Parathyroid hormone-related (
PTHrP), the major mediator of
humoral hypercalcemia of malignancy, may also regulate placental
calcium flux, uterine contraction and fetal tissue development. In the present study, we demonstrated that the mean immunoreactive
PTHrP concentrations in amniotic fluid at mid-gestation (21.2 +/- 3.7 pmol/l) and at term (19.0 +/- 2.7 pmol/l) were 13-16-fold higher than levels measured in either fetal (1.6 +/- 0.1 pmol/l) or maternal plasma (1.4 +/- 0.3 pmol/l) at term and equal to levels found in plasma of patients with
humoral hypercalcemia of malignancy. In vitro studies pointed to three possible sources of
PTHrP in amniotic fluid: cultured amniotic fluid cells, cells derived from the amniotic membrane overlying the placenta and placental villous core mesenchymal cells. Treatment of cultured amniotic fluid cells with human
prolactin,
human placental lactogen (hPL) or
human growth hormone (100 micrograms/l) increased
PTHrP secretion after 24 h by 43%, 109% and 90%, respectively.
Insulin-like growth factors I and II (100 micrograms/l),
insulin (100 micrograms/l) and
epidermal growth factor (
EGF) (10 micrograms/l) increased
PTHrP secretion by 53%, 46%, 68% and 118%, respectively. The stimulation of
PTHrP secretion by
EGF or by hPL was both time- and dose-dependent. In contrast,
calcitriol and
dexamethasone (10 nmol/l) decreased
PTHrP secretion by 32% and 75%, respectively.
Estradiol,
progesterone,
dihydrotestosterone and
human chorionic gonadotropin had no effect on
PTHrP secretion. These findings support the notion that
PTHrP may play a physiological role in the uteroplacental unit and demonstrate that human amniotic fluid cells could be a useful model for studying the regulation of
PTHrP production and secretion by
hormones and
growth factors.