Juilee Rege | University of Michigan (original) (raw)

Papers by Juilee Rege

Research paper thumbnail of Bone morphogenetic protein-4 (BMP4)- A paracrine regulator of human adrenal C19 steroid synthesis

Bone morphogenetic proteins (BMPs) comprise one of the largest subgroups in the transforming grow... more Bone morphogenetic proteins (BMPs) comprise one of the largest subgroups in the transforming growth factor-␤ (TGF-␤) ligand superfamily. We have identified a functional BMP system equipped with the ligand (BMP4), receptors (BMP type-II receptor, BMP type IA receptor also called ALK3) and the signaling proteins (SMADs 1, 4 and 5) in the human adrenal gland and the human adrenocortical cell line H295R. Microarray, quantitative RT-PCR (qPCR) and immunohistochemistry confirmed that BMP4 expression was highest in the adrenal zona glomerulosa (ZG) followed by the zona fasciculata (ZF) and zona reticularis (ZR). Treatment of H295R cells with BMP4 caused phosphorylation of the SMADs and a profound decrease in synthesis of the C 19 steroids dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S) and androstenedione (A4). Administration of BMP4 to cultures of H295R cells also caused a profound decrease in the mRNA and protein levels of 17␣-hydroxylase/17,20-lyase (CYP17A1 and P450c17, respectively) but no significant effect on the mRNA levels of cholesterol side-chain cleavage cytochrome P450 (CYP11A1) or type 2 3␤-hydroxysteroid dehydrogenase (HSD3B2). Furthermore, Noggin (a BMP inhibitor) was able to reverse the negative effects of BMP4 with respect to both CYP17A1 transcription and DHEA secretion in the H295R cell line. Collectively, the present data suggest that BMP4 is an autocrine/ paracrine negative regulator of C 19 steroid synthesis in the human adrenal and works by suppressing P450c17.

Research paper thumbnail of Transcriptome profiling reveals differentially expressed transcripts between the human adrenal zona fasciculata and zona reticularis

The Journal of Clinical Endocrinology & Metabolism, 2013

The human adrenal zona fasciculata (ZF) and zona reticularis (ZR) are responsible for the product... more The human adrenal zona fasciculata (ZF) and zona reticularis (ZR) are responsible for the production of cortisol and 19-carbon steroids (often called adrenal androgens), respectively. However, the gene profiles and exact molecular mechanisms leading to the functional phenotype of the ZF and ZR are still not clearly defined. In the present study, we identified the transcripts that are differentially expressed in the ZF and ZR.

Research paper thumbnail of Liquid Chromatography–Tandem Mass Spectrometry Analysis of Human Adrenal Vein 19-Carbon Steroids Before and After ACTH Stimulation

The Journal of Clinical Endocrinology & Metabolism, 2013

Objective: The objective of this study was to define the adrenal androgen metabolome in women bef... more Objective: The objective of this study was to define the adrenal androgen metabolome in women before and after ACTH infusion.

Research paper thumbnail of Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency

Context: Marked elevations of 17-hydroxyprogesterone (17OHP) are characteristic of classic 21hydr... more Context: Marked elevations of 17-hydroxyprogesterone (17OHP) are characteristic of classic 21hydroxylase deficiency (21OHD). Testing of 17OHP provides the basis for 21OHD diagnosis, although it suffers from several pitfalls. False-positive or false-negative results and poor discrimination of nonclassic 21OHD from carriers limit the utility of serum 17OHP and necessitate dynamic testing following cosyntropin stimulation when values are indeterminate.

Research paper thumbnail of Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein corticosteroids before and after adrenocorticotropic hormone stimulation

Clinical Endocrinology, 2012

Context Although steroid hormones produced by the adrenal gland play critical roles in human phys... more Context Although steroid hormones produced by the adrenal gland play critical roles in human physiology, a detailed quantitative analysis of the steroid products has not been reported. The current study uses a single methodology (liquid chromatography-tandem mass spectrometry, LC-MS/MS) to quantify ten corticosteroids in adrenal vein (AV) samples pre-and post-adrenocorticotropic hormone (ACTH) stimulation. Design/methods Three men and six women with a diagnosis of an adrenal aldosterone-producing adenoma (APA) were included in the study. Serum was collected from the iliac vein (IV) and the AV contralateral to the diseased adrenal. Samples were collected, before and after administration of ACTH. LC-MS/MS was then used to quantify serum concentrations of unconjugated corticosteroids and their precursors. Results Prior to ACTH stimulation, the four most abundant steroids in AV were cortisol (90%), cortisone (4%), corticosterone (3%) and 11-deoxycortisol (0AE8%). Post-ACTH administration, cortisol remained the major adrenal product (79%); however, corticosterone became the second most abundantly produced adrenal steroid (11%) followed by pregnenolone (2AE5%) and 17a-hydroxypregnenolone (2%). ACTH significantly increased the absolute adrenal output of all ten corticosteroids measured (P < 0AE05). The four largest post-ACTH increases were pregnenolone (300-fold), progesterone (199-fold), 17a-hydroxypregnenolone (187-fold) and deoxycorticosterone (82-fold). Conclusion Using LC-MS/MS, we successfully measured 10 corticosteroids in peripheral and AV serum samples under pre-and post-ACTH stimulation. This study demonstrates the primary adrenal steroid products and their response to ACTH.

Research paper thumbnail of THEMATIC REVIEW The steroid metabolome of adrenarche

Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates incr... more Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates increase adrenal output of a series of steroids, especially DHEA and DHEAS. The timing of adrenarche varies among primates, but in humans serum levels of DHEAS are seen to increase at around 6 years of age. This phenomenon corresponds with the development and expansion of the zona reticularis of the adrenal gland. The physiological phenomena that trigger the onset of adrenarche are still unknown; however, the biochemical pathways leading to this event have been elucidated in detail. There are numerous reviews examining the process of adrenarche, most of which have focused on the changes within the adrenal as well as the phenotypic results of adrenarche. This article reviews the recent and past studies that show the breadth of changes in the circulating steroid metabolome that occur during the process of adrenarche.

Research paper thumbnail of The steroid metabolome of adrenarche

Journal of Endocrinology, 2012

Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates incr... more Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates increase adrenal output of a series of steroids, especially DHEA and DHEAS. The timing of adrenarche varies among primates, but in humans serum levels of DHEAS are seen to increase at around 6 years of age. This phenomenon corresponds with the development and expansion of the zona reticularis of the adrenal gland. The physiological phenomena that trigger the onset of adrenarche are still unknown; however, the biochemical pathways leading to this event have been elucidated in detail. There are numerous reviews examining the process of adrenarche, most of which have focused on the changes within the adrenal as well as the phenotypic results of adrenarche. This article reviews the recent and past studies that show the breadth of changes in the circulating steroid metabolome that occur during the process of adrenarche.

Research paper thumbnail of Clinical, Biochemical, and Molecular Characterization of Macronodular Adrenocortical Hyperplasia of the Zona Reticularis: A New Syndrome

Endocrine Reviews, 2010

Context: Macronodular adrenocortical hyperplasia classically presents with progressive hypercorti... more Context: Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS).

Research paper thumbnail of Bone morphogenetic protein-4 (BMP4)- A paracrine regulator of human adrenal C19 steroid synthesis

Bone morphogenetic proteins (BMPs) comprise one of the largest subgroups in the transforming grow... more Bone morphogenetic proteins (BMPs) comprise one of the largest subgroups in the transforming growth factor-␤ (TGF-␤) ligand superfamily. We have identified a functional BMP system equipped with the ligand (BMP4), receptors (BMP type-II receptor, BMP type IA receptor also called ALK3) and the signaling proteins (SMADs 1, 4 and 5) in the human adrenal gland and the human adrenocortical cell line H295R. Microarray, quantitative RT-PCR (qPCR) and immunohistochemistry confirmed that BMP4 expression was highest in the adrenal zona glomerulosa (ZG) followed by the zona fasciculata (ZF) and zona reticularis (ZR). Treatment of H295R cells with BMP4 caused phosphorylation of the SMADs and a profound decrease in synthesis of the C 19 steroids dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S) and androstenedione (A4). Administration of BMP4 to cultures of H295R cells also caused a profound decrease in the mRNA and protein levels of 17␣-hydroxylase/17,20-lyase (CYP17A1 and P450c17, respectively) but no significant effect on the mRNA levels of cholesterol side-chain cleavage cytochrome P450 (CYP11A1) or type 2 3␤-hydroxysteroid dehydrogenase (HSD3B2). Furthermore, Noggin (a BMP inhibitor) was able to reverse the negative effects of BMP4 with respect to both CYP17A1 transcription and DHEA secretion in the H295R cell line. Collectively, the present data suggest that BMP4 is an autocrine/ paracrine negative regulator of C 19 steroid synthesis in the human adrenal and works by suppressing P450c17.

Research paper thumbnail of Transcriptome profiling reveals differentially expressed transcripts between the human adrenal zona fasciculata and zona reticularis

The Journal of Clinical Endocrinology & Metabolism, 2013

The human adrenal zona fasciculata (ZF) and zona reticularis (ZR) are responsible for the product... more The human adrenal zona fasciculata (ZF) and zona reticularis (ZR) are responsible for the production of cortisol and 19-carbon steroids (often called adrenal androgens), respectively. However, the gene profiles and exact molecular mechanisms leading to the functional phenotype of the ZF and ZR are still not clearly defined. In the present study, we identified the transcripts that are differentially expressed in the ZF and ZR.

Research paper thumbnail of Liquid Chromatography–Tandem Mass Spectrometry Analysis of Human Adrenal Vein 19-Carbon Steroids Before and After ACTH Stimulation

The Journal of Clinical Endocrinology & Metabolism, 2013

Objective: The objective of this study was to define the adrenal androgen metabolome in women bef... more Objective: The objective of this study was to define the adrenal androgen metabolome in women before and after ACTH infusion.

Research paper thumbnail of Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency

Context: Marked elevations of 17-hydroxyprogesterone (17OHP) are characteristic of classic 21hydr... more Context: Marked elevations of 17-hydroxyprogesterone (17OHP) are characteristic of classic 21hydroxylase deficiency (21OHD). Testing of 17OHP provides the basis for 21OHD diagnosis, although it suffers from several pitfalls. False-positive or false-negative results and poor discrimination of nonclassic 21OHD from carriers limit the utility of serum 17OHP and necessitate dynamic testing following cosyntropin stimulation when values are indeterminate.

Research paper thumbnail of Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein corticosteroids before and after adrenocorticotropic hormone stimulation

Clinical Endocrinology, 2012

Context Although steroid hormones produced by the adrenal gland play critical roles in human phys... more Context Although steroid hormones produced by the adrenal gland play critical roles in human physiology, a detailed quantitative analysis of the steroid products has not been reported. The current study uses a single methodology (liquid chromatography-tandem mass spectrometry, LC-MS/MS) to quantify ten corticosteroids in adrenal vein (AV) samples pre-and post-adrenocorticotropic hormone (ACTH) stimulation. Design/methods Three men and six women with a diagnosis of an adrenal aldosterone-producing adenoma (APA) were included in the study. Serum was collected from the iliac vein (IV) and the AV contralateral to the diseased adrenal. Samples were collected, before and after administration of ACTH. LC-MS/MS was then used to quantify serum concentrations of unconjugated corticosteroids and their precursors. Results Prior to ACTH stimulation, the four most abundant steroids in AV were cortisol (90%), cortisone (4%), corticosterone (3%) and 11-deoxycortisol (0AE8%). Post-ACTH administration, cortisol remained the major adrenal product (79%); however, corticosterone became the second most abundantly produced adrenal steroid (11%) followed by pregnenolone (2AE5%) and 17a-hydroxypregnenolone (2%). ACTH significantly increased the absolute adrenal output of all ten corticosteroids measured (P < 0AE05). The four largest post-ACTH increases were pregnenolone (300-fold), progesterone (199-fold), 17a-hydroxypregnenolone (187-fold) and deoxycorticosterone (82-fold). Conclusion Using LC-MS/MS, we successfully measured 10 corticosteroids in peripheral and AV serum samples under pre-and post-ACTH stimulation. This study demonstrates the primary adrenal steroid products and their response to ACTH.

Research paper thumbnail of THEMATIC REVIEW The steroid metabolome of adrenarche

Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates incr... more Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates increase adrenal output of a series of steroids, especially DHEA and DHEAS. The timing of adrenarche varies among primates, but in humans serum levels of DHEAS are seen to increase at around 6 years of age. This phenomenon corresponds with the development and expansion of the zona reticularis of the adrenal gland. The physiological phenomena that trigger the onset of adrenarche are still unknown; however, the biochemical pathways leading to this event have been elucidated in detail. There are numerous reviews examining the process of adrenarche, most of which have focused on the changes within the adrenal as well as the phenotypic results of adrenarche. This article reviews the recent and past studies that show the breadth of changes in the circulating steroid metabolome that occur during the process of adrenarche.

Research paper thumbnail of The steroid metabolome of adrenarche

Journal of Endocrinology, 2012

Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates incr... more Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates increase adrenal output of a series of steroids, especially DHEA and DHEAS. The timing of adrenarche varies among primates, but in humans serum levels of DHEAS are seen to increase at around 6 years of age. This phenomenon corresponds with the development and expansion of the zona reticularis of the adrenal gland. The physiological phenomena that trigger the onset of adrenarche are still unknown; however, the biochemical pathways leading to this event have been elucidated in detail. There are numerous reviews examining the process of adrenarche, most of which have focused on the changes within the adrenal as well as the phenotypic results of adrenarche. This article reviews the recent and past studies that show the breadth of changes in the circulating steroid metabolome that occur during the process of adrenarche.

Research paper thumbnail of Clinical, Biochemical, and Molecular Characterization of Macronodular Adrenocortical Hyperplasia of the Zona Reticularis: A New Syndrome

Endocrine Reviews, 2010

Context: Macronodular adrenocortical hyperplasia classically presents with progressive hypercorti... more Context: Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS).