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Perinatal development of gubernacular cones in rats and rabbitsEffect of exposure to anti-androgens.

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THE ANATOMICAL RECORD 236:399-407 (1993)
Perinatal Development of Gubernacular Cones in Rats and Rabbits:
Effect of Exposure to Anti-Androgens
Department of Endocrinology and Reproduction, Faculty of Medicine and Health Sciences,
Erasmus University Rotterdam, The Netherlands (P.S.); Institute for Hormone and
Fertility Research, 2000 Hamburg, 54 Germany (W.E.)
In male rats gubernacular cones develop during the latter
half of prenatal life. Inversion of these papilla-like organs after birth is the
first step to postnatal growth of the muscular cremaster sacs. The factors
regulating prenatal growth and differentiation or postnatal inversion of
these gubernacular cones are unknown. The lack of a detailed and unequivocal description of the normal gubernacular cone growth is judged at
least partially responsible for this ignorance. The present study therefore
describes the normal development of the gubernacular cones in male and
female rats from day 14 of fetal life.
Androgens are hypothesized to control male gubernacular cone development but recent evidence throws doubt upon this proposal. Therefore, the
second part of this study describes perinatal development of gubernacular
cones in male rat foetuses exposed to the anti-androgen flutamide from day
10 after conception. Quantitatively normal growth occurred prior to birth,
indicating no role of androgen in this process. Excessive growth in length
was noticed during the neonatal period together with delay of gubernacular cone inversion. These developmental alterations did not represent direct anti-androgen-induced modifications of gubernacular cones development as the alterations were not observed in flutamide-exposed neonatally
castrated animals.
Failure of androgens to affect directly perinatal gubernacular cone
growth could represent a rat-specific feature. Fetal rabbits show the development of similar structures during the second half of fetal life. The third
part of this study examined the effect on the development of these structures of exposure of male and female foetuses to the anti-androgen cyproterone acetate. The latter compound inhibited male internal and external
genital development but allowed unaltered gubernacular cone growth.
The observations in this report thus present the normal pattern of perinatal gubernacular cone growth in rats together with evidence that these
organs show male-specific growth independent of androgen. Further work
should reveal the testicular or other factors responsible for this part of
male bodily sexual differentiation processes. o 1993 Wiley-Liss, Inc.
Key words: Gubernaculum, Testis descent, Sex differences, Inguinal
Mammalian testis descent is of vital importance for
the development of reproductive ability during adulthood (Gier and Marion, 1970). While adult testicular
hormonal activity does not require intrascrotal testis
position, this position is an absolute requirement for
spermatogenesis. The intrascrotal, “extra-abdominal”
position allows testes temperature to remain at the required level below body core temperature (Frankenhuis and Wensing, 1979).
Disturbed testis descent is the most often occurring
disturbance of male human sexual development (Rajfer
and Walsh, 1977). Despite its frequent occurrence and
major impact on the prospect of infertility and malignant testis disease there is no detailed insight into the
development of normal or disturbed testis descent
(Hadziselimovic and Herzog, 1980; Hutson and Donahue, 1986). Disturbed testis descent occurs mostly as
Received July 9, 1992; accepted November 9, 1992.
Address reprint requests to P. van der Schoot, Erasmus University
Rotterdam, Department of Endocrinology and Reproduction, P.O. Box
1738,3000 DR Rotterdam, The Netherlands.
a surprise without a clear etiology (Hutson et al., 3 h after birth ( = day 1 of postnatal life) under cold
anaesthesia (Wiesner, 1935). Of these animals the abStudies of the factors governing testis descent are domen was fixed in Bouin’s solution on day 7 after
hampered by the normal occurrence of this process birth and parasagittal sections (mounted 1:lO) were
prior to birth. Cross-species generalizations from ani- studied for development of the muscular cremaster
mal studies to man are difficult to reconcile with the sacs.
claim that distinct developmental processes underlie
Sprague Dawley females (Harlan Sprague Dawley,
testis descent in various animal species. Wensing and Madison, WI) and Wistar rats were impregnated by
coworkers (Wensing et al., 1980; Wensing, 1986) have male colony-mates and injected daily with 10 mg fluproposed the view to distinguish between two types of tamide (SCH 13521; Schering Ltd, Bloomfield, NJ) disdescent. The first type occurs in many small laboratory solved in propanediol from day 10 of pregnancy. The
animals as rats, mice, rabbits, hamsters, and guinea pregnant rats were killed on day 18-22 of pregnancy
pigs. Testis descent is preceded by the growth of guber- and the male and female fetal histology was studied as
nacular or inguinal cones. These are paired structures described above. Two further groups of flutamide-exdeveloping at the caudal end of the gubernaculum tes- posed Wistar males were studied on day 7 after birth.
tis on the inguinal abdomen bottom and giving rise, The first was left intact after birth. The second conthrough their postnatal inversion, to the wall of the sisted of animals which were castrated within 3 h after
muscular cremaster sacs. The schemes of gubernacular birth. Both groups were studied for the postnatally decone development as proposed by Wensing (1986) differ veloping muscular cremaster sacs. Histological analygreatly from those proposed by other workers (e.g., sis was performed of serial transverse or parasagittal
Radhakrishnan and Donahue, 1981). Not unexpect- sections of male and female rat fetuses between day 14
edly, then, controversy persists with regard to hor- post conception and the immediate postnatal period
monal or other factors in control of gubernacular cone (last day: day 7 after birth)
growth. There is, to start with, obvious need for insight
Pregnant rabbits had been daily injected S.C. with 40
into the normal growth process. The present report of- mg per kg bodyweight (BW) of the anti-androgen
fers the description of the development of the guber- cyproterone-acetate (Schering, Berlin, Germany) on
nacular cones as the caudal parts of the gubernaculum days 13-24 of pregnancy (Elger, 1966). Control pregin male and female rat foetuses.
nant rabbits had received injections of the solvent (40%
Recently a discrepancy emerged between reported benzyl benzoate, 60% ricinus oil). Foetuses were colandrogen receptors and androgen effects on gubernac- lected on day 30 of pregnancy (close to the expected
ular cones (George, 1989; Husmann and McPhaul, time of birth). The lower body halves had been sec1991) and failure to detect in vivo effects of androgen or tioned transversely (section size 5 pm) and every twenanti-androgen on the pre- and postnatal development tieth section mounted and stained with haematoxylin
of gubernacular cones (van der Schoot, 1992).As a fur- and eosin. These sections were reexamined for the purther step to establish whether or not androgens affect pose of the present study on gubernacular cones develgubernacular cone growth, the second part of this pa- opment.
per describes gubernacular cone growth in rats and
rabbits exposed to the anti-androgen flutamide and
Gubernacular Cones in Male and
cyproterone-acetate, respectively. Rats and rabbits
Female Rats
show a similar growth of gubernacular cones. The animals differ, however, with respect to the completeness
On day 14 of pregnancy (mean foetal BW 140 mg) no
(rabbits more than rats) with which development of the structures resembling gubernacular cone anlagen
androgen-dependent Wolffian duct derivatives can be could be distinguished. However, on day 15 (mean foeprevented through anti-androgen (Jost, 1971172).
tal BW 250 mg) male and female gubernacular cone
Together, the data should provide insights into nor- anlagen were unequivocally distinguishable. Further
mal and experimentally modified gubernacular cone developmental stages of these anlagen could be identigrowth, and effects of (non-androgenic) hormonal fied in the inguinal abdomen wall just lateral to the
andlor other factors on normal or disturbed testicular paired umbilical arteries (Fig. la,b). The latter strucdescent.
tures appeared equally well developed on the left and
right side and were embedded in the abdomen bottom.
On days 16 (mean foetal BW 500 mg) to 21 (mean
Wistar rats were obtained commercially (TNO, Rijs- foetal BW 3,800 mg) male gubernacular cones develwijk, The Netherlands) and the day of mating ( = day 0 oped (Fig. 2a-5a) to well-differentiated and prominent
of pregnancy) was verified by establishing the presence organs with a muscular wall (part of the M. obliquus
of vaginal copulatory plugs during the morning hours. internus), a mesenchymatous core and bottom, and a
Pregnant rats were killed by cervical dislocation and clearly differentiated connective tissue tip. During this
the uterus was taken out immediately. Foetuses were same period gubernacular cones developed in females
removed in toto and submersed in Bouin’s fixative. Af- as well but the size and structural differentiation in
ter 24 h the bodies were cut into two pieces. The lower females remained less obvious than in males (Figs. 2bbody halves (without extremities and tail) were fixed 5b).
during a further 24 h period and then embedded in
On day 22 (the expected day of birth with a mean
paraffin wax. Sections (of 0.01 mm) were mounted se- foetal BW of 5,000-5,500 mg) or the day after birth the
rially (day 14-16 foetuses) or 1:lO (day 17-22 foetuses) female cones did not undergo structural changes comand stained with haematoxylin and eosin. An addi- pared with previous days. In day 22 males, however,
tional group of newborn male rats was castrated within the cones started to undergo marked structural
Figs. 1, 2. Parasagittal sections through the lower abdomen of a
15-day-old (Fig. 1; BW around 250 mg) and 16-day-old (Fig. 2; BW
around 500 mg) male (a) and female (b)foetus. x 25. Slight elevations
(*) of the inguinal abdomen epithelium indicate the gubernacular
cone anlagen, just behind the M . rectus abdominis (MR) anlagen. On
day 16 the anlage of the M . obliguus internus becomes distinguishable
as a minor ‘line’ just caudaI to MR anlage. The umbilical arteries
(UA) are close to the cones’ anlagen: serial sections reveal that the UA
pass medially to the gubernacular cone anlagen in their course between dorsal and ventral abdomen. The arteries are part of the abdomen bottom throughout. The ventral abdomen wall (to the upper left
side of the pictures) is thin and shows no (day 15) or slight (day 16)
differentiation of the abdomen wall muscles. WD, Wolffian duct; MD,
Mullerian duct.
changes as the first step towards the postnatal formation of the muscular cremaster sacs. In some newborn
males the cones seemed simply enlarged compared
with previous days (Fig. 6). Growth and differentiation
of the muscular wall had resulted in distinct layers of
muscle cells surrounding a connective tissue core. At
the medial aspect of the cones’ base, sections were visible of branches of the N. genito-femoralis which innervated the muscles of the gubernacular cones and other
inguinal abdomen wall structures.
In other day 22 males and, more obviously, in newborn males, gubernacular cones had started inversion
(Fig. 7). The plane of inversion (the earlier base of the
gubernacular cone) could be identified by the site of the
sections through the N. genito-femoralis. The earlier
core of loose mesenchymatous tissue became transformed into a mesenchymatous cover closely adhering
to the inverting muscle layers and separated from the
remaining connective tissue through tissue spaces.
One male was killed on the day of birth while its
bladder was greatly extended through its being filled
with urine. The gubernacular cones in this animals
offered an unusually large appearance (Fig. 8a,b).
Males castrated at birth and killed 7 days later
showed complete inversion of the gubernacular cones
to muscular cremaster sacs. At their entrance these
sacs showed sections through the N. genito-femoralis
at their medial aspect indicative of the site of the earlier base of the gubernacular cone. At their bottom
they showed structures which should be considered the
products of the development of the dense connective
tissue tips of the gubernacular cones (Fig. 9a,b).
Development of Gubernacular Cones and Internal and
External Genitalia in Male Rats Exposed to Flutamide
From Day 10 After Conception
On days 19-21 the gubernacular cones of flutamideexposed male foetuses appeared indistinguishable from
those of untreated male foetuses. On day 22 no sign of
imminent gubernacular cone inversion was observed
in any of 12 males. In contrast the cones had developed
to a larger size (length) than ever seen in normal male
Figs. 3, 4. Parasagittal sections through the lower abdomen of a
17-day-old (Fig. 3; BW around 900 mg) and 18-day-old (Fig. 4)male
(a)and female (b) foetus. ~ 2 5 Marked
growth and differentiation
has occurred in the gubernacular cones (*). The size of the male cone
is larger than that of the female. The M . obliquus znternus (MO)
anlage merges with the muscle cells developing in the gubernacular
cone wall. The testis (T) is situated close to the gubernacular cone and
is surrounded by the differentiating Wolfian duct (WD). In the females the Mullerian duct (MD) is distinguishable. BL, bladder (wall).
Fig. 5. Parasagittal sections through the lower abdomen of a 19day-old (BW around 1,800 mg) male (a)and female (b) foetus. x 25.
Differentiation of the component parts of the male gubernacular cone
has resulted in a distinct “ball” of dense connective tissue at its tip, a
basal loose connective tissue core, and muscle cells layers covering the
whole wall. Tissue spaces (TS) have developed between the loose connective tissue at the base and the further surrounding connective
tissue. BL, bladder (lumen or wall).
Fig. 6. Parasagittal section through the non-inverted gubernacular
cone of a 22-day-old male foetus (BW 5,120 mg). X 25. The length of
the cone has increased compared to Figure 5a but similar components
can be distinguished, including the tissue spaces (TS)between the
connective tissue a t its base and the surrounding connective tissue.
foetuses (Fig. 10a,b). At the cones’ base there was
the normal appearance of the N. genito-femoralis
Seven-day-old males exposed to flutamide prenatally
showed a n unusually shaped gubernacular cone in the
majority (11of 16 cones in 8 males) of cases. The organs
had not inverted but had grown to a n excessive size and
projected from the abdomen bottom into the abdomen
lumen (Fig. lla,b). The shape was similar to, but the
size larger than, the unusually shaped gubernacular
cone of the normal newborn male with bladder extension (compare Fig. l l a with Fig. 8a). The core of the
large-sized gubernacular cones showed tissue spaces
lined by a n intact epithelial-like layer of cells (Fig. l l b ;
compare with Fig. 8b). The remaining 5 gubernacular
cones had inverted. All inverted muscle layers were
covered, on their outer side, with the loose connective
tissue which had made up the core of the earlier gubernacular cone a t the end of foetal life (see Fig. 10a)
and which remained enclosed within the non-inverted
cones (see Figs. 8a, l l a ) . In 7 neonatally castrated rats,
which had been exposed to flutamide prenatally, all 14
gubernacular cones had inverted: cremaster sacs were
present similar to those of neonatally castrated rats not
exposed to flutamide prior to birth (Fig. 9a,b).
It was noticed that exposure to flutamide had been
effective to prevent the masculine development of the
external genitalia, the growth of the prostate and muscles at the base of the penis, and the regression of the
nipples of the mammary glands. However, Wolffian
duct derivatives’ development (epididymis, seminal
vesicles, and deferent ducts) was completely suppressed in only one r a t and partially, but variably, in
the other animals.
Fig. 7. Parasagittal section through the gubernacular cone of a 22day-old male rat foetus (BW 5,340 mg) after the start of the inversion
of the gubernacular cone. x 25. The dense connective tissue tip of the
gubernacular cone is now at the bottom of the inverting organ. The
epididymis (the coiled tube in the upper half of this figure) is connected to this tip via the gubernacular ligament. The muscular wall
of the inverting gubernacular cone is covered on its outer side with
the loose connective tissue which made up the core of the gubernacular cone during earlier developmental stages.
lower abdomen of control 30-day-old male and female
foetuses and foetuses exposed to CA. The gubernacular
cones in males were larger than those in females.
There was 0.1 mm between the upper end of the gubernacular cones and the lower limit of the epididymis.
The testes were in close proximity to the body axis in
the lower abdomen while the ovaries were present far
lateral in the upper abdomen.
Female foetuses exposed to CA showed significantly
smaller ovarian length (1.6 t 0.2 mm) and cross-sectional diameter (0.5 ? 0.02 mm) than controls (2.4 t
0.3 mm and 0.8 2 0.06 mm, respectively; P < 0.01 in
both cases). The distance between the lower pole of the
ovaries and the lower end of the gubernacular cones
was unaffected through CA.
Male foetuses exposed to CA showed similar testis
length (1.6 2 0.1 mm) as controls (1.6 0.02 mm; P >>
0.05), but the cross-sectional diameter (0.8 -t 0.03 mm)
was significantly below that of controls (1.0 c 0.03; P <
0.001). In contrast with the above flutamide-exposed
male rats, male rabbit foetuses exposed to CA showed
no remnants of the Wolffian ducts in the ligaments
between testes and the dorsal and caudal abdomen
wall. The distance between the lower testis pole and
Development of Gubernacular Cones, Gonads, and the
the upper end of the gubernacular cones was signifiInternal and External Genitalia in Rabbits Exposed to
cantly larger in CA-exposed males (1.9 0.2 mm) than
Cyproterone Acetate (CA) on Days 13-24 Post Conception in control males (0.9 t 0.1; P < 0.01). The gubernacuFigure 12 shows a schematic reconstruction, from lar cone length was not affected through CA (controls:
transverse sections, of the urogenital organs in the 2.6 i 0.3 mm; CA exposed: 2.2 ? 0.3; P > 0.05).
Fig. 8. Parasagittal section through an unusually shaped gubernacular cone in a newborn male rat killed while the bladder was fully
distended. a: x 25. b: x 100. The bladder (BL) was greatly enlarged
and the testes were present craniolateral to it. The gubernacular
cones were not inverting but, rather, protruded into the abdomen
lumen over considerable distance. The core of loose connective tissue
is clearly distinguishable from the dark stained muscular wall. In the
core tissue spaces are present (b) with a structured lining of epithelial-like cells (arrows).
Fig. 9. Parasagittal section through the muscular cremaster sac, on
day 7 after birth, of a neonatally castrated male rat. a: x 25. b x 100.
Complete inversion of the gubernacular cones has occurred despite
castration immediately after birth. The “sac” is lined with muscles:
the mass of them is greater than on the day of birth. The tissue at the
medial side of the bottom of the sac (**; detail in the lower right
part of b) is different from the remaining tissues and represents the
structure developing as a ball a t the tip of the gubernacular cone
during prenatal life. Remnants of the tissue spaces (TS) a t the base of
the gubernacular cone during prenatal life are still identifiable. The
arrow points to a section through the genito-femoral nerve.
Fig. 10. Parasagittal section through the non-inverted gubernacular cone of a 22-day-old male foetus (BW 5,400 mg) exposed to flutamide from day 10 of prenatal life. a: x 25. b: X 250. The gubernacular
cone shows the same structural elements as in a normal male foetus.
The dense connective tissue a t the tip of the gubernacular cone shows
signs of growth (mitoses: arrows in b; detail of the gubernacular cone
tip in [a]).
Fig. 1 1. Frontal section through the non-inverted gubernacular
cone of a postnatal 7-day-old male rat exposed to flutamide from day
10 of prenatal life. a: x 25. b: X 100. In this animal the right gubernacular cone had inverted to become a normally shaped cremaster
sac. The left gubernacular cone had not inverted and developed to a
papilla of exaggerated size. The core of loose connective tissue shows
tissue spaces (TS) with epithelial cell-like lining (b).
similarity in male and female foetuses at that time
indicates that their early emergence occurs independent of specific gonadal hormonal stimuli.
Beyond day 15 obvious sex differences develop in gubernacular cone growth. During further development
The present report describes the normal development of the gubernacular cones in male and female
rats from day 14 of fetal life. These organs can be distinguished from day 15 after conception. The observed
30 days old rabbit fetuses
mothers treated days 13-24 p.c.
(40 rngikglday)
3 5,mm
Fig. 12. Schematic drawing (based upon mean results of 4-7 animals per group) of the position of gonads and related organs in 30day-old male and female rabbit foetuses and the effect of exposure to
cyproterone acetate (CA), via injections into their mothers (40 mgikgi
day), between days 13 and 24 of fetal life (mean sizes and distances
given in mm). The position of all organs and structures is given relative to the sexually “neutral” position of the aortic bifurcation. The
distance between the bifurcation and the lowest point of the abdomen
cavity is similar in the four groups of foetuses. CA reduced ovarian
size significantly but did not affect the further urogenital architecture
(lines running caudally from a site lateral to the ovaries indicate the
Miillerian ducts and caudal genital ligaments; the shaded areas represent the ovarian vasculature). CA did not affect testis length but
reduced significantly the cross-sectional testis diameter. CA prevented stabilization of the Wolffian duct without preventing the development of “empty ligaments” between the caudal testis poles and
the gubernacular cone tip and urogenital sinus. The cranial testis
vasculature developed in CA-exposed foetuses and normal male foetuses (the shaded areas medial to the testes) but the size of the vessels
was less in CA-exposed foetuses. In control males the testis vasculature hit the dorsal body wall just above the middle of the ureters; in
CA-exposed foetuses this occurred lateral to the ureters.
in males the tip of the growing gubernacular cones
becomes structurally different from the basal part. The
tip shows persisting mitotic activity with cells laid
down in circular layers. In transverse sections a similar pattern appears identifiable (Radhakrishnan and
Donahue, 1981; Wensing, 1986; George, 19891, thus
suggesting that the tip of the cones develops like a ball
of concentrically deposited cell layers. The connective
tissue at the base of the males’ cones develops differently from the further connective tissue in the abdomen bottom. After day 18 the cones’ base becomes
dissociated from the surrounding tissue through structured tissue spaces.
Inversion of the gubernacular cones, as the first step
to cremaster sac development, starts around birth, The
course of the inversion process described in the present
report differs from earlier notions (Radhakrishnan and
Donahue, 1981; Wensing, 1986; George, 1989). There
was no evidence of regression of the loose connective
tissue in the cones as the initial step of inversion, nor
was necrosis seen in the tissue or reduction in size of
the mesenchymatous cells. It rather seemed that the
tissue changed its location: from constituting the core
and base of the foetal gubernacular cone to shaping a
sheath around the inverting muscular cone wall. This
altered location of connective tissue could occur
through the growth of tissue spaces between the cones
and the further surrounding mesenchyme (see also
Hutson and Beasley, 1992). In retrospect, the altered
location can also be identified in earlier papers (e.g.,
Wensing, 1986) but it was apparently not recognized as
such (George, 1989; Husmann and McPhaul, 1991).
Growth and subsequent regression of the mesenchymatous core plays a key role in a proposed “balloon
theory” for the mechanism of perinatal gubernacular
cone inversion and subsequent testis descent (Wensing,
1968; Wensing et al., 1980; Hutson and Donahue,
1986). Earlier criticism against this hypothesis was
based upon failure to identify the proposed sequence of
processes in human and animal fetuses of increasing
age (Hadziselimovic, 1983). The present findings further substantiate that regression does not occur with
the cones’ mesenchymatous core. Further work should
be undertaken to further analyse the mechanism of
growth of tissue spaces.
Fetal exposure to anti-androgen did not inhibit gubernacular cone growth: there appeared quantitatively
normal development of these organs until the end of
fetal life. After birth, differences developed between
normal and flutamide-exposed male rats: postnatal inversion was delayed and non-inverted gubernacular
cones in flutamide exposed males developed to a n excessively large size. While it would be attractive to
relate this abnormal postnatal gubernacular cone
growth pattern to prenatal inhibition of androgen action upon this organ, results of further experiments
suggested a different answer. Neonatal castration, after exposure to flutamide prior to birth, prevented the
delay in gubernacular cone inversion and the excessive
gubernacular cone growth. Apparently, the postnatal
presence of testes was required in order for these processes to take place. Possibly, mechanical factors associated with the presence of testes with intact cranial
suspensory ligaments (van der Schoot and Elger, 1992)
should be judged responsible for abnormal gubernacular cone development after birth.
Failure to find a n effect of anti-androgen on gubernacular cone growth is difficult to reconcile with reports on androgen receptors and androgen effects upon
these structures (Husmann and McPhaul, 1991) but
easy to understand with a view upon seemingly normal
testicular descent in the syndrome of androgen insensitivity in animals and man. However, the normal development of inguinal cones in anti-androgen exposed
rats occurred together with a n incomplete suppression
of androgen-dependent differentiation and growth of
the internal genitalia. More convincing proof for the
absence of androgen action on gubernacular cone
growth was then provided by analysis of anti-androgen-exposed rabbit foetuses: while androgen dependent differentiation of the Wolffian duct derivatives
was completely inhibited in them, there was unaltered
gubernacular cone development. Further work is required to reveal the nature of the apparently non-an-
drogenic male specific stimuli which are responsible for
gubernacular cone growth.
Thanks are due to Dr I. Tabachnick (Schering Ltd,
Bloomfield, NJ) for providing flutamide, to Dr. A.O.
Brinkmann for support throughout these studies and
for critically reading earlier draughts of this MS, and
to Mrs P. van der Vaart for preparation of the histological slides and microphotographs.
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