Ferdinand Roelfsema - Academia.edu (original) (raw)
Papers by Ferdinand Roelfsema
The Journal of Clinical Endocrinology & Metabolism, 2016
Context: Optimal blood sampling schemas of GH for the estimation of the 24-hour secretion rate ha... more Context: Optimal blood sampling schemas of GH for the estimation of the 24-hour secretion rate have not been established in acromegalic patients. Objective: By censoring available 24-hour GH serum profiles, we investigated the reliability of such simplified schemas. Design, Subjects, and Methods: We used 24-hour serum GH concentration profiles obtained with 10-minute sampling in a large cohort of healthy subjects (n ϭ 130; mean age, 42; range, 18-77 years) and acromegalic patients (n ϭ 87; mean age, 48; range 18-72 years). Patient categories were active disease, surgically cured, and somatostatin analog-treated individuals. The regression coefficients of determination (R 2) and the linear slopes () between 24-hour secretion rates or mean concentrations (144 samples) on the one hand and mean values with less frequent sampling on the other, decreased in controls and in patients a short (1-2 weeks) or long (2-5 years) time after successful surgery. By contrast, the regression parameters remained essentially unchanged in patients with active acromegaly and those under GH suppressive treatment. Excellent correlations (R 2 Ն 0.90) without GH underestimation existed between mean GH of daytime profiles and mean GH of 24-hour profiles and GH secretion rates estimated by deconvolution in patients with active acromegaly and patients treated with somatostatin analogs. Conclusion: Simplified sampling schemes, particularly a day profile, can be used for the estimation of GH secretion in patients with active acromegaly and under medical treatment. However, in healthy controls and patients after successful surgery, prolonged and frequent sampling schemes, at least at 2-hour intervals, reliably reflect 24-hour secretion.
Neuroendocrinology, 2015
Background: Studies on 24-hour growth hormone (GH) secretion are rare. The influences of sex, age... more Background: Studies on 24-hour growth hormone (GH) secretion are rare. The influences of sex, age, and adiposity are well recognized but generally derived from specific, selected subject groups, not spanning sexes, many age decades, and a range of body weights. Objective: Our goal was to investigate GH dynamics in a group of 130 healthy adult subjects, both men and women, across 5 age decades as well as a 2.5-fold range of body mass index (BMI) values. Methods: GH was measured by a sensitive immunofluorometric assay. Secretion parameters were quantified by automated deconvolution and relative pattern randomness by approximate entropy (ApEn). Results: The median age was 40 years (range 20-77). The median BMI was 26 (range 18.3-49.8). Pulsatile 24-hour GH secretion was negatively correlated with age (p = 0.002) and BMI (p < 0.0001). Basal GH secretion negatively correlated with BMI (p = 0.003) but not with age. The sex- dependent GH secretion (greater in women) was no longer detect...
Pituitary, 2018
In rare disease research, most randomized prospective clinical trials can only use limited number... more In rare disease research, most randomized prospective clinical trials can only use limited number of patients and are comprised of highly heterogeneous populations. Therefore, it is crucial to report the results in such a manner that it allows for comparison of treatment effectiveness and biochemical control between studies. The aim of this review was to investigate the current methods that are being applied to measure and report growth hormone (GH) and insulin-like growth factor-1 (IGF-1) as markers for drug effectiveness in clinical acromegaly research. A systematic search of recent prospective and retrospective studies, published between 2012 and 2017, that studied the effects of somatostatin analogues or dopamine agonists in acromegaly patients was performed. The markers of interest were GH, IGF-1, and the suppression of GH after an oral glucose tolerance test (OGTT). Additionally, the use of pharmacokinetic (PK) measurements in these studies was analyzed. The sampling design, c...
Journal of the Endocrine Society, 2018
Controlled, blinded studies of sex-hormone replacement in postmenopausal women using natural estr... more Controlled, blinded studies of sex-hormone replacement in postmenopausal women using natural estradiol (E) and native progesterone (P) are few. To delineate the effect of E alone or with P on lipids and inflammatory markers. A placebo-controlled, double-masked, prospectively randomized study of 40 healthy, postmenopausal volunteers assigned to four treatment groups: placebo, intramuscular E, and/or micronized oral P for 23 (±2) days. Treatment with E alone compared with placebo lowered total cholesterol (TC; = 0.006), non-high-density lipoprotein cholesterol (nonHDL-C; = 0.004), low-density lipoprotein cholesterol (LDL-C; = 0.012), and apolipoprotein B (Apo B; = 0.02) levels, and raised HDL-C levels ( = 0.03 the 3 other groups). Conversely, addition of P to E reduced HDL-C levels ( = 0.015). Triglyceride concentrations manifested no effect on E or P. High-sensitivity C-reactive protein (hsCRP) level was highest in women with E and P replacement ( = 0.018 placebo). Leptin and IL-6 co...
The Journal of clinical endocrinology and metabolism, Jan 18, 2018
Sex steroids regulate growth hormone (GH) secretion in men and women. Testosterone (T) increases ... more Sex steroids regulate growth hormone (GH) secretion in men and women. Testosterone (T) increases GH secretion in older men with a relative lack of T, in hypogonadal men of all ages, and in patients undergoing gender reassignment. The role of estradiol (E2) in men less well defined. The goal is to assess the contribution of aromatization of testosterone to spontaneous nocturnal and stimulated GH secretion. Four groups of healthy older men (N = 74, age range 57-77 yr) were studied. The gonadotropic axis was clamped with the gonadotropin-releasing hormone antagonist, degarelix. Three groups received T and one group placebo addback. Two T-replaced groups were treated with anastrozole (an aromatase inhibitor) and either placebo or E2 addback. Ten-min GH concentration profiles were quantified by deconvolution analysis, after (1) overnight (2200-0800 h) sampling, and (2) (i) combined iv injection of GH-releasing hormone [GHRH] (0.3 µg/kg) and GH-releasing peptide-2 [GHRH-2] (0.3 µg/kg), an...
Journal of the Endocrine Society, 2018
Experimentally controlled studies of estrogenic regulation of lipid measures and inflammatory cyt... more Experimentally controlled studies of estrogenic regulation of lipid measures and inflammatory cytokines in men are rare. To delineate the effect of estradiol (E) on lipids and inflammatory markers. This was a placebo-controlled, single-masked, prospectively randomized study comprising experimentally degarelix-downregulated healthy men [n = 74; age 65 years (range, 57 to 77)] assigned to four treatment groups: (1) IM saline and oral placebo; (2) IM testosterone and oral placebo; (3) IM testosterone and oral anastrozole (aromatase inhibitor); and (4) IM testosterone, oral anastrozole, and transdermal E for 22 (±1) days. Mean mass spectrometry-quantified serum E concentrations ranged from 1.2 to 82 pg/mL in the four treatment groups. E extremes did not alter total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol (HDL-C) , non-HDL-C, apolipoprotein B, lipoprotein (a), IL-6, or high-sensitivity C-reactive protein (hsCRP) concentra...
Journal of medical genetics, 2018
Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but... more Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and and mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. We found mutations in the insulin receptor substrate 4 () gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers...
Bone, Jan 3, 2018
The process of bone turnover displays variations over 24 h, with C-terminal cross-linked telopept... more The process of bone turnover displays variations over 24 h, with C-terminal cross-linked telopeptide of type 1 collagen (CTX) and osteocalcin exhibiting a nadir in the afternoon and a peak in the night. In contrast, N-terminal propeptide of type 1 procollagen (P1NP) did not display an apparent 24-hour rhythm. Other emerging novel biomarkers of bone, sclerostin and Dickkopf-related protein 1 (DKK1), are markers of osteocyte activity with limited data available regarding their 24-hour profiles. In this study, we aimed to extend available data on 24-hour profiles of CTX, osteocalcin, and P1NP and to assess the 24-hour profiles of sclerostin and DKK1 in healthy older men and women and to compare these between men and women. We measured these five bone markers in EDTA plasma collected every 4 h during 24 h in 37 healthy older men and women (range 52-76 years). Differences between time points were determined using repeated measures ANOVA and cosinor analyses were performed to determine ci...
Endocrine connections, Jan 31, 2017
Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol lev... more Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol levels, often restricted to one or a few samples, are well recognized, but conflicting. To investigate cortisol dynamics in 143 healthy men and women, spanning 7 decades and with a 2-fold body mass index (BMI) range with different analytic tools. Clinical Research Unit. Cortisol concentrations in 10-min samples collected for 24 h. Outcomes were mean levels, deconvolution parameters, approximate entropy (ApEn, regularity statistic), and 24-h rhythms. Mean 24-h cortisol concentrations were lower in premenopausal women than men of comparable age (176±8.2 vs 217± 9.4 nmol/L, P=0.02), but not in subjects older than 50 y. This was due to lower daytime levels in women, albeit similar in the quiescent overnight period. Aging increased mean cortisol by 10 nmol/L per decade during the quiescent secretory phase, and advanced the acrophase of the diurnal rhythm by 24 min/decade. However, total 24-h cor...
The Journal of clinical endocrinology and metabolism, Jul 28, 2017
Studies of ACTH secretion are hampered by unobservable hypothalamic CRH and AVP pulses. Clamping ... more Studies of ACTH secretion are hampered by unobservable hypothalamic CRH and AVP pulses. Clamping one of the secretagogues could allow indirect quantification of the impact of the endogenous heterotypic hormone. Randomized, double-blind, placebo-controlled cross-over study in 28 healthy adults (16 men), mean age 55 yr. Volunteers received leuprolide, followed by placebo or sex-steroid addback. Eucortisolemia was accomplished by oral ketoconazole and continuous iv cortisol administration with 10 h of 10-min sampling. To clamp secretagogue inputs overnight double-blind continuous iv infusions of CRH, AVP, both peptides, or saline were employed, followed by a single bolus dose of the non-infused peptide with blood sampling for 2.5 h. Mean ± SEM 10-h ACTH concentrations (ng/L) in the gender-combined analysis were: saline 32±4.6, AVP 29±4.6, CRH 67±6.2 and CRH-AVP 67±8.8: CRH vs AVP, P<0.0001. Mean 10-h cortisol was higher in women than men (P<0.0001), and higher during CRH than AVP...
The Journal of clinical endocrinology and metabolism, Jul 27, 2017
Exercise elicits incompletely defined adaptations of metabolic and endocrine milieu, including th... more Exercise elicits incompletely defined adaptations of metabolic and endocrine milieu, including the gonadotropic and the corticotropic axes. To quantify the impact of acute exercise on coordinate LH and testosterone and ACTH and cortisol secretion in healthy men in relation to age. Prospectively randomized, within-subject cross-over, study in 23 men, aged 19-77 yr. Subjects underwent rest and 30 min of mixed exercise at 65% of maximal aerobic capacity with 10-min blood sampling between 0700 and 1300 h 2 wks apart. Incremental changes in LH, testosterone, ACTH and cortisol concentrations, the feedforward and feedback strength between exercise and rest, quantified by approximate entropy (ApEn), and bihormonal synchrony, quantitated by cross ApEn. Mean hourly exercise-minus-rest LH and ACTH increments increased from -0.055±0.187 to 0.755±0.245 IU/L (P=0.003), and from 2.9±2.2 to 71.2±16.1 ng/L (P<0.0001), respectively, during exercise. Testosterone and cortisol increments increased c...
Frontiers in endocrinology, 2016
A trade-off between fertility and longevity possibly exists. The association of the male hypothal... more A trade-off between fertility and longevity possibly exists. The association of the male hypothalamic-pituitary-gonadal (HPG) axis with familial longevity has not yet been investigated. To study 24-h hormone concentration profiles of the HPG axis in men enriched for familial longevity and controls. We frequently sampled blood over 24 h in 10 healthy middle-aged male offspring of nonagenarian participants from the Leiden Longevity Study together with 10 male age-matched controls. Individual 24-h luteinizing hormone (LH) and testosterone concentration profiles were analyzed by deconvolution analyses to estimate secretion parameters. Furthermore, the temporal relationship between LH and testosterone was assessed by cross-correlation analysis. We used (cross-)approximate entropy to quantify the strength of feedback and/or feedforward control of LH and testosterone secretion. Mean [95% confidence interval (CI)] total LH secretion of the offspring was 212 (156-268) U/L/24 h, which did not...
Expert Review of Endocrinology & Metabolism, 2015
Acromegaly is an insidious disease of the pituitary caused by a growth hormone-secreting adenoma.... more Acromegaly is an insidious disease of the pituitary caused by a growth hormone-secreting adenoma. Generally, the diagnosis is made rather late in the course of the disease. Currently, acromegaly can be cured in about half of the patients with the disease by expert surgery. The remainder of non-surgically cured patients often can be effectively treated with somatostatin analogs; either with the new generation of dopaminergic drugs or with Pegvisomant, a GH-receptor blocking agent. However, at the time of diagnosis many patients suffer from serious comorbidities, including hypertension, heart disease, arthrosis, sleep apnea and diabetes mellitus. Recent reports have shown that mortality risk can be normalized. Nevertheless, all efforts should be undertaken to treat comorbidities. New strategies for surgery and medical treatment are discussed.
Sex-Steroid Interactions with Growth Hormone, 1999
Growth hormone (GH) plays a crucial role in postnatal growth. Disorders in the molecular processi... more Growth hormone (GH) plays a crucial role in postnatal growth. Disorders in the molecular processing of GH, its secretion, or its peripheral tissue effects result in short stature. GH replacement therapy has been used for more than three decades in children. Initially, however, only moderate success was observed in terms of ultimate height, mainly because of the limited supply of GH. With the unlimited availability of recombinant human GH (rhGH), treatment became more efficient, with most GH-deficient children reaching their target height. Pediatric endocri- nologists targeted GH therapy on final height and stopped treatment when this goal was reached. However, clinical observations revealed that GH deficiency (GHD) in adults was associated with nonspecific signs and symptoms, including increased fat mass, reduced lean body mass and muscle strength, decreased extracellular water, decreased bone density, poor physical performance, and impaired sense of well-being. The first recorded GH substitution therapy in the adult human was reported by Raben (1). About 25 years later, the first results in groups of adults with GHD were published (2,3). Both studies provided strong evidence that GH treatment in adults with GHD has beneficial effects on body composition, quality of life, and bone mass.
Acromegaly: Diagnosis & Treatment, 2013
Journal of the Endocrine Society, 2018
Estrogens amplify spontaneous and stimulated growth hormone (GH) secretion, whereas they diminish... more Estrogens amplify spontaneous and stimulated growth hormone (GH) secretion, whereas they diminish GH-dependent insulin-like growth factor (IGF)-I in a dose-dependent manner. Selective estrogen receptor modulators (SERMs), including tamoxifen and toremifene, are widely adjunctively used in breast and prostate cancer. Although some endocrine effects of tamoxifen are known, few data are available for toremifene. To explore sex-dependent effects of toremifene on spontaneous 10-hour overnight GH secretion, followed by GH-releasing hormone-ghrelin stimulation. Additionally, effects on IGF-I, its binding proteins, and sex hormone-binding globulin (SHBG) were quantified. Twenty men and 20 women, within an allowable age range of 50 to 80 years, volunteered for this double-blind, placebo-controlled prospective crossover study. Ten-minute blood sampling was done for 10 hours overnight and then for 2 hours after combined GH-releasing hormone-ghrelin injection. Pulsatile GH and stimulated GH sec...
Aging Cell, 2016
Reduced growth hormone (GH) signaling has been consistently associated with increased health and ... more Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128-216) mU L(-1) ] compared with controls [238 (193-284) mU L(-1) ]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39-0.53)] compared with controls [0.66 (0.56-0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.
The Journal of Clinical Endocrinology and Metabolism, 2010
Twenty-four-hour TSH secretion profiles in primary hypothyroidism have been analyzed with methods... more Twenty-four-hour TSH secretion profiles in primary hypothyroidism have been analyzed with methods no longer in use. The insights afforded by earlier methods are limited. We studied TSH secretion in patients with primary hypothyroidism (eight patients with severe and eight patients with mild hypothyroidism) with up-to-date analytical tools and compared the results with outcomes in 38 healthy controls. Patients and controls underwent a 24-h study with 10-min blood sampling. TSH data were analyzed with a newly developed automated deconvolution program, approximate entropy, spikiness assessment, and cosinor regression. Both basal and pulsatile TSH secretion rates were increased in hypothyroid patients, the latter by increased burst mass with unchanged frequency. Secretory regularity (approximate entropy) was diminished, and spikiness was increased only in patients with severe hypothyroidism. A diurnal TSH rhythm was present in all but two patients, although with an earlier acrophase in severe hypothyroidism. The estimated slow component of the TSH half-life was shortened in all patients. Increased TSH concentrations in hypothyroidism are mediated by amplification of basal secretion and burst size. Secretory abnormalities quantitated by approximate entropy and spikiness were only present in patients with severe disease and thus are possibly related to the increased thyrotrope cell mass.
The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013
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Clin Endocrinol, 2001
Several studies have established that in treated acromegaly mortality is only normalized in patie... more Several studies have established that in treated acromegaly mortality is only normalized in patients achieving a serum GH concentration below 5 mU/l. Few studies however, have addressed results of radiotherapy using this strict criterion. The aim of our study was to assess the efficacy of postoperative radiotherapy in reducing serum GH concentration below 5 mU/l. Forty acromegalic patients who underwent radiotherapy for postoperative persistent disease after transsphenoidal surgery were studied. Mean time of follow-up after radiotherapy was 123+/-11.1 months. A serum GH concentration of <5 mU/l was used to define remission. Following surgery mean GH concentration decreased from 120.8+/-21 mU/l to 24.4+/-5.2 mU/l and mean GH concentration prior to radiotherapy, administered after a mean of 8.2+/-2.7 (0.5-96) months postoperatively was 26.0+/-5.1 mU/l. Using individual regression plots, GH was reduced to 50% by radiotherapy after a mean of 27+/-5 months (range 3-105 months). The observed mean GH concentration as measured at follow-up visits was reduced by 55% (-36-95%) after the first year, by 65% (-29-97.3%) after 2 years and by 78% (-29-99%) after 5 years. We could not demonstrate a significant correlation between a normalized GH concentration on the one hand and tumour size, preradiotherapy GH concentration or duration of follow-up on the other hand. During follow-up, GH-suppressive medical therapy was used in 11 patients, five of whom were still using medication at the end of follow-up. Eight patients had a follow-up of less than 5 years and three of them had a serum GH concentration of <5 mU/l at their latest follow-up visit (38%). At 5 years of follow-up after radiotherapy, 24 out of 32 patients had a GH level of <5 mU/l without medication (75%). At 10 years following irradiation, 16 of 21 patients (76%) had a GH level of <5 mU/l without medical treatment. At 15 years follow-up, a serum GH concentration of <5 mU/l was observed in 13 out of 15 patients (87%) without GH suppressive medication. At the latest follow-up visit, serum GH concentration below 5 mU/l was present in 75% of patients (30 out of 40) without medical therapy after a mean of 10.4+/-0.9 years, but five patients required octreotide up to the end of follow-up. Twenty-seven out of 37 patients with available IGF-I data had normal IGF-I at the end of follow-up (73%). Fifty percent of patients needed substitution therapy for (partial) hypopituitarism after 10 years and 75% after 15 years of radiotherapy. In our group of patients who were incompletely cured by surgery, but had a significant postoperative decrease of serum GH concentrations, radiotherapy was able to achieve 'safe' serum GH concentrations in the majority in the long term.
The Journal of Clinical Endocrinology & Metabolism, 2016
Context: Optimal blood sampling schemas of GH for the estimation of the 24-hour secretion rate ha... more Context: Optimal blood sampling schemas of GH for the estimation of the 24-hour secretion rate have not been established in acromegalic patients. Objective: By censoring available 24-hour GH serum profiles, we investigated the reliability of such simplified schemas. Design, Subjects, and Methods: We used 24-hour serum GH concentration profiles obtained with 10-minute sampling in a large cohort of healthy subjects (n ϭ 130; mean age, 42; range, 18-77 years) and acromegalic patients (n ϭ 87; mean age, 48; range 18-72 years). Patient categories were active disease, surgically cured, and somatostatin analog-treated individuals. The regression coefficients of determination (R 2) and the linear slopes () between 24-hour secretion rates or mean concentrations (144 samples) on the one hand and mean values with less frequent sampling on the other, decreased in controls and in patients a short (1-2 weeks) or long (2-5 years) time after successful surgery. By contrast, the regression parameters remained essentially unchanged in patients with active acromegaly and those under GH suppressive treatment. Excellent correlations (R 2 Ն 0.90) without GH underestimation existed between mean GH of daytime profiles and mean GH of 24-hour profiles and GH secretion rates estimated by deconvolution in patients with active acromegaly and patients treated with somatostatin analogs. Conclusion: Simplified sampling schemes, particularly a day profile, can be used for the estimation of GH secretion in patients with active acromegaly and under medical treatment. However, in healthy controls and patients after successful surgery, prolonged and frequent sampling schemes, at least at 2-hour intervals, reliably reflect 24-hour secretion.
Neuroendocrinology, 2015
Background: Studies on 24-hour growth hormone (GH) secretion are rare. The influences of sex, age... more Background: Studies on 24-hour growth hormone (GH) secretion are rare. The influences of sex, age, and adiposity are well recognized but generally derived from specific, selected subject groups, not spanning sexes, many age decades, and a range of body weights. Objective: Our goal was to investigate GH dynamics in a group of 130 healthy adult subjects, both men and women, across 5 age decades as well as a 2.5-fold range of body mass index (BMI) values. Methods: GH was measured by a sensitive immunofluorometric assay. Secretion parameters were quantified by automated deconvolution and relative pattern randomness by approximate entropy (ApEn). Results: The median age was 40 years (range 20-77). The median BMI was 26 (range 18.3-49.8). Pulsatile 24-hour GH secretion was negatively correlated with age (p = 0.002) and BMI (p < 0.0001). Basal GH secretion negatively correlated with BMI (p = 0.003) but not with age. The sex- dependent GH secretion (greater in women) was no longer detect...
Pituitary, 2018
In rare disease research, most randomized prospective clinical trials can only use limited number... more In rare disease research, most randomized prospective clinical trials can only use limited number of patients and are comprised of highly heterogeneous populations. Therefore, it is crucial to report the results in such a manner that it allows for comparison of treatment effectiveness and biochemical control between studies. The aim of this review was to investigate the current methods that are being applied to measure and report growth hormone (GH) and insulin-like growth factor-1 (IGF-1) as markers for drug effectiveness in clinical acromegaly research. A systematic search of recent prospective and retrospective studies, published between 2012 and 2017, that studied the effects of somatostatin analogues or dopamine agonists in acromegaly patients was performed. The markers of interest were GH, IGF-1, and the suppression of GH after an oral glucose tolerance test (OGTT). Additionally, the use of pharmacokinetic (PK) measurements in these studies was analyzed. The sampling design, c...
Journal of the Endocrine Society, 2018
Controlled, blinded studies of sex-hormone replacement in postmenopausal women using natural estr... more Controlled, blinded studies of sex-hormone replacement in postmenopausal women using natural estradiol (E) and native progesterone (P) are few. To delineate the effect of E alone or with P on lipids and inflammatory markers. A placebo-controlled, double-masked, prospectively randomized study of 40 healthy, postmenopausal volunteers assigned to four treatment groups: placebo, intramuscular E, and/or micronized oral P for 23 (±2) days. Treatment with E alone compared with placebo lowered total cholesterol (TC; = 0.006), non-high-density lipoprotein cholesterol (nonHDL-C; = 0.004), low-density lipoprotein cholesterol (LDL-C; = 0.012), and apolipoprotein B (Apo B; = 0.02) levels, and raised HDL-C levels ( = 0.03 the 3 other groups). Conversely, addition of P to E reduced HDL-C levels ( = 0.015). Triglyceride concentrations manifested no effect on E or P. High-sensitivity C-reactive protein (hsCRP) level was highest in women with E and P replacement ( = 0.018 placebo). Leptin and IL-6 co...
The Journal of clinical endocrinology and metabolism, Jan 18, 2018
Sex steroids regulate growth hormone (GH) secretion in men and women. Testosterone (T) increases ... more Sex steroids regulate growth hormone (GH) secretion in men and women. Testosterone (T) increases GH secretion in older men with a relative lack of T, in hypogonadal men of all ages, and in patients undergoing gender reassignment. The role of estradiol (E2) in men less well defined. The goal is to assess the contribution of aromatization of testosterone to spontaneous nocturnal and stimulated GH secretion. Four groups of healthy older men (N = 74, age range 57-77 yr) were studied. The gonadotropic axis was clamped with the gonadotropin-releasing hormone antagonist, degarelix. Three groups received T and one group placebo addback. Two T-replaced groups were treated with anastrozole (an aromatase inhibitor) and either placebo or E2 addback. Ten-min GH concentration profiles were quantified by deconvolution analysis, after (1) overnight (2200-0800 h) sampling, and (2) (i) combined iv injection of GH-releasing hormone [GHRH] (0.3 µg/kg) and GH-releasing peptide-2 [GHRH-2] (0.3 µg/kg), an...
Journal of the Endocrine Society, 2018
Experimentally controlled studies of estrogenic regulation of lipid measures and inflammatory cyt... more Experimentally controlled studies of estrogenic regulation of lipid measures and inflammatory cytokines in men are rare. To delineate the effect of estradiol (E) on lipids and inflammatory markers. This was a placebo-controlled, single-masked, prospectively randomized study comprising experimentally degarelix-downregulated healthy men [n = 74; age 65 years (range, 57 to 77)] assigned to four treatment groups: (1) IM saline and oral placebo; (2) IM testosterone and oral placebo; (3) IM testosterone and oral anastrozole (aromatase inhibitor); and (4) IM testosterone, oral anastrozole, and transdermal E for 22 (±1) days. Mean mass spectrometry-quantified serum E concentrations ranged from 1.2 to 82 pg/mL in the four treatment groups. E extremes did not alter total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol (HDL-C) , non-HDL-C, apolipoprotein B, lipoprotein (a), IL-6, or high-sensitivity C-reactive protein (hsCRP) concentra...
Journal of medical genetics, 2018
Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but... more Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and and mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. We found mutations in the insulin receptor substrate 4 () gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers...
Bone, Jan 3, 2018
The process of bone turnover displays variations over 24 h, with C-terminal cross-linked telopept... more The process of bone turnover displays variations over 24 h, with C-terminal cross-linked telopeptide of type 1 collagen (CTX) and osteocalcin exhibiting a nadir in the afternoon and a peak in the night. In contrast, N-terminal propeptide of type 1 procollagen (P1NP) did not display an apparent 24-hour rhythm. Other emerging novel biomarkers of bone, sclerostin and Dickkopf-related protein 1 (DKK1), are markers of osteocyte activity with limited data available regarding their 24-hour profiles. In this study, we aimed to extend available data on 24-hour profiles of CTX, osteocalcin, and P1NP and to assess the 24-hour profiles of sclerostin and DKK1 in healthy older men and women and to compare these between men and women. We measured these five bone markers in EDTA plasma collected every 4 h during 24 h in 37 healthy older men and women (range 52-76 years). Differences between time points were determined using repeated measures ANOVA and cosinor analyses were performed to determine ci...
Endocrine connections, Jan 31, 2017
Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol lev... more Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol levels, often restricted to one or a few samples, are well recognized, but conflicting. To investigate cortisol dynamics in 143 healthy men and women, spanning 7 decades and with a 2-fold body mass index (BMI) range with different analytic tools. Clinical Research Unit. Cortisol concentrations in 10-min samples collected for 24 h. Outcomes were mean levels, deconvolution parameters, approximate entropy (ApEn, regularity statistic), and 24-h rhythms. Mean 24-h cortisol concentrations were lower in premenopausal women than men of comparable age (176±8.2 vs 217± 9.4 nmol/L, P=0.02), but not in subjects older than 50 y. This was due to lower daytime levels in women, albeit similar in the quiescent overnight period. Aging increased mean cortisol by 10 nmol/L per decade during the quiescent secretory phase, and advanced the acrophase of the diurnal rhythm by 24 min/decade. However, total 24-h cor...
The Journal of clinical endocrinology and metabolism, Jul 28, 2017
Studies of ACTH secretion are hampered by unobservable hypothalamic CRH and AVP pulses. Clamping ... more Studies of ACTH secretion are hampered by unobservable hypothalamic CRH and AVP pulses. Clamping one of the secretagogues could allow indirect quantification of the impact of the endogenous heterotypic hormone. Randomized, double-blind, placebo-controlled cross-over study in 28 healthy adults (16 men), mean age 55 yr. Volunteers received leuprolide, followed by placebo or sex-steroid addback. Eucortisolemia was accomplished by oral ketoconazole and continuous iv cortisol administration with 10 h of 10-min sampling. To clamp secretagogue inputs overnight double-blind continuous iv infusions of CRH, AVP, both peptides, or saline were employed, followed by a single bolus dose of the non-infused peptide with blood sampling for 2.5 h. Mean ± SEM 10-h ACTH concentrations (ng/L) in the gender-combined analysis were: saline 32±4.6, AVP 29±4.6, CRH 67±6.2 and CRH-AVP 67±8.8: CRH vs AVP, P<0.0001. Mean 10-h cortisol was higher in women than men (P<0.0001), and higher during CRH than AVP...
The Journal of clinical endocrinology and metabolism, Jul 27, 2017
Exercise elicits incompletely defined adaptations of metabolic and endocrine milieu, including th... more Exercise elicits incompletely defined adaptations of metabolic and endocrine milieu, including the gonadotropic and the corticotropic axes. To quantify the impact of acute exercise on coordinate LH and testosterone and ACTH and cortisol secretion in healthy men in relation to age. Prospectively randomized, within-subject cross-over, study in 23 men, aged 19-77 yr. Subjects underwent rest and 30 min of mixed exercise at 65% of maximal aerobic capacity with 10-min blood sampling between 0700 and 1300 h 2 wks apart. Incremental changes in LH, testosterone, ACTH and cortisol concentrations, the feedforward and feedback strength between exercise and rest, quantified by approximate entropy (ApEn), and bihormonal synchrony, quantitated by cross ApEn. Mean hourly exercise-minus-rest LH and ACTH increments increased from -0.055±0.187 to 0.755±0.245 IU/L (P=0.003), and from 2.9±2.2 to 71.2±16.1 ng/L (P<0.0001), respectively, during exercise. Testosterone and cortisol increments increased c...
Frontiers in endocrinology, 2016
A trade-off between fertility and longevity possibly exists. The association of the male hypothal... more A trade-off between fertility and longevity possibly exists. The association of the male hypothalamic-pituitary-gonadal (HPG) axis with familial longevity has not yet been investigated. To study 24-h hormone concentration profiles of the HPG axis in men enriched for familial longevity and controls. We frequently sampled blood over 24 h in 10 healthy middle-aged male offspring of nonagenarian participants from the Leiden Longevity Study together with 10 male age-matched controls. Individual 24-h luteinizing hormone (LH) and testosterone concentration profiles were analyzed by deconvolution analyses to estimate secretion parameters. Furthermore, the temporal relationship between LH and testosterone was assessed by cross-correlation analysis. We used (cross-)approximate entropy to quantify the strength of feedback and/or feedforward control of LH and testosterone secretion. Mean [95% confidence interval (CI)] total LH secretion of the offspring was 212 (156-268) U/L/24 h, which did not...
Expert Review of Endocrinology & Metabolism, 2015
Acromegaly is an insidious disease of the pituitary caused by a growth hormone-secreting adenoma.... more Acromegaly is an insidious disease of the pituitary caused by a growth hormone-secreting adenoma. Generally, the diagnosis is made rather late in the course of the disease. Currently, acromegaly can be cured in about half of the patients with the disease by expert surgery. The remainder of non-surgically cured patients often can be effectively treated with somatostatin analogs; either with the new generation of dopaminergic drugs or with Pegvisomant, a GH-receptor blocking agent. However, at the time of diagnosis many patients suffer from serious comorbidities, including hypertension, heart disease, arthrosis, sleep apnea and diabetes mellitus. Recent reports have shown that mortality risk can be normalized. Nevertheless, all efforts should be undertaken to treat comorbidities. New strategies for surgery and medical treatment are discussed.
Sex-Steroid Interactions with Growth Hormone, 1999
Growth hormone (GH) plays a crucial role in postnatal growth. Disorders in the molecular processi... more Growth hormone (GH) plays a crucial role in postnatal growth. Disorders in the molecular processing of GH, its secretion, or its peripheral tissue effects result in short stature. GH replacement therapy has been used for more than three decades in children. Initially, however, only moderate success was observed in terms of ultimate height, mainly because of the limited supply of GH. With the unlimited availability of recombinant human GH (rhGH), treatment became more efficient, with most GH-deficient children reaching their target height. Pediatric endocri- nologists targeted GH therapy on final height and stopped treatment when this goal was reached. However, clinical observations revealed that GH deficiency (GHD) in adults was associated with nonspecific signs and symptoms, including increased fat mass, reduced lean body mass and muscle strength, decreased extracellular water, decreased bone density, poor physical performance, and impaired sense of well-being. The first recorded GH substitution therapy in the adult human was reported by Raben (1). About 25 years later, the first results in groups of adults with GHD were published (2,3). Both studies provided strong evidence that GH treatment in adults with GHD has beneficial effects on body composition, quality of life, and bone mass.
Acromegaly: Diagnosis & Treatment, 2013
Journal of the Endocrine Society, 2018
Estrogens amplify spontaneous and stimulated growth hormone (GH) secretion, whereas they diminish... more Estrogens amplify spontaneous and stimulated growth hormone (GH) secretion, whereas they diminish GH-dependent insulin-like growth factor (IGF)-I in a dose-dependent manner. Selective estrogen receptor modulators (SERMs), including tamoxifen and toremifene, are widely adjunctively used in breast and prostate cancer. Although some endocrine effects of tamoxifen are known, few data are available for toremifene. To explore sex-dependent effects of toremifene on spontaneous 10-hour overnight GH secretion, followed by GH-releasing hormone-ghrelin stimulation. Additionally, effects on IGF-I, its binding proteins, and sex hormone-binding globulin (SHBG) were quantified. Twenty men and 20 women, within an allowable age range of 50 to 80 years, volunteered for this double-blind, placebo-controlled prospective crossover study. Ten-minute blood sampling was done for 10 hours overnight and then for 2 hours after combined GH-releasing hormone-ghrelin injection. Pulsatile GH and stimulated GH sec...
Aging Cell, 2016
Reduced growth hormone (GH) signaling has been consistently associated with increased health and ... more Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128-216) mU L(-1) ] compared with controls [238 (193-284) mU L(-1) ]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39-0.53)] compared with controls [0.66 (0.56-0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.
The Journal of Clinical Endocrinology and Metabolism, 2010
Twenty-four-hour TSH secretion profiles in primary hypothyroidism have been analyzed with methods... more Twenty-four-hour TSH secretion profiles in primary hypothyroidism have been analyzed with methods no longer in use. The insights afforded by earlier methods are limited. We studied TSH secretion in patients with primary hypothyroidism (eight patients with severe and eight patients with mild hypothyroidism) with up-to-date analytical tools and compared the results with outcomes in 38 healthy controls. Patients and controls underwent a 24-h study with 10-min blood sampling. TSH data were analyzed with a newly developed automated deconvolution program, approximate entropy, spikiness assessment, and cosinor regression. Both basal and pulsatile TSH secretion rates were increased in hypothyroid patients, the latter by increased burst mass with unchanged frequency. Secretory regularity (approximate entropy) was diminished, and spikiness was increased only in patients with severe hypothyroidism. A diurnal TSH rhythm was present in all but two patients, although with an earlier acrophase in severe hypothyroidism. The estimated slow component of the TSH half-life was shortened in all patients. Increased TSH concentrations in hypothyroidism are mediated by amplification of basal secretion and burst size. Secretory abnormalities quantitated by approximate entropy and spikiness were only present in patients with severe disease and thus are possibly related to the increased thyrotrope cell mass.
The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013
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Clin Endocrinol, 2001
Several studies have established that in treated acromegaly mortality is only normalized in patie... more Several studies have established that in treated acromegaly mortality is only normalized in patients achieving a serum GH concentration below 5 mU/l. Few studies however, have addressed results of radiotherapy using this strict criterion. The aim of our study was to assess the efficacy of postoperative radiotherapy in reducing serum GH concentration below 5 mU/l. Forty acromegalic patients who underwent radiotherapy for postoperative persistent disease after transsphenoidal surgery were studied. Mean time of follow-up after radiotherapy was 123+/-11.1 months. A serum GH concentration of <5 mU/l was used to define remission. Following surgery mean GH concentration decreased from 120.8+/-21 mU/l to 24.4+/-5.2 mU/l and mean GH concentration prior to radiotherapy, administered after a mean of 8.2+/-2.7 (0.5-96) months postoperatively was 26.0+/-5.1 mU/l. Using individual regression plots, GH was reduced to 50% by radiotherapy after a mean of 27+/-5 months (range 3-105 months). The observed mean GH concentration as measured at follow-up visits was reduced by 55% (-36-95%) after the first year, by 65% (-29-97.3%) after 2 years and by 78% (-29-99%) after 5 years. We could not demonstrate a significant correlation between a normalized GH concentration on the one hand and tumour size, preradiotherapy GH concentration or duration of follow-up on the other hand. During follow-up, GH-suppressive medical therapy was used in 11 patients, five of whom were still using medication at the end of follow-up. Eight patients had a follow-up of less than 5 years and three of them had a serum GH concentration of <5 mU/l at their latest follow-up visit (38%). At 5 years of follow-up after radiotherapy, 24 out of 32 patients had a GH level of <5 mU/l without medication (75%). At 10 years following irradiation, 16 of 21 patients (76%) had a GH level of <5 mU/l without medical treatment. At 15 years follow-up, a serum GH concentration of <5 mU/l was observed in 13 out of 15 patients (87%) without GH suppressive medication. At the latest follow-up visit, serum GH concentration below 5 mU/l was present in 75% of patients (30 out of 40) without medical therapy after a mean of 10.4+/-0.9 years, but five patients required octreotide up to the end of follow-up. Twenty-seven out of 37 patients with available IGF-I data had normal IGF-I at the end of follow-up (73%). Fifty percent of patients needed substitution therapy for (partial) hypopituitarism after 10 years and 75% after 15 years of radiotherapy. In our group of patients who were incompletely cured by surgery, but had a significant postoperative decrease of serum GH concentrations, radiotherapy was able to achieve 'safe' serum GH concentrations in the majority in the long term.