It has been shown that rats chronically hyperprolactinemic with anterior pituitary grafts present an augmentation in duration and frequency of REMS during the 12-h light period (Obal, Kacsoh, Bredow, Guha-Thakurta, and Krueger 1997). However, patients with prolactinoma did not show significant differences in REMS quantity, in contrast an NREMS increase was observed (Frieboes, Murck, Stalla, Antonijevic, and Steiger 1998). Conversely, rats with hypophysectomy (HYPOX) exhibit a decrease in NREMS and REMS (Obal, Floyd, Kapas, Bodosi, and Krueger 1996). However, there is also evidence showing rats with HYPOX have decreased or normal REMS and decrease, normal, or increased NREMS (Valatx, Chouvet, and Jouvet 1975). Perhaps, the time lapse between HYPOX rats and recording might contribute to the divergent findings, because it has been demonstrated that the amount of REMS is practically compensated 30 days after HYPOX surgery (Valatx et al. 1975).
Among pituitary tumors, 60% secrete PRL and cause a state of chronic hyperprolactinemia. In certain asymptomatic subjects with hyperprolactinemia, stable circulating complexes of immunoglobulin and PRL have been identified (Bonhoff, Vuille, Gomez, and Gallersen 1995; Hattori and Inagaki 1998), suggesting that antiprolactin autoantibodies may occasionally neutralize the activity of the hormone. Pituitary adenomas reveal pathophysiologic effects of PRL in men by inducing decreased libido, impotence, gynecomastia, galactorrhea, hypospermia, and occasionally reduced beard growth (Thorner et al. 1998). In premenopausal women, the cardinal effects of hyperprolactinemia are amenorrhea, a cessation of the normal cyclic ovarian function, galactorrhea, decreased libido, and an increased long-term risk of osteoporosis (Thorner et al. 1998; Palermo, Albano, Mangione, and Napoli 1994).
Data suggest that an elevated PRL level represents a risk factor for certain autoimmune diseases in humans and rodents. These include adjuvant arthritis in rats, collagen type II-induced arthritis in rats and mice, type I diabetes in mice, and systemic lupus erythematosis (SLE) in mice and humans. Furthermore, a connection between an elevated PRL level and rheumatoid arthritis (RA) has also been suggested (Brennan, Ollier, Worthington, Hajeer, and Silman 1996), as well an involvement of PRL in the development and progression of leukemia and lymphoma. PRL may promote the growth of hematopoietic cancers. In fact, elevated serum PRL was detected in more than 50% of patients with acute myeloid leukemia (Hatfill, Kirby, Hanley, Rybicki, and Bohm 1990), although this observation might be the result of an associated stress response. There is, to date, no disease known to cause by mutation of the PRLR, or even of its ligand. Interestingly, in vitro studies have shown that antihuman PRL antibodies can prevent proliferation of breast cancer cell lines induced by locally produced PRL (Ginsburg and Vonderhaar 1995).
In knockout mice, the data suggested that PRL is critical for fertility and mammary development in female, whereas PRL deficiency can be compensated with regard to male fertility and general hematopoiesis and immune system development. Besides, PRL receptor knockout mice presented multiple reproductive defects in female mice as sterility caused by complete failure of embryonic implantation, and almost complete loss of lactation after the first but not subsequent pregnancies. Furthermore, half of the male PRL receptors knockout mice were infertile or showed reduced fertility. Knockout mice for PRLR indicated that this receptor is not absolute requirement for fetal development. The main phenotypes of PRLR knockout mice are linked to sterility of double negative females, due to a failure of embryo implantation. No immunological phenotype was observed in either PRLR or PRL knockout mice. This suggests that PRL- or PRLR knockout mice can probably compensate for the lack of receptor functions via redundancy of other cytokine(s) (Goffin et al. 2001).
Meanwhile, transgenic PRL overexpression led to an increased rate of mammary tumor formation in females (Wennbo, Gebre-Medhin, Gritli-Linde, Ohlsson, Isaksson, and Tornell 1997). In addition, advanced prostate hyperplasia was observed in male mice, an effect that was associated with a moderate elevation of circulating testosterone level (Wennbo, Kindblom, Isaksson, and Tornell 1997).
In conclusion, both VIP and PRL cytokines are two of the most relevant sleep regulatory substances. Those cytokines are related to REMS regulation in mammals. However, the relationship between VIP, PRL, and the immune system is not clear. Thereby more studies are necessary to understand their role in both immune diseases and sleep disorders.
Acknowledgments. This work was supported in part by Programa del Mejoramiento del Profesorado (PROMEP) UVER-PTC-118, CONACYT 25122-M and Fideicomiso to R.D.C.
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