Soluble delta-like 1 homolog decreases in patients with acromegaly following pituitary surgery: A potential mediator of adipogenesis suppression by growth hormone?

OBJECTIVE: GH excess in acromegaly leads to lower fat mass and insulin resistance; both reverse following pituitary surgery. Soluble delta like-1 homolog (sDlk1) inhibits adipocyte differentiation and may mediate the antiadipogenic effects of GH. It is released into the circulation by ectodomain shedding through 'A Disintegrin And Metalloproteinase domain 17' (ADAM17), which also sheds soluble α-Klotho (sKlotho). Klotho is a transmembrane protein, which influences life span. sKlotho inhibits insulin signalling, and is markedly elevated in acromegaly and decreases after surgery. Therefore, we examined if sDlk1 parallels the course of sKlotho, which could explain the well-known changes in fat mass in patients with acromegaly after surgery. DESIGN: We measured serum levels of GH, IGF-1, sDlk1 and sKlotho (both by ELISA) in 42 treatment-naïve acromegaly patients (20 females/22 males) before and 1-3 months after transsphenoidal surgery. Data are presented as median(interquartile range). RESULTS: GH decreased in all patients postoperatively (in 32/42 to <1 ng/ml during oral glucose tolerance testing). Likewise, IGF-1 and sKlotho decreased in all patients, from 587 (432-708) to 195 (133-270) ng/ml, and from 4.0 (2.7-5.9) to 0.7 (0.6-1.2) ng/ml, respectively; sDlk1 fell in 40/42 subjects, from 10.7 (5.8-13.4) to 7.1 (3.7-10.4) ng/ml following pituitary surgery. P < 0.0001 for all parameters. CONCLUSIONS: sDlk1 declined after pituitary surgery in our patients with acromegaly, but to a lesser extent than sKlotho. It remains to be seen whether this may contribute to the well-known postoperative changes in body composition. Our findings may extend beyond the scope of acromegaly, and thus further elucidate mechanisms in the fields of obesity and anti-ageing.

Gender dependence of serum soluble Klotho in acromegaly.

OBJECTIVES: In acromegaly, disease activity is biochemically assessed by growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. However, they are often discrepant, as several factors including gender influence their relationship. We recently found excessively high serum levels of soluble Klotho (sKl) in acromegalic patients, which depended on GH to a comparable extent as IGF-1. To further elucidate the relationship between GH and sKl, we examined the effect of gender on sKl in patients with untreated acromegaly. PATIENTS AND DESIGN: We determined GH, IGF-1 and sKl in sera of 62 consecutive patients with newly diagnosed acromegaly (31 females/31 males, aged 20-85 years). RESULTS: For their given GH excess at presentation with acromegaly, females had lower IGF-1 (490 ± 33 vs 604 ± 33 ng/ml, P = 0·02), but higher sKl [5171 ± 590 vs 3439 ± 431 pg/ml (mean ± SE), P = 0·02] levels than males. In multiple regression analysis, IGF-1 was closely associated with logGH (estimate 139, SE 47, P = 0·005) and BMI (estimate 14·2, SE 4·8, P = 0·005). sKl was closely associated with logGH (estimate 3088, SE 652, P = 0·0001) and gender (estimate 2034, SE 612, P = 0·002), and to a lesser extent with BMI (estimate 174, SE 66, P = 0·01). CONCLUSIONS: For a given GH status, sKl concentrations are higher and IGF-1 concentrations are lower in women than in men. GH is the strongest predictor for both sKl and IGF-1, but gender needs to be considered when using these parameters for monitoring acromegalic patients.

Impact of Growth Hormone on Cystatin C.

BACKGROUND: Cystatin C (CysC) is an alternative marker to creatinine for estimation of the glomerular filtration rate (GFR). Hormones such as thyroid hormones and glucocorticoids are known to have an impact on CysC. In this study, we examined the effect of growth hormone (GH) on CysC in patients with acromegaly undergoing transsphenoidal surgery. METHODS: Creatinine, CysC, GH and insulin-like growth factor-1 (IGF-1) were determined in 24 patients with acromegaly before and following transsphenoidal surgery. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. RESULTS: In all patients, surgical debulking resulted in decreased clinical disease activity and declining GH/IGF-1 levels. Postoperatively, biochemical cure was documented in 20 out of 24 patients. Creatinine levels (mean ± SEM) increased from 72 ± 3 to 80 ± 3 µmol/l (p = 0.0004) and concurrently, estimated GFR decreased from 99 ± 3 to 91 ± 3 ml/min (p = 0.0008). In contrast to creatinine, CysC levels decreased from 0.72 ± 0.02 to 0.68 ± 0.02 mg/l (p = 0.0008). CONCLUSIONS: Our study provides strong evidence for discordant effects of GH on creatinine and CysC in patients with acromegaly undergoing transsphenoidal surgery, thus identifying another hormone that influences CysC independent of renal function.

Growth hormone and Klotho.

Acromegaly is characterized by excessively high GH and IGF1 levels. Recent data suggest that soluble Klotho (sKlotho) is also elevated in patients with active acromegaly. sKlotho decreases towards normal following removal of the GH-producing pituitary adenoma. The Klotho gene was identified in mice following its accidental disruption by ectopic DNA. It is an ageing suppressor gene of restricted expression (mainly in kidneys, brain, and parathyroid and pituitary glands) encoding a transmembrane protein, mKlotho. mKlotho serves as a co-receptor in fibroblast growth factor 23 (FGF23) signalling. FGF23 promotes urinary phosphate excretion and inhibits the synthesis of calcitriol. The ectodomain of mKlotho is enzymatically released to result in a humoral factor, sKlotho, which exerts systemic effects (on ion channels and signalling pathways), possibly by working as an enzyme that modifies glycans of cell surface glycoproteins. GH enhances renal phosphate reabsorption and calcitriol production, i.e. exerts effects in the proximal tubule opposing those attributed to mKlotho, and attenuates calciuria in the distal tubule similar to sKlotho. sKlotho can be measured in extracellular fluids (serum, urine and cerebrospinal fluid (CSF)) by an ELISA. In line with predominant expression of Klotho in kidneys and choroid plexus, concentrations of sKlotho are particularly high in urine and CSF. Determination of sKlotho in serum and urine (both presumably reflecting GH action on the kidneys) could be used as a supplementary tool in the diagnosis and follow-up of patients with acromegaly. The question arises whether GH exerts selected actions via modifying activities of Klotho.

Prognostic factors for impaired plasma sodium homeostasis after transsphenoidal surgery.

OBJECTIVE: Surgical manipulation of the pituitary stalk, neurohypophysis or the hypothalamus may disturb control of the plasma sodium level. The factors that might predict the risk of postoperative sodium imbalance are not clear, and were investigated in this study. METHODS: A retrospective survey of 129 surgical records for the occurrence of plasma sodium levels outside the normal range, following transsphenoidal procedures. Median patient age was 49 (range 20-78) years, 65 female. 73 of the operated lesions were non-functioning pituitary adenomas. Patients were considered to have impaired plasma sodium balance if the range of 135-145 mmol/L was not maintained. RESULTS: Of all 129 surgical cases, 68 (53%) experienced an imbalance in sodium levels. Severe sodium imbalance (≥ 149 or ≤ 131 mmol/L) was observed in 28 patients (22%). 13 showed hypernatraemia (median day 1), and 15 hyponatraemia (median day 6). Tumour size was associated with an increased incidence of sodium imbalance, particularly in patients younger than 49 years; surgery resulted in sodium imbalance in 38% of young patients operated on for tumours < 22 mm and in 76% of young patients, operated on for tumours ≥ 22 mm. Overall, tumour size increased with patients' age, and tumour size was less predictive for sodium disturbances in elderly patients. Median time in hospital was 5 days for patients without sodium imbalance, 6 days for patients with hypernatraemia and 11 days for patients with hyponatraemia. CONCLUSIONS: Following pituitary surgery, patients with large tumours, in particular those of young age, are at higher risk for losing control of their plasma sodium level. Increased ADH secretion (hyponatraemia), but not transient diabetes insipidus was associated with a prolonged hospital stay. Postoperative follow-up of patients with sellar tumours should include careful monitoring of plasma sodium levels within the first two postoperative weeks and clear patients' instructions.

Impact of intraoperative MRI-guided transsphenoidal surgery on endocrine function and hormone substitution therapy in patients with pituitary adenoma.

BACKGROUND: Pituitary adenomas are rare with an incidence of 0.4-8.2 per 105 inhabitants. Symptoms range from headaches to pituitary insufficiency or excessive output of hormones with associated disease. Except for prolactinomas, surgery is recommended as the first line and most effective treatment for the majority of these tumours. One of the refinements of surgical therapy introduced was intraoperative magnetic resonance imaging (iMRI). OBJECTIVE: The aim of this study was to analyse the postoperative pituitary function and the general outcome of patients treated for non-functioning and GH-producing pituitary adenomas with a transsphenoidal iMRI-assisted approach using the PoleStar™ N20 imager. METHODS: A total of 148 consecutive iMRI-guided surgeries for GH-producing and non-functioning pituitary adenomas were retrospectively analysed. Patients' clinical data, endocrinological parameters, clinical examinations and pre-/post- and intraoperative imaging studies were evaluated. RESULTS: A total of 101 patients could be classified as being in remission at follow-up; 26 (17.6%) of them due to iMRI allowing additional tumour removal. A total of 44 patients (29.7%) had more complete tumour removal because remnants were detected by iMRI. The mean hormone levels of patients did not differ significantly between pre- and postoperative examinations. There were 62 patients with preoperative, and 43 patients with postoperative pituitary insufficiency, thus, due to surgery there were 19 (12.8%) patients with improved pituitary function. CONCLUSIONS: The results show this method to be a safe and effective treatment option increasing remission rate and keeping complication rate low. Postoperative pituitary function was preserved or improved - possibly due to more exact iMRI-assisted tumour removal.

Pituitary apoplexy: re-evaluation of risk factors for bleeding into pituitary adenomas and impact on outcome.

OBJECTIVE: To assess frequency, symptoms and outcome of pituitary apoplexy (PA) among pituitary adenoma patients, to gain better insight into risk factors for bleeding into pituitary adenoma and to estimate the sequelae of PA by means of a matched control group. METHOD: By reviewing charts of 574 patients with pituitary adenoma, we analysed incidence, symptoms and outcome of PA and potential risk factors for developing PA by means of a control group (patients with pituitary adenoma without PA). RESULTS: In total, 42 suffered from PA, all had macroadenomas; 30/217 male (14%) and 12/179 female (7%) macroadenoma patients, 32/194 patients with clinically non-functioning (16.5%) and 10/202 with clinically active (5.0%) macroadenoma were affected. Antithrombotic therapy predisposed patients to PA (P=0.026), diabetes mellitus and hypertension did not (P=1.00). Patients with PA and pituitary adenoma patients without PA had similar frequencies of hypopituitarism (45 vs 48%, P>0.05) and visual field defects (38 vs 55%, P>0.05), but ophthalmoplegia was significantly more common (76 vs 5%, P<0.001) in patients with PA. Nearly all patients were treated by surgery; most recovered from ophthalmoplegia, whereas visual function improved only moderately. Endocrine outcome was worse in patients with PA than in patients without PA. CONCLUSIONS: Male sex and characteristics of the adenoma itself (especially tumour size and tumour type) rather than patient's cardiovascular risk factors such as diabetes and hypertension seem to predispose to PA; antithrombotic therapy may also be important.

Olfactory improvement in acromegaly after transnasal transsphenoidal surgery.

OBJECT: The direct transnasal transsphenoidal approach to the sellar region has become a widely adopted surgical procedure among neurosurgeons and ear, nose, and throat specialists. Nasal complications and their incidence have been investigated, but a systematic testing of olfactory disturbance has not previously been performed. Considering that the sense of smell is deeply anchored and interwoven within the CNS, and that its impairment implies a considerable loss in quality of life, surgical practice should aim at its preservation. METHODS: In this retrospective study, pre- and postoperative olfactory performance, nasal airway passage, septal perforation, and epistaxis were assessed in 96 patients who underwent direct transnasal transsphenoidal microsurgery at the authors' department between January 2007 and August 2009. Olfactory performance was assessed using the Sniffin' Sticks test and/or the Zürcher Geruchstest. RESULTS: After surgery, 47 (49%) of 96 patients improved, 34 (35%) of 96 deteriorated, and 15 (16%) of 96 presented with unchanged olfactory performance. With respect to the underlying pathological entity, the authors noticed a remarkable difference between patients with acromegaly (23 cases) and all other patients (73 cases). Fifteen (65%) of 23 patients with acromegaly improved (others 44%), only 3 (13%) of 23 deteriorated (others 42%), and 5 (22%) of 23 remained unchanged (others 14%) in their ability to distinguish odors. This illustrates a significant shift toward improved postoperative olfactory performance (cross-tabulation, Fisher exact test; p = 0.028) in patients with acromegaly. In nasal breathing, 77 (80%) of 96 patients noticed no change, 11 (12%) of 96 improved, and 8 (8%) of 96 worsened postoperatively. Of the 11 patients with improved breathing, 6 (55%) had acromegaly. Improved nasal airway patency was more frequent in patients with acromegaly (cross-tabulation, Fisher exact test; p = 0.002). CONCLUSIONS: The data provide the first significant evidence for improvement in olfactory performance in patients with acromegaly after transsphenoidal surgery (TSS) of growth hormone-producing adenomas. Furthermore, postoperative olfactory disturbance in patients treated with transnasal TSS is more frequent than previously reported. Nevertheless, recurrent transnasal TSS can be performed successfully, even multiple times, and does not involve a higher risk of nasal complications.

Intraoperative magnetic resonance imaging-assisted transsphenoidal pituitary surgery in patients with acromegaly.

OBJECT: Acromegaly is a rare disease, usually caused by a growth hormone (GH)-producing pituitary adenoma. If untreated, severe cardiovascular, metabolic, cosmetic, and orthopedic disturbances will result. Surgery is generally recommended as the first-line treatment. Transsphenoidal surgical techniques were recently extended by the introduction of intraoperative MR (iMR) imaging. In the present study, the contribution of ultra-low-field (0.15-T) iMR imaging to tumor resection, complication avoidance, and endocrinological and neurological outcome was analyzed. METHODS: A series of 39 consecutive transsphenoidal iMR imaging-guided (using the PoleStar N20 device) surgical procedures performed between September 2005 and August 2009 for GH-producing pituitary adenomas was retrospectively analyzed. In addition to the patients' clinical data, the following criteria were evaluated independently: duration of surgery; length of hospital stay; endocrinological parameters; results of neurological examinations; and pre-, post-, and intraoperative MR imaging results. RESULTS: Thirty-seven patients with acromegaly underwent 39 transsphenoidal surgeries for pituitary adenomas. During a median follow-up period of 30 months (range 9-56 months), the remission rate was 73.5% in 34 patients with primary surgery and 20% in 5 cases with previous surgery; overall the remission rate was 66.7%. There were no serious postoperative complications. Detection of tumor remnant on iMR imaging led to a 5.1% increase in remission rate. CONCLUSIONS: In this largest study to date of GH-producing pituitary adenomas in which iMR imaging-guided transsphenoidal surgery was analyzed, the results suggest that this method is a highly effective and safe treatment modality, even compared with previously published surgical series in which high-field iMR imaging was used. Limitations of iMR imaging are the detection of small residual tumor in the cavernous sinus and persisting disease that could not be observed, even on diagnostic high-field follow-up MR images. This points to a general limitation regarding remission rates that can be achieved using iMR imaging. Nevertheless, iMR imaging led to an increase of the remission rate in this study.

Effects of thyroxine replacement on serum creatinine and cystatin C in patients with primary and central hypothyroidism.

BACKGROUND: Serum cystatin C (CysC) is a marker for kidney function, possibly superior to serum creatinine (Cr). Cr is increased and CysC decreased in primary hypothyroidism; these changes are reversed upon thyroxine (T4) replacement therapy. This (pilot) study was performed to see whether these opposing changes of CysC and Cr could be confirmed in patients with central hypothyroidism. METHODS: Prospective case series of consecutively referred patients with primary and central hypothyroidism. CysC and Cr were determined at the time of diagnosis and following T4 replacement therapy. RESULTS: 32 patients with newly diagnosed hypothyroidism were included. In 16 patients with primary hypothyroidism, mean fT4 was 4.4 +/- 2.5 pmol/l (normal range 12 to 22) at diagnosis and increased to 20.1 +/- 5.2 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.79 +/- 0.27 mg/l (normal range 0.63 to 1.33) to 1.03 +/- 0.42 mg/l (p = 0.007) whereas Cr declined from 104 +/- 21 micromol/l to 90 +/- 19 micromol/l (p <0.001). In 16 patients with central hypothyroidism, mean fT4 was 6.5 +/- 1.6 pmol/l at diagnosis and increased to 15.7 +/- 3.3 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.74 +/- 0.27 mg/l to 0.83 +/- 0.30 mg/l (p = 0.01) whereas Cr was not elevated at baseline (83 +/- 11 micromol/l) and did not decrease following treatment (84 +/- 10 micromol/l). CONCLUSIONS: CysC was low at diagnosis of hypothyroidism and significantly increased following T4 replacement in patients with primary as well as central hypothyroidism. T4 replacement decreased Cr levels in patients with primary hypothyroidism whereas Cr remained unchanged in;patients with central hypothyroidism. CysC may not accurately reflect kidney function in patients with primary and central thyroid dysfunction.

Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme.

OBJECTIVES: Glioblastoma multiforme (GBM) may potentially be responsive to antiangiogenic therapies as these tumors are highly vascularized and overexpress angiogenic factors. Thalidomide exhibits antiangiogenic activity and may provide additive or synergistic antitumor effects when given concurrently with temozolomide, an alkylating agent. To further evaluate this new concept of combining an antiangiogenic with an alkylating agent, efficacy and tolerability of thalidomide alone and in combination with temozolomide were explored in a single-institution, nonrandomized open-label phase II study. PATIENTS AND METHODS: Forty-four patients with GBMs, who received thalidomide for a period of at least three months, were evaluated for survival, time to tumor progression (TTP), and side effects. Microsurgical tumor extirpation and radiotherapy preceded chemotherapy. Nineteen patients (43%) received thalidomide only (T), and 25 patients (57%) had a combined chemotherapy of thalidomide and temozolomide (TT). Median thalidomide dosage was 200 mg/day. Median temozolomide dosage was 200 mg/m2/day for five days, in monthly cycles. Neuroradiological outcomes were assessed by a semiquantitative grading system. RESULTS: Median survival was 103 weeks (95% CI, 65-141 weeks) for TT-patients and 63 weeks (95% CI, 49-77 weeks) for T-patients (p < 0.01). Median TTP for the TT-group was 36 weeks (95% CI, 20-52 weeks) and 17 weeks (95% CI, 13-21 weeks) for the T-group (p < 0.06). Neuroradiologically, 14 patients (56%) of the TT-group and six (32%) of the T-group had evidence of stable disease on at least two successive neuroradiological follow-ups. Progressive disease was found in nine patients (36%) of the TT-group and in 13 (68%) of the T-group. In two patients (8%) of the TT-group, a response with tumor regression was found. Thalidomide and concurrent temozolomide were safe and well tolerated with mild to moderate toxicities. CONCLUSIONS: The combination of thalidomide and temozolomide in the treatment of GBM appears to be more effective than that of thalidomide alone with respect to survival, TTP, and neuroradiological documentation of progression, stable disease or response. Further concurrent prospective studies of these agents in a larger group of patients with GBM will be required to establish the soundness of these intriguing observations.

Histological yield, complications, and technological considerations in 114 consecutive frameless stereotactic biopsy procedures aided by open intraoperative magnetic resonance imaging.

OBJECT: The authors undertook a prospective study of frameless, magnetic resonance (MR)-guided stereotactic brain biopsy procedures performed with the aid of an open MR system. Morbidity and mortality rates, frequency of postoperative hemorrhage, and histological yield were evaluated, as well as the size and location of the lesions under investigation. METHODS: During a period of 51 months (July 1996-November 2000), 114 consecutive frameless stereotactic biopsy procedures were performed with the aid of an open intraoperative MR system to investigate supratentorial lesions in 113 patients. The median volume of the lesions was 33.5 cm3, and 31.9% were deep seated. All biopsy samples comprised pathological tissue and in 111 (97.4%) of 114 a specific neuropathological diagnosis was made. A follow-up computerized tomography (CT) scan was obtained on the 1st postoperative day in all patients to evaluate postoperative complications. In two cases (1.8%), a hemorrhage was found on postoperative CT scans, with no neurological worsening of the patients. Morbidity with neurological worsening was seen in three patients; it was transient in two of them (1.8%), and in one (0.9%) subsequent emergency craniotomy was necessary because of increased edema. There were no infections, but there was one death (0.9%) CONCLUSIONS: Open intraoperative MR imaging transforms a blind conventional stereotactic procedure into a visually controlled procedure that is adaptable to dynamic anatomical changes. Routine postprocedural MR imaging makes follow-up CT scanning obsolete. This largest reported series of intraoperative MR-guided biopsy procedures shows results that are at least comparable with those in reports of larger series of conventional stereotactic biopsy sampling. The mean procedure time was 60 minutes including planning, and this method produced low morbidity and complication rates and a high histological yield.

Interventional MR-guided neuroendoscopy: A new therapeutic option for children.

Neuroendoscopic treatment of hydrocephalic children is an established surgical modality. Open magnetic resonance imaging (MRI) technology introduces new imaging features that, in combination with endoscopy, seem particularly valuable for performing these operations. "Near" real-time production of MR images in 3 dimensions during the procedure allows real-time neuronavigation, thus, facilitating guidance of an endoscope. Additionally, intraoperative changes such as brain shift, effects of perforation, and drainage of cysts are shown during an ongoing procedure. The patency of cysts or fluid compartments inside the ventricular system can be controlled by intraoperative injection of diluted gadolinium into the cystic compartments. These new therapeutic options were applied in 2 hydrocephalic children with complex ventricular cysts: a 3-month-old girl with a large, septated arachnoidal cyst and internal hydrocephalus and a boy of 7 years, 2 months with congenital hydrocephalus and premature closure of the coronary sutures.