Figure 31–1 Relationships between hypothalamic hormones, pituitary hormones, and target organs. Numerous hormone-releasing and hormone-inhibiting factors formed in the arcuate and other hypothalamic nuclei are transported to the anterior pituitary by hypophysioportal vessels. In response to hypothalamic hormones, the anterior pituitary secretes the following: corticotropin, which evokes corticosteroid secretion by the adrenal cortex; growth hormone (GH), which elicits production of insulin-like growth factors (IGF) by the liver; follicle-stimulating hormone (FSH), which stimulates spermatogenesis and facilitates ovarian follicle development; luteinizing hormone (LH), which elicits testosterone secretion by the testes, facilitates ovarian follicle development, and induces ovulation; thyroid-stimulating hormone (TSH), which stimulates thyroxin secretion by the thyroid gland; and prolactin, which induces breast tissue growth and lactation. The posterior pituitary hormones, which are formed in the supraoptic and paraventricular nuclei, are transported by nerve axons to the posterior lobe, where they are released by physiologic stimuli. Oxytocin induces milk ejection by the breast and stimulates uterine contractions during labor. Vasopressin increases water and sodium reabsorption by the kidneys.
The secretion of anterior pituitary hormones is controlled by several hormone-releasing and hormone-inhibiting factors that are formed in the hypothalamus. These hypothalamic hormones include the following: (1) corticotropin-releasing hormone; (2) growth hormone–releasing hormone (GHRH); (3) somatostatin (growth hormone–inhibiting hormone); (4) gonadotropin-releasing hormone (GnRH); (5) thyrotropin-releasing hormone (TRH); and (6) prolactin-inhibiting hormone (PIH). Evidence also suggests the presence of one or more prolactin-releasing factors. The various hypothalamic hormones are secreted by the arcuate and other hypothalamic nuclei, and they are transported to the anterior pituitary via the hypophysioportal circulation.
The anterior pituitary hormones are transported to their target organs via the systemic circulation. In the target organs, they stimulate growth, development, and the secretion of other hormones, which both activate specific functions in various organs and exert negative feedback inhibition of the corresponding hypothalamic and pituitary hormones.
Neurohypophysis
The neurohypophysis secretes oxytocin and vasopressin. These posterior pituitary hormones are synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei of the hypothalamus. The hormones are transported down the nerve axons to their endings in the posterior pituitary, where they are released in response to electrical activity in the nerve terminals.
Uses of Hypothalamic and Pituitary Hormones
Hypothalamic and pituitary hormones are used for both diagnostic and therapeutic purposes. Hypothalamic hormone–releasing factors are helpful in assessing the functional capacity of the anterior pituitary to secrete particular pituitary hormones. Anterior pituitary hormones are used to evaluate the functional capacity of their target organs, to stimulate hypofunctional target organs, and to provide replacement therapy in hormone deficiency states. Posterior pituitary hormones are used therapeutically to activate specific physiologic functions.
All of the hypothalamic and pituitary hormones are peptides or small proteins that are extensively degraded in the gut following oral administration. For this reason, most of these hormones are administered parenterally. A few of them are available as a spray for intranasal administration.
ANTERIOR PITUITARY HORMONES
Corticotropin and Related Drugs
Corticotropin is a 39-amino-acid peptide that is released from the anterior pituitary in response to corticotropin-releasing hormone stimulation. Corticotropin then stimulates the adrenal cortex to produce cortisol, aldosterone, and adrenal androgens by increasing the activity of the enzyme that converts cholesterol to pregnenolone and is the rate-limiting enzyme in corticosteroid production.
Corticotropin Preparations
Two corticotropin preparations are available for clinical use: porcine corticotropin and a synthetic form of human corticotropin called cosyntropin. Cosyntropin contains the first 24 amino acids of human corticotropin, which are the ones necessary for its biologic activity. Cosyntropin is preferable for clinical use because it produces fewer allergic reactions.
Cosyntropin is used in two diagnostic tests. First, it is used to distinguish congenital adrenal hyperplasia from ovarian hyperandrogenism. Second, and more commonly, it is used to diagnose adrenal insufficiency in a test that measures plasma cortisol levels before and after a cosyntropin injection. Cosyntropin increases cortisol levels in healthy individuals but fails to increase cortisol levels in persons with adrenal insufficiency. Then to distinguish primary adrenal insufficiency from secondary adrenal insufficiency, endogenous plasma corticotropin concentrations are measured. In patients with primary adrenal insufficiency, corticotropin concentrations are high because of the lack of negative feedback inhibition of the hypothalamus and pituitary gland by the adrenal corticosteroids. In patients with secondary adrenal insufficiency, corticotropin concentrations are low because of inadequate production of corticotropin by the pituitary gland.
Corticotropin-Releasing Hormone
Corticorelin ovine triflutate is a preparation containing recombinant ovine corticotropin-releasing hormone. Intravenous administration of this preparation stimulates secretion of corticotropin and cortisol in normal subjects. Corticorelin is used as a diagnostic test to determine whether the excessive levels of cortisol that occur in persons with Cushing’s syndrome are caused by excessive corticotropin secretion from a pituitary adenoma or by excessive secretion of cortisol by an adrenal tumor.
Growth Hormone and Related Drugs
Growth hormone (somatotropin), a large peptide that contains 191 amino acids, is produced by the anterior pituitary and has both direct and indirect actions on target organs. Growth hormone acts directly to stimulate lipolysis and antagonize insulin to elevate blood glucose levels. Most of the effects of growth hormone, however, are mediated by insulin-like growth factors (IGF), which are peptides produced in the liver and cartilage. The IGF stimulate skeletal growth, amino acid transport, protein synthesis, nucleic acid synthesis, and cell proliferation.
The secretion of growth hormone is stimulated by GHRH and is inhibited by somatostatin. Several preparations of growth hormone, GHRH, and somatostatin are available for use in the diagnosis and treatment of growth disorders associated with excessive or inadequate secretion of growth hormone.
Growth Hormone Preparations
Growth hormone preparations obtained from animal sources are not active in humans. In the past, growth hormone obtained from human cadavers was used to treat patients with growth hormone deficiency and short stature, but some of the patients subsequently developed Creutzfeldt-Jakob disease. This fatal disease, as with mad cow disease and kuru, is characterized by spongiform encephalopathy and is thought to be transmitted by unconventional neurotoxic agents called prions.
Today, two biosynthetic growth hormone preparations are available for treatment of growth hormone deficiency. One that is identical to human growth hormone is called somatropin recombinant. The other, a human growth hormone analogue that contains one additional amino acid, is called somatrem. These preparations have been used to treat children with a variety of growth disorders including growth hormone deficiency, Turner syndrome, chronic renal failure, Prader-Willi syndrome, and cystic fibrosis. Growth hormone preparations have been clearly shown to improve height velocity and final height in these conditions. Children who received craniospinal irradiation for treatment of a childhood malignancy are less responsive to growth hormone replacement than children with idiopathic growth hormone deficiency and they have a tendency to enter puberty at an earlier age. These children may respond to supraphysiologic doses of growth hormone preparations and suppression of early puberty using a gonadotropin releasing hormone analogue (see below). Somatropin and somatrem are usually administered subcutaneously once daily to persons with growth hormone deficiency. Growth hormone deficiency is often accompanied by other pituitary hormone deficiencies, which should also be treated with appropriate hormones.
Growth Hormone–Releasing Hormone Preparations
Sermorelin, a synthetic analogue of GHRH, is available for use in a test to determine whether growth hormone deficiency is secondary to hypothalamic insufficiency or to pituitary insufficiency. In this test, plasma levels of growth hormone are measured before and after a single injection of sermorelin. A normal response indicates that the pituitary is capable of secreting growth hormone and that the patient’s growth hormone deficiency is caused by hypothalamic insufficiency.
Sermorelin has orphan drug status for the treatment of growth hormone deficiency and the treatment of weight loss associated with acquired immunodeficiency syndrome (AIDS).
Growth Hormone–Inhibiting Hormone Preparations
Somatostatin (growth hormone–inhibiting hormone) inhibits growth hormone secretion, but it also exerts effects on several endocrine glands, including the pancreas, and this limits its therapeutic usefulness. Scientists searching for somatostatin preparations that were more selective for growth hormone inhibition discovered octreotide, a somatostatin analogue that consists of 8 amino acids. In comparison with somatostatin, octreotide is 45 times more potent in inhibiting growth hormone secretion but only 2 times as potent in inhibiting insulin secretion by the pancreas.
Octreotide is used to treat patients with acromegaly. This endocrine disorder, which is caused by excessive growth hormone secretion, is characterized by acral enlargement and soft tissue overgrowth of the hands and feet, coarsening of facial features, thickening and oiliness of the skin, and increased sweating. It is often accompanied by numerous other metabolic and endocrine abnormalities. Octreotide also has been used successfully in the treatment of several neoplastic diseases, including carcinoid syndrome, pituitary adenomas that secrete thyrotropin, and tumors that produce vasoactive intestinal polypeptide.
Octreotide is usually administered subcutaneously every 8 hours. A sustained-release preparation for intramuscular administration has also been developed. Adverse effects of octreotide treatment include nausea, vomiting, abdominal cramps, steatorrhea (excessive fat in the feces), and gallstones.
In patients with acromegaly, the use of cabergoline (see below) and other dopamine agonists can reduce circulating levels of growth hormone, IGF, and prolactin. These drugs are particularly useful in the treatment of persons with elevated growth hormone and prolactin secretion.
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