Why do cyclic adenosine monophosphate (cAMP) levels increase in pseudohypoparathyroidism (PHP)?

Cyclic AMP Increases in Pseudohypoparathyroidism Due to Resistance to PTH Action

In pseudohypoparathyroidism (PHP), cyclic adenosine monophosphate (cAMP) levels increase in response to parathyroid hormone (PTH) infusion because of a defect in the PTH-responsive adenylate cyclase system in target tissues, particularly the kidneys.

Pathophysiology of Pseudohypoparathyroidism and cAMP Response

• PHP is characterized by resistance to the action of PTH despite normal or elevated levels of the hormone circulating in the blood 1.
• The primary defect in most PHP type I patients is a deficiency in the activity of Ns-protein, which normally couples hormone receptors to adenylate cyclase for cAMP production 2.
• When PTH binds to its receptor in normal individuals, it activates adenylate cyclase, leading to increased cAMP production and subsequent phosphaturic response 1.
• In PHP patients, despite high circulating PTH levels, there is a defective excretion of urinary cAMP in response to PTH infusion, indicating resistance to the hormone's action 1.

Types of Pseudohypoparathyroidism and cAMP Response

• In PHP type I, there are two main subtypes with different patterns of cAMP response:

  • Type Ia: Characterized by generalized deficient activity of Ns-protein, affecting multiple hormone systems that work via cAMP 2.
  • Type Ib: Shows more selective resistance to PTH with normal Ns-protein activity 2.

• Mental deficiency is associated with PHP type Ia (9 of 14 patients) but not with type Ib (0 of 11 patients), suggesting that Ns-protein deficiency or reduced cAMP levels may be involved in cognitive function 2.

Variations in cAMP and Phosphaturic Response

• Some PHP patients show a positive phosphaturic response to PTH despite a negative cAMP excretion response, indicating that different pathways may be affected 3.
• The phosphaturic response in PHP type I patients is strongly dependent on endogenous PTH levels and serum calcium levels 4.
• Treatment with vitamin D metabolites (such as 1α(OH)D3) can improve the phosphaturic response to PTH in some PHP patients 3, 4.

Diagnostic Implications

• Testing urinary excretion of cAMP in response to PTH infusion is considered an accurate and sensitive index for establishing the diagnosis of PHP 1.
• Basal excretion of cAMP is typically less than normal in patients with hypocalcemic disorders like PHP 1.
• PTH circulates in abnormally high concentrations in PHP patients, but secretion of the hormone responds normally to physiological control by calcium 1.

Clinical Considerations

• PHP represents a genotypically diverse group of syndromes characterized by primary resistance to hormones whose actions are mediated by cAMP 5.
• The largest subgroup of patients with PHP, characterized by Albright's hereditary osteodystrophy, exhibits generalized deficient activity of the membrane protein that couples hormone receptors to adenylate cyclase 5.
• Phenotypic expression varies greatly between families, within families, and even during the clinical course of individual patients 5.

Treatment Considerations

• Calcium antagonists (like diltiazem) may affect the phosphaturic response to PTH in PHP patients 3.
• Treatment with vitamin D metabolites can improve renal responses to PTH in some PHP patients, though reports are conflicting 4.
• The renal handling of calcium and sodium in response to exogenous PTH appears to be normal in treated PHP patients 4.