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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5976-5980
Copyright © 2003 by The Endocrine Society

Association of the (TAAAA)n Repeat Polymorphism in the Sex Hormone-Binding Globulin (SHBG) Gene with Polycystic Ovary Syndrome and Relation to SHBG Serum Levels

Nectaria Xita, Agathocles Tsatsoulis, Anthi Chatzikyriakidou and Ioannis Georgiou

Division of Endocrinology (N.X., A.T.), Department of Medicine and Genetics Unit (A.C., I.G.), Department of Obstetrics and Gynecology, University of Ioannina, Ioannina 45110, Greece

Address all correspondence and requests for reprints to: Agathocles Tsatsoulis, M.D., Ph.D., FRCP, Professor of Medicine/Endocrinology, Division of Endocrinology, Department of Medicine, University of Ioannina, Ioannina 45110, Greece. E-mail: atsatsou{at}cc.uoi.gr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
SHBG levels are frequently low in women with polycystic ovary syndrome (PCOS) and may contribute to increased tissue exposure to free androgens. A (TAAAA)n repeat polymorphism in the promoter of the SHBG gene has been described recently, and its transcriptional activity has been shown to be related to the number of tandem repeats. Recent evidence also suggests that prenatal exposure to androgen excess may program for the development of the PCOS phenotype during adulthood. Our aim was to investigate the possible association of the functional (TAAAA)n polymorphism in the promoter of the SHBG gene with PCOS and its relation to SHBG levels. We studied 185 women with PCOS and 324 normal controls. Genotype analysis revealed six (TAAAA)n alleles containing 6–11 repeats. The distribution of these alleles was different in the two groups. Women with PCOS had a significantly greater frequency of longer (TAAAA)n alleles (more than eight repeats) than normal women who had shorter alleles (less than eight repeats) in higher frequency (P = 0.001). Furthermore, in the PCOS group, carriers of the longer allele genotypes had lower SHBG levels [1.17 ± 0.68 µg/dl (35.1 ± 20.5 nmol/liter)] than those with shorter alleles [1.51 ± 0.93 µg/dl (45.3 ± 28 nmol/liter P = 0.02). A novel (TAAAA)n allele, which has not been previously reported, was found in low frequency, mainly in the control population. From these results, there is evidence that there may be a genetic contribution to decreased SHBG levels frequently seen in women with PCOS. The SHBG gene may act as a susceptibility gene for PCOS and may provide the genetic link for the developmental origin hypothesis for PCOS that was recently proposed on the basis of experimental observation in prenatally androgenized sheep and primates.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is a common endocrine disorder in women of reproductive age, characterized by anovulation and hyperandrogenism (1, 2, 3). It is also associated with metabolic aberrations manifested by central adiposity, insulin resistance, and hyperinsulinism (4). PCOS is a complex and heterogeneous disorder, the etiology of which remains elusive, but there is increasing evidence for a significant genetic contribution (5, 6).

A two-hit hypothesis has been suggested for the pathogenesis of PCOS. The first hit relates to dysregulation of steroidogenic enzymes involved in ovarian and/or adrenal androgen biosynthesis, and the second hit involves defects responsible for insulin resistance and hyperinsulinemia that further exacerbates the hyperandrogenism (7). Recently, a unifying linear model based on the developmental origin hypothesis has been proposed. According to this hypothesis, the phenotype of PCOS can arise as a consequence of genetically determined exposure to androgen excess during prenatal life. This programs the hypothalamic-pituitary unit in favor of LH secretion and enhances the development of abdominal obesity that predisposes to insulin resistance (8).

The access of androgens to target tissues is regulated by SHBG in human blood. Serum SHBG levels are frequently low in patients with hyperandrogenism, especially in association with PCOS, and in individuals at risk for diabetes and heart disease (9, 10). Also, SHBG levels vary among individuals and are influenced by hormonal, metabolic and nutritional factors (11, 12, 13). The reason that SHBG levels are low in many women with PCOS is unclear. Both high androgens and high insulin have been known to lower SHBG (12, 14), but SHBG values may also be genetically determined.

Human SHBG is a homodimeric glycoprotein produced by hepatocytes and is encoded by a 4-kb gene spanning eight exons in the short arm of chromosome 17 (15, 16). Recently, a (TAAAA)n pentanucleotide repeat polymorphism at the 5' boundary of the human SHBG promoter has been described and reported to influence its transcriptional activity in vitro (17). It has also been suggested that this functional polymorphism could contribute to individual differences in plasma SHBG levels and thereby influence the access of sex steroids to their target tissues.

In the light of these observations, the aim of our study was to investigate whether the (TAAAA)n polymorphism of the SHBG gene is associated with PCOS and whether polymorphic variants of the gene are related to serum SHBG levels in women with PCOS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study population consisted of 185 Greek women (14–42 yr, mean age 23.04 yr) with PCOS. The diagnosis was based on the criteria proposed by the 1990 National Institutes of Health–National Institute of Child Health and Human Development conference on PCOS. These criteria are ovulatory dysfunction; clinical evidence of hyperandrogenism; and/or hyperandrogenemia and exclusion of related disorders such as congenital adrenal hyperplasia, hyperprolactinemia, or Cushing’s syndrome (3). Hyperandrogenism was defined by the clinical presence of hirsutism (Ferriman Gallwey score > 8), acne ,or alopecia and/or elevated androgen levels. Menstrual dysfunction was defined by the presence of oligomenorrhea or amenorrhea. In those patients who were on medication, treatment was discontinued at least 6 months before their inclusion in the study with the exception of two patients who were taking estrogen therapy, and their serum SHBG values were not included in the analysis. The control group consisted of 324 women with normal menstrual cycles (28–30 d), no signs of hyperandrogenism, and normal TSH levels.

All patients were studied in the early follicular phase (d 3–5) of a spontaneous or progestin-induced menstrual cycle. The body mass index (BMI) of each patient, calculated as weight (kilograms)/height2 (meters), was recorded. Blood samples were drawn after overnight fasting for the measurement of fasting serum glucose and insulin, serum gonadotropins (LH, FSH), total testosterone, SHBG, and dehydroepiandrosterone sulfate. The free androgen index (FAI) was calculated using the formula: (total testosterone/SHBG) x 100. From both patients and controls, whole blood samples were used for isolation of peripheral blood leukocytes for the genetic analysis. The study protocol was approved by the Hospital Ethics Committee, and all subjects studied gave their informed consent.

Hormonal assays

Serum glucose was determined by the hexokinase method using a glucose analyzer (Olympus 600, Clinical Chemistry Analyser, Olympus Diagnostica GmbH, Ireland). The coefficient of variation (CV) of this method was less than 3%. Insulin was measured by microparticle enzyme immunoassay on an AXSYM immunoanalyzer (Abbott Laboratory, Abbott Park, IL). The CV of this method was 5%. Total testosterone and serum gonadotropins (LH, FSH) were determined by chemiluminescent microparticle immunoassay on an Abbott-ARCHITECT Immunoanalyzer (Abbott Laboratory). The CVs were 4% for total testosterone, 3.5% for LH, and 4% for FSH. Dehydroepiandrosterone sulfate and SHBG were measured by chemiluminescent immunometric method (IMMULITE 2000 immunoanalyzer, Diagnostic Products Co., Los Angeles, CA), and the CVs were 9% and 5.5%, respectively.

Genotype analysis

Genomic DNA was isolated from peripheral blood leukocytes of women with PCOS and the controls. Amplification of the TAAAA repeat region within the Alu sequence in the SHBG promoter was accomplished using PCR with a forward primer (5'-GCTTGAACTCGAGAGGCAG) and a reverse primer (5'-CAGGGCCTAAACAGTCTAGCAGT) corresponding to a sequence at -651/-673 nt within the upstream promoter sequence. Amplified products were separated by 10% PAGE followed by silver staining, and the number of individual alleles was determined. The number of TAAAA repeats in every particular allele was analyzed by sequencing the appropriate PCR products. A quality control assessment of our PCR method was done by random sampling and sequencing of the PCR products and duplication of PCR assays.

Statistical analysis

Statistical analysis of differences in genotype frequencies between PCOS and controls was performed using the {chi}2 test. For the genotypes found to present a statistically significant difference among patients and controls, the odds ratios were estimated. Differences in serum SHBG levels were assessed with the nonparametric Mann-Whitney U test. To adjust SHBG levels for confounding factors, analysis of covariance was performed including age, total testosterone, BMI, and fasting serum insulin levels (ANOVA). P < 0.05 was set as statistically significant. All results are reported as the mean ± SD. All analyses used the SPSS statistical package (version 11.0, SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Endocrine and anthropometric data of women with PCOS and controls are shown in Table 1Go. BMI, LH:FSH ratio, testosterone levels, and FAI were higher, whereas SHBG levels were lower in the PCOS group compared with controls, as expected.


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  		TABLE 1. Anthropometric and endocrine data of PCOS women and controls

 
Genotype analysis for the (TAAAA)n polymorphism of the SHBG gene in the patients and controls revealed six alleles having 6–11 TAAAA repeats. The distribution of the alleles between PCOS and the control group showed statistically significant differences. In particular, 37.65% of women with PCOS had alleles with more than eight repeats, whereas in the control group, the frequency of these alleles was 31.48% [P = 0.03, odds ratios 1.31, 95% confidence interval (CI) = 1.01–1.72]. In PCOS, 28.76% of women had alleles with less than eight repeats, compared with 39.51% of the control group (P = 0.0006, odds ratios 0.61, 95% CI = 0.47–0.81), whereas there was no significant difference in the frequency of (TAAAA)8 allele between the two groups. Taking into consideration that the majority of the control group were lean women, we assigned the women with PCOS into lean PCOS (46%) and overweight-obese PCOS (BMI > 25 kg/m2). The comparison of allele distribution between each PCOS subgroup and controls revealed statistically significant differences, whereas there was no difference in the distribution of alleles between the two PCOS subgroups. This leads to the observation that women with PCOS are more frequently carriers of longer (TAAAA)n alleles than normal women who have shorter alleles at a higher frequency (Fig. 1Go).



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  		FIG. 1. Shift in the distribution of grouped (TAAAA)n alleles in PCOS, compared with controls (ns, Nonsignificant).

 
The distribution and frequencies of the SHBG (TAAAA)n genotypes also shows a shift toward genotypes with long repeats in the PCOS and short repeats in the control group (Fig. 2Go). Short-allele genotypes were defined as those genotypes with 6/6, 6/7, 6/8, 7/7, or 7/8 tandem repeats, whereas long allele genotypes were defined as those with 8/8, 8/9, 8/10, 8/11, 9/9, 9/10, 9/11, or 10/10 repeats.



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  		FIG. 2. Upper panel, frequency of genotypes, grouped in short and long allele genotypes, show significant differences between PCOS and controls (P = 0.009). Lower panel, correlation of (TAAAA)n genotypes with SHBG levels. PCOS women with short allele genotypes had higher SHBG level, compared with women with long allele genotypes (P = 0.02). No statistically significant difference was observed in the control groups (P = 0.27). In the group of short allele genotypes, genotypes 6/6, 6/7, 6/8, 7/7, and 7/8 were included, whereas in the long allele genotypes, genotypes 8/8, 8/9, 8/10, 8/11, 9/9, 9/10, 9/11, and 10/10 were included. Conversion factor for SHBG: 30 (nmol/liter).

 
Serum SHBG levels were also analyzed with respect to their (TAAAA)n genotypes. There was a statistically significant difference in serum SHBG levels [1.17 ± 0.68 µg/dl (35.1 ± 20.5 nmol/liter)] between patients with PCOS having alleles with eight or more TAAAA repeats and those with shorter than eight repeat alleles [1.51 ± 0.93 µg/dl (45.3 ± 28.0 nmol/liter), P = 0.02]. From this comparison, extreme genotype combinations, having one shorter and one longer than eight repeats allele, were excluded (genotypes 7/9, 6/9, and 6/10). A statistically significant difference was also found in FAI levels between these two groups, with the longer allele genotype group having higher FAI levels (12.58 ± 10.12), compared with the shorter allele genotype group (6.78 ± 5.68, P = 0.006). There were no statistically significant differences with regard to age, BMI, total testosterone, LH:FSH ratio, and fasting glucose:insulin ratio in these two groups (Table 2Go). The above impact of (TAAAA)n genotypes on SHBG levels and FAI was limited to the women with PCOS and was not statistically significant in the control group (Fig. 2Go).


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  		TABLE 2. Demographic and biochemical parameters in PCOS women with short and long allele genotypes

 
In addition, more than eight repeat alleles were statistically more frequently found among patients with the lowest serum SHBG levels [less than 0.6 µg/dl (18 nmol/liter), which is the lowest normal limit], compared with less than eight repeats alleles (50% vs. 18.4%). All these factors lead to the conclusion that shorter TAAAA alleles are associated with higher serum SHBG levels in PCOS.

Further analysis showed that, in women with PCOS, fasting insulin levels were positively correlated with FAI (r = 0.264, P = 0.002). However, there was no correlation between insulin and SHBG levels in these women (r = 0.09, P = 0.28). Moreover, linear regression analysis showed that FAI was inversely correlated to SHBG levels in women with PCOS (r = 0.489, P = 0.000).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we analyzed a polymorphic (TAAAA)n repeat in the human SHBG promoter in a group of Greek women with PCOS and ethnically matched controls to evaluate whether variations in this pentanucleotide repeat are associated with PCOS and serum SHBG levels. The genotype analysis revealed six alleles containing 6–11 repeats. A novel allele, the (TAAAA)11, which was not reported previously, was observed at a low frequency, mainly in the control population. On comparing the distribution of the polymorphic alleles between the PCOS and control groups, we found that women with PCOS had alleles with longer repeats (more than eight repeats) more frequently than normal women who had shorter alleles (less than eight repeats) in a much higher frequency. Furthermore, in the PCOS group, genotypes with long alleles were associated with lower SHBG levels and higher FAI levels than those with shorter alleles. It appears, therefore, that women with PCOS are more frequently carriers of long (TAAAA)n alleles in the promoter of the SHBG gene, and these are associated with lower SHBG levels.

This is the first case-control population study to examine the association of SHBG gene polymorphism with PCOS and its relation to SHBG levels. The findings of this study are important for two reasons. First, they suggest that there may be a genetic contribution to decreased SHBG levels frequently seen in women with PCOS, in addition to the previously suggested hormonal, metabolic, and nutritional factors (11, 12, 13). It is believed that women with PCOS have low SHBG levels as a result of androgen excess (12). Another factor contributing to this is hyperinsulinemia, which is thought to play an important role in PCOS (14). Besides these physiological mechanisms that may influence SHBG levels in women with PCOS, the possibility of a genetic basis contributing to this characteristic is suggested in the present study.

Second, female carriers of the genetic variants associated with low SHBG levels may be exposed to higher-than-normal free androgens at the tissue level, and this may also occur during prenatal life. This observation may, in turn, provide a genetic explanation for the developmental origin hypothesis for PCOS recently suggested by Abbott et al. (8). This hypothesis was based on experimental animal studies and some clinical observations. The animal studies convincingly showed that experimentally induced prenatal androgen excess in rhesus fetal monkeys and sheep results in changes that, in later life, resemble those observed in PCOS. By adulthood, these animals exhibit LH hypersecretion and hyperresponsiveness in ovarian steroidogenesis at human chorionic gonadotropin as well as impaired insulin secretion and action accompanied by hyperandrogenism, anovulation, and polycystic appearing ovaries (17, 18, 19, 20, 21). Clinical observations also support a fetal origin of PCOS. Features characteristic to those of PCOS are found in women exposed to fetal 21-hydroxylase deficiency (despite the normalization of the adrenal androgen excess after birth) or congenital fetal virilizing tumor (despite the removal of the tumor at birth) (22). In the light of these observations, it has been suggested that fetal exposure to androgen excess may simultaneously program multiple organ systems that will later manifest the heterogeneous phenotype of PCOS (8).

Although direct evidence is lacking, we speculate, from the results of our study, that genetically determined polymorphic variants in the SHBG gene may provide the link to the developmental origin hypothesis for PCOS described above. Thus, women with PCOS have a significantly greater frequency of longer (TAAAA)n alleles than healthy fertile women. Preferential expression of longer alleles in women with PCOS is associated with lower SHBG levels and, indirectly, with excess androgen exposure at the target tissue throughout life but more importantly during fetal life when programming of the differentiating tissues takes place. This, however, may not be the only explanation of how genetically determined low SHBG levels contribute to the expression of PCOS. Decreased SHBG levels may also lead to the development of PCOS phenotype by contributing to the increase in biologically active androgen levels during the postpubertal period.

Our findings are in line with a recent report by Hogeveen et al. (23) with the identification of two sequence variants of the coding region of human SHBG accounting for unusually low serum SHBG levels in a woman with severe hyperandrogenism. Furthermore, one of these sequence variants was associated with the hyperandrogenic state and ovarian dysfunction in four other patients. This polymorphism, however, is very rare among patients with PCOS. Nevertheless, this observation gives another example of human SHBG variants linked to hyperandrogenism or ovarian dysfunction.

The results of our study also indicate that longer (TAAAA)n alleles may decrease the transcriptional ability of the SHBG gene and shorter alleles may increase it, thus establishing the functional significance of the polymorphism in vivo. This is supported by the fact that no differences in BMI or other biochemical parameters that might influence serum SHBG levels were observed in women with PCOS with longer alleles in comparison with women with PCOS with shorter alleles.

Until recently only insulin gene variable number tandem repeat has been associated with PCOS, and there is evidence that another variable number tandem repeat in the CYP11a gene is associated with this syndrome, at least in some populations (24, 25, 26, 27, 28). It is important to stress that the present study adds an equally significant association of a similar polymorphism in the SHBG gene with PCOS. Taking into consideration that low serum SHBG levels have been reported to be prognostic indicators for the onset of type 2 diabetes and cardiovascular disease (9, 10), two conditions that have been linked to PCOS, we assume that women with PCOS having shorter TAAAA alleles might consist a low-risk group for developing these complications. We could also assume that various treatments that increase the levels of serum SHBG could possibly benefit most women with PCOS having long alleles. Further studies in different populations with PCOS are needed to confirm our findings.

In summary our study, for the first time, provides evidence that variation in a polymorphic (TAAAA)n repeat in the human SHBG promoter is significantly associated with PCOS, at least in the Greek population. Taking into consideration that Greek women with PCOS do not differ phenotypically or biochemically from other Caucasian populations (2), it would be interesting to see whether our results can be replicated in association studies in other populations.

In conclusion, this study indicates that the SHBG gene may act as a susceptibility gene for PCOS. Furthermore, this variation may contribute to low SHBG levels frequently seen in PCOS. Those individuals with genetically determined low SHBG levels may be exposed to high free androgen levels during fetal life programming their future PCOS phenotype and also during the pubertal period contributing to manifestations of hyperandrogenism.


   Footnotes
 
Abbreviations: CI, Confidence interval; CV, coefficient of variation; FAI, free androgen index; PCOS, polycystic ovary syndrome.

Received February 6, 2003.

Accepted September 8, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Common Genetic Variation in the Sex Steroid Hormone-Binding Globulin (SHBG) Gene and Circulating SHBG Levels among Postmenopausal Women: The Multiethnic Cohort
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