Adiponectin in diabetes mellitus.

Adiponectin represents one of the most abundant and well-studied adipokines that has been implicated as a major protective factor against the adverse metabolic and cardiovascular consequences of obesity. The main insulin-sensitizing action of adiponectin results from decrease in hepatic gluconeogenesis and increase in muscle glucose transport and, secondly from enhancement of energy consumption and fatty acid oxidation in peripheral tissues with the aim of increasing ATP production. Besides these effects, the potential role of adiponectin on insulin secretion, as well as on energy expenditure, through central action, has also been investigated. Accumulating evidence from clinical, experimental animal and genetic studies support a close association between hypoadiponectinemia and insulin resistance/ type 2 diabetes. The question that arises is whether hypoadiponectinemia is the result of insulin resistance/type 2 diabetes or the cause of this disorder. Based on the observation that various drug classes exert beneficial effects on insulin resistance partly by increasing plasma adiponectin levels, it could hypothesized that substances that enhance or mimic adiponectin to activate its receptors and/or postreceptor signaling pathway may be a promising therapeutic strategy in the prevention and treatment of diabetes. However, many questions need to be addressed before adiponectin can be used as a potent therapeutic target.

The (TAAAA)n polymorphism of the SHBG gene in men with the metabolic syndrome.

OBJECTIVE: Low serum Sex Hormone-Binding Globulin (SHBG) has been proposed as an indicator of the Metabolic Syndrome (MS) and cardiovascular disease in men. On the other hand, the (TAAAA)n repeat polymorphism in the SHBG gene has been shown to affect SHBG levels. The possible role of this polymorphism in the MS was examined in the present study. DESIGN: The study population consisted of 83 men with MS aged 54.9±14.8 years and 166 healthy men of the same age. The diagnosis of MS was based on the criteria proposed by the National Cholesterol Education Program - Third Adult Treatment Panel (NCEP-ATP III). The waist circumference was recorded and blood samples were obtained after overnight fasting for biochemical and hormonal tests. The SHBG(TAAAA)N polymorphism was genotyped in peripheral blood leucocytes. RESULTS: Genotype analysis for the (TAAAA)n polymorphism of the SHBG gene in the patients and controls identified 6 alleles having 6-11 TAAAA repeats. Patients with MS had more frequently short-allele genotypes (with 6/6, 6/7, 6/8, 7/7, 7/8 or 8/8 tandem repeats) compared to controls (53% vs. 39.8%, p=0.047). In the entire study population, men homozygous for the 6 TAAAA repeat allele had lower SHBG levels (p=0.01) and higher waist circumference (p=0.006) than men heterozygous or non-carriers of this allele. CONCLUSION: Short SHBG(TAAAA)N allele genotypes may play a role in the development of the MS. The mechanism of this contribution remains unclear.

The (TTTA)n polymorphism of aromatase (CYP19) gene is associated with age at menarche.

BACKGROUND: Twin studies have shown that age at menarche may be subject to hereditary influences but the specific determinants are unknown. Estrogens are known to have an important role in menarche. Since the enzyme aromatase is responsible for the conversion of androgens to estrogens, the aromatase (CYP19) gene could be a candidate gene for the regulation of menarche. The aim of this study was to investigate the possible association of the CYP19(TTTA)(n) polymorphism with age at menarche. METHODS: We studied 130 healthy adolescent females from a closed community in North-Western Greece. Information on menarche was obtained through interviews. The BMI was recorded. The CYP19(TTTA)(n) polymorphism was genotyped. RESULTS: The mean age at menarche was 12.9 ± 1.2 years and the BMI = 19.8 ± 2.3 kg/m(2). Genotype analysis revealed 5 CYP19(TTTA)(n) alleles containing 7-11 TTTA repeats. Girls homozygous for the allele with 7 TTTA repeats had earlier menarche (12.45 ± 0.9 years) than girls carrying other genotypes (13.0 ± 1.2 years, P = 0.025), whereas the BMI was not different between these two subgroups. Carriers of the allele with 11 TTTA repeats had later menarche compared with non-carriers (14.1 ± 0.75 versus 12.8 ± 1.2 years, P< 0.001), whereas no difference was found in BMI values. Comparing girls with early menarche (<12 years, 25th percentile) with girls with late menarche (>13.75 years, 75th percentile), we found that 31% of the girls with early menarche were homozygous for the (TTTA)(7) allele compared with 6.9% among girls with late menarche (P = 0.018). In addition, none of the girls carrying the (TTTA)(11) allele was found among the subgroup with early menarche, whereas 24.1% of girls with late menarche had the (TTTA)(11) allele (P = 0.001). No association between other alleles and age at menarche was found. CONCLUSIONS: There is evidence for a genetic contribution of the CYP19 gene to the age at menarche.

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis.

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options.

Detection of herpes virus DNA in post-operative thyroid tissue specimens of patients with autoimmune thyroid disease.

AIM: To demonstrate any differences in the detection of herpes simplex virus type 1 and 2, cytomegalovirus, human herpes virus type 6 and 7 DNA from thyroid tissue blocks of patients with autoimmune thyroid disease and multi-nodular goiter and to propose few mechanisms, which could explain the possible role of herpesvirus infection in the development of thyroid autoimmune responses. MATERIAL-METHODS: Thyroid tissue specimens were obtained postoperatively from 4 patients with multinodular goiter and 18 patients with autoimmune thyroid disease (Graves' disease and Hashimoto thyroiditis). Herpes virus DNA was detected using polymerase chain reaction based assays. RESULTS: No statistically significant differences were observed between autoimmune thyroid disease and multinodular goiter tissue specimens concerning herpes simplex virus type 1, 2 DNA isolation (44.4% vs 0%, P=0.094), human herpes virus type 6 DNA isolation (11.1% vs 0%, P=0.48), human herpes virus type 7 DNA isolation (33.3% vs 25%, P=0.75). No CMV DNA was isolated from any tissue specimen. At least one kind of herpes virus DNA was detected in 13 out of 18 (72.22%) AITD tissue specimens and in 1 out of 4 (25%) MNG tissue specimens (P=0.01). CONCLUSIONS: Although no data are available relating the direct effect of herpes infection on thyroid epithelial cells, a better understanding of how an aberrant immune response against the thyroid gland is initiated and propagated through herpes virus infection is required. Elucidation of the underlying mechanisms may allow the development of new etiologically based therapeutic modalities.

The role of sex hormone-binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) may be programmed in utero by androgen excess. Our aim was to examine the role of the sex hormone-binding globulin (SHBG) and androgen receptor (AR) gene polymorphisms, in the phenotypic expression of PCOS. METHODS: A cohort of 180 women with PCOS and 168 healthy women of reproductive age were investigated. BMI was recorded and the hormonal profile was determined on Day 3-5 of menstrual cycle. DNA was extracted from peripheral blood leucocytes and the SHBG(TAAAA)n and AR(CAG)n polymorphisms were genotyped by PCR. RESULTS: Genotype analysis revealed six SHBG(TAAAA)n alleles with 6-11 repeats and 19 AR(CAG)n alleles with 6-32 repeats, present in both PCOS and control women. Long SHBG(TAAAA)n alleles (>8 repeats) were at greater frequency in PCOS than normal women (P = 0.001), whereas short AR(CAG)n alleles (

Possible reasons for different pattern disappearance of thyroglobulin and thyroid peroxidase autoantibodies in patients with differentiated thyroid carcinoma following total thyroidectomy and iodine-131 ablation.

The purpose of this study was to reveal some possible factors for the differences between the pattern of disappearance of thyroglobulin autoantibodies (anti-Tg) and thyroid peroxidase autoantibodies (anti-TPO) in patients with differentiated thyroid carcinoma following thyroidectomy and iodine-131 ablation. Patients with a history of follicular cell derived cancer (papillary, follicular, both papillary and follicular, Hürthle cell) and high pre-operative titers of anti-TPO and/or anti-Tg autoantibodies were retrospectively studied. Thyroglobulin (Tg) levels were measured using radio-immunometric assay (RIA). Anti-Tg and anti-TPO levels during the first 6 yr' follow-up were measured by passive agglutination, during the following 10 yr by ELISA method and during the last 2 yr by chemiluminescence assay. A statistically significant difference was observed between median time (72 months) of disappearance of anti-TPO and median time (39 months) of disappearance of anti-Tg in patients with complete ablation of thyroid tissue, following iodine-131 administration (p=0.0395, Logrank statistic=4.24, Kaplan-Meier method). A statistically significant difference was observed between median time (106 months) of disappearance of anti-TPO and median time (33 months) of disappearance of anti-Tg in patients >45 yr of age (p=0.034) and between median time (111 months) of disappearance of anti-TPO and median time (41 months) of disappearance of anti-Tg in patients with tumor size <2 cm (p=0.0175). We concluded that patients with differentiated thyroid carcinoma and pre-surgical elevated titers of both Tg and anti-TPO tend to become earlier anti-Tg seronegative. Although tumor size and age may influence the pattern of thyroid autoantibody reduction, the exact reasons for the different rhythm of autoantibodies decrease must further be evaluated.

Fine needle aspiration biopsy-RT-PCR molecular analysis of thyroid nodules: a useful preoperative diagnostic tool.

Fine needle aspiration biopsy (FNAB)-based cytology is an accurate preoperative diagnostic method for the evaluation of thyroid nodules. Despite its high specificity and sensitivity, the results are non-diagnostic in a significant number of cases, commonly due to inadequacy of the samples or the presence of undetermined cellular morphology. Overlap-ping cytologic features among follicular-derived lesions are the most common causes of cyto-histopathologic discordances. The management of thyroid nodules with a non-diagnostic FNAB remains controversial. The significant probability of malignancy imposes either the repeat of the procedure or direct surgery. Recent studies have demonstrated the important role of molecular-based techniques such as RT-PCR in the diagnosis of thyroid lesions. Follicular cells obtained from the remaining material within the needle can be used for RNA extraction and then for RT-PCR amplification of specific mRNAs that are expressed in benign or malignant thyroid nodules. Furthermore, FNAB-RT-PCR in combination with molecular scanning techniques or direct sequencing provides a valuable screening tool for mutations. The present review highlights the applications of FNAB-RT-PCR method in the identification of new diagnostic molecular markers. The parallel molecular and cytological analysis of FNABs may contribute to a more accurate diagnosis and, thus, to a more specific clinical management of thyroid nodules.

Correlation of estrogen receptor beta gene polymorphisms with spinal bone mineral density in peri- and post-menopausal Greek women.

Estrogens play a significant role in bone physiology. Their action is mainly exerted through their receptors. Estrogen receptor alpha (ERalpha) plays a major role in bone homeostasis and there is evidence suggesting that estrogen receptor beta (ERbeta) has also an effect on BMD. We investigated the possible effect of two ERbeta gene polymorphisms on spinal bone mineral density (BMD) and metabolic bone markers in Greek women. Spine BMD as well as biochemical bone markers were measured in 147 healthy peri- and post-menopausal women [mean age (S.D.) 54 (7.9) years]. Genotyping was performed for two restriction fragment length polymorphisms (RFLPs) of ERbeta gene, RsaI in exon 5 and AluI in exon 8. For each polymorphism studied the cohort was divided into two groups: the "wild-type" group (RR and AA, respectively) and the "carrier" group including subjects with at least one allele with the restriction site (Rr&rr and Aa&aa, respectively). The distribution of RsaI genotypes was RR: 91.2% (n = 134), Rr: 8.2% (n = 12), and rr: 0.6% (n = 1) and of AluI genotypes AA: 36.7% (n = 54), Aa: 57.2% (n = 84), and aa: 6.1% (n = 9). No linkage disequilibrium was found between the two polymorphic sites studied. Spine BMD did not differ significantly in the two groups of either polymorphism, after adjusting for age, weight, height, and years since menopause [mean BMD (S.D.) for RR 0.841 (0.17) g/cm(2) versus Rr&rr 0.798 (0.13) g/cm(2), p = 0.25, and mean BMD (S.D.) for AA 0.828 (0.16)g/cm(2) versus Aa&aa 0.848 (0.17) g/cm(2), p = 0.32]. No significant differences were noted in metabolic bone markers except for a marginal difference of RR versus Rr/rr in urinary hydroxyproline/creatinine ratio [median (IQR) 3.88 (6.04) micromol/mmol in RR versus 8.2 (4.32) micromol/mmol in Rr/rr, p = 0.05]. Furthermore, no interaction between the two polymorphisms on BMD was found. In conclusion, in a Greek female post-menopausal population, the two ERbeta gene polymorphisms were not associated with BMD, or metabolic bone markers.

Combined estrogen receptor alpha and estrogen receptor beta genotypes influence the age of menarche.

BACKGROUND: Age at menarche has a strong genetic influence. We reported recently an association between the XbaI (351A-->C)and PvuII (397T-->C) polymorphisms of the estrogen receptor (ER)alpha gene with the age of menarche in Greek adolescents. In the present study, we examined whether ERbeta genotypes alone, or in combination with ERalpha genotypes, may also influence onset of menarche. METHODS: We performed genotyping for the single nucleotide polymorphisms 1730A-->G and 1082G-->A of the ERbeta gene and examined their association with the age of menarche in the same cohort of 145 Greek girls. We then looked for a possible effect of combined ERalpha and beta genotypes on the age of menarche. RESULTS: Menarche occurred 7 months later in girls with the AA genotype of the 1730A-->G polymorphism than in girls with the AG genotype (mean +/- SD: 13.23 +/- 1.24 versus 12.66 +/- 1.26 years, respectively; P = 0.005). The 1082G-->A polymorphism was not detected in any of the girls examined. A significant effect of combined ERalpha and beta genotypes was also apparent. Menarche occurred 11 months later in girls bearing the AA/TT,AA (ERalpha, ERbeta) genotypes compared with girls with the CC/CC,AG genotype (13.30 +/- 1.27 nersus 12.41 +/- 1.28 years; P = 0.042). The difference remained significant after adjusting for body mass index (P = 0.034). CONCLUSION: Combined ERalpha and ERbeta polymorphisms may influence the age of menarche.

Association of SHBG gene polymorphism with menarche.

The age of menarche may be subject to hereditary influences but the specific determinants are unknown. Our aim was to investigate the possible association of a functional (TAAAA)n polymorphism in the promoter of the sex hormone-binding globulin (SHBG) gene with the timing of menarche. This polymorphism has been associated with polycystic ovary syndrome (PCOS) and is considered to contribute to SHBG levels. We studied 130 healthy normal-weight adolescent females from a closed community in North-Western Greece. Information on menarche was obtained through interviews. The BMI was recorded. Genomic DNA was isolated from peripheral blood leukocytes for genotyping the TAAAA repeat region. We subdivided our subjects into two groups based on median age of menarche: those with menarche <13 years and those with menarche > or =13 years. Genotype analysis revealed six (TAAAA)n alleles containing 5-10 TAAAA repeats. The distribution of alleles was different in the two groups. Girls with late menarche had more frequently longer TAAAA alleles (>8 repeats), while girls with early menarche had shorter alleles at a greater frequency (P=0.048). The major contribution to early menarche was by the 6 TAAAA repeat allele. Furthermore, carriers of the longer allele genotypes had later menarche (13.24+/-1.15 years) than those with shorter allele genotypes (12.67+/-1.15, P=0.018). These findings provide evidence for a genetic contribution of SHBG gene to the age of menarche.

The role of fine-needle aspiration biopsy in the management of patients with thyroid nodules.

Fine-needle aspiration biopsy (FNAB) of the thyroid gland is the most cost-effective examination in the evaluation of thyroid nodules. The aim of this study was to present our experience from all patients who underwent thyroid FNA in the University Hospital of Ioannina, Greece, in the period 1993-2003, and its value in the diagnostic management of patients with thyroid nodules. FNA was performed in 900 patients of whom 753 were females and 147 males. The cases were classified according to diagnosis into five groups: benign/negative 628, primary carcinoma 28, metastatic carcinoma 5, suspicious/indeterminate 60 and non-diagnostic 179. Cytological findings were compared with histopathological findings and the statistical analysis in our data yielded the following results: sensitivity 92.1%, specificity 93.2%. These results are in accordance with the already published data in the international literature. In cases of differential diagnosis between adenomatoid hyperplasia and follicular neoplasia, four cases were diagnosed as hot nodules. In the benign group, three cases were diagnosed as nodular hyperplasia with cystic degeneration on FNA, but, after surgical treatment, histologically were diagnosed as papillary carcinomas. In the group of suspicious/indeterminate, two cases were diagnosed as suspicious for follicular neoplasia on FNA and, after surgical treatment, were diagnosed histopathologically as medullary carcinomas. In conclusion, we suggest that routine measurement of serum calcitonin is useful and mandatory in the detection of medullary carcinoma among patients with nodular thyroid diseases. Taking into consideration the clinical data can minimize false-positive and false-negative rates. We conclude that FNA is an effective screening test in the evaluation of the necessity for surgical treatment in patients with thyroid nodules.

Apolipoprotein E polymorphism is not associated with spinal bone mineral density in peri- and postmenopausal Greek women.

OBJECTIVES: A number of studies have shown a positive relation between ApoE gene and osteoporosis or fracture risk but this finding has not been uniform in all populations studied. The aim of the present study was to determine the possible effect of ApoE gene polymorphism on spinal bone mineral density and metabolic bone markers in Greek women. METHODS: One hundred and forty-seven healthy peri- and postmenopausal women (mean age 54.3 +/- 7.8 years) participated in the study. In all participants, ApoE gene genotype was determined and spinal bone mineral density (BMD) as well as biochemical bone markers were measured. The ApoE genotypes distribution was 0.7% (n = 1) for E2/2, 5.4% (n = 8) for E2/3, 2% (n = 3) for E2/4, 73.5% (n = 108) for E3/3, 16.3% (n = 24) for E3/4 and 2% (n = 3) for E4/4. Participants were divided in two groups according to the presence of the E4 haplotype: E4 carriers (n = 30) and E4 non-carriers (n = 117). RESULTS: Spinal BMD was similar in the two groups, after adjusting for age, weight, height and years since menopause (mean +/- S.D., 0.835 +/- 0.16 g/cm2 in E4 non-carriers versus 0.831 +/- 0.16 g/cm2 in E4 carriers, P = 0.99). Serum osteocalcin levels did not differ significantly in the two groups (median (interquartile range, IQR), 0.55 (0.58) nmol/l in E4 non-carriers versus 0.51 (0.43) nmol/l in E4 carriers), whereas urinary hydroxyproline/creatinine ratio was significantly higher in the E4 non-carriers group (median (IQR), 5.18 (6.04) micromol/mmol in E4 non-carriers versus 1.73 (3.45) micromol/mmol in E4 carriers, P < 0.01). Urinary pyridinoline/creatinine and deoxypyridinoline/creatinine ratios, measured in a subgroup of 51 women, were similar between ApoE carriers and non-carriers, respectively (median (IQR), 25.1 (9.3) nmol/mmol in E4 non-carriers versus 21.8 (7) nmol/mmol in E4 carriers and 6.7 (3.1) nmol/mmol in E4 non-carriers versus 7 (2.2) nmol/mmol in E4 carriers). CONCLUSION: In conclusion, in a Greek female postmenopausal population, ApoE gene does not seem to play an important role in determining BMD and neither does it affect the majority of metabolic bone markers.

A case of insulin edema with inappropriate hyperaldosteronism.

Edema of variable severity is an uncommon complication of insulin treatment. Increased sodium reabsorption, transient proteinuria and hypoalbuminemia are the most frequently reported laboratory disorders at the time of edema formation. This case report describes a 44-yr-old man with a 4-month history of anorexia, polyuria, polydipsia and weight loss of 25 kg who presented with diabetic ketoacidosis. On admission, there were no clinical or laboratory signs of volume depletion. Following insulin treatment he developed marked insulin edema and a cluster of abnormalities, including decreased sodium excretion, hypokalemia, hypouricemia, proteinuria, hypoalbuminemia and anemia. The diagnostic work-up showed the presence of high renin and aldosterone values despite the absence of evident hypovolemia and no evidence of gastrointestinal, cardiovascular, renal, thyroid, hepatic or other endocrine disorder. Complement values were normal; autonomic neuropathy and venoocclusive intraabdominal lesions were excluded and no other drugs except insulin were administered. Initiation of spironolactone was associated with prompt resolution of the edema and gradual correction of the laboratory abnormalities. Our findings show that hyperaldosteronism may occur in patients with insulin edema, even in the absence of volume depletion, contributing to the development of increased sodium reabsorption and of other laboratory disorders.

Isolated ACTH deficiency associated with Crohn's disease.

We report a case of a 37-yr-old man with a 11-yr history of Crohn's disease (CD), who presented with mucous diarrheas of 1-week duration and a 3-month history of anorexia, increasing fatigue and weight loss of 7 kg. The patient was treated with sulfasalazine 3 g/day until 2 weeks prior to the present admission, when he reduced the dose to half as he considered the drug responsible for his symptoms. Despite aggressive iv rehydration and resolution of diarrheas with an increase in sulfasalazine dose, the patient remained hemodynamically unstable, while laboratory results showed anemia, hypoglycemia, hypertransaminasemia and hyponatremia with marked natriuresis. Thyroid function tests were consistent with primary hypothyroidism, without evidence of autoimmunity. Further laboratory investigation revealed a low basal cortisol and undetectable ACTH with preserved secretory responses of the other trophic pituitary hormones, establishing the diagnosis of isolated ACTH deficiency. Hydrocortisone replacement treatment induced a clinical and laboratory improvement. The autoimmune basis of isolated ACTH deficiency is discussed in association with the presumed contribution of immunologic reactions in the pathogenesis of CD. However more evidence is needed before isolated ACTH deficiency is added to the list of extraintestinal manifestations of CD.

The genetic basis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The disorder is characterized by clinical features of hyperandrogenism, menstrual irregularities and often central obesity and hyperinsulinaemia. PCOS may increase the risk for infertility, type 2 diabetes mellitus, dyslipidaemia, cardiovascular disease and endometrial cancer, emphasizing the need for early diagnosis of the syndrome. The genetic basis of PCOS is unknown. There is a strong familial component but the mode of inheritance is uncertain and several candidate genes have been proposed to contribute to susceptibility. Not only genes involved in steroid hormone biosynthesis have been studied but also genes associated with the regulation of insulin secretion and action since hyperinsulinaemia is a characteristic of PCOS. So far there is evidence that INS VNTR (insulin variable number of tandem repeats) or CYP11alpha (cholesterol side chain cleavage) genes are associated with this syndrome. PCOS appears, however, to be an oligogenic disorder and more studies are necessary to define the genetic basis.

The role of apoptosis in thyroid disease.

Increasing evidence suggests that apoptosis plays an important role in the pathogenesis of autoimmune and proliferative thyroid diseases, and that the apoptotic pathways involved are complex and highly regulated. Autoimmune thyroid diseases such as Hashimoto's thyroiditis and Graves' disease have been associated with differential expression of Fas and TRAIL receptor-mediated apoptosis. Thus, the thyroid cell destruction characteristic of autoimmune thyroiditis can be seen as the consequence of inappropriate expression of Fas or TRAIL death pathway molecules and down-regulation of the apoptosis controlling protein Bcl-2, which may be induced by cytokines released locally by infiltrating lymphocytes. In contrast, Graves' thyrocytes are protected from apoptotic death possibly by the anti-apoptotic action of thyrotrophin receptor antibodies or soluble Fas and/or the overexpression of Fas ligand which all create an anti-apoptotic potential for the thyroid cells and favor apoptosis of the infiltrating lymphocytes. On the other hand, an imbalance between thyroid cell proliferation and cell death may be crucial for goiter formation or cancer development and progression. In human thyroid goiter, Fas-mediated apoptosis is suppressed, leading to thyroid cell hyperplasia. Furthermore, malignant thyroid cells may escape immune attack by over expressing Fas ligand and inducing apoptosis in the invading immune cells. However, the exact mechanisms involved in the regulation of apoptosis in thyroid disease remain unclear. Further investigation is needed that may provide new strategies in the prevention and treatment of these diseases.

Association of polymorphisms of the oestrogen receptor alpha gene with the age of menarche.

BACKGROUND: The age of menarche may be subject to hereditary influences, but the specific genetic determinants are largely unknown. We evaluated whether the XbaI and PvuII polymorphisms of the estrogen receptor alpha gene are associated with the age of menarche. METHODS: We performed genotyping for XbaI and PvuII in a cohort of 145 adolescent females from a closed community in North-Western Greece. RESULTS: There was strong linkage disequilibrium between the two polymorphisms. Menarche occurred later in girls with the XX genotype than in girls with the Xx or xx genotype (mean +/- SD: 13.36 +/- 1.24 versus 12.80 +/- 1.14 and 12.75 +/- 1.35 years respectively; P = 0.017). Menarche also tended to occur later in PP homozygotes than in Pp and pp subjects, but the difference was not significant (mean +/- SD: 13.09 +/- 1.29 versus 12.80 +/- 1.19 and 12.85 +/- 1.33 years respectively). The strongest effect was seen when the PX haplotype was considered [mean +/- SD: 13.43 +/- 1.18 years for homozygotes versus 12.76 +/- 1.25 years in heterozygotes and in subjects without the PX allele, P = 0.006]. CONCLUSIONS: We document that the XbaI polymorphism, and possibly PvuII, may be genetic determinants of the age of menarche.