Goodman and Gilman Manual of Pharmacology and Therapeutics
Hormones and Hormone Antagonists
Introduction to Endocrinology: The Hypothalamic-Pituitary Axis
ENDOCRINOLOGY AND HORMONES: GENERAL CONCEPTS
Endocrinology analyzes the biosynthesis of hormones, their sites of production, and the sites and mechanisms of their action and interaction. The major functions of hormones include the regulation of energy storage, production, and utilization; the adaptation to new environments or conditions of stress; the facilitation of growth and development; and the maturation and function of the reproductive system. Although hormones were originally defined as products of ductless glands, we now appreciate that many organs not classically considered as “endocrine” (e.g., the heart, kidneys, GI tract, adipocytes, and brain) synthesize and secrete hormones that play key physiological roles. In addition, the field of endocrinology has expanded to include the actions of growth factors acting by means of autocrine and paracrine mechanisms, the influence of neurons—particularly those in the hypothalamus—that regulate endocrine function, and the reciprocal interactions of cytokines and other components of the immune system with the endocrine system.
Conceptually, hormones may be divided into 2 classes:
• Hormones that act predominantly via nuclear receptors to modulate transcription in target cells (e.g., steroid hormones, thyroid hormone, and vitamin D)
• Hormones that typically act via membrane receptors to exert rapid effects on signal transduction pathways (e.g., peptide and amino acid hormones)
The receptors for both classes of hormones provide tractable targets for a diverse group of compounds that are among the most widely used drugs in clinical medicine.
THE HYPOTHALAMIC-PITUITARY-ENDOCRINE AXIS
Many of the classic endocrine hormones (e.g., cortisol, thyroid hormone, sex steroids, growth hormone) are regulated by complex reciprocal interactions among the hypothalamus, anterior pituitary, and endocrine glands (Table 38–1). The basic organization of the hypothalamic-pituitary-endocrine axis is summarized in Figure 38–1.
Hormones that Intergrate the Hypothalamic-Pituitary-Endocrine Axis
Figure 38–1 Organization of the anterior and posterior pituitary gland. Hypothalamic neurons in the supraoptic (SON) and paraventricular (PVN) nuclei synthesize arginine vasopressin (AVP) or oxytocin (OXY). Most of their axons project directly to the posterior pituitary, from which AVP and OXY are secreted into the systemic circulation to regulate their target tissues. Neurons that regulate the anterior lobe cluster in the mediobasal hypothalamus, including the PVN and the arcuate (ARC) nuclei. They secrete hypothalamic releasing hormones, which reach the anterior pituitary via the hypothalamic-adenohypophyseal portal system and stimulate distinct populations of pituitary cells. These cells, in turn, secrete the trophic (signal) hormones that regulate endocrine organs and other tissues. See Table 38–1 for abbreviations.
Discrete sets of hypothalamic neurons produce different releasing hormones, which are axonally transported to the median eminence. Upon stimulation, these neurons secrete their respective hypothalamic-releasing hormones into the hypothalamic-adenohypophyseal plexus, which flows to the anterior pituitary gland. The hypothalamic-releasing hormones bind to membrane receptors on specific subsets of pituitary cells and stimulate the secretion of the corresponding pituitary hormones. The pituitary hormones, which can be thought of as the master signals, then circulate to the target endocrine glands where they activate specific receptors to stimulate the synthesis and secretion of the target endocrine hormones. These interactions are feed-forward regulation in which the master (signal) hormones stimulate the production of target hormones by the endocrine organs.
Superimposed on this positive feed-forward regulation is negative feedback regulation, which permits precise control of hormone levels (Figure 38–2; see Figure 38–6). Typically, the endocrine target hormone circulates to both the hypothalamus and pituitary, where it acts via specific receptors to inhibit the production and secretion of both its hypothalamic-releasing hormone and the regulatory pituitary hormone. In addition, other brain regions have inputs to the hypothalamic-releasing neurons, further integrating the regulation of hormone levels in response to diverse stimuli.
Figure 38–2 Growth hormone secretion and actions. Two hypothalamic factors, growth hormone-releasing hormone (GHRH) and somatostatin (SST) stimulate or inhibit the release of growth hormone (GH) from the pituitary, respectively. Insulin-like growth factor-1 (IGF-1), a product of GH action on peripheral tissues, causes negative feedback inhibition of GH release by acting at the hypothalamus and the pituitary. The actions of GH can be direct or indirect (mediated by IGF-1). See text for discussion of the other agents that modulate GH secretion and of the effects of locally produced IGF-1. Inhibition, -; stimulation, +;.
PITUITARY HORMONES AND THEIR HYPOTHALAMIC-RELEASING FACTORS
The anterior pituitary hormones can be classified into 3 different groups based on their structural features (Table 38–2):
Properties of the Protein Hormones of the Human Adenohypophysis and Placenta
• Pro-opiomelanocortin (POMC)-derived hormones include corticotropin (adrenocorticotrophic hormone [ACTH]) and α-melanocyte-stimulating hormone (α-MSH). These are derived from POMC by proteolytic processing (see Chapters 18 and 42).
• Somatotropic hormones include growth hormone (GH) and prolactin. In humans the somatotropic family also includes placental lactogen.
• The glycoprotein hormones—thyroid-stimulating hormone (TSH; also called thyrotropin), luteinizing hormone (LH; also called lutropin), and follicle-stimulating hormone (FSH; also called follitropin). In humans, the glycoprotein hormone family also includes human chorionic gonadotropin (hCG).
The synthesis and release of anterior pituitary hormones are influenced by the central nervous system (CNS). Their secretion is positively regulated by a group of peptides referred to as hypothalamic-releasing hormones (see Figure 38–1). These include corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GHRH), gonadotropin-releasing hormone (GnRH), and thyrotropin-releasing hormone (TRH). Somatostatin (SST), another hypothalamic peptide, negatively regulates secretion of pituitary GH and TSH. The neurotransmitter dopamine inhibits the secretion of prolactin by lactotropes.
The posterior pituitary gland, also known as the neurohypophysis, contains the endings of nerve axons arising from the hypothalamus that synthesize either arginine vasopressin or oxytocin (see Figure 38–1). Arginine vasopressin plays an important role in water homeostasis (see Chapter 25); oxytocin plays important roles in labor and parturition and in milk letdown, as discussed in the following sections and in Chapter 66.
SOMATOTROPIC HORMONES: GROWTH HORMONE AND PROLACTIN
GH and prolactin are structurally related members of the somatotropic hormone family and share many biological features. The somatotropes and lactotropes, the pituitary cells that produce and secrete GH and prolactin, respectively, are subject to strong inhibitory input from hypothalamic neurons; for prolactin, this negative dopaminergic input is the dominant regulator of secretion. GH and prolactin act via membrane receptors that belong to the cytokine receptor family and modulate target cell function via very similar signal transduction pathways (see Chapter 3). Several drugs that are used to treat excessive secretion of these hormones are effective to varying degrees for both GH and prolactin.
Table 38–2 presents some features of the somatotrophic hormones.
GH is secreted by somatotropes as a heterogeneous mixture of peptides; the principal form is a single polypeptide chain of 22 kDa that has 2 disulfide bonds and is not glycosylated. Alternative splicing produces a smaller form (~20 kDa) with equal bioactivity that makes up 5-10% of circulating GH. Recombinant human GH consists entirely of the 22 kDa form, which provides a way to detect GH abuse. In the circulation, a 55 kDa protein binds approximately 45% of the 22 kDa and 25% of the 20 kDa forms. A second protein unrelated to the GH receptor also binds approximately 5-10% of circulating GH with lower affinity. Bound GH is cleared more slowly and has a biological t1/2 ~10 times that of unbound GH, suggesting that the bound hormone may provide a GH reservoir that dampens acute fluctuations in GH levels associated with its pulsatile secretion.
REGULATION OF SECRETION
GH secretion is high in children, peaks during puberty, and then decreases in an age-related manner in adulthood. GH is secreted in discrete but irregular pulses. The amplitude of secretory pulses is greatest at night. GHRH, produced by hypothalamic neurons, stimulates GH secretion (see Figure 38–2) by binding to a specific GPCR on somatotropes. The stimulated GHRH receptor couples to Gs to raise intracellular levels of cyclic AMP and Ca2+, thereby stimulating GH synthesis and secretion. Loss-of-function mutations of the GHRH receptor cause a rare form of short stature in humans. GH and its major peripheral effector, insulin-like growth factor 1 (IGF-1), act in negative feedback loops to suppress GH secretion. The negative effect of IGF-1 is predominantly through direct effects on the anterior pituitary gland, while the negative feedback action of GH is mediated in part by SST, synthesized in more widely distributed neurons.
SST is synthesized as a 92–amino acid precursor and processed by proteolytic cleavage to generate 2 peptides: SST-28 and SST-14 (Figure 38–3). SST exerts its effects by binding to and activating a family of 5 related GPCRs that signal through Gi to inhibit cyclic AMP formation and to activate K+ channels and protein phosphotyrosine phosphatases.
Figure 38–3 Structures of somatostatin-14 and selected synthetic analogs. Residues that play key roles in binding to SST receptors are shown in red. Octreotide and lanreotide are clinically available synthetic analogs of somatostatin. D-Nal, 3-(2-napthyl)-D-alanyl.
Ghrelin, a 28-amino acid peptide, stimulates GH secretion. Ghrelin is synthesized predominantly in endocrine cells in the fundus of the stomach but also is produced at lower levels at a number of other sites. Both fasting and hypoglycemia stimulate circulating ghrelin levels. Ghrelin acts primarily through a GPCR called the GH secretagogue receptor. Ghrelin also stimulates appetite and increases food intake, apparently by central actions on NPY and agouti-related peptide neurons in the hypothalamus. Thus, ghrelin and its receptor act in a complex manner to integrate the functions of the GI tract, the hypothalamus, and the anterior pituitary.
Several neurotransmitters, drugs, metabolites, and other stimuli modulate the release of GHRH and/or SST and thereby affect GH secretion. DA, 5HT, and α2 adrenergic receptor agonists stimulate GH release, as do hypoglycemia, exercise, stress, emotional excitement, and ingestion of protein-rich meals. In contrast, β adrenergic receptor agonists, free fatty acids, glucose, IGF-1, and GH itself inhibit release. Many of the physiological factors that influence prolactin secretion also affect GH secretion. Thus, sleep, stress, hypoglycemia, exercise, and estrogen increase the secretion of both hormones.
Prolactin is unique among the anterior pituitary hormones in that hypothalamic regulation of its secretion is predominantly inhibitory. The major regulator of prolactin secretion is DA, which interacts with the D2 receptor, a GPCR on lactotropes, to inhibit prolactin secretion (Figure 38–4). Prolactin acts predominantly in women, both during pregnancy and in the postpartum period in women who breast-feed. During pregnancy, the maternal serum prolactin level starts to increase at 8 weeks of gestation, peaks to 250 ng/mL at term, and declines thereafter to prepregnancy levels unless the mother breast-feeds the infant. Suckling or breast manipulation in nursing mothers cause elevation of circulating prolactin levels. Prolactin levels can rise 10- to 100-fold within 30 min of stimulation. This response is distinct from milk letdown, which is mediated by oxytocin release from the posterior pituitary gland. The suckling response becomes less pronounced after several months of breastfeeding, and prolactin concentrations eventually decline to prepregnancy levels. Prolactin also is synthesized in lactotropes near the end of the luteal phase of the menstrual cycle and by decidual cells early in pregnancy (accounting for the high levels of prolactin in amniotic fluid during the first trimester of human pregnancy).
Figure 38–4 Prolactin secretion and actions. Prolactin is the only anterior pituitary hormone for which a unique stimulatory releasing factor has not been identified. Thyrotropin-releasing hormone (TRH), however, can stimulate prolactin release; dopamine inhibits it. Suckling induces prolactin secretion, and prolactin affects lactation and reproductive functions but also has effects on many other tissues. Prolactin is not under feedback control by peripheral hormones.
MOLECULAR AND CELLULAR BASES OF SOMATOTROPIC HORMONE ACTION
Receptors for GH and prolactin belong to the cytokine receptor superfamily; they contain an extracellular hormone-binding domain, a single membrane-spanning region, and an intracellular domain that mediates signal transduction.
GH receptor activation results in the binding of a single GH to 2 receptor monomers and to form a GH-GH receptor ternary complex (initiated by high-affinity interaction of GH with 1 monomer of the GH receptor dimer [mediated by GH site 1], followed by a second, lower affinity interaction of GH with the GH receptor [mediated by GH site 2]); these interactions induce a conformational change that activates downstream signaling. The ligand-occupied GH receptor dimer lacks inherent tyrosine kinase activity but provides docking sites for 2 molecules of JAK2, a cytoplasmic tyrosine kinase of the Janus kinase family. The juxtaposition of 2 JAK2 molecules leads to trans-phosphorylation and autoactivation of JAK2, with consequent tyrosine phosphorylation of cytoplasmic proteins that mediate downstream signaling events (Figure 38–5). Pegvisomant is a GH analog with amino acid substitutions that disrupt the interaction at site 2; pegvisomant binds to the receptor and causes its internalization but cannot trigger the conformational change that stimulates downstream events in the signal transduction pathway.
Figure 38–5 Mechanisms of growth hormone and prolactin action and of GH receptor antagonism. A. Binding of GH to a growth hormone receptor (GHR) homodimer induces autophosphorylation of JAK2. JAK2 then phosphorylates cytoplasmic proteins that activate downstream signaling pathways, including STAT5 and mediators upstream of MAPK, which ultimately modulate gene expression. The structurally related prolactin receptor also is a ligand activated homodimer that recruits the JAK-STAT signaling pathway. GHR also activates IRS-1, which may mediate the increased expression of glucose transporters on the plasma membrane. B. Pegvisomant, a recombinant pegylated variant of human GH, is a high affinity GH antagonist that interferes with GH signaling. JAK2, Janus kinase 2; IRS-1, insulin receptor substrate-1; PI3K, phosphatidyl inositol-3 kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; SHC, Src homology-containing proteins.
The effects of prolactin on target cells also result from interactions with a cytokine family receptor that is widely distributed and signals through many of the same pathways as the GH receptor. Unlike human GH and placental lactogen, which also bind to the prolactin receptor and thus are lactogenic, prolactin binds specifically to the prolactin receptor and has no somatotropic (GH-like) activity.
PHYSIOLOGICAL EFFECTS OF THE SOMATOTROPIC HORMONES
The most striking physiological effect of GH is the stimulation of the longitudinal growth of bones. GH also increases bone mineral density after the epiphyses have closed. GH also increases muscle mass (in human subjects with GH deficiency), increases glomerular filtration rate, and stimulates of preadipocyte differentiation into adipocytes. Growth hormone acts directly on adipocytes to increase lipolysis and on hepatocytes to stimulate gluconeogenesis, but its anabolic and growth-promoting effects are mediated indirectly through the induction of IGF-1. IGF-1 interacts with receptors on the cell surface that mediate its biological activities.
Prolactin effects are limited to tissues that express the prolactin receptor, particularly the mammary gland. Prolactin plays an important role in inducing growth and differentiation of the ductal and lobuloalveolar epithelia and is essential for lactation. Prolactin receptors are present in many other sites, including the hypothalamus, liver, adrenal, testes, ovaries, prostate, and immune system, suggesting that prolactin may play multiple roles outside of the breast. The physiological effects of prolactin at these sites remain poorly characterized.
PATHOPHYSIOLOGY OF THE SOMATOTROPIC HORMONES
EXCESS PRODUCTION OF SOMATOTROPIC HORMONES. Syndromes of excess secretion of GH and prolactin typically are caused by somatotrope or lactotrope adenomas that oversecrete the respective hormones.
Clinical Manifestations of Excess GH. GH excess causes distinct clinical syndromes depending on the age of the patient. If the epiphyses are unfused, GH excess causes increased longitudinal growth, resulting in gigantism. In adults, GH excess causes acromegaly. The symptoms and signs of acromegaly (e.g., arthropathy, carpal tunnel syndrome, generalized visceromegaly, macroglossia, hypertension, glucose intolerance, headache, lethargy, excess perspiration, and sleep apnea) progress slowly, and diagnosis often is delayed. Mortality is increased at least 2-fold relative to age-matched controls, predominantly due to increased death from cardiovascular disease.
Clinical Manifestations of Excess Prolactin. Hyperprolactinemia is a relatively common endocrine abnormality that can result from hypothalamic or pituitary diseases that interfere with the delivery of inhibitory dopaminergic signals, from renal failure, from primary hypothyroidism associated with increased TRH levels, or from treatment with dopamine receptor antagonists. Most often, hyperprolactinemia is caused by prolactin-secreting pituitary adenomas. Manifestations of prolactin excess in women include galactorrhea, amenorrhea, and infertility. In men, hyperprolactinemia causes loss of libido, erectile dysfunction, and infertility.
IMPAIRED PRODUCTION OF THE SOMATOTROPIC HORMONES
Clinical Manifestations of Growth Hormone Deficiency. Children with GH deficiency present with short stature, delayed bone age, and a low age-adjusted growth velocity. GH deficiency in adults is associated with decreased muscle mass and exercise capacity, decreased bone density, impaired psychosocial function, and increased mortality from cardiovascular causes. The diagnosis of GH deficiency should be entertained in children with height >2 to 2.5 standard deviations below normal, delayed bone age, a decreased growth velocity, and a predicted adult height substantially below the mean parental height. In adults, overt GH deficiency usually results from pituitary lesions caused by a functioning or nonfunctioning pituitary adenoma, secondary to trauma, or related to surgery or radiotherapy for a pituitary or suprasellar mass. Almost all patients with multiple deficits in other pituitary hormones also have deficient GH secretion.
Prolactin Deficiency. Prolactin deficiency may result from conditions that damage the pituitary gland, but prolactin is not given as part of endocrine replacement therapy.
PHARMACOTHERAPY OF SOMATOTROPIN HORMONE DISORDERS
GROWTH HORMONE EXCESS
Treatment options in gigantism/acromegaly include transsphenoidal surgery, radiation, and drugs that inhibit GH secretion or action.
SOMATOSTATIN ANALOGS. The development of synthetic analogs of SST has revolutionized the medical treatment of acromegaly. The goal of treatment is to decrease GH levels to <2.5 ng/mL after an oral glucose-tolerance test and to bring IGF-1 levels to within the normal range for age and sex. The 2 SST analogs used widely are octreotide and lanreotide, synthetic derivatives that have longer half-lives and bind preferentially to SST2 and SST5 receptors (see Figure 38–3). Octreotide (100 μg) administered subcutaneously 3 times daily is 100% bioactive; peak effects are seen within 30 min, serum t1/2is ~90 min, and duration of action is ~12 h. A long-acting, slow-release form (SANDOSTATIN-LAR DEPOT) greatly reduces the injection frequency. Administered intramuscularly in a dose of 20 or 30 mg once every 4 weeks, octreotide LAR is at least as effective as the regular formulation and as well tolerated. A lower dose of 10 mg per injection should be used in patients requiring hemodialysis or with hepatic cirrhosis. In addition to its effect on GH secretion, octreotide can decrease tumor size, although tumor growth generally resumes after octreotide treatment is stopped.
Lanreotide is a long-acting octapeptide SST analog that causes prolonged suppression of GH secretion when administered in a 30-mg dose intramuscularly. Its efficacy appears comparable to that of the long-acting formulation of octreotide; its duration of action is shorter; thus, it is administered at 10- or 14-day intervals. A supersaturated aqueous formulation of lanreotide, lanreotide autogel (SOMATULINEDEPOT), has been approved for use in the U.S. It is supplied in prefilled syringes containing 60, 90, or 120 mg lanreotide and administered by deep subcutaneous injection once every 4 weeks.
Pasireotide (SIGNIFOR) is a cyclohexapeptide SST analog that is approved for the treatment of Cushing disease in patients who are ineligible for pituitary surgery or in whom surgery has failed. Pasireotide binds to multiple SST receptors (1, 2, 3, and 5) but has the highest affinity for SST5 receptor. The recommended dose range is 0.3 to 0.9 mg administered by subcutaneous injection twice daily.
Adverse Effects. GI side effects—including diarrhea, nausea, and abdominal pain—occur in up to 50% of patients receiving octreotide. These symptoms usually diminish over time and do not require cessation of therapy. Approximately 25% of patients receiving octreotide develop gallstones, presumably due to decreased gallbladder contraction and bile secretion. Compared with SST, octreotide reduces insulin secretion to a lesser extent and only infrequently affects glycemic control. Bradycardia and QT prolongation may occur in patients with underlying cardiac disease. Inhibitory effects on TSH secretion may lead to hypothyroidism, and thyroid function tests should be evaluated periodically. The incidence and severity of side effects associated with lanreotide and pasireotide are similar to those of octreotide. Pasireotide suppresses of ACTH secretion in Cushing disease and may lead to a decrease in cortisol secretion and to hypocortisolism.
Other Therapeutic Uses. SST blocks not only GH secretion but also the secretion of other hormones, growth factors, and cytokines. Thus, octreotide and the slow-release formulations of SST analogs have been used to treat symptoms associated with metastatic carcinoid tumors (e.g., flushing and diarrhea) and adenomas secreting vasoactive intestinal peptide (e.g., watery diarrhea). Octreotide also is the treatment of choice for patients who have thyrotrope adenomas that oversecrete TSH.
GROWTH HORMONE ANTAGONISTS. Pegvisomant (SOMAVERT) is a GH receptor antagonist approved for the treatment of acromegaly. Pegvisomant binds to the GH receptor but does not activate JAK-STAT signaling or stimulate IGF-1 secretion (see Figure 38–5). Pegvisomant is administered subcutaneously as a 40-mg loading dose followed by administration of 10 mg/day. Based on serum IGF-1 levels, the dose is titrated at 4- to 6-week intervals to a maximum of 40 mg/day. Pegvisomant should not be used in patients with an unexplained elevation of hepatic transaminases, and liver function tests should be monitored in all patients. In addition, lipohypertrophy has occurred at injection sites, sometimes requiring cessation of therapy; this is believed to reflect the inhibition of direct actions of GH on adipocytes. Because of concerns that loss of negative feedback by GH and IGF-1 may increase the growth of GH-secreting adenomas, careful follow-up by pituitary MRI is strongly recommended.
The therapeutic options for patients with prolactinomas include transsphenoidal surgery, radiation, and treatment with DA receptor agonists that suppress prolactin production via activation of D2 receptors.
DOPAMINE RECEPTOR AGONISTS. Bromocriptine, cabergoline, and quinagolide relieve the inhibitory effect of prolactin on ovulation and permit most patients with prolactinomas to become pregnant. Bromocriptine generally is recommended for fertility induction in patients with hyperprolactinemia. Quinagolide should not be used when pregnancy is intended. These agents generally decrease both prolactin secretion and the size of the adenoma. Over time, especially with cabergoline, the prolactinoma may decrease in size to the extent that the drug can be discontinued without recurrence of the hyperprolactinemia.
BROMOCRIPTINE. Bromocriptine (PARLODEL) is the dopamine receptor agonist against which newer agents are compared. Bromocriptine is a semisynthetic ergot alkaloid that interacts with D2 receptors to inhibit spontaneous and TRH-induced release of prolactin; to a lesser extent, it also activates D1 receptors. The oral dose of bromocriptine is well absorbed; however, only 7% of the dose reaches the systemic circulation because of extensive first-pass metabolism in the liver. Bromocriptine has a short elimination t1/2 (between 2 and 8 h). A slow-release oral form is available outside of the U.S. Bromocriptine may be administered vaginally (2.5 mg once daily), with fewer GI side effects. Bromocriptine normalizes serum prolactin levels patients with prolactinomas and decreases tumor size in >50% of patients. The underlying adenoma, and hyperprolactinemia and tumor growth recur upon cessation of therapy. At higher concentrations, bromocriptine is used in the management of acromegaly, and at still higher concentrations is used in the management of Parkinson disease (see Chapter 22).
Adverse Effects. Frequent side effects include nausea and vomiting, headache, and postural hypotension. Less frequently, nasal congestion, digital vasospasm, and CNS effects such as psychosis, hallucinations, nightmares, or insomnia are observed. These adverse effects can be diminished by starting at a low dose (1.25 mg) administered at bedtime with a snack. Patients often develop tolerance to the adverse effects.
CABERGOLINE. Cabergoline (DOSTINEX) is an ergot derivative with a longer t1/2 (~65 h), higher affinity, and greater selectivity for the D2 receptor than bromocriptine. It undergoes significant first-pass metabolism in the liver. Cabergoline is the preferred drug for the treatment of hyperprolactinemia. Therapy is initiated at a dose of 0.25 mg twice a week or 0.5 mg once a week. The dose can be increased to a maximum of 1.5-2 mg 2 or 3 times a week as tolerated; the dose should only be increased once every 4 weeks. Cabergoline induces remission in a significant number of patients with prolactinomas. At higher doses, cabergoline is used in some patients with acromegaly.
Adverse Effects. Compared to bromocriptine, cabergoline has a much lower tendency to induce nausea, although it still may cause hypotension and dizziness. Cabergoline has been linked to valvular heart disease, an effect proposed to reflect agonist activity at the serotonin 5HT2B receptor.
QUINAGOLIDE. Quinagolide (NORPROLAC) is a non-ergot D2 agonist with a t1/2 (22 h). Quinagolide is administered once daily at doses of 0.1-0.5 mg/day. It is not approved for use in the U.S. but has been used in the E.U.
GROWTH HORMONE DEFICIENCY
SOMATROPIN. Replacement therapy is well established in GH-deficient children and is gaining wider acceptance for GH-deficient adults. Currently, human GH is produced by recombinant DNA technology. Somatropin refers to the many GH preparations whose sequences match that of native GH (ACCRETROPIN, GENOTROPIN, HUMATROPE, NORDITROPIN, NUTROPIN, OMNITROPE, SAIZEN, SEROSTIM, TEV-TROPIN, VALTROPIN, and ZORBTIVE); somatrem refers to a derivative of GH with an additional methionine at the amino terminus that is no longer available in the U.S.
Pharmacokinetics. As a peptide hormone, GH is administered subcutaneously, with a bioavailability of 70%. Although the circulating t1/2 of GH is only 20 min, its biological t1/2 is considerably longer, and once-daily administration is sufficient.
Indications for Growth Hormone Treatment. GH deficiency in children is a well-accepted cause of short stature. With the advent of essentially unlimited supplies of recombinant GH, therapy has been extended to children with other conditions associated with short stature despite adequate GH production, including Turner syndrome, Noonan syndrome, Prader-Willi syndrome, chronic renal insufficiency, children born small for gestational age, and children with idiopathic short stature (i.e., >2.25 standard deviations below mean height for age and sex but with normal laboratory indices of GH levels). Severely affected GH-deficient adults may benefit from GH replacement therapy. The FDA also has approved GH therapy for AIDS-associated wasting and for malabsorption associated with the short bowel syndrome (based on the finding that GH stimulates the adaptation of GI epithelial cells).
Contraindications. GH should not be used in patients with acute critical illness due to complications after open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure. GH also should not be used in patients who have any evidence of neoplasia, and antitumor therapy should be completed before GH therapy is initiated. Other contraindications include proliferative retinopathy or severe nonproliferative diabetic retinopathy. In Prader-Willi syndrome, sudden death has been observed when GH was given to children who were severely obese or who had severe respiratory impairment.
Therapeutic Uses. In GH-deficient children, somatropin typically is administered in a dose of 25-50 μg/kg/day subcutaneously in the evening; higher daily doses (e.g., 50-67 μg/kg) are employed for patients with Noonan syndrome or Turner syndrome, who have partial GH resistance. In children with overt GH deficiency, measurement of serum IGF-1 levels sometimes is used to monitor initial response and compliance; long-term response is monitored by close evaluation of height, sometimes in conjunction with measurements of serum IGF-1 levels. GH is continued until the epiphyses are fused and also may be extended into the transition period from childhood to adulthood. For adults, a typical starting dose is 150-300 μg/day, with higher doses used in younger patients transitioning from pediatric therapy. Either an elevated serum IGF-1 level or persistent side effects mandates a decrease in dose; conversely, the dose can be increased (typically by 100-200 μg/day) if serum IGF-1 has not reached the normal range after 2 months of GH therapy. Because estrogen inhibits GH action, women taking oral—but not transdermal—estrogen may require larger GH doses to achieve the target IGF-1 level.
Adverse Effects of Growth Hormone Therapy. In children, GH therapy is associated with remarkably few side effects. Rarely, patients develop intracranial hypertension, with papilledema, visual changes, headache, nausea, and/or vomiting. Because of this, funduscopic examination is recommended at the initiation of therapy and at periodic intervals thereafter. The consensus is that GH should not be administered in the first year after treatment of pediatric tumors, including leukemia, or during the first 2 years after therapy for medulloblastomas or ependymomas. Because an increased incidence of type 2 diabetes mellitus has been reported, fasting glucose levels should be followed periodically during therapy. Finally, too-rapid growth may be associated with slipped epiphyses or scoliosis. Side effects associated with the initiation of GH therapy in adults include peripheral edema, carpal tunnel syndrome, arthralgias, and myalgias, which occur most frequently in patients who are older or obese and generally respond to a decrease in dose. Estrogens (e.g., birth control medications and estrogen supplements) inhibit GH action. GH therapy can increase the metabolic inactivation of glucocorticoids in the liver.
INSULIN-LIKE GROWTH FACTOR 1. Based on the hypothesis that GH predominantly acts via increases in IGF-1 (see Figure 38–2), IGF-1 has been developed for therapeutic use. Recombinant human IGF-1 (mecasermin [INCRELEX]) and a combination of recombinant human IGF-1 with its binding protein, IGFBP-3 (mecasermin rinfabate [IPLEX]), are FDA-approved. The latter formulation was subsequently discontinued for use in short stature due to patent issues, although it remains available for other conditions such as severe insulin resistance, muscular dystrophy, and HIV-related adipose redistribution syndrome.
ADME. Mecasermin is administered by subcutaneous injection and absorption is virtually complete. IGF-1 in circulation is bound by 6 proteins; a ternary complex that includes IGFBP-3 and the acid labile subunit accounts for >80% of the circulating IGF-1. This protein binding prolongs the t1/2 of IGF-1 to ~6 h. Both the liver and kidney have been shown to metabolize IGF-1.
Therapeutic Uses. Mecasermin is FDA-approved for patients with impaired growth secondary to mutations in the GH receptor or postreceptor signaling pathway, patients who develop antibodies against GH that interfere with its action, and patients with IGF-1 gene defects that lead to primary IGF-1 deficiency. Typically the starting dose is 40-80 μg/kg per dose twice daily by subcutaneous injection, with a maximum of 120 μg/kg per dose twice daily. In patients with impaired growth secondary to GH deficiency or with idiopathic short stature, mecasermin stimulates linear growth but is less effective than conventional therapy using recombinant GH.
Adverse Effects. Side effects of mecasermin include hypoglycemia and lipohypertrophy. To diminish the frequency of hypoglycemia, mecasermin should be administered shortly before or after a meal or snack. Lymphoid tissue hypertrophy, including enlarged tonsils, also is seen and may require surgical intervention. Other adverse effects are similar to those associated with GH therapy.
Contraindications. Mecasermin should not be used for growth promotion in patients with closed epiphyses. It should not be given to patients with active or suspected neoplasia and should be stopped if evidence of neoplasia develops.
GROWTH HORMONE-RELEASING HORMONE
Sermorelin (GEREF) is a synthetic form of human GHRH that corresponds in sequence to the first 29 amino acids of human GHRH (a 44–amino acid peptide) and has full biological activity. Although sermorelin is FDA-approved for treatment of GH deficiency and as a diagnostic agent to differentiate between hypothalamic and pituitary disease, the drug was withdrawn from the U.S. market in late 2008.
THE GLYCOPROTEIN HORMONES: TSH AND THE GONADOTROPINS
The gonadotropins include LH, FSH, and hCG. They are referred to as the gonadotropins because of their actions on the gonads. Together with TSH, they constitute the glycoprotein family of pituitary hormones (see Table 38–2). Each hormone is a glycosylated heterodimer containing a common α subunit and a distinct β subunit that confers specificity of action.
LH and FSH are synthesized and secreted by gonadotropes, which make up ~10% of the hormone-secreting cells in the anterior pituitary. hCG is produced by the placenta only in primates and horses. GnRH stimulates pituitary gonadotropin production, which is further regulated by feedback effects of the gonadal hormones (Figure 38–6; see Figure 40–2 and Chapters 40 and 41). TSH is measured in the diagnosis of thyroid disorders, and recombinant TSH is used in the evaluation and treatment of well-differentiated thyroid cancer (see Chapter 39).
Figure 38–6 The hypothalamic-pituitary-gonadal axis. A single hypothalamic-releasing factor, gonadotropin-releasing hormone (GnRH), controls the synthesis and release of both gonadotropins (LH and FSH) in males and females. Gonadal steroid hormones (androgens, estrogens, and progesterone) exert feedback inhibition at the level of the pituitary and the hypothalamus. The preovulatory surge of estrogen also can exert a stimulatory effect at the level of the pituitary and the hypothalamus. Inhibins, a family of polypeptide hormones produced by the gonads, specifically inhibit FSH secretion by the pituitary.
PHYSIOLOGY OF THE GONADOTROPINS
STRUCTURE-FUNCTION ASPECTS OF THE GONADOTROPINS. The carbohydrate residues on the gonadotropins influence their rates of clearance from the circulation, and also play a role in activating the gonadotropin receptors. Among the gonadotropin β subunits, that of hCG is most divergent because it contains a carboxy-terminal extension of 30 amino acids and extra carbohydrate residues that prolong its t1/2. The longer t1/2 of hCG has some clinical relevance for its use in assisted reproduction technologies (see Chapter 66).
REGULATION OF GONADOTROPIN SYNTHESIS AND SECRETION. The predominant regulator of gonadotropin synthesis and secretion is the hypothalamic peptide GnRH. It is a decapeptide with blocked amino and carboxyl termini derived by proteolytic cleavage of a 92–amino acid precursor peptide.
GnRH release is pulsatile and is governed by a hypothalamic neural pulse generator (primarily in the arcuate nucleus) that controls the frequency and amplitude of GnRH release. The GnRH pulse generator is active late in fetal life and for ~1 year after birth but decreases considerably thereafter. Shortly before puberty, CNS inhibition decreases and the amplitude and frequency of GnRH pulses increase, particularly during sleep. As puberty progresses, the GnRH pulses increase further in amplitude and frequency until the normal adult pattern is established. The intermittent release of GnRH is crucial for the proper synthesis and release of the gonadotropins; the continuous administration of GnRH leads to desensitization and downregulation of GnRH receptors on pituitary gonadotropes.
Molecular and Cellular Bases of GnRH Action. GnRH signals through a specific GPCR on gonadotropes that activates Gq/11 and stimulates the PLC-IP3-Ca2+ pathway (see Chapter 3), resulting in increased synthesis and secretion of LH and FSH. Although cyclic AMP is not the major mediator of GnRH action, binding of GnRH to its receptor also increases adenylyl cyclase activity. GnRH receptors also are present in the ovary, testis, and other sites, where their physiological significance remains to be determined.
Other Regulators of Gonadotropin Production. Gonadal steroids regulate gonadotropin production at the level of the pituitary and the hypothalamus, but effects on the hypothalamus predominate (seeFigure 38–6). The feedback effects of gonadal steroids are dependent on sex, concentration, and time. In women, low levels of estradiol and progesterone inhibit gonadotropin production, largely through opioid action on the neural pulse generator. Higher and more sustained levels of estradiol have positive feedback effects that ultimately result in the gonadotropin surge that triggers ovulation. In men, testosterone inhibits gonadotropin production, in part through direct actions and in part via its conversion by aromatase to estradiol. Gonadotropin production also is regulated by the inhibins, which are members of the bone morphogenetic protein family of secreted signaling proteins. Inhibin A and B are made by granulosa cells in the ovary and Sertoli cells in the testis in response to the gonadotropins and local growth factors. They act directly in the pituitary to inhibit FSH secretion without affecting that of LH.
MOLECULAR AND CELLULAR BASES OF GONADOTROPIN ACTION. The actions of LH and hCG on target tissues are mediated by the LH receptor; those of FSH are mediated by the FSH receptor. The FSH and LH receptors couple to Gs to activate the adenylyl cyclase-cyclic AMP pathway. At higher ligand concentrations, the agonist-occupied gonadotropin receptors also activate PKC and Ca2+ signaling pathways via Gq-mediated effects on PLCβ. Most actions of the gonadotropins can be mimicked by cyclic AMP analogs.
PHYSIOLOGICAL EFFECTS OF GONADOTROPINS., In men, LH acts on testicular Leydig cells to stimulate the de novo synthesis of androgens, primarily testosterone, from cholesterol. FSH acts on the Sertoli cells to stimulate the production of proteins and nutrients required for sperm maturation. In women, the actions of FSH and LH are more complicated. FSH stimulates the growth of developing ovarian follicles and induces the expression of LH receptors on theca and granulosa cells. FSH also regulates the expression of aromatase in granulosa cells, thereby stimulating the production of estradiol. LH acts on the theca cells to stimulate the de novo synthesis of androstenedione, the major precursor of ovarian estrogens in premenopausal women (see Figure 40–1). LH also is required for the rupture of the dominant follicle during ovulation and for the synthesis of progesterone by the corpus luteum.
CLINICAL DISORDERS OF THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS
Clinical disorders of the hypothalamic-pituitary-gonadal axis can manifest either as alterations in levels and effects of sex steroids (hyper- or hypogonadism) or as impaired reproduction. Deficient sex steroid production resulting from hypothalamic or pituitary defects is termed hypogonadotropic hypogonadism because circulating levels of gonadotropins are either low or undetectable. In contrast, reproductive disorders caused by processes that directly impair gonadal function are termed hypergonadotropic because the impaired production of sex steroids leads to a loss of negative feedback inhibition, thereby increasing the synthesis and secretion of gonadotropins.
GnRH AND ITS SYNTHETIC AGONIST ANALOGS
A synthetic peptide comprising the native sequence of GnRH has been used both diagnostically and therapeutically in human reproductive disorders. In addition, a number of GnRH analogs with structural modifications have been synthesized and brought to market.
SYNTHETIC GnRH. Synthetic GnRH (gonadorelin [FACTREL, LUTREPULSE]) is FDA-approved; problems with availability have limited its clinical use in the U.S. As a peptide, gonadorelin is administered either subcutaneously or intravenously. It is well absorbed following subcutaneous injection and has a circulating t1/2 of 2-4 min. For therapeutic uses, it must be administered in a pulsatile manner to avoid downregulation of the GnRH receptor.
GnRH CONGENERS. Synthetic agonist congeners of GnRH have longer half-lives than native GnRH. After a transient stimulation of gonadotropin secretion, they downregulate the GnRH receptor and inhibit gonadotropin secretion. The available GnRH agonists contain substitutions of the native sequence at position 6 that protect against proteolysis and substitutions at the carboxyl terminus that improve receptor-binding affinity. Compared to GnRH, these analogs exhibit enhanced potency and prolonged duration of action (see Table 38–3 in the 12th edition of the parent text).
Pharmacokinetics. The myriad formulations of GnRH agonists provide for diverse applications, including relatively short-term effects (e.g., assisted reproduction technology) and more prolonged action (e.g., depot forms that inhibit gonadotropin secretion in GnRH-dependent precocious puberty). The rates and extents of absorption thus vary considerably. The intranasal formulations have bioavailability (~4%) that is considerably lower than those of the parenteral formulations.
Clinical Uses. The depot form of the GnRH agonist leuprolide (LUPRON) has been used diagnostically to differentiate between GnRH-dependent and GnRH-independent precocious puberty. Leuprolide depot (3.75 mg) is injected subcutaneously, and serum LH is measured 2 h later. A plasma LH level of >6.6 mIU/mL is diagnostic of GnRH-dependent (central) disease. Clinically, the various GnRH agonists are used to achieve pharmacological castration in disorders that respond to reduction in gonadal steroids. A clear indication is in children with GnRH-dependent precocious puberty, whose premature sexual maturation can be arrested with minimal side effects by chronic administration of a depot form of a GnRH agonist. Long-acting GnRH agonists are used for palliative therapy of hormone responsive tumors (e.g., prostate or breast cancer), generally in conjunction with agents that block steroid biosynthesis or action to avoid transient increases in hormone levels (see Chapters 40-42). The GnRH agonists also are used to suppress steroid-responsive conditions such as endometriosis, uterine fibroids, acute intermittent porphyria, and priapism. Depot preparations can be administered subcutaneously or intramuscularly monthly or every 3 months. The long-lasting GnRH agonists have been used to avoid a premature LH surge, and thus ovulation, in various ovarian stimulation protocols for in vitro fertilization.
Adverse Effects. The long-acting agonists generally are well tolerated, and side effects are those that would be predicted to occur when gonadal steroidogenesis is inhibited (e.g., hot flashes and decreased bone density in both sexes, vaginal dryness and atrophy in women, and erectile dysfunction in men). Because of these effects, therapy in non-life-threatening diseases such as endometriosis or uterine fibroids generally is limited to 6 months. Postmarketing surveillance noted an increase in the incidence of pituitary apoplexy, a syndrome of headache, neurological manifestations, and impaired pituitary function that usually results from infarction of a pituitary adenoma. GnRH agonists are contraindicated in pregnant women (FDA Category X).
Formulations and Indications. Leuprolide (LUPRON, ELIGARD) is formulated in multiple doses for injection: subcutaneous (500 mg/day), subcutaneous depot (7.5 mg/month; 22.5 mg/3 months; 30 mg/4 months; 45 mg/6 months), and intramuscular depot (3.75 mg/month; 11.25 mg/3 months). It is approved for endometriosis, uterine fibroids, advanced prostate cancer, and central precocious puberty.Goserelin (ZOLADEX) is formulated as a subcutaneous implant (3.6 mg/month; 10.8 mg/12 weeks). It is approved for endometriosis and advanced prostate and breast cancer. Histrelin (VANTAS, SUPPRELINLA) is formulated as a subcutaneous implant (50 mg/12 months). It is approved for central precocious puberty and advanced prostate cancer. Nafarelin (SYNAREL) is formulated as a nasal spray (200 μg/spray). It is approved for endometriosis (400 dg/day) and central precocious puberty (1600 μg/day). Triptorelin (TRELSTAR DEPOT, TRELSTAR LA) is formulated for depot intramuscular injection (3.75 mg/month; 11.25 mg/12 weeks) and approved for advanced prostate cancer. Buserelin and Deslorelin are not available in the U.S.
GnRH ANTAGONIST ANALOGS
Two GnRH antagonists, ganirelix (ANTAGON) and cetrorelix (CETROTIDE), are FDA-approved to suppress the LH surge and thus prevent premature ovulation in ovarian-stimulation protocols (see Chapter 66).
Both GnRH antagonists are formulated for subcutaneous administration. Bioavailability exceeds 90% within 1-2 h, and the t1/2 varies depending on the dose. Once-daily administration suffices for therapeutic effect. Hypersensitivity reactions, including anaphylaxis, have been noted in postmarketing surveillance, some with the initial dose. When used in conjunction with gonadotropin injections for assisted reproduction, the effects of estrogen withdrawal (e.g., hot flashes) are not seen. GnRH antagonists are contraindicated in pregnant women (FDA Category X).
Cetrorelix is also used off label for endometriosis and uterine fibroids, both of which are estrogen dependent. As antagonists rather than agonists, these drugs do not transiently increase gonadotropin secretion and sex steroid biosynthesis.
NATURAL AND RECOMBINANT GONADOTROPINS
The gonadotropins are used for both diagnosis and therapy in reproductive endocrinology. For further discussion of the uses of gonadotropins in female reproduction, see Chapter 66.
The original gonadotropin preparations for clinical therapy were prepared from human urine and included chorionic gonadotropin, obtained from the urine of pregnant women, and menotropins, obtained from the urine of postmenopausal women. Highly purified preparations of human gonadotropins now are prepared using recombinant DNA technology and exhibit less batch-to-batch variation. This technology is being used to produce forms of gonadotropins with increased half-lives or higher clinical efficacy. One such “designer” gonadotropin, FSH-CTP, contains the β subunit of FSH fused to the carboxy-terminal extension of hCG, thereby increasing considerably the t1/2 of the recombinant protein.
FSH has long been a mainstay of regimens for either ovarian stimulation or in vitro fertilization. The original menotropin formulations (REPRONEX) contained roughly equal amounts of FSH and LH, as well as a number of other urinary proteins, and were administered intramuscularly to diminish local reactions. Urofollitropin (uFSH; BRAVELLE, MENOPUR), prepared by immunoconcentration of FSH with monoclonal antibodies, is pure enough to be administered subcutaneously. The amount of LH contained in such preparations is diminished considerably. Recombinant FSH (rFSH) is prepared by expressing cDNAs encoding the α and β subunits of human FSH in mammalian cell lines, yielding products whose glycosylation pattern mimics that of FSH produced by gonadotropes. The 2 available rFSH preparations (follitropin [GONAL-F] and follitropin [FOLLISTIM, PUREGON]) differ slightly in their carbohydrate structures; both can be administered subcutaneously because they are considerably purer. The relative advantages of recombinant FSH versus urine-derived gonadotropins have not been definitively established.
HUMAN CHORIONIC GONADOTROPIN
The hCG used clinically originally came from the urine of pregnant women. Several urine-derived preparations are available (NOVAREL, PREGNYL, PROFASI); all of them are administered intramuscularly due to local reactions. Recombinant hCG (choriogonadotropin alfa [OVIDREL]) also has reached clinical use.
RECOMBINANT HUMAN LH
Human LH produced using recombinant DNA technology and designated lutropin alfa (LUVERIS, LHADI) now is available (see Chapter 66).
Pregnancy Testing. During pregnancy, the placenta produces significant amounts of hCG, which can be detected in maternal urine. Over-the-counter pregnancy kits containing antibodies specific for the unique β subunit of hCG qualitatively assay for the presence of hCG and can detect pregnancy within a few days after a woman’s first missed menstrual period.
Timing of Ovulation. Ovulation occurs ~36 h after the onset of the LH surge. Therefore, urinary concentrations of LH, as measured with an over-the-counter radioimmunoassay kit, can be used to predict the time of ovulation.
Localization of Endocrine Disease. Measurements of plasma LH and FSH levels with β subunit–specific radioimmunoassays are useful in the diagnosis of several reproductive disorders. Low or undetectable levels of LH and FSH are indicative of hypogonadotropic hypogonadism and suggest hypothalamic or pituitary disease, whereas high levels of gonadotropins suggest primary gonadal diseases. A plasma FSH level of ≥ 10-12 mIU/mL on day 3 of the menstrual cycle, is associated with reduced fertility.
The administration of hCG can be used to stimulate testosterone production and thus to assess Leydig cell function in males suspected of having primary hypogonadism (e.g., in delayed puberty). Serum testosterone levels are assayed after multiple injections of hCG. A diminished testosterone response to hCG indicates Leydig cell failure; a normal testosterone response suggests a hypothalamic-pituitary disorder and normal Leydig cells.
Male Infertility. In men with impaired fertility secondary to gonadotropin deficiency (hypogonadotropic hypogonadism), gonadotropins can establish or restore fertility. Treatment typically is initiated with hCG (1500-2000 IUs intramuscularly or subcutaneously) 3 times per week until the plasma testosterone level indicate full induction of steroidogenesis. Thereafter, the dose of hCG is reduced to 2000 IU twice a week or 1000 IU 3 times a week, and menotropins (FSH + LH) or recombinant FSH is injected 3 times a week (typical dose of 150 IU) to fully induce spermatogenesis.
The most common side effect of gonadotropin therapy in males is gynecomastia, which presumably reflects increased production of estrogens due to the induction of aromatase. Maturation of the prepubertal testes typically requires treatment for >6 months. Once spermatogenesis has been initiated, ongoing treatment with hCG alone usually is sufficient to support sperm production.
Cryptorchidism. Cryptorchidism, the failure of 1 or both testes to descend into the scrotum, affects up to 3% of full-term male infants and becomes less prevalent with advancing postnatal age. Cryptorchid testes have defective spermatogenesis and are at increased risk for developing germ cell tumors. Hence, the current approach is to reposition the testes as early as possible, typically at 1 year of age but definitely before 2 years of age. The local actions of androgens stimulate descent of the testes; thus, hCG has been used by some to induce testicular descent if the cryptorchidism is not secondary to anatomical blockage. Therapy usually consists of injections of hCG (3000 IU/m2 body surface area) intramuscularly every other day for 6 doses.
POSTERIOR PITUITARY HORMONES: OXYTOCIN AND VASOPRESSIN
The structures of the neurohypophyseal hormones oxytocin and arginine vasopressin (also called antidiuretic hormone, or ADH) and the physiology and pharmacology of vasopressin are presented in Chapter 25. The following discussion emphasizes the physiology of oxytocin. Therapeutic uses of synthetic oxytocin as a uterine-stimulating agent to induce or augment labor in selected pregnant women and to decrease postpartum hemorrhage are described in Chapter 66.
PHYSIOLOGY OF OXYTOCIN
Oxytocin is a cyclic nonapeptide that differs from vasopressin by only 2 amino acids (see Chapter 25). It is synthesized as a larger precursor in neurons whose cell bodies reside in the paraventricular nucleus and, to a lesser extent, the supraoptic nucleus in the hypothalamus. The precursor peptide is rapidly cleaved to the active hormone and its neurophysin, packaged into secretory granules as an oxytocin-neurophysin complex, and secreted from nerve endings that terminate primarily in the posterior pituitary gland (neurohypophysis). In addition, oxytocinergic neurons that regulate the autonomic nervous system project to regions of the hypothalamus, brainstem, and spinal cord. Other sites of oxytocin synthesis include the luteal cells of the ovary, the endometrium, and the placenta. Oxytocin acts via a specific GPCR (OXT) closely related to the V1a and V2 vasopressin receptors. In the human myometrium, OXT couples to Gq/G11, activating the PLCβ-IP3-Ca2+ pathway and enhancing activation of voltage-sensitive Ca2+ channels.
Stimuli for oxytocin secretion include sensory stimuli arising from dilation of the cervix and vagina and from suckling at the breast. Estradiol stimulates oxytocin secretion, whereas the ovarian polypeptiderelaxin inhibits its release. Other factors that primarily affect vasopressin secretion also have some impact on oxytocin release: ethanol inhibits release; pain, dehydration, hemorrhage, and hypovolemia stimulate release. Based on the behavior of intravenously administered oxytocin during labor induction, the plasma t1/2 of oxytocin is ~13 min.
PHYSIOLOGICAL EFFECTS OF OXYTOCIN
Uterus. Oxytocin stimulates the frequency and force of uterine contractions. Uterine responsiveness to oxytocin roughly parallels this increase in spontaneous activity and is highly dependent on estrogen, which increases the expression of the oxytocin receptors. Because of difficulties associated with the measurement of oxytocin levels and because loss of pituitary oxytocin apparently does not compromise labor and delivery, the physiological role of oxytocin in pregnancy is debated. Exogenous oxytocin can enhance rhythmic contractions at any time, but an 8-fold increase in uterine sensitivity to oxytocin occurs in the last half of pregnancy, and is accompanied by a 30-fold increase in oxytocin receptor numbers. The oxytocin antagonist atosiban is effective in suppressing preterm labor. Progesterone antagonizes the stimulatory effect of oxytocin in vitro, and refractoriness to progesterone in late pregnancy may contribute to the normal initiation of human parturition.
Breast. Oxytocin plays an important physiological role in milk ejection. Stimulation of the breast through suckling or mechanical manipulation induces oxytocin secretion, causing contraction of the myoepithelium that surrounds alveolar channels in the mammary gland. This action forces milk from the alveolar channels into large collecting sinuses, where it is available to the suckling infant.
Brain. Studies in rodents and humans have implicated oxytocin as an important CNS regulator of trust and of autonomic systems linked to anxiety and fear.
CLINICAL USE OF OXYTOCIN
Oxytocin is used therapeutically only to induce or augment labor and to treat or prevent postpartum hemorrhage (see Chapter 66). Deficiencies of oxytocin associated with disorders of the posterior pituitary impair milk letdown after delivery and may be one of the earliest signs of pituitary insufficiency secondary to postpartum hemorrhage (Sheehan syndrome); oxytocin is not used clinically in this setting.