Pharmacology: Hypothalamic And Pituitary Drugs

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Corticotropin and Related Drugs

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•Cosyntropin
•Corticorelin ovine triflutate (Acthrel)

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Growth Hormone and Related Drugs

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•Somatropina
•Octreotide (Sandostatin)
•Pegvisomant (Somavert)

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Gonadotropins and Related Drugs

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•Chorionic gonadotropin and menotropins
•Leuprolide (Lupron)
•Abarelix (Plenaxis)

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Other Drugs

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•Cabergoline (Costinex)

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Posterior Pituitary Hormones and Related Drugs

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•Desmopressin and vasopressin
•Oxytocin

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The hypothalamus and pituitary gland constitute an important neuroendocrine system that regulates

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growth, reproduction, metabolic rates, and other important body functions.

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The pituitary gland is divided into two major lobes:

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the adenohypophysis (anterior lobe) and the neurohypophysis (posterior lobe). Various hormones are secreted by each of these lobes and by the hypothalamus.

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The adenohypophysis secretes six hormones:

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(1) corticotropin (adrenocorticotropic hormone, ACTH);
(2) somatotropin (growth hormone);
(3) follicle-stimulating hormone (FSH);
(4) luteinizing hormone (LH);
(5) thyrotropin (thyroid-stimulating hormone, TSH); and
(6) prolactin.

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The secretion of anterior pituitary hormones is controlled by

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several hormone-releasing and hormone-inhibiting factors that are formed in the hypothalamus.

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These hypothalamic hormones include:

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(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).

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The various hypothalamic hormones are secreted by the

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arcuate and other hypothalamic nuclei, and they are transported to the anterior pituitary via the hypophysioportal circulation.

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In the target organs, anterior pituitary hormones stimulate

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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.

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The neurohypophysis secretes

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oxytocin and vasopressin

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posterior pituitary hormones are synthesized in the

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cell bodies of neurons in the supraoptic and paraventricular nuclei of the hypothalamus

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corticotropin

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evokes corticosteroid secretion by the adrenal cortex

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growth hormone (GH),

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elicits production of insulin-like growth factors (IGF) by the liver

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follicle-stimulating hormone (FSH)

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stimulates spermatogenesis and facilitates ovarian follicle development

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luteinizing hormone (LH)

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elicits testosterone secretion by the testes, facilitates ovarian follicle development, and induces ovulation

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thyroid-stimulating hormone (TSH)

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stimulates thyroxin secretion by the thyroid gland

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prolactin

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induces breast tissue growth and lactation.

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Oxytocin

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induces milk ejection by the breast and stimulates uterine contractions during labor

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Vasopressin

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increases water and sodium reabsorption by the kidneys

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Hypothalamic and pituitary hormones are used for

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both diagnostic and therapeutic purposes

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Hypothalamic hormone-releasing factors are helpful in assessing

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the functional capacity of the anterior pituitary to secrete particular pituitary hormones

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Anterior pituitary hormones are used to

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evaluate the functional capacity of their target organs, to stimulate hypofunctional target organs, and to provide replacement therapy in hormone deficiency states.

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Posterior pituitary hormones are used therapeutically to

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activate specific physiologic functions

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Why are hypothalamic and pituitary hormones administered parenterally?

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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.

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Corticotropin

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a 39-amino-acid peptide that is released from the anterior pituitary in response to corticotropin-releasing hormone stimulation.

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Corticotropin then stimulates the adrenal cortex to produce

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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.

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Two corticotropin preparations are available for clinical use:

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porcine corticotropin and a synthetic form of human corticotropin called cosyntropin.

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Cosyntropin

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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.

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Cosyntropin is used in two diagnostic tests:

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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.

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Cosyntropin increases cortisol levels in healthy individuals but

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fails to increase cortisol levels in persons with adrenal insufficiency

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Corticorelin ovine triflutate is a

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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.

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Growth hormone (somatotropin), a large peptide that contains 191 amino acids, is produced by

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the anterior pituitary and has both direct and indirect actions on target organs.

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Growth hormone acts directly to stimulate

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lipolysis and antagonize insulin to elevate blood glucose levels.

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Most of the effects of growth hormone, however, are mediated by

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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.

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The secretion of growth hormone is stimulated by

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GHRH

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The secretion of growth hormone is inhibited by

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somatostatin

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Several preparations of growth hormone, GHRH, and somatostatin are available for use in the diagnosis and treatment of

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growth disorders associated with excessive or inadequate secretion of growth hormone.

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Growth hormone preparations obtained from animal sources are not

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active in humans

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In the past, growth hormone obtained from human cadavers was used to treat patients with

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growth hormone deficiency and short stature, but some of the patients subsequently developed Creutzfeldt-Jakob disease.

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biosynthetic growth hormone preparations are available for treatment of growth hormone deficiency. One that is identical to human growth hormone is called

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somatropin recombinant

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a human growth hormone analogue that contains one additional amino acid, is called

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somatrem

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These preparations have been used to treat children with a variety of growth disorders including

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growth hormone deficiency, Turner syndrome, chronic renal failure, Prader-Willi syndrome, and cystic fibrosis

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Somatropin and somatrem are usually administered

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subcutaneously once daily to persons with growth hormone deficiency

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Sermorelin

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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

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Sermorelin

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has orphan drug status for the treatment of growth hormone deficiency and the treatment of weight loss associated with acquired immunodeficiency syndrome (AIDS).

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Somatostatin (growth hormone-inhibiting hormone) inhibits growth hormone secretion, but it also exerts effects on

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several endocrine glands, including the pancreas, and this limits its therapeutic usefulness

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octreotide

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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.

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Octreotide is used to treat patients with

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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.

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Octreotide also has been used successfully in the treatment of several neoplastic diseases, including

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carcinoid syndrome, pituitary adenomas that secrete thyrotropin, and tumors that produce vasoactive intestinal polypeptide.

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Octreotide is usually administered subcutaneously every

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8 hours

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Adverse effects of octreotide treatment include

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nausea, vomiting, abdominal cramps, steatorrhea (excessive fat in the feces), and gallstones.

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In patients with acromegaly, the use of cabergoline and other dopamine agonists can reduce

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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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Pegvisomant

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is a pegylated analogue of growth hormone that acts as a growth hormone receptor antagonist in target organs and thereby normalizes serum IGF-I concentrations in 97% of persons with acromegaly

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Pegylation (addition of polyethylene glycol to the molecule) significantly increases

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the half-life of peptide drugs

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Pegvisomant improves signs and symptoms of

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growth hormone excess in persons with acromegaly, including patients who were wholly or partially resistant to somatostatin analogues such as octreotide. In one study, pegvisomant reduced serum IGF levels and finger ring size in a dose-dependent manner while improving symptoms of tissue swelling, arthralgia, headache, perspiration, and fatigue. The drug appears to have a good safety profile, but liver function tests should be regularly monitored.

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The pituitary secretes two gonadotropins, namely,

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FSH and LH, in response to pulsatile stimulation by GnRH.

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In females, FSH stimulates

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ovarian follicle maturation

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LH assists FSH in

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follicle development, induces ovulation, and stimulates the corpus luteum to produce progesterone and androgen

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In males, FSH stimulates

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spermatogenesis

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LH stimulates Leydig's cells in the testes to produce

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testosterone

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menotropins

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(human menopausal gonadotropin) is obtained from the urine of menopausal women

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chorionic gonadotropin

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(human chorionic gonadotropin); it is produced by the placenta and isolated from the urine of pregnant women.

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In women with infertility caused by failure to ovulate

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menotropins and chorionic gonadotropin are used sequentially

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A dose of menotropins is administered

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each day for 9 to 12 days to stimulate maturation of the ovarian follicle

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Menotropins therapy is used to stimulate spermatogenesis in men with

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hypogonadotropic hypogonadism

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In prepubertal boys with cryptorchidism (undescended testes) and hypogonadism

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chorionic gonadotropin is administered to stimulate testosterone production and descent of the testes.

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Two classes of drugs target pituitary receptors for gonadotropin-releasing hormone:

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the GnRH agonists and the GnRH antagonist called abarelix.

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GnRH agonists include

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gonadorelin, goserelin, leuprolide, and nafarelin

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Pulsatile administration mimics

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the natural secretion of GnRH and is used therapeutically to stimulate the release of FSH and LH from the anterior pituitary.

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continuous administration of GnRH agonists leads to

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down-regulation of GnRH receptors and decreased secretion of FSH and LH. GnRH agonists are used in this manner to suppress gonadotropin stimulation of target organs.

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Gonadorelin has a half-life of about

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5 minutes

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gonadorelin can be administered in a pulsatile manner via a portable infusion pump that injects a small bolus of the drug subcutaneously every

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60 to 120 minutes

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In women with infertility caused by hypothalamic amenorrhea, pulsatile treatment for 10 to 20 days is given to induce

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ovulation

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Gonadorelin is also used diagnostically to evaluate the functional capacity of

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the gonadotropin-secreting cells of the pituitary. For this purpose, plasma gonadotropin concentrations are measured before and after a single dose of gonadorelin is injected.

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Goserelin, leuprolide, and nafarelin are administered continuously and act to

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down-regulate pituitary GnRH receptors and thereby reduce gonadotropin secretion.

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GnRH analogues are effective in the treatment of

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precocious puberty in boys or girls and in the treatment of prostate cancer, breast cancer, and endometriosis in adults.

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Nafarelin is used to

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manage endometriosis in women and central precocious puberty in children. It is administered as a nasal spray. Leuprolide and goserelin are administered as pellets that slowly release the drug following subcutaneous implantation. They are used to treat advanced prostate cancer, breast cancer, and endometriosis.

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Abarelix is

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the newest development in the treatment of advanced prostate cancer.

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Abarelix

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is a synthetic decapeptide that blocks GnRH receptors and thereby reduces pituitary secretion of LH and FSH, leading to reduced secretion of testosterone. The drug appears to be suitable for treating advanced symptomatic prostate cancer in men who are not good candidates for GnRH agonists and who refuse surgical castration.

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Thyrotropin (thyroid-stimulating hormone, TSH) is secreted in response to stimulation of

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the anterior pituitary by thyrotropin-releasing hormone (TRH)

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protirelin

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A preparation of TRH employed in the diagnosis of central hypothyroidism caused by inadequate secretion of TSH

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Prolactin contains 198 amino acids and acts on the

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mammary gland to stimulate tissue growth and promote lactation (milk production) in the presence of adequate levels of estrogens, progestins, and other hormones.

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The secretion of prolactin is inhibited by

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prolactin-inhibiting hormone (dopamine) and is stimulated by hypothalamic prolactin-releasing factors.

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Excessive prolactin secretion causes

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hyperprolactinemia and often leads to galactorrhea (excessive milk production), hypogonadism, and infertility.

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hyperprolactinemia occurs secondary to

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prolactin-secreting pituitary adenomas.

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the idiopathic and secondary forms of hyperprolactinemia can be treated with a dopamine agonist such as

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cabergoline or bromocriptine

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cabergoline or bromocriptine

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mimic the action of PIH and thereby reduces prolactin secretion. In patients with prolactin-secreting adenomas, treatment with either drug also produces a significant reduction in tumor size.

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Bromocriptine and cabergoline are both

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ergot alkaloid derivatives

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Cabergoline selectively activates

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dopamine D2 receptors in the pituitary gland and thereby suppresses the secretion of prolactin

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Cabergoline has an elimination half-life of about

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65 hours, which provides a long duration of action.

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The most common adverse effects of cabergoline are

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nausea, headache, and dizziness.

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Oxytocin and vasopressin are 9-amino-acid peptides that are released from the

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posterior pituitary in response to specific physiologic stimuli

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Oxytocin is a hormone that increases the strength of

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uterine contractions and causes milk ejection (milk let-down) by contracting myoepithelial cells that line the ducts of the breast.

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Oxytocin is released via a reflex that is triggered by

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dilation of the uterine cervix, uterine contractions, or breast suckling

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Synthetic oxytocin has several uses in obstetrics. The drug is given intravenously to induce or enhance

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uterine contractions during labor, and it is injected intramuscularly to prevent postpartum uterine hemorrhage by causing the uterine muscle to contract. In addition, a nasal spray preparation of oxytocin is available to stimulate milk let-down in nursing mothers. The spray is inhaled 2 to 3 minutes before breastfeeding.

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Adverse reactions to oxytocin are

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uncommon. They include cardiac arrhythmias, central nervous system stimulation, excessive uterine contraction, and hyponatremia.

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Use of synthetic oxytocin is contraindicated in instances of

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fetal distress, abnormal fetal presentation, prematurity, or cephalopelvic disproportion.

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Preterm labor is defined as

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labor that begins before completion of the 37th week of gestation and is associated with adverse neonatal outcomes

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Atosiban is

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a peptide of 9 amino acids that acts as a competitive antagonist of oxytocin. It has been approved in European countries for treatment of preterm labor, but a recent analysis of clinical trials shows that atosiban did not reduce the incidence of preterm birth or improve neonatal outcome compared to placebo. In fact, atosiban was associated with lower birth weights and more maternal adverse effects than placebo, and atosiban appeared to increase neonatal mortality if used before the 28th week of gestation

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Vasopressin (arginine vasopressin) is secreted by the

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posterior pituitary in response to a decrease in extracellular fluid volume or an increase in plasma osmotic pressure. The hormone interacts with two types of vasopressin receptors to exert its antidiuretic and vasoconstrictive effects.

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The renal actions of vasopressin are mediated by

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V2 receptors via production of cyclic adenosine monophosphate. Activation of V2 receptors increases water reabsorption by the kidney by causing the insertion of water channels (aquaporins) in the luminal membranes of renal tubule cells in the collecting ducts. This action expands extracellular fluid volume and concentrates the urine.

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vasopressin is also called

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antidiuretic hormone

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A deficiency of pituitary vasopressin secretion leads to

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diabetes insipidus, a condition characterized by excessive water excretion (polyuria) and increased water intake (polydipsia).

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Diabetes insipidus is usually treated with

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desmopressin, a long-acting synthetic analogue of vasopressin. This agent has potent antidiuretic activity but causes less vasoconstriction than natural vasopressin. Desmopressin solutions are available for injection and as a nasal spray that is used to prevent nocturnal urine production and enuresis in patients with diabetes insipidus. Desmopressin overdosage can result in dilutional hyponatremia.

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Desmopressin is also used in treating children with

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nocturnal enuresis

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Vasopressin causes vasoconstriction in several vascular beds by stimulating

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V1 receptors in vascular smooth muscle

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injectable vasopressin preparation is used to control

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bleeding caused by esophageal varices or colonic diverticula. It should be used cautiously in persons with coronary artery disease.

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Desmopressin is also used for its vasoconstrictive effect, and it is employed in treating a variety of

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hemorrhagic conditions, including von Willebrand disease, mild hemophilia A, and congenital or drug-induced platelet function defects.

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•Cosyntropin is a synthetic corticotropin analogue used to diagnose

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adrenal insufficiency

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corticorelin ovine triflutate is a corticotropin-releasing hormone used as a diagnostic test to distinguish

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adrenal and pituitary origins of Cushing's syndrome.

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•Recombinant somatropin and somatrem are growth hormone preparations used to treat

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growth hormone deficiency in children with a low growth rate.

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•Octreotide is a synthetic growth hormone-inhibiting hormone (somatostatin) analogue used in the treatment of

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acromegaly, carcinoid syndrome, pituitary adenomas that secrete thyrotropin, and tumors that secrete vasoactive intestinal polypeptide

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•Pegvisomant is a growth hormone analogue and growth hormone receptor antagonist used to treat

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acromegaly

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•Menotropins and chorionic gonadotropin are human gonadotropin preparations used to induce

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ovulation in infertile women

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Chorionic gonadotropin is also used to stimulate spermatogenesis in men with

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hypogonadotropic hypogonadism and to treat cryptorchidism in prepubertal boys.

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•Gonadorelin is a gonadotropin-releasing hormone (GnRH) preparation administered in pulsatile fashion to induce

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ovulation in women with hypothalamic amenorrhea.

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•Goserelin and leuprolide are synthetic GnRH preparations administered continuously to

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suppress gonadotropin secretion in children with precocious puberty and in adults with prostate cancer, breast cancer, and endometriosis.

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•Nafarelin is a GnRH preparation administered as a nasal spray to treat

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precocious puberty in children and endometriosis in women.

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•Abarelix is a GnRH antagonist that reduces

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gonadotropin and gonadal steroid secretion, and is used to treat advanced prostate cancer.

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•Dopamine agonists, cabergoline and bromocriptine, are used to

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suppress prolactin secretion in women with hyperprolactinemia.

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hyperprolactinemia is often associated with

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galactorrhea, hypogonadism, and infertility

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Cabergoline may also reduce

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excessive growth hormone secretion in some persons with acromegaly and hyperprolactinemia

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•Oxytocin, which stimulates uterine contractions at term, is used to

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induce or augment labor, to prevent postpartum uterine hemorrhage, and to stimulate milk let-down in nursing women.

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•Desmopressin is a synthetic vasopressin analogue that retains the antidiuretic activity of the natural hormone but lacks

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the vasoconstrictive effect

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•Desmopressin is administered parenterally and intranasally to treat

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diabetes insipidus resulting from deficient pituitary vasopressin secretion.

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Synthetic vasopressin is used to control

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gastrointestinal bleeding by causing vasoconstriction.