Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.
46, XX Disorders of Sex Development/genetics* ; Adult ; Aromatase/metabolism* ; Female ; Gynecomastia/genetics* ; Humans ; Infertility, Male ; Male ; Metabolism, Inborn Errors ; Mutation ; Pregnancy

Sexual orientation is influenced by both environmental factors and biological factors. Family and twin studies have shown that genetic factors play an important role in the formation of male homosexuality. Genome-wide scan also revealed candidate chromosomal regions which may be associated with male homosexuality, but so far no clearly related genes have been found. This article reviews the progress of relevant studies and candidate genes which are related to male homosexuality.
Animals ; Aromatase ; genetics ; Catechol O-Methyltransferase ; genetics ; Homosexuality, Male ; genetics ; Humans ; LIM-Homeodomain Proteins ; genetics ; Male ; Receptors, Dopamine D1 ; genetics ; Transcription Factors ; genetics

An aromatase encoded by the CYP19 gene catalyzes the final step in the biosynthesis of estrogens, which is related to endometriosis development. To assess the association of CYP19 gene polymorphisms with the risks of endometriosis, chocolate cysts and endometriosis-related infertility, a case-control study was conducted in Chinese Han women by recruiting 225 healthy control females, 146 patients with endometriosis, 94 endometriosis women with chocolate cyst and 65 women with infertility resulting from endometriosis, as diagnosed by both pathological and laparoscopic findings. Individual genotypes at rs2236722:T>C, rs700518:A>G, rs10046:T>C and [TTTA]n polymorphisms were identified. Allelic and genotypic frequencies were compared between the control group and case groups by chi-square analysis. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined by logistic regression analysis to predict the association of CYP19 gene polymorphisms with the risk of endometriosis, the related chocolate cysts and infertility. The genotype distributions of the tested CYP19 gene polymorphisms were not significantly different between the healthy control group and the endometriosis/endometriosis with the chocolate cyst group. However, the CYP19 rs700518AA genotype was significantly associated with an increased risk of endometriosis-related infertility (55.4% in the infertility group vs 25.3% in the control group, P<0.001; OR (95% CI): 3.66 (2.06-6.50)) under the recessive form of the A allele. Therefore, we concluded that in Chinese Han females CYP19 gene polymorphisms are not associated with susceptibility to endometriosis or chocolate cysts, whereas CYP19 rs700518AA genotype confers genetic susceptibility to endometriosis-related infertility.
Adult ; Aromatase/*genetics ; Case-Control Studies ; China ; Endometriosis/complications/*genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Infertility, Female/complications/*genetics ; Middle Aged ; *Polymorphism, Single Nucleotide

OBJECTIVETo construct eukaryotic expression plasmids containing green fluorescent protein gene and CYP19 wild-type or its variants (W39R, R264C, W39R-R264C) and to observe its expression in MCF-7 and Bcap-37 cells.

METHODSThe aromatase WT cDNA sequence was obtained by RT-PCR amplification and cloned into the eukaryotic expression vector pcDNA3.1(+). pcDNA3.1(+)-CYP19-GFP plasmid was then used as the template for site-directed mutation to create variant constructs (W39R, R264C, W39R-R264C). pcDNA3.1(+)-CYP19-GFP was transfected and expressed in MCF-7 and Bcap-37 cells.

RESULTThe construction of pcDNA3.1(+)-CYP19-GFP plasmid was confirmed by enzyme digestion and DNA sequencing. pcDNA3.1(+)-CYP19(W39R)-GFP, pcDNA3.1(+)-CYP19(R264C)-GFP, pcDNA3.1(+)- CYP19(W39R-R264C)-GFP plasmids were confirmed by DNA sequencing. The MCF-7 and Bcap-37 cells transfected with the pcDNA3.1(+)-CYP19-GFP plasmid expressed reporter gene of GFP.

CONCLUSIONThe eukaryotic expression plasmids have been constructed and expressed in MCF-7 and Bcap-37 cells successfully, which lays the foundation for the research of biological activities of CYP19 variant allozymes.

Aromatase ; genetics ; Cell Line, Tumor ; Genetic Vectors ; Green Fluorescent Proteins ; genetics ; Humans ; Mutagenesis, Site-Directed ; Plasmids ; genetics ; Recombinant Fusion Proteins ; genetics ; Transfection

Estrogen is implicated as playing an important role in aging and tumorigenesis of estrogen responsive tissues; however the mechanisms underlying the mitogenic actions of estrogen are not fully understood. Here we report that estrogen deficiency in mice caused by targeted disruption of the aromatase gene results in a significant inhibition of telomerase maintenance of telomeres in mouse ovaries in a tissue-specific manner. The inhibition entails a significant shortening of telomeres and compromised proliferation in the follicular granulosa cell compartment of ovary. Gene expression analysis showed decreased levels of proto-oncogene c-Myc and the telomerase catalytic subunit, telomerase reverse transcriptase (TERT), in response to estrogen deficiency. Estrogen replacement therapy led to increases in TERT gene expression, telomerase activity, telomere length and ovarian tissue growth, thereby reinstating ovary development to normal in four weeks. Our data demonstrate for the first time that telomere maintenance is the primary mechanism mediating the mitogenic effect of estrogen on ovarian granulosa cell proliferation by upregulating the genes of c-Myc and TERT in vivo. Estrogen deficiency or over-activity may cause ovarian tissue aging or tumorigenesis, respectively, through estrogen regulation of telomere remodeling.
46, XX Disorders of Sex Development ; drug therapy ; genetics ; metabolism ; Aging ; genetics ; metabolism ; Animals ; Aromatase ; deficiency ; genetics ; metabolism ; Cell Proliferation ; drug effects ; Estrogen Replacement Therapy ; Estrogens ; deficiency ; pharmacology ; Female ; Gene Expression ; Genes, myc ; genetics ; Granulosa Cells ; drug effects ; metabolism ; pathology ; Gynecomastia ; drug therapy ; genetics ; metabolism ; Humans ; Infertility, Male ; drug therapy ; genetics ; metabolism ; Metabolism, Inborn Errors ; drug therapy ; genetics ; metabolism ; Mice ; Mice, Knockout ; Telomerase ; genetics ; metabolism ; Telomere ; chemistry ; metabolism ; pathology

OBJECTIVETo investigate whether the 115T/C, 240A/G and 1531C/T polymorphisms of CYP19 gene are associated with the risk of moderate/severe endometriosis.

METHODSPolymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to identify the CYP19 gene polymorphism in Chinese patients with endometriosis of III-IV stage (n= 102) and individuals without endometriosis (n= 100).

RESULTSThe frequencies of CYP19 gene 115T/C, TT, TC and CC were 0.9118, 0.0882 and 0 in the endometriosis group, and 0.8800, 0.1100 and 0.0100 in the control group, respectively. The frequencies of 115T and C alleles in both groups were 0.9559 and 0.0441, and 0.9350 and 0.0650, respectively (P> 0.05). The frequencies of CYP19 gene 240AA, AG and GG were 0.2745, 0.4902 and 0.2353 in the endometriosis group, and 0.4500, 0.4100 and 0.1400 in the control group, respectively. The frequencies of 240A and G alleles in both groups were 0.5196 and 0.4804, and 0.6550 and 0.3450, respectively (P< 0.05). The frequencies of CYP19 gene 1531C/T, CC, CT and TT were 0.4118, 0.4706 and 0.1176 in the endometriosis group, and 0.3800, 0.4200 and 0.200 in the control group, respectively. The frequencies of 1531C and T alleles in both groups were 0.6471 and 0.3529, and 0.5900 and 0.4100, respectively (P> 0.05).

CONCLUSIONCYP19 gene 240G/G polymorphism may contribute to the susceptibility of stages III and IV endometriosis but there was no association between CYP19 gene 115T/C and 1531C/T polymorphisms and stage III and IV endometriosis.

Aromatase ; genetics ; Case-Control Studies ; Endometriosis ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Polymorphism, Genetic ; genetics

OBJECTIVETo explore the relationship between the polymorphism of estrogen-biosynthesis genes (CYP17, CYP19, HSD17beta1) and risk of breast cancer.

METHODSA matched case-control study was designed. From May 2007 to July 2008, 200 pairs of subjects with and without breast cancer were enrolled, who were matched by age and menstruation status. Demographical characteristics, dietary factors and reproductive factors were investigated by questionnaire. CYP17 locus 1931 (T-->C), CYP19 codon 264 (Arg-->Cys) and HSD17beta1 locus 1954 (A-->G) were identified by AS-PCR (allele-specific PCR). The gene-gene interaction were analyzed with the MDR model (multifactor dimensionality reduction). Based on the results of MDR model, an unconditional logistic regression model was simulated to estimate the ORs of interaction factors and other risk factors.

RESULTSThe main effect of CYP17, CYP19 and HSD17beta1 susceptible genotypes were not correlated to breast cancer (OR approximately 1, P > 0.05). The positive interaction effect between CYP17 (T 1931C) and HSD17beta1 (A1954G) was discovered by MDR model with a statistically significant difference (Sign test, P = 0.05). The model's testing balance accuracy was 56.00%, and crossing validation consistency was 10/10. Multivariable unconditional logistic regression showed that after adjusting BMI, intake of estrogen, age of first birth, number of abortion and period of breast feeding, the interaction item of CYP17 (T1931C) and HSD17beta1 (A1954G) was strongly and positively correlated to breast cancer (OR = 2.52, 95%CI = 1.54 to 4.11).

CONCLUSIONThe estrogen-biosynthesis genes CYP17 (T1931C) and HSD17beta1 (A1954G) polymorphism may jointly increase the risk of breast cancer.

Aromatase ; genetics ; Breast Neoplasms ; genetics ; pathology ; Carcinoma, Ductal, Breast ; genetics ; pathology ; Case-Control Studies ; Estradiol Dehydrogenases ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Logistic Models ; Polymorphism, Single Nucleotide ; Risk Factors ; Steroid 17-alpha-Hydroxylase ; genetics

OBJECTIVETo investigate the expression status of the P450arom mRNA in breast tissue of pubertal mammary hypertrophy and then explore the possible etiology of pubertal mammary hypertrophy.

METHODS15 patients were selected for pubertal mammary hypertrophy group. Breast hypertrophy tissue specimens were collected from the gland excised during reduction mammaplasty. 15 patients with pathologically simple fibroadenoma were used as another control group. Patient approval of participation in this study was obtained preoperatively. The expression of P450arom mRNA was detected by RT-PCR in all the cases above.

RESULTSThere was no significant difference between the pubertal mammary hypertrophy groups and normal groups on the expression rates of P450arom mRNA. But among the positive cases, the expression of P450arom mRNA within breast tissue were 0.202 +/- 0.048 in pubertal mammary hypertrophy group; and 0.159 +/- 0.068 in normal group. There was significant difference between the pubertal mammary hypertrophy and normal groups (P < 0.05).

CONCLUSIONThe expression of P450arom mRNA in pubertal mammary hypertrophy are significantly higher than in normal mammary glandular tissue. The pubertal mammary hypertrophy may be related to the expression status of P450arom mRNA within breast tissue.

Adolescent ; Adult ; Aromatase ; genetics ; metabolism ; Breast ; metabolism ; pathology ; Female ; Humans ; Hypertrophy ; metabolism ; pathology ; Puberty ; RNA, Messenger ; genetics ; Young Adult

AIMTo investigate the effects of 17beta-estradiol (E2), Peganum harmala extract (PHE) and caloric restriction (CR) on various testis parameters during aging.

METHODSTwelve month-old male rats were treated for 6 months with either E2 or PHE, or submitted to CR (40%).

RESULTSOur results show that estrogens and CR are able to protect the male gonad by preventing the decrease of testosterone and E2 levels as well as the decrease of aromatase and estrogen receptor gene expressions. Indeed, E2, PHE and CR treatments induced an increase in the superoxide dismutase activities and decreased the activity of testicular enzymes: gamma-glutamyl transferase, alkaline phosphatase, lactate deshydrogenase as well as the aspartate and lactate transaminases in aged animals. In addition, the testicular catalase and gluthatione peroxidase activities were enhanced in E2, PHE and CR-treated rats compared to untreated animals at 18 months of age. Moreover, the positive effects of estradiol, PHE and CR were further supported by a lower level of lipid peroxidation. Recovery of spermatogenesis was recorded in treated rats.

CONCLUSIONBesides a low caloric diet which is beneficial for spermatogenesis, a protective antioxydant role of estrogens is suggested. Estrogens delay testicular cell damage, which leads to functional senescence and, therefore, estrogens are helpful in protecting the reproductive functions from the adverse effects exerted by reactive oxygen species (ROS) produced in large quantities in the aged testis.

Aging ; physiology ; Animals ; Antioxidants ; metabolism ; Aromatase ; biosynthesis ; genetics ; Caloric Restriction ; Estradiol ; metabolism ; pharmacology ; Estrogens ; pharmacology ; Lipid Peroxidation ; drug effects ; Male ; Oxidative Stress ; drug effects ; Peganum ; chemistry ; Plant Extracts ; pharmacology ; RNA ; biosynthesis ; genetics ; Rats ; Rats, Wistar ; Receptors, Estrogen ; biosynthesis ; genetics ; Testis ; drug effects ; enzymology ; growth & development ; Testosterone ; metabolism ; Thiobarbituric Acid Reactive Substances ; metabolism

Flavonoids are present in fruits, vegetables and beverages derived from plants, and in many dietary supplements or herbal remedies. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction or inhibition of these enzymes. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzyme CYP1, 2E1, 3A4 and 19. Flavonoids alter CYPs by various mechanisms, including the stimulation of gene expression via specific receptors and/or CYP protein, or mRNA stabilization and so on. But in vivo and in vitro, the effects of flavonoids are not always coincident as a result of concentrations of flavonoids, genetic and environmental factors. As well, flavonoids may interact with drugs through the induction or inhibition of their metabolism. Much attention should be paid to the metabolism interaction of the flavonoids when coadministered with other drugs.
Animals ; Aromatase ; genetics ; metabolism ; Cytochrome P-450 CYP1A1 ; antagonists & inhibitors ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 Inhibitors ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Cytochrome P-450 CYP3A Inhibitors ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Enzyme Activation ; drug effects ; Flavonoids ; pharmacology ; Humans ; RNA, Messenger ; genetics ; metabolism