IGF-I is a key factor in intrauterine development and postnatal growth and metabolism. The secretion of IGF-I in utero is not dependent on GH, whereas in childhood and adult life, IGF-I secretion seems to be mainly controlled by GH, as revealed from studies on patients with GHRH receptor and GH receptor mutations. In a 55-yr-old male, the first child of consanguineous parents, presenting with severe intrauterine and postnatal growth retardation, microcephaly, and sensorineural deafness, we found a homozygous G to A nucleotide substitution in the IGF-I gene changing valine 44 into methione. The inactivating nature of the mutation was proven by functional analysis demonstrating a 90-fold reduced affinity of recombinantly produced for the IGF-I receptor. Additional investigations revealed osteoporosis, a partial gonadal dysfunction, and a relatively well-preserved cardiac function. Nine of the 24 relatives studied carried the mutation. They had a significantly lower birth weight, final height, and head circumference than noncarriers. In conclusion, the phenotype of our patient consists of severe intrauterine growth retardation, deafness, and mental retardation, reflecting the GH-independent secretion of IGF-I in utero. The postnatal growth pattern, similar to growth of untreated GH-deficient or GH-insensitive children, is in agreement with the hypothesis that IGF-I secretion in childhood is mainly GH dependent. Remarkably, IGF-I deficiency is relatively well tolerated during the subsequent four decades of adulthood. IGF-I haploinsufficiency results in subtle inhibition of intrauterine and postnatal growth.

To evaluate the long-term impact of cured Cushing's disease on subjective well-being, we assessed quality of life by validated health-related questionnaires in 58 patients cured from Cushing's disease by transsphenoidal surgery (n = 58), some of whom received additional radiotherapy (n = 11) and/or bilateral adrenalectomy (n = 3). The mean duration of remission was 13.4 +/- 6.7 yr (range of 2-25 yr). Patient data were compared with a control group of 98 healthy subjects with the same age and sex distribution and with age-adjusted reference values available from the literature. General perceived well-being, measured by the Nottingham Health Profile and the Short Form, was reduced compared with controls for all subscales (P < 0.001). Patients with Cushing's disease had worse scores on subscales of fatigue Multidimensional Fatigue Index and anxiety and depression (Hospital Anxiety and Depression Scale). Compared with reference values from the literature, quality of life was also reduced in the patients according to all questionnaires and all items, except pain (Short Form), sleep (Nottingham Health Profile), and reduced activity (Multidimensional Fatigue Index). Despite conventional hormone replacement therapy, hypopituitarism was an important independent predictor of reduced quality of life. Patients without hypopituitarism (n = 28) showed reduced scores on physical items but normal scores on mental items compared with controls. In conclusion, despite long-term cure of Cushing's disease, patients experience a considerable decrease in quality of life, with physical and psychosocial impairments, especially in the presence of hypopituitarism.

The long-term impact of acromegaly on subjective well-being after treatment of GH excess is unclear. Therefore, we evaluated quality of life by validated questionnaires in a cross-sectional study of 118 successfully treated acromegalic patients. The initial treatment was transsphenoidal surgery in most patients (92%), if necessary followed by radiotherapy or octreotide. All patients were in remission at the time of assessment (GH, <1.9 mug/liter; normal IGF-I for age). General perceived well-being was reduced compared with controls for all subscales (P < 0.001) as measured by the Nottingham Health Profile and the Short Form-36. Acromegalic patients also had lower scores on fatigue (Multidimensional Fatigue Index) and anxiety and depression (Hospital Anxiety and Depression Scale). Radiotherapy was associated with decreased quality of life in all subscales except for the Hospital Anxiety and Depression Scale, and worsened quality of life significantly, according to the fatigue scores. Somatostatin analog treatment was not associated with improved quality of life. Independent predictors of quality of life were age (physical subscales and Nottingham Health Profile), disease duration (social isolation and personal relations), and radiotherapy (physical and fatigue subscales). In conclusion, patients cured after treatment for acromegaly have a persistently decreased quality of life despite long-term biochemical cure of GH excess. Radiotherapy especially is associated with a reduced quality of life.

Craniopharyngioma is associated with excessive long-term multisystem morbidity and mortality, especially in female patients, despite a high cure rate. These observations indicate that dedicated long-term follow-up of these patients is required. The purpose of the follow-up should be: first, to look for recurrences and to ensure appropriate endocrine replacement, especially oestrogen replacement in premenopausal females; and second, to achieve intensive control of glucose, lipids, blood pressure and weight, as in any other patient with increased risk for cardiovascular disease.

We evaluated survival after optimal treatment for acromegaly and assessed the predictive effects of different remission criteria for survival in 164 consecutive acromegalic patients, treated by transsphenoidal surgery and adjuvant therapy between 1977 and 2002. The goal of treatment was a mean GH less than 5 mU/liter, a normal glucose-suppressed GH, and a normal IGF-I for age in all patients. Surgery initially cured 108 patients (66%). Adjuvant therapy for persistent disease was given to 49 patients. At the end of follow-up (mean, 12.3 yr), remission rates for surgery and multimodality treatment were 54% and 90%, respectively. In 2033 person-years of follow-up, 28 of 164 patients died, resulting in an observed:expected mortality ratio of 1.3 (confidence interval, 0.87-1.87). Significant predictors for survival were the duration of disease and the postoperative glucose-suppressed GH. The effects of these predictors became less significant with increasing follow-up duration. A time-dependent effect on survival was observed for serial IGF-I concentrations, but not for serial GH concentrations. Of the three remission criteria, IGF-I was the only one to be significantly associated with survival in this study, with a relative risk of 4.78 for an elevated as opposed to a normal IGF-I concentration.