J Med Sci 25(1): 1-12

5<em>α</em>-Reductase Isozymes in the Prostate

5α-REDUCTASE ISOZYMES

Steroid 5α-reductase isozymes are microsomal NADPH-dependent proteins that reduce the double bond steroids at the 4–5 position of a variety of C₁₉ and C₂₁ including testosterone (Fig. 1). Although testosterone is the primary androgen synthesized and secreted from the testes, it functions as a prohormone in certain tissues such as prostate where it converts to DHT, a more potent androgen, by 5α-reductase isozymes¹. Although testosterone and DHT produce some distinct biological responses, they bind to the same intracellular androgen receptor (Fig. 1), which is a member of the nuclear steroid/thyroid hormone receptor superfamily, to regulate target gene expression². The molecular mechanism for the differential testosterone and DHT action is unclear though differences in receptor binding³ and DNA interaction⁴ between testosterone and DHT have been reported.

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Fig. 1

Illustrations of the 5 α-reductase action and the pathway of androgen action on target gene expression. 5α-reductases (5αRD) converts testosterone (T) to dihydrotestosterone (DHT) in the cell (top panel). Both T and DHT bind to androgen receptor (AR), resulting in a conformational change in AR and translocation of the receptor complex to nucleus. This complex interacts with androgen response element (ARE) on the target gene, and induces gene expression in concert with coregulators (SRC1, CBP, SRA), transcription factors (TF) and the general transcription complex. The function of AR can be activated or modified by non-ligand factors such as growth factors.

In the early 60’s, it was theorized that multiple 5α-reductase isozymes existed⁵. Two different pH optima for 5α-reductase activity in genital and nongenital skin were detected in the 70’s⁶7. The major peak of 5α-reductase activity with a narrow, acidic pH optimum of 5.5, was found to be low in the genital skin of male pseudoherma-phrodites with 5α-reductase deficiency. Another broader peak of activity which had a neutral to alkaline pH (pH 7–9), and was present in both genital and nongenital skin, was found to be normal in the genital skin of male pseudoherma-phrodites with 5α-reductase deficiency. Kinetic analysis of 5α-reductase activity in the epithelium and stroma of the prostate also suggested different 5α-reductase activities⁸9. Studies of specific 5α-reductase inhibitors further indicated that multiple 5α-reductase isozymes were present in human prostate tissues¹⁰.

In the early 90’s, two genes encoding two 5α-reductase isozymes were eventually identified, and named steroid 5α-reductase type 1 (gene symbol: SRD5A1) and steroid 5α-reductase type 2 (gene symbol: SRD5A2)¹¹14. The characteristics of two human 5α-reducases are listed in Table 1. Both human 5α-reductase-2 and 5α-reductase-1 genes have 5 exons and 4 introns, and encode a highly hydrophobic 254 and 259 amino acid protein with a molecular weight of approximately 28.4 and 29.5 kilodaltons, respectively. 5α-reductase-2 is mapped to the short arm of chromosome 2p23, and 5α-reductase-1 to chromosome 5p15. There are 50% homology in amino acid compositions between human type-1 and type-2 isozymes. The type-2 isozyme has a much higher affinity than type-1 isozyme for substrates such as testosterone. The type-2 isozyme is sensitive to finasteride, a 5α-reductase-2 inhibitor, while the type-1 has a lower sensitivity. The apparent Km (3–10μM) for the NADPH cofactor is similar for both isozymes.

Table 1

Comparison of human 5 α-reductase isozymes

	Type 1	Type 2
Gene structure	5 exons, 4 introns	5 exons, 4 introns
Gene, chromosome location	SRD5A1, 5p15	SRD5A2, 2p23
Size	259 amino acids, Mr=29,462	254 amino acids, Mr=28,398
Tissue distribution	Liver, nongenital skin, prostate, brain	Prostate, epididymis, seminal vesicle, genital skin, uterus, liver, breast, hair follicle, placenta, brain
pH optima	Neutral to basic	Acidic or neutral
Prostate level	Low	High
Substrate (T) affinity	Km = 1–5μM	Km = 0.004–1μM^*
Activity in 5α-reductase deficiency	Normal	Mutated
Finasteride inhibition	Ki ≧ 300 nM	Ki ≧ 3–5 nM

^{Note: - The Km of 5}α-reductase-2 for testosterone (T) is dependent on the assay condition¹⁵.

The type-2 isozyme has an acidic pH optimum in the enzymatic assays, while the type-1 has a broad alkaline pH optimum¹²14. However, studies with transfected Chinese hamster ovary cells suggest that the type-2 isozyme may actually have a neutral pH optimum in its native state, and that the acidic optimum described may actually be an artifact of cell lysis¹⁵. Additionally, the affinity of the type -2 isozyme for steroid substrates is higher at a neutral pH than an acidic pH (pH 5.0), suggesting that this isozyme acts at neutral pH in the cell¹⁵16.

The functional domains of 5α-reductase-2 have been deduced from in vitro mutagenesis-transfection analysis of natural mutations of 5α-reductase-2 gene in cultured mammalian cells¹⁴1718, and mutagenesis analysis of 5α-reductase-1 isozyme¹⁹. Mutations affecting NADPH binding map to the last half of type-2 isozyme, suggesting that the carboxyl-terminal of the isozyme appears to be a cofactor-binding domain even though consensus adenine dinucleotide-binding sequences are not identified. In contrast, 5α-reductase-2 mutations that affect substrate (testosterone) binding appear to be located at both ends of the protein. However, the amino acid determinants of the substrate binding domain appear to be mainly located at the amino terminal of the protein¹⁴.

At birth 5α-reductase-1 is detected in the liver and nongenital skin, and is present throughout life. Its expression in embryonic tissues, however, is quite low. In adulthood, it is expressed in nongenital skin, liver and certain brain regions; whereas its presence in the prostate, genital skin, epididymis, seminal vesicle, testis, adrenal and kidney is low. The function of 5α-reductase-1 in human physiology remains to be defined.

5α-reductase-2 is expressed in external genital tissues early in gestation²⁰. In adulthood, its expression in prostate, genital skin, epididymis, seminal vesicle and liver is relatively high, while it is quite low in other tissues. This isozyme also appears to be expressed in the ovary and hair follicles²¹22.

In the human prostate, both 5α-reductase isozymes are present in epithelial cells and stromal cells, while 5α-reductase-2 is the predominant isozyme expressed in the stromal cells¹⁴2023. Both isozymes are expressed in BPH and prostate cancer tissues, and in prostate tumor cells²⁴28 (Table 1).

It is the mutations in the 5α-reductase-2 gene that are responsible for male pseudehermophridism due to 5α-reductase deficiency¹²29. The type-1 isozyme is normal in these patients.

5α-REDUCTASE-2 DEFICIENCY SYNDROME

The clinical syndrome of 5α-reductase deficiency was first described in a large Dominican kindred³⁰, and in two siblings from Dallas³¹. Subsequently large cohorts in New Guinea³² and Turkey were described¹⁸3334 as well as many other cases worldwide¹.

Most affected 46XY subjects with 5α-reductase-2 deficiency have ambiguous external genitalia with a clitoral-like phallus, severely bifid scrotum, pseudovaginal perine-oscrotal hypospadias and a rudimentary prostate (see below for details)²⁹3035. More masculinized subjects have been described; they either lack a separate vaginal opening³⁶, or have a blind vaginal pouch which opens into the urethra³⁷, penile hypospadias³⁸ or even a penile urethra³⁹. Wolffian duct differentiation in affected males is normal with seminal vesicles, vasa deferentia, epididymides and ejaculatory ducts; no Mullerian structures are present. Cryptorchidism is frequently described though it is not invariably present with testes usually found in the inguinal canal or scrotum and occasionally located in the abdomen.

In humans, with the onset of puberty, the affected males have increased muscle mass and deepening of the voice³⁰. The genitalia enlarge with growth of the phallus as well as rugation and hyperpigmentation of the scrotum. The inguinal testes have been observed in some subjects to descend into the scrotum at puberty¹36. Libido is intact and affected men are capable of erections⁴⁰. Although most subjects studied are generally oligo- or azoospermic due to undescended testes; normal sperm concentrations have been reported in subjects with descended testes⁴¹43. Affected men from the Dominican kindred⁴³ and from Sweden⁴⁴ have been reported to father children. These findings suggest that pubertal events, including male sexual function and spermatogenesis, appear to be primarily testosterone mediated. The other possibility is that the amount of DHT derived from 5α-reductase-1 action is enough for spermatogenesis.

The facial and body hair is decreased, and male pattern baldness has never been observed in genetic males with this condition³⁰3233. Sebum production is normal in 5α-reductase-2 deficient subjects although it is an androgen-dependent process⁴⁵.

The biochemical features of this syndrome have been well defined over the years¹40. These include: (a) high normal to elevated levels of plasma testosterone; (b) low normal to decreased levels of plasma DHT; (c) an increased testosterone to DHT ratio at baseline and/or following hCG stimulation; (d) decreased conversion of testosterone to dihydrotestosterone in vivo; (e) normal metabolic clearance rates of testosterone and DHT; (f) decreased production of urinary 5α-reduced androgen metabolites with increased 5β/5α urinary metabolite ratios; (g) decreased plasma and urinary 3α-androstanediol glucuronide, a major metabolite of DHT; (h) a global defect in steroid 5α-reduction as demonstrated by decreased urinary 5α-reduced metabolites of both C21 steroids and C19 steroids other than testosterone, i.e. cortisol, corticosterone, 11β-hydroxy-androstenedione and androstenedione; (i) increased plasma levels of LH and an increased LH pulse amplitude with a normal LH frequency; and (j) plasma FSH levels may be elevated.

5α-REDUCTASES ON PROSTATE DEVELOPMENT AND GROWTH

The prostate is a ductal-acinar gland whose growth and development initiates in fetal life and completes at sexual maturity. Development of prostate begins when prostatic buds emerge from the urogenital sinus that derived from endoderm at 10th week in human fetuses, on day 17 in embryonic mice and on day 19 in embryonic rats. The urogenital sinus also forms the bulbourethral glands, and the prostatic and membranous portion of the urethra. Normal prostate development requires many coordinated cellular processes and involves multiple genes and hormonal actions⁴⁶. DHT plays an essential role in the prostate development and growth.

Studies in rabbit, rat⁴⁷, and human⁴⁸ fetuses have shown that 5α-reductase activity is present in the urogenital sinus and external genital anlage prior to prostate and external genital differentiation. However, 5α-reductase activity is not present in the Wolffian duct, at the time of epididymal, vas deferens, and seminal vesicle differentiation. Thus, testosterone and its 5α-reduced metabolite DHT have selective roles in male sexual differentiation during embryogenesis. Testosterone mediates Wolffian ductal differentiation, while DHT mediates male external genital and prostate differentiation. This hypothesis is confirmed by the study of 5α-reductase-2 deficiency syndrome.

Patients with 5α-reductase-2 deficiency syndrome have decreased circulating and prostatic DHT concentration due to attenuated 5α-reductase activity. In the affected male adults, the prostate is nonpalpable on rectal examination³⁰49 and is found to be rudimentary on transrectal ultrasound and MRI visualization³⁵. Prostatic volumes are approximately 1/10th of age-matched normal controls (Fig. 2). Histological analysis of prostate biopsy from these patients reveals fibrous connective tissue, smooth muscle, and no identifiable epithelial tissue, suggesting atrophic epithelium or lack of epithelial differentiation³⁵. Plasma PSA is low or undetectable in these patients. Administration of DHT results in enlargement of the prostate (Fig. 2)⁴⁰50, and an elevation of plasma PSA levels. These findings provide clinical evidence that prostate differentiation and growth as well as circulating PSA level is mediated largely by DHT. However, the mere presence of a prostate in these individuals supports the notion that other growth factors are also involved in its organogenesis.

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Fig. 2

Comparison of prostate sizes between age-matched normal adult males and 5α-reductase-2 deficient patients before (Pre-DHT) and after (Post-DHT) DHT treatment for 3 to 6 months. Panels A and B show representative sonograms of prostate in a 5 α-reductase-2 deficient patient pre-DHT treatment (A) and post 2% DHT cream (B) applied to the genital area for approximately 3 months. Note the crosses at the outer edges of the prostate. Panel C shows the prostate volume as determined by sonogram in 5α-reductase-2 deficient patients and age-matched normal male controls.

Further supportive evidence is provided by animal studies using 5α-reductase-2 inhibitors and gene knockout. Administration of a 5α-reductase-2 inhibitor, finasteride, in rats⁵¹52 and monkeys⁵³ impairs male sexual differentiation and prostate development. The prostate in mice with genetic disruption of either 5α-reductase-2 or 5α-reductase-2 plus 5α-reductase-1 gene is small, but it is puzzling that these knockout animals has normal genitalia in male offsprings⁵⁴.

5α-REDUCTASES AND BPH

BPH is responsible for considerable morbidity due to urethral obstruction. Histological evidence of BPH is found in 50% of males by the age of 50 and 90% of males by the age of 80⁵⁵. The development of BPH is exclusively dependent on androgens, and BPH does not occur in men castrated prior to puberty⁵⁶. Although testosterone is the major androgen from the testes, DHT is known to be the major intracellular androgen to mediate androgen actions in the prostate cells²⁸5758. Androgen withdrawal by castration leads to atrophy of prostate gland due to prostatic cell apoptosis⁵⁹. In a classic study by White in 1895, 111 men with bladder outlet obstruction were castrated⁶⁰. Nearly 87% had rapid atrophy of their enlarged prostate and almost 58% had relief of symptoms. Administration of either DHT or testosterone to castrated dogs results in an increase in intraprostatic DHT, and in BPH⁶¹. However, the concomitant administration of testosterone with a 5α-reductase inhibitor results in a decreased DHT formation and a prevention of BPH⁶²63. Administration of finasteride, a specific 5α-reductase-2 inhibitor causes a selective decrease in both circulating and intraprostatic DHT, a significant decrease in prostate size due to prostatic cell apoptosis⁶⁴65, and an improvement of clinical symptoms in BPH⁶⁶. In human prostates examined after finasteride administration, the atrophy of glandular tissue in the prostate proceeds from the distal to the proximal acinar ducts. Marks et al.⁶⁷ found that finasteride triggers a similar reduction in morphometric and volumetric measures in the transition and peripheral zones of the prostate. However, Montironi et al.⁶⁸ noted that shrinkage is predominantly in the transition zone. It is known that BPH originates in the transition zone, while prostate cancer originates in the peripheral zone of the prostate. In addition, finasteride has been shown to reduce blood flow in both the ventral and dorsal lobes of the rat prostate, which may be mediated by decreasing vascular-derived endothelial growth factor gene expression⁶⁹.

The specific 5α-reductase-2 inhibitor, finasteride has now been used for the treatment of BPH. This novel therapeutic strategy evolved from the clinical observation that adult male pseudohermaphrotides with 5α-reductase-2 deficiency and a deficiency in DHT production have rudimentary prostate³⁰3540. Recently, specific 5α-reductase-1 inhibitor and dual 5α-reductase-1 and 2 inhibitor have been developed. Pre-clinical and preliminary clinical studies have shown that inhibition of both 5α-reductase isozymes resulted in greater and more consistent suppression of circulating DHT than that observed with the selective inhibitor of 5α-reductase-2, finasteride⁷⁰. However, whether inhibition of both 5α-reductase isozymes is more efficacious in the treatment of BPH than 5α-reductase-2 inhibition alone remains to be defined.

5α-REDUCTASES AND PROSTATE CANCER

Prostate cancer is the most commonly diagnosed and the second leading cause of cancer death in Western males⁷¹. The importance of DHT in prostate development and growth, and the dependence of prostate cancer on androgens indicate that DHT may play a role directly or indirectly in the onset, maintenance, or progression of prostate adenocarcinoma. Epidemiological studies indicate that although the autopsy prevalence of latent non-infiltrating prostate cancer appears to be similar in many different racial groups, there is a 50-fold difference between Asian males and American black males in the incidence of clinically overt disease⁷²73. Analyses of the 5α-reductase activity in these ethnic groups demonstrate that 5α-reductase activity in Asian males is lower than African-Americans and American Whites⁷⁴77, and is increased in Asian males who live in North American compared to Asians in Asia⁷⁷. These data correlate with the progressive increase in clinical prostate cancer incidence in immigrants who have moved from Asia to United States, in the second-generation Asian-American males when compared to the first-generation immigrants⁷⁸79. These data suggest that increased 5α-reductase activity may relate to the pathogenesis of prostate cancer.

Studies in various ethnic groups and in patients with prostate cancer suggest that allelic variants in 5α-reductase-2 gene may be associated with prostate cancer risk and prostate cancer progression. Makridakis et al.⁸⁰ reported that a missense polymorphism, V89L, which has a substitution of leucine for valine at amino acid position 89 of the enzyme was associated with lower 5α-reductase activity. The prevalence of this variant in African-American, Asian, and Latino men parallels the frequency of prostate cancer in these races. Another 5α-reductase-2 gene polymorphism, A49T, which changes an alanine to a threonine residue at amino acid 49 with an increase in 5α-reductase activity has found to be associated with prostate cancer risk in African-American, Latino and Hispanic men, and be most common in African-American and Latino men with advanced prostate cancer⁸¹. Recently, Jaffe et al.⁸² has found that the presence of the A49T variant is associated with a greater frequency of extracapsular disease, a higher pathological tumor-lymph node-metastasis and a poorer prognosis, while V89L genotypes has no association with any of the characteristics studied. However, such association between 5α-reductase-2 gene polymorphism and prostate cancer has not been demonstrated in other studies⁸³85.

Further supporting evidences come from the clinical studies of male pseudohermaphrodites with an inherited DHT deficiency due to 5α-reductase-2 gene mutations from the Dominican kindred, the largest pedigree in the world. As stated above, these patients have an underdeveloped prostate and undetectable plasma PSA levels. After followed for many years, neither BPH nor prostate cancer has been observed in these patients⁴⁰.

Studies of specific 5α-reductase inhibitors provide additional evidence. Administration of a 5α-reductase inhibitor prevents the development of spontaneous prostate cancer in animals⁸⁶ and in humans⁸⁷. In a large randomized, placebo controlled chemoprevention trail⁸⁷, prophylactic use of finastride in males over 50 years old decreases the incidence of prostate cancer by 25% compared to those in the placebo group. However, the tumor malignancy is increased in the finasteride-treated group, a dilemma in using finasteride for the prevention of prostate cancer.

Although both type 1 and 2 5α-reductases are expressed in prostate tumor cells²⁸, and the administration of 5α-reductase inhibitor alone or in combination with androgen antagonist inhibits prostate tumor cell growth in culture⁸⁸89, the efficacy of finasteride in the treatment of prostate cancer is disappointed⁹⁰. Since the 5α-reductase-1 activity is 3 to 4 times greater in malignant than in benign prostate tissues, while the 5α-reductase-2 activity is similar in these 2 diseases⁹¹, whether inhibition of both isozymes by combination of specific type 1 and type 2 inhibitor or using dual inhibitor is more effective in the prevention and therapy of prostate cancer is an interesting strategy and remains to be determined.

A high dietary fat intake is a major risk factor of prostate cancer⁹²93. However, how dietary fat stimulate prostate growth and prostate cancer development is unclear. We have recently demonstrated that a high dietary fat intake increased prostate 5α-reductase-2 gene expression and circulating DHT levels in the rat without significant alteration in prostate and hepatic 5α-reductase-1 gene expression and plasma testosterone concentration⁹⁴, suggesting that alteration in prostate 5α-reductase activity after a high-fat diet may be a potential mechanism for dietary fat stimulation of prostate growth and pathogenesis (Fig. 3).

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Fig. 3

An illustration of a hypothetic model of dietary fat promotion of prostate growth and tumerogenesis, and the potential actions of genistein in this process. A high dietary fat intake induces prostate 5α-reductase gene expression and potentiates androgen action by increasing the conversion of testosterone (T) to DHT. The elevated androgen action subsequently stimulates the proliferation and then transformation of prostate cells in concert with other dietary fat actions. These processes could be blocked by the administration of genistein.

Numerous studies have supported the concept that genistein, a phytoestrogen, has beneficial effects on the prevention and treatment of prostate cancer⁹⁵96, acting via multiple mechanisms such as inhibiting 5α-reductase activity⁹⁷, and tyrosine kinase activity⁹⁵. Recently, we have also observed that genistein completely blocked the dietary fat induced increases in prostate 5α-reductase-2 gene expression and plasma DHT levels⁹⁸, as well as inhibited DHT actions via estrogen receptors⁹⁹. These data provide further evidence to support the above concept.

CONCLUSION AND PROSPECTIVE

There are two natural potent androgens, testosterone and DHT in humans and animals. DHT, a more potent androgen, is converted from testosterone by 5α-reductase isozymes, and is the major intracellular androgen and the major mediator of androgen action in the prostate cells. Two 5α-reductases, type 1 and 2 are identified in the mammals with distinct biochemical features and differential spatial and temporal expression. Studies of male pseudohermaphrodites with 5α-reductase-2 deficiency over the last 2–3 decades has highlighted the difference between testosterone and DHT in male sexual development, elucidated the significant roles of DHT in prostate physiology and pathophysiology, and led to the development of a specific 5α-reductase-2 inhibitor, finasteride, for the treatment of BPH and male pattern baldness. Although a variety of studies indicate the significance of 5α-reductases and DHT in the pathogenesis of prostate cancer, the prophylactic use of finasteride for the prevention of prostate cancer is still controversial.

Inhibition of both 5α-reductase isozymes by combination of a specific 5α-reductase-1 and a 5α-reductase-2 inhibitor or using a dual inhibitor has shown greater and more stable suppression of circulating DHT than finasteride alone. This additional decrease in circulating DHT level could potentially translate into greater reduction in prostatic size and additional improvement in lower urinary tract symptoms caused by BPH. Clinical trials are under way to ascertain whether additional blockade of type-1 5α-reductase results in any further increase in efficacy with minimal side effects in the therapy of BPH.

Both 5α-reductase-1 and 5α-reductase-2 are expressed in prostate tumor cells. Whether blockade of both 5α-reductase isozymes has greater efficacy in prevention and therapy of prostate cancer is an interesting question and remains to be determined.

Acknowledgments

We are very grateful to Dr. Imperato-McGinley for her long-term and enthusiastic support of our study. These researches are partially supported by NIH, the Department of Defense of USA and the Merck Foundation.

^{Department of Medicine/Endocrinology, Cornell University Medical College, New York, USA}

^{Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China}

*Corresponding author: Yuan-Shan Zhu, Department of Medicine/Endocrinology, Cornell University Medical College, 1300 York Avenue, Box 149, Room F-233, New York, NY 10021, USA. Tel and Fax: +1-212-746-8348; E-mail: ude.llenroc.dem@2002zuy

Abstract

5α-reductases convert testosterone to dihydrotestosterone (DHT). There are two 5α-reductase isozymes, type 1 and type 2 in humans and animals. Mutations in type 2 isozyme with decreased enzymatic activity cause male pseudohermaphroditism. The affected 46XY individuals have high normal or elevated plasma testosterone levels with low normal or decreased DHT levels, resulting in an elevated testosterone/DHT ratios. They are born with ambiguous external genitalia and normal Wolffian differentiation. Their prostate is small and rudimentary, and plasma levels of prostate specific antigen (PSA) are low or undetectable in adulthood. Prostate cancer and benign prostate hyperplasia (BPH) have never been reported in these patients. Similar defects in prostate development are observed in animals with either 5α-reductase-2 or 5α-reductase-2 plus 5α-reductase-1 gene knockout, and in animals treated with specific 5α-reductase inhibitor. 5α-reductase isozymes are expressed in multiple tissues, and the predominant isozyme in human prostate is 5α-reductase-2. The expression of 5α-reductase-2 gene in prostate cells is regulated by various factors. A high dietary fat intake, a risk factor of prostate cancer, induces prostate 5α-reductase-2 gene expression and subsequently stimulates prostate growth, which is blocked by genistein, a phytoestrogen. Inhibition of 5α-reductase activity by medication is used in the treatment of BPH and male-pattern baldness, while its use in prostate cancer prevention is still controversial although it can decrease the incidence of prostate cancer. The analyses of 5α-reductases in humans and animals highlight the differences between testosterone and DHT, and the significance of DHT in male sexual differentiation and prostate physiology and pathophysiology.

Keywords: 5α-reductase, androgen, gene mutation, gene expression, prostate

Abstract

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