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The influence of progestin and androgen on the fine structure of the male reproductive tract of the rat. II. Epididymis and sex accessory glands

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The Influence of Progestin and Androgen on the
Fine Structure of the Male Reproductive
Tract of the Rat
11. EPlDlDYMlS AND SEX ACCESSORY GLANDS
CHARLES J. FLICKINGER
Department of'Anatomy, Sclzool of Medicine, Unic'erslty of V i r g i n i n ,
C h u r l o t t e w i l l e , Virginin 22901
ABSTRACT
Young adult male rats were administered medroxyprogesterone
(Provera, Upjohn) alone and in combination with testosterone, as has been done
to inhibit male fertility. The histology and fine structure of several segments of
the epididymis, the ventral prostate, and the seminal vesicle were studied a t
intervals after treatment for up to 16 weeks. The epididymides of treated animals
weighed less than those of control rats. Microscopic alterations in the epididymis
were similar i n rats treated with Provera alone and in those animals that received Provera and testosterone, but the changes varied with the segment of
the epididymis. In the middle segment i n the caput epididymidis, the normally
abundant luminal sperm were absent but the epithelium retained its normal
ultrastructural features. In the terminal segment in the cauda epididymidis,
different changes were observed in the proximal and distal portions. In the
proximal cauda epididymidis, the lumen was small, irregular i n outline, and
virtually devoid of sperm. The light cells of the epididymal epithelium in the
proximal cauda contained extremely large numbers of dense bodies resembling
lysosomes, which occupied most of the supranuclear and basal cytoplasm. In
contrast, in the distal part of the cauda epididymidis: the epithelium had a
normal appearance but the lumen was filled with debris, sperm, and spherical
masses of cytoplasm that were apparently derived from germ cells. It is suggested that the clearing of the lumen of the proximal cauda epididymidis may
reflect the greater activity of light cells of the epididymal epithelium i n that
region. Although alterations i n spermatogenesis may be most important in the
antifertility effect of progestin and androgen, these alterations i n epididymal
sperm and epithelium may also play a role.
The weights of the prostate and seminal vesicles of rats treated with Provera
(1 mg/100 g/day) were greatly reduced compared to those of control rats. Although there was considerable variation, i n many specimens treated with
Provera alone the epithelium of the prostate showed a change from a columnar
to a cuboidal or squamous shape, and there was a reduction i n the size and
abundance of organelles involved in the formation of secretions. The microscopic structure of the seminal vesicle of rats treated with Provera was less
severely affected than the prostate. Although the seminal vesicle epithelium of
Provera-treated rats was generally not as tall as in control animals, the cells
possessed parallel cisternae of rough endoplasmic reticulum, secretory vacuoles,
and a n active-appearing Golgi apparatus, suggesting that they continued to be
able to form secretions in the presence of Provera. The weights of the sex accessory glands were maintained a t control levels by the administration of testosterone, 100 pg/lOO g/day, along with the Provera. A normal fine structure was
present in the epithelium of both the prostate and seminal vesicle of rats administered this amount of testosterone in addition to Provera. Lower doses of
testosterone (15 or 30 pg/lOO g/day) were insufficient to maintain normal
weight or ultrastructure of the sex accessory glands i n the presence of Provera.
Received Mar. 18, '76. Accepted Oct. 1, '76.
ANAT. REC., 187: 4 3 1 4 6 2 .
43 1
432
CHARLES J . FLICKINGER
The combination of a progestin and
testosterone is believed to have promise
as a male contraceptive (Segal, '73) and
is being tested i n men for this purpose
(Frick, '73; Coutinho and Melo, '73).
The progestin is thought to suppress
spermatogenesis, while the accessory sex
organs and sexual characteristics are
maintained by the simultaneous administration of testosterone (Terner and MacLaughlin, '73; Kragt et al., '73). To determine the effects of these agents on the
structure of the male reproductive organs
and to aid in understanding the mechanisms of their antifertility action, we
have studied the histology and ultrastructure of parts of the male reproductive
tract of rats treated with these compounds.
In the preceding paper (Flickinger,
'77), alterations in the testes of rats treated
with a progestin and testosterone were
described. Although the effects of these
agents on spermatogenesis may be most
consequential for influencing fertility, it
is important to consider also the epididymis i n studies of antifertility compounds, because sperm must traverse the
entire length of the duct and i t is known
that they normally undergo changes in
their properties i n the epididymis, including aquisition of fertilizing ability
and a mature motility pattern (Hamilton,
'75; Bedford, '75; Orgebin-Crist et al.,
'75). Therefore, a n objective of this part
of the study was to determine the nature
of possible alterations of the epididymal
epithelium and luminal contents i n rats
treated with a progestin and with progestin plus testosterone.
The epididymis is not uniform from
start to finish, but exhibits regional differences in both structure and function
(Reid and Cleland, '57; Nicander, '57;
Glover and Nicander, '71; Hamilton, '75),
and the parts of the epididymis might
be expected to respond differently to
antifertility compounds. The total number of different regions distinguished has
varied with the criteria used and the
methods of specimen preparation. The
terminology proposed by Glover and
Nicander ('71) is simpler than many, being based a n broad histological and functional characteristics, and it will be used
in the present paper. According to this
scheme, the epididymis is divided into
initial, middle, and terminal segments,
the first two having to do with sperm
maturation and the latter with sperm
storage. We elected to study the two largest regions of the rat epididymis: the
middle segment, which makes up the bulk
of the caput epididymidis; and the terminal segment, which forms the cauda
epididymidis (Glover and Nicander, '71).
An important feature of the progestinandrogen combination for male contraception is that despite the suppression of
spermatogenesis and of testosterone secretion by the progestational agent, secondary sex characteristics, libido, and the
accessory sex organs are believed to be
maintained by the administration of exogenous testosterone (Terner and MacLaughlin, '72; Kragt et al., '73). Thus it is
important to ascertain not only that spermatogenesis is altered and infertility
achieved i n the presence of these compounds, but also whether the other male
characteristics are adequately maintained.
The weight and the microscopic appearance of the prostate and seminal vesicles
can serve as one index of the extent
to which such maintenance has been
achieved, at least with respect to the functions of the sex accessory glands. Therefore, further objectives of this part of our
study of the effects of progestin and androgen on the male reproductive tract of
the rat were to determine, first, the alterations in the sex accessory glands produced
by a progestin, and, second, the extent to
which these changes are prevented by
the simultaneous administration of testosterone.
MATERIALS AND METHODS
Young adult male rats were injected
subcutaneously with medroxyprogesterone
(Provera, Upjohn), or with Provera and
testosterone for 4, 8, or 16 weeks as described in detail in the preceding paper
(Flickinger, '77). The doses of steroids
administered in different experiments
are summarized below.
Experiment I. Progesterone, 2 or 10
mglratlday. As described in the section
on general effects in the companion paper
(Flickinger, '77), histological changes after this treatment were small, and further
studies with this regimen were discontinued. The experiment is noted here for
PROGESTIN AND ANDROGEN. I1
uniformity with the companion paper in
numbering of the experiments.
E x p e r i m e n t 2. Provera 1 mgllOO g
body weightlday.
Experzment 3 . F’rovera 1 mgllOO g/
day plus testosterone propionate 15 pgl
100 glday.
E x p e r i m e n t 4 . Provera 1 mgl100 gl
day plus testosterone 30 pg1100 glday.
E x p e r i m e n t 5. Provera 1 mgllOO gl
day plus testosterone 100 pg/lOO g/day.
Control rats received the sesame oil
vehicle alone.
Some rats were permitted to recover
for up to 12 weeks after the end of treatment (table 3 in Flickinger, ’77).
The rats were killed and the epididymides, ventral prostate, and seminal
vesicles were removed and weighed. The
major portion of the caput epididymidis,
corresponding to the middle segment of
the epididymis (Glover and Nicander,
’71), was bisected and immersed in Karnovsky’s fixative for one hour. The cauda
epididymidis, which contains the terminal segment of the epididymis (Glover
and Nicander, ’71), was similarly cut and
immersed in fixative. In the later experiments, care was taken to divide it into
two specific parts, one corresponding to
the proximal part of the cauda which
has the smaller diameter (regions 5B
and 6 A of Reid and Cleland, ’57) and
the other comprising the distal part of the
cauda (region 6B of Reid and Cleland).
After one hour the epididymal tissue was
diced and immersed in fixative for an
adchtional one hour. Pieces of the prostate
were placed for one hour in a glutaraldehyde, formaldehyde, and picric acid fixative (Ito and Karnovsky, ’68), and then
diced into 1-2 mm cubes and fixed for an
additional one hour. The seminal vesicles
were diced into 2 mm cubes and placed
for two hours in Karnovsky’s fixative
(Karnovsky, ’65). The samples were postfixed in Os04, dehydrated, and embedded
in Araldite. Sections for light and electron microscopy were prepared as described in the preceding paper (Flickinger , ’77).
RESULTS
Epididymis
Normal a n d control rats
The structure of the normal rat epididy-
433
mis has recently been reviewed (Hamilton,
’75). Briefly, the rat epididymis is lined
by a columnar epithelium that generally
decreases in height along the length of
the duct. The principal cells are the
most numerous type, and they are characterized by the presence of long microvilli
on the luminal surface, apical vesicles,
vacuoles and multivesicular bodies, a large
Golgi apparatus, and both rough and
smooth endoplasmic reticulum. The principal cells are accompanied in the middle
and tcrminal segments by smaller numbers of basal cells and by “halo” cells,
which are believed to be migrating lymphocytes (Hoffer et al., ’73). The principal cells of the middle segment in the
caput epididymidis are tall (fig. 1) and
have a large number of apical vacuoles.
In the terminal segment in the cauda
epididymidis, the principal cells have a
short columnar shape (figs. 4, 6). In the
cauda epididymidis, an additional cell
type, the “light” or “clear” cells, form a
significant part of the epithelium (fig. 4).
These cells are so-called because their cytoplasm is usually less dense than adjacent
principal cells and because they have a
large number of electron-lucent vesicles
and vacuoles in their apical cytoplasm.
Vacuoles found deeper in their cytoplasm
have a greater internal density as does the
content of membrane-bounded bodies of
the perinuclear and basal regions that resemble lysosomes (Flickinger, ’72). Both
the proximal and distal regions of the
cauda epididymidis were studied because
they showed different changes in treated
animals. In normal rats the epithelium
of the proximal part is slightly taller and
contains more light cells than that of the
distal portion (Reid and Cleland, ’57; figs.
4, 6). Large numbers of sperm are normally present in the lumen of both the middle
segment in the caput and the terminal segment in the cauda epididymidis (figs. 1,
4, 6). No differences were detected between normal rats and control animals
that received the oil vehicle.
Treated a n i m a l s
The epididymides of animals treated with
Provera (Experiment 2 ) weighed approximately 25-30% of controls (table 1). When
testosterone was administered along with
the Provera (Experiments 3, 4, 5), the
434
CHARLES J. FLICKINGER
TABLE 1
The j i i i n l weiqlita of the ventral prostote und seminal r'eszcles o f r a t s tierrted w i t h
Prooera 0 7 w i t h Proiierri und testopterotw for 4,8,or 16 w e e k s
shown as % cvntrol ualues
Weight, ' i ~ o n t r o l
Time
(wk)
Expt
No
4
Treatment
Epididyinms
Prostate
Seminal vesicle
-
-
-
2
Control
Pv
3
4
5
P v + T 15pg
P v f T 30pg
Pv T 100 p g
+
27
36
45
73
Control
-
-
-
Pv
31
38
14
43
31
43
100
25
50
63
8
2
3
4
18
45
64
127
14
57
57
86
5
h + T 15pg
P V + T 3oflg
Pv T 100 pg
Control
-
-
-
2
Pv
29
23
43
3
4
P v + T iziflg
P v f T 30pg
43
36
38
31
57
16
+
62
150
86
Each value was calculated i n the following w a y . ( 1 ) the organ weight ( g ) w a s expressed a s g per 100 g
of final body w e i g h t , ( 2 ) the individual organ weights (g/100 g ) from two rats were averaged, except i n
the case of PU 16 weeks in which three rats were used; ( 3 ) the average organ weight w a s expressed as
Fi. the accompanying control. The data i s from table 2 in the companion paper (Flickinger, '77) and i s
repeared here for convenience. Ahbrwintions: F'v. Provcra 1 mgil0O g body weightlday (Experiment 21;
P v + T , Provera 1 mnilOO glday plus testosterone 15, 30, or 100 pg/lOO giday (Experiments 3, 4 , 5 respectively)
weight was greater than in the presence of
Provera alone but did not exceed half
that of the epididymides from control rats,
except at the highest level of testosterone
(Experiment 5 , 100 pg/100 glday).
Alterations were observed in the microscopic structure of the epididymis from
treated animals at all the intervals studied.
Since the microscopic changes were similar
in rats treated with Provera alone and in
those administered Provera and different
amounts of testosterone, the results of the
various treatments will be considered together. In addition, since no consistent
progression of changes was detected in
rats treated for longer than four weeks, to
reduce redundancy the individual intervals
are not separately described and illustrated.
The large numbers of sperm normally
visible in the lumen of the middle segment
of the caput epididymidis in light microscope preparations (fig. 1) were greatly
diminished in treated animals, and the
circular profiles of the lumen were virtually
empty (fig. 2). The lumen contained only
a few round cells that resembled spermatocytes or early spermatids and some masses
of cytoplasm with degenerating sperm nu-
clei, mitochondria, tail fibers and other organelles haphazardly arranged in their interiors. Although the epithelium of the
middle segment in treated animals was
sometimes shorter than in control rats
(figs. 1 , 2), the shape of its component
principal cells remained columnar.
The principal cells of the middle segment (fig. 3 ) retained normal ultrastruct u r d characteristics, including the following. Many microvilli projected from the
apical surface into the lumen. The cytoplasm of the apical region contained many
electron-lucent vesicles of both smooth
and coated varieties, and a smaller number
of larger vacuoles and multivesicular
bodies with a content of a fine flocculent
substance and some membranous material.
Tubular profiles of smooth-surfaced endoplasmic reticulum had a moderately dense
content and were numerous in the supranuclear and apical cytoplasm. The large
Golgi apparatus consisted of stacks of cis400 A vesicles.
ternae and a myriad of
Cisternae of rough endoplasmic reticulum
were most abundant in the basal part of
the cell. The nuclei had oval or irregular
outlines and displayed central euchromatin
PROGESTIN AND ANDROGEN. I1
with a rim of condensed chromatin immediately inside the nuclear envelope. In
some profiles, one or two nucleoli were
visible. Junctional specializations were
found between principal cells next to the
lumen. Basal cells were recognized as
small cells adjacent to the basal lamina.
They had nuclei with much heterochromatin and scant cytoplasm with only a
small number of organelles. “Halo” cells
were scattered throughout the epithelium.
They displayed an irregular outline, very
dense nuclei, and a small amount of electron-lucent cytoplasm that was characterized by the presence of membrane-bound
cytoplasmic granules.
The appearance of the cauda epididymidis differed in its proximal and distal
regions. In the pro xim a l portion of t h e
c n u d a epididymidis, the normally abundant
sperm were absent from sections viewed
with the light microscope (fig. 5). The
lumen was much smaller than normal (cf.
fig. 4) and the undulating contour of the
tall columnar epithelium lent i t an irregular stellate appearance (fig. 5). Examination with the electron microscope
showed that the “light” cells of the epididymal epithelium were extremely distended with vacuoles (fig. 8) and a very
large number of dense boQes that resembled lysosomes in their polymorphous
content (figs. 8-10). The dense bodies were
present not only in the supranuclear cytoplasm (fig. 9) but also extended into the
basal parts of the light cells (fig. 10). Because of variations in the plane of section
and the shape of the cell, it was difficult
to compare the light cells of treated animals with those of normal rats in a quantitative sense. The impression was gained,
however, that the light cells of treated
rats were unusually large, because extensive
fields of cytoplasm were occupied almost
entirely by dense bodies, even at low magnification in the electron microscope.
A different picture was observed in the
distal portion of t h e ca u d a epididymidis.
It had a greater calibre than the proximal
part, and the epithelium had a smooth contour (fig. 7). The lumen was large and was
filled with material (fig. 7) consisting of
spheres of cytoplasm, parts of sperm, and
large amounts of cellular debris (fig. 11).
The spherical masses of cytoplasm con-
435
tained granules, lipid droplets, membranes,
and sometimes organelles such as mitochondria or a round nucleus. In some instances, they contained parts of spermatids
or sperm such as tail fibers. The light cells
of the epididymal epithelium in the distal
part of the cauda contained many lysosomelike bodies, but these were not as prominent as in the epithelium of the proximal
portion.
In both the proximal and distal parts of
the cauda epididymidis, the principal cells
of the epithelium remained the most numerous cell type. They did not appear to be
altered by the treatment since they echibited their usual complement of organelles
(fig. 12). Microvilli were present on the
surface of the principal cells, and the
apical cytoplasm contained some vesicles
and vacuoles, although these were not as
numerous as in the principal cells of the
middle segment. Many tubules of smooth endoplasmic reticulum were present, mainly
in the cytoplasm apical to the nucleus,
while moderate amounts of rough endoplasmic reticulum were present toward the
base of the cell. Multiple stacks of Golgi
cisternae and associated vesicles were a
prominent feature of the supranuclear cytoplasm. Mitochondria were scattered
throughout the cytoplasm, and lysosomes
were common in the supranuclear position.
Contents of the interior of nuclei varied
from fine dispersed chromatin to a coaser
pattern of clumps of chromatin, but a rim
of condensed chromatin inside the nuclear
envelope was a constant feature. Junctional specializations were recognizable between
the cells next to the lumen. Basal cells in
the terminal segment had a morphology
similar to that described above for the
middle segment.
Of the rats allowed to recover after the
end of treatment, epididymal changes persisted in all those killed three weeks after
the end of treatment and in half of those
killed six weeks after the cessation of treatment. In all the animals killed after recovery for 9 or 12 weeks, the epididymides
had a normal microscopic appearance. This
included a normal appearing columnar
epithelium and many sperm in the lumen
of the caput epididymidis (fig. 13), and
normal epithelium and luminal content
of sperm in the cauda epididymidis (fig.
436
CHARLES J . FLICKINGER
14). Information on recovery of spermatogenesis in the testes is considered in the
companion paper (Flickinger, '77).
Sex accessory glands
Norm a 1 and control rats
The structure of the epithelium of the
rat ventral prostate and seminal vesicle
has been described in detail on several occasions (Price and Williams-Ashman, '61 ;
Brandes, '66, '74; Flickinger, '74a,b).
Briefly, the epithelium lining the acini
of the ventral prostate (fig. 15) is a columnar type and has a prominent basophilia
in light microscope preparations. The
columnar pseudostratified epithelium of
the seminal vesicle (fig. 18) has many folds
that project into the glandular lumen. At
the electron microscope level, the epithelial cells of the both glands are characterized by an abundance of the organelles
known to participate in the formation of
secretions (Flickinger, '74a,b). They contain many cisternae of rough endoplasmic
reticulum, a large Golgi apparatus, and
numerous secretory vacuoles that apparently arise in the Golgi apparatus. The
rough endoplasmic reticulum of the prostate is distended with a flocculent precipitate of newly synthesized secretory protein. The secretory vacuoles of the seminal
vesicle are distinctive, containing a central
electron dense secretory granule surrounded
by a clear rim, while those of the prostate
have a homogeneous interior.
Provera treatment
The weights of the ventral prostate and
seminal vesicles of rats administered
Provera (Experiment 2) were reduced to
approximately 1525% those of control rats
at all of the intervals studied with the
exception of the seminal vesicles of rats
treated with Provera for 16 weeks (table 1;
also Flickinger, '77). Despite this large
decrease in the weight of the prostate and
seminal vesicles in the presence of Provera,
there was great variation in the cytology
of the epithelium in these glands, not only
from one animal to another but also between different parts of the same gland.
In general, microscopic changes were
more pronounced in the prostate than in
the seminal vesicle. In the prostate of treated
animals (fig. 16), the epithelium usually
was a short columnar type, and in some
instances of animals treated for 8 or 16
weeks, the normally columnar epithelium
was reduced to a cuboidal or squamous
shape. These severely altered specimens
also showed obviousultrastructural changes
(fig. 17). Most striking was the reduction
in cisternae of rough endoplasmic reticulum
from the usual parallel arrays that occupy
much of the cytoplasm (Flickinger, '74b;
Brandes, '74) to only a few narrow, dispersed cisternae. In addition, the Golgi apparatus was small and the forming secretory vacuoles that are normally seen in
the Golgi apparatus (Flickinger, '74b) were
absent. Mature secretory vacuoles at the
apical ends of the cells were few in number and sometimes were absent within the
plane of a given section. Nuclei occupied
a large part of the cell, being surrounded
by a greatly reduced amount of cytoplasm
(fig. 17). It should be noted, however, that
there was much variation, and other prostatic cells appeared to retain larger, more
active cytoplasmic organelles.
In the case of the seminal vesicle, although the height of the epithelial cells
was usually less than normal (fig. 19), secretory vacuoles persisted and cisternae of
rough endoplasmic reticulum remained
prominent (fig. 20), even in the samples
from animals treated for 16 weeks. This
suggested that these cells were able to
continue the formation of secretions in
the presence of Provera.
Prouera and testosterone
The administration of testosterone 15 or
30 pg/lOO glday along with Provera (Experiments 3, 4) was not sufficient to maintain the weights of the prostate and seminal vesicles at control levels (table 1). Similarly, this amount of testosterone did not
appear to be adequate to maintain a normal
cytology of the prostatic epithelium, since
regions of cuboidal epithelial cells containing few secretory organelles were regularly encountered in specimens from animals
treated in this way. It was difficult to
assess the effect on the seminal vesicle
epithelium of adding 15 or 30 pg testosterone/100 g/day to the Provera (Experiments 3, 4) because as described above,
ultrastructural changes in the seminal
vesicle epithelium after treatment with
Provera alone (Experiment 2) were not
striking.
437
PROGESTIN AND ANDROGEN. I1
When testosterone was administered at
a level of 100 Fg/lOO g/day along with
Provera (Experiment 5 ) , the weights of
the prostate and seminal vesicles approximated or exceeded control values (table 1).
The epithelium of the prostate was columnar and exhibited normal cytological characteristics in light microscope preparations
(fig. 21), including intense cytoplasmic
basophilia and images of the Golgi apparatus as a clear area in the supranuclear cytoplasm. The variation in different
regions and different glands made it difficult to assess the height of the epithelial
cells, but the impression was gained from
viewing many samples that despite the
maintenance of normal weights the epithelium in Provera and testosterone-treated
rats (fig. 21) did not often attain the high
columnar shape common in normal rats
(fig. 15). In the seminal vesicles of rats
treated with Provera and testosterone (Experiment 5, 100 p g ) , the tall epithelium
(fig, 22) was indistinguishable from that
of normal rats (fig. 18) with the light microscope.
The h e structure of the epithelium of
the prostate and seminal vesicle of most
animals treated with Provera and 100 pg/
100 g/day of testosterone (Experiment 5)
did not appear to differ from that of normal
and control rats. In the prostate (fig. 23),
parallel cisternae of rough endoplasmic reticulum were very numerous in the basal,
supranuclear and apical cytoplasm, and
were distended with a moderately dense
material that probably represents newly
synthesized secretory protein (Flickinger,
'74b). The Golgi apparatus was very large,
and in addition to stacks of cisternae and
vesicles, many forming secretory vacuoles
were present. The density of the content
of the numerous secretory vacuoles increased toward the apical ends of the cells,
and as in normal rats dense secretory
vacuoles accumulated immediately beneath
the apical plasma membrane. In the seminal vesicle (fig. 24), cisternae of rough endoplasmic reticulum also were numerous
and occupied much of the cytoplasm.
Dense material resembling the secretory
granules was present in parts of Golgi
cisternae. The characteristic secretory
vacuoles with a dense core and a clear
rim were abundant in the Golgi region and
in the apical cytoplasm. In the seminal
vesicle of one rat treated with Provera
and testosterone for eight weeks (Experiment 5 ) , cells that appeared to be degenerating were interspersed with the more
numerous normal epithelial cells. This observation is noted because it is an unusual
finding that occurred under treatment, but
its significance is unknown since it was
not observed in the other animals.
DISCUSSION
Epzdidymis
Alterations in the epididymis varied with
the segment of the duct, and this may reflect different activities of the epididymal
epithelium in the different parts. In the
caput epididymidis, the fine structure of
the epithelial cells of the middle segment
did not appear significantly affected, but
the lumen contained greatly reduced numbers of sperm. This could be explained by
decreased production of sperm in the
testes and by transport of sperm in the middle segment when treatment was begun to
the cauda epididymidis where sperm are
normally stored. In the case of the middle
segment, there were no morphological indications of uptake of sperm by the epithelium or migration of phagocytes into
the lumen.
In the proximal part of the cauda epididymidis, the lumen also lacked the usually abundant sperm, but in this portion, the
light cells of the epithelium were distended
with a remarkably large number of vacuoles
and dense bodies resembling lysosomes.
The function of the light cells is not definitely established, but recent evidence has
shown that they are not holocrine secretory cells as once supposed (Clermont and
Flannery, '70). There are indications instead that they are absorptive cells and
the dense bodies in their cytoplasm are
lysosomes (Nicander, '70; Flickinger, '72).
If this is correct, then the lumen of this
segment might have been cleared by uptake
of some of its contents by the epithelium,
particularly by the light cells. Since parts
of sperm were not identified in the epithelium this may have included soluble
material or possibly parts of sperm that
had undergone prior degenerative changes.
The accumulation of material in the distal
cauda also suggests that some sperm from
the proximal part were transported to the
438
CHARLES J . FLICKINGER
more distal portions of the cauda epididymidis.
In the distal part of the cauda epididymidis, the lumen was not clear as in the
proximal part, but instead was distended
with a polymorphous material comprising
parts of degenerating sperm, cells, debris,,
and spheres of cytoplasm. The cellular
material seems most likely to be of germ
cell origin because of the resemblance of
some of its granular and lipid inclusions
and mitochondria to the components of
residual bodies normally found in the seminiferous tubules, and the identification in
some instances of axonemes, tail fibers,
and other spermatid structures in it. These
components may be remnants of sperm produced prior to treatment, or some might
be derived from a small number of germ
cells that reached the later stages of development in treated animals. Both the
presence of so much material in the lumen
and the relatively normal appearance of
the epithelium of the distal cauda epididymidis suggest that material was not
taken up avidly from the lumen in the
distal part. If the light cells play a role
in the absorption of material from the lumen
as suggested above, their fewer numbers
and apparently lesser activity (Reid and
Cleland, '57) in the distal part of the cauda
epididymidis may help to account for the
differences from the proximal portion. The
ultimate fate of the degenerating material
in the lumen of the distal cauda is not
known, since it persisted for 16 weeks,
throughout the duration of the experiment.
It might slowly be absorbed by the epithelium in quantities insufficient to produce
noticeable morphological effects, or it might
be expelled through the remainder of the
duct system.
It was not surprising to find the epididymis affected in rats treated with ProVera, but when testosterone, even at a dose
that maintained the prostate and seminal
vesicles at a normal or slightly elevated
weight, was administered along with ProVera, the microscopic changes in the epididymis were still present. One possible
explanation for this is that the alterations
in the epididymis reflect the responses of
different parts of the organ to changes
in spermatogenesis and in luminal sperm,
rather than being the result of decreased
stimulation of the epididymal cells by
testosterone. For example, the reduced bulk
of sperm reaching the epididymis may
have influenced its appearance, and perhaps the sperm or spermatids that did
each the cauda epididymidis during treatment were defective and this led to their
degeneration in the epididymis with the
ensuing epididymal changes. In addition,
it seems likely that androgen stimulation
of the epididymal epithelium was actually less than normal in Provera and testosterone-treated animals despite the administration of exogenous tertosterone,
because androgen normally reaches the epididymis through the luminal fluid (White
and Hudson, '68; Waites and Setchell, '69;
Hansson et al., '75) as well as through
the blood, and androgen in the luminal
fluid may not have been replaced effectively by testosterone injection. Furthermore, the androgen-binding protein (ABP)
produced by Sertoli cells in the testis has
an important role in the transport of testosterone in the luminal fluid (Hansson et
al., '74, '75). Thus if the production of
ABP in the testis was decreased in Provera
and testosterone treated rats, as discussed
in the preceding paper (Flickinger, '77),
the normal accumulation of androgen in
the lumen of the epididymis would have
been diminished and the amount of testosterone available to the epididymal epithelium further decreased.
Alterations in spermatogenesis, including degeneration of spermatids, were described in the preceding paper (Flickinger,
'77). It seems likely that these testicular
changes are a major factor in the antifertility effect of progestin and androgen.
The alterations in the epididymis may play
a contributory role, however, because a
few sperm seemed to mature in treated
animals and some appeared to undergo
degeneration in the epididymis. In addition, the lumen of the distal cauda epididymidis was full of debris, which, if
transported less easily than sperm, might
impede the passage of any surviving sperm.
The epididymal changes might be more
critical in reducing fertility in animals
treated with a lower dose of progestin and
androgen, which results in lesser suppression of spermatogenesis. In any event, the
epididymal alterations were reversible, as
PROGESTIN AND ANDROGEN. I1
shown by the return to normal of the microscopic appearance of the different regions
in some animals within six weeks and in
all those studied by 9 to 12 weeks after the
end of treatment. The return to normal of
the epididymis, however, required approximately three weeks longer than the reappearance of normal spermatogenesis in
the testis (Flickinger, '77).
Accessory glands
As anticipated, the weights of the prostate and seminal vesicles were reduced
in the presence of Provera, apparently as
the result of a decrease in gonadotropin
release, suppression of Leydig cell function,
and decreased testosterone secretion. In
accord with the decrease in weight, the epithelial cells of the prostate in many specimens showed a decrease in height and in
their complement of organelles. In view
of the large reduction in the weight of the
glands, however, it was surprising that
fine structural changes were not more
pronounced in the case of the seminal
vesicle, which retained abundant amounts
of rough endoplasmic reticulum and secretory vacuoles. The observation that the
prostate showed more extensive changes
is in accord with the notion that the rat
ventral prostate is more dependent upon
androgen than the seminal vesicle (Surfin
and Coffey, '74). Paradoxically, however,
other studies have indicated that the seminal vesicles are more sensitive to antiandrogens (Neumann, '66; h v i n g and Flickinger, '76).
Decline in weight and the presence of
alterations in the function of the sex accessory organs in animals administered
progestins have been reported by others
(Patanelli and Nelson, '59; Setty and Kar,
'67; Browning and Larke, '68; Terner and
MacLaughlin, '73), although in castrated
animals large doses of progestational agents
had a stimulating effect on the sex accessory glands (Price et al., '55). The
changes in the prostate observed in the
present study, consisting of declines in
the organelles involved in the formation
of secretions, resembled those observed in
the prostates of rats treated with cyproterone acetate (Dahl and Tveter, '74; Loving
and Flickinger, '76) and in rats after castration or estrogen treatment (Price and Wil-
439
liams-Ashman, '61; Brandes et al., '62;
Brandes, '66; Helminen and Ericsson, '71;
Dahl and Kjaerheim, '73; Dahl and Tveter,
'73). Such a similarity might be expected,
since the amount of testosterone stimulating the prostate is reduced through removal of the testes in castrated animals
and probably is lowered through a suppression of gonadotropin release in rats treated
with estrogen or Provera, while cyproterone is known to compete with testosterone for receptots in target cells (Fang
and Liao, '69).
In the present it was possible to maintain a normal ultrastructural appearance
as well as normal weight of the prostate
and seminal vesicles by administration of
testosterone along with Provera, but the
amount required was more than initially
was thought necessary. Only 10 pg of
testosterone/lOO g/day sufficed to reverse
biochemical effects of Provera on lipid
metabolism in testicular cells (Terner and
MacLaughlin, '73). In a different study,
testosterone at a level of 40 pg/100 glday
was found to be the optimal replacement
in castrated rats and 50 pg/lOO glday prevented atrophy of sex accessory glands in
the presence of Provera (Kragt et al.. '73),
although the dose of Provera used was
lower than in our experiments. In the
present study, testosterone 100 pg/lOO
glday maintained nearly normal accessory
gland weights in the presence of Provera.
Thus our results resembled those of
Ramirez and McCann ('65), who found
that in castrated adult rats testosterone
75 pg1100 glday produced accessory gland
weights slightly less than normal, while 100
pg/lOO glday resulted in weights slightly
above normal.
Interestingly, i t has been proposed that
in the presence of Provera more testosterone than usual is converted to estradiol
(Kragt et al., '73). If this occurs, more
testosterone may be required to overcome
the effects of Provera than is required to
maintain the accessory glands in castrates.
Although the fine structural changes
brought about by Provera seemed to be
overcome by the presence of testosterone,
it should be kept in mind that it is still
not known whether there are qualitative
or quantitative abnormalities in the accessory gland secretions. Furthermore, the
440
CHARLES J. FLICKINGER
question of long term changes in the accessory glands under this regimen remains
uninvestigated.
ACKNOWLEDGMENTS
The author is indebted to Mrs. Jeannette Charlton and Miss Sharon Odum for
technical assistance. This research was
supported by a grant from the Population
Council (M74.82), a contract with the National Institute of Child Health and Human
Development (NOl-HD-1-2506), and a
grant from NIH (1 R 0 1 HD10073-01).
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and E. B. Astwood, eds. American Physiological Society, Washington, pp. 303-317.
Brandes, D. 1966 The fine structure and histochemistry of prostatic glands in relation to sex
hormones. Int. Rev. Cytol., 20: 207-276.
1974 Fine structure and cytochemistry
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Brandes, D., D. P. Groth and F. Gyorkey 1962
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Browning, H . C., and G. Larke 1968 Response
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Clermont, Y., and J. Flannery 1970 Mitotic activity i n the epithelium of the epididymis i n
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Coutinho, E. M., and J. F. Me10 1973 Successhl
inhibition of spermatogenesis in man without
loss of libido: A potential new approach to male
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Dahl, E., and A. Kjaerheim 1973 The ultrastructure of the accessory sex organs of the
male rat. 11. The post-castration involution of
the ventral, lateral and the dorsal prostate. 2 .
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Dahl, E., and K . J. Tveter 1973 The ultrastructure of the accessory sex organs of the male
rat. 111. The post-castration involution of the
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Zellforsch., 144: 179-189.
- 1974 The ultrastructure of the accessory sex organs of the male rat: the effect of
cyproterone acetate. J. Endocrinol., 62: 251255.
Fang, S., and S . Liao 1969 Antagonistic action
of anti-androgens on the formation of a specific
dihydrotestosterone-receptor protein complex
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Flickinger, C. J. 1972 Alterations i n the fine
structure of the rat epididymis after vasectomy.
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1974a Synthesis,intracellulartransport,
and release of secretory protein in the seminal
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1974b Protein secretion i n the rat ventral prostate, and the relation of Golgi vesicles,
cisternae and vacuoles, as studied by electron
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1977 The influence of progestin and
androgen on the fine structure of the male reproductive tract of the rat. I. General effects
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405-430.
Frick, J. 1973 Control of spermatogenesis i n
men by combined administration of progestin
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39-50.
Hamilton, D. W. 1975 Structure and function
of the epithelium lining the ductuli efferentes,
ductus epididymidis, and ductus deferens in
the rat. In: Handbook of Physiology. Vol. V,
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System. R. 0. Greep and E. B. Astwood, eds.
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pp. 259-301.
Hansson, V., E. M. Ritzen, F. S. French and S. N.
Nayfeh 1975 Androgen transport and receptor mechanisms in testis and epididymis. In:
Handbook of Physiology, Vol. V, Endocrinology.
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Greep and E. B. Astwood, eds. American Physiological Society, Washington, pp. 173-201.
Hansson, V . , 0. Trygstad, F. S. French, W. S.
McLean, A. A. Smith, D. J. Tindall, S. C.
Weddington, P. Petrusz, S. N. Nayfeh and E.
M. Ritzkn 1974 Androgen transport and receptor mechanisms i n testis and epididymis.
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Helminen, H. J., and J. L. E. Ericsson 1971
Ultrastructural studies on prostatic involution
in the rat. Mechanism of autophagy in epithelial
cells, with special reference to the rough-surfaced
endoplasmic reticulum. J. Ultrastruct. Res.,
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Hoffer, A. P., D. W. Hamilton and D. W. Fawcett
1973 The ultrastructure of the principal cells
and intraepithelial leukocytes i n the initital segment of the rat epididymis. Anat. Rec., 175:
169-202.
Ito, S., and M. J. Karnovsky 1968 Formaldehyde-glutaraldehyde fixatives containing trinitro
compounds. J. Cell Biol., 39: 168A.
Karnovsky, M. J. 1965 A formaldehyde-glutaraldehyde fixative of high osmolality for use in
electron microscopy. J. Cell Biol., 27: 137A.
Kragt, C. L., K. K. Bergstrom, K. T. Kirton and
S . E. Porteus 1973 Male antifertility: a n approach. Contraception, I 1 : 91-104.
Loving, C. K., and C. J . Flickinger 1976 Alterations i n the fine structure of the prostate and
seminal vesicle of rats treated with cyproterone
acetate. Anat. Rec., 185: 13-30.
Neumann, F. 1966 Methods for evaluating antisexual hormones. In: Methods in Drug Evalua-
PROGESTIN AND ANDROGEN. TI
tion. P. Mantegazza and F. Piccinini, eds. North
Holland, Amsterdam, pp. 548-573.
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and cytochemistry of the ductus epididymidis
in rabbits. Acta. Morph. Need.-Scand., 1: 99118.
1970 Morphological evidence of secretion
and absorption in the epididymis. In: Morphological Aspects of Andrology. Vol. I. A. F. Holstein and E. Horstman, eds. Grosse Verlag, Berlin, pp. 121-124.
Orgebin-Crist, M. C., B. J. Danzio and J. Davies
1975 Endocrine control of the development
and maintenance of sperm fertilizing ability i n
the epididymis. In: Handbook of Physiology.
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eds. American Physiological Society, Washington, pp. 3 1 9 4 3 8 .
Patanelli, D. J., and W. 0. Nelson 1959 The effect of certain 19-norsteroids and related compounds on spermatogenesis in male rats. Arch.
Anat. Microscop. Morph. Exptl. (Suppl.), 48:
199-222.
Price, D., T. Mann and C. Lutwak-Mann 1955
The stimulating effect of female hormones on the
metabolic activity and histological structure of
male rat accessory reproductive glands. Anat.
R ~ c .122:
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Price, D., and H. G. Williams-Ashman 1961
The accessory reproductive glands of mammals.
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Ramirez, V. D., and S . M. McCann 1965 Inhibitory effect of testosterone on lutenizing
hormone secretion i n immature and adult
rats. Endocrinology, 76: 4 1 2 4 1 7 .
Reid, B . L., and K. W. Cleland 1957 The structure and function of the epididymis. I. The
histology of the rat epididymis. Aust. J. Zool.,
5 : 223-246.
Segal, S. J . 1973 Male fertility control studies:
An editorial comment. Contraception, 8: 187189.
Setty, B. S., and A. B. Kar 1967 Interruption
of spermatogenesis by percutaneous application of steroids. Steroids, 10: 687-698.
Surfin, G.; and D. S. Coffey 1974 A comparison
of hormone responsiveness of the prostate and
seminal vesicle. Invest. Urol., I 1 : 386-391.
Terner, C., and J. MacLaughlin 1973 Effects
of sex hormones on germinal cells of the rat
testis: a rationale for the use of progestin and
androgen combinations i n the control of male
fertility. J. Reprod. Fertil., 32: 453-464.
Waites, G. M. H., and B. P. Setchell 1969
Physiology of the testis, epididymis and scrotum. Adv. Reprod. Physiol., 4: 1-63.
White, I. G., and B. Hudson 1968 The testosterone dehydroepiandrosterone concentration
in fluids of the mammalian male reproductive
tract. J. Endocrinol., 41: 291-292.
PLATE 1
EXPLANATION OF FIGURES
442
1
Light micrograph of the caput epididymidis of a normal rat. A tall
columnar epithelium (E) lines the lumen (Lj, which contains many
sperm. X 300.
2
Light micrograph of the caput epididymidis of a rat treated with
Provera for 1 6 weeks (Experiment 2). The lumen (L)is devoid of sperm.
The epithelium (E) remains columnar, but it appears somewhat shorter
than in the normal rat illustrated i n figure 1. x 300.
3
An electron micrograph of portions of several principal cells in the caput
epididymidis of a rat treated with Provera for 1 6 weeks (Experiment 2).
Even after treatment for this length of time, and although sperm are
absent from the lumen, the principal cells of the epithelium retain their
characteristic organelles, such as many apical vesicles (U)and vacuoles
(Vj, a large Golgi apparatus ( G ) , and smooth endoplasmic reticulum
(R). L, lumen. x 12,000.
PROGESTIN AND ANDROGEN. I1
Charles J. Flickinger
PLATE 1
443
PLATE 2
E X P L A N A T I O N OF FIGURES
Light micrographs of the proximal and distal parts of the
Figs. 4-7
cauda epididymidis of normal and treated rats.
Proximal cauda epididymidis of a normal rat. A columnar epithelium
of moderate height surrounds a lumen that contains many sperm.
The epithelium consists mainly of principal cells (P) and abundant
light cells (arrows). X 300.
Proximal cauda epididymidis of a rat treated with Provera and testosterone for 16 weeks (Experiment 3). The small lumen (L) lacks sperm
and has an irregular outline. The epithelium is tall and the light cells
(arrows), identifiable by their pale-staining nuclei, contain many darkly stained granules. X 320.
Distal cauda epididymidis of a normal rat. The large lumen (L) contains many sperm. The low to medium columnar epithelium (E) is
encircled by a smooth muscle coat (M). X 300.
Distal cauda epididymidis of a rat treated with Provera and testosterone
for eight weeks (Experiment 5). The lumen (L) remains large, but it is
filled with debris, sperm, and round structures, which in some cases
contain a nucleus (arrow). X 300.
444
PROGESTIN A N D ANDROGEN. I1
Charles J. Flickinger
PLATE 2
445
PLATE 3
EXPLANATION O F FIGURE
8
An electron micrograph of the apical portion of a large light cell from
the proximal part of the cauda epididymidis of a rat administered
Provera and testosterone for four weeks (Experiment 3). The apical
cytoplasm contains many electron-lucent vesicles (U) and vacuoles (V).
Deeper i n the cytoplasm the vacuoles are intermingled with dense
bodies (D). The light cells of treated animals were seemingly distended
with large numbers of these dense bodies. The mitochondria (M) contain a dense inclusion. L, lumen. X 17,000.
446
PROGESTIN AND ANDROGEN. I1
Charles J. Flickinger
PLATE 3
44 7
PLATE 4
EXPLANATION O F FIGURES
9,10
448
Electron micrographs of parts of light cells i n the proximal cauda
epididymidis of a rat treated with Provera for 16 weeks (Experiment
2 ) . The cytoplasm of the light cells in this part of the epididymis contained very large numbers of dense bodies (D) that morphologically
resembled lysosomes. These were found in both the supranuclear cytoplasm (fig. 9) and i n the basal parts of the cells (fig. 10). N,
nucleus. Figure 9, X 9,200; figure 10, X 8,200.
PROGESTIN A N D ANDROGEN. I1
Charles J. Flickinger
PLATE 4
449
PLATE 5
EXPLANATION OF FIGURES
Figs. 11, 1 2 Electron micrographs of portions of the distal cauda epididymidis of a rat treated with Provera and testosterone for eight weeks
(Experiment 3).
450
11
The content of the lumen of the distal cauda epididymidis in treated
rats includes debris, parts of sperm ( S ) , and spheres of cytoplasmic
material (K) bounded by a membrane. X 12,500.
12
Principal cells of both the proximal and distal cauda epididymidis of
treated rats did not appear to be significantly altered. As shown i n
this micrograph they contained normal organelles such a s the large
Golgi apparatus (G), endoplasmic reticulum (R),and apical microvilli
(F). N, nucleus. X 13,000.
PROGESTIN AND ANDROGEN. I1
Charles J . Flickinger
PLATE 5
45 1
PLATE 6
EXPLANATION O F FIGURES
Figs. 13, 14 Light micrographs of the epididymis of a rat permitted to
recover for nine weeks after the end of treatment for eight weeks with
Provera and testosterone (Experiment 5).
452
13
The caput epididymidis presents a normal appearance. Many sperm
are present in the lumen (L), which is encircled by a tall columnar
epithelium (E). X 300.
14
In the cauda epididymidis, the lumen (L) is full of sperm and the epithelium (E) has a smooth contour. X 300.
PROGESTIN AND ANDROGEN. I1
Charles J. Flickinger
PLATE 6
453
PLATE 7
EXPLANATION O F FIGURES
15
Light micrograph of ventral prostate of a normal rat. A columnar
epithelium (E) lines the prostatic acini. The light regions immediately
apical to the nuclei represent the Golgi apparatus (arrow). X 300.
16
Light micrograph of the prostate of a rat treated with Provera for 16
weeks (Experiment 2). The epithelium is shorter than in the normal
rat shown i n figure 15. but its height is variable. In some locations
(A) the epithelium is very low and has almost a squamous appearance,
while in other acini (B), it is cuboidal or low columnar. Some vacuoles
are present in the apical cytoplasm but the lightly staining images of
the Golgi apparatus are not apparent (c.f. fig. 15). X 300.
17
454
Electron micrograph of the ventral prostate following treatment with
Provera for eight weeks (Experiment 2 ) . The epithelium is much shorter
than normal, its entire height &om basal lamina (B) to lumen (L) being
visible within the field. The normally abundant cistemae of rough endoplasmic reticulum are reduced to a few small profiles (R) and the
Golgi apparatus (G)is small. No secretory vacuoles are visible i n this
section. N, nucleus. An electron micrograph of normal prostate is not
shown, but this micrograph can be compared with figure 23, which
illustrates the normal-appearing prostatic epithelium of an animal
treated with Provera and testosterone. X 26,000.
PROGESTIN A N D ANDROGEN. I1
Charles J. Flickinger
PLATE 7
455
PLATE 8
EXPLANATION O F FIGURES
456
18
Light micrograph of the seminal vesicle of a normal rat. The tall
columnar epithelium (E)is highly folded. Secretory granules (arrow)
are readily visible i n the apical cytoplasm. The lumen (L) contains
some densely staining secretory material. x 300.
19
Light micrograph of the seminal vesicle of a rat treated with Provera
for 16 weeks (Experiment 2). The epithelium (E)i s not as tall and secretory granules are not as numerous as i n the normal specimen (fig.
18). Secretory material remains in the lumen (L) of the gland; it has
separated from the surface of the epithelium. X 300.
20
Electron micrograph of the epithelium of the seminal vesicle of a rat
treated with Provera for eight weeks (Experiment 2). Although the
cells do not appear as tall as normal (cf. figs. 18, 19), they display
numerous secretory vacuoles (V), parallel cistemae of rough endoplasmic reticulum (R), and a Golgi apparatus (G) i n which there i s
dense secretory material. X 13,000.
PROGESTIN A N D ANDROGEN. I1
Charles J. Flickinger
PLATE 8
457
PLATE 9
EXPLANATION O F FIGURES
Figs. 21, 22 Light micrographs of sex accessory glands of a rat treated
with Provera and testosterone (100 pg) for eight weeks (Experiment 5).
Both specimens are from the same rat. The weights of the glands were
maintained approximately at control values with this treatment.
458
21
The prostatic acini are lined by a columnar epithelium. The Golgi
apparatus (arrow) is visible a s a lightly staining region above the nucleus, as in normal animals. In many specimens such as this, however,
the epithelium did not appear to attain the height of the tall columnar
cells i n normal rats (cf. fig. 15).
22
The highly folded epithelium of the seminal vesicle is composed of tall
columnar cells that contain many secretory granules. It closely resembles that of normal animals (fig. 18). X 300.
PROGESTIN A N D ANDROGEN. I1
Charles J . Flickinger
PLATE 9
459
PLATE 10
EXPLANATION OF FIGURES
Figs. 23, 24 Electron micrographs of the sex accessory glands of rats
treated with Provera and testosterone (100 p g ) for eight weeks (Experiment 5 ) . The cells ofboth glands resemble those of normal rats.
460
23
Ventral prostate in the presence of Provera and testosterone. Normal
appearing organelles include rough endoplasmic reticulum (R), Golgi
apparatus (G), and dense secretory vacuoles (V) in the apical cytoplasm. L, lumen. x 12,000.
24
Portions of several epithelial cells in the seminal vesicle of a rat treated
with F’rovera and testosterone display abundant secretory vacuoles
(V) and profiles of rough endoplasmic reticulum (R). L, lumen. X 12,000.
PROGESTIN A N D ANDROGEN. I1
Charles J. Flickinger
PLATE 10
46 1
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