Renal Capture and Oxidation of Cortisol in Man<sup>1</sup>

Hellman, Louis M.; Nakada, Fujinori; Zumoff, Barnett; Fukushima, David K.; Bradlow, H. Leon; Gallagher, T. F.

doi:10.1210/jcem-33-1-52

Cited by 79 publications

(28 citation statements)

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“…Cortisol secretion rate and cortisol half-life were determined as described (1,2,22,44). To establish the (45). The tritiated water was recovered from the plasma by lyophilization.…”

Section: Methodsmentioning

confidence: 99%

A genetic defect resulting in mild low-renin hypertension

Wilson

Dave-Sharma

Wei

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

129

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Severe low-renin hypertension has few known causes. Apparent mineralocorticoid excess (AME) is a genetic disorder that results in severe juvenile low-renin hypertension, hyporeninemia, hypoaldosteronemia, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. In 1995, it was shown that mutations in the gene (HSD11B2) encoding the 11␤-hydroxysteroid dehydrogenase type 2 enzyme (11␤-HSD2) cause AME. Typical patients with AME have defective 11␤-HSD2 activity, as evidenced by an abnormal ratio of cortisol to cortisone metabolites and by an exceedingly diminished ability to convert [11-3 H]cortisol to cortisone. Recently, we have studied an unusual patient with mild low-renin hypertension and a homozygous mutation in the HSD11B2 gene. The patient came from an inbred Mennonite family, and though the mutation identified her as a patient with AME, she did not demonstrate the typical features of AME. Biochemical analysis in this patient revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared with 0-6% in typical patients with AME whereas the normal conversion is 90-95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous C3T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L). The parents and sibs were heterozygous for this mutation. In vitro expression studies showed an increase in the K m (300 nM) over normal (54 nM). Because Ϸ40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene.

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“…Cortisol secretion rate and cortisol half-life were determined as described (1,2,22,44). To establish the (45). The tritiated water was recovered from the plasma by lyophilization.…”

Section: Methodsmentioning

confidence: 99%

A genetic defect resulting in mild low-renin hypertension

Wilson

Dave-Sharma

Wei

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

129

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“…An increase in the level of circulating cortisol may be related to stimulation of 11β-HSD type 1 or by inhibition of 5α-or 5β-R due to administration of 5α-R inhibitors (5α-R inhibitors) in patients with BPH. The balance between the activities of these enzymes maintains the physiological concentration of active GCs [25][26][27].…”

Section: Peripheral Physiological Effects Of 5α-rs Activitiesmentioning

confidence: 99%

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Traish

Melcangi

Bortolato

et al. 2015

Rev Endocr Metab Disord

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Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings.

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“…However, it has been shown by Cope & Pearson (1965) that essentially similar results are obtained for determination of cortisol secretion rate whether ['4C]cortisol or [3H]cortisol were administered (and also whether they were administered orally or intravenously). Hellman, Nakada, Zumoff, Fukushima, Bradlow & Gallagher (1971) have found an isotope effect when studying the metabolism of 1 la-[3H]cortisol relative to [4-i4C]cortisol, though it must be noted that here the 3H atom is in a very sensitive position on the molecule. In order to investigate the possible role of an isotope effect on the tissue uptake and release of cortisol we administered a mixture of [3H]-and [14C]-cortisol to two subjects (V and W).…”

Section: Discussionmentioning

confidence: 90%

Arteriovenous Studies on the Uptake and Metabolism of Cortisol in the Human Forearm

et al. 1974

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1. Cortisol metabolism in human forearm tissues has been investigated by measurement of arteriovenous plasma differences.2. There were no detectable differences in plasma cortisol concentration in fifty-four pairs of arterial and venous samples collected from twenty subjects at rest, nor in experiments in which 5 mg of cortisol was infused intravenously over a period of 30 min.3. When [3H]cortisol was infused intra-arterially into the forearm for 10 min, radiochemical analysis of paired arterial and venous samples provided evidence for retention of cortisol in the local tissues and subsequent release into the venous effluent, and conversion of a small fraction of the infused cortisol into a substance chromatographically similar to cortisone. 4. It was demonstrated by the use of i251-labelled albumin as a plasma marker that retention of the cortisol was due to penetration of the tissues by cortisol and not to a prolonged transit time in the vascular bed.The liver removes cortisol from the blood relatively rapidly and it is generally acknowledged that the major part of degradative metabolism takes place at this site. At least a threefold decrease in the metabolic clearance of cortisol occurs in cirrhosis (Peterson, 1960) and although this does not preclude inhibition of peripheral metabolism it is likely that at least 70% (I) Present address: D e m e n t

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Renal Capture and Oxidation of Cortisol in Man¹

Cited by 79 publications

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A genetic defect resulting in mild low-renin hypertension

A genetic defect resulting in mild low-renin hypertension

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Arteriovenous Studies on the Uptake and Metabolism of Cortisol in the Human Forearm

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Renal Capture and Oxidation of Cortisol in Man1

Cited by 79 publications

References 0 publications

A genetic defect resulting in mild low-renin hypertension

A genetic defect resulting in mild low-renin hypertension

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Arteriovenous Studies on the Uptake and Metabolism of Cortisol in the Human Forearm

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Renal Capture and Oxidation of Cortisol in Man¹