Marianne Klose

Prevalence and predictive factors of post-traumatic hypopituitarism.

Objective  To estimate the prevalence and predictive factors of hypopituitarism following traumatic brain injury (TBI).

Acute and long‐term pituitary insufficiency in traumatic brain injury: a prospective single‐centre study

Objective  To assess the prevalence of hypopituitarism following traumatic brain injury (TBI), describe the time‐course and assess the association with trauma‐related parameters and early post‐traumatic hormone alterations.

Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself

Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years. Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor the duration of treatment can be used reliably to predict adrenal function after glucocorticoid withdrawal. Also the recovery rate of the adrenal glands shows individual variation, which may be why there is currently insufficient evidence to prove the efficacy and safety of different withdrawal regimens. Whether a patient with an insufficient response to an adrenal stimulating test develops clinically significant adrenal insufficiency depends on the presence of stress and resulting glucocorticoid demand and it is thus totally unpredictable and can change relative fast. Adrenal insufficiency should therefore always be taken seriously. Individual variation in hypothalamic-pituitary-adrenal axis function might be due to differences in glucocorticoid sensitivity and might be genetic. Further awareness of the potential side effect of withdrawal of glucocorticoid and further research are urgently needed.

Hypopituitarism is uncommon after aneurysmal subarachnoid haemorrhage

Objective  Aneurysmal subarachnoid haemorrhage (SAH) has recently been reported as a common cause of chronic hypopituitarism, and introduction of routine neuroendocrine screening has been advocated. We aimed at estimating the risk of hypopituitarism after SAH using strict criteria including confirmatory testing in case of suggested insufficiency.

Prevalence of Posttraumatic Growth Hormone Deficiency Is Highly Dependent on the Diagnostic Set-up: Results From The Danish National Study on Posttraumatic Hypopituitarism

CONTEXT Recent international guidelines suggest pituitary screening in patients with moderate and severe traumatic brain injury (TBI). Predominantly isolated GH deficiency (GHD) was reported in the literature, raising the question of potential methodological bias. OBJECTIVE Our objective was to assess the prevalence of GHD in patients admitted in 2008 with TBI, with concurrent assessment of methodological bias. DESIGN AND SETTING We conducted a nationwide population-based cohort study at tertiary referral university hospitals. PARTICIPANTS Participants were Danish patients with a head trauma diagnosis from the Danish Board of Health diagnostic code registry; 439 patients and 124 healthy controls underwent dynamic assessment of GH secretion 2.5 years (median) after TBI. MAIN OUTCOME We evaluated the prevalence of GHD given use of 1) local versus guideline cutoffs, 2) insulin tolerance test (ITT), pyridostigmine (PD)-GHRH or GHRH-arginine (arg) test, 3) single versus repeated testing, and 4) GH assessment by assays with different isoform specificities. RESULTS The prevalence of GHD was lower by local than by guideline cutoffs (12% vs 19% [PD-GHRH/GHRH-arg, P<.001]; 4.5% vs 5% [ITT, P=.9]), and by ITT than by PD-GHRH/GHRH-arg (P=.006 [local cutoffs]; P<.001 [guideline cutoffs]). Only 1% of patients had GHD according to 2 tests. GH assessment by the Immulite or iSYS assay caused no significant diagnostic differences. CONCLUSIONS The study confirmed a high risk of bias in the management of pituitary testing of patients with TBI and stresses the importance of a proper control group and stringent GH testing including confirmatory testing in cohorts with low a priori likelihood of GHD such as in TBI. Our results question the evidence for newly introduced recommendations for routine pituitary assessment in TBI.

Adrenocortical insufficiency after pituitary surgery : an audit of the reliability of the conventional short synacthen test

Background  Assessment of the hypothalamic–pituitary–adrenal (HPA) axis after pituitary surgery is important for appropriate decision making regarding replacement therapy. The synacthen test is often used but is questioned, as time has to elapse for adrenal atrophy to develop.

Single determination of plasma ACTH using an immunoradiometric assay with high detectability differentiates between ACTH-dependent and -independent Cushing's syndrome

The purpose of this retrospective study was to elucidate the value of an ACTH assay with high detectability to differentiate between ACTH-dependent and -independent Cushings syndrome. The study was based on the case records of 56 patients with Cushings syndrome comprising 34 patients with ACTH-dependent Cushings syndrome and 22 patients with ACTH-independent Cushings syndrome. Basal morning plasma 1-39 ACTH was measured using an immunoradiometric assay (IRMA) with a normal range of 1.8-11 pmol/L. Peripheral corticotrophin-releasing hormone (CRH ) tests were performed in 24 and 17 patients with ACTH-dependent and-independent Cushings syndrome, respectively. Using a single ACTH measurement, a complete separation was observed between the two defined groups, with a cut-off value of 2.4 pmol/L. Mean ACTH concentration was 14.4 pmol/L (range 2.5-47.7 pmol/L) in ACTH-dependent Cushings syndrome and 0.6 pmol/L (range 0.2-2.2 pmol/L) in ACTH-independent Cushings syndrome. The range of separation between the two groups was further increased by using two ACTH measurements in each patient or peripheral stimulation with CRH. It is concluded that in the majority of patients with Cushings syndrome a single basal morning ACTH determination is sufficient to discriminate between ACTH-dependent and ACTH-independent Cushings syndrome. In borderline cases with ACTH in the range 2-3 pmol/L, repeated measurements might be necessary. The peripheral CRH test was not superior to repeated ACTH measurements.

Pegylated Long-Acting Human Growth Hormone Possesses a Promising Once-Weekly Treatment Profile, and Multiple Dosing Is Well Tolerated in Adult Patients with Growth Hormone Deficiency

BACKGROUND Recombinant human GH (rhGH) replacement therapy in children and adults currently requires daily sc injections for several years or lifelong, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed for once-weekly administration. OBJECTIVES Our objective was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of NNC126-0083 in adult patients with GH deficiency (GHD). SUBJECTS AND METHODS Thirty-three adult patients with GHD, age 20-65 yr, body mass index 18.5-35.0 kg/m(2), and glycated hemoglobin of 8.0% or below. Fourteen days before randomization, subjects discontinued daily rhGH. NNC126-0083 (0.01, 0.02, 0.04, and 0.08 mg/kg) was given sc once weekly for 3 wk (NNC126-0083 for six subjects and placebo for two subjects). Blood samples were collected up to 168 h after the first and up to 240 h after the third dosing. Physical examination, antibodies, and local tolerability were assessed. RESULTS NNC126-0083 was well tolerated with no difference in local tolerability compared with placebo and with no signs of lipoatrophy. A more than dose-proportional exposure was observed at the highest NNC126-0083 dose (0.16 mg protein/kg). Steady-state pharmacokinetics seemed achieved after the second dosing. A clear dose-dependent pharmacodynamic response in circulating IGF-I levels was observed [from a predose mean (SD) IGF-I SD score of -3.2 (1.7) to peak plasma concentration of -0.5 (1.3), 1.6 (1.3), 2.1 (0.5), and 4.4 (0.9) in the four dose groups, respectively]. CONCLUSION After multiple dosing of NNC126-0083, a sustained pharmacodynamic response was observed. NNC126-0083 has the potential to serve as an efficacious, safe, and well-tolerated once-weekly treatment of adult patients with GHD.

Central hypothyroidism and its replacement have a significant influence on cardiovascular risk factors in adult hypopituitary patients.

CONTEXT Thyroid dysfunction may have detrimental effects on patient outcomes. Few studies have assessed this issue in patients with secondary hypothyroidism. OBJECTIVE Our objective was to test the hypothesis that thyroid hormone status has an impact on cardiovascular risk factors in adult patients with hypopituitarism. DESIGN AND SETTING This was a retrospective observational study (1993-2012) at a tertiary referral university hospital. PATIENTS All GH-deficient patients starting GH replacement (1993-2009) with measured free T4 (fT4) (n = 208). Baseline fT4 defined patients as TSH-sufficient and TSH-deficient (further divided into tertiles according to baseline fT4; first tertile had lowest fT4). MAIN OUTCOME MEASURES Anthropometric (body mass index [BMI], waist circumference, total fat (fat mass) and lean body mass [LBM]) and biochemical (lipids and fasting plasma glucose) data were collected at baseline and a median 4.1 years after commencement of GH. RESULTS At baseline, fT4 was negatively associated with BMI and waist circumference, but positively with high-density lipoprotein, independent of age, gender, and IGF-I (SD score). Only first-tertile TSH-deficient patients had higher BMI (P = .02), fat mass (P = .03), total cholesterol (P = .05), triglycerides (P < .01), and waist circumference (P = .01), and lower high-density lipoprotein cholesterol (P = .03) as compared with TSH-sufficient patients. At follow-up, IGF-I, LBM, and plasma glucose had increased in all subgroups (P < .01). The change in fT4 (ΔfT4) (follow-up - baseline) was negatively correlated to ΔBMI, ΔLBM, Δtotal cholesterol, and Δlow-density lipoprotein cholesterol (all P < .05, adjusted for ΔIGF-I and ΔGH and hydrocortisone dose). The negative correlation to Δtotal cholesterol and Δlow-density lipoprotein cholesterol persisted only in first-tertile TSH-deficient patients. CONCLUSION This single-center study over a 20-year period has strengthened the importance of improved awareness of thyroid status and optimal thyroid replacement of hypopituitary patients to reduce cardiovascular risks in hypopituitary patients.

Hypopituitarism in Traumatic Brain Injury—A Critical Note

While hypopituitarism after traumatic brain injury (TBI) was previously considered rare, it is now thought to be a major cause of treatable morbidity among TBI survivors. Consequently, recommendations for assessment of pituitary function and replacement in TBI were recently introduced. Given the high incidence of TBI with more than 100 pr. 100,000 inhabitants, TBI would be by far the most common cause of hypopituitarism if the recently reported prevalence rates hold true. The disproportion between this proposed incidence and the occasional cases of post-TBI hypopituitarism in clinical practice justifies reflection as to whether hypopituitarism has been unrecognized in TBI patients or whether diagnostic testing designed for high risk populations such as patients with obvious pituitary pathology has overestimated the true risk and thereby the disease burden of hypopituitarism in TBI. The findings on mainly isolated deficiencies in TBI patients, and particularly isolated growth hormone (GH) deficiency, raise the question of the potential impact of methodological confounding, determined by variable test-retest reproducibility, appropriateness of cut-off values, importance of BMI stratified cut-offs, assay heterogeneity, pre-test probability of hypopituitarism and lack of proper individual laboratory controls as reference population. In this review, current recommendations are discussed in light of recent available evidence.