Mareike R. Stieg

Leptin: A hormone linking activation of neuroendocrine axes with neuropathology

Leptin, a peptide hormone secreted by adipocytes, plays a central role in controlling appetite and weight in both rodents and humans. Basic science and clinical research suggest that this hormone not only affects the regulation of the neuroendocrine axes, but also exerts effects on the central nervous system with subsequent alterations in psychological functions. For instance, leptin suppresses cortisol secretion during stress-related activation of the adrenal axis. As psychiatric disorders like depression are associated with hypercortisolism, leptin is proposed to exert anti-depressant-like effects due to its inhibition of chronically overactive hypothalamo-pituitary-adrenal axis function. Moreover, leptin status of depressed patients could serve as a prognostic marker for therapy response. Besides its influence on neuroendocrine pathways leptin seems to have direct central effects on brain development and neuroplasticity. Low leptin levels have been shown to be associated with increased risk of developing dementia, supporting the idea of a pro-cognitive effect of leptin. These areas may have direct clinical implications and deserve to be studied further in the future.

Diagnosis of Primary Hypophysitis in Germany.

CONTEXT Representative data on diagnostic findings in primary hypophysitis (PrHy) are scarce. OBJECTIVE The objective of the study was to collate consistent data on clinical features in a large series of patients with PrHy. Another objective was to gain information on current practice in a diagnostic work-up. DESIGN The Pituitary Working Group of the German Society of Endocrinology conducted a nationwide retrospective cross-sectional cohort study in Germany. PATIENTS Seventy-six patients with PrHy were identified. MAIN OUTCOME MEASURES Clinical and endocrinological features were assessed. RESULTS Headache (50%) and increase in body mass (18%) were the most frequent nonendocrine symptoms. Hypophysitis was associated with pregnancy in only 11% of the female patients. Diabetes insipidus was found in 54% of the patients at presentation. Hypogonadotropic hypogonadism was the most frequent endocrine failure (62%), whereas GH deficiency was the least frequent (37%). With 86%, thickening of the pituitary stalk was the prevailing neuroradiological sign. Compared with surgical cases, the cases without histological confirmation presented more often with suprasellar lesions and had less severe nonendocrine symptoms. Granulomatous hypophysitis was associated with more severe clinical symptoms than lymphocytic hypophysitis. Examination of cerebrospinal fluid was predominantly performed in participating neurosurgical centers, whereas thyroid antibodies were almost exclusively assessed in endocrinological centers. CONCLUSION In contrast to the literature, hypogonadism was found to be the most frequent endocrine failure in PrHy. Weight gain was identified as a clinical sign of PrHy. In the majority of patients, PrHy can be reliably identified by characteristic clinical signs and symptoms, obviating histological confirmation. The diagnostic approach should be standardized in PrHy.

Persistence of myopathy in Cushing's syndrome: evaluation of the German Cushing's Registry

BACKGROUND Cushings syndrome (CS) is characterized by an excessive secretion of glucocorticoids that results in a characteristic clinical phenotype. One feature of clinical hypercortisolism is breakdown of protein metabolism translating into clinical consequences including glucocorticoid-induced myopathy. While surgery is effective in control of cortisol excess, the effect of biochemical remission on muscular function is yet unclear. METHODS In a cross-sectional study we analyzed 47 patients with CS during the florid phase (ActiveCS). 149 additional patients were studied 2-53 years (mean: 13 years) after surgery in biochemical long-term remission (RemissionCS). Also, 93 rule-out CS patients were used as controls (CON). All subjects were assessed for grip strength using a hand grip dynamometer and underwent the chair rising test (CRT). RESULTS Hand grip strength (85% vs 97% of norm, P = 0.002) and the CRT performance (9.5 s vs 7.1 s, P = 0.001) were significantly lower in ActiveCS compared to the CON group. Six months after treatment grip strength further decreased in CS (P = 0.002) and CRT performance remained impaired. The RemissionCS group (mean follow-up 13 years) had reduced hand grip strength (92% compared to normal reference values for dominant hand, P < 0.001). The chair rising test performance was at 9.0 s and not significantly different from the ActiveCS group (P = 0.45). CONCLUSION CS affects muscle strength in the acute phase, but functional impairment remains detectable also during long-term follow-up despite biochemical remission.

Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor

OBJECTIVE Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushings disease (CD). Corticotroph tumor progression, the so-called Nelsons syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelsons tumors has not been studied in detail so far. DESIGN AND METHODS Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing. RESULTS Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelsons tumor. CONCLUSION Somatic mutations in USP8 are common in Nelsons tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelsons tumor.

Advances in understanding hypopituitarism

The understanding of hypopituitarism has increased over the last three years. This review provides an overview of the most important recent findings. Most of the recent research in hypopituitarism has focused on genetics. New diagnostic techniques like next-generation sequencing have led to the description of different genetic mutations causative for congenital dysfunction of the pituitary gland while new molecular mechanisms underlying pituitary ontogenesis have also been described. Furthermore, hypopituitarism may occur because of an impairment of the distinctive vascularization of the pituitary gland, especially by disruption of the long vessel connection between the hypothalamus and the pituitary. Controversial findings have been published on post-traumatic hypopituitarism. Moreover, autoimmunity has been discussed in recent years as a possible reason for hypopituitarism. With the use of new drugs such as ipilimumab, hypopituitarism as a side effect of pharmaceuticals has come into focus. Besides new findings on the pathomechanism of hypopituitarism, there are new diagnostic tools in development, such as new growth hormone stimulants that are currently being tested in clinical trials. Moreover, cortisol measurement in scalp hair is a promising tool for monitoring cortisol levels over time.

Is insulin-like growth factor-I a good marker for treatment adherence in growth hormone deficiency in adulthood?

There is a paucity of studies on adherence to growth hormone treatment in growth hormone deficient (GHD) adults. Therefore, this study reports on adherence to GH‐replacement therapy in adults with GHD, with a special focus on the course and potential predictors of nonadherence.

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