PTH activates its target cells by increasing the activity of adenylyl cyclase, thereby increasing cellular levels of cyclic AMP. Cyclic AMP activates a cascade of proteins that produces the physiologic effect. Patients with PHP type 1 have heterozygous mutations of the maternally derived allele that reduce expression or function of the α-subunit of the heterotrimeric G protein Gs, which couples receptors for hormones such as PTH, thyroid-stimulating hormone (TSH), and others to activation of adenylyl cyclase. Patients with PHP type 1a have mutations in the GNAS gene that directly affect production of Gα_s, whereas patients with PHP type 1b have mutations in or near GNAS that disrupt genomic imprinting and thereby reduce synthesis of Gα_s. Although PTH binds to the cell, it fails to elicit an effect because the lack of functional Gα_s “uncouples” the receptor from adenylyl cyclase. Hence, there is no production of its second messenger, cyclic AMP, and the biochemical abnormalities of hypoparathyroidism develop. Hypocalcemia occurs because of decreased calcium absorption from the intestine due to low PTHmediated synthesis of 1,25(OH)₂D. The serum phosphate level is high because the proximal renal tubule is resistant to PTH, and as a result the tubular reabsorption of phosphate is very high. In contrast to true hypoparathyroidism, the serum PTH level is elevated in response to hypocalcemia.

Because Gα_s couples receptors for many different hormones to adenylyl cyclase, patients with PHP type 1a have impaired responsiveness not only to PTH but also to other hormones such as TSH, growth hormone–releasing hormone (GHRH), and gonadotropins and develop obesity. By contrast, the defect in PHP type 1b tends to be less severe, and PTH resistance is the principal manifestation of the disorder. Bone is variably responsive to PTH; in most patients bone density is increased, although in some cases, osteitis fibrosa cystica occurs as a result of high PTH levels. As in hypoparathyroidism, the hypocalcemia ranges from latent to severe. Treatment of pseudohypoparathyroidism is the same as that for hypoparathyroidism, but patients rarely develop hypercalciuria because the distal renal tubule remains responsive to PTH.