Digit ratios by computer-assisted analysis confirm lack of anatomical evidence of prenatal androgen exposure in clinical phenotypes of polycystic ovary syndrome.

BACKGROUND: We recently showed that women with four clinical phenotypes of polycystic ovary syndrome (PCOS) do not demonstrate anatomical evidence of elevated prenatal androgen exposure as judged by a lower ratio of the index (2D) to ring (4D) finger. However, those findings conflicted with a previous study where women with PCOS had lower right hand 2D:4D compared to healthy female controls. Both these studies used Vernier calipers to measure finger lengths--a method recently shown to be less reliable at obtaining finger length measurements than computer-assisted analysis. METHODS: Ninety-six women diagnosed with PCOS according to the 2003 Rotterdam criteria had their finger lengths measured with computer-assisted analysis. Participants were categorized into four recognized phenotypes of PCOS and their 2D:4D compared to healthy female controls (n = 48) and men (n = 50). RESULTS: Digit ratios assessed by computer-assisted analysis in women with PCOS did not differ from female controls, but were significantly lower in men. When subjects were stratified by PCOS phenotype, 2D:4D did not differ among phenotypes or when compared to female controls. CONCLUSION: Computer-assisted measurements validated that digit ratios of women with PCOS do not show anatomical evidence of increased prenatal androgen exposure.

Digit ratios do not serve as anatomical evidence of prenatal androgen exposure in clinical phenotypes of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is heterogeneous in its clinical presentation and four major phenotypes have been identified. The precise etiology of PCOS is unknown; however, variable exposure to prenatal androgens may be responsible for the spectrum of endocrine and metabolic disturbances characteristic of this syndrome. Since prenatal testosterone exposure is known to decrease the ratio of the second to fourth finger lengths (2D:4D), we characterized the left and right hand 2D:4D in women with clinical variants of PCOS. We hypothesized that if prenatal androgens were involved in the development of the phenotypic spectrum of PCOS, then lower 2D:4D would be differentially expressed among clinical variants of the syndrome. METHODS: Digit ratios were determined in 98 women diagnosed with PCOS by the 2003 international consensus guidelines and in 51 women with regular menstrual cycles, no clinical or biochemical signs of hyperandrogenism and normal ovarian morphology. Women with PCOS were categorized into four clinical phenotypes (i.e. Frank, Non-PCO, Ovulatory and Mild) and 2D:4D among groups were compared by Tukey-Kramer multiple comparisons tests. RESULTS: Left (P = 0.77) and right (P = 0.68) hand 2D:4D were similar among the four clinical phenotypes and no phenotype of PCOS demonstrated a 2D:4D that differed from controls (Left Hand, P = 0.44 and Right Hand, P = 0.75). CONCLUSIONS: Women with PCOS do not demonstrate finger length patterns that are consistent with increased prenatal androgen exposure. These findings do not preclude a role for prenatal androgens in the development of PCOS; however, low 2D:4D are not a characteristic of PCOS.

Mass spectrometric and physiological validation of a sensitive, automated, direct immunoassay for serum estradiol using the Architect.

BACKGROUND: Measurement of estradiol (E(2)) plays a critical role in the diagnosis and clinical management of reproductive disorders. The challenge for all currently available direct methods for measuring E(2) is to provide accuracy and precision across a wide dynamic range. METHODS: We describe the development and multi-site performance evaluation of a direct E(2) assay on the Architect i2000. Assay performance and method comparisons were performed by testing specimens from men, healthy women with regular menstrual cycles, and post-menopausal women using the Architect assay and isotope dilution, gas chromatography-mass spectrometry (ID/GC-MS). Reference intervals were established by testing prospectively collected daily blood draws from 42 healthy women, 72 postmenopausal women and 101 males. RESULTS: No unexpected cross-reactivity or interference was observed for over 40 compounds tested. Recovery was 100+/-10% in the presence of estrone and estriol. Functional sensitivity (%CV<20%) was <15 pg/ml.(1) The imprecision of the assay was <7.1% (total CV), <2.5%, and <2.3% for control sera containing 45, 190, and 600 pg/ml estradiol, respectively. The assay had a correlation of y=1.033 x+0.3156, r(2)=0.99, n=131 compared to ID/GC-MS. Reference intervals for the current Architect Estradiol assay are reported. CONCLUSIONS: Format changes resulted in dramatic improvement in the performance and accuracy of this direct, fully automated assay. The assay is standardized by ID/GC-MS. The assay is clinically useful for serum concentrations from 15 to >4000 pg/ml.

Lipid peroxidation and protein modification in a mouse model of chronic iron overload.

Iron-storage diseases are believed to cause organ damage through generation of reactive oxygen species. Using a murine model of iron overload, we found that hepatic iron stores increased logarithmically during 3 weeks of chronic intraperitoneal administration of iron dextran, while hepatic glutathione peroxidase activity declined linearly by approximately 50% during the same period. Plasma concentrations of aliphatic aldehydes increased by 2- to 3-fold, and plasma malondialdehyde (MDA) by 6-fold. Modification of total liver protein by products of lipid peroxidation, including MDA-lysine, 4-hydroxynonenal-lysine, and N(epsilon)-(carboxymethyl)lysine (CML), increased by approximately 3-fold, while levels of the protein oxidation marker, methionine sulfoxide (MetSO), were unchanged. Skin collagen was resistant to modification until the third week, when 2- to 3-fold increases in both CML and MetSO were observed. Our results document that iron overload increases lipid peroxidation, with concomitant increases in reactive aldehydes in plasma and chemical modification of tissue proteins. CML was a sensitive indicator of hepatocellular oxidative stress, compared to MetSO, while extensive modification of extracellular skin collagen was not observed until the late stages of iron overload and oxidative stress. These observations provide direct evidence for the contribution of reactive oxygen species, lipid peroxidation, and reactive carbonyl intermediates to the pathogenesis of iron-overload diseases.