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Changes with Aging in Human Seminal Vesicle Fluid Fructose Concentration and Seminal Vesicle Weight
THE JOURNAL OF UROLOGY
Vol. 86, No. 1 July 1961 Copyright © 1961 by The Williams & Wilkins Co. Printed in U.S.A.
CHANGES WITH AGING IN HUMAN SEMINAL VESICLE FLUID FRUCTOSE CONCENTRATION AND SEMINAL VESICLE WEIGHT JOHN T. GRAYHACK From the Northwestern University Medical School, Chicago, Ill.
This is a report of the variation in the weight of the left seminal vesicle and in the fructose content of human seminal vesicle fluid noted in the evaluation of autopsy specimens obtained from males ranging from 29-82 years of age. This study was undertaken in an attempt to utilize the changes that occur in the seminal vesicles with aging as an index of biological activity of substances controlling the growth of the accessory sex glands in man. It was stimulated by a desire to enhance understanding of factors possibly related to the increasing incidence of both benign and malignant new growths of the prostate with aging. 1 • 4 The size of the mammalian prostate normally is controlled primarily by testicular secretions and these presumably are principally androgenic in character. 5- 12 Biological and chemical assays Accepted for publication January 19, 1961. This study was supported wholly from the Lucy and Edwin Kretschmer Fund of Northwestern University Medical School. 1 Moore, R. A.: Benign hypertrophy of the prostate. J. Urol., 50: 680, 1943. 2 Smith, K. J. and Jaffe, R.H.: The comparative frequency of prostatic hypertrophy in the white and colored races. Urol. & Cutan. Rev., 36: 661, 1932. 3 Moore, R. A.: The morphology of small prostatic carcinoma. J. Urol., 33: 224, 1935. 4 Rich, A. R.: On the frequency of occurrence of occult carcinomas of the prostate. J. Urol., 33: 215, 1935. 6 McCullagh, E. P. and Schaffenburg, C. A.: The Testes, in Glandular Physiology and Therapy, 5th ed. Philadelphia: J. B. Lippincott Co., 1954, p. 220. 6 Howard, J.E. and Scott, W.W.: The Testes, in Williams, Robert H.: Textbook of Endocrinology, Philadelphia: W. B. Saunders Co., 1955, p. 316. 7 Dorfman, R. I. and Shipley, R.H.: Androgens. New York: John Wiley & Sons, Inc., 1956. 8 Huggins, C. and Sommer, J. L.: Quantitative studies of prostatic secretion, III. Simultaneous measurement of size and secretion of the canine prostate and the interaction of androgenic and estrogenic substances thereon. J. Exp. Med., 97: 663, 1953. 9 Thorborg, J. V.: On the influence of oestrogenic hormones on the male accessory genital system. Acta endocrinol., 1 (suppl. 2): 1-214, 1948. 1°McCullagh, E. P. and Renshaw, J. F.: The effects of castration in the adult male. J.A.M.A., 103: 1140, 1934. 11 Vest, S. A. and Howard, J.E.: Clinical experi-
indicate a progressive decrease in activity and/or content of androgenic steroids in the urine and blood of the human male as he gets older.13-1 6 If the continued growth of the prostate is induced or controlled by hormones, it is paradoxical. Of course, androgenic substances are not the only hormones capable of increasing prostatic size. Estrogenic, 9 • 11-2° progestational, 21 • 22 and pituitary hormones2a-2 5 may participate in the stimulation of mammalian prostatic growth. ence with the use of male sex hormones, I. Use of testosterone propionate in hypogonadism. J. Urol., 40: 154, 1938. 12 Kenyon, A. T.: The effect of testosterone propionate on the genitalia, secondary sex characters and body weight in eunuchoidism. Endocrinol., 23: 121, 1938. 13 Hamilton, H. B. and Hamilton, J. B.: Aging in apparently normal men. I. Urinary titers of ketosteroids and of alpha-hydroxy and betahydroxy ketosteroids. J. Clin. Endocrinol., 8: 433, 1948. 14 Hamburger, C.: Normal urinary excretion of neutral 17-ketosteroids with special reference to age and sex variations. Acta Endocrinol., 1: 19, 1948. 15 Pincus, G.: Aging and Urinary Steroid Excretion, in Hormones and the Aging Process, ed. Earl T. Engle and Gregory Pincus. New York: Academic Press, Inc., 1955, p. 1. 16 Migeon, C. J., Kelly, A. R., Lawrence, B. and Shepard, T. H.: Dehydroepiandrosterone and androsterone levels in human plasma. Effect of age and sex; day to day and diurnal variations. J. Clin. Endocrinol., 17: 1051, 1957. 17 David, K., Freud, J. and DeJongh, S. E.: Conditions of hypertrophy of seminal vesicles in rats. IL The effect of derivatives of oestrone (menformon). Biochem. J., 28: 1360, 1934. 18 Korenchevsky, V. and Dennison, M.: The effect of oestrone on normal and castrated male rats. Biochem. J., 28: 1474, 1934. 19 Korenchevsky, V. and Dennison, M.: The effect on male rats of the simultaneous administration of male and female sexual hormones and the relation to the assay of the hormones. Biochem. J., 28: 1486, 1934. 20 Van Wagenen, G.: The effects of oestron on the urogenital tract of the male monkey. Anat. Rec., 63: 387, 1935. 21 Greene, R. R., Burill, M. W. and Thomson, D. M.: Further studies on the androgenicity of progesterone. Endocrinol., 27: 469, 1940. 22 Lyster, S. C., Lund, G. H., Dulen, W. E. and Stafford, R. 0.: Ability of some progestational steroids to stimulate male accessory glands of reproduction in the rat. Proc. Soc. Exp. Biol. & Med., 100: 540, 1959.
142
CHAXGI~S ,,Trn AGIXG lN SEMINAL VESICLll\ FLUID FRUCTOSE COXCEWl'HATIOt,t WJtIGHT
Under normal that of n,ndrogen. The observed weight response of the seminal 1·csicle of rodents and to the withdrn.,1·u,l ancl administmtion of hormonal substa11ces 1s similar to that of the prostatL:9 · 1;-zo. the gbmls do ~how a variatio11 m cwuv""'" rnsponse. 2,- 29 The aml of seminal Yesicle weight. have allmn,d its me as m1 indi8ator in rat hormone assay If, as might be expected, tbe seminal vesic-le and prostate of man show a uniformity of response, systemic substance8 ~tinrnlating the prostutc would be expected to stimulate the St'.minal YC;sicle. Seminal wsicle weight changes 1rnuld be likely to reflect qua11titati1·e ncriation in accessory sex gland stimulating sulistances. This considemtion, fortifiecl by the that pathologic changes in the vesicles are rnrc, prompt.eel the determinaticm of seminal ,·esicfo weight in males of different ages, The n1lur of the S(:minal vc,stclc as a biological i11rlicator of horm011:1J Htatus i~ enhanced by the fact. that it is a site of formation of fructose in the genital trnct of man °1 ::'.\umcrnus obsern1.t.ions in other have shom1 a direct rela.between the fructose content of the ac-
l. and Bern, II. of iu response of male rnt iiex accesROrics to a.ndrogen. Proc. Soc. Exper. Biol. & :I.led., 94: 680, 1957 "' Listroh, A. J alld Choh Hao Li. Stimulation of 1.lw sex accessmies ol' hypophysectomized male rnts by non-gona.dotrnpbic hormones of the pilnil,ai·y gland. Acl.a Enclororinol., 25: 1, 1957. 20 Ptrnqualini, R. Aceion de la lnt.eotrofrna Sohre Ins Vesicnln.s de la. Rata Macho. 1953.
, mammals. 40: 1030.
:F.: Threshold
bonnonc indicators in Pharm. & Exper. Thcr.,
2s , R. K. and Deanesly, Rnth: Effect of anclroster011c :me! of male hormone concentrat.cs on 1he accessor,' ropnHl ncti ve organ, of castrated rnicc, and gnincn. pi!;s, Biocliem. J., 29: 1424,
A. S.: ComparaLive the an
'°
-U
cessory sex glands or their secretions and thP quantity of androgen administered. Landan's dcm onstrntion 3'' of an increasing fructose r:oncentr:1 tion in the semen of hypogon:1.dal ma le" androgen suggests that this bct\\'i:cn androgen and fructose is present in man. The assumption that the frm:tosc concentration would reflect quantitatively the activity of the androgen present stimulatcrl the determination of fructose in of humm1 seminal vPsicle fluid obtained at irntopsy. MATJi)RlAI, AND IIH:THODii
Specimen:,; were obtained from 1D4 tmsdcdcd autopsies,* with the exception that knowu :wtin, pulmonary tuberculo,;is was avoided and mens from patients e,;trogem; or androgens were not included i11 this ln most instanees, the prostate, rectum, nnd bladder were removed en 1nasse the and the dissection completed On a few u'·'"''°''w" however, the specm1en wacS stored in the ice box for sm·cral hours t.o completion of the dissection. Tlie from death to dissection of the ,, :\8 recorded. The left. vesicle was earefully dissc:ct.r,d from the surrounding tissue and H1 the area. where it appeared to narrow to the ejaculatory duct. The right vesicle was rnrncn:cr! with its surrounding tissue. Semirml. ve:,ielr, fluid ,nts obtained applying pressnrc to the vPsicle or by scraping the opcll vesicle on tlH' lip of a centrifuge tube. U the fluid obtained froni each vesicle exceeded 0.1. cc, the wet'(' analyzed sepnrn.tely; otherwise, the fluid fron1 the two vesicles 1vas combined. Tlw pnwt.atc 1vm1 then measured with :t centirnel,er rule, nm! trans,·erse. sections taken. One of these 1YHR fixed in alcohol; another was pl,1ced in J'onn,1lin. Sections of the right Y('Sicle were also rn tliese fixatives. The left vesicle ,1·as opcm!d and hlottc>rl on absorbent paper until rlry. Tli(, f'ntirc vrsiclc was then weiglied to the ncare~t milli gram on a clmin halancP. A portion of' the left vesicle wn~ then placed in a cont.:1inr·r and dried at 100°(: until u ron8tant \Y~L'~ achievecl. The remainder of tl1i~ ,·esidP ,;_-:1,s placed in formalin. " 2 L:md:111, R. L. and Lon~;hend, R. · 8<:rninal fn1eto,e concen trat.ion as n.n index of activity in man. J. Clin, Endoerinol., H: Hl51 * Performed nt the V A, Rcscard1 Hospitcd :m;: Ea8L Huron, Chirng;o, 111., 195G HJ5(L
144
JOHN T. GRAYHACK 600 ',~Q
'iOO 41j0
400 ~
"' 0
350
.µ 0
l
300
!,-~
r:'°"
250 200 150
100
:· , .
. .• .
50
25
:· :-i!i);;;~:!• .... 30
~
~
~
~
½
W
M
W
H
M
M
Age in yea.rs
FIG. 1. Fructose concentration of seminal vesicle fluid obtained at autopsy from men of varying ages. Each dot represents fructose concentration in single specimen. The fructose concentration of the seminal vesicle fluid was determined using resorcinol and following the procedure outlined by Mann. 33 Transmittance was determined at 500 mu using the Coleman model 14 universal spectrophotometer. Duplicate determinations were performed if possible. If fructose concentrations were determined in fluid from each vesicle, the average of these values was utilized in the final analyses. Vesicles yielding too little fluid for analysis (0.1 cc) were excluded from consideration in determining average fructose concentrations. In 25 instances, a second determination of the fructose concentration was carried out after the seminal vesicle fluid had been allowed to remain in the test tube at room or ice box temperature for a known interval of time. In 7 cases there was sufficient fluid in the right vesicle to allow the vesicle to be divided by a ligature either before or after an initial sample of right seminal vesicle fluid was obtained. The ligated vesicle was allowed to remain in a centrifuge tube occluded with moist absorbent paper for a known interval of time. Then a second specimen of fluid was obtained for determination of fructose concentration. 33 Mann, T.: Fructose and fructolysis in semen in relation to fertility. Lancet, 1: 446, 1948.
RESULTS
The results of the determination of fructose concentration of the seminal vesicle fluid provide more exciting material for analysis than do the weight determinations of the left vesicle. Although there was considerable variation in the fructose concentration in the vesicle fluid in every age group, there was an obvious trend toward a decreased fructose concentration associated with increasing age. This is readily apparent in figure 1 in which each dot represents the fructose concentration in an autopsy specimen. Table 1 presents these data in a different manner; in this table the average fructose concentrations for age groups approximately representing decade groupings* are given. The gradual decrease in average fructose concentration from 264 mg. per cent in the 29-39 age group to 38 mg. per cent in the 71 and over age group is apparent. The average fructose concentration of the 61-70 age group differs significantly (P = .05) from the fructose concentration of the 51-60 age group and the other younger groups. The average fructose concentration of the 51-60 age group differs significantly (P = .0005) from * The specimens were obtained from patients varying from 29-82 years of age; tho8e specimens from patients 50 and below were grouped in two 11 year groups.
CHANGES WITH AUL\(l IN NEMTNAL VE::\lCLJ,] FLUID FRl'CTOSJi; COl\C~:l\T!-lATlON ,n,;rGJ-JT'
TABLE
l. A vcraye fructose c:onccntralion in seminal ve8ic:lc fluid in varyinu nuc yrnups to of
2D
:m
.f()./j()
51-CO
2li·I ± :lT' t52 10\
± :io ± 21
l0.8 12.fi 11.2
(ii iO
Iii±
l:3 .8
71-
:l8 ± D
]Ii.:'>
.,, St:1ndard error
the an,rage frnctosc conc(mtration of the 2H-:3D age group. The decrease of the Fructose eoner:ntration with increasing age adds l;o tlie importance of all these observations. fn addition to the fructose concentration, crude obscrnttions were made with to the gross character the volume, :11Hl the stability of the fntdosc concentration n[ the sen1irwl vcsicln Jfoid The variation in tlic frud,00c concentration in th,, vcsic:le fluid from p:1.ired seminal ve,,iclcR was also evaluated. Observation of neither the, gross cippcamnce nor the volume of 8eminal YE:8iele fit.tid permitted acc11nl1;e prediction of the fructose concentration. The \Yith hig;lier fructose concentrations \\'ere most often assoeiatccl with large volume's ot seminal \'Psicle flttid. 11owen,r, many sample~ with l:nge volume; fo.iled to show u. hi,gb fructlme Clli1Cl:ntrati011. Tlic stability of tlw conc·eHtration of frncto,sc in the yesidc fluid 1rns evaluated in 2ii specimens nHe1· rcn101 al frnm l'Ontuc:t with the ,,esicle and ill 7 in which continued coutact with tlw vesicle l\llS permitted. FnHtosc couc·entrn. tions remained cow,tant in 20 of the 25 i11 which duplic,atc 1\'ct·e cnrried oul, prior to :1ml following storage for 2-200 pins lHmrs in test tulws at room or ice bo:,, temperntures. There w:12 a 50 per cent cleerease in frud,ose concPnt.rntiori in only :3 specinwns. In eont.r:1st. to this relative , fluid allmvPd to n·rnain in c011tad, with the vesicle showed an appre('i:thk dccn,asc' in c·om·cnt.rntion of fructose. in (j of 7 2). The vari:ition bctwe('!l fructose c·oucentn1tions m fluid from paired vesicles is the obscrn1tion that the fructose illustra(.ed concentnt.tion of the fluiJl from one vesicle c,i'.eeded that of its m,1.tn lOO mg;. per ,·1,nt in
4r,
dcterminn ·
tinns mi eacb sidl' werr A 100 per c1·Jl /, difference between the fructose conc:<:ntrntim1 m paired vesicles existed in rn of those 54 Hmvevcr, the average, fructose l'oncrntratiun uf the, mediau 51--60 age group mg. per eent, table l) was exceeded by thr: conct'ntratiou m the fluid from one, vesicle while not or e:swc:edecl the conc:entrntion in tlw fluid ol. its mate in (i nist.ances. In contrast. to the in fructose eoncen· trntion of the seminal vesicle fluid in association with incrr,asing age, the wc,t und of the left. seminal vcstcle sho\\ed no r:onsl,nn t change, The results of the weight cletcrminati01rn of the left. vesic:Jc are presented in tigme 2 ,rnd table 3. In figure 2, each clot rqiresents Uw wet weight. detennination of a left vesicl,>. In tu.bk the average wet and wc:ight8 of tlw left vesicle for age groups approximately ",-"""'""''d-,,-
dec:ade groupings arc: given. A.~ can be scerL th,, a,veragc: weights are rr.latively cm1sta.nt for 11JJ age groups. DIRCl::--;SJON
The dissociation in tlie m ,;emimll vesicle fluid fructose concentration and scmi1wJ vesicle weight that occurn 1vith Rtriking. Tlie data are m figure :3. In t.lrn presence: of a n·bti1-ely ,·011:4:rnl r,eminal ve~iclc· ,veight, there is :1. marked clc:d1n(' in sernimtl vesicle flttid frnd.ocoe (·onc·cntn1tion Cnide Pt;timates indicated tlrnt iI ae.c1wutc rneasmemcnts of the volume of seminal 1·e,;iclc Huid were possible, C'akulations of total frud,ONf· content would serve to the decli1w rn fructose proclllction by the older age gn>UJh 2. Ch11.n.11c in fructose c:oneentrn.Lion noted rn .scn,.inal i:es1:cle jiu.id in continued con/11ct 'With serninal vesicle
TABLic
TcmJlerature
22[,
11:;
lee box
l88
1'72
5_1/2
frp box
11'.2
211
t
202 2f,1
20
20 171~ \I" "2
l~il 100 120 21:
24\)
5)2
Hoom temp. foe box lee bo_, Hoorn IPn1p. lC'e hox
\\)[i
146
JOHN T. GRAYHACK 4.0
3.5
3.0
..µ
2.5
..<1
:;r ~ 2.0
... ..
.µ
~
8 1.5
[c)
1.0
0.5
~
~
~
~
~
~
A~a
M
~
~
W
~
M
M
in y<2ars
FIG. 2. Wet weight of left seminal vesicle obtained at autopsy from men of varying ages. Each dot represents weight of single specimen. TABLE
3. Average wet and dry weight of left seminal vesicle in varying age groups
Age Group
Average Wet Weight No. of of Left Vesicle, Specimens Mg.
350
Average Dry
---, ..........
300
Wt. of Left Vesicle, l\1g.
....
/
,,..,,
,,.,
''
----~----
29-39 40-50 51-60 61-70 71-
21 23 35 89 13
1480 1453 1371 1499 12,5;3 ------
± ± ± ± ±
95* 89 75 77 177
---·-
307 311 290 330 270
-----
± ± ± ± ±
18 22 15 2:3 44
-------
* Standard error These observations are evidence for the presence of substances which arc capable of maintaining vesicle weight but do not stimulate secretion of fructose. The reduction in fructose concentration suggests a decrease in biological activity of androgens. The striking parallel between the gradual decrease in average fructose concentration in the seminal vesicle fluid and the reduction in androgen excretion in the urine noted as the human male ages,1 5 strengthens the hypothesis that a decreased secretion of androgens is the probable cause for both these changes. A definite interpretation of the significance of the observations with regard to the fructose concentration in the seminal vesicle fluid is hindered by gaps in our knowledge. The possi-
250
jl i,
C'
'
V)
:-S" c, 200 ..,j
"'0
'
.µ
- - - D~ w-eight
u
1.,
;:J
VQ01cle
-FructosQ
J:: 150 ~ ~
'o0
:s
~ 100
50
29-39
40-50
51-60
61-70
71-
A1e in years FIG. 3. Comparison of changes in average fructose concentration of seminal vesicle fhiid and average dry weight values of left seminal vesicle with increasing age.
bility that the decreased secretion of fructose by the vesicle of the aging male represents a decreased responsiveness to androgens or suppression by inhibitory substances cannot be
CHAKGES 1YITH AGING TN i::,E!J\ff\,AL VE!::,ICLE FLUID FRUCTOSE CONCEKTRNI'IO'.'s '\\'ElGHT
completely excluded. However, the individual data nr,,aPnt.,YI in figure 1 demonstrate that aging alone does not the production of a vesicle fluid containing a higb fructose concentration. The possibility exists that the reduction in fructo8e concentration of vesicle fluid in the presence of a stable seminal v,:sicle weight rncrely reflects a more response of the fructose concentration than the vesicle weight to a pretenninal in honnonal status. This hypothesis would not explain the graJual decrease in fructose concentration noted witli increa.sing age Lrnless one postulates some basic diffornnce in tb,, preterminal course in the various age groups, sueh as increasing chronicity of illness in the aged. On the cam,es of death in this no such variation was evident. Furthermort\ altJ1ough the data in table 2 suggest that continued contact with the vesicle would reduce the postmorte1n concentration of seminal vesicle fructose below that prcGent at the time of the differences in time from (leath to collection of the specimen recorded in table l seem insufficient to have had aiiy appreciable effect on tbe differences in Inu:tose concentration between age groups. If prolonged postmortem contact of vesicle aml vesicle fluid \,-ould. seem most likely to produce a greater decrease in c:oncentrntion of fluirl in those with higher initial :imounts :md reduce the observed absolute differences between age groups. Finally, while the differences in fructoHc conccntmtion noted in the fluid from paired vesicles demonstrate that tlw le\·el of androgen stimulation is not the only factor controlling [ructom,' the fact that the range of response 1n1H usually the same (48 of 54 observations) is compatible with tbe concr;pt of regulation of this response by systemic fact.on:. None of the evidence twailablr; contmdids the n.ssurnption that thr fructose concentmtion in human tieminal fluid docs not differ from that of other rnannnals in reflecting the biological activity of present. The failure of botb the seminal vesicle and the prostate to undergo 11 regression in size rlcspite the appareut decrease in androgenic in the aging mak favors a systemic r:ausc for the weight mailltenanco of these orgm1s, 'fhc nature of the factor or factors OJlernting to maintain weigbt of those accessory sex glarnfo remains unknown altlwugh animal
experiments indicate that <'strogens, progcstational, and/or pituitary substaiH·es could the necessi1ry stimulus. These or other substam·c·s may simply function enhancing onR or mm·p of the effects of the decreased The ol:mervations rcµorted Uw stability of the weight of the seminal vesic,ic. with aging arc in essential agreement with iJh· more genr;ra.] estimations of semirnd vesicle :,i~c made Lowsley'" some years ago and witb tJ1e recent observations reported Chwalla and Zandanell 35 with regard to wrnght anrl "ize the vesicles. The latter group also undertook their study in an attempt to utilize the in the vesicle as a biological indicator of tliL, activity of substances controlling accessory sc:-; gland growth. As pointed out the the observations and conclusion~ with weight arc handicappnd by th,2 fact Umt the vesicles were weighed with tl1eir fluid; m gc:neral this tends to prodnc(: 11·ide variation:, ,u weight which do not reflect variatiom in fa:s1,,: growth. Their calc:ulati.on of average n::,,idr: weights in the presence and absence of adenoma a somewhat greu.ter avcm.gc weight in patients with adenoma. Prnstatic enlargement was more as:,ociat,1:rl with enlarged rather than small semi1rnl vcsi,,Jr:r Although it seerns unlikelr, the objection th:11' data obt,1ined from examination of nni,oµ,,y specimens of clying from diseasn in no way reflect the status of tl1e human male cannot be the difficulty in interpreting the data tlw i result from a lack of exact infonnation ia Uw human with regard to factors influencing seruirnil vesicle weight and scmirn11 ,-esiele fruct,ose cuncentrntion must be admitt€'d. The reservations engendered these far:ts by no means invalidate the observation,, reported, but should serve as a stimulus to tlie accumulation of more information in thc:'K' regards. 0 •
8UMJ\1AHY AND CONCLUSIONS
The fructose concentration of seminal vesicle flnid and/or the wet and dry of Urn Jdi "Lowsley, 0. S.: The gross human prostate gland and contiguous Surg., Gynec. & Olmt., 20: 188, 1[)16. 3 " Chwalht, R. and ½andanell, E .. llnternud111n. gen tiber die Samenblasengri:isse hei Prosta.tikem, uber die diffuse Prosta.ta.hyperplasie u111l dic Samenblasenhyperplasie. Urologia internal , 7. l\l9, 1958.
148
JOHN T. GRAYHACK
seminal vesicle were determined in 194 specimens obtained at autopsy in men ranging in age from 29-82 years of age. There was a gradual decrease in the average fructose concentration of the seminal vesicle fluid with increasing age. The average weight of the left seminal vesicle varied little with increasing age. These observations suggest that there is present in the aging male a substance or substances which are capable of maintaining the weight of the seminal vesicles
but incapable of maintaining the fructose concentration of the seminal vesicle fluid. The failure of both the seminal vesicle and the prostate to undergo regression in weight with increasing age provides evidence for the continued presence of accessory sex gland stimulating factors which are systemic rather than local. The decrease in fructose concentration noted in the seminal vesicle fluid with aging suggests these factors are not androgenic.
Vol. 86, No. 1 July 1961 Copyright © 1961 by The Williams & Wilkins Co. Printed in U.S.A.
CHANGES WITH AGING IN HUMAN SEMINAL VESICLE FLUID FRUCTOSE CONCENTRATION AND SEMINAL VESICLE WEIGHT JOHN T. GRAYHACK From the Northwestern University Medical School, Chicago, Ill.
This is a report of the variation in the weight of the left seminal vesicle and in the fructose content of human seminal vesicle fluid noted in the evaluation of autopsy specimens obtained from males ranging from 29-82 years of age. This study was undertaken in an attempt to utilize the changes that occur in the seminal vesicles with aging as an index of biological activity of substances controlling the growth of the accessory sex glands in man. It was stimulated by a desire to enhance understanding of factors possibly related to the increasing incidence of both benign and malignant new growths of the prostate with aging. 1 • 4 The size of the mammalian prostate normally is controlled primarily by testicular secretions and these presumably are principally androgenic in character. 5- 12 Biological and chemical assays Accepted for publication January 19, 1961. This study was supported wholly from the Lucy and Edwin Kretschmer Fund of Northwestern University Medical School. 1 Moore, R. A.: Benign hypertrophy of the prostate. J. Urol., 50: 680, 1943. 2 Smith, K. J. and Jaffe, R.H.: The comparative frequency of prostatic hypertrophy in the white and colored races. Urol. & Cutan. Rev., 36: 661, 1932. 3 Moore, R. A.: The morphology of small prostatic carcinoma. J. Urol., 33: 224, 1935. 4 Rich, A. R.: On the frequency of occurrence of occult carcinomas of the prostate. J. Urol., 33: 215, 1935. 6 McCullagh, E. P. and Schaffenburg, C. A.: The Testes, in Glandular Physiology and Therapy, 5th ed. Philadelphia: J. B. Lippincott Co., 1954, p. 220. 6 Howard, J.E. and Scott, W.W.: The Testes, in Williams, Robert H.: Textbook of Endocrinology, Philadelphia: W. B. Saunders Co., 1955, p. 316. 7 Dorfman, R. I. and Shipley, R.H.: Androgens. New York: John Wiley & Sons, Inc., 1956. 8 Huggins, C. and Sommer, J. L.: Quantitative studies of prostatic secretion, III. Simultaneous measurement of size and secretion of the canine prostate and the interaction of androgenic and estrogenic substances thereon. J. Exp. Med., 97: 663, 1953. 9 Thorborg, J. V.: On the influence of oestrogenic hormones on the male accessory genital system. Acta endocrinol., 1 (suppl. 2): 1-214, 1948. 1°McCullagh, E. P. and Renshaw, J. F.: The effects of castration in the adult male. J.A.M.A., 103: 1140, 1934. 11 Vest, S. A. and Howard, J.E.: Clinical experi-
indicate a progressive decrease in activity and/or content of androgenic steroids in the urine and blood of the human male as he gets older.13-1 6 If the continued growth of the prostate is induced or controlled by hormones, it is paradoxical. Of course, androgenic substances are not the only hormones capable of increasing prostatic size. Estrogenic, 9 • 11-2° progestational, 21 • 22 and pituitary hormones2a-2 5 may participate in the stimulation of mammalian prostatic growth. ence with the use of male sex hormones, I. Use of testosterone propionate in hypogonadism. J. Urol., 40: 154, 1938. 12 Kenyon, A. T.: The effect of testosterone propionate on the genitalia, secondary sex characters and body weight in eunuchoidism. Endocrinol., 23: 121, 1938. 13 Hamilton, H. B. and Hamilton, J. B.: Aging in apparently normal men. I. Urinary titers of ketosteroids and of alpha-hydroxy and betahydroxy ketosteroids. J. Clin. Endocrinol., 8: 433, 1948. 14 Hamburger, C.: Normal urinary excretion of neutral 17-ketosteroids with special reference to age and sex variations. Acta Endocrinol., 1: 19, 1948. 15 Pincus, G.: Aging and Urinary Steroid Excretion, in Hormones and the Aging Process, ed. Earl T. Engle and Gregory Pincus. New York: Academic Press, Inc., 1955, p. 1. 16 Migeon, C. J., Kelly, A. R., Lawrence, B. and Shepard, T. H.: Dehydroepiandrosterone and androsterone levels in human plasma. Effect of age and sex; day to day and diurnal variations. J. Clin. Endocrinol., 17: 1051, 1957. 17 David, K., Freud, J. and DeJongh, S. E.: Conditions of hypertrophy of seminal vesicles in rats. IL The effect of derivatives of oestrone (menformon). Biochem. J., 28: 1360, 1934. 18 Korenchevsky, V. and Dennison, M.: The effect of oestrone on normal and castrated male rats. Biochem. J., 28: 1474, 1934. 19 Korenchevsky, V. and Dennison, M.: The effect on male rats of the simultaneous administration of male and female sexual hormones and the relation to the assay of the hormones. Biochem. J., 28: 1486, 1934. 20 Van Wagenen, G.: The effects of oestron on the urogenital tract of the male monkey. Anat. Rec., 63: 387, 1935. 21 Greene, R. R., Burill, M. W. and Thomson, D. M.: Further studies on the androgenicity of progesterone. Endocrinol., 27: 469, 1940. 22 Lyster, S. C., Lund, G. H., Dulen, W. E. and Stafford, R. 0.: Ability of some progestational steroids to stimulate male accessory glands of reproduction in the rat. Proc. Soc. Exp. Biol. & Med., 100: 540, 1959.
142
CHAXGI~S ,,Trn AGIXG lN SEMINAL VESICLll\ FLUID FRUCTOSE COXCEWl'HATIOt,t WJtIGHT
Under normal that of n,ndrogen. The observed weight response of the seminal 1·csicle of rodents and to the withdrn.,1·u,l ancl administmtion of hormonal substa11ces 1s similar to that of the prostatL:9 · 1;-zo. the gbmls do ~how a variatio11 m cwuv""'" rnsponse. 2,- 29 The aml of seminal Yesicle weight. have allmn,d its me as m1 indi8ator in rat hormone assay If, as might be expected, tbe seminal vesic-le and prostate of man show a uniformity of response, systemic substance8 ~tinrnlating the prostutc would be expected to stimulate the St'.minal YC;sicle. Seminal wsicle weight changes 1rnuld be likely to reflect qua11titati1·e ncriation in accessory sex gland stimulating sulistances. This considemtion, fortifiecl by the that pathologic changes in the vesicles are rnrc, prompt.eel the determinaticm of seminal ,·esicfo weight in males of different ages, The n1lur of the S(:minal vc,stclc as a biological i11rlicator of horm011:1J Htatus i~ enhanced by the fact. that it is a site of formation of fructose in the genital trnct of man °1 ::'.\umcrnus obsern1.t.ions in other have shom1 a direct rela.between the fructose content of the ac-
l. and Bern, II. of iu response of male rnt iiex accesROrics to a.ndrogen. Proc. Soc. Exper. Biol. & :I.led., 94: 680, 1957 "' Listroh, A. J alld Choh Hao Li. Stimulation of 1.lw sex accessmies ol' hypophysectomized male rnts by non-gona.dotrnpbic hormones of the pilnil,ai·y gland. Acl.a Enclororinol., 25: 1, 1957. 20 Ptrnqualini, R. Aceion de la lnt.eotrofrna Sohre Ins Vesicnln.s de la. Rata Macho. 1953.
, mammals. 40: 1030.
:F.: Threshold
bonnonc indicators in Pharm. & Exper. Thcr.,
2s , R. K. and Deanesly, Rnth: Effect of anclroster011c :me! of male hormone concentrat.cs on 1he accessor,' ropnHl ncti ve organ, of castrated rnicc, and gnincn. pi!;s, Biocliem. J., 29: 1424,
A. S.: ComparaLive the an
'°
-U
cessory sex glands or their secretions and thP quantity of androgen administered. Landan's dcm onstrntion 3'' of an increasing fructose r:oncentr:1 tion in the semen of hypogon:1.dal ma le" androgen suggests that this bct\\'i:cn androgen and fructose is present in man. The assumption that the frm:tosc concentration would reflect quantitatively the activity of the androgen present stimulatcrl the determination of fructose in of humm1 seminal vPsicle fluid obtained at irntopsy. MATJi)RlAI, AND IIH:THODii
Specimen:,; were obtained from 1D4 tmsdcdcd autopsies,* with the exception that knowu :wtin, pulmonary tuberculo,;is was avoided and mens from patients e,;trogem; or androgens were not included i11 this ln most instanees, the prostate, rectum, nnd bladder were removed en 1nasse the and the dissection completed On a few u'·'"''°''w" however, the specm1en wacS stored in the ice box for sm·cral hours t.o completion of the dissection. Tlie from death to dissection of the ,, :\8 recorded. The left. vesicle was earefully dissc:ct.r,d from the surrounding tissue and H1 the area. where it appeared to narrow to the ejaculatory duct. The right vesicle was rnrncn:cr! with its surrounding tissue. Semirml. ve:,ielr, fluid ,nts obtained applying pressnrc to the vPsicle or by scraping the opcll vesicle on tlH' lip of a centrifuge tube. U the fluid obtained froni each vesicle exceeded 0.1. cc, the wet'(' analyzed sepnrn.tely; otherwise, the fluid fron1 the two vesicles 1vas combined. Tlw pnwt.atc 1vm1 then measured with :t centirnel,er rule, nm! trans,·erse. sections taken. One of these 1YHR fixed in alcohol; another was pl,1ced in J'onn,1lin. Sections of the right Y('Sicle were also rn tliese fixatives. The left vesicle ,1·as opcm!d and hlottc>rl on absorbent paper until rlry. Tli(, f'ntirc vrsiclc was then weiglied to the ncare~t milli gram on a clmin halancP. A portion of' the left vesicle wn~ then placed in a cont.:1inr·r and dried at 100°(: until u ron8tant \Y~L'~ achievecl. The remainder of tl1i~ ,·esidP ,;_-:1,s placed in formalin. " 2 L:md:111, R. L. and Lon~;hend, R. · 8<:rninal fn1eto,e concen trat.ion as n.n index of activity in man. J. Clin, Endoerinol., H: Hl51 * Performed nt the V A, Rcscard1 Hospitcd :m;: Ea8L Huron, Chirng;o, 111., 195G HJ5(L
144
JOHN T. GRAYHACK 600 ',~Q
'iOO 41j0
400 ~
"' 0
350
.µ 0
l
300
!,-~
r:'°"
250 200 150
100
:· , .
. .• .
50
25
:· :-i!i);;;~:!• .... 30
~
~
~
~
½
W
M
W
H
M
M
Age in yea.rs
FIG. 1. Fructose concentration of seminal vesicle fluid obtained at autopsy from men of varying ages. Each dot represents fructose concentration in single specimen. The fructose concentration of the seminal vesicle fluid was determined using resorcinol and following the procedure outlined by Mann. 33 Transmittance was determined at 500 mu using the Coleman model 14 universal spectrophotometer. Duplicate determinations were performed if possible. If fructose concentrations were determined in fluid from each vesicle, the average of these values was utilized in the final analyses. Vesicles yielding too little fluid for analysis (0.1 cc) were excluded from consideration in determining average fructose concentrations. In 25 instances, a second determination of the fructose concentration was carried out after the seminal vesicle fluid had been allowed to remain in the test tube at room or ice box temperature for a known interval of time. In 7 cases there was sufficient fluid in the right vesicle to allow the vesicle to be divided by a ligature either before or after an initial sample of right seminal vesicle fluid was obtained. The ligated vesicle was allowed to remain in a centrifuge tube occluded with moist absorbent paper for a known interval of time. Then a second specimen of fluid was obtained for determination of fructose concentration. 33 Mann, T.: Fructose and fructolysis in semen in relation to fertility. Lancet, 1: 446, 1948.
RESULTS
The results of the determination of fructose concentration of the seminal vesicle fluid provide more exciting material for analysis than do the weight determinations of the left vesicle. Although there was considerable variation in the fructose concentration in the vesicle fluid in every age group, there was an obvious trend toward a decreased fructose concentration associated with increasing age. This is readily apparent in figure 1 in which each dot represents the fructose concentration in an autopsy specimen. Table 1 presents these data in a different manner; in this table the average fructose concentrations for age groups approximately representing decade groupings* are given. The gradual decrease in average fructose concentration from 264 mg. per cent in the 29-39 age group to 38 mg. per cent in the 71 and over age group is apparent. The average fructose concentration of the 61-70 age group differs significantly (P = .05) from the fructose concentration of the 51-60 age group and the other younger groups. The average fructose concentration of the 51-60 age group differs significantly (P = .0005) from * The specimens were obtained from patients varying from 29-82 years of age; tho8e specimens from patients 50 and below were grouped in two 11 year groups.
CHANGES WITH AUL\(l IN NEMTNAL VE::\lCLJ,] FLUID FRl'CTOSJi; COl\C~:l\T!-lATlON ,n,;rGJ-JT'
TABLE
l. A vcraye fructose c:onccntralion in seminal ve8ic:lc fluid in varyinu nuc yrnups to of
2D
:m
.f()./j()
51-CO
2li·I ± :lT' t52 10\
± :io ± 21
l0.8 12.fi 11.2
(ii iO
Iii±
l:3 .8
71-
:l8 ± D
]Ii.:'>
.,, St:1ndard error
the an,rage frnctosc conc(mtration of the 2H-:3D age group. The decrease of the Fructose eoner:ntration with increasing age adds l;o tlie importance of all these observations. fn addition to the fructose concentration, crude obscrnttions were made with to the gross character the volume, :11Hl the stability of the fntdosc concentration n[ the sen1irwl vcsicln Jfoid The variation in tlic frud,00c concentration in th,, vcsic:le fluid from p:1.ired seminal ve,,iclcR was also evaluated. Observation of neither the, gross cippcamnce nor the volume of 8eminal YE:8iele fit.tid permitted acc11nl1;e prediction of the fructose concentration. The \Yith hig;lier fructose concentrations \\'ere most often assoeiatccl with large volume's ot seminal \'Psicle flttid. 11owen,r, many sample~ with l:nge volume; fo.iled to show u. hi,gb fructlme Clli1Cl:ntrati011. Tlic stability of tlw conc·eHtration of frncto,sc in the yesidc fluid 1rns evaluated in 2ii specimens nHe1· rcn101 al frnm l'Ontuc:t with the ,,esicle and ill 7 in which continued coutact with tlw vesicle l\llS permitted. FnHtosc couc·entrn. tions remained cow,tant in 20 of the 25 i11 which duplic,atc 1\'ct·e cnrried oul, prior to :1ml following storage for 2-200 pins lHmrs in test tulws at room or ice bo:,, temperntures. There w:12 a 50 per cent cleerease in frud,ose concPnt.rntiori in only :3 specinwns. In eont.r:1st. to this relative , fluid allmvPd to n·rnain in c011tad, with the vesicle showed an appre('i:thk dccn,asc' in c·om·cnt.rntion of fructose. in (j of 7 2). The vari:ition bctwe('!l fructose c·oucentn1tions m fluid from paired vesicles is the obscrn1tion that the fructose illustra(.ed concentnt.tion of the fluiJl from one vesicle c,i'.eeded that of its m,1.tn lOO mg;. per ,·1,nt in
4r,
dcterminn ·
tinns mi eacb sidl' werr A 100 per c1·Jl /, difference between the fructose conc:<:ntrntim1 m paired vesicles existed in rn of those 54 Hmvevcr, the average, fructose l'oncrntratiun uf the, mediau 51--60 age group mg. per eent, table l) was exceeded by thr: conct'ntratiou m the fluid from one, vesicle while not or e:swc:edecl the conc:entrntion in tlw fluid ol. its mate in (i nist.ances. In contrast. to the in fructose eoncen· trntion of the seminal vesicle fluid in association with incrr,asing age, the wc,t und of the left. seminal vcstcle sho\\ed no r:onsl,nn t change, The results of the weight cletcrminati01rn of the left. vesic:Jc are presented in tigme 2 ,rnd table 3. In figure 2, each clot rqiresents Uw wet weight. detennination of a left vesicl,>. In tu.bk the average wet and wc:ight8 of tlw left vesicle for age groups approximately ",-"""'""''d-,,-
dec:ade groupings arc: given. A.~ can be scerL th,, a,veragc: weights are rr.latively cm1sta.nt for 11JJ age groups. DIRCl::--;SJON
The dissociation in tlie m ,;emimll vesicle fluid fructose concentration and scmi1wJ vesicle weight that occurn 1vith Rtriking. Tlie data are m figure :3. In t.lrn presence: of a n·bti1-ely ,·011:4:rnl r,eminal ve~iclc· ,veight, there is :1. marked clc:d1n(' in sernimtl vesicle flttid frnd.ocoe (·onc·cntn1tion Cnide Pt;timates indicated tlrnt iI ae.c1wutc rneasmemcnts of the volume of seminal 1·e,;iclc Huid were possible, C'akulations of total frud,ONf· content would serve to the decli1w rn fructose proclllction by the older age gn>UJh 2. Ch11.n.11c in fructose c:oneentrn.Lion noted rn .scn,.inal i:es1:cle jiu.id in continued con/11ct 'With serninal vesicle
TABLic
TcmJlerature
22[,
11:;
lee box
l88
1'72
5_1/2
frp box
11'.2
211
t
202 2f,1
20
20 171~ \I" "2
l~il 100 120 21:
24\)
5)2
Hoom temp. foe box lee bo_, Hoorn IPn1p. lC'e hox
\\)[i
146
JOHN T. GRAYHACK 4.0
3.5
3.0
..µ
2.5
..<1
:;r ~ 2.0
... ..
.µ
~
8 1.5
[c)
1.0
0.5
~
~
~
~
~
~
A~a
M
~
~
W
~
M
M
in y<2ars
FIG. 2. Wet weight of left seminal vesicle obtained at autopsy from men of varying ages. Each dot represents weight of single specimen. TABLE
3. Average wet and dry weight of left seminal vesicle in varying age groups
Age Group
Average Wet Weight No. of of Left Vesicle, Specimens Mg.
350
Average Dry
---, ..........
300
Wt. of Left Vesicle, l\1g.
....
/
,,..,,
,,.,
''
----~----
29-39 40-50 51-60 61-70 71-
21 23 35 89 13
1480 1453 1371 1499 12,5;3 ------
± ± ± ± ±
95* 89 75 77 177
---·-
307 311 290 330 270
-----
± ± ± ± ±
18 22 15 2:3 44
-------
* Standard error These observations are evidence for the presence of substances which arc capable of maintaining vesicle weight but do not stimulate secretion of fructose. The reduction in fructose concentration suggests a decrease in biological activity of androgens. The striking parallel between the gradual decrease in average fructose concentration in the seminal vesicle fluid and the reduction in androgen excretion in the urine noted as the human male ages,1 5 strengthens the hypothesis that a decreased secretion of androgens is the probable cause for both these changes. A definite interpretation of the significance of the observations with regard to the fructose concentration in the seminal vesicle fluid is hindered by gaps in our knowledge. The possi-
250
jl i,
C'
'
V)
:-S" c, 200 ..,j
"'0
'
.µ
- - - D~ w-eight
u
1.,
;:J
VQ01cle
-FructosQ
J:: 150 ~ ~
'o0
:s
~ 100
50
29-39
40-50
51-60
61-70
71-
A1e in years FIG. 3. Comparison of changes in average fructose concentration of seminal vesicle fhiid and average dry weight values of left seminal vesicle with increasing age.
bility that the decreased secretion of fructose by the vesicle of the aging male represents a decreased responsiveness to androgens or suppression by inhibitory substances cannot be
CHAKGES 1YITH AGING TN i::,E!J\ff\,AL VE!::,ICLE FLUID FRUCTOSE CONCEKTRNI'IO'.'s '\\'ElGHT
completely excluded. However, the individual data nr,,aPnt.,YI in figure 1 demonstrate that aging alone does not the production of a vesicle fluid containing a higb fructose concentration. The possibility exists that the reduction in fructo8e concentration of vesicle fluid in the presence of a stable seminal v,:sicle weight rncrely reflects a more response of the fructose concentration than the vesicle weight to a pretenninal in honnonal status. This hypothesis would not explain the graJual decrease in fructose concentration noted witli increa.sing age Lrnless one postulates some basic diffornnce in tb,, preterminal course in the various age groups, sueh as increasing chronicity of illness in the aged. On the cam,es of death in this no such variation was evident. Furthermort\ altJ1ough the data in table 2 suggest that continued contact with the vesicle would reduce the postmorte1n concentration of seminal vesicle fructose below that prcGent at the time of the differences in time from (leath to collection of the specimen recorded in table l seem insufficient to have had aiiy appreciable effect on tbe differences in Inu:tose concentration between age groups. If prolonged postmortem contact of vesicle aml vesicle fluid \,-ould. seem most likely to produce a greater decrease in c:oncentrntion of fluirl in those with higher initial :imounts :md reduce the observed absolute differences between age groups. Finally, while the differences in fructoHc conccntmtion noted in the fluid from paired vesicles demonstrate that tlw le\·el of androgen stimulation is not the only factor controlling [ructom,' the fact that the range of response 1n1H usually the same (48 of 54 observations) is compatible with tbe concr;pt of regulation of this response by systemic fact.on:. None of the evidence twailablr; contmdids the n.ssurnption that thr fructose concentmtion in human tieminal fluid docs not differ from that of other rnannnals in reflecting the biological activity of present. The failure of botb the seminal vesicle and the prostate to undergo 11 regression in size rlcspite the appareut decrease in androgenic in the aging mak favors a systemic r:ausc for the weight mailltenanco of these orgm1s, 'fhc nature of the factor or factors OJlernting to maintain weigbt of those accessory sex glarnfo remains unknown altlwugh animal
experiments indicate that <'strogens, progcstational, and/or pituitary substaiH·es could the necessi1ry stimulus. These or other substam·c·s may simply function enhancing onR or mm·p of the effects of the decreased The ol:mervations rcµorted Uw stability of the weight of the seminal vesic,ic. with aging arc in essential agreement with iJh· more genr;ra.] estimations of semirnd vesicle :,i~c made Lowsley'" some years ago and witb tJ1e recent observations reported Chwalla and Zandanell 35 with regard to wrnght anrl "ize the vesicles. The latter group also undertook their study in an attempt to utilize the in the vesicle as a biological indicator of tliL, activity of substances controlling accessory sc:-; gland growth. As pointed out the the observations and conclusion~ with weight arc handicappnd by th,2 fact Umt the vesicles were weighed with tl1eir fluid; m gc:neral this tends to prodnc(: 11·ide variation:, ,u weight which do not reflect variatiom in fa:s1,,: growth. Their calc:ulati.on of average n::,,idr: weights in the presence and absence of adenoma a somewhat greu.ter avcm.gc weight in patients with adenoma. Prnstatic enlargement was more as:,ociat,1:rl with enlarged rather than small semi1rnl vcsi,,Jr:r Although it seerns unlikelr, the objection th:11' data obt,1ined from examination of nni,oµ,,y specimens of clying from diseasn in no way reflect the status of tl1e human male cannot be the difficulty in interpreting the data tlw i result from a lack of exact infonnation ia Uw human with regard to factors influencing seruirnil vesicle weight and scmirn11 ,-esiele fruct,ose cuncentrntion must be admitt€'d. The reservations engendered these far:ts by no means invalidate the observation,, reported, but should serve as a stimulus to tlie accumulation of more information in thc:'K' regards. 0 •
8UMJ\1AHY AND CONCLUSIONS
The fructose concentration of seminal vesicle flnid and/or the wet and dry of Urn Jdi "Lowsley, 0. S.: The gross human prostate gland and contiguous Surg., Gynec. & Olmt., 20: 188, 1[)16. 3 " Chwalht, R. and ½andanell, E .. llnternud111n. gen tiber die Samenblasengri:isse hei Prosta.tikem, uber die diffuse Prosta.ta.hyperplasie u111l dic Samenblasenhyperplasie. Urologia internal , 7. l\l9, 1958.
148
JOHN T. GRAYHACK
seminal vesicle were determined in 194 specimens obtained at autopsy in men ranging in age from 29-82 years of age. There was a gradual decrease in the average fructose concentration of the seminal vesicle fluid with increasing age. The average weight of the left seminal vesicle varied little with increasing age. These observations suggest that there is present in the aging male a substance or substances which are capable of maintaining the weight of the seminal vesicles
but incapable of maintaining the fructose concentration of the seminal vesicle fluid. The failure of both the seminal vesicle and the prostate to undergo regression in weight with increasing age provides evidence for the continued presence of accessory sex gland stimulating factors which are systemic rather than local. The decrease in fructose concentration noted in the seminal vesicle fluid with aging suggests these factors are not androgenic.