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INTRODUCTION

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The pituitary gland is a midline structure located within the sella turcica recess of the sphenoid bone at the base of the brain; it plays a vital role in orchestrating complex functions of the body including growth, metabolism, homeostasis, reproduction, lactation, and the stress response. The anterior pituitary gland consists of five distinct cell types that are responsible for the synthesis, storage, and release of six hormones: growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), prolactin (PRL), and adrenocorticotropin hormone (ACTH). Under the influence of the hypothalamus and regulated through feedback loops, all anterior pituitary hormones are secreted in a pulsatile fashion and follow a circadian rhythm. When deficiencies of either isolated or multiple pituitary hormones occur, they do so through both congenital and acquired mechanisms.

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Gene mutations that impact anterior pituitary function can affect either the hypothalamic-releasing hormone receptors, the pituitary hormones themselves, regulatory transcription factors, or signaling molecules, which are critical to the normal anatomic development and cellular differentiation of the pituitary gland. Mutations in the genes encoding regulatory transcription factors or signaling molecules cause a disruption of normal pituitary development, resulting in pituitary hormone deficiencies. The advent of molecular biology, genomics, and animal models has allowed for greater insight into these genetic causes of abnormal pituitary development.

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PITUITARY DEVELOPMENT

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The pituitary develops through a temporal and spatial interaction of an invagination of the oral ectoderm (Rathke’s pouch) with the brain neuroectoderm originating from the base of the diencephalon. The final organ is composed of three lobes which are derived from dual-embryonic ectodermal origins; the endocrine hormone-producing anterior and intermediate lobes originate from the oral ectoderm and the posterior lobe develops from the overlying neural ectoderm. Many steps and multiple transcriptions factors (Figures 33-1 and 33-2) contribute to the differentiation of the ectoderm of Rathke’s pouch into the five mature cell types: somatotropes (50% of total cell mass), lactotropes (15%–20%), gonadotropes (10%), and thyrotropes and corticotropes (15%). This cascade of differentiation has been chiefly elucidated by studies in the mouse and other mammals.

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FIGURE 33-1.

Stages of anterior pituitary development and key signaling molecules. Anterior pituitary development can be described as involving four stages: 1) pituitary placode, which forms as a thickening of the oral ectoderm when in contact with the neuroectoderm of the diencephalon; 2) rudimentary Rathke’s pouch, formed by an invagination of the oral ectoderm; 3) definitive Rathke’s pouch, formed by further development of this tissue; and finally 4) mature pituitary gland, formed by the final differentiation into the five major cell lines (somatotropes, lactotropes, corticotropes, gonadotropes, and thyrotropes). Multiple signaling molecules and transcription factors are involved in this process. Time in embryonic development for both mouse (embryonic day) and human (embryonic week) indicated below each stage. Arrows denote signaling. (Adapted and reproduced with permission from Mullis PE. Genetic control of growth. Eur J Endocrinol. 2005;152(1):11–31.)

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