Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 37. Hypothalamic & Pituitary Hormones

Hypothalamic & Pituitary Hormones: Introduction

The hormones produced by the hypothalamus and pituitary gland are key regulators of metabolism, growth, and reproduction. Preparations of these hormones, including products made by recombinant DNA technology and drugs that mimic or block their effects, are used in the treatment of a variety of endocrine disorders.

High-Yield Terms to Learn

Acromegaly A syndrome of growth hormone (GH) excess in adults that is characterized by abnormal growth of tissues—particularly connective tissue—metabolic abnormalities, and cardiac dysfunction Central diabetes insipidus A syndrome of polyuria, polydipsia, and hypernatremia caused by inadequate production of vasopressin Gigantism A syndrome of GH excess in children and adolescents with open long bone epiphyses that results in excessive height Gonadotropins The 2 anterior pituitary hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) that regulate reproduction in males and females Insulin-like growth factor-1 (IGF-1) A growth factor that is the primary mediator of GH effects Prolactinoma Pituitary tumor that secretes excessive amounts of prolactin and is associated with a syndrome of infertility and galactorrhea Tocolytics Drug used to inhibit preterm labor (eg, the oxytocin receptor antagonist atosiban; magnesium sulfate; nifedipine; 2 agonists)

Anterior Pituitary Hormones & Their Hypothalamic Regulators

The hypothalamic and pituitary hormones and their antagonists are often grouped according to the anatomic site of release of the hormone that they mimic or block—the hypothalamus for gonadotropin-releasing hormone (GnRH); the anterior pituitary for growth hormone (GH), the 2 gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and prolactin; or the posterior pituitary for oxytocin and vasopressin (antidiuretic hormone [ADH]). This chapter focuses on the agents used commonly; it does not discuss the hypothalamic and pituitary hormones that are either not used clinically or are used rarely for specialized diagnostic testing (thyrotropin-releasing hormone [TRH], thyroid-stimulating hormone [TSH], corticotropin-releasing hormone [CRH], adrenocorticotropic hormone [ACTH], and growth hormone-releasing hormone [GHRH]). Hormones of the anterior pituitary are central links in the hypothalamic-pituitary endocrine system (or axis; Figure 37-1). All the anterior pituitary hormones are under the control of a hypothalamic hormone and, with the exception of prolactin, all mediate their ultimate effects by regulating the production by peripheral tissues of other hormones (Table 37-1). Four anterior pituitary hormones (TSH, LH, FSH, and ACTH) and their hypothalamic regulators are subject to feedback regulation by the hormones whose production they control. The complex systems that regulate hormones of the anterior pituitary provide multiple avenues of pharmacologic intervention.

FIGURE 37-1

The hypothalamic-pituitary endocrine system. Hypothalamic factors regulate the release of anterior pituitary hormones. Pituitary hormones either stimulate the release of other hormones or act directly on target tissues. ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone (vasopressin); CRH, corticotropin-releasing hormone; DA, dopamine; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth-hormone releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; SST, somatostatin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 37-1.)

TABLE 37-1 Links between hypothalamic, anterior pituitary, and target organ hormones or mediators.a

Anterior Pituitary Hormone Hypothalamic Hormone Target Organ Primary Target Organ Hormone(s) or Mediator(s) Growth hormone (GH, somatotropin) Growth hormone-releasing hormone (GHRH) (+) Somatostatin (-) Liver, muscle, bone, kidney, and others Insulin-like growth factor-1 (IGF-1) Thyroid-stimulating hormone (TSH) Thyrotropin-releasing hormone (TRH) (+) Thyroid Thyroxine, triiodothyronine Adrenocorticotropin (ACTH) Corticotropin-releasing hormone (CRH) (+) Adrenal cortex Glucocorticoids, mineralocorticoids, androgens Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Gonadotropin-releasing hormone (GnRH) (+)b

Gonads Estrogen, progesterone, testosterone Prolactin (PRL) Dopamine (-) Breast —

(+), stimulant; (-), inhibitor.

aAll of these hormones act through G protein-coupled receptors except GH and prolactin, which act through JAK/STAT receptors.

bEndogenous GnRH, which is released in pulses, stimulates LH and FSH release. When administered continuously as a drug, GnRH and its analogs inhibit LH and FSH release.

Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.

Growth Hormone (GH) and Mecasermin

GH

Growth hormone is required for normal growth during childhood and adolescence and is an important regulator throughout life of lipid and carbohydrate metabolism and lean body mass. Its effects are primarily mediated by regulating the production in peripheral tissues of insulin-like growth factor 1 (IGF-1) and 2 (IGF-2).

Somatropin is a recombinant form of human GH that is used in the treatment of GH deficiency in children and adults and in the treatment of children with genetic diseases associated with short stature (eg, Turner's syndrome, Noonan syndrome, Prader-Willi syndrome). GH treatment also improves growth in children with failure to thrive because of chronic renal failure or the small-for-gestational-age condition. The most controversial use of GH is for children with idiopathic short stature who are not GH deficient. In this group of children, multiple years of GH therapy at great cost and some risk of toxicity results in a small (1-3 inches) average increase in final adult height.

In adults, GH has efficacy in treatment of AIDS-associated wasting and GH deficiency, and it may improve gastrointestinal function in patients who have undergone intestinal resection and have subsequently developed a malabsorption syndrome. GH is a popular component of antiaging programs even though studies in model animal systems have consistently found that analogs of GH and IGF-1 shorten lifespan. GH is also used by athletes for a purported increase in muscle mass and athletic performance and is one of the drugs banned by the Olympic Committee and professional sports associations. Recombinant bovine GH is used in dairy cattle to increase milk production.

Adults generally tolerate GH less well than children. Adverse effects include peripheral edema, myalgia, and arthralgia. Rarely, GH causes intracranial hypertension.

Mecasermin

A small group of children with growth failure unresponsive to GH therapy are deficient in IGF-1 and a binding protein (insulin-like growth factor-binding protein-3) that maintains an adequate half-life of the IGF-1. Mecasermin, a complex of recombinant human IGF-1 and the binding protein, is administered parenterally to children with IGF-1 deficiency. Its most important toxicity is hypoglycemia, which can be prevented by consumption of a snack or meal shortly before mecasermin administration.

Growth Hormone Antagonists

Growth hormone-secreting pituitary adenomas cause acromegaly in adults and, rarely, gigantism in children and adolescents who have not completed their growth phase. Pharmacologic treatment of GH excess seeks to inhibit GH secretion or interfere with GH effects.

Somatostatin Analogs

Somatostatin, a 14-amino-acid peptide, inhibits the release of GH, glucagon, insulin, and gastrin. Octreotide and lanreotide, long-acting synthetic analogs of somatostatin, are used to treat acromegaly, carcinoid, gastrinoma, glucagonoma, and other endocrine tumors. Regular octreotide must be administered subcutaneously 2-4 times daily whereas a slow-release intramuscular formulation of octreotide or lanreotide is administered every 4 wk for long-term therapy. Octreotide and lanreotide cause significant gastrointestinal disturbances, gallstones, and cardiac conduction abnormalities.

Dopamine D2 Receptor Agonists

Dopamine D2 receptor agonists such as bromocriptine are more effective at inhibiting prolactin release than inhibiting GH release (see following text). However, high doses of D2 receptor agonists have some efficacy in the treatment of small GH-secreting tumors.

Pegvisomant

Pegvisomant is a GH receptor antagonist that is approved for treatment of acromegaly. Normally, GH, which has 2 distinct receptor binding sites, initiates cellular signaling cascades by dimerizing 2 GH receptors. Pegvisomant is a long-acting derivative of a mutant GH that is able to cross-link GH receptors but is incapable of inducing the conformational changes required for receptor activation.

Follicle-Stimulating Hormone (FSH), Luteinizing Hormone, and Their Analogs

In women, FSH directs follicle development, whereas FSH and LH collaborate in the regulation of ovarian steroidogenesis. In men, FSH is the primary regulator of spermatogenesis, whereas LH is the main stimulus for testicular androgen production. The gonadotropins and their analogs are used in combination to stimulate spermatogenesis in infertile men and to induce ovulation in women with anovulation that is not responsive to less complicated treatments (see Chapter 40).

Ovulation induction protocols are increasingly complex. They require significant close monitoring to ensure successful insemination or retrieval of mature oocytes and to prevent the 2 most serious complications of ovulation induction—multiple pregnancies and the ovarian hyperstimulation syndrome, a syndrome of ovarian enlargement, ascites, hypovolemia, and possibly shock. All ovulation induction protocols that use gonadotropins have 3 basic steps. First, endogenous gonadotropin production is inhibited by administration of a GnRH agonist or antagonist (see text that follows). Second, follicle development is driven by daily injections of a preparation with FSH activity (menotropins, FSH, or an FSH analog). Last, the final stage of oocyte maturation is induced with an injection of LH or the LH analog human chorionic gonadotropin (hCG). The treatment of male infertility that is due to hypogonadism requires months of administration of a mixture of drugs with LH and FSH activity.

A variety of gonadotropin preparations are available. All are administered parenterally.

Menotropins

These gonadotropins consist of a mixture of FSH and LH purified from the urine of postmenopausal women (who produce high levels of FSH and LH owing to the disinhibition of pituitary gonadotropin production that results from cessation of ovarian steroidogenesis).

FSH and Its Analogs

Three forms of FSH are available. Urofollitropin is a purified preparation extracted from the urine of postmenopausal women. The 2 recombinant forms of human FSH—follitropin alpha and follitropin beta—differ in the composition of their carbohydrate side chains.

LH and Its Analogs

Human chorionic gonadotropin (hCG), the placental protein that supports the corpus luteum during the early stages of pregnancy, has a structure that is nearly identical to LH and mediates its effects through activation of LH receptors. hCG purified from human urine or recombinant hCG is used commonly for an LH activity. Lutropin, a recombinant form of human LH, is also available.

Gonadotropin-Releasing Hormone (GnRH) and Its Analogs

GnRH is a decapeptide that stimulates gonadotropin release when it is secreted in a pulsatile pattern by the hypothalamus. Leuprolide was the first of a set of synthetic peptides with long-acting GnRH agonist activity. Other long-acting GnRH agonists include goserelin, histrelin, nafarelin, and triptorelin.

In men and women, steady dosing with these GnRH agonists inhibits gonadotropin release by downregulating GnRH receptors in the pituitary cells that normally release gonadotropins. Continuous GnRH agonist treatment is used to suppress endogenous gonadotropin secretion in women undergoing ovulation induction with gonadotropins, in women with gynecologic disorders that benefit from ovarian suppression (eg, endometriosis, uterine leiomyomata), in children with precocious puberty, and in men with advanced prostate cancer.

In women, continuous treatment with a GnRH agonist causes the typical symptoms of menopause (hot flushes, sweats, headache). Long-term treatment is avoided because of the risk of bone loss and osteoporosis. In men treated continuously with a GnRH agonist, adverse effects include hot flushes, sweats, gynecomastia, reduced libido, decreased hematocrit, and reduced bone density. In men with prostate cancer and children with precocious puberty, the first few weeks of therapy can temporarily exacerbate the condition.

Gonadotropin-Releasing Hormone (GnRH) Antagonists

Ganirelix and cetrorelix are GnRH antagonists that can be used during ovulation induction in place of GnRH agonists to suppress endogenous gonadotropin production. Abarelix and degarelix are GnRH antagonists that are approved for the treatment of advanced prostate cancer. The adverse effects of GnRH antagonists are similar to those associated with continuous treatment with a GnRH agonist except that they do not cause a tumor flare-up when used for treatment of advanced prostate cancer and they may be less likely to cause the ovarian hyperstimulation syndrome when used for ovulation induction.

Prolactin Antagonists (Dopamine D2 Receptor Agonists)

The anterior pituitary hormone prolactin regulates lactation. In women and men, hyperprolactinemia and an associated syndrome of infertility and galactorrhea can result from prolactin-secreting adenomas. Dopamine is the physiologic inhibitor of prolactin release (Figure 37-1). Prolactin-secreting adenomas usually retain their sensitivity to dopamine. In hyperprolactinemia, bromocriptine and other orally active D2 dopamine receptor agonists (eg, cabergoline, pergolide; see Chapter 16) are effective in reducing serum prolactin concentrations and restoring fertility. As previously mentioned, high doses of a dopamine agonist can also be used in the treatment of acromegaly.

Skill Keeper: Drugs That Cause Hyperprolactinemia

(See Chapter 29)

As many as 25% of infertile women have hyperprolactinemia. In women, hyperprolactinemia causes galactorrhea, oligomenorrhea, or amenorrhea as well as infertility (the amenorrhea-galactorrhea syndrome). Although prolactin-secreting tumors are the most common cause of hyperprolactinemia, the condition can also be precipitated by drugs that interfere with the control of prolactin release.

1. What types of pharmacologic actions are most likely to cause hyperprolactinemia?

2. Name several drugs with this type of pharmacologic action.

The Skill Keeper Answers appear at the end of the chapter.

Posterior Pituitary Hormones

Oxytocin

Oxytocin is a nonapeptide synthesized in cell bodies in the paraventricular nuclei of the hypothalamus and transported through the axons of these cells to the posterior pituitary (Figure 37-1). Oxytocin is an effective stimulant of uterine contraction and is used intravenously to induce or reinforce labor. Atosiban is an antagonist of the oxytocin receptor that is used in some countries as a tocolytic , a drug used to treat preterm labor.

Vasopressin (Antidiuretic Hormone [ADH])

Vasopressin is synthesized in neuronal cell bodies in the hypothalamus and released from nerve terminals in the posterior pituitary (Figure 37-1). As discussed in Chapter 15, vasopressin acts through V2 receptors to increase the insertion of water channels in the apical membranes of collecting duct cells in the kidney and to thereby provide an antidiuretic effect. Extrarenal V2-like receptors regulate the release of coagulation factor VIII and von Willebrand factor (see Chapter 34). Desmopressin, a selective agonist of V2 receptors, is administered orally, nasally, or parenterally in patients with pituitary diabetes insipidus and in patients with mild hemophilia A or von Willebrand disease.

Vasopressin also contracts vascular smooth muscle by activating V1 receptors. Because of this vasoconstrictor effect, vasopressin is sometimes used to treat patients with bleeding from esophageal varices or colon diverticula.

Several antagonists of vasopressin receptors (eg, conivaptan, tolvaptan) have been developed to offset the fluid retention that results from the excessive production of vasopressin associated with hyponatremia or acute heart failure (see Chapter 15).

Skill Keeper Answers: Drugs That Cause Hyperprolactinemia

(See Chapter 29)

1. Drugs that block dopamine D2 receptors cause hyperprolactinemia by blocking the inhibitory effects of endogenous dopamine on the pituitary cells that release prolactin.

2. The older antipsychotic drugs (eg, phenothiazines, haloperidol), with their strong dopamine D2 receptor-blocking activity, are most likely to be the pharmacologic cause of hyperprolactinemia (see Chapter 29). This adverse effect is less likely with atypical antipsychotic drugs (eg, olanzapine). Drugs or drug groups that cause hyperprolactinemia through mechanisms that are not well characterized include methyldopa (an antihypertensive), amphetamines, tricyclic and other types of antidepressants, and opioids.

Checklist

When you complete this chapter, you should be able to:

Diagram the hypothalamic-pituitary endocrine system, and indicate the sites of release of and links between the hormones in the system.

 Describe the drugs used as substitutes for the natural pituitary hormones, and list their clinical uses.

List the gonadotropin analogs and GnRH agonists and antagonists, and describe their clinical use in treating male and female infertility, endometriosis, and prostate cancer.

 Describe the drugs used for treatment of acromegaly and hyperprolactinemia.

Drug Summary Table: Drugs That Mimic or Inhibit Hypothalamic & Pituitary Hormones

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Growth hormone (GH) Somatropin Recombinant form of human GH; acts through GH receptors to increase the production of insulin growth factor-1 (IGF-1) Replacement in GH deficiency; increased final adult height in children with certain conditions associated with short stature; wasting in HIV infection; short bowel syndrome Administered as a subcutaneous (SC) injection 3-7 x/wk Scoliosis, edema, gynecomastia, intracranial hypertension, myalgia, arthralgia, carpal tunnel syndrome, increased CYP450 activity IGF-1 agonist Mecasermin Recombinant form of IGF-1 that stimulates IGF-1 receptors Replacement in IGF-1 deficiency that is not responsive to exogenous GH This preparation also contains recombinant human IGF-binding protein 3, which prolongs the half-life of the rIGF-1 SC injection 2 x/d Hypoglycemia, intracranial hypertension, increased liver enzymes Somatostatin analogs Octreotide Agonist of somatostatin receptors Acromegaly and several other hormone-secreting tumors; acute control of bleeding from esophageal varices Administered as a SC injection 3-7 x/d; long-acting formulation injected intramuscularly (IM) monthly GI disturbances, gallstones, bradycardia and other cardiac conduction anomalies Lanreotide: Similar to octreotide and available as a long-acting formulation for acromegaly Growth hormone receptor antagonist Follitropin alfa Agonist of the follicle-stimulating hormone (FSH) receptor Controlled ovulation hyperstimulation in women; infertility due to hypogonadism in men Administered as a SC injection 3-7 x/wk Ovarian hyperstimulation syndrome and multiple pregnancies in women; gynecomastia in men; headache, depression, edema in both sexes Follitropin beta: Recombinant product with the same peptide sequence as follitropin alfa but differs in its carbohydrate side chains Urofollitropin: Human FSH purified from the urine of postmenopausal women Menotropins (hMG): An extract of the urine of postmenopausal women that contains both FSH and LH activity Gonadotropins: Luteinizing hormone (LH) analogs Leuprolide Agonist of the LH receptor Ovarian suppression; controlled ovarian hyperstimulation; central precocious puberty; advanced prostate cancer Administered IV, SC, IM, or intranasally; depot formulations are available Headache, lightheadedness, nausea, injection site reactions; with continuous treatment symptoms of hypogonadism Gonadorelin: Synthetic human GnRH Other GnRH analogs: Goserelin, histrelin, nafarelin, and triptorelin GnRH receptor antagonists Ganirelix Antagonist of GnRH receptors Prevention of premature LH surges during controlled ovulation hyperstimulation Administrated by SC injection Nausea, headache Cetrorelix: Similar to ganirelix and approved for controlled ovarian hyperstimulation Abarelix and degarelix: Approved for advanced prostate cancer Dopamine agonists Bromocriptine Agonist of dopamine D2 receptors

Treatment of hyper-prolactinemia and Parkinson's disease (see Chapter 28) Administered orally or vaginally Gastrointestinal disturbances, orthostatic hypotension, headache, psychiatric disturbances, vasospasm and pulmonary infiltrates in high doses Cabergoline: An ergot derivative with similar effects Oxytocin Oxytocin Agonist of oxytocin receptor Induction and augmentation of labor; control of uterine hemorrhage after delivery Administration as an IV infusion Fetal distress, placental abruption, uterine rupture, fluid retention, hypotension Oxytocin receptor antagonist Atosiban Antagonist of oxytocin receptor Tocolysis for preterm labor Administered as an IV infusion Concern about rates of infant death Vasopressin receptor agonists Desmopressin Agonist of vasopressin V2 receptors

Pituitary diabetes insipidus; hemophilia A and von Willebrand disease Available for oral, IV, SC, or intranasal administration GI disturbances, headache, hyponatremia, allergic reactions Vasopressin: Available for treatment of diabetes insipidus and sometimes used to control bleeding from esophageal varices Vasopressin receptor antagonist Conivaptan Antagonist of vasopressin V1a and V2 receptors

Hyponatremia in hospitalized patients Administered as an IV infusion Infusion site reactions Tolvaptan: Similar but more selective for vasopressin V2 receptors



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