emitters in nuclear medicine imaging and therapy have further enhanced the opportunity of this technique for diagnosis and therapy. Some specific and promising radiotracers have recently reported for the identification and management of PCa [ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ]. It is recognized that enzyme 5α-reductase (5α-Rds) has facilitated the synthesis of dihydrotestosterone (DHT) from testosterone. DHT is the primary steroid hormone accountable for the excessive enlargement of the prostate, which is characteristic of benign
DOI 10.1515/jpem-2012-0115 J Pediatr Endocr Met 2012; 25(11-12): 1077–1082
Yan Yang, Bao-an Wang, Qing-hua Guo, Jing-tao Dou, Zhao-hui Lv, Jian-ming Ba,
Ju-ming Lu, Chang-yu Pan and Yi-ming Mu *
Clinical and genetic analysis of three Chinese
patients with steroid 5α -reductase type 2
Abstract: Steroid 5α -reductase type 2 deficiency (5 α -RD2)
is a rare autosomal recessive inherited disorder caused by
mutations in the SRD5A2 gene. Its clinical features and
pathogenesis in Chinese patients are poorly understood
Background. Steroid 5-α-reductase type 2 (5-ARD) deficiency is a rare autosomal recessive genetic condition causing a 46,XY disorder of sexual differentiation (DSD) with unknown incidence [ 1 ]. Patients affected by 5-ARD cannot convert testosterone to dihydrotestosterone (DHT), which is a more potent androgen than testosterone and is responsible for male external genitalia phenotype formation. Furthermore, these patients present with under virilized external genitalia. The genital phenotype can vary greatly, from complete female external genitalia on the one
Background: Finasteride is a 5α-reductase inhibitor that has received clinical approval for the treatment of human benign prostatic hyperplasia and androgenetic alopecia. The treatment is practically without side effects, although some occasional cases of depression syndrome have been reported. 5α-Reductase is an enzyme responsible for the reduction of testosterone, progesterone or deoxycorticosterone to their 5α-reduced derivatives possessing anticonvulsant, antidepressant, and anxiolytic activity. Therefore, the formation of GABAergic neuroactive steroids is likely to be impacted by finasteride.
Objective: The objective of the study was to show how the treatment of premature androgenetic alopecia with low doses (1 mg/day) of finasteride influences the broad spectrum of steroids with potential neuroactivity.
Methods: A group of 12 men with premature androgenetic alopecia participated in the present study. The steroid hormone profile was determined for all individuals. Finasteride was administered for 4 months at a daily dose of 1 mg. After the treatment, the same hormonal profile was determined again.
Results: 5α-Reduced steroids, e.g., 5α-dihydrotestosterone, androsterone, epiandrosterone, 5α-androstene-3α,17β-diol, allopregnanolone, isopregnaolone, and some 5-ene steroids, such as dehydroepiandrosterone and pregnenolone, decreased gradually during treatment.
Conclusions: The decrease of 5α-reduced steroids, especially of allopregnanediol, dihydrotestosterone, and pregnenolone, is probably one of the factors responsible for the increased occurrence of depression in men treated with finasteride, even at low doses.
Intratumoral biosynthesis of sex steroids is thought to play a role in the pathogenesis and development of human breast cancer. There is evidence that androgens can inhibit the development and progression of breast cancer. Among the enzymes involved in the biosynthesis of androgens, 5α-reductase plays a key role by reducing testosterone to dihydrotestosterone, the most potent androgen. Two isoforms of 5α-reductase have been characterized and 5α-reductase type 1 is predominant in breast cancer tissue. We developed specific antibodies to 5α-reductase type 1 and studied the expression of the enzyme in 84 specimens of breast carcinoma and adjacent non-malignant tissues by immunohistochemistry. The results were correlated with the expression of androgen receptor, estrogen receptor α, progesterone receptor and CDC47, a cell division marker as well as the tumor stage, tumor size, nodal status and menopausal status. The expression of 5α-reductase type 1 in 61% of breast cancer specimens appeared significantly lower than that observed in normal adjacent tissues (87% of cases being positive). There was no significant correlation between 5α-reductase type 1 expression and the clinicopathological parameters studied. The decrease in 5α-reductase type 1 expression in breast cancer as compared to that observed in the adjacent normal tissues could play a role in the development and/or progression of the cancer by modifying the intratumoral levels of androgens.
Background: Although it is well recognized that 5α-reductases possess higher affinity for 4-androstenedione than testosterone, and the affinity of 4-androstenedione is higher for 5α-reductases than 17β-hydroxysteroid dehydrogenases, it is generally believed that dihydrotestosterone is necessarily produced by the transformation of testosterone into dihydrotestosterone, suggesting that the step catalyzed by 17β-hydroxysteroid dehydrogenase precedes the step catalyzed by 5α-reductase. This interpretation is in contradiction with the enzymatic kinetic law that suggests that the 5α-reduction step that catalyzes the transformation of 4-dione into 5α-androstane-3,17-dione precedes the 17keto-reduction step.
Materials and methods: To verify which of these two pathways is operative, we quantified mRNA expression levels of steroidogenic enzymes in prostate carcinoma DU-145 cells by real-time PCR and determined the metabolites produced after incubation with [14C]4-dione in the presence and absence of a 5α-reductase inhibitor and analyzed the metabolites produced by thin layer chromatography and HPLC.
Results: Real-time PCR analysis strongly suggests that the new type 3 5α-reductase is responsible for 5α-reductase activity in DU-145 cells. Steroid profile analysis shows that in the absence of inhibitor 5α-androstanedione is first produced, followed by the production of androsterone and dihydrotestosterone. The concentration of testosterone was not detectable. In the presence of Finasteride, an inhibitor of 5α-reductase, there was no transformation of 4-androstenedione and also there was no production of testosterone. The present data clearly indicate that the biosynthesis of dihydrotestosterone in DU-145 cells does not require testosterone as intermediate, and the step catalyzed by 5α-reductase precedes the step catalyzed by 17β-hydroxysteroid dehydrogenase.
with the γ-tubulin complex. Int. J Cancer. 2003; 104(3): 283-288. Rebbeck TR, Walker AH, Zeigler-Johnson C, Weisburg S, Martin A, Nathanson KL, Wein AJ, Malkowicz B. Association of HPC2/ELAC2 genotypes and prostate cancer. Am J Hum Genet. 2000; 67(4): 1010-1019. Thigpen AE, Cala KM, Russell DW. Characterization of Chinese hamster ovary cell lines expressing human steroid 5α-reductase isozymes. J Biol Chem. 1993; 268 (23): 17404-17412. Reichardt JKV, Makridakis N, Henderson BE, Yu MC, Pike MC, Ross RK. Genetic variability of the human SRD5A2 gene: implications for
References 1. Elterman DS, Lawrentschuk N, Guns E, Hersey K, Adomat H, Wood CA, Fleshner N. Investigating contamination of phytotherapy products for benign prostatic hyperplasia with α-blockers and 5α-reductase inhibitors. J Urol 2010; 183(5):2085-9. 2. Yamaguchi O. Latest treatment for lower urinary tract dysfunction: therapeutic agents and mechanism of action. Int J Urol 2013; 20(1):28-39. 3. Lowe FC, Fagelman E. Phytotherapy in the treatment of benign prostatic hyperplasia. Curr Opin Urol 2002; 12(1):15-8. 4. Von Löw EC, Perabo FG, Siener R, Müller SC. Review
5α-Reductases play a critical role in glucocorticoid metabolism Glucocorticoids (GCs) elicit their physiological responses via metabolic or immunologic pathways. GCs’ metabolic functions encompass the regulation of carbohydrate metabolism, gluconeogenesis in the liver as well as lipolysis in adipose tissues. The immunologic function of GCs is intertwined with the inflammatory responses, where a downregulation of GCs produces a proinflammatory response. Cortisol and aldosterone and their metabolites play a critical role in regulating basal metabolism, salt and
5α-Reductases are crucial enzymes involved in the biosynthesis of dihydrotestosterone, the most potent natural androgen. To date, three types of 5α-reductases, chronologically named types 1, 2 and 3 5α-reductases (SRD5a-1, 2 and 3) have been described. In the present paper, we characterized the activity and compared the mRNA expression levels of SRD5a-3 with those of SRD5a-1 and 2 in various human tissues, and determined its sensitivity to finasteride and dutasteride. We have established HEK-293 cell line that stably expressed SRD5a-3 for studying its activity and the inhibitory effect of finasteride, using [14C]labeled steroids. mRNA expression levels were quantified using real-time PCR in many male and female human tissues including the prostate, adipose tissue, mammary gland, as well as breast and prostate cancer cell lines. Incubation of HEK-SRD5a-3 cells with [14C]4-androstenedione and [14C]testosterone allowed us to show that SRD5a-3 can catalyze very efficiently both substrates 4-androstenedione and testosterone into 5α-androstanedione and dihydrotestosterone, respectively. We observed that the affinity of the enzyme for 4-androstenedione is higher than for testosterone. The activity of SRD5a-3 and SRD5a-2 are similarly sensitive to finasteride, whereas dutasteride is a much more potent inhibitor of SRD5a-3 than SRD5a-2. Tissue distribution analysis shows that SRD5a-3 mRNA expression levels are higher than those of SRD5a-1 and SRD5a-2 in 20 analyzed tissues. In particular, it is highly expressed in the skin, brain, mammary gland and breast cancer cell lines, thus suggesting that SRD5a-3 could play an important role in the production of androgens in these and other peripheral tissues.