Acromegaly and Cushing's Syndrome

Acromegaly and Cushing’s syndrome: LIFE AFTER CURE MARGREET WAGENMAKERS Acromegaly and Cushing’s syndrome: LIFE AFTER CURE MARGREET WAGENMAKERS Colofon The research in this thesis was financially supported by de stichting Bijnierfonds and Ipsen. Printing of this thesis was financially supported by Ipsen and Pfizer bv. Cover illustration & book design: Ilse Schrauwers, isontwerp.nl - Den Bosch Printed by: Gildeprint Drukkerijen ISBN: 978-94-92303-04-2 © Margreet Wagenmakers All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without prior written permission of the author. The copyright of the arti- cles that have been published has been transferred to the respective journals. Acromegaly and Cushing’s syndrome: LIFE AFTER CURE Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus, volgens besluit van het college van decanen in het openbaar te verdedigen op donderdag 30 juni 2016 om 10.30 uur precies door Margaretha Albertina Elisabeth Maria Wagenmakers geboren op 22 september 1980 te Nijmegen Promotoren: Prof. dr. A.R.M.M. Hermus Prof. dr. J.W.A. Smit Copromotor: Dr. R. T. Netea-Maier Manuscriptcommissie: Prof. dr. N.P. Riksen (voorzitter) Prof. dr. J.H.W. de Wilt. Prof. dr. A.M. Pereira (Leiden UMC) ”Ieder mens is anders dan anderen. Altijd verschillen arts en patiënt van elkaar: in geografische herkomst, religie, opleiding of (medische) kennis, en macht. Goede zorgverleners erkennen deze verschillen, en schenken aandacht aan de individuele context van de patiënt.” M.E.T.C. van den Muijsenbergh, NTVG 2013 Contents 1 General introduction and outline of this thesis 9 PART 1 37 Treatment of acromegaly and Cushing’s disease by transsphenoidal surgery 2 Results of endoscopic transsphenoidal pituitary surgery in forty patients 39 with a growth hormone secreting macroadenoma Acta Neurochir (Wien), 2011. 153(7): p. 1391-9 3 Endoscopic transsphenoidal pituitary surgery: a good and safeprimary 61 treatment option for Cushing’s disease, even in case of macroadenomas or invasive adenomas Eur J Endocrinol, 2013. 169(3): p. 329-37. 4 Repeated transsphenoidal pituitary surgery via the endoscopic technique: 81 a good therapeutic option for recurrent or persistent Cushing’s disease Clinical Endocrinology, 2009. 70(2): p. 274-280. PART 2 99 Long-term quality of life after treatment of acromegaly and Cushing’s syndrome 5 Persistent self-consciousness about facial appearance, measured with 101 the Derriford appearance scale 59, in patients after long-term biochemical remission of acromegaly Pituitary. 2015 Jun;18(3):p. 366-75 6 Impaired quality of life in patients in long-term remission ofCushing’s 121 syndrome of both adrenal and pituitary origin: a remaining effect of longstanding hypercortisolism? Eur J Endocrinol, 2012. 167(5): p. 687-95 6 Contents PART 3 139 Long-term physical sequelae after treatment of acromegaly and Cushing’s syndrome 7 Three-dimensional facial analysis in acromegaly: a novel tool to quantify 141 craniofacial characteristics after long-term remission Pituitary, 2015. 18(1): p. 126-34. 8 Persistent centripetal fat distribution and metabolic abnormalities in 161 patients in long-term remission of Cushing’s syndrome Clinical Endocrinology. 2015 Feb;82(2):180-7 9 Vascular health in patients in long-term remission of Cushing’s syndrome 181 and no or adequately treated comorbidity is comparable to BMI-matched subjects Submitted for publication. 10 General discussion and summary 201 11 Appendix 231 Nederlandstalige samenvatting 233 List of publications 242 Dankwoord 244 Curriculum Vitae 250 7 1 8 1 General introduction 1 and outline of this thesis 9 10 1) Introduction General Introduction and Outline of this Thesis 1 In 1905 Ernest Starling used the word “hormone” (derived from the ancient Greek word óρμαω, “to set in motion”) for the first time to describe the recently discovered “internal chemical messengers that are carried from the organ they are produced to the organ they affect by the blood stream” 1. Nowadays we know that hormones are essential for the wellbeing of every human being. Moreover, human life would be impossible without hormones. This thesis focuses on the treatment and long-term effects of two diseases that are caused by overproduction of two very important hormones: acromegaly caused by growth hormone (GH) overproduction and Cushing’s syndrome (CS) caused by cortisol overproduction. In both diseases the pituitary gland plays a key role. The pituitary gland Anatomy and function The pituitary gland (or hypophysis) is an endocrine gland, about the size of a pea and approximately 0.6 grams in weight, which is located in the midline of the base of the skull 2. It is frequently called “the master gland” as it orchestrates the complex regula- tory functions of many other endocrine glands. The pituitary gland (Figure 1) consists of 2 lobes: the anterior pituitary gland (or adenohypophysis) and the posterior pituitary gland (or neurohypophysis). The anterior pituitary gland, which is of endodermal origin, produces six major hormones: 1) prolactin, 2) GH, 3) adrenocorticotropic hormone (ACTH), 4) luteinizing hormone (LH), 5) folli- cle-stimulating hormone (FSH), and 6) thyroid-stimulating hormone (TSH). These hormones are secreted in a pulsatile manner, in response to specific hypothalamic releasing and inhibiting factors and each of these hormones exerts specific responses in its peripheral target tissues. The hormonal products of peripheral target glands, in turn, have feedback control at the level of the hypothalamus and pituitary gland. The posterior pituitary gland consists of pituicytes, modified glial cells, and axons whose cell bodies are located in the hypothalamus. It stores and releases hormones such as antidiuretic hormone (ADH) and oxytocin. The pituitary gland lies outside the dura, below the optic chiasm and the hypothalamus (Fig 3). It rests in the sella turcica, which is part of the sphenoid bone. 11 Neurons that Hypothalamus synthesize posterior pituitary hormones Neurons that secrete Superior hypothalamic releasing hypophyseal hormones artery Hypophyseal Neurohypophysis potal veins Adenohypophysis Venous drainage Venous drainage Inferior hypophyseal artery Figure 1) Anatomy of the pituitary gland. (www.medscape.com) Optic chiasm CN III Internal carotid artery CN IV Piuitary gland CN VI Cavernous sinus CN V1 Sphenoidal sinus CN V2 Nasopharynx Figure 2) Anatomy of structures surrounding the pituitary gland. (www.medscape.com) Anteroinferior to the sella turcica lies the sphenoid sinus. Bilateral to the sella turcica (thus in the parasellar region) lie the cavernous sinuses (Fig 2). The cavernous sinuses are built up by a multi-loculated venous structure containing a part of the internal carotid artery, the oculomotor nerve (cranial nerve III), the trochlear nerve (cranial nerve IV), the abducens nerve (cranial nerve VI) and the V1 and V2 branches of the trigeminal nerve. Thus, one can imagine that large expanding pituitary tumors may cause significant morbidity. The blood supply of the pituitary gland originates from the superior and inferior hypophyseal arteries (Figure 1). The hypothalamic-pituitary portal plexus provides the major blood source for the anterior pituitary gland, so pulses of hypothalamic hormones can directly be transmitted without significant systemic dilution. 12 1) Introduction 1 A B Figure 3) Anatomy of the normal pituitary gland. (From Williams Textbook of endocrinology, Melmed et al, 2011, Figure 7,2., published with permission from Elsevier) PP, posterior pituitary gland; AP, anterior pituitary gland; oc, optic chiasm; cc, corpus callosum; MB, mammillary body; pc, posterior commissure; ac; anterior commissure. The somatotropic axis GH is the most abundant anterior pituitary hormone. It is secreted by somatotroph cells, which account for up to 50% of the total anterior pituitary cell population2. GH secretion is controlled by both hypothalamic and peripheral factors (Figure 4). In short, GH is secreted under dual hypothalamic control: GH–releasing hormone (GHRH) induces and somatostatin suppresses GH secretion. In healthy individuals GH is released in approximately 10 intermittent pulses per 24 hours, mostly during the night, with GH levels unde- tectable during most of the day 3. 13 The peripheral action of GH is mediated via the GH receptor, which is expressed mainly in the liver and cartilage. GH induces the production of insulin-like growth factor type-1 (IGF-1) in the liver. IGF-I directly causes proliferation and inhibition of apoptosis of virtu- ally all cell types and has negative feedback control on GHRH and GH production. Besides GHRH and IGF-1 many other factors have a significant influence on the somatotropic axis. For example: secretion of both GH and IGF-1 is influenced by available nutrients: GH production increases during fasting and IGF-1 levels are suppressed in malnourished patients. Furthermore GH production diminishes during aging and in obesity and IGF-I is suppressed in patients with liver disease, hypothyroidism, or poorly controlled diabetes 4 . Hypothalamic–pituitary–adrenal (HPA) axis ACTH producing cells (corticotropic cells) account for about 20% of the pituitary cell population2. Corticotropin-releasing hormone (CRH), which is produced in the hypothalamus, is the most important stimulator of ACTH production. ACTH stimulates the adrenal glands to produce cortisol. In healthy individuals ACTH secretion has a

Load more