2886 PART 12 Endocrinology and Metabolism

synthesize clinically useful antagonists (e.g., tamoxifen) and selective

estrogen response modulators (SERMs) such as raloxifene. These compounds generate distinct estrogen receptor conformations that alter

receptor interactions with components of the transcription machinery

(see below), thereby conferring their unique actions.

■ HORMONE SYNTHESIS AND PROCESSING

The synthesis of peptide hormones and their receptors occurs through

a classic pathway of gene expression: transcription → mRNA →

protein → posttranslational protein processing → intracellular sorting,

followed by membrane integration or secretion.

Many hormones are embedded within larger precursor polypeptides that are proteolytically processed to yield the biologically active

hormone. Examples include proopiomelanocortin (POMC) → ACTH;

proglucagon → glucagon; proinsulin → insulin; and pro-PTH → PTH,

among others. In many cases, such as POMC and proglucagon, these

precursors generate multiple biologically active peptides. For example,

proglucagon generates glucagon, as well as glucagon-like peptide 1

(GLP1), among other peptides. It is provocative that hormone precursors are typically inactive, presumably adding an additional level of

control through peptide processing. Prohormone conversion occurs not

only for peptide hormones but also for certain steroids (testosterone →

dihydrotestosterone) and thyroid hormone (T4 → T3

).

Peptide precursor processing is intimately linked to intracellular

sorting pathways that transport proteins to appropriate vesicles and

enzymes, resulting in specific cleavage steps, followed by protein

folding and translocation to secretory vesicles. Hormones destined for

secretion are translocated across the endoplasmic reticulum guided

by an amino-terminal signal sequence that subsequently is cleaved.

Cell-surface receptors are inserted into the membrane via short segments of hydrophobic amino acids that remain embedded within the

lipid bilayer. During translocation through the Golgi and endoplasmic

reticulum, hormones and receptors are subject to a variety of posttranslational modifications, such as glycosylation and phosphorylation,

which can alter protein conformation, modify circulating half-life, and

alter biologic activity.

Synthesis of most steroid hormones is based on modifications of the

precursor, cholesterol. Multiple regulated enzymatic steps are required

for the synthesis of testosterone (Chap. 391), estradiol (Chap. 392),

cortisol (Chap. 386), and vitamin D (Chap. 409). This large number of

synthetic steps predisposes to multiple genetic and acquired disorders

of steroidogenesis.

Endocrine genes contain regulatory DNA elements similar to those

found in many other genes, but their exquisite control by hormones

reflects the presence of specific hormone response elements. For example, the TSH genes are repressed directly by thyroid hormones acting

through the thyroid hormone receptor (TR), a member of the nuclear

receptor family. Steroidogenic enzyme gene expression requires specific transcription factors, such as steroidogenic factor 1 (SF1), acting

in conjunction with signals transmitted by trophic hormones (e.g.,

ACTH or LH). Once activated, SF1 functions as a master regulator,

inducing a large array of genes required for steroidogenic and metabolic pathways required for steroid synthesis. For some hormones,

substantial regulation occurs at the level of translational efficiency.

Insulin biosynthesis, although it requires ongoing gene transcription, is

regulated primarily at the translational and secretory levels in response

to the levels of glucose or amino acids.

■ HORMONE SECRETION, TRANSPORT,

AND DEGRADATION

The circulating level of a hormone is determined by its rate of secretion and its half-life. After protein processing, peptide hormones (e.g.,

GnRH, insulin, growth hormone [GH]) are stored in secretory granules. As these granules mature, they are poised beneath the plasma

membrane for imminent release into the circulation. In most instances,

the stimulus for hormone secretion is a releasing factor or neural signal

that induces rapid changes in voltage-gated channel activity or intracellular calcium concentrations, leading to secretory granule fusion with

the plasma membrane and release of its contents into the extracellular

environment and bloodstream. Steroid hormones, in contrast, diffuse

into the circulation as they are synthesized. Thus, their secretory rates

are closely aligned with rates of synthesis. For example, ACTH and LH

induce steroidogenesis by stimulating the activity of the steroidogenic

acute regulatory (StAR) protein, which transports cholesterol into the

mitochondrion, along with other rate-limiting steps (e.g., cholesterol

side-chain cleavage enzyme, CYP11A1) in the steroidogenic pathway.

Hormone transport and degradation dictate the rapidity with which

a hormonal signal decays. Some hormone signals are evanescent (e.g.,

somatostatin), whereas others are longer-lived (e.g., TSH). Because

somatostatin exerts effects in virtually every tissue, a short half-life

allows its concentrations and actions to be controlled locally. Structural

modifications that impair somatostatin degradation have been useful

for generating long-acting therapeutic analogues such as octreotide

(Chap. 380). In contrast, the actions of TSH are highly specific for

the thyroid gland. Its prolonged half-life generates relatively constant

serum levels even though TSH is secreted in discrete pulses.

An understanding of circulating hormone half-life is important for

achieving physiologic hormone replacement, as the frequency of dosing

and the time required to reach steady state are intimately linked to rates

of hormone decay. T4

, for example, has a circulating half-life of 7 days.

Consequently, >1 month is required to reach a new steady state, and

single daily doses are sufficient to achieve constant hormone levels. T3

,

in contrast, has a half-life of 1 day. Its administration is associated with

more dynamic serum levels, and it must be administered two to three

times per day. Similarly, synthetic glucocorticoids vary widely in their

half-lives; those with longer half-lives (e.g., dexamethasone) are associated with greater suppression of the hypothalamic-pituitary-adrenal

(HPA) axis. Most protein hormones (e.g., ACTH, GH, prolactin [PRL],

PTH, LH) have relatively short half-lives (<20 min), leading to sharp

peaks of secretion and decay. The only accurate way to profile the pulse

frequency and amplitude of these hormones is to measure levels in

frequently sampled blood (every 10 min or less) over long durations

(8–24 h). Because this is not practical in a clinical setting, an alternative

strategy is to pool three to four blood samples drawn at about 30-min

intervals or interpret the results in the context of a relatively wide normal range. Rapid hormone decay is useful in certain clinical settings.

For example, the short half-life of PTH allows the use of intraoperative

PTH levels to confirm successful removal of a parathyroid adenoma.

This is particularly valuable diagnostically when there is a possibility

of multicentric disease or parathyroid hyperplasia, as occurs with multiple endocrine neoplasia (MEN) or renal insufficiency.

Many hormones circulate in association with serum-binding proteins. Examples include (1) T4

 and T3

 binding to thyroxine-binding

globulin (TBG), albumin, and thyroxine-binding prealbumin (TBPA);

(2) cortisol binding to cortisol-binding globulin (CBG); (3) androgen

and estrogen binding to sex hormone–binding globulin (SHBG); (4)

IGF1 and IGF2 binding to multiple IGF-binding proteins (IGFBPs);

(5) GH interactions with GH-binding protein (GHBP), a circulating

fragment of the GH receptor extracellular domain; and (6) activin

binding to follistatin. These interactions provide a hormone reservoir,

prevent otherwise rapid degradation of unbound hormones, restrict

hormone access to certain sites (e.g., IGFBPs), and modulate the levels

of unbound, or “free,” hormone concentrations. Although a variety of

binding protein abnormalities have been identified, most have little

clinical consequence aside from creating diagnostic problems. For

example, TBG deficiency can reduce total thyroid hormone levels

greatly, but the free concentrations of T4

 and T3

 remain normal. Liver

disease and certain medications can also influence binding protein levels (e.g., estrogen increases TBG) or cause displacement of hormones

from binding proteins (e.g., salsalate displaces T4

 from TBG). In general, only unbound hormone is available to interact with receptors and

thus elicit a biologic response. Short-term perturbations in binding

proteins change the free hormone concentration, which in turn induces

compensatory adaptations through feedback loops. SHBG changes

in women are an exception to this self-correcting mechanism. When

SHBG decreases because of insulin resistance or androgen excess, the

unbound testosterone concentration is increased, potentially contributing to hirsutism in women with polycystic ovary syndrome (PCOS)

2887 Mechanisms of Hormone Action CHAPTER 377

Activin/MIS/BMP

TGF-β Serine kinase

Growth factor

Tyrosine kinase

Membrane

Nucleus

Target gene

Cytokine/GH/PRL

Insulin/IGF-I

Tyrosine kinase

G protein–coupled

Seven transmembrane

G protein

PKA, PKC Ras/Raf

MAPK

JAK/STAT

Smads

FIGURE 377-1 Membrane receptor signaling. MAPK, mitogen-activated protein kinase; PKA, C, protein

kinase A, C; TGF, transforming growth factor. For other abbreviations, see text.

β γ Gαs

Membrane

G protein-coupled

receptor

Ligand

bound

Cycling

Ligand

unbound

GTP

GDP

Cell growth

and signaling

cAMP

β γ

Gαs

GTP GDP

FIGURE 377-2 G protein signaling. G protein–coupled receptors (GPCRs) signal via the family of G proteins, so

named because they bind guanylyl nucleotides. In the example shown, a GPCR bound to a ligand induces GDP

dissociation, allowing Gs

α to bind GTP and dissociate from the βγ complex. GTP-bound Gs

α increases cAMP

production by adenylyl cyclase and activates the protein kinase A pathway. Not shown are separate signaling

pathways activated by the βγ complex. When GTP is converted to GDP by an intrinsic GTPase, the βγ subunits

reassociate with GDP-bound Gs

α and the complex returns to an inactive state. As noted in the text, mutations in

Gs

α that eliminate GTPase activity result in constitutive activation of receptor signaling pathways because GTPbound Gs

α cannot be converted to its GDP-bound inactive state. cAMP, cyclic adenosine 5′-monophosphate;

GDP, guanosine diphosphate; Gs

α, G protein α; GTP, guanosine triphosphate.

(Chap. 394). The increased unbound testosterone

level does not result in an adequate compensatory

feedback correction because estrogen, not testosterone, is the primary regulator of the reproductive

axis.

An additional exception to the unbound hormone hypothesis involves megalin, a member of the

low-density lipoprotein (LDL) receptor family that

serves as an endocytotic receptor for thyroglobulin,

carrier-bound vitamins A and D, and SHBG-bound

androgens and estrogens. After internalization, the

carrier proteins are degraded in lysosomes and

release their bound ligands within the cells. Other

membrane transporters have also been identified

for thyroid hormones.

Hormone degradation can be an important

mechanism for regulating concentrations locally.

As noted above, 11β-hydroxysteroid dehydrogenase

inactivates glucocorticoids in renal tubular cells,

preventing actions through the mineralocorticoid

receptor. Thyroid hormone deiodinases convert T4

to T3

 and can inactivate T3. During development,

degradation of retinoic acid by Cyp26b1 prevents

primordial germ cells in the male from entering

meiosis, as occurs in the female ovary.

■ HORMONE ACTION THROUGH RECEPTORS

Receptors for hormones are divided into two major classes: membrane

and nuclear. Membrane receptors primarily bind peptide hormones and

catecholamines. Nuclear receptors bind small molecules that can diffuse

across the cell membrane, such as steroids and vitamin D. Certain

general principles apply to hormone-receptor interactions regardless

of the class of receptor. Hormones bind to receptors with specificity

and an affinity that generally coincides with the dynamic range of circulating hormone concentrations. Low concentrations of free hormone

(usually 10–12 to 10–9 M) rapidly associate and dissociate from receptors

in a bimolecular reaction such that the occupancy of the receptor at

any given moment is a function of hormone concentration and the

receptor’s affinity for the hormone. Receptor numbers vary greatly

in different target tissues, providing one of the major determinants

of tissue-specific responses to circulating

hormones. For example, ACTH receptors

are located almost exclusively in the adrenal

cortex, and LH receptors are found predominantly in the gonads. In contrast, insulin

and TRs are widely distributed, reflecting the

need for metabolic responses in all tissues.

■ MEMBRANE RECEPTORS

Membrane receptors for hormones can

be divided into several major groups:

(1) seven transmembrane GPCRs, (2)

tyrosine kinase receptors, (3) cytokine

receptors, and (4) serine kinase receptors

(Fig. 377-1). The seven transmembrane

GPCR family binds a huge array of hormones, including large proteins (e.g., LH,

PTH), small peptides (e.g., TRH, somatostatin), catecholamines (epinephrine,

dopamine), and even minerals (e.g., calcium). The extracellular domains of GPCRs

vary widely in size and are the major binding

site for large hormones. The transmembrane-spanning regions are composed of

hydrophobic α-helical domains that traverse

the lipid bilayer. Like some channels, these

domains are thought to circularize and form

a hydrophobic pocket into which certain

small ligands fit. Hormone binding induces

conformational changes in these domains, transducing structural

changes to the intracellular domain, which is a docking site for G

proteins.

The large family of G proteins, so named because they bind guanine

nucleotides (guanosine triphosphate [GTP], guanosine diphosphate

[GDP]), provides great diversity for coupling receptors to different

signaling pathways. G proteins form a heterotrimeric complex that is

composed of various α and βγ subunits (Fig. 377-2). The α subunit

contains the guanine nucleotide–binding site and an intrinsic GTPase

that hydrolyzes GTP → GDP. The βγ subunits are tightly associated

and modulate the activity of the α subunit as well as mediating their

own effector signaling pathways. G protein activity is regulated by a

cycle that involves GTP hydrolysis and dynamic interactions between

the α and βγ subunits. Hormone binding to the receptor induces GDP

2888 PART 12 Endocrinology and Metabolism

TABLE 377-2 Genetic Causes of G protein Receptor Disorders

RECEPTOR DISORDER GENETICS

LH Leydig cell hypoplasia (male)

Primary amenorrhea, resistance

to LH (female)

Familial male precocious puberty

(male)

Leydig cell adenoma, precocious

puberty (male)

AR, inactivating

AR, inactivating

AD, activating

Sporadic, activating

FSH Hypergonadotropic ovarian failure

(female)

Hypospermia (male)

Ovarian hyperstimulation (female)

AR, inactivating

AR, inactivating

Sporadic, activating

TSH Congenital hypothyroidism, TSH

resistance

Nonautoimmune familial

hyperthyroidism

Hyperfunctioning thyroid adenoma

AR, AD, inactivating

AD, activating

Sporadic, activating

GnRH Hypogonadotropic hypogonadism AR, inactivating

Kisspeptin Hypogonadotropic hypogonadism

Precocious puberty

AR, inactivating

AD, activating

Prokineticin Precocious puberty Sporadic, activating

TRH Central hypothyroidism AR, inactivating

GHRH GH deficiency AR, inactivating

PTH Blomstrand chondrodysplasia

Jansen metaphyseal

chondrodysplasia

AR, inactivating

AD, activating

Calcium sensing

receptor

Familial hypocalciuric

hypercalcemia

Neonatal severe

hyperparathyroidism

Familial hypocalcemic

hypercalciura

AD, inactivating

AR, inactivating

AD, activating

Arginine

vasopressin

receptor 2

Nephrogenic diabetes insipidus

Nephrogenic SIADH

XL, inactivating

XL, activating

ACTH Familial ACTH resistance

ACTH-independent Cushing

syndrome

AR, inactivating

Sporadic, activating

Melanocortin 4 Severe obesity Codominant, inactivating

Abbreviations: ACTH, adrenocorticotropin hormone; AD, autosomal dominant;

AR, autosomal recessive; FSH, follicle-stimulating hormone; GH, growth hormone;

GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing

hormone; LH, luteinizing hormone; PTH, parathyroid hormone; SIADH, syndrome of

inappropriate antidiuretic hormone secretion; TRH, thyrotropin-releasing hormone;

TSH, thyroid-stimulating hormone; XL, X-linked.

dissociation, allowing Gα to bind GTP and dissociate from the βγ complex. Under these conditions, the Gα subunit is activated and mediates

signal transduction through various enzymes, such as adenylate cyclase

and phospholipase C. GTP hydrolysis to GDP allows reassociation with

the βγ subunits and restores the inactive state. G proteins interact with

other cellular proteins, including kinases, channels, G protein–coupled

receptor kinases (GRKs), and arrestins, that mediate signaling as well

as receptor desensitization and recycling.

A variety of endocrinopathies result from mutations in GPCRs that

alter their interactions with G proteins (Table 377-2). Loss-of-function

mutations are generally recessive and inactivate the relevant hormone

signaling pathway. Because many of these receptors are important

for development as well as signaling, patient presentations resemble

glandular failure syndromes (e.g., mutations in LH-R, FSH-R, TSH-R).

Gain-of-function (GOF) mutations are more complex. Selected GOF

mutations induce conformational changes in the GPCR that mimic

the activated state normally induced by hormone binding. These GOF

mutations result in a constitutively active state in which G protein

coupling stimulates cell signaling pathways, most commonly via cyclic

adenosine 5′-monophosphate (cAMP) and protein kinase A. When

mutations occur in the germline, the conditions are heritable and

present in early life (e.g., LH-R, TSH-R). Sporadic, somatic mutations

can also occur and result in clonal expansion of hyperfunctioning cells.

Mutations in the TSH-R illustrate the range of possible clinical consequences of GPCR mutations. Recessive inactivating mutations in the

TSH-R cause congenital hypothyroidism with thyroid gland hypoplasia

and resistance to TSH. Clinically, the hormone profile resembles primary hypothyroidism with low T4

 and high TSH. On the other hand,

germline activating mutations cause congenital hyperthyroidism. The

disorder is autosomal dominant because an activating mutation of one

TSH-R allele is sufficient to induce cellular hyperfunction and disease.

Because the TSH-R is activated in every cell of the thyroid, there is

hyperplastic growth and hyperfunction that resembles the pathology

seen in Graves’ disease. This unusual disorder presents in infancy and

must be distinguished from the more common clinical circumstance in

which maternal antibodies in women with active or previously treated

Graves’ disease cross the placenta and stimulate the thyroid gland of

the fetus. If an activating TSH-R mutation occurs later in life, in the

somatic tissue, there is clonal expansion of the thyrocyte harboring

the mutation, ultimately leading to an autonomous hyperfunctioning

thyroid nodule. Of note, a similar condition can be caused by somatic

mutations in Gs

α. In this case, the Gs

α GTPase is inactivated and GTP

cannot be converted to GDP. Consequently, the Gs

α signaling pathway

in this particular cell is constitutively active, mimicking chronic TSH

stimulation and again leading to clonal expansion and an autonomous

hyperfunctioning thyroid nodule. About one-third of hyperfunctioning “hot” thyroid nodules harbor sporadic mutations in either the

TSH-R or Gs

α (TSH-R mutations are more common).

Gs

α mutations in tissues other than the thyroid can also cause endocrine disease. For example, Gs

α mutations in pituitary somatotropes

mimic activation of the growth hormone–releasing hormone (GHRH)

pathway and lead to GH-producing adenomas and acromegaly. Rarely,

mutations in other components of the protein kinase A pathway in

somatotropes can also cause GH-producing adenomas. Gs

α mutations

that occur early in development (typically mosaic) cause McCune-Albright syndrome (Chap. 412), and the clinical features are manifest

because the activated G protein pathway mimics the actions of various hormones (PTH, melanocyte-stimulating hormone [MSH], TSH,

GHRH) in different tissues. Germline inactivating Gs

α mutations cause a

range of disorders that are transmitted and expressed in a complex manner because the locus is imprinted (Chap. 410). These conditions include

Albright’s hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and pseudohypoparathyroidism types 1b, 1c, and 2.

The tyrosine kinase receptors transduce signals for insulin and

a variety of growth factors, such as IGF1, epidermal growth factor

(EGF), nerve growth factor, platelet-derived growth factor, and fibroblast growth factors. The cysteine-rich extracellular domains contain

binding sites for the growth factors. After ligand binding, this class

of receptors undergoes autophosphorylation, inducing interactions

with intracellular adaptor proteins such as Shc and insulin receptor

substrates (IRS). In the case of the insulin receptor, multiple kinases

are activated, including the Raf-Ras-MAPK and the Akt/protein kinase

B pathways. The tyrosine kinase receptors play a prominent role in cell

growth and differentiation as well as in intermediary metabolism.

The GH and PRL receptors belong to the cytokine receptor family.

Analogous to the tyrosine kinase receptors, ligand binding induces

receptor interaction with intracellular kinases—the Janus kinases

(JAKs), which phosphorylate members of the signal transduction

and activators of transcription (STAT) family—as well as with other

signaling pathways (Ras, PI3-K, MAPK). The activated STAT proteins

translocate to the nucleus and stimulate expression of target genes.

The serine kinase receptors mediate the actions of activins, transforming growth factor β, müllerian-inhibiting substance (MIS; also known

as anti-müllerian hormone [AMH]), and bone morphogenic proteins

(BMPs). This family of receptors (consisting of type I and II subunits)

signals through proteins termed smads (fusion of terms for Caenorhabditis elegans sma + mammalian mad). Like the STAT proteins, the

smads serve a dual role of transducing the receptor signal and acting

as transcription factors. The pleomorphic actions of these growth factors dictate that they act primarily in a local (paracrine or autocrine)

2889 Mechanisms of Hormone Action CHAPTER 377

Ligands

DNA response

elements

Hormone

Gene Expression

– + + Basal +– –

Hormone Receptor

Homodimer Steroid

Receptors

ER, AR, PR, GR

Ligand induces

coactivator binding

Ligand dissociates corepressors

and induces coactivator binding

Constitutive activator

or repressor binding

Heterodimer Receptors

TR, VDR, RAR, PPAR

Orphan Receptors

SF-1, DAX-1, HNF4α

Activated Activated

Silenced

Activated

FIGURE 377-3 Nuclear receptor signaling. AR, androgen receptor; DAX, dosage-sensitive sex-reversal, adrenal

hypoplasia congenita, X chromosome; ER, estrogen receptor; GR, glucocorticoid receptor; HNF4α, hepatic

nuclear factor 4α; PPAR, peroxisome proliferator activated receptor; PR, progesterone receptor; RAR, retinoic

acid receptor; SF-1, steroidogenic factor-1; TR, thyroid hormone receptor; VDR, vitamin D receptor.

manner. Binding proteins such as follistatin

(which binds activin and other members of

this family) function to inactivate the growth

factors and restrict their distribution.

Disease-causing mutations also occur in

each of these classes of receptors. For example,

insulin receptor mutations cause an extreme

form of insulin resistance. GH receptor mutations cause Laron-type dwarfism, characterized

by low IGF1 and high GH. AMH receptor

mutations cause persistent müllerian duct syndrome. These hormone resistance syndromes

are autosomal recessive and relatively uncommon. Unlike the GPCRs, activating mutations

are unusual, although they do occur for the

RET tyrosine kinase receptor, which causes

the autosomal dominant disorder MEN type 2

(MEN2) (Chap. 388).

■ NUCLEAR RECEPTORS

The family of nuclear receptors has grown to

nearly 100 members, many of which are still

classified as orphan receptors because their

ligands, if they exist, have not been identified

(Fig. 377-3). Otherwise, most nuclear receptors are classified on the basis of their ligands.

Although all nuclear receptors ultimately act

to increase or decrease gene transcription, some (e.g., glucocorticoid

receptor) reside primarily in the cytoplasm, whereas others (e.g., TR)

are located in the nucleus. After ligand binding, the cytoplasmically

localized receptors translocate to the nucleus. There is growing evidence that certain nuclear receptors (e.g., glucocorticoid, estrogen)

can also act at the membrane or in the cytoplasm to activate or repress

signal transduction pathways, providing a mechanism for cross-talk

between membrane and nuclear receptors.

The structures of nuclear receptors have been studied extensively,

including by x-ray crystallography. The DNA-binding domain, consisting of two zinc fingers, contacts specific DNA recognition sequences

in target genes. Most nuclear receptors bind to DNA as dimers. Consequently, each monomer recognizes an individual DNA motif, referred

to as a “half-site.” The steroid receptors, including the glucocorticoid,

estrogen, progesterone, and androgen receptors, bind to DNA as

homodimers. Consistent with this twofold symmetry, their DNA recognition half-sites are palindromic. The thyroid, retinoid, peroxisome

proliferator activated, and vitamin D receptors bind to DNA preferentially as heterodimers in combination with retinoid X receptors

(RXRs). Their DNA half-sites are typically arranged as direct repeats.

The carboxy-terminal hormone-binding domains mediate transcriptional control. For type II receptors such as TR and retinoic acid

receptor (RAR), co-repressor proteins bind to the receptor in the

absence of ligand and silence gene transcription. Hormone binding

induces conformational changes, triggering the release of co-repressors

and the recruitment of coactivators that stimulate transcription. Thus,

these receptors are capable of mediating dynamic changes in the level

of gene activity. Disease states can be associated with defective regulation of these events. For example, in promyelocytic leukemia, fusion

of RARα to other nuclear proteins causes aberrant gene silencing that

prevents normal cellular differentiation. Treatment with retinoic acid

reverses this repression and allows cellular differentiation and apoptosis to occur. Most type 1 steroid receptors interact weakly with co-repressors, but ligand binding still induces interactions with an array of

coactivators. X-ray crystallography shows that various SERMs induce

distinct estrogen receptor conformations. The tissue-specific responses

caused by these agents in breast, bone, and uterus appear to reflect

distinct interactions with various coactivators. The receptor-coactivator

complex stimulates gene transcription by several pathways, including

(1) recruitment of enzymes (histone acetyl transferases) that modify

chromatin structure, (2) interactions with additional transcription

factors on the target gene, and (3) direct interactions with components

of the general transcription apparatus to enhance the rate of RNA

polymerase II–mediated transcription. Studies of nuclear receptor–

mediated transcription reveal relatively rapid (e.g., 30–60 min) cycling

of transcription complexes on any specific target gene.

Nuclear receptor mutations are an important cause of endocrine disease. Androgen receptor mutations cause androgen insensitivity syndrome (AIS) (Chap. 390). Because the androgen receptor is located on

the X chromosome, phenotypic expression is more commonly manifest

than with other nuclear receptor disorders. Affected individuals with

AIS are XY phenotypic females with retained testes and male-range

testosterone levels. Tissue insensitivity to androgens varies based on

the severity of the mutation. Müllerian structures are absent because

Sertoli cells of the testis produce AMH during development. Female

carriers of androgen receptor mutations are phenotypically normal.

Recessive mutations of the estrogen, glucocorticoid, and vitamin D

receptors occur but are rare.

Thyroid hormone receptor β (TRβ) mutations have an unusual

pathophysiology. They are autosomal dominant and function via a

“dominant negative” mechanism to cause resistance to thyroid hormone

(RTH) (Chap. 382). The mutations occur in selected regions of the TRβ

hormone-binding domain and preserve the ability of the mutant receptor to heterodimerize with RXR, interact with co-repressors, and bind

to DNA regulatory sites. The mutant receptors function as antagonists

of receptors from the normal copy of the TRβ gene. Affected patients

have high T4

 and T3

 and inappropriately elevated (unsuppressed)

TSH, reflecting impaired feedback regulation of the hypothalamicpituitary-thyroid axis. Organ systems are variably resistant to thyroid

hormones based on the relative expression of TRβ and TRα. Mutations

in the genes encoding TRα and PPARγ can also cause disease by functioning in an analogous dominant negative manner.

FUNCTIONS OF HORMONES

The functions of individual hormones are described in detail in

subsequent chapters. Nevertheless, it is useful to illustrate how most

biologic responses require the integration of several different hormone

pathways. The physiologic functions of hormones can be divided into

three general types: (1) growth and differentiation, (2) maintenance of

homeostasis, and (3) reproduction.

■ GROWTH

Multiple hormones and nutritional factors mediate the complex phenomenon of growth (Chap. 378). Short stature may be caused by GH

2890 PART 12 Endocrinology and Metabolism

deficiency, hypothyroidism, Cushing’s syndrome, precocious puberty,

malnutrition, chronic illness, or genetic abnormalities that affect the

epiphyseal growth plates (e.g., FGFR3 and SHOX mutations). Many

factors (GH, IGF1, thyroid hormones) stimulate growth, whereas

others (sex steroids) lead to epiphyseal closure. Understanding these

hormonal interactions is important in the diagnosis and management

of growth disorders. For example, delaying exposure to high levels of

sex steroids may enhance the efficacy of GH treatment.

■ MAINTENANCE OF HOMEOSTASIS

Although virtually all hormones affect homeostasis, the most important among them are the following:

1. Thyroid hormone—controls ~25% of basal metabolism in most

tissues.

2. Cortisol—exerts a permissive action for many hormones in addition

to its own direct effects.

3. PTH—regulates calcium and phosphorus levels.

4. Vasopressin—regulates serum osmolality by controlling renal

free-water clearance.

5. Mineralocorticoids—control vascular volume and serum electrolyte

(Na+, K+) concentrations.

6. Insulin—maintains euglycemia in the fed and fasted states.

The defense against hypoglycemia is an impressive example of integrated hormone action (Chap. 406). In response to the fasting state

and falling blood glucose, insulin secretion is suppressed, resulting

in decreased glucose uptake and enhanced glycogenolysis, lipolysis,

proteolysis, and gluconeogenesis to mobilize fuel sources. If hypoglycemia develops (usually from insulin administration or sulfonylureas),

an orchestrated counterregulatory response occurs—glucagon and

epinephrine rapidly stimulate glycogenolysis and gluconeogenesis,

whereas GH and cortisol act over several hours to raise glucose levels

and antagonize insulin action.

Although free-water clearance is controlled primarily by vasopressin,

cortisol and thyroid hormone are also important for facilitating renal

tubular responses to vasopressin (Chap. 381). PTH and vitamin D

function in an interdependent manner to control calcium metabolism

(Chap. 409). PTH stimulates renal synthesis of 1,25-dihydroxyvitamin D,

which increases calcium absorption in the gastrointestinal tract and

enhances PTH action in bone. Increased calcium, along with vitamin D,

feeds back to suppress PTH, thus maintaining calcium balance.

Depending on the severity of a specific stress and whether it is acute

or chronic, multiple endocrine and cytokine pathways are activated

to mount an appropriate physiologic response. In severe acute stress

such as trauma or shock, the sympathetic nervous system is activated,

and catecholamines are released, leading to increased cardiac output

and a primed musculoskeletal system. Catecholamines also increase

mean blood pressure and stimulate glucose production. Multiple stressinduced pathways converge on the hypothalamus, stimulating several

hormones, including vasopressin and CRH. These hormones, in addition

to cytokines (tumor necrosis factor α, interleukin [IL] 2, IL-6), increase

ACTH and GH production. ACTH stimulates the adrenal gland, increasing cortisol, which in turn helps sustain blood pressure and dampen the

inflammatory response. Increased vasopressin acts to conserve free water.

■ REPRODUCTION

The stages of reproduction include (1) sex determination during

fetal development (Chap. 390); (2) sexual maturation during puberty

(Chaps. 391 and 392); (3) conception, pregnancy, lactation, and child

rearing (Chap. 392); and (4) cessation of reproductive capability at

menopause (Chap. 395). Each of these stages involves an orchestrated

interplay of multiple hormones, a phenomenon well illustrated by the

dynamic hormonal changes that occur during each 28-day menstrual

cycle. In the early follicular phase, pulsatile secretion of LH and FSH

stimulates the progressive maturation of the ovarian follicle. This

results in gradually increasing estrogen and progesterone levels, leading to enhanced pituitary sensitivity to GnRH, which, when combined

with accelerated GnRH secretion, triggers the LH surge and rupture of

the mature follicle. Inhibin, a protein produced by the granulosa cells,

enhances follicular growth and feeds back to the pituitary to selectively

suppress FSH without affecting LH. Growth factors such as EGF and

IGF1 modulate follicular responsiveness to gonadotropins. Vascular

endothelial growth factor and prostaglandins play a role in follicle

vascularization and rupture.

During pregnancy, the increased production of PRL, in combination

with placentally derived steroids (e.g., estrogen and progesterone),

prepares the breast for lactation. Estrogens induce the production of

progesterone receptors, allowing for increased responsiveness to progesterone. In addition to these and other hormones involved in lactation, the nervous system and oxytocin mediate the suckling response

and milk release.

HORMONAL FEEDBACK REGULATORY

SYSTEMS

Feedback control, both negative and positive, is a fundamental feature

of endocrine systems. Each of the major hypothalamic-pituitaryhormone axes is governed by negative feedback, a process that maintains hormone levels within a relatively narrow range (Chap. 378).

Examples of hypothalamic-pituitary negative feedback include (1) thyroid hormones on the TRH-TSH axis, (2) cortisol on the CRH-ACTH

axis, (3) gonadal steroids on the GnRH-LH/FSH axis, and (4) IGF1

on the GHRH-GH axis (Fig. 377-4). These regulatory loops include

both positive (e.g., TRH, TSH) and negative (e.g., T4

, T3

) components,

allowing for exquisite control of hormone levels. As an example, a small

reduction of thyroid hormone triggers a rapid increase of TRH and

TSH secretion, resulting in thyroid gland stimulation and increased

thyroid hormone production. When thyroid hormone reaches a normal level, it feeds back to suppress TRH and TSH, and a new steady

state is attained. Feedback regulation also occurs for endocrine systems

that do not involve the pituitary gland, such as calcium feedback on

PTH, glucose inhibition of insulin secretion, and leptin feedback on

the hypothalamus. An understanding of feedback regulation provides

important insights into endocrine testing paradigms (see below).

Positive feedback control also occurs but is not well understood. The

primary example is estrogen-mediated stimulation of the midcycle LH

surge. Although chronic low levels of estrogen are inhibitory, gradually rising estrogen levels stimulate LH secretion. This effect, which is

+

+

Adrenal Gonads

Thyroid

Hypothalamus

CNS

Releasing

 factors

Pituitary

Trophic

hormones

Target hormone

feedback

inhibition

–

–

FIGURE 377-4 Feedback regulation of endocrine axes. CNS, central nervous

system.

2891Physiology of Anterior Pituitary Hormones CHAPTER 378

illustrative of an endocrine rhythm (see below), involves activation of

the hypothalamic GnRH pulse generator. In addition, estrogen-primed

gonadotropes are extraordinarily sensitive to GnRH, leading to amplification of LH release.

■ PARACRINE AND AUTOCRINE CONTROL

The previously mentioned examples of feedback control involve classic

endocrine pathways in which hormones are released by one gland and

act on a distant target gland. However, local regulatory systems, often

involving growth factors, are increasingly recognized. Paracrine regulation refers to factors released by one cell that act on an adjacent cell in

the same tissue. For example, somatostatin secretion by pancreatic islet

δ cells inhibits insulin secretion from nearby β cells. Autocrine regulation describes the action of a factor on the same cell from which it is

produced. IGF1 acts on many cells that produce it, including chondrocytes, breast epithelium, and gonadal cells. Unlike endocrine actions,

paracrine and autocrine control are difficult to document because local

growth factor concentrations cannot be measured readily.

Anatomic relationships of glandular systems also greatly influence

hormonal exposure: the physical organization of islet cells enhances

their intercellular communication; the portal vasculature of the

hypothalamic-pituitary system exposes the pituitary to high concentrations of hypothalamic releasing factors; testicular seminiferous tubules

gain exposure to high testosterone levels produced by the interdigitated

Leydig cells; the pancreas receives nutrient information and local exposure to peptide hormones (incretins) from the gastrointestinal tract;

and the liver is the proximal target of insulin action because of portal

drainage from the pancreas.

■ HORMONAL RHYTHMS

The feedback regulatory systems described above are superimposed

on hormonal rhythms that are used for adaptation to the environment.

Seasonal changes, the daily occurrence of the light-dark cycle, sleep,

meals, and stress are examples of the many environmental events that

affect hormonal rhythms. The menstrual cycle is repeated on average

every 28 days, reflecting the time required to follicular maturation,

ovulation, and potential implantation (Chap. 392). Essentially all pituitary hormone rhythms are entrained to sleep and to the circadian cycle,

generating reproducible patterns that are repeated approximately every

24 h. The HPA axis, for example, exhibits characteristic peaks of ACTH

and cortisol production in the early morning, with a nadir during the

night. Recognition of these rhythms is important for endocrine testing

and treatment. Patients with Cushing’s syndrome characteristically

exhibit increased midnight cortisol levels compared with normal individuals (Chap. 386). In contrast, morning cortisol levels are similar in

these groups, as cortisol is normally high at this time of day in normal

individuals. The HPA axis is more susceptible to suppression by glucocorticoids administered at night as they blunt the early-morning rise

of ACTH. Understanding these rhythms allows glucocorticoid replacement that mimics diurnal production by administering larger doses

in the morning than in the afternoon. Disrupted sleep rhythms can

alter hormonal regulation. For example, sleep deprivation causes mild

insulin resistance, food craving, and hypertension, which are reversible, at least in the short term. Emerging evidence indicates that circadian clock pathways not only regulate sleep-wake cycles but also play

important roles in virtually every cell type. For example, tissue-specific

deletion of clock genes alters rhythms and levels of gene expression, as

well as metabolic responses in liver, adipose, and other tissues.

Other endocrine rhythms occur on a more rapid time scale. Many

peptide hormones are secreted in discrete bursts every few hours. LH

and FSH secretion are exquisitely sensitive to GnRH pulse frequency.

Intermittent pulses of GnRH are required to maintain pituitary

sensitivity, whereas continuous exposure to GnRH causes pituitary

gonadotrope desensitization. This feature of the hypothalamicpituitary-gonadotrope axis forms the basis for using long-acting GnRH

agonists to treat central precocious puberty or to decrease testosterone

levels in the management of prostate cancer. It is important to be aware

of the pulsatile nature of hormone secretion and the rhythmic patterns

of hormone production in relating serum hormone measurements

to normal values. For some hormones, integrated markers have been

developed to circumvent hormonal fluctuations. Examples include

24-h urine collections for cortisol, the measurement of IGF1 as a biologic marker of GH action, and HbA1c as an index of long-term (weeks

to months) blood glucose control.

Often, one must interpret endocrine data only in the context of other

hormones. For example, PTH levels typically are assessed in combination with serum calcium concentrations. A high serum calcium level

in association with elevated PTH is suggestive of hyperparathyroidism,

whereas a suppressed PTH in the setting of hypercalcemia is more

likely to be caused by hypercalcemia of malignancy, or other causes of

hypercalcemia. Similarly, when T4

 and T3

 concentrations are low, TSH

should be elevated, reflecting reduced feedback inhibition. When this

is not the case, it is important to consider secondary hypothyroidism,

which is caused by a defect at the level of the pituitary.

■ FURTHER READING

Evans RM, Mangelsdorf DJ: Nuclear receptors, RXR, and the big

bang. Cell 157:255, 2014.

Fukami M et al: Gain-of-function mutations in G-protein-coupled

receptor genes associated with human endocrine disorders. Clin

Endocrinol 88:351, 2018.

Jameson JL, De Groot LJ (eds): Endocrinology: Adult and Pediatric,

7th ed. Philadelphia, Elsevier, 2016.

Kim YH, Lazar MA: Transcriptional control of circadian rhythms and

metabolism: A matter of time and space. Endocr Rev 41:707, 2020.

Smith RL et al: Metabolic flexibility as an adaptation to energy

resources and requirements in health and disease. Endocr Rev

39:489, 2018.

The anterior pituitary often is referred to as the “master gland” because,

together with the hypothalamus, it orchestrates the complex regulatory

functions of many other endocrine glands. 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) thyroidstimulating hormone (TSH) (Table 378-1). Pituitary hormones are

secreted in a pulsatile manner, reflecting regulation by an array of specific hypothalamic releasing factors. Each of these pituitary hormones

elicits specific trophic responses in peripheral target tissues including

the adrenal, thyroid, and gonads, as well as tissues involved in metabolism (e.g., liver, breast, bone). Elicited hormonal products of peripheral

glands, in turn, exert feedback control at the level of the hypothalamus

and pituitary to modulate pituitary function (Fig. 378-1). Pituitary

tumors cause characteristic hormone excess syndromes. Hormone

deficiency may be inherited or acquired. Fortunately, there are efficacious treatments for many pituitary hormone excess and deficiency

syndromes. Nonetheless, these diagnoses are often elusive; this emphasizes the importance of recognizing subtle clinical manifestations and

performing the correct laboratory diagnostic tests. For discussion

of disorders of the posterior pituitary or neurohypophysis, see

Chap. 381.

ANATOMY AND DEVELOPMENT

■ ANATOMY

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

378 Physiology of Anterior

Pituitary Hormones

Shlomo Melmed, J. Larry Jameson