Six major hormones are secreted by the anterior lobe of the pituitary: TSH, FSH, LH, ACTH, growth hormone, and prolactin. Each hormone is secreted by a different cell type (except FSH and LH, which are secreted by the same cell type). The cell types are denoted by the suffix “troph,” meaning nutritive. Thus, TSH is secreted by thyrotrophs (5%), FSH and LH by gonadotrophs (15%), ACTH bycorticotrophs (15%), growth hormone by somatotrophs(20%), and prolactin by lactotrophs (15%). (The percentages give the representation of each cell type in the anterior pituitary gland.)
Each of the anterior pituitary hormones is a peptide or polypeptide. As described, the synthesis of peptide hormones includes the following steps: transcription of DNA to mRNA in the nucleus; translation of mRNA to a preprohormone on the ribosomes; and posttranslational modification of the preprohormone on the endoplasmic reticulum and the Golgi apparatus to produce the final hormone. The hormone is stored in membrane-bound secretory granules for subsequent release. When the anterior pituitary is stimulated by a hypothalamic-releasing hormone or a release-inhibiting hormone (e.g., thyrotrophs are stimulated by TRH to secrete TSH), there is exocytosis of the secretory granules; the anterior pituitary hormone (e.g., TSH) enters capillary blood and is delivered by the systemic circulation to the target tissue (e.g., thyroid gland).
The hormones of the anterior lobe are organized in “families,” according to structural and functional homology. TSH, FSH, and LH are structurally related and constitute one family, ACTH is part of a second family, and growth hormone and prolactin constitute a third family.
TSH, FSH, LH, and ACTH are discussed briefly in this section and later in the chapter in the context of their actions. (TSH is discussed within the context of the thyroid gland. ACTH is discussed in the context of the adrenal cortex. FSH and LH are discussed in Chapter 10 with male and female reproductive physiology.) Growth hormone and prolactin are discussed in this section.
TSH, FSH, and LH Family
TSH, FSH, and LH are all glycoproteins with sugar moieties covalently linked to asparagine residues in their polypeptide chains. Each hormone consists of two subunits, α and β, which are not covalently linked; none of the subunits alone is biologically active. The α subunits of TSH, FSH, and LH are identical and are synthesized from the same mRNA. The β subunits for each hormone are different and, therefore, confer the biologic specificity (although the β subunits have a high degree of homology among the different hormones). During the biosynthetic process, pairing of the α and β subunits begins in the endoplasmic reticulum and continues in the Golgi apparatus. In the secretory granules, the paired molecules are refolded into more stable forms prior to secretion.
The placental hormone human chorionic gonadotropin (HCG) is structurally related to the TSH-FSH-LH family. Thus, HCG is a glycoprotein with the identical α chain and its own β chain, which confers its biologic specificity.
The ACTH family is derived from a single precursor, pro-opiomelanocortin (POMC). The ACTH family includes ACTH, γ- and β-lipotropin, β-endorphin, and melanocyte-stimulating hormone (MSH). ACTH is the only hormone in this family with well-established physiologic actions in humans. MSH is involved in pigmentation in lower vertebrates but has little activity in humans. β-Endorphin is an endogenous opiate.
The preprohormone for this group, prepro-opiomelanocortin, is transcribed from a single gene. The signal peptide is cleaved in the endoplasmic reticulum, yielding POMC, the precursor to the ACTH family. Endopeptidases then hydrolyze peptide bonds in POMC and intermediates to produce the members of the ACTH family (Fig. 9-10). The anterior pituitary in humans produces mainly ACTH, γ-lipotropin, and β-endorphin.
Figure 9–10 The hormones derived from pro-opiomelanocortin (POMC). The fragment contains γ-MSH; ACTH contains α-MSH; and γ-lipotropin contains β-MSH. ACTH, Adrenocorticotropic hormone; MSH, melanocyte-stimulating hormone.
It is noteworthy that MSH activity is found in POMC and in several of its products: The “fragment,” which is left over from hydrolysis of the ACTH intermediate, contains γ-MSH; ACTH contains α-MSH; and γ-lipotropin contains β-MSH. These MSH-containing fragments can cause skin pigmentation in humans if their blood levels are increased. For example, in Addison disease (primary adrenal insufficiency), POMC and ACTH levels are increased by negative feedback. Because POMC and ACTH contain MSH activity, skin pigmentation is a symptom of this disorder.
Growth hormone is secreted throughout life. It is the single most important hormone for normal growth to adult stature. Considering the broad nature of this task (growth), it is not surprising that growth hormone has profound effects on protein, carbohydrate, and fat metabolism.
Chemistry of Growth Hormone
Growth hormone is synthesized in the somatotrophs of the anterior lobe of the pituitary and also is called somatotropin or somatotropic hormone. Human growth hormone contains 191 amino acids in a straight-chain polypeptide with 2 internal disulfide bridges. The gene for growth hormone is a member of a family of genes for related peptides, prolactin and human placental lactogen. The synthesis of growth hormone is stimulated by GHRH, its hypothalamic-releasing hormone.
Human growth hormone is structurally similar to prolactin, which is synthesized by lactotrophs in the anterior lobe, and to human placental lactogen, which is synthesized in the placenta. Prolactin, a 198-amino acid straight-chain polypeptide with 3 disulfide bridges, has 75% homology with growth hormone. Human placental lactogen, a 191-amino acid straight-chain polypeptide with two disulfide bridges, has 80% homology.
Regulation of Growth Hormone Secretion
Growth hormone is secreted in a pulsatile pattern, with bursts of secretion occurring approximately every 2 hours. The largest secretory burst occurs within 1 hour of falling asleep (during sleep stages III and IV). The bursting pattern, in terms of both frequency and magnitude, is affected by several agents that alter the overall level of growth hormone secretion (Table 9-4).
Table 9–4 Factors Affecting Growth Hormone Secretion
Decreased glucose concentration
Decreased free fatty acid concentration
Fasting or starvation
Hormones of puberty (estrogen, testosterone)
Stage III and IV sleep
Increased glucose concentration
Increased free fatty acid concentration
Growth hormone secretory rates are not constant over a lifetime. The rate of secretion increases steadily from birth into early childhood. During childhood, secretion remains relatively stable. At puberty,there is an enormous secretory burst, induced in females by estrogen and in males by testosterone. The high pubertal levels of growth hormone are associated with both increased frequency and increased magnitude of the secretory pulses and are responsible for the growth spurt of puberty. After puberty, the rate of growth hormone secretion declines to a stable level. Finally, in senescence, growth hormone secretory rates and pulsatility decline to their lowest levels.
The major factors that alter growth hormone secretion are summarized in Table 9-4. Hypoglycemia (a decrease in blood glucose concentration) and starvation are potent stimuli for growth hormone secretion. Other stimuli for secretion are exercise and various forms of stress including trauma, fever, and anesthesia. The highest rates of growth hormone secretion occur during puberty, and the lowest rates occur in senescence.
Regulation of growth hormone secretion is illustrated in Figure 9-11, which shows the relationship between the hypothalamus, the anterior lobe of the pituitary, and the target tissues for growth hormone. Secretion of growth hormone by the anterior pituitary is controlled by two pathways from the hypothalamus, one stimulatory (GHRH) and the other inhibitory (somatostatin, also known as somatotropin release–inhibiting factor [SRIF]).
Figure 9–11 Regulation of growth hormone secretion. GHRH, Growth hormone–releasing hormone; IGF, insulin-like growth factor; SRIF, somatotropin release–inhibiting factor.
GHRH acts directly on somatotrophs of the anterior pituitary to induce transcription of the growth hormone gene and, thereby, to stimulate both synthesis and secretion of growth hormone. In initiating its action on the somatotroph, GHRH binds to a membrane receptor, which is coupled through a Gs protein to both adenylyl cyclase and phospholipase C. Thus, GHRH stimulates growth hormone secretion by utilizing both cAMP and IP3/Ca2+ as second messengers.
Somatostatin (somatotropin release–inhibiting hormone, SRIF) is also secreted by the hypothalamus and acts on the somatotrophs to inhibit growth hormone secretion. Somatostatin inhibits growth hormone secretion by blocking the action of GHRH on the somatotroph. Somatostatin binds to its own membrane receptor, which is coupled to adenylyl cyclase by a Gi protein, inhibiting the generation of cAMP and decreasing growth hormone secretion.
Growth hormone secretion is regulated by negative feedback (see Fig. 9-11). Three feedback loops including both long and short loops are involved. (1) GHRH inhibits its own secretion from the hypothalamus via an ultrashort-loop feedback. (2) Somatomedins, which are by-products of the growth hormone action on target tissues, inhibit secretion of growth hormone by the anterior pituitary. (3) Both growth hormone and somatomedins stimulate the secretion of somatostatin by the hypothalamus. The overall effect of this third loop is inhibitory (i.e., negative feedback) because somatostatin inhibits growth hormone secretion by the anterior pituitary.
Actions of Growth Hormone
Growth hormone has multiple metabolic actions on liver, muscle, adipose tissue, and bone, as well as growth-promoting actions in virtually every other organ. The actions of growth hormone include effects on linear growth, protein synthesis and organ growth, carbohydrate metabolism, and lipid metabolism.
Some of the actions of growth hormone result from the hormone’s direct effect on target tissues such as skeletal muscle, the liver, or adipose tissue. Other actions of growth hormone are mediated indirectlythrough the production of somatomedins (or insulin-like growth factors [IGFs]) in the liver. The most important of the somatomedins is somatomedin C or IGF-1. Somatomedins act on target tissues through IGF receptors that are similar to the insulin receptor, having intrinsic tyrosine kinase activity and exhibiting autophosphorylation. The growth-promoting effects of growth hormone are mediated largely through production of somatomedins.
The actions of growth hormone are described as follows:
Diabetogenic effect. Growth hormone causes insulin resistance and decreases glucose uptake and utilization by target tissues such as muscle and adipose tissue. These effects are called “diabetogenic” because they produce an increase in blood glucose concentration, as occurs when insulin is lacking or when tissues are resistant to insulin (e.g., diabetes mellitus). Growth hormone also increases lipolysis in adipose tissue. As a consequence of these metabolic effects, growth hormone causes an increase in blood insulin levels.
Increased protein synthesis and organ growth. In virtually all organs, growth hormone increases the uptake of amino acids and stimulates the synthesis of DNA, RNA, and protein. These effects account for the hormone’s growth-promoting actions: increased lean body mass and increased organ size. As noted, many of the growth effects of growth hormone are mediated by somatomedins.
Increased linear growth. The most striking effect of growth hormone is its ability to increase linear growth. Mediated by the somatomedins, growth hormone alters every aspect of cartilage metabolism: stimulation of DNA synthesis, RNA synthesis, and protein synthesis. In growing bones, the epiphyseal plates widen and more bone is laid down at the ends of long bones. There also is increased metabolism in cartilage-forming cells and proliferation of chondrocytes.
Pathophysiology of Growth Hormone
The pathophysiology of growth hormone includes deficiency or excess of the hormone, with predictable effects on linear growth, organ growth, and carbohydrate and lipid metabolism.
Growth hormone deficiency in children results in failure to grow, short stature, mild obesity, and delayed puberty. The causes of growth hormone deficiency include defects at every step in the hypothalamic–anterior pituitary–target tissue axis: decreased secretion of GHRH due to hypothalamic dysfunction; primary deficiencies of growth hormone secretion from the anterior pituitary; failure to generate somatomedins in the liver; and deficiency of growth hormone or somatomedin receptors in target tissues (growth hormone resistance). Growth hormone deficiency in children is treated with human growth hormone replacement.
Growth hormone excess causes acromegaly and is most often due to a growth hormone–secreting pituitary adenoma. The consequences of excess growth hormone differ, depending on whether the excess occurs before or after puberty. Before puberty, excessive levels of growth hormone cause gigantism (increased linear growth) because of intense hormonal stimulation at the epiphyseal plates. After puberty, when linear growth is complete and can no longer be influenced, excess levels of growth hormone cause increased periosteal bone growth, increased organ size, increased hand and foot size, enlargement of the tongue, coarsening of facial features, insulin resistance, and glucose intolerance. Conditions with excess secretion of growth hormone are treated with somatostatin analogues (e.g., octreotide), which, like endogenous somatostatin, inhibit growth hormone secretion by the anterior pituitary.
Prolactin is the major hormone responsible for milk production and also participates in the development of the breasts. In nonpregnant, nonlactating females and in males, blood levels of prolactin are low. However, during pregnancy and lactation, blood levels of prolactin increase, consistent with the hormone’s role in breast development and lactogenesis (milk production).
Chemistry of Prolactin
Prolactin is synthesized by the lactotrophs, which represent approximately 15% of the tissue in the anterior lobe of the pituitary. The number of lactotrophs increases during pregnancy and lactation when the demand for prolactin is increased. Chemically, prolactin is related to growth hormone, having 198 amino acids in a single-chain polypeptide with three internal disulfide bridges.
Stimuli that increase or decrease prolactin secretion do so by altering transcription of the prolactin gene. Thus, TRH, a stimulant of prolactin secretion, increases transcription of the prolactin gene, whereas dopamine, an inhibitor of prolactin secretion, decreases transcription of the gene.
Regulation of Prolactin Secretion
Figure 9-12 illustrates the hypothalamic control of prolactin secretion. There are two regulatory paths from the hypothalamus, one inhibitory (via dopamine, which acts by decreasing cAMP levels) and the other stimulatory (via TRH).
Figure 9–12 Regulation of prolactin secretion. TRH, Thyrotropin-releasing hormone.
In persons who are not pregnant or lactating, prolactin secretion is tonically inhibited by dopamine (prolactin-inhibiting factor, PIF) from the hypothalamus. In other words, the inhibitory effect of dopamine dominates and overrides the stimulatory effect of TRH. In contrast to other hypothalamic-releasing or release-inhibiting hormones, which are peptides, dopamine is a catecholamine.
Two questions arise regarding this inhibitory action of dopamine: What is the source of hypothalamic dopamine? How does dopamine reach the anterior lobe? There are three sources and three routes: (1) The major source of dopamine is dopaminergic neurons in the hypothalamus, which synthesize and secrete dopamine into the median eminence. This dopamine enters capillaries that drain into the hypothalamic-hypophysial portal vessels and deliver dopamine directly and in high concentration to the anterior pituitary, where it inhibits prolactin secretion. (2) Dopamine also is secreted by dopaminergic neurons of the posterior lobe of the pituitary, reaching the anterior lobe by short connecting portal veins. (3) Finally, nonlactotroph cells of the anterior pituitary secrete a small amount of dopamine that diffuses a short distance to the lactotrophs and inhibits prolactin secretion by a paracrine mechanism.
The factors that alter prolactin secretion are summarized in Table 9-5. Prolactin inhibits its own secretion by increasing the synthesis and secretion of dopamine from the hypothalamus (see Fig. 9-12). This action of prolactin constitutes negative feedback because stimulation of dopamine secretion causes inhibition of prolactin secretion. Pregnancy and breast-feeding (suckling) are the most important stimuli for prolactin secretion. For example, during breast-feeding, serum prolactin levels can increase to more than tenfold the basal levels. During suckling, afferent fibers from the nipple carry information to the hypothalamus and inhibit dopamine secretion; by releasing the inhibitory effect of dopamine, prolactin secretion is increased. The effects of dopamine, dopamine agonists, and dopamine antagonists on prolactin secretion are predictable, based on feedback regulation (see Fig. 9-12). Thus, dopamine itself and dopamine agonists such as bromocriptine inhibit prolactin secretion, whereas dopamine antagonists stimulate prolactin secretion by “inhibiting the inhibition” by dopamine.
Table 9–5 Factors Affecting Prolactin Secretion
Bromocriptine (dopamine agonist)
Prolactin (negative feedback)
TRH, Thyrotropin-releasing hormone.
Actions of Prolactin
Prolactin, in a supportive role with estrogen and progesterone, stimulates development of the breasts, promotes milk secretion from the breasts during lactation, and suppresses ovulation.
Breast development. At puberty, prolactin, with estrogen and progesterone, stimulates proliferation and branching of the mammary ducts. During pregnancy, prolactin (again with estrogen and progesterone) stimulates growth and development of the mammary alveoli, which will produce milk once parturition occurs.
Lactogenesis (milk production). The major action of prolactin is stimulation of milk production and secretion in response to suckling. (Interestingly, pregnancy does not have to occur for lactation to be possible; if there is sufficient stimulation of the nipple, prolactin is secreted and milk is produced.) Prolactin stimulates milk production by inducing the synthesis of the components of milk including lactose(the carbohydrate of milk), casein (the protein of milk), and lipids. The mechanism of action of prolactin on the breast involves binding of prolactin to a cell membrane receptor and, via an unknown second messenger, inducing transcription of the genes for enzymes in the biosynthetic pathways for lactose, casein, and lipid.
Although prolactin levels are high during pregnancy, lactation does not occur because the high levels of estrogen and progesterone down-regulate prolactin receptors in the breast and block the action of prolactin. At parturition, estrogen and progesterone levels drop precipitously and their inhibitory actions cease. Prolactin can then stimulate lactogenesis, and lactation can occur.
Inhibition of ovulation. In females, prolactin inhibits ovulation by inhibiting the synthesis and release of gonadotropin-releasing hormone (GnRH) (see Chapter 10). Inhibition of GnRH secretion and, secondarily, inhibition of ovulation account for the decreased fertility during breast-feeding. In males with high prolactin levels (e.g., due to a prolactinoma), there is a parallel inhibitory effect on GnRH secretion and spermatogenesis, resulting in infertility.
Pathophysiology of Prolactin
The pathophysiology of prolactin can involve either a deficiency of prolactin, which results in the inability to lactate, or an excess of prolactin, which causes galactorrhea (excessive milk production).
Prolactin deficiency can be caused by either destruction of the entire anterior lobe of the pituitary or selective destruction of the lactotrophs. Prolactin deficiency results, predictably, in a failure to lactate.
Prolactin excess can be caused by destruction of the hypothalamus, interruption of the hypothalamic-hypophysial tract, or prolactinomas (prolactin-secreting tumors). In cases of hypothalamic destruction or interruption of the hypothalamic-hypophysial tract, increased prolactin secretion occurs because of the loss of tonic inhibition by dopamine. The major symptoms of excess prolactin secretion are galactorrheaand infertility (which is caused by inhibition of GnRH secretion by the high prolactin levels). Whether the result of hypothalamic failure or a prolactinoma, prolactin excess can be treated by administration ofbromocriptine, a dopamine agonist. Like dopamine, bromocriptine inhibits prolactin secretion by the anterior pituitary.