**8. 11β –hydroxysteroid dehydrogenase in the ovary – cellular localization/distribution and relation to Polycistic Ovaries Syndrome and obesity in women**

Glucocorticoids exert their effects in all parts of the body and they are involved in a number of physiological processes, including female reproduction. The ovary is also affected by the glucocorticoids and it is well known that the reproductive function may be impaired in cases of adrenal hyperactivity. The ovaries express glucocorticoid receptors and one of the prominent glucocorticoids affecting ovarian function is the cortisol [157]. Ovaries lack the necessary enzymes for cortisol synthesis and cortisol is not produced *de novo* [158] but it was delivered by the circulation. The 11β-HSD enzymes play a crucial role in controlling the

tissue concentration of cortisol. The two types of 11β-HSD (1 and 2) with opposite action modifies cortisol exposure by interconversion between active and inactive glucocorticoids [159,160].

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 135

In the rare syndrome of cortisone reductase deficiency, impaired ability of 11β-HSD1 to convert cortisone to cortisol, results in compensatory activation of ACTH secretion and adrenal hyperandrogenism [177,178]. This syndrome has been associated with the polymorphisms in the *HSD11B1* gene, which encodes 11β-HSD1, and female patients affected by cortisol reductase deficiency exhibited hyperandrogenism and a phenotype resembling PCOS [179,180]. Lower ratios of cortisol/cortisone metabolites in urine in patients with PCOS were found compared to controls, suggesting a reduced 11β-HSD1 activity [179]. Gambineri et al., [180] reported that polymorphism, predicting lower peripheral regeneration of cortisol by 11β-HSD1, is related to PCOS status and it is associated with increased adrenal hyperandrogenism in lean PCOS. These data strongly support a role for the *HSD11B1* gene in the pathogenesis of PCOS. According to Gambineri et al. [180], the association of the *HSD11B1* genotype with PCOS was mainly attributable to lean rather than obese PCOS patients, suggesting that in obese PCOS women adrenal hyperandrogenism must have a different pathogenetic mechanism as hyperinsulinemia [181] or increased cortisol clearance [182]. The above mentioned findings differ from studies by San Milla´n et al. [183] and White [184] where no association between *HSD11B1* genotype and PCOS was found. This fact suggests that *HSD11B1* polymorphisms may be relevant only in some subgroups of patients and that the pathogenesis of PCOS is different among the different phenotypes of the syndrome [180]. Recently, the functional consequences in these polymorphisms in *HSD11B1* gene were examined and the results confirm previous reports that the variant in *HSD11B1* confer increased 11β-HSD1 expression and activity, that are associated with the metabolic syndrome [183, 185] but are not associated with the prevalence of PCOS [186]. These findings are confirmed by study by Mlinar et al. [187], reporting that PCOS is not associated with increased *HSD11B1* expression. The elevated expression of this gene correlates with markers of adiposity and predicts insulin resistance

and an unfavorable metabolic profile, independently of PCOS.

**obesity and metabolic syndrome** 

normal or even reduced in simple obesity [189].

**9. 11β –hydroxysteroid dehydrogenase in adipose tissue – relation to** 

The metabolic syndrome describes a cluster of risk factors like insulin resistance, type 2 diabetes, dyslipidemia, hypertension [188] and co-occurrence of visceral (abdominal, central) obesity. There are strong morphological and metabolic similarities between the Cushing's syndrome of endogenous or exogenous glucocorticoid excess and the metabolic syndrome [189]. Glucocorticoid excess exerts opposing effects on adipose tissue, with an increase in central fat deposition through stimulation of preadipocyte differentiation, gluconeogenesis and triglyceride synthesis, while peripheral fat is reduced as a result from increased lipolysis and lipoprotein lipase downregulation [108]. Glucocorticoid-induced obesity has been investigated in animal models and in humans. It has been shown that cortisol levels are modestly elevated in patients with the metabolic syndrome and tend to be

The preponderance of data suggest that the intracellular glucocorticoid reactivation was elevated in adipose tissue of obese rodent models and humans [108, 190]. The enzyme that

In the human ovary expression of 11β-HSD types 1 and 2 is well documented. 11β-HSD type 2 expression is most prominent during the luteal phase in the corpus luteum and in nonluteinized granulosa cells from follicles before the mid-cycle surge of gonadotrophins. In contrast 11β-HSD type 1 is only seen in granulosa cells from preovulatory follicles [161]). As a result, developmentally regulated pattern of 11β-HSD types 1 and 2 promotes high levels of cortisol during the mid-cycle surge of gonadotrophins, immediately prior to ovulation, whereas reduced levels are maintained throughout the rest of the menstrual cycle [162,163]. Therefore the high levels of local free cortisol are suggested to act as anti-inflammatory agent that limited the tissue damage occurring in connection with follicular rupture [163,164]. This considerations suggest that the regulation of concentration of biologically active cortisol in the ovary may be an important physiological mechanism by which glucocorticoids affect female reproductive organs.

The polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among premenopausal women. The symptoms include the consequences of excessive androgen production (hyperandrogenemia), anovulation and infertility. The hallmark of PCOS is follicular maturation arrest and hyperandrogenemia that is believed to be a critical component of the syndrome [165, 66]. Studies regarding the pathophysiology of PCOS focus attention to primary defects in the hypothalamic–pituitary axis, ovarian function, insulin secretion and action but none of these hypotheses can fully elucidate the multiple clinical phenotypes of PCOS [167-169]. Insulin resistance and the associated compensatory hyperinsulinemia and centripetal obesity, perhaps reflect an association and linkage of the insulin gene with PCOS [170]. PCOS is of unknown etiology, but several lines of evidence suggest that there is an underlying genetic cause for PCOS. Ovarian androgen production occurs primarily in the theca cells and examination of the metabolism of radiolabeled steroid hormone precursors and steady-state levels of mRNAs, encoding steroidogenic enzymes, revealed that there are multiple alterations in the steroidogenic machinery of PCOS theca cells [171-173]. These observations are consistent with the notion that dysregulation of androgen biosynthesis is intrinsic property of PCOS theca cells and that PCOS may develop as a consequence of a primary genetic abnormality in ovarian androgen production [174]. Elevated adrenal androgen levels are common in PCOS, but the underlying pathogenetic mechanisms are poorly understood. One proposed contributing mechanism is altered cortisol metabolism. Moreover, PCOS and obesity are independently associated with increased expression of 11β-HSD1 mRNA in subcutaneous abdominal tissue from lean and obese women with and without PCOS. Decreased peripheral insulin sensitivity and central obesity were associated with increased expression of 11β-HSD1 but not of 11β-HSD2 mRNA expression [175]. Previous studies have described an increased 5alpha-reduction of cortisol and impaired regeneration of cortisol from cortisone by 11β-HSD1 in PCOS, supporting the concept of an altered cortisol metabolism in POCS [176].

In the rare syndrome of cortisone reductase deficiency, impaired ability of 11β-HSD1 to convert cortisone to cortisol, results in compensatory activation of ACTH secretion and adrenal hyperandrogenism [177,178]. This syndrome has been associated with the polymorphisms in the *HSD11B1* gene, which encodes 11β-HSD1, and female patients affected by cortisol reductase deficiency exhibited hyperandrogenism and a phenotype resembling PCOS [179,180]. Lower ratios of cortisol/cortisone metabolites in urine in patients with PCOS were found compared to controls, suggesting a reduced 11β-HSD1 activity [179]. Gambineri et al., [180] reported that polymorphism, predicting lower peripheral regeneration of cortisol by 11β-HSD1, is related to PCOS status and it is associated with increased adrenal hyperandrogenism in lean PCOS. These data strongly support a role for the *HSD11B1* gene in the pathogenesis of PCOS. According to Gambineri et al. [180], the association of the *HSD11B1* genotype with PCOS was mainly attributable to lean rather than obese PCOS patients, suggesting that in obese PCOS women adrenal hyperandrogenism must have a different pathogenetic mechanism as hyperinsulinemia [181] or increased cortisol clearance [182]. The above mentioned findings differ from studies by San Milla´n et al. [183] and White [184] where no association between *HSD11B1* genotype and PCOS was found. This fact suggests that *HSD11B1* polymorphisms may be relevant only in some subgroups of patients and that the pathogenesis of PCOS is different among the different phenotypes of the syndrome [180]. Recently, the functional consequences in these polymorphisms in *HSD11B1* gene were examined and the results confirm previous reports that the variant in *HSD11B1* confer increased 11β-HSD1 expression and activity, that are associated with the metabolic syndrome [183, 185] but are not associated with the prevalence of PCOS [186]. These findings are confirmed by study by Mlinar et al. [187], reporting that PCOS is not associated with increased *HSD11B1* expression. The elevated expression of this gene correlates with markers of adiposity and predicts insulin resistance and an unfavorable metabolic profile, independently of PCOS.

134 Dehydrogenases

[159,160].

tissue concentration of cortisol. The two types of 11β-HSD (1 and 2) with opposite action modifies cortisol exposure by interconversion between active and inactive glucocorticoids

In the human ovary expression of 11β-HSD types 1 and 2 is well documented. 11β-HSD type 2 expression is most prominent during the luteal phase in the corpus luteum and in nonluteinized granulosa cells from follicles before the mid-cycle surge of gonadotrophins. In contrast 11β-HSD type 1 is only seen in granulosa cells from preovulatory follicles [161]). As a result, developmentally regulated pattern of 11β-HSD types 1 and 2 promotes high levels of cortisol during the mid-cycle surge of gonadotrophins, immediately prior to ovulation, whereas reduced levels are maintained throughout the rest of the menstrual cycle [162,163]. Therefore the high levels of local free cortisol are suggested to act as anti-inflammatory agent that limited the tissue damage occurring in connection with follicular rupture [163,164]. This considerations suggest that the regulation of concentration of biologically active cortisol in the ovary may be an important physiological mechanism by which

The polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among premenopausal women. The symptoms include the consequences of excessive androgen production (hyperandrogenemia), anovulation and infertility. The hallmark of PCOS is follicular maturation arrest and hyperandrogenemia that is believed to be a critical component of the syndrome [165, 66]. Studies regarding the pathophysiology of PCOS focus attention to primary defects in the hypothalamic–pituitary axis, ovarian function, insulin secretion and action but none of these hypotheses can fully elucidate the multiple clinical phenotypes of PCOS [167-169]. Insulin resistance and the associated compensatory hyperinsulinemia and centripetal obesity, perhaps reflect an association and linkage of the insulin gene with PCOS [170]. PCOS is of unknown etiology, but several lines of evidence suggest that there is an underlying genetic cause for PCOS. Ovarian androgen production occurs primarily in the theca cells and examination of the metabolism of radiolabeled steroid hormone precursors and steady-state levels of mRNAs, encoding steroidogenic enzymes, revealed that there are multiple alterations in the steroidogenic machinery of PCOS theca cells [171-173]. These observations are consistent with the notion that dysregulation of androgen biosynthesis is intrinsic property of PCOS theca cells and that PCOS may develop as a consequence of a primary genetic abnormality in ovarian androgen production [174]. Elevated adrenal androgen levels are common in PCOS, but the underlying pathogenetic mechanisms are poorly understood. One proposed contributing mechanism is altered cortisol metabolism. Moreover, PCOS and obesity are independently associated with increased expression of 11β-HSD1 mRNA in subcutaneous abdominal tissue from lean and obese women with and without PCOS. Decreased peripheral insulin sensitivity and central obesity were associated with increased expression of 11β-HSD1 but not of 11β-HSD2 mRNA expression [175]. Previous studies have described an increased 5alpha-reduction of cortisol and impaired regeneration of cortisol from cortisone by 11β-HSD1 in PCOS, supporting the concept of an altered cortisol metabolism in POCS [176].

glucocorticoids affect female reproductive organs.
