[Genetic Causation Analysis of Hyperandrogenemia Testing Indicators and Preeclampsia]. / é«˜é›„æ¿€ç´ è¡€ç—‡æ£€æµ‹æŒ‡æ ‡ä¸Žå­ç—«å‰æœŸçš„é—ä¼ å› æžœæ€§ç ”ç©¶.

Objective: Some epidemiological studies have shown that pregnant women who develop preeclampsia (PE) have elevated levels of testosterone in their maternal plasma compared to women with normal blood pressure during pregnancy, revealing a potential association between hyperandrogenism in women and PE. To explore the causal relationship between hyperandrogenism and PE, this study selected total testosterone (TT), bioavailable testosterone (BIOT), and sex hormone binding globulin (SHBG) as exposure factors and PE and chronic hypertension with superimposed PE as disease outcomes. Two-sample Mendelian randomization (MR) analyses were used to genetically dissect the causal relationships between the three exposure factors (TT, BIOT, and SHBG) and the outcomes of PE and chronic hypertension with superimposed PE. Methods: Two independent genome-wide association study (GWAS) databases were used for the two-sample MR analysis. In the GWAS data of female participants from the UK Biobank cohort, single nucleotide polymorphisms (SNPs) associated with TT, BIOT, and SHBG were analyzed, involving 230454, 188507, and 188908 samples, respectively. GWAS data on PE and chronic hypertension with superimposed PE from the Finnish database were used to calculate SNP, involving 3556 PE cases and 114735 controls, as well as 38 cases of chronic hypertension with superimposed PE and 114735 controls. To meet the assumptions of instrumental relevance and independence in MR analysis, SNPs associated with exposure were identified at the genome-wide level (P<5.0×10-8), and those in linkage disequilibrium interference were excluded based on clustering thresholds of R 2<0.001 and an allele distance greater than 10000 kb. Known confounding factors, including previous PE, chronic kidney disease, chronic hypertension, diabetes, systemic lupus erythematosus, or antiphospholipid syndrome, were also identified and the relevant SNPs were removed. Finally, we extracted the outcome data based on the exposure-related SNPs in the outcome GWAS, integrating exposure and outcome data, and removing palindromic sequences. Five genetic causal analysis methods, including inverse variance-weighted method (IVW), MR-Egger regression, weighted median method, simple mode method, and weighted mode method, were used to infer causal relationships. In the IVW, it was assumed that the selected SNPs satisfied the three assumptions and provided the most ideal estimate of the effect. IVW was consequently used as the primary analysis method in this study. Considering the potential heterogeneity among the instrumental variables, random-effects IVW was used for MR analysis. The results were interpreted using odds ratios (OR) and the corresponding 95% confidence interval (CI) to explain the impact of exposure factors on PE and chronic hypertension with superimposed PE. If the CI did not include 1 and had a P value less than 0.05, the difference was considered statistically significant. Sensitivity analysis was conducted to assess heterogeneity and pleiotropy. Heterogeneity was examined using Cochran's Q test, and pleiotropy was assessed using MR-Egger intercept analysis. Additionally, leave-one-out analysis was conducted to examine whether individual SNPs were driving the causal associations. To further validate the findings, MR analyses were performed using the same methods and outcome variables, but with different exposure factors, including waist-to-hip ratio adjusted for BMI (WHRadjBMI) and 25-hydroxyvitamin D levels, with MR results for WHRadjBMI and PE serving as the positive controls and MR results for 25-hydroxyvitamin D levels and PE as the negative controls. Results: According to the criteria for selecting genetic instrumental variables, 186, 127, and 262 SNPs were identified as genetic instrumental variables significantly associated with testosterone indicators TT, BIOT, and SHBG. MR analysis did not find a causal relationship between the TT, BIOT, and SHBG levels and the risk of developing PE and chronic hypertension with superimposed PE. The IVW method predicted that genetically predicted TT (OR [95% CI]=1.018 [0.897-1.156], P=0.78), BIOT (OR [95% CI]=1.11 [0.874-1.408], P=0.392), and SHBG (OR [95% CI]=0.855 [0.659-1.109], P=0.239) were not associated with PE. Similarly, genetically predicted TT (OR [95% CI]=1.222 [0.548-2.722], P=0.624), BIOT (OR [95% CI]=1.066 [0.242-4.695], P=0.933), and SHBG (OR [95% CI]=0.529 [0.119-2.343], P=0.402) were not significantly associated with chronic hypertension with superimposed PE. Additionally, MR analysis using the MR-Egger method, weighted median method, simple mode method, and weighted mode method yielded consistent results, indicating no significant causal relationship between elevated testosterone levels and PE or chronic hypertension with superimposed PE. Heterogeneity was observed for SHBG in the analysis with PE (Cochran's Q test, P=0.01), and pleiotropy was detected for BIOT in the analysis with PE (MR-Egger intercept analysis, P=0.014), suggesting that the instrumental variables did not affect PE through BIOT. Other instrumental variables did not show significant heterogeneity or pleiotropy. Leave-one-out analysis confirmed that the results of the MR analysis were not driven by individual instrumental variables. Consistent with previous MR studies, the results of the control MR analyses using WHRadjBMI and 25-hydroxyvitamin D levels supported the accuracy of the MR analysis approach and the methods used in this study. Conclusion: The MR analysis results suggest that current genetic evidence does not support a causal relationship between TT, BIOT, and SHBG levels and the development of PE and chronic hypertension with superimposed PE. This study suggests that elevated testosterone may be a risk factor for PE but not a direct cause.

Anti-Müllerian Hormone: A Molecular Key to Unlocking Polycystic Ovary Syndrome?

Anti-Müllerian hormone (AMH) is an important component within androgen receptor (AR)-regulated pathways governing the hyperandrogenic origin of polycystic ovary syndrome (PCOS). In women with PCOS, granulosa cell AMH overexpression in developing ovarian follicles contributes to elevated circulating AMH levels beginning at birth and continuing in adolescent daughters of PCOS women. A 6 to 7% incidence among PCOS women of gene variants coding for AMH or its receptor, AMHR2, suggests genetic contributions to AMH-related pathogenesis. Discrete gestational AMH administration to pregnant mice induces hypergonadotropic hyperandrogenic, PCOS-like female offspring with high circulating AMH levels that persist over three generations, suggesting epigenetic contributions to PCOS through developmental programming. Moreover, adult-onset, selective hyperactivation of hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH) induces hypergonadotropic hyperandrogenism and PCOS-like traits in female mice. Both gestational and adult AMH inductions of PCOS-like traits are prevented by GnRH antagonist coadministration, implicating luteinizing hormone-dependent ovarian theca cell testosterone (T) action, mediated through the AR in AMH-induced pathogenesis. Interestingly, gestational or peripubertal exogenous T or dihydrotestosterone induction of PCOS-like traits in female mice, rats, sheep, and monkeys fails to elicit ovarian AMH hypersecretion; thus, AMH excess per se may lead to a distinct pathogenic contribution to hyperandrogenic PCOS origins.

Investigating GABA Neuron-Specific Androgen Receptor Knockout in two Hyperandrogenic Models of PCOS.

Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links developmental or chronic exposure to hyperandrogenism with programming and evoking the reproductive and metabolic traits of PCOS. While critical androgen targets remain to be determined, central GABAergic neurons are postulated to be involved. Here, we tested the hypothesis that androgen signaling in GABAergic neurons is critical in PCOS pathogenesis in 2 well-characterized hyperandrogenic mouse models of PCOS. Using cre-lox transgenics, GABA-specific androgen receptor knockout (GABARKO) mice were generated and exposed to either acute prenatal androgen excess (PNA) or chronic peripubertal androgen excess (PPA). Females were phenotyped for reproductive and metabolic features associated with each model and brains of PNA mice were assessed for elevated GABAergic input to gonadotropin-releasing hormone (GnRH) neurons. Reproductive and metabolic dysfunction induced by PPA, including acyclicity, absence of corpora lutea, obesity, adipocyte hypertrophy, and impaired glucose homeostasis, was not different between GABARKO and wild-type (WT) mice. In PNA mice, acyclicity remained in GABARKO mice while ovarian morphology and luteinizing hormone secretion was not significantly impacted by PNA or genotype. However, PNA predictably increased the density of putative GABAergic synapses to GnRH neurons in adult WT mice, and this PNA-induced plasticity was absent in GABARKO mice. Together, these findings suggest that while direct androgen signaling in GABA neurons is largely not required for the development of PCOS-like traits in androgenized models of PCOS, developmental programming of GnRH neuron innervation is dependent upon androgen signaling in GABA neurons.

Developmental programming: Testosterone excess masculinizes female pancreatic transcriptome and function in sheep.

Hyperandrogenic disorders, such as polycystic ovary syndrome, are often associated with metabolic disruptions such as insulin resistance and hyperinsulinemia. Studies in sheep, a precocial model of translational relevance, provide evidence that in utero exposure to excess testosterone during days 30-90 of gestation (the sexually dimorphic window where males naturally experience elevated androgens) programs insulin resistance and hyperinsulinemia in female offspring. Extending earlier findings that adverse effects of testosterone excess are evident in fetal day 90 pancreas, the end of testosterone treatment, the present study provides evidence that transcriptomic and phenotypic effects of in utero testosterone excess on female pancreas persist after cessation of treatment, suggesting lasting organizational changes, and induce a male-like phenotype in female pancreas. These findings demonstrate that the female pancreas is susceptible to programmed masculinization during the sexually dimorphic window of fetal development and shed light on underlying connections between hyperandrogenism and metabolic homeostasis.

Serum Expression of miR-23a-3p and miR-424-5p Indicate Specific Polycystic Ovary Syndrome Phenotypes: A Pilot Study.

MicroRNAs (miRNAs) are single-stranded, non-coding RNAs that regulate mRNA expression on a post-transcriptional level. Observational studies suggest an association of serum miRNAs and polycystic ovary syndrome (PCOS), a common heterogeneous endocrinopathy characterized by hyperandrogenism (HA), oligo- or amenorrhea (OM) and polycystic ovaries. It is not known whether these miRNA profiles also differ between PCOS phenotypes. In this pilot study, we compared serum expression profiles between the four PCOS phenotypes (A-D) and analyzed them both in PCOS (all phenotypes) and in phenotypes with HA by quantitative-real-time PCR (qRT-PCR). The serum expression of miR-23a-3p was upregulated in phenotype B (n = 10) and discriminated it from phenotypes A (n = 11), C (n = 11) and D (n = 11, AUC = 0.837; 95%CI, 0.706-0.968; p = 0.006). The expression of miR-424-5p was downregulated in phenotype C (n = 11) and discriminated it from phenotypes A, B and D (AUC = 0.801; 95%CI, 0.591-1.000; p = 0.007). MiR-93-5p expression was downregulated in women with PCOS (all phenotypes, n = 42) compared to controls (n = 8; p = 0.042). Phenotypes with HA (A, B, C; n = 32) did not show differences in the analyzed expression pattern. Our data provide new insights into phenotype-specific miRNA alterations in the serum of women with PCOS. Understanding the differential hormonal and miRNA profiles across PCOS phenotypes is important to improve the pathophysiological understanding of PCOS heterogeneity.

miRNA expression in PCOS: unveiling a paradigm shift toward biomarker discovery.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that affects a substantial percentage of women, estimated at around 9-21%. This condition can lead to anovulatory infertility in women of childbearing age and is often accompanied by various metabolic disturbances, including hyperandrogenism, insulin resistance, obesity, type-2 diabetes, and elevated cholesterol levels. The development of PCOS is influenced by a combination of epigenetic alterations, genetic mutations, and changes in the expression of non-coding RNAs, particularly microRNAs (miRNAs). MicroRNAs, commonly referred to as non-coding RNAs, are approximately 22 nucleotides in length and primarily function in post-transcriptional gene regulation, facilitating mRNA degradation and repressing translation. Their dynamic expression in different cells and tissues contributes to the regulation of various biological and cellular pathways. As a result, they have become pivotal biomarkers for various diseases, including PCOS, demonstrating intricate associations with diverse health conditions. The aberrant expression of miRNAs has been detected in the serum of women with PCOS, with overexpression and dysregulation of these miRNAs playing a central role in the atypical expression of endocrine hormones linked to PCOS. This review takes a comprehensive approach to explore the upregulation and downregulation of various miRNAs present in ovarian follicular cells, granulosa cells, and theca cells of women diagnosed with PCOS. Furthermore, it discusses the potential for a theragnostic approach using miRNAs to better understand and manage PCOS.

Fructose intake from sugar-sweetened beverages is associated with a greater risk of hyperandrogenism in women: UK Biobank cohort study.

OBJECTIVE: To assess the association between fructose consumption and serum sex hormone-binding globulin (SHBG), (free) testosterone, and risk of hyperandrogenism in a population-based cohort. DESIGN: An observational and genetic association study in participants of the UK Biobank (n = 136 384 and n = 383 392, respectively). METHODS: We assessed the relationship of (1) the intake of different sources of fructose (ie, total, fruit, fruit juice, and sugar-sweetened beverages [SSBs]) and (2) rs2304681 (a missense variant in the gene encoding ketohexokinase, used as an instrument of impaired fructose metabolism), with SHBG, total and free testosterone levels, and risk of hyperandrogenism (free androgen index >4.5). RESULTS: The intake of total fructose and fructose from fruit was associated with higher serum SHBG and lower free testosterone in men and women and lower risk of hyperandrogenism in women. In contrast, fructose intake from SSB (≥10 g/day) was associated with lower SHBG in men and women and with higher free testosterone levels and risk of hyperandrogenism in women (odds ratio [OR]: 1.018; 95% confidence interval [CI]: 1.010; 1.026). Carriers of the rs2304681 A allele were characterized by higher circulating SHBG (both men and women), lower serum free testosterone (women), and a lower risk of biochemical hyperandrogenism (OR: 0.997, 95% CI: 0.955; 0.999; women) and acne vulgaris (OR: 0.975, 95% CI: 0.952; 0.999; men and women combined). CONCLUSIONS: The consumption of ≥10 g/day fructose from SSB, corresponding to ≥200 mL serving, is associated with a 2% higher risk of hyperandrogenism in women. These observational data are supported by our genetic data.

Avaliação antropométrica e metabólica de parentes de primeiro grau do sexo masculino de mulheres com síndrome do ovário policístico / Anthropometric and metabolic evaluation of first-degree male relatives of women with polycystic ovary syndrome

OBJETIVO: avaliar as características clínicas e laboratoriais de parentes de primeiro grau do sexo masculino de pacientes com diagnóstico confirmado de síndrome de ovários policísticos (SOP) e comparar os achados com um grupo controle sem história familiar de SOP. MÉTODOS: foram selecionados aleatoriamente 28 homens com idade entre 18 e 65 anos que possuíam parentesco de primeiro grau com mulheres diagnosticadas com SOP e 28 controles pareados por idade, cintura e índice de massa corporal (IMC). RESULTADOS: homens com parentesco de 1º grau com mulheres com SOP comparados ao Grupo Controle apresentaram níveis mais elevados de triglicerídeos (189,6±103,1 versus 99,4±37,1; p<0,0001), HOMA-IR (Homeostase Model Assesment) (3,5±9,1 versus 1,0±1,0; p=0,0077) e glicemia (130,1±81,7 versus 89,5±7,8; p=0,005), além de menores níveis da globulina ligadora de hormônios sexuais (SHBG) (23,8±13,8 versus 31,1±9,1; p=0,003). Os níveis de SHBG se correlacionaram independentemente com os níveis de triglicérides. Os parentes de 1º grau também apresentavam mais sinais clínicos de hiperandrogenismo. CONCLUSÕES: parentes de primeiro grau do sexo masculino das pacientes com SOP apresentam maior grau de dislipidemia e de resistência à insulina, além de níveis mais baixos de SHBG com mais sinais clínicos de hiperandrogenismo. Esses achados sugerem que a resistência à insulina pode ter origem hereditária em indivíduos com história familiar de SOP, independentemente de parâmetros antropométricos.

PURPOSE: to evaluate clinical and laboratory characteristics of first-degree male relatives of patients with a confirmed diagnosis of polycystic ovary syndrome (PCOS) and to compare the findings with a control group with no family history of PCOS. METHODS: we randomly selected 28 male individuals aged 18 to 65 years who were first-degree relatives of women diagnosed with PCOS and 28 controls matched for age, waist and body mass index (BMI). RESULTS: men with 1st degree kinship with women with PCOS had higher levels of triglycerides (189.6±103.1 versus 99.4±37.1, p<0.0001), Homeostasis Model Assessment (HOMA-IR) (3.5±9.1 versus 1.0±1.0, p=0.0077) and glucose (130.1±81.7 versus 89.5±7.8, p=0.005), and lower levels of sex hormone binding globulin (SHBG) (23.8±13.8 versus 31.1±9.1, p=0.003). SHBG levels correlated independently with triglyceride levels. These individuals also had more clinical signs of hyperandrogenism. CONCLUSIONS: male individuals who are first-degree relatives of patients with PCOS have a higher degree of dyslipidemia and insulin resistance, lower levels of SHBG, and more evident clinical signs of hyperandrogenism. These findings suggest that insulin resistance may be of hereditary origin in individuals with a family history of PCOS regardless of anthropometric parameters.

Espectro fenotípico del síndrome de ovario poliquístico / Phenotypic spectrum of polycystic ovary syndrome

Antecedentes: El síndrome de ovario poliquístico (SOP) es la endocrinopatía más frecuente en la mujer de edad reproductiva, de etiología incierta y presentación clínica heterogénea. Su diagnóstico y defnición es aún controversial. La introducción de los criterios del Consenso de Rotterdam generó nuevos fenotipos al incorporar la ecografía transvaginal como elemento diagnóstico, aumentando aún más la heterogeneidad del síndrome. Objetivo: Determinar en una cohorte consecutiva de 102 pacientes con diagnóstico de SOP, su frecuencia, las características clínicas, hormonales y metabólicas, de los cuatro fenotipos posibles según Rotterdam. Resultados: Fenotipo A 62 por ciento, Fenotipo B 21 por ciento, Fenotipo C 9 por ciento y Fenotipo D 8 por ciento. El síndrome metabólico se presentó en 29 por ciento de las pacientes, siendo mayor en los fenotipos A (30 por ciento) y B (43 por ciento) que en los fenotipos C (11 por ciento) y D (13 por ciento). El 82 por ciento presentaba sobrepeso, siendo signifcativamente mayor en los fenotipos A (88 por ciento) y B (90 por ciento). Hubo diferencias signifcativas al comparar las variables puntaje de hir-sutismo, SHBG, testosterona total, IAL, volumen ovárico, colesterol total, colesterol HDL, colesterol LDL y glicemia en ayuno. No existieron diferencias signifcativas entre los grupos al comparar las variables edad, IMC, DHEA-SO4 y triglicéridos. Conclusión: El consenso de Rotterdam agruparía a diferentes fenotipos en un mismo síndrome, que podrían representar distintos grados de severidad de una misma enfermedad. Se desconoce si estos fenotipos poseen los mismos riesgos a largo plazo y sería apresurado tratarlos como una misma entidad.

Background: Policystic ovary syndrome (PCOS) is a very common endocrine disease in women of reproductive age, of uncertain etiology and heterogeneous clinical presentation. The introduction of the Rotterdams Consensus criteria generated new phenotypes by incorporating transvaginal ultrasound, thus increasing the heterogenity of PCOS. Objectives: To determine in a cohort of 102 patients with the diagnosis of PCOS the prevalence, clinical, hormonal and metabolic profle according to Rotterdam. Results: It was determined the Phenotype A 62 percent Phenotype B 21 percent, Phenotype C 9 percent and Phenotype D 8 percent of the patients. The metabolic syndrome was present in 29 percent of the PCOS patients, being it more frequent in the phenotypes A (30 percent) and B (43 percent) than C (11 percent) and D (13 percent). The 82 percent of the patients were overweigth, especially in the phenotypes A (88 percent) and B (90 percent). Also, statistically signifcant differences were observed when comparing the variables score of hirsutism, free androgen index, total testosterone, HDL cholesterol SHBG, ovarian volume, total cholesterol, glycemia and LDL cholesterol. There were no signifcant differences between the groups to compare variables such as age, BMI, DHEA and triglycerides. Conclusion: These fndings indicate that the consensus of Rotterdam would agroup different phenotypes in the same syndrome and that it may represent different degrees of severity of the same disease. Even though, we do not know if these phenotypes posses the same health risks, therefore it is soon to manage the phenotypes as equal entities.

Relación entre el polimorfismo -34 Bp de la región promotora del gen CYP17 con el perfil hormonal y metabólico en mujeres con diabetes mellitus tipo 1 / Relationship of -34 Bp polymorphism in the promoter of Cyp17 gene with hormonal and metabolic profile in women with type 1 diabetes mellitus

The P450c17a enzyme has a central role in ovarian hyperandrogenism, which is a characteristic of polycystic ovary syndrome (PCOS). Several studies have suggested a possible role for the CYP17 gene, which codes for the enzyme P450c17a and the -34bp T-C polymorphism in the development of hyperandrogenism. The presence of the cytosine, know as A2 allele, has been associated with hyperandrogenism in patients with PCOS. Objective: To evaluate the frequency and association of the -34bp polymorphism in the CYP17 gene and determine its association with hormonal and metabolic characteristics in women with DM1. Patients and Methods: The CYP17 polymorphism was studied in 72 DM1 and 71 control women by PCR and RFLP analysis. The CYP17 genetic dosage was compared with the antropometrical characteristics and the serum concentrations of testosterone, androstenedione, DHEAS and 17OH progesterone in women with DM1. Results: Genotype A2/A2 was present in 20.8 percent and 7.1 percent of DM1 and controls, respectively (p = 0,034). Allele A2 was present in 40.3 percent and 27.5 percent of DM1 and healthy women, respectively (p = 0,031). No association between CYP17 genotypes and hormonal or metabolic characteristics was observed. Conclusion: This study shows that the frequency of the A2/A2 genotype was higher in women with DM1 than in the control group. However, no association between the presence of the polymorphism and circulating steroid levels or BMI was observed.

Polimorfismos en los genes CYP11α y CYP17 y etiología del hiperandrogenismo en pacientes con poliquistosis ovárica / Polymorphism in CYP11alpha and CYP17 genes and the etiology of hyperandrogenism in patients with polycystic ovary syndrome

El síndrome de poliquistosis ovárica (PCOS) es un desorden endocrino-metabólico de naturaleza multifactorial, con una marcada predisposición genética, que afecta al 6% de las mujeres en edad reproductiva. Se caracteriza por la presencia de hiperandrogenismo, oligo-anovulación y ovarios poliquísticos. Entre los genes candidatos se encuentran aquellos que codifican para enzimas que actúan en la síntesis de andrógenos. Dos de los genes candidatos son el CYP17 y el CYP11alfa que codifican para la 17alfa hidroxilasa (P45017alfa) y para el P450scc (colesterol side chain cleavage) respectivamente. Los polimorfismos en estos genes están asociados al desarrollo del fenotipo hiperandrogénico. Nuestro objetivo fue analizar las frecuencias alélicas de los polimorfismos de los dos genes mencionados en población con PCOS, compararla con población normal y analizar la relación de cada variante alélica con el fenotipo hiperandrogénico correspondiente. Se analizaron 65 pacientes y 58 controles sanos en los que se determinaron niveles de testosterona y frecuencia de polimorfismos en los genes mencionados. Se observó una diferencia estadísticamente significativa cuando se asoció el grupo de mayor nivel de androgenemia con la presencia del genotipo A2/A2 del gen CYP17, y se hallaron mayores niveles de andrógenos circulantes en las pacientes con PCOS portadoras del alelo 216- del gen CYP11alfa. Nuestros resultados sugieren que ambos alelos juegan un rol menor en el desarrollo de PCOS y podrían ser considerados como potenciales marcadores de riesgo genético para el desarrollo del fenotipo hiperandrogénico.

The polycystic ovary syndrome (PCOS) is a heterogeneous multifactorial endocrine metabolic disorder with genetic predisposition affecting 6% of women in the reproductive age. This syndrome is characterized by the presence of oligo-anovulation, hyperandrogenism and polycystic ovaries. Several genes have been postulated as responsible for the etiology of this disorder. Among these genes are those encoding the enzymes involved in the ovarian androgen biosynthesis. Two of the candidate genes are the CYP17 and the CYP11alpha, encoding the 17-alpha-hydroxylase (P45017alpha) and the cholesterol side chain cleavage (P450scc) respectively. The polymorphisms of these genes are linked to the development of an hyperandrogenic phenotype. The aim of this work was to analyze the allelic frequencies of such polymorphisms in a cohort of women with PCOS and to compare them with those of healthy women. Furthermore, the correlation between each allelic variant and the corresponding hyperandrogenic phenotype was also assessed. Therefore, 65 patients and 58 age matched healthy controls were analyzed. The serum levels of testosterone and the frequency of each polymorphism were determined. When the PCOS population was analyzed, a significant statistical difference was found when relating the group with the highest androgenemia level with the presence of A2/A2 genotype of CYP 17 gene, and a higher level of circulating androgen was found in PCO women carrying the 216- allele of CYP11alpha gene (that did not reach statistical significance). Our results suggest that both alleles play a minor role in the development of PCOS and could be a genetic risk marker of the hyperandrogenic phenotype.