REVIEW Spermatogenesis and Aging

ARTICLE

in the Human
LARRY JOHNSON

From the Department of Cell Biology and Anatomy, the University of Texas Health Science Center at Dallas, Dallas, Texas
The consensus of reports on the endocrine func-

tion of the production Ishimara Sparrow

testis in older men is reduced with age et al, 1977; Harman Dai

is that (Horton and

testosterone et al, 1975; 1980; et al, Harman

Tsitouras,

et al, 1980;

et al, 1981;

Key words:
duction, J Androl germ

aging,
1986;

human,

spermatogenesis,

sperm

pro-

cell degeneration.
7:331-354.

1982; Yoshida et al, 1982; Winters and Troen, 1982; Bremner et al, 1983; Davidson et al, 1983; Johnson et al, 1984c; Neaves et al, 1984; Warner et al, 1985). In a summary of 14 recent papers based on 417 old and 384 young adult serum testosterone the older men. men, Neaves concentration Furthermore, 1980; Murono that et al (1984) found that was 14% lower for many researchers Nankin et al, 1981;

The

effect

of age

on

human

organs

is becoming of people live fertile spermatimpor-

(Harman Harman Troen, ability tropin

and

Tsitouras,

more important as a higher percentage longer. The production of sufficient ozoa tant and by the testis of aging men

et al, 1982; 1982) agree to secrete stimulation

et at, 1982; Winters and the testis has a reduced in response men. Although to gonadothe testis

is increasingly

as couples wait until later in life to have children as more aging men are available to become parknowledge be important hyperplasia and of testicular in disorders impotence. function such as

testosterone in aged

ents. Furthermore, in aging men may benign prostatic

in older men has been studied (Blum, 1936; MacLeod and Gold, 1953; Molnar, 1965; Sasano and Ichijo, 1969; Bishop, 1970; Homonnai et al, 1982; Nieschlag et al, aspects sperm (Amann, 1986b; 1982), only recently of spermatogenesis, production rates, been 1981; Neaves Johnson et al, 1984). revealed lower (20-48 (Johnson years) that daily in older men with sperm (50-80 simor lower have the expressed evaluated quantitative in terms of in aging men 1984c, 1984d;

Reprint requests: Larry Johnson, Ph.D., Department of Cell Biology, the University of Texas Health Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Most of our original studies reviewed here were supported in part by NIH Grants AG 2260 (W. B. Neaves, P.!.) and HD 16773 (L. Johnson, P.!,) and United States Air Force contract C-0616 (R. M. Lebovitz, P.!.). Submitted for publication April 2, 1986; accepted for publication May 20, 1986.

et al, 1984b,

The quantitative studies production is significantly years) than in younger weights ilar testicular

et al, 1984b)

331

332

Journal

of Andrology

November/December

1986

Vol.

testicular 1984c). genesis sperm 1984c; related tubules

weights Moreover, 1983) where production Johnson differences (Johnson the

(Neaves, using determined

et al, 1984; Johnson et al, novel techniques, Johnson the steps in spermatoin al, daily 1984b,

on vent tion

seminal

characteristics

(Amann, review considers by examination has been

1981).

To

pre-

et al (1981,

duplication, this of spermatogenesis spermatogenesis

only evaluaof testicular evaluated tubules Mannion by (Basand

age-related reduction occurs (Johnson et Neaves, 1986). in characteristics Leydig

tissue. Human

and

Likewise, ageof seminiferous cells (Kaler and inter(Johnson

the general appearance of seminiferous corn and Osterud, 1925; Nelson, 1953;

et al, 1986b),

Neaves, 1978; Neaves et al, 1984), non-Leydig stitial cells (Neaves et al, 1985), myoid cells

Cottrell, 1961; Johnsen, 1970; Agger and Johnsen, 1978). The general appearance of seminiferous tubules, even as observed by scanning electron microscopy (Johnson et al, 1978), can predict impression of the activity of spermatogenesis Likewise, the general appearance of tubules allow sis. Differential quantitatively (Roosen-Runge, tial cell counts cell counts have been employed in humans of to evaluate spermatogenesis detection of minor changes only an (Fig. 1). will not

et al, 1986b) and Sertoli cells (Johnson et al, 1984d) have been detected. Age-related changes in spermatogenesis also occur in bulls (Milk Marketing Board, 1950, 1967), rabbits (Ewing et al, 1972), mice (Gosden et al, 1982), rats (Purvis et al, 1980; Neaves, 1983), and horses (Johnson
1981;

in spermatogene-

Johnson and and Neaves,

Johnson

and

Thompson,

1983).

Evaluation in the The review Journal on the

of Spermatogenesis Human Testis excellent based

1956; Mancini et al, 1965). Differenhave been expressed as the number

of Andrology evaluation

published an of spermatogenesis

germ cells per unit length of seminiferous tubular circumference (Steinberger and Tjioe, 1968; Zukerman et al, 1978), number of germ cells per Sertoli cell

Fig. 1. spermatids

Scanning electron (TS) are evident.

micrograph Bar length

of testicular parenchyma is equal to 50 m. (Johnson

in the stallion. et al, 1978).

Seminiferous

tubules

(ST)

and

tails

of developing

No.6

SPERMATOGENESIS

AND

AGING

IN THE

HUMANS

Johnson

333

(Rowley

and

Heller,

1971;

Skakkebaek

and

Heller, cells

durations cell type determined. of specific

of each occurs,

stage the life

of the span

cycle of that

in which cell type

a given can be

1973; Zukerman per tubule cross 1981; Silber, approaches centration (Zukerman

et at, 1978), or number of germ section (Silber and Rodriguez-Rigau, Results obtained by each

1984).

of these

Given the life span and cell types, sperm production

theoretical yield rate obtained

were positively correlated with the conof spermatozoa in ejaculated semen et at, 1978; Silber, 1984). Counting the with elongated nuclei per tuin testicular biopsies is particuwhere ease of cell and good correlain the has ejaculate are

by counting numbers of germ be expressed on a daily basis 1964; Swierstra, 1967; Amann Amann, 1970a). The 2, where n equals between theoretical tids), the potential 1983). It is only potential for humans al, 1980a, a specific

cells in both testes can (Kennelly and Foote, and Lambiase, 1969;

number of spermatids bular cross section larly suited recognition, tions with important Human in terms of duction,

theoretical yield is calculated by the number of cell divisions cell type and spermatozoa. for If the spermais called et al, or one (the value sperm production production that daily sperm has

for the clinical setting, low time requirement, sperm concentration (Silber, 1984). spermatogenesis also daily sperm production. expression

yield is above expression of daily sperm

(Johnson production been

been expressed Daily sperm proproduced 1970a). per Daily of

recently daily sperm

a quantitative

of spermatogene-

production

estimated

sis, is the total day (Kennelly sperm production

number of spermatozoa and Foote, 1964; Amann can be measured and Barden, 1972; from the number

(Amann and Howards, 1980; Johnson et 1980b; 1981, 1983, 1984b, 1984c, 1984d; et at, 1984; daily sperm parenchyma Johnson producfaciliof

by cannulation

the rete testis (Lino 1974) or calculated

Amann et al, of testicular theoreticounted

1986b; Amann, 1981; Neaves and Neaves, 1986). Calculating tion per g decapsulated testicular tates comparisons among species efficiency regardless of spermatogenesis of testicular size

germ cells of a given type corrected for the cal yield and life span of the cell types (Amann, 1970a).

as it is a measure

(of sperm production) (Amann, 1970a; Amann 1981;

X 106/g)

Clermont (1963) described the cellular associations of germ cells constituting the six different stages of the cycle of the seminiferous epithelium in humans. This classification scheme kinetics of spermatogenesis by autoradiographic studies the cycle of the seminiferous mined (Heller and Clermont,
IDaily
sperm

et al, 1976). Humans (Amann, 1981) have a lower efficiency (6 genesis primates (26-28 1970a; than (23
X

Johnson et at, of spermato-

other
X

still is used today. The in humans were revealed in which the duration of epithelium was deter1964). By adding the
number of spermatozoa pro-

106/g),

106/g)

species rats and horses et at,

including non-human (20-24 X 106/g), rabbits (19 X 106/g) (Amann, 1976; Robb et al, 1978; Johnson 1983; and Neaves, Lebovitz and (74 days) in and a lower

1981;

Amann

Johnson et at, 1983; Johnson Johnson, The humans number (density)

1980a, 1984a; and Thompson,

production

is the

total

duced by paired testes each day. This is usually calculated from the number of spermatids in the testis or the number of spermatozoa leaving the testis (Amann, 1970a). Potential daily sperm product ion is the potential total number of spermatozoa produced by paired testes each day, assuming no significant degeneration subsequent to the specific cell type being counted. Specific cell types counted may include type B spermatogonia, primary spermatocytes, or secondary spermatocytes (Johnson et al, 1983). Efficiency of spermatogenesis is a relative measure of efficiency of sperm production obtained by dividing daily sperm production or potential daily sperm production by the paired parenchymal weight. This value facilitates comparisons among species that have varied testicular weights (Amann, 1970a) and allows comparisons of sperm production rates at different matrrational steps during spermatogenesis (Johnson et al, 1983, 1984a; Johnson, 1985). Daily sperm oulpul is the total number of spermatozoa released daily by paired testes. This can be estimated by the number of spermatozoa obtained by cannulation of the excurrent ducts of the testis, spermatozoa recovered from the urine or the ejaculate (Amann, 1970a). Daily sperm output has been reevaluated in humans following stabilization of extragonadal sperm reserves (Johnson, 1982).

1983; Johnson, 1985a). long duration of spermatogenesis (Heller and Clermont, 1964) of germ cells per unit volume compared with other more 3) contribute in humans. to the The

of parenchyma efficient species low efficiency human testis of also

(Figs. 2 and spermatogenesis has lower iniferous testis from

percentages epithelium, rats

of seminiferous and germ cell (Fig.

tubule, semnuclei than the spermatids

or horses

2). Using

with a spherical nucleus (round spermatids) to depict the density of germ cells in the stage of the cycle in which spermiation occurs, the human testis is compared with the rat and horse testis (Fig. 3). The reduced density of spermatids with a spherical nucleus in the human testis compared with other species can be seen in regions of tubules where these germ cells are relatively abundant. Unlike seminiferous tubules from rats or horses, tubules in humans are not consistent in the abundance of germ cells

334

Journal

of Andrology

November/December

1986

Vol.

U
,-

sEt.WEROUS
TUBULES

sEM*EROUS EPm#{128}WM

ROUM MJc1El

SPERMATI

>-

I 0

z
LU

0 U0 I-

z
LU
0

Ui 0

RAT N=3
Fig. 2. Comparison of the relative spherical nuclei of round spermatids percentage of testicular (Golgi and cap phases)

HORSE N3
parenchyma occupied by seminiferous in rats, horses, and humans. (Johnson

HUMAN N=3
tubules, seminiferous et al, 1980; Johnson, epithelium, 1985a). and

within

a specific

stage

of the

cycle.

Figure with tubules

4 illustrates a spherical at the same in the same

In

the

latter

comparison,
(32

daily 1 year) in the last

sperm

output

was the daily

the relative paucity of spermatids nucleus in several seminiferous stage of the cycle (that

estimated number

in nine men of spermatozoa

by averaging three of five

of spermiation)

human testis as in Figure 3. Other stages of the cycle often have missing generations of germ cells characteristic of that specific stage. Low numbers and the lack of all generations of germ cells in each stage of the cycle contribute to the relatively low number of conIt is germ cells in the human testis, which in turn tributes to the low efficiency of spermatogenesis.

ejaculates. The the extragonadal

first ejaculates sperm reserves two

were had

excluded since to be stabilized

by depletion of epididymal 1970a). It was found that sufficient to stabilize the in men following build up (sexual sperm reserves depletion rest for (Johnson,

spermatozoa (Amann, daily ejaculates were sperm reserves

extragonadal

(frequent ejaculations) or 6 days) of these epididymal 1982). Daily sperm producof similar age in the testis (35 3 (John-

unclear why the human testis differs from that of other species in the composition and duration of spermatogenesis. Values for daily sperm production for a species are similar to the number of spermatozoa ejaculated daily (daily sperm output; output daily is true 1970b), et al, Amann, is the by paired bulls
1974)

tion was estimated years) from counts

from 10 men of spermatids

son et al, 1981). Although daily sperm production is inherently higher than daily sperm output (Amann, 1970a), the similarity between them gives validity to the concept of daily sperm measure of spermatogenesis al, 1981; Johnson, 1982). production in humans as a direct (Johnson et

1970a)

for

that

species. Daily sperm spermatozoa released 1970a; rabbits horses 1981). (Amann, (Gebauer This

total number of testes (Amann, (Swierstra,

1968),

for boars

(Amann and dogs

et al, 1974), (Olar et al, produc1982).

Degeneration of germ cells during spermatogenesis has been estimated by comparing daily sperm production or potential daily sperm production based
on steps given in germ

1983). Even in humans tion is similar to daily

(Fig. 5), daily sperm sperm output (Johnson,

cell

types

spermatogenesis

at different in bulls

maturational
(Kennelly

and

Fig. 3. Comparison of seminiferous Golgi and cap phase spermatids with

human. tubules In the case of the human, in the same stage of the

epithelium

in the a) rat,

spherical

nuclei

called

this tubule was selected cycle (compare with Fig.

and c) human in the stage of the cycle when spermiation occurs. spermatids (RS) are more abundant in the rat and horse than in the for the relative abundance of spermatids with spherical nuclei in relation to other b) horse,

round

4). Bar

length

equals

10

sm.

#{149}
.,

s,.

1/

#{149}

Fig. 4. Comparison of within 20 mm of castration (especially pachytene old germ cells do not appear affected with incubation

seminiferous epithelium and Leydig cells from the same human testis depicted in Fig. 3. Specimens were a) fixed orb) fixed after 12 hours of incubation at room temperature in an air-tight vial. Quality of fixation of germ cells primary spermatocytes lOPS]) is reduced with incubation time. The size of cell boundaries and nuclei of these to be affected. However, the cytoplasm is contracted from the cell boundary. Leydig cells (LC) appear to be less time than do primary spermatocytes. Bar length equals 10 zm.

No.6

SPERMATOGENESIS

AND

AGING

IN THE

HUMAN.

Johnson

337

z
0

200z

-J
-

I ___ I
I-. D 0 I-.
0

U J I

YJGER

ADILT P1-89

MEN

RIG4T
MEN

TESTIS

OLD#{128}R ADILT

p1-43

ct
Lii

100-

0 IC) D 0

aIii
U)

a-

LiJ

a.
U) >-

>_

-J

-J

0#{149}
-

DAILY SPERM PRODUCTION VS DAILY SPERM OUTPUT IN HUMANS

WEIGHT OF TUNICA ALBUGINEA Fig. 6. Effect of age on the weight of the

PERCENT OF WHOLE tunica

TUNIC TESTIS and yr)

Fig. 5. Comparison
by evaluation of testes

between
in 10 men

daily sperm production

aged

estimated
eta!.,

26 to 53 yrs (Johnson

the percent
and older

tunic
adult

1981) and daily sperm number of spermatozoa

similarly aged men

output determined by counting in the last 3 of 5 daily ejaculations

1982).

the in 9

of the whole testis in younger adult (51-80) men. (Johnson et al, 1984b).

albuginea (21-50

(Johnson,

to 80 years Foote, (Johnson, son 1986). Age-related Differences in the Human Testis Our research has used autopsy specimens from individuals who died of heart attack or traumatic injury (i.e. automobile accident or gun shot wound). Study subjects included only men serious illness (other than coronary and no extended hospitalization Details death, on the ethnic subjects origin, with no history of arteriosclerosis) prior to death. health body prior to weight, et al, 1964), 1985a) 1981, rats and 1983, (Johnson humans 1984c; et (Barr Johnson at, 1984a), et al, 1971; and horses JohnNeaves,

old,

testicular

weights

were

similar

for

both

the right (18.9 tively) or left (17.2 tively) testis (Johnson with similar testicular

0.5 and 19.2 0.9 g, respec 0.5 and 17.5 0.9 g, respecet al, 1984b). This is consistent volumes reported for young 1974). However, and the percent-

and old men (Kothari and Gupta, the weight of the tunica albuginea

age of total testicular weight represented by the tunica albuginea were greater (P < 0.01) for the older men (Fig. 6). Subsequent studies on 15 men aged 20 to 48 years and 15 men aged 50 to 76 years revealed an age-related difference the testicular parenchyma 2.4 ml, respectively) per

(P<

0.01) in the volume of (40.2 2.3 ml and 28.2 man (Neaves et al, 1984).

apparent good cause of death,

blood alcohol concentration, and ratio of body weight to height have been described (Neaves et al, 1984; Johnson et al, 1986b). the quality of fixation Postmortem and cause changes contraction reduce of the

The age-related increase in the weight of the tunica sometimes may be sufficient to mask differences in parenchymal weight. Our recent study (Johnson et al., 1986b), based on 28 men 20 to 48 years old and 28 men 50 to 90 years old, revealed age-related differences

(P<

0.01)

in both

testicular

weight

and differences or paired

parenin tesmen have not a

cytoplasm in primary spermatocytes (Fig. 4). However, we have been unable to show an effect of postmortem time on daily sperm production (Johnson et al, 1984b). Age-related testicular in humans. increase ing data differences volume are However, in testicular inconsistent testicular features weight weight and

chymal weight (Table parenchymal weights tis in younger (50-90 reported years) that adult

i). Age-related in the left, right, years) and

(20-48

older

adult

are illustrated in Figure 7. Others changes in testicular volume are (Sterns testis

of aging does not Compar43 men 51

after age 20 to 30 years in humans. for 89 men 21 to 50 years old and

consistent characteristic of aging Nieschlag et al, 1982). The composition of the human with age. Comparing 28 men

et al, 1974; is modified and 28

20 to 48 years

338

Journal

of Andrology

November/December

1986

Vol.

U)

D
40-

YOU*GER

ADCLT

MEN

OLDER

ADCLT N44

MEN

.4

N50

..L

.1

U)

I-

(9 L&J

-J .4

20-

Fig. 7. Effect of age on parenchymal (decapsulated testicular tissue) weight of the left, right, or total (paired) testes in younger adult (20-48 yrs) and older adult (50-90 yrs) men. (Johnson et al, 1984b).

C)

Ui

a-

.4

I
NO.01

I
P<0.01 NO.01

men

50

to 90 years in older difference

old

(Johnson epithelium

et al, 1986b), was

the

(Table

1). Tubular

diameter

was

similar

but

tubular

percentage

of seminiferous

reduced

(P < 0.01) significant

adult men (Fig. 8). However, no was found in volume density

length per man was reduced men (Fig. 10). The thickness percent number boundary tissue in

(P< 0.01)
of the the

in older adult boundary tissue, and

parenchyma,

(percentage of parenchymal volume occupied by a given component) of seminiferous tubules or tubular lumen. (myoid increased density similar 1986b). renchymal bules per in The volume density of boundary tissue cells and associated extracellular components)

(P<

0.01)

with cells and

age in the older

(Fig. men

9), but

the

volume was et al., in patumen

of myoid cells per cross section increased (P <0.01) in older adult men (Fig. 9). Where there was tubule hyalinization in the human testis, an increased deposition of collagen fibers was reported (Soderstom, 1986). The age-related thickening of the boundary tissue boundary in our study was not due to an increase tissue itself, but resulted from a reduction in tubule length per man total volume of boundary conclusions, based without tissue on in

of myoid younger Partly due weight, man was

boundary

tissue (Johnson

to age-related the volume less

differences of seminiferous in the older

(P< 0.01)
tion (Table in the

a reducper man

(P < 0.01)

1). These

examination

COMPOSITION

(VOLUME
OLD#{128}R

DENSITY)

L
>-

P1-28

L:I P1-28

I C)

z
0
Li 0

Lii

Fig. 8. Effect
of the tubules thelium 48 yrs) (Johnson

of age on the percentage testis occupied by seminiferous (P> 0.05) and seminiferous epi(P < 0.01) in younger adult (20and older adult (50-90 yrs) men. et al, 1986b).

H-

z
0

Lii

lx
Lii

0
SEMINIFEROUS TUBULES SEMINIFEROUS EPITHELIUM

No.6

SPERMATOGENESIS

AND

AGING

IN THE

HUMAN

Johnson

339

UYOUNGER

3OLDER 2e

Fig. 9. Effect of age on boundary tissue thickness (P < 0.01), percent boundary tissue (P < 0.01), and number of myoid cells per cross section (P < 0.01) in younger adult (20-48 yrs) and older adult (50-90 yrs) men. (Johnson et al, 1986b).

BCUIARY T1IOPESS

TISS.E U14)

PEREHT BO(1IARY 715511

M1ER OF KYO SELLS PER CROSS SECTION

TABLE

1.

Age-related

Variation

in Sem iniferous

Tubules

and Daily Age Group

S perm

Production

in Men*

Testicular

Component

20-48 yr (n = 28) 77.6 3.3t 46.8 1.8 40.7 1.7 23.81.0 3.5 0.2 3.5 0.4 16.9 0.7

50-90 yr (n = 28) 79.2 3.7 37.8 2.0 31.4 1.8 18.01.2 3.4 0.2 3.2 0.4 11.40.9

Significance

Weight Body (kg) Paired testes (g) Paired testicular parenchyma Volume per man (ml) Seminiferous tubule Boundary tissue Lumen Seminiferous epithelium Myoid cell Volume density Total Volume volume

(g)

NS P <0.01 P <0.01 P<O.O1 NS NS P <0.01

of boundary per man (iiI)

tissue

(%)

32.1 2.2 1109 51

28.9 2.3 970 51 1322 66

NS NS NS

of average

individual

cell (Il)

1197 54

Number of cells Sertoli cells (106) Per g parenchyma Perman Spermatids with round nucleus Per g parenchyma Perman Spermatid with round nucleus to Sertoli Daily sperm production Per g parenchyma Per man
*

23.9 1.1 97761 53.5 3.4 2226194 2.3 0.2 6.0 0.4 22

16.9 1.0 55151

34.1 2.9 1075104 2.1 0.2

P< 0.01 P<0.O1 P <0.01 P<O.O1 NS P <0.01 P <0.01

cell ratio

(106) 250

3.8 0.3 121 12

From

Johnson SEM.

et al, 1986b.

tMean

340

Journal

of Andrology

November/December

1986

Vol.

YOUNGER P1=28

AGE

vs

SPERM

PRODUCTION

MOLDER
N28

TUBULAR DIAMETER (UM) Fig. 10.

ri#{149}
TUBULAR LENGTH/MAN (M) (P>0.05) and tubuadult (20-48 yrs) and

lar length older adult

Effect of age on tubular diameter per man (P < 0.01) in younger

(50-90

yrs) men.

(Johnson

et al, 1986b).

AGE,

years

of the whole testis instead to earlier, more subjective,

of biopsies, studies

are in contrast that concluded

Fig. 11. Effect of age on daily sperm production per gram parenchyma (efficiency of spermatogenesis) in 132 men. Regression line (y = 7.7-0.065X; P = -0.33) is drawn with the 95% confidence limit. (Johnson et al, 1984b).

that the age-related thickening resulted from deposition of new tissue mans spermia tubules 1969), (Holstein (Engle, are 1942; changes evident in semen devoid of tubules and with et al, 1984), spermatids Molnar, in a higher from older spermatids dislocated Age-related in sperm

of boundary tissue layers of connective production percentage men (Blum, (Sasano and type A spermatogonia in huof azoo1936), Ichijo,

matogenesis (Johnson and caudal (Johnson

is uniformly et al, 1984b) thirds of the et al, 1984c). and

distributed in the cranial, testis of young the right production

in each or older of the

testis men

1965).

equatorial, efficiency

Comparisons

of spermatogenesis between and amount of daily sperm

and left testis in different

cytes
Honore human nuclear

or multinucleated spermato(Holstein and Eckmann, 1986). that age-related changes tubular sclerosis, focal dilation of the rete testis. in the monoBishop

regions can be seen in Figure 12. Serum concentrations of LH and FSH were positively correlated with age and duction negatively (Johnson correlated et al, 1984c). with daily sperm pro-

(1978) noted testis included orchitis, and

Age-related cells or daily

differences in sperm production

the number in the testis

of germ of older

(1970) reported a thinning epithelium, decreased diameter tual men. men obliteration of the Lower seminiferous is associated per with man the and

of the spermatogenic of tubules, and even-

(36-month-old) rabbits (Ewing et al, (Gosden et al, 1982) and rats (Johnson 1983) have production been reaches reported. its peak In horses, at about

1972), mice and Neaves, daily sperm to 5 years of

tubular lumen in some old epithelial volume in older lower

(P

< 0.01)

daily

sperm et al, studan agein men. studies et (daily 1970a) adult of sper-

production 1986b). Combining ies (Amann

(Table

1; Fig. data 1980;

11; Johnson different

reported

from Johnson

age and remains at this level until at least 20 years of age (Johnson and Neaves, 1981; Johnson and Thompson, 1983). What happens to sperm production after years of age in stallions remains unknown. The

20

Howards,

et al, 1980a,

1980b), Amann (1981) reported a trend for related difference in daily sperm production This trend has been confirmed by subsequent (Johnson et al, 1984b; 1984c; 1984d; 1986b; al, 1984). The efficiency sperm production/gram in older men men is less of spermatogenesis parenchyma; Amann, 0.01) the than low in younger efficiency

fact that some the advancement bulls 19 years paternity

males retain their fertility even with of age is indicated by fertility in of age (Bishop, 1970) and a successful man (Seymour et al, 1935).

in a 94-year-old

Neaves

Degeneration

of Germ Spermatogenesis cells has

Cells

(P<

During
Degeneration

(Table

1). Moreover,

of germ

a pivotal

role

in the

No.6

SPERMATOGENESIS

AND

AGING

IN THE

HUMAN.

Johnson

341

quantitative 1978; Johnson the mechanisms approaches Three

aspects of spermatogenesis (Huckins, et al, 1983; Johnson, 1985a). However, of degeneration, its etiology, and remain unclear. been used to quanitify steps The extent of spermatothe of

significant togenesis ces in the (Johnson evaluating siderable that

degeneration (Fig. 13; Table types et al, germ germ of

of germ cells during 2) and age-related germ cells All have that three have led

spermadifferenof con-

degenerate methods revealed to the of

for prevention approaches have

1983, 1984c). cell degeneration cell loss of and

amount of germ cell germ cell degeneration

degeneration. at different

concept

degeneration

a percentage

developing

genesis has been determined ing germ cells of different Clermont, ins, 1978) germ cells
1962;

by counting degenerattypes (Oakberg, 1956;

and

Russell and Clermont, 1977; Huckby calculating ratios of specific types of 1955; 1973; Oakberg, 1971; Wing 1962; Amann, Hochereau-de 1962; Barretal, Reviers, 1981;

germ cells is a normal phenomenon of spermatogenesis (Roosen-Runge, 1955; 1973; Clermont, 1962; Barr et al, 1971; Russell and Clermont, 1977; Huckins, 1978; Johnson et at, 1983). associated During with sperprogeny in mice Germ cell three critical matogonial from type (Oakberg, (Clermont, Dawley greater lowing count (Oakberg, sen-Runge, Sherman (Swierstra in stallions seasons, (1958) following eration degeneration has been steps in spermatogenesis.

(Roosen-Runge,

1956; Clermont, Huckins, 1978; and Christensen, cells and the fact quickly limits third approach, of degeneration daily germ sperm cells production the

1982). The identity that degenerating

of degenerating cells are removed approach. A the impact genesis on rates of 1970a). of sperm developing The last the promost and

mitoses, 25% A spermatogonia 1956), 1962),

of the potential are not produced

usefulness of the first which directly estimates at given steps in spermato is to compare on various 1967; types Amann,

11% are lost in Sherman rats and 75% are lost in adult Sprague1978). Ortavant of spermatogonia Meiotic of potential (1958) found in rams foldivisions acin mice rats (Roo27% loss in in rabbits

rats (Huckins, degeneration long for day a 13% loss

production, based (Swierstra,

illumination.

production

approach (Table 2) has been employed to estimate effect of microwave irradiation of rats on sperm duction from type B spermatogonia to the mature maturation-phase Johnson in germ adult man, spermatids (Lebovitz Johnson, 1983; sonal differences B spermatogonia 1985a). In the

1956), 2% in Sprague-Dawley 1955; Johnson et al, 1984a), rats (Clermont, 1962), 25% and Foote, 1963), and during the breeding

6% and 15% losses and non-breeding 1985a). spermatids Ortavant in rams

et at, 1984a) as well as seacell degeneration from type in stallions approach has (Johnson, revealed this

respectively, (Johnson, found 40 to 50% fewer long during day illumination. spermiogenesis

to spermatids

Losses due to degenare undetermined in

U,

0
N=1O

YOUNG

ADULT

MEN

Zj 0I-

0 Fig. 12. Daily

parenchyma and caudal men aged 1984c).

sperm

production

per g

cr>c-Z IX
.4

in the cranial, equatorial, regions of paired testes from 20 to 48 yrs. (Johnson et al,

a>-

U) -J<

IX UJ

a-

CRANIAL

EQUATORIAL

CAUDAL

342

Journal

of Andrology

November/December

1986

Vol.

TABLE

2.

The

Effect of Germ Cell Degeneration at Different Steps in Spermatogenesis on Sperm Production in Adult Rats, Horses, and Humans* Species

Criterion Parenchymal weight (9) parenchyma (106)t

Rat 1.60 0.04

Horse 151 8

Human 16 1

Potential daily sperm production/g Type B spermatogonia Young primary spermatocytes Old primary spermatocytes Secondary spermatocytes Daily sperm production/g (106) Young spermatids Old spermatids Potential daily sperm production/testis Type B spermatogonia Young primary spermatocytes Old primary spermatocytes Secondary spermatocytes Daily sperm production/testis (106) Young spermatids Old spermatids *Data horses (mean SEM) compiled season

20 2 20 2 24 1
-

32 21 22
-

12 2 1

10 l 12 2
6

20

20 1

25 (106)t

19 1z

6 1z

32 4 33 2 37 1
-

4000 2OO 2100 20(f 2000 200z

-

216 34 172 22 210 47 100 17z 96 14 et al, 1984a), 28

31 1 41 1 our studies 1985a), on 14 adult (>4009) rats (Lebovitz and 10 humans ages 26 to 53 years possible

1700 200 1700 2002 and Johnson, (Johnson when 1983; Johnson

from (Johnson,

in the breeding

et al, 1984c). based on numbers of designated cell

tPotential daily sperm production is the predicted number types younger than spermatids. Means in columns with different superscripts are different 2Evaluated in the contralateral testis for the rat and horse.

of spermatozoa (P <0.05).

Sherman 1956) and

rats 6%

(Clermont, or less

1962) in stallions

and

mice

(Oakberg, 1985a).

13). Based in humans

on the (Johnson

magnitude

of cell loss daily

late sperm

in meiosis produc-

(Johnson,

et al, 1983),

Bulls (Amann, 1962) and adult (>400 g) SpragueDawley rats (Lebovitz and Johnson, 1983; Johnson et al, 1984a) appear to have no significant germ cell loss during spermiogenesis. There was cells between spermatocytes matocyte of germ spermatogonia. degeneration occurs during amount meiosis -0.86) chyma no significant degeneration type B spermatogonia and (Table
2). The

tion almost could be doubled if this loss was eliminated. In adult humans, there is little degeneration of spermatids during spermiogenesis (Table 2; Johnson et al, 1981). In summary, the effect of germ cell degeneration on daily sperm production (Table 2; Fig. 13) was negligible in adult (>400 g) rats subsequent to type B

of germ secondary on sperof by

lack

of details

formation in humans prevents evaluation cell degeneration during proliferation A significant (Barr et al, 1971; meiotic divisions loss of sperm 36% to 45% loss

spermatogonia, the end of adult humans osis (subsequent The reasons

while adult spermatocyte had

horses had formation

losses toward and younger of meiunclear.

Johnson et al, 1983) in humans. The production per late in

=

great losses to secondary cells

after the end spermatocytes). are

(1962)

germ

degenerate may

of potential

is significantly and negatively with daily sperm production in humans (Johnson

correlated (r gram parenThe majority

Oakberg (1956) the degeneration for eliminating the and However, togonia

and Clermont of germ cells cells with

proposed that be a mechanism chromosomes. types in the of spermamagnitude

abnormal

et at, 1983).

of the germ cell degeneration detected late in meiosis occurred during the second meiotic division (Johnson et al, 1981, 1984c). The percentage of germ cell degeneration correlated either known rate late during with postprophase of meiosis was age or serum concentrations not of

greater loss of certain the relative constancy

of degeneration are not consistent with simple selection to eliminate chromosomal abnormalities (Huckins, 1978). Alternatively, degeneration might be a mechanism be sustained 1978). per Indeed, testis has to limit germ cells to the number by the Sertoli cell population the been number correlated of type with numbers that can (Huckins, of Ser-

LH or FSH (Johnson why humans have in meiosis than other

et al, 1984c). It is not a greater degeneration species (Table

2; Fig.

A spermatogonia

No.6

SPERMATOGENESIS

AND

AGING

IN THE

HUMAN.

Johnson

343

Fig. 13. Potential daily sperm tion per g parenchyma evaluated

ferent steps in spermatogenesis

producat difin the

rat, horse, and human. Cell types on which potential daily sperm production per g or daily sperm production per g was based included: type B spermatogonia (BS), preleptotene plus leptotene (young
primary) spermatocytes plus diplotene (old (YPS), primary) pachytene spermato-

40
I-z C-)0 0=:!

30

I .1 1
T
,-

cytes (OPS), secondary spermatocytes (SS), Golgi and cap phase spermatids (young spermatids) (YS), and maturation-phase spermatids (old spermatids) (OS). Adult (>400 g) rats experienced no
significant steps in loss during spermatogenesis these different (Lebovitz and

.1.

z >-w
<.4
-:

20

fJ

r
.1.

Tj

IT

I
.1.

Johnson, 1983; Johnson et al, 1984a). Adult horses had early losses in spermatogenesis (end of spermatocyte formation) with no subsequent losses (Johnson, 1985a). Younger adult humans had significant losses during postprophase of meiosis after secondary spermatocytes (Johnson et al, 1984c). Specific values and significance levels are given in Table 2.

10

mm
ssscsvs Os esypsops sos ssapsss vs as

zC,
OLd
00

RAT

HORSE

- HflH#{24
HUMAN
on men years was a A pale in A dark difference men aged between 52 to 90 number of type

toli and son,

cells in rats, rams, Courot, 1978) and 1983; Johnson, the

bulls stallions 1985a).

(Hochereau-de (Johnson

and

Reviers Thomp-

numbers of each type as a function of age. Based the number of spermatogonia per gram parenchyma, there aged in was no 20 to 48 significant years and

Given that nia in stallions season and degeneration

population increases

of type A spermatogotwo-fold in the breeding increase (Table have to 1985a).

that there between

is no offsetting type B spermatogonia

(Johnson and trend toward spermatogonia the older men.

Neaves, 1986). However, there more type A dark and type and fewer type B spermatogonia While the

2) and spermatids, accommodate 60%

each Sertoli cell would more germ cells (Johnson,

28:1

The ratio of all types would increase from breeding Our studies degeneration germ cells cell-Sertoli related mans of Sertoli matocytes affected (Table cells or by age the

of germ cells to Sertoli cells (Johnson, 1986) to 44:1 in the premise the number that of

spermatogonia per man was not significantly less in the older men, the numbers of type A pale per man and type B per man were significantly less in the older men.

season. with humans support has a role in regulating to that which cell interactions in daily 1) is associated can

be sustained by germ (Huckins, 1978). Ageproduction an age-related in huloss with

OF

reduction

sperm

SERTOLI 200 I

CELLS

PER 490 I

TESTIS

(MILLIONS) 690

(Fig. 14); the number of primary sperspermatids per Sertoli cell was not (Table 1; Johnson et at, 1984d).

I--.

Age-related Difference in Germ Cell Degeneration in Humans Details matocyte of spermatogonial formation are division during for humans. sperHence,

lacking

precise identification of different subtypes of spermatogonia that degenerate during spermatogonial mitosis is impossible. (Fig. 15) comparisons However, have three types of spermatogonia 1963), and been identified have been made (Clermont, between the

YOIM P37

aaLT

OLD(R

DLT P1-34

Il

Fig. 14. Effect of age on the number of Sertoli cells per testis in younger adult (20-48 yrs) men and older adult (50-85 yrs) men. (Johnson et al, 1984d).

344

Journal

of Andrology

November/December

1986

Vol.

The age-related difference in daily sperm production largely resulted from germ cell degeneration during the prophase of meiosis in older adult men (Fig. 16; Johnson and Neaves, in the number 1986). There was primary no difference

flected spherical

(Fig. 13) nucleus

at the level of spermatids with a (Johnson et al, 1984c, 1986b) and

(P> 0.05)

of young

maturation-phase spermatids (Johnson et al, 1984b). Both age groups experienced significant degeneration at the end of meiosis (Johnson et al, 1984c). Since these losses were proportional between age groups, it did not contribute to age-related differences in daily sperm production. The difference in the number of spermatids with a spherical nucleus per man between younger and older adult men (older men have 66% or less than that of younger men; Johnson et al, 1984c) is similar to the difference in the number of maturation-phase spermatids Johnson age-related miogenesis based on compared number total men, per man et al, 1984b). difference in humans. spermatids (older Thus, 71% there of younger men; appears to be no during sper-

spermatocytes and older adult icant reduction between young Hence, the or pachytene men ence out, was in daily however,

per g parenchyma between younger men. Only the older men had a signifin potential and old daily primary sperm production spermatocytes.

degeneration primary the major sperm that per cell man type

of late leptotene, zygotene, spermatocytes in older adult source of the age-related differproduction. the number as well was less It should be pointed of type A pale speras the number of each in the older age-related formation was during primary re-

matogonia subsequent

(P < 0.01)
with some spermatocyte effect of pachytene was

in degeneration

men. While this is consistent difference occurring during in humans, prophase The spermatocytes the major of meiosis. in older

When daily sperm production with a spherical nucleus was production spermatids based on the or on the in the same spermato-

age-related

with daily sperm of maturation-phase

difference

in numbers men

subsequently

number of all types of spermatids no degeneration was found during

Fig. 15. Types

A dark (Ad) and A pale (Ap) spermatogonia,

preleptotene

and leptotene

primary

spermatocytes,

collectively

called young

pimary spermatocytes (YPS), pachytene an i cap phase spermatids, collectively Epon sections of human seminiferous length is 10 zm.

plus diplotene primary spermatocytes, collectively called old primary spermatocytes (OPS), Golgi called young spermatids (YS), and Sertoli cells (SC) as observed in 1.0-him toluidine blue-stained tubule (Stage III) following vascular perfusion with glutaraldehyde and fixation with 0s04. Bar

No.

SPERMATOGENESIS

AND

AGING

IN THE

HUMAN

Johnson

345

I,,

z
0

-J -J

I I
C, L&I

E
T

CILT

tI

iWILT

tl

a-

U) -J -J Lii
C)

i-I

Fig. 16. a) Effect

of various germ types compared).

of age on the number cells per g (P> 0.05 on all

b) Effect of age on

I w
C, Ii 0 Ui

potential daily sperm production per g parenchyma. Significant differences between age groups were found for old primary spermatocytes (pachytene plus
diplotene) and young spermatids and cap phases). In the younger age the value for young spermatids was (P< 0.05) than values for other cell (Golgi group, lower

ri
ADAC APaLE

S SP!R45.TOCY1U

types. In only the older men, there was a significant reduction in potential daily sperm production between young (preleptotene and leptotene) and old primary spermatocytes. It is this degeneration or loss of late leptotene, zygotene, or pachytene primary spermatocytes that largely explains age-related differences in daily sperm production per g parenchyma.
(Johnson and Neaves, 1986).

z-s

2(/)
I-z

O=j

LIi>
U)0

>W
=

z T
.1.

-:
Z(D LiJ

Ow a-aB
SP46TOGOI6 P4RY SPE4ATOCYTE5 5P4ATOCYTES

a-a
1s

YOU.

b
in the parenchyma, cells per (Neaves total number gram et at, of

genesis

(Table Age-related

2; Fig.

13; Johnson

et al, 1981). in Numbers Cells of the teset a!, 1982) number relationships cells McKaler and in the of of

volume

density

of

Leydig

cells

Difference

and the volume or number of Leydig parenchyma is reduced in older men 1984), Leydig (1974) Leydig there cells and cells is a reduction in the

Nongerminal The age-related tis to hCG (Nankin may Leydig be related cells in to

Testicular

decline in the response et a!, 1981; Murono the reduction men. in the older Negative

per man. In contrast, Kothari and Gupta Honore (1978) reported hyperplasia of with advancing age in humans. ComparEwing et al. (1979) found that Leydig cell not related to the amount during in vitro perfusion. found that the of testosterone However, Zirkin of smooth

ing species, mass was produced et at (1980)

between age and have been reported Donald, and Johnson, 1948; 1985). Neaves, 1978;

numbers (Teem, Neaves Since there

or mass of Leydig 1935; Sargent and 1957; Harbitz, are reductions 1973; Neaves et a!, 1984;

Tillinger,

percentage

endoplasmic reticulum totally explained the

in the Leydig cell almost variation in the in vitro produc-

346

Journal

of Andrology

November/December

1986

Vol.

tion lated Leydig

of testosterone in the with LH. In rats and cells were not reduced Johnson 1986). cycles

testis horses,

maximally stimuthe numbers of males (Kaler Johnof the of

cells (Neaves corresponding interstitial Apparently, dedifferentiate Neaves percentage older men et a!,

et a!, 1984), was not associated with increase in the number of non-Leydig cells in the same Leydig cells into 1985). Myoid men (Neaves degenerate cells cells occupy et a!, 1985). rather than (Sniffen, the in younger total volume 1950; same

in aged

and Neaves, 1981; son and Thompson, Leydig cell population

and Neaves, 1981; In addition, the size annually and regardless 17; Johnson cells

mesenchymal

age in adult horses (Fig. 1986). The number of Leydig

Thompson, (r
=

of the boundary tissue and there is a comparable per man (Table

1; Johnson

and of

is correlated

0.76;

these

cells

et a!, 1986b).

<0.01) with daily sperm production in horses (Johnson and Thompson, 1986), and a seasonal increase in the number of Leydig cells precedes increases in daily sperm is no production relationship (Johnson, between 1985b). number However, of Leydig there cells et a!, to

The number of myoid cells per man tended to decrease with age; however, significant differences in number were not found by either of the methods employed Neither to calculate method indicated myoid cell numbers in the (Fig.
19).

an increase the volume and older

number

and daily sperm production 1984; Neaves and Johnson,

in humans (Neaves 1985). Even attempts

of myoid cells. Likewise, cell is similar in younger thickening due to an adult men 3.4 0.2 reduction the reduction The total increased Sertoli niferous support, of the increase had

of a single myoid men. Age-related

enhance the likelihood of a significant relationship between Leydig cell number and daily sperm production by evaluating only older men (50-80 years), who should paucity relationship In humans, ture zumi of Leydig et a!, 1967), have of lost Leydig the cells, ability failed (Neaves changes have been a detailed to compensate to yield and in the reported description Johnson, for a significant 1985). ultrastruc(Yasuof Leydig described studies of Scott, 1950) the

tubular boundary tissue was not in boundary tissue itself (young ml and from (Fig. older adult men had with
19).

3.5 0.2

ml) but resulted in tubular length in the number volume of boundary with age (Johnson cells are the somatic epithelium nutrition

a disproportionate 10) compared cells (Fig. was

in humans age-related cell nuclei and

of myoid

tissue per man et a!, 1986b). component

not

of the semi-

cell ultrastructure (Mon et al, 1982). Leydig cells

in aged men has been Earlier light microscopic men (Lynch and

and are critical for the structural and protection of germ cells (Dym
1977;

in aging

revealed decreased frequency of Leydig cells with small lipid droplets and increased numbers of pigmented Leydig cells. However, the ultrastructure of Leydig normal cells present (Fig. 18). reduction in aging men can number
U)

and Madhwa Raj, generally accepted stable berger

that

Feig et a!, 1980). While it is the number of Sertoli cells is and Perey, Hochereau-de 1957; SteinReviers,

in the adult (Clermont and Steinberger, 1971;

appear of

quite Leydig

Age-related

in the

1981), there are seasonal fluctuations in the number of Sertoli cells in stallions (Fig. 20; Johnson and Thompson, 1983; Johnson and Nguyen, 1986; John-

Fig. 17. The annual cycle of the Leydig cell population in stallions revealed by evaluation of each 3-month period for one year. The numbers of Leydig cells per g parenchyma were similar (P > 0.05) among the four 3-month time periods. The number of Leydig cells per testis for May to July was higher (P < 0.05) than
to October or February to April and higher (PJ 0.01) than in November August

U, I(I) Ui U, -J -J Iii C.) C, 0 Id -J

U,

-s
-J Id
0

<I

to January.
cells
per

While
testis

the numbers
were similar

of Leydig
(P > 0.05)

between February to April and August to October and between August to October and November to January, values for February to April were significantly (P < 0.05) higher than those in November to January.

C, 0
>-

Id

-J

I
NOV-JAN FEB-APR MAY-JU.. AUG-OCT

No.6

SPERMATOGENESIS

AND

AGING

IN THE

HUMAN-

Johnson

347

Fig. 18. Electron micrographs of Leydig cells in a 66-yr-old man. These cells appear to be normal, with an abundance endoplasmic reticulum (SER) and mitochondria (M). Also, the Golgi complex (GC) and lysosomal bodies (L) are present. Length equals 2 m.

of smooth of each bar

son, 1986) and cell population Johnson Sertoli cells

an age-related decline in the Sertoli in humans (Table 1; Figs. 14 and 21; In stallions, sperm there production are more daily is high;

there ratio season 1985b,

also

is a slight cells to

but

significant cells

increase in the

in the breeding Johnson, decline in

of germ

Serto!i

et a!, 1984d). when

(Johnson and Thompson, 1983; 1986). In humans, the age-related

z <1 w
Fig. 19. Effect of age on the number of myoid cells, as calculated by two approaches, in younger adult (20-48 yrs) and older adult (50-90 yrs) men. The reduction in the number of myoid cells in older men was not significant when based on calculations including the number per cross section and tubular length. The
reduction in older men calculated from

D
1

...J ..J LI-I 0

-

the primary data of percent nuclei in the parenchyma and the diameter (or volume) of nuclei was significant (P <I 0.05). (Johnson et al, 1986c).

LU

PUW

PER R0SS MC

SEC11ON

PERCENT

P&CL

MC

348

Journal

of Andrology

November/December

1986

Vol.

U)

z
0

z
0

(/)

-J -i

I I

40

NUMBER/GRAM

_J -J

U)

.4 C.
(1)

NUMBER/TESTiS

41U)

30-

Ui

Fig. 20. Number of Sertoli cells found in 41 to 50 adult horses during each 3month period throughout one year. The

IU)

-J -J Lii
0

-J -J Ui
0

number of Sertoli cells per g was greater (P< 0.05) from May to July than in other
periods. The number per testis was

-J
0

-J

IU)

2#{176} ILii
U)

greater from May to July than from August to October or February to April (P < 0.05) and than from November to January (P< 0.01). (Johnson and Nguyen,
1986).

Li.
0

10-

U..
0

Iii

U
.1

I z

I
z

NOV-JAN

FEB-APR

MAY-JUL

AUG-OCT

the

number

of Sertoli

cells

is not

associated

with

change in the ratio of germ cells to Sertoli cells (Table 1; Johnson et a!, 1984d). If the germ ce!l:Serto!i cell ratio is an indication of the function of individual Sertoli cells, these data in Sertoli cell function function of individual Sertoli cells are evenly tubules throughout the age (Johnson et a!, 1984d). the may imply in stallions a seasonal increase but no decline in

toli cell supports relatively few germ a!., 1984d) compared with other

cells (Johnson species (Fig.

et 22;

Sertoli cells in aging men. distributed in seminiferous human testis regardless of The average human Ser-

Wing and Christensen, 1982; Johnson and Thompson, 1983; Russell and Peterson, 1984; Johnson, 1986). Russell and Peterson (1984) found that the elongated spermatid:Sertoli cell ratio averaged 6 to 14 for the rat, hamster, gerbil, guinea pig, rabbit, vole and monkey; all had greater ratios than did humans (Fig. 22). This and spermatids) paucity of germ accommodated cells (spermatocytes by average individreduced further et a!, 1984d). In

ual Sertoli cells in humans with advancing age (Table

U

is not 1; Johnson

1.
F

Y
#{163} #{163}

735

7X,

rho

-0.54

men 20 to 85 years of age, daily sperm production was significantly correlated with the number of Sertoli cells per testis (Fig. 23). Ultrastructure of Sertoli cells in aging 24) is similar Roose-Runge, men with active spermatogenesis (Fig. to that of younger men (Holstein and 1981; Johnson et a!, 1984d) and to 5a-reductase deficiency between the (Johnson stallion et al, testis in

C,)

-s -J

A ALa A A

w
I-.

males 1986a). There

A

with

C.) -J
0

AA
A

are similarities

I-

LA

w
C..,

IL
0

the nonbreeding season and the testis in aging men. Both experience significant germ cell degeneration during postprophase of meiosis (Johnson, 1985a; Table 2) and both have significantly low numbers of
LA
A

w
A

Leydig cells (Neaves eta!, 1984; Johnson and Thompson, 1986) and Sertoli cells (Johnson, 1986; Figs. 14, 21). In conclusion, age-related changes in humans include a reduction in the numbers of Leydig cells and of Sertoli sperm cells, Serto!i cells is producnon-Leydig cells. The interstitial cells, myoid decline in the number with a reduction in daily

AGE

(years)

Fig. 21. The relationship between number age in 71 men aged 20 to 85 years. (Johnson

of Sertoli cells and et al, 1984d).

associated tion.

No.

SPERMATOGENESIS
-J
-J ILl 0 -J 0

AND

AGING

IN THE

HUMAN.

Johnson

349

E10L0

WflV4AT$

IU
U)

Fig. 22. Ratio of the number of primary spermatids per Sertoli cell in the rat, horse, and human. Data on rats was taken from Wing and Christensen (1982), horses from Johnson (1986), and humans from Johnson et al (1984d).

U
U)

a-J
-J Id 0 Id C, 0 Id

RAT

HORSE

HUMAN

Possible Changes Sasano techniques relationship seminiferous degeneration. by microvascular Regadera and of

Etiology in Human

of Age-related Spermatogenesis Suoranta to (1971) illustrate used the

was

involved

in the

decline

of testicular with

function

with

Ichijo (1969) and microangiography age-related or Leydig

age. They eromatosis fibrosed (1979) to locally culty testes from

found that elderly men had testicu!ar parenchyma sc!erosed some ischemia.

severe aththat appeared et a!. atrophy diffi-

between tubular Vascular lesions

degeneration of cells and vascular was revealed blood supply. arteriosclerosis

with attributed limited

tubules. Hatakeyama types of focal tubular We have had greater

degeneration and diminished reported that

obtaining good fixation by vascular from old men than from younger autopsy. However, it is not clear

perfusion of men obtained if vascular

et al (1985)

A C 0

300

18.8

O.2X,

rho
A

= +0.70
A
A

Fig. 23. The relationship between the number of Sertoli cells per man and daily sperm production per man in 71 men

z
-4

200

IC.) 0 0 A #{163}

aged 20 1984d).

to

85 years.

(Johnson

et al,

#{163}
A

aE

100

#{163}

w arI,
>-

fr
A A

-J
p-i

A
-

#{163}
I. . . .
. . . -

:, #{246}
NUMBER OF

5#{212}0
SERTOLI CELLS (mt

idoo
I I tons)

Fig. 24. Electron micrograph of seminiferous epithelium in a 66-yr-old man. The Sertoli cells (SC) appear to be normal in the adluminal compartment (Panel A) with a Golgi complex (CC) present in this view. Junctional complexes (JC) between adjacent Sertoli cells above the basal compartment (Panel B), rod-like mitochondria (M), profiles of smooth endoplasmic reticulum (SER), rough endoplasmic reticulum (RER), and lipid droplets (LD) of various densities characterize these Sertoli cells. Spermatogonia (SC) and Colgi spermatids with a spherical nucleus called round spermatids (RS) are present between Sertoli cells. Bar length is equal to 2 m.

No.

SPERMATOGENESIS

AND

AGING

IN THE

HUMAN-

Johnson

351

insufficiency is itself aging. Given in or a result that around

is the

cause

of tubular other cells

degeneration process been in the observed testis

or of 1. The efficiency production humans of 2. Testicular seminiferous 3. than

Conclusions of spermatogenesis species. weight, and dai!y percentage of sperm produc-

of some

underlying have

per g parenchyma)
in other parenchymal epithelium,

(daily sperm is much lower in

inflammatory
degenerating

tubules

aged men (Frick, 1969; Suoranta, 1971), that agerelated changes include focal mononuclear orchitis (Honore, 1978), and that there is an increased percentage of older men with blood antibodies that cross-react with spermatozoa (Hamer!ynck, 1970; Fjal!brant, 1975), autoimmunity could cause tubular degeneration (Harman, 1978). However, release of antigens from already degenerated tubules could be responsible for the autoimmunization (Harman, 1978). Age-related loss of Sertoli cells (Johnson et al, 1984d) could compromise to the release the blood-testis barrier antimay take activity of and contribute gens. of sperm-specific

tion are significantly reduced in aging men. Degeneration of germ cells occurs during spermatogonial mitosis, meiosis, and/or spermiogenesis in various species including humans. reduction in sperm production in cells, cells human myoid decreases with appears Sertoli by or loss the age-related in humans. occurs Leydig cells and with daily to be cells the of

4. Age-related

during meiosis in humans. 5. Age-related reductions occur cells, 6. non-Leydig interstitial of human Sertoli Sertoli cells. The number

The initial event of aging in the testis place in the seminiferous tubules. Reduced Leydig cells lar disorders was thought

age and is significantly correlated sperm production. However, there no decline in function of individual present
7.

in older

adult

men

as measured

has been demonstrated in several testicuin which the seminiferous epithelium to be primarily involved (de Kretser et of a lack response 1983). of advanced in young Tubule germ cells or men is reduced damage has been cells of Leydig

germ cell:Sertoli cell ratio. Vascular degeneration, autoimmunity, Sertoli reduction cells may contribute sperm References to production of daily

a!., 1975). In case aplasia, the hCG (Baker associated and Hudson, with

hyperresponsiveness

Agger

to LH in rats (Jansz and Pomerantz, 1986). Progressive deterioration of Sertoli cell function (Baker and Hudson, 1983) or reduced numbers of Sertoli (Figs. 12 and 20; Johnson et a!, 1984d) may reduced daily sperm production. The decrease number occurs Sertoli of primary spermatocytes or at the same rate as the cells with age (Johnson loss in the number et a!, 1984d). cells cause in the of

F, Johnsen SC. sies in varicocele. Amann RP. Reproductive

Quantitative Fertil Steril capacity

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germ

evaluation of testicular biop1978; 29:52-57. of dairy bulls: IV. Spermatogencell degeneation. Am J Anat 1962; rates. testis. ln:Johnson AD, Comes WR, Vol. 1 New York: Academic testicular histology production as deteroutput. Fertil Steril of sperma1981; 2:37-

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spermatids

Press, 1970a; 433-482. Amann RP. The male rabbit:

and comparisons between

IV. Quantitative
daily sperm

mined

histologically

and

daily

sperm

Reduced numbers of reduced numbers of germ tubules, tubular Increased cause olites or hormones However, responsible and which boundary thickness further damage hormones leaving, leads to

Sertoli cells could cause cells and reduced length of increased thickness of the a!, 1986b). itself could of metabor products epithelium.

1970b; 21:662-672. Amann RP. A critical review togenesis from seminal 58.

of methods characteristics.

for evaluation J Androl

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and

J Urol
of

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the same underlying for age-related losses

could be Sertoli cells effect in the that etiology Improving

germ cells. It is difficult to separate cause and aging process. However, it is important studies of the aging process be continued.

production of Holstein bulls determined from testicular spermatid reserves, after cannulation of rete testis or vas deferens, and by daily ejaculation. J Dairy Sci 1974; 57:93-99. Amann RP, Johnson L, Thompson DL Jr. Pickett BW. Daily spermatozoal production, epididymal spermatozoal reserves and transit time of spermatozoa through the epididymis of the rhesus monkey. Biol Reprod 1976; 15:586-592. Baker HWG, Hudson B. Changes in the pituitary-testicular axis with age. In: de Kretser DM, Burger HG, Hudson B eds. Monographs on endocrinology. Vol. 25: The pituitary and testis. Clinical and experimental studies. Berlin, Heidelberg, New York: Springer-Verlag 1983; 71-184.

our understanding of the aging process in the testis should lead to a greater understanding of some forms of infertility.

352

Journal

of Andrology

November/December

1986

Vol.

Barr

AB,

Moore

Dl, Paulsen

CA.

Germinal

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human

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SM,

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Johnson L, Neaves WB. Age-related changes in the Leydig cell population, seminiferous tubules, and sperm production in stallions. Biol Reprod 1981; 24:703-712. Johnson L, Neaves WB. Enhanced daily sperm production in the remaining testis of aged rats following hemicastration. Androl 1983; 4:162-166. Johnson L, Neaves WB. Effect of germ cell loss during spermatogenesis on sperm production in young and older adult men. Biol Reprod (Suppl 1) 1986;34:61. Johnson L, Nguyen HB. Annual cycle of the Sertoli cell population in adult stallions. J Reprod Fertil 1986; 76:311-316. Johnson L, Thompson DL. Age-related and seasonal variation in

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SPERMATOGENESIS

AND

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HUMAN.

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Seventh This Residents

Annual

Microsurgery

at the

Mardi

Gras Surgeons, Orleans, and LA. It

symposium for Urologists, will be held at Southern

Andrologists, Pediatric Baptist Hospital, New

will be in two parts.

The first section, entitled MICROSURGICAL LECTURES AND LABORATORY, will be held February 26-28,1987, and will emphasize a current series of Microsurgical Applications in UrologyAndrology. A 24-hour lab session will provide hands-on experience in
basic and advanced microsurgica! techniques.

The second ANDROLOGY, function and

tion?, computerized

lecture series, entitled will be held February epididymovasostomy,

semen analysis-is

CURRENT
28, 1987,

CONTROVERSIES
and include epydidyma!

IN or fic-

anti-sperm
it clinically

antibodies-fact
practical?, and

more.

CME

credits

offered

through

Southern

Baptist
topics,

Hospital.
contact Beth extension

For more information, planned lecture Norwood, Microsurgery Lab Administrator, 75911; in Louisiana, 1-800-942-4330.

and faculty, 1-800-621-1986,