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Biol Reprod 2004, 10.1095/biolreprod.103.026732
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BIOLOGY OF REPRODUCTION 71, 83–88 (2004)
DOI: 10.1095/biolreprod.103.026732
© 2004 by the Society for the Study of Reproduction, Inc.

Mechanisms of Hormone Action

Colocalization of P450c17 and Cytochrome b5 in Androgen-Synthesizing Tissues of the Human1

Sejal Dharia3, Audry Slane3, Ming Jian3, Michael Conner4, Alan J. Conley5, and C. Richard Parker, Jr2,3

Department of Obstetrics and Gynecology3 Department of Anatomic Pathology,4 University of Alabama at Birmingham, Birmingham, Alabama 35249-7333 Department of Population Health and Reproduction,5 University of California Davis, Davis, California 95616


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Androgens are an integral part of human physiology. The de novo production of androgens is generally limited to the adrenal cortex and the gonads. Androgen synthesis by these steroidogenic tissues requires the bifunctional enzyme cytochrome P450c17, which catalyzes both 17 hydroxylase and 17,20 lyase activities. 17,20-lyase activity is relevant to the regulation of androgen production, and is allosterically modulated through the action of an accessory protein, cytochrome b5 (CytB5). Our objective was to determine the cellular localization of P450c17 and CytB5 in androgen-synthesizing tissues of the human. Immunohistochemical analyses of P450c17 and CytB5 were performed on fetal and adult human adrenals, ovaries, and testes. In the fetal adrenal, CytB5 and P450c17 were both found in the cells of the fetal zone, but not in the neocortex. In the adult adrenal, the zona fasciculata was immunoreactive for P450c17 only, whereas the zona reticularis was immunopositive for both P450c17 and CytB5. In the adult gonads, P450c17 and CytB5 were colocalized in the Leydig cells of the testis, theca interna cells of the follicle, theca lutein cells, and isolated cell clusters in the ovarian stroma. Whereas P450c17 and CytB5 were colocalized in the Leydig cells of the fetal testes, there was no immunostaining for either in the midgestational fetal ovary. Our findings of colocalization of CytB5 and P450c17 are strongly supportive of the view that CytB5 plays an important role in the regulation of the androgen biosynthetic pathway in the fetal and adult human.

adrenal cortex, aging, Leydig cells, steroid hormones, theca cells


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the human, androgen production occurs in both the adrenal cortex and the gonads. During fetal development, the fetal adrenal gland produces large quantities of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), which serve as placental estrogen precursors during human pregnancy [1]. Whereas androgen production by the adrenal during infancy is minimal, there is reacquisition of DHEA/DHEAS production during adrenarche [2] that coincides with genesis of the zona reticularis of the adrenal gland [3]. In aging adults, adrenal androgen production decreases in concert with reductions in the width of the zona reticularis [2, 4]. DHEA and DHEAS are the predominant androgens produced by the adrenal cortex, but their biological activity is weak, corresponding to 5% of the potency of testosterone [5]. Cell populations within the zona reticularis of the adrenal gland appear to be responsible for the production of DHEA/ DHEAS; it is unlikely that the zona fasciculata produces a significant amount of DHEA/DHEAS, because of the presence of 3ß hydroxysteroid dehydrogenase [6].

In the ovary of several species, including the human, the theca cells are primarily responsible for the production of androstenedione, which serves as precursor for aromatization to estrogens in the granulosa cells of the ovarian follicle [7, 8] and conversion to circulating testosterone [5]. In the testis, the Leydig cells are the sites of testosterone production [9].

The production of androgens in these diverse cell populations suggests a shared steroidogenic pathway [10]. Cytochrome P450c17 is a bifunctional enzyme that catalyzes both 17 hydroxylation and the 17,20-lyase reaction [11– 14]. The hydroxylase reaction is important in the formation of intermediates in the glucocorticoid and androgen synthetic pathways, whereas the 17,20-lyase activity is essential only for androgen production. The bifunctionality of the single gene product cytochrome P450c17 might lead to the assumption that 17 hydroxylase and 17,20-lyase activities are always linked. However, there are many situations in which the dual activities of cytochrome P450c17 appear to be dissociated. In aging and severe stress, for example, glucocorticoid production is maintained or increased whereas adrenal androgen production diminishes [2, 15]. Adrenarche, in contrast, is associated with dramatically increased adrenal androgen production relative to glucocorticoid synthesis [16]. Further evidence for selective regulation of 17,20-lyase activity is provided by studies on mutations of the P450c17 gene [17, 18], located on chromosome 10q24.3 [19], which are characterized by a clinical spectrum ranging from ambiguous genitalia to delayed puberty with normal glucocorticoid production [20]. It is unclear to what extent, if any, 17 hydroxylation and 17,20-lyase activities are physiologically disconnected in the testis and the ovary.

Modulation of 17,20-lyase activity is influenced by many factors, including, but not limited to, P450 oxidoreductase, phosphorylation of serine and threonine residues, and an accessory protein, cytochrome b5 (CytB5). P450c17 is enzymatically inactive until it forms a complex with the flavoprotein NADPH-cytochrome P450 oxidoreductase that enables the transfer of electrons from the cofactor NADPH. Although requisite for both activities of P450c17, NADPH-cytochrome P450 oxidoreductase can also selectively enhance 17,20-lyase activity [21]. A second mechanism specific for 17,20-lyase activity is the phosphorylation of serine and threonine residues of the P450c17 enzyme; however, the precise mechanism by which phosphorylation promotes 17,20-lyase selectively is not known [22]. Additionally, 17,20-lyase activity can be augmented by an accessory protein, CytB5 [23, 24]. CytB5 has been shown to preferentially enhance 17,20-lyase activity as compared to 17 hydroxylase activity, with a subsequent increase in androgen production [23, 24]. The importance of CytB5 in androgen synthesis is further supported through the work of Sakai et al., who demonstrated high levels of CytB5 in androgen-producing tumors of the adrenal cortex as compared to those in non-androgen-producing tumors [25].

Although there is evidence supportive of a physiologic role for CytB5 in androgen production, little is known of the distribution or the factors that regulate CytB5 production in steroidogenic tissues of the human. Our objective was to determine the cellular localization of P450c17 and CytB5 in steroidogenic tissues in the human during various physiologic states to provide greater insight into the roles of CytB5 and P450c17 in androgen production.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Human fetal adrenal glands, ovaries, and testes were obtained at autopsy from four fetuses at midgestation (aged 17.5–20.5 wk) within 24 h postmortem. Four adult adrenal glands were obtained at autopsy from men and women (aged 28–45 yr) who suffered a sudden, traumatic death. Ovarian tissues were obtained at surgery from four premenopausal women (aged 27–43 yr) with no known endocrinopathy, all of whom underwent incidental oophorectomy for unrelated pathology (e.g., leiomyomata, carcinoma in situ of the cervix). Testicular tissues were obtained from four adult men (aged 32–51 yr) at surgery for incidental orchiectomy with no known endocrine pathology. The tissues were obtained through the University of Alabama at Birmingham's tissue procurement and the Department of Pathology in accordance with protocol established by the Institutional Review Board of the University of Alabama at Birmingham.

Immunohistochemistry

Tissues were fixed in buffered formalin and embedded in paraffin. Thin sections (5 µm) from the paraffin blocks were processed for routine hematoxylin-eosin staining and immunohistochemistry as is currently performed in our lab. After deparaffinization and hydration, the endogenous peroxidase activity was quenched with 3% hydrogen peroxide. Then, sections were rinsed in Tris buffer (pH 7.4) and were incubated in 5% goat serum for 30 min at 25°C. The sections were drained and incubated for 1 h at 25°C with a rabbit polyclonal antiserum directed against human CytB5 and a mouse monoclonal antiserum directed against human P450c17. The CytB5 antiserum was developed by Dr. Conley against purified recombinant human CytB5, which was kindly provided by Ron Estabrook and Manju Shet (University of Texas Southwestern Medical Center, Dallas, TX). The P450c17 antiserum was developed by Dr. Parker against purified recombinant human P450c17 that was generated by use of an expression plasmid generously donated by Mike Waterman (Vanderbilt University, Nashville, TN). The dilutions of primary antibodies used in our study were 1:25;th000 for anti-human CytB5 and 1:20 for anti-human P450c17. Then, sections were incubated with species-appropriate biotinylated second antibodies followed by treatment with streptavidin-peroxidase (Biogenix, San Ramon, CA). Immunoreactivity was detected by incubation of the tissue sections in DAB as the chromagen (Biogenix). Hematoxylin was used as a nuclear counterstain. To evaluate the possible presence of nonspecific staining (negative controls), we incubated tissue sections with nonimmune serum rather than the usual primary antisera and then completed the immunostaining procedure as outlined above.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Adult Adrenals

All adrenal specimens demonstrated P450c17 and CytB5 immunoreactivity to varying degrees. In the adult adrenal, the capsule, zona glomerulosa, and medulla were negative for both P450c17 and CytB5 (Fig. 1A). As shown in Figure 1, A and B, the zona fasciculata was immunopositive only for P450c17, whereas the inner cortical zone, the zona reticularis, was immunopositive for both P450c17 and CytB5. The intensity of staining for P450c17 was usually greater in the zona reticularis than in the zona fasciculata. As can be seen in Figure 1, A and B, clusters of cortical cells in the medulla also were positive for both P450c17 and CytB5. Whenever we noted such cells in the medulla, they were always positive for both factors. Negative controls displayed no immunostaining for either P450c17 or CytB5 (Fig. 1E).



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  		FIG. 1. Colocalization of CytB5 and P450c17 in adult and fetal human adrenal cortices. A) The adult adrenal cortex (x10) demonstrates immunoreactivity for CytB5 in the cells that comprise the zona reticularis (ZR). Note the immunonegative capsule (C), the zona glomerulosa (ZG), the zona fasciculata (ZF), and the medulla (M). B) Immunopositive cell populations for P450c17 (x10) include both the zona fasciculata and the zona reticularis in the adult adrenal cortex. C) In the fetal adrenal (x4), the fetal zone (FZ) is immunopositive for CytB5 and the definitive zone (DZ) is immunonegative. D) P450c17 has the same colocalization (x4). E and F) The cells of the zona reticularis and the fetal zone respectively are immunonegative in the negative controls (primary antiserum was replaced by nonimmune serum) for the adult (E) and the fetal (F) adrenal gland

Fetal Adrenals

The human fetal adrenal gland is structurally different from the adult adrenal gland, and histologically can be divided into an inner cortical zone known as the fetal zone, which is composed of large eosinophilic cells that have a pale nucleus, and an outer cortical zone termed the definitive zone (or neocortex), which is composed of a thin band of small cells that have darkly stained nuclei and scant cytoplasm. The fetal zone was immunopositive for CytB5 and P450c17 at midgestation (Fig. 1, C and D). The definitive zone was immunonegative for CytB5 and P450c17 at midgestation as was the capsule (Fig. 1, C and D). Negative controls displayed no immunostaining for either CytB5 or P450c17 (Fig. 1F).

Adult and Fetal Ovaries

In the adult premenopausal ovary, CytB5 and P450c17 were colocalized in cells of the ovarian follicle (Fig. 2, A and B), corpus luteum (Fig. 2, E and F), and occasionally in clusters of cells scattered throughout the ovarian stroma (not shown). There was no immunostaining for either P450c17 or CytB5 in the granulosa cells or the bulk of the stroma. Ovarian follicles ≥0.4 mm contained theca cell populations that were immunopositive for P450c17 and CytB5 (Fig. 2, A, B, and D). Primordial, primary, and secondary follicles <0.4 mm in diameter were immunonegative for both factors, as shown in Figure 2C. Theca lutein cell populations within the corpus luteum were immunopositive for both CytB5 and P450c17, whereas the granulosa lutein cells were immunonegative (Fig. 2, E and F). Ovaries from midgestation fetuses were immunonegative for both P450c17 and CytB5 (not shown). Negative controls for adult ovaries were found to have no immunostaining for either CytB5 or P450c17 (Fig. 2K).



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  		FIG. 2. Gonadal colocalization of CytB5 and P450c17. A) CytB5 immunopositive secondary follicle (x20) and (B) the same follicle immunopositive for P450c17. The immunopositive cells are the theca interna (arrow). The ovum (O), the granulosa cells (G), and the remaining stroma, including the theca externa (S) are immunonegative for both CytB5 and P450c17. C and D) An immunonegative (0.2 mm diameter) primary follicle (x60) is shown adjacent to a CytB5 immunopositive (1.8 mm diameter) tertiary follicle (x10). E) CytB5 immunoreactivity is found in theca lutein (arrow) cells of the corpus luteum (x4), (F) with the same colocalization for P450c17 (x4). The fetal testicular Leydig cells (arrow) are immunopositive for (G) CytB5 (x20) and (H) P450c17 (x20) with immunonegative seminiferous tubules (ST). I) Similarly in the adult testes, the cells immunopositive for CytB5 (x20) and (J) P450c17 (x20) are the Leydig cells (arrow) with immunonegative seminiferous tubules (S). K and L) The cells of the theca interna (T) and testicular Leydig cells (arrow) respectively are immunonegative in the negative controls (primary antiserum was replaced by nonimmune serum) for the adult ovary (K) and the fetal testis (L)

Fetal and Adult Testes

Immunoreactivity was present in the fetal testicular Leydig cells for both CytB5 and P450c17 (Fig. 2, G and H). Sertoli cells were immunonegative, as were seminiferous tubules of the testis. CytB5 and P450c17 also were found in the Leydig cells of the adult testes, but not in any other cell type (Fig. 2, I and J). Negative controls for adult and fetal testes did not exhibit any immunostaining for either CytB5 or P450c17 (Fig. 2L).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our findings of colocalization of CytB5 and P450c17 in tissues of the fetal and adult human that are widely recognized sites of androgen production is strongly supportive of the concept that CytB5 has an important role in the modulation of androgen biosynthesis. The present study supports the earlier reports by other investigators. Mapes et al. localized CytB5 to the zona reticularis of the primate adrenal gland, which is responsible for the production of adrenal androgens in the primate [26]. We and others [27, 28] find CytB5 expression to be restricted to the zona reticularis, whereas an earlier report by Yanase et al. showed the distribution of CytB5 in the adrenal gland to be more diffuse [29]. The reason for such a difference is unclear at present. We consider the presence of CytB5 to be indicative of enhanced 17,20-lyase activity in adrenal cells that also express P450c17. Such a role for CytB5 is consistent with its presence in androgen-producing tumors of the adrenal cortex [25].

In the human fetal adrenal gland, our findings of the localization of CytB5 and P450c17 support the work of others [30, 31] who demonstrated the presence of P450c17 and CytB5 in the fetal zone but not the definitive zone at midgestation. This is not true of all primates with prominent fetal zones. Despite clear expression in the reticularis of the adult [26], CytB5 only appears in the fetal zone of rhesus macaques in late gestation, coinciding with enhanced DHEAS secretion and the formation of a fully functional androgen-secreting, adrenocortical zone [32]. Together with the present data, this suggests that the rhesus macaque may be a useful model of human adrenal gland development and the regulation of androgen synthesis.

To our knowledge, CytB5 has not been previously immunolocalized in the human ovary. Our findings of colocalization for P450c17 and CytB5 in the maturing follicles (≥0.4 mm diameter) of the premenopausal ovary provides the basis for theca cell production of estrogen precursors. Continued expression of P450c17 and CytB5 in theca lutein cells would allow the production of estrogen precursors during the luteal phase. Exaggerated activity of the theca cell may provide a link to ovarian hyperandrogenism [33]. Indeed, Wood et al. reported that CytB5 mRNA expression was increased in theca cells from women with polycystic ovarian syndrome compared to normal controls [34]. The expression of P450c17 and CytB5 in the theca-lutein cells of the corpus luteum is suggestive that the corpus luteum also can produce androgens. Bradshaw et al. revealed an association between theca lutein cysts and hyperandrogenism during pregnancy [35]. This is in contrast to the midgestational fetal ovary, which synthesizes nominal amounts of steroids [36] and appears to be devoid of immunoreactivity for CytB5 and P450c17, as demonstrated in our study.

Alterations in theca cell expression of CytB5 also may impact the androgen status in aging. Some senescent ovaries have been found to contain enzymatically active cell clusters in the ovarian stroma (EASA) [37]. In vitro, the EASA cells were designated as such by their expression of glucose-6 phosphate dehydrogenase, lactic dehydrogenase, isocitric dehydrogenase bioactivities, and occasionally others. We find ovarian cell clusters immunopositive for CytB5 and P450c17 in the normal premenopausal ovary that may correspond to such EASA cells or may represent luteinized stromal cells. The presence of cell clusters in the stroma that contain both P450c17 and CytB5 may account for continued androgen production in the postmenopausal ovary. The identity and possible function of such stromal cell clusters remain to be further elucidated.

Human fetal and adult testicular tissues demonstrate an abundance of P450c17 and CytB5 in the Leydig cells with an absence in the Sertoli cells or seminiferous tubules in the testes. Our findings may provide an explanation for the increased catalytic efficiency for the delta 5-steroidogenic pathway in the human fetal testis [38].

Our findings additionally reinforce the essential role of P450c17 in the regulation of androgen synthesis by its localization in androgen-synthesizing tissues. The role of P450c17 is versatile through the dual activities of 17 hydroxylase in the formation of corticosteroids and androgen precursors, and 17,20 lyase in the formation of DHEA/ DHEAS, androstenedione, and testosterone. In addition, Soucy et al. have reported on a role for P450c17 in catalyzing the formation of 16-ene steroids (including androstenol) from C21 precursors [39].

The human ovary, testis, and adrenal cortex share the common biosynthetic pathway for androgen production: 17,20-lyase activity of the P450c17 enzyme, which can be modulated by CytB5. Although many factors have been found to play a role in regulation of the expression of P450c17 [40], there is a paucity of data regarding the mechanisms that control the cell-specific expression of CytB5. The colocalization of CytB5 and P450c17 in key steroidogenic tissues of the human provides for additional avenues of investigation of glandular androgen production in various aspects of normal physiology and pathological conditions throughout the life cycle.


   FOOTNOTES
 
1 Supported by grants from the Office of Naval Research, the National Institute of Aging, and ACOG/Ortho-McNeil. Back

2 Correspondence: C. Richard Parker Jr., Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 618 South 20th Street, 360 Old Hillman Building, Birmingham, AL 35294-7333. FAX: 205 934 6296; crparker{at}uab.edu Back

Received: 19 December 2003.

First decision: 7 January 2004.

Accepted: 13 February 2004.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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