Title
'Adverse Side Effects of 5?-Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients'
Link
http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract
Some highlights from the text
To date, the adverse side effects of 5a-RIs on sexual function, gyneco- mastia, and the impact on the overall health have received minimal attention. However, in some patients, these side effects are persistent with regard to sexual function and with an emotional toll including decreased quality of life.
In the brain, the products of 5a-Rs are trans- formed by another group of specific enzymes known as 3a-hydroxysteroid dehydrogenases (3a-HSD), which reduce 5a-DHT to 3a, 5a-androstane 17b-diol (3a-diol) and 5a-DHP to 3a, 5a-tetrahydroprogesterone (allopreg- nanolone). Similarly, 5a-DHDOC is further reduced to 3a, 5a-tetrahydrodeoxycorticosterone (THDOC). These derivatives are thought to func- tion as neurosteroids in the central nervous system (Figure 3), with important physiological functions including modulation of gamma-aminobutyric acid type A (GABAA) receptor, sigma receptor function, nicotinic acetylcholine receptor, voltage- gated calcium channels, and synaptic and brain plasticity. These physiological functions may impact mood, rhythm, stress, sleep, memory, anxiety, and sexual function [11]. 3a-HSD utilizes NADPH as a cofactor, and this reaction is revers- ible [10–12]. In transformation of these 3a, 5a reduced steroids; the 5a-R reaction is the rate-
limiting step [12,13].
The two most investigated inhibitors of 5a-R are finasteride and dutasteride (Figure 1) [10]. Dutasteride is a selective inhibitor of 5a-R1 and 5a-R2 in most tissues examined [9]. Dutasteride approaches maximum inhibition at 1 mg/kg/day, with a peak blood concentration of 140 ng/mL [10], and it reduces serum 5a-DHT by approxi- mately 90% [9,14]. Finasteride is maximally effec- tive at 70 mg/kg/day, with a peak blood level of 7,840 ng/mL in humans [10], and it reduces serum 5a-DHT by approximately 70% [14,15]. Finas- teride is considered mainly an inhibitor of 5a-R2 and is approximately 50 times weaker in inhibiting 5a-R1 than 5a-R2 [9]. Finasteride is thought to cross the blood–brain barrier and inhibits 5a-Rs in the central nervous system [16].
Finasteride was thought to be a competitive inhibitor of both 5a-Rs isozymes, with an inhibi- tor dissociation constant (Ki) varying from 3 to 26 nM [17–19]. Recently, finasteride was shown to catalyze T to 5a-DHT via a mechanism- based inhibitor of 5a-R2, with formation of enolate intermediates. The enzyme/NADP- dihydrofinasteride complex is stable, with a half-life of approximately 1 month, and the reaction produces dihydrofinasteride [20]. Finasteride also inhibits 5b-reductase [21]. 5b and 5a-reductases are involved in hepatic steroid metabolism, and thus finasteride might affect liver function [21]. Inhibition of 5b-reductase may impair CYP3A4 activity [21], which is the enzyme responsible for finasteride metabolism [22]. Dutasteride also involves a two-step mechanism and is a time- dependent inhibitor of 5a-R2 [23,24].
Adverse Effects of 5a-R inhibitor Therapy
A host of adverse effects had been observed in the clinical settings as a result of 5a-RIs therapy; however, some of these adverse events are consid- ered either insignificant or temporary, and may not exhibit long-term effects in patients’ overall health. Other adverse events including sexual dysfunction appear to either become severe or persistent. In the study by Wessells et al. [25], only 50% of patients experienced resolution of their sexual adverse events after discontinuation. Furthermore, Erdemir et al. [26] stated that “While sexual dys- function induced by Finasteride and dutasteride
diminishes over time, resolving completely with discontinuation of therapy and discontinuation due to sexual adverse events occurs in up to 4% of patients.†Additional evidence is found in clinical studies and in the Merck database, which strongly suggest that in some patients, the sexual adverse effects are persistent. In the medicine health care products regulatory agency (MHRA) public assess- ment report on the risk of finasteride published in December of 2009 in Section 4.8 Undesirable Effects, it was stated that “In addition, the following have been reported in post-marketing use: persis- tence of ED after discontinuation of treatment with PROPECIA.†Clearly, the sexual adverse events do not necessarily resolve completely in all patients, who discontinue use of finasteride, again support- ing the premise that in some patients these sexual side effects remain “persistent.†In the proceeding section, we will discuss the impact of these drugs on sexual function, gynecomastia, and depression.
Unfortunately the article does not give potential causes as its a review of other articles. Confirms what we know to the scientific community and was only published in Dec 2010.
'Adverse Side Effects of 5?-Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients'
Link
http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract
Some highlights from the text
To date, the adverse side effects of 5a-RIs on sexual function, gyneco- mastia, and the impact on the overall health have received minimal attention. However, in some patients, these side effects are persistent with regard to sexual function and with an emotional toll including decreased quality of life.
In the brain, the products of 5a-Rs are trans- formed by another group of specific enzymes known as 3a-hydroxysteroid dehydrogenases (3a-HSD), which reduce 5a-DHT to 3a, 5a-androstane 17b-diol (3a-diol) and 5a-DHP to 3a, 5a-tetrahydroprogesterone (allopreg- nanolone). Similarly, 5a-DHDOC is further reduced to 3a, 5a-tetrahydrodeoxycorticosterone (THDOC). These derivatives are thought to func- tion as neurosteroids in the central nervous system (Figure 3), with important physiological functions including modulation of gamma-aminobutyric acid type A (GABAA) receptor, sigma receptor function, nicotinic acetylcholine receptor, voltage- gated calcium channels, and synaptic and brain plasticity. These physiological functions may impact mood, rhythm, stress, sleep, memory, anxiety, and sexual function [11]. 3a-HSD utilizes NADPH as a cofactor, and this reaction is revers- ible [10–12]. In transformation of these 3a, 5a reduced steroids; the 5a-R reaction is the rate-
limiting step [12,13].
The two most investigated inhibitors of 5a-R are finasteride and dutasteride (Figure 1) [10]. Dutasteride is a selective inhibitor of 5a-R1 and 5a-R2 in most tissues examined [9]. Dutasteride approaches maximum inhibition at 1 mg/kg/day, with a peak blood concentration of 140 ng/mL [10], and it reduces serum 5a-DHT by approxi- mately 90% [9,14]. Finasteride is maximally effec- tive at 70 mg/kg/day, with a peak blood level of 7,840 ng/mL in humans [10], and it reduces serum 5a-DHT by approximately 70% [14,15]. Finas- teride is considered mainly an inhibitor of 5a-R2 and is approximately 50 times weaker in inhibiting 5a-R1 than 5a-R2 [9]. Finasteride is thought to cross the blood–brain barrier and inhibits 5a-Rs in the central nervous system [16].
Finasteride was thought to be a competitive inhibitor of both 5a-Rs isozymes, with an inhibi- tor dissociation constant (Ki) varying from 3 to 26 nM [17–19]. Recently, finasteride was shown to catalyze T to 5a-DHT via a mechanism- based inhibitor of 5a-R2, with formation of enolate intermediates. The enzyme/NADP- dihydrofinasteride complex is stable, with a half-life of approximately 1 month, and the reaction produces dihydrofinasteride [20]. Finasteride also inhibits 5b-reductase [21]. 5b and 5a-reductases are involved in hepatic steroid metabolism, and thus finasteride might affect liver function [21]. Inhibition of 5b-reductase may impair CYP3A4 activity [21], which is the enzyme responsible for finasteride metabolism [22]. Dutasteride also involves a two-step mechanism and is a time- dependent inhibitor of 5a-R2 [23,24].
Adverse Effects of 5a-R inhibitor Therapy
A host of adverse effects had been observed in the clinical settings as a result of 5a-RIs therapy; however, some of these adverse events are consid- ered either insignificant or temporary, and may not exhibit long-term effects in patients’ overall health. Other adverse events including sexual dysfunction appear to either become severe or persistent. In the study by Wessells et al. [25], only 50% of patients experienced resolution of their sexual adverse events after discontinuation. Furthermore, Erdemir et al. [26] stated that “While sexual dys- function induced by Finasteride and dutasteride
diminishes over time, resolving completely with discontinuation of therapy and discontinuation due to sexual adverse events occurs in up to 4% of patients.†Additional evidence is found in clinical studies and in the Merck database, which strongly suggest that in some patients, the sexual adverse effects are persistent. In the medicine health care products regulatory agency (MHRA) public assess- ment report on the risk of finasteride published in December of 2009 in Section 4.8 Undesirable Effects, it was stated that “In addition, the following have been reported in post-marketing use: persis- tence of ED after discontinuation of treatment with PROPECIA.†Clearly, the sexual adverse events do not necessarily resolve completely in all patients, who discontinue use of finasteride, again support- ing the premise that in some patients these sexual side effects remain “persistent.†In the proceeding section, we will discuss the impact of these drugs on sexual function, gynecomastia, and depression.
Unfortunately the article does not give potential causes as its a review of other articles. Confirms what we know to the scientific community and was only published in Dec 2010.