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Ultrastructure of immature leydig cells in the human prepubertal testis.

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THE ANATOMICAL RECORD 209:165-176 (1984)
Ultrastructure of Immature Leydig Cells in the Human
Prepubertal Testis
Department of Pathology, Children’s Hospital, Columbus, OH 43205
The cellularity of the human prepubertal testicular interstitium has not been well studied a t the ultrastructural level. In this study,
testicular biopsies were obtained from 35 boys aged three to nine years and
examined by electron microscopy to clarify and quantitate the cell types present during the prepubertal period.
The prepubertal testicular interstitium is found to consist of immature Leydig cells (9%),primitive fibroblastic cells (63%)(intertubular in location), and
attenuated peritubular fibroblasts (28%).The primitive fibroblastic cells and
peritubular fibroblasts appear closely related, being distinguished mainly by
shape and location. The immature Leydig cell type contrasts with the fibroblastic cell types by exhibiting a n irregular nucleus with relatively little
heterochromatin. The most impressive cytoplasmic feature is the moderate to
extensive development of smooth endoplasmic reticulum in the form of anastamosing tubules. In contrast, the rough endoplasmic reticulum is not well
developed. Other cytoplasmic characteristics are the highly developed Golgi
elements and occasional lipid droplets and lysosomes. Glycogen is also often
present and is generally found in those cells that do not contain a welldeveloped smooth endoplasmic reticulum. The ultrastructure of the immature
Leydig cell is compared with that of the mature fetal and adult Leydig cells.
Although generally found in small clusters between tubules, these cells are
often attenuated and closely associated with the seminiferous tubules. Occasional intermediate cell morphologies suggest a relationship between the primitive fibroblasts and immature Leydig cells.
The presence of small cells exhibiting a steroid-producing morphology, classified as immature Leydig cells, in the prepubertal testicular interstitium is a n
interesting finding and is in accordance with earlier studies on nonhuman
mammals. It is unknown whether these cells are remnants of the fetal Leydig
cell population or have differentiated neonatally from the primitive fibroblastic cells. It is suggested that the immature Leydig cells are the progenitors
of the adult Leydig cell population.
In humans, the Leydig cell development
follows a biphasic pattern with two temporally discrete mature Leydig cell populations, fetal and adult. A biphasic development of Leydig cells, although often not as
distinct as in the human, is found to be a
common phenomenon among mammalian
species (e.g., mouse-Pehlemann and Lombard, 1978; rat-Lording and de Kretser,
1972; rabbit-Gondos et al., 1976; rhesus
monkey-Van Wagenen and Simpson, 1954).
The fetal Leydig cell differentiation has been
0 1984 ALAN R. LISS, INC.
correlated with the development of the male
ductular system (see review by Gondos, 1980)
and with “imprinting” of the hypothalamus
(e.g., Abramovich and Rowe, 19731, while the
adult Leydig cell population is correlated
with pubertal development. The morphology
of these two populations of Leydig cells has
been described in numerous nonhuman
mammals (fetal-Black and Christensen,
1969; Russo and de Rosas, 1971; Bjerregaard
Received August 15,1983; accepted November 21, 1983.
et al. 1974; Gondos et al., 1974, 1976; Pehlemann and Lombard, 1978; adult-e.g., Connell and Christensen, 1975; Gondos et al.,
1976; Mori and Christensen, 1980) and humans (fetal-Pelliniemi and Niemi, 1969;
adult-Fawcett and Burgos, 1960; de Kretser, 1967; Christensen, 1970).
The fetal Leydig cell population is rather
transient in its appearance and has been
shown in numerous mammalian species to
undergo degeneration or regress to less differentiated cells (Moon and Hardy, 1973;
Gondos et al., 1976; Tseng et al., 1975; Van
Straaten and Wensing, 1978; Pehlemann and
Lombard, 1978).The presence of partially differentiated (immature ) Leydig cells during
the period between the fetal and adult Leydig cell populations has been demonstrated
in ultrastructural studies of the rabbit (Gondos et al., 1976) and mouse (Aoki, 1970)testis.
Histologic studies of human material, however, have not reported the presence of either
mature or partially differentiated Leydig
cells during the period from the first year of
life until puberty. These studies generally
support fetal Leydig cell degeneration (Sniffen, 1950; Charney et al., 1952; de la Balze et
al. 1960; Pelliniemi and Niemi, 1969; Vilar,
1970; Hayashi and Harrison, 1971). The evidence, however, is not always convincing and
some authors have suggested regression is
present to some degree (Ottowicz, 1963; Mietkiewski, 1966). Ultrastructural studies of fetal Leydig cell development in humans have
concluded that the “majority” of fetal Leydig
cells degenerate in the late fetal period (Pelliniemi and Niemi, 1969; Pelliniemi et al.,
Although there has been much controversy
regarding the fate of the fetal Leydig cell
population, as well a s concerning the possibility of partially developed Leydig cells
being present during the period between the
fetal and adult Leydig cell populations, the
prepubertal period in humans has been given
little attention in the ultrastructural literature. In this study, a large series of testicular
biopsies was obtained from boys aged three
to nine and examined by electron microscopy
to clarify and quantitate the cell types found
in the testicular interstitium during the prepubertal years.
Bilateral testicular biopsies were obtained
at Children’s Hospital (Columbus, Ohio) from
prepubertal boys in leukemic remission for
the purpose of establishing the presence or
absence of leukemic infiltration. In 35 prepubertaI cases found free of leukemic celIs
the interstitial components were examined
for normal constituents.
Sampling and Tissue Preparation
Observation of large tissue sections (up to
5 mm x 12 mm) prepared for histologic examination and stained with hematoxylin and
eosin reveals a homogeneous distribution of
interstitial cells in the prepubertal testis.
Due to this homogeneous distribution, it was
not difficult to obtain a representative sample. A contiguous segment of the biopsy was
prepared for electron microscopy. This specimen was diced and fixed by immersion in
2.5% glutaraldehyde. Following the primary
fixation, the tissue was post-fixed in 1%osmium tetroxide, dehydrated in graded alcohols, and embedded in epon 812 or Medcast.
In each case, 10 to 20 blocks were thick sectioned and stained with toluidine blue. Of
these, two to six blocks were thin sectioned.
Thin sections were stained with uranyl acetate followed by lead citrate and viewed with
a Hitachi HS-7 (50 kV) electron microscope.
These patients had undergone previous
chemotherapy, including vincristine, prednisone, methotrexate, and L-asparaginase.
These chemotherapy regimens have been
shown, in some instances, to cause variable
tubular necrosis, a decrease in the Tubular
Fertility Index, thickening of the basal lamina of the tubules, and variable interstitial
fibrosis (Lendon et al., 1978; Marboe et al.,
1982).No damage has been found to interstitial cells during chemotherapy. Leydig cell
function, assessed by luteinizing hormonereleasing hormone and human chorionic gonadotrophin stimulation tests, has been shown
to remain normal after chemotherapy (Shalet
et al., 1981).
In 15 cases free of leukemic infiltration and
also without obvious fibrosis, tubular necrosis, or tubular basal lamina thickening, the
relative percentage of each cell type comprising the interstitial area was quantitated. To
determine a relative percentage of each of
the three cell types, specimens (two to four
representative blocks per subject) were
viewed on the screen of the electron microscope, and all interstitial cells present on the
TABLE 1. Distribution of cell types during prepubertal period
Age group
Subjects (N)
Mean No. cells/N
Primitive fibroblastic cells
Peritubular fibroblasts
Immature Levdie cells
65.1 (4.9)
27.0 (4.7)
7.9 (1.9)
62.5 (2.4)
27.6 (2.0)
9.8 (1.9)
63.3 (2.1)
28.1 (1.9)
62.3 (4.0)
29.8 (3.5)
7.8 (1.0)
8.6 (0.9)
Values are given as mean percentaee with standard error in parenthesis. No significant differences are found between
age groups.
section were classified and tabulated. Only
cells with a nucleus in the plane of section
were included. Sections were examined until
approximately 500 cells (mean, 545) were
counted per subject. Thus the quantitative
results are based on examination of 8,200
interstitial cells. Schwann cells, macrophages, and mature lymphocytes were very
infrequent and insignificant in terms of the
quantitation. The subjects were divided into
three age groups (ages three to four, five to
six, and seven to eight) with five subjects per
group. The results are summarized in Table
1. The data were analyzed by analysis of
variance, as well as Student's t-test.
Histologic examination of the prepubertal
testis reveals a n interstitial region containing numerous cells distributed in a homogeneous manner. There appear to be no
distinctive cell subtypes with the exception
that some cells are attenuated and closely
associated with the seminiferous tubules
(Fig. 1). Occasional relatively plump cells
with prominent nucleoli are also apparent,
often being found in small clumps. This histologic pattern is constant in all ages studied,
with the exception that larger plump cells
are more prominent in the biopsies from the
older boys. Plastic embedded tissue processed
for electron microscopy presents better histologic detail when thick sectioned and
stained with toluidine blue. With this preparation, the cells comprising the clumps, as
well as isolated cells, are rather irregular in
shape and also exhibit irregular nuclei. Vacuoles are commonly seen in the cytoplasm
(Fig. 2).
At the ultrastructural level, three cell categories can be distinguished, and are designated as 1) immature Leydig cells, 2)
primitive fibroblastic cells (intertubular in
location), and 3) peritubular fibroblasts.
The immature Leydig cells and the fibroblastic cells (both intertubular and peritubu-
lar) are readily distinguished from one
another a t low magnification by their contrasting nuclear features (Fig. 3). The nucleus of the immature Leydig cell is very
irregular and exhibits relatively little heterochromatin, whereas the nucleus of the primitive fibroblast and peritubular fibroblast
is regular in contour and contains a greater
amount of heterochromatin.
The fibroblastic cells are segregated into
two classifications based on location and
morphology. The intertubular fibroblasts
tend to be rather primitive in morphology,
generally containing numerous free ribosomes (Fig. 4).Their shape is variable, with
fusiform, rounded, and irregular profiles
present. The rough endoplasmic reticulum
(RER) is often moderately developed and
bundles of filaments are not infrequent. The
peritubular fibroblasts are attenuated and in
close association with the seminiferous tubules. These cells contain relatively few free
ribosomes and are characterized by numerous filaments (Fig. 5), as well as RER. It is
apparent that there is a continuum of cell
morphologies relating these two fibroblastic
cell categories.
The immature Leydig cells are variable in
shape and contrast with the fibroblastic cells
in cytoplasmic characteristics, as well as the
nuclear differences. The most impressive cytoplasmic feature is the presence of moderate
to extensive elements of smooth endoplasmic
reticulum (SER) in the form of anastamosing
tubules (Figs. 4,6-9). A vesicular appearance
of the SER is rarely observed. The RER is
relatively inconspicuous. The Golgi apparatus is well developed, and mitochondria are
moderately abundant. Mitochondria1 cristae
are of the flattened type. A number of cytoplasmic inclusions are frequently found in
the immature Leydig cell, including lipid
droplets, myelin figures, and lysosomes. Glycogen is often a prominent feature of these
cells, most notably in those that do not contain a well-developed SER (Fig. 6). Reinke
Fig. 1. Prepubertal testis at three (A), five (B), and
eight (C) years. The interstitial cellularity is similar
throughout these years, exhibiting numerous cells of
rather diverse shape. Attenuated cells in a peritubular
location are observed (arrows). Also, occasional rela-
tively plump cells with prominent nucleoli are found
(chevrons). These plumper cells are often found in small
clumps and are more apparent in the eight and 9-yearold boys. H & E x500.
Fig. 2. Plastic-embedded preparation indicating the
presence of vacuoles (arrow) in the cytoplasm of some
interstitial cells. Toluidine blue x 530.
Fig. 3. Low-power electron micrograph demonstrating the nuclear differences between the primitive fibroblastic cells (three upper cells) and the immature Leydig
cells (three lower cells.) ~7,800.
Fig. 4. A primitive fibroblast (top) and an immature
Leydig cell in the interstitium. Free ribosomes (chevron)
are often a prominent feature of the primitive fibroblasts. Rough endoplasmic reticulum (wide arrow) is also
a common cytoplasmic component. The oustanding cytoplasmic feature of the immature Leydig cell type is the
extensive network of tubular elements of smooth endoplasmic reticulum (long arrow). x 14,400.
Fig. 5. An attenuated peritubular fibroblast exhibiting a dense accumulation of filaments (wide arrow). Cytoplasmic extensions from other peritubular fibroblasts
are present, and exhibit rough endoplasmic reticulum.
large arrowhead-basal lamina of seminiferous tubule.
x 11,900.
Fig. 6. Two immature Leydig cells of prepubertal testis. A prominent nucleolus (N) is present. The cytoplasm
exhibits numerous profiles of smooth endoplasmic reticulum (arrowheads)and weI1-developed Golgi regions (G).
Glycogen deposits (large arrowhead) are also present.
Glycogen is generally associated with those cells that do
not contain an extensive development of the smooth
endoplasmic reticulum. x 13,900.
Fig. 7. High magnification of cytoplasm of an immature Leydig cell illustrating the typical cytoplasmic features of this cell type. Arrowhead, profile of smooth
endoplasmic reticulum; G, Golgi region; L, lysosome; Li,
lipid droplet. x28,200.
Fig. 8. A cell classified as a n immature Leydig cell
due to the presence of smooth endoplasmic reticulum
Oong arrows), but that also exhibits features more typical
of the primitive fibroblastic cell type, e.g., numerous
ribosomes (chevron), a relatively prominent development of the rough endoplasmic reticulum (wide arrow)
and relatively prominent heterochromatin. X 13,700.
crystals are absent.
The majority of the immature Leydig cells
are found in the “intertubular” areas, often
in clusters; however, many are attenuated
and closely associated with the seminiferous
tubules pig. 9). It is apparent that the more
prominent immature Leydig cells correspond
to the plump cells seen in the histologic
Cell profiles that possess nuclear and cytoplasmic features intermediate between the
primitive fibroblastic cell and immature Leydig cell are encountered (Fig. 8). These cells
are included in the immature Leydig cell
group based on the presence of elements of
SER in their cytoplasm.
The quantitative results indicate stable cell
populations through the ages of three to eight
with the primitive fibroblastic cells comprising approximately 63%of the interstitial cell
population, peritubular fibroblasts 28%, and
immature Leydig cells 9%(Table 1).Schwann
cells and mature lymphocytes are infrequently found and are insignificant in terms
of cell quantitation.
The consensus of the histologic literature
on human testicular development is that
Leydig cells, either mature or partially developed, do not exist during the prepubertal
period. In the late prepubertal period, an in-
Fig. 9. An attenuated immature Leydig cell closely
associated with a seminiferous tubule (ST).Large arrowhead, basal lamina of seminiferous tubule; arrowheads,
profiles of smooth endoplasmic reticulum; L, lipid.
creasing heterogeneity in cellularity has
been described, prompting classification
schemes for different “types” of fibroblasts
(e.g., Tillinger et al., 1955; de la Balze et al.,
1960; Vilar, 1970). The majority of these
studies report that Leydig cells begin development a t approximately 11 to 14 years of
age (Sniffen, 1950; Charney et al., 1952;
Mancini et al., 1952; de la Balze et al., 1960;
Vilar, 1970). The earliest evidence of the
“reappearance” of small Leydig cells has
been a t approximately eight years of age
(Hayashi and Harrison, 1971). In the present
study, infrequent, relatively plump cells (although quite small compared with a mature
Leydig cell) with prominent nucleoli are apparent in the histologic material throughout
the prepubertal ages studied.
The prepubertal testis has been given little
attention by electron microscopists. Previous
ultrastructural studies are not in agreement
as to the presence or absence of partially
developed Leydig cells during this period.
Leeson (1966) and Vilar (1970) report only
primitive fibroblastic cells during the prepubertal years. Nistal and Paniagua (1979)
give brief comment to the presence of SER in
cells from four prepubertal controls in a manuscript that emphasizes the effects of human
chorionic gonadotropin on two 26-year-old
patients with hypogonadotropic hypogonadism. Hadziselimovic (1977) reported remnants of the fetal Leydig cell population in a
one year old and also described Leydig cells
in a six year old. The Leydig cells of the six
year old are reported to be unlike those of
the neonatal specimen, being smaller and
having a more prominent nucleolus. His figure also shows a more highly irregular nucleus. Both of these latter studies also report
fibroblasts to be present. Nistal and Paniagua (1979)indicate those in association with
the tubules are myofibroblastic (not the
myoid cell of the adult).
The current study of a large series of prepubertal biopsies has clarified the diversity
in cell morphology present in the prepubertal
interstitiurn and demonstrated a constant
cell constituency during this period. The cellularity has been classified into three general types: 1)immature Leydig cells (9%), 2)
primitive fibroblastic cells (intertubular location) (63%), and 3) peritubular fibroblasts
(28%). The occurrence of partially differentiated Leydig cells in humans during the period between the fetal and adult Leydig cell
populations is the most impressive finding
and is in accordance with previous studies on
nonhuman mammals (Aoki, 1970; Gondos et
al., 1977).
The major cytoplasmic feature of the immature Leydig cell is the widespread network of tubular elements of SER. The SER
has been shown to be of major involvement
in the synthesis of steroids (Murota et al.,
1965; Christensen, 1969) and is the predominate fine structural feature of the fetal and
adult Leydig cell populations (see review by
Christensen, 1975). The report of Hadziselimovic (1977) differs from the current study
in that it reports a vesicular appearance of
the SER. The material in that study was
obtained postmortem, however. In studies of
the adult Leydig cell it has been shown that
vesicular SER is a n artifact of nonoptimal
fixation (Christensen, 1975). The morphological description of partially differentiated
Leydig cells in the human prepubertal testis
is supported by the histochemical findings of
Wolfe and Cohen (1964). They examined the
activity of glucose-6-phosphate-dehydrogenase (G-6-PD),a n enzyme of the hexose phosphate shunt that has been shown to be
important in the production of steroid hormone by supplying NADH. Their findings
revealed the presence, during the prepubertal period, of “fibrocyte-like cells in the testicular interstitium which are metabolically
related to the mature Leydig cell.”
The immature Leydig cells found during
the prepubertal years differ from the mature
fetal and adult Leydig cells in a number of
cytoplasmic features, as well a s by their
small size. The irregularity of the nucleus is
quite impressive. In contrast, the fetal and
adult Leydig cells generally exhibit circular
nuclear profiles (Christensen, 1975; Pelliniemi et al., 1980),although a certain degree
of irregularity is present in a segment of the
mature populations. Although the SER is
abundant, it is not as extensive as in the
mature Leydig cells. The Golgi apparatus is
well developed, as is the case in the mature
Leydig cells. Mitochondria of the immature
Leydig cells are less pleomorphic than the
adult Leydig cells and exhibit flattened cristae, as opposed to tubular cristae. The RER
is not found segregated in the cytoplasm, as
is the case in the fetal and adult populations.
Cellular inclusions, such as lysosomes and
lipid are also less apparent. The presence of
glycogen is interesting in that it is generally
not a feature of the adult Leydig cell population (human-Fawcett and Burgos, 1960; de
Kretser, 1967; Christensen, 1975; non-human-Ichihara, 1970; Gondos et al, 19761, but
has been reported in immature Leydig cells
found during the prepubertal period in the
mouse (Ichihara, 1970). Reinke crystals are
not present. These inclusions are a distinctive feature of the adult Leydig cells, but are
not found in the fetal Leydig cell population.
The description of partially developed Leydig cells during the prepubertal years will
stimulate interest into their physiological
significance. Although these cells are generally found in small clumps in the intertubular region many are attenuated and
intimately associated with the seminiferous
tubules, suggesting a functional relationship. The low level of testosterone found in
the serum throughout the prepubertal years
(August et al., 1972; Winter et al., 1972) may
be indicative of production from these cells
or perhaps they produce other steroids.
The majority of the cells in the prepubertal
interstitium do not exhibit a steroid-producing morphology. These cells have been subdivided by location and morphology into two
groups, peritubular fibroblasts and primitive
fibroblasts (intertubular location). There is a
continuum of cell morphologies that relates
the intertubular cells to those surrounding
the tubules. The rather primitive nature of
the intertubular fibroblastic cells of the prepubertal testis has been noted by previous
studies. An early histologic study (de la Bake
et al., 1960) distinguished a “type a” fibroblast, intertubular in location, of the prepubertal period as different from the inner
peritubular fibroblasts and also from the fibroblasts of the adult testis. Previous ultrastructural studies also recognized the
primitive nature of these cells and used terminologies such as “primitive fibroblasts”
(Leeson, 1966) and ‘Ijuvenile fibroblasts” (Vilar, 1970) to describe them. It is interesting
that the [‘undifferentiated mesenchymal”
cells described in the eight-week human fetus by Pelliniemi and Niemi (1969) differ
from the primitive fibroblasts of the prepubertal period. The fetal cells are more irregular in shape and exhibit less heterochromatin in the nucleus.
The peritubular fibroblasts have a more
typical fibroblast shape (elongate) and generally do not contain as many free ribosomes
as the primitive fibroblasts. These peritubular cells are characterized by RER and
numerous filaments. They do not show, however, the extensive filaments and dense
plaques of the myoid cells found in the adult
peritubular region in humans (personal obervation; Bustos-Obregon and Holstein, 1973;
Hermo et al, 1977).
The occurrence of cells with a morphology
intermediate between the primitive fibroblasts and immature Leydig cells raises the
possibility of a relationship between these
cell types. This, however, is speculative and
will require further study to substantiate. At
present, it is best to maintain the terminology “primitive fibroblasts” to describe the
primitive cells of the prepubertal interstitium. A cause of confusion in the literature
is the presumptive terminology that is occasionally applied to this primitive cell population. Hadziselimovic (1977) described these
cells as a “second type of Leydig cell . . . the
so-called ‘precursor’ Leydig cell,” referring to
the description by Fawcett and Burgos (1960)
of fusiform interstitial cells in the testis of
mature men.
This study indicates a constant cell constituency in the interstitium during the years
three to eight. Whether the immature Leydig cell population is a remnant of the fetal
Leydig cell population or has developed neonatally from the primitive fibroblastic cells
is unknown. A study of early neonatal tissue
is necessary to resolve this question.
The cell or origin of the adult Leydig cell
has been a topic of controversy. Although the
consensus of the histologic literature has
been that the adult Leydig cells arise from
primitive mesenchymal (fibroblastic) cells,
the exact nature of these cells has been unknown. The described immature Leydig cells
of the prepubertal testis are very likely precursors of the adult Leydig cell population.
Pubertal biopsies are being examined to elucidate this maturation.
Discussion with Dr. Nigel Palmer is appreciated. Also appreciated is the excellent technical assistance of Mrs. Melinda Little in EM
preparation and the members of the histology lab (Mr. Louis Wensloff, Mrs. Vera
Small, and Mrs. Flora Jaynes) in histologic
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ultrastructure, testis, immature, prepubertal, leydig, human, cells
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