Seminar Hypopituitarism Harald Jörn Schneider, Gianluca Aimaretti, Ilonka Kreitschmann-Andermahr, Günter-Karl Stalla, Ezio Ghigo Incidence and prevalence of hypopituitarism are estimated to be 4·2 per 100 000 per year and 45·5 per 100 000, Lancet 2007; 369: 1461–70 respectively. Although the clinical symptoms of this disorder are usually unspecifi c, it can cause life-threatening Division of Endocrinology and events and lead to increased mortality. Current research has refi ned the diagnosis of hypopituitarism. Identifi cation Metabolism, Department of of growth hormone and corticotropin defi ciency generally requires a stimulation test, whereas other defi ciencies can Internal Medicine, University of Turin, Turin, Italy be detected by basal hormones in combination with clinical judgment. Newly developed formulations of replacement (H J Schneider MD, hormones are convenient and physiological. Work has shown that many patients with brain damage—such as Prof G Aimaretti MD, traumatic brain injury or aneurysmal subarachnoid haemorrhage—are at high risk of (sometimes unrecognised) Prof E Ghigo MD); Clinical hypopituitarism. Thus, a much increased true prevalence of this disorder needs to be assumed. As a result, Neuroendocrinology Group, Max Planck Institute of hypopituitarism is not a rare disease and should be recognised by the general practitioner. Psychiatry, Munich, Germany (H J Schneider, Pituitary insuffi ciency was the topic of a 1998 Lancet together, 35% and 48% of the investigated patients were Prof G-K Stalla MD); seminar.1 Since then, new insights in the areas of diagnosed with some degree of hypopituitarism after Endocrinology, Department of Medical and Experimental epidemiology, diagnosis, and treatment of hypo- traumatic brain injury and subarachnoid haemorrhage, Medicine, University of pituitarism have taken place that deserve to be respectively. In most individuals, only single pituitary axes Piemonte Orientale, Novara, summarised in a current seminar. were aff ected. Pituitary irradiation is a well-known cause Italy (G Aimaretti); and Hypopituitarism, fi rst described clinically by Simmonds of hypopituitarism.25 Findings of a study of patients Department of Neurosurgery, RWTH Aachen University, 2 in 1914, is the inability of the pituitary gland to provide irradiated for brain tumours distant from the hypothalamo- Aachen, Germany suffi cient hormones adapted to the needs of the organism. pituitary axis showed that 41% developed hypopituitarism.10 (I Kreitschmann-Andermahr MD) It might be caused by either an inability of the gland itself In individuals undergoing surgery for non-pituitary brain Correspondence to: to produce hormones or an insuffi cient supply of tumours and in those with ischaemic stroke, rates of Dr Harald Jörn Schneider, hypothalamic-releasing hormones. Figure 1 shows how hypopituitarism were 38% and 19%, respectively.8,9 Clinical Neuroendocrinology Group, Max Planck Institute of changes in hormones that regulate pituitary and To date, traumatic brain injury and subarachnoid Psychiatry, Kraepelinstr 10 hypothalamic function might lead to hypopituitarism. haemorrhage have been best characterised as causes 80804 Munich, Germany Generally, hypopituitarism is chronic and lifelong, unless of hypopituitarism. Respective incidences of these [email protected] successful surgery or medical treatment of the underlying disorders leading to admission are 80 and 10 cases disorder can restore pituitary function. Patients with per 100 000 per year.26,27 The estimated overall incidence hypopituitarism have increased mortality.3–5 of traumatic brain injury in Europe is even higher than these values, at 235 cases per 100 000 per year.28 Causes and epidemiology Application of the above-mentioned frequencies of As far as we know, only one population-based study has hypopituitarism to these incidences would result in an assessed the incidence and prevalence of hypopituitarism.6 estimated incidence of 31 cases of hypopituitarism These researchers noted a prevalence of 45·5 cases attributable to traumatic brain injury and subarachnoid per 100 000 in a Spanish population. Incidence was haemorrhage per 100 000 per year, when using the most 4·2 cases per 100 000 per year and increased with age. conservative data. This number might still be an The causes of hypopituitarism were pituitary tumorous overestimate because of possible preselection of severely (61%), non-pituitary lesions (9%), and non-cancerous traumatised patients or varying defi nitions of pituitary causes (30%), including 11% idiopathic cases.6 Other disorders that classically have been regarded as rare causes of hypopituitarism include perinatal insults, Search strategy and selection criteria 1 genetic causes, or trauma. The panel summarises causes We searched Medline with the main search term of hypopituitarism. “hypopituitarism” in combination with “epidemiology”, Since the beginning of the 21st century, the importance “diagnosis”, or “treatment”. We further combined these terms 7 of brain damage attributable to traumatic brain injury, with “hypocortisolism”, “hypothyroidism”, “hypogonadism”, 7 aneurysmal subarachnoid haemorrhage, ischaemic or “growth hormone defi ciency”. We largely selected articles 8 9 10 stroke, neurosurgery, and cranial irradiation as a major from 1998 to 2006 but did not exclude frequently referenced and formerly underestimated cause of hypothalamic- and highly regarded older publications. We also searched the pituitary dysfunction has been highlighted. Ten systematic reference lists of articles identifi ed by this search strategy and studies of endocrine function in a total of 749 patients in selected those we judged relevant. Review articles and book the chronic phase after admission for traumatic brain chapters are cited to provide readers with further details and injury (most patients were studied at least 6 months after references than this Seminar has room for. The contents of 11–20 trauma) and fi ve studies of 122 individuals with this article are based on reviewed published work, our clinical 11,21–24 aneurysmal subarachnoid haemorrhage have been and scientifi c judgment, and on feedback from peer reviewers. published. Tables 1 and 2 summarise the results. Taken www.thelancet.com Vol 369 April 28, 2007 1461 Seminar mechanical compression of portal vessels and the Central input pituitary stalk, and ischaemic necrosis of portions of the anterior lobe, have been postulated to be the pre dominant mechanism causing hypopituitarism. Moreover, Hypothalamus Releasing hormones increases in intrasellar pressure have been recorded in and inhibiting patients with pituitary macroadenomas, which could be factors the cause of reduced blood fl ow through the portal vessels and the pituitary stalk, resulting in diminished delivery of hypothalamic hormones to the anterior pituitary.33 Anterior Empty sella is caused by herniation of the subarachnoid pituitary space and associated with fl attening of the pituitary gland. This process is sometimes, but not necessarily, - Posterior accompanied by hypopituitarism.34 pituitary The pathway by which radiation induces hypo- Negative feedback pituitarism is largely unresolved. Sparse data favour ADH Panel: Causes of hypopituitarism Oxytocin GH ACTH PRL Brain damage* LH/FSH TSH • Traumatic brain injury Target glands • Subarachnoid haemorrhage Peripheral hormones • Neurosurgery • Irradiation Figure 1: Regulation of hypothalamic-pituitary-peripheral function The anterior pituitary produces adrenocorticotropic hormone (ACTH), • Stroke thyrotropic hormone (TSH), luteinising hormone (LH), follicle-stimulating Pituitary tumours* hormone (FSH), prolactin (PRL), and growth hormone (GH). Their secretion is • Adenomas regulated by hypothalamic releasing and inhibiting factors and by negative feedback inhibition of their peripheral hormones. The posterior pituitary is a • Others storage organ for the hypothalamic hormones antidiuretic hormone (ADH) and Non-pituitary tumours oxytocin. Hypopituitarism can arise at hypothalamic, stalk or pituitary level. • Craniopharyngiomas • Meningiomas dysfunction used in the studies mentioned above. • Gliomas However, without doubt, a large amount of hypo- • Chordomas pituitarism related to brain damage remains undiagnosed. • Ependymomas Patients with brain pathological disorders have many • Metastases 29 somatic, psychiatric, and neurological symptoms that Infections could well mask the typically subtle signs of • Abscess hypopituitarism. Additionally, clinicians who treat these • Hypophysitis patients have very little awareness of this risk, and • Meningitis endocrine assessment is usually not considered after • Encephalitis brain damage.30,31 Infarction Pathophysiology • Apoplexia • Sheehan’s syndrome The pituitary gland is supplied with blood by branches of the internal carotid artery. These vessels form a capillary Autoimmune disorders plexus in the region of the median eminence of the • Lymphocytic hypophysitis hypothalamus. Blood from this area reaches the anterior Haemochromatosis, granulomatous diseases, histiocytosis pituitary by means of long and short portal veins via the Empty sella pituitary stalk. The middle and inferior hypophyseal arteries supply the pituitary stalk and neurohypophysis Perinatal insults with arterial blood. However, the anterior lobe is not Pituitary hypoplasia or aplasia included in this arterial blood supply; it is provided with Genetic causes oxygenated blood only through the internal and external Idiopathic causes plexus of the median eminence.32