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Original Studies |
Division of Reproductive Endocrinology (J.S.G., B.R.C., B.A., W.E.R.), Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology (H.S.), Tohoku University School of Medicine, Sendai, Japan; Department of Pathology (L.M.), Children’s Medical Center, Dallas, Texas; Department of Clinical Biochemistry (J.I.M.), University of Edinburgh, Edinburgh, United Kingdom
Address all correspondence and requests for reprints to: William E. Rainey, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9032.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase/17,20-lyase (CYP17) can metabolize
pregnenolone through to DHEA. The enzyme 3ßHSD competes for substrate
with CYP17 and effectively removes steroid precursor from the pathway
leading to DHEA. On the other hand, deficiency in CYP21 expression is
known to cause excessive production of adrenal C19
steroids, suggesting that CYP21 could play a role in adrenarche. Thus,
a decrease in 3ßHSD or CYP21 expression would allow substrate to flow
toward the synthesis of DHEA. To determine whether adrenarche results
from a decreased expression of 3ßHSD or CYP21 in the reticularis,
immunohistochemical localization of 3ßHSD and CYP21 was performed,
and staining intensities compared using adrenal glands from children
ages 4 months to 4 yr (n = 12), ages 5–7 yr (n = 9), ages
8–13 yr (n = 9), and adults ages 25–56 yr (n = 8). There
were no differences in the zonal expression of CYP21. No difference in
3ßHSD staining was observed between the glomerulosa and fasciculata
from any age group. However, children age 8 yr and older show a
significant decrease in 3ßHSD expression in reticularis as compared
with the fasciculata. No significant difference was noted for 3ßHSD
levels between the fasciculata and reticularis for children age 7 yr or
younger. The level of 3ßHSD expression in the reticularis continued
to decrease in the adult adrenals examined. These findings suggest that
as children mature there is a decreased level of 3ßHSD in the adrenal
reticularis that may contribute to the increased production of DHEA and
DHEAS seen during adrenarche. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The adrenal reticularis is one of three histologically distinct regions
of the adrenal cortex. These zones include the zona glomerulosa and the
zona fasciculata, as well as the zona reticularis. Besides being
histologically different, these zones have functionally distinct roles
in steroid hormone production, namely, the glomerulosa synthesizes
mineralocorticoids, the fasciculata produces glucocorticoids, and, in
the human, the zona reticularis produces C19 steroids,
including DHEA and DHEAS. Like all steroidogenic cells, each adrenal
zone synthesizes its steroid products from the same substrate,
pregnenolone, which is formed from cholesterol. Within the human
adrenal cortex, steroids can be metabolized by five forms of cytochrome
P450 and the enzyme 3ß-hydroxysteroid dehydrogenase (3ßHSD). It is
the differential expression of these enzymes within the three
adrenocortical zones that causes the wide array of steroid hormones
secreted from the adrenal cortex. The formation of DHEA and DHEAS
within the adrenal reticularis is initiated by the conversion of
cholesterol to pregnenolone. Subsequently,
17-hydroxylase/17,20-lyase (CYP17) metabolizes pregnenolone to DHEA,
which may then be sulfated to form DHEAS by steroid sulfotransferase.
In addition, enzymes such as 3ßHSD and 21-hydroxylase (CYP21)
normally act to decrease DHEAS production through competition with
CYP17 in the case 3ßHSD and through the removal of steroid precursors
in the case of CYP21. The effects of CYP21 are illustrated in cases of
CYP21 deficiency in which there is an enhanced adrenal C19
steroid production (7). On the other hand, 3ßHSD expression can
effectively remove steroid precursors from the pathway leading to DHEA.
Indeed the expression of 3ßHSD in the normal adult human adrenal
reticularis and fetal adrenal are low to nondetectable under
nonpathological conditions (6, 8). Therefore, alterations in
intra-adrenal expression of steroidogenic enzymes within the inner
reticularis zone may play a role in the increased production of
C19 steroids seen at adrenarche. In the current study, we
found that children less than age 5 yr have a small reticularis that
strongly expresses 3ßHSD, whereas children greater than age 7 yr have
a reticularis with minimal 3ßHSD expression. CYP21 expression was
similar in all adrenal zones and did not appear to change with
adrenarche. Our data suggest that adrenarche may result from the
development of an adrenal reticularis that is relatively devoid of
3ßHSD.
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Materials and Methods |
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Sections of adrenal glands from children age 4 months to 13 yr and adults age 25–56 yr were retrieved from autopsy files or, in the case of the adults, at time of surgical excision. Tissues samples were fixed in 10% neutral formalin and then embedded in paraffin before sectioning and mounting on glass slides. Adrenal sections from children were excluded if there was significant adrenal pathology or a history of corticosteroid treatment before death. Diagnoses at time of death varied and included congenital heart disease (n = 5), hypertrophic heart disease (n = 1), restrictive cardiomyopathy (n = 1), malignancy (n = 8), renal failure (n = 1), Wiskott Aldrich syndrome (n = 1), carbon monoxide poisoning (n = 1), smoke inhalation (n = 1), traffic accident (n = 1), sepsis (n = 2), Reye’s syndrome (n = 1), hyperammoninemia (n = 1), defective carnitine synthesis (n = 1), eosinophilic cellulitis (n = 1), hepatic failure (n = 1), bowel infarct (n = 1), acute Epstein-Barr infection (n = 1), and ruptured cerebellar arteriovenous malformation (n = 1). The children’s adrenal glands used in this study did not have significant pathological abnormalities including nodules or neoplasms.
Immunohistochemistry
Immunohistochemical staining was performed as has been described previously using the manufacturer’s protocol (Histostain-SP Kit; Zymed Labs., South San Francisco, CA) (9). Before immunohistochemical staining, the sections were deparaffinized with xylene then rehydrated with graded series of diluted ethanol in deionized water. The sections were allowed to equilibrate in 10 mM PBS solution. Endogenous tissue peroxidases were neutralized with a 1:9 solution of 30% hydrogen peroxide in absolute methanol. Thereafter, the sections were washed by immersing into PBS for 8 min. To eliminate nonspecific staining, the sections were incubated with 10% nonimmune goat serum for 10 min. Next, sections were incubated for 60 min with the primary antibody (rabbit antiplacental 3ßHSD diluted 1:1000 or rabbit antihuman CYP21 antibody diluted 1:4000) under gentle agitation in a humidified chamber at room temperature. Although two separate isoforms of 3ßHSD exist in the human, the antibody against placental 3ßHSD cross-reacts with both isoforms. The antibody directed against 3ßHSD has been previously characterized as specific for immunohistochemistry and Western analyses (8, 10, 11). The antibody directed against CYP21 was developed through overexpression in bacterial cells allowing for antiserum production (12). After washing with PBS, the tissues were incubated in sequence with biotinylated goat antirabbit antibody for 10 min and then with horseradish peroxidase-streptavidin enzyme conjugate for 10 min with washes of PBS in between. Color development was achieved by exposing the treated tissue sections to 0.6% hydrogen peroxide and the chromagen, 3,3'-diaminobenzidine tetrahydrochloride (DAB). Horseradish peroxidase reacts with hydrogen peroxide and the chromogen to form a brown precipitate at the site of the antigen-antibody-enzyme complex. Counterstaining was conducted using hematoxylin, which stains cell nuclei blue. For each specimen, serial sections were treated as follows: 1) staining using previously characterized rabbit antibodies directed against human 3ßHSD (6); 2) staining using previously characterized rabbit antibodies directed against human CYP21 (12); and 3) staining using rabbit antibodies directed against human tyrosine hydroxylase to better delineate the interface between the medulla and the reticularis (data not shown). Immunohistochemical localization of 3ßHSD or CYP21 was compared using adrenal glands of children ages 4 months to 4 yr (n = 12), age 5–7 yr (n = 9), age 8–13 yr (n = 9), and adults age 25–56 yr (n = 8). Histological identification of the three zones of the adrenal cortex was based on previously published descriptions (13). Specifically, the glomerulosa was identified as discontinuous subcapsular aggregates of small cells with small nuclei and few lipid droplets. The fasciculata was identified as the large, lipid laden cells arranged in a cordlike pattern. The reticularis was identified by the lack of cordlike organization and the compact and lipid-poor nature of the cells (13). Staining intensities for each zone of the adrenal were determined by blind ranking of each slide by three observers. Interobserver differences were less than 15%. Within each adrenal section the most intensely stained region was given an arbitrary ranking of 5 and the medulla, which was negative, was designated 0. (Numerical values from each observer were then averaged.)
Statistical significance was determined by comparing the average staining intensity of the reticularis to the fasciculata within each age group by the Mann-Whitney test for nonparametric data. A P value < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Hematoxylin and eosin staining (H
& E) delineates the histologically distinct zona glomerulosa, zona
fasciculata, and zona reticularis, as well as the adrenal capsule and
medulla (Fig. 1B). A high level of 3ßHSD was seen in the glomerulosa
and fasciculata but not in the capsule or the medulla (Fig. 1A). In
addition, 3ßHSD was seen in the reticularis in this age group (Fig. 1A). However, it should be noted that the reticularis in children of
this age was represented as a thin region when compared with
older children or adults. No significant difference in the expression
of 3ßHSD was seen between the fasciculata and reticularis (Table 1). A high level of CYP21 expression was
seen in the glomerulosa, fasciculata, and reticularis but not in the
capsule or medulla (Fig. 1C). No significant difference in the
expression of CYP21 was seen between the fasciculata and reticularis
(Table 2).
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). A high level of CYP21 was
seen in the glomerulosa, fasciculata, and reticularis but not in the
capsule or the medulla. No significant difference in CYP21 expression
was seen between the fasciculata and reticularis (Table 2). The
variable expression of 3ßHSD in the reticularis in children age 5–7
yr suggests a transition between the high expression of 3ßHSD in the
younger children and the diminished expression of 3ßHSD in older
children and adults.
Adrenal glands from children age 8–13 yr (n = 9) were fixed,
embedded, sectioned, and then used for immunohistochemical localization
of 3ßHSD or CYP21. A representative section from a 9-yr-old child is
shown in Fig. 2. H & E staining
delineated the histologically distinct glomerulosa, fasciculata, and
reticularis as well as the adrenal capsule and medulla (Fig. 2B). A
high level of 3ßHSD was seen in the glomerulosa and fasciculata but
not in the capsule or the medulla (Fig. 2A). However, in children age
8–13 yr there was a significant decrease in immunodetectable 3ßHSD
in the reticularis as compared with the fasciculata (Table 1). A high
level of CYP21 was seen in the glomerulosa, fasciculata, and
reticularis but not in the capsule or the medulla (Fig. 2C). There was
no significant difference in CYP21 staining intensity between the
fasciculata and reticularis (Table 2).
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. H & E
staining delineates the histologically distinct glomerulosa,
fasciculata, and reticularis as well as the adrenal capsule and medulla
(Fig. 3B). A high level of 3ßHSD was detected in the glomerulosa and
fasciculata but not in the capsule or the medulla (Fig. 3A). Therefore,
under normal conditions, the human adult adrenal exhibits significantly
decreased 3ßHSD expression in the reticularis as compared with the
fasciculata (Table 1). Interestingly, 3ßHSD expression was observed
in the cortical cuff cells located adjacent to the medulla. In
addition, minimal immunodetectable 3ßHSD was observed in the
reticularis compared with the glomerulosa and fasciculata (Fig. 3A). A
high level of CYP21 was detected in the glomerulosa, fasciculata, and
reticularis but not in the capsule or the medulla (Fig. 3C). There was
no significant difference in immunodetectable CYP21 between the
fasciculata and reticularis (Table 2). However, two out of the five
adult adrenals examined had decreased expression of CYP21 in the
reticularis.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Multiple factors have been postulated to initiate adrenarche including ACTH, estrogen, PRL, and other peptides (15). ACTH has been hypothesized to initiate adrenarche because it stimulates the secretion of both glucocorticoids and C19 steroids from the adrenal cortex. However, ACTH concentrations do not change during the time period when DHEA levels rise (16). In addition, children with hypercortisolism have normal DHEA and DHEAS levels (17). Estrogen added to fetal and adult adrenal cells grown in culture increases DHEAS production presumably through its direct inhibition of 3ßHSD enzyme activity (18, 19, 20). Studies evaluating children with gonadal dysgenesis, however, report a normal progressive rise of DHEAS with advancing bone age and chronological age, which does not support estrogen as a major factor in the initiation of adrenarche (21). Finally, a subset of women with hyperprolactinemia have been observed to have elevated DHEAS levels that normalize after bromocriptine theory (22). However, investigators have been unable to demonstrate an in vitro response of human adrenocortical cells to PRL (23). In addition, PRL levels do not change as children mature, and values remain similar to those found in nonpregnant adults (24). Thus, whereas DHEAS synthesis in the adrenal appears to fluctuate dramatically during normal development and in aging, a hormonal regulator of these processes has not been found. Therefore, we have focused on the changes that occur within the adrenal itself.
Adult adrenal glands have been shown to strongly express 3ßHSD primarily in the glomerulosa and fasciculata with minimal expression in the reticularis (6, 8). Herein, we observed diminished 3ßHSD immunoreactivity in the adult reticularis of the adult adrenals examined. Because adrenal DHEAS is mainly produced in the reticularis, we questioned whether the increasing levels of DHEAS and DHEA at adrenarche are because of decreasing expression of 3ßHSD in the reticularis. Adrenal sections of children less than age 5 yr demonstrated greater immunodetectable levels of 3ßHSD in the reticularis than was observed in the reticularis of children age 8–13 yr. This decline of 3ßHSD expression may play a key role in the increase in adrenal DHEAS and DHEA secretion at adrenarche. Individual adrenal sections of children age 5–7 yr demonstrated variable expression of 3ßHSD, suggesting a transition in the steroidogenic potential of the reticularis at the time of adrenarche.
Alternatively, adrenarche may be associated with the age-dependent growth of a 3ßHSD-deficient adrenal reticularis and the subsequent production of DHEA and DHEAS. Dhom (25) characterized the emergence of the reticularis in children. He observed that in children at about age 3 yr focal islands of adrenal reticularis appear, whereas a continuous reticularis began to develop at age 6 yr, which would correspond to the increased circulation of C19 steroids. Herein, adrenals from the younger children were noted to have a thin reticularis as compared with the older children. However, the reticularis cells from children less than age 5 yr did express 3ßHSD. There are two possible explanations for the expression of 3ßHSD in the younger children’s reticularis. First, the thin zone may be partially composed of cortical cuff cells, which are known to express 3ßHSD. The cortical cuff cells are cortical cells that lie in close proximity to the medulla and receive their blood supply from the medullary arterioles. Secondly, these cells, which resemble the adult reticularis, may be partially composed of a reticularis precursor cell. Finally, the reticularis of young children may just express 3ßHSD. Therefore, although adrenarche may correspond to the morphological development of a distinct reticularis, the cells that make up this zone are 3ßHSD-deficient, which appears to be a key factor allowing C19 steroid production.
As opposed to 3ßHSD, cholesterol side-chain cleavage (CYP11A) and
CYP17 are the enzymes directly involved in DHEA and DHEAS synthesis.
Although CYP11A is involved in the synthesis of all steroid hormones,
alterations in CYP17 activity have been proposed as a potential
mechanism regulating adrenal C19 steroid hormone synthesis
and specifically adrenarche (26). CYP17 catalyzes both
17-hydroxylase and 17,20 lyase reactions, which are necessary for
pregnenolone conversion to DHEA. These activities were originally
thought to be caused by different enzymes, which made it attractive to
hypothesize that the enzyme responsible for the 17,20 lyase reaction
was induced in the reticularis of the adrenal at adrenarche, allowing
production of the C19 steroids. Although it is now known
that these activities are accomplished by a single enzyme, there is
considerable evidence that the 17,20 lyase activity can be
independently regulated by the presence of cytochrome b5
and cytochrome P450 oxidoreductase (27, 28). To date the localization
of cytochrome b5 or P450 oxidoreductase has not been
examined within the adrenal. In addition, it has been suggested that
phosphorylation of CYP17 increases 17,20 lyase activity without
affecting 17-hydroxylase activity causing an increase in DHEA
production (29). However, altered phosphorylation of this enzyme has
yet to be demonstrated in children of advancing age. Thus, a role for
the intraenzyme regulation of the 17,20 lyase activity of CYP17 needs
further study to define its role in physiological situations such as
adrenarche.
Although CYP21 is not directly involved in the production of DHEA, its presence metabolizes steroid products of 3ßHSD towards the formation of mineralocorticoids and glucocorticoids. Deficient 21-hydroxylase activity leads to increased C19 steroid production and the clinical manifestations of androgen excess (7). Therefore, it can be hypothesized that alterations in zonal CYP21 expression may influence the increased adrenal DHEA and DHEAS production seen at adrenarche. To this end, we evaluated the immunolocalization of CYP21 as children mature. We found that the reticularis continues to express CYP21 as children undergo adrenarche. Our observation agrees with a previous examination of adult adrenals in which no difference was observed in reticularis expression of CYP21 (30). This suggests that the adrenarchal increase in C19 steroids does not result from diminished CYP21 expression within the reticularis.
Studies designed to examine changes in adrenal enzymatic activity as an
explanation for increased adrenal C19 steroids at
adrenarche have focused on 3ßHSD activity as well as on CYP17
activity. Schiebinger and colleagues (26) measured 3ßHSD, 17,20
lyase, and 17-hydroxylase activity in adrenal microsomes prepared
from adrenal glands obtained at surgery or autopsy from 12 individuals
ranging from age 3 months to 60 yr (26). These adrenal microsomes were
divided into three groups: group 1, age 3 months to 8 months; group 2,
age 2.5–9 yr; and group 3, age 20–60 yr. They found no significant
difference in 3ßHSD activity between the age groups, whereas 17,20
lyase activity and 17-hydroxylase activity was elevated in the
adults age 20 yr and older. They concluded that adrenarche may be
because of increased 17-hydroxylase and 17,20 lyase activity.
However, the enzymatic activity was measured in adrenal microsomes
prepared from whole adrenal homogenates, making it impossible to
examine changes in the specific site of C19 steroid
production. Also, the age group encompassing adrenarche included only
four adrenal specimens, making it difficult to identify subtle
differences.
Rich et al (31) hypothesized that adrenarche is associated with alterations in the steroid metabolizing enzymes within the adrenal. He measured the ratio of the change in plasma precursor-product relationships to determine the apparent adrenal enzymatic efficiencies. He calculated 17,20 lyase efficiency and 3ßHSD efficiency in prepubertal children age 2–12 yr, children with isolated pubic hair development age 2–8 yr, and adults age 18–24 yr. He found that 17,20 lyase efficiency increased in the children with pubic hair, whereas 3ßHSD efficiency decreased. It may be difficult to extrapolate these results to normal children undergoing adrenarche, because the study group had evidence of excess C19 steroid production. However, using this methodology, the detected decrease in 3ßHSD efficiency would agree with our observations.
In summary, the increase in C19 steroids that occurs at adrenarche is associated with a decrease in 3ßHSD expression in the adrenal reticularis. A transition occurs as children age; specifically, the adrenal reticularis in young children expresses a high level of 3ßHSD within a thin reticularis, whereas the reticularis in children closer to puberty is a larger zone with minimal 3ßHSD expression, similar to that seen in adults. This loss of 3ßHSD expression would allow for steroid precursors to proceed towards the synthesis of DHEA and DHEAS. Thus, the regulation of 3ßHSD may play a crucial role in adrenocortical synthesis of C19 steroids.
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Acknowledgments |
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Footnotes |
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Received September 19, 1997.
Revised May 19, 1998.
Accepted May 30, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 isomerase
from placenta: expression in nonsteroidogenic cells of a protein that
catalyzes the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology. 126:2493–2498.[Abstract]
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