The role of androgen and its related signals in PCOS

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women at reproductive age. However, the underlying pathogenic mechanisms have not been completely understood. Hyperandrogenism is an important clinic feature in patients with PCOS, suggesting its pathologic role in the development and progression of PCOS. However, the actual role of androgen and the related signals in PCOS and PCOS-related complications have not yet been clarified. In this review, we surveyed the origin and effects of androgen on PCOS and the related complications, highlighted the cellular signals affecting androgen synthesis and summarized the pathological processes caused by hyperandrogenism. Our review well reveals the important mechanisms referring the pathogenesis of PCOS and provides important clues to the clinic strategies in patients with PCOS.     

Polycystic ovary syndrome: evidence for a primary disorder of ovarian steroidogenesis

Polycystic ovary syndrome (PCOS) is a very common endocrinopathy of uncertain aetiology in which the most consistent biochemical abnormality is hypersecretion of androgens. In this review, evidence is presented to support the view that a primary abnormality of ovarian androgen biosynthesis provides the basis for the syndrome. PCOS is a familiar disorder and we demonstrate, in molecular genetic studies, that CYP11a, the gene coding for P450 side chain cleavage, is a key susceptibility locus for development of hyperandrogenism.     

Steroidogenic alterations and adrenal androgen excess in PCOS

BACKGROUND: This cross-sectional study was undertaken to improve our understanding of the steroidogenic alterations leading to adrenal hyperandrogenism in polycystic ovarian syndrome (PCOS). METHODS: Two-hundred and thirty-four women with clinical and biochemical features suggestive of PCOS underwent metabolic and hormonal evaluation. We used the androstenedione/DHEAS ratio as a surrogate for the level of ovarian 3betaHSD activity. We then selected the 90th percentile for the ratio in those with elevated DHEAS (>9 micromol/l) as the cut-off level beyond which excess DHEAS production will be minimized by excess ovarian 3betaHSD activity. This cut-off level was at a ratio of 1.5 and all PCOS women were then divided into two groups, the higher (>1.5) being the group with excess ovarian 3betaHSD activity. We hypothesized that women with a high ratio would be unlikely to have DHEAS excess due to the rapid conversion of DHEA to androstenedione. Those with a low ratio (concordant ovarian and adrenal steroidogenesis) could then either have high DHEAS or normal DHEAS, depending on whether CYP17 activity was higher or lower respectively. RESULTS: Insulin resistance was found to be associated with decreased CYP17 activity while irregular cycles and neuroendocrine dysfunction were determined to be associated with higher ovarian 3betaHSD activity. CONCLUSION: Adrenal androgen excess in PCOS seems to be related to insulin sensitivity as well as decreased activity of 3betaHSD, the latter being preferentially present in those women with regular cycles or without neuroendocrine dysfunction.     

高雄激素相关的慢性炎症与多囊卵巢综合征的研究进展

多囊卵巢综合征是育龄妇女常见的慢性炎症代谢性疾病,70%以上患者出现高雄激素血症。下丘脑-垂体-性腺相关激素是月经周期和卵巢活动的调节器,脑神经元分泌的Kisspeptin、褪黑素通过下丘脑-垂体-卵巢轴调节Gn RH神经元AMH、Gn RH的表达,卵巢促性腺激素、雄激素水平增高,有利于慢性炎症的形成,促进多囊卵巢综合征的发生发展。本文综述了近几年多囊卵巢综合征中雄激素相关的慢性炎症研究,并根据相关研究提出了一些见解,希望能为多囊卵巢综合征的研究提供一些新的思路。     

Heritability estimation of conventional cardiovascular disease risk factors in Asian Indian families: The Calcutta family study

The genetic causes of the components of cardiovascular disease (CVD) risk factors and their intercorrelation are indeed complex and only partly understood. Keeping this view in mind, the present work was undertaken to estimate the heritability of conventional CVD risk factors using family study method. A total of twenty-four nuclear families inhabiting in Calcutta and adjacent areas was chosen randomly. Up to first degree relatives including father, mother and other sibs of the proband were considered as participants in the study. Anthropometric measures namely height, weight, waist circumference as well as skinfold thickness at biceps, triceps, subscapular and suprailiac were obtained using standard techniques. Body mass index (BMI), percentage of body fat (PBF), fat mass (FM), waist-hip ratio (WHR), sum of four skinfolds (SF₄ ), arm muscle circumference (AMC), arm muscle area (AMA), arm fat area (AFA), systolic (SBP) and diastolic blood pressure (DBP) were also considered. To estimate’heritability’ in the study, the mid parent-offspring model was used where’heritability’ (h² ) was equivalent to regression co-efficient (b). The regression sum of square (RSS) and total sum of square (TSS) ratio was also calculated both for mid parent-offspring and single parent-offspring. This ratio was considered as a measure of’heritability’ in the study with consideration that RSS is the variation due to genetic factor and the TSS is due to genetic and other additive factor. It was observed that the estimated heritability for BMI ranges from 0.69 to 0.31 using mid-parent off spring model while the range using single parent-offspring model was from 0.40 to 0.16. The range of heritability for SBP in mid parent-offspring model was 0.16 to 0.44 and 0.05 to 0.54 for single parent-offspring model. To conclude, it seems reasonable to argue that in the study a moderate to high h² was evident for body fat level, body composition and blood pressure measures which indicate a moderate to high aggregation of gene(s) in the family.     

Heritability of dispersal in the great reed warbler

Dispersal is commonly considered to be a condition‐dependent behaviour with no or low heritability. Here, we show that dispersal in the great reed warbler (Acrocephalus arundinaceus) has a high heritability. Analyses of capture–recapture data of male great reed warblers gathered from the species’ whole Swedish breeding range revealed a remarkable offspring–parent resemblance in dispersal behaviour (philopatry vs. inter‐population dispersal). Also, the degree of dispersal differed between cohorts, which shows that dispersal was partly conditionally dependent. The offspring to mid‐parent estimate of heritability was 0.50. In a previous study of the same data set of male offspring, we did not detect associations between dispersal and several relevant environmental, parental and offspring condition factors. Thus, our results indicate that variation in dispersal partly has a genetic basis in great reed warblers.     

Heritability: uses and abuses

This paper begins with a brief summary of the history of the development of ideas in the field of quantitative genetics. Next there is discussion of the controversy surrounding the contention that IQ tests validly estimate some highly heritable general intelligence factor. The validity of the reasoning supporting this contention is questioned. The theory of correlation between relatives has been of vast importance in plant and animal breeding because it is possible to design and carry out experiments to estimate variance components in expressions for covariances between relatives. However, data on humans is observational and individuals are not randomly assigned to environments, so that estimation of heritability from such data is not on the same firm foundation as it is in plant and animal breeding contexts. This revised version was published online in August 2006 with corrections to the Cover Date.     

普通甜荞主要数量性状相关遗传力的测定

对24个普通甜荞品种,7个主要数量性状,进行了遗传力、遗传相关和相关遗传力的测定．结果表明：株粒数与株粒重h_xy~2=0.8208,有效花序数与株粒重h_xy~2=0.6829,千粒重与株粒重h_xy~2=0.4498;株高、主茎节数,一级分枝数3个性状与株粒重的相关遗传力差异均不显著。     

Serum bisphenol a concentrations showed gender differences, possibly linked to androgen levels

To investigate human exposure to bisphenol A (BPA), a widely used endocrine disruptor, we measured serum BPA concentrations and analyzed the interrelation of BPA with sex-related hormones. BPA was detected in all human sera by a novel enzyme-linked immunosorbent assay. Serum BPA concentrations were significantly higher in normal men (1.49 +/- 0.11 ng/ml; P < 0.01) and in women with polycystic ovary syndrome (1.04 +/- 0.10 ng/ml; P < 0.05) compared with normal women (0.64 +/- 0.10 ng/ml). There were significant positive correlations between serum BPA and total testosterone (r = 0.595, P < 0.001) and free testosterone (r = 0.609, P < 0.001) concentrations in all subjects and likewise between serum BPA and total testosterone (r = 0.559, P < 0.01) and free testosterone (r = 0.598, P < 0.001) concentrations in all female subjects, but not between serum BPA and other sex-related hormone concentrations in any group. These findings showed that there are gender differences in serum BPA concentrations, possibly due to differences in the androgen-related metabolism of BPA.     

Heritability of age at menarche in girls from the Fels Longitudinal Study

Menarche is the hallmark maturational event of female childhood. Many studies indicated a significant genetic contribution to the timing of the onset of menstruation, but most of these studies were limited by the use of retrospective data and by the use of data from only certain types of relatives (i.e., mothers and daughters, sisters, or twin sisters). The primary goal of this study was to use a modern maximum likelihood quantitative genetic method to estimate the heritability (h(2)) of age at menarche, using familial data collected over the course of the 74-year-old Fels Longitudinal Study. The secondary goal was to review earlier studies of the heritability of age at menarche. The study of the heritability of age at menarche presented here is unique for two reasons. First, because of the Fels Longitudinal Study's serial design, age-at-menarche data were collected prospectively from most participants. Second, because the Fels Longitudinal Study is a family study that has been conducted for decades, age-at-menarche data are available from many types of female relatives spanning multiple households and generations. The best-fitting and most parsimonious quantitative genetic model included provision for a secular decrease in age at menarche, and estimated the h(2) of age at menarche to be 0.49+/- 0.13 (95% confidence interval of h(2),=0.24-0.73). The results of this study are in general agreement with the findings of most previous studies of genetic influences on age at menarche, and suggest that it is reasonable to consider it well-established that approximately half the phenotypic variation among girls from developed nations in the timing of menarche is due to genetic factors.     

Androgen effects on the solubility and conformational change of the androgen receptor in baculovirus expression system

To purify the androgen receptor (AR) efficiently from baculovirus expression system, we fused 6 histidine residues with the N-terminal domain of AR as a tag to specifically bind to Ni+2-affinity column. Our data indicated that adding androgen can increase the binding capacity of his-tag AR to the Ni+2-affinity column, and this increased binding capacity of AR could be due to the exposure of histidine residues of N-terminal domain induced by androgen. The androgen-enhanced binding to Ni+2-column also correlated with the increasing solubility of AR. Electrophoretic mobility shift assay further indicated that only purified AR could interact with androgen response element. Together, our data suggest that the binding of androgen to the hormone binding domain of AR may result in the conformational change of the N-terminal domain of AR and increase the hydrophilic property of AR.     

Heritability of resistance against ectoparasitism in the Drosophila-Macrocheles system

Ectoparasites are abundant in natural communities, can have pronounced deleterious fitness consequences to their host and are important vectors of transmissible parasitic disease. Yet very few studies have estimated the magnitude of heritable genetic variation underlying resistance against ectoparasitism, which significantly limits our ability to predict the evolution of this ecologically important character. The present paper reports results of artificial selection for increased resistance in Drosophila nigrospiracula against ectoparasitic, haematophagous mites, Macrocheles subbadius. In this system, which occurs naturally in the Sonoran Desert of North America, ectoparasitism significantly damages the expression of host fitness traits, including longevity, fecundity and male mating success. In the present study, resistance, which was modelled as a threshold trait, responded significantly to selection applied on either sex. Realized heritability, calculated as a mean across four replicates, was estimated to be 0.152 +/- 0.014 (SE). The heritability estimate from selection on males did not differ from that on females, but both estimates differed significantly from zero. This documented presence of additive genetic variation for resistance, coupled with knowledge of the fitness consequences of ectoparasitism, indicates that the host population possesses significant evolutionary potential. Selection was applied on the pre-attachment phase, thereby targeting behavioural forms of defence. This study therefore establishes parallels between insects and other animals in their ability to protect themselves and evolve behavioural defences against ectoparasites.     

Molecular defects of the androgen receptor

Defects of the androgen receptor cause a wide spectrum of abnormalities of phenotypic male development, ranging from individuals with mild defects of virilization to those with complete female phenotypes. In parallel with this phenotypic spectrum, a large number of different mutations have been identified that alter the synthesis or functional activity of the receptor protein. In many instances, the genetic mutations identified lead to an absence of the intact, full-length receptor protein. Such defects (splicing defects, termination codons, partial or complete gene deletions) invariably result in the phenotype of complete androgen insensitivity (complete testicular feminization). By contrast, single amino acid substitutions in the androgen receptor protein can result in the entire phenotypic spectrum of androgen resistant phenotypes and provide far more information on the functional organization of the receptor protein. Amino acid substitutions in different segments of the AR open-reading frame disturb AR function by distinct mechanisms. Substitutions in the DNA binding domain of the receptor appear to comprise a relatively homogeneous group. These substitutions impair the capacity of the receptor to bind to specific DNA sequence elements and to modulate the function of responsive genes. Amino acid substitutions in the hormone-binding domain of the receptor have a more varied effect on receptor function. In some instances, the resulting defect is obvious and causes an inability of the receptor to bind hormone. In other instances, the effect is subtler, and may result in the production of a receptor protein that displays qualitative abnormalities of hormone binding or from which hormone dissociates more rapidly. Often it is not possible to correlate the type of binding defect with the phenotype that is observed. Instead, it is necessary to measure the capacity of the receptor that is synthesized in functional assays in order to discern any type of correlation with phenotype. Finally, two types of androgen receptor mutation do not fit such a categorization. The first of these—the glutamine repeat expansion that is observed in spinal and bulbar muscular atrophy—leads to a reduction of receptor function that can be measured in heterologous cells or in fibroblasts established from such patients. The expression of ARs containing such expanded repeats in men is associated with a degeneration of motor neurons in the spinal cords of affected patients. Likewise, the alterations of androgen receptor structure that have been detected in advanced forms of prostate cancer also behave as gain-of-function mutations. In this latter type of mutation, the exquisite specificity of the normal androgen receptor is relaxed and the mutant receptors can be activated by a variety of steroidal and non-steroidal ligands.     

Heritability: the link between development and the microevolution of molar tooth form

Abstract

The developmental gene expression, morphogenesis, and population variation in mammalian molar teeth has become increasingly well understood, providing a model system for synthesizing evolution and developmental genetics. In this study, we estimated additive genetic covariances in molar shape (G) using parent-offspring regression in Cryptotis parva, the Least Shrew. We found that crown shape had an overall h² value of 0.34 (±0.08), with higher heritabilities in molar cusps than notches. We compared the genetic covariances to phenotypic (P) and environmental (E) covariances, and to the covariances in crown features expected from the enamel knot developmental cascade (D). We found that G and D were not strongly correlated and that major axes of G (evolutionary lines of least resistance) are better predictors of evolutionary divergences in soricines than is D. We conclude that the enamel knot cascade does impose constraints on the evolution of molar shape, but that it is so permissive that the divergences among soricines (whose last common ancestor lived about 14 million years ago) do not fully explore its confines. Over tens of millions of years, G will be a better predictor of the major axes of evolution in molar shape than D.     

Estimation of Epistatic Variance Components and Heritability in Founder Populations and Crosses

Genetic association studies have explained only a small proportion of the estimated heritability of complex traits, leaving the remaining heritability “missing.” Genetic interactions have been proposed as an explanation for this, because they lead to overestimates of the heritability and are hard to detect. Whether this explanation is true depends on the proportion of variance attributable to genetic interactions, which is difficult to measure in outbred populations. Founder populations exhibit a greater range of kinship than outbred populations, which helps in fitting the epistatic variance. We extend classic theory to founder populations, giving the covariance between individuals due to epistasis of any order. We recover the classic theory as a limit, and we derive a recently proposed estimator of the narrow sense heritability as a corollary. We extend the variance decomposition to include dominance. We show in simulations that it would be possible to estimate the variance from pairwise interactions with samples of a few thousand from strongly bottlenecked human founder populations, and we provide an analytical approximation of the standard error. Applying these methods to 46 traits measured in a yeast (Saccharomyces cerevisiae) cross, we estimate that pairwise interactions explain 10% of the phenotypic variance on average and that third- and higher-order interactions explain 14% of the phenotypic variance on average. We search for third-order interactions, discovering an interaction that is shared between two traits. Our methods will be relevant to future studies of epistatic variance in founder populations and crosses.