Cushing’s disease

Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies

Outcomes and optimal treatment of patients with Acromegaly

This thesis defines mortality in acromegaly in a modern patient cohort, elucidates underlying explanations for the increased mortality and explores the impact of treatment, focussing on somatostatin analogue therapy. Results confirm there remains a 30% increase in mortality in patients with acromegaly. Mortality was increased in patients with GH >2µg/L, but not in patients with raised IGF-I. This is the first study showing reduced survival in patients with acromegaly following pituitary radiotherapy. Somatostatin analogue therapy was shown to be efficacious and safe. I also explored factors influencing pituitary tumourigenesis by characterising mRNA levels for 11β-HSD isozymes in normal and neoplastic pituitary tissue. Results demonstrated reduced 11β-HSDl expression and 10-fold increased 11β-HSD2 expression in pituitary tumours compared with normal pituitary, resulting in reduced active glucocorticoid concentrations within the pituitary. This may diminish the antiproliferative effects of glucocorticoids, thus contributing to the process of pituitary tumourigenesis. Finally, I explored complications of pituitary adenomas by evaluating outcome in patients presenting acutely with pituitary apoplexy. Patients presenting without visual deficit or showing evidence of early improvement in visual deficit can be managed without acute neurosurgical intervention. Results of this research will undoubtedly improve the management and outcome of patients with acromegaly and pituitary tumours.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Diagnosis and treatment of pituitary tumours: a starting-point for manipulation of cancer with hypothalamic hormones

In order to make a well-founded choice between the therapeutic modalities presently available it is important to have a clear picture of the differences in the natural history of the various types of pituitary tumours. One of the most important questions regards possible differences in the tendency of the various tumours to grow extrasellarly. A related question concerns the relationship between the secretion rate of growth hormone, prolactin etc. and the size of the respective tumour. In other words: do high serum levels of these hormones in general indicate the presence of a large tumour and do moderately increased levels point to a smaller tumour? A parallel and for the management sometimes crucial question is a possible relationship between tumour growth rate and the age of the patient. Furthermore, one can ask what - in a therapeutic sense - may be the significance of a combined secretion of growth hormone and prolactin by a pituitary tumour. The therapeutic part of our study concerns the efficacy and the rapidity, with which the desired therapeutic endpoint may be reached by means of (transsphenoidal) surgery, irradiation or the combination of these treatments in the various types of pituitary tumours. Furthermore, we have considered the value of medical treatment as an additional or - possibly - as primary therapy

The Deleterious Effects of Glucocorticoids: From epidemiology to molecular perspective

Background: Cushing’s syndrome (CS) is caused by prolonged and inappropriately excessive tissue exposure to glucocorticoids (GC) [1]. CS results in significant morbidity and excess mortality. Increased 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1) activity at local tissue has been documented for adverse cortisol effects. Aim: To explore the deleterious effects of systemic and local GC excess in man at molecular and epidemiological levels, which focuses on the outcomes that enable the quantification of disease burden and further avoidable premature death or morbidity. Methods: The epidemiological studies focused on a meta-analysis of mortality and causes of death in endogenous and exogenous CS. Mortality is a crucial health problem, and meta-analyses systematically explore the issue. The molecular study investigates 11β-HSD1 expression in hypoxia in human dermal fibroblasts. This is the preliminary research of 11β-HSD1 role in ischaemic/diabetic wounds, the worldwide health burden. The understanding of 11β-HSD1 in hypoxic skin may yield a new treatment for diabetic/ischaemic wounds. Results: The pooled proportion of death for endogenous CS was 5%, 4% in Cushing's disease (CD), 2% in adrenal adenoma, but 8% in bilateral adrenal hyperplasia. The standardised mortality ratio (SMR) was 3.0 for all CS. ACS was associated with a worse SMR than CD (p=0.003). Mortality was higher in publications published before 2000, active disease, and macroadenomas. Cumulative, average, and initial GC doses are associated with increased mortality in exogenous CS. Cardiovascular diseases, infection and malignancy, are the major contributors to deaths for all CS. Hypoxia increases 11β-HSD1 expression and activity in HDF, particularly in inflammatory conditions for the molecular study. Conclusion: CS confirmed the association with an increase in mortality. The causes of death highlight the need for aggressive management. The 11β-HSD1 role in hypoxia requires further research in ischaemic or diabetic human skin with is the new hope for curing the wound

Molecular mechanisms of glucocorticoid resistance in Cushing’s disease

La maladie de Cushing est caractérisée par une sécrétion excessive de l’hormone adrénocorticotrope (ACTH) à partir des tumeur corticotropes de l'hypophyse. Un excès d'ACTH entraîne un hypercortisolisme et provoque des symptômes tels que diabète, hypertension, obésité et les maladies cardiovasculaires entraînant un risque accru de mortalité si la maladie n’est pas traitée. Les tumeurs corticotropes sont caractérisées par la perte du rétro-contrôle négatif exercé par les glucocorticoïdes (GCs) sur la proopiomélanocortine (POMC) qui est le précurseur de l’ACTH : c'est la caractéristique majeure de la maladie de Cushing. Les causes de la résistance aux GC dans les adénomes corticotropes sont encore mal connues. Des études récentes ont montré une surexpression du récepteur du facteur de croissance épidermique (EGFR) dans les adénomes corticotropes provoquant une augmentation de l'activité du gène POMC et de la sécrétion d'ACTH. Les principaux objectifs de ce travail étaient de comprendre la relation entre la signalisation dérégulée de EGF et la résistance aux GCs. Dans le présent travail, nous avons identifié la voie JAK/STAT3 comme la principale voie de signalisation EGFR qui active la transcription du gène POMC. De plus, nous montrons que l'activation de la signalisation EGFR entraîne une résistance du promoteur POMC aux GCs et que l’activation de STAT3 est responsable de cette résistance. STAT3 affecte le mécanisme de transrepression de GR sans affecter le recrutement de GR au promoteur POMC. L’utilisation d’un inhibiteur de STAT3 restaure la répression de la transcription du promoteur POMC par les GCs. Nous avons aussi trouvé que 50% des adénomes corticotropes humains montrent une surexpression de la forme active de STAT3. Nous avons aussi étudié les mécanismes sous le contrôle des GCs qui régulent la prolifération cellulaire et qui pourraient être dérégulés dans la maladie de Cushing. CABLES1 est un régulateur négatif du cycle cellulaire et son expression est sous le contrôle des GCs. L’expression de CABLES1 est perdue dans 55 % des adénomes hypophysaires corticotropes, mais la cause de cette perte est encore mal comprise. Dans ce travail, nous avons identifié quatre variants faux-sens dans le gène CABLES1, deux chez de jeunes adultes (c.532G > A, c.718C > T) et deux chez des enfants (c.935G > A, et c.1388A > G) atteints de la maladie de Cushing. Les quatre variants touchent une région de la protéine CABLES1 qui est proche du motif de liaison de la kinase-3 dépendante des cyclines (CDK3). Ces variants ont perdu la capacité d’inhiber la croissance de cellules corticotropes tumorales (AtT20). Les quatre variantes sont donc des mutations de perte de fonction. En résumé, nos travaux révèlent le rôle important de STAT3 dans la résistance aux GC et ainsi, le blocage de l'action de STAT3 peut être une nouvelle stratégie pour le traitement de la maladie de Cushing. Nous avons aussi supporté un rôle de CABLES1 en tant que nouveau gène prédisposant aux tumeurs hypophysaires.Cushing’s disease (CD) is characterized by excess secretion of adrenocorticotropic hormone (ACTH) from corticotroph tumors of the pituitary gland. Excessive ACTH leads to hypercortisolism that causes disabling symptoms such as diabetes, hypertension, obesity and cardiovascular disease resulting in an increased risk of mortality if it is not treated. Corticotroph tumors are characterized by the loss of glucocorticoid (GC) feedback repression of the proopiomelanocortin (POMC) that encodes the precursor of ACTH: this is the hallmark of CD. The causes of GC resistance in corticotroph adenomas of CD patients remain unknown. Recent findings showed overexpression of epidermal growth factor receptor (EGFR) in corticotroph adenomas causing increased POMC activity and ACTH secretion. The main objectives of this work were to understand the relationship between deregulated EGF signaling and GC resistance in the tumorigenesis of CD. In the present work, we identified the JAK/STAT3 pathway as the main EGFR pathway activating transcription of the POMC gene. We found that sustained activation of EGFR signaling or overactivation of STAT3 causes unresponsiveness of the POMC promoter to GCs and that activated STAT3 is responsible for GC resistance. STAT3 affects the transrepression mechanism of GR without affecting GR recruitment to the POMC promoter. The use of STAT3 inhibitor restores the repressive effect of GC on POMC transcription. Importantly, 50% of human corticotroph adenomas showed overexpression of activated STAT3. We also studied the mechanisms under the control of GCs that regulate cell proliferation and that could be deregulated in CD. CABLES1 is a negative cell cycle regulator, its expression is under the control of GC. CABLES1 expression is lost in 55 % of corticotroph adenomas and the underlying reasons remain unclear. In this work, we identified the presence of four missense variants in CABLES1 gene, two in young adults (c.532G > A, c.718C > T) and two in children (c.935G > A, and c.1388A > G) with CD. The four variants are close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein. The variants have lost the ability to inhibit growth of corticotropinoma cells (AtT20). The four variants are thus loss of function mutations. In summary, our work revealed the important role of STAT3 in GC resistance and further indicates that inhibition of STAT3 action may be a novel strategy for CD treatment. We also provided evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene

Cushing syndrome and disease:a study of the diagnosis, treatment, clinical consequences, and Health-related Quality of Life associated with these medical conditions

Introduction Cushing syndrome and disease are classified as rare diseases. The estimated incidence of CS (2021), was 10 to 15 per million people worldwide per year and can occur in any age group, mostly diagnosed in females with a median age of 41 years. The mortality rate is reported to be between 2-4 times higher than the general population. This study was conducted following my diagnosis of CS to compare other patients experiences of these medical conditions with my own, and the clinical consequences following a diagnosis and treatment of CS. Methods A HRQoL survey was conducted on members of the Pituitary Associations using a disease-specific on-line questionnaire. Quantitative and Qualitative analysis was performed. Semi-structured interviews were also conducted on a range of Health Professions disciplines. Results The study population was 86. The 71 female members median age was 42 and the 15 males was 39.4 years. The results showed a strong correlation between age and QoL scores, (rConclusions The wide clinical spectrum of CS produces medical dilemmas as symptoms vary and therefore patients can be sent to a range of Physicians prior to a definitive diagnosis. The prolonged consequences of excess cortisol affected my own and their HRQoL, even after remission, mainly due to the persistence of physical and neuropsychological morbidity. There remains a lack of psychological support and Health Professionals awareness. A patient’s perspective should be recognised to be an integral part of the management of CS

Cushing syndrome and disease: a study of the diagnosis, treatment, clinical consequences, and health-related quality of life associated with these medical conditions

Introduction: Cushing syndrome and disease are classified as rare diseases. The estimated incidence of CS (2021), was 10 to 15 per million people worldwide per year and can occur in any age group, mostly diagnosed in females with a median age of 41 years. The mortality rate is reported to be between 2-4 times higher than the general population. This study was conducted following my diagnosis of CS to compare other patients experiences of these medical conditions with my own, and the clinical consequences following a diagnosis and treatment of CS. Methods: A HRQoL survey was conducted on members of the Pituitary Associations using a disease-specific on-line questionnaire. Quantitative and Qualitative analysis was performed. Semi-structured interviews were also conducted on a range of Health Professions disciplines. Results: The study population was 86. The 71 female members median age was 42 and the 15 males was 39.4 years. The results showed a strong correlation between age and QoL scores, (r<1, P < .03). The median length of time for a diagnosis of CS was 5.4 years (females), and 3.7years for the males. The median number of Physicians consulted prior to a diagnosis was 2. The results showed a strong correlation between the number of Physicians and their QoL scores, (r .78, P < .05). Both genders reported physical and psychological conditions. Conclusions: The wide clinical spectrum of CS produces medical dilemmas as symptoms vary and therefore patients can be sent to a range of Physicians prior to a definitive diagnosis. The prolonged consequences of excess cortisol affected my own and their HRQoL, even after remission, mainly due to the persistence of physical and neuropsychological morbidity. There remains a lack of psychological support and Health Professionals awareness. A patient’s perspective should be recognised to be an integral part of the management of CS

Morphological and functional correlations in normal and neoplastic tissues

This thesis deals with experimental aspects of morphological and functional correlations at the histological and biochemical levels in various normal and neoplastic tissues. A physiological section examines functions and effects of the normal foetal testis, and a clinicopathological section is concerned with morphological and functional features of testicular and adrenocortical neoplasms. The normal foetal testis. The foetal testis is hormonally active, producing androgenic steroids which cause masculinisation of the sex ducts and urogenital sinus: and a separate Mullerian inhibitory factor (MIF) which actively suppresses the female sex duct. MIF is not a steroid molecule in free form, and at least part of it is a protein. I set up an organ culture bioassay system to study aspects of Mullerian duct inhibition. Foetal rat genital tracts, containing Mullerian and Wolffian ducts, were explanted from foetal rats and maintained in organ culture for 3 days. The development of gonads and sex ducts in vitro followed the normal in vivo pattern. The Wolffian ducts were stabilised by androgens, by autologous or homologous foetal rat testes, and by heterologous human foetal testes. The Mullerian ducts regressed in the presence of autologous, homologous or heterologous foetal testes. On theoretical grounds, I wondered if foetal testicular progesterone, probably attached to a carrier protein analogous to the androgen binding protein produced by the adult testicular Sertoli cells, may be involved in Mullerian duct inhibition. Addition of progesterone to the culture medium did cause Mullerian duct regression, but it was difficult to be certain that this was a specific physiological effect rather than a non-specific cytotoxic effect. Progesterone v/as also found to stabilise the Wolffian duct in organ culture. Substantiation of the possible physiological role of foetal testicular progesterone necessitated verification that the foetal testis is capable of progesterone production and secretion. This was attempted using monolayer cultures of rat foetal testes maintained with and without trophic hormonal stimulation. The endogenous steroid production and secretion was determined by radioimmunoassay (RIA) for progesterone and testosterone, and by high pressure liquid chromatography (HPLC) which could efficiently separate, identify and quantitate 47 different standard steroid molecules. A testosterone RIA had been established in our laboratory, and I developed a similar assay for progesterone paying particular attention to precision, sensitivity, specificity and choice of method for separating free and bound labelled progesterone. HPLC was used to examine the profile of steroids secreted by the foetal testicular cells in monolayer culture. Foetal testes secrete testosterone and progesterone in monolayer culture. Testes from 1