CYP19A1
Aromatase (EC 1.14.14.14) (CYPXIX) (Cytochrome P-450AROM) (Cytochrome P450 19A1) (Estrogen synthase) [ARO1] [CYAR] [CYP19]
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Testicular aging leads to a decrease in spermatogenesis and steroidogenesis. Vitamin D plays an important role in reproduction by modulating testicular steroidogenesis. As the role of vitamin D3 in testicular steroidogenesis during aging has not been explored, the aim of this study was to evaluate the effects of vitamin D3 on testicular functions in d-gal-induced aged rats. Vitamin D3 treatment on d-gal-induced aged rats resulted in significant improvement in sperm parameters, histoarchitecture, serum testosterone, and rostenedione and estrogen levels. The results of both in vivo and in vitro studies showed that vitamin D3 directly regulates testicular steroidogenic markers. Vitamin D3 treatment also increased CYP19A1 and decreased AR expression in the testes of d-gal-induced aged and normal rats. These results suggest that estrogen-mediated action may be responsible for an improvement in spermatogenesis in aged testis. Furthermore, it may be suggested vitamin D3 has a protective role in the aged testis and unaffected spermatogenesis in normal rats treated with vitamin D3 could be due to a balance between estrogen and androgen action.
MeSH Terms
- Aging
- Animals
- Cholecalciferol
- Estrogens
- Male
- Rats, Wistar
- Spermatogenesis
- Spermatozoa
- Steroids
- Testis
- Testosterone
- Vitamins
Keywords
- Aging
- Estrogen
- Testis
- Testosterone
- VDR
- d-Galactose
Advancing age is accompanied by an accumulation of ill health and shortening of chromosomal telomeres signifying biological aging. T is metabolized to DHT by 5α-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro. The objective of the study was to establish whether circulating T or its metabolites, DHT or E2, and single-nucleotide polymorphisms in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men. Early-morning serum T, DHT, and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 single-nucleotide polymorphisms and LTL analyzed by PCR in 980 men from the Western Australian Busselton Health Survey who participated in the study. LTL was expressed as the T/S ratio. Men were aged (mean ± SD) 53.7 ± 15.6 years. LTL decreased linearly with age, from the T/S ratio of 1.89 ± 0.41 at younger than 30 years to 1.50 ± 0.49 at 70 to younger than 80 years (r = -0.225, P < .0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT, r = 0.069, P = .030; E2, r = 0.068, P = .034). The SRD5A2 rs9282858 polymorphism was associated with serum DHT but not with LTL. Three dominant alleles of CYP19A1 were each associated with lower serum E2 and shorter LTL: rs2899470 T (E2, 59.3 vs 68.6 pmol/L, P < .0001; T/S ratio, 1.54 vs 1.62, P = .045), rs10046 C (60.5 vs 68.1 pmol/L, P = .0005, 1.54 vs 1.62, P = .035), and rs700518 A (59.9 vs 68.9 pmol/L, P < .0001, 1.54 vs 1.63, P = .020). A single-copy haplotype C/T/I/A/T rs10046/rs2899470/rs11575899/rs700518/rs17703883 (52% prevalence) was associated with both lower E2 and shorter LTL. In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include three dominant alleles that are associated with both lower serum E2 and shorter LTL. E2 influences telomere length in vivo, thus warranting further studies to examine whether hormonal interventions might slow biological aging in men.
MeSH Terms
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Aromatase
- Dihydrotestosterone
- Estradiol
- Genetic Association Studies
- Humans
- Leukocytes
- Male
- Membrane Proteins
- Mendelian Randomization Analysis
- Middle Aged
- Polymorphism, Single Nucleotide
- Telomere
- Telomere Homeostasis
- Western Australia
- Young Adult
Serum estradiol (E2) levels are preserved in older reproductive-aged women with regular menstrual cycles despite declining ovarian function. The objective of the study was to determine whether increased granulosa cell aromatase expression and activity account for preservation of E2 levels in older, regularly cycling women. The protocol included daily blood sampling and dominant follicle aspirations at an academic medical center during a natural menstrual cycle. Healthy, regularly cycling older (36-45 y; n = 13) and younger (22-34 y; n = 14) women participated in the study. Hormone levels were measured in peripheral blood and follicular fluid aspirates and granulosa cell CYP19A1 (aromatase) and FSH-R mRNA expression were determined. Older women had higher FSH levels than younger women during the early follicular phase with similar E2 but lower inhibin B and antimullerian hormone levels. Late follicular phase serum E2 did not differ between the two groups. Follicular fluid E2 [older (O) = 960.0 [interquartile range (IQR) 765.0-1419.0]; younger (Y) = 994.5 [647.3-1426.5] ng/mL, P = 1.0], estrone (O = 39.6 [29.5-54.1]; Y = 28.8 [22.5-42.1] ng/mL, P = 0.3), and the E2 to testosterone (T) ratio (O = 109.0 ± 41.9; Y = 83.0 ± 18.6, P = .50) were preserved in older women. Granulosa cell CYP19A1 expression was increased 3-fold in older compared with younger women (P < .001), with no difference in FSH-R expression. Ovarian aromatase expression increases with age in regularly cycling women. Thus, up-regulation of aromatase activity appears to compensate for the known age-related decrease in granulosa cell number in the dominant follicle to maintain ovarian estrogen production in older premenopausal women.
MeSH Terms
- Adult
- Aging
- Aromatase
- Estradiol
- Female
- Follicle Stimulating Hormone
- Follicular Fluid
- Granulosa Cells
- Humans
- Inhibins
- Luteinizing Hormone
- Menstrual Cycle
- Middle Aged
- Ovarian Follicle
- Ovary
- Receptors, FSH
- Testosterone
- Up-Regulation
- Young Adult
Previous analysis of aromatase gene and protein expression in peripheral blood leucocytes (PBLs), studied in children and adults, was extended to elderly subjects. In addition, we assessed whether aromatase expression in PBLs could be used as a parameter of aromatase expression in other tissues, using the cynomolgus monkey as model. Real-time PCR analysis of aromatase gene expression and protein evaluation by Western blot was performed in PBLs of human elderly subjects and in various tissues from cynomolgus monkeys. No gender-related difference in CYP19A1 mRNA and protein expression in PBLs from human elderly women and men was found. In elderly male cynomolgus monkeys, CYP19A1 mRNA and protein were expressed in all cells and tissues analysed, with the lowest levels in PBLs but no clear-cut correlation with other tissues. Aromatase expression in PBLs in elderly human subjects is not gender-related and cannot be a surrogate of aromatase expression for other tissues.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Animals
- Aromatase
- Epididymis
- Estradiol
- Female
- Fibroblasts
- Gene Expression
- Humans
- Hypothalamus
- Leukocytes
- Liver
- Macaca fascicularis
- Male
- Middle Aged
- RNA, Messenger
- Real-Time Polymerase Chain Reaction
- Testis
- Testosterone
Polymorphisms in genes involved in regulation, biosynthesis, metabolism, and actions of testicular sex hormones may influence hormone balance and phenotype of aging men. We investigated the relationships between polymorphisms in genes related to pituitary-testicular endocrine function and health status. Using cross-sectional baseline data, we conducted a multinational prospective cohort observational study consisting of a population survey of community-dwelling men. A total of 2748 men, aged 40-79 (mean /- sd, 60.2 11.2) yr, were randomly recruited from eight European centers. Forty-three polymorphisms were genotyped in the following genes: androgen receptor (AR), estrogen receptor-alpha and -beta (ESR1 and ESR2), steroid 5alpha-reductase type II (SRD5A2), 17alpha-hydroxylase/17,20-lyase (CYP17A1), aromatase (CYP19A1), sex hormone-binding globulin (SHBG), LH beta-subunit (LHB), and LH receptor (LHCGR). We measured the associations between gene polymorphisms and endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. Several polymorphisms in SHBG, ESR2, AR, CYP19A1, and LHB were significantly associated with circulating levels of SHBG, LH, total, free, and bioavailable testosterone and estradiol, the LH x testosterone product, and indices of insulin sensitivity. Apart from several previously reported associations between genes affecting estrogen levels and heel ultrasound parameters, no associations existed between polymorphisms and nonhormonal variables (anthropometry, blood lipids, blood pressure, hemoglobin, prostate symptoms, prostate-specific antigen, sexual dysfunction, cognition). In aging men, polymorphisms in genes related to the pituitary-testicular endocrine function significantly influence circulating LH, testosterone, and estradiol levels, but the downstream effects may be too small to influence secondary phenotypic parameters.
MeSH Terms
- Adult
- Aged
- Aging
- Cohort Studies
- Cross-Sectional Studies
- DNA
- Databases, Genetic
- Europe
- Gene Frequency
- Genotype
- Gonadal Steroid Hormones
- Health Status
- Humans
- Male
- Middle Aged
- Phenotype
- Pituitary Gland
- Polymorphism, Genetic
- Polymorphism, Single Nucleotide
- Prospective Studies
- Sex Hormone-Binding Globulin
- Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
- Testis
Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle-aged and elderly European men. Men 40-79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 /- 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 /- 18.9 dB/Mhz, SOS was 1550.2 /- 34.1 m/s, and BMD was 0.542 /- 0.141 g/cm(2). Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (beta =-0.016, p = -0.005) and homozygotes (beta = -0.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.
MeSH Terms
- Aged
- Aging
- Aromatase
- Bone Density
- Calcaneus
- European Continental Ancestry Group
- Genetic Variation
- Genotype
- Gonadal Steroid Hormones
- Humans
- Male
- Middle Aged
- Polymorphism, Genetic
- Repetitive Sequences, Nucleic Acid
- Ultrasonography
Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate > or =80%, minor allele frequency > or =10%, Hardy-Weinberg test p > or = 0.001). In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10(-5)). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.
MeSH Terms
- Adult
- Cardiovascular Diseases
- Cohort Studies
- Female
- Genetic Linkage
- Genetic Markers
- Genome, Human
- Genotype
- Humans
- Longevity
- Male
- Middle Aged
- Phenotype
- Polymorphism, Single Nucleotide