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Chapter 8 anterior pituitary from kronenberg: williams textbook of endocrinology on md consult


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  • 1. Kronenberg: Williams Textbook of Endocrinology, 11th ed. Copyright © 2008 Saunders, An Imprint of Elsevier CHAPTER 8 – ANTERIOR PITUITARY Shlomo Melmed David Kleinberg ▪ Development, Anatomy, and Overview of Control of Hormone Secretion, 155 ▪ Pituitary Masses, 159 ▪ Physiology and Disorders of Pituitary Hormone Axes, 180 ▪ Pituitary Failure, 235 DEVELOPMENT, ANATOMY, AND OVERVIEW OF CONTROL OF HORMONE SECRETION The pituitary gland, situated within the sella turcica, derives its name from the Greek ptuo and Latin pituita, “phlegm,” reflecting its nasopharyngeal origin. Galen hypothesized that nasal phlegm originated from the brain and drained via the pituitary gland. It is now clear that together with the hypothalamus, the pituitary orchestrates the structural integrity and function of endocrine glands including the thyroid, adrenal, and gonads, in addition to target tissues including cartilage and breast. The pituitary stalk serves as an anatomic and functional connection to the hypothalamus. Preservation of the hypothalamic-pituitary unit is critical for integration of anterior pituitary control of sexual function and fertility, linear and organ growth, lactation, stress responses, energy, appetite, and temperature regulation and secondarily for carbohydrate and mineral metabolism. Integration of vital body functions by the brain was first proposed by Descartes in the 17th century. In 1733, Morgagni recorded the absence of adrenal glands in an anencephalic neonate, providing early evidence for a developmental and functional connection between the brain and the adrenal glands. In 1849, Claude Bernard set the stage for the subsequent advances in neuroendocrinology by demonstrating that central lesions to the area of the fourth ventricle resulted in polyuria. [1] Subsequent studies led to the identification and chemical isolation of pituitary hormones, and astute clinical observations led to the realization that pituitary tumors were associated with functional hypersecretory syndromes, including acromegaly and Cushing's disease. [2] [3] [4] In 1948, Geoffrey Harris, the father of modern neuroendocrinology, in reviewing anterior pituitary gland hormone control, proposed their hypothalamic regulation, predicting the subsequent discovery of specific hypothalamic regulating hormones. [5] Anatomy The pituitary gland comprises the predominant anterior lobe, the posterior lobe, and a vestigial intermediate lobe ( Fig. 8-1 ). The gland is situated within the bony sella turcica and is overlaid by the dural diaphragma sella, through which the stalk connects to the median eminence of the hypothalamus. The adult pituitary weighs about 600 mg (range 400-900 mg) and measures about 13 mm in the longest transverse diameter, 6 to 9 mm vertically, and about 9 mm anteroposteriorly. Structural variation can occur in multiparous women, and gland volume also changes during the menstrual cycle. During pregnancy these measurements may be increased in either dimension, with pituitary weight increasing up to 1 gram. Recently, normal pituitary hypertrophy without evidence for the presence of an adenoma was described in seven eugonadal women with pituitary height greater than 9 mm and a convex upper gland boundary observed on magnetic resonance imaging (MRI). [6]
  • 2. Figure 8-1 Schematic representation of the blood supply of the hypothalamus and pituitary (From Scheithauer BW. The hypothalamus and neurohypophysis. In Kovacs K, Asa SL, eds. Functional Endocrine Pathology. Boston: Blackwell Science, 1991:170244.) The sella turcica, located at the base of the skull, forms the thin bony roof of the sphenoid sinus. The lateral walls comprising, either bony or dural tissue, abut the cavernous sinuses, which are traversed by the third, fourth, and sixth cranial nerves and the internal carotid arteries ( Fig. 8-2 ). Thus, the cavernous sinus contents are vulnerable to increased intrasellar expansion. The dural roofing protects the gland from compression by fluctuant cerebrospinal fluid (CSF) pressure. The optic chiasm, located anterior to the pituitary stalk, is directly above the diaphragma sella. The optic tracts and central structures are therefore vulnerable to pressure effects by an expanding pituitary mass, which likely follows the path of least tissue resistance by lifting the diaphragma sella ( Fig. 8-3 ). The intimate relationship of the pituitary and chiasm is borne out in optic chiasmic hypoplasia associated with developmental pituitary dysfunction seen in patients with septo-optic dysplasia. The posterior pituitary gland, in contrast to the anterior pituitary, is directly innervated by supraopticohypophyseal and tuberohypophyseal nerve tracts of the posterior stalk. Hypothalamic neuronal lesions, stalk disruption, or direct systemically derived metastases therefore are often associated with attenuated
  • 3. vasopressin (AVP) (diabetes insipidus) or oxytocin secretion, or both. Figure 8-2 Coronal section of the sellar structures and cavernous sinus showing the relationship of the oculomotor (III), trochlear (IV), trigeminal ophthalmic and maxillary divisions (V1 and V2), and abducent (VI) cranial nerves to the pituitary gland. (From Stiver SI, Sharpe JA. Neuro-ophthalmologic evaluation of pituitary tumors. In Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors Totowa, NJ: Humana Press, 2001:173-200).
  • 4. Figure 8-3 Relationship of the pituitary gland to the optic chiasm. The intracranial optic nerve/chiasmal complex lies up to 10 mm above the diaphragma sellae (C represents the anterior clinoid process and D represents the dorsum of the sella turcica). (From Miller NR. Walsh and Hoyt's Clinical Neuro-Opthalmology, 4th ed, Vol 1. Baltimore: Williams and Wilkins, 1985:60-69). The hypothalamus contains nerve cell bodies that synthesize hypophysiotropic releasing and inhibiting hormones, as well as the neurohypophyseal hormones of the posterior pituitary (AVP and oxytocin). Five distinct hormone-secreting cell types are present in the mature anterior pituitary gland. Corticotroph cells express pro-opiomelanocortin (POMC) peptides includ-ing adrenocorticotropic hormone (ACTH); somatotroph cells express growth hormone (GH); thyrotroph cells express the common glycoprotein α-subunit and the specific thyroid-stimulating hormone (TSH) β-subunit; gonadotrophs express the α and β subunits for both follicle-stimulating hormone (FSH) and luteinizing hormone (LH); the lactotroph expresses prolactin (PRL). Each cell type is under highly specific signal controls, which regulate their respective differentiated gene expression. Pituitary Development The pituitary gland arises from within the rostral neural plate. Rathke's pouch, a primitive ectodermal invagination anterior to the roof of the oral cavity, is formed by the fourth to fifth week of gestation
  • 5. and gives rise to the anterior pituitary gland ( Fig. 8-4 ). [7] [8] The pouch is directly connected to the stalk and hypothalamic infundibulum, and it ultimately becomes distinct from the oral cavity and nasopharynx. Rathke's pouch proliferates toward the third ventricle, where it fuses with the diverticulum, and subsequently obliterates its lumen, which sometimes persists as Rathke's cleft. The anterior lobe is formed from Rathke's pouch, and the diverticulum gives rise to the adjacent posterior lobe. Remnants of pituitary tissue can persist in the nasopharyngeal midline, and they rarely give rise to functional ectopic hormone-secreting tumors in the nasopharynx. The neurohypophysis arises from neural ectoderm associated with third ventricle development. [9] Figure 8-4 Model for development of the human anterior pituitary gland and cell lineage determination by a cascade of transcription factors. Trophic cells are depicted with transcription factors known to determine cell-specific human or murine gene expression. ACTH, adrenocorticotropic hormone; BMP, bone morphogenetic protein; FSH, follicle-stimulating hormone; GH, growth hormone; FGF, fibroblast growth factor; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone. (Adapted from Melmed S. Anterior Pituitary. In Conn P, Melmed S, eds. Scientific Basis of Endocrinology. Totowa, NJ: Humana Press, 1996:30-48; Amselem S. Perspectives on the molecular basis of developmental defects in the human pituitary region. In Rappaport R, Amselem S, eds. Hypothalamic-Pituitary Development. Basel: Karger, 2001:30-47; Dasen JS, Rosenfeld MG. Signaling mechanisms in pituitary morphogenesis and cell fate determination. Curr Opin Cell Biol 1999;11:669-677.) Functional development of the anterior pituitary cell types involves complex spatiotemporal
  • 6. regulation of cell lineage–specific transcription factors expressed in pluripotential pituitary stem cells, as well as dynamic gradients of locally acting soluble factors. [10] [11] [12] Critical neuro-ectodermal signals for organizing the dorsal gradient of pituitary morphogenesis include infundibular bone morphogenetic protein 4 (BMP4) required for the initial pouch invagination, [8] fibroblast growth factor 8 (FGF-8), Wnt 5, and Wnt 4. Subsequent ventral developmental patterning and transcription factor expression is determined by spatial and graded expression of BMP2 and sonic hedgehog protein (shh) which appears critical for directing early patterns of cell proliferation. [13] The human fetal Rathke's pouch is evident at 3 weeks, and the pituitary grows rapidly in utero. By 7 weeks, the anterior pituitary vasculature begins to develop, and by 20 weeks, the entire hypophyseal-portal system is already established. The anterior pituitary undergoes major cellular differentiation during the first 12 weeks, by which time all the major secretory cell compartments are structurally and functionally intact, except for lactotrophs. Totipotential pituitary stem cells give rise to acidophilic (mammosomatotroph, somatotroph, and lactotroph) and basophilic (corticotroph, thyrotroph, and gonadotroph) differentiated pituitary cell types, which appear at clearly demarcated developmental stages. At 6 weeks, corticotroph cells are morphologically identifiable, and immunoreactive ACTH is detectable by 7 weeks. At 8 weeks, somatotroph cells are evident, with abundant immunoreactive cytoplasmic GH expression. Glycoprotein hormone–secreting cells express a common α-subunit for TSH, and at 12 weeks, differentiated thyrotrophs and gonadotrophs express immunoreactive β-subunits LH and FSH, respectively. Interestingly, in female fetuses, LHand FSH-expressing gonadotrophs are equally distributed, whereas in the male fetus, LH-expressing gonadotrophs predominate. [14] Fully differentiated PRL-expressing lactotrophs are only evident late in gestation (after 24 weeks). Before then, immunoreactive PRL is only detectable in mixed mammosomatotrophs, also expressing GH, reflecting the common genetic origin of these two hormones. [15] Pituitary Transcription Factors Determination of anterior pituitary cell type lineages results from a temporally regulated cascade of homeodomain transcription factors. Although most pituitary developmental information has been acquired from murine models, [16] histologic and pathogenetic observations in human subjects have largely corroborated these developmental mechanisms (see Fig. 8-4 ). Early cell differentiation requires intracellular Rpx and Ptx expression. Rathke's pouch expresses several transcription factors of the LIM homeodomain family, including Lhx3, Lhx4, and IsI-1, [17] which are early determinants of functional pituitary development. Pitx1 is expressed in the oral ectoderm, and subsequently in all pituitary cell types, particularly those arising ventrally. [18] Rieger's syndrome, characterized by defective eye, tooth, umbilical cord, and pituitary development, is caused by defective related Pitx2. [19] [20] Ptx behaves as a universal pituitary regulator and activates transcription of the α-glycoprotein subunit (a-GSU), POMC, and LHb (Ptx1) and GH (Ptx2). Lhx3 determines GH-, PRL-, and TSH-cell diffentiation, and Prop-1 behaves as a prerequisite for Pit-1, which activates GH, PRL, TSH, and growth hormone–releasing hormone (GHRH) receptor transcription. TSH and gonadotropinexpressing cells share a common α-subunit (aGSU) expression under developmental control of GATA-2. [11] These specific anterior pituitary transcription factors participate in a highly orchestrated cascade leading to the commitment of the five differentiated cell types (see Fig. 8-4 ). The major proximal determinant of pituitary cell lineage derived from a totipotential stem cell is thus Prop-1 expression, which determines subsequent development of PIT-1–dependent and gonadotroph cell lineages. [21] POU1F1, the renamed Pit-1, is a POU-homeodomain transcription factor, which determines development and appropriate temporal and spatial expression of cells committed to GH-, PRL-, TSH, and GHRH-receptor expression. POU1F1 binds to specific DNA motifs and activates and regulates somatotroph, lactotroph, and thyrotroph development and mature secretory function. Signal-
  • 7. dependent coactivating factors also cooperate with Pit-1 to determine specific hormone expression. Thus, in POU1F1-containing cells, high estrogen receptor levels induce a commitment to express PRL, whereas thyrotroph embryonic factor (TEF) favors TSH expression. Selective pituitary cell-type specificity is also perpetuated by binding of POU1F1 to its own DNA regulatory elements as well as those contained within the GH, PRL, and TSH genes. Steroidogenic factor (SF-1) and DAX-1 determine subsequent gonadotroph development. [22] [23] Corticotroph cell commitment, although occurring earliest during fetal development, is independent of POU1F1-determined lineages, and Tpit protein appears to be a prerequisite for POMC expression. [24] Hereditary mutations arising within these transcription factors can result in isolated or combined pituitary hormone failure syndromes (see later). Pituitary Blood Supply The pituitary gland enjoys an abundant blood supply derived from several sources (see Fig. 8-1 ). The superior hypophyseal arteries branch from the internal carotid arteries to supply the hypothalamus, where they form a capillary network in the median eminence, external to the bloodbrain barrier. Both long and short hypophyseal portal vessels originate from infundibular plexuses and the stalk, respectively. These vessels form the hypothalamic-portal circulation, the predominant blood supply to the anterior pituitary gland. They deliver hypothalamic releasing and inhibiting hormones to the trophic hormone-producing cells of the adenohypophysis, without significant systemic dilution, allowing the pituitary cells to be sensitively regulated by timed hypothalamic hormone secretion. Vascular transport of hypothalamic hormones is also locally regulated by a contractile internal capillary plexus (gomitoli) derived from stalk branches of the superior hypophysial arteries. [25] Retrograde blood flow toward the median eminence also occurs, facilitating bidirectional functional hypothalamic-pituitary interactions. [26] Systemic arterial blood supply is maintained by inferior hypophysial arterial branches, which predominantly supply the posterior pituitary. Disruption of stalk integrity can lead to compromised pituitary portal blood flow, depriving the anterior pituitary cells of hypothalamic hormone access. Pituitary Control Three levels of control subserve the regulation of anterior pituitary hormone secretion ( Fig. 8-5 ). Hypothalamic control is mediated by adenohypophysiotropic hormones, which are secreted into the portal system and impinge directly upon anterior pituitary cell surface receptors. G-protein–linked cell surface membrane binding sites are highly selective and specific for each of the hypothalamic hormones, and they elicit positive or negative signals mediating pituitary hormone gene transcription and secretion. Peripheral hormones also participate in mediating pituitary cell function, predominantly by negative feedback regulation of trophic hormones by their respective target hormones. Intrapituitary paracrine and autocrine soluble growth factors and cytokines act to locally regulate neighboring cell development and function.
  • 8. Figure 8-5 Model for regulation of anterior pituitary hormone secretion by three tiers of control. Hypothalamic hormones traverse the portal system and impinge directly upon their respective target cells. Intrapituitary cytokines and growth factors regulate tropic cell function by paracrine and autocrine control. Peripheral hormones exert negative feedback inhibition of respective pituitary trophic hormone synthesis and secretion. CNS, central nervous system. (From Ray D, Melmed S. Pituitary cytokine and growth factor expression and action. Endocr Rev 1997;18:206-228.) The net result of these three tiers of complex intracellular signals is the controlled pulsatile secretion of the six pituitary trophic hormones, ACTH, GH, PRL, TSH, FSH, and LH, through the cavernous sinus, petrosal veins, and ultimately the systemic circulation via the superior vena cava ( Fig. 8-6 ). The temporal and quantitative control of pituitary hormone secretion is critical for physiologic integration of peripheral hormonal systems, such as the menstrual cycle, which relies on complex and precisely regulated pulse control.
  • 9. Figure 8-6 Control of hypothalamic-pituitary target organ axes. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropinreleasing hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; T3, triiodothyronine; T4, thyroxine; TRH, thyrotrophinreleasing hormone; TSH, thyroid-stimulating hormone. Adapted from Melmed S, Mechanisms for pituitary tumorigenesis. The plastic pituitary. J Clin Investigation 2003 112:1603-1618. Copyright © 2008 Elsevier Inc. All rights reserved. -