Relative effects of prolactin excess and estrogen deficiency on bone in rats

Humans with prolactinoma are at risk for osteoporosis. The relative contributions of hyperprolactinemia-induced hypogonadism and the prolactin (PRL) excess per se have been unclear from clinical studies. To determine the effects of PRL excess, two models of chronic hyperprolactinemia were used. In one, mild hyperprolactinemia was produced in rats bearing extra anterior pituitary glands under the kidney capsule. Severe hyperprolactinemia was produced by subcutaneously transplanting the PRL-secreting MMQ tumor into other rats. To control for estrogen deficiency, the rats were ovariectomized. In some experiments, estrogen replacement was provided. Urinary calcium excretion was increased in hyperprolactinemic rats compared with controls, regardless of severity of PRL excess and estrogen status. This suggested that PRL excess itself had some effect on calcium balance. More importantly, however, the spinal bone mineral density (BMD; measured by dual-energy x-ray densitometry) of mildly hyperprolactinemic ovariectomized rats was the same as control ovariectomized rats. Similarly, tibial dry weight and ash weight were affected by the estrogen status, but not by the severe PRL excess of the tumor-implanted rats. Thus, despite the evidence for an increase in urinary calcium excretion in hyperprolactinemic rats, estrogen deficiency is much more important in determining bone mineral. Therefore, the present data indicate that the osteoporosis of hyperprolactinemia is likely due to PRL-induced hypogonadism, rather than a direct effect of PRL on calcium homeostatis.