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Departments of Internal Medicine and Pharmacology (T.H., L.Z.,
G.M., K.L.P.) University of Texas Southwestern Medical Center
Dallas, Texas 75235
Department of Pathology (K.M.C.)
University of North Carolina-Chapel Hill Chapel Hill, North
Carolina 27599
Department of Pathology (T.S., S.S., H.S.)
Tohoku University School of Medicine Sendai, Miyagi, Japan,
980-8575
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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To further our understanding of the pathogenesis of lipoid CAH, we generated StAR knockout mice (5). These mice established essential roles of StAR in regulated steroidogenesis in mice and demonstrated a spectrum of severity of lipid deposits in the primary steroidogenic cells. In newborn StAR knockout mice, the adrenal glands lacked their normal cellular architecture and had abundant lipid deposits, presumably reflecting the fact that the mouse adrenal cortex normally produces steroids in utero. In contrast, the testes contained only scattered lipid deposits, while the ovaries appeared completely normal. Based on a similar hierarchy in the impairment of steroid production in patients with lipoid CAH, Bose et al. (4) proposed a two-hit model of lipoid CAH. According to this model, lipoid CAH patients initially retain some capacity for StAR-independent steroidogenesis; thereafter, progressive lipid accumulation in steroidogenic cells, driven at least partly by trophic hormone stimulation, kills the cells and completely abrogates steroidogenic capacity.
In this report, we used corticosteroid replacement to keep StAR knockout mice alive for differing periods of time after birth, thereby allowing us to assess the temporal effects of StAR deficiency. Our results, which demonstrate progressive pathological changes in the gonads after the time of normal sexual maturation, strongly support the two-hit model of lipoid CAH.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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, plasma
corticosterone, the major circulating glucocorticoid in mice, was
markedly decreased in StAR knockout mice at 8 weeks of age, although
levels still exceeded the lower limit of assay sensitivity. This
finding suggests that the adrenal cortex retained some residual
capacity for corticosteroid production, even at 8 weeks. Although
markedly decreased, plasma testosterone in males also was detectable.
In females, progesterone was decreased and ovarian morphology was
markedly abnormal (see below), Surprisingly, estradiol levels in StAR
knockout females did not differ significantly from wild-type values.
Given the low levels of circulating estradiol, it is unclear whether
this finding reflects unimpeded production of ovarian steroids or
limitations in the assay that mask defects in ovarian steroidogenesis.
As discussed below, the uterus and oviducts of StAR knockout females
were markedly hypoplastic, suggesting that estrogen action on target
tissues is impaired despite the "normal" circulating levels.
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) and marked lipid deposits demonstrated
by oil red O staining (Fig. 2). At 8
weeks, these changes were especially marked in the zona glomerulosa and
zona fasciculata, while the zona reticularis was relatively preserved
and the adrenal medulla lacked discernable pathological findings.
Unlike human patients with lipoid CAH (6), cholesterol crystals were
not present in the mouse adrenal sections, and there was no evidence of
adrenocortical hyperplasia at 8 weeks (i.e. the
cortex-medulla ratio was not increased in StAR knockout adrenals). The
postnatal administration of corticosteroids to StAR knockout mice
before weaning at 3 weeks may have partially suppressed ACTH release
and ameliorated the progression of the adrenal lesions. By 16 weeks,
adrenocortical hyperplasia was apparent, accompanied by markedly
increased lipid deposits (data not shown).
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and 3, the
testes of newborn StAR knockout mice appeared relatively intact, with
only scattered foci of lipid deposits in the interstitial region. These
deposits presumably are in remnants of fetal Leydig cells, a distinct
population of cells that produce androgens in utero and then
regress postnatally (10, 11). As StAR knockout mice aged, lipid
accumulated throughout the interstitial region, consistent with
recruitment of the adult population of Leydig cells. At 8 weeks of age
(Fig. 3), the cytoplasm of the Leydig
cells appeared foamy, and oil red O staining (Fig. 2) revealed
progression in the severity of their lipid deposits. Moreover, Leydig
cell hyperplasia was noted in the StAR knockout testes (Fig. 3G); at 8
weeks of age, oil red O-positive areas accounted for 10.5% of the area
of StAR knockout testes (vs. 3.18% of wild-type testes).
These studies document a progressive worsening in the integrity of the
steroidogenic cells, precisely as predicted by the two-stage model.
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) and
mature spermatids were detected in the epididymis (data not shown). In
addition, as shown in Fig. 4, StAR
knockout testes at 8 weeks had comparable immunohistochemical staining
for CREM, a marker for postmeiotic germ cells (13), and cyclin
A1, which is expressed during the first meiotic division (14). These
results, in conjunction with the low-butdetectable plasma
testosterone levels (Table 1), indicate that StAR knockout testes
retain sufficient androgen biosynthesis to support germ cell
maturation, a finding that persists even at 24 weeks of age (data not
shown). Examination at earlier stages of development, however, showed
that the initial wave of spermatogenesis in StAR knockout testes is
delayed. Whereas wild-type seminiferous tubules at 4 weeks contained
mature elongated spermatids (Fig. 3B), germ cell maturation in StAR
knockout mice had not progressed beyond step 14 [stage II/III
elongating spermatids (Fig. 3E)]. Moreover, the tubules contained
multinucleated giant cells (Fig. 3H, solid arrow), and
individual germ cells exhibited chromatin condensation (dashed
arrow), features consistent with programmed cell death. TUNEL
assays (Fig. 4) revealed considerably increased labeling in
germ cells of some tubules, consistent with DNA fragmentation.
Collectively, these findings suggest that androgen production in
StAR knockout mice is inadequate to maintain optimal
spermatogenesis.
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), and no lipid deposits were seen in
oil red O staining (Fig. 2). By 8 weeks of age, when sexual maturation
normally has occurred, the StAR knockout ovaries exhibited impaired
follicular maturation and contained abundant lipid deposits, primarily
in stromal cells that exhibited a luteinized appearance (Fig. 2) and
expressed high levels of the cholesterol side-chain cleavage enzyme
(Fig. 5, N and P). Although some follicles contained luteinized theca
cells, there were no corpora lutea (i.e. structures composed
of well developed luteinized granulosa and theca interna cells with
dissolution of the basement membrane) in any section examined (Fig. 5
and data not shown). The markedly decreased level of circulating
progesterone further suggests that the decreased steroidogenesis
impaired ovulation. In contrast, both granulosa cells and theca interna
cells appeared relatively normal in the remaining follicles. Although
their circulating estrogen levels were not clearly decreased, StAR
knockout females had sexually immature uterus and oviducts (data not
shown), suggesting impaired estrogen action.
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, I and L). These studies,
which provide the first detailed analyses of ovarian histopathology in
the absence of StAR, again are consistent with the two-hit model of
lipoid CAH.
Developmental Effects of StAR Deficiency on Accessory Sex
Organs
Limited analyses of 46, XY patients with lipoid CAH suggested that
structures derived from the wolffian ducts were normal, while the
external genitalia were completely feminized (15). In contrast, there
were well documented examples of 46, XX patients who underwent menarche
and breast development (4). The ability to maintain StAR knockout mice
until the time of normal puberty allowed us to examine the effect of
StAR deficiency on development of accessory sex organs. We noted
previously that the epididymal structures of wild-type and StAR
knockout mice were indistinguishable at birth (5); comparable histology
of the epididymis and vas deferens also was seen in older StAR knockout
mice (data not shown). In contrast, while the seminal vesicles appeared
relatively normal at birth, they were clearly hypoplastic at 4 and 8
weeks of age (Fig. 6). Microscopically,
the seminal vesicles contained only simple tubular structures with few
convolutions (data not shown). Finally, the prostate was hypoplastic,
both immediately after birth and at 8 weeks of age (Fig. 6), and on
microscopic examination contained only primary branching tubules (data
not shown). These findings suggest that residual capacity for androgen
synthesis in the absence of StAR, although sufficient to support
survival of wolffian structures in utero, is insufficient to
virilize more distal accessory sex glands at the time of normal
puberty.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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).
These findings strongly support the concept that persistent trophic
hormone stimulation of StAR-deficient steroidogenic organs leads to
progressively worsening lipid deposits and diminished function of
steroidogenic cells. Steroidogenic cells obtain cholesterol from multiple sources, including de novo biosynthesis, hydrolysis of cholesterol esters, and uptake from circulating lipoproteins [in mice, predominantly high density lipoprotein (HDL) taken up by the scavenger receptor-B1 pathway]. The StAR knockout mice provide a model system to address the relative contributions of these different pathways to the lipid deposits that accumulate in steroidogenic cells. In situ hybridization analyses did not reveal increased expression of SR-B1 in StAR knockout adrenals or testes (T. Hasegawa, unpublished observation). However, preliminary studies indicate that double knockout mice lacking both ApoA1 and StAR, although severely deficient in steroidogenesis, accumulate considerably less lipid in their steroidogenic cells (T. Hasegawa, unpublished observation). These findings implicate circulating HDL as the major source of the cholesterol that accumulates in StAR knockout mice.
Few studies have examined testicular structure, spermatogenesis, or development of male secondary sexual organs in 46,XY subjects with lipoid CAH. Although differing in age and location of testes (i.e. abdominal vs. inguinal), most lipoid CAH patients have had normal appearing Sertoli cells, Leydig cell hyperplasia, and decreased numbers of germ cell precursors; internal genitalia have included normal epididymis and vas deferens, with no description of the prostate. Similarly, StAR knockout mice had normal appearing epididymis and vas deferens and mature spermatids within the epididymis (data not shown), supporting some residual capacity for androgen biosynthesis. They did exhibit some signs of impaired spermatogenesis, with delayed germ cell maturation at 4 weeks of age and increased apoptosis in developing spermatocytes. Moreover, the seminal vesicles and prostate were markedly hypoplastic, and there was no virilization of external genital structures.
Developmentally, the seminal vesicles, epididymis, and ductus deferens
all arise from the Wolffian ducts, whereas the prostate develops from
the urogenital sinus. The apparent discrepancy in the development of
organs derived from the wolffian ducts probably reflects differing
thresholds for paracrine actions of androgens in the immediate vicinity
of the testes (i.e. epididymis and ductus deferens)
vs. endocrine actions at more distal sites (i.e.
seminal vesicles). The necessity to convert testosterone to
dihydrotestosterone for full virilization may further exacerbate the
effects of the testosterone deficiency, as supported by the prostate
hypoplasia in patients with genetic defects in the type 2 isozyme of
steroid 5
-reductase (16). However, knockout mice lacking both type 1
and 2 isozymes of 5-reductase undergo normal male sexual
differentiation (M. Mahendroo and D. Russell, personal communication),
suggesting that there may be species-dependent differences in these
processes.
In part because their gonads are not removed to prevent malignant transformation, even less is known about the structure and function of ovaries in 46,XX patients with lipoid CAH. The spontaneous onset of breast development and menarche in 46,XX patients with lipoid CAH was one factor that prompted the two-hit model. The worsening ovarian histopathology in StAR knockout mice, beginning at the time of normal puberty, is entirely consistent with this model. Under persistent gonadotropin stimulation, the ovaries of StAR knockout mice developed progressive lipid deposition, particularly within the stromal cells. Although their serum estradiol levels did not differ from those in wild-type mice, the uterus and oviducts of StAR knockout mice were markedly hypoplastic, indicating that estrogen production was inadequate to stimulate normal development of these secondary sex organs. No corpora lutea were detected, and progesterone levels were markedly impaired, indicating that the ovaries of StAR knockout mice were anovulatory. In this regard, the relative roles of defects in estrogen vs. progesterone biosynthesis in the ovaries of StAR knockout mice warrant further study. Ovulation also is impaired in knockout mice lacking progesterone receptor (17), suggesting that abnormal production of progesterone at least partly explains the ovarian phenotype.
A recent study documented the expression of StAR transcripts in the rat brain, colocalizing with transcripts for cholesterol side chain cleavage enzyme and 3ß-hydroxysteroid dehydrogenase in the hippocampus, dentate gyrus, and granular and Purkinje cells of the cerebellum (18). Given the proposed roles of endogenous steroids, designated neurosteroids, within the central nervous system (19), it is of interest to analyze neuronal function in StAR knockout mice. To date, the histology of different brain regions where StAR is expressed does not appear distinguishable from the same regions in wild-type mice (L. Zhao, unpublished observation). However, it is important to note that neurophysiological analyses of StAR knockout mice have not been performed, and this area needs further investigation. Ultimately, we may need to make tissue-specific knockouts that ablate StAR in the brain but retain its expression in the primary steroidogenic tissues to delineate specific roles of StAR in the central nervous system.
We noted previously that some StAR knockout mice exhibited signs of respiratory distress. However, analyses of the lungs of newborn StAR knockout mice did not reveal any consistent histological abnormalities, and in situ hybridization analyses showed comparable expression of genes encoding surfactant proteins A and C in wild-type and knockout mice (T. Hasegawa, unpublished observation). Although it is tempting to ascribe the apparent respiratory distress to impaired lung maturation secondary to glucocorticoid deficiency, results to date have not elucidated the molecular basis for this aspect of the StAR knockout phenotype.
In summary, our studies, which demonstrate progressive histopathological changes in the gonads after the time of normal puberty, strongly support the two-hit model of lipoid CAH. The StAR knockout mice, and immortalized cell lines derived from their steroidogenic organs, hold considerable promise as a system to expand our understanding of the mechanisms by which StAR facilitates cholesterol translocation to the inner mitochondrial membrane. Through studies such as these, we hope to increase our understanding of how StAR makes its essential contributions to adrenocortical and gonadal steroidogenesis and endocrine function.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Generation of StAR Knockout Mice
All animal studies were approved by the Institutional
Review Committee at University of Texas Southwestern Medical Center.
The StAR knockout mice were generated as previously described (5) and
maintained as +/- heterozygotes, which were crossed to produce StAR
knockout pups. Mice were maintained in the University of Texas
Southwestern Animal Resources Center on a 12-h light, 12-h dark cycle
and were given food and water ad libitum. StAR genotypes
were determined by PCR analyses of tail DNA using forward
(5'-AAGAGCTCAACTGGAGAGCAC-3') and reverse (5'-TACTTAGCACTTCGTCCCCGT-3')
primers. Genetic sex was determined by PCR analyses for Sry as
previously described (20).
Corticosteroid Rescue of StAR Knockout Mice
StAR knockout mice were rescued with a modification of a
previously described steroid replacement regimen that includes both
glucocorticoids and mineralocorticoids (21). Stock solutions of
dexamethasone 21-phosphate (4 mg/ml in H2O),
fludrocortisone acetate (5 mg/ml in 95% ethanol), and hydrocortisone
(4 mg/ml in 95% ethanol) were prepared and stored at 4 C. A
corticosteroid cocktail was made by diluting the stock solutions in
olive oil (1:10,000 for dexamethasone and fludrocortisone, 1:10 for
hydrocortisone). All newborn pups were injected with 0.05 ml sc once
daily until StAR knockout pups were identified by PCR analysis. Steroid
injections then were continued in StAR knockout pups until weaning,
when the mice were provided ad libitum with 0.9% sodium
chloride as drinking solution and all steroid injections were
stopped.
Histological Analyses
Histological analyses were carried out with 4%
paraformaldehyde or Bouin’s fixed tissue specimens with hematoxylin
and eosin staining, or frozen tissue sections for oil red O staining
with hematoxylin counterstaining. Areas positive for oil red O staining
were measured in 20 high-power fields (40x: 3.2 x 1–8 mm) in
representative specimens using CAS 200 morphometrical analysis as
described (22). To examine prostate morphology, glandular and stromal
compartments were separated by a modification of a published method
(23). Immunohistochemical analyses were carried out with primary
antibodies including anti-CREM (1:100 dilution) and anti-cyclin A1
(1:500 dilution). Control reactions were performed with normal rabbit
serum (DAKO Corp., Carpinteria, CA). The TUNEL assay for
DNA fragmentation was performed with a kit purchased from
Intergen (Purchase, NY) according to the manufacturer’s
protocol. In situ hybridization was performed with an
antisense probe specific for the cholesterol side-chain cleavage enzyme
as previously described (24).
Hormone Assays
RIAs were performed by Dr. David Hess, Oregon
Regional Primate Center using serum collected from +/+ and -/- mice
at 8 weeks of age. Steroids analyzed included corticosterone [limit of
detection, 2 ng/ml; intraassay % coefficient of variation (CV), 8.5%;
% recovery, 88.3], progesterone (limit of detection, 30 pg/ml;
intraassay % CV, 10.7%; % recovery, 87.8), testosterone (limit of
detection, 0.1 ng/ml; intraassay % CV, 6.2%; % recovery, 69.1), and
estradiol (limit of detection, 3.0 pg/ml; intraassay % CV, 9.5%; %
recovery, 79.1). The means and SEs of each group were
calculated, and the statistical significance of differences was
determined by the Mann-Whitney U test.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by grant support from the NIH (DK-54028 and DK-54480 to K.L.P.).
Received for publication April 11, 2000. Revision received May 22, 2000. Accepted for publication May 30, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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H. Li, M. Brochu, S. P. Wang, L. Rochdi, M. Cote, G. Mitchell, and N. Gallo-Payet Hormone-Sensitive Lipase Deficiency in Mice Causes Lipid Storage in the Adrenal Cortex and Impaired Corticosterone Response to Corticotropin Stimulation Endocrinology, September 1, 2002; 143(9): 3333 - 3340. [Abstract] [Full Text] [PDF]
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S. Eimerl and J. Orly Regulation of Steroidogenic Genes by Insulin-Like Growth Factor-1 and Follicle-Stimulating Hormone: Differential Responses of Cytochrome P450 Side-Chain Cleavage, Steroidogenic Acute Regulatory Protein, and 3{beta}-Hydroxysteroid Dehydrogenase/Isomerase in Rat Granulosa Cells Biol Reprod, September 1, 2002; 67(3): 900 - 910. [Abstract] [Full Text] [PDF]
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C. L. Coulter, I. C. McMillen, I. M. Bird, and M. D. Salkeld Steroidogenic Acute Regulatory Protein Expression Is Decreased in the Adrenal Gland of the Growth-Restricted Sheep Fetus During Late Gestation Biol Reprod, August 1, 2002; 67(2): 584 - 590. [Abstract] [Full Text] [PDF]
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P. R. Manna, M. T. Dyson, D. W. Eubank, B. J. Clark, E. Lalli, P. Sassone-Corsi, A. J. Zeleznik, and D. M. Stocco Regulation of Steroidogenesis and the Steroidogenic Acute Regulatory Protein by a Member of the cAMP Response-Element Binding Protein Family Mol. Endocrinol., January 1, 2002; 16(1): 184 - 199. [Abstract] [Full Text] [PDF]
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T. Tajima, K. Fujieda, N. Kouda, J. Nakae, and W. L. Miller Heterozygous Mutation in the Cholesterol Side Chain Cleavage Enzyme (P450scc) Gene in a Patient with 46,XY Sex Reversal and Adrenal Insufficiency J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3820 - 3825. [Abstract] [Full Text] [PDF]
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