madman
Super Moderator
Finasteride and dutasteride, synthetic 5α-reductase inhibitors (5ARIs) are recommended in many guidelines for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms and alopecia despite a variety of side effects like sexual, neurological, psychiatric, endocrinological, metabolic and ophthalmological dysfunctions and the increased incidence of high grade prostate cancer. The sexual side effects are common during the use of the drug but in a small subgroup of patients, they can persist after stopping the drug. This so-called post-finasteride syndrome has serious implications for the quality of life without a clear etiology or therapy. Three types of 5α-reductases are present in many organs in- and outside the brain where they can be blocked by the two 5ARIs. There is increasing evidence that 5ARIs not only inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT) in the prostate and the scalp but also in many other tissues. The lipophilic 5ARIs can pass the blood-brain barrier and might block many other neurosteroids in the brain with changes in the neurochemistry and impaired neurogenesis. Further research and therapeutic innovations are urgently needed that might cure or relieve these side effects. More awareness is needed for physicians to outweigh these health risks against the benefits of 5ARIs.
*MECHANISM OF ACTION OF 5α-REDUCTASE INHIBITORS IN BPH AND AGA
*SIDE EFFECTS AND ADVERSE EFFECTS OF 5ARIS
Part I: Sexual side effects, depressive symptoms and suicide
Part II: Adverse effects in liver, ocular system and kidney; impaired spermatogenesis
Part III: Finasteride, dutasteride and prostate cancer
*WHAT ARE THE POSSIBLE ETIOLOGICAL MECHANISMS OF ACTION THAT CAUSE THE SIDE EFFECTS?
DISCUSSION AND CONCLUSIONS
The 5ARIs finasteride and dutasteride are widely used drugs over 20 years for alopecia and BPH/LUTS with a variety of side effects like sexual, neurological, psychiatric, endocrine, metabolic, ophthalmological, testicular dysfunctions and the increased incidence of high-grade prostate cancer [17, 21, 54]. The sexual side effects are common and transient, but in a small subgroup of patients these side effects can persist even years after discontinuation of the drug [48, 88, 89]. This so-called PFS has serious implications for the quality of life and unfortunately till now no effective therapy exists [17, 54].
Physiological mechanisms of PED and genital anesthesia are yet to be understood; is there an endocrinological, psychological or neurological cause (central or peripheral) [90]? The above mentioned etiological mechanisms like the change in neurochemistry and neurogenesis, the novel state of androgen deficiency and the nocebo-effect are steps further but by far insufficient to explain why there are subgroups of patients with side effects during and after use of 5ARIs and to reach in the end a concrete therapy.
For a better understanding of the existing relations between hormonal and cerebral symptoms a consistent cross-consultation is needed between urologists/sexologist/endocrinologist/dermatologists on one end and psychiatrists/neurologists/researchers on the other hand. In general it is sometimes difficult for patients and professionals to recognize the link between symptoms and the 5ARIs because symptoms exist or appear (long time) after discontinuation of the drug. A very interesting and promising development is the identification of genetically influenced metabotypes, so called GIMS [91], that represent the genetic basis of chemical individuality, which gave new biological insights. With the help of these GIMS it was possible to prove a consistent genetic association between greater 5α-reductase activity and the risk of male-pattern hair loss [61].The investigators also observed genetic associations consistent with lower 5α-reductase activity with lower levels of metabolites downstream of 5α-reduction of androgenic steroids. Another study identified a separate genetic association between androsterone sulfate, epiandrosterone sulfate and depression [92]. This chemical individuality might be the way to identify subgroups of patients at risk for side effects due to 5ARIs.
The lack of quality studies is a major problem in assessing the presence and frequency of the side effects. Further research is warranted with PCRCT including validated questionnaires at baseline with detailed history regarding past psychiatric disorders, the use of medications or drugs and relevant comorbidities, and with a follow up for several years. But this is unlikely to happen due to a lack of funding. Until then it is utmost important to identify individuals with a previous history of depression, sexual dysfunction or infertility who may be more susceptible for the various side effects [93]. The possible risks should than be discussed with the patient and weighed out against the benefits of the use of 5ARIs as mentioned in the introduction. Men under the age of 40 who use finasteride for alopecia are at risk for suicide if they develop persistent sexual adverse effects and insomnia [94]. Physicians need more awareness regarding the decrease of PSA due to 5ARIs of 50% after 6 to 12 months use [6] which can mask high-grade prostate cancer [21]. They should restrict the 5ARIs to patients with a prostate volume of >40 ml according the EAU guideline 2023 [12]. Therapeutic innovation is urgently needed that might cure or relieve this wide range of health risks.
*MECHANISM OF ACTION OF 5α-REDUCTASE INHIBITORS IN BPH AND AGA
*SIDE EFFECTS AND ADVERSE EFFECTS OF 5ARIS
Part I: Sexual side effects, depressive symptoms and suicide
Part II: Adverse effects in liver, ocular system and kidney; impaired spermatogenesis
Part III: Finasteride, dutasteride and prostate cancer
*WHAT ARE THE POSSIBLE ETIOLOGICAL MECHANISMS OF ACTION THAT CAUSE THE SIDE EFFECTS?
DISCUSSION AND CONCLUSIONS
The 5ARIs finasteride and dutasteride are widely used drugs over 20 years for alopecia and BPH/LUTS with a variety of side effects like sexual, neurological, psychiatric, endocrine, metabolic, ophthalmological, testicular dysfunctions and the increased incidence of high-grade prostate cancer [17, 21, 54]. The sexual side effects are common and transient, but in a small subgroup of patients these side effects can persist even years after discontinuation of the drug [48, 88, 89]. This so-called PFS has serious implications for the quality of life and unfortunately till now no effective therapy exists [17, 54].
Physiological mechanisms of PED and genital anesthesia are yet to be understood; is there an endocrinological, psychological or neurological cause (central or peripheral) [90]? The above mentioned etiological mechanisms like the change in neurochemistry and neurogenesis, the novel state of androgen deficiency and the nocebo-effect are steps further but by far insufficient to explain why there are subgroups of patients with side effects during and after use of 5ARIs and to reach in the end a concrete therapy.
For a better understanding of the existing relations between hormonal and cerebral symptoms a consistent cross-consultation is needed between urologists/sexologist/endocrinologist/dermatologists on one end and psychiatrists/neurologists/researchers on the other hand. In general it is sometimes difficult for patients and professionals to recognize the link between symptoms and the 5ARIs because symptoms exist or appear (long time) after discontinuation of the drug. A very interesting and promising development is the identification of genetically influenced metabotypes, so called GIMS [91], that represent the genetic basis of chemical individuality, which gave new biological insights. With the help of these GIMS it was possible to prove a consistent genetic association between greater 5α-reductase activity and the risk of male-pattern hair loss [61].The investigators also observed genetic associations consistent with lower 5α-reductase activity with lower levels of metabolites downstream of 5α-reduction of androgenic steroids. Another study identified a separate genetic association between androsterone sulfate, epiandrosterone sulfate and depression [92]. This chemical individuality might be the way to identify subgroups of patients at risk for side effects due to 5ARIs.
The lack of quality studies is a major problem in assessing the presence and frequency of the side effects. Further research is warranted with PCRCT including validated questionnaires at baseline with detailed history regarding past psychiatric disorders, the use of medications or drugs and relevant comorbidities, and with a follow up for several years. But this is unlikely to happen due to a lack of funding. Until then it is utmost important to identify individuals with a previous history of depression, sexual dysfunction or infertility who may be more susceptible for the various side effects [93]. The possible risks should than be discussed with the patient and weighed out against the benefits of the use of 5ARIs as mentioned in the introduction. Men under the age of 40 who use finasteride for alopecia are at risk for suicide if they develop persistent sexual adverse effects and insomnia [94]. Physicians need more awareness regarding the decrease of PSA due to 5ARIs of 50% after 6 to 12 months use [6] which can mask high-grade prostate cancer [21]. They should restrict the 5ARIs to patients with a prostate volume of >40 ml according the EAU guideline 2023 [12]. Therapeutic innovation is urgently needed that might cure or relieve this wide range of health risks.
