f g erm ce lls in each stag e o fthe cyc le co n trib u te to the re la tive ly low num ber o fge rm ce lls in the hum an testis , w h ich in tu rn con -trib u te s to the low eff ic ien cy of sp e rm a tog enesis . I t isun clea r w hy the hum an te stis d iffe rs from th a t o fo th er specie s in the com po sition and duratio n of spe r-matogenesis .

V a lues fo r da ily sp erm p ro duc tion fo r a sp ecie s a resim ila r to the num ber o f spe rm ato zo a e jacu latedda ily (da ily spe rm ou tp u t; A m ann , 19 70a ) fo r th a tspec ie s . D a ily spe rm ou tp u t is th e to tal n um ber o fspe rm a tozoa re leased da ily by p aired te ste s (A m ann ,19 70a ; 1 981 ). Th is is true fo r boa rs (Sw ie rstra , 1968) ,rab b its (A m ann , 19 70b ), bu lls (A m ann e t a l, 19 74) ,ho rse s (G ebau er e t a l, 1974) an d dogs (O la r e t a l,19 83) . E ven in h um an s (F ig . 5 ), d aily spe rm prod uc -tion is sim ilar to da ily spe rm ou tp u t (Jo hnso n , 1982) .

In the la tter com parison , d aily sp erm ou tp u t w asestim a ted in n in e m en (3 2 1 y ear) by averag ing th enum ber o f spe rm a tozoa in the la st th ree o f f ive da ilye jacu late s . T he firs t e jacu la tes w ere exc luded sincethe ex trag onad al sp erm rese rves had to be s tab ilizedby dep le tio n of ep id id ym a l spe rm a tozoa (A m ann ,197 0a ). It w as fou nd th at tw o da ily e jacu late s w eresu ff icien t to stab ilize the ex trag onada l spe rm rese rv esin m en fo llow ing dep le tion (frequ en t ejacu la tions ) o rbu ild up (sexu a l re st fo r 6 days ) o f these ep id id ym a lsp erm reserves (Joh nson , 1982) . D aily spe rm p ro duc -tion w as estim a ted from 10 m en of s im ila r ag e (35 3yea rs ) from coun ts o f spe rm a tid s in the te stis (Joh n-so n et al, 1 981 ). A ltho ugh da ily spe rm produ ctio n isinh e ren tly h igh er th an d a ily sp erm ou tp u t (A m ann ,197 0a ), the sim ila rity be tw een them gives v alid ity tothe con cep t o f da ily spe rm p ro duc tion as a d irec tm easu re o f spe rm a togenesis in hum an s (Joh nson e ta l, 198 1 ; Jo hnso n , 19 82).

D egene ra tion of g erm cells du rin g spe rm a togene -sis has b een estim a ted by com paring d aily spe rmprod uc tion or po ten tia l d aily spe rm p rod uc tion b asedon g iven germ ce ll types at d iffe ren t m a tu ratio na ls tep s in sp erm atog enesis in bu l ls (Kenne l ly an d


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Fig . 3. C o m p ariso n o f s em in ife ro us e p ith e lium in th e a ) ra t, b ) h o rs e , an d c ) hu m a n in th e s ta g e o f th e cyc le w h en s pe rm ia tio n o ccu rs .G o lg i a nd ca p p h ase s pe rm a tid s w ith sp he ric a l n uc le i ca lled rou n d sp erm atids (R S ) a re m ore a bu nd an t in the ra t an d ho rs e than in thehu m a n . In th e c as e o f the hu m an , th is tub u le w as s e lec ted fo r the re la tiv e a b un da n ce of s pe rm atid s w ith sp h erica l nu c le i in re la tio n to o th e rtub u le s in th e s a m e s tag e o f th e c y c le (c om pa re w ith F ig . 4 ). B a r le ng th eq ua ls 1 0 s m .


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F ig . 4 . C o m p aris on o f s e m in ife rou s ep ithe liu m a nd L ey d ig c e lls from th e s am e hum a n te s tis d ep ic ted in F ig . 3 . S pe c im e ns w e re a ) f ix e dw ith in 20 m m of c as tra tio n o rb ) f ixed a fte r 12 h ou rs o f in c ub a t ion a t ro om tem pe ra tu re in a n a ir-tig h t v ia l. Q ua lity o f f ix a tio n o f ge rm c e lls(e s pe c ia lly pa c h y te ne o ld p rim a ry s pe rm a to c y tes lO P S ]) is red uc ed w ith in c u ba t ion t im e . T h e s iz e o f c e ll b ou nda rie s a nd nu c le i o f the s eg e rm c e lls do n o t a pp ea r to be a ffec ted . H ow ev e r , the c y top las m is c on tra c te d from the c e ll b ou nd a ry . L ey d ig c e lls (LC ) ap pe a r to be les sa f fec ted w ith inc ub a tion tim e than do p rim ary s pe rm a to c y tes . B a r leng th eq ua ls 10 z m .


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b y ev a lu a tion o f tes tes in 1 0 m e n a ged 26 to 5 3 y rs (J o hn s o n e ta . ,1 9 81 ) an d da ily s pe rm o u tp u t de term in ed b y co u ntin g th en u m b er o f sp erm a to zo a in the la s t 3 o f 5 da ily e jac u la tio n s in 9s im ila r ly ag ed m e n (J o hn s on , 1 98 2 ).

Foo te , 196 4) , ra ts (Joh nson e t at, 198 4a ), h o rses(Joh nso n , 19 85a ) and hum ans (B arr et a l, 1 971 ; John -son e t a l, 1 981 , 198 3 , 198 4c ; Jo hnson and N eaves,1986) .

A ge -rela ted D iffe ren cesin the H u m a n Test is

O u r re sea rch has u sed au to psy sp ec im ens fromin d iv id ua ls w ho d ied of heart a ttack or traum a ticin ju ry (i.e . au tom ob ile acc iden t o r gu n sho t w ound).S tud y sub jec ts inc luded on ly m en w ith no h isto ry o fse rio us illn e ss (o the r th an co ro na ry a rte r io sc le ros is)and n o ex tended hosp ita liz a tion p rio r to d ea th .D eta ils on the sub jec ts appa ren t g ood hea lth p rio r tod ea th , eth n ic o rig in , cause o f death , b ody w eig h t,b lood a lcoh o l co ncen tra tion , and ratio o f b ody w e igh tto h eig h t h ave been d escribed (N eaves e t a l, 1 984 ;John son et a l, 198 6b). P ostm o rtem changes red uceth e qu a lity o f fix atio n and cau se co n trac tion of thecy to p la sm in p rim ary spe rm a tocy te s (F ig . 4 ). H ow -eve r , w e have b een unab le to sh ow an e ffect o f pos t-m ortem tim e on da ily spe rm p rod uc tion (Joh nso n e tal, 1 984 b).

A ge -re lated d iffe ren ces in te sticu la r w eig h t an dte sticu la r v o lum e a re incons isten t fea tu re s o f ag in gin h um ans. H ow eve r , te sticu la r w eig h t do es no tin crease a fter age 20 to 3 0 y ea rs in hum an s. C om par-in g d ata fo r 89 m en 21 to 50 years o ld and 43 m en 51

F ig . 6 . E ffec t o f a ge o n the w e igh t o f th e tun ic a a lbu g in ea an dthe p erc en t tun ic o f th e w h o le te s tis in yo un g er a d u lt (21 -5 0 y r )an d o lde r adu lt (51 -8 0) m en . (Jo h nso n e t a l, 19 84 b ).

to 8 0 yea rs o ld , te sticu la r w eig h ts w ere sim ilar fo rbo th the righ t (18 .9 0 .5 and 19 .2 0 .9 g , re sp ec -tive ly ) o r le f t (17 .2 0 .5 an d 17 .5 0 .9 g , re spec-tive ly ) tes tis (Jo hnso n et al, 198 4b). T h is is con sis ten tw ith sim ila r te sticu la r v o lum es reported fo r yo ungand o ld m en (K otha ri an d G up ta , 197 4) . H ow ev er ,the w e igh t o f the tun ica a lbug inea and the p ercen t-age o f to ta l tes ticu lar w e igh t rep resen ted by the tu -n ica alb ug in ea w ere g rea te r P < 0 .01 ) fo r the o lde rm en (F ig . 6 ) . S u bsequ en t stu d ie s on 1 5 m en aged 20to 48 yea rs and 15 m en ag ed 50 to 76 years revealedan age -re lated d iffe rence P < 0 .01 ) in th e v o lum e ofthe testicu la r p arenchym a (4 0 .2 2 .3 m l an d 28 .2 2 .4 m l, re spec tive ly ) p er m an (N eaves e t a l, 1 98 4).Th e age -rela ted inc rea se in the w e igh t o f th e tun icasom etim es m ay b e su ffic ien t to m ask d iffe ren ces inp arenchym al w e ig h t. O ur recen t stu dy (Joh nso n e ta l., 198 6b), b ased on 28 m en 20 to 48 years o ld and 28m en 50 to 90 y ea rs o ld , revea led age -re la ted d iffe r-en ces P < 0 .01 ) in bo th te sticu la r w eig h t and pa ren -chym a l w e igh t (T ab le i) . A g e-re la ted d iffe ren ces inpa ren ch ym a l w eig h ts in th e le ft, r igh t, o r pa ired te s-tis in yo ung er adu lt (20 -48 years) and o ld er ad u lt m en(5 0-90 y ea rs) a re illu stra ted in F ig u re 7 . O th ers haverep orted tha t chang es in te sticu la r v o lum e a re n o t aco nsis ten t cha rac te ris tic o f ag ing (S te rns e t a l, 19 74 ;N iesch lag e t a l, 19 82) .

T he com pos ition of the hum an tes tis is m od ifiedw ith ag e. C om parin g 28 m en 20 to 4 8 y ea rs and 28

SPE R M A T O G E N E S IS A N D A G IN G IN TH E H U M A N . Johnson


8/24

U).4

U)I-=(9L& J-J.4

C)zUi.4a-

D YO U*G ER A DC LT M EN O LD ER AD C LT M E NN 50 N4 4

40 - ..L.1

20 -

- I INO.01 P< 0 .01 NO .0 1

L P1 - 2 8 OLD {128 }RL :I P1 - 2 8

33 8 Jo urna l o f A nd ro logy . N ovem ber/D ecem ber 1986 V ol. 7

SEM IN I F EROUSTUBULES

SEM IN I F EROUSEP I THEL IUM

Fig. 7 . E ffe ct o f ag e o n pa ren c h y m a l(d ec aps u la te d tes tic u la r tis s ue ) w e ig h t o fth e le ft , r igh t, o r to ta l (p a ired ) te s te s iny ou nge r ad u lt (2 0 -4 8 y rs ) an d o lde r ad u lt(5 0 -9 0 y rs ) m en . (J o hn s o n e t a l, 19 84b ).

m en 50 to 9 0 yea rs o ld (Jo hnson e t a l, 19 86b ), thep ercen tage of sem in ife ro us ep ith e lium w as redu cedP < 0 .01 ) in o lde r adu lt m en (F ig . 8 . H ow ever, nos ign if ican t d iffe rence w as fo und in v o lum e density(pe rcen tage of p arenchym al v o lum e occup ied by ag iven com pon en t) o f sem in ife ro us tubu le s o r tu bu la rlum en . T he vo lum e den sity o f bo und ary tissue(m yo id ce lls and asso cia ted ex trace llu la r com pon en ts)increased P < 0 .01 ) w ith age (F ig . 9 ) , bu t the vo lum edensity o f m yo id ce lls in the b ounda ry tissu e w assim ila r in yo ung er an d o ld e r m en (Jo hn son et a l.,198 6b). Pa rtly du e to ag e-re la ted d iffe rences in pa -ren ch ym a l w eig h t, the vo lum e o f sem in ife ro us tu -bu les pe r m an w as le ss P < 0 .0 1 ) in th e o lde r m en

(T ab le 1 ) . Tu bu la r d iam e te r w as s im ila r bu t tu bu la rleng th pe r m an w as red uced P < 0 .01 ) in o lde r adu ltm en (F ig . 10 ) . T he th ick ness o f the bound ary tissue ,p ercen t b ounda ry tis sue in the p arenchym a , andnum ber o f m yo id ce lls pe r c ro ss sec tion inc rea sed P-IC )zLi i

0Li0H -zLi i0lxLi i0

C O M P O S I T I O N (V O L U M E D E N S IT Y )

Fig . 8 . E ffec t o f ag e on the p erce nta geo f th e te s tis o c c up ied by s e m in ife ro ustubu les P > 0 .05 ) an d s em in ife rous ep i-thel ium P < 0 .01 ) in y o un ge r a du lt (20 -4 8 yrs ) an d o ld er adu lt 50 -90 yrs ) m en .(J oh ns on e t a l, 1 986 b ) .


9/24


10/24

UO U N G E RP 1 = 2 8

M O L D E RN2 8

r i {149}U B U L A R

L E N G T H /M A N (M )

AGE , years

34 0 Jou rn al o f A ndro lo gy N ovem ber/D ecem ber 1986 V ol. 7

D egene ratio n o f ge rm ce lls h as a p ivo ta l ro le in th e

T U B U L A RD IA M E T E R (U M )

F ig . 1 0 . E ffe c t o f age on tu bu la r d iam e te r (P > 0 .05 ) a nd tu bu -la r le ng th pe r m an P < 0 .0 1 ) in y o un ge r a du lt (20 -48 y rs ) ando lde r a d u lt (50 -9 0 yrs) m e n. (J oh ns on et a l, 1 9 86 b) .

o f th e w ho le testis in stead o f b iop sies , a re in con tra stto ear lie r, m ore sub jec tive , s tud ie s tha t con c ludedtha t the ag e-rela ted th icken ing of bo und ary tissu ere su lted from depo sition of new laye rs o f co nnec tivetis sue (E ng le , 194 2 ; M olna r , 19 65) .

A g e-re la ted ch an ges in sp e rm produ ctio n in hu-m an s are ev iden t in a h ighe r pe rcen tage of azoo -sp erm ia in sem en from old er m en (B lum , 1936),tub u le s devo id o f sp erm a tid s (S asano and Ich ijo ,196 9) , tubu les w ith d isloca ted ty pe A spe rm a togo n ia(H o ls tein e t a l, 1 9 8 4 , or m ultinu clea ted sp erm a to -cy te s and spe rm a tid s (H o lste in and Eckm ann , 198 6).H onore (1 978 ) n o ted tha t age -rela ted changes in theh um an te stis inc luded tub u la r sc lerosis , fo ca l m ono-n uc lear o rch itis , and d ila tion o f the re te te stis . B isho p(1970) rep orted a th in n ing o f the sp erm a tog en icep ithe lium , d ec reased d iam e ter o f tub u le s , and even-tu al o b lite ra tion of th e tu bu la r lum en in som e o ldm en . Low er sem in iferou s ep ithe lial vo lum e in o lde rm en is a ssoc ia ted w ith low er P < 0 .0 1 ) da ily spe rmprodu ctio n pe r m an (T ab le 1 ; F ig . 11 ; Jo hnso n et al,1986b).

C om bin ing the reported da ta from diffe ren t stu d -ie s (A m ann and H ow ards, 19 80 ; Joh nso n e t a l, 198 0a ,198 0b), A m ann (1 981 ) reported a trend fo r an age -rela ted d ifference in da ily sp e rm p rod uc tion in m en .Th is tren d has been con firm ed by sub sequen t stud ie s(Jo hnson e t a l, 198 4b ; 198 4c ; 1 984d ; 198 6b ; N eaves e ta l, 19 84) . T he eff iciency of sp erm a tog en esis (d ailyspe rm produ ctio n /g ram parenchym a ; A m ann , 19 70a )in o lde r m en is le ss P < 0 .0 1 ) th an in yo ung er adu ltm en (T ab le 1 ) . M oreo ve r, th e low eff iciency of spe r-

A GE vs S P E R M P R O DU C T IO N

F ig . 11 . E ffe c t o f a g e o n d a ily s pe rm pro d uction pe r gr ampa re nc hym a (e ffic ie n cy o f sp erm ato ge ne s is ) in 1 32 m en . R e gres-s ion line (y = 7 .7 - 0 .065X; P = -0 .33 ) is d ra w n w ith the 95 %co nfide nc e lim it. (Jo hn so n e t a l, 19 8 4b ).m atog en es is is u n ifo rm ly d istr ibu ted in each te stis(John son e t a l, 198 4b ) and in the c ran ia l, eq ua to r ial,and cau da l th irds o f th e te stis o f y oung or o lde r m en(John son et al, 1 984 c ). C om parisons o f the e ff ic ien cyo f spe rm a tog en esis be tw een th e righ t an d le ft te stisand am oun t o f da ily spe rm prod uc tion in d ifferen treg ion s can be seen in F ig u re 1 2 . S erum concen tra-tio ns o f LH and FSH w ere p ositiv ely co rre la ted w ithag e and neg ativ ely co rre la ted w ith d aily spe rm p ro -d uc tion (John son et a l, 198 4c ).

A ge -rela ted d iffe ren ces in the num ber o f ge rmce lls o r d aily spe rm pro duc tio n in the testis o f o lde r(36 -m on th -o ld ) rab b its (Ew ing et al, 19 72 ), m ice(G o sden e t a l, 198 2) and rats (Jo hnson and N eaves,1 983 ) have b een rep orted . In ho rse s, da ily spe rmprodu ctio n reach es its p eak a t abo u t 4to 5 y ea rs o fag e and rem a ins a t th is leve l un til a t le a st 20 yea rs o fag e (Jo hnso n and N eav es, 19 81 ; John son and Thom p -son , 198 3). W ha t happ en s to sp erm produ ctio n a fte r20ea rs o f age in sta llion s rem a ins unknow n . T hefac t tha t som e m ale s reta in the ir fer tility even w iththe adv an cem en t o f age is ind ica ted by fer tility inbu lls 19 yea rs o f age (B isho p , 1 970 ) an d a su ccessfu lpa te rn ity in a 9 4-year-o ld m an (S eym our et a l, 19 35) .

D egene ra tion of G erm C e llsDur ing Spermatogenesis


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N = 1 O Y O U N G A D U L T M E N

F ig . 12 . D a ily sp e rm p ro du ctio n p er gp arenc hy m a in th e c ra n ia l, eq ua to ria l,an d c a ud a l re g io ns o f p a ired tes tes fro mm e n ag ed 20 to 4 8 y rs . (J o hn s o n e t a l,1984c ) .

N o.6 SPER M A TO G EN ES IS A N D A G IN G IN T H E H U M A N . Johnson 34 1

CRAN IA L EQUATOR IA L CAUDAL

quan tita tive aspects o f spe rm a togen esis (H uck in s,1 978 ; John son e t a l, 1 983 ; Joh nson , 1 985 a ). H ow ev er ,th e m echan ism s o f degene ratio n , its e tio lo gy , andap pro ach es fo r p reven tio n rem ain un clea r.

T hree app roaches h av e b een u sed to q uan itify th eam oun t o f ge rm cell degene ratio n . T he ex ten t o fg erm ce ll d eg ene ra tion a t d iffe ren t steps o f sp erm a to -g en es is has been de term in ed by coun ting degene rat-ing g erm ce lls o f d iffe ren t types (O akbe rg , 1 956 ;C l e rmon t , 1962 ; R u sse ll and C lerm on t, 197 7 ; H uck-ins, 19 78) and by calcu la ting ra tio s o f spec ific ty pes o fg erm cells (R oosen -R unge , 1 955 ; 197 3 ; O akbe rg ,195 6 ; C le rm on t, 196 2 ; A m ann , 19 62 ; B a rreta l, 1 971 ;H uck ins , 19 78 ; H o ch ereau -d e R ev iers , 198 1 ; W in gand C hristensen , 1 982 ). T he iden tity o f degene ratin gce lls and the fact th at degene ratin g ce lls a re rem ovedqu ick ly lim its th e u se fu ln es s o f the f irs t app roach . Ath ird app roach , w h ich d irec tly e stim a te s th e im p ac to f degene ra tion a t g iven steps in sp erm a to genesis ond aily spe rm p ro duc tion , is to com pare ra tes o f spe rmp rod uc tion based o n va rio us ty pes o f d ev elo p ingg erm ce lls (Sw ierstra , 196 7 ; A m ann , 1 970 a) . T he la stapp ro ach (T ab le 2 ) h as b een em plo yed to estim a te thee ffec t o f m ic row ave irrad ia tion of ra ts on spe rm pro -d uc tion from typ e B spe rm ato gon ia to th e m o stm a tu re m a tu ra tion -ph ase spe rm a tid s (L ebov itz andJohn son , 198 3 ; Jo hnson e t a t, 198 4a ) a s w e ll a s sea -son al d iffe ren ces in ge rm cell degene ra tion from ty peB spe rm ato gon ia to sp erm a tid s in sta llion s (Jo hnso n ,198 5a ). In the adu lt m an , th is ap pro ach has rev ea led

U,z0Z j0-I-

0c r> -c-ZIX

.4a-U)>--J 4 00 9) ra ts (L eb ov itz an d Joh n son , 1 9 83 ; Jo h nso n e t a l, 19 8 4a ), 28

ho rse s in th e bre e d ing se a son (Jo hn so n, 1 98 5 a), a n d 1 0 h um an s a g es 2 6 to 5 3 ye ars (Joh n son e t a l, 19 8 4c).tP o te n tia l d a ily s pe rm p ro du ctio n is the p red ic te d nu m b e r o f s pe rm a tozo a p oss ib le w h en ba se d on nu m b e rs o f d es ig na ted ce lltypes yo un ger th an spe rm atid s.M e an s in c o lum ns w ith d iffe ren t sup e rscrip ts a re d iffe re n t P 4 00 g) Sprague -D aw ley ra ts (L ebov itz and Jo hnson , 19 83 ; Jo hnso n e ta l, 198 4a ) appea r to have n o sign ifican t g erm ce ll lo ssdur ing spermiogenesis .

T h ere w as no sign ifican t d eg ene ra tion of g ermce lls be tw een ty pe B sp e rm a to gon ia and secon da ryspe rm a to cy tes (T ab le 2) . T he lack of de ta ils on spe r-m ato cy te fo rm a tion in hum ans p reven ts ev alu atio nof g erm ce ll degene ratio n during pro lifera tion ofspe rm ato gon ia . A sig n if ican t 3 6% to 45% lo ss b ydegene ratio n (B arr e t a l, 1 971 ; Jo hnson et a l, 1 983 )occu rs du ring m e io tic d iv is ions in hum ans. T heam oun t o f p o ten tia l lo ss o f spe rm pro duc tion la te inm e ios is is s ign if ican tly an d nega tive ly co rre lated (r =-0 .86 ) w ith da ily spe rm p ro duc tion pe r g ram paren -chym a in hum an s (Joh nson et a t, 19 83 ). T he m ajo rityo f the ge rm ce ll degen era tio n de tec ted la te in m eio sisoccu rred du rin g the seco nd m e io tic d iv is io n (John sonet a l, 19 81 , 19 84c ) . Th e pe rcen tage of ge rm ce ll degen-era tion du ring po stp roph ase o f m e iosis w as n o tco rre la ted w ith age or se rum con cen tra tions o fe ithe r L H o r FSH (Joh nson e t a l, 198 4c ). I t is n o tkn ow n w hy hum ans have a greate r degen era tionra te late in m e iosis than o the r spec ies (T ab le 2 ; F ig .

13). B ased on the m agn itu de o f ce ll lo ss la te in m e iosisin hum an s (Jo hnso n et al, 1 983 ), da ily sp erm p ro duc -tion a lm os t co u ld be doub led if th is lo ss w as e lim i-na ted . In adu lt hum ans, the re is little d eg ene ra tion ofsp erm a tid s du ring spe rm iogenesis (T ab le 2; Johnsone t a l, 198 1) .

In sum m ary , the e ffect o f g erm ce ll degene ratio no n da ily sp e rm produ ctio n (T ab le 2 ; F ig . 1 3 ) w asn eg lig ib le in adu lt (> 400 g ) ra ts sub sequen t to typ e Bsp erm a tog on ia , w h ile ad u lt ho rse s h ad lo sse s tow ardthe en d o f spe rm ato cy te fo rm a tion an d younge radu lt h um ans had grea t lo sses a fte r the end of m e i-o sis (sub sequen t to second a ry spe rm ato cy te s).

T h e reaso ns ge rm ce lls degene ra te a re unc lea r.O akbe rg (19 56) and C le rm on t 1962 propo sed th atth e degene ratio n of g erm cells m ay be a m echan ismfor elim ina ting ce lls w ith ab norm a l ch rom o som es .H ow eve r, the g rea te r lo ss o f ce rta in ty pes o f spe rm a-to gon ia and th e re lativ e constan cy in th e m agn itud eo f d eg en era tion a re n o t co nsis ten t w ith sim p le se lec -tio n to elim ina te ch rom o som al abno rm alitie s (H uck-in s, 19 78) . A lte rna tive ly , degene ratio n m igh t be am ech an ism to lim it g erm ce lls to the n um ber th at canb e su sta ined by th e S e rto li ce ll po pu la tion (H u ck ins,19 78) . In deed , the num ber o f typ e A spe rm a togo n iap e r testis has been correla ted w ith n um bers o f S er-


13/24

F ig . 1 3 . P o ten tia l d a ily spe rm p ro du c-tio n pe r g p are nc hy m a ev a lu a ted a t d if-fe ren t s tep s in s p e rm a tog en es is in th era t, ho rse , a nd h um an . C e ll type s onw hich po ten tia l da ily sp e rm prod uc tionpe r g or da ily sp e rm p ro du ctio n p er g w asba se d inc lud e d: typ e B s pe rm a tog o n ia(B S ), p re lep to te ne p lu s le p to te n e (yo un gpr im a ry ) s p e rm a toc y te s (Y P S ), p ac hy ten ep lus d ip lo te ne (o ld p rim ary ) s pe rm a to -cy te s (O PS ), se co nd a ry sp e rm ato cy te s(S S ), G o lg i a nd ca p p ha se sp e rm a tids(yo un g sp erm atids ) (Y S ), a nd m atu ra-tion -p ha se spe rm atid s (o ld spe rm atid s)(O S). A du lt > 4 0 0 g ) ra ts ex pe rien c e d nos ig n ific a n t los s d u ring the s e d iffe re n ts teps in s pe rm a to ge nes is (L eb ov itz a ndJo h nso n , 1 98 3; Jo h ns on et a l, 19 84 a ).A d u lt h orses h ad ea rly los se s i n s p er m at o-ge n es is (e nd o f spe rm ato cy te fo rm atio n)w ith no su bse q ue nt lo sse s (Joh n so n,1 9 85 a) . Y o u ng er a d u lt hu m a ns ha d s ig -n ifica n t lo sse s du rin g p o stpro p ha se o fm eio s is a fte r se co nd ary s pe rm atoc y tes(Jo hn so n et a l, 1 9 84 c). S p ec ific va lu e s a nds ign ific an ce le ve ls a re g iv en in Tab le 2.

I.1

40 -

30 -1

T

20 - f J10 -

I- zC-)00=:

z> -w


14/24

34 4 Jo urna l o f A nd ro logy - N ovem ber/D ecem ber 1986 V ol. 7

T he ag e-re la ted d iffe ren ce in da ily spe rm pro duc -tion la rge ly re su lted from germ ce ll d eg en era tiondu rin g the p roph ase o f m e iosis in o lde r adu lt m en(F ig . 1 6 ; Joh nso n and N eav es , 198 6) . T he re w as nod ifference P > 0 .0 5 ) in the n um ber o f yo ung prim aryspe rm a tocy te s pe r g p arenchym a b etw een younge rand o ld er adu lt m en . O n ly the o lde r m en h ad a sign if-ican t reduc tion in po ten tial da ily spe rm p ro duc tionbe tw een young and o ld p rim ary spe rm ato cy tes .H ence, th e degene ra tion o f la te lep to tene , zyg o tene ,o r p ach y tene p rim ary sp erm a tocy te s in o lde r adu ltm en w as the m a jo r sou rce o f th e age -re la ted d iffe r-ence in da ily spe rm produ ctio n . It shou ld be po in tedou t, h ow eve r, tha t the n um ber o f typ e A pale spe r-m a tog on ia pe r m an as w e ll as th e num ber o f eachsu bsequ en t ce ll typ e w as le ss P < 0 .01 ) in the o ld erm en . W h ile th is is co nsis ten t w ith som e age -re la tedd ifference occurrin g during spe rm a to cy te fo rm atio nin hum ans, the m a jo r age -rela ted e ffec t w as duringp ro phase o f m e io sis .

T h e d iffe ren ce in n um bers o f p achy ten e prim arysp e rm a tocy tes in o lde r m en w as subseq uen tly re -

f lec ted (F ig . 1 3 ) a t the lev el o f sp erm a tid s w ith asph e rica l nu cleu s (Joh nso n e t a l, 1 984 c, 1 986b) andm a tu ra tion -ph ase spe rm a tid s (Jo hnso n e t a l, 1 984 b).B o th age g rou ps exp e rienced sig n if ican t degene ra -tion a t the end of m e iosis (Joh nso n e t a l, 198 4c ). S incethese los ses w ere p ro portion al b etw een age g ro ups ,it d id no t con trib u te to age -rela ted d iffe rences inda ily spe rm p ro duc tion .

Th e d ifference in the num ber o f spe rm atid s w ith asp he rica l n uc leus pe r m an be tw een younge r ando lde r ad u lt m en (o ld er m en have 66% or less th anth at o f y ounge r m en ; John son et a l, 198 4c ) is sim ila rto the d ifference in th e num ber o f m a tu ratio n -phasespe rm atid s pe r m an (o lde r 71% of young er m en ;Jo hnso n e t a l, 1 984 b). Th us, the re ap pea rs to b e noage -rela ted d iffe ren ce in d eg en era tion du ring spe r-m iog en es is in hum ans. W hen d aily spe rm prod uc tionbased o n sp erm a tid s w ith a sph erical nu cleus w ascom pared w ith da ily sp erm p ro duc tion based on thenum ber o f m a tu ra tion -ph ase sp erm a tid s o r o n theto ta l n um ber o f all typ es o f sp erm a tid s in th e sam em en , n o degene ra tion w as foun d during spe rm a to -

F ig . 15 . Ty pe s A d ark (A d ) an d A p a le (A p ) sp erm ato go n ia , p re le p to ten e a n d le p to ten e p rim ary sp erm ato cy te s , co lle c tive ly ca lled yo u ngp im a ry s p e rm a toc y te s (Y P S ), p ac h y tene p lus d ip lo ten e p rim ary s p e rm a toc y te s , c o l lec tiv e ly c a lled o ld p rim a ry s pe rm a to c y tes (O P S ), G o lg ia n i c ap ph as e s p e rm a tids , c o lle c t iv e ly c a lled y ou ng s pe rm a tids (Y S ) , a nd S er to li c e lls (S C ) a s ob s e rv e d in 1 .0 -h im to lu id in e b lu e -s ta ine dE p on s ec t ion s o f h um an s em in ife rou s tu bu le (S tag e III) fo llo w in g v as c u la r p e rfu s io n w ith g lu ta ra lde hy de an d f ix a tion w ith 0s 04 . B a rlen g th is 10 z m .


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E -ILT tI iW IL T t lTi- I

F ig . 1 6. a) E ffe c t o f a g e o n th e nu m b ero f v a rio us ge rm c e lls pe r g P> 0 .05 o n a llty pe s c om pa re d ). b ) E ffec t o f a ge o np o te n tia l d a ily sp erm p rod uc tion p er gp are n chy m a . S ign ifican t d iffe ren ce s b e-tw ee n a ge gro u ps w e re fo u nd fo r o ldp rim ary sp e rm a tocy te s (pa ch yten e p lusd ip lo ten e ) a nd y oun g s pe rm a tids (G o lg ia nd c a p p ha s e s ). In the y ou ng e r ag e g ro up ,th e v a lue fo r y oun g s pe rm a tid s w as low erP< 0 .05 ) th an va lue s fo r o th e r ce ll typ e s .In on ly th e o lde r m e n, th ere w as a s ign ifi-ca n t re d uction in p o te n tia l da ily s pe rmp rod u ctio n b etw ee n yo un g (pre le p to ten ea nd le p to ten e) a nd o ld prim a ry spe rm a-tocy te s . It is th is d eg en e ra tion o r loss o fla te lep to te ne , zy go ten e, o r p ach yte nep rim ary sp erm ato cy te s th a t la rg e ly ex -p la in s a ge -re la ted d iffe ren ce s in d a ilysp e rm prod uc tion p er g p aren ch ym a .(J o hn s o n an d N e av es , 198 6 ) .

r iA D A C A PaLE S

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gen esis (T ab le 2 ; F ig . 1 3 ; Joh nso n e t a l, 1 981 ).A ge -re la ted D iffe rence in N um bers o f

N onge rm ina l T es ticu lar C ellsThe age -re la ted declin e in the re sp onse o f the tes-

tis to hC G (N ank in e t a , 19 81 ; M urono e t a , 1982m ay be re lated to the red uc tion in th e num ber o fL ey d ig cells in o ld e r m en . N ega tive rela tion sh ip sbe tw een ag e and num bers o r m ass o f L eyd ig ce llshav e been reported (T eem , 1935 ; S argen t and M c-D ona ld , 19 48 ; T illin ge r, 19 57 ; H arb itz , 197 3 ; K ale rand N eaves, 197 8 ; N eav es e t a , 19 84 ; N eav es andJohn son , 1 985 ). S ince th ere a re red uc tions in the

bvo lum e density o f L ey d ig ce lls in th e pa ren ch ym a ,and th e vo lum e o r num ber o f L eyd ig ce lls p er g ramparen ch ym a is redu ced in o lde r m en (N eav es e t a t,1 984 ), th e re is a reduc tion in the to tal num ber o fL eyd ig cells pe r m an . In con tra st, K o tha ri and G up ta(19 74) and H onore 1978 repo rted h yp erp la sia o fL eyd ig cells w ith advanc ing age in hum an s. C om par-ing spec ies , Ew ing e t a l. (197 9) foun d tha t L eyd ig ce llm ass w as no t rela ted to the am oun t o f tes to ste ro neprodu ced du rin g in v itr o p erfu sion . H ow ev er , Z irk ine t a t (1 980 ) foun d tha t th e p ercen tage o f sm oo thendop la sm ic reticu lum in the Leyd ig ce ll a lm os tto ta lly exp la ined the va ria tion in the in v itro produc-


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F ig . 1 7. T he an nu a l cyc le o f the L ey d igce ll p op u la tion in s ta llion s re ve a led bye va lua tio n o f e ac h 3 -m o nth p eriod fo ro ne ye ar . T h e nu m b ers o f L ey d ig c e lls pe rg p a ren ch ym a w e re s im ila r P > 0 .05 )a m o ng th e fo ur 3 -m o nth tim e p e rio ds .T h e n u m b er o f Le yd ig ce lls pe r tes tis fo rM a y to Ju ly w a s h igh e r P < 0 .0 5 ) tha nA ugu s t to O c to be r o r F e b rua ry to A prila nd h ig he r P J < I 0 .01 ) tha n in N ov em be rto Ja nu ary . W h ile th e n um be rs o f Le yd igcel ls pe r tes tis w ere s im ila r P > 0 .05 )b etw e en F eb ru ary to A p ril a n d A ug u st toO c to b er a nd be tw e en A u gu st to O ctob e ran d N o ve m b er to Ja nu a ry , va lu es fo rF eb rua ry to A pr il w e re s ig n ific an tly P -Id

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34 6 Jou rn al o f A ndro lo gy - N ovem ber/D ecem ber 1986 Vo l . 7

N O V -JA N F E B -A P R M A Y -JU .. A U G -O C T

tio n o f te sto s te rone in th e te stis m ax im a lly stim u-lated w ith LH . In rats and horse s, the num bers o fL eyd ig ce lls w ere n o t redu ced in aged m a le s (K a le rand N eaves, 19 81 ; Joh nso n and N eav es, 19 81 ; John -son and T hom pson , 198 6). In add itio n , th e size o f theL eyd ig ce ll pop u la tion cy cle s annu ally rega rd les s o fag e in adu lt h o rses (F ig . 17 ; Joh nso n an d Thom pson ,1986).

Th e num ber o f L eyd ig ce lls is co rre la ted (r = 0 .76 ; P


17/24

No.6 SPE R M A T O G E N E S IS A N D A G IN G IN TH E H U M A N - Johnson 34 7

F ig . 1 8 . E le c tron m icrog raphs o f Leyd ig ce lls in a 66 -y r -o ld m an . These ce lls appea r to b e n orm al, w ith an abundance o f s mo o the nd op la sm ic re tic u lum (S E R ) an d m itoc ho nd ria (M ). Als o , th e G o lg i com plex G C ) a nd ly sos om al b od ie s (L ) are p re sen t. L eng th o f e ach ba re qu a ls 2 m .son , 19 86) an d an age -re la ted d ec line in the S erto licell p opu latio n in h um ans (T ab le 1 ; F igs. 1 4 an d 21 ;Jo hnso n e t a , 1 984d). In s tallio ns, th ere a re m o reS e rto li ce lls w h en d aily sp erm prod uc tion is h igh ;

the re a lso is a s lig h t bu t sig n ifican t inc rea se in thera tio o f g e rm ce lls to S erto i cells in the b reed ingseason (Joh nso n an d T hom pson , 19 83 ; Jo hnson ,1 985b , 19 86). In hum ans, th e age -re lated d ec line in

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m yo id ce lls , as ca lcu la te d b y tw o ap - ...Jp ro ac he s, in you n ge r a d u lt (2 0 -48 yrs ) ..Ja n d o ld er a d u lt (5 0-9 0 yrs) m en . T h e L I-Ired uc tion in th e n um b e r o f m yo id c e lls in 0o ld e r m e n w as n ot s ig n ifica n t w he n ba se do n c a lcu la tion s in c lu d ing th e nu m b er pe r -cro ss sec tion an d tub u la r le ng th . T h e 0red uc t ion in o ld e r m en c a lc u la te d fro mth e p rim ary da ta o f p e rce nt nu c le i in th ep a ren ch ym a an d the d iam ete r (o r vo lu m e)of nu cle i w as s ig nifica nt P < I 0 .05 ) . 0(Joh n son e t a l, 1986c ) .

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18/24


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SPER M A TO G EN E SIS A N D A G IN G IN T H E H U M A N . Johnson

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F ig . 2 2 . R atio o f th e nu m b e r o f p ri-m ary s pe rm a tid s p e r S e rto li ce ll in thera t, ho rse , a n d hu m a n . D ata on ra ts w asta ke n fro m W in g an d C h ris ten se n (1 98 2) ,h o rse s from Jo hn so n (1 98 6) , a nd h um an sfro m Jo hn so n et a l (19 8 4d ).

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F ig . 23 . T he re la t ion s h ip b e tw ee n thenu m b er o f S e rto li c e lls pe r m an a nd da ilys p e rm pro du c tion p e r m an in 71 m enag e d 2 0 to 8 5 ye ars . (Jo h nso n et a l,1984d) .

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S asano and Ich ijo (19 69) and Suoran ta (19 71) usedtechn iq ues o f m ic ro an g iog raph y to illu strate there latio nsh ip be tw een age -re la ted d eg ene ra tion ofsem in ife ro us tub u la r o r L eyd ig cells and vascu la rd eg ene ra tion . V ascu la r degene ratio n w as revealedb y m ic ro vascu la r le sion s an d d im in ish ed b lo od su pp ly .R egade ra e t a l (198 5) repo rted tha t ar te rio scle rosis

w as in vo lv ed in th e dec line o f te sticu la r fun ctio n w ithage . T hey fou nd th at eld er ly m en w ith sev ere a th -e rom a tosis had te sticu ar pa renchym a tha t ap pearedfib ro sed w ith sc e ro sed tubu les . H a takeyam a e t a .(1 979 ) a ttribu ted som e typ es o f foca l tub u la r a tro phyto locally lim ited is ch em ia . W e h av e h ad g rea ter d iff i-c ulty ob ta in in g good f ixa tion b y v ascu lar p erfu sion o ftes tes from old m en than from younge r m en ob ta inedfrom au top sy . H ow eve r, it is n o t c lea r if va scu la r

{246} 5 {212}0 idooNUMBER OF SERTOLI CELLS mt I I tons )


20/24

F ig . 2 4 . E lec tron m icro gra ph of se m in ife ro u s e p ithe lium in a 6 6 -yr-o ld m a n. T he S e rto li ce lls (S C ) ap p ea r to b e no rm al in th e ad lu m ina lc om pa rtm e nt (P an e l A ) w ith a G olg i com plex (C C ) p re sen t in th is v ie w . J un ctio na l com plex es ( J C ) b e tw e en ad ja ce nt S erto li ce lls ab ov e theb a sa l com pa rtm e nt (P a n e l B ), rod -like m ito cho n dria (M ), p ro file s o f sm o oth e nd o p lasm ic re ticu lu m (S E R ), ro u gh en d op la sm ic re ticu lu m(R E R ), a n d lip id drop le ts (LD ) o f va rio u s d en s ities c ha rac te rize th ese S e rto li ce lls . S p e rm a tog on ia (S C ) a nd C o lg i sp e rm a tid s w ith as ph er ica l n u c le u s ca lle d ro un d s pe rm a tid s (R S ) a re p re se nt be tw e e n S e rto li c e lls . B a r le n g th is eq ua l to 2 m .


21/24


22/24

352 Jou rn al o f And ro logy . N ovem ber/D ecem ber 1986 Vo l . 7

B arr A B , M oo re D l, P a u ls en C A . G e rm ina l c e l l lo s s d u r ing h um ans pe r ma togenes is . J R e pro d F e rtil 1 97 1 ; 25 :75 -80 .

B as c om K F , O s te rud H L . Q u an t ita tiv e s tud ies on the tes tic u le : I I.P a tte rn an d to ta l tub u le len g th in th e tes tic les o f c e rta inm am m a ls . A na t R e c 1 925 31 :15 9 -169 .

B is h op M W H . A g e in g an d rep rod uc tion in the m a le . J R epr odF e rtil 19 70 ; (S up p l. 12 ) 6 5 -8 7 .

B lum V . D as p ro b le m d es m an n lic he n k l im a k te riu m s . W ien K imW chn s h r 1 93 6 ; 49 :1 133 -1 13 9 .

B re m n er W J , V itie llo M V , P rin z P N . Lo s s o f c irc ad ian rh y th m ic ityin b lo od tes tos te ro ne lev e ls w ith ag ing in no rm a l m en . J C linE n do c rino l M eta b 19 83 ; 56 :12 78 -12 81 .

C le rm on t Y . Q u an tita tiv e a na ly s is o f s p e rm a tog en es is o f th e ra t :a re v is ed m od e l fo r the re ne w a l o f s pe rm a to go n ia . A m J A n a t1 96 2; 1 11 :1 11 -1 29 .

C le rm on t Y . T he c y c le o f the s e m in ife rou s ep ith e liu m in m a n .A m J A na t 19 63 ; 11 2 :3 5 -51 .

C le rm on t Y , P e re y B . Q ua n t ita t iv e s tu dy o f the c e ll po pu la t ion o fth e s em in ife ro us tub u les in im m atu re ra ts . A m J A na t 1 95 7 ;100 :241 - 267 .D ai W S , K u lle r L H , L aP orte R E , G uta i J P , F a lv o -C e ra rd L , C a g-g iu la A . T he e p id em io logy o f p la s m a tes tos te ro ne lev e ls inm id d le -ag ed m en . A m J E p ide m io l 1 98 1 ; 1 14 :80 4 -816 .

D a v id s o nJ M , C he nJ J , C ra po L , G ray G D , G ree n le a f W J , C a tan iaJ A . H o rm o na l c han ge s a nd s e x u a l fu nc t ion in a g in g m en . JC lin E ndo c r ino l M e tab 1 983 ; 57 :71 -77 .

d e K re ts e r D M , B u rge r H G , H u ds on B , K e ogh E J . T h e H C Cs tim u la tion te s t in m en w ith tes tic u la r d is o rde rs . C Iin E n do-c r ino l (O x f) 1 97 5 ; 4 :5 91 -59 6 .

D y m M , M a dh w a R a j H G . R e s p on s e o f a du lt ra t S e rto li c e lls a ndLe y d ig c e lls to de p le tion o f lu te in iz ing ho rm one an d te s to s te r-o ne . B io l R ep rod 19 77 ; 1 7 :6 76 -69 6 .

E ng le E T . T he te s tis and ho rm o ne s . In : C o w d ry E V , ed . C ow dry sp rob lem s o f ag e ing . B a ltim o re : W illia m s a nd W ilk ins , 19 42 ;475 - 494 .

E w ing LL , J o hn s on B H , D es ;a rd in s C , C le gg R F . E ffe c t o f a geu po n the s p e rm a tog en ic an d s te ro ido ge n ic e lem en ts o f rab b itte s te s . P roc S o c E x p B io l M e d 19 72 ; 1 40 :90 7 -9 10 .

E w ing LL , Z irk in B R , C oc h ra n R C , K ro m a nn N , P e te rs C , R u iz -B rav o N . T e s to s te ron e s ec re t ion b y ra t, ra bb it, gu ine a p ig ,d og an d h am s te r tes te s pe rfus ed in v itro : c o rre la tion w ithL ey d ig c e ll m a s s . E nd oc r ino log y 19 79 ; 1 05 :11 35 -11 42 .

F e ig L A , B e llv e A R , E ric k s o n N H , K la gs b ru n M . S erto li c e llsc on ta in a m ito ge n ic po ly p ep tid e . P ro c N a tI A c a d S c i 1 98 0 ;77 :4774 - 4778 .

F ja llb ra n t B . A u to im m une hu m a n s pe rm a n tibo d ie s an d ag e inm a l e s . J R ep rod F er til 1 975 ; 43 :14 5 -148 .

F r ic k J . D a rs te llu ng e in e r M e th od e z u r be s tim m un g de s tes tos -te ro n -s p ieg e ls im P las m a an d s tu d ie ub e r d en te s to s te ro nm e-tab o lis m u s be im u ber 6 0 J ah re . U ro l In t 196 9 ; 2 4 :481 -5 01 .

C eb au er M R , P ic k e tt B W , S w ie rs tra E E . R e pro du c tiv e ph y s io logyo f th e s ta ll ion : II . D a ily p ro du c tio n an d ou tpu t o f s p e rm .A n im S c i 1 97 4 ; 39 :7 32 -73 6 .

G os de n R C , R ic h a rds o n D W , B row n N , D av ids on D W . S tru c tu rea nd g am eto ge n ic po te n tia l o f s e m in ife ro us tu bu les in a ge ingm i c e . J R ep ro d F e rtil 1 982 ; 64 :12 7 -13 3 .

H a m e rly n c k J V T H . C y to tox ic a nd o the r an tib od ies a ga ins t s pe r -m a to z o a in re la tio n to in fe rtili ty in th e hu m a n m a le . T he s is ,A m s te rdam , 1 97 0 .

H a rb itz T B . M orp ho m e tric s tu d ies o f the Le y d ig c e l ls in e lde r lym en w ith s p ec ia l re fe ren c e to the h is to log y o f th e p ros ta te .A c ta P a tho l M ic rob io l S c a nd 19 73 ; 81 :30 1 -3 14 .

H a rm an S M . C lin ic a l as pe c ts o f ag in g o f the m a le rep ro duc tiv es y s tem . In : S c h ne ide r E L , ed . T he ag in g re p ro du c tiv e s y s te m(A g ing V o lu m e 4) . N ew Y o rk : R av e n P re s s , 19 78 ; 2 9 -5 8 .

H a rm an S M , T s itou ras P D . R e pro du c tiv e ho rm o ne s in ag ingm en : I. M ea s u rem en t o f s e x s te riods , ba s a l lu te in iz in g ho r-m one , an d L ey d ig c e ll res pon s e to h um an c ho rion ic g on ado -tropin. J C lin E nd oc r ino l M e tab 19 80 ; 51 :35 -40 .

H arm an S M , T s itou ra s P D , C os ta P T , B lac k m an M R . R ep ro duc -tiv e ho rm one s in a g in g m en : II. B as a l p itu ita ry go na do trop insan d go na do trop in res p on s e s to lu te in iz in g ho rm o ne -re lea s in gho r mone . J C lin E n d o c rin o l M eta b 1 98 2; 5 4:5 47 -5 51 .

H a ta k e y am a 5 , T a k iz aw a T , K aw ah ara Y . F oc a l a trop hy o f th es e m in ife ro us tu bu le in the hu m a n tes tis . A c ta P a th o l J pn1 97 9; 2 9:9 01 -9 10 .

H e lle r C C , C le rm on t Y . K ine tic s o f g e rm in a l ep ithe liu m in m an .R e c e n t F ro g H orm R es 1 96 4 ; 20 :54 5 -575 .

H oc he rea u -de R ev ie rs M T . C on tro l o f s p e rm a tog on ia l m u ltip li-c a tio n . In : M c K ern s , K W , ed . R e produ c t iv e p ro c e s s e s a ndc on trac ep tio n . N ew Y ork : P lenu m P ub lis he rs , 19 81 ; 307-3 3 1 .

H oc h e reau -d e R e v ie rs M T . C ou ro t M . S e rto li c e l ls a nd de v e lop -m en t o f s em in ife rou s e p ithe lium . A nn B io l A n im B ioc h emB io phy s (2 B ) 1 978 ; 1 8 :5 73 -5 83 .

H o ls te in A F, E c k m an n C . M u ltin uc lea ted s pe rm a to c y tes an ds pe rm a tid s in hu m an s e m in ife rou s tub u le s . A n d ro log ia 19 86 ;18 :5 - 16 .

H o ls te in A F , R o os en -R u ng e E C . A tla s o f hu m a n s p e rm a tog ene -s is . B e rlin : G ro s s e V er lag , 198 1 .

H o ls te in A F , B us to s -O brego n E , H ar tm a nn M . D is loc a ted ty pe -As p e rm a tog on ia in hu m a n s e m in ife ro us tub u le s . C e ll T is s u eR e s 19 84 ; 2 36 :3 5 -4 0 .

H om on na i Z T , F a in m a n N , D av id M P , P az C F . S em en qu a li ty a nds e x h o rm o ne pa tte rn o f 39 m id d le a ge d m en . A nd ro log ia1 98 2; 1 4:1 64 -1 70 .

H ono re L H . A g e in g c ha ng es in th e h um an tes t is : a ligh t-m ic ro s c o p ic s tud y . G eron to lo gy 19 78 ; 24 :58 -6 5 .

H orton R , H s ie h P . B a rbe ria J , P a ge s L , C os g ro v e M . A lte re db lo od a nd rog en s in e ld e r ly m en w ith p ros ta te hy pe rp la s ia .C lin E nd oc r ino l M e tab 1 97 5 ; 41 :7 93 -79 6 .

H uc k in s C . T h e m orpho lo gy an d k ine tic s o f s pe rm a to go n ia lde ge ne ra t ion in n o rm a l a du lt ra ts : an an a ly s is u s in g a s im p li-fie d c la s s if ic a tio n o f th e ge rm ina l ep ith e lium . A n a t R ec 1 97 8 ;190 :905 - 926 .

Is h im a ra T , P ag es L , H orton R . A lte red m eta bo lis m o f a nd ro gen sin e lde rly m e n w ith b en ign p ro s ta tic hy p e rp la s ia . J C lin E n do -c r ino l M e ta b 1 977 ; 45 :69 5 -7 01 .

J an s z C F , P om eran tz D K . A c om pa ris on o f Le y d ig c e ll fun c tiona fte r un ila te ra l an d b ila te ra l c ry p to rc h id is m a nd e ffe ren t-du c t-lig a tio n . B io l R ep ro d 1 98 6 ; 3 4 :3 16 -32 1 .

J oh ns en S C . T e s tic u la r b iop s y s c o re c ou n t-a m e tho d fo r re g is -tra tio n o f s pe rm a to gen es is in hu m a n te s te s : n o rm a l v a lu esan d re s u lts in 3 35 hy pog on ad a l m a le s . H o rm on es 1 97 0 ;1 :2 - 25 .

J oh ns on L . A re -e v a lua tion o f da ily s p e rm ou tpu t o f m en . F e rti lS te ril 19 82 ; 37 :81 1-8 16 .

J oh ns on 1 . Inc rea s e d d a ily s pe rm p rod uc tio n in th e b re ed ings e as on o f s ta llio ns is e x p la in ed by a n e lev a te d pop u la tio n o fs p e rm a tog on ia . B io l R ep ro d 1 98 5a ; 3 2 :1 18 1 -1 19 0 .

J oh ns on L . T e m p ora l re la tio ns h ips a m o ng s ea s o na l v a ria tio ns innu m bers o f S e rto li, g e rm , a nd Le y d ig c e lls in ad u lt s ta ll ion s .B io l R e p ro d (S up p l 1 ) 19 85 b ; 32 :21 4 .

J oh ns on L . A new a pp roa c h to qu an t ific a tion o f S e rto l i c e l ls th a ta v o ids p ro b le m s a s s o c ia te d w ith the irre gu la r nu c le a r s u r-fa c e . A na t R ec 19 86 ; 2 14 :23 1 -2 87 .

J o hn s on L , N ea v e s W B . A g e-re la ted c h an ges in th e L ey d ig c e llp op u la tion , s e m in ife ro us tu bu les , a nd s p e rm p ro du c tio n ins ta llions . B io l R e p ro d 19 81 ; 2 4 :7 03 -71 2 .

J o hn s on L , N e av es W B . E nh an c ed d a ily s pe rm prod uc t ion in th ere m a in ing te s t is o f ag ed ra ts fo l low ing he m ic as tra tion .A nd ro l 19 83 ; 4 :1 62 -16 6 .

J o hn s on L , N e av es W B . E ffec t o f ge rm c e ll los s d u ring s p e rm a to -gen es is o n s pe rm prod uc t ion in y o un g a nd o lde r adu lt m e n .B io l R e p ro d (S up p l 1 ) 1 986 ;3 4 :6 1 .

J o hn s on L , N gu y e n H B . A nn ua l c y c le o f the S er to li c e ll p op u la tio nin adu lt s ta llio ns . J R e pro d F e rtil 1 98 6 ; 76 :31 1 -3 16 .

J o hn s on L , T ho m ps o n D L . A g e -re la ted and s ea s o na l v a ria tio n in


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th e S er to li c e ll pop u la tio n , da ily s p e rm p ro duc tio n an d s e ru mc on c e n tra tio ns o f fo llic le -s tim u la t ing h o rm on e , lu te in iz ingh o rm on e a nd tes tos te ro ne in s ta l lion s . B io l R ep ro d 19 83 ;29:777 -789 .

J oh ns o n L , T hom p s on D L J r. S e as o na l v a ria t ion in th e to ta lv o lu m e o f L ey d ig c e lls in s ta llio ns is e x p la in ed by v a r ia tion inc e ll n um be r ra the r tha n c e ll s iz e . B io l R e p rod 1 98 6 (in p res s ).

J o hn s o n L , A m a nn R P , P ic k e tt B W . S c an n ing e lec tron an d ligh tm ic ros c op y o f the eq u in e s em in ife rou s tub u le . F e rtil S te ri l1 97 8; 2 9:2 08 -2 15 .

J o hn s o n L , P e tty C S , N e av e s W B . A c o m p ara tiv e s tu dy o f da ilys pe rm p rod uc tion an d tes tic u la r c o m p os itio n in h um an s andra ts . B io l R ep rod 1 98 0a ; 22 :12 33 -1 243 .

J o hn s o n L , P e tty C S , N e av es W B . T he re la tio ns h ip o f b io ps ye v a lua tion s an d tes tic u la r m ea s u rem en ts to ov e r-a ll da ilys pe rm prod uc tion in hu m a n tes te s . F e rt il S te r il 19 80 b ;34 :36 - 40 .

J o hn s o n L , P e tty C S , N e av es W B . A n ew a pproa c h to q ua n t ific a -tion o f s pe rm a to ge nes is an d its ap p lic a t ion to g e rm in a l c e lla trit ion du rin g hu m a n s pe rm io ge ne s is . B io l R ep ro d 19 81 ;25 :217 - 226 .

J o hn s o n L , P e tty C S , N eav es W B . F u r the r q ua n ti fic a tio n o fh um an s pe rm a to ge nes is : ge rm c e ll lo s s du rin g p os tp roph as eo f m e ios is an d its re la t ion s h ip to da ily s p e rm p ro du c tio n . B io lR ep rod 19 83 ; 2 9 :2 07 -21 5 .

J o hn s o n 1 , Le bo v itz R M , S a m s on W K . G e rm c e ll de gen e ra tion inn o rm a l a nd m ic row av e -irra d ia ted ra ts : p o te n t ia l s pe rm p ro -d uc t ion ra tes a t d iffe ren t de v e lop m e n ta l s te ps in s pe rm a to -g en es is . A na t Re c 1 98 4a ; 2 09 :5 01 -5 07 .

J o hn s o n L , P e tty C S , N e av es W B . In flue nc e o f a ge on s p e rmp rod uc tion a nd tes tic u la r w e igh ts in m e n . J R e prod F e rti l1 98 4b ; 7 0:2 11 -2 18 .

J o hn s o n L , P e tty C S , P o rte r J C , N ea v e s W B . G erm c e ll de ge ne ra -tion du rin g po s tp ro pha s e o f m e io s is a nd s e ru m c on c en tra -tions o f go na do trop in s in y o un g a du lt a nd o lde r a du lt m e n .B io l R e p ro d 19 84c ; 31 :77 9 -7 84 .

J o hn s o n L , Z a ne R S , P e tty C S , W ea v e s W B . Q ua n tific a tio n o f th eh um an S er to li c e l l po pu la tion : its d is trib u tion , re la tion tog e rm c e ll nu m b ers , a nd a ge -re la te d d ec l ine . B io l R e p ro d1 98 4d ; 3 1:7 85 -7 95 .

J o hn s o n L , G e org e F W , N ea v es W B , R os en tha l IM , C hr is tens enR A , S c hw e ik e r t H A , S a ue r M V , S w erd lo f f R S , Le s h in M ,G riff in J E , W ils o n J D . C h ara c te riz a tion o f the tes t ic u la ra bn o rm a lity in S o -red uc tas e de fic ien c y . J C lin E nd ocrin olM etab 19 86 a ; (in p re s s ).

J o hn s on L , P e tty C S , N ea v e s W B . A ge-re la te d v a ria tio n in s e m in if -e rou s tub u le s in m e n : a s te reo log ic ev a lu a tio n . J Andr o l1 98 6b ; 7 :3 16 -3 22 .

K a le r LW , W e av es W B . A ttr itio n o f th e h um an Le y d ig c e ll pop u la -tio n w ith a dv an c in g ag e . A n a t R e c 1 97 8 ; 192 :5 13 -51 8 .

K a le r L W , W ea v e s W B . T h e a ndrog en s ta tus o f a g ing m a le ra ts .E n do c rino log y 1 98 1 ; 1 08 :71 2 -719 .

Kenne l l y JJ , F oo te R H . S a m p lin g bo a r te s te s to s tud y s p e rm a to -g en es is q ua n t ita t iv e ly an d to p re d ic t s pe rm p ro du c tio n .A n im S c i 1 96 4 ; 23 :16 0 -167 .

K o th a r i L K , G up ta A S . E ffec t o f a ge ing o n th e v o lu m e , s tru c tu rea nd to ta l Le y d ig c e ll c o n te n t o f the h um an te s tis . In t J Fer t i l1 97 4; 1 9:1 40 -1 46 .

L eb ov itz R M , J oh ns o n L . T e s tic u la r fu nc tio n o f ra ts fo llo w inge x po s u re to m ic row av e ra d ia tio n . B ioe lec tro m a gn e tic s 19 83 ;4 :107 - 114 .

L ino B F , B a rd en A W H . T he o u tp u t o f s pe rm a to z o a in ram s : I.R e la tion s h ip w ith te s tic u la r ou tpu t o n s pe rm a to z o a a nd thee ffe c t o f e ja c u la tions . A ns t J B io l S c i 19 72 ; 2 5 :3 5 1 -3 58 .

L y n c h K M J r. S c o tt W W . T h e lip id c o n ten t o f the L ey d ig c e ll a ndS e rto li c e ll in th e h um an te s t is as re la ted to a ge , be n ig np ros ta t ic hy pe rp la s ia , an d p ros ta tic c a nc e r. J U ro l 19 50 ;64 :767 - 776 .

M a c L e o d J, C o ld R Z . T h e m a le fa c to r in fe r tility an d in fe rtil ity :

V II. S e m e n q ua lity an d re la tio n to a ge a nd s e x ua l a c t iv ity .F e rtil S te ril 19 53 ; 4 :19 4 -2 09 .

M anc in i R E , R o s e m b erg E , C u lle n M , L av ie r i J C , V ila r 0 , B e rga daC , A nd ra da J A . C ry p to rc h id a nd s c ro ta l hu m a n te s te s . I .C y to lo g ic a l, c y toc hem ic a l an d qu an tita tiv e s tud ies . J ClinE n do c rin o l M e ta b 196 5 ; 2 5 :9 27 -9 42 .

M ann ion R A , C o ttre l l T L C . C o rre la tion be tw e en tes tic u la rb io ps y an d s pe rm c ou n t. J U ro l 1 96 1 ; 85 :95 3 -955 .M ilk M ark e ting B oa rd . T h e bu lls a ge a nd h is c on c e p tio n ra te . R e pPr od D iv M ilk M k tg B d 19 50 ; 1 :31 .

M ilk M a rk e tin g B o ard . T h e e ffe c t o f a ge on th e fe rt ility o f H e re -fo rd bu lls in th e A .I. s tud . R e p B reed P rod O rg M ilk M k tg B d1 96 7; 17 :1 02 .

Mo lna r J. T e s t ic u la r a c tiv ity in o ld ag e . In te rn C o n f o n C ero n t.B a laz s A , e d . B ud ap es t, P ub lis h in g ho us e o f th e H un ga ria nA c ade m y o f S c ie nc es , 1 96 5 .

M on H , H irom o to N , N a k ah a ra M , S h ira is h i T . S te reo lo g ic a lan a ly s is o f Le y d ig c e ll u lt ras tru c tu re in ag ed hum a ns . J C linE n do c rin o l M e ta b 198 2 ; 5 5 :6 34 -6 41 .

M uro no E P , N an k in H R . L in T , O s te rm an J . T h e a g in g L e y d igc e ll: V I. R e s p on s e o f tes to s te ron e p re c u rs o rs to gon ad o tro -p in in m e n . A c ta E nd oc rin o l (C ope nh ) 1 98 2 ; 10 0 :4 55 -46 1 .

N an k in H R , L in T , M uro no E l, O s te rm an J . T h e a g in g L e y d igc e ll: III. G on ad o trop in s tim u la tio n in m e n . J A n dro l 19 81 ;2 :181 - 189 .

N ea v es W B , J o hn s o n L . S em in ife rou s tub u le s an d d a ily s p e rmprod uc t ion (D S P ) in o ld e r ad u lt m en with v a rie d n um be rs o fLe y d ig c e l ls . B io l R ep ro d 1 98 5 ; (S u pp l. 1 ) 3 2 :8 6 .

W ea v e s W B , J oh ns o n L , P o r te r J C , P a rk e r C R J r, P e tty C S . L ey d igc e ll nu m b ers , d a i ly s p e rm prod uc t ion , a nd s e rum go na do -tro p in le v e ls in a g in g m en . J C lin E n d oc rin o l M e ta b 1 9 8 4 ;59 :756 - 763 .

W ea v e s W B , J oh ns on L , P e tty C S . A g e-re la te d c ha ng e in n um be rso f o th e r in te rs titia l c e lls in tes tes o f ad u lt m en : ev ide nc ebe a r ing o n the fa te o f Le y d ig c e lls lo s t w ith inc rea s in g ag e .B io l R e p ro d 198 5 ; 3 3 :2 59 -26 9 .

N e ls on W O . In te rp re ta tio n o f tes tic u la r b iop s y . J A M A 1 95 3 ;151 :449 - 454 .

N ies c h lag E , L am m e rs U , F re is c h em C W , La nge r K , W ic k ing s E J .R eprod uc t iv e fun c tions in y ou ng fa the rs a nd g ran d fa the rs .C lin E n doc rin o l M e tab 1 98 2 ; 5 5 :6 76 -68 1 .

O a k be rg E F . A d es c rip tio n o f s pe rm iog en es is in the m ou s e a nd itsu s e in a na ly s is o f the c y c le o f the s e m in ife ro us e p ithe lium an dg erm c e ll re ne w a l. A m J A n a t 19 56 ; 9 9 :391 -4 13 .

O la r T T , A m an n R P , P ic k e tt B W . R e la tion s h ips a m o ng tes tic u la rs iz e , da ily p rod uc tion an d ou tpu t o f s pe rm a toz o a , a nd e x tra -g on ad a l s p e rm a toz oa l res e rv es in the do g . B io l R e p ro d 19 83 ;29 :1114 - 1120 .

O rtav a n t R . Le c y c le s p e rm a tog en e tiq ue c he z le B e lie r. D S cT he s is , U n iv o f P a ris , F ran c e , 1 958 .

P u rv is K , C la us e n O P F , H an s s on V . E ffec ts o f ag e a nd h y p op hy -s ec tom y on re s po ns iv e ne s s o f ra t L ey d ig c e lls to h C G . JR ep rod F er til 1 98 0 ; 60 :77 -8 6 .

R egader a J, N is ta l M , P an ia gua R . T es t is , ep id idy m is , an d s pe r-m a t ic c o rd in e ld e rly m e n . C orre la tion o f a ng iog ra ph ic an dh is to lo g ic s tud ies w ith s y s tem ic a rte r ios c le ros is . A rc h P a th o lL ab M e d 19 85 ; 1 09 :66 3 -6 67 .

R ob b C W , A m ann R P , K illian C J . D a ily s pe rm pro du c tion an de p id id y m a l s p e rm res e rv es o f p ub e rta l an d ad u lt ra ts .R ep ro d F ertil 1 97 8; 5 4: 10 3-1 07 .

R oo s e n -R un ge E C . U n te rs uc hu ng en u ber d ie deg en e r tion s am en -b ild en de r z e lle n in d e r no rm a len s pe rm a tog en es e de r ra t te . ZM ik ros k A n a t F o rs c h 19 55 ; 4 1 :2 21 -23 5 .

R oo s e n -R un ge E C . Q u an tita tiv e in v es tig a tio ns on h um an tes tic -u la r b iops ies : I . N o rm a l te s tis . F e rtil S te ril 1 95 6; 7 :2 51 -2 61 .

R oo s e n -R un ge E C . C e rm ina l-c e ll lo s s in no rm a l m e taz oan s p e r-ma togenes is . J R ep ro d F ertil 1 97 3; 3 5:3 39 -3 48 .

R ow le y M J , H e lle r C C . Q ua n tita tio n o f th e c e lls o f th e s e m in ife r-o us e p ith e l ium o f the hum a n te s tis e m p lo y in g the S e rto li c e ll


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a s a c o ns tan t. Z Mikrosk A n a t F o rs c h 19 71 ; 1 15 :46 1 -4 72 .R u sse ll L D , C le rm o nt Y . D eg e ne ra tion o f g erm ce lls in n o rm a l,

hy pophy s ec tom iz ed an d ho rm on e trea ted h ypo p hys ecto m -iz ed ra ts . A na t R ec 1 97 7; 1 87 :3 47 -3 66 .

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S arg e nt JW , M c D o n a l d JR . A m eth od fo r th e q ua ntita tive es t i-m a te o f L ey d ig c e lls in the hu m an tes t is . P roc . S ta ff M ee ting sM a y o C l in ic , 1 94 8; 2 3:2 49 -2 54 .

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S ilb e r S J . M ic ro s u rge ry fo r v as ec tom y rev e rs a l an d v as oe p id i-d ym osto m y. U ro lo gy 1 9 84 ; 23 :505 - 524 .

S ilbe r S J, R odr igu ez -R igau U . Q ua n t ita t iv e ana ly s is o f tes tic leb io p sy : d e te rm ina tio n o f p a rtia l ob s tru c tio n a n d pre d ic tio n o fspe rm c o un t a fte r s u rge ry fo r obs tru c tion . F e rti l S te ri l 1 98 1 ;36:480-485.

S k ak k eb ae k N E , H e lle r C C . Q ua n t ific a tio n o f h um an s e m in ife r-ou s ep ith e iu m : I. H is to log ic a l s tud ies in tw en ty -one fe rtilem en w ith no rm a l c hro m o so m e co m plem en ts . J R e prod F er til1 97 3; 3 2:3 79 -3 89 .S niffe n R C . T h e tes tis : I. T he n orm a l te s tis . A rc h P a tho l 19 50 ;50:259-284.S o de rs tro m K -0 . T ub u la r h ya lin iz a tion in h um an tes tis . A nd ro -lo gia 1 986 ; 1 8:9 7-10 3.

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S te inb e rge r E , T jio e D Y . A m eth od for q ua n tita tiv e an a lys is o fhu m a n se m in ife ro us e p ith e liu m . F e rtil S te r il 1 96 8; 19 :96 0-9 7 0 .

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A rc h [P a tho l A na tj 1 97 1 ; 35 2 :1 65 -18 1 .S w ie rs tra E E . S truc tu ra l c om po s it ion o f s h o r tho rn bu ll tes tes an d

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S w ie rs tra E E . A c o m par is o n o f s pe rm a to z o a p rodu c t ion an ds pe rm a tozo a ou tpu t o f Y o rksh ire a n d La co m b e b o ars . JR ep rod F e rtil 196 8 ; 17 :45 9 -469 .

S w ie rs tra E E , F oo te R H . C y to lo gy a nd k in e tic s o f s p e rm a tog en e -s is in the rab b it. J R e pr od F er til 1 963 ; 5 :30 9 -322 .

T e em M V B . T he re la t ion o f the in te rs ti tia l c e lls o f the tes tis top ro sta tic h yp ertro ph y. J U ro l 19 35 ; 3 4 :6 92 -71 3 .

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W in te rs S J , T roe n P . E p is o d ic L H s ec re t ion a nd the re s po ns e o fL H an d F S H to LH R H to a ge d m en : ev id enc e fo r c oe x is ten tp rim ary tes t ic u la r ins u ffic ie nc y a nd an im p a irm en t in gon a -do trop in s ec re t ion . J C lin E n do c rino l M e tab 1 98 2 ; 55 :56 0 -5 6 5 .Y a s u z u m i C , N a k a i Y , T s ub o I, Y asu d a M , S u g io ka T . T h e fin es tru c tu re o f n uc le i a s rev ea led b y e le c tro n m ic ros c op y . IV .T h e in tra nu c lea r in c lus ion fo rm a tio n in L eyd ig ce lls o f a g in gh um an tes tes . E x p C e ll R es 196 7 ; 4 5 :2 61 -27 6 .

Y o sh id a K I, La N a sa JA J r, T a ka ha sh i J , W in te rs S J , O s h im a H ,T roe n P . S tud ies o f th e hu m an tes tis . X V I. E v a lua tio n o fm u ltip le inde x e s o f te s tic u la r fun c t ion in re la tion to ad v a nc edag e , id iop a th ic o lig os pe rm ia , o r v a ric o c e le . F e rtil S te ril 1 982 ;38 :712 - 720 .

Zirk in B R , E w ing L U , K rom an n N , C o ch ra n R C . T esto s te ron es ec re tion by ra t, ra bb it, gu ine a p ig , d og , an d ha m s te r tes tespe r fus ed in v if ro : c o rre la tion w ith L ey d ig c e ll u ltra s truc tu re .E nd oc rino lo gy 198 0 ; 1 07 :18 67 -1 874 .Z u k e rma n Z , R o dr igu ez -R igau U , W e is s D B , C ho w d hu ry A K ,S m ith K D , S te inb e rge r E . Q ua n t ita t iv e an a ly s is o f the s em i-n ife ro us ep ith e liu m in h um an tes tic u la r b io ps ies , and there la tio n o f s pe rm a to ge nes is to s pe rm d en s ity . F e r til S te r il1 97 8; 3 0:4 48 -4 55 .

Sev en th A nnua l Mic rosu rge ry a t the M ard i G rasTh is sym posium fo r U ro log is ts , A ndro lo g ists , P ed ia tric S urgeon s, and

R esiden ts w ill be h eld at S o u the rn B ap tis t H osp ita l, N ew O rleans, LA . Itwi l l be in tw o p arts. T h e firs t se c tion , en t itled M IC R O SU R G IC A L LEC -TU R ES A N D LA B O R A TO R Y , w ill be h eld F eb rua ry 26-28 ,1987 , an d w illem phas ize a cu rren t se rie s o f M icro su rg ica l A pp lic a tion s in U ro log y -A nd ro lo gy . A 24 -hou r lab sess io n w il l p rov ide h an ds-on ex pe rience inbasic and advanced m ic ro su rg ica techn iq ues.The secon d le ctu re se ries , en titled C U R R EN T C O N TR O V ER S IES INA N D R O LO G Y , w ill b e h eld F eb rua ry 28 , 1 98 7 , an d in c lude epyd idym afunc t ion and ep id idym ovasos tom y , an ti-spe rm an tibo d ie s-fac t o r fic-tio n? , com pu te rized sem en an aly sis-is it clin ica lly p rac tica l?, an d m ore.

C M E cred its o ffe red th rou gh S ou the rn B ap tis t H osp ita l.Fo r m ore in fo rm a tion , p lan ned lec tu re to p ic s , an d facu lty , co n tact B e th

N orw ood , M ic rosu rg e ry Lab A dm in is tra to r , 1 -800 -6 21-19 86 , ex ten sion7 5911 ; in Lou isiana , 1 -80 0-942 -4 330 .

aging men spermatogenesis

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