Inhibitors 5α-reductase prevent the action of this enzyme in converting Testosterone em DHT (dihydrotestosterone). They act in many organs where their receptors exist. Therefore, intracellular androgens decrease. Thus, they can cause the slow onset of common and little-recognized diseases that started with their use.
Testosterone acts on cells in organs that express their receptors, therefore on target cells. In addition, 5α-reductase (5α-Rs) stimulates the formation of steroids in neurons. Certainly, they are critical for the proper functioning of the central and peripheral nervous system. Without them, there is a drop in brain performance, even worsening logical reasoning.
Treatment of benign prostatic hyperplasia (HPB) is indicated for patients with moderate / severe symptoms. However, when the improvement of symptoms is not adequate, the surgery imposes itself.
Recent medical literature shows that inhibiting the action of 5α-DHT (dihydrotestosterone) causes a change in the function of liver cells, pancreatic ß cells (which produce insulin), tear glands and renal physiology. Several studies show that the intracellular drop in DHT is related to the administration of Finasteride e Dutasteride.
They are often prescribed to reduce lower urinary tract symptoms (LUTS) Of the HPB or alopecia. Generally, patients use it for a long time, if not for a lifetime. Treatment can cause non-alcoholic fatty liver disease, insulin resistance, diabetes type 2, dry eye disease, kidney damage and other metabolic disorders.
Alteration of androgens and glucocorticoids disrupts lipids and carbohydrates. Thus, when used, it is important to monitor susceptible organs.
5α-Rs are highly expressed in the liver and the inhibition of these enzymes has adverse metabolic consequences. Dutasteride causes insulin resistance and accumulation of liver lipids, decreased lipid mobilization of adipose tissue, without affecting peripheral insulin sensitivity.
These findings suggest that deficiencies of 5α-R or its pharmacological inhibition contribute to the appearance of insulin resistance e Hepatic steatosis. In a population study, men with fatty liver had a reduction in the relative excretion of cortisol metabolites and accumulation of liver fat. In addition, increased expression of the type 5 1α-Rs protein in the liver caused steatohepatitis. Thus, transaminases, TGO and TGP, increase during the first 3 years, revealing the onset of liver inflammation.
They irreversibly inhibit the action of 5α-Rs, decreasing the clearance rates of glucocorticoids, androgens and mineralocorticoids. These metabolic changes potentiate lipid dysregulation and the accumulation of fat in the liver. Therefore, it promotes insulin resistance and the beginning of d Type 2.
Insulin sensitivity is impaired in several organs such as the use of Dutasteride. It is more important for muscle and fat metabolism. Adverse changes to insulin resistance can be caused by difficulty in eliminating glucose, especially in the muscle where there is type 5α-R.
In 230 men treated with Dutasteride followed for 36 to 42 months, there was an increase in blood glucose, glycosylated hemoglobin, total cholesterol and HDL (good cholesterol). In addition, it increased the enzymes TGO and TGP. Therefore, indicating the appearance of liver dysfunction.
The onset of diabetes occurred during the monitoring of 3.600 men for 5,2 ± 3,1 years. Diabetes reached 15% after 10 years. The risk of type 2 diabetes was higher for patients who received 5α-reductase inhibitors compared to Tamsulosin (risk ratio = 1,34), that is, a 34% increase. However, another study did not confirm these findings.
A androgen deficiency reduces tear production. THE Finasteride decreased androgen receptors in the lacrimal gland. Thus, the tear flow decreases around 50%, accompanied by intense infiltration of inflammatory cells.
Specifically, there is an increase in the expression of inflammatory markers, B-72, interleukin (IL) -1β, IL-4, IL-6, IL-10, matrix metalloproteinase-8, Fas ligand, tumor necrosis factor (TNF) - α and metalloproteinase 1 inhibitor, in the lacrimal gland of the patient with dry eye.
Androgen receptors occur in most nephron cells. Androgen deprivation therapy or its inhibition can affect kidney function. Recently it has been shown that Finasteride decreases the expression of androgen receptor in the cortex of the kidney.
The treatment resulted in the reduction of the androgen receptor in the cells of the renal corpuscle (0,06% ± 0,03%) compared to untreated animals (0,14% ± 0,12%). Likewise, the percentage of RA-positive cells in the proximal contoured tubule treated with Finasteride also showed a marked reduction compared to controls (0,16% ± 0,17% vs. 0,69% ± 0,32%, respectively ).
The decrease in the expression of androgen receptor led to histopathological changes in the renal cortex, such as apoptosis, fibrosis and mononuclear cell infiltration. The treatment increased glomerulosclerosis, tubulointerstitial fibrosis and mononuclear cell infiltration. Possibly, the lesions may be more intense in patients with hypertension and diabetes.
In the target cells, both testosterone and 5α-DHT interact with the androgen receptor (RA). However, 5α-DHT binds to RA, with 10 times greater affinity compared to atsteroid. This major difference makes 5α-DHT the critical androgenic modulator in many tissues and, therefore, its inhibition may result in a state of cellular intracellular androgen deficiency.
The binding of 5α-DHT to RA results in activation and consequent transformation into a complex with greater affinity to DNA. After this phase, therefore, it moves from the cytoplasm to the cell nucleus. There, they interact with the elements that respond to the action of androgens. This linkage activates DNA sequences that regulate specific genes. The 5α-reductase inhibitors decrease DHT and therefore reduce cellular metabolism. Thus, there is a fall in the Testosterone target tissues.
One example is the role of 5α-DHT in maintaining erectile physiology. Men treated with Finasteride or Dutasteride for HPB or alopecia have a higher risk of erectile dysfunction, loss of libido and ejaculatory dysfunction. Thus, these changes are more significant compared to placebo, however, the greatest deterioration is the ejaculatory.
The biosynthesis of 5α-DHT impairs the growth of the corpora cavernosa, the relaxation of the smooth trabecular muscle, the endothelial function of the vessels. Therefore, they lead to increased collagen deposition, that is, they cause fibrosis.
All of these changes culminate in the erectile dysfunction, even in the presence of physiological blood testosterone levels. However, there is a variation in these side effects among patients.
It is interesting to note that in most cases, neither the patient nor the doctor is aware that erectile deficiency was caused by the use of these drugs. In addition, 5α-DHT is critical to activate gene expression in nitric oxide synthetases, neuronal and endothelial, which are indispensable mediators for erection to occur.
A second example for the critical role of 5α-DHT is related to fertility. The progression of spermatogenesis is reduced in men without the expression of 5α-R type 2, thus suggesting that the decrease in 5α-reductase is critical for spermatogenesis.
The role of DHT it is important and indisputable for prostate growth and penile physiology. In addition, recent literature has highlighted the role of DHT in liver function, in the pancreatic ß cell, in the eye and in the kidney. This introduced a new paradigm. Therefore, although testosterone is the most important blood androgen, its derivative, DHT is the most potent intracellular androgen.
More recently, its cellular actions are being known. However, the skeletal system is not entirely dependent on the transformation of testosterone to DHT for your action. If they were, atrophy and, consequently, pronounced muscle weakness would occur.
The inhibition of 5α-DHT biosynthesis occurs through an irreversible 5α-Rs inhibition mechanism. Therefore, it induces a new form of androgen deficiency which results in physiological changes not yet well known.
Finasteride and Dutasteride act by inhibition, with a slow and almost irreversible dissociation rate. Therefore, once they are linked to the active site, they are strongly linked to the enzyme, resulting in long-lasting inactivation of 5α-reductase.
It is worth mentioning that the initial clinical trials that recruited a huge number of patients in the research for approval of these drugs failed to detect these metabolic disorders. Apparently, possibly because its manifestations are late, appearing years after the beginning of its use.
Gild et al identified 82.938 men over 66 years of age diagnosed with prostate cancer located in the Medicare databases, from 1992 to 2009. In this study, patients with non-alcoholic fatty liver disease preexisting liver disease, diabetes or metabolic syndrome were excluded.
Androgen therapy has caused more diagnoses of non-alcoholic fatty liver disease (HR = 1,54), cirrhosis (HR = 1,35), necrosis (HR = 1,41) and any liver disease (HR = 1,47), compared to men without androgenic treatment. Therefore, they suggest that androgen deficiency is independently associated with non-alcoholic fatty liver disease.
Os androgens increase insulin receptor expression and activity, glycogen synthesis and cholesterol synthesis and absorption in the liver. Thus, androgens suppress the formation of fat, the uptake of glucose and the removal of cholesterol in the liver. They predispose to the development of steatosistherefore, from non-alcoholic fatty liver disease.
This pathology is an important metabolic complication and represents a spectrum of pathologies that include the accumulation of triglycerides, fat (steatosis), diffuse inflammation or non-alcoholic hepatitis, which can progress to fibrosis and cirrhosis.
Recent studies show a new situation of action of 5α-reductase inhibitors. Therefore, one must investigate the main cause of diseases or organic deficiencies in the lives of the elderly. These changes, initially sub-clinical, may be related to the treatment of BPH.
The concern is important, since diseases increase at this stage of life. Therefore, these drugs considered safe, can be the root of complex medical problems, and can even put their lives at risk.
Consequently, this new paradigm of 5α-reductase inhibitors must be under medical investigation.
However, if you would like to know more about this and other diseases of the genitourinary tract, access our content area for patients to understand and gain knowledge. There are more than 140 articles on various urological subjects available for your reading. Culture always makes a difference. You will be surprised!
The impact of the bladder wall thickness on the outcome of the medical treatment using alpha-blocker of BPH patients with LUTS. https://pubmed.ncbi.nlm.nih.gov/25295872/
Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It's Time to Sound the Alarm. https://pubmed.ncbi.nlm.nih.gov/32202088/
Traish AM. Negative Impact of Testosterone Deficiency and 5α-Reductase Inhibitors Therapy on Metabolic and Sexual Function in Men. Adv Exp Med Biol. 2017; 1043: 473-526. https://pubmed.ncbi.nlm.nih.gov/29224108/
European Urology association. https://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/