Chapter 15 / Endocrine Disease 233

15 Endocrine Disease
Value For Understanding Hormonal Actions

Anthony P. Heaney, MD, PhD

CONTENTS
INTRODUCTION
PATHOPHYSIOLOGY OF ENDOCRINE DISEASES
EXAMPLES OF CLINICAL SYNDROMES WITH MULTIPLE PATHOPHYSIOLOGIC MECHANISMS
CONCLUSION

1. INTRODUCTION
Disorders involving the endocrine glands, their hor- pathophysiology, the clinical manifestations of diseases
mones, and the targets of the hormones may cover the leading to over- or underexpression of hormone action
full spectrum ranging from an incidentally found, insig- are quite similar.
nificant abnormality that is clinically silent to a flagrant, 2. PATHOPHYSIOLOGY
life-threatening metabolic derangement. Some endo- OF ENDOCRINE DISEASES
crine diseases such as well-differentiated thyroid carci-
noma present as neoplastic growths, which rarely are Endocrine diseases can occur on a congenital, often
associated with evidence of endocrine dysfunction. genetic, basis or can be acquired. Many of the congeni-
However, most clinically relevant endocrine disorders tal abnormalities are from mutations that result in struc-
are associated with over- or underexpression of hor- tural abnormalities, defects in hormone biosynthesis, or
mone action. There is a great deal of phenotypic vari- abnormalities in hormone-receptor structure or
ability in the clinical manifestations of each of the postreceptor signaling mechanisms. Tables 1 and 2 pro-
vide examples of identified mutations that result in over-
endocrine disorders, reflecting in part the severity of the
and underexpression of hormone action. Most endocrine
derangement and the underlying pathophysiologic
diseases are acquired and fit broadly into the categories
mechanisms. Although most of the individual clinical
of neoplasia, destruction or impairment of function of
endocrine syndromes have multiple pathophysiologic
the endocrine gland through infection, infiltrative pro-
mechanisms, the qualitative manifestations of the dis-
cesses, vascular disorders, trauma, or immune-mediated
ease states are similar owing to the relatively limited
injury, as well as functional aberrations owing to
ways in which the body responds to too much or too
multiorgan dysfunction, metabolic abnormalities, or
little hormone action.
drugs.
This chapter emphasizes the diversity of pathophysi-
These processes may disrupt the biosynthesis of pro-
ologic mechanisms responsible for endocrine diseases
tein hormones through interference with transcrip-
and illustrates the concept that despite the underlying
tion, mRNA processing, translation, posttranslational
From: Endocrinology: Basic and Clinical Principles, Second Edition protein modifications, protein storage, degradation, or
(S. Melmed and P. M. Conn, eds.) © Humana Press Inc., Totowa, NJ secretion. Abnormalities in steroid hormone, thyroid
233
234 Part IV / Hypothalamic–Pituitary

Table 1
Examples of Mutations That Cause Endocrine Hyperfunction
Type of mutation Disorder
Membrane receptor
• TSH receptor constitutive activation Thyroid adenoma; hyperthyroidism
• LH/hCG receptor constitutive activation Familial male precocious puberty (testotoxicosis)
• Calcium-sensing receptor defect Familial hypocalciuric hypocalcemia; neonatal hyperparathyroidism
Signal pathway
• Pituitary Gsα activation Acromegaly
• Thyroid Gsα activation Thyroid adenoma; hyperthyroidism
• Generalized Gsα activation McCune-Albright syndrome
• Temperature-sensitive Gsα activation Testotoxicosis and pseudohypoparathyroidism
• Thyroid p53 Neoplasia
• Ret protooncogene MEN 2a
• Cyclin D1 fusion to PTH promoter (PRAD-1) activation Parathyroid adenoma
• (PRAD-1) activation
• G1α (gip oncogene in adrenal and ovaries) Adrenocortical and ovarian tumors
• MENIN gene MEN 1
Enzyme
• Aldosterone synthase-11β-hydroxylase chimera Glucocorticoid-remediable hypertension

Table 3
Pathophysiology of Endocrine Diseases
hormone, and calcitriol production may result from
Neoplastic growth of endocrine glands without hyper-
loss of the orderly enzymatic conversion of precursor or hypofunction.
molecules into active hormones. Many disease states Overexpression of hormone action
as well as medications may alter the transport and meta- • Excessive production of hormones
bolism of hormones. Finally, there is a multitude of 䉬 Eutopic
lesions that can affect hormone-receptor interaction, 䊏
Autonomous
as well as postreceptor signal pathways. From a func- 䊏
Excessive physiologic stimulation
tional standpoint, clinical endocrine disease can be 䊏
Altered regulatory feedback set point
broadly classified into diseases of the endocrine glands 䉬 Ectopic
that are not associated with hormonal dysfunction, dis-
䊏
Direct secretion by tumor
䊏
Indirect
eases from overexpression of hormone action, and dis- 䊏
Dysregulation
eases characterized by underexpression of hormone • Excessive activation of hormone receptors
action (Table 3). Occasionally, situations exist in Constitutively activated receptors
which endocrine testing with immunoassays detects Hormone mimicry
elevated hormones, but no clinical endocrine syndrome Receptor crossreactivity
is apparent. An example of this is so-called idiopathic • Postreceptor activation of hormone action
hyperprolactinemia, in which prolactin (PRL) is bound • Altered metabolism of hormones
by a circulating immunoglobulin or the PRL protein is Underexpression of hormone action
modified by glycation resulting in delayed degrada- • Aplasia or hypoplasia of hormone source
• Acquired destruction of source of hormone
tion and excretion of often biologically inactive PRL.
• Congenital absence of hormone
Endocrine diseases without hormonal aberrations are • Production of inactive forms of hormone
generally nonfunctional neoplasms such as thyroid car- • Substrate insufficiency
cinoma or the frequently found incidental pituitary and • Destruction of target organ
adrenal adenomas. These neoplasms generally cause • Enzyme defects in hormone production
symptoms through their anatomic effects on the sur- • Antihormone antibodies
• Hormone resistance
rounding structures or, in the case of some malignant
Absent or altered receptor
neoplasms, through their metastases.
• Receptor occupancy
2.1. Overexpression of Hormone • Downregulation of normal receptors
• Postreceptor defects
Most endocrine disorders that result in overexpres- Altered metabolism of hormones
sion of hormone action do so through excessive produc-