The Interdisciplinary Management of Newly Diagnosed Pituitary Tumors.

BACKGROUND: The increasing use of cranial tomographic imaging has led to the more frequent discovery of pituitary tumors. In this review, we discuss the clinical symptoms that point toward a pituitary tumor, the required diagnostic studies, the potential need for follow-up studies, and the indications for neurosurgical treatment. METHODS: This review is based on pertinent publications from the years 2005-2020 that were retrieved by a selective search in PubMed, as well as on the current German S2k guideline, which was created with the present authors playing a coordinating role, and on further guidelines from abroad. Relevant information from older reviews was also considered. RESULTS: The reported prevalence of pituitary tumors varies depending on the method of data acquisition. Autopsy studies yield a figure of 10.7%, while population-based studies reported 77.6-115.6 cases per 100 000 inhabitants. These lesions are nearly always benign, and 85% of them are pituitary adenomas. Pituitary adenomas measuring less than 1 cm in diameter are called microadenomas, while those measuring 1 cm or more are called macroadenomas. According to magnetic resonance imaging (MRI) studies, the prevalence of microadenomas in the general population is in the range of 10-38%, while that of macroadenomas is 0.16-0.3%. Pituitary adenomas can be either hormonally inactive or hormonally active. Half of all patients with hormonally inactive microadenomas display no endocrine abnormality, while 37-85% of patients with hormonally inactive macroadenomas manifest at least partial pituitary insufficiency. The clinical spectrum of pituitary tumors ranges from a fully asymptomatic state to visual disturbances, neurologic deficits, severe hormone excess (e.g., in Cushing disease), and life-threatening pituitary insufficiency. Pituitary adenomas are often diagnosed only after a latency of many years, even when they are symptomatic. If an imaging study shows the tumor to be in contact with the visual pathway, an ophthalmological evaluation should be performed. There are clear indications for surgery, e.g., imminent loss of vision, but most asymptomatic pituitary tumors can be observed only. CONCLUSION: The manifestations of pituitary tumors are first recognized by primary care physicians. The further diagnostic evaluation of these patients should be carried out in standardized and interdisciplinary fashion.

First German Guideline on Diagnostics and Therapy of Clinically Non-Functioning Pituitary Tumors.

Although non-functioning pituitary tumors are frequent, diagnostic and therapeutic concepts are not well standardized. We here present the first German multidisciplinary guideline on this topic. The single most important message is to manage the patients by a multidisciplinary team (consisting at least of an endocrinologist, a neurosurgeon, and a (neuro-) radiologist). The initial diagnostic work-up comprises a detailed characterization of both biochemical (focusing on hormonal excess or deficiency states) and morphological aspects (with magnetic resonance imaging of the sellar region). An ophthalmological examination is only needed in presence of symptoms or large tumors affecting the visual system. Asymptomatic, hormonally inactive tumors allow for a 'wait and scan' strategy. In contrast, surgical treatment by an experienced pituitary surgeon is standard of care in case of (impending) visual impairment. Therapeutic options for incompletely resected or recurrent tumors include re-operation, radiotherapy, and observation; the individual treatment plan should be developed multidisciplinary. Irrespective of the therapeutic approach applied, patients require long-term follow-up. Patient with larger pituitary tumors or former surgery/radiotherapy should be regularly counseled regarding potential symptoms of hormonal deficiency states.

Hormonal Contraception. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry Number 015/015, January 2020).

Aims This is an official interdisciplinary guideline published and coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking regions and is backed by numerous professional societies and organizations. The aim of this guideline is to provide an evidence- and consensus-based overview of the diagnostic approach and the management of hormonal contraception based on a systematic evaluation of the relevant literature. Methods To compile this S3-guideline, a systematic search for evidence was carried out in PubMed and the Cochrane Library to adapt existing guidelines and identify relevant reviews and meta-analyses. A structured evaluation of the evidence was subsequently carried out on behalf of the Guidelines Commission of the DGGG, and a structured consensus was achieved based on consensus conferences attended by representative members from the different specialist societies and professions. Recommendations Evidence-based recommendations about the advice given to women requesting contraception were compiled. The guideline particularly focuses on prescribing contraceptives which are appropriate to women's individual needs, take account of her personal circumstances, and have few or no side effects.

[Non-functioning pituitary tumors - short presentation of the first German guideline]. / Hormoninaktive Hypophysentumoren ­ Kurzpräsentation der ersten deutschen Leitlinie.

Pituitary tumors are frequent (estimated prevalence in adults up to 10 %). However, diagnostic work-up and therapeutic concepts are not well standardized; especially for non-functioning tumors. In the beginning of 2020, the first German interdisciplinary guideline on these topics was published. Here, we present shortly the most important aspects of this guideline. One key message is that all patients with pituitary tumors should be managed by an interdisciplinary team (consisting at least of an endocrinologist, a neurosurgeon, and a (neuro-)radiologist). At first presentation, detailed morphological characterization (with magnet resonance imaging) and endocrine work-up to exclude (or prove) hormonal excess or deficiency states is required. An ophthalmological examination is needed only in presence of symptoms or large tumors affecting the visual system. In asymptomatic, hormonally inactive tumors a 'wait and scan' strategy is standard of care. In case of an (impending) visual impairment, surgical treatment shall be performed by an experienced pituitary surgeon. If the surgical resection was incomplete or if tumors are recurrent, therapeutic modalities (e. g. re-operation, radiotherapy, observation) should be interdisciplinary considered. In all patients with or without therapeutic intervention, long-term follow-up is required. Patient with larger pituitary tumors or former surgery/radiotherapy should be regularly counseled regarding potential symptoms of hormonal insufficiency.

Incidence of myocardial infarction and stroke in acromegaly patients: results from the German Acromegaly Registry.

PURPOSE: Acromegaly is a rare disease generally brought about by a benign tumour in the pituitary and characterized by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess. Increased mortality has been related to cardiovascular events that could be linked to these hormones and patients suffer from high rates of diabetes and hypertension. In this study, we examine if the incidence of myocardial infarction (MI) and stroke differ from that of the general population. METHODS: Data from the German Acromegaly Registry in seven specialized endocrine centres were analysed (n = 479, 56% female, 46 years old at diagnosis, 5549 person-years from diagnosis). Standardized incidence ratios (SIR) were calculated as compared to the general population. RESULTS: MI and stroke incidences were very close to those of the general population with an SIR (95% CI) of 0.89 (0.47-1.52, p = 0.80) for MI and 1.17 (0.66-1.93, p = 0.61) for stroke. Acromegaly was uncontrolled in 16% of patients with MI or stroke versus 21% in those without (p = 0.56). Prevalence of hypertension at the initial visit was much higher in those with MI or stroke than those without (94 vs. 43%, p < 0.001). No association was seen between radiation therapy and stroke. CONCLUSIONS: For acromegaly patients being treated at specialized centres, the incidence of MIs and strokes does not seem to differ from the general population. Certainty regarding such statements requires large, prospective studies however.

The Incidence of Cancer Among Acromegaly Patients: Results From the German Acromegaly Registry.

CONTEXT: Acromegaly is a rare disease characterized by high serum levels of GH and IGF-1. Animal studies have demonstrated links between these hormones and cancer, but data regarding cancer incidence among acromegaly patients are inconsistent. Moreover, therapy options have changed considerably since many of the aforementioned data were collected. OBJECTIVE: The objective was to determine whether the overall and site-specific incidence of cancer is comparable to that of the general population. DESIGN AND SETTING: Data from the German Acromegaly Registry for 446 patients (6656 person-years from diagnosis) treated in seven specialized endocrine centers were analyzed. MAIN OUTCOME MEASURE: Standard incidence ratios (SIRs) were calculated as compared to the general population. RESULTS: Overall cancer incidence was slightly but not significantly lower than in the general population (SIR, 0.75; 95% confidence interval, 0.55 to 1.00; P = .051) and was not significantly higher for colorectal, breast, thyroid, prostate, and lung cancers. The SIRs of those with GH in the ranges <1, 1-2.5, and ≥ 2.5 ng/mL were 0.75, 0.44, and 0.92, respectively (P = .94). There was not a significant dependence on normal vs elevated IGF-1 (P = .87), radiation therapy (P = .45), disease duration (P = .96), age at diagnosis (P = .15), or during a period of high GH and IGF-1 from 8 years before to 2 years after diagnosis of acromegaly (P = .41). CONCLUSIONS: Cancer screening strategies need to take incidence into account, which does not seem to be substantially higher in treated acromegaly patients than in the general population for any site of cancer.

Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study.

CONTEXT: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. OBJECTIVE: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. DESIGN: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. INTERVENTION: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. RESULTS: Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. CONCLUSIONS: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register.

BACKGROUND: Acromegaly is a rare disease with significant morbidity and increased mortality. Epidemiological data about therapeutic outcome under 'real life' conditions are scarce. OBJECTIVE: To describe biochemical long-term outcome of acromegaly patients in Germany. DESIGN AND METHODS: Retrospective data analysis from 1344 patients followed in 42 centers of the German Acromegaly Register. Patients' data were collected 8.6 (range 0-52.6) years after diagnosis. Controlled disease was defined by an IGF1 within the center-specific reference range. RESULTS: Nine hundred and seventeen patients showed a normalized IGF1 (157 (range 25-443) ng/ml). In patients with a diagnosis dated back >2 years (n=1013), IGF1 was normalized in 76.9%. Of the patients, 19.5% had an elevated IGF1 and a random GH ≥1 ng/ml, 89% of the patients had at least one surgical intervention, 22% underwent radiotherapy, and 43% received medical treatment. After surgery 38.8% of the patients were controlled without any further therapy. The control rates were higher in surgical centers with a higher caseload (P=0.034). Of the patients with adjunctive radiotherapy 34.8% had a normal IGF1 8.86 (0-44.9) years post irradiation, 65.2% of the medically treated patients were controlled, and 47.2% of the patients with an elevated IGF1 received no medical therapy. CONCLUSION: The majority of acromegaly patients were controlled according to their IGF1 status. Long-term outcome could be improved by exploiting medical treatment options especially in patients who are not controlled by surgery and/or radiotherapy.

Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey.

OBJECTIVE: Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium-sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long-term treatment. DESIGN: Nationwide retrospective collaborative study. PATIENTS: We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases. MEASUREMENTS: Activating CaSR mutations and clinical and biochemical findings were evaluated. RESULTS: Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 µg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%). CONCLUSION: This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.

Coronary artery flow reserve in diabetics with erectile dysfunction using sildenafil.

BACKGROUND: Diabetics with erectile dysfunction have a high prevalence of microvascular disturbance of the coronary circuit as measured by coronary flow reserve (CFR). PURPOSE: We aimed to evaluate the effects of the phosphodiesterase 5 inhibitor sildenafil on CFR in diabetics with erectile dysfunction. METHODS: Diabetics seeking diabetes refinement therapy were screened for vascular or neurogenic erectile dysfunction which was confirmed in 43 patients. No ischemic ECG changes were found in any of the ECG stress tests at the 100 W level. Cardiologic examinations raised suspicion of coronary artery disease in 16 patients; coronary angiography confirmed severe coronary artery lesions in 12, who were excluded from further analysis. CFR measurements were not possible in 10 participants. The 21 diabetics eligible for CFR measurements aged 60 years (50-69) had known diabetes for 11 years (3-30) and a BMI of 27 kg/m2 (24-36). CFR of the left anterior descending artery was assessed at baseline and 1 hour after 50 mg sildenafil, using transthoracic Doppler echocardiography. RESULTS: Baseline CFR was at the lower level of the normal range (median 245%, range 210-490%). After sildenafil administration, CFR decreased insignificantly (DeltaCFR -10%, p = 0.3). Patients with a BMI > 25 kg/m2 and left ventricular hypertrophy exhibited the highest reduction of CFR after sildenafil. No decrease of CFR below 200 % was observed. Systemic blood pressure dropped from 130/80 mmHg to 120/72 mmHg (p < 0.002). CONCLUSIONS: Diabetics with erectile dysfunction exhibit a CFR in the lower normal range indicating severe microvascular disturbance. Sildenafil did not alter CFR in those patients. A high prevalence of severe coronary macroangiopathy was identified in asymptomatic diabetic patients screened for contraindications for sildenafil.

Problems in differential diagnosis of non Langerhans cell histiocytosis with pituitary involvement: case report and review of literature.

Differentiation among various non Langerhans cell histiocytoses granulomatous in adults is often difficult. Patients, moreover, may not have endocrinologic abnormalities. A 53-yr-old patient was admitted owing to central diabetes insipidus and partial hypopituitarism. Magnetic resonance imaging revealed a space-occupying lesion near the hypophyseal stalk, along with diffuse signal uptake in the cerebellar region. Laboratory chemistry showed monoclonal gammopathy of IgGkappa, and hormone tests disclosed insufficiency in the gonadotropic and somatotropic axes. The clinical picture was marked by multiple cutaneous xanthogranulomas, ataxic gait with blurred speech, compatible with pseudobulbar pontocerebellar symptomatology. Stereotactic pituitary biopsy was histologically classified as nonspecific granulomatous disease. Supplemental biopsies taken from the cutaneous periorbital xanthogranulomas were histologically and immunohistochemically consistent with non Langerhans cell histiocytosis. Systemic cortisone treatment as well as local radiotherapy to the pituitary lesion with a total of 18.0 gy had no impact on the progression of disease-growing tumor and progressing neurologic symptoms. Systemic granulomatoses cannot always be classified according to specific defined diseases. Differential diagnosis in the current patient should include the possibility of Erdheim-Chester disease, necrobiotic xanthogranuloma, and adult disseminated xanthoma.