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Prostate Cancer
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Karl H. Pang, James W.F. Catto
ADT aims to lower/block androgen activity:Lowering testosteroneBilateral orchidectomy to remove testosterone-producing Leydig cells.GHRH agonist: downregulates GnRH receptors.GHRH antagonist: blocks GnRH receptors.CYP17A1 inhibitor (Abiraterone): inhibits androgen synthesis.Blocking androgen effectNon-steroidal anti-androgens (Bicalutamide): block androgen receptors.
Variation of sex differentiation
Published in Joseph S. Sanfilippo, Eduardo Lara-Torre, Veronica Gomez-Lobo, Sanfilippo's Textbook of Pediatric and Adolescent GynecologySecond Edition, 2019
Anne-Marie Amies Oelschlager, Margarett Shnorhavorian
17α-Hydroxylase/17.20 lyase deficiency is caused by a mutation in the cytochrome P450c17 gene (CYP17A1). The gene is located at 10q24.32. The CYP17A1 enzyme converts pregnenolone to 17-hydroxypregnenolone and progesterone to 17-hydroxyprogesterone by hydroxylation. Also, 17,20 lyase activity converts 17-hydroxypregnenolone to DHEA (Figure 7.1). A genetic mutation may result in deficiency in hydroxylation and/or lyase reactions. This results in low androgen and estrogen levels. Affected 46,XY individuals appear phenotypically female with absent Müllerian structures and typical external female genitalia. Individuals not identified at birth may present with pubertal delay. Cortisol synthesis is blocked, but due to elevated ACTH, there is an increase in aldosterone with resultant hypokalemia and hypertension. Glucocorticoid treatment addresses the ACTH overproduction and, therefore, suppresses corticosterone overproduction. Sex steroid hormonal induction and maintenance are necessary at puberty.
Environmental toxicants on Leydig cell function
Published in C. Yan Cheng, Spermatogenesis, 2018
Leping Ye, Xiaoheng Li, Xiaomin Chen, Qingquan Lian, Ren-Shan Ge
CYP17A1 is a P450 cytochrome enzyme. It is located in the smooth endoplasmic reticulum. CYP17A1 catalysis depends on cytochrome P450 oxidoreductase, cytochrome b5, and phosphorylation.31 Cytochrome b5 acts to facilitate CYP17A1 17, 20-lyase. Human CYP17A1 is phosphorylated on serine and threonine residues by a cAMP-dependent protein kinase and the phosphorylated CYP17A1 has increased 17,20-lyase activity.31 Human CYP17A1 requires cytochrome P450 oxidoreductase for the transfer of electrons. Both human and rat CYP17A1 enzymes catalyze two steps of reaction: 17α-hydroxylation and 20-lyation. Each reaction requires cofactor NADPH.14 Human CYP17A1 primarily catalyzes pregnenolone to 17-hydroxyprogenolone and then to dehydroepiandrosterone (Figure 20.1).32 However, rat CYP17A1 primarily catalyzes progesterone into 17-hydroxyprogesterone and then to androstenedione.33
CircEpha5 regulates the synthesis and secretion of androgen in mouse preantral follicles by targeting miR-758-5p
Published in Journal of Obstetrics and Gynaecology, 2023
Xueying Zhang, Jiaxuan Liu, Hao Wu, Yan Chen, Xuesen Zhang, Boqun Xu
Cyp17a1 has a clear physiological role in increasing the expression level of testosterone (Yang et al.2021, Chen et al.2022). Higher levels of Cyp17a1 and androgens were respectively found in follicles and their culture media overexpressing circEpha5. In addition, we have found lower levels of Cyp17a1 in follicles overexpressing miR-758-5p. This indicates that circEpha5 may regulate the synthesis and secretion of androgens in follicles by targeting miR-758-5p. It is undeniable that this study has certain limitations. In the future, more experiments, such as circEpha5 knockdown experiments, need to be conducted to demonstrate the role of circEpha5/miR-758-5p/Cyp17a1 cascade regulation in steroid production in polycystic ovary syndrome; More clinical samples need to be collected to clarify the reliability of molecular markers in disease diagnosis and treatment; meanwhile, the role of circEpha5 in improving PCOS symptoms such as reducing androgens and improving fertility (Laganà et al.2022, Mikuš et al.2022) needs to be focused.
FSHR antagonists can trigger a PCOS-like state
Published in Systems Biology in Reproductive Medicine, 2022
Faiza Hanif Waghu, Karishma Desai, Sumana Srinivasan, Kaushiki S. Prabhudesai, Vikas Dighe, Kareenhalli V. Venkatesh, Susan Idicula-Thomas
In ovaries, during the progression of folliculogenesis from pre-antral to antral stage, theca cells differentiate to express LHCGR (Orisaka et al. 2009; Young and McNeilly 2010). Interaction of LH with LHCGR on theca cells induces expression of a microsomal enzyme, CYP17A1, that is a major regulator of androgen production. Under the influence of 17α-hydroxylase activity of CYP17A1 enzyme, pregnenolone, a precursor of steroids is converted to 17 α-hydroxypregnenolone. This is further cleaved through 17,20-lyase (lyase) activity of CYP17A1 enzyme to form dehydroepiandrosterone which gets converted into T and dihydrotestosterone (Maity et al. 2016). Hyperandrogenism in PCOS is attributed to excessive androgen production by theca cells of the ovaries. This theory is supported by observations from in vitro studies, wherein an increased production of androgens was reported from theca cells isolated from women with PCOS (Gilling-Smith et al. 1994; Nelson et al. 1999). Further, Jakimiuk et al. reported higher mRNA levels of LHCGR and CYP17A1 in thecal cells of follicles harvested from women with PCOS as compared to size-matched control follicles (Jakimiuk et al. 2001). Similarly, protein levels of LHCGR and CYP17A1 were found to be elevated in theca cells and antral follicles obtained from women with PCOS (Comim et al. 2013). In concordance with the above reports, we observed higher mRNA levels of Lhcgr and Cyp17a1 in ovaries of peptide-treated rats as compared to ovaries of vehicle-treated rats (Figure 1).
Polycystic ovarian syndrome: signs and feedback effects of hyperandrogenism and insulin resistance
Published in Gynecological Endocrinology, 2022
Jenifer Lizbet Hernández-Jiménez, David Barrera, Emilio Espinoza-Simón, James González, Rosario Ortíz-Hernández, Luisa Escobar, Olga Echeverría, Nayeli Torres-Ramírez
In summary, the intrinsic IR and compensatory IH of each organism contribute to the development of HA, which together lead to COA and PCOM (Figure 5). The pathways in these alterations have not yet been fully elucidated; however, mitochondrial function and CYP17A1 17,20-lyase activity represent two possible therapeutic targets for the treatment of PCOS. This review presents evidence supporting the use of metformin to alleviate the metabolic and hormonal disturbances of PCOS. Part of the actions of metformin presented here are: (i) a decrease in oxidative stress, (ii) the restoration of mitochondrial oxidative function, (iii) the inhibition of the activity and expression of the CYP17A1 gene, and (iv) a decrease in androgen concentration. Nonetheless, more research is necessary to confirm this relationship.