Johannes Hensen

Lymphocytic and granulomatous hypophysitis: experience with nine cases.

OBJECTIVE Lymphocytic hypophysitis and granulomatous hypophysitis are rarely encountered. The aim of this study was to demonstrate their clinical peculiarities among pituitary disorders and to provide an approach for their clinical management. METHODS In a retrospective study, we reviewed our surgical experience with nine patients harboring hypophysitis. The series included six cases of lymphocytic hypophysitis, two cases of granulomatous hypophysitis, and one case with evidence of coexisting lymphocytic and granulomatous hypophysitis. RESULTS A striking similarity of clinical signs was found for our nine patients. Headache or aseptic meningitis, thickening of the sphenoid sinus mucosa, pituitary stalk enlargement, and tongue-shaped extension of the lesion along the basal hypothalamus were characteristic signs. Lymphocytic hypophysitis was not associated with pregnancy in any of the seven cases. No recurrence has been observed in six cases with total removal of the inflammatory tissue. CONCLUSION Lymphocytic hypophysitis and granulomatous hypophysitis represent related inflammatory disorders. Their conspicuous clinical features frequently allow preoperative diagnosis of hypophysitis. In view of their sometimes insidious clinical course, early surgical exploration is justified.

Endothelin-like immunoreactivity in aqueous humor of patients with primary open-angle glaucoma and cataract

Abstract• Background: Experimental evidence suggests a role of endothelin-1 (ET) in the regulation of intraocular pressure (IOP). • Method: Therefore, inpatients undergoing cataract surgery, ET-like immunoreactivity (STIR) was measured by radioimmunoassay in pooled samples of aqueous humor of eyes with primary open-angle glaucoma (POAG) and normotensive eyes with cataract only. • Results: ETIR was significantly (P < 0.05) higher in patients with cataract and POAG (20.5 ± 1.8 pg/ml,n = 12; preoperative IOP 21.4 ± I.1 mmHg,n = 33) than in patients with cataract only (15.8 ± 1.6 pg/m1,n = 15; preoperative IOP 16.0 ± 0.6 mmHg,n = 77). • Conclusion: This finding may indicate a role of ET in POAG or ocular antihypertensive treatment, and its relevance should be further investigated.

Prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after transsphenoidal surgery for pituitary adenomas

Disturbances of osmoregulation, leading to diabetes insipidus and hyponatraemia are well known complications after surgery in the sella region. This study was performed to examine the prevalence and predictors of polyuria and hyponatraemia after a complete and selective removal of pituitary adenomas was attempted via the transnasal–transsphenoidal approach.

Endothelin-like immunoreactivity in the aqueous humour and in conditioned medium from cultured ciliary epithelial cells

Endothelin-like immunoreactivity was detected in human (15.6 +/- 2.7 pg/ml) and bovine (11.1 +/- 0.98 pg/ml) aqueous humour of the eye. These concentrations are 2-3 times higher than the corresponding plasma levels. Cultured human nonpigmented ciliary epithelial cells released endothelin-like immunoreactivity with a maximum of 2.1 +/- 0.32 pg/(cm2* 48 h). The release was stimulated by fetal calf serum, thrombin, carbachol and phorbol ester and blocked by cycloheximide. Immunocytochemistry showed cytoplasmic staining of cultured human nonpigmented ciliary epithelial cells for endothelin-1. Endothelin-1 was shown to induce contractions in isolated human ciliary muscle by isometric force measurements. Endothelin in the aqueous humour may play a role in the regulation of intraocular pressure.

Endokrine Orbitopathie: Vergleich der Langzeitergebnisse und Klassifikationen nach Radiotherapie

ZusammenfassungHintergrundDiese Studie vergleicht vier verschiedene Klassifikationen bei Patienten mit fortgeschrittener, therapierefraktärer endokriner Orbitopathie und untersucht deren prognostische Wertigkeit.Patienten und MethodeVon 1984 bis 1994 wurden 60 konsekutive Patienten (49 Frauen, elf Männer) wegen progredienter, therapierefraktärer endokriner Orbitopathie bestrahlt (Linac 6 MV, 10mal 2 Gy). Im Verlauf wurden die Symptome und funktionellen Einschränkungen nach vier Klassifikationen bewertet: Werner-Score, modifizierter ATA-Score, Standford-Score und Ophthalmopathieindex (OI) nach Grussendorf [26, 27]. Außerdem notierten alle Patienten das subjektive Ansprechen auf einer linearen Skala (0 bis 100%).ErgebnisseIm Verlauf eines Jahres nach Radiotherapie besserten sich der Werner-Score bei 28 (47%) Patienten um ≥1 Kategorie, nach modifizierten ATA-Score 48 (80%), nach Stanford-Score 47 (78%) und nach OI-Score 55 (92%) Patienten (Reduktion um >2 Punkte). Der Werner-Score korrelierte kaum mit den anderen Scores (Koeffizient r<0,5), während diese untereinander hoch korrelierten (r ∼0,9). Der modifizierte ATA-Score besserte sich in den einzelnen Symptomkategorien zwischen 47% (Stadium VI) und 87% (Stadium V). Der OI-Score reduzierte sich im Mittel um sechs Punkte. Das subjektive Befinden besserte sich um +70±25%. Akute oder chronische Nebenwirkungen traten nicht auf. In multivariater Analyse waren das „männliches Geschlecht” (p=0,08)., die „Symptomdauer vor Radiotherapie >1 Jahr” (p=0,14) und die „hohe Symptomkategorie” (p=0,11) tendenziell negative Prognosefaktoren.SchlußfolgerungDie Radiotherapie ist auch bei schwerer progredienter endokriner Orbitopathie effektiv. Zur Bewertung sind mindestens zwölf Monate Nachbeobachtung und einheitliche Bewertungskriterien erforderlich.AbstractBackgroundThis study compares 4 classifications in patients with progressive refractory Graves orbitopathy (GO) and examines their prognostic value in long-term follow-up.Patients and MethodsFrom 1984 to 1994, 60 consecutive patients (49 female, 11 male) received 20 Gy (10×2 Gy) radiotherapy with 6 MV Linac photons. Ocular symptoms and functional impairment was evaluated according to 4 GO-classification systems: Werner-, modified ATA- and Stanford-Score and Ophthalmopathy-Index (OI) according to Grussendorf [26, 27]. In addition, all patients noted their subjective response on a linear scale (0 to 100%).ResultsImprovement was achieved within 1 year after radiotherapy according to the Werner-Score in 28 (47%) patients in ≥1 symptom category, according to the modified ATA-score in 48 (80%), the Stanford-score in 47 (78%) and the OI-Score in 55 (92%) patients (reduction of >2 points). The Werner-Score correlated less to the other scores (coeffizient r<0.5) than the other scores among themselves (r ∼0.9). The ATA-Score improved in the different symptom categories between 47% (stage VI) and 87% (stage V). The OI-Score was reduced by a mean of 6 points. The patients reached a mean subjective improvement of +70±25%. Acute or chronic side effects were not observed. In multivariate analysis the “male gender” (p=0.08), a “symptom duration prior to radiotherapy >1 year” (p=0.14) and a “high symptom category” (p=0.11) indicated a negative prognostic trend.ConclusionsExternal radiotherapy is effective for severe, progressive GO after pretreatment. A minimum follow-up of at least 12 months and standardized classification and success criteria are required.

Long-Term Follow-Up of Childhood-Onset Hypopituitarism in Patients with the PROP-1 Gene Mutation

Objective: The PROP-1 gene mutation is a rare disorder leading to combined pituitary hormone deficiencies over time. The aim was to analyze the clinical picture of 40 years of an almost untreated PROP-1 gene mutation. Methods: We describe the clinical and hormonal data of 2 brothers from childhood to adulthood as well as imaging procedures (MRI of the pituitary gland, bone mineral density by QCT and DPX). The PROP-1 gene mutation (301–302delAG) was confirmed by DNA sequencing. Results: Although long-standing untreated hypopituitarism was present, there was normal physical and professional activity. Bone mineral density was low only in 1 patient. Adrenocortical deficiency occurred late at 45 and 39 years. Conclusions: The biological evolution of the PROP-1 gene mutation illustrates the importance of continuous care for these patients. Hormonal deficiencies do not necessarily lead to the same phenotype as is obvious in differences of bone age and bone mineral density.

Doxorubicin and streptozotocin after failed biotherapy of neuroendocrine tumors.

Background: Well-differentiated neuroendocrine tumors are treated primarily with somatostatin analogs and interferon-α. It is not clear what therapy should be applied after failed biotherapy. Our aim was to establish whether patients whose tumors rapidly progress under biotherapy may benefit from chemotherapy.Patients and Methods: In 10 patients with metastatic neuroendocrine tumors (4 foregut, 3 midgut, 1 retroperitoneal, and 2 of unknown origin) streptozotocin and doxorubicin were used as second-line or third-line therapy. Tumor response was assessed by computed tomography of the abdomen and thorax and measurement of tumor secretion products (serum chromogranin A, urinary 5-hydroxyindoleacetic acid).Results: Three patients showed a radiological response over a mean time of 30 mo (range: 7–67 mo). Median survival after initiation of chemotherapy was 50 mo in patients with a response and 8 mo in non-responders. Three patients developed major side effects (nephrotoxicity, diabetes, and encephalopathy).Conclusion: Streptozotocin and doxorubicin produce poor response rates in patients with progressive neuroendocrine tumors after failed biotherapy, but may prolong life in those patients who show a tumor response.

Verminderte Inzidenz von Nebenwirkungen einer Wachstumshormonsubstitution bei 404 Patienten mit Hypophyseninsuffizienz

Zusammenfassung□ HintergrundDie Substitutionstherapie bei hypophyseninsuffizienten Patientten mit rekombinantem, menschlichen Wachstumshormon (rhGH) zusätzlich zur konventionellen Substitution mit Glucocorticoiden, L-Thyroxin und Geschlechtshormonen ist seit 1995 zugelassene Indikation mit der Auflage der Zulassungsbehörden, Anwendungsbeobachtungen zur Dokumentation der Langzeitsicherheit durchzuführen.□ Patienten und MethodeEs wird über die ersten deutschen Ergebnisse der Kabi-International-Metabolic-Study-(KIMS-) Anwendungsbeobachtung von Pharmacia & Upjohn, Erlangen, berichtet. In KIMS eingeschlossen wurden 404 Patienten aus 35 Zentren (227 Männer=56% und 177 Frauen=44%). 32 Patienten (8%) beendeten die Therapie. 25% der Patienten hatten einen Wachstumshormonmangel (GHD), der in der Kindheit aufgetreten war.□ Ergebnisse24% aller Patienten waren im zweiten Jahr ihrer Therapie, 15% in ihrem vierten Jahr, die längste Behandlung dauerte sechs Jahre. Bei der Altersverteilung wurden zwei Spitzen beobachtet: 30 bis 39 Jahre (24%) und 50 bis 59 Jahre (24%). Die Ursachen der Hypophyseninsuffizienz waren wie folgt: Hypophysenadenome (47%), idiopathisch (16%), Kraniopharyngeome (16%) und andere (21%). Die mittlere GH-Dosis lag bei 1,5 IU/Tag (0,4 bis 4 IU/Tag). Hierunter stieg das Serum-IGF-1 (insulinähnlicher Wachstumsfaktor) um 159 bis 192% bei Frauen bzw. Männern nach sechs Monaten Behandlung signifikant an. Der Taillenumfang nahm bei Männern um 2% ab, das Serumcholesterin wurde um 5,5% gesenkt. Bei zwei Patienten wurde während des Beobachtungszeitraums ein neues Karzinom diagnostiziert, eine Patientin verstarb, ein Patient entwickelte einen Diabetes mellitus II. Die Inzidenz unerwünschter Ereignisse (AEs) in KIMS wurde mit der Inzidenz in den Verum-(GH-) Gruppen bzw. Placebo-(Pl-) Gruppen früherer Zulassungsstudien verglichen (in Prozent): Ödeme: KIMS 10, GH 37, Pl3; Arthralgien: KIMS 8, GH 19, Pl 2; Muskelschmerzen: KIMS 2, GH 3, Pl 2; andere: KIMS 2, GH 22, Pl 13. Die angegebene Inzidenz an AEs in KIMS war signifikant niedriger als in den vorangegangenen Zulassungsstudien. Hierfür gibt es drei Gründe: 1. AEs, die scheinbar nicht mit einer GH-Therapie in Zusammenhangstehen, werden weniger häufig gemeldet. 2. Die verwendeten Dosen lagen in KIMS um die Hälfte niedriger als in den Zulassungsstudien. 3. In KIMS erfolgte eine Dosistitrierung für jeden individuellen Patienten.□ SchlußfolgerungDie Daten zeigen, daß Anwendungsbeobachtungen gut geeignet sind, um die Langzeitwirkungen und -sicherheit einer GH-Therapie zu dokumentieren. Eine dosistitrierte GH-Substitution bei hypophyseninsuf fizienten Patienten führt zu einer geringeren Nebenwirkungsrate.Abstract□ BackgroundSubstitution of pituitary insufficient patients with recombinant human growth hormone (rhGH) in addition to the conventional substitution with glucocorticoids, L-thyroxine and sex hormones has been approved by the regulatory authorities in 1995 with the imposition to conduct surveillance studies to monitor drug safety.□ Results24% of all patients were within their 2nd treatment year, 15% within their 4th year, maximum treatment period was 6 years. There were 2 peaks within the patients age distribution: 30 to 39 years (24%) and 50 to 59 years (24%). The causes for pituitary disease were as follows: pituitary adenomas (47%), idiopathic (16%), craniopharyngeomas (16%) and others (21%). Mean GH dose was 1.5 IU/ds. c. (range 0.4 to 4 IU/d). Serum-IGF-1 increased by 159 and 192% in females and males. Waist circumference decreased by 2% and serum cholesterol was lowered by 5.5% in males. There were 2 cases with new carcinomas, 1 diabetes mellitus II and 1 death. Adverse events (AEs) within KIMS were compared to those of the treatment (GH) and placebo (Pl) groups of the previous admission trials (in percent): edema: KIMS 10, GH 37, Pl 3; arthralgia: KIMS 8, GH 19, Pl 2; muscle pain: KIMS 3, GH 16, Pl 3; dizziness: KIMS 2, GH 1, Pl 3; headache: KIMS 2, GH 3, Pl 2; others: KIMS 2, GH 22, Pl 13. The reported incidence of AEs in KIMS was lower than in previous clinical trials. There might be 3 reasons for this: 1. under-reporting, particularly those AEs not likely to be related to GH treatment; 2. doses used in trials were 2-fold higher than in KIMS; 3. dose titration for individual patients.□ ConclusionSurveillance programs are important for monitoring of drug long-term efficacy and safety.BACKGROUND Substitution of pituitary insufficient patients with recombinant human growth hormone (rhGH) in addition to the conventional substitution with glucocorticoids, L-thyroxine and sex hormones has been approved by the regulatory authorities in 1995 with the imposition to conduct surveillance studies to monitor drug safety. RESULTS 24% of all patients were within their 2nd treatment year, 15% within their 4th year, maximum treatment period was 6 years. There were 2 peaks within the patients age distribution: 30 to 39 years (24%) and 50 to 59 years (24%). The causes for pituitary disease were as follows: pituitary adenomas (47%), idiopathic (16%), craniopharyngeomas (16%) and others (21%). Mean GH dose was 1.5 IU/d s.c. (range 0.4 to 4 IU/d). Serum-IGF-1 increased by 159 and 192% in females and males. Waist circumference decreased by 2% and serum cholesterol was lowered by 5.5% in males. There were 2 cases with new carcinomas, 1 diabetes mellitus II and 1 death. Adverse events (AEs) within KIMS were compared to those of the treatment (GH) and placebo (PI) groups of the previous admission trials (in percent): edema: KIMS 10, GH 37, Pl 3; arthralgia: KIMS 8, GH 19, Pl 2; muscle pain: KIMS 3, GH 16, Pl 3; dizziness: KIMS 2, GH 1, Pl 3; headache: KIMS 2, GH 3, Pl 2; others: KIMS 2, GH 22, Pl 13. The reported incidence of AEs in KIMS was lower than in previous clinical trials. There might be 3 reasons for this: 1. under-reporting, particularly those AEs not likely to be related to GH treatment; 2. doses used in trials were 2-fold higher than in KIMS; 3. dose titration for individual patients. CONCLUSION Surveillance programs are important for monitoring of drug long-term efficacy and safety.

Osteoporose und Mehrlingsgravidität – ein Erfahrungsbericht mit positivem Ausgang

ZusammenfassungHintergrund: Die schwangerschaftsassoziierte Osteoporose ist ein seltenes Ereignis. Deshalb bestehen keine klaren therapeutischen Richtlinien, wobei die Therapie aufgrund der potentiellen Teratogenität vieler Resorptionshemmer ohnehin limitiert ist. Fallbericht: Bei einer 30-jährigen Patientin kam es im Verlauf der ersten Schwangerschaft zu einer Schambeinfraktur. Osteodensitometrisch konnte eine ausgeprägte Osteoporose nachgewiesen werden. Unter Therapie mit Alendronat, 1 000 mg Calcium und 1 000 IE Cholecalciferol/die und sequenzieller Östrogen-/Gestagensubstitution konnte die Knochendichte angehoben werden, lag aber noch im osteoporotischen Bereich, als die Patientin 3 Jahre später erneut schwanger wurde. Nach Absetzen von Alendronat konnte bei bestehender Drillingsschwangerschaft durch Erhöhung der Calciumsupplementation auf 3 000 mg/die und der Cholecalciferolgabe auf 1 500 IE/die ein Status idem zur Knochendichte unmittelbar vor der zweiten Schwangerschaft beibehalten werden. Schlussfolgerung: Mit diesem Konzept könnte der eigentlich in der Schwangerschaft zu befürchtende Knochenmasseverlust verhindert worden sein; dies bedarf aber noch der Überprüfung an größeren Fallzahlen.AbstractBackground: Pregnancy-associated osteoporosis is a rare condition. Due to the rareness of pregnancy-associated osteoporosis, no guidelines concerning an adequate therapy exist. However, since many antiresorptive drugs are potentially teratogenous, the therapeutic approach is limited. Case Report: In a 30-year-old patient, pubic fracture occurred during her first pregnancy. Osteodensitometry revealed a distinct osteoporosis. The bone density improved under therapy with sex hormones, alendronate, 1,000 mg calcium and 1,000 IU cholecalciferol daily, but still remained osteoporotic when the patient again became pregnant 3 years later. During her triplet pregnancy the patient was treated with 3,000 mg calcium and 1,500 IU cholecalciferol daily. After delivery the bone density remained at the same level as immediately before the second pregnancy. Conclusion: Regarding the nonoccurrence of the expected considerable bone loss with this treatment the efficacy of this therapeutic approach during pregnancy warrants further study.

Thyroid disorders and pregnancy

ZusammenfassungSchilddrüsenerkrankungen sind bei Frauen im reproduktionsfähigen Alter häufig. Eine falsche oder zu spät begonnene Therapie während der Schwangerschaft kann erhebliche negative Auswirkungen auf Mutter und Kind haben. Für eine korrekte Beurteilung der Schilddrüsenfunktion während der Schwangerschaft ist die Kenntnis der typischen schwangerschaftsbedingten physiologischen Veränderungen erforderlich. Schilddrüsendysfunktionen, insbesondere die Hypothyreose, bedingen Fertilitätseinschränkungen. Eine Autoimmunthyreoiditis ist mit einem höheren Abortrisiko assoziiert. Bei substituierter Hypothyreose der Mutter muss die Levothyroxindosis an den erhöhten Bedarf angepasst werden. Für die fetale Entwicklung ist eine ausreichende Versorgung mit Schilddrüsenhormon wichtig. Schwangerschaft und Stillzeit erfordern außerdem eine zusätzliche Zufuhr von Jodid. Eine mütterliche Hyperthyreose muss konsequent behandelt werden. Mittel der Wahl ist Propylthiouracil in niedrigst-effektiver Dosis. Antikörper gegen den Thyreotropinrezeptor (TRAK) können diaplazentar übertragen werden und eine Hyperthyreose beim Feten und Neugeborenen auslösen.AbstractDisorders of the thyroid in women are common during the reproductive years. Incorrect or delayed treatment during pregnancy can adversely affect the health of mother and child. Knowledge of the physiological changes during this time is essential. Thyroid disorders, in particular hypothyroidism, may compromise fertility. Autoimmune thyroiditis is associated with a higher risk of fetal loss. In women on thyroid hormone replacement therapy, the thyroxine dose has to be adjusted to meet the enhanced requirement during pregnancy. Thyroid hormone is vital to fetal brain development. During pregnancy and lactation, iodine supplementation is also recommended due to alterations in iodine metabolism. Hyperthyroidism during pregnancy can adversely affect pregnancy outcome and has to be treated accordingly. Propylthiouracil should be given using the least effective dose to keep free thyroxine levels at the upper limit of normal or slightly above. Hyperthyroidism in the fetus and the neonate can be induced by thyroid stimulating antibodies capable of passing the placenta.Disorders of the thyroid in women are common during the reproductive years. Incorrect or delayed treatment during pregnancy can adversely affect the health of mother and child. Knowledge of the physiological changes during this time is essential. Thyroid disorders, in particular hypothyroidism, may compromise fertility. Autoimmune thyroiditis is associated with a higher risk of fetal loss. In women on thyroid hormone replacement therapy, the thyroxine dose has to be adjusted to meet the enhanced requirement during pregnancy. Thyroid hormone is vital to fetal brain development. During pregnancy and lactation, iodine supplementation is also recommended due to alterations in iodine metabolism. Hyperthyroidism during pregnancy can adversely affect pregnancy outcome and has to be treated accordingly. Propylthiouracil should be given using the least effective dose to keep free thyroxine levels at the upper limit of normal or slightly above. Hyperthyroidism in the fetus and the neonate can be induced by thyroid stimulating antibodies capable of passing the placenta.