<p>In this thesis, the importance of the growth hormone (GH)/insulin-like growth factor (IGF) system and sex steroids for male bone metabolism has been investigated, and the effects of continuous low dose GH replacement in GH deficient (GHD) adults. In a population-based sample of men, positive correlations were found between bone mineral density (BMD) and IGF-I, IGF-II, IGF binding protein (IGFBP)-3 and the testosterone/sex hormone binding globulin (SHBG) ratio. Serum IGFBP-3 and testosterone levels and weight accounted for 34% to 48% of the variation in BMD at different sites. Compared to healthy age matched controls, men with idiopathic osteoporosis had lower estradiol/SHBG ratio and higher SHBG levels. There were no differences between the groups in serum levels of IGF-I, IGFBP-3, 24 hour cumulated GH secretion or peak GH secretion. In the patients, there was a positive correlation between the estradiol/SHBG ratio and BMD in femoral neck. Treatment of patients and controls with GH 0.8 mg/day for one week resulted in similar increases in serum markers for bone turnover in both groups. Several positive correlations between indices of GH secretion and markers for bone turnover were found in the patients. Men with idiopathic osteoporosis were treated with GH, continuously (0.4 mg/day) or intermittently (0.8 mg/day for two weeks every third month), for two years followed by one year of follow-up. After two years, the BMD and bone mineral content in lumbar spine and total body and serum osteocalcin levels were increased in both groups. This increase was sustained one year post treatment. Treatment of GHD adults with a low fixed dose of GH (0.17 mg/day) for three months, resulted in increases in serum IGF-I and IGFBP-3 levels and lean body mass, and a reduction in fat mass and total and low-density lipoprotein cholesterol levels. These beneficial effects were accomplished without serious side effects. These findings indicate that: i) the sex hormone and GH/IGF systems are important in male bone metabolism, ii) a combination of subtle disturbances in these two systems could contribute to the development of male idiopathic osteoporosis, iii) GH treatment could be considered as a treatment option in this condition.</p>

<p>The goals of this thesis are to evaluate quality of life (QoL) in adult patients with growth hormone deficiency (GHD) in relation to population normative data, to construct a preference-weighted index (utility) from a disease-specific QoL measure and to assess it in a clinical context.</p><p>The study included samples from the general population and patients with GHD from four European populations: England & Wales, the Netherlands, Spain and Sweden. The country-specific patient cohorts were retrieved from KIMS (Pfizer International Metabolic Database). </p><p>A questionnaire was developed that contained items from existing QoL questionnaires including, among others, Quality of Life Assessment in Growth Hormone Deficiency in Adults (QoL-AGHDA) and the EQ-5D. The QoL-AGHDA is a disease-specific measure for use in adults with GHD. The EQ-5D is a generic instrument which describes health states for which country-specific preference-based weights are available. Thus, it was possible to generate preference-weighted indices (utilities) based on data generated by both instruments. </p><p>This thesis reports QoL-AGHDA normative values for the populations of England & Wales, the Netherlands, Spain and Sweden, and confirms the extent of QoL impairment in patients with GHD in comparison with the general population. Long-term GH replacement resulted in sustained improvements in overall QoL towards normative country-specific values, as well in most of the dimensions that were impaired before treatment. </p><p>For use in health economic evaluations, models for generating utilities (QoL-AGHDA_utility) from QoL-AGHDA were developed. It is believed that these models may facilitate medical decision making, given that they provide a tool for obtaining utilities in the absence of directly collected preference-weighted indices.</p><p>QoL-AGHDA_utility effectively monitored treatment effects in patients with GHD. Moreover, this study confirmed a QoL-AGHDA_utility deficit before treatment and a gain after starting GH replacement. </p><p>The novel aspect of the present approach was to apply preference-weighted indices derived from a disease-specific measure to assess QoL in the clinical context, together with patient demographic and clinical characteristics. The robustness of this analysis is reinforced by the fact that utilities in both general and patient populations were generated using the same methodology. </p>

In this thesis, the importance of the growth hormone (GH)/insulin-like growth factor (IGF) system and sex steroids for male bone metabolism has been investigated, and the effects of continuous low dose GH replacement in GH deficient (GHD) adults. In a population-based sample of men, positive correlations were found between bone mineral density (BMD) and IGF-I, IGF-II, IGF binding protein (IGFBP)-3 and the testosterone/sex hormone binding globulin (SHBG) ratio. Serum IGFBP-3 and testosterone levels and weight accounted for 34% to 48% of the variation in BMD at different sites. Compared to healthy age matched controls, men with idiopathic osteoporosis had lower estradiol/SHBG ratio and higher SHBG levels. There were no differences between the groups in serum levels of IGF-I, IGFBP-3, 24 hour cumulated GH secretion or peak GH secretion. In the patients, there was a positive correlation between the estradiol/SHBG ratio and BMD in femoral neck. Treatment of patients and controls with GH 0.8 mg/day for one week resulted in similar increases in serum markers for bone turnover in both groups. Several positive correlations between indices of GH secretion and markers for bone turnover were found in the patients. Men with idiopathic osteoporosis were treated with GH, continuously (0.4 mg/day) or intermittently (0.8 mg/day for two weeks every third month), for two years followed by one year of follow-up. After two years, the BMD and bone mineral content in lumbar spine and total body and serum osteocalcin levels were increased in both groups. This increase was sustained one year post treatment. Treatment of GHD adults with a low fixed dose of GH (0.17 mg/day) for three months, resulted in increases in serum IGF-I and IGFBP-3 levels and lean body mass, and a reduction in fat mass and total and low-density lipoprotein cholesterol levels. These beneficial effects were accomplished without serious side effects. These findings indicate that: i) the sex hormone and GH/IGF systems are important in male bone metabolism, ii) a combination of subtle disturbances in these two systems could contribute to the development of male idiopathic osteoporosis, iii) GH treatment could be considered as a treatment option in this condition.

The goals of this thesis are to evaluate quality of life (QoL) in adult patients with growth hormone deficiency (GHD) in relation to population normative data, to construct a preference-weighted index (utility) from a disease-specific QoL measure and to assess it in a clinical context. The study included samples from the general population and patients with GHD from four European populations: England &amp; Wales, the Netherlands, Spain and Sweden. The country-specific patient cohorts were retrieved from KIMS (Pfizer International Metabolic Database). A questionnaire was developed that contained items from existing QoL questionnaires including, among others, Quality of Life Assessment in Growth Hormone Deficiency in Adults (QoL-AGHDA) and the EQ-5D. The QoL-AGHDA is a disease-specific measure for use in adults with GHD. The EQ-5D is a generic instrument which describes health states for which country-specific preference-based weights are available. Thus, it was possible to generate preference-weighted indices (utilities) based on data generated by both instruments. This thesis reports QoL-AGHDA normative values for the populations of England &amp; Wales, the Netherlands, Spain and Sweden, and confirms the extent of QoL impairment in patients with GHD in comparison with the general population. Long-term GH replacement resulted in sustained improvements in overall QoL towards normative country-specific values, as well in most of the dimensions that were impaired before treatment. For use in health economic evaluations, models for generating utilities (QoL-AGHDAutility) from QoL-AGHDA were developed. It is believed that these models may facilitate medical decision making, given that they provide a tool for obtaining utilities in the absence of directly collected preference-weighted indices. QoL-AGHDAutility effectively monitored treatment effects in patients with GHD. Moreover, this study confirmed a QoL-AGHDAutility deficit before treatment and a gain after starting GH replacement. The novel aspect of the present approach was to apply preference-weighted indices derived from a disease-specific measure to assess QoL in the clinical context, together with patient demographic and clinical characteristics. The robustness of this analysis is reinforced by the fact that utilities in both general and patient populations were generated using the same methodology.