Nieke E. Kokshoorn

Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing’s Disease

CONTEXT AND OBJECTIVE Active Cushings disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushings disease results in irreversible impairments in cognitive functioning. Therefore, our aim was to assess cognitive functioning after long-term cure of Cushings disease. DESIGN Cognitive assessment consisted of 11 tests, which evaluated global cognitive functioning, memory, and executive functioning. PATIENTS AND CONTROL SUBJECTS We included 74 patients cured of Cushings disease and 74 controls matched for age, gender, and education. Furthermore, we included 54 patients previously treated for nonfunctioning pituitary macroadenomas (NFMA) and 54 controls matched for age, gender, and education. RESULTS Compared with NFMA patients, patients cured from Cushings disease had lower scores on the Mini Mental State Examination (P = 0.001), and on the memory quotient of the Wechsler Memory Scale (P = 0.050). Furthermore, patients cured from Cushings disease tended to recall fewer words on the imprinting (P = 0.013), immediate recall (P = 0.012), and delayed recall (P = 0.003) trials of the Verbal Learning Test of Rey. On the Rey Complex Figure Test, patients cured from Cushings disease had lower scores on both trials (P = 0.002 and P = 0.007) compared with NFMA patients. Patients cured from Cushings disease also made fewer correct substitutions on the Letter-Digit Substitution Test (P = 0.039) and came up with fewer correct patterns on the Figure Fluency Test (P = 0.003) compared with treated NFMA patients. CONCLUSIONS Cognitive function, reflecting memory and executive functions, is impaired in patients despite long-term cure of Cushings disease. These observations indicate irreversible effects of previous hypercortisolism on cognitive function and, thus, on the central nervous system. These observations may also be of relevance for patients treated with high-dose exogenous glucocorticoids.

Hypopituitarism following traumatic brain injury: prevalence is affected by the use of different dynamic tests and different normal values

OBJECTIVE Traumatic brain injury (TBI) has emerged as an important cause of hypopituitarism. However, considerable variations in the prevalence of hypopituitarism are reported. These can partly be explained by severity of trauma and timing of hormonal evaluation, but may also be dependent on endocrine tests and criteria used for diagnosis of hypopituitarism. METHODS Systematic review of studies reporting prevalence of hypopituitarism in adults >or=1 year after TBI focusing on used (dynamic) tests and biochemical criteria. RESULTS We included data from 14 studies with a total of 931 patients. There was considerable variation in definition of hypopituitarism. Overall, reported prevalences of severe GH deficiency varied between 2 and 39%. Prevalences were 8-20% using the GHRH-arginine test (cutoff <9 microg/l), 11-39% using the glucagon test (cutoff 1-5 microg/l), 2% using the GHRH test (no cutoff), and 15-18% using the insulin tolerance test (ITT; cutoff <3 microg/l). Overall, the reported prevalence of secondary adrenal insufficiency had a broad range from 0 to 60%. This prevalence was 0-60% with basal cortisol (cutoff <220 or <440 nmol/l), 7-19% using the ACTH test, and 5% with the ITT as first test (cutoff <500 or <550 nmol/l). Secondary hypothyroidism was present in 0-19% (free thyroxine) or 5-15% (thyroid-releasing hormone stimulation). Secondary hypogonadism was present in 0-29%. CONCLUSION The reported variations in the prevalence rates of hypopituitarism after TBI are in part caused by differences in definitions, endocrine assessments of hypopituitarism, and confounding factors. These methodological issues prohibit simple generalizations of results of original studies on TBI-associated hypopituitarism in the perspective of meta-analyses or reviews.

Pituitary Dysfunction in Adult Patients after Cranial Radiotherapy: Systematic Review and Meta-Analysis

CONTEXT Cranial radiotherapy is an important cause of hypopituitarism. The prevalence of hypopituitarism varies considerably between studies. OBJECTIVE We conducted a systematic review and meta-analysis of reported prevalences of hypopituitarism in adults radiated for nonpituitary tumors. DATA SOURCES We searched PubMed, EMBASE, Web of Science, and the Cochrane Library to identify potentially relevant studies. STUDY SELECTION Studies were eligible for inclusion with the following criteria: 1) cranial radiotherapy for nonpituitary tumors and/or total body irradiation for hematological malignancies; 2) adult population (>18 yr old); and 3) report on endocrine evaluation. DATA EXTRACTION Data review was done by two independent reviewers. Besides extraction of baseline and treatment characteristics, also endocrine tests, definitions, and cutoff values used to define pituitary insufficiency were extracted. RESULTS Eighteen studies with a total of 813 patients were included. These included 608 patients treated for nasopharyngeal cancer (75%) and 205 for intracerebral tumors. The total radiation dose ranged from 14 to 83 and 40 to 97 Gy for nasopharyngeal and intracerebral tumors, respectively. The point prevalence of any degree of hypopituitarism was 0.66 [95% confidence interval (CI), 0.55-0.76]. The prevalence of GH deficiency was 0.45 (95% CI, 0.33-0.57); of LH and FSH, 0.3 (95% CI, 0.23-0.37); of TSH, 0.25 (95% CI, 0.16-0.37); and of ACTH, 0.22 (95% CI, 0.15-0.3), respectively. The prevalence of hyperprolactinemia was 0.34 (95% CI, 0.15-0.6). There were no differences between the effects of radiotherapy for nasopharyngeal vs. for intracerebral tumors. CONCLUSION Hypopituitarism is prevalent in adult patients after cranial radiotherapy for nonpituitary tumors. Therefore, all patients treated by cranial radiotherapy should have structured periodical assessment of pituitary functions.

Low prevalence of hypopituitarism after traumatic brain injury: a multicenter study

OBJECTIVE Hypopituitarism after traumatic brain injury (TBI) is considered to be a prevalent condition. However, prevalence rates differ considerably among reported studies, due to differences in definitions, endocrine assessments of hypopituitarism, and confounding factors, such as timing of evaluation and the severity of the trauma. Aim To evaluate the prevalence of hypopituitarism in a large cohort of TBI patients after long-term follow-up using a standardized endocrine evaluation. Study design Cross-sectional study. PATIENTS AND METHODS We included 112 patients with TBI, hospitalized for at least 3 days and duration of follow-up >1 year after TBI from five (neurosurgical) referral centers. Evaluation of pituitary function included fasting morning hormone measurements and insulin tolerance test (n=90) or, when contraindicated, ACTH stimulation and/or CRH stimulation tests and a GH releasing hormone-arginine test (n=22). Clinical evaluation included quality of life questionnaires. RESULTS We studied 112 patients (75 males), with median age 48 years and mean body mass index (BMI) 26.7±4.8 kg/m(2). Mean duration of hospitalization was 11 (3-105), and 33% of the patients had a severe trauma (Glasgow Coma Scale <9) after TBI. The mean duration of follow-up was 4 (1-12) years. Hypopituitarism was diagnosed in 5.4% (6/112) of patients: severe GH deficiency (n=3), hypogonadism (n=1), adrenal insufficiency (n=2). Patients diagnosed with pituitary insufficiency had significantly higher BMI (P=0.002). CONCLUSION In this study, the prevalence of hypopituitarism during long-term follow-up after TBI was low. Prospective studies are urgently needed to find reliable predictive tools for the identification of patients with a significant pre-test likelihood for hypopituitarism after TBI.

GH replacement therapy in elderly GH-deficient patients: a systematic review.

Context Recombinant human GH (rhGH) is prescribed for the treatment of adults with GH deficiency (GHD). However, conflicting data are available on the efficacy of rhGH treatment in elderly GHD patients. Objective To assess the efficacy of rhGH treatment in elderly GHD subjects. Methods We searched the available literature in PubMed, Cochrane Library, Web of Science and EMBASE. Study selection Studies on GHD patients, aged >60 years, treated with rhGH were eligible for inclusion. Data extraction was performed by two reviewers independently. Results We found 11 eligible studies with a total of 534 patients. Only two studies had prospective, randomized, placebo-controlled study designs of rhGH treatment with a duration of 6 (n=15) and 12 months (n=62), respectively. Treatment with rhGH decreased total and low density lipoprotein (LDL) cholesterol levels by 4-8 and 11-16%, respectively, but did not alter high density lipoprotein or triglyceride levels. RhGH did not affect body mass index, but decreased waist circumference (by ∼3 cm) and waist/hip ratio. RhGh did not consistently affect blood pressure or bone mineral density. RhGH increased lean body mass by 2-5% and decreased total fat mass by 7-10% in four studies, but did not affect body composition in two other studies. RhGH consistently improved quality of life (QoL) parameters reflected in AGHDA-scores. There were no explicit data on elderly GHD patients aged >80 years. Conclusion RhGH replacement in elderly subjects with GHD decreases LDL cholesterol levels and improves QoL, but the effects on other parameters are not unequivocal. There were no data on the efficacy and safety of rhGH treatment in octogenarians with GHD.

Low Incidence of Adrenal Insufficiency after Transsphenoidal Surgery in Patients with Acromegaly: A Long-Term Follow-Up Study

CONTEXT The long-term prevalence of adrenal insufficiency after transsphenoidal surgery for GH-secreting pituitary adenomas is unknown. However, recently a single study reported a high prevalence of adrenal insufficiency in acromegalic patients after surgical and/or medical treatment without postoperative radiotherapy. OBJECTIVE The objective of the study was to assess the prevalence and incidence rates of adrenal insufficiency in consecutive patients during long-term follow-up after successful transsphenoidal surgery for acromegaly. DESIGN In 91 consecutive patients in remission after transsphenoidal surgery only, we retrospectively reviewed insulin tolerance tests, CRH stimulation tests, metyrapone tests, and ACTH stimulation tests used to assess corticotrope function. RESULTS Early postoperatively, insufficient adrenal function was observed in 16 patients (18%), which was transient in eight and irreversible in eight other patients in the first year of postoperative follow-up. Therefore, after the first year, the prevalence of adrenal insufficiency was 9%. Late, new-onset adrenal insufficiency developed in only three patients 13, 18, and 24 yr after surgery. The incidence rate of late adrenal insufficiency after successful surgery was 2/1000 person-years. After long-term follow-up, a median of 8.1 (1-31 yr), the prevalence of secondary adrenal insufficiency was 12% in patients in remission after surgery for acromegaly. CONCLUSION The prevalence of adrenal insufficiency 1 yr after surgery was 9%, whereas during prolonged follow-up, the incidence rate of adrenal insufficiency was only 2/1000 person-years in patients in remission after surgery. Therefore, development of late-onset adrenal insufficiency is a very infrequent complication in patients with acromegaly in remission after transsphenoidal surgery only.