Endocrine Pharmacology PDF

Section V Endocrine Pharmacology Chapter 46. Introduction to Endocrinology: The Hypothalamic-Pituitary Axis / 923 Chapter 47. Thyroid and Antithyroid Drugs / 941 Chapter 48. Estrogens, Progestins, and the Female Reproductive Tract / 959 Chapter 49. Androgens and the Male Reprod...

Section V Endocrine Pharmacology Chapter 46. Introduction to Endocrinology: The Hypothalamic-Pituitary Axis / 923 Chapter 47. Thyroid and Antithyroid Drugs / 941 Chapter 48. Estrogens, Progestins, and the Female Reproductive Tract / 959 Chapter 49. Androgens and the Male Reproductive Tract / 991 Chapter 50. Adrenocorticotropic Hormone, Adrenal Steroids, and the Adrenal Cortex / 1003 Chapter 51. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia / 1023 Chapter 52. Agents Affecting Mineral Ion Homeostasis and Bone Turnover / 1049 https://ebooksmedicine.net/ This page intentionally left blank  46 Chapter ENDOCRINOLOGY AND HORMONES: GENERAL CONCEPTS Introduction to Endocrinology: The Hypothalamic-Pituitary Axis Dequina A. Nicholas and Mark A. Lawson PITUITARY GLYCOPROTEIN HORMONES: TSH AND GONADOTROPINS Structure and Function of the Gonadotropins THE HYPOTHALAMIC-PITUITARY-ENDOCRINE AXIS Physiology of the Gonadotropins Molecular and Cellular Basis of Gonadotropin Action PITUITARY HORMONES AND THEIR HYPOTHALAMIC- RELEASING FACTORS CLINICAL DISORDERS OF THE HYPOTHALAMIC- PITUITARY-GONADAL AXIS GROWTH HORMONE AND PROLACTIN Treatment and Diagnosis of Gonadal Disorders Structures of Growth Hormone and Prolactin Regulation of Growth Hormone Secretion NATURAL AND RECOMBINANT GONADOTROPINS Regulation of Prolactin Secretion Preparations Molecular and Cellular Basis of Growth Hormone and Prolactin Action Diagnostic Uses Physiology of Growth Hormone and Prolactin Therapeutic Uses Pathophysiology of Growth Hormone and Prolactin POSTERIOR PITUITARY HORMONES: OXYTOCIN AND PHARMACOTHERAPY OF GROWTH HORMONE AND VASOPRESSIN PROLACTIN DISORDERS Physiology of Oxytocin Treatment of Growth Hormone Excess Regulation of Oxytocin Secretion Treatment of Prolactin Excess Sites of Oxytocin Action Treatment of Growth Hormone Deficiency Clinical Use of Oxytocin Notably, the steroid hormones operate through both mechanisms, and Endocrinology and Hormones: General Concepts their effect on cells is determined by the receptor complement in an indi- Endocrinology analyzes the biosynthesis of hormones, their sites of pro- vidual cell. The receptors for both classes of hormones provide tractable duction, and the sites and mechanisms of their action and interaction. The targets for a diverse group of compounds that are among the most widely term hormone is of Greek origin and classically refers to a chemical messen- used drugs in clinical medicine. ger that circulates in body fluids and produces specific effects on cells dis- tant from the hormone’s point of origin. The major functions of hormones include the regulation of energy storage, production, and utilization; the The Hypothalamic-Pituitary-Endocrine Axis adaptation to new environments or conditions of stress; the facilitation of Many of the classic endocrine hormones (e.g., cortisol, thyroid hormone, growth and development; and the maturation and function of the repro- sex steroids, GH) are regulated by complex reciprocal interactions ductive system. Although hormones were originally defined as products among the hypothalamus, anterior pituitary, and target organs or tissues of ductless glands, we now appreciate that many tissues and cell types not (Table 46–1). The basic organization of the hypothalamic-pituitary- classically considered as “endocrine” (e.g., the heart, kidneys, GI tract, adi- endocrine axis is summarized in Figure 46–1. pocytes, stem cells, and neurons) synthesize and secrete hormones that play Discrete sets of hypothalamic neurons produce different releasing key physiological roles. The current understanding of hormones empha- and inhibiting hormones, which are axonally transported to the median sizes their cellular origin and action. Broadly, the field of endocrinology eminence. On stimulation, either synaptic or by other intrahypotha- also includes the consideration of substances that act by means of autocrine lamic hormones, these neurons secrete their respective hypothalamic and paracrine mechanisms, the influence of neurons—particularly those in hormones into the hypothalamic-adenohypophyseal portal veins, which the hypothalamus—that regulate endocrine function through synaptic or connect to the anterior pituitary gland. The hypothalamic hormones bind peptide hormone action, and the reciprocal interactions of cytokines and to membrane receptors on specific subsets of pituitary cells and regulate other components of the immune system with the endocrine system. the secretion of the corresponding pituitary hormones. The pituitary hor- Conceptually, hormones may be divided into two classes based on mones circulate to the target tissues where they activate cognate receptors mechanism of action: to exert cell-specific effects or stimulate the synthesis and secretion of the Hormones that act predominantly via nuclear receptors to modulate target endocrine hormones. These interactions follow feed-forward reg- transcription in target cells (e.g., steroid hormones, retinoids, thyroid ulation in which the originating hypothalamic signal is amplified by the hormone, and vitamin D) anterior pituitary, then elicits a regulated response from target tissues and Hormones that typically act via membrane receptors to exert rapid stimulates the production of hormones by the endocrine targets. In con- effects on signal transduction pathways (e.g., peptide and amino acid trast, the posterior pituitary contains the endings of nerve axons arising hormones) from the hypothalamus, forming the neurohypophysis, which has direct https://ebooksmedicine.net/  924 Abbreviations TABLE 46–1 HORMONES THAT INTEGRATE THE HYPOTHALAMIC-PITUITARY-ENDOCRINE AXIS AC: adenylyl cyclase EFFECT ON PITUITARY ACTH: corticotropin, formerly adrenocorticotrophic hormone HYPOTHALAMIC TROPHIC (SIGNAL) TARGET ADH: antidiuretic hormone HORMONE HORMONE HORMONE(S) CG: chorionic gonadotropin Growth hormone– ↑↑ Growth hormone IGF-1 COX: cyclooxygenase releasing hormone CRH: corticotropin-releasing hormone Somatostatin ↓ Growth hormone DA: dopamine ELISA: enzyme-linked immunosorbent assay ↓ Thyroid-stimulating FP: prostaglandin F receptor hormone CHAPTER 46 INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS FSH: follicle-stimulating hormone, follitropin Dopamine ↓ Prolactin — GH: growth hormone Corticotropin- ↑ Corticotropin Cortisol GHR: GH receptor releasing hormone GHRH: growth hormone–releasing hormone GI: gastrointestinal Thyrotropin- ↑ Thyroid-stimulating Thyroid hormone releasing hormone hormone GnRH: gonadotropin-releasing hormone GPCR: G protein-coupled receptor ↑ Prolactin hCG: human chorionic gonadotropin Gonadotropin- ↑ Follicle-stimulating Estrogen (f) 5HT: 5-hydroxytryptamin serotonin releasing hormone hormone Progesterone/ IGF-1: insulin-like growth factor 1 ↑ Luteinizing hormone estrogen (f) IGFBP: IGF-binding protein Testosterone (m) IRS: insulin receptor substrate f, female; m, male; ↑, increased production; ↓, decreased production. LH: luteinizing hormone; lutropin MRI: magnetic resonance imaging These are derived from POMC by proteolytic processing (see α-MSH: α-melanocyte–stimulating hormone Figures 23–3 and 50–1). NO: nitric oxide Somatotropic hormones include growth hormone (GH) and prolactin NPY: neuropeptide Y (PRL). In humans, the somatotropic family also includes placental OXTR: oxytocin receptor lactogen. POMC: pro-opiomelanocortin PRL: prolactin Hypothalamus SC: subcutaneous PVN SHC: Src homology-containing protein (TRH, CRH, SST) SHP2: Src-homology-2-domain-containing protein tyrosine SON, PVN (AVP, OXY) ARC phosphatase 2 (GHRH, GnRH, SST: somatostatin DA) SSTR: SST receptor TRH: thyrotropin-releasing hormone TSH: thyroid-stimulating hormone, thyrotropin Posterior VIP: vasoactive intestinal peptide lobe Pituitary Anterior Releasing access to the circulation and does not rely on intermediate action of the lobe factors pituitary (see Figure 46–1). Typically, feed-forward signals are controlled by negative feedback, Portal which permits precise regulation of hormone levels and reestablishment system of homeostasis after activation of a secretory event (Figure 46–2). The endocrine target hormone circulates to both the hypothalamus and pitu- AVP, itary, where it acts via specific receptors to inhibit the production and OXY Trophic hormones secretion of both its hypothalamic-releasing hormone and the regulatory Target organs (ACTH, TSH, GH, pituitary hormone. In addition, other brain regions have inputs to the and tissues LH, FSH, prolactin) hypothalamic hormone–producing neurons, and hormones produced independently by other tissues target both the hypothalamus and anterior Figure 46–1 Organization of the anterior and posterior pituitary gland. Hypo- pituitary, further integrating the regulation of hormone levels in response thalamic neurons in the supraoptic (SON) and paraventricular (PVN) nuclei to diverse stimuli. 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. Neu- Pituitary Hormones and Their Hypothalamic- rons that regulate the anterior lobe cluster in the mediobasal hypothalamus, including the PVN and the arcuate (ARC) nuclei. They secrete hypothalamic Releasing Factors releasing hormones, which reach the anterior pituitary via the hypothalamic- The anterior pituitary hormones can be classified into three different adenohypophyseal portal system and stimulate distinct populations of pitu- groups based on their structural features (Table 46–2): itary cells. These cells, in turn, secrete the trophic (signal) hormones, which regulate endocrine organs and other tissues. ARC, arcuate; AVP, arginine Pro-opiomelanocortin (POMC)-derived hormones include cortico- vasopressin; OXY, oxytocin; PVN, paraventricular nuclei; SON, supraoptic tropin (ACTH) and α-melanocyte–stimulating hormone (α-MSH). nuclei; see Abbreviations list for other abbreviations.  + TSH. The neurotransmitter dopamine (DA) inhibits the secretion of PRL 925 – by lactotropes. Hypothalamus Posterior pituitary hormones, which are synthesized by hypothalamic – GHRH SST – neurons and secreted from the neurohypophysis, include oxytocin and – arginine vasopressin (also called antidiuretic hormone [ADH]). Arginine vasopressin plays an important role in water homeostasis (see Chapter 29); + – oxytocin plays important roles in labor and parturition and in milk let- Anterior Growth down as discussed in the sections that follow. In contrast to other anterior Ghrelin pituitary – hormone + pituitary hormone regulatory models, oxytocin is not regulated by feed- back control. Rather, only the feed-forward component of the axis exists, and secretion is reduced by cessation of the stimulatory input. SECTION V ENDOCRINE PHARMACOLOGY Growth Hormone and Prolactin Target Liver Bone Adipocyte Muscle Growth hormone and PRL are structurally related members of the soma- tissues totropic hormone family and share many biological features. The soma- totropes and lactotropes, the pituitary cells that produce and secrete GH and PRL, respectively, are subject to strong inhibitory input from hypo- IGF-1 thalamic neurons. For PRL, dopaminergic input is the dominant nega- tive regulator of secretion. GH and PRL act via membrane receptors that belong to the class 1 cytokine receptor family and modulate target cell Secondary function via very similar signal transduction pathways (see Chapter 3). target tissues Figure 46–2 Growth hormone secretion and actions. Two hypothalamic fac- Structures of Growth Hormone and Prolactin tors, GHRH and SST, stimulate or inhibit the release of GH from the pituitary, Table 46–2 presents some features of the somatotropic family of hor- respectively. Insulin-like growth factor-1 (IGF-1), a product of GH action on mones. GH is secreted by somatotropes as a heterogeneous mixture of peripheral tissues, causes negative-feedback inhibition of GH release by acting peptides. The principal form is a single unglycosylated polypeptide chain at the hypothalamus and the pituitary. The actions of GH can be direct or of 22 kDa that has two disulfide bonds. Alternative splicing produces indirect (mediated by IGF-1). See text for discussion of the other agents that a smaller form (~20 kDa) with equal bioactivity that makes up 5% to modulate GH secretion and of the effects of locally produced IGF-1. Inhibi- 10% of circulating GH. Recombinant human GH consists entirely of the tion, −; stimulation, +. 22 kDa form, which allows detection of GH abuse. In the circulation, a 55 kDa protein, which is derived from the extracellular domain of the The glycoprotein hormones include thyroid-stimulating hormone proteolytically cleaved GHRH receptor, binds approximately 45% of (TSH, also called thyrotropin), luteinizing hormone (LH, also called the 22 kDa and 25% of the 20 kDa forms. A second protein unrelated lutropin), and follicle-stimulating hormone (FSH, also called fol- to the GHR also binds approximately 5% to 10% of circulating GH with litropin). In humans, the glycoprotein hormone family also includes lower affinity. Bound GH is cleared more slowly and has a biological t1/2 placental human chorionic gonadotropin (hCG). about 10 times that of unbound GH, suggesting that the bound hormone The synthesis and release of anterior pituitary hormones are influenced may provide a GH reservoir that dampens acute fluctuations in GH levels by the CNS. Their secretion is positively regulated by a group of pep- associated with its pulsatile secretion. tides referred to as hypothalamic-releasing hormones (see Figure 46–1). Human PRL is synthesized by lactotropes. A portion of the secreted These include corticotropin-releasing hormone (CRH), growth hormone– hormone is glycosylated at a single Asn residue. In the circulation, mul- releasing hormone (GHRH), gonadotropin-releasing hormone (GnRH), timeric forms of PRL occur, as do degradation products of 16 kDa and and thyrotropin-releasing hormone (TRH). Somatostatin (SST), another 18 kDa. As with GH, the biological significance of these polymeric and hypothalamic peptide, negatively regulates secretion of pituitary GH and degraded forms is not known. TABLE 46–2 PROPERTIES OF THE PROTEIN HORMONES OF THE HUMAN ADENOHYPOPHYSIS AND PLACENTA MASS PEPTIDE CLASS AND HORMONE (daltons) CHAINS AMINO ACID RESIDUES AND COMMENTS POMC-derived hormonesa These peptides are derived by proteolytic processing of the Corticotropin 4500 39 1 common precursor, POMC. α-Melanocyte–stimulating hormone 1650 13 Somatotropic family of hormones Growth hormone 22,000 191 Receptors for these hormones belong to the cytokine Prolactin 23,000 1 199 superfamily. Placental lactogen 22,125 190 Glycoprotein hormones Luteinizing hormone 29,400 β-121 These are heterodimeric glycoproteins with a common Follicle-stimulating hormone 32,600 2 β-111 α subunit of 92 amino acids and unique β subunits that Human chorionic gonadotropin 38,600 β-145 determine biological specificity and t1/2. Thyroid-stimulating hormone 28,000 β-118 https://ebooksmedicine.net/ See Figures 23–3 and 50–1 and associated text for further discussion of POMC-derived peptides, including ACTH and α-melanocyte–stimulating hormone. a  926 Human placental lactogen, structurally similar to GH and PRL, is Ala Gly Cys Lys Asn Phe Phe synthesized in pregnant females, with maximal levels near term. Human placental lactogen alters the mother’s metabolism mainly by reducing S Trp maternal insulin sensitivity to favor fetal nutrition (Cattini et al., 2020). SST-14 S Lys Regulation of Growth Hormone Secretion Cys Ser Thr Phe Thr Daily GH secretion varies throughout life. GH secretion is high in chil- dren, peaks during puberty, and then decreases with age in adulthood. D-Phe Cys Phe D-Nal Cys Tyr GH is secreted in discrete but irregular pulses, and the amplitude of S D-Trp S D-Trp secretory pulses is greatest at night. GH secretion is stimulated by GHRH and ghrelin and is subject to feedback inhibition by GH itself, SST, and S S Lys Lys insulin-like growth factor 1 (IGF-1; see Figure 46–2). CHAPTER 46 INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS Thr(ol) Cys Thr Thr Cys Val Growth Hormone–Releasing Hormone Octreotide Lanreotide GHRH, a peptide with 44 amino acids produced by hypothalamic neu- rons, stimulates GH secretion (see Figure 46–2) by binding to a specific PGly GPCR on somatotropes in the anterior pituitary. The stimulated GHRH APro D-Trp receptor couples to Gs to raise intracellular levels of cAMP and Ca2+, thereby stimulating GH synthesis and secretion. Loss-of-function muta- tions of the GHRH receptor cause a rare form of short stature in humans. Phe Lys BTyr Ghrelin Ghrelin, a 28-amino-acid peptide, stimulates GH secretion through Pasireotide actions on a GPCR called the GH secretagogue receptor. Ghrelin is syn- Figure 46–3 Structures of SST-14 and selected synthetic analogues. Residues thesized predominantly in endocrine cells in the fundus of the stomach that play key roles in binding to SST receptors are shown in red. Octreotide, but also is produced at lower levels at several other sites, including the lanreotide, and pasireotide are clinically available synthetic analogues pituitary and hypothalamus. Hypothalamic ghrelin is thought to be a of SST. APro, [(2-aminoethyl) aminocarboxyl oxy]-L-proline; D-Nal, stimulus for GH release through actions on pituitary somatotropes and 3-(2-napthyl)-D-alanyl; PGly, phenylglycine; BTyr, benzyltyrosine. hypothalamic GHRH-secreting neurons. Both fasting and hypoglycemia increase circulating stomach-derived There are five SSTR subtypes. SSTR1–4 bind the two forms of SST with ghrelin levels, and this, in turn, stimulates appetite and increases food approximately equal affinity. SSTR5 has a 10- to 15-fold greater affinity intake, apparently by central actions on NPY and agouti-related peptide for SST-28. SSTR2 and SSTR5 are the most important for regulation of GH neurons in the hypothalamus. The physiologic role of stomach-derived secretion, and studies suggested that these two SSTRs form functional ghrelin in GH secretion is unclear due to a lack of phenotype in ghrelin heterodimers with distinctive signaling behavior (Grant et al., 2008). SST and GH secretagogue receptor knockout models and conflicting results exerts direct effects on somatotropes in the pituitary and indirect effects of clinical studies attempting to correlate circulating levels of ghrelin with mediated via GHRH neurons in the arcuate nucleus. GH secretion (Nass et al., 2011). Other Stimuli Regulation of Prolactin Secretion Several neurotransmitters, drugs, metabolites, and other stimuli modu- Prolactin is unique among the anterior pituitary hormones in that hypo- late the release of GHRH or SST and thereby affect GH secretion. DA, thalamic regulation of its secretion is predominantly inhibitory. The 5HT, and α2 adrenergic receptor agonists stimulate GH release, as do major regulator of PRL secretion is DA, which interacts with the D2 hypoglycemia, exercise, stress, emotional excitement, sex steroids, and receptor, a GPCR on lactotropes, to inhibit PRL secretion (Figure 46–4). ingestion of protein-rich meals. In contrast, β adrenergic receptor ago- TRH and hypothalamic VIP have PRL-releasing properties, but their nists, free fatty acids, glucose, IGF-1, and GH itself inhibit release. physiologic significance is uncertain. Many of the physiological factors Feedback Control of GH Secretion that influence GH secretion also affect PRL secretion. Thus, sleep, stress, Growth hormone secretion is regulated by negative-feedback loops. The hypoglycemia, exercise, and sex steroids increase the secretion of both negative-feedback action of GH is mediated through GH itself, in part by hormones. SST, which is synthesized in widely distributed neurons (Ergun-Longmire and Wajnrajch, 2013) and via its major peripheral effector IGF-1 (see Hypothalamus TRH Dopamine Figure 46–2). Insulin-like Growth Factor 1. The inhibitory effect of IGF-1 on GH secretion is predominantly through direct effects on the anterior pituitary Anterior gland but also at the hypothalamus via stimulation of SST secretion. After Prolactin pituitary its synthesis and release, IGF-1 interacts with receptors on the cell surface that mediate its biological activities. This receptor is present in essentially Suckling all tissues and binds IGF-1 and the related growth factor, IGF-2, with high affinity. The type 1 IGF receptor is closely related to the insulin receptor and consists of a heterotetramer with intrinsic tyrosine kinase activity. The signal transduction pathway for the insulin receptor is described in Target Other Breast detail in Chapter 51. tissue tissues Somatostatin. SST is synthesized as a 92-amino-acid precursor and Figure 46–4 Prolactin secretion and actions. PRL is the only anterior pitu- processed by proteolytic cleavage to generate two peptides: SST-28 and itary hormone for which a unique stimulatory releasing factor has not been SST-14 (Figure 46–3). SST exerts its effects by binding to and activating identified. TRH and VIP, however, can stimulate PRL release; DA inhibits it. a family of five related GPCRs that signal through Gi to inhibit cAMP Suckling induces PRL secretion, and PRL not only affects lactation and repro- formation and to activate K+ channels and protein phosphotyrosine ductive functions but also has effects on many other tissues. PRL is not under phosphatases. feedback control by peripheral hormones.  PRL acts predominantly in women, both during pregnancy and in the Instead, GH binding induces a conformational change that juxtaposes 927 postpartum period while breastfeeding. During pregnancy, the maternal the JAK2 molecules and leads to trans-phosphorylation and autoac- serum PRL level starts to increase at 8 weeks of gestation, peaks to 150 to tivation of JAK2, with consequent tyrosine phosphorylation of dock- 250 ng/mL at term, and declines thereafter to prepregnancy levels unless ing sites on the cytoplasmic segments of the GHR and of proteins that the mother breastfeeds the infant. Suckling or breast manipulation in mediate downstream signaling events (see Figure 46–5; Chia, 2014). nursing mothers transmits signals from the breast to the hypothalamus These include STAT proteins, SHC (an adapter protein that regulates the via the spinal cord and the median forebrain bundle, causing elevation Ras/MAPK signaling pathway), and IRS-1 and IRS-2 (insulin receptor of circulating PRL levels. PRL levels can rise 10-fold within 30 min of substrates 1 and 2, proteins that activate the PI3K pathway). One criti- stimulation. This response is distinct from milk letdown, which is medi- cal target of STAT5 is the gene encoding IGF-1, a mediator of many of ated by oxytocin release from the posterior pituitary gland. The suckling the effects of GH (see Figure 46–2). The fine control of GH action also response becomes less pronounced after several months of breastfeed- involves feedback regulatory events that subsequently turn off the GH ing, and PRL concentrations eventually decline to prepregnancy levels. signal. As part of its action, GH induces the expression of a family of SECTION V ENDOCRINE PHARMACOLOGY PRL also is synthesized by decidual cells early in pregnancy (accounting suppressor of cytokine signaling (SOC) proteins and a group of pro- for the high levels of PRL in amniotic fluid during the first trimester of tein tyrosine phosphatases (including SHP2) that, by different mech- human pregnancy). anisms, disrupt the communication of the activated GHR with JAK2 (Flores-Morales et al., 2006). The effects of PRL on target cells also result from interactions with a Molecular and Cellular Basis of Growth Hormone cytokine family receptor that is widely distributed and signals through and Prolactin Action many of the same pathways as the GHR (Bernard et al., 2015). Alternative All effects of GH and PRL result from their interactions with specific splicing of the PRL receptor gene on chromosome 5 gives rise to multi- membrane receptors on target tissues (Figure 46–5). Receptors for ple forms of the receptor that are identical in the extracellular domain GH and PRL belong to the class 1 cytokine receptor family and thus but differ in their cytoplasmic domains. In addition, soluble forms that have sequence homology with the receptors for leptin, erythropoie- correspond to the extracellular domain of the receptor are found in circu- tin, granulocyte-macrophage colony-stimulating factor, and several of lation. Unlike human GH and placental lactogen, which also bind to the the interleukins. Within this receptor family (except for GHR), a Trp- PRL receptor and thus are lactogenic, PRL binds specifically to the PRL Ser-X-Trp-Ser motif is conserved in the extracellular ligand-binding receptor and has no somatotropic (GH-like) activity. domain. In addition to this domain, these receptors also have a single membrane-spanning region and an intracellular domain that mediates sig- Physiology of Growth Hormone and Prolactin nal transduction in response to ligand-induced conformational changes. The most striking physiological effect of GH is the stimulation of the lon- Growth hormone receptor is activated by the binding of a single GH gitudinal growth of bones. GH also increases bone mineral density after to two receptor monomers to form a GH-[GHR]2 ternary complex. GH the epiphyses have closed, increases muscle mass, increases the glomeru- first binds one monomer of the GHR dimer at the high-affinity GH lar filtration rate, and stimulates preadipocyte differentiation into adipo- site 1, followed by a second, lower-affinity interaction of GH with the cytes. GH has potent anti-insulin actions in both the liver and peripheral other GHR at GH site 2. The ligand-occupied GHR dimer lacks inher- tissues (e.g., adipocytes and muscle) that decrease glucose utilization and ent tyrosine kinase activity but provides docking sites for two mole- increase lipolysis, but most of its anabolic and growth-promoting effects cules of JAK2, a cytoplasmic tyrosine kinase of the Janus kinase family. are mediated indirectly through the induction of IGF-1. IGF-1 interacts A B GH GH GH GH Pegvisomant G G G G G G H H H H H H R R R R R R J J A A K K 2 2 No GH RS-1 signaling SHC STAT5 P 3K MAPK Gene expression (e.g., GF-1) Glucose Nucleus transporter Figure 46–5 Mechanisms of GH and PRL action and of GHR antagonism. A. GH and two GHRs form a ternary complex that induces association and Tyr auto- phosphorylation of JAK2 and of docking sites on the cytoplasmic tail of GHRs. JAK2 phosphorylates cytoplasmic proteins that activate downstream signaling pathways, including STAT5 and mediators upstream of MAPK, which ultimately modulate gene expression. The structurally related PRL 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 binding. https://ebooksmedicine.net/  928 with receptors on the cell surface that mediate its biological activities. moderate elevations in PRL (e.g., antipsychotics, metoclopramide), as can Circulating IGF-1 is associated with a family of IGF-binding proteins primary hypothyroidism, pituitary mass lesions that interfere with DA (IGFBP) that serve as transport proteins and may mediate certain aspects delivery to the lactotropes, and pregnancy. Thus, thyroid function and of IGF-1 signaling. Most IGF-1 in circulation is bound to IGFBP-3 and pregnancy tests are indicated, as is MRI to look for a pituitary adenoma another protein called the acid-labile subunit. or other defect that might elevate serum PRL. The essential role of IGF-1 in growth is evidenced by patients with loss-of-function mutations in both alleles of the IGF1 gene. These Impaired Production patients have severe intrauterine and postnatal growth retardation that Clinical Manifestations of Growth Hormone Deficiency. Children is unresponsive to GH but responsive to recombinant human IGF-1 with GH deficiency present with short stature, delayed bone age, and (Walenkamp and Wit, 2008). a low age-adjusted growth velocity. GH deficiency in adults is associ- The PRL effects are limited primarily to the mammary gland, where ated with decreased muscle mass and exercise capacity, decreased bone PRL plays an important role in inducing growth and differentiation of density, impaired psychosocial function, and increased mortality from the ductal and lobuloalveolar epithelia and is essential for lactation. Tar- cardiovascular causes. The diagnosis of GH deficiency should be con- CHAPTER 46 INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS get genes by which PRL induces mammary development include those sidered in children with height more than 2 to 2.5 standard deviations encoding milk proteins (e.g., caseins and whey acidic protein), genes below normal, delayed bone age, a decreased growth velocity, and a important for intracellular structure (e.g., keratins), and genes important predicted adult height substantially below the mean parental height. In for cell-cell communication (e.g., amphiregulin). PRL receptors are pres- adults, overt GH deficiency usually results from pituitary lesions caused ent in many other sites, including the hypothalamus, liver, adrenal glands, by a functioning or nonfunctioning pituitary adenoma, secondary to testes, ovaries, prostate, and immune system, suggesting that PRL may trauma, or related to surgery or radiotherapy for a pituitary or suprasel- play multiple roles outside the breast. The physiological effects of PRL at lar mass (Ergun-Longmire and Wajnrajch, 2013). Almost all patients these sites remain poorly characterized. with multiple deficits in other pituitary hormones also have deficient GH secretion. Pathophysiology of Growth Hormone and Clinical Manifestations of Prolactin Deficiency. PRL deficiency may Prolactin result from conditions that damage the pituitary gland. Inasmuch as the sole clinical manifestation of PRL deficiency is failure of postpartum lac- Distinct endocrine disorders result from either excessive or deficient GH tation, PRL is not given as part of endocrine replacement therapy. production. In contrast, PRL predominantly affects endocrine function when produced in excess. Excess Production Pharmacotherapy of Growth Hormone and Syndromes of excess secretion of GH and PRL typically are caused by Prolactin Disorders somatotrope or lactotrope adenomas that oversecrete the respective hor- mones. These adenomas often retain some features of the normal regula- Treatment of Growth Hormone Excess tion described previously, thus permitting pharmacological modulation The initial treatment modality in gigantism/acromegaly is selective of secretion—an important modality in therapy. removal of the adenoma by transsphenoidal surgery. Radiation and drugs Clinical Manifestations of Excess Growth Hormone. GH excess that inhibit GH secretion or action are given if surgery does not result causes distinct clinical syndromes depending on the age of the patient. in cure (Katznelson et al., 2014). Pituitary irradiation may be associated If the epiphyses are unfused, GH excess causes increased longitudinal with significant long-term complications, including visual deterioration growth, resulting in gigantism. In adults, GH excess causes acromegaly. and pituitary dysfunction. Thus, increased attention has been given to the The symptoms and signs of acromegaly (e.g., arthropathy, carpal tun- pharmacological management of acromegaly. nel syndrome, generalized visceromegaly, macroglossia, hypertension, glucose intolerance, headache, lethargy, excess perspiration, and sleep Somatostatin Analogues apnea) progress slowly, and diagnosis is often delayed. Mortality is The development of synthetic analogues of SST has revolutionized the increased at least 2-fold relative to age-matched controls, predominantly medical treatment of acromegaly. The goal of treatment is to decrease due to increased death from cardiovascular disease. Treatments that nor- GH levels to less than 2.5 ng/mL after an oral glucose tolerance test and malize GH and IGF-1 levels reverse this increased risk of mortality and to bring IGF-1 levels to within the normal range for age and sex. The two ameliorate most of the other symptoms and signs. SST analogues used widely are octreotide and lanreotide, synthetic deriv- atives that have longer half-lives than SST and bind preferentially to SST2 Clinical Manifestations of Excess Prolactin. Hyperprolactinemia is a and SST5 receptors (see Figure 46–3). relatively common endocrine abnormality that can result from hypotha- lamic or pituitary diseases that interfere with the delivery of inhibitory Octreotide. Octreotide exerts pharmacological actions similar to those dopaminergic signals, from renal failure, from primary hypothyroidism of SST. Octreotide (100 μg) administered subcutaneously three times associated with increased TRH levels, or from treatment with DA receptor daily is 100% bioactive. Peak effects are seen within 30 min, serum t1/2 is antagonists. Most often, hyperprolactinemia is caused by PRL-secreting about 90 min, and duration of action is about 12 h. An equally effective, pituitary adenomas. Manifestations of PRL excess in women include long-acting, slow-release form, octreotide LAR, is administered intramus- galactorrhea, amenorrhea, and infertility. In men, hyperprolactinemia cularly in a dose of 10, 20, or 30 mg once every 4 weeks. In addition to causes loss of libido, erectile dysfunction, and infertility. its effect on GH secretion, octreotide can decrease tumor size, although tumor growth generally resumes after octreotide treatment is stopped. Diagnosis of Growth Hormone and Prolactin Excess. Although acromegaly should be suspected in patients with the appropriate symp- Lanreotide. Lanreotide autogel is a long-acting octapeptide SST ana- toms and signs, diagnostic confirmation requires the demonstration of logue that causes prolonged suppression of GH secretion when adminis- increased circulating GH or IGF-1. The definitive diagnostic test for tered by deep subcutaneous injection of 60, 90, or 120 mg every 4 weeks. acromegaly is the oral glucose tolerance test. Whereas normal subjects Its efficacy appears comparable to that of the long-acting formulation of suppress their GH level to less than 1 ng/mL in response to an oral glu- octreotide. cose challenge, patients with acromegaly either fail to suppress or show a Pasireotide. Pasireotide is a long-acting cyclohexapeptide SST analogue paradoxical increase in GH level. that is approved for the treatment of Cushing disease (excessive cortisol In patients with hyperprolactinemia, the major question is whether production triggered by increases in ACTH release due to a pituitary ade- conditions other than a PRL-producing adenoma are responsible for noma; see Chapter 50) in patients who are ineligible for pituitary surgery the elevated PRL level. Medications that inhibit DA signaling can cause or in whom surgery has failed. Pasireotide binds to multiple SST receptors (1, 2, 3, and 5) but has its highest affinity for the SST5 receptor. In a head- that suppress PRL production via activation of D2 receptors. Because of 929 to-head study, a greater percentage of subjects administered pasireotide the very high efficacy of DA receptor agonists, they are generally regarded LAR reached treatment goals compared to those given octreotide LAR. as the initial treatment of choice, with surgery and radiation reserved for Pasireotide LAR also is approved for treatment of acromegaly. patients who either do not respond or are intolerant of DA receptor ago- Adverse Effects. Gastrointestinal side effects—including diarrhea, nau- nists (Melmed et al., 2011). sea, and abdominal pain—occur in up to 50% of patients receiving all Dopamine Receptor Agonists three SST analogues. The incidence and severity of these side effects are Bromocriptine, cabergoline, and quinagolide effectively reduce PRL lev- similar for the three analogues. The symptoms usually diminish over time els, thereby relieving the inhibitory effect of hyperprolactinemia on and do not require cessation of therapy. Approximately 25% of patients ovulation and permitting most patients with prolactinomas to become receiving these drugs develop multiple tiny gallstones, presumably due to pregnant. Quinagolide should not be used when pregnancy is intended. decreased gallbladder contraction and bile secretion. Bradycardia and QT These agents generally decrease both PRL secretion and the size of the prolongation may occur in patients with underlying cardiac disease. Inhib- adenoma. Over time, especially with cabergoline, the prolactinoma may SECTION V ENDOCRINE PHARMACOLOGY itory effects on TSH secretion rarely lead to hypothyroidism, but thyroid decrease in size to the extent that the drug can be discontinued without function should be evaluated periodically. Pasireotide suppresses ACTH recurrence of the hyperprolactinemia. secretion in Cushing disease and may lead to a decrease in cortisol secre- Bromocriptine. Bromocriptine is the DA receptor agonist against which tion and to hypocortisolism. All SST analogues decrease insulin secretion, newer agents are compared. Bromocriptine is a semisynthetic ergot alka- but the simultaneous reduction in GH levels results in a reduction in insu- loid (see Chapter 15) that interacts with D2 receptors to inhibit release lin resistance. For octreotide and lanreotide, most patients will experience of PRL; to a lesser extent, it also activates D1 dopamine receptors. The no change in glucose tolerance; however, depending on the relative effects oral dose of bromocriptine is well absorbed; however, only 7% of the dose on insulin secretion versus resistance, some patients may experience a reaches the systemic circulation because of extensive first-pass metabo- worsening and others an improvement in glucose tolerance. Pasireotide, lism in the liver. Bromocriptine has a short elimination t1/2 (between 2 and in addition, decreases the secretion of glucagon-like peptide 1 and glucose 8 h) and thus is usually administered in divided doses. To avoid the need insulinotropic peptide, two incretins that facilitate insulin secretion and for frequent dosing, a slow-release oral form is available outside the U.S. inhibit glucagon secretion. As a result, glucose tolerance usually worsens Bromocriptine may be administered vaginally (2.5 mg once daily), with significantly and antihyperglycemic therapy is often needed. fewer GI side effects. Other Therapeutic Uses. SST blocks not only GH secretion but also Bromocriptine normalizes serum PRL levels in 70% to 80% and the secretion of other hormones, growth factors, and cytokines. Thus, decreases tumor size in more than 50% of patients with prolactino- the slow-release formulations of SST analogues have been used to treat mas. Hyperprolactinemia and tumor growth recur on cessation of symptoms associated with metastatic carcinoid tumors (e.g., flushing and therapy in most patients. At higher concentrations, bromocriptine is diarrhea) and adenomas secreting VIP (e.g., watery diarrhea). Octreotide used in the management of Parkinson disease (see Chapter 21). Brom- and lanreotide can also be used to treat patients with thyrotrope ade- ocriptine mesylate (1.6–4.8 mg/day) is approved as an adjunct to diet nomas that oversecrete TSH who have failed surgery. Octreotide is used and exercise to improve glycemic control in adults with type 2 diabe- for treatment of acute variceal bleeding and for perioperative prophylaxis tes mellitus. in pancreatic surgery. Modified forms of octreotide labeled with indium Adverse Effects. Frequent side effects include nausea and vomiting, head- or technetium have been used for diagnostic imaging of neuroendocrine ache, and postural hypotension, particularly on initial use. Less fre- tumors, such as pituitary adenomas and carcinoids; modified forms quently, nasal congestion, digital vasospasm, and CNS effects such as labeled with β emitters such as 90Y have been used in selective destruction psychosis, hallucinations, nightmares, or insomnia are observed. These of SST2 receptor–positive tumors. adverse effects can be diminished by starting at a low dose (1.25 mg) Growth Hormone Receptor Antagonist administered at bedtime with a snack and then slowly increasing the dose as needed by monitoring PRL levels. Patients often develop tolerance to Pegvisomant. Pegvisomant is approved for the treatment of acromeg- the adverse effects. aly. It is a GH analogue with amino acid substitutions that disrupt the interaction at GH site 2, effectively functioning as a GHR antagonist. Peg- Cabergoline. Cabergoline is an ergot derivative with a longer t1/2 visomant binds to the receptor and causes its internalization but cannot (~65 h), higher affinity, and greater selectivity for the DA D2 receptor trigger the conformational change that stimulates JAK-STAT signaling or compared to bromocriptine. Cabergoline undergoes significant first-pass IGF-1 secretion (see Figure 46–5). metabolism in the liver. The drug is administered subcutaneously as a 40-mg loading dose, Cabergoline is the preferred drug for the treatment of hyperprolactine- followed by administration of 10 mg/day. Based on serum IGF-1 levels, mia because of greater efficacy and lower adverse effects. Therapy is ini- the dose is titrated at 4- to 6-week intervals to a maximum of 30 mg/day. tiated at a dose of 0.25 mg twice a week or 0.5 mg once a week. The dose Pegvisomant should not be used in patients with an unexplained elevation can be increased to 1.5 to 2 mg two or three times a week as tolerated; the of hepatic transaminases, and liver function tests should be monitored in all dose should be increased only once every 4 weeks. Doses of 2 mg/week or patients. In addition, lipohypertrophy has occurred at injection sites, some- less normalize PRL levels in 80% of patients. Cabergoline induces remis- times requiring cessation of therapy; this is believed to reflect the inhibition sion in a significant number of patients with prolactinomas. At higher of direct actions of GH on adipocytes. Because of concerns that loss of neg- doses, cabergoline is used in some patients with acromegaly alone or in ative feedback by GH and IGF-1 may increase the growth of GH-secreting conjunction with SST analogues. adenomas, careful follow-up by pituitary MRI is strongly recommended. Adverse Effects. Compared to bromocriptine, cabergoline has a much lower Pegvisomant can also be given weekly, in addition to SST analogues, tendency to induce nausea, although it still may cause hypotension and when IGF-1 levels are not fully controlled by the latter drugs (Lim and dizziness. Cabergoline has been linked to valvular heart disease, an effect Fleseriu, 2017). Pegvisomant differs structurally from native GH and proposed to reflect agonist activity at the serotonin 5HT2B receptor. How- induces the formation of specific antibodies in about 15% of patients. ever, this effect is seen primarily at the high doses used in patients being Nevertheless, the development of tachyphylaxis due to these antibodies treated for Parkinson disease and is not seen in the conventionally used has not been reported. doses (≤2 mg/week) for patients with prolactinomas. Quinagolide. Quinagolide is a nonergot D2 receptor agonist with a t1/2 Treatment of Prolactin Excess of about 22 h. Quinagolide is administered once daily at doses of 0.1 to The therapeutic options for patients with prolactinomas include trans- 0.5 mg/day. It is not approved for use in the U.S. but has been used in the sphenoidal surgery, radiation, and treatment with DA receptor agonists European Union and Canada. https://ebooksmedicine.net/  930 Treatment of Growth Hormone Deficiency women taking oral, but not transdermal, estrogen may require larger GH doses to achieve the target IGF-1 level. Somatropin Replacement therapy is well established in GH-deficient children Adverse Effects. In children, GH therapy is associated with remarkably (Richmond and Rogol, 2016) and is gaining wider acceptance for GH- few side effects. Rarely, patients develop intracranial hypertension with deficient adults (He and Barkan, 2020). Humans do not respond to GH papilledema, visual changes, headache, nausea, or vomiting. Because of from nonprimate species. In the past, when GH for therapeutic use was this, funduscopic examination is recommended at the initiation of ther- purified from human cadaver pituitaries, GH availability was limited apy and at periodic intervals thereafter. The consensus is that GH should and ultimately linked to the transmission of Creutzfeldt-Jakob disease. not be administered in the first year after treatment of pediatric tumors, Currently, human GH is produced by recombinant DNA technology. including leukemia, or during the first 2 years after therapy for medul- Somatropin refers to the many GH preparations whose sequences match loblastomas or ependymomas. Because an increased incidence of type that of native GH. 2 diabetes mellitus has been reported, fasting glucose levels should be followed periodically during therapy. Finally, too-rapid growth may be Pharmacokinetics. As a peptide hormone, GH is administered subcu- CHAPTER 46 INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS associated with slipped epiphyses or scoliosis. taneously with a bioavailability of 70%. Although the circulating t1/2 of Side effects associated with the initiation of GH therapy in adults GH is only 20 min, its biological t1/2 is considerably longer, and once-daily (peripheral edema, carpal tunnel syndrome, arthralgias, and myalgias) administration is sufficient. occur most frequently in older or obese patients and generally respond to Indications for Treatment. Deficiency in children is a well-accepted a decrease in dose. Estrogens (e.g., birth control medications and estro- cause of short stature. With the advent of essentially unlimited supplies gen supplements) inhibit GH action so that a larger dose is needed to of recombinant GH, therapy has been extended to children with other maintain the same IGF-1 level. GH therapy can increase the metabolic conditions associated with short stature despite adequate GH produc- inactivation of cortisol in the liver. tion, including Turner syndrome, Noonan syndrome, Prader-Willi syn- Drug Interactions. The effects of estrogen on GH therapy were noted drome, chronic renal insufficiency, children born small for gestational above. This effect is much less marked with transdermal estrogen prep- age, and children with idiopathic short stature (i.e., >2.25 standard devi- arations. Recent studies suggested that GH therapy can increase the ations below mean height for age and sex but with normal laboratory metabolic inactivation of glucocorticoids in the liver. Thus, GH may pre- indices of GH levels). Severely affected GH-deficient adults may benefit cipitate adrenal insufficiency in patients with occult secondary adrenal from GH replacement therapy. The FDA also has approved GH therapy insufficiency or in patients receiving replacement doses of glucocorti- for AIDS-associated wasting and for malabsorption associated with the coids. This has been attributed to the inhibition of the type 1 isozyme short-bowel syndrome (based on the finding that GH stimulates the of steroid 11β-hydroxysteroid dehydrogenase, which normally converts adaptation of GI epithelial cells). Adults considered for GH treatment inactive cortisone into the active 11-hydroxy derivative cortisol (see should have organic etiologies for the GH deficiency and must demon- Figure 50–6). GH treatment may decrease insulin sensitivity. Therefore, strate low GH production in response to standardized stimulation tests or the dose of insulin and/or other hypoglycemic agents may need to be have at least three other pituitary hormone deficiencies. adjusted when GH therapy is initiated. Contraindications. GH is contraindicated for promotion of growth in pediatric patients with closed epiphyses. GH should not be used in Somapacitan patients with acute critical illness due to complications after open heart Somapacitan, approved by the FDA in 2020, is a human GH analogue or abdominal surgery, multiple accidental trauma, or acute respiratory designed with a 1.2-kDa albumin-binding moiety. This moiety extends failure. GH also should not be used in patients who have any evidence the half-life and reduces the clearance of somapacitan by allowing revers- of active malignancy. Other contraindications include proliferative retin- ible binding to endogenous albumin. This modification makes possible opathy or severe nonproliferative diabetic retinopathy. GH therapy for once-weekly administration instead of the standard daily injection. Prader-Willi syndrome with a diagnosis of GH deficiency must be care- Pharmacokinetics. As a modified form of GH, greater than 99% of fully supervised. Sudden death has been observed when GH was given somapacitan is bound to plasma proteins. A maximum concentration to children with Prader-Willi syndrome who were severely obese or who after initial subcutaneous injection is reached in 4 to 24 h, with steady- had severe respiratory impairment. GH treatment should be avoided in state concentrations achieved within 2 weeks of administration. The patients with known hypersensitivity. plasma t1/2 is 2 to 3 days. The improved pharmacokinetics of somapacitan Therapeutic Uses. In GH-deficient children, somatropin typically is over GH make somapacitan the first human GH therapy that is adminis- administered in a dose of 25 to 50 μg/kg per day subcutaneously in the tered to patients only once a week. evening; higher daily doses (e.g., 50–67 μg/kg) are employed for patients Therapeutic Uses. Somapacitan is approved in the U.S. only for adults with Noonan syndrome or Turner syndrome, who have partial GH resis- with GH deficiency with similar outcomes to native GH. Administration tance. In children with overt GH deficiency, measurement of serum follows the same indications and contraindications for GH in adults. The IGF-1 levels sometimes is used to monitor initial response and compli- typical starting dose is 1.5 mg weekly. This dose is increased in incre- ance. Long-term response is monitored by close evaluation of height, ments of 0.5 to 1.5 mg (weekly dose no higher than 8 mg) until the sometimes in conjunction with measurements of serum IGF-1 levels. GH desired clinical response and serum IGF-1 concentrations are achieved. is continued until the epiphyses are fused and may be extended into the Adverse Effects. Side effects from somapacitan were reported in less transition period from childhood to adulthood. Children with idiopathic than 2% of treated patients. The most common adverse effects of soma- rather than organic GH deficiency need retesting after growth has ceased pacitan include back and joint pain, indigestion, sleep disorder, dizziness, before continuing GH treatment as adults; many with this diagnosis will tonsillitis, peripheral edema, vomiting, adrenal insufficiency, hyperten- have normal GH levels on stimulation testing as adults. sion, increase in blood creatine phosphokinase, weight gain, and anemia. Benefits of GH treatment in GH-deficient adults include a decrease Less common adverse effects reported are arthralgia and dyspepsia. in fat mass and increases in muscle mass, exercise capacity, energy, bone mineral density, and quality of life. For adults, a typical starting dose is Insulin-like Growth Factor 1 150 to 300 μg/day (these doses may vary depending on brand product), Based on the hypothesis that GH predominantly acts via increases in with higher doses used in younger patients transitioning from pediatric IGF-1 (see Figure 46–2), IGF-1 has been developed for therapeutic use therapy. Either an elevated serum IGF-1 level or persistent side effects (Cohen et al., 2014). Recombinant human IGF-1 (mecasermin) and a mandates a decrease in dose; conversely, the dose can be increased combination of recombinant human IGF-1 with its binding protein, (typically by 100–200 μg/day) if serum IGF-1 has not reached the normal IGFBP-3 (mecasermin rinfabate), are FDA-approved. The latter formula- range after 2 months of GH therapy. Because estrogen inhibits GH action, tion was subsequently discontinued for use in short stature due to patent issues, although it remains available for other conditions, such as severe Hypothalamus 931 GnRH insulin resistance, muscular dystrophy, and HIV-related adipose redistri- bution syndrome. Mecasermin is administered by subcutaneous injection, and absorp- tion is virtually complete. IGF-1 is bound by six proteins: a ternary Anterior