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Frontiers in Pharmacology, 2022
Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhoo... more Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously c...
Springer Reference Medizin, Nov 17, 2019
n = 272. After two years ’ GH treatment, change in height standard deviation score (SDS) was +1.0... more n = 272. After two years ’ GH treatment, change in height standard deviation score (SDS) was +1.03 in SGA and +0.84 in ISS vs. +0.97 in IGHD (p = 0.047; p< 0.001 vs. IGHD, respectively). Height gain was comparable between IGHD and MPHD. In pre-pubertal children vs. total population, height SDS change after two years was: IGHD, +1.24 vs. +0.97; SGA, +1.17 vs. +1.03; ISS, +1.04 vs. +0.84; and MPHD, +1.16 vs. +0.99 (all p< 0.001). Conclusions: After two years ’ GH treatment, change in height SDS was greater in SGA and less in ISS, compared with IGHD; the discrepancy in responses may be due to the disease nature or confounders (i.e. age). Height SDS increase was greatest in pre-pubertal children, supporting early treatment initiation to optimize growth outcomes.
Endocrine Abstracts, 2018
Nature medicine, Jan 7, 2018
Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe ob... more Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.
The Journal of clinical endocrinology and metabolism, Jan 9, 2018
The optimal levothyroxine (LT4) dose required to treat congenital hypothyroidism (CH) remains unc... more The optimal levothyroxine (LT4) dose required to treat congenital hypothyroidism (CH) remains unclear, with a debate if higher starting doses (>10µg/kg) are necessary and safe for normal Intelligence Quotient (IQ). To examine the psychomotor, metabolic and quality of life outcome in patients with CH treated with a mean high initial LT4 dose. A cross- sectional cohort study of CH patients identified in the Berlin newborn screening programme from 1979-2003. Total of 76 CH patients (mean age 18 years, mean initial LT4 dose 13.5µg/kg) and 40 siblings completed the study. Psychomotor (Wechsler Intelligence Test, CNS Vital Signs), quality of life (QoL, SF 36 Health Survey), anthropometric (BMI, height) and metabolic (Intima Media Thickness, laboratory parameters) outcomes were compared to healthy siblings. Mean values and percentage of episodes of elevated T4, T3 and suppressed TSH before age two years were analysed. A meta- analysis of treatment CH studies was performed. There were no...
Journal of the Endocrine Society, 2017
Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing h... more Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). Objective: To determine the role of LHCGR in transient, pregnancy-induced CS. Design, Setting, Patient, and Intervention: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. Main Outcome Measures and Results: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)-increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone-positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R.
Das Gesundheitswesen, 2013
ABSTRACT 10 of the 13 federal states presented their structures, implementation methods and resul... more ABSTRACT 10 of the 13 federal states presented their structures, implementation methods and results as part of the nationwide workshop for children's preventative medicine and early recognition projects for Germany on 9th September 2011 in Frankfurt am Main. This was the first time a full overview of all programmes of this kind in Germany has been possible. The programmes and data from these 10 presentations were analysed and compared. Despite the many differences between the legal frameworks and structural implementation, the programmes also displayed similarities in the implementation and in the problems which arise. Significantly improved participation rates for early recognition check-ups have been achieved in the context of the programmes. Previously, only a few detailed evaluations for the detection of risks to children's welfare and other effects such as vaccination rates and improvements in children's health through more advice and care were available.
Endocrine Abstracts, 2021
European Journal of Endocrinology, 2022
Objectives International guidelines recommend additional salt supplementation during infancy in c... more Objectives International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0–3 years. Methods Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5–4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were o...
Pädiatrische Endokrinologie und Diabetologie, 2018
Context: Alkindi® (Hydrocortisone granules in capsules for opening), was developed by Diurnal Ltd... more Context: Alkindi® (Hydrocortisone granules in capsules for opening), was developed by Diurnal Ltd., a pharmaceutical company developing endocrine products, and was recently licensed for oral administration to children with adrenal insufficiency (AI) from birth to 18 years. Previously, children received pharmacy compounded capsules to achieve age appropriate dosing, however almost 25% of batches were out of specification for mass and content uniformity and clinically evident underand over-dosing was reported.
Hormone Research in Paediatrics, 2017
Objectives: Physiological replacement is important for optimal control of congenital adrenal hype... more Objectives: Physiological replacement is important for optimal control of congenital adrenal hyperplasia (CAH). We examined glucocorticoid and mineralocorticoid replacement in children and adults with CAH. Methods: Data were extracted in February 2017 for 22 centres in 14 countries from the international I-CAH registry (www.i-cah.org). 1501 events from 269 patients seen between 1987 and 2017 were analyzed.
Frontiers in Pharmacology, 2022
Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhoo... more Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously c...
Springer Reference Medizin, Nov 17, 2019
n = 272. After two years ’ GH treatment, change in height standard deviation score (SDS) was +1.0... more n = 272. After two years ’ GH treatment, change in height standard deviation score (SDS) was +1.03 in SGA and +0.84 in ISS vs. +0.97 in IGHD (p = 0.047; p< 0.001 vs. IGHD, respectively). Height gain was comparable between IGHD and MPHD. In pre-pubertal children vs. total population, height SDS change after two years was: IGHD, +1.24 vs. +0.97; SGA, +1.17 vs. +1.03; ISS, +1.04 vs. +0.84; and MPHD, +1.16 vs. +0.99 (all p< 0.001). Conclusions: After two years ’ GH treatment, change in height SDS was greater in SGA and less in ISS, compared with IGHD; the discrepancy in responses may be due to the disease nature or confounders (i.e. age). Height SDS increase was greatest in pre-pubertal children, supporting early treatment initiation to optimize growth outcomes.
Endocrine Abstracts, 2018
Nature medicine, Jan 7, 2018
Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe ob... more Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.
The Journal of clinical endocrinology and metabolism, Jan 9, 2018
The optimal levothyroxine (LT4) dose required to treat congenital hypothyroidism (CH) remains unc... more The optimal levothyroxine (LT4) dose required to treat congenital hypothyroidism (CH) remains unclear, with a debate if higher starting doses (>10µg/kg) are necessary and safe for normal Intelligence Quotient (IQ). To examine the psychomotor, metabolic and quality of life outcome in patients with CH treated with a mean high initial LT4 dose. A cross- sectional cohort study of CH patients identified in the Berlin newborn screening programme from 1979-2003. Total of 76 CH patients (mean age 18 years, mean initial LT4 dose 13.5µg/kg) and 40 siblings completed the study. Psychomotor (Wechsler Intelligence Test, CNS Vital Signs), quality of life (QoL, SF 36 Health Survey), anthropometric (BMI, height) and metabolic (Intima Media Thickness, laboratory parameters) outcomes were compared to healthy siblings. Mean values and percentage of episodes of elevated T4, T3 and suppressed TSH before age two years were analysed. A meta- analysis of treatment CH studies was performed. There were no...
Journal of the Endocrine Society, 2017
Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing h... more Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). Objective: To determine the role of LHCGR in transient, pregnancy-induced CS. Design, Setting, Patient, and Intervention: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. Main Outcome Measures and Results: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)-increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone-positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R.
Das Gesundheitswesen, 2013
ABSTRACT 10 of the 13 federal states presented their structures, implementation methods and resul... more ABSTRACT 10 of the 13 federal states presented their structures, implementation methods and results as part of the nationwide workshop for children's preventative medicine and early recognition projects for Germany on 9th September 2011 in Frankfurt am Main. This was the first time a full overview of all programmes of this kind in Germany has been possible. The programmes and data from these 10 presentations were analysed and compared. Despite the many differences between the legal frameworks and structural implementation, the programmes also displayed similarities in the implementation and in the problems which arise. Significantly improved participation rates for early recognition check-ups have been achieved in the context of the programmes. Previously, only a few detailed evaluations for the detection of risks to children's welfare and other effects such as vaccination rates and improvements in children's health through more advice and care were available.
Endocrine Abstracts, 2021
European Journal of Endocrinology, 2022
Objectives International guidelines recommend additional salt supplementation during infancy in c... more Objectives International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0–3 years. Methods Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5–4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were o...
Pädiatrische Endokrinologie und Diabetologie, 2018
Context: Alkindi® (Hydrocortisone granules in capsules for opening), was developed by Diurnal Ltd... more Context: Alkindi® (Hydrocortisone granules in capsules for opening), was developed by Diurnal Ltd., a pharmaceutical company developing endocrine products, and was recently licensed for oral administration to children with adrenal insufficiency (AI) from birth to 18 years. Previously, children received pharmacy compounded capsules to achieve age appropriate dosing, however almost 25% of batches were out of specification for mass and content uniformity and clinically evident underand over-dosing was reported.
Hormone Research in Paediatrics, 2017
Objectives: Physiological replacement is important for optimal control of congenital adrenal hype... more Objectives: Physiological replacement is important for optimal control of congenital adrenal hyperplasia (CAH). We examined glucocorticoid and mineralocorticoid replacement in children and adults with CAH. Methods: Data were extracted in February 2017 for 22 centres in 14 countries from the international I-CAH registry (www.i-cah.org). 1501 events from 269 patients seen between 1987 and 2017 were analyzed.