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The etiological spectrum of pituitary stalk lesions (PSL) is wide and yet specific compared to the other diseases of the sellar and suprasellar region. Because of the pituitary stalk’s (PS) critical location and role, biopsies of these lesions are rarely performed, and their underlying pathology is often a conundrum for clinicians. A pituitary MRI in association with a clinical context can facilitate their diagnosis. To present the various causes of PSL—their clinical, hormonal, histopathological, and MRI characteristics in order to gain better insight into this pathology. A retrospective observational study consisting of 53 consecutive patients with PSL of the mean age 32 ± 4.2 years (range 6–67), conducted at the Department for Neuroendocrinology, Clinical Center of Serbia 2010–2018. Congenital malformations were the most common cause of PSL in 25 of 53 patients (47.1%), followed by inflammatory (9/53; 16.9%) and neoplastic lesions (9/53; 16.9%). The exact cause of PSL was established in 31 (58.4%) patients, of whom 23 were with congenital PS abnormalities and 8 with histopathology of PSL (7 neoplastic and 1 Langerhans Cell Hystiocytosis). A probable diagnosis of PSL was stated in 12 patients (22.6%): 6 with lymphocytic panhypophysitis, while Rathke cleft cyst, tuberculosis, dissemination of malignancy in PS were each diagnosed in 2 patients. In 10 patients (18.8%), the etiology of PSL remained unknown. Due to the inability of establishing an exact diagnosis, the management and prognosis of PSL are difficult in many patients. By presenting a wide array of causes implicated in this condition, we believe that our study can aid clinicians in the challenging cases of this pathology.

People are at higher risk for malignancy as they get older or have a strong family history of cancer. This study aims to collect family history of cancer in a large cohort of patients with pituitary adenomas (PA) in outpatient clinic from years 2005-2017. Overall, 46.6% of 1062 patients with PA had a family member affected with cancer. Breast cancer in family members was reported in 15.3% of patients with prolactinomas which was significantly higher than in families of patients with non-functioning pituitary adenomas (NFPA) (10.0%) or acromegaly (6.8%) (p = 0.004). Lung cancer in family members was reported in 12.1% of patients with prolactinomas, significantly higher than in families of NFPA patients (7.0%, p = 0.049). Colorectal cancer in relatives of patients with PA was reported with any type of PA. Furthermore, patients with a positive family history of malignancy were diagnosed with PA at an earlier age than patients with a negative family history (43.6 ± 15.9 vs 46.0 ± 16.4 years, p = 0.015). Female patients with prolactinoma are more commonly diagnosed before the age of 25 years. Forty-two percent of patients with PA diagnosed before the age of 25 years had a second- and third-degree relative with cancer, significantly higher than patients with PA diagnosed later in life (25.8%, p lt; 0.001). Breast, lung, and colon cancers in second- and third-degree relatives were reported in significantly higher proportion of patients with PA diagnosed before the age of 25 years, compared with patients with PA diagnosed later in life (breast cancer: 10.9 vs 6.1%, p = 0.033; lung cancer: 10.9 vs 5.8%, p = 0.02; colon cancer: 9.5 vs 4.0%, p = 0.004). These results suggest familial cancer clustering in patients with prolactinoma and young patients with PA (younger than 25 years at diagnosis of PA). In particular, there is a strong association between prolactinoma and family history of breast and lung cancers. Further research of possible shared genetic susceptibility of prolactinoma and breast and lung cancers is needed.

Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal β-galactosidase (SA-β-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-β-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-β-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-β-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.

In familial cases of combined pituitary hormone deficiency the most common mutations are that of Prophet of Pit 1 (PROP1) gene. PROP1 mutations are associated with deficiencies of growth hormone, thyrotropin, prolactin, and gonadotropins (follicle-stimulating hormone and luteinizing hormone), with evolving adrenocorticotropin (ACTH) deficiency in some cases. On imaging in most patients the pituitary gland is hypoplastic, but occasionally transient pituitary enlargement is found. We report a 22-year-old female initially diagnosed at age 12 with familial hypopituitarism due to PROP1 mutation, who presented with coma and respiratory arrest (acute hyponatremia). She was urgently treated in Intensive Care Unit of Emergency Center with hypertonic saline and stress doses of hydrocortisone, which resulted in the fast increase of plasma osmolality resulting in the osmotic demyelination syndrome. Simultaneously and incidentally on computed tomography scan a large sellar and suprasellar mass were reported as possible Rathke's cleft cyst or craniopharyngioma. Once the patient was stable, ACTH deficiency was documented. She remained replaced with hydrocortisone and subsequently underwent transphenoidal surgery. The removed sellar content revealed no pituitary adenoma or pituitary cells, but only an eosinophilic, colloid-like mass, and necrotic acellular debris. Her sister with hypopituitarism had an empty sella. Genetic testing in both sisters revealed the same homozygous c.150delA mutation in PROP1 gene. Here we report two sisters with the same PROP1 mutation who presented in adulthood with different pituitary morphology, one of them with a large sellar and suprasellar mass, in which transphenoidal surgery provided an extremely rare opportunity for a histopathological analysis of the sellar content. Due to the lack of endocrine care during the transition period hypocortisolism which evolved, a consequence of PROP1 mutation, was not recognized. Empirical use of hydrocortisone in the Intensive Care in our patient with life-threatening acute hyponatremia was appropriate but because glucocorticoid therapy on its own corrects hyponatremia even after stopping hypertonic saline infusion, the risk for over-correction of hyponatremia in ACTH deficiency is high.

Background: Overexpression of ghrelin and vasopressin (V3) receptors demonstrated on corticotrophe adenomas accounts for exaggerated ACTH and cortisol responses to ghrelin and desmopressin (DDAVP) in patients with Cushing’s disease (CD). Aim: In this study we have compared ACTH and cortisol responsiveness to DDAVP and ghrelin in CD patients with and without adrenal enlargemenent. Subjects and methods: Ghrelin and DDAVP tests were performed in 15 patients with CD (7 with and 8 without signs of adrenal enlargement) with CRH test in 8 patients. In 7 ageand sex-matched healthy subjects, ghrelin test was performed. Plasma ACTH and serum cortisol concentrations were measured after ghrelin, DDAVP and CRH. Growth hormone was measured after stimulation with ghrelin. Results: Significantly higher baseline and peak ACTH and cortisol concentrations after ghrelin were observed in all patients with CD compared to healthy control subjects. Patients with CD and adrenal enlargement had significantly lower baseline and peak ACTH concentrations after stimulation with ghrelin compared to CD patients without adrenal enlargement, while cortisol levels at baseline and after ghrelin administration were similar. Three out of seven patients with CD and adrenal enlargement did not respond to DDAVP while they responded well to CRH and ghrelin. Conclusion: Patients with CD and adrenal enlargement pose special diagnostic problems. They may have lower baseline ACTH levels and may not respond to DDAVP while they respond to ghrelin and CRH. Despite increased endogenous cortisol levels in CD, cortisol responses to ghrelin and CRH are preserved in patients with CD and adrenal enlargement.

Anorexia nervosa (AN) is an eating disorder characterized by self-induced starvation due to fear of adiposity. Ghrelin, gastric peptide with potent orexigenic, adipogenic, GH-releasing and metabolic properties, is elevated in AN. We have previously shown that intervention with exogenous ghrelin is not effective in terms of inducing neuroendocrine and appetite responses in AN. In this arm of the same study protocol we investigated glucose metabolism responses to 5 h i.v. infusion of active ghrelin in a) 9 severely malnourished AN patients, b) 6 AN patients who partially recovered body weight (PRAN), c) 10 constitutionally thin female subjects with regular menstrual cycles. At baseline, no significant differences were observed in blood glucose, insulin, c-peptide, adiponectin, and homeostasis model assessment index values, between the studied groups. During ghrelin infusions, blood glucose levels significantly increased in all groups although significantly less in low-weight AN; insulin levels were not significantly affected, while c-peptide levels were significantly suppressed only in the constitutionally thin and PRAN subjects. In addition to our previous findings of impaired neuroendocrine and appetite responses in patients with AN, we conclude that metabolic responses to ghrelin are attenuated in these patients, which tend to recover with weight gain.

Recent studies have demonstrated that hypopituitarism, in particular GH deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or yr following head trauma. We present the results of endocrine, neurological, neuropsychological and psychiatric evaluation in a group of 67 patients who suffered TBI at least one yr ago. Our study shows that decreased endocrine function is either restricted to one or more anterior pituitary hormones and is present in 34% of patients with any pituitary hormone deficit, while multiple pituitary hormone deficiencies are found in 10% of patients. GH/IGF-I axis was evaluated by GHRH+GHRP-6 test and IGF-I measurement. Severe GHD is the most frequent deficiency present in 15% of TBI patients. Gonadotrophin deficiency was present in 9% of patients with TBI, while thyrotroph and corticotroph function seemed more refractory to impairment. Patients with moderate-to-severe trauma are not necessarily more likely to have hypopituitarism than those with mild injury. Neuropsychological testing revealed a significant positive correlation of peak GH levels after GHRH+GHJRP-6 test with verbal learning and verbal short term memory (RAVLT total score p = 0.06, immediate free recall p = 0.02 and delayed free recall p = 0.04). Verbal and visual memory was significantly lower in elderly patients and in males. Visoconstructional abilities (RCF copy) were significantly lower in the elderly (p0.01) and undereducated (p = 0.02). Visual memory (free recall of complex figure after 30 min) significantly correlated with lower IGF-I levels (p = 0.01). Gonadotrophins and testosterone correlated significantly with visoconstructional abilities. Simple and complex conceptual tracking (TMT A and B) was significantly more impaired in older TBI patients (p0.01) and with longer time from trauma (TMT B only, p = 0.03). The psychiatric evaluation by using two different scales showed depression, phobic anxiety and psychoticism to be more prominent in the TBI group. Paranoid ideation and somatization negatively correlated with the peak GH responses to GHRH+GHRP-6 test (p = 0.04 and p = 0.03, respectively). Depression scale showed that nearly half of patients suffered from mild to moderate depression. The benefits of hormone replacement therapy on cognitive functioning and mental distress in TBI patients are eagerly awaited.

The aim of this study was to evaluate the influence of circulating cortisol levels on the somatotroph responsiveness to the most potent stimuli of growth hormone (GH) secretion, the GHRH+GHRP-6 test. We studied 12 patients with hypocortisolism (10 with Addison's disease and 2 with isolated ACTH deficiency) before and after glucocorticoid (GC) replacement therapy and compared them with 14 healthy subjects. In the 10 patients with Addison's disease, GH responses (GH peak, microg/L) to GHRH+GHRP-6 were similar both during GC, (68.2+/-12.8) and off GC (60.3+/-14.1) therapy and did not differ from those in controls (61.5+/-6.0). In a subgroup of 4 patients with newly diagnosed Addison's disease, GH responsiveness to GHRH+GHRP-6 prior to GC replacement (26.4+/-4.1) was significantly lower than in the 6 patients with long-standing Addison's disease after short-term GC withdrawal (82.9+/-18.2). In the newly diagnosed Addison's patients, after one month of GC replacement, mean GH peak value increased to 40.7+/-11.8. In the 2 patients with isolated ACTH deficiency, GH responses to GHRH+GHRP-6 did not differ off and on GC therapy (60.3+/-14.1 and 41.5+/-2.0, respectively). Our data suggest that short-term GC deprivation does not have a major impact on GH responsiveness to GHRH+GHRP-6. However, in patients with long-standing hypocortisolism, GH response is blunted but still within normal range (> 15 microg/L).

The effect of the tumor size on the anterior pituitary hypofunction is analyzed in 29 patients with acromegaly and 34 patients with clinically non-functioning pituitary tumor (NFPA). Gonadotrophin and free alpha-subunit (SU) concentrations during daytime variations (samples were taken hourly for 24 h) and after stimulation with TRH were measured as well. Patients with NFPA had a higher prevalence of isolated secondary hypogonadism (20.6% vs 10.3%) and more severe pituitary failure (52.9% vs 6.9%) in comparison with acromegalic patients (p0.0001). However, there was no association between the tumor size and the anterior pituitary hypofunction (p = 0.1 and p = 0.9) in patients with NFPA and acromegaly respectively. In premenopausal women and in men with normal/low gonadotrophin levels, mean daytime levels of LH (0.75 +/- 0.6 vs 1.5 +/- 1.9 mlU/ml; p = 0.002) and FSH (2.1 +/- 2.7 vs 4.1 +/- 4.9 mlU/ml; p = 0.009) were higher in patients with acromegaly. There was no difference in the alpha-SU level (p = 0.9). Women with gonadotrophin levels compatible with menopause and men with elevated gonadotrophin levels had the same degree of gonadotrophin and alpha-SU elevation regardless of the tumor type. TRH induced significant rise of LH in 8 (23.5%), FSH in 5 (14.7%) and alpha-SU in 10 (29.4%) patients with NFPA. Among 29 patients with acromegaly LH rose in 6 (20.7%), FSH in 5 (17.2%) and alpha-SU in 3 (10.3%) patients. In conclusion, the anterior pituitary function is better preserved in patients with acromegaly than in patients with NFPA. It seems that the size of pituitary tumor is not the major factor in the pathogenesis of hypopituitarism in patients with macroadenomas. Gonadotrophin and possibly alpha-SU response to TRH exists not only in some patients with clinically non functioning pituitary tumors but also in some patients with acromegaly. Further investigations are need to explain if it represents a biochemical marker of a plurihormonal pituitary tumor in these patients.

Hypopituitarism and hyponatremia, especially when severe, are infrequent findings particularly when the cause of hypopituitarism at presentation is unknown and untreated. Interestingly, hyponatremia is usually seen in elderly patients with hypopituitarism due to various causes. We present a case with unrecognized and untreated hypopituitarism due to a large aneurysm of the internal carotid artery in the sellar region causing the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).