Josef Marek

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

Gamma knife radiosurgery for acromegaly – long‐term experience

Objective  The Leksell gamma knife (LGK) is one of the treatment options for pituitary adenomas. We report on our long‐term experience treating acromegaly using LGK.

Radiation Tolerance of Functioning Pituitary Tissue in Gamma Knife Surgery for Pituitary Adenomas

OBJECTIVEThis study is intended to contribute to a determination of the sensitivity of preserved hypophyseal function to focal radiation in pituitary adenomas. METHODSWe compared two subgroups of patients followed up for a median of 5 years after gamma knife surgery (GKS). Subgroup 1 (n = 30) showed postirradiation hypopituitarism. Subgroup 2 (n = 33) was continually eupituitary. These subgroups were taken from a previously published study relating to a larger group of 163 patients with pituitary adenomas treated by GKS and evaluated after a median follow-up period of 2 years. A relatively high treatment dose was used in this larger group (median, 20 Gy to the tumor margin for growth control in nonfunctioning adenomas; median, 35 Gy for hypersecreting adenomas). Early results approached those of microsurgery, and there were only a few side effects. In the present study, we compared 16 different variables in the same two subgroups to discover the relationships that caused a delayed appearance of postirradiation hypopituitarism. The main pretreatment and treatment parameters were measured on reconstructed treatment plans. This database was used for statistical evaluation. RESULTSThe relationship between the mean dose and the volume of functioning hypophysis was stronger in terms of worsening of pituitary function than that of the spot dose to different intrasellar structures. We found that for our group of patients, the safe mean dose of radiation to the hypophysis was 15 Gy for gonadotropic and thyrotropic functions and 18 Gy for adrenocorticotropic function. The worsening of pituitary function was also significantly dependent on the dose to different anatomic levels of the infundibulum, but we did not succeed in fully characterizing this relationship. In addition, we discovered significant levels of dependency of postirradiation pituitary damage to different pretreatment and treatment variables. CONCLUSIONKnowledge of the radiation tolerance of functioning pituitary structures subjected to GKS can ensure better preservation of pituitary function after irradiation. This is valid for the group of patients we studied. Our study’s findings can be used as a guideline for GKS treatment of new patients with pituitary adenomas, and it can serve for comparison with the experience of other gamma knife centers.

Regression of acromegalic left ventricular hypertrophy after lanreotide (a slow-release somatostatin analog)

A group of 13 acromegalic patients was treated with lanreotide for 18 months and followed-up echocardiographically; these patients showed significant correlations between the decrease of both growth hormone (GH) and insulin-like growth factor-1 and the decrease of left ventricular mass index. This documents a regression of left ventricular hypertrophy in acromegaly after lanreotide treatment, the degree of which is dependent on the magnitude of the decrease of GH and insulin-like growth factor-1 serum levels.

Prevalence of the sleep apnea syndrome in acromegaly population

The prevalence of sleep apnea syndrome (SAS) in acromegaly is high. Consequences of SAS are serious and are associated with increased morbidity and mortality. The aim of this study was to assess the relative frequency and predictive factors for SAS in a group of patients with acromegaly (n=55). The presence of SAS was evaluated using the Polymesam device. Hormonal and clinical examination consisted of assessment of growth hormone, insulin-like growth factor I plasma levels, body mass index (BMI), neck circumference, age, sex, treatment modes of acromegaly and ear, nose and throat (ENT) examination. The relative frequency of SAS in our group of patients with acromegaly was 75%. Independent predictors of SAS were: increased activity of acromegaly, higher age and neck circumference. No association between SAS and BMI and ENT findings was observed. The role of gender was controversial.

Perturbations in adiponectin, leptin and resistin levels in acromegaly: lack of correlation with insulin resistance

background Insulin resistance, impaired glucose tolerance and type 2 diabetes are common in acromegalic subjects. The mechanism underlying this insulin resistance is unclear.

Gamma knife radiosurgery for endocrine-inactive pituitary adenomas

SummaryBackground. The goal of nonsecreting pituitary adenoma radiosurgery is to halt tumour growth and to maintain normal performance of the hypophysis and the functionally important structures around the sella. The effectiveness of gamma knife radiosurgery was evaluated. Method. Over a period of 10 years (1993–2003), 140 patients with nonsecreting pituitary adenoma were treated by Leksell gamma knife at our Centre. Seventy-nine of them were followed up for longer than 3 years. Their age range was 24–73 years, with a median of 54 years. Eighty-five percent of them had previous open surgery. Fifteen patients had adenoma contact with the optic tract. Fourteen patients had a normally functioning hypophysis, 48 patients had complete panhypopituitarism, while the rest retained partial functions of the normal hypophysis. Adenoma volumes ranged between 0.1 and 31.3, the median being 3.45 ccm. The marginal dose ranged between 12 and −35 Gy, with a median of 20 Gy. Findings. The follow-up ranged from 36 to 122 months, with a median of 60 months. No adenoma growth was detected; 89% of treated adenomas decreased in size, with a median volume reduction of 61%. There was no perimeter vision impairment after radiosurgery, while 4 out of 52 patients with abnormal perimeter vision reported improvement. There was no impairment of oculomotor nerve function. Impairment of hypophysis function was observed in 2 patients. Conclusions. Radiosurgery has a reliable antiproliferative effect on nonsecreting pituitary adenomas. It is a safe treatment with a low risk of morbidity. Short contact between a nonsecreting pituitary adenoma and the optic pathway is not an absolute contraindication for Gamma knife radiosurgery.

Recurrent ACTH‐independent Cushing's syndrome in multiple pregnancies and its treatment with metyrapone

A 17‐year‐old primigravid woman presented with Cushings syndrome. Typical clinical symptoms and signs developed at the beginning of pregnancy. By week 17 of gestation, plasma cortisol diurnal rhythm was absent and there was a paradoxical increase in plasma cortisol after a 1‐mg dexamethasone overnight suppression test. Basal urinary free cortisol was 10 times above the upper limit (in pregnancy) and ACTH levels were suppressed. The diagnosis of ACTH – independent Cushings syndrome was established. MRI scans revealed normal adrenal and pituitary glands. To control hypercortisolism, the patient was treated with metyrapone. At 34 weeks of gestation, the patient developed preeclampsia and underwent caesarean section. A female infant weighing 1070 g was delivered. No apparent metyrapone‐induced teratogenic effects were observed. Cushings syndrome in the patient resolved within three weeks of delivery. No corticosteroid replacement therapy either for child or mother was needed. Eight months after delivery the patient became pregnant again and rapidly developed Cushings syndrome with typical clinical symptoms and signs and laboratory results (urinary free cortisol 6464 nmol/24 h). This second pregnancy was unwanted and terminated by artificial abortion that was followed by rapid resolution of hypercortisolism. A third pregnancy, 12 months after delivery was also accompanied by the rapid development of hypercortisolism which recovered after artificial termination.

Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone

OBJECTIVE To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120  mg/month) and pegvisomant (40-120  mg/week) in acromegaly. DESIGN This is a 28-week, multicenter, open-label, single-arm sequential study. METHODS Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120  mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120  mg/month plus pegvisomant (60  mg once weekly, adapted every 8 weeks based on IGF1 levels to 40-80  mg once weekly or 40 or 60  mg twice weekly). RESULTS In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60  mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60  mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (-0.6 ± 1.6) and soft tissue swelling (-0.6 ± 1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related - thrombocytopenia, urticaria; not treatment related - abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5 × upper limit of normal with normalization after withdrawal). CONCLUSIONS In patients partially controlled by SSAs, LA (120  mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60  mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.

Cephalometric assessment of cranial abnormalities in patients with acromegaly

OBJECTIVE AND PATIENTS Patients with acromegaly (12 women, 26 men) and a control group (36 women, 50 men) were chosen for cephalometry to assess the size, shape and positional characteristics of the craniofacial bones and the upper airways. RESULTS When compared with the controls, patients of both sexes with acromegaly were found to have significant anomalies in the orofacial skeleton: increased facial height, elongated ascending ramus mandibulae and greater basion-supramentale distance, a negative difference between maxillary and mandibular protrusions, enlarged lower part of the gonion angle and of the angle of inclination of the maxilla, as well as alterations in the neurocranium: enlargement of sella turcica and of sinus frontalis and protrusion of the supraorbital ridges. As for the soft tissues, patients with acromegaly exhibited an elongated soft palate and a diminished angle between the uvular axis and the palatal plane. A comparison between the cephalometric parameters of patients with active acromegaly and those without active disease revealed no significant differences in either sex. CONCLUSION Patients with acromegaly exhibited an enlargement of all parts of the neurocranium and orofacial bones except the maxilla. The greatest anomaly was seen in the mandible, with greater enlargement of the ascending ramus than of the body of the mandible. The shape of this bone was also altered.