It is widely believed that benign prostatic hyperplasia (BPH) is associated with aging. Thus, the question arises whether or not a correlation exists between the well known prostatic androgen and estrogen accumulation and aging. To address this question, we measured 5 alpha-dihydrotestosterone (DHT), testosterone, estradiol, and estrone in epithelium and stroma of six normal (NPR) and 19 BPH and correlated the values with the age of the donors (26-87 yr). The mean DHT level in NPR epithelium was significantly higher than in NPR stroma, and also significantly higher than in epithelium and stroma of BPH. The epithelial DHT level of NPR and BPH decreased with age, the correlation being statistically significant. The stromal DHT level of NPR and BPH showed no correlation with age. Concerning testosterone, generally rather low values were found which showed no correlation with age. The mean levels of estradiol and estrone were significantly higher in BPH stroma as compared to BPH epithelium as well as to NPR epithelium and stroma. In NPR, the mean levels of estradiol and estrone were significantly higher in epithelium than stroma. In NPR and BPH, the stromal estradiol and estrone levels increased significantly with age. In epithelium such a correlation between the estrogen levels and age was not found. Our results indicate that the prostatic accumulation of DHT, estradiol, and estrone is in part intimately correlated with aging, leading with increasing age to a dramatic increase of the estrogen/androgen ratio particularly in stroma of BPH.

/pdf/effect-of-aging-on-endogenous-level-of-5-alpha-57d2o7tfqt.pdf

Effect of aging on endogenous level of 5 alpha-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate.

Extract from fruit of Sabal serrulata are used in the treatment of human benign prostate hyperplasia (BPH). Therefore, it is of interest whether this phytopharmacon has any influence on the androgen metabolism in the human prostate. It was found that the extract IDS 89 of Sabal serrulata inhibited dose dependently 5 alpha-reductase activity in the epithelium and stroma of human BPH, the mean inhibition being 29% and 45%, respectively. This inhibitory effect is mainly due to the saponifiable subfraction of IDS 89 showing a mean 5 alpha-reductase inhibition of 39% and 38% in epithelium and stroma, respectively. The inhibition was dose dependent and noncompetitive. At a testosterone concentration of 580 nM as substrate for 5 alpha-reductase, the main fatty acids of the extract IDS 89 gave rise to a percentual enzyme inhibition in the epithelium and stroma as follows: 51% and 42% (lauric acid), 5% and 0% (oleic acid), 43% and 34% (myristic acid), 2% and 0% (palmitic acid), respectively. The inhibitory effect of lauric acid was noncompetitive and dose dependent up to a concentration of 0.2 nM, the maximal inhibition in the epithelium and stroma being 52% and 45%, respectively. The nonsaponifiable subfraction, consisting mainly of phytosterols, showed a mean inhibition of 5 alpha-reductase in the epithelium and stroma of 15% and 10%, respectively. Finally, the hydrophilic subfraction, containing carbohydrates, amino acids, and polysaccharides, showed no inhibitory effect. The present in vitro studies suggest that the Sabal serrulata extract IDS 89 has an inhibitory effect on 5 alpha-reductase in the epithelium and stroma of human BPH. This inhibition is mainly due to the fatty acids of the saponifiable subfraction.

Effects of the Sabal serrulata extract IDS 89 and its subfractions on 5α‐reductase activity in human benign prostatic hyperplasia

Potential activities of androgen metabolizing enzymes in human prostate.

Androgen metabolism in the human prostatic cancer cell line LNCaP.

5α-Reductase inhibition by finasteride (proscar®) in epithelium and stroma of human benign prostatic hyperplasia

The accumulation of 5 alpha-dihydrotestosterone (DHT), particularly in stroma, is a possible etiological factor in regard of the age-dependent development of benign prostatic hyperplasia (BPH). In this context, we have recently demonstrated age-dependent alterations of 5 alpha-reductase, which is responsible for the irreversible conversion of testosterone to DHT. Therefore, it was also of interest to study possible age-dependent alterations of those enzymes mainly involved in the reversible metabolism of DHT to 5 alpha-androstanediols. Thus, we determined, in the presence of NADPH/NADP+, kinetic parameters [Km and maximum velocity (Vmax)] of 3-hydroxysteroid oxidoreductases (3 alpha-HSORred, 3 beta-HSORred, and 3 alpha-HSORox) in separated epithelium and stroma of 10 normal (NPR) and 20 hyperplastic prostates (BPH) and correlated the data with the age of the donors (15-86 yr). The mean Km (nanomolar concentrations +/- SEM) of 3 alpha-HSORred was significantly (P less than 0.01) higher in epithelium (NPR, 1391 +/- 181; BPH, 2150 +/- 157) than in stroma (NPR, 778 +/- 22; BPH, 749 +/- 62), indicating the presence of epithelial and stromal enzymes. The mean Km values of 3 beta-HSORred and 3 alpha-HSORox were similar. Concerning 3 alpha-HSORred, the mean potential capacity, i.e. the quotient of Vmax/Km (+/- SEM), was significantly (P less than 0.01) higher in epithelium (0.56 +/- 0.08) than in stroma (0.19 +/- 0.02) of NPR, while in BPH nearly identical mean potential capacities were found in epithelium (0.33 +/- 0.04) and stroma (0.26 +/- 0.02). The respective Vmax/Km of 3 beta-HSORred and 3 alpha-HSORox were significantly (P less than 0.05) lower. In addition, the potential capacity of all three enzymes was distinctly lower than the potential DHT-forming capacity of 5 alpha-reductase. With advancing age, the Vmax/Km decreased significantly (P less than 0.001; 3 alpha-HSORred and 3 beta-HSORred) or tendentiously (3 alpha-HSORox) in epithelium, while in stroma a significant (P less than 0.001; 3 alpha-HSORred and 3 alpha-HSORox) or tendentious (3 beta-HSORred) increase with age was found. Our results indicate that aging has a significant impact on DHT-removing enzymes. However, these enzymes counterbalance only in part the strong potential capacity of 5 alpha-reductase.

Effect of Aging on Kinetic Parameters of 3α(β)-Hydroxysteroid Oxidoreductases in Epithelium and Stroma of Human Normal and Hyperplastic Prostate

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a notoriously difficult tumor to treat, with an overall survival of DIPG patients being only 11 months. One of the major obstacles for the effective treatment of DIPG is the blood–brain barrier (BBB). In order to circumvent the BBB, drug delivery methods are needed that target the pontine area. One such approach is microbubble-mediated focused ultrasound (FUS)—a non-invasive method that can temporarily and locally open the BBB. Previously, it was shown that FUS is safe with minimal side effects and rapid recovery times in preclinical animal models with different DIPG tumors. However, recent studies have shown that combining FUS with a single treatment of the chemotherapeutic drug doxorubicin did not improve survival in a DIPG xenograft model. As the duration of doxorubicin exposure might play a role in tumor response, we hypothesized that the use of a long-circulation (PEGylated) liposomal formulation of doxorubicin could lead to improved overall survival through a longer exposure time to the tumor. Method DIPG xenograft models were established with orthotopic injections of HSJD-DIPG-07 tumor cells into the pontine area of female athymic nude-foxn1 nu mice. Tumor engraftment was confirmed with bioluminescence imaging (BLI) 40 days post-inoculation. Mice were randomized into groups receiving either liposomal formulations of doxorubicin (2B3-101 or Caelyx®) or free doxorubicin in combination with or without FUS treatment. Treatment groups received 5 mg/kg 2B3-101 or Caelyx® 1 h before FUS treatment or 5 mg/kg free doxorubicin immediately after FUS. Results Histological analysis, however, revealed liposome extravasation in healthy controls but not in HSJD-DIPG-07 xenograft 24 h after treatment. Furthermore, BLI monitoring did not show reduced signal after treatment, which was further illustrated with a survival analysis, showing no significant difference between treated and control animals ( p = 0.3). Conclusion We did not observe a treatment effect after a single dose of free doxorubicin or the liposomal formulations 2B3-101 or Caelyx® in combination with FUS in DIPG-bearing mice. 

https://transmedcomms.biomedcentral.com/track/pdf/10.1186/s41231-022-00115-7

Imaged-guided focused ultrasound in combination with various formulations of doxorubicin for the treatment of diffuse intrinsic pontine glioma

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Effect of Aging on Kinetic Parameters of 3α(β)-Hydroxysteroid Oxidoreductases in Epithelium and Stroma of Human Normal and Hyperplastic Prostate

Imaged-guided focused ultrasound in combination with various formulations of doxorubicin for the treatment of diffuse intrinsic pontine glioma