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PubMed2005

New 5alpha-reductase inhibitors: in vitro and in vivo effects.

The enzyme 5alpha-reductase is responsible for the conversion of testosterone (T) to its more potent androgen dihydrotestosterone (DHT). This steroid had been implicated in androgen-dependent diseases such as: benign prostatic hyperplasia, prostate cancer, acne and androgenic alopecia. The inhibition of 5alpha-reductase enzyme offers a potentially useful treatment for these diseases. In this study, we report the synthesis and pharmacological evaluation of several new 3-substituted pregna-4, 16-diene-6, 20-dione derivatives. These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological activity of the new steroidal derivatives was determined in vivo as well as in vitro experiments. In vivo experiments, the anti-androgenic effect of the steroids was demonstrated by the decrease of the weight of the prostate gland of gonadectomized hamster treated with T plus finasteride or the new steroids. The IC50 value of these steroids was determined by measuring the conversion of radio labeled T to DHT. The results of this study carried out with 5alpha-reductase enzyme from hamster and human prostate showed that four of the six steroidal derivatives (5, 7, 9, 10) exhibited much higher 5alpha-reductase inhibitory activity, as indicated by the IC50 values than the presently used Proscar 3 (finasteride). The comparison of the weight of the hamster's prostate gland indicated that compound 5 had a comparable weight decrease as finasteride. The overall data of this study showed very clearly those compounds 5, 7, 9, 10 are good inhibitors for the 5alpha-reductase enzyme.

Androgen Antagonists↗
PubMed1999

Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group.

OBJECTIVES: Prostate-specific antigen (PSA) is produced exclusively in the prostate gland and is currently the most useful clinical marker for the detection of prostate cancer. In this report, we examine whether serum PSA is also a predictor of important benign prostatic hyperplasia (BPH)-related outcomes, acute urinary retention (AUR), and the need for BPH-related surgery. METHODS: Three thousand forty men were treated with either placebo or finasteride in a double-blind, randomized study of 4-year duration. Serum PSA was measured at baseline, and baseline prostate volume was measured in a 10% subset of 312 men. Probabilities and cumulative incidences of AUR and BPH-related surgery, as well as reduction in risk of events with finasteride, were calculated for the entire patient population, stratified by treatment assignment, baseline serum PSA, and prostate volume. RESULTS: The risk of either needing BPH-related surgery or developing AUR ranged from 8.9% to 22.0% during the 4 years in placebo-treated patients stratified by increasing prostate volume and from 7.8% to 19.9% when stratified by increasing serum PSA. In comparison with symptom scores, flow rates, and residual urine volume, receiver operating characteristic curve analyses showed that serum PSA and prostate volume were the most powerful predictors of spontaneous AUR in placebo-treated patients (area under the curve 0.70 and 0.81, respectively). Finasteride treatment reduced the relative risk of needing surgery or developing AUR by 50% to 74% and by 43% to 60% when stratified by increasing prostate volume and serum PSA, respectively. CONCLUSIONS: Serum PSA and prostate volume are powerful predictors of the risk of AUR and the need for BPH-related surgery in men with BPH. Knowledge of baseline serum PSA and/or prostate volume are useful tools to aid physicians and decision makers in predicting the risk of BPH-related outcomes and choosing therapy for BPH.

Acute Disease↗
PubMedDate not supplied

The impact of different therapies on symptoms of benign prostatic hyperplasia: a prospective study.

We conducted an observational study to evaluate prospectively the effectiveness of four modes of treatment for benign prostatic hyperplasia (BPH)-watchful waiting, alpha-blocker therapy, finasteride therapy, and surgery (transurethral prostatectomy). A total of 1459 men aged 48 to 84 years, who were diagnosed for the first time by physicians as having BPH in 1994 and who had not received treatment, participated in the study. During 1 year of follow-up, 1064 (72.9%) men remained on no treatment (watchful waiting), 156 (10.7%) were treated with finasteride, 198 (13.6%) were treated with an alpha-blocker, and 41 (2.8%) underwent prostatectomy. The American Urological Association (AUA) Symptom Index was administered to the cohort before the initiation of treatment in 1994, as well as 1 year later. Improvements in lower urinary tract symptoms, as measured by the AUA Symptom Index, were assessed using linear and logistic regression, adjusting for age and baseline. Men who underwent prostatectomy reported the biggest improvements in lower urinary tract symptoms, whether assessed by mean changes in symptom scores relative to no treatment (-5.44; 95% confidence interval [CI]-6.91 to -3.97) or by the odds of improving by 5 or more points on the AUA Symptom Index (odds ratio, 12.66; 95% CI, 5.93 to 27.0). Irrespective of the initial degree of symptom severity, prostate surgery resulted in larger improvements than those reported for either finasteride or alpha-blocker therapy. In this prospective, observational study, prostatic surgery was associated with statistically and clinically significant improvements in BPH symptoms.

Adrenergic alpha-Antagonists↗
PubMed2001

Efficacy and tolerability of drugs for treatment of benign prostatic hyperplasia.

It has long been recognised that neural factors are of considerable importance in lower urinary tract function. Whilst reduction in the bulk of the human prostate is feasible, experience on this therapeutic approach proved to be disappointing. Existing trial data with the agent finasteride are reviewed. A number of formulations derived from plant extracts have been advocated but their mechanism of action remain largely obscure and there is a dearth of placebo controlled information to support their efficacy. Experience over the last 10 years has demonstrated efficacy with the use of alpha adrenoceptor blockade in the management of BPH. Alpha adrenoceptor antagonists relax the prostatic smooth muscle by interrupting the sympathetic pathway at the receptor level. Recent developments in this field include the recognition that there are alpha I adrenoceptor subtypes. The functional adrenoceptor in the human prostate is predominantly the alpha IA - subtype. Of the alpha 1-adrenoceptor antagonists only tamsulosin discriminates between the alpha 1-adrenoceptor subtypes. Alpha 1-blockers should be used in first-line medical therapy for BPH and 5-alpha-reductase inhibitors reserved for those patients in whom alpha-blocker therapy fails. Alpha I-blockers such as doxazosin, tamsulosin, terazosin, alfuzosin are effective in the treatment of BPH both in younger and in older men. The drugs are well tolerated. The majority of side effects were classified as minor and mild. The most common complaints, as with other alpha-blockers, are dizziness, fatigue and headache, and these are often transient. In contrast, finasteride can lead to impotence, reduced libido. gynaecomastia or ejaculatory disorders. Men with small prostates may not be suitable candidates for finasteride therapy.

Adrenergic alpha-Antagonists↗
PubMed2004

Propecia-associated bilateral cataract.

A 43-year-old man presented suffering from decreasing vision in both eyes for 3 months. The patient's visual acuity was 6/20 (non-corrected) in the right eye and 6/10 (-1.75/-1.00 x 91) in the left. Ocular examination of both eyes revealed anterior subcapsular opacities of both lenses with the right eye being more severe than the left. He had been taking finasteride (Propecia; Merck, Sharp and Dohme) at 1 mg/day for 3 years to treat early stage of androgenic alopecia. It was highly suspected that finasteride was associated with the anterior subcapsular opacity on the lens, and the patient therefore discontinued use of finasteride. He underwent uneventful cataract extraction surgery and intraocular lens implantation of the right eye. One month after cataract surgery in the right eye, the best-corrected visual acuity was right 6/6 (-1.25) and left 6/10 (-2.00/-0.50 x 100). To the best of the authors' knowledge, this is the first reported case of Propecia-associated cataract.

Adult↗
PubMed1999

Modulation of steroidal levels by adrenalectomy/castration and inhibition of neurosteroid synthesis enzymes affect sigma1 receptor-mediated behaviour in mice.

The interaction between neurosteroids and sigma1 (sigma1) receptors may be of therapeutic interest during physiological or pathological ageing, particularly concerning their neuromodulatory role on cognitive functions. Neurosteroids modulate memory processes through a mechanism involving interactions with GABAA, N-methyl-D-aspartate and/or sigma1 receptors. To measure the contribution of endogenous neurosteroid levels to the antiamnesic effects of sigma1 agonists, we investigated the effects of inhibitors of key enzymes involved in neurosteroid synthesis, in adrenalectomized/castrated (AdX/CX) mice to avoid the effect of circulating steroids. Trilostane, a 3beta-hydroxysteroid-deshydrogenase inhibitor, blocks the pregnenolone to progesterone conversion and leads to a decrease of progesterone. Finasteride, a 5alpha-reductase inhibitor, blocks the progesterone to 5alpha-pregnane-3,20-dione conversion and leads to an accumulation of progesterone. The in vivo binding of (+)-[3H]SKF-10 047 to sigma1 sites was measured in the mouse hippocampus and cortex. The attenuating effect of the selective sigma1 agonist PRE-084 (0.1-3 mg/kg) against dizocilpine (0.15 mg/kg)-induced learning impairment was examined using spontaneous alternation behaviour, step-down passive avoidance and place learning in the elevated plus-maze. The in vivo (+)-[3H]SKF-10 047 binding appeared significantly increased in AdX/CX mice and after trilostane treatment (10 mg/kg twice a day, 7 days), compared with sham-operated animals. The finasteride treatment (25 mg/kg, 7 days) significantly decreased binding levels. The learning deficits induced by dizocilpine were not affected by the treatments. The antiamnesic effect of PRE-084 was facilitated in AdX/CX mice and even more after trilostane treatment, as several parameters for animals treated with both PRE-084 and dizocilpine returned to control values. The PRE-084 effect was blocked after finasteride. These results confirmed that endogenous neurosteroidal levels modulate sigma1 receptor-mediated behaviour directly, and revealed that, among neurosteroids, progesterone may be the main modulator of sigma1 receptors.

Adrenalectomy↗
PubMed1991

Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase.

Dihydrotestosterone, the primary mediator of prostate growth, is synthesized in target tissues from the circulating androgen testosterone through the action of steroid 5 alpha-reductase (EC 1.3.99.5). The expression of 5 alpha-reductase and the level of 5 alpha-reductase messenger RNA in rat ventral prostate are regulated by androgens. To determine whether this control is mediated by dihydrotestosterone or testosterone, we investigated the effect of finasteride, a potent inhibitor of steroid 5 alpha-reductase, on the expression of 5 alpha-reductase in the prostate. The administration of finasteride to intact rats for 7 days caused a 55% decrease in prostate weight and an 87% decrease in 5 alpha-reductase enzyme activity. Furthermore, the restoration of prostate growth after castration and the enhancement in 5 alpha-reductase enzyme activity and 5 alpha-reductase messenger RNA level by testosterone administration were blocked by finasteride, whereas the inhibitor had no effect on dihydrotestosterone-mediated increases in 5 alpha-reductase activity or messenger RNA level. These findings indicate that dihydrotestosterone itself controls prostate growth and 5 alpha-reductase activity. They further suggest that prostate growth is controlled by a feed-forward mechanism by which formation of trace amounts of dihydrotestosterone induces 5 alpha-reductase, thereby increasing dihydrotestosterone synthesis and triggering a positive developmental cascade.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

New progesterone derivatives as inhibitors of 5alpha-reductase enzyme and prostate cancer cell growth.

In this study we report the synthesis and pharmacological evaluation, in vivo as well as in vitro, of four new progesterone derivatives 4-7. The evaluation in vivo was carried out on gonadectomized male hamsters that were injected subcutaneously daily with 1 mg/Kg of testosterone (T) and/or 1 mg/Kg of finasteride, or with 2 mg/Kg of the novel compounds. It was observed that when testosterone (T) and finasteride or compound 4 were injected together, the weight of the prostate decreased significantly as compared to that oftestosterone-treated animals. Compounds 5-7 did not show any in vivo activity. The 5alpha-reductase inhibitory activity of the novel compounds was determined in vitro using human prostate homogenates; the steroids 4-7 inhibited the 5alpha-reductase activity with IC50 values lower than that for the reference compound finasteride. 3. The effect of compounds 4-7 on the growth of lymphocytes and prostate cancer culture cells line was that steroid 4 inhibited the growth of both cells lines at a concentration of 50 microM and showed a cytotoxic effect whereas compounds 5-7 showed a much lower inhibition. Nevertheless steroids 4-7 didn't exhibit any toxic effects in vivo since the animals remained alive during the six days of treatment.

Animals↗
PubMed2003

5 alpha-reductase inhibitors: what's new?

PURPOSE OF REVIEW: Medical therapy is now the first-line treatment for most men with symptomatic benign prostatic hyperplasia. This review aims to highlight the recent contributions to our understanding of 5 alpha-reductase inhibitor usage. RECENT FINDINGS: For the last decade, finasteride has been the only available 5 alpha-reductase inhibitor, acting upon the type 2 isoenzyme of 5-alpha reductase. Dutasteride is the first drug that can inhibit both isoenzymes and is soon to be available. Biochemically it achieves greater and more rapid dihydrotestosterone suppression compared with finasteride. Clinically, it appears to be at least as good in terms of improving symptoms and flow rates, and reducing the risk of acute urinary retention or the requirement for benign prostatic hyperplasia-related surgery. However, until these two drugs are formally compared, the true benefits of additional type 1 isoenzyme inhibition are unknown. The recently reported Medical Therapy of Prostatic Symptoms trial has convincingly demonstrated superior outcomes with combination therapy compared with monotherapy, unlike previous trials of shorter duration. The ability of 5 alpha-reductase inhibitors to prevent disease progression was also confirmed. Newer roles for 5 alpha-reductase inhibitors are also being defined. Finasteride has been shown to reduce and control benign prostatic hyperplasia-related haematuria, although its value in controlling perioperative bleeding is less clear. Their role as chemopreventive agents for prostate cancer is also under investigation. SUMMARY: Recent studies have both clarified and extended the roles of 5 alpha-reductase inhibitors in benign prostatic hyperplasia, and these may expand further if chemopreventive abilities are proved. In addition, dual isoenzyme inhibition will soon be available.

5-alpha Reductase Inhibitors↗
PubMed2004

Update on chemoprevention of prostate cancer.

PURPOSE OF REVIEW: Prostate cancer remains the most commonly diagnosed visceral cancer in men in the United States, with almost 200,000 newly diagnosed cases in 2003. Prevention of this disease would have a major impact on disease-associated cost, morbidity, and mortality for a large segment of the population. A major advance in prevention of prostate cancer came in 2003 with the publication of the Prostate Cancer Prevention Trial. This overview summarizes the results of that trial, the design of other large-scale trials, and advances in understanding of the molecular mechanisms underlying the effect of other promising agents. RECENT FINDINGS: The Prostate Cancer Prevention Trial demonstrated that use of finasteride is associated with a 25% reduction in the 7-year period prevalence of prostate cancer in men over age 55 years with normal digital rectal exam and initial prostate specific antigen <3.0 ng/ml. Use of finasteride was associated with a slightly higher risk of Gleason sum 7-10 tumors, some sexual side effects, and fewer urinary symptoms. A substantial body of new molecular evidence supports the existing body of clinical and epidemiological data leading to testing of vitamin E and selenium as preventative agents in men at risk for prostate cancer. Epidemiologic and molecular evidence also makes cyclooxygenase-2 inhibitors, lycopene, soy, and green tea promising agents. SUMMARY: Results of a population-based, randomized phase III trial demonstrates that finasteride can prevent prostate cancer. A large amount of data supports the use of other agents as potential preventatives, including selenium, vitamin E, vitamin D, other 5-alpha-reductase inhibitors, cyclooxygenase-2 inhibitors, lycopene, and green tea. Some of these agents are being tested in new large-scale phase III clinical trials.

Aged↗
PubMed2003

Changes in nocturia from medical treatment of benign prostatic hyperplasia: secondary analysis of the Department of Veterans Affairs Cooperative Study Trial.

PURPOSE: We evaluate the efficacy of medical therapy on nocturia in men with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We performed a secondary analysis of data from the VA Cooperative Study Program Trial in which 1,229 men with BPH 45 to 80 years old were randomly assigned to receive terazosin, finasteride, combination or placebo. RESULTS: The 1,078 men who completed 12 months of the trial are included in this study. Of those men 1,040 (96.5%) had at least 1 episode of nocturia at baseline and 38 (3.5%) had less than 1 episode (baseline nocturia is an average of 2 measures). Of those 1,040 men 788 (75.8%) had 2 or more nocturia episodes. Overall, nocturia decreased from a baseline mean of 2.5 to 1.8, 2.1, 2.0 and 2.1 episodes in the terazosin, finasteride, combination and placebo groups, respectively. Of men with 2 or more episodes of nocturia 50% reduction in nocturia was seen in 39%, 25%, 32% and 22% in the terazosin, finasteride, combination and placebo groups, respectively. Changes in nocturia were correlated with changes in reported bother from nocturia (Pearson correlation 0.48), BPH impact index (0.32) and overall satisfaction with urinary symptoms (0.33). CONCLUSIONS: Terazosin and combination therapy reduced nocturia in men with BPH, yet the net advantage of terazosin over placebo was a net reduction of 0.3 nocturia episode. For a person to reach a 50% or greater reduction in nocturia, the advantage of terazosin over placebo was 17 percentage points. Changes in nocturia had a moderate impact on symptom specific quality of life measures.

Adrenergic alpha-Antagonists↗
PubMed2004

The Prostate Cancer Prevention Trial: current status.

PURPOSE: The rationale, design considerations and current status of the Prostate Cancer Prevention Trial (PCPT) are presented. MATERIALS AND METHODS: The design considerations for a prevention study involving finasteride were reviewed. Most notable was the end of study biopsy planned for all participants to eliminate any detection bias caused by the effect of finasteride on prostate specific antigen. RESULTS: During a 3-year period 18,882 men were randomized in the PCPT. The final end of study biopsy is planned for May 2004. The study was closed 15 months before the final anticipated participant biopsy by the independent Data and Safety Monitoring Committee due to a 24.8% reduction in prostate cancer with finasteride. CONCLUSIONS: The extraordinary accrual of PCPT of healthy men in a prospective study to test an intervention for prostate cancer prevention illustrates the potential for future studies. The positive results of the trial as well as many observations that have been made of the study population argue for increased emphasis on prevention research for highly prevalent genitourinary malignancies.

Anticarcinogenic Agents↗
PubMed2006

Pharmacologic basis for the enhanced efficacy of dutasteride against prostatic cancers.

PURPOSE: Prostatic dihydrotestosterone (DHT) concentration is regulated by precursors from systemic circulation and prostatic enzymes of androgen metabolism, particularly 5alpha-reductases (i.e., SRD5A1 and SRD5A2). Therefore, the levels of expression SRD5A1 and SRD5A2 and the antiprostatic cancer growth response to finasteride, a selective SRD5A2 inhibitor, versus the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, were compared. EXPERIMENTAL DESIGN: Real-time PCR and enzymatic assays were used to determine the levels of SRD5A1 and SRD5A2 in normal versus malignant rat and human prostatic tissues. Rats bearing the Dunning R-3327H rat prostate cancer and nude mice bearing LNCaP or PC-3 human prostate cancer xenografts were used as model systems. Tissue levels of testosterone and DHT were determined using liquid chromatography-mass spectrometry. RESULTS: Prostate cancer cells express undetectable to low levels of SRD5A2 but elevated levels of SRD5A1 activity compared with nonmalignant prostatic tissue. Daily oral treatment of rats with the SRD5A2 selective inhibitor, finasteride, reduces prostate weight and DHT content but did not inhibit R-3327H rat prostate cancer growth or DHT content in intact (i.e., noncastrated) male rats. In contrast, daily oral treatment with even a low 1 mg/kg/d dose of the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, reduces both normal prostate and H tumor DHT content and weight in intact rats while elevating tissue testosterone. Daily oral treatment with finasteride significantly (P < 0.05) inhibits growth of LNCaP human prostate cancer xenografts in intact male nude mice, but this inhibition is not as great as that by equimolar oral dosing with dutasteride. This anticancer efficacy is not equivalent, however, to that produced by castration. Only combination of dutasteride and castration produces a greater tumor inhibition (P < 0.05) than castration monotherapy against androgen-responsive LNCaP cancers. In contrast, no response was induced by dutasteride in nude mice bearing androgen-independent PC-3 human prostatic cancer xenografts. CONCLUSIONS: These results document that testosterone is not as potent as DHT but does stimulate prostate cancer growth, thus combining castration with dutasteride enhances therapeutic efficacy.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2000

Prostate volume and serum prostate-specific antigen as predictors of acute urinary retention. Combined experience from three large multinational placebo-controlled trials.

OBJECTIVES: We evaluated prostate volume and prostate-specific antigen (PSA) as predictors of acute urinary retention (AUR) in men with benign prostatic enlargement (BPE). METHODS: Data were pooled from 3 identical 2-year, multinational, multicenter, non-US, placebo-controlled finasteride trials in 4,222 men with BPE and no evidence of prostate cancer. RESULTS: The 2-year incidence of spontaneous AUR was higher in placebo patients with enlarged prostates (4.2% in men with prostate volume > or =40 ml vs. 1.6% in the <40 ml group) and higher PSA levels (3.9% in men with PSA > or =1.4 ng/ml vs. 0.5% in the <1.4 ng/ml group) at baseline. Finasteride reduced AUR incidence by 61% in men with larger prostates, by 63% in men with higher PSA levels, and by 47% in men with smaller prostates, compared with placebo. CONCLUSIONS: BPE patients with larger prostate volumes, higher PSA levels and no evidence of prostate cancer have an increased risk of developing AUR and therefore derive the greatest benefit from the risk reduction seen with finasteride therapy.

Acute Disease↗
PubMed1998

Seizure activity is increased in endocrine states characterized by decline in endogenous levels of the neurosteroid 3 alpha,5 alpha-THP.

To examine the role of progesterone (P) and its 5alpha-reduced metabolite, the neurosteroid 5alpha-pregnan-3alpha-ol-20-one (3alpha, 5alpha-THP), in endogenous variations in ictal activity rats were tested for kainic acid-induced seizures in different hormonal milieu. Corresponding plasma and central P and 3alpha,5alpha-THP levels were measured. Cycling Long-Evans rats in estrus and proestrus had seizures of significantly shorter duration and more central and plasma 3alpha,5alpha-THP and P than animals in metestrus or diestrus. Females with luteal functioning had seizures of significantly shorter duration and increased central and plasma 3alpha,5alpha-THP and P compared to animals that recently had luteal functioning discontinued. Pregnant rats had significantly shorter seizures and greater central and plasma 3alpha,5alpha-THP and central P than animals tested 1-2 days postparturition. In all test paradigms, seizure activity was increased in animals that had decreased 3alpha, 5alpha-THP or P; overall, central 3alpha,5alpha-THP was more inversely related to ictal activity than central P or plasma P and 3alpha,5alpha-THP. To investigate a causal relationship between 3alpha,5alpha-THP and seizures, a 5alpha-reductase inhibitor, finasteride, or vehicle was administered to pregnant rats. Finasteride administration significantly decreased central and plasma 3alpha,5alpha-THP, but had no significant effect on plasma or central P of pregnant rats. Finasteride, but not vehicle administration, to pregnant rats significantly increased seizure duration. These findings support the hypothesis that variations in seizure threshold over endogenous hormonal milieu may be related to endogenous 3alpha,5alpha-THP. Of all of the endocrine conditions, seizure durations were greatest in diestrus animals; this group did not experience the lowest or the greatest decrease in 3alpha, 5alpha-THP concentrations; however, of all of the endocrine conditions, cycling rats experienced the most rapid cycles of 3alpha, 5alpha-THP variation. This suggests that cycles of endogenous variations in 3alpha,5alpha-THP may influence seizure threshold.

Animals↗
PubMed1995

Dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat.

Androgens are essential for the expression of normal libido in the male, but their role in the maintenance of the erectile response in humans is controversial. It has been shown previously in the rat that castration induces 1) loss of penile reflexes; and 2) considerable reduction in the erectile response to electric field stimulation (EFS) of the cavernosal nerve. Both of these effects can be reversed by testosterone replacement. The current study was performed to determine whether these testosterone effects are mediated via its conversion to dihydrotestosterone (DHT), and to what extent the synthesis of the mediator of penile erection, nitric oxide, is affected by castration and androgen replacement. Five-month-old rats were either castrated or left intact. The orchiectomized rats were implanted with SILASTIC brand silicon tubing (Dow Corning) containing testosterone or DHT with or without daily injections of the 5 alpha-reductase inhibitor finasteride. After 7 days, rats were submitted to EFS and the intracavernosal pressure was recorded. Castration reduced the EFS-induced erectile response by 50% in comparison with intact rats and testosterone restored this decrease to normal. When finasteride was given to these testosterone-treated castrate rats, erectile response was not restored. DHT was as effective as testosterone in restoring response to EFS in castrates and this effect was not decreased by finasteride. Nitric oxide synthase activity in the penile cytosol was measured by the arginine-citrulline conversion and was found to correlate with the EFS determinations. These results show that DHT is the active androgen in the prevention of erectile failure seen in castrated rats, and suggest that this effect may be mediated, at least partially, by changes in nitric oxide synthase levels in the penis.

Amino Acid Oxidoreductases↗
PubMed1993

The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity.

To evaluate the androgen control of sebum, subjects with complete androgen insensitivity and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency and decreased dihydrotestosterone (DHT) production had sebum production studied. A hydrophobic polymeric film applied to the forehead was used to measure sebum production through the use of air filled micropores. Sebum scores of normal preadrenarchal children (ages 2-6), and normal age-matched adult males and females, were studied as well as males treated with the 5 alpha-reductase inhibitor, finasteride, for benign prostatic hyperplasia who were studied at baseline and after drug therapy. Androgen insensitive subjects had no sebum production by this methodology, and the results were identical to preadrenarchal children. In contrast, adult male pseudohermaphrodites with 5 alpha-reductase deficiency and a selective decrease in DHT production had sebum production scores identical to normal age-matched males. Males with benign prostatic hyperplasia treated with the 5 alpha-reductase inhibitor, finasteride, to lower DHT levels did not decrease the sebum score from baseline values. The lack of demonstrable sebum in androgen-insensitive subjects clearly demonstrates the absolute androgen control of sebum production. The DHT dependency of the sebaceous gland, however, could not be demonstrated in this study. Two 5 alpha-reductase isoenzymes 1 and 2, have been described. 5 alpha-reductase-2 is the gene responsible for inherited 5 alpha-reductase deficiency. Although the degree of inhibition of DHT in utero and in adulthood in male pseudohermaphrodites with a defect in 5 alpha-reductase-2 enzyme activity caused severe impairment of external genital and prostate differentiation and decreased facial and body hair, it had no demonstrable effect on sebaceous gland development or function. Furthermore, lowering DHT levels in adulthood had no effect on sebum production. If the gland is rich in the enzyme 5 alpha-reductase-2, it is proposed that the sebaceous gland is either exquisitely sensitive to DHT, requiring only small amounts for normal development and function, or that male levels of testosterone compensate for DHT and maintain normal sebaceous gland activity throughout life. It is also possible that 5 alpha-reductase-1 is the enzyme of the sebaceous gland and is unaffected in the inherited condition and by finasteride.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

Perifollicular fibrosis: pathogenetic role in androgenetic alopecia.

Androgenetic alopecia (AGA) is a dihydrotestosterone (DHT)-mediated process, characterized by continuous miniaturization of androgen reactive hair follicles and accompanied by perifollicular fibrosis of follicular units in histological examination. Testosterone (T: 10(-9)-10(-7) M) treatment increased the expression of type I procollagen at mRNA and protein level. Pretreatment of finasteride (10(-8) M) inhibited the T-induced type I procollagen expression at mRNA (40.2%) and protein levels (24.9%). T treatment increased the expression of transforming growth factor-beta 1 (TGF-beta1) at protein levels by 81.9% in the human scalp dermal fibroblasts (DFs). Pretreatment of finasteride decreased the expression of TGF-beta1 protein induced by an average of T (30.4%). The type I procollagen expression after pretreatment of neutralizing TGF-beta1 antibody (10 microg/ml) was inhibited by an average of 54.3%. Our findings suggest that T-induced TGF-beta1 and type I procollagen expression may contribute to the development of perifollicular fibrosis in the AGA, and the inhibitory effects on T-induced procollagen and TGF-beta1 expression may explain another possible mechanism how finasteride works in AGA.

Alopecia↗