Temporal and spatial distribution of Corticosteroidogenic Enzymes Immunoreactivity in developing human adrenal

Narasaka, Toshiaki; Suzuki, Takashi; Moriya, Takuya; Sasano, Hironobu

doi:10.1016/s0303-7207(00)00445-7

Cited by 101 publications

(106 citation statements)

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“…More recent studies have shown that the fetal adrenal gland synthesizes little HSD3B2 mRNA or protein (4,5). Immunohistochemical analysis of HSD3B2 during human fetal adrenal development has demonstrated the presence of HSD3B2 in the neocortex and the transitional zone of the fetal adrenal gland (8,9). However, the fetal zone, which secretes large amounts of DHEA(S), expresses little or no HSD3B2 protein throughout gestation.…”

Section: Discussionmentioning

confidence: 99%

“…Localization of NGFIB in the Fetal Adrenal Gland-HSD3B2 is present in the nuclei of the definitive and transitional zones of late gestation fetal adrenal gland, a time when cortisol is being produced at high levels, but is essentially absent from the fetal zone at this time (9). In order to determine whether the presence of HSD3B2 was correlated with the expression profile of NGFIB, we examined expression of both proteins in fetal adrenal sections using immunohistochemistry (Fig.…”

Section: The Expression Profile Of the Ngfib Family Of Transcription mentioning

confidence: 99%

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The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3β-Hydroxysteroid Dehydrogenase

Bassett

Suzuki

Sasano

et al. 2004

Journal of Biological Chemistry

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118

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3␤-Hydroxysteroid dehydrogenase type 2 (HSD3B2) is a steroid-metabolizing enzyme that is essential for adrenal production of mineralocorticoids and glucocorticoids. Thus, HSD3B2 is expressed at high levels in the glomerulosa and fasciculata, where these steroids are produced. In contrast, the production of dehydroepiandrosterone (DHEA) and DHEA sulfate in the adrenal reticularis is inversely correlated with the expression of HSD3B2. The reasons for the zonal expression of HSD3B2 are not known but represent an important aspect in the biochemical zonation of the adrenal. Using microarray, real time reverse transcriptase-PCR, immunohistochemistry, and HSD3B2 promoter analysis, we demonstrate that the NGFIB family of nuclear hormone receptors plays a critical part in the regulation of HSD3B2 transcription and may play an important role in the functional zonation of the adrenal gland. Microarray analysis of cortisol-versus DHEA sulfate-producing adrenal tissue demonstrated that NGIFB paralleled expression of HSD3B2 with expression much higher in cortisol-producing adrenal tissue; this observation was also demonstrated using real time reverse transcriptase-PCR analysis. In addition, immunohistochemistry confirmed that within adult and fetal adrenal gland NGFIB expression paralleled expression of HSD3B2. Transient transfections into H295R adrenal cells demonstrated that NGFIB family members enhanced HSD3B2 reporter activity but had no effect on a 17␣-hydroxylase (CYP17) promoter construct. Deletion and mutational analyses of the 5-flanking region of the HSD3B2 gene identified a consensus NGFIB response element that bound NGFIB in mobility shift assays. Infection of cultured human adrenal cells with adenovirus-containing NGFIB increased cortisol production by 8-fold and increased expression of HSD3B2 mRNA 26-fold over that observed in mock-infected cells. In primary cultures of adrenal cells, ACTH, an activator of HSD3B2, rapidly induced expression of NGFIB. These results suggest that NGFIB plays a crucial role in adrenal zonation by regulating HSD3B2 gene transcription.The enzyme 3␤-hydroxysteroid dehydrogenase type 2 (HSD3B2) 1 is essential for the adrenal biosynthesis of mineralocorticoids (aldosterone) and glucocorticoids (cortisol), but its expression is inversely associated with that of the adrenal androgens (DHEA) (1). HSD3B2 catalyzes the oxidation and isomerization of 3␤-hydroxy-5-ene (⌬ 5 ) steroids into 3-keto-4-ene (⌬ 4 ) steroids, thereby permitting the adrenal gland to synthesize progesterone and 17␣-hydroxyprogesterone from their pregnenolone and 17␣-hydroxypregnenolone precursors (2). HSD3B2 can compete with CYP17 for the metabolism of pregnenolone and 17␣-hydroxypregnenolone and thus influence the production of aldosterone versus cortisol or DHEA (3). High HSD3B2 expression combined with low CYP17 activity will favor aldosterone synthesis and oppose cortisol and adrenal androgen synthesis. Conversely, low HSD3B2 expression coupled with high CYP17 activity will favor adrenal androgen production.The human...

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Section: Discussionmentioning

confidence: 99%

Section: The Expression Profile Of the Ngfib Family Of Transcription mentioning

confidence: 99%

The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3β-Hydroxysteroid Dehydrogenase

Bassett

Suzuki

Sasano

et al. 2004

Journal of Biological Chemistry

Self Cite

118

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“…The human adrenal produces DHEA at high levels within the fetal adrenal and in the zona reticularis of the adult adrenal. Both of these tissues express low levels of HSD3B2 mRNA and protein [6,[27][28][29][30][31][32]. Thus, a detailed understanding of the mechanisms that regulate HSD3B2 expression would help in efforts to understand adrenal physiology.…”

Section: ) 3β-hydroxysteroid Dehydrogenase Type 2 (Hsd3b2)mentioning

confidence: 99%

Regulation of the adrenal androgen biosynthesis

Rainey

Nakamura

2008

The Journal of Steroid Biochemistry and Molecular Biology

143

107

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The human adrenal reticularis produces the so-called adrenal androgens, dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S). As opposed to the cortisol and aldosterone little is known regarding the mechanisms that regulate the production of the adrenal androgens. Several recent studies have shown that type II 3β-hydroxysteroid dehydrogenase (HSD3B2), cytochrome b5 (CYB5), and steroid sulfotransferase (SULT2A1) play an important role in the regulation of adrenal androgen production. Specifically, adrenal production of DHEA-S is correlated with reticularis expression of SULT2A1 and CYB5. In contrast, HSD3B2 has an inverse correlation with adrenal androgen production likely due to its unique ability to remove precursors from the pathway leading to DHEA. Therefore, its expression is limited to the adrenal glomerulosa/fasciculata but not in reticularis. The differential expression of these three proteins appears to be critical for reticularis function. In this review, we focus on studies that have begun to define the mechanisms regulating the transcription of these genes. Understanding the mechanisms controlling differential expression of these proteins should provide novel information about the human adrenal reticularis and its production of DHEA and DHEA-S. KeywordsAdrenal; Androgen; Cytochrome b5; DHEA-sulfotransferase; 3β-hydroxysteroid dehydrogenase II. Background & SignificanceThe fetal adrenal produces large amounts of dehydroepiandrosterone (DHEA) and DHEAsulfate (DHEAS) during fetal development (Fig. 1). DHEA-S concentrations are also high in the newborn (Fig. 1) [1]. However, by age 1, the specialized fetal zone is lost and replaced by the definitive adrenal cortex, which initially synthesizes little DHEA-S (Fig. 1). Hence, DHEA-S production declines precipitously during the first months of life and remains low until adrenarche commences at about age 6-8 [2]. This rise in the circulating concentrations of DHEA and DHEA-S is the biochemical hallmark of adrenarche [3]. Importantly, the rise in DHEA-S occurs prior to the increase of either estrogens or androgens associated with puberty [4]. Circulating DHEA-S concentrations continue to rise and peak during the second decade of life, with levels being higher in males than in females (Fig. 1) [3,5]. While circulating concentrations of DHEA and DHEA-S rise progressively in adrenarche, cortisol and ACTH concentrations do not change significantly in this period, indicating that adrenarche is not simply a global activation of the pituitary-adrenal axis.Correspondence and reprint requests addressed to: William E Rainey, Ph.D. Department of Physiology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912,, Email: E-mail: wrainey@mcg.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its f...

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“…In particular, first-trimester cortisol is assumed to maintain negative feedback upon ACTH secretion. However, an important enzyme for cortisol biosynthesis, type 2 3b-hydroxysteroid dehydrogenase (HSD3B2), has only been detected late in the second trimester (3,5) (Figure 1). Although ACTH at least partially regulates adrenal steroidogenesis after 12 wpc (3), earlier immunoreactivity in the human fetal anterior pituitary (6) has never been correlated to adrenal function.…”

Section: Introductionmentioning

confidence: 99%

In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development

Goto¹

2006

Journal of Clinical Investigation

246

191

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In humans, sexual differentiation of the external genitalia is established at 7-12 weeks post conception (wpc). During this period, maintaining the appropriate intrauterine hormone environment is critical. In contrast to other species, this regulation extends to the human fetal adrenal cortex, as evidenced by the virilization that is associated with various forms of congenital adrenal hyperplasia. The mechanism underlying these clinical findings has remained elusive. Here we show that the human fetal adrenal cortex synthesized cortisol much earlier than previously documented, an effect associated with transient expression of the orphan nuclear receptor nerve growth factor IB-like (NGFI-B) and its regulatory target, the steroidogenic enzyme type 2 3b-hydroxysteroid dehydrogenase (HSD3B2). This cortisol biosynthesis was maximal at 8-9 wpc under the regulation of ACTH. Negative feedback was apparent at the anterior pituitary corticotrophs. ACTH also stimulated the adrenal gland to secrete androstenedione and testosterone. In concert, these data promote a distinctive mechanism for normal human development whereby cortisol production, determined by transient NGFI-B and HSD3B2 expression, provides feedback at the anterior pituitary to modulate androgen biosynthesis and safeguard normal female sexual differentiation.

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Temporal and spatial distribution of Corticosteroidogenic Enzymes Immunoreactivity in developing human adrenal

Cited by 101 publications

References 42 publications

The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3β-Hydroxysteroid Dehydrogenase

The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3β-Hydroxysteroid Dehydrogenase

Regulation of the adrenal androgen biosynthesis

In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development

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