Hormones of the Hypothalamus and Pituitary

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Chapter 550 Hormones of the Hypothalamus and Pituitary

John S. Parks, Eric I. Felner

The pituitary gland is the major regulator of an elaborate hormonal system. The pituitary gland receives signals from the hypothalamus and responds by sending pituitary hormones to target glands. The target glands produce hormones that provide negative feedback at the level of the hypothalamus and pituitary. This feedback mechanism enables the pituitary to regulate the amount of hormone released into the bloodstream by the target glands. The pituitary’s central role in this hormonal system and its ability to interpret and respond to a variety of signals has led to its designation as the “master gland.”

Anatomy

The pituitary gland is located at the base of the skull in a saddle-shaped cavity of the sphenoid bone called the sella turcica. The bony structure protects and surrounds the pituitary bilaterally and inferiorly. The dura, a dense layer of connective tissue, forms the roof of the sella. An external layer of the dura continues into the sella to form its lining. As a result, the pituitary is extradural and is not normally in contact with cerebrospinal fluid. The pituitary gland is connected to the hypothalamus by the pituitary stalk. The pituitary gland is composed of an anterior (adenohypophysis) and a posterior (neurohypophysis) lobe. The anterior lobe constitutes about 80% of the gland.

Embryology

The anterior pituitary gland originates from the Rathke pouch as an invagination of the oral ectoderm. It then detaches from the oral epithelium and becomes an individual structure of rapidly proliferating cells. By 6 wk of gestation, the connection between the Rathke pouch and the oropharynx is completely obliterated, and the pouch establishes a direct connection with the downward extension of the hypothalamus, which gives rise to the pituitary stalk. Persistent remnants of the original connection between the Rathke pouch and the oral cavity can develop into craniopharyngiomas, the most common type of tumor in this area.

Vascular Supply

The arterial blood supply of the pituitary gland originates from the internal carotid via the inferior, middle, and superior hypophyseal arteries. This network of vessels forms a unique portal circulation connecting the hypothalamus and pituitary. The branches of the superior hypophyseal arteries penetrate the stalk and form a network of vessels that traverse the pituitary stalk and terminate in a network of capillaries within the anterior lobe. It is through this portal venous system that hypothalamic hormones are delivered to the anterior pituitary gland. Anterior pituitary hormones, in turn, are secreted into a secondary plexus of portal veins that drain into the dural venous sinuses.

Anterior Pituitary Cell Types

A series of sequentially expressed transcriptional activation factors directs the differentiation and proliferation of anterior pituitary cell types. These proteins are members of a large family of DNA-binding proteins resembling homeobox genes. The consequences of mutations in several of these genes are evident in human forms of multiple pituitary hormone deficiency. Five cell types in the anterior pituitary produce 6 peptide hormones. Somatotropes produce growth hormone (GH), lactotropes produce prolactin (PRL), thyrotropes make thyroid-stimulating hormone (TSH), corticotropes express pro-opiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), and gonadotropes express luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Growth Hormone

Human GH is a 191-amino-acid single chain polypeptide that is synthesized, stored, and secreted by somatotropes in the pituitary. Its gene (GH1) is the first in a cluster of 5 closely related genes on the long arm of chromosome 17 (q22-24). The four other genes (CS1, CS2, GH2, and CSP) have greater than 90% sequence identity with the GH1 gene.

GH is secreted in a pulsatile fashion under the regulation of hypothalamic hormones. The alternating secretion of growth hormone–releasing hormone (GHRH), which stimulates GH release, and somatostatin, which inhibits GH release, accounts for the rhythmic secretion of GH. Peaks of GH occur when peaks of GHRH coincide with troughs of somatostatin. Ghrelin, a peptide produced in the arcuate nucleus of the hypothalamus and in much greater quantities by the stomach, also stimulates GH secretion. In addition to the 3 hypothalamic hormones, physiologic factors play a role in stimulating and inhibiting GH. Sleep, exercise, physical stress, trauma, acute illness, puberty, fasting, and hypoglycemia stimulate the release of GH whereas hyperglycemia, hypothyroidism, and glucocorticoids inhibit GH release.

GH binds to receptor molecules on the surface of target cells. The GH receptor is a 620-amino-acid, single-chain molecule with an extracellular domain, a single membrane-spanning domain, and a cytoplasmic domain. Proteolytically cleaved fragments of the extracellular domain circulate in plasma and act as a GH-binding protein. As in other members of the cytokine receptor family, the cytoplasmic domain of the GH receptor lacks intrinsic kinase activity; instead, GH binding induces receptor dimerization and activation of a receptor-associated Janus kinase (Jak2). Phosphorylation of the kinase and other protein substrates initiates a series of events that leads to alterations in nuclear gene transcription. The signal transducer and activator of transcription 5b (STAT5b) plays a critical role in linking receptor activation to changes in gene transcription.

The biological effects of GH include increases in linear growth, bone thickness, soft tissue growth, protein synthesis, fatty acid release from adipose tissue, insulin resistance, and blood glucose. The mitogenic actions of GH are mediated through increases in the synthesis of insulin-like growth factor-1 (IGF-1), formerly named somatomedin C, a 70-amino-acid and single-chain peptide coded for by a gene on the long arm of chromosome 12. IGF-1 has considerable homology to insulin. Circulating IGF-1 is synthesized primarily in the liver and formed locally in mesodermal and ectodermal cells, particularly in the growth plates of children, where its effect is exerted by paracrine or autocrine mechanisms. Circulating levels of IGF-1 are related to blood levels of GH and to nutritional status. IGF-1 circulates bound to several different binding proteins. The major one is a 150-kd complex (IGF-BP3) that is decreased in GH-deficient children. Human recombinant IGF-1 might have therapeutic potential in conditions characterized by end organ resistance to GH such as Laron syndrome and the development of antibodies to administered GH. IGF-2 is a 67-amino-acid single-chain protein that is coded for by a gene on the short arm of chromosome 11. It has homology to IGF-1. Less is known about its physiologic role, but it appears to be an important mitogen in bone cells, where it occurs in a concentration many times higher than that of IGF-1.

Prolactin

PRL is a 199-amino-acid peptide made in pituitary lactotropes. The regulation of PRL is unique because PRL is consistently secreted unless it is actively inhibited by dopamine, a peptide produced by neurons in the hypothalamus. Disruption of the hypothalamus or pituitary stalk can result in elevated PRL levels. Dopamine antagonists, states of primary hypothyroidism, administration of thyrotropin-releasing hormone (TRH), and pituitary tumors result in increased serum levels of PRL. Dopamine agonists and processes causing destruction of the pituitary cause reduced levels of PRL.

The primary physiologic role for PRL is the initiation and maintenance of lactation. PRL prepares the breasts for lactation and stimulates milk production postpartum. During pregnancy, PRL stimulates the development of the milk-secretory apparatus, but lactation does not occur because of the high levels of estrogen and progesterone. After delivery, the estrogen and progesterone levels drop and physiologic stimuli such as suckling and nipple stimulation signal PRL release and initiate lactation.

Thyroid-Stimulating Hormone

TSH consists of 2 glycoprotein chains (α, β) linked by hydrogen bonding; the α-subunit, which is composed of 89 amino acids and is identical to other glycoproteins (FSH, LH, and human chorionic gonadotropin [hCG]), and the β-subunit, composed of 112 amino acids, that is specific for TSH.

TSH is stored in secretory granules and released into circulation primarily in response to thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus. TRH is released from the hypothalamus into the hypothalamic–pituitary portal system and ultimately stimulates TSH release from pituitary thyrotropes. TSH stimulates release of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland through the formation of cyclic adenosine monophosphate (cAMP) and the G protein second messenger system. In addition to the negative feedback inhibition by T3, the release of TRH and TSH are inhibited by dopamine, somatostatin, and glucocorticoids.

Deficiency of TSH results in inactivity and atrophy of the thyroid gland, whereas excess TSH results in hypertrophy and hyperplasia of the thyroid gland.

Adrenocorticotropic Hormone

ACTH is a 39-amino-acid single-chain peptide that is derived by proteolytic cleavage from POMC, a 240-amino-acid precursor glycoprotein product of the pituitary gland. POMC also contains the sequences for the lipotropins (LPHs), melanocyte-stimulating hormones (MSHs), and β-endorphin (β-END).

Secretion of ACTH is regulated by corticotropin-releasing hormone (CRH), a 41-amino-acid peptide found predominantly in the median eminence but also in other areas in and outside of the brain. ACTH is secreted in a diurnal pattern. It acts on the adrenal cortex to stimulate cortisol synthesis and secretion. ACTH and cortisol levels are highest in the morning at the time of waking, are low in the late afternoon and evening, and reach their nadir an hour or two after beginning sleep. ACTH also appears to be the principal pigmentary hormone in humans. Similar to TRH and TSH, CRH and ACTH function through the formation of cAMP and the G protein second-messenger system. Although CRH is the primary regulator of ACTH secretion, other hormones play a role. Arginine vasopressin (AVP), oxytocin, angiotensin II, and cholecystokinin stimulate release of CRH and ACTH, whereas atrial natriuretic peptide (ANP) and opioids inhibit release of CRH and ACTH. Similar to the feedback inhibition T3 has on TRH and TSH, cortisol also inhibits CRH and ACTH. Physiologic conditions such as stress, fasting, and hypoglycemia also stimulate release of CRH and ACTH.

Luteinizing Hormone and Follicle-Stimulating Hormone

Gonadotropic hormones include two glycoproteins, LH and FSH. They contain the same α subunit as TSH and hCG but distinct β subunits. Receptors for FSH on the ovarian Granulosa cells and on testicular Sertoli cells mediate FSH stimulation of follicular development in the ovary and of gametogenesis in the testis. On binding to specific receptors on ovarian theca cells and testicular Leydig cells, LH promotes luteinization of the ovary and Leydig cell function of the testis. The receptors for LH and FSH belong to a class of receptors with 7 membrane-spanning protein domains. Receptor occupancy activates adenylyl cyclase through the mediation of G proteins.

Luteinizing hormone–releasing hormone, a decapeptide, has been isolated, synthesized, and widely used in clinical studies. Because it leads to the release of LH and FSH from the same gonadotropic cells, it appears that there is only one gonadotropin-releasing hormone.

Secretion of LH is inhibited by androgens and estrogens, and secretion of FSH is suppressed by gonadal production of inhibin, a 31-kd glycoprotein produced by the Sertoli cells. Inhibin consists of α and β subunits joined by disulfide bonds. The β-β dimer (activin) also occurs, but its biologic effect is to stimulate FSH secretion. The biologic features of these more recently identified hormones are being delineated. In addition to its endocrine effect, activin has paracrine effects in the testis. It facilitates LH-induced testosterone production, indicating a direct effect of Sertoli cells on Leydig cells.

Posterior Pituitary Cell Types

The posterior lobe of the pituitary is part of a functional unit, the neurohypophysis, that consists of the neurons of the supraoptic and paraventricular nuclei of the hypothalamus; neuronal axons, which form the pituitary stalk; and neuronal terminals in the median eminence or in the posterior lobe. Arginine vasopressin (AVP; antidiuretic hormone [ADH]) and oxytocin are the 2 hormones produced by neurosecretion in the hypothalamic nuclei and released from the posterior pituitary. They are octapeptides and differ by only 2 amino acids.

Antidiuretic Hormone

ADH regulates water conservation at the level of the kidney by increasing the permeability of the renal collecting duct to water. ADH stimulates translocation of water channels through its interaction with vasopressin 2 receptors in the collecting duct, which act through G proteins to increase adenylyl cyclase activity and increase permeability to water. V2 receptors also mediate the von Willebrand factor and tissue plasminogen activator. At higher concentrations, ADH activates V1 receptors in smooth muscle cells and hepatocytes and exerts pressor and glycogenolytic effects through mobilization of intracellular calcium stores. Separate V3 receptors mediate stimulation of ACTH secretion. These effects involve phosphotidylinositol hydrolysis rather than cAMP production.

ADH and its accompanying protein neurophysin II are encoded by the same gene. A single pre-prohormone is cleaved and the 2 are transported to neurosecretory vesicles in the posterior pituitary. The 2 are released in equimolar amounts.

ADH has a short half-life and responds quickly to changes in hydration. The stimuli for its release are increased plasma osmolality, perceived by osmoreceptors in the hypothalamus, and decreased blood volume, perceived by baroreceptors in the carotid sinus of the aortic arch.

Oxytocin

Oxytocin stimulates uterine contractions at the time of labor and delivery in response to distention of the reproductive tract and stimulates smooth muscle contraction in the breast during suckling, which results in milk letdown. Studies suggest that oxytocin also plays a role in orgasm, social recognition, pair bonding, anxiety, trust, love, and maternal behavior.

Bibliography

Alatzoglou KS, Dattani MT. Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Hum Dev. 2009;85:705-712.

Ciccone NA, Kaiser UB. The biology of gonadotroph regulation. Curr Opin Endocrinol Diabetes Obes. 2009;16:321-327.

Kageyama H, Takenoya F, Shiba K, et al. Neuronal circuits involving ghrelin in the hypothalamus-mediated regulation of feeding. Neuropeptides. 2010;44:133-138.

Lee HJ, Macbeth AH, Pagani JH, et al. Oxytocin: the great facilitator of life. Prog Neurobiol. 2009;88:127-151.

Stanley TL, Levitsky LL, Grinspoon SK, et al. Effect of body mass index on peak growth hormone response to provocative testing in children with short stature. J Clin Endocrinol Metab. 2009;94:4875-4881.

van Vught AJ, Nieuwenhuizen AG, Gerver WJ, et al. Pharmacological and physiological growth hormone stimulation tests to predict successful GH therapy in children. J Pediatr Endocrinol Metab. 2009;22:679-694.

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