Targeted overexpression of luteinizing hormone causes ovary-dependent functional adenomas restricted to cells of the Pit-1 lineage.

The majority of pituitary adenomas in humans are nonmetastasizing, monoclonal neoplasms that occur in approximately 20% of the general population. Their development has been linked to a combination of extrinsic factors and intrinsic defects. We now demonstrate with transgenic mice that targeted and chronic overexpression of LH causes ovarian hyperstimulation and subsequent hyperproliferation of Pit-1-positive cells that culminates in the appearance of functional pituitary adenomas ranging from focal to multifocal expansion of lactotropes, somatotropes, and thyrotropes. Tumors fail to develop in ovariectomized mice, indicating that contributions from the ovary are necessary for adenoma development. Although the link between chronic ovarian hyperstimulation and PRL-secreting adenomas was expected, the involvement of somatotropes and thyrotropes was surprising and suggests that multiple ovarian hormones may contribute to this unusual pathological consequence. In support of this idea, we have found that ovariectomy followed by estrogen replacement results in the expansion of lactotropes selectively in LH overexpressing mice, but not somatotropes and thyrotropes. Collectively, these data indicate that estrogen is sufficient for the formation of lactotrope adenomas only in animals with a hyperstimulated ovary, whereas the appearance of GH- and TSH-secreting adenomas depends on multiple ovarian hormones. Together, our data expand current models of pituitary tumorigenesis by suggesting that chronic ovarian hyperstimulation may underlie the formation of a subset of pituitary adenomas containing lactotropes, somatotropes, and thyrotropes.

Degenerative phenotypes caused by the combined deficiency of murine HIP1 and HIP1r are rescued by human HIP1.

The members of the huntingtin-interacting protein-1 (HIP1) family, HIP1 and HIP1-related (HIP1r), are multi-domain proteins that interact with inositol lipids, clathrin and actin. HIP1 is over-expressed in a variety of cancers and both HIP1 and HIP1r prolong the half-life of multiple growth factor receptors. To better understand the physiological importance of the HIP1 family in vivo, we have analyzed a large cohort of double Hip1/Hip1r knockout (DKO) mice. All DKO mice were dwarfed, afflicted with severe vertebral defects and died in early adulthood. These phenotypes were not observed during early adulthood in the single Hip1 or Hip1r knockouts, indicating that HIP1 and HIP1r compensate for one another. Despite the ability of HIP1 and HIP1r to modulate growth factor receptor levels when over-expressed, studies herein using DKO fibroblasts indicate that the HIP1 family is not necessary for endocytosis but is necessary for the maintenance of diverse adult tissues in vivo. To test if human HIP1 can function similar to mouse HIP1, transgenic mice with 'ubiquitous' expression of the human HIP1 cDNA were generated and crossed with DKO mice. Strikingly, the compound human HIP1 transgenic DKO mice were completely free from dwarfism and spinal defects. This successful rescue demonstrates that the human HIP1 protein shares some interchangeable functions with both HIP1 and HIP1r in vivo. In addition, we conclude that the degenerative phenotypes seen in the DKO mice are due mainly to HIP1 and HIP1r protein deficiency rather than altered expression of neighboring genes or disrupted intronic elements.

Elevated prolactin levels immediately precede decisions to babysit by male meerkat helpers.

Recent studies suggest that decisions to care for the offspring of others in societies of cooperative vertebrates may have a hormonal basis. The crucial question of whether changes in hormone levels immediately precede or merely follow bouts of offspring care, however, remains largely unanswered. Here, we show that in wild groups of cooperatively breeding meerkats, male helpers that decided to babysit for the day had significantly higher levels of prolactin, coupled with lower levels of cortisol, before initiating a babysitting session compared with similarly aged individuals that decided to forage. In addition, these hormonal differences disappeared over the course of the day, suggesting that hormone levels changed in a fundamentally different way in meerkats that babysat versus those that foraged. In contrast, long-term contributions to babysitting were not significantly associated with plasma levels of prolactin, cortisol, or testosterone in individual male helpers. Our results show, for the first time, that elevated levels of prolactin may immediately precede bouts of helping behavior but differ from recent findings on the same study population in which plasma levels of cortisol, but not prolactin, were significantly and positively associated with rates of pup feeding by male helpers. Together, these results lend significant weight to the idea that decisions to help in cooperative vertebrates have a hormonal basis, although different hormones appear to be associated with different types of care.

Radioimmunoassay of prolactin for the meerkat (Suricata suricatta), a cooperatively breeding carnivore.

We report the development and validation of a highly specific heterologous radioimmunoassay (RIA) to measure meerkat prolactin (PRL) by using rabbit antiserum to human prolactin and canine [125I]iodo-PRL. Dilutions of meerkat pituitary standard and plasma gave parallel inhibition curves in the assay. Gel filtration of meerkat pituitary extracts and canine [125I]iodo-PRL run separately on a Sephadex G-100 generated identical peaks of activity, and Western blot analysis of meerkat pituitary extract with the human prolactin antiserum used in the RIA gave a molecular weight similar to canine prolactin (21kDa). We carried out a biological validation of the prolactin assay by administering three different doses each of sulpiride and cabergoline to adult male meerkats. Increasing doses of sulpiride and cabergoline caused substantial increases and decreases, respectively, in the plasma prolactin of the study animals as expected. Activation of the stress response in meerkats by capture and ketamine hydrochloride anesthesia caused short-term but significant increases in prolactin levels in individuals bled repeatedly. The RIA developed and described here was able to determine plasma concentrations of prolactin in all animals sampled. We conclude, however, that it will be important in all future studies to confine blood sampling times to 4-7 min after capture/administration of anesthesia to avoid the confounding effects of the stress response on prolactin levels.