Plasma levels of parathyroid hormone-related peptide are elevated in hyperprolactinemia and correlated to bone density status

Osteopenia is an important clinical manifestation of hyperprolactinemia. Bone loss in these patients has mainly been attributed to concomitant deficiency of gonadal hormones rather than to hyperprolactinemia per se. Parathyroid hormone-related peptide (PTHrP) is expressed in human mammary tissue, and elevated circulating PTHrP levels as well as concomitant hypercalcemia have been described during lactation. We sought to determine circulating PTHrP levels in patients with long-standing hyperprolactinemia and whether PTHrP may exert possible systemic effects on bone and mineral metabolism. We studied 45 patients (30 women and 15 men) with persisting hyperprolactinemia 6 ± 4 years (mean ± SD) after trans-sphenoidal surgery for prolactin-producing pituitary adenomas. PTHrP levels in 117 healthy controls were 10.6 ± 73 pmol-eq/l (mean ± SD). In hyperprolactinemic patients, plasma PTHrP was elevated to 303 ± 13.4 pmol-eq/l (p 2 SD). Retrospective immunocytochemical studies of the removed pituitary adenomas from 19 patients generally showed a higher degree of immunoreactivity for PTHrP (1–34) in all but one case when compared with normal pituitary tissue. Patients with elevated circulating PTHrP levels showed in most instances strong immunoreactivity to PTHrP in 70–100% of tumor cells. PTHrP was significantly correlated to blood pressure (systolic: r = –0.42, p < 0.005; diastolic: r = –0.41, p < 0.01), serum calcium (r = 0.40, p < 0.01), parathyroid hormone (r = –0.43, p < 0.005), and bone density measurements (r = –0.41, p < 0.005). Patients taking low doses of bromocriptine (n = 15) had similar reductions in bone mineral density despite lower prolactin levels (p < 0.005), and there was no correlation between either prolactin levels or estrogen status and bone mineral density measurements (r = –0.12 and r = –0.28, respectively). Our data demonstrate that circulating PTHrP levels are clearly elevated in approximately 50% of patients with pituitary hyperprolactinemia and suggests the pituitary adenomas to be the major source of PTHrP production. Independent of gonadal function and the degree of hyperprolactinemia, PTHrP functions as an active hormone and contributes substantially to bone loss seen in these patients.