¿Tiene el tratamiento previo con inhibidores de la 5-alfa reductasa repercusión en la enucleación prostática con láser holmium? Resultados de un estudio prospectivo observacional y revisión de la literatura / Evaluating the effects of preoperative treatment with 5-alpha reductase inhibitors in holmium laser enucleation of the prostate

Introducción y objetivos Los pacientes tratados con HoLEP frecuentemente han recibido tratamientos previos, incluyendo los inhibidores de la 5-alfa-reductasa (5ARI). Nuestro objetivo es evaluar el efecto del tratamiento previo con 5ARI en los parámetros perioperatorios y del postoperatorio immediato en pacientes tratados con HoLEP. Materiales y métodos Se ha llevado a cabo un estudio retrospectivo utilizando una base de datos recogida prospectivamente, de todos los pacientes tratados con HoLEP en nuestro centro entre enero de 2017 y enero de 2023. Se han analizado los gramos de resección, la eficiencia de enucleación y morcelación (gramos enucleados/tiempo de enucleación y gramos de morcelación/tiempo de morcelación), las complicaciones postoperatorias, el tiempo de hospitalización y el descenso de hemoglobina. Resultados Se han incluido 327 pacientes; 173 de ellos (52,9%) fueron tratados con 5ARI. Entre los parámetros perioperatorios estudiados para determinar la eficiencia no se encontraron diferencias. No se observaron diferencias en las complicaciones peri o postoperatorias, estancia hospitalaria o descenso de hemoglobina. Conclusiones El uso de 5ARI no tuvo repercusión en el postoperatorio immediato de los pacientes tratados con HoLEP. En nuestra cohorte el uso de 5ARI no ha demostrado alterar la eficiencia quirúrgica, ni en la enucleación ni en la morcelación. Futuros estudios multicéntricos serán necesarios para corroborar estos hallazgos. (AU)

Introduction and aim Patients treated with HoLEP are frequently treated with previous treatments, including 5-alpha-reductase inhibitors (5-ARIs). We investigated the impact of pretreatment with 5-ARIs on perioperative and immediate postoperative parameters in patients treated with HoLEP. Material and Methods A retrospective study was performed using a prospectively collected database including all patients treated with HoLEP at our center between January 2017 and January 2023. The resected tissue weight, enucleation and morcellation efficiency (enucleation weight/time and morcellation weight/ time), postoperative complications, hospital stay and hemoglobin drop have been analyzed. Results A total of 327 patients were included. Of these, 173 (52.9%) were treated with 5-ARIs. No differences were found among the perioperative parameters investigated to determine efficiency. No differences were observed in peri- or postoperative complications, hospital stay or hemoglobin drop. Conclusions Therapy with 5-ARIs had no impact on the immediate postoperative outcomes of patients treated with HoLEP. In our cohort, we observed that the use of 5-ARIs did not affect surgical efficiency, enucleation or morcellation. Further multicenter studies will be necessary to validate these findings. (AU)

Effects of testosterone administration (and its 5-alpha-reduction) on parenchymal organ volumes in healthy young men: findings from a dose-response trial.

Animal data shows that testosterone administration increases the volume of some parenchymal organs. However, the effects of exogenous testosterone on solid abdominal organs in humans remain unknown. The present study evaluated the effects of testosterone administration on the volume of liver, spleen and kidneys in a dose-response trial. Young healthy men aged 18-50 years participating in the 5α-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone secretion and weekly injections of 50, 125, 300 or 600 mg of testosterone enanthate, and were randomized to receive either 2.5 mg dutasteride (5 α-reductase inhibitor) or placebo daily for 20 weeks. Liver, spleen and kidney volumes were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose-effect of testosterone on changes in the volume of parenchymal organs was evaluated by linear regression model. The association between changes in total testosterone (TT) levels and changes in organ volumes were assessed. Testosterone administration increased liver volume dose-dependently (17.4 cm3 per 100 mg of weekly testosterone enanthate; p = 0.031); the increase in liver volume was positively associated with changes in TT levels (R2  = 0.08, p = 0.024). A dose-dependent, but non-significant, increase in kidney volumes was also seen. Inclusion of dutasteride use into the models showed an independent association of randomization to dutasteride group with liver volume increase. In conclusion, Testosterone administration increased the liver volume in a dose-dependent manner. The potential changes in parenchymal organs should be considered when interpreting apparent changes in lean mass in response to anabolic interventions.

Do alpha-reductase inhibitors prevent prostate cancer? 2008 practice guideline from the American society of clinical oncology and American urological association.

As new guidelines on the use of 5-alpha-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention produced by the American Society of Clinical Oncology (ASCO) and American Urological Association (AUA) have recently been published, the use of 5-ARIs is becoming of increasing interest. We analyzed the current evidence to support the use of 5-ARIs in the prevention of prostate cancer. We therefore compared the new guidelines of the ASCO and AUA with the current data concerning the use of 5-ARIs in the prevention of prostate cancer. At present, there is still an open debate going on whether or not it is advisable to incorporate the use of 5-ARIs as chemopreventive agents in daily practice.

Aromatase-independent testosterone conversion into estrogenic steroids is inhibited by a 5 alpha-reductase inhibitor.

Estrogens are generated mainly by the action of aromatase, which converts testosterone to estradiol and androstenedione to estrone. However, in addition to estradiol and estrone, a variety of other steroids, whose synthesis is not dependent on aromatase, can stimulate the estrogen receptor. Here we show that testosterone is converted into such estrogenic steroids by aromatase-negative HeLa cells. This aromatase-independent generation of estrogenic steroids is seen in aromatase-positive MCF-7 cells as well. In both cell lines, the synthesis of estrogenic steroids was blocked by inhibition of testosterone conversion into dihydrotestosterone using a 5 alpha-reductase inhibitor finasteride, suggesting that they are generated downstream of dihydrotestosterone. This finding raises the possibility that the combination of a 5 alpha-reductase inhibitor and an aromatase inhibitor may reduce estrogenic steroids in vivo more completely than an aromatase inhibitor alone.

Anabolic effects of androgens on muscles of female pelvic floor and lower urinary tract.

PURPOSE OF REVIEW: This review discusses recently published data concerning the anabolic effects of androgens on muscle and the mechanism by which testosterone regulates body composition with special emphasis on the anabolic effects of androgens on the muscles of the pelvic floor and lower urinary tract. RECENT FINDINGS: Androgens have direct anabolic effects on skeletal muscle. Testosterone increases lean body mass and decreases fat mass in a dose- and concentration-dependent fashion. The action of testosterone on muscle involves multiple mechanisms, including its effects on inducing protein synthesis, recruiting satellite cells, and modulating the commitment of pluripotent mesenchymal cells to myogenic lineage. Levator ani and other muscles of the pelvic floor and lower urinary tract are sensitive to the anabolic effects of testosterone. Androgen receptors are also expressed in the pelvic floor and lower urinary tract of both animals and humans. Anabolic effects of androgens may play an important role in the female pelvic-floor and lower-urinary-tract disorders. Furthermore, the interactions between androgen and nitric oxide synthase and arginase have been demonstrated, suggesting that androgens may also participate in modulating the physiological functions of lower urinary tract through nitric oxide. SUMMARY: Androgens induce muscle hypertrophy and reduce fat mass. The action of androgens in the lower urinary tract and pelvic floor is complex and may depend on their anabolic effects, hormonal modulation, receptor expression, interaction with nitric oxide synthase, or a combination of these effects. Further studies are needed to determine the precise role of androgens in women with urinary incontinence and pelvic organ prolapse.

Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line.

BACKGROUND: Reduction of T to DHT by 5alphaR in the prostate enhances androgenic activity for most targets. Inhibition of 5alphaR activity with finasteride attenuates androgen action in men and animal models. The objective of this study was to compare and contrast the effects of a potent new 5alphaR inhibitor, dutasteride, with finasteride in the LNCaP prostate cancer cell line. METHODS: LNCaP cells were incubated for varying times with T or DHT in steroid-free medium in the absence or presence of increasing doses of dutasteride or finasteride and the effects on 5alphaR activity, PSA accumulation in the medium, and on cell proliferation were determined. Drug effects on apoptosis were investigated using Annexin V staining and a cell death ELISA assay. Effects of the drugs on AR ligand-binding activity and on AR protein levels were determined. RESULTS: Dutasteride inhibited (3)H-T conversion to (3)H-DHT and, as anticipated, inhibited T-induced secretion of PSA and proliferation. However the drug also inhibited DHT-induced PSA secretion and cell proliferation (IC(50) approximately 1 microM). Finasteride also inhibited DHT action but was less potent than dutasteride. Dutasteride competed for binding the LNCaP cell AR with an IC(50) approximately 1.5 microM. High concentrations of dutasteride (10-50 microM), but not finasteride, in steroid-free medium, resulted in enhanced cell death, possibly by apoptosis. This was accompanied by loss of AR protein and decreased AR ligand-binding activity. Occupation of AR by R1881 partly protected against cell death and loss of AR protein. PC-3 prostate cancer cells, which do not contain AR, also were killed by high concentrations of dutasteride, as well as by 50 microM finasteride. CONCLUSIONS: Dutasteride exhibited some inhibitory actions in LNCaP cells possibly related to 5alphaR inhibition but also had antiandrogenic effects at relatively low concentrations and cell death-promoting effects at higher concentrations. Finasteride also was antiandrogenic, but less than dutasteride. The antiandrogenic effects may be mediated by the mutant LNCaP cell AR. Promotion of cell death by dutasteride can be blocked, but only in part, by androgens.

La hipertrofia benigna de próstata y los alfabloqueantes / Benign prostatic hypertrophy and alpha blockers

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Pharmacokinetics and pharmacodynamics of TF-505, a novel nonsteroidal 5alpha-reductase inhibitor, in normal subjects treated with single or multiple doses.

AIMS: To assess the tolerability, pharmacokinetics and pharmacodynamics of a novel nonsteroidal and noncompetitive inhibitor of type I and type II 5alpha-reductases, (-)-(S)-4-[1-[4-[1-(4-isobutylphenyl) butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), after single and multiple oral doses in healthy volunteers. METHODS: In the single-dose study, six young adult males in each dose group received 25 mg or 50 mg of TF-505, and six older males (>or= 40 years) in each dose group received 75 mg or 100 mg of TF-505. The subjects were given the drug in ascending dose and in the fasting state. Six subjects also received 50 mg of TF-505 after breakfast in a two-period crossover manner. In the multiple-dose study, six older males in each dose group received 12.5 mg or 25 mg TF-505 after breakfast daily for 7 days. Plasma concentrations of TF-505, dihydrotestosterone (DHT) and testosterone were measured. The pharmacokinetics of TF-505 were analysed by a compartment model with first-order absorption, first-order elimination and a lag time. Pharmacokinetic and pharmacodynamic relationships were evaluated by indirect response modelling with inhibition of input. RESULTS: Maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased proportionately after the single dose up to 50 mg and with the multiple doses. Linearity was not detected between 75 and 100 mg of TF-505. Dose dependency was also noted for the effect of TF-505 on DHT concentrations following single doses up to 50 mg and multiple doses. Plasma DHT concentrations decreased maximally to 58.2, 49.5, 54.2 and 49.8% of basal values at 8-12 h after single administration of 25, 50, 75 and 100 mg TF-505, respectively, and to 60.5 and 49.4% at the 7th and 5th dose following multiple doses of 12.5 and 25 mg TF-505, respectively. The predicted effect curves matched the observed data when the indirect response model was applied to the time course of the suppressant effect of TF-505 on plasma DHT concentrations after both the single and multiple studies. Fifty percent inhibitory concentrations (IC50) of 0.82, 1.48, 1.31 and 0.88 micro g ml(-1), zero-order rate constants for the onset of plasma DHT concentration changes (kin) of 17.8, 17.4, 17.0 and 10.7% h(-1) and first-order rate constants for increase in plasma DHT concentrations to basal values (kout) of 0.17, 0.16, 0.17 and 0.10 h(-1) for the single study at doses of 25, 50, 75 and 100 mg, respectively, were attained. In the multiple-dose study, IC50s were 1.74 and 1.49 micro g ml(-1) for the 12.5 and 25 mg doses, respectively. No serious adverse events related to TF-505 were observed. CONCLUSIONS: TF-505 was well tolerated in healthy male volunteers. Accumulation of TF-505 in plasma was not observed during multiple dosing. The indirect response model described the relationships between pharmacokinetics and pharmacodynamics of TF-505. Such modelling is expected to yield an appropriate dosage regimen in subsequent clinical trials.

[Androgenetic alopecia]. / L'alopécie androgénogénétique.

Androgenetic alopecia (AGA) is the combined result of an androgen-dependent process and genetic transmission. These characteristics have mainly, if not exclusively, been demonstrated in men and perhaps improperly extended to women. When considering the androgen-dependent process, AGA must only be limited to the androgen receptor areas. In the scalp, these receptors have only been detected in the frontal and vertex areas but never in the temporal or the occipital areas. Male AGA exhibits these clinical features, whereas in women hair loss is rarely limited to this localization, even when large areas of hair loss often appear with age. It is now commonly accepted that male AGA is associated with an increase in 5 alpha reductase activity leading to an increase in local production of dihydrotestosterone. The mechanism by which the local dihydrotestosterone increase leads to hair follicle loss is not clearly demonstrated. Inhibition of cell proliferation in the dermal papilla and a vascular process based on the inhibition in local production of vascular endothelial growth factor (VEGF) have been proposed. The increase in 5 alpha reductase activity is genetic and depends on androgen receptor polymorphism, characterized by a decrease in the number of CAG sequences on the exon 1. Male AGA is associated with an insulin-resistant process and to a higher risk of polycystic ovary in the lineage. Therapeutically, this hormone-dependent process explains the well demonstrated efficacy of 5 alpha reductase inhibitors. In women, except in some rare cases, alopecia is diffuse and the mechanisms are different. Their origin is unknown, and probably ambiguous. Based on an association with Hashimoto's thyroiditis, an auto-immune origin could be suggested in some cases. Alopecia is unaffected by thyroid substitution. Pharmacological doses of oestrogens (pregnancy, contraception) have a beneficial effect on such alopecia, probably through different mechanisms: anti-androgen effect, increased VEGF, proliferative effect of dermal papilla cells. However, it is important to mention that the dermal papilla has an aromatase, particularly in the occipital area, the activity of which has not been assessed in female alopecia. In practice 5 alpha reductase inhibitors are ineffective in women. It is likely that the predominance observed in the frontal and vertex areas, occasionally in elderly women, is a result of the two combined disorders, the almost physiological androgen-dependent hair loss combined with diffuse loss. Pharmacological doses of oestrogens associated with anti-androgen progesterone-like agents are widely used with positive results, but not demonstrated by clinical trials.

A five-alpha reductase inhibitor or an antiandrogen prevents the progression of microscopic prostate carcinoma to macroscopic carcinoma in rats.

BACKGROUND: The objective of this study was to elucidate the prophylactic effects of 5-alpha reductase inhibitor (e.g., finasteride) and a pure antiandrogen (e.g., casodex) on rat prostate carcinogenesis and to determine whether latent prostate carcinoma can be prevented to develop to clinically significant cancer by use of these drugs. METHODS: F344 rats were subcutaneously administered 3,2'-dimethyl-4-aminobiphenyl (DMAB) for the first 20 weeks and testosterone propionate throughout the 60-week study. Finasteride (5 mg/kg and 15 mg/kg, 2 times per week) and casodex (15 mg/kg, 30 mg/kg, and 60 mg/kg, 3 times per week) were administered orally during the last 40 weeks of the study. Tumors were classified as visible prostate carcinoma when they could be recognized with the naked eye and as microscopic prostate carcinoma when detectable only with a microscope. RESULTS: The incidence of visible prostate carcinoma was 51% (18 of 35 rats) in the positive control group, whereas it was 40% (4 of 10 rats) in the finasteride 5 mg/kg group, 16.7% (2 of 12 rats, P = 0.0091) in the finasteride 15 mg/kg group, 20% (4 of 20 rats, P = 0.05) in the casodex 15 mg/kg group, 14.3% (3 of 21 rats, P = 0.0008) in the casodex 30 mg/kg group, and 0% (0 of 11 rats, P = 0.0002) in the casodex 60 mg/kg group. On the other hand, when visible carcinomas and microscopic carcinomas were handled together, only casodex 60 mg/kg significantly inhibited the carcinogenesis rate. CONCLUSIONS: Finasteride achieved dose-dependent inhibition of macroscopic rat prostate carcinogenesis, and casodex also inhibited macroscopic prostate carcinogenesis. However, both drugs showed insufficient prevention of carcinogenesis at the microscopic level. These findings indicate that, in clinical medicine as well, such drugs may also be able to prevent the progression of latent prostate carcinoma to life-threatening disease.

Lack of influence of aromatase and 5 alpha-reductase inhibition on [3H]imipramine binding in the male rat brain.

In intact adult male rats an inhibitor of aromatase and an inhibitor of 5 alpha-reductase did not change the characteristics of [3H]imipramine binding sites in cerebral cortex, hypothalamus, and hippocampus. Testosterone, estradiol and dihydrotestosterone prevented the effect of castration on the number of [3H]imipramine binding sites, but had no effect in non-castrated animals. These data suggest that testosterone and its major metabolites, estradiol and dihydrotestosterone, are equally effective with regard to imipramine binding sites.