Anterior pituitary hyperfunction is most often caused by tumors.

Tumors are the most important lesions of the pituitary. Even so, they are quite rare. These tumors may produce hormones and cause one of the typical pituitary hormonal syndromes.

The most common pituitary tumor, the prolactinoma, is typically associated with galactorrhea–amenorrhea syndrome in women and loss of libido and impotence in men. Other syndromes related to pituitary hyperfunction are uncommon. This group of diseases includes acromegaly/gigantism, Cushing’s disease due to corticotropic adenoma, pituitary hyperthyroidism, and disturbances of reproductive function due to gonadotropic tumors.

Prolactinoma. These tumors composed of lactotrophic cells account for approximately one third of all hormonally active pituitary adenomas. They occur eight times more frequently in women than in men. Hyperprolactinemia stimulates the production of milk, causing galactorrhea. It also interferes with the normally pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), causing amenorrhea, anovulation, infertility, and loss of libido. In men it causes erectile dysfunction, loss of libido, infertility, and gynecomastia (Fig. 11-5).

Figure 11-5 Prolactinoma. The tumor in the anterior pituitary leads to galactorrhea, anovulation, and amenorrhea. Inhibition of dopamine with bromocriptine reduces the prolactinemia.

Tumors secreting prolactin may be classified as microadenomas or macroadenomas. Microadenomas do not affect the function of the surrounding normal pituitary, but the large macroadenomas may compress other cells and impede their function. The diagnosis is made by measuring prolactin in the blood and by demonstrating the tumor radiologically in the anterior lobe of the pituitary. Note, however, that hyperprolactinemia may be caused by a number of other conditions besides tumors (Table 11-5). In these conditions prolactin levels in the blood are usually less than 100 μg/L. A concentration of prolactin greater than 300 μg/L is virtually diagnostic of prolactinoma.

Table 11-5 Causes of Hyperprolactinemia

Normal secretion of prolactin is inhibited by dopamine. Dopamine agonists such as bromocriptine inhibit prolactin secretion even in patients who have adenomas. This type of treatment may suffice for treating microadenomas, but macroadenomas must be treated surgically.

Somatotropic adenoma. These tumors secrete growth hormone. Childhood tumors found before the closure of epiphysis cause gigantism, and tumors of adulthood cause acromegaly. Gigantism is extremely rare, and acromegaly is somewhat more common. About 15% of all somatotropic adenomas also secrete prolactin and gonadotropic hormones.

Acromegaly. Acromegaly presents with acral enlargement due to thickening of the skin, excessive growth of subcutaneous tissue and bone, generalized organomegaly, and metabolic changes (Fig. 11-6). The most common findings include the following:

Figure 11-6 Acromegaly. ACTH, adrenocorticotropic hormone; GH, growth hormone; IGF-I, insulin-like growth factor I.

The diagnosis is confirmed by measuring GH in the blood. Secretion of GH is pulsatile, and thus single measurements are not informative. Instead, it is recommended to give glucose by mouth and measure GH 1 hour thereafter. In normal persons glucose suppresses GH to 2 μg/L or less, but in patients with somatotropic adenomas GH levels are not suppressed and actually may paradoxically rise. Instead of GH somatomedin C (IGF-1) can be measured. Note that somatomedin C is a very good test for somatotropic hormones, but it must be adjusted for the age and sex of the patient. It may be abnormally low in patients who have chronic liver or kidney disease.

Tumors also may compress local structures. Compression of the optic chiasms results in bitemporal hemianopsia.

Hypopituitarism may be caused by many diseases affecting the anterior lobe of the pituitary, the pituitary stalk, or the hypothalamus.

Pituitary insufficiency is an uncommon condition that may manifest as panhypopituitarism or a deficiency of a single pituitary hormone or hypothalamic-releasing hormone. The latter group includes mostly genetic disorders.

A mnemonic for memorizing the causes of pituitary insufficiency is that all begin with a letter I (Table 11-6).

Table 11-6 Causes of Hypopituitarism

Clinical signs and symptoms of pituitary insufficiency do not become apparent until at least 75% of the pituitary is destroyed. The most common causes are tumors, such as craniopharyngioma (in children), brain or meningeal tumors at the base of the brain, and nonfunctioning pituitary tumors. Pituitary ischemia and injury of the hypothalamus during surgery or head trauma are another important group of pituitary lesions. Sheehan’s syndrome caused by hemorrhagic infarction of an enlarged pituitary is an important cause of pituitary insufficiency in underdeveloped countries.

Panhypopituitarism presents with signs of deficiency of all pituitary hormones. Growth hormone (GH) deficiency predisposes to hypoglycemia. Thyroid-stimulating hormone (TSH) deficiency causes hypothyroidism. Adrenocorticotropic hormone (ACTH) deficiency leads to adrenocortical insufficiency and a tendency to hypoglycemia. Gonadotropin deficiency leads to a loss of libido, amenorrhea, and infertility. Prolactin deficiency leads to cessation of lactation and typical features of Sheehan’s syndrome.

Pituitary deficiency in childhood and adolescence leads to pituitary dwarfism. A deficiency of gonadotropins causes delayed puberty.

Panhypopituitarism presents with decreased secretion of pituitary, thyroid, adrenocortical, and sex hormones. The diagnosis of panhypopituitarism thus requires extensive testing for pituitary hormones as well as hormones from other endocrine glands. These findings must be subsequently confirmed by stimulatory tests. For example, GH secretion can be monitored after stimulation with insulin, or levodopa or L-arginine. Growth hormone and cortisol secretion can be assessed by glucagon injection.

Diabetes insipidus is caused by a deficiency of antidiuretic hormone released from the posterior lobe of the pituitary.

The posterior pituitary consists of nerve endings (i.e., axons of nerve cells) located in the hypothalamic nuclei–supraoptic nucleus and paraventricular nucleus. As such, the posterior pituitary serves as a storage site for hormones produced in the hypothalamic nuclei, most notably antidiuretic hormone (ADH) and oxytocin.

Antidiuretic hormone, also known as arginine vasopressin (AVP), is a nonapeptide synthesized by nerve cells and stored in the posterior lobe of the pituitary. It promotes the reabsorption of water in the collecting ducts of the kidneys (antidiuretic effect) and is a potent vasoconstrictor (vasopressin effect). It is released normally in response to increased osmolality of the plasma, which stimulates the osmoreceptors in the anterior hypothalamus (Fig. 11-7). Blood volume loss is yet another mechanism that leads to a release of ADH. This mechanism is initiated by low-pressure baroreceptors in the heart. Arterial hypotension, hypercapnia, hypoxia, pain, and nausea may all increase ADH release, causing vasoconstriction and antidiuresis.

Figure 11-7 Two major antidiuretic hormone/vasopressin control loops. ADH, antidiuretic hormone.

Diabetes insipidus is a condition characterized by polyuria—excessive water loss through the kidneys. Two forms of diabetes insipidus are recognized (Fig. 11-8):

Figure 11-8 Diabetes insipidus. It may be central (1) or nephrogenic (2). ADH, antidiuretic hormone.

Diabetes insipidus is characterized by polyuria, which may be in the range of 5 to 15 L/day. The urine is hypo-osmotic: typically the osmolality of urine is less than that of serum (<290 mOsm/kg; specific gravity < 1.010). A loss of water results in mild hypernatremia and increased serum osmolality, usually in the range of 290 to 295 mOsm/kg. Loss of water causes polydipsia, and thus the osmolality of the plasma returns to the normal range. If access to water is restricted, hypernatremia and increased plasma osmolality may develop. Increased sodium concentration in the serum may cause muscle weakness, prostration, fever, and coma.

Diabetes insipidus is a relatively rare condition, which must be distinguished from polyuria in diabetes mellitus and psychogenic polydipsia/polyuria.

The diagnosis of diabetes insipidus may be confirmed by the water deprivation test and/or injection of an analogue of ADH (desmopressin test). In patients with central diabetes insipidus water deprivation increases serum osmolality and raises the concentration of sodium, but does not increase the osmolality of the urine. Desmopressin injection increases urine osmolality over 50% from the baseline. In psychogenic polydipsia, water deprivation does not change serum osmolality and does not raise the serum sodium concentration, but the frequency of urination and the volume of urine increase, indicating that the kidney can concentrate urine. Desmopressin injection has no effect or only mildly increases serum osmolality (20–40% over the baseline).

Syndrome of inappropriate antidiuretic hormone secretion is characterized by water retention.

The syndrome of inappropriate ADH secretion (SIADH) is characterized by an excess of ADH in spite of low plasma osmolality. The syndrome of inappropriate ADH secretion may result from:

The main causes of SIADH are listed in Table 11-7.

Table 11-7 Important Causes of Syndrome of Inappropriate ADH Secretion (SIADH)

An excess of ADH results in retention of water and expansion of plasma volume. Serum osmolality is low (<270 mOsm/kg), sodium concentration is low (<130 mmol/L), and the urine is hypertonic (>300 mOsm/kg) compared with serum. Urine contains increased amounts of sodium in excess of 20 mmol/L.

Most patients with SIADH have no clinical symptoms, and typically there is no peripheral edema or any evidence of dehydration. In severe hyponatremia weakness, mental confusion, and lethargy begin to appear, and convulsions and coma may be encountered when the serum sodium concentration drops below 110 mmol/L.

Follicular cells of the thyroid take up iodine and synthesize thyroid hormones from tyrosine.

Follicular epithelial cells synthesize thyroglobulin and secrete it into the lumen of the follicles as colloid (Fig. 11-10). The synthesis of thyroid hormones requires iodine, which is taken up by the follicular cells from the interstitial fluid (“iodine trapping”). Iodine is transported to the colloidal surface by a transport protein and “organified,” or attached to thyrosine to form monoiodotyrosine and diiodotyrosine. Coupling of these iodinated tyrosine derivatives leads to the formation of triiodotyronine (T₃) and tetraiodothyronine (thyroxine, T₄). Thyroglobulin is then endocytosed into the cytoplasm of follicular cells and cleaved by proteolysis, ultimately resulting in the formation of free T₄. This process also leads to removal of iodine from monoiodothyronene and diiodothyronine molecules. T₄ is converted in part to T₃ by 5′-monodeiodinase, and both T₃ and T₄ are secreted into the circulation. Thyroxine predominates and accounts for the bulk of thyroid hormone secretion. Thus, only 15% of the total T₃ is secreted in that form from the thyroid, whereas 85% of T₃ is produced from circulating T₄ in the periphery. Thyroxine can also be converted into a metabolically inactive form, reverse T₃ (rT₃). Serum levels of rT₃ are typically elevated in acute nonthyroidal disease, reflecting a decreased concentration of T₃.

Figure 11-10 Structure and function of the thyroid follicular cell. 1, Follicular epithelial cells synthesize thyroglobulin (TG) and secrete it into the lumen of the follicles as colloid. 2, The synthesis of thyroid hormones requires iodine, which is taken up by the follicular cells from the interstitial fluid (“iodine trapping”). 3, Iodine is transported to the colloidal surface by a transport protein and “organified,” that is, attached to thyrosine to form monoiodothyrosine (MIT) and diiodothyrosine (DIT). 4, Coupling of these iodinated thyrosine derivatives leads to the formation of triiodothyronine (T₃) and tetraiodothyronine (thyroxine,T₄). 5–6, Thyroglobulin is then endocytosed into the cytoplasm of follicular cells and cleaved by proteolysis, ultimately resulting in the formation of free T₄. This process also leads to removal of iodine from monoiodothyronine and diiodothyronine molecules. 7, Iodine is recirculated. 8 and 9, Thyroxine is converted in part to T₃ by 5′-monodeiodinase, and both T₃ and T₄ are secreted into the circulation 10, In the circulation thyroid hormones circulate in a free form or bound to a transport protein, thyroid-binding globulin (TBG). 11, Free T₄ and T₃ provide a negative feedback to the pituitary and hypothalamus. T₄ can be converted into a metabolically inactive form, reverse T₃.

(Modified from Boon NA, Colledge NR, Walker BR, Hunter JAA [eds]: Davidson’s Principles and Practice of Medicine, 20th ed. Edinburgh, Churchill Livingstone, 2006, p. 745.)

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