The microsomal enzyme steroid 5 alpha-reductase is responsible for the conversion of testosterone into the more potent
androgen dihydrotestosterone. In man, this steroid acts on a variety of androgen-responsive target tissues to mediate such
diverse endocrine processes as male sexual differentiation in the fetus and prostatic growth in men.
Harris et al. (1992) concluded that SRD5A1 is a minor component of the reductase activity in prostate although the gene was
originally cloned from prostate. On the other hand, SRD5A1 appears to be the predominant isozyme of steroid
5-alpha-reductase in the scalp and elsewhere in the skin.
From a population survey of 828 healthy families comprising 3,000 individuals, Ellis et al. (1998) identified 58 young bald
men (aged 18 to 30 years) and 114 older nonbald men (aged 50 to 70 years) for a case-control comparison. No significant
differences were found between cases and controls in allele, genotype, or haplotype frequencies for RFLPs related to either
the SRD5A1 or the SRD5A2 gene. These findings suggested that the genes encoding the two 5-alpha-reductase
isoenzymes are not associated with male pattern baldness.
NCBI Summary:
Steroid 5-alpha-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT). Also see SRD5A2 (MIM 607306).[supplied by OMIM, Mar 2008]
Stewart PM et al 1990 reported 11 patients with polycystic ovary syndrome (hirsutism and oligomenorrhoea), but with no deficiency
of 21-hydroxylase or 3 beta-hydroxysteroid dehydrogenase, had abnormal cortisol metabolism. The
high ratio of 5 alpha to 5 beta cortisol metabolites in the urine is consistent with enhanced activity of 5
alpha-reductase. Urinary total cortisol metabolites were higher in patients than controls. Increased 5
alpha-reductase activity in liver and skin enhances hepatic cortisol metabolism at the expense of
androgen excess and may be the underlying abnormality in polycystic ovary syndrome.
Haning RV Jr, et al determined whether
5alpha-reductase 1 and 2 were expressed in the human ovary, and to determine the relative activity of
the two enzymes in various ovarian tissues. The ovary apparently expressed mRNA for only
5alpha-reductase 1, whereas the foreskin expressed both 5alpha-reductase 1 and 2. They compared the
5alpha-reductase activity at both pH 5.5 (optimum for 5alpha-reductase 2 activity) and 8.0 (optimum
for 5alpha-reductase 1 activity). 5alpha-reductase activity of foreskin at pH 5.5 was 3900 times
higher than small follicles, 1500 times higher than ovarian stroma, and 240 times higher than corpora
lutea. 5alpha-reductase activity of corpora lutea at pH 5.5 was 17-fold higher than that
of follicles (P < 0.01) and 6.5-fold higher than that of ovarian stroma (P < 0.05). 5alpha-Reductase
activity of foreskin at pH 8.0 was 93 times higher than small follicles, 51 times higher than corpora
lutea, and 170 times higher than ovarian stroma (all P < 0.01). The ratio of 5alpha-reductase activity
at pH 5.5 to that at pH 8.0 was higher in foreskin than in corpus luteum (P < 0.05), ovarian stroma (P
< 0.01), or ovarian follicles. The ratio was lower in ovarian follicles than in stroma or
corpus luteum.
Expression regulated by
Growth Factors/ cytokines
Comment
Ovarian localization
Granulosa, Theca
Comment
Stimulatory Effect of Insulin on 5{alpha}-Reductase Type 1 (SRD5A1) Expression through an Akt-Dependent Pathway in Ovarian Granulosa Cells. Kayampilly PP et al. Elevated levels of 5alpha-reduced androgens have been shown to be associated with hyperandrogenism and hyperinsulinemia, the leading causes of ovulatory dysfunction in women. 5alpha-Dihydrotestosterone reduces ovarian granulosa cell proliferation by inhibiting FSH-mediated mitogenic signaling pathways. The present study examined the effect of insulin on 5alpha-reductase, the enzyme that catalyses the conversion of androgens to their 5alpha-derivatives. Granulosa cells isolated from immature rat ovaries were cultured in serum-free, phenol red-free DMEM-F12 media and treated with different doses of insulin (0, 0.1, 1.0, and 10.0 mug/ml) for different time intervals up to 12 h. The expression of 5alpha-reductase type 1 mRNA, the predominant isoform found in granulosa cells, showed a significant (P < 0.05) increase in response to the insulin treatment up to 12 h compared with control. The catalytic activity of 5alpha-reductase enzyme was also stimulated in a dose-depended manner (P < 0.05). Inhibiting the Akt-dependent signaling pathway abolished the insulin-mediated increase in 5alpha-reductase mRNA expression, whereas inhibition of the ERK-dependent pathway had no effect. The dose-dependent increase in 5alpha-reductase mRNA expression as well as catalytic activity seen in response to insulin treatment was also demonstrated in the human granulosa cell line (KGN). In addition to increased mRNA expression, a dose-dependent increase in 5alpha-reductase protein expression in response to insulin was also seen in KGN cells, which corroborated well with that of mRNA expression. These results suggest that elevated levels of 5alpha-reduced androgens seen in hyperinsulinemic conditions might be explained on the basis of a stimulatory effect of insulin on 5alpha-reductase in granulosa cells. The elevated levels of these metabolites, in turn, might adversely affect growth and proliferation of granulosa cells, thereby impairing follicle growth and ovulation.
Follicle stages
Antral
Comment
Jakimiuk AJ, et al reported 5alpha-reductase activity in women with polycystic ovary syndrome.
5alpha-Reductase 1 and 5alpha-reductase 2 mRNAs were measured in thecal
(TC) and granulosa (GC) cells from individual follicles of 18 women with PCOS and 26 regularly cycling control women.
Both 5alpha-reductase 1 and 2 mRNA expression was higher in GC than in TC, and 5alpha-reductase 2 mRNA levels were
approximately 3-fold higher than 5alpha-reductase 1 mRNA. 5alpha-Reductase 1 and 2 mRNA expression were similar in
GC from PCOS and control women, but 5alpha-reductase mRNA was decreased in TC from PCOS follicles. In control
women, 5alpha-reductase 2 mRNA was highest in GC from 3- to 5-mm follicles and decreased to undetectable levels in GC
from 7-mm follicles. A similar pattern of expression was present in GC from PCOS follicles, but detectable levels of
5alpha-reductase 2 mRNA were present in GC from 7-mm follicles. 5alpha-Reductase activity was measured in whole
follicles by measuring the conversion of radiolabeled testosterone to dihydrotestosterone. Kinetic analysis of total
5alpha-reductase activity at physiological pH revealed a Km of 1.46 micromol/L and a maximal velocity of 0.31 nmol/min x
mg protein, indicating predominantly type 1 activity. The total 5alpha-reductase activity was approximately 4-fold higher in
PCOS follicles than in control follicles. These data demonstrate elevated 5alpha-reductase activity in polycystic ovaries and
support the hypothesis that 5alpha-reduced androgens may play a role in the pathogenesis of PCOS.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Mahendroo MS et al reported that female mice deficient in steroid 5alpha-reductase type 1 have a decreased litter size. The average
litter in homozygous deficient females is 2.7 pups vs. 8.0 pups in wild type controls. Oogenesis,
fertilization, implantation, and placental morphology appear normal in the mutant animals. Fetal loss
occurs between gestation days 10.75 and 11.0 commensurate with a midpregnancy surge in placental
androgen production and an induction of 5alpha-reductase type 1 expression in the decidua of wild
type mice. Plasma levels of androstenedione and testosterone are 2- to 3-fold higher on gestation day
9, and estradiol levels are chronically elevated by 2- to 3-fold throughout early and midgestation in
the knockout mice. Administration of an estrogen receptor antagonist or inhibitors of aromatase
reverse the high rate of fetal death in the mutant mice, and estradiol treatment of wild type pregnant
mice causes fetal wastage. The results suggest that in the deficient mice, a failure to 5alpha-reduce
androgens leads to their conversion to estrogens, which in turn causes fetal death in midgestation.
These findings indicate that the 5alpha-reduction of androgens in female animals plays a crucial role
in guarding against estrogen toxicity during pregnancy.
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Association of genetic variants in the two isoforms of 5a-reductase, SRD5A1 and SRD5A2, in lean patients with polycystic ovary syndrome. Graupp M et al. OBJECTIVE: Given its role in converting testosterone to dihydrotestosterone and cortisol to dihydrocortisol, 5a-reductase may be important in the pathophysiology of the polycystic ovary syndrome (PCOS). Increased activity of this enzyme has already been demonstrated in ovaries of affected women, and might be caused by genetic alterations. The aim of this study was to analyze representative genetic variants of both isoforms of 5a-reductase with regard to PCOS parameters in lean and obese women. STUDY DESIGN: We analyzed one single nucleotide polymorphism (SNP) (rs523349) of the isoform 2 (SRD5A2) and one haplotype of the isoform 1 (SRD5A1), consisting of the two SNPs rs39848 and rs3797179, in 249 women with PCOS and 226 healthy women using a 5'-exonuclease-assay. The genotypes were associated with anthropometric, metabolic and hormonal as well as functional tests in these women. RESULTS: In the investigated haplotype of SRD5A1, the TA variant was associated with an increased frequency of PCOS (P=0.022) and an increased Ferriman-Gallwey Score (hirsutism) (P=0.016) in women with normal weight. The G allele at the examined position of the SRD5A2 showed a decreased frequency of PCOS (P=0.03) in women with normal weight. CONCLUSION: One of the keys in the development of the PCOS is hyperandrogenism, which might be caused by an increased 5a-reductase activity, as it is often seen in obesity. This mechanism might therefore be of importance in lean PCOS patients and contribute to the clinical findings.
Evaluating reported candidate gene associations with polycystic ovary syndrome. Pau C et al. OBJECTIVE: To replicate variants in candidate genes associated with polycystic ovary syndrome (PCOS) in a population of European women with PCOS and control subjects. DESIGN: Case-control association analysis and meta-analysis. SETTING: Major academic hospital. PATIENT(S): Women of European ancestry with PCOS (n = 525) and controls (n = 472), aged 18-45 years. INTERVENTION(S): Variants previously associated with PCOS in candidate gene studies were genotyped (n = 39). Metabolic, reproductive, and anthropomorphic parameters were examined as a function of the candidate variants. All genetic association analyses were adjusted for age, body mass index, and ancestry and were reported after correction for multiple testing. MAIN OUTCOME MEASURE(S): Association of candidate gene variants with PCOS. RESULT(S): Three variants, rs3797179 (SRD5A1), rs12473543 (POMC), and rs1501299 (ADIPOQ), were nominally associated with PCOS. However, they did not remain significant after correction for multiple testing, and none of the variants replicated in a sufficiently powered meta-analysis. Variants in the FBN3 gene (rs17202517 and rs73503752) were associated with smaller waist circumferences, and variant rs727428 in the SHBG gene was associated with lower sex hormone-binding globulin levels. CONCLUSION(S): Previously identified variants in candidate genes do not seem to be associated with PCOS risk. CLINICAL TRIAL REGISTRATION NUMBER: NCT00166569.