Since the isolation and characterization of parathyroid hormone-related protein (PTHrP) in 1987, the accumulated evidence is overwhelmingly in support of its role as the primary endocrine factor responsible for the syndrome of humoral hypercalcaemia of malignancy (HHM)(Martin & Suva, 1989). Thus PTHrP has been shown to have properties which explain most of the biochemical and pathological findingsinHHM. Furthermore, sensitive, specific immunoassays for plasma PTHrP have confirmed the presence of increased levels in the majority of patients with hypercalcaemiaandsolid tumours (Ratcliffeetal., 1991; Griller al., 1991). Although the exact physiological roles of PTHrP have yet to be determined, PTHrP and PTHrP mRNA have been localized in a wide range of normal and malignant tissues (Kramer et al., 1991). The finding that PTHrP has activity similar to transforming growth factor-fl (TGF-fl)(Insogna et al., 1989), its developmental and transient expression (Moseley et al., 1991), the presence of features in the gene structure characteristic of a high turnover cytokine (Martin et al., 1991), and the rapid response of PTHrP mRNA to inducing agents (Streutker & Drucker, 1991), have suggested that PTHrP may act predominantly as a paracrine factor affecting growth and development of cells. In addition, certain of the physiological actions of PTHrP may be mediated by endocrine mechanisms. For example there is convincing evidence that PTHrP from fetal parathyroid glands may regulate calcium transport across the placenta (Care et al., 1990). Measurement of circulating PTHrP concentrations in physiological conditions remains difficult. Even the most sensitive of the validated immunoassays available to date measure levels which are close to, or below, the detection limit of assays, suggesting physiological concentrations are in the subpicomolar range. Further gains in assay sensitivity are therefore required (eg to 0.01 pmolar) in order to establish whether PTHrP circulates under physiological conditions. Measurement of PTHrP bioactivity will ultimately be required to confirm its biological significance. The PTH-like bioactivity of PTHrP arises by interaction with PTH receptors, and reflects homology at its aminoterminus with that of PTH (Juppner et al., 1988). Although much of the initial interest in PTHrP was focussed on its PTH-like actions in HHM, recent evidence suggests that other regions of the molecule possess their own distinct biological activities which may be mediated via unique PTHrP receptors. The stimulation of calcium transport across the placenta has been localized to the 75-85 region of PTHrP (Care et al., 1990); while PTHrP (107-111)(osteostatin), is a potent inhibitor ofosteoclastic bone resorption (Fenton etal., 1991); and TGF-fl-like activity has been localized to PTHrP (1-36) amide (Insogna et al., 1989). Thus the possibility exists that PTHrP may function as a polyhormone with the potential for different biological actions depending on the molecular species present which may be regulated by tissue-specific processing by target tissues.

Recent studies have indicated that PTHrP may have a number of important actions in lactation, affecting the mammary gland itself, and also calcium metabolism in the fetus and mother. PTHrP is expressed by the lactating mammary gland (Thiede & Rodan, 1988) and secreted into milk. PTHrP concentrations in milk are approximately 10 000-100000-fold higher than corresponding levels in plasma, and they increase with the duration of lactation, reaching 100 nM in the rat (Yamamoto et al., 1992), and 40 nM in the cow (Law et al., 1991). In the rat, suckling increased expression of PTHrP mRNA in the …