Human Proopiomelanocortin-(79–96), a Proposed Cortical Androgen- Stimulating Hormone, Does not Affect Steroidogenesis in Cultured Human Adult Adrenal Cells*

Penhoat, Armelle; Sanchez, Pierre; Jaillard, C.; Langlois, Dominique; Bégeot, Martine; Saez, J.M.

doi:10.1210/jcem-72-1-23

Cited by 61 publications

(31 citation statements)

References 12 publications

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“…The well-known orphan nuclear receptor SF1 is a critical factor in the regulation of transcription of the genes encoding the adrenal cytochrome P450 enzymes [14,15]. We demonstrated that specific SF1 binding cis-regulatory elements are necessary for trans-activation of SULT2A1 promoter [16].…”

Section: ) Sult2a1mentioning

confidence: 82%

“…While the enzymatic activity of SULT2A1 has been studied in some detail, only recently have studies focused on the regulation of human SULT2A1 expression. Herein, we discuss the role of three transcription factors, steroidogenic factor 1 (SF1 or NR5A1), GATA-6, and estrogen-related receptor α (ERRα) in the regulation of SULT2A1 transcription.The well-known orphan nuclear receptor SF1 is a critical factor in the regulation of transcription of the genes encoding the adrenal cytochrome P450 enzymes [14,15]. We demonstrated that specific SF1 binding cis-regulatory elements are necessary for trans-activation of SULT2A1 promoter [16].…”

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confidence: 82%

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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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Section: ) Sult2a1mentioning

confidence: 82%

mentioning

confidence: 82%

Regulation of the adrenal androgen biosynthesis

Rainey

Nakamura

2008

The Journal of Steroid Biochemistry and Molecular Biology

143

107

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“…For example, some proopiomelanocortin-related peptides, and in particular the joint peptide and beta-endorphin, could stimulate the androgen secretion (80,81), although some authors did not confirm such action (82,83). The possible role of a specific pituitary adrenal androgen-stimulating factor, identified by Parker et al (81), is still debated.…”

Section: Dehydroepiandrosterone Sulfate (Dheas) and Agingmentioning

confidence: 99%

Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates

Ferrari

Cravello

Muzzoni

et al. 2001

European Journal of Endocrinology

245

156

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The aim of this review was to examine the evidence for age-related changes of the hypothalamic± pituitary±adrenal (HPA) axis in both physiological and pathological aging, on the basis of the many data in the literature, as well as of our personal findings.A statistically significant circadian rhythmicity of serum cortisol was maintained in elderly subjects, even if with a reduced amplitude of the 24 h fluctuations and a trend to an increase of the serum levels in the evening and at night-time, in comparison with young controls. Furthermore, an age-related impairment of HPA sensitivity to steroid feedback was present in elderly people.The occurrence of senile dementia amplified the changes already present in physiological aging. While the cortisol secretion was generally well maintained in aging, the adrenal production of dehydroepiandrosterone and of its sulfate (DHEAS) exhibited an age-related decline. Therefore, the cortisol/DHEAS molar ratio was significantly higher in elderly subjects and even more in demented ones, than in young controls.Due to the opposite effects of cortisol and DHEAS on the brain and particularly on the hippocampal region, the imbalance between glucocorticoids and androgens occurring in physiological and even more in pathological aging, may have adverse effects on the function of this region, whose key role in learning and memory is well known.

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“…Using our human adrenal cell preparations, we have reported that joining peptide and b-endorphin, peptides arising from the ACTH precursor pro-opiomelanocortin, have androgen-stimulating properties (21). Parker et al (22) also reported stimulatory effects of joining peptide on adrenal androgen production, but others have not confirmed this (24,25). Evidence also exists that gonadal steroids influence adrenal glucocorticoid and androgen secretion: for example, testosterone increases the adrenal response to ACTH stimulation (19,20).…”

Section: Figurementioning

confidence: 99%

“…Alternatively, factors outside the adrenal gland have been proposed, such as prolactin (16), growth hormone (17), insulin (18), sex steroids (19,20) and fragments of the ACTH precursor molecule, pro-opiomelanocortin, such as b-endorphin (21) and joining peptide (21,22). The existence of such a cortical androgen stimulating hormone has been disputed (23)(24)(25). The present study was designed to examine the influence of ageing and sex on the relative production of cortisol, androstenedione and dehydroepiandrosterone (DHEA), basally and in response to ACTH, and thus enable us to examine the influence of possible endogenous maturational changes that may influence differential production of cortisol and androgens.…”

Section: Introductionmentioning

confidence: 99%

Intra-adrenal factors are not involved in the differential control of cortisol and adrenal androgens in human adrenals

Fearon

Clarke²,

McKenna³

et al. 1998

European Journal of Endocrinology

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The differential control of adrenal androgens and cortisol may be due to intra-adrenal factors, which may be age-or sex-related, or due to extra-adrenal factors, such as circulating hormones. The purpose of this study was to identify any intrinsic differences that may exist in steroidogenic production occurring within adrenals obtained from males and females, and any maturational differences that may evolve with age. Using human adrenals from 48 transplant donors (32 males, 16 females; ages 5-60 years), the influences of age and sex on basal production of and ACTH-stimulated cortisol, androstenedione and dehydroepiandrosterone (DHEA) were examined in freshly prepared adrenal cell suspensions. Basal and ACTH-stimulated cortisol, androstenedione and DHEA production were similar in adrenals from males and females and did not correlate significantly with age when the whole group was examined. When steroidogenesis in male and female adrenals was examined separately against age, a significant correlation was observed only for basal and ACTH-stimulated androstenedione in adrenals from males in the younger age group, 5-30 years (basal: r ¼ 0.84, P ¼ 0.0001; ACTH-stimulated: r ¼ 0.52, P ¼ 0.007). Examination of the relationships between the steroids disclosed that the basal and ACTH-stimulated cortisol/androgen ratios did not correlate significantly with age, but the androstenedione/DHEA ratio showed a significant direct relationship with age in males only (basal: r ¼ 0.53, P ¼ 0.006; ACTH-stimulated: r ¼ 0.5, P=0.01).These data suggest that the influences of sex and age are minor in the modulation of adrenal steroidogenesis and support the concept that extra-adrenal factors dominate in the differential modulation of adrenal androgens and cortisol. The relationship between the androstenedione/ DHEA ratio and increasing age in men is consistent with the recently reported stimulatory effect of testosterone on adrenal steroidogenesis by induction of the conversion of DHEA to androstenedione.

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Human Proopiomelanocortin-(79–96), a Proposed Cortical Androgen- Stimulating Hormone, Does not Affect Steroidogenesis in Cultured Human Adult Adrenal Cells*

Cited by 61 publications

References 12 publications

Regulation of the adrenal androgen biosynthesis

Regulation of the adrenal androgen biosynthesis

Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates

Intra-adrenal factors are not involved in the differential control of cortisol and adrenal androgens in human adrenals

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