SAT-304 Pituitary Stem Cells May Drive Adenomas Causing Cushing’s Disease

Introduction:Cell rests of self-renewing Sox2+ progenitor cells have been identified in the normal pituitary glands1, however their role in human pituitary tumorigenesis is not understood. Adrenocorticotropic hormone (ACTH) producing microadenomas that cause Cushing’s disease frequently (~70%) lack pathogenic genetic mutations.2 In mice, targeted expression of oncogenic β-catenin in Sox2+ cells generate microadenomas. Interestingly, the Sox2+ cells reside within the adjacent normal gland and drive adenomas in a paracrine fashion.3 We hypothesized that Sox2+ progenitors in human pituitary gland may drive the formation of microadenomas that cause Cushing’s disease (CD). Methods:Four ACTH producing adenomas and two non-functional adenomas (NFPA) with separately annotated adjacent normal tissue (henceforward called ‘microenvironment’) were procured for this study (NCT00060541). We performed RNA deep sequencing (RNAseq) and compared expression of lineage-specific markers and progenitor markers using two-sample T-tests after testing for variance equality and using Welch’s approximation for degrees of freedom. Results:We found expected overexpression of ACTH preprohormone POMC in CD adenomas compared to adjacent microenvironment (?-fold) and NFPA (?-fold). The microenvironment in Cushing’s disease showed increased expression of progenitor markers including SOX2, SOX9, CDH1, GRFA2, and KLF4 compared with microenviroment in NFPA. Likewise, the Cushing’s disease microenvironment showed increased expression ofPOMC (26.98 - fold, P = 0.004) as well as PRLR (FC 17.39, P = 0.006) and GH1 (FC 29.91, P = 0.003) implying that increased Sox2+ progenitors contribute to terminally differentiated corticotrope, lactotroph and somatotroph lineages in-vivo. Conclusions:We report increased expression of several progenitor markers and concomitant elevation in tissues-specific markers in the microenvironment of Cushing’s disease patients. Our results indicate that increased pituitary progenitors in the microenvironment of human corticotropinomas may signal in paracrine fashion and may contribute to the pathogenesis of Cushing’s disease. References:1. Cox, B. et al. J. Endocrinol.234, R135-R158 (2017).2. Bi, W. L. et al. Clin. Cancer Res.23, 1841-1851 (2017).3. Andoniadou, C. L. et al. Cell Stem Cell13, 433-445 (2013).

Variation in Weight of the Human Pituitary Gland in Different Age & Sex

Contrext: The pituitary gland produces several hormones that regulate growth, metabolism and reproduction. Deviations from the normal functions of the gland certainly derange the harmony of life. Therefore, this study is important to identify variation in the weight of human pituitary gland in relation to age and sex. Materials & Methods: A cross-sectional analytical type of study was conducted in the department of Anatomy, Dhaka Medical College, on sixty (40 of male and 20 of female) human pituitary glands were collected from unclaimed dead bodies that were under examination in the morgue of department of Forensic Medicine, Dhaka Medical College, Dhaka. The samples were divided into four groups. i.e. Group-A (20-29 years), Group-B (30-39 years), Group-C (40-49 years) and Group-D (50-59 years). The weight of the gland with the stalk was measured by means of a digital electric balance. Results: In male the mean± SD weight of the pituitary gland was found 355.56 ± 49.78, 261.18 ± 52.31, 244.44 ± 51.26 and 210 ± 18.71 mg in group A, B, C and D respectively. In female the mean± SD weight was 381.11 ± 14.53 mg, 345 ± 19.27 mg and 313.33 ± 11.53 mg in group A, B, and C respectively. Conclusion: The weight of the pituitary gland showed gradual decreasing values with advancing age. The mean ± SD weight of male gland in this study was significantly lower than that of female glands. DOI: http://dx.doi.org/10.3329/bja.v11i1.20505 Bangladesh Journal of Anatomy, January 2013, Vol. 11 No. 1 pp 25-29

Morphometric Study of the Human Pituitary Gland

DOI: http://dx.doi.org/10.3329/bja.v9i2.15276 Bangladesh Journal of Anatomy 2011 Vol.9(2) pp.79-83

Opposite effects of serum- and glucocorticoid-regulated kinase-1 and glucocorticoids on POMC transcription and ACTH release

Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a glucocorticoid early-response gene; its function, however, has been elucidated mainly in the context of mineralocorticoid signaling. Here, we investigate the expression and function of SGK1 in the pituitary gland, one of the primary glucocorticoid targets. SGK1 is expressed in the human pituitary gland and colocalizes to ACTH. The AtT-20 murine corticotroph cell line was used for functional experiments. Glucocorticoids upregulated SGK1 mRNA and protein levels, parallel to decreasing proopiomelanocortin (POMC) transcription and ACTH release. Dexamethasone-induced changes in SGK1 protein were abolished by the steroid receptor antagonist RU-486 and reduced by the inhibition of PI 3-kinase with LY-294002. SGK1 overexpression increased CREB- and activator protein-1-dependent transcription, POMC transcription, and ACTH secretion but did not influence intracellular cAMP levels. SGK1 overexpression and corticotropin-releasing hormone had additive effects on POMC promoter activity but not on ACTH secretion. SGK1 knockdown by RNA interference decreased POMC promoter activity, demonstrating the importance of SGK1 for basal POMC signaling. In summary, SGK1 is strongly stimulated by glucocorticoids in pituitary corticotrophs; however, its effects on POMC transcription are antagonistic to the classical inhibitory glucocorticoid action, suggesting a cell-regulated counterregulatory mechanism to potentially detrimental glucocorticoid effects.

Histopathology of pituitary tumours

The human pituitary gland consists of two major components: the adenohypophysis comprising the hormone producing cells of the pars anterior, pars intermedia, and pars tuberalis, and the neurohypophysis, also called pars nervosa or posterior lobe (1). In contrast to most mammalian species, the human gland has no anatomically distinct pars intermedia (2). The exclusively proopiomelanocortin (POMC)-producing cells of the pars intermedia are sandwiched between the anterior and posterior lobes in the majority of mammals, whereas in the human they are incorporated within the pars anterior, thereby constituting the pars distalis (3). The pars tuberalis is a minor upward extension of the adenohypophysis attached to the exterior of the lower pituitary stalk. In this chapter we deal only with adenohypophyseal tumours. Histologically, the adenohypophysis consists of a central median (or mucoid) wedge flanked by the two lateral wings. The hormone-producing cell types are distributed in an uneven, but characteristic manner. The cells are arranged within evenly sized acini surrounded by a delicate but well-defined reticulin fibre network giving the pituitary its distinct architecture (4). In the center of the acini is the long-neglected pituitary follicle composed of the agranular nonendocrine folliculo-stellate cells (5).