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1.  The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS 
Journal of Medicine and Life  2013;6(1):18-25.
Polycystic ovary syndrome (PCOS), one of the most common and complex endocrine disorders affecting up to 15 % of reproductive age women, is considered a predominantly hyperandrogenic syndrome according to the Androgen Excess Society. It is generally accepted that androgens determine the characteristic features of PCOS; in this context, a hyperactive androgen receptor (AR) at the levels of the GnRH pulse generator in the hypothalamus and at the granulosa cells in the ovary, skeletal muscle or adipocytes senses initially normal testosterone and dihydrotestosterone as biochemical hyperandrogenism and might be a crucial connection between the vicious circles of the PCOS pathogenesis.
Polymorphism of the AR gene has been associated with different androgen pattern diseases. Several studies have demonstrated an association between AR with increased activity encoded by shorter CAG repeat polymorphism in the exon 1 of the AR gene and PCOS, although there are conflicting results in this field. The phenomenon is more complex because the AR activity is determined by the epigenetic effect of X chromosome inactivation (XCI). Moreover, we must evaluate the AR as a dynamic heterocomplex, with a large number of coactivators and corepressors that are essential to its function, thus mediating tissue-specific effects. In theory, any of these factors could modify the activity of AR, which likely explains the inconsistent results obtained when this activity was quantified by only the CAG polymorphism in PCOS.
PMCID: PMC3624640  PMID: 23599814
CAG repeat polymorphism; AR; PCOS
2.  Androgen Receptor CAG Repeats Length Polymorphism and the Risk of Polycystic Ovarian Syndrome (PCOS) 
PLoS ONE  2013;8(10):e75709.
Polycystic ovarian syndrome (PCOS) refers to an inheritable androgen excess disorder characterized by multiple small follicles located at the ovarian periphery. Hyperandrogenism in PCOS, and inverse correlation between androgen receptor (AR) CAG numbers and AR function, led us to hypothesize that CAG length variations may affect PCOS risk.
CAG repeat region of 169 patients recruited following strictly defined Rotterdam (2003) inclusion criteria and that of 175 ethnically similar control samples, were analyzed. We also conducted a meta-analysis on the data taken from published studies, to generate a pooled estimate on 2194 cases and 2242 controls.
CAG bi-allelic mean length was between 8.5 and 24.5 (mean = 17.43, SD = 2.43) repeats in the controls and between 11 and 24 (mean = 17.39, SD = 2.29) repeats in the cases, without any significant difference between the two groups. Further, comparison of bi-allelic mean and its frequency distribution in three categories (short, moderate and long alleles) did not show any significant difference between controls and various case subgroups. Frequency distribution of bi-allelic mean in two categories (extreme and moderate alleles) showed over-representation of extreme sized alleles in the cases with marginally significant value (50.3% vs. 61.5%, χ2 = 4.41; P = 0.036), which turned insignificant upon applying Bonferroni correction for multiple comparisons. X-chromosome inactivation analysis showed no significant difference in the inactivation pattern of CAG alleles or in the comparison of weighed bi-allelic mean between cases and controls. Meta-analysis also showed no significant correlation between CAG length and PCOS risk, except a minor over-representation of short CAG alleles in the cases.
CAG bi-allelic mean length did not differ between controls and cases/case sub-groups nor did the allele distribution. Over-representation of short/extreme-sized alleles in the cases may be a chance finding without any true association with PCOS risk.
PMCID: PMC3792992  PMID: 24116069
3.  Role of Androgen Receptor CAG Repeat Polymorphism and X-Inactivation in the Manifestation of Recurrent Spontaneous Abortions in Indian Women 
PLoS ONE  2011;6(3):e17718.
The aim of the present study was to investigate the role of CAG repeat polymorphism and X-chromosome Inactivation (XCI) pattern in Recurrent Spontaneous Abortions among Indian women which has not been hitherto explored. 117 RSA cases and 224 Controls were included in the study. Cases were recruited from two different hospitals - Lakshmi Fertility Clinic, Nellore and Fernandez Maternity Hospital, Hyderabad. Controls were roughly matched for age, ethnicity and socioeconomic status. The CAG repeats of the Androgen Receptor gene were genotyped using a PCR-based assay and were analysed using the GeneMapper software to determine the CAG repeat length. XCI analysis was also carried out to assess the inactivation percentages. RSA cases had a significantly greater frequency of allele sizes in the polymorphic range above 19 repeats (p = 0.006), which is the median value of the controls, and in the biallelic mean range above 21 repeats (p = 0.002). We found no evidence of abnormal incidence of skewed X-inactivation. We conclude that longer CAG repeat lengths are associated with increased odds for RSA with statistical power estimated to be ∼90%.
PMCID: PMC3056719  PMID: 21423805
4.  Anthropometric and Biochemical Characteristics of Polycystic Ovarian Syndrome in South Indian Women Using AES-2006 Criteria 
Polycystic ovarian syndrome (PCOS) is one of the most common endocrine conditions affecting women of reproductive age with a prevalence of approximately 5-10% worldwide. PCOS can be viewed as a heterogeneous androgen excess disorder with varying degrees of reproductive and metabolic abnormalities, whose diagnosis is based on anthropometric, biochemical and radiological abnormalities. To our knowledge, this is the first study investigating the anthropometric, biochemical and ultrasonographic characteristics of PCOS in Asian Indians of South India, using the Androgen Excess Society (AES-2006) diagnostic criteria.
To assess anthropometric, biochemical and ultrasonographic features of PCOS subgroups and controls among South Indian women using the AES-2006 criteria.
Materials and Methods:
Two hundred and four women clinically diagnosed with PCOS, and 204 healthy women controls aged 17 to 35 years were evaluated. PCOS was diagnosed by clinical hyperandrogenism (HA), irregular menstruation (IM), and polycystic ovary (PCO). PCOS was further categorized into phenotypic subgroups including the IM+HA+PCO (n = 181, 89%), HA+PCO (n = 23, 11%), IM+HA (n = 0), and also into obese PCOS (n = 142, 70%) and lean PCOS (n = 62, 30%) using body mass index (BMI). Anthropometric measurements and biochemical characteristics were compared among the PCOS subgroups.
The PCOS subgroups with regular menstrual cycles (HA+PCO), had more luteinizing hormone (LH), follicle stimulating hormone (FSH), fasting glucose, fasting insulin, and high insulin resistance (IR) expressed as the Homeostasis Model Assessment (HOMA) score, compared with the IM+HA+PCO subgroups and controls. Similarly, the obese PCOS had high BMI, waist to hip ratio (WHR), fasting glucose, LH, LH/FSH, fasting insulin, HOMA score (IR), and dyslipidemia, compared with lean PCOS and controls. Unilateral polycystic ovary was seen in 32 (15.7%) patients, and bilateral involvement in 172 (84.3%) patients. All the controls showed normal ovaries.
Anthropometric, biochemical, and ultrasonographic findings showed significant differences among PCOS subgroups. The PCOS subgroups with regular menstrual cycles (HA+PCO), had high insulin resistance (IR) and gonadotropic hormonal abnormalities, compared with the IM+HA+PCO subgroups and controls.
PMCID: PMC3968989  PMID: 24696694
Polycystic Ovarian Syndrome; Body Mass Index; HOMA Score; Insulin Resistance
5.  Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases 
Arthritis Research & Therapy  2009;11(4):R106.
The majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases.
We examined XCI profiles of females affected with RA (n = 106), AITDs (n = 145) and age-matched healthy women (n = 257). XCI analysis was performed by enzymatic digestion of DNA with a methylation sensitive enzyme (HpaII) followed by PCR of a polymorphic CAG repeat in the androgen receptor (AR) gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X-chromosome.
Skewed XCI was observed in 26 of the 76 informative RA patients (34.2%), 26 of the 100 informative AITDs patients (26%), and 19 of the 170 informative controls (11.2%) (P < 0.0001; P = 0.0015, respectively). More importantly, extremely skewed XCI, defined as > 90% inactivation of one allele, was present in 17 RA patients (22.4%), 14 AITDs patients (14.0%), and in only seven controls (4.1%, P < 0.0001; P = 0.0034, respectively). Stratifying RA patients according to laboratory profiles (rheumatoid factor and anti-citrullinated protein antibodies), clinical manifestations (erosive disease and nodules) and the presence of others autoimmune diseases did not reveal any statistical significance (P > 0.05).
These results suggest a possible role for XCI mosaicism in the pathogenesis of RA and AITDs and may in part explain the female preponderance of these diseases.
PMCID: PMC2745787  PMID: 19589151
6.  Associations between androgen receptor CAG & GGN repeat polymorphism & recurrent spontaneous abortions in Chinese women 
Background & objectives:
Recurrent spontaneous abortion (RSA) is a reproductive problem that occurs in women in reproductive age with a frequency of 1-3 per cent. Previous studies have reported high levels of serum androgens to be associated with RSAs. At the molecular level, the effect of androgens is mediated through the activation of the androgen receptor (AR). The CAG and GGN repeat polymorphisms of the AR gene are associated with the AR activity. We hypothesize that the AR CAG/GGN repeat polymorphism may be associated with levels of serum androgens. Thus, this study as undertaken to evaluate the relationship between CAG/GGN repeats in exon 1 of the AR gene in women with RSAs.
This case-control study was performed in Ningxia, PR China, including 149 women with RSAs and 210 controls. The CAG and GGN repeats of the AR gene were genotyped using a PCR-based assay and were analyzed using Peak Scanner Software v1.0 to determine the CAG/GGN repeat length.
CAG repeats ranged from 15 to 29 in the RSA patients, compared to 14 to 35 in the control group. The median value of CAG repeats was 22 for the RSA group and 24 for control group. The total AR CAG alleles (≤22 repeats), shorter AR CAG alleles (≤22 repeats), and biallelic means (≤22.5 repeats) were significantly different in the RSA group in comparison to the control group (P<0.001, P<0.01). The median value of the GGN repeats was 23 for the cases and 22 for controls. The total number of AR GGN alleles (≤23 repeats) was significantly different in the RSA group compared to the control group (P<0.5). There was no difference between the RSA group and the control groups in regards to shorter alleles, longer alleles, and biallelic means.
Interpretation & conclusions:
Our observation suggests that the CAG and GGN repeat length is shorter in women with RSAs as compared with controls and that shorter CAG and GGN repeats may be pathogenic for RSAs in Chinese women. Further studies need to be done in different ethnic populations.
PMCID: PMC4140038  PMID: 25027083
Androgen; androgen receptor gene; CAG repeats; GGN repeats; recurrent spontaneous abortion
7.  CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India 
Polycystic ovary syndrome (PCOS) is a condition with central feature of hyperandrogensism that affects 5-12 % of women worldwide. P450sec the cholesterol side chain cleavage enzyme encoded by CYP11A1 gene is instrumental in the synthesis of sex hormones. A promoter pentanucleotide repeat (tttta)n polymorphism of this gene is reported to be associated with several hormone related diseases including PCOS. Here we aimed to examine the involvement of CYP11A1 polymorphism with PCOS susceptibility in a case–control study conducted among South Indian women.
A total of 542 subjects comprised of 267 PCOS patients and 275 controls were recruited. DNA was extracted from blood and CYP11A1 (tttta)n polymorphism was genotyped by PCR-PAGE.
Fifteen different alleles ranging between 2–16 repeats were identified in the studied group and the most frequent allele observed in controls was of 8 repeats. The presence of >8 repeat allele was common in patients (64 % vs. 38 %) and showed a three-fold risk for PCOS susceptibility than controls (OR = 2.93; p < 0.05). PCOS women with higher BMI were markedly elevated in early quartile (p < 0.05).
CYP11A1 (tttta)n repeat polymorphism appeared to be a potential molecular marker for PCOS risk in our population. Gene-gene and gene-environmental interactions with respect to obesity may play a role in the early onset of this multifactorial condition. This is the first report from South India; however, replicative studies considering other probable causative factors for PCOS risk are warranted.
PMCID: PMC4096885  PMID: 24793009
CYP11A1; (tttta)n polymorphism; Hyperandrogenism; BMI
8.  Association of PPARG Pro12Ala polymorphism with insulin sensitivity and body mass index in patients with polycystic ovary syndrome 
Biomedical Reports  2013;2(2):199-206.
Insulin resistance is one of the key factors in the pathogenesis of polycystic ovary syndrome (PCOS). The peroxisome proliferator-activated receptor gamma (PPARG) plays a role in the regulation of insulin sensitivity. The aim of the present study was to establish a possible association of the PPARG Pro12Ala polymorphism with PCOS and its effect on family and personal history, as well as on the metabolic and endocrine parameters in PCOS patients. A total of 151 PCOS patients and 179 healthy women of reproductive age were enrolled. History, body mass index (BMI), waist-to-hip ratio and the presence of phenotypic hyperandrogenism were recorded. Hormonal, metabolic and biochemical profiles were assessed. A molecular analysis for the genetic polymorphism was performed. One third (29.8%) of the PCOS patients were found to be carriers of at least one variant of the Ala allele (X/Ala), while 70.2% carried two wild-type Pro alleles (Pro/Pro), with an equal distribution observed in the control group. The PCOS patients carrying the X/Ala alleles exhibited lower serum fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) and BMI compared to Pro/Pro carriers. This finding was significant only in the lean PCOS group. The polymorphic genotype exerted no effect on history, hormonal and clinical hyperandrogenism, lipid status or C-reactive protein, leptin, adiponectin, resistin and ghrelin serum levels in women with PCOS. In conclusion, although the PPARG Pro12Ala polymorphism is not a major determinant of PCOS in the Croatian population, it may exert a positive effect on insulin sensitivity and BMI. As these associations were recorded exclusively in the lean group of patients with PCOS, this polymorphism potentially contributes to a protective role against hyperinsulinemia and obesity.
PMCID: PMC3917751  PMID: 24649096
peroxisome proliferator-activated receptor gamma; polymorphism; polycystic ovary syndrome; glucose metabolism; reproductive hormones
9.  Small Glutamine-Rich Tetratricopeptide Repeat Containing Protein Alpha (SGTA), a Candidate Gene for Polycystic Ovary Syndrome 
Human reproduction (Oxford, England)  2008;23(5):1214-1219.
Polycystic ovary syndrome (PCOS) is a heterogenic, complex common genetic disease. Multiple pathways are involved in its pathogenesis, including the androgen signaling pathway and insulin signaling pathway. Small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA) is a putative member of the androgen receptor-chaperone-cochaperone complex, and may play a role in androgen signaling as a co-chaperone. Polymorphisms in the SGTA gene have not been evaluated for a role in PCOS.
Women with and without PCOS (287 cases, 187 controls) were genotyped for three single nucleotide polymorphisms (SNPs) in SGTA. SNPs and haplotypes were determined and tested for association with PCOS and component traits of PCOS.
For SNP rs1640262, homozygotes for the minor allele were protected against PCOS (P=0.009). Haplotype 1 (G-A-T) was associated with increased risk of PCOS (P=0.015). In women with PCOS, haplotype 2 (A-G-C) was associated with increased insulin resistance (P=0.013), consequently resulting in increased insulin secretion (P=0.014).
This study presents genetic evidence suggesting a potential role of SGTA in the pathogenesis of PCOS. SGTA may provide a connection between multiple pathways in PCOS.
PMCID: PMC2767244  PMID: 18332089
Polycystic ovary syndrome; small glutamine-rich tetratricopeptide repeat-containing; alpha; single nucleotide polymorphism; haplotype; association
10.  Androgen receptor CAG repeats, non-random X chromosome inactivation, and loss of heterozygosity at Xq25 in relation to breast cancer risk 
BMC Cancer  2014;14:144.
The aim of this study was to examine the association of non-random X chromosome inactivation (XCI) and loss of heterozygosity (LOH) at Xq25 with breast cancer development.
Seventy-nine breast cancer patients, 39 female lung cancer patients, 30 other cancer patients and 77 healthy females were analysed for LOH using a panel of 11 microsatellite markers spanning Xq25. The androgen receptor (AR) gene was chosen as an XCI marker.
LOH of at least one microsatellite locus at Xq25 was identified in 46/65 breast cancers examined, while only 10/25 cancers of other origins demonstrated LOH in this region (p = 0.014). The critical deletion region in breast cancer was around marker DXS1047 (47.23%). Moreover, we found that tissues from eight breast cancers showed LOH at all of the informative loci tested at Xq25, while the other 38 showed partial (interstitial or telomeric) alterations at Xq25. Interestingly, the pattern of XCI of these eight breast cancers tended to be non-random. We estimated the frequencies of AR alleles and found that women with two long AR alleles (≥21 CAG repeats) had an increased risk of developing breast cancer, while those with two short AR alleles (<21 CAG repeats) were likely to be normal (p = 0.00069).
The extraordinary high frequencies of LOH at Xq25 found in this study strongly imply that there might be one or more tumour suppressor genes (TSGs) related to the development of breast cancer at Xq25 in the Taiwanese female population.
PMCID: PMC3975944  PMID: 24581183
Breast cancer; Androgen receptor; Non-random X-chromosome inactivation; Loss of heterozygosity; Xq25
11.  The role of X-chromosome inactivation in female predisposition to autoimmunity 
Arthritis Research  2000;2(5):399-406.
We propose that the phenomenon of X-chromosome inactivation in females may constitute a risk factor for loss of T-cell tolerance; specifically that skewed X-chromosome inactivation in the thymus may lead to inadequate thymic deletion. Using a DNA methylation assay, we have examined the X-chromosome inactivation patterns in peripheral blood from normal females (n = 30), female patients with a variety of autoimmune diseases (n = 167). No differences between patients and controls were observed. However, locally skewed X-chromsome inactivation may exist in the thymus, and therefore the underlying hypothesis remains to be disproved.
A reduction in the sex ratio (male : female) is characteristic of most autoimmune disorders. The increased prevalence in females ranges from a modest 2:1 for multiple sclerosis [1], to approximately 10:1 for systemic lupus erythematosus [2]. This tendency toward autoimmunity in females is often ascribed to hormonal differences, because in a number of experimental disease models estrogens exacerbated disease, and androgens can inhibit disease activity [3,4]. However, human studies have failed to demonstrate a clear-cut influence of hormonal environment on disease susceptibility to lupus or other autoimmune disorders. In addition, many childhood forms of autoimmunity, such as juvenile rheumatoid arthritis, exhibit female predominance [5]. Interestingly, juvenile (type 1) diabetes is an exception to this general trend, with a sex ratio close to 1 in most studies [6]. Therefore, it is reasonable to consider alternative explanations for the increased prevalence of autoimmune diseases in human females.
A unifying feature of autoimmune disorders appears to be the loss of immunologic tolerance to self-antigens, and in many of these diseases there is evidence that T-cell tolerance has been broken. The most profound form of T-cell tolerance involves deletion of potentially self-reactive T cells during thymic selection. Thus, lack of exposure to a self-antigen in the thymus may lead to the presence of autoreactive T cells and may increase the risk of autoimmunity. An elegant example of this has recently been reported [7].
The existence of X-chromosome inactivation in females offers a potential mechanism whereby X-linked self-antigens may escape presentation in the thymus or in other peripheral sites that are involved in tolerance induction. Early in female development, one of the two X chromosomes in each cell undergoes an ordered process of inactivation, with subsequent silencing of most genes on the inactive X chromosome [8]. This phenomenon occurs at a very early embryonic stage [9], and thus all females are mosaic and may occasionally exhibit extreme skewing towards one or the other parental X chromosome. In theory, this may result in a situation in which polymorphic self-antigens on one X chromosome may fail to be expressed at sufficiently high levels in a tolerizing compartment, such as the thymus, and yet may be expressed at a considerable frequency in the peripheral soma. Thus, females may be predisposed to a situation in which they can occasionally express X-linked autoantigens in the periphery to which they have been inefficiently tolerized. Stewart [10] has recently speculated that such a mechanism may play a role in the predisposition to systemic lupus.
This hypothesis predicts that females with autoimmunity may be particularly prone to this mechanism of `inadequate tolerization' by virtue of extremely skewed X-chromosome inactivation. We therefore performed a comprehensive analysis of X-chromosome inactivation patterns in populations of females with multiple sclerosis, systemic lupus erythematosus, juvenile rheumatoid arthritis, and type 1 (insulin-dependent) diabetes mellitus, and in female control individuals. The results do not provide support for a major role for skewed X-chromosome inactivation in female predisposition to autoimmunity; however, neither is the underlying hypothesis disproved by the present data.
Materials and method:
DNA was obtained from female patients from the following sources: 45 persons with juvenile diabetes seen at the Virginia Mason Research Center in Seattle, Washington; 58 multiple sclerosis patients seen at the New York Hospital Multiple Sclerosis Center; 46 patients with systemic lupus erythematosus seen at the Hospital for Special Surgery (New York); 18 patients with juvenile rheumatoid arthritis seen at the Children's Hospital Medical Center in Cleveland. In addition, 30 healthy age-matched females were studied as normal controls.
Employing a modification of previously described methods [11], we utilized a fluorescent Hpa II/PCR assay of the androgen receptor (AR) locus to assess X-chromosome inactivation patterns. The AR gene contains a polymorphic CAG repeat, which is flanked by Hpa II sites. These Hpa II sites are methylated on the inactive X chromosome, and are unmethylated on the active X chromosome. By performing PCR amplification across this region after cutting with the methylation-sensitive enzyme Hpa II, the relative amounts of the methylated AR alleles can be quantitatively determined with a high degree of accuracy; variance on repeated assays is approximately 4% [12].
Skewing of X-chromosome inactivation is expressed as percentage deviation from equal (50:50) inactivation of the upper and lower AR alleles. Therefore, the maximal possible deviation is 50%, in which case all of the X chromosomes bearing one of the AR alleles are inactivated.
We examined X-chromosome inactivation patterns in several different populations. The results are summarized in Fig. 1. A wide range of X-inactivation skewing was observed in all five groups. Approximately 5% (nine out of 197) of individuals exhibited extreme skewing (greater than 40% deviation from a 50:50 distribution). However, there was no difference between the groups, either in the overall mean skewing, or in the fraction of individuals with extreme skewing (>40%).
Although the present study was not initiated in order to examine allelic variation in the AR gene per se, the data provide an opportunity to address this question. Excessively long CAG repeats in the AR are a rare cause of spinal-bulbar muscular atrophy [13], and AR repeat length appears to have an influence on the biology of certain tumors [14,15]. In this context, it has been shown that transcription of AR correlates inversely with repeat length [16]. We therefore compared AR repeat length in control individuals and patients with autoimmunity. No differences were observed for mean repeat length, or for maximum and minimum repeat length, among the five groups.
The reason for the female predominance in most autoimmune diseases remains obscure. The present study was initiated in order to address the hypothesis that a nonhormonal mechanism related to X inactivation might be involved. The hypothesis rests on the idea that skewing of X inactivation might lead to a deficiency of tolerance induction in the thymus, particularly with respect to polymorphic X-linked autoantigens. The hypothesis predicts that skewed X inactivation would be more prevalent in females with autoimmune diseases than in female control individuals. This was not observed.
Nevertheless, these negative data do not rule out a role for X inactivation in female predisposition to loss of tolerance. A general model for how this mechanism might operate is shown in Fig. 2. Thymocytes undergo selection in the thymic parenchyma and, in the case of negative selection, the selecting elements appear to be derived from the bone marrow and consist mainly of thymic dendritic cells. If the thymic dendritic cell population exhibits random X inactivation, it is highly likely that differentiating thymocytes will contact dendritic cells that express self-antigens on both X chromosomes. This situation is outlined schematically on the left side of Fig. 2. However, if there is extremely skewed X inactivation in the thymic dendritic cell population, a particular thymocyte might not come into contact with dendritic cells that express one of the two X chormosomes. This would lead to a situation where T cells may undergo thymic maturation without having been negatively selected for antigens that are expressed on the predominantly inactive X chromosome. This situation is shown on the right side of Fig. 2.
In order for this mechanism to be physiologically relevant, some assumptions must be made. First, defective tolerance from skewed X inactivation should only be directed at X-linked antigens that are polymorphic, and for which the individual is heterozygous. Thus, this mechanism would not be expected to lead to lack of tolerance commonly, unless there are at least several highly polymorphic X-linked autoantigens in the population that are involved in thymic deletion events. Second, if this actually leads to autoimmunity, it also predicts that the initial break in tolerance that leads to disease should involve an X-linked autoantigen that is expressed in a peripheral nontolerizing site or circumstance.
A recent report [7] has elegantly demonstrated the importance of thymic deletion events in predisposition to autoimmune disease. The proteolipid protein (PLP) autoantigen is expressed in alternatively spliced forms, which exhibit tissue specific expression. A nonspliced variant is expressed in peripheral neural tissue. However, in the thymus a splice variant results in the lack of thymic expression of an immunodominant peptide. This results in loss of tolerace of T cells to this peptide, presumably on the basis of lack of thymic deletion of thymocytes that are reactive with this antigen. Interestingly, PLP is encoded on the X chromsome. However, there is no evidence that genetic polymorphisms control the level splicing of PLP within the thymus. Nevertheless, these data illustrate the potential importance of deficiencies in thymic deletion for autoimmune T-cell reactivity.
The present results suggest that if skewed X inactivation is relevant to thymic tolerance induction, then the effect does not depend on global skewing of X-chromosome inactivation, at least in the hematopoietic compartment. In this study we examined X-inactivation patterns in peripheral blood mononuclear cells, and the results should reflect the state of X inactivation in all mesenchymal tissues, including dendritic cells. X inactivation occurs at a very early time point in development, and thus the results in one tissue should reflect the general situation in the rest of the body. However, there may be exceptions to this. We have occasionally observed differences in X-inactivation patterns between buccal mucosa (an ectodermally derived tissue) and peripheral blood in the same individiual (unpublished observations). This could be a chance event, or it may result from selection for certain X-linked alleles during embryonic development, as has been described in carriers of X-linked immunodeficiencies [17].
Another consideration is that certain tissue microenvironments may be derived from very small numbers of founder cells, and thus may exhibit skewed utilization of one or the other X chromosome, even if the tissue as a whole is not skewed. This situation could vary over time. Thus, there may be time points at which certain thymic microenvironments are populated by dendritic cells that, for stochastic reasons, all utilize the same X chromosome. This would create a `window of opportunity' in which a given thymocyte, in a given selecting location, could escape negative selection by antigens on the inactive X chromosome. The likelihood of this happening would obviously depend on the number of dendritic cells that are usually contacted by a thymocyte during thymic selection. There is limited information on this point, although Stewart [10] has theorized that this number may be as low as 15. If this is the case, then escape from thymic deletion may still occur in females who are heterozygous for a relevant X-linked antigen, even if the hematopoietic cells in general do not exhibit extreme skewing.
In conclusion, we suggest that X-chromosome inactivation needs to be considered as a potential factor in the predominance of females in most autoimmune diseases. Our inability to show an increase in X-chromosome skewing in females with autoimmunity does not eliminate this as an etiologic contributor to loss of immunologic tolerance. Future experiments must be directed at a detailed analysis of tissue patterns of X inactivation, as well as at a search for potential X-linked autoantigens.
PMCID: PMC17816  PMID: 11056674
autoimmunity; gender; immune tolerance; X chromosome
12.  Adrenocortical steroid response to ACTH in different phenotypes of non-obese polycystic ovary syndrome 
Adrenal androgen excess is frequently observed in PCOS. The aim of the study was to determine whether adrenal gland function varies among PCOS phenotypes, women with hyperandrogenism (H) only and healthy women.
The study included 119 non-obese patients with PCOS (age: 22.2 ± 4.1y, BMI:22.5 ± 3.1 kg/m2), 24 women with H only and 39 age and BMI- matched controls. Among women with PCOS, 50 had H, oligo-anovulation (O), and polycystic ovaries (P) (PHO), 32 had O and H (OH), 23 had P and H (PH), and 14 had P and O (PO). Total testosterone (T), SHBG and DHEAS levels at basal and serum 17-hydroxprogesterone (17-OHP), androstenedione (A4), DHEA and cortisol levels after ACTH stimulation were measured.
T, FAI and DHEAS, and basal and AUC values for 17-OHP and A4 were significantly and similarly higher in PCOS and H groups than controls (p < 0.05 for all) whereas three groups did not differ for basal or AUC values of DHEA and cortisol. Three hyperandrogenic subphenotypes (PHO, OH, and PH) compared to non-hyperandrogenic subphenotype (PO) had significantly and similarly higher T, FAI, DHEAS and AUC values for 17-OHP, A4 and DHEA (p < 0.05). All subphenotypes had similar basal and AUC values for cortisol.
PCOS patients and women with H only have similar and higher basal and stimulated adrenal androgen levels than controls. All three hyperandrogenic subphenotypes of PCOS exhibit similar and higher basal and stimulated adrenal androgen secretion patterns compared to non-hyperandrogenic subphenotype.
PMCID: PMC3523978  PMID: 23216997
Adrenal androgen; PCOS; ACTH; DHEAS
13.  Depression Symptoms and Body Dissatisfaction Association Among Polycystic Ovary Syndrome Women 
Journal of psychosomatic research  2011;71(4):270-276.
One publication reported that lower body satisfaction and lower education were independent predictors of depression in polycystic ovary syndrome (PCOS) women. This study replicates that analysis using different instruments, and adds androgen levels to the model.
Cross-sectional analysis of questionnaires (Quick Inventory of Depressive Symptomatology-Self-Report, Body Esteem Scale) and serum androgens from a community cohort with (n=94) and without (n=96) PCOS, matched by BMI category. Non-parametric tests, Spearman correlations, and negative binomial regression models were analyzed.
Depression symptoms were common (40–60% in lean, overweight and obese BMI categories) in the PCOS cohort, albeit generally of mild severity. The PCOS women had similar depression symptom severity (P > 0.20) and similar body dissatisfaction (P ≥ 0.25) as the regularly cycling women in total and stratified by BMI category. In both the PCOS and non-PCOS cohorts, depression symptom severity was positively correlated with dissatisfaction with physical appearance and physical conditioning (P < 0.02). Body dissatisfaction (especially perception of physical conditioning) was strongly associated with more severe depression symptoms in non-obese PCOS women (BMI<30, P < 0.04) before and after controlling for age, testosterone and free testosterone. In contrast, for obese women with PCOS, depression was unrelated to body dissatisfaction after controlling for age.
Among non-obese PCOS women, their subjective body image was strongly associated with the severity of their depression symptoms. Most of the obese PCOS cohort had low body satisfaction and depression symptoms, therefore individual differences in the body dissatisfaction scores were not helpful in identifying depression symptom severity. Neither testosterone nor free testosterone were associated with depression symptom severity in PCOS women after controlling for body dissatisfaction and age.
US Clinical Trials government registry, NCT00602940
PMCID: PMC3172572  PMID: 21911106
Androgens; Body image; Body mass index; Body satisfaction; Depression; Endocrinology; Polycystic ovary syndrome
14.  Digit ratios do not serve as anatomical evidence of prenatal androgen exposure in clinical phenotypes of polycystic ovary syndrome 
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.
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.
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).
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.
PMCID: PMC2894079  PMID: 19855107 CAMSID: cams561
digit ratios; polycystic ovary syndrome; prenatal androgen exposure
15.  CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk 
British Journal of Cancer  1999;81(4):672-676.
The length of the polymorphic CAG repeat in the N-terminal of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Some studies have indicated that short CAG repeats are related to higher risk of prostate cancer. We performed a case–control study to investigate relations between CAG repeat length and prostate cancer risk, tumour grade, tumour stage, age at diagnosis and response to endocrine therapy. The study included 190 AR alleles from prostate cancer patients and 186 AR alleles from female control subjects. All were whites from southern Sweden. The frequency distribution of CAG repeat length was strikingly similar for cases and controls, and no significant correlation between CAG repeat length and prostate cancer risk was detected. However, for men with non-hereditary prostate cancer (n = 160), shorter CAG repeats correlated with younger age at diagnosis (P = 0.03). There were also trends toward associations between short CAG repeats and high grade (P = 0.07) and high stage (P = 0.07) disease. Furthermore, we found that patients with long CAG repeats responded better to endocrine therapy, even after adjusting for pretreatment level of prostate-specific antigen and tumour grade and stage (P = 0.05). We conclude that short CAG repeats in the AR gene correlate with young age at diagnosis of prostate cancer, but not with higher risk of the disease. Selection of patients with early onset prostate cancer in case–control studies could therefore lead to an over-estimation of the risk of prostate cancer for men with short CAG repeats. An association between long CAG repeats and good response to endocrine therapy was also found, but the mechanism and clinical relevance are unclear. © 1999 Cancer Research Campaign
PMCID: PMC2362888  PMID: 10574254
prostatic neoplasms; cancer risk; androgen receptor; genetics; epidemiology
16.  Association between circulating adiponectin levels and polycystic ovarian syndrome 
Low adiponectin levels in polycystic ovarian syndrome (PCOS) have been largely attributed to obesity which is common among these patients. In addition, evidence also suggests that low adiponectin in PCOS may be related to insulin resistance (IR) in these women. However, studies on the role of adiponectin in younger and lean patients are limited. Therefore, the aim of the present study was to examine the association of adiponectin levels in young and lean women with PCOS.
A case–control study was conducted at the Dow University of Health Sciences, Karachi, Pakistan. Cases were 75 patients of PCOS with Body Mass Index (BMI) &23 aged 16–35 years and 75 healthy age and BMI matched controls were selected from family and friends of the cases. Demographic details, family history and past medical history were obtained through interview by a physician. Anthropometric measurements included weight and height of the participants. Fasting glucose, total cholesterol, high-density lipoprotein (HDL), insulin, adiponectin, and androgen levels were determined. IR was calculated using homeostasis model assessment for insulin resistance (HOMA-IR). Logistic regression models were used to assess the association between adiponectin and PCOS after adjusting for co-variates.
On multivariable analysis, PCOS cases were 3.2 times more likely to have low adiponectin level (OR = 3.2, 95% CI 1.49-6.90, p-value 0.003) compared to the controls after adjustment for age, BMI, family history, marital status, total cholesterol, HDL level and IR. Females with a family history of PCOS were significantly more likely to have lower adiponectin (OR = 3.32, 95% CI 1.27-8.67, p-value 0.014) compared to those who did not have a family history of PCOS. The associations of IR and family history with low adiponectin level also remained statistically significant after adjustments for covariates.
Serum adiponectin levels are independently associated with PCOS and are only partly explained by IR. Adiponectin level may serve as a potential independent biomarker for diagnosis of PCOS in young and lean women with fewer symptoms, or women with a family history of PCOS.
PMCID: PMC3928320  PMID: 24502610
17.  X Chromosome Inactivation in Women with Alcoholism 
All female mammals with two X chromosomes balance gene expression with males having only one X by inactivating one of their Xs (X chromosome inactivation, XCI). Analysis of XCI in females offers the opportunity to investigate both X-linked genetic factors and early embryonic development that may contribute to alcoholism. Increases in the prevalence of skewing of XCI in women with alcoholism could implicate biological risk factors.
The pattern of XCI was examined in DNA isolated in blood from 44 adult females meeting DSM IV criteria for an Alcohol Use Disorder, and 45 control females with no known history of alcohol abuse or dependence. XCI status was determined by analyzing digested and undigested polymerase chain reaction (PCR) products of the polymorphic androgen receptor (AR) gene located on the X chromosome. Subjects were categorized into 3 groups based upon the degree of XCI skewness: random (50:50–64:36), moderately skewed (65:35–80:20) and highly skewed (>80:20).
XCI status from informative females with alcoholism was found to be random in 59% (n=26), moderately skewed in 27% (n=12) or highly skewed in 14% (n=6). Control subjects showed 60%, 29% and 11%, respectively. The distribution of skewed XCI observed among women with alcoholism did not differ statistically from that of control subjects (χ2 =0.14, 2 df, p=0.93).
Our data did not support an increase in XCI skewness among women with alcoholism or implicate early developmental events associated with embryonic cell loss or unequal (non-random) expression of X-linked gene(s) or defects in alcoholism among females.
PMCID: PMC3371305  PMID: 22375556
Alcoholism; Women; X Chromosome Inactivation; Skewness; AR Gene
18.  Association of CAPN10 SNPs and Haplotypes with Polycystic Ovary Syndrome among South Indian Women 
PLoS ONE  2012;7(2):e32192.
Polycystic Ovary Syndrome (PCOS) is known to be characterized by metabolic disorder in which hyperinsulinemia and peripheral insulin resistance are central features. Given the physiological overlap between PCOS and type-2 diabetes (T2DM), and calpain 10 gene (CAPN10) being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results. Our study is first of its kind to investigate the association pattern of CAPN10 polymorphisms (UCSNP-44, 43, 56, 19 and 63) with PCOS among Indian women. 250 PCOS cases and 299 controls from Southern India were recruited for this study. Allele and genotype frequencies of the SNPs were determined and compared between the cases and controls. Results show significant association of UCSNP-44 genotype CC with PCOS (p = 0.007) with highly significant odds ratio when compared to TC (OR = 2.51, p = 0.003, 95% CI = 1.37–4.61) as well as TT (OR = 1.94, p = 0.016, 95% CI = 1.13–3.34). While the haplotype carrying the SNP-44 and SNP-19 variants (21121) exhibited a 2 fold increase in the risk for PCOS (OR = 2.37, p = 0.03), the haplotype containing SNP-56 and SNP-19 variants (11221) seems to have a protective role against PCOS (OR = 0.20, p = 0.004). Our results support the earlier evidence for a possible role of UCSNP-44 of the CAPN10 gene in the manifestation of PCOS.
PMCID: PMC3285666  PMID: 22384174
19.  Salivary Testosterone and a Trinucleotide (CAG) Length Polymorphism in the Androgen Receptor Gene Predict Amygdala Reactivity in Men 
Psychoneuroendocrinology  2010;35(1):94-104.
In studies employing functional magnetic resonance imaging (fMRI), reactivity of the amygdala to threat-related sensory cues (viz., facial displays of negative emotion) has been found to correlate positively with interindividual variability in testosterone levels of women and young men and to increase on acute administration of exogenous testosterone. Many of the biological actions of testosterone are mediated by intracellular androgen receptors (ARs), which exert transcriptional control of androgen-dependent genes and are expressed in various regions of the brain, including the amygdala. Transactivation potential of the AR decreases (yielding relative androgen insensitivity) with expansion a polyglutamine stretch in the N-terminal domain of the AR protein, as encoded by a trinucleotide (CAG) repeat polymorphism in exon 1 of the X-chromosome AR gene. Here we examined whether amygdala reactivity to threat-related facial expressions (fear, anger) differs as a function of AR CAG length variation and endogenous (salivary) testosterone in a mid-life sample of 41 healthy men (mean age = 45.6 yr, range: 34–54 yr; CAG repeats, range: 19–29). Testosterone correlated inversely with participant age (r = −0.39, p = 0.012) and positively with number of CAG repeats (r = 0.45, p = 0.003). In partial correlations adjusted for testosterone level, reactivity in the ventral amygdala was lowest among men with largest number of CAG repeats. This inverse association was seen in both the right (rp = −0.34, p<0.05) and left (rp = −0.32, p<0.05) hemisphere. Activation of dorsal amygdala, correlated positively with individual differences in salivary testosterone, also in right (r = 0.40, p<0.02) and left (r = 0.32, p<0.05) hemisphere, but was not affected by number of CAG repeats. Hence, androgenic influences on threat-related reactivity in the ventral amygdala may be moderated partially by CAG length variation in the AR gene. Because individual differences in salivary testosterone also predicted dorsal amygdala reactivity and did so independently of CAG repeats, it is suggested that androgenic influences within this anatomically distinct region may be mediated, in part, by non-genomic or AR-independent mechanisms.
PMCID: PMC2825741  PMID: 19493626
testosterone; androgen receptor; CAG repeat polymorphism; fMRI; amygdala; facial expressions of emotion
20.  Association between FSHR polymorphisms and polycystic ovary syndrome among Chinese women in north China 
Polycystic ovary syndrome (PCOS) is a common endocrine disorder disease among women in reproductive-age. Since follicle stimulating hormone (FSH) exerts important biological functions, the association between PCOS and FSH receptor (FSHR) polymorphisms attracts wide attention. The aim of this study was to evaluate whether polymorphisms of FSHR at 307 and 680 codons are associated with PCOS patients in China.
Patients with PCOS (n = 215) and controls (n = 205) were recruited from Shanxi Province in north China. They are Han ethnics. Genomic DNA was isolated from the venous blood. The Ala307Thr and Ser680Asn polymorphisms of FSHR were analyzed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and direct DNA sequencing.
The distributions of genotype and allele of Ala307Thr and Ser680Asn polymorphisms of FSHR were not statistically different between the PCOS patients and the controls. Analysis of the frequency of FSHR polymorphisms showed no statistical difference among the PCOS patients with different obesity standards. Although there were no statistical differences in the most of the endocrine parameters including LH, LH/FSH, E2, P and T as well as the clinical pregnancy rate, there were significant differences in the levels of FSH and PRL among PCOS patients carrying different genotypes of Ala307Thr and Ser680Asn polymorphisms.
The Ala307Thr and Ser680Asn polymorphisms of FSHR are not associated with PCOS in Han ethnic Chinese women in north China. The FSHR polymorphisms was related to the levels of FSH and PRL but not other PCOS-associated endocrine hormones as well as clinical pregnancy rate in PCOS patients of Han Chinese ethnical population.
PMCID: PMC3947065  PMID: 24390680
Polycystic ovary syndrome; Follicle-stimulating hormone receptor; Genetic polymorphisms; Single nucleotide polymorphisms
21.  5meCpG Epigenetic Marks Neighboring a Primate-Conserved Core Promoter Short Tandem Repeat Indicate X-Chromosome Inactivation 
PLoS ONE  2014;9(7):e103714.
X-chromosome inactivation (XCI) is the epigenetic transcriptional silencing of an X-chromosome during the early stages of embryonic development in female eutherian mammals. XCI assures monoallelic expression in each cell and compensation for dosage-sensitive X-linked genes between females (XX) and males (XY). DNA methylation at the carbon-5 position of the cytosine pyrimidine ring in the context of a CpG dinucleotide sequence (5meCpG) in promoter regions is a key epigenetic marker for transcriptional gene silencing. Using computational analysis, we revealed an extragenic tandem GAAA repeat 230-bp from the landmark CpG island of the human X-linked retinitis pigmentosa 2 RP2 promoter whose 5meCpG status correlates with XCI. We used this RP2 onshore tandem GAAA repeat to develop an allele-specific 5meCpG-based PCR assay that is highly concordant with the human androgen receptor (AR) exonic tandem CAG repeat-based standard HUMARA assay in discriminating active (Xa) from inactive (Xi) X-chromosomes. The RP2 onshore tandem GAAA repeat contains neutral features that are lacking in the AR disease-linked tandem CAG repeat, is highly polymorphic (heterozygosity rates approximately 0.8) and shows minimal variation in the Xa/Xi ratio. The combined informativeness of RP2/AR is approximately 0.97, and this assay excels at determining the 5meCpG status of alleles at the Xp (RP2) and Xq (AR) chromosome arms in a single reaction. These findings are relevant and directly translatable to nonhuman primate models of XCI in which the AR CAG-repeat is monomorphic. We conducted the RP2 onshore tandem GAAA repeat assay in the naturally occurring chimeric New World monkey marmoset (Callitrichidae) and found it to be informative. The RP2 onshore tandem GAAA repeat will facilitate studies on the variable phenotypic expression of dominant and recessive X-linked diseases, epigenetic changes in twins, the physiology of aging hematopoiesis, the pathogenesis of age-related hematopoietic malignancies and the clonality of cancers in human and nonhuman primates.
PMCID: PMC4117532  PMID: 25078280
22.  Construction of a polycystic ovarian syndrome (PCOS) pathway based on the interactions of PCOS-related proteins retrieved from bibliomic data 
Polycystic ovary syndrome (PCOS) is a complex but frequently occurring endocrine abnormality. PCOS has become one of the leading causes of oligo-ovulatory infertility among premenopausal women. The definition of PCOS remains unclear because of the heterogeneity of this abnormality, but it is associated with insulin resistance, hyperandrogenism, obesity and dyslipidaemia. The main purpose of this study was to identify possible candidate genes involved in PCOS. Several genomic approaches, including linkage analysis and microarray analysis, have been used to look for candidate PCOS genes. To obtain a clearer view of the mechanism of PCOS, we have compiled data from microarray analyses. An extensive literature search identified seven published microarray analyses that utilized PCOS samples. These were published between the year of 2003 and 2007 and included analyses of ovary tissues as well as whole ovaries and theca cells. Although somewhat different methods were used, all the studies employed cDNA microarrays to compare the gene expression patterns of PCOS patients with those of healthy controls. These analyses identified more than a thousand genes whose expression was altered in PCOS patients. Most of the genes were found to be involved in gene and protein expression, cell signaling and metabolism. We have classified all of the 1081 identified genes as coding for either known or unknown proteins. Cytoscape 2.6.1 was used to build a network of protein and then to analyze it. This protein network consists of 504 protein nodes and 1408 interactions among those proteins. One hypothetical protein in the PCOS network was postulated to be involved in the cell cycle. BiNGO was used to identify the three main ontologies in the protein network: molecular functions, biological processes and cellular components. This gene ontology analysis identified a number of ontologies and genes likely to be involved in the complex mechanism of PCOS. These include the insulin receptor signaling pathway, steroid biosynthesis, and the regulation of gonadotropin secretion among others.
PMCID: PMC2743649  PMID: 19723303
23.  Visfatin and Resistin Serum Levels in Normal-Weight and Obese Women With Polycystic Ovary Syndrome 
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of reproductive age that is linked to insulin resistance and obesity. While studies have shown that plasma levels of resistin and visfatin increase with obesity, the association between PCOS and these markers has not been described well.
This case-control study aimed to compare the serum levels of visfatin and resistin in women with PCOS in comparison with the healthy controls matched for age and body mass index (BMI).
Patients and Methods:
A total of 80 women consisted of 40 women with PCOS and 40 matched eumenorrheic women without hyperandrogenism enrolled in the study. They were subcategorized into obese and normal-weight women according to their BMI. Serum visfatin and resistin levels were assessed using sandwich enzyme-linked Immunosorbent assay (ELISA).
Serum levels of resistin were higher among both obese and normal-weight women with PCOS in comparison with the controls (2.36 and 1.58 ng/mL in normal-weight women with PCOS and controls, respectively; and 2.10 and 1.91 ng/mL in obese women with PCOS and controls, respectively). Serum visfatin levels was higher in both obese women with PCOS and controls (3.46 and 3.49 ng/mL PCOS and control groups, respectively) in comparison with normal-weight women in both groups (3.16 and 3.15 in PCOS and control groups, respectively); however; there were no statistically significant differences in serum resistin and visfatin levels between PCOS and control groups (P > 0.05).
While the expression of visfatin and resistin may be upregulated in women with PCOS, it is not translated at serum level.
PMCID: PMC4166205  PMID: 25237319
Polycystic Ovary Syndrome; Visfatin; Resistin; Obesity; Body Mass Index
24.  Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation 
To detect expression of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) in oocytes, and their receptor type 2 receptor for BMPs (BMPR2) in cumulus cells in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF), and determine if BMPR2, BMP15, and GDF9 expression correlate with hyperandrogenism in FF of PCOS patients.
Prospective case–control study. Eighteen MII-oocytes and their respective cumulus cells were obtained from 18 patients with PCOS, and 48 MII-oocytes and cumulus cells (CCs) from 35 controls, both subjected to controlled ovarian hyperstimulation (COH), and follicular fluid (FF) was collected from small (10–14 mm) and large (>18 mm) follicles. RNeasy Micro Kit (Qiagen®) was used for RNA extraction and gene expression was quantified in each oocyte individually and in microdissected cumulus cells from cumulus-oocyte complexes retrieved from preovulatory follicles using qRT-PCR. Chemiluminescence and RIA assays were used for hormone assays.
BMP15 and GDF9 expression per oocyte was higher among women with PCOS than the control group. A positive correlation was found between BMPR2 transcripts and hyperandrogenism in FF of PCOS patients. Progesterone values in FF were lower in the PCOS group.
We inferred that BMP15 and GDF9 transcript levels increase in mature PCOS oocytes after COH, and might inhibit the progesterone secretion by follicular cells in PCOS follicles, preventing premature luteinization in cumulus cells. BMPR2 expression in PCOS cumulus cells might be regulated by androgens.
PMCID: PMC3492567  PMID: 22825968
BMP15; GDF9; BMPR2; PCOS; COH; hyperandrogenism; mature oocyte
25.  Anteroposterior diameter of the infrarenal abdominal aorta is higher in women with polycystic ovary syndrome 
Women affected by polycystic ovary syndrome (PCOS) are known to be at higher risk of cardiovascular disease. The aim of this study was to identify the artery that first is affected by early pre-atherosclerotic changes in PCOS.
Twenty-nine women with PCOS aged 17 to 27 years and 26 healthy nonhyperandrogenic volunteers with regular menses (control women) aged 16 to 28 years were enrolled. All PCOS patients were overweight or obese (body mass index [BMI] ≥ 25). Diagnosis of PCOS was performed in line with the 2003 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Accordingly, PCOS was defined when at least two of the following three features were present after exclusion of other etiologies: 1) oligomenorrhea and or anovulation; 2) hyperandrogenism and/or hyperandrogenemia; and 3) polycystic ovaries visible at ultrasound. Androgen excess or related disorders were excluded. The intima-media thickness (IMT) of common carotid arteries and common femoral arteries and the anteroposterior diameter of the infrarenal abdominal aorta were measured by ultrasound. Lutenizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, total testosterone, androstenedione, and sex hormone-binding globulin (SHBG) serum levels were measured between the 3rd and the 6th day of spontaneous or progestin-induced menstrual cycle. Our study was performed in the absence of any medical treatment.
Women with PCOS showed a higher LH to FSH ratio (p < 0.01), increased fasting insulin (p < 0.001), total testosterone (p < 0.001), and androstenedione (p < 0.001) levels, and lower SHBG concentrations (p < 0.001) compared to control women. BMI and waist-to-hip ratio were also higher in women with PCOS (p < 0.000 and p < 0.001, respectively). Women with PCOS also showed increased total cholesterol (p < 0.001), triglyceride (p < 0.001), and apolipoprotein B (p < 0.001) levels. Vascular data showed women with PCOS had a higher anteroposterior diameter than control women (p < 0.005). However, when analysis of covariance was performed and BMI was entered into the model as a covariate, anteroposterior diameter did not maintain a significant association with PCOS.
This study shows that anteroposterior diameter of the infrarenal abdominal aorta, but not IMT of common carotid arteries or common femoral arteries, is higher in women with PCOS than in women without this disease. This represents the earliest atherosclerotic change in women with PCOS. However, this alteration seems to be due to body weight secondary to PCOS and not due to PCOS per se.
PMCID: PMC2704897  PMID: 19590590
polycystic ovary syndrome; antero-posterior diameter; infrarenal abdominal aorta; intimia-media thickness

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