Acronyms

ACTH: Adrenocorticotropic hormone (corticotropin)

CRH: Corticotropin-releasing hormone

FSH: Follicle-stimulating hormone

GH: Growth hormone

GHRH: Growth hormone-releasing hormone

GnRH: Gonadotropin-releasing hormone

hCG: Human chorionic gonatropin

hMG: Human menopausal gonadotropins

IGF: Insulin-like growth factor

LH: Luteinizing hormone

PRL: Prolactin

rhGH: Recombinant human growth hormone

SST: Somatostatin

TRH: Thyrotropin-releasing hormone

TSH: Thyroid-stimulating hormone (thyrotropin)

^*The author is grateful for the contributions of the previous author, Dr. P. A. Fitzgerald.

Case Study

An 8-year-old, 23-kg (50.7-lb) girl presents with Turner syndrome, a genetic disorder with partial or complete absence of one X chromosome. Karyotyping reveals a 45,X karyotype. At the time of her diagnosis, she is in the second percentile for height and has a bone age of 6.8 years. In addition to her short stature, she has a bicuspid aortic valve and orthodontic anomalies characteristic of the syndrome. She is doing well in school and seems well adjusted socially. Her thyroid function is normal. Although girls with Turner syndrome have normal growth hormone (GH) levels, they have reduced responsiveness to GH that often responds to supraphysiologic concen-trations of the hormone. The patient is started on a daily dose of 0.05 mg/kg of subcutaneously administered recombinant human GH (Humatrope). After 1 year of therapy, her height velocity has increased from 4.0 cm/year to 8.2 cm/year. To help this patient achieve a maximal final height, the plan is to continue GH treatment until she reaches a bone age of 14 years and to begin estrogen supplementation when she reaches age 12. How does recombinant GH stimulate growth in children? Why is this patient likely to also require supplementation with estrogen?

Hypothalamic & Pituitary Hormones: Introduction

The control of metabolism, growth, and reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland. The pituitary weighs about 0.6 g and rests at the base of the brain in the bony sella turcica near the optic chiasm and the cavernous sinuses. The pituitary consists of an anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis) (Figure 37–1). It is connected to the overlying hypothalamus by a stalk of neurosecretory fibers and blood vessels, including a portal venous system that drains the hypothalamus and perfuses the anterior pituitary. The portal venous system carries small regulatory hormones (Figure 37–1, Table 37–1) from the hypothalamus to the anterior pituitary.

The posterior lobe hormones are synthesized in the hypothalamus and transported via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe, from which they are released into the circulation.

Drugs that mimic or block the effects of hypothalamic and pituitary hormones have pharmacologic applications in three primary areas: (1) as replacement therapy for hormone deficiency states; (2) as antagonists for diseases that result from excess production of pituitary hormones; and (3) as diagnostic tools for identifying several endocrine abnormalities.

Anterior Pituitary Hormones & Their Hypothalamic Regulators

All the hormones produced by the anterior pituitary except prolactin (PRL) are key participants in hormonal systems in which they regulate the production by peripheral tissues of hormones that perform the ultimate regulatory functions. In these systems, the secretion of the pituitary hormone is under the control of a hypothalamic hormone. Each hypothalamic-pituitary-endocrine gland system or axis provides multiple opportunities for complex neuroendocrine regulation of growth, development, and reproductive functions.

Anterior Pituitary & Hypothalamic Hormone Receptors

The anterior pituitary hormones can be classified according to hormone structure and the types of receptors that they activate. Growth hormone(GH) and prolactin, single-chain protein hormones with significant homology, form one group. Both hormones activate receptors of the JAK/STAT superfamily (see Chapter 2). Three pituitary hormones— thyroid-stimulating hormone (TSH, thyrotropin), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)—are dimeric proteins that activate G protein-coupled receptors (see Chapter 2). TSH, FSH, and LH share a common chain. Their chains, though somewhat similar to each other, differ enough to confer receptor specificity. Finally, adrenocorticotropic hormone (ACTH), a single peptide that is cleaved from a larger precursor that also contains the peptide -endorphin (see Chapter 31), represents a third category. It does, however, like TSH, LH, and FSH, act through a G protein-coupled receptor.

TSH, FSH, LH, and ACTH share similarities in the regulation of their release from the pituitary. Each is under the control of a distinctive hypothalamic peptide that stimulates their production by acting on G protein-coupled receptors (Table 37–1). TSH release is regulated by thyrotropin-releasing hormone (TRH), whereas the release of LH and FSH (known collectively as gonadotropins) is stimulated by pulses of gonadotropin-releasing hormone (GnRH). ACTH release is stimulated by corticotropin-releasing hormone (CRH). The final important regulatory feature shared by these three structurally related hormones is that they and their hypothalamic releasing factors are subject to feedback inhibitory regulation by the hormones whose production they control. TSH and TRH production is inhibited by the two key thyroid hormones, thyroxine and triiodothyronine (see Chapter 38). Gonadotropin and GnRH production is inhibited in women by estrogen and progesterone, and in men by androgens such as testosterone. Production of ACTH is inhibited by cortisol. Feedback regulation is critical to the physiologic control of thyroid, adrenal cortical, and gonadal function and is also important in pharmacologic treatments that affect these systems.

The hypothalamic hormonal control of GH and prolactin differs from the regulatory system for TSH, FSH, LH, and ACTH. The hypothalamus secretes two hormones that regulate GH; growth hormone-releasing hormone (GHRH) stimulates GH production, whereas the peptide somatostatin (SST) inhibits GH production. GH and its primary peripheral mediator, insulin-like growth factor-1 (IGF-1), also provide feedback to inhibit GH release. Prolactin production is inhibited by the catecholamine dopamine acting through the D₂ subtype of dopamine receptors. The hypothalamus does not produce a hormone that stimulates prolactin production.

Whereas all the pituitary and hypothalamic hormones described previously are available for use in humans, only a few are of major clinical importance. Because of the greater ease of administration of target endocrine gland hormones or their synthetic analogs, the related hypothalamic and pituitary hormones (TRH, TSH, CRH, ACTH, GHRH) are either not used clinically or are used rarely for specialized diagnostic testing. These agents are described in Tables 37–2 and 37–3 and are not discussed further in this chapter. In contrast, GH, SST, LH, FSH, GnRH, and dopamine or analogs of these hormones are commonly used and are described in the following text.

Growth Hormone (Somatotropin)

Growth hormone, one of the peptide hormones produced by the anterior pituitary, is required during childhood and adolescence for attainment of normal adult size and has important effects throughout postnatal life on lipid and carbohydrate metabolism, and on lean body mass. Its effects are primarily mediated via insulin-like growth factor 1 (IGF-1, somatomedin C) and, to a lesser extent, both directly and through insulin-like growth factor 2 (IGF-2). Individuals with congenital or acquired deficiency of GH during childhood or adolescence fail to reach their predicted adult height and have disproportionately increased body fat and decreased muscle mass. Adults with GH deficiency also have disproportionately low lean body mass.

Chemistry & Pharmacokinetics

Structure

Growth hormone is a 191-amino-acid peptide with two sulfhydryl bridges. Its structure closely resembles that of prolactin. In the past, medicinal GH was isolated from the pituitaries of human cadavers. However, this form of GH was found to be contaminated with prions that could cause Creutzfeldt-Jakob disease. For this reason, it is no longer used. Somatropin , the recombinant form of GH, has a 191-amino acid sequence that is identical with the predominant native form of human GH.

Absorption, Metabolism, and Excretion

Circulating endogenous GH has a half-life of 20–25 minutes and is predominantly cleared by the liver. Recombinant human GH (rhGH) is administered subcutaneously 3–7 times per week. Peak levels occur in 2–4 hours and active blood levels persist for approximately 36 hours.

Pharmacodynamics

Growth hormone mediates its effects via cell surface receptors of the JAK/STAT cytokine receptor superfamily. Dimerization of two GH receptors is stimulated by a single GH molecule and activates signaling cascades mediated by receptor-associated JAK tyrosine kinases and STATs (see Chapter 2). GH has complex effects on growth, body composition, and carbohydrate, protein, and lipid metabolism. The growth-promoting effects are mediated through an increase in the production of IGF-1. Much of the circulating IGF-1 is produced in the liver. GH also stimulates production of IGF-1 in bone, cartilage, muscle, and the kidney, where it plays autocrine or paracrine roles. GH stimulates longitudinal bone growth until the epiphyses close—near the end of puberty. In both children and adults, GH has anabolic effects in muscle and catabolic effects in lipid cells that shift the balance of body mass to an increase in muscle mass and a reduction in central adiposity. The effects of GH on carbohydrate metabolism are mixed, in part because GH and IGF-1 have opposite effects on insulin sensitivity. GH reduces insulin sensitivity, which results in mild hyperinsulinemia. In contrast, in patients who are unable to respond to endogenous GH because of mutated GH receptors, IGF-1 acting through its own IGF-1 receptors and through insulin receptors lowers serum glucose and reduces circulating insulin.

Clinical Pharmacology

Growth Hormone Deficiency

GH deficiency can have a genetic basis or can be acquired as a result of damage to the pituitary or hypothalamus by a tumor, infection, surgery, or radiation therapy. In childhood, GH deficiency presents as short stature and adiposity. (Neonates with isolated GH deficiency are of normal size at birth, presumably because fetal GH is not required for normal prenatal growth.) Another early sign of GH deficiency is hypoglycemia due to unopposed action of insulin, to which young children are especially sensitive. Criteria for diagnosis of GH deficiency usually include (1) a growth rate below 4 cm per year and (2) the absence of a serum GH response to two GH secretagogues. The incidence of congenital GH deficiency is approximately 1:4000 live births. Therapy with rhGH permits many children with short stature due to GH deficiency to achieve normal adult height.

In the past, it was believed that adults with GH deficiency do not exhibit a significant syndrome. However, more detailed studies suggest that adults with GH deficiency often have generalized obesity, reduced muscle mass, asthenia, and reduced cardiac output. GH-deficient adults who have been treated with GH have been shown to experience a reversal of many of these manifestations.

Growth Hormone Treatment of Pediatric Patients with Short Stature

Although the greatest improvement in growth occurs in patients with GH deficiency, exogenous GH has some effect on height in children with short stature that is due to factors other than GH deficiency. GH has been approved for several conditions (Table 37–4) and has been used experimentally or off-label in many others. Prader-Willi syndrome is an autosomal dominant genetic disease that is associated with growth failure, obesity, and carbohydrate intolerance. In pediatric patients with Prader-Willi syndrome and growth failure, GH treatment decreases body fat and increases lean body mass, linear growth, and energy expenditure.

GH treatment has also been shown to have a strong beneficial effect on final height of girls with Turner syndrome, the syndrome associated with a 45,X karyotype. In clinical trials, GH treatment has been shown to increase final height in girls with Turner syndrome by 10–15 cm (4–6 inches). Because girls with Turner syndrome also have either absent or rudimentary ovaries, GH must be judiciously combined with gonadal steroids to achieve the maximal height effect, as in the case study patient. Other conditions of growth failure for which GH treatment is approved include chronic renal failure in pediatric patients and small-for-gestational-age condition at birth in which the child has failed to catch up by age 2. In all of these pediatric patients as well as in patients with GH deficiency, it is critical to start GH treatment before the long bone epiphyses have closed.

The most controversial approved use of GH is for children with idiopathic short stature, also known as non–growth-hormone-deficient short stature. This is a heterogeneous population that is defined clinically by a height that is 2.25 standard deviations or more below the national norm for children of the same age. Eligible children also have growth rates that are unlikely to result in an adult height in the normal range and the absence of a condition known to be associated with impaired growth. In this group of children, many years of GH therapy result in an average increase in adult height of 4–7 cm (1.57–2.76 inches) at an average cost of $35,000 per inch of height gained. The complex issues involved in the cost-risk-benefit relationship of this use of GH are important because an estimated 400,000 children in the USA fit the diagnostic criteria for idiopathic short stature.

Treatment of children with short stature should be carried out by specialists experienced in the use of GH. Treatment is begun with 0.025 mg/kg daily and may be increased to a maximum of 0.045 mg/kg daily. Children must be observed closely for slowing of growth velocity, which could indicate a need to increase the dosage or the possibility of epiphyseal fusion or intercurrent problems such as hypothyroidism or malnutrition. Children with Turner syndrome or chronic renal insufficiency require somewhat higher doses.

Other Uses of Growth Hormone

Growth hormone affects many organ systems and also has a net anabolic effect. It has been tested in a number of conditions that are associated with a severe catabolic state and is approved for the treatment of wasting in patients with AIDS. In 2004, GH was approved for treatment of patients with short bowel syndrome who are dependent on total parenteral nutrition (TPN). After intestinal resection or bypass, the remaining functional intestine in many patients undergoes extensive adaptation that allows it to adequately absorb nutrients. However, other patients fail to adequately adapt and develop a malabsorption syndrome. GH has been shown in experimental animals to increase intestinal growth and improve its function. Results of GH treatment of patients with short bowel syndrome and dependence on total parenteral nutrition have been mixed in the clinical studies that have been published to date. Growth hormone is administered with glutamine, which also has trophic effects on the intestinal mucosa.

GH is a popular component of anti-aging programs. Serum levels of GH normally decline with aging; anti-aging programs claim that injection of GH or administration of drugs purported to increase GH release are effective anti-aging remedies. These claims are largely unsubstantiated. It is interesting that a number of studies in mice and the nematode C elegans have clearly demonstrated that analogs of human GH and IGF-1 consistently shorten life span and that loss-of-function mutations in the signaling pathways for the GH and IGF-1 analogs lengthen life span. Another use of GH is by athletes for a purported increase in muscle mass and athletic performance. GH is one of the drugs banned by the Olympic Committee.

Although GH has important effects on lipid and carbohydrate metabolism and on lean body mass, it does not seem likely to be a fruitful direct target for efforts to develop new drugs to treat obesity. However, some of the hormonal and neuroendocrine systems that regulate GH secretion are being investigated as possible targets for antiobesity drugs (see Treatment of Obesity).

In 1993, the FDA approved the use of recombinant bovine growth hormone (rbGH) in dairy cattle to increase milk production. Although milk and meat from rbGH-treated cows appear to be safe, these cows have a higher incidence of mastitis, which could increase antibiotic use and result in greater antibiotic residues in milk and meat.

Toxicity & Contraindications

Children generally tolerate GH treatment well. A rarely reported adverse effect is intracranial hypertension, which may manifest as vision changes, headache, nausea, or vomiting. Some children develop scoliosis during rapid growth. Patients with Turner syndrome have an increased risk of otitis media while taking GH. Hypothyroidism is commonly discovered during GH treatment, so periodic assessment of thyroid function is indicated. Pancreatitis, gynecomastia, and nevus growth have occurred in patients receiving GH. Adults tend to have more adverse effects from GH therapy. Peripheral edema, myalgias, and arthralgias (especially in the hands and wrists) occur commonly but remit with dosage reduction. Carpal tunnel syndrome can occur. GH treatment increases the activity of cytochrome P450 isoforms, which could reduce the serum levels of drugs metabolized by that enzyme system (see Chapter 4). There has been no increased incidence of malignancy among patients receiving GH therapy, but GH treatment is contraindicated in a patient with a known malignancy. Proliferative retinopathy may rarely occur. GH treatment of critically ill patients appears to increase mortality.

Mecasermin

A small number of children with growth failure have severe IGF-1 deficiency that is not responsive to exogenous GH. Causes include mutations in the GH receptor and development of neutralizing antibodies to GH. In 2005, the FDA approved mecasermin for treatment of severe IGF-1 deficiency that is not responsive to GH. Mecasermin is a complex of recombinant human IGF-1 (rhIGF-1) and recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3). The IGF-1 activates transmembrane receptors that, like insulin and EGF receptors, manifest tyrosine kinase activity at their intracellular domains (see Chapters 2 and 41). The binding protein rhIGFBP-3 is needed to maintain an adequate half-life of rhIGF-1. Normally, over 80% of the circulating IGF-1 is bound to IGFBP-3, which is produced by the liver under the control of GH. Patients with severe IGF-1 deficiency that is secondary to aberrant GH signaling also have deficiency of IGFBP-3, so it is important to supply this with the IGF-1 replacement. Mecasermin is administered subcutaneously twice daily at a recommended starting dosage of 0.04–0.08 mg/kg and increased weekly up to a maximum twice-daily dosage of 0.12 mg/kg.

The most important adverse effect observed with mecasermin is hypoglycemia. To avoid hypoglycemia, the prescribing instructions require consumption of a meal or snack 20 minutes before or after mecasermin administration. Several patients have experienced intracranial hypertension and asymptomatic elevation of liver enzymes.

Growth Hormone Antagonists

The need for antagonists of GH stems from the tendency of GH-producing cells (somatotrophs) in the anterior pituitary to form secreting tumors. Pituitary adenomas occur most commonly in adults. In adults, GH-secreting adenomas cause acromegaly, which is characterized by abnormal growth of cartilage and bone tissue, and many organs including skin, muscle, heart, liver, and the gastrointestinal tract. Acromegaly adversely affects the skeletal, muscular, cardiovascular, respiratory, and metabolic systems. When a GH-secreting adenoma occurs before the long bone epiphyses close, it leads to the rare condition, gigantism. Small GH-secreting adenomas can be treated with GH antagonists. Somatostatin analogs and dopamine receptor agonists reduce the production of GH, whereas the novel GH receptor antagonist pegvisomant prevents GH from activating its receptor. Larger pituitary adenomas, which produce greater amounts of GH and also can impair visual and central nervous system function by encroaching on nearby brain structures, are treated with transsphenoidal surgery or radiation.

Somatostatin Analogs

Somatostatin, a 14-amino-acid peptide (Figure 37–2), is found in the hypothalamus, other parts of the central nervous system, the pancreas, and other sites in the gastrointestinal tract. It inhibits the release of GH, glucagon, insulin, and gastrin.

Exogenous somatostatin is rapidly cleared from the circulation, with an initial half-life of 1–3 minutes. The kidney appears to play an important role in its metabolism and excretion.

Somatostatin has limited therapeutic usefulness because of its short duration of action and its multiple effects in many secretory systems. A series of longer-acting somatostatin analogs that retain biologic activity have been developed. Octreotide, the most widely used somatostatin analog (Figure 37–2), is 45 times more potent than somatostatin in inhibiting GH release but only twice as potent in reducing insulin secretion. Because of this relatively reduced effect on pancreatic beta cells, hyperglycemia rarely occurs during treatment. The plasma elimination half-life of octreotide is about 80 minutes, 30 times longer in humans than that of somatostatin.

Octreotide, 50–200 mcg given subcutaneously every 8 hours, reduces symptoms caused by a variety of hormone-secreting tumors: acromegaly; the carcinoid syndrome; gastrinoma; glucagonoma; nesidioblastosis; the watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome; and diabetic diarrhea. Somatostatin receptor scintigraphy, using radiolabeled octreotide, is useful in localizing neuroendocrine tumors having somatostatin receptors and helps predict the response to octreotide therapy. Octreotide is also useful for the acute control of bleeding from esophageal varices.

Octreotide acetate injectable long-acting suspension is a slow-release microsphere formulation. It is instituted only after a brief course of shorter-acting octreotide has been demonstrated to be effective and tolerated. Injections into alternate gluteal muscles are repeated at 4-week intervals in doses of 20–40 mg.

Adverse effects of octreotide therapy include nausea, vomiting, abdominal cramps, flatulence, and steatorrhea with bulky bowel movements. Biliary sludge and gallstones may occur after 6 months of use in 20–30% of patients. However, the yearly incidence of symptomatic gallstones is about 1%. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%). Pain at the site of injection is common, especially with the long-acting octreotide suspension. Vitamin B12 deficiency may occur with long-term use of octreotide.

A long-acting formulation of lanreotide, another octapeptide somatostatin analog, was approved by the FDA in 2007 for treatment of acromegaly. Lanreotide appears to have effects comparable to those of octreotide on reducing GH levels and normalizing IGF-1 concentrations.

Pegvisomant

Pegvisomant is a GH receptor antagonist that is useful for the treatment of acromegaly. Pegvisomant is the polyethylene glycol (PEG) derivative of a mutant GH, B2036, which has increased affinity for one site of the GH receptor but a reduced affinity at its second binding site. This allows dimerization of the receptor but blocks the conformational changes required for signal transduction. Pegvisomant is a less potent GH receptor antagonist than is B2036, but pegylation reduces its clearance and improves its overall clinical effectiveness. When pegvisomant was administered subcutaneously to 160 patients with acromegaly daily for 12 months or more, serum levels of IGF-1 fell into the normal range in 97%; two patients experienced growth of their GH-secreting pituitary tumors, and two patients developed increases in liver enzymes.

The Gonadotropins (Follicle-Stimulating Hormone & Luteinizing Hormone) & Human Chorionic Gonadotropin

The gonadotropins are produced by a single type of pituitary cell, the gonadotroph. These hormones serve complementary functions in the reproductive process. In women, the principal function of FSH is to direct ovarian follicle development. Both FSH and LH are needed for ovarian steroidogenesis. In the ovary, LH stimulates androgen production by theca cells in the follicular stage of the menstrual cycle, whereas FSH stimulates the conversion by granulosa cells of androgens to estrogens. In the luteal phase of the menstrual cycle, estrogen and progesterone production is primarily under the control first of LH and then, if pregnancy occurs, under the control of human chorionic gonadotropin (hCG). Human chorionic gonadotropin is a placental protein nearly identical with LH; its actions are mediated through LH receptors.

In men, FSH is the primary regulator of spermatogenesis, whereas LH is the main stimulus for the production of testosterone by Leydig cells. FSH helps to maintain high local androgen concentrations in the vicinity of developing sperm by stimulating the production of androgen-binding protein by Sertoli cells. FSH also stimulates the conversion by Sertoli cells of testosterone to estrogen.

FSH, LH, and hCG are commercially available in several forms. They are used in states of infertility to stimulate spermatogenesis in men and to induce ovulation in women. Their most common clinical use is for the controlled ovulation hyperstimulation that is the cornerstone of assisted reproductive technologies such as in vitro fertilization (IVF, see below).

Chemistry & Pharmacokinetics

All three hormones—FSH, LH, and hCG—are heterodimers that share an identical chain in addition to a distinct chain that confers receptor specificity. The chains of hCG and LH are nearly identical, and these two hormones are used interchangeably. All the gonadotropin preparations are administered by subcutaneous or intramuscular injection, usually on a daily basis. Half-lives vary by preparation and route of injection from 10 to 40 hours.

Menotropins

The first commercial gonadotropin product was extracted from the urine of postmenopausal women, which contains a substance with FSH-like properties (but with 4% of the potency of FSH) and an LH-like substance. This purified extract of FSH and LH is known as menotropins, or human menopausal gonadotropins (hMG).

Follicle-Stimulating Hormone

Three forms of purified FSH are available. Urofollitropin, also known as uFSH, is a purified preparation of human FSH that is extracted from the urine of postmenopausal women. Virtually all the LH activity has been removed through a form of immunoaffinity chromatography that uses anti-hCG antibodies. Two recombinant forms of FSH (rFSH) are also available: follitropin alfa and follitropin beta. The amino acid sequences of these two products are identical to that of human FSH. They differ from each other and urofollitropin in the composition of the carbohydrate side chains. The rFSH preparations have a shorter half-life than preparations derived from human urine but stimulate estrogen secretion at least as efficiently and, in some studies, more efficiently. The rFSH preparations are considerably more expensive.

Luteinizing Hormone

Lutropin alfa, the recombinant form of human LH, was introduced in the USA in 2004. When given by subcutaneous injection, it has a half-life of about 10 hours. Lutropin has only been approved for use in combination with follitropin alfa for stimulation of follicular development in infertile women with profound LH deficiency. It has not been approved for use with the other preparations of FSH nor for simulating the endogenous LH surge that is needed to complete follicular development and precipitate ovulation.

Human Chorionic Gonadotropin

hCG is produced by the human placenta and excreted into the urine, whence it can be extracted and purified. It is a glycoprotein consisting of a 92-amino-acid chain virtually identical to that of FSH, LH, and TSH, and a chain of 145 amino acids that resembles that of LH except for the presence of a carboxyl terminal sequence of 30 amino acids not present in LH. Choriogonadotropin alfa (rhCG) is a recombinant form of hCG. Because of its greater consistency in biologic activity, rhCG is packaged and dosed on the basis of weight rather than units of activity. All of the other gonadotropins, including rFSH, are packaged and dosed on the basis of units of activity. The preparation of hCG that is purified from human urine is administered by intramuscular injection, whereas rhCG is administered by subcutaneous injection.

Pharmacodynamics

The gonadotropins and hCG exert their effects through G protein-coupled receptors. LH and FSH have complex effects on reproductive tissues in both sexes. In women, these effects change over the time course of a menstrual cycle as a result of a complex interplay between concentration-dependent effects of the gonadotropins, cross-talk between LH, FSH, and gonadal steroids, and the influence of other ovarian hormones. A coordinated pattern of FSH and LH secretion during the menstrual cycle (see Figure 40–1) is required for normal follicle development, ovulation, and pregnancy.

During the first 8 weeks of pregnancy, the progesterone and estrogen required to maintain pregnancy are produced by the ovarian corpus luteum. For the first few days after ovulation, the corpus luteum is maintained by maternal LH. However, as maternal LH concentrations fall owing to increasing concentrations of progesterone and estrogen, the corpus luteum will continue to function only if the role of maternal LH is taken over by hCG produced by the embryo and its new placenta.

Clinical Pharmacology

Ovulation Induction

The gonadotropins are used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other causes. Because of the high cost of gonadotropins and the need for close monitoring during their administration, gonadotropins are generally reserved for anovulatory women who fail to respond to other less complicated forms of treatment (eg, clomiphene; see Chapter 40). Gonadotropins are also used for controlled ovarian hyperstimulation in assisted reproductive technology procedures. A number of protocols make use of gonadotropins in ovulation induction and controlled ovulation hyperstimulation, and new protocols are continually being developed to improve the rates of success and to decrease the two primary risks of ovulation induction: multiple pregnancies and the ovarian hyperstimulation syndrome (OHSS; see below).

Although the details differ, all of these protocols are based on the complex physiology that underlies a normal menstrual cycle. Like a menstrual cycle, ovulation induction is discussed in relation to a cycle that begins on the first day of a menstrual bleed (Figure 37–3). Shortly after the first day (usually on day 3), daily injections with one of the FSH preparations (hMG, urofollitropin) are begun and are continued for approximately 7–12 days. In women with hypogonadotropic hypogonadism, follicle development requires treatment with a combination of FSH and LH because these women do not produce the basal level of LH that is required for adequate ovarian estrogen production and normal follicle development. The dose and duration of FSH treatment are based on the response as measured by the serum estradiol concentration and by ultrasound evaluation of ovarian follicle development and endometrial thickness. When exogenous gonadotropins are used to stimulate follicle development, there is risk of a premature endogenous surge in LH owing to the rapidly changing hormonal milieu. To prevent this, gonadotropins are almost always administered in conjunction with a drug that blocks the effects of endogenous GnRH—either continuous administration of a GnRH agonist, which down-regulates GnRH receptors, or a GnRH receptor antagonist (see below and Figure 37–3).

When appropriate follicular maturation has occurred, the FSH and GnRH agonist or GnRH antagonist injections are discontinued; the following day, hCG (5000–10,000 IU) is administered intramuscularly to induce final follicular maturation and, in ovulation induction protocols, ovulation. The hCG administration is followed by insemination in ovulation induction and by oocyte retrieval in assisted reproductive technology procedures. Because use of GnRH agonists or antagonists during the follicular phase of ovulation induction suppresses endogenous LH production, it is important to provide exogenous hormonal support of the luteal phase. In clinical trials, exogenous progesterone, hCG, or a combination of the two have been effective at providing adequate luteal support. However, progesterone is preferred for luteal support because hCG carries a higher risk of the ovarian hyperstimulation syndrome (see below).

Male Infertility

Most of the signs and symptoms of hypogonadism in males (eg, delayed puberty, retention of prepubertal secondary sex characteristics after puberty) can be adequately treated with exogenous androgen; however, treatment of infertility in hypogonadal men requires the activity of both LH and FSH. For many years, conventional therapy has consisted of initial treatment for 8–12 weeks with injections of 1000–2500 IU hCG several times per week. After the initial phase, hMG is injected at a dose of 75–150 units three times per week. In men with hypogonadal hypogonadism, it takes an average of 4–6 months of such treatment for sperm to appear in the ejaculate. With the more recent availability of urofollitropin, rFSH, and rLH, a number of alternative protocols have been developed. An advance that has indirectly benefited gonadotropin treatment of male infertility is intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature oocyte that has been retrieved after controlled ovarian hyperstimulation of a female partner. With the advent of ICSI, the minimum threshold of spermatogenesis required for pregnancy is greatly lowered.

Toxicity & Contraindications

In women treated with gonadotropins and hCG, the two most serious complications are the ovarian hyperstimulation syndrome and multiple pregnancies. Overstimulation of the ovary during ovulation induction often leads to uncomplicated ovarian enlargement that usually resolves spontaneously. The ovarian hyperstimulation syndrome is a more serious complication that occurs in 0.5–4% of patients. It is characterized by ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in shock. Hemoperitoneum (from a ruptured ovarian cyst), fever, and arterial thromboembolism can occur.

The probability of multiple pregnancies is greatly increased when ovulation induction and assisted reproductive technologies are used. In ovulation induction, the risk of multiple pregnancy is estimated to be 15–20%, whereas the percentage of multiple pregnancies in the general population is closer to 1%. Multiple pregnancies carry an increased risk of complications, such as gestational diabetes, preeclampsia, and preterm labor. For in vitro fertilization procedures, the risk of multiple pregnancy is primarily determined by the number of embryos transferred to the recipient. A strong trend in recent years has been to transfer fewer embryos.

Other reported adverse effects of gonadotropin treatment are headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG. In men treated with gonadotropins, the risk of gynecomastia is directly correlated with the level of testosterone produced in response to treatment. An association between ovarian cancer, infertility, and fertility drugs has been reported. However, it is not known which, if any, fertility drugs are causally related to cancer.

Gonadotropin-Releasing Hormone & Its Analogs

Gonadotropin-releasing hormone is secreted by neurons in the hypothalamus. It travels through the hypothalamic-pituitary venous portal plexus to the anterior pituitary, where it binds to G protein-coupled receptors on the plasma membranes of gonadotroph cells. Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH.

Sustained nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadism. GnRH agonists are used to produce gonadal suppression in men with prostate cancer. They are also used in women who are undergoing assisted reproductive technology procedures or who have a gynecologic problem that is benefited by ovarian suppression.

Chemistry & Pharmacokinetics

Structure

GnRH is a decapeptide found in all mammals. Gonadorelin  is an acetate salt of synthetic human GnRH. Synthetic analogs include goserelin, histrelin, leuprolide, nafarelin,  and triptorelin.  These analogs all have D-amino acids at position 6, and all but nafarelin have ethylamide substituted for glycine at position 10. Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin.

Pharmacokinetics

Gonadorelin can be administered intravenously or subcutaneously. GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant. The half-life of intravenous gonadorelin is 4 minutes, and the half-lives of subcutaneous and intranasal GnRH analogs are approximately 3 hours. The duration of clinical uses of GnRH agonists varies from a few days for ovulation induction to a number of years for treatment of metastatic prostate cancer. Therefore, preparations have been developed with a range of durations of action from several hours (for daily administration) to 1, 4, 6, or 12 months (depot forms).

Pharmacodynamics

The physiologic actions of GnRH exhibit complex dose-response relationships that change dramatically from the fetal period through the end of puberty. This is not surprising in view of the complex role that GnRH plays in normal reproduction, particularly in female reproduction. Pulsatile GnRH release occurs and is responsible for stimulating LH and FSH production during the fetal and neonatal period. Subsequently, from the age of 2 years until the onset of puberty, GnRH secretion falls off and the pituitary simultaneously exhibits very low sensitivity to GnRH. Just before puberty, an increase in the frequency and amplitude of GnRH release occurs and then, in early puberty, pituitary sensitivity to GnRH increases, which is due in part to the effect of increasing concentrations of gonadal steroids. In females, it usually takes several months to a year after the onset of puberty for the hypothalamic-pituitary system to produce an LH surge and ovulation. By the end of puberty, the system is well established so that menstrual cycles proceed at relatively constant intervals. The amplitude and frequency of GnRH pulses vary in a regular pattern through the menstrual cycle with the highest amplitudes occurring during the luteal phase and the highest frequency occurring late in the follicular phase. Lower pulse frequencies favor FSH secretion, whereas higher pulse frequencies favor LH secretion. Gonadal steroids as well as the peptide hormones activin and inhibin have complex modulatory effects on the gonadotropin response to GnRH.

In the pharmacologic use of GnRH and its analogs, pulsatile intravenous administration of gonadorelin every 1–4 hours stimulates FSH and LH secretion. Continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response. During the first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females; this initial phase is referred to as a flare. After this period, the continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids. The inhibitory action is due to a combination of receptor down-regulation and changes in the signaling pathways activated by GnRH.

Clinical Pharmacology

The GnRH agonists are occasionally used for stimulation of gonadotropin production. They are used far more commonly for suppression of gonadotropin release.

Stimulation

Female Infertility

In the current era of widespread availability of gonadotropins and assisted reproductive technology, the use of pulsatile GnRH administration to treat infertility is uncommon. Although pulsatile GnRH is less likely than gonadotropins to cause multiple pregnancies and the ovarian hyperstimulation syndrome, the inconvenience and cost associated with continuous use of an intravenous pump and difficulties obtaining native GnRH (gonadorelin) are barriers to pulsatile GnRH. When this approach is used, a portable battery-powered programmable pump and intravenous tubing deliver pulses of gonadorelin every 90 minutes.

Gonadorelin or a GnRH agonist analog can be used to initiate an LH surge and ovulation in women with infertility who are undergoing ovulation induction with gonadotropins. Traditionally, hCG has been used to initiate ovulation in this situation. However, there is some evidence that gonadorelin or a GnRH agonist is less likely than hCG to cause multiple ova to be released and less likely to cause the ovarian hyperstimulation syndrome.

Male Infertility

It is possible to use pulsatile gonadorelin for infertility in men with hypothalamic hypogonadotropic hypogonadism. A portable pump infuses gonadorelin intravenously every 90 minutes. Serum testosterone levels and semen analyses must be done regularly. At least 3–6 months of pulsatile infusions are required before significant numbers of sperm are seen. The preferable alternative to intravenous gonadorelin treatment is the gonadotropin treatment with hCG and hMG or their recombinant equivalents described above.

Diagnosis of LH Responsiveness

GnRH can be useful in determining whether delayed puberty in a hypogonadotropic adolescent is due to constitutional delay or to hypogonadotropic hypogonadism. The LH response (but not the FSH response) to a single dose of GnRH can distinguish between these two conditions. Serum LH levels are measured before and at various times after an intravenous or subcutaneous bolus of GnRH. An increase in serum LH with a peak that exceeds 15.6 mIU/mL is normal and suggests impending puberty. An impaired LH response suggests hypogonadotropic hypogonadism due to either pituitary or hypothalamic disease, but does not rule out constitutional delay of adolescence.

Suppression of Gonadotropin Production

Controlled Ovarian Hyperstimulation

In the controlled ovarian hyperstimulation that provides multiple mature oocytes for assisted reproductive technologies such as in vitro fertilization, it is critical to suppress an endogenous LH surge that could prematurely trigger ovulation. This suppression is most commonly achieved by daily subcutaneous injections of leuprolide or daily nasal applications of nafarelin. For leuprolide, treatment is commonly initiated with 1.0 mg daily for about 10 days or until menstrual bleeding occurs. At that point, the dose is reduced to 0.5 mg daily until hCG is administered (Figure 37–3). For nafarelin, the beginning dosage is generally 400 mcg twice a day, which is decreased to 200 mcg when menstrual bleeding occurs. In women who respond poorly to the standard protocol, alternative protocols that use shorter courses and lower doses of GnRH agonists may improve the follicular response to gonadotropins.

Endometriosis

Endometriosis is a syndrome of cyclical abdominal pain in premenopausal women that is due to the presence of estrogen-sensitive endometrium-like tissue outside the uterus. The pain of endometriosis is often reduced by abolishing exposure to the cyclical changes in the concentrations of estrogen and progesterone that are a normal part of the menstrual cycle. The ovarian suppression induced by continuous treatment with a GnRH agonist greatly reduces estrogen and progesterone concentrations and prevents cyclical changes. The recommended duration of treatment with a GnRH agonist is limited to 6 months because ovarian suppression beyond this period can result in decreased bone density. Leuprolide, goserelin, and nafarelin are approved for this indication. Leuprolide and goserelin are administered as depot preparations that provide 1 or 3 months of continuous GnRH agonist activity. Nafarelin is administered twice daily as a nasal spray at a dose of 0.2 mg per spray.

Uterine Leiomyomata (Uterine Fibroids)

Uterine leiomyomata are benign, estrogen-sensitive, fibrous growths in the uterus that can cause menorrhagia, with associated anemia and pelvic pain. Treatment for 3–6 months with a GnRH agonist reduces fibroid size and, when combined with supplemental iron, improves anemia. Leuprolide, goserelin, and nafarelin are approved for this indication. The doses and routes of administration are similar to those described for treatment of endometriosis.

Prostate Cancer

Antiandrogen therapy is the primary medical therapy for prostate cancer. Combined antiandrogen therapy with continuous GnRH agonist and an androgen receptor antagonist such as flutamide (see Chapter 40) is as effective as surgical castration in reducing serum testosterone concentrations and effects. Leuprolide, goserelin, histrelin, and triptorelin are approved for this indication. The preferred formulation is one of the long-acting depot forms that provide 1, 3, 4, 6, or 12 months of active drug therapy. During the first 7–10 days of GnRH analog therapy, serum testosterone levels increase because of the agonist action of the drug; this can precipitate pain in patients with bone metastases, and tumor growth and neurologic symptoms in patients with vertebral metastases. It can also temporarily worsen symptoms of urinary obstruction. Such tumor flares can usually be avoided with the concomitant administration of bicalutamide or one of the other androgen receptor antagonists (see Chapter 40). Within about 2 weeks, serum testosterone levels fall to the hypogonadal range.

Central Precocious Puberty

Continuous administration of a GnRH agonist is indicated for treatment of central precocious puberty (onset of secondary sex characteristics before 8 years in girls or 9 years in boys). Before administering a GnRH agonist, one must confirm central precocious puberty by demonstrating a pubertal, not childhood, gonadotropin response to GnRH and a bone age at least 1 year beyond chronologic age. Pretreatment evaluation must also include gonadal steroid levels compatible with precocious puberty and not congenital adrenal hyperplasia; an hCG level that is low enough to exclude a chronic gonadotropin-secreting tumor; an MRI of the brain to exclude an intracranial tumor; and ultrasound examination of the adrenals and ovaries or testes to exclude a steroid-secreting tumor.

Treatment can be carried out with injections of leuprolide or nasal application of nafarelin. Leuprolide treatment is usually initiated at a dosage of 0.05 mg/kg body weight injected subcutaneously daily and then adjusted on the basis of the clinical response. Pediatric depot preparations of leuprolide are also available. The recommended initial dosage of nafarelin for central precocious puberty is 1.6 mg/d. This is achieved with two-unit dose sprays (each spray contains 0.1 mL, 0.2 mg) into each nostril twice daily. Treatment with a GnRH agonist is generally continued to age 11 in females and age 12 in males.

Other

Other clinical uses for the gonadal suppression provided by continuous GnRH agonist treatment include advanced breast and ovarian cancer; thinning of the endometrial lining in preparation for an endometrial ablation procedure in women with dysfunctional uterine bleeding; and treatment of amenorrhea and infertility in women with polycystic ovary disease.

Toxicity

Gonadorelin can cause headache, light-headedness, nausea, and flushing. Local swelling often occurs at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration. Rare acute hypersensitivity reactions include bronchospasm and anaphylaxis. Sudden pituitary apoplexy and blindness have been reported following administration of GnRH to a patient with a gonadotropin-secreting pituitary tumor.

Continuous treatment of women with a GnRH analog (leuprolide, nafarelin, goserelin) causes the typical symptoms of menopause, which include hot flushes, sweats, and headaches. Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur. Ovarian cysts may develop within the first 2 months of therapy and generally resolve after an additional 6 weeks; however, the cysts may persist and require discontinuation of therapy. Reduced bone density and osteoporosis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses. Depending on the condition being treated with the GnRH agonist, it may be possible to ameliorate the signs and symptoms of the hypoestrogenic state without losing clinical efficacy by adding back a small dose of a progestin and an estrogen. Contraindications to the use of GnRH agonists in women include pregnancy and breast-feeding.

In men treated with continuous GnRH agonist administration, adverse effects include hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, and injection site reactions. GnRH analog treatment of children is generally well tolerated. However, temporary exacerbation of precocious puberty may occur during the first few weeks of therapy. Nafarelin nasal spray may cause or aggravate sinusitis.

GnRH Receptor Antagonists

Four synthetic decapeptides that function as competitive antagonists of GnRH receptors are available for clinical use. Ganirelix, cetrorelix, abarelix, and degarelix inhibit the secretion of FSH and LH in a dose-dependent manner. Ganirelix and cetrorelix are approved for use in controlled ovarian hyperstimulation procedures, whereas abarelix and degarelix are approved for men with advanced prostate cancer.

Pharmacokinetics

Ganirelix and cetrorelix are absorbed rapidly after subcutaneous injection. Administration of 0.25 mg daily maintains GnRH antagonism. Alternatively, a single 3.0-mg dose of cetrorelix suppresses LH secretion for 96 hours. Abarelix is absorbed slowly after intramuscular injection and reaches a peak concentration 3 days after injection. It has a half-life of 13 days. After three initial doses on days 1, 13, and 28, abarelix is administered every 4 weeks.

Clinical Pharmacology

Suppression of Gonadotropin Production

GnRH antagonists are approved for preventing the LH surge during controlled ovarian hyperstimulation. They offer several advantages over continuous treatment with a GnRH agonist. Because GnRH antagonists produce an immediate antagonist effect, their use can be delayed until day 6–8 of the in vitro fertilization cycle (Figure 37–3), and thus the duration of administration is shorter. They also appear to have a less negative impact on the ovarian response to gonadotropin stimulation, which permits a decrease in the total duration and dose of gonadotropin. Finally, GnRH antagonists are associated with a lower risk of ovarian hyperstimulation syndrome, which can lead to cycle cancellation. On the other hand, because their antagonist effects reverse more quickly after their discontinuation, adherence to the treatment regimen is critical. The antagonists produce a more complete suppression of gonadotropin secretion than agonists. There is concern that the suppression of LH may inhibit ovarian steroidogenesis to an extent that impairs follicular development when recombinant or the purified form of FSH is used during the follicular phase of an in vitro fertilization cycle. Clinical trials have shown a slightly lower rate of pregnancy in in vitro fertilization cycles that used GnRH antagonist treatment compared with cycles that used GnRH agonist treatment.

Advanced Prostate Cancer

Abarelix is approved for the treatment of symptomatic advanced prostate cancer in men for whom a GnRH agonist is not appropriate (eg, in men who experience a severe tumor flare in response to the surge of LH and testosterone that occurs during the first 2–3 days of GnRH agonist therapy) and who decline surgical castration. This GnRH antagonist reduces concentrations of gonadotropins and androgens significantly more rapidly than GnRH agonists and avoids the testosterone surge seen with GnRH agonist therapy. Abarelix reduced symptoms in patients with vertebral or skeletal metastasis, or bladder outlet obstruction. Degarelix appears to be similar.

Toxicity

When used for controlled ovarian hyperstimulation, ganirelix and cetrorelix are well tolerated. The most common adverse effects are nausea and headache. During the treatment of men with prostate cancer, abarelix has elicited immediate-onset allergic responses that manifested as skin reactions or as hypotension and syncope, and it also prolonged the QT interval. Like continuous treatment with a GnRH agonist, abarelix leads to signs and symptoms of androgen deprivation, including hot flushes and sweats, gynecomastia, decreased libido, decreased hematocrit, and reduced bone density.

Prolactin

Prolactin is a 198-amino-acid peptide hormone produced in the anterior pituitary. Its structure resembles that of GH. Prolactin is the principal hormone responsible for lactation. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present. A deficiency of prolactin—which can occur in rare states of pituitary deficiency—is manifested by failure to lactate or by a luteal phase defect. In rare cases of hypothalamic destruction, prolactin levels may be elevated as a result of impaired transport of dopamine (prolactin-inhibiting hormone) to the pituitary. Much more commonly, however, prolactin is elevated as a result of prolactin-secreting adenomas. Hyperprolactinemia produces a syndrome of amenorrhea and galactorrhea in women, and loss of libido and infertility in men. In the case of large tumors (macroadenomas), it can be associated with symptoms of a pituitary mass, including visual changes due to compression of the optic nerves. The hypogonadism and infertility associated with hyperprolactinemia result from inhibition of GnRH release.

No preparation of prolactin is available for use in prolactin-deficient patients. For patients with symptomatic hyperprolactinemia, inhibition of prolactin secretion can be achieved with dopamine agonists, which act in the pituitary to inhibit prolactin release.

Dopamine Agonists

Adenomas that secrete excess prolactin usually retain the sensitivity to inhibition by dopamine exhibited by the normal pituitary. Bromocriptine and cabergoline are ergot derivatives (see Chapters 16 and 28) with a high affinity for dopamine D₂ receptors. Quinagolide, a drug approved in Europe, is a nonergot agent with similarly high D₂ receptor affinity. The chemical structure and pharmacokinetic features of ergot alkaloids are presented in Chapter 16.

Dopamine agonists suppress prolactin release very effectively in patients with hyperprolactinemia. GH release is reduced in patients with acromegaly, although not as effectively. Cabergoline and bromocriptine are also used in Parkinson's disease to improve motor function and reduce levodopa requirements (see Chapter 28). Newer, nonergot D₂ agonists used in Parkinson's disease (pramipexole and ropinirole; see Chapter 28) have been reported to interfere with lactation, but they are not approved for use in hyperprolactinemia.

Pharmacokinetics

All available dopamine agonists are active as oral preparations, and all are eliminated by metabolism. They can also be absorbed systemically after vaginal insertion of tablets. Cabergoline, with a half-life of approximately 65 hours, has the longest duration of action. Quinagolide has a half-life of about 20 hours, whereas the half-life of bromocriptine is about 7 hours. After vaginal administration, serum levels peak more slowly.

Clinical Pharmacology

Hyperprolactinemia

A dopamine agonist is the standard medical treatment for hyperprolactinemia. These drugs shrink pituitary prolactin-secreting tumors, lower circulating prolactin levels, and restore ovulation in approximately 70% of women with microadenomas and 30% of women with macroadenomas (Figure 37–4). Cabergoline is initiated at 0.25 mg twice weekly orally or vaginally. It can be increased gradually, according to serum prolactin determinations, up to a maximum of 1 mg twice weekly. Bromocriptine is generally taken daily after the evening meal at the initial dose of 1.25 mg; the dose is then increased as tolerated. Most patients require 2.5–7.5 mg daily. Long-acting oral bromocriptine formulations (Parlodel SRO) and intramuscular formulations (Parlodel L.A.R.) are available outside the USA.

Physiologic Lactation

Dopamine agonists were used in the past to prevent breast engorgement when breast-feeding was not desired. Their use for this purpose has been discouraged because of toxicity (see Toxicity & Contraindications).

Acromegaly

A dopamine agonist alone or in combination with pituitary surgery, radiation therapy, or octreotide administration can be used to treat acromegaly. The doses required are higher than those used to treat hyperprolactinemia. For example, patients with acromegaly require 20–30 mg/d of bromocriptine and seldom respond adequately to bromocriptine alone unless the pituitary tumor secretes prolactin as well as GH.

Toxicity & Contraindications

Dopamine agonists can cause nausea, headache, light-headedness, orthostatic hypotension, and fatigue. Psychiatric manifestations occasionally occur, even at lower doses, and may take months to resolve. Erythromelalgia occurs rarely. High dosages of ergot-derived preparations can cause cold-induced peripheral digital vasospasm. Pulmonary infiltrates have occurred with chronic high-dosage therapy. Cabergoline appears to cause nausea less often than bromocriptine. Vaginal administration can reduce nausea, but may cause local irritation.

Dopamine agonist therapy during the early weeks of pregnancy has not been associated with an increased risk of spontaneous abortion or congenital malformations. Although there has been a longer experience with the safety of bromocriptine during early pregnancy, there is growing evidence that cabergoline is also safe in women with macroadenomas who must continue a dopamine agonist during pregnancy. In patients with small pituitary adenomas, dopamine agonist therapy is discontinued upon conception because growth of microadenomas during pregnancy is rare. Patients with very large adenomas require vigilance for tumor progression and often require a dopamine agonist throughout pregnancy. There have been rare reports of stroke or coronary thrombosis in postpartum women taking bromocriptine to suppress postpartum lactation.

Posterior Pituitary Hormones

The two posterior pituitary hormones—vasopressin and oxytocin—are synthesized in neuronal cell bodies in the hypothalamus and transported via their axons to the posterior pituitary, where they are stored and then released into the circulation. Each has limited but important clinical uses.

Oxytocin

Oxytocin is a peptide hormone secreted by the posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women. During the second half of pregnancy, uterine smooth muscle shows an increase in the expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. Pharmacologic concentrations of oxytocin powerfully stimulate uterine contraction.

Chemistry & Pharmacokinetics

Structure

Oxytocin is a 9-amino-acid peptide with an intrapeptide disulfide cross-link (Figure 37–5). Its amino acid sequence differs from that of vasopressin at positions 3 and 8.

Absorption, Metabolism, and Excretion

Oxytocin is administered intravenously for initiation and augmentation of labor. It also can be administered intramuscularly for control of postpartum bleeding. Oxytocin is not bound to plasma proteins and is eliminated by the kidneys and liver, with a circulating half-life of 5 minutes.

Pharmacodynamics

Oxytocin acts through G protein-coupled receptors and the phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine contraction. Oxytocin in small doses increases both the frequency and the force of uterine contractions. At higher doses, it produces sustained contraction.

Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection. Without oxytocin-induced contraction, normal lactation cannot occur. At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors.

Clinical Pharmacology

Oxytocin is used to induce labor for conditions requiring early vaginal delivery such as Rh problems, maternal diabetes, preeclampsia, or ruptured membranes. It is also used to augment abnormal labor that is protracted or displays an arrest disorder. Oxytocin has several uses in the immediate postpartum period, including the control of uterine hemorrhage after vaginal or cesarean delivery. It is sometimes used during second-trimester abortions.

Before delivery, oxytocin is usually administered intravenously via an infusion pump with appropriate fetal and maternal monitoring. For induction of labor, an initial infusion rate of 0.5–2 mU/min is increased every 30–60 minutes until a physiologic contraction pattern is established. The maximum infusion rate is 20 mU/min. For postpartum uterine bleeding, 10–40 units are added to 1 L of 5% dextrose, and the infusion rate is titrated to control uterine atony. Alternatively, 10 units of oxytocin can be administered by intramuscular injection after delivery of the placenta.

During the antepartum period, oxytocin induces uterine contractions that transiently reduce placental blood flow to the fetus. The oxytocin challenge test measures the fetal heart rate response to a standardized oxytocin infusion and provides information about placental circulatory reserve. An abnormal response, seen as late decelerations in the fetal heart rate, indicates fetal hypoxia and may warrant immediate cesarean delivery.

Toxicity & Contraindications

When oxytocin is used judiciously, serious toxicity is rare. The toxicity that does occur is due either to excessive stimulation of uterine contractions or to inadvertent activation of vasopressin receptors. Excessive stimulation of uterine contractions before delivery can cause fetal distress, placental abruption, or uterine rupture. These complications can be detected early by means of standard fetal monitoring equipment. High concentrations of oxytocin with activation of vasopressin receptors can cause excessive fluid retention, or water intoxication, leading to hyponatremia, heart failure, seizures, and death. Bolus injections of oxytocin can cause hypotension. To avoid hypotension, oxytocin is administered intravenously as dilute solutions at a controlled rate.

Contraindications to oxytocin include fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, and other predispositions for uterine rupture.

Oxytocin Antagonist

Atosiban is an antagonist of the oxytocin receptor that has been approved outside the USA as a treatment for preterm labor (tocolysis). Atosiban is a modified form of oxytocin that is administered by IV infusion for 2–48 hours. In a small number of published clinical trials, atosiban appears to be as effective as -adrenoceptor-agonist tocolytics and to produce fewer adverse effects. In 1998, the FDA decided not to approve atosiban based on concerns about efficacy and safety.

Vasopressin (Antidiuretic Hormone, ADH)

Vasopressin is a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure. Vasopressin possesses antidiuretic and vasopressor properties. A deficiency of this hormone results in diabetes insipidus (see Chapters 15 and 17).

Chemistry & Pharmacokinetics

Structure

Vasopressin is a nonapeptide with a 6-amino-acid ring and a 3-amino-acid side chain. The residue at position 8 is arginine in humans and in most other mammals except pigs and related species, whose vasopressin contains lysine at position 8 (Figure 37–5). Desmopressin acetate (DDAVP, 1-desamino-8-D -arginine vasopressin) is a long-acting synthetic analog of vasopressin with minimal V₁ activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin. Desmopressin   is modified at position 1 and contains a D-amino acid at position 8. Like vasopressin and oxytocin, desmopressin has a disulfide linkage between positions 1 and 6.

Absorption, Metabolism, and Excretion

Vasopressin is administered by intravenous or intramuscular injection. The half-life of circulating vasopressin is approximately 15 minutes, with renal and hepatic metabolism via reduction of the disulfide bond and peptide cleavage.

Desmopressin can be administered intravenously, subcutaneously, intranasally, or orally. The half-life of circulating desmopressin is 1.5–2.5 hours. Nasal desmopressin is available as a unit dose spray that delivers 0.1 mL per spray; it is also available with a calibrated nasal tube that can be used to deliver a more precise dose. Nasal bioavailability of desmopressin is 3–4%, whereas oral bioavailability is less than 1%.

Pharmacodynamics

Vasopressin activates two subtypes of G protein-coupled receptors (see Chapter 17). V₁ receptors are found on vascular smooth muscle cells and mediate vasoconstriction. V₂ receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules. Extrarenal V₂-like receptors regulate the release of coagulation factor VIII and von Willebrand factor.

Clinical Pharmacology

Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus. The dosage of desmopressin is 10–40 mcg (0.1–0.4 mL) in two to three divided doses as a nasal spray or, as an oral tablet, 0.1–0.2 mg two to three times daily. The dosage by injection is 1–4 mcg (0.25–1 mL) every 12–24 hours as needed for polyuria, polydipsia, or hypernatremia. Bedtime desmopressin therapy, by intranasal or oral administration, ameliorates nocturnal enuresis by decreasing nocturnal urine production. Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding.

Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand's disease (see Chapter 34).

Toxicity & Contraindications

Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. Overdosage can result in hyponatremia and seizures.

Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with coronary artery disease. Nasal insufflation of desmopressin may be less effective when nasal congestion is present.

Vasopressin Antagonists

A group of nonpeptide antagonists of vasopressin receptors is being investigated for use in patients with hyponatremia or acute heart failure, which is often associated with elevated concentrations of vasopressin. Conivaptan has high affinity for both V_1a and V₂ receptors. Tolvaptan has a 30-fold higher affinity for V₂ than for V₁ receptors. In several clinical trials, both agents relieved symptoms and reduced objective signs of hyponatremia and heart failure. Conivaptan is approved by the FDA for intravenous administration in hyponatremia but not in congestive heart failure. Several other nonselective nonpeptide vasopressin receptor antagonists are being investigated for these conditions.

Summary: Hypothalamic and Pituitary Hormones

Preparations Available

Growth Hormone Agonists & Antagonists

Gonadotropin Agonists & Antagonists

Prolactin Antagonists (Dopamine Agonists)

Oxytocin

Vasopressin Agonists and Antagonists

Other

References

Obesity