Hyperandrogenism in Polycystic Ovary Syndrome -- Evidence of Dysregulation of 11β-Hydroxysteroid Dehydrogenase

Rodin, Alvin E.; Thakkar, Hemangini; Taylor, Norman; Clayton, Richard N.

doi:10.1056/nejm199402173300703

Cited by 188 publications

(117 citation statements)

References 37 publications

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“…Some authors have reported an increased enzyme activity in PCOS women, as compared to controls (18,20,25). However, these findings were not confirmed by others (19,22).…”

Section: Discussionmentioning

confidence: 83%

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Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

Tosi

Negri²,

Brun³

et al. 2011

European Journal of Endocrinology

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Objective: In hyperandrogenic women, hyperinsulinaemia amplifies 17a-hydroxycorticosteroid intermediate response to ACTH, without alterations in serum cortisol or androgen response to stimulation. The aim of the study is to assess whether acute hyperinsulinaemia determines absolute changes in either basal or ACTH-stimulated adrenal steroidogenesis in these subjects. Design and methods: Twelve young hyperandrogenic women were submitted in two separate days to an 8 h hyperinsulinaemic (80 mU/m 2 !min) euglycaemic clamp, and to an 8 h saline infusion. In the second half of both the protocols, a 4 h ACTH infusion (62.5 mg/h) was carried out. Serum cortisol, progesterone, 17a-hydroxyprogesterone (17-OHP), 17a-hydroxypregnenolone (17-OHPREG), DHEA and androstenedione were measured at basal level and during the protocols. Absolute adrenal hormone secretion was quantified by measuring C19 and C21 steroid metabolites in urine collected after the first 4 h of insulin or saline infusion, and subsequently after 4 h of concurrent ACTH infusion. Results: During insulin infusion, ACTH-stimulated 17-OHPREG and 17-OHP were significantly higher than during saline infusion. No significant differences in cortisol and androgens response to ACTH were found between the protocols. Nevertheless, urinary excretion of ACTH-stimulated C19 and C21 steroid metabolites was significantly higher during hyperinsulinaemia than at basal insulin levels (both P!0.005). Changes in steroid metabolites molar ratios suggested stimulation by insulin of 5a-reductase activity. Conclusions: These in vivo data support the hypothesis that insulin acutely enhances ACTH effects on both the androgen and glucocorticoid pathways.

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“…Some authors have reported an increased enzyme activity in PCOS women, as compared to controls (18,20,25). However, these findings were not confirmed by others (19,22).…”

Section: Discussionmentioning

confidence: 83%

“…Previous studies compared these ratios in PCOS and healthy women (19)(20)(21)(22)(23)(24), although none of them assessed the effects of hyperinsulinaemia on these features. As a whole, these studies suggest an increased activity of 5a-reductase in PCOS women.…”

Section: Discussionmentioning

confidence: 99%

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

Tosi

Negri²,

Brun³

et al. 2011

European Journal of Endocrinology

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“…A number of studies have found (19,20). The mechanisms for the adrenal hyperandrogenism remain unclear and several hypotheses have been put forward to explain the association between PCOS and adrenal hyperandrogenism: enhanced ovarian and adrenal P450c17a enzyme activity (21), increased activity of enzymes involved in cortisol clearance such as 11b-hydroxysteroid dehydrogenase (22) and the possible role of hyperinsulinemia (5,23). Additionally, the role of the ovary in adrenal androgen hypersecretion is a matter of debate.…”

Section: Discussionmentioning

confidence: 99%

A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome

Çolak

Keleştimur

Ünlühızarcı³

et al. 2002

European Journal of Endocrinology

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A comparison between the effects of low dose (1 mg) and standard dose (250 mg) ACTH stimulation tests on adrenal P450c17a enzyme activity in women with polycystic ovary syndrome AbstractObjective: Numerous studies have found elevated androgen production by the adrenal glands in patients with polycystic ovary syndrome (PCOS). However, the role and the mechanisms responsible for the adrenal androgen excess in women with PCOS are not well understood. Design: Our aim was to compare 17-hydroxyprogesterone (17-OHP), androstenedione, dehydroepiandrosterone sulfate (DHEAS) and cortisol responses to a low dose (1 mg) ACTH stimulation test (LDT) with the responses to a standard dose (250 mg) ACTH stimulation test (SDT) in patients with PCOS.Methods: Fifty women with PCOS (mean age 25:4^0:7 years) and 20 healthy women (mean age 27:3^2:2 years) were included in the study. The patients and controls underwent ACTH stimulation tests with 1 mg and 250 mg synthetic ACTH in the follicular phase of their cycles. Venous blood was drawn at 0, 30 and 60 min for determination of serum cortisol, 17-OHP, androstenedione and DHEAS levels.Results: In PCOS subjects, peak and area under the curve (AUC) 17-OHP ð9:3^0:3 nmol=l; 378:46 1 nmol=l £ 60 minÞ; androstenedione ð15:6^0:6 nmol=l; 806:4^52 nmol=l £ 60 minÞ and DHEAS ð7:5^0:4 mmol=l; 385:6^25:5 mmol=l £ 60 minÞ responses to SDT were significantly higher than the levels in healthy women (respectively 5:7^0:3 nmol=l and 249:4^52:2 nmol=l £ 60 min for 17-OHP; 9:1^0:3 nmol=l and 413:7^31:6 nmol=l £ 60 min for androstenedione; 4:3^0:4 mmol=l and 224:9^24:5 mmol=l £ 60 min for DHEAS) ðP , 0:05Þ: Peak and AUC cortisol responses to SDT were similar in PCOS and control subjects. Peak and AUC cortisol and 17-OHP responses to LDT in women with PCOS were similar to the values obtained in healthy women. Peak androstenedione ð12:5^0:6 nmol=lÞ and peak ð6:5^0:5 nmol=lÞ and AUC ð336:3^22:4 mmol=l £ 60 minÞ DHEAS responses to LDT were significantly higher in women with PCOS. Conclusions: These results show that LDT is capable of revealing the adrenal hyperactivity in women with PCOS. Adrenal P450c17a enzyme dysregulation in PCOS is revealed by ACTH stimulation at a pharmacological dose (250 mg) but not by a physiological dose (1 mg). LDT is able to demonstrate adrenal hyperactivity characterized by an increase in DHEAS levels.

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“…This suggests that in these patients a dysregulation of the HPA axis may exist. The aforementioned data produced by Rodin and colleagues 42 suggest that in PCOS women an increased catabolism of cortisol may determine a compensatory hyperactivation of the HPA axis with the subsequent increased androgen formation by the adrenal gland. According to an increased response of adrenal androgens 68 and of ACTH and cortisol 41 to CRH administration the existence of a PCOS women subset has been proposed.…”

Section: Neuroendocrine Factorsmentioning

confidence: 99%

“…14 Interleukin-6 (IL-6) has also been proposed to modulate intra-adrenal steroidogenesis, by the ability of this cytokine to increase DHEA secretion. 38 An interesting hypothesis was produced by Rodin and collegues, 42 who reported that the activity of 11b-hydroxysteroid dehydrogenase enzyme, which interconverts cortisol to its inactive compound cortisone, may be increased in PCOS women. The enhanced oxidation of cortisol in PCOS may result in compensatory overstimulation of the hypothaObesity and the polycystic ovary syndrome A Gambineri et al lamic -pituitary -adrenal (HPA) axis that could, in turn, increase the adrenal androgen formation.…”

Section: Shbgmentioning

confidence: 99%

Obesity and the polycystic ovary syndrome

et al. 2002

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The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype.Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and=or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.

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Hyperandrogenism in Polycystic Ovary Syndrome -- Evidence of Dysregulation of 11β-Hydroxysteroid Dehydrogenase

Abstract: Adrenal secretion of cortisol and androgens is increased in women with the polycystic ovary syndrome. The increases may be explained by dysregulation of 11 beta-hydroxysteroid dehydrogenase causing increased oxidation of cortisol to cortisone, which cannot be accounted for by obesity.

Cited by 188 publications

References 37 publications

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome

Obesity and the polycystic ovary syndrome

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