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■ The second messenger for PTH actions on its target tissues is cAMP.

a.  PTH increases bone resorption, which brings both Ca2+ and phosphate from bone mineral into the ECF. Alone, this effect on bone would not increase the serum ionized [Ca2+] because phosphate complexes Ca2+.

■Resorption of the organic matrix of bone is reflected in increased hydroxyproline excretion.

b.  PTH inhibits renal phosphate reabsorption in the proximal tubule and, therefore, increases phosphate excretion (phosphaturic effect). As a result, the phosphate resorbed from

bone is excreted in the urine, allowing the serum ionized [Ca2+] to increase.

■cAMP generated as a result of the action of PTH on the proximal tubule is excreted in the urine (urinary cAMP).

c.  PTH increases renal Ca2+ reabsorption in the distal tubule, which also increases the serum [Ca2+].

d.  PTH increases intestinal Ca2+ absorption indirectly by stimulating the production of 1,25-dihydroxycholecalciferol in the kidney (see VII C).

3.  Pathophysiology of PTH (Table 7.12) a.  Primary hyperparathyroidism

■is most commonly caused by parathyroid adenoma.

■is characterized by the following:

(1)  ↑ serum [Ca2+] (hypercalcemia)

(2)  ↓ serum [phosphate] (hypophosphatemia)

(3)  ↑ urinary phosphate excretion (phosphaturic effect of PTH)

(4)  ↑ urinary Ca2+ excretion (caused by the increased filtered load of Ca2+)

(5)  ↑ urinary cAMP

(6)  ↑ bone resorption

↑ Resorption (caused by ↑ PTH)

cAMP = cyclic adenosine monophosphate; GFR = glomerular filtration rate. See Table 7.1 for other abbreviation.

254Brs Physiology

b. Humoral hypercalcemia of malignancy

■is caused by PTH-related peptide (PTH-rp) secreted by some malignant tumors (e.g.,

breast, lung). PTH-rp has all of the physiologic actions of PTH, including increased bone resorption, increased renal Ca2+ reabsorption, and decreased renal phosphate reabsorption.

■is characterized by the following:

(1) ↑ serum [Ca2+] (hypercalcemia)

(2) ↓ serum [phosphate] (hypophosphatemia)

(3) ↑ urinary phosphate excretion (phosphaturic effect of PTH-rp)

(4) ↓ serum PTH levels (due to feedback inhibition from the high serum Ca2+) c. Hypoparathyroidism

■ is most commonly a result of thyroid surgery, or it is congenital. ■ is characterized by the following:

(1) ↓ serum [Ca2+] (hypocalcemia) and tetany

(2) ↑ serum [phosphate] (hyperphosphatemia)

(3) ↓ urinary phosphate excretion

d. Pseudohypoparathyroidism type Ia—Albright hereditary osteodystrophy

■ is the result of defective Gs protein in the kidney and bone, which causes end-organ resistance to PTH.

■Hypocalcemia and hyperphosphatemia occur (as in hypoparathyroidism), which are not correctable by the administration of exogenous PTH.

■Circulating PTH levels are elevated (stimulated by hypocalcemia).

e.Chronic renal failure

■Decreased glomerular filtration rate (GFR) leads to decreased filtration of phosphate, phosphate retention, and increased serum [phosphate].

■Increased serum phosphate complexes Ca2+ and leads to decreased ionized [Ca2+].

■Decreased production of 1,25-dihydroxycholecalciferol by the diseased renal tissue also contributes to the decreased ionized [Ca2+] (see VII C 1).

■Decreased [Ca2+] causes secondary hyperparathyroidism.

■The combination of increased PTH levels and decreased 1,25-dihydroxycholecalcif- erol produces renal osteodystrophy, in which there is increased bone resorption and osteomalacia.

f.familial hypocalciuric hypercalcemia (fHH)

■autosomal dominant disorder with decreased urinary Ca2+ excretion and increased serum Ca2+

■caused by inactivating mutations of the Ca2+-sensing receptors that regulate PTH secretion.

C.vitamin D

■provides Ca2+ and phosphate to ECF for bone mineralization.

■In children, vitamin D deficiency causes rickets.

■In adults, vitamin D deficiency causes osteomalacia.

1.vitamin D metabolism (Figure 7.14)

■ Cholecalciferol, 25-hydroxycholecalciferol, and 24,25-dihydroxycholecalciferol are inactive.

■ The active form of vitamin D is 1,25-dihydroxycholecalciferol.

■ The production of 1,25-dihydroxycholecalciferol in the kidney is catalyzed by the

enzyme 1α-hydroxylase.

■ 1a-hydroxylase activity is increased by the following:

a.↓ serum [Ca2+]

b.↑ PTH levels

c.↓ serum [phosphate]

fIGUre 7.15 Sexual differentiation in males and females.

B.female phenotype

■The ovaries of gonadal females secrete estrogen, but not anti-müllerian hormone or testosterone.

■Without testosterone, the wolffian ducts do not differentiate.

■Without anti-müllerian hormone, the müllerian ducts are not suppressed and therefore develop into the female internal genital tract.

Ix. mAle rePrODUCTIOn

A.synthesis of testosterone (figure 7.16)

■Testosterone is the major androgen synthesized and secreted by the leydig cells.

■Leydig cells do not contain 21β-hydroxylase or 11β-hydroxylase (in contrast to the adrenal cortex) and, therefore, do not synthesize glucocorticoids or mineralocorticoids.

■LH (in a parallel action to ACTH in the adrenal cortex) increases testosterone synthesis by stimulating cholesterol desmolase, the first step in the pathway.

■Accessory sex organs (e.g., prostate) contain 5a-reductase, which converts testosterone to its active form, dihydrotestosterone.

■5a-reductase inhibitors (finasteride) may be used to treat benign prostatic hyperplasia because they block the activation of testosterone to dihydrotestosterone in the prostate.

B.regulation of testes (figure 7.17)

1.Hypothalamic control—GnrH

■Arcuate nuclei of the hypothalamus secrete GnRH into the hypothalamic–hypophysial portal blood. GnRH stimulates the anterior pituitary to secrete FSH and LH.

2.Anterior pituitary—fsH and lH

■fsH acts on the sertoli cells to maintain spermatogenesis. The Sertoli cells also secrete inhibin, which is involved in negative feedback of FSH secretion.

■lH acts on the leydig cells to promote testosterone synthesis. Testosterone acts via an intratesticular paracrine mechanism to reinforce the spermatogenic effects of FSH in the Sertoli cells.