Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 38 Introduction to Endocrine Pharmacology and Hormones of the Hypothalamus and Pituitary Gland


Hypothalamic hormones and analogs

Pituitary hormones and analogs

The endocrine system is a complex communication system responsible for maintaining homeostasis throughout the body, and it is vital to individual and species survival and propagation as well as adaptation to the environment. The system consists of a diverse group of ductless glands that secrete chemical messengers called hormones into the circulation. The secreted hormones are transported in the bloodstream to target organs, where they act to regulate cellular activities. For a hormone to elicit a response, it must interact with specific receptors on the cells of the target organ, much like the interaction between neurotransmitters and receptors involved in the process of neurotransmission in the central and peripheral nervous systems (see Chapters 9 and 27). Receptors play a key role in the mechanisms of action of endocrine hormone systems; key receptor mechanisms pertinent to endocrine systems are summarized in Chapter 1.

In general, all endocrine systems share several common features. At the uppermost level, the secretion of each hormone is controlled tightly by input from higher neural centers in response to alterations in plasma levels of the hormone or other substances. The second component is the gland itself, where hormone synthesis and secretion occur in specialized cells. After synthesis, hormones are typically packaged and stored for later release, as needed. Signals from the nervous system or special releasing hormones, or both, bring about secretion of stored hormone.


Hormones are chemically and structurally diverse compounds and can be divided into three main classes based on chemical composition, viz., the amino acid analogs, the peptides, and the steroids. The amino acid analogs, often termed amine hormones, are all derived from tyrosine and include epinephrine (Epi) and the iodothyronines or thyroid hormones. The peptide hormones are subclassified on the basis of size and glycosylation state and may be single- or double-chain peptides. The steroid



Adrenocorticotropic hormone


Arginine vasopressin, antidiuretic hormone


Cyclic adenosine monophosphate


Central nervous system


Corticotropin-releasing hormone






Diabetes insipidus


Deoxyribonucleic acid




United States Food and Drug Administration


Follicle-stimulating hormone


Growth hormone


Growth hormone-releasing hormone




Hypothalamic gonadotropin-releasing hormone


Human chorionic gonadotropin


Human growth hormone


Human menopausal gonadotropin


Insulin-like growth factor-1






Luteinizing hormone


Ribonucleic acid




Somatostatin, somototropin-release inhibiting hormone


Thyrotropin-releasing hormone


Thyroid-stimulating hormone

hormones are all derived from cholesterol and may be subclassified as adrenal steroids or sex steroids, the former synthesized primarily in the adrenal cortex and the latter synthesized in the ovaries or testes. The major endocrine glands and their associated hormones are listed in Box 38-1.

BOX 38–1 Major Endocrine Glands and Their Hormones


Cortisol, corticosterone, aldosterone

Ovaries, Testes

Estradiol, progesterone, testosterone


Thyroid hormones


Insulin, glucagon, somatostatin, pancreatic polypeptide


Antidiuretic hormone, oxytocin, adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, gonadotropin-releasing hormone, luteinizing-hormone-releasing hormone, thyrotropin-releasing hormone, prolactin-inhibiting factor


Parathyroid hormone, calcitonin

Hormones are generally distinguished from other types of modulatory factors (i.e., neurotransmitters) by a longer duration of effect and more extensive circulation in the body. While in the circulation, a hormone is frequently associated with one or more types of transport proteins from which it must dissociate to interact with responsive receptors. In addition, availability to tissues is dependent upon membrane exclusion mechanisms, susceptibility to tissue modification, and ultimately the rate of renal or hepatic metabolism, inactivation, and excretion. As mentioned, hormones exert their effects by binding to and activating receptors on target cells. These receptors can be located on the cell surface, as for peptide hormones, or within the cell, as in the case of steroids and thyroid hormones. After receptor activation, intracellular signaling pathways (e.g., second messenger systems or ligand-activated transcription factors) are modulated, which acutely or chronically alter cellular physiology and potentially whole organism physiology.

The endocrine hormones affect the activities of most organs and many types of cells. These actions occur by means of extremely intricate pathways, including positive- and negative-feedback control loops and sequences involving hormones from endocrine glands that act to control hormones secreted by other glands. A given hormone typically exerts multiple actions, and several different hormones influence a given function. Physiological functions affected by endocrine systems include:

• Fluid volume regulation of circulatory system

• Control and maintenance of fertility, reproduction, pregnancy, and parturition

• Regulation of storage, availability, and utilization of dietary molecules including vitamins and minerals

• Responses to stress or perceived threats

• Regulation of cellular processes and promotion of somatic growth

• Maintenance of circulating and cellular ion homeostasis

To facilitate the appropriate biological response, hormone levels must be maintained within a physiological range, which can be cyclic or relatively constant. Failed regulation of cell processes leads to increased or decreased levels of metabolic products, which become disruptive to cellular, organ, and whole body processes and function. Altered circulating levels of hormones are often related to defects in regulation of hormone release, distribution, metabolism, and excretion, or hormone-secreting organ pathology. In addition, alterations in target tissue hormone sensitivity may be involved and result from defects in the levels or affinities of hormone receptors, effectiveness of second messenger transduction mechanisms, or defective receptor-mediated cellular/metabolic processes.

To understand and manage this problem, an association among hormone levels, tissue sensitivity, and symptoms must be properly established by measuring the levels of appropriate hormone(s). This assessment allows development of rational pharmacological approaches to reverse an abnormal process; dampen physiological consequences of hormonal imbalance; and restore or mimic normal endocrine function. When decreased hormone levels are detected, hormonal balance may be restored by increasing the production of endogenous hormones or by administering exogenous hormones or hormone analogs. The effectiveness of this approach depends on the success of restoration of the natural pattern of hormone levels without producing periods of excessive or deficient biological activity that can provoke pathological conditions. Failure of this approach can be associated with tissue insensitivity, which, if treatable, requires modification of hormone-responsive cellular metabolism.

Excessive levels of endogenous hormones may result from excessive organ secretion or unregulated ectopic formation. Hormone overproduction by a secreting organ is commonly associated with excessive stimulation or a malignancy (or hyperplasia). Successful management of this situation includes blockade of the stimulatory agent, if identifiable, or interference with hormone formation, secretion, or action. Ectopic production of a biologically active form of the hormone by tissues is complicated by the lack of feedback mechanisms to regulate hormone production and is typically associated with tissue malignancy or infection. The primary determinant of successful intervention frequently requires a combination of ablation of the secreting tissue and pharmacological agents to antagonize the effects of elevated hormone levels. The success of this technique hinges on the ability of the responsible tissue to respond to pharmacological intervention. If it is not possible or detrimental to directly reduce hormone levels, a situation often encountered before or immediately after surgery, or when the cause of the elevated hormone levels is unknown or uncorrectable, alternative, patient-specific strategies to reduce the effects of elevated hormone levels must be used. A summary of strategies to manage the levels and action of hormones is presented in Box 38-2. A list of drugs that affect hormonal balance and their mechanisms of action are in Box 38-3.

BOX 38–2 Strategies to Manage the Levels and Action of Hormones

Mechanisms to Increase Hormone Levels and Activity

Increase endogenous hormone synthesis, release, and transport

Reduce endogenous hormone metabolism and excretion

Increase peripheral activation of circulating hormone (if required)

Hormone replacement therapy

Mechanisms to Decrease Hormone Levels and Activity

Lower endogenous hormone synthesis, release, or both

Reduce peripheral conversion to activated forms

Promote hepatic/renal metabolism/excretion

Decrease receptor activity by reducing receptor number or affinity for hormone or use competitive receptor antagonists

Suppress response of target tissue to receptor-hormone interaction by interfering with generation of second messengers

Modify tissue metabolism to blunt the effects of hormone excess

BOX 38–3 Drugs Known to Affect Hormonal Balance

Effectors of Hormone Release/Reuptake

Bromocriptine—antagonizes release of GH and prolactin

Octeride—inhibits selective release of GH

Analogs of GnRH—elevated levels desensitize anterior pituitary GnH release; pulsatile exposure to physiological levels simulates GnRH release

Sulfonylureas and incretins—promote insulin release from pancreatic beta cells

Pramlintide—inhibits glucagon secretion

Sibutramine—blocks reuptake of monoamines

Effectors of Hormone Synthesis

Thioamides—inhibit synthesis of thyroid hormones

Metyrapone—inhibits synthesis of cortisol

Alteration of Peripheral Conversion of Hormones

Finesteride—blocks conversion of testosterone to 5α-dihydrotestosterone

Aromatase inhibitors—antagonize interconversion of estrogen and androgens

Propylthiouracil—blocks conversion of thyroxine to triiodothyronine in tissues

Dipeptidyl peptidase-IV inhibitors—block the digestion of incretins

Competitive Receptor Antagonists

Spironolactone—aldosterone receptor antagonist

Raloxifene—estrogen receptor tissue-specific agonist/antagonist

Tamoxifen/Clomiphene—estrogen receptor agonist/antagonist

Mifprostone—progesterone receptor antagonist

Danazol/Cyproterone acetate/Flutamide—androgen receptor antagonists

Alteration of Metabolism

Metformin—decreases hepatic glucose production

Thiazolidinediones—improves insulin-facilitated metabolic effects in patients with insulin resistance

Bisphosphonates—cytotoxic effects on osteoclasts

Orlistat—blocks gastrointestinal metabolism of fats

Steroid Biochemistry and Physiology

All secreted steroids are synthesized from cholesterol, which can be synthesized de novo or derived from circulating lipoproteins. Similar metabolic pathways mediate steroid synthesis in all organs (Fig. 38-1). The organ-specific formation of secreted steroids depends on the presence of specific catalytic enzymes (Table 38-1).


FIGURE 38–1 Steroid metabolism. The biosynthesis of the steroids is illustrated. The enzymes with the prefix CYP represent the mitochondrial cytochrome P450 mixed function oxidases, and the numbers indicate the site of steroid hydroxylation. The other enzymes are located primarily at the endoplasmic reticulum or both endoplasmic reticulum and mitochondria. The steroids indicated in bold are the primary secreted steroids.

TABLE 38–1 Enzymes Present in Different Tissues Mediating the Organ- or Tissue-Specific Formation of Steroid Hormones


The action of steroids is mediated largely by altering gene transcription through interaction with promoter deoxyribonucleic acid (DNA) of genes. Steroid receptors are dimeric and coupled with accessory proteins until activated by ligands outside the nucleus. The steroid-receptor complex is phosphorylated and translocated to the nucleus through a nuclear pore, facilitated by the importin protein. The interaction with the gene promoter region occurs through steroid-specific palindromic nucleotide sequences within the receptor. The interaction of DNA and the steroid-receptor complex is dependent on steroid structural differences, amino acid sequence of the DNA binding domain, the nucleotide sequence of the DNA binding site, and the architecture of the gene promoter. The structures of the primary circulating steroids are shown in Figure 38-2.


FIGURE 38–2 Structures of the primary circulating steroids. Steroids may be classified broadly as 19- or 21-carbon steroids on the basis of the number of carbon atoms in the steroid structure. The 19-carbon forms, testosterone and the estrogens, are released from gonadal tissues; although DHEA is formed in these tissues, its release is normally less than from the adrenal gland. Progesterone is released from the corpus luteum and placenta. Cortisol, DHEA, and aldosterone are released primarily from the zona fasciculata, zona reticularis, and zona glomerulosa, respectively. Note that the numbering system shown for cortisol applies to all steroids.


In the adrenal gland, the primary secreted steroids are aldosterone, cortisol, and dehydroepiandrosterone (DHEA) (see Fig. 38-2). Aldosterone is the primary mineralocorticoid and acts at the luminal epithelia to promote renal reuptake of Na+, which conserves Na+ and can elevate blood pressure. In the zona glomerulosa, the lack of CYP17 is associated with nearly exclusive formation of aldosterone. Further, the release of aldosterone from the zona glomerulosa is regulated by the renin-angiotensin pathway as a result of activation angiotensin II-receptors, which are linked to the formation of 1,4,5-inositol triphosphate. The amount of aldosterone released is relatively low (50 to 150 µg/day); aldosterone is transported in the blood through an interaction with albumin with a bound/free ratio of 70/30.

The primary adrenal androgen DHEA is released from the zona reticularis, and daily secretion levels can reach 30 mg. DHEA has weak androgenic activity and can be converted to testosterone and ultimately estradiol in tissues expressing aromatase, for example, adipose tissue. Although DHEA production is relatively high, with levels rivaling that of cortisol, synthesis declines with age; the biological role of DHEA remains poorly understood, but it has been implicated to play a role in the aging process.

The complement of enzymes in the zona fasciculata and zona reticularis permits the formation of cortisol, the primary circulating glucocorticoid (see Chapter 39). The release of cortisol is dependent on a tightly regulated hypothalamic-anterior pituitary-adrenal cortex axis. The biological role of glucocorticoids is complex and temporal. The liver has the greatest level of nuclear receptors or steroid-activated transcription factors, although they are present in many tissues. The primary systems affected by cortisol include self-regulation of formation via suppression of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion, storage of hepatic glycogen, response to stress, and suppression of the immune system. The daily production of cortisol ranges from 10 to 20 mg, and plasma levels follow a diurnal pattern with the highest levels in the morning. In the blood, cortisol is bound to a specific hepatic protein, corticosteroid-binding protein (aka transcortin), which promotes its transport and increases its duration of action.

Ovarian Steroids

The secretion of estrogen (β-estradiol) and progesterone from the ovary is regulated by hypothalamic gonadotropin-releasing hormone (GnRH), anterior pituitary follicle-stimulating hormone (FSH), and leutenizing hormone (LH). Release of the gonadotropic hormones and the ovarian steroids during the menstrual cycle is episodic, and the highest levels of β-estradiol or progesterone occur during the late follicular phase or midleutal phase, respectively (see Chapter 40). Most of these circulating steroids (98%) are bound to specific steroid hormone-binding globins.

Androgenic Steroids

The primary testicular androgen, testosterone, is converted to dihydrotestosterone (DHT) in tissues expressing 5α-reductase. The actions of androgens include development of male reproductive tract and accessory tissues, stimulation of secondary sexual traits, growth, and development of the central nervous system (CNS) (see Chapter 41). As shown in Figure 38-1, the expression of steroid metabolizing enzymes promotes the formation of DHEA and androstenedione leading to the formation of testosterone; the expression of aromatase in ovarian cells permits conversion of testosterone to β-estradiol.

Therapeutic Overview

Pharmacology of Hypothalamic and Pituitary Hormones

The hypothalamus and pituitary gland work in concert to regulate endocrine systems throughout the body. Peptides and biogenic amines synthesized and secreted by specialized neurons within the hypothalamus are transported to the anterior pituitary by the hypothalamic-hypophyseal portal circulation, where they act through specific receptors to stimulate or inhibit hormone secretion (Fig. 38-3).Anterior pituitary hormones trigger peripheral endocrine organs to produce hormones, which have individual functions and provide feedback to the hypothalamus and pituitary to regulate the synthesis and release of their tropic hormones. As mentioned, GnRH (also called luteinizing hormone releasing hormone) stimulates the secretion of LH and FSH by the pituitary. LH and FSH promotegametogenesis and gonadal hormone production by the ovaries and testes (see Chapters 40 and Chapter 41). Thyrotropin-releasing hormone (TRH) stimulates secretion of thyroid-stimulating hormone (TSH), which in turn controls thyroid function (see Chapter 42) CRH stimulates the secretion of ACTH, which promotes the secretion of cortisol by the adrenal cortex (see Chapter 39). Growth hormone-releasing hormone (GHRH) stimulates and somatostatin (also called somatotropin-release inhibiting factor, SRIF) inhibits the production of growth hormone (GH), which has numerous effects on growth and metabolism. Hypothalamic dopamine functions to tonically inhibit secretion of prolactin, the hormone primarily responsible for lactation and suppression of fertility while nursing.


FIGURE 38–3 Relationships among hypothalamic releasing and inhibiting factors, the anterior pituitary hormones controlled by hypothalamic hormones, and their respective target organs or tissues. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; SRIF, somatotropin-release inhibiting factor (somatostatin); TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

Unlike the anterior pituitary, the posterior pituitary (or neurohypophysis) consists of neurons with cell bodies in the hypothalamus. These cells secrete oxytocin and arginine vasopressin (AVP; also known as antidiuretic hormone), which are transported by carrier proteins (neurophysins) through axons to the posterior pituitary for storage and release directly into the systemic circulation.

GHRH, TRH, CRH, TSH, and ACTH are used primarily for diagnostic purposes. In contrast, the hypothalamic hormones (or their analogs) GnRH, dopamine, and somatostatin, the anterior pituitary hormones GH and LH/FSH, and the posterior pituitary hormone AVP, are used therapeutically. A summary of hypothalamic and pituitary hormones is presented in the Therapeutic Overview Box.

Therapeutic Overview

Hypothalamic Hormones


Replacement therapy for idiopathic hypogonadotropic hypogonadism

GnRH analogs

Prostate and breast cancer

Idiopathic precocious puberty



Dopamine agonists

Pathological hyperprolactinemia


Parkinson’s disease

Somatostatin and analogs


Carcinoid and vasoactive intestinal peptide-secreting tumors

Pituitary Hormones

LH and FSH

Infertility in women

Infertility in men with hypogonadotropic hypogonadism

GH agonists

Adult GH deficiency

Growth failure

AVP agonists and antagonists

Diabetes insipidus

Syndrome of inappropriate antidiuretic hormone

Mechanisms of Action

Hypothalamic Hormones

Most GnRH-positive neurons in humans are located in the medial basal hypothalamus between the third ventricle and the median eminence. Projections from these neurons terminate in the median eminence, in contact with the capillary plexus of the hypothalamic-hypophyseal portal circulation. This allows GnRH to reach the circulation without passing through a blood-brain barrier. GnRH is formed by processing of a larger prohormone, preproGnRH, and transported in secretory granules to nerve terminals for storage, degradation, or release into pituitary portal blood vessels.

GnRH-receptor interaction initiates secretion of LH and FSH. The GnRH receptor gene consists of a 327-amino acid protein with seven transmembrane domains but lacks the typical intracellular C-terminus of a G protein-coupled receptor. Microaggregation stimulates up regulation of GnRH receptors and is followed by internalization of the hormone-receptor complex (see Chapter 1). Receptor activation results in increased intracellular Ca++.

GnRH is released in a pulsatile manner by the so-called “hypothalamic GnRH pulse generator.” This pattern of intermittent bursts is essential for normal function. Continuous administration of GnRH will initially produce an increase in serum gonadotropin concentrations. However, this is followed by a decrease in gonadotropin secretion caused by pituitary GnRH receptor down regulation, a decrease in expression of GnRH receptors, and desensitization of pituitary gonadotrophs. GnRH analog agonists and antagonists have been synthesized through selective substitution of amino acids in the GnRH peptide (Fig. 38-4). These GnRH analogs have greater receptor binding and reduced susceptibility to enzymatic degradation, resulting in prolonged biological activity.


FIGURE 38–4 Structure of gonadotropin-releasing hormone (GnRH).

GnRH secretion is increased by norepinephrine, Epi, neuropeptide Y, galanin, and N-methyl-D-aspartic acid and decreased by endogenous opioids, progesterone, and prolactin. Estradiol inhibits GnRH secretion except for a brief period of stimulation, which results in the midcycle LH surge.

Secretion of GH is regulated by two opposing hypothalamic hormones: GHRH and somatostatin (Fig. 38-5). Somatostatin is a cyclic peptide that is processed from a preprohormone into two molecular forms: SRIF-14 and SRIF-28. The 14-amino acid sequence at the carboxyl terminal of SRIF-28 is identical to SRIF-14. In addition to its presence in the hypothalamus, somatostatin is widely distributed throughout the CNS, the gastrointestinal (GI) tract, pancreas, thyroid, thymus, heart, skin, and eye. Somatostatin has multiple actions including inhibition of GI hormone secretion (e.g., gastrin, vasoactive intestinal peptide, motilin, and secretin), pancreatic exocrine secretion (e.g., gastric acid, pepsin, pancreatic bicarbonate), pancreatic endocrine secretion (e.g., insulin, glucagon), GI motility, gastric emptying, and gallbladder contraction. Somatostatin also decreases GI absorption and mesenteric blood flow. In the CNS, somatostatin acts as both a neurotransmitter and a neuromodulator.


FIGURE 38–5 Regulation of growth hormone secretion in humans. Growth hormone-releasing hormone (GHRH) and somatostatin (SRIF) are the primary stimulatory and inhibitory peptides, respectively. IGF-1, Insulin-like growth factor 1.

There are five somatostatin receptor subtypes (SSTR1-SSTR5), which are G protein-coupled but differ in tissue distribution and signaling pathways. SRIF-14 and SRIF-28 bind all five receptor subtypes. Binding of SRIF to SSTR2 and SSTR5 suppresses GH secretion and the secretion of TSH.

Dopamine is synthesized in the tuberoinfundibular neurons of the hypothalamus and transported to the anterior pituitary gland via the hypothalamic-hypophyseal portal system. Dopamine acts at its type 2 (D2) receptors on the pituitary lactotrophs to inhibit prolactin secretion. Prolactin is the only anterior pituitary hormone under tonic inhibition by a hypothalamic hormone.

Pituitary Hormones

The gonadotropins LH and FSH are structurally similar, each consisting of two polypeptide subunits. Subunit structure is imposed by internal cross-linking disulfide bonds, and subunit interactions are mediated largely through hydrogen bonding. LH and FSH are composed of an identical 89-amino acid α-chain and a unique 115-amino acid β-chain, which confer receptor specificity. After synthesis, both subunits are glycosylated. Specifically, two complex carbohydrates are attached to the FSH-β-subunit and one to the LH-β-subunit. A terminal sialic acid is found on approximately 5% and 1% of FSH and LH carbohydrate molecules, respectively. Sialic acid prolongs the metabolic clearance of glycoproteins and results in a longer half-life for FSH than for LH. There is no evidence that other molecular forms of LH and FSH, such as prohormones and fragments, circulate in the plasma. The pituitary gonadotropes secrete LH and FSH.

Gonadotropins bind with high affinity to membrane receptors in the testes and ovaries. The LH and FSH receptors are glycoproteins encoded by homologous genes and are characterized by seven transmembrane-spanning domains. A large N-terminal region forms the binding site for the specific gonadotropin. The activation of LH and FSH receptors is associated with distinctive Ca++ signaling properties and increased 3’-5’ cyclic adenosine monophosphate (cAMP) production, which increases phosphorylation of proteins involved in steroidogenesis through activation of cAMP-dependent protein kinase.

In addition to regulating estrogen production, gonadotropins have multiple effects on ovarian follicles. FSH directly stimulates follicular growth and maturation and enhances granulosa cell responsiveness to LH. LH is essential for the breakdown of the follicular wall, resulting in ovulation, and for the subsequent resumption of oocyte meiosis.

By contrast, testicular steroidogenesis requires only LH. The Leydig cells, which constitute approximately 10% of testicular volume, are stimulated to produce testosterone by the binding of LH to surface receptors. FSH binds to Sertoli cells, and with testosterone is essential for mediating cellular maturation and spermatid differentiation, the first step of spermatogenesis. The Sertoli cell is necessary for maintenance of seminiferous tubule function and germ cell development.

GH is a 191-amino acid polypeptide belonging to a family of structurally similar hormones, including prolactin and chorionic somatomammotropin (also known as human placental lactogen). GH is synthesized by somatotropes of the anterior pituitary. The major product is a peptide with two disulfide bonds. The precise signaling mechanism by which GH exerts its intracellular effects likely involves its interaction with specific plasma membrane receptors and activation of the JAK family of intracellular tyrosine kinases and the STAT family of nuclear transcription factors (see Chapter 1). In addition, GH binds to proteins in both the cytosol and plasma. The specificity of the circulating binding protein is similar to that of the GH receptor.

Most actions of GH are mediated through stimulation of insulin-like growth factor-1 (IGF-1) produced in liver, cartilage, bone, muscle, and kidney. Other direct effects of GH on tissue include DNA and ribonucleic acid (RNA) synthesis, plasma protein synthesis, and amino acid transport and incorporation into proteins.

AVP, also known as antidiuretic hormone, is a polypeptide that functions as the primary antidiuretic hormone in humans (Fig. 38-6). Synthesized primarily in the magnocellular neuronal systems of the supraoptic and paraventricular nuclei of the hypothalamus, the AVP precursor molecule contains a signal peptide, a neurophysin, and a glycosylated moiety, in addition to the AVP sequence. After translation of the messenger RNA to form a preprohormone (166 amino acids), the signal peptide is cleaved, forming a prohormone. The prohormone is stored in neurosecretory granules that travel down the supraoptico-hypophyseal tract to the posterior pituitary. The primary stimuli for AVP release are hyperosmolarity, as measured by osmoreceptors in the supraoptic and paraventricular nuclei, and volume depletion, detected by baroreceptors in the vascular bed and heart. Nausea, emesis, and hypoglycemia may also stimulate AVP release.


FIGURE 38–6 Amino acid sequences of arginine vasopressin (AVP) and 1-desamino-8-D-arginine-vasopressin (desmopressin).

AVP acts via V1 and V2 receptors in smooth muscle and renal collecting tubules, respectively. V1 receptors mediate vasoconstriction, while V2 receptors mediate antidiuretic effects. Specifically, AVP binding to V2 receptors activates adenylyl cyclase and a subsequent cascade resulting in fusion of the water channel, aquaporin-2, with the luminal membrane, thereby allowing water reabsorption.


The pharmacokinetic parameters for the hypothalamic and pituitary hormones and analogs are summarized in Table 38-2.

TABLE 38–2 Pharmacokinetic Parameters


Hypothalamic Hormones


Continuous SC infusions of GnRH in hypogonadotropic patients produce steady-state concentrations that are one third less than those achieved with the IV route. Therefore SC administration results in delayed and prolonged absorption and lower serum concentrations. In patients receiving SC pulsatile GnRH therapy, these characteristics cause significant dampening of plasma GnRH concentration peaks. The lack of a pulsatile GnRH concentration may lead to desensitization and diminish pituitary responsiveness, which likely explains the decreased success rate for induction of ovulation associated with SC as compared with IV administration.

Initially, GnRH analog agonists were administered daily either intranasally or by SC injection. More recently, long-acting depot formulations have been developed. For example, a long-acting suspension of leuprolide can be administered either SC or IM monthly or every 1, 3, or 4 months depending on dose. Leuprolide is also available as an implant placed SC in the inner area of the upper arm, releasing 120 µg of leuprolide acetate every day for 1 year. Similarly, goserelin is administered as an SC implant every 28 days or every 3 months. Triptorelin can be administered as a short-acting SC injection or as a long-acting IM formulation in biodegradable polymer microspheres that last for a month. Nafarelin is administered intranasally.

GnRH is not significantly bound to plasma proteins. Because renal excretion represents its primary route of elimination, renal insufficiency increases the overall clearance rate. Moderate abnormalities of hepatic function do not affect GnRH clearance.

Somatostatin and Analogs

Somatostatin is rapidly inactivated by peptidase enzymes and cannot be administered orally. Although the IV administration of native somatostatin results in a prompt decline in serum GH concentrations, because it must be administered by continuous IV infusion, it is unsuitable for therapeutic use.

There are two cyclic octapeptide somatostatin analogs, octreotide and lanreotide. As compared with somatostatin, octreotide and lanreotide are more potent inhibitors of GH, glucagon, and insulin secretion because of their increased duration of action. Octreotide is administered by SC injection three times a day. A long-acting release formulation of octreotide dispersed in microspheres of a biodegradable polymer can be administered IM once a month.

Dopamine Agonists

Dopamine, in addition to being a neurotransmitter, is a sympathomimetic and is commonly used to treat cardiogenic shock, septic shock, acute myocardial infarction, and renal failure (see Chapter 23). Because of its vasoconstrictor properties, it is not administered SC or IM. It has a short half-life (2 minutes) and must be administered by continuous IV infusion. Therefore it is not used in treatment of hyperprolactinemia, although it does effectively decrease serum prolactin levels.

Bromocriptine is a long-acting dopamine agonist (see Chapter 28). After oral administration, approximately 28% of bromocriptine is absorbed, with peak plasma levels reached in 1 hour. It is transported primarily by serum albumin (90% to 96%) and has a half-life of approximately 6 hours. An intravaginal route can be used effectively to avoid drug sensitivity. Bromocriptine is metabolized by the liver and excreted in bile (84.6% within 120 hours).

Cabergoline is another long-acting dopamine agonist with a high affinity for D2 receptors. After a single oral dose, mean peak plasma levels are observed within 2 to 3 hours. A significant fraction of the administered dose undergoes first-pass metabolism. The elimination half-life is 63 to 69 hours, allowing twice-weekly administration.

Pituitary Hormones

LH and FSH

The absorption characteristics and subsequent metabolism of the gonadotropins LH and FSH have not been elucidated, but the liver appears to be the major route of clearance after the enzymatic removal of sialic acid. The estimated half-life of LH is shorter than that of FSH because the latter has a higher sialic acid content and consequently a decreased hepatic uptake. The clearance of LH is approximately 30 mL/min in women and 50 mL/min in men. The clearance of FSH is approximately 15 mL/min in women and has not been determined in men.


Endogenous GH has a short half-life. GH produced from recombinant DNA, which is administered three to six times per week, has a mean half-life of approximately 4 hours and is metabolized by both liver and kidney.


AVP, vasopressin tannate, and desmopressin circulate unbound to plasma proteins. All are metabolized in liver and kidney and may be initially inactivated by cleavage of the C-terminal glycinamide. A small amount of AVP is excreted intact in urine.

The durations of action of the three preparations differ. When administered SC, AVP is effective for only 2 to 8 hours. After IM administration, vasopressin tannate is often absorbed erratically, with a duration of action of 48 to 96 hours; desmopressin has a longer half-life than AVP.

Relationship of Mechanisms of Action to Clinical Response

Hypothalamic Hormones

GnRH and Analogs

GnRH and analogs approved by the United States Food and Drug Administration (FDA) have indications for two therapeutic categories, which require different administration strategies:

• Replacement therapy in disorders characterized by isolated abnormal function of the hypothalamic pulse generator

• Promotion of pituitary desensitization, thus producing a functional orchiectomy or ovariectomy

GnRH has been used successfully to induce ovulation in women with primary hypothalamic (or central) amenorrhea. This disorder is characterized by abnormal functioning of the GnRH pulse generator, resulting in inadequate gonadotropin secretion, failure of ovarian follicular development, and amenorrhea. Because the pituitary is intrinsically normal and will release LH and FSH in response to GnRH, pulsatile administration of GnRH can compensate for the underlying defect. A portable infusion pump that administers GnRH IV at 90-minute intervals frequently restores LH, FSH, estradiol, and progesterone profiles to those observed in normal spontaneous menstrual cycles. Clomiphene and human menopausal gonadotropin are also used for treatment of central amenorrhea. These methods may have a successful history of inducing ovulation but are associated with two major complications:

• Ovarian hyperstimulation syndrome

• Increased incidence of multiple gestation pregnancies

The incidence of complications may be less for pulsatile GnRH therapy because it maintains the integrity of the pituitary-ovarian axis and more accurately reproduces the physiology of the normal menstrual cycle. GnRH agonists and antagonists administered as SC injections are frequently used in in vitro fertilization approaches to prevent premature LH surges in women undergoing controlled ovarian hyperstimulation.

Faulty GnRH secretion in men is referred to as idiopathic hypogonadotropic hypogonadism. A small clinical study using long-term pulsatile administration of GnRH for at least 3 months demonstrated significant increases of serum testosterone concentrations and testicular size. Mature spermatogenesis was achieved in 50% of patients, and men with unfused epiphyses experienced linear bone growth. Idiopathic or surgically induced hypogonadotropic hypogonadism is treated with testosterone (see Chapter 41) to promote masculinization and to preserve bone mineral density. Human chorionic gonadotropin and human menopausal gonadotropin are used to promote spermatogenesis and restore fertility in male hypogonadotropic hypogonadism.

The association of orchiectomy and regression of prostate cancer led to the development of approaches to decrease serum androgen concentrations in men with metastatic prostate cancer. Methods to induce androgen deprivation include orchiectomy, estrogen therapy, GnRH analogs, and antiandrogens (see Chapter 41). Combined androgen blockade, in which orchiectomy or GnRH analogs are combined with an antiandrogen, is also used in treating metastatic hormone-dependent prostate cancer.

Orchiectomy is an effective and relatively safe surgical procedure that significantly lowers testosterone levels (90%). The emotional impact of orchiectomy decreases its desirability for men with metastatic prostate cancer. Another approach is to use estrogens to suppress LH secretion, which promotes decreased serum androgen levels in men. However, estrogen therapy in men has been linked with an increased incidence of deep venous thrombosis and gynecomastia.

Long-acting GnRH agonists can be used to down regulate pituitary gonadotropin receptors and suppress release of LH (Fig. 38-7), resulting in reduction of serum testosterone concentrations comparable to that seen with orchiectomy. However, continuous GnRH agonist therapy will initially increase LH secretion from the pituitary, causing a transient increase in serum testosterone. This “flare” response occurs approximately 72 hours after initiating therapy and can exacerbate symptoms of metastatic prostate cancer, such as bone pain and ureteral obstruction. Coadministration of the antiandrogen flutamide with a GnRH agonist can prevent these negative effects. Pituitary gonadotroph desensitization occurs 1 to 2 weeks after starting the GnRH agonist, with castrate levels of testosterone seen in 2 to 4 weeks.


FIGURE 38–7 Luteinizing hormone (LH) serum concentration profile in a normal subject, showing initial LH pulses resulting from gonadotropin-releasing hormone (GnRH) pulse generator. Administration of a long-acting GnRH agonist (orange arrow) down regulates receptors and leads to decreased LH secretion.

GnRH antagonists can also dramatically reduce serum testosterone. Unlike agonists, GnRH antagonists suppress pituitary gonadotrophs immediately, thereby avoiding the undesired transient increases in LH secretion and serum testosterone concentrations and obviating the need for coadministration of an antiandrogen.

GnRH agonists and antagonists have also been used in premenopausal women with hormone-dependent metastatic breast cancer as an alternative to oophorectomy to decrease serum estrogen to menopausal levels. Breast cancer “flare” reactions have occurred in some women treated with continuous GnRH agonists and are likely related to a transient increase in gonadotropin secretion from the pituitary. Comparison of the GnRH agonist, goserelin, with ovariectomy in premenopausal women with estrogen-receptor-positive or progesterone-receptor-positive metastatic breast cancer indicated that response rates, failure-free survival, and overall survival were equivalent.

GnRH analog therapy is approved as a means of obtaining a medical oophorectomy for treatment of endometriosis and uterine leiomyomas. Treatment with GnRH agonists for 6 months has been shown to be as effective as danazol in reducing the size of endometrial implants and decreasing clinical symptoms, including pelvic pain, dysmenorrhea, and dyspareunia. In addition, GnRH agonists have been used for treatment of hirsutism and other manifestations of hyperandrogenism in women who have failed conventional therapies (oral contraceptives or antiandrogens). Histrelin, a synthetic GnRH analog, is also used to treat acute intermittent porphyria associated with menses. Idiopathic precocious puberty has been treated successfully with GnRH agonists.

Somatostatin and Analogs

The short half-life and requirement for continuous IV administration limit the usefulness of somatostatin. The analogs octreotide and lanreotide, however, have many uses including treatment for excessive GH secretion. Gigantism occurs if GH hypersecretion is present before epiphyseal closure during puberty, and acromegaly occurs if hypersecretion develops after puberty. Excessive GH secretion has many deleterious effects such as tissue growth stimulation and altered glucose and fat metabolism.

Generally, patients with gigantism or acromegaly are treated by transsphenoidal resection of the GH-secreting adenoma. Some patients, however, cannot be surgically cured and receive adjuvant treatment with irradiation, medical therapy, or both. Medical therapy for treatment of acromegaly includes dopamine agonists, pegvisomant (a GH receptor antagonist), or somatostatin analogs. Somatostatin analogs bind to pituitary somatostatin receptors and block GH secretion. SSTR2 and SSTR5 are the main somatostatin receptors found in GH-secreting pituitary tumors and are the receptors for which octreotide and lanreotide have the highest affinity. Several studies show that long-acting somatostatin analogs are useful as adjunct therapy in acromegaly. Improvement in symptoms can be seen even without normalization of serum GH and IGF-1 levels, most likely because even small reductions in GH secretion will result in a clinical response. Such therapy can also lead to tumor shrinkage in 30% of patients treated for acromegaly.

Somatostatin analogs have also been approved for use in the treatment of carcinoid syndrome and vasoactive intestinal peptide tumors. In addition, because most neuroendocrine tumors express somatostatin receptors, radiolabeled somatostatin analogs have been used to image these tumors (scintigraphy) and to deliver isotopes to the tumors to inhibit their growth.

Dopamine Agonists

Physiological hyperprolactinemia normally occurs during pregnancy, lactation, nipple stimulation, and stress. Pathologic hyperprolactinemia is most commonly caused by a prolactin-secreting pituitary adenoma. Other causes of pathologic hyperprolactinemia include lactotroph hyperplasia, caused by decreased dopamine inhibition of prolactin secretion and decreased clearance of prolactin. Hyperprolactinemia can result in galactorrhea in both women and men. More importantly, hyperprolactinemia results in suppression of gonadotropin secretion, with resulting sex steroid deficiency. Women with hyperprolactinemia commonly present with oligomenorrhea or amenorrhea or infertility. Men with hyperprolactinemia commonly present with decreased libido, erectile dysfunction, and other signs of low testosterone, including osteoporosis.

Dopamine agonists are used to treat hyperprolactinemia caused by both prolactinomas and lactotroph hyperplasia. Dopamine agonists bind to D2 receptors on the lactotrophs, resulting in decreased prolactin synthesis and secretion. Decreases in prolactin concentration can be seen within 2 to 3 weeks of initiating therapy. Dopamine agonists also decrease the size of the lactotroph, leading to shrinkage of the prolactinoma. Within a few days, significant abatement of the clinical signs and symptoms of the intracranial tumor are noted. For many patients a significant reduction of tumor size can be seen upon imaging within 6 weeks of initiating the dopamine agonist. Prolactinomas are the only type of pituitary adenoma in which medical therapy, as opposed to transsphenoidal resection, is first-line treatment. With reduction of the serum prolactin concentration to normal, galactorrhea is abolished and gonadal function restored. Patients who do not respond to one dopamine agonist may respond to another, and cabergoline may be more effective than bromocriptine.

Dopamine agonists also inhibit GH secretion and can be used in the treatment of acromegaly, with bromocriptine less effective than cabergoline. The combination of a dopamine agonist with a somatostatin analog may be effective when neither agent alone is adequate.

Women with pathological hyperprolactinemia requiring treatment with a dopamine agonist who desire pregnancy should be treated with bromocriptine. There have been no reports of an increased incidence of birth defects in infants of mothers who took bromocriptine during pregnancy, and it is not known whether cabergoline is safe in pregnancy; therefore women taking cabergoline who desire pregnancy should be switched to bromocriptine.

Pituitary Hormones

LH and FSH

The first report of pregnancy resulting from treatment with human urinary gonadotropin was in 1962. Presently, human menopausal gonadotropins (hMG), purified urinary FSH, and recombinant FSH are used for induction of ovulation. hMG consists of a purified preparation of LH and FSH extracted from the urine of postmenopausal women. Administered either SC or IM, hMG is indicated for ovulation induction in women with amenorrhea caused by hypogonadotropic hypogonadism (including hypothalamic amenorrhea) or normogonadotropic amenorrhea, including women with polycystic ovary syndrome who have failed to ovulate with clomiphene. More recently, purified forms of urinary FSH and recombinant FSH have become available. In a recent study, the use of gonadotropins for ovulation induction in women with polycystic ovary syndrome was successful in approximately 70% of patients, with 40% achieving pregnancy. Multiple gestation births occur in approximately 10% to 15% of patients receiving gonadotropins.

The gonadotropins, both urinary and recombinant, can be used to induce spermatogenesis in treatment of male-factor infertility. Men with hypogonadotropic hypogonadism caused by hypothalamic or pituitary disease are candidates for treatment with human chorionic gonadotropin (hCG), hMG, or both. Because hCG has LH biologic activity, it is used to stimulate testosterone production from Leydig cells and subsequently spermatogenesis. If the onset of hypogonadism occurs after puberty, Sertoli cells will have already been primed by FSH, and hCG alone could be effective. Onset before puberty will likely require FSH in addition to LH, and treatment with hMG (containing both) is indicated.


Clomiphene is a compound with both estrogenic and antiestrogenic activity that is indicated for women with normogonadotropic anovulation (see Chapter 40). The use of clomiphene results in lower rates of multiple gestation births (~ 5%), compared with the incidence using gonadotropins.

Growth Hormone

GH promotes linear growth by causing generation of IGF-1 and influences all aspects of metabolism. GH is anabolic, lipolytic, and diabetogenic, that is, it promotes insulin resistance. Replacement of GH in children with GH deficiency stimulates the incorporation of amino acids into muscle protein and promotes long bone growth. Although the treatment of GH deficiency with GH can promote severe glucose intolerance and aggravate diabetes mellitus, improper management or unsupervised use leading to excessive serum GH concentrations will promote gigantism in children or acromegaly in adults.

GH purified from human cadaver pituitary glands was used originally for treating GH deficiency in children, but this was halted in 1985 when cases of spongiform encephalopathy were found to be associated with the use of human cadaver GH. That same year the FDA expedited approval for the use of recombinant human GH (hGH) to treat GH deficiency in children. With the ample supply of hGH, it is also possible to treat GH-deficient adults to attain maximum size, decrease adipose mass, and increase muscle mass compared with untreated GH-deficient adults. However, abuse of hGH by normal individuals seeking to enhance athletic performance is a concern, because hGH is difficult to detect. Amateur and professional sport regulatory groups condemn this practice.


Three forms of AVP are approved for clinical use: native AVP, vasopressin tannate, and desmopressin. Clinical indications include diabetes insipidus (DI), GI variceal hemorrhage, nocturnal enuresis, bleeding diatheses, and cardiac arrhythmia.

Central (or neurogenic) DI is characterized by polyuria and polydipsia and results from inadequate secretion of AVP from the posterior pituitary. Nephrogenic DI results from failure of the kidney to respond to secreted AVP. The diagnosis of DI is confirmed by using AVP during a water deprivation test. The water deprivation test is also used to distinguish between central and nephrogenic DI. During water deprivation and subsequent elevation of plasma osmolality, patients with DI exhibit an inability to retain water or concentrate their urine. Patients with central DI exhibit an increase in urine osmolality after administration of AVP, whereas patients with nephrogenic DI exhibit little to no response.

AVP is also used for treatment of certain bleeding disorders such as mild hemophilia A and mild to moderate von Willebrand’s disease. AVP increases circulating concentrations of factor VIII (antihemophilic factor; see Chapter 26), perhaps by stimulating its release from cells in the vascular endothelium. Desmopressin is used for treatment of acute bleeding in patients with platelet dysfunction caused by uremia and is preferred to AVP because of its lack of vasopressor activity.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Side effects and clinical problems associated with the use of the hypothalamic and pituitary hormones and their analogs are summarized in the Clinical Problems Box.

Hypothalamic Hormones

GnRH is generally well tolerated, but occasionally nausea, light-headedness, headache, and abdominal discomfort are reported. SC administration is associated with antibody formation in a few patients. GnRH agonist and antagonist therapy is associated with hot flashes/flushes, decreased libido, fatigue, and decreased bone mineral density.

GI side effects such as nausea, vomiting, diarrhea, and abdominal cramps have been reported after treatment with native somatostatin. Hyperglycemia, hypoglycemia, and hypothyroidism caused by somatostatin inhibition of TSH may also be manifest. After discontinuing an IV infusion of somatostatin, rebound hypersecretion of GH, insulin, and glucagon can occur. Side effects of somatostatin analogs are similar to those of the native peptide. In addition, patients may develop gallbladder sludge or cholelithiasis.

When a dopamine agonist is first administered, patients may experience nausea, vomiting, dizziness, or orthostatic hypotension. These effects can be minimized if therapy is begun with low doses and the drug is taken with food and at bedtime, with a gradual increase in frequency to a full dose regimen. A few patients experience headache, fatigue, abdominal cramping, nasal congestion, drowsiness, or diarrhea.

Pituitary Hormones

The major adverse reactions of hMG are multiple gestation pregnancy and the ovarian hyperstimulation syndrome. Ovarian enlargement and extravascular accumulation of fluid resulting in ascites, pleural and pericardial effusions, renal failure, and hypovolemic shock are potentially life-threatening. Ovarian enlargement can be classified as mild, moderate, or severe; the incidence of massive ovarian enlargement of greater than 12 cm is rare (< 2%).

Administration of hGH can result in formation of anti-GH antibodies. Additional adverse effects include hyperglycemia, peripheral edema, arthralgias, paresthesias, and carpal tunnel syndrome. Benign intracranial hypertension (pseudotumor cerebri) has rarely been associated with children receiving hGH therapy. A dosage appropriate for size


Hypothalamic hormones and analogs


Breast tenderness, decreased sex drive; hot flashes/sweating; impotence

Occasional nausea or vomiting, headache, abdominal discomfort; difficulty sleeping

Anaphylaxis (rare) with IV use

Localized problems at injection site

Somatostatin analogs

Hyperglycemia, loose stools, gallstones

Dopamine agonists

Nausea, orthostatic hypotension initially

Confusion, headache, dizziness, drowsiness, faintness

Pituitary hormones and analogs

LH and FSH

Multiple gestation pregnancy

Gynecomastia in men

Occasional febrile reactions



Blurred vision, unusual tingling feelings, dizziness, nervousness, severe headache, altered heartbeat

Abuse in athletics


Nausea, vertigo, headache


Angina, myocardial infarction


Rare side effects include chills, confusion, drowsiness, convulsions, fever, breathing problems, skin rash

Drug interactions


Phenothiazine or butyrophenones: prevent dopamine agonist action

Vasopressin analogs

Carbamazepine, chlorpropamide, clofibrate, fludrocortisone, tricyclic antidepressants: potentiate action

Lithium, heparin, alcohol: inhibit action


(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Hypothalamic Hormones and Analogs

GnRH agonists

Buserelin (Suprefact)

Gonadorelin (Factrel)

Goserelin (Zoladex)

Histrelin (Supprelin)

Leuprolide (Lupron, Lupron Depot, Viadur)

Nafarelin (Synarel)

Triptorelin (Trelstar Depot, Trelstar LA)

GnRH Antagonists

Abarelix (Plenaxis)

Cetrorelix (Cetrotide)

Ganirelix (Antagon)

Dopamine Agonists

Bromocriptine (Parlodel)

Cabergoline (Dostinex)

Somatostatin Analog

Octreotide (Sandostatin, Sandostatin LAR)

Lanreotide (Somatuline LA)

Vapreotide (Sanvar IR)

Pituitary hormones and analogs

Growth hormone receptor antagonist; Pegvisomant (Somavert)

Desmopressin (DDAVP, Stimate nasal spray)

Vasopressin (Pitressin)

ADH receptor antagonists (Conivaptan, Tolvaptan, and Lixivaptan)

Clomiphene (Clomid, Milophene, Serophene)

Human chorionic gonadotropin (Ovidrel)

Human recombinant GH (Genotropin, Humatrope, Norditropin, Nutropin, Protropin, Saizen, Serostim)

LH-FSH (Pergonal, Repronex)

Urofollitropin (Bravelle, Fertinex, Follistim, Gonal-F, Metrodin)

and age must be used to prevent gigantism. Because hGH is potentially diabetogenic, care must be given when administering to a patient with a personal or family history of abnormal glucose tolerance.

Nonspecific adverse reactions to AVP that may occur include nausea, vertigo, headache, and anaphylaxis. Other signs and symptoms may relate directly to specific pressor and antidiuretic effects. Vasoconstriction may occur and cause relatively mild problems, such as skin blanching or abdominal cramping, or such life-threatening events as angina or myocardial infarction. All preparations should be used with caution in patients with coronary artery disease, but desmopressin has lower pressor effects and may be a drug of choice. All vasopressins may cause water retention and hyponatremia. Signs and symptoms of hyponatremia include drowsiness, listlessness, weakness, headaches, seizures, and coma, requiring close supervision.

Several drugs, if administered simultaneously, potentiate or inhibit the effects of AVP. Potentiators include carbamazepine, chlorpropamide, clofibrate, fludrocortisone, and tricyclic antidepressants; inhibitors include lithium carbonate, heparin, and alcohol.

New Horizons

There is a significant role for the use of long-acting depot forms of GnRH analogs to treat androgen-dependent neoplasms such as prostate cancer and to use GnRH agonist therapy to manage male and female infertility. Further, the ability of GnRH analogs to diminish gonadotropic hormones suggests a potential adjunct role in female and male contraception.


Anonymous. Cool.Click: A needle-free device for growth hormone delivery. Med Lett. 2001;43:2-3.

Anonymous. Pegvisomant (Somavert) for acromegaly. Med Lett. 2003;45:55-56.

Anonymous. Growth hormone for normal short children. Med Lett. 2003;45:89-90.

Additional information on this topic:



1. A pediatric patient with a medical history of syndrome of inappropriate antidiuretic hormone (SIADH) is being treated by Na+ replacement, loop diuretic, and fluid restriction. Because the pediatrician had eliminated lung cancer or infection and drug-induced disease, genetic testing was ordered and revealed an ADH receptor point mutation. Presently, current therapeutic intervention is not sustaining adequate blood levels of Na+. Considering this patient’s medical history, which of the following would be the best course of treatment to reduce the effect of the elevated ADH?

A. Add a mineralocorticoid to current regimen.

B. Administer an agent that antagonizes the transduction of ADH-ADH receptor interaction.

C. Introduce bromocriptine to suppress release of ADH.

D. Replace the loop diuretic with a Na+-sparing thiazide diuretic.

E. Use an ADH receptor antagonist to counter effects of elevated ADH.

2. A 4-year-old male child, who was seen by his pediatrician 1 year after a severe head trauma, was found to have severe growth retardation. Laboratory studies revealed a profound GH deficiency. GH replacement therapy was started, and the parents were trained how to properly administer GH. Although normal circulating levels of GH could be attained, a normal growth rate was not achieved. Considering his medical history, which of the following is the most likely explanation for failure of GH replacement?

A. Decreased GH receptor expression.

B. Development of secondary hypothyroidism.

C. Loss of dopaminergic stimulation of the anterior pituitary.

D. Hypersecretion of somatostatin.

E. Onset of GH insensitivity leading to suppressed IGF-1 levels.

3. Treatment of patients with acromegaly before surgery can involve the administration of long-acting somatostatin analogs or alternatively GH hormone receptor antagonists. Which of the following is the primary advantage of GH receptor antagonists compared with long-acting somatostatin analogs?

A. Blockade of GH receptors reduces size of pituitary macroadenomas.

B. Does not form active metabolites.

C. Independent of responsiveness of GH-secreting tumor.

D. Least likely to form autoantibodies.

E. Not susceptible to proteolysis like a somatostatin analog.

4. To treat central diabetes insipidus, which of the following is the primary advantage of desmopressin compared with arginine vasopressin?

A. Has greater affinity for the vasopressin receptor.

B. Increased duration of action regardless of route of administration.

C. Less likely to form autoantibodies because it is a synthetic compound.

D. More effectively controls polyuria, polydipsia, and dehydration.

E. Reduced incidence of cardiovascular side effects.