Maria Wichers

The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone.

ObjectiveTo investigate the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with severe sepsis by stimulating with corticotropin-releasing hormone (CRH). DesignProspective observational study in consecutive intensive care unit patients with severe sepsis. SettingSurgical intensive care unit and outpatient department of endocrinology in a university hospital. PatientsThe study included 20 patients with the diagnosis of severe sepsis; six critically ill, nonseptic patients after major surgery; ten patients with primary adrenal insufficiency; ten patients with anterior pituitary insufficiency; and ten individuals without clinical signs of HPA axis disturbance. InterventionsCRH tests were performed with an intravenous bolus injection of 100 &mgr;g of human CRH. Measurements and Main Results We studied the functional integrity of the HPA axis in patients with severe sepsis by performing the CRH test. In addition, during the period of severe sepsis, we repeatedly measured basal plasma concentrations of adrenocorticotropin hormone (ACTH) and cortisol. The mean basal plasma cortisol concentration was decreased significantly in nonsurvivors with severe sepsis (288.8 ± 29.1 [sem] nmol/L) compared with survivors (468.1± 18.6 nmol/L;p < .01). By calculating the ACTH/cortisol indices, we found no evidence for adrenal insufficiency in patients with severe sepsis. The mean ACTH/cortisol indices of nonsurvivors with severe sepsis (0.02 ± 0.008) and survivors (0.01 ± 0.002) were significantly lower compared with the index of patients with primary adrenal insufficiency (6.8 ± 1.0;p < .001). In contrast, in nonsurvivors with severe sepsis, the plasma cortisol response to CRH stimulation was impaired compared with survivors: The mean basal cortisol concentration within the CRH test was 269.4 ± 39.8 nmol/L in nonsurvivors compared with 470.8 ± 48.4 nmol/L in survivors and increased to a peak value of 421.6 ± 72.6 nmol/L in nonsurvivors and 680.7 ± 43.8 nmol/L in survivors (p < .02). However, the change in plasma cortisol, expressed as mean ± sem and calculated by subtracting the basal cortisol from the peak cortisol after CRH stimulation, was not significantly different in survivors with severe sepsis (243.5 ± 36.1, range 111.0–524.0 nmol/L, n = 15) compared with nonsurvivors (161.0 ± 38.9, range 42.0–245.0 nmol/L, n = 5;p > .05). ConclusionsWe found lower basal plasma cortisol concentrations in nonsurvivors compared with survivors of severe sepsis. In addition, the plasma cortisol response to a single CRH stimulation was impaired in nonsurvivors compared with survivors. Reduced responses to CRH stimulation may reflect a state of endocrinologic organ dysfunction in severe sepsis.

Testicular function after radioiodine therapy for thyroid carcinoma

Abstract.Radiotherapy can cause infertility in both men and women. However, few data are available concerning the effects of radioiodine therapy for thyroid carcinoma on testicular function. We investigated 25 men (age 23–73 years) with differentiated thyroid carcinoma in a longitudinal prospective trial. Follicle-stimulating hormone (FSH), inhibin B, luteinising hormone (LH) and testosterone were measured before (n=25) and 3 months (n=11), 6 months (n=18), 12 months (n=22), and 18 months (n=18) after radioiodine therapy [radioiodine dose (mean ± SEM): 9.8±0.89 GBq]. Before therapy, FSH was 5.4±0.77 IU/l; it increased significantly (P<0.001) to 21.3±2.4 IU/l after 6 months and fell to 7.4±1.3 IU/l after 18 months (normal range: 1.8– 9.2 IU/l). Inhibin B was significantly decreased (P<0.001) from 178±25.3 pg/ml before therapy to 22.2±5.5 pg/ml after 3 and 29.4±5.7 pg/ml after 6 months and rose to 154±23.3 pg/ml after 18 months (normal range 75– 350 pg/ml). LH and testosterone were within the normal range during the whole study (1.6–9.2 IU/l and 10.4–34.7 nmol/l, respectively). LH was significantly increased (P<0.001) from 2.8±0.33 IU/l before therapy to 5.9±0.69 IU/l 6 months after therapy and then fell slowly to 4.0±0.45 IU/l after 18 months. Total testosterone was significantly increased (P<0.01) from 12.8±0.99 nmol/l at baseline to 19.8±1.7 nmol/l after 12 months and 19.6±1.7 nmol/l after 18 months. The testosterone/LH ratio (normal range: 3.3–17.9 nmol/IU) fell from 5.8±0.66 nmol/IU to 3.0±0.36 nmol/IU after 3 months (P<0.01); it remained close to the latter value after 6 months (3.4±0.49 nmol/IU) and then rose to 5.5± 0.6 nmol/IU after 18 months. In conclusion, 3 and 6 months after radioiodine therapy all patients showed elevated FSH and decreased inhibin B levels, reflecting severely impaired spermatogenesis. At the same time a compensated insufficiency of the Leydig cell function was observed. Eighteen months after the last radioiodine therapy, mean values of gonadal function had completely recovered.

Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation

Skewing of X inactivation may contribute to the manifestation of symptoms in adrenoleukodystrophy carriers. We observed highly skewed X inactivation in 32% of 22 symptomatic and asymptomatic carriers but not in 7 related and 35 unrelated controls. Skewing of X inactivation correlated with clinical neurological scores but not with the extent of very long‐chain fatty acid accumulation. Transcript analysis in cultured fibroblasts revealed that skewing could occur both in favor of the mutant and the wild‐type allele. Adrenoleukodystrophy carriers are more susceptible to develop skewing of X inactivation in favor of the mutant allele beiing associated with the manifestation of symptoms.

The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism

Hydrocortisone replacement regimes remain rather empirical and produce serum cortisol profiles very different from normal physiology. We have analysed the effects of different dosages of hydrocortisone (HC) replacement therapy on the health perception and general well‐being of patients with secondary hypocortisolism. We also evaluated the effects of these regimens on bone metabolism.

Endocrinological Outcome Following First Time Transsphenoidal Surgery for GH-, ACTH-, and PRL-Secreting Pituitary Adenomas

Summary.Background: To study remission rates and pituitary functions following transsphenoidal surgery of newly diagnosed GH-, ACTH-, and PRL-secreting pituitary adenomas.Methods: Out of a series of 329 newly diagnosed pituitary adenomas, 131 (39.8%) were hormone (67 GH-, 27 ACTH-, 37 PRL-) secreting. PRL-secreting adenomas were subjected to surgery because they failed to respond to previous medical treatment therapy. The data on secreting adenomas, regarding the results of standardised endocrinological testing, MRI findings and water metabolism disturbances, were extracted retrospectively from the pituitary data-base of the hospital. The mean follow-up was 3.7 years.Results: The overall remission rate for PRL-secreting adenomas (27%) was significantly lower than for GH- (71.6%) and ACTH-secreting (81.5%) ones. Remission rates correlated negatively with the magnitude of preoperative hormone excess (not in Cushings disease), tumour size (not in prolactinoma) and invasiveness. Generally, the improvement of the adenopituitary functions was statistically significant during the first three postoperative months, and thereafter remained unchanged. Diabetes insipidus persisting for more than three months occurred with similar frequency in the three patient groups (in 9.4% of GH-, in 6.7% of ACTH-, and in 10% of PRL-secreting adenomas). Tumour regrowths occurred more often in PRL-(20%) than in ACTH- (9.1%) and GH- (0%) secreting tumours.Conclusions: In GH- and ACTH-secreting pituitary adenomas, remission rates were significantly higher and recurrence rates lower than in PRL-secreting adenomas, which had failed to respond to previous medical therapy. The overall postoperative adenopituitary function was improved in all patient groups. Diabetes insipidus occurred with similar frequency in all patient groups. When reporting on results of surgery for secreting pituitary adenomas, not only remission and recurrence rates, but also the results of the pituitary function should be included.

Pituitary apoplexy with spontaneous cure of acromegaly and its possible relation to Gd-DTPA-administration.

SummaryA case of pituitary apoplexy occurring after Gd-DTPA-administration for contrast enhanced MRI in a patient with an hGH-producing macro-adenoma is presented. Within days the initially increased hGH level fell to the normal range, the oral glucose tolerance test (OGTT) showed a normal suppression of hGH and complete anterior pituitary insufficiency developed. At this time repeated MRI suggested a haemorrhagic infarction of the macroadenoma. Fourteen months later re-examination confirmed spontaneous cure of the acromegaly, improvement of adenopituitary function and shrinkage of the sellar content. The causal linkage between the pituitary adenoma apoplexy and Gd-DTPA-administration is unclear. It might be due to contrast induced blood pressure and endothelial permeability changes, possibly promoted by pre-existing diabetes mellitus associated vasculopathy.

Peri-operative glucocorticoid replacement therapy in transsphenoidal pituitary adenoma surgery: a prospective controlled study.

SummaryBackground. We set out to prospectively study the peri-operative changes of the hypothalamic-pituitary-adrenal axis (HPA), and to test the hypothesis that the peri-operative corticoid replacement regimen used at the authors’ institution in patients with impaired HPA undergoing transsphenoidal pituitary adenoma surgery is adequate.Method. Thirty seven patients (21 females, 16 males, mean age 50.6 years) underwent transsphenoidal pituitary adenoma surgery (mean tumour diameter 20.6 mm, 13 tumours hormone-secreting). The HPA functions of these patients were classified as impaired (group A, n = 15) or preserved (group B, n = 22) according to the results of a pre-operative corticotrophin releasing-hormone test (CRHT). Eleven patients (9 female, 2 male, mean age 53.6 years) without pituitary adenomas and with a preserved HPA (as assessed by medical history and morning serum cortisol (MSC) measurements), undergoing decompressive surgery for degenerative lumbar disc disease, were also studied (group C). On the day of surgery, the patients of group A received 100 mg hydrocortisone (HC) replacement therapy, which was thereafter gradually tapered off in a standardised fashion. The patients of groups B and C were not treated with corticoids. Pre-operative, intra-operative and post-operative variables of these three patient groups were compared.Findings. The urinary free cortisol excretion (UFC) in group A declined from 6732 ± 7683 µg/d on the day of surgery to 305 ± 358 µg/d on the 10th post-operative day. In group B, the respective UFC values were 12851 ± 16278 µg/d and 223 ± 235 µg/d. In both of these groups, the mean UFC did not fall into the normal range during the first ten post-operative days. On none of the post-operative days, was there a significant difference between the UFC of groups A and B. The UFC values of group C dropped from 177 ± 157 µg/d on the day of surgery to 87 ± 61 µg/d on post-operative day six, reaching the normal range from the 2nd post-operative day onwards. All UFC values of group C were significantly lower than those of group A and B. None of the evaluated clinical, laboratory and MRI parameters, as disclosed by uni- and multivariate analysis, showed any significant influence on the peri-operative UFC values.Conclusions. The peri-operative UFC of pituitary adenoma patients with preserved HPA was very high, as compared to patients with degenerative lumbar disc disease. The present study showed for the first time, that the proposed regimen of peri-operative corticoid replacement therapy used in patients with pituitary adenomas and impaired HPA raised cortisol levels to match the physiological increase of UFC in patients with pituitary adenoma surgery and preserved HPA. However, although statistically not significant, the UFC of patients with pituitary adenomas and preserved HPA seemed considerably higher on the day of surgery than in patients with pituitary adenomas and HPA impairment. Although there is no evidence to make it mandatory, administration of 150 mg instead of 100 mg HC substitution on the day of pituitary adenoma surgery in patients with HPA impairment may be prudent.

How hydrocortisone substitution influences the quality of life and the bone metabolism of patients with secondary hypocortisolism

Even in the setting of chronic glucocorticoid substitution in hypocortisolaemic patients, severe side‐effects will eventually occur when the dosage is inappropriately high. This study evaluates the effect of usual hydrocortisone substitution dosages on the well‐being of the patients and on parameters of the bone metabolism to establish an optimum substitution dosage.