Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: A randomized clinical trial in adult growth hormone deficiency

BACKGROUND: The aim of the present study was to investigate the effect of low-normal and high-normal levels of IGF-1 in growth hormone (GH) deficient adults on cognition and wellbeing during GH treatment. METHODS: A randomized, open-label, clinical trial including 32 subjects receiving GH therapy for at least 1 year. Subjects were randomized to receive either a decrease (IGF-1 target level of - 2 to - 1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Memory was measured by the Cambridge Neuropsychological Test Automated Battery, selecting the Pattern Recognition Memory task and the Spatial Working Memory. Wellbeing was measured as mood by the Profile of Moods States questionnaire, and quality of life by the Nottingham Health Profile and QoL Assessment in GH Deficiency in Adults questionnaires. RESULTS: Data from 30 subjects (65.6% male, mean age 46.6 (9.9 SD) years), who fulfilled the target levels, were analyzed. Females in the low dose treatment arm were found to have a better working memory and a better strategic memory control after 24 weeks as opposed to the females in the high treatment arm. With respect to mood, the decrease in IGF-1 levels in females within the low treatment arm was associated with more fatigue and less vigor. CONCLUSIONS: The adjustment of GH dose in female patients seems to have a narrow window. A dose too high may impair prefrontal cognitive functioning, while a dose too low may result in decreased vigor

Personalized approach to growth hormone replacement in adults

Growth hormone (GH) deficiency (GHD) in adults is well-characterized and includes abnormal body composition, reduced bone mass, an adverse cardiovascular risk profile, and impaired quality of life. In the early 1990s, it was also shown that patients with hypopituitarism without GH replacement therapy (GHRT) had excess mortality.Today, GHRT has been shown to decrease or reverse the negative effects of GHD. In addition, recent papers have shown that mortality and morbidity are approaching normal in hypopituitary patients with GHD who receive modern endocrine therapy including GHRT. Since the first dose-finding studies, it has been clear that efficacy and side effects differ substantially between patients. Many factors have been suggested as affecting responsiveness, such as sex, age, age at GHD onset, adherence, and GH receptor polymorphisms, with sex and sex steroid replacement having the greatest impact. Therefore, the individual tailoring of GH dose is of great importance to achieve sufficient efficacy without side effects. One group that stands out is women receiving oral estrogen replacement, who needs the highest dose. Serum insulin-like growth factor-1 (IGF-1) is still the most used biochemical biomarker for GH dose titration, although the best serum IGF-1 target is still debated. Patients with GHD due to acromegaly, Cushing’s disease, or craniopharyngioma experience similar effects from GHRT as others

Exploring the sex difference in cardiovascular risk during growth hormone therapy in adults

Objective: Given the previously identified sex differences in cardiovascular (CV) morbidity and mortality in patients with growth hormone deficiency (GHD) receiving GH replacement therapy (GHRT), our aim is to investigate sex-specific differences in the efficacy of (long-term) GHRT on CV risk profile and disease in subjects with GHD. Our hypothesis is that women will experience less beneficial effects than men. Design: Retrospective nationwide cohort study. Methods: We compared all men (n = 1335) and women (n = 1251) with severe GHD registered in the Dutch National Registry of GH Treatment in Adults database with respect to CV risk profile and morbidity at baseline and during follow-up. Results: Men had a more unfavourable CV risk profile at baseline. During the first years of GHRT, the reduction in waist circumference, waist-to-hip ratio, total cholesterol, and triglyceride levels was greater in men than in women (all P &lt;. 05). Between-sex differences in effects during later follow-up were less clear. No sex differences were found in the risk of developing non-fatal cardiovascular or cerebrovascular diseases during GHRT. Conclusions: Our results suggest that men with GHD did indeed experience more beneficial effects of GHRT on body composition and lipoprotein metabolism than women, at least in the early years of treatment. Also, the more unfavourable CV risk profile at baseline in men did not translate into a sex difference in the risk of developing CV and cerebrovascular morbidity during GHRT.</p

Comparison of low-normal and high-normal IGF-1 target levels during growth hormone replacement therapy: A randomized clinical trial in adult growth hormone deficiency

BACKGROUND: Current guidelines state that the goals of growth hormone (GH) therapy in adults should be an appropriate clinical response, avoidance of side effects, and an IGF-1 value within the age-adjusted reference range. There are no published studies on the target level for IGF-1 that offer specific guidance in this regard. OBJECTIVES: To compare low-normal and high-normal target levels of IGF-1 on efficacy and safety of GH treatment. METHODS: A randomized, open-label, clinical trial including thirty-two adults from one university hospital receiving GH therapy for at least one year with a stable IGF-1 concentration between -1 and 1 SD score (SDS). Subjects were randomized to receive either a decrease (IGF-1 target level of -2 to -1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24weeks. The effect on cardiovascular risk factors and physical performance, next to tolerability, was compared. RESULTS: Thirty subjects (65.6% men, mean age 46.6 (SD 9.9) years) could be analyzed. In subjects with a high-normal IGF-1 target level, waist circumference decreased (p=0.05), and overall they felt better (p=0.04), compared to subjects with a low-normal IGF-1 target level. However, increasing IGF-1 levels led to more myalgia, and decreasing IGF-1 levels to more fatigue. There was a gender-dependent difference in effect on HDL cholesterol. CONCLUSION: Although increasing GH dose to IGF-1 levels between 1 and 2 SDS improved waist circumference and well-being, safety was not guaranteed with the demonstrated effect on HDL cholesterol in men, and reported myalgia

Sex Differences in Long-Term Safety and Tolerability of GH Replacement Therapy in GH Deficient Adults

CONTEXT: Previous studies report that outcomes of growth hormone (GH) replacement therapy (GHRT) might be less beneficial in growth hormone deficient (GHD) women compared with men. OBJECTIVE: This study investigated possible contributing factors regarding this previously found sex difference. METHODS: This retrospective cohort study, conducted at a nationwide outpatient clinic (the Dutch National Registry of GH Treatment in Adults), included Dutch adult GHD men (n = 1335) and women (n = 1251) treated with GHRT. The patients' baseline characteristics, details of GHRT, and the tolerability and long-term safety of GHRT were measured. RESULTS: During treatment, sensitivity analysis showed that insulin-like growth factor-1 (IGF-1) SD scores remained subnormal more often in women (P &lt; 0.001), while scores above normal were more frequent in men (P &lt; 0.001). Women reported more adverse events (P &lt; 0.001), especially symptoms related to fluid retention, and more often needed a dose reduction or temporary stop of GHRT (P = 0.001). In percentages, both sexes equally discontinued GHRT, as was also true for the risk in developing type 2 diabetes mellitus, benign neoplasms, and tumor recurrence. The risk of developing malignant neoplasms was higher in men (P = 0.012). CONCLUSION: Data obtained from the Dutch National Registry of GH Treatment in Adults indicate that GHD women might be treated suboptimally, reflected as lower IGF-1 status and lower GHRT tolerability, leading to more frequent changes in treatment regimen but not discontinuation of GHRT. Regarding long-term safety, we found a higher risk for development of malignancies in GHD men.</p

Impaired neuropsychological functioning in patients with hypopituitarism

Background Treatment of pituitary pathology mostly does not result in complete recovery of impairment in cognitive functioning. The primary aim of the current study was to assess cognitive impairment in patients with stable replacement therapy for hypopituitarism during the last 6 months prior to inclusion. It was expected that patients showed subjective and objective subnormal scores on neuropsychological functioning. Methods Forty‐two patients (40% men, 49 ± 15 years) treated for hypopituitarism conducted a neuropsychological test battery, including the Cognitive Failures Questionnaire (CFQ), 15‐Word test (15‐WT), Cambridge Neuropsychological Test Automated Battery (CANTAB) Motor Screening Task (MOT), Spatial Working Memory (SWM) and Affective Go/No‐go (AGN). Results were compared to reference values of healthy norm groups. Results Male and female participants scored significantly worse on the CFQ (P < .01, d = 0.91‐4.09) and AGN mean correct latency (P < .01, d = 1.66 and 1.29, respectively). Female participants scored significantly worse on 15‐WT direct recall (P = .01, d = 0.66), 15‐WT delayed recall (P = .01, d = 0.79), SWM total errors (P = .05, d = 0.41), SWM strategy (P = .04, d = 0.43), AGN errors of commission (P = .02, d = 0.56) and omission (P = .04, d = 0.41). Conclusion This study shows that subjective cognitive functioning is worse in patients treated for hypopituitarism compared to reference data. Also, female participants treated for hypopituitarism score worse on objective aspects of memory and executive functioning compared to reference data. Besides worse focus attention, this objective cognitive impairment was not found in male participants. It is recommended to conduct additional research, which focuses on the design and evaluation of a cognitive remediation therapy, aimed at compensation of impairments in different aspects of memory and executive functioning

Cardiovascular risk profile in growth hormone-treated adults with craniopharyngioma compared to non-functioning pituitary adenoma: a national cohort study

Context: Cardiovascular (CV) risk profile might differ between growth hormone-treated patients with craniopharyngioma and non-functioning pituitary adenoma (NFPA), since patients with craniopharyngioma more frequently suffer from hypothalamic metabolic disruption. Objective: The aim of this study is to investigate the CV risk profile in adult patients with craniopharyngioma compared to NFPA before and after treatment with growth hormone (GH) replacement therapy due to severe GH deficiency. Design: A sub-analysis of the Dutch National Registry of Growth Hormone Treatment in Adults was performed, in which we compared 291 patients with craniopharyngioma to 778 patients with NFPA. CV risk profile and morbidity were evaluated at baseline and during long-term follow-up within and between both groups. Results: At baseline, patients with craniopharyngioma demonstrated higher BMI than patients with NFPA, and men with craniopharyngioma showed greater waist circumference and lower HDL compared to men with NFPA. During follow-up, BMI, as well as diastolic blood pressure among patients using antihypertensive drugs, deteriorated in the craniopharyngioma group compared to the NFPA group. Lipid profile improved similarly in both groups over time. No differences were found between groups in the occurrence of diabetes mellitus, cerebrovascular accidents, CV disease, or overall mortality. Conclusion: This study suggests that overall CV risk profile is worse in craniopharyngioma patients with GH deficiency compared to patients with NFPA. During GH replacement therapy, patients with craniopharyngioma demonstrated an increase in BMI over time, where BMI remained stable in patients with NFPA. Also, diastolic blood pressure did not improve with antihypertensive drugs in craniopharyngioma patients as seen in patients with NFPA

Psychological well-being and illness perceptions in patients with hypopituitarism

Objective The primary aim of the current study was to objectify a spectrum of persisting subjective psychological complaints in patients with hypopituitarism, at least six months after normalizing of the hormonal disturbances. Also, gender differences on these outcomes were investigated. The secondary aim was to identify illness perceptions and causal attributions within this patient group. Methods A total of 42 adult participants (60% females) with treated hypopituitarism once filled out a number of psychological questionnaires. The Profile of Mood States (POMS) and the Hospital Anxiety and Depression Scale (HADS) assessed mood and the Symptom Checklist-90 (SCL-90) and the Work and Social Adjustment Scale (WSAS) assessed well-being. Illness perceptions were identified using the Illness Perceptions Questionnaire-Brief Dutch Language Version (IPQ-B DLV) and causal attributions by using the Causal Attribution List (CAL). Patient outcomes were compared to reference values of healthy norm groups. Results Participants scored significantly worse on the POMS depression, anger, fatigue and tension subscales, the SCL-90 psychoneuroticism, depression, inadequacy of thinking and acting and sleeping problems subscales and all subscales of the WSAS when compared to reference data. Women also scored worse on depression (HADS) and somatic symptoms (SCL-90). Compared to other illnesses, patients with hypopituitarism have more negative and realistic illness perceptions on consequences, timeline, identity and emotions. Participants attributed their complaints more to physical causes than psychological causes. Conclusion Despite normalization of hormonal disturbances, patients with hypopituitarism in general can still experience problems during daily living, such as negative mood states and a decreased psychological well-being

Psychological well-being and illness perceptions in patients with hypopituitarism

Objective: The primary aim of the current study was to objectify a spectrum of persisting subjective psychological complaints in patients with hypopituitarism, at least six months after normalizing of the hormonal disturbances. Also, gender differences on these outcomes were investigated. The secondary aim was to identify illness perceptions and causal attributions within this patient group. Methods: A total of 42 adult participants (60% females) with treated hypopituitarism once filled out a number of psychological questionnaires. The Profile of Mood States (POMS) and the Hospital Anxiety and Depression Scale (HADS) assessed mood and the Symptom Checklist-90 (SCL-90) and the Work and Social Adjustment Scale (WSAS) assessed well-being. Illness perceptions were identified using the Illness Perceptions Questionnaire-Brief Dutch Language Version (IPQ-B DLV) and causal attributions by using the Causal Attribution List (CAL). Patient outcomes were compared to reference values of healthy norm groups. Results: Participants scored significantly worse on the POMS depression, anger, fatigue and tension subscales, the SCL-90 psychoneuroticism, depression, inadequacy of thinking and acting and sleeping problems subscales and all subscales of the WSAS when compared to reference data. Women also scored worse on depression (HADS) and somatic symptoms (SCL-90). Compared to other illnesses, patients with hypopituitarism have more negative and realistic illness perceptions on consequences, timeline, identity and emotions. Participants attributed their complaints more to physical causes than psychological causes. Conclusion: Despite normalization of hormonal disturbances, patients with hypopituitarism in general can still experience problems during daily living, such as negative mood states and a decreased psychological well-being

Titrating growth hormone dose to high-normal IGF-1 levels has beneficial effects on body fat distribution and microcirculatory function despite causing insulin resistance

To clarify the mechanism underlying the described U-shaped relation of both low and high levels of IGF-1 with cardiovascular disease this study explores the effect of decreasing and increasing growth hormone dose in GH deficient adults on (micro)vascular function, body composition and insulin resistance. In this randomized clinical trial, thirty-two subjects receiving GH therapy with an IGF-1 concentration between −1 and 1 SD score (SDS) for at least one year were randomized to receive either a decrease (IGF-1 target level of −2 to −1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Microvascular endothelium (in)dependent vasodilatation and vasomotion, vascular stiffness by pulse wave analysis, and HOMA-IR were measured. At the end of the study 30 subjects (65.6% men, mean age 46.6 (SD 9.9) years) were analyzed. There was a favorable effect of increasing the IGF-1 level on waist circumference compared to decreasing the IGF-1 level (p=0.05), but a detrimental effect on insulin resistance (p=0.03). Decreasing IGF-1 level significantly lowered the endothelial domain of vasomotion (p=0.03), whereas increasing IGF-1 level increased the contribution of the neurogenic domain (p=0.05). This change was related to the favorable change in waist circumference. In conclusion, increasing IGF-1 levels was beneficial for body composition but detrimental with respect to insulin resistance. The contribution of the neurogenic vasomotion domain increased in parallel, and could be explained by the favorable change in waist circumference. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01877512