Current knowledge of the multifunctional 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1). He W et al. (2016) At the late 1940s, 17β-HSD1 was discovered as the first member of the 17β-HSD family with its gene cloned. The three-dimensional structure of human 17β-HSD1 is the first example of any human steroid converting enzyme. The human enzyme's structure and biological function have thus been studied extensively in the last two decades. In humans, the enzyme is expressed in placenta, ovary, endometrium and breast. The high activity of estrogen activation provides the basis of 17β-HSD1's implication in estrogen-dependent diseases, such as breast cancer, endometriosis and non-small cell lung carcinomas. Its dual function in estrogen activation and androgen inactivation has been revealed in molecular and breast cancer cell levels, significantly stimulating the proliferation of such cells. The enzyme's overexpression in breast cancer was demonstrated by clinical samples. Inhibition of human 17β-HSD1 led to xenograft tumor shrinkage. Unfortunately, through decades of studies, there is still no drug using the enzyme's inhibitors available. This is due to the difficulty to get rid of the estrogenic activity of its inhibitors, which are mostly estrogen analogues. New non-steroid inhibitors for the enzyme provide new hope for non-estrogenic inhibitors of the enzyme.//////////////////
In mammalian tissues, at least two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyze the interconversion of hormonally active C11-hydroxylated corticosteroids (cortisol, corticosterone) and their inactive C11-keto metabolites (cortisone, 11-dehydrocorticosterone). The type 1 and type 2 11 beta-HSD isozymes share only 14% homology and are separate gene products with different physiological roles, regulation, and tissue distribution. 11 beta-HSD1 acts predominantly as a reductase in vivo, facilitating glucocorticoid hormone action in key target tissues. Over the 10 years, 11 beta-HSD has progressed from an enzyme merely involved in the peripheral metabolism of cortisol to a crucial pre-receptor signaling pathway in the analysis of corticosteroid hormone action. This review details the enzymology, molecular biology, distribution, regulation, and function of the 11 beta-HSD isozymes and highlights the clinical consequences of altered enzyme expression (Stewart and Krozowski, 1999).
NCBI Summary:
The protein encoded by this gene is a microsomal enzyme that catalyzes the conversion of the stress hormone cortisol to the inactive metabolite cortisone. In addition, the encoded protein can catalyze the reverse reaction, the conversion of cortisone to cortisol. Too much cortisol can lead to central obesity, and a particular variation in this gene has been associated with obesity and insulin resistance in children. Mutations in this gene and H6PD (hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase)) are the cause of cortisone reductase deficiency. Alternate splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, May 2011]
General function
Metabolism, Enzyme, Oxidoreductase
Comment
Genetic variants of the HSD11B1 gene promoter may be protective against polycystic ovary syndrome. Grolmusz VK 2014 et al.
The HSD11B1 gene encodes the type 1 isoform of the 11--hydroxysteroid dehydrogenase that is responsible for the regeneration of glucocorticoids from hormonally-inactive metabolites into active forms in a tissue-specific manner. Altered activity of the enzyme, and certain genetic variants of the HSD11B1 gene, has been associated with various metabolic morbidities. In this study, our aim was to systematically test the potential role of the HSD11B1's single nucleotide polymorphisms (SNPs) in polycystic ovary syndrome (PCOS). Nine HSD11B1 SNPs were selected and genotyped using Taqman SNP assays on real-time PCR in a group of PCOS patients (n=58) and in age-matched healthy controls (n=64). Genotype-phenotype correlations were determined and haplotype analysis was performed. An in silico prediction for potential transcription factor binding sites was also performed. Of the 5 promoter SNPs, 3 (rs760951; rs4844880; rs3753519) were less frequent in the PCOS group compared to healthy controls. SNPs rs4844880 and rs3753519 were in a complete linkage and the mutant haplotype (AA) was less frequent in the PCOS group. No association between HSD11B1 variants and clinical, pathological findings was observed in patients, but in healthy women the rs4844880 and the AA haplotype were associated with higher levels of homeostasis model assessment of beta cell function. The polymorphic form of the rs4844880 was predicted to bind Pbx-1. Promoter SNPs of the HSD11B1 gene might exert a potential genetic protective role against the development of PCOS, possibly via their beneficial effect on carbohydrate homeostasis due to facilitation of insulin efflux from pancreatic beta-cells.
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The enzyme 11 beta HSD catalyzes the interconversion of the biologically active cortisol and the biologically inactive cortisone. There are two distinct isozymes: 11 beta HSD type 1 is mainly expressed in liver and is a bidirectional enzyme, with both dehydrogenase and reductase activity (Kerstens and Dullaart, 1999).
Cellular localization
Cytoplasmic
Comment
candidate123
Ovarian function
Follicle development, Steroid metabolism
Comment
Local regeneration of cortisol by 11β-HSD1 contributes to insulin resistance of the granulosa cells in PCOS. Zhu Q et al. (2016) Insulin resistance (IR) of the granulosa cells may account for the ovarian dysfunctions observed in polycystic ovarian syndrome (PCOS). The underlying mechanism remains largely unresolved. To investigate the relationship of IR of the granulosa cells with cortisol in the follicular fluid and 11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1 and 2) in the granulosa cells in PCOS. Follicular fluid and granulosa cells were collected from non-PCOS and PCOS patients with and without IR to measure cortisol concentration and the amounts of 11β-HSD1 and 2, which were then correlated with IR status. The effects of cortisol on the expression of genes pertinent to IR were studied in cultured human granulosa cells. Cortisol concentration in the follicular fluid, 11β-HSD1 but not 2 mRNA in the granulosa cells were significantly elevated in PCOS with IR. Increased reductase and decreased oxidase activities of 11β-HSD were observed in granulosa cells in PCOS with IR. In cultured granulosa cells, insulin-induced Akt phosphorylation was significantly attenuated by cortisol. Cortisol not only increased PTEN, an inhibitor of Akt phosphorylation, but also 11β-HSD1 in the cells. Increased 11β-HSD1 expression and its reductase activity in granulosa cells are the major causes of increased cortisol concentration in the follicular fluid of PCOS with IR. The consequent excessive cortisol might contribute to IR of the granulosa cells in PCOS patients by attenuating Akt phosphorylation via induction of PTEN expression, which might be further exacerbated by the induction of 11β-HSD1.//////////////////
ROLE FOR PROSTAGLANDINS IN THE REGULATION OF TYPE 1 11{beta} HYDROXYSTEROID DEHYDROGENASE IN HUMAN GRANULOSA-LUTEIN CELLS. Jonas KC et al. 11beta-hydroxysteroid dehydrogenase (11betaHSD) enzymes regulate glucocorticoid availability in target tissues. 11betaHSD1 is the predominant isoenzyme expressed and active in human granulosa-lutein (hGL) cells. This study investigated the effects of pharmacological inhibitors of prostaglandin (PG) synthesis on 11betaHSD1 activities and expression in hGL cells. The consequences for 11betaHSD1 of increasing exposure of hGL cells to PGs, either by treatment with exogenous PGs or by challenging cells with interleukin-1beta (IL-1beta), were also assessed. Suppression of basal PG synthesis using 4 different inhibitors of prostaglandin H synthase enzymes (indomethacin, niflumic acid, meclofenamic acid (MA) and N-(2-cyclohexyloxy-4-nitorophenyl) methane sulfonamide (NS-398)) each resulted in significant decreases in both cortisol oxidation and cortisone reduction. Both activities of 11betaHSD1 were suppressed by up to 64 +/- 6% (P < 0.05). Over 4 and 24 h, neither MA nor NS-398 affected the expression of 11betaHSD1 protein, suggesting enzyme regulation by PGs at the post-translational level. When cells were co-treated for 4 h with PGHS inhibitors plus 30 nM PGD2, PGF2alpha or PGE2, each PG overcame the suppression of cortisol oxidation by indomethacin or MA. Treatment of hGL cells with IL-1beta increased the concentrations of both PGE2 and PGF2alpha, accompanied by a 70 +/- 25% increase in net cortisol oxidation. All 3 responses to IL-1beta were abolished when cells were co-treated with MA. These findings suggest a role for prostaglandins in the post-translational regulation of 11betaHSD1 activities in hGL cells.
Expression regulated by
FSH, LH, Interleukin-1 beta
Comment
Tetsuka et al. (1999) reported the regulation of 11
beta-hydroxysteroid dehydrogenase type 1 gene expression by LH and interleukin-1 beta in cultured rat granulosa cells.
Yong PYK, et al 2000 reported development-related increase in cortisol biosynthesis by human
granulosa cells.
After administration of human (h)CG
for ovulation induction, luteinized granulosa cells (LGC) abundantly express
11 beta -hydroxysteroid dehydrogenase type 1 (11 beta HSD1) messenger RNA but
not 11 beta HSD type 2 (11 beta HSD2) messenger RNA. 11 beta HSD1 is
responsible for the reversible formation of antiinflammatory F from its
inactive precursor cortisone (E), whereas 11 beta HSD2 unidirectionally
converts F to E through 11-oxidation. This pattern of gene expression predicts
that LGC from periovulatory follicles would show increased activation of E to
F, compared with granulosa cells from immature follicles (IGC), and that
follicular fluid concentrations of E and F would alter accordingly. To test
this hypothesis, the authors isolated IGC, thecal cells (TC), and follicular fluid,
from ovaries of cyclic. LGC and follicular fluid were aspirated from periovulatory follicles,
35 h after hCG injection, in patients undergoing in vitro fertilization
treatment. In an 11 beta HSD assay based on interconversion of tritiated E and
F by cell suspensions in vitro, IGC (% conversion, 0.0 +/- 0.4, mean +/- SEM)
and collagenase-dispersed TC (0.2 +/- 0.1%) were unable to convert E to F,
whereas LGC (36.3 +/- 3.7%) were highly efficient at this reaction. Immature
granulosa cells, LGC, and (to a lesser extent) TC were all able to convert F
to E. Culturing IGC for 48 h in the presence of hFSH resulted in
increased 11 beta HSD1 reductase activity, paralleling stimulation of estrogen
(aromatase activity) and progesterone biosynthesis. These data
confirm that 11 beta HSD activity in the human ovary is developmentally
regulated and gonadotropin responsive, favoring metabolism of F to E in
immature follicles and E to F in periovulatory follicles. Increased formation
of F by LGC in periovulatory follicles is consistent with an antiinflammatory
function for this glucocorticoid at ovulation.
Ovarian localization
Oocyte, Cumulus, Granulosa, Luteal cells
Comment
Activation of HSD11B1 in the bovine cumulus oocyte complex during IVM and IVF. Tetsuka M et al. (2019) The bovine cumulus-oocyte complex (COC) is capable of converting cortisone, an inert glucocorticoid to active cortisol. This mechanism is mediated by 11β-hydroxysteroid oxidoreductase type 1 (HSD11B1), whose expression dramatically increases in the mature COC. In this study, we investigate the time course expression of HSD11B1 and the enzyme activity in the bovine COC undergoing maturation and fertilization in relation to key events taking place in the COC. Bovine COCs were subjected to in vitro maturation (IVM) and fertilization (IVF). The activities of HSD11B1 and HSD11B2, which mediates the opposite reaction, were measured by using a radiometric conversion assay. In parallel studies, cumulus expansion, P4 production, and the expression of genes associated with ovulation were measured. The reductive activity of HSD11B1 increased in the latter half of IVM and remained high during IVF, whereas the oxidative activity of HSD11B2 remained unchanged over both periods. Consequently, the net glucocorticoid metabolism in the bovine COC shifted from inactivation to activation around the time of ovulation and fertilization. The increase in HSD11B1 expression lagged behind that of P4 increase and cumulus expansion but ahead of the expressions of genes responsible for PGE2 synthesis. The reductive activity of HSD11B1 was well correlated with the cumulus expansion rate. This outcome indicates that the ability of the cumulus to activate glucocorticoids is related to its ability to synthesize hyaluronan. These results also indicate that the activation of HSD11B1 is an integral part of the sequential events taking place at the ovulation and fertilization in the bovine COC.//////////////////
Glucocorticoid Metabolism in the Bovine Cumulus-Oocyte Complex matured in vitro. Tetsuka M et al. (2015) Glucocorticoid action in target organs is regulated by relative activities of 11β-HSD type1 (HSD11B1) that mainly converts cortisone to active cortisol, and type2 (HSD11B2) that inactivates cortisol to cortisone. HSD11Bs have been shown to be expressed in the ovary in various species. However, little is known about the expression and activity of HSD11Bs in the bovine cumulus-oocyte complex (COC). In the present study, we investigated expressions and activities of HSD11Bs in in vitro-matured (IVM) bovine COCs. Bovine COCs were matured in M199 supplemented with/without FSH and FCS. The expression of HSD11Bs was measured by using quantitative RT-PCR in denuded oocytes (DO) and cumulus cells (CC). Reductive and oxidative activities of HSD11Bs were determined by radiometric conversion assay using labeled cortisol, cortisone or dexamethasone in intact COC, DO or CC in the presence/absence of 11-keto-progesterone (11kP), a selective inhibitor of HSD11B2. The presence of 11HSDs in the oocyte was examined by immunofluorescence microscopy. Oocyte exclusively expressed HSD11B2 and its expression and activity were largely unchanged during IVM. Cumulus cells, on the other hand, exclusively expressed HSD11B1 and its expression and activity were up regulated as IVM progressed. As the results, the net glucocorticoid metabolism shifted from inactivation to activation towards the end of IVM. These results indicate that the bovine COC is capable to modulate local glucocorticoid concentration and by doing so, may create environment that is favorable to ovulating oocyte for maturation, fertilization and subsequent development.//////////////////
Localization of 17beta-hydroxysteroid dehydrogenase type 1 mRNA in mouse tissues. Pelletier G et al. The enzyme 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 1 catalyzes the conversion of estrone (E1) into 17beta estradiol (E2). To gain information about the cellular localization of 17beta-HSD mRNA type 1 expression, we performed in situ hybridization using a 35S-labeled cRNA probe in several tissues of adult mice of both sexes. In the ovary, high expression was found in granulosa cells of growing follicles. No specific labeling could be observed in corpora lutea or interstitial cells. In the pituitary gland of animals of both sexes, 17beta-HSD type 1 mRNA was expressed in the intermediate lobe melanotrophs while no specific signal could be detected in the anterior or posterior lobes of the pituitary. In the prostate, 17beta-HSD type 1 mRNA was exclusively found in the epithelial cells. In both male and female mouse dorsal skin, a specific hybridization signal was seen in the sebaceous glands while the epidermis, stroma, hair follicles and sweat glands were unlabeled. In the testis, a hybridization signal was detected in germ cells of the seminiferous tubules, Leydig cells being unlabeled. The present data indicate that E2 can be formed through the action of 17beta-HSD type 1 in specific cells of the gonads and peripheral tissues. In the testes and peripheral tissues, the action of E2 is probably limited to the cells involved in its formation in an intracrine fashion.
Inactivation of glucocorticoids by 11{beta}-hydroxysteroid dehydrogenase(11{beta}HSD) enzymes increases during the meiotic maturation of porcine oocytes. Webb R et al. Recent reports have shown that glucocorticoids can modulate oocyte maturation in both teleost fish and mammals. Within potential target cells, the actions of physiological glucocorticoids are modulated by 11beta-hydroxysteroid dehydrogenase (11BetaHSD) isoenzymes which catalyse the inter-conversion of cortisol and cortisone. Hence the objective of this study was to establish whether 11betaHSD enzymes mediate cortisol-cortisone metabolism in porcine oocytes and, if so, whether the rate of glucocorticoid metabolism changes during oocyte maturation. Enzyme activities were measured in cumulus-oocyte complexes (COCs) and denuded oocytes (DOs) using radiometric conversion assays. While COCs and DOs oxidised cortisol to inert cortisone, there was no detectable regeneration of cortisol from cortisone. The rate of cortisol oxidation was higher in expanded COCs than in compact COCs containing germinal vesicle (GV) stage oocytes (111+/-6 vs 2041+/-115 fmol cortisone/oocyte.24h; P<0.001). Likewise, 11betaHSD activities were 17+/-1 fold higher in DOs from expanded COCs than in those from compact COCs (P<0.001). When GV stage oocytes were subject to a 48 hour in vitro maturation protocol, the enzyme activities were significantly increased from 146+/-18 to 1857+/-276 fmol cortisone/oocyte.24h in GV versus MII, respectively (P<0.001). Cortisol metabolism was inhibited by established pharmacological inhibitors of 11betaHSD (glycyrrhetinic acid and carbenoxolone), and by porcine follicular and ovarian cyst fluid. We conclude that an 11betaHSD enzyme (or enzymes) functions within porcine oocytes to oxidise cortisol, and that this enzymatic inactivation of cortisol increases during oocyte maturation.
Immunoperoxidase studies on liver, adrenal, ovary, decidua, and adipose tissue indicated positive cytoplasmic staining for 11betaHSD1. In the human ovary, immunoreactivity was observed in the developing oocyte and the luteinized granulosa cells of the corpus luteum. No staining was observed in granulosa cells, thecal cells, or ovarian stroma (Ricketts et al., 1998) and (Benediktsson et al., 1992).
Follicle stages
Corpus luteum
Comment
See (Ricketts et al., 1998)
Tissue-specific increases in 11beta-hydroxysteroid dehydrogenase type 1 in normal weight postmenopausal women. Andersson T et al. With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11betaHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11betaHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11betaHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5alpha-tetrahydrocortisol+5beta-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11betaHSD1 activity. Postmenopausal women had higher 11betaHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11betaHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11betaHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
3 mutations
Species: mouse
Mutation name: None
type: None fertility: fertile Comment: A mouse tool for conditional mutagenesis in ovarian granulosa cells. Grabner B et al. Here we describe the generation of an inducible Cre transgenic line allowing conditional mutagenesis in ovarian granulosa cells. We have expressed the tamoxifen inducible CreER(T)? fusion protein from a Bacterial Artificial Chromosome (BAC) containing the regulatory elements of the hydroxysteroid (17-beta) dehydrogenase 1 (Hsd17b1) gene. Hsd17b1-iCreER(T)? transgenic mice express the iCreER(T)? fusion protein exclusively in ovarian granulosa cells. Recombination analysis at the genomic DNA level using mice with 'floxed' Stat3 alleles showed no Cre activity in absence of tamoxifen whereas tamoxifen treatment induced Cre activity solely in the ovaries. Further characterization of Hsd17b1-iCreER(T)? mice using a Cre reporter line demonstrated that Cre-mediated recombination was restricted to ovarian granulosa cells. Therefore, Hsd17b1-iCreER(T)? mice should be a useful tool to analyze the gene functions in ovarian granulosa cells.
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: Association Analysis between the Polymorphisms of HSD11B1 and H6PD and Risk of Polycystic Ovary Syndrome in Chinese Population. Ju R et al. (2015) To evaluate whether single nucleotide polymorphisms of HSD11B1 (rs846908) and H6PD (rs6688832 and rs17368528) are associated with polycystic ovary syndrome (PCOS) in Chinese population. A case-control study was implemented to investigate the association between HSD11B1 and H6PD polymorphisms and PCOS. Patients with PCOS (n = 335) and controls (n = 354) were recruited in this study. Genetic variants of HSD11B1 (rs846908) and H6PD (rs6688832 and rs17368528) were analyzed by TaqMan method. We found a significantly 0.79-fold lower risk of G allele of rs6688832 in control group compared with the patients with PCOS (adjusted OR, 0.79; 95%CI = 0.63-0.99; P = 0.040). Additionally, significant difference in the levels of follicle stimulating hormone (FSH) was observed between AA and AG genotype in rs6688832. The rs6688832 AG genotype was associated with lower level of FSH (P = 0.039) and higher risk of hyperandrogenism (P = 0.016) in patients with PCOS. When all subjects were divided into different subgroups according to age and body mass index (BMI), we found that the frequency of G allele of rs6688832 was significantly higher in controls than that in PCOS patients in the subgroup of BMI > 23 (adjusted OR, 0.70; 95% CI = 0.50-0.98; P = 0.037). Our findings showed a statistical association between H6PD rs6688832 and PCOS risk in Chinese population. The G allele of rs6688832 in H6PD might exert potential genetic protective role against the development of PCOS, especially in overweight women. PCOS patients with AG genotype of rs6688832 might confer risk to the phenotype of hyperandrogenemia of PCOS.//////////////////
Species: human
Mutation name: type: None fertility: None Comment: ///Fluorescence microscopy demonstrated the localization of both 11beta-HSD1 and 11beta-HSD2 exclusively to the endoplasmic reticulum (ER) membrane. Immunohistochemistry revealed that the N terminus of 11beta-HSD1 is cytoplasmic, and the catalytic domain containing the C terminus is protruding into the ER lumen. The subcellular localization of 11beta-HSD1 was not affected by mutations of the tyrosine motif or of a di-lysine motif in the N terminus. However, residue Lys(5), but not Lys(6), turned out to be critical for the topology of 11beta-HSD1. Mutation of Lys(5) to Ser inverted the orientation of 11beta-HSD1 in the ER membrane without loss of catalytic activity (Odermatt et al., 1999).
Ovarian 11?Hydroxysteroid Dehydrogenase (11?SD) Activity is Suppressed in Women with Anovulatory Polycystic Ovary Syndrome (PCOS): Apparent Role for Ovarian Androgens. Michael AE et al. Context:Altered hepatic cortisol-cortisone metabolism by type 1 11?hydroxysteroid dehydrogenase (11?SD1) has previously been linked with PCOS.Objective:To establish whether ovarian 11?SD activities are also altered in PCOS and to determine whether any changes in ovarian cortisol metabolism might reflect exposure to elevated concentrations of insulin or androgens.Design:Cortisol and cortisone concentrations were measured in follicular fluid aspirated from size-matched follicles dissected from normal, ovulatory and anovulatory polycystic ovaries (PCO). Human granulosa-lutein cells, recovered during oocyte retrieval for assisted conception, were maintained in primary culture for 4 days, after which 11?SD1 activities were measured as the net oxidation of (3)H-cortisol (100 nmol/L) in the absence and presence of insulin (100 nmol/L) ? metformin (1 ?mol/L) or a range of androgens/oxy-androgen metabolites (0.01-10 ?mol/L).Results:Intra-follicular cortisol:cortisone ratios were elevated in anovulatory PCO (2.1?0.4; P<0.05, n=13) but did not differ between follicles from ovulatory PCO (1.6?0.1, n=24) and normal ovaries (1.2?0.1, n=14). 11?SD1 activities were lower in granulosa-lutein cells recovered from patients with PCOS compared to all other causes of infertility (median = 5.8 vs 14.9 pmol cortisone/4h, respectively; P<0.05). Cortisol oxidation was unaffected by insulin ? metformin, dehydroepiandrosterone (DHEA) and androstenedione, but was inhibited in a concentration-dependent manner by testosterone, 11?hydroxyandrostenedione, 7a- and 7?hydroxy-DHEA (P<0.01).Conclusions:There is decreased inactivation of cortisol in follicles from anovulatory PCOS. This may reflect inhibition of 11?SD1 by androgens and their 7/11-oxy-metabolites, local concentrations of which are increased in PCOS, and may contribute to the block to folliculogenesis seen in PCOS.