Role of cytochrome P450c17 in polycystic ovary syndrome

Qin, Kenan; Rosenfield, Robert L.

doi:10.1016/s0303-7207(98)00177-4

Cited by 70 publications

(42 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In both type of the-cal cells, the combination of physiological doses of LH and insulin synergistically increases androgen biosynthesis [93,95]. Androgenesis is also increased in long-term cultures of PCOS thecal cells, as compared with normal ones, suggesting that this hyperandrogenism may be an intrinsic property of PCOS thecal cells [96,97]. Taken together, these observations support that PCOS thecal cells present an androgenic hyperresponsiveness that involves a crosstalk between LH and insulin pathways.…”

Section: 22supporting

confidence: 53%

Insulin and hyperandrogenism in women with polycystic ovary syndrome

Baptiste

Battista

Trottier

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

246

189

View full text Add to dashboard Cite

Polycystic ovary syndrome (PCOS) is a very common endocrine disorder characterized by chronic anovulation, clinical and/or biochemical hyperandrogenism, and/or polycystic ovaries. But most experts consider that hyperandrogenism is the main characteristic of PCOS. Several theories propose different mechanisms to explain PCOS manifestations: (1) a primary enzymatic default in the ovarian and/or adrenal steroidogenesis; (2) an impairment in gonadotropin releasing hormone (GnRH) secretion that promotes luteal hormone (LH) secretion; or (3) alterations in insulin actions that lead to insulin resistance with compensatory hyperinsulinemia. However, in the past 20 years there has been growing evidence supporting that defects in insulin actions or in the insulin signalling pathways are central in the pathogenesis of the syndrome. Indeed, most women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. But some women with typical PCOS do not display insulin resistance, which supports the hypothesis of a genetic predisposition specific to PCOS that would be revealed by the development of insulin resistance and compensatory hyperinsulinemia in most, but not all, women with PCOS. However, these hypotheses are not yet appropriately confirmed, and more research is still needed to unravel the true pathogenesis underlying this syndrome. The present review thus aims at discussing new concepts and findings regarding insulin actions in PCOS women and how it is related to hyperandrogenemia.

show abstract

Section: 22supporting

confidence: 53%

Insulin and hyperandrogenism in women with polycystic ovary syndrome

Baptiste

Battista

Trottier

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

246

189

View full text Add to dashboard Cite

show abstract

“…We observed no alteration in the expression of CYP21 at either the mRNA or protein level in the presence of insulin, moreover insulin appeared to abrogate increases in CYP21 protein seen in the presence of forskolin. Conversely, forskolin and insulin have been implicated in the upregulation of CYP17 (Bird et al 1993b, Qin & Rosenfield 1998, whereas the role of A-II remains to be fully elucidated (Lebrethon et al 1994, Parker & Schimmer 1994, Viard et al 1994. In this study CYP17 mRNA and protein expression were found to be upregulated in the presence of forskolin and insulin.…”

Section: Discussionmentioning

confidence: 58%

“…ACTH is the classic secretagogue for both cortisol and adrenal androgens, whereas A-II, though primarily concerned with the production of aldosterone, has also been shown to upregulate cortisol production (Bird et al 1993a, Rainey et al 1993. Both clinical and in vitro studies have implicated insulin in the regulation of adrenal androgen production (Kristiansen et al 1997, Qin & Rosenfield 1998. In this study, we found that H-295 cells produced significantly more cortisol relative to androstendione in the presence of forskolin and forskolin in combination with A-II.…”

Section: Discussionmentioning

confidence: 99%

“…Classic secretagogues including adrenocorticotrophin (ACTH), angiotensin II (A-II) and more recently novel factors such as insulin, upregulate steroid production through the regulation of key steroidogenic enzymes (Bird et al 1993b, Qin & Rosenfield 1998. 21-hydroxyalse (CYP21) regulates cortisol and aldosterone production by conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to 11-deoxycorticosterone in the aldosterone pathway, whereas 17-hydroxylase/17-20-lyase (CYP17) is primarily concerned with androgen production through the conversion of pregnenolone to 17 -hydroxypregnenolone and on to dehydroepiandrosterone and progesterone to 17 -hydroxyprogesterone.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modulation of steroidogenic enzymes by orphan nuclear transcriptional regulation may control diverse production of cortisol and androgens in the human adrenal

Kelly¹,

McKenna²,

Young³

2004

Journal of Endocrinology

View full text Add to dashboard Cite

The capacity of the adrenal to produce cortisol is controlled in part by 21-hydroxylase (CYP21) and the production of androgens by 17-hydroxylase/17-20-lyase (CYP17), in response to secretagogues including ACTH, angiotensin-II (A-II) and insulin. In this study we examined the capacity of human adrenocortical cells to produce cortisol and androgens in response to these secretagogues and their ability to regulate the expression of CYP21 and CYP17. In H-295 cells, forskolin and A-II were found to stimulate production of cortisol relative to androstenedione and a similar pattern of steroid production was noted in primary human adrenocortical cells. Both mRNA and protein expression of CYP21 was upregulated with forskolin and A-II alone and in combination, as detected by Northern and Western blotting. Whereas expression of CYP17 mRNA and protein was upregulated in the presence of forskolin and forskolin in combination with insulin. The ability of steroidogenic factor-1 (SF-1) and nur77 to regulate transcription of these enzymes was examined. Forskolin, A-II and insulin increased the protein expression of SF-1. Increased binding of SF-1 to its response element in the presence of forskolin, A-II and insulin was observed. Nur77 was expressed primarily in the zona glomerulosa and fasciculata. Increased protein expression of nur77 and the greatest binding of nur77 to its response element was seen when cells were stimulated with A-II in combination with forskolin. These data indicate that nur77 may preferentially regulate steroid enzyme genes relevant to cortisol production and thereby regulate differential cortisol and adrenal androgen production.

show abstract

“…1); zona glomerulosa lacks CYP17 and consequently produces mineralocorticoids. CYP17 dysfunction has been associated with a number of diseases including polycystic ovary syndrome (Qin & Rosenfield 1998, Miller 2002, Strauss 2003), Cushing's syndrome (Ogo et al 1991), congenital adrenal hyperplasia (Maitra & Shirwalkar 2003) and prostate cancer (Lunn et al 1999, Madigan et al 2003. The key towards alleviation of these endocrine-related human disorders lies in deciphering the mode of functioning of this important enzyme.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome b5 modulation of 17α hydroxylase and 17–20 lyase (CYP17) activities in steroidogenesis

Akhtar¹,

Kelly²,

Kaderbhai³

2005

Journal of Endocrinology

View full text Add to dashboard Cite

CYP17 is a steroidogenic enzyme located in the zona fasciculata and zona reticularis of the adrenal cortex and gonad tissues and which has dual functions -hydroxylation and as a lyase. The first activity gives hydroxylation of pregnenolone and progesterone at the C 17 position to generate 17 -hydroxypregnenolone and 17 -hydroxyprogesterone, while the second enzymic activity cleaves the C 17 -C 20 bond of 17 -hydroxypregnenolone and 17 -hydroxyprogesterone to form dehydroepiandrosterone and androstenedione respectively. The modulation of these two activities occurs through cytochrome b 5 . Association of cytochrome b 5 and CYP17 is thought to be based primarily on electrostatic interactions in which the negatively charged residues pair up with positively charged residues on the proximal surface of the CYP17 molecule. Non-specific interactions of the hydrophobic membrane regions of cytochrome b 5 and CYP17 are also thought to play a crucial role in the association of these two haemoproteins. Although cytochrome b 5 is known to stimulate CYP activity by contributing the second electron in the catalytic cycle, in the case of CYP17, the mechanism of cleavage stimulation proceeds via an allosteric mode. It is hypothesised that cytochrome b 5 promotes the cleavage by aligning the iron-oxygen complex attack onto the C 20 rather than the C 17 atom of the steroid substrate molecule. Thus, further understanding of the mechanism of modulation by cytochrome b 5 of the hydroxylase and lyase activities should shed new insights on developing therapeutic targets in CYP17-linked biochemical processes such as adrenarche, polycystic ovary syndrome and prostate cancer.

show abstract

Role of cytochrome P450c17 in polycystic ovary syndrome

Cited by 70 publications

References 112 publications

Insulin and hyperandrogenism in women with polycystic ovary syndrome

Insulin and hyperandrogenism in women with polycystic ovary syndrome

Modulation of steroidogenic enzymes by orphan nuclear transcriptional regulation may control diverse production of cortisol and androgens in the human adrenal

Cytochrome b5 modulation of 17α hydroxylase and 17–20 lyase (CYP17) activities in steroidogenesis

Contact Info

Product

Resources

About