An increased adrenal androgen production found in 25% of PCOS women (Ehrmann et al., 1992; Turner et al., 1992), possibly as a result of a genetic trait or secondary to ovarian hormonal secretion (Moran & Azziz, 2001). A more recently proposed mechanism is an alteration in cortisol metabolism. The principal pathways of cortisol metabolism include irreversible inactivation by 5α-reductase (5α-R) and 5β-reductase (5β-R) in liver, and reversible interconversion with cortisone by 11βHSD in liver and adipose tissue. According to this theory, increased peripheral cortisol metabolism either by increased 5α-R activity and thus increased inactivation of cortisol (Stewart et al., 1990; Chin et al., 2000) or impaired 11βHSD activity and thus impaired regeneration of cortisol (Rodin et al., 1994) results in 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 (Fig. 3). In support of this hypothesis, urinary metabolites of cortisol were found to be abnormal in women with PCOS.
Stewart et al. (1990) first documented increased total cortisol metabolite excretion in the urine of PCOS women using gas chromatography and mass spectrometry, compared to controls. In particular, they found that the ratio of 5α to 5β cortisol metabolites were higher in PCOS subjects than in controls, indicating enhanced 5α-R activity. This steroidogenic enzyme is responsible for both 5α-reduction of testosterone to 5α-dihydrotestosterone in skin and cortisol to 5α-dihydrocortisol in liver. Therefore, it was suggested that increased activity of 5α-R mediates both hirsutism and enhanced hepatic cortisol metabolism. Previous in vitro studies in genital skin fibroblasts have shown that 5α-R activity is upregulated by androgens (Mowszowicz et al., 1983), an effect that might be mediated by IGF-I (Horton et al., 1993). Finally, a downregulation of this enzyme by high prolactin levels has been supported as a protective mechanism against clinical presentation of unwanted hair growth in hirsute women (Seppala & Hirvonen, 1975). Luppa et al. (1995) have documented changes in the excretion of urinary androgen and gestagen metabolites in response to GnRH agonist stimulation, suggesting a functional alteration of the pituitary-ovarian axis.
Increased Peripheral Cortisol Metabolism
ReplyDeleteAn increased adrenal androgen production found in 25% of PCOS women (Ehrmann et al., 1992; Turner et al., 1992), possibly as a result of a genetic trait or secondary to ovarian hormonal secretion (Moran & Azziz, 2001). A more recently proposed mechanism is an alteration in cortisol metabolism. The principal pathways of cortisol metabolism include irreversible inactivation by 5α-reductase (5α-R) and 5β-reductase (5β-R) in liver, and reversible interconversion with cortisone by 11βHSD in liver and adipose tissue. According to this theory, increased peripheral cortisol metabolism either by increased 5α-R activity and thus increased inactivation of cortisol (Stewart et al., 1990; Chin et al., 2000) or impaired 11βHSD activity and thus impaired regeneration of cortisol (Rodin et al., 1994) results in 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 (Fig. 3). In support of this hypothesis, urinary metabolites of cortisol were found to be abnormal in women with PCOS.
Stewart et al. (1990) first documented increased total cortisol metabolite excretion in the urine of PCOS women using gas chromatography and mass spectrometry, compared to controls. In particular, they found that the ratio of 5α to 5β cortisol metabolites were higher in PCOS subjects than in controls, indicating enhanced 5α-R activity. This steroidogenic enzyme is responsible for both 5α-reduction of testosterone to 5α-dihydrotestosterone in skin and cortisol to 5α-dihydrocortisol in liver. Therefore, it was suggested that increased activity of 5α-R mediates both hirsutism and enhanced hepatic cortisol metabolism. Previous in vitro studies in genital skin fibroblasts have shown that 5α-R activity is upregulated by androgens (Mowszowicz et al., 1983), an effect that might be mediated by IGF-I (Horton et al., 1993). Finally, a downregulation of this enzyme by high prolactin levels has been supported as a protective mechanism against clinical presentation of unwanted hair growth in hirsute women (Seppala & Hirvonen, 1975). Luppa et al. (1995) have documented changes in the excretion of urinary androgen and gestagen metabolites in response to GnRH agonist stimulation, suggesting a functional alteration of the pituitary-ovarian axis.