madman
Super Moderator
ABSTRACT
The 5-reductases (5α-reductase types 1, 2 and 3 [5αR1− 3], 5β-reductase [5βR]) are steroid hormone metabolizing enzymes that hold fundamental roles in human physiology and pathology. They possess broad substrate specificity converting many steroid hormones to their 5α- and 5β-reduced metabolites, as well as catalyzing crucial steps in bile acid synthesis. 5αRs are fundamentally important in urogenital development by converting testosterone to the more potent androgen 5α-dihydrotestosterone (5αDHT); inactivating mutations in 5αR2 lead to disorders of sexual development. Due to the ability of the 5αRs to generate 5αDHT, they are an established drug target, and 5αR inhibitors are widely used for the treatment of androgen-dependent benign or malignant prostatic diseases.
There is an emerging body of evidence to suggest that the 5-reductases can impact aspects of health and disease (other than urogenital development); alterations in their expression and activity have been associated with metabolic disease, polycystic ovarian syndrome, inflammation, and bone metabolism. This review will outline the evidence base for the extra-urogenital role of 5-reductases from in vitro cell systems, pre-clinical models and human studies, and highlight the potential adverse effects of 5αR inhibition in human health and disease.
1. Steroid hormones and pre-receptor steroid hormone metabolism
Steroid hormones, including glucocorticoids (GCs), androgens, and estrogens, are synthesized within the adrenal glands and gonads and play a crucial role in embryonic development, cellular differentiation, and metabolic homeostasis [1]. They exert a wide variety of effects in the body across almost all tissues. Steroid hormones are fat-soluble molecules and, via the circulation, pass through the cell membrane and bind to cytoplasmic or nuclear steroid hormone receptors. The potent impact of steroid hormones is demonstrated by states of excess and deficiency. For example, androgen deficiency in men and estrogen deficiency in women is associated with adverse metabolic features, including insulin resistance and decreased bone mineral density [2–4]. GC excess is associated with central obesity, hypertension, hyperlipidemia, and glucose intolerance, whilst glucocorticoid deficiency, as a result of adrenal or pituitary pathology can lead to a life-threatening crisis characterized by hypotension and electrolyte abnormalities [5,6].
However, the availability of these hormones to bind to their receptors is not only dependent on circulating levels but also tightly controlled by the expression and activity of a series of enzymes that are able to metabolize steroid hormones before binding to their cognate receptors, in so-called ‘pre-receptor metabolism’. With regards to GCs, the roles of the isoforms of 11β-hydroxysteroid dehydrogenase (11βHSD, type 1 and 2), which interconvert inactive cortisone and active cortisol, are well described, and their activity has been implicated in the pathogenesis of many aspects of health and disease including obesity, insulin resistance, hypertension and fetal development [7–13]. The 5-reductases (5α-reductase type 1 and 2 [5αR1 and 2] and 5β-reductase [5βR]) have a role to clear GCs but, in addition, have broad substrate specificity and, therefore, the potential to regulate the availability of several classes of steroid hormones [14] (Fig. 1). 5αR2 has an established role in male sexual development (in which it activates testosterone to the more potent 5α-dihydrotestosterone [5αDHT]), with inactivating mutations leading to 46XY Disorder of Sexual Development (DSD) [15,16]. However, there is now increasing evidence to suggest that altered 5-reductase activity and expression can impact other aspects of health and disease, along with their established role in urogenital development or regulating androgen availability, for example in the context of prostate enlargement and malignancy. The current review will focus on the extra-urogenital role of these enzymes and will try to describe the advancements from in vitro, in vivo, and human studies.
2. 5α-reductases
2.1. Type 1 and 2 5αR gene structure and protein properties
2.2. Tissue distribution
2.3. Type 3 5αR gene structure and protein properties
2.4. 5αR inhibitors
2.5. 5αR in adipose tissue
2.6. 5αR and metabolic syndrome
2.7. 5αR and polycystic ovarian syndrome (PCOS)
2.8. 5αR and bone
2.9. 5αR and inflammation
3. 5β-reductase (5βR)
3.1. 5βR gene structure and protein properties
3.2. Tissue distribution
3.3. 5βR mutations
3.4. 5βR inhibitors
3.5. Role of 5βR in metabolic syndrome
4. Conclusions and future directions
Steroid hormones, including GCs and androgens, regulate multiple aspects of health and disease, and there is now a rapidly growing body of evidence to implicate the 5-reductases in controlling phenotype outside their perceived traditional role to regulate androgen availability in urogenital tissues. The full translational potential of the 5-reductases is yet to be fully explored. Targeted inhibition appears to have a complex, sexually dimorphic impact reflecting their diverse array of substrates and enzymatic products. However, assessment of their activity may provide a tool to predict the future development of adverse metabolic consequences. Furthermore, given their role in the metabolism of exogenous steroids, determination of their activity may have the potential to predict the development of adverse side effects and ultimately aid dose selection and titration
The 5-reductases (5α-reductase types 1, 2 and 3 [5αR1− 3], 5β-reductase [5βR]) are steroid hormone metabolizing enzymes that hold fundamental roles in human physiology and pathology. They possess broad substrate specificity converting many steroid hormones to their 5α- and 5β-reduced metabolites, as well as catalyzing crucial steps in bile acid synthesis. 5αRs are fundamentally important in urogenital development by converting testosterone to the more potent androgen 5α-dihydrotestosterone (5αDHT); inactivating mutations in 5αR2 lead to disorders of sexual development. Due to the ability of the 5αRs to generate 5αDHT, they are an established drug target, and 5αR inhibitors are widely used for the treatment of androgen-dependent benign or malignant prostatic diseases.
There is an emerging body of evidence to suggest that the 5-reductases can impact aspects of health and disease (other than urogenital development); alterations in their expression and activity have been associated with metabolic disease, polycystic ovarian syndrome, inflammation, and bone metabolism. This review will outline the evidence base for the extra-urogenital role of 5-reductases from in vitro cell systems, pre-clinical models and human studies, and highlight the potential adverse effects of 5αR inhibition in human health and disease.
1. Steroid hormones and pre-receptor steroid hormone metabolism
Steroid hormones, including glucocorticoids (GCs), androgens, and estrogens, are synthesized within the adrenal glands and gonads and play a crucial role in embryonic development, cellular differentiation, and metabolic homeostasis [1]. They exert a wide variety of effects in the body across almost all tissues. Steroid hormones are fat-soluble molecules and, via the circulation, pass through the cell membrane and bind to cytoplasmic or nuclear steroid hormone receptors. The potent impact of steroid hormones is demonstrated by states of excess and deficiency. For example, androgen deficiency in men and estrogen deficiency in women is associated with adverse metabolic features, including insulin resistance and decreased bone mineral density [2–4]. GC excess is associated with central obesity, hypertension, hyperlipidemia, and glucose intolerance, whilst glucocorticoid deficiency, as a result of adrenal or pituitary pathology can lead to a life-threatening crisis characterized by hypotension and electrolyte abnormalities [5,6].
However, the availability of these hormones to bind to their receptors is not only dependent on circulating levels but also tightly controlled by the expression and activity of a series of enzymes that are able to metabolize steroid hormones before binding to their cognate receptors, in so-called ‘pre-receptor metabolism’. With regards to GCs, the roles of the isoforms of 11β-hydroxysteroid dehydrogenase (11βHSD, type 1 and 2), which interconvert inactive cortisone and active cortisol, are well described, and their activity has been implicated in the pathogenesis of many aspects of health and disease including obesity, insulin resistance, hypertension and fetal development [7–13]. The 5-reductases (5α-reductase type 1 and 2 [5αR1 and 2] and 5β-reductase [5βR]) have a role to clear GCs but, in addition, have broad substrate specificity and, therefore, the potential to regulate the availability of several classes of steroid hormones [14] (Fig. 1). 5αR2 has an established role in male sexual development (in which it activates testosterone to the more potent 5α-dihydrotestosterone [5αDHT]), with inactivating mutations leading to 46XY Disorder of Sexual Development (DSD) [15,16]. However, there is now increasing evidence to suggest that altered 5-reductase activity and expression can impact other aspects of health and disease, along with their established role in urogenital development or regulating androgen availability, for example in the context of prostate enlargement and malignancy. The current review will focus on the extra-urogenital role of these enzymes and will try to describe the advancements from in vitro, in vivo, and human studies.
2. 5α-reductases
2.1. Type 1 and 2 5αR gene structure and protein properties
2.2. Tissue distribution
2.3. Type 3 5αR gene structure and protein properties
2.4. 5αR inhibitors
2.5. 5αR in adipose tissue
2.6. 5αR and metabolic syndrome
2.7. 5αR and polycystic ovarian syndrome (PCOS)
2.8. 5αR and bone
2.9. 5αR and inflammation
3. 5β-reductase (5βR)
3.1. 5βR gene structure and protein properties
3.2. Tissue distribution
3.3. 5βR mutations
3.4. 5βR inhibitors
3.5. Role of 5βR in metabolic syndrome
4. Conclusions and future directions
Steroid hormones, including GCs and androgens, regulate multiple aspects of health and disease, and there is now a rapidly growing body of evidence to implicate the 5-reductases in controlling phenotype outside their perceived traditional role to regulate androgen availability in urogenital tissues. The full translational potential of the 5-reductases is yet to be fully explored. Targeted inhibition appears to have a complex, sexually dimorphic impact reflecting their diverse array of substrates and enzymatic products. However, assessment of their activity may provide a tool to predict the future development of adverse metabolic consequences. Furthermore, given their role in the metabolism of exogenous steroids, determination of their activity may have the potential to predict the development of adverse side effects and ultimately aid dose selection and titration
