Glycoprotein hormones are among the largest hormones known to date. They include TSH, FSH, LH, and human chorionic gonadotropin (HCG) produced by the placenta. These hormones are heterodimeric glycoproteins consisting of a common α-subunit and a unique β-subunit, which confers the biologic specificity of each hormone.
TSH is a glycoprotein synthesized and secreted from thyrotrophs of the anterior pituitary gland. Thyrotrophs synthesize and release TSH in response to thyrotropin-releasing hormone (TRH) stimulation. TRH is synthesized in the paraventricular nuclei of the hypothalamus, predominantly by parvicellular neurons, and is released from nerve terminals in the median eminence. TRH binds to a Gq/11 protein–coupled receptor, which activates phospholipase C, leading to increased phosphoinositide turnover, calcium mobilization, and release of TSH into the circulation. TSH binds to a Gs protein–coupled receptor in the thyroid gland, activating adenylate cyclase and leading to increased intracellular cyclic 3′,5′-adenosine monophosphate (cAMP) formation and stimulation of the protein kinase A signaling pathway. TSH stimulates all the events involved in thyroid hormone synthesis and release (see Chapter 4). In addition, it acts as a growth and survival factor for the thyroid gland. The release of TSH from the anterior pituitary gland is under negative feedback inhibition by thyroid hormone, particularly triiodothyronine, as discussed in detail in Chapter 4.
Gonadotropins (Follicle-Stimulating Hormone and Luteininzing Hormone)
The gonadotropic hormones LH and FSH are synthesized and secreted by gonadotrophs of the anterior pituitary in response to stimulation by gonadotropin-releasing hormone (GnRH). Most of the gonadotrophs produce both LH and FSH; with a fraction of the gonadotroph population producing LH or FSH exclusively. GnRH is synthesized and secreted by the hypothalamus in a pulsatile manner. GnRH binds to the GnRH Gq/11 protein–coupled receptor on pituitary gonadotrophs and produces activation of phospholipase C, leading to phosphoinositide turnover and Ca2+ mobilization and influx. This signaling cascade increases the transcription of the FSH and LH α-subunit and β-subunit genes and increases the release of FSH and LH into the circulation.
FSH and LH exert their physiologic effects on the testes and ovaries by binding to Gs protein–coupled receptors and activating adenylate cyclase. Among the target cells for gonadotropins are ovarian granulosa cells, theca interna cells, testicular Sertoli cells, and Leydig cells. The physiologic responses produced by the gonadotropins include stimulation of sex hormone synthesis (steroidogenesis), spermatogenesis, folliculogenesis, and ovulation. Therefore, their central role is the control of reproductive function in both males and females. GnRH controls the synthesis and secretion of both FSH and LH by the pituitary gonadotroph cell. Gonadotropin synthesis and release, as well as differential expression, is under both positive and negative feedback control by gonadal steroids and gonadal peptides (Figure 3–3). Gonadal hormones can decrease gonadotropin release both by decreasing GnRH release from the hypothalamus and by affecting the ability of GnRH to stimulate gonadotropin secretion from the pituitary itself. Estradiol enhances LH and inhibits FSH release, whereas inhibins A and B, gonadal glycoprotein hormones, reduce FSH secretion (see Chapter 9).
Feedback regulation of pituitary hormone release. Hypothalamic neurohormones (eg, gonadotropin-releasing hormone) stimulate the anterior pituitary to produce and release tropic hormones (eg, follicle-stimulating hormone and luteinizing hormone). Tropic hormones bind to receptors in target organs and elicit a physiologic response. In most cases, the response involves the production of a target organ hormone, which, in turn, mediates physiologic effects at the target organ (eg, uterus). In addition, the target organ hormone is involved in feedback mechanisms (negative or positive) that regulate the production and release of the tropic hormone and the hypothalamic factor that regulates pituitary hormone release.
The complexity of the regulation of synthesis and release of anterior pituitary hormones is best illustrated by the cyclic nature of FSH and LH release. The pattern of GnRH pulses changes during the menstrual cycle in women, as summarized in Table 3–2 and discussed in detail in Chapter 9. During the luteal to follicular phase transition, pulses of GnRH release occur every 90–120 minutes, and FSH secretion predominates. In the mid-to-late follicular phase, GnRH frequency increases to 1 pulse every 60 minutes, favoring LH secretion over FSH. After ovulation, ovarian progesterone production predominates. Progesterone increases hypothalamic opioid activity and slows GnRH pulse secretion. This slower GnRH pulse pattern (1 pulse per 3–5 hours) favors FSH production. However, at the same time, estradiol and inhibin A produced by the corpus luteum inhibit FSH release, leading to increased FSH stores. With involution of the corpus luteum and the sharp decline in estradiol, inhibin A, and progesterone, the frequency of GnRH pulse secretion is increased. In the absence of estradiol and inhibin A (inhibitors of FSH release), a selective FSH release predominates and initiates the next wave of follicular development.
Table 3–2. Regulation of Gonadotropin Release in Ovulating Females |Favorite Table|Download (.pdf)
Table 3–2. Regulation of Gonadotropin Release in Ovulating Females
|Phase of menstrual cycle||Gonadal hormones||GnRH pulses||Gonadotropin release|
|Luteal to follicular transition||Low estradiol, low inhibin||90–120 min||FSH > LH|
|Mid to late follicular phase||Increasing estradiol and inhibin B||Increased pulsatility; 60 min||LH > FSH|
|Post ovulation||Increased estradiol, inhibin A, and progesterone||Decreased GnRH pulsatility||Increased FSH synthesis; inhibited release|
|Corpus luteum involution||Decreased estradiol, inhibin A, and progesterone||Increased GnRH pulsatility||FSH|
POMC is a precursor pro-hormone produced by the corticotrophs of the anterior pituitary. The production and secretion of POMC-derived hormones from the anterior pituitary are regulated predominantly by corticotropin-releasing hormone (CRH) produced in the hypothalamus and released in the median eminence. CRH binds to a Gs protein–coupled receptor whose actions are mediated through activation of adenylate cyclase and elevation of cAMP production (see Figure 3–3). Two types of remarkably homologous (approximately 70% amino acid identity) CRH receptors have been identified. Both CRH-1 and CRH-2 receptors belong to the family of transmembrane receptors that signal by coupling to G proteins and use cAMP as a second messenger. Stimulation of POMC synthesis and peptide release is mediated by the CRH-1 receptor, which is expressed in many areas of the brain as well as in the pituitary, gonads, and skin. CRH-2 receptors are expressed on brain neurons located in neocortical, limbic, and brainstem regions of the central nervous system and on pituitary corticotrophs and in peripheral tissues (eg, cardiac myocytes, gastrointestinal tract, lung, ovary, and skeletal muscle). The role of CRH-2 receptors is not completely understood.
POMC is posttranslationally cleaved to ACTH; β-endorphin, an endogenous opioid peptide; and α-, β-, and γ-melanocyte-stimulating hormones (MSHs) (see Figure 3–5). The biologic effects of POMC-derived peptides are largely mediated through melanocortin receptors (MCRs), of which 5 have been described. MC1R, MC2R, and MC5R have defined roles in the skin, adrenal steroid hormone production, and thermoregulation, respectively. MC4R is expressed in the brain and has been implicated in feeding behavior and appetite regulation. The role of MC3R is not well defined.
The main hormone of interest produced by the cleavage of POMC is ACTH. The release of ACTH is stimulated by psychologic and physical stress such as infection, hypoglycemia, surgery, and trauma and is considered critical in mediating the stress or the adaptive response of the individual to stress (see Chapter 10). ACTH is released in small amounts, and circulating levels average 2–19 pmol/L in healthy individuals. The hormone is released in pulses, with the highest concentrations occurring at approximately 4:00 am and the lowest concentrations in the afternoon. ACTH released into the systemic circulation binds to a Gs protein–coupled receptor, part of the MCR superfamily (MC2R), and activates adenylate cyclase, increases cAMP formation, and activates protein kinase A (Figure 3–4). The physiologic effects of ACTH at the adrenal cortex are to stimulate the production and release of glucocorticoids (cortisol) and, to a lesser extent, mineralocorticoids (aldosterone) (see Chapter 6). Although all 5 MCRs can bind ACTH to some extent, MC2R binds ACTH with the highest affinity and is expressed almost exclusively in the adrenal cortex; thus, it is considered the physiologic ACTH receptor. The release of cortisol follows the same diurnal rhythm as that of ACTH (see Chapter 1, Figure 1–8). The feedback inhibition of ACTH and of CRH release by cortisol is mediated by glucocorticoid receptor binding in the hypothalamus and in the anterior pituitary.
Cellular signaling pathways involved in hypothalamo-pituitary hormone-mediated effects. All hypothalamic releasing and inhibiting factors mediate their effects predominantly via G protein–coupled receptors. Anterior pituitary hormones bind to either G protein–coupled receptors (thyroid-stimulating hormone [TSH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], adrenocorticotropic hormone [ACTH]) or class 1 cytokine receptors (growth hormone [GH] and prolactin [Prl]). Most of the cellular responses elicited by anterior pituitary hormones that bind to G protein–coupled receptors are mediated by modulation of adenylate cyclase activity. The cellular responses evoked by anterior pituitary binding to class 1 cytokine receptors are mediated through protein kinase activation. AC, adenylate cyclase; CRH, corticotropin-releasing hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; PLC, phospholipase C; TRH, thyrotropin-releasing hormone.
α-MSH is produced by the proteolytic cleavage of POMC, mainly in the pars intermedia of the pituitary gland (Figure 3–5). Only small amounts of α-MSH are produced in the pituitary under normal conditions. Melanocortin peptides exert their effects through MC1R found in melanocytes, which are key components of the skin’s pigmentary system, endothelial cells, monocytes, and keratinocytes. Binding of α-MSH to MC1R activates adenylate cyclase, which in turn causes an increase in intracellular cAMP. This is the classic pathway by which α-MSH is believed to increase melanin synthesis in melanocytes. The peripheral production of α-MSH by nonendocrine cells, particularly by melanocytes, has been described. The involvement of this paracrine system in the development of skin cancer has received considerable attention because of the localized production and paracrine actions of this peptide and the greater expression of MC1R in melanoma than in normal skin.
Proopiomelanocortin (POMC) processing. Corticotropin-releasing hormone stimulates the production, release, and processing of POMC, a preprohormone synthesized in the anterior pituitary. POMC is post-translationally cleaved to adrenocorticotropic hormone (ACTH); β-endorphin, an endogenous opioid peptide; and α-, β-, and γ-melanocyte-stimulating hormones (MSHs). The cellular effects of these peptides are mediated via melanocortin (ACTH and MSH) or opiate (β-endorphin) receptors. LPH, β-lipotropin.
β-Endorphin, the most abundant endogenous opioid peptide, is another product of POMC processing in the pituitary (see Figure 3–4). The physiologic effects of this opioid peptide are mediated by binding to opiate receptors. Because these receptors are expressed in multiple cell types in the brain as well as in peripheral tissues, their effects are pleiotropic. The physiologic actions of endorphins include analgesia, behavioral effects, and neuromodulatory functions. Among the effects on endocrine function is inhibition of GnRH release. Endogenous opioids have also been implicated in the mechanisms involved in alcohol and drug addiction and have led to therapies such as the use of naltrexone, an opiate receptor antagonist, in the management of alcohol dependency.
Growth Hormone and Prolactin Family
GH is a 191 amino acid peptide hormone, with a molecular weight of approximately 22 kDa and structural similarity to prolactin and chorionic somatomammotropin, a placental-derived hormone. GH exists in various molecular isoforms, and this heterogeneity is reflected in the wide variability in GH levels determined by different immunoassays. However, it is the 22 kDa that is the principal form with physiologic effects found in humans. GH is released from the somatotrophs, an abundant cell type in the anterior pituitary. GH is released in pulsatile bursts, with the majority of secretion occurring nocturnally in association with slow-wave sleep (Figure 1–8). The basis of the pulsatile release of GH and the function of this pattern are not fully understood; however, nutritional, metabolic, and age-related sex steroid mechanisms, adrenal glucocorticoids, thyroid hormones, and renal and hepatic functions are all thought to contribute to the pulsatile release of GH and appear to be essential in achieving optimal biologic potency of the hormone. Most of the GH in the circulation is bound to growth hormone binding protein.
The 2 principal hypothalamic regulators of GH release from the anterior pituitary are growth hormone-releasing hormone (GHRH) and somatostatin, which exert stimulatory and inhibitory influences, respectively, on the somatotrophs (Figure 3–6). GH release is also inhibited by insulin-like growth factor 1 (IGF-1), the hormone produced in peripheral tissues in response to GH stimulation. IGF-1 derived from hepatic synthesis is part of a classic negative feedback mechanism of GH release. Ghrelin a peptide released predominantly from stomach, but also expressed in the pancreas, kidney, liver, and in the arcuate nucleus of the hypothalamus (see Chapter 10) has been identified as an additional GH secretagogue. The overall contribution of ghrelin to regulation of GH release in humans is still not fully elucidated.
Growth hormone (GH) release and effects. GH release from the anterior pituitary is modulated by several factors. The primary controllers of GH release are growth hormone-releasing hormone (GHRH), which stimulates both the synthesis and secretion of GH, and somatostatin (SS), which inhibits GH release in response to GHRH and to other stimulatory factors such as low blood glucose concentration. GH secretion is also part of a negative feedback loop involving insulin-like growth factor 1 (IGF-1). IGF-1 suppresses secretion of GH not only by directly suppressing the somatotroph, but by stimulating release of SS from the hypothalamus. GH also feeds back to inhibit GHRH secretion and probably has a direct (autocrine) inhibitory effect on secretion from the somatotroph. Integration of all the factors that affect GH synthesis and secretion lead to a pulsatile pattern of release. GH effects in peripheral tissues are mediated directly by GH binding to its receptor and through the synthesis of IGF-1 by the liver and at the tissue level. The overall effects of GH and IGF-1 are anabolic. AA, amino acid; FFA, free fatty acid.
Growth Hormone-Releasing Hormone
GHRH stimulates GH secretion from somatotrophs through increases in GH gene transcription and biosynthesis and somatotroph proliferation. GHRH binds to Gs protein–coupled receptors on anterior pituitary somatotrophs, activating the catalytic subunit of adenylate cyclase. The stimulation of adenylate cyclase by Gs protein leads to intracellular cAMP accumulation and activation of the catalytic subunit of protein kinase A (see Figure 3–4). Protein kinase A phosphorylates cyclic 3′,5′-adenosine monophosphate response element binding protein (CREB), leading to CREB activation and enhanced transcription of the gene encoding pituitary-specific transcription factor (Pit-1). Pit-1 activates transcription of the GH gene, leading to increased GH mRNA and protein and replenishing cellular stores of GH. Pit-1 also stimulates transcription of GHRH receptor gene, resulting in increased numbers of GHRH receptors on the responding somatotroph cell.
The stimulated release of GH is inhibited by somatostatin, a peptide synthesized in most brain regions, predominantly in the periventricular nucleus, arcuate nucleus, and ventromedial nucleus of the hypothalamus. Somatostatin is also produced in peripheral organs, including the endocrine pancreas, where it also plays a role in the inhibition of hormone release. Axons from somatostatin neurons run caudally through the hypothalamus to form a discrete pathway toward the midline that enters the median eminence. Somatostatin produces its physiologic effects through binding to the Gi protein–coupled somatostatin receptors, resulting in decreased activity of adenylate cyclase, intracellular cAMP, and Ca2+ concentrations and stimulation of protein tyrosine phosphatase. In addition, somatostatin binding to receptors coupled to K+ channels causes hyperpolarization of the membrane, leading to cessation of spontaneous action potential activity and a secondary reduction in intracellular Ca2+ concentrations. The expression of somatostatin receptors is modulated by hormones and by the nutritional state of the individual.
In addition to regulation by GHRH and somatostatin, GH is regulated by other hypothalamic peptides and neurotransmitters, which act by regulation of GHRH and somatostatin release, as summarized in Table 3–3. Catecholamines, dopamine, and excitatory amino acids increase GHRH and decrease somatostatin release, resulting in an increase in GH release (see Figure 3–6). Hormones such as cortisol, estrogen, androgens, and thyroid hormone can also affect somatotroph responsiveness to GHRH and somatostatin and consequently GH release. Metabolic signals such as glucose and amino acids can affect GH release. Decreased blood glucose concentrations (hypoglycemia) stimulate GH secretion in humans. In fact, insulin-induced hypoglycemia is used as a clinical test to provoke GH secretion in GH-deficient children and adults. Glucose and nonesterified fatty acids decrease GH release. In contrast, amino acids, particularly arginine, increase GH release by decreasing somatostatin release. Consequently, arginine administration is also an effective challenge to elicit an increase in GH release in the clinical setting.
Table 3–3. Factors that Regulate Growth Hormone Release |Favorite Table|Download (.pdf)
Table 3–3. Factors that Regulate Growth Hormone Release
|Stimulation of GH release||Inhibition of GH release|
|Excitatory amino acids||FFA|
GH is released from the anterior pituitary into the systemic circulation. Circulating GH levels are less than 3 ng/mL, and the majority (60%) is bound to GH-binding protein. This protein is derived from proteolytic cleavage of the GH membrane receptor by metalloproteases and serves as a reservoir for GH, prolonging its half-life by decreasing its rate of degradation. The half-life of the hormone averages 6–20 minutes. GH is degraded in the lysosomes following binding to its receptor and internalization of the hormone-receptor complex.
Physiologic Effects of GH
GH can have direct effects on cellular responses, by binding to the GH receptor at target tissues and indirectly, by stimulating the production and release of IGF-1, a mediator of several of growth hormone’s effects at target tissues. IGF-1 is a small peptide (about 7.5 kDa) structurally related to proinsulin that mediates several of the anabolic and mitogenic effects of GH in peripheral tissues (see Figure 3–6). The most important physiologic effect of GH is stimulation of postnatal longitudinal growth. GH also plays a role in regulation of substrate metabolism, adipocyte differentiation; maintenance and development of the immune system; and regulation of brain and cardiac function.
In the peripheral tissues, GH binds to specific cell surface receptors belonging to the class 1 cytokine receptor superfamily (see Figures 1–6 and 3–4). This family of receptors includes those for prolactin, erythropoietin, leptin, interferons, granulocyte colony-stimulating factor, and interleukins. GH receptors are present in many biologic tissues and cell types, including liver, bone, kidney, adipose tissue, muscle, eye, brain, heart, and cells of the immune system. The GH molecule exhibits 2 binding sites for the GH receptor, resulting in dimerization of the receptor, a step that is required for biologic activity of the hormone. Receptor dimerization is followed by activation of a receptor-associated kinase, Janus-kinase 2. This kinase acts via special signal transducers and activators of transcription proteins (STATs), which dimerize and translocate to the nucleus, transmitting signals to specific regulatory DNA response elements.
GH Effects at Target Organs
GH stimulates longitudinal growth by increasing the formation of new bone and cartilage. The growth effects of GH are not critical during the gestational period, but begin gradually during the first and second years of life and peak at the time of puberty. Before the epiphyses in long bones have fused, GH stimulates chondrogenesis and widening of the cartilaginous epiphysial plates, followed by bone matrix deposition. In addition to its effects on linear growth stimulation, GH plays a role in regulating the normal physiology of bone formation in the adult by increasing bone turnover, with increases in bone formation and, to a lesser extent, bone resorption. The effects of GH at the epiphysial growth plate are thought to be mediated directly through stimulation of chondrocyte precursor differentiation and indirectly through enhancement of the local production of and responsiveness to IGF-1, which, in turn, acting in an autocrine or paracrine fashion, stimulates clonal expansion of differentiating chondrocytes (see Figure 3–6).
GH stimulates release and oxidation of free fatty acids, particularly during fasting. These effects are mediated by a reduction in the activity of lipoprotein lipase, the enzyme involved in clearing triglyceride-rich chylomicrons and very low-density lipoprotein particles from the bloodstream. Thus, GH favors the availability of free fatty acids for adipose tissue storage and skeletal muscle oxidation.
GH has anabolic actions on skeletal muscle tissue. GH stimulates amino acid uptake and incorporation into protein, cell proliferation, and suppression of protein degradation.
GH stimulates hepatic IGF-1 production and release. GH stimulates hepatic glucose production.
GH affects multiple aspects of the immune response, including B-cell responses and antibody production, natural killer cell activity, macrophage activity, and T-lymphocyte function.
GH also has central nervous system effects by modulating mood and behavior. Overall, GH counteracts the action of insulin on lipid and glucose metabolism, by decreasing skeletal muscle glucose utilization, increasing lipolysis, and stimulating hepatic glucose production.
Key aspects of GH physiology can be summarized as follows:
- GH is produced and stored in somatotrophs in the anterior pituitary.
- The production of GH is pulsatile, mainly nocturnal, and is controlled mainly by GHRH and somatostatin.
- Circulating levels of GH increase during childhood, peak during puberty, and fall with aging.
- GH stimulates lipolysis, amino acid transport into cells, and protein synthesis.
- GH stimulates the production of IGF-1, which is responsible for many of the activities attributed to GH.
Insulin-Like Growth Factors
Many of the growth and metabolic effects of GH are mediated by the insulin-like growth factors (IGFs), or somatomedins. These small peptide hormones are members of a family of insulin-related peptides including relaxin, insulin, IGF-1, and IGF-2.
Regulation of IGF-1 Production
IGF-1 is produced primarily in the liver in response to GH stimulation. IGF-1 is transported to other tissues, acting as an endocrine hormone. IGF-1 secreted by extrahepatic tissues, including cartilaginous cells, acts locally as a paracrine hormone. GH, parathyroid hormone, and sex steroids regulate the production of IGF-1 in bone, whereas sex steroids are the main regulators of local production of IGF-1 in the reproductive system. The binding proteins regulate the biologic actions of the IGFs.
Unlike insulin, IGF-1 retains the C peptide and circulates at higher concentrations than insulin either free (half-life is approximately 15–20 minutes) or bound to one of several specific binding proteins that prolong the half-life of the peptide. These binding proteins, like the IGFs, are synthesized primarily in the liver and are produced locally by several tissues, where they act in an autocrine or paracrine manner.
Insulin-Like Growth Factor-Binding Proteins (IGFBPs)
Six IGFBPs have been identified and constitute an elaborate system for regulating IGF-1 activity. IGFBPs regulate the availability of IGF-1 to its receptor in target tissues. IGFBPs generally inhibit IGF-1 action by binding competitively to it and thereby reducing its bioavailability; however, in some cases, they appear to enhance IGF-1 activity or to act independently of IGF-1. In humans, almost 80% of circulating IGF-1 is carried by IGFBP-3, a ternary complex consisting of 1 molecule of IGF-1, 1 molecule of IGFBP-3, and 1 molecule of a protein named acid-labile subunit (ALS). In this form, IGFBP-3 sequesters IGF-1 in the vascular system, increasing its half-life and providing an IGF-1 reservoir at the same time that it prevents excess IGF-1 binding to the insulin receptor. Other IGFBPs form binary complexes with IGF-1 that may cross the capillary boundary, allowing selective transport of IGF-1 to various tissues. The interaction between IGFBPs and IGFs is controlled by 2 different mechanisms: (1) proteolytic cleavage by a family of specific serine proteases, which decreases IGF binding affinity; and (2) binding to the extracellular matrix, which potentiates IGF actions. Cleavage of IGFBPs by their specific proteases also influences IGF-1 bioavailability by reducing the amount of bioavailable IGFBPs. Overall IGF-1 bioactivity in vivo, therefore, represents the combined effect of interactions involving endocrine, autocrine, and paracrine sources of IGF-1, IGFBPs, and IGFBP proteases.
The IGFBPs are produced by a variety of different tissues. Hepatic IGFBP-3 and production of its acid-labile subunit are under stimulation by GH. Insulin is the primary regulator of hepatic IGFBP-1 production. Relatively little is known about the principal regulatory mechanisms that control the expression of IGFBP-2, IGFBP-4, IGFBP-5, and IGFBP-6.
Physiologic Effects of IGF-1
IGF-1 exerts its physiologic effects by binding to specific cell surface receptors. Although IGF-1 binds primarily to the IGF-1 receptor, some effects may be mediated through the IGF-2 and insulin receptors. The similarity in structure to insulin explains the ability of IGF-1 to bind (with low affinity) to the insulin receptor. The main effects of IGF-1 are regulation of somatic growth, cell proliferation, transformation, and apoptosis.
IGF-1 mediates the anabolic and linear growth-promoting effects of pituitary GH. IGF-1 stimulates bone formation, protein synthesis, glucose uptake in muscle, neuronal survival, and myelin synthesis. In cartilage cells, IGF-1 has synergistic effects with GH. IGF-1 increases replication of cells of the osteoblastic lineage, enhances osteoblastic collagen synthesis and matrix apposition rates, and decreases collagen degradation in calvariae. IGF-1 is also thought to stimulate bone resorption by enhanced osteoclastic recruitment, thus acting on both bone formation and resorption, possibly coupling the 2 processes. IGF-1 also reverses negative nitrogen balance during food deprivation and inhibits protein degradation in muscle. The importance of this hormone in linear growth is clearly demonstrated by the severe growth failure in children with congenital IGF-1 deficiency.
IGFs act as mitogens, stimulating DNA, RNA, and protein synthesis. Both of the IGFs are essential to embryonic development, and nanomolar concentrations of both persist in the circulation into adult life. After birth, however, IGF-1 appears to have the predominant role in regulating growth, whereas the physiologic postnatal role of IGF-2 is unknown. IGF-1 concentrations are low at birth, increase substantially during childhood and puberty, and begin to decline in the third decade, paralleling the secretion of GH. In adults, IGF-2 occurs in quantities 3-fold higher than those of IGF-1, is minimally GH dependent, and decreases modestly with age.
The IGF receptors are heterotetramers that belong to the same family of receptors as insulin. IGF-1 and IGF-2 bind specifically to 2 high-affinity membrane-associated receptors that are ligand-activated receptor kinases that become autophosphorylated on hormone binding. The receptor for IGF is composed of 2 extracellular spanning α-subunits and transmembrane β-subunits. The α-subunits have binding sites for IGF-1 and are linked by disulfide bonds. The β-subunit has a short extracellular domain, a transmembrane domain, and an intracellular domain. The intracellular part contains a tyrosine kinase domain, which constitutes the signal transduction mechanism. Ligand binding results in autophosphorylation of the receptor, increasing the kinase activity and allowing it to phosphorylate multiple substrate proteins, such as insulin receptor substrate 1 (IRS1). This produces a continued cascade of enzyme activation via phosphatidylinositol-3 kinase, Grb2 (growth factor receptor-bound protein 2), Syp (a phosphotyrosine phosphatase), Nck (an oncogenic protein), and Shc (src homology domain protein), in association with Grb2. This signaling cascade leads to activation of protein kinases including Raf, mitogen-activated protein kinase, 5 G kinase, and others involved in mediating growth and metabolic responses. A third receptor, the IGF-2 mannose-6-phosphate receptor, binds IGF-2 but has no known intracellular signaling actions.
The insulin and IGF-1 receptors, although similar in structure and function, play different physiologic roles in vivo. In healthy individuals, the insulin receptor is primarily involved in metabolic functions, whereas the IGF-1 receptor mediates growth and differentiation. The separation of these functions is controlled by several factors, including the tissue distribution of the respective receptors, the binding with high affinity of each ligand to its respective receptor, and the binding of IGF to IGFBPs.
Prolactin is a polypeptide hormone synthesized and secreted by lactotrophs in the anterior pituitary gland. The lactotrophs account for approximately 15%–20% of the cell population of the anterior pituitary gland. However, this percentage increases dramatically in response to elevated estrogen levels, particularly during pregnancy. Prolactin levels are higher in females than in males, and the role of prolactin in male physiology is not completely understood. Plasma concentrations of prolactin are highest during sleep and lowest during the waking hours in humans.
Regulation of Prolactin Release
Prolactin release is predominantly under tonic inhibition by dopamine derived from hypothalamic dopaminergic neurons. In addition, prolactin release is also under inhibitory control by somatostatin (SST), and γ-aminobutyric acid (GABA). However, the overall regulation of prolactin release is complex and involves not only inhibition by dopamine, but also stimulation by serotoninergic and opioidergic pathways, GnRH, and possibly galanin.
Dopaminergic inhibition of lactotroph release of prolactin is mediated by dopaminergic (D2) Gi protein–coupled receptors, resulting in inhibition of adenylate cyclase and inositol phosphate metabolism (see Figure 3–4). In addition, activation of the D2 receptor modifies at least 5 different ion channels. In particular, dopamine activates potassium current that induces plasma membrane hyperpolarization while decreasing voltage-activated calcium currents. Therefore, dopamine-induced inhibition of prolactin secretion is a function of the inhibition of adenylate cyclase activity, activation of voltage-sensitive potassium channels, and inhibition of voltage-sensitive calcium channels.
Prolactin release is affected by a large variety of stimuli provided by the environment and the internal milieu, the most important being sucking, and increased levels of ovarian steroid hormones, primarily estrogen (Figure 3–7). The release of prolactin in response to sucking is a classical neuroendocrine reflex also referred to as a stimulus-secretion reflex. This surge in prolactin release in response to a sucking stimulus is mediated by a decrease in the amount of dopamine released at the median eminence, relieving the lactotroph from tonic inhibition. The growth of lactotrophs and the expression of prolactin gene are increased by high estrogen concentrations, such as those that occur during pregnancy.
Physiologic effects of prolactin. Prolactin plays an important role in the normal development of mammary tissue and in milk production. Prolactin release is predominantly under negative control by hypothalamic dopamine. Sucking stimulates the release of prolactin. Prolactin inhibits its own release by stimulating dopamine release from the hypothalamus. AVP, arginine vasopressin; DA, dopamine; GPCR, G protein–coupled receptor; OT, oxytocin; TRH, thyrotropin-releasing hormone.
Several neuropeptides have been identified as prolactin releasing factors. These include TRH, oxytocin, vasoactive intestinal peptide, and neurotensin. These releasing factors fall into two categories of peptides: those which are active in the presence of the physiologic inhibitory tone of dopamine and those that have an effect only when dopamine inhibitory tone has been removed. TRH belongs to the first category and is a potent stimulus for the release of prolactin through stimulation of TRH receptors on the lactotroph cell membrane. However, the physiologic role of TRH-induced prolactin release is unclear. Although exogenous administration of TRH can elevate levels of prolactin; it is important to note that release of TSH and prolactin do not always occur hand in hand under physiologic conditions.
Prolactin regulates its own secretion through a short-loop feedback mechanism by binding to prolactin receptors located in neuroendocrine dopaminergic neurons; resulting in increased hypothalamic dopamine synthesis (see Figure 3–7). When the concentration of dopamine in the hypothalamo-hypophysial portal blood rises, the release of prolactin from the lactotrophs is suppressed.
Physiologic Effects of Prolactin
The physiologic effects of prolactin are mediated by the prolactin receptor; a single membrane-bound protein that belongs to class 1 of the cytokine receptor superfamily (see Figure 3–4). Prolactin receptors are found in the mammary gland and the ovary, 2 of the best-characterized sites of prolactin actions in mammals, as well as in various regions of the brain. Activation of the prolactin receptor involves ligand-induced sequential receptor dimerization. Prolactin-mediated activation of prolactin receptor results in tyrosine phosphorylation of numerous cellular proteins, including the receptor itself.
The main physiologic effects of prolactin are stimulation of growth and development of the mammary gland, synthesis of milk, and maintenance of milk secretion (see Figure 3–7 and Chapter 9). Prolactin stimulates glucose and amino acid uptake and synthesis of the milk proteins β-casein and α-lactalbumin, the milk sugar lactose, and milk fats by the mammary epithelial cells. During pregnancy, prolactin prepares the breast for lactation. The production and secretion of milk is prevented during pregnancy by the high progesterone levels. Additional effects of prolactin include inhibition of GnRH release, progesterone biosynthesis, and luteal cell hypertrophy during pregnancy. Prolactin also modulates reproductive and parental behavior.