Pregnancy Inhibits Mammary Carcinogenesis by Persistently Altering the Hypothalamic–Pituitary Axis

Early full-term pregnancy is known to reduce the lifetime risk of breast cancer. Although the phenomenon of parity-induced protection is well-established, the physiological mechanisms involved in this protection are not clear. Earlier reports have shown that pregnancy results in alterations of hormone levels. How pregnancy affects hypothalamic hormones and how the change, if any, influences breast cancer is not well understood. Seven-week-old female Lewis rats were given N-methyl-N-nitrosourea. Two weeks post carcinogen exposure, a set of females were housed with males to generate the parous rats and another set of rats served as the nulliparous controls. Mammary tumorigenesis was assessed for 9 months. Hypothalamic and pituitary levels of hormones were measured at various timepoints. Further, animals were also challenged with growth hormone and prolactin secretagogues to test the effect of pregnancy on the hypothalamic–pituitary hormonal axis. Persistent alterations in the level of growth hormone-releasing hormone, thyrotropin releasing hormone, dopamine, and somatostatin in the hypothalamus of parous animals was observed. Further, we also observed that pregnancy had a significant effect on the pituitary gland and its response to growth hormone and prolactin secretagogues. Our studies using the rodent model system demonstrate that pregnancy could be reducing the risk of breast cancer by persistently altering the hypothalamic–pituitary axis, which could have implications for breast cancers in humans as well.

Anterior pituitary function in critical illness

Critical illness is hallmarked by major changes in all hypothalamic–pituitary–peripheral hormonal axes. Extensive animal and human studies have identified a biphasic pattern in circulating pituitary and peripheral hormone levels throughout critical illness by analogy with the fasting state. In the acute phase of critical illness, following a deleterious event, rapid neuroendocrine changes try to direct the human body toward a catabolic state to ensure provision of elementary energy sources, whereas costly anabolic processes are postponed. Thanks to new technologies and improvements in critical care, the majority of patients survive the acute insult and recover within a week. However, an important part of patients admitted to the ICU fail to recover sufficiently, and a prolonged phase of critical illness sets in. This prolonged phase of critical illness is characterized by a uniform suppression of the hypothalamic–pituitary–peripheral hormonal axes. Whereas the alterations in hormonal levels during the first hours and days after the onset of critical illness are evolutionary selected and are likely beneficial for survival, endocrine changes in prolonged critically ill patients could be harmful and may hamper recovery. Most studies investigating the substitution of peripheral hormones or strategies to overcome resistance to anabolic stimuli failed to show benefit for morbidity and mortality. Research on treatment with selected and combined hypothalamic hormones has shown promising results. Well-controlled RCTs to corroborate these findings are needed.

The unappreciated roles of the cholecystokinin receptor CCK(1) in brain functioning

The CCK(1) receptor is a G-protein-coupled receptor activated by the sulfated forms of cholecystokinin (CCK), a gastrin-like peptide released in the gastrointestinal tract and mammal brain. A substantial body of research supports the hypothesis that CCK(1)r stimulates gallbladder contraction and pancreatic secretion in the gut, as well as satiety in brain. However, this receptor may also fulfill relevant roles in behavior, thanks to its widespread distribution in the brain. The strategic location of CCK(1)r in mesolimbic structures and specific hypothalamic and brainstem nuclei lead to complex interactions with neurotransmitters like dopamine, serotonin, and glutamate, as well as hypothalamic hormones and neuropeptides. The activity of CCK(1)r maintains adequate levels of dopamine and regulates the activity of serotonin neurons of raphe nuclei, which makes CCK(1)r an interesting therapeutic target for the development of adjuvant treatments for schizophrenia, drug addiction, and mood disorders. Unexplored functions of CCK(1)r, like the transmission of interoceptive sensitivity in addition to the regulation of hypothalamic hormones and neurotransmitters affecting emotional states, well-being, and attachment behaviors, may open exciting roads of research. The absence of specific ligands for the CCK(1) receptor has complicated the study of its distribution in brain so that research about its impact on behavior has been published sporadically over the last 30 years. The present review reunites all this body of evidence in a comprehensive way to summarize our knowledge about the actual role of CCK in the neurobiology of mental illness.