Biomedical subjects

Frank H de Jong

Publications and source records attributed to Frank H de Jong.

At least 19 recordsLinked to original sources

PubMed2006

Glucocorticoid receptor variant and risk of dementia and white matter lesions.

OBJECTIVE: Elevated glucocorticoid levels are associated with dementia. A glucocorticoid receptor gene variant (ER22/23EK) is related to relative glucocorticoid resistance. We investigated whether the ER22/23EK allele is associated with dementia and structural brain abnormalities. METHODS: This study was performed in two prospective population-based cohort studies among elderly. The first study included 6034 participants who were screened for dementia (mean follow-up 5.8 years). The second study included 1011 elderly subjects with an MRI at baseline and follow-up. The ER22/23EK allele was assessed for association with dementia, cognitive function and white matter lesions. RESULTS: The ER22/23EK allele was associated with a decreased risk of dementia. Among non-demented participants, ER22/23EK-carriers had a better performance on psychomotor speed tests than non-carriers. No differences were found in memory function between genotypes. In addition, both presence and progression of white matter lesions was lower in ER22/23EK-carriers. No association was found with brain atrophy on MRI. CONCLUSIONS: Our findings suggest a protective effect of the ER22/23EK allele on the risk of dementia and white matter lesions.

Aged↗

PubMed2006

Lack of Association of the 11beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia.

CONTEXT: Recently, it was proposed that a combination of the 83,557insA polymorphism in the 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene and the R453Q polymorphism in the hexose-6-phosphate dehydrogenase (H6PD) gene interacts to cause cortisone reductase deficiency (CRD) when at least three alleles are affected. OBJECTIVE: The aim was to study the separate and combined effects of these polymorphisms on body composition, adrenal androgen production, blood pressure, glucose metabolism, and the incidence of dementia in the healthy elderly population. DESIGN/SETTING/PARTICIPANTS: The Rotterdam study (n = 6105) and the Frail Old Men study (n = 347) are population-based cohort studies in the elderly. MAIN OUTCOME MEASURES: Genotype distributions and influences of (combined) genotypes on body mass index, adrenal androgen production, waist to hip ratio, systolic and diastolic blood pressure, fasting glucose levels, glucose tolerance test, and incidence of dementia were measured. RESULTS: No influence of the HSD11B1 83,557insA (allele frequencies 22.0 and 21.5%) and H6PD R453Q (allele frequencies 22.9 and 20.2%) variants was found for the different outcome measures that were investigated, either separately or when at least three alleles were affected. CONCLUSIONS: Two population-based studies among Caucasian elderly showed no evidence for (combined) effects of two polymorphisms in the HSD11B1 and H6PD genes on body composition, adrenal androgen production, blood pressure, glucose metabolism, and incidence of dementia. Moreover, the high frequencies observed for these two polymorphisms do not correspond to the low incidence of CRD observed in the general population. Altogether, it is unlikely that these polymorphisms cause CRD.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2006

Anti-Müllerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation.

CONTEXT: Anti-Müllerian hormone (AMH), a quantitative marker for ovarian reserve, has been suggested to be independent of the classical endocrine fluctuations of the menstrual cycle. OBJECTIVE: The objective of the study was to determine whether AMH levels are constant throughout the menstrual cycle, compared with those of FSH, LH, and estradiol. DESIGN/PATIENTS: Frequent blood sampling was performed in 44 fertile, regularly cycling, female volunteers during one full menstrual cycle. SETTING: The study was conducted at a university hospital. MAIN OUTCOME MEASURES: AMH, FSH, LH, and estradiol measurements were allocated to one of seven cycle phases, and a multilevel analysis was performed. Consistent fluctuation patterns were tested by fitting sine patterns to the data. Finally, the frequency in which randomly selected individual samples would remain in one of five preset level categories (quintiles) for each of the variables was studied. RESULTS: A sine pattern fitted to the AMH data was not statistically significant (P = 0.40). In contrast, sine patterns for FSH, LH, and estradiol were highly significant. Comparing the seven cycle phases, no significant differences could be observed between phase-specific AMH levels (P = 0.06). Repeated selection of AMH samples for each individual showed that in 71.5% of selections, AMH values remained in the same quintile, whereas in 27.9% values fell in an adjacent quintile. CONCLUSIONS: AMH levels measured through a full menstrual cycle did not show consistent fluctuation patterns in contrast to levels of FSH, LH, and estradiol. Furthermore, random fluctuations were small, indicating that AMH can be relied on as a cycle-independent marker for ovarian reserve.

Adult↗

PubMed2006

Calculation of bioavailable and free testosterone in men: a comparison of 5 published algorithms.

BACKGROUND: Estimation of serum concentrations of free testosterone (FT) and bioavailable testosterone (bioT) by calculation is an inexpensive and uncomplicated method. We compared results obtained with 5 different algorithms. METHODS: We used 5 different published algorithms [described by Sodergard et al. (bioTS and FTS), Vermeulen et al. (bioTV and FTV), Emadi-Konjin et al. (bioTE), Morris et al. (bioTM), and Ly et al. (FTL)] to estimate bioT and FT concentrations in samples obtained from 399 independently living men (ages 40-80 years) participating in a cross-sectional, single-center study. RESULTS: Mean bioT was highest for bioTS (10.4 nmol/L) and lowest for bioT(E) (3.87 nmol/L). Mean FT was highest for FTS (0.41 nmol/L), followed by FTV (0.35 nmol/L), and FTL (0.29 nmol/L). For bioT concentrations, the Pearson correlation coefficient was highest for the association between bioTS and bioTV (r = 0.98) and lowest between bioTM and bioTE (r = 0.66). FTL was significantly associated with both FTS (r = 0.96) and FTV (r = 0.88). The Pearson correlation coefficient for the association between FTL and bioTM almost reached 1.0. Bland-Altman analysis showed large differences between the results of different algorithms. BioTM, bioTE, bioTV, and FTL were all significantly associated with sex hormone binding globulin (SHBG) concentrations. CONCLUSION: Algorithms to calculate FT and bioT must be revalidated in the local setting, otherwise over- or underestimation of FT and bioT concentrations can occur. Additionally, confounding of the results by SHBG concentrations may be introduced.

Adult↗

PubMed2006

In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion.

CONTEXT: Estradiol inhibits gonadotropin release in men by an action at the hypothalamus and pituitary. Because of the tissue-specific regulation of aromatase, peripheral estradiol levels may not reflect brain estradiol concentrations. OBJECTIVE: We evaluated whether local aromatization of testosterone in the hypothalamus or pituitary is important for gonadotropin release and to what extent circulating estrogens affect gonadotropin levels and peripheral testosterone levels. DESIGN, SUBJECTS, AND INTERVENTIONS: We suppressed aromatase activity in 10 young healthy men with letrozole 2.5 mg once daily, restored plasma estradiol levels with estradiol patches (100 microg/d for the first week, 50 microg/d the second week, 25 microg/d the third week, and no estradiol patch the fourth week) and measured plasma testosterone, estradiol, LH, FSH, and SHBG levels. RESULTS: The mean estradiol and testosterone levels during the study ranged between 68.6 +/- 38.3 and 12.6 +/- 7.21 pg/ml for estradiol and 179 +/- 91 and 955 +/- 292 ng/dl (mean +/- sd) for testosterone. Levels of testosterone, LH, and FSH were inversely related to peripheral estradiol levels. During letrozole use, the mean plasma estradiol level needed to restore testosterone, LH, and FSH levels to baseline levels was not significantly different from the baseline mean estradiol level. CONCLUSIONS: Local aromatization of testosterone in the hypothalamo-pituitary compartment is not a prerequisite for expression of the inhibitory action of estrogens on gonadotropin secretion in men. Peripheral estradiol levels directly reflect the inhibitory tone exerted by estrogens on gonadotropin release and are a major determinant of peripheral testosterone, LH, and FSH levels.

Adult↗

PubMed2006

Glucocorticoid receptor polymorphism affects transrepression but not transactivation.

CONTEXT: Glucocorticoids (GCs) are extensively used in the treatment of inflammatory and autoimmune diseases. Their beneficial effects are thought to be mediated by GC transrepression on gene expression. However, their use is limited by serious adverse effects, presumably mediated by GC transactivation of gene expression. OBJECTIVE: The objective of the study was to investigate the effect of the GC receptor haplotype, characterized by the GR-9beta polymorphism, on GC transactivation and transrepression. DESIGN AND METHODS: This was a cross-sectional study in 216 persons randomly selected from participants in The Rotterdam Study, a population-based cohort study in the elderly. Clinical and biochemical parameters of GC sensitivity were measured: weight, height, waist to hip ratio, glucose, insulin, total cholesterol, high-density lipoprotein, and C-reactive protein. In a dexamethasone suppression test, the response of serum cortisol concentrations was studied. Genotyping for four GC receptor polymorphisms was performed. In addition, ex vivo experiments were performed with leukocytes of 10 healthy controls and two persons homozygous for the GR-9beta polymorphism, in which the expression of two GC-sensitive genes, GC-induced leucine zipper and IL-2, was measured. RESULTS: Persons carrying the GR-9beta haplotype without 22/23EK (n = 53) revealed no significant differences in their body mass index, waist to hip ratio, fat spectrum, and insulin sensitivity or in their cortisol response to dexamethasone and levels of C-reactive protein, compared with noncarriers (n = 113). Ex vivo, GC-induced up-regulation of GC-induced leucine zipper mRNA via transactivation did not significantly differ in GR-9beta homozygotes, whereas the down-regulation of IL-2 expression via transrepression was decreased. CONCLUSION: Persons carrying the GR-9beta haplotype seem to have a decreased GC transrepression with normal transactivation.

Aged↗

PubMed2006

Serum anti-mullerian hormone levels reflect the size of the primordial follicle pool in mice.

Reproductive aging is the decline of female fertility with age. It is caused by the decrease in the number of growing follicles, resulting from primordial follicle pool depletion. Recently, we have shown that anti-Müllerian hormone (AMH) is produced by growing follicles, and studies in women indicate that serum AMH levels decrease with age and correlate with antral follicle count. However, whether serum AMH levels correlate directly with the size of the primordial follicle pool cannot be determined in women. In this work, we describe studies in mice in which we determined the dynamics of ovarian follicles during aging. Furthermore, we describe the development of a mouse AMH ELISA, allowing us to measure AMH levels in mice, for the first time. We observed that serum AMH levels decline with increasing age, whereas expression of AMH in individual growing follicles, studied by immunohistochemistry, did not change with age. Thus, the decline in serum AMH correlates directly with the decline in the number of growing follicles (r = 0.86, P < 0.0001). We observed that the number of growing follicles correlated with the number of primordial follicles (r = 0.93, P < 0.0001). Similarly, we found a strong correlation between AMH levels and number of primordial follicles (r = 0.83, P < 0.0001). In conclusion, serum AMH levels reflect the size of the primordial follicle pool in aging mice. Therefore, AMH is an excellent marker to assess the quantitative aspect of ovarian reserve, which may be useful for women at risk for early ovarian aging such as survivors of childhood cancers.

Aging↗

PubMed2006

Relations between body composition, functional and hormonal parameters and quality of life in healthy postmenopausal women.

OBJECTIVE: To investigate whether body composition, functional status and serum hormone levels are associated with quality of life in healthy postmenopausal women. DESIGN: A cross-sectional study among 402 women aged 56-73 years, 8-30 years postmenopausal. Quality of life (QoL) was assessed using the questionnaire on life satisfaction (QLS), with two modules directed at general factors (QLS-general) and health factors (QLS-health). Muscle strength was measured using dynamometry. Functional ability was estimated by physical performance (PPS), physical activity during the preceding year, and impairment in activities of daily living (ADL). Bone mineral density, lean mass and fat mass were assessed by dual-energy X-ray absorptiometry. Fasting levels of serum oestradiol, oestrone, and sex hormone-binding globulin (SHBG), testosterone, cortisol, androstenedione, DHEA and DHEAS, insulin-like growth factor (IGF-1), its binding proteins (IGFBP-1 and -3) and insulin, were determined. RESULTS: Both QLS modules did not decrease with age. The major positive predictor of QLS-general module was the presence of a partner. Higher physical performance and higher educational level of participants' partners were significantly related to higher QLS-general, while smoking and presence of co-morbidities were significantly associated with a lower QLS-general. The determinants studied were mostly related to the QLS-health module, the major negative predictor of QLS-health being the presence of co-morbidities, followed by physical activity, physical performance and grip strength. Higher educational level of participants was related with higher QLS-health module, while higher BMI, fat mass and presence of disability were associated with significantly lower QLS-health. No consistent relation was found between serum levels of hormones measured and both QLS modules. CONCLUSIONS: The most important and specific determinant for psychological well-being was having a partner. Physical and psychological well-being are further strongly associated in this population of healthy postmenopausal women below 75 years of age, while increasing fat mass was related to decreased well-being. Our results suggest that in elderly and late postmenopausal women hormonal factors do not predict quality of life.

Absorptiometry, Photon↗

PubMed2006

Soluble Fas, a mediator of apoptosis, C-reactive protein, and coronary and extracoronary atherosclerosis. The Rotterdam Coronary Calcification Study.

RATIONALE: Findings from laboratory studies strongly suggest a role for apoptosis, the process of programmed cell death, in cardiovascular disease. No population-based study has yet investigated whether serum levels of soluble forms of Fas, a receptor capable of inducing the apoptosis cascade, are associated with coronary and extracoronary atherosclerosis. METHODS: Within the Rotterdam Coronary Calcification Study, a population-based cohort study, we measured coronary calcification using electron-beam computed tomography, abdominal aortic calcification by abdominal X-ray, carotid plaques and common carotid intima-media thickness (IMT) by ultrasonography, and lower extremity atherosclerosis by computation of the ankle-arm index. Levels of sFas and of the inflammatory mediator C-reactive protein (CRP) were measured in 1036 participants. RESULTS: Levels of sFas were not related to coronary or extracoronary atherosclerosis. CRP showed strong associations with measures of atherosclerosis, including coronary atherosclerosis, which largely remained after adjustment for traditional cardiovascular risk factors. CONCLUSION: The results of this study do not support a role for sFas in the identification of subjects with atherosclerosis.

Apoptosis↗

PubMed2006

FSH receptor genotype is associated with pregnancy but not with ovarian response in IVF.

Two very common single nucleotide polymorphisms at positions 307 and 680 in exon 10 of the FSH receptor gene have been associated with ovarian response in IVF. This observational study evaluated the role of the FSH receptor genotype in the prediction of poor response and clinical pregnancy in IVF in comparison with other markers, such as age, basal FSH, anti-Müllerian hormone and antral follicle count. In addition, the in-vitro cAMP response towards recombinant FSH in cultured granulosa cells of patients with different FSH receptor genotypes was determined. A total of 105 IVF patients undergoing ovarian stimulation in a long suppression protocol were included in the study. The ovarian response was comparable between patients with different FSH receptor genotypes. Patients with polymorphism Ser/Ser had implantation and pregnancy rates that were three times higher compared with patients with polymorphism Asn/Asn. FSH receptor genotype was not associated with a poor response in IVF, but showed a positive association with pregnancy, independent of age. There was no difference in cAMP production in cultured granulosa cells of patients with different FSH receptor genotypes (n=62). It is concluded that FSH receptor genotype is associated with pregnancy in IVF, but not with ovarian response.

Adult↗

PubMed2006

Use of ovarian reserve tests for the prediction of ongoing pregnancy in couples with unexplained or mild male infertility.

The chance of infertile patients conceiving is related to factors like female age and duration of infertility. This prospective observational study evaluated whether the results of ovarian reserve tests, including the novel marker serum anti-Mullerian hormone (AMH), were of additional value in predicting ongoing pregnancy. Two hundred and twenty-two patients diagnosed with unexplained infertility or mild male factor (total motile count>10x10(6)) on the basis of the infertility work-up were prospectively included. Antral follicle count, AMH, inhibin B, FSH and oestradiol concentrations were determined during the early follicular phase. Outcome measures were treatment-dependent and treatment-independent ongoing pregnancy and time to ongoing pregnancy. There were 159 ongoing pregnancies, 52 of which occurred spontaneously. Pregnant patients were significantly younger than those who did not become pregnant (median age 32.4 versus 34.9 years, P<0.001) and FSH concentrations were higher in non-pregnant patients (median 6.8 versus 7.6 IU/l, P=0.04). Only age (hazard ratio 0.93, 95% CI 0.90-0.97) and whether or not the patient was undergoing treatment (hazard ratio 8.10, 95% CI 5.66-11.61) were significantly associated with time to ongoing pregnancy. Ovarian reserve tests, other than chronological age, seem of limited value in predicting (time to) ongoing pregnancy in patients with unexplained and mild male infertility.

Adult↗

PubMed2006

The early luteal phase administration of estrogen and progesterone does not induce premature luteolysis in normo-ovulatory women.

OBJECTIVE: The luteal phase after ovarian hyperstimulation for in vitro fertilization (IVF) is insufficient. Therefore, luteal phase supplementation is routinely applied in IVF. It may be postulated that premature luteolysis after ovarian hyperstimulation is due to supraphysiological steroid levels in the early luteal phase. In the present study, high doses of steroids are administered after the LH surge in normo-ovulatory volunteers in order to investigate whether this intervention gives rise to endocrine changes and a shortening of the luteal phase. DESIGN: Randomized controlled trial. METHODS: Forty non-smoking, normal weight women, between 18 and 37 years of age, with a regular menstrual cycle (24-35 days), received either high dosages of estradiol (E2), progesterone (P), E2+P or no medication. Blood sampling was performed every other day from the day of the LH surge until LH+14. Duration of the luteal phase and endocrine profiles were the main study outcomes. RESULTS: Early luteal phase steroid concentrations achieved by exogenous administration were comparable with levels observed following ovarian hyperstimulation for IVF. No difference in the luteal phase length was observed comparing all groups. However, a significant decrease in LH levels could be observed 6 days after the mid-cycle LH surge (P<0.001) in women receiving P, resulting in accelerated decrease of inhibin A production by the corpus luteum (P=0.001). CONCLUSION: The present intervention of high-dose steroid administration shortly after the LH surge failed to induce a premature luteolysis regularly in cyclic women. It seems that the induced transient suppression in LH allowed for a timely recovery of corpus luteum function. Other additional factors may be held responsible for the distinct reduction in luteal phase length observed after ovarian hyperstimulation for IVF.

Adolescent↗

PubMed2006

Anti-Müllerian hormone: a new marker for ovarian function.

Anti-Müllerian hormone (AMH) is a member of the transforming growth factor beta family of growth and differentiation factors. In the ovary, AMH has an inhibitory effect on primordial follicle recruitment as well as on the responsiveness of growing follicles to follicle-stimulating hormone (FSH). The ovary-specific expression pattern in granulosa cells of growing nonselected follicles makes AMH an ideal marker for the size of the ovarian follicle pool. This review summarizes recent findings concerning AMH and its role as a marker for the quantitative aspect of ovarian reserve as well as ovarian dysfunction.

Aging↗

PubMed2005

Strategies for the characterization of disorders in cortisol sensitivity.

CONTEXT: The clinical presentation of abnormalities in glucocorticoid (GC) sensitivity is diverse, and therefore it is difficult to diagnose this condition. OBJECTIVE AND DESIGN: The objective of the study was to develop strategies for the characterization of GC sensitivity disorders. SETTING: The study was conducted in an outpatient clinic. PATIENTS: Nine patients with GC sensitivity disorders participated. INTERVENTIONS: Sequence analysis of the GC receptor (GR), determination of GR number per cell, GR ligand-binding affinity, and GR splice regulation were performed in freshly prepared peripheral blood mononuclear lymphocytes and Epstein-Barr virus-transformed lymphoblasts. Cellular GC sensitivity was determined ex vivo by measuring the effect of dexamethasone on GC-induced leucine-zipper and IL-2 mRNA levels and on cell proliferation. RESULTS: Differences in GR number per cell, GR affinity, GR splice variants, and effects on transactivation or transrepression of GC-sensitive genes were observed between patients and controls. Epstein-Barr virus transformation of lymphoblasts had no influence on GR affinity but increased the GR number 5-fold in healthy controls. In patients diagnosed as cortisol resistant, however, GR number after transformation was increased significantly less than 5-fold, whereas a higher GR number was observed in a patient suspected of cortisol hypersensitivity. CONCLUSION: This study illustrates several strategies to define abnormalities in GC sensitivity by describing nine patients with affected GC sensitivity, all with a unique clinical course and background.

Adolescent↗

PubMed2005

Expression of the human glucocorticoid receptor splice variants alpha, beta, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper- and hypocortisolism.

CONTEXT: The effects of cortisol are mediated by the alpha-isoform of the glucocorticoid receptor (GR). GR-alpha levels and activity are modulated by alternative splicing of the common pre-mRNA into mRNAs for the GR-beta and GR-P isoforms. OBJECTIVE: The objective of this study was to investigate whether chronic hypercortisolism, chronic hypocortisolism, or acute, relative hypocortisolism influences the expression levels of the GR splice variants in mononuclear leukocytes. DESIGN: This was a case-control study. SETTING: The study was performed at a university hospital. PARTICIPANTS: Eighteen patients with Cushing's syndrome, five patients with hypocortisolemia, seven patients undergoing metyrapone testing, and 14 controls were studied. MAIN OUTCOME MEASURES: The main outcome measures were mRNA levels, GR affinity, and number per cell. RESULTS: All three GR mRNA isoforms were detected in participants from all groups at relative levels of alpha/P/beta = 1:0.25:0.001. There was a significant correlation between the expression levels of the three splice variants and between the mRNA levels and the number of receptors per cell. The GR in Cushing patients had an increased Kd (P < 0.05) preoperatively. GR number was not significantly different. Postoperatively, the Kd decreased. GR-beta mRNA expression was increased compared with controls (P < 0.05) and was decreased after surgery (P < 0.05). In patients with chronic hypocortisolism, GR-alpha mRNA expression was increased, and receptor numbers were increased (P < 0.05), whereas GR affinity was normal. No changes were observed in patients undergoing a metyrapone test. CONCLUSIONS: Cushing's syndrome is accompanied by a reversible decrease in GR affinity, possibly related to an increased GR-beta expression, which may be a compensatory mechanism to GC excess. In chronic hypocortisolism, adaptive changes in GR status seem to occur at the level of GR number.

Adult↗

PubMed2005

Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression.

CONTEXT: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively. OBJECTIVE AND DESIGN: We examined the basis of this altered GC sensitivity by expressing GR(N363S) and GR(ER22/23EK) in COS-1 cells and investigating their transactivating and transrepressing capacities using a GC response element-luciferase reporter and a p65-activated nuclear factor kappaB-luciferase reporter, respectively. Furthermore, we evaluated the transactivating and transrepressing capacities of the GR in peripheral blood mononuclear lymphocytes of homozygous and heterozygous carriers of these polymorphisms by determining the maximum effect of dexamethasone on transactivation of the GC-induced leucine-zipper and transinhibition of the IL-2 gene by means of real-time RT-PCR. RESULTS: The effects of the polymorphisms in the GR gene previously observed in population studies were also detected at the level of gene expression. The ER22/23EK polymorphism resulted in a significant reduction of transactivating capacity, in both transfection experiments (-14 +/- 5%, P < 0.05) and peripheral blood mononuclear lymphocytes of carriers of this polymorphism (homozygous: -48 +/- 6%, P < 0.01, n = 1; heterozygous: -21 +/- 4%, P = 0.08, n = 3). The N363S polymorphism, associated with increased GC sensitivity, resulted in a significantly increased transactivating capacity, both in vitro (8 +/- 3%; P < 0.02) and ex vivo (homozygous: 204 +/- 19%, P < 0.0001, n = 1; heterozygous: 124 +/- 8%, P = 0.05, n = 3). Neither the ER22/23EK nor the N363S polymorphism seemed to influence the transrepressing capacity of the GR. CONCLUSION: The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting.

Animals↗

PubMed2005

A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels.

CONTEXT: CYP3A7, expressed in the human fetal liver and normally silenced after birth, plays a major role in the 16alpha-hydroxylation of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and estrone. Due to a replacement of part of the CYP3A7 promoter with a sequence identical with the same region in the CYP3A4 promoter (referred to as CYP3A7*1C), some individuals still express a variant of the CYP3A7 gene later in life. OBJECTIVE: The objective of this study was to examine the effect of the CYP3A7*1C polymorphism on serum steroid hormone levels. DESIGN, SETTING, PARTICIPANTS: Two population-based cohort studies were performed. Study group 1 consisted of 208 subjects randomly selected from the Rotterdam Study, and study group 2 consisted of 345 elderly independently living men. MAIN OUTCOME MEASURES: Serum DHEA(S), androstenedione, estradiol, estrone, and testosterone levels were the main outcome measures. RESULTS: In study groups 1 and 2, heterozygous CYP3A7*1C carriers had almost 50% lower DHEAS levels compared with homozygous carriers of the reference allele [study group 1, 1.74 +/- 0.25 vs. 3.33 +/- 0.15 micromol/liter (P = 0.02); study group 2, 2.09 +/- 0.08 vs. 1.08 +/- 0.12 micromol/liter (P < 0.001)]. No differences in circulating DHEA, androstenedione, estradiol, or testosterone levels were found. However, in study group 2, serum estrone levels were lower in heterozygous CYP3A7*1C carriers compared with homozygous carriers of the reference allele (0.11 +/- 0.002 vs. 0.08 +/- 0.006 nmol/liter; P < 0.001). CONCLUSION: The CYP3A7*1C polymorphism causes the persistence of enzymatic activity of CYP3A7 during adult life, resulting in lower circulating DHEAS and estrone levels.

Aged↗

PubMed2005

Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality.

CONTEXT: Adequate adrenal function is pivotal to survive meningococcal sepsis. OBJECTIVES: The objective of the study was to evaluate adrenocortical function in meningococcal disease. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a university-affiliated pediatric intensive care unit. PATIENTS: Sixty children with meningococcal sepsis or septic shock participated in the study. MAIN OUTCOME MEASURES: The differences in adrenal function between nonsurvivors (n = 8), shock survivors (n = 43), and sepsis survivors (n = 9) on pediatric intensive care unit admission were measured. RESULTS: Nonsurvivors had significantly lower median cortisol to ACTH ratio than shock survivors and sepsis survivors. Because cortisol binding globulin and albumin levels did not significantly differ among the groups, bioavailable cortisol levels were also significantly lower in nonsurvivors than sepsis survivors. Nonsurvivors had significantly lower cortisol to 11-deoxycortisol ratios but not lower 11-deoxycortisol to 17-hydroxyprogesterone ratios than survivors. Using multiple regression analysis, decreased cortisol to ACTH ratio was significantly related to higher IL-6 levels and intubation with etomidate (one single bolus), whereas decreased cortisol to 11-deoxycortisol ratio was significantly related only to intubation with etomidate. Aldosterone levels tended to be higher in nonsurvivors than shock survivors, whereas plasma renin activity did not significantly differ. CONCLUSIONS: Our study shows that the most severely ill children with septic shock had signs of adrenal insufficiency. Bioavailable cortisol levels were not more informative on adrenal function than total cortisol levels. Besides disease severity, one single bolus of etomidate during intubation was related to decreased adrenal function and 11beta-hydroxylase activity. Decreased adrenal function was not related to decreased 21-hydroxylase activity. Based on our results, it seems of vital importance to take considerable caution using etomidate and consider combining its administration with glucocorticoids during intubation of children with septic shock.

17-alpha-Hydroxyprogesterone↗