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Original Studies |
Center for Research on Reproduction and Women’s Health (S.E.P., C.B.K., F.A., M.K., J.F.S.) and Departments of Obstetrics and Gynecology (S.E.P., C.B.K., F.A., M.K., J.F.S.), Pathology and Laboratory Medicine (E.E.F., J.F.S.), and Cellular and Molecular Engineering (K.F.K.), University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Jerome F. Strauss III, M.D., Ph.D., 778 Clinical Research Building, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104. E-mail: jstrauss{at}obgyn.upenn.edu
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Abstract |
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Primordial follicles of adult ovaries did not contain StAR, whereas antral follicles stained intensely in the thecal layer, with occasional staining of granulosa cells. Corpora lutea were intensely stained, but with a patchy distribution. Corpora albicantia did not stain. A luteoma of pregnancy stained with patches of moderate intensity. Ovaries with hyperthecosis contained areas of intense thecal staining. An ovarian Leydig cell tumor stained intensely, whereas granulosa cell tumors were negative. Ovarian adenocarcinomas, borderline tumors, teratomas, cystadenomas, and a Brenner tumor displayed no specific StAR immunostaining. Testicular Leydig cells stained moderately to intensely, as did a testicular Leydig cell tumor. Sertoli cells stained weakly in some specimens. Seminomas and testicular germ cell tumors were negative. There was minimal to moderate staining in the adrenal glomerulosa and faciculata and minimal staining in the reticularis, while the medulla was negative. Adrenal cortical adenomas, hyperplasias, and carcinomas all contained areas of StAR staining. The renal distal tubules stained with moderate to marked intensity. Renal carcinomas had occasional modest staining.
No immunostaining was found in the placenta. Fetal ovaries contained sporadic stromal cells displaying intense StAR staining, particularly in the hilar region. Oocytes from a 32-week fetal ovary showed moderate to intense staining. Fetal testes displayed intense Leydig cell staining. The neocortex of the fetal adrenal glands displayed only minimal StAR staining, whereas moderate to intense staining was found in the fetal zone. The fetal kidneys had moderate StAR staining of the distal convoluted tubules.
We conclude that StAR is localized to normal and neoplastic cells in the gonads and adrenal cortex, which produce large amounts of pregnenolone. StAR protein was not detected in the placenta, documenting that placental progestin synthesis occurs through StAR-independent mechanisms. The presence of StAR in cells that do not express cholesterol side-chain cleavage enzyme cytochrome P450, including renal distal tubules, Sertoli cells, and fetal oocytes, suggests that StAR has roles in metabolic processes in addition to stimulating pregnenolone synthesis.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The evidence that StAR plays a critical role in steroid hormone synthesis includes the demonstration by Sugawara et al. (4) of enhanced steroidogenesis in monkey kidney COS-1 cells after transfection with human StAR complementary DNA (cDNA) and the cholesterol side-chain cleavage enzyme system, and the finding that mutations in the StAR gene cause congenital lipoid adrenal hyperplasia, an autosomal recessive disorder in which the synthesis of all adrenal and gonadal steroid hormones is severely impaired at the cholesterol side-chain cleavage step (5, 6, 7).
StAR messenger ribonucleic acid (mRNA) has been detected in human adrenal cortex, testis, ovary, and kidney, but not in placenta, liver, or brain (4, 8, 9). Sugawara et al. (4) proposed that tissues that express StAR are exclusively those that carry out regulated mitochondrial sterol hydroxylations. Although the expression of StAR mRNA in human tissues has previously been reported, the localization of StAR protein in human tissue has heretofore not been described. In addition, the presence of StAR in human fetal and neoplastic tissues has not been examined. The objectives of the present study were to generate an antiserum against human StAR protein and to use it to localize StAR in various human tissues.
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Materials and Methods |
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Adult and fetal tissues analyzed in this study were identified by searching the SNOMED diagnostic retrieval system of the Department of Pathology and Laboratory Medicine of the University of Pennsylvania Medical Center (Philadelphia, PA) and review of autopsy records. Autopsy specimens were derived from postmortem examinations carried out within 18 h of death. We analyzed 13 normal ovaries containing follicles of various stages, 1 ovarian Brenner tumor, 2 ovaries with hyperthecosis, 1 luteoma of pregnancy, 2 ovarian cystadenomas, 5 ovarian teratomas, 1 struma ovarii, 1 ovarian borderline tumor, 4 ovarian adenocarcinomas, 3 ovarian granulosa cell tumors, 1 ovarian Leydig cell tumor, 10 normal testes, 6 testicular seminomas, 3 testicular Leydig cell tumors, 2 testicular mixed germ cell tumors, 15 normal adrenals, 1 adrenal hyperplasia, 7 adrenal adenomas, 3 adrenal cortical indeterminate neoplasms for which a diagnosis of adenoma vs. carcinoma could not be made with certainty, 1 adrenal cortical carcinoma, 5 normal kidneys, 5 renal cell carcinomas, and 3 placentas. Fetal tissues studied included 12 adrenals, 10 kidneys, 3 testes, 7 ovaries, 2 brains, 2 spinal cords, 5 thymuses, 2 hearts, 4 livers, 1 bone specimen, 1 lung, 1 intestine, and 2 stomachs.
Ovarian follicles were classified according to the criteria of Clement (10). Of the 13 normal ovaries studied, the following number and types of ovarian structures were studied: 17 primordial/primary follicles, 10 antral follicles, 1 luteinized follicle, 2 corpora lutea, 3 degenerating corpora lutea, and 16 corpora albicantia. An oocyte surrounded by a single layer of flattened, mitotically inactive, granulosa cells was considered a primordial follicle, and an oocyte surrounded by a single layer of cuboidal to columnar granulosa cells was considered a primary follicle. For the purposes of this study, these two categories were grouped together.
Production of rabbit antihuman StAR polyclonal antiserum
A cDNA encoding StAR sequences from amino acid residues 63–285 was cloned into the pQE-30 vector (Qiagen, Chatsworth, CA) which places a six-histidine residue tag at the amino-terminus. The six-histidine-tagged recombinant protein was purified on nickel-nitrilotriacetic acid resin (Qiagen). The eluted protein was dialyzed against 4 L phosphate-buffered saline containing 0.1 mmol/L phenylmethylsulfonylfluoride, 1 mmol/L dithiothreitol, and 10% glycerol three times for 4 h each time. Soluble protein was then concentrated using Ultrafree-15 centrifugal filters (Millipore, Bedford, MA) and used to inoculate rabbits (Rockland, Gilbertsville, PA). Some aliquots of antiserum were affinity purified on a column of immobilized antigen before use.
To determine the specificity of the polyclonal rabbit StAR antiserum, we probed Western blots containing extracts of COS-1 cells that do not normally express StAR and extracts of COS-1 cells transfected with a human StAR expression plasmid (pSV-SPORT-1) or the empty vector (4, 11). Extracts of human fetal adrenal cortex and placenta were also probed. In addition, we prepared a recombinant replication-deficient adenovirus vector with the human StAR cDNA under the control of the sheep metallothionein promoter, which will be described elsewhere, to infect COS-1 cells for immunocytochemical studies. The COS-1 cells were cultured to 60% confluence and infected with the adenovirus vector. Treatment with ZnCl2 (80 µmol/L) for 24 h was used to activate the promoter. A similar virus containing a lacZ cDNA insert in place of the StAR cDNA was used as a control. The COS-1 cells were fixed with 4% paraformaldehyde, and immunohistochemistry was performed as described below.
Immunohistochemical localization of StAR
Formalin-fixed paraffin-embedded tissue sections of 5 µm were mounted on ProbeOn Plus slides (Fisher Scientific, Pittsburgh, PA). The tissues were then stained using a modified avidin-biotin complex technique with Ventana/Biotek solutions (Ventana Medical Systems, Tucson, AZ) using capillary gap technology (FisherBiotech MicroProbe Staining System). Endogenous peroxidase activity was blocked with 2% H2O2 methyl alcohol treatment for 20 min. Incubation with Ventana/Biotek blocking serum (containing rabbit, goat, and mouse sera) was used to decrease nonspecific binding. The StAR antiserum was used at dilutions from 1:200 to 1:1000, with a majority of slides stained at a 1:500 dilution. A secondary antibody of biotinylated goat antirabbit IgG was used at a dilution of 1:2000. Color development used 3,3'-diaminobenzidine tetrahydrochloride. The sections were counterstained with hematoxylin. Controls consisted of preimmune serum at an equivalent dilution as the primary antibody and immune serum neutralized with recombinant six-histidine residue tagged N-62 StAR protein.
The results of the immunohistochemical studies were evaluated by two observers. The staining was graded by a subjective semiquantitative scale of 0 for no staining, + for minimal staining, ++ for moderate staining, and +++ for intense staining.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The rabbit anti-StAR antiserum did not react with proteins present
in extracts of human term placenta or COS-1 cells transfected with an
empty plasmid vector (Fig. 1A
). However,
the 30-kDa mature StAR protein was detected in COS-1 cell extracts from
cells transfected with the StAR expression plasmid and in extracts of
human fetal adrenal cortex (Fig. 1A).
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). No
staining was observed in COS-1 cells infected with a recombinant
adenovirus expressing lacZ with or without ZnCl2
treatment. The localization of StAR to the mitochondria was confirmed
in experiments in which StAR-expressing COS-1 cells were labeled with
Mitotracker dye (red fluorescence) and simultaneously stained with
fluorescein-conjugated antibody (green fluorescence) to detect StAR.
Observation of the preparation using a filter detecting signal from
both fluorophores revealed yellow veriform organelles reflecting the
colocalization of the mitochondrion-specific dye and StAR (data not
shown). Immunohistochemical localization of StAR
StAR immunoreactivity was observed exclusively in the cytoplasm in a granular pattern regardless of the tissue type studied. Crude antiserum and affinity-purified antibody gave identical results in immunohistochemical studies.
Normal adult ovaries
Primordial and primary follicles in adult ovaries did not display
immunoreactivity for StAR (Fig. 2B and
Table 1). Antral follicles stained
intensely in the thecal layer, with occasional granulosa cell staining
in the larger follicles (Fig. 2C and Table 1). The luteinized follicle
stained moderately in the granulosa cell layer and intensely in the
thecal layer. Corpora lutea stained intensely, but with a patchy
distribution (Fig. 2D and Table 1). Regressing corpora lutea also
stained with a patchy distribution, but with more heterogeneous
intensity, ranging from modest to intense staining (Table 1). Corpora
albicantia did not stain for StAR (Table 1).
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The luteoma of pregnancy stained with patches of varying
intensity, from no staining to intense staining (Table 2). Ovaries with hyperthecosis stained in
a heterogeneous pattern, containing areas of intense staining for StAR
in the hyperplastic theca (Fig. 3A). The
cystadenomas, Brenner tumor (Fig. 3A), teratomas, struma ovarii,
borderline tumor, and adenocarcinomas displayed no specific StAR
immunostaining (Table 2). The ovarian Leydig cell tumor stained
moderately to intensely (Table 2), whereas the granulosa cell tumors
(Fig. 3B) gave no signal for StAR.
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In the normal testes, Leydig cells stained moderately to intensely
(Fig. 4 and Table 1). Specific Sertoli
cell staining was seen in some specimens. The seminomas and germ cell
tumors were negative for StAR signal, whereas the testicular Leydig
cell tumors had variable staining, with some areas of intense staining
(Table 2).
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Minimal to moderate StAR staining was observed in the zona
glomerulosa and zona faciculata (Table 2); rare minimal staining was
found in the reticularis, and no staining for StAR was observed in the
medulla (Table 1). The adrenal hyperplasia, adenomas, indeterminate
neoplasms for which a histological diagnosis of adenoma vscarcinoma could not be made with certainty, and carcinoma all
displayed StAR staining; however, there was variable staining intensity
among specimens (Table 2). Additionally, within a given specimen, the
StAR signal was heterogeneous, showing some areas without signal and
some areas with an intense signal.
Normal and pathological renal tissues
Normal kidneys contained a heterogeneous population of tubules,
some that stained with moderate intensity and others that did not stain
(Fig. 5 and Table 1). The stained tubules
were morphologically identified as distal convoluted tubules. The
glomeruli did not stain. In the five renal cell carcinomas examined,
there was occasional staining of modest intensity (Table 2).
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Specimens of fetal ovaries from fetuses 19 weeks or older all
displayed sporadic stromal cells with intense StAR staining (Table 3). There appeared to be a tendency for
more of these intensely stained stromal cells to be located in the
hilar region. One 32-week ovary displayed moderate to intense staining
of the oocytes (Fig. 2A). However, this was the only specimen available
for study at this gestational age. An ovary from a 24-week fetus did
not show oocyte staining, nor did oocytes in adult ovaries.
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). All displayed intense Leydig cell staining for StAR (Fig. 4C).
Fetal adrenals, ranging in age from 10–32 gestational weeks, were
examined (Fig. 6). When a neocortex,
which will give rise to the permanent adult adrenal cortex (12), was
present on the preserved specimen, it contained areas of only minimal
StAR staining. The fetal adrenal zone stained moderately to intensely
at all gestational ages examined.
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).
However, the 12-week fetal kidney tubules displayed no StAR staining.
The other specimens (gestational ages ranging from 14.5–24 weeks) all
displayed tubules with specific StAR staining of moderate intensity.
Interestingly, the less mature renal tubules, which are located closer
to the renal capsule (12), did not stain, whereas the more mature renal
tubules, located more centrally, yielded a StAR signal. These
observations suggest a differentiation dependence of StAR expression in
the tubules. Fetal specimens containing neural tissue including fetal brains and fetal spinal cords gave no StAR signal, nor did fetal thymuses, fetal hearts, fetal livers, fetal bone, fetal lung, fetal intestines, and fetal stomach. Term placenta did not stain for StAR, consistent with the previously noted absence of detectable StAR protein by Western blot analysis.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylation of vitamin D in response to
PTH. Moreover, myelomonocytic cells express vitamin D 1-hydroxylase
(13). Thus, the presence of StAR mRNA in kidney and formed blood
elements is consistent with a role for StAR in mitochondrial sterol
hydroxylations. We localized StAR protein to cells in human gonads, adrenal cortex, and kidneys that carry out mitochondrial sterol hydroxylations. In adult human ovaries, StAR was not present in immature follicles. In the antral follicles, the thecal cells were positive for StAR, with granulosa cell StAR staining in the larger antral and luteinized follicles. The corpora lutea displayed StAR staining, with a diminution of staining intensity in the aged corpora lutea and corpora albicantia. These immunohistochemical results are similar to those of our previously published study of the distribution of StAR mRNA detected in human ovarian sections by in situ hybridization histochemistry (14). The expression of StAR correlates both temporally and spatially with the expression of SF-1, an oxysterol-activated nuclear receptor that regulates StAR and steroidogenic enzyme gene expression (15, 16, 17).
Immunoreactive StAR was detected in low levels in Sertoli cells. This
observation is consistent with reports demonstrating StAR in rodent
Sertoli cells (18). In the kidneys, there were interspersed tubules
that contained a StAR signal of moderate intensity. These positive
tubules were morphologically consistent with distal convoluted tubules,
which are the sites of mitochondrial sterol hydroxylation by
1-hydroxylation of vitamin D. It is noteworthy that SF-1 mRNA is
also present in human monocyte cells and at modest levels in human
kidney (19).
The presence of StAR in ovarian hyperthecosis, ovarian luteomas, ovarian Leydig cell tumors, and testicular Leydig cell tumors suggests that StAR plays an important role in steroidogenesis in hyperplastic and neoplastic tissues. The variable staining of different specimens seen in the adrenal hyperplasias, adenomas, indeterminate neoplasms, and carcinomas might be due to different levels of steroid production in these tumors or might reflect regional differences in tumor steroidogenic activity. The variable expression of StAR mRNA in adrenal neoplasms has previously been reported (9). The ovarian cystadenomas, Brenner tumor, teratomas, stroma ovarii, borderline tumors, and adenocarcinomas all displayed no specific StAR immunostaining, which is consistent with their lack of steroidogenic activity. The granulosa cell tumors, seminomas, and germ cell tumors also displayed no specific StAR staining, reflecting the generally low levels of pregnenolone synthesis by these tumors due to their variable expression of P450scc (20, 21). Characteristically, granulosa cell tumors and seminomas do not secrete steroid hormones in quantities comparable to those in normal ovarian thecal cells, luteal cells, or testicular Leydig cells. Thus, the absence of detectable immunoreactive StAR in the tumors we studied is not unexpected based on the quantities of hormone they usually produce.
The detection of immunoreactive StAR in oocytes of primordial follicles in a single fetal ovary specimen is of interest. Because this finding could not be replicated in specimens from other gestational ages and adult ovarian tissue, it must be considered preliminary. However, P450scc has recently been detected in murine oocytes (22), raising the possibility that germ cells are capable of producing pregnenolone at least at some stages of development.
The primary tissues in which we found StAR have a common embryological derivation. The gonads and distal convoluted renal tubules are derived from the intermediate mesoderm of the urogenital ridge (12). The adrenal is also derived from mesoderm (12). We found specific StAR staining in all specimens of fetal cortex and minimal to no staining in the neocortex. This is a pattern of StAR expression consistent with the fact that the fetal cortex is the steroidogenically active component of the fetal adrenal gland, whereas the neocortex does not begin to differentiate into the characteristic adult cortical zones until the late fetal period (12). The substantial steroidogenic activity of the fetal zone and the relative inactivity of the neocortex account for the significant impairment of fetal zone function in fetuses affected with lipoid congenital hyperplasia, characterized by diminished provision of androgen precursors for placental aromatization and consequently markedly reduced estriol production and later impairment of cortisol production (6).
We found StAR staining in Leydig cells of fetal testes ranging from 14.5–19 gestational weeks. These observations are consonant with the fetal production of testosterone, which peaks at 14 weeks gestation (23). Genetic males affected with inactivating mutations of the StAR gene are pseudohermaphrodites as a result of deficient fetal testicular androgen formation (5, 6).
The fetal kidneys displayed StAR staining in a pattern suggestive of
differentiation-dependent regulation. The outer cortical region of the
kidneys, which did not display a StAR signal, contains undifferentiated
mesenchyme from which new nephrons develop, whereas the more mature
centrally located tubules were StAR positive. Symptoms of vitamin D
deficiency have not been reported in cases of congenital lipoid adrenal
hyperplasia. However, the presence of StAR in the distal tubules and
the theoretical possibility that StAR plays a role in controlling
1-hydroxylation of vitamin D raise the possibility that provocative
testing might disclose abnormalities in vitamin D 1-hydroxylation in
individuals lacking functional StAR.
In summary, we have demonstrated immunoreactive StAR in both normal and pathological human steroidogenic tissues. In addition, our work substantiates our earlier report of the presence of StAR mRNA in human kidney and its absence in the placenta. The detection of StAR in certain cells that do not express P450scc suggests that StAR has roles beyond the stimulation of pregnenolone synthesis, possibly the production of hydroxysterols (24), which are regulators of cellular sterol homeostasis and activators of SF-1 (25). The absence of StAR from the placenta affirms the existence of StAR-interdependent mechanisms of pregnenolone synthesis. A protein with significant homology to StAR, MLN64, which displays steroidogenic activity and is expressed in the human placenta, may subserve StAR’s function in this organ (26).
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Acknowledgments |
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Footnotes |
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Received July 15, 1997.
Revised August 29, 1997.
Accepted September 8, 1997.
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References |
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