Each anterior pituitary hormone is under unique control, and each exhibits highly specific normal and dysregulated secretory characteristics.
PRL consists of 198 amino acids and has a molecular mass of 21,500 kDa; it is weakly homologous to GH and human placental lactogen (hPL), reflecting the duplication and divergence of a common GH-PRL-hPL precursor gene. PRL is synthesized in lactotropes, which constitute about 20% of anterior pituitary cells. Lactotropes and somatotropes are derived from a common precursor cell that may give rise to a tumor that secretes both PRL and GH. Marked lactotrope cell hyperplasia develops during pregnancy and the first few months of lactation. These transient functional changes in the lactotrope population are induced by estrogen.
Normal adult serum PRL levels are about 10–25 μg/L in women and 10–20 μg/L in men. PRL secretion is pulsatile, with the highest secretory peaks occurring during rapid eye movement sleep. Peak serum PRL levels (up to 30 μg/L) occur between 4:00 and6:00 a.m. The circulating half-life of PRL is about 50 min.
PRL is unique among the pituitary hormones in that the predominant central control mechanism is inhibitory, reflecting dopamine-mediated suppression of PRL release. This regulatory pathway accounts for the spontaneous PRL hypersecretion that occurs with pituitary stalk section, often a consequence of compressive mass lesions at the skull base. Pituitary dopamine type 2 (D2) receptors mediate inhibition of PRL synthesis and secretion. Targeted disruption (gene knockout) of the murine D2 receptor in mice results in hyperprolactinemia and lactotrope proliferation. As discussed below, dopamine agonists play a central role in the management of hyperprolactinemic disorders.
Thyrotropin-releasing hormone (TRH) (pyro Glu-His-Pro-NH2) is a hypothalamic tripeptide that elicits PRL release within 15–30 min after intravenous injection. The physiologic relevance of TRH for PRL regulation is unclear, and it appears primarily to regulate TSH (Chap. 405). Vasoactive intestinal peptide (VIP) also induces PRL release, whereas glucocorticoids and thyroid hormone weakly suppress PRL secretion.
Serum PRL levels rise transiently after exercise, meals, sexual intercourse, minor surgical procedures, general anesthesia, chest wall injury, acute myocardial infarction, and other forms of acute stress. PRL levels increase markedly (about tenfold) during pregnancy and decline rapidly within 2 weeks of parturition. If breast-feeding is initiated, basal PRL levels remain elevated; suckling stimulates transient reflex increases in PRL levels that last for about 30–45 min. Breast suckling activates neural afferent pathways in the hypothalamus that induce PRL release. With time, suckling-induced responses diminish and interfeeding PRL levels return to normal.
The PRL receptor is a member of the type I cytokine receptor family that also includes GH and interleukin (IL) 6 receptors. Ligand binding induces receptor dimerization and intracellular signaling by Janus kinase (JAK), which stimulates translocation of the signal transduction and activators of transcription (STAT) family to activate target genes. In the breast, the lobuloalveolar epithelium proliferates in response to PRL, placental lactogens, estrogen, progesterone, and local paracrine growth factors, including insulin-like growth factor I (IGF-I).
PRL acts to induce and maintain lactation, decrease reproductive function, and suppress sexual drive. These functions are geared toward ensuring that maternal lactation is sustained and not interrupted by pregnancy. PRL inhibits reproductive function by suppressing hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin secretion and by impairing gonadal steroidogenesis in both women and men. In the ovary, PRL blocks folliculogenesis and inhibits granulosa cell aromatase activity, leading to hypoestrogenism and anovulation. PRL also has a luteolytic effect, generating a shortened, or inadequate, luteal phase of the menstrual cycle. In men, attenuated LH secretion leads to low testosterone levels and decreased spermatogenesis. These hormonal changes decrease libido and reduce fertility in patients with hyperprolactinemia.
GH is the most abundant anterior pituitary hormone, and GH-secreting somatotrope cells constitute up to 50% of the total anterior pituitary cell population. Mammosomatotrope cells, which coexpress PRL with GH, can be identified by using double immunostaining techniques. Somatotrope development and GH transcription are determined by expression of the cell-specific Pit-1 nuclear transcription factor. Five distinct genes encode GH and related proteins. The pituitary GH gene (hGH-N) produces two alternatively spliced products that give rise to 22-kDa GH (191 amino acids) and a less abundant 20-kDa GH molecule with similar biologic activity. Placental syncytiotrophoblast cells express a GH variant (hGH-V) gene; the related hormone human chorionic somatotropin (HCS) is expressed by distinct members of the gene cluster.
GH secretion is controlled by complex hypothalamic and peripheral factors. GH-releasing hormone (GHRH) is a 44-amino-acid hypothalamic peptide that stimulates GH synthesis and release. Ghrelin, an octanoylated gastric-derived peptide, and synthetic agonists of the GHS-R induce GHRH and also directly stimulate GH release. Somatostatin (somatotropin-release inhibiting factor [SRIF]) is synthesized in the medial preoptic area of the hypothalamus and inhibits GH secretion. GHRH is secreted in discrete spikes that elicit GH pulses, whereas SRIF sets basal GH secretory tone. SRIF also is expressed in many extrahypothalamic tissues, including the central nervous system (CNS), gastrointestinal tract, and pancreas, where it also acts to inhibit islet hormone secretion. IGF-I, the peripheral target hormone for GH, feeds back to inhibit GH; estrogen induces GH, whereas chronic glucocorticoid excess suppresses GH release.
Surface receptors on the somatotrope regulate GH synthesis and secretion. The GHRH receptor is a G protein–coupled receptor (GPCR) that signals through the intracellular cyclic AMP pathway to stimulate somatotrope cell proliferation as well as GH production. Inactivating mutations of the GHRH receptor cause profound dwarfism. A distinct surface receptor for ghrelin, the gastric-derived GH secretagogue, is expressed in both the hypothalamus and pituitary. Somatostatin binds to five distinct receptor subtypes (SSTR1 to SSTR5); SSTR2 and SSTR5 subtypes preferentially suppress GH (and TSH) secretion.
GH secretion is pulsatile, with highest peak levels occurring at night, generally correlating with sleep onset. GH secretory rates decline markedly with age so that hormone levels in middle age are about 15% of pubertal levels. These changes are paralleled by an age-related decline in lean muscle mass. GH secretion is also reduced in obese individuals, although IGF-I levels may not be suppressed, suggesting a change in the setpoint for feedback control. Elevated GH levels occur within an hour of deep sleep onset as well as after exercise, physical stress, and trauma and during sepsis. Integrated 24-h GH secretion is higher in women and is also enhanced by estrogen replacement likely reflective of increased peripheral GH-resistance. Using standard assays, random GH measurements are undetectable in ~50% of daytime samples obtained from healthy subjects and are also undetectable in most obese and elderly subjects. Thus, single random GH measurements do not distinguish patients with adult GH deficiency from normal persons.
GH secretion is profoundly influenced by nutritional factors. Using newer ultrasensitive GH assays with a sensitivity of 0.002 μg/L, a glucose load suppresses GH to <0.7 μg/L in women and to <0.07 μg/L in men. Increased GH pulse frequency and peak amplitudes occur with chronic malnutrition or prolonged fasting. GH is stimulated by intravenous L-arginine, dopamine, and apomorphine (a dopamine receptor agonist), as well as by α-adrenergic pathways. β-Adrenergic blockade induces basal GH and enhances GHRH- and insulin-evoked GH release.
The pattern of GH secretion may affect tissue responses. The higher GH pulsatility observed in men compared with the relatively continuous basal GH secretion in women may be an important biologic determinant of linear growth patterns and liver enzyme induction.
The 70-kDa peripheral GH receptor protein has structural homology with the cytokine/hematopoietic superfamily. A fragment of the receptor extracellular domain generates a soluble GH binding protein (GHBP) that interacts with GH in the circulation. The liver and cartilage contain the greatest number of GH receptors. GH binding to preformed receptor dimers is followed by internal rotation and subsequent signaling through the JAK/STAT pathway. Activated STAT proteins translocate to the nucleus, where they modulate expression of GH-regulated target genes. GH analogues that bind to the receptor but are incapable of mediating receptor signaling are potent antagonists of GH action. A GH receptor antagonist (pegvisomant) is approved for treatment of acromegaly.
GH induces protein synthesis and nitrogen retention and impairs glucose tolerance by antagonizing insulin action. GH also stimulates lipolysis, leading to increased circulating fatty acid levels, reduced omental fat mass, and enhanced lean body mass. GH promotes sodium, potassium, and water retention and elevates serum levels of inorganic phosphate. Linear bone growth occurs as a result of complex hormonal and growth factor actions, including those of IGF-I. GH stimulates epiphyseal prechondrocyte differentiation. These precursor cells produce IGF-I locally, and their proliferation is also responsive to the growth factor.
Insulin-Like Growth Factors
Although GH exerts direct effects in target tissues, many of its physiologic effects are mediated indirectly through IGF-I, a potent growth and differentiation factor. The liver is the major source of circulating IGF-I. In peripheral tissues, IGF-I also exerts local paracrine actions that appear to be both dependent on and independent of GH. Thus, GH administration induces circulating IGF-I as well as stimulating local IGF-I production in multiple tissues.
Both IGF-I and IGF-II are bound to high-affinity circulating IGF-binding proteins (IGFBPs) that regulate IGF bioactivity. Levels of IGFBP3 are GH-dependent, and it serves as the major carrier protein for circulating IGF-I. GH deficiency and malnutrition usually are associated with low IGFBP3 levels. IGFBP1 and IGFBP2 regulate local tissue IGF action but do not bind appreciable amounts of circulating IGF-I.
Serum IGF-I concentrations are profoundly affected by physiologic factors. Levels increase during puberty, peak at 16 years, and subsequently decline by >80% during the aging process. IGF-I concentrations are higher in women than in men. Because GH is the major determinant of hepatic IGF-I synthesis, abnormalities of GH synthesis or action (e.g., pituitary failure, GHRH receptor defect, GH receptor defect or pharmacologic GH receptor blockade) reduce IGF-I levels. Hypocaloric states are associated with GH resistance; IGF-I levels are therefore low with cachexia, malnutrition, and sepsis. In acromegaly, IGF-I levels are invariably high and reflect a log-linear relationship with circulating GH concentrations.
Injected IGF-I (100 μg/kg) induces hypoglycemia, and lower doses improve insulin sensitivity in patients with severe insulin resistance and diabetes. In cachectic subjects, IGF-I infusion (12 μg/kg per hour) enhances nitrogen retention and lowers cholesterol levels. Longer-term subcutaneous IGF-I injections enhance protein synthesis and are anabolic. Although bone formation markers are induced, bone turnover also may be stimulated by IGF-I. IGF-I has only been approved for use in patients with GH-resistance syndromes.
IGF-I side effects are dose-dependent, and overdose may result in hypoglycemia, hypotension, fluid retention, temporomandibular jaw pain, and increased intracranial pressure, all of which are reversible. Avascular femoral head necrosis has been reported. Chronic excess IGF-I administration presumably would result in features of acromegaly.
ACTH-secreting corticotrope cells constitute about 20% of the pituitary cell population. ACTH (39 amino acids) is derived from the POMC precursor protein (266 amino acids) that also generates several other peptides, including β-lipotropin, β-endorphin, met-enkephalin, α-melanocyte-stimulating hormone (α-MSH), and corticotropin-like intermediate lobe protein (CLIP). The POMC gene is potently suppressed by glucocorticoids and induced by corticotropin-releasing hormone (CRH), arginine vasopressin (AVP), and proinflammatory cytokines, including IL-6, as well as leukemia inhibitory factor.
CRH, a 41-amino-acid hypothalamic peptide synthesized in the paraventricular nucleus as well as in higher brain centers, is the predominant stimulator of ACTH synthesis and release. The CRH receptor is a GPCR that is expressed on the corticotrope and signals to induce POMC transcription.
ACTH secretion is pulsatile and exhibits a characteristic circadian rhythm, peaking at about 6 a.m. and reaching a nadir about midnight. Adrenal glucocorticoid secretion, which is driven by ACTH, follows a parallel diurnal pattern. ACTH circadian rhythmicity is determined by variations in secretory pulse amplitude rather than changes in pulse frequency. Superimposed on this endogenous rhythm, ACTH levels are increased by physical and psychological stress, exercise, acute illness, and insulin-induced hypoglycemia.
Glucocorticoid-mediated negative regulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs as a consequence of both hypothalamic CRH suppression and direct attenuation of pituitary POMC gene expression and ACTH release. In contrast, loss of cortisol feedback inhibition, as occurs in primary adrenal failure, results in extremely high ACTH levels.
Acute inflammatory or septic insults activate the HPA axis through the integrated actions of proinflammatory cytokines, bacterial toxins, and neural signals. The overlapping cascade of ACTH-inducing cytokines (tumor necrosis factor [TNF]; IL-1, -2, and -6; and leukemia inhibitory factor) activates hypothalamic CRH and AVP secretion, pituitary POMC gene expression, and local pituitary paracrine cytokine networks. The resulting cortisol elevation restrains the inflammatory response and enables host protection. Concomitantly, cytokine-mediated central glucocorticoid receptor resistance impairs glucocorticoid suppression of the HPA. Thus, the neuroendocrine stress response reflects the net result of highly integrated hypothalamic, intrapituitary, and peripheral hormone and cytokine signals acting to regulate cortisol secretion.
The major function of the HPA axis is to maintain metabolic homeostasis and mediate the neuroendocrine stress response. ACTH induces adrenocortical steroidogenesis by sustaining adrenal cell proliferation and function. The receptor for ACTH, designated melanocortin-2 receptor, is a GPCR that induces steroidogenesis by stimulating a cascade of steroidogenic enzymes (Chap. 406).
GONADOTROPINS: FSH AND LH
Gonadotrope cells constitute about 10% of anterior pituitary cells and produce two gonadotropin hormones—LH and FSH. Like TSH and hCG, LH and FSH are glycoprotein hormones that comprise α and β subunits. The α subunit is common to these glycoprotein hormones; specificity of hormone function is conferred by the β subunits, which are expressed by separate genes.
Gonadotropin synthesis and release are dynamically regulated. This is particularly true in women, in whom rapidly fluctuating gonadal steroid levels vary throughout the menstrual cycle. Hypothalamic GnRH, a 10-amino-acid peptide, regulates the synthesis and secretion of both LH and FSH. Brain kisspeptin, a product of the KISSI gene regulates hypothalamic GnRH release. GnRH is secreted in discrete pulses every 60–120 min, and the pulses in turn elicit LH and FSH pulses (Fig. 401e-3). The pulsatile mode of GnRH input is essential to its action; pulses prime gonadotrope responsiveness, whereas continuous GnRH exposure induces desensitization. Based on this phenomenon, long-acting GnRH agonists are used to suppress gonadotropin levels in children with precocious puberty and in men with prostate cancer (Chap. 115) and are used in some ovulation-induction protocols to reduce levels of endogenous gonadotropins (Chap. 412). Estrogens act at both the hypothalamus and the pituitary to modulate gonadotropin secretion. Chronic estrogen exposure is inhibitory, whereas rising estrogen levels, as occur during the preovulatory surge, exert positive feedback to increase gonadotropin pulse frequency and amplitude. Progesterone slows GnRH pulse frequency but enhances gonadotropin responses to GnRH. Testosterone feedback in men also occurs at the hypothalamic and pituitary levels and is mediated in part by its conversion to estrogens.
Although GnRH is the main regulator of LH and FSH secretion, FSH synthesis is also under separate control by the gonadal peptides inhibin and activin, which are members of the transforming growth factor β (TGF-β) family. Inhibin selectively suppresses FSH, whereas activin stimulates FSH synthesis (Chap. 412).
The gonadotropin hormones interact with their respective GPCRs expressed in the ovary and testis, evoking germ cell development and maturation and steroid hormone biosynthesis. In women, FSH regulates ovarian follicle development and stimulates ovarian estrogen production. LH mediates ovulation and maintenance of the corpus luteum. In men, LH induces Leydig cell testosterone synthesis and secretion, and FSH stimulates seminiferous tubule development and regulates spermatogenesis.
TSH-secreting thyrotrope cells constitute 5% of the anterior pituitary cell population. TSH shares a common α subunit with LH and FSH but contains a specific TSH β subunit. TRH is a hypothalamic tripeptide (pyroglutamyl histidylprolinamide) that acts through a pituitary GPCR to stimulate TSH synthesis and secretion; it also stimulates the lactotrope cell to secrete PRL. TSH secretion is stimulated by TRH, whereas thyroid hormones, dopamine, somatostatin, and glucocorticoids suppress TSH by overriding TRH induction.
Thyrotrope cell proliferation and TSH secretion are both induced when negative feedback inhibition by thyroid hormones is removed. Thus, thyroid damage (including surgical thyroidectomy), radiation-induced hypothyroidism, chronic thyroiditis, and prolonged goitrogen exposure are associated with increased TSH levels. Long-standing untreated hypothyroidism can lead to elevated TSH levels as well as thyrotrope hyperplasia and pituitary enlargement, which may be evident on magnetic resonance imaging.
TSH is secreted in pulses, although the excursions are modest in comparison to other pituitary hormones because of the low amplitude of the pulses and the relatively long half-life of TSH. Consequently, single determinations of TSH suffice to precisely assess its circulating levels. TSH binds to a GPCR on thyroid follicular cells to stimulate thyroid hormone synthesis and release (Chap. 405).