Long Term Effects of Nightly Dexamethasone Administration in Patients with Polycystic Ovarian Disease

Lachelin, GlLLlAN C. L.; Judd, Howard L.; Swanson, Sherri C.; Hauck, Margeret E.; Parker, Donal C.; Yen, S. S. C.

doi:10.1097/00006254-198307000-00014

Cited by 10 publications

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“…In addition, epidemiologic data suggest that girls with premature exaggerated adrenarche have a significantly higher risk to develop the polycystic ovary syndrome (PCOS), the most common hyperandrogenic disorder affecting 5-10% of women (Escobar-Morreale et al 2005). Elevated serum androgens in PCOS have been shown to originate from both the ovaries and the adrenals (Lachelin et al 1982, Barnes et al 1989, Ehrmann et al 1992. Studies of the steroid metabolism of ovarian theca cells isolated from PCOS women demonstrated enhanced 3bHSDII and P450c17 activities in PCOS compared with normal cells (Nelson et al 1999(Nelson et al , 2001).…”

Section: Discussionmentioning

confidence: 99%

Human adrenal corticocarcinoma NCI-H295R cells produce more androgens than NCI-H295A cells and differ in 3β-hydroxysteroid dehydrogenase type 2 and 17,20 lyase activities

Samandari¹,

Kempná²,

Nuoffer³

et al. 2007

Journal of Endocrinology

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The human adrenal cortex produces mineralocorticoids, glucocorticoids, and androgens in a species-specific, hormonally regulated, zone-specific, and developmentally characteristic fashion. Most molecular studies of adrenal steroidogenesis use human adrenocortical NCI-H295A and NCI-H295R cells as a model because appropriate animal models do not exist. NCI-H295A and NCI-H295R cells originate from the same adrenocortical carcinoma which produced predominantly androgens but also smaller amounts of mineralocorticoids and glucocorticoids. Research data obtained from either NCI-H295A or NCI-H295R cells are generally compared, although for the same experiments no direct comparison between the two cell lines has been performed. Therefore, we compared the steroid profile and the expression pattern of important genes involved in steroidogenesis in both cell lines. We found that steroidogenesis differs profoundly. NCI-H295A cells produce more mineralocorticoids, whereas NCI-H295R cells produce more androgens. Expression of the 3b-hydroxysteroid dehydrogenase (HSD3B2), cytochrome b5, and sulfonyltransferase genes is higher in NCI-H295A cells, whereas expression of the cytochrome P450c17 (CYP17), 21-hydroxylase (CYP21), and P450 oxidoreductase genes does not differ between the cell lines. We found lower 3b-hydroxysteroid dehydrogenase type 2 but higher 17,20-lyase activity in NCI-H295R cells explaining the 'androgenic' steroid profile for these cells and resembling the zona reticularis of the human adrenal cortex. Both cell lines were found to express the ACTH receptor at low levels consistent with low stimulation by ACTH. By contrast, both cell lines were readily stimulated by 8Br-cAMP. The angiotensin type 1 receptor was highly expressed in NCI-H295R than NCI-H295A cells and angiotensin II stimulated steroidogenesis in NCI-H295R but not NCI-H295A cells. Our data suggest that comparative studies between NCI-H295A and NCI-H295R cells may help find important regulators of mineralocorticoid or androgen biosynthesis.

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Section: Discussionmentioning

confidence: 99%

Human adrenal corticocarcinoma NCI-H295R cells produce more androgens than NCI-H295A cells and differ in 3β-hydroxysteroid dehydrogenase type 2 and 17,20 lyase activities

Samandari¹,

Kempná²,

Nuoffer³

et al. 2007

Journal of Endocrinology

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“…When ovarian androgen synthesis is suppressed with GnRH agonists, PCOS women were found to have higher androgen levels in comparison to normal women, thus suggesting adrenal overproduction of androgens [31][32][33][34][35]. Similarly, when adrenal androgen synthesis is suppressed with dexamethasone, PCOS women again display higher androgen levels in comparison to normal women, indicating exaggerated ovarian production [36,37]. Low levels of sex-hormone binding globulin (SHBG) also contribute to high free testosterone levels in women with PCOS, by reducing testosterone binding.…”

Section: Origins Of Hyperandrogenemia In Pcosmentioning

confidence: 99%

Insulin and hyperandrogenism in women with polycystic ovary syndrome

Baptiste

Battista

Trottier

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

249

199

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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.

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“…The pathophysiological mechanism(s) underlying PCOS are unknown, as is the exact physiological regulation of androgen biosynthesis. Elevated circulating androgen concentrations in women with PCOS may originate from the ovaries and/or the adrenal cortex (Lachelin et al, 1982;Barnes et al, 1989;Ehrmann et al, 1992). Enhanced androgen biosynthesis in PCOS is caused by an increased expression of the steroidogenic enzymes P450c17 (17␣-hydroxylase, 17,20-lyase) and 3␤HSDII, which are essential for the production of androgens (Nelson et al, 1999(Nelson et al, , 2001.…”

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confidence: 99%

Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2

Kempná

Hofer²,

Mullis³

et al. 2006

Mol Pharmacol

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Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3␤HSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor ␥ (PPAR␥) is the nuclear receptor for TZDs, suppression of PPAR␥ by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPAR␥. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.The gonads and the adrenals are the main sources of human androgens and express common genes for the biosynthesis of androgens. P450c17 and 3␤HSDII, encoded by the CYP17 and HSD3B2 genes, are key enzymes involved in biosynthesis of androgens. The mature adrenal cortex in humans produces androgens from cholesterol in a multistep pathway. In a first step, cholesterol is converted to pregnenolone by the P450 side-chain cleavage system. Second, pregnenolone then may be converted to 17␣-hydroxypregnenolone and to dehydroepiandrostenedione (DHEA) by the 17␣-hydroxylase and 17,20-lyase activities of P450c17. Third, DHEA is converted to androstenedione by 3␤-hydroxysteroid dehydrogenase type 2 (3␤HSDII). Although the fetal adrenals predominantly produce androgens, postnatal androgen production ceases only to resume at the age of 6 to 7 years, after the development of the zona reticularis, the third layer of the mature adrenal cortex.Thiazolidinediones (TZDs) are a class of oral insulin-sensitizing agents that are generally believed to exert their action as...

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Long Term Effects of Nightly Dexamethasone Administration in Patients with Polycystic Ovarian Disease

Cited by 10 publications

References 0 publications

Human adrenal corticocarcinoma NCI-H295R cells produce more androgens than NCI-H295A cells and differ in 3β-hydroxysteroid dehydrogenase type 2 and 17,20 lyase activities

Human adrenal corticocarcinoma NCI-H295R cells produce more androgens than NCI-H295A cells and differ in 3β-hydroxysteroid dehydrogenase type 2 and 17,20 lyase activities

Insulin and hyperandrogenism in women with polycystic ovary syndrome

Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2

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