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

Abstract

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 +/- 7.3 pmol-eq/l (mean +/- SD). In hyperprolactinemic patients, plasma PTHrP was elevated to 30.3 +/- 13.4 pmol-eq/l (p < 0.001, n = 45), and in patients with humoral hypercalcemia of malignancy PTHrP levels were 52.9 +/- 29.6 (p < 0.001 to controls and hyperprolactinemic patients). Fifty-three percent of hyperprolactinemic patients (n = 24) had clearly elevated PTHrP levels (> 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals

“…The presence of the autocrine 5-HT-PTHrP signaling system in breast cancer cells also indicates that this same system contributes to local bone loss and systemic hypercalcemia in metastatic cancers. It has been evident that PTHrP is involved in bone mobilization during lactation and hyperprolactinemia and in hypercalcemia caused by cancers (5,47,48,53). The transcription factor Runx2 is an important regulator of the metastatic and bone-homing phenotypes of breast cancer cells (41).…”

“…In addition, antidepressant and antipsychotic drugs tend to cause hyperprolactinemia, and the degree of hyperprolactinemia can be substantial (4,33). Demineralization of the bones is also commonly associated with hyperprolactinemia resulting from prolactinomas (12,27,44,48). One explanation for bone loss in hyperprolactinemic patients is the antigonadal effect of PRL, which reduces estrogen secretion in females.…”

“…One explanation for bone loss in hyperprolactinemic patients is the antigonadal effect of PRL, which reduces estrogen secretion in females. In addition, hyperprolactinemic patients had elevated circulating PTHrP levels, and PTHrP concentrations were directly correlated with bone loss (48). Mammary gland 5-HT biosynthesis was discovered because TPH1 was highly induced by hyperprolactine- mia (31).…”

“…PTHrP is undetectable in the circulation except during lactation, in advanced metastastic disease, or in patients with hyperprolactinemia (5,6,9,24,42,48). Despite obvious correlations with states of elevated prolactin (PRL), PRL did not induce PTHrP in conventional cell cultures of mammary epithelium (29, 52), and our laboratory has done numerous experiments that confirmed that PRL does not induce PTHrP in mammary cells by a direct mechanism (unpublished results).…”

“…PTHrP was originally discovered as the factor responsible for humoral hypercalcemia of malignancy and is secreted from a variety of advanced soft-tissue cancers (5,8,28,47). The NH 2 -terminal portion of PTHrP is similar to that of parathyroid hormone (PTH) and acts via the type 1 PTH receptors (PTH1R) to induce the receptor activator of NF-B ligand (RANKL) (34).PTHrP is undetectable in the circulation except during lactation, in advanced metastastic disease, or in patients with hyperprolactinemia (5,6,9,24,42,48). Despite obvious correlations with states of elevated prolactin (PRL), PRL did not induce PTHrP in conventional cell cultures of mammary epithelium (29, 52), and our laboratory has done numerous experiments that confirmed that PRL does not induce PTHrP in mammary cells by a direct mechanism (unpublished results).…”