Endocrine Regulation of Androgen Levels Paper Example

Introduction

The hypothalamic-pituitary axis is responsible for the control of androgen testosterone production. 'Testosterone is produced by testicular Leydig cells after the luteinizing hormone stimulates it' [1]. The hypothalamus secretes a gonadotropin-releasing hormone which stimulates the pituitary gland to release luteinizing hormone. According to Dr. Ong 23.45, stimulation takes place hence releasing androgen. The released androgen testosterone suppresses further secretion of luteinizing hormone resulting in a negative feedback loop. The homeostatic loop is crucial for maintaining the testosterone concentrations in the male.

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Androgen/androgen receptor signalling pathway

An understanding of the androgen receptor (AR) signaling pathway is crucial to the development of therapies required in the handling of progressive prostate cancer patients. According to Dr. Ong, the androgen deprivation therapy is so far the ultimate model of care for patients with advanced prostate cancer [2]. The AR signaling pathway is dependent on factors such as fluctuation in the metabolism of androgen, AR expression, and specifications of the ligand among others. During prostate cancer progression several changes in AR signaling pathway occur. The prostrate tissues incorporate dihydrotestosterone (DHT) that is converted from testosterone. The two hormones bind with DHT having the highest affinity in AR; as a result, activating AR-targeted genes. Lonegan and Tindall are of the view that AR is located at the cytoplasm when the ligand is not present resulting in an interaction with protein Filamin-A which facilitates the translocation of AR to the nucleus [3].

Molecular targets for treatment of prostate cancer

Shitivelman, Beer, and Evans purported that the inter-chromosomal rearrangements occur in 40 to 60% of prostate cancer incidences and facilitate the ERG fusions initiated by androgen-responsive promoters (TMPRSS2) [4]. The fusion results in overexpression of EZH2 and SOX9 which are crucial molecular targets during prostate cancer treatment. 'EZH2 plays a significant role in the development and progression of prostate cancer'[5]. Drugs introduced for treatment target the enzymatic activities which are responsible for fusion development. Androgen is responsible for the fusions through cytidine deaminase and endonuclease enzymatic activities. The double-stranded DNA stop breaking upon inhibition of the enzymatic activities resulting in the control of EZH2 and SOX9. 'The regulation of overexpression of proteins such as EZH2 results in the reduction of tumorigenicity' [6].

The cases of cancer transmission incidence from organ donors after a transplant are low. According to Chapman, Webster, and Wong, there are few incidences when cancers exhibiting high levels of metastasis for the transplanted organs result in cancer transmission [8]. 'Tumor cells that have a low neoantigen presentation undergo somatic mutation at a low level resulting in their ability to avoid elimination during immunoediting' [9]. Figure 1 above is a representation of the different somatic levels exhibited by the tumor cells which are a significant determiner of the neoantigen burden. The car crash victim was diagnosed with lung cancer and had undergone radiation therapy, but cancerous cells were transmitted to the transplant recipient.

References

O'Hara L, Curley M, Tedim Ferreira M, Cruickshanks L, Milne L, Smith L. Pituitary androgen receptor signalling regulates prolactin but not gonadotrophins in the male mouse. PLoS ONE. 2015 Mar; 10(3): e0121657.

Ong C. Cancer models. Canada: University of British Columbia; 2018.

Lonergan P, Tindall D. Androgen receptor signaling in prostate cancer development and progression. Journal of Carcinogenesis. 2011 Aug; 10(20): 1-10.

Shtivelman E, Beer T, Evans C. Molecular pathways and targets in prostate cancer. Oncotarget. 2014 Sep; 5(17): 7217-7259.

Melling N, Thomsen E, Tsourlakis M, Kluth M, Hube-Magg C, Minner S, Koop C, Graefen M, Heinzer H, Wittmer C, Sauter G, Wilczak W, Huland H, Simon R, Schlomm T, Steurer S, Krech T. Overexpression of enhancer of zeste homolog 2 (EZH2) characterizes an aggressive subset of prostate cancers and predicts patient prognosis independently from pre- and postoperatively assessed clinicopathological parameters. Carcinogenesis. 2015 Nov; 36(11): 1333-1340.

Karanikolas B, Figueiredo M, Wu L. Comprehensive evaluation of the role of EZH2 in the growth, invasion, and aggression of a panel of prostate cancer cell lines. The Prostate. 2010 May; 70(6): 675-88.

Alexandrov L, Nik-Zainal S, Stratton M. Signatures of mutational processes in human cancer. Nature International Journal of Science. 2013 Aug; 500: 415 -421.

Chapman J, Webster A, Wong G. Cancer in the transplant recipient. Cold Spring Harbor Perspectives in Medicine. 2013 Jul; 3(7): a015677.

Reid G. Immunotherapy in cancer. Canada: University of British Columbia; 2018: 1-15.