PubMed Health⌕ Search

Biomedical subjects

Wiebke Arlt

Publications and source records attributed to Wiebke Arlt.

At least 19 recordsLinked to original sources
PubMed2007

Congenital adrenal hyperplasia and P450 oxidoreductase deficiency.

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders, which are usually due to inactivating mutations in single enzymes involved in adrenal steroid biosynthesis. The characteristics of the biochemical and clinical phenotype depend on the specific enzymatic defect. In 21-hydroxylase and 11beta-hydroxylase deficiency only adrenal steroidogenesis is affected, whereas a defect in 3beta-hydroxysteroid dehydrogenase or 17alpha-hydroxylase also involves gonadal steroid biosynthesis. Recently, mutations in the electron donor enzyme P450 oxidoreductase were identified as the cause of CAH with apparent combined 17alpha-hydroxylase and 21-hydroxylase deficiency, thereby illustrating the impact of redox regulation enzymes on steroidogenesis. P450 oxidoreductase deficiency (ORD) has a complex phenotype including two unique features not observed in any other CAH variant, skeletal malformations and severe genital ambiguity in both sexes. Despite invariably low circulating androgens, females with ORD may present with virilized genitalia and mothers may suffer from virilization during pregnancy. This apparently contradictory finding may be explained by the existence of an alternative pathway in human androgen biosynthesis, with important implications for physiology and pathophysiology. This review discusses the biochemical and clinical presentation and the genetic and functional basis of the currently known CAH variants, with a specific focus on ORD.

Adrenal Hyperplasia, Congenital↗
PubMed2006

The human fetal adrenal cortex and the window of sexual differentiation.

Understanding normal development is fundamental to appreciating postnatal morphology, physiology and, in some instances, pathophysiology. Developmental biology tends to interrogate models in nonprimate species, for instance the mouse, where genetic manipulation gives privileged insight into the function of particular genes. Some human developmental processes, as occur in the adrenal gland, are not faithfully reproduced in these rodent models, yet have an impact on the pathophysiology and treatment of endocrine disorders, such as congenital adrenal hyperplasia. In this setting, in vitro research of normal human development complements clinical investigation of patients born with congenital disorders.

Adrenal Cortex↗
PubMed2006

Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock.

CONTEXT: Dehydroepiandrosterone (DHEA) replacement in sepsis has been advocated because of the sepsis-associated decrease in serum DHEA sulfate (DHEAS). However, experimental sepsis in rodents leads to down-regulation of DHEA sulfotransferase, which inactivates DHEA to DHEAS, theoretically resulting in higher DHEA levels. OBJECTIVE: The objective of the study was to test whether serum DHEA and DHEAS are dissociated in septic shock and to determine their association with circulating cortisol in the context of severity of disease and mortality. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study consisting of 181 patients with septic shock, 31 patients with acute trauma, and 60 healthy controls. MAIN OUTCOME MEASURES: Serum cortisol, DHEA, and DHEAS were measured before and 60 min after ACTH stimulation. RESULTS: Serum cortisol was increased and DHEAS was decreased in both septic shock and trauma patients (all P < 0.001). However, compared with healthy controls, DHEA was significantly increased in sepsis but decreased after trauma (all P < 0.001). In sepsis, neither cortisol nor DHEA increased significantly after ACTH. Most severely ill patients had higher cortisol (P = 0.069) and lower DHEA (P = 0.076) and a significantly higher cortisol to DHEA ratio (P = 0.004). Similarly, the cortisol to DHEA ratio was significantly increased in nonsurvivors of septic shock (P = 0.026), whereas survivors did not differ from controls (P = 0.322). CONCLUSIONS: The observed dissociation of DHEA and DHEAS in septic shock contradicts the previous concept of sepsis-associated DHEA deficiency. Increased DHEA levels may maintain the balance between glucocorticoid- and DHEA-mediated immune and vascular effects. However, most severe disease and mortality is associated with an increased cortisol to DHEA ratio, which may represent a novel prognostic marker in septic shock.

Adrenocorticotropic Hormone↗
PubMed2006

Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements.

OBJECTIVE: Evaluation of glucocorticoid replacement quality in adrenal insufficiency (AI) relies primarily on clinical judgement and thus largely depends on the physician's expertise. It is a matter of debate whether cortisol day curves are of value in assessing glucocorticoid replacement quality. Here we compared the results of a structured clinical assessment to the outcome of repeated, timed serum cortisol measurements. DESIGN: Cross-sectional study in the outpatient department of a university teaching hospital. PATIENTS: Forty-six patients (19 men, 27 women, age range 16-76 years) with primary (n = 23) and secondary (n = 23) AI on stable replacement with a median dose of 37.5 mg cortisone acetate (range 25-50 mg) since 10 +/- 7 years (range 1-31 years). MEASUREMENTS: Clinical performance was scored by structured assessment of signs and symptoms, physical examination and routine biochemical tests. Serum cortisol was measured on two to three separate occasions in three timed samples after the morning glucocorticoid dose. Bone mineral density was measured in 15 patients with long-standing glucocorticoid replacement. RESULTS: Thirty-seven patients were considered well replaced, whereas clinical scores suggested over- or under-replacement in five and four, respectively. There was no correlation of the clinical score with total or body weight-adjusted glucocorticoid dose. The mean z score of serum cortisol differed significantly between under- and over-replaced patients (P < 0.05) but neither group differed significantly from well-replaced patients. Bone mineral density was normal in all patients studied. CONCLUSIONS: Our results suggest that serum cortisol day curves are of limited value in the monitoring of glucocorticoid replacement. Bone mineral density in AI is generally normal and does not require routine follow-up.

Absorptiometry, Photon↗
PubMed2006

Androgen therapy in women.

Androgens in women either derive from direct ovarian production or from peripheral conversion of the adrenal sex steroid precursor, dehydroepiandrosterone, towards active androgens. Therefore, loss of adrenal or ovarian function, caused by Addison's disease or consequent to bilateral oophorectomy, results in severe androgen deficiency, clinically often associated with a loss of libido and energy. Importantly, physiological menopause does not necessarily lead to androgen deficiency, as androgen synthesis in the ovaries may persist despite the decline in estrogen production. However, the definition of female androgen deficiency, as recently provided by the Princeton consensus statement, is not precise enough and may lead to over-diagnosis due to the high prevalence of its diagnostic criteria: androgen levels below or within the lower quartile of the normal range and concurrent sexual dysfunction. Importantly, physiological menopause is not necessarily associated with androgen deficiency and therefore does not routinely require androgen therapy. Current replacement options include transdermal testosterone administration or dehydroepiandrosterone treatment, both of which have been shown to result in significant improvements, in particular in libido and mood, while effects on body composition and muscular function are not well documented. It is important to keep in mind that the number of randomized controlled trials is still limited and that currently none of the available preparations is officially approved for use in women. Currently, androgen replacement should be reserved for women with severe androgen deficiency due to an established cause and matching clinical signs and symptoms.

Adolescent↗
PubMed2005

Sex steroid metabolism in human peripheral blood mononuclear cells changes with aging.

CONTEXT: Dehydroepiandrosterone (DHEA) mainly exerts indirect action via downstream conversion toward sex steroids within peripheral target cells including immune cells. In vitro DHEA has been shown to enhance IL-2 release from T lymphocytes, whereas it inhibits IL-6 secretion. Conversely, aging is associated with a decline in both DHEA and IL-2, whereas IL-6 increases. OBJECTIVE: The objective of the study was to investigate age-related differences in expression and functional activity of steroidogenic enzymes involved in downstream conversion of DHEA in peripheral blood mononuclear cells (PBMCs). DESIGN: This study was cross-sectional. PARTICIPANTS/SETTING: Healthy young men (n = 8; age range, 23-29 yr) and healthy middle-aged men (n = 8; age range, 52-66 yr) were studied in an academic setting. MEASURES: mRNA expression of steroidogenic enzymes in PBMCs was measured by qualitative and quantitative RT-PCR analysis and enzyme activity assays after incubation of PBMCs with radiolabeled DHEA, 4-androstene-3,17-dione (androstenedione), and testosterone. RESULTS: RT-PCR analysis showed expression of all enzymes required for DHEA conversion toward active androgens and to the immune-stimulatory metabolite androstenediol. Steroid conversion patterns indicated a particularly increased activity of 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5) in the older men, demonstrated by significantly higher conversion rates of DHEA to androstenediol and of androstenedione to testosterone (all P < 0.05). By contrast, conversion of DHEA to androstenedione via 3beta-HSD occurred at a similar rate. Quantitative RT-PCR analysis revealed increased expression of 17beta-HSD 5 mRNA in PBMCs from the older men. CONCLUSIONS: Our results provide evidence for significant changes in sex steroid metabolism by human PBMCs with aging, which may represent an endocrine link to immune senescence.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

OX40 ligand and CD30 ligand are expressed on adult but not neonatal CD4+CD3- inducer cells: evidence that IL-7 signals regulate CD30 ligand but not OX40 ligand expression.

In this report, we have examined the expression of the T cell survival signals, OX40 ligand (OX40L) and CD30 ligand (CD30L) on CD4(+)CD3(-)CD11c(-)B220(-)IL-7Ralpha(+) inducer cells from birth to adulthood in mice. We found that adult but not neonatal inducer cells expressed high levels of OX40L and CD30L, whereas their expression of TNF-related activation-induced cytokine (TRANCE) and receptor activator of NF-kappaB (RANK) was comparable. The failure of neonatal inducer cells to express the ligands that rescue T cells helps to explain why exposure to Ag in neonatal life induces tolerance rather than immunity. The expression of OX40L and CD30L on inducer cells increased gradually in the first few weeks of life achieving essentially normal levels around the time mice were weaned. We found that IL-7 signaling through the common cytokine receptor gamma-chain was critical for the optimal expression of both TNF-related activation-induced cytokine and CD30L but not OX40L. Furthermore, glucocorticoids, which potently suppress T effector function, did not influence the expression of OX40L and CD30L in the presence of IL-7.

Animals↗
PubMed2005

No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies.

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant steroid in the human circulation and is thought to be the circulating hydrophilic storage form of DHEA. It is generally accepted that DHEA and DHEAS inter-convert freely and continuously via hydroxysteroid sulfotransferases and steroid sulfatase and that only desulfated DHEA can be converted downstream to sex steroids. Here we analyzed DHEA/DHEAS interconversion in vivo and in vitro. We administered oral DHEA (100 mg) and iv DHEAS (25 mg) to eight healthy young men, resulting in similar increases in serum DHEAS compared with baseline. However, although DHEA administration significantly increased serum DHEA (P < 0.05), no such increase was observed after DHEAS. Similarly, DHEA but not DHEAS was converted downstream to androstenedione, estrone, and androstanediol glucuronide. The striking absence of conversion of DHEAS to DHEA was mirrored by our in vitro findings in HepG2 cells, revealing dose-dependent conversion of DHEA (0.1-2 mum) to DHEAS but no conversion of DHEAS (0.1-2 mum). These results clearly illustrate a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free interconversion of DHEA and DHEAS. DHEAS does not seem to represent a circulating storage pool for DHEA regeneration, and therefore serum DHEAS is unlikely to reflect bioavailable DHEA.

Adolescent↗
PubMed2005

Adrenal corticosteroid biosynthesis, metabolism, and action.

Adrenal corticosteroids are essential for life, and an appreciation of the mechanisms underpinning their synthesis, secretion, and mode of action in normal physiology is essential if the physician is to diagnose and treat patients who have Cushing's syndromes effectively. In each case, there have been clinically significant advances in the knowledge base over recent years, notably in the understanding of steroidogenesis, cortisol action, and metabolism. This article describes corticosteroid biosynthesis, metabolism, and action.

Adrenal Cortex↗
PubMed2005

Androgen replacement therapy in women.

Physiologically, androgens in women either derive from direct ovarian production or from the peripheral conversion of the adrenal sex steroid precursor dehydroepiandrosterone to the active androgens. Therefore, loss of adrenal or ovarian function, as in Addison's disease or after bilateral oophorectomy, usually results in severe androgen deficiency. Androgen replacement in these women may produce significant improvements, particularly in libido and mood. Physiological menopause is not necessarily associated with androgen deficiency and therefore does not routinely require androgen therapy. The number of randomized controlled trials of androgen use in women is still limited. Choosing both a convenient and efficient mode of androgen administration in women remains a challenge and currently none of the available preparations is officially approved for use in women.

Adrenal Insufficiency↗
PubMed2004

Gorham-Stout disease--stabilization during bisphosphonate treatment.

A 45-year-old woman presented with recent onset of left-sided chest pain. On clinical examination, these symptoms seemed to be strictly localized to a region that was marked by a long-standing cutaneous erythematous lesion. Laboratory results showed no gross abnormalities. Radiological imaging including conventional X-ray, MRI scans, and 3D CT reconstruction of the rib cage revealed circumscript destruction of the left lateral ribs 9-11. Histological analysis of a rib biopsy showed angiomatous hypervascularization and intracortical fibrosis. In keeping with these findings, the patient's condition was diagnosed as Gorham-Stout disease, a rare condition with localized, often unilateral, bone destruction. Monotherapy with bisphosphonates (pamidronate 30 mg i.v. every 3 months) was initiated, leading to rapid disappearance of local pain. Follow-up over 24 months documented a stable clinical and radiological picture without evidence of progressive bone destruction.

Biopsy↗
PubMed2004

Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype.

We report studies on the second pregnancy of a woman who had previously given birth to a virilized female infant. The cause of the virilization had not been established, but common forms of congenital adrenal hyperplasia (CAH) were excluded. Longitudinal monitoring of the second pregnancy revealed that estriol excretion failed to increase normally, reaching a maximum 0.7 mg/24 hr at the end of pregnancy (normal mean 30 mg/24 hr). The mother showed signs of virilization by the 23rd week of gestation and aromatase deficiency was suspected. However, predicted urinary metabolites for diagnosis of aromatase deficiency (for example, 16alpha-hydroxyandrosterone) were not increased significantly during the pregnancy. Interestingly, excretion of the androgen metabolite androsterone increased rapidly at the beginning of pregnancy and peaked around the 20th week, suggesting increased production of testosterone and 5alphaDHT, probably the cause of maternal virilization. Urine steroid analysis by GC/MS showed gradually increasing excretion (9 mg/24 hr) of the normally minor metabolite 5alpha-pregnane-3beta,20alpha-diol (epiallopregnanediol), an epimer of the dominant progesterone metabolite pregnanediol (5beta-pregnane-3alpha,20alpha-diol). We believe epiallopregnanediol is largely the maternal urinary excretion product of fetal 5-pregnene-3beta,20alpha-diol, the principal metabolite of pregnenolone, implying a build-up of the latter steroid in the fetal adrenal. These findings suggested that the 'block' in the estriol biosynthetic pathway occurs at an early stage with 17-hydroxylation of pregnenolone being affected. The male baby born of this pregnancy had normal genitalia but showed a urinary steroid profile indicating partial deficiencies of P450c17 and P450c21. However, no mutations in the corresponding CYP17 and CYP21 genes were identified. Urinary steroid analysis carried out on his virilized older sibling showed the same pattern of metabolites. Recently, we determined that this disorder is caused by mutations in P450 oxidoreductase (OR), the essential redox partner for CYP17 and CYP21 hydroxylases. The novel metabolic profile has now been seen in many patients, most diagnosed with the skeletal dysplasia Antley-Bixler syndrome. We propose that excessive excretion of epiallopregnanediol together with low estriol may be prenatally diagnostic for OR deficiency (ORD).

Adult↗
PubMed2004

Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis.

Antley-Bixler syndrome (ABS, MIM 207410) is a skeletal abnormality syndrome primarily affecting head and limbs. Little is known of the origin of the condition but inactivating mutations in the fibroblast growth factor receptor (FGFR2) has been found in some patients. Genital ambiguity is seen occasionally in this condition, suggesting possible disordered steroidogenesis in early pregnancy. We report the steroid excretion of eight patients diagnosed with the syndrome and one with a related condition, a mild phenotype of the disorder since skeletal and genital abnormalities were not evident. The steroid excretion pattern was consistent and very distinctive in all nine patients. Metabolites of the two primary precursors of steroid hormones, pregnenolone and progesterone, were elevated as were the classical diagnostic metabolites for 17- and 21-hydroxylase deficiencies. Cortisol production was typically within the normal range but generally had blunted response to ACTH. Androgen metabolite excretion tends to be low in patients over 2 months of age, but may be elevated in the newborn period. The metabolome suggested attenuated steroid hydroxylation (including 17,20-lyase activity) although underlying cause is yet to be established. Mutations in CYP17 and CYP21 have not been found and currently the prime suspect is an abnormality in an essential redox partner (P450 oxidoreductase). This paper proposes use of the distinctive steroid metabolome as the primary biochemical parameter for diagnosis of ABS, at least the form not associated with FGFR2 mutations.

Abnormalities, Multiple↗
PubMed2004

Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.

BACKGROUND: Congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency is associated with accumulation of steroid metabolites, indicating impaired activity of 17alpha-hydroxylase and 21-hydroxylase. However, no mutations have been reported in the CYP17 and CYP21 genes, which encode these P450 enzymes. Affected girls are born with ambiguous genitalia, but their circulating androgens are low, and virilisation does not progress. We aimed to investigate the underlying molecular basis of congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency in affected children. METHODS: We did sequence analysis of the human gene encoding P450 oxidoreductase, an enzyme that is important in electron transfer from NADPH to P450C17 and P450C21. We studied two unrelated families with a total of three affected children and 100 healthy controls. Wild-type and mutant P450 oxidoreductase proteins were bacterially expressed, purified, and assayed for cytochrome c reductase activity. FINDINGS: We identified four mutations encoding single aminoacid changes in P450 oxidoreductase. All patients were compound heterozygotes, whereas their parents and an unaffected sibling harboured a mutation in only one allele. By contrast, no mutations were noted in the controls. Bacterial expression of recombinant mutant proteins revealed deficient or reduced enzyme activity. INTERPRETATION: Molecular pathogenesis of this form of congenital adrenal hyperplasia is caused by mutations in the gene encoding P450 oxidoreductase. Deficiency of this enzyme could suggest an alternative pathway in human androgen synthesis, present only in fetal life, which explains the combination of antenatal androgen excess and postnatal androgen deficiency.

Adolescent↗
PubMed2004

Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.

Deficient activities of multiple steroidogenic enzymes have been reported without and with Antley-Bixler syndrome (ABS), but mutations of corresponding cytochrome P450 enzymes have not been found. We identified mutations in POR, encoding P450 oxidoreductase, the obligate electron donor for these enzymes, in a woman with amenorrhea and three children with ABS, even though knock-out of POR is embryonically lethal in mice. Mutations of POR also affect drug-metabolizing P450 enzymes, explaining the association of ABS with maternal fluconazole ingestion.

Craniosynostoses↗
PubMed2004

Dehydroepiandrosterone and ageing.

Dehydroepiandrosterone (DHEA) is the major steroid produced by the adrenal zona reticularis and, in contrast to cortisol and aldosterone, its secretion declines with ageing. This has generated major interest in its putative role as an 'anti-ageing' hormone. However, it is not clear that the age-associated, physiological decline in DHEA secretion represents a harmful deficiency. DHEA exhibits its action mainly by conversion to sex steroids. In addition, DHEA has neurosteroidal properties and may exhibit direct action via specific binding sites on endothelial cells. There is convincing evidence for beneficial effects of DHEA in patients with adrenal insufficiency and future research will hopefully elucidate its role in patients receiving pharmacological glucocorticoid treatment. However, in healthy elderly subjects, current evidence from randomised, controlled trials does not justify the use of DHEA, with no major beneficial effects reported and, in addition, potentially adverse effects on sex steroid-dependent tumour growth need to be considered.

Adrenal Insufficiency↗