The Pituitary

Shlomo Melmed

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780128134214
• Edition: 4
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

The Pituitary, Fourth Edition, continues the tradition of a cogent blend of basic science and clinical medicine which has been the successful hallmark of prior editions. This comprehensive text is devoted to the pathogenesis, diagnosis, and treatment of pituitary disorders. The new edition has been extensively revised to reflect new knowledge derived from advances in molecular and cell biology, biochemistry, diagnostics, and therapeutics as they apply to the pituitary gland.

The wide spectrum of clinical disorders emanating from dysfunction of the master gland is described in detail by experts in the field. Fundamental mechanisms underlying disease pathogenesis are presented to provide the reader with an in-depth understanding of mechanisms subserving both normal and disordered pituitary hormone secretion and action.

This extensive body of knowledge is useful for students, trainees, physicians, and scientists who need to understand critical pituitary functions and how to care for patients with pituitary disorders. Chapters provide medical students, clinical and basic endocrinology trainees, endocrinologists, internists, pediatricians, gynecologists, and neurosurgeons with a comprehensive, yet integrated, text devoted to the science and art of pituitary medicine.

• Brings together pituitary experts from all areas of research and practice who take readers all the way from bench research, to genomic and proteomic analysis, clinical analysis, and new therapeutic approaches to pituitary disorders
• Saves researchers and clinicians time in quickly accessing the very latest details on a broad range of issues related to normal and diseased pituitary function
• Provides a common language for endocrinologists, neurosurgeons, OB/GYNs, and endocrine researchers to discuss how the pituitary gland and hormones affect each major organ system

Section I

Hypothalamic–Pituitary Function

Outline

Chapter 1 Pituitary Development

Chapter 2 Hypothalamic Regulation of Anterior Pituitary Function

Chapter 3 Adrenocorticotrophin

Chapter 4 Growth Hormone

Chapter 5 Prolactin

Chapter 6 Thyroid-Stimulating Hormone

Chapter 7 Gonadotrophin Hormones

Chapter 8 The Posterior Pituitary

Chapter 1

Pituitary Development

Jacques Drouin

Abstract

The pituitary gland has a relatively simple organization despite its central role as chef d’orchestre of the endocrine system. Indeed, the glandular portion of the pituitary, comprised of the anterior and intermediate lobes, contains six secretory cell types, each dedicated to the production of a different hormone. Long thought to be a random patchwork of cells, we are just now discovering that pituitary cells are organized in three-dimensional structures and that the tissue develops following a precise stepwise plan. As for most tissues and organs, numerous signaling pathways are involved in pituitary organogenesis but it is mostly the discovery of regulatory transcription factors that has provided insight into mechanisms of pituitary development. Genetic analyses of the genes encoding these transcription factors have defined mechanisms for the formation of Rathke’s pouch, the pituitary anlage, and for expansion and differentiation of this simple epithelium into a complex network of endocrine cells that produce hormones while integrating complex inputs from the hypothalamus and bloodstream. The understanding of normal developmental processes provides a novel insight into mechanisms of pathogenesis: e.g., critical regulators of pituitary cell differentiation become the cause of hormone deficiencies when their genes carry mutations. This chapter surveys current notions of pituitary development highlighting the impact of this knowledge on understanding pituitary pathologies as well as identifying the challenges and gaps for the future.

Keywords

Organogenesis; cell differentiation; gene expression; epigenetics; Rathke’s pouch; hormone deficiencies

Introduction

The pituitary gland has a relatively simple organization despite its central role as chef d’orchestre of the endocrine system. Indeed, the glandular portion of the pituitary, comprised of the anterior and intermediate lobes, contains six secretory cell types, each dedicated to the production of a different hormone. Long thought to be a random patchwork of cells, we are just now discovering that pituitary cells are organized in three-dimensional structures and that the tissue develops following a precise stepwise plan. As for most tissues and organs, numerous signaling pathways are involved in pituitary organogenesis but it is mostly the discovery of regulatory transcription factors that has provided insight into mechanisms of pituitary development. Genetic analyses of the genes encoding these transcription factors have defined mechanisms for the formation of Rathke’s pouch, the pituitary anlage, and for expansion and differentiation of this simple epithelium into a complex network of endocrine cells that produce hormones while integrating complex inputs from the hypothalamus and bloodstream. The understanding of normal developmental processes provides a novel insight into mechanisms of pathogenesis: e.g., critical regulators of pituitary cell differentiation become the cause of hormone deficiencies when their genes carry mutations. This chapter surveys current notions of pituitary development highlighting the impact of this knowledge on understanding pituitary pathologies as well as identifying the challenges and gaps for the future.

The Pituitary Gland

The pituitary gland was ascribed various roles by anatomists over the centuries, including the source of phlegm that drained from the brain to the nose or the seat of the soul. It was at the beginning of the 20th century that its endocrine functions became recognized [1] and thereafter the various hormones produced by the pituitary were characterized, isolated and their structure determined. The major role of the hypothalamus in the control of pituitary function was recognized by Harris in the mid-20th century and that marked the beginning of the new discipline of neuroendocrinology [2]. The adult pituitary is linked to the hypothalamus through the pituitary stalk that harbors a specialized portal system through which hypophysiotrophic hypothalamic hormones directly reach their pituitary cell targets [3,4]. The adult pituitary is composed of three lobes, the anterior and intermediate lobes that have a common developmental origin from the ectoderm, and the posterior lobe that is an extension of the ventral diencephalon or hypothalamus. Whereas the intermediate pituitary is a relatively homogeneous tissue containing only melanotroph cells that produce α-melanotrophin (αMSH), the anterior lobe contains five different hormone-secreting lineages, including the corticotrophs that produce adrenocorticotrophin (ACTH), the gonadotrophs that produce the gonadotrophins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the somatotrophs that produce growth hormone (GH), the lactotrophs that produce prolactin (PRL) and, finally, the thyrotrophs that produce thyroid-stimulating hormone (TSH). In addition, these tissues contain support cells, known as pituicytes or folliculostellate cells. The neural or posterior lobe of the pituitary is largely constituted of axonal projections from the hypothalamus that secrete arginine vasopressin and oxytocin (OT) as well as support cells. The intermediate lobe is present in many species, in particular in rodents, mice and rats, that have been used extensively to study pituitary development and function, but it regresses in humans at about the 15th week of gestation: it is thus absent from the adult human pituitary gland. In view of the critical importance of the intermediate lobe in embryonic development, it is possible that the tissue is maintained in the developing human embryo for this very reason. Most of our recent insight into the mechanisms of pituitary development has come from studies in mice: the review of our current knowledge presented in this chapter will therefore primarily focus on mouse development with references to other species (including humans) when significant differences are known or in cases of direct clinical relevance.

Formation of Rathke’s Pouch

The glandular or endocrine part of the pituitary gland derives from the most anterior segment of the surface ectoderm. It ultimately comprises the anterior and intermediate lobes of the pituitary. This was shown using chick-quail chimeras [5,6]. It is thus the most anterior portion of the midline surface ectoderm, the anterior neural ridge, which harbors the presumptive pituitary. Interestingly, fate-mapping studies also indicated that the adjoining neural territory will form the ventral diencephalon and hypothalamus. As head development is initiated and the neuroepithelium expands to form the brain, the anterior neural ridge is displaced ventrally and eventually occupies the lower facial and oral area. It is thus the midline portion of the oral ectoderm that invaginates to become the pituitary anlage, Rathke’s pouch. This invagination does not form through an active process but it rather appears to result from sustained contact between neuroepithelium and oral ectoderm at the time when derivatives of prechordal mesoderm and neural crest invade the space between neuroepithelium and surface ectoderm and thus separate these tissue layers everywhere except in the midline at the pouch level. Rathke’s pouch is thus a simple epithelium that is a few cells thick extending at the back of the oral cavity towards the developing diencephalon, with which it maintains intimate contact. This contact is essential for proper pouch and pituitary development since its rupture either physically [7–10] or through genetic manipulations [11,12] leads to aborted pituitary development. Indeed, a number of transcription factors expressed in diencephalon and infundibulum, but not in the pituitary itself, such as Nkx2.1 [11,13], Sox3 [14], and Lhx2 [12], are required for proper diencephalon development and secondarily affect pituitary formation. In humans, SOX3 mutations have been associated with hypopituitarism [14]. Collectively, these data have supported the importance of signal exchange between diencephalon and forming pituitary [15] for proper development of both tissues.

Rathke’s pouch rapidly forms a closed gland through disruption of its link with the oral ectoderm. This occurs through apoptosis of the intermediate epithelial tissue [16]. The oral ectoderm and Rathke’s pouch are marked by expression of transcription factors that are essential for early pouch development (Fig. 1.1). The earliest factors are the pituitary homeobox (Pitx, Ptx) factors, Pitx1 and Pitx2 [17,18]. Indeed, these two related transcription factors are coexpressed throughout the oral ectoderm and their combined inactivation results in blockade of development at the early pouch stage [16]. The double mouse mutant Pitx1^−/−Pitx2^−/− exhibits delayed and incomplete disruption of tissues between developing pituitary and oral ectoderm, and pituitary development does not appear to be able to progress beyond this stage. The single Pitx2^−/− mutant is somewhat less affected, reaching the late pouch stage [19–21]. The Pitx1^−/− mutant has relatively normal pituitary organogenesis, except for underrepresentation of the gonadotroph and thyrotroph lineages [22] that express higher levels of Pitx1 protein in the adult [23]. The two Pitx factors thus have partly redundant roles in early pituitary development with Pitx2 having predominant and unique functions in organogenesis.

Figure 1.1 Development of the pituitary gland in mouse. Critical steps, signaling molecules, and transcription factors for pituitary development are highlighted on drawings representing the developing pituitary or Rathke’s pouch (red) from e9.5 to e17.5 of mouse embryonic development. At e9.5 and e10.5, the ventral diencephalon sequentially expresses Bmp4 and Fgf8 that are critical for Rathke’s pouch development; also, sonic hedgehog (Shh) expressed throughout the oral ectoderm, but exclu...