PITUITARY

Feb 7, 2009

Embryology and Anatomy

The pituitary gland lies within the sella turcica in the sphenoid bone. The sphenoid sinus wall forms the anterior and inferior aspect of the bony sella, giving direct access to the gland by this route. Soft-tissue boundaries include the lamina dura, forming the floor of the sella; the cavernous sinus with its contents laterally; the optic chiasm superiorly; and the diaphragma sellae, forming the dural roof. The blood supply of the pituitary is from the internal carotid system through the hypophyseal arteries. The predominant venous drainage is directly into the cavernous sinus system.

The gland is made of two embryologically and histologically distinct lobes. The posterior pituitary (i.e., neurohypophysis) is derived as an outpouching of the floor of the third ventricle and consists of nerve endings of neurons whose cell bodies reside in the supraoptic and paraventricular nuclei of hypothalamus. The neurohypophysis produces two octapeptides, oxytocin and vasopressin or antidiuretic hormone (ADH), which are mediated by neural reflexes. These control functions such as uterine contraction, milk letdown, and blood osmolality. The anterior pituitary (i.e., adenohypophysis) is derived from the oropharyngeal ectoderm of Rathke’s pouch and has no direct nerve supply. It is controlled by chemical messages released into the anterior pituitary blood supply from hypothalamic and posterior pituitary cells (hypophyseal–portal system) and is regulated by input from many parts of the brain and by feedback from target organs such as the thyroid, adrenal cortex, and gonads. It is made of distinct cell types that produce characteristic hormones. Originally, these were classed in three groups: acidophils, basophils, and chromophobes.

Physiology

Antidiuretic Hormone

ADH, also called arginine vasopressin, is the major posterior pituitary hormone in humans. Secretion is triggered by central nervous system osmoreceptors and baroreceptors supplied by cranial nerves IX and X. They respond to an increase of as little as 2% in plasma osmolality above 280 mOsm/kg or a decrease in circulating volume of about 10% precipitated by conditions such as hypotension, hypovolemia, and vomiting.

The two primary regions of the nephron affected by ADH are the medullary thick ascending Limb of Henle and the collecting duct. The ascending limb is the diluting segment, where most of the filtered load of sodium chloride is reabsorbed, developing medullary hypertonicity. ADH increases the water permeability of the collecting ducts, allowing osmotic equilibration of tubular fluid with the medullary interstitium, resulting in decreased urine volume.

Adrenocorticotropic Hormone

Adrenocorticotropic hormone (ACTH), a corticotropin, is derived from the prohormone proopiomelanocortin, which also contains melanotropins, lipotropins, and beta endorphin. Pulsatile secretion from the anterior pituitary follows a circadian rhythm and is responsive to certain stimuli (e.g., pain, hemorrhage, anxiety, pyrogens, hypoglycemia). The lowest level of ACTH in the serum occurs between 10 p.m. and 3 a.m. and peaks between 6 and 8 a.m. ACTH actions include stimulation of steroidogenesis by the adrenocortical cells, lipolysis in fat cells, amino acid and glucose uptake in muscle, the secretion of insulin by the pancreatic beta cells, and GH secretion by the somatotropic cells of the pituitary. Regulation of ACTH secretion is under hypothalamic control by corticotropin-releasing factor and feedback inhibition by circulating adrenal cortisol.

Thyroid-stimulating Hormone

Thyroid-stimulating hormone (TSH), a glycoprotein hormone, is produced by the thyrotropic cells of the anterior pituitary gland. TSH increases concentrations of cyclic AMP in the thyroid gland, resulting in the phosphorylation of key proteins and leading to increased size and vascularity of the gland, increased follicular epithelium height, reduction of the amount of colloid, increase in iodide transport, stimulation of the synthesis, and release of thyroxine (T4) and triiodothyronine (T3).

Regulation is somewhat complex. Secretion is stimulated by hypophyseal thyrotropin-releasing hormone and inhibited by hypophyseal somatostatin and anterior pituitary growth hormone. Negative feedback of secretion is by T3, the major inhibiting hormone. Intracellular T3 regulates TSH secretion, but plasma T4 levels correlate better with TSH release. When serum T4 approaches the lower limits of normal, TSH begins to rise exponentially. Of the intracellular T3, 75% is derived from conversion of plasma T4 by 58-deiodinase and the remainder comes from plasma T3 uptake.

Growth Hormone

Growth hormone (GH) is secreted by somatotropic cells. Secretion is pulsatile and peaks 2 to 3 hours into sleep (i.e., stage III or IV). The major actions involve the stimulation of bone and cartilage growth, nitrogen and protein metabolism, fat metabolism, carbohydrate metabolism, and soft-tissue growth (3). Secretion is regulated by hypothalamic peptides. It is stimulated by GH releasing hormone (GH-RH), or somatocrinin, and inhibited by somatostatin. Somatomedins and GH inhibit release by promoting somatostatin release. Exercise, stress, some neurogenic stimuli, and central a-adrenergic agonists augment secretion, but emotional deprivation in some children, a-adrenergic blockers, and b-adrenergic agonists inhibit secretion.

Prolactin

Prolactin is a single-chain peptide similar to GH. It is secreted in a diurnal pattern by the lactotropic cells of the anterior pituitary gland. Peak secretion occurs in the later hours of sleep. Prolactin acts directly on the mammary gland to initiate and maintain lactation but requires preparation of the breast tissue by estrogens and progesterone. It also acts on receptors on the granulosa cells of the ovary to inhibit follicular steroidogenesis.

Follicle-stimulating and Luteinizing Hormones

The glycoproteins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are secreted by the gonadotropic cells in the anterior pituitary gland. Secretion levels vary in premenopausal and postmenopausal women with a 3- to 15-fold increase in women after menopause. In men, FSH acts on the Sertoli’s cells to indirectly stimulate spermatogenesis, and LH acts on the Leydig’s cells to stimulate testosterone synthesis. In women, LH acts on multiple ovarian cells. The preovulatory surge is important in follicular rupture and luteinization. It alone stimulates progesterone and androgen production and is necessary for the normal secretion of estrogen. FSH acts on the granulosa cells to stimulate gametogenesis and also stimulates the production of estradiol. Ovulation is provoked by a combination of an elevated estradiol level and a midcycle rise in FSH level.

Regulation of secretion is by pulsatile release of gonadotropin releasing hormone (GnRH) from the hypothalamus, stimulating release of LH and FSH. Secretion is affected by gonadal steroids by means of a negative feedback mechanism, probably acting at the pituitary and the hypothalamus.

Dysfunction

Central hypothalamic diabetes insipidus is caused by inadequate synthesis or release of ADH. In 50% of cases, the cause is idiopathic. Other causes include basilar skull fractures, tumors of the intrasellar or suprasellar regions, encephalomalacia secondary to cerebrovascular accidents, and the histiocytoses associated with large temporal or mastoid lytic lesions. Patients who have undergone hypophysectomy are also at risk, but this complication is unusual now because of better surgical techniques and less pituitary stalk damage. Symptoms include polyuria (3 to 15 L/day), thirst, nocturia, hyposthenuria (specific gravity, 1.005), low urine osmolality (less than 200 mOsm/kg of H2O), and plasma hypertonicity (plasma osmolality more than 287 mOsm/kg H2O). Treatment is with Pitressin or 1-deamino-8-D-arginine vasopressin), which has negligible pressor effects and can be taken as a nasal spray.

The syndrome of inappropriate secretion of ADH (SIADH) is a common problem with numerous causes, including central nervous system infections, pulmonary diseases, trauma, many drugs, and bronchogenic or gastrointestinal cancers, especially oat cell tumors. The increased secretion of ADH causes retention of ingested water and hyponatremia.

Excess secretion of ACTH presents as Cushing’s syndrome. ACTH deficiency is associated with symptoms similar to those of Addison’s disease, except for the hyperpigmentation. Sodium and potassium levels are usually normal because aldosterone secretion is only partly regulated by ACTH; however, low cortisol levels may cause water retention with subsequent hyponatremia. With age, there may be diminished sensitivity of ACTH to negative feedback by glucocorticoids, and the ectopic ACTH syndrome is more common due to the increased incidence of malignancies.

The mean level of TSH is normally 1.8 mU/mL. This level may rise above 5 mU/mL when the plasma T3 and T4 are still within normal range in early hypothyroidism. Hypothalamic or pituitary failure prevents TSH levels from rising. TSH levels may be normal or slightly elevated in secondary hypothyroidism because TSH is not bioactive.

Excess GH secretion early in life is manifested as gigantism and as acromegaly after growth centers have closed. Deficiencies may be isolated or occur with other hormone deficiencies with or without an adenoma. If onset is early, the result is short stature; however, if it occurs with other deficiencies, the diagnosis may be difficult before puberty, because ACTH and TSH have large secretory reserves. With age, the plasma somatomedin C level is decreased, basal GH levels fall in females, the sleep-related pulsatile secretion declines, and the response to GH-RH or insulin-induced hypoglycemia may be attenuated.

Excess prolactin production is the most common hypothalamic–pituitary disorder in clinical endocrinology. The high levels inhibit the release of GnRH from the hypothalamus, causing hypogonadism. Failure of lactation is associated with deficiency of prolactin due to postpartum necrosis of the pituitary (Sheehan’s syndrome from ischemia caused by hemorrhage or shock), or it can be an isolated deficiency after an uncomplicated delivery. Pituitary necrosis also is seen in severe anoxia or long-standing diabetes mellitus.

Pituitary dysfunction can be related to developmental abnormalities associated with midline structural defects involving isolated or combined cell types. For example, Kallmann’s syndrome, due to the maldevelopment of the olfactory lobes and related hypothalamic lesions, is characterized by hyposmia or anosmia and an isolated GnRH deficiency with the associated gonadal dysfunctions. Pituitary necrosis is also seen in severe anoxia or long-standing diabetes mellitus.

Infectious causes include encephalitis, abscess, tuberculosis, or syphilis involving the hypothalamus or pituitary. A viral infection of selected neurohypophyseal nuclei may be a possible mechanism of acquired “idiopathic” diabetes insipidus. Other causes include noninfectious granulomas or infiltrations, such as the histiocytoses in children and sarcoidosis or excessive iron deposition from hemochromatosis in adults. In several autoimmune disorders, there may be circulating antibodies to lactotropic or somatotropic cells. Lymphocytic hypophysitis is seen in some postpartum women.

Pituitary damage can occur in children as a result of chemotherapy and radiation therapy. Accidental and surgical trauma is thought to be due to stalk separation or damage. In other cases, although the gross appearance is normal, abnormal hormones that are not biologically active may be produced.

Pituitary adenomas are classified by hormonal immunostaining of secretory granules within the cell or cells of origin and by radiologic appearance. Using computed tomographic or magnetic resonance studies, the tumor is classified as “enclosed” if there is no evidence of invasion of the bony sellar floor. Class I tumors or microadenomas are smaller than 10 mm in diameter, class II tumors or macroadenomas are larger than 10 mm in diameter, and invasive tumors are considered class III if part of the sellar floor is involved or class IV if all of the floor is destroyed. This classification does not limit the superior extension of the tumors. Functioning adenomas secrete the hormone(s) related to its cell(s) of origin. Some adenomas have no hormonal granules (i.e., null cell adenoma) or may have increased mitochondria (i.e., oncocytoma). Prolactinomas, the most common type of functional pituitary adenoma, can be found as part of the multiple endocrine neoplasia type I (MEN I) syndrome. Adenomas are thought also to develop as a result of untreated Addison’s disease, congenital adrenal hyperplasia, previous hypothyroidism, or hypogonadism. Pituitary changes associated with aging are seen, such as a diminished capacity to adapt to salt restriction or salt load with age. Basal levels of vasopressin are increased, but volume–pressure stimulation is decreased and kidney responsiveness may also be reduced.

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