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Hypothalamus |
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TRH |
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Anterior pituitary |
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TSH |
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T3, T4 |
Thyroid |
fIGUre 7.9 Control of thyroid hormone secretion. T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroidstimulating hormone.
b.TsH increases both the synthesis and the secretion of thyroid hormones by the follicular cells via an adenylate cyclase–cAmP mechanism.
■ Chronic elevation of TSH causes hypertrophy of the thyroid gland.
c.T3 down-regulates TrH receptors in the anterior pituitary and thereby inhibits TSH secretion.
2.Thyroid-stimulating immunoglobulins
■ are components of the immunoglobulin G (IgG) fraction of plasma proteins and are antibodies to TsH receptors on the thyroid gland.
■ bind to TSH receptors and, like TSH, stimulate the thyroid gland to secrete T3 and T4.
■ circulate in high concentrations in patients with Graves disease, which is characterized
by high circulating levels of thyroid hormones and, accordingly, low concentrations of TSH (caused by feedback inhibition of thyroid hormones on the anterior pituitary).
C.Actions of thyroid hormone
■T3 is three to four times more potent than T4. The target tissues convert T4 to T3 (see IV A 8).
1.Growth
■Attainment of adult stature requires thyroid hormone.
■Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation.
■Thyroid hormones stimulate bone maturation as a result of ossification and fusion of the growth plates. In thyroid hormone deficiency, bone age is less than chronologic age.
2.Central nervous system (Cns) a. Perinatal period
■Maturation of the CNS requires thyroid hormone in the perinatal period.
■Thyroid hormone deficiency causes irreversible mental retardation. Because there is
only a brief perinatal period when thyroid hormone replacement therapy is helpful, screening for neonatal hypothyroidism is mandatory.
b.Adulthood
■Hyperthyroidism causes hyperexcitability and irritability.
■Hypothyroidism causes listlessness, slowed speech, somnolence, impaired memory, and decreased mental capacity.
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3.Autonomic nervous system
■Thyroid hormone has many of the same actions as the sympathetic nervous system because
it up-regulates b1-adrenergic receptors in the heart. Therefore, a useful adjunct therapy for hyperthyroidism is treatment with a β-adrenergic blocking agent, such as propranolol.
4.Basal metabolic rate (Bmr)
■O2 consumption and Bmr are increased by thyroid hormone in all tissues except the brain, gonads, and spleen. The resulting increase in heat production underlies the role of thyroid hormone in temperature regulation.
■Thyroid hormone increases the synthesis of na+, K+-ATPase and consequently increases O2 consumption related to Na+–K+ pump activity.
5.Cardiovascular and respiratory systems
■Effects of thyroid hormone on cardiac output and ventilation rate combine to ensure that more O2 is delivered to the tissues.
a.Heart rate and stroke volume are increased.These effects combine to produce increased cardiac output. Excess thyroid hormone can cause high output heart failure.
b.Ventilation rate is increased.
6.metabolic effects
■ Overall, metabolism is increased to meet the demand for substrate associated with the increased rate of O2 consumption.
a.Glucose absorption from the gastrointestinal tract is increased.
b.Glycogenolysis, gluconeogenesis, and glucose oxidation (driven by demand for ATP) are increased.
c.Lipolysis is increased.
d.Protein synthesis and degradation are increased. The overall effect of thyroid hormone is catabolic.
D.Pathophysiology of the thyroid gland (Table 7.5)
v. ADrenAl COrTex AnD ADrenAl meDUllA (fIGUre 7.10)
A.Adrenal cortex
1.synthesis of adrenocortical hormones (Figure 7.11)
■The zona glomerulosa produces aldosterone.
■The zonae fasciculata and reticularis produce glucocorticoids (cortisol) and androgens (dehydroepiandrosterone and androstenedione).
a.21-carbon steroids
■include progesterone, deoxycorticosterone, aldosterone, and cortisol.
■Progesterone is the precursor for the others in the 21-carbon series.
■Hydroxylation at C-21 leads to the production of deoxycorticosterone, which has mineralocorticoid (but not glucocorticoid) activity.
■Hydroxylation at C-17 leads to the production of glucocorticoids (cortisol).
b.19-carbon steroids
■have androgenic activity and are precursors to the estrogens.
■If the steroid has been previously hydroxylated at C-17, the C20,21 side chain can be cleaved to yield the 19-carbon steroids dehydroepiandrosterone or androstenedione in the adrenal cortex.
■Adrenal androgens have a ketone group at C-17 and are excreted as 17-ketosteroids in the urine.
■In the testes, androstenedione is converted to testosterone.
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t a b l |
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7.5 |
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Hyperthyroidism |
Hypothyroidism |
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Symptoms |
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↑ metabolic rate |
↓ metabolic rate |
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Weight loss |
Weight gain |
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Negative nitrogen balance |
Positive nitrogen balance |
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↑ heat production (sweating) |
↓ heat production (cold sensitivity) |
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↑ cardiac output |
↓ cardiac output |
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Dyspnea |
Hypoventilation |
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Tremor, weakness |
Lethargy, mental slowness |
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Exophthalmos |
Drooping eyelids |
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Goiter |
Myxedema |
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Growth and mental retardation(perinatal) |
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Goiter |
Causes |
Graves disease (antibodies to TSH |
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receptor) |
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Thyroid neoplasm |
TSH levels |
↓ (because of feedback inhibition on |
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anterior pituitary by high thyroid |
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hormone levels) |
Thyroiditis (autoimmune thyroiditis; Hashimoto thyroiditis)
Surgical removal of thyroid I− deficiency
Cretinism (congenital) ↓ TRH or TSH
↑(because of decreased feedback inhibition on anterior pituitary by low thyroid hormone levels)
↓(if primary defect is in hypothalamus or anterior pituitary)
Treatment |
Propylthiouracil (inhibits thyroid hormone |
Thyroid hormone replacement |
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synthesis by blocking peroxidase) |
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Thyroidectomy |
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131I (destroys thyroid) |
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β-blockers (adjunct therapy) |
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See Table 7.1 for abbreviations.
c. 18-carbon steroids
■have estrogenic activity.
■Oxidation of the A ring (aromatization) to produce estrogens occurs in the ovaries and placenta, but not in the adrenal cortex or testes.
2. Regulation of secretion of adrenocortical hormones
Aldosterone
Glucocorticoids
Adrenal medulla |
Adrenal cortex |
Figure 7.10 Secretory products of the adrenal cortex and medulla. |
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ACTH |
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Cholesterol |
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cholesterol desmolase |
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Pregnenolone |
17α-hydroxylase |
17-Hydroxypregnenolone17,20-lyase |
Dehydroepiandrosterone |
3β-hydroxysteroid |
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3β-hydroxysteroid |
3β-hydroxysteroid |
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dehydrogenase |
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dehydrogenase |
dehydrogenase |
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Progesterone 17α-hydroxylase |
17-Hydroxyprogesterone 17,20-lyase |
Androstenedione |
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21β-hydroxylase |
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21β-hydroxylase |
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11-Deoxycorticosterone |
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Testosterone |
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11β-hydroxylase |
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Cortisol |
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aldosterone synthase |
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Aldosterone |
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Angiotensin II |
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Product of |
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Product of |
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Products of |
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zona glomerulosa |
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zona fasciculata |
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zona reticularis |
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Figure 7.11 Synthetic pathways for glucocorticoids, androgens, and mineralocorticoids in the adrenal cortex. ACTH = adrenocorticotropic hormone.
a. Glucocorticoid secretion (Figure 7.12)
■oscillates with a 24-hour periodicity or circadian rhythm.
■For those who sleep at night, cortisol levels are highest just before waking (ª8 am) and lowest in the evening (≈12 midnight).
(1) Hypothalamic control—corticotropin-releasing hormone (CRH)
■CRH-containing neurons are located in the paraventricular nuclei of the hypothalamus.
■When these neurons are stimulated, CRH is released into hypothalamic–hypoph- ysial portal blood and delivered to the anterior pituitary.
■CRH binds to receptors on corticotrophs of the anterior pituitary and directs them to synthesize POMC (the precursor to ACTH) and secrete ACTH.
■The second messenger for CRH is cAMP.
(2) Anterior lobe of the pituitary—ACTH
■ACTH increases steroid hormone synthesis in all zones of the adrenal cortex by stimulating cholesterol desmolase and increasing the conversion of cholesterol to pregnenolone.
Higher centers
–
Hypothalamus
CRH
+
–
Anterior pituitary
ACTH
+
Cortisol Adrenal cortex
Figure 7.12 Control of glucocorticoid secretion. ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone.
■ACTH also up-regulates its own receptor so that the sensitivity of the adrenal cortex to ACTH is increased.
■Chronically increased levels of ACTH cause hypertrophy of the adrenal cortex.
■The second messenger for ACTH is cAMP.
(3) Negative feedback control—cortisol
■Cortisol inhibits the secretion of CRH from the hypothalamus and the secretion of ACTH from the anterior pituitary.
■When cortisol (glucocorticoid) levels are chronically elevated, the secretion of CRH and ACTH is inhibited by negative feedback.
■The dexamethasone suppression test is based on the ability of dexamethasone (a synthetic glucocorticoid) to inhibit ACTH secretion. In normal persons, low-
dose dexamethasone inhibits or “suppresses” ACTH secretion and, consequently, cortisol secretion. In persons with ACTH-secreting tumors, low-dose dexametha-
sone does not inhibit cortisol secretion but high-dose dexamethasone does. In persons with adrenal cortical tumors, neither lownor high-dose dexamethasone inhibits cortisol secretion.
b. Aldosterone secretion (see Chapter 3, VI B)
■is under tonic control by ACTH, but is separately regulated by the renin–angiotensin system and by serum potassium.
(1) Renin–angiotensin–aldosterone system
(a) Decreases in blood volume cause a decrease in renal perfusion pressure, which
in turn increases renin secretion. Renin, an enzyme, catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE).
(b) Angiotensin II acts on the zona glomerulosa of the adrenal cortex to increase the conversion of corticosterone to aldosterone.
(c) Aldosterone increases renal Na+ reabsorption, thereby restoring extracellular fluid (ECF) volume and blood volume to normal.
(2) Hyperkalemia increases aldosterone secretion. Aldosterone increases renal K+ secretion, restoring serum [K+] to normal.
