Association of the (TAAAA)n repeat polymorphism of SHBG gene with the age at menopause in Greek postmenopausal women.

OBJECTIVE: To assess the potential association of the pentanucleotide (TAAAA)n repeat polymorphism in the promoter of SHBG gene with the age at menopause in a Greek female population. STUDY DESIGN: Cross-sectional study. Two hundred and ten postmenopausal women aged 46-63 years were enrolled. The age at the last menstrual period and anthropometric parameters were recorded in all participants. Blood sampling for genotyping of the (TAAAA)n polymorphism of SHBG gene was performed. MAIN OUTCOME MEASURE(S): Frequency and association of the (TAAAA)n alleles with age at menopause. RESULTS: The alleles with seven and eight TAAAA repeats were associated with the age at menopause. The age at menopause was higher in carriers than in non-carriers of the (TAAAA)7 allele (50.2±3.1 years vs. 48.0±4.8 years, p=0.026). Furthermore, the age at menopause was lower in women carrying the (TAAAA)8 allele (47.5±4.8 years) than in women not carrying this allele (48.8±4.4 years, p=0.048). CONCLUSIONS: The (TAAAA)7 and (TAAAA)8 alleles of the SHBG (TAAAA)n polymorphism may contribute to variation in the timing of natural menopause in postmenopausal women of Northwestern Greece.

Influence of FSHR diplotypes on ovarian response to standard gonadotropin stimulation for IVF/ICSI.

OBJECTIVE: To explore the association of FSHR 307 (T/A)/FSHR 680(N/S) diplotypes with ovarian response to follicle stimulating hormone (FSH) stimulation of women undergoing medically assisted reproduction (in vitro fertilization [IVF] or intracytoplasmic sperm injection [ICSI]). STUDY DESIGN: The study population consisted of 304 women undergoing IVF/ICSI and 300 women with at least 1 spontaneous pregnancy as controls. FSHR polymorphisms were genotyped. Controlled ovarian stimulation and IVF/ICSI were performed in the 304 couples. During oocyte retrieval the follicular size, the follicle and oocyte numbers were recorded. Serum FSH, luteinizing hormone and estradiol were determined at the third day of the menstrual cycle. RESULTS: The FSHR 307(T/A)/FSHR 680(N/S) diplotype analysis revealed lower serum FSH levels, higher follicle and oocyte numbers, increased numbers of large follicles as well as decreased empty follicle numbers in Thr307Thr/Asn680Asn women as compared to Thr307 Ala/Asn680Ser and Ala307Ala/Ser680Ser women (p < 0.006, p < 0.01, p < 0.008, p < 0.01, p < 0.005, respectively). CONCLUSION: FSHR diplotypes were significantly associated with ovarian response to gonadotropin stimulation. FSHR diplotype analysis could be informative for ovarian stimulation outcome and the selection of the proper stimulation protocol, which would ensure a sufficient number of mature oocytes for IVF/ICSI.

CYP19 gene variants affect the assisted reproduction outcome of women with polycystic ovary syndrome.

OBJECTIVE: Cytochrome P450 aromatase catalyzes the irreversible transformation of androgens into estrogens. The association of CYP19(TTTA)n polymorphism with the hormonal profile and the assisted reproduction outcome of women with polycystic ovary syndrome (PCOS) was explored. METHODS: One hundred and thirty-two women with PCOS and 200 with male-factor infertility, as controls, participated in the current study. The CYP19(TTTA)n polymorphism was genotyped, while the hormonal profile was determined at the third day of the menstrual cycle. During oocyte retrieval, the follicular size, the follicle and oocyte numbers were recorded. RESULTS: Genotype analysis revealed 6 CYP19(TTTA)n alleles with 7-12 repeats. In PCOS women, the CYP19(TTTA)7 allele presence was associated with lower serum E2 levels at the third day of the menstrual cycle (p < 0.009), lower large follicle (p < 0.02) and total oocyte numbers (p = 0.006), but with significantly higher pregnancy rates after assisted reproduction (p < 0.004). CONCLUSIONS: Potential associations of the CYP19(TTTA)7 allele with ovarian response to standard gonadotrophin stimulation and with assisted reproduction outcome were found in PCOS women, probably due to androgen/estrogen ratio alterations.

The ovarian response to standard gonadotrophin stimulation depends on FSHR, SHBG and CYP19 gene synergism.

PURPOSE: Follicle stimulating hormone, sex hormone-binding globulin and cytochrome P450 aromatase play crucial roles in the regulation of mammalian reproduction. The synergistic effect of FSHR 307(T/A)/FSHR 680(N/S), SHBG(TAAAA) ( n ) and CYP19(TTTA) ( n ) genotypes on ovarian response to standard gonadotrophin stimulation of women undergoing medically assisted reproduction (IVF/ICSI) was explored. METHODS: The study population consisted of 300 women under IVF/ICSI treatment and 300 women with at least with at least one successful child birth as controls. The polymorphisms were genotyped while the follicular size, the follicle and oocyte numbers were recorded during oocyte retrieval. RESULTS: The genotype analysis, excluding heterozygotes for each particular polymorphism, revealed eight combined homozygotic FSHR/SHBG/CYP19 genotypes. A gradual reduction in the number of follicles and oocytes from FSHR 307Thr/680Asn allele/long SHBG allele/long CYP19 allele homozygotes to FSHR 307Ala/680Ser allele/short SHBG allele/short CYP19 allele homozygotes was observed (20.36 ± 6.74 vs. 8.05 ± 2.47, p < 0.008 and 13 ± 4.63 vs. 6.1 ± 2.32, p < 0.02, respectively). CONCLUSIONS: FSHR/SHBG/CYP19 combined genotypes are associated with ovarian response to standard gonadotrophin stimulation of women undergoing medically assisted reproduction.

Phosphatidylethanolamine N-methyltransferase and choline dehydrogenase gene polymorphisms are associated with human sperm concentration.

Choline is a crucial factor in the regulation of sperm membrane structure and fluidity, and this nutrient plays an important role in the maturation and fertilizing capacity of spermatozoa. Transcripts of phosphatidylethanolamine N-methyltransferase (PEMT) and choline dehydrogenase (CHDH), two basic enzymes of choline metabolism, have been observed in the human testis, demonstrating their gene expression in this tissue. In the present study, we explored the contribution of the PEMT and CHDH gene variants to sperm parameters. Two hundred oligospermic and 250 normozoospermic men were recruited. DNA was extracted from the spermatozoa, and the PEMT -774G>C and CHDH +432G>T polymorphisms were genotyped. The genotype distribution of the PEMT -774G>C polymorphism did not differ between oligospermic and normozoospermic men. In contrast, in the case of the CHDH +432G>T polymorphism, oligospermic men presented the CHDH 432G/G genotype more frequently than normozoospermic men (62% vs. 42%, P<0.001). The PEMT 774G/G genotype was associated with a higher sperm concentration compared to the PEMT 774G/C and 774C/C genotypes in oligospermic men (12.5 ± 5.6 × 10(6) spermatozoa ml(-1) vs. 8.3 ± 5.2 × 10(6) spermatozoa ml(-1), P<0.002) and normozoospermic men (81.5 ± 55.6 × 10(6) vs. 68.1 ± 44.5 × 10(6) spermatozoa ml(-1), P<0.006). In addition, the CHDH 432G/G genotype was associated with higher sperm concentration compared to CHDH 432G/T and 432T/T genotypes in oligospermic (11.8 ± 5.1 × 10(6) vs. 7.8 ± 5.3 × 10(6) spermatozoa ml(-1), P<0.003) and normozoospermic men (98.6 ± 62.2 × 10(6) vs. 58.8 ± 33.6 × 10(6) spermatozoa ml(-1), P<0.001). In our series, the PEMT -774G>C and CHDH +432G>T polymorphisms were associated with sperm concentration. This finding suggests a possible influence of these genes on sperm quality.

Association of TNFα, TNFR1, and TNFR2 polymorphisms with sperm concentration and motility.

Tumor necrosis factor α (TNFα) is a multifunctional cytokine that regulates various cellular processes related to spermatogenesis. Two types of cell receptors, TNFR1 and TNFR2, mediate TNFα activity. In the present study, we sought to explore the association of TNFα -857C→T, TNFR1 36A→G, and TNFR2 676T→G polymorphisms with sperm concentration and motility. Two hundred ninety men were examined during infertility investigation; of those, 170 men were normozoospermic and 120 were oligospermic. Polymerase chain reaction analysis revealed significant differences in genotype distribution of the TNFR1 36A→G polymorphism between normozoospermic and oligospermic men. Men with oligozoospermia presented TNFR1 36A/A genotypes less frequently than normozoospermic men (P < .001). The presence of the TNFR1 36G allele was significantly increased in oligospermic men (P < .001). Furthermore, the presence of the TNFR1 36G allele was associated with lower sperm concentration in normozoospermic men (P < .03) and in the total study population (P < .001), and with lower sperm motility in normozoospermic men (P < .007) and in the total study population (P < .001). No significant associations were found between TNFα -857C→T and TNFR2 676T→G polymorphisms and semen quality. The TNFR1 36A allele is associated with increased sperm concentration and motility in our series, supporting the significance of TNFR1 gene in semen quality.

Aromatase (CYP19) gene variants influence ovarian response to standard gonadotrophin stimulation.

PURPOSE: The association of cytochrome P450 aromatase gene CYP19(TTTA) ( n ) polymorphism with ovarian response to FSH stimulation was explored. METHODS: Three hundred women undergoing medically assisted reproduction and 300 women with at least one spontaneous pregnancy participated in the study. CYP19(TTTA) ( n ) polymorphism was genotyped, while serum hormones were determined. During oocyte retrieval, the follicular size, the follicle and oocyte numbers were recorded. RESULTS: Six CYP19(TTTA) ( n ) alleles with 7 to 12 repeats were revealed. Women homozygous for long CYP19(TTTA) ( n ) alleles presented with lower serum FSH levels at the third day of the menstrual cycle (p < 0.001) and higher large follicle numbers (p < 0.01), compared to women homozygous for short CYP19(TTTA) ( n ) alleles. The CYP19(TTTA) ( 7 ) allele was associated with higher serum FSH levels (p < 0.003), with lower total follicle (p < 0.02) and large follicle numbers (p < 0.03), while CYP19(TTTA) ( 7 ) allele-carriers presented more frequently with small follicles than CYP19(TTTA) ( 7 ) allele-non carriers (p < 0.01). CONCLUSIONS: CYP19 genetic variants were associated with ovarian reserve and response to standard gonadotrophin stimulation of women undergoing in vitro fertilization.

The association of aromatase (CYP19) gene variants with sperm concentration and motility.

The irreversible transformation of androgens into oestrogens is catalysed by cytochrome P450 aromatase. In the present study, we explored the contribution of the (TTTA)(n) polymorphism in the aromatase gene (CYP19) to sperm concentration and motility. Ninety normozoospermic and 60 oligospermic men were examined during infertility examinations. DNA was extracted from spermatozoa, and the CYP19 (TTTA)(n) polymorphism was genotyped by PCR. Genotype analysis revealed six CYP19 (TTTA)(n) alleles with 7-12 repeats. The allelic distribution of the CYP19 (TTTA)(n) polymorphism differed between normozoospermic and oligospermic men (P<0.01). Oligospermic men less frequently had long CYP19 alleles than did normozoospermic men (25 and 37.8%, respectively; P<0.02). The higher frequency of short CYP19 alleles in oligospermic men compared to normozoospermic men (43.3 and 28.3%, respectively; P<0.01) was primarily due to the distribution of the CYP19 (TTTA)(7) allele. The CYP19 (TTTA)(7) allele was associated with lower sperm concentration in normozoospermic men (P<0.01) and in the total study population (P<0.01); it was also associated with lower sperm motility in normozoospermic men (P<0.05) and in the total study population (P<0.01). In conclusion, the CYP19 (TTTA)(7) allele probably impairs aromatase activity, which in turn alters aromatase and oestrogen levels in the testis, leading to decreased sperm concentration and motility. These findings support the significance of cytochrome P450 aromatase in human spermatogenesis and consequently in semen quality.

Association of serum and follicular fluid SHBG levels and SHBG (TAAAA)n polymorphism with follicle size in women undergoing ovarian stimulation.

OBJECTIVE: Sex hormone-binding globulin (SHBG) is the main transport protein of sex steroids. Recently, it has been found to be produced by granulosa lutein cells, suggesting a local role of SHBG in the ovary. The aim of this study was to investigate whether serum and follicular fluid SHBG levels and SHBG (TAAAA)(n) polymorphism are related to follicle size and pregnancy rate in women undergoing in vitro fertilisation. METHODS: The study population consisted of 154 women with tubal and/or male-factor infertility undergoing IVF/ICSI and follicular fluid with oocytes from small (diameter ≤12 mm) and large (diameter ≥18 mm) follicles were studied. Genotyping of SHBG (TAAAA)(n) polymorphism was performed in peripheral blood samples. Serum and follicular fluids were used for hormones determination. RESULTS: Women with short allele genotypes (with less than 8 TAAAA repeats) had higher number of small follicles compared to women with long allele genotypes (5.6 ± 3.9 vs. 3.5 ± 3.2 small follicles, p < 0.003). Follicular fluid SHBG levels correlated positively with serum SHBG levels (p < 0.001) and with the total number of follicles (p < 0.02). Furthermore, small follicles had higher follicular fluid SHBG concentration compared to large follicles (102.9 ± 35.0 nmol/l vs. 85.85 ± 34.88 nmol/l, p < 0.028). CONCLUSION: SHBG levels and the SHBG (TAAAA)(n) polymorphism are associated with follicle size.

Association of paraoxonase gene polymorphisms with sperm parameters.

Paraoxonase (PON) is a high-density lipoprotein-associated enzyme that prevents low-density lipoprotein oxidation. PON proteins, localized in the seminiferous tubules and in spermatozoa, have been implicated in the pathogenesis of male infertility. In the present study, we sought to explore the contribution of the PON gene variants to sperm parameters. One hundred twenty oligospermic and 170 normozoospermic men were examined during infertility investigation. DNA was extracted from spermatozoa, and the PON1(L/M) 55, PON1(Q/R) 192, and PON2(S/C) 311 polymorphisms were genotyped by polymerase chain reaction and digestion with restriction enzymes. The analysis revealed that oligospermic men presented PON1 55L/L, PON1 192Q/Q, and PON2 311S/S genotypes less frequently than normozoospermic men (P < .01, P < .01, and P < .001, respectively), whereas the PON1 55M, PON1 192R, and PON2 311C alleles were significantly increased in oligospermic men (P < .004, P < .008, and P < .008, respectively). The presence of PON1 55L allele was associated with higher sperm motility in oligospermic men (P < .001), in normozoospermic men (P < .01), and in the total study population (P < .01), and the PON1 192Q allele was associated with higher sperm motility in oligospermic men (P < .01), in normozoospermic men (P < .04) and in the total study population (P < .03). On the other hand, the PON2 311S was associated with higher sperm concentration in oligospermic men (P < .03), in normozoospermic men (P < .008), and in the total study population (P < .001). In our series, the PON1 55M and PON1 192R alleles were associated with decreased sperm motility whereas the PON2 311C allele was associated with decreased concentration, supporting the significance of PON genes in semen quality.

CYP19 gene: a genetic modifier of polycystic ovary syndrome phenotype.

OBJECTIVE: To evaluate the possible contribution of the (TTTA)n polymorphism of aromatase gene (CYP19) to the hyperandrogenic phenotype of polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: Endocrine outpatients' clinic of a tertiary university hospital. PATIENT(S): One hundred eighty women with PCOS and 160 healthy controls of reproductive age. INTERVENTION(S): Blood sampling for genotype analysis, and measurement of androgens, E(2), LH, FSH, and fasting glucose and insulin. MAIN OUTCOME MEASURE(S): Frequency of the CYP19(TTTA)n polymorphism and association with hormone concentrations. RESULT(S): Women with PCOS tended to have more frequently short (TTTA)n alleles (with nine or fewer repeats) than healthy controls (33.1% vs. 29.5%), although the difference was not statistically significant. However, patients in the highest quartile for serum T were more frequently homozygous for short alleles compared with controls (59.1% vs. 42.1%) and patients in lower quartiles (59.1% vs. 36.9%). Furthermore, the patients homozygous for short alleles had higher T/E(2) ratios, higher T levels, and higher LH/FSH ratios compared with those with longer alleles. CONCLUSION(S): Although CYP19 may not be a major genetic determinant of PCOS, it may act as a genetic modifier of the hyperandrogenic phenotype of PCOS. The presence of short CYP19(TTTA)n alleles may contribute to prenatal androgenization programming the development of PCOS phenotype in adult life.

Estrogen receptor alpha and beta polymorphisms are associated with semen quality.

The role of estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) gene polymorphisms on semen quality is the aim of our study. One hundred fourteen men were examined in the In Vitro Fertilization Unit of Ioannina Medical School, and it was found that 85 men had normal sperm count and 29 were oligozoospermic. The genotype analysis, on DNA extracted from spermatozoa, revealed that in men with oligozoospermia (sperm concentration <20 x 10(6) spermatozoa/mL), those with ER alpha 397T/C and 397C/C genotypes had higher sperm motility whereas those with 397T/T genotype had lower sperm motility (P = .003). In addition, men with ER alpha 351A/A genotype had lower sperm motility compared with 351A/G and 351 G/G genotypes (P = .013). Furthermore, normal-sperm-count men with ER alpha 397T/T genotype had higher sperm concentration compared with 397T/C and 397C/C genotypes (P = .016), whereas men with ER alpha 351A/A genotype had higher sperm concentration than those with 351A/G and 351G/G genotypes (P = .05). In contrast, no significant associations were found between ER beta (1082G-->A and 1730A-->G) polymorphisms and sperm concentration or motility. In conclusion, ER alpha polymorphisms were found to be associated with sperm motility and concentration. supporting the significance of this gene in spermatogenesis and semen quality.

Genetic variants of sex hormone-binding globulin and their biological consequences.

Several hormonal and metabolic factors have been found to influence the production of sex hormone-binding globulin (SHBG). In addition, twin studies have suggested that genetic factors may also contribute to variation in SHBG levels. Given the clinical significance of SHBG in regulating bioavailable sex steroid hormones, a number of studies examined the potential association between polymorphisms of SHBG gene and serum SHBG levels as well as their possible contribution in the pathogenesis of common diseases. Thus, polymorphisms of SHBG, altering either the production or the metabolism of the protein, may represent part of the genetic background of sex steroid hormone activity in humans. There is considerable heterogeneity in the results of these studies indicating the multiplicity of the factors influencing SHBG variation. However, the weight of evidence suggests that some common genetic variants of SHBG may influence SHBG levels and in part contribute to the phenotypic expression of human diseases.

The Pro12Ala polymorphism of the PPAR-gamma gene is not associated with the polycystic ovary syndrome.

OBJECTIVE: Insulin resistance is a key factor in the pathogenesis of polycystic ovary syndrome (PCOS). Peroxisome proliferator-activated- receptor-gamma (PPAR-gamma) has been implicated in insulin resistance and adiposity. The aim of the study was to investigate the possible involvement of the Pro12Ala polymorphism of the PPAR-gamma gene in the pathogenesis of PCOS. DESIGN: We studied 180 women with PCOS and 140 healthy controls. Body mass index (BMI) was recorded. Blood samples were drawn after overnight fasting and serum glucose, insulin, lipid and hormonal profiles were determined. The fasting glucose/insulin ratio and HOMA index were calculated. Moreover, 100 women with PCOS underwent a 75g oral glucose tolerance test and the area under the curve for insulin and glucose was estimated. DNA was extracted from peripheral blood leucocytes and the Pro12Ala polymorphism was genotyped. RESULTS: The PPAR-gamma genotypes were found to be in the Hardy-Weinberg equilibrium in both study groups. No difference was found in the distribution of the Pro12Ala polymorphism between PCOS and controls. Insulin resistance indices and lipid and hormonal profile were not different among the various genotypes of the Pro12Ala polymorphism. CONCLUSIONS: The Pro12Ala polymorphism of the PPAR-gamma gene is not involved in the pathogenesis or the phenotypic expression of PCOS.

The synergistic effect of sex hormone-binding globulin and aromatase genes on polycystic ovary syndrome phenotype.

OBJECTIVE: Experimental evidence suggests that fetal exposure to androgen excess may program the development of polycystic ovary syndrome (PCOS) in utero. The aim of this study was to examine whether the sex hormone binding globulin (SHBG)(TAAAA)n and the cytochrome P450, family 19 (CYP19)(TTTA)n polymorphisms, known to influence sex hormone-binding globulin (SHBG) levels and aromatase activity respectively, play a synergistic role in the development of PCOS. DESIGN AND METHODS: We studied 180 women with PCOS and 160 healthy women of reproductive age. The body mass index (BMI) was recorded and the hormonal profile determined from the third to fifth day of menstrual cycle. DNA was extracted from blood leucocytes and the SHBG(TAAAA)n and CYP19(TTTA)n polymorphisms were genotyped. RESULTS: Genotype analysis revealed 6 SHBG(TAAAA)n alleles with 6-11 repeats and 6 CYP19(TTTA)n alleles with 7-12 repeats. Women were subdivided into four groups: those with short SHBG (< or = 8 TAAAA repeats) and CYP19 alleles (< or = 9 TTTA repeats), those with short SHBG-long CYP19 alleles, those with long SHBG-short CYP19 alleles, and those with long SHBG and CYP19 alleles. Women with PCOS tended to have at greater frequency, long SHBG-short CYP19 alleles compared with controls (57.3 vs 42.4%, P=0.07). Importantly, PCOS women with long SHBG-short CYP19 alleles had the lowest SHBG levels (P=0.02) and the highest total testosterone (P=0.008), free androgen index (P=0.002), DHEAS (P=0.02), and testosterone/estradiol ratio (P=0.03), compared with those with other genotypes. This association was independent of age, BMI, and insulin resistance indexes. CONCLUSION: We speculate that the SHBG and CYP19 genes may have a synergistic role in the developmental programming of PCOS, by affecting androgen bioavailability and aromatization respectively.

The importance of the (TAAAA)n alleles at the SHBG gene promoter for the severity of coronary artery disease in postmenopausal women.

OBJECTIVE: Androgen may be detrimental in the development of coronary artery disease (CAD) in women. We investigated possible associations between the (TAAAA)n polymorphism of sex hormone-binding globulin (SHBG) gene promoter, which influences transcriptional efficiency of the SHBG gene and the severity of CAD in women. DESIGN: In this prospective clinical study, 146 postmenopausal women (46-88 y) undergoing coronary angiography were studied. CAD severity, history of angina and myocardial infarction, and reproductive history were recorded and hormonal parameters measured. According to the number of SHBG gene promoter repeat polymorphisms, participants were classified into short (seven or fewer), medium length (eight), and long repeat (nine or more) allele groups. RESULTS: Significant CAD was more prevalent in the long repeat allele carrier group: 65% of the participants with three vessels with severe stenosis belonged to the long repeat allele group, whereas only 37% of participants with mild CAD belonged to this group (P=0.01). A history of angina and prevalence of hyperlipidemia was more frequent in the long repeat allele group (P<0.05). Calculated free testosterone levels were higher in the long repeat allele groups (P<0.05), whereas SHBG levels tended to be lower (P=0.06). SHBG levels correlated inversely with body mass index and waist circumference (P<0.05). CONCLUSIONS: Longer (TAAAA)n repeats in the SHBG gene promoter are associated with more severe CAD in women undergoing coronary angiography, a finding not previously reported. This association may reflect the lifelong tissue exposure to higher free androgens and supports the adverse cardiovascular effect of androgenic exposure in this highly selected group of women.

The adiponectin-to-leptin ratio in women with polycystic ovary syndrome: relation to insulin resistance and proinflammatory markers.

Central adiposity plays an important role in the insulin resistance of the polycystic ovary syndrome (PCOS) through the dysregulated production of various adipokines. Polycystic ovary syndrome has also been described as a low-grade inflammation state characterized by elevated levels of C-reactive protein (CRP). Furthermore, CRP is a strong independent predictor of the metabolic syndrome and cardiovascular disease. Recently, the adiponectin-to-leptin (A/L) ratio has been proposed as a potential atherogenic index in obese type 2 diabetic patients. The aim of this study was to evaluate the potential role of the A/L ratio in the metabolic and proinflammatory phenotype of PCOS. We studied 74 Greek women with PCOS (38 normal-weight and 36 overweight-obese women). The A/L ratio was negatively correlated with BMI (r = -0.79 P < .001), homeostasis model assessment (r = -0.642, P < .001), triglycerides (r = -0.67, P < .001), and total cholesterol (r = -0.38, P < .01), and positively correlated with high-density lipoprotein cholesterol (r = 0.38, P < .01) and sex hormone-binding globulin (r = 0.39, P = .001). After controlling for BMI, the A/L ratio was independently associated with insulin resistance indexes and triglycerides. Furthermore, the A/L ratio was negatively correlated with CRP (r = -0.746, P < .0001). Multiple regression analysis revealed that BMI and the A/L ratio were the only independent significant determinants of CRP (beta = .436, P = .003 and beta = -.398, P = .007, respectively). Studying normal-weight and overweight-obese women separately, we found an independent association between the A/L ratio and CRP in both groups (beta = -.460, P = .009 in normal-weight women and beta = -.570, P = .001 in overweight-obese women). In conclusion, the A/L ratio may serve as a biomarker of both insulin resistance and low-grade inflammation, providing the link between these cardiovascular risk factors in women with PCOS.

Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder of premenopausal women, characterized by hyperandrogenism, polycystic ovaries, and chronic anovulation along with insulin resistance and abdominal obesity as frequent metabolic traits. Although PCOS manifests clinically during adolescence, emerging data suggest that the natural history of PCOS may originate in intrauterine life. EVIDENCE ACQUISITION: Evidence from experimental, clinical, and genetic research supporting the hypothesis for the fetal origins of PCOS has been analyzed. EVIDENCE SYNTHESIS: Female primates, exposed in utero to androgen excess, exhibit the phenotypic features of PCOS during adult life. Clinical observations also support a potential fetal origin of PCOS. Women with fetal androgen excess disorders, including congenital 21-hydroxylase deficiency and congenital adrenal virilizing tumors, develop features characteristic of PCOS during adulthood despite the normalization of androgen excess after birth. The potential mechanisms of fetal androgen excess leading to a PCOS phenotype in humans are not clearly understood. However, maternal and/or fetal hyperandrogenism can provide a plausible mechanism for fetal programing of PCOS, and this, in part, may be genetically determined. Thus, genetic association studies have indicated that common polymorphic variants of genes determining androgen activity or genes that influence the availability of androgens to target tissues are associated with PCOS and increased androgen levels. These genomic variants may provide the genetic link to prenatal androgenization in human PCOS. CONCLUSION: Prenatal androgenization of the female fetus induced by genetic and environmental factors, or the interaction of both, may program differentiating target tissues toward the development of PCOS phenotype in adult life.