This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsilchorozidou, T. Articles by Conway, G. S. Search for Related Content PubMed PubMed Citation Articles by Tsilchorozidou, T. Articles by Conway, G. S.

Altered Cortisol Metabolism in Polycystic Ovary Syndrome: Insulin Enhances 5-Reduction But Not the Elevated Adrenal Steroid Production Rates

Departments of Endocrinology and Chemical Biochemistry, University College London Hospitals, London W1T 3AA, United Kingdom

Address all correspondence and requests for reprints to: Dr. Gerard S. Conway, Department of Endocrinology, The Middlesex Hospital, Mortimer Street, London W1T 3AA, United Kingdom. E-mail: g.conway{at}ucl.ac.uk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Androgen excess in women with polycystic ovary syndrome (PCOS) may be ovarian and/or adrenal in origin, and one proposed contributing mechanism is altered cortisol metabolism. Increased peripheral metabolism of cortisol may occur by enhanced inactivation of cortisol by 5-reductase (5-R) or impaired reactivation of cortisol from cortisone by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) resulting in decreased negative feedback suppression of ACTH secretion maintaining normal plasma cortisol concentrations at the expense of androgen excess. We have tested whether any enzyme dysregulation was related to circulating insulin or androgen concentrations in women with PCOS and have sought to clarify their relationship with obesity.

First, to avoid obesity-related effects on cortisol metabolism, 18 lean women with PCOS were compared with 19 lean controls who were closely matched for body mass index (BMI). Second, the impact of obesity was studied in a cross-section of 42 PCOS women of a broad range of BMI. We measured 24-h urinary excretion of steroid metabolites by gas chromatography/mass spectrometry and fasting metabolic and hormone profiles.

Urinary excretion of androgens [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P = 0.009)], cortisone metabolites [tetrahydrocortisone (THE) (P = 0.02), -cortolone (P < 0.001), ß-cortol + ß-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)], and TCM (P = 0.002) were raised in lean PCOS subjects when compared with controls. A significantly higher 5-tetrahydrocortisol (5-THF)/5ß-THF ratio (P = 0.04) and a significantly lower -THF + THF + -cortol/THE + cortolones ratio (P = 0.01) were found in lean PCOS women compared with lean controls, indicating both enhanced 5-R and reduced 11ß-HSD1 activities. A decreased THE/cortolones ratio (P = 0.03) was also found in lean PCOS women compared with lean controls, indicating increased 20 /ß-HSD activity.

In the group of 42 PCOS subjects, measures of 5/5ß reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): -THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5 /total 5ß and HOMA-R (r = 0.37; P = 0.02). A positive correlation was also found between measures of 5-R and BMI (r = 0.37; P = 0.02). No correlation was found between measures of 11ß-HSD1 activity and indices of insulin sensitivity or BMI.

We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. Insulin seems to enhance 5 reduction of steroids in PCOS but was not associated with the elevated cortisol production rate. The changes in 5-R, 11ß-HSD1, and 20/ß-HSD enzyme activities observed in PCOS may contribute to the increased production rates of cortisol and androgens, supporting the concept of a widespread dysregulation of steroid metabolism. This dysregulation does not seem to be the primary cause of PCOS because no correlation was found between serum androgen levels or urinary excretion of androgens with measurements of either 5-R or 11ß-HSD1 activities.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
AMONG THE UNCERTAINTIES surrounding the etiology of polycystic ovary syndrome (PCOS) the role of altered cortisol metabolism has become prominent. Enhanced 5-reductase (5-R) activity, dysregulation of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD) activity and increased total adrenal steroid production rates have been previously described in PCOS and implicated as possible mechanisms of pathogenesis. According to this theory, increased peripheral cortisol metabolism results in a compensatory increase of ACTH secretion via a decrease in the negative feedback signal, maintaining normal serum cortisol levels at the expense of adrenal androgen excess.

The pathways of cortisol metabolism include irreversible inactivation by 5- and 5ß-R and reversible interconversion with cortisone by 11ß-HSD (Fig. 1). 5-R is a steroidogenic enzyme responsible for both 5-reduction of cortisol to 5-dihydrocortisol in liver and testosterone to 5-dihydrotestosterone (5-DHT) in skin. In humans, two isoenzymes have been described, each encoded by a separate gene, type 1 enzyme found in skin and liver and type 2 reductase predominately expressed in reproductive tissues (1). Stewart and colleagues (2) first documented that the ratio of 5 to 5ß cortisol metabolites in urine of PCOS women were higher than in controls, indicating enhanced 5-R activity in these subjects. It was suggested that the increased activity of 5-R mediated both hirsutism and enhanced hepatic cortisol metabolism in PCOS women. Previous in vitro studies in genital skin fibroblasts have shown that 5-R activity is up-regulated by androgens (3), an effect that might be mediated by IGF-I (4). An oral dehydroepiandrosterone (DHEA) challenge with measurements of androgens downstream in blood and urine has recently confirmed the increased peripheral 5-R activity in PCOS (5).

View larger version (27K): [in this window] [in a new window]   FIG. 1. Principal metabolites of cortisol in urine measured by gas chromatography and mass spectrometry.

Expression of 11ß-HSD1 is down-regulated by GH/IGF-I, progesterone, and possibly by insulin (11, 12, 13, 14). Although some in vitro studies have shown an inhibitory effect of insulin on 11ß-HSD1 expression (15, 16), these findings have not been confirmed in studies on primary cultures of human adipose stromal cells (17). Similarly, there is only one in vivo study that was conducted in subjects with hypopituitarism that showed positive correlation between measures of 11ß-HSD1 enzyme activity with insulin sensitivity (18), findings that have not been confirmed in centrally obese, but otherwise healthy individuals (19). Finally, in rats and perhaps in humans, regulation of 11ß-HSD1 is gender specific and inhibited by estradiol (11, 18, 20).

The mechanism of altered 5-R and/or 11ß-HSD1 activities in women with PCOS is still uncertain. Although obesity may cause abnormalities of cortisol metabolism, such alteration cannot fully account for abnormalities of 5-R and 11ß-HSD1 activities in PCOS. Stewart et al. (2) found increased 5-R activity in PCOS subjects compared with controls of similar weights. Similarly, the altered 11ß-HSD1 activity in PCOS reported by Rodin et al. (6) was also confirmed in lean PCOS subjects. Recently, Walker et al. (21) have excluded the increased production of endogenous inhibitors of 11ß-HSD1, measured in urine, as a mechanism of abnormal cortisol metabolism in PCOS. Another proposed mechanism is that high estrogen levels in PCOS, especially in the form of estrone, could down-regulate 11ß-HSD1 activity in liver. However, recent evidence suggests that estrogen does not have a potent effect on 11ß-HSD1 activity in humans (20, 22). Finally, PCOS is associated with insulin resistance and hyperinsulinemia, independently of obesity (23, 24, 25, 26), which might explain the altered cortisol metabolism in these women. Indeed, liver, a major site of both 5-R and 11ß-HSD1 activities, and adipose tissue, another site of 11ß-HSD1 activity, are also targets of insulin action.

In the present study, we sought to determine whether enzyme abnormalities are related to insulin levels in women with PCOS and, therefore, possibly play a role in the pathogenesis of the characteristic hyperandrogenism and subsequent development of PCOS. We also sought to clarify their relationships with obesity and to explore the possibility that they are part of a more generalized alteration of cortisol metabolism with hyperandrogenism and hypercortisolism.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Eighteen lean women with PCOS [median body mass index (BMI), 22.4 kg/m² (range, 18.7–25.5 kg/m²); median age, 28 yr (range, 19–33 yr)] were compared with 19 lean controls [median BMI, 22.6 kg/m² (range, 19.0–24.9 kg/m²); median age, 30 yr (range, 20–37 yr)] who were closely matched for BMI and age (Table 1). We were most interested in studying lean PCOS subjects because adiposity constitutes a modifier of the syndrome and also has been implicated in affecting both 5-R (23, 10) and 11ß-HSD1 enzyme activities in human obesity (8, 9, 19). The ethnic origin and family history of type 2 diabetes in a first-degree relative were also similarly represented in both groups. An additional 24 women with PCOS but of varying BMI were added to the initial 18 to allow for regression analysis of the influence of obesity in 42 women [median BMI, 26.9 kg/m² (range, 18.6–42.8 kg/m²); median age, 27 yr (range, 19–42 yr)]. The inclusion criteria for PCOS were clinical and/or biochemical features of hyperandrogenism together with oligomenorrhoea (length of cycle > 45 d) in 72% and amenorrhea (no period for the past 6 months) in the remaining 28%. Eighty-three percent had clinical hirsutism, whereas 38% had elevated LH (>10 IU/liter), and 60% had raised testosterone levels (greater than upper normal quartile). Subjects (either PCOS patients or controls) were excluded from the study if they 1) were on any hormone treatment or any other medication that could affect steroidogenesis (oral contraceptive pill, antiandrogens, hydrocortisone or inhaled steroids, or ketokonazole) within 3 months before participation in the study, 2) had adrenal gland disturbance (all had normal 17-OH progesterone levels), or 3) had type 2 diabetes [fasting glucose < 126 mg/dl (7 mmol/liter)], because these subjects could have variable degrees of insulin resistance, a well-known confounding factor. All the participants but one (an obese PCOS patient) had fasting glucose less than 110 mg/dl (6.1 mmol/liter). However, two of the PCOS patients had a previous history of gestational diabetes, and three had acanthosis nigricans. Another two PCOS subjects had mild hypertension treated with diuretics, and two were taking antidepressants (selective serotonin reuptake inhibitors) for depression. All subjects had normal renal, liver, and thyroid function and normal serum prolactin levels. Healthy controls had normal menstrual cyclicity and no clinical evidence of hirsutism.

Plasma glucose, serum triglycerides, and cholesterol were measured using standard laboratory methods. Serum testosterone, free T₄, and TSH were measured by automated chemiluminescent immunoassays (Abbott Architect, Abbott Corp., Abbott Park, IL). Androstenedione was measured by RIA (Diagnostic Products Corp., Los Angeles, CA). DHEA sulfate (DHEA-S) was measured on Immulite 2000 (Diagnostic Products). Because the calculation of free androgen index is not universally accepted and because testosterone assays tend to have large confidence variations, we chose to use androstenedione as a non-steroid hormone-binding globulin-bound androgen (bound to plasma SHBG less than 6.6%). Insulin was measured using an immunoenzymometric assay (Abbott Axysm) with no significant cross-reactivity with intact or partially processed proinsulins. Insulin sensitivity was derived from fasting glucose and fasting insulin (FI) data, using the homeostasis model insulin resistance index (HOMA-R) [fasting glucose (mmol/liter) x FI (mU/liter)/22.5].

Urinary metabolite analysis

The 24-h urine collections were stored at -20 C until analysis by gas chromatography and mass spectrometry was performed, according to published methods (27). The ratios of 5-tetrahydrocortisol (5-THF)/5ß-THF, androsterone (a 5 C19 steroid)/etiocholanolone (a 5ß C19 steroid) and total 5/total 5ß were used as an index of 5-R activity. The ratios of -THF + THF/tetrahydrocortisone (THE) and -THF + THF + -cortol/THE + cortolones were used as an index of 11ß-HSD1 activity. The sum of the concentrations of the principal cortisol metabolites (5-THF + THF + THE + cortolones + cortols) was used as an assessment of total daily cortisol production rate (Table 3). The ratio of THE/cortolones was introduced as a marker of 20/ß-HSD activity. Values were expressed as micrograms per 24 h.

All the data of the urine steroid metabolites are given as median (range). Comparisons between groups were made by using the Mann Whitney test. Estimation of the direction and strength of the relationships between variables was made with simple Pearson correlations. Multiple regression analysis was undertaken to define the relative influence of each variable.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Lean PCOS patients differ from lean control subjects in terms of LH (P = 0.03) and androstenedione levels (P = 0.02) but not in terms of insulin sensitivity or testosterone levels (Table 2).

The comparison of urine steroid metabolites of lean PCOS subjects and lean controls (Table 3) showed 1) increased urinary androgen excretion [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P < 0.009)]; 2) increased 5-THF urinary excretion (a 5-reduced cortisol metabolite), although this did not reach statistical significance [there was no difference in 5ß-THF (5ß-reduced cortisol metabolite) or -cortol (a 20-reduced THF metabolite)]; 3) highly significant increase of cortisone metabolite excretion [THE (P < 0.02), -cortolone (P < 0.001), ß-cortol + ß-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)]; and 4) increased total cortisol metabolites (TCM) (P = 0.002), which is a marker of total daily cortisol production rate.

The comparison of urinary steroid metabolite pair ratios of lean PCOS subjects and lean controls (Table 4) showed a significantly higher 5-THF/5ß-THF ratio (P = 0.04) as well as a significantly lower -THF + THF + -cortol/THE + cortolones ratio (P = 0.01), indicating both enhanced 5-R and reduced 11ß-HSD1 activities in lean PCOS women. However, androsterone/etiocholanolone and total 5 /total 5ß metabolite pair ratios (other markers of 5-R activity) and -THF + THF/THE metabolite pair ratio (another index of 11ß-HSD activity) showed no difference. A significantly lower THE/cortolones ratio was also found in lean PCOS women, indicating increased 20/ß-HSD activity (P = 0.03).

Correlations between urinary steroid metabolite pair ratios and indices of insulin sensitivity (Table 5) showed a positive relationship between measurements of 5-R activity and FI levels for androsterone/etiocholanolone and FI (r = 0.33; P = 0.04), for -THF/THF and FI (r = 0.033; P = 0.04), and for total 5/total 5ß and FI (r = 0.38; P = 0.02). A positive relationship also found between markers of 5-R activity and HOMA-R with -THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5/total 5ß and HOMA-R (r = 0.37; P = 0.02). No correlation was found between indices of insulin sensitivity and measures of 11ß-HSD1 activity.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study, we have demonstrated for the first time in vivo a relationship between 5-R activity and indices of insulin sensitivity in women with PCOS. Our findings suggest that the increased 5-R activity in women with PCOS may be secondary to hyperinsulinemia often reported in this condition. Previous studies have documented increased 5-R activity in the skin of PCOS women, so that testosterone is converted to the more potent androgen, 5-DHT, leading to hirsutism (28, 29, 30). Additionally, we found no relationship between measures of 11ß-HSD activity and circulating insulin concentrations, excluding hyperinsulinemia as a major regulator of 11ß-HSD activity.

We confirm the previously reported urine steroid profile alterations associated with PCOS that indicated increased 5-R activity or altered 11ß-HSD1 activity and show that they coexist. The daily excretion rates of adrenal androgens and cortisol metabolites were higher in PCOS women than normal controls as seen in other studies of smaller groups of PCOS patients (5). The increased urinary cortisol metabolites were mainly due to raised THE and cortolones. Decreased 11ß-HSD type 1 activity rather than type 2 hyperactivity based on the evidence of impaired conversion of oral cortisone to cortisol was demonstrated in obese women by Rask and colleagues (9). Our data are in agreement with previous studies that showed increased 5-R activity in PCOS as assessed by the 5-THF/5ß-THF metabolite pair ratio, the most representative index of 5-R activity (2, 31, 32). Our data are also in agreement with the study by Rodin et al. (6), which was the only one that has showed evidence of dysregulation of 11ß-HSD activity in PCOS subjects, as documented by an increased ratio of 11-oxo/11-OH metabolites of cortisol in urine [THE + -cortolones + (ß-cortol + ß-cortolones) x 0.5]/[-THF + THF + -cortol + (ß-cortol + ß-cortolones) x 0.5]. However, in the same study an increased total 5 /total 5ß pair ratio indicating increased 5-R activity in PCOS nearly achieved significance (P = 0.05). It is of note that no correlation was found between indices of insulin sensitivity and 5-R or 11ß-HSD activities in control subjects.

The overall pattern of steroid metabolites in PCOS women could be described as lying between normal and a patient with apparent 11ß-HSD type 1 deficiency (33), with urinary cortisone metabolite excretion rate being consistently high. In PCOS, cortolones were prominent metabolites (Fig. 2). The profile also reflected high adrenal androgen output.

View larger version (18K): [in this window] [in a new window]   FIG. 2. Steroid profile analysis of urine from normal adult female (A), patient with PCOS (B), and patient with 11ß-HSD type 1 defect (C). A, S, and C are internal standards. The numbered steroids are: 1) androsterone, 2) etiocholanolone, 3) 11ß-hydroxyandrosterone, 4) THE, 5) THF, 6) allo-THF, 7) -cortolone, 8) ß-cortolone + ß-cortol (mainly cortolone in B and C), and 9) -cortol. The progressive increase in steroid peak heights from sample A to C relative to the internal standards reflects increased excretion (cortisol production) rates due to raised THE and cortolones.

We also included THE/cortolones metabolite ratio as a marker of 20/ß-HSD activity. A significantly lower THE/cortolones ratio found in lean PCOS women was compatible with increased 20 /ß-HSD activity, which can partly explain the predominance of cortolones relative to THE in the urinary steroid profile of these women. The fact that this enzyme was also altered in PCOS suggests a widespread dysregulation of steroid metabolism in PCOS.

An important factor we must consider in the interpretation of the results is the effect of obesity. Recent studies showed increased cortisol metabolite excretion of obese men and women with both increased activity of 5-R (23, 34, 10) and altered 11ß-HSD1 activity (8, 9, 19). Both Stewart and Rodin concluded, however, that these enzyme abnormalities in PCOS could not be solely explained by obesity. These data have also been confirmed in our study on direct comparison of the lean PCOS subgroup with lean controls. Furthermore, we found that higher BMI (and waist) is associated with higher 5-R activity in women with PCOS, whereas 11ß-HSD1 activity is increased with increasing waist, an indicator of central obesity. The positive relation between -THF + THF + -cortol/THE + cortolones ratio, an index of 11ß-HSD activity, and waist, but not BMI, is important because it indicates that 11ß-HSD activity in visceral fat can make a significant contribution to the circulating cortisol pool. The fact, however, that markers of 11ß-HSD1 activity do not correlate with BMI in our subjects may indicate that factors other than adiposity could determine 11ß-HSD1 activity. Finally, a representative example of a multiple regression analysis testing the effects of insulin and BMI on the 5/5ß ratio showed that insulin and BMI are interdependent. That is, the significance of BMI with the 5/5ß ratio is removed when insulin is added as a covariate.

No correlation was found between serum androgen levels or urinary excretion of androgens with 5/5ß, 11-OH/11-oxo, or TCM. Measurements of DHT and androstanediol glucuronide are needed before excluding hyperandrogenism as a major regulating factor of enzyme activity in PCOS women. However, a positive relationship was found between DHEA-S metabolites in urine and TCM, reflecting adrenal cortical hyperfunction. Previous literature is highly inconsistent regarding ACTH responses to CRH (35, 36) and cortisol responses to ACTH (31, 32) in PCOS. Whatever these differences in the hypothalamic-pituitary-adrenal axis, however, it is believed that they do not result in major alterations in circulating cortisol concentrations in PCOS and that the compensatory activation of the hypothalamic-pituitary- adrenal axis, due to increased 5-R and/or altered 11ß-HSD activities, is responsible for the increased TCM excretion in this syndrome. Indeed, the excessive excretion of both DHEA steroid sulfates and TCM in our subjects is clearly due to increased adrenal synthesis. In support of this, a strong positive relationship was found between TCM and C19 steroid sulfates, whereas no correlation was found between TCM and androsterone and etiocholanolone excretion in urine.

We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. One could expect these abnormalities in the adrenal cortisol and androgen profile to be exaggerated when a substantial insulin resistance or obesity is present. Insulin enhances 5 reduction of steroids in PCOS but does not affect the elevated cortisol production rate. The changes in 5-R, 11ß-HSD1, and 20/ß-HSD enzyme activities observed in PCOS contribute to the increased production rates of cortisol and androgens. Our results exclude hyperandrogenism as a major regulating factor of either 5-R or 11ß-HSD1 activities without additional blood hormone measurements. Regulation of 5-R by insulin in women with PCOS could have important metabolic implications. Insulin-sensitizing agents have provided the basis for recent advances in treatment strategies for women with PCOS. Additional clinical trials are required to establish whether any beneficial effects of metformin treatment are through changes in peripheral cortisol metabolism in PCOS.

	Acknowledgments

 
We are grateful to Cherie Nelson, Research Nurse, for patients’ coordination and Elvira Conway for excellent technical support.

	Footnotes

 
Abbreviations: BMI, Body mass index; DHT, dihydrotestosterone; FI, fasting insulin; HOMA-R, homeostasis model insulin resistance index; HSD1, hydroxysteroid dehydrogenase type 1; PCOS, polycystic ovary syndrome; R, reductase; TCM, total cortisol metabolites; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

Received February 12, 2003.

Accepted September 8, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Russell DW, Wilson JD 1994 Steroid 5-reductase: two genes/two enzymes. Annu Rev Biochem 63:25–61[Medline]
2. Stewart PM, Shackleton CH, Beastall GH, Edwards CR 1990 5-Reductase activity in polycystic ovary syndrome. Lancet 335:431–433[CrossRef][Medline]
3. Mowszowicz I, Melanitou E, Kirchhoffer MO, Mauvais-Jarvis P 1983 Dihydrotestosterone stimulates 5-reductase activity in pubic skin fibroblasts. J Clin Endocrinol Metab 56:320–325[Abstract]
4. Horton R, Pasupuletti V, Antonipillai I 1993 Androgen induction of steroid 5-reductase may be mediated via insulin-like growth factor-I. Endocrinology 133:447–451[Abstract]
5. Fassnacht M, Schlenz N, Schneider SB, Wudy SA, Allolio B, Arlt W 2003 Beyond adrenal and ovarian androgen generation: increased peripheral 5-reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88:2760–2766[Abstract/Free Full Text]
6. Rodin A, Thakkar H, Taylor N, Clayton R 1994 Hyperandrogenism in polycystic ovary syndrome. Evidence of dysregulation of 11ß-hydroxysteroid dehydrogenase. N Engl J Med 330:460–465[Abstract/Free Full Text]
7. Katz JR, Mohamed-Ali V, Wood PJ, Yudkin JS, Coppack SW 1999 An in vivo study of the cortisol-cortisone shuttle in subcutaneous abdominal adipose tissue. Clin Endocrinol (Oxf) 50:63–68[CrossRef][Medline]
8. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker BR 2001 Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86:1418–1421[Abstract/Free Full Text]
9. Rask E, Walker BR, Soderberg S, Livingstone DE, Eliasson M, Johnson O, Andrew R, Olsson T 2002 Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11ß-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87:3330–3336[Abstract/Free Full Text]
10. Seckl JR, Walker BR 2001 Minireview: 11ß-hydroxysteroid dehydrogenase type 1, a tissue-specific amplifier of glucocorticoid action. Endocrinology 142:1371–1376[Abstract/Free Full Text]
11. Low SC, Chapman KE, Edwards CR, Wells T, Robinson IC, Seckl JR 1994 Sexual dimorphism of hepatic 11ß-hydroxysteroid dehydrogenase in the rat: the role of growth hormone patterns. J Endocrinol 143:541–548[Abstract]
12. Weaver JU, Thaventhiran L, Noonan K, Burrin JM, Taylor NF, Norman MR, Monson JP 1994 The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults. Clin Endocrinol (Oxf) 41:639–648[Medline]
13. Walker BR, Andrew R, MacLeod KM, Padfield PL 1998 Growth hormone replacement inhibits renal and hepatic 11ß-hydroxysteroid dehydrogenases in ACTH-deficient patients. Clin Endocrinol (Oxf) 49:257–263[CrossRef][Medline]
14. Gelding SV, Taylor NF, Wood PJ, Noonan K, Weaver JU, Wood DF, Monson JP 1998 The effect of growth hormone replacement therapy on cortisol-cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11ß-hydroxysteroid dehydrogenase activity. Clin Endocrinol (Oxf) 48:153–162[Medline]
15. Hammami MM, Siiteri PK 1991 Regulation of 11ß-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. J Clin Endocrinol Metab 73:326–334[Abstract]
16. Jamieson PM, Chapman KE, Edwards CR, Seckl JR 1995 11ß-Hydroxysteroid dehydrogenase is an exclusive 11ß-reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. Endocrinology 136:4754–4761[Abstract]
17. Bujalska IJ, Kumar S, Stewart PM 1997 Does central obesity reflect "Cushing’s disease of the omentum"? Lancet 349:1210–1213[CrossRef][Medline]
18. Weaver JU, Taylor NF, Monson JP, Wood PJ, Kelly WF 1998 Sexual dimorphism in 11ß-hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity: a study in hypopituitary subjects. Clin Endocrinol (Oxf) 49:13–20[CrossRef][Medline]
19. Stewart PM, Boulton A, Kumar S, Clark PM, Shackleton CH 1999 Cortisol metabolism in human obesity: impaired cortisonecortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 84:1022–1027[Abstract/Free Full Text]
20. Finken MJ, Andrews RC, Andrew R, Walker BR 1999 Cortisol metabolism in healthy young adults: sexual dimorphism in activities of A-ring reductases, but not 11ß-hydroxysteroid dehydrogenases. J Clin Endocrinol Metab 84:3316–3321[Abstract/Free Full Text]
21. Walker BR, Rodin A, Taylor NF, Clayton RN 2000 Endogenous inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 do not explain abnormal cortisol metabolism in polycystic ovary syndrome. Clin Endocrinol (Oxf) 52:77–80[CrossRef][Medline]
22. Andrew R, Phillips DI, Walker BR 1998 Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab 83:1806–1809[Abstract/Free Full Text]
23. Chang RJ, Nakamura RM, Judd HL, Kaplan SA 1983 Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 57:356–359[Abstract]
24. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174[Abstract]
25. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T 1992 Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41:1257–1266[Abstract]
26. Morales AJ, Laughlin GA, Butzow T, Maheshwari H, Baumann G, Yen SS 1996 Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 81:2854–2864[Abstract]
27. Honour JW 1997 Steroid profiling. Ann Clin Biochem 34:32–44
28. Phillipou G, Seaborn CJ 1984 Urinary steroid measurements in hirsute women. Clin Chem 30:1579–1580[Medline]
29. Mauvais-Jarvis P 1986 Regulation of androgen receptor and 5-reductase in the skin of normal and hirsute women. Clin Endocrinol Metab 15:307–317[CrossRef][Medline]
30. Dijkstra AC, Goos CM, Cunliffe WJ, Sultan C, Vermorken AJ 1987 Is increased 5-reductase activity a primary phenomenon in androgen-dependent skin disorders? J Invest Dermatol 89:87–92[CrossRef][Medline]
31. Chin D, Shackleton C, Prasad VK, Kohn B, David R, Imperato-McGinley J, Cohen H, McMahon DJ, Oberfield SE 2000 Increased 5-reductase and normal 11ß-hydroxysteroid dehydrogenase metabolism of C19 and C21 steroids in a young population with polycystic ovarian syndrome. J Pediatr Endocrinol Metab 13:253–259[Medline]
32. Moghetti P, Castello R, Negri C, Tosi F, Spiazzi GG, Brun E, Balducci R, Toscano V, Muggeo M 1996 Insulin infusion amplifies 17-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrinol Metab 81:881–886[Abstract]
33. Phillipou G, Higgins BA 1985 A new defect in the peripheral conversion of cortisone to cortisol. J Steroid Biochem 22:435–436[CrossRef][Medline]
34. Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JM 1999 Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension 33:1364–1368[Abstract/Free Full Text]
35. Ehrmann DA, Rosenfield RL, Barnes RB, Brigell DF, Sheikh Z 1992 Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med 327:157–162[Abstract]
36. Kondoh Y, Uemura T, Ishikawa M, Yokoi N, Hirahara F 1999 Classification of polycystic ovary syndrome into three types according to response to human corticotropin-releasing hormone. Fertil Steril 72:15–20[CrossRef][Medline]

This article has been cited by other articles:

				J. W. Tomlinson, J. Finney, B. A. Hughes, S. V. Hughes, and P. M. Stewart Reduced Glucocorticoid Production Rate, Decreased 5{alpha}-Reductase Activity, and Adipose Tissue Insulin Sensitization After Weight Loss Diabetes, June 1, 2008; 57(6): 1536 - 1543. [Abstract] [Full Text] [PDF]

				T. Remer, T. Dimitriou, and C. Maser-Gluth Renal Net Acid Excretion and Plasma Leptin Are Associated with Potentially Bioactive Free Glucocorticoids in Healthy Lean Women J. Nutr., February 1, 2008; 138(2): 426S - 430S. [Abstract] [Full Text] [PDF]

				C. Roberge, A. C. Carpentier, M.-F. Langlois, J.-P. Baillargeon, J.-L. Ardilouze, P. Maheux, and N. Gallo-Payet Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1465 - E1478. [Abstract] [Full Text] [PDF]

				R. H. Stimson, A. M. Johnstone, N. Z. M. Homer, D. J. Wake, N. M. Morton, R. Andrew, G. E. Lobley, and B. R. Walker Dietary Macronutrient Content Alters Cortisol Metabolism Independently of Body Weight Changes in Obese Men J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4480 - 4484. [Abstract] [Full Text] [PDF]

				S. A. Wudy, M. F. Hartmann, and T. Remer Sexual dimorphism in cortisol secretion starts after age 10 in healthy children: urinary cortisol metabolite excretion rates during growth Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E970 - E976. [Abstract] [Full Text] [PDF]

				M. O. Goodarzi, N. A. Shah, H. J. Antoine, M. Pall, X. Guo, and R. Azziz Variants in the 5{alpha}-Reductase Type 1 and Type 2 Genes Are Associated with Polycystic Ovary Syndrome and the Severity of Hirsutism in Affected Women J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4085 - 4091. [Abstract] [Full Text] [PDF]

				T. Remer, K. R. Boye, M. F. Hartmann, and S. A. Wudy Urinary Markers of Adrenarche: Reference Values in Healthy Subjects, Aged 3-18 Years J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2015 - 2021. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsilchorozidou, T. Articles by Conway, G. S. Search for Related Content PubMed PubMed Citation Articles by Tsilchorozidou, T. Articles by Conway, G. S.