Prolactinomas comprise 30–50% of all pituitary neuroendocrine tumors, frequently occur in females aged 20 to 50, and cause hypogonadism and infertility. In typical cases, female patients exhibit galactorrhea and amenorrhea due to serum prolactin (PRL) elevation, and patients during pregnancy should be carefully treated. During diagnosis, other causes of hyperprolactinemia must be excluded, and an MRI is useful for detecting pituitary neuroendocrine tumors. For treating prolactinoma, dopamine agonists (DAs) are effective for decreasing PRL levels and shrinking tumor size in most patients. Some DA-resistant cases and the molecular mechanisms of resistance to a DA are partially clarified. The side effects of a DA include cardiac valve alterations and impulse control disorders. Although surgical therapies are invasive, recent analysis shows that long-term remission rates are higher than from medical therapies. The treatments for giant or malignant prolactinomas are challenging, and the combination of medication, surgery, and radiation therapy should be considered. Regarding pathogenesis, somatic SF3B1 mutations were recently identified even though molecular mechanisms in most cases of prolactinoma have not been elucidated. To understand the pathogenesis of prolactinomas, the development of new therapeutic approaches for treatment-resistant patients is expected. This review updates the recent advances in understanding the pathogenesis, diagnosis, and therapy of prolactinoma.

Although glucocorticoid-induced hyperphagia is observed in the patients with glucocorticoid treatment or Cushing’s syndrome, its molecular mechanism is not clear. We thus explored the expression of neuropeptide mRNAs in the hypothalamus related to appetite regulation in CRH over-expressing transgenic mice (CRH-Tg), a model of Cushing’s syndrome. We measured food intake, body weight (including body fat weight) and plasma corticosterone levels in CRH-Tg and their wild-type littermates (WT) at 6 and 14 weeks old. We also examined neuropeptide Y (NPY), proopiomelanocortin (POMC) and Agouti-related protein (AgRP) mRNAs in the arcuate nucleus (ARC) using in situ hybridization. Circulating corticosterone levels in CRH-Tg were markedly elevated at both 6 and 14 weeks old. Body fat weight in CRH-Tg was significantly increased at 14 weeks old, which is considered as an effect of chronic glucocorticoid excess. At both 6 and 14 weeks old, CRH-Tg mice showed significant hyperphagia compared with WT (14w old: WT 3.9±0.1, CRH-Tg 5.1±0.7 g/day, p<0.05). Unexpectedly, NPY mRNA levels in CRH-Tg were significantly decreased at 14 weeks old (WT: 1571.5±111.2, CRH-Tg: 949.1±139.3 dpm/mg, p<0.05), and there were no differences in POMC mRNA levels between CRH-Tg and WT. On the other hand, AgRP mRNA levels in CRH-Tg were significantly increased compared with WT at both ages (14w old: WT 365.6±88.6, CRH-Tg 660.1±87.2 dpm/ mg, p<0.05). These results suggest that glucocorticoid-induced hyperphagia is associated with increased hypothalamic AgRP. Our results also indicate that hypothalamic NPY does not have an essential role in the increased food intake during glucocorticoid excess.

We have shown in a previous study that high corticosterone levels during repeated immobilization stress result in a reduction of glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus (PVN) and the hippocampus. The reduction of GR presumably accounts for loss of or decrease in glucocorticoid-negative feedback, and thus hyperfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis persists during chronic stress. Starvation is a stress state in which the counterregulatory responses against the loss of food occur in the central nervous system. We explored the impact of starvation on the HPA axis, GR and mineralocorticoid receptor (MR) mRNAs in the hippocampus, the PVN, and the anterior pituitary (AP) of rats. Rats were starved for 4 days and sacrificed in the morning. Starved rats showed high levels of plasma corticosterone, whereas neither plasma corticotropin (ACTH), AP proopiomelanocortin (POMC) mRNA nor AP type-1 corticotropin-releasing hormone (CRH) receptor mRNA was altered in the starved rats. In the presence of high corticosterone, starvation resulted in a decrease in both CRH mRNA and type-1 CRH receptor mRNA in the PVN. Consistently, the starved rats did not show any changes in GR mRNA in the hippocampus (CA1-2, CA3, and dentate gyrus), the PVN or the AP despite the elevation of plasma corticosterone. A significant decrease in MR mRNA was seen in the dentate gyrus and the AP, but not in CA1–2, CA3 or PVN. The lack of reduction of GR may be one of the organism’s counterregulatory responses during starvation, which allows an intact glucocorticoid negative feedback, thereby resulting in decreased anorectic neuropeptide levels, namely CRH, in the PVN. The results also indicate that GR mRNA in the hippocampus and other brain regions is not solely regulated by circulating glucocorticoids. The mechanism underlying the regulation of GR mRNA in the central nervous system remains to be clarified.

Endogenous Cushing’s syndrome is characterized by unique clinical features and comorbidities, and progress in the analysis of its genetic pathogenesis has been achieved. Moreover, prescribed glucocorticoids are also associated with exogenous Cushing’s syndrome. Several animal models have been established to explore the pathophysiology and develop treatments for Cushing’s syndrome. Here, we review recent studies reporting animal models of Cushing’s syndrome with different features and complications induced by glucocorticoid excess. Exogenous corticosterone (CORT) administration in drinking water is widely utilized, and we found that CORT pellet implantation in mice successfully leads to a Cushing’s phenotype. Corticotropin-releasing hormone (CRH) overexpression mice and adrenal-specific Prkar1a deficient mice have been developed, and AtT20 transplantation methods have been designed to examine the medical treatments for adrenocorticotropic hormone (ACTH)-producing pituitary neuroendocrine tumors. We also review recent advances in the molecular pathogenesis of glucocorticoid-induced complications using animal models.

Summary: Langerhans cell histiocytosis (LCH) is a rare disease characterized by the proliferation of abnormal Langerhans cells in various tissues and organs, including bone, skin, the lungs, and the pituitary gland. Hypothalamic–pituitary lesions in LCH often cause central diabetes insipidus (CDI), but the natural course of LCH in the CNS remains to be elucidated. In this study, we report an interesting case of altered LCH lesions in the CNS from the pituitary to the hypothalamus in a 45-year-old woman. She developed symptoms of polyuria and was diagnosed with CDI with lymphocytic hypophysitis due to an enlarged pituitary gland with stalk thickening shown on MRI. Short-term glucocorticoid therapy cured pituitary enlargement, but serum prolactin levels gradually increased. Six years later, the immunohistological findings of a skin biopsy revealed positive for leukocyte common antigen, S-100, and CD1a expression, indicating a diagnosis of LCH. MRI revealed a new lesion in the hypothalamus without pituitary involvement, likely due to LCH. Chemotherapy improved LCH lesions both in the skin and hypothalamus, but therapy was stopped on the patient’s request. Although adult-onset LCH is rare, it should be considered as a differential diagnosis in cases of CDI as the primary disease. The clinical course in the present case indicated that LCH lesion was altered from pituitary to suprasellar extension; where such changes were observed, the possibility of LCH should be considered. Learning points: Diagnosing the primary disease of CDI is challenging; therefore, careful observation is necessary in pathologically unknown cases. Enhanced MRI should be performed in cases with suspected hypothalamic lesions, such as elevated serum prolactin. Although adult-onset LCH is rare, it should be considered a differential diagnosis in cases of CDI as the primary disease. The direction of changing CNS lesion from pituitary to suprasellar extension might be a unique MRI finding in LCH.