Basic and Clinical Pharmacology, 13th Ed.

Hypothalamic & Pituitary Hormones

Roger K. Long, MD, & Hakan Cakmak, MD

CASE STUDY

A 3-year-old boy (height 85 cm, –3 standard deviations [SD]; weight 13 kg, approximately 10th percentile) presents with short stature. Review of the past history and growth chart demonstrates normal birth weight and birth length, but a progressive fall off in height velocity relative to age-matched normal ranges starting at 6 months of age. Physical examination demonstrates short stature and mild generalized obesity. Genital examination reveals descended but small testes and a phallic length of –2 SD. Laboratory evaluations demonstrate growth hormone (GH) deficiency and a delayed bone age of 18 months. The patient is started on replacement with recombinant human GH at a dose of 40 mcg/kg/d subcutaneously. After 1 year of treatment, his height velocity has increased from 5 cm/y to 11 cm/y. How does GH stimulate growth in children? What other hormone deficiencies are suggested by the patient’s physical examination? What other hormone supplementation is this patient likely to require?

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 37–1Table 37–1) from the hypothalamus to the anterior pituitary.

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FIGURE 37–1 The hypothalamic-pituitary endocrine system. Hormones released from the anterior pituitary stimulate the production of hormones by a peripheral endocrine gland, the liver, or other tissues, or act directly on target tissues. Prolactin and the hormones released from the posterior pituitary (vasopressin and oxytocin) act directly on target tissues. Hypothalamic factors regulate the release of anterior pituitary hormones. ACTH, adrenocorticotropin; ADH, antidiuretic hormone [vasopressin]; CRH, corticotropin-releasing hormone; DA, dopamine; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; SST, somatostatin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

TABLE 37–1 Links between hypothalamic, anterior pituitary, and target organ hormone or mediator.1

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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 there 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 caused by excess production of pituitary hormones; and (3) as diagnostic tools for identifying several endocrine abnormalities.

image ANTERIOR PITUITARY HORMONES & THEIR HYPOTHALAMIC REGULATORS

All the hormones produced by the anterior pituitary except prolactin are key participants in hormonal systems in which they regulate the production of hormones and autocrine-paracrine factors by endocrine glands and other peripheral tissues. In these systems, the secretion of the pituitary hormone is under the control of one or more hypothalamic hormones. Each hypothalamic-pituitary-endocrine gland system or axis provides multiple opportunities for complex neuroendocrine regulation of growth and development, metabolism, and reproductive function.

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 (PRL), 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 α subunit. Their β subunits, though somewhat similar to each other, differ enough to confer receptor specificity. Finally, adrenocorticotropic hormone (ACTH), a single peptide cleaved from a larger precursor, pro-opiomelanocortin (POMC), that can be cleaved into various other biologically active peptides like α-melanocyte-stimulating hormone (MSH) and β-endorphin (see Chapter 31), represents a third category. Like TSH, LH, and FSH, ACTH acts through a G protein-coupled receptor. A unique feature of the ACTH receptor (also known as the melanocortin 2 receptor) is that a transmembrane protein, melanocortin 2 receptor accessory protein, is essential for normal ACTH receptor trafficking and signaling.

ACRONYMS

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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). An important regulatory feature shared by these four 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 are 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 testosterone and other androgens. ACTH and CRH production are 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 systems 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-I (IGF-I), 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 specifically stimulates prolactin secretion, although TRH can stimulate prolactin release, particularly when TRH concentrations are high in the setting of primary hypothyroidism.

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 used infrequently as treatments. Some, such as ACTH, are used 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.

TABLE 37–2 Clinical uses of hypothalamic hormones and their analogs.

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TABLE 37–3 Diagnostic uses of thyroid-stimulating hormone and adrenocorticotropin.

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GROWTH HORMONE (SOMATOTROPIN)

Growth hormone, an anterior pituitary hormone, 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 and bone density. Its growth-promoting effects are primarily mediated via IGF-I (also known as somatomedin C). Individuals with congenital or acquired deficiency of GH during childhood or adolescence fail to reach their midparental target 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

A. 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.

B. Absorption, Metabolism, and Excretion

Circulating endogenous GH has a half-life of approximately 20 minutes and is predominantly cleared by the liver. Recombinant human GH (rhGH) is administered subcutaneously 6–7 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. The hormone has two distinct GH receptor binding sites. 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). The hormone has complex effects on growth, body composition, and carbohydrate, protein, and lipid metabolism. The growth-promoting effects are mediated principally, but not solely, through an increase in the production of IGF-I. Much of the circulating IGF-I is produced in the liver. Growth hormone also stimulates production of IGF-I in bone, cartilage, muscle, kidney, and other tissues, where it has autocrine or paracrine roles. It 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 adipose cells that shift the balance of body mass to an increase in muscle mass and a reduction in adiposity. The direct and indirect effects of GH on carbohydrate metabolism are mixed, in part because GH and IGF-I have opposite effects on insulin sensitivity. Growth hormone reduces insulin sensitivity, which results in mild hyperinsulinemia and increased blood glucose levels, whereas IGF-I has insulin-like effects on glucose transport. In patients who are unable to respond to growth hormone because of severe resistance (caused by GH receptor mutations, post- receptor signaling mutations, or GH antibodies), the administration of recombinant human IGF-I may cause hypoglycemia because of its insulin-like effects.

Clinical Pharmacology

A. Growth Hormone Deficiency

Growth hormone deficiency can have a genetic basis, be associated with midline developmental defect syndromes (eg, septo-optic dysplasia), or be acquired as a result of damage to the pituitary or hypothalamus by a traumatic event (including breech or traumatic delivery), intracranial tumors, infection, infiltrative or hemorrhagic processes, or irradiation. Neonates with isolated GH deficiency are typically of normal size at birth because prenatal growth is not GH-dependent. In contrast, IGF-I is essential for normal prenatal and postnatal growth. Through poorly understood mechanisms, IGF-I expression and postnatal growth become GH-dependent during the first year of life. In childhood, GH deficiency typically presents as short stature, often with mild adiposity. Another early sign of GH deficiency is hypoglycemia due to the loss of a counter-regulatory hormonal response to hypoglycemia; young children are at risk for this condition due to high sensitivity to insulin. Criteria for diagnosis of GH deficiency usually include (1) a subnormal height velocity for age and (2) a subnormal serum GH response following provocative testing with at least two GH secretagogues. Clonidine (α2-adrenergic agonist), levodopa (dopaminergic agonist), and exercise are factors that increase GHRH levels. Arginine and insulin-induced hypoglycemia cause diminished SST, which increases GH release. The prevalence of GH deficiency is approximately 1:5000. If therapy with rhGH is initiated at an early age, many children with short stature due to GH deficiency will achieve an adult height within their midparental target height range.

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, diminished bone mineral density, dyslipidemia, and reduced cardiac output. Growth hormone-deficient adults who have been treated with GH experience reversal of many of these manifestations.

B. 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 caused by conditions other than GH deficiency. Growth hormone 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 associated with growth failure, obesity, and carbohydrate intolerance. In children with Prader-Willi syndrome and growth failure, GH treatment decreases body fat and increases lean body mass, linear growth, and energy expenditure.

TABLE 37–4 Clinical uses of recombinant human growth hormone.

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Growth hormone treatment has also been shown to have a strong beneficial effect on final height of girls with Turner syndrome (45 X karyotype and variants). 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 maximal height. Other conditions of pediatric growth failure for which GH treatment is approved include chronic renal insufficiency pre-transplant and small-for-gestational-age at birth in which the child’s height remains more than 2 standard deviations below normal at 2 years of age.

A controversial but approved use of GH is for children with idiopathic short stature (ISS). This is a heterogeneous population that has in common no identifiable cause of the short stature. Some have arbitrarily defined ISS clinically as having a height at least 2.25 standard deviations below normal for children of the same age and a predicted adult height that is less than 2.25 standard deviations below normal. 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 a cost of $5000–$40,000 per year. 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 United States fit the diagnostic criteria for ISS.

Treatment of children with short stature should be carried out by specialists experienced in GH administration. Dose requirements vary with the condition being treated, with GH-deficient children typically being most responsive. 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.

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. Growth hormone has been shown to increase intestinal growth and improve its function in experimental animals. Benefits of GH treatment for patients with short bowel syndrome and dependence on TPN have mostly been short-lived 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.

Growth hormone 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. In contrast, studies in mice and the nematode Caenorhabditis elegans have clearly demonstrated that analogs of human GH and IGF-I consistently shortenlife span and that loss-of-function mutations in the signaling pathways for the GH and IGF-I analogs lengthen life span. Another use of GH is by athletes for a purported increase in muscle mass and athletic performance. Growth hormone is one of the drugs banned by the International Olympic Committee.

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 growth hormone treatment well. Adverse events are relatively rare and include pseudotumor cerebri, slipped capital femoral epiphysis, progression of scoliosis, edema, hyperglycemia, and increased risk of asphyxiation in severely obese patients with Prader-Willi syndrome and upper airway obstruction or sleep apnea. Patients with Turner syndrome have an increased risk of otitis media while taking GH. In children with GH deficiency, periodic evaluation of the other anterior pituitary hormones may reveal concurrent deficiencies, which also require treatment (ie, with hydrocortisone, levothyroxine, or gonadal hormones). 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. Growth hormone treatment increases the activity of cytochrome P450 isoforms, which may 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 such treatment is contraindicated in a patient with a known active malignancy. Proliferative retinopathy may rarely occur. Growth hormone treatment of critically ill patients appears to increase mortality. The long-term health effects of GH treatment in childhood are unknown. The preliminary results from the Safety and Appropriateness of GH in Europe (SAGHE) study are variable. A higher all-cause mortality (mostly due to cardiovascular disease) was found in the GH treatment group in the French arm of the study, but no long-term risks of GH treatment were observed in the study arm from another region of Europe.

MECASERMIN

A small number of children with growth failure have severe IGF-I deficiency that is not responsive to exogenous GH. Causes include mutations in the GH receptor and in the GH receptor signaling pathway, neutralizing antibodies to GH, and IGF-I gene defects. In 2005, the FDA approved two forms of recombinant human IGF-I (rhIGF-I) for treatment of severe IGF-I deficiency that is not responsive to GH: mecasermin and mecasermin rinfabate. Mecasermin is rhIGF-I alone, while mecasermin rinfabate is a complex of rhIGF-I and recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3). This binding protein significantly increases the circulating half-life of rhIGF-I. Normally, the great majority of the circulating IGF-I is bound to IGFBP-3, which is produced principally by the liver under the control of GH. Mecasermin rinfabate is not currently available in the United States. 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 carbohydrate-containing meal or snack 20 minutes before or after mecasermin administration. Several patients have experienced intracranial hypertension, adenotonsillar hypertrophy, and asymptomatic elevation of liver enzymes.

GROWTH HORMONE ANTAGONISTS

Antagonists of GH are used to reverse the effects of GH-producing cells (somatotrophs) in the anterior pituitary that tend to form GH-secreting tumors. Hormone-secreting 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. Larger pituitary adenomas produce greater amounts of GH and also can impair visual and central nervous system function by encroaching on nearby brain structures. The initial therapy of choice for GH-secreting adenomas is transsphenoidal surgery. Medical therapy with GH antagonists is introduced if GH hypersecretion persists after surgery. These agents include somatostatin analogs and dopamine receptor agonists, which reduce the production of GH, and the novel GH receptor antagonist pegvisomant, which prevents GH from activating GH signaling pathways. Radiation therapy is reserved for patients with inadequate response to surgical and medical therapies.

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 functions primarily as an inhibitory paracrine factor and inhibits the release of GH, TSH, glucagon, insulin, and gastrin. Somatostatin is rapidly cleared from the circulation, with a half-life of 1–3 minutes. The kidney appears to play an important role in its metabolism and excretion.

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FIGURE 37–2 Above: Amino acid sequence of somatostatin. Below: Sequence of the synthetic analog, octreotide.

Somatostatin has limited therapeutic usefulness because of its short duration of action and 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 than that of somatostatin.

Octreotide, 50–200 mcg given subcutaneously every 8 hours, reduces symptoms caused by a variety of hormone-secreting tumors: acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, insulinoma, VIPoma, and ACTH-secreting tumor. Other therapeutic use indications include diarrhea—secretory, HIV associated, diabetic, chemotherapy, or radiation induced—and portal hypertension. 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 10–40 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, is approved for treatment of acromegaly. Lanreotide appears to have effects comparable to those of octreotide in reducing GH levels and normalizing IGF-I concentrations.

Pegvisomant

Pegvisomant is a GH receptor antagonist used to treat acromegaly. It is the polyethylene glycol (PEG) derivative of a mutant GH, B2036. Pegylation reduces its clearance and improves its overall clinical effectiveness. Like native GH, pegvisomant has two GH receptor binding sites. However, one of its GH receptor binding sites has increased affinity for the GH receptor, whereas its second GH receptor binding site has reduced affinity. This differential receptor affinity allows the initial step (GH receptor dimerization) but blocks the conformational changes required for signal transduction. In clinical trials, pegvisomant was administered subcutaneously to patients with acromegaly; daily treatment for 12 months or more reduced serum levels of IGF-I into the normal range in 97%. Pegvisomant does not inhibit GH secretion and may lead to increased GH levels and possible adenoma growth. No serious problems have been observed; however, increases in liver enzymes without liver failure have been reported.

THE GONADOTROPINS (FOLLICLE-STIMULATING HORMONE & LUTEINIZING HORMONE) & HUMAN CHORIONIC GONADOTROPIN

The gonadotropins are produced by gonadotroph cells, which comprise 7–15% of the cells in the pituitary. These hormones serve complementary functions in the reproductive process. In women, the principal function of FSH is to stimulate 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 of androgens to estrogens by granulosa cells. 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 glycoprotein 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 testosterone synthesis in Leydig cells. FSH helps maintain high local androgen concentrations in the vicinity of developing sperm by stimulating the production of androgen-binding protein in Sertoli cells. FSH also stimulates the conversion by Sertoli cells of testosterone to estrogen that is also required for spermatogenesis.

FSH, LH, and hCG are available in several pharmaceutical forms. They are used in states of infertility to stimulate spermatogenesis in men and to induce follicle development and ovulation in women. Their most common clinical use is for the controlled ovarian stimulation 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 α subunit in addition to a distinct β subunit that confers receptor specificity. The β subunits 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.

A. Menotropins

The first commercial gonadotropin product containing both FSH and LH was extracted from the urine of postmenopausal women. This purified extract of FSH and LH is known as menotropins, or human menopausal gonadotropins (hMG). From the early 1960s, these preparations were used for the stimulation of follicle development in women. The early extraction techniques were very crude, requiring around 30 L of urine to manufacture enough hMG needed for a single treatment cycle. These initial preparations were also contaminated with other proteins; less than 5% of the proteins present were bioactive. The FSH-to-LH bioactivity ratio of these early preparations was 1:1. As purity improved, it was necessary to add hCG in order to maintain this ratio of bioactivity.

B. Follicle-Stimulating Hormone

Three forms of purified FSH are available. Urofollitropin, also known as uFSH, is a purified preparation of human FSH extracted from the urine of postmenopausal women. Virtually all the LH activity has been removed through a form of immuno-affinity 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 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. Compared with urine derived gonadotropins, rFSH preparations have little protein contamination, much less batch-to-batch variability, and may cause less local tissue reaction. The rFSH preparations are considerably more expensive.

C. Luteinizing Hormone

Lutropin alfa, the first and only recombinant form of human LH, was introduced in the United States 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 hypogonadotropic hypogonadal women with profound LH deficiency (< 1.2 IU/L). Lutropin alfa with follitropin alfa may also be of benefit in certain subgroups of normogonadotropic women (eg, those with an inadequate response to prior follitropin alfa monotherapy). It has not been approved for use with the other preparations of FSH or for induction of ovulation. Lutropin alfa was withdrawn from the U.S. market in 2012.

D. Human Chorionic Gonadotropin

Human chorionic gonadotropin 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 α subunit virtually identical to that of FSH, LH, and TSH, and a β subunit 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. Both the hCG preparation that is purified from human urine and rhCG can be administered by subcutaneous or intramuscular 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 among concentration-dependent effects of the gonadotropins, cross-talk of 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 syncytiotrophoblast cells in the placenta.

Clinical Pharmacology

A. Ovulation Induction

The gonadotropins are used to induce follicle development and 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, they 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 stimulation in assisted reproductive technology procedures. Currently, a number of different protocols use gonadotropins in ovulation induction and controlled ovulation stimulation, 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 2), daily injections with one of the FSH preparations (hMG, urofollitropin, or rFSH) are begun and 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 normal follicle development. The dose and duration of gonadotropin treatment are based on the response as measured by the serum estradiol concentration and by ultrasound evaluation of ovarian follicle development. When exogenous gonadotropins are used to stimulate follicle development, there is risk of a premature endogenous surge in LH owing to the rapidly increasing serum estradiol levels. 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).

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FIGURE 37–3 Controlled ovarian stimulation in preparation for an assisted reproductive technology such as in vitro fertilization. Follicular phase: Follicle development is stimulated with gonadotropin injections that begin about 2 days after menses begin. When the follicles are ready, as assessed by ultrasound measurement of follicle size, final oocyte maturation is induced by an injection of hCG. Luteal phase: Shortly thereafter oocytes are retrieved and fertilized in vitro. The recipient’s luteal phase is supported with injections of progesterone. To prevent a premature luteinizing-hormone surge, endogenous LH secretion is inhibited with either a GnRH agonist or a GnRH antagonist. In most protocols, the GnRH agonist is started midway through the preceding luteal cycle.

When appropriate follicular maturation has occurred, the gonadotropin and the GnRH agonist or GnRH antagonist injections are discontinued and hCG (3300–10,000 IU) is administered subcutaneously 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 OHSS in patients with high follicular response to gonadotropins.

B. 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 in up to 90% of patients, but often not at normal levels. Even if pregnancy does not occur spontaneously, the number of sperm is often sufficient that pregnancy can be achieved by insemination with the patient’s semen (intrauterine insemination) or with the help of an assisted reproductive technique such as in vitro fertilization with or without intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature oocyte that has been retrieved after controlled ovarian stimulation of a female partner. With the advent of ICSI, the minimum threshold of spermatogenesis required for pregnancy is greatly lowered.

C. Outdated Uses

Chorionic gonadotropin is approved for the treatment of prepubertal cryptorchidism. Prepubertal boys were treated with intramuscular injections of hCG for 2–6 weeks. However, this clinical use is no longer supported because the long-term efficacy of hormonal treatment of cryptorchidism (~ 20%) is much lower than the long-term efficacy of surgical treatment (> 95%), and because of concerns that early childhood treatment with hCG treatment has a negative impact on germ cells in addition to increasing the risk of precocious puberty.

In the United States, chorionic gonadotropin has a black-box warning against its use for weight loss. The use of hCG plus severe calorie restriction for weight loss was popularized by a publication in the 1950s claiming that the hCG selectively mobilizes body fat stores. This practice continues today, despite a preponderance of subsequent scientific evidence from placebo-controlled trials that hCG does not provide any weight loss benefit beyond the weight loss associated with severe calorie restriction alone.

Toxicity & Contraindications

In women treated with gonadotropins and hCG, the two most serious complications are OHSS and multiple pregnancies. Stimulation of the ovary during ovulation induction often leads to uncomplicated ovarian enlargement that usually resolves spontaneously. However, OHSS may occur and can be associated with ovarian enlargement, intravascular depletion, ascites, liver dysfunction, pulmonary edema, electrolyte imbalance, and thromboembolic events. Although OHSS is often self-limited, with spontaneous resolution within a few days, severe disease may require hospitalization and intensive care. Triggering the final oocyte maturation with hCG carries the risk of inducing OHSS. GnRH agonists also induce this final oocyte maturation by promoting the release of endogenous gonadotropin stores from the hypophysis and can be used as an alternative to hCG. Use of the GnRH agonist trigger dramatically reduces the risk of OHSS, owing to the short half-life of the GnRH agonist-induced endogenous LH surge.

The probability of multiple pregnancies is greatly increased when ovulation induction and assisted reproductive technologies are used. In ovulation induction, the risk of a multiple pregnancy is estimated to be 5–10%, 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 a multiple pregnancy is primarily determined by the number of embryos transferred to the recipient. A strong trend in recent years has been to transfer single 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 gonadotrophs. Pulsatile GnRH secretion is required to stimulate the gonadotrophs 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 hypogonadotropic hypogonadism. GnRH agonists are used to induce gonadal suppression in men with prostate cancer or children with central precocious puberty. 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

A. Structure

GnRH is a decapeptide found in all mammals. Gonadorelin is an acetate salt of synthetic human GnRH. Substitution of amino acids at the 6 position or replacement of the C-terminal glycine-amide produces synthetic agonists. Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin. Such analogs of GnRH include goserelin, buserelin, histrelin, leuprolide, nafarelin, and triptorelin.

B. Pharmacokinetics

Gonadorelin can be administered intravenously or subcutaneously. GnRH agonists 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 controlled ovarian stimulation 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, inhibin, and follistatin 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 (ie, hypogonadotropic hypogonadal state). 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.

A. Stimulation

1. Female infertilityIn 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 OHSS, 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 OHSS.

2. Male infertilityIt 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. As described above, treatment of hypogonadotropic hypogonadism is more commonly done with hCG and hMG or their recombinant equivalents.

3. Diagnosis of LH responsivenessGnRH may 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 may distinguish between these two conditions; however, there can be significant individual overlap in the LH response between the two groups. 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 is greater than 5–8 mIU/mL suggests early pubertal status. An impaired LH response suggests hypogonadotropic hypogonadism due to either pituitary or hypothalamic disease, but does not rule out constitutional delay of puberty.

B. Suppression of Gonadotropin Production

1. Controlled ovarian stimulationIn the controlled ovarian stimulation 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 mg daily for about 10 days 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 may improve the follicular response to gonadotropins.

2. EndometriosisEndometriosis is defined as the presence of estrogen-sensitive endometrium outside the uterus that results in cyclical abdominal pain in premenopausal women. 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 preferred duration of treatment with a GnRH agonist is limited to 6 months because ovarian suppression beyond this period can result in decreased bone mineral density. When relief of pain from treatment with a GnRH agonist supports continued therapy for more than 6 months, the addition of add-back therapy (estrogen or progestins) reduces or eliminates GnRH agonist-induced bone mineral loss and provides symptomatic relief without reducing the efficacy of pain relief. 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.

3. Uterine leiomyomata (uterine fibroids)Uterine leiomyomata are benign, estrogen-sensitive, smooth muscle tumors 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. The effects of GnRH agonists are temporary, with gradual recurrent growth of leiomyomas to previous size within several months after cessation of treatment. GnRH agonists have been used widely for preoperative treatment of uterine leiomyomas, both for myomectomy and hysterectomy. GnRH agonists have been shown to improve hematologic parameters, shorten hospital stay, and decrease blood loss, operating time, and postoperative pain when given for 3 months preoperatively.

4. Prostate cancerAndrogen deprivation therapy is the primary medical therapy for prostate cancer. Combined antiandrogen therapy with continuous GnRH agonist and an androgen receptor antagonist is as effective as surgical castration in reducing serum testosterone concentrations and effects. Leuprolide, goserelin, histrelin, buserelin, 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 an androgen receptor antagonist (flutamide, bicalutamide, or nilutamide) (see Chapter 40). Within about 2 weeks, serum testosterone levels fall to the hypogonadal range.

5. Central precocious pubertyContinuous administration of a GnRH agonist is indicated for treatment of central precocious puberty (onset of secondary sex characteristics before 7–8 years in girls or 9 years in boys). Before embarking on treatment with a GnRH agonist, one must confirm central precocious puberty by demonstrating a pubertal gonadotropin response to GnRH or a “test dose” of a GnRH analog. Treatment is typically indicated in a child whose final height would be otherwise significantly compromised (as evidenced by a significantly advanced bone age) or in whom the early development of pubertal secondary sexual characteristics or menses causes significant emotional distress. While central precocious puberty is most often idiopathic, it is important to rule out central nervous system pathology with MRI imaging of the hypothalamic-pituitary area.

Treatment is most commonly carried out with either a monthly or three-monthly intramuscular depot injection of leuprolide acetate or with a once-yearly implant of histrelin acetate. Daily subcutaneous regimens and multiple daily nasal spray regimens of GnRH agonists are also available. Treatment with a GnRH agonist is generally continued to age 11 in females and age 12 in males.

6. OtherThe gonadal suppression provided by continuous GnRH agonist treatment is used in the management of advanced breast and ovarian cancer. In addition, recently published clinical practice guidelines recommend the use of continuous GnRH agonist administration in early pubertal transgender adolescents to block endogenous puberty prior to subsequent treatment with cross-gender gonadal hormones.

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 month of therapy due to its flare effect on gonadotropin secretion and generally resolve after an additional 6 weeks. Reduced bone mineral 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 alone or in combination with a low dose of 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 stimulation procedures, whereas degarelix and abarelix 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. Degarelix therapy is initiated with 240 mg administered as two subcutaneous injections. Maintenance dosing is with an 80-mg subcutaneous injection every 28 days. The recommended dosage of abarelix is 100 mg administered intramuscularly every 2 weeks for three doses and every 4 weeks thereafter.

Clinical Pharmacology

A. Suppression of Gonadotropin Production

GnRH antagonists are approved for preventing the LH surge during controlled ovarian stimulation. 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 suppressive effect on the ovarian response to gonadotropin stimulation, which permits a decrease in the total duration and dose of gonadotropin. 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 LH secretion than agonists. The suppression of LH may impair follicular development when recombinant or the purified form of FSH is used during 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.

B. Advanced Prostate Cancer

Degarelix and abarelix are approved for the treatment of symptomatic advanced prostate cancer. These GnRH antagonists reduce concentrations of gonadotropins and androgens more rapidly than GnRH agonists and avoid the testosterone surge seen with GnRH agonist therapy.

Toxicity

When used for controlled ovarian stimulation, ganirelix and cetrorelix are well tolerated. The most common adverse effects are nausea and headache. During the treatment of men with prostate cancer, degarelix caused injection-site reactions and increases in liver enzymes. Like continuous treatment with a GnRH agonist, degarelix and abarelix lead to signs and symptoms of androgen deprivation, including hot flushes and weight gain.

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. No preparation of prolactin is available for use in prolactin-deficient patients.

In pituitary stalk section from surgery or head trauma, stalk compression due to a sellar mass, or 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, prolactin is elevated as a result of prolactin-secreting adenomas. In addition, a number of drugs elevate prolactin levels. These include antipsychotic and gastrointestinal motility drugs that are known dopamine receptor antagonists, estrogens, and opiates. Hyperprolactinemia causes hypogonadism, which manifests with infertility, oligomenorrhea or amenorrhea, and galactorrhea in premenopausal women, and with loss of libido, erectile dysfunction, 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. 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 and GH release is reduced in patients with acromegaly, although not as effectively. Bromocriptine has also been 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

A. Hyperprolactinemia

A dopamine agonist is the standard first-line 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 United States.

image

FIGURE 37–4 Results from a clinical trial of cabergoline in women with hyperprolactinemia and anovulation. A: The dashed line indicates the upper limit of normal serum prolactin concentrations. B:Complete success was defined as pregnancy or at least two consecutive menses with evidence of ovulation at least once. Partial success was two menstrual cycles without evidence of ovulation or just one ovulatory cycle. The most common reasons for withdrawal from the trial were nausea, headache, dizziness, abdominal pain, and fatigue. (Adapted from Webster J et al: A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904.)

B. 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).

C. 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 treatment at high doses for Parkinson’s disease is associated with higher risk of valvular heart disease, but probably not at the lower dose used for hyperprolactinemia. 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.

image 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. Oxytocin stimulates muscular contractions in the uterus and myoepithelial contractions in the breast. Thus, it is involved in parturition and the letdown of milk. 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.

Chemistry & Pharmacokinetics

A. 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.

image

FIGURE 37–5 Posterior pituitary hormones and desmopressin. (Adapted, with permission, from Ganong WF: Review of Medical Physiology, 21st ed. McGraw-Hill, 2003. Copyright © The McGraw-Hill Companies, Inc.)

B. 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 rapidly 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. In small doses oxytocin 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 letdown. 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 expedited vaginal delivery such as uncontrolled maternal diabetes, worsening preeclampsia, intrauterine infection, or ruptured membranes after 34 gestational weeks. It is also used to augment protracted labor. Oxytocin can also be used in the immediate postpartum period to stop vaginal bleeding due to uterine atony.

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.

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. 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, fetal malpresentation, placental abruption, and other predispositions for uterine rupture, including previous extensive uterine surgery.

OXYTOCIN ANTAGONIST

Atosiban is an antagonist of the oxytocin receptor that has been approved outside the United States as a treatment (tocolysis) for preterm labor. Atosiban is a modified form of oxytocin that is administered by intravenous infusion for 2–48 hours. In a small number of published clinical trials, atosiban appears to be as effective as β-adrenoceptor-agonist tocolytics and to produce fewer adverse effects. In 1998, however, 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. It possesses antidiuretic and vasopressor properties. A deficiency of this hormone results in diabetes insipidus (see also Chapters 15 and 17).

Chemistry & Pharmacokinetics

A. 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 pressor 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.

B. 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 10 mcg 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 via the coupling protein Gq and phospholipase C. V2receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules via Gs and adenylyl cyclase. Extrarenal V2-like receptors regulate the release of coagulation factor VIII and von Willebrand factor, which increases platelet aggregation.

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. High-dose vasopressin as a 40-unit intravenous bolus injection may be given to replace epinephrine in the Advanced Cardiovascular Life Support (ACLS) resuscitation protocol for pulseless arrest.

Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand 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 has been 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 V1a and V2 receptors. Tolvaptan has a 30-fold higher affinity for V2 than for V1 receptors. In several clinical trials, both agents promoted the excretion of free water, relieved symptoms, and reduced objective signs of hyponatremia and heart failure. Conivaptan, administered intravenously, and tolvaptan, given orally, are approved by the FDA for treatment of hyponatremia. Tolvaptan treatment duration is limited to 30 days due to risk of hepatotoxicity, including life-threatening liver failure. Several other nonselective nonpeptide vasopressin receptor antagonists are being investigated for these conditions (see Chapter 15).

SUMMARY Hypothalamic & Pituitary Hormones1

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PREPARATIONS AVAILABLE

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CASE STUDY ANSWER

While growth hormone (GH) may have some direct growth-promoting effects, it is thought to mediate skeletal growth principally through epiphyseal production of insulin-like growth factor-I (IGF-I), which acts mainly in an autocrine/paracrine manner. IGF-I may also promote statural growth through endocrine mechanisms. The findings of small testes and a microphallus in this patient suggest a diagnosis of hypogonadism, likely as a consequence of gonadotropin deficiency. This patient is at risk for multiple hypothalamic/pituitary deficiencies. He may already have or may subsequently develop ACTH/cortisol and TSH/thyroid hormone deficiencies and thus may require supplementation with hydrocortisone and levothyroxine, in addition to supplementation with GH and testosterone. He should also be evaluated for the presence of central diabetes insipidus and, if present, treated with desmopressin, a V2 vasopressin receptor-selective analog.