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The goal of this observational study is to evaluate, retrospectively and prospectively, the effect of different hormonal and neuropeptide dysfunctions on the body composition of patients suffering from hypothalamic-pituitary pathologies, and to evaluate the potential beneficial effect of surgical and medical treatments with agonists and antagonists of hypothalamic neuropeptides, currently available, on the development and treatment of adiposity and negative cross-talk between adiposity and muscle/bone tissue

Neuroendocrine Mechanisms in Adiposity: An Integrated Approach to the Characterization of Potential Pharmacological Novel Targets Based on Experimental and Clinical Models

The study aims to evaluate, retrospectively and prospectively, the effect of different hormonal and neuropeptide dysfunctions on the body composition of patients suffering from hypothalamic-pituitary pathologies

IRCCS San Raffaele

Professor of Endocrinology and Metabolism

Behaviors and Mental Disorders

Quality of Life

Anti-Inflammatory Agents

All Drugs and Chemicals

Vasoconstrictor Agents

Respiratory System Agents

Gastrointestinal Agents

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Hormones

Epinephrine

Estrogens

Glucagon

Testosterone

Glucagon-Like Peptide 1

Racepinephrine

Epinephryl borate

All enrolled patients will undergo standardised pituitary hormone assessments.

Pituitary Function Assessment:

Baseline assessment of pituitary function by measuring ACTH, cortisol, FSH, LH, oestrogen (in females), testosterone (in males), sex hormone binding globulin, thyroid function tests, prolactin and IGF-1\].

Dynamic testing of pituitary function:

* Patients will undergo dynamic testing of the ACTH and growth hormone axes using a glucagon stimulation test (GST).
* Patients whose GST identifies cortisol deficiency will undergo a short synacthen test to confirm adrenal insufficiency as the GST has a false positive rate of approximately 20% for ACTH deficiency.

Dynamic testing of Pituitary Function

Mark Sherlock, MD PhD

Background:

Approximately 480 primary, non-pituitary, brain tumours were diagnosed in Ireland each year between 1994 and 2013. Recent developments in treatment have greatly improved survival for younger patients in the 15-54 age range. The Irish National Neurosurgical Centre and the St Luke's Radiation Oncology Centre at Beaumont Hospital and treat approximately 200 patients with brain tumours per year with a combination of surgery, radiotherapy (RT) and chemotherapy with RT being the most commonly used treatment modality. With improved survivorship, the prospect of individuals living for several decades with co-morbidities induced by the tumour itself or surgical and RT treatments, raises new and complex issues for patients and clinicians.

The hypothalamus and pituitary gland in the brain are the key regulators of hormone action. They control several hormone systems including reproductive function (FSH, LH) growth (growth hormone), thyroid (TSH) and adrenal function (ACTH) as well as many other homeostatic mechanisms. It has long been recognised that therapeutic cranial RT to the pituitary gland causes hypothalamic-pituitary dysfunction (hypopituitarism). Traditionally, high-risk groups for post-irradiation hypopituitarism were considered to be patients with pituitary tumours, survivors of childhood cancer and patients who received high-dose RT to treat nasopharyngeal cancers. The potential for cranial radiotherapy to cause significant pituitary dysfunction in adult patients with brain tumours has received little attention. The assumption has been that the hypothalamic-pituitary axis is more resistant in adults than in children to the effect of cranial RT. However, it is likely that the higher doses of RT, used to treat primary brain tumours in adults, causes significant hypothalamic-pituitary dysfunction resulting in hypopituitarism. Preliminary data from the National Pituitary Centre in Beaumont Hospital has revealed that adult patients, treated with cranial radiotherapy for primary, non-pituitary brain tumours, are at risk of hypopituitarism. Approximately 40% of patients had pituitary deficiencies in at least one hormone axis, while 25% of patients had deficiencies in multiple hormone axes. Hypopituitarism confers significant morbidity and increased mortality to patients. At present, adult survivors of brain tumours are referred to the pituitary service for assessment on an ad-hoc basis meaning that many patients with hypopituitarism may go undiagnosed.

In addition to the challenges caused by hypopituitarism, long-term neuropsychological outcomes following a brain tumour cause significant functional impairments and reduced HR-QOL. Patients can present with impairments in specific cognitive domains such as memory and executive functioning or more global systems such as attention as well as significant issues with fatigue. In addition to these primary deficits, patients can also present with significant distress, fluctuant mood and anxiety. Despite the impact of brain tumours can exert, the National Cancer Control Program's National Survivorship Needs Assessment Review (2019) did not identify any studies reporting the needs of adult survivors of brain tumours in Ireland.

There is an urgent need to understand the impact of hypopituitarism and its treatment on HR-QOL and neuropsychological functioning. The proposed study will add to the limited existing literature on the prevalence of hypopituitarism in adult survivors of brain tumours treated with radiotherapy and generate detailed information on deficiency rates for individual pituitary hormones and how these deficiencies emerge over time. This will also be the first study to examine if treatment of radiotherapy-induced hypopituitarism (as part of routine clinical care) is associated with improved HR-QOL and neuropsychological functioning.

Hypothesis Adult survivors of primary, non-pituitary brain tumours have an increased risk of hypopituitarism and experience impairments in HR-QOL and neuropsychological functioning. We hypothesise that diagnosis of these deficiencies and the subsequent active replacement of pituitary hormone deficits (as part of routine clinical care) will lead to an improvement in neuropsychological functioning and HR-QOL in adult survivors of primary brain tumours.

Objectives:

1. To examine the impact of radiotherapy on pituitary hormone function in adult survivors of primary, non-pituitary brain tumours.
2. To assess HR-QOL and neuropsychological functioning in adult survivors of primary, non-pituitary brain tumours.
3. To examine the impact of pituitary hormone replacement and optimisation (as part of routine clinical care) on HR-QOL and neuropsychological functioning in adult survivors of primary, non-pituitary brain tumours.

   Methods

   Study Design \& Setting:

   A cross-sectional study will be conducted in the RCSI clinical research centre, located on the Beaumont Hospital campus. The study will be conducted over three years from September 2023 to September 2025.

   Participants:

   The study population will consist of adults who have previously received cranial radiotherapy for a primary, non-pituitary brain tumour.

   Patient Recruitment:
   * Participants will be identified in Professor Clare Faul's, Dr David Fitzpatrick's and Dr Nazmi ElBeltagi's clinic in St Luke's Radiation Oncology Centre at Beaumont Hospital.
   * Patients will be approached by the research fellow during routine clinical consultations.
   * The nature, purpose, benefits and risks of the study will be discussed with potential participants. They will be given the opportunity ask questions about the study. The patients' medical history will be reviewed to ensure they meet the study inclusion criteria.
   * Patients will be given a patient information leaflet and asked to read this at home.
   * The research fellow will follow up with a phone call within 72 hours and offer patients the opportunity to participate in the study. A first research study visit will be arranged for those who agree to participate.

   Study Procedure

   Study Visit One:

   Consent:
   * Participants will be asked to attend study visit one in the RCSI Clinical Research Centre (CRC).
   * Participants will be given the opportunity to ask questions and to have any concerns addressed by the research team.
   * They will then be asked by the research fellow to provide their informed consent to (i) participate in the study and (ii) allow their data to be processed by the research team.

   Assessments:
   * Participants will be asked to fast from midnight the previous evening as per Beaumont Hospital protocol for dynamic testing of pituitary function.
   * They will be advised to take their usual medications with a small sip of water on the morning of the test.
   * The research fellow will assess the participants' blood pressure, height, weight and body composition (using the bioimpedance technique with the Tanita® BC-418 segmental body composition analyser).
   * Women of childbearing age will be questioned to ensure they are not pregnancy. If there is any uncertainty, they will be asked to take a pregnancy test.

   Baseline blood sampling:
   * A fasting 9am blood sample will be taken to assess pituitary function \[ACTH, cortisol, FSH, LH, oestrogen (in females), testosterone (in males), sex hormone binding globulin, thyroid function tests, prolactin, IGF-1\] and metabolic phenotype \[full blood count, renal/ liver profile, cholesterol, HbA1c, homeostatic model assessment for insulin resistance (HOMA-IR)\].

   Dynamic testing of pituitary function:

   • Patients will undergo dynamic testing of the ACTH and growth hormone axes using a glucagon stimulation test (GST).

   • The Beaumont Hospital GST protocol will be followed throughout.

   • A cannula will be inserted into the patient's forearm. Baseline serum samples for glucose, cortisol and growth hormone will be drawn from the cannula.
   * Glucagon will then be injected into the lateral aspect of the mid quadriceps (vastus lateralis) by the research nurse/ fellow. A glucagon dose of 1mg will be used in adults less than 90kg and 1.5mg in adults greater than 90kg.
   * Serum samples will be drawn from the cannula for glucose, cortisol and GH at 90, 120, 150 and 180 minutes.

   Neuropsychological assessment:

   • A battery of neuropsychological tests to assess for cognitive, memory, language and visuo-spatial dysfunction will be performed. These tests are fully validated and have been widely used in the research setting.
   * Cognitive dysfunction: Stroop colour-word test, phonemic verbal fluency, backward digital span
   * Language dysfunction: Boston naming test
   * Memory dysfunction: Logical memory, verbal paired associate and auditory delayed recognition task
   * Visuo-spatial dysfunction Rey-osterrieth complex figure test

   HR-QOL assessment:
   * Participants' HR-QOL will be measured using extensively validated assessment tools including the Short Form-36 (SF-36), Nottingham Health Profile and EQ-5D-5L.
   * The SF-36 is a widely used HR-QOL assessment tool consisting of 4 physical and 4 mental domains which are combined to give physical and mental component summary scores. The Nottingham Health Profile consists of two components; a subjective assessment of their general health and the impact on their activities of daily living. The EQ-5D-5L assesses level of difficulty with five aspects of daily living.
   * The research fellow will ask participants the assessment questions, document their responses and calculate the overall scores (where necessary).

   Study visit one is then complete.

   Review of Pituitary Assessments:

   • Baseline and dynamic test results will be reviewed after study visit one by the principal investigator and research fellow.

   • Selected patients whose GST identifies cortisol deficiency will be asked to attend the RCSI-CRC for an additional study visit to undergo a short synacthen test (SST). This is to confirm adrenal insufficiency as the GST has a false positive rate of approximately 20% for ACTH deficiency.
   * A SST involves a cannula being inserted into the forearm and baseline serum samples for ACTH and cortisol being taken. Synacthen® 250mcg will then be administered intravenously. A second cortisol sample will be taken after 30 mins.
   * Patients diagnosed with hypopituitarism will have their hormone deficits replaced as per best clinical practice by the endocrinology service. In the event of a patient being diagnosed with growth hormone deficiency, growth hormone replacement will be discussed with the radiation oncology team is not appropriate in all types of brain tumours.
   * Patients will be counselled on the diagnosis of hypopituitarism and any questions or concerns addressed.
   * Follow up blood tests may be required to assess the adequacy of pituitary hormone replacement, as per routine clinical practice.

   Treatment History and Radiotherapy Dose Calculation:

   • The patient's tumour histology, staging and neurosurgical treatment history will be obtained from their physical and electronic medical records in Beaumont Hospital and St Luke's Centre Radiation Oncology at Beaumont Hospital.

   • The type, dose, dose per fraction of radiotherapy received by the hypothalamus/ pituitary (which will be estimated from planning scans using the biological equivalent dose) will be recorded in collaboration with Professor Clare Faul, Dr David Fitzpatrick's and Dr Nazmi ElBeltagi's in St Luke's Radiation Oncology Centre at Beaumont Hospital.

   Study Visit Two • All study participants will be asked to return for a second study visit, four months after their first visit.
   * Repeat measurements will be taken including:

     o Weight, blood pressure and body composition.

     o Fasting 9am blood samples to assess baseline pituitary function and metabolic phenotype \[as previously outlined\].
   * All patients will have their HR-QOL and neuropsychological functioning reassessed to measure the change over the course of the study.

   End of study

   • Patients diagnosed with hypopituitarism during the study will be followed up in the endocrinology clinic in Beaumont Hospital (as is the case for all patients with hypopituitarism).

Improving Survivorship and Health-related Quality of Life in Patients With Primary Brain Tumours

Prevalence of pituitary hormone deficiencies in adult survivors of primary, non-pituitary brain tumours, previously treated with radiotherapy.

The Short Form-36 will be used to assess HR-QOL in the study population relative to a published normative population. The SF-36 is a generic questionnaire consisting of 8 domains; physical function, bodily pain, role physical, general health, vitality, social functioning, role emotional, mental health. Each domain is scored form 0-100, with higher scores indicating better quality of life.

HR-QOL will be reassessed at 16 weeks using the SF-36 in (i) participants with hypopituitarism and (ii) participants with normal pituitary function. The SF-36 is a generic questionnaire consisting of 8 domains; physical function, bodily pain, role physical, general health, vitality, social functioning, role emotional, mental health. Each domain is scored form 0-100, with higher scores indicating better quality of life.

Beaumont Hospital

Royal College of Surgeons, Ireland

Neoplasm Metastasis

Hyperlipidemias

Hyperlipoproteinemias

Hypothyroidism

Neoplastic Processes

Dyslipidemias

Metabolic Diseases

Lipid Metabolism Disorders

Thyroid Diseases

Central Congenital Hypothyroidism

Thyroxin, Triiodothyronine

Prof Dr Martin Reincke, MD

The purpose of this study is to determine whether a body weight adjusted dose of thyroxin is superior to treatment guided by laboratory results of thyroxin hormones in patients with central hypothyroidism. Moreover beneficial effects of triiodthyronine supplementation are investigated.

Backround: A normal thyroid function is critical for metabolism, well-being and cognitive function. It is now well accepted that primary subclinical hypothyroidism, characterized by normal circulating thyroid hormones (fT3 and fT4) and elevated TSH, should be treated to improve reduced quality of life and abnormalities of lipid metabolism. In central hypothyroidism (CH) the dose of replacement therapy aims to achieve normal thyroxin (T4) concentrations as defined by appropriate reference populations. Adequate thyroxin treatment is especially challenging, as T4 cannot be titrated according to endogenous TSH levels because of the impaired hypothalamic-pituitary unit. The majority of untreated CH patients show normal (40 %) or elevated TSH levels (35 %) while only a minority has reduced concentrations (25 %) {Faglia, 1979 #1}. These findings are explained by the lack of pulsatile secretion and nocturnal TSH surge, which has been attributed to impaired thyrotroph function in CH patients {Caron, 1986 #2}. Moreover, impaired biological activity of TSH itself due to reduced glycosylation has been described in secondary hypothyroidism.

In a cross sectional study performed in patients with central hypothyroidism, we found elevated cholesterol levels and increased ankle reflex time suggesting subtle hypothyroidism, though fT3 and fT4 serum concentrations were within the normal range. The average dose of thyroxin (T4) applied in these patients with central hypothyroidism was 1.1 µg/kg bw, which is below the average dose recommended in primary hypothyroidism (1.6 µg/kg bw). We hypothesized that these results might indicate suboptimal T4 replacement therapy, not detectable by current laboratory testing.

Hypothesis: To investigate the effects of a body weight adjusted T4 or T3T4 dose on metabolism, well-being and cognitive function.

Study design: Placebo controlled trial in patients with central hypothyroidism following a double blind cross-over design.

Intervention: Three different treatment regimes (5 weeks each) were compared: "CON-T4", empirically chosen, current dose of T4 (1 ± 0.05 μg/kg body weight (bw); "OPT-T4", optimized T4 treatment (1.6 μg/kg bw T4); "T3T4", combination of triiodothyronine (T3, 0.16) and T4 (1.44 μg/kg bw). Biochemical parameters, ankle reflex time and neurocognitive functions were assessed.

Phase 4 Study in Secondary Hypothyroidism: Body Weight Adapted Thyroxin Treatment and Triiodothyronine Supplementation

A Randomised, Controlled, Crossover Study: Treatment With Thyroxin Compared to Thyroxin + Triiodothyronin in Patients With Secondary Hypothyroidism

University Hospital Freiburg

Heart and Blood Diseases

Atherosclerosis

Metabolic Syndrome

Insulin Resistance

Arteriosclerosis

Arterial Occlusive Diseases

Vascular Diseases

Growth Hormone Deficiency

Isolated Growth Hormone Deficiency

Hypoglycemic Agents

Insulin

Insulin, Globin Zinc

Hormone Antagonists

Recombinant Growth Hormone, Genotropin (Pfizer)

Annamaria AL Colao, Prof.

Adult patients with hypopituitarism under adequate conventional hormone replacement therapy have reduced life expectancy due to excess vascular events (1-4). Deficiency in GH secretion (GHD) is likely to play a major role in determining the excess mortality, since it is associated with lipid abnormalities, visceral adiposity, glucose intolerance, insulin resistance, hypertension, cardiac abnormalities and increased intima-media thickness (IMT) at major arteries (5).

Beneficial effects of growth hormone (GH) replacement on cardiovascular risk factors have been demonstrated in several studies of hypopituitary GHD patients (5). GH replacement improves body composition and lipid profile (5): it is accepted that management of dyslipidaemia is crucial in primary and secondary prevention of cardiovascular disease and part of the excess vascular risk associated with hypopituitarism is likely to be due to dyslipidaemia (6). A meta-analysis of blinded, randomized, placebo-controlled trials with low doses and long-duration GH treatment showed that GH replacement has beneficial effects on cardiovascular risk by improving lean and fat body mass, total and LDL cholesterol levels, and diastolic blood pressure (7). Besides, GH replacement also induces improvement in cardiovascular markers (8), and cardiac performance (9). In small cohorts of GHD adults, beneficial effects of GH replacement for 6-24 mos have also been reported on surrogate parameters of atherosclerosis, such as intima-media thickness (IMT) at major arteries (10-13), while 6 months of GH deprivation is associated with an impairment of the cardiovascular risk profile (12). In a consistent series of men and women with hypopituitarism we reported, however, that two years of GH replacement is not adequate to normalize IMT levels at common carotid arteries (13).

To give further insights on the likelihood of reversal of early atherosclerosis in severe GHD patients after prolonged GH replacement, we designed this 5-yr prospective, controlled study. Only men aged ≤50 yrs and with severe GHD were enrolled to avoid gender and aging interference (13). Main outcome measure was IMT at common carotid arteries; secondary measure was prevalence of insulin-resistance syndrome according with the American College of Endocrinology (14).

This is an observational,5-yr prospective, controlled study. At study entry, all subjects underwent serum assay of IGF-I, systolic and diastolic blood pressure (SBP, DBP) measurement, total-, and HDL-cholesterol, triglycerides, glucose, and insulin level after an overnight fasting, and common carotid arteries ultrasonography. The oral glucose load (oGTT) was performed by measuring blood glucose every 30 minutes for 2 hours after the oral administration of 75 g of glucose diluted in 250 ml of saline solution. The conversion factors (mg/dl to mmol/l) for lipids and glucose were as follows: cholesterol 0.02586, triglycerides 0.01129, and glucose 0.05551. According with previous studies (13,19-21) blood pressure was measured at the right arm, with the subjects in relaxed sitting position. The average of six measurements (three taken by each of two examiners, in the same day, between 8.00-9.00 in the morning) with a mercury sphygmomanometer was used in all analysis.

In the patients, all parameters and carotid ultrasonography were re-evaluated after 12, 24, 36, 48 and 60 months while in controls they were re-evaluated after 60 months.

At study entry and at study end, in all of the patients and controls the prevalence of insulin-resistance syndrome (IRS) was evaluated according with the American College of Endocrinology (14) based on the presence of at least two criteria of the following: triglycerides levels ≥1.7 mmol/liter, HDL-cholesterol levels ≤1.0 mmol/liter, blood pressure above 130/85 mmHg, fasting glucose between 6.1 and 7 mmol/liter or 2 hr after oGTT between 7.7 and 11.1 mmol/liter.

Effect of 5 Years of GH Replacement on Atherosclerosis

Phase 4 Study of Recombinant GH on Intima-Media Thickness at Common Carotids and on Cardiovascular Risk Factors in Hypopituitary Patients

Federico II University

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neuroendocrine Mechanisms in Adiposity: An Integrated Approach to the Characterization of Potential Pharmacological Novel Targets Based on Experimental and Clinical Models	NCT06326853	Endocrine Disor... Adiposity Pituitary Adeno... Cushing Syndrom... Acromegaly Hypopituitarism		18 Years -	IRCCS San Raffaele
Improving Survivorship and Health-related Quality of Life in Patients With Primary Brain Tumours	NCT06014398	Hypopituitarism Radiotherapy-In... Brain Tumor	Dynamic testing...	16 Years -	Royal College of Surgeons, Ireland
Phase 4 Study in Secondary Hypothyroidism: Body Weight Adapted Thyroxin Treatment and Triiodothyronine Supplementation	NCT00360074	Secondary Hypot... Hypopituitarism Hyperlipidemias	Thyroxin, Triio...	18 Years - 75 Years	University Hospital Freiburg
Improving Survivorship and Health-related Quality of Life in Patients With Primary Brain Tumours	NCT06014398	Hypopituitarism Radiotherapy-In... Brain Tumor	Dynamic testing...	16 Years -	Royal College of Surgeons, Ireland
Effect of 5 Years of GH Replacement on Atherosclerosis	NCT00462475	Hypopituitarism Pituitary Tumor... Growth Hormone ...	Recombinant Gro...	18 Years - 50 Years	Federico II University

Spots Global Cancer Trial Database for hypopituitarism