| 1. |
- Holmer, Helene, et al.
(författare)
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Nonfatal stroke, cardiac disease, and diabetes mellitus in hypopituitary patients on hormone replacement including growth hormone
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 92:9, s. 3560-3567
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Tidskriftsartikel (refereegranskat)abstract
- Context: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown. Objective: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus ( T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls. Design and Participants: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively. Results: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication. Conclusions: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity.
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| 2. |
- Gil Berglund, E, et al.
(författare)
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Growth hormone replacement therapy induces codeine clearance.
- 2002
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Ingår i: European journal of clinical investigation. - : Wiley. - 0014-2972. ; 32:7, s. 507-12
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Tidskriftsartikel (refereegranskat)abstract
- The increasing clinical use of growth hormone (GH) has raised questions about other than growth-related metabolic effects of this treatment. GH regulates the expression of several hepatic drug metabolising enzymes in the rat, but it is not known whether GH treatment alters the expression of such liver enzymes in man. We have investigated the effects of GH on codeine clearance and two enzymes of the cytochrome P450 (CYP) family, CYP3A and CYP2D6, and UDP-glucuronosyl transferase (UDPGT). These enzymes have a superior importance in hepatic biotransformation of numerous drugs. In addition, CYP3A and UDPGT are catalysts of many reactions with endobiotics such as steroid hormones.We used codeine as a probe drug for assessment of the enzyme activities. Codeine was administered as a single-dose prior to, and after 3 months of GH substitution in GH-deficient patients. Total clearance, and clearance along each of the three primary metabolic pathways of codeine, was assessed.Three months of GH substitution increased the total clearance of codeine (21%, P < 0.01) and clearance catalysed by UDPGT significantly (31%, P < 0.05). The treatment tended to increase the clearance via the CYP3A pathway (83%, P = 0.05).The effects of GH replacement therapy on drug metabolism may have clinical implications when combined with drugs that are substrates of UDPGT and CYP3A. Effects on steroid hormone metabolism with endocrine consequences can not be ruled out.
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| 3. |
- Gillberg, P, et al.
(författare)
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Commencing growth hormone replacement in adults with a fixed low dose. Effects on serum lipoproteins, glucose metabolism, body composition, and cardiovascular function.
- 2001
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Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - : Elsevier BV. - 1096-6374. ; 11:5, s. 273-81
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Tidskriftsartikel (refereegranskat)abstract
- The safety and effects of a fixed low dose of growth hormone (GH), 0.17 mg/day was evaluated for 3 months, on glucose metabolism, serum lipids, body composition and cardiac function in 53 GH deficient adults aged 18-78 years. Body composition was determined by dual energy X-ray absorptiometry and total body water was determined by bioelectrical impedance. Echocardiography was used to assess cardiac function and bicycle ergonometry was used to determine exercise capacity. All investigations were performed at baseline and after 3 months. At 3 months, serum levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and lipoprotein (a) and lean body mass were increased (P<0.05). Total and low density lipoprotein cholesterol levels and fat mass were reduced (P<0.05). There was an increase in the serum glucose value at 120 min after an oral glucose tolerance test performed at 3 months (P<0.05), no other changes in glucose metabolism or in cardiac function were noted. Side-effects were few and mild. This fixed low-dose regime resulted in improvements in body composition and lipid profile, without causing serious side effects. This is therefore a valid method to institute GH replacement in adults.
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| 4. |
- Sigurjónsdóttir, Helga A, 1964, et al.
(författare)
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GH effect on enzyme activity of 11betaHSD in abdominal obesity is dependent on treatment duration.
- 2006
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 154:1, s. 69-74
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In the past years the interaction of GH and 11beta hydroxysteroid dehydrogenase (11betaHSD) in the pathogenesis of central obesity has been suggested. DESIGN: We studied the effects of 9 months of GH treatment on 11betaHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48-66 years, in a randomised, double-blind, placebo-controlled trial. METHODS: Urinary steroid profile was used to estimate 11betaHSD type 1 and 2 (11betaHSD1 and 11betaHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic-hyperinsulinaemic glucose clamp was used to assess insulin sensitivity. RESULTS: In the GH-treated group the 11betaHSD1 activity decreased transiently after 6 weeks (P < 0.01) whereas 11betaHSD2 increased after 9 months of treatment (P < 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11betaHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11betaHSD1 and 11betaHSD 2 and changes in GDR. DISCUSSION: The study demonstrates that short- and long-term GH treatment has different effects on 11betaHSD1 and 11betaHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11betaHSD.
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| 5. |
- Sigurjónsdóttir, Helga A, 1964, et al.
(författare)
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Liquorice in moderate doses does not affect sex steroid hormones of biological importance although the effect differs between the genders.
- 2006
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Ingår i: Hormone research. - : S. Karger AG. - 0301-0163. ; 65:2, s. 106-10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIM: Liquorice is commonly consumed, at least in the western world, and we have earlier shown that even moderate doses of liquorice have significant effects on the cortisol metabolism by inhibiting 11beta-hydroxysteroid dehydrogenase type 2. The suggestion that liquorice decreases the testosterone levels in men makes it vital to study the effect of moderate doses of liquorice on sex steroid hormones. METHODS: Fifteen women and 21 men (healthy volunteers and subjects with essential hypertension) consumed 100 g of liquorice (150 mg glycyrrhetinic acid) daily in a 9-week, open-treatment trial. Blood and 24-hour urine samples were collected for hormone analysis before and after 4 weeks of liquorice consumption and 4 weeks after cessation of liquorice intake. RESULTS: The liquorice induced a moderate decrease in the serum concentrations of dehydroepiandrostenedione sulphate in men (p = 0.002). The relative change in serum levels of dehydroepiandrosterone sulphate differed between the genders (p = 0.03). No significant changes were observed in the serum testosterone levels after 4 weeks of liquorice consumption, and the urine excretion of androgens (etiocholanolone and androstenedione) did not change. CONCLUSIONS: Liquorice in moderate doses primarily affects the cortisol metabolism and only marginally the androgen hormones. Gender may influence the action of liquorice.
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| 6. |
- Sigurjónsdóttir, Helga A, 1964, et al.
(författare)
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The liquorice effect on the RAAS differs between the genders.
- 2006
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Ingår i: Blood pressure. - : Informa UK Limited. - 0803-7051 .- 1651-1999. ; 15:3, s. 169-72
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Liquorice-induced increase in blood pressure (BP) is more profound in subjects with essential hypertension (HT) than in healthy individuals. Liquorice induces pseudohyperaldosteronism by inhibiting the 11beta-hydroxysteroid dehydrogenase type 2 and is also known to inhibit the renin-angiotensin-aldosterone system (RAAS). We explored the difference in response in BP, considering the RAAS and the genders. DESIGN: Patients with HT (eight men and three women, mean age 40.7 years) and healthy controls (13 men and 12 women, mean age 31.2 years) consumed 100 g of liquorice (150 mg glycyrrhetinic acid) daily for 4 weeks. METHODS: Blood, urine samples and BP were evaluated before and after 4 weeks of liquorice consumption and 4 weeks after cessation of liquorice consumption. RESULTS: The relative change in serum aldosterone levels differed between the genders (p < 0.02), men being more responsive than women, but not between patients with HT and healthy subjects. CONCLUSION: The liquorice-induced inhibition of aldosterone secretion differs between the genders and is not influenced by the BP levels. This difference between the genders has not been exposed before.
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| 7. |
- Filipsson, Helena, 1966, et al.
(författare)
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The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:10, s. 3954-61
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hypopituitary patients with untreated GH deficiency and patients on inappropriately high doses of glucocorticoid (GC) share certain clinical features. OBJECTIVE: The aim of the study was to examine the influence of GC substitution on clinical characteristics in hypopituitary patients before and after GH replacement therapy. METHOD: A total of 2424 hypopituitary patients within the KIMS (Pfizer International Metabolic Database) were grouped according to ACTH status. Comparisons were performed between subjects on hydrocortisone (HC) (n = 1186), cortisone acetate (CA) (n = 487), and prednisolone/dexamethasone (n = 52), and ACTH-sufficient patients (AS) (n = 717) before and after 1 yr of GH treatment in terms of body mass index, waist and hip circumference, blood pressure, glucose, glycosylated hemoglobin (HbA1c), serum lipids, IGF-I, and comorbidity. Hydrocortisone equivalent (HCeq) doses were calculated, and measurements were adjusted for sex and age. RESULTS: At baseline, the HC group had increased total cholesterol, triglycerides, waist circumference, and HbA1c, and the prednisolone/dexamethasone group had increased waist/hip ratio as compared with AS. After HCeq dose adjustment, the HC group retained higher HbA1c than the CA group. GC-treated patients showed a dose-related increase in serum IGF-I, body mass index, triglycerides, low-density lipoprotein cholesterol and total cholesterol levels. Subjects with HCeq doses less than 20 mg/d (n = 328) at baseline did not differ from AS in metabolic endpoints. The 1-yr metabolic response to GH was similar in all GC groups and dose categories. All new cases of diabetes (n = 12), stroke (n = 8), and myocardial infarction (n = 3) during GH treatment occurred in GC-treated subjects. CONCLUSION: HCeq doses of at least 20 mg/d in adults with hypopituitarism are associated with an unfavorable metabolic profile. CA replacement may have metabolic advantages compared with other GCs.
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| 8. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study.
- 2009
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X .- 0804-4643. ; 161:1, s. 119-30
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Endogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile. OBJECTIVE: To determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets in healthy volunteers. In addition, the effect of food intake was investigated for the 20 mg dose. DESIGN: A randomised, controlled, two-way cross-over, double-blind, phase I study of oral hydrocortisone (modified (dual) release; 5 and 20 mg) with an open food-interaction arm. METHODS: The single dose pharmacokinetic studies were performed with betamethasone suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in a fasting state. The third day was open with a 20 mg tablet taken 30 min after a high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC-MS/MS and an immunoassay. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis. RESULTS: The time to reach a clinically significant plasma concentration of cortisol (>200 nmol/l) was within 20 min and a mean peak of 431 (s.d. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 h thereafter and all plasma concentrations 18-24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC-MS/MS and immunoassay, respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully dose proportional. CONCLUSION: The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.
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| 9. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Long-acting hydrocortisone for glucocorticoid replacement therapy.
- 2007
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Ingår i: Hormone research. - : S. Karger AG. - 1423-0046 .- 0301-0163. ; 68 Suppl 5, s. 182-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Glucocorticoid (GC) deficiency is a consequence of various disorders that are by themselves rare. Because of this low prevalence, the low cost of GC replacement therapy and the belief that existing outcomes are good, there has been little interest in development of new and improved pharmaceutical products for treatment of GC deficiency. However, GC replacement therapy is complex: diurnal variation of endogenous cortisol must be replicated, GC needs may change during times of physical and psychological stress and there is no biomarker of its action that can be used to monitor individual dose response. CURRENT LIMITATIONS: Recent data suggest that the outcome of established long-term GC replacement therapy may not be as good as previously believed. Short-acting GCs such as hydrocortisone (HC) and cortisone acetate for replacement therapy require 2 to 3 administrations per day. DEVELOPING ALTERNATIVES: Drug delivery system technologies are now available that could permit design and manufacture of a formulation that could accommodate once-daily administration of HC. Such a formulation would enable more physiological serum cortisol-time profiles than are possible with currently available formulations. This short review provides some background on GC replacement therapy, along with recent data on the outcome of patient groups with GC insufficiency, and briefly discusses some general principles for a controlled-release ('long-acting') HC formulation.
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| 10. |
- Koltowska-Häggström, Maria, et al.
(författare)
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Does long-term GH replacement therapy in hypopituitary adults with GH deficiency normalise quality of life?
- 2006
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 155:1, s. 109-19
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether impaired quality of life (QoL) in adults with GH deficiency (GHD) is reversible with long-term GH therapy and whether the responses in QoL dimensions differ from each other. METHODS: QoL was measured by the Quality of Life-Assessment for Growth Hormone Deficiency in Adults (QoL-AGHDA) in general population samples in England & Wales, The Netherlands, Spain and Sweden (n = 892, 1038, 868 and 1682 respectively) and compared with corresponding patients' data from KIMS (Pfizer International Metabolic Database) (n = 758, 247, 197 and 484 respectively) for 4-6 years a follow-up. The subsets of patients from England and Wales, and Sweden with longitudinal data for 5 years' follow-up were also analysed. The change of the total QoL-AGHDA scores and responses within dimensions were evaluated. Subanalyses were performed to identify any specificity in response pattern for gender, age, disease-onset and aetiology. RESULTS: Irrespective of the degree of impairment, overall QoL improved dramatically in the first 12 months, with steady progress thereafter towards the country-specific population mean. Problems with memory and tiredness were the most serious burden for untreated patients, followed by tenseness, self-confidence and problems with socialising. With treatment, these improved in the reverse order, normalising for the latter three. CONCLUSIONS: Long-term GH replacement results in sustained improvements towards the normative country-specific values in overall QoL and in most impaired dimensions. The lasting improvement and almost identical pattern of response in each patient subgroup and independent of the level of QoL impairment support the hypothesis that GHD may cause these patients' psychological problems.
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