on 22-Oct-2021 (Fri)

The anterior pituitary gland produces six major hormones: (1) prolactin (PRL), (2) growth hormone (GH), (3) adrenocorticotropic hormone (ACTH), (4) luteinizing hormone (LH), (5) follicle-stimulating hormone (FSH), and (6) thyroid-stimulating hormone

Each of these pitu- itary hormones elicits specific trophic responses in peripheral target tissues. The hormonal products of those peripheral glands, in turn, exert feedback control at the level of the hypothalamus and pituitary to modulate pituitary function

The pituitary gland weighs ~600 mg and is located within the sella turcica ventral to the diaphragma sella; it consists of anatomically and functionally distinct anterior and posterior lobes. The bony sella is con- tiguous to vascular and neurologic structures, including the cavernous sinuses, cranial nerves, and optic chiasm. Thus, expanding intrasellar pathologic processes may have significant central mass effects in addi- tion to their endocrinologic impact.

The posterior pituitary is supplied by the inferior hypophyseal arter- ies. In contrast to the anterior pituitary, the posterior lobe is directly innervated by hypothalamic neurons (supraopticohypophyseal and tuberohypophyseal nerve tracts) via the pituitary stalk (Chap. 374) . Thus, posterior pituitary production of vasopressin (antidiuretic hor- mone [ADH]) and oxytocin is particularly sensitive to neuronal dam- age by lesions that affect the pituitary stalk or hypothalamus.

it is weakly homologous to GH and human placen- tal lactogen (hPL), reflecting the duplication and divergence of a com- mon GH-PRL-hPL precursor gene

PRL consists of 198 amino acids and has a molecular mass of 21,500 kDa; it is weakly homologous to GH and human placen- tal lactogen (hPL), reflecting the duplication and divergence of a com- mon 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 popula- tion are induced by estrogen

Normal adult serum PRL levels are about 10–25 g/L in women and 10–20 g/L in men. PRL secretion is pulsatile, with the highest secretory peaks occurring during rapid eye movement sleep

PRL is unique among the pituitary hormones in that the predom- inant central control mechanism is inhibitory, reflecting tonic dopa- mine-mediated suppression of PRL release. This regulatory pathway accounts for the spontaneous PRL hypersecretion that occurs with pituitary stalk section, often a consequence of head trauma or com- pressive mass lesions at the skull base. Pituitary dopamine type 2 (D 2 ) receptors mediate inhibition of PRL synthesis and secretion.

TRH primarily regulates TSH, and the physiologic relevance of TRH for PRL regulation is unclear (Chap. 375). 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 afferent neural pathways in the hypothalamus that induce PRL release.

he 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. Heterozygous mutations of the PRL receptor result in PRL insensitivity, hyperprolactinemia, and oligomenorrhea. 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.

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 hypoestro- genism 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.

GH is the most abundant anterior pituitary hormone, and GH-secreting somatotrope cells constitute up to 50% of the total anterior pituitary cell population.

Somatotrope development and GH transcription are determined by expression of the cell-specific Pit-1 nuclear tran- scription factor.

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. Ghre- lin, 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 synthe- sized 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 gluco- corticoid 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.

GH secretion is pulsatile, with highest peak levels occurring at night, generally correlating with sleep onset.

GH secretory rates decline mark- edly 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.

GH secretion is profoundly influenced by nutritional factors.

Increased GH pulse frequency and peak amplitudes occur with chronic malnutrition or prolonged fasting.

GH binding to preformed receptor dimers is followed by internal rotation and subsequent signaling through the JAK/STAT pathway.